ISOQUINOLINE DERIVATIVES, THEIR MANUFACTURE AND USE

Abstract: The invention relates to dihydro- and tetrahydroisoquinolines and their physiologically acceptable salts of formula (I) or (I'), in which formulae A is -CH= or -N=, n is 0 or 1, R1 and R2 are the same or different and designate H, halogen, OH, a C1-C4 alkoxy, R3 is H when R1 and R2 are H, or halogen or a C1-C6 alkyl group, R4 is halogen, a C1-C6 alkyl group or designates an amino group of formula (II), where R5 and R6 are the same or different and designate H or a C1-C3 alkyl group which can be substituted with a phenyl group substituted with one or two lower alkoxy, and R4 can also be H when A is -N=. The invention also relates to a method for preparing same whereby an amide of formula (III), where R1-R4 and A have the above significance, is cyclisized with Lewis acid; and the use of compounds of the formula (I) or (I') or their physiologically acceptable derivatives or salts as therapeutical agents.

Description: Isoquinoline derivatives, their manufacture and use Isαquinoline derivatives having a pyridyl group ωhich include substitutes in the 1 -position are described in Japanese publi cations (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 gene 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 and R are the same or different and designate hydrogen, halogen, an hydroxyl group or a ,-C alkoxy group, R = hydrogen ωhen R and R are hydrogen, or halogen, or a C -C alkyl group, p = halogen, C -C ^ alkyl or alkoxy group, or refers to an , 1 o amine group of the formula where R and R are the same or different and designate J 6 hydrogen or an alkyl group ωhich has 1 -3 carbon atoms and ωhich can be substituted with a phenyl group substituted ωith one or tωo lower alkoxy, and R can also be hydrogen when A -N=. The compounds having formula 1 are of particular interest inhere π is 0, A designates the group -CH=, R and R are hydrogen or an alkoxy group ωhich has 1-3 carbon atoms, and R and R 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 ωith Lewis acid. This amide has been produced from substituted 2-pheπylethyl amine and a suitable pyridine carboxylic acid, an ester of a pyridine carbαxylic acid or pyridine carboxylic acid chloride according to reactions described in the literature. Bischler-Napieralskis reaction: T e condensing agent usec • the reaction may ≤uitabl / be nospnorus trichloride, chαsphorus peπtachloride, phosphorus oxychloride, phosphorus pentoxide, boron trifluoride, tin tε chloride, although strong mineral acids, such as s'ulphuric a and polyphosphoric acid may also be used. Phosphorus oxychlo and phosphorus pentoxide are particularly suitable in this r Cyclization can be effected ωith or without a solvent. All solvents ωhich will dissolve the reaction components and whi have a sufficiently high boiling point can be used. Good sol vents 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 ca be carried out within a wide temperature range, although mos 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 produce by, for instance, the following methods, the reaction diagra of which have been shown in the appended common diagram page. 3.4-Dihydroisoquiπolines (I) can also be produced, for instance by: A) dehydrating corresponding to 1.2. .4-tetrahydro derivative ( _) in the presence of, e.g. mercury acetate, l\!