AU623659B2 - New benzazole derivatives, processes for their preparation and pharmaceutical preparations containing such compounds and use thereof - Google Patents

Description

I.,

Our Ref: 280657 623659

AUSTRALIA

Patents Act F~ORM COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: i. i

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*1 I

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C i~ t £1

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C C Ct I Applicant(s): Ciba-Geigy AG Klybeckstrasse 141 4002 BASL.E

SWITZERLAND

Address for Service: ARTHUR S. CAVE Co.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled JNew Benzazole Devivatives, Processes for their Preparation and Pharmaceutical Preparations Containing such Compounds and Use thereof".

t t t The followik~g statement is a full description of this invention, including the best method of performing it known to me:- -1I- 5020 S I, lA The invention relates to new benzazole derivatives of the formula I -R

(I)

R- \X/ wherein X is oxygen or sulphur, RI is lower alkyl, lower alkenyl or cycloalkyl, optionally substituted, k and X3 independently of one another are each hydrogen, lower alkyl or cycloalkyl radicals or taken together are a substituted or unsubstituted bivalent hydrocarbon residue ,of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, Ri, is either a group rtR C wherein Rs and Rs independently of one another are each hydrogen, lower alkyl or cycloalkyl radicals, optionally substituted, or taken togecher

R

5 and R6 are a substituted or unsubstituted bivalent hydrocarbon residue of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, or, R4 is a group S i t -S-CHZ- H-NH-CO-R 7 where R7 is a lower alkyl group, and their salts and N-oxides and processes for their preparation, pharmaceutical preparations contaninig them and their uses.

The term 'lower' used to qualify radicals denotes that these contain upto 7 carbon atoms, preferably upto 4 carbon atoms.

1 2 Lower alkyl and alkenyl radicals may be straight-chain or branched-chain radicals substituted by free, esterified or etherified hydroxy groups such as lower alkanoyloxy, lower alkoxy or lower alkenyloxy groups, free or esterified carboxyl groups such as lower alkoxycarbonyl, as for example, methoxv or ethoxy-carbonyl, dialkylamino, lower alkyl thio and lower alkenyl thio or halogen atoms.

Halogen atoms are in particular fluorine, chlorine or bromine atoms but can also be iodine atoms.

Lower alkyl groups are, for example, preferably methyl groups and also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

Lower alkenyl groups are, for example, the allyl group or 2-methyl-allyl t C C( S, group. Substituted lower alkyl groups are, for example, the trifluoromethyl group or a free or esterified carboxymethyl group, for example, the methoxycarbonylmethyl group.

A cycloalkyl group is primarily a monoryclic residue having, for example, 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms, for example, a cyclopentyl, cyclohexyl and cycloheptyl group.

I tc Cc The groups RZ and R3 or R5 and Rs when taken together represent an optionally substituted bivalent hydrocarbon residue of aliphatic character which contains between 4 and 7 carbon atoms in the chain. The substituents on the bivalent hydrocarbon may be one or more lower alkyl groups or an optionally substituted phenyl radical. Thus the substituted bivalent hydrocarbon radical, e.g. as lower alkylene together with the Sctnitrogen atom represents a heterocyclic radical such as pyrrolidino, piperidino, 4-methyl or 4-phenyl piperidino, hexahydroazepino or octahydroazocino group. The bivalent hydrocarbon chain may be interrupted by a hetero atom, for example, oxygen, sulphur, substituted or unsubstituted nitrogen representing as oxa-lower alkyleneamino, for example, morpholino, ,6-dimethylmorpholino, or as thia-lower alkyleneamino, for example, thiamorpholino, or optionally substituted aza-lower alkylenenmino, for example, N-methyl, N-phenyl, N-acetyl, N-methoxycarbonyl, N-ethoxycarbonyl- or N-methanesulphonyl piperazino groups as well as

I

3 their N-oxides. Substituents on the optionally substituted nitrogen atom which interrupt the bivalent hydrocarbon chain as indicated above may be an optionally substituted lower alkyl group or an arvyl group such as phenyl groups, an acyl group such as lower alkanoyl, e.g. acetyl, or aroyl, e.g. benzoyl, or a lower alkoxycarbonyl group such as ethoxycarbonyl or methoxycarbonyl or an alkanesulphonyl group such as methanesulphonyl.

The benzene nucleus may be optionally substituted by lower alkyl, alkoxy, carbalkoxy groups or halogen atoms.

