Methoxy derivatives of 1,4-dithiepino-[2,3-c]-pyrrole

Compounds of the formula: ##STR1## wherein A represents pyrid-2-yl, quinol-2-yl or 1,8-naphthyridin-2-yl, each such radical being optionally substituted by a halogen atom, or an alkyl or alkoxy radical of 1 through 4 carbon atoms, and R represents hydrogen, an alkyl radical of 1 through 4 carbon atoms, an alkenyl radical of 2 through 4 carbon atoms or an alkanoyl radical of 1 through 4 carbon atoms, are new compounds possessing pharmacological properties. They are particularly active as tranquillizers, anti-convulsants, decontracturants and hypnogenic agents.

DESCRIPTION 
This invention relates to new therapeutically useful 
1,4-dithiepino[2,3-c]pyrrole derivatives, processes for their preparation 
and pharmaceutical compositions containing them. 
The new 1,4-dithiepino[2,3-c]pyrrole derivatives of the present invention 
are those compounds of the general formula: 
##STR2## 
wherein A represents a pyrid-2-yl, quinol-2-yl or 1,8-naphthyridin-2-yl 
radical, each such radical being optionally substituted by a halogen atom 
(preferably chlorine), an alkyl radical containing 1 to 4 carbon atoms 
(preferably methyl) or an alkoxy radical containing 1 to 4 carbon atoms 
(preferably methoxy), and R represents a hydrogen atom or an alkyl radical 
containing 1 to 4 carbon atoms (preferably methyl), an alkenyl radical 
containing 2 to 4 carbon atoms (preferably allyl) or an alkanoyl radical 
containing 1 to 4 carbon atoms (e.g. propionyl or isobutyryl), and--when 
appropriate--acid addition salts thereof. 
Due to the presence of two asymmetric carbon atoms in the molecule, the 
compounds of general formula I, and--when appropriate--their acid addition 
salts, can exist in the form of diastereoisomers; the present invention 
includes the diastereoisomeric forms of the compounds of general formula I 
and also mixtures thereof. 
According to a feature of the invention, the compounds of general formula I 
are prepared by the process which comprises reacting a 
1-chlorocarbonylpiperazine of the general formula: 
##STR3## 
(wherein R is as hereinbefore defined) with a 1,4-dithiepino[2,3-c]pyrrole 
derivative of the general formula: 
##STR4## 
wherein A is as hereinbefore defined. 
The reaction can be carried out by reacting a compound of general formula 
II with a compound of general formula III in the form of an alkali metal 
salt, optionally prepared in situ, in an anhydrous organic solvent, such 
as dimethylformamide or tetrahydrofuran, at a temperature below 60.degree. 
C. 
It is also possible to react a compound of general formula II, optionally 
in the form of an acid addition salt (preferably the hydrochloride), with 
a compound of general formula III, the reaction being carried out in 
pyridine and, when an acid addition salt of the reactant of formula II is 
used, optionally in the presence of a tertiary amine such as triethylamine 
which liberates the compound of general formula II from its salt. 
The 1,4-dithiepino[2,3-c]pyrrole derivatives of general formula III can be 
obtained by partial reduction of an imide of the general formula: 
##STR5## 
wherein A is as hereinbefore defined. The reduction is generally effected 
by means of an alkali metal borohydride, in an organic or aqueous-organic 
solution, for example in a dioxan-tetrahydrofuran or dioxan-methanol or 
dioxan-water or methanol-water or ethanol-water mixture. 
The imides of the general formula IV can be obtained by reacting an amine 
of the general formula: 
EQU H.sub.2 N--A V 
(wherein A is as hereinbefore defined) with the anhydride of 
6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid. The 
reaction is generally carried out by heating the reactants in an organic 
solvent such as acetic acid, dimethylformamide, acetonitrile or diphenyl 
ether, or a mixture of such solvents, in the presence or absence of a 
carbodiimide such as dicyclohexylcarbodiimide or 
3-(3-diethylaminopropyl)-1-isopropylcarbodiimide. 
The anhydride of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic 
acid can be prepared by reacting an inorganic base, such as sodium 
hydroxide, with 
3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole, 
and then reacting an acid, such as hydrochloric acid, with the resulting 
mixture. 
3-Methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole 
can be obtained by reacting anhydrous hydrogen chloride with a suspension 
of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarbonitrile in formic 
acid at a temperature below 28.degree. C. 
6-Methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarbonitrile can be obtained 
by reacting 1,3-dibromo-2-methoxypropane with the disodium salt of 
2,3-dimercaptomaleonitrile, the reaction being carried out in an organic 
solvent, such as dimethylformamide, at a temperature of about 100.degree. 
C. 
1,3-Dibromo-2-methoxypropane can be prepared in accordance with the process 
described by D. E. Horning et al., Can. J. Chem., 48, 975-982 (1970). 
The disodium salt of 2,3-dimercaptomaleonitrile can be prepared in 
accordance with the process described by H. R. Schweizer, Helv. Chim. 
Acta., 52, 2228 (1969). 
The piperazine derivatives of general formula II, wherein R represents an 
alkanoyl radical, can be obtained by the action of phosgene in toluene 
solution at a temperature of about -5.degree. C. on a piperazine 
derivative of the general formula: 
##STR6## 
wherein R.sub.1 represents the corresponding alkanoyl radical containing 1 
to 4 carbon atoms. 
