FR2470772A1 - 3-Substd. imino 1,5,10,10a-tetra:hydro thiazolo(3,4-b)-isoquinoline - antiviral esp. for rhino viruses some of which have analgesic, antiinflammatory and antipyretic activity - Google Patents

Abstract

3-A-imino-1,5,10,10a-thiazolo (3,4-b)-isoquinoline derivs. of formula (I), in the (S) or (R,S) form or their mixts. are new, (where A is 8-isoquinolyl, 3-methyl-8-isoquinolyl, 3-hydroxymethyl-5-isoquinolyl, 3-carboxymethyl-5-isoquinolyl, 5-quinolyl, thienopyridyl, benzimidazolyl, thienyl, thiazolyl, 4- (or 5)-carboxyalkyl-2-thiazolyl (where the alkyl part is opt. branched, 1-4C), 1,3,4-thiadiazol-2-yl, pyrazolyl, imidazoyl, pyrimidinyl, pyridazinyl or pyrazinyl. The monocyclic heterocyclics may be substd. by an opt. branched, 1-4C alkyl. When A is other than thienyl, acid addn. salts are included and when A contains a carboxy gp., metallic salts and salts with nitrogen-containing bases are included). (I) have antiviral activity and are esp. active against rhinoviruses. In MRC-5 human fibroblast cellular cultures infected with human IB rhinovirus (strain R1112) the cpds. has a MICof0.016-30micrograms/mlandamax.non-cytotoxicconcn.of M-125 micrograms/ml. Some of the cpds. have analgesic, anti-pyretic and antiinflammatory activity (20-200 mg/kg). The oral LD50 in mice is 300-900 or more mg/kg.

Description

dans laquelle A représente pyridyl-3 ou -4 ou isoquinolyl-5 et X1, X2 et X3 représentent notamment des atomes d'hydrogene. In Belgian patent 844 927, the thiazolo [3,4-b] isoquinolines of general formula have been described.

in which A represents pyridyl-3 or -4 or isoquinolyl-5 and X1, X2 and X3 represent in particular hydrogen atoms.

These products show analgesic and antipyretic activity.

dans laquelle R est un radical alcoyle contenant 1 à 10 atomes de carbone.In Belgian patent 863 083, the thiazolo [3,4-b] isoquinoline analgesic, anti-inflammatory and antipyretic agents corresponding to the general formula have been described.

in which R is an alkyl radical containing 1 to 10 carbon atoms.

de forme (S), à l'état pur ou en mélange avec une proportion substantielle de forme (R), leurs sels lorsqu'ils existent, leur préparation et les médicaments qui les contiennent. The present invention relates to new thiazolo [3,4-bJ isoquinoline derivatives of general formula

of form (S), in the pure state or mixed with a substantial proportion of form (R), their salts when they exist, their preparation and the medicaments which contain them.

In the general formula (I), the symbol A represents an isoquinolyl-8, 3-methyl isoquinolyl-8, 3-hydroxymethyl-5-isoquinolyl, 5-carboxymethyl-5-isoquinolyl, 5-quinolyl, thienopyridyl, benzimidazolyl, thienyl, thiazolyl , thiadiazol-1,3,4 yl-2, pyrazolyle, imidazolyle, pyrimidinyle, pyridazinyle, or pyrazinyle, the above monocyclic heterocycles can be substituted by a straight or branched alkyl radical containing 1 to 4 carbon atoms.

dans laquelle R1 represente un atome de chlore ou un radical alcoylthio contenant 1 à 4 atomes de carbone ou benzylthio et A1 représente un anion.According to the invention, the products of general formula (I) can be obtained by action of lamin of general formula A - NH2 (il) on a salt of general formula:

in which R1 represents a chlorine atom or an alkylthio radical containing 1 to 4 carbon atoms or benzylthio and A1 represents an anion.

When R1 represents a chlorine atom and a chloride ion, the reaction is carried out in an organic solvent such as acetonitrile, in the presence of a base such as triethylamine, at a temperature of 15 to 500 C.

 When R1 represents an alkylthio or benzylthio radical, and 49 a iodide, sulfate, tetrafluoroborate or fluorosulfonate ion, the reaction is carried out in a basic organic solvent such as pyridine, at a temperature of 15 to 500 C.

The salt of general formula (III) can be prepared according to the method described in Belgian patent 844,927.

The 2-amino thiophene can be obtained in the hydrochloride state, by the action of hydrogen sulfide on bis tetrachlorostannate (2-amino thiophene hydrochloride).

 Amino-8 isoquinoline can be prepared according to the method of D.H. HEY, J. Chem. Soc., 3882 (1961).