The novel compounds have valuable pharmacological properties. They are useful in the control of parasitic helminths such as nematodea, ceszodes and trematodes. They are particularly useful in the control of parhogens o °in filariasis such as Litomosoides carinii, Jrugia malavi, Brugia pahangi and Dipetalonema vjteae and of their developmental stages. In the p0 p0 0 treatment of filariasis in multimammate rat (Mastotvs natalensis) and jirds (Meriones unguiculatus), the new compounds ha':re proved to be very o potent as macro and microfilaricides on administration orally 1 5 times of dose of 6.25 to 25 mg/kg.

Particularly useful by virtue of their potent antifilarial activity are compounds qf the formula I wherein X is sulphur or oxygen, Ri is lower C t alkyl, an R 2 and Ra together represent lower alkylene optionally interrupted by oxygen, sulphur or nitrogen with a total of 4 to 6 carbon atoms whrein nitrogen is nptioiailly substituted by lower alkyl, lower alkanoyl or lower alkoxycarbonyl group and R4 is a group Ct C R6 wherein R 5 and R 6 taken together are lower alkylene optionally interrupted by oxygen or optionally substituted ni':rogen with a total of 4 to 6 carbon atoms, R, eg. thus constituting a heterocyclic group such as pyrrolidino, piperidino, hexahydroazepino,- morpholino, piperazino, 4-methyl piperazino and its N-oxide, 4-acefylpiperaijino, 4-carbethoxypiperazino groups, or, Ri 1 is a group -S-CH2- H-NR-CO-R 7 C0OH sulphur, RI is lower alkyl with 3 and 4 carbon atoms, and RI and R 3 together represent lower alkylene with a total of 4 to 6 carbon atoms in the chain optionally interrupted by oxygen or nitrogen wherein nitrogen is optionally substituted by lower alkyl or lower alkoxy carbonyl, and R4 '44 is a group where R5 and Rs together are lower alkylene with a total of 4 to 6 carbon atoms in the chain optionally interrupted by oxygen or nitrogen wherein nitrogen is optionally substituted by lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R4 thus constituting eg. a heterocyclic group such as a piperidino group, piperazino group and 4-methylpiperazino group and its N-oxide thereof or Rik is a group 0 a

-S-CH

2 H-NH-CO-R7 where R 7 is a lower alkyl group, e.g. methyl.

4 SThe most preferred compounds of formula I are compounds, wherein X is sulphur, Ri is tert-butyl, R 2 and Ra together with the nitrogen atom form S. a heterocyclic group, such as piperidino optionally substituted by lower alkyl group, R is a group -N(R 5

R

6 wherein R 5 and R6 together with the nitrogen atom form a heterocyclic group, such as piperidino or piperazino S with a lower alkyl, alkanoyl or alkoxycarbonyl group as substituent on 4 4 a I 4 tIe nitrogen atom of the piperazine, or R4 is -S-CHa-CH(COOH)-NH-CO-R7 I wherein R 7 is a methyl group, and their pharmaceutically acceptable salts.

The invention relates especially to compounds o ehe formula I mentioned in the Examples and their salts, Particularly me, 'oned are the following compounds; 2-Tert-butyl-6-L(4-methylpiperazin-1-yl)thiocarbonylaminao-5-(4-methylpiperidin-l-yl)benzothiazole.

2-Tert-butyl-6-[ 4-rethylpiper azin-1I -yl) thioc arbonyl amino J piperidin-1yl)benzothiazole.

piperidin-l--yl (pipe ridin-1-yl) thiocarbonyl amino ]be nzothiazole.

2-Tert-butyl-6-[ (morpholin-4-yl) thiocarbonyl amino 1-5-(piperidin- I-vl)benzothiazole.

2-Tert-butyl-6-C (pipe ridin-1-yl thiocarbonylamino J 4-me thy lpiperaz in- 1-yl)benzothiazole.

:0 00S- (Ace tamido-2-carboxyethy-i -tN-f2-tert-butyl-5-(4-methylpiperidin-1- *go yl)benzothiazol-6-ylldihiocarbanate.

S-(Acetamido-2-carboxyethyl)-N-(2-tert-butyl-5-(piperidin-1-yl)bnzothia- 6. 0 zol-6--yl Jdi thiocarbamate.

00000 o 0 According to the present invention there is provided a process for the preparation of novel benzazole derivatives of the formula 1E, wherein X, ~0 RI, R2, R3 and R 4 have the meanings defined above, which comprises the reaction of an isothiocyartatobenzazole of the formula II g~ 0 wherein X, RI R 2 and R 3 have the meanings defined above, with a nucleoo0 phili c compound of the formula R4-H. Theonuc3.aophile Rig-i can have either the formula IIT

(II

I 6 wherein Rs and Rg independently of one another are each hydrogen, lower alkyl or cycloalkyl radicals, optionally substituted, or taken together

R

5 and Rg are a substituted or unsubstituted bivalent hydrocarbon residue of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, or, R|4-H can have the formula IV

HS-CH

2

-H-NH-CO-R

7

(IV)

COOH

where Ry is a lower alkyl group.