The piperazine derivatives of general formula VI can be obtained from 
piperazine by applying methods known per se for the preparation of amides, 
such as the action of an acid of the general formula: 
EQU R.sub.2 --COOH VII 
(wherein R.sub.2 represents a hydrogen atom or an alkyl radical containing 
1 to 3 carbon atoms), or of a derivative of such an acid such as a halide, 
an ester, the anhydride, a mixed anhydride, the amide or the azide, on 
piperazine. The piperazine derivatives of general formula VI can be 
separated from the disubstituted piperazine, which is formed 
simultaneously, by application of physical or chemical methods. 
According to another feature of the invention, the compounds of general 
formula I are prepared by the process which comprises reacting a 
piperazine of the general formula: 
##STR7## 
(wherein R is as hereinbefore defined) with a mixed carbonate of the 
general formula: 
##STR8## 
wherein A is as hereinbefore defined and Ar represents a phenyl radical 
which is optionally substituted by an alkyl radical containing 1 to 4 
carbon atoms or by a nitro radical. The reaction is generally carried out 
in an anhydrous organic solvent such as acetonitrile at a temperature 
between 0.degree. and 50.degree. C. 
The mixed carbonates of general formula IX can be obtained by reacting a 
chloroformate of the general formula: 
EQU Cl--CO--O--Ar X 
(wherein Ar is as hereinbefore defined) with a 1,4-dithiepino[2,3-c]pyrrole 
derivative of general formula III. The reaction is generally carried out 
in a basic organic solvent such as pyridine or in an organic solvent such 
as tetrahydrofuran in the presence of an alkaline condensation agent. 
According to a still further feature of the invention, the compounds of 
general formula I, wherein R represents an alkanoyl radical, are prepared 
by reacting an acid of general formula VII, or a reactive derivative of 
the acid such as a halide (preferably the chloride), the anhydride, a 
mixed anhydride, the amide or the azide, with a compound of general 
formula I wherein R represents a hydrogen atom, that is to say a compound 
of the general formula: 
##STR9## 
wherein A is as hereinbefore defined. 
When an acid of the general formula VII is used, the reaction is generally 
carried out in an inert organic solvent, such as acetonitrile, methylene 
chloride, dimethylformamide or ethyl acetate, in the presence of a 
condensation agent such as dicyclohexylcarbodiimide or 
N,N-carbonyl-diimidazole at a temperature between 20.degree. and 
60.degree. C. 
When a halide of an acid of general formula VII (preferably the chloride) 
is used, the reaction is carried out in an organic solvent such as 
methylene chloride in the presence of an acid acceptor, for example 
pyridine or triethylamine, at a temperature between 0.degree. and 
30.degree. C. 
When the anhydride of an acid of general formula VII or a mixed anhydride 
is used, the reaction is generally carried out by heating the reactants at 
a temperature of between 30.degree. and 100.degree. C. 
When the amide of an acid of general formula VII is used, the reaction is 
generally carried out by heating at a temperature above 100.degree. C., 
optionally in an organic solvent such as an aromatic hydrocarbon and 
preferably in the presence of iodine. 
When the azide of an acid of general formula VII is used, the reaction is 
generally carried out in an organic solvent such as dioxan in the presence 
of magnesium oxide at a temperature between 25.degree. and 60.degree. C. 
The compounds of general formula XI can be obtained by the action of 
1-chlorocarbonylpiperazine on a 1,4-dithiepino[2,3-c]pyrrole derivative of 
general formula III or by the action of piperazine on a mixed carbonate of 
general formula IX. 
The compounds of general formula XI can also be obtained, according to 
another feature of the invention, from a compound of the general formula: 
##STR10## 
(wherein A is as hereinbefore defined) by treatment with trifluoroacetic 
acid, preferably at a temperature between 0.degree. and -10.degree. C. 
The compounds of general formula XII can be obtained by the action of 
4-chlorocarbonyl-1-t.-butoxycarbonylpiperazine on a 
1,4-dithiepino[2,3-c]-pyrrole derivative of general formula III. The 
reaction is generally carried out in an organic solvent such as methylene 
chloride in the presence of an acid acceptor, for example pyridine or 
triethylamine, at a temperature between 0.degree. and 30.degree. C. 
4-Chlorocarbonyl-1-t.-butoxycarbonylpiperazine can be obtained by the 
action of phosgene, in toluene solution, on 1-t.-butoxycarbonylpiperazine 
at a temperature of about -5.degree. C. 
1-t.-Butoxycarbonylpiperazine can be obtained by the action of piperazine 
hydrochloride on t.-butyl azidoformate. 
The diastereoisomeric forms of the products of general formula I can be 
separated from their mixtures by applying physico-chemical methods such as 
fractional crystallisation. 
The 1,4-dithiepino[2,3-c]pyrrole 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 methods 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 compounds of general formula I, and more particularly those wherein R 
represents a hydrogen atom or an alkyl or alkenyl radical, may be 
converted by methods known per se into acid addition salts. 
The acid addition salts may be obtained by the action of acids on the new 
compounds 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 concentration of the solution, 
and is isolated by filtration or decantation. 
In French Pat. No. 2,341,312 and U.S. Pat. No. 4,124,711 there are 
disclosed 1,4-dithiepino[2,3-c]pyrrole derivatives which are active as 
tranquillisers, anti-convulsants, decontracturants and hypnogenic agents. 
