NZ199762A - Amino-2,1,3-benzothiadiazole and-benzoxadiazole derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99762 19976 Priority CamtfM* SpesKicaSon Filad: v.

CIMK s3'1^' 30 APR 1985 Pub?{oat!cn Date: J.0. Journal Wo: <2 -82 '-i S a 9&U No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION AMINO—2,1,3-BENZOTHIADIAZOLE AND -BENZOXADIAZOLE DERIVATIVES, THEIR PREPARATIOST AND PHARMACEUTICAL COMPOSITIONS CCMTAINING THEM X/ We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss. Body Corporate; hereby declare the invention for which MX/ we pray that a patent may be granted to poe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) <J Cv 9 7 ^ y soo-ra^- - la - AMINO-2,1,3-BENZOTHIADIAZOLE AND -BENZOXADIAZOLE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to amino-2,1,3-benzo-5 thiadiazole and -benzoxadiazole derivatives, their preparation and pharmaceutical compositions containing them.

In particular, the invention provides compounds of formula I A I B ! c wherein A is an optionally substituted 2,1,3-benzothiadiazole or 2,1,3-benzoxadiazole moiety, B is a trisubstituted amino group and C is an optionally 1-substituted 4,5-dihydro-lH-imidazol-2-yl or >Lan optionally 3-substituted 3,4,5,6-tetrahydro- [ pyrimidin-2-yl" moiety, hereinafter referred to as "the compounds of the invention".

I 1997 - 2 - -500 5563- In accordance with the invention, there are especially provided compounds of formula la, la (CH2)n wherein ^ n is 2 or 3, X is oxygen or sulfur, Y is a bond or oxygen, R^, and R^ independently are hydrogen, halogen of atomic number of from 9 to 53, cyano, hydroxy, alkyl of 1 to 4 10 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkylthio of 1 to 4 carbon atoms, R4 is i) alkyl of 1 to 6 carbon atoms optionally monosubstituted by hydroxy or halogen of atomic number of from 9 to 53 and 15 wherein the hydroxy or halogen moiety is separated from Y by at least 2 carbon atoms; alkenyl of 3 to 6 carbon atoms optionally monosubstituted by halogen of atomic number of from 9 to 53 and wherein the double bond and the halogen moiety are separated from Y by at least 2 carbon atoms; 20 alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from Y by at least 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof; 199763- ii) 2,2,5,5~tetraalkylpyrrolidin-l-ylalkyl or 2,2,6,6-tetra~ ■ alkylpiperidirr-1—ylylkyl. independently of I to ^ carbon atomsi neach of the a Iky 1 moi eti es'ofthe ~py r r o 1 idine or piperidine moiety, of 2 to 5 carbon atoms in the alkyl 5 moiety bound to Y and wherein the nitrogen atom of the pyrrolidine or piperidine moiety is separated from Y by at least 2 carbon atoms; furanylalkyl, thienylalkyl or py-~ridylalkyl each of l td" 4 carbon atoms" in the alkyl moiety thereof; or morpholin-1-ylalkyl of 2 to 5 carbon atoms 10 in the alkyl moiety thereof and wherein the nitrogen atom of the morpholine moiety is separated from Y by at least 2 carbon atoms; iii)phenylalkyl of 7 to 11 carbon atoms, phenoxyalkyl of 8 to 12 carbon atoms wherein the oxygen atom is separated from Y by at least 2 carbon atoms, phenylcarbonylalkyl of 8 to 12 carbon atoms, phenylalkoxyalkyl of 1 to 4 carbon atoms in the alkoxy and of 2 to 5 carbon atoms in the alkyl moiety thereof and wherein the oxygen atom is separated from Y by at least 2 carbon atoms, phenylalkenyl of 9 to 13 carbon atoms wherein the double bond is sepa rated from Y by at least 2 carbon atoms, phenylalkinyl of 9 to 13 carbon atoms wherein the triple bond is separated from Y by at least 2 carbon atoms, all the phenyl rings in the six above-mentioned substituents optionally being mono- or independently di-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53 or, when Y is a bond, alternatively or additionally also by hydroxy; or ' iiii) when Y is oxygen, additionally hydrogen, and 30 R^ is hydrogen or alkyl of 1 to 4 carbon atoms. f-G -tilt is to be appreciated that the compounds" of the invention are defined with reference to one specific tautomeric form, e.g. that of formula la, only for the sake of simplicity. However, the invention extends to all tautomeric forms of the compounds of formula la.

It is also to be appreciated that any carbon chain of more than 2 carbon atoms may be branched or straight-chained.

