JP2849608B2 - Prostaglandin analog - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to specific prostaglandin analogs useful as pharmaceuticals.

[0002]

2. Description of the Related Art In 1960, prostaglandins (hereinafter, referred to as PG) were PGE ₁ , PGE ₂ , PGE ₃ ,
PGF ₁ α, PGF ₂ α, since six of the structure of PGF ₃ alpha is determined, after another discovery of PG analogues also been revealed one after another also physiological effects. The PGE ₁ analogs, for example, the compounds of Japanese Patent Publication 60- 33827 JP are known.

On the other hand, another literature predicts that these PG analogs will play a large role in the future, and PG analogs are typical of local hormones, and are produced locally as needed. And since they are local acting hormones, these PG related drugs are autakoid (auta
It has been proposed that a drug delivery system that takes into account the properties and chemical properties of the drug as a coid) is required. The conventional method of systemic administration is less effective and has less systemic side effects. Because it appears strongly,
Lipid microsphere (hereinafter, L
M) as a carrier in a drug release system of a PG analog.
).

[0004] That is, a target therapeutic agent encapsulating the PGE ₁ in LM having a diameter of 0.2 [mu] m, the fat emulsion -P
By using GE ₁ , stability in vivo increases,
To exhibit a strong vasodilating action and inhibiting platelet aggregation than PGE ₁ alone is reported (Sim, AK, et al, Arzne
im-Forsch / Drug Res., 1206-1209, 1986). Further, when the fat emulsion -PGE ₁ was administered in vivo, PGE
It has been clarified that ₁ is considerably released from LM, and studies to suppress the release amount have been reported (Rika Igarashi et al., Inflammation, 8, [3], 243-246 (1988)).

[0005] According to this report, the methyl ester, ethyl ester, butyl ester, pivalic acid ester and octyl ester of PGE ₁ enter the living body and cut off the ester bond by esterase even if the ester form is not active. by, in order to examine whether the effect is exhibited, that platelet aggregation inhibiting effect of each ester of PGE ₁ was measured, and LM in the blood
For the purpose of predicting the stability of the formulation, an isotonic salt (BSA-salin
incubated in e), in order to study the release of PGE ₁ ester from LM, the respective esters of PGE ₁ L
It has been reported that the stability as an M preparation was measured.

[0006]

In order to enhance the sustained release of the above-mentioned PGE ₁ esters, P
The GE ₁ esters need to be finely dispersed in the LM. Therefore, as described below, it is necessary to homogenize PGE ₁ esters, fats and oils and other materials at a high temperature of about 80 to 90 ° C., and at such a high temperature, conventional PGE ₁ esters are rapidly cooled. Decomposition had occurred.
Further, the fat emulsion of the conventional PGE _1, even in product distribution channel, degradation of PGE ₁ was rapid.

An object of the present invention is to develop a PGE ₁ analog having good stability even when formulated at a high temperature.

[0008]

SUMMARY OF THE INVENTION The present invention provides a novel PGE
_One analog, butyl 9-butyroxy-11α, 1,
5S-dihydroxyprosta-8,13E-diene-1
-Oart.

The butyl 9-butyroxy-11 of the present invention
α, 15S-Dihydroxyprosta-8,13E-diene-1-oart is a compound represented by the following formula [1].

[0010]

Embedded image

The PG analog of the present invention represented by the formula [1] can be produced by a known method. For example, 1-
After protecting the hydroxyl group of iodo-3-hydroxy-1-octene and reacting it with alkyllithium to form a 1-lithioalkene, it is reacted with a trialkylphosphine-copper (I) complex to give an organolithiocuprate. next,
This organolithiocuprate is converted to a hydroxyl-protected 4
-Hydroxy-2- (6-carbobutoxyhexyl)-
1,4-conjugate addition to 2-cyclopenten-1-one,
It is then produced by quenching the reaction mixture with butyric anhydride or butyric halide. For details of this method, see, for example, JP-B-60-33827 and the literature (Sih, et al., J. Am. Chem. Soc., 97, 857-865 (1975),
J. Am. Chem. Soc., 110, 3588 (1988)).

