New derivatives of the thioformamide and their method of preparation.

The present invention relates to novel derivatives of general formula tfaioforaamide:

(I-)

In the general formula (I-), H represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain and

- either HET represents a heterocyclic radical to aromatic character containing one or two nitrogen atoms such as pyridyl-3, pyridyl-4) pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, imidazolyl, naphtyridiny1e, quinoxalinyl or quinazolinyl, X is sulfur or oxygen and? is sulfur or oxygen, a valence bond or a methylene radical,

hET represents the radical - or pyridyl-2, X is sulfur or oxygen and Y is sulfur or oxygen or a methylene radical,

hET represents the radical - or pyridyl-2, X represents an oxygen atom and Y is each valence bond.

Already known by the requests French patents published under numbers 2,100 970 and 2,250 173 derivatives of thioacetamide and acids heterocyolylalcansthioearboxylic that inhibit gastric secretion. None of CEE document does describes nor suggests the products of general formula

(the I) in which X and Y have the above definitions.

According to the invention, the products of general formula (I-) wherein the symbols R, wherein HET, X and Y are as defined above may be prepared by the action of an amine

of general formula:

(II)

wherein R is defined as above on a dithioester of general formula:

(III)

2

in which the symbols placemat, X and 7 are defined as above and B ' represents an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain or a benzyl or carboxymethyl.

Generally, it is carried out with an excess of amine of general formula (III), without a solvent or in an organic solvent such as an aromatic hydrocarbon, an ether or a low molecular weight alcohol or a mixture of these solvents, at a temperature between 20 and 130 °c, optionally under pressure.

The dithioester of general formula (Ill-) can be obtained by the action of an organolithium derivative on a product of general formula:

in which Het, X and Y are as defined above, followed by the action of carbon disulfide and then of a product of general formula:

(7) A Z - Β·

wherein b * is as defined above and Z represents a halogen atom, preferably chlorine, bromine, or iodine atom or a residue of a reactive ester, preferably a mesyloxy or tosyloxy.

The reaction is generally carried out in an anhydrous organic solvent such as 1' hexaméthylphosphorotriaaids, added generally of an ether such as tetrahydrofuran, at a temperature between - 4ô -80 and^I C..

The organometallic derivatives lithdess particularly well suited are preferably the alcoylures lithium such as butyllithium and 1 'isopropyllithiua or phenyllithium, in solution in an inert solvent as 1' hexane diisocyanate, or the lithium amides such as lithium hydroxide or diéthylamidureisopropylami " hard lithium.

According to the definitions of X and 7, the products of general formula (VI) may be prepared as follows 9.ï

a) the products of general formula (VI) wherein

- or Het is Het ^ representing a heterocyclic aromatic nature containing one or two nitrogen atoms as pyridyie and 3, pyridyl-4" pyridasinyle, pyraziryle, pyrinidinyle, quinolyl, imidazolyl, naphthyridinyl, quinoxalinyl or quinazolinyl, X represents a sulfur atom and Y represents a valence bond or a methylene radical, it is to say products of the general formula O

- or HET represents the radical pyridyl 2, X represents a sulfur atom and Y represents a methylene radical, it is to say the product of formula T-

(VIII)

can be prepared by cyclization using an organic base, such as an alkoxide or an alkali metal amide, a derivative of general formula :

Human gh - Hetg₂ O (CH2₂ )₅ Y - Z -⁰ (IX)

wherein HET represents Het ^₁ or the radical pyridyl 2, X and Y are defined as described above and said z°représente halogen preferably chlorine or bromine or a residue of a reactive ester, preferably killed remains aésyloxy or tosyloxy, by operating within an anhydrous organic solvent such as tetrahydrofuran or * the hexaméthylphosphorotriamide or a mixture of these solvents, at a temperature between -80 et + 25 °c. As organic base, it is particularly advantageous to use t. potassium butoxide, lithium or the diéthylaaidure lithium diisopropylamide.

The heterocyclic derivatives of formula (IX-) can be obtained by alkaline hydrolysis, preferably using an aqueous solution of an alkali hydroxide "' as soda, a salt of an isothiourea of general formula:

^:

5 * ^ Wherein HET - EMC-s a CT (the X)

^X Η ¾

at a temperature of between 50^has C and the boiling temperature of the reaction mixture, followed by the action of a product of formula

t-general

the Z ' - {HM₂ )₃ - y-Z in " (IX)

1Ô wherein Y is defined as above and the symbols Z¹ , same or different, each represent a halogen preferably chlorine or bromine, or a residue of a reactive ester, preferably a mesyloxy or tosyloxy, at a temperature close to 2q^I G in the presence of an alkali hydroxide

15 such as soda.

It is possible intermediate isolation of the heterocyclic derivative of the general formula ii

Hetg-to-Ch SH (XIII)

from alkaline hydrolysis of 1' isothiourea of formula

General AOO (s), and then reacting the product of general formula (Xï) in the presence of an alkali hydroxide such as sodium hydroxide "

Isothioureas of general formula (X-), in the form of salts such as hydrochlorides, may be obtained panel action the thiourea and a heterocyclic derivative of general formula 9.ï

25 Hetg-to-Ch a-Z " (XIII.)

wherein Z " represents a halogen atom, preferably a chlorine atom or bromine atom, optionally in the form of a salt such as a hydrohalide, working in an organic solvent such as an alcohol (ethanol) to the reflux temperature of the mixture

3G reaction.

The heterocyclic derivatives of formula (XIII-) may be prepared by employing, according 1' heterocycle selected, either method of W, mathes and H schïjly, Angew. Mal. Labeling. 2 Ed. _, 144 (1963), either method of H, O. The Mosher and J.E. îessieri,

The AM. J. Mal. Share. 21 "(1957) 4925" is still those of

K Y NOVOTSrn et, Khim. Getérotsikl. Soedin. (3), 412 (19? 0) F. AC 21, (1970) 25535 ζ or A. Hirschberg Test and E.P.. SPOERRI,

J 92. Mal. 26, 2356 Ü961).

b) the products of general formula (VI) wherein SET as defined hereinbefore, X represents an oxygen or sulfur atom and Y represents a sulfur or oxygen atom may be prepared by action of a derivative of general formula T-

The HX - (CHj, Y-hr (-XIV)

"■ ?

on an aldehyde of general formula:

Wherein HET-held cells (Xv frames)

in a eolvant by azeotropic distillation to remove water formed during the reaction. In practice, preferred are benzene, toluene, xylenes or poly-î, 2 ethane.

c) the products of general formula (VI) wherein HET is as defined hereinbefore, X represents a lifeless O and Y is a valence bond or a methylene radical can be prepared by cyclization of a product of general formula!

HET-RISK CHOE (ch2₎ the n₀ THE R - " (XIV)

wherein R " is a radical protecting alcohol such as t. butyl, pentyl or tetrahydropyranyl and T-.

r is equal to 3 or 4. Generally it is carried out by heating under reflux in a solvent such as toluene in the presence of para-toluenesulphonic acid; this treatment may optionally be followed by heating in polyphosphoric acid at a temperature of between 50 and 120 °c.

e

The products of general formula (XIV) may be prepared by action of a derivative of general formula magnesian;

A Z "' - mgs (HM₂ )_{the n} 0-TH " (X7II)

wherein R "and n are defined as above and" represents a halogen atom such as a bromine atom or iodine atom " on an aldehyde of general formula (x7), by operating by analogy with the method described by W. B. REHFROW, J 92. Mal. 26 9 όΐ 955, 0).

According to the invention, the products of general formula (I-) wherein a set, X and Y are as defined above and

R represents a radical containing 4 to ii alccyle carbon atoms in a straight or branched chain can be obtained by the action of an organolithium derivative on a product of general formula (ii?) followed by the action of an isothiocyanate of general formula ii the R "<- N.₌ c=s (um)

wherein 1? " represents alkyl containing T to 4 carbon atoms in straight or branched chain.

The organolithium derivatives which are particularly suitable are preferably the alcoylures lithium such as butyllithium and 1 'isopropyllithium or phenyllithium " in solution in an inert solvent as 1' normal hexane, or amides such as lithium or diéthylamidure lithium diisopropylamide.

When the product of general formula (Xv frames) is obtained " as mentioned previously has), from a product of general formula (IX-) and an alkali metal amide, it is not necessary to isolate the product of general formula (VI) prior to reacting 1 'isothiocyante * it is sufficient to use two equivalents to' amide.

The reaction is generally carried out in an anhydrous organic solvent such as 1' hexaméthylphosphorotriamide generally supplemented by an ether such as tetrahydrofuran, at a temperature between -80 -40 °c and₀

The novel products of the present invention can be purified by the usual physical methods, such as crystallization and chromatography.

The novel products of the invention have

particularly interesting pharmacological properties associated with low toxicity. They exhibit an anti-ulcer activity and an antisecretory activity. These properties can be highlighted in rats, at doses between 1 and 100 mg/kg orally, in particular using Rossi and Call. Cdj share. Biol., 150, 2124 (1956) and that of SHAY et, gastro-enterology, dd, 45, 0945) · their lethal dose (LD ^ Q-) in mouse, is generally greater than 300 TGA/kg orally.

Have more particularly these properties astiulcères the products of general formula (I-) wherein

- either EETs represents Tubulo heterocyclic radical to aromatic character containing one or two nitrogen atoms, attached in the row the (or one of these) (e) nitrogen atom selected from pyrida-to-zinyle and 3, pyrazinyl, pyrimidinyl-2 or 4" quinolyl-2, imida-to-zolyle-a 2 or 4i naphthyridine-a 1.8 yl-2, quinoxalyl and 2 or quinazo-to-Petersen-a 2 or 4, X is sulfur or oxygen and Y is sulfur or oxygen, a valence bond or a methylene radical

hET represents the radical - or pyridyl-2, X is sulfur or oxygen and Y is sulfur or oxygen or a methylene radical,

hET represents the radical - either pyriâyls-to-2, X represents an oxygen atom and I represents a valence bond.

