NZ207453A

NZ207453A - 1-phenyl-2-azole-ethylaminocarbonyl derivatives and pharmaceutical compositions

Info

Publication number: NZ207453A
Application number: NZ207453A
Authority: NZ
Inventors: A Stutz; H Egger
Original assignee: Sandoz Ltd
Priority date: 1983-03-11
Filing date: 1984-03-09
Publication date: 1987-09-30
Also published as: PH24667A; DE3408127A1; PL146072B1; AU571494B2; GB2136801B; FR2542315A1; KR890000377B1; DK149784D0; CA1242723A; CH655103A5; GR81869B; ZA841782B; DK149784A; FR2542315B1; IT1199085B; SE8401321L; IT8447817A0; GB2136801A; PL246600A1; KR850006386A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £07453 Priority Date(s): 11.3 Complete Specification Filed: Class: KZl/.Mfi.Zf.?,. At « '3 osep iSar Publicstion Dsto: •«•■••••■••••••••••■•» P.O. Journal, No: /300 HO DRAWINGS NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NOVEL AZOLES, PROCESSES FOR THEIR PREPARATION AND THEIR USE */We, SANDOZ LTD., 35 Lichtstrasse, CH-4002, Basle, Switzerland, a Swiss Body Corporate, hereby declare the invention for which £ / we pray that a patent may be granted toxxx/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by la) 207453 NEW AZOLES. PROCESSES FOR THEIR PREPARATION ANO THEIR USE The present invention concerns l-phenyl-2-azole-ethylaminocarbonyl-derivatives, processes for their production, compositions containing them and their use as pharmaceuticals e.g. as anti-mycotics and as agrochemicals e.g. as fungicides. In particular the invention concerns compounds of formula I Rj and Rg each represent independently an optionally substituted aliphatic cycloaliphatic, heteroaryl or aryl group or Rj may also represent hydrogen, Rg and R^ each represent independently hydrogen, halogen, nitro, an optionally substituted aliphatic group which is optionally attached via S, 0, SO or SOgt or optionally substituted phenyl or phenoxy and X represents N or CH; in free form or in the form of acid addition salts thereof. More particularly the invention concerns compounds of formula I wherein Rj and Rg each represent independently, alkyl# cycloalkyl, cycloalkyl-alkyl, alkenyl or optionally substituted aralkyl, aralkenyl, heteroaryl or aryl or may also represent hydrogen, Rg and R^ each represent independently, hydrogen, halogen, nitro, optionally mono- or poly-halogen or-phenyl substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or optionally substituted phenyl or phenoxy, and X represent N or CH;in free form or in acid addition salt form. Preferred compounds of formula I are those CH, -CH-N-C-R, wherein 207453 wherein Rj represents hydrogen or alkyl, R2 represents alkyl, cycloalkyl, cycloalkylalkyl or alkenyl or aralkyl, aralkenyl, heteroaryl or aryl each of which may be unsubstituted or mono-5 or poly-substituted by halogen, cyano, trifluoromethyl, lower alkyl, lower alkynyl, lower alkoxy, optionally acyl bearing lower amino, alkylamino or dialkylamino, cyclic amino optionally containing a second heteroatom and optionally acylated, phenyl, phenoxy or heteroaryl whereby any cyclic amino, phenyl, phenoxy, lower alkynyl or heteroaryl optionally present 0 as a substituent may itself in turn be substituted by a further group as Rg' whereby Rg' has the same meaning as Rg, R3 and R4each represent independently hydrogen or halogen and X represents N or CH;in free forrn or in acid addition salt form. Alkyl moieties present in or as substltuents preferably contain 1 to 5 10, especially 1 to 7 carbon atoms. Lower alkyl groups contain 1 to 4 carbon atoms, lower alkenyl and alkynyl 2 to 4. Bridging alkyl groups contain e.g. 1 to 4 preferably 1 or 2 carbon atoms, bridging alkenyl groups may contain 2 to 4 especially 2 carbon atoms. Cycloalkyl preferably contains 3 to 6. Aryl preferably stands for phenyl. Heteroaryl !0 preferably contains 