CA1057292A - Amino-2 thiazoles - Google Patents

Abstract

2-amino thiazole derivatives corresponding to the general formula: (I) in which R is a group of formula: linked to the sulfur atom by its second carbon atom, R1 and R2, identical or different one of the other, are hydrogen or radicals, optionally halogenated and / or hydroxylated, alkenyl, alkyl, cycloalkyl, aryl or arylalkyl or form, together with the nitrogen atom to which they are linked, a morpholino, methyl nucleus -4 piperazino or piperazino, and R3 and R4, identical or different from each other, are hydrogen, alkyl or cycloalkyl, or form, together with the nitrogen atom to which they are connected, a nucleus morpholino, piperidino or pyrrolidino, piperazino, phenylpiperazino, trifluromethylphenylpiperazino, halophenylpiperazino or methoxyphenylpiperazino, whenever they are obtained by a process according to claim 1 or its manifest chemical equivalents. The derivatives according to the invention enjoying valuable anti-inflammatory and cholesterol-lowering properties.

Description

The present invention relates to new derivatives 2-amino thiazole, their preparation process and their applications in human and veterinary medicine.
The derivatives of the invention correspond to the formula:

~ - C ~ ~ -CH N / 3 (I) R / ~ ~ R4 in which R is a group of formula:
-CH -C = CH- or -CH2 - CH - CH2 connects to the sulfur atom through its second carbon atom, Rl and R2, identical or different from each other, are of hydrogen or radicals, optionally halogenated and / or hydroxyls, alkenyl, alkyl, cycloalkyl, aryl or arylal-coyle or form, together with the nitrogen atom to which they are connected, a morpholino, 4-methyl piperazino or piperazino nucleus, and R3 and R4, identical or different from each other, are hydrogen, alkyl or cycloalkyl, or together form with the nitrogen atom to which they are connected, a morpholino nucleus, piperidino or pyrrolidino, piperazino, phenylpiperazino, tri-1uorom ~ thylphenylpip ~ razino, halophenylpiperazino or methoxy-ph ~ nylpip ~ razino, each ~ they are obtained by a proc ~ d ~ according to claim 1 or its chemical equivalents mani ~ estes.
The alkyl and alkyl radicals and the portions Alkyls of arylalco radicals ~ the participant in the structure of ~ d ~ riv ~ s (I) are advantageously lower radicals flax ~ areas or rami ~ i ~ s having from 1 to 12 carbon atoms and in particular from 1 to 4 carbon atoms in their linear chain.
When Rl or R2 are aryl or arylalkyl, they are notably phenyle, while the cycloalkyl radicals appearing at the definition of the derivatives ~ I) most often have from 4 to 12 carbon atoms and, in gener ~, from 5 ~ 8 carbon atoms in . . .

lOS7 ~
their cycle.
The derivatives (I) have anti-valuable inflammatory and hypocholesterolemic agents.
These properties, combined with low toxicity, are particularly marked for derivatives (I) comprising two heterocycles and in particular a heterocyle with two nitrogen atoms including ~ 057Z9Z
one carries an alkyl radical.
A process for the preparation of the derivatives (I) consists mel: tre to react a a ~ ine ~ 11 on an i.sothiocy ~ llate nN = c = sl ~
being - N (RlR2) when B is -C112 -Ro -C112 -N (R3R4) and, ~ the Col ~ -dition that R2 is hydrogen, being N (R3R4) -C112-Ro -Cl-12-NTI-when B is Rl-, Ro being the vinylene radical (-C ~ = CH-) or ethynylene (-C = C-), to form the transitory compound of form-mule:

~ ~ 1 -C1l2 - Ro -Cll2- ~
R2 or H R4 then, by heating in an acid medium, to cyclize this transparent compound in the thiazolinic derivative of formula:

R ~ / ~ ~ 3 ~ NC ~ / -C ~ 12-N (Ia) H or R2 ~ ~ R4 in which R is the saturated trivalent radical, when Ro is vinylene, or is the trivalent unsaturated radical linked to the atom

