Thiazolo[3,4-b]isoquinoline derivatives and pharmaceutical compositions containing them

Abstract

Thiazolo[3,4-b]isoquinoline derivatives of the general formula: ##STR1## wherein A represents 3-pyridyl, 4-pyridyl or 5-isoquinolyl and, when A represents 3-pyridyl, X.sub.1 represents hydrogen, halogen, dimethylamino or cyano, X.sub.2 represents hydrogen or fluorine and X.sub.3 represents hydrogen or nitro, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen, or X.sub.1 X.sub.2 together represent methylenedioxy and X.sub.3 represents hydrogen, and when A represents 4-pyridyl or 5-isoquinolyl, X.sub.1, X.sub.2 and X.sub.3 each represent hydrogen, and non-toxic pharmaceutically acceptable acid addition salts thereof, possess useful pharmacodynamic properties, in particular analgesic and antipyretic activity. This invention relates to new therapeutically useful thiazolo[3,4-b]isoquinoline derivatives, to processes for their preparation and to pharmaceutical compositions containing them.The new thiazolo[3,4-b]isoquinoline derivatives of the present invention are those of the general formula: ##STR2## wherein A represents a heterocyclic radical containing one nitrogen atom, selected from 3-pyridyl, 4-pyridyl and 5-isoquinolyl and, when A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom, or a dimethylamino or cyano radical, X.sub.2 represents a hydrogen or fluorine atom and X.sub.3 represents a hydrogen atom or a nitro radical, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen atoms, or X.sub.1 and X.sub.2 together represent a methylenedioxy radical and X.sub.3 represents a hydrogen atom, and when A represents a 4-pyridyl or 5-isoquinolyl radical X.sub.1, X.sub.2 and X.sub.3 each represent a hydrogen atom, and acid addition salts thereof.The compounds of general formula I can exist in (R)- and (S)- forms and the invention includes both such forms and mixtures thereof.According to a feature of the present invention the thiazolo[3,4-b]isoquinoline derivatives of general formula I are prepared by one of the following processes:1. Compounds of general formula I wherein A represents a 3-pyridyl or 5-isoquinolyl radical and when A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom, X.sub.2 represents a hydrogen or fluorine atom, X.sub.3 represents a hydrogen atom or a nitro radical, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen atoms, or X.sub.1 and X.sub.2 together represent a methylenedioxy radical and X.sub.3 represents a hydrogen atom, and when A represents a 5-isoquinolyl radical, X.sub.1, X.sub.2 and X.sub.3 represent hydrogen atoms, are prepared by cyclisation of a 1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR3## wherein A.sub.1 represents a 3-pyridyl or 5-isoquinolyl radical and, when A.sub.1 represents a 3-pyridyl radial, X.sub.4 represents a hydrogen or halogen atom, X.sub.5 represents a hydrogen or fluorine atom, X.sub.6 represents a hydrogen atom or a nitro radical, at least two of X.sub.4, X.sub.5 and X.sub.6 representing hydrogen atoms, or X.sub.4 and X.sub.5 togther represent a methylenedioxy radical and X.sub.6 represents a hydrogen atom, and when A.sub.1 represents a 5-isoquinolyl radical X.sub.4, X.sub.5 and X.sub.6 represent hydrogen atoms.The reaction is generally carried out by heating in an acid medium. It is particularly advantageous to carry out the reaction at a temperature from 65.degree. to 100.degree. C. in an aqueous inorganic acid, for example in hydrochloric acid.The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula II can be obtained by reacting an isothiocyanate of the general formula:S.dbd.C.dbd.N--A.sub.1 III(wherein A.sub.1 is as hereinbefore defined), with a 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR4## wherein X.sub.4, X.sub.5 and X.sub.6 are as hereinbefore defined. The reaction is generally carried out in an organic solvent such as an alcohol, for example ethanol, at a temperature from 15.degree. to 70.degree. C.The isothiocyanate of general formula III wherein A.sub.1 represents a 3-pyridyl radical can be prepared in accordance with the method described by J. C. Jochims, Chem. Ber. 101, 1746 (1968).The isothiocyanate of general formula III wherein A.sub.1 represents a 5-isoquinolyl radical can be obtained by condensing carbon disulphide with 5-aminoisoquinoline, followed by addition of dicyclohexylcarbodiimide. The condensation is generally carried out in the presence of a base such as a tertiary amine, for example triethylamine. The reaction is advantageously carried out in an organic solvent, such as pyridine, at a temperature from -10.degree. to 25.degree. C.The 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline derivatives of general formula IV can be obtained by reduction of a 1,2,3,4-tetrahydroisoquinoline derivative of the general formula: ##STR5## (wherein R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and X.sub.4, X.sub.5 and X.sub.6 are as hereinbefore defined) or of an acid addition salt thereof.When R in general formula V represents a hydrogen atom, the reduction is preferably carried out using lithium aluminium hydride, in tetrahydrofuran, at a temperature from 20.degree. to 70.degree. C.When R in general formula V represents