JPS5837294B2 - Carbon Sanesterno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to long chain unsaturated carboxylic acid esters useful as pharmaceuticals, more specifically 5,9,13,17tetramethyl-
The present invention relates to a novel method for producing 4,8,12,16-octadecatetraenoic acid ester.

The object compound of the present invention is a 5-9-13 compound represented by the general formula (I) (wherein R represents a lower alkyl group, an unsaturated alkyl group having 5 to 20 carbon atoms, a benzyl group or a substituted penzyl group).・17-tetramethyl-4
- 8,12,16-octadecatetraenoic acid esters, these compounds show therapeutic effects in acetic acid ulcer, a pathological model of ulcer, and are useful for treating gastric and duodenal ulcers.

In the general formula (I), the group CH3 1 H4CH2-C=CHCH2 is a geranyl group CH
3 1 Since it is considered to be a geranyl group substituted with [HXCH2-C=CHCH2-+2], it is abbreviated as geranylgeranyl group. Therefore, the compound of general formula (I) is an ester of acetic acid substituted with a geranylgeranyl group, so it is called geranylgeranyl acetic acid. It is abbreviated as ester.

In the R group in the above general formula, examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, etc., and examples of the unsaturated alkyl group having 5 to 20 carbon atoms include prenyl and keranyl. , neryl, citronellyl, farnesyl, geranylgeranyl, phytyl, etc., and examples of substituted benzyl groups include lower alkyl groups having 1 to 4 carbon atoms and 1 to 4 carbon atoms as substituents of phenyl groups.
Those having alkoxy groups, methylenedioxy groups, halogens such as fluorine, chlorine, bromine, and iodine, acetamino groups, etc., and substituents of methylene groups with carbon numbers of 1 to 1.
Examples include those having four lower alkyl groups.

Among the target compounds of the present invention, only geranylgeranyl acetate keranyl ester is a known compound.

This compound is conventionally known as 3・7・■1・l5-tet-y)
-J-#-6・10・14-Hexade force triene-2-
4.8.12.l6-
Tetramethyl-7,11,15-hebutadecatriene-
Obtain 3-one-1 monocarboxylic acid and react it with geraniol to obtain 4,8,12,16-tetramethyl-7,1
It was obtained by obtaining 1,15-hebutadecatrien-3-one-l-carboxylic acid geranyl ester, reducing it with sodium borohydride, and dehydrating it with phosphorus oxychloride, but this method requires a few steps. This method is complicated and has a low yield, so it is not preferred.

The present invention provides an industrially extremely advantageous production method that allows geranylgeranyl acetate containing geranylgeranyl acetate to be produced in high yield and quality through simple reaction operations.

That is, in the present invention, the compound represented by the general formula (I) has the general formula (n) RX (n) (wherein R means the same as above, and X is・Representing halogen) can be very easily removed by reacting with a halogen compound.

Examples of X in the general formula (II) include chlorine, bromine, and iodine.

Examples of the compound represented by the general formula (n) include methyl bromide, ethyl bromide, n-
Propyl bromide, isopropyl furomide, n-butylfuromide, inbutylfuromite, SeC-butylfuromide, frenylfuromide, geranyl bromide, neryl bromide, citronellyl bromide, farnesyl furomide, geranylgeranyl bromide, phytyl bromide, penzyl Furomide, p-chlorobenzylfuromide, hyperonyl bromide, p-methoxybenzyl bromide, p-acetaminohensyl furomide, p-methylbenzyl bromide, α-methylbenzyl bromide and their corresponding chlorides and iodides It can be cited as a suitable option.

The reaction is particularly preferably carried out by reacting 1 mole of the alkali metal salt of geranylgeranylacetic acid with about 1 mole of the halogen compound in a polar aprotic solvent at 0 to 70 DEG C. for 10 minutes to several hours.

In the esterification reaction of the present invention, in which geranylgeranyl acetic acid, which has a long chain of 18 carbon atoms and has many unsaturated bonds, is reacted with a halogen compound, a solvent such as ether, chloroform, etc., which is used in a normal esterification reaction, is used. , carbon tetrachloride, benzene, xylene, dichlorobenzene, etc., of course at room temperature.
Even after heating, the reaction is so slow that the product is detected only after several hours, and many by-products are produced, making industrial implementation impossible.