5 or 6 ring members and may represent e.g. pyridyl or thienyl. When Rg stands for unsubstituted aryl this may be e.g. phenyl or naphthyl. Unsubstituted aralkyl and aralkenyl are preferably phenalkyl and phenalkenyl respectively. Heteroaryl contains preferably 5 or 6 ring members and as heteroatoms one or more sulphur or nitrogen atoms and stands !5 for e.g. thienyl or pyridyl. Aryl, aralkyl, aralkenyl and heteroaryl may also be mono- or poly-substituted. Examples of suitable substituents are halogen such as chlorine, bromine, iodine and fluorine; C-j^alkyl especially methyl; amino which may optionally be substituted by one or two alkyl, especially methyl, groups, in particular dimethylamino; or 30 phenyl. A cyclic amino group, which may contain a second heteroatom e.g. nitrogen; or a heterocycle may each also serve as substituents. All these substituents (on Rg) may in turn be further substituted by the substituent groups mentioned above. 2"7453 -3- Rg and R^ may be for example halogen, mono- or poly-, halogen or phenyl-substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or optionally substituted phenyl- or phenoxy; preferably halogen or hydrogen. 5 A particular compound group is that wherein in formula I R.j and Rg ieach independently represent alkyl, cycloalkyl, cycloalkyl alkyl, aralkyl, alkenyl, aralkenyl, heteroaryl or aryl whereby heteroaryl and aryl may be optionally substituted, orRj may also represent hydrogen, R3 and R^ each independently represent hydrogen, halogen, nitro,optionally 10 mono- or poly-halogen substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or optionally substituted phenyl or phenoxy,and X represents N or CH;in free form or in acid addition salt form. The compounds of formula I may be prepared according to the invention 15 by acylating a compound of formula II o N 11 CH2 - CH - NH *3 4 wherein Rj, R^, and X are as defined above. The reaction may for example be carried out in conventional manner by reacting a compound of formula II with the acid halide of the appropriate R2 bearing group in a solvent such as e.g. an organic or 20 inorganic base which may at the same time act as an acid binding agent, such as pyridine and optionally with addition of an acylatlon accelerator such as 4-dimethyl aminopyridine. The reaction may also be carried out 2074 5 3 -4- 90G-9373- by reacting a compound of formula II with an active ester of the R2 bearing acid. The reaction can thus for example be carried out with a pyr1dyl-2-th1olester 1n an Inert solvent such as a dl-lower alkyl carboxyllc acid amide such as dimethylformamlde at room temperature. and recovered 1n free form or 1n the form of an acid addition salt. The starting materials of formula II are In part new and may be prepared by a) when Rj 1s other than hydrogen especially alkyl, converting a compound 10 of formula III 5 The end products may be Isolated and purified In conventional manner CH2 - C » 0 III to the corresponding Schiff's base of formula IV IV CH2 - C = M}' which 1s then reduced, or b) when R, 3 hydrogen reacting a compound of formula V o N CH2 - CH - Y V 207453 -5- £9(K9d23~ with an azide e.g. UN^ and reducing the compound of formula VI thus obtained o N CH, whereby 1n the formulae Illto VI; X, Rg and R4 are as defined above, Rj* has the same meaning as Rj except for hydrogen and 1s especially alkyl and Y Is halogen especially chlorine. These processes are carried out In conventional manner e.g. as described In the examples. The products may be Isolated and purified In conventional manner or directly further reacted as appropriate. The intermediates of formula III and V and the acylatlng agents are known or may be prepared analogously to knowm methods and/or analogously to the examples hereinafter. The compounds of formula I exhibit chemotherapeutic, 1n particular anti-mycot1c activity as Indicated In vitro on mycelial forms of Candida albicans in series dilution tests analogous to J. van Cutsem et al. (Mykosen, 24, 596-602, 1981) at concentrations of ca. 0.05 to 12.0 ug/ml and 1n vivo against 1ntravag1na1 Candida albicans Infestions in rats following systemic, peroral use at dosages of ca. 1 to 25 mg/kg animal body weight. 