an alkyl radical containing from 1 to 4 carbon atoms, the reduction is preferably caried out by means of an alkali metal borohydride, such as sodium borohydride, in an organic solvent or an aqueous-organic medium, such as an ethanol-water mixture, and at a temperature from 10.degree. C. to the reflux temperature of the reaction mixture.When a product of general formula IV in which X.sub.6 represents a nitro radical is required it is preferable to use an ester of general formula V (R = alkyl), the reduction of which takes place under conditions which do not affect the nitro radical.The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula V, wherein R represents an alkyl radical containing 1 to 4 carbon atoms, can be obtained by esterification of a 1,2,3,4-tetrahydroisoquinoline derivative of general formula V, wherein R represents a hydrogen atom, by known methods for the conversion of an acid into an ester without affecting the rest of the molecule.By the term "known methods" as used in this Specification and accompanying claims is meant methods heretofore used or described in the chemical literature.The 1,2,3,4-tetrahydroisoquinoline derivatives of general formula V wherein R represents a hydrogen atom, X.sub.4 and X.sub.5 are as hereinbefore defined and X.sub.6 represents a hydrogen atom can be obtained from a phenylalanine derivative of the general formula: ##STR6## (wherein X.sub.4 and X.sub.5 are as hereinbefore defined) by application of the method described by A. Pictet and Th. Spengler, Chem. Ber., 44, 2030 (1911).When the L-form of a phenylalanine derivative of general formula VI is used, the product of general formula I obtained via the compound of general formula V is in the (S)-form. When a phenylalanine derivative of general formula VI in the D-form is used the product of general formula I is obtained in the (R)-form. When a mixture of the D- and L-forms of the phenylalanine derivative of general formula VI is used, the product of general formula I is obtained in the (R,S)-form.The compounds of general formulae II, IV and V wherein the symbol X.sub.6 represents a nitro radical can be obtained by nitration of a compound of general formula II, IV or V wherein X.sub.6 represent a hydrogen atom. The nitration is generally carried out by means of a mixture of nitric and sulphuric acid at a temperature of about -20.degree. C. or with a mixture of sodium nitrate and trifluoroacetic acid at a temperature of about 20.degree. C., followed, if desired, by separation of the isomers obtained.2. Compounds of general formula I wherein X.sub.1 represents a hydrogen or halogen atom or a cyano radical and A, X.sub.2 and X.sub.3 are as hereinbefore defined are prepared by reaction of an amine of the general formula:H.sub.2 N -- A VII(wherein A is as hereinbefore defined) with a salt of the general formula: ##STR7## wherein X.sub.7 represents a hydrogen or halogen atom or a cyano radical, R.sub.1 represents a chloride atom, an alkylthio radical containing 1 to 4 carbon atoms (preferably a methylthio radical) or a benzylthio radical, A.sub.2.sup.- represents an anion, such as a chloride, iodide, sulphate, tetrafluoroborate or fluorosulphonate ion, and X.sub.2 and X.sub.3 are as hereinbefore defined. When R.sub.2 represents a chlorine atom, A.sub.2.sup.- represents a chloride ion. When R.sub.1 represents an alkylthio or benzylthio radical A.sub.2.sup.- represents an anion such as an iodide, sulphate tetrafluoroborate or fluorosulphonate ion.When R.sub.1 represents a chlorine atom and A.sub.1.sup.- represents a chloride ion, the reaction is preferably carried out in an organic solvent, such as acetonitrile, in the presence of an alkaline condensation agent, such as triethylamine, at a temperature of about 20.degree. C.When R.sub.1 represents an alkylthio or benzylthio radical and A.sub.2.sup.- represents an iodide, sulphate, tetrafluoroborate or fluorosulphonate ion, the reaction is preferably carried out in a basic organic solvent, such as pyridine, at a temperature of about 20.degree. C.The salt of general formula VIII wherein R.sub.1 represents a chlorine atom and A.sub.2.sup.- represents a chloride ion can be obtained by the reaction of a chlorinating agent, such as phosgene, phosphorus pentachloride, thionyl chloride or oxalyl chloride on a thiazolo[3,4-b]isoquinoline-3-thione derivative of the general formula: ##STR8## wherein X.sub.2, X.sub.3 and X.sub.7 are as hereinbefore defined. The reaction is generally carried out in an organic solvent or a mixture of organic solvents, such as a mixture of toluene and tetrahydrofuran, at a temperature from 0.degree. to 70.degree. C.The salts of general formula VIII wherein R.sub.1 represents an alkylthio or benzylthio radical and A.sub.2.sup.