CS203935B2 - Process for preparing new /1,3-thiazino//3,4-b/isoqunolines - Google Patents

Description

The present invention relates to a process for the preparation of novel isoquinoline derivatives of the general formula I

N-A (!) Where

A represents 3-pyridyl, 5-isoquinolyl or 3-alkyl-5-isoquinolyl, wherein the alkyl moiety contains from 1 to 10 carbon atoms in the straight or branched chain in free form or in the form of acid addition salts.

The compounds of the formula I can be obtained by the process according to the invention by treatment with an amine of the formula II

A — NHz (Π) where

A is as defined above for the salt of formula III

where

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

Ai means anion.

In case that R represents a chlorine atom, is Al ^- chloride ion and the reaction is conducted in an organic solvent such as acetonitrile in the presence of an alkaline condensing agent, for example triethylamine at a temperature of 20 ° C.

When R1 is alkylthio, preferably methylthio or benzylthio, Ar is iodide ion, sulfate ion, tetrafluorohorate ion or fluorosulfonate ion and the reaction is carried out in a basic organic solvent, for example pyridine, at a temperature of 30 to 50 ° C.

The salt of formula III in which R 1 is a chlorine atom and A 1 is a chloride ion can be obtained by treating a 1,6,6,11,11a-tetrahydro- [1,3-thiazino] by the action of a chlorinating agent such as phosgene, phosphorus pentachloride, thionyl chloride or oxalyl chloride. j [3,4-b] isoquinoline-4-thione of formula IV

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 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 benzyl a

A 1 represents a reactive ester residue such as an iodine atom or an alkyloxyxysulfonyloxy group or a compound of formula IV by treatment with triethyloxonium tetrafluoroborate or methylfluorosulfonate.

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

1,6,6,11,11a-Tetrahydro- [1,3-thiazino] [3,4-b] -4-isoquinolinethione IV can be obtained by treatment with 3- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinoline) sequentially with carbon disulfide in the presence of triethylamine and then with methanesulfonyl chloride or tosyl chloride, followed by cyclization of the thus formed intermediate.

The reaction with carbon disulfide is usually carried out in the presence of a base, for example a tertiary amine such as triethylamine.

The reaction with carbon disulfide and then with methanesulfonyl chloride or tosyl chloride is preferably carried out in an organic solvent, for example pyridine, at a temperature of -10 to 20 ° C.

The cyclization is usually carried out by heating in an organic solvent, for example dimethylformamide or in a mixture of organic solvents, for example dimethylformamide and pyridine, at a temperature of 50 to 100 ° C. It is not necessary to isolate the intermediate obtained to effect cyclization.

3- (2-Hydroxyethyl) -1,2,3,4-tetrahydroisoquinoline can be obtained from 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline by the method of TA Grabb et al., JCS Parkin II, 370 ( 1977).

3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline can be obtained from phenylalanine by the method of S. Yamada and T. Kunleda, Chem. Pharm. Bull., 15, 490 (1987).

When L-phenylalanine is used, the compound of formula I is obtained in the form of S.

When D-phenylalanine is used, the compound of formula I is obtained in the form of R.

When D, L-phenylalanine is used, the compound of formula 1 is obtained in the form of R, S.

The novel products obtained by the process according to the invention can optionally be converted into acid addition salts. These acid addition salts can be obtained by reacting the compounds of formula I with acids in an appropriate solvent. Organic solvents include alcohols, ketones, ethers or chlorinated solvents. The resulting salt precipitates upon optional concentration of the solution and is then isolated usually by filtration or decantation.

The novel compounds of the formula I and / or their salts can optionally be purified by physical processes such as crystallization or chromatography.

The novel compounds obtained by the process according to the invention have interesting pharmacological properties, namely analgesic, anti-inflammatory and antipyretic properties.

Analgesic efficacy can be demonstrated in mice at a dose of 0.25 to 100 mg / kg by oral administration as described by Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729 (1957).

The anti-inflammatory effect can be demonstrated in rats at a dose of 0.25 to 100 mg / kg by oral administration as described by K.F. Benitz and L.M. Halí, Arch. Int. Pharmacodyn. 144: 185 (1963).

The antipyretic effect can be demonstrated in rats at doses of 0.25 to 50 mg / kg when administered orally as described by J. J. Loux et al., Toxicol. Appl. Pharmacol., 22, 674 (1972).

In addition, the compounds of the invention have very low toxicity. Their acute toxicity to mice is 500 to 5000 mg / kg when administered orally.

Of particular interest are compounds of formula I wherein A is 5-isoquinolyl or 3-alkyl-5-isoquinolyl with a straight or branched chain alkyl moiety of 1 to 8 carbon atoms, of which A is 5- isoquinolyl or 3-methyl-5-isoquinolyl, in particular

4- (5-isoquinolylimino) -1,6,11,11a-tetrahydr o [1,3-thiazino] [3,4-b] isoquinoline- (R, Sj)

4 - [(3-methyl-5-isoquinolylimino) -1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinoline- (R, S) slou3 β

Which, in free form or in pharmaceutically acceptable salt form, are nontoxic at the doses used.

The invention will be illustrated by the following examples.

