EP0351399A1 - Isoquinoline derivatives, their manufacture and use - Google Patents

Isoquinoline derivatives, their manufacture and use

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Publication number
EP0351399A1
EP0351399A1 EP87902089A EP87902089A EP0351399A1 EP 0351399 A1 EP0351399 A1 EP 0351399A1 EP 87902089 A EP87902089 A EP 87902089A EP 87902089 A EP87902089 A EP 87902089A EP 0351399 A1 EP0351399 A1 EP 0351399A1
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EP
European Patent Office
Prior art keywords
pyridyl
carbon atoms
dihydroisoquinoline
formula
hydrogen
Prior art date
Legal status (The legal status 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 status listed.)
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EP87902089A
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German (de)
French (fr)
Inventor
Hannu Allonen
Hannu Nikander
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Huhtamaki Oyj
Original Assignee
Huhtamaki Oyj
Huhtamaki Yhtyma OY
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Publication of EP0351399A1 publication Critical patent/EP0351399A1/en
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    • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic 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.The present invention relates to dihydroisoquinolines and tetrahydroisoquinolines as well as to their physiologically acceptable salts, represented by the formula (I) or (I '), in which A represents -CH = or -N =, n is equal to 0 or 1, R1 and R2 are the same or different and represent H, a halogen, OH, an alkoxy of 1 to 4 carbon atoms, R3 represents H when R1 and R2 represent H, or a halogen or an alkyl group of 1 with 6 carbon atoms, R4 represents a halogen, an alkyl group of 1 to 6 carbon atoms or an amino group represented by the formula (II), where R5 and R6 are identical or different and represent H or an alkyl group of 1 with 3 carbon atoms which can be substituted by a phenyl group substituted by one or two lower alkoxy and R4 can also represent H when A represents -N =. The present invention also relates to a process for preparing these isoquinoline derivatives, in which an amide represented by formula (III), where R1-R4 and A have the same meaning as in formulas (I) or (I '), is cyclized with Lewis acid. The present invention further describes the use, as therapeutic agents of compounds of formula (I) or (I ') or their physiologically acceptable derivatives or salts.

Description

Isoquinoline derivatives, their manufacture and use
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'
or
and their pysiologically acceptable salts, and to methods for preparing such isoquinolines and their use as therapeutic substances (medicines).
In formula I and formula I' A = -CH= or -N= n = 0 or 1
R 1 and R2 are the same or different and designate hydrogen, halogen, an hydroxyl group or a C1-C4 alkoxy group,
R3 = hydrogen when R1 and R2 are hydrogen, or halogen, or a C1-C6 alkyl group,
R4 = halogen, C1-C6 alkyl or alkoxy group, or refers to an amino group of the formula
where R5 and R6 are the same or different and designate hydrogen or an alkyl group which has 1 -3 carbon atoms and which can be substituted with a phenyl group substituted with one or two lower alkoxy, and R4 can also be hydrogen when A -N=.
The compounds having formula 1 are of particular interest inhere n is 0, A designates the group -CH=, R1 and R2 are hydrogen or an alkoxy group which has 1-3 carbon atoms, and
R3 and R4 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. In this 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.
The 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.
Compounds which have the formula I and I'can also be produced by, for instance, the following methods, the reaction diagram of which have been shown in the appended common diagram page.
