IE60173B1

IE60173B1 - Novel thiazole derivatives active on the cholinergic system, process for preparation and pharmaceutical compositions

Info

Publication number: IE60173B1
Application number: IE72188A
Authority: IE
Inventors: Kathleen Biziere; Dominique Olliero; Paul Worms
Original assignee: Sanofi Sa
Priority date: 1987-03-12
Filing date: 1988-03-11
Publication date: 1994-06-15
Also published as: JPS63243080A; FR2612187B1; TNSN88020A1; EP0283390A3; KR880011135A; YU49688A; DK170162B1; DE3878708T2; ATE86249T1; FI881152A; HU198916B; MA21207A1; NO881093D0; PL151889B1; DD274028A5; EP0283390A2; NO170081B; ZA881764B; NO881093L; IE880721L

Abstract

L'invention concerne des nouveaux dérivés du thiazole repondant à la formule générale dans laquelle: - R1 et R2 représentent chacun indépendamment l'hydrogène ; un groupe alkyle en Ci-C4 ; un groupe phényle ; un groupe phényle substitué une ou plusieurs fois par un atome d'halogène, un groupe alkyle en Ci-C4, un groupe alcoxy en Ci-C4, un groupe nitro, ou un groupe hydroxy ; ou l'un des groupes R1 et R2 désigne l'hydrogène et l'autre représente: un groupe naphtyle ; un groupe benzyle ; un groupe aa-diméthyl-benzyle ; un groupe cyclohexyle ; un groupe biphényle ; un groupe thiényle ; un groupe adamantyle, ou encore Ri et R2 considérés ensemble représentent un groupe : où le groupe phényle est lié en position 4 du thiazole et le groupe (CH2)m en position 5 et dans lequel m représente un nombre entier égal à 2 ou 3 et R5 désigne l'hydrogène ou un groupe nitro occupant l'une des positions libres du cycle ; - R3 représente l'hydrogène ou un groupe alkyle en Ci-C4 - R4 représente notamment un alkyle substitué par un groupe amino, pyrrolidino ou pyridino.

Description

NOVEL THIAZOLE DERIVATIVES ACTIVE ON THE CHOLINERGIC SYSTEM, PROCESS FOR ΡΗΕΡΑΚνΠΕΝ AND PHARMACEUTICAL COMPOSITIONS The present invention relates to novel thiazole derivatives, a process for their preparation and their application in therapy.

According to a first aspect, the invention relates, by way of novel products, to'thiazole derivatives corresponding to the general formula : in which : - R^ and R2 each independently represent hydrogen ; a alkyl group ; a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, or by a C^-C^ alkyl group, or by a C^-C^ alkoxy, a nitroOr'hydroxyl group ; or one of the groups and R^ denotes hydrogen and the other represents a naphthyl group ; a benzyl group ; an o<*,o<"dimethyl-benzyl group; a cyclohexyl group; a biphenyl group; a thienyl group or an adamantyl group ; or alternatively R^ and R2» taken together, represent a group : A> in which the phenyl group is bonded to the 4-position of the thiazole and the group (CHj) to the 5-position, and in which m represents an integer equal to 2 or 3 and R5 denotes hydrogen or 017 3 a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups Rj or R2 denotes hydrogen, the other is different from H or methyl; R^ represents hydrogen or a Cj - alkyl group: R^ represents: - a group: ίο in which Aj denotes a linear or branched C2 alkyl group;- Rg and Ry, taken independently, represent hydrogen, a Cj-C^ alkyl group, a C^-Cg cyclo alkyl group, or alternatively Rg and Ry, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkylpiperazine rings; - a group: * in which A2 denotes a group (CH2)m, where ro - 0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position; - a group: in which A2 is as indicated above; or - a group: in which Rg denotes a Cj - C4 alkyl group; RI 3 or alternatively the substituent -N-R^ represents a group: — Ν N— w in which Ra is as indicated above, with the proviso in this case, that if represents hydrogen or a C^-C^alkyl group, R2 is other than a C^-C^ alkyl group or a cyclohexyl group,and also their addition salts with mineral or organic acids.

The phenyl group is preferably substituted one or several times by a chlorine or fluorine atom or by a methyl group.

If the substituent contains an asymmetric carbon atom, the compounds (I) exist in the form of 2 optical isomers. These optical isomers form an integral part of the invention.

It will be noted that the compounds of formula (I) in which and R^ are hydrogen, are excluded from the above definition, on account of the teachings of SHIGEYA SAIJO published in J. PHARM. Soc. Japan 1952, 72. 1009-1013 which describes 2-amino thiazoles unsubstituted in the 4and 5~positions, having an antihistaminic activity. -3aThe relations between the structure and the antihistaminic activity of said 2-amino thiazoles have been reported in the article of Η H. Fox et al. J. ORG. CHEM., 1951, 16 . 225-231. Their preparation is described by I.A. KAYE et al. J. AM. CHEM. SOC., 1452, 74, 2271-2273 and 2921-2922.

The compounds of formula (I) in which one of the groups Rj or R2 is hydrogen and the other is a methyl group are excluded from the definition of the compounds of the invention due to a chemical unfeasibility.

The compounds of formula (I) in which -NR^R^ represents the group -Γ\-, R^ represents hydrogen or a C^-C^ alkyl group and R2 is a C^-C^ alkyl group or a cyclohexyl, are described in US patent No. 4 064 244 as anorexigenic agents, antimigraine agents or vigilance increasing agents.

According to a second aspect, the invention relates to a process for the preparation of the compounds of formula (I).

The process according to the invention for the preparation of the thiazole derivatives, as hereinabove defined,comprises the steps of heating in an acid medium of pH 1 to 6, a substituted thiourea of the formula: in which R^ has the meaning indicated above and R'^ has the same meanings as R^ except in cases where R^ contains a primary or secondary amine when R'^ denotes the group corresponding to in which a hydrogen belonging to the said amine group has been replaced by a protective group which is resistant to hydrolysis in an alkaline medium, with an alpha-brominated carbonyl derivative of the formula : R. - CH - C - R„ ·*· t II Br II or with the corresponding bromine derivative in which the carbonyl group is protected in the form of an acetal, to give the compounds (I), and of converting the compound I to a salt, if desired, by a known process.

The substituted thiourea used in the invention process can be obtained by conventional processes, for example by action of a benzoyl isothiocyanate or a pivaloylisothiocyanate on a primary amine /.

If R^ is hydrogen, this, process can be represented by* the following reaction scheme: h2n-r4 s n NH-C-NH-R, Br (I) Reaction of benzoyl isothiocyanate with the primary amine 1_ gives the substituted benzoylthiourea 2.

