JP2000302751A - Prostaglandin e1 derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having vascular smooth muscle growth inhibitory activity, and therefore useful as a prophylactic or therapeutic agent for restenosis after percutaneous coronary artery plasty. SOLUTION: This new compound is a compound of formula I [A is ethylene, vinylene, ethylene, OCH2 or the like; R is H or a (cyclo)alkyl; (m) is 0-5; and (n) is 1-8], e.g. 16,17,18,19,20-pentanol-15,15-pentamethylene-13,14-didehydro-PGE1 methyl ester. The compound of formula I is obtained, for example, by reacting a compound of formula II (TBSO is tert-butyldimthylsilyl) with a compound of formula III (TESO is triethylsilyl) to form a compound which is then reacted with an organocopper compound of the formula: IznCu(CN)(CH2)mA'CO2R1 (A' is ethylene or the like) and trimethylchlorosilane followed by hydrolyzing the reaction product with an inorganic or organic acid in an organic solvent to eliminate the protective group for the hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel prostaglandin derivative or a pharmaceutically acceptable salt or hydrate thereof, and a prostaglandin derivative containing the same, which has an excellent smooth muscle growth inhibitory activity and is effective in regenerating after PTCA. The present invention relates to a novel prostaglandin derivative as an agent for preventing or treating stenosis.

[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 and biological activity of natural PG and a large number of its derivatives are intended for pharmaceutical applications. Has been studied, including a large number of documents, for example, Japanese Patent Application Laid-Open No. 52-1004.
No. 46, U.S. Pat. No. 4,131,738 and the like.

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 A represents an ethylene group, a vinylene group, an ethynylene group, OCH ₂ or S (O) _p CH ₂ , and R represents a hydrogen atom, a C _1-10 alkyl group or a C _3-10 cycloalkyl group. An alkyl group; m represents an integer of 0 to 5; n represents an integer of 1 to 8; and p represents an integer of 0 to 2). It is an acceptable salt or a hydrate thereof.

The present invention is also a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof.

In the present invention, a vinylene group means a cis or trans vinylene group.

[0013] Examples of cycloalkyl groups of C _{3 over 10,}
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

The C _1-10 alkyl group means a C _1-10 linear or branched alkyl group, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-ethylpropyl, hexyl, isohexyl, 1-ethylbutyl, heptyl, isoheptyl, octyl, nonyl, decyl 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, cyclopentylamine , Benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane and the like.

[0016]

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

[0017]

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(In the reaction formula, A 'represents an ethylene group, a vinylene group, an ethynylene group, OCH ₂ or SCH ₂ , and R ¹ represents a C _1-10 linear or branched alkyl group or C ₃ -C _{3 10 represents} a cycloalkyl group, TBS represents a tert-butyldimethylsilyl group, TES represents a triethylsilyl group, and X, m, n, and p are as defined above.) (1) First, a compound of formula (II) known by the method of Sato et al. [Journal of Organic Chemistry (J. Org. Chem.), Vol. 53, p. 5590 (1988)] is added to a compound of formula (II). 0.8 to 2.0 equivalents of the organoaluminum compound represented by (III) is added to -10 to 30
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 mixed 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, p-
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. The tert-butyldimethylsilyl group and the triethylsilyl group, which are hydroxyl-protecting groups, are removed from a mixed solvent of water and water to obtain a PG derivative of the formula (Ia).

(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 (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 (for example, enzymes produced by microorganisms belonging to the genera Candida and Pseudomonas), enzymes prepared from animal organs (for example, 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.

(5) The compound of the formula (Ib) is treated with diethyl ether, methanol using an oxidizing agent such as sodium metaperiodate, aqueous hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid and tert-butyl hydroperoxide. In ethanol, methylene chloride, water or a mixed solvent thereof,
The reaction is carried out at 20 to 50 ° C to obtain the PG derivative according to the present invention, formula (Id).

