BE645532A - - Google Patents

Description

  

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 EMI1.1
 



  Antholointhiquoo and method for pr <ptW <Antr, rtèsiquoe zut proadda pcur lr: .14
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 . The invention concerns 4, ... 18 do oation. disi3b sol. qua.ma1r .. de tortnul. l which have antb.1Id.ntb1qu activity. with regard to d. matode partsltts d .. mam # 1t'.r ... 1.: '
 EMI1.3
 
 EMI1.4
 In this formula and in the following ones, R is an alphitic hydrocarbon radical of 1 to 3 carbon atoms, and Xw are each an aliphatic hydrooarbon radical of 2 to 5 carbon atoms and each lum 'group comprises at least 4 carbon atoms.



  Aliphatic hydrocarbon radicals. of 3 or more carbon atoms may or may not be branched, saturated or unsaturated. The oa-
 EMI1.5
 tions in which R is a methyl radical have coefficients

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 EMI2.1
 Part1oul1re therapeutic # ent Interesting # * Salts of 4ilt11balôl cations. quaternary 4 <.fefaul <1 are prepared by condensation, in pr4sonot * IY # r bI.1quI, of a quaternary 2,6-lutidint salt containing a cation of formula II with about a equivalents of a & ' 'Minob <Mtld <hyd <de foraulo IIXO
 EMI2.2
 
Methanol is a suitable solvent as other lower alcohols can be used. The basic catalyst is advanced
 EMI2.3
 Tags: piperidint, pyrroid, ne, lx 1-igithylpyrrolidino ,, d1m4thyla = in.

   or an amine of comparable basicity and molecular weight.



  The salts of the dlstllbazolt <) uatemaiye <cations of formula 1 are highly colored solids which form intense red solutions. However, many of these salts (eg iodides) are
 EMI2.4
 almost entirely insoluble in water, and the aqueous phase in contact with the solid salt remains almost colorless. Salts which contain smaller anions such as the chloride anion are significantly more soluble.
 EMI2.5
 



  The anthel, irth.ue activity of the salts is linked to the distilbazole cation of Foraul I and the nature of the anion associated with this
 EMI2.6
 The cation is of secondary importance as long as it is lo1tphrmacolog1c acceptable and gives a salt having pharaaceutically acceptable physical properties. as obtained by condensation, the salts of
 EMI2.7
 Quaternary distilbasoles comprise the anion of the quaternary lutine salt of formula II. This anion advantageously corresponds to the reactive ester group X of the foraul's reagent R @ X used.

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 EMI3.1
 for quatemistr a, 6-1ut141n ..

   The anion is therefore generally a lodide ion, bromide, chloride, alkylsulfate or ht4.rooarbyJ.J \ J1lo- net # 00 = 0 M-tolUbMaUltonate'OR m4tnane.u1tonAtt, which has interesting X radicals * and we desire # $ Iranian linked to the quaternary lutidine 26 * cation can be exchanged through a double 4'0011 ... 'position.

   For example, if Bu must be the ethyl radical and if the ion must be an iodide ion or a <thy3L <ulftt $, I # iodurs 4'4thyl are used respectively. or 1 <Mifâtw 41'tb, tqu. to quaternize 2.g6-lutidine) and and iodide is prepared when chloride is desired., a double decomposition can be carried out by heating the iodide with hydrochloric acid, .. them in solution in the xdthancle Same as yesteryear associated with the cation 41.t11b & .ol. quaternary ry of formula 1 can be exchanged by double decomposition, for example with a sol such as a silver sol of the desired anion. In this way, anions such as lactate ions # citrate, soda tate and toithionate can give more soluble salts of ettiea d1ttilbltol.

   Conversely, a double ddoompositton with ... 1. soluble other anions .; horn ions. # bonAt., nuphtoates, 2 * hydroxy-3-naphthoate and naphthalene-sulfonateo, gives dittîlbazole tele having # solubility @ even more tk1 ...