Alkyl of 1 to 4 carbon atoms or of 1 to 6 carbon atoms and/or alkoxy and/or alkylthio preferably are of 1 or 2, especially of 1 carbon atom- Halogen preferably is chlorine or bromine, especially chlorine. When alkyl of 1 to 6 carbon atoms is substituted by hydroxy, it is especially substituted in the distal position. Alkenyl is preferably of 3 or 4 carbon atoms, it especially is allyl. VThen it is substituted by halogen, it preferably is substituted at a carbcn atom bound to the double bond* it is then especially 2-chloro-2-propenyl. Alkinyl preferably is of 3 or 4 carbon atoms' it especially is 2-propinyl. Cycloalkyl preferably is of 3,5 or 6 carbon atoms* it especially is cyclopentyl. Cycloalkylalkyl preferably is of 3, 5 or 6, especially of 3 carbon atoms in the cycloalkyl moiety thereof and preferably of 1 or 2, especially of 1 carbon atom in the alkyl moiety thereof. In 2,2,5,5-tetra-alkylpyrroliain-l-ylalkyl and 2 ,2,6,6-tetraalkylpiperidin-1-ylalkyl the alkyl substituents preferably are methyl or ethyl, especially methyl", they preferably are identical) the bridging alkylene moiety preferably is ethylene. Furanylalkyl preferably is furanylmethyl, especially 2-furanylmethyl.Thienyl-alkyl preferably is thienylmethyl, especially 2-thienyl-methyl. Pyridylalkyl preferably is pyridylmethyl, especially 2-or 3~, especially 2-pyridylme thyl. Morpholin-1-ylalkyl pre-^ ferably is morpholin-l-ylethyl. Phenylalkyl preferably is benzyl or phenethyl, optionally substituted. Phenoxyalkyl ';*/ , ,C T r- 199762 - 5 - §00 55-63- preferably is phenoxyethyl, optionally substituted. Phenyl-alkoxyalkyl preferably is benzyloxyethyl, optionally substituted. Phenylalkenyl preferably is cinnamyl, optionally substituted. Phenylalkinyl preferably is 3-phenyl-5 2-propinyl, optionally substituted.

When a phenyl ring as part of a substituent R^ is substituted, it preferably is substituted in the para position. When it is disubstituted, it preferably is substituted in the meta and para positions. The substituents 10 preferably are identical. Preferred as substituents are halogen, alkyl and alkoxy, especially alkoxy. n preferably is 2. X preferably is sulfur. Y preferably is a bond. R^ and/or R^ preferably' are" hydrogen ,harogeri7 alkyl, alkoxy or cyano, especially hydrogen. They preferably.are 15 identical when they both are other than hydrogen. R^ preferably is hydrogen, hydroxy, alkyl, alkoxy or halogen, especially halogen.-The nitrogen atom carrying Y-R preferably is botnd at the 4 position of the 2,1,3-benzothiadiazole or 2,1,3-benzoxadiazole ring. R, ?o 4 preferably has the above-defined significance i) or iii), especially significance i). R^ preferably is hydrogen. Significance i) preferably is alkyl optionally substituted by hydroxy, especially alkyl,or is alkenyl or cycloalkylalkyl,it especially is alkenyl.The above-defined significance ii) prefer-25 "aFly ~ l's~morphbT irly la Iky IT STgni Fi c an ce i i i ) yreferabTy is optionally substituted phenylalkyl, phenoxyalkyl, phenyl-alkoxyalkyl or phenylalkenyl. 19976 - 6 - .500-5563 One group of compounds of the invention is the compounds i) alkyl of 1 to 6 carbon atomsj alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 2 carbon atoms; 2-chloro-2-propenyl; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen atom by at least 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof, the total number of carbon atoms not exceeding 7; ii) thienylmethyl,.2-furanylmethyl or pyridylmethyl; or iiij benzyl or cinnamyl. of formula Ipa R Ipa 199762 500 5563- A further group of compounds of the invention is the compounds of formula Ipb Ipb wherein DP R,» R„. R, and R. are as defined above. 12 3 A A compound of the invention may be obtained by a process comprising a) appropriately substituting a corresponding compound of formula II A I B' I II wherein A and C are as defined above and B1 is a secondary amino group or b) reacting a corresponding compound of formula III 199762 - 8 - S0&-55&3- A I B III I Q wherein A and B are as defined above and Q is a group capable of cyclization with a diamine, with a corresponding, optionally 1-substituted ethylene or propylene diamine.

In particular, a compound of formula la may be obtained by a) appropriately substituting the bridging nitrogen atom in a corresponding compound of formula Ila Rl.

N Ila (C1V„ wherein n, X, R^,R^, R^ and R^_ are as defined above or b) for the production of a compound of formula Iaa, 1997 506-5553" (C1I2>„ laa wherein n, X and to R^ are as defined above, reacting a corresponding compound of formula Ilia Rn Ilia wherein Q, X and R, to R, are as defined above, 1 4 with a corresponding compound of formula IV H N-(CH ) -NHR 2 2 n 5 IV wherein n and R^ are as defined above.

Process variant a) may be effected in con-10 ventional manner for the production of analogous trisub- stituted amines by substitution of a secondary amine. 19976 - 10 - 500 5563 For the production of a. compound, wherein the substituent to be introduced is to be bound to the nitrogen atom over a carbon atom, the reaction conditions of an N-alkylation of a secondary amine may be used.

An appropriate N-alkylating agent is e.g. a compound of formula Z-R wherein R, is as defined above and Z is 4 4 a leaving group, e.g. halogen or a group R -SO -0-, wherein z 2 Rz is phenyl, tolyl or lower alkyl. Z especially is bromine or chlorine. The reaction is conveniently effected in an 10 organic solvent such as dimethylformamide or an alcohol.

Preferably a basic condensation agent such as sodium carbo-T^at:e» Pyridine or N-ethyl-N,N-diisopropylainine is used.The reaction temperature may vary between room temperature and approximately 100°C.

For the production of a compound therein the substituent to be introduced is to be bound to the nitrogen atom over an oxygen atom, the reaction preferably is effected in two stages, e.g. as follows: In a first stage, a compound of formula II is substi-20 tuted at the secondary amino group with hydroxy. To this effect a compound of formula II is oxidized with an oxidizing agent such as 3-chloroperbenzoic acid. Conveniently an inert solvent such as methylene chloride is used. The reaction preferably is effected at a temperature from about °° 25 to about 25° C . A corresponding compound substituted at the nitrogen atom by hydroxy is obtained.