2 ~ d ~ nitrogen by its carbon atom not adjacent to its double bond bran, qualld Ro is ethynylene, ek, to prepare the thia- derivative zolic of ~ ormule (I) in which R is connected ~ the atom of a-7.0 ~ e by its adjacent carbon atom ~ its double lialson, lsom ~ riser the d ~ riv ~ ~ Ia) da ~ s which R has a double The reason.
The starting amines of N (~ 3R4) -CH2-Ro-CH2 NH2 are kes and can be prepared by the process indicated by R. Dahlbom, 10 ~ 7Z92 B. Karlen, A. Lindquist, R. George and DJ Jendcn dal1s Acta P ~ larm.
Suedica, 4, ~ 4), 247, (1967) or Chcm. Abst. 68.2805k (1968) when Ro is ethynylene. When Ro is vinyl, they are described and can be prepared by lc procedc in ~ i ~ uc I ~ ar T. Singh, R. Stiel and J..Biel in J. Med. Chem., 1969, 12, 368.
The preparation of the new starting isothiocyanates;
N (R3R4) -CH2-Ro-CI ~ 2-N = C = S is carried out, in the conventional manner, by treating an amine of type N (R3R4) -C ~ 12-Ro-CI12-NH2 with lc carbon sulfide in the presence of cyclohexylcarbodiimide, in operating at low temperature (-20 ~ -10C) in a solv.lnt, such than ether.
The reaction of the amine AH on senevol BN- C = S
is generally carried out by meeting ~ e separate solutions of stoichiometric amounts of the two reactants in a solvent identical, such as an aromatic hydrocarbon, with cventuellcmcllt reflux heating for 15 minutes to three hours depending on the nature of A and B, evaporation of the solvent under vacuum, recovery of the residue, g ~ generally oily, with an acidic aqueous solution, heating of this solution at approximately 100C for at least 1 hour approximately, cooling and separation of the principle or dc the oily phase which forms by basifying.
We can isomize the precipitate by heating it up roflux in a solvent ~ high boiling point ~, for example sup ~ rleurc ~ 100C, or by treating it with a concentrated acid, such quc concentrated sulfuric acid, ~ 80C about pendal1t a lal ~ s dc tcmps varying from a few minutes to several hcurcs.
~ d ~ riv ~ s (I) can be in the form of their single or multiple addition salts with acids min ~ raux ou or ~ aniqucs, te] s as their halohydr.ltcs, notclmmcnt their hydrochlorides, their bromhyclrates, their sulfates, their oxalates, their m ~ thanesulfonates, lcurs malcates, their lactates, their tartrates, etc ... or in the form of their ammonium q ~ a-_3_ . .
.

ternaries. These salts are prepared by dissolving the free bases in ethereal solutions including stoechiome-triques of the chosen acid.
The following examples illustrate the invention.

Preparation of cyclohexylamino-2 ~ -diethylamino-ethylidene-5 ~ 2-thiazoline (derivative n 1) and its hydrochloride. R1 = cyclo-hexyl; R2 = H; R3 = R4 = ethyl-a) In a solution of 21 g (0.15 mole) of amino-1 `
4-diethylamino-butyne-2 in 50 ml of benzene, the following are introduced, drop- ~ drop, a solution of 21 g (0.15 mole) of isothiocyanate of cyclohexyl in 50 ml of benzene.
The mixture is heated at reflux for 40 minutes, then the benzene is evaporated under vacuum. The residual oil is taken up in 150 ml of C1H 2N and the mixture is heated for 1 hour ~ 100C. After cooling, the reaction medium is neutralized by adding a 2N NaOH solution. The precept ~ orm ~ is ~ illiterate and dry.
38.2 g of crude product are thus obtained ~ yield 90 ~) which, after puriication, by recrystallization from a mixture ~ ther of petroleum / cyclohexane, provide 29 g of crystals trendemont 70 ~) whose melting point, determined at hloc ~ oe ~ ler, ost from 125-126C, b) ~ in a flask containing 8.25 g ~ 0.04 mole) of ~ `
dlcyclohexylcarbodimidc, 30 ml of carbon sulfide and 100 ml of ~ thQr, we introduce ~ l drop- ~ drop, a solution of 5.6 g ~ 0.04 mole) of amino-l diethyl-amino-4 butyne-2 in 5 ml of the same solvent. The temperature of the mixture is maintained between -10 and -12 ~ C during the dur ~ e of the introduction of the amine, then the me-Diaper is left at room temperature for 18 hours.
After filtration, the ether solution is evaporated in vacuo. The : 1057292 oily residue, consisting of 4-diethylamino isothiocyanato-l butyne-2 is dissolved in 25 ml of benzene, then introduced into a mixture of 3.96 g (0.04 mole) of cyclohexylamine dissolved in 25 ml of the same solvent.
The mixture is heated at reflux for 40 minutes, then the benzene is evaporated under vacuum. The residual oil is taken up in a solution of CIH 2N and the mixture is heated during for 1 hour at 100C. After cooling, the medium, reaction-It is neutralized by adding a 2N NaOH solution. The pr ~ precipitate formed is filtered, dried, and then recrystallized from a mixture of petroleum ether and cyclohexane. We thus obtain, with a yield of 43 ~, 4.8 g of crystals identical to those obtained previously held.
c) The precipitate obtained previously in the raw state is dissolved in the ~ ther. Ether is added to the solution saturated with hydrochloric acid. The precipitate of hydrochloride is collected and recrystallized from a melan ~ e of isopropanol and ether isopropyl. We obtain crystals, the point of use of which, determined at Koefler block, is 225C.