However, when a polar aprotic solvent such as hexamethylphosphoramide is used as a solvent, the reaction time is significantly shortened and the formation of by-products is sufficiently suppressed, so that the esterification reaction between a long-chain unsaturated carboxylic acid and a halogen compound can be easily performed. Industrial implementation becomes possible.

Examples of alkaline agents for converting geranylgeranyl acetic acid into alkali metal salts include alkali metal hydrides such as sodium hydride, potassium hydride, and lithium hydride, sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butyrate, and potassium methoxide. lat, potassium ethylate, potassium te
Examples include alkali metal alcoholates such as rt-butyrate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metals such as sodium, potassium, and lithium.

Examples of the polar aprotic solvent include hexamethylphosphoramide (hereinafter referred to as HMPA), dimethyl sulfoxide, diphenyl sulfoxide, dimethyl formamide, dimethyl acetamide, ethylene glycol dimethyl ether, cyethylene glycol dimethyl ether, and sulfolane.

Depending on the temperature, a mixed solvent of the above-mentioned solvent and lower alcohol or water may be used.

Among the solvents, HMPA, dimethyl sulfoxide, and dimethyl formamide are more preferable, especially I{MPA
gives very good results.

In other words, when HMPA is used as a solvent, the reaction proceeds at an extremely high rate even if the reaction temperature is below room temperature.
Therefore, a reaction time of about 1 hour is sufficient, and since the reaction conditions are mild, side reactions are sufficiently suppressed and the target compound can be obtained in high yield and quality.

Geranylgeranyl acetic acid in the method of the present invention is a new compound, which can be used, for example, as homogeranylgeranyl bromide [M, Julia et al. / S oc lete Chi m iqued
France), 1960, 1072-8] with potassium cyanide to give geranylgeranylacetonitrile, which is then hydrolyzed with alkaline.

Since the object compound of the present invention contains at least four double bonds, it may contain many isomers depending on whether each double bond is trans or cis.

These isomers are produced in the same relationship as the isomers of geranylgeranyl acetic acid or isomers of norogen compounds used as starting materials (they are not affected in any way during the synthesis reaction).

The target compounds of the present invention are new compounds with the exception of geranylgeranilic acid geranyl ester, and have these compounds been tested in the pathological model of ulcers in rats? It has an excellent therapeutic effect on acetic acid ulcers, which is equivalent to or better than commercially available ulcer treatment agents gefarnate and solcoseril.
It is useful for treating duodenal ulcers, etc.

Next, the present invention will be explained with reference to reference examples, examples, and test examples.

Reference Example [Production of geranylgeranyl acetic acid] (1) Production of geranylgeranyl acetonitrile 16.3 f of homogeranylgeranyl bromide and 3.51 g of potassium cyanide were stirred at 70°C for 12 hours in a mixed solvent of 30 ml of dimethylformamide and 7 ml of water.

Water was added to the resulting reaction mixture, which was extruded twice with benzene.

The benzene layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain geranylgeranyl acetonitrile 13 as a yellow oil.
I got 1.

(11) Production of geranylgeranyl acetic acid 13i of oil obtained in (1), potassium hydroxide 251
A mixture of 50 liters of water and 120 liters of ethanol was refluxed for 8 hours, then ethanol was distilled off from the mixture under reduced pressure, diluted hydrochloric acid was added, and the mixture was extracted with ether.

The ether layer was dried over anhydrous sodium sulfate and concentrated to give a yellow oil 1
I got 2g.

This was purified by silica gel column chromatography to obtain geranylgeranyl acetic acid 61 as a pale yellow oil.