- represents an iodide, sulphate, tetrafluoroborate or fluorosulphonate ion can be obtained by the reaction of a reactive ester of the general formula:R.sub.2 -- A.sub.2 X(wherein R.sub.2 represents an alkyl radical containing from 1 to 4 carbon atoms or a benzyl radical and A.sub.2 represents the residue of a reactive ester such as an iodine atom, or an alkoxysulphonyloxy radical) or of triethyloxonium tetrafluoroborate or methyl fluorosulphonate and a compound of general formula IX. The reaction is generally effected, optionally in the presence of an organic solvent such as methylene chloride, at a temperature of about 20.degree. C.The thiazolo[3,4-b]isoquinoline-3-thione derivatives of general formula IX wherein X.sub.2, X.sub.3 and X.sub.7 are as hereinbefore defined (with the exception of those derivatives wherein X.sub.7 represents a cyano radical) can be obtained by the reaction of carbon disulphide, in a basic medium, with an isoquinoline derivative of the general formula: ##STR9## wherein X.sub.8 represents a hydrogen or halogen atom, E represents a halogen, e.g. bromine or chlorine, atom or a hydroxysulphonyloxy radical, and X.sub.2 and X.sub.3 are as hereinbefore defined. The reaction is generally carried out in the presence of sodium or potassium hydroxide at a temperatue of about 20.degree. C.Compounds of general formula XI can be obtained by the action of an inorganic acid on a 3-hydroxymethylisoquinoline derivative of general formula IV wherein X.sub.5 and X.sub.6 are as hereinbefore defined and X.sub.4 represents a hydrogen or halogen atom. Compounds of general formula XI wherein E represents a hydroxysulphonyloxy radical are generally prepared by treatment of the derivative of general formula IV with sulphuric acid in an aqueous medium at a temperature of about 100.degree. C., or in an organic solvent (such as dimethylformamide) in the presence of dicyclohexylcarbodiimide at a temperature of about 20.degree. C.Compounds of general formula XI wherein E represents a bromine atom are generally prepared by treatment of the derivative of general formula IV with aqueous hydrobromic acid (48% w/v) at the reflux temperature of the reaction medium, and isolating the product of general formula XI as its hydrobromide.Compounds of general formula XI wherein E represents a chlorine atom, are generally prepared by treatment of the derivative of general formula IV with thionyl chloride in an organic solvent, such as chloroform, saturated with hydrogen chloride gas, and at the reflux temperature of the reaction mixture and isolating the product of general formula XI as its hydrochloride.Compounds of general formula IX or XI, wherein X.sub.3 represents a nitro radical, can also be obtained by nitration of a compound of general formula IX or XI wherein X.sub.3 represents a hydrogen atom. The nitration is generally carried out with a mixture of nitric and sulphuric acid at a temperature of about -20.degree. C., or with nitronium fluoroborate in acetonitrile at a temperature of about 20.degree. C., or with sodium nitrate in trifluoroacetic acid at a temperature of about 20.degree. C., followed, if desired, by separation of the isomers obtained.The compounds of general formula IX wherein X.sub.7 represents a cyano radical and X.sub.2 and X.sub.3 are as hereinbefore defined, can be obtaned from a compound of general formula IX wherein X.sub.7 is replaced by a nitro radical, i.e. from a compound of the general formula: ##STR10## (wherein X.sub.2 and X.sub.3 are as hereinbefore defined) by known methods for the conversion of a nitro radical to a cyano radical, via the corresponding amine intermediate.Compounds of general formula XII can be obtained from a compound of general formula IX wherein X.sub.1 represents a hydrogen atom in accordance with the method hereinbefore described for the preparation of compounds of general formula IX wherein X.sub.3 represents a nitro radical from compounds of general formula IX wherein X.sub.3 represents a hydrogen atom.3. Compounds of general formula I wherein A represents a 3-pyridyl radical, X.sub.1 represents a hydrogen or halogen atom or a dimethylamino or cyano radical, X.sub.2 represents a hydrogen or fluorine atom and X.sub.3 represents a hydrogen atom, (wherein X.sub.1 and X.sub.2 are different and one of them represents a hydrogen atom) are prepared by reducing by methods known per se the nitro radical in a compound of the general formula: ##STR11## (wherein A.sub.3 represents a 3-pyridyl radical, and one of X.sub.9 and X.sub.10 represents a nitro radical and the other represents a hydrogen atom) to obtain a corresponding amino compound of the general formula: ##STR12## (wherein A.sub.3 is as hereinbefore defined and one of X.sub.11 and X.sub.12 represents an amino radical and the other represents a hydrogen atom), and conversion of the amino radical in the compound of general formula XIV by methods known per se to a halogen atom, or to a dimethylamino or cyano radical. The reduction of the nitro radical to the amino radical is advantageously carried out in an acid medium (for example hydrochloric acid) in the presence of a metal, such as tin, at a temperature from 10.degree. to 40.degree. C.Compounds of general formula I wherein X.sub.1 represents a chlorine atom, are generally prepared from the compound of general formula XIV obtained as hereinbefore described, by preparation in situ of a diazonium salt in an aqueous medium at a temperture from -5.degree. to +5.degree. C. using sodium nitrite in the presence of an acid (such as hydrochloric acid), and decomposition of the diazonium salt using cuprous chloride at a temperature from 