Pr ~ preparation of cyclohexylamino-2 ~ -diethylamino-ethyl-5 thiazole ~ d ~ riv ~ n 2, thiazolic isomar ~ of d ~ riv ~ n 1).
On chau ~ e, ~ re ~ lux, for 16 hours, a solution of 6 ~ of derivative n 1 in 100 ml of a constituted mixture of 4 volumes acetic acid ~ lacial for a volume of aqueous hydrobromic acid at 40 ~. The cooled solution is neutralized by a solution aqueous NaO} I 2N, then extracted with ~ ther. The organic phase is s ~ by ~ e, washed ~ e ~ water, s ~ ch ~ e on SO4Na2, then evaporated. We obtains 5.6 g of a crude product ~ yield 93 ~), which, after recris-tallization in petroleum ether, provide crystals of which the melting point is 89-90C.

.., ",,..., -,...

~ 057Z ~ 32 By the action of a solution of hydrochloric acid in ether, a dihydrochloride is obtained whose melting point is 190C.

Preparation of cyclohexylamino-2 ~ -diethylamino ethyl-5 ~ 2-thiazoline (derivative 3).
By keeping the temperature between 5 and 10 ~ C, we mixing a solution of 7.05 g (0.05 mole) of isothiocyanate cyclohexyl in 25ml of benzene and a solution of 7.1g (0.05 mole) of amino-1 diethylamino-4 butene ~ 2 in 25 ml of the same solvent.
After 2 hours, the benzene is evaporated and 14 g of a residual oil, which is dissolved in a mixture of 4 volumes glacial acetic acid per 1 volume of `aqueous solution Br H ~ 40 ~.
The mixture is heated for 15 hours at reflux, then reroidi, diluted ~ ice water, neutralized by adding a 2N NaOH solution and extracted with ~ ther.
The combined organic solutions are washed with water, s ~ chées on SO4Na2 and evaporated. The solid residue is taken up by ~ ther and additionn8 of a solution of CIH in ether.
We get dihydrochloride crystals, the point of which ~
of ~ usion is 238-240C ~ yield 90 ~
Many other rivals responding to the formula ~ I ~ on ~ ~ t ~ synth8tis ~ s by the procedure ~ according to the invention, notam-is lying :
- The ~ -hydroxyph ~ n ~ 2-thylamino tN-diethylaminoethylidene ~ -5 ~ 2-thiazoline (40% yield): melting point: 129-131C ~ d ~ riv ~
n 4); R ~ hydroxy phenetyl; R2 = H; R3; R4 = ethyl.
- ~ e dioxalate of N-diethylamino-2 (N-cyclohexyl N-methyl amino-~ thylidene) -5 ~ 2-thiazoline (33% yield): melting point:
170-172C (derivative 5); R1 = R2 = ethyl; R3 = cyclohexyl;
R4 - methyl.

- Cyclohexylamino-2 ~ N-cyclohexyl N-methylaminoethylidene) -5a 2-thiazoline ~ yield 74 ~): melting point: 113-115C
~ derivative n 6); R1 = R3 = cyclohexyl; R2 = 11; R4 = methyl.
- 2-amino dihydrochloride ~ -N-diethylaminoethylidene-5 4 2-thiazoline ~ yield 12 ~ o): melting point: 210C (derivative n7) R1 R2 H, ~ 3 = R4 = ethyl.
- cyclohexylamino-2 ~ -morpholinoethylidene-5a 2-thiazoline (yield 73 ~): melting point: 144-146C ~ derivative n 8) R1 = cyclohexyl; R2 = H; N (R3R4) = morpholino-Butylamino-2 ~ -diethylaminoethyl-5 thiazole dihydrochloride (yield 55 ~ 0): melting point: 188-190C ~ derivative n 9) R1 = normal butyl; R2 = H; R3 = R4 = ethyl.
- (~ -diethylaminoethylidene) -5 (N-ethyl N-cyclo-) oxalate hexylamino) -2 ~ 2-thiazoline (yield 43 ~ 0): melting point:
138-140C (derivative n10) R1 = R3 = R4 = ethyl; R2 = cyclo-hexyl.
- The dioxalate of (~ -diethylaminoethylid ~ ne) -5 (N-methyl N-cyclohexylamino) -2 ~ 2-thiazoline (yield 52 ~ o); point of fusion: 172-174C (derivative n 11) R1 = methyl; R2 = cyclo-hexyl; R3 = R4 = ethyle.
- The tetrachlorhydrate of ~ di ~ 2-ethylaminoethylidene) -5 (me-4-thyl pip6razinyl-1) -2d 2-thiazoline (yield 23 ~: point usion: 220C ~ d ~ riv ~ n 12) N ~ R1R2) - m ~ thyl ~ 4-pip ~ razinyl;
R ~ ~ R ~ w ~ thylc.
- Cyclohexylamino-2 ~ -piperidyl ~ thylidene) -5 ~ 2-thiazoline ~ yield 76 ~): melting point 134-136C ~ derivative n 13) Rl ~ cyclohexyl; R2 ~ H; N ~ R3R4) = piperidino-- The oxalate of ~ -diethylaminoethylidene-5 morpholino-2 ~ 2-thiazoline (yield 49 ~) melting point: 170-172C (derivative n 14) N ~ R1R2) = morpholino; R3 = R4 = ethyl.
- Diethylamino-2 dioxalate (2-diethylamino ethylidene) -5Q 2-thiazoline (yield 43 ~): melting point: 134 -135C