Starting compounds of the formula II can be prepared by methods described in European Patent Application No. 85810418.5 published under No. 0175650 from the corresponding 6-amino benzazoles. The preferred procedures for o, this conversion are the reaction of the amines with ammonium thiocyanate Sto yield the thioureas and pyrolysis of the latter to yield the isothiocyanates or the direct conversion of the amines by treatment with thiophosgene to yield the isothiocyanates.

S* I The reaction of the isothiocyanates II with the nucleophile Ri-H can be carried out in solvents such as chloroform, methylene dichloride, ethanol or dimethyl formamide.

The process described can be carried out in the conven'ional manner at ambient temperature, with cooling or warming, under normal pressure or elevated pressure and, if necessary, in the presence or absence of a diluent, catalyst or condensing agent. If necessary, the reaction can also be carried out in the atmosphere of an inert gas, for example, nitrogen.

In resulting compounds substituents can be introduced, modified or detached within the scope of the definition of the end products.

Compounds of the formula I wherein R4 4* 4 .44 4. 4 0 0* *0

U

o *4* 9 0* 0 4 04** 4* *0 9 1 6 (4 4 4 4,

I

4' C '4 7 can also be obtained by the reaction of 6-aminobenzazoles of the formula V i i N. /Rl (V) with a thiocarbamoYl halide of formula VI Hal--CS-L R6

(VI)

bromine in the presence of an acid binding in which Hal is chlorine or agent, Another method of obtaining compounds of the formula I wherein R4 -1V Rs \R6 is to react a thiocarbamio, acid derivative of formula VII,

N

/N (VII1) C 44 41 4 '.4 wherein X, R 1 RZ, and have the meanings as defined above under formula T, with an amine of the formula 1211

R

5 NH

(III)

(4 1 4 41 4 44 Compounds of formula VII are obtained by reacting a 6-mminobenzazole of formula V with a halothlocarboxylic acid-Q--phenyl ester or 0, 0-diphenyl thio carbonate.

The invuntion also relates to these embodiments of a process in which a process is discontinued at any stage or in -iiich a compound obtainable as an intermediate at any stage is used as a starting material and the missing process steps are carried out, or a starting. material is formed 8 under the reaction conditions, or if desired, is used in the form of a salt. The invention also includes novel intermediates resulting therefrom.

Depending on the process conditions and the starting materials the end products are obtained in the free form or in the form of their salts, especially acid addition salts which are also included in the invention.

SThe acid addition salts of the novel compounds can be converted to the free compound in a manner known per se for example with basic agents such as alkali or ion exchangers. On the other hand the resulting free bases can form salts with organic or inorganic acids. Acids used to prepare acid addition salts are in particular those which are suitable for forming therapeutically usable salts.

0* 0 The following may be ment,'oned as examples of suitable acids; hydrohalic 0, acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic alicyclic, aromatic or heterocyclic carboxylic or sulfonic t acids, such as formic acid, acetic acid, propionic acid, succinic acid, o, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid; phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicyclic acid, embonic acid, methane-sulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, or ethylenesulfonic acid; halogenobenzenesulfonic acid, toluene- S sulfonic acid, naphthalenesulfonic acid or sulfaniic acid; and methionine, tryptophane, lysine or arginine.

Evaluation in the animal test systems mentioned above show the excellent potential of the novel compounds as micro and macrofilaricides, for example, for lymphatic filariasis and anchocerciasis for which an effective dosage range of 6.25 to 50 mg/kg daily by oral administration over a period of one to 5 days is to be used, The compotunds may be used for the treatment of lymphatic and tissue-dwelling filarial infection in man, The compounds may tlso be used for the treatment of intestinal helminthic infections like ancylostomiasis; ascariasis, oxyuriasis and trichuriasis and also schistosomiasis in animals and in human beings at di se range of 10 to 500 mg/kg.

9 The pharmaceutical preparations according to the invention, which contain compounds of the formula I or pharmaceutically icceptable salts thereof, are those for enteral, such as oral or rectal, and parenteral, administration to warm-blooded animals, that contain the pharmacologically active substance alone or together with a pharmacologically acceptable carrier. The dosage of the active substance depends on the species of warm-blooded animal, the age and the individual condition, and on the method of administration.