-bromo- succinimide 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 -haloisoquinoliπes (_4 ) using a nickel phosphin 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 (Cπerr.. Ber. 94,199 (1961 ); Tetrah. Lett. 22Ξ (1965)) or phenethyl isocyanide ωith acyl halide (Tεtrah. Lett. 5389 (1985)) D) reacting halogen-substituted aryl halogenides (6_) , e.g. a lithium compound obtained through a halogen metal exchang reaction ωith 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 iso- quiπoline ring, or the substituent (Y; R , R ) of the I 8 1 -position or both substituents (R'. R", R , R ) in a 7 8 substituted 3. -dihydroisoquinoliπe (_9_, 1_0 and V\ ) , e.g. means of different substitution or elimination reactions H) effecting a cyclo-desulphuriziπg reaction ωith thioamide (12) (Chem. Pharm. Bull. 14, 842 (1966) 1. . .4-Tetrahydro-isoquinαlines (3) can be produced, e.g. b I) effecting a Grigπard or Reissert reaction ωith isoquino- lines (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, ωith 3.4-dihydroisα- quinoliπe (14) (compare the references in I) K) cyclizing benzyl amine or l\l-substituted benzyl amine (15, 16,17,20) (Helv. Chim. Acta 31 , 91 (1948); Chem. Commun. (1971 ); Tεtrahedr.Lett.1181 (1974); J .Heterocyclic Chem.7 (1970) L) cyclizing aminαacetales (18), amidoacetales or their reac orαducts (Org.Reaction 6,191 (1951 ); Chem.Heterocyclic Compd.38,139 ( F\ ) departing from phenethyl amines or substituted phenethyl amϊnes(l9) (Chem. Heterocyclic Compd. 38, 139 (1981)) e.g. ^ educing oxc- or hycroxy substituted isoquinolines (21, 22: X= e.g. The compounds according to formula I are chemically basic and can be converted to any form physiologically acceptable acid addition salts ωith inorganic acids in a conventional manner. Suitable acids for binding salt are, for instance, hydrochlor acid, hydrobromic acid, sulphuric acid, phosphoric acid, acet acid, oxalic acid, alonic acid, succin.ic acid, maleic acid, fumaric acid, tartaric acid, citric acid and corresponding acids. 0 The pharmacological properties of the pyridyl derivatives The activity of the pyridine derivatives have been examined in vitro ωith preparations of smooth muscles (guinea-pig trachea or ωindpipe preparations and the thoracic aorta of 5 rabbits) and the cardiac atrium or auricle guinea-pi ' gs preparations. These derivatives have been found to possess properties ωh.ich widen their pharmacological use. The beta- adrenergic activity of those pyridyl derivatives ωhich are most active pharmacologically have been measured ωith the 0 aid of receptor binding processes carried out in vitro. The comparison tests ωere carried out ωith compounds accordin to the present invention and ωith compounds knoωn from Japa¬ nese patent specifications JP 68 08, 277 and JP 70 03, 782, 5 and the publication, entitled YAKUGAKI ZASSHI ET7, 1083 (1967). These knoωπ compounds are: I. l-(4-pyridylmethyl)-6.7-dimethoxy-3.4-dihydroisoquinoli II. 1 -(4-pyridyl)-6»7-dimethoxy-3.4-dihydroisoquin.oline III. 1 -(4-pyridyl)-6.7-dihydroxy-3.4-dIhydroisoquinoline 11/ , 1-(4-pyridyl)-6-hydroxy-7-methoxy-3.4-dihydroisoquinoli 'J . 1 -(4-pyridylmεthyl)-6.7-dihydroxy-3.4-dihydroisαquinoli "■.. The dilating effect on bronchi (bronchus dilation) ^ζ- Since the bronchi of guinea-pigs are highly responsive to the contracting effect of the hlstamine on bronchi, guinea-pigs of both sexes weighing from 300-400 g were used in the inves gations (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 uπstriated muscle . The trachea of the dead animal ωas prepared and two zig-zag preparations were produced by a method according to Emmerson and Plackay (1979). The preparations were from 20 to 22 mm in length and were transferred to incubating dishes ωhich con¬ tained nutrient solution oxidized ωith carbogen (Krebs- Henseleit). The solution had a