't 057292 (derivative n 15) Rl = R2 = R3 = R4 = ethyl-- the oxalate of (2-dimethylamino ethylidene) -5 ~ thylamino-2Q 2-thiazoline (yield 35 ~); melting point: 145C (derivative n 16) R1 = H; R2 = ethyl; R3 = R4 = methyl - Butylamino-2 dihydrochloride (2-diethylamino ethylidene) -5a 2-thiazoline (yield 52%): melting point: 190-194C
(derivative n 17) R1 = normal butyl; R2 = H; R3 = R4 = ethyl.
- (~ -diethylamino ethylidene) -S (tetramethyl-1,1,3,3-butyl-amino) -2 ~ 2-thiazoline (yield 39%): melting point. 200C
(derivative No. 18) R1 = tetramethyl-1,1,3,3-butyl; R2 = H; R3 =
R4 = ethyl.
- Ethylamino-2 ~ (pyrrolidinyl-1) -2 ethylidene] -5 a2-thiazoline (yield 45%): melting point 84-86C ~ derivative n3 19) Rl = ethyl; R2 = H; N (R3R4) = pyrolidinyl.
- Cyclohexylamino-2 L ~ pyrrolidinyl-1) -2 ethylidene] -S ~ 2-thiazoline (yield 64 ~): melting point 133- 134C (derivative N 20) R1 = cyclohexyl; R2 = H; N (R3R4) = pyrrolidinyl. ~;
- The oxalate of (~ -diethylaminoethylidene) -5 m ~ thylamino-2 ~ 2-thiazoline (yield 50 ~ 0); point of - ~ usion; 178 - 180 C
~ d ~ riv ~ N 21) Rl ~ m ~ thyle; R2 'H; R3 = R4 = ethyl.
- The bioxalate of ~ -di ~ thylamino ~ thyl-5 ~ N-methyl N-cyclohexylami-no) -2-thiazole (yield 70 ~: melting point: 80C ~ d ~ riveted N 22 ~ Rl am ~ thyle; R2 ~ cyclohexyl; R3 = R4 = ethyle.
- Benzylamino-2 ~ dihydrochloride ~ -diethylaminoethylidene-5 ~ 2-thiazoline (yield 63%): melting point 235C ~ derivative ~
N 23 ~ Rl ~ benzyl; R2 ~ ~ l; R3 ~ R4 ~ ethyl-- ~ t ~ -diethylaminoethylidane bioxalate) -5 isopropylamino-2 2-thiazoline (yield 46 ~): melting point: 164 - 166C
(d ~ riv ~ N 24) Rl = H; R2 = isopropyl; R3 = R4 = ethyl. -- (4-Chloro-benzylamino) - 2 ~ - diethylamino- dihydrochloride;
~ thylid ~ ne-5 ~ 2-thiazoline (yield 35%): melting point:
210 - 220 C (d ~ rivé N25) R1 = H; R2 = (4-chloro benzyl);

'':.

R3 = R4 - ethyl.
- Cyclopentylamino-2 ~ -diethylaminoethylid ~ ne-5 ~ 2-thiazoline (yield 47 ~) melting point: 89 - 90C (drift N26) R1 = H; R2 = cyclopentyl; R3 = R4 = ethyl.
- Cyclo-octylamino-2 ~ -diethylaminoethylidene-S has 2-thiazoline (yield 46 ~): melting point; 70C (derivative N 27) R1 = H;
R2 = cyclo-octyl; R3 = R4 = ethyl.
- Cycloheptylamino-2 ~ -diethylaminoethylidene-5 ~ 2-thiazoline (yield 44%) melting point 92C (derivative N28) R1 = H;
R2 = cycloheptyl; R3 = R4 = ethyl.
- Cyclododecylamino-2 ~ -diethylaminoethylidene-5 ~ 2-thiazoline (yield 50 ~): melting point: 93C (derivative N29) R1 = H;
R2 = cyclododecyl, R3 = R4 = ethyl.
- 2-allylamino dihydrochloride ~ -diethylaminoethylidene-5 ~ "
2-thiazoline (yield 31 ~ o): melting point; 190C (derivative N 30) R1 5 ~ 1; R2 ~ allyl; R3 = R4 = ethyl.
- Dicyclohexylamino-2 ~ -diethylaminoethylidene-5 oxalate ~ 2-thiazoline trendement 40 ~): melting point: 210C (drift N 31) R1 = R2 ~ cyclohexyl; R3 = R ~ = ethyle.
The results of toxicological and pharmacological tests gics which are reported, below, highlight the int ~ -main activities of the invention, in particular hypocho-ballast ~ rol ~ miante and anti-inflammatory.
- ~ TUD ~ ~ XICOLO ~ IQU ~
This study highlighted the low toxicity of d ~ r ~ v ~ s of the invention.
As an indication, the LD 50/24 h / kg of body weight, calculated according to the Miller and Tainter method, by the intra-venous ~ is in mice 90 mg for the derivative N 12, of 4S mg for derivative 18, 105 mg for derivative 14, of 92 mg for derivative 21 and 42 mg for derivative 1.
During acute, chronic or _9_ t ::
. . .

