AU612350B2

AU612350B2 - Novel thiazole derivatives active on the cholinergic system, process for obtention and pharmaceutical compositions

Info

Publication number: AU612350B2
Application number: AU12662/88A
Authority: AU
Inventors: Kathleen Biziere; Dominique Olliero; Paul Worms
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 1987-03-12
Filing date: 1988-03-03
Publication date: 1991-07-11
Anticipated expiration: 2008-03-03
Also published as: DK170162B1; AU1266288A; PL151889B1; PH25389A; DD274028A5; ATE86249T1; ES2053778T3; EP0283390A2; OA08871A; FR2612187B1; MY103233A; FI881152A7; NZ223845A; DE3878708T2; IE60173B1; JPS63243080A; PL271132A1; SU1604157A3; AR243515A1; MA21207A1

Description

F. B. RICE CO PATENT ATTORNEYS 'lhis s lr lll Is i i ir il I% 'I t Ii t L I I\t, itw Nu. 't l I isI imlll tll riqul rIIinl C

J

COMMONWEALTH OF AUSTRALI Patent Act 1952 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number Lodged Complete Specification Lodged Accepted Published S0 Priority 12 March 1987 Related Art Name of Applicant Address of Applicant

SANOFI

S40, Avenue George V, 75008 Paris, France Kathleen BIZIERE; Dominique OLLIERO; Paul WORMS RICE CO., Patent Attorneys, 28A Montague Street, BALMAIN 2041.

Actual Inventor/s Address for Service Complete Specification for the invention entitled: NOVEL THIAZOLE DERIVATIVES ACTIVE ON THE CHOLINERGIC SYSTEM, PROCESS FOR OBTENTION AND PHARMACEUTICAL COMPOSITIONS The following statement is a full description of this invention including the best method of performing it known to usdan:la The present invention relates to novel Lhianz ole 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 R S R N1 S

S

a i 10 N R

(I)

0 R 2 in which R1 and R 2 each independently represent hydrogen a C1-C4 alkyl group a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, preferably chlorine or fluorine, by a C -C alkyl group, preferably the methyl group, or by a C 1

-C

4 alkoxy, nitro or hydroxyl group or one of the groups R 1 and

R

2 denotes hydrogen and the other represents a naphthyl group a benzyl group an c,c>-dimethyl-benzyl group; a cyclohexyl group; a biphenyl group; a thienyl group or an adamantyl group or alternatively R 1 and R2, taken together, represent a group (CII2) in which the phenyl group is bonded to the 4-position of the thiazole and the group (CH 2 to and in which m represents an integer equal to 2 or 3 and R 5 denotes hydrogen or 2 a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups R 1 or R 2 denotes hydrogen, the other is different from H or methyl;

-R

3 represents hydrogen or a C 1

C

4 lower alkyl group; and

R

4 represents: a group: A

N

1

I

Odl re if ii 10 in which A 1 denotes a linear or branched C 2

C

alkyl group and R 6 and R7, taken independently, represent hydrogen, a C 1

-C

4 alkyl group or C 3

-C

6 cycloalkyl group, or alternatively R 6 and R 7 taken with the nitrogen atom to which they are bonded, form a 5-membored or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkylpiperazine rings; a group:

A

in which A 2 denotes a group (CH 2 where m 0, 1, 2 or 3, which substitutes the pyridine ring in the 3- or 4-position; a group: S2

N

CH

3 i j 3 in which A 2 is as indicated above; or a group:

R

8 in which R 8 denotes a C 1

C

4 alkyl group;

R

13 or alternatively the substituent -N-R 4 represents a group: -N N- R 8 in which R 8 is as indicated above, and also their addition salts with mineral or organic acids.

If the substituent R 4 contains an asymmetric carbon atom, the compounds exist in the form of 2 optical isomers. These optical isomers form an integral part of the invention.

According to a second aspect, the invention relates to a process for the preparation of the compounds of formula The process 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 ,3 H2N C N R'4

S

in which R 3 has the meaning indicated above and R' 4 has the same meanings as R 4 except in cases where R 4 contains a primary or secondary amine, when R'4 denotes the group corresponding to R 4 in which a hydrogen belonging to the said amine group has been replaced by a protective group 4 which is resistant to hydrolysis in an alkaline medium, with an alpha-brominated carbonyl derivative of the formula R CH C R 1 11 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 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 1.

If R3 is hydrogen, this process can be represented by" the following reaction scheme: H2N-R4 -C-NH-C-NH-R 4 1 2 R /S 1) NaOH NH-R

N

0 R II 2 2) R 1

-CII-C-R

Br (I) 5 Reaction of benzoyl isothiocyanate with the primary amine 1 gives the substituted benzoylthiourea 2.

