JPH05294924A - Prostaglandin e1 analog - Google Patents

Abstract

PURPOSE:To obtain a new PGE1 analog having platelet aggregationsuppressing action, more excellent in drug effect than a conventional prostaglandin (PG)F1 analog and reduced in side effects. CONSTITUTION:The objective PGE1 analog of formula I (R is H or 1-6C alkyl; A is vinylene or ethynylene) and its salt, e.g. (2E)-2,3,13,14-tetradehydro-PGE1- methyl ester. This compound can readily be produced from a compound of formula II (R<1> and R<2> are protecting group of OH) and a compound of formula III (R<3> is R excluding H) through a compound of IV to a compound of V. Furthermore, the compound of formula V can stereo-selectively be produced by reacting a compound of formula II with a compound of formula III and chlorotrimethylsilane in an inert solvent and then hydrolyzing the resultant compound of formula IV. The compound of formula I and its salt have strong platelet aggregation suppressing action and good long acting property of the action and hardly induce diarrhea at a dose capable of exhibiting sure pharmacological action. Therefore, the compound of formula I and its salt are useful for treatment for various kinds of diseases such as peripheral circulation disorder.

Description

[Detailed description of the invention]

[0001]

BACKGROUND OF THE INVENTION _1. Field of the Invention The present invention relates to novel prostaglandin (hereinafter abbreviated as PG) E1 analogues.

[0002]

2. Description of the Related Art Since PG exerts various important physiological actions even in a very small amount, natural PG and a large number of its derivatives have been synthesized and examined for their biological activities with the intention of applying them to medicine. Among them, PGE ₁ has a platelet aggregation inhibitory effect,
It has been put to practical use as a drug that improves peripheral circulatory disorders with characteristic effects such as blood pressure lowering effects.
GE ₁ derivatives have also been investigated. However, conventional PGE ₁ analogues are metabolized rapidly in vivo, and thus have the drawback of not sustaining their effects. In addition, conventional PGE ₁
When administered orally, the analogues induce diarrhea as a side effect, so they could not be administered at high doses, and sufficient effects could not be obtained.

On the other hand, 13,14-didehydro PGE ₁ methyl ester and 6-hydroxy-13,14 are examples of 13,14-didehydro PGE ₁ analogues in which the double bonds at the 13,14 positions of PGE ₁ are replaced with triple bonds. -didehydro P
GE ₁ is known.

[0004]

SUMMARY OF THE INVENTION The present invention is a conventional PGE.
It is an object of the present invention to provide a novel PGE ₁ analogue which has superior efficacy, long-lasting efficacy and reduced side effects as compared to the ₁ analogue.

[0005]

Means for Solving the Problems As a result of extensive studies, the present inventors have found that PGE ₁ analogs have triple bonds at positions 13 and 14 and unsaturated bonds at positions 2 and 3. The inventors have found that a compound can solve the above problems, and completed the present invention. That is, the present invention provides the formula

[0006]

(In the formula, R is a hydrogen atom or a
∼6 alkyl groups and A represents a vinylene or ethynylene group. ), the prostaglandin E ₁
analogs and their salts.

In the present invention, the term "alkyl group having 1 to 6 carbon atoms" refers to a linear or branched alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n- butyl group, isobutyl group, t-butyl group, n
-pentyl group, isopentyl group, and the like.

The compounds of formula (I) can be readily prepared, for example, by the methods given below.

[0010]

[0011]

(In the reaction formula, R ¹ and R ² are the same or different and represent a hydroxyl-protecting group, R ³ is R
and A has the same meaning as above. Here, the hydroxyl-protecting group is one commonly used in the field of prostaglandins, such as t-butyldimethylsilyl, triethylsilyl, phenyldimethylsilyl, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl groups, ethoxyethyl groups, benzyl groups, and the like. ) That is, first, the method of Sato et al. [Journal of
Organic Chemistry (J.Org.Che
m. ), Vol. 56, p. 3205 (1991)]
0.5 to 4 equivalents of the organocopper compound of formula (III) and 0.5 to 4 equivalents of chlorotrimethylsilane and an inert solvent (e.g. tetrahydrofuran, diethyl ether, methylene chloride, toluene, n-hexane, etc.) at -78 to 40°C to give the compound of formula (IV). Here, the organocopper compound of formula (III) is an iodine compound represented by formula I-( _CH2 ) ₃ -A- ^COOR3 (VI) ⁽ wherein R3 has the same meaning as defined above). from the known method [P. Knochel et al., Journal of Organic Chemistry, No. 53
2390 (1988)]. That is, the iodine compound of formula (VI) is, for example, 1,
0.8-5 equivalents of zinc activated with 2-dibromomethane, chlorotrimethylsilane, iodine, etc. and an inert solvent (e.g. tetrahydrofuran, diethyl ether, n-
hexane, n-pentane, dioxane, etc.) to obtain an organozinc compound represented by the formula ^IZn- ( _CH2 ) ₃ -A- ^COOR3 (wherein R3 has the same meaning as defined above). lead to At this time, it may be heated as necessary. Although the heating temperature depends on the boiling point of the solvent, it is usually 30
~150°C, preferably 40-80°C. The obtained organic zinc compound is reacted at -50 to 10°C in an inert solvent containing copper cyanide (1 to 2.5 equivalents) and lithium chloride (2 to 5 equivalents) to give the formula ( III) organocopper compounds can be obtained.

