JPS5959646A - Clavulone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> together form keto group or one of them is H and the other is OH; R<3> is H or acetoxy; n is 0 or 1; when the bond between 8 and 12 positions is double, n is 0; a-e are 1 or 2; the dotted line represents single or double bond). USE:Antiphlogistic agent. PROCESS:Clavularia viridis (a kind of coral) is roughly extracted with ethanol, and the extract is concentrated and further extracted with ethyl acetate in an aqueous system. The obtained extract is fractionated by silica gel chromatography, and the compounds of formula II, III and IV are separated from each fraction. The compounds are subjected to e.g. reduction, oxidation, acetylation, etc. to afford another compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel labrone derivatives, and furthermore, T is a compound of the general formula [wherein k and 2 together represent a keto group or one is a hydrogen atom and the other is a It is a hydroxyl group, and ■(
3 is a hydrogen atom or an acetoxy group, 11 is 0 or l, and 2. iIj result now +
1 is 0. al;], (, (1, J: and C are respectively l or 2, and the dotted line is 1 cedar ((: l14J
5. is a bond in one or a bond in two. Ti′1. The present invention relates to a clubron derivative represented by the following.

The club of the present invention [Jn q1 is a type of coral called Crabularia hyridis (C, lav + mountain + ri; 1 vi
Compounds that are extracted from 1ζIE and also circumferentially derived from anti;(,: 41
1 action, and is useful as an anti-flame 4i sharpener.

The Clavulon derivatives of the present invention are specific (here);
Included are compounds represented by the formula r+2.

(6) (7) [Wherein, AC means acetylno].

Among the above-mentioned clubron derivatives, compound (1) (hereinafter referred to as clubron-1), compound (2) (hereinafter referred to as clubron-2), and compound (3) c below, 7-3) is extracted from a type of coral.11 sl
and other compounds can be chemically derived from them.

That is, the coral Clabraria viridis was crudely extracted with methanol, the extract was concentrated, extracted with ethyl acetate using an aqueous trowel, the extracted extract was subjected to silica gel chromatography to be fractionated, and Clavulone-1 was extracted from each fraction. , -2 and -3 to 1.17. 1 (to do 1)

Thus, when Labron-1, -2, and -3 are reduced by a conventional method using a borohydride reducing agent such as sodium borohydride or aluminum borohydride, the double viscosity of the cyclobencune nucleus is saturated. and the corresponding compounds (4
), (4“) and (4).
Treatment with any conventional acetylating agent will yield a compound in which the hydroxy group at the 9-position is acedylated. For example, by treating compound (4) with acetic anhydride in a conventional manner, compound (4') is obtained.
is obtained. In addition, by oxidizing the above-reduced compound using an appropriate oxidizing agent such as pyridinium chlorochromate, the 9-position (hydroxyl group) can be converted to a After treatment with chlorochrome-1, compound (5) is obtained.

Furthermore, if Claburon-11-2 and -Co-3 are hydrogenated in the presence of a catalytic reduction catalyst such as palladium-carbon by a conventional method (by catalytic reduction), double viscosity can be obtained from either compound. Compounds (6) and (7) which are fully or partially saturated are 111.

The Clavulone derivative of the present invention has anti-inflammatory properties of 1'llll+5.
For example, granulation tissue proliferation 1, which is a type of anti-inflammatory assay.
Through experiments related to 111 production, the following suppression t
Showed X.

[Experiment on inhibitory effect on granulation tissue proliferation ~ 1 Method (fertilized egg method): Fertilized eggs of the Dabkotsuku species were incubated for 911 days in S sc, and on day io, the method of Darcy et al. (I) Arcy, 1'
,F,ctal.

Brlt, J., Pharmac, Chcmothcr.
, 29, 378 (1967)), the eggshell and eggshell membrane are excised, and a P paper disk with a diameter of 9 rrm is placed on the chorioallantoic membrane. Next, the closed shell part was closed with cellophane tape and the eggs were incubated for another 4 days.The chorioallantoic membrane was cut out along the paper disk and dried at 60°C for 12 hours.

