CS197277B2 - Method of producing new 1,5,10,10a-tetrahydrothiazolo/3,4-b/isoquinolines - Google Patents

Description

A represents a heterocyclic radical having 1 nitrogen atom, namely 3-pyridyl, 4-pyridyl or

5-isoquinololyl, wherein when A is 3-pyrldyl, it is

X 1 is hydrogen, halogen or cyano,

X2 is hydrogen or fluorine; and

X 3 is a hydrogen atom or a nitro group, but at least two of the symbols

X 1, X ₂ and X ₅ are hydrogen or together X ₁ and X _{2 are} methylenedioxy and X ₅ is hydrogen when

A is 4-pyridyl or 5-isoquinolyl

X 1, X 2 and X 3 are hydrogen, as well as a process for preparing salts of these compounds and forms (R) and (S) of the compounds of formula I and mixtures thereof.

The process of the present invention provides compounds of formula I by treatment of an amine of formula II MOON (Π), where

A is as defined above for the salt of formula III

where

X 1, X 2 and X 3 are as defined above,

R 1 represents a chlorine atom or an alkylthio group having from 1 to 4 carbon atoms or a benzylthio group; and

A 1 is anion, or R 1. A is a chlorine atom and A 1 is a chloride ion, or R 1 is an alkylthio group, preferably methylthio or benzylthio, and A 1 is an anion, for example an iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion.

In the case that Ri is Cl and Al © is a chloride ion, the reaction is carried out in an organic solvent such as acetonitrile in the presence of an alkaline condensing agent, for example triethylamine at 20 ^Q C.

When R1 is alkylthio or benzylthio and A1 is iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion, the reaction is carried out in a basic organic solvent, for example pyridine at 20 ° C.

The salt of formula III wherein R 1 is chlorine and Al 2 is chloride ion can be obtained by treating a 1,5,10,10a-tetrahydrothiazole [3,4-b] with a chlorinating agent such as phosgene, phosphorus pentachloride, thionyl chloride or oxalyl chloride. isoquinolin-3-quinone of formula IV

1,2,3,4-tetrahydroisoquinoline of formula VI

where

X 1, X 2 and X 5 have the above-mentioned meaning and

E represents a halogen atom or a hydroxysulfonyloxy group.

The reaction is usually carried out in the presence of sodium or potassium hydroxide at 20 ° C.

Compounds of formula (VI) may be obtained by treating an compound of formula (VII) with an inorganic acid

where

X 1, X 2 and X 3 are as defined above.

The reaction is usually carried out in an organic solvent or in a mixture of organic solvents, for example a mixture of toluene and tetrahydrofuran at a temperature of 0 to 70 ° C.

A salt of formula III wherein R 1 is alkylthio or benzylthio and A 1 is iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion can be obtained by treatment with a reactive ester of formula V

Ri‘ — Ai (V) where

R 1 represents an alkyl radical of 1 to 4 carbon atoms or a benzyl group and

A 1 represents a reactive ester residue, for example an iodine atom or an alkoxysulfonyloxy group, or a compound of formula IV by the action of triethyloxonium tetrafluoroborate or methyl fluorosulfonate.

The reaction is usually carried out in the presence or absence of an organic solvent, for example methylene chloride, at 20 ° C.

The thiazoloisoquinoline derivative of the general formula IV in which X1, X2 and X3 are as defined above with the exception of the cyano group in the case of X1 may be obtained by treatment with carbon disulfide in a basic environment where:

X 1, X 2 and X 3 are as defined above.

In order to obtain compounds of formula VI in which E is hydroxysulfonyloxy, the process is generally carried out by treatment with sulfuric acid in an aqueous medium at 100 ° C or in an organic solvent such as dimethylformamide in the presence of dicyclohexylcarbodiimide at 20 ° C.

In order to obtain compounds of the formula VI in which E is bromine, the process is usually carried out by treatment with a 48% aqueous solution of hydrobromic acid at the reflux temperature of the reaction mixture, whereupon the resulting product is isolated as the hydrobromide.