 Amino-3 thieno [2,3-c] pyridine can be prepared according to the method of L.H. KLEMM, J. Het. Chem., 14, 299 (1977).

dans laquelle A est défini comme ci-dessus.According to the invention, the products of general formula (I) for which A is an isoquinolyl-8, 3-methyl isoquinolyl-8, 3-hydroxymethyl-isoquinolyl-5, 3-carboxymethyl-isoquinolyl-5, pyrimi dinyl-2 or thienyl- radical. 2 (optionally substituted by an alkyl radical), thienopyridyl, benzimidazolyl-6 or quinolyl-5, can also be obtained by cyclization of a 1,2,3,4-tetrahydro isoquinoline of general formula

where A is defined as above.

 The reaction is generally carried out by heating in an acid medium. It is particularly advantageous to operate at a temperature between 650C and the reflux temperature of the reaction mixture in a mineral acid in aqueous solution, for example in hydrochloric acid (preferably 4N to 8N).

The 1,2,3,4-tetrahydro isoquinoline of general formula (IV) can be obtained by the action of an isothiocyanate of general formula
S = C = N - A (v) in which A is defined as above, on 3-hydroxymethyl-1,2,3,4-tetrahydro isoquinoline.

Generally the reaction is carried out in an organic solvent such as an alcohol, for example ethanol, operating at a temperature between 0 and 500cl
3, 3, 3-hydroxymethyl tetrahydro isoquinoline can be prepared from phenylalanine according to the method described by S. HAMADA and T. KUNIEDA, Chem. Phare Bull.-, 159 490 (1967).

When a phenylalanine of form L is used, the product of general formula (I) is obtained in form (S) o
When a DL form phenylalanine is used, the product of general formula (I) is obtained in the form (RS) o
The isothiocyanate of general formula (V) in which
A is defined as above, with the exception of representing pyrimidinyl-2 or thienyl-2 (optionally substituted by an alkyl radical) can be obtained by condensation of carbon sulphide with the amine of general formula (II) in which A is defined as above, followed by the addition of dicyclohexylcarbodiimide.

The condensation is generally carried out in the presence of a base such as a tertiary amine, for example triethylamine.

It is advantageously carried out in an organic solvent such as pyridine, at a temperature between -10 and 250 C.

2-isothiocyanato-pyrimidine (optionally substituted with an alkyl radical) can be prepared by the method described by
W. ABRAHAM and G. BARNIKOW, Tetrahedron, 29, 691 (1973).

2-Thiophene isothiocyanato (optionally substituted by an alkyl radical) can be prepared by the method described by
WC Mc CARTHY and LE FOSS, J. Org. Chem., 42, 1508 (1977).

dans laquelle alk est un radical alcoyle contenant 1 à 4 atomes de carbone.According to the invention, the new product of general formula (I) in which A is a 3-hydroxymethyl-isoquinolyl-5 radical can also be obtained by reduction of an ester of general formula:

in which alk is an alkyl radical containing 1 to 4 carbon atoms.

The reduction is carried out by any method known per se to reduce an ester into alcohol. One operates in particular by action of lt-boron hydride and lithium prepared in situ, at a temperature between
O and 20 C, in an organic solvent such as diglyme or by the action of boron and calcium hydride prepared in siu, at a temperature close to 200C, in an organic solvent such as tetrahydrofuran.

dans laquelle alk est défini comme précédemment, par toute méthode connue pour obtenir un acide à partir d'un ester sans toucher au reste de la molécule.According to the invention, the new product of general formula (I) in which A represents a 3-carboxymethyl-isoquinolyl-5 radical can also be obtained from the corresponding ester of general formula

in which alk is defined as above, by any known method for obtaining an acid from an ester without affecting the rest of the molecule.

The operation is carried out in particular by acid hydrolysis using hydrochloric acid at a temperature in the region of 100 ° C., preferably in aqueous acid 2 to 4 N.

 The products of general formula (VI) and (VII) can be prepared according to the method described above for the products of general formula (I).

When A is other than thienyl, the new products according to the invention can be converted into addition salts with acids. The addition salts can be obtained by the action of the product on acids in suitable solvents; as organic solvents, for example, alcohols, ketones, ethers or chlorinated solvents are used; the salt formed precipitates after optional concentration of its solution, it is separated by filtration or decantation.

When A represents a 3-isoquinolyl-5 carboxymethyl radical, the new product according to the invention can be transformed into a metal salt or an addition salt with a nitrogenous base. These salts can be obtained by the action of a metallic base (in particular alkaline or alkaline-earth), ammonia or an organic nitrogenous base, in an appropriate solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid.