207453 -6- The compounds are therefore indicated for use as pharmaceuticals particularly as antl-mycotics. An Indicated suitable daily dosage for use as an anti-mycotic is from 70 to 2000 mg. If desired this may be administered in divided doses 2 to 4 times a day in unit dosage form containing about 17.5 to 1000 mg of the compound or in sustained release form. The compounds may be used in free base form or In the form of chemotherapeutlcally acceptable acid addition salts e.g. as the hydrochloride, hydrogen fumarate or naphtha1in-1,5-disulfonate. Such salt forms exhibit the same order of activity as the free base forms. The compounds may be admixed with conventional chemotherapeutlcally acceptable diluents and carriers, and, optionally other exciplents and administered orally, topically, 1.v. or parenterally 1n such forms as tablets, capsules, creams, tinctures or injectable preparations. Such compositions also form part of the invention. The Invention therefore also concerns a compound of formula I or a chemotherapeutlcally acceptable acid addition salt thereof suitable for use as a chemotherapeutic agent, in particular as an anti-mycotic agent. The compounds of the invention 1n free form or in agriculturally acceptable salt or metal complex form are also suitable for combatting phytopathogenic fungi. This fungicidal activity can be demonstrated i.a. in in vivo tests against Uromyces appendiculatus (bean rust) on runner beans as well as against other rust fungi (e.g. Hemileia, Puccini a) on coffee, wheat, flax and ornamentals (e.g. pelargonium, snapdragon); and against Erysiphe cichoracearum on cucumber as well as against other powdery mildews (e.g. E. graminis f. sp. tritici. E. gram. f. sp. hordei, Podosphaera leucotricha, Uncinula recator) on wheat, barley, apple and vines. Preferred substituent meanings are for R1 = a) hydrogen or b) lower alkyl, especially methyl for Rg = a) straight chain or branched alkyl especially with 1 to 7 carbon atoms b) aralkyl especially phenalkyl which may be optionally substituted c) aralkenyl especially phenalkenyl d) heteroaryl preferably with 5 or 6,ring members and S and/or N as heteroatom(s) e) unsubstituted aryl especially phenyl or naphthyl f) aryl (especially phenyl) mono- or poly-substituted by halogen, lower alkyl, amino or dialkylamino g) aryl substituted by phenyl which itself may be mono- or poly-substituted by halogen, lower alkyl, amino or dialkylamino h) aryl substituted by a cyclic amino group which may contain a second heteroatom e.g. nitrogen and which itself may be substituted by amlnoacyl (including mono- or dialkylamino), aracyl, alkanoyl, aralkyl, or alkyl, 207453 o -8- i) aryl substituted by heteroaryl j) aryl substituted by alkynyl which itself may be substituted by aryl, for R3 and R4 independently a) hydrogen 5 or b) halogen, 3 for X ■ a) N b) CH. Especially preferred are combinations of the particular substituent meanings mentioned hereinbefore. 