JPS6144853A - Gamma-linoleic acid derivative and thrombocyte coagulation suppressing agent containing same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is group of formula II, formula III, formula IV, etc.). EXAMPLE:alpha-Tocopherol gamma-linoleic acid ester. USE:Preventive for thrombosis caused by the coagulation of thrombocyte (e.g. myocardial infarction, ischemic fit after cerebral hemorrhage, cerebral infarction, etc.). It can be used also as a preventive for metastasis of cancer. It remarkably suppresses the thrombocyte-coagulation induced by arachidonic acid or collagen. PREPARATION:The compound of formula I can be prepared by condensing gamma- linoleic acid or its reactive derivative (e.g. thiazolidine-thionamide derivative of carboxylic acid) with alpha-tocopherol, 3-oxymethylpyridine, pyridoxamine or methyl 4-aminobenzoate, in the presence of a condensation agent such as dicyclohexylcarbodiimide.

Description

Detailed Description of the Invention (3) Background of the Invention Technical Field The present invention relates to a novel γ-lylunic acid derivative and a platelet aggregation inhibitor containing the same. The γ-lylunic acid derivative provided by the present invention is a new compound and has a strong platelet aggregation inhibiting effect. Therefore, it is effective in preventing diseases caused by platelet aggregation, such as thrombosis.

Furthermore, platelet aggregation is known to be involved in cancer metastasis, and the compounds of the present invention also have a preventive effect on cancer metastasis.

Prior art γ-lylunic acid is an important compound as it is known to be converted in vivo to dihomo-γ-lylunic acid, which is a precursor of antithrombotic prostaglandin E1. Thrombosis, such as myocardial infarction and cerebral thrombosis, has recently come to account for a large proportion of adult diseases, and there is a strong desire for the emergence of a drug that can effectively prevent this.

■9 Purpose of the Invention As a result of synthesizing various γ-lylunic acid derivatives and intensively researching their pharmacological activities, the present inventors found that the γ-lylunic acid according to the present invention has an excellent platelet aggregation inhibiting effect. Heading: The present invention has been completed.

An object of the present invention is to provide a novel γ-lylunic acid derivative and a platelet aggregation inhibitor containing the same. The γ-lylunic acid derivative according to the present invention has a strong platelet aggregation inhibitory effect and is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis.

The object of the present invention is achieved by the configuration shown below. The present invention is a γ-Rirun MM conductor represented by the general formula (1) General formula <1) [wherein R is a Ct13 group (1), a group (II[)], or a γ-Rirun MM conductor. Further, the present invention relates to the general formula (1
) In the formula, R is CH.

γ represented by a group selected from (n), a group (Il [), and II (V)]
- A platelet aggregation inhibitor containing a lylunic acid derivative.

In the present invention, the term "platelet aggregation inhibitor" means a preparation that has the effect of inhibiting platelet aggregation.

0 Detailed Description of the Invention The γ-lylunic acid derivative of the present invention is a combination of γ-lylunic acid or a reactive derivative thereof and α-tocof I role, 3-oxymethylpyridine, pyridoxamine, or 4-aminobenzoic acid methylnisder. Obtained by condensation.

As the condensing agent used in the condensation, for example, dicyclohexyl carposi and imide are preferably used.

Examples of the reactive derivatives include thiazolidinedionamide derivatives of carboxylic acids. Furthermore, the γ-lylunic acid derivative of the present invention can be used as an active ingredient or one of the active ingredients of a platelet aggregation inhibitor, and is effective in treating diseases caused by platelet aggregation, but is particularly effective as an antithrombotic agent or cancer-causing agent. It is used as a metastasis preventive agent, and the dosage is generally 100 to 1500 mg per day for adults, preferably divided into 1 to 3 doses if necessary. The method of administration can take any form suitable for administration, with oral administration being particularly preferred, although intravenous injection is also possible.

The compound of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, and the like. In addition to the above-mentioned solid formulations, the compounds of the present invention can also be used in oily suspensions,
It can also be made into a liquid preparation such as syrup.

The compounds of the present invention can also be stabilized by inclusion with cyclodextrin.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 Drying 6.9.12-octadecatrienoic acid 454I Q (1,63111o1) 1,2 under argon atmosphere
- 4-dimethylaminopyridine 201119 (0,1
6+1111101), N, N'-dicyclohexylcarbodiimidrol 626 mlJ <1.47 mmol) was dried 1
, 2-dichloroethane (2 ml) were sequentially added. After reacting overnight at room temperature, the resulting precipitate was filtered, water was added to the mother liquor, extracted three times with dichloromethane, and washed with water. After drying the extracted organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an extraction residue of 1038111 (l).The residue was subjected to silica gel column chromatography and eluted with 1]-hexane-benzene (2:1.) From the fraction, α-tocopherol γ-lylphuric acid ester 9 1 6 m o (1
, 331+1a+of) was obtained. The spectroscopic data of (D) supports the structure of formula (VI) below.

