JP2001055375A - Prostaglandin e derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new prostaglandin E derivative having triple bonds at 13- and 14-positions, shows excellent antiproliferative activity to vascular smooth muscle cells and is useful for an inhibitor or a prophylactic and/or therapeutic agent for hyperplasia and/or emphraxis of a blood vessel. SOLUTION: This new compound is a compound represented by formula I (R is H, a 1-10C alkyl or a 3-10C cycloalkyl; m is 0 to 5; n is 1 to 8), its pharmaceutically permissible salt or its hydrate and is e.g. 2,3,4,16,17,18,19,20- octanol-1,5-inter-p-phenylene-13,14-didehydro-15,15-tetramethylene-pro staglandin E2 methyl ester. The compound of formula I can be obtained by employing a compound of formula II (TBS is tert-butylmethylsilyl) and a compound of formula III (TES is triethylsilyl) as starting substances and eliminating a protecting group for hydroxy group of a compound of formula IV (R1 is a 1-10C alkyl or a 3-10C cycloalkyl) obtained via an intermediate compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel E-type prostaglandin derivatives, pharmaceutically acceptable salts and hydrates thereof.

[0002]

2. Description of the Related Art Since prostaglandin (hereinafter referred to as PG) exerts various important physiological actions in a very small amount, synthesis of a large number of derivatives and bioactivity of natural PG for the purpose of application to medicine. The study was conducted and
No. 100446, US Pat. No. 4,131,738
No. has been reported.

Physiological actions of PG and its derivatives include vasodilatory action, inflammatory action, platelet aggregation inhibitory action, uterine muscle contraction action, intestinal contraction action, intraocular pressure lowering action, etc., and myocardial infarction, angina pectoris. It is useful for treating or preventing arteriosclerosis, hypertension, labor induction, and the like.

On the other hand, percutaneous coronary angioplasty (PTCA)
Is a surgical technique that has been rapidly progressing in recent years because of its low invasiveness to patients and an excellent initial therapeutic effect as a treatment for ischemic heart disease. However, the drawback that coronary artery restenosis appears with a frequency of 30-40% within months after PTCA remains unsolved.

[0005] Compounds that suppress the migration of vascular smooth muscle cells from the intima to the media and the proliferation of the media, which are strongly involved in the occurrence of restenosis, are strongly expected as agents for preventing restenosis. No clinically useful drug has been found.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel PG derivative having a vascular smooth muscle growth inhibitory action.

[0007]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a novel prostaglandin derivative represented by the following formula (I) having a triple bond at the 13th and 14th positions achieves the above object. We have found that we can do this and completed the present invention.

That is, the present invention provides a compound of the formula (I)

[0009]

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(Wherein, R represents a hydrogen atom, a C _1-10 alkyl group or a C _3-10 cycloalkyl group, m represents an integer of 0 to 5, and n represents an integer of 1 to 8) ), A pharmaceutically acceptable salt thereof or a hydrate thereof.

In the present invention, examples of the C _3-10 cycloalkyl group include a cyclopropyl group, a cyclobutyl group,
Examples thereof include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

The C _1-10 alkyl group means a linear or branched alkyl group, for example, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-ethylpropyl, hexyl, isohexyl, 1-ethylbutyl, heptyl, isoheptyl, octyl , Nonyl group, decyl group and the like.

Examples of pharmaceutically acceptable salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine and cyclopentylamine. , Benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane and the like.

[0014]

The compounds of formula (I) can be prepared, for example, by the methods summarized in the following schemes.

[0015]

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(In the reaction formula, TBS represents a tert-butyldimethylsilyl group, TES represents a triethylsilyl group, and R ¹ represents a C _1-10 linear or branched alkyl group or a C _3-10 alkyl group. It represents a cycloalkyl group, and m and n have the same meanings as described above.) To explain the above reaction formula, (1) First, the method of Sato et al. [Journal of Organic Chemistry (J. Org. Chem.)] 53, p. 5590 (1988)] to the compound of the formula (II), adding 0.8 to 2.0 equivalents of the organoaluminum compound of the formula (III) to -10 to 30 equivalents.
Reaction in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) at 0 DEG C., preferably 0 DEG-10 DEG C., to give the compound of formula (IV) stereospecifically. .