In a second stage, if required, the resultant hydroxy compound is then O-alkylated. Conveniently, reaction conditions similar to those indicated above for N-alkylation may be 1997 - 11 - 500 5563 used. Preferably strongly alkaline conditions, as e.g. in the presence of sodium ethylate, are used.

The reactivities of any substituents present should be taken into account. Thus, when the 2,1,3-benzothiadiazole or 5 2,1,3-benzoxadiazole ring is substituted e.g. by hydroxy, it may be indicated to effect the above-mentioned oxydation and 0-alkylation with the phenolic hydroxy group or groups in protected form, and to deprotect thereafter. Methyl is an example of a phenolic hydroxy protecting group. It 10 may be split off e.g. with trimethylsilyl iodide or the lithium salt of ethyl mercaptan. When is phenylcarbonyl-alkyl the carbonyl moiety may also be temporarily protected e.g. in the form of a 1,3-dioxolane ring.

Process variant b) may also be effected in con-15 ventional manner for the production of analogous 2-amino-4,5-dihydro-lH-imidazoles or .2-amino-3,4,5,6-tetrahydropyri-midines.

Q is e.g. cyano, -C(NH2)=NH, -C(SAlk)=NH or -C(0Alk)=NH wherein Alk is lower alkyl, preferably methyl,or is e.g. -COOAlk' 20 wherein Alk' is lower alkyl, preferably ethyl.Q especially is cyano.

The reaction preferably is effected in an inert organic solvent, e.g. an alcohol of 3 to 8 carbon atoms such as n-pentanol or a hydrocarbon such as xylol. The reaction 25 preferably is effected in the presence of an excess of a monovalent salt of the ethylene or propylene diamine.When "a" large excess of the diamine in free base form is used, then , it may also serve as a solvent. The reaction temperature is 1 9976 - 12 - -500-5563 about 50° to about 200°C, preferably about 110° to about 150°C.

The compounds of the invention may be isolated from the reaction mixture and purified in a manner analogous to known methods.

The compounds of the invention may exist in free form.normally as a base, or in salt form. Free forms may be converted _into salt forms in conventional manner and vice-versa. Suitable acids for acid addition salt formation include hydrochloric, 10 malonic, p-toluene-sulfonic and methanesulfonic acid. Suitable bases for anionic salt formation, e.g. when R^, R^ and/or R^ is hydroxy, include sodium and potassium hydroxide.

The starting materials may be obtained in known manner.

A compound of formula Ilia wherein Q is cyano may e.g. be obtained by appropriately substituting the bridging nitrogen atom in a corresponding N-cyano-2,1,3-benzo-thiadiazol"or N-cyano-2,1,3-benzoxadiazol-4~amine.

Insofar as the preparation of any particular starting 20 material is not particularly described, this may be effected in conventional manner or in analogous manner to that described herein.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected. 199762 Example 1: N-allyl-5-chloro-N-(4,5-dihydro-lH-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine (process variant a) 38 g Allyl bromide are added to a solution of 20 g 5 5-chloro-N-(4,5-dihydro-lH-imidazol-2-yl)-2,1,3-benzothiadiazol- 4-amine in 500 ml methanol, 20 ml dimethylformamide and 9 ml pyridine. The mixture is stirred and heated for 19 hours under reflux, and then the pale yellow solution evaporated under reduced pressure. The residue is stirred in water and the re-10 suiting crystalline hydrobromide of the title compound filtered and washed with cold water. The salt is made alkaline with 20% sodium hydroxide,and the "free base" extracted with methylene chloride. The organic phase is dried with sodium sulfate and the solvent evaporated. The residue is recrystallized from 15 ethyl acetate. The title compound is obtained (M.P. of the free base form 140-142°; M.P. of the hydrochloride salt form 218-219°).

Example 2: 5-chloro-N-hydroxy-N-(4,5-dihydro-lH-imidazol-2-yl)~2 ,1,3-benzothiadiazol-4-amine 20 (process variant a) To a stirred suspension of 7.5 g 5-chloro-N-(4,5-dihydro-lH-imidazol-2-yl)-2,1, 3-benzothiadiazol-4-amine in 600 ml of methylene chloride are added at 5° over 20 minutes 7.5 g of nr chloroperbenzoic acid. The solution is stirred for 100 minutes 25 at room temperature and then extracted successively with 60 ml and twice 30 ml of 2N sodium hydroxide.The combined extract are then acidified with IN aqueous hydrochloric acid solution. The precipitated nnchlorobenzoic acid is filtered off, the solvent evaporated to dryness, the residue dissolved in 500 - J 199762 - 14 - S©0=5§&3- ethanol, the precipitated sodium chloride filtered off, the filtrate treated with charcoal and the solvent evaporated to dryness. The residue is recrystallized from isopropanol. The title compound is obtained (M.P. of the hydrochloride salt 5 form 220-222°; [dec.]).

Example 3: ^-chloro-N-(4,5~dihydro-lH-imidazol-2-yl)-N- (2-phenoxyethoxy)-2,1,3~benzothiadiazol-4-amine (process variant a) g 5-chloro-N-hydroxy-N(4,5~dihydro-lH-imidazol-10 2-yl~2,l,3-benzothiadiazol-4-amine hydrochloride (obtained according to Example 2 above) are added to a solution of 0.68 g sodium in 70 ml ethanol followed by 3.77 g 2-bromoethyl phenyl ether. The mixture is stirred for 2 hours at room temperature. The resulting precipitate is filtered off and the filtrate 15 evaporated under reduced pressure. The residue is dissolved in methylene chloride and washed with IN hydrochloric acid. The organic phase is dried with sodium sulfate and the solvent evaporated. The title compound is obtained (M.P. of the hydrochloride salt form 161-162°).