The salt formed precipitates after optional concentration of its solution 9 and is separated by filtration or decantation.

The new products of general formula (i) and / or their salts when they exist can be optionally purified by physical methods such as crystallization or chromatography.

 The new products according to the invention and their pharmaceutically acceptable salts have remarkable pharmacological properties.

They exhibit antiviral activity which is exerted in particular on viruses of the rhinovirus group.

 On cell cultures of human MRC-5 fibroblasts infected with human rhinovirus type 1B (strain R 1112), the products according to the invention cause complete inhibition of the cytopathogenic effect and the multiplication of viruses at concentrations of between 7 at 30 pg / cm3 (maximum non-cytotoxic concentration) and 0.016 at 1.5 Fg / cm3 (minimum inhibitory concentration).

 Some of them are also useful analgesic, anti-thermal and anti-inflammatory agents.

 Anti-inflammatory activity is manifested in rats at doses between 50 and 200 mg / kg orally according to the technique of K.F. BENITZ and L.M. HAll, Arch. Int. Pharmacodyn., 144, 185 (1963).

Analgesic activity occurs in rats at doses between 20 and 200 mg / kg orally in the art of
E. SIEGMUND et al., Proc. Soc. Exp. Biol. Med., 95, 729 (1957).

 The anti-thermal activity is manifested in rats at doses of between 20 and 200 mg / kg orally in the technique of J.J. LOUX et al., Toxicol. Appl. Pharmacol., 22, 674 (1972).

Furthermore, the acute toxicity of the products according to the invention expressed by their LD50 (lethal dose 50%) is greater than or equal to 900 mg / kg orally in mice.

For medicinal use, new compounds may be used in the form of pharmaceutically acceptable salts, that is to say nontoxic at the doses of use.

 Examples of pharmaceutically acceptable addition salts which may be mentioned are salts of mineral acids (such as hydrochlorides, sulfates, nitrates, phosphates) or organic acids (such as acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophillineacetates , salicylates, phenolphthalinates, methylene bis-p-oxynaphtoates or derivatives of these acids).

 As examples of metal salts or addition salts with nitrogenous bases, mention may be made in particular of the sodium, potassium, calcium, lysine, ethanolamine salts.

 The following examples, given without limitation, show how the invention can be put into practice.

Example 1
A stream of hydrogen sulphide is passed through a solution of 10 g of bis tetrachlorostannate (2-damino hydrochloride thiophene) in 500 cm 3 of water until the end of the tin disulphide precipitation. The insoluble matter is separated by filtration. The filtrate is freed from hydrogen sulphide. residual by a stream of nitrogen and then added dropwise to a suspension of 13.7 g of 3-methylthio-1,5,10-tetrahydro iodide, thiazolo [3,4-b] isoquinolinium- ( S) in 300 cm3 of pyridine. After 17 hours of stirring at a temperature in the region of 20 ° C., it is concentrated to dryness under reduced pressure (25 mm of mercury 3.3 kpa) at 600 ° C. The residue is dissolved in a mixture of 250 cm3 of 2N sodium hydroxide and 250 cm3 of methylene chloride.

The organic phase is decanted, dried over magnesium sulfate, treated with bleaching black and then concentrated to dryness under reduced pressure (40 ani of mercury; 5.3 kPa) at 400C. The residue is dissolved in 100 cm3 of boiling acetonitrile; after cooling to 50C, the crystals formed are separated by filtration and washed with 10 cm3 of ice-cold acetonitrile. After drying at 400C under reduced pressure (1 mm of mercury; 0.13 kPa), 5.4 g of (2-thienyl imino) -3-tetrahydro-1,5,10,10a thiazolo [3,4-b are obtained. ] isoquinoline- (S) in the form of white crystals melting at 1120C.

[e] 20 = ~ 273 + 40 (c = 0.5; chloroform)
D
Bis tetrachlorostannate (2-amino-thiophene hydrochloride) can be prepared according to the method of W. STEINKOPF reproduced in H. HARTOUGH, The Chemistry of Heterocyclic Compounds
Thiophene and its derivatives, Interscience Publishers, (1952), po 513.