3.4-Dihydroisoquinolines (I) can also be produced, for instance by:
A) dehydrating corresponding to 1.2.3.4-tetrahydro derivatives (3) in the presence of, e.g. mercury acetate, N-bromosuccinimide or Freym-salt. (Bull. Chem. Soc. Japan 39, 2012 (1966) J. Heterocyclic Chem. 21, 525 (1984) J. Med. Chem. 25, 1240 (1982))
B ) alkylating 1-haloisoquinolines (4) using a nickel phosphine complex as a catalyst. (Tetrahedron 38, 3354 (1982))
C) react a suitable phenethyl derivative ( 5 ), e.g. phenethyl halide, with a nitrile-tin tetrachloride complex (Cnem. Ber. 94,199 (1961); Tetrah. Lett. 225 (1965)) or phenethyl isocyanide with acyl halide (Tetrah. Lett. 5389 (1985))
D) reacting halogen-substituted aryl halogenides ( 6), e.g. a lithium compound obtained through a halogen metal exchange reaction with a suitable nitrile (Tetrah. Lett. 4145 (1977))
E) reacting phenylazide (7) with suitable nitriles in the presence, of, e.g., nitrosonium ions
(J. Heterocyclic Chem. 12, 263 (1975))
F) effecting a Reissert reaction with dihydroisoquinoline (8) (Adv. Heterocyclic Chem. 24, 187 (1979)) G) converting in. a suitable manner the (R', R") of the isoquinoline ring, or the substituent (Y; R7 , R8 ) of the
1-position or both substituents (R'. R", R7 , R8 ) in a substituted 3.4-dihydroisoquinoline (9, 10 and 11 ), e.g. by means of different substitution or elimination reactions H) effecting a cyclo-desulphurizing reaction with thioamide (12) (Chem. Pharm. Bull. 14, 842 (1966)
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,
16,17,20) (Helv. Chim. Acta 31, 914 (1948); Chem. Commun. 7 99 (1971); Tetrahedr. Lett.1181 (1974); J. Heterocyclic Chem.7. 91 (1970)
L) cyclizing aminoacetales (18), amidoacetales or their reaction oroducts (Org.Reaction 6,191 (1951); Chem.Heterocyclic Compd.38,139 (1981) M ) departing from phenethyl amines or substituted phenethyl amines(19) (Chem. Heterocyclic Compd. 38, 139 (1981)) N ) e.g. reducing oxo- or hydroxy substituted isoquinolines (21, 22) The compounds according to formula I are chemically basic and can be converted to any form physiologically acceptable acid addition salts with inorganic acids in a conventional manner. 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 pharmacological properties of the pyridyl derivatives
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.
The comparison tests were carried out with compounds according to the present invention and with compounds known from Japanese patent specifications JP 68 08, 277 and JP 70 03, 782, and the publication, entitled YAKUGAKI ZASSHI 87, 1083 (1967). These known compounds are:
I. 1-(4-pyridylmethyl)-6.7-dimethoxy-3.4-dihydroisoquinoline
II. 1-(4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline
III. 1-(4-pyridyl)-6.7-dihydroxy-3.4-dIhydroisoquinoline
IV. 1-(4-pyridyl)-6-hydroxy-7-methoxy-3.4-dihydroisoquinoline V. 1-(4-pyridylmethyl)-6.7-dihydroxy-3.4-dihydroisoquinoline
1. The dilating effect on bronchi (bronchus dilation)
Since the bronchi of 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. After 60 minutes 2 μmole/l histamine were used to induce contraction of the smooth muscle, which constituted about 50-60% of the maximum response of the preparation. Subsequent hereto the relaxing action of the test and control compounds were examined by cumulative dosing of the test compound until maximum (100%) relaxation was reached. The response of the trachea preparation was measured isotonically. Using linear regression, there was calculated from the graphic presentation of the effect of the test doses the ED50-value, i.e. the concentration, which induces a 50%-relaxation of the maximum response for the contraction of smooth muscle caused by histamine. At least two measurements were taken with each compound, on average 4-5. The relaxation effects (ED50) in respect of the compound investigated have been combined in Table I below. The values recited are the average values of measurements made. Table 1 The relaxing effect of the derivatives on the smooth muscle of guineapig tracheae, where contraction has been induced with histamines (2 μmole/l) and which resulted in a 50-60%-contraction in relation to the maximum contraction of the preparation. ED50 is the concentration of the examined derivative resulting in a 50%-reduction in the induced contraction, n designates the number of measurement/ derivatives.
Derivative Salt ED50 μmole/l
1212 HCl 6 0.7
1209 HCl 9 1.2
1217 HCl 9 1.4
185 HCl 3 2.5
184 HCl 3 4.2
1219 HCl 3 4.4
1210 HCl 3 5.1
1208 HCl 5 6.0
183 HCl 2 9.4
1205 HCl 19 11.0
1224 HCl 3 11.0 1222 HCl 5 31.7
1218 HCl 4 36.0
1205 HBr 4 36.5
1216 HBr 3 48.4
1206 HBr 3 68.5
1207 HBr 2 68.9
1204 HCl 2 212.8 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Comparison :
I HBr 4 21.1
II HCl 4 32.8
III HBr 2 53.3
IV HBr 7 66.5
V HBr 4 82.8
Papaverine HCl 7 2.4
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.