The new pharmaceutical preparations contain, for example, from approximately 10 to approximately 80 preferably from approximately 20 to approximately 60 of the active substance. Pharmaceutical preparations Saccording to the invention for enteral or parenteral administration are, for example, those in dosage unit forms, such as dragess, tablets, capsules, suppositories, or also ampoules. These are produced in a manner t known per se, for example by means of conventional mixing, granulating, I coating, dissolving or vyophilising processes, Thus, pharmaceutical preparations for oral administration can be obtained by combining the active substance with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate to form tablets or dragee cores, if desired or necessary after the addition of suitable Sc adjuncts.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or if desired, disintegrators, such as the above-mentioned starches, and also carboxymethylstarch, cross-linked polyvinylpyrrolidone, agar, SiTinic acid or a salt thereof, such as sodium alignate. Adjuncts are especially flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesijm or calcium stearate, and/or polyethylene glycol, Dragee cores are provided with suitable, optionally gastric juice-resistant coating, there being used, inter alia, concentrated sugar solutions, L_ i lilr___Il_^_lll--L.l~_riT-- _EC 10 which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, to produce gastric juiceresistant coating, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

Colouring matter or pigments may be added to the tablets or dragee coating, for example for identification purposes or for indicating Sdifferent doses of active substance.

Other pharmaceutical preparations for oral administration are dry-filled capsules made of gelatin, and soft sealed capsules consisting of gelatin and a plasticiser, such as glycerin or sorbitol, The ury-filled capsules may contain the active substance in the form of a granulate, for example, in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or mangesium stearate, and optionally, %t stabilisiers. In soft capsules th eactive substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likeweise being possible for t stabilisers to be added.

These come into consideration as rectally adminieterable pharmaceutical 'preparations, for example, suppositories consisting of a combination of the active substance with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols, It is also possible to use gelatin rectal capsuleo that contain combination of the active substance with base substances, for example, liquid triglycerides, Spolyethylene glycols or paraffin hydrocarbons.

I Especially suitable forms for parenteral administration are aqueous solutions of an active substance in water-soluble form, for example, a water-soluble salt, or suspensions of the active uubstance, such as corresponding oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or teiglycerides, being used, or 11 aqueous injection suspensions that contain viscosity-increasing substances, for example, sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilisers.

Tinctures and solutions usually have an aqueous ethanolic base, to which there are added, inter alia, polyalcohols, for ex'ample, glycerin, glycol and/or polyethylene glycol, as moisture-retaining agents for reducing evaporation, and fat-restoring sabstances, such as fatty acid esters with low polyethylene glycols, that is to say lipophilic suibstances soluble in aqueous mixture as a replacement for the fatty substances removed from the skin by the alcohol, if necessary, other adjuncts and adiditives.- The present invention relates also to the use of the compounds of the formula I and the salts of such compounds with salt-form'ing properties, preferably for combating parasitising belminths, especially those of the families mentioned above, The following Examples illustrate the above-desncribed invention but -ire 0 in no way intended to limit the scope thereof, In the following Fxamples temperatures are in degrees centigrade, Example 1:To a stirred solution of 90 g of 2-tert-butyl"6-isoth.o cyanato- 5- (4-methy lpiporidin- 1-Vl) benzo thia4Q le irt 900 Ml of mothylene chloride is added dropwlse 26 g of N-methylpiperazine, The solution is stirred for 1 hour, washed with water, dried over anhydrous sodium sulphate end evaporated to give 110 g of 2-tert-hutyl-6-t(4-ethylpipe to zin- I-yl) thio carbony lamino 1- 5- (4-me thy 1pipe ridin-l-y!) benz othiaaole, melting at 192 IWO, Thq starting material for the above synthesis is prepared as follows: A solution of 32,4 g of 2-tert-butyl-5-chloro-6-nitrobenzOthiazole, (described in turopean patent application 85810418.5 published under No. 0175650) in 300 ml of dimetbylsulphoxide, is stirred and heoted at 140'~ for 6 hours with 12.8 g of 4-methylpi~oridine and 35.8 g of anhydtoua potassium carbonate) cooled arid poured into water. The solid obtained is dissolved ini chloroform and filtered through a silical gel and R 6 are a substituted or unsubstituted bivalent hydrocarbon residue of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, or, R4 is a group /2 S12 column. The filtate is evaporated to give 2-tert-butyl-5-( 4-methylpiperidin-1-yl)-6-nitrobenzothiazole melting at 116 1200 A solution of 15.2 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-nitrobenzothiazole in 600 mi of methanol is hydrogenated in presence of 6.5 g of Raney Nicket at room temperature. After removing the catalyst the solution is concentrated and the sclid filtered to give 6-amino-2-tertbutyl-5-(4-methylpiperidin-1-yl)benzothiazole melting at 146 1480 To a cooled mixture of 2.1 g of 6-amino-2-tert-butyl-5-(4-methy. iperidin-1-yl)benzothiazole and 2.8 g of potassium bicarbonate in 20 ml of chloroform is added dropwise 1,6 g of thiophosgene in 5 ml of chloroform under stirring. The stirring is continued for 2 hours maintaining the tempevatura at 0 20. The solid is filtered and the filtrate is evaporatod. The solid thus obtained is dissolved in chloroform and filtered throdgh a silica gel column. The filtrate is evaporated to give 2-tert- S butyl-6-isothiocyanato-5-(4-methyl-piperidin-1-yl)benzothiazole, melting at 54 58 0 4 4 1 Example 2: Using the procedure described in Example 1 by reaction of 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole with 4-methylpiperazine is obtained 2-tert-butyl-6-[L(4-methylpiperazin- 4-methyl-piperazin-1-yl)benzothiazole, melting at 190 1930.