Next, the compound of formula (IV) is treated with an inorganic acid (e.g., aqueous solution of hydrochloric acid) or an organic acid or its amine salt (e.g., p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, etc.) to form an organic in a solvent (e.g. acetone, methanol, ethanol, isopropanol, diethyl ether or a mixed solvent thereof)
Hydrolysis at 40° C. stereoselectively gives compounds of formula (V).

Finally, the hydroxyl-protecting group of the compound of formula (V) is deprotected using conventional methods in the field of prostaglandins to give the compound of formula (I) in which R is a group other than hydrogen. [compound of formula (Ia)] is obtained.

The compound of the present invention [compound of formula (Ib)] in which R is a hydrogen atom in formula (I) can be obtained by hydrolyzing the ester moiety of the compound of formula (Ia). Hydrolysis can be carried out by reacting the compound of formula (Ia) in a buffer such as phosphate buffer, Tris-HCl buffer, or the like, optionally using an organic solvent (mixed with water such as acetone, methanol, or ethanol). by reacting with the enzyme. Enzymes to be used include enzymes produced by microorganisms (e.g., enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), and enzymes prepared from animal organs (e.g., enzymes prepared from porcine liver and porcine pancreas).
A specific example of commercially available enzymes is lipase
VII (manufactured by Sigma, derived from microorganisms of the genus Candida), Lipase AY (manufactured by Amano Pharmaceutical Co., derived from microorganisms of the genus Candida), Lipase MF (manufactured by Amano Pharmaceutical Co., derived from microorganisms of the genus Pseudomonas), PLE-A (Amano Pharmaceutical Co., prepared from porcine liver), Esterase (Sigma, prepared from porcine liver), Lipase II (Sigma, prepared from porcine pancreas), Lipoprotein Lipase (Tokyo Kasei Kogyo Co., Ltd., prepared from porcine pancreas) and so on. The amount of enzyme to be used may be appropriately selected depending on the potency of the enzyme and the amount of the substrate [compound of formula (Ia)], but is usually 0.1 to 20 parts by weight of the substrate. The reaction temperature is 25 to 50°C, preferably 30 to
35°C.

The compounds of this invention can be administered orally or parenterally (eg, intravenously, rectally, intravaginally). Dosage forms for oral administration include tablets, granules,
Solid formulations such as capsules, and liquid formulations such as solutions, fat emulsions and liposome suspensions can be used. When used as this oral preparation, it can be prepared by forming an inclusion compound with α-, β-, or γ-cyclodextrin, methylated cyclodextrin, or the like. As preparations for intravenous administration, aqueous or non-aqueous solutions, emulsifiers, suspensions, solid preparations dissolved in a solvent for injection immediately before use, and the like can be used. In addition, dosage forms such as suppositories can be used as preparations for rectal administration, and pessaries and the like can be used as preparations for intravaginal administration. Dosage is 0.1
~100 μg, given in 1-3 divided doses per day.

[0017]

INDUSTRIAL APPLICABILITY The compounds of the present invention have a strong platelet aggregation-inhibitory action and a good persistence thereof. In addition, since the compound of the present invention hardly induces diarrhea, which is the most serious problem in PG, at a dose that exhibits a definite pharmacological action, it is useful as a drug for treating various diseases including peripheral circulatory disorders. Hereinafter, the effects of the present invention will be specifically described with reference to test examples.