Example 2
To a solution of 10.0 g of 2-amino thiazole in 500 cm3 of pyridine, 18.2 g of 3-methylthio-tetrahydro iodide 1,5,10,10a thiazolo [3,4-b] isoquinoline are added. - (s). The suspension gradually goes into solution. After 3 days at a temperature in the region of 200C, the mixture is concentrated under reduced pressure (25 mm of mercury; 3.3 kPa); the residue is dissolved in a mixture of 300 cm3 of water and 300 cm3 of methylene chloride. The organic phase is decanted, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (25 mm of mercury; 3.3 kPa). 250 cm3 of propanol are added to the residue; it is brought to a boil and filtered hot. After cooling, the crystals formed are separated by filtration and washed with three times 10 cm3 of propanol. After drying at 400C under reduced pressure (1 mm of mercury; 0.13 kPa), 11.9 g of product are obtained, which l ', recrystallized from 250 cm3 of acetonitrile. After drying at 600C under reduced pressure (0.1 mm of mercury; 0.013 kPa), 10.6 g of (2-thiazolyl imino) -3 tetrahydro-1,5,10,10a thiazolo [3,4-b are obtained. ] isoquinoline- (S) in the form of white crystals melting at 158 C.

[a] 20 = - 235 + 20 (c = 2; chloroform).

D
Example 3
By operating as at 11, example 2, but starting from 18.2 g of 3-methylthio-tetrahydro-iodide 1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) and 15,7 g of 2-amino-5-1,3-thiadiazole-1,3,4, 7.0 g of (tert.-butyl-5 thiadiazol-1,3,4 yl-2) imino-3-1,5-tetrahydro is obtained, 10,10a thiazolo [3,4-b] isoquinoline- (S) in the form of white crystals melting at 1370C.

[a] 20 = - 203 + 20 (c = 2, chloroform)
D
2-amino tert.butyl-5 thiadiazole-1,3,4 can be prepared according to the method of F. CHUBB, Canad. J. Chem., 37, 1121 (1959).

Example 4
By operating as in Example 2 but using 18.2 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo L3,4-b] isoquinolinium- (S) and 8.3 g of amino-3 pyrazole, 7.0 g of (pyrazolyl-3 imino) -3 tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of white crystals melting at 1610C.

[a] 20 = - 256 + 30 (c = 1; chloroform)
D
Example 5
By operating as in Example 2 but using 18.2 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo [3,4-b] isoquinolinium- (S) and 8.0 g of 2-amino-4-methyl pyrimidine, 3.0 g of (4-methyl-2-pyrimidinyl) imino-3-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained ) in the form of white crystals melting at 1790C.

[α] 20 = - 266 + 30 (c = 1; chloroform)
D
Example 6
By operating as in Example 2, but starting with 18.2 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo [3,4-b] isoquinoleinium- (S) and 9, 5 g of 3-amino pyridazine, 9.3 g of (3-pyridazinyl imino) -3-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of crystals light beige melting at 140-1420C.

Ca] D20 = -276 + 30 (c = 2 i chloroform)
Example 7
By operating as in Example 2, but from 16.3 g of 3-methylthio-tetrahydro-iodide 1,5,10,10a thiazolo [3 4-b] isoquinoline- (S) and 8.5 g of 2-amino pyrazine, 7.6 g of (2-pyrazinyl-imino) -3-tetrahydro-1,5.10, is obtained thiazolo [3,4-b] isoquinoline- (S) in the form of white crystals melting at 1400C
[a] 20 = - 283 + 30 (c = 1; chloroform)
D
Example 8
By operating as in Example 2, but starting with 10.1 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo [3,4-b] isoquinolinium- (S) and 6, 4 g of amino-3 thieno [2v3-c] pyridine, 6.4 g of (thieno [2,3-c] pyridyl-3) imino -3 tetrahydro-i, 5, lO, lOa thiazolo [3 , 4-b] isoquinoline- (S) in the form of white crystals melting at 180 C.

20
[α] D = - 205 + 3 (c = 1; chloroform)
Amino-3 thieno [2,3-cl pyridine can be prepared according to the method of LH KLEMM, J. Het. Chem., 14, 299 (1977).

Example 9
By operating as in Example 2 but starting with 6.7 g of 3-methylthio-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoliniumium (S) and 2.8 g of diodide amino-3 thieno [2,3-b] pyridine, 4.6 g of (thieno [2,3-b] pyridyl-3) imino -3 1,5-tetrahydro, lo, loa thiazolo [3, 4-b] isoquinoline- (S) in the form of beige crystals melting at 145-146 C.

[a] 20 = ~ 204 + 30 (c = 0.5; chloroform)
Amino-3 thieno [2,3-b] pyridine can be prepared according to the method of LH KLEMM et al., J. Het. Chem. 7, 373 (1970).

Example 10
By operating as in Example 2 but using 18 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo [3,4-bJ isoquinolinium- (S) and 10 g of hydrochloride 5-amino benzimidazole, 11.7 g of [benzimidazolyl-5 (or -6) imino] -3 tetrahydro1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of pink crystals melting at 2200 C.

