JPS59227885A - 1-oxaquinolizidine - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H or hydroxyl group; R2 and R3 are H or lower alkyl and both or either one of R2 and R3 represents H) and a salt thereof. EXAMPLE:Xestospongin A of formula II. USE:Useful for treating a wide range of cardiac infarction, hypertension, angina pectoris and cerebral circulatory disorder, etc., and having vasodilator action. PREPARATION:A sponge is frozen with liquid nitrogen or air, and crushed at <=-150 deg.C to give a finely divided material, which is then extracted with an organnic solvent, e.g. benzene, at room temperature or below, The resultant extract is then concentrated and fractionated by the adsorption chromatography, etc. and purified to afford the aimed compound of formula I .

Description

Detailed Description of the Invention Technical Field (In the formula, R1 represents a hydrogen atom or a hydroxyl group, R2 represents a hydrogen atom or a lower alkyl group, and each island represents a hydrogen atom or a lower alkyl group. The present invention relates to 1-oxaquinolitidines having a vasodilating effect, one of which represents a hydrogen atom, and salts thereof. The compound represented by the above general formula (I) having a vasodilatory effect is expected to be an effective compound for a wide range of treatments such as myocardial infarction, hypertension, angina pectoris, and cerebral circulation disorders.

BACKGROUND OF THE INVENTION In recent years, research on marine organisms has become more and more active, and many physiologically active substances have been isolated from S. Marine organisms live in environments that are completely different from those of terrestrial organisms, and have metabolic mechanisms that are different from those of terrestrial organisms. Therefore, many compounds with novel skeletons have been discovered in marine organisms. Sponges (Verongia fistulari) are known as pharmacologically active ingredients in marine organisms, especially those that act on the cardiovascular system.
s) to autonomylum (K, H, l1ollen
beak, F.J., Schmitz, P.N.
, Kaul.

Proc, Food Drugs Sea Conf
, Washington, D.C.: Marine
Technol, Soc 282-287.1976
) and another sponge (Cryptotethya Cryp
ta) to Svongosin (S, G, Zele
nski, A. J., Weinheimer.
, Proc, FoodDrugs Sea,
Washington D, C, Marine Te
chnolSoc, 288.1976) etc. have been obtained.

Purpose and Structure of the Invention The present inventors planned to develop a new drug, conducted extensive research on lower marine organisms belonging to the phylum Porifera, and collected samples from around Hook Island in Queensland, Australia. Sponge (Xestospong)
The present invention was completed based on the discovery that an extract obtained from the plant (Ia exigua) has an excellent vasodilatory effect.

That is, according to the present invention, l represented by the general formula (1)
- Oxaquinolitidines and salts thereof are provided.

Summary of the Invention The general formula (1) having a vasodilatory effect according to the present invention
The 1-oxaquinolitidines can be produced from sponges as follows. That is, first of all, sponges (Xesto
Spongia exigua) is frozen with liquid nitrogen or liquid air, and then crushed using a crusher, homogenizer, etc. at -150°C or lower to obtain a finely divided product. Next, this finely divided product is extracted with an organic solvent. Examples of organic solvents include ethers, benzene/esters, acetone,
Chlorinated organic solvents can be used. The extraction operation is carried out according to conventional methods, usually at temperatures below room temperature.

The obtained extract is concentrated and then fractionated and purified by adsorption chromatography, partition chromatography, ion exchange chromatography, etc., or by adsorption chromatography, partition chromatography, etc. and distribution using a solvent.
The 1-oxaquinolitidines represented by the general formula (1) can be obtained by purifying the sieve fraction by changing the acidity, etc., and further purifying by high performance liquid chromatography if necessary. .

If necessary, the compound obtained from the sponge by the above method can be made into a powdered salt by treating it with an aluminous acid such as hydrochloric acid or sulfuric acid, or an organic acid such as oxalic acid, citric acid, or succinic acid. .

Physical properties of the compound of the present invention The 1-oxaquinolitidines according to the present invention thus obtained are novel compounds having the following physical properties.

Properties: Colorless columnar crystals Melting point: 120-122°C (recrystallization solvent, ethyl ether) MS (electron impact method): M+446 (C,H,.