(6) The compound of the formula (Ia) is
The compound of formula (Ic) is obtained by oxidation in the same manner as in the above, and then hydrolyzed using an enzyme in the same manner as in (4) to obtain the PG derivative of the present invention, formula (Id). it can.

Incidentally, S (O) _p in the α chain is as follows when p = 1.

[0026]

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And when p = 2,

[0028]

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Represents the following.

The compounds of the present invention are administered systemically or topically orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously transdermally, etc., preferably by oral or intravenous administration. Is good. These are, for example, tablets, powders, granules, powders that can be produced by ordinary methods,
It can be administered orally in the form of capsules, solutions, emulsions, suspensions and 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.

[0032]

[Table 1] Table 1

[0033]

[Table 2] Continued from Table 1

[0034]

Industrial Applicability The present invention has an excellent inhibitory action on vascular smooth muscle cell proliferation, and has an effect of suppressing thickening of blood vessels (for example, the cause of restenosis after costly coronary angioplasty), an agent for suppressing occlusion or an effect of thickening or occluding blood vessels. Useful as prophylactic and therapeutic agents.

[0035]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention. In the compound naming, “16,
“Nor” in “17, 18, 19, 20-pentanor” means that there is no carbon chain at that position.

Reference Example 1 1-ethynyl-1-triethylsiloxycyclohexane 1-ethynyl-1-hydroxycyclohexane (20.
60 g, 166 mmol) of dimethylformamide (1
66 ml) solution at room temperature with imidazole (22.58).
g, 332 mmol) and triethylchlorosilane (33.4 ml, 199 mmol) were added and stirred for 30 minutes. The reaction solution was added to n-hexane: saturated aqueous sodium hydrogen carbonate, and 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 give the title compound (3
8.77 g).

B. p. 72 ° C./0.80 torr. ¹ H-NMR (CDCl ₃ , 200 MHz) δ ppm;
0.58-0.78 (m, 6H), 0.87-1.08
(M, 9H), 1.14-1.95 (m, 10H),
2.45 (s, 1H) IR (neat); 3309, 2937, 2876, 1
459,1415,1378,1341,1283,1
240, 1150, 1155, 1105, 1058, 1
004,950,905,884,868,843,8
15,797,743,728,654,626,55
1,519 cm ^-1 .

Example 1 16, 17, 18, 19, 20-Pentanol-15,1
5-pentamethylene-13,14-didehydro-PGE
_1- methyl ester (compound 7) (1) 1-ethynyl-1-triethylsiloxycyclohexane (5.58 g, 23.4 mmol) was dissolved in toluene (72 ml), and n-butyllithium (2.5 M, hexane) was added at 0 ° C. Solution, 8.6 ml) and stirred at the same temperature for 30 minutes. This solution was added to diethylaluminum chloride (0.95 M, hexane solution, 26.degree. C.) at 0.degree.
5 ml) and stirred for 30 minutes to room temperature. At room temperature, (4R) -2- (N, N-diethylamino) methyl-4- (tert-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25 M, toluene solution, 72 ml) was added to this solution. And stirred for 15 minutes. The reaction solution was poured into a mixed solution of hexane (120 ml) -saturated aqueous ammonium chloride solution (170 ml) -hydrochloric acid aqueous solution (3 M, 50 ml) with stirring, and then the organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (50 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was subjected to silica column chromatography (eluent: hexane:
Purification with ethyl acetate = 49: 1) gave (3R, 4R)-
2-methylene-3- [3,3-pentamethylene-3-
(Triethylsiloxy) prop-1-ynyl] -4-
(Tert-Butyldimethylsiloxy) cyclopentan-1-one (3.07 g) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.11 (s, 3H), 0.14 (s, 3
H), 0.54-0.73 (m, 6H), 0.80-
1.02 (m, 9H), 0.90 (s, 9H), 0.8
0-1.02 (m, 9H), 1.12-1.90 (m, 9H)
10H), 2.34 (dd, J = 18.0, 7.1H)
z, 1H), 2.74 (dd, J = 18.0, 6.4H
z, 1H), 3.50-3.62 (m, 1H), 4.2
3-4.37 (m, 1H), 5.57 (dd, J = 2.
6, 0.7 Hz, 1 H), 6.17 (dd, J = 2.
9, 0.7 Hz, 1 H) IR (neat); 2935, 2876, 2858, 2
209, 1736, 1715, 1621, 1462, 1
412, 1362, 1289, 1255, 1104, 1
063, 1005, 942, 905, 867, 837,
812,779,744,672 cm ^-1 .

