• 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:
    A process for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains comprising reacting an oxophthalizinyl acetic acid ester with an aniline derivative is disclosed. Also disclosed are processes for the preparation of such oxophthalizinyl esters.
    公开号:SU1678208A3
    申请号:SU884355901
    申请日:1988-06-08
    公开日:1991-09-15
    发明作者:Лакшмана Милари Банавара；Джеймс Зембровски Вилльям
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    Example 1: Ethyl-3- (5-trifluoromethyl-benzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-yl acetate.
    A, A mixture of ethyl 3-zmenomethyl-4-oxo-3H-talazi-1-ylacetate (2.71 g), 2-amino-4-rifluoro-methyl-thiophenol hydrochloride 2.40 g) m ethanol (20 ml) is subjected reflux for 8 hours, a T precipitate, obtained by cooling, is separated by filtration and the collected solid is dried with air to obtain the desired compound (yield 4.3 g; mp. 136 ° C),
    B. A mixture of ethyl 3-cyanomethyl-4-oxo-ZN-phthalazin-1-yl-acetate (0.27 g) and 2-amino-4-trifluoromethylthiophenol hydrochloride (0.23 g) is heated to mp, 180 ° C, which is held for 10 minutes. The motive fluid is cooled and then suspended in water. Filtration of the mixture gives the desired compound a yield of 75%.
    Example 2. Ethyl 3- (5,7-difluorobenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazine-1 acetate.
    A mixture of ethyl 13-ciaiomethyl-4-oxo-ZN-phthalazin-1-ylacetate (1.29 g), -2-amino-4, b-difluorothiophenol hydrochloride (0.98 g) and ethanol (20 ml) is refluxed in for 6 hours. After cooling, the title compound precipitates as a pale yellow solid (yield 1.62 g; mp. 115-117 ° C).
    EXAMPLE 3, 3- (5-Trifluoromegylbenzothiazol-2-ylmethyl - (- 4-oxo-3H-phthalazin-1-ml-acetic acid.
    A. A mixture of ethyl 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl-acetate (5.0 g), methanol (60 ml), tetrahydrofuran (30 ml) ml) and a 10% aqueous solution of potassium hydroxide (20 ml) is stirred for 10 minutes at room temperature. The solution is concentrated to a volume of 20 ml and then diluted with water (50 ml). The resulting solution is acidified to about pH 4.0 by the addition of a sufficient amount of a 10% HCI solution. The precipitated off-white solid is collected and air dried (yield 4.8 g; mp. 197-198 ° C).
    B A mixture of ethyl 3-cyanomethyl-4-oxo-3N- "β-stalysin-1-ylacetate (2.71 g), 2-amino-4-triFluoromethylthiophenol hydrochloride (2.40 g) and ethanol (20 ml) is refluxed for nights The reaction mixture is cooled to 40 ° C and tetrahydrofuran (10 ml) and a 5% potassium hydroxide aqueous solution (10 ml) are added to it. The mixture was stirred for 1 hour at room temperature and the solvents were removed by evaporation. The residue is diluted with water (50 ml) and the resulting solution is extracted with ether (20 ml). The main aqueous layer is collected and acidified to about
    pH 4.0 by adding a sufficient amount of a 10% solution of HC, The precipitated solid is collected and dried in air (yield 3.68 g; mp. 197-198 ° C).
    For example. 3- (5,7-Difluorobenzothiazol2-ylmethyl) -4-oxo-3H-phthalazin-1-yluxus - pa acid,
    Ethyl 3- (5,7-difluorobenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-ylacetate (1.0 g) is hydrolyzed in the same way as in example
    3, A. Obtain the target compound (so pl. 178 ° C).
    five
    PR-and MIR 5. 3- (5-Trifluoromethylbenzothiazol-2-ylethyl) -4-oxo-ZN-phthalazin-1-yl acetic acid,
    A mixture of ethyl 3-cyanoethyl-4-oxo-3H-phta-lasine-1-ylacetate (2.71 g), 2-amino-4-trifluoro-methylthiophenol hydrochloride (2.29 g) and ethanol (20 ml) is refluxed during the night. The crude product obtained after evaporation of ethanop is purified using chromatography on silica gel, eluting with a mixture of hexane and tetrahydrofuran (4: 1). The resulting white solid (0.3 g) is used directly in the next step, which consists in dissolving this compound in ethanol (20 ml) containing 5% aqueous solution of KCl (2 ml) and stirring at room temperature for 2 The ethanol is evaporated, the residue is diluted with water (10 ml), extracted with ether (2 x 10 ml) and the aqueous extract is acidified to pH 2.0. The precipitated solid is collected and then crystallized from ethanol (yield 0.12 g, mp. 184-185 ° C).