In order to obtain a compound of formula (VI) in which E is a chlorine atom, the reaction is usually carried out by treatment with thionyl chloride in an organic solvent such as chloroform saturated with gaseous hydrogen chloride at the reflux temperature of the reaction mixture. hydrochloride.

Compounds of formulas IV or VI in which X5 is nitro may also be obtained by nitration of a compound of formula IV or VI wherein X3 is hydrogen.

The nitration is usually carried out with nitric acid in sulfuric acid at a temperature of -20 ° C or nitronium fluoroborate in acetonitrile at 20 ° C or with sodium nitrate in trifluoroacetic acid at 20 ° C, optionally followed by separation of the isomers thus obtained.

The compound of formula IV wherein X 1 is cyano and X 2 and X 3 are as defined above can be obtained from a compound of formula IV wherein X 1 is nitro by any means by which the nitro group can be converted to the cyano group via the corresponding amino derivative.

The compound of formula IV wherein X 1 is nitro can be obtained from a compound of formula IV wherein X 1 is hydrogen as described above to obtain compounds of formula IV wherein X 3 is nitro.

The 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline of formula VII can be obtained by reducing the 1,2,3 ', 4-tetrahydroisoquinoline of formula VIII

where

X 1, X 2 and X 3 are as defined above and

R represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms, or by reducing some of the salts thereof.

When R is hydrogen, the reduction is preferably carried out with lithium aluminum hydride in tetrahydrofuran at 20 to 70 ° C.

When R is C1 -C4 alkyl, the reduction is preferably carried out with an alkali metal borohydride such as sodium borohydride in an organic solvent or in a mixture of water and an organic solvent such as ethanol and water and the process is carried out at 10 ° C. ° C to the reflux temperature of the reaction mixture.

In order to obtain a compound of formula (VII) in which X 3 is nitro, it is preferred to use an ester in which R is an alkyl moiety, since the reduction in the conditions under which the nitro is retained must be observed.

The 1,2,3,4-tetrahydroisoquinoline of formula VIII wherein R is C1-C4 alkyl can be obtained by esterification of the 1,2,3,4-tetrahydroisoquinoline of formula V wherein R is hydrogen by methods generally known to convert an acid to an ester without affecting the rest of the molecule.

The 1,2,3,4-tetrahydroisoquinoline of formula VIII wherein R is hydrogen, X 1 and X 2 are as defined above and X 3 is hydrogen may be obtained from phenylalanine of formula IX

where

X 1, X 2 and X 5 are as defined above, as described in A. Pictet and Th. Spengler, Chem. Ber., 44, 2030 (1911).

When phenylalanine IX in form L is used, the resulting product of formula I in form (S) is obtained.

When phenylalanine (IX) in form D is used, the resulting product of formula (I) is obtained in form (R).

When phenylalanine IX in the form D, L is used, the product of the formula I in the form (RS) is obtained.

Compounds of formulas VII or VIII in which X 3 is nitro can be obtained by nitration of compounds of formulas VII or VIII in which the radical is hydrogen.

This nitration is usually carried out with a mixture of nitric acid and sulfuric acid at a temperature of -20 ° C or a mixture of sodium nitrate and trifluoroacetic acid at a temperature of 20 ° C and, if necessary, subsequent separation of the isomers thus obtained.

The novel compounds of the invention can optionally be converted into acid addition salts. Addition salts must be obtained by treating the resulting products with acids in suitable solvents. Organic solvents include, for example, alcohols, ketones, ethers or chlorinated solvents. The resulting salt precipitates upon optional concentration of the solution and is isolated by filtration or by alloying.

The novel compounds of formula (I) and / or salts thereof can be purified by physical means, for example, crystallization or chromatography.

The novel compounds obtained by the process of the invention and their salts have interesting pharmacological properties. These are analgesics and antipyretics. Their anti-inflammatory activity is less pronounced.