Test Examples [Rabbit Platelet Aggregation Inhibition Test] New Zealand white rabbits weighing 2.5 to 4.0 kg were divided into groups of 4 and subjected to the test. Under ether anesthesia, 9 volumes of blood per 1 volume of 3.2% sodium citrate solution were collected from the common carotid artery of this rabbit. The collected blood was centrifuged at 1100 rpm for 15 minutes, and the upper layer was platelet-rich plasma (PRP). Measurement of platelet aggregation was carried out by Born's method (Nature, Vol. 194, Vol. 9).
27, 1962). PRP
Various concentrations of test drug 1 dissolved in ethanol in 275 μl
After 3 minutes with stirring at 37° C. and 1000 rpm, 25 μl of an aggregating agent [adenosine diphosphate (ADP) final concentration 5 μM] was added, and the maximum aggregation rate (platelet aggregation The maximum change in light transmittance within 5 minutes after induction) was measured. Aggregation-inhibiting activity was calculated by calculating the aggregation-inhibiting rate against aggregation when physiological saline was used instead of the test drug solution, and the IC ₅₀ value was obtained from the dose-response curve. The results are shown in Table 1. The compound numbers in the table are the compound numbers shown in Examples below. The _IC50 values are shown as mean values.

[0019]

[Table 1]

[0020]

EXAMPLES The present invention will now be described in more detail with reference to examples. Example 1 (2E)-2,3,13,14-tetradehydro-PG
E 1 methyl ester (compound 1) (1) (4E)-5-carbomethoxypent-4-enyl zinc (II) iodide (0.78 M
A tetrahydrofuran solution (2.81 ml) of copper (I) cyanide.lithium dichloride (489 mg) was added to the tetrahydrofuran solution (2.88 ml), and the mixture was stirred at the same temperature for 15 minutes. To this solution at -70°C was added (3R,4R)-2-methylene-3-[(3'S)-3'-t-butyldimethylsiloxy]-cyclopentan-1-one (522 mg,
1.123 mmol) and trimethylsilyl chloride (0.257 ml) in diethyl ether (4 ml)
was added, and the temperature was raised to room temperature over about 2 hours while stirring. Saturated ammonium chloride aqueous solution (17 ml) was added to the reaction solution.
was added and extracted with n-hexane. The organic layer was washed with saturated brine, dried and concentrated.
g) was added, followed by stirring at room temperature for 12 hours. n in the reaction solution
-Hexane (20 ml) and saturated aqueous sodium bicarbonate solution (10 ml) were added for extraction, the organic layer was dried and concentrated, and the obtained residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ether = 4:1). Nikake (2E)-2,3,13,14-tetradehydro-PG
386 _mg of E1 methyl ester 11,15-bis(t-butyldimethylsilyl ether) were obtained. ¹ H-NMR (CCl ₄ , PhH, 90 MHz) δpp
m: 0.06 and 0.10 (2s, 12H), 0.7
0-1.12 (m, 3H), 0.86 and 0.90
(2s, 18H), 1.11-1.76 (m, 14
H), 1.90-2.27 (m, 4H), 2.30-
2.73 (m, 2H), 3.60 (s, 3H), 3.9
0-4.37 (m, 2H), 5.69 (d, J=15.
8 Hz, 1 H), 6.84 (dt, J = 6.3 Hz, 1
5.8Hz, 1H)

(2) The compound (325m
g) was dissolved in acetonitrile (18 ml) and dissolved at 0° C. for 5
A 0% aqueous solution of hydrofluoric acid (4.39 ml) was added. 0
After stirring for 90 minutes at ℃, the reaction was added to ethyl acetate (25 mL
l) and saturated aqueous sodium bicarbonate (156 ml). Extract with ethyl acetate, wash with saturated aqueous sodium bicarbonate solution and saturated brine, dry and concentrate. The residue obtained is purified by silica gel column chromatography (developing solvent: ethyl acetate:methanol=40:1). 175 mg of the title compound were obtained. 1H ^- NMR ( _CDCl3 , _Me4Si , 300 MHz)
δ ppm: 0.71 to 0.93 (m, 6H), 1.12
~1.86 (m, 15H), 2.04 ~ 2.30 (m,
4H), 2.61 (ddd, J=1.8Hz, 8.5H
z, 11.5 Hz, 1 H), 2.74 (dd, J=7.
3Hz, 18.6Hz, 1H), 3.72(s, 3
H), 4.16-4.42 (m, 1H), 4.39 (d
t, J = 1.8Hz, 6.6Hz, 1H), 5.82
(d, J = 15.6 Hz, 1H), 6.95 (dt, J
= 7.0Hz, 15.6Hz, 1H) IR (neat): 3380, 2925, 2855, 2
225, 1740, 1720, 1650, 1440, 1
270, 1150, 1030, 980, 710 cm ^-1