  It was discovered that the .., 1. 41.t11 - .. 01, quaternary cations of formula 1 are particularly active with respect to ti1ndltro, YluB b8'11! (to. uri,), very resistant parasitic necatode of young rats. The activity towards this parasite is often an index of activity towards neaatodee doomically important parasites of ruminants, in particular sheep and bovids * Indeed, it has been observed in sheep that oon-f salts holding the cations of formula Z good activity with regard to H., qeM2nehljs e9ntQrts, Pi! 'i & app. and Trietgntrgngvlgs AII1 in the abomasum, with respect to 'fr1h!: trQn'Yllulpp. of '09D'rJ.I ct1ce1! from .'7aMTM8 PP # * from:

  tr2ngvl2j4u na2lllemma in the small intestine and with respect to Oceoohaoatoua venulosum

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 EMI4.1
 and of caâbtttîà ominâ in the large intestines Certain the of 4i.t11bllol. apparent "as the iodur. of l-Eethyl-2,6-bl -Ca-dlaéthyIaalnûit / ryl) pyridiniua, l'odur. 4 l.methyl-2,6 -, ..;. stthylasnotxy), yra .t l'104r. dt l.6.hyl-, 6-btr.-t-Yrolidirostyry.jY '"idiniua tent d'3 asur
 EMI4.2
 in particular to have a trbe-éliv4o activity in liétard. Natural infection of mice by Iloxyur4 âàmhâ ". JiH 2by.tLata which often indicates activity with regard to lb; Eero.M.u8 3 (," ", 'w $ Che fhomme. The first of 4ef1 6dàih W
 EMI4.3
 is also reported as 4 tantaotît with regard to natural 1nt80UOJW "4 'by various nematodes in the oh1en, the cat and # ît; J | monkey.

   The salts comprising the cations of formula I have
 EMI4.4
 high therapeutic coefficients for pinworms than these compounds, but much greater activity against 1D9 @ tr9UA r¯ '.. 8i and parasitic nîmatodes; economically important. sheep. The thdrapoutically effective dose is between 1 and 20 mg / kg of weight. For the treatment of ndmatodeo infections, the salts of the quaternary distilbazole cations of formula I can advantageously be administered orally, for example in the form of aqueous suspensions.

   They can be presented confessing a vehicle
 EMI4.5
 Pharmaceutically acceptable molecule in a pharmaceutical composition prepared by a customary method, such as 1. lanl "Fine salts and granules of the salts may contain diluents, dispersants and t.nI1o-Qot1t. if they can be used. presented in drink or drink in the form of a suspension in water, a syrup or an oil or a water-dane-oil emulsion, and in this case, of)! perfume *), preservatives, suspensions ,
 EMI4.6
 thickening and imulsifying agents can be added) they can be present in tablets and in this case binding and lubricating agents can also be incorporated;

     they can be presented in capsules or cachets containing a dry mixture or a suspension and in this case a suspending agent

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 can be incorporated finally it * can draw presented in the - = ru riture of the parasitized breast * The granules and the coapriaes can
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 be coated *.,;, '"The following examples illustrate the invention' # '#', r, t ,. D.Qb.nJn²1 ,. n, r Phosphoryl chloride (61.5 1, 0 # 4 mol.) 1 "slowly added all stirring, 5 to 10 = 1nut .. To cooled d1m'thYltO4 '(125 est'3) * After Additionna * 1 * ii-aethyl-JS-tt-propjrl * -
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 n111n. (60 bzz, 0.4 mole) is added or stirred and rotroidiounb for 10 minutes.

   The faction mixture is abandoned, tD4 & n '15 minutes at room temperature then heated k 100 * 6 poc4Mt 2 collision. The mixture is poured onto ice and brought to a µl greater than 11 by the addition of one. 50% aqueous solution 4'bydrQx14.
 EMI5.6
 of sodium (100 in). The product separates into an oil which is
 EMI5.7
 taken * in the ither and the ethereal phase is mecha * on earboaate
 EMI5.8
 potassium then filtered and evaporated * Distillation of the residue
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 gives ± .N.m'th11-.n-proP1lnobenzald'hYd '(58 g).



  Phosphoryl chloride (56 "0.36 mole) is added * with stirring, over time to cooled d1 = 4thyltormamid (93rd * 1-ethyl -! - n-propylan111ne (50 g, z mole) is This mixture is left at room temperature for 15 minutes and then heated for 3 hours at 100Co The mixture is poured onto ice and made basic by adding an aqueous solution to 0 of codl = (80) hydroxide. ca).