[a] 20 = ~ 236 + 30 (c = 1; methanol) D
The 5-amino benzimidazole hydrochloride can be prepared according to the method of D. WOOLLEY, J. Biol. Chem., 152, 225 (1944).

Example 11
By operating as in Example 2 but using 18.2 g of 3-methylthio-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline-iodide iodide (10,9) g of 8-amino isoquinoline, 11.8 g of (isoquinolyl-8 imino) -3-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of crystals pale yellow melting at 2060 C.

[a] 20 = - 197- + 20 (c = 1; chloroform) D
Amino-8 isoquinoline can be prepared according to the method of DH HEY, J. Chem. Soc., 3882 (1961).

Example 12
By operating as in Example 2, but starting from 8 g of 3-methylthio-1,5-tetrahydro iodide 1,5,10,10a thiazolo [3,4-b] isoquinolinium- (S) and 3,5 g of 8-amino-3-methyl isoquinoline, 4.1 g of (3-methyl-isoquinolyl-8) imino-3, 1,5-tetrahydro, 10, 10, thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of pale yellow crystals melting at 156 G.

[a] 20 = ~ 1860 + 30 (c = 1; chloroform)
D
8-amino-3-methyl isoquinoline can be prepared from the following dewlap
To a solution of 10.8 g of 5-bromo-3-methyl-8-nitro isoquinoline in 200 cm 3 of ethanol is added 5 g of catalyst consisting of palladium on carbon (3-97 by weight). This suspension is stirred while heating to reflux under a nitrogen atmosphere, and 25 cm3 of hydrazine hydrate are added dropwise over 30 minutes. After the end of the addition, the mixture is further heated for 2 hours at reflux. The suspension is filtered hot on diatomaceous silica and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400cl
The residue is dissolved in 200 cm3 of 0.5 N aqueous hydrochloric acid solution and extracted with twice 50 cm3 of methylene chloride. The aqueous phase is then basified to pH 10 by addition of sodium hydroxide and extracted three times with 150 cm3 of methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400C. 4.4 g of amino-8 methyl-3 isoquinoline are obtained, a beige solid melting at 1750C.

5-bromo-3-methyl-8-nitro isoquinoline can be prepared from the following baleen
17.2 g of 5-bromo-3-methyl isoquinoline are dissolved in 100 cm 3 of sulfuric acid (density 1.83; 34N). This solution is stirred and added in 30 minutes 891 g of potassium nitrate while maintaining the temperature between 0 and 50C by an ice bath, then the temperature is allowed to rise to around 200 C. It is stirred again for 5 hours at this temperature then the solution is poured into 600 cm3 of water and ice mixture and ammonia containing 20% NH3 (density 0.9) is added until pH 10 is obtained without exceeding 300C. The yellow precipitate obtained is separated by filtration, washed with water, dried and recrystallized from 300 cm3 of ethanol.

After filtration and drying, 12.3 g of 5-bromo-3-methyl-8-nitro-isoquinoline are obtained in the form of a beige solid melting at 1460C.

5-bromo-3-methyl isoquinoline can be prepared by the method described by M. GORDON and paste J. Het. Chem., 4, 410 (1967).

Example 13
By operating as in Example 2, but starting from 18.2 g of 3-methylthio-tetrahydro-1,5,1o iodide, ÎOa thiazolo [3,4-b] isoquinolinium- (S) and 14,4 g of 5-aminoquinoline, 15.0 g of (5-quinolylimino) -3 tetrahydro4,5,10,10a thiazolo [3,4-b] isoquinoline- (S) are obtained in the form of light beige melting crystals to 1940C.

[a] 20 = ~ 195 + 20 (c = 2; chloroform)
D
Example 14
1.01 g of lithium chloride, 0.91 g of sodium borohydride and 100 cm3 of diglyme (diethylene glycol dimethyl ether) are mixed at 0 ° C. The mixture is stirred for 30 minutes at 0 ° C. and 4.7 g of [( 3-methoxycarbonyl-isoquinolyl-5) imino] -3-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S). Stirring is continued for 1 hour at 0 ° C. and then 2 hours at 200 ° C. 1 liter of water is added and extracted with three times 150 cm 3 of methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (40 mm of mercury 5.3 kPa) at 400 C. The residue is dissolved in 20 cm 3 of methylene chloride and the solution is poured onto a column 3 cm in diameter containing 120 g of silica gel in methylene chloride. Eluted with a mixture of ethyl acetate and cyclohexane (70-30 by volume), collecting fractions of 300 cm3. Fractions 7 to 11 are combined and concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at 400C. The residue is recrystallized from 100 cm 3 of butyl acetate. After separation on a filter, washing with isopropyl oxide and drying, 2 g of (3-hydroxymethyl-isoquinolyl-5) imino-3-tetrahydro-1.5.10 are obtained, 10a thiazolo [3,4-b] isoquinoline- (S), white solid melting at 2100 C. [α] 20 = -1720 + 30 (c = 0.5; chloroform)
D
The (3-methoxycarbonyl-isoquinolyl-5) imino -3 tetrahydro-1,5,10,10a isoquinoline- (S) can be prepared in the following way:
To a solution of 13 g of 5-amino-3-methoxycarbonyl isoquinoline in 400 cm 3 of pyridine is added 22.4 g of 3-methylthio-tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinolinium- (S).

