NZ223845A

NZ223845A - Thiazole derivatives as medicaments

Info

Publication number: NZ223845A
Application number: NZ223845A
Authority: NZ
Inventors: Kathleen Biziere; Dominique Olliero; Paul Worms
Original assignee: Sanofi Sa
Priority date: 1987-03-12
Filing date: 1988-03-10
Publication date: 1990-11-27
Also published as: DE3878708T2; AU612350B2; YU49688A; IL85704A0; FR2612187A1; ES2053778T3; DK128688A; ZA881764B; FI881152A0; MA21207A1; DK170162B1; JPS63243080A; DD274028A5; NO881093D0; HU198916B; AR243515A1; EP0283390A3; EP0283390B1; IL85704A; TNSN88020A1

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £23845 cl^Vj m ! m 22 3 8 4 5 © Priority Date(s) i* Compieie Specification Filed: Class: <£csa D <*n.[iz. /.ekw 2 7 NOV 1990 Publication Date: " "r P.O. Journal, No: Class Cont: &Q71Q~££>1 i&£>j ' Patents Form No. 5 Class Cont* NEU ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION I y : v 1 ^ i :£'? win >: "« -'-uo PROCESS FOR OBTENTION AND PHARMACEUTICAL COMPOSITIONS //We, SANOFI/ a French company of 40/ Avenue George V 75008 Paris, FRANCE hereby declare the invention, for which X/vie pray that a patent may be granted to y&/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) - r~*tt£j±r -wytit. 0W..V 22 3 8 4 5 - 1 a- Novel thiazole derivatives active on the cholinergic system, process for obtention and pharmaceutical compositions . The present invention relates to novel thiazole 5 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 : 10 (I) in which : 15 - Rj and Rj each independently represent hydrogen ; a C^-C^ alkyl group ; a phenyl group or a phenyl group raonosubstituted or po1ysubstituted by a halogen atom, preferably chlorine or fluorine, by a C^-C^. alkyl group; preferably the methyl group, or by a C^-C^ alkoxy, 2o nitro or hydroxyl group ; or one of the groups and R2 denotes hydrogen and the other represents a naphthyl group ; a benzyl group ; an o^, c*T-dime thy 1-ben zy 1 group; a cyclohexyl group; a biphenyl group; a thienyl group or an adamantyl group ; or alternatively R^ and R2, 25 taken together, represent a group : /y (CH2) R5 2 m in which the phenyl group is bonded to the 4-position 30 of the thiazole and the group (CI^) to 5-position, and in which m represents an integer equal to 2 or 3 and R,. denotes hydrogen or (followed by page 2) 22 3 8 4 5 - 2 - a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups Rj or denotes hydrogen, the other is different from H or methyl; 5 - R3 represents hydrogen or a Cj - lower alkyl group; and - R ^ represents: - a group: 10 in which Aj denotes a linear or branched C2 - 0^ alkyl group and Rg and R^, taken independently, represent hydrogen, a'C^-C^ alkyl group or C^-C^cyclo-alkyl group, or alternatively Rg and R^ , taken with the nitrogen atom to which they are bonded, form a 15 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkyl-piperazine rings; - a group: in which A2 denotes a group (CH2)m, where m = 0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position; - a group: 22 3 8 4 - 3 - in which i s as indicated above; or - a group: in which Rg denotes a Cj - alkyl group; R, I ^ or alternatively the substituent -N-R^ represents a group: /A -N N- R„ V/ 8 in which Rg is as indicated above, and also their addition salts with mineral or organic acids. 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. According to a second aspect, the invention relates to a process for the preparation of the compounds of formula (I). 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 : h H2N - C - N - R'4 s in which has the meaning indicated above and R'^ has the same meanings as R^ except in cases where 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 Ht §>!>' %'>!• viri tit 2$\t m 'M © O 22 3 8 4 5 - 4 - which is resistant to hydrolysis in an alkaline medium, with an alpha-brominated carbonyl derivative of the formula : R - CH - C - R„ J- I II * 5 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 (1), and of converting the compound I to a salt, if desired, by a known process. 