It has been found that the compounds according to the present invention, 
the structure of which differs from that of the compounds of the prior art 
by the presence of a methoxy group on the dithiepino[2,3-c]-pyrrole ring, 
exhibit a greater activity than their non-methoxylated homologues. 
The compounds of general formula I and, where appropriate, their acid 
addition salts therefore possess valuable pharmacological properties. They 
are particularly active as tranquillisers, anti-convulsants, 
decontracturants and hypnogenic agents. 
In animals (mice), they have proved active as such at doses of between 0.5 
and 25 mg/kg animal body weight administered orally, in particular in the 
following tests: 
(i) the electrical battle test according to a technique similar to that of 
Tedeshi et al., J. Pharmacol., 125, 28 (1959), 
(ii) the pentetrazole-induced convulsion test according to a technique 
similar to that of Everett and Richards, J. Pharmacol., 81, 402 (1944), 
(iii) the supramaximal electroshock testing according to the technique of 
Swinyard et al., J. Pharmacol., 106, 319 (1952), 
(iv) the strychnine mortality test according to a technique similar to that 
of F. Barzaghi et al., Arzneimittel-Forschung, 23, 683 (1973), and 
(v) the locomotor activity test according to the technique of Courvoisier, 
Congres des Medecins Alienistes et Neurologistes, Tours, 8th-13th June 
1959, and Julou, Bulletin de la Societe de Pharmacie de Lille, No. 2, 
January 1967, page 7. 
Furthermore, these compounds exhibit the advantage of having a long 
duration of action. 
The compounds of general formula I exhibit a low toxicity; their LD.sub.50 
when administered orally to mice is generally greater than 900 mg/kg 
animal body weight. 
Preferred 1,4-dithiepino[2,3-c]pyrrole derivatives of the invention are 
those of general formula I wherein A represents a pyrid-2-yl or 
1,8-naphthyridin-2-yl radical optionally substituted by a halogen 
(preferably chlorine) atom or an by an alkoxy radical containing 1 to 4 
carbon atoms (preferably methoxy), and R represents an alkyl radical 
containing 1 to 4 carbon atoms (preferably methyl), and in particular 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)car 
bonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole. 
For therapeutic purposes, the 1,4-dithiepino[2,3-c]pyrrole 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, theophylline-acetates, 
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.

The following non-limitative Examples illustrate the invention. 
EXAMPLE 1 
Triethylamine (42 cc) is added, at about 15.degree. C., to a suspension of 
7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H- 
1,4-dithiepino[2,3-c]pyrrole (7.4 g) and 
1-chlorocarbonyl-4-methylpiperazine hydrochloride (43.0 g) in anhydrous 
methylene chloride (215 cc), and anhydrous pyridine (90 cc) is then added 
to the resulting mixture. The reaction mixture is heated for 10 hours at 
45.degree. C. After cooling, the mixture is diluted by adding methylene 
chloride (250 cc). The organic phase is washed three times with an N 
aqueous sodium hydroxide solution (total 300 cc) and three times with 
distilled water (total 750 cc), dried over anhydrous sodium sulphate and 
evaporated. The residue is dissolved in boiling ethanol (50 cc). After 
cooling the solution for 20 hours at 2.degree. C., the resulting crystals 
are filtered off, washed three times with ice-cooled ethanol (total 30 cc) 
and dried under reduced pressure (20 mm Hg). The resulting product (5.1 g; 
m.p. 197.degree. C.) is dissolved in boiling ethanol (80 cc). After 
filtering the boiling solution and then cooling the filtrate for 16 hours 
at 2.degree. C., the resulting crystals are filtered off, washed with 
ice-cooled ethanol (8 cc) and dried under reduced pressure (0.2 mm Hg) at 
55.degree. C. 
7-(5-Chloropyrid-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8-o 
xo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (3.2 g), which 
melts at 199.degree. C., is obtained. 
7-(5-Chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1 
,4-dithiepino-[2,3-c]pyrrole used as starting material can be prepared in 
the following manner: 
Preparation of the disodium salt of 2,3-dimercaptomaleonitrile in 
accordance with the method of H. R. Schweizer, Helv. Chim. Acta, 52, 2228 
(1969). 
Preparation of 1,3-dibromo-2-methoxypropane (b.p. 98.degree. C./28 mm Hg) 
in accordance with the method of D. E. Horning et al., Can. J. Chem., 48, 
975-982 (1970). 
Preparation of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarbonitrile 
(m.p. 105.degree. C.; 44.4 g) by reacting 1,3-dibromo-2-methoxypropane 
(116 g) with the disodium salt of 2,3-dimercaptomaleonitrile (155 g) in 
dimethylformamide (1.25 liters) at about 95.degree.-100.degree. C. 
Preparation of 
3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole 
(m.p. 185.degree. C.; 237 g) by reacting anhydrous hydrogen chloride with 
a suspension of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarbonitrile 
(217 g) in formic acid (2600 cc) at a maximum of 28.degree. C. 
Preparation of the anhydride of 
6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid (m.p. 
141.degree. C.; 162.3 g) by reacting a 5.4 N aqueous solution of sodium 
hydroxide (222 cc) in distilled water (1100 cc), under reflux, for 30 
minutes, with 
3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole 
(237 g) and then reacting an 11.8 N aqueous solution of hydrochloric acid 
(150 cc) with the resulting mixture. 