Analgesic efficacy can be demonstrated in rats at doses of 2 to 50 mg / kg by oral administration according to the method of L. O. Tandall and J. J. Selitto, Arch. Int. Pharmacodyn., 111, 409 (1957), in the modification described by K. F. Swingle et al., Proc. Soc. Exp. Biol. Med., 137, 536 (1971). Most compounds are also active in mice at a dose of 20 to 200 mg / kg by oral administration, as evidenced by the method of E. Siegmund, Proc. Soc. Exp. Biol. Med., 95, 729 (1957).

The antipyretic activity of the compounds of the invention can be demonstrated in rats at a dose of 5-50 mg / kg by oral administration as described by J. J. Loux et al., Toxicol. Appl. Pharmacol., 22, 674 (1972).

The anti-inflammatory activity of the compounds of the invention can be demonstrated in rats at dosages of 5 to 50 mg / kg when administered orally as described by K. F. Benitz and L. M. Halí, Arch. Int. Pharmacodyn., 144,185 (1963).

Compounds of the invention are generally more potent than glafenine (French drug no. 2413 M), as shown in the following table:

Compound Analgesic Activity The antipyretic activity of the example

The Randall / Siegmund Method. Loux / Selitto method DAso mg / kg DAso mg / kg orally DAso mg / kg orally orally rat rat rat

13 5 45 8 2, 4 8 30 5 5 22nd 100 ALIGN! 45 6 5 65 15 Dec 7 10 35 8 50 30 9 30 140 15 Dec 10 30 40 glafénine 15 Dec 45 25

In addition, the compounds of the invention have low toxicity. Their DL 50 is 300 mg / / kg to 3000 mg / kg or higher.

For medical use, the compounds of the invention may be used in free form or in the form of salts, non-toxic at the dosages employed.

Of particular interest are compounds of formula I wherein A is 3-pyrldyl,

4-pyridyl or 5-isoquinolinyl and X 1, X 2 and X 3 are hydrogen atoms in the form of (R) and (S) or in the form of mixtures of these isomers.

The invention will be illustrated by the following examples.

He did

To a suspension of 1.3 g of 3-chloro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) chloride in 15 ml of acetonitrile is added slowly a suspension of 0.5 g of 3- aminopyridine in 10 ml of acetonitrile, and then dropwise 2.9 ml of triethylamine in 5 ml of acetonitrile. A slight precipitate forms, upon heating of the reaction mixture it partially dissolves, and a new precipitate is formed. The mixture is stirred at 20 ° C for 2 hours and then evaporated under reduced pressure at 50 kPa (3.3 kPa). The residue is dissolved in a mixture of 25 ml of water and 50 ml of methylene chloride. The organic phase is decanted and extracted with 2 x 33 ml of 1N hydrochloric acid. The aqueous extracts are combined and basified by the addition of 10N sodium hydroxide solution, followed by extraction with 2 x 30 ml of methylene chloride. The organic phase was washed with water and dried over magnesium sulfate. After filtration, the mixture is evaporated to dryness under reduced pressure (50 mm Hg) to give 0.5 g of 3- (3-pyridyliminojo-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S). mp 111 ° C after recrystallization from benzene / iso-propyl oxide 1: 3 v / v.

_{[W] d} 20 = _260 ± 7 ° (c = 2, ethanol).

3-Chloro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (S) chloride can be prepared as follows:

To a solution of 2,2-gl, 5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline-thion- (S) in 25 ml tetrahydrofuran was added dropwise 50 ml of toluene solution with stirring at 20 ° C. phosgene concentration of 2 moles in 1 liter. After 15 minutes, the mixture becomes cloudy and then stirred for 5 hours, further heated at 50 ° C for 1 hour. The solvent was evaporated under reduced pressure. 3.3 kPa at 60 ° C to give 2.6 g of 3-chloro-1,5,10,10a-tetrahydro-drothiazolo [3,4-b] isoquinolinium chloride (Sj) as a white crystalline powder which is very hygroscopic.