This is accurately weighed, the filtration paper disk weight is subtracted to obtain the granulation weight, and the effect is determined based on the inhibition rate and statistical significance of the drug administration group compared to the control group. The specimen is dissolved in an immersion solvent, 20 μm of air is added per P paper disk, and the solvent is removed under reduced pressure before use.

Results: Clavulon-1 and Clavulon-2 as test compounds
As a result of experiments using this method, the inhibition rate was shown in the following table.

Arbitrarily give an example) i
J6t made by l'i yohi j, , 7), ini and only 1
Tree-wise explanation/Jbe, 3゜Example Crab D-], Crabron-2, 1, ; Extraction of Yohi Craso D-3, '11p+fl: (2I) Taraphraria billy ice l &' i
+'ll'15 K9 f-Crush in methanol 2O-Il [7, -Ita IJ! After cooling, filter the residue and add 20% methanol to the boiling water.
11111. -CI+l III t,, this extraction, night 1. Note 71 II ('i, l= ('rth - 1r
') f) "C, L'J.

At 1, set θ, &ll: to 1. j1? was given
IA 41'! ” 4-no, ri・4<, in '31 (quiet^;) saze, acid 1 dredger 2/(2211++ 1
11 outi′ζ.

. Combine the acetic acid 1-del layers (-7-1σL & I N 79
'μ, :gt1'i L- 2r! , <'IF'5
(('+pi) Extracted hair Y-su: (obtain Og.

1, write down Itko 4 = S: 30g Sirino J) l Le Casino Ri (comatography (6\40cm ”'Y '1: +!2 "del(10:l)tl)2bl',
Elute at night, h-1 (approximately 2), evaporate the solvent 1 ton (after 1 time 1゛1 (, 2, 8!), I-'I
-2 (,17,12=1'1), 1-3 (0,54!
, 247) and 1-4(2,5), 3.2!7)
Old 7 Rakukon Fuji? (1).

(I)) 1411 [-1, 11 orders and 21 crabs in the edict - 4 (3, 2 ri): i-drink, suru l ko (V) l koborist L/n. Gel Q) Punorano (this i1!j L, remove 1 volume of methanol, 1
11? 1' out-r, -1-su 11-silino J gel color lz (4X 70cm, dry pa+k
, manufactured by Norkun 1), tune I7, benzene: acid-resistant toble (1
5: i) mountain 1〆fν - is Furukawa 1y, R'
) Layer chroma i.claphy (benzenylic acid enal (5:
1), K i c to clgcl -60, Melkun 1:
4) chromatographically while turning the cod)
Take 4 portions of the bot, and remove the resulting solution 1"1" under reduced pressure and reduce to a pale ♂l ((!-s).
Tube-shaped Clafron-1 (240]ηy)? [Iru. Ha'o, fL1 si I con ゛11- no iz 1ll
j Il Nagu・Aimuwarakushi 1in], 1! ':r
kl'-run. .

1. Complete set of compound 6 obtained in 02. ■；340
742 (J) has a structure represented by the formula (1) and exhibits the physical properties of I.-.