    0
    five
    Example 6, Step 1, Ethyl 3 hydrochloride (ethyl acetate imidate) -4-oxo-3H-phthalazin-1-ylacetate.
    Dry hydrogen chloride (in gaseous form) is passed for 5 minutes through a solution of 3-cyanomethyl-4-oxo-3H-phta-lasine-1-ylacetate (27.1) in dry tetrahydrofuran (200 ml) and absolute ethanol (5, 9 ml). A precipitate formed after the reaction mixture was kept at a room temperature, overnight, and separated by filtration. Get the target product
    (13.05 g, mp. 208-210 ° C).
    Step 2. Ethyl-3 (5-trifluoromethyl-benzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-ylacetate,
    A mixture of ethyl 3- (ethylacetamidate) -4-oxo-3H-phthalazine hydrochloride, 1-l l acetate (0.35 g) and 2-amino-5-trifluoromethylthiophenol hydrochloride (0.23 g) in toluene (20 ml ) is refluxed for 16 hours. The precipitate obtained during cooling is crystallized from ethanol, as a result of which the desired product is obtained (mp. 136 ° C).
    Similarly, the compounds of Examples 7-33 shown in the table are prepared.
    The ability of the compounds obtained by the proposed method to inhibit aldose reduction was studied in experiments in vitro.
    Comparisons were made with the closest analogue in structure and action - 2- (4-bromobenzyl} -1,2-dihydro-1-oxophthalazine-4-yl-acetic acid.
    In vitro testing method.
    Enzyme preparation.
    Aldosreductase (AP) is partially purified from human placenta using the modified Hyman and Kinoshita method described for rat eye lenses. Freshly received placentas are homogenized in 3 volumes of a 0.1 molar potassium phosphate buffer solution with a pH of 7.0, which contains 5 mol of 2-mercaptoethanol, and rotated in a centrifuge for 20; min at 4 ° C and acceleration 33000 xg (9.8 m2 / s). The combined supernatants from the previous steps are fractionated with 30-75% ammonium sulfate. The resulting tablets are resuspended together in a minimum volume of buffer and dialyzed overnight. The dialysis product is purified by chromatography on a DEAE-cellulose column, and the aldose reductase is eluted with a linear gradient of sodium chloride (0-1 mol / l). Peak fractions containing active aldose reductase are combined, and their eliquot solutions are stored in a frozen state. This technique leads to a preparation that is enriched more than 30 times in the activity of aldose reductase.
    Conduct testing.
    An aldose reductase was tested on a Abchbromatic Clinical Analyzer Abbot Wi-Pi by measuring the decrease in the oxidation rate of nicotinamide dihydropyridine (NADHP) at 24 ° C for 10 minutes at a wavelength of 340 nm. The unit of aldose reduction is defined as 1 micromole of NADHP, which is oxidized at 25 ° C per minute with dl-glyceraldehyde as a substrate. Subjects are evaluated at various concentrations. Results are reported as percent inhibition of the control oxidation rate of NADHP.
    Test conditions.
    The aldose reductase is tested in 0.25 ml of a buffer solution (50 mmol / l) of potassium phosphate, pH 7.1, which contains 400 mmol / l of ammonium sulfate, 0.067 mmol / l of NADHP and 0.5 mmol / l of dl-glyceraldehyde. Enough enzyme is added to provide an NADHP oxidation rate of 4 honey. within 10 min.
    The test results are presented in the table (efficacy of an aldose reduction inhibitory effect is expressed as a molar concentration of inhibition of 50%: 1 Xbo (mol ph).