(2) A compound of the formula (IV) is combined with 0.5 to 4 equivalents of the organic copper compound represented by the formula (V) and 0.5 to 4.0 equivalents of trimethylchlorosilane in an inert solvent (for example, benzene, Toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, n-pentane, etc.)
In the medium, the reaction is carried out at −78 to 40 ° C., and an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) or an organic acid (eg, acetic acid,
0 to 40 ° C. in an organic solvent (for example, acetone, methanol, ethanol, isopropanol, diethyl ether or a mixed solvent thereof) using toluenesulfonic acid or an amine salt thereof (for example, pyridine salt of p-toluenesulfonic acid). To give the compound of formula (VI) stereoselectively.

(3) Methanol, ethanol, acetonitrile, a mixed solvent thereof or a mixture thereof using a compound of formula (VI) using hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid or the like under conditions usually used. Tert-butyldimethylsilyl group and triethylsilyl group, which are hydroxyl-protecting groups, are removed from a mixed solvent of water and water, and the PG derivative of the formula (Ia) wherein R ¹ is a group other than a hydrogen atom in the formula (I) Get.

(4) In a buffer such as a phosphate buffer or a Tris-HCl buffer, a compound of the formula (Ia) is mixed, if necessary, with an organic solvent (one which is miscible with water such as acetone, methanol and ethanol). The PG derivative according to the present invention is hydrolyzed by reacting with the enzyme,
Formula (Ib) is obtained. Examples of enzymes include enzymes produced by microorganisms (eg, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), enzymes prepared from animal organs (eg, enzymes prepared from pig liver and pig pancreas), and the like. Specific examples of commercially available enzymes include lipase VII (manufactured by Sigma, derived from a microorganism of Candida genus), lipase AY (manufactured by Amano Pharmaceutical, derived from a microorganism of the genus Candida), lipase AY (manufactured by Amano Pharmaceutical, Lipase PS (manufactured by Amano Pharmaceuticals, derived from Pseudomonas spp.), Lipase MF (manufactured by Amano Pharmaceuticals, derived from Pseudomonas spp.), PLE (manufactured by Sigma, prepared from pig liver), lipase II ( Sigma, prepared from pig pancreas), lipoprotein lipase (Tokyo Kasei Kogyo, prepared from pig pancreas), etc. That.

The amount of the enzyme to be used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound of the formula (Ia)], and is usually 0.1 to 20 parts by weight of the substrate. The reaction temperature is 25-50 ° C, preferably 30-40 ° C.

The compounds of the present invention can be administered systemically or locally orally or parenterally in conventional dosage forms. These are, for example, tablets, powders, granules, powders, capsules, which can be produced by ordinary methods.
It can be administered orally in the form of a solution, emulsion, suspension or the like. As preparations for intravenous administration, aqueous or non-aqueous solutions, emulsions, suspensions, solid preparations used by dissolving in an injection solvent immediately before use, and the like can be used. The compound of the present invention can also be formulated by forming an inclusion compound with α, β or γ-cyclodextrin or methylated cyclodextrin. Further, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. The dose varies depending on the age, body weight, etc., but is 1 ng to 1 mg / day for an adult, and is administered once or several times a day.

Representative compounds of the formula (I) according to the present invention include the following.

[0023]

[Table 1] Table 1

[0024]

Industrial Applicability The present invention shows excellent vascular smooth muscle cell proliferation inhibitory action, and is an agent for suppressing thickening of blood vessels (for example, the cause of restenosis after percutaneous coronary angioplasty), an agent for suppressing occlusion, or thickening or occlusion of blood vessels. It is useful as a prophylactic and therapeutic agent.