(2) 5-Carbomethoxypentylzinc (II) iodide (0.92 M, tetrahydrofuran solution, 3.6 ml,
3.3 mmol) of copper (I) cyanide · lithium dichloride (1.0 M, tetrahydrofuran solution, 2.9 ml,
2.9 mmol) and stirred at the same temperature for 20 minutes. The compound (0.25) obtained in the above (1) was added to this solution at -70 ° C.
M, diethyl ether solution, 8.8 ml, 2.2 mmol
l) and chlorotrimethylsilane (0.59 ml, 3.5
mmol) and the temperature was raised to 0 ° C. over about 1 hour with stirring. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with hexane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue obtained was diethyl ether (1.76 m
l) -Isopropyl alcohol (7.04 ml) was dissolved in p-toluenesulfonic acid pyridine salt (27.6 m
g, 0.11 mmol) and 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 = 15: 1). ) To give 16,17,18,19,20-pentanor-15,15-pentamethylene-13,14-didehydro-PGE ₁ methyl ester 11- (tert-butyldimethylsilyl) -15-triethylsilyl ether (610 mg).

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.09 (s, 3H), 0.13 (s, 3
H), 0.56-0.73 (m, 6H), 0.80-
1.04 (m, 9H), 0.90 (s, 9H), 1.1
2-1.90 (m, 20H), 2.09-2.38
(M, 1H), 2.18 (dd, J = 18.1, 6.9)
Hz, 1H), 2.30 (t, J = 7.5 Hz, 2
H), 2.68 (ddd, J = 18.1, 6.7, 1..
3Hz, 1H), 2.72 (dd, J = 9.4, 6.6)
Hz, 1H), 3.67 (s, 3H), 4.22-4.
37 (m, 1H) IR (neat); 2934, 2875, 2857, 2
234,1747,1462,1413,1375,1
290, 1254, 1100, 1059, 1005, 9
05,869,838,811,779,743,67
0 cm ^-1 .

(3) The compound obtained in (2) (95 mg,
0.16 mmol) to an acetonitrile (5.3 ml) solution at 0 ° C. was added a hydrofluoric acid aqueous solution (1.2 ml),
The mixture was stirred at the same temperature for an hour. The reaction solution was treated with ethyl acetate (10 m
1) After pouring into saturated aqueous sodium hydrogen carbonate (36 ml) with stirring, the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1) to give the title compound (54 mg).

Example 2 (2E) -16,17,18,19,20-Pentanol-15,15-pentamethylene-2,3,13,14-
Tetradehydro-PGE ₁ methyl ester (Compound 1
7) (1) In Example 1 (2), instead of 5-carbomethoxypentylzinc (II) iodide, (E) -5-carbomethoxy-4-pentenylzinc (II) iodide was used. In substantially the same manner as (2), (2E) −
16,17,18,19,20-Pentanol-15,1
5-pentamethylene-2,3,13,14-tetradehydro-PGE ₁ methyl ester 11-tert-butyldimethylsilyl-15-triethylsilyl ether was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.09 (s, 3H), 0.13 (s, 3
H), 0.57-0.72 (m, 6H), 0.84-
1.02 (m, 9H), 0.90 (s, 9H), 1.1
5-1.88 (m, 16H), 2.09-2.30
(M, 3H), 2.18 (dd, J = 18.2, 6.8
Hz, 1H), 2.61-2.77 (m, 1H), 2.
71 (dd, J = 9.3, 6.7 Hz, 1H), 3.7
3 (s, 3H), 4.22-4.36 (m, 1H),
5.82 (dt, J = 15.6, 1.5 Hz, 1H),
6.96 (dt, J = 15.6, 6.9z, 1H) IR (neat); 2934, 2875, 2858, 2
233,1748,1728,1658,1462,1
437, 1412, 1376, 1257, 1197, 1
177, 1100, 1056, 1004, 869, 83
8,811,779,743,670 cm ^-1 .