Example 4: N-allyl-5-chloro-N-(4,5-dihydro-lH-imidazol-2-yl)- 2,1,3-benzothiadiazol-4~amine (process variant b) 9.5 g toluene sulfonic acid monohydrate and 3 g i: yl ethylene diamine are dissolved in 3 ml water and reacted with 25 a solution of 2.5 g N-allyl-5-chloro-N-cyano-2,1,3-benzothia- diazol-4-amine in 10 ml xylol. The mixture is heated 4 hours under refluxing; after cooling 100 ml of 2N hydrochloric acid solution are added and the mixture is extracted twice with 1997 6 £. - 15 - -500 5563' 60 ml methylene chloride. The aqueous phase is treated with charcoal,,made alkaline with concentrated aqueous ammonia solution and then extracted with methylene chloride. The organic phase is dried and the solvent evaporated. The residue 5 is recrystallized from ethyl acetate. The title compound is ob tained (M.P. of the free base form 140-142°J M.P. of the hydrochloride salt form 218-219°).

The starting material is obtained as follows: 5 g 5-chlo-ro-N-cyano-2,1,3-benzothiadiazol-4-amine are added to a 10 solution of 0.55 g sodium in 60 ml ethanol and the mixture is reacted with 3 g allyl bromide. The mixture is agitated 3 hours under refluxing and the solvent evaporated under vacuum. The residue is extracted with methylene chloride. N-allyl- -chloro-N-cyano-2,1,3-benzothiadiazol-4-amine (M.P. 62-63°) is obtained.

The following compounds of formula I may be obtained in ~an analogous manner"by appropriate substi tution of a corresponding compound of formula II wherein B' is ^ NH. (process; variant.-a) or by reaction of a corresponding 20 compound of formula III wherein Q is cyano with a corresponding ethylene or propylene diamine (process variant b): Exampk Nr.

Analogous to Ex.No.

I) N-C-bond 5 8 9 11 12 13 14 1 and 4 1 and 4 1 and 4 1 and 4 1 and 4 1. and 4 ^ and 4 1 and 4 1. and 4 1 and 4 1 and 4 -chloro-2,1,3-benzothiadiazol* 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,J> 3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol-4-yl ^N-Me ^N-Me ^N-Et )N-Bz ^N-crotyl. )n-ch2c=ch2 Me )n-ch2c=ch2 )N-CH„CH=CMe„ ' 2 2 )H-CH2CK=CH-Phe |>N-i -iPr ^N-iBu 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-1H-1-methylimidazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl 4,5-dihydro-lH-imi-dazol-2-yl b 128-131° b 165-185° b 132-135° b 132-134° b 1.51-154° b 131-134° b 139-141.5 b 112-114° b 136-140° b 138-141° b 154° Example No.

Analogous to Ex.No.

A 4. b c m p. 16 1 and 4 -chloro-7-methyl-2,1,3-benzothia-diazol-4-yl ^N-allyl 4,5-dihydro-1H-imidazol-2-yl b 153-157° 17 land 4 4-methyl-2,1,3-benzothiadiazol- -yl \N-allyl 4,5-dihydro-1H-imidazol-2-yl b 122-124° 18 land 4 -chloro-2,1,3-benzothiadiazol-4-yl ..^N-allyl / 4,5-dihydro-lH-r methylimidazol-2- yl - b 108-110° 19 land 4 -chloro-2,1,3-benzothiadiazol-^-4-yl )n-ch2-<s 4,5-dihydro-lH-imidazol-2-yl b 165-167° land 4 4-bromo-2,1,3-benzothiadiazol- -yl ^N-allyl 4,5-dihydro-1H-imidazol-2-yl b 143-147° 21 land 4 7-chloro-5-methyl-2,1,3-benzo~ thiadiazol-4-yl )N-allyl 4,5-dihydro-1H-imidazol-2-yl b 162-165° 22 l.and 4 -methyl-2,1,3-benzothiadiazol-4-yl ^N-allyl 4,5-dihydro-1H-imidazol-2-yl b 127-130° 23 l.and 4 -methyl-2,1,3-benzoxadiazol-4-yl >N-allyl 4,5-dihydro-lH-imidazol-2-yl b 125-127° 24 1 and 4 ,7-dimethyl-2,1,3-benzoxadiazol-4-yl ^N-allyl 4,5-dihydro-lH-imidazol-2-yl b 161-164° l*and4!'{A -chloro-2,1,3-benzothiadiazol-4-yl ;n-(ch2)3co-@>-f 4,5-dihydro-lH-imidazol-2-yl ta 201-203° 26 1 and 4 -chloro-2,1,3-benzothiadiazol-4-yl )n-ch2ch2-o -Phe 4,5-dihydro-lH-imidazol-2-yl ifu 175-178° Example Nr.

