JPS60136538A - Benzylidene derivative - Google Patents

Abstract

NEW MATERIAL:A benzylidene derivative of formula I (X1, X2 are same or different acyloxy). EXAMPLE:3,4-Diacetoxybenzylidene acetate. USE:It has excellent action of inhibiting granuloma proliferation, suppressing adjuvant arthritis as well as leukocytoplania and is used as an anti-inflammatory and antirheumatism against rheumatoid arthritis, systemic lupus erythematosus. It can be used as an anticancer against cancers with cell proliferation. It has very low toxicity and is given orally or parenterally. PREPARATION:For example, dihydroxybenzaldehyde of formula II is combined with a more than 4 molar equivalent amount of an acetylating reagent such as acetic anhydride, then a strong acid such as conc. sulfuric acid is added and they are stirred. The reaction is effected in the absence or presence of a solvent such as benzene usually at room temperature to 100 deg.C for 1min to 1hr, preferably for 1-5min to obtain the compound of formula III among formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of benzylidene derivatives and the above-mentioned nine-shelf bodies as anti-inflammatory agents.

Dihydroxybenzaldehyde has recently been used as an anticancer agent (Japanese Patent Laid-Open No. 55-51018) or as an anti-inflammatory agent (Japanese Patent Laid-open No. 55-51018).
8-83619).

However, in in vitro tests, dihydroxybenzaldehyde shows excellent pharmacological effects such as inhibiting facet platelet aggregation and white ball migration even at very low concentrations; v
In the iv test), the metabolism is fast, so the (+ effect (7Ht+i
Physical action effects (i.e. require only one clear interjection 5 in large quantities, and 1:11 intense 111 due to aldehyde part)
It is a compound with a score of 5!11 for its oxidizability.

The inventor of the tree, Gu9, has an effective effect in small amounts when administered to the body of cattle.
A compound represented by the following general formula [11] synthesized by the acylation reaction of dihydroxybenzaldezide with 9 and J, which has been researched to find a drug that exhibits a certain raccoon effect and has few side effects. reached.

(In the formula, X, ×2 is the same or different acyloxy7:
! 4) The above 7syl Aoxy group is represented by RCoo-,
R is straight or branched alkyl having 1 to 18 carbon atoms! or), [aromatic residues such as nyl groups, alkylphenyl groups, etc. may be included.

Hereinafter, dialethoxybenzylidene arethe-1~='[rest (hereinafter referred to as the present substance) and Anti-inflammatory agents using this substance alone or as an active ingredient in a mulberry agent phase composition will be described in detail, but other compounds represented by the above general formula 1 [I] also have various pH effects similar to this substance. This substance represented by the above general formula [TI] includes the following compounds.

2.3-Diacetoxybenzylidene acetate 2.4- 2.5- 2, G -- 3,4- 3,! i-one product ffl is synthesized according to a known method. Below 1・
, dihydro rl-1 = acedylation of sibenzaldehyde j
This is an example of a composite payout for the real v1.

The reaction between benzj'rugeghyde and the aretylating agent is potassium hydroxide lx' + monolithium hydroxide, sodium acetate,
Although it can be carried out in the presence of a strong alkali, the following reaction 1
℃, it is advantageous in terms of yield to conduct the reaction in the presence of a mineral acid such as sulfuric acid.

[Eeee 1 [Eel] After adding 4 mol equivalent m or more of an aredelifying agent such as anhydrous 'hj acid to dihydroxybenzaldehyde represented by the general formula r Tll 1 'ill', immediately add a strong acid such as concentrated sulfuric acid. When stirred, the reaction proceeds while generating heat.

The reaction hot stone is usually selected from the hot stone range of room temperature to 100℃ 11-
be done. The reaction time is preferably 1 minute to 1 hour, and the reaction time is 1 to 5 minutes. In the above reaction, it is not preferable to leave the addition of the aretylating agent for a long period of time or to react for a long period of time, as this may involve more side reactions and reduce the yield of the target product.

The acetylation reaction may be carried out without a solvent, or in the presence of acetic acid, benzene, heluene, ether, etc.
<Carry out in the presence of a high organic solvent.

After the reaction is complete, the reaction solution is poured into water, for example, to decompose and remove the excess aretylating agent. If necessary, the organic solvent is further removed and used for arbitrary C recrystallization, etc. The desired substance can be obtained by processing using a known method such as J-Zuru.