In practice, the benzoyl isothiocyanate is formed in situ by reacting benzoyl chloride with potassium thiocyanate in a solvent such as anhydrous acetone .

A solution of the amine derivative Γ in a suitable solvent, especially methylene chloride, is added to the resulting solution of benzoyl isothiocyanate and the mixture is heated at a temperature between 50°C and 100°C for £ to 3 hours.

After removal of the solvents, the reaction mixture is taken up in water and the product 2^ is isolated in the usual way, either by solvent extraction and purification, or by chromatography, or by direct crystallization.

The product (I) is obtained in 2 steps from the benzoylthiourea.

First of all, the benzoyl group removed by heating the compound / with a dilute aqueous solution of sodium hydroxide. The reaction mixture is acidified by the addition of an acid, for example concentrated hydrochloric acid up to a pH between 1 and 6, after which a solution of the bromine derivative 3_ in a water-miscible solvent, preferably an alcohol, is added.

The mixture is heated for a few hours at a temperature between 70 and 100’C.

After evaporation of the solvents, the reaction mixture is taken up in a solution of sodium bicarbonate or carbonate and the product (I) is isolated by extraction with a solvent such as methylene chloride.

After purification hy the usual methods, the compound (I) is converted to a salt, if desired, by reaction with an acid in accordance with a known process.

In this process, if the bromine derivative 3 is not very stable or not readily available, it can be' replaced with tbe corresponding dimethylacetal.

Finally, if contains a primary or secondary amine group, it has to be blocked in order to avoid a side-reaction with the benzoyl chloride. It is possible to use any protective group which is resistant to hydrolysis in an alkaline medium, such as for example a tert, butoxycarbonyl group(Boc).

The corresponding benzoylthiourea 2 is obtained from the amine R^NH^ protected in this way. Reaction with dilute sodium hydroxide removes the benzoyl group and direct reaction with the bromine derivative 3_ at an acid pH causes the formation of the thiazole ring and the removal of the group Boc, leading to the compounds (1) in which R^ contains a primary or secondary amine group.

The starting materials 1_ and 3 are known compounds or can be prepared by known processes. Processes for obtaining compounds 3_ are notably disclosed by HOUBEN WEYL Methoden der Organischen Chemie 4th edition , vol. 5/4 p. 171-188-Georg Thieme Verlag.

In the particular case where R^ represents a group - A, - N R. in which at least one of the substituents Rg and Ry is hydrogen, the protected amine derivatives / can be prepared from the aminonitrile RyNH-A^J -CN (4). When treated with the anhydride (Boc^O, this gives the aminonitrile Boc-N-A’.-CN, which, on reduction, leads to the corresI 1 R7 ponding primary amine Boc-N-A’^-CHjNHj, in which A’^ re11, presents A^ minus a methylene group.

In all cases, and particularly if the substituent Rj is other than hydrogen, the compounds (I) can be prepared from pivaloyl isothiocyanate according to the scheme: H+ (I) Reaction of pivaloyl isothiocyanate with the amine 4^ gives the pivaloylthiourea 5^.

In practice, the pivaloyl isothiocyanate is formed in situ by reacting pivaloyl chloride with an alkali metal thiocyanate in an anhydrous solvent, such as acetone, and at a moderate temperature (0 to 10°C). The amine k. is then added and the mixture is left to react for a few hours at the same temperature.

The compound 5_ is deacylated by hydrolysis under the action of heat in a strong acid medium, giving the thiourea 6.

This is converted to the compound (I) by reaction with a bromine derivative .3, as indicated previously.

The non-limiting examples which follow will provide a clearer understanding of the invention.

EXAMPLE 1: 2-[(2-Diethylaminoethy1)amino]-5-phenyIthiazole dihydrochloride (SR 44318 A) A) N-Benzoyl-N* -(diethylaminoethy1)thiourea A solution of 70 ml of benzoyl chloride in 100 ml of anhydrous acetone is added dropwise, at room temperature, to a suspension of 51 g of potassium > thiocyanate in 300 ml of anhydrous acetone. When the addition is complete, the reaction mixture is refluxed for 5 minutes. A solution of 85 ml of 2-diethylaminoethylamine in 100 ml of methylene chloride is added slowly to the resulting hot solution, with vigorous stirring, so as to keep the mixture under reflux. When the addition is complete, the mixture is stirred for 1 hour at room temperature, the solvents are then evaporated off and the residue is taken up in iced water. Extraction is carried out twice with 200 ml of methylene chloride and the solution is dried over magnesium sulfate. The-solvent is evaporated off to dryness and the oily product obtained is purified by chromatography on a silica column. Impurities of low polarity are removed by elution with an 80/20 (vol/vol) methylene chloride/ethyl acetate mixture. The expected product is then obtained by elution with a 95/5 (vol/vol) methylene chloride/methanol mixture.

Weight: 78 g; m.p.: 54-56°C.

B) SR 44318 A 3.5 g of the compound prepared above are refluxed in 18 ml of a 2.5 N solution of sodium hydroxide under a nitrogen atmosphere for 30 minutes. After cooling, concentrated hydrochloric acid is added until the pH is about 6. A solution of 2.48 g of alpha-bromophenylacetaldehyde in 25 ml of 95° ethanol is added and the mixture is refluxed for 1 hour under a nitrogen atmosphere .

It is evaporated in vacuo and a 10Z aqueous solution of sodium carbonate is added. Extraction is carried out twice with methylene chloride and the solutidn is dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on a silica column by elution with a 95/5 (vol/vol) methylene chloride/methanol mixture, giving an oil (1.46 g).

This oil is dissolved in anhydrous ether, a solution of hydrogen chloride in anhydrous ether is added and the mixture is left to crystallize. The crystals are filtered off, washed with anhydrous ether and dried in vacuo.

M.p.: 178°C.

EXAMPLES 2 TO 108: A) The substituted thioureas collated in Table 1 below are obtained by following the procedure of Example 1-A but varying the amine compounds used.

TABLE 1 s II CO - NH - C - NH - R.