2. Blood-vessel dilation effect (vasodilation)
The 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). Several preparations were obtained from a single thoracic aorta, and these preparations were transferred to an incubation dish containing an oxidized Krebs-Hanseleit solution (37ºC, pH = 7.4) for investigation. 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.
Contraction of the blood vessel was induzed with noradrenaline, which was dosed to the incubation dish cumulatively, until the maximum contraction of the preparation was reached. Na3EDTA (10-5 mole/l), which prevents premature inactivation of the noradrenaline, was also added to the Krebs-Henseleit solution.
The ED50-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 ED50-value of noradrenaline in the presence of the test derivatives:
ED50 noradrenaline + test derivative (antagonisten) / ED50 noradrenaline.
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.
Concentration. Dosing Derivative Salt μmole/l ratio
185 HCl 0.1 3.9
1208 HCl 3.3 4.3
1209 HCl 3.3 3.7 1205 HCl 10.0 4.5
1218 HCl 33.0 4.1
1219 HCl 33.0 5.4
Papaverine HCl 1.0 3.2
The above table refers to dosing ratios = The derivatives listed in the table displace the cumulative dosing curve of the noradrenaline to the right. 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.
3. The effect on adrenergic receptors
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 radioligand (final concentration 39.5 pM) and the membrane suspension (40-100 μg protein) were incubated at 37ºC for 60 minutes, either in the presence of propranolil (10 μm = unspecified bonding) or in the absence thereof (total bonding) to show specific bonding above 95% of the total bonding. 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 IC50- 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 IC50-values calculated were 1.2 x 10-3M 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 absence of effect on beta-adrenergic receptors was supported by the fact that propranolol ( 10-6μM) in vitro displaced the dosing curve for salbutamol relaxation in the guinea-pig trachea preparation to the right, whlle no such property was found in the case of 1217. Neither did the derivatives 1209,
1201, 1205, 1208, 1209 and 1210, cumulatively dosed (0.01 -
1 μmole/l) cause any clear change in the beat frequency in the guinea-pig auricle preparation in vitro, i.e. the derivatives do not have a beta-receptor stimulating or inhibiting effect.
The isoprenaline, on the other hand, increased the beat frequency of the avricle preparation with a maximum change at a concentration of 1 μmole/l.
The tests show that the pyridyl derivatives have a pronounced therapeutic effect on smooth muscle preparations. On the other hand, the derivatives have no effect on beta-adrenergic receptors. Certain comparison, compounds, on the other hand, did have an effect on such receptors. Novel therapeutical properties are thus associated with the novel inventive derivatives.
References:
Engel G, Hoyer D,Berthold R et al. (1981)
Naunyn-Schmiedeberg's Arch Pharmacol 317, 227 - 285
Emmersor J & Mackay D (1979) J Pham Pharmacol 31, 798 Furchgott R F & Bhadrakom S (1953) J Pharmacol Exc Ther 108, 129 - 143 Reitz A B, Sonv eaux E, Rosenkranz R P et al. (1985) J Med Chem 28, 634 - 642
The invention will now be described in more detail with reference to the following working examples.
Example 1 Methyl-5-bromonicotinate
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%).
Example 2
1-(5-Bromo-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline
(1209)
A small amount of pyridine (0.3 ml) was added to a mixture of methyl-5-bromonicotinate (5 g, 0.023 mole) and homoveratryl amine (4.2 g, 0.023 mole) and the mixture heated to 1 00 ºC over a period of 4-5 hours. The resultant amide was not separated, but was used as such in future processes.
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.
m . p base 1 26 - 1 28 ºC ( cryst . from isopropanol ) Ms: 237 (M), 315 (N-CH3OH)
NFIR: (ppm) 3.76 s (3 H, MeO) 3.96 s (3 H, MeO)
2.76 t (2 H, CH2 ) 3.84 t (2 H, CH2)
6.70 s (1 H, ar.CH) 6.82 s (1 H, ar.CH) 8.15 s (1 H, pyr.CH) 8.77 s (2 H, pyr.CH)
The following compounds were produced by the methods described in Examples 1 and 2.