The starting material for the above synthesis is prepared as follows: A solution of 171 g of N-tert-butylthiocarbonyl-2,5-dichloro-4-nitroaniline (described in European patent application No. 85810418.5 published under No. 0175650) and 605 ml of N-methylprperazine in 1700 mi of dimethylsulphoxide is heated at 1400 for 8 hours, cooled and poured into water. The solid is filtered, washed with w* er and cold isopropanol to yield 2-tert-butyl-5-(4-methylpiperazin-1-yl)-6-nitrobenzothiazole, melting at 132 135'.

-13- A solution of 86 g of the above nitro compound in 150 ml of ethanol is hydrogenated in presence of 30 a of Raney nickel at 45'. The solution is filt~ered to give 6-airir.-2-tert-butyl--5-(4-methylpiperazin-l-yl)benzothiazole, melting at 136'C.

I'p a stirred mixture of 75 g of 6-Amino-2-tert-butyl-5-(4-methvlpiperazin-1-yl)benzothiazole and 29 g of sodium bicarbonate in 1100 ml of chloroform 4t 0' is added 41 q of thiophosgene and the mixture stirred at for 4 hours. After filtering off the solid, the solution is evaporated to get a yellow solid which is dissolved in water and the pH of the solution is brought to 7 by the addition of dilute sodium hydroxide. The solid separated is extracted with hexane and filtered through 150 g of neutral alumina to give 2-terr-butyl-6-iso thiocyanato-5-( 4-methyl-piperazin-1-y1)benzotbiazole, melting at 124 126'.

Examnle 3: Reaction of 2-tert-butyl-6-isothiocanato-5-(4-methl--p perazin-1--yl)benzothiazole described in Example 2 with piperidine under *conditions described in Example 1 gives 2 -te rt-bu tyl-6- t(pipe ridin-I yl)thiocarbonylaminoj-5-(4-nethyl-piperazin-1-yl)benzothiazole, melting 4 at 202 2060.

Examnle 4: The foll,,)ing compounds can be prepared by the process derocribed in Example 1 by reaction of 2-tert-butyl-6-isothiocyanato-5- (piperidin-1-yl)benzothiazole (described in European Patent application t tt No. 85810418.5) with the appropriate amine: 2 -te rt-butyl.-5-.>(pipe ridin-I -yl) -6 (piperidin-11 -yl) thiocarbonylamino benzothiazole, melting at 183 186*; 44 t 2-.tert-butyl-6-[ (4-methylpiperazin-1-y1)thiorarbonylamino)-5-(piperidin- 4 4i-1-yl)benzothiazole, melting at 191 19; 2-tert-butyl-6-t (morpholin-4-yl) thiocarbonylamino) piporidin-1 benzothiazole, melting at 187 1910; -14- -2-tert-btvtyl-6-f (he xamethyleneiniin-1-y) thiocarbonylamino l-yl)benzothiazole, iaielting at 185 1880; N- [2-tert-bu tyl- 5- (pipe ridin- 1-yl) ben z othiazol1-6-yl 2-dinethylaminoethyl)thiourea, melting at 61 N- 2-tert-butyl-5- (piperidin- I -yl) ben zo t:h iaz o1-6-y I 2-die thylaminoethyl)thiourea, melting at 102 104'; 1-yl)propyl] thiourea, melting at 113 1150; N-t2--tert-butyl-5-(piperidin-1-yl)benzorhiazol-6-yl]-N'.43-(4,-diethylamino) propyl Ithiourea, melting at 155 -1570; t 4c ethyl)thiourea, xneltinu atl li? 1780; 2-tert-butyl-6-[ (4-methyJlpiperidin-1-yl) thiocarbonylamino (piperdin- 1-yl)benzothiazole, melting at 214 2170; L-N- (2-ta 'r butyl-5- (pipe ridin- 1-yl) ben zo thiazal-6-yl amino thio carbonylc L a- 2-tert-butyl-5-.(piperidin--1-yl)benzothiazol-6-yl) Jaminothiocartr d e te t n t 1 8 8 bonylarginine, rneli~ing at 175 1780; Example 5: A solution of 3.45 g of 2-trrt-butyl-6-isothiocyanato-5-(4methylpiperidin-1-yl)benzothiazole, described in Example 1, and 8,6 g of anhydrous piperazine in 30 ml of chloroform is stirred for 3 hours, washed with water, dried. over anhydrous sodium sulphate and evaporat to