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

A solution of the amine derivative 1 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 0 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 S 15 isolated in the usual way, either by solvent extraction Sand purification, or by chromatography, or by direct crystallization.

The product is obtained in 2 steps from the benzoylthiourea.

Firsc of all, the benzoyl groun is removed by heating the compound 2 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 0

C.

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

After p.irification by the usual methods, the compound is converted to a salt, if desired, by reaction with an acid in accordance with a known process.

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

Finally, if R 4 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 a 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 2 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 in which R 4 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. 4/5 p. 171-18 8 -Georg Thieme Verlag.

'o In the particular case where R 4 represents a group 6 A -N 1\ R7 in which at least one of the substituents R 6 and R is hydrogen, the protected amine derivatives 1 can be prepared from the aminonitrile R7NH-A'-CN. When treated 7 -1 with the anhydride (Boc) 2 0, this gives the aminonitrile Boc-N-A'1-CN, which, on reduction, leads to the corres-

R

ponding primary amine Boc-N-A' -CHNH 2 in which A' re- R7 presents A 1 minus a methylene group.

In all cases, and particularly if the substituent

R

3 is other than hydrogen, the compounds can be L IC _I _Ij_* 7 prepared from pivaloyl isothiocyanate according to the scheme: R S R 3 II 3 (CH3)3C-CON=C=S HN-R 4 (CH3)3C-CO-NH-C-N

R

4 4

SR

11 13 H2N-C-N-R

(I)

6 Reaction of pivaloyl isothiocyanate with the amine 4 gives the pivaloylthiourea 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 0

C).

The amine 4 is tken 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 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-Diethylaminoethyl)amino]-5-phenylthiazole dihydrochloride (SR 44318 A) A) N-Benzoyl-N'-(diethylaminoethyl)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 k- 8 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 methy l'ne 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 mixt.ure.

Weight: 78 g; 54-56°C.

B) SR 44318 A 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 950 ethanol is added and the mixture is refluxed for 1 hour under a nitrogen atmosphere.

It is evaporated in vacuo and a 10% aqueous solution of sodium carbonate is added. Extraction is carried out twice with methylene chloride and the solution 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 -9- 46 g).

Thi*s oil is dissolved in anhydrous ether, a solution of hydrogen chloride in anhydrous ether is added and the miXture is left to crystalliize. Th e crysta-ls rire filtered off, washed with anhydrous ether and dried in vacuo.

M 178 0 C E XA MP LES T 18 A Thr o t it u t ed t hi uour e as coI Ia t ed i n T a Ic I b e I are obtan- fI by following the procedure of Example 1-A but vary ii the amine compounds used.

to1. TABLE 1

S

CO NH C NHf R R4 Physical constant (CH 2 2 N 0

V--

(CH) 2 2 3 (CH9 2 )2

H

(CH9 2-

NQ

M.P. 119 12 20 0

C

Oil, TLC: Rf =0.51 C 11 2 C1 2 /MeOIH 90/10 Vol/Vol M.P. 67 69'C Oil M.P. 98 99'C M.P. 70 71'C /12 11 (CH 2 )3 C11 C H 2 2 N l 1

CI)CII)

32 (CH N CH(CH 3 2 (CUf)L -N" 2 (CiU 2 2

(CH

2 3 N N- C11 (Ci 2) /cif(Cli 3 2 (CII (C N) CHI CU 1 _3 3 (CII 2C-CU NC CII2

CII

(CU2 N/ 1

CI

2 3 Boc M.P. 48 49'C M.P. 93 94'C 0Oil M.P. 6-5 67'C' N.p. 55 -57 0

C

0il M.P. 5*7 -58'C M.P. 73 0.1i M.P. 72 W 4C d YLUUPJ.

/13 12 (Cif 2 2 N" CH C11 (m 2 4 N~

CH

(CH2 3- NCH 3 (CH 2 3

NA

CHCH

22

-CH

2 1u -1 (CH 2 2 (CH 2 2 N-1 (011 2)2 M-p. 31 35 0

C

Oil M.P. =45 48'C I p. 152 153'C M.P. =98 100'C M.P. =158 159'C M.P. =146 147'C M.P. 74 M.P. 118 119,C M.P. 142 143'C 13 (CHI2) 3 (CH2) 5

-N

M.p. 81 82°C M.p. 118 120°C B) The products of formula 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.