   The product and $ separates into an oil which is taken up in ether and dried.
 EMI5.10
 anhydrous potassium carbonate, after distillation, we obtain
 EMI5.11
 45 <of .i-'thyl.l.n.proP11am1nob.nza14dh1d 'pure *
 EMI5.12
 
 EMI5.13
 The others, a- # 11nob.nzaldehydl. are prepared by an in4L1-d1alkylan111n process. is mixed with an equimolecular amount of phosphoryl chloride previously added in excess d1m'thyltor = ac1de. The reaction mixture is heated for 2 to 3 hours at 100 ° 0, then placed on ice and left at a pH lupdr1eur to 11 by addition of an aqueous solution.

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 EMI6.1
 of sodium hydroxide.

   The product and separates an oil which is taken up in 4th.r, dried and distilled *, The properties of the aldehydes thus obtained are y <Ma <! <
 EMI6.2
 in the following table.
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  R L t L 8 ', 2.9t. 02 1M'tiAel \ odthyle n-propyl 1a9-191 '/ 15 aa 80% methyl isopropyl 166-168 "7 sa z methyl n-bUtYlt 185-1880 / 10 = 80; zdthyle isobutyl 170-173 * / 6 mm 80 ethyl n-propyl. 171-173 * / 7 mm 80% ethyl ally 173-175 * / 6 year n-propyla n-propyl 180-1820 / 6 ma 80%
 EMI6.4
 féDrnoJi9 ela de 2.6-luiine P're8.



  A ndlang of, b ... ut, 4lra (21 g, 0.2 = le) and n-pentyl iodide (90, bd, 45 sole) is refluxed for bzz hours in a metal bath at 1BO C After several or1ata1111.- tions in mixed alcohol / ether and todtont / ethor $ the 1-n-pentyl-2 6-dimdthylpyridinium iodide is obtained by melting colorless crystals (28 g, yield 45-5 ;), mp 115-117110.
 EMI6.5
 



  (the carbon / hydrogen analysis of this salt which probably contains
 EMI6.6
 a small amount of 2.6-lutidin hydrochloride is never setlsfatranta. It and behaves satisfactorily in condensations with -M5inobenzaldehydea and the product yields indicate that it has a purity of at least 70 to 80; :). Other useful quaternary 2,6-lutidine iodides are prepared in an analogous manner, such as Jl..to3.un ... ultonat. and i * thylaui, l.thyi aEe, -2, bdimthylpyridiniPst and 1-allyl-2 bromide # 6 dimethylpytidini = o 1-ethyl iodide .-, ditaëthy.pyridl.um (10 S) is dissolved in methanol (200 cat) and gaseous hydrochloric acid is passed through the solution until absorption of 20 C.

   The,
 EMI6.7
 solution is then heated in a steam bath. the major part

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 EMI7.1
 of the solvent being gradually removed by distillation. Galous hydrochloric acid in solution in <4thaMl (10% t 100 in 3) is then added and the process is repeated * the flask is placed under vacuum and heated in a steam bath to give a residue of DO 1 chloride. ..4-ethyl-2,6..d1m4thylpy: r1d1N-W aonvemt for the condensation with -1nobentad4hyd'l. l: lnarat10n 411 8¯1 & of quaternary diltiaz9 '.. S'1' From the p1pér1din.

   (2 Ma) is added 1 # 10dure 41 .. 1-.ethyl-26-diay3.pyridinium (2.7 gel, 0.01 mol) and ± &# m'th11 -! .. 1sopropylam1nob. nlaldÓhyde (45 gt 0 # 025 drowned) in solution in methanol (25 mp) and the mixture is re-heated for 24 hours, the product is precipitated by adding ether, isolated by tiltration, washed with cold water then with ether and r.cr1stal11, 'in a zdlango =' thanol / ether to give the 10du'l of l * thyl-2,6-bia- (R-- ' B! <Thylisopropylaainoetyyyl) -pypidiM !! t (5.8 g).



  A solution of 1,4-ethyl-2,6-4im'th, 19, r14in1 iodide.