The above-mentioned synthesis method is an implementation example for obtaining the present substance.
There is b (DC") which shows this, so the manufacturing method of this substance is limited to this. In addition, the necessary allepurating agent may be used to synthesize the compound represented by the general formula (1). .

As a result of a group in vivo test, this substance has a leukocyte fugue inhibitory effect, a granuloma growth inhibitory effect, and an arthritis inhibitory effect as a compound, and is less toxic than known substances such as dihydroxybenzaldehyde. 'l 'cIshi)
Low/T throw! I 5i has zero effect, so anti-inflammatory drugs, chronic ('1. I!I rheumatoid arthritis, systemic lupus erythema 1--
It has been found that it is suitable as a wide range of anti-inflammatory agents, such as anti-rheumatic agents such as Slr, or agents for treating autoimmune diseases such as glomerulonephritis, and is also expected to have antitumor effects.

Below are the genuine v'I 7f51 nol and the physical characteristics f/i
About RU; 2 Ming (do).

(1) Acute toxicity The substance, 3,4-dihydroxybenzaldehyde, has a concentration of 0.
Dispersed in 2% CMC solution 1! , this was adjusted to a predetermined value of 141 and administered orally to -C1 order tel JCL, -I C]n mice using a stomach probe! I got it.

The lDso value of 3,4-thiat-xybenzylidene 1-do-chi-1- of this substance is 4,000111! +/
kg or more.

At the studs, 2.3-, 2.4-, 2.5-,
2. G-.

3.5-Diacetoxybenzyliner 1? As a result of examining the acute toxicity of Qi 1, all ID5o vessels (Feng [1) had concentrations below 2,000 mg/ko.

On the other hand, the LD50 value of 3.4-dihydroxybenzaldehyde is 1503 mg/kg, which indicates that this substance has extremely low toxicity.

■ Leukocyte fugue suppression effect Using 5-week-old jJF i11 Donryu Rat 1-c as By 64-c, 1t1-1 was applied to the CM Cpo+1cb method (?Ei Kawa et al.'s magazine challenge, 1472. 1968). 7. In a polymorphonuclear leukocyte exudation test into the inflamed site, the leukocyte fuget inhibitory effect was investigated. The test drug was 0.2% (dispersed in MG solution) and a predetermined amount was administered orally.
In addition, the control group received only 0.2% CMG solution. I got it. After CMC injection, measure the number of polymorphonuclear leukocytes (PMN) in the exudate.

The result C is as shown in Table 1, and this substance has a low amount of Cb.
Significantly suppresses exudation of polymorphonuclear white spheres into the inflammatory site i1+ll
It turned out that Ll.

Forked, 2.3-, 2.4-, 2.5-, 2.6-,
3.5-di' th l dibenzylidene ahite
The inhibitory effect on leukocyte fugue migration was also confirmed for 1~.

Table 1 6 meetings p<0.005 (:() Sarcoma growth 1 suppression f+II] Sarcomus i Liver hatred suppression rr River 511 weeks old〃1↑11Doryurat1~*f11!Y Gt tag) The method of Rimura et al. [Applied Pharmacology 13-(3), 32!] (1ri 80)
I got +4 according to 1. Paper lr'/I;1
．． , 13mmφ, 28mg paper with 2% CMCFt
j 'd (contains 0.1 mq/m of dihydride [l-1 cystrebutomycin, 1 part per million penicillin)]
One of these discs was implanted under dorsal ether anesthesia in the dorsal skin of knot 1 using 20 ml of treatment.

1 skin test a! ++, t Dispersed in 0.3% CMC solution,
For 10 mouths, 1 J was administered, the granulation was removed at 111-1112, and the weight of the granulated liver was measured. In addition, −]n i~1]
0.3% CM (': (El'Li) alone was administered orally to the 100% group.

Results (11 Shown in Table 2; l, :0 Table 2 Note) * P < 0.05 Axis p < 0.01 1 meeting p < 0.005 Also, test answer ? H111 constant 1-j <'+: As a result, the control group (indomethacin and prednisolone) showed gastric mucosal protrusion and iL'J tumor formation in the control group (indomethacin and prednisolone).
Prednisolone) Throw! In jnY, thymus atrophy was observed at 0. Is there any abnormality compared to this substance (1.1.1)?
l Go, I (4) Aji] Banto arthritis inhibitory effect Ajicoban 1 ~ Effect of preventing the onset of arthritis in 8-week-old dark blue eyes I
t J CL-8I) strain 1 to 6 rats were used in each group, and the I shell! ', Ri's method (Applied Pharmacology! i(2), 7
69. [71] tl (1 di 3 bt was investigated. That is, -
[-Pull Freund's C01 into the tail to anesthetized rat 1
11pletO azicobant (0.6 mg, '0.I
mQ) 4-inoculated. Two weeks after vaccination, apply the test patch 1
The drug was orally administered on day 1 and once for 20 consecutive days.