Analogous to Ex.No. 27 28 29 31 32 33 34 1 and 4 1 and 4 ! ' J 1 and 4 l.and 4 l.and 4 1 and 4 1,and 4 1 and 4 ipN-O-bond . 35 , 36 37 '2 + 3 2 + 3 2 + 3 -chlcro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol •. 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol-4-yl ~chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol- 4-yl -chloro-2,1,3-benzothiadiazol-4-yl /nN-ch2CH2-O-^0)-oh ;N-CH2CH2-0CH^@>-0 Me JN-CH CH -Phe ;N-CH2CH2-^)-Me )N-ch2CH2~<@M)H ;N-ch2CH2-NQO ;N-CH C=CH Me Me v; >N-CH„CH Me^Me ^N-O.-allyl >N-0-Me )n-o-ch2 4,5-dihydro-lH-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-lH-inudazol-2-yl 4,5-dihydro-lH-imidazol-2-yl 4,5-dihydro-lH-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl 4,5-dihydro-1H-imidazol-2-yl M.P. fu 276-278' h& 161-163° hfu 217-218° br 262-264° hfu 221-223° fu 185-187° hfu 210-211° fu 255-257' b 136-138° b 127-129° b 118-120° Example No.

Analogous to Ex.No.

A B c M.P. 38 .2 + 3 -chloro-2,1,3-benzothiadiazol- )N-0-CH C=CH 4,5-dihydro-1H- ch 183° (dec.) 4-yl imidazol-2-yl .39 .2 + 3 -chloro-2,1,3-benzothiadiazol- )N-0-CH OCH„ f 9.0 4,5-dihydro-1H- hfu 146-147° 4-yl I | I Me itnidazol-2-yl 40 .2 + 3 ~chloro-2,1,3-benzothiadiazol- ■)N-0-CH„CH=CHCH_ / O 0 4,5-dihydro-1H- hfu 155-156° 4-yl L J imidazol-2-yl 41 2 + 3 -chloro-2,1,3-benzothiadiazol- )N-0-CHoCH=CH-Phe 4,5-dihydro-lH- hfu 178-179° 4-yl imidazol-2-yl 42 .2 + 3 -chloro-2,1,3-benzothiadiazol- )N-0-CH CH OH 4,5-dihydro-lH- hfu 144-146° 4-yl L L imidazol-2-yl * The substitution reaction of 5-chloro-N-(4,5-dihydro-lH-iirddazol-2-yl)-2,l,3-benzothiadiazol- 4-amine may also be effected with 4-chlqro-p-fluorobutyrophenonein protected. form,i .e .wherein-the--keto moiety is protected in the form of a 1,3-dioxolone-2-yl moiety and the resultant compound may thereafter be deprotected using dilute aqueous hydrochloric acid solution ** The cyclization reaction may also be effected with the starting compound.having the keto moietyiih-th* p—fluorobutyrophenone group protected in the form of a 1,3—dioxolone—2—yl moiety and the resultant compound may thereafter be deprotected using dilute aqueous hydrochloric acid solution.

M.P. = melting point dec. ■= decomposition b «= in free base form br «* in hydrobromide acid addition salt form ch a in hydrochloride acid addition salt form fu " in fumarate acid addition salt form hfu = in hydrogen fumarate acid addition salt form ta = in acid addition salt form as tartrate iBu SB isobutyl Bz a benzyl Et ■= ethyl Me C8 methyl Phe C= phenyl iPr s isopropyl r h* VO I On (5 O 11 VI o N. 0V K» 199762 - 20 - -500^5563 The compounds of the invention exhibit pharmacological activity in animals.

In particular, the compounds possess bradycardiac activity, as indicated by standard tests. For example, in the spontaneous-5 ly-beating right ventricle of the guinea pig (method of Dixon, A.K. et al., Arzneim.F. 27 [1977] 1968-1979) a decrease in the heart rate is observed at a bath concentration of from about 1 ^jM to about 100 ^iM.

In the pithed rat preparation (method of H. Kleinlogel 10 et al., Europ. J. Pharmacol. 33 [1975] 159-163) the compounds exhibit heart rate decreasing activity at a dosage of about 0.3 to about 10 mg/kg i.v.

The compounds are devoid of peripheral a-mimetic activity, as evidenced by the observation that the bradycardiac activity 15 is not accompanied by any significant vasoconstriction or blood pressure increase.

The compounds of the invention are therefore indicated for use as bradycardiac agents, e.g. for the prophylaxis and treatment of cardiac disorders such as Angina pectoris or heart 20 rhythm disturbances such as sinus tachycardia.

Preferred in this indication are the compounds of Examples 1, 3, 10, 15, 19, 23, 28, 30 and 41, especially of Examples 1, 3 and 10, particularly of Example 1.

Additionally, some of the compounds, in particular those of formula la wherein Y is oxygen, exhibit a pronounced 19.976 - 21 - 500-5563 degree of membrane-stabilizing activity which may make them particularly useful in the treatment of heart rhythm disturbances not necessarily related to a sinus tachycardia.

An indicated daily dosage is from about 5 mg to about 5 100 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 mg to about 50 mg, or in sustained release form.