20.degree. to 70.degree. C.Compounds of general formula I wherein X.sub.1 or X.sub.2 represents a fluorine atom are generally prepared by decomposition of the diazonium salt prepared as hereinbefore described, at a temperature of about -10.degree. C., using hexafluorophosphoric acid.Compounds of general formula I wherein X.sub.1 represents a cyano radical are generally prepared by decomposition of the diazonium salt prepared as hereinbefore described, using potassium cyanide and copper sulphate. The reaction is advantageously carried out in an aqueous organic medium, for example in a water/toluene mixture, at a temperature from 0.degree. to 50.degree. C.Compounds of general formula I wherein X.sub.1 represents a dimethylamino radical can be obtained from a compound of general formula XIV by treatment with formaldehyde in the presence of a reducing agent. Advantageously sodium cyanoborohydride is used as reducing agent in the presence of an acid such as acetic acid, at a temperature of about 20.degree. C., in an aqueous-organic medium, such as a mixture of water and acetonitrile.Compounds of general formula XIII wherein X.sub.9 and X.sub.10 are as hereinbefore defined can be obtained from a compound of general formula I wherein A represents a 3-pyridyl radical and X.sub.1, X.sub.2 and X.sub.3 represent hydrogen atoms, by application of the methods hereinbefore described for the preparation of a compound of general formula I wherein A, X.sub.1 and X.sub.2 are as hereinbefore defined and X.sub.3 represents a nitro radical.The thiazolo[3,4-b]isoquinoline derivatives of general formula I obtained by the aforementioned processes can be purified by physical methods such as crystallisation or chromatography, or by chemical methods such as the formation of salts, crystallisation of the salts and decomposition of them in an alkaline medium. In carrying out the said chemical method the nature of the anion of the salt is immaterial, the only requirement being that the salt must be well-defined and readily crystallisable.The thiazolo[3,4-b]isoquinoline derivatives of general formula I may be converted by known methods into acid addition salts. The acid addition salts may be obtained by the action of acids on the thiazolo[3,4-b]isoquinoline derivatives in appropriate solvents. As organic solvents there may be used alcohols, ketones, ethers or chlorinated hydrocarbons. The salt which is formed is precipitated, if necessary after concentrating the solution, and is isolated by filtration or by decantation.The thiazolo[3,4-b]isoquinoline derivatives of general formula I and their acid addition salts possess useful pharmacodynamic properties. They are particularly active as analgesics and antipyretics. They exhibit a slight antiinflammatory activity.In rats they have proved active as analgesics at doses from 2 to 50 mg./kg., by oral administration, according to the technique of L. O. Randall and J. J. Selitto, Arch. Int. Pharmacodyn. 111, 409 (1957), modified by K. F. Swingle et al., Proc. Soc. Exp. Biol. Med., 137, 536 (1971). The majority of the derivatives have also proved active in mice at doses from 20 to 200 mg./kg., by oral administration, according to the technique of E. Siegmund, Proc. Soc. Exp. Biol. Med. 95, 729 (1957).The antipyretic activity of the thiazolo[3,4-b]isoquinoline derivatives of general formula I is demonstrated in rats at doses from 5 to 50 mg./kg., by oral administration, according to the technique of J.J. Loux et al., Toxicol. Appl. Pharmacol., 22, 674 (1972).The anti-inflammatory activity is demonstrated in rats for most of the derivatives at doses from 5 to 50 mg./kg., by oral administration, according to the technique of K. F. Benitz and L. M. Hall, Arch. Int. Pharmacodyn., 144, 185 (1963). In addition, the thiazolo[3,4-b]isoquinoline derivatives of general formula I have low toxicity. The LD.sub.50 is between 300 mg./kg. and a dose greater than 3,000 mg./kg.Of particular interest are those thiazolo[3,4-b]isoquinoline derivatives of general formula I wherein A represents a 3-pyridyl, 4-pyridyl or 5-isoquinolyl radical, and X.sub.1, X.sub.2 and X.sub.3 represent a hydrogen atom, in the (R)-and (S)-forms and mixtures thereof, and acid addition salts thereof, more particularly (S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline, (R)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline, (R,S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline, (S)-3-(pyrid-4-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline,(S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and (R)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and acid addition salts thereof.For therapeutic purposes, the thiazolo[3,4-b]isoquinoline derivatives of general formula I may be employed as such or in the form of non-toxic acid addition salts, i.e. salts containing anions which are relatively innocuous to the animal organism in therapeutic doses of the salts (such as hydrochlorides, sulphates, nitrates, phosphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophyllinacetates, salicylates, phenolphthalinates and methylene-bis-.beta.-hydroxynaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side effects ascribable to the anions.