R4 Physical constant -«M2)2 0 1 M.p. - 119 - 120°C -2)3 /C2H5 Vs Oil, TLC: Rf = 0.51 CH2Cl2/MeOH -2)3 /CK3 - N x‘3 90/10 vol/vol M.p. - 67 - 69°C - <°Ά .n // Oil -CCH2)2 •o M.p. - 98 - 99eC —(ch2)2 -a M.p. = 70 - 71*C (CH,),CH, /23 3 M.p. » 48 - 49°C -CCH2)2 - N |ch2)3ch3 <;h(ch3)2 M.p. = 93 - 94°C -(CH2)2 - N CH(CH3)2 C„Hr / 2 5 - CCH2)4-N^ Oil c2h5 -(¾ -Π N · M.p. = 65 - 67°C 1 CH, 3 -(CH,),- CH, M.p. = 55 - 57°C23 w 3 CH(CH3)2 ~(CH2)3 - NXCH(CH3)2 Oil CH, CH, 1 3 / 3 —ch,-c-ch,n; M.p. = 57 - 58°C 2 | 2 \ ch3 ch3 -CCH2)3 - / j M.p. . 73 - 75°C -o Oil \ηΛ ch3 —(ch,), - n; M.p. = 72 - 74°C 2 3 BOC M.p. = 74 - 75°C M.p. = 31 - 35°C Oil M.p. = 45 - 48°C M.p. = 152 - 153°C M.p. = 98 - 1OO°C M.p. = 158 - 159°C M.p. = 146 - 147°C M.p. « 118 - 119°C M.p. = 142 - 143eC B) The products of formula (I) collated in Table 2 below are obtained by following the procedure of Example 1-B, starting from these different thioureas and varying the oxohalogen derivative reacted therewith TABLE 2 Ex. no. SR code no.R1 r2 *4 Salt M.p.°C (solvent) Dihydrochloride 2 44244 A H Ό -CCH2)2-/\ 220-221 (iPrOH/EtjO) Dihydrochloride 3 44284 A II It .(CK2)3-N 0 216-217 (iPrOH) Dihydrochloride 4 44285 A _n H - (CH ) -N^A) 264-265 u22\J (iPrOH/EtOH 95) A /2*5 Succinate 5 44286 A H -Π -(CK2’2-\ 110-111 X=J c2k5 (iPrOH/iPr2O) CH, 6 44345 A II It Z 3 —(CH_)-N Dihydrochloride2 3 \ 181-182 ch3 7 44346 A Ό H ,C2K5 -OT253-\ C2KS (Et2O) Dihydrochloride O.5H2O 143-144 ! (acetone) 44347 A 44372 A 44373 A 44374 A 44421 A 44422 A 44424 A 44434 A 44435 A Dihydrochloride 199-200 (cyclohexane, Et20) Dihydrochloride 1H2O 147-148 (acetone, Et20) Dihydrochloride 0.5H20 184-5 (acetone, Et20) Dimaleate 109-111 (iPrOH, Et90) Dihydrochloride 224-226 (iPrOH, Et20) Dihydrochloride 162-163 (iPrOH, Et2O) Dihydrochloride 216-217 (iPrOH, Et2O) Dihydrochloride O.5H2O 148-149 (iPrOH, Et2O) Dihydrochloride 0.5H?0 167-168 (iPrOH, iPr20) 44436 A II -CH. /=2¾ X=2«s 44437 A -CCH2)2-N /=2¾ \„5 44438 A 44451 A 44465 A II -(CH2)2-N VJ (CH_),CH och3 -(CH-).-N 2 2 x (ch2)3ch3 /H3 -(CH3’3-\ =¾ -CH -(CH2>2 44468 A 44469 -CH.

/CH3 -2)3-nx CH3 >HS -(ch2)2-n< >2h5 Dihydrochloride O.5H2O 154-155 (Et20) Dihydrochloride 193-194 (Et2O) Dihydrochloride O.5H2O 190-195 (dec) (Et20) Dihydrochloride 141-142 (Et2O, PrOH) Dihydrochloride 184-186 (dec) (iPrOH, Et2O) Dihydrochloride 204-207 (dec) (iPrOH) Dihydrochloride 235-236 (dec) (iPrOH, iPr20) Dihydrochloride 196-199 (iPrOH, iPr20) Dihydrochloride 185-190 (dec) (iPrOH, Et2O) -CH -cch2)2 26 44488 A ϋ 27 44489 A It 28 44490 A ft 29 44491 A It 30 44492 A It 31 44493 A H 32 44494 A H 33 44515 A Ό 34 44516 A H ΖΊ j \J It -(CH2)2-N CH(CH,)_ / 32 CH(CH3)2 -2)2 CH(CH3)2 -CCH2)2-Nx CH(CH3)2 (ch2)3ch3 -CCh2)2-Nx (ch2)3ch3zCH3 (ch2)3 -n uh3 /»3 -CCH2)3-N ch3zC2H5 -(ch2)3-nx c2h5 -CCH2)2 I Dihydrochloride 178-180 (Er.2O) Dihydrochloride 1H9O 130-135 (iPrOH, iPr20) Dihydrochloride 250 (dec) (Et2O) Dihydrochloride 1H2O 93 (Et2O) Dihydrochloride 147 (acetone, Et2O) Dihydrochloride 1H2O 141 (iPrOH, iPr20, H20) Dihydrochloride 1H2O 114 (iPrOH, Et2O) Dihydrochloride 1H2O 88-89 (Et20) Dihydrochloride 1H2O 91-93 (Et20) I 44573 A H 36 44574 A H 37 44575 A H 38 44576 A H 39 44749 A H 40 44750 A H V Cl Λ c2h5 ZCH3 CH. -«"ζ’ζ-(CH2)5CH.

-(CH2)3V CH, -cch2)4-n; /C2H5 c2h5 Dihydrochloride 96°C (Et2O) Dihydrochloride 155eC (Et2O/iPrOH) Dihydrochloride 182°C (EtOH 95/iPrOH) Dihydrochloride 150-155 (Et20) Dihydrochloride 194-196°C (Et20) Fumarate 121-3°C (Et20) 41 44768 A H 42 44769 A ch3 43 44770 A H 44 44786 A H 45 44791 A H 46 44814 A H "2 -H2)3/ C2H5 CH CCH^-l/ CH I CH, CH, CH, Fumarate 182-4°C (Et.,0) Dihydrochloride 191°C (Et2O) Dihydrochloride (1H2O) 168°C (Et2O) Difumarate 138-140°C (Et20) Dihydrochloride (0.5H20) 175-6"C (Et2O) Difumarate 140-4°C (Et2O) 47 44832 A 48 44862 A 49 44887 A 50 44907 A .51 44908 A 52 44914 A 53 44915 A HgC 1 CH.

-Cch2)3-nx z3 CH.

