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    • 专利摘要:
    The present invention discloses prostaglandin analogs or their pharmaceutically acceptable salts or hydrates thereof represented by the formula: <Formula I> In the formula, A represents an ethylene group, a vinylene group or an ethynylene group, Y 1 and Y 2 are independently of each other a hydrogen atom, a halogen atom, a cyano group, CONR 3 R 4 (R 3 and R 4 independently of each other represent a hydrogen atom or an alkyl group of C 1-6 or R 3 and R 4 Together with adjacent nitrogen atoms form a C 4-8 cyclic amine), C 1-3 aminoalkyl group, C 1-6 hydroxyalkyl group, NR 5 R 6 (R 3 and R 4 are each independently hydrogen Atom or C 1-6 alkyl group), hydroxyl group, C 1-6 alkoxy group, C 1-9 alkyl group, C 1-6 halogen substituted alkyl group, C 1-5 acyl group, and COOR 7 ( R 7 represents a hydrogen atom, an alkyl group of C 1-6 or a phenyl group), R 1 and R 2 independently of one another represent a hydrogen atom, a halogen atom, an alkyl group of C 1-9 , a halogen substituted alkyl group of C 1-6 , m represents the integer of 0-6, n represents the integer of 0-3.
    公开号:KR20020033785A
    申请号:KR1020027002917
    申请日:2000-09-05
    公开日:2002-05-07
    发明作者:후미에 사또；도오루 다나미；히데오 다나까；나오야 오노；마고또 야기
    申请人:사또, 후미에；우에하라 아끼라；다이쇼 세이야꾸 가부시끼가이샤；
    IPC主号:
    专利说明:

    Prostaglandin E Analogues {Prostaglandin E Analogues}
    [2] Since PG (hereinafter PG stands for prostaglandin) exerts various physiological actions, a large number of analogue synthesis and biological activity studies have been conducted. For example, Japanese Patent Application Laid-open No. 52-100446 , US Pat. No. 4,131,738, and the like.
    [3] Physiological actions of PG and its analogues include vasodilation, gastritis, platelet aggregation, uterine muscle contraction, intestinal contraction, and intraocular pressure lowering. Myocardial infarction, angina pectoris, arteriosclerosis, hypertension, duodenum It is useful for the treatment or prevention of ulcers, furthermore inducing labor, abortion, and the like.
    [4] PTCA, on the other hand, is a method of treating ischemic heart disease, and has been rapidly developed recently because of low invasiveness to patients and excellent initial treatment effect. However, there is an unresolved deficiency in which restenosis of coronary arteries occurs at a frequency of 30 to 40% within months after PTCA.
    [5] Although compounds that inhibit the proliferation in the media by moving from the inner membrane to the media of vascular smooth muscle cells deeply involved in the restenosis development are expected as a drug for preventing restenosis, no clinically useful drugs have yet been found. .
    [6] An object of the present invention is to provide a drug for preventing or treating diseases caused by restenosis after PTCA, having a vascular smooth muscle proliferation inhibitory effect.
    [7] As a result of the intensive studies, the present inventors have found that the prostaglandin analogue represented by the following general formula (I) has a characteristic of inhibiting vascular smooth muscle proliferation, and completed the present invention.
    [8] That is, the present invention relates to a prostaglandin analog, a pharmaceutically acceptable salt thereof, or a hydrate thereof represented by the following formula (I).
    [9]
    [10] In the formula,
    [11] A represents an ethylene group, a vinylene group or an ethynylene group,
    [12] Y 1 and Y 2 are the same or different, a hydrogen atom, a halogen atom, a cyano group, CONR 3 R 4 (R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group of C 1-6 or Or together with the adjacent nitrogen atom form a C 4-8 cyclic amine), C 1-3 aminoalkyl group, C 1-6 hydroxyalkyl group, NR 5 R 6 (R 5 and R 6 are the same or different And a hydrogen atom or a C 1-6 alkyl group), a hydroxyl group, a C 1-6 alkoxy group, a C 1-9 alkyl group, a C 1-6 halogen substituted alkyl group, a C 1-5 acyl group, COOR 7 (R 7 represents a hydrogen atom, an alkyl group of C 1-6 or a phenyl group),
    [13] R 1 and R 2 are the same or different and represent a hydrogen atom, a halogen atom, a C 1-9 alkyl group, a C 1-6 halogen substituted alkyl group,
    [14] m represents the integer of 0-6, n represents the integer of 0-3.
    [15] <Embodiment of the Invention>
    [16] In the present invention, a vinylene group means a cis or trans vinylene group. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, but preferably a fluorine atom or a chlorine atom.
    [17] The C 1-3 aminoalkyl group means a straight or branched chain aminoalkyl group having 1 to 3 carbon atoms, and examples thereof include aminomethyl group, aminoethyl group, aminopropyl group and the like, but are preferably aminomethyl group.