10 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 K If is hydrogen, this process can be represented by" the following reaction scheme: 0 S 15 "2N"R4 > "C" NH-C-NH-R, 1) NaOH > 20 2) R -CH-C-R 1 | L Br (I) 3 *"W' a'l ,!&■< 22 3 8 4 - 5 - Reaction of benzoyl isothiocyanate with the primary amine 1_ gives the substituted benzoylthiourea 2. In practice, the benzoyl isothiocyanate is 5 formed in situ by reacting benzoyl chloride with potassium thiocyanate in a solvent such as anhydrous acetone. A solution of the amine derivative _1. *n a suitable solvent, especially methylene chloride, is 10 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 15 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. 20 First of all, the benzoyl group 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 25 a solution of the bromine derivative 3 in a water-mis-cible 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 by the usual methods, the compound (I) is converted to a salt, if desired, by reac- 3 5 tion with an acid in accordance with a known process. i.wtnf'A* -TV"- *»>.•<«• V '«" ' ' '• *----- . . I, ■ - , I ( - «v * 22 3 8 4 5 In this process, if the bromine derivative _3 is not very stable or not readily available, it can be replaced with the corresponding dimethy1 aceta 1. Finally, if contains a primary or secondary 5 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. butoxycarbony1 group(Boc). ^he corresponding benzoylthiourea 2^ is obtained from the amine R^Nl^ 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 15 removal of the group Boc, leading to the compounds (I) 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 2o WEYL "Methoden der Organischen Chemie" 4th edition , vol. 4/5 p. 171-188-Georg Thierae Verlag. In the particular case where R^ represents a group : yRb O - Ai - 25 R7 in which at least one of the substituents Rg and R^ is hydrogen, the protected amine derivatives 1_ can be prepared from the aminonitrile RyNH-A^-CN. When treated (^) with the anhydride (Boc^O, this gives the aminonitrile 30 Boc-N-A' -CN, which, on reduction, leads to the corres- R7 ponding primary amine Boc-N-A' » in which A'^ r e- R7 presents A^ minus a methylene group. 35 In all cases, and particularly if the substituent R^ is other than hydrogen, the compounds (I) can be 'vj;. , ,, ..r-.". if'. : ' '" '"'- 1 ■ ■ "- .V.'" ' 22 3 8 4 5 H O - 7 - prepared from pivaloyl isothiocyanate according to the scheme: Ho S R I3 II / 3 (CH, ) ,C -CON'=C=S + H.S'-R. > (CH,),C-CO-NH-C-N J J 4 3 J \ R4 H-f- S R II I 3 -> H2N-C-N-R4 > (I) 5 Reaction of pivaloyl isothiocyanate with the amine 4_ gives the pivaloylthiourea j>. In practice, the pivaloyl isothiocyanate is formed in situ by reacting pivaloyl chloride with an alkali metal thiocyanate in an anhydrous solvent, such 10 as acetone, and at a moderate temperature (0 to 10°C). The amine 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 15 thiourea j6. This is converted to the compound (I) by reaction with a bromine derivative _3, as indicated previously. The non-limiting examples which follow will 20 provide a clearer understanding of the invention. EXAMPLE 1: 2-[(2-Diethylaminoethyl)amino]-5-phenylthiazole di-hydrochloride (SR 44318 A) A) N-Benzoyl-N'-(diethylaminoethyl)thiourea 25 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 22 3 8 4 5 - 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-diethylamino-ethylamine in 100 ml of methylene chloride is added 5 , 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. 10 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 15 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. 