The suspension gradually goes into solution. After 3 days of stirring at a temperature close to 200C, it is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 600C. The residue is dissolved in 500 cm 3 of methylene chloride and washed with three times 300 cm 3 of aqueous N sodium hydroxide solution, then with water. After drying over sodium sulfate and filtration, it is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 40 Co The residue is recrystallized from 500 cm3 of acetonitrile. After separation on a filter, washing with isopropyl ether and drying, 12.8 g of (3-methoxycarbonyl-isoquinolyl-5) imino-3 tetrahydro-1, 5,1O, iso-isoquino lein- (S) are obtained. pale yellow melting at 2000Co
Lgamino-5 methoxycarbonyl-3 isoquinoline can be prepared as follows
25 g of 5-amino-isoquinolinecarboxylic acid-3 are added to 2 liters of methanol. The mixture is heated to reflux and a stream of dry gaseous hydrochloric acid is bubbled for 3 hours. It is further heated for 3 hours at reflux, then concentrated to dryness under reduced pressure (20 mm of mercury T 2.7 kPa) at 600 ° C. The residue is dissolved in 200 cm3 of water and washed twice with 100 cm3 of ethyl acetate. The aqueous solution is made alkaline at pH 9 by addition of potassium carbonate.

The precipitate formed is separated by filtration, washed with water and dried
20.3 g of 5-amino-3-methoxycarbonyl isoquinoline are obtained.

5-amino-isoquinoline-3-carboxylic acid can be prepared as follows
44 g of 5-isoquinolinecarboxylic acid-3 are dissolved in 3 liters of methanol and 15% of catalyst consisting of palladium on carbon (3-97 by weight) are added. Hydrogenated at atmospheric pressure at a temperature between 20 and 250Co After 5 hours of stirring, the volume of hydrogen absorbed is 13.9 liters
Filtered on diatomaceous silica and the filtrate is concentrated to dryness under reduced pressure (20 Tmn of mercury; 2.7 kPa) at 600C. 35 g of 5-amino-isoquinollinecarboxylic-3 acid are obtained.

 The 5-nitro-isoquinoline carboxylic acid can be prepared by the method described by R.C. ELDERFTELD and paste J. Org.

Chem., 23, 435 (1958).

Example 15
Is heated at 1000C for 6 hours, a solution of 3.8 g of (ethoxycarbonylmethyl-3 isoquinolyl-5) imino -3 tetrahydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) 60 cm3 of 3N hydrochloric acid.

After cooling, the pH of the solution is adjusted to 7 by the addition of 5 N sodium hydroxide, then extraction is carried out with 2 times 200 cm 3 of methylene chloride. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness. The residue obtained is dissolved in 60 cm3 of a mixture of dimethylformamide and water (2: 1 by volume) brought to the boil, 0.3 g of bleaching black is added and the mixture is filtered while hot. After cooling to 50C for 20 hours, the crystals which appear are separated by filtration, washed with clean iso oxide and then dried at 700C under reduced pressure (0.1 mm of mercury 0.013 kPa). 1.7 g of (carboxymethyl-3 isoquinolyl-5) imino -3-tetrahydro-1,5,10, îOa thiazolo [3,4-b] isoquinoline- (S) melting around 2000C (with decomposition) are thus obtained.

F 120 = - 152 + 20 (c = 1; chloroform)
(3-ethoxycarbonylmethyl-isoquinolyl-5) imino -3 tetra hydro-1,5,10,10a thiazolo [3,4-b] isoquinoline- (S) can be prepared as follows: In a solution of 15, 8 8 g of 5-amino-isoquinoline 3-ethyl acetate in 200 cm3 of pyridine, 18.5 g of 3-methylthio-tetrahydro-1,5,10,10a thiazolo [3,4-b] are added isoquinolinium- (S).

After 15 hours at a temperature in the region of 200 ° C., the solution is concentrated under reduced pressure (25 mm of mercury; 3.3 kPa). The residue is dissolved in a mixture of 2 liters of methylene chloride and 1 liter of 5N sodium hydroxide. The organic phase is decanted, washed with 3 times 1 liter of water, dried over sodium sulfate and then concentrated to approximately 100 cm3. , under reduced pressure (25 mm of mercury; 353 kPa).