    [18] Examples of the C 4-8 cyclic amine include pyrrolidine, piperidine, morpholine and the like, and are preferably piperidine.
    [19] The C 1-6 hydroxyalkyl group means a straight or branched chain hydroxyalkyl group having 1 to 6 carbon atoms, for example, a hydroxymethyl group, a dimethylhydroxymethyl group, a dihydroxymethyl group, or the like.
    [20] The C 1-6 alkoxy group means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and is a methoxy group, an ethoxy group, a propoxy group and the like.
    [21] The halogen substituted alkyl group of C 1-6 means a straight or branched chain alkyl group having 1 to 6 carbon atoms substituted with a fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably it is a perfluoroalkyl group, More preferably, it is a trifluoromethyl group.
    [22] An alkyl group of C 1-6 means a straight or branched chain alkyl group having 1 to 6 carbon atoms, and for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, Pentyl group, isopentyl group, 2-ethylpropyl group, hexyl group, isohexyl group, 1-ethylbutyl group and the like.
    [23] The C 1-9 alkyl group means the C 1-6 alkyl group and C 7-9 straight or branched alkyl group, and examples thereof include a heptyl group, an octyl group, and a nonyl group.
    [24] The acyl group of C 1-5 means a straight or branched chain alkanoyl group, alkenoyl group or alkinoyl group having 1 to 5 carbon atoms, for example, an acetyl group, propionyl group, crotonoyl group, propiono Diary etc.
    [25] Pharmaceutically acceptable salts include salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanol amine, di Salts such as ethanol amine, monomethyl monoethanol amine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) amino methane and the like.
    [26] When Y 1 or Y 2 is NR 5 R 6 , R 5 and R 6 are preferably a methyl group.
    [27] Compounds of formula (I) in accordance with the present invention can be prepared specifically by, for example, the methods outlined in the following scheme.
    [28]
    [29] In the scheme, TBS represents tert-butyldimethylsilyl group, A 'represents ethylene or vinylene group, Et represents ethyl group, and A, Y 1 , Y 2 , R 1 , R 2 , m, n are same.
    [30] Explaining the reaction scheme
    [31] (1) First, 0.8 to 2.0 equivalents of the compound represented by the formula (III) or (IV) to the compound of the formula (II) known by the method of Sato et al. (Journal of Chemistry, Vol. 53, p. 5590 (1988)) Compounds of formula V are stereospecifically obtained by reacting in an inert solvent (eg, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) at 78 to 30 ° C. Here, in order to obtain a compound of A is an ethylene group or a vinylene group (that is, a compound of which A is A ') at -78 to 0 ° C using a compound of Formula III, in order to obtain a compound of A is an ethynylene group, The reaction is carried out at 0 to 30 ° C. using the compound of IV.
    [32] The organocopper compound of the general formula (III) used as a raw material can be produced by, for example, a method shown in the following scheme.
    [33]
    [34] In the above scheme, A ', R 1 , R 2 and TBS are the same as above.
    [35] That is, the aldehyde compound represented by VIII and (triphenylphosphoranilidene) acetic acid methyl ester are reacted in an inert solvent (for example, methylene chloride, benzene, toluene xylene, etc.) at 0 ° C to solvent reflux, followed by diisobutylaluminum Reducing agents such as hydrides are used to obtain compounds of formula (IX).
    [36] Next, the compound of formula IX is stereosterically selected by reacting the compound of formula IX with tert-butylhydroperoxide and methylene chloride at -20 ° C using L-(+)-diisopropyl tartarate and titanium tetraisopropoxide. Oxidation yields an epoxy compound. The obtained epoxy compound is further methanesulfonylated and substituted with lithium chloride to obtain a compound of formula (X).
    [37] The compound of formula (X) is obtained by protecting the hydroxyl group of the acetylene analog produced by reacting with n-butyllithium at -70 ° C in tetrahydrofuran under ordinary conditions to obtain the compound of formula (XI).
    [38] Compounds of formula XI are radicals, in the presence of 0.5 to 4.0 equivalents and 0.05 to 2.0 equivalents of a radical generator (e.g., azobisisobutylonitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide, triethylborane, etc.) 1-5 equivalents of a reducing agent (e.g., trimethyltin hydride, tributyltin hydride, triphenyltin hydride, etc.) at -78 to 100 캜, followed by iodine in a mixed solution of diethyl ether and saturated sodium bicarbonate water. By reacting the compound of formula (XII).
    [39] The compound of formula XII is prepared by reacting with tert-butyllithium followed by reaction with lithium 2-thienylcyanocuplate.
