JPS6226296A - Homosesterterpene compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula [R<1> is formyl or H; R<2> is formyl or carboxyl; X is -C(OR<3>)- (R<3> is lower alkylacyl or H) or carbonyl]. EXAMPLE:12-Acetyl-20-methyl-20-oxoscala-16-ene-19,23-dial. USE:An easily administrable remedy for thrombosis, etc., having platelet coagulation inhibiting action and free from side effects such as bleeding. PREPARATION:For example, sponge is frozen with liquid nitrogen, etc., and pulverized with a pulverizer at <=-150 deg.C. The powder is extracted with an organic solvent (preferably methylene chloride, etc.) preferably below room temperature. The obtained extract liquid is concentrated and purified by adsorption column chromatography, etc.

Description

Detailed Description of the Invention (Industrial Application Field) (In the formula, R1 is a formyl group or a hydrogen atom, R2 is a formyl group or a carboxyl group, X is a formula% formula% (wherein, R3 is a lower alkylacyl group or a hydrogen atom) or C20) which has a platelet aggregation inhibiting effect.

(Prior art) Marine organisms have very different living environments from those on land, so marine organisms cannot be ignored by land organisms.
It is expected that new compounds with new physiological activities will be obtained. In fact, many compounds with novel skeletons have been discovered from marine organisms. In particular, as an example of one having an anti-inflammatory effect, R. Quinn
1 from a sponge (Tedania digitata)
- Methylic anosine is obtained [R Kin (R
, Quinn) et al., Tetrahedron Letters (Tet-
rahedron 1etters), Z Yu, 56
7, (1980)] et al., J.M.
Caulocystis ce
6-dridecasalicylic acid and related compounds [J8Mul
der) et al., Australian Journal of Chemistry (Aust, J. Chem, ).

55, 2097. (1980)), Ecchi Kikuchi (H
, Kikuchi ) et al.
[L Kikuchi et al.,
Chemical Pharmaceutical Bulletin (Ch.
em, Pharm, Bull, ),”n, 14
92. (1981)'l- (Problems to be Solved by the Present Invention) The present inventors have planned the development of medicinal substances with new skeletons and conducted research on marine animals. We conducted extensive research on lower marine organisms belonging to the genus Porifera, and collected sponges (Djctyoceratida s.
p, and Halichondria sp.

Recognizing that the two-layered structure of the anti-platelet membrane has an excellent anti-platelet aggregation effect, we conducted research to discover its active substance.

(Means for Solving the Problems) According to the present invention, homocesterterpe of the general formula (Il, where R1 is a formyl group or a hydrogen atom, R2 is a formyl group or a carboxyl group, and X is a formula% formula% (wherein, R3 is a lower alkyl group or a hydrogen atom) or /C=0) is provided.

The homocesterterpenes of the general formula (Il) according to the present invention can be produced as follows.

That is, first, the sponge (Dictyoceratida sp.
, and Ha-1ichondria sp.) are frozen with liquid nitrogen or liquid air, and then crushed using a crusher, homogenizer, etc. at -1506C or lower to obtain a finely divided product.

Next, this finely divided product is extracted with an organic solvent. Preferred organic solvents include, for example, ether, benzene, ester, acetone, and chlorine solvents. The extraction operation can be carried out according to conventional methods, but is preferably carried out at room temperature or below.

After concentration, the obtained extract is fractionated by adsorption chromatography, partition chromatography, etc., and if necessary, further purified by high performance liquid chromatography to obtain the novel homocesterterpene represented by the general formula (I). You can get similar results.

(Function) The compound of the above formula (I) and sponges (Dictyoceratida sp. and Hali.
The extract of cho-ndria sp. (two-layered structure) has a platelet aggregation inhibiting effect, and is therefore a substance expected to be applied to antiplatelet therapy. Conventionally, anticoagulant therapy and fibrinolytic therapy have been mainly used to treat thrombosis. They have a major effect on the coagulation and fibrinolytic system of the patient's blood, and accidents such as bleeding can be expected, so their administration requires very strict clinical laboratory monitoring and management. Under these circumstances, antiplatelet therapy is attracting attention as a simpler countermeasure against blood clots. Furthermore, the compounds of the present invention are expected to be effective in treating not only blood clots but also inflammation, allergies, hypertension, and the like.

(Example) Hereinafter, the present invention will be explained in more detail according to Examples, but it goes without saying that the scope of the present invention is not limited to these Examples. Hal
ichond-ria sp.) was frozen in liquid nitrogen and then pulverized using a pulverizer in liquid nitrogen. This product was then freeze-dried to form a fine powder.

58 g of the finely divided product was extracted with 11 methylene chloride at room temperature, and the solvent was removed under reduced pressure to obtain 4.7 g of crude extract.

The crude extract was subjected to silica gel column chromatography with elution solvent: methanol: methylene chloride = 0.5:
99.5 to 1:9), and the resulting fraction (fraction when using an elution solvent with methanol:methylene chloride = around 3:97) was subjected to high performance liquid chromatography (Waters Radial Pack Si). did. At this time, methanol:
The target compound (1) 16rn9 was obtained by elution using a mixture of methylene chloride=199 as an eluent at a flow rate of 1.5++t//min, and methanol:methylene chloride-5
:95 mixture was used as eluent, flow rate 1.5ml
The target compound (2181 to 9
and (3) 8m9 was obtained.

The physical properties of the obtained compound were as follows.