1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinoline-thione- (S) can be prepared as follows:

To a solution of 100 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline- (S) in 4000 ml of 0.25 N sodium hydroxide is added dropwise with vigorous stirring at 20 DEG C. 40 g of: carbon. The reaction is exothermic. A precipitate formed and the reaction mixture was stirred for a further 3 hours, then neutralized by the addition of 4 N hydrochloric acid. 10,10a-tetrahydrothiazolo197277 [3,4-b] -3-isoquinolinithione- (S) as white crystals, m.p. 150 ° C. [.alpha.] D @ ²⁰ = -377 + 4 DEG (c = 1, chloroform).

3-Hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (S) can be prepared as follows:

A solution of 41 g of 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline- (S) in a mixture of 13 ml of 1.83 sulfuric acid and 70 ml of water is heated to 110 ° C. Approximately 50 ml of water is distilled off, and then the mixture is concentrated under reduced pressure of 2.6 kPa at 100 ° C. The oily brown residue was mixed with a mixture of 14 ml. Of 1.84 density sulfuric acid and 70 ml. Of water. Water (50 ml) was distilled off again and the mixture was concentrated again as above and finally evaporated to dryness at 100 ° C and 1 mm Hg. The residue crystallizes by cooling. The crystalline residue is recrystallized from a mixture of 140 ml of ethanol and 60 ml of water. After cooling to 5 ° C for 15 hours, the crystals are collected by filtration and washed with 20 ml of a 3: 1 mixture of ethanol and water and 2 x 25 ml of ethanol. The crystals were then dried at 60 ° C under a reduced pressure of 1 mmHg to give 48 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline- (S) as white crystals.

[.alpha.] D @ ²⁰ = -55 ± 1 DEG (c = 1, dimethyl sulfoxide). Example 1 ad 2

The procedure is as in Example 1, but starting from 7.8 g of 3-chloro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium chloride (S) and 3 g of 4-aminopyridine, to give 2.5 g of 3- (4-pyridylimino) -1,5,10,10a-itetrahydrothiazolo [3,4-b] isoquinoline- (S), m.p. 110-115 ° C after recrystallization from toluene. and isopropyl oxide melts the resulting product at 130 ° C.

_{[W] D20 =} -258 ± 3 ° (c = 1, etanolj.

K Γ i k 1 and d 3

To a solution of 15 g of 3-aminopyridine in 1 liter of pyridine is added in small portions 36.3 g of 3-methylthlo-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium- (Sj). After 24 hours at 20 DEG C., the reaction mixture is evaporated to dryness under reduced pressure (50 mm Hg) and the residue is dissolved in a mixture of 250 ml of methylene chloride, 200 ml of 2N sodium hydroxide and 200 ml of water. The mixture is filtered, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure at 40 ° C.

The residue was recrystallized from 150 ml of acetonitrile to give 22.4 g of 3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- [S] as white crystals of m.p. mp 111 ° C.

[α] D ²³ == -258 + 3 [c-2, ethanol].

3-Methylphthio-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide (S) can be prepared as follows:

Dissolve 38 g of 1,5,10,10a-tetrahydro-thiazolo [3,4-b] -3-isoquinolinthione (S) in 500 ml of methylene iodide. After 15 hours at 20 ° C, the crystals formed are collected by filtration, washed with 2 x 50 ml of ether and then dried at 20 ° C and 1 mbar to give 61.5 g of 3-methylthio-1,5, 10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide- [α] m.p. 140-150 ° C with decomposition.

Example 1 a d 4

To a solution of 7.5 g of 4-aminopyridine in 300 ml of pyridine was added in small portions 14.5 g of 5-methylthio-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide- (S). The suspension slowly goes into solution. After 24 hours at 20 ° C, the mixture is evaporated to dryness under reduced pressure (3.3 kPa). The residue is dissolved in a mixture of 250 ml of methylene chloride and 200 ml of water. The organic phase is decanted, dehydrated with magnesium sulfate, filtered and concentrated to 100 ml under reduced pressure.

This solution is applied to a 3 cm diameter column containing 300 g of silica gel and the column is washed with methylene chloride and 1% methanol and 500 ml fractions are collected. Fractions 2 and 3 were evaporated to dryness to give 2.0 gl-5,10,10a tetrahydrcithiazolo [3,4 b ^j J isochinolinthionu- -3- (S).