    [40] (2) 0.5 to 4.0 equivalents of the organic copper compound represented by the formula (VI) and 0.5 to 4.0 equivalents of the trimethylchlorosilane are added to the compound of the formula (V) with an inert solvent (for example, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, in n-hexane, n-pentane, etc.) at -78 to 40 ° C, and also inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, etc.) or organic acids (e.g. acetic acid, p-toluenesulfonic acid, etc.) or Using an amine salt (e.g., p-toluenesulfonic acid pyridine salt, etc.), in an organic solvent (e.g. acetone, methanol, ethanol, isopropanol, diethyl ether or a mixed solvent thereof, etc.) By cleavage, the compound of formula (VII) is obtained stereoselectively.
    [41] In addition, 0.5 to 4.0 equivalents of a compound represented by the formula (V) and a radical generator (for example, azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide, triethylborane, etc.) To 2.0 equivalents, and also 1 to 5 equivalents of a radical reducing agent (e.g. tributyltin hydride, triphenyltin hydride, dibutyltin hydride, diphenyltin hydride, etc.) in an inert solvent (e.g., benzene, toluene, Xylene, n-hexane, n-pentane, acetone and the like), at -78 to 100 ° C to give a compound of formula VII.
    [42] (3) Compounds of formula (VII) in methanol, ethanol, acetonitrile or a mixed solvent thereof, or a mixed solvent of these and water under conditions usually performed using hydrofluoric acid, pyridinium poly (hydrogenfluoride), hydrochloric acid, or the like The tert-butyldimethylsilyl group which is a protecting group of the hydroxyl group is removed to obtain a PG analogue of the formula (I) according to the present invention.
    [43] The compounds of the present invention may be administered systemically or topically or parenterally or parenterally, subcutaneously, intramuscularly, intravenously, transdermally, etc., but preferably orally or intravenously. They can be administered orally, for example, in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions and the like which can be prepared by conventional methods. As the preparation for intravenous administration, an aqueous or non-aqueous solution, an emulsion, a suspension, a solid preparation used by dissolving in an injection solvent immediately before use can be used. In addition, the compound of the present invention can be formulated by forming a clathrate compound with α, β or γ-cyclodextrin or methylated cyclodextrin. In addition, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. The dosage varies depending on age, weight, etc., but is 1 ng to 1 mg / day for the adult, which is administered once a day or divided into several times.
    [44] Representative compounds of formula (I) relating to the present invention are shown in Table 1.
    [45]
    [46]
    [47]
    [48]
    [49] Piperdi-CO: piperidinocarbonyl
    [50] Industrial availability
    [51] Compounds of the present invention exhibit excellent anti-proliferative action of vascular smooth muscle cells and have fewer side effects, thus preventing vascular thickening (e.g., restenosis after percutaneous coronary angioplasty) and blocking of obstruction or vascular thickening and obstruction. It is useful as a therapeutic agent.
    [1] The present invention relates to an agent for the prevention or treatment of restenosis after excellent percutaneous coronary angioplasty (PTCA) containing the prostaglandin analog, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.
    [52] Hereinafter, although an Example and a reference example are given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by this description. In addition, in the naming of a compound, "nor" as in "2,3,4-trinor-1,5-inter-m-phenylene" means that there is no carbon chain at the position (in the above example, 2 , Means that there is no carbon chain in the 3, 4 position, "interphenylene" means that the benzene ring is inserted in the middle (in the above example, the carbon at position 1 and 5 are bonded at the meta position of the benzene ring, respectively) I mean doing).
    [53] Reference Example 1
    [54] (1E, 3S) -1-iodine-3- (tert-butyldimethylsiloxy) -5-phenyl-1-pentene
    [55] (1) To a solution of methylene chloride (200 ml) of hydrocinnamaldehyde (25.64 g), (triphenylphosphoranilidene) acetate methyl ester (63.9 g) was added at 0 ° C, and stirred at room temperature overnight. The insolubles were filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 30: 1) to obtain methyl (2E) -5-phenyl-2-penteno. Eight (30.22 g) was obtained.
    [56]
    [57] (2) To a diethyl ether (200 mL) solution of compound (19.37 g) obtained in (1) above, diisobutylaluminum hydride (1.5 M, toluene solution, 149.4 mL) was added at -70 ° C and at room temperature Stir for 1.5 hours. Acidified with hydrochloric acid under ice-cooling, the organic layer was washed with saturated sodium bicarbonate and saturated brine. The crude product obtained by drying and concentrating an organic layer with magnesium sulfate anhydride was distilled under reduced pressure, and (2E) -5-phenyl-2-penten-1-ol (13.9 g) was obtained.
