• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Prostaglandin analogs wherein the C-2 carboxy is replaced by an aminomethyl or (substituted amino)methyl are disclosed along with intermediates useful in their preparation and processes for their preparation. These analogs are useful for the same pharmacological purposes as the prostaglandins.
    公开号:SU731895A3
    申请号:SU762434653
    申请日:1976-12-28
    公开日:1980-04-30
    发明作者:Аллан Нельсон Норман
    申请人:Дзе Апджон Компани (Фирма)；
    IPC主号:
    专利说明:

    to some prostaglandin derivatives, it was possible to obtain new prostaglandins with valuable pharmacological properties.
    The method according to the invention consists in that the compound of the general formula II
    TVCHa-ij-CON Lj
    % -C-C-R. HI LI
    where L, M, R- ,, Z ,, and D
    have
    Yi is the above, a trans CH CH, cis-CHU CH-, or (Na), where Haf is chlorine or bromine, if D is a carbonyl-containing cyclopentane ring, is subjected to reduced lithium atomomethane, preferably in an organic solvent, such as tetrahydrofuran, and if necessary, the reaction product is dehydrohalogenated when Y is (HaE). The desired products are isolated by known methods in free form or in the form of a salt.
    Example 1. 2-Decarboxy-2-aminomethyl-RSH (2 means
    Нц - hydroxy group; Y - (CH2) (, R.
    link L. trans-CH CH; R.j and
    R link M means all hydrogen; R means n-butyl).
    A. (150 mg) is treated with an excess ethereal solution of diazomethane and the reaction mixture is evaporated to give PGF methyl ester. The residue is dissolved in 1 ml of 95% ethanol. The mixture was placed in a Parr steel bomb, washed with 2.5 mol of 95% ethanol and 200 mg of ammonium chloride was added. The mixture is cooled with dry ice and 5-10 ml of ammonia is added. The bomb is sealed and allowed to warm to room temperature, then kept in the oven for 2 days, cooled with dry ice and opened. The residual ammonia is evaporated with nitrogen. And the product is extracted with ethyl acetate, washed with water and saturated brine, dried with sodium sulfate and evaporated to give PGF amide
    B, Lithium aluminum hydride (100 mg) is dissolved in .5 ml of dry tetrahydrofuran a in a nitrogen atmosphere. The product obtained according to A (dissolved in a small amount of dry tetrahydrofuran) is slowly added to a solution of 100 ml of lithium aluminum hydride in 5 ml of dry THF. The resulting mixture was stirred at room temperature for 48 hours, then 0.10 ml of water was added, and the mixture was cooled in an ice bath. 0.1 ml of 15% sodium hydroxide and 0.3 ml of water are added. Then filter the suspension.
    dried on magnesium sulfate, washed with ethyl acetate and evaporated to give crystalline 2-decarboxy-2-aminomethyl-PCH d ((40 mg).
    The IR spectrum shows a characteristic absorption of 2700-3400 cm.
    The mass spectrum shows peaks at 450, 449, 408, 407, 390, 389, 348, 347 and 329.
    Example 2. 2-Decarboxy-2-aminomethyl-PCP, (Z means cis-CH CH- (CH2) s-;
    V -
    trans-CH-CH-; R
    and R,
     and R link L
    M units are all hydrogen; R denotes n-butyl-).
    Crude 2-decarboxy-2-azidomethyl-PGFjct (0.364 g) in 12 ml of diethyl ether is added with stirring to a suspension of lithium aluminum hydride (0.380 g) in 20 ml of diethyl ether. The reaction temperature is maintained at about 0 and continued to be added dropwise over 4 minutes. After addition is complete, the mixture is stirred at room temperature for 1.5 hours and placed in an ice-cold bath (0-5C). The excess reducing agent is removed by the addition of saturated sodium sulfate. After cessation of gas formation, the product obtained is coagulated with sodium sulfate, triturated with diethyl ether, and the solid salts are removed by filtration. The filtrate is dried with sodium sulfate, evaporated in vacuo to give 0.304 g of a pale yellow oil. The resulting oil (100 mg) is purified by thin-layer chromatography to obtain 42 g of 2-decarboxy-2-azidomethyl-PGF2j.
    NMR spectrum rf, MD: 0.90, 1.102, 80, 3.28.
    Example 3. 2-Decarboxy-2-methyl-aminomethyl-2-nop-PGF2ri (L is methyl; L means cis-CH CH- (CH2) C-
    RB-hydroxy; Y, means trans-CH CH-;
    H
    Rj and R
    the links M of the hero of L. and R.

    start all hydrogen; R-, means n-butyl).
    A. A mixture consisting of 2-carbomethoxyaminomethyl-2-decarboxy-2-HOp-PGF. (3.17 g), 30 ml of methylene chloride, 10 ml of double distilled dihydropyran in 2 ml of methylene chloride, saturated with chloride, pyridine, incubated for 16 h at room temperature. The mixture is then diluted with diethyl ether and quickly washed with ice-cold dilute hydrochloric acid solution, diluted with potassium carbonate and brine. The resulting mixture is then dried over magnesium sulfate and concentrated in vacuo. The residue (5.3 g) was subjected to chromatography on a silica gel column (500 g) containing 100 ml of 30% ethyl acetate in scelisolve B. The column was eluted with 30-50% ethyl acetate in skelezolve and pure 2-decarbox-2-carbomethoxyaminomethyl pure tris-tetrahydropyrannol ester was obtained. -2-nor-RSH (4.4 g). NMR spectrum 6 MD: 5.26-5.69, 4.52-4.8, 3.64 and 2.97-2.38. B. To a suspension of 5 g of lithium aluminum hydride in 250 ml of tetrahydrofuran are added 12 g of the reaction product obtained in A in 50 ml of benzene. The mixture is stirred and heated at boiling point for 24 hours and then cooled. A solution of 5 ml of water in 20 ml of tetrahydrofuran is then carefully added with stirring, followed by the addition of 20 ml of 10% aqueous sodium hydroxide solution. The resulting mixture is filtered and the filtrate is concentrated in vacuo to give 10.7 g of tris (tetrahydropyranyl ether) 2-decarboxy-2-methylaminomethyl-2-nor-PCG 1 C. The mixture of the product obtained according to B (0.6 g), 7 ml of acetic acid and 3 ml of water are stirred and heated to 20 hours. The resulting mixture is cooled and shaken with 50 ml of ethyl acetate and a mixture of 7 ml of a 50% aqueous solution of sodium hydroxide and 30 ml of ice water. The organic layer is washed with brine, dried, and concentrated in vacuo to obtain 0.3 g of residue. The residue is subjected to chromatography on a silica gel column with a solution of 1% ammonium hydroxide in methanol. Elute with the same solvent (1% ammonium hydroxide in methanol) and the fractions containing pure product are concentrated in vacuo. The residue obtained is mixed with ethyl acetate, filtered to remove traces of silica gel, and the filtrate is concentrated under reduced pressure to give 2 g of 2-decarboxy-2-methylaminomethyl-2-HOp-PGF 2. NMR spectrum (f, MD: 5.23-5 61, 3.4-3.7, 2.45-2.73 and 2.38 The mass spectrum shows the main peak at 627 and other peaks at 555, 484 466, 394, 217 and 173. Example 4, 2 - Decarboxy-2-dimethylaminomethyl-2-HOp-PGF2rf (L is methyl; means cis-CH CH- (CH2) is hydroxy, Y means trans-CH CH-; R and Kd are linked to L, j and R of the link " all hydrogen; -, - n-butyl.) A. To a mixture of 1.0 lithium aluminum hydride in 100 ml of tetrahydrofuran is added with stirring, a solution of 2.08 tris-tetrahydropyramyl ester of 2-decarboxy-2-carbmethoxime tylaminomethyl-2-Hop-PGF 2 g of benzene. The mixture is heated to boiling point for 20 hours and then cooled. With stirring, carefully add solution 1 ml of water and ml of tetrahydrofuran, after which 4 ml of a 10% aqueous solution of sodium hydroxide are added. The mixture is filtered and the filtrate is concentrated under reduced pressure to obtain 1.95 g of pure tris (tetrahydropyranyl ether) 2-decarboxy-2-diethylaminomethyl- 2-HOp-PGF cL NMR spectrum 5, m.d.: 5.25-5.67, 4.52-4.80 and 2.18. B. A mixture containing 8.6 g of the reaction product according to part A, 90 ml of