JPS59231085A - Alkaloid - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R is H or acyl). EXAMPLE:2-Amino-5-[3-(4-bromopyrrole-2-carboxamido)-1-propenyl]-1-meth ylimidazole. USE:It selectively suppresses the constricting activity of serotonin, and is expected e.g. as a hypotensor. PREPARATION:The compound of formula is obtained by crushing the sponge (Agelas species) of Kerama Islands, Okinawa Prefecture, Japan, extracting with a solvent such as methanol, and purifying by column chromatography.

Description

[Detailed description of the invention] In the present invention, H is added to an alkaloid.

The present inventors are searching for physiologically active substances contained in the bodies of various marine animals, and found that a new substance contained in a certain Zen sponge has the effect of selectively suppressing the contraction effect of serotonin on smooth muscles, such as blood vessels. Confirmed that it has anti-serotonin effect).

The present invention was achieved based on this knowledge.

That is, the gist of the present invention is as follows.

It exists in an alkaloid represented by the formula (in the formula, R represents a hydrogen atom or an acyl group).

To explain the present invention in detail, among the compounds of the present invention represented by the above formula [/], R is a hydrogen atom, that is, co-amino-s-[3-(gupromobilol-cocarboxamide)-/ -Flobenil]-/-mef limitasol (hereinafter referred to as compound l) is a substance that is found in certain sponges (A
gelai 5pecies), extracted with an appropriate solvent, and purified by one-column chromatography as shown in the Examples below.

In addition, forepaw [compounds in which R in formula 73 is an acyl group (acetyl group, glopionyl group, butyryl group, etc.), for example, an acetyl group, that is, coacetylamino-5-(3-
(4t-bromopyrrole-2-lupoxamide)-/-
Propenyl]-/-methylimidazole (hereinafter referred to as compound 1) can be obtained by acetylating compound 6fJ in an appropriate solvent.

The above compound/and is a new compound that has not been published in any literature. Mass spectra, UV absorption spectra, IR absorption spectra, 'H-NMR and IJC shown in Examples
-The respective structures were confirmed from the results of measurements such as NMR.

The compound of the present invention exhibits anti-serotonin action as shown in Reference Example Shunki. Serotonin is a substance present in the serum, platelets, and other brains of mammals, and causes blood aa and other smooth muscles to contract.

It has the effect of selectively suppressing the contraction effect caused by serotonin, and is expected to be used as a hypotensive agent, for example.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to the Examples below.

Example/ Co-amino s-[, y-(derphlomopyrrole-, l
−force/l/ foxaamide)−/−propenyl]−/
- Isolation of methylimidazole (compound/) The sponge Agelas sp, 31# (wet weight) from Okinawa's Arayatoi Islands was crushed and homogenized, extracted three times at room temperature using 6 tons of methanol, and the extract was extracted under reduced pressure. Concentrate to dryness gt, F
! A crude extract of - was obtained. Dissolve this crude extract in 7007 methanol, remove insoluble matter, and add 1liiL of P solution.
7 gf of oil was obtained.

The above oil was divided into two equal parts, each of which was adsorbed on a separate silica gel column (a column filled with silica gel/q, diameter 2 cm, height gs (1)), and chloroform-methanol (qs: 5) tt. .

HA secondary elution using chloroform-methanol (?:/) t, chloroform-methanol (g:a), chloroform-methanol (/2/) and 6 t of methanol. It was fractionated into 11- fractions. Both fractions from the 10th to 12th scans were combined and concentrated, resulting in a brown oil (171-kg), which was poured into a flash column of silica gel.[Column: Silica gel! ;20'1-
1Sx s g cm; % solution: chloroform-n
-butanol-acetic acid-water (25:/, <7:/6:10
)) and 20θOm6~. The eluted fractions of 2,700- were collected and concentrated to obtain 6-t of oil. This oily 9 is essential, and the h'J exudate is inamyl alcohol - acetic acid - water <
Flash column chromatography on silica gel as above but using 3o:i3:io);
/2/, Od-/3g0- elution fractions were collected and concentrated to obtain 11oonq of oil.
-20 (Pharmacia product) column chromatography (column: 2.9 X g l, cm, elution 1
The eluate fractions from 2go- to 39θ- were collected and diluted, and 5 liters of the obtained oil was further subjected to the Sephadex LH-20 column chromatography [column: unit]. 6 x s3cwr, eluent: chloroform-methanol (/:/) EK applied, /'
The eluted fractions from IO+nl to 2/θ- were collected and concentrated to give a yellowish brown oil with IO+nl to 2 A mf/. This oily wJwo is subjected to reverse phase high performance liquid chromatography [column:
Develosil-ODSOtanol (6:
Flow rate: 3 hours/min; Detector: ultraviolet chamber 27θ], collect the peak at 6 minutes; ;-[3-(11,-mopyrrole-λ-poxamide)-/-propenyl]-i-methylimidazole (compound l) trifluoroacetate, ? l1lp was obtained. Melting point of ice crystals/g3
~/g7c'i, and the FD-mass spectrum is m/g7c'i.
z, 7.24', and 3.2B, give the ion/beam of M +H, and from this result, the molecular formula C (p 1114 N5
It turned out to be in 2008. Its structure was determined as the above compound from the following UV absorption spectrum, IR absorption spectrum, 'H-NMR and 'C-NMR data.
child.