14 TABLE 2 NH -R4 a a 44 ft ft a a D~O a, ft ft ft ft o ftC ft a a a ft ft 444 a a a o aa afta r r I r r

SR

code no Salt 0

C

solIv enit) I- -I 4 1 44244 A 44284 A 44285 A 44286 A 44345 A 44346 A

H

-(Cli 2)3

(CHI

2 2 Nf' 252 3 -(CH 2 3

N\

CH 3 253 Dihydrochl )1 ide '20-22'1 (iPrOHl/Et Di hydrochloride 216-217 (iPrOH) Dihydrochioride 264-265 (iPrOHI/EtOIH S ucci nate 110-1.ll (iPr0HI/iPr,0) Dih y droc hlor i ie 181-182 (Et 2 0) Dih ydr ochl1or ide 0.51 1 ,0 143-144 (acetone) 15 44347 A 44372 A 44373 A 44374 A 44421 A 44422 A 44424 A 44434 A 44435 A -c1l 3

H

if

H

-CH 3

CH

1'3 C 2H -(Ci)N 2 25 2 5 -(CH 2)3

N'<

CH

253 C 3 -(CH 2 )2N\ C H -(CH N

CH

-(CH 2)3- N/2 2 H5 Di hy droe hind e 199-200 (cycl-ohexane, Et 2 0) Dihydrochloride 11-2 0 147-148 (acetone, Et 2 O0) Dih ydr oc hior i 0.5H 2 0 184-5 (acetone, Et 2 0) Dimaicate 109-111 (iPrOH, Et 2 0) IDi hyd roc hior ide 2 24-226 (iPr0Hl, Et 2 0) Di hydrochloride 162-163 (iPrOll, Et,0) Dihydrochioride 2 16-217 (iPr0Hl, Et 2 O0) Di hydrochloride 0.511 20 148-149 (iOr0H, Ext 2 0) Di h3rd roch 1 or ide 0.5H 2 0 167-168 (iVrOli, iPr 2 0) '1 1 6 44436 A 44437 A 44438 A 44451 A 44465 A 44466 A 44467 A -Cll 3

H

FCH

-CiH 3 -(CH 2 )2 2 N -(CH )CH 5 -(Cl 2 2 1 ~Nj (CH H)CH (CH 2 2 N N\ (Cl H 2 3 Cif 3 CH 3 CH 3 )3 N (CH 2 2 l Dihydrochioride 0.5112 0 154-155 (Etj) Dihydrochi cride 1 93-194 (Et 9 0) Dihydrochi oride 0.51-12 0 190-195 (der (Ft2 D i hydrocli tor ide 141-142 (Et 2 0, PrOll) D)i hy~d roc hI or i 4Il 184-186 (dec) i.prOl, 1li) IDihydrochl oride 204-207 (dec) (iPr0H) Dihiydrochioride 235-236 (dec) (iPrOHl, iPr 9 0O) IDi hy d r cc h Ir id 196-199) (IrOH, iPr 2 Dihydrochloride 185-190~ jdec) (iPrOll, Ft 2 O0) -CH1 3 24 1 44468 A S

-N

(CH 2 2 7 44469 A I i 17

I

29 31 32 33 44488 A 44489 A 44490 A 44491 A 44492 A 44493 A 44494 A 44515 A

-CH

3 H if

£H

2- -(CI12)2

-N

C H(CH H

(CH

2 2

-N

CH(CHl 3 2 C[(C11 3 2

-(C

2

-N

2

CH(CH

3 2

(CH

9

)H

3 )c

-(CH

2 2

-N

(CIICH

3

CH

/3 (C (CH2 3 -N CH 3 Di hydrochlori.Ie 178-180 (Et 2

O)

Dihvdrochlori de 1H 0 130-135 2 (.iPrl, Or 2 Dihydroc hiori de 250 (dec) (1190) Di thydrorI Ii br i, (EL 0) D i hy d roch or i d e 147 (acetone, 11,0 1/L1 Dihyd rochlori de 11120 114 2 0 (iPrOll, Et 2

O)

Dihydrochloride 11120 S1-89 (Et 2 0) Dihlydroch or idee (Ft,O)

CH

/3

CH

3 C H

-(CH

2

N/

(C92) 2

-N

34 1 44516 A 18 36 37 38 39 44573 A 44574 A 44575 A 44576 A 44749 A C H5 (CH2)3

CR

eli 3 Dihydrochloride 96 0 C (Et 2 O0) Di y d ro hi. orid e 155oC (Et 2 O/iPr0H) Di hydrochloride 182 0

C

(EtCH Dihydrochi oride 150-155 (Et 2 O0) Dihydrochioride 194-196 0

C

(E t 2 o)

-(CH

2 -NO 144750 A C H

(CHR

2 )4 /2 C Fumarate 121-3 0 C (Et 2 0) tion with an acid in accurdance with a known process.