10 A particularly preferred compound group is that comprising compounds of formula I wherein R-j represents hydrogen Rg represents C^alkyl, unsubstituted phenyl or naphthyl, unsubstituted heteroaryl with 5 or 6 ring members and S or N as heteroatom(s), 15 unsubstituted or halogen substituted phen-(C-|_4)-a1ky1, unsubstituted or halogen substituted styryl, phenyl mono- or poly-substituted by halogen, lower alkyl, or dialkylamino, phenyl substituted by phenyl itself optionally substituted by halogen, lower alkyl or dialkylamino, phenyl substituted by a cyclic amino group which may contain as a second 20 heteroatom nitrogen and which itself may be substituted by phenalkyl, phenacyl, phenyl, amlnoacyl (including mono- or di-alkylamino) or alkyl, heteroaryl substituted phenyl or phenalkynyl substituted phenyl, Rg and R^ each represent independently hydrogen or halogen and X stands for N or CH;in free base form or in the form of an acid 25 addition salt. Particularly preferred within this group are compounds wherein Rg is substituted phenyl. 0 The following examples illustrate the invention, temperatures being in degrees celcius. /'V -7AUG1 2074 5 -9- |90O-$3?3 Example 1 : N;Pivalo^]-l;^214-d1chloroghen^l];2;(lH-imidazo]-l-^l]-eth^lamlne 1 g of 1-(2 f 4-d1ch1oropheny 1)-2-(1H-imi dazo1-1-y1)et hy 1 amine are dissolved in pyridine, mixed with 470 mg plvaloylchlorlde and if desired 5 1-equivalent of 4-dimethylaminopyrldlne and stirred at room temperature until completion of reaction (ca. 1 hour). The solvent as removed by rotation under vacuum, the residue partitioned between water and methylene chloride and the organic phase washed, dried and evaporated under rotation. The crude title compound 1s purified by crystallisation 10 from isobutyl methyl ketone/dilsopropylether and is obtained as colourless crystals, m.p. 84-88°. Example 2 : N;[f;i^;Chloroghen^l2benzo^l]-l-(2t4-dichlorogheny12-2-[lH-!(DiJ!§22!;!:¥]]S£!2¥l25iOS 1.6 g of 4-(4-ch1orophenyl)benzo1c acid pyr1dyl-2-th1olester and 15 1.26 g of l-(2,4-d1ch1orophenyl)-2-(1H-1m1dazo1-1-y1)ethylam1ne are stirred at room temperature with 50 ml of dimethylformamlde until completion of reaction (ca. 1 hour). The solvent 1s removed under vacuion and the residue partitioned between methylene chloride and aqueous NaHCOg. The organic phase is washed, dried and concentrated under 20 vacuum and the residue crystallised from ethanol. Colourless crystals are obtained m.p. 246-250°. The following compounds may be obtained analogously to Examples 1 and 2. Ex. Ri R2 R3 R4 X m.p. 3 H -C(CH3)3 , 2-CI 4-Ci N 139-140° 4 CHj - M - 2-Cl 4-C1 N 144-145° 5 H 2-C1 4-C1 N 218-220° 6 H /—x C1 -\\ //-C1 2-CI 4-CI CH 188-191° - 10 - 207.4 5 Ex. R1 R? *4 X ID* p ■ 7 ch3 oh, 2-c1 4-cl ch oil 8 h 2-ci 4-cl ch 170-173° 9 h /—\ QJ ~~\\ // 3 • • h h ch 195-196° 10 h / ~~" \ p —\\ // h h ch 195° 11 12 h h II H -cm '— ^2 \\ // • «w • h h h h ch ch 205-206° 166-167° 13 h -(ay2-\w> • h h ch 151-152° 14 h -CH(CH3)2 h h ch 191-194° 15 h 1 L II •^>53 h h ch 152-154° 16 ch3 /'=\ c, —\\ //-a 2-CI 4-Cl ch 157-158° 17 h —// ^ cm, v=/ 3 2-CI 4-Cl ch 214° 18 h -11 1! s 2-CI 4-Cl ch 180° 19 h 2-CI 4-Cl ch 219° 20 h 2-CI 4-Cl ch 144° 21 h rt_C7HX5 2-CI 4-Cl ch 105° 22 h • ^ ^ • _// \\_// \\ / \ - / • i • «• • 2-CI 4-Cl ch 151° 23 h - // \\- p v=/ 2-ci 4-Cl ch 173° 2074 53 - 11 - Ex. K1 R2 *3 R4 X m.p. 24 H W-N 3 \=/ xCH3 2-CI 4-Cl CH 228-233° 25 H -£$-a 2-CI 4-Cl N 237-240° 26 27 H H -c (ch3) 2.//™n\—ci 1 ll^l 2-CI 2-CI 4-Cl 4-Cl CH CH 162-165° 162-167° 28 H —// \\—J V / 2-CI 4-Cl CH 228-235° 29 H -// \\—Br \—/ 2-CI 4-Cl N 241-244° 30 H • -// W-// w \=/ \=/ 2-CI 4-Cl N 265-268° 31 H -!/ —Br \ — / 2-CI 4-Cl CH 199-206° 32 H I? fli 1 2-CI 4-Cl N 205-209° 33 H _// x\—// \\-ci V— / N — / • ■MM • » • 2-CI 4-Cl N 250-252° 34 H O1 A 1 1 i 'J' 1 2-CI 4-Cl CH 90-95° <3*3 •» 1 w -// W-N N N \ — / \ / \ « —« • —« l| "OH 1 Q Ul3 CO 35 36 H H 2-C1 2-C1 4-Cl 4-Cl CH CH 110-112° 146-160° 37 H _// \\. // \\—CI \=/ \=/ H H CH 207-214° 38 H . it . H 4-Cl CH 216-219° 39 H -// W-Cl \— / H 4-Cl N 181-186° 207/f. 12- Ex. R1 R2 *3 R4 X m.p. 40 41 H H —It \\-ci / *^C1 •—• • •; v. -// \\-rf N \x A \-/ \-/ • 0 2-C1 2-C1 4-Cl 4-Cl CH CH 120-126° 115-125° 42 H —1/ \\-Cl \ — / 2-CI 6-C1 CH 85-87° 43 H -// \\-// w \=/ \—/ 2-CI 6-C1 CH 90-93° 44 H _ //""/7"\\- ci \— / \—. / • • • — • 2-CI •6-C1 CH 195-196° 45 H .;/ \\j< {)-// v. \—! \ / \—/ » » • • • 2-C1 4-Cl CH 223-226° 46 H 2-C1 4-Cl CH 240-245° | N M R - Spectra Ex. Spectra 1 6.8-7.5 (m, 6H); 6.4 (dbr, NH)j 5.56 (qua, J = 6.5 Hz, 1H); 4.4 (d, J = 6.5 Hz, 2H); 1.18 (s, 9H). 