• 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:
    Isoquinoline derivatives of the formula: <IMAGE> wherein R represents alkyl of 1 through 10 carbon atoms, which are new compounds, possess pharmacological properties and are particularly active as anti-inflammatory, analgesic and antipyretic agents.
    公开号:SU776560A3
    申请号:SU792720496
    申请日:1979-02-08
    公开日:1980-10-30
    发明作者:Фарж Даниель；Жоссен Ален；Понсине Жерар；Рейсдорф Даниель
    申请人:Рон-Пуленк Эндюстри (Фирма)；
    IPC主号:
    专利说明:

    ~ The invention relates to a method for producing new compounds 3- £ (3-alkyl-5-isoquinolyl) imino] -1,5,10,10a-tetrahydrothiaeolo | s, 4] isoquinolines $ of formula I in the form of individual isomers: · Or mixtures thereof, or their acid addition salts having pharmacological properties.
    A known method of producing derivatives of 3- (pyridylimino) -1,5,10,10ag-tetrahydrothiaeolo [3,4-b] isoquinoline by cyclization under heating in acidic medium of the corresponding derivative of N-pyridyl-3-hydroxymethyl-1,2,3,4 Tetrahydroisoquinoline-2-carbothioamide [1].
    These compounds are obtained as individual isomers or mixtures thereof, in free form or in the form of acid-addition salts.
    They have pharmacological properties, in particular analgesic, antipyretic and anti-inflammatory.
    . The aim of the invention is to obtain new substances that expand the arsenal of means of exposure to a living organism.
    This goal is achieved based on the fact that the compound is cyclized by - ~ ’heating in an acidic medium of the general formula II
    I
    the number of carbon atoms is 1 to 10, and the target product is isolated in the form of individual isomers or their mixtures, in free form or in the form of acid addition salts.
    It is especially advisable to work at a temperature of 65 to 100 ° C in the known reaction £ 1] ^ 2] by the method of βθ aqueous solution of inorganic acid
    R is alkyl from the genus of
    lots, for example, hydrochloric, with a concentration of 4 to 8 and.
    1,2,3, 4-tetra gyZh ^> c ^ zo yodaO I "'^: the general formula II can be obtained and the action of the total isothiocyanate The formula
    in which R has the above meaning, to 3-hydroxymethyl-1,2,3,4-tetrahydrois oxy noli and formula IV
    CH g OH
    Typically, the reaction is carried out in an organic solvent such as alcohol, for example ethyl alcohol, operating at 2050 ° C. .
    Z-hydroxymethyl — 1,2,3,4-tetrahydroisoquinoline can be prepared starting from phenylalanine.
    If L-phenylalanine is used, then the product of the general formula I is obtained in the form [$].
    If D-phenylalanine is used, the product of the general formula I is obtained in the form (R).
    If D, L-phenylalanine is used, the product of the general formula I is obtained in the form [R, S].
    Isothiocyanate of general formula III can be obtained by condensation of seros with 5-aminoisoquinoline of general formula V
    in which R has the above meaning, followed by the addition of dicyclohexylcarbodiimide.
    condensation is usually carried out in the presence of a base such as a tertiary amine, for example triethylamine. It is advisable to work in an organic solvent, for example in pyridine, at a temperature of from -10 to + 25 ° C.
    New products according to the invention can be converted into acid addition salts. Additive salts may be prepared by exposing the product to acids in suitable solvents. As organic solvents, for example, alcohols, ketones, ethers or chlorinated hydrocarbons are used. Salk; precipitated after concentration of its solution, separated by filtration or decantation.
    New products of the general formula and / or their salts can be purified, if necessary, by conventional physical methods, for example, crystallization or chromatography.
    The new products of the invention and their salts are particularly interesting anti-inflammatory, analgesic and antipyretic agents.
    . Anti-inflammatory activity in 3 rats occurs with oral doses
    5-80 mg / kg.
    Analgesic activity appears in rats at oral doses. 2.5-50 mg / kg.