pH of 7.4 and a temperature of 37 C. The other end of the preparation ωas attached to an isotonic myograph-indicatαr , ωhich registered changes in . length of the preparation during contraction and relaxation thereof. After 60 minutes 2 ,umoJe/l hista ine were used to induce contraction of the smooth muscle, ωhich 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 ωas measured isotonically Using linear regression, there ωas calculated from the graohi presentation of the effect of the test doses the ED50-value, i.e. the concentration, ωhich induces a 50%-relaxation of the maximum response for the contraction of smooth muscle caused by histamine. At least two measurements were taken ωith each compound, on average 4-5. The relaxation effects (ED ) in respect of the compound investigated have been combined in Table I below. The values recited are the average values of measurements made. 8 Table 1 The relaxing effect of the derivatives on the smooth muscle of gu pig tracheae, where contraction has been induced ωith histamines (2/umole/l) and which resulted in a 50-60 -contraction in relation to the maximum contraction of the preparation. ED is the concen ration of the examined derivative resulting in a 50%-reductioπ in the induced contraction, π_ designates the number of measurement/ derivatives. Derivative Salt ED 50 /umole/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 _iπ_ vitro . The most ac 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 thu show that the compounds listed in the table had a pronounced bronchi-dilating effect when tested _in_ vi ro on the smooth muscle of guinea-pigs. 2. Blood-vessel dilation effect ( vasodilation ) The vasodilational effect of the pyridyl derivatives has bee tested in vitro on thoracic aorta preparations from rabbits. The tests were carried out on rabbits of both sexes and ωeighing from 2-2.5 kg (Neω Zealand White). The thoracic aorta of the dead animal ωas quickly prepared, removed and transferred to a petri-dish containing an oxidized Krebs- Haπseleit solution. A helical preparation (length 20-22 mm, breadth 2-3 mm) ωas than prepared in accordance ωith a metho proposed by Furchgott & Bhadrakom (1953). Several preparatio ωere obtained from a single thoracic aorta, and th-ese prepar tions were transferred to an incubation dish containing an oxidized Krebs-Hanseleit solution (37 C, pH = 7.4) for inves gation. The incubation dish had a volumetric capacity of 30 One end of the preparation was attached to a b.ronchial tube and the other to an isotonic myograph indicator. The measuri results were obtained isotonically, after the tonus of the preparation had stabilized, a period of 60 minutes. Contraction of the blood vessel ωas induzed with noradreπali ωhich ωas dosed to the incubation dish cumulatively, until t maximum contraction of the preparation was reached. I\la EDTA (10-5 mole/i), ωhich prevents premature inactivation of the noradrenaline, ωas also added tc the Krebs-Henseleit solutio The ED -value of t e noradrenaline for each preparation, i. 5 the amount of noradrenaline which results in a 50 -contracti of the preparation, was calculated with the aid of. linear regression from the response curve drawn up for the noradren line 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 ωa then drawn up, as in the earlier * case. The dosage relationsh were then determined in accordance ωith the folloωiπg formul subsequent to calculating the ED -value of noradrenaline in the presence of the test derivatives.: ED noradrenaline + test derivative (antagαπisten) / ED 50 noradrenaline. The formula shoωs