Example 1

To a solution of 0.42 g of 5-aminoisoquinoline in 20 ml of pyridine is added 0.67 g of 4-methylthio-1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinolinium iodide- ( R, S), then heated at 40 ° C for 48 hours. The mixture is evaporated to dryness under reduced pressure at 50 ° C. The residue is dissolved in a mixture of 50 ml of methylene chloride and 20 ml of 2 N sodium hydroxide solution. Deň: 29 ° C. The residue is chromatographed on 6 g of silica gel in a 0.7 cm diameter column, eluting with methylene chloride and collecting 30 ml fractions. Fractions 3 to 5 are combined and evaporated to dryness under reduced pressure (5.3 kPa) at 30 ° C. In this way 0.14 g of 4- (5-isoquinolylimino) -1,11,11a-tetrahydro-1,3-thiazino] [3,4-b] isoquinoline- (R, S) is obtained in the form of white crystals. mp 150 ° C.

4-methylthio-1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinolinium iodide (RS) can be obtained as follows:

0.67 g, 6,11,11a-tetrahydro- [1,3-thiazinoy [3,4-b] isoquinoline-4-thione- (RSj) is dissolved in 20 ml of methyl iodide. After standing for 15 hours at 20 ° C the mixture is concentrated at 20 mm Hg and 20 ° C.

1.05 g of 4-methylthio-1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinolinium iodide (RS) is obtained.

1,6,11,11a-Tetrahydro- [1,3-thiazino [3,4-b] isoquinoline-4-thione- (RS) can be obtained as follows:

To a solution of 5.3 ml of triethylamine and 3 ml of carbon disulphide in 10 ml of pyridine was added dropwise a solution of 3.1 g of 3- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinoline while stirring at -10 ° C. - (RS) in 15 ml pyridine. The mixture was maintained at this temperature for 17 hours, then a solution of 1.35 ml of methanesulfonyl chloride in 10 ml of pyridine was added dropwise, and the reaction mixture was allowed to stand for 2 hours, warming to 20 ^° C. the mixture is evaporated to dryness under reduced pressure at 80 ° C.

The residue is chromatographed on 60 g of silica gel in a 2 cm diameter column. The column was eluted with methylene chloride, collecting 200 ml fractions. Fractions 2 to 5 are combined and evaporated to dryness under reduced pressure (5.3 kPa) at 30 ° C. 0.68 g of 1,6,11,11a-tetramethyl- [1,3-thlazino] [3,4-b] isoquinoline-4-thione (RS) is obtained in the form of white crystals, m.p. Mp 162 ° C.

In a similar manner, the compounds of the following examples can be obtained.

Example 2

4- (3-Pyridylimino) -1,6,11,11-tetrahydro- [1,3-thiazino] [3,4-b] isoquinoline (RS), the neutral fumarate of which melts at 150 ° C.

Example 1 a d 3

4 - [(3-Methyl-5-isoquinolyl) imino] -1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinoline (RSJ), white crystals melting at 158 ° C.

Example 1 a d 4

4- (3-Propyl-5-isoquinolyl) -1,6,11,11a-tetrahydro- [1,3-thiazino] [3,4-b] isoquinoline (RS), whose neutral fumarate melts at 145 ° C.

Example 5

4 - [(3-octyl-5-isoquinolylimino) -1,6,11,11a- [1,3-thiazino] [3,4-b] isoquinoline (RS), the acid fumarate of which melts at 144 Deň: 32 ° C.

283883

Pharmacotagic activity of the compounds of the invention

Example

Acute toxicity DL 50 mg / kg per os

Anti-inflammatory effect Analgesic effect Antipyretic effect carrageenan abscess Reaction to phenylbene- Reaction to brew (Benitz and Halí) (rat)

DA50 mg / kg p osinquinone (Siegmund) (mouse) DA50 mg / kg p os yeast (IJ Loux) (rat) DE50 mg / kg p os non-toxic up to 900 70 approximately 300 3,2

1200 1,5

300 to 900 8 nontoxic to 900 10 to 100

2

16 approximately 2 1 9

Claims (2)

A process for the preparation of novel [1,3-thiazino] [3,4-bisoquinoline derivatives of the general formula I N-A (I) wherein A is 3-pyridyl, 5-isoquinolyl or 3-alkyl-5-isoquinolyl, wherein the alkyl moiety contains from 1 to 10 carbon atoms in a straight or branched chain in free form or in the form of acid addition salts, characterized in that: in the reaction of an amine of formula II A — NHz (Π) where A is as defined above, with a salt of formula III OF THE INVENTION where A represents a straight-chain or branched 3-alkyl-5-isoquinolyl radical having 1 to 10 carbon atoms, in the form of R or S or in the form of a mixture thereof, in free form or in the form of an acid addition salt, characterized by The reaction is carried out by reacting an amine of the formula II A-NHz (H) where A is as defined above, with a salt of formula III wherein R 1 is chlorine, C 1 -C 4 alkylthio or benzylthio; and A 1 is an anion, whereupon the resulting product is optionally converted to its acid addition salt. 3. The process of item 1, for the preparation of novel isoquinoline derivatives of the general formula I wherein R 1 is chlorine, C 1 -C 4 alkylthio or benzylthio; and A 1 is an anion, whereupon the resulting product is optionally converted into its acid addition salt. 2. The process according to item 1, for the preparation of novel isoquinoline derivatives of the general formula I N-A (I) N-A (I) wherein A represents a 3-pyridyl or 3-isoquinolyl radical, in the form of R or S or in the form of a mixture thereof, in free form or in the form of an acid addition salt, characterized in that the amine of formula II is reacted A - NHz (II), where 20393S A is as defined above, with a salt of formula III wherein R1 is chlorine, C1-C4alkylthio or benzylthio; and Ai ^_ is neither one, then optionally converting the resulting product to its acid addition salt.