6 7.1-7.8 (m, 5H); 7.0 (s, 1H); 6.84 ($, 1H); 5.75 (qua, J = 6.5 Hz, 1H); 4.48 (d, J - 6.5 Hz, 2H). 7 6.9-7.7 (m, 6H)j 5.5 (dd, J * 9 u. 6 Hz, 1H)j 4.9 (dd, J * 9 u. 14 Hz, 1H)j 4.4 (dd, J = 14 u. 6 Hz, 1H); 2.75 (a, 3H); 2.02 (s, 3H). The required starting materials may be obtained as follows: 207453 -13- «0CP9373^ A) l-(2.4-D1chloropheny1)-2-(lH-im1dazol-l-v1)ethyl amine (for examples 1,2,6,8, 17 to 24, 26 to 28, 31, 34 to 36, 40, 41 and 45) 17.6 g of l-(2,4-d1chlorophenyl)-2-(lH-1m1dazol-l-y1)chloroethane are stirred for 2 hours at 90° with 3.8 g of lithiumazlde 1n dimethylformamide, 5 Water is then added, the solvent largely removed under vacuum, the residue \ partitioned between water and methylene chloride and the organic phase * washed, dried and concentrated under vacuum. The crude l-(2,4-dichloropheny1)-2-(1H-im1dazo1-1-y1)az1doethane (Rf value in TLC Identical with starting material, albeit with strong 10 IR band at 2100 cm"^) is hydrogenated in a hydrogenatlon apparatus under normal pressure with 1 g of Pd/C (10X) and glacial acetic acid as solvent. The solvent is then largely removed and the residue diluted with water. The acid aqueous phase is shaken with methylene chloride made alkaline with caustic soda solution and again extracted with methylene chloride. 15 This organic phase 1s washed, dried, concentrated and after conversion to the dihydrochlorlde the title product obtained as crystals (ethanol/ ether m.p. 227-240°). NMR: 7.2-7.55 (m, 4H); 7.08 (t, J»lHz, 1H); 6.94 (t, J«lHz, 1H); 4.72 (dd, J*8 + 4Hz, 1H); 4.08 (AB- part of an ABX-System, 14 Hz, 20 JAX » 4 Hz, JBX » 8 Hz, 2H); 1.2-1.9 (br, NHg). B) 1-(2.4-dichloropheny1)-2-(lH-1,2,4-triazo1-l-yl)ethy1am1ne (for Examples 3,5, 25,29, 30, 32 and 33) Analogous to A), m.p. 107-110°. C) N-Methy1-1-(2.4-d1chlorophenyl >2-(lH-imidazo1-l-vDethy1am1ne 25 (for Examples 7 and 16). a) 2.4-01ch1oro-a-(1H-im1dazo1-1-yl)-N-methy1acetophenonimlne 18 g of a- (1H-Imldazol-1-y1 )-2,4-d1 chl oroacetophenone and 30 ml of a 30% alcoholic methyl amine solution are heated together for 16 hours at 90° 1n an autoclave. The result is concentrated and the crude Schlff's 30 base directly further reacted. / 2074 «? 3 -14- 90<M3W^ b) N-Methyl-l-(2.4-d1chlorophenyl)-2-(lH-1midazol-l-yl)ethylam1ne 18.9 g of crude 2,4-d1chloro-a-(lH-1m1dazol-l-y1)-N-methylacetophenon-1m1ne are dissolved 1n methanol mixed with a drop of alcoholic methyl-orange solution and alcoholic hydrochloric acid added until the colour 5 changes. Following addition of 4.44 g of NaCNBH^ stirring is carried out for 1 hour at room temperature and pH 3-4 (after two further additions of alcoholic hydrochloric acid). The mixture is then concentrated under rotation, the residue partitioned between methylene chloride and aqueous NaHCOg and the organic phase dried and concentrated. The residue 1s 10 chromatographed over silica gel (methylene chloride/ethanol « 9/1) to obtain the title compound as an oil. NMR: 7.44 (m, 2H); 7.33 (m, 2H); 7.08 (m, 1H); 6.9 (m, 1H); 3.8-4.5 (ABM-System, JAB « 14 Hz, = 4 Hz, iJBM = 8 Hz, 3H); 2.25 (s, 3H); 1.6-2.1 (br, NH). 15 D) N-Methy1-l-(2.4-dichloropheny1)-2-(lH-l,2,4-triazol-l-yl)ethylam1ne (for Example 4) Analogous to C), m.p. 71-72°. NMR: 7.96 (s, 2H)); 7.2-7.5 (m, 3H); 4.1-4.6 (m, 3H); 2.26 (3, 3H); 2.0 (br, NH). 