. -~ 057Z9Z

the derivatives of the invention have shown excellent lérance: they did not cause any disorder, no local reaction or general, no disturbance in the hiological controls.
II - PHAR ~ ACOLOCIC STUDY
1 / cholesterol-lowering action .
a) Propyl-thiouracid test (RANNEY et al., J. Pharmacol. Exper. the herap. 1963, 142, 132-136).
Administration of propyl-thiouracide to rats adults make them hypercholesterolemic: indeed, the rate plasma cholesterol is increased by about 15 ~. The experimenta-tion is carried out on two batches of rats, the control batch receiving propyl-thiouracide only, while the treated batch receives in addition 100 mg / kg of the derivative to be tested by the oral route.
On the 11th day of the experiment, the samples blood are made and we dose the ~ -lipoproteins, choles-t ~ free rol and total cholesterol. The dosa ~ es show ~ eu in milking animals, free cholesterol and cholesterol levels total rol are markedly reduced. The results obtained for some a few dives are summarized in the following table:

... ~ ..... . . ..., ...................... ~ ~
free cholesterol total cholesterol ... . _. _ .. _ T ~ less 0.20 0.86 . , D ~ riv6 N ~ 1 0.14 0.60 .... ~ .. _. _ .... ..
D ~ rolled N 9 0.15 0.58 l .... _ ..

... ... .
. librc cholesterol total cholestcrol g / 1 g / l Derivative N 12 0.15 0.61 Derivative N 15 0.12 0.58 b) Triton test.
Intravenous injection of the newt WR 1339 (poly-alkylaryl ether alcohol provided by Rohm and Haas) allows cl'aume artificially ter, in the rat, certain lipid fractions of serum and thus evaluate the hypocholesterolemill action d ~ rivés of the invention.
These are administered orally at a dose of 100 mg / kg immediately after intravenous injection of newt.
Eighteen hours later, the blood is drawn and a dose ~ -lipoproteins, free cholesterol and total cholesterol ~ rol.
We observe, as in the previous test, significant drops free cholesterol and total cholesterol ~ around 2So po-lr the d8riv ~ Nl, of 24S for the drift N9, dc ~ for lc dcrivc Nl ~
ct of 22 ~ for the d ~ riv ~ N15.
2 / ~ anti-inflammatory action a) M8thode of the edema localized by the carrag ~ nine.
A solution of carrageenan ~ 0.1 ml) to 1 ~ is injected ~ e in the ~ tatarsal chisscurs of the right hind paw of rat at time 0.
The animals in the treated batch also receive, by the oral, 100 m / kg of the derivative to be tested, respectively, before treatment, at the same time as the injection of the phlogogenic agent, then , -~ L057Z ~ Z