Are especially useful as anti-ulcer the products of general formula (I) wherein the symbol wherein HET as just defined, represents pyridyl 2, quinolyl-2 or pyridasinyle-a 3 *

Are particularly interesting ii

- n-methyl (quinonyl and 2) -2 tétrahydrothiophènecarbcthioamiie-C.

the - (pyridyl 2)~2 tetrahydrothiopyraanecarbothieaniie L

- the H-aéthyl (~2 pyridyI) -2 dithdith.ianne-to-1.3 t-c-b-c-ARs hioamide-a 2

n-methyl - (pyridyl 2) -2 tétrahydrofurannecarbcthioamide-a 2

- the (pyriàyl and 2) -2 dithianne-to-1.3 carbothioamide-a 2

- n-methyl (pyhdazinyl and 3) -2 tétrahydrotfaiophènecarbothioamide-a 2 furthermore, the products of general formula (I) wherein HET represents a heterocyclic radical to aromatic character containing one or two nitrogen atoms, attached in 6 of this (or these) (e) nitrogen atom selected from pyridyl 3, pyridazinyl and 4 "pyrimidinyl-5" quinolyl-3, imidazolyl-5, napfctyridine-a 1.8 yl-,X 3 is sulfur or oxygen and Y is sulfur or oxygen, a valence bond or a methylene radical are specifically active regulators of the cardiovascular system, especially as antihypertensive agents. With doses between 0.1 and 100 mg orally, they lower blood pressure in spontaneously hypertensive rats (rats sEH) of sotiche0XAM0TQ - A0KI. The use of the spontaneously hypertensive rat for the study of antihypertensive products is described by J.L. r0ba, IaB. Ducing, itself. 26, 305 (1976).

Are especially useful as anti-hypertensive, the products of general formula (I-) wherein the symbol wherein HET represents pyridyl-3 or quinolyl-3.

Particularly interesting as anti-hypertensive agents are:

- n-methyl (pyriâyl and 3) T-O T of said HL -2 étrahydr ophene C. ARs oasni Bo is T-hi and of - 2

n-methyl - (pyridyl 3) -2 tétrahydrothiopyrannecarbothioamide-a 2

n-methyl - (pyridyl 3) -2 oxathianne-to-1.3 earbothioamide-a 2

- n-methyl (quinonyl and 3) -2 tétrahyàrothiopfeèneearbothioamide and 2 the following examples, non-limiting exemplary, shows how the invention may be practiced.

Mainly in the examples that follow, the chromatography were performed with the siliee 0,063 - 0,20 mm particle size for having or alumina having particle size 0,125 - 0,15 mth.

EXAMPLE 1 -

To a solution of 14.3 g of (pyridyi and 3) -2 iétrahydro-to-thiophthioph.ènecarbodithioate-a 2 methyl in ethanol 50 cm3 maintained at a temperature close to 20 °c, is added dropwise in 5 min 11 cm3 solution to 33 ${weight/volume of) methylamine in ethanol. The solution is then stirred for 5 hours at the same temperature and then cooled to 0^I C. the crystals appeared are separated by filtration, washed with ethanol and then 2 times 8 cm3 20 cm3 by total isopropyl oxide and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 20^I GM.

The resulting product (7.2 grams) is dissolved in boiling ethanol 35 cm3; the solution is added with 0.4 g of black decolorizer, hot filtered and cooled during 1 hour at a temperature close to 5^I C. the crystals appeared are separated by filtration, washed with ethanol and then 2 times 5 cm3 14 cm3 by total isopropyl oxide and dried under reduced pressure (1 mm mercury? 0.13 kPa gauge) to 40 °c. The result is 5.8 grams n-methyl (pyridyi and 3) -2 tétrahydrothiophènecarbothioamide-to-2 melts at 133 * 0.

The (pyridyl 3) -2 tétrahydrothiophènecarboditfcioate and 2 methyl can be prepared in the following manner:

1.6 Solution has 170 cm3 K n. butyllithiua in 1' normal hexane, maintained under argon atmosphere and cooled to -50^I C., is added dropwise in 15 minutes at 125 cm3 hexaméthylphosphorotriamide a mixture of anhydrous and tetrahydrofuran (47 - 53 had volume). Then added, in 10 minutes and to -60 °0, a solution of 30 g of (3~pyridyI) -2 tétrahydrothiophene 125 cm3 in a mixture at ' hexaméthylphosphorotriaaide and tetrahydrofuran anhydrous (47 - 53 had volume). After 15 minutes of stirring at -65 °c, added 15 min 20.7 g of carbon sulfide dissolved in the mixture of 16.5 cm3 hexaméthylphosphorotriamiie and tetrahydrofuran anhydrous (47 - 55 in volumes). After 5 minutes of stirring at -65 °c, added " in 15 min, to~65 °0, 33, C. iodize g of methyl dissolved in the mixture of 125 cm3 hexaméthylphosphorotriamide and tétrahyàrofuranne anhydrous (47 - 55 in volumes). The reaction mixture is then stirred for 45 minutes at the same temperature and then 1 hour during progressively by allowing the temperature to 0 °c. After adding " 000 cm3 of distilled water, the reaction mixture is extracted 2 times with 950 cm3 total of ethyl acetate. The organic extracts, are gathered and washed 3 times per 3000 cm3 total of distilled water. After drying over anhydrous sodium sulfate, filtering and concentrating to dryness under reduced pressure (20 mm of mercury; 2.7 îcPa) to 60 °c, there is obtained a brown oil (56.9 grams) which is chroaatographiée on 550 g of silica gel contained in a column of 5.4 cm in diameter. Is eluted by 18 liters of a mixture cyclohexane ethyl acetate (95 - 5 had volume) by collecting fractions of 1000 cm3. The fractions 8 to 18 are pooled and concentrated to dry under reduced pressure (20 mm of mercury;

2.7 kPa gauge) to 70 °c. This provides 19.6 g of (pyridyl 3) -2 tétrahydrothiophènecarbodithioate and 2 methyl as a clear amber oil.

[hf=0, 50 ii thin layer chromatography silica gel j-solvent ii cyclohexane aeétate ethyl 50 - 50 by volume)].

The~2 (pyridyl 3) tetrahydrothiophene can be prepared in the following manner:

59 g of sulfide pyridyl-3 methyl and chloro-3 propyl in solution in 75 cm3 of anhydrous tetrahydrofuran are added dropwise in 15 minutes and while maintaining the temperature below 32 °c, to a solution of 50.8 g of potassium tert-butoxide in a mixture of 77 cm3 hexaméthylphosphorotriaaide of anhydrous tetrahydrofurane and 410 cm3.

After stirring for 1 hour at a temperature close to 20^I C., the reaction mixture is added to a mixture of 750 cm3 water hr

420 cm3 distilled and ethyl ether. After decantation, the aqueous phase is extracted again by 200 cm3 ethyl ether. The ethereal phases joined, are washed 3 times by 2100 cm3 total of distilled water, dried on anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 45 °c. This results in 30 g of (pyridyl 3) -2 tétrahydrothiophene as a brown oil.

[Rf=0.36 5 thin layer chromatography silica gel; solvent ii ethyl acetate - hexane (50 - 50 by volume)].

The pyridyl-3 methyl sulfide and chloro-3 propyl can be prepared in the following manner:

To a solution cooled to 12^I 100 G of c monohydrochloride (pyridyl 3 methyl) -2 isothiourea in 250 cm3 of distilled water is added, in 10 minutes and allowing the temperature to rise to 14^I C., 50 cm3 of an aqueous sodium hydroxide solution 10 n after heating for 30 minutes at a temperature of 100 °c and then cooling to 12° g, is added dropwise in 10 min and 60 cm3 of an aqueous sodium hydroxide solution 10 H is then added under stirring 82 g of bromine-1 chloro 3 propane and stirring for 20 hours continued at a temperature close to 20 °c. The reaction mixture is then extracted 3 times with 430 cm3 total of methylene chloride. The organic extracts are combined and washed by distilled water and then 250 cm3 dried on anhydrous magnesium sulfate. After filtration, the solution obtained is poured onto 100 g of silica gel contained in a column 3 cm diameter j of the column is then eluted by 2300 cm3 of methylene chloride. The first fraction

(700 cm3) is removed f be the second fraction (16oo cm3) is collected and concentrated to dryness under reduced pressure (20 mA mercury; 2.7 kPa gauge) to 35 °c " is thus obtained 59 grams sulfide pyridyl-3 methyl and chloro-3 propyl in the form of a yellow oil.

[Wherein R=GBP 0, 33 ii thin layer chromatography silica gel? of ethyl cyclohexane solvent S acetate 50 - 50 by volume)].

The monohydrochloride (pyriâyl~3 methyl) -2 isoihiourée may be prepared in the following manner:

55 HAS S thiourea suspended in ethanol houillant 510 cm3, added dropwise in 15 minute and, 100 g of hydrochloride of chloromethyl-3 310 cm3 pyridine solution in ethanol to 60 °c " the reaction mixture is stirred for

1 hour 45 minutes to boiling and then cooled to 30° g. After settling, the supernatant solution is removed. The remaining gummy solid is added 400 cm3 of ethanol and stirred for 63 hours at a temperature close to 20 * 0. The crystals which have formed are separated by filtration, washed 2 times with 60 cm3 total of ethanol and dried under reduced pressure (20 AIMs mercury; 2.7 kPa gauge) at a temperature close to 20^I C. and 100 g of monochlorhydrata of (pyridyl 5 methyl) isothiourea °0 -2 melts at 220.

EXAMPLE 2 -

To a solution of 16 g of (pyridyl 4) methyl -2 tétrahydrothiophènecarbodithioate-a 2 35 cm3 in ethanol maintained 20 °c, is added dropwise in 15 min, a solution of 12 cm3 (weight/volume of) 33 $methylamine in ethanol. The solution is then stirred for 1 hour at a temperature close to 20 °c then cooled to 0 °c. The crystals appeared are separated by filtration, washed 2 times by THE Q % cm3 total of ethanol and dried under reduced pressure (20 mm of mercury;

2.7 kPa gauge) at a temperature close to 20^I C. and 11 g of crude product crystallized is redissolved in 100 om3 of boiling ethanol; the resulting solution is added with 0.5 g of black decolorizer, hot filtered and then is cooled to 0° g for one hour. The crystals appeared are separated by filtration, washed 2 times with 20 cm3 total of ethanol and dried under reduced pressure (20 mm of mercury 5, 2.7 kPa gauge) at a temperature close to 20 °c. The resulting product (9 grams) is chromatography on 20 grams gel neutral silica contained in a column of 1.7 cm in diameter. Is eluted by 1000 cm3 of methylene chloride followed by 250 cm3 a mixture of methylene chloride-ethanol (90 - 10 by volume) by collecting fractions of 250 cm3 " fractions

1 to 5 are pooled and concentrated to dry under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 50 °c. The resulting product (8 grams) is dissolved in boiling ethanol 94 cm3; the solution is added with 0.4 g of decolorizing - black, hot filtered and cooled during 15 hours at a temperature close to 5 °c.

The crystals appeared are separated by filtration, washed 2 times with 14 cm3 total of ethanol and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20 °c. The resulting product (6.9 grams) is dissolved in acetonitrile 75 cm3 boiling and the solution, supplemented with 0.2 grams black bleach, is hot filtered and then is cooled during 1 hour to 0^I C. the crystals appeared are separated by filtration, washed by 7 cm3 of acetonitrile and dried under reduced pressure (1 mm of mercury;

0.13 kPa gauge) to 60^I C. and 5 * 9 grams n-methyl (pyridyl 4) -2 tétrahydrothiophènecarbothioaaids-to-2 melts at 178 °c.