Dihydrochloride (0.5H20) 165°C (Et20) -23 VJ 3 CH(CH,)_ Z 32 -(CH2)3NX CH(CH3)2 CH, CH, j 3 /3 ch2c-ch2/ ch3 ch3 -(CH2>2< CH(CH,) chcch3)2 fH3 /CH3 -ch2c-ch2n^ ch3 ch3 Trihydrochloride (1H2O) 249-251 °C (Et2O) Dihydrochloride (1.5H20) 78-82°C (Et2O) Difumarate (0.5H20) 173-4°C (Et2O) Dihydrochloride 114-6°C (Et20) Dihydrochloride 180-5°C (Et20) /"\ Ν N v? -(ch2)3-n n-ch3 Trihydrochloride 145-150’C (Et2O/iPrOH) 54 44916 A H 55 44963 A A 56 44964 A H 57 44965 A H 58 44967 A A V 59 45001 A H 60 45015 A Λ H3C ch3 -c2h5 CH, -(ch2)3n ™(™3)2 \l(CH,) j Dihydrochloride 165-7°C I (iPrOH/Et2O) -2)3n /C2H5 2H5 •2)3n CH2CH3 (ch2)3n; - II II i I Dihydrochloride ί (1H„O) 155-6°C I I (acetone) · I I I ί Difumarate j 147-8°C (Et2O) I I I Fumarate (1H2O) 226-8°C (Et2O) Dihydrochloride 82°C (Et20) Fumarate 123°C (Et2O) Dihydrochloride (0.5H20) 210°C (Et2O) 61 45016 A ό 62 45018 A H 63 45023 A H 64 45030 A H 65 45035 A H 66 45038 A H ι CH.

OCH.

II II II II II II -(CH2)3NHCH3 -(CH ,/ 2'3‘\ CH.

II II Dihydrochloride j (O.5H2O) ' 207-8°C (Et9O) ί I Dihydrochloride (O.5H2O) 165-7°C (Et20) Dihydrochloride ι 238-24O°C ! I (Et2O) , I I I I Difumarate , ι 138-14O°C ί Dihydrochloride (0.5H20) 222-5°C (Et2O) Trihemifumarate 129-130°C (Et2O) 45043 A 45079 A 45080 A 45088 A 45107 A 45108 A 45125 A /H3 2\ ca3 2)2mx CH, - 25O°C (Et2O) Monohydrochloride 184°C (Et2O) Dihydrochloride 201-4°C (iPrOH/EtOH) Base (1H2O) 163°C (Et2O) 102 45221 A H 0 -«a-Q· Dihydrochloride 207-9°C (iPrOH) Y F ί i 103 45253 A H 0 Monohydrochloride J 160°C (Et2O) 104 45240 A H V «1 II -„,-Q Dihydrochloride 191-2°C (Et20) 105 45239 A H HC 1 CH v -3-A NmZ Dihydrochloride 221-3°C y (iPr0H/Et20) 108 45258 A H ch3 If ’(ch2)3-nh-^ Oxalate 170-172°C (acetone) iPrOH = isopropanol; PrOH = propanol; EtOH 95 « 95° ethanol; Et2O = anhydrous ethyl ether; iPr2O = isopropyl ether - 29 EXAMPLE 109: 2-[(3-Aminopropyl)amino]-5-methyl-4-phenylthiazole dihvdrochloride (SR 44514 A) A) 3-N-Boc-aminopropionitrile ml of triethylamine are added to a solution of 26 g of 3-aminopropionitrile fumarate in 100 ml of water and the mixture is then heated to 50°C. A solution of 46 g of dicarbonic acid bis-tert.-butyl ester (Boc20) in 100 ml of dioxane is then added with vigorous stirring.

After evaporation of the solvent, the residue is taken up with methylene chloride. The organic solution is washed with a 5% aqueous solution of sodium carbonate and then with sulfate buffer of pH 2. The solution is dried over magnesium sulfate and the, solvent is evaporated off. The residue (38.8 g) crystallizes .

B) 3-N-Boc-aminopropylamine g of the above product are dissolved in a mixture of 400 ml of water, 40 ml of aqueous ammonia and 50 ml of ethanol. Raney nickel is added and the mixture is hydrogenated at ordinary temperature and pressure.

After the catalyst has been filtered off, the solvents are evaporated off in vacuo. The residue is taken up in an aqueous solution of sodium chloride and extracted with ethyl acetate. The solution is dried over magnesium sulfate and the solvent is evaporated off to give 12.6 g of the expected product.

C) N-Benzoyl-N * - (3-N-Boc-aminopropyl)thiourea A solution of 6.38 ml of benzoyl chloridein 20 ml of anhydrous acetone is added dropwise to a suspension of 7.05 g of potassium thiocyanate in 50 ml of anhydrous acetone and the mixture is then refluxed for 5 minutes. - 30 A solution of 12.6 g of 3-N-Boc-aminopropylamine in 20 ml of methylene chloride is added slowly to the hot solution, with vigorous stirring.

When the addition is complete, the mixture is stirred for 1 hour, the solvents are then evaporated off and the residue is taken up in iced water. Extraction is carried out with ethyl acetate and the solution is dried over magnesium sulfate. The solvent is evaporated off and the residue is taken up in 100 ml of cold anhydrous ether.

The crystals formed are filtered off, washed with cold ether and dried in an oven at 70°C.

Weight: 8.3 g; m.p.: 104-105°C.

D) SR 44514 A 3.37 g of the product obtained above are refluxed in 14 ml of a 2.5 N solution of sodium hydroxide for 15 minutes.

After cooling, concentrated hydrochloric acid is added until the pH is 1. A solution of 2.13 g of 2-bromopropiophenone in 20 ml of ethanol is added and the mixture is refluxed for 1 hour under a nitrogen atmosphere.

The mixture is treated as indicated in Example 1-B to give an oil.

The dihydrochloride is formed in solution in methanol by the addition of a solution of hydrogen chloride in ether.

M.p.: 100-110°C.

EXAMPLES 110 AND 111: The following are obtained in the same way, starting' from the substituted thiourea prepared in Example 109-C and following the procedure of Example IO97D but varying the bromine derivative used: EXAMPLE 1 10 2-[(3-Aminopropyl)amino]-4-(4-fluorophenyl) - 31 thiazole (SR 44886 A) isolated in the form of the fumarate (0.5H20). M.p.: 162-4°C.

EXAMPLE 111 2-[(3-Aminopropy1) amino]-4-(2,4,6-trimethylpheny1)thiazole (SR 44949 A) isolated in the form of the fumarate. M.p.: 163-4°C.