UV (CH301-I) λmax:
272 nm (ε iqgoo) I l'L
(KBr) )/max: 33'lθ, , 32
70, #90, /4. ? θ.

/36! , /323,1200,1/spinning, l/110
t-nr-''II-NMR (DMSO-d, δ
in pprr3) + 3. ．． 3g (3H
,S).

'AO/ (,2H,t, J = k, AHz),!
r, g hiro (/H, ABX2 center.

dt, J=//,! ;, AH2), l-2θ(/H, d
, A B center , J=/ /H1).

t, go (/H, dd, J-=2ri, /jHz), (-
9,2 (/H, dd, J=Utah.

1jHz), 702(/H,S), 2! r9(2H,b
rsJ disappeared by adding water), g; 22 (/H, brt, J
=! LAHz, j4 Disappears by adding water//, 3g (/H,
, bra , 'M disappears by adding water) /191(/f(
, bro, disappeared by addition of city water) 1sC-NMR (DMSO-d, , δ in p
pm) : 2q, -Xq) +J&A(tL
qSakus), ///7(d), //, 24d), //J
8g(d), /, 2/, 7(d).

/, 2J, 7(a), /, 2/, 7(s), /
,? ,? ,,? (d), /da&9(s), 1
55!4(s) Example Cocoacetylamino-5-(,7-(y-promopyrrole-eucarboxamide)-t-propenyl-7-methylimidazole (Compound, 2) Compound obtained in Example 91/ 7 <3.s my) with pyridine 0, / d
0.0 μl of acetic anhydride was added to the mixture, and the mixture was reacted at room temperature for several hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel thin layer chromatography using chloroform-methanol (15%) as a developing solvent.
'N Coacetelamino-6-- produced as colorless crystals
[',? -(gubromovirol-λ-carboxamide)-/-flobenil]-/-7'-7-limitasol (chemical compound) θA my was obtained. The melting point of Motoichi was 2AO to 264'C (decomposition), and the measured values of EI-mass spectrum, UV absorption spectrum, IR absorption spectrum, and 'H-NMR were as follows.

EI-to'is:, 3A7, 3 otsu jt,, 3j3'2.
3! i0.3 ivy, 32λ.

/93 UV(CH30H)λmax:ηi 'I nrn (
ε, 2/11.0θ) IR (KBr) 1/Irna
x:, 3.170,2930. /Ag! r, /l,,
3θ.

tsss, tg; to cm-''H-, NMm (DMso-d6.δin ppm)
:, 2.0'1(3H,S) +3.34'(JH,S
),'AOk(!H,m),Jnear0(dt.

J=//, Mu/I(z), 4.70(d, J=//Hz
).

/, Ii/(dd, J=14L, 3.θHz), &de3
(dtl, J=llI.

,? 01(z), Mu? ,7(S) ,g,/7(br
s), //j? (brs) Reference Example A male rabbit (!j~3 kti) was sacrificed, and after exsanguination, the thoracic aorta was removed, cut in a rectangular shape at 1 septum 1III711, and sections with length p II+ were prepared. This was poured into a Magnus tube with a capacity of λθtnl containing Krebs-Ringer's solution, and the temperature of the solution was set to ? The temperature was maintained at 7C and a 9J% 02-left% CO2 mixture was introduced. A resting tension of lψ was applied to this aortic section, and drug administration AfJ
/ hours of incubation. Then, the compound obtained in Example/(/!jX#)-'M) was administered to this,
After 30 minutes, serotonin (/×lθ-6M).

Norepinephrine: / (/

As a result, by administering the compound, the contraction response of the slices caused by serotonin was completely suppressed, but the contraction response of the slices caused by norepinephrine and KCI was hardly suppressed. That is, compound / exhibits an anti-serotonin effect that selectively inhibits the serotonin-induced captivity reaction in the rabbit aorta.

Applicant: Mitsubishi Chemical Industries, Ltd. Agent: Patent Attorney Hase - Others/names Continuation of page 1 0 shots: Yasushi Oizumi 916, Minamiinuya Aza 11, Machida City 2 Mitsubishi Kasei Life Science Institute Co., Ltd. Inside the laboratory

Claims (1)

[Claims] (1) An alkaloid represented by the following formula (in the formula, R represents a hydrogen atom or an acyl group).