CA1195993A

CA1195993A - Benzamide derivatives

Info

Publication number: CA1195993A
Application number: CA000435172A
Authority: CA
Inventors: Bernard T. Bull; Michael J. Ashton; Jeremy D. Pratt; Anthony H. Loveless; Colin J. Daniels; David C. Cook
Original assignee: May and Baker Ltd
Current assignee: May and Baker Ltd
Priority date: 1982-08-24
Filing date: 1983-08-23
Publication date: 1985-10-29
Also published as: CS612483A2; BE897580A; NO833024L; JPS5955873A; IT8322629A0; ES8505935A1; GB8322539D0; DK386783D0; GB2126225A; US4507315A; DE3330403A1; FR2532310B1; FI832989A; GB2126225B; PT77219B; FI832989A0; SE8304545D0; LU84974A1; ES525099A0; ZA836191B

Abstract

ABSTRACT
"BENZAMIDE DERIVATIVES"

Benzamide derivatives of the general formula:

I

wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and R1 represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkoxy-carbonyl, dialkylamino, alkylcarbamoyl or alkanoylamino group and n represents zero or the integer 1 or 2, R4 represents an alkyl radical and p represents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, possess useful pharmacological properties.

Description

3~3 DESCRIPTIO~
BENZAMIDE DERIVATIVES
This inv~ntion relate~ to new therapeutically us~ful hcn7.~m;de derivative~, to proces~ for preparing them, and to p~Arm~ceutical compo~itions cont~;n;n~ th~m.
The be~Amide derivatives of the pre~en~ invention S are those compound~ of the general formula (R4)~
(R3~ ~ CO~H - A - N

S2~\
~2 ~Rl~m wherein A repre~ents a divalent straight- or branched-chai~
alkyl~ne gxoup cont~; n; n~ from 1 to 6, preferably 2, 3, or 4, carbon atom~ and Rl represent~ a halogen, i~e. fluorine, 10 chlorine, bromine or iodine, atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl (e.g~ trifluoromethyl~, alkoxy, alkylthio, alkylsulphinyl, alk~lslllphonyl, alkoxycar~onyl, alk~lamino, dialkylamino, alkylcarbamoyl, d.ialkylcarbamoyl, 15 ~lk~noyl, alkanoyloxy or alkanoylamino group and m xepresents zexo or the int~ger 1 t 2 or 3, R represent~ a hy~rogen atom or an alkyl group, R3 represent~ a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or car~amoyl group or an alkyl, fluvrlne-~ub~tituted alkyl, ~.g. trifluoromethyl, alko~y, 20 alkoxycarbonyl, dialkylamino, alkylcarbam~yl or alkanoyl~mino group and n repre~ent~ zero or the integer 1 or 2, R4 represent~ an alkyl radical and ~ represents zero or he ~5~3 in~eger 1 or 2, and pharmaceutically acceptable salts thereof.
In accordance with another aspect the present invention provides a process for the preparation of a benzamide derivative of the general formula (I):

(R )~
~ CONH - A - N

~l - SO2 12 (Rl~_ wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl/ alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano~ carboxy or carbamoyl group or an alkyl, fluorine~substituted alkyl, alkoxy~ alkoxycarbonyl, dialkyl-amino, alkylcarbamoyl or alkanoylamino group and n repre-sents zero or the integer 1 or 2, R represents an alkyl radical and ~ xepresents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in 0 that either (i) a compound of the general formula (II):

.~

~S~S93 - 2a -~ IR4~
(R ~n ~ CONH ~ A ~ (II) H

wherein A, R , R , R , n and ~ are as defined above, R3 when hydroxy, amino or carboxy being, if desired, protected by a suitable protecting group, is reacted with a sulphonating agent of the general formula (III3:

~ S2 Hal (III) (Rl) wherein Rl and m are as defined above, Rl when hydroxy, amino r carboxy or alk~lamino, being, if desired, protected by a suitable protecting group, and Hal represents a halogen atom, any protecting group present being thereafter removed, to obtain a com-pound of the general formula (I) as defined above, and if desired~ the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof, (ii) a compound of the general formula (IV):

{ ~ (R ~m 5~

- 2b -wherein Rl R~, R3; m and n are as defined above, R when hydroxy, amino, carboxy or alkylamino, being, if desired, protected by a suitable protec-ting group, R3 when hydroxy, amino or carboxy, being, if desired, pro-tected by a suitable protecting group, or a suitable reactive derivati.ve thereof, is reacted with a compound of the general formula (V):