This 1υIY'i (2,3-, 2,5-, 3,4-thia 1?1-xybenzylidene acetate-1-) all showed excellent therapeutic effects on adjuvant arthritis in the evening and afternoon. Ta. Y, contrast mulberry (prednisone) throw! Group J is i4\
The increase in Φ was suppressed, and right laxity <i: k new 1 was observed in the dissected and removed thymus gland, but water ￥fIJQ!
JfiY F showed no inhibition of body weight gain or thymic atrophy, and had few side effects.

Therefore, this substance is extremely effective as a therapeutic agent for chronic +j1 inflammation f1r such as rheumatism.

Based on the above results, it can be seen that this substance has an excellent inhibitory effect on meat proliferation, anti-arthritis, and leukocyte migration, and has an extremely low m1'I C. . Therefore, authentic %+i is anti-inflammatory agent and iQ t
! L joint rheumatoid arthritis, systemic T ridema i~-death (Slr
') and other anti-rheumatic drugs 'C'4^te Vi II
I use the right J. In addition, cancer with cell proliferation h°1
1 is also useful.

This substance may be carried in a medically acceptable carrier and/or #:L? +
In this case, the present invention can be used as a stimulant for sexual administration. The compound may be used in combination with 2) one or more active substances, or may be used in combination with other active substances.

Food warehouse 1. L, can also be applied intravenously or [J, non-verbally (・, one of these! i. The substance of the present invention is available in a dosage form of 12 servings (J) (12 servings) (11 servings per serving), containing 11 servings, 2 tablets of granules, sugar-coated tablets, 1 gulp of turnip, and zabo.

It is available in various forms such as suspensions, solutions, emulsions, ampoules, and injection solutions.

11--) (It should be understood that the adhesive of the present invention can be prepared by applying any horn stiffening means known in the art. tJ as an auxiliary agent
The amount of this substance (active ingredient) can be adjusted within a wide range of 0.01 to 100%, preferably 0.1 to 70% (magic).

The auxiliary agents of the present invention are shown in the previous 3 (shita J, sea urchin, hi 1~ and Ul
Administer orally or parenterally to objects! ) will be done (
, especially when it comes to oral IQ.
I IQ! jl;L sublingual throw is also included,
Parenteral 1TI i'z 'J is subcutaneous, intramuscular, and intravenous injection.
This includes γI injections and intravenous drips.

Injection of the sugar drug of the present invention
Since it is affected by J or Hi 1~, J, Su, age 9 individual differences, disease 1 λ, etc., in some cases J will be excluded if the following range is outside the range Q ', but in general When targeting humans, the effects of this substance on the body are
0.1 to 500 mg per F1, preferably 0.5-2
00111j), and the non-light Russian throw is the body fI'!
lk! 1. 0.01 to 200t++ per 1r1, preferably 0.1 to 1100II1 divided into 1 to 4 times ()'
CIQ! j.

Hereinafter, the present invention will be revised with examples. 1 (ηK2゜Friend 1
9L3,4-diace1~xybenzylizo''/2L comfort j-
1 to 51 + 1 2 O (l mff Erlenmeyer flask 1 to protokana. 1
-1 aldehyde 3Oi1 and ;++! (Water resistance 92.4Q
Add 1 drop of concentrated sulfuric acid and cover with 4he 7%.The reaction starts immediately, generates heat, and the aldehyde of the halide material dissolves, forming a uniform red color. The reaction solution was shaken for 3 minutes and poured into 500 mQ of water, yielding a crude product in the form of a colorless powder. After drying this product, The yield was G8.OQC, and the yield was 96.6%.Thus, 11)
This Phase 11 product was mixed with r-thyl alcohol-ethyl acetate (approximately 2
Recrystallization was performed using a mixed solvent of :1), and no [! - norhythmic /1 composition59. ! 1g (yield 85.0%)
1-11 1. The physical properties of this product are shown below.