The (pyridyl 4) -2 tétrahydrothiophènecarbodithioate and 2 methyl can be prepared in the following manner:

Has 265 cm3 1.6 m solution of n-butyllithium in 1' hexane and maintained under a nitrogen atmosphere at a temperature close to -60 °c, is added dropwise in 15 minute and, 192 cm3 hexaméthylphosphorotriamide a mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). Then added in 20 minutes a solution of 46.7 g of (pyridyl 4) -2 tetrahydrothiophene in

192 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). After 20 minutes of stirring at the same temperature, added 20 minutes a solution of 52 grams 192 cm3 Bulfure of carbon in the mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47 - 53 in volumes). After 5 minutes of stirring at the same temperature, added 15 minutes a solution of 60.5 g of methyl iodide in 192 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). The reaction mixture is then stirred for 45 minutes at 25 min and then during -60 °g by allowing the temperature to 5 °c gradually. It is poured over a mixture of 1500 cm3 of water, distilled water and the 900 cm3 of ethyl acetate.

U

After decanting, the aqueous solution is extracted by 500 cm3 of ethyl acetate. The organic phases are combined and washed 3 times by 4500 cm3 total of distilled water and then 2 times per 250 cm3 total 2 3s an aqueous solution of hydrochloric acid.

The organic extracts are eliminated; the aqueous extracts are washed 2 times with 300 cm3 total of ethyl acetate, then neutralized to ph=8 - by addition of sodium bicarbonate; they are extracted 3 times per 600 ca3 total of ethyl acetate. Ües novel organic extracts are washed 3 times with joined and 600 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm mercury? 2.7 kPa gauge) to 50° g. (58 Grams) is chromatography on 450 g of silica gel contained in a column of 5 cm in diameter; the column is then eluted by 1500 cm3 a mixture cyclohexane ethyl acetate (95 - 5 had volume), by 4000 cm3 a mixture cyclohexane ethyl acetate (90 - 10 by volume), by 2000 cm3 a mixture cyclohexane ethyl acetate (85 - 15 had volume) and by 2500 cm3 a mixture cyclohexane ethyl acetate (80 - 20 by volume) by collecting fractions of 500 cm3. 10 To 12 fractions are pooled and concentrated to OTA (5, 2.7 kPa to 20 mm of mercury) to 50^I C and the product partially obtained crystallized (10 grams) is filtered, washed 2 times with 30 cm3 total isopropyl oxide and dried under reduced pressure (20 mm mercury? 2.7 kPa gauge) at a temperature close to 20 °0; this provides a first batch of 6 g of product. 13 To 20 fractions are pooled and concentrated to dry under reduced pressure (20 mm ls mercury;

2.7 kPa gauge) to 50 °c. The second batch obtained (34 grams) is joined with the first batch of 6 g and dissolved in 180 cm3 oxide, isopropyl boiling; the solution is added with 0.4 g of black decolorizer, hot filtered and cooled during 1 hour at 0° o * the crystals appeared are separated by filtration, washed 2 times with 52 cm3 total isopropyl oxide and dried under reduced pressure (L-mm of mercury} 0.13 kPa gauge) to 35 °C, This gives 28.3 g of (pyridyl 4)" 2 tétrahyàrothiophènecarbodithioate-a 2 64° g methyl melts.

The (pyridyl 4) -2 tétrahydrothiophene can be prepared in the following manner ii

A solution of 81 g of sulfide and methyl pyridyl-4 chloro-3 propyl in 100 cm3 of anhydrous tetrahydrofuran is added dropwise, in 20 min, and maintaining the temperature below 33 °c "to a solution of 69" 5 grams of potassium tert-butoxide in a mixture of 108 cm3 hexasérhylphosphorotriamide of anhydrous tetrahydrofurane and 560 cm3. The reaction mixture is then stirred for 1 hour 30 minutes at a temperature close to 20 °c? it is poured over a mixture of distilled water and 1000 cm3 600 cm3 ethyl ether. After decantation, the aqueous phase is extracted 2 times with 400 cm3 year total of ethyl ether. The ethereal extracts are combined, washed 3 times per 3000 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 40^I C 0a 46.7 g of thus obtained (pyridyl 4) -2 tetrahydrothiophene as a brown oil.

[Rf=0, 55 9.ï thin layer chromatography silica gel ; solvent ii cyclohexane aeétate ethyl (5o - 5o by volume)].

The sulfide and methyl pyridyl-4 chloro-j-propyl can be prepared in the following manner ii

To a solution of 116.5 grams of dichlorhyàrate of (pyridyl 4 methyl) -2 240 cm3 * d-isothiourea in distilled water, is added dropwise, in 15 minutes and while maintaining the temperature below 14 °c_F. 97 cm3 of an aqueous sodium hydroxide solution of n * 10 after heating for 20 minutes and then cooling to 12 °c °0 83, is added under stirring 60 cm3 of aqueous soda solution 10 D and 81.5 grams bromo-1 chloro 3 propane and stirring for 15 hours the continued at a temperature close to 20^C C., the reaction mixture is then extracted 3 times with 430 cm3 total of methylene chloride, the organic extracts are combined *, washed by 250 cm3 of distilled water and dried on anhydrous sodium sulfate. After filtration, the solution obtained is poured on 125 g of silica gel contained in a column 3" 2 in diameter; the column is then outcry by 1600 cm3 ls methylene chloride. The first fraction (400 cm3) is removed ; the second

moiety (1200 cm3) is collected® and concentrated to dry under pressure *■

reduced (20 mm of mercury; 2.7 k3? O) to 40^I GB hereby 31 grams

pyridyl-4 sulfide and methyl propyl ohloïo and 5 in the form of a brown oil.

[ïtf=0.3 I-thin layer chromatography silica gel; solvent: cyclohexane acetate'd ' ethyl (50 - 50 by volume)]"

The dichlorhydraie of (pyridyl 4 methyl) -2 isothiourea can be prepared as follows T-

With a suspension of 45 sec. 5 S © d-thiourea in 260 cm3 of boiling ethanol, are added dropwise and 50 min, 82 g of hydrochloride chloroaéiIiyl-to-4 pyridine to 260 cm3 suspension in ethanol to simmer. The reaction mixture 1 hour 30 minutes at estagity during boiling and then cooled to 5 °c. The crystals appeared are separated by filtration, washed 2 times with 60 cm3 total of ethanol and dried under reduced pressure (20 mm of mercury 5, 2.7 kPa gauge) at a temperature close to 20° g. This provides 116 g of diehlorhydrate of (pyridyl 4 2methyl) isothiourea -2 melts at 260 °c "

EXAMPLE 3 -

With a suspension of 20 g of (ouinolyl and 2) methyl -2 tétrahyàrothiophènecarbodithioate-a 2 42 cm3 in ethanol maintained at a temperature close to 20 °0₅ added dropwise in 10 minutes at 13.5 cm3 and a solution (weight/volume of) 33 $of aétàyiamine in 1' ethanol. The reaction mixture is then stirred for 15 hours at a temperature close to 2g °C " the crystals appeared are separated by filtration, washed 2 times per 24 cm3 if total of ethanol and dried under reduced pressure (20 mA mercury;

2.7 kPa gauge) at a temperature close to 2q^I Gm "thus 12.1 g of crude product crystallized" redissolved product in boiling ethanol 75 cm3 j of the solution is added with 0.6 g of black decolorizer, filtered the Lrticcàsadrsfrciàitpsad&ATs 3 hours' to ' at around 3 * 0 · appeared the LOS crystals are separated by filtration, washed 2 times not¹ If the total heading if the d^! ethanol and dried under reduced pressure® (L-SOI. for Cl -; asrciatt§(13 K. lifi) to 60⁹ C.

11 Thus•gms of e-œéthyl (mizoiyl " 0) -, 2 tétrc&therein drothiophènecarbo-to-thioamiàe-to-2 flux % 124 * 0 -•

the (^ ^ uincljlëj-s-loirahycirothioÿhsnecarboéithioate ^, methyl isopropyl-to-jpsrtItrs can the I 1&&. am® tuivrnteO

À 138 cm? eftittGclvtiisa\ M and I-■_I in Ithiuinhutyll. 1' normal hexane, maintained fools the ATIA Spius® of £pargon at neighboring. of -60^Ô C., is goatt additions "has gemtts - IC 10 minute ORIs cm3 mixture to * hexaaéthylphosÿ ic.vc.tr of £arnife and C clos e cooper ahydrof URs anae anhydrous (47 - 53 th" tôItkiss), ", T-patuits in 15 minutes a solution of 31 g of (çuinolyl I-{■■-": ^ OitcJvdrc thiophene compounds in 100 cm3 mixture to ' hexaméthylpl, otplci._; the IC® T® I: Fe and due ùitrahydxofurancë anhydrous (EDD volume 47 - 53)_T- 5 iprscoinutes D.^! stirring, is added dropwise, in 15 sec.® - ffiiiiïitsiafso lM-stage ausrature "a solution of 17 g of sulfide-© because! **-S" ItntvjO>sb3 the mixture of hexaméthylphosphorotriamide and/iétràrsanyar-to-SP(4? - 53 in volumes). After 5 minutes of shaking * where cc.jtat® goutt® to drop and in

25 min, each solution is ; ¾ g to⁵ methyl iodide to® 100 cm3 in the mixture of hexaœéihylghc-to-sjpiiPr: © and " © tétr of anhydrous tetrahydrofran (47 - 53 in volumec) - 1?. rélUuïfsrtactioanel is then stirred for 45 5 - A ainutes νν ptij Pt nfer V 43 min by allowing progressively yew, ictylru-a curly ;? 20 hr^ÙC about. It is then poured into a&onth ;•." graze'd•". at distilled and 450 cm3 acetate'd * étfeyls" ^ d-oevvsaiicnj. the aqueous phase is extracted, by ethyl 1 - 250 cm3 of ecétits.. 1®®organic extracts are combined, washed 5 both by 1050 cm3 has®, dimensioned of distilled water, dried on sulfate-TLS " odimmanity• > grams filfil.ré * - if concentrated to dry under reduced pressure (20 mm * ii shooter® 2pf>? has) to 70^I C (57 grams) tOS chrcvtücgrtphié on 550 g of silica gel in a neutral c,-to-,itenus CTL I®; i. 0 · - 3._; : i wherein and éé .iss payment be 1 the column is then eluted by 1000 © t'AEG-v'v' rng® cyclohexane acetaxe ethyl (EDD volume 95 - 5) pure s5 l x; J. T. "; AF mixture cyclohexane acetate to ethyl * (90 - 10 its volume) © collecting moieties has 500 cm3®. The fractions 1 to 3 are renal and concentrated to dry under reduced pressure © (20 mA mercury ξ 2.1 The ID? has) to 50 °c ii

this provides 56.6 g of crude product is dissolved in 14 * grams in 70 cm? © isopropyl oxide boils? the solution is added with 0.3 grams black decolorizer, hot filtered and cooled during 2 hours at a temperature of 5 © neighbor^SG₀ The crystals appeared are separated by filtration ., washcoat by 7 th®5 © isopropyl oxide and then 2 times per 30 cb5 total of petroleum ether * after drying under reduced pressure (L is its. mercury. $0.13 kPa gauge) to 45 °c, obtained 8.9 grams (qtdnolyl-in 2) of -2 tetrahydrothiephene-to-carbodithioate and 2 methyl flux hr ?2 °0_{the O}