    Antipyretic activity in rats at oral doses
    1.5 -25 mg / kg. '
    In addition, the toxicity of products for mice is higher than 300 mg / kg at 15 oral doses and most products do not show signs of toxicity in mice at oral doses. 900 mg / kg.
    For medical use, the new 20 compounds are used in the form of bases or in the form of pharmaceutically acceptable salts, i.e., non-toxic in the doses used. . ,
    Of particular interest are the products of general formula 1, in which R * is alkyl containing from 1 to 5 carbon atoms with a linear or branched chain, and among them are especially active products in which R-alkyl is containing from 1 to 4 carbon atoms. 30 The following examples, given without limitation, show how the invention can be practiced.
    Example!. Suspension 12.1 g of 35 N - (3-ethyl-5-isoquinolyl) -3-hydroxymethyl ~.
    -1,2,3,4 ~ tetrahydroisoquinolyl-2-carbothioamide (S) in 100 ml of 6 N hydrochloric acid is heated for 1 hour at a temperature of 100 ° C, the resulting solution is cooled, and then it is concentrated under reduced pressure (20 mm Hg) up to 1/3 of the original volume. The solution was made basic with 100 ml of 4 N sodium hydroxide solution and extracted with 100 ml of chloris45 of methylene three times. The organic extracts were combined and dried over magnesium sulfate. After filtering and concentrating to dryness the filtrate under reduced pressure (25 mmHg) at 40 ° С, the residue is recrystallized from 100 mp ethanol and obtained after drying at 60 ° С under reduced pressure (1 mmHg) 7.0 g 3-C-ethyl-5-i-oquinolyl-amines (D) -1,5,10,10a-tetrahydro55 thiaeolo [h, 4, -b] isoquinoline- (S) in the form of yellow crystals having so pl. 140 ° C.
    N- (3-Ethyl-5-isoquinolyl) -oxymethyl-1,2,3,4, -tetrahydroisoquinolyl-2-car4Q botioamide- (S) can be prepared by the following method.
    To a solution of 5.3 g of 3-hydroxymethyl-1,2,
    3,4-tetra hydroisoquinol and na- (S) in 100 ml of ethanol add 6.9 g of 3-ethyl-545 isothiocyanathiooquinoline, the reaction mixture is kept for 20 hours at a temperature of about 20 ° C, after which it is distilled off to dryness under reduced pressure ( 20 mmHg) and a temperature of 40 ° C. The residue is crushed in isopropyl oxide, thus obtaining the way ι
    12.1 g of N- (3-ethyl-5-isoquinolyl) -3-hydroxy- * methyl-1,2,3,4-τetrahydroisoxinolin-2 ~ carbo-thioamide- (S) as a brown solid, which is used hereinafter Directly without cleaning. YU
    3-Ethyl-5-iethiocyanatisoquinoline1 was prepared as follows.
    To a solution of 4.0 g of triethylamine, 16 ml of carbon disulfide in 15 mp pyridine is added dropwise with stirring at 15 ° C at a temperature of about -10 ° C. A solution of 7.0 g
    5-amino-3-ethylisoquinoline in 30 mp pyridine. The reaction mixture was kept for 4 hours at the indicated temperature, after which a solution of 8.5 g of N, ди-dicyclohexylcarbodiimide in 15 ml of pyridine was added dropwise to it. The reaction mixture is stirred for 3 hours, while its temperature gradually rises from -10 to + 20 ° C, after which it is left for 20 hours at a temperature of about 20 ° C. The solvent is distilled off to dryness under reduced pressure (20 mmHg) at 40 ° C, the residue is taken up with 150 mp of methylene chloride, the insoluble residue is separated by filtration and washed with 15 ml of methylene chloride, after which the filtrate is distilled off to dryness under reduced pressure. pressure (20 mmHg) at 40 ° C. The solid residue is crushed, in 150 mp · 35 isopropyl oxide, the insoluble fraction is separated by filtration, the filtrate is distilled off to dryness under reduced pressure (20 mm Hg) at 40 ° C.
