WO1988007041A1 - Derives d'isoquinoline, fabrication et utilisation - Google Patents

Derives d'isoquinoline, fabrication et utilisation Download PDF

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Publication number
WO1988007041A1
WO1988007041A1 PCT/FI1987/000032 FI8700032W WO8807041A1 WO 1988007041 A1 WO1988007041 A1 WO 1988007041A1 FI 8700032 W FI8700032 W FI 8700032W WO 8807041 A1 WO8807041 A1 WO 8807041A1
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WO
WIPO (PCT)
Prior art keywords
pyridyl
dihydroisoquinoline
hydrogen
formula
group
Prior art date
Application number
PCT/FI1987/000032
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English (en)
Inventor
Hannu Allonen
Hannu Nikander
Original Assignee
Huhtamäki Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Huhtamäki Oy filed Critical Huhtamäki Oy
Priority to PCT/FI1987/000032 priority Critical patent/WO1988007041A1/fr
Priority to EP87902089A priority patent/EP0351399A1/fr
Publication of WO1988007041A1 publication Critical patent/WO1988007041A1/fr
Priority to NO1988885020A priority patent/NO885020D0/no
Priority to DK632988A priority patent/DK632988D0/da
Priority to FI894086A priority patent/FI894086A0/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Isoquinoline derivatives having a pyridyl group which include substitutes in the 1-position are described in Japanese publications (e.g. Yakugski Zasshi: 87(9), 1083 - 1088 (1967) and in patent specifications JP 70 03,782, JP 68 08,277 and Japan Tokyo Koho 58 26,350).
  • the described compounds however include solely non-substituted pyridyl groups or pyridyl meth groups.
  • This invention relates to 1-substituted isoquinolines of the general formula I or I'
  • R 1 and R 2 are the same or different and designate hydrogen, halogen, an hydroxyl group or a C 1 -C 4 alkoxy group,
  • R 3 hydrogen when R 1 and R 2 are hydrogen, or halogen, or a C 1 -C 6 alkyl group,
  • R 4 halogen, C 1 -C 6 alkyl or alkoxy group, or refers to an amino group of the formula
  • the compounds having formula 1 are of particular interest inhere n is 0,
  • R 3 and R 4 are hydrogen, halogen, or an alkoxy group having 1-4 carbon atoms.
  • the compounds of formula I can be produced according to the Bischler-Napieralskis reaction.
  • an amide is cyclized with Lewis acid.
  • This amide has been produced from substituted 2-phenylethyl amine and a suitable pyridine carboxylic acid, an ester of a pyridine carboxylic acid or pyridine carboxylic acid chloride according to reactions described in the literature.
  • Bischler-Napieralskis reaction
  • the condensing agent used in the reaction may suitably be phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus pentoxide, boron trifluoride, tin tetrachloride, although strong mineral acids, such as sulphuric acid and polyphosphoric acid may also be used.
  • Phosphorus oxychloride and phosphorus pentoxide are particularly suitable in this regard
  • Cyclization can be effected with or without a solvent. All solvents which will dissolve the reaction components and which have a sufficiently high boiling point can be used. Good solvents in this regard are, for instance, toluene, chloroform, actonitrile and xylene.
  • the actual cyclizing agent e.g. phosphorus oxychloride, may itself be used as a solvent.
  • reaction temperature is not critical and the reaction can be carried out within a wide temperature range, although most suitably while warming or heating the system to the boiling point of the solvent.
  • 3.4-Dihydroisoquinolines (I) can also be produced, for instance by:
  • phenethyl derivative e.g. phenethyl halide
  • a suitable phenethyl derivative e.g. phenethyl halide
  • a nitrile-tin tetrachloride complex Cnem. Ber. 94,199 (1961); Tetrah. Lett. 225 (1965)
  • phenethyl isocyanide Tetrah. Lett. 5389 (1985)
  • halogen-substituted aryl halogenides e.g. a lithium compound obtained through a halogen metal exchange reaction with a suitable nitrile (Tetrah. Lett. 4145 (1977))
  • 1.2.3.4-Tetrahydro-isoquinolines (3) can be produced, e.g. by: I) effecting a Grignard or Reissert reaction with isoquinolines (13) (Adv. Heterocyclic Chem. 24, 187 (1979); Chem. Pharm. Bull. 29, 1848 (1981); J. Org. Chem. 48, 1621 (1983)) J) effecting, e.g., a Grignard reaction with 3.4-dihydroisoquinoline (14) (compare the references in I) K) cyclizing benzyl amine or N-substituted benzyl amine (15,