~II

get a sticky residue which is trituirated with isopropanol and filtered to obtain 3 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-t(piperaziil-yl)thiocarbonylaminolbenzothiazole, melting at 278 2810.

Example 6: A solution of 2.0 g of 2-tert-butyl-6-isothioc'ranato-5-(4methylpiperidin-l-yl)benzothiazole and 0.78 g of 1-acetyl.-piperazine in ml of chloroform is stirred for 30 minutes and the proc.uct triturated with petroleum ether to obtain 6-[(4-acetyl-piperazin-1-yl)thiocarbonylamino]-2-tert-butyl-5-(4-methylpi peridin-1-yl)benzothiazole, melting at 187 19U.

Example 7: To a freshly prepared solution of sodium ethoxide (1.4 g of sodium in 100 ml of absolute ethanol) is added 5.2 g of 1-methyl-ioxido-piperazine dihydrochloride. The mixture is stirred at 500 for 15 to minutes and then at room temperature for 1 hour. The precipitated sodium chloride is filtered off and the filtrate is treated with a :suspension of 8,6 g of 2-.tet-butyl6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole, described in Example 1, in 25 ml of ethanol undk'r too stirring. The mixture is refluxed fur 1 hour, cooled, concentrated under reduced pressure and the solid filtered to yield 3 8 of 2-tert-butyl- 5-(4-methyl-piperidin-1-yl)--6-(4-methyl-4-oxopiperazinl-yl thiocarbonylaminobenzothiazole, melting at 115 1170.

Examale 8: A mixture of 69 g of 2-tert-butyl-6-isothiocyanato-5-(k mmthylpiperidin-1-yl)benzothiazole and 39.2 g of N-acetyl-L-cvsteinl, in 250 ml of dimethyl formamide is stirred under nitrogen atmosphere at room temperature for 79 hours, poured into water, the solid filtered and washed with water. The wet cake is dissolved in 500 ml of wmthylene chloride, dried over anhydrous sodium sulphate and treated wtht 1.5 1. of hexane. The solid is filtered to give 85 g of S-(acetaid-2-carbokvethyl) f 2-tort-butyl.-5-( 4-methylpiperidin-1 -yl) benzothiazol-6yl)dithiocarbamate, melting at 140 143'.

Example 9: Using the procedure described in Examplo 8, S-(acetamido-2carboxyethyl)-N-t2-ter-butyl-5-(piperidinl-yl)-6.benzothiazol-6-ylIdithiocarbamate, melting at 138 140' can be prepared.

-16 ExaMDle 10: To a solution of 0.6 g of 6-amino-2-tert--butyl-5-(4-methvlpipe ridin-1I-yl) benz othiaz ole and 0.36 a of 1-cloro-thiocarbonyl-4methylpiperazine in 30 ml of dioxane is added 0. 3 g, of ,8-diazabicyclo undec-7-ene (DBU) and the mixture heated at 1000 for 6 hours. The reaction mixture is evaporated to dryness, the residue triturated with water and the solid filtered. Chromatography of the solid over silica gel and elution with methylene dichioride-methanol (98:2) gives 2-tertbu tyl-6- (4-methylpiperaz in---yl) thiocarbonylamino 4-me thyl pipe ridin-l-yl)benzothiazole, identical with the compound described in Example 1.