    The residue is a resinous 4Q different yellow substance and weighs 6.9 g; it consists of 3-ethyl-5-isothiocyanatisoquinoline; 5556 ° C, after recrystallization from petroleum ether. .
    Carrying out the same operations and starting from the corresponding starting materials, it is possible to obtain in this way.
    Example 2. 3- [(3-Methyl-5-isoquinolyl) -imino] -1,5,10,10a-tetrahydrothiaeolo [3,4-bj isoquinoline- (S) mp. 181 ° C.
    Example 3. 3- £ (3-Methyl-5-isoquinolyl) -imino -1,5,10,10a-tetrahydrothiazolilo [h, 4-b] isoquinoline- (R, S) with so pl. 159 ° C. '5
    Example 4.3 [(3-Butyl-5-isoquinolyl) imino] -1,5,10,10a-tetrahydrothiazolo (3,4-b] isoquinoline- (S), mp 82 ° C.
    Example 5. 3- [(3-Propyl-5-isoquinolyl) -imino] -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolyl- (S) m.p. 95-96 ° C.
    Example 6. 3 - [(3-Octyl-5-isoquinolyl) -imino] -1,5,10,10a-tetrahydro-thiazolo ^ 3, 4-b] isoquinoline- (S) with so pl. 112 ° C (neutral fumarate).
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining 3- £ (3-alkyl-5-isoquinolyl) -imino-1,5,10,10a-tetrahydrothiazolo (3,4-y-isoquinolines of the general formula 1 in which R-alkyl with carbon atoms from 1 up to 10, in the form of individual isomers or a mixture thereof, or their acid addition salts, characterized in that the compound of general formula II in which -R has the indicated meaning is cyclized when heated in an acidic medium, and the target product is isolated as individual isomers or their mixtures, in free form or in the form of acid addition salts.
    [2]
    2. The method according to claim 1, which requires heating to a temperature of 65-100 ° C in the presence of an inorganic acid with a concentration of 4 to 8 N.
    Priority on the grounds of 01.20.77 with R-methyl.
    12/23/77 at R-alkyl with the number of carbon atoms from 2 to 10.
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NL169076C|1975-08-06|1982-06-01|Rhone Poulenc Ind|METHOD FOR PREPARING OR MANUFACTURING PHARMACOLOGICAL PREPARATIONS WITH ANALGETIC AND ANTIPYRETIC ACTION, AND METHOD FOR PREPARING MEDICINAL COMPOUNDS, SUITABLE FOR USE IN SUCH PREPARATIONS|SU797580A3|1977-11-10|1981-01-15|Рон-Пуленк Эндюстри |Method of preparing isoquinoline derivatives, their salts, racemates or optical isomers|
    NL8002540A|1979-05-09|1980-11-11|Rhone Poulenc Ind|NEW ISOCHINOLINE DERIVATIVES, METHODS FOR PREPARING THEM AND PHARMACEUTICAL PREPARATIONS CONTAINING THE NEW DERIVATIVES.|
    FR2456098B2|1977-12-23|1982-05-21|Rhone Poulenc Ind|
    NL7908655A|1978-12-07|1980-06-10|Rhone Poulenc Ind|NEW THIENOPYRIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE NEW DERIVATIVES.|
    FR2456111B1|1979-05-09|1982-05-21|Rhone Poulenc Ind|
    EP0030198B1|1979-12-04|1983-03-02|Rhone-Poulenc Sante|Isoquinoline derivatives, their preparation and pharmaceutical compositions containing them|
    US4269842A|1979-12-05|1981-05-26|Rhone-Poulenc Industries|Method for treating rhinoviral complaints|
    US6582728B1|1992-07-08|2003-06-24|Inhale Therapeutic Systems, Inc.|Spray drying of macromolecules to produce inhaleable dry powders|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7701516A|FR2378030B1|1977-01-20|1977-01-20|
    FR7739028A|FR2412545B1|1977-12-23|1977-12-23|
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