The compounds of the invention additionally exhibit anti-tremor activity, as indicated by standard tests. This 10 appears from a tremor antagonism in mice on p.o. administration of from about 10 to about 100 mg/kg animal body weight of the compounds in accordance with the following test: The evening before the test day the mice used for the test (50% males and 50% females) are deprived of feed. 15 Groups of ten animals each are used for the test, one group forming the control group. The compound to be tested is administered to the animals in each group, the doses increasing from group to group. A physiological saline solution is given to the animals of the control group. 30 20 minutes after administration of the compound to be tested, 100 mg/kg animal body weight of a tremor-producing compound (2,6-dichlorophenyl-acetimidoyl ureide) is administered p.o. to all the animals. 5, 10, 15 and 20 minutes after administration of the tremor-producing compound the animals 25 are judged in accordance with the following scale: 2 = strong tremor; 1 = weak tremor; 0 = no tremor. Evaluation is then effected: for the three first measurements (5, 10 and 15 minutes after administration), the behavious of each mouse is determined, and the group average values are estimated as 30 follows: 199762 - 22 - 500=5563- group with strong tremor = averages 1.5 - 2.0 group with weak tremor = averages 0.5 - 1.5 group with tremor = averages 0 - 0.5 The compounds of the invention are therefore indicated 5 for use as anti-tremor agents.

The compounds also exhibit anti-rigor activity, as indicated by standard tests. This appears from a rigor antagonism in rats on i.v. administration of from about 0.001 to about 10 mg/kg animal body weight of the compounds, in accordance 10 with the following test: Rats are injected i.p. with 7.5 mg/kg animals body weight of Thalamonal (Registered Trade Mark), whereupon these animals develop a rigor which can be measured with an electro-myograph. The dose of active compound which must be injected 15 i.v. in order to inhibit the rigor of the rats is then ascertained.

The compounds are therefore further indicated for use as anti-rigor agents.

The compounds of the invention also exhibit myotonolytic 20 activity, as indicated by standard tests. For example, in rabbits on i.v. administration of from 0.001 to 0.1 mg/kg animal body weight of the compounds a significant muscle relaxing effect is observed in accordance with the method of Teschendof et al., Arch.Exp. Pharmacol. 266, 467-468 (1970). \ 199762 - 23 - 500-5563 The compounds are therefore further indicated for use as myotonolytics, for example for the treatment of spastic conditions of different etiology (neurological, inflammatory, rheumatic, etc.) and muscle relaxants.

The compounds also exhibit tranquillizing and sedating' activity, as indicated by standard tests. Thus, the compounds suppress motility, as can be demonstrated in mice. In one test two groups, each comprising four mice (one group as a control group), administered with 0.01 mg/kg to 1.0 mg/kg 10 p.o. of the test compound is placed in a cage in redlight (Electronic Motility Testing obtainable from Motron-Pro-ducter, Stockholm, Sweden). The number of times the mice interrupt the light beams is counted electronically every fifteen minutes over a period o£ 60 minutes. Furthermore, 15 the compounds reduce defensive ambivalence behaviour (a form of conflict behaviour) and increase social contact in standard animal introduction tests. In one test a male mouse administered with 0.1 to 1 mg/kg p.o. of the compound is placed for 6 minutes into the home cage of an isolated, 20 aggressive male mouse. The behaviour of the introduced mouse is then statistically analysed according to the method of A.K. Dixon and J.R. Mackintosh, Anim. Behav. 19, 138-140 (1971) using the behavioural categories outlined by A.K.

Dixon "Rodent Social Behaviour in Relation to Biomedical 25 Research" in "Das Tier im Experiment", Ed. W. Weihe, Hans Huber Verlag, Bern 1978, e.g. nonsocial activity, social investigation and mating, aggression, defensive ambivalence, fleeing or retreating and feeding behaviour. Furthermore, on administration of 0.3 to 3 mg/kg p.o. of 30 the compounds to rats in the sleep/wake cycle carried out in accordance with the principles of H. Kleinlogel et al., \ 199762 - 24 - 600 5503 European J. Pharmacol. 33, 159rl63 (1975) an increase of dozing is observed. The EEG is recorded over 8 hours.

The compounds are therefore indicated for use as tranquillizers and sedatives.

The compounds also exhibit antidepressive activity, as indicated by standard tests. Thus, an inhibition of tetrabenazine-induced catalepsy and ptosis in rats is observed upon intraperitoneal administration of from 5 to 20 mg/kg animal body weight of the compounds in accordance 10 with the method described by Stille (Arzneimitte1-Forsch.

[1964] 14^ , 534). Furthermore, the compounds on administration of from 1 to 30 mg/kg i.p. to mice reduce the immobility induced by water-immersion according to the method described by R.D. Porsolt et al., Arch. Int. Pharmacodyn. 229 15 327-336 (1977).

The compounds are therefore indicated for use as antidepressants, e.g. for the treatment of somatogenic, endogenous and psychogenous depressions.

For. the_above-meationed•uses. as anti-tremor,anti-rigor, myo- tonolytic and. muscle relaxant, ^tranquillizing and_ sedative, and .antidepressant agents an indicated daily., dosage . is from about 0.2 mg to about 200 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.05 mg to about 100 mg, or in:;sustained release form.