  • Suitable acids for binding salt are, for instance, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid and corresponding acids.
  • the activity of the pyridine derivatives have been examined in vitro with preparations of smooth muscles (guinea-pig trachea or windpipe preparations and the thoracic aorta of rabbits) and the cardiac atrium or auricle guinea-pigs preparations. These derivatives have been found to possess properties wh.ich widen their pharmacological use.
  • the betaadrenergic activity of those pyridyl derivatives which are most active pharmacologically have been measured with the aid of receptor binding processes carried out in vitro.
  • guinea-pigs are highly responsive to the contracting effect of the histamine on bronchi
  • guinea-pigs of both sexes weighing from 300-400 g were used in the investigations ( Duncin-Hartley, Pigment). Since tracheae are easier to separate and exhibit the same reactions as the bronchi to contracting and relaxing agents, trachea preparations were used in the tests instead of bronchi smooth or unstriated muscle.
  • the trachea of the dead animal was prepared and two zig-zag preparations were produced by a method according to Emmerson and Mackay (1979).
  • the preparations were from 20 to 22 mm in length and were transferred to incubating dishes which contained nutrient solution oxidized with carbogen (Krebs-Henseleit).
  • the solution had a pH of 7.4 and a temperature o f 37 o C .
  • Th e o ther en d of th e preparat i on was at tac he d to an isotonic myograph-indicator, which registered changes in length of the preparation during contraction and relaxation thereof.
  • Table 1 The relaxing effect of the derivatives on the smooth muscle of guineapig tracheae, where contraction has been induced with histamines (2 ⁇ mole/l) and which resulted in a 50-60%-contraction in relation to the maximum contraction of the preparation.
  • ED 50 is the concentration of the examined derivative resulting in a 50%-reduction in the induced contraction, n designates the number of measurement/ derivatives.
  • Theoohylline HCl 7 94.4 The test values show that the broncho-dilation effect of all derivatives, with the exception of 1204, are at least of the same magnitude as that of theophylline in vitro.
  • the most active derivatives are 1217, 1209 and 1212. Their activity is from 2 to 3 times greater than that of papaverine and from 60 to 135 times greater than that of theophylline. The results thus show that the compounds listed in the table had a pronounced bronchi-dilating effect when tested in vitro on the smooth muscle of guinea-pigs.
  • vasodilational effect of the pyridyl derivatives has been tested in vitro on thoracic aorta preparations from rabbits.
  • the tests were carried out on rabbits of both sexes and weighing from 2-2.5 kg (New Zealand White).
  • the thoracic aorta of the dead animal was quickly prepared, removed and transferred to a petri-dish containing an oxidized Krebs-Hanseleit solution.
  • a helical preparation (length 20-22 mm, breadth 2-3 mm) was than prepared in accordance with a method proposed by Furchgott & Bhadrakom (1953).
  • the incubation dish had a volumetric capacity of 30 ml.
  • One end of the preparation was attached to a bronchial tube and the other to an isotonic myograph indicator. The measuring results were obtained isotonically, after the tonus of the preparation had stabilized, a period of 60 minutes.
  • the ED 50 -value of the noradrenaline for each preparation i.e. the amount of noradrenaline which results in a 50%-contraction of the preparation, was calculated with the aid of linear regression from the response curve drawn up for the noradrenaline dosing. This measurement was then repeated, by first placing the derivative to be examined into the dish and allowing the derivative to react for a period of 10 minutes. A preparation response curve for the noradrenaline dosage was then drawn up, as in the earlier case. The dosage relationships were then determined in accordance with the following formula, subsequent to calculating the ED 50 -value of noradrenaline in the presence of the test derivatives:
  • the formula shows at which test-derivative concentration a ratio in the proximity of 4 (four) is reached, i.e. how effectively each of the derivatives displaces the response curve for the dosing of noradrenaline to the right.
  • Table 2 The relaxing effect of the pyridyl derivatives on the smooth muscle of the thoracic aorta of a rabbit when contracting of the muscle preparation is induced with noradrenaline.
  • the derivatives 185, 1208 and 1209 had an effect corresponding to that of the papaverine, the vasodilationary effect of the derivative 185 being ten times more effective than that of the papaverine. These derivatives also had a relaxing effect on the smooth muscle of the blood vessels.
  • the beta-receptor activity of the most active bronchi-dilating derivatives 1209 and 1217 was measured by a receptor binding method in vitro with the aid of iodocyanopindolol (125 ICYP) as a radio-active ligand and lung membrane from guinea-pigs as the beta-receptor sources.
  • the membrane receptor preparations or compounds were prepared by, and the actual bonding tests carried out in accordance with a method described by Engels working group (1981), although with certain minor modifications.
  • the membrane ligand with bound ligands was isolated by filtration and the radioactivity calculated with a gamma counter. The ability of these compounds to compete with the radioligands for binding to the beta-receptors was determined by incubating the test derivative in different concentrations.
  • the IC 50 - value indicates the test derivative concentration which inhibits 50%-bonding of the radioligand, this value being calculated by linear regression subsequent to 3 logit-log conversion of the binding results.
  • the IC 50 -values calculated were 1.2 x 10 -3 M in the case of 1209 and 0.4 x 10 -3 in the case of 1217 and the Hill-constant deviated markedly from 1, and was 1.84 in the case of 1209 and 1.81 in the case of 127 when the correlation constants of the regression lines were 1.00 and 0.95 respectively. No appreciable binding to beta-3 receptors could be shown.
  • the isoprenaline increased the beat frequency of the avricle preparation with a maximum change at a concentration of 1 ⁇ mole/l.
  • 5-Bromonicotinic acid (10 g, 0.05 mole) was admixed with 100 methanol and the mixture heated to almost boiling point. 3.5 of thionylchloride were added to the mixture over a period of 15 minutes. The mixture was reflux boiled for 3 hours, and then cooled and the solvent removed under vacuum. The solid residue was redissolved in a small amount of methanol, neutralized with trethylamine and the solvents vaporized off. The ester was extracted from the evaporation residue with diisopropyl ether. The yield was 10.7 g (99%).
  • the oily amide was dissolved in 50 ml of toluene and 10 ml of phosphorus oxychloride were added to the solution. The mixture was boiled under reflux for four hours, cooled and the solvent oecanted off. The tough residue was washed with hexane, to remove non-reacted phosphorus oxychloride, and dissolved in a 25%-ethanol solution and was basified with an NaOH-solution. The product was extracted with diisopropyl ether. The yield was 6.4 g.
  • the title compound was produced from methyl-2-chloronicotinat (6.8 g, 0.04 mole) and homoveratryl amine (7.8 g, 0.043 mole).
  • Tne title compound was produced from methy 1-6-chloronicotinate (7.0 g, 0.041 mole) and homoveratryl amine (7.9 g, 0.044 mole).
  • the title compound was produced from methy 1-2-chloronicotinate (7.2 g, 0.044 mole) and 2-(4-methoxyphenyl)-ethylamine (8.5 g, 0.056 mole).
  • the title compound was prepared from methyl-2-chloronicotinate (7.5 g, 0.044 mole) and 2-(2-methoxyohenyl)-etnyl amine (8.5 g, 0.056 mole)
  • the title compound was prepared from methyl-5-bromonicotinate (5.0 g, 0.023 mole) and 2-(4-methoxy phenyl)-ethyl amine (4.0 g, 0.026 mole)
  • Tne title comcound was produced from methy 1-5-bromonicotinate
  • the title compound was produced from methyl-2-hydroxy-6-methylnicotinate (4.0 g, 0.024 mole) and homoveratryl amine (4.8 g, 0.026 mole). (POCl 3 as condensing agent)