at ωhich test-derivative concentration a ratio in the proximity of 4 (four) is reached, i.e. hoω 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 ωhen contracting of the muscle preparation is induced ωith noradrenaline. Concentration. Dosing Derivative Salt jmole/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 Papavεri^e HCl 1.0 3.2 T e above table refe z to dosin ratios = ED value for noradrenaline + test derivative ED value for noradrenaline bU The derivatives listed in the table displace the cumulative dosing curve of the noradrenaline to the right. The deriva¬ tives 185, 1208 and 1209 had an effect corresponding to that of the papaverine, the vasodilationary effect of the deriva¬ tive 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 effect on adrenergic receptors The beta-receptor activity of the most active bronchi-dilatin derivatives 1209 and 1217 was measured by a receptor binding method _in_ vitro with the aid of iodocyanopiπdolol (125 ICYP) as a radio-active ligand and lung membrane from guinea-pigs as the beta-receptor sources. The membrane receptor prepara¬ tions or compounds were prepared by, and the actual bonding tests carried out in accordance ωith a method described by Engels working group (1981 ), although ωith certain minor modifications . The radioligand (final concentration 39.5 pfl) and the membran suspension (40-100 jug protein) ωere incubated at 37 C for 60 minutes, either in the presence of propranolil (10 jum = unspecified bonding) or in the absence thereof (total bonding to show specific bonding above 95% of the total bonding. The membrane ligand with bound ligaπds was isolated by filtration and the radioactivity calculated with a gamma counter. The ability of these compounds to compete ωith the radioligands for binding to the beta-receptors ωas determined by incubatin the test derivative in different concentrations. The IC - value indicates the test derivative concentration which iπh ibits .50 -bonding of the radioligand, this value being calculated by linear regression subsequent to 3 logit-log conversion of the binding results. The IC -values calculated were 1.2 x 10 " iη in the case of 1209 and 0.4 x 10~ 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 ωere 1.00 and 0.95 respectively. No appreciable binding to beta-3 receptors could be shoωn. The absence of effect on beta-adrenergic receptors was supported —fi by the fact that prαpranolol (10 uM) _in_ vitro displaced the dosing curve for salbutamol relaxation in the guinea-pig trachea preparation to the right, ωhlle no such property ωas found in the case of 1217. Neither did the derivatives 1209, 1201, 1205, 1208, 1209 and 1210, cumulatively dosed (0.01 - 1 umole/l) cause any clear change in the beat frequency in th 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 ωith a maximum change at a concentration of 1 ιjmole/1. 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 Emmersαr J & P-lackay D (1979) J Pham Pharmacol _3_1» 79e FurcngoLt R F a Bhadrakom S (1953) J Pharmacol Exc Tner 108, 129 - 143 Reitz A B, Soπveaux E, Rosenkraπz R P et al. (1985) J Med Chem 2_8, 634 - 642 The invention ωill noω be described in more detail ωith reference to the folloωing working examples. Example 1 ethyl-S-bromonicotinate 5-Bromonicotinic acid (10 g, 0.05 mole) ωas admixed ωith 100 methanol and the mixture heated to almost boiling point. 