20 E) 4-(4-Chlorophenyl)benzo1c acid pyridyl-2-thiolester (for Example 2) A mixture of 4-(4-ch1oropheny1)benzo1c acid, 10.4 g of triphenylphos-phlne and 8.8 g of 2,2'-d1thiod1pyridine 1n 80 ml of methylene chloride 1s stirred for 2 hours at room temperature. The solvent 1s then removed 1n vacuum, the residue dissolved In a little ethanol and mixed with ether 25 until cloudy. Shortly thereafter crystallisation begins. The title compound is obtained following suck1ng-off and drying as colourless crystals, m.p. 153-160°. 2074 5 3 -15- WOWS" P) i-(4-carboxypheny1)-4-cH methylcarbamoylp1perazlne (for Example 35) a) 1-(4-Ethoxycarbony1phenylM-dimethylcarbamoylpiperazire 2.04 g of dlmethylcarbamoylchlorlde are added dropwlse to a solution of 4.4 g of i-(4-ethoxycarbony1pheny1)p1peraz1ne in chloroform warmed to 50° and the 5 resulting mixture refluxed for 2 hours. The solution is removed under vacuum, the residue mixed with 60 ml of aq. 30% NaOH and the resulting solution stirred for ^2 an hour at room temperature with 200 ml of toluene. The organic phase is separated, washed, dried and evaporated. The residue is purified by silica gel filtration (methylene chloride/ 10 ethanol ■ 9/1) and the title compound obtained as colourless crystals, m.p. 79-83°. b) 1 - (4-Carboxyphenyl )-4-dimethyl carbamoyl pi perazl ne 2.4 g of l-(4-ethoxycarbonylpheny1)-4-d1methy1carbamoy1p1peraz1ne are refluxed for 3 hours in a mixture of 70 ml of ethanol, 8 ml of water and 15 0.8 g of NaOH. The reaction mixture Is then acidified, shaken with methylene chloride, the organic phase dried and evaporated and the crude title compound thus obtained directly further reacted. G) 4-Benzy1-1-(4-carboxyphenyl)p1peraz1ne (for Ex. 34) a) 4-Benzy1-1-(4-ethoxycarbonylpheny1)piperazine 20 5 g of l-(4-Ethoxycarbonylphenyl)p1peraz1ne 5.9 g of KgCOj and 3.6 g of benzylbromlde are heated at 100° for 1 hour in dimethylformamide. The solvent 1s removed under vacuum and the residue partitioned between methylene chloride and aqueous NaHCO^.The organic phase Is washed, dried and evaporated under rotation and the crude title compound thus obtained 25 directly further reacted. R^»0.9 (eluant CHgClg/CgHgOH ■ 9/1). b) 4-Benzyl-l-(4-carboxyphenyl)piperaz1ne Analogous to Fb) m.p. 221-229°. H) 4-Benzoy1-1-(4-carboxypheny1)p1perazine (for Example 41) Analogous to G). 207 -16- >$90*927^ a) 4-Benzoy1-1-(4-ethoxycarbony1phenyl)p1peraz1ne m.p. 127-132°. b) 4-Benzoyl-1-(4-carboxyphenv1)p1perazlne Directly further reacted. 5 I) 1-(2.6-D1chloropheny1)-2-(lH-1midazo1-1-y1)ethy1amine (for Examples 42 to 44). a) 2,6—Pichloro-a-bromoacetophenone 50 g 2,6-D1ch1oroacetophenone are dissolved 1n 50 ml of abs. dlethylether and then mixed with 0.5 g of finely powdered aluminlumchloride. To this 10 mixture are added dropwise over 15 minutes with thorough stirring and ice-cool1ng 41.6 g of bromine. After complete addition the solvent is removed under vacuum and the semi-solid yellow mass directly further reacted. NMR (CDC12) 3 4.44 (2H, s, CHgBr); 7.3-7.5 (3H, m# subst.phenyl). 15 b) a-(1H-Imidazol-1-yl)-2.6-dich1oroacetophenone 30 g of crude 2,6-dichloro-a-bromoacetophenone are dissolved 1n 50 ml of abs. dlmethylformamide mixed with 22.9 g of Imidazole and allowed to react for 24 hours at room temperature. For working up the reaction mixture 1s poured into about twice the quantity of sat. NaCI, extracted 20 with ethylacetate, the extract dried over sodium sulphate, the solvent removed on a rotary evaporator and the residue chromatographed over silica gel 60 (dlchloromethane/methanol/petroleum ether = b.p.60-80° = 7/1/4). A sticky, colourless oil results which 1s homogenous according to TIC. NMR: 5.15 (2H, s, CH2); 7.02 (1H, t); 7.14 (1H, t) + 7.58 (1H, t); 25 Im1dazo1e-r1ng; 7.40 (3H, s, subst. phenyl). 