N202) Optical rotation: [+6.90° to α (C=0.
840. (in chloroform) Infrared spectrum (potassium bromide tablet method, c+n') 28
51, 2B12. 2758. 1473. 115
8. 1133. 1098°1039'H-NMR (in deuterated chloroform, δppm, 360
MIIz) 1.10-1.74 (3811),
1.98 (ddd, J= 11.9. 11.9
゜3.9tlz, 211), 2.78
(ddd, J= 12.1. 12.1°3.21
1z, 211), 2.75 (br, d
, J=10.811z, 2H).

2.93 (ddd, J=11.2. 4.3.
2.211z, 211).

3.06 (d, J=8.611z, 211
), 3.34 (br, t, J= 10.
811z, 211) 13C-NMR (in heavy benzene, δppm, 25M1
lZ) 25.5 (t), 25.88 (t
), 26.00 (t).

29.36 (t), 29.60 (t)
, 31.94 (t).

32.17 (t), 32. '67 (t
), 35.95 (t).

40.95 (d), 54.35 (t)
, 54.55 (t).

75.35 (d), 96.32 (d) (2
) Gestospondin-A2 hydrochloride Properties: White powder MS (electron impact method): m/z446 (M-2HCj
2) Infrared spectrum (potassium bromide tablet method, Cm') 3
419.2926.2719, 1634, 1467.1
075'H-NMR (in heavy water, δppffl+ 300
MHz)1.08-2.06 (38)1),
2.98 (ddd, J= 13.3°13.3.
2.7Hz, 2H), 3.27 (ddd, J=
13.3113.3.3.6Hz, 2H), 3.
39 (br, d, J=11.9Hz.

2tl), 3.57 (br, d, J=12.
6Hz, 2H), 3.98(m, 2H),
4.48 (d, J=10.3.2H) (3) Zestosbonjin-B aC Properties: colorless columnar crystals Melting point: 179-181°C (recrystallization solvent: ethyl ether) MS (electron impact method): m/ z 477 (M++1
゜CpH5YN,Oyo+H) Infrared spectrum (potassium bromide tablet method, falsified) 3521.
2B50, 1467.1456, 1420, 1140,
1102°1040.1018.963'H-NMR (in deuterated chloroform, δppm+ 360
MHz)0.68 (d, J=6.5)1z,
3H), 1.03 (br, d, J-1
3,4Hz, IH), 1.1-1.85
(35H), 2.33(br, d, J=1
0.211z, 111), 2.45 (b
r, s, OH).

2.46 (br, d, 1J=10.4Hz,
IH), 2.72 (t, J-13,4H
z, LH), 2.83 (dd, J=
13.4. 4.5Hz.

18), 2.93-3.15 (5H),
3.56 (br, t, J = 10.8Hz
, IH), 4.05 (s, IH)
, 4.28 (d, J-2,8Hz, l
t+) 'H-NMR (in heavy benzene, δppm+ 360MH
z) 0.51 (d, J=6.5Hz, 3H), 0.
65 (br, d, J-13, 5Hz, LH), 1.1
5-1.90 (35H), 2.09 (br, d,
J=10.5Hz, 1B), 2.45 (
br, d, J=10.2Hz, IH),
2.64-2.77 (4H), 2.90 (
ddd, J=13.7. 13.7. 3.3Hz
, IH), 2.95(ddd, J=1
3.7. 13.7. 2.7Hz, 1B)
, 3.01-3.15 (3H), 3.4
3 (br, t, J=11.3Hz, LH)
.

4.17 (s, 18), 4.40 (
br, s, IH) 13C-nmr (in heavy benzene,
δppm, 25MHz) 14.62 (q),
21.38 (t), 23.43 (t)
.

25.38 (t), 26.29 (t)
, 27.23 (t).

27.99 (t), 28.69 (d)
, 29.98 (t).

30.30 (t), 32.35 (t)
, 32.82 (t).

33.43 (t), 33.87 (t)
, 36.62 (t).

37.85 (t), 39.05 (t)
, 40.83(d).

44.46 (t), 46.56 (t)
, 52.74 (t).

61.10 (t), 70.64 (s)
, 76.28(d).