High resolution mass spectrum 446.2305 (error 02
+nMU): [Mount Id) (C11C)3)-28,
9°(c==0.36)1':toll;U■λmax ('''')230 (ε-□1:1
, 600), 292fi1m −H (ε−=17,300); IRν Ccm )
17: (0,111aX 700.1635.1230; Ill-NMR (270N IHy, ) (CI)C
,/! 3, δl+ I) III) 0.8B(3
u, t, J = 6.711z), 2.01 (3
+1, S), 2°05 (311, s), 2.38
(211,t, J-7,7117), 2.66
(Ill, dd, J-7, 14,5111)
, 2.97 (III, dd, J = 7, 1
4. ．． 511z), 3. −1 (1(:(If,
s ), 5.22 (111, dL, J = 10.9.71
1z, ), 5°45 (III, (I L , J=1
0.9, 311z), 5.78 (I It,
III), 5.86 (iIl, '+, I・1Qtlz
), 6.42 (I If , (1,,1=63■7
), 6.59 (1[I, (Id,, 1-1.0, 12.
511Z), 7.25(111, (1, J=12.50
J, 7J7 (Ill, d, l = 6.3 eyes 7); 13 (: -N kIR (67,8M II y, )
((,:IIC/:s,tl) 1)III)1
411 ((+), 20.9 ((1), 21.2 (++
), 22.5(fl, 27.4(Ll, 29.0(L
), 29.8(11,29,8(tl, 31.4(1)
, 35.9 (Ll, 51.7 (9), 69° 4. ((
1), 85.2 (S ), 12], 0 ((1),
124. ．． 3((+), 124.4((1), 134.
9((1), 134.9((1), ]-knee 37.5
(S ), 1.38.7 ((++, 157.8((I
), 169.0 (S), 169.7 (!;), ■72.
7(S), 193.0(S) (C) Polystyrene gel (3X45cm, n; t; id+i 3
010), extracted with methanol, treated in the same manner as the eluted extract ((1) above), collected the fractions that uniformly contained the tS points by chromatography, and collected the fractions for 4 months. The mixture is then concentrated to obtain a light-colored syrup-like Claburon-2 (5:30 mW). In addition, fractions o and 3iq containing other impurities are obtained.

The compound represented by Tl has the molecular formula C251Natsu3407 as Fr, and the structure represented by the above iIl formula (2) as H, and exhibits the physical properties described in 1.

partial resolution mass) Le 44 G, 2292 (erroneous, >, '-], Q mMLT); (α]
, ((:III,:] March-10,!n 0 (fO
X□31": Lu11 5): UVλ (n+n)230(ε";■4,5
(10), Ill a X 292 (g = 19,300'); IIζ +
', j+ I;+ (Cm-1) 1730, l 7
(10,1640, l 230 :,, 111-N conversion ('270 Mtly, ) ((:I)(:, A
3, δ1)1111,)0.3B(311,L,
l=6.9”1), 2.07 (:l II, s)
, 2.0+3 (311,S), 2.38 (21+,
l , , l 7.5■/, ), 2.69 (111
, dd, J=8.14.511J, 2.88 (Ill
, (ld, J=7, 14.511z), 3. (
i 8 (3+1.s), 5.22 (III, +n),
5. '52 (III, dt.

J ==-10,9,8+1z), 5.42(III
, q , , 1 7111), 6.02 (ill,
(1(1, J=7, l/1.5+17.), (i,
41 (III, d, J = 6,311z),
6.75 (1■, (■(1,I-[1.6 , 14.5
11z), 6.87 (111, II, ,'l
i, i, 611z), 7.47(ill, cl, J
=6.311Z); 13cmrnvuζ(7.8M
old) (CI) /, 3. δl) 1)Ill)1
4-0 (q), 21.0 (q), 21.2 ((+)
, 22.5 (Ll, 27, 4 (L), 29.1 (L
), 29.1+1), 29.6(su, 31.5(Ll
, 36, 0 (L), 51.8 (q), 72.8 (
d), 85.1(S), 121.1((1), 126.
9(d), 129.3 ((S, 135, O((+)
, 135.0(d), 137.0(s), 141.3(
d), 158.1 (('), 169.5 (S), 169
．． 9(S), 172.9(S), 193.4(S)(d
) Isolation of Claburon-3 The above Fr-2 (12,4 g) was placed on a Boris Dillen gel column (4 x 60 cm) until L to decolorize it.
, eluted with methanol to give a pale Ll'l ('E + 3.65f?, this extract was used in (1) above).
The fractions obtained by chromatography to obtain a uniform spot were collected in the same manner as above, and concentrated under reduced pressure to obtain Clavulon-3 (2557 kg) in the form of a pale yellow lump.

This compound is 1' m 02 s l l =, 3407
This has the structure 111t shown by the above formula (3) and exhibits the following physical properties.