19- 41 42 43 44 46 44768 A 447o9 A 44770 A 44786 A 44791 A 44814 A o 11 -(CH CH 253 CH 3 Cif3

C

2 2 UrN Fumarate 182-4 0 C (Ft 2 D h y droc 1 1or ide 191 0 C (Et 9 o) Dihydrochiori 1e (1Hl)0) 168C (Ft- 2 0) Difumarate 138-1400C (Etl.)) 1)1hyd rot hior i de (0.511 175-6 0 C (Ft,0) Difumara Le 140-40C (Et 2 0)

H

if K(l )2 20 44832 A 44862 A 49 1 44887 A

H

H3

F

H3C C"3 3 i 3 /1 t 44907 A 44908 A 44914 A 44915 A

CH

/if3 -(Cui).NF -l 2 C3uj 3 Cli(Cff 3 2 -(CH 2 3

N

Cif (Cl 3 2 CH Cif 13 /3 C C- CH 2 2 CH(CH 3 2

CH(CH

3 1 3 cI 3 -CH 2 C-CH N\~ CHl Cu -(CH 2 3 N N-CH 3 Dihydrochiori de 5f1120) 165 ~C (Et 2 O0) Trihydrochi oride 111 2-49-251 0

C

(Et 2 O0) Dihyrdroch I or de (1.5 52 0) 78-82 0 C (i0 Difumarate 51400) 173-4.C (Et 2 0) Di hydrochloride 114-6 0 C (Et 2 0) Dihydrochl oride 180-5 0 C (Et 9

)O)

Trihydroclil oride 145-150 0

C

(Et 2 O/iPrOH) 21 44916 A 44963 A 44964 A C; o o Q,~ C CC o ,C C' Q 000 00 57 1 44965 A

H

F

H 3C CH3 3 H 3 CH 3 0

X

CH (C C U 2 3 3 N I l 2 H5 -(CUi 2 )3 (CH 2 3 N CH 2CH3 CH 3 (CHU)3

CH

3 (Cli 3 N CH 3 it 11 Dihydrochioride 165-70C (iPrOH/Et 2 O0) Dihydrochloride (1H 2 0) 155-6-C (acetone) Difumarate Fumarate (Et Di h ydroc hior ide 820C (Et 2 O0) Puma rate 1230C (Et 2 O0) Di hydrochloride (0.51-12 0) 21000 E t 2 0) 58 144967 A 0. 0 0O 0 59 1 45001 A 45015 A 22 o 0 a 00 0 0 0 0 0 0 0, 0. o 0 0 0 0 0. 0 0,0' 0~0, 0 0 0 0 o 00 0 00 00 00 63 64 65 66 45016 A 45018 A 45023 A 45030 A 45035 A 45038 A

II

H

11

II

-(CH 2 )3 MICH 3

(C

2 3 CH 3 Di hyd roc hiori1(1 (0.511 207-8 0 C (EtI)) Dihydrochl oricle (0.51 5 2 0) 16)5-7 0 C 2 O0) Ilihydroc hl1or ut- 2013-240 0

C

(h 2 IDifumarate I 38-1/60 C Di hy droc hi oride (0.511 222-5-C (Et.

0 0) Trihenii rumarato 1 29-i30 0 c (pt~0) Itf I 23 45043 A 67 68145079 A 'C ~C C, ~C 0 ('CC 00 o 'C C, 0 69 71 72 73 45080 A 45088 A 45107 A 45108 A 45125 A

H

N~3 /CH 3 Cl Cl C-C H N, 3 if3 H C CH 3 /i fI I I It fII III t Trihenrifumarate 102-3 0 C (Et 2 0) Di hydrochloride (1H 2 0) 130-2 C (Pt 2 0) Dihydrochloride (0.511 20) 228 0

C

(EL 2 0) Trihemifumarat' 125-6 0 C (Et 2 0) Fumarate 114 0 C (Et 2 0) Monohydrochion le (1H 2 0) 202 0

C

(Et 2 0) Difumarate I 32-:3 0 C (Ft 2

CH

-(CH 2 )2 /3

CH

3 .(CH 2 2N CH 3

CH

3 -(Cf92 4 N Cif 3 24 45137 A 45154 A 45190 A 44813 A CH 2

H

if

CH

C H3 CH3 -4C H 253 C 3 3 CH 3 -CH 2 Monohydrochioride 183 0 C (Et 9

O)

Difumarate 126-7 0 C (Et 2 O0) Difumarate 5H 2 0) Dihydrochioride 246-8 0 C (Et 2 O0) D ihy droc hior ide 125-6 0 C (Et 2 O0) Dihydrachloride (0.5H12 0) 245 0

C

(Et 2 0) 44833 A I H 44839 A -CH 2-

.N

25 44840 A 44856 A 44863 A

IE

I.E

~-CH.