Elemental analysis value: C2H3602 Theoretical value (%): C79.46 H10.92 actual value (
%): C79.40 Hl1.15 IR spectrum: 1710' (νCOOH) NMR spectrum: (in carbon tetrachloride, same below) δ: 1
．． 60~1.68 (15 H1s, CH3)
, 2 0 0 ( 1 2 H, rn, CH2)
, 2.28 (4 H, m, C black CH, COO)
, 502 (4H, m, > C=CH-), 9.75 (IH
, br, COOH) MS spectrum: m/e 332 (M+), 69 (base pe
ak) Example 1 [Production of methyl geranylgeranyl acetate] Add 0.5 ml of 50% sodium hydride to 8 ml of dry HMPA.
Add 145S' and stir at room temperature.Geranylgeranyl acetate 11
A mixture of 3 rills of dry HMPA was added dropwise, and then methionide #0.6! A mixed solution of dry HMPA3 rrLl and dry HMPA3 rrLl was added dropwise, and the mixture was stirred at room temperature for 30 minutes.

The resulting reaction mixture was poured into dilute hydrochloric acid topped with ice, and extracted with ether.

The ether layer was thoroughly washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting oil was purified by silica gel column chromatography to give a boiling point of 133-5°C/0.
．． 0.91 methyl geranylgeranyl acetate with a refractive index (nv″5) of 1.4882 was obtained (yield: 86 mmHg).
．． 5%).

Elemental analysis value 'C23H3802 as theoretical value (%)
:C79.71 H11.05 actual value (%): C79
．． 54 H11.18IR spectrum: 4745crfL'M spectrum: δ: 3.6 0 (3H, s, CH30CO
) MS spectrum: m/e 3 4 6 (M+), 332, 6 9 (
basepeak) Example 2 [Production of ethyl geranylgeranyl acetate] 0.72 ethyl iodide instead of 0.65 P methyl iodide
? The boiling point was 150 to 150 in the same manner as in Example 1 except that
5℃/O. O l wing 0.9P of ethyl geranylgeranyl acetate was obtained (yield: 83%).

Elemental analysis value: C24H4002 Theoretical value (%): C79.94 H11.18 actual value
%): C79.78 H11. OIIR spectrum: 1735-” (νCOO) Seed spectrum: δ: 1.30 (3H, t, J=8Hz,
COOCH2C 曵), 4.2 3 (2H, q, J
-8 Hz, COOCJ{2CH3) MS spectrum: m/e360 (M+), 69 (bas
e peak) Example 3 [Production of geranylgeranyl acetate] Example 1 except that 0.86 P of 50% sodium hydride, 6 g of geranylgeranyl acetate, and 4.51 g of geranyl bromide were used.
Similarly, boiling point 175-7-182℃/0. 0
0 4 imHg, refractive index (nW”5) 1.4980
of geranylgeranyl geranyl acetate was obtained (yield: 8
3%).

Elemental analysis value: Theoretical value as C32 H52 o2 (%
): C81.99 H11.18 actual value (%): C8
1.78 H10.95IR spectrum: 1735cIrL-1 (νcOO) NMR spectrum: δ: 1.60 ~ 1.68 (24H, S,
CH3), 2.0 0 (1 6H, m, CH2
), 2.2 5 ( 4H, m, CH2CH2COO)
, 4.4 6 (2L d, J = 7 Hz,
OCR2), 5.0 2 (5H, m, >C=CH
), 5.25 (LH, t, J=7 Hz, O
CH2-C1C< )MS spectrum m/e 4 68 (M+), 6 9 (base
peak) Example 4 [Production of geranylgeranyl geranyl acetate] 50% sodium hydride 0.07 in dry dimethylformamide 5yd
Add 2P and add geranylgeranyl acetic acid 0 to this under stirring at room temperature.
．． 332P and dry dimethylformamide was added dropwise, followed by geranyl bromide O.332P and dry dimethylformamide. : After dropping a mixture of 1 and dry dimethylformamide, 1 was added at room temperature.
Stir for hours.

The obtained reaction mixture was poured into water and treated in the same manner as in Example 1 to obtain geranylgeranyl geranyl acetate. was obtained (yield 80%).

The physical properties of this product were similar to those obtained in Example 3.

Example 5 [Production of geranylgeranyl geranyl acetate] 0.332 P of geranyl geranyl 4E acid with sodium methyla} 0.06
2f of methanol solution, and the solvent was distilled off under reduced pressure. 5TLl of dry dimethyl sulfoxide was added to the resulting residue, and a mixed solution of 0.3P of geranyl furomide and 11rLl of dry dimethyl sulfoxide was added dropwise thereto. Stir for hours.