20 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 25 about 6. A solution of 2.48 g of alpha-bromopheny1-acetaldehyde 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 10% aqueous 30 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) 35 methylene chloride/methanol mixture, giving an oil 22 3 8 4 5 - 9 - (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 5 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 10 are obtained by following the procedure of Example 1-A but varying the amine compounds used. -.«5SSr.;-V-r; • -V - 10 - TABLE 1 22 3 8 s n CO - NH - C - NH - R, o o I v (CH.)« - N 0 22 V__/ /2H5 (CH2)3 - < C2H5 (C»2)3 - N, / \ CH„ CH. (ch2)3 - CCH2>2 " CCH2)2 - N /" V Physical constant M.p. = 119 - 120°C Oil, TLC: Rf = 0.51 CH2Cl2/MeOH 90/10 vol/vol M.p. = 67 - 69°C Oil M.p. = 98 - 99°C M.p. = 70 - 71°C ■ y. M- - 11 - « M H o o (ch2)2 - n (CH2)3CH3 (ch2)2 " N )CH2)3CH3 ^H(ch3)2 ch(ch3)2 (ch2)4-n/ c2h5 c2h5 (ch2)2 n I ch, (ch2}3" N\^yN" c"3 ch(ch3)2 (ch2)3 " < ch, I 3 y 3 ch2-c-ch2nx ch3 ch3 (ch2)3 - n ch(ch3)2 ch \h2ch3 ch, (CH2)3 ■ M.p. - 48 - 49°C M.p. = 93 - 94°C Oil M.p. = 65 - 67°C M.p. = 55 - 57°C Oil M.p, = 57 - 58°C M.p. = 73 - 75°C Oil M.p. = 72 - 74°C OoC^I - ZVl = 'd'W 3o6II ~ 811 = *d*w OoZ.VI - 9VI = *d*W 0o 6SI ~ 8SI = -d'W OoOOI - 86 = *d'H 3o£SI - 3SI = -d*H Oo8!7 - SV = *d'W ITO OoSe - le = -d-H OoSL - Pi * 'd'N ZCZH3) Z(ZH3) OOQ \ e 2 n - e(zh0) Va \ *v/ N - HD \ «h/ ,N - H\. 6h/ N c(zhd) Vh3) ZiZ\\0) r\ zi - m $ }$? k .--..< S-W» .■V'J^-'*-'*M*.4--^..^H.«.v„.w.., .■..~„_,r I,. >.- ' '" <■" ' ' ' ' ' %'-~l 22 3 8 4 5 - 13 - <cv3 -^y M.p. « 81 - 82°C <CH2>3 -<Q> M.p. = 118 - 120°C 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 5 and varying the oxohalogen derivative reacted therewith. ■ ,,........ ! - 14 table 2 22 3 8 4 5 Rx ,s. II T NH"R' o o Ex. sr Sa It no. code no. Ri r2 *4 M.p.°C (solvent) Dihydrochlor ide 2 44244 A H -o -(C«p2-/^ r\ 220-221 (iPr0H/Et20) Dihydrochloride 3 44284 A tt tt _(Ch2)3-N^O 216-217 (iPrOH) Dihydrochloride 4 44285 A ~Q H -(CH.)9-/~\) 2 v_y 264-265 (iPrOH/EtOH 95) 5 44286 A h -0 /C2H5 -(CH2^2-\ C2H5 Succinate 110-111 w (iPr0H/iPr20) 6 7 44345 A 44346 A tt tt H /»3 -<CH2V\ ch3 C2H5 -(ch2)3< C2H5 Dihydrochloride 181-182 (Et20) Dihydrochloride 0.5H20 143-144 \zrJ (acetone) - 15 - 22 3 8 4 44347 a h 44372 a ii 44373 a 44374 a h 44421 a h 44422 a h 44424 a h 44434 a -ch3 44435 a -0 w -CH„ CI -(ch2)3n c2h5 c2h5 (ch2)2N/ c2h5 C2HS •(ch2)3n c2h5 c2hs ■(ch2)3 -nx ch. / : ch, /C2H5 .(ch2)2-n^ c2h5 (ch2)2-n (ch2)3-n( . c2h5 .Cch2)3-n; >H5 \hs Dihydrochloride 199-200 (cyclo-hexane, Et20) Dihydrochloride 1H20 147-148 (acetone, Et20) Dihydrochloride 0.5H20 184-5 (acetone, Et20) Diraaleate 109-111 (iPrOH, Et20) Dihydrochloride 224-226 (iPrOH, Et20) Dihydrochloride 162-163 (iPrOH, Et20) Dihydrochloride 216-217 (iPrOH, Et20) Dihydrochloride 0.5H20 148-149 (iPrOH, Et,0) Dihydrochloride 0.5H,;0 167-168 (iPrOH, iPr20) J fi s f£i i m - 16 - 22 3 8 4 H o o 17 44436 A ii 18 44437 A -0 19 44438 A II 20 44451 A H 21 44465 A H 22 44466 A -0 23 44467 A -0 24 44468 A H 25 44469 A H -CH. {y och, -ch, -ch. "0~N°2 -CCH2)2N •(CH2)2-N. C2HS c2h5 c„h- /2 5 -(CH2)2-N \ n I \_ '2H5 •(CH2)2-N (CH^CH, (ch2)3ch3 /H3 -(CH3)3-N ch3 •(CH2)2 CH3 (CH2)3-N( ch3 FzH5 CCH2V\ 2H5 (ch2)2 C2H5 c2h5 Dihydrochloride 0.5h90 154-155 (Ec20) Dihydrochloride 193-194 (Et20) Dihydrochloride 0.5H20 190-195 (dec) (Et20) Dihydrochloride 141-142 (Et20, PrOH) Dihydrochloride 184-186 (dec) (iPrOH, Et20) Dihydrochloride 204-207 (dec) (iPrOH) Dihydrochloride 235-236 (dec) (iPrOH, iPr20) Dihydrochloride 196-199 (iPrOH, iPr20) Dihydrochloride 185-190 (dec) (iPrOH, Et20) I' . X'A ;'"' •ii^v''-T1^"',j^.;.,^.1-,^v;-r>'1" ,s-r; -> t,r' .' 22 3 8 4 ig I - 17 - I © 26 44488 a "0 27 44489 a It o 28 44490 a tt 29 44491 a It 30 44492 a tt 31 44493 a h o 32 44494 a h 33 44515 a O o f - • 34 44516 a h -CH, _A.ci -CH -(CH2)2 -N n i V- •(CH2)2-NV CH(CH ) / J - CH(CH3)2 •cch2)2 -n CH(CIL), ■tc»2)2-( • CH(CH3)2 (CH2)3Ch3 -(ch2)2"Nn CCH2)3CH3 -(ch2)3 -n /CH- -3 .