[0025]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited by these descriptions. In the compound naming, “2,
“Nol” as in “3,4-trinor-1,5-inter-m-phenylene” means that there is no carbon chain at that position (in the case of the example, the carbon chain at the 2 to 4 position is not substituted). “Interphenylene” means that a benzene ring was inserted between them (in the case of the example, 1).
Means that the carbons at the 5th and 5th positions are respectively bonded at the meta position of the benzene ring. ).

Reference Example 1-ethynyl-1-triethylsiloxycyclopentane 1-ethynyl-1-hydroxycyclopentane (5.4
5 g, 49.5 mmol) of dimethylformamide (4
9.5 ml) solution at room temperature with imidazole (6.74).
g, 99.0 mmol) and triethylchlorosilane (9.97 ml, 59.4 mmol) were added and stirred for 30 minutes. The reaction solution was added to n-hexane: saturated aqueous sodium bicarbonate,
The organic layer was separated. After the aqueous layer was extracted with hexane, the organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was distilled under reduced pressure to obtain the title compound (9.26 g).

B. p. 98 ° C / 10.0 torr. ¹ H-NMR (CDCl ₃ , 200 MHz) δ ppm;
0.45-1.15 (m, 15H), 1.48-2.0
4 (m, 8H), 2.43 (s, 1H) IR (neat); 3308, 2956, 2913, 2
876, 1459, 1415, 1321, 1239, 1
204, 1116, 1059, 1008, 946, 85
0,743,729,655,623,519 c
m ^-1 .

Example 1 2,3,4,16,17,18,19,20-octanol-1,5-inter-p-phenylene-13,14-
Didehydro-15,15-tetramethylene-PGE ₁
Methyl ester (compound 16) (1) 1-ethynyl-1-triethylsiloxycyclopentane (1.02 g) was dissolved in toluene (14 ml), and n-butyllithium (2.5 M in hexane, 1. 68 ml) and stirred at the same temperature for 30 minutes. To this solution was added diethylaluminum chloride (0.95 M, hexane solution, 5.17 ml) at 0 ° C.
Stirred to room temperature for 30 minutes. At room temperature (4R)
-2- (N, N-diethylamino) methyl-4- (te
rt-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25 M, toluene solution, 14 ml)
Was added and stirred for 30 minutes. The reaction solution was treated with hexane (25 m
1) The mixture was poured into a mixed solution of a saturated aqueous solution of ammonium chloride (35 ml) and an aqueous solution of hydrochloric acid (3 M, 10 ml) with stirring, and then the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (10 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was subjected to silica column chromatography (developing solvent; hexane: ethyl acetate = 49:
Purified in 1) to give (3R, 4R) -2-methylene-3-
[3,3-tetramethylene-3- (triethylsiloxy) prop-1-ynyl] -4- (tert-butyldimethylsiloxy) cyclopentan-1-one (1.23
g) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.11 (s, 3H), 0.14 (s, 3
H), 0.54-0.72 (m, 6H), 0.80-
1.02 (m, 9H), 0.90 (s, 9H), 1.6
0-1.90 (m, 8H), 2.33 (dd, J = 1
7.9, 7.4 Hz, 1H), 2.72 (dd, J = 1
7.9, 6.5 Hz, 1H), 3.48-3.59
(M, 1H), 4.20-4.35 (m, 1H), 5.
56 (dd, J = 2.6, 0.7 Hz, 1H), 6.1
6 (dd, J = 3.1, 0.7 Hz, 1H).

IR (neat);
2876, 2210, 1737, 1714, 1621,
1463, 1412, 1362, 1255, 1187,
1109, 1063, 1007, 941, 889, 83
7,779,744,671 cm ^-1 .