The reaction solution was then poured into water and treated in the same manner as in Example 1 to obtain geranylgeranyl geranyl acetate 0.35P (yield 75%).

The physical properties of this product were similar to those obtained in Example 3.

Example 6 [Production of farnesyl geranylgeranyl acetate] Farnesyl geranylgeranyl acetate 6.
21 was obtained (yield 55%).

IR Spect #21 7 3 5cr! L' (ν
cOo) NMR spectrum: δ: 1.60 ~ 1.68 (27H, s,
CH3), 2. O O (1 8 H, m, C
H2 ), 2.25 (4H, m, CH2CH2COO)
, 4.4 6 (2H, d, J = 7 Hz
, OCH2 ), 5.0 2 ( 6H, m, >C=
CH-), 5.25 (IH...t,.J-7H
z, OCH2-CH-C〈) MS spectrum: m/e 536 (M+), 69 (base
peak) Example 7 [Production of piperonyl geranylgeranyl acetate] 50% sodium hydride 0.86S', geranylgeranyl acetate 1'
and geranylgeranyl acetate piperonyl 6.3 in the same manner as in Example 1 except that piperonyl bromide 5z was used.
1 (yield 75%).

IR spectrum: 1735CIrL71 (νCOO), 933crIL
-1 (νCO, methylenedioxy) Width ■Spectrum: δ: 4. 8 7 (2H,.s, OCH2φ
), 5.85 (2H,s, OCH2 0 ), 6.
6 5 - 6.7 3 (3H, m, C6H3) MS spectrum: m/e 4 6 6 (M+) Example 8 [Production of p-chlorobenzyl keranylgeranyl acetate] 50% sodium hydride 0.108, geranylgeranyl acetate 0.7 P and p-chlorobenzyl chloride 0
．． 0.4f of p-chlorobenzyl keranylcheranyl acetate was obtained in the same manner as in Example 1 except that 5P was used (yield: 4
2%).

☆IR spectrum: 1740 (X” (νcOo) NMR spectrum: δ: 5.0 3 (2H, s, OCH2φ)
, 7.3 2 (4H, s, C6H4) MS spectrum: 456 (M+) Test example [Pharmacological test of geranylgeranyl acetate] Among the target compounds of the present invention, ethyl geranylgeranyl acetate, geranylgeranyl acetate, farnesyl geranylgeranyl acetate, and geranylgeranyl acetate The antiacetic acid ulcer effect of piperonil was investigated.

For comparison, similar tests were conducted on gefarnate and solcoseryl, which are commercially available as ulcer treatment agents.

(1) Test method As a pathological model of gastric ulcer, Takagi et al.'s acetic acid ulcer (Jap
, J. Pharmac. 1 vol. 9, p. 418, 1
969] was used.

That is, each group of 15 male Wistar rats weighing 180 to 2,001 kg was subjected to laparotomy under ether anesthesia, the stomach was removed, and 0.05 ml of 20% acetic acid was injected under the serosa of the glandular stomach region.

After acetic acid injection, the stomach was returned to its original position and the abdominal muscles and skin were sutured using Mitsuhel forceps.

Test compound @'! ．． It was suspended in physiological saline containing 0.25% Tween 80 and orally administered for 15 days from the third day after surgery.

Note that solcoseril alone was administered by subcutaneous injection.

On the 18th day, the rats were sacrificed, the stomachs were taken out, the long and short axes of the ulcer were measured, and the product was defined as the ulcer coefficient.

In addition, the healing rate was calculated using the following formula.

From the above table, it can be seen that some of the target compounds of the present invention have better therapeutic effects than gefarnate and solcoseryl.

Claims (1)

[Claims] 1 5.9.13.17-tetramethyl-4.8l2.
The alkali metal salt of 16-octadecatetraenoic acid has the general formula RX (wherein, R represents a lower alkyl group, an unsaturated alkyl group having 5 to 20 carbon atoms, a benzyl group or a substituted benzyl group, and X represents a halogen). 5,9,13,17-tetramethyl-4,8,12,16 represented by the general formula (wherein R means the same as above) characterized by being reacted with a halogen compound represented by - A method for producing octade tetraenoic acid ester.