Example 3 1-(2-Chloro-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1205)
The title compound was produced from methyl-2-chloronicotinat (6.8 g, 0.04 mole) and homoveratryl amine (7.8 g, 0.043 mole).
The yield was 9.7 g (crude product: 80% of the theoretical)
m.p. base 119.5 - 120.5°C hydrochloride 209.5 - 211°C Ms: 302 (M), 267 (M-CI)
NMR: (ppm) 3.69 s (3 H, MeO) 3.95 s (3 H, MeO)
2.81 t (2 H, CH2) 3.80 t (2 H, CH2)
6.38 s (1 H, ar.CH) 6.78 s (1 H, ar.CH) 7.37 m (1 H, pyr.CH) 7.82 d (1 H, pyr.CH)
8.50 d (1 H, pyr.CH)
Example 4
1-(6-Chloro-3-pyridyl)-6.7-dimεthoxy-3.4-dihydroisoquinoline (1208)
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 yield was 7.8 g (crude produce: 63% of the theoretical) m.p. base 109 - 112.5°C hydrochloride 197 - 198.5°C
Ms: 302 (M) , 287 (N-Me), 271 (M-MeO), 267 (M-Cl)
NMR: (ppm) 3.76 s (3 H, MeO) 3.96 s (3 H, MeO)
2.72 t (2 H, CH2 ) 3.84 t (2 H, CH2)
6.69 s (1 H, ar.CH) 6.82 s (1 H, ar.CH) 7.40 d (1 H, pyr.-CH) 7.95 d (1 H, pyr.CH) 8.63 s (1 H, pyr.CH)
Example 5
1.-(2-Chloro-3-pyridyl)-7-methoxy-3.4-dihydroisoquinoline (1224)
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 yield was 6.6 g (crude product: 55% of the theoretical) m.p. hydrochloride 206.5 - 208 ºC
Ms: 272 (M), 237 (M-Cl
NP1R: (ppm^ 3.67 s (3 H, MeO)
2.81 t (2 H, CH2) 3.87 t (2 H, CH2)
6.42 d (1 H, ar.CH) 6.94 kv. (1 H, ar.CH)
7.19 d (1 H, ar.CH) 7.37 kv. (1 H, pyr.CH)
7.78 d (1 H, pyr.CH) 8.47 d (1 H, pyr.CH)
Example 6
1-(2-Chloro-3-pyτidyl)-5-methoxy-3.4-dihydroisoquinoline (1222)
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 yield was 6.6 g (crude product: 55% of the theoretical) m.p. hydrochloride 238 - 240°C
Ms: 272 (M), 237 (M-Cl)
NMR: (ppm) 3.89 s (3 H, MeO)
2.89 t (2 H, CH2 ) 3.87 t (2 H, CH2 ) 6.52 d (1 H, ar.CH) 6.97 d (1 H, ar.CH)
7.17 t (1 H, ar.CH) 7.35 t (1 H, pyr.CH)
7.78 d (1 H, pyr.CH) 8.47 d (1 H, pyr.CH)
Example 7 1-(5-Bromo-3-pyridyl)-7-methoxy-3.4-dihydroisoquinoline (1217)
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)
The yield was 5.2 g (71% of the theoretical) m.p. hydrochloride 203.5 - 206 ºC
Ms: 317 (M), 237 (M-Br), 285 (M-CH3OH)
NMR: (ppm) 3.70 s (3 H, MeO)
2.70 t (2 H, CH2) 3.80 t (2 H, CH2)
7.10 s (1 H, ar.CH) 7.10 d (1 H, ar.CH)
6.73 d (1 H, ar.CH) 8.08 s (1 H, pyr.CH) 8.67 s (2 H, pyr.CH)
Example 8
1-(5-Bromo-3-pyridyl)-5-methoxy-3.4-dihydroisoquinoline (1218)
Tne title comcound was produced from methy 1-5-bromonicotinate
(5.0 g, 0.023 mole) and 2-(2-methoxy phenyl)-ethyl amine (4.0 g, 0.025 mole). The yield was 3.7 g (51% of the theoretical) m.p. base 133.5 - 135.5ºC hydrochloride 226 - 232°C Ms: 317 (M), 285 (M-H-CH3O) 237 (M-Br)
NMR: (ppm) 3.90 s (3 H, MeO) 2.79 t (2 H, CH2) 3.84 t (2 H, CH2) 6.81 d (1 H, ar.CH) 7.03 d (1 H, ar.CH) 7.26 kv (1 H, ar.CH) 9.10 s (1 H, pyr.CH) 8.73 s (1 H, pyr.CH) 8.73 s (1 H, pyr.CH)