Preparation of 
7-(5-chloropyrid-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-di 
thiepino[2,3-c]pyrrole (m.p. 217.degree. C.; 13.5 g) by reacting 
2-amino-5-chloropyridine (6.4 g) with the anhydride of 
6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid (11.6 g) in 
diphenyl ether (25 cc) at 170.degree.-180.degree. C. for 1 hour, in the 
presence of acetic acid (0.4 cc). 
Preparation of 
7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H- 
1,4-dithiepino[2,3-c]pyrrole (m.p. 147.degree. C.; 7.5 g) by reacting 
potassium borohydride (1.8 g) with 
7-(5-chloropyrid-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-di 
thiepino[2,3-c]pyrrole (13.5 g) in a mixture of tetrahydrofuran (120 cc) 
and methanol (36 cc) at a temperature between -10.degree. C. and 
+20.degree. C. 
EXAMPLE 2 
Triethylamine (29.5 cc) is added, at about 15.degree. C., to a suspension 
of 7-(7-chloroquinol-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H 
,6H-1,4-dithiepino[2,3-c]pyrrole (6.0 g) and 
1-chlorocarbonyl-4-methylpiperazine hydrochloride (30.2 g) in anhydrous 
methylene chloride (150 cc), and anhydrous pyridine (65 cc) is then added 
to the resulting mixture. The reaction mixture is heated for 10 hours at 
45.degree. C. After cooling, the mixture is diluted by adding methylene 
chloride (300 cc). The organic phase is washed twice with an N aqueous 
sodium hydroxide solution (total 600 cc) and five times with distilled 
water (total 1000 cc), dried over sodium sulphate and evaporated. The 
residue is treated with boiling ethanol (50 cc). After cooling the mixture 
for 1 hour at 2.degree. C., the crystals are filtered off, washed twice 
with ice-cooled ethanol (total 20 cc) and dried under reduced pressure (20 
mm Hg). The resulting product (4.6 g; m.p. 228.degree. C.) is dissolved in 
a boiling mixture of acetonitrile (50 cc) and ethanol (150 cc). After 
cooling the solution for 16 hours at 2.degree. C., the resulting crystals 
are filtered off, washed with ice-cooled ethanol (5 cc) and dried under 
reduced pressure (0.2 mm Hg) at 55.degree. C. 
7-(7-Chloroquinol-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8- 
oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (3.3 g), melting 
at 228.degree. C., is obtained. 
7-(7-Chloroquinol-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H- 
1,4-dithiepino[2,3-c]pyrrole used as starting material can be prepared in 
the following manner: 
Preparation of 
7-(7-chloroquinol-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-d 
ithiepino[2,3-c]pyrrole (m.p. 170.degree. C.; 6.1 g) by reacting 
2-amino-7-chloroquinoline (3.6 g) with the anhydride of 
6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid (4.65 g) in 
diphenyl ether (10 cc) at 170.degree.-180.degree. C. for 1/2 hour in the 
presence of acetic acid (0.1 cc). 
Preparation of 
7-(7-chloroquinol-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H 
-1,4dithiepino[2,3-c]pyrrole (6.0 g) by reacting sodium borohydride (0.46 
g) with 
7-(7-chloroquinol-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro-2H,6H-1,4-d 
ithiepino[2,3-c]pyrrole (6.0 g) in a mixture of tetrahydrofuran (52 cc) and 
methanol (20 cc) at between -12.degree. C. and +2.degree. C. 
EXAMPLE 3 
Triethylamine (144 cc) is added, at about 15.degree. C., to a suspension of 
7-(7-chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (36.0 g) and 
1-chlorocarbonyl-4-methylpiperazine hydrochloride (162 g) in anhydrous 
methylene chloride (900 cc), and anhydrous pyridine (360 cc) is then added 
to the resulting mixture. The reaction mixture is heated for 5 hours at 
45.degree. C. After cooling, the mixture is diluted by adding methylene 
chloride (900 cc). The organic phase is washed three times with distilled 
water (total 750 cc), dried over anhydrous sodium sulphate and evaporated. 
The residue is treated with boiling ethanol (750 cc). After cooling the 
mixture for 2 hours at 2.degree. C., the crystals are filtered off, washed 
with ice-cooled ethanol (100 cc) and then twice with distilled water 
(total 200 cc) and dried in air. The resulting product (36.5 g; m.p. 
206.degree. C.) is dissolved in boiling acetonitrile (3000 cc). After 
cooling the solution for 3 hours at 20.degree. C., the resulting crystals 
are filtered off, washed twice with acetonitrile (total 200 cc) and dried 
under reduced pressure (0.2 mm Hg) at 50.degree. C. 
7-(7-Chloro-1,8-naphthyridin-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)-ca 
rbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (26.6 
g), melting at 250.degree. C., is obtained (in the form of a mixture of 
virtually equal amounts of the A and B forms of the diastereoisomers). 
7-(7-Chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrah 
ydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole used as starting material can be 
prepared in the following manner: 
Preparation of 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro- 
2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 264.degree. C.; 72.6 g) by 
reacting 2-amino-7-chloro-1,8-naphthyridine (48.3 g) and 
3-(3-diethylaminopropyl)-1-isopropylcarbodiimide (53.0 g) with the 
anhydride of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid 
(62.4 g) in acetonitrile (625 cc) at 55.degree.-60.degree. C. for 8 hours. 