The (quinonyl and 2) -2 tetrahydrothiophene can be prepared in the following manner e

A solution of 82 grams sulfide quinolyl-2 methyl and chloro-3 propylbiphenyl © in 100 cm3 of tétrahydrofurezm © is added dropwise to anhydrous in 55 minutes maintaining the temperature below 33^I C. to a solution of 56.5 s of tsrtiobutylat® potassium in a mixture of 85 ca5 of hessaéthylpfeosphorotriemide and 455 cm3 of anhydrous tétrahydrofursmne " the reaction mixture is then stirred for 1 19th-s-saia® 15 minutes at the temperatures and then is cast ' on a mixture of 800 cm3 distilled water © T 500 cm3 ethyl ether " after decantation, the aqueous phase is extracted 2 times per 320 "sa3 ethyl ether" ethereal extracts are combined, washed 3 times by 2400 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated sound reduced pressure (20 mm of mercury 5 2.7 staphylococcus) to 35 °0° (50 grams) is chromium plated on 500 g is © c-w communication GSL neutral silica contained in a column'd © 5 cm diameter? the column is eluted by a mixture of 2000 cm3 cycloheraae-to-aeétats ethyl (95 - 5 by volume) and then a mixture of 1008 cm3 cyclehsrane-to-acétats ethyl (90 - 10 by volume) by collecting fractions in ES 500 3" 3 and 4 the moieties are joined © T-concentrated to dry under reduced uression (20 mm of mercury % 2.7 aHP) to 40^IC%

this provides 31 grams d. © crystallized product used as is

what in the reaction described above " for identification in the pure state, is redissolved and 0.3 grams c © product in

1.5 cm3 boiling isopropyl oxide and cools the solution obtained during 30 min, at a temperature close to 0 °c. The crystals appeared are separated by filtration, washed by 0.5 cm3 isopropyl oxide and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 20 °c, thus 0.2 g of (quinonyl and 2) -2 tetrahydrothiophene melts b3 °C.

The sulfide quinolyl-2 methyl and chloro-5 propyl can be prepared in the following manner.*

To a solution of 141 g of dihydrochloride (quinonyl and 2 methyl) isothiourea -2 240 cm3 in distilled water, is added dropwise to 15^I C and in 15 min 97 th®5 of an aqueous sodium hydroxide solution 10 K after heating for 20 minutes to " 3^{the O} 0 and then cooling to 10 °c, is added under stirring 60 CMY of an aqueous sodium hydroxide solution and then 81.5 g of 10 ii bromo 1 chloro 3 propane and continued stirring hang 15 hours at a temperature close to 20 °0. The reaction mixture is then extracted 3 times with 430 cm3 total of methylene chloride; the organic extracts are combined, washed by 250 cm3 of distilled water and dried on anhydrous sodium sulfate® after filtration, the solution obtained is poured onto 250 g of silica gel contained in a column of 4" diameter 3 cm VBE1 the column is then eluted with methylene chloride 1180 cm3, the first fraction (700 cm3) is eliminated. The second fraction (430 cm3) is collected and concentrated to dryness under reduced pressure (20 mm of mercury;

2.7 kPa gauge) to 35 °c. This provides 82 g of sulfide quinolyl-2 methyl and chloro-3 propyl as an orange oil.

[Rf=0.3 } thin layer chromatography silica gel? solvent S cyclohexane ethyl acetate (5o - 5o by volume)].

The dihydrochloride in DS (methyl-quinonyl and 2) -2 isothiourea can be prepared as follows %

With a suspension of 45? 5 G 260 cm3 of thiourea in boiling ethanol, are added dropwise and 15 minutes a slurry maintained at 70 °0 of 107 g of hydrochloride of chlorine-methyl 2 450 cm3 quinoline in ethanol. The reaction mixture is stirred for 1 hour>9 denying? e I, I-⁵ boiling and then cooled: 20 to^I C. the crystals appeared are separated not filtering " washed 2 times per 100 total SJT-d-ethanol and dried under reduced pressure (20 mm of meror © % 2.7 IF? has) at a temperature close to 20 °0. This provides 141 £of diehlorhydrâte of (methyl-quinonyl and 2) isothiourea -2 melts at 25^: 0^IC_{the O}

EXAMPLE 4 **

Â. flush® solution de .9 g of (I-yl=2) - 2 Py and GBP&tétrahyàrotkio-to-pyrannecarbodithioaie and 2 methyl® in 60 SJT ethanol maintained at a temperature close to 20 * 0". " its additions dropwise in 15 min 7 and_S an isolator 5 cm3 35 hr * F. (weight/volnme) methylamine in ethanol " the solution is then® stirred for 16 hours at a temperature close to 20° 0₃ GEA crystals appeared are separated by filtration, washcoat 2 faith-s by 20 YAC total of ethanol and dried under reduced pressure (20 its they mercury F. 2.7&? has) at a temperature close to® 20^I 0 0s 7.8 g of product is thus obtained which is redissolved brui crystallized ûmis 96 c © 3 of boiling ethanol|the solution thus obtained is added with 0.4 © S black decolorizer, hot filtered and cooled during 30 minutes to than1^I C." the crystals appeared are separated by filtration, washed 2 times with 20 cm3 in total -'d ' ethanol and direction sounds reduced pressure (1 has mercury; 0.13 kPa gauge) to 45®C.₀ This provides 6.3 S h-methyl (pyridyl 2; 2 - tétrahydrothiopyrssnecarbothioaaide-to-2 melts at 153 * 3"

The (pyridyl 2) -2 tstrahydrothiopyrsnaecarbodithioaie-s-methyl may be prepared in the following manner e

WITH 265 cm3 solution 1.6 hr of n " butyllithium in 1' hexane and kept under atmosphere - D.³ argon teEç>érature close -60 °c, is added dropwise in 10 min ' 192 cm3 a mixture of anhydrous tétrahydrefurasaehexaaéthylphcsphorotriamide and (47 "53 in volumes)" then added in 15 minutes at the same temperature from a solution. - 5e 50s 6, 8' of (pyridyl 2) -2 tétrahydrothiopyranas in 192 of the mixture of sajhexsaaétfcylph © spheretriad of and tétrahydrefuraan-th sahydrss (47=53 in volumes).

After 5 minutes of stirring, added 13 minutes a solution of 32 g of sulfide letlet us carbons in the c ^ 1 $2 3 the mixture of feesaméthylphosphoretriaside and d® T-étrshydre aminofuran anhydrous (47~53 in volumes).

Then added in 15 minutes a solution of 60.5 g of methyl iodide in the mixture of 192 cm3¹hexaméthylphosphorotriamide and tetrahydrofuran anhydrous (47 - 53 had volume). The reaction mixture is then stirred for 45 minutes at -65®C and during 2 heuree leaving gradually raised the temperature to 5 * 0, it is then cast sxxr 1500 cm3 a mixture of distilled water and 900 cm3 of ethyl acetate. After decantation, the aqueous phase is extracted by ethyl acetate 500 cm3. The organic extracts are combined, washed 3 times by 4500 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 70^I Gm " (87 grams) is chromatographed on 800 g of silica gel contained in a column 6 in diameter j of the column is eluted by 5700 cm3 a mixture cyclohexane ethyl acetate (95 - 5 by volume) by collecting 1 1000 cm3 friction, 1 800 cm3 fraction, fraction 1 and 1 900 cm3 3000 cm3 fraction. Oette last is concentrated to dry under reduced pressure (2 mm mercury? 2.7 AHP) to 50 * 0. (24 Grams) is dissolved in boiling isopropyl oxide 100 cm3; the solution is added with 0.4 g of black decolorizer, hot filtered and cooled during 1 hour at 0 °c. The crystals appeared are separated by filtration, washed 2 times with 30 cm3 total isopropyl oxide and dried under reduced pressure (1 mm mercury 5, 0.13 K.? has) to 35 * 0, the result is 14 "5 g of (pyridyl 2) -2 tétrahydrothiopyranaecarbodithioate and 2 methyl melts at 79 * 0"

The (pyridyl 2) -2 tetrahydr0thiopyramy can be prepared as follows T-

82 g of ïïne solution pyridyl-2 methyl sulfide

and chloro-4 butyl in 100 cm3'd® anhydrous tetrahydrofuran is added dropwise in 15 minutes and while maintaining the temperature below 30 * 0, to a solution of 66 - grams of potassium tert-butoxide in a mixture of 100 cm3 feexsméthylphosphorotriamide of anhydrous tetrahydrofurane and 530 cm3. After shaking for 1 hour at a temperature close to 20®C., added 20 g of potassium tertiobuiylate and proceeds with the stirring for 45 minutes to 1s same temperature. 1s reaction mixture is added to a mixture of 1000 SJT D.^J © e, U-distilled water and the YAC 600 ethyl ether Y after decanting, the aqueous phase is extracted 3 times with 400 ℮ β 2 in total of ethyl ether. The ethereal extracts are combined_O washed 5 3000 cm3 times in total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 ms of mercury? 2.7 kPa gauge) to 35 °c•hereby 50.6 g of (~2 pyridy!) -2 tétrahyârethlopyranne as a brown oil

[RF ≈ 0.7 ii chromatography overlying thin layer silica gel|solvent ss.eyclohsxase-to-aeétate ethyl (50 - 50 by volume)]"

The pyridyl-2 methyl sulfide and chloro-4 butyls can be prepared in the following manner e

To a solution of 120. g of dihydrochloride (pyridyî and 2 methyl) -2 isothiourea in 250 cm3 distilled water cooled to 15 °c, is added dropwise, in ES 20 minutes whilst maintaining the temperature below 15 °c, 100 cm3 of each aqueous soda solution after heating for 10 H 2 © minutes to 75' IC and then cooling to 13 °c, is added under stirring OS ca5'd® aqueous soda solution 10 D and 85 grams bromo-L-chloro 4 butane and stirring for 15 hours the continued at a temperature close to 20^I G the reaction mixture is then extracted 3 times with methylene chloride - 450 cm3; the organic extracts are combined, washcoat by 300 cm3 of distilled water, dried on anhydrous sodium sulfate and filtered. The solution, 100 g of drinking is poured silica gel contained in a column 3 © diameter;

the column is eluted® by 3700 EYC custom methylene chloride.