 This solution is poured onto a column of 600 g of silica gel (column diameter: 5.5 cm) and then eluted with methylene chloride, collecting eluate fractions of 500 cm3.

The fractions 18 to 24 are evaporated; the residue is crystallized from an acetonitrile-ether mixture (10-50 by volume). 9.1 g of (3-ethoxycarbonylmethyl-5-isoquinolyl) are thus obtained imino -3-tetrahydro-1,5,10,10a thiazolo [3,4-b] iso4uinoline- (S) in the form of yellow crystals melting at 112 C .

lazzi = - 146 + 20 (c = 1; chloroform)
5-amino-isoquinoline-3-ethyl acetate can be prepared as follows
20 g of 5-nitro-isoquinoline acetate-3 ethyl are dissolved in 1 liter of methyl acetate and 21 g of catalyst consisting of palladium on carbon (3-97 by weight) are added. We hydrogenate at pressure
atmospheric at a temperature close to 500C for 2 hours.

Filtered on diatomaceous silica and then concentrated the filtrate to dryness under reduced pressure (20 mm of mercury; 2.7 kpa) at 50 C. This gives 15.8 g of 5-amino-isoquinolineacetate-3 ethyl in the form beige crystals melting at 90 C.

Nitro-5 isoquinoline acetate-3 ethyl can be prepared as follows
A solution of 300 cm 3 of methylene chloride containing 21.5 g of isoquinoline ethyl acetate 3 is poured dropwise into a suspension of 1700 cm 3 of methylene chloride cooled to 10 C, containing nitronium trifluoromethanesulfonate prepared in situ by addition successive of 70 cm3 of trifluoro methanesulfonic acid and 15.1 cm3 of nitric acid (d = 1.52; 23 N) e
The reaction medium is kept at 100C for 2 hours and then allowed to warm up to a temperature close to 20oC.

Neutralization is carried out by adding a sodium carbonate solution with stirring. The organic phase is decanted, washed with 3 times 1 liter of water, dried over sodium sulfate and then concentrated to dryness. Purification is carried out by chromatography on 400 g of silica gel contained in a column 4.5 cm in diameter. Elution is carried out with 2 liters of methylene chloride and 2 liters of methylene chloride-methanol mixture (98-2 by volume) and 4 liters of methylene chloride-methanol mixture (96-4 by volume), collecting the eluate in fractions of 800 cm3. After evaporation to dryness of fractions 7 to 9, 20 g of 5-nitro-isoquinoline acetate-3 ethyl are obtained in the form of brown crystals melting around 900C.

Ethyl lisoquinoline acetate-3 can be prepared according to the method of P. CROOKS, J. Med. Chem., 21, 585 (1978).

 The drugs constituted by a new derivative of general formula (I) in the pure state, optionally in the form of a pharmaceutically acceptable salt, and the pharmaceutical compositions which contain it in combination with at least one diluent or adjuvant compatible and pharmaceutically acceptable, constitute a another object of the present invention. These drugs can be used intranasally, orally, rectally, parenterally or topically.

As solid compositions for oral administration, tablets, pills, powders (preferably contained in gelatin capsules) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch.

These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

 The compositions according to the invention for intranasal or parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive, almond or coconut oil and injectable organic esters, for example ethyl oleate, may be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants (soy lecithin). Sterilization can be done in several ways, for example by incorporating sterilizing agents into the composition, by irradiation, by heating or by adding a preservative. They can be presented in the form of sterile solid compositions which will be dissolved at the time of use in a sterile injectable medium.

The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

 The topicals are particularly in the form of ointments.

The compositions according to the invention are particularly useful in human therapy for their anti-viral and optionally anti-inflammatory, analgesic and anti-pyretic action. They are particularly indicated for the treatment of viral affections of the respiratory tract and possibly inflammatory diseases (ankylosing arthritis sponds, rheumatic fever, arthritis), acute and chronic pain, rheumatic and traumatic pain, dental, neurological and visceral pain, various pain (pain of cancer) and febrile states
In human therapy, the doses depend on the desired effect and on the duration of the treatment; they are generally between 100 and 2000 mg per day for an oral adult
They can reach 100 mg per day by the nasal route (drops or nebulizations).

 In general, the doctor will determine the dosage which he considers most appropriate according to the age, weight and any other factors specific to the subject to be treated.

The following examples, given without limitation, illustrate compositions according to the invention.