Fractions 6-9 were also pooled and evaporated to dryness to give 5.1 g of 3- [4-pyridylimino] -1,5,10,10a-tetrahydrothiazolo] 3,4-bisisoquinolin-5S as white crystals of m.p. recrystallization from toluene / isopropyloxide (1: 3 by volume) melted at 130 ° C.

[ _.alpha. ] _D @ ²⁰ = -2.59. + -. 3 DEG (c = 1, ethanol).

Example 1 a d 5

To a solution of 3 g of 3-aminopyridine in 100 ml of pyridine was added 6 g of 3-methylthio-9-nitro-1,5,10,10a-itetrahydrothiazolo [3,4-b] isoquinolinium iodide- (S). After 6 hours at 20 DEG C., the reaction mixture is evaporated to dryness under reduced pressure (50 mm Hg). The residue is dissolved in a mixture of 300 ml of methylene chloride and 200 ml of water. The organic phase is decanted, washed with 3 x 200 ml of water, dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained is recrystallized from 40 ml of acetonitrile. 3.9 g of 9-nitro-3- [3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) are thus obtained in the form of white crystals, m.p. 144 Deň: 32 ° C.

[.alpha.] D @ ²³ = -5.5 ± 5 DEG (c = 2, chloroform).

3-Methylthlo-9-nitro-1,5,10,10-tetrahydro-thiazolo [3,4-b] isoquinolinium] -ide (S) can be produced as follows:

Dissolve 40 g of 9-nitro-droithiazolo 5,10,10a-tetrahydro [3,4 b ^j] -3-isochinolinthionu * (S) in 100 ml of methylene iodide. After 48 hours at 20 ° C, the crystals formed are collected by filtration, washed with 2 x 30 ml of ether and then dried at 20 ° C under reduced pressure. 6.0 g of 3-methylthio-9-nitro-1,5,10,10a-tetrahydrothlazolo [3,4-bisoquinolinium iodide- (S) are thus obtained.

7-nitro-, 8-nitro- and 9-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthiones (Sj) can be obtained as follows:

To a solution of 122 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline- (S) in 1000 ml of trifluoroacetic acid was added 85 g of anhydrous sodium nitrate as a fine powder. The mixture is stirred at 20 DEG C. for 5 hours and then concentrated under reduced pressure (50 mm Hg) and then at 100 mbar. The residue was washed with ether (3.times.200 ml). A clear yellow solid is obtained, which is crushed and dried at 40 ° C under reduced pressure of 1 mmHg.

The solid thus obtained was dissolved in 5000 ml of 0.3 N sodium hydroxide solution. While stirring, 35 ml of carbon disulfide was added to the solution, and the mixture was further stirred at 20 ° C for 17 hours. The mixture was neutralized by the addition of 4 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with plenty of water and then with ethanol, dried under reduced pressure (13.3 Pa) and then dissolved in 3200 ml of boiling toluene. The insoluble matter was collected by filtration and the filtrate was cooled to 10 ° C. The crystals formed are collected by filtration, washed with 100 ml of ethanol, dried at 80 DEG C. under a reduced pressure of 13.3 Pa and recrystallized from 1000 ml of a 1: 1 mixture of acetonitrile and ethanol to give 45 g of 7- nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione (S), m.p. 182 ° C.

[.Alpha.] D @ ²⁰ = -458 ± 5 DEG (c ~ 2, chloroform).

The toluene filtrate is evaporated to dryness and the residue is dissolved in boiling acetonitrile (600 ml). The resulting crystals were collected by filtration and dried at 60 ° C and 13.3 Pa. 29 g of a mixture of 8-nitro- and 9-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthiones- (S) are thus obtained. The two products were separated by chromatography on 2.4 kg silica gel in a 7 cm diameter column. The column is eluted with a 1: 1 by volume mixture of methylene12 chloride and cyclohexane and 1000 ml fractions are collected.

Fractions 6 to 15 are pooled and evaporated to dryness. The residue is recrystallized from 150 ml of anisole and 150 ml of acetonitrile. After drying at 60 ° C and 13.3 Pa, 6.2 g of 9-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione- (S) o was obtained. mp 203 ° C, [α] D ²³ = -654 ± 7 ° (c = 1, chloroform).