82.22 (d), 87.72 (d)
, 91.08 (d) Properties: colorless columnar crystals Melting point = 149-150°C (recrystallization solvent: ethyl ether) Optical rotation: [αr knee 2.41° (C, 0,540:
(in chloroform) MSC high resolution mass): 446.387B <calculated value: 446.3869 (C29HSON 0.) Infrared spectrum (potassium bromide tablet method, c+n) 2760, 1
463.1345.1160.1140.1097.9
73'H-NMR (in heavy chlorophonium, δppm,
360MB21.03 (br, d, J=12.0
Hz, LH), 1.1-1.8 (37H),
1.97 (ddd, J= 11.5.11.5.3
．． 1) 1!1B) , 2.17 (ddd, J=1
2.2.12.2.3.1) 1z, 1) 2.39 (
br, d, J”11.OHz, IH), 2.
75 (br, d.

J=11.5)1z, IH), 2.93 (m,
2H), 3.05(m, IH,), 3.0
7 (d, J=7.41(z, 18).

3.18 (ddd, J”12.7.12.7.3.
6Hz, LH).

3.33 (br, t, J=lO,3H2,1)1
), 3.52 (br, t.

J = 11.0Hz, IH), 4.28 (b
r, d, J = 2.6 Hz, H'H-NMR (in heavy benzene, δppm, 360 MHz) 0.77 (br
, d, J=13.011z, IH), 1.
2-1.95 (3811), 2.04 (ddd,
J = 12.0.12.0.2.8Hz.

ill), 2.36 (br, d, J=10.
911z, 1ll), 2.64(br, d,
J=11.211z, 01), 2.82 (m
, 2H).

3.11 (m, 1)1 ), 3.13 (d,
J=8.6B2.18).

3.30 (br, t, J-10,8Hz, IH
), 3.48 (br, t.

J = 10.9Hz, lH), 4.40 (br
, d, J=1.4Hz.

LH) "C-NMR (in deuterated chloroform, δppm+ 25M
t(z)) 24.8(t), 25.0(t),
25.1(t), 25.3(t), 25.8(t
), 26.3 (t), 26.5 (t).

27.1 (t), 28.8 (t), 28.
9 (t), 29.4> (t), 29.7
'(t), 31.2(t), 31.6(t).

32.3 (t), 32.8 (t), 35.
6 (t), 36.0 (t), 40.3 (d
), 40.6 (d), 45.3 (t).

52.8(t), 54.1(t), 54.3(
t), 75.4(d), ? 5.9 (d)',
87.5 (d) The results of the direct X-ray crystal analysis of Zestospondin C are as follows, and the atomic arrangement model is shown in FIG.

Orthorhombic, space group: P2.2.2゜2 =
16.771 (2), b = 16.386 (
2).

c = 9.799 (1) A, v = 2692
．． 8 (5) people.

z=4. Dm =1.103. Dx=1.
101 Mg m.

11 (Cu Rn) = 5.3 (hi',
R = 0.06 + R = 0.058 (5) Intrusion 1 Mu y & Otsu 2 9 moxibustion star 隨 refreshing Properties: White powder MS (electron impact method): m/z 446 (M
+-211C:I) Infrared spectrum (potassium bromide tablet method, cm') 3418, 2934.2574.1631
．． 1464.1135.874゜81'H-NMR (in heavy water, δPl'1l11300MlI
2) 1.08-2.04 (381(>, 2.9
7 (ddd, J= 12.8°12.8.2.3 [
1z, l11), 3.10 (br, d, J
=11.911z, In), 3.27 (dd
d, J = 2.8.2.8.2.9Hz.

Ift), 3.38 (m, 2H), Ca
3.55 (m, IH).

3.56 (br, d, J=11.9Hz, LH>
, 3.62 (ddd.

J = 13.5.13.5.4.111z, lfl
), 3.98 (m.

211), 4.48 (d, J=9.7Hz,
ill), 4.98(d, J=2.7Hz,
IH) (6) Zestospondin D Properties: Colorless columnar crystals Melting point: 8156-157°C (Recrystallization solvent: ethyl ether) Optical rotation: (α) F+ 18.43° (C, 1,08
: in chloroform) Elemental analysis values: Actual value C: 72.81%, H: 10.68%.

N: 6.22% Calculated value C: 72.68%, H: 10.89%.

N: 6.05% (calculation formula -115,,N2O3) MS (electronic FII firing method): m/Z 462 (M:
C2911-NzO,) Infrared spectrum (potassium bromide tablet method, cm) 3533, 2762.1466, 134
3.1162.1130.1097°1031,949'H-NMR (in deuterated chloroform', δppm, 36
0 MIIz ) 1.05 (br, d, J=13.
8Hz, 01), 1.1-1.85 (3611)
, 1.98 (ddd, J= 11.0.11.
0. '3.2Hz.

l1l), 2.17 (ddd, 12.L 12
．． 1.2.711z+IH).