EXAMPLE 112: 2-[N-Methy1—N— (pyridyl-3-methyl) amino]-4-(2,4,6trimethylpheny1)thiazole oxalate (SR 45206 A) A) N-Methyl-N-(pyridy1-3-methyl) thiourea 24.6 ml of pivaloyl chloride are added dropwise, with thorough stirring, to a suspension of 16.2 g of sodium thiocyanate in 90 ml of anhydrous acetone, cooled to +4°C. The mixture is stirred for 3 hours at +4°C and 25 g of 3-methylaminomethylpyridine are then added dropwise so as to keep the temperature between 0 and +4°C. The temperature is allowed to rise to 20°C and the mixture is stirred for 15 hours at this temperature. It is evaporated in vacuo and the residue is taken up in 100 ml of concentrated hydrochloric acid. The solution is heated at 95°C for 1 hour. After cooling, extraction is carried out twice with methylene chloride and the aqueous phase is then rendered alkaline with a concentrated solution of sodium hydroxide. Extraction is carried out 4 times with 200 ml of methylene chloride. The organic extracts are combined and dried over magnesium sulfate. The solvent is evaporated off and the residue crystallizes. The crystals are triturated with 100 ml of ether and filtered off. After drying, 26.7 g of the expected compound are obtained. M.p.: 119-12O°C. - 32 B) SR 45206 A A mixture of 3.6 g of the thiourea prepared above, 6 g of 2,4,6-trimethylphenacy1 bromide, 20 ml of water, 50 ml of ethanol and 2 ml of concentrated hydrochloric acid is refluxed for 4 hours.

After evaporation in vacuo, the residue is taken up in 150 ml of methylene chloride and extraction is carried out with 150 ml of a 1 N aqueous solution of hydrochloric acid. The organic phase is re-extracted 3 times with 100 ml of 1 N hydrochloric acid and the acid extracts are combined. They are rendered alkaline with sodium hydroxide solution and extracted 4 times with 150 ml of methylene chloride. The organic extracts are combined and dried over magnesium sulfate and the solvent is evaporated off. The oily residue is chromatographed on a silica column (100 g). Elution with a 97/3 vol/vol methylene chloride/methanol mixture gives 4.5 g of oily product.

OXALATE The 4.5 g of the above product are dissolved in 30 ml of acetone and a solution of 1.4 g of oxalic acid in 40 ml of acetone is added.

The pale yellow crystals formed are filtered off, washed with a small volume of acetone and dried. 4.3 g of the expected product are obtained. M.p.: 16O-1°C.

EXAMPLES 113 TO 117: The substituted thioureas collated in Table 3 are obtained in the same way by following the procedure of Example 112-A. - 33 TABLE 3 Κ2Ν - 8 ./ N /R3 N K4 Melting point -KTI-CB, w M.p.: 174-5°C ,¾ -/ CH, TABLE 4 Ex. no. SR code no. *1 *2 N X K4 Salt isolated Melting point I °C i 113 45215 A H H,C 1 CH, ϋ ch3 -nQn-ch, Monohydrochlorideι (1H2O) 145-7°C (Et2O) 1 1 j i 1 ch2 1 1 114 45216 A 6 H It II Monohydrochloride; 210-1 °C (Et2O) 115 45223 A H 1 C-CH, i' II II Dihydrochloride 231-2’C (Et2O) 116 45191 A H H,C 1 CH CH3 ?2H5 < Λ 1ch2)3-h oh3 1 1 j 1 I Oxalate 44-5°C 117 45257 A H It II y1*3 \q-™3 Dihydrochloride 224-6’C (iPrOH/iPr2O) EXAMPLE 118; 2-(2-Morpholinoethylamino)-4,5-dihydronaphtho[1,2-d]thiazole dihydrochloride (SR 44273 A) 3.66 g of N-benzoyl-N’-(morpholinoethy1)5 thiourea are refluxed in 17.5 ml of a 2.5 N solution of sodium hydroxide under a nitrogen atmosphere for 15 minutes. After cooling, concentrated hydrochloric acid is added until the pH is 7. A solution of 3 g of 2-bromo-l,2,3,4-tetrahydronaphthalen-l-one in 20 ml IQ of ethanol is added and the mixture is refluxed for 1 hour. After evaporation of the solvent, the residue is neutralized by the addition of sodium bicarbonate and extraction is carried out twice with methylene chloride. The organic phase is dried over magnesium sulfate and chromatographed on a silica column by elution with a dichloromethane/methanol mixture (95/5 vol/vol).

After evaporation of the solvents, the oily residue is taken up in ether and the hydrochloride is 2q precipitated in ether. It is filtered off and recrystallized from an isopropanol/950 ethanol mixture.

M.p.: 255-257°C.

EXAMPLES 119 TO 124: The products of formula (I) collated in Table are obtained by following the procedure of Example 118 but varying the bromine derivatives and/or the benzoylthioureas. 1 Ex. no. SR code no. m n 7* -N Xr7 Salt M.p.°C (solvent) 119 44317 A 3 2 -H^O \J Dihydrochloride 217 (iPrOH/EtOH 95) 120 44323 A 3 2 ,C2H5 c2hs Dihydrochloride 170 (iPrOH/Et2O) 121 44326 A 3 3 II Dihydrochloride 0.5H20 192 (iPrOH/iPr2O) 122 44327 A 3 3 z™3 -N\ CH3 Dihydrochloride 1H2O 198 (Et2O) 123 44392 A 3 3 \_/ Dihydrochloride O.5H2O 245 dec (Et2O) 124 i _ 44393 * A 2 2 ./A \h5 Dihydrochloride O.5H2O 181 (EtjO/PrOH) EXAMPLE 12 5: 2-[(2-Diethylaminoethy1)amino]-9-nitro-5,6-dihydro4H-benzo[6,7]cyclohepta[l,2-d]thiazole dihydrochloride (SR 44411 A) The procedure of Example 118 is followed using N-benzoyl-N’-(3-diethylaminopropy1) thiourea and 2bromo-8-nitrobenzocycloheptan-l-one as the starting materials.

The expected product is obtained in the same way in the form of the dihydrochloride.

M.p.: 192-195°C (isopropanol/950 ethanol).

The products according to the invention were studied for their pharmacological properties and in particular for their affinity for muscarinic cholinergic receptors.

The study was carried out by means of in vitro biochemical tests and also by means of pharmacological tests performed on animals.

IN VITRO BIOCHEMICAL STUDY There are two subclasses of muscarinic cholinergic receptors in mammals: the M^ and M2 receptors.