~ (~4) H2N -A ~

wherein A, R and ~ are as defined above, any protecting group present being there-after removed, to obtain a compound of the general formula (I1 as defined above, and, if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof, (iii~ a compound of the general formula (I~
wherein Rl, R3 or both Rl and R3 repxesent a nitro group, p~1 when hydroxy, carboxy or alk~lamino being, if desired, protected by a suitable protec-ting group, R3 when hydroxy or carboxy being protected by a suitable protecting group, is treated to conYert said nitro group into an amino group, any protecting group present being thereafter removed, to obtain a compound of the general formula (I) as defined above wherein Rl, R3 o.r both R and R3 represent an amino group and, if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically ~5~

acceptable salt thereof, or (iv) a compound of the general formula (I) wherein Rl, R3 or both Rl and R3 represent an amino group, Rl when hydroxy, carhoxy or S alkylamino being, if desired, protected by a suitable protectiny group, R3 wh~n hydroxy or carboxy being protected by a suitable protecting group, is treated to convert said amino group into a halogen atom, an~ protecting group present being thereafter removed, to obtain a compound of the general formula (I) as defined above wherein R or R3 or both Rl and R3 represent a haloyen atom and, if desired, the so obtained com-pound of the general formula ~I) is converted into a pharmaceutically acceptable salt thereof.
Fluorine-substituted alkyl groups within the definitions of the substituents Rl and R3 may be substituted by one or more fluorine atoms. Alkyl groups or moieties, alkoxy groups or moieties and alkanoyl groups or moieties above may be stxaight- or branched-chain and contain from 1 to 10 (preferably 1 to 4) carbon atoms. The alkyl moieties in the dialkylamino and dialkylcarbamoyl groups above ma~ be the same or different.
When any of the symbols m, n and ~ îepresent the integer 2 or 3, the groups represented by the corresponding symbol Rl, R3 or R4 may be the same or different.
In certain cases the substituents R , R ? R , R4 and alkylene group A contribute to optical isomerismO All such forms are embraced by the present invention.
By the term pharmaceutically acceptable salt in relation to compounds of general formula I is meant a salt formed by reaction with an acid or, when Rl or ~3 represents a carboxy group, by reaction with a base, so that ~5~

- 2d -the anion (in the case of an acid addition salt) ox the cation (in the case of a salt formed by a compound of general formula I wherein R or R represents a carboxy group) is relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the parent compcund of general formula I are not vitiated by side effects ascrib-able to the said anion or cation.

S~3~3 Suitable acid addition salts include salts derived from inorganic acids ~ for exa~le hydrochloride~, hydro-bromides, phosph~tes, sulphates and nit:rate~, and organic ~alts, for exan~le me~h~3nesulphonate~, 2 hydroxyetharle-5 sulphonates, oxalaterq, lactates, tartrate~, acetates,salicylates, citrates, propiorlilt~ uccinat~s, furrL~rates, maleates, methylene bi~ hydroxynaphthoate~, genti~ates and ~ 2 toluoyltarl:rates.
Suitable salt~ formed by compounds of general fo~mula I
10 wherein Rl or R3 repre3en~s a carboxy group include the alkali xnetal ( e. g. sadium and pota~ ), alkaline earth metal ( e. gO cal~ium and mA~nesium~, and alr~nonium salts, and salt~ of am~ne~ known in the art to be p~ ceutically acceptable, e . y. ethylene diamine, choline, diethanolaTnine, triethano1a~nine" octadecyl ~m; ne, diethyl ~m; ne, triethylamine,

2-amino-2- (hydroxymethyl )propane-l, 3 diol and 1~(3,4-dihydroxypheny1)-2-isopropy1aminoe~hano1.
It i~ to be understood that, where in thi3 spec~ficatio~ reference i~ made ~o compounds of genera1 formula I, it i~ intended ~o refer al~o to their ~h~r~ceutically acceptab1e ~alts ~s indicated above, w~ere the context 30 permits.
Preferred compounds of g~nera1 fonmu1a I are thos~
wherein A repre~ents an ethylene, trimethy1ene, 3-methyl~
trimethy1ene ox tetramethylene group and Rl represents a halogen atom or an amino, nitro, trif1uoromethy1 or acet-amido group or an alkyll e.g. methy1, alkoxycarbonyl or C1 4a1koxy group and m represent~ zero o t~e integer 1, 2 or 3, R repre~ent~ a hydrogen a~-om, R repre~ent~ a ha1Ogen, preferab1y chlorine, ~tom a~d represen~s zero OE
the integer 1, and R4 repre~ents an alkyl, ~.g. methyl, group in ~he 2- or 4~po~ition and ~ repre3ent~ zero or the integar 1.
E~pecia11y preferred compound~ of genera1 fo~nu1a I are tho~e w~ere1n A repre~ents an ethy1ene, tr ~eth~1ene or 3-methy1trimethy1ene group and R1 xepresent~ a ha1Ogen atom) tri~1uoromethy1 group, ox an a1ky1/ e.g. msk~y1 group and m represent~ ~he 1nteger 1 or 2, ~2