Preparation of 
7-(7-chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 150.degree. C.; 130.8 g) by 
reacting a solution of potassium borohydride (19.7 g) in distilled water 
(450 cc) with 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-6,8-dioxo-3,4,7,8-tetrahydro- 
2H,6H-1,4-dithiepino[2,3-c]pyrrole (143 g) in methanol (1800 cc) at between 
30.degree. and 35.degree. C. or 11/2 hours. 
The mixture of the A and B forms of the diasteroisomers can be separated in 
the following manner: 
Preparation of 1:1 mixture (36.6 g) in accordance with the procedure 
described above (the proportion of the diastereoisomers is determined by 
high performance thin layer chromatographic analysis). 
Obtention of the A form 
Fractional crystallisations are carried out by following the procedure 
shown in the following Table. 
TABLE 
__________________________________________________________________________ 
No. of Recrystal- 
recrystal- lisation Washing Weight 
Composition % 
lisation 
Solvent used 
time solvent obtained 
A form 
B form 
__________________________________________________________________________ 
1 Acetonitrile: 
1360 cc 
3 hours at 20.degree. C. 
Acetonitrile: 40 cc 
23.0 g 
70 30 
DMF: 340 cc 
1 hour at 20.degree. C. 
2 Acetonitrile: 
2400 cc Acetonitrile: 40 cc 
15.4 g 
80 20 
3 hours at 2.degree. C. 
Acetonitrile: 
1620 cc 
1 hour at 20.degree. C. 
3 Acetonitrile: 60 cc 
10.6 g 
87 13 
DMF: 180 cc 
3 hours at 2.degree. C. 
Acetonitrile: 
1080 cc 
1 hour at 20.degree. C. 
4 Acetonitrile: 60 cc 
8.6 g 
92 8 
DMF: 120 cc 
3 hours at 2.degree. C. 
Acetonitrile: 
900 cc 
1 hour at 20.degree. C. 
5 Acetonitrile: 50 cc 
6.8 g 
96 4 
DMF: 100 cc 
3 hours at 2.degree. C. 
Acetonitrile: 
828 cc 
1 hour at 20.degree. C. 
6 Acetonitrile: 50 cc 
5.6 g 
&gt;97 &lt;3 
DMF: 92 cc 
3 hours at 2.degree. C 
__________________________________________________________________________ 
DMF = dimethylformamide 
After drying at 80.degree. C. under reduced pressure (0.2 mm Hg), the A 
form of 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)-ca 
rbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (5.6 
g), which contains less than 3% of the B form and melts at 288.degree. C., 
is obtained. 
The mother liquors from recrystallisation No. 1 are evaporated to dryness 
under reduced pressure (20 mm Hg and then 0.2 mm Hg) at a temperature 
below 50.degree. C. The resulting crystals (13.6 g) are recrystallised six 
times from acetonitrile, as indicated in the Table for the preparation of 
the B form; the recrystallisation times are identical for each of the 
recrystallisations (1 hour at 20.degree. C. and then 3 hours at 2.degree. 
C.). 
The mother liquors from recrystallisation No. 2 for the obtention of the A 
form are evaporated to dryness under reduced pressure (20 mm Hg and then 
0.2 mm Hg) at a temperature below 50.degree. C. The resulting crystals 
(7.0 g) are recycled to recrystallisation No. 5 for the obtention of the B 
form. 
______________________________________ 
Preparation of the B form 
Aceto- 
No. of Amount of nitrile 
recrystal- 
aceto- for Weight Composition % 
lisation 
nitrile washing obtained 
A form 
B form 
______________________________________ 
1 1300 cc 30 cc 11.0 g 30 70 
2 900 cc 20 cc 8.1 g &lt;30 &gt;70 
3 650 cc 20 cc 6.2 g 25 75 
4 550 cc 20 cc 4.8 g 20 80 
5 1300 cc 40 cc 5.55 g &lt;10 &gt;90 
6 600 cc 20 cc 4.2 &lt;2 &gt;98 
______________________________________ 
After drying at 60.degree. C. under reduced pressure (0.2 mm Hg), the B 
form of 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)car 
bonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (4.2 
g), which contains less than 2% of the A form and melts at 255.degree. C., 
is obtained. 
EXAMPLE 4 
The procedure of Example 3 is followed except that 
7-(7-chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.9 g) and 
4-allyl-1-chlorocarbonylpiperazine hydrochloride (13.5 g) in a mixture of 
methylene chloride (200 cc) and anhydrous pyridine (80 cc), in the 
presence of triethylamine (32 cc) are heated at 45.degree. C. for 3 hours. 
After recrystallisation of the product from dimethylformamide (120 cc), 
6-(4-allylpiperazin-1-yl)-carbonyloxy-7-(7-chloro-1,8-naphthyridin-2-yl)-3 
-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.5 
g), melting at 255.degree. C., is obtained. 
4-Allyl-1-chlorocarbonylpiperazine hydrochloride can be prepared from 
1-allylpiperazine (63.0 g) and phosgene (99.0 g) in diethyl ether (400 cc) 
at 0.degree. C. 4-Allyl-1-chlorocarbonylpiperazine hydrochloride (86.1 g), 
which decomposes at about 200.degree. C., is thus obtained. 