207453 -17- 9o0p93wt c) 2-(1H-Imldazo1-1-y1)-1-(2.6-di ch1orophenyl)ethan—1-o 1 20 g of a-(lH-Imidazol-l-yl)-2,6-dichloroacetophenone are dissolved In 100 ml of ethanol, mixed at room temperature and with thorough stirring with 2.95 g of NaBH4 and stirring continued for a further 4 hours at room 5 temperature. The working up proceeds by decomposition of excess hydride with a few drops of dilute HC1, dilution with water and removal of most of the ethanol under vacuum. The residue 1s shaken with dlchloro-methane and saturated NaHCOg, dried over NagSO^ and evaporated. Chromatography on silica gel 60 (dlchloromethane/methanol/petroleum ether ■ b.p. 10 60-80° = 7/1/4) yields colourless crystals m.p. 137-141°. d) 2-(1H-Imidazo1-1-y1)-1-(2.6-dich1orophenvl)-1-methanesulfonvloxvethane A solution of 12.8 g of 2-(lH-1midazol-l-yl)-1-(2,6-d1chlorophenyl)ethan-l-ol In 50 ml abs. dlchloromethane is mixed successively under 1ce-cool1ng with 5.03 g of triethylamine and 5.7 g of methanesulfonylchlorlde. After 15 5 hours' stirring, working up proceeds by shaking with dlchloromethane and saturated NaHCOg. After drying over Na2S04 the organic phase 1s concentrated under vacuum and the residue chromatographed over silica gel 60 (eluant as Ic)). A sticky colourless oil is obtained. NMR: 2.70 (3H, s, CHgSOg); 4.42 + 4.50 (2H, dq, AB- part of an ABX-System, 20 JAB * 14 Hz, CH2); 5,76 (1H, dd, X-part, JAX + JBX = 14 Hz, -CH0-); 6,97 (1H, t, J » 1 Hz); 7.10 (1H, t, J = 1Hz) + 7.51 (1H, t, J « 1 Hz): Im1dazo1e-r1ng; 7.20-7.45 (3H, m, subst.phenyl). e) 2-(lH-Imidazol-l-yl)-l-(2t6-dichlorophenyl)-l-azidoethane A mixture of 12.9 g of 2-(lH-1midazol-l-yl )-l-(2,6-d1chlorophenyl)-l-25 methanesulfonyloxyethane, 3.77 g of sodlumazlde and 2.45 g of Hthlumchlorlde 1n 25 ml abs. dimethylformamide 1s thoroughly stirred for 4 hours at 100°. The result 1s diluted with water, extracted with ether, </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 207453 -18- WfrWW the ether phase washed with saturated NaCI, dried over Na2S04 and concentrated on a rotary evaporator. The resulting colourless crystals (m.p. 45-49°) are further reacted without further purification. f) 2- (1H- Im1 d azo 1 -1 -y U-T4 (2.6-d i ch 1 oropheny 1) ethyl ami ne 7 g of 2-(lH-Im1dazol-l-yl)-l-(2,6-d1chlorophenyl)-1-az1doethane are dissolved 1n 70 ml of pyridine and mixed with so much water that 1t just remains clear. Hydrogen sulfide 1s then passed 1n for 30 minutes at 35-40° After a further 2 hours excess hydrogen sulfide 1s blown off with nitrogen the pyridine removed under vacuum and the residue taken up in 2N HC1 and finally shaken with dlchloromethane and 20% aqueous NaOH. The organic phase is washed with saturated NaCI dried over Na2S04 and evaporated. The colourless, sticky residue 1s directly further reacted. NMR: 1.96 (2H, b, -NHg); 4,42 (2H, d, J * 7 Hz, -CHg); 5,06 (1H, t, J -7Hz, -CH); 6,97 (1H, b), 7.04 (1H, b) + 7.50 (1H, b): Imidazole ring; 7.10-7,40 (6H, m).;J) 1-(4-Ch1oropheny1)-2-(1H-i mi dazo1-1 -y 1)ethy1ami ne (for Example 38) Analogous to I).;m.p. (dlhydrochlorlde) 262-270°.;K) 1-(4-Ch1oropheny!)-2-(1H-1,2.4-tr i azo1-1-y1)ethyl ami ne (for Example 39) Analogous to I.;m.p. (dihydrochloride) 214-220°.;207453;-19-;WHAT WE CLAIM IS:;1. Compounds of formula I;N R;I;ch2 -ch-n-c-r2;wherein 3 4;Rj and R2 each represent independently an optionally substituted aliphatic, cycloaliphatic, heteroaryl or aryl group or Rj may also represent hydrogen, R3;5 and each represent independently hydrogen, halogen, nitro, an optionally substitu ted aliphatic group which is optionally attached via S, 0, SO or S02, or optionally substituted phenyl or phenoxy and X represents N or CH; in free form or in the form of acid addition salts thereof.;2. A compound according to Claim 1 wherein;10;Rj and R2 each represent independently, alkyl, cycloalkyl, cycloalkyl alkyl, alkenyl or optionally substituted aralkyl, aralkenyl, heteroaryl or aryl or Rj may also represent hydrogen,;Rj and R^ each represent independently, hydrogen, halogen, nitro, optionally mono- or poly-halogen or-phenyl substituted lower 15 alkyl, lower alkenyl, lower alkynyl, lower alkylthlo, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or optionally substituted phenyl or phenoxy, and X represent N or CH;1n free form or in acid addition salt form.;-20-;20745.3;3. A compound according to Claim 1 wherein R.