(2) 2- (4-carbomethoxyphenyl) ethylzinc (II) iodide (0.88M, tetrahydrofuran solution, 7.6 ml) was added to copper (I) cyanide. Lithium dichloride (1.0 M, tetrahydrofuran solution, 8.4 ml) was added, and the mixture was stirred at the same temperature for 20 minutes. The compound obtained in the above (1) (0.25 M, diethyl ether solution, 13.4 ml) and chlorotrimethylsilane (0.76 ml) were added to the solution at -70 ° C, and the mixture was stirred at 0 ° C for about 1 hour. Temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by hexane extraction. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate.
The residue obtained by filtration and concentration was treated with diethyl ether (3.
0 ml) -isopropyl alcohol (12.0 ml), and p-toluenesulfonic acid pyridine salt (42 m
g) was added and the mixture was stirred at room temperature for 12 hours. Hexane was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 50: 1). )
4,16,17,18,19,20-octanol-1,
5-inter-p-phenylene-15,15-tetramethylene-13,14-didehydro-PGE ₁ methyl ester 11- (tert-butyldimethylsilyl)-
15-Triethylsilyl ether (920 mg) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.08 (s, 3H), 0.11 (s, 3
H), 0.54-0.72 (m, 6H), 0.79-
1.02 (m, 9H), 0.88 (s, 9H), 1.2
0-1.90 (m, 12H), 2.16 (dd, J = 1
8.3, 7.1 Hz, 1H), 2.15 to 2.30
(M, 1H), 2.60-2.75 (m, 4H), 3.
90 (s, 3H), 4.20-4.34 (m, 1H),
7.19-7.29 (m, 2H), 7.90-8.00
(M, 2H).

IR (neat); 2952, 2874,
2858, 1749, 1724, 1610, 1462,
1435, 1414, 1376, 1309, 1279,
1251, 1178, 1111, 1058, 1019,
971,882,837,778,764,744,7
05,670,418 cm ^-1 .

(3) The compound obtained in (2) (380 mg)
Aqueous hydrofluoric acid solution (4.7 ml) was added to an acetonitrile (21 ml) solution at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (20 ml) -saturated aqueous sodium hydrogen carbonate (1
After stirring, the mixture was poured into 40 ml) with stirring, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 2) to obtain the title compound (220 mg).

¹ H-NMR (CDCl ₃ , 300 MHz)
δ ppm; 1.56-1.95 (m, 13H), 2.2
0-2.32 (m, 1H), 2.22 (dd, J = 1
8.6, 9.0 Hz, 1H), 2.50 (d, J = 3.
4Hz, 1H), 2.58-2.76 (m, 2H),
2.62 (dd, J = 11.4, 8.2 Hz, 1H),
2.75 (ddd, J = 18.6, 7.3, 1.1H
z, 1H), 3.90 (s, 3H), 4.27-4.3
8 (m, 1H), 7.22-7.28 (m, 2H),
7.92-7.98 (m, 2H) IR (neat); 3416, 2950, 2864, 2
235, 1744, 1723, 1610, 1574, 1
510,1436,1415,1362,1311,1
283, 1179, 1153, 1110, 1020, 9
95,907,857,838,763,706,63
6,516 cm ^-1 .

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hideo Tanaka 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Naoya Ono 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Shin Yagi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C086 AA03 DA03 NA14 ZA36 ZA45 4H006 AA01 AB20 AB23 AB24 AB26 UE14 UE32 UE33 UE52

Claims (2)

[Claims] 1. A compound of the formula (I) Wherein R is a hydrogen atom, a C _1-10 alkyl group or a C _3-10
Represents a cycloalkyl group, m represents an integer of 0 to 5,
n shows the integer of 1-8. ), A pharmaceutically acceptable salt thereof or a hydrate thereof. 2. The prostaglandin derivative according to claim 1, wherein m is an integer of from 2 to 4, and n is an integer of from 1 to 5, and a pharmaceutically acceptable salt thereof. Or its hydrate.