Incidentally, butyl 9-butyroxy-11α,
15S-dihydroxyprosta-8,13E-diene-
Storage stability when 1-oart is emulsified in fat (40 ° C
(Remaining rate after storage for 2 weeks at a temperature of 80.9%) was 80.9%.
With PGE _1, results of testing under the same conditions, its stability was 15.0%. According to yet another stabilization test, P
The storage stability of GE ₁ alkyl ester fat emulsion is PG
Of E ₁ it was lower than that.

The above fat emulsification is performed by adding 1.2 g of purified egg yolk lecithin to 10 g of purified soybean oil to 500 μg of the target compound, heating and dissolving at 90 ° C. using a homogenizer at 90 ° C., and adding 2.5 g of glycerin in Japanese Pharmacopoeia and Add 90 ml of distilled water for injection,
The emulsion was roughly emulsified at 90 ° C. using a homogenizer, and emulsified using a Manton-Gaurin homogenizer to obtain a fat emulsion having a final concentration of 5 μg / ml.

The synthesis examples of the compound of the present invention are shown below.
The method for synthesizing the compound of the present invention is not limited to this example.

[0015]

【Example】

Example 1 (1E, 3S) -1-iodo-3- (t-
Butyldimethylsiloxy) -1-octene (1.11 g, 3.
03 mmol) in ether (12.7 ml) was cooled to −78 ° C.
-Butyl lithium (f = 1.6 hexane solution 3.8 ml, 5.68
mmol) was added dropwise. After stirring at the same temperature for 2 hours, tributylphosphine-copper (I) iodide complex (1.04 g, 2.78 mmol
l), a solution of tributylphosphine (0.69 ml, 2.75 mmol) in ether (10.1 ml) was added dropwise. After stirring at -78 ° C for 50 minutes,
A solution of (4R) -t-butyldimethylsiloxy-2- (6-carbobutoxyhexyl) -2-cyclopenten-1-one (1.00 g, 2.53 mmol) in ether (40.3 ml) was added dropwise.

At −78 ° C. for 20 minutes, and further at −30 to −20 ° C. for 30 minutes
After stirring for minutes, butyric anhydride (1.12 ml, 6.82 mmol) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C to room temperature for 15 hours. The mixture was poured into a saturated aqueous solution of ammonium sulfate (100 ml), the organic layer was separated, and the aqueous layer was extracted with ether (100 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.

The residue was cooled to 0 ° C. and chromatographed on silica gel (hexane: ethyl acetate = 100: 1-63:
Purification was performed in 1) to obtain an adduct. Manufactured adduct (461 mg,
0.7 mmol) in acetonitrile (14.3 ml) and
% Hydrofluoric acid aqueous solution (1.88 ml) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was treated with a 20% aqueous potassium carbonate solution (100 ml)
And methylene chloride (30 ml). After drying over magnesium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. Residue at 0 ° C
And purified by silica gel chromatography (methylene chloride: acetone = 5: 1 to 3: 1) using butyl 9-butyroxy-11α, 15S-dihydroxyprosta-8,1.
3E-diene-1-oart was obtained (243 mg, yield 73.6).
%).

¹ H-NMR (CDCl ₃ ): δ 0.86 (9H, m), 1.2-2.42
(29H, m), 2.8-2.95 (1H, m), 3.0-3.1 (1H, m), 4.0-4.2 (4H,
m), 5.4-5.7 (2H, m)

[0019]

The butyl 9-butyroxy-11 of the present invention
alpha, 15S- dihydroxy prostacyclin -8,13E- dien-1 Oato are novel PGE ₁ analogues, in vivo can be expected to exert a PGE ₁ equivalent physiological activity is a compound useful as a medicament.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hiroshi Mizushima 1-1-11 Umeoka, Setagaya-ku, Tokyo (72) Inventor Toshihide Inomata 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo Inside Seikagaku Corporation (72) Inventor Yasuda Arata 1150 Hazawacho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Asahi Glass Co., Ltd. Central Research Laboratory (56) References JP-A-3-204853 (JP, A) JP-A-58-39660 (JP, A) (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 405/00 A61K 31/557 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A butyl 9-butyroxy-11α, 15S
-Dihydroxyprosta-8,13E-diene-1-oart.