The M^-type receptors are concentrated in certain regions of the brain, such as the hippocampus, the cerebral cortex and the striatum, and also in the sympathetic ganglia. These binding sites can be selectively labeled with tritiated pirenzepine ( H-PZ).

The M2~type receptors predominate in the heart and the ileum and can be labeled with tritiated N-methyl3 3q scopolamine ( H-NMS). The selectivity of the products of the invention with respect to the M^ and M2 sites was determined by studying their in vitro interaction 3 with H-PZ and H-NMS firmly bound with a high affinity to rat hippocampus membranes and smooth guinea-pig ileum muscle, respectively.

Methodologies A) Testing for affinity for the M^-type muscarinic cholinergic receptor The interaction of the molecules with the Mjtype muscarinic receptors was studied by in vitro measurement, on a rat hippocampus homogenate, of the displacement of tritiated pirenzepine from its specific binding sites. Aliquots (10 jil) of a 5% (w/v) rat hippo,campus homogenate in an Na2HP04 buffer (50 mM, pH 7.40) are incubated for 2 hours at 4°C in the presence of H-PZ (76 Ci/mmol; final concentration 1 nM) and increasing concentrations of the test product. The final volume is 2 ml. The reaction is stopped by centrifugation for 10 minutes at 50,000 x g. After decantation and washing of the residues, the bound radioactivity is counted by liquid scintillation. The non-specific binding is determined in the presence of .10 |iM atropine sulfate. The 50% inhibitory concentration (IC5Q) is determined graphically. (Ref.: J.D. Watson, W.R. Roeskoe and H.I. Yamamura, Life Sci., 1982, 3_1_, 2019-2029.) B) Testing for affinity for the M2~type muscarinic cholinergic receptor The interaction with the M2~type muscarinic receptors was studied by in vitro measurement, on a smooth guinea-pig ileum muscle homogenate, of the displacement of tritiated N-methylscopolamine from its specific binding sites. Aliquots (50 jil) of a 0.625% (w/v) smooth guinea-pig ileum muscle homogenate in 20 mM HEPES buffer - 2-(2-hydroxy-4-ethylpiperazin-ly1)ethanesulfonic acid containing NaCl (100 mM) and MgCl2 (10 mM) (final pH: 7.5) - are incubated for minutes at 30°C in the presence of H-NMS (85 Ci/ mmol; final concentration 0.3 nM) and increasing concentrations of the test products. The final volume is 1 ml. The reaction is stopped by centrifugation for 5 minutes at 15,000 x g. The non-specific binding is determined in the presence of 10 mM atropine sulfate. (Ref.: R. Hammer et al., Nature, 1980, 283, 90-92; E.C. Hulme et al., Mol. Pharmacol., 1978, 14, 737-750.) Results Table 6 indicates the affinities of the products of the invention for the M^ and M2 receptors. The results are expressed as 50 per cent inhibitory concentrations (ΙΟ^θ), i.e. the concentration (in jiM) which induces the displacement of 50X of the tritiated ligand bound to the membrane receptors. The for ^H-PZ displacement represents the affinity for the 3 Μ^ receptor; the IC^q for H-NMS displacement represents the affinity for the M2 receptor.

Also, the next column of the table indicates the ratio R of the values for the Mj and M2 receptors, which expresses the selectivity of the products with respect to one of the receptor types.

By way of comparison., Table 6 indicates the results obtained with 3 reference products.

TABLE 6 Product no.3H-PZ(M[) IC50}·3H-NMS(M,) IC50 /R . IC5OIC5(/M P SR 44284 A 8 40 5 SR 44286 A 6 100 16 SR 44318 A 3.4 38 11 SR 44323 A . l·7 8.5 5 SR 44326 A 2.2 > 100 > 45 SR 44327 A 1.9 38 20 SR 44345 A 1 70 70 SR 44346 A 2 25 12.5 SR 44347 A 0.35 13 37 SR 44372 A 0.12 . 5 41 SR 44373 A 0.70 15 21 SR 44374 A 0.40 8 20 SR 44393 A 2.7 42 15 SR 44411 A 0.9 6.7 7 SR 44421 A 3.6 > 100 > 27 SR 44422 A 8.1 100 12 SR 44423 A 6.4 100 15 SR 44434 A 1.5 70 46 SR 44435 A 0.36 3 8 SR 44436 A 1.7 50 29 SR 44437 A 0.43 3 7 SR 44438 A 1 60 60 SR 44451 A 6 80 13 SR 44465.A 2.6 40 15 SR 44467 A 1.5 38 25 SR 44468 A 1.2 22 18 SR 44469 A 2.6 60 23 SR 44488 A 1.7 34 20 SR 44489 A 0.3 2 6 SR 44490 A 1.5 25 16 SR 44451 A 0.8 8.5 10 SR 44492 A 3.6 28 8 SR 44493 A 1.6 45 28 SR 44494 A 0.8 80 100 SR 44514 A O.S > 100 > 200 SR 44515 A 0.2 3.4 17 SR 44516 A 3.4 75 22 SR 44573 A 1.8 13 7 SR 44574 A 0.2 24 120 SR 44575 A 7 > 100 > 14 SR 44749 A 1.8 ' 26 14 SR 44769 A 2 30 15 SR 44770 A 0.6 26 43 SR 44786 A 0.6 40 67 SR 44791 A 5 40 8 SR 44792 A 1.8 30 17 SR 44813 A 6 > 100 > 17 SR 44814 A 1.4 10 7 SR 44832 A 2.4 > 100 > 42 SR 44839 A 0.4 100 250 SR 44840 A 0.6 > 100 > 167 SR 44856 A 0.3 > 100 > 300 SR 44862 A 3 34 11 SR 44864 A 0.28 > 100 >. 360 SR .44886 A 6.3 70 11 SR 44904 A 6 > 100 > 17 SR 44905 A 2.4 60 25 SR 44906 A 2.4 > 100 > 42 SR 44908 A 0.13 4 31 SR 44915 A 0.4 40 100 SR 44916 A 0.13 5 38 SR 44963 A 0.12 6 50 SR 44964 A 0.9 28 31 SR 44965 A 1.260 50 SR 44966 A 4.5 100 22 SR 44967 A 1.8 40 22 SR 45001 A 2.60 30 11 . SR 45015 A 0.3 4 13 SR 45016 A 0.10 5.5 55 SR 45030 A 1.60 80 50 SR 45106 A 3 > 100 > 33 Oxotremorine 0.24 • 0.2 1 Arecoline 17 4.5 0.3 Pilocarpine 2.5 7 3 The results show that the compounds according to the invention have a strong affinity for muscarinic cholinergic receptors, with a marked specificity for the Mj-type central receptors.