Description

Claims

1. A thiazolo[3,4-b]isoquinoline derivative of the general formula: ##STR13## wherein A represents 3-pyridyl, 4-pyridyl or 5-isoquinolyl and, when A represents 3-pyridyl, X.sub.1 represents hydrogen, halogen, dimethylamino or cyano, X.sub.2 represents hydrogen or fluorine and X.sub.3 represents hydrogen or nitro, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen, or X.sub.1 and X.sub.2 together represent methylenedioxy and X.sub.3 represents hydrogen, and when A represents 4-pyridyl or 5-isoquinolyl, X.sub.1, X.sub.2 and X.sub.3 each represent hydrogen and its nontoxic pharmaceutically acceptable acid addition salts.

2. A thiazolo[3,4-b]isoquinoline derivative according to claim 1 wherein A represents 3-pyridyl or 4-pyridyl and, when A represents 3-pyridyl, X.sub.1 represents hydrogen, halogen, dimethylamino or cyano, X.sub.2 represents hydrogen or fluorine and X.sub.3 represents hydrogen or nitro, at least two of X.sub.1, X.sub.2 and X.sub.3 representing hydrogen, or X.sub.1 and X.sub.2 together represent methylenedioxy and X.sub.3 represents hydrogen, and when A represents 4-pyridyl, X.sub.1, X.sub.2 and X.sub.3 each represent hydrogen and its non-toxic pharmaceutically acceptable acid addition salts.

3. A thiazolo[3,4-b]isoquinoline derivative according to claim 1 wherein A represents 5-isoquinolyl and X.sub.1, X.sub.2 and X.sub.3 each represent hydrogen, and its non-toxic pharmaceutically acceptable acid addition salts.

4. A thiazolo[3,4-b]isoquinoline derivative according to claim 1 wherein A represents 3-pyridyl, 4-pyridyl or 5-isoquinolyl and X.sub.1, X.sub.2 and X.sub.3 represent hydrogen, and its non-toxic pharmaceutically acceptable acid addition salts.

5. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

6. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (R)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

7. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (R,S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

8. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (R,S)-8-fluoro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

9. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (R,S)-7,8-methylenedioxy-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

10. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

11. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-3-(pyrid-4-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

12. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-9-nitro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

13. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (R)-3-(isoquinol-5-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

14. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-7-chloro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

15. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-7-fluoro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

16. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-7-dimethylamino-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothizolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

17. The thiazolo[3,4-b]isoquinoline derivative according to claim 1 which is (S)-7-cyano-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline and non-toxic pharmaceutically acceptable acid addition salts thereof.

18. A pharmaceutical composition useful as an analgesic, antipyretic or anti-inflammatory which comprises as active ingredient an effective amount of a thiazolo[3,4-b]isoquinoline derivative of the general formula depicted in claim 1, wherein A, X.sub.1, X.sub.2 and X.sub.3 are as defined in claim 1, or a non-toxic pharmaceutically acceptable acid addition salt thereof, in association with a significant amount of a pharmaceutically acceptable carrier.