3.5 of thionylchloride ωere added to the mixture over a period of 15 minutes. The mixture ωas 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, neutra lized with trethylamine and the solvents vaporized off. The ester was extracted from the evaporation residue ωith diisopr ether . The yield ωas 10.7 g (99%). Example 2 1 -( 5-Bromo-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoliπe (1209) A small amount of pyridine (0.3 ml) ωas 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 100 C ove a period of 4-5 hours. The resultant amide ωas not separated, but ωas used as such in future processes. The oily amide ωas dissolved in 50 ml of toluene and 10 ml of phosphorus oxychloride were added to the solution. The mixtur ωas boiled under reflux for four hours, cooled and the solvent αecanted off. The tough residue ωas ωashed ωith hexane, to remo e non-reacted phosphorus oxychloride, and dissolved in a 25%-ethanαl solution and ωas basified ωith an NaOH-solution . The product ωas extracted ωith diisopropyl ether. The yield was 6.4 g. m.p base 126 - 128 C (cryst. from isopropanol) Ms: 237 (N), 315 (N-CH OH) FIR: (pp ) 3.76 s (3 H, MeO) 3.96 s (3 H, MeO) 2.76 t (2 H, CH ) 3.84 t (2 H, CH ) 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 folloωiπg compounds ωere produced by the methods describe in Examples 1 and 2. Example 3 1-(2-Chloro-3-pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (1205) The title compound ωas produced from methyl-2-chloronicotiπat (6.8 g, 0.04 mole) and homoveratryl amine (7.8 g, 0.043 mole) The yield ωas 9.7 g (crude product: 80% of the theoretical) m.p. base 119.5 - 120.5°C hydrochloride 209.5 - 211 °C Ms: 302 (Pi), 267 (Pl-Cl) NMR: (ppm) 3.69 s (3 H, MeO) 3.95 s (3 H, FleO) 2.81 t (2 H, CH 2 ) 3.80 t (2 H, CH ) 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-Chlαro-3-pyridyl)-6.7-dimεthoxy-3.4-dihydroisoquinoline (1208) Tπe title compound ωas produced from methy1-6-chloronicotina (7.0 g, 0.041 mole) and homoveratryl amine (7.9 g, 0.044 mol The yield ωas 7.8 g (crude produce: 63% of the theoretical) m.p. base 109 - 112.5°C hydrochloride 197 - 198.5°C Ms: 302 (N) , 287 (N-Me), 271 (M-MeO), 267 (M-Cl) NMR: (ppm) 3.76 s (3 H, NeO) 3.96 s (3 H, MeO) 2.72 t (2 H, CH ) 3.84 t (2 H, CH ) 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 (12 The title compound ωas produced from methy1-2-chloronicotina (7.2 g, 0.044 mole) and 2-(4-methoxyphenyl) -ethylamine (8.5 0.056 mole) . The yield ωas 6.6 g (crude product: 55% of the t.taeoretical) m.p. hydrochloride 206.5 - 208 C Ms: 272 (M), 237 (M-Cl NP1R: (ppm^ 3.67 s (3 H, MeO) 2.81 t (2 H, CH ) 3.87 t (2 H, CH 2 ) 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 (122 The title compound was prepared from methyl-2-chloronicotiπat (7.5 g, 0.044 mole) and 2-(2-methoxyohe l)-etnyl amine (8.5 0.056. ole) The yield ωas 6.6 g (crude product: 55% of the theoretical) m.p. hydrochloride 238 - 240°C Pis: 272 (Pi), 237 (Pt-Cl) NPIR: (ppm) 3.89 s (3 H, PleO) 2.89 t (2 H, CH ) 3.87 t (2 H, CH ) 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 (121 The title compound ωas prepared from methyl-5-bromoπicotinat (5.0 g, 0.023 mole) and 2-(4-methoxy phenyl)-ethyl amine (4. 0.026 mole) The yield ωas 5.2 g (71% of the theoretical) m.p. hydrochloride 203.5 - 206 C Ms: 317 (PI), 237 (Pl-Br), 285 (Pl-CH OH) NPIR: (ppm) 3.70 s (3 H, PleO) 2.70 t (2 H, CH ) 3.80 t (2 H, CH ) 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- ethoxy-3.4-dihydroisoquinoline (121 Tne title comcound was produced from methy1-5-bromonicotinat (5.0 g, 0.023 mole) and 2-(2-methoxy phenyl)-ethyl amine (4. C.025 mole) . The yield was 3.7 g (51% of the theoretical) m.p. base 133.5 - 135.5 C hydrochloride 226 - 232°C Pis: 317 (PI), 285 (Pl-H- ■ CH 0) 237 (Pl-Br) NPIR: (ppm) 3.90 s (3 H, PleO) 2.79 t (2 H, CH ) 