Example 9
1-(2-Chloro-6-methyl-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1210)
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). (POCl3 as condensing agent)
The yield was 4.0 g (crude product: 53% of the theoretical) m.p. base 140 - 143°C hydrochloride 206 - 208°C Ms: 316 (M), 301 (M-Me), 281 (M-Cl)
NMR: (ppm) 3.69 s (3 H, MeO) 3.94 s (3 H, MeO)
2.80 t (2 H, CH2) 3.85 t (2 H, CH2) 6.44 s (1 H, ar.CH) 6.79 s (1 H, ar.CH)
7.24 d (1 H, pyr.CH) 7.83 d (1 H, pyr.CH)
2.63 s (3 H, Me)
Examp 1 e 10 1-(5-Bromo-3-pyridyl)-5.7-diethoxy-3.4—dihydroisoquinoline (1212)
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 yield was 4.2 g (60% of the theoretical) m.p. base 96 - 99 ºC hydrochloride 220 - 223.5 ºC
Ms: 375 (M), 330 (M-EtO), 346 (M-Et)
NMR: (ppm) 1.38 t (3 H, EtO 1.50 t (3 H, EtO)
3.96 kv (2 H, EtO) 4.16 t (2 H, EtO)
2.73 t (2 H, CH2) 3.84 t (2 H, CH2)
6.71 s (1 H, ar.CH) 6.79 s (1 H, ar.CH)
8.12 s (1 H, pyr.CH) 8.74 s (2 H, pyr.CH)
Example 11
1-(2.6-Dichloro-4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (183)
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 yield was 3.2 g (79% of the theoretical) m.p. base 117 - 120°C hydrochloride 208 - 210.5°C
Ms: 336 (M), 301 (M-Cl)
NMR: (ppm) 3.79 s (3 H, MeO) 3.96 s (3 H, MeO)
2.73 t (2 H, CH2 ) 3.84 t (2 H, CH2)
6.62 s (1 h, ar.CH) 6.79 s (1 H, ar.CH)
7.5.0 d (2 H, pyr.CH)
Example 12
1-(2-Pyrazyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1206) The title compound was produced from the methyl ester of 2-pyrazine carboxylic acid (7.3 g, 0.05 mole) and homoveratryl amine (10.9 g, 0.06 mole).
The yield was 9.5 g (63% of the theoretical) m.p. hydrochloride 185 - 188°C
Ms: 269 (M), 254 (M-Me), 238 (M-MeO)
NMR: (ppm) 3.77 s (3 H, MeO) 3.80 s (3 H, MeO) 2.73 t (2 H, CH2 ) 3.88 t (2 H, CH2 )
6.73 s (1 H, ar.CH) 7.05 s (1 H, ar.CH)
8.58 s (2 H, pyr.CH) 9.12 s (1 H, pyr.CH)
Example 13 1-(5-n-Butyl-2-pyridyl)-6.7-dimethoxy-3.5-dihydroisoquinoline (1219)
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 yield was 4.6 g (62% of the theoretical) m.p. base 116.5 - 119°C hydrochloride 170.5 173°C
Ms: 324 (M), 309 (M-Me), 293 (M-MeO)
NMR (ppm) 3.78 s (3 H, MeO) 3.93 s (3 H, MeO)
2.71 t (2 H, CH2) 3.84 t (2 H, CH2)
0.95 t (3 H, Bu-CH3) 1.39 kv (2 H, Bu-CH2)
1.63 kv (2 H, Bu-CH2) 2.73 kv (2 H, Bu-CH2) 6.75 s (1 H, ar.CH) 7.07 s (1 H, ar.CH)
7.62 d (1 H, pyr.CH) 7.77- d (1 H, pyr.CH) 8.47 s (1 H, pyr.CH) Example 14
1-(2-(2'-(3.4-Dimethoxy phenyl)-ethyl amino)-6-chloro-4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (184)
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)
The surplus amine used replaces the second chloro substitute in the isonicotinate.