-(I

2 2

-/N

Dihydrochlor de (311,2 0) 219-220(' JL D)i hydrochl o ride 225- W'C (E 2 0) bi hydroc hl i ido

CH

2 CH 2-/N 83 1 44864 A 84 86 44902 A 44903 A 44904 A

H

2 2 Dthydrorh3 ut LI! Di hydrochi ori de (0.51190) 183"('

(F

2 D ihydrochioni de 200-2 0 C ME,110) Di hy ciroc hlo r i d (111 20) 133-5TC (E

-CG

2 c 26- 44905 A H 88 1 44906 A 189 44913 A 00 0 0 CO 1 44911 A 3 -(CH 2

N_

-(CUI

2 2

F

(CH

2 2

/PN

H CH -C 2 H -(CHU 2 2 H CH 2 H (CU 2 2 Dihydrochloride 5H 2 0) 12200 (Et 2 O0) Dihydrochloride (11120) 173-C (Et 2 0) Monohydrochioride 1710C (Et 2 0) Mon ohy d roc hioride 22100 (Et 2 O0) Monoiydrochlori de 150-C (Et 2 0) Fumarate 14800 (Et 2 O0) Fumarate 147-80C (Et 2 Dihy drochi arid e (111 20) 2110C Et 2 0)

I

44912 A 44966 A 44968 A 44998 A I t t I I I I I 27 145002 A H 96 1 45106 A

H

c-Clu 3 Ci

H

3 i 84 4 0 3 I 0 0 0~ o -I 4 44 4044 40 404000 0 0 0 0 97 45124 A 98 45122 A 99 45123 A 100 45169 A 101 45185 A

H

2 CH 2

-N

Dihydrochioride (21-1 2 0) 94C (Ft 2 0) DihydrochlIor ide 137 0 C 1)1h yd ruchi (rid C MonohlydroclioriI 250 0 C (Et 2 Mono h y dr o h 1840C Et 2 O0) Di hydrochloride 201-40C (iPrOH-,/FEtOlI) Base (111,,0) 163 0 C (Ftl0) I. I 28 1021 45221 A 103 104 105 106 107 45253 A 45240 A 45239 A 45255 A 45264 A (CUi 2 2 CH 2- (Gli 2 3 No Dihydrochioride 207-9'C (iPrO-) Monohydrochioride 160 0 C (Et 2 O0) Dihydi n)chloride 191-2 0 C (Et 2 O0) Dihydrochioride 227-9 0 C (Et 2 Monohydrochioride 5H 9 200-1 0 C (Et 2 O0) Dihydrochloride 221-3 0

C

(iPrOfI/Et 2 0) 44 4 4 44 4 4 4 a 44

I

AH Oxalat 108 45258 A 11 -(CH 2 3 -NH 170-17 N (aceto iPrOI isopropanol; PrOl propanol; EtOlM 95 95' ethanol; Et 2 0 anhydrous ethyl. ether; O~r 2 0 isopropyl ether e 2 0

C

ne) 29 EXAMPLE 109: 2-[(3-Aminopropyl)amino]-5-methyl-4-phenylthiazole dihydrochloride (SR 44514 A) A) 3-N-Boc-aminopropionitrile 56 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 500C. A solution of 46 g of dicarbonic acid bis-tert.-butyl ester (Boc 2 0) 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 o"o o carbonate and then with sulfate buffer of pH 2. The S 15 solution is dried over magnesium sulfate and the solvent is evaporated off. The residue (38.8 g) crystallizes.

o B) 3-N-Boc-aminopropylamine 20 g of the above product are dissolved in a mixture of 400 ml of water, 40 ml of aqueous ammonia o and 50 ml of ethanol. Raney nickel is added and the mixture is hydrogenated at ordinary temperature and o 0 a oo pressure.

.o .O After the catalyst has been filtered off, the 0 25 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 chloride in 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 0

C.

Weight: 8.3 g; 104-105 0

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.

100-110 0

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 109-D but varying the bromine derivative used: EXAMPLE 110 2-[(3-Aminopropyl)amino]-4-(4-fluorophenyl)- 1 31 thiazole (SR 44886 A) isolated in the form of the fumarate (0.51120). 162-4 0

C.

EXAMPLE 111 2-[(3-Aminopropyl)amino]-4-(2,4,6-trimethylphenyl)thiazole (SR 44949 A) isolated in the form of the fumarate. 163-4 0

C.

EXAMPLE 112: 2-[N-Methyl-N-(pyridyl-3-methyl)amino]-4-(2,4,6trimethylphenyl)thiazole oxalate (SR 45206 A)

CH

R

1 H; R 2 -C11; R CH R 4 -112

N

Cl13 A) N-Methyl-N-(pyridyl-3-methyl)thiourea 24.6 ml of plvaloyl 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 +40C. The mixture is stirrud for 3 hours at +4 0 C and 25 g of 3-methylaminomethylpyridine are.

then added dropwise so as to keep the temperature between 0 and +4 0 C. The temperature is allowed to rise to 20 0 C'and the mixture is stirred for 15 hours at this temperature. It is evaporated in vacuo and the 20 residue is taken up in 100 ml of concentrated hydrochloric acid. The solution is heated at 95°C for 1 Shour. 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. 119-120 0

C.