The compounds of the invention in free form or in the form of their pharmaceutically acceptable salts|inay be administered alone or in suitable dosage forms. The present in-

Claims (67)

199762, - 25 - 500 5563 vention also provides a pharmaceutical composition comprising a compound of the invention in free form or in salt, preferably acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions, e.g. a solution or a tablet, may be produced according to known methods. > 1997 - 26 _ .500-5563 ' *v'^AT^Wf5 CLAM «S:';

1. A process for the production of a compound of formula I;A I;B 1;C;wherein;A is an optionally substituted 2,1,3-benzothiadiazole or 5 2,1,3-benzoxadiazole moiety,;B is a trisubstituted amino group and;C is an optionally 1-substituted 4,5-dihydro-IH-imidazol-2-yl or an optionally 3-substituted 3,4,5,6-tetrahydro-pyrimidin-2-yl moiety,;10 which comprises a) appropriately substituting a corresponding compound of formula II;B' II;l;C;wherein A and C are as defined above and B' is a secondary 15 amino group or b) reacting a corresponding compound of formula III;t;B III;\;Q;wherein A and B are as defined above and Q is a group capable of cyclization with a diamine,;199762;-21 _;with a corresponding, optionally 1-substituted ethylene or propylene diamine.;2.;A process according to claim 1 for the production of a;10;15;20;compound of formula 1^;la;(CV„;wherein n is 2 or 3,;X is oxygen or sulfur,;Y is a bond or oxygen,;R^, and R^ independently are hydrogen, halogen of atomic number of from 9 to 53, cyano, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkylthio of 1 to 4 carbon atoms,;R. is 4;i);alkyl of 1 to 6 carbon atoms optionally monosubstituted by hydroxy or halogen of atomic number of from 9 to 53 and wherein the hydroxy or halogen moiety is separated from Y by at least 2 carbon atoms; alkenyl of 3 to 6 carbon, atoms optionally monosubstituted by halogen of atomic number of from 9 to 53 and wherein the double bond and the halogen moiety are separated from Y by at least 2 carbon atoms; alkinyl of 3 to 6 carbon atoms wherein the triple ^bond is separated from Y by at least 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon.;;' - '2d* » 199762 -28- atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof; ii) 2,2,5,5-tetraalkylpyrrolidin-1-ylalkyl "or 2,2,6,6-tetraal- kylpiperidin-l-ylalkyl independently of 1 to_4_carbon atoms 5 in each of the alkyl moieties of the pyrrolidine or piperidine moiety, of 2 to 5 carbon atoms in the alkyl moiety bound to Y and wherein the nitrogen atom of the pyrrolidine or piperidine moiety is separated from Y by at least 2 carbon atoms; furanylalkyl, thienylalkyl or 10 pyridylalkyl each of 1 to 4 carbon atoms in the alkyl moiety thereof; or morpholin-1-ylalkyl of 2 to 5 carbon atoms in the alkyl moiety thereof and wherein the nitrogen atom of the morpholine moiety is separated from Y by at least 2 carbon atoms: 15 iii)phenylalkyl of 7 to 11 carbon atoms, phenoxyalkyl of 8 to 12 carbon atoms wherein the oxygen atom is separated from Y by at least 2 carbon atoms, phenylcarbonylalkyl of 8 to 12 carbon atoms, phenylalkoxyalky1 of 1 to 4 carbon atoms in the alkoxy and of 2 to 5 carbon atoms in the 20 alkyl moiety thereof and wherein the oxygen atom is separated from Y by at least 2 carbon atoms, phenylalkenyl of 9 to 13 carbon atoms wherein the double bond is separated from Y by at least 2 carbon atoms, phenylalkinyl of 9 to 13 carbon atoms wherein the triple bond is separated 25 from Y by at least 2 carbon atoms, all the phenyl rings in the six above-mentioned substituents optionally being mono- or independently di-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53 or, whea Y is a bond, al- 30 ternatively or additionally also by hydroxy; or :'.iiii)when Y is oxygen, additionally hydrogen, and R,. is hydrogen or alkyl of 1 to 4 carbon atoms, 199762 500 55G3 which comprises a) appropriately substituting the bridging nitrogen atom in a corresponding compound of formula Ila Ila («5"~S-R 5 z n 10 wherein n, X, R,, R , R„ and R_ are as defined above or ^ 2 3 5 b) for the production of a compound of formula Iaa, R Iaa (CVn wherein n, X and R^ to R^ are as defined above, reacting a corresponding compound of formula Ilia Ilia wherein X and to R^ are as defined above and Q is as defined - 30 - in claim 1, with a corresponding compound of formula IV H N-(CH-) -NHR IV

2 2 n 5 wherein n and are as defined above.

3. A process for the production of a compound of formula I, as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples.

4. A compound of formula I, as defined in claim 1, whenever produced by a process according to claims 1 to 3.

5. A compound of formula I, as defined in claim 1, in free form or in salt form.

6. A compound of claim 5 of formula la, as defined in claim 2.

7. A compound of claim 6 of formula la wherein X is sulfur.

8. A compound of claim 6 of formula la wherein Y is a bond.

9. A compound of claim 6 of formula la wherein Y is oxygen.

10. A compound of claim 6 of formula la wherein and are hydrogen.

11. A compound of claim 6 of formula la wherein is halogen.

12. A compound of claim 6 of formula la wherein the nitrogen atom carrying Y-R^ is bound at the 4 position of the 2,1,3- 1997 62 - 31 - 500-5563- benzothiadiazole or 2,1,3-benzoxadiazole ring.

13. A compound of claim 6 of formula la wherein R^ has significance i).

14. A compound of claim 6 of formula la wherein R^ has significance iii)

15. A compound of claim 6 of formula la wherein R^ is hydrogen.

16. A compound of claim 6 of formula la wherein R^, is alkenyl.

17. A compound of claim 6 of formula la wherein R^ is optionally substituted phenylalkyl, phenoxyalkyl, phenylalkoxy-alkyl or phenylalkenyl.