    [58] b.p. 91.5 ~ 92.0 ℃ / 0.56 torr
    [59]
    [60] (3) To a mixture of molecular sieve 4A (8.2 g) of powder and methylene chloride (125 mL) of titanium tetraisopropoxide (5.1 mL) under an argon stream, L-(+)-diartary tartarate at -20 ° C. Propyl ester (4.4 ml) was added dropwise and stirred for 30 minutes under the same conditions. Subsequently, a methylene chloride (41 mL) solution of the compound (13.9 g) obtained in the above (2) was added, and the mixture was stirred at -20 ° C for 1 hour. The mixture was cooled to -30 deg. C, tert-butylhydroperoxide (3.2 M, methylene chloride solution, 48.3 ml) was added dropwise over 30 minutes, and after the dropwise addition was completed, the mixture was stirred at -20 deg. Feed (14 mL) was added and stirred at the same temperature for 3 hours. Subsequently, an aqueous solution of tartaric acid (10%, 9.3 mL) was added, and sodium fluoride (60 g) was added at room temperature for 1 hour, and then, celite (34 g) and diethyl ether (96 mL) were added for 1 hour. Each was stirred over time. The oily substance (41.9 g) obtained by filtration and concentration was further dissolved in diethyl ether (109 mL), an aqueous sodium hydroxide solution (1N, 60 mL) was added thereto, stirred at room temperature for 1.5 hours, and then the organic layer was separated, The aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a residue obtained by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1), followed by (2S, 3S) -2, 3-epoxy-5-phenyl-1-pentanol (14.2 g) was obtained.
    [61]
    [62] (4) Triethylamine (13.3 mL) was added dropwise under ice-cooling to a methylene chloride (150 mL) solution of compound (14.1 g) and methanesulfonyl chloride (6.8 mL) obtained in (3) above. After the addition, the mixture was stirred for 30 minutes at room temperature and washed with water, saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (2S, 3S) -2,3-epoxy-1-methanesulfonyloxy-5-phenylpentane (20.0 g).
    [63]
    [64] (5) An N, N-dimethylformamide (110 mL) solution of the compound (19.5 g) and lithium chloride (6.44 g) obtained in the above (4) was heated and stirred at 55 ° C. for 2.5 hours under an argon stream. After cooling, water (35 mL) and saturated brine (105 mL) were added, extracted with ethyl acetate: hexane (1: 1), and the organic layer was washed with saturated brine. The residue obtained by drying and concentrating the organic layer with magnesium sulfate anhydride was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 20: 1), and then (2R, 3S) -1-chloro-2,3-epoxy. -5-phenylpentane (14.2 g) was obtained.
    [65]
    [66] (6) n-butyllithium (2.5 M, hexane solution, 82.4 ml) was added dropwise to tetrahydrofuran (67 ml) of the compound (13.5 g) obtained in the above (5) at -70 ° C under an argon stream. After the addition, the mixture was stirred for 30 minutes under the same conditions, and then saturated aqueous ammonium chloride solution (84 ml) was added, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The crude product obtained by drying and concentrating an organic layer with magnesium sulfate anhydride was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1), and (3S) -5-phenyl-1-pentin-3- Obtained 10.96 g.
    [67]
    [68] (7) tert-butyldimethylchlorosilane (12.3 g) was added to an N, N-dimethylformamide (67 mL) solution of the compound (10.9 g) and imidazole (9.3 g) obtained in the above (6) under ice-cooling. It was. After stirring at room temperature overnight, the mixture was poured into saturated sodium bicarbonate (300 mL) and stirred at room temperature for 15 minutes, hexane extracted, and the organic layer was washed with saturated sodium bicarbonate and saturated brine. The residue obtained by drying and concentrating an organic layer with magnesium sulfate anhydride was distilled under reduced pressure, and (3S) -3- (tert-butyldimethylsiloxy) -5-phenyl-1-pentine (16.2 g) was obtained.
    [69] b.p. 108 ℃ / 1.8 torr
    [70]
    [71] (8) A mixture of the compound (34.27 g), tributyltin hydride (50 g) and azobisisobutyronitrile (20 mg) obtained in the above (7) was stirred at 160 ° C under an argon stream for 1 hour. After cooling at room temperature, distillation under reduced pressure afforded a crude product (75.8 g).
    [72] (9) A solution of iodine (37.43 g) tetrahydrofuran (20 mL) in a mixture of compound (75.8 g), diethyl ether (496 mL) and saturated brine (496 mL) obtained in (8) above at 0 ° C Added dropwise. After dropping, the mixture was stirred at the same temperature for 30 minutes, and then, an aqueous sodium thiosulfate solution was added to extract hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dissolve the residue in methylene chloride (670 mL), potassium fluoride (38.92 g) and water (12.1 mL) were added, and the mixture was stirred vigorously at room temperature for 1 hour. . Magnesium sulfate anhydride was added, and after filtration, the residue obtained by concentration was distilled off under reduced pressure to obtain the title compound (29.8 g).