    The inhibition concentration (by 50%) of the compound to be compared - 2- {4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl-acetic acid - 1.0 mol / L.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 3- (benzothiazol-2-ylalkyl) -4-oxo-3H-phthalazic-1-acetic acid derivatives or (and alkyl esters of the formula I O
    C-orj
    (about R2s R6
    where RI is a hydrogen atom or Ci-Gj-alkyl;
    R2 is a hydrogen atom or methyl;
    n 0 or 1;
    R3 and RA, the same or different, are a hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl, C1-C4 alkyl, Ci-Ci-alkoxy, or nitro;
    Rs and Re, the same or different, is a hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl, CrC 3 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or nitro, characterized in that the compounds of the formula II
    about
    g
    N
    N-CH2-fcH2) fi-Q
    About R2
    where R2, n, Rs and R4 have the indicated values RI is CrCd-alkyl; Q is a cyano group or a group of the formula
    OR-,
    in which RT-C- | -C4-alkyl, or its additive salt with hydrohalic acid, reacts with the additive
    R
    ; NH
    salt with hydrohalic acid compounds of formula I
    -Re
    H2N HS
    during reflux and, if necessary, the desired product obtained as an alkyl ester is subjected to hydrolysis to give RS and Re as indicated, in the 5th desired product, in which RI is a melt atom or s organic hydrogen solvent.
    V
    at reflux and, if necessary, the desired product obtained as an alkyl ester is subjected to hydrolysis to obtain
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    同族专利:
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    引用文献:
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    IE47592B1|1977-12-29|1984-05-02|Ici Ltd|Enzyme inhibitory phthalazin-4-ylacetic acid derivatives, pharmaceutical compositions thereof,and process for their manufacture|
    JPS5931509B2|1979-06-06|1984-08-02|Showa Denko Kk|
    IL80475A|1985-11-07|1993-01-31|Pfizer|Heterocyclic-substituted 4-oxo -3h- phthalazinyl-acetic acid derivatives and pharmaceutical compositions containing them|EP0322153A3|1987-12-21|1990-08-16|Pfizer Inc.|Heterocyclic oxophtalazinyl acetic acids|
    WO1989006651A1|1988-01-19|1989-07-27|Pfizer Inc.|1h-indazole-3-acetic acids as aldose reductase inhibitors|
    US4904782A|1988-02-29|1990-02-27|Pfizer Inc.|Process for the production of phthalazineacetic acid ester derivatives and a novel intermediate|
    US4954629A|1989-05-11|1990-09-04|Pfizer Inc.|Process and intermediates for the preparation of oxophthalazinyl acetic acids and analogs thereof|
    FR2647676A1|1989-06-05|1990-12-07|Union Pharma Scient Appl|New pyridazinone derivatives, processes for preparing them and medicaments containing them which are useful, in particular, as aldose reductase inhibitors|
    US5304557A|1989-12-15|1994-04-19|Pfizer Inc.|Substituted oxoophthalazinyl acetic acids and analogs thereof|
    US5064830A|1990-08-02|1991-11-12|Pfizer Inc.|Lowering of blood uric acid levels|
    WO1992003432A1|1990-08-28|1992-03-05|Pfizer Inc.|3--4-oxo-3h-phythalazin-1-ylacetic acid monohydrate|
    EP0582643A1|1991-03-28|1994-02-16|Pfizer Inc.|Pyridazinone acetic acids|
    FR2682108B1|1991-10-07|1994-01-07|Lipha|3,4-DIHYDRO-4-OXO-3-1-PHTHALAZINEACETICS AND DERIVATIVES, THEIR PREPARATIONS AND MEDICINES CONTAINING THEM.|
    DE69405193T2|1993-10-06|1998-01-02|Sumika Fine Chemicals Co Ltd|Process for the preparation of alkyl 3-phthalidylidene acetate|
    US5700819A|1994-11-29|1997-12-23|Grelan Pharmaceutical Co., Ltd.|2-substituted benzothiazole derivatives and prophylactic and therapeutic agents for the treatment of diabetic complications|
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    法律状态:
    优先权:
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    US5989987A| true| 1987-06-09|1987-06-09|
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