2.33 (br, d, J=9.3Hz, III
), 2.47 (s, Off).

2.76 (br, d, J=11.0Hz, 1ll
), about 3.0 (m.

411), 3.07 (d, J=8.911z,
III), 3.34 (br, t, 'J=1
0.5Hz, III), 3.56 (br, t,
J= 10.1112. LH), 4.05 (
sI ill )'H-NMR (in heavy benzene, δpp
m, 360M1lz) 0.68 (br, d,
J=13.1Hz, LH), 1.15-1.95
(37H), 2.02 (ddd, J=11.0
．． 11.0.3.111z.

1ll), 2.09 (br, d, J=10.
411z, LH), 2.65(br, d, J
=17.111z, IH), 2.66 (br,
s, OH).

2.71 (br, d, , J=3.6Hz, IH
), 2.78 (ddd.

J = 11.2. 3.9. , 1.911z, IH
), 2.88 (ddd.

J-13,1,13,1,3,411z, ill
), 2.94 (ddd.

J = 11.1. , 11.1. 3.1Hz, I
II), 3.13 (d.

J = 8.511z, III), 3.28
(br, t, J=11.01lz.

10), 3.43 (br, t, J-11,
011z, 1ll), 4.17'(sI I
H) '-'C-NMR (in heavy benzene, δppm, 75.
456MHz) 21.36 (t) + 23.28
(t), 25.34 (t).

25.50 (t), 25.55 (t),
, 25.96 (t).

26.31 (t), 29.44 (t)
, 29.98 (t).

31.81 (t), 32.12 (t)
, 32.31 (t).

32.78 (t), 36.10 (t)
, 36.49 (t).

38.94 (t), 40.77 (d)
, 44.55 (t).

52.74 (t), 54.44 (t)
, 54.57 (t).

70.67 (s), 75.31 (d)
, 76.35(d).

91.22 (d), 96.00 (d)
(7) Zestospondin-D2 hydrochloride Properties: White powder MS (electron impact method): m/z 463 (M
-2HC1+ H) Infrared spectrum (KH5-5 thin film method, C11) 3390, 2940.2580. 146
3. 1137.10B0. 1010°48 1 H-NMR (in heavy water, δPP11+ 360MHz)
1.05-2.1 (3711), 2. ．． 9
0 (br, t, J=11.9Hz+l1l)
, 3.30 (br, d, J=11.5Hz
, III).

3.24 (ddd, J= 12.6. 12.6.
3.2Hz, IH).

Approximately 3.37 (2H), approximately 3.45 (3H), approximately 3.97 (211), 4.45 (d, J=1
0.3Hz, IH), 4.63(s, 01
) Pharmacological effect of the compound of the present invention The pharmacological effect of the compound of the present invention on vertebral artery blood flow and coronary artery blood flow in anesthetized dogs was tested as follows.

After induction anesthesia of male and female mongrel dogs (7-14 kg) with sodium thiobental (35+ng/kg intraperitoneal administration), urethane (400 μg/kg, intravenous administration) and alpha floralose (64 μg/kg intravenous administration) anesthesia was maintained. The animals were restrained in the dorsal position and the chest was opened through a midline and left fourth intercostal incision under positive pressure ventilation (200 mA/stroke, 20-3 o strokes/min). For cerebral blood flow, a cannula was inserted through the internal thoracic artery, and the vertebral artery was self-perfused with blood drawn from the left subclavian artery, and for coronary blood flow, the left coronary artery was self-perfused with blood drawn from the left femoral artery. The flow rate at each time was measured using an extracorporeal probe placed within the perfusion route. At the same time, the perfusion pressure was measured and the vascular resistance of each was calculated. Drug is 0, 1 m IL
/10 kg in weight, and administered directly into the artery through a vertebral artery cannula or a coronary artery cannula. All test compounds were dissolved in physiological saline before use.

The results obtained are not shown in Tables 1 and 2.

As shown in Tables 1 and 2, all three compounds of the present invention caused dose-dependent increases in blood flow and decreases in vascular resistance in both the vertebral and coronary arteries, and the effects were comparable to those of papaverine hydrochloride. Met.

Below is a margin. Example of production of the compound of the present invention A sponge (Xestospongia exigua) was frozen in liquid nitrogen and pulverized using a pulverizer in liquid nitrogen.