an hour and two and a half hours after. The measures that are performed using the micrometer at time 0, one hour, two hours, three hours and five hours after administration of the carrageenan, make it possible to determine, as a function of time, the percentage of anti-inflammatory activity compared to batch t ~ -less. The results are summarized in the following table:
~ '.
. - ' Products 1st hour 2nd hour 3rd hour 5th hour ~ ' Derivative N3 37 39 46 48 Derivative N4 40 49 53 D ~ rivé N10 44 47 52 56 . _ Drift N22 42 46 54 56 b) Method of edema g ~ generalized ~ ovalbumin.
IJne simultaneous intraperitoneal injection of 1 ml of oval-bumina and 0.5 ml of an aqueous solution of Evans blue at 1 for `
thousand by weight is performed on the rat.
On the other hand, 100 mg of the d ~ riv ~ to be tested are administered by bone to the animals of the lottraite one hour before and at the same time than ovalbumin. The intensity of the phenomenon thus caused is noted by a number ranging from 1 to 5 depending on the progression of the syndrome inflammatory.
We thus determine the mean of the oedematous intensity and 1 ~ pourccnta ~ e of reduction of the edematous r ~ action by compared to witnesses. The results are summarized in the table following :
._ _ Products 28 hours 3 hours, deriv ~ N354 60 ``
3erive N459 65 _ _ ~ 057Z92 . ._ _ _.
Products 2nd hour 3 ~ me hour ....
Derivative N10 57 64 Deriv ~ N22 5Z 60 The toxicological and pharmacological studies that come nent to be reported show that the compounds of the invention have good tolerance and have activities cholesterol-lowering and anti-inflammatory.
It follows from the above that the derivatives of the invention tion and their non-toxic salts can be used with profit in medicine.
By regulating the metabolism of cholesterol and blood lipids, they effectively protect the body from vascular shades of atherosclerotic origin and their compli-cardiac, cereal and peripheral cations.
They also intervene effectively in the reaction inflammatory to reduce or prevent edema, hypersecretion and exudation.
They are indicated in the treatment of hypercholesto-rolémios and hyperlipid ~ mies and their complica ~ ions, rhu-chronic inflammatory matisms, degenerative rheumatism, af-~ abarticular ectlons ~ s, in acute and subacute inflammations of otorhinolaryngological spharQ, in repair surgery and ,; ~,.:.
plastlque and reduction ~ unctctional.
In these indications, the medicament of the invention can very present, for oral administration, in the form of a tablet m ~ s, drag ~ ifiés tablets, capsules, drops or syrup.
It can also be presented, for the rec-tale, in the form of suppositories and, for parenteral administration t ~ rale, in the form of an injectable solution.

In these presentations and formulations, the principle tif is associated with a solid or liquid excipient or vehicle ~ e st ~ ri-the and / or flavored in the form of unit doses, the active principle representing 0.01 ~ 80 ~ by weight ~ e formulation.
Each unit dose advantageously contains 0.050 g at 0.500 g of active principle, the doses administered per 24 hours can vary from 0.050 g to 1.50 g depending on the severity of the condition treated and the patient's age.
By way of nonlimiting example, we will give below, some pharmaceutical formulations of the medicament of the invention.

Derivative N ~ 1 ...................................... 0.100 g Lactose ......................................... 0.010 g Methyl cellulose ................................ 0.005 g ~ artrazine ...................................... Traces Microcrystalline cellulose ...................... 0.010 g Corn starch .................................. 0.025 g Magnesium st8arate ........................... 0.010 g 2 - DRAGEI ~ IES TABLETS
Core :
Deriv ~ N12 ..................................... 0.100 g Lactose ......................................... 0.015 g Corn starch .................................. 0.005 g Magnesium st ~ arnte ......... ~ ....... 0.005 g ~ nroba ~ e:
Shellac ............................ 0.001 g Gum arabic ......................... 0.005 g ~ alc ................................... 0.010 g Carnauba wax ....................... 0.003 g Orange S codex ......................... Traces Officinal white sugar .... p..s..p..1 .... Tablet coated -14_ ~ 05729Z

3 - CAPSULES
Derivative N3 .............................. 0.150 g Corn starch .......................... 0.020 g Magnesium stearate ................... 0.010 g

4 - SYRUP
Derivative N22 ............................. 2 g Excipient ............................... 100 ml

5 - INJECTABLE SOLUTE
Derivative N15 ............................. 0.100 g Isotonic solution ......... q ... s .. p ...... 5 ml