  • the title compound was produced from methyl-5-bromonicotinate (4.0 g, 0.0185 mole) and 2-(3.4-diethoxy phenyl)-ethyl amine (4.0 g, 0.019 mole).
  • the title compound was produced from methyl-2.6-dichloronicotinate (2.5 g, 0.012 mole) and homoveratryl amine (2.8 g, 0.016 mole).
  • the title compound was produced from the methyl ester of fusaric acid (4.5 g, 0.023 mole) and homoveratryl amid (5.0 g, 0.028 mole).
  • the title compound was produced from methyl-2.6-dichloroisonicotinate (2.5 g, 0.012 mole) and homoveratryl amine (4.3 g, 0.024 mole)
  • Example 15 1 (2-(2'-(3.4-Dimethoxy phenyl)-ethyl-amino-3-pyridyl)-6.7- dimethoxy-5.4-dihydroisoquinoline (1207)
  • the title compound was produced from methyl-2-chloronicotinate (3.4 g, 0.02 mole) and homoveratryl amine (7.2 g, 0.04 mole).
  • the title compound was produced from methyl-2-chloro-6-methoxyisonicotinate (1.8 g, 0.009 mole) and homoveratryl imine (2.0 g, 0.011 mole)
  • the product was produced from corresponding dimethoxy derivative 1209 (2.4 g, 0.006 mole) as recited in Example 19.
  • the 2-chloro-3-pyridyl derivative (1205) (1.5 g, 0.005 mole) was dissolved in an ethanol solution of methyl amine ( 3 g methyl amine in 30 ml ethanol). The solution was boiled in a closed bomb at 140 oC for 15 hours. The solvent and non-reacted amine were evaporated off, and the product was isolated from the evaporation residue by flash-chromatography (the column material was silicagel Merck, 230 - 400 mesh) end the eluate was toluene-acetone (1:1).
  • 5-Bromo-3-pyridine carboxaldehyd (5.5 g, 0.03 mole ) was dissolved in ethanol.
  • Homoveratryl amine (5.4 g, 0.03 mole) was added to the solution, whereafter the solution was heated in a water bath until the major part of the ethanol had vapourized. Cooling of the residue resulted in a crystallized product.
  • the Schiff base obtained was dissolved in a minor quantity of methylene chloride, and the solution was added slowly to a hot (80 - 90°C) 20%-HCl-solution and boiled with reflux for 30 minutes. Subsequent to cooling in ice, the crystallized product was fil tered-off, i.e. the hydrochloride of the tetrahydroisoquinoline.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte à des dihydroisoquinolines et à des tétrahydroisoquinolines ainsi qu'à leurs sels physiologiquement acceptables, représentés par la formule (I) ou (I'), dans lesquelles A représente -CH= ou -N=, n est égal à 0 ou à 1, R1 et R2 sont identiques ou différents et représentent H, un halogène, OH, un alkoxy de 1 à 4 atomes de carbone, R3 représente H lorsque R1 et R2 représentent H, ou un halogène ou un groupe alkyle de 1 à 6 atomes de carbone, R4 représente un halogène, un groupe alkyle de 1 à 6 atomes de carbone ou un groupe amino représenté par la formule (II), où R5 et R6 sont identiques ou différents et représentent H ou un groupe alkyle de 1 à 3 atomes de carbone qui peut être substitué par un groupe phényle substitué par un ou deux alkoxy inférieurs et R4 peut également représenter H lorsque A représente -N=. La présente invention se rapporte également à un procédé servant à préparer ces dérivés d'isoquinoline, dans lequel un amide représenté par la formule (III), où R1-R4 et A ont la même signification que dans les formules (I) ou (I'), est cyclisé avec de l'acide de Lewis. La présente invention décrit en outre l'utilisation, comme agents thérapeutiques de composés de la formule (I) ou (I') ou de leurs dérivés ou sels physiologiquement acceptables.
PCT/FI1987/000032 1987-03-12 1987-03-12 Derives d'isoquinoline, fabrication et utilisation WO1988007041A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/FI1987/000032 WO1988007041A1 (fr) 1987-03-12 1987-03-12 Derives d'isoquinoline, fabrication et utilisation
EP87902089A EP0351399A1 (fr) 1987-03-12 1987-03-12 Derives d'isoquinoline, fabrication et utilisation
NO1988885020A NO885020D0 (no) 1987-03-12 1988-11-10 Isokinolinderivater, deres fremstilling og anvendelse.
DK632988A DK632988D0 (da) 1987-03-12 1988-11-11 Isoquinolinderivater
FI894086A FI894086A0 (fi) 1987-03-12 1989-08-31 Isokinolinderivater; deras framstaellning och anvaendning.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/FI1987/000032 WO1988007041A1 (fr) 1987-03-12 1987-03-12 Derives d'isoquinoline, fabrication et utilisation