The first fraction (700 JME) © CD eliminated " the second (2000 cm3) is concentrated to dry direction reduced pressure (2ô AM of mercury;

2.7 kPa gauge) to 55 °c. This provides 82 g of sulfide and methyl pyridyl-2 chloro-4 butyls.

[An RF ≈ 0, 00 g of chromium plated|© graphy on thin film

silica gel $ solvent S cyclohexane acstate ethyl (50 - 50 by volume)].

The dihydrochloride (pyridyl 2 methyl) -2 isothiourea can be prepared as follows ii

1 a suspension of 17" 6 g of thiourea in boiling ethanol 100 cm3 is added dropwise in 15 minute and, 50 g of hydrochloride of chloromethyl-2 pyridine solution in 100 cm3 ethanol to 60 °c. Boiling is maintained for

90 minutes and then, after cooling, the crystals appeared are separated by filtration, washed 2 times with 100 cm3 total of ethanol and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20 °c in the presence of potassium hydroxide pellets. This provides 41" 7 g of dihydrochloride (methyl-pyridyl 2) isothiourea -2 220®C. melting.

The chloromethyl-2 pyridin hydrochloride may be prepared according to the method described dandan.a German Patent 1,204 251.

EXAMPLE 5 -

Has a temperature close to 20 °c during 45 min is saturated by a current of anhydrous ammonia solution of 10.4 g of (pyridyl 2) -2 dithianne-to-1.3 carboàithioaie and 2 methyl 69o cm3 in a mixture of anhydrous ethanol and ethyl ether (75 - 25 by volume). After stirring to tee hours

the same temperature, the ammonia is again admitted during 1 hour until saturation. The crystals appeared are separated by filtration, washed 2 times with 30 cm3 total of anhydrous ethyl ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20° g. Obtained a first fraction of 6.2 g of product. The filtrate is concentrated under reduced pressure (20 mm of mercury % 2.7 kPa gauge) to 50^I C. cooling is added anhydrous ethyl ether 100 cm3 to residue, obtained. The crystals appeared are filtered, washed 2 times with 30 cm3 total of anhydrous ethyl ether and dried under reduced pressure (20 mm of mercury 5, 2.7 AHP) at a temperature close to 20 degrees €. (0.5 Grams) is dissolved in boiling acetonitrile derivative 30 cm3'd *? the solution is filtered hot and then cooled at a temperature close to 0 °c. The crystals appeared are separated by filtration, washed by 3 cm3 * d-acetonitrile and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20 °c.

The result is a second fraction of 0.4 gm " The two fractions (6.2 g and 0.4 grams) are combined and dissolved in 400 cm3 D.^! boiling acetonitrile derivative; the solution, added with 0.1 g of black decolorizer is hot filtered and cooled during 30 minutes at a temperature close to 0 °c. The crystals appeared are separated by filtration, washed 2 times with 40 cm3 at. the total * d-acetonitrile and dried under reduced pressure (1 mm mercury; 0.13 kPa gauge) to 55 °0.

The result is 5" 5 g of (2~pyridyI) -2 dithianne-to-1.3 carbothioamide-to-2 melts at 214 °c.

The (pyridyl 2)" 2 dithianne above 1.5 carbodithioats and 2 methyl can be prepared in the following manner:

Has 140 cm3 solution 1.6 rubutyllithium II in 1' normal hexane, kept under ambience " nitrogen and cooled to -60 °c, is added dropwise in 10 minutes at 140 cm3 and a mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47 - 55 had volume). Then added in 20 minutes at the same temperature a solution of 36 g of (pyridyl 2)" 2 dithianne and 1.3 in the mixture of 140 cm3 hexaméthylphosphorotriaaide (47 - 55 in volumes). After 15 minutes of stirring, added 10 minutes a solution of 17 g of carbon disulfide in 70 cm3 of the mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriaaide (47 - 53 in volumes), after 5 minutes of stirring at -60 °c, added 10 minutes a solution of 32 g of methyl iodide in? 0 cm3 of hexaméthylphosphorotriamide and tetrahydrofuran anhydrous.

After 1 hour 30 minutes of stirring at a temperature close to

-40 °0, distilled water is added 500 cm3 j of the mixture is then extracted 4 times per 1100 cm3 total of ethyl acetate. The organic extracts are combined, washed 3 times by 1200 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm mercury? 2.7 kPa gauge) to 40 * 0. (57 Grams) is chromatography on 1080 g of neutral alumina contained in a column of 5.2 cm in diameter. Is elected® with 6000 cm3 cyclohexane by collecting fractions of 1000 cm3 and then with 2500 cm3 a mixture cyclohexane ethyl acetate (99 - 1 by volume) by collecting fractions of 500 cm3 " 7 to 11 fractions are pooled and concentrated to dry under reduced pressure (20 mA mercury; 2.7 kPa gauge) to - 40 * c. (15 Grams) is dissolved in boiling ethanol 30 cm3 and the solution is cooled to 0 °c during 1 hour. The crystals appeared are separated by filtration, washed 2 times with 20 cm3 total of ethanol and dried under reduced pressure (20 mm of mercury;

2.7 kPa gauge) at a temperature close to 20 °c. This provides 7 * 7 g of (pyridyl 2) -2 dithianne-to-1.3 carbodithioate and 2 methyl melts at 91 * 0.

The (pyridyl 2) -2 dithianne and 1.3 may be prepared as follows:

A solution of 2é, 7 g of pyridinecarboxaldehyde 2, of 94 * 4 g of propanedithiol-to-1.3 and 3>7 g of toluenesulfonic acid in 2500 cm3 of dichloro-1.2 ethane is kept boiling for 20 hours to remove water formed by azeotropy. After cooling to 5 * 0" the reaction mixture EETs washed 2 times by 540 cm3 total of an aqueous solution about 7 n of potash and then 4 times by 1400 cm3 total of distilled water. The organic solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 40 * 0. This provides 41 "9 g of (pyridyl 2) -2 dithianne-to-1.3"

[Rf=0, 6; thin layer chromatography silica gel} solvent; cyclohexane ethyl acetate (50 - 50 by volume)].

EXAMPLE 6 -

To a solution of 17 * 5 g of (pyridyl 2) -2 oxathianne-to-1.3 carbodithioate and 2 methyl in 60 cm3 of ethanol, are added dropwise, in 10 minutes and at a temperature between 34 * 0 and 37 * 0, 35 to 6.5 cm3 solution (weight/volume of) methylamine in ethanol. The reaction mixture is then stirred for 30 minutes to 2®C. the crystals appeared are separated by filtration, washed 2 times with 40 cm3 total D.¹ petroleum ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20° g, (13 * 4 - g) is dissolved in boiling ethanol 80 cm3? the solution is added with 0.2 g of black decolorizer, hot filtered and cooled during 1 hour at a temperature of around 0° Q_has The crystals appeared are separated by filtration, washed 2 times with 20 cm3 total of ethanol and dried under reduced pressure (1 mm mercury; 0.13 kPa gauge) to 50 °0. This gives 12 g of n-methyl (pyridyl 2) -2 oxathianne-to-1.3 carbothioamide-a 2 * melts at 157 °c

The (pyridyl 2) -2 oxathianne-to-1.3 carbodithioate-a 2

methyl may be prepared in the following manner:

Has 212 cm3 solution. 1.6 m out of n butyllithium in 1' normal hexane, maintained under nitrogen atmosphere and cooled to a temperature close -60 °g, added dropwise in 15 minutes at 155 cm3 and a mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47" 53 in volumes). Then added in 25 minutes at the same temperature a solution of 54" 4 g of (pyridyl 2) 153 cm3 -2 oxathianne and 1.3 in the mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47 - 53 in volumes). After 15 minutes of stirring, is added, in 15 min, a solution of 23.3 g of carbon disulfide in 153 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 53 had volume). After 5 minutes of stirring at -70 °c, added 10 minutes a solution of 43>4 g of methyl iodide in 153 cm3 D.¹hexaméthylphosphorotriamide and tetrahydrofuran anhydrous (47 - 53 in volumes). The reaction mixture is stirred for 45 minutes to 1 hour and then during -70 °c by allowing the temperature to 20° g about gradually. The reaction mixture is poured over a mixture of distilled water and 1200 cm3 800 cm3 of ethyl acetate. After decantation, the aqueous phase is extracted 2 times per 1200 cm3 if total of ethyl acetate; the organic phases are combined, washed 3 times with distilled water if total of 1500 cm3, dried on anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 45 °c * (69.3 grams) is chromatographed on 700 g of silica gel contained in a column of 5.4 cm in diameter. 2300 Cm3 is eluted successively with cyclohexane, 4000 cm3 a mixture cyclohexane ethyl acetate (98 - 2 by volume), 7000 cm3 a mixture cyclohexane ethyl acetate (95 - 5 by volume) and 3000 cm3 a mixture cyclohexane ethyl acetate (9o-to-lo in volumes) by collecting a first fraction of 2300 cm3 14 and then 1000 cm3 fractions. 11 To 15 fractions are pooled and concentrated to dry under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 45^I C. and 17.5 g of (pyridyl 2) -2 oxathianne-to-1.3 carbodithioate-a 2 116° g crude methyl melts.

The -2 (pyridyl 2) can be prepared oxathianne-to-1.3

as follows:

A solution of 26.7 g of pyridinecarboxaldehyde 2,

of 81.1 g of mercapto 3 propanol derivatives thereof 1 and 3.7 g of toluenesulfonic acid in 2500 cm3 of dichloro-1.2 ethane is kept boiling for 15 hours to remove water formed by aséotropie. After cooling at a temperature close to 20 °c, the reaction mixture is washed 3 times by 1200 cm3 at.

total of an aqueous solution 5 n of soda and then 5 times in total of 2400 cm3 Pax-distilled water. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 5û °C. 36.6 G of obtained (pyridyl 2) -2 oxathianne-a 1" 3 in the form of a oil toto brunclair.

[Rf=0.45 ii thin layer chromatography silica gel; solvent: eye1ohsxane acetate-ethyl (50 - 50 by volume)].

The mercapto 3 propanol derivatives and 1 may be prepared as described in the literature [rr.o. Clinton and transporter. Dermatitis. Mal. Soc., 61, 594 (1945)].