  (2.7 9 # 0.02 $ mol) in methanol (25 = 3) containing pi- p4ridin <t (2 cc) is refluxed for 18 hours with, U-li-methyl "'li .... 180buty1 at41t1o.nzald; h) "d. (11.3 gb 0.062 mole).
 EMI7.2
 



  The product is precipitated by adding excess ether, filtered all vacuum, washed with excess cold water and with ether.
 EMI7.3
 and finally recreated twice in a methanol / ether mixture to give 1-ethyl-2,6-bis- (ji-K-flethyl-] l-1aobUty1am1no.tyryl) -pyridln1um iodide (5.4 9) pure.
 EMI7.4
 



  This iodide is treated with a suspension of chloride
 EMI7.5
 silver in methanol to give 1-ith71-2.6 chloride. bl s- (û Ji-a4thyl ± i8obutylafflina8tyryl) -pyridinius Unlike the corresponding iodide, which is practically insoluble, this chloride dissolves in water to give a red solution with a concentration of 0.005-0 , 01, 1-, thyl chloride ... 2, Ó-b1 .- {- d11thflaa1noltyr11) -
 EMI7.6
 pyridiniua. is prepared in an analogous manner and is identical

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 EMI8.1
 to the product obtained by condensation of 1-'tb71.a chloride, 6. d1m & thylpyr1d1n1um with .d1th11am1nobtnla1d.h, 4 .. This ohlur treated with silver 4 ethanerultonate similarly gives 1.-ethyl ethanesulfonate, 6 'b, r (, dütiylam, i. zastyrr pyridlnium.



  1.'thyl.2,6.41ta.1. Ethantoultonate, 1am1no. st1r11) -pyr1d1n1 (560 mg is dissolved in a mixture
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 of water (15 cc3) and a # 6thami (3 exa3. A solution of sodium naphthalene 2-sultonate (430 sg) in water (40 macaws) is added
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 slowly * A gelatinous mass becomes strong at the start of the addition and a red crystalline solid is then deposited.
 EMI8.5
 1-'thyl-2,6-bil-t-diÍthylamino.tyryl) -pyrid1n1u 2-sulfonate # obtained is recriotallized in a mixture of ethanol and ether (yield 632 mg) <From the same, the - oh1orobenl'n'Gultonut. is obtained from ethanasulfonate, bromide is obtained from ethyleulfate, and eabonate is obtained from chloride and 4thylsulfate. quaternary solo of 44etîlbazole
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 obtained are summarized in the following table.

   The composed
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 are all analytically pure, but often merge with ddegopo-
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 sition and it is difficult to determine the melting point with
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 precision due to the intense color of the compounds * In general
 EMI8.10
 the solubility of the products in hot alcohol increases in a homologous series and is minimum for the lower terms.
 EMI8.11
 e 3 Rw and anfon P.

   E., - 0 r6 Yield ethyl ethyl ethyl 1 231-2336 95% ethyl ethyl ethyl Cl 2326 80 ethyl ethyl ethyl Br 210-2110 8'7; * ethyl ethyl ethyl es 73% ethyl ethyl ethyl Es 63- 66 * 8tu * (b ethyl ethyl ethyl Ti 168-170 *. 60 ethyl ethyl ethyl Co 1900 ethyl ethyl ethyl Mb 133-138 "75% * (d) ethyl ethyl n-propyl 1 208-211 * '' '100%

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 EMI9.1
 ethyl ethyl allyl Br 147,150% ethyl ethyl allyl 1,174-176 ethyl ethyl n-butyl 1,219-200 * a;

   ethyl ethyl n-ptntylt X $ 22-2264 SO% methyl n-propylt ethyl 1,232-234 * 80 methyl n-propyl $ n-propyl 1,223-225 * 100% methyl n.prtpyle n-butylt 1,213-215 * 100 'methyl n-propyl n-pentyl 1 Z1L-zlb. 35jJ '# -methyl loopropyl ethyl 1 205-207 * 100% methyl iaopropyl 8-propyl X 206-2070 80' methyl inopropyl n-butyl 1 202-204 * 61 '. ,. ' ethyl JLooppopylt n-pentyl 1,186-188 * 5 ± * ly ethyl n-propyK ethyl 1,235-237 * 100% ethyl n-propyl n-propyl 1,198 * 199 * $ 4% ethyl n-propylt allyl 1,125-130 * '** -' ethyl n-propyl n-butyl 1 213..214 * B3 ':' dthyl n-propyl n-pentyl 1 209-211 * $ 0j {, '' ethyl allyl ethyl 1 246-247 '\> [-, ethyl allyl α-propyl zur 187-190 * bzz ethyl allyl allyl x 120-125 * #.} '#; / ethyl allyl n-butylt 1 194-197 * z methyl c-butyl ethylt 1 206-208. .r;

   a, 'methyl a-butylt n-propylt 1: U 0-212' 'IJi1; 1 methyl buiyls n buty .6'10 "7, 19 z - methyl n-butyl n-butylt 165-167 * 100 # morne% b "a '#>'