(CH2)3-NX CH3 /C2H5 -<CH2V\ C2H5 (ch2)2-n Di hydrochloride 178-180 (Et20) Dihydrochloride 1H20 130-135 (iPrOH, iPr20) Dihydrochloride 250 (dec) (Et20) Dihydrochloride 1H20 93 (Et20) Dihydrochloride 147 (acetone, Et20) Dihydrochloride 1H20 141 (iPrOH, iPr20, H20) Dihydrochloride 1H20 114 (iPrOH, Et20) Dihydrochloride 1H20 88-89 (Et20) Dihydrochloride 1H?0 91-93 (Et20) 22 3 8 4 5 - 18 - -(C1,2>3-\ C2HS -(ch2)3-\ /CH3 CH. -(ch2)2-/~1) u -(ch2)s-n /CH3 -CCH2)3-Nf 3 -(ch2)4-n, fl*S \ C2H5 Dihydrochloride 96°C (Et20) Dihydrochloride 155°C (Et20/iPr0H) Dihydrochloride 182°C (EtOH 95/iPrOH) Dihydrochloride 150-155 (Et20) Dihydrochloride 194-196°C (Et20) Fumarate 121-3°C (Et20) *'»\ 1 yj« Sj>;* fs t< it m <*■> s o o 41 44768 a h 42 44769 a ch3 43 44770 a h 44 44786 a h 45 44791 a h 46 44814 a h - 19- /c2h5 -(ch2)3-Nx c2h5 ch, -(CH2)3-n/ " ch. It It -(CH2)2 N I ch, ch, -(ch2)3/ ch, -(CH2)2- k 22 3 8 4 5 Fumarate 182-4°C (Et,jO) Dihydrochloride 191°C (Et20) Dihydrochloride (1H20) 168°C (Et20) Difumarate 138-140°C (Et20) Dihydrochloride (0.5H20) 175-6°C (Et20) Difumarate 1A0-4°C (Et20) - 20 - 47 44832 a h 48 44862 a h 49 44887 a h 50 44907 a h 51 44908 a h 52 44914 a h 53 44915 a h H3C,^H3 h3c c,h3 '(ch2d3"n\ 7ch3 ch. •(ch-)_r/"y \J ch. ■(CH253NC chcch3)2 ch(ch3)2 fh3 ps CH2?-CH2\ ch3 ch3 chcch3)2 -(ch2)2n( chcch3)2 ck-\ ych3 i 3 si -CH2f-CH2N\ ch3 ch3 r\ •(ch.)_-n n-ch \J Dihydrochloridc (0.5H2< (Et20) (0.5H20) 165°C Trihydrochloride (1H20) 249-251°C (Et20) Dihydrochloride (1.5H20) 78-82°C (Et20) Difumarate (0.5H20) 173-4°C CEt20) Dihydrochloride 114-6°C (Et20) Dihydrochloride 180-5°C (Eto0) Trihydrochloride 145-150°C (Et20/iPr0H) 223845 - 21 - © 54 44916 a h o 55 44963 a A 56 44964 a h 57 44965 a h 58 44967 a A o 59 45001 a h w 60 45015 a 0 "c2h5 h3c i ch3 ch. -CCH2)3H \ H(CH3)2 c„h -CCH2)3N / 2 5 \hs •(0H2)3N VJ \ ch2ch3 ch„ (CH^/ ch. ch, / 3 -(ch2)3n^ ch„ tl ii Dihydrochloride 165-7°C (iPrOH/Et20) Dihydrochloride (1H20) 155-6°C (acetone) Difumarate 147-8°C (Et20) Fumarate (1H20) 226-8°C (Et20) Dihydrochloride 82°C (Et20) Fumarate 123°C (Et20) Dihydrochloride (0.5H20) 210°C (Et20) :i t 22 3 8 4 5 Dihydrochloride (0.5H20) 207-8°C (Et20) Dihydrochloride (0.5H20) 165-7°C (Et20) Dihydrochloride 238-240°C (Et20) Difumarate 138-140°C Dihydrochloride (0.5H20) 222-5°C (Et20) Trihemifumarate 129-130°C (Et20) • (:> ai 23 - 223845 l?® o o 67 68 69 70 71 45043 a 45079 a 45080 a 45088 a 72 73 45107 a 45108 a 45125 a 9 V H c-ch. "c2h5 c-ch. ft If ft II tt tt /H3 ■<CH2>2\ CH3 -(ch2)2nn ch, / 3 ch. ch3 (ch2)4/ ch3 Trihemifumarate 102-3°C (Et,0) Dihydrochloride (1H20) 130-2°C (Et20) Dihydrochloride (0.5H20) 228°C (Et20) Trihemifumarate 125-6°C (Et20) Fumarate 114°C (Et20) Monohydrochloride (1H20) 202 °C (Et20) Difumarate 132-3°C (Et20) 22 3 8 4 5 - 24 - 74 45137 a 75 45154 a 76 45190 a 77 44813 a 78 44833 a 79 44839 a CH, h H H3C^ch3 ch. H3c ch. c1l h3c l ch3 ch 3 CI CI h3cach3 ch. /CIl3 -<ch2)2nn ch3 ch3 -(CH^t/ c2»5 -(ch2)3n \ ch. ~C"2V it ii 'CVU Monohydrochloride 183°C (Et20) Difumarate 126-7°C (Et20) Difumarate (0.5H20) 116-8°C (Et20) Dihydrochloride 246-8°C (Et,0) Dihydrochloride 125-6°C (Et20) Dihydrochloride (0.5H20) 245°C (Et20) - 25 - 22 3 8 4 ci -CV A _CCH252-rrJ -cv 0 IP\ — ch - /' ^ -ch2-// nn -(ch2)2-fi -ch, Dihydrochloride (1H20) 219-220°C (Et20) Dihydrochloride 225-6°C (Et,0) Dihydrochloride (2H20) 111-2°C (Et20) Dihydrochloride (2H20) 237-9°C CEt20) Dihydrochloride (0.5H20) 183°C (Et20) Dihydrochloride 200-2°C (Et20) Dihydrochloride (1H20) 133-5°C (Et2Q) 22 3 8 4 5 -cch2)2-/v\ Dihydrochloride (1.5H20) 122°C (Et20) ,(C H2 Dihydrochloride •(ch2)2 <0VJ % -ch. • CCH2)2-// \ / -CH2-//\\ •(ch2)2- (1»20) 173°C (Et20) Monohydrochloride 171°C (Et20) Monohydrochloride 221°C (Et20) Monohydrochloride 150°C (Et20) Fumarate 148°C (Et20) Fumarate 147-8°C (Et20) Dihydrochloride (1H20) 211°C (Et20) - 27 - 22 3 8 4 5 (O) n 95 45002 a If If 96 45106 a h 97 45124 a V 98 45122 a h 99 45123 a h 100 45169 a h ch„ I2 101 45185 a b V c2h5 h3c ch3 ch, CI h ch, — ch jl \ II II ch2-/ \ o \=n Dihydrochloride (2H20) 94°C (Et20) Dihydrochloride 137°C (Et20) Dihydrochloride 213-6°C (Et20) Monohydrochloride > 250°C (Eto0) Monohydrochloride 184°C (Et20) Dihydrochloride 201-4°C (iPrOH/EtOH) Base (1H20) 163°C (Et,0) - 28 - 22 3 8 4 © 102 45221 a H o 103 45253 a H 104 45240 a H 105 45239 a H 106 45255 a H *o> 107 45264 a H o 108 45258 a H H3C 1 CH3 -CCHjJ ') - ch, -ch, -«h2,2-Q - ch, -(CH2)3 -o -(ch2)3-nh- Dihydrochloride 207-9°C (iPrOH) Monohydrochloride 160°C (Et20) Dihydrochloride 191-2°C (Et20) Dihydrochloride 227-9°C (Et20) Monohydrochloride (0.5H20) 200-1°C (Et20) Dihydrochloride 221-3°C (iPr0H/Et20) Oxalate 170-172°C (acetone) iPrOH = isopropanol; PrOH = propanol; EtOH 95 = 95° ethanol; Et20 = anhydrous ethyl ether; iPr20 = isopropyl ether 22 3 8 4 5 H H m m o - 29 - EXAMPLE 109: 2-[(3-Aminopropyl)amino]-5-methyl-4-phenylthiazole dihydrochloride (SR 44514 A) A) 3-N-Boc-aminopropionitrile 5 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 50°C. A O solution of 46 g of dicarbonic acid bis-tert.-butyl ester (B0C2O) in 100 ml of dioxane is then added with 10 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 15 solution is dried over magnesium sulfate and the, solvent is evaporated off. The residue (38.8 g) crystallizes. B) 3-N-Boc-aminopropylamine 20 g of the above product are dissolved in a 20 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 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. 30 C) N-Benzoyl-N1-(3-N-Boc-aminopropyl)thiourea A solution of 6.38 ml of benzoyl chloride in 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 35 for 5 minutes. r\ \ 1 22 3 8 4 5 - 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 5 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 10 100 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 15 3.37 g of the product obtained above are re fluxed 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 20 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. 25 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: 30 The following are obtained in the same way, starting from the substituted thiourea prepared in Example 10 9-C and following the procedure of Example 109-D but varying the bromine derivative used: EXAMPLE 1 10 2-[(3-Aminopropyl)amino]-4-(4-fluorophenyl)- M- m 22 3 8 4 5 fc - 31 - M "m thiazole (SR 44886 A) isolated in the form of the If fumarate (0.5Ho0). M.p.: 162-4°C. 1 O EXAMPLE 111 2-[(3-Aminopropyl)amino]-4-(2,4,6-tri- I i methy1pheny1)thiazole (SR 44949 A) isolated in the | f 5 form of the fumarate. M.p.: 163-4°C. EXAMPLE 112: G 2-[N -Methyl-N-(pyridyl-3-methyl)amino]-4-(2,4,6- trimethyIpheny1)thiazole oxalate (SR 45206 A) (i) rj = h; r2 =\ \*ch3; r3 = ch3' ch3 10 A) N-Methyl-N-(pyridyl-3-me thyl)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 15 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 20 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 25 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 30 ether and filtered off. After drying, 26.7 g of the expected compound are obtained. M.p.: 119-120°C. ^ i5®«? *ftC^fr?.7<c 22 3 8 4 5 - 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 5 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 10 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 15 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 20 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. 25 4.3 g of the expected product are obtained. M.p.: 160-1°C. EXAMPLES 113 TO 117: The substituted thioureas collated in Table 3 are obtained in the same way by following the procedure 30 of Example 112-A. wst"; •?