    [73] b.p. 130-14- ℃ / 0.60 torr
    [74]
    [75] <Example 1>
    [76] 2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-PGE 1 methyl ester (Compound 10)
    [77] (1) To a solution of (1E, 3S) -1-iodo-3- (tert-butyldimethylsiloxy) -5-phenyl-1-pentene (29.7 g) in diethyl ether (295 mL) at -78 deg. tert-butyllithium (2.13 M, pentane solution, 69 mL) was added and stirred for 40 minutes at the same temperature. To this solution were added lithium 2-thienylcyanocuplate (0.25 M, tetrahydrofuran solution, 344 mL) at -78 ° C and stirred for 30 minutes at the same temperature. (4R) -2- (N, N-diethylamino) methyl-4- (tert-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25 M, diethyl) Ether solution, 246 mL) was added dropwise and the temperature was raised to 0 ° C for about 1.5 hours.
    [78] The reaction solution was poured into a mixed solution of hexane (600 mL) -saturated ammonium chloride solution (600 mL) with stirring, the organic layer was separated, and the aqueous layer was extracted with hexane (300 mL). The obtained organic layer was dried over anhydrous magnesium sulfate and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 49: 1) to give (3R, 4R)-(2-methylene-3-[(lE, 3S). ) -3- (tert-butyldimethylsiloxy) -5-phenylpent-1-enyl] -4- (tert-butyldimethylsiloxy) cyclopentan-1-one (20.42 g) was obtained.
    [79]
    [80] (2) Copper cyanide (I) .2 chloride in 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide (0.95 M, tetrahydrofuran solution, 64.5 ml) at -70 ° C under argon stream Lithium (1.0 M, tetrahydrofuran solution, 53.1 ml) was added and stirred for 20 minutes at the same temperature. The compound (0.25 M, diethyl ether solution, 163 mL) and chlorotrimethylsilane (11.0 mL) obtained in the above (1) were added to the solution at -70 ° C, and the temperature was raised to 0 ° C over about 1 hour with stirring. Aqueous solution of saturated ammonium chloride was added to the reaction solution, followed by hexane extraction. The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a residue obtained by dissolving in diethyl ether (40.8 ml) -isopropyl alcohol (163.2 ml), and then p-toluenesulfonic acid. Pyridine salt (100 mg) was added and it stirred at room temperature for 12 hours. Hexane was added to the reaction solution, the mixture was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 15: 1). Purified and 2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-PGE 1 methyl ester 11,15-bis (tert-butyldimethylsilylether) ( 16.75 g) was obtained.
    [81]
    [82] (3) A 46% aqueous hydrofluoric acid solution (189 ml) was added to an acetonitrile (840 ml) solution of the compound (16.75 g) obtained in (2) at 0 ° C, and stirred for 1 hour at the same temperature. The reaction solution was poured into ethyl acetate (500 mL) -saturated sodium bicarbonate (5.71) with stirring, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried using magnesium sulfate anhydride and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 4) to obtain the title compound (8.91 g).
    [83]
    [84] <Example 2>
    [85] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (2-trifluoromethylphenyl) -17-phenyl-PGE 1 (compound 16)
    [86] (1) In Example 1 (2), 2- (2-trifluoromethylphenyl) ethylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Substantially the same as in Example 1 (2), using 2-decarboxy-2,3,4,18,19,20-hexanor-5- (2-trifluoromethylphenyl) -17-phenyl -PGE 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [87]
    [88] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [89]
    [90] <Example 3>
    [91] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (3-trifluoromethylphenyl) -17-phenyl-PGE 1 (compound 17)
    [92] (1) In Example 1 (2), 2- (3-trifluoromethylphenyl) ethylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide 2-decarboxy-2,3,4,18,19,20-hexanor-5- (3-trifluoromethylphenyl) -17-phenyl in substantially the same manner as in Example 1 (2) using -PGE 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [93]
    [94] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [95]
    [96] <Example 4>
    [97] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-trifluoromethylphenyl) -17-phenyl-PGE 1 (compound 18)
    [98] (1) In Example 1 (2), 2- (4-trifluoromethylphenyl) ethylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-trifluoromethylphenyl) -17-phenyl in substantially the same manner as in Example 1 (2) using -PGE 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [99]
    [100] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [101]
    [102] Example 5
    [103] 2-Decarboxy-2,3,18,19,20-pentanono-4- (4-methylphenyl) -17-phenyl-PGE 1 (compound 25)
    [104] (1) In Example 1 (2), using 3- (4-methylphenyl) propylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Example 1 Substantially the same as in (2), 2-decarboxy-2,3,18,19,20-pentanonor-4- (4-methylphenyl) -17-phenyl-PGE 1 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
    [105]
    [106] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [107]
    [108] <Example 6>
    [109] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (2-methylphenyl) -17-phenyl-PGE 1 (compound 27)
    [110] (1) In Example 1 (2), using 2- (2-methylphenyl) ethylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Example 1 substantially the same as (2), 2-decarboxy-2,3,4,18,19,20-hexanor-5- (2-methylphenyl) -17-phenyl-PGE 1 11,15 -Bis (tert-butyldimethylsilyl ether) was obtained.