3~

represents a hydrogen atom, R3 represents a halogen, preferably chlorine atom and n represents zero or the integer 1, and R4 represents an alkyl, e.g. methyl, group in the 4 position and ~ represents zero or the integer 1.
When m is the integer 1, the group Rl is in preferably the 2, 3 or 4-position, or 3-positîon when Rl represents a trifluoromethyl group. When _ is the inte~er 2, the groups Rl are preferably the same and in positions 2,4; 3,4 or 2,5 when halogen atoms and in positions 3,4 when methyl groups~
The symbol A preferably represents trimethylene.
In accordance with the present invention an alkyl group may contain 1 to 4 carbon atoms; an alkoxycarbonyl group may contain 2 to 5 carbon atoms.
The compounds of general formula I possess useful pharmacological properties, in particular hypoglycaemic activity, and some are intermediates for the preparation of the other therapeutically useful d~rivatives. The compounds of general formula I lower blood glucose levels in mice suffering from diabetes mellitus. They lower the concen-trations o cholesterol and of txiglycerides in the blood.Thus, they are of utility in the prevention or treatment of diabetes mellitus, hyperlipoproteinaemic states and of atherosclerosis.

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~5~3 Com~ounds of general fomrula I wllich ~re of particular interest inGlude the following con~unds, and their ~alt~
Compound A 2- ( 4 chlorobenze}le~ulphonarnido ) N- ( 3 imidazol-l-ylpropyl ) b~n ~;~m; de B 2-(3-chlorobenzene~ hon~m; do )~- ( 3-imidazol-l-ylpropyl) b~n 7~m; de C 2-~2-chlorobenzenesulphon~m;do)- -(3~imidazol~
l-ylpropyl1bPn7.~mide D 2-~4-bromob~n~n~.sl]lp~on~m;do)-N-(3-imidazol-l~ylpropyl)bPn7.~mide E 2-(benzene~ulr~o~mido) ~3-imidaæol-1-ylpropyl ben~ mi d~
F 2- ~ 4-methylbPn 7~ne.~ulphonamidc) ) -N- ( 3~ Li dazol-l-ylpropyl ) b~n Y~:~m; cl~
G 2- ( 3, 4-dimethylbF~r~Yene~ulphon~m; do ~ ( 3-imidazol-1--ylpropyl ) b~n ~m; de H 2 - ( 4~nitrohen 7,ene~l1 1 Fihon ~m; do ) ~ ( 3 - imida2:01 1 ylp~o~ h~n7~m; ~le S-chloro 2~4--cl~lorobenæenesulpl oni3m;do) ( 3-imidazol-1 ylpropyl ~bPn~m; d~3 J 2~ ( 2, 5 dichlorobe~zene3ulp~0namid 9 ) -N~ ( 3~imidazol~
l~ylprop~l ) b;~n ~ m; de ~5~3 ( - 6 -K 2-(2~nitrobe~zene~ulp~on~m;do)-~-(3-imidazol-1-ylpropyl)ben%ami~e L 2-~4-fluorobenzenesulphonamido~ 3_imidazol_1 ylpropyl)ben~m;d~
M 2-(4-chlorobenzene~l r~ ~n~mido)-N-~3-(2 methylimidazo~ yl)~
propyl7bPn7.~m;de 5 ~ 2-(4~chlo:robenzenesulI)h~nF~m; do)-N-~3-t4-methylimi L~zol-1-y~
p~opyl7bPnY.~m;~
2-~4-nitrobenYerlesl~lrh~nqmido) ~3~ msth;ylimiaazol~l-yl)propyl~-~n~.~m;de P 2-~4-a ~ oben~a.nQRlllphr~n~mido)-N~ imidazol-l-ylp:ropyl)benziamide 10 Q 2-(4-methoxyb~nY.~n~ulph~n~m;do)-~-(3-imid3zol-1-ylpropyl)b~qnY.~m;de R 2-(4-acetamidoken~enPsul~h~n~;do)-~-(3-imidazol-1 ylpropyl )b~qn~q~ide S 2-(4-isopropylb~n~ nQ~ulr~ t~nqmiao3 }~(~;mi~q~ol-~-ylpropy~ pny~qm;( T 2-~4-t- ~ tylbenzene~ulp~-)n~mido)-~ m;~ o~ ylpropyl)benz ~ de U 2-(4-octylben~.~nPsulphnn~m;do)-N-~3-imidazol-1-ylpropyl )bQn v~mi de I5 V 2-~4-ethoxycarbony1~en7Pnesulp~on~m~do)-~-~3 imidazol-1-ylpropyl)b~nv~m;ae W 2-(3-trifluoromethylbenzenesulr~nn~m;do)-N-(3-imi dazol-1 ylpropyl3-benv.~ ~1P
X 2-(3~4-dichlorobenzenesulp,hl-n~;do)-N~ imidazol-1-ylpropyl)ben7~m;~
Y 2-(29 4 dichlorobenzene~ulphon~mido)~ 3-imidazol-1~ylpropyl)bPnv.~mi~lP
20 Z 2-(2y6-dichlorob~n~n~sulph~n~ido)~ 3-imidazol-1-ylprop~l)bpn7~
AA 2-(273-dichlorobpn~7pnp3~ hrln~mido3-~ 3-imidazol-l-ylRropyl)ben~:~mide B~ 2-(2-tri~luoromethylkenven~ulrh~n~m; do)~(3-imidazol-1-ylpropyl)-b~
CC 2-(4-ohloro-2-trifluoro~ethylb~pnv~neslllphr-- ido)~ ~mida~;ol-1 ~5 ~lpropyl)b~n~;d~
D~ 2-~3,5-bistrifluo~ ~t~ylbenzene~ul~hnn~do)-~-(3~ rbol~1-ylpropyl)be~n ~