32 B) SR 45206 A A mixture of 3.6 g of the thiourea prepared above, 6 g of 2,4,6-trimethylphenacyl 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 anU 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 I 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 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 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.

160-1 0

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 S R it 3 R3

N

Melting point 4- 4 0 -CH 3 C CH (CH

)NI

C11 /H 3 \<N-CH 3 174-5'C 40-4'C 141-3'C B) The compounds I in Table 4 are obtained from these different thioureas by following the procedure of Example 112-B.

I

34 TABLE 4 35 EXAMPLE 118: 2-(2-Morpholinoethylamino)-4,5-dihydronaphtho[1,2-d]thiazole dihydrochloride (SR 44273 A) 3.66 g of N-benzoyl-N'-(morpholinoethyl)thiourea are refluxed in 17.5 ml of a 2.5 N solution of sodium hydroxide under a nitrogen atmosphere for minutes. After cooling, concentrated hydrochloric acid is added until the pl is 7. A solution of 3 g of 2-bromo-l,2,3,4-tetrahydronaphthalen-l-one in 20 ml 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 methylene chloride/methanol mixture (95/5 vol/vol).

After evaporation of the solvents, the oily residue is taken up in ether and the hydrochloride is precipitated in ether. It is filtered off and recrystallized from an isopropanol/95 0 ethanol mixture.

255-257 0

C.

EXAMPLES 119 TO 124: The products of formula collated in Table 5 are obtained by following the procedure of Example 118 but varying the bromine derivatives and/or the benzoylthioureas.

36 TABLE 6 (Gil)NH (CHl 2

~N

m 2 nR 7 Ex. SR code R Salt no. no. M-n 6 -N (solvent) 119 44317 A 3 2 -N 0 Dihydrochioride 217 (iPr-Oi/EtCHl C9 11 5 Dihydrochloride 120 44323 A 3 2 170 C 2 H 5 (iPr0Hi/Et 2 0) U~ hydrochloride 121 44326 A 3 3 0.5f 2 0 192 (iPrOHi/iPr 2 O0) GIl H Dihydrochioride 122 44327 A 3 3 1H12 0 198 Gif 3 (Et 2 0) Dihydrochioride 123 44392 A 3 3 0 245 dec (Et,,0) C 2H 124 44393'A 2 2 -N \0.5H12 0 181 2 5 (Et 2 0/Pr0Hl) 37 EXAMPLE 12 2-[(2-Diethylaminoethyl)amino]-9-nitro-5,6-dihydro- 4H-benzo[6,7]cyclohepta[l,2-d]thiazole dihydrochloride (SR 44411 A) The procedure of Example 118 is followed using N-benzoyl-N'-(3-diethylaminopropyl)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.

192-195°C (isopropanol/95' 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 1 and M 2 receptors.

The M 1 -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-methylscopolamine H-NMS). The selectivity of the products of the invention with respect to the M 1 and M 2 sites was determined by studying their in vitro interaction with 3 Z and 3H-NMS firmly bound with a high affinity with H-PZ and NMS firmly bound with a high affinity 38 to rat hippocampus membranes and smooth guinea-pig ileum muscle, respectively.

Methodologies A) Testing for affinity for the Ml-type muscarinic cholinergic receptor The interaction of the molecules with the M type 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 p 1 of a 5% rat hippocampus h-omogenate in an Na21PO 4 buffer (50 rmM, pfH 7.40) are incubated for 2 hours at 4 0 C in thL, presence of 3'1-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 uM atropine sulfate. The 50% inhibitory concentration (IC 50 is determined graphically. (Ref.: J.D.

Watson, W.R. Roeskoe and H.T. Yamamura, Life Sci., 1982, 31, 2019-2029.) B) Testing for affinity for the M 2 -type muscarinicholinergic receptor The interaction with the M 2 -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 l) of a 0.625% smooth guinea-pig ileum muscle homogenate in mM IIEPES buffer 2-(2-hydroxy-4-ethylpi perazin-1yl)ethanesulfonic acid containing NaCI (100 mM) and MgCl2 (10 mM) (final pll: 7.5) are incubated for I ~2_1 39minutes at 30 0 C in the presence of 3H-NMS (85 Ci/ mmol; final concentration 0.3 nM) and increasing concentrations of the test products. The final volume is 1 m] 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. Hai--mcr et al., Nature, 1980, 283, 90-92; E.C. Hulme et al., i ol. Pharmacol., 1978, 14, 737-750.) Results Table 6 indicates the affinities of the products of the invention for the M 1 and M 2 receptors. The results are expressed as 50 per cent inhibitory concentrations (IC 5 0 i.e. the concentration (in pM) which induces the displacement of 50% of the tritiated ligand bound to the membrane receptors. The IC50 3 for H-PZ displacement represents the affinity for the

M

1 receptor; the IC50 for 3H-NMS displacement represents the affinity for the M 2 receptor.