(3) Using the compound obtained in the above (2), the title compound was obtained in substantially the same manner as in Example 1 (3).

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 1.06-1.96 (m, 17H), 2.1
4-2.32 (m, 3H), 2.24 (dd, J = 1
8.5, 9.0 Hz, 1H), 2.56 (d, J = 3.
3 Hz, 1 H), 2.64 (dd, J = 11.2, 8.
1 Hz, 1 H), 2.76 (ddd, J = 18.5,
7.3, 1.3 Hz, 1H), 3.73 (s, 3H),
4.24-4.42 (m, 1H), 5.83 (dt, J
= 15.6, 1.5 Hz, 1H), 6.97 (dt, J
= 15.6, 7.0 Hz, 1H) IR (KBr); 3413, 3361, 3259, 29
42,2859,2239,1745,1727,16
60, 1437, 1392, 1328, 1290, 12
61, 1179, 1121, 1068, 1028, 96
3,902,842,701,613,533c
m ^-1 .

Example 3 (2E) -16,17,18,19,20-Pentanol-15,15-pentamethylene-2,3,13,14-
Tetradehydro-PGE ₁ (Compound 18) The compound obtained in Example 1 (62 mg, 0.17 mmol) was added to a suspension of lipase PS (1.74 g) in water (37 ml).
l) in acetone (4.2 ml), phosphate buffer (p
H = 7.0, 0.2 M, 2.1 ml) and stirred at 40 ° C. overnight. The reaction solution was filtered, the filtrate was acidified with 1N hydrochloric acid, salted out with ammonium sulfate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate-hexane,
The title compound (50 mg) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 1.09-2.06 (m, 19H), 2.1
5-2.26 (m, 3H), 2.24 (dd, J = 1
8.7, 9.0 Hz, 1H), 2.59-2.86
(M, 1H), 2.65 (dd, J = 11.4, 8.4)
Hz, 1H), 4.27-4.41 (m, 1H), 5.
85 (dt, J = 15.7, 1.4 Hz, 1H), 7.
06 (dt, J = 15.7, 7.1 Hz, 1H) IR (KBr); 3409, 3230, 2944, 28
62, 2239, 1747, 1694, 1639, 14
64, 1351, 1310, 1284, 1231, 11
81, 1145, 1125, 1078, 1030, 98
9,968,906,878,664,613,584
cm ^-1 .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/00 643 A61K 31/00 643B 31/557 602 31/557 602 (72) Inventor Hideo Tanaka Tokyo 3-24-1, Takada, Toshima-ku Taisho Pharmaceutical Co., Ltd. (72) Inventor Naoya Ono 3-24-1, Takada, Toshima-ku, Tokyo Inside Taisho Seiyaku Co., Ltd. (72) Inventor Shin Yagi Toshima-ku, Tokyo 3-24-1, Takada Taisho Seiyaku Co., Ltd. F-term (reference) 4C086 AA03 DA03 NA14 ZA40 ZC12 4H006 AA01 AB23 UE14 UE32 UE33 UE52

Claims (2)

[Claims] (1) Formula (1) (Where A is an ethylene group, a vinylene group, an ethynylene group,
OCH ₂ or S (O) _p CH ₂ , where R is a hydrogen atom, C
_Represents an alkyl group of _1-10 or a cycloalkyl group of C _3-10 , m represents an integer of 0 to 5, n represents an integer of 1 to 8, and p represents an integer of 0 to 2. ), A pharmaceutically acceptable salt thereof or a hydrate thereof. 2. In the formula (I), m is 2 to 4;
Is an integer of 1 to 6, and p is an integer of 0 to 2. The prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof.