• 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:
    Compounds which have the general formula (I> <IMAGE> wherein R is hydrogen, lower alkanoyl or <IMAGE> m is 1 or 2; n is 0 or 1; R1 is hydrogen or lower alkyl; R2 and R'2 each is hydrogen or halogen; R3 is hydrogen, lower alkyl or CF3, and also halogen when n is 1; R4 is hydrogen, lower alkyl or trifluoromethyl; R6 is hydrogen, and also halogen when m is 1; at least one of R2, R'2, R3, R4 and R6 being halogen or CF3 as represented by the symbols and only R2 and R'2 can both be halogen at the same time, and basic salts thereof may be used as hypotensive agents.
    公开号:SU882409A3
    申请号:SU802878653
    申请日:1980-02-04
    公开日:1981-11-15
    发明作者:Анджел Ондетти Мигуел；Витни Спрейг Питер
    申请人:Е.Р. Сквибб Энд Санз, Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the production of new derivatives of toacylproline of the general formula to methods mercap5
    VTs 3 . , I
    Hg-dH-cJH-Co-N — Coon 10 where R q is H or CFj at R 3 = H, Rj is H, lower alkyl, F, CFj · Rj and K 'are H, F, provided that one of Rj, R denotes 5 F, at R 3 - H, lower alkyl, which can be used as antihypertensive agents.
    t , 20 there is a known method for producing the corresponding mercaptans by hydrolysis of the corresponding esters of thiol carboxylic acids in an acidic or alkaline environment [11. 25
    The aim of the invention is to develop, on the basis of the known method, a method for producing new compounds with biological activity.
    The goal is achieved according to the method, which consists in the fact that the compounds of General formula
    IN"
    A * in 7 do - $ - dH-dH-do-: N - * - d un where Ry is lower alkyl, the values of R ^, R g , R 3 , Rq are indicated above, are subjected to acid hydrolysis or ammonolysis at room temperature .
    PRI me R 1. 1- (3-Acetylthio-2-trifluoromethylpropanoyl) -L-proline.
    1- (3-Acetylthio-2-trifto.rmethylpropanoyl) -L-proline tert-butyl ester (8 g) was dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After holding for one hour at room temperature, the solvent was distilled off in vacuo and the residue was precipitated several times from ether-hexane to give 1- (3-acetylthio-2-trifluoromethylpropanoyl) -L-proline, melting point 108-110 '(sintus 103 °) after fractional recrystallization from toluene, the rotation of the plane of polarization of GcSv is 110 °, MeOH 15 mg / ml.
    Example 2. 1- (3-Mercapto-4,4,4-trifluorobutanoyl) -L-proline.
    Thiolacetic acid (1.5 ml) was mixed with 1- (4, .4,4-trifluoro-2-butanoyl) -L-proline (720 mg, 3 mmol) in an argon gas atmosphere and the mixture was stirred overnight at room temperature. The excess thiolacetic acid was removed in vacuo and the residual 1 - (3-Acetylthio-4,4,4-trifluorobutanoyl) -1-proline was mixed with aqueous ammonia (15 ml of conc. NH + Ϊ5 ml of water) and stirred g at room temperature. Then the mixture was diluted with ice and acidified with concentrated hydrochloric acid. The acidic mixture was extracted with methylene chloride (3 x 50 ml), the extracts were dried over sodium sulfate and concentrated to give an oil. It is purified by dissolution in water (double distillate), the solution is treated with charcoal and filtered through a microporous filter (Millipore, first 0.4 μm, then 0.08 μm). Lyophilization of this solution gives 700 mg of 1- (3-Mescapto-4,4,4-trifluorobutanoyl) -L-proline as a colorless glass Rf (benzene: acetic acid 7: 1) 0.24.
    Example 3. Cis-4-fluoro-1- (D-3-mercapto-3-methylpropanoyl) -L-proline.
    Cis-1- (D-3- (acetylthio) -2-methylpropanoyl] -4-φτορ-ί-προπΗΗ (3.9 g, 0.014 mol) is hydrolyzed in 22 ml of water containing 9 ml of concentrated ammonium oxide hydrate. acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated to dryness to obtain 3.3 g of a glassy product, which slowly crystallizes upon drying at 0.2 mm and at 50 °. The material is triturated in 20 ml of ethyl acetate (with gentle heating under argon atmosphere) , diluted with 25 ml of hexane, tinder and cooled overnight (in argon atmosphere). filtration in an argon atmosphere, washing with hexane and drying under vacuum gives a colorless solid: cis-4-fluoro-1- (0-3-mercapto-2-methylpropanoyl) -L-npoline, weighing 2.8 g (85%) , mp 135137C (S, 129 °), U1d 116 ° (s = Newanol).
    Example 4. Trans-4-fluoro-1- (0-3-mercapto-2-methyl-1-oxopropyl) -Lf-proline. Argon is passed through a cold solution of 4.2 ml of concentrated ammonium hydroxide in 16 ml of water. To this solution, 1.8 g of trans-1-1D-3- (acetylthio) - are added, with stirring, in an argon atmosphere. -2-methyl-1-oxopropyl Z 4-fluoro-L-npoline. The reaction mixture was stirred for another 2 hours and then extracted with ethyl acetate, which was drained. The aqueous layer was stirred, 30 ml of ethyl acetate was added and the aqueous layer was acidified with concentrated hydrochloric acid. The aqueous layer was saturated with sodium chloride and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 30 ml). The mixed ethyl acetate extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired product, trans-4-fluoro -1- (0-3-mercapto-2-methyl-1-oxopropyl) -L-proline, ίΧΙ p 6 = 112 e (c = 1% in methanol).
    PRI me R 5. 4,4-Difluoro-1- (D-3-mercapto-2-methyl-1-oxopropyl) - L-proline. Argon is passed through a cold solution of 4.6 ml of concentrated ammonium hydroxide in 11 mn water. To this solution, 2.1 g of 1— [0-3— (acetylthio) -2-methyl-1-oxapropyl] -4,4-difluoro-L-proline are added with stirring in an argon atmosphere. The reaction mixture was stirred further * and then extracted with ethyl acetate, which was drained. The aqueous layer was stirred, 30 ml of ethyl acetate was added and the aqueous layer was acidified with concentrated hydrochloric acid. The aqueous layer was saturated with sodium chloride and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (3 x x 25 ml). The mixed ethyl acetate extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired product, 4,4-difluoro-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline in the form of a viscous, syrupy product, rotation of the plane of polarization [<£] о - 85 е , 1% in MeOH.
    Elementary analysis data for C 9 H / i F 2 N0 3 S
    Calculated,%: C 42.68, H 5.17, N 5.53, S 12.68.
    Found,%: C 42.59, H 5.49, N 5.62, S 12.41.
    The proposed compounds can be used as antihypertensive agents. They inhibit the conversion of decapeptide angiotensin 1 to angiotensin 11 and therefore can be used to reduce or alleviate hypertension associated with angiotensin. When the renin enzyme acts on the angiotensinogen, pseudoglobulin in the blood plasma, angiotensin 1 is formed. Angiotensin 1 is converted by the enzyme that converts angiotensin into angiotensin 11.
    权利要求:
    Claims (1)
    [1]
    1. Weigand - Hilgetag. Experimental methods in organic chemistry, M., Himi, 1968, p. 580.
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    同族专利:
    公开号 | 公开日
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    PL118158B1|1981-09-30|
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    DD141827A5|1980-05-21|
    IL56662D0|1979-05-31|
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    PH15381A|1982-12-17|
    SE431643B|1984-02-20|
    ES479833A1|1979-11-16|
    PT69254A|1979-03-01|
    FR2417499B1|1982-06-04|
    IE790297L|1979-08-21|
    PL213593A1|1980-02-25|
    JPS54125656A|1979-09-29|
    RO77228A|1981-08-17|
    CS230562B2|1984-08-13|
    GR82336B|1984-12-13|
    DK73379A|1979-08-22|
    CA1124723A|1982-06-01|
    LU80946A1|1979-06-18|
    FR2417499A1|1979-09-14|
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    HK41383A|1983-10-21|
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    NL7901319A|1979-08-23|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    AU509899B2|1976-02-13|1980-05-29|E.R. Squibb & Sons, Inc.|Proline derivatives and related compounds|CA1144930A|1978-08-11|1983-04-19|Menarini International Operations Luxembourg S.A.|Mercaptoacyl derivatives of substitutedprolines|
    NL7809120A|1978-09-07|1980-03-11|Oce Andeno B V Grubbenvorsterw|PROCESS FOR THE PREPARATION OF PROLINE DERIVATIVES.|
    US4483861A|1978-10-31|1984-11-20|Santen Pharmaceutical Co., Ltd.|Antihypertensive sulfur-containing compounds|
    CA1132985A|1978-12-22|1982-10-05|John Krapcho|Ketal and thioketal derivatives ofmercaptoacyl prolines|
    ZA802420B|1979-05-18|1981-04-29|Squibb & Sons Inc|Aminoacyl derivatives of mercaptoacyl amino acids|
    US4288368A|1979-07-30|1981-09-08|E. R. Squibb & Sons, Inc.|Dithioacylproline derivatives|
    AU542211B2|1980-03-07|1985-02-14|Gruppo Lepetit S.P.A.|Mercaptocycloalkyl carbonyl prolines|
    JP2005213165A|2004-01-28|2005-08-11|Mitsui Chemicals Inc|Method for producing fluoroproline compounds|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US87903278A| true| 1978-02-21|1978-02-21|
    US93914878A| true| 1978-09-01|1978-09-01|
    US05/939,147|US4154935A|1978-02-21|1978-09-01|Halogen substituted mercaptoacylamino acids|
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