Fractions 17 to 26 are combined and evaporated to dryness under reduced pressure. The residue is recrystallized from 170 ml of anisole and then from 170 ml of acetonitrile. After drying at 60 DEG C. under a reduced pressure of 13.3 Pa, 3.9 g of 8-nitro-1,5,10,10-aetrothiazol [3,4-b] -3-isoquinolinthione ( S), melting point 220 ° C.

[α] ²⁰ = -338 + 3 ° (c = 0.5, chloroform).

Example 6

To a solution of 18.2 g of 3-methylthio-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodo (S) in 500 ml of pyridine is added 10.8 g of 5-aminoisoquinoline. After 5 hours at 20 ° C the mixture was completely dissolved and allowed to settle for 10 hours. Thereafter, the solution is evaporated to dryness under reduced pressure at 60 ° C. The residue is dissolved in a mixture of 250 ml of 1N sodium hydroxide solution and 250 ml of methylene chloride. The organic phase is decanted, washed with 2 x 100 ml of water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure at 40 ° C. Isopropanol (150 ml) was added to the residue and the mixture was boiled and further filtered while hot. After cooling to 5 ° C, the crystals formed were collected by filtration and washed 3 times with 10 ml of isopropanol. After drying at 60 [deg.] C. and 13.3 Pa, 13.0 g of 3- (5-isoquinolylimino) -1,5,10,10a-tetrahydro-thiazolo [3,4-b] isoquinoline [ S) in the form of white crystals having a melting point of 164 ° C.

[α] D ²⁰ = -198 ± 2.5 ° (c = 2, chloroform). Example 7

The procedure was as in Example 6, but starting from 3-methylthio-1,5,10,10-tetrahydrohydrothiazolo [3,4-b] isoquinolinium iodide (R) and 21.6 g of 5-aminoisoquinoline, whereby 27.4 g of 3- (5-isoquinolylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (R), m.p. 164 DEG C., are obtained after recrystallization from acetonitrile.

[Α] D ²⁰ = +199 ± 2.5 ° (c = 2, chloroform).

3-Methylthio-1,5,10,10a-tetrahydrothiazole [3,4-b] isoquinolinium iodide (R) may be prepared as follows:

Dissolve 30.0 g of 1,5,10,10a-telhydrhydriazolo [3,4-b] -3-isoquinolinthione (R) in a mixture of 13 ml of methyl iodide and 150 ml of methylene chloride. After 20 hours at 20 DEG C., the crystals formed are collected by filtration, washed with 2.times.50 ml of ether and then dried at 20 DEG C. and under a pressure of 20 mm Hg. In this way, 38.5 g of 3-methylthio-1,5,10,10a-tetrahydrothiazolo [3,4-bisoquinolinium iodide (R), m.p. 140 DEG-150 DEG C., with decomposition, is obtained.

1,5,10,10a-tetrahydrothiazolo [3,4- b] -3-isoquinolinthione (R) may be prepared as follows:

To a solution of 33.9 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (R) in 1000 ml of 0.6 N sodium hydroxide solution is added dropwise with vigorous stirring 14 g of carbon disulphide. The mixture was stirred at 20 ° C for 1 hour and stirred for 15 hours after the precipitate had formed.

The mixture was neutralized by the addition of 4 N hydrochloric acid. The formed crystals were collected by filtration and washed with water and then with ethanol to give 30.0 g of 1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione - (R) in the form of white crystals of melting point 150 ° C.

3-Hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (R) may be prepared as follows:

A solution of 2.8 g of 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (R) in a mixture of 7.9 ml of 1.83 sulfuric acid and 50 ml of water is heated at 100 ° C for one hour under reduced pressure 2. 66 kPa and then at 160 ° C for an hour. The crystalline residue was cooled to give 33.9 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (RJ) as a white crystalline solid, m.p. 318 ° C.