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 EMI10.1
 and ¯ Jill .11 \.!. and poo% 11 'tJ1 4 Mtnt methyl 1.0but) l'l. ethyl 1221-aa, - 100 methylo loobgtyl4 ethyl ci 220 methyl 1aobut) l18 n ... propyl. 1 232023) 6. 100 methyl irobutyl n-butyl 243-2M * '9M methyl isobutyl n-pentyl 236-S37 55 / i 11.1 r "1 lJl:

  "n-propyl n-propyl ethyl X. 231-233 * 93% n-propyl n-propyl n-propyl 1228-2290 95% n-propyl n-propyl. n-butyl m 218-2190 9 $ ± n- propyl n-propyl n-pentyl 1 205''20? <60 't? 9t' t AT \ 1 ta H.tMS.Ay & t) elt <1 iodide - prepared by exchange
 EMI10.2
 
<tb> Cl <SEP> anion <SEP> chloride
<tb> Br <SEP> bromide <SEP> (a) <SEP> 2 <SEP> 1/2 <SEP> H2O
<tb>
 
 EMI10.3
 es èthyloultate En éthnnecultona te (b) à K90 Ts tolubne-a-NUlfOMtt Co jB .'- ohlûrobenznesulfûnat <(0) 1 B20 Rb emboraute (half-amon) (d) HO - (0 H..0pt! 'anion
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<tb> embonate <SEP> integer)
<tb>
 
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 lrLTJ8J'atPl1.de epmt? r1f3L DhaM & ceutiûue
The tablets are prepared for their ordinary oral administration or with the aid of an automatic device.
 EMI10.6
 than.

   These tablets contain the equivalent of 42 and 1.'thy1- 2,6-bis- (u-d1'thyluino.tyryl) -pyr1d1n1U11 bute free (hereinafter referred to as 61-256).
 EMI10.7
 
<tb> a) <SEP> Compressed <SEP> to <SEP> slow disintegration <SEP>
<tb>
<tb> On <SEP> prepare <SEP> a <SEP> mix <SEP> of <SEP> lodge
<tb>
 
 EMI10.8
 4thy1.ultate of 61-2 $ 6 5 '",
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<tb> Lactose <SEP> 525.0
<tb>
<tb> Sucrose <SEP> in <SEP> powder <SEP> 150.0
<tb>
<tb>
<tb> Starch <SEP> 37.5
<tb>
 
 EMI10.10
 Strarttt de atgndtiua L .;

  1 .a.Û..T

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 which is granulated by the usual method using a solution of
 EMI11.1
 5i # of polyvinylpyrroltdonte These granules are mixed with inert granules prepared from mg.
 EMI11.2
 
<tb> Lactose <SEP> 140.0
<tb>
<tb>
<tb>
<tb> Sucrose <SEP> in <SEP> powder <SEP> 40.0
<tb>
<tb>
<tb>
<tb>
<tb> Starch <SEP> 20.0
<tb>
<tb>
<tb>
<tb>
<tb> Magnesium <SEP> <SEP> stearate <SEP> 2.0
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 202.0
<tb>
 
 EMI11.3
 and the mixture of the granules is pressed into a normal denft1onl tablet.

   (diameter and height 10.2 ma) in ua * ttJLUeut * pro. Tond .. The tablets are then coated with a tuort due once until and are almost spherical (d1amtr. la, 6 sua). b) Rapidly disintegrating tablet
The tablets have the same dimension as in paragraph 4) and are prepared as follows but the aotifs granules are prepared from mg
 EMI11.4
 ethyl sulfata 61-256 53 # $ 6 Lactoos rr, 0
 EMI11.5
 
<tb> Cetrimide <SEP> 1.5
<tb>
<tb>
<tb>
<tb> Starch <SEP> 68.0
<tb>
<tb>
<tb>
<tb>
<tb> Stearate <SEP> of <SEP> magnesius <SEP> 7,

  5
<tb>
 
 EMI11.6
  wall * -M ** WMM
 EMI11.7
 the inert granules # have prepared from 41.
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<tb> lactose <SEP> 180
<tb>
 
 EMI11.9
 Aaddon M ",. # 'Starch." .01 ".



  StMO.ttÙO 'Mgn <)! Ti !! Mt 2 t St'Iratl man.81wa #' j. (

 <Desc / Clms Page number 12>

 c) Tablets are also prepared which comprise a core prepared from granules containing the active component with a minimum of dilution, and a coating of inert granules giving the tablets the desired size *.