6 - SUPPOSITORIES
D ~ rivé N9 .................... ... ....... 0.150 g -Triglycerides 3emi- ~ ynthétiqu ~ ..qspl ~ upp ~ sito; ~
Among the starting isothiocyanates, that for which .
R3 = R4 = ethyl has a melting point of 103C under 0.3 mm mercury.
Other examples are shown below:
Diethylamino ~ tl1yl-5 cyclododecylamino-2 thiazole trendy 55 ~) -p. ~. 100-102 ~ C (drift n 32); R1 = Il, R2 = cy-clo ~ odecyl`e; R3 = R4 - 6thyle.
Cyclod ~ cylamino-2 ~ N-benzyl N-ethyl amino ~ thylidcnc) -S ~ 2-thiazoline ~ yield 623 ~ -pf i7Ç (dcrive n33 ~ R1 =
~, R ~ ~ cyclodod6cyle; R3 ~ benzyl; R ~ ~ ethyle EXE ~ IPLE 34 Preparation of the ~ -parachlorophcnyl) -4 pipcrazino ~ thylid ~ ne ~ -5 cyclohexylamioo-2a 2-thiazoline - (dcrivc n34) R1 -cyclohcxyl; R2 =} 1.
~ years a mixture of ~ g (0.019 mole) of amino-1 (T); ~ c ~ h1O-ro ~ h ~ nyl-4) pip ~ r ~ zino-4 butyne-2 and 50 ml dc chlororormc, we in-product, drop ~ drop, a solution of 2.68 g (0.01 ~ mole) ~ 0 57 Z9 Z
of isothiocyanate cI ~ cyclohexylc (1 ~ I] IS 50 ml of chloroforrlc.
The mixture is agitated l ~ cndaIlt 2 hc-Ircs 2I la t (~ Inl) ~ r ~ lltlrc ambian-te then the solvent is év ~ poré. The residue is received by G5 Inl of ~ IC1 2N then heated for 1 hour at reflux. A ~ rcs refroi ~ issc-ment, the solution is neutralized by a ~ lition ~ 'uIIC so I ~ It; on clc NaO ~ I 2N. The precipitate formed is filtered, washed with water, dried and then recrystallized from the cyclohexane / benzcne mixture.
We collect crystals (yield 44 ~. 100) of which lc melting point, determined at the Koeffler block, is 180C.
By the same method, the following derivatives were obtained:
Cyclohexylamino-2 @ ~ pbcnyl-4 piperazino ~ tI1ylid ~ n ~ -5 ~ 2-thiazoline (derivative 35) yield 52 p. 100 - 145C fusion.
R1 = cyclohexyl; R2 = H;
Cyclohexylamino-2 ~ (metatrifluorométh ~ L phenyl ~ -4 pi-perazino ethylidene] - S ~ 2-thiazoline (derivative no. 36) - rendemcnt 47 p. 100 - fusiol1 192C.
R1 = cyclohexyl; R2 = H;
The [~ (orthochlorophcnyl) -4 pilcra7iIloéthylidcll ~ -5 cyclo hcxylamino-2 ~ 2- thiazoline (derivative ~ N37) - yield 58 p. 100 -usion 175C.
R1 ~ cyclohexyl: R2 = H;
Cyclohexylamino-2 ~ (paramethoxyphcl1yl) - ~ 1 pipcra7ino ~ thylid ~ ne ~ -S a 2- thiazoline (derivative n 38) - rendemcnt ~ 7 p. 100 ~ usion 1 60C.
R1 ~ cyclohexyl; R2 a ~ 1 L ~ L;
The drifts 34 ~ 38 have shown, throughout the tests, an excellent tol ~ rancc; indeed, they did not cause .IUC-lllC ~ ction sccon ~; rc indcsir. ~ c aux therapeutic do5 ~ s.
As an indication, the DL 5D / 24 ~ Ieurcs / k ~ of weight corI) orel, calcu] c ~ c seloIlla method of iiller and antero, intravenously is dc 35 mg for the d ~ riv ~ n 34 of 48 mg for the derivative1 35, 65 mg for the described n 36, de57 m ~ ~ for the d ~ riv ~ n 37 and 52 m ~ for the lc cI ~ rivcl1 38.

. ... .

~ 057Z9Z
E STUDY Pl IAR ~ IACOLOG I QUE
1 / Action hy ~ ocholesterolemic)) rest at ~ ro ~ yl-thiouracile rRanney ~ and Coll. J.
Pharmacol. Exper. Therap. 1963, 142, 132-136). ~ was ex ~ experimental-tion highlighted the clearly favorable action ~ es derived from the invention at a dose of 50 mg / kg.
The results are summarized in the following table:
~. , Free cholesterol total cholesterol g / lg / l . .. _ Witness 0.25 0.89 .:
Derivative n 34 0.13 0.55 Derivative n 35 0.11 0.61 ..
Derivative n 36 0.13 0.63 . ~ ._. . ~
Derivative n 37 0.10 0.60 ~ -._ ...., _ Drift ~ n 38 _ _ 0.58 a) Newt test This test which makes it possible to evaluate the hypocholesterolated action crumbling derivatives ~ test on the low rates of certain ~ lipid reactions, highlighted the remarkable effect of d ~ riv ~ s of the invention. ~ n ef ~ and, free cholesterol levels and total cholesterol are considerably reduced in animals treated with oral doses of S0 mg / Kg of the derivatives of 1 ~ invGn ~ ion ~
These decreases are in the order of 34%. 100 for the drift n ~ 34, 29 p. 100 for drift n35, 27 p. 100 for the d ~ riv ~ n 36, 41 p. 100 for the drift ~ n 37 and 44 p. 100:
for drift no 38.
2 / Action year i-ln ~ lammatory ~
a) method of localized edema ~ ar carragenin.
_____________________________ ___________ _____, 1 ~ 57292 Oral administration of 50 mg / Kg of the derivatives ~ test produces a marked decrease in the inflammatory reaction provo-quée.
~ The results are summarized in the following table: -'~ o ~ ~ e ~ ~ h ~ T ~ ~ r ~ Sème uh]
derivative n34 40 44 50 53 55 derivative n35 45 46 55 57 58: ~
derivative n36 46 50 S9 61 62 _. . .
derivative n37 38 43 48 52 57 ._ ._ ~ up n38 _. 53 56 60 61, b) method of generalized edema ~ with ovalbumin The percentages of decrease in the edema reaction are determined in relation to the controls in subjects treated with the oral route by the administration of SO mg / Kg of the derivative to be tested highlight the clear anti-in ~ lammatory action of the daggerboards of the invention.

