• 专利附录
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  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    11-Desoxy-16-aryl- omega -tetranorprostaglandins and various intermediates and processes employed in their preparation are disclosed. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins but they exhibit a greater tissue specificity of action.
    公开号:SU727139A3
    申请号:SU762414464
    申请日:1976-10-21
    公开日:1980-04-05
    发明作者:Фредерик Эгглер Джеймс；Сингх Биндра Джасджит；Эрнст Гесс Ханс-Юрген
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:

    and X is an oxo group and, if it is desired to obtain a compound of formula I, where X is a hydroxy group, during the oxidation process, the hydroxy group is protected as CL-acetoxy or (B-aceto-sigroup, followed by alkaline hydrolysis to remove the acetyl group, and if necessary The resulting compound, wherein Q-COOH, is esterified or salified. Preferred compounds obtained by the proposed method are compounds of formula I, where Ar is phenyl, P) naphthyl and X is oxo group, Example 1. 9-OXO -15- (tetra hydropyran-2-yloxy) -16-phenyl4 {-thet ranorpro ta-cis-5-ene-13-ins acid. To a solution of 990 mg (2.25 mol) 9 Agoxy-15-tetrahydropyran-2-yloxy -1 b-phenyl- (L) -tetranorprost-cis-5-enic acid in 45 ml of acetone at -10 ° C in a dry atmosphere nitrogen, 0.91 ml (2.47 mol) of 2.67 Jones reagent was added. After ten minutes of exposure, the mixture is poured onto 250 ml of ethyl acetate, washed with 2 x X 50 ml of water, dried over sodium sulfate, and concentrated to give 933 mg of crude. Example 2. 9-OXO-15-OXI-16-phenyl-OU-tetranorprost-cis-15-ene-13-inoic acid. . A solution of 933 mg (2.2 mol) of 9-oxo-15-tetrahydropyran-2-yloxy-1b-phenyl-Oi-tetranorprost-cis-5-en-13-inoic acid in 50 ml of a mixture of glacial acetic acid and water ( 65:35) stirred under nitrogen for three days at 21 ° C, concentrated in a rotary evaporator, the oil which is chilled is chromatographed on 65 silica gel (Mallinkrod CC-7, 100-200 mesh). After elution with polar impurities, 450 mg of product are isolated. In the NMR spectrum (CDCEg), a singlet was detected at 7.30 cU (5H) for proton-phenyl, a broad singlet at 6.56 t (2H) for protons of acid and GID) ACS group, multiplet at 5.55-5.230 ( 2H) for olefinic protons, at 2.94 ((2H) for benzyl schaeotons, a triplet at 4.59cH (1H) and a 5RI diffusion pair 2.80-1.30 s (14H) for the remaining protons. In the IR spectrum (CHSb) the presence of the carboxylic acid and ketone is found to be present at 1700 and 1730, respectively. The compounds of Example 1 can be converted into analogous TG-deoxy-PGF in a similar way. Example 3. P-Biphenyl ester 9-oxo-15 -OK si-16-feni-1O-tetranorprost-cis-5-en-13-butanoic acid. To a solution of 106 mg (0.3 mol) of 9-oxo-15-hydroxy-16-phenyl-etheranorprost-cis-5- en-13-inic acid and 510 mg (3 mol) of p-diphenyl alcohol in 30 ml of methylene chloride, 93 mg (0.45 mol) of dicyclohexylcarbodiimide are added. After stirring for 18 hours at room temperature, the solution is concentrated on a rotary evaporator and chromatographed in a column on silica gel (Baker Anaised Reagent). After elution with less polar impurities, the product is isolated. Example 4. 