*• v: 1 • -•'-' m - 33 - 22 31 TABLE 3 S >»R3 II ^ J H2N - C - N \ R, (C^ /R3 N \ R4 Melting point \-CH, V/ M.p.: 174-5 °C y 2H5 "N\ CH3 (CH2)3N/ CH3 M.p.: 40-4 °C /CH3 Xh M.p.: 141-3 °C o 5 B) The compounds I in Table 4 are obtained from these different thioureas by following the procedure of Example 112-B. m §i{ I - 34 - 22 3 8 4 5 TABLE 4 o Ex. no. SR code no. R1 R2 /R3 n Xr4 Salt isolated Melting point °c o 113 45215 A h 1 CI{2 1 H,C i CH, CH3 Monohydrochloride (1H20) 145-7°C (Et20) 114 45216 A 6 h II It Monohydrochloride 210-1°C (Et20) 0 115 45223 A h 1 c-ch, 6 II tt Dihydrochloride 231-2°C (Et20) /"""n 116 45191 A h h,c I ch, ch3 yC2H5 : -n ch, \ / 3 (ch2)3-n^ CH3 Oxalate 44-5°C 117 45257 A h II It : /Il3 "\Q^ Dihydrochloride 224-6°C (iPr0H/iPr20) 7 -'. r.M..: 22 3 8 4 5 o o - 35 - EXAMPLE 118; 2-(2-Morpholinoethylamino)-4,5-dihydronaphtho[l,2-d]-thiazole dihydrochloride (SR 44273 A) 3.66 g of N-benzoyl-N'-(morpholinoethyl)-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-1-one in 20 ml 10 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 15 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 20 precipitated in ether. It is filtered off and re- crystallized from an isopropanol/950 ethanol mixture. O' M.p.: 255-257 °C. EXAMPLES 119 TO 124: The products of formula (I) collated in Table 25 5 are obtained by following the procedure of Example 118 but varying the bromine derivatives and/or the benzoylthioureas. - 36 - 22 38 4 TABLE 5 Ex. no. SR code no. m n /*« -N Xr7 Salt M.p.°C (solvent) 119 44317 A 3 2 w s°2H5 Dihydrochloride 217 (iPrOH/EtOH 95) Dihydrochloride 120 44323 A 3 2 / "N\ C2»5 170 (iPr0H/Et20) Dihydrochloride 121 44326 A 3 3 11 0.5H20 192 (iPr0H/iPr2O) yPH3 "\ CH3 Dihydrochloride 122 44327 A 3 3 1H20 198 (Et20) -/A V/ Dihydrochloride 123 44392 A 3 3 0.5H20 245 dec (EtgO) 124 44393 A 2 2 AS -N C2H5 Dihydrochloride 0.5H20 181 (Et20/Pr0H) 22 3 8 4 5 EXAMPLE 12 5: 2-[(2-Diethylaminoethyl)amino]-9-nitro-5,6-dihydro-4H-benzo[6,7 ]cyclohepta[1, 2-d]thiazole dihydrochloride (SR 44411 A) 5 The procedure of Example 118 is followed using N-benzoyl-N'-(3-diethylaminopropyl)thiourea and 2-bromo-8-nitrobenzocycloheptan-l-one as the starting ma terials . The expected product is obtained in the same 10 way in the form of the dihydrochloride. M.p.: 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 15 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 20 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, 25 the cerebral cortex and the striatum, and also in the sympathetic ganglia. These binding sites can be 3 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-methyl- 3 30 scopolamine ( H-NMS). The selectivity of the products of the invention with respect to the and M2 sites was determined by studying their in vitro interaction 3 3 with H-PZ and H-NMS firmly bound with a high affinity r# Sp * _,.. 22 3 845 | - 38 - $ t? to rat hippocampus membranes and smooth guinea-pig ileum muscle, respectively. •WJS^ Methodologies A) Testing for affinity for the M^-type muscarinic 5 cholinergic receptor The interaction of the molecules with the M,- r> type muscarinic receptors was studied by in vitro measurement, on a rat hippocampus homogenate, of the displacement of tritiated pirenzepine from its specific 10 binding sites. Aliquots (10 jil) of a 5% (w/v) rat hippocampus homogenate in an ^£^0^ buffer (50 mM, pH 7.40) are incubated for 2 hours at 4°C in the presence 3 of H-PZ (76 Ci/mmol; final concentration 1 nM) and increasing concentrations of the test product. The 15 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 ^ 20 10 jiM atropine sulfate. The 50% inhibitory concentra- 'v>' tion (IC5Q) is determined graphically. (Ref.: J.D. Watson, W.R. Roeskoe and H.I. Yamamura, Life Sci., 1982, 31, 2019-2029.) B) Testing for affinity for the M2~type muscarinic 25 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-l-yl)ethanesulfonic acid containing NaCl (100 mM) and MgCl, (10 mM) (final pH: 7.5) - are incubated for 30 5 10 15 22 38 4 5 20 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, 1_4, 737-750.) Results Table 6 indicates the affinities of the products of the invention for the Mj and M2 receptors. The results are expressed as 50 per cent inhibitory concentrations (IC^q), i.e. the concentration (in jiM) which induces the displacement of 50% of the tritiated ligand bound to the membrane receptors. The IC,-,-. 