The yield was 2.1 g (35% of the theoretical) m.p. hydrochloride 165 - 167ºC
Ms: 481 (M), 330 (M- diMeO-Ph-CH2)
NMR (ppm) 3.78 s (3 H, MeO) 3.97 s (3 H, MeO)
2.74 t (2 H, CH2 ) 3.83 t (2 H, CH2)
6.68 s (1 H, ar.CH) 6.82 s (1 H, ar.CH)
6.72 s (1 H, pyr.CH) 7.12 s (1 H, pyr.CH)
3.83 s (6 H, MeO) 2.60 t (2 H, CH2)
3.68 t (2 H, CH2 ) 6.80 s (3 H, ar.CH)
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 yield was 2.0 g (22% of the theoretical) m.p. - (decomposes) Ms: 447 (M)
NMR: (opm) - 3.74 s (3 H, MeO) 3.95 s (3 H, MeO)
2.89 t (2 H, CH2) 3.86 t (2 H, CH2 )
5.75 z, (1 H, ar.CH) 6.80 s (1 H, ar.CH) 6.53 t (1 H, pyr.CH) 7.48 d (1 H. pyr.CH)
8.18 d (1 H, pyr.CH)
3.84 s (6 H, MeO) 2.61 t (2 H, CH2)
3.67 t (2 H, CH2) 6.78 s (3 H, ar.CH)
Example 16
1-(2-Chloro-6-methoxy-4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (185)
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 yield was 2.2 g (74% of the theoretical) m.p. base 116.5 - 120°C hydrochloride 201 - 203°C
Ms: 332 (M), 301 (M-MeO), 297 (M-Cl)
NMR: (ppm) 3.78 s (3 H, MeO) 3.96 s (3 H, MeO)
3.98 s (s H, MeO)
2.73 t (2 H, CH2) 3.83 t (2 H, CH2)
6.69 s (1 H, ar.CH) 6.84 s (1 H, ar.CH)
6.77 s (1 H, pyr.CH) 7.14 s (2 H, pyr.CH)
Example 17
1 -(5-Bromo-3-pyridyl)-6.7-dimethoxy-1.2.3.4-tetrahydroisoquinoline (1204)
The 1209 hydrochloride of the dihydro-derivative (2.0 g,
0.005 mole) was dissolved in methanol. The solution was cooled to 10 - 15ºC and small quantities of sodium borohydride (0.5 g, 0.013 mole) were added over a period of 20 minutes, whereafter the mixture was stirred for two hours at 40ºC, and then cooled and acidified with a 10%-HCl solution. The solution was then evaporated off to leave hydrochloride. The yield was 2.0 g (95% of the theoretical) m.p. (HCl salt) 208 - 210°C
Ms: 349 (M), 348 (M-1), 317 (M-CH3OH)
NMR: (ppm) 3.63 s (3 H, MeO) 3.85 s (3 H, MeO)
3.0 - 3.3 (5 H, CH2 , CH)
6.30 s (1 H, ar.CH) 6.81 s (1 H, ar.CH)
8.26 s (1 H, pyr.CH) 8.71 s (1 H, pyr.CH) 8.82 s (1 H, pyr.CH)
Example 18
1-(2-Hydroxy-6-methyl-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1220)
Homoveratryl amine (12.7 g, 0.07 mole) mεthyl-2-hydroxy-6-methylnicotinate (10.5 g, 0.07 mole) and pyridine (0.5 g) were heated for 5 hours at 130 C. The mixture was cooled and dissolved in 100 ml of xylene. 20 g of phosphorus pentoxide were added to the solution and the mixture boiled under reflux for 4 hours and then cooled. The solvent was decantered and the solidified residue dissolved carefully in 100 ml of water. The solution was basified with an ammonium solution and extracted with chloroform. The solvent was evaporated off to leave a 9 g crude-product residue (43%). m.p. base 192 - 196°C hydrochloride 207 - 213°C Ms: 298 (M), 283 (M-Me), 267 (M-MeO)
NMR: (ppm) 3.77 s (3 H, MeO) 3.94 s (3 H, MeO)
2.33 s (3 H, Me)
2.76 t (2 H, CH2) 3.75 s (2 H, CH2 )
5.74 s (1 H, ar.CH) 6.86 s (1 H, ar.CH)
6.31 d (1 H, pyr.CH) 7.69 d (1 H, pyr.CH) Example 19
1-(2-Chloro-3-pyridyl)-6.7-dihydroxy-3.4-dihydroisoquinoline (1215)
The hydrochloride (5 g, 0.15 mole) of 1-(2-Chloro-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline was dissolved in 40 ml of an HBr-solution (48%). The solution was boiled in a nitrogen atmosphere for 5 hours and the solvent then evaporated off in a vacuum environment. The product was crystallized from an ethanol-etyl-acetate mixture.