9-OXO-15- (tetrahydropyran-2-yloxy) -16- (fb-naphthyl) -Sh-tetranorprost-cis-5-ene-13-inic acid. To a solution of 1.15 g (2.1 mol) 9c (g-hydroxy-15- (tetrahydropyranyloxy) -16- (jb-naphthyl) - (-tetranorprost-cis-5-en-13-inic acid in 25 ml of acetone 0.89 ml (2.4 mol) of 2.67 M Jones reagent is added at dry nitrogen atmosphere. After holding at -10 ° C for 10 min, poured into 150 ml of ethyl acetate, washed with 2x50 ml of water, dried over sodium sulfate And concentrated to obtain 1.16 mg of crude. Pp and Mp 5. 9-OXO-15-OXY-16- ((L-naphthyl) ChU-tetranorprost-1 5-en-13-inoic acid. Solution 480 mg of 9-oxo-15- (tetrahydropyran-2-yloxy) -16- (ji-naphthyl) -and tetranorprost-cis-5-ene-13-inoic acid 20 ml of a mixture of glacial acetic acid and water (65:35) are stirred at 27 ° C overnight, concentrated on a rotary evaporator, and the remaining oily product is chromatographed on 50 g of silica gel (Mullincrod CC-7, 100-200 mesh). After elution less polar impurities (124 mg of product are obtained.) The NMR spectrum (CDCBg) revealed the presence of a multiplet at 8.20-7.19d (7H) for proton naphthyl, a singlet at 6.66 cG (2H) for protons of the hydroxy group and acid , multiplet at 5.30 {f (2H), singlet at 3.8od (lH), doublet at 3.43 cf (2H) and multiplet at 2.80-1.10 s (14H) for the remaining proton at. Example 6: 9o (hydroxy-15-hydroxy-16- (p-naphthyl) -Sh-tetranorprost-cis-15-en-13-inoic acid. 400 mg solution (0.817 mol) -9-oC-hydroxy-15 -tetrahydropyran-2-yloxy-16- (| 3-naphthyl) -Oi-tetranorprost-cis-5-en-13-inoic acid in 20 ml of a mixture of glacial acetic acid and water (65:35) is stirred under a nitrogen atmosphere overnight and concentrated on a rotary evaporator. The resulting oil is chromatographed on 35 g of silica gel (Mallinkrod CC-7, 100-220 mesh). After elution of less polar impurities, 148 mg of product is obtained. Example 7. Methyl ester of 9-OXO-15 -oxy-1b-phenylCHL1-tetra chor growth-cis-5-ene-13-inoic acid To a solution of 106 mg (0.3 mol) of 9oxo-15-OXI-1b phenyl-oi-tetranorprost-cis-5-en-13-inoic acid in 20 ml of ether an ether solution of diazomethane prepared from 100 (0.68 mol) N-methyl-N-nitro-N-nitro zoguanidine is added. After stirring at room temperature for 5 minutes, acetic acid is added to destroy the excess diazomethane. The ether solution is washed with 20 ml sodium bicarbonate, 20 ml of water, dried over sodium sulfate and concentrated in a rotary evaporator. Example 8. The cyclohexyl ester of 9-oxo-15-hydroxy-1b-phenyl-III-tetranorprost-cis-5-ene-13-inoic acid. To a solution of 65 mg of 9-oxo-15-hydroxy-1b-phenyl-s-tetranorprost-cis-5-ene-13-inoic acid in 3 ml of methylene chloride were added 21 mg of triethylamine. After 5 minutes, 25 mg of trimethylacetic acid chloride are added, stirred for 10 minutes, added with 0.2 ml of cyclohexanol and 0.3 ml of pyridine, stirred at room temperature for 2 hours, diluted with ethyl acetate, the organic layer is washed with water, dried over magnesium sulfate and concentrate. The residue is chromatographed on a column of silica gel, after removal of the less polar impurities, the desired compound is obtained. Example 9. 