IN VIVO PHARMACOLOGICAL STUDY Pirenzepine (PZ) is a specific antagonist of the M^ central muscarinic cholinergic receptors. The intrastriatal injection of PZ into mice induces rotatory behavior. The antagonism of this behavior by the products according to the invention was studied.

The products according to the invention are administered either intraperitoneally (i.p.) or orally (p.o.) after solubilization in distilled water or < suspension in a 5% solution of gum arabic. The control animals receive the pure solvent under the same conditions .

The animals used are female mice (Swiss, CD 1, Charles River, France) with a body weight of between 25 and 30 grams.

The pirenzepine is dissolved in a phosphate buffer and the pH of the solution is 6.

The test products or their solvents are administered in a volume of 0.4 ml per 20 g of body weight, either by i.p. injection or orally via an esophageal tube. Administration takes place either 15 minutes (i.p.) or 30 minutes (p.o.) before a direct injection of pirenzepine into the right striatum of the mouse at a dose of 1 pg in 1 jxl of solvent, according to the method described by P. WORMS et al. in Eur. J. Pharmacol. 1986, 121, 395-401 .

The number of contralateral rotations (rotations in the opposite direction to the side injected) was counted for three 2-minute periods after injection of the pirenzepine: 2nd to 4th, 8th to 10th and 13th to 15th minutes. Each treatment consists of 3 to 4 doses and 10 animals per dose. The total number of rotations and the percentage antagonism with respect to the control group are calculated for each treatment.

The 50% effective dose (Εϋ^θ), i.e. the dose which causes a 50% reduction in the number of rotations induced by pirenzepine, is determined graphically for each product. The results are reported in Table 7.

Table 7 indicates, for each product tested, the 50% effective dose (Εϋ^θ) in mg/kg in mice for the antagonism of the rotations induced by pirenzepine, either 'by i.p. administration or by oral administration.

By way of comparison, the results obtained with reference products have been reported.

TABLE 7 Product no. Pirenzepine antagonism ED5O mg/k8 i,p· Pirenzepine antagonism ^50 mg/kg p.o. SR 44244 A 8 20 SR 44284 A 8 - SR 44285 A 3 - SR 44286 A 3 10 SR 44318 A 1.5 3 SR 44323 A 10 r SR 44326 A 3 - SR 44327 A 10 - SR 44345 A 0.5 1 SR 44346 A 1 - SR 44347 A 0.03 0.20 SR 44372 A 1 3 SR 44373 A 0.3 1 SR 44374 A 3 SR 44392 A 3 SR 44393 A 3 w SR 44411 A 15 - SR 44421 A - 0.2 SR 44435 A 2 « SR 44467 A - 3 SR 44493 A - 0.3 SR 44494 A - 2 SR 44514 A 3 SR 44573 A - 2.50 SR 44749 A 3 SR 44770 A 3 SR 44792 A - 3 SR 44814 A - 0.2 SR 44839 A - 0.2 SR 44856 A * 3 SR 44862 A - 3 SR 44887 A - 0.3 .. SR 44915 A - 3 SR 44949 A - 10 SR 44964 A - 3 SR 44965 A - 3 SR 45001 A - 3 SR 45015 A - 0.70 SR 45016 A - 2 SR 45030 A - 1 Oxotremorine * . 0.005 - Arecoline * 1 0.5 Pilocarpine * 1 io * Strong induction of side-effects (trembling, salivation, lacrimation, defecation, piloerection, hypothermia, sedation) at doses close to the active doses in these tests.

The results in Table 7 show that the compounds according to the invention are active in stimulating central cholinergic transmission and are therefore capable of being used as agonists of muscarinic receptors.

.Furthermore, some of the products according to the invention displayed an antagonistic activity towards the effect of excitatory amino acids in the brain. This activity was measured in the test for the - 46 release of acetylcholine caused by N-methy1-D-aspartic acid (NMDA) on sections of rat striatum (J. Lehmann and B. Scatton, Brain Research 1982, 252, 77-89).

Finally, the acute toxicity was determined for 5 various products according to the invention. The products were administered intraperitoneally in increasing doses to groups of 10 female mice (Swiss, CD 1, Charles River, France) with a body weight of 20 g.

The mortality caused by the products studied 10 was noted for 24 hours following administration of the product. The 50% lethal dose (LD^q), i.e. the dose which causes the death of 50% of the animals, was determined for each of the products.

The results obtained are collated in Table 8 below.

TABLE 8 Product no. LD50 (mg/kg) i.p. SR 44244 A 250 SR 44273 A > 100 SR 44284 A 450 SR 44286 A 200 SR 44345 A 200 SR 44347 A60 SR 44372 A 75 SR 44373 A 75 SR 44374 A 150 The products according to the invention therefore have a low toxicity and show no signs of toxicity for the doses at which they are active.

Consequently, the compounds (I) can be used as drugs .

The results indicated above make it possible to consider using the products according to the invention for treating degenerative syndromes associated with senescence, and especially memory disorders and senile dementia.

According to another of its aspects, the present Application therefore relates to pharmaceutical compositions which contain at least one of the compounds of formula (I) or one of their salts as the active ingredient.

In the pharmaceutical compositions of the present invention for oral, sublingual, percutaneous or rectal administration, the active ingredients of formula I above can be administered to humans in single dosage forms, mixed with the conventional pharmaceutical excipients, especially for the treatment of senile dementia. The appropriate unit dosage forms include oral dosage forms, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal dosage forms, subcutaneous, intramuscular or intravenous dosage forms and rectal dosage forms.

To achieve the desired effect, the dose of active principle can vary between 20 and 500 mg per day.

Each unit dose can contain from 5 to 200 mg of active ingredient combined with a pharmaceutical excipient. This unit dose can be administered 1 to 4 times per day.

When a solid composition is prepared in the « form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other appropriate substances, or else they can be treated so as to have a sustained or delayed activity and continuously release a predetermined amount of active principle.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

Water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, and with sweeteners or taste correctors.

For rectal administration, suppositories are used; these 'are prepared with binders which melt at the temperature of the rectum, for example cacao butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic salt solutions or solutions which are sterile and injectable are used; these contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, together with one or more excipients or additives if appropriate.

As an example of a pharmaceutical preparation, it is possible to prepare gelatin capsules containing: SR 44421 A 0.010 g lactose 0.050 g magnesium stearate 0.005 g by intimately mixing the above ingredients and pouring the mixture into hard gelatin capsules.