__............ ~. . ._. .
Products 2nd hour 3rd hour ~. . . _ d8riv ~ n 34 58 62 .w ................................. .. ..... _ d8 ~ iv ~ n 35 62 65 ~.
. . _ d ~ r iv ~ n 3 6 5 5 61 ~. . . .__. ~ d d ~ riv8 n 37 60 68 ~ .................... _ ._ d ~ riv8 n 38 64 70 ~ ~ ~. ,. -. . . . .

Claims (9)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, its defined as follows: 1. Process for the preparation of formula drifts (I) in which R is a group of formula:
linked to the sulfur atom by its second carbon atom, R1 and R2, identical or different from each other, are hydro-gene or radicals, optionally halogenated and / or hydroxylated, alkenyl, alkyl, cycloalkyl, aryl or arylalkyl or form, together with the nitrogen atom to which they are connected, a nucleus morpholino, 4-methyl piperazino or piperazino, and R3 and R4, identical or different from each other, are hydrogen, alkyl or cycloalkyl, or form, together with the atom nitrogen to which they are connected, a morpholino, piperidino nucleus or pyrrolidino, piperazino, phenylpiperazino, trifluromethylphenylpiperazino halophenylpiperazino or methoxyphenylpiperazino, characterized in that it consists in reacting an HA amine on an isothiocyanate BN = C = S; A being -N (R1R2) when B is -CH2R0-CH2-N (R3R4) and, provided that R2 is hydrogen, being N (R3R4) -CH2-R0-CH2-NH- when B is R1-, R0 being the radical vinylene -CH = CH- or ethynylene -C? C-, to form the compound transient formula:

then, by heating in an acid medium, to cyclize this transi-roof in the thiazolinic derivative of formula:

(Ia) in which R is the saturated trivalent radical, when R0 is vi-nylene, or is the trivalent unsaturated radical linked to the atom of azo-te by its carbon atom not adjacent to its double bond, when R0 is ethynylene, and, to prepare the thiazolic derivative of formula (I) in which R is linked to the nitrogen atom by its carbon atom adjacent to its double bond, to isomerize the derivative (Ia) in which R has a double bond. 2 - Method according to claim 1, characterized in that that it consists in carrying out the reaction of the amine AH on the se-nevol B - N = C = S by reflux heating in a solvent, such aromatic hydrocarbon, evaporation of the solvent, recovery of residue with an acid solution, heating this solution to 100 ° C
approximately and separation of the precipitate or of the oily phase which forms by basifying. 3 - Method according to claim 1 or 2, characterized in that it consists in carrying out isomerization by heating with reflux in a high boiling solvent or by treating with a concentrated acid at around 80 ° C. 4 - Method according to claim 1, characterized in what it consists of preparing isothiocyanates starting from formula by treating an amino N (R3R4) -CH2-R0-CH2-NH2 with sulfide carbon in the presence of cyclohexylcarbodiimide at low temperature. 5. Method according to claim 1, characterized in that the derivatives of formula (I) are biheterocyclic. 6. Process following the claim 1, characterized in that R1 is cycloalkyl. 7. New derivatives of 2-amino thiazole general formula (I):

(I) in which R is a group of formula:
linked to the sulfur atom by its second carbon atom, R1 and R2, identical or different from each other, are hy-drogen or radicals, optionally halogenated and / or hydroxylated, alkenyl, alkyl, cycloalcoylo, arylo or arylalkoyl or form, together with the nitrogen atom to which they are connected, a morpholino, 4-methyl plperazino or piperazino nucleus, and R3 and R4, identical or different from each other, are do hydrogen, alkyl or cycloalkyl, or form together with the nitrogen atom to which they are linked, a mor-pholino, piperidino or pyrrolidino, piperazino, phenylpiperazino, tri-fluromethylphenylpiperazino, halophenylpiperazino or methoxy-phenylpiperazino, whenever they are obtained by a process according to claim 1 or its chemical equivalents manifestos. 8. New biheterocyclic derivatives of amino-2 thiazole of general formula (I) defined according to claim 7, each time they are obtained by a process according to the claim 5 or its obvious chemical equivalents. 9. New 2-amino thiazole derivatives of formula general (I) defined according to claim 7 and characterized in that R1 is a cycloalkyl radical, whenever they are obtained by a process according to claim 6 or its manifest chemical equivalents.