3 for H-PZ displacement represents the affinity for the 3 M^ 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 IC^q values for the M^ 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. -Hi ■*«* m §t - 40 - 22 38 4 5 TABLE 6 O /"N Product no. 3H-PZ(Mj) IC50 ^ 3h-nms(m2) IC5o R = IC50(M2} ICgoCMp SR 44284 A 8 40 5 SR 44286 A 6 100 16 SR 44318 A 3.4 38 11 SR 44323 A 1.7 8.5 5 SR 44326 A 2.2 > 100 > 45 SR 44327 A 1.9 38 20 SR 44345 A I 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 444S1 A 6 80 13 SR 44465 A 2.6 40 15 SR 44467 A 1.5 38 25 ; ' r ;• M 1 - 41 - 22 38 45 o "**r .'I -! H) O 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 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 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 4° 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 *?s % Jvt f - 42 22 3845 o v 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 1.2 60 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 O to the invention have a strong affinity for muscarinic cholinergic receptors, with a marked specificity 5 for the M^-type central receptors. IN VIVO PHARMACOLOGICAL STUDY » 1 Pirenzepine (PZ) is a specific antagonist of the Mj central muscarinic cholinergic receptors. The intra striatal injection of PZ into mice induces rotatory 10 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 15 suspension in a 5% solution of gum arabic. The control - A3 - 22 3845 o 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 5 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.A ml per 20 g of body weight, 10 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 jig in 1 jil of solvent, according to the 15 method described by P. WORMS et al. in Eur. J. Pharmacol., 1986, 1^1, 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 20 the pirenzepine: 2nd to Ath, 8th to 10th and 13th to 15th minutes. Each treatment consists of 3 to A 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^q), 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 30 50% effective dose (ED^q) 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. {...•oc-ViSAK,-, 'law I '%) *)l,il i t I - 44 - 22 3 B 4 5 TABLE 7 nj/*1 Product no. Pirenzepine Pirenzepine antagonism antagonism ED50 mg/kg i.p. ED50 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 - 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 - 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 - 45 - 22 3 8 4 5 o o SR 44770 A . 3 SR 44792 A - 3 SR 44814 A - 0.2 SR 44839 A - 0.2 SR 448S6 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 10 10 * 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 22 3845 - 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 15 below. TABLE 8 O Product no. LD5q (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 A 60 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 20 the doses at which they are active. Consequently, the compounds (I) can be used as - 47 - 22 3845 drugs. The results indicated above make it possible to consider using the products according to the invention for treating degenerative syndromes associated with 5 senescence, and especially memory disorders and senile dementia. According to another of its aspects, the present 0^ Application therefore relates to pharmaceutical compo sitions which contain at least one of the compounds of 10 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 15 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, 20 powders, granules and solutions or suspensions to be taken orally, sublingual and buccal dosage forms, sub-cutaneous, intramuscular or intravenous dosage forms and rectal dosage forms. To achieve the desired effect, the dose of 25 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. 30 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 35 appropriate substances, or else they can be treated so </div>