EXAMPLE 7 -

500 Cm3 has a solution. 1.6 M out of n. butyllithium in 1' hexane can be maintained in an argon atmosphere at a temperature close to -60 °c, © n-added dropwise and 22 min, a mixture d * 225 cm3 hexaméthylphosphorotriamide and tetrahydrofuran anhydrous (4? " 53 in volumes). Then added in 30 minutes a solution of 56 grams of (pyridyl 2) in 225 cm3 -2 dithianne and 1.3 of the mixture of anhydrous tetrahydrofurane and hexamsfehylphosphorotriamide (47 - 53 if volume). After 15 minutes of stirring, added 15 min 31 grams of methyl isothiocyanate dissolved in 225 cm3 mixture hexaméthylphosphorotriamide and tétrahydrofuraase anhydrous (47 - 53 had volume). The reaction mixture is then stirred for 1 hour to 1 hour and then during -65 °c by allowing the temperature to 20 °c about gradually. It is poured over a mixture of distilled water and 1500 cm3 1500 cm3 of ethyl acetate. After decanting, the aqueous solution is extracted 2 times with 2500 cm3 total of ethyl acetate. The organic extracts are combined, washed 3 times by 4500 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 IfPa) to 50° g " (90 grams) is dissolved in boiling ethanol 600 cm3 and the solution is cooled during 50 minutes at a temperature of about 5 °c.

The crystals appeared are separated by filtration, washed with ethanol and then 2 times 20 cm3 40 cm3 by total isopropyl oxide and dried under reduced pressure (20 mm mercury} 2.7 kPa gauge) at a temperature close to 20 °c. (23.7 Grams) joined

to 0.7 g of a product prepared under the same conditions in other similar operation, is dissolved in ' JBQ $cm3 of boiling ethanol solution is added with 2.5 grams black decolorizer, hot filtered and cooled during 1 hour at a temperature of around 5 °C. The crystals appeared are separated by filtration, washed 2 times per 50 cm3 in total of ethanol followed by 25 cm3 cxyde of isopropyl and dried under reduced pressure (20 mm mercury? 2.7 Kea in) at a temperature close to 20 °c " the product thus obtained (19 grams)•is dissolved in boiling ethanol 600 cm3; the solution is supplemented with 5 g of black bleach, hot filtered and cooled during 15 hours at a temperature close to 5 °c. The crystals appeared are separated by filtration, washed 2 times per 50 cm3 in total of ethanol followed by 25 cm3 isopropyl oxide and dried under reduced pressure (1 mm of mercury;

0.13 kPa gauge) to 55 °c. This provides 15" 9 g of n-methyl (pyridyl 2) -2 dithianne above 1.5 carbothioamide-a 2 159 °c melts.

Has 119 cm3 solution. 1.6 m out of n butyllithium in 1' hexane and maintained under a nitrogen atmosphere at a temperature close to -60 °c, is added dropwise in 15 minute and, 70 cm3 hexaméthylphosphorotriamide a mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). Then added in 15 timed a solution of 19" 5 g of substituted pyrazinyl and 2 the mixture of tetrahydrothiophene in 70 cm3 hexaméthylphosphorotriamide and tetrahydrofuran anhydrous (47 - 53 in volumes). After 15 minutes of stirring, added 15 minutes a solution of 12.7 g of methyl isothiocyanate in 30 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). The reaction mixture is then stirred for 45 minutes to 1 hour and then during -65 °c by allowing the temperature to 20° g about gradually. It is then poured onto a mixture of ethyl acetate and 300 cm3 of 500 cm3 of distilled water. After decanting, the aqueous solution is extracted 2 times with 400 cm3 total of ethyl acetate. The organic extracts are combined, washed

3 times per 1500 cm3 total of distilled water, dried sxtr anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to ' JQ °C. (33 * 5 Grams) is chromatography on 330 grams silica gel contained in a column 4" 2 cm in diameter. By eluting successively with 4000 cm3 a mixture cyclohexane ethyl acetate (9o-to-lo in volumes) and then with 7000 cm3 a mixture cyclohexane ethyl acetate (80 - 20 by volume) by collecting fractions of 500 cm3. Fractions 13 to 22 are pooled and concentrated to dry under reduced pressure (20 mm mercury j. 2.7&AI) to 60 °c. (1.1 ' grams) 48 cm3 is dissolved in a mixture ' boiling of propanol and isopropyl oxide (75 - 25 in volumes);

the solution is added with 0.2 grams black decolorizer, hot filtered and cooled during 18 hours at 5 °c " the crystals appeared are separated by filtration, washed by 10 cm3 mixture propanoloxyde isopropyl (75 - 25 by volume) and dried under reduced pressure (1 mm mercury|0.13 h3? confectioneries) to 45^I 0 Thus 4.9 g of n-methyl pyraslnyl-to-2 tétrahydrothiophènecarbothioamide-to-2 melts at 12J °C.

The substituted pyrazinyl and 2 tetrahyarothiophene can be prepared in the following manner:

A solution of 59 cautious sulfide pyrazinylmethyl and chloro-3 propyl in 75 cm3 of anhydrous tetrahydrofuran is added dropwise, in 15 minutes and while maintaining the temperature below 30 °c, to a solution of 51 cautious of potassium tert-butoxide in a mixture of 75 cm3 hexaméthylphosphorotriamide of anhydrous tetrahydrofurane and 400 cm3. After 30 minutes of stirring at the same temper attracts, added 10 g of potassium tert-butoxide and continued agitation during

30 mins. The reaction mixture is then poured onto a mixture of distilled water and 800 cm3 400 cm3 ethyl ether. After decantation, the aqueous phase is extracted 2 times with 300 cm3 total of ethyl ether. The organic extracts are combined, washed 5 times by 2400 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm Hg $2.7 èp&) to 35 °0. (30 Grams) is chromatographed on 100 g of silica gel contained in a column 3 cm in diameter; the column is eluted by 750 cm3 cyclohexane, by 2500 cm3 a mixture cyclohexane ethyl acetate (50 ≈ 10 volumes) and by 500 cm3 of ethyl acetate by collecting fractions of 250 cm3, 4 to 15 hES-moieties are pooled and concentrated to dry under reduced pressure (20 mm mercury? 2.7 AHP) to 35 °0. The result is

19.5 S pyrazinyl and 2 tetrahydrothiophene as a brown oil.

[Rf=0, 52; thin layer chromatography silica gel; solvent ii cyclohexane ethyl acetate (50 - 50 by volume)}.

The sulfide pyrazinylmethyl and chloro-3 propyl can be prepared in the following manner:

To a solution of 77" 6 g of monohydrochloride (pyrazinylméthyl) -2 isothiourea in 250 cm3 of distilled water, is added dropwise, in 15 minutes and at a temperature close to 10 °c, 39 C.®3 of ion in an aqueous sodium hydroxide solution. After heating for 30 minutes at OJ °C and then cooling to 15 °c, added 47 cm3 of aqueous soda solution and then 10n 66.5 grams ââ.e bromine-1 chloro 3 propane and the agitation is continued for 15 hours at a temperature close to 20 °0. The reaction mixture is then extracted 3 times with 280 cm3 total of methylene chloride. The organic extracts are combined, washed 2 times with 200 cm3 total of distilled water, dried on anhydrous sodium sulfate and filtered. The solution obtained is poured on 80 g of silica gel contained in a column of 2.7 cm diameter; the column is then eluted with methylene chloride 900 cm3, the first fraction (300 cm3) is eliminated; the second fraction (600 cm3) is collected and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 55 °c * hereby 59 S sulfide pyrazinylmethyl and chloro-3 propyl as an oil yellow-orange.

[Rf - 0.47 ii thin layer chromatography silica gel; solvent S cyclohexane ethyl acetate (50 - 50 by volume)].

Hydrochloride (pyrasinylméthyl) isothiourea -2

can be prepared in the following manner;

With a suspension of 68 g of thiourea in 370 cm3 of boiling ethanol, are added dropwise and 15 minutes a solution of 88 g of chlorométhylpyrazine 200 cm3 in ethanol. After 1 hour 30 minutes of shaking at boiling point, the reaction mixture is cooled during 15 hours at a temperature close to 5 °c. The crystals appeared are separated by filtration, washed 2 times with 120 cm5 of ethanol and dried under reduced pressure (20 mm mercury j. 2.7 kPa gauge) at a temperature close to 2ûe^C . This provides 74 grams hydrochloride (pyrazinylméthyl) isothiourea -2 melts at 183®C..

The chlorométhylpyrazine can be prepared as described in the literature [has, HIRSCEBERT and P. SPQERRI, J - gm gold.•Chem., 26" 2556 (l96l)].

EXAMPLE 9 -

Has 75 cm3 solution. butylliihium 1.6 m out of n in hexane, maintained under a nitrogen atmosphere at a temperature close to -60 °c, is added dropwise in 15 minutes at 80 cm3 and a mixture of anhydrous tetrahydrofurane and hexaméihylphosphorotriamide (47 - 53 in. volume). Then added in 20 minutes a solution of 15 s of (pyridyl 2} - 2 of the mixture of tetrahydrofuran in 80 cm3 hexaméthylphosphorotriaraide and tetrahydrofuran anhydrous (AE volume 47 - 53). After 30 minutes of stirring at the same temperature, added 20 minutes a solution of 8.8 g of methyl isothiocyanate 80 cm3 in a mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (AE volume 47 - 53).

The reaction mixture is then stirred for 45 minutes to about 1 hour and then during -60 °c by allowing the temperature to 20° g about gradually. 11 is then poured over a mixture of distilled water and 600 cm3 400 cm3 of ethyl acetate. After decanting, the aqueous solution is extracted

2 times per 800 cm3 total of ethyl acetate. The organic extracts are combined, washed 3 times with 1500 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge)

to 45 * 0. (6.6 Grams) is dissolved in boiling isopropyl oxide 350 cm3} .the solution is added with 0.5 g of black decolorizer, hot filtered and cooled during 30 minutes at 0 °c. The crystals appeared are separated by filtration, washed

2 times per 10 cm3 total isopropyl oxide and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to leak from temperature, close to 20 °c, (7.7 S) joined to 0.8 g of product prepared under the same conditions is dissolved in boiling ethanol 30 cm3 ; the solution is added with 0.2 g of black decolorizer, hot filtered and then cooled for 1 hour at 0 °c. The crystals appeared are separated by filtration, washed

2 times per 10 cm3 in total of ethanol and dried under reduced pressure (1 mm mercury; 0.13 kPa gauge) to 45° g. The result is 6 key g of n-methyl (pyridyl 2) -2 tétrahydrofurannecarbothioamide-to-2 melts at 115 °c.

The -2 (pyxidyl and 2) tetrahydrofuran can be prepared in the following manner:

ïïne 122 g of solution (dimethyl 1.1 propoxyl) (pyridyl 2) -4 -1-butanol 1 and 107.4 grams ρ acid ARs atoluenesultonic 1000 cm3 in toluene is kept boiling for 28 hours to remove water formed by aséotropie.

After cooling at a temperature close to 20^G C., is added 250 cm3 of distilled water. The organic phase is decanted and washed by 50 cm3 of distilled water; the aqueous phases are combined and neutralized by addition of 49 g of sodium bicarbonate. The mixture is extracted 3 times with 1500 cm? total of ethyl acetate; the organic extracts are combined, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 40° g.