Axamnle 11: A solution of 0.5 g of 2-tert-butyl-5-(4-methyl-piperidin- 1-yl)-6-phenoxythiocarbonylaminobenzothiazole and 0.11 g of 4-methylpiperazine in 20 ml of dioxane is refluxed for 16 hours. Evaporation of the solvent and chromatography of the residue over silica gel and elution with methylene dichloride-methanol (98:2) gives 2-tert-butyl-6-[(4a a methylpiperazin-1-yl)thiocarbonylamino 1-5- (4-methylpiperidin-I -yl) benat* zothiazole, icAentic:al with the compound described in Example 1.

ateThe starting material for the above synthesis is prepared as follows: A mixture of 1.5 g of 6-amino-2-tert-butyl-5-(4-methylpiperidin-lcc; yl)henzothiazole and 1.15 g of 0,0-dip'nenylthiocarbonate in 8 ml of a pyridine is refluxed for 3.5 hours. The solvent is evaporated and the residue purified by chromatography over silica gel. Elution with methyla4t eeicord gie2-tert-butyl-5-( 4-methylpiperidin-1-yl )-6-phenoxythiocarbonylaminobenzothiazole melting at 201 205'.

4 '1:

Claims (5)

1. Benzazole derivatives of the formula I R 3 R I 2 I (I) wherein X is oxygen or sulphur, RI is lower alkyl, lower alkenyl or cycloalkyl, optionally substituted, R2 and R3 independently of one an- S other are each hydrogen, lower alkyl or cycloalkyl radicals or taken together are a substituted or unsubstituted bivalent hydrocarbon residue of aliphatic character in which the carbon atoms of the chain may be S* interrupted by a heteroatom, R4 is either a group ftft t W cc \R wherein Rs and R 6 independently of one another are each hydrogen, lower alkyl or cycloalkyl radicals, optionally substituted, or taken together R 5 and R 6 are a substituted or unsubstituted bivalent hydrocarbon residue of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, or, R4 is a group -S-CH 2 -H-NH-CO-R 7 COOH where R 7 is a lower alkyl group, and their salts, and N-oxides.

2. A compound of formula I according to claim 1, wherein X is oxygen or sulphur, Ri is lower alkyl, and R2 and R3 together represent lower alkylene optionally interrupted ty oxygen, sulphur or nitrogen with a total of 4 to 6 chain atoms wherein nitrogen is optionally substituted by lower alkyl, lower alkanoyl or lower alkoxycarbonyl group, and R4 is a group 18 _s \R6 wherein Rs and Rs taken together are lower alkylene with a total of 4 to 6 carbon atoms in the chain optionally interrupted by oxygen or optio- nally substituted nitrogen, or R4 is a group -S-CH 2 H-NH-CO-R 7 COOH where R 7 is a lower alkyl group, and their salts and N-oxides.

3. A compound of formula I according to claim 1, wherein X is sulphur, R 1 S is lower alkyl with 3 or 4 carbon atoms, Rz and R 3 together represent lower alkylene with a total of 4 to 6 carbon atoms in the chain optio- o. nally interrupted by oxygen or nitrogen wherein nitrogen is optionally substituted by lower alkyl or lower alkoxycarbonyl, and R4 is a group 9 wherein Rs and R 6 together are lower alkylene with a total of 4 to 6 Scarbon atoms in the chain optionally interrupted by oxygen or nitrogen d where nitrogen is optionally substituted by lower alkyl, lower alkanoyl S or lower alkoxycarbonyl group, or R4 is a group -S-CH 2 -H-NH-CO-R 7 OOH where R 7 is a lower alkyl group, and their salts and N-oxides.