    [111]
    [112] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [113]
    [114] <Example 7>
    [115] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (3-methylphenyl) -17-phenyl-PGE 1 (compound 28)
    [116] (1) In Example 1 (2), instead of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide, 2- (3-methylphenyl) ethylzinc (II) iodide was used. Example 1 (2), substantially the same as 2-decarboxy-2,3,4,18,19,20-hexanor-5- (3-methylphenyl) -17-phenyl-PGE 1 11,15 -Bis (tert-butyldimethylsilyl ether) was obtained.
    [117]
    [118] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [119]
    [120] <Example 8>
    [121] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-methylphenyl) -17-phenyl-PGE 1 (compound 29)
    [122] (1) In Example 1 (2), 2- (4-methylphenyl) ethylzinc (II) iodide was used in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Example 1 (2) substantially the same as 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-methylphenyl) -17-phenyl-PGE 1 11,15 -Bis (tert-butyldimethylsilyl ether) was obtained.
    [123]
    [124] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [125]
    [126] Example 9
    [127] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-acetylphenyl) -17-phenyl-PGE 1 (Compound 31)
    [128] (1) In Example 1 (2), 2- (4-acetylphenyl) ethylzinc (II) iodide is used instead of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-acetylphenyl) -17-phenyl-PGE l 11 substantially the same as in Example 1 (2). , 15-bis (tert-butyldimethylsilyl ether) was obtained.
    [129]
    [130] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [131]
    [132] <Example 10>
    [133] 2-Decarboxy-2,3,18,19,20-pentanonor-4- (4-methoxyphenyl) -17-phenyl-PGE 1 (Compound 41)
    [134] (1) In Example 1 (2), 3- (4-methoxyphenyl) propylzinc (II) iodide is substituted for 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. 2-decarboxy-2,3,18,19,20-pentanonor-4- (4-methoxyphenyl) -17-phenyl-PGE 1 11, substantially the same as in Example 1 (2). , 15-bis (tert-butyldimethylsilyl ether) was obtained.
    [135]
    [136] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [137]
    [138] <Example 11>
    [139] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-methoxyphenyl) -17-phenylPGE 1 (Compound 43)
    [140] (1) In Example 1 (2), 2- (4-methoxyphenyl) ethylzinc (II) was used in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Example 1 substantially the same as (2), 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-methoxyphenyl) -17-phenyl-PGE 1 11 , 15-bis (tert-butyldimethylsilyl ether) was obtained.
    [141]
    [142] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [143]
    [144] <Example 12>
    [145] 2-Decarboxy-2,3,18,19,20-pentanono-4- (4-hydroxyphenyl) -17-phenyl-PGE 1 (compound 44)
    [146] (1) In Example 1 (2), 3- (4-hydroxyphenyl) propylzinc (II) iodide is substituted for 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. 2-decarboxy-2,3,18,19,20-pentanonor-4- (4-hydroxyphenyl) -17-phenyl-PGE 1 11, substantially the same as in Example 1 (2). , 15-bis (tert-butyldimethylsilyl ether) was obtained.
    [147]
    [148] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [149]
    [150] Example 13
    [151] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-hydroxyphenyl) -17-phenyl-PGE 1 (compound 45)
    [152] (1) In Example 1 (2), 2- (4-hydroxyphenyl) ethylzinc (II) iodide was substituted for 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-hydroxyphenyl) -17-phenyl-PGE, substantially the same as in Example 1 (2). 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [153]
    [154] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [155]
    [156] <Example 14>
    [157] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-fluorophenyl) -17-phenyl-PGE 1 (compound 50)
    [158] (1) In Example 1 (2), 2- (4-fluorophenyl) ethylzinc (II) iodide is substituted for 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-fluorophenyl) -17-phenyl-PGE, substantially the same as in Example 1 (2). 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [159]
    [160] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [161]
    [162] <Example 15>
    [163] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4-hydroxymethylphenyl) -17-phenyl-PGE 1 (compound 55)
    [164] (1) In Example 1 (2), 2- (4-hydroxymethylphenyl) ethylzinc (II) iodide was substituted for 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4-hydroxymethylphenyl) -17-phenyl-PGE substantially the same as in Example 1 (2). 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [165]
    [166] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [167]
    [168] <Example 16>
    [169] 2-Decarboxy-2,3,4,18,19,20-hexanor-5- (4- (N, N-dimethylamino) phenyl) -17-phenyl-PGE 1 (Compound 57)
    [170] (1) In Example 1 (2), 2- (4- (N, N-dimethylamino) phenyl) ethylzinc in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide (II) 2-decarboxy-2,3,4,18,19,20-hexanor-5- (4- (N, N), substantially the same as in Example 1 (2) using iodide -Dimethylamino) phenyl) -17-phenyl-PGE 1 11,15-bis (tert-butyldimethylsilylether) was obtained.