(1) &i (1 point; to 126.0, 127.0℃
(Capillary method) (2) No.1. Moisture 41r value: C(
%) 11 (%) K1 Single 11 White 55,56 4.
97 actual measurement value 55. ．． 70 4.90 (3) Infrared absorption spectrum (K [3+/tablet method) shown in Figure 1.

(4) Nuclear magnetic resonance spectrum Shown in Figure 2.

δ (DM S 0-d6) ppm.

2.12(s), [Δaffect(0cocH3)2. (611
)12.28 (S), [Ar-0COCH3,
(61(1)7, 37--7, 42, [Ar-H,
(3H) ]7.55 (S), [Ar-Co○H
, (IH)] 41. to the method of Example 1. Di(2,3-dialeto-1 cybenzylidene arethe-1 to obtain the crude product,
Recrystallization was carried out with ethyl acetate to obtain a colored powdery product (yyyy% yield). This product, product 11 (target 4) 1YT, was received as follows.

(1) ijiQ: 1(18,0~109.0'C(
2r Yahira',) r)*) (2) original;)・, Analysis 111'l: CM) (+) lhuge%)+ll'
r':' It white 55.56 4.97 actual measurement 11+'
15! +, 70 4.80]) Akata 1. Line absorption spectrum (KBr tablet method) shown in Figures 1 and 3.

(4) Nuclear magnetic jl sound spectrum i'1/1 Shown in Figure 1.

δ(1)MSO-66)ρpm.

2, (IQ (S), [Ar-C(OCOCH3
), (61-1117,37-7,5'), [A
r-T(,(3H)]7.70(s),l Ar-C
0OH, (LH)]]ノζ/a-M:s-2,s2'
) 7 t folded twice to prepare the crude product of 2,5-diaceto4-dibenzylidene]iL!tate using the method h of Example 1. J, crystallize in ethyl acetate, and give a
The product (yield 81.3%) was synthesized (yield 81.3%).
J's 1111 items are shown below.

(1) Melting point; 125, ! + ・〜・ 126,5
Te; (-1-11 Bisiri one person) ■Elemental analysis value; C (
%) 11 (%) dl cutting (11 white 5!i, 56 4.07 actual measurement 1 shift
55,70 4. ! 1 (1 (3) Infrared absorption spectrum (1 < [i-tablet method) 5th
Accept the illustration.

(4) Nuclear magnetic ringing spectrum It is shown in FIG.

δ(DM SO-(16) p, pm.

2, 10 (S), [Ar-C(OCOCH3
12, (61'l 17.27-7.38, [A
r-H, (3H)17.70 (S), rAr-
C00T (, (nr)) made of 1"L4v" - A (1 V"i (3,4 shear L? I-21 = dibenzylideneacetic acid 1.-1,) 10 parts gi Φv° (15 parts of magnesium oxide and 15 parts of lactose are mixed evenly and made into a powder or granules.
, Also, is this powder 1 turnip? Put it in a container and drink it.

Kasumigun ILI sex"L Genuine Y'j (2,!i-Sial?+-Xybenzylidene acetate-1,) 45 Jujubatake, "Nzon 15 Juyumibe"? 1. Sugar 16 Jushinabu Crystal 1 Lire 11-Sugar 21 Ichishinabu Polyvinyl alcohol 3m 6 parts Water 30 parts evenly 1. - Mix and put in a CI tube i! After heating, it is crushed, granulated, dried, sorted, and the granules are removed.

1 main substance on the sexual membrane (3,/1.-Diare 1~:1-Shibenzily J
゛Innonote-1~) Add 10 Φ suspension benzyl alcohol 3 parts 1 part physiological saline 87 parts, heat and mix, sterilize, and use 1 shot as 4! ? ／、：
.

[Brief explanation of drawings]

Figures 1, 3 and 5 show the infrared absorption spectra of the real product y°t, and Figures 2, 4 and 6 show the real product v
1 nuclear magnetic ringing spectrum. Agent ㅅP site officer Ima Muramoto

Claims (4)

[Claims] (1) A benzylidene derivative represented by the general formula [I] (wherein X and x2 represent the same or different acyloxy groups). (2) X, is ×2 at? The benzylidene derivative according to claim 1, which is a t~4 di group. (3) An anti-inflammatory agent containing a benzylidene derivative represented by the general formula [11 (wherein xi and x2 represent the same or different acyloxy groups) as an active ingredient. (4) The anti-inflammatory agent according to claim 3, wherein Xi and X2 are acetoxy groups.