4. A compound of formula I according to claim 1, where X is sulphur, RI is tert-butyl, Rz and R 3 together with the nitrogen form a heterocyclic radical such as piperidyl optionally substituted by lower alkyl groups, R4 is a group -<R -19- where R5 and R 6 together with the nitrogen form a heterocqyclic group such *as piperidino or piperazino with a lower alkyl, alkanoyl or alkoxycarbo- nyl group on the nitrogen of the piperazine, or R4 is a group -S-C H 2 H-NH-CO-R 7 where R 7 is a methyl group, and their pharmaceutically acceptable zalts and N-oxides. Compounds according to claim 1 which comprises that said compounds are: 2-Tert-butyl-6-[ (4-methylpiperazin-1-yl)thiocarbonylamino-5-(4- methy'Lpiperidin-1 -yl)benzothiazole and pharmaceutically acceptable salts thereof; 2-Tert-butyl-6-[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methyl- piperazin-1-yl)benzothiazole and pharmaceutically acceptable salts thereof; ~qt:2-Tert-bu tyl-6- [(pipe ridin-I -yl) thiocarbonylamino]1-5-(4-me thylpipoi-azin- x-_yl)benzothiazole and pharmaceutically acceptable salts thereof; 2-Tert-butyl-5-(piperidin-1-yl)-6-[(piperidin-1-yl)thiocarbonylanino]- benzothiazole and pharmaceutically acceptable salts thereof; 2-Tert-butyl--6-[ (4-methylpiperazin-1-yl) din-1-yl)benzothiazole and pharmaceutically acceptable salts thereof; 2-Tert-butyl-6-[ (4-carbethoxypiperazin-1-yl) thiocarbonylamino (piperidiLn-1-yl)benzothiazole and pharmaceutically acceptable salts thereof; 2-Tert-butyl-6-[ (mrblI--l boabnlmio]--(ierdnl-l benzothiazole and pharmaceutically acceptable salts thereof; 2 -Ter t-bu tyl- (hexame thylene imin-I -yl) thio ca rbonylamino 1-5- (pipe ridin- 1-yl)benzo' ,azole and pharmaceutically acceptable salts thereof; Z 2-Tert-butyl-5-(piperid,;n-1-yl)benzothiazol-6-yl]-N' -(2-dimethylamino- ethyl)thiourea and pharmaceutically acceptable salts thereof; N-[2-Tert-butyl-5-(piperidin-1-yl)benzothiazol-6-yl]--N'-(2-diethylaanino- ethyl)thiourea and pharmaceutically acceptable salts thereof; N-[2-Tert-butyl-5-(piperidin--yl)benzothiazol-6y]N'[3-(piperidin-l yl)propyllthiourea and pharmaceutically acceptable salts thereof; N-[2-Tert-butyl-5--(piperidin-1-yl)benzothiazol-6-yl]-N'-[ 4-miethyl- piperazin-1-yl)ptopyll thiourea and pharmaceutically acceptable salts thereof; 9 0

992-etbtl5(ieii--lbnztizl6y]N-2hdoyty) amn~plthiourea 4nd pharmaceutically acceptable salts thereof; LN- 2-Tert-bu tyl-5-(pipe riin- 1-y)ben z othia zol- 6-yl ]amino -hd rbtyl)- cioure and pharmaceutically acceptable salts thereof; 2-Tert-butyl-6-[(4-methylpiperidi-y)6[ppeain-1-yl)thiocarbonylamn]--(iei amino1-ybenzothiazle and pharmaceutically acceptable salts thereof; 2-erttyl-5eazn-(iperincaybnzotiao-2tryl6-yI amnothocabnyl- pira in-I-l ez bae and pharmaceutically acceptable salts teef ariieadpamcuial cetbeslsthereof; 21 2-Tert-butyl-5-(4-methyl-piperidin-1-yl)-6-[(4-methyl-4-oxopiperazin-l- yl)thi-,arbonylamino]benzothiazole and pharmaceutically acceptable salts thereof; S-(Acetamido-2-carboxyethyl)-N-[2-tert-butyl-5-(4-methyl-piperidin-1-yl)- benzothiazol-6-yl]dithiocarbamate and pharmaceutically acceptable salts thereof; S-(Acetamido-2-carboxyethyl)-N-[2-tert-butyl-5-(piperidin-l-yl)-6-benzo- thiazol-6-yl]dithiocarbamate and pharmaceutically acceptable salts thereof. 6. A pharmaceutical composition containing an effective amount of a com- pound of formula I of claim 1 for the treatment of filarial infections and intestinal helmintic infections together with one or more pharma- aI ceutical excipients or dilutant,. too 7. A compound of the formula I of claim 1 for application in a process S« for the therapeutic treatment of the human or animal body. 8. Method of treating filarial infections and intestinal helmintic S: infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of formula I of claim 1 or a pharmaceutical composition comprising an effective amount of said excipients or dilutants. 9. A process for producing compounds of formula I as defined in claim 1, which comprises a) treating compounds of formula II R2- (I) S=C=N/ -22 with a compound of formula R4.-H wherein X, Ri, R2, R 3 and R4. have the meanings defined under formula I, b) treating compounds of formula V i H *-R 1 MV 11 with a thiocarbamoyl halide of formula VI Hal-CS-1 (VI) V. wherein R 5 and R 6 have the meanings defined under formula I, S c) treating compounds of the formula VII 000- *0 0 A 01 -Rx CVII) wihan amine of formula III 0>H S 10. A pr.ucess for producing compounds cef formula I substantially as herein described with reference to any Examples 1 to 11. 11. A-compouind of formula I obtained by any one of the processes in Examples 1 to 11. DATED this 19th day of February 1992. CIBA-GEIGY AG By Their Patent Attorneys DAVIES COLLISON CAVE