Component breakability mass spectrum 446.228 (3 (error 1
．． 6mMLJ) ; [α”] II (C1lO
)3)' l・45.5°c +: -o:1':
t o+ + 22'); uv, t, (nm) 230 (
ε-17,,200Ill a X tilln, yo), 295(e-L7,600): I'lν (
on) 111;lK 1735.1690.1640.1230;”II-
NMR (270 Mll y, ) (CI) CJI! 3
, δl) p m ) 0.88 (3#E, L,
J = -6,9110,2,04(311,S),2
゜10(311,s), 2.39(20(,,1==7
．． 511 Otsu), 2.66 (tll, dd,, l-, -7
, +4.511z), 2.8 (i (In, dd
, J = 7, 14,511z), 3.67 (3
11, S), 5.21 (lII, dt, J
=11,'711Z),5.52(1",(I
L, J-41, 811Z), 5.44 (111,
q, shi=5, IIJ, 6.02(lII, d(1, J
=6.15.5'11. ), 6°36 (ill,
(l , , 1 = 6.3 fll), 7j 4. (
l If , +1 (1°J = 1 ], , 2 , 1
5.511y, ), 6.52[xll, d, J=1.
1゜2117), 7.50 (l II, d,
, 1) (i, 3 ” 7); +3 to Nh4Rc 6
7.88・ll1z) (CI) to 43. δl) l
) Hl ) 14.0 (Q), 21.0 ((1), 2
1.7((+), 22.5((1, :27.4(Ll,
29.1((1,29,2(Ll,29.8(L),3
1.5(t), 35.6(t), 51.7((1), 7
2.5 ((,1), 85.3(S), 121.4 (
'(1), 126.5 ((1), ], 33.4((+
), 134.8 ((1), 135.7(S), 136
．． 7(('), 141, (1(d ), 156.1(d
), 1 (+41.7 (S ), 170.1 (S)
, 173.1(S), 194.1(s) Ron 0.31!
i' and silica gel ■ J7 Tokurafui (3,5
x45cm), benzene:ethyl acetate (15
:1), Clafuron-1 (54
0■] and Clafuron-2 (214m?) were obtained.

Therefore, 111■ (11 with a lower pestle) et al. (soil extract 307, 780 m7 of Crablon-1, 744 m7 of Crablon-2,
2557 ηg of Craft Con-3 was obtained.

Example 2 Club lower 1 (100”!?) methanol 5
ml and add borohydride to this solution.
Add 0"g and stir in chamber 1!A for 30 minutes. Reaction 1
Add 0.5 ml of acetone to decompose the excess reducing agent (71) Then, add 50 ml of saturated brine and extract with 50 ml of ethyl acetate. 'l + 6, purified with sulfuric anhydride)
After drying with IJum, the bath medium was distilled off under reduced pressure to obtain a colorless oil (110"j). This sheet was subjected to low-pressure liquid chromatography using a silica gel column (McCrck f! 1-Graph (n-hex→)-ethyl acetate=1+1) to obtain compound +4+ 40 fil'/ (yield 4j 40%) as a colorless ridge-like substance.

This compound has the molecular formula C25":3807 f1")
) IS notation (4) and reduce 1 + r'M clear to YT I,
Deori l, written thing ↑11 small, t also [, y ), (C
ffl to Il: 3) -109,5°: to UV +; tx
(Old Isu 248 (ε-24,700) Example 3 1) In the same manner as in Example 2 of 11, excursion with Kunno [1 to 2 sodium borohydride] and combine.
(-1'') (yield 36゛) is obtained.
The above formula (4') shows ((゛・exp′・(1(,t), its [α],, (C:IIC/3) is -24
, 5', Il, Kanjio side 4 Same as Example 2 (at 17 for sheep, graph r + 'y-, 3
1:) Reduction of sodium borohydride 1. Shiteka rs
'l:'/J (=1) (yield: 36%) 'i
? ! ;? N. r-no compound iJ min J' formula (+2.l
L,, (Attach λ7, 1)
Mountain) ((River (-13) is -5,8'-(-Mountain・1..