18. A compound of claim 5 of formula Ipa, R2, fl ipa wherein R^ and R2 are as defined in claim 2 R^ has the significance indicated in claim 2 for R^ and R^ is 4 199762 - 32 - 500 5563 10 15 i) alkyl of 1 to 6 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 2 carbon atoms; 2~chloro-2-propenyl; alkinyl. of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen atom by at least 2 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 6 carbon atoms in the" cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof, the total number of carbon atoms not exceeding 7; ii) thienylmethyl, 2-furanyImethyl-or Pyri- dylme thyl ; ov_

19, iii) benzyl or cinnamyl. A compound of claim 6 of formula Ipb, Ri Ipb wherein R, and R„ are as defined in claim 2 and R^ and R^ 12 3 4 are as defined in claim 18.

20. The compound of claim 5 which is N-allyl-5-chloro-N-(4,5-dihydro-lH-imidazol~2-yl)-2,1,3-benzothiadiazol-4-amine. 20 21. The compound of claim 5 which is 5-chloro-N-hydroxy-N-(4,5-dihydro-lH-imidazol-2-yl)-2,1,3~benzothiadiazol-4-amine. v

I - 33 - ■30Q=33€rd~

22. The compound of claim 5 which is 5-chloro-N-^(4,5-di-hydro-lH-imidazol-2-y1)-N-(2-phenoxyethoxy)-2,1,3-benzothia-diazol-4-amine.

23. A compound of claim 5 of formula I wherein A is 5-chloro-5 2,1,3-benzothiadiazol-4-yl and C is 4,5-dihydro-lH-imidazol-2- yi.

24. The compound of claim 23 wherein B is /N-Me.

25. The compound of claim 23 wherein B is >N-Et.

26. The compound of claim 23 wherein B is ^sN-Bz. 10

27. The compound of claim 23 wherein B is ^>N-crotyl.

28. The compound of claim 23 wherein B is ^N-CH„C=CH„. 21 2 Me

29.- The compound of claim 23 wherein B is ^-N-CH^CK!^. CI

30. The compound of claim 23 wherein B is ^N-CH2CH=CMe2.

31. The compound of claim 23 wherein B is ^.N-CI^CI^CH-Phe. 15

32. The compound of claim 23 wherein B is ^.N-iPr.

33. The compound of claim 23 wherein B is )xN-iBu.

34. The compound of claim 23 wherein B is )-N-CH - 500 5563

35. The compound of claim 23 wherein B is ^N-(CH?) ^C0-{O^~F.

36. The compound of claim 23 wherein B is ^N-CH^CH^-O-Phe.

37. The compound of claim 23 wherein B is ^•N-CH2CH2-0—^3^--0H.

38. The compound of claim 23 wherein B is >N-CH2CH2~0CH2-(5^-0Me.

39. The compound of claim 23 wherein B is^N-CH2CH2-Phe.

AO. The compound of claim 23 wherein B is M3-CH?CH?-^Q^-Me.

41. The compound of claim 23 wherein B is ^N-CH^CH^-^O^-OH.

42. The compound of claim 23 wherein B is ^N-CH2CH2-N^ ^0.

43. The compound of claim 23 wherein B is ^N-CH C=CH. 2 Me Me Vk

44. The compound of claim 23 wherein B is ^N-CH CH„~N ) A

45. The compound of claim 23 wherein B is ^>N-0-allyl.

46. The compound of claim 23 wherein B is^N-0-Me.

47. The compound of claim 23 wherein B is^N-0-CH2"^

48. The compound of claim 23 wherein B is^:N-0-CH2C=CH.

49. The compound of claim 23 wherein B is^N-0-CH2C=CH2. Me 199762 - 35- - $ee-55fr3"

50. The compound of claim 23 wherein B is^N-O-Cl^CI^CHCH^•

51. The compound of claim 23 wherein B is ^N-O-Cl^CH^H-Phe.

52. The compound of claim 23 wherein B is ^N-0-CH Ci^OH.

53. A compound of claim 5 of formula I wherein B is>N-allyl and C is 4,5-dihydro-lH-imidazol-2-yl.

54. The compound of claim 53 wherein A is 5-chloro-7-methyl-2,1,3-benzothiadiazol-4-yl.

55. The compound of claim 53 wherein A is 4-methyl-2,1,3-benzothiadiazol-5-yl.

56. The compound of claim 53 wherein A is 4-bromo-2,1,3-benzo-thiadiazol-5-yl.

57. The compound of claim 53 wherein A is 7-chloro-5-methy1— 2,1,3-benzothiadiazol-4-yl.

58. The compound of claim 53 wherein A is 5-methyl-2,1,3-benzothiadiazol-4-yl.

59. The compound of claim 53 wherein A is 5-methyl-2,1,3-benzoxadiazol-4-yl.

60. The compound of claim 53 wherein A is 5,7-dimethyl-2,1,3-benzoxadiazol-4-y1. - 36 -

61. The compound of claim 5 wherein A is 5-chloro-2,l,3-benzothiadiazol-4-yl, B is >N-Me and C is 4,5-dihydro-lH-l-methylimidazol-2-yl.

62. The compound of claim 5 wherein A is 5-chloro-2,l,3-benzothiadiazol-4-yl, B is >N-allyl and C is 4,5-dihydro-lH-l-methylimidazol-2-yl.

63. A compound of any one of claims 5 to 62 in free form.

64. A compound of any one of claims 5 to 62 in salt form.

65. A compound of any one of claims 5 to 62 in acid addition salt form.

66. A pharmaceutical composition which comprises a compound of any one of claims 5 to 62 in free form or in pharmaceutically acceptable salt form in association with a pharmaceutical carrier or diluent.

67. A compound of claim 5 for use as a pharmaceutical.