    [171]
    [172] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [173]
    [174] <Example 17>
    [175] 2-decarboxy-2,3,18,19,20-pentanonor-4,17-diphenylPGE 1 (compound 38)
    [176] (1) Example 1 In (2), Example 1 using 3-phenylpropylzinc (II) iodide in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide Substantially the same as in (2), 2-decarboxy-2,3,18,19,20-pentano-4,17-diphenyl-PGE 1 11,15-bis (tert-butyldimethylsilyl ether) Got.
    [177]
    [178] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [179]
    [180] Example 18
    [181] 2-Decarboxy-2,3,4,18,19,20-hexanor-5,17-diphenylPGE 1 (Compound 36)
    [182] (1) Example 1 In (2), Example 1 (2-phenylethylzinc (II) iodide is used in place of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide. Substantially the same as 2), 2-decarboxy-2,3,4,18,19,20-hexanor-5,17-diphenyl-PGE 1 11,15-bis (tert-butyldimethylsilylether )
    [183]
    [184] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [185]
    [186] Example 19
    [187] 2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-13,14-didehydro-PGE 1 methyl ester (Compound 74)
    [188] (1) n-butyllithium (2.5 M, hexane solution) at 0 ° C. in a toluene (22 mL) solution of (3S) -3- (tert-butyldimethylsiloxy) -5-phenyl-1-pentine (1.96 g) , 2.64 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Diethyl aluminum chloride (0.95 N, hexane solution, 8.10 mL) was added to this solution at 0 degreeC, and it stirred at room temperature for 30 minutes. To this solution at room temperature was added (4R) -2- (N, N-diethylamino) methyl-4- (tert-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25 M, toluene solution, 22.0 Ml) was added and stirred for 15 minutes. The reaction solution was poured into a mixed solution of hexane (53 mL)-saturated aqueous ammonium chloride solution (53 mL)-aqueous hydrochloric acid solution (3N, 15.4 mL), and then the organic layer was separated and washed with saturated aqueous sodium bicarbonate (20 mL). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a residue obtained by silica gel column chromatography- (developing solvent; hexane: ethyl acetate = 49: 1), followed by (3R, 4R) -2-methylene- 3-[(3S) -3-tert-butyldimethylsiloxy-5-phenylpent-1-ynyl] -4- (tert-butyldimethylsiloxy) cyclopentan-1-one (1.65 g) was obtained.
    [189]
    [190] (2) Using the compound obtained in the above (1), substantially the same as in Example 1 (2), 2,3,4,18,19,20-hexanor-1,5-inter-p- Phenylene-17-phenyl-13,14-didehydro-PGE 1 methyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
    [191]
    [192] (3) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (2).
    [193]
    [194] Example 20
    [195] 2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-13,14-didehydro-PGE 1 (Compound 75)
    [196] (1) (3R, 4R) -2-methylene-3-[(3S) -3-tert-butyldimethylsiloxy-5-phenylpent-1-ynyl] -4- (obtained in Example 1 (1) tert-Butyldimethylsiloxy) cyclopentan-1-one (494 mg), 4- (2-iodoethyl) benzoic acid (1.49 g), tributyltin hydride (1.45 mL), triethylborane (1.0 M, hexane Solution, 0.18 mL) of acetone (43 mL) solution was stirred overnight at 10 ° C. The reaction solution was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 3) to obtain a crude product. Subsequently, the title compound (176 mg) was obtained in the same manner as in Example 1 (3).
    [197]
    [198] Comparative Example
    [199] (2E) -18,19,20-trinor-17-phenyl-2,3,13,14-tetradehydro-PGE 1 methyl ester
    [200] (1) Using the compound obtained in Example 19 (1), in Example 1 (2), instead of 2- (4-methoxycarbonylphenyl) ethylzinc (II) iodide, (4E)- Substantially the same as in Example 1 (2) using 5-methoxycarbonylpent-4-enylzinc (II) iodide, (2E) -18,19,20-trinor-17-phenyl- 2,3,13,14-tetradehydro-PGE 1 methyl ester 11,15-bis (tert-butyldimethylsilyl ether) was obtained.
    [201]
    [202] (2) The title compound was obtained in the same manner as in Example 1 (3) using the compound obtained in the above (1).
    [203]
    [204] <Manufacture example 1>
    [205] Compound 1 (100 μg), microcrystalline cellulose (190 mg), and amorphous silicic acid (10 mg) were mixed in sufficient quantities to fill a hard gelatin capsule to obtain a capsule.
    [206] <Manufacture example 2>
    [207] Compound 29 (100 µg) was dissolved in soybean oil (300 mg), mixed with egg yolk lecithin (50 mg), and glycerin (70 mg) was added thereto, followed by addition of water for injection to make 3 ml. The solution was emulsified by a mixer, and further emulsified with a homogenizer at a pressure of 800 psi, then filled into an ampoule and autoclaved to obtain an ampoule.