EXAMPLE 5 
The procedure of Example 3 is followed except that 
7-(7-chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.9 g) and 
1-chlorocarbonyl-4-propionylpiperazine (8.2 g) in a mixture of methylene 
chloride (100 cc) and anhydrous pyridine (40 cc), in the presence of 
triethylamine (2.8 cc), are heated at 45.degree. C. for 2 hours. After 
recrystallisation of the product from acetonitrile (140 cc), 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(4-propionylpiperazin 
-1-yl)-carbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole 
(6.5 g), melting at 216.degree. C., is obtained. 
1-Chlorocarbonyl-4-propionylpiperazine can be prepared in the following 
manner: 
Preparation of 1-propionylpiperazine (b.p 110.degree. C./1 mm Hg; 
hydrochloride: m.p. 167.degree. C.) (1020 g) by reacting anhydrous 
piperazine (1135 g) with propionamide (965 g) in anhydrous xylene (965 
cc), under reflux, for 48 hours, in the presence of resublimed iodine (8 
g). 
Preparation of 1-chloroformyl-4-propionylpiperazine (oil, 552 g) by 
reacting phosgene (297 g) with 1-propionylpiperazine (852 g) in anhydrous 
toluene (12 liters), at 0.degree. C. 
EXAMPLE 6 
Triethylamine (34.5 cc) is added, at about 15.degree. C., to a suspension 
of 6-hydroxy-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-t 
etrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (10.7 g) and 
1-chlorocarbonyl-4-methylpiperazine hydrochloride (16.4 g) in anhydrous 
methylene chloride (440 cc), and anhydrous pyridine (195 cc) is then added 
to the resulting mixture. The reaction mixture is heated for 3 hours at 
45.degree. C. After cooling, the mixture is diluted by adding methylene 
chloride (300 cc). The organic phase is washed three times with distilled 
water (total 600 cc), dried over anhydrous sodium sulphate and evaporated. 
The resulting residue (41.0 g) is treated with boiling methanol (150 cc). 
After cooling the mixture for 1 hour at 2.degree. C., the crystals are 
filtered off, washed twice with ice-cooled methanol (total 40 cc) and 
dried under reduced pressure (20 mm Hg) at 20.degree. C. The resulting 
product (9.0 g; m.p. 215.degree. C.) is dissolved in boiling methanol (175 
cc). After cooling the solution for 2 hours at 2.degree. C., the resulting 
crystals are filtered off, washed twice with ice-cooled methanol (total 20 
cc) and dried under reduced pressure (0.2 mm Hg) at 50.degree. C. 
3-Methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)ca 
rbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.4 
g), melting at 218.degree. C., is obtained. 
6-Hydroxy-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole used as starting material can be 
prepared in the following manner: 
Preparation of 
6,8-dioxo-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-3,4,7,8-tetrahydro 
-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 196.degree. C.; 11.6 g) by 
reacting 2-amino-7-methoxy-1,8-naphthyridine (7.5 g) and 
3-(3-diethylaminopropyl)-1-isopropylcarbodiimide (8.5 g) with the 
anhydride of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid 
(10.0 g) in acetonitrile (150 cc), under reflux for 41/2 hours. 
Preparation of 
6-hydroxy-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetr 
ahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 192.degree. C.; 10.7 g) by 
reacting potassium borohydride (1.32 g) with 
6,8-dioxo-3-methoxy-7-(7-methoxy-1,8-naphthyridin-2-yl)-3,4,7,8-tetrahydro 
-2H,6H-1,4-dithiepino[2,3-c]pyrrole (12.7 g) in a mixture of 
tetrahydrofuran (100 cc) and methanol (30 cc) at between -10.degree. C. 
and 0.degree. C. 
EXAMPLE 7 
Triethylamine (24.5 cc) is added, at about 15.degree. C., to a suspension 
of 6-hydroxy-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-te 
trahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.3 g) and 
1-chlorocarbonyl-4-methylpiperazine hydrochloride (11.7 g) in anhydrous 
methylene chloride (300 cc), and anhydrous pyridine (130 cc) is then added 
to the resulting mixture. The mixture is heated at 45.degree. C. for 3 
hours. 1-Chlorocarbonyl-4-methylpiperazine hydrochloride (6.0 g) is then 
added and the mixture is heated for a further 1/2 hour at 45.degree. C. 
After cooling, the mixture is diluted by adding methylene chloride (300 
cc). The organic phase is washed three times with distilled water (total 
600 cc), dried over sodium sulphate and evaporated. The resulting residue 
(25.0 g) is dissolved in boiling acetonitrile (70 cc). After cooling the 
solution for 48 hours at 2.degree. C., the resulting crystals are filtered 
off, washed twice with ice-cooled acetonitrile (total 20 cc) and dried 
under reduced pressure (20 mm Hg) at 20.degree. C. The resulting product 
(5.25 g; m.p. 220.degree. C.) is dissolved in methylene chloride (100 cc) 
and the solution is filtered through silica (0.2-0.5 mm; 200 g) contained 
in a column of diameter 2.1 cm. Elution is carried out with methylene 
chloride (400 cc); the eluate is discarded. Elution is continued with a 
mixture of methylene chloride (784 cc) and methanol (16 cc); this eluate 
is evaporated under reduced pressure (20 mm Hg) at a temperature below 
60.degree. C. The residue is dried under reduced pressure (0.2 mm Hg) at 
50.degree. C. 
3-Methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)car 
bonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (4.2 
g), melting at 225.degree. C., is obtained. 