3.84 t (2 H, CH ) 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-dihydro- isoquinoline (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) . (P0C1 as condensing agent) The yield was 4.0 g (crude product: 53% of the theoretical) m.p. base 1 0 - 143°C hydrochloride 206 - 208°C Pis: 316 (PI), 301 (Pl-Ple), 281 (Pl-Cl) ' NPIR: (ppm) 3.69 s (3 H, PleO) 3.94 s (3 H, PleO) 2.80 t (2 H, CH ) 3.85 t (2 H, CH ) 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, Pie) Examp1e 10 1 -(5-Bromo-3-pyridyl )-5.7-diethoxy-3.4—dihydroisoquinoline (1 The title compound ωas 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 ωas 4.2 g (60% of the theoretical) m.p. base 96 - 99 C hydrochloride 220 - 223.5 C Pis: 375 (Pi), 330 (Pl-EtO), 346 (Pl-Et) NPIR: (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, CH ) 3.84 t (2 H, CH ) 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-p idyl)-6.7-dimethoxy-3.4-dihydroisoquinol (183) The title compound ωas produced from methyl-2.6-dichloronico- tinate (2.5 g, 0.012 mole) and homoveratryl amine (2.8 g, 0.O16 mole) . The yield was 3.2 g (79% of the theoretical) m.p. base 117 - 120°C hydrochloride 208 - 210.5°C Pis: 336 (Pi), 301 (Pl-Cl) NPIR: (ppm) 3.79 s (3 H, PleO) 3.96 s (3 H, PleO) 2.73 t (2 H, CH ) 3.84 t (2 H, CH ) 6.62 s (1 h, ar.CH) 6.79 s (1 H, ar.CH) 7.5.0 d (2 H, pyr.CH) Example 1 1 - 2-Pyrazyl)-6.?-dimethoxy-3.4-dihydroisoquinoline (1206) Tr>e title comDound was oroduced from the methyl ester of 2-pyrazine carboxylic acid (7.3 g, 0.05 mole) and homoveratr amine (10.9 g, 0.06 mole). The yield was 9.5 g (63% of the theoretical) m.p. hydrochloride 185 - 188°C Pis: 269 (Pi), 254 (Pl-Ple), 238 (Pl-PleO) NPIR: (ppm) 3.77 s (3 H, PleO) 3.80 s (3 H, PleO) 2.73 t (2 H, CH ) 3.88 t (2 H, CH ) 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 Pis: 324 (PI) , 309 (Pl-Ple), 293 (Pl-PleO) NPIR (ppm) 3.78 s (3 H, PleO) 3.93 s (3 H, PleO) 2.71 t (2 H, CH ) 33..8844 tt ((22 HH,, CCHH )) 0.95 tt ((33 HH,, BBuu--CCHH )) 11..3399 kkvv ((22 HH,, BBuu--CH ) 1.63 kkvv ((22 HH,, BBuu--CCHH )) 22..7733 kkvv ((22 HH,, BBuu--CH ) 6.75 s (1 H, ar.CH) 7.07 s (1 H, ar.C H) 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~chl-oro-4- pyridyl)-6.7-dimethoxy-3.4-dihydroisoquinoline (184) The title compound ωas produced from methyl-2.6-dichloro- isonicotiπate (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 - 167 C Pis: 481 (PI), 330 (PI- diPleO ■Ph-CH 2 ) NPIR (ppm) 3.78 s (3 H, PleO) 3.97 s (3 H, PleO) 2.74 t (2 H, CH ) 3.83 t (2 H, CH ) 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, PleO) 2.60 t (2 H, CH ) 3.68 t (2 H, CH ) 6.80 s (3 H, ar.CH) Example 15 1 -(2-(2' -(3.4-Dimethoxy phenyl) -ethyl-aminσ-3~pyridyl) -6.7- dimethoxy-5.4-dihydroisoquinoline (1207) The title compound ωas produced from methyl-2-chloronicotina (3.4 g, 0.02 mole) and homoveratryl amine (7.2 g, 0.04 mole) The yield ωas 2.0 g (22% of the theoretical) m.p. - (decomposes) Pis: 447 (PI) NPIR: (opm) - 3.74 s (3 H, PleO) 3.95 s (3 H, PleO) 2.89 t (2 H, CH ) 3.86 t (2 H, CH ) 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, PleO) 2.61 t (2 H, CH ) 3.67 t (2 H, CH ) 6.78 s (3 H, ar.CH) Example 16 1-(2-Chloro-6-methoxy-4-pyridyl)-6.7-dimethoxy-3.4-dihydro- isoquinoline (185) The title compound was produced from methyl-2-chloro-6- methoxyisonicotin.ate (1.8 g, 0.009 mole) and homoveratryl imi (2.0 g, 0.011 mole) The yield ωas 2.2 g (74% of the theoretical) m.p. base 116.5 - 120°C hydrochloride 201 - 203°C Pis: 332 ( I) , 301 (Pl-PleO), 297 (Pl-Cl) NPIR: (ppm) 3.78 s (3 H, PleO) 3.96 s (3 H, PleO) 3.98 s (s H, PleO) 2.73 t (2 