| represents hydrogen or alkyl,;R2 represents alkyl, cycloalkyl, cycloalkylalkyl or alkenyl or aralkyl, aralkenyl, heteroaryl or aryl each of which may be unsubstituted or mono-or poly-substituted by halogen, cyano, trifluoromethyl, lower alkyl, lower alkynyl, lower alkoxy, optionally acyl bearing lower amino, alkylamino or dialkylamino, cyclic amino optionally containing a second heteroatom and optionally acylated, phenyl, phenoxy or heteroaryl whereby any cyclic amino, phenyl, phenoxy, lower alkynyl or heteroaryl optionally present as a substituent may itself in turn be substituted by a further group as;R2' whereby Rg' has the same meaning as R2,;Rg and R^ each represent independently hydrogen or halogen and X represents N or CH; in free form or in acid addition salt form.;4. A compound according to Claim 1 wherein;Rj represents hydrogen;R2 represents Chalky!, unsubstituted phenyl or naphthyl, unsubstituted heteroaryl with 5 or 6 ring members and S or N as heteroatom(s), unsubstituted or halogen substituted phen-(C-|v^)-alky1, unsubstituted or halogen substituted styryl, phenyl mono- or poly-substituted by halogen, lower alkyl, or dialkylamino, phenyl substituted by phenyl itself optionally substituted by halogen, lower alkyl or dialkylamino, phenyl substituted by a cyclic amino group which may contain as a second heteroatom nitrogen and which itself may be substituted by phenalkyl, phenacyl, phenyl, amlnoacyl (including mono- or di-alkylamino) or alkyl, heteroaryl substituted phenyl or phenalkynyl substituted phenyl,;Rg and R^ each represent independently hydrogen or halogen and;X stands for N or CH; in free base form or in the form of an acid addition salt.;5. A compound according to Claim 1 or 2 wherein in formula I;-7augi987s;20745.3;-21-;R^ and each independently represent alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkenyl, aralkenyl, heteroaryl or aryl whereby heteroaryl and aryl may be optionally substituted, or may also represent hydrogen,;R3 and R^ each independently represent hydrogen, halogen, nitro,optionally 5 mono- or poly-halogen substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or lower alkoxy or optionally substituted phenyl or phenoxy,and;X represents N or CH;in free form or in acid addition salt form.;6. A process for preparing a compound according to Claim 1 which 10 comprises acylating a compound of formula II;II;wherein Rj, R^, R^ and X are as defined in Claim 1 and recovering the compound obtained in free form or in acid addition salt form.;7. A process for preparing a compound according to Claim 1, substantially as hereinbefore described with reference to any one of the Examples.;8. A pharmaceutical composition comprising a compound of formula I according to Claim 1 or a chemotherapeutically acceptable acid addition salt thereof together with a chemotherapeutically acceptable diluent or carrier.;9. A compound of formula I according to Claim 1 or a chemotherapeutically acceptable acid addition salt thereof suitable for use pharmaceutical. A1* f-TAUGWfci 207453 -22- 10. A compound of formula I according to Claim 1 or a chemotherapeutically acceptable acid addition salt thereof suitable for use as an anti-mycotic. 11. A compound of formula I according to Claim 1 substantially as hereinbefore described with reference to the examples. DAI THIS DAY Of- GUsfuseJ- A. J. & SON AGENTS FOR THE APPLICANT^ </div>