9,15-Dioxo-16-phenyl-H Tetranorprost-cis-3-3-enoic acid. To a solution of 356 mg (1 mol) of 9c, 1-dioxy-16-phenyl-01-tetranor simple a-cis-5-en-13-ynOBY acid in 30 ml of acetone at 10 ° C in an atmosphere of dry nitrogen is added 0, 89 ml (2.4 mol) 2.67 M Jones reagent. After ten minutes at t = 1 ° C, the mixture is poured into 100 ml of ethyl acetate, washed with 2x50 ml of water, dried over sodium sulfate and concentrated to give 360 mg of raw chromium on a silica gel column (Baker Analyzed Reagent). After removing less polar impurities release the desired product. Similarly, the compounds of Examples 2,3,5-8 can be converted to the corresponding 11-deoxy-15-keto-PGF-2 analogues. Example 10. 9vC-Acetoxy-15- (tetrahydropyran-2-yloxy) -16-phenyl-C-tetranorprost-cis-5-ene-13-inic acid. To a solution containing 2 ml of pyridine, 2 ml of acetic anhydride and 10 ml of methylene chloride, was added a solution of 440 mg (1 mol) of 9cC-oxy-15- (tetrahydropyran-2-yloxy) -16-phenyl-and-tetranor simple a-cis-5-ene-13-inic acid in 2 ml of methylene chloride, stirred for 1 hour at room temperature, diluted with 100 ml of ether. The ether layer is washed with 2x20 ml of 1 M hydrochloric acid, 2x20 ml of water, dried over sodium sulfate, concentrated on a rotary evaporator and a product is obtained, which is used without further purification. Example 11: 9c (, - Acetoxy-15-β-oxy-1 6-phenyl- {e-tetranorprost-cis-5-en-13-ynovoic acid. A solution of 500 mg (1.1 mol) of 9-6 acetoxy-15- ( tetrahydropyran-2-yloxy) -16-phenyl-Cl-tetranorprost-cis-5-ene-13-inoic acid in 20 ml of a mixture of glacial acetic acid and water (65:35) is stirred under nitrogen at night, concentrated on a rotary evaporator, the oily residue is chromatographed on 35 g of silica gel (Baker Analyzed Reagent). After elution of less polar impurities, the product is isolated. In a similar way, the compounds of Example 10 can be converted to the corresponding hydroxy derivatives. Example 12. 9 ° C-Acetoxy-15-, -oxo-16-phenyl-3-tetranorprost-cis-5 en-13-inoic acid To a solution of 396 mg (1 mol) 9c (g-detoxy-5 -oxy-16-phenyl-i-tetranorprost-cis-5-ene-13-inoic acid in 20 ml of acetone, under an atmosphere of dry nitrogen, 0.45 ml (1.2 mol) of 2.67 M reagent-Tszons was added. For ten minutes at -10 ° C, it is poured into 150 ml of ethyl acetate, 2x50 ml of water are walked through, dried over sodium sulfate and concentrated to give the product, which is used without further purification. In a similar manner, the compounds of Example 11 can be converted to the corresponding oxo derivatives. Example 13. 9bC-Oxy-15-oxo-16-phenylCHO-tetranorprost-cis-5-ene-13-inoic acid. A solution of 300 mg (0.76. Mol) 9 c6-acetoxy-15-oxo-16-phenyl-C1b-tetranorprost-cis-5-en-13-inoic acid in 20 ml of a mixture of methyl alcohol and water (50:50) containing 900 mg of sodium hydroxide, stirred for 5 hours at room temperature, neutralized with 1N. hydrochloric acid and concentrated on a rotary evaporator, the residue is chromatographed on a silica gel column (Baker Analyzed Reagent) and the desired product is isolated after elution of less polar impurities. In a similar way, the compounds of Example 12 can be converted to the corresponding 11-deoxy-15-kb-PGF2c-analogs.
    1 b-Phenyl-sg-tetranorprostaglandin analogs and their p-biphenyl more difficult esters can be used as hypotensive npes drugs. They can be administered systemically or preferably intravenously at a dose of 0.01-1.0 mg / kg of live weight per day.