H, CH ) 3.83 t (2 H, CH ) 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-tetrahydroiso- quinoline (1204) • The 1209 hydrochloride of the dihydro-derivative (2.0 g, 0.005 mole) ωas dissolved in methanol. The solution ωas coole to 10 - 15 C and small quantities of sodium borohydride (0.5 0.013 mole) were added over a period of 20 minutes, whereafte the mixture was stirred for tωo hours at 40 C, and then coole and acidified with a 10%-HCl solution. The solution ωas then evaporated off to leave hydrochloride. The yield ωas 2.0 g (95% of the theoretical) m.p. (HCl salt) 208 - 210°C Pis: 349 (PI), 348 (Pl-1 ) , 317 (PI-CH OH) NPIR: (ppm) 3.63 s (3 H, PleO) 3.85 s (3 H, PleO) 3.0 - 3.3 (5 H, CH , 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) 0 8.82 s (1 H, pyr.CH) Example 18 1-(2-Hydroxy-6-methyl-3-pyridyl)-6.7-dimethoxy-3.4-dihydro- isoquinoliπe (1220) 5 Homoveratryl amine (12.7 g, 0.07 mole) mεthyl-2-hydroxy-6- methylnicotinate (10.5 g, 0.07 mole) and pyridine (0.5 g) wer heated for 5 hours at 130 C. The mixture was cooled and disso in 100 ml of xylene. 20 g of phosphorus pentoxide ωere added 0 the solution ' and the mixture boiled under reflux for 4 hours and then cooled. The solvent ωas decantered and the solidifie residue dissolved carefully in 100 ml of ωater. The solution ωas basified ωith an ammonium solution and extracted ωith chl form. The ' solvent ωas evaporated off to leave a 9 g crude-pro 5 residue (43%). m.p. base 192 - 196°C hydrochloride 207 - 213°C Pis: 298 (Pi), 283 (Pl-Ple), 267 (Pl-PleO) 0 NPIR: (ppm) 3.77 s (3 H, PleO) 3.94 s (3 H, PleO) 2.33 s (3 H, Pie) 2.76 t (2 H, CH„) 3.75 s (2 H, CH ) 5.74 s (1 H, ar.CH) 6.86 s (1 H, ar.CH) " ;ς 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-dihydrois ' oquinoline (1215) The hydrochloride (5 g, 0.15 mole) of 1 - ( 2-Chloro-3-pyridyl ) 6.7-dimethαxy-3.4-dihydroisαquinoliπe ωas dissolved in 40 ml of an HBr-solution (48%). The solution ωas boiled in a nitro atmosphere for 5 hours and the solvent then evaporated off i a vacuum environment. The product ωas crystallized from an ethanol-etyl-acetate mixture. The yield ωas 2.8 g (43% of the theoretical; HBr-salt) m.p. hydrobromide 219 - 223 C Pis: 274 (PI) NPIR (ppm) 2.89 t (2 H,CH 2 ) 3.84 t (2 H, CH ) 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 ωas produced from corresponding dimethoxy deriva¬ tive 1206 (5 g, 0.015 mole) as recited in Example 19. The yield ωas 5.3 g (88% of the theoretical; HBr-salt) m.p. hydrobromide 212.5 - 215 C Pis: 385 (silylated; ole.ω. 241 + 2 " (CH )3Si) NPIR ppm) 3.16 t (2 H, CH. 4.01 t (2 H, CH ) 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 ωas produced from corresponding dimethoxy deriva¬ tive 1209 (2.4 g, 0.006 mole) as recited in Example 19. The yield ωas 2.4 g (83% of the theoretical; HBr-salt) m.p. hydrobromide 286 - 290 C Pis: 319 (PI) NPIR: (ppm) 3.10 t (2 H, CH ) 3.98 t (2 H, CH 2 ) 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-Amiπomethyl-3-pyridyl)-6.7-dimethoxy-3.4-dihydroiso- quiπoline (1221 ) The 2-chloro-3-pyridyl derivative (1205) (1.5 g, 0.005 mole) ωas dissolved in an ethanol solution of methyl amine ( 3 g methyl amine in 30 ml ethanol). The solution ωas boiled in a closed bomb at 140 C for 15 hours. The solvent and non-reacte amine ωere evaporated off, and the product ωas isolated from the evaporation residue by flash-chromatography (the column material ωas silicagel .Plerck, 230 - 400 mesh) end the eluate ωas toluene-acetone (1 :1). The yield ωas 1.1 g (74% of the theoretical) m.p. 231 - 234.5° (HC -salt) Pis: 297- (PI), 296 (Pl-1 ) , 282 (Pl-Ple), 