Example A
Tablets containing 100 mg of active product, having the following composition, are prepared according to the usual technique: - L-2-thiazolyl imino] -3 tetrahydro-1, 5, 10, 10a
thiazolo [3,4-b] isoquinoline- (S) ... 0.100 g - starch ... 0s110 g - precipitated silica ... 0.035 g - magnesium stearate ... 0.005 g
Example B
Tablets containing 100 mg of active product, having the following composition - Lpyridazinyl-3 imino] -3 tetrahydro-1, 5,1O, 10a, are prepared according to the technique below.
thiazolo L 3,4 ~ b] isoquinoline - (S) o .. 0.100 g - wheat starch ... 0.137 g - dicalcium phosphate ... 0.040 g - sodium carboxymethyl starch o .. 0.015 g - magnesium stearate ... 0.008 g
The active substance, dicalcium phosphate and approximately 90/0 of the starch are mixed and then sieved (mesh size: 0.5 mm). A 10% starch paste prepared from the starch stored is added, the paste obtained is granulated, by passage through a sieve (mesh opening 0.8 mm) and the granules are dried in an oven 500 C. The carboxymethyl starch and the magnesium stearate are then added and the tablets are pressed.

Example C
A 1% oily solution is prepared for intranasal administration by dissolving 1 g of (2-thiazolyl) imino -3 tetrahydro-S, 5,10,10a thiazolo [3,4-b] isoquinoline- (S) in 100 cm3 of olive oil at 40-500C and filtering the solution obtained on a Millipore filter. For use, the solution is applied to the nasal mucosa using a dropper.

Claims (6)

1 - A new derivative of thiazolo [3,4-b] isoquinoline characterized in that it corresponds to the general formula:

in which the symbol A represents an isoquinolyl-8, 3-methyl isoquinolyl-8, 3-hydroxymethyl-isoquinolyl-5, carboxymethyl-3 isoquinolyl-5, quinolyl-5, thienopyridyl, benzimidazolyl, thienyl, thiazolyl, thiadiazol-1,3 radical , 4 yl-2, pyrazolyle, imidazolyle, pyrimidinyle, pyridazinyle or pyrazinyle, the above monocyclic heterocycles being able to be substituted by a straight or branched alkyl radical containing 1 to 4 carbon atoms, in form (S) in the pure state or mixed with a substantial proportion of form (R), as well as, when A is other than thienyl, its addition salts with acids and, when A is 3-carboxymethyl-5-isoquinolyl, its metal salts or its salts 'addition with nitrogenous bases. 2 - A process for the preparation of a product according to claim 1, characterized in that an amine of general formula A - NH2 in which A is defined according to claim 1 is made to act on a salt of general formula:

in which R1 represents a chlorine atom and Are represents a chloride ion, or else R1 represents an alkylthio radical containing 1 to 4 carbon atoms or benzylthio and A10 represents an iodide, sulfate, tetrafluoroborate or fluorosulfonate ion, then optionally transforms the product obtained into addition salt with an acid when A is other than thienyl, or with a metal salt or addition salt with a nitrogenous base when A is 3-carboxymethyl-5-isoquinolyl. 3 - A procedure for the preparation of a product according to claim 1, for which A is an isoquinolyl-8, 3-methyl isoquinolyl-8, 3-hydroxymethyl isoquinolyl-5, carboxyrnethyl3 isoquinolyl-5, pyrimidinyl-2 or thienyl- radical. 2 (the latter two possibly being substituted by an alkyl radical), thienopyridyle, benzimidazolyl-6 or quinolyl-5, characterized in that an 1,2,3,4 isoquinoleine is cyclized in the acid medium general:

 in which A is defined as above, then optionally transforms the product obtained into an addition salt with an acid when A is other than thienyl, or into a metal salt or into an addition salt with a nitrogenous base when A is 3-carboxymethyl isoquinblyl-5. 4 - A process for the preparation of a product according to claim 1, for which A is 3-hydroxymethyl-isoquinolyl-5, characterized in that an ester of general formula is reduced:

 in which alk is an alkyl radical containing 1 to 4 carbon atoms, then optionally transforms the product obtained into an addition salt with an acid. 5 - A process for the preparation of a product according to claim 1, for which A is 3-carboxymethyl-5-isoquinolyl, characterized in that an ester of general formula is transformed:

 in which alk is an alkyl radical containing 1 to 4 carbon atoms, by any method known per se to obtain an acid from an ester without touching the rest of the molecule, then optionally transforms the product obtained into addition salt with an acid, as a metal salt, or as an addition salt with a nitrogen base. 6 - Medicinal product, characterized in that it consists of a product according to claim 1 in the pure state or in the form of a pharmaceutical composition in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.