Publications (1)

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WO1988007041A1 true WO1988007041A1 (fr) 1988-09-22

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PCT/FI1987/000032 WO1988007041A1 (fr) 1987-03-12 1987-03-12 Derives d'isoquinoline, fabrication et utilisation

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EP (1) EP0351399A1 (fr)
DK (1) DK632988D0 (fr)
FI (1) FI894086A0 (fr)
NO (1) NO885020D0 (fr)
WO (1) WO1988007041A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617022A1 (fr) * 1993-02-25 1994-09-28 Banyu Pharmaceutical Co., Ltd. 6,7-dialkyl-3,4-dihydroisoquinolin-3-ol, procédé pour sa préparation et procédé utilisant ce composé pour la préparation de 6,7-dialkyl1,2,3,4-tétrahydroisoquinolin-8-ol
WO1999032449A2 (fr) * 1997-12-19 1999-07-01 Zambon Group S.P.A. Derives de phtalazine inhibiteurs de phosphodiesterase 4
WO2000021947A1 (fr) * 1998-10-15 2000-04-20 Zambon Group S.P.A. Derives de benzazine utilises comme inhibiteurs de phosphodiesterase 4

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1795787A1 (de) * 1966-10-31 1975-04-10 Pfizer 4-(6,7-dimethoxyisochinolin-1-yl)- piperazin-1-carbonsaeureester, verfahren zu deren herstellung und diese enthaltende pharmazeutische zubereitungen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1795787A1 (de) * 1966-10-31 1975-04-10 Pfizer 4-(6,7-dimethoxyisochinolin-1-yl)- piperazin-1-carbonsaeureester, verfahren zu deren herstellung und diese enthaltende pharmazeutische zubereitungen

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617022A1 (fr) * 1993-02-25 1994-09-28 Banyu Pharmaceutical Co., Ltd. 6,7-dialkyl-3,4-dihydroisoquinolin-3-ol, procédé pour sa préparation et procédé utilisant ce composé pour la préparation de 6,7-dialkyl1,2,3,4-tétrahydroisoquinolin-8-ol
US5498717A (en) * 1993-02-25 1996-03-12 Banyu Pharmaceutical Co., Ltd. 6,7-dialkoxy-3,4-diydroisoquinolin-8-yl compounds
WO1999032449A2 (fr) * 1997-12-19 1999-07-01 Zambon Group S.P.A. Derives de phtalazine inhibiteurs de phosphodiesterase 4
WO1999032449A3 (fr) * 1997-12-19 1999-09-30 Zambon Spa Derives de phtalazine inhibiteurs de phosphodiesterase 4
US6297257B1 (en) 1997-12-19 2001-10-02 Zambon Group S.P.A. Benzazine derivatives phosphodiesterase 4 inhibitors
WO2000021947A1 (fr) * 1998-10-15 2000-04-20 Zambon Group S.P.A. Derives de benzazine utilises comme inhibiteurs de phosphodiesterase 4
US6358973B1 (en) 1998-10-15 2002-03-19 Zambon Group S.P.A. Benzazine derivatives as phosphodiesterase 4 inhibitors
AU769338B2 (en) * 1998-10-15 2004-01-22 Zambon Group S.P.A. Benzazine derivatives as phosphodiesterase 4 inhibitors

Also Published As

Publication number Publication date
FI894086A (fi) 1989-08-31
NO885020L (no) 1988-11-10
EP0351399A1 (fr) 1990-01-24
NO885020D0 (no) 1988-11-10
FI894086A0 (fi) 1989-08-31
DK632988A (da) 1988-11-11
DK632988D0 (da) 1988-11-11

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