    [208] <Test Example>
    [209] Measurement of DNA Synthesis Inhibitory Activity of Human Vascular Smooth Muscle Cells of PGE 1 Analogues
    [210] Fifth culture cells of normal human aortic derived vascular cells (Kurabou) were seeded in 1 × 10 4 cells / well in a 24-well plate (manufactured by Corning), and cultured for 2 days. The medium was changed from growth medium (SG2; manufactured by Kurabo Industries) to basal medium (SB2; manufactured by Kurabo Industries), and cultured for 24 hours. The growth medium (SG2) which added the ethanol solution containing a test compound to this was added. At this time, 3 H-thymidine (manufactured by the first chemical) was added at 0.01 mci / well for 24 hours of incubation, and the culture supernatant was aspirated and washed with phosphate buffer (PBS).
    [211] 5% trichloroacetic acid (TCA) was added and left to stand at 4 ° C for 20 minutes, and then washed once with TCA. After washing in PBS, it was dissolved in 0.5 N KOH. 20 µL of KOH in which 3 H-thymidine was inserted into the nucleus was taken, and the insertion amount of 3 H-thymidine was measured using a liquid scintillation counter (manufactured by Hewlett-Packard).
    [212] The results are shown in Table 2.
    [213] IC50 (μM) Compound 180.66 Compound 290.73 Comparative example4.36
    [214] Note) Compounds 18 and 29 in Table 2 are the compounds prepared in Examples. The test compound was used as an ethanol solution, and the control was compared as a solvent treatment group.
    [215] The above results show that the compounds 18 and 29 have high proliferation inhibitory activity against human vascular smooth muscle cells.
    权利要求:
    Claims (6)
    [1" claim-type="Currently amended] Prostaglandin analogues represented by Formula I, pharmaceutically acceptable salts thereof or hydrates thereof.
    <Formula I>

    In the formula,
    A represents an ethylene group, a vinylene group or an ethynylene group,
    Y 1 and Y 2 are the same or different, a hydrogen atom, a halogen atom, a cyano group, CONR 3 R 4 (R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group of C 1-6 or Or R 3 and R 4 together with the adjacent nitrogen atom form a C 4-8 cyclic amine), an aminoalkyl group of C 1-3 , a hydroxyalkyl group of C 1-6 , NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or an alkyl C 1-6), a hydroxyl group, a halogen-substituted alkyl group of the alkyl group, C 1-6 alkoxy group, C 1-9 of C 1-6, C 1 -5 represents an acyl group, and represents COOR 7 (R 7 represents a hydrogen atom, an alkyl group of C 1-6 or a phenyl group),
    R 1 and R 2 are the same or different and represent a hydrogen atom, a halogen atom, a C 1-9 alkyl group, a C 1-6 halogen substituted alkyl group,
    m represents the integer of 0-6, n represents the integer of 0-3.
    [2" claim-type="Currently amended] The prostaglandin analogue, pharmaceutically acceptable salt thereof or hydrate thereof of claim 1, wherein A in the formula (I) is a transvinylene group.
    [3" claim-type="Currently amended] The prostaglandin analogue, pharmaceutically acceptable salt thereof or hydrate thereof of claim 1, wherein A in formula (I) is an ethynylene group.
    [4" claim-type="Currently amended] The prostaglandin analogue according to any one of claims 1 to 3, wherein m represents an integer of 1 to 6, a pharmaceutically acceptable salt thereof or a hydrate thereof.
    [5" claim-type="Currently amended] The prostaglandin analogue, pharmaceutically acceptable salt thereof or hydrate thereof according to any one of claims 1 to 3, wherein in formula (I) m is an integer from 2 to 3 and n is 2.
    [6" claim-type="Currently amended] An agent for preventing or treating restenosis after percutaneous coronary angioplasty (PTCA), comprising as an active ingredient the prostaglandin analogue according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
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    同族专利:
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    US6482990B1|2002-11-19|
    HK1051179A1|2005-05-06|
    CN1170817C|2004-10-13|
    CN1384819A|2002-12-11|
    EP1211241A4|2004-10-27|
    CA2384148A1|2001-03-15|
    AU6871200A|2001-04-10|
    AU770343B2|2004-02-19|
    EP1211241A1|2002-06-05|
    WO2001017957A1|2001-03-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-09-06|Priority to JP25224799
    1999-09-06|Priority to JPJP-P-1999-00252247
    2000-09-05|Application filed by 사또, 후미에, 우에하라 아끼라, 다이쇼 세이야꾸 가부시끼가이샤
    2000-09-05|Priority to PCT/JP2000/006021
    2002-05-07|Publication of KR20020033785A
    优先权:
    申请号 | 申请日 | 专利标题
    JP25224799|1999-09-06|
    JPJP-P-1999-00252247|1999-09-06|
    PCT/JP2000/006021|WO2001017957A1|1999-09-06|2000-09-05|Prostaglandin e analogues|
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