Claims

1. Novel thiazole derivatives of the general formula: in which: - R^ and Rg each independently represent hydrogen; a C^-C^ alkyl group; a phenyl group; a phenyl group monosubstituted or polysubstituted by a halogen atom, or by a C^-C^ alkyl group, or by a C^-C^ alkoxy group, a nitro group or an hydroxyl group; or one of the groups R^ and Rg denotes hydrogen and the other represents a naphthyl group; a benzyl group; an alpha, alpha-dimethylbenzyl group; a cyclohexyl group; a biphenyl group; a thienyl group; an adamantyl group; or alternatively R^ and Rg, taken together, represent a group: in which the phenyl group is bonded to the 4-position of the thiazole and the group “(CHg)- to the 5-position, and in which m represents an integer equal to 2 or 3 and R,- denotes hydrogen or a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups or Rg denotes hydrogen, the other is different from H or methyl; R g represents hydrogen or e C^-C^ alkyl group; represents: a group: in which denotes a linear or branched Cg-Cg alkyl group; and R g and Ry, taken independently, represent hydrogen, a C 1-C 4 alkyl group or a Cj-Οθ cycloalkyl group, or alternatively R& and Ry, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkyl-piperazine rings; a group: - A in which Ag denotes a group (CHg)^, where m = 0, i, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position; s group: in which Ag is as indicated above; or - a group: in which Rg denotes a C^-C^ alkyl group; or Rι 3 alternatively the substituent -N-R^ represents a group: /—\ - W’ 8 in which Rg is as indicated above, with the proviso that if R^ represents hydrogen or a C^-C^ alkyl group, then R 2 is other than a alkyl group or a cyclohexyl group, and also their pharmaceutically acceptable addition salts with mineral or organic acids.

2. Compounds according to claim 1, characterized in that R^ and Rg each independently represent a phenyl group monosubstited or polysubstituted by a chlorine atom, a fluorine atom or a methyl group.

3. Compounds according to one of claims 1 or 2, characterized in that R^ represents a group: in which A^ denotes a linear or branched Cg-Cg a^yl group; R g and Ry, taken independently, represent hydrogen, a C^-C^ alkyl group or a Cg-Cg cycloalkyl group, or alternatively Rg and Ry, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkylpiperazine rings.

4. Compounds according to any one of claims 1 to 3, characterized in that R^ represents a group: // Aj W in which Ag denotes a group where m = 0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position.

5. Compounds according to anyone of claims 1 to 3, characterized in that R^ represents a group: in which Ag is as defined above.

6. Compounds according to any one of claims 1 to 5, characterized in that R^ and Rg each independently denote hydrogen, a C^-C^ alkyl group; a phenyl group; a phenyl group monosubstituted or polysubstituted by a halogen atom; a C^-C^ alkyl group, a nitro group or e hydroxyl group; or one of the groups denotes hydrogen and the other represents a naphthyl group; a benzyl g?oup; an alpha, alpha-dimethylbenzyl group; a cyclohexyl group; a biphenyl group or an adamantyl group, with the proviso that if one of the groups or Rg denotes hydrogen, the other is different from H or methyl.

7. Compounds characterized in represent a group: according (CH,) 2 m to anyone of claims 1 to 5, and Rg, taken together, in which the phenyl group substitutes the thiazole in the 4-position and the group (CHg) m substitutes the thiazole in the 5-position, and in which m represents an integer equal to 2 or 3 and Rg denotes hydrogen or a nitro group.

8. Thiazole derivative of formula (I): (I) in which: - is the phenyl group; - Rg is the benzyl group; - Rg is hydrogen and - is the group (CHg)g-N(CgHg)g under the form of the dihydrochloride.

9. A process for the preparation of the compounds of formula I, characterized in that a substituted thiourea of the formula: in which Rg has the meaning indicated above and R’^ has the same meanings as except in cases where R^ contains a primary or secondary amine, when R' 4 denotes the group corresponding to in which a hydrogen belonging to the said amine group has been replaced by a protective group which is resistant to hydrolysis in alkaline medium, is heated, in an acid medium of pH 1 to 6, with an alpha-brominated carbonyl derivative of the formula: R - CH - C - R 1 l H Br 0 or with the corresponding bromine derivative in which the carbonyl group is protected in the form of an acetal, to give the compounds (I), and wherein the compound I is optionally converted to a salt by a known process.

10. Pharmaceutical compositions containing, as the active principle, a compound of the formula (I) or one of its pharmaceutically acceptable salts according to any one of claims 1 to 8, in combination with a pharmaceutically acceptable vehicle.

11. Pharmaceutical compositions according to claim 10, containing from 20 to 500 mg of active principle.

12. Use of the thiazole derivatives of formula: N - R. CI) in which: - and Rg each independently represent hydrogen; a alkyl group; a phenyl group; a phenyl group monosubstituted or polysubstituted by a halogen atom, or by a C^-C^ alkyl group, or by a alkoxy group, a nitro group or an hydroxyl group; or one of the groups and Rg denotes hydrogen and the other represents a naphthyl group; a benzyl group; an alpha, alpha-dimethylbenzyl group; a cyelohexyl group; a biphenyl group; a thienyl group; an adamantyl group; or alternatively and Rg, taken together, represent a group: in which the phenyl group is bonded to the 4-position of the thiazole and the group —(CHg)- to the 5-position, and in which m represents an integer equal to 2 or 3 and Rg denotes hydrogen or a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups R^ or Rg denotes hydrogen, the other is different from H or methyl; Rg represents hydrogen or a C^-C^ alkyl group; represents: a group: - , -/ 1 \ in which denotes a linear or branched Cg-Cg alkyl group; Rg and Ry, taken independently, represent hydrogen, a C 1 -C 4 alkyl group or a Cg-Cg eycloalkyl group, or alternatively Rg and Ry, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, N-alkyl-piperazine rings; a group: morpholine and A2 W in which Ag denotes a group (CHg) m , where m = 0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position; a group: in which Ag is as indicated above; or a group: n in which R g denotes a C 2 -C 4 alkyl group; R|3 or alternatively the substituent -N-R 4 represents s group: - n - R in which R g is as indicated above or of one of their pharmaceutically acceptable addition salts with mineral or organic acids, for the preparation of drugs useful for the treatment of degenerative syndromes associated 5 with senescence.

13. Thiazole derivatives of the general formula I according to claim 1 or 8, substantially as herein described in the-Examples.

14. A process for the preparation of compounds of formula I, according to claim 9, substantially as herein described in the examples.