  Core: 'mg
 EMI12.1
 micro-crystalline 61-256 ethyleulfate µ3.36 Cellulose 100.0 ,, 11IS, 56 * '
 EMI12.2
 the mixture is granulated, via of 1 $ 4 & u and Pressed To tO'7 10 Core.



  Coating: mg
 EMI12.3
 Lactose 600 Lactose Starch 120 Magniol stearate = 7 # 2 727.2 The granules are prepared by the usual method using a 10% solution of gelatin in aqueous alcohol.



   These granules are then pressed on the cores to give understandings of normal size. , 'a diameter and
 EMI12.4
 from a height of 10 # 2 Mar. The tablets were then coated with sugar until it. have a substantially spherical shape with a diameter of 12.6 mm.
 EMI12.5
 



  1 .e ;, .t.LX..J1. l C lA! ' '"B.

** ATTENTION ** end of DESC field can contain start of CLMS **.

 

Claims (1)

1- Process for preparing a new salt of the quaternary distilbazole cation of formula 1 having anthelmin- activity EMI12.6 ethics with regard to parasitic nematodes of .1têr.a, caraot4. characterized in that a quaternary 2,6-lutidine salt containing a cation of formula II is condensed with about 2 equivalents of a p- EMI12.7 aminobensaldehyde of formula 111 in the presence of a strong catalyst: <Desc / Clms Page number 13> EMI13.1 EMI13.2 o R dot un '14: 011 hydroarboté .11pb & '1U' 48 i. , $ Më of carbon, 90 and A * are each a radical ht4f ... * ttl4 lilf, with 2 to 5 carbon atoms, and the, lOUp .. UP ±) $ êj4 <MM & each at least 4 carbon atoms 2 a A process according to claim Ip ...... t4ri.4 ... that R is the mithyl radical. 3 - Process according to r.v, nd1.Uot1 l, O.1.tltil4 tA 164 that URRP is the diithylamino radical. 1 d Method of treating a 1ftt.otS..n. lamât "oh un & amm1trl caraot'r1 ... n ce quion & 4mtn1." ... * "âté paradité by the nem todt a must tb4rapaut1qVdtftt ettî" arm salt of the distilbatole cation quct <rnai do férfetiië t) ê6m $ t'liai in either of, eVtnd1ch, tSton '1; 2 and 5 - Process for the preparation of a Uni composition z tick for the treatment of a parasitized mammal pif of t'a a4a1tod8 ', characterized in that a salt of a cation distiÏba # 61, b tîiat # M4i 4t formula 1 conae defined in one. or the other must J * Vthli # itl * n 1 & and 3 have A..oo1é. a vehicle ph &] h && 8 $ utiq <M! K <nt i $ i pibit 6. Process for the preparation of a 4üat.tftli iiït bet sol of a quaternary distilbâtole cation of the formula t 4bWM 4ilifti 4 = 9 one. or the other of claims 1, 2 and 3, described in ai-d..8UI with reference to examples. 7. A salt of a quaternary distilbazole cation 4. Z $ foil prepared by a method according to either of the above. a 3 and 6 or by a process ChiMl4Uettât S "i1tn'i <Desc / Clms Page number 14> EMI14.1 8 - Sol of a cation 41.t11ba.ol. çiatttwsâirt of # tor8U1. X EMI14.2 EMI14.3 OR R is an aliphatic hydrooarboné1 radical of 1 to 3 carbon atoms, RD and, R "August each an aliphatic hJ4rooa'bOl \ 4 radical of 2 to 5 carbon atoms, and each MRR 'group contains at least 4 carbon atoms @ EMI14.4 9 - Salt of a d1.tl1'lol cation. Quaternary of formula 1 according to claim 8, which is methyl. EMI14.5 10 - Salt of a quaternary didtilbazole cation of formula 1 according to claim 8, characterized * in that NRR 'is the diethylamino radical. EMI14.6 11 - Ethylsulfate de 1-'th11-2,6-b1 .- (- 414tbrl..1no- Ityryl) -pyr1d1niu #. 12 - Medicament comprising such of a cation, U..t11balol. Quaternary of formula I, according to either of claims 8, 9, 10 and 11, in admixture with an acceptable gramacutlqiàe-vehicle.