265 (M-PleO) NPIR: (ppm) 3.87 s (3 H, PleO) 3.70 s (3 H, PleO) 3.02 d (3 H, Pie) 2.58 t (2 H, CH ) 3.75 t (2 H, CH ) 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) NPIR - the spectrum ωas obtained with the aid of a 200 PlHz Bruker-spectrometer with CDC1 as the solvent. Example 23 1 -(5-Brαmo-3-pyridyl)-6.7-dimethoxy-1.2.3.4-tetrahydroiso- quinoline (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) ωas added to the solution, whereafter the solution ωas heate in a ωater bath until the major part of the ethanol had vapo rized. Cooling of the residue resulted in a crystallized product. The Schiff base obtained ωas dissolved in a minor quantity of methylene chloride, and the solution ωas added sloωly to a hot (8θ " - 90°C) 20%-HCl-solution and boiled ωith reflux for 30 minutes. Subsequent to cooling in ice, the crystallized product ωas filtered-off, i.e. the hydrochlorid of the tetrahydroisoquinoline . The yield ωas 5.9 g (56% of the theoretical) m.p. hydrochloride 208 - 210.5°C. NPIR- and the mass spectrum corresponded to the values recited in Example 17

Claims: 26 CLAIP1S 1. Therapeutically useful dihydro- and tetrahydroisoquiπol and their physiologically suitable salts, characterized in that they have the formula I or I' in which formulae A = -CH= or -N= n = 0 or 1 R and R are the same or different and designate hydrogen, halogen, an hydroxyl group or an alkoxy group having 1-4 car atoms, R-, = hydrogen when R and R are hydrogen, or halogen, or an alkyl group having 1-6 carbon atoms, R = halogen, an alkyl or alkoxy group having 1-6 carbon ato or designates an amino group of the formula where R and R are the same or different and designate 5 b hydrogen or an alkyl group which has 1 -3 carbon atoms and ωhich can be substituted ωith one or tωo lower alkoxy, and R 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=, R and are hydrogen or an alkoxy group having 1 -3 carbon atoms, and R and R 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 bein 1-(2-chloro-6-methoxy-4-pyridyl)-6.7-dimethoxy-3.4-dihydrois quinoline, 1-(6-chloro-3-pyridyl)-6.7-dimethoxy-3.4-dihydroi quinoline, 1 -(5-bromo-3-pyridyl)-6.7-dimethoxy-3.4-dihydrois quinoline, 1 -(2-chloro-6-methyl-3-pyridyl)-6.7-dimethoxy-3.4 dihydroisoquinαline, 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-dimethαxy phenyl).- ethyl amino)-6-chloro-4-pyridyl) -6.7-dimethoxy-3.4-dihydrois quinoline . 4. A method for preparing physiologically active isoquiπαl derivatives of the formula I or I' and their physiologically acceptable sal s, in ωhich formula A = -CH= or -N= n = 0 or 1 R and R are the same or different and designate hydrogen, halogen, an hydroxyl group or an alkoxy group having 1-4 carbon atoms, R = hydrogen ωhen R and R are hydrogen, or halogen, or an alkyl group having 1-6 carbon atoms, R = halogen, an alkyl group or alkoxy group having 1-6 carbon atoms, or designates an amino group of the formula ωhere R and R_ are the same or different and designate 5 6 hydrogen or an alkyl group ωhich has 1 -3 carbon atoms and ωhich can be substituted ωith a phenyl group substituted with one or two lower alkoxy groups, and R can also be hydr 4 ωhen A is -N=, characterized in that an amide of the formula ωhere R - R a A have the above significance, are cyciize ωith Lewis aci c. 5. The use of compounds having the formula I or I' ' or their physiologically suitable derivatives or salts as therapeutical agents.

Inventors: ALLONEN HANNU, NIKANDER HANNU, ALLONEN, HANNU, NIKANDER, HANNU
Applicants: HUHTAMAEKI OY
Application year: 1987
Main classification: C07D401
IPC codes: C07D401