Also, the next column of the table indicates the ratio R of the IC50 values for the M 1 and M 2 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.

40 TABLE 6 Product 3 H-PZ(M 1 3 H- I S (~I 2 1c 50

(M)

no. IC 50 piM IC 50 PM R 50 C 5 0 M 1 SR 44284 A 8 40 SR 44286 A 6 100 16 SR 44318 A 3.4 38 11 SR 44323 A .1.7 8,5 SR 44326 A 2.2 >100 SR 44327 A 1.9 38 SR 44345 A 1 710 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 SR 44393 A 2,7 42 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 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 SR 44451 A 6 80 13 SR 44465 A 2.6 40 SR 44467 A 1.5 I 38 41 SR 44468 A 1.2 22 18 SR 44469 A 2.6 60 23 SR 44488 A 1.7 34 SR 44489 A 0.3 2 6 SR 44490 A 1.5 25 16 SR 44491 A 0.8 8.5 SR 44492 A 3.6 28 8 SR 44493 A 1.6 45 28 SR 44494 A 0.8 80 100 0/ SR 44514 A 0.5 100 200 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 o 0 SR 44575 A 7 100 14 SR 44749 A 1.8 26 14 0 SR 44769 A 2 30 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 SR 44906 A 2.4 100 42 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 SR 44964 A 0,9 28 31 SR 44965 A 1,2 60 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 SR 45030 A 1.60 80 SR 45106 A 3 100 33 Oxotromorine 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 affini t y for muscarinic cholinergic receptors, with a marked specificity for the M 1 -type central receptors.

IN VIVO PHARMACOLOGICAL STUDY Pirenzepine (PZ) is a specific antagonist of the M 1 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 or orally after solubilization in distilled water or suspension in a 5% solution of gum arabic. The control

I

43 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 or 30 minutes before a direct injection of pirenzepine into the right striatum of the mouse at a dose of 1 pg in 1 pl 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 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.

25 The 50% effective dose (ED 50 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 (ED 50 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 3 reference products have been reported.

44 TABLE 7 44244 A 44284 A 44285 'A 44286 A 44318 A 44323 A 44326 A 44327 A 44345 A 44346 A 44347 A 44372 A 44373 A 44374 A 44392 A 44393 A 44411 A 44421 A 44435 A 44467 A 44493 A 44494 A 44514 A 44573 A 44749 A 8 8 3 3 3 1 0.03 1 0.3 3 3 3 0.20 3 1 2.50 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 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 Pilocarpine 1 a a 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 invent on 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

I

46 release of acetylcholine caused by N-methyl-D-aspartic acid (NMDA) on sections of rat striatum Lehmann and SB. Scatton, Brain Research 1982, 252, 77-89).

Finally, the acute toxicity was determined for 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 was noted for 24 hours following administration of the product. The 50% lethal dose (LD 5 0 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 LD 5 0 (mg/kg) i.p.

no.

SR 44244 A 250 SR 44273 A 100 SR 44284 A 450 SR 44286 A 200 SR 44345 A 200 SR 44347 A SR 44372 A SR 44373 A 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 can be used as -47 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 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 phalrmaceutical 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 he 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 48 a- 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 d ispersants 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 t.o 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 thiozole derivatives of the general forniulc: RI R3 R 4 R in which R1 and R 2 each independently represent hydrogen a C 1 C 4 alkyl group a phenyl group or a phenyl group monosubstituted or polysubstituted by one or more halogen atoms, C 1 C 4 alkyl groups, or by C 1 C 4 alkoxy, nitro or hydroxyl groups; or one of the groups R 1 and R 2 denotes hydrogen and the other represents a naphthyl group a benzyl group an o<-dimethylbenzyl group a cyclohexyl group a biphenyl group a thienyl group or an adamantyl group; or alternatively R 1 and R 2 taken together, represent a group: (Ci 2 )M RS in which the phenyl group is bonded to the 4-position of the thiazole and the group (CH 2 )m to the 5-position, and in which m represents an integer equal to 2 or 3 and R 5 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 1 or R 2 denotes hydrogen, the other is different from H or methyl R 3 represents hydrogen or a C 1 C 4 lower alkyl group and jI:)"a Rq represents: a group: R. U 7 in which A 1 denotes a linear or branched C 2 C 5 alkyl group and R 6 and R 7 taken independently, represent hydrogen, a C1-C alkyl group or a C 3 -CG cycloalkyl group, or alternatively RG and R7, taken with the nitrogen atom to which they are bonded, from a