3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (R) can be obtained from D-phenylalanine by the method of S. Yamada and T. Kunieda, Chem. Pharm. Bull., 15, 490 (1967) for L-phenylalanine.

In a similar manner, the compounds of the following examples can be obtained using the appropriate starting materials.

Example 8

3- [3-pyridylimino] -1,5,10,10a-tetrahydrothiazolo [3,4-h] isoquinoline (R), m.p. 112 ° C.

[α] _D 20 = +260 + 3 ° (c = 2, ethanol-i.

Example 1 9

3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (R, Sj), m.p. 110 ° C.

Example 10

8-fluoro-3- [3-pyridylimino] -1,5,10,10a-tetrahydro-thiazolo [3,4-b] isoquinoline- [R, S] m.p. 139 ° C.

They did

7,8-methylenedioxy-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (R, S), pale yellow crystals, m.p. 201 ° C.

Example 1 a d 12

7-chloro-3- (3-pyridylimino) -1,5,10,10a-tetrahydro-thiazolo [3,4-b] isoquinoline (S), m.p. 125 ° C.

[a] ,, ² _»= -273 ± 3 ° (c = 1.1, chloroform). Example 13

7-fluoro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (S), m.p. 99 ° C.

_{[W] D20 =} -227 ± 3 ° (c = 1, methanol).

Example 14

7-Cyano-3- (3-pyridylimino) -1,5,10,10a-tetrahydro-thiazolo [3,4-b] isoquinoline (S) m.p. 172 ° C.

[Α] ²⁰ = -300 ± 3 ° (c = 1, chloroform).

Subject

Claims (3)

Subject A process for the preparation of the novel 1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline derivatives of the general formula I wherein: A represents a heterocyclic radical having 1 ring nitrogen atom, namely 3-pyridyl, 4-pyridyl and 5-isoquinolyl, and when A represents 3-pyridyl means X 1 is hydrogen, halogen or cyano, X2 is hydrogen or fluorine; and X 5 is a hydrogen atom or a nitro group, but at least two of the symbols. X 1, X 2 and X 5 are hydrogen or together X 1 and X 2 are methylenedioxy and X 3 is hydrogen if A is 4-pyridyl or 5-isoquinolyl A hydrogen atom, a process for preparing salts of these compounds, and a form (R1 and S) of the compounds of formula I and mixtures thereof, characterized in that the amines of formula II are reacted H2N — A (Π) where A is as defined above, with a salt of formula III wherein Χι, X2 and X3 are as defined above, R1 represents a chlorine atom and the C1-6 chloride anion or R1 represents an alkylthio group having from 1 to 4 carbon atoms or a benzylthio group; and A 1 represents an iodide anion, then optionally converting the product thus obtained into its acid addition salt. 2. The process of item 1, for the preparation of 1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline derivatives of formula I INVENTION where A is 3-pyridyl or 4-pyridyl, and when A is 3-pyridyl, it is X 1 is hydrogen or halogen or cyano, X2 is hydrogen or fluorine and X3 is hydrogen or nitro, wherein at least two of X, X2 and X3 are hydrogen or together X1 and X2 are methylenedioxy and X5 is hydrogen when A is 4-pyridyl, is ,Ι, X2 and X3 are hydrogen, in the form of (R) and (Sj) or in the form of mixtures of these isomers, also in the form of acid addition salts, characterized in that the amine of the general formula II is reacted H2N — A cm where A is as defined above, with a salt of formula III wherein Χι, X2 and X3 are as defined above, R 1 is chlorine, C 1 -C 4 alkylthio or benzylthio; A 1 represents a chloride or iodide anion and optionally converts the resulting product to its acid addition salt. 3. The process according to item 1, for the preparation of new 1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline derivatives of the formula in the form of (R) and (S) or as a mixture of these forms, and also in the form of addition salts of these compounds with acids, characterized by reacting 5-aminoisoquinoline with a salt of the formula R 1 is chlorine, C 1 -C 4 alkylthio or benzylthio; A 1 represents a chloride or iodide anion, then optionally converting the product so obtained into its acid addition salt. Severography, n. P., Plant 7, Most