6-Hydroxy-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetrah 
ydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole used as starting material can be 
prepared in the following manner: 
Preparation of 
6,8-dioxo-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-3,4,7,8-tetrahydro- 
2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 245.degree. C.; 7.7 g) by reacting 
2-amino-7-methyl-1,8-naphthyridine (5.9 g) and 
3-(3-diethylaminopropyl)-1-isopropylcarbodiimide (8.1 g) with the 
anhydride of 6-methoxy-6,7-dihydro-5H-1,4-dithiepine-2,3-dicarboxylic acid 
(8.6 g) in acetonitrile (130 cc) under reflux for 6 hours. 
Preparation of 
6-hydroxy-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 170.degree. C.; 7.3 g) by 
reacting potassium borohydride (1.13 g) with 
6,8-dioxo-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-3,4,7,8-tetrahydro- 
2H,6H-1,4-dithiepino[2,3-c]pyrrole (10.4 g) in a mixture of tetrahydrofuran 
(80 cc) and methanol (24 cc) at between -10.degree. C. and 0.degree. C. 
EXAMPLE 8 
A solution of 1-propionylpiperazine (6.8 g) in anhydrous acetonitrile (50 
cc) is added, at 20.degree. C., to a suspension of 
7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrah 
ydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (11.15 g) in anhydrous acetonitrile 
(80 cc). The reaction mixture is heated under reflux for 6 hours. The 
acetonitrile is evaporated off under reduced pressure (20 mm Hg; 2.67 
kPa). The residue is treated with water (100 cc) and extraction is carried 
out three times with methylene chloride (total 210 cc); the organic 
extracts are washed twice with distilled water (total 200 cc), dried over 
anhydrous sodium sulphate and evaporated to dryness. The resulting residue 
(14.7 g; oily) is dissolved in a mixture of chloroform and methanol (97:3 
by volume; 50 cc). The solution is chromatographed on silica (0.04-0.063 
mm; 400 g) contained in a column of diameter 6 cm, under a pressure of 140 
kPa. Elution is carried out with the solvent mixture mentioned above under 
a pressure of 140 kPa. 1800 cc of eluate are collected and discarded, and 
then 600 cc of eluate are collected and evaporated to dryness under 
reduced pressure (20 mm Hg; 2.67 kPa). The resulting partially crystalline 
residue (11.0 g) is dissolved in a boiling mixture of acetonitrile (10 cc) 
and diisopropyl ether (50 cc). After cooling the solution for 2 hours at 
2.degree. C., the resulting crystals are filtered off, washed twice with 
diisopropyl ether (total 20 cc) and dried under reduced pressure (20 mm 
Hg; 2.67 kPa) at 20.degree. C. The resulting product (4.1 g; m.p. 
160.degree. C.) is dissolved in boiling acetonitrile (60 cc). After 
cooling the solution for 2 hours at 2.degree. C., the resulting crystals 
are filtered off, washed twice with diisopropyl ether (total 80 cc) and 
dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at 50.degree. C. 
7-(5-Chloropyrid-2-yl)-3-methoxy-8-oxo-6-(4-propionylpiperazin-1-yl)carbon 
yloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (1.2 g), 
melting at 226.degree. C., is obtained. 
7-(5-Chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahy 
dro-2H,6H-1,4-dithiepino[2,3-c]pyrrole used as starting material can be 
prepared in the following manner: 
By reacting phenyl chloroformate (16.7 g) with 
7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H- 
1,4-dithiepino[2,3-c]-pyrrole (prepared as described in Example 1; 12.3 g) 
in anhydrous pyridine (100 cc) at between -10.degree. C. and +20.degree. 
C., 
7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrah 
ydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 167.degree. C.; 10.1 g) is 
obtained. 
1-Chlorocarbonyl-4-propionylpiperazine can be prepared as described in 
Example 5. 
EXAMPLE 9 
Isobutyric acid (2.20 cc) is added, in the course of 5 minutes, at 
20.degree. C. to a suspension of 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(piperazin-1-yl)carbo 
nyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (8.0 g) and 
dicyclohexylcarbodiimide (4.85 g) in anhydrous methylene chloride (160 
cc). The reaction mixture is stirred for 1 hour at 20.degree. C. The 
dicyclohexylurea formed is filtered off and washed twice with methylene 
chloride (total 20 cc). The filtrate is evaporated to dryness under 
reduced pressure (20 mm Hg; 2.67 kPa). The resulting crystals are treated 
with boiling ethanol (80 cc); the mixture is filtered hot and the 
insoluble crystals are washed with boiling ethanol (10 cc) and dried in 
air. The resulting product (7.6 g; m.p. 205.degree. C.) is dissolved in 
boiling acetonitrile (80 cc) and the boiling solution is filtered. After 
cooling the filtrate for 4 hours at 2.degree. C., the crystals which have 
formed are filtered off, washed twice with ice-cooled acetonitrile (total 
15 cc) and dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at 
60.degree. C. 
7-(7-Chloro-1,8-naphthyridin-2-yl)-6-(4-isobutyrylpiperazin-1-yl)carbonylo 
xy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole 
(4.6 g), melting at 232.degree. C., is thus obtained. 