acetic acid, 45 ml of water and 20 ml of methanol is stirred at 40 ° C for 20 hours. The mixture is cooled, diluted with ethyl acetate (800 ml) and the resulting mixture The mixture is washed with a mixture of 90 ml of 50% sodium hydroxide solution and 400 ml of ice water. The organic layer is washed with brine, dried and concentrated to give 5.3 g of residue. The latter is subjected to chromatography on a dryly packed column of silica gel moistened with a solution of 10 ml of concentrated ammonium hydroxide, 50 ml of methanol and 50 ml of chloroform. The column is eluted with 1% concentrated ammonium hydroxide and 15% methanol in chloroform, then 1% aqueous ammonium hydroxide and 25% methanol in chloroform. 2-decarboxy-2-dimethylaminomethyl-2-nop-PGF, (3.85 g) is obtained. Nuclear Magnetic Resonance Spectrum: cf, ppm: 5.23-5.60, 4.48 and 2.21. Example 5. 2-Decarboxy-2-aminomethyl-15-methyl-PGF 2ri. A. To a cold mixture (0 ° C) consisting of 3.68 g of 15-methyl-PGF 16 ml of tetrahydrofuran, 5 ml of water and 1.11 g of triethylamine are added with stirring 1.50 g of isobutyl chloroformate over 5 min After stirring the mixture, an excess of liquid ammonia is added for 25 minutes and stirring is continued for 3 hours. The resulting mixture is concentrated under reduced pressure, maintaining the bath temperature below 30 ° C, and the residue, which is dissolved in 125 ml of ethyl acetate and 7.5 ml of ethanol , washed with brine, dried and concentrated under reduced pressure. The resulting residue is then diluted with toluene and the solution is concentrated in vacuo to yield 3.6 g of amide 15-methyl PGF2d (NMR spectrum cf MD: 3.6, 3.59, and 5.3-5.6. B. K a mixture of 5.0 g of lithium aluminum hydride in 400 ml of tetrahydrofuran is added dropwise with stirring a solution of 3.6 g of the reaction product according to part A in 50 ml of tetrahydrofuran. The mixture is heated to boiling point for 16 h and then cooled to 0 ° C. The mixture 5 ml water and 40 ml THF cautiously (dropwise)
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing prostaglandin analogs of the general formula where D is
    OH ON i / R S%
    ώ '
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    同族专利:
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    引用文献:
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    US2166971A|1932-09-14|1939-07-25|Ig Farbenindustrie Ag|Production of amines|
    FR3124M|1961-02-02|Boots Pure Drug Co Ltd|
    US3647804A|1970-02-27|1972-03-07|Upjohn Co|Cycloalkanecarboxamides|
    US3852296A|1971-07-16|1974-12-03|Richardson Merrell Spa|Mannich bases of cyclopentanones and cyclopent-2-enones and process of preparing the same|
    US3987087A|1971-07-29|1976-10-19|The Upjohn Company|Phenyl-substituted prostaglandin-f type analogs|
    US3954741A|1972-06-07|1976-05-04|Pfizer Inc.|N-substituted prostaglandin carboxamides|
    US3987085A|1972-09-15|1976-10-19|The Upjohn Company|8β,11β,12α-PGF2.sub.α compounds|US4048058A|1975-08-13|1977-09-13|Standard Oil Company |Methods to be used in reforming processes employing multi-metallic catalysts|
    US4267315A|1979-05-01|1981-05-12|The Upjohn Company|2-Decarboxy-2-aminomethyl-11a-methano-TXA2 compounds|
    US4292445A|1980-04-28|1981-09-29|The Upjohn Company|Amide and sulfonamide derivatives of 2-decarboxy-2-aminomethyl-PG-type compounds|
    CA1241324A|1984-03-08|1988-08-30|Paul A. Aristoff|Interphenylene carbacyclin derivatives|
    JPH0121948Y2|1985-03-29|1989-06-29|
    US5270049A|1990-11-09|1993-12-14|Allergan, Inc.|2-decarboxyl-2-aminoalkyl-prostaglandins as ocular hypotensives|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US64527675A| true| 1975-12-29|1975-12-29|
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