This provides a first oil fraction of? 0, concerns grams. The aqueous phase is again extracted 5 preceding both by 2500 cm3 total of methylene chloride ; the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 millimeters mercury;

2.7 kPa gauge) to 35 * 0. This results in a second oil fraction of 11.2 grams. The 2 moieties (50.6 grams and 11.2 grams) are joined, cast 30 minutes on 200 grams o0 °C to polyphosphoric acid. After 10 minutes of stirring at the same temperature and then refroi1issement at a temperature close to 20 °c, the mixture sheave T-λ: · ;η℮. 1 is toward! 400 cm3 in distilled water. 450 Cm3 is then added an aqueous solution of soda 10u in maintaining the temperature below 20 °c to. the crystals appeared are separated by filtration and washed by 500 cm3 of ethyl acetate. The filtrate after decantation, the aqueous phase is extracted 3 total of 1500 cm3 times with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 40^I Thus g 26 g of (pyriàyl and 2) -2 tetrahydrofuran.

[fîf" 0.57 i-thin layer chromatography silica gel; ethyl acetate solvent S]

the (dimethyl-1.1 propoxyl) (pyridyl 2) -4 -1-butanol 1 can be prepared according to the method described in the literature for the (dimethyl-1" 1 and propoxy) phenyl-1 -4-butanol 1 [ww.b. S03mov et, J 92. Mal, 26, 935 (19 ^ 1) 3®

EXAMPLE 10 -

55 Cm3 has a solution 1.6 H has, butyl lithium in 1' normal hexane, maintained under a nitrogen atmosphere at a temperature close to -60 °g, added dropwise in 15 minute and, a mixture of 36 cm3 hexaméthylphosphorotriamide and tétrahydrofuraane anhydrous (47 - 55 in volumes)" OA is then added in 20 minutes a solution of 9.7 S (pyridasinyl and 3) of -2 tetrahydrothiophene in 36. cm3 the mixture of anhydrous tetrahydrofuran and hexaméthylphosphorotriamide * (47 - 55 in volumes). After 15 minutes of stirring at the same temperature, OA is added 15 min 6.4 g of methyl isothiocyanate in the isolator in 56 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 55 in volumes). The reaction mixture is then stirred for 1 hour and then during a -65 °0 © hour by allowing the temperature to gradually -10 °6, it is then cast on a mixed 550 cm3 distilled water © I 300 cm3 of ethyl acetate. After decanting, the aqueous solution is extracted by ethyl acetate 200 cm3. The organic extracts are combined, washed 3 900 cm3 times in total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 £AI) to 55^I C (12.4 grams) is joined to 1 g of product prepared under the same conditions, and chromatography on 154 g of silica gel contained in a column of 5.2 cm in diameter. The column is eluted by 500 cm3 of a mixture cyclohexane ethyl acetate (90 - 10 by volume), 1000 cm3 a mixture cyclohexane ethyl acetate (80 - 20 by volume), 2250 cm3 a mixture cyclohexane ethyl acetate (70 - 30 in volumes) and 2500 cm3 a mixture cyclohexane ethyl acetate (50 - 50 by volume) by collecting fractions of 250 cm3. The fràctions 19 to 25 are pooled and concentrated to dry under reduced pressure (20 mm of mercury; 2.7 CHPE) to 55 °c. (2.4 Grams) is dissolved in boiling ethanol 50 cm3; the solution is added 0.15 g of black bleach and hot filtered and then is cooled during 30 min to 0 °C. The crystals appeared feels separated by filtration, washed by 2 cm3 of ethanol and then 2 times per 6 ea3 total oxide isopropyls and dried under reduced pressure (1 mm mercury; 0.13 kPa gauge) to 60 °c. This gives 0.8 g of n-methyl (pyhdazinyl and 3) -2 tétrahydrothiophènecarbothioamide-to-2 199 °0 melts.

The (substituted pyridazinyl and 3) -2 tetrahydrothiophene can be prepared in the following manner:

A solution of 28.2 g of sulfide and methyl substituted pyridazinyl and 3 chloro-3 prcpyle in 35 cm3 T and rahydro furan is added dropwise to anhydrous, in 15 minutes and while maintaining the temperature below -20^I 0, to a solution of 24 g of potassium tert-butoxide in a mixture of 55 cm3 of hexaméthylphosphorotri amide and 190 cm3 of tatrshydrofuranne anhydrous.

The reaction mixture is then stirred for 1 hour 30 minutes to -40 °c then being cast 500 cm3 0° g on a mixture of distilled water and ethyl ether 500 cm3. After decantation, the aqueous phase is extracted by ethyl ether 250 cm3. The ethereal extracts are combined, washed 3 times with 1500 cm3 total of distilled water, dried on. anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury;

2.7 kPa gauge) to 30 °c. This gives 10.5 g of (substituted pyridazinyl and 5) -2 tetrahydrothiophene as a brown oil.

[LF e 0.4 j-thin layer chromatography silica gel} solvent; ethyl acetate].

The sulfide pyridasinyl-to-3 methyl and chloro-3 propyl can be prepared in the following manner e

To a solution of 106 g of diehlorhydrate of (methyl substituted pyridazinyl and 3) -2 isothiourea in 220 cm3 of distilled water, is added dropwise, in 10 minutes and EA for keeping the temperature below 18 °c, 34 cm3 of 10n an aqueous sodium hydroxide solution. After heating for 20 min. to 75 °c followed by cooling to 10®C., added with stirring 50 cm3 of aqueous soda solution and then t-OH 6 $ g SSRB © a-1 chloro 3 propane and the agitation is continued for 15 hours at a temperature close to 20^I C. the reaction mixture is then extracted 3 times with 340 cm3 total of methylene chloride * organic extracts are combined, washed by 250 cm3 of distilled water and dried on anhydrous sodium sulfate "after filtration" the solution obtained is poured on 80 g of silica gel contained in a column of 2.7 cm diameter 5 the column is then eluted by 700 cm3 of methylene chloride. the first fraction (200 cm3) is eliminated. The second fraction (500 cm3) is collected and concentrated to dryness under reduced pressure (20 mm of mercury, 2₅ 7 kilopascals) to 35^I C. and 60 g of sulfide confectioneries® pyhdazinyl-a 5 methyl and chloro-3 propyl under closes 4' tax rouga oil "

[yew=0, 1; chromatography on strain thin silica gel} solvent S cyclohexane acetate ethyl (50 - 50 by volume)].

The dihydrochloride (pyridasinyl and 3 methyl) -2 isothiourea can be prepared as described in literature 1s [NOVITSKII, kk.yii. et al *" chi®. Gsterotsikl " Ssedin ., (5) (1970) - 412, AC zi are, 5 253 β ζ (1570)}"

EXAMPLE 11 -

44 Cm3 has a solution 1.6 K of n-butyllithium in 1' normal hexane, maintained under atmosphere of asote and cooled to -70 °c, is added, dropwise in 10 min and, 50 th^3 a mixture of hexaméthylphosphorotriamide and tetrahydrofuran anhydrous (47 - 53 had volume). Then additions is 25 minutes at the same temperature a solution of s; 5 g of (pyridyl 3) in 50 cm3 -2 oxathianne and 1.3 of the mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47 - 53 in volumes). After 15 minutes of stirring, added 15 minutes a solution of 5.4 S of iaothiocyanate methyl in the mixture of 50 cm3 hexaméthylphosphorotriamide and tétrahydrofuraïuiÆ anhydrous (47 - 53 in volumes). The reaction mixture is stirred for 45 minutes to 1 hour and then during -70 °c by allowing the temperature to 20 gradually^I G to about. It is then cast onto a mixture stirred 300 cm3 240 cm3 distilled water and ethyl acetate. After decantation " the aqueous phase is extracted 2 times with 400 cm3 total of ethyl acetate. The organic phases are combined, washed 3 times with 600 cm3 total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dry boil reduced pressure (20 mm mercury j. 2.7 kPa gauge) to 50 °0. , 70 Cm3 supplemented with a mixture of metal oxide ** D. isopropyls and ethyl acetate (90 - 10 by volume), is stirred for 10 minutes at 20 °c. The crystals appeared are separated by filtration, washed 2 am by total metal oxide 20 cm3^Iisopropyls, and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20 °c. (4.4 Grams) is chromatography on OA g of silica gel contained in a 2.6 cm diameter column, eluted with a mixture of cyclohexane omj 2000 - ethyl acetate (40 - 60 in volumes) and then with ethyl acetate 800 cm3, by collecting fractions of 200 omj_I The fractions 4 to 14 are pooled and concentrated to dry under reduced pressure (20 in mercury VBE1 2.7 kilopascals) to 50 °c. (3S9 grams) is dissolved in boiling acetonitrile 45 cm3. The solution, supplemented with 0.2 g of black bleach, is hot filtered and then retained after cooling, during 1 hour to Q °C. The crystals appeared are separated by filtration, washed 2 times with 10 cm3 in total of acetonitrile and dried under reduced pressure (1 mm mercury; 0.15 AHP) to 60 °c, thus 2.9 g of N-métàyl (pyridyl 5) -2 oxathianne above 1.5 carbothioamide-a 2 194 °0 melts.

The (the pyridyl " 5) -2 oxathianne above 1.5 can be prepared as follows 2

A solution of 16 g of pyridinecarboxaldehyde 3"

of 48 g of mercapto 3 - propanol derivatives "! © 2 and₅ 25 g acid paratoluenesulfouic in 1500 cm5 of dichloro-1.2 urethane linkages is maintained at 1 'boiling for 15 hours to remove by toto azéoir' opie water formed. After cooling at a temperature close to 20 °c, the reaction mixture is washed 3 times with 750 W&3 total of an aqueous solution 5 H of soda and then 3 times per 1500 cm3 total of distilled water, the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury 5, 2.7 kPa gauge) to 50° g. (15.8 Grams) is chromatography on 200 g of silica gel contained in a column 3" 7 cm in diameter. By eluting successively with a mixture of cyclohexane - 600 cm3 ethyl acetate (80 - 20 by volume), 2700 cm3 of a cyclohexane - ethyl acetate (7o - 3o by volume), collecting fractions

300 cm3. 5 To î1 fractions are pooled and concentrated to dry under reduced pressure (20 mm mercury§2.7 kPa gauge) to $0®C._{the O} The result is 8.6 g of (pyridyl 3) -2 oxathianne L, 3 in the form of a yellow oil.

(Εf " 0.6 ii chromatography large? thin layer silica gel; solvent ii ethyl acetate).

The mercapto 3 isopropanol-I can be prepared corm described in the literature of £th. 0. CLIIfOîî et al. Dermatitis. Ohes. Plow "_F.The £LT. 594 (1945)].