Claims

<div id="claims" class="application article clearfix printTableText"> m © 10 15 20 O 25 V(7»2W*Nwnv*ww-«t~.U'^»iwtv\i««a«,<i!l<lMIW''W' 22 3 84! 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. 22384 - 49 - WHAT WE CLAIM IS: Mitt&XXlSC GKXIMEBXE3C:

1.

EstoWGit Hhiazole derivatives of the general formula:

R

R,

(I)

2

in which :

- R^ and Rg each independently represent hydrogen ; a alkyl group ; a phenyl group or a phenyl group monosubstituted or polysubstituted by one or more halogen atoms, C^ - C^ alkyl groups, or by alkoxy, nitro or hydroxyl groups; or one of the groups R^ and Rg denotes hydrogen and the other represents a naphthyl group ; a benzyl group ; an J., pC-dimethylbenzyl group ; a cyclohexyl group ; a biphenyl group ; a thienyl group or an adamantyl group; or alternatively R1 and R2, taken together, represent a group:

in which the phenyl group is bonded to the 4-position of the thiazole and the group (C^m 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 R^ or Rg denotes hydrogen, the other is different from H or methyl ;

- Rg represents hydrogen or a C^ - lower alkyl group ;

and

I

V«..„

, W-„!4,. ,,

223845

- 50 -

- R^ represents:

- a group:

05

in which denotes a linear or branched Cg - Cg alkyl group and Rg and R^, taken independently, represent hydrogen, a C^-C^ alkyl group or a C^-Cg cycloalkyl group, or alternatively Rg and Ry, taken with the nitrogen atom to which they are bonded, form a 10 5-membered or 6-membered heterocycle optionally containing a second heteroatom,

- a group:

15

in which Ag denotes a group (C^m' where m = 0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position;

I

ch3

in which Ag is as indicated above; or - a group:

q

R8

in which Rg denotes a alkyl group;

30

/

/ 6 - A1 - \

r7

- a group:

20

35

- 51 -

223845

N N - Rg

R<J I 3

or alternatively the substituent -N-R^ represents a group :

vy in which Rg is as indicated above; with the proviso that when -jj-r represents a group - N - Rg, if R^ represents hydrogen or a

C^-C^ alkyl group, then Rg is different from a alkyl group or a cyclohexyl group ;

and also their addition salts with pharmaceutical^ acceptable mineral or organic acids.

2. Compounds as claimed in claim 1 in which represents a group:

-v<

r7

in which A1 denotes a linear or branched Cg - Cg alkyl group and Rg and Ry, taken independently, represent hydrogen, a alkyl group or a C^-Cg cycloalkyl group, or alternatively Rg and R^, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom.

3. Compounds as claimed in one of claims 1 or 2 in which R^ represents a group:

/R6

- A1 - N

XR7

in which

A^ denotes a linear or branched Cg-C^ alkyl (group Rg and R^, taken with the nitrogen atom to which they're bonded, form the pyrrolidine, piperidine, morpholine or N-alkylpiperazine rings.

- 52 -

223845

*

4.

group:

Compounds as claimed in claim 1 in which represents a

<0

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.

5. Compounds as claimed in claim 1 in which represents a group:

N N I

ch3

in which Ag is as defined above.

6. Compounds as claimed in one of claims 1 to 4 in which R^ and Rg each independently denote hydrogen; a C^-C4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstitued by one or more halogen atoms alkyl groups, nitro groups or hydroxyl groups; or one of the groups and Rg denotes hydrogen and the other represents a naphthyl group; a benzyl group; an^i, c^-dimethylbenzyl group; a cyclohexyl group; a biphenyl group or an adamantyl group; with the proviso that if one of the groups R^ or Rg denotes hydrogen, the other is different from H or methyl.

7. Compounds as claimed in claim 6 in which R^ and Rg each independently represent hydrogen; a C^-C^ 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^-C^ nitro or hydroxy groups.

8. Compounds as claimed in one of claims 1 to 5 in which and R?, taken together, represent a group:

/\-

RS

\ , <CH2V

*'• w. *U. oUZXMiSMM I#**

223

- 53 -

in which the phenyl group substitutes the thiazole in the

4-position and the group (CH^)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.

9. ,A_.process for the preparation of the compounds of the as defined in claim 1

formula V, wherein a substituted thiourea of the formula:

b ■

H,N - C - N - R'

-i || 4

S

in which R^ has the meaning indicated above and R1^ has the same meanings as R^ except in cases where R^ contains a primary or secondary amine, in which case R'4 denotes the group corresponding to R^ 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:

R, - CH - C - R,

1 1 H 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 (I) , and wherein the compounds of the formula (I) are converted to salts, if desired, by a known process.

10. Pharmaceutical compositions containing, as the active as defined in claim 1 principle, a compound of the formula (I) / or one of its pharmaceutically acceptable salts in combination with a pharmaceutically acceptable vehicle.

11. Pharmaceutical compositions as f ctaiffred in claim io,

; ^*£7^—

containing from 20 to 500 mg of active principle.

L.

—.

n

- 54 s

223845

o o

05

12. A compound as claimed in claim 1 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.

10

15

O

35

sanofi

By bal;

Attorneys IN, SON & CAREY

</div>