The yield was 2.8 g (43% of the theoretical; HBr-salt) m.p. hydrobromide 219 - 223 ºC
Ms: 274 (M)
NMR (ppm) 2.89 t (2 H,CH2) 3.84 t (2 H, CH2)
6.60 (1 H, ar.CH) 6.75 (1 H, ar.CH) 6.97 kv (1 H, pyr.CH) 8.18 d (1 H, pyr.CH) 8.57 d (1 H, pyr.CH)
Example 20
1 -(2-Pyrazyl)-6.7-dihydroxy-3.4-dihydroisoquinoline (1216)
The product was produced from corresponding dimethoxy derivative 1206 (5 g, 0.015 mole) as recited in Example 19.
The yield was 5.3 g (88% of the theoretical; HBr-salt) m.p. hydrobromide 212.5 - 215 ºC Ms: 385 (silylated; mole.w. 241 + 2* (CH3)3Si)
NMR ppm) 3.16 t (2 H, CH2 4.01 t (2 H, CH2)
6.99 s (1 H, ar.CH) 7.13 s (1 H, ar.CH) 8.98 s (1 H, pyr.CH) 9.01 s (1 H, pyr.CH) 9.16 s (1 H, pyr.CH) Example 21
1-(5-Bromo-3-pyridyl)-6.7-dihydroxy-3.4-dihydroisoquinoline (1221)
The product was produced from corresponding dimethoxy derivative 1209 (2.4 g, 0.006 mole) as recited in Example 19.
The yield was 2.4 g (83% of the theoretical; HBr-salt) m.p. hydrobromide 286 - 290 ºC
Ms: 319 (M)
NMR: (ppm) 3.10 t (2 H, CH2 ) 3.98 t (2 H, CH2)
6.88 s (1 H, ar.CH) 6.98 s (1 H, ar.CH) 8.43 s (1 H, pyr.CH) 8.87 s (1 H, pyr.CH) 8.98 s (1 H, pyr.CH)
Example 22
1-(2-Aminomethyl-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1221)
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).
The yield was 1.1 g (74% of the theoretical) m.p. 231 - 234.5°C (HCl-salt)
Ms: 297 (M), 296 (M-1), 282 (M-Me), 265 (M-MeO) NMR: (ppm) 3.87 s (3 H, MeO) 3.70 s (3 H, MeO)
3.02 d (3 H, Me)
2.58 t (2 H, CH2) 3.75 t (2 H, CH2)
6.70 s (1 H, ar.CH) 6.73 s (1 H, ar.CH) 6.45 kv (1 H, pyr.CH) 7.42 kv (1 H, pyr.CH)
8.10 kv (1 H, pyr.CH)
NMR - the spectrum was obtained with the aid of a 200 MHz Bruker-spectrometer with CDCl3 as the solvent.
Example 23
1 -(5-Bromo-3-pyridyl)-6.7-dimethoxy-1.2.3.4-tetrahydroisoquinoline (Pictet-Spengler)
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.
The yield was 5.9 g (56% of the theoretical) m.p. hydrochloride 208 - 210.5°C.