IR 1,l, ;, halo (cm-1) 1755"
l-INMR (deuterated chloroform) δ: 1.97 (314
bs), 2.00 (3 days, bs), 2.08 (
3H.

bs), 2. 60 (4) 1, bt, J=6.
5Hz), 2, 8 2 (4H, bt, J=
5Hz), 5'. 2.3 ~5, 50. (6
H) <Example 2 6,9.12-octadecatrienoic acid 5QQm Q (1, 796+a+llof) under argon atmosphere
22 mg of 4-dimethylaminopyridine was added to a solution of 10 a+l of dry 1,2-dichloroethane at room temperature.
(0.18Qviol), N,N'-dicyclohexylcarbodiimide 408mg (1.977mm
ol), 3-pyridine methanol 216 mg (1.9
79 ml Ilol) was dried, and a solution dissolved in 2 ml of 1,2-dichloroethane was sequentially added. After the reaction was allowed to stand overnight at room temperature, the resulting precipitate was filtered, water was added to the mother liquor, and the mixture was extracted with dichloromethane three times and washed with water. After drying the extracted organic layer over anhydrous sodium sulfate, the VI medium was distilled off under reduced pressure, leaving an extraction residue of 87.
9111 () was obtained. The residue was subjected to silica gel column chromatography, and benzene/chloroform (2:1
) 6.9.12-octadecatrienoyl-3-hydroxymethylpyridine 378m O(1,0
23111 mol) was obtained. Spectroscopic data of this product support the structure of the following formula (■).

IRν crane (cm-'): 1745,'l-1
l-1-N deuterated chloroform) δ: 0.77-0°99
(3H), 1.17-2.60 (16)-1), 2,
77 (41-1, bt, J=5.5Hz), 5
．． 10 (2H, bs), 5.33 (6H, bt,
5.5Hz), 7.27 (1", dd, J"
=8Hz, 4Hz), 7, 68 (1H, ddd
, J-81-1z, 2Hz, 2l-1z
), 8. 55 (IH, dd,
J=4Hz, 2Hz), 8.5
8 (1H, bd, J=2Hz), Example 3 Drying f3,9.12-octadecatrinic acid 500n+(1 (1,796 vnol) under argon atmosphere 1.2
- in a solution dissolved in 10 ml of dichloromethane at room temperature
01) ,N,N'-disycOhexylrecarbodiimide 407II1g (1,97311mol)2
-Mercaptothiazoline 215mo (1,970m
mol) were added in order. After reacting for 2 hours at room temperature,
The resulting precipitate was filtered, and 1M iced aqueous sodium hydroxide solution was added to the mother liquor, extracted three times with dichloromethane, and washed with water.

After drying the extracted organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the extraction residue 671 m'Q was collected. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform was extracted with N-(6,9,12-octadecatrienoyl)-2-thiothiazoline 573119 (
1.55 mmol) was obtained.

Under an argon atmosphere, it's exciting υ minni MAW! i salt 349
mg (1,447111Il101) was suspended in 12ml of tetrahydrofuran and 1.0mg of triethylamine was added at room temperature. Olml (7,246 mmol) was added.

N-(6,9,12
-octadecatri-1-noyl)-2-thiothiazoline 55
A solution of 0m a (1,44911RIO+> dissolved in 2 ml of tetrahydrofuran was added and allowed to react overnight at room temperature. The reaction mixture was diluted to 3 times the volume with water, then extracted 3 times with ethyl acetate and washed with water. The extracted organic layer was After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the extraction residue 630111 (J
I got it. The residue was subjected to silica gel column chromatography, and N-(6,9,12-octadecatrienoyl)pyridoxamine 323+11(1(0,754mmol)
l) was obtained. The spectroscopic data of this is the following formula (■)
support the structure of

IRv desired j (cm-1): 3600, 3440
゜1635.1515'l-1l-1-N deuterium chloroform) δ: 0.77-0
゜99 (31-1), 1, 17-2.33 (
16H), 2.43 (3H, S), 2.60-2.9
3 (4H>, 440 (2H, y, J=f3H2>,
4. eO(2H,1)S), 5.17-5.50(6
8).