EXAMPLE 12 -

Has 625 cm3 solution 1.6 m out of n~butyllithium in 1' normal hexane, maintained under nitrogen atmosphere and cooled to - 60 * c " is added dropwise in 10 minutes a solution of diisopropylamine in 225 cm3 101 grams of a mixture of anhydrous tetrahydrofurane and hexaméthylphosphorotriamide (47 - 55 had volume).

After 10 minutes of stirring, is added in 30 minutes at the same temperature a solution of 84 S sulfide pyridyl-3 methyl and chloro-4 butyl in 300 cm3 mixture hexaméthylphoephorotriamide and tétrahydrofuraune anhydrous (47 - 5? had volume).

The reaction mixture is stirred for 1 hour at a temperature close to 20 -65 °c then cast in minute temperature a solution of 117 grams of methyl isothiocyanate in 225 cm3 hexaméthy1phosphorotriamide mixture. and tétrahydrofurarme anhydrous (47 - 53 had volume)* the mixture is stirred for 30 minutes at enatûte -60 °g during 1 hour and then gradually by allowing the temperature to 10 °c. After addition of 1 liter of distilled water, the mixture is extracted 6 times per

5 liters in total of ethyl acetate. The organic extracts are combined, washed 5 times per 5 liters in total to ' distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (30 mm of mercury; 4 ïd? has) to 40 °c, (167 grams) is chromâtographié on 1500 g of silica gel contained in a column 7" 4 cm diameter.

Impurities are removed. by eluting with about

50 liters of a mixture of cyclohexane and ethyl acetate content of ethyl acetate 0 varies gradually to 30 then is eluted by ethyl acetate-d * by collecting pure ethyl

3 fractions of 1 liter and then 8 fractions of 0.7 liter. These 8 last fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 k3? has) to 6c ° 0. (20 Grams) is dissolved in a mixture of 80 cm3 boiling isopropyl oxide ℮ and 40 cm3 of ethanol. After cooling during 1 hour at 0° g, the crystals appeared are separated by filtration, washed by 25 cm3 oxide isopropyls and dried under reduced pressure (20 mm of mercury; 2.7 kPa gauge) at a temperature close to 20 °c. (14.2 Grams) is dissolved in boiling acetonitrile 43 cm3; the solution, added® erffective powerU_O E g of black bleach, is hot filtered, and preserved, after cooling, during 45 minutes at a temperature of 5 °c neighbor " the crystals appeared are separated by filtration, washed with acetonitrile then 2 times 4 cm3 8 cm3 by total oxide isopropyls.

After drying under reduced pressure (T-mm of mercury; 0.15 kilopascals) to 60 °c, obtained 10.6 g of N-méihyl (pyridyl 3) -2 tétrahydrothiopyrannecarbothioamide-to-2 melts at 151 °c.

The pyridyl-5 methyl sulfide and chloro-4 butyl may be prepared in the following manner e

To a solution of 173 g of ddchiorhydrate of (pyridyl 3 methyl) isothiourea -2 530 cm3 in distilled water cooled to 4^I C., is added, dropwise in 25 minutes whilst maintaining the temperature below 12^I C., 144 cm3 of an aqueous sodium hydroxide solution 10 hr, after heating for 25 minutes to? 0 °C and then cooling to 11° g, 89 cm3 is added under stirring of aqueous soda solution 10 D and 125.5 g bromine " 1 chloro 4 butane and continued the stirring for 15 hours at a temperature of 20 °c neighbor. The reaction mixture is then extracted 4 times with 560 cm3 year total methylene chloride§organic extracts are combined, washed 2 times with 800 cm3 year total of distilled water, dried on anhydrous sodium sulfate and filtered. The solution is poured onto 150 g of freezing neutral silica contained in a column of 3.7 cm diameter % the column is elected® by 2500 cm3 of methylene chloride. The first fraction (600 cm3 ' is removed. The second (2500 cm3) is concentrated to dry under reduced pressure (25 mm of mercury 5, 3.4 kilopascals) without exceeding 30° g.

One obtains thus 110 g of sulfide pyridyl-3 methyl and butyl chloro-4.

[Rf * 0.31 5 thin layer chromatography silica gel *, solvent: hexane - acetate to ' ethyl (50 - 50 by volume)].

The dihydrochloride (pyridyl 3 methyl) -2 isotbiaurée can be prepared in the following manner ii

To a solution of $1 g of thiourea in 510 cm? ethanol " boiling, * is added dropwise in 20 min and, 164 grams hydrochloride chlorométbyl and 3 510 cm3 pyridine solution in ethanol 50®grams "the reaction mixture is stirred for 3 hours 50 minutes to boiling and then cooled at 26 °c" the crystals appeared are separated by filtration, washed 2 times with 400 cm3 total of ethanol and dried under reduced pressure (25 mm mercury j. 2.7 kPa gauge) at a temperature close to 20 °c.

This provides 173 g of dich10rhy Dr. ATE (pyridyl 3 methyl) isothiourea -2 melts at 212 °c.>

EXAMPLE 15 -

Has 59 cm3 to⁵ a solution of n-butyllithium 1.6 m of

in 1 'normal hexane, maintained under atmosphere d-'asote and cooled to

-50 °c, * is added dropwise in 11 min, a solution of 9.6 g of isopropylamine in a mixture to 22 cm3 ' hexaaéthylphosphorotxiamide and tetrahydrofuran anhydrous (47 * 53 had volume). Then added in 20 minutes at a temperature close -60 °c a solution of 9" 2 grams sulfide quinolyl-3 methyl and chloro-3 propyl in 28 cm3 hexaméthylphosphorotriamide mixture of anhydrous and tetrahydrofuran (47 - 53 in volumes). The reaction mixture is stirred for 30 minutes at the same temperature is cast in 15 minutes a solution of 11.1 g of methyl isothiocyamate SS in the mixture of 22 cm3 hexaméthylphosphorotriaœide and tëtrahydrofuranne anhydrous (47 - 53 in volumes). The mixture is further stirred for 25 minutes at

- 65 * 0 and then during 30 minutes leaving gradually raised the temperature to 10 * 0. After addition of 100 cm3 of distilled water, the mixture is extracted 3 times with 500 cm3 year total of ethyl acetate. The organic extracts are combined, washed 5 times with distilled water in total of 500 cm3, dried on anhydrous sodium sulfate and concentrated to dryness under reduced pressure (20 mm mercury? 2.7 K.? O) to 6û °C " - the product obtained (20 grams) is chromatography on gjnl g of gel cilice neutral contained in a column 3" 8 cm diameter,

OA is eluted successively with 1200 YAC of a mixture of cyclohexane-acetate⁸ the Barangays ethyl ethyl acetate content varies gradually © e O to 10 with 2400 cm3 of a cyclohexane " acetate to ' sthyis (EDD volume f0=10), 1080 cm3 with a mixture sycloksxsmaeltat © © - ethyl (85 - 15 EDD volume), with 1080 cm3 a mixture eyslohesaae - ethyl acetate (80 - 20 voluaes EDD) and 144 $ea3 avse confectioneries' ATT cyclohexane - ethyl acetate (70 - 30 in ES volume), by collecting fractions of 120 cm3. 5 * A 5§moieties and the ISS -SX are pooled and concentrated to dry under reduced pressure © (2 © es® mercury j. 2.7 kPa gauge) to 55^I 0. (the L, 3 grams) © if dissolved in 17 j of the cm3 of boiling ethanol is added with 0.4 grams solutiôa

•black bleach and then® filters th hot © T-conserved, tough cooling, during 3 hour © th a VAS at around 5 * 0" the crystals appeared are separated by filtration, washed by

1 cm3 of ethanol and 2 times per 2 ea3 has® the total D.^O oxide layer^O isoproyl th. After drying under reduced pressure (1 ES mercury;

0.13 eCPE) to 40^I C., 0.8 g of I-obtained sétayl ^ (quinonyl and 3) -2 tétrahydrothiophènecarhotMoaai&© '=2 melt at 159° g®

Le. sulfide quiaolyl-to-3 séthyle and d® chloso and 3

■propyl can be prepared as follows e

To a solution cooled to 1®59 g of " 2 g of dishlcrhydrate of (cuinolyl-to-5 methyl) -2 isothiouré® DCSA 100 oa5 of distilled water is added, in 9 minutes and - its leaving the temperature up to 10®C., 40 * 8 cm3 asusuasusu.se solution soda OJ hr, after heating for, a® temperature close to 20 minutas © D. 70°ü and then cooling to 12 * 0, OA is adding®, dropwise ' drop in 5 min, 25 cm3 an aqueous solution 10 with H-® soda then adding #35 * 6 g of hromo-to-1 chloro 3 progsas and continued ii⁸ stirring for 20 hours at a temperature close to © 20 sec.^I 0_{the O} The reaction mixture is then 3 times per 400 cm3 © logging and e "total methylene chloride" as Straits © the organic are combined,

100 cm3 washed by water distillate, dried® on anhydrous sodium sulfate and concentrated sua pressure reduces © (20 its mercury; 2.7 Kl³ s) to 35®0 to rsaea SR-the valum® to

Mamore cin5. about. the Guernsey lull a thus obtained is chromatographed over silica gel 25ü g of neutral " untenus in a 5.8 cm column of diamèlre. By eluting with 13üo cms} of chlofure methylene by collecting 1 moiety T>u0 cm5 and 1 900 cm3 fraction. The latter is concentrated to dryness under reduced pressure (20 mm of mercury ii 2.7 kPa gauge) to 35 °c. This gives 9.2 g of sulfide quinolyl-3 methyl and chloro-3 propyl in the form of a yellow oil.

(hf - 0.6; thin layer chromatography gel

silica; solvanL: ethyl acetate).

The dihydrochloride (quinonyl and 3 methyl)* 2 - isothiourea can be prepared as follows;

WITH 19.7 ℮ thiourea 110 cm3 suspended in boiling ethanol, is added, dropwise in 10 min, 4&" 4 g of hydrochloride chlororaéthyl-to-3 quinoline in solution in ethanol to 70 °c 160 cm3. The reaction mixture is stirred for 1 hour 30 minutes to boiling and then cooled to 10 °c, the crystals which have formed are separated by filtration, washed 2 liver by 100 cm3 total of ethanol and dried under reduced pressure (20 mm mercury} 2.7 kPa gauge) at a temperature close to 20 °c. This gives 39.5 g of diuhloi * hydrate (quinonyl and 3 methyl) isothiourea -2 melts at 226 and 228° "

Hydrochloride clilorométhyl-to-3 quinoline can be prepared according to the method described by J. The KOTLBB-to-ARO JTBURG,

WTA. The pol. Apotex. (4), 585 (1968)} AC ' J0, 87518 sec.

It will be understood that the present invention does not relate to the compounds described as felt used in therapy.