5-membered or 6-membered heterocycle selected from a morpholino group, a pyrrolidino group a piperazino group which may be substi- tuted on the nitrogen atom by a C 1 -C 4 alkyl group, or a piperidino group, a group: A 2 in which A 2 denotes a group (CH 2 where m 0, 1, 2 or 3, which substitutes the pyridine ring in the 3- or 4-position; a group: -A 2 CH 3 in which A 2 is as indicated above; or a group: 3Nc 8 v in which R 8 denotes a C 1 -C 4 alkyl group; R or alternatively the substituent -N-R 4 represents a group in which R is as indicated above; with the proviso that when R represents a group N N R8, if R 1 represents hydrogen or a C 1 -C 4 alkyl group, then R 2 is different from a C 1 -C 4 alkyl group C1 or a cyclohexyl group and also their addition salts with pharmaceutically acceptable mineral or organic acids. 2. Compounds as claimed in claim 1 in which R 4 represents a group: R RJ -A -N 7 R 7 in which A 1 denotes a linear or branched C 2 C 5 alkyl group and R 6 and R 7 taken independently, represent hydrogen, a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group, or alternatively R 6 and R7' taken with the nitrogen atom to which they are bonded, form a or 6-membered heterocycle selected from a morpholino group, a pyrrolidino group, a piperazino group which may be substi- tuted on the nitrogen atom by a C 1 -C 4 alkyl group, or a piperidino group. 3. Compounds as claimed in one of claims 1 or 2 in which R 4 represents a group: A 1 -N R 7 in which Al denotes a linear or branched C2-C 5 alkyl group R 6 and R7 taken with the nitrogen atom to which they are bonded, form the pyrrolidine, piperidine, morpholine groups or a piperazine group which may be substituted on the nitrogen atom by a C 1 -C 4 alkyl Sgroup, 4. Compounds as claimed in claim 1 in which R 4 represents n group: -A2, in which A 2 denotes a group (CH 2 where m 0, 1, 2 or 3, which substitutes the pyridine ring in the 3- or 4-position. Compounds as claimed in claim 1 in which R 4 represents a group: -A 2 C 3 in which A 2 is as defined above.

6. Compounds as claimed in one of claims 1 to 4 in which R 1 and R 2 each independently denote hydrogen; a C 1 -C 4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstitued by one or more halogen atoms C 1 -C 4 alkyl groups, nitro groups or hydroxyl groups; or one of the groups R 1 and R2 denotes hydrogen and the other represents a naphthyl group; a benzyl group; an e, dimethylbenzyl group; a cyclohexyl group; a biphenyl group or an adamantyl group; with the proviso that if one of the groups R 1 or R 2 denotes hydrogen, the other is different from-H or methyl.

7. Compounds as claimed in claim 6 in which R 1 and R 2 each independently represent hydrogen; a C 1 -C 4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstituted by one or more chlorine or fluorine atoms, methyl groups or by C 1 -C 4 alkoxy, nitro or hydroxy groups.

8. Compounds as claimed in one of claims 1 to 5 in which R 1 and R 2 taken together, represent a group: S2A, (CH{9; 53 in which the phenyl group substitutes the thiazole in the 4-position and the group (CH 2 )m substitutes the thiazole in the and in which m represents an integer equal to 2 or 3 and R 5 denotes hydrogen or a nitro group.

9. A process for the preparation of the compounds of the formula I, wherein a substituted thiourea of the formula: f N C N -R' S in which R 3 has the meaning indicated above and R' has the same meanings as R 4 except in cases where R 4 contains a primary or secondary amxie, in which case R' 4 denotes the group corresponding to R 4 in which any 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: 2R CH C R 1 r 2 Br 0 or with the corresponding alpha-brominated carbonyl derivative in which the carbonyl group is protected in the form of an acetal, to give the compounds of the formula or optionally, converted to salts thereof. Pharmaceutical compositions containing, as the active principle, a compound of the formula or one of its pharmaceutically acceptable salts in combination with a pharmaceutically acceptable vehicle.

11. Pharmaceutical compositiors as claimed in claim 8, containing from 20 to 500 mg of active principle. r I--i

12. A compound as claimed in claim 1 substantially as hereinbefore described with reference to the examples as specifically set forth herewith.

13. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the examples. DATED this 20th Cylv of March 1991 SANOFI Patent Attorneys for the Applicant: F.B. RICE CO.