Example 5 1) Compound ill 4911 obtained in iJ Example 2
1g 5□Dissolve in 2 ml of carbon tetrachloride, add 0.2 ml of Nishi'1 acid anhydride, and 0.5 of Nisylamine'
ml and 0 dimethylaminoviridi 710”Vk sequentially 1
．． +t+ E, V? A-A-('E 21 hours 1i
Hit 11. Add 50 ml of acetic acid to this reaction mixture, add 1, (-2) liter of aqueous solution, 2, 1, 1, of water,
After 78 liters of saturated copper ice water, water and 1-bubble saline solution, dry with 1 sulfuric acid solution.Then, the solvent was distilled off under reduced pressure and the mixture substance 64
Get m2. Coat 1 with silica gel carano・(Mcrc:
k Lobar column) once per month: /fν(
book ■] 71゛ Kurafui (n-=heki→non-F+T
Ethyl acid 2:1) - c + I shi, pale yellow uras-like rostrum (1', sound (4) 4. Q 7 + 1 zo (accumulation, i,
75%).

This compound Ig1 has the formula C27114o087'-(
−;'! ,,,Structure represented by the above formula 1・+(,)I 1 (4)<;・rl” L, LI
VλIll; IX (formerly 247 (ε 27,00
0) is shown.

X male side 6 1) (J record male side 2 and 1', 1 compound 14)]
-51ノ'! 77-Chloride/Dylene 2 mf to m I'1
'1' L, this (kobirijiu l, ri c+ +-+ chromate 60Tn!/4 addition, chamber 'tj+-11+-<-
: Stir vigorously for 4 hours. This reaction mixture is ・Silica/
7-Runonoshino・(koj(1-1(7)) was washed with methylene chloride, and 1l-141(:"rr ll
'i, are combined and reduced by 1 (remove the solvent to + to make green 7), and one color of urasei substance is -1 (). This is the old one.
Mc r r k CIl 11・I+') J Rano・]
Tt port) and low I
The product was purified with ↑-Zan-ethyl acetate (1:]) to give Compound (5) (yield: 95%) as a colorless, curved substance.

This compound has the fractional formula C2, ■3607, r)ij
The substance t'l having the structure shown in formula (5) and written in F
:, 6;1Xit-0 high resolution mass spectrum 388
．． 2230 (tlvL-A+(month 1)(error-1,,
7mM [J): [α mountain, (ClIC-/I)
−G 8 ■ et Lu11 2 ° ; Uv λ (Ilnl)
287 (g" 21.50 (1) Example 7 Club o 7-1 (100"!?) 'c "ri/
30 mg of 5% palladium-carbon was added thereto, and stirred vigorously for 3 minutes at room temperature in the presence of hydrogen. The reaction mixture was filtered to remove the catalyst. , the solvent was distilled off from the V solution under reduced pressure, and Jliu Color Pu 1
Separation 1~ with low pressure liquid (1)-hexane-acetic acid 1-f-ru 1:1) using color paste 1 dog substance 69777 Mcrd+ Lol)ar column), compound of non-f Haura-like substance +7 )1
-1 p ) and 1!1 (
Compound of color urafushi substance +6) 3 6 mL/(yield 4
1%).

-1- The obtained compound 'j'.
) the structure shown by f-end-(neeori1,:'H')
Resolution mass spectrum 394.2706 (wrong i ~ J.O
E t o1+ 01ML+): (α), (CIIC)3)+7. (
10: to L'λIll; IX (formerly 235 (
ε=14,200).

Compound (7) has the formula (:23114005+
(i, i' + shown in the above formula (7).
-1']' L 'C J ri, rFj+ 5) i
11'l'ability-7 7.

Spectrum 3 9 6. 2 8 99 (error 2,
5 ml'vlt. l) to 1(s).

In the above method, when Crablon-2 or -3 is used in place of Z1, the yield (6) and (7) is ?1?

Claims (1)

[Scope of Claims] (1) -- General formula [wherein ■ (and ≮ 2 are both f, 1--C ge) ・Group 4-Small or one is hydrogen atom P (11L is 1-doll-no, (, I (3 is a hydrogen atom or aceto-1-no, 15, u i; 10 or l,
When there is a bond between 12 positions or two small bonds, ■1 is 0. Jiang, 1), (-1 (1 o, 1, hici, respectively, are 1 or 2, and dotted line 11. ] Clavulon derivative represented by.