7-(7-Chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(piperazin-1-yl)carbon 
yloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole used as 
starting material can be prepared in the following manner: 
Preparation of 
6-(4-t-butoxycarbonylpiperazin-1-yl)carbonyloxy-7-(7-chloro-1,8-naphthyrin 
-2-yl)-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrol 
e (m.p. 210.degree. C.; 32.0 g) by reacting t-butyl 
(4-chlorocarbonylpiperazin-1-yl)-carboxylate (27.4 g) with 
7-(7-chloro-1,8-naphthyridin-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetra 
hydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (prepared as described in Example 
3; 27.2 g) in methylene chloride (280 cc), in the presence of anhydrous 
pyridine (140 cc) and triethylamine (9.7 cc), at about 50.degree. C. for 8 
hours. 
Preparation of 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(piperazin-1-yl)carbo 
nyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. about 
320.degree. C.; 13.0 g) by reacting trifluoroacetic acid (190 cc) with 
6-(4-t-butoxycarbonylpiperazin-1-yl)carbonyloxy-7-(7-chloro-1,8-naphthyrid 
in-2-yl)-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrr 
ole (32.0 g) at -5.degree. C., for 1 hour. 
t-Butyl (4-chlorocarbonylpiperazin-1-yl)carboxylate can be prepared in the 
following manner: 
Preparation of t-butyl piperazin-1-ylcarboxylate (m.p. 60.degree. C.; 91.0 
g) by reacting t-butoxycarbonylazide (259.0 g) with piperazine 
monohydrochloride (310.0 g) in a mixture of water and dioxan (1:2 by 
volume) at 45.degree. C. 
Preparation of t-butyl (4-chlorocarbonylpiperazin-1-yl)carboxylate (m.p. 
99.degree. C.; 24.8 g) by reacting phosgene (11.0 g) with t-butyl 
piperazin-1-ylcarboxylate (40.8 g) in toluene at -5.degree. C. 
EXAMPLE 10 
By following the procedure of Example 9 but starting with 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(piperazin-1-yl)carbo 
nyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (1.0 g), 
dicyclohexylcarbodiimide (0.61 g) and propionic acid (0.22 cc) in 
methylene chloride (20 cc), 
7-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxy-8-oxo-6-(4-propionylpiperazin 
-1-yl)carbonyloxy-3,4,7,8-tetrahydro-2H, 6H-1,4-dithiepino[2,3-c]pyrrole 
(0.57 g), melting at 216.degree. C., is obtained. 
The present invention includes within its scope pharmaceutical compositions 
which comprise, as active ingredient, at least one of the compounds of 
general formula I, or--when appropriate--a non-toxic acid addition salt 
thereof, in association with a pharmaceutically acceptable carrier, 
adjuvant or coating. The invention includes especially such preparations 
made up for oral, parenteral, rectal or percutaneous administration. 
Solid compositions for oral administration include tablets, pills, powders 
and granules. In such solid compositions the active compounds is admixed 
with at least one inert diluent such as sucrose, lactose or starch. The 
compositions may also comprise, as is normal practice, additional 
substances other than inert diluents, e.g. lubricating agents, such as 
magnesium stearate. Liquid compositions for oral administration include 
pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and 
elixirs containing inert diluents commonly used in the art, such as water 
or liquid paraffin. Besides inert diluents such compositions may also 
comprise adjuvants, such as wetting, emulsifying and suspending agents, 
and sweetening, flavouring and aromatizing agents. The compositions 
according to the invention, for oral administration, also include capsules 
of absorbable material (preferably gelatin) containing the active 
substance with or without the addition of diluents or excipients, e.g. in 
the form of a powder. 
Preparations according to the invention for parenteral administration 
include sterile aqueous or non-aqueous solutions, suspensions or 
emulsions. Examples of non-aqueous solvents or vehicles are propylene 
glycol, polyethylene glycol, vegetable oils such as olive oil, and 
injectable organic esters such as ethyl oleate. These compositions may 
also contain adjuvants such as preserving, wetting, emulsifying and 
dispersing agents. They may be sterilized by, for example, filtration 
through a bacteria-retaining filter, by incorporation in the compositions 
of sterilizing agents, by irradiation, or by heating. They may also be 
manufactured in the form of sterile solid compositions, which can be 
dissolved in sterile water or some other sterile injectable medium 
immediately before use. 
Compositions for rectal administration are suppositories which contain, in 
addition to the active substance, excipients such as cacao butter or a 
suitable wax base. 
Compositions for percutaneous administration are creams, ointments, lotions 
and liniments, in which the active substance is associated with liquid or 
pasty excipients, preferably in association with a vehicle which assists 
percutaneous migration. 
The pharmaceutical compositions according to the invention are particularly 
useful in human therapy by virtue of their tranquillising, 
anti-convulsive, decontracturant and hypnogenic action. 
In human therapy, the doses of active ingredient depend on the desired 
effect and the duration of the treatment; for an adult, they are generally 
between 0.5 and 25 mg of active substance per day, administered orally. 
In general, the physician will determine the posology considered 
appropriate, taking into account the age, weight and all the other factors 
intrinsic to the patient to be treated. 
The following Example illustrates pharmaceutical compositions according to 
the invention. 
EXAMPLE 11 
Tablets containing 5 mg doses of active product and having the following 
composition are prepared in accordance with the usual technique: 
______________________________________ 
form A of 7-(7-chloro-1,8-napthyridin-2-yl)- 
3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy- 
8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4- 
dithiepino[2,3-c]pyrrole 0.005 g 
starch 0.100 g 
precipitated silica 0.018 g 
magnesium stearate 0.002 g 
______________________________________