Properties: White powder High resolution mass spectrum: 456, 2878 (as CuI-14005 45
6.2876) Infrared spectrum: (Potassium bromide tablet method α4) 2940.2736.1739.1722.1
662°1389.1377.1241.1036.7
87.765') I-NMR spectrum: (in deuterated chloroform, δppm, 270 MHz)
:0.80 (S, 3H), 0.84 (8,3
H), 0.88 (3,3I().

0.94 (S, 3H), 2.16 (8, 3H), 2.5
4 (S, 3H).

3.53 (m, 1H), 4.78 (m, IH), 7.0
6 (m, IH) = 9.40 (d, J-4,0Hz, IH
), 10.09 (S, IH) (in heavy benzene, δI)T
) m, 270M le): 0.45 (S, 3H), 0.4
8 (S, 3H), a65 (S, 3H).

0.77 (S, 3H), 147 (m, IH), 232 (
dd, J=14.2.2.3Hz, IH), 262
(brd, J=125 HzlH), 3.66(
brs, IH), 4.92 (m, IH), 6.25 (m
, IH), 9.51 (d, J=4.3Hz,
IH), 1O-0(S.

IH) "C-NMR spectrum: (in deuterated chloroform, δppm, 67.5 MHz
) 15.1 (q), 17.4 (q and t), 19.2 (
t), 20.8 (CI).

21.4((1), 22.1(t), 24.0(
t), 25.1 ((1).

31.8(q), 33.6(s), 34+(t
), 37.5(s).

39.9(s), 40.3(t), 41.6(t)
= 47.9(d).

52.4(s), 525(d), 53.1(d), 54
．． 8(a).

74.3(d), 137.4(s), 141.9(d)
, 169.5(s).

198.5(s), 200.5(d), 208.9(d
) (M in benzene, δppm, 67.5MHz):
14.9((1), 17.2(q), 1st 6(t), 1
9.5(t).

20.9 ((1 and t), 22.6(t), 23.
8(t), 24.8(q).

61.9(q), 33.6(s), 34.7(t), 3
7.5(s).

4o, 0(t), 40.4(t), 41.8(t), 4
82(d).

525(s), 52.7(d), 53.5(d), 55
．． 0(d).

74.4(d), 137.8(s), 140-6(d)
, 168.8 (s,).

197.3(s), 199.2(d), 204.0(d
) Properties: White powder Mass spectrum: (electron impact method, m/z) 430 (
Octopus infrared spectrum: (potassium bromide tablet method, crrT
” )3477.2930.2733.1782.17
24.17[]9゜1658,1457.1391.1
252.1050.735'H-NMR spectrum: (m in chloroform, δppm, 270 MHz)
0.84 (S, 3H), 0.87 (S, 3H
), 0.89 (S, 3H).

0.91 (S, 3H), 236 (S, 3H)
, 3.40 (brs, IH).

3.49 (brs, 1H), 7.1'5 (m, IH),
9.38 (d, J = 5.31 (z, IH)"C-NMR spectrum: (M chloro (+ in form, δppm, 67.5 MHz
)13.8.15.1.18.6.20.2.22B
, 24.3.24.8゜26.0.33.4.33.
7.37.9.5B. 3.41.4.41.6゜422
, 47.9.48.1 , 50.3.53.6.55.
9.71.4°136.8.144.0.180.6.
198.4.203.8゜Properties - White powder mass vector: ([child 'Fj'' 3 method, m/z) 40
0(M+)'H-NMR spectrum: (in deuterated chloroform, δpI)m, 270M soil)0.
88 (S, 3H), 0.93 (3,3H),
0.98 (S, 3H).

1.06 (S, 3H), 1.94 (brd, J=126
Hz, IH).

228 (8,3H), 2.63 (dd, J=13.
9.3.3I(z, IH).

275 (dd, J=13.9.13.9Hz,
IH), 6.82 (br, s.

IH) "C-NMR spectrum: (in heavy-gutoroform, δppm, 67.5Hz) 1
3.3.185.18.6.20.1.225.23.
5.25.5゜33.4.33.8.35. ．． 3.36
．． 9. 7.5, 38.3.41.2゜42.1, 4
6.4.48.6.52.9.56.2.57.6.1
37.5°138.0.178.7.198.7.21
3.8° Example 2 A test was conducted on the platelet aggregation inhibitory effect of the homocesterterpenes compounds of the present invention.

Test method Using a male Japanese white rabbit weighing 4.0 kg, 3.
．． Using a syringe containing 1 d of 8% citric acid, collect 9 d of blood.
After collecting, 100kl? The supernatant was used as platelet rich plasma (PRP), and the lower layer was further centrifuged for 45 minutes.
The mixture was centrifuged at 0g for 10 minutes to obtain platelet-poor plasma CPPP].

Measurement of platelet aggregation ability is performed using Alibometer Cagg-re.
gometer, RIKADENKI
) made aggregometer (AGG part ■ πER) RAM
-61). As aggregating agents, adenosine diphosphate CAD P] (10uM), arachidonic acid (0.3mM), and collagen (37uJ/
d), and the test drug was dimethyl sulfoxide CDMS.
The mixture was dissolved in O) and added to PRP for 1 minute before adding a flocculant to react.

IC, which shows the platelet aggregation inhibiting effect of the compound (1) of the present invention as a result of the test. are 5.3Hg, <4 for ADP aggregation, arachidonic acid aggregation, and collagen aggregation, respectively.
．． It was 0■/m1.6.2■7ml.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a formyl group or a hydrogen atom, R^2 is a formyl group or a carboxyl group, and X is a formula >C-O-R
^3 (Here, R^3 is a lower alkyl acyl group or a hydrogen atom) or >C=O. ) homocesterterpenes. 2. The compound according to claim 1, wherein R^3 is an acetyl group.