    权利要求:
    Claims (4)
    [1]
    1. A method for producing optically active 11-deoxy-16-aryl-III-tetranorprostaglandins of general formula X
    or their racemates, or their salts, where X and M is an oxo group, or Q is tetrazol-5-yl or COOR, where R is the hydrogen, phenyl alkyl or p-biphenyl; Ar is phenyl, oL-naphthyl p-naphthyl, characterized in that the compound total (FS) is omly
    x
    II
    ss:
    V
    eix) the optical antipode or its racemate, where Ar has the above meaning; Q-COOH or tetrazol-5-yl;
    X-OXO-, oC-oxy-, 5 -OXI-, oC-acetoxy- or 1% -acetoxy;
    M - c., Where R is tetrahydropyranyl, is subjected to acidic: hydrolysis with aqueous acetic acid 5 to form a compound,.
    Formula I, where M is r., or
     Hn he
    and, if desired, the resulting compound is reacted with an oxidizing agent to obtain a compound of formula I, where M is an oxo group or both M and X is an oxo group and, if it is desired to obtain a compound of formula I, where X is a hydroxy group, during the oxidation process, the hyisoxy group is protected as acetoxy or% acetoxy, followed by alkaline hydrolysis to remove the acetyl group, and, if necessary, the resulting compound, where Q-COOH, is sterilized or salified, followed by isolation of the desired product.
    [2]
    2. The method according to claim 1, 1, and also with the fact that Jones reagent is used as an oxidizing agent.
    [3]
    3. A method according to claims 1 and 2, characterized in that Ar-phenyl or Ji-naphthyl.
    [4]
    4. Method according to paragraphs. 1-3, which is based on the fact that X is an oxo group.
    Sources of information taken into account in the examination
    1. TotaE Synthesis of Prostagtan-dins F2oC and Eg as the Naturatty Occuring Forms E.P. Corey, Thomas K, Lchaaf, W. Huber, KoeEEiker, 0 Ned. M. Weinshenker. - J, Amer. Chem, Soc; 92, 397 (1970).
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    引用文献:
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    US3840573A|1970-12-21|1974-10-08|Searle & Co|2--3-hydroxy-5-oxygenated cyclopent-1-enealkanoic acids,optical isomers thereof and esters corresponding|
    US3932389A|1974-12-11|1976-01-13|Pfizer Inc.|2-Descarboxy-2--11-desoxy-15-substituted-.omega.-pentanorprostaglandins|US4365077A|1975-06-23|1982-12-21|Pfizer Inc.|11-Desoxy-16-aryloxy-ω-tetranorprostaglandins|
    ZA77160B|1976-02-13|1977-11-30|Upjohn Co|Prostaglandin analogs|
    US4058564A|1976-07-26|1977-11-15|The Upjohn Company|Aliphatic 2-decarboxy-2-hydroxymethyl-13,14-didehydro-PG compounds|
    US4140721A|1976-07-26|1979-02-20|The Upjohn Company|2-Decarboxy-2-hydroxymethyl-13,14-didehydro-17-phenyl-PGA, PGD and PGE compounds|
    US4177346A|1976-08-06|1979-12-04|Pfizer Inc.|1,5-Disubstituted-2-pyrrolidones|
    JPS6210843Y2|1981-01-23|1987-03-14|
    JPS59190734U|1983-06-06|1984-12-18|
    US4576962A|1983-10-19|1986-03-18|The Procter & Gamble Company|Prostaglandin analogues|
    US4780251A|1984-07-27|1988-10-25|Hoffman-La Roche Inc.|Phenyl substituted-2,4,6,8-nonatetraenoic acid|
    US4883614A|1984-07-27|1989-11-28|Hoffman-La Roche Inc.|Phenyl substituted-2,4,6,8-nonatetraenoic acid|
    WO2013024051A1|2011-08-12|2013-02-21|Ascendis Pharma A/S|Sustained release composition of prostacyclin|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/624,486|US3984400A|1975-10-21|1975-10-21|11-Desoxy-16-aryl-ω-tetranorprostaglandins|
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