100g of the freeze-dried micronized sample was 1. ．． Extraction was performed using 5I2 of ethanol below room temperature, and the solvent was removed under reduced pressure to obtain 6.8 g of crude extract.

This crude extract was adsorbed onto silica gel, and chloroporum:
The lower layer of a mixture of methanol:water-7=3=1 was used for elution. The obtained active fraction was then applied to a reverse phase distribution column (pre-punk column RP-8 manufactured by Merck & Co.) and eluted using a 5% water-methanol solution. The active fraction obtained by concentrating the eluate was 302.

Next, high-performance liquid chromatography (Radialback C19, Walks Co., Ltd.) was performed using a developing solvent of methanol:acetone:
Cestospondin D (7
0mg), sestospondin A (28N), sestospondin B (28n+g) and sestospondin C (17
■) was obtained.

Example 2: Preparation of sestospondin dihydrochloride salts Hydrochlorides thereof were prepared using 10 ml each of sestospondins D and C obtained in Example 1.

Dissolve 10 ■ of the sample in 1 m II of benzene,
Add 0.2 m j of hydrochloric acid gas saturated ether solution to this! 0°
Added with C. After keeping it at room temperature for about 10 minutes, the desired sestospondin D.
11 volumes each of dihydrochloride and sestospondin C dihydrochloride were obtained.

Example 3: Production of sestospondin dihydrochloride sestospondin A10nw obtained in Example 1 was used.

Dissolve 10 ■ samples in l m it ether,
Add to this 0.2 m of hydrochloric acid gas saturated ether solution 7! to 0℃
I added it. After leaving it at room temperature for about 10 minutes, the solvent was distilled off under reduced pressure to obtain the desired sestospondin A.
11 ml of dihydrochloride was obtained.

Example 4: Production example of Zestosbongins (2) Sponge (Xes
tospongia exigua) was frozen in liquid nitrogen, dried and ground in 2β methylene chloride.

The obtained finely divided product was placed in a brown column with a diameter of 10 cm and a length of 1 m, and after being kept at 4° C. or lower for 3 days, it was extracted.

After separating the methylene chloride layer, fresh methylene chloride 2β
was added and soaked in cold for 3 days.

The extract was concentrated under reduced pressure to obtain 43 g of crude extract.

2 g of this crude extract was adsorbed on silica gel and eluted using the lower layer of a mixture of chloroporum: methanol: water = 10:2:1 (7) to obtain 840 ml of active fraction.

This active fraction 840 Akebono was dissolved in 50 ml of benzene, and an ether solution IQm4 saturated with hydrochloric acid gas was added. The reaction solution was concentrated under reduced pressure to remove excess hydrochloric acid gas and solvent, and 200 m 12 of water was added to the residue, which was extracted twice with methylene chloride to remove the ta-containing solvent-soluble portion. The aqueous layer was made alkaline by adding 20 m4 of IN aqueous sodium hydroxide solution, and then extracted twice with methylene chloride. The methylene chloride extract was washed with water, dried using magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 387 ml of a mixture of zestospondins. 387 ml of this mixture was subjected to high performance liquid chromatography (Radialvac C1g, Walks Co., Ltd.) as eluent methanol:acetone:water nitriethylamine=5:5:0.520.
2, holding time 8 minutes under the condition of flow rate 1 mβ/min, 1
Sestospondin D (99■) and Sestospondin A (40■) at 2, 13.5 and 15.5 minutes, respectively.
), Sestospondin B (40■) and Sestospondin C (23■) were obtained.

[Brief explanation of drawings]

FIG. 1 is an atomic arrangement model diagram of sestospondin C according to the present invention obtained by direct X-ray analysis.

Claims (1)

[Scope of Claims] 1. General formula (in the formula, R represents a hydrogen atom or a hydroxyl group, R represents a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower alkyl group, but R2 and 1-oxaquinolitidines (both or one of which represents a hydrogen atom) and salts thereof. 2. The compound according to claim 1, wherein in the general formula (1), R, , R2 and each other are hydrogen atoms. 3. In the general formula (I), R1 is a hydroxyl group,
The compound according to claim 1, wherein & and Rφ are hydrogen atoms. 4. The compound according to claim 1, wherein R2 is a hydroxyl group, R2 is a methyl group, and M (a hydrogen atom).