7,43 (I H, bs) Example 4 Under an argon atmosphere, 2-chromium-1 iodide was added to a solution of 300 mQ (1,078 vnol) of 6,9.12-ocucudeca-l-rienoic acid dissolved in 6 ml of dry acetonitrile. -Methylpyridinium 386mo (1,511
111I1101), triethylamine 0.47ml
(3°372 mmol) 1 g (1,078 mmol) of methyl 4-aminobenzoate was added in order, and the mixture was reacted for 1 hour and 20 minutes under heating under reflux. The mixture was allowed to cool to room temperature, added with water, extracted three times with dichloromethane, and washed with water. After drying the extracted organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an extracted residue of 589 ma. The residue was subjected to silica gel column chromatography, and the fractions eluted with benzene and ethyl acetate were extracted with N-(6,'9.12-octadecatrienoyl)-4-aminobenzoic acid 240+no.
(0,583a+mol) was obtained.

Under an argon atmosphere, 91m9 (0,2
27 mmol) dissolved in methanol 41111, 2 ml of water, 88 subg of sodium hydroxide (2,200 m
mol) and then heated at room temperature for 40 minutes at 65 to 70°C.
After cooling to room temperature, water was added,
The mixture was acidified with 3M constant hydrochloric acid, extracted three times with chloroform, and washed with water. After drying the extracted organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain N-(6,9,12-octadecatrienoyl)-4-aminobenzoic acid 851119.
(0,214mllol) was obtained. The optical structure of this material supports the structure of the following formula (IX).

IR: 4F (CI-'): 3360.1700°1615.1520°'H-NMR (deuterated chloroform) δ: 077-1.03 (3H), 1.10-2°60 (
16H), 2.78 (4H, bt, J=5Hz)
, 5.31 (6H, bt, J-5Hz), 7
．． 53 (2H,d, J=8.5Hz, 8゜00<28.d, J-8,5H2) Platelet aggregation inhibitory effect Using a syringe containing 3.8% sodium citrate solution (1 volume), rabbit Nine volumes of blood are collected from the carotid artery. The blood is centrifuged to obtain platelet-rich plasma (PRP: 5
x 10' pieces/Ill, ) are obtained.

The PPP268 μa was placed in a cuvette, heated at 37° C. for 2 minutes, added with 2 μL of an ethanol solution of the γ-lylunic acid derivative to be tested, and incubated for 3 minutes, followed by adding the aggregation inducing agent Arakito 21m solution or collagen solution. Platelet aggregation was determined using Born's turbidimetry [
For example, the Journal of Physiology (J,
P hysiol, 168%, page 178, 1968
It was measured using the method described in Arachidon 1
Presentation 1 shows the 50% inhibitory concentration for platelet aggregation induced by lt (100 μM) and collagen (10 μg/l).

As a result of the test, significant anti-platelet aggregation activity was found as shown in Table 1. Furthermore, in the table, 50% inhibition Ii! Maro means that when the aggregation ability of platelets without introducing the γ-lyrunic acid derivative according to the present invention is set as 100%, the aggregating ability of platelets is suppressed to 50% by introducing the γ-lyrunic acid derivative. It means the m degrees of γ-lyrinnic acid derivative solution required.

(Margins below) Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (53 years old). LD51 of compounds of the present invention
)l were all 2Q/kQ or higher, confirming high safety.

(1) Effects of the Invention According to the present invention, a novel γ-lylunic acid derivative J5 and a platelet aggregation inhibitor containing the same are provided.

The above-mentioned compounds of the present invention effectively inhibit platelet aggregation induced by arachidonic acid or collagen, so they can be used to treat diseases caused by platelet aggregation, particularly myocardial infarction, ischemic attack after cerebral hemorrhage, and cerebral infarction, which are associated with platelet aggregation. It can be used as a prophylactic agent for persistent thrombosis. Furthermore, since platelet aggregation is involved in cancer metastasis, the above compounds of the present invention can also be used as agents for preventing cancer metastasis.

Claims (2)

[Claims] (1) General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) Group (II), ▲ Numerical formulas, chemical formulas , tables, etc. ▼ (III) Groups that become (III), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) Groups that become (IV) and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) Groups that become ( γ-, which represents a group selected from V)
Linolenic acid derivative. (2) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Group (II) ▲Mathematical formulas, chemical formulas, tables, etc. There are ▼ (III) Basics (III), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) Groups that become (V) γ−, which represents a group selected from
Platelet aggregation inhibitor containing linolenic acid.