Example 2 2,2,3,3,13,14-hexadehydro-PGE
1 methyl ester (compound 2) In Example 1(1), (4E)-5-carbomethoxypent-4-enylzinc(II) iodide was
-Carbomethoxypent-4-ynylzinc(II) iodide was used in substantially the same manner as in Example 1 to obtain the title compound. 1H ^- NMR ( _CDCl3 , _Me4Si , 300 MHz)
δ ppm: 0.89 (t, J = 6.7 Hz, 3H),
1.17-1.87 (m, 14H), 2.14-2.4
0(m, 1H), 2.23(dd, J=9.3Hz, 1
8.6 Hz, 1H), 2.35 (t, J = 6.6 Hz,
2H), 2.63(ddd, J=1.7Hz, 8.3H
z, 11.5Hz, 1H), 2.75 (ddd, J =
1.1Hz, 7.3Hz, 18.6Hz, 1H), 3.
75 (s, 3H), 4.24-4.43 (m, 1H),
4.38 (dt, J=1.7Hz, 6.7Hz, 1H) IR (neat): 3380, 2920, 2850, 2
230, 1735, 1710, 1430, 1250, 1
150, 1075, 910, 730 cm ^-1

Example 3 (2E)-2,3,13,14-tetradehydro-PG
E 1 (Compound 3) 97.5 mg of the compound obtained in Example 1 was added to 4.9 ml of 50
% (v/v) acetone-water mixture and added to 44 ml of phosphate buffer (10 mM, pH 7.0),
Further, 97.5 mg of lipase VII was added and stirred at 30°C. After tracking the reaction by thin-layer chromatography and confirming the disappearance of the raw materials (about 12 hours), the reaction mixture was extracted with 200 ml of ethyl acetate, washed with saturated brine, dried and concentrated to give a crude product. was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 48.7 mg of the title compound. 1H ^- NMR ( _CDCl3 , _Me4Si , 300 MHz)
δ ppm: 0.89 (t, J = 6.6 Hz, 3H),
1.01-1.89 (m, 14H), 1.95-2.4
8 (m, 4H), 2.47-2.89 (m, 1H),
2.75 (dd, J = 7.1 Hz, 18.5 Hz, 1
H), 4.17-4.50 (m, 2H), 5.82
(d, J = 15.7 Hz, 1H), 7.05 (dt, J
= 7.0Hz, 15.7Hz, 1H)

Example 4 2,2,3,3,13,14-hexadehydro-PGE
1 (Compound 4) In substantially the same manner as in Example 3, except that the compound obtained in Example 2 was used in place of the compound obtained in Example 1, the title compound was obtained. 1H ^- NMR ( _CDCl3 , _Me4Si , 300 MHz)
δ ppm: 0.89 (t, J = 6.6 Hz, 3H),
1.13-1.92 (m, 14H), 2.12-2.4
9(m, 3H), 2.25(dd, J=9.5Hz, 1
8.5 Hz, 1H), 2.57-2.89 (m, 1
H), 2.79 (dd, J = 6.9Hz, 18.5H
z, 1H), 4.25-4.49 (m, 1H), 4.4
0 (dt, J=1.7Hz, 6.7Hz, 1H), 4.
88 (br.s, 3H)

──────────────────────────────────────────────────── ──── continuation of the front page (72) Inventor Kazuya Kameo Made in Taisho, 3-24-1 Takada, Toshima-ku, Tokyo Yaku Co., Ltd. (72) Inventor Toru Tanami Made in Taisho, 3-24-1 Takada, Toshima-ku, Tokyo Yaku Co., Ltd. (72) Inventor Ken Muto Made in Taisho, 3-24-1 Takada, Toshima-ku, Tokyo Yaku Co., Ltd. (72) Inventor Naoya Ono Made in Taisho, 3-24-1 Takada, Toshima-ku, Tokyo Yaku Co., Ltd. (72) Inventor Jun Goto Made in Taisho, 3-24-1 Takada, Toshima-ku, Tokyo Yaku Co., Ltd.

Claims (1)

[Claims] [Claim 1] Formula (In formula, R shows a hydrogen atom or a C1-C6 alkyl group, A shows a vinylene group or an ethynylene group.) _The prostaglandin E1 analogue represented by and its salt.