NMR- and the mass spectrum corresponded to the values recited in Example 17

Claims

CLAI MS
1. Therapeutically useful dihydro- and tetrahydroisoquinolines and their physiologically suitable salts, characterized in that they have the formula I or I'
or
in which formulae
A = -CH= or -N= n = 0 or 1
R1 and R2 are the same or different and designate hydrogen, halogen, an hydroxyl group or an alkoxy group having 1-4 carbon atoms,
R3 = hydrogen when R1 and R2 are hydrogen, or halogen, or an alkyl group having 1-6 carbon atoms,
R4 = halogen, an alkyl or alkoxy group having 1-6 carbon atoms, or designates an amino group of the formula
where R5 and R6 are the same or different and designate hydrogen or an alkyl group which has 1 -3 carbon atoms and which can be substituted with one or two lower alkoxy, and R4 can also be hydrogen when A is -N=.
2. A compound according to Claim 1, characterized in that in the formula I or I' n is 0, A designates the group -CH=,
R1 and R2 are hydrogen or an alkoxy group having 1-3 carbon atoms, and R3 and R4 are hydrogen, halogen or an alkyl group or alkoxy group having 1-4 carbon atoms.
3. A compound according to Claim 1 or 2 said compound being: 1-(2-chloro-6-methoxy-4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline, 1-(6-chloro-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline, 1 -(5-bromo-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline, 1 -(2-chloro-6-methyl-3-pyridyl)-6.7-dimethoxy-3.4- dihydroisoquinoline, 1 -(5-bromo-3-pyridyl)-7-methoxy-3.4- dihydroisoquinoline, 1 -(5-n-butyl-2-pyridyl)-6.7-dimethoxy- 3.4-dihydroisoquinoline, 1-(5-bromo-3-pyridyl)-6.7-diethoxy- 3.4-dihydroisoquinoline, or 1-(2-(2'-(3.4-dimethoxy phenyl)- ethyl amino)-6-chloro-4-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline.
4. A method for preparing physiologically active isoquinoline derivatives of the formula I or I'
or and their physiologically acceptable salts, in which formula
A = -CH= or -N= n = 0 or 1
R1 and R2 are the same or different and designate hydrogen, halogen, an hydroxyl group or an alkoxy group having 1-4 carbon atoms,
R3 = hydrogen when R1 and R2 are hydrogen, or halogen, or an alkyl group having 1-6 carbon atoms,
R4 = halogen, an alkyl group or alkoxy group having 1-6 carbon atoms, or designates an amino group of the formula
where R5 and R6 are the same or different and designate hydrogen or an alkyl group which has 1-3 carbon atoms and which can be substituted with a phenyl group substituted with one or two lower alkoxy groups, and R4 can also be hydrogen when A is -N=, characterized in that an amide of the formula
where R1 - R4 and A have the above significance, are cyclized with Lewis acic.
5. The use of compounds having the formula I or I' or their physiologically suitable derivatives or salts as therapeutical agents.
EP87902089A 1987-03-12 1987-03-12 Isoquinoline derivatives, their manufacture and use Withdrawn EP0351399A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/FI1987/000032 WO1988007041A1 (en) 1987-03-12 1987-03-12 Isoquinoline derivatives, their manufacture and use

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EP0351399A1 true EP0351399A1 (en) 1990-01-24

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EP (1) EP0351399A1 (en)
DK (1) DK632988D0 (en)
FI (1) FI894086A (en)
NO (1) NO885020D0 (en)
WO (1) WO1988007041A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06247935A (en) * 1993-02-25 1994-09-06 Banyu Pharmaceut Co Ltd 6,7-dialkoxy-3,4-dihydroisoquinolin-8-ol, its production and production of 6,7-dialkoxy-1,2,3,4-tetrahydroisoquinolin-8-ol using the same
IT1296985B1 (en) 1997-12-19 1999-08-03 Zambon Spa BENZAZINIC DERIVATIVES INHIBITORS OF PHOSPHODIESTERASE 4
IT1302677B1 (en) * 1998-10-15 2000-09-29 Zambon Spa BENZAZINIC DERIVATIVES INHIBITORS OF PHOSPHODIESTERASE 4

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8807041A1 *

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NO885020L (en) 1988-11-10
NO885020D0 (en) 1988-11-10
WO1988007041A1 (en) 1988-09-22
FI894086A0 (en) 1989-08-31
DK632988A (en) 1988-11-11
FI894086A (en) 1989-08-31
DK632988D0 (en) 1988-11-11

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