f EE 2-(294,5~trichloroben~.~nesulphonamido)-N-(3-.imidazol-1-ylpropyl)-ben~;de FF 2-(27374-t~ichloro~n~Pn~ulrhnn~ do)-N-(~-ii dazol-1-ylpropyl)-b~n ~n; de S GG 2-(4chloro-3-trifluoromethylbpn~enp~l~rh~ n~i ao)~ ~imida ylpropyl)ben~ ;de HH 5-chloro-2-(~-trifluoromethylbenzene~vlph-.n~mido)-N~ ;m;~ol-1-~lpropyl)ben~ ;de II 5-chloro-2-(3,5-bi3trifluoromethylbenzenesulrhon~i do)-~-(3-lO ;~ 7o~ propyl)~Pn 7.~
~J 5-chloro-2-(3-chlorobenzene~lphnn~ o3-~-(3-imidazol~1-ylp~opyl)-~
b~n~m;~
KK 2-(3 fluorob~n~.enF~ phon~ido)-~-(~imi~.ol-l-ylpropyl)ben~omid~
LL 2-( 3-fluoro-4-methylbenzenesulphnro~i d~3-~-( 3-imidazol-1-ylpropyl3-15 bF~n~ mil~fi ~M 2-(3-b~omob~n~enPsulrh~n~m;do)-~-( 3-; m; ~ ~ zol-1-ylpropyl )b~n ~m ide ~D~ 2-(3-~itrobPn~.en~ulrhon~;do)-~-~3-imidazol-1-ylpropyl) b~n~; de 00 2-(2~4-difluaroben7pne~llrhr~n~i do)-~ imiclszol-l-ylpropyl~b~n~
PP 2-(3-~methylbpn~npgulrhnn~m;do)-~-(3-i~idazo~ ylpropyl)b~l~ ;d~
20 QQ 2-(2-methylh~n~n~sulp~r- -do)-- -(3-im;f7~ol-~ ylpropyl)b~n~miclR
.RR 2-(2-fluorobpn~pnf~ lrh~-- do) -(3-iEidazol-1-ylpropyl)bPn~m;dP
5S 2-(2~ohloro-5 trifluorome~hylb-~,n~Pne~llrh~n~;do)~N-(3 imi~.ol_1_ ylpropyl)bPn~m;d~
T~ 2-(4-iodobçns~n~ h~n~ do)-~3-imida~ol-1-ylpropyl)b~n~ P
25 ~nJ ~ - (4~chlarobpn~np~ulph-~n- ~aO~ (4~ o~ yl~u~yl)~pn ~-7 W 2-(4- c~llorolben2:~!ne~ o~ (2- jm; -7z~ ~:ol -1-yl~t~l) ben~ d~
WW Z-(4-f~hlo robpn~n~ rhon5~m; ao)~ ol 1-glbtl~yl)b2nzamid~3 The l~tter~ A to WW aTO ~ a ~0 the oc ~ or eaDy rer~noe l~ter ln ttae ~p~oi~icatio~ ~or ~ in ~h0 ~ollo~in~ T~bl~

Compounds A, W and W hydrochloride are preferred compound~ of the invention.
~ he phArm~cological properties of the ~o--~o~ld~q of general formula I or ~alts thereof were ~m~trated in 5 the following teqts:
HvpcqlycAPm;c Activity i~ Diabetic Mice Diabetic mice (~train C 57, black, MRI derived Obe~e/Obese) of either sex each weighing between ~5 and 70 g were give~ the te3t compound orally in tragacanth ~lcil~ge ~ a dose o~ 5,10~30,100,200 or 500 mg~kg body weight per day for 3 days. ~hxee hours after the last dose ~he .~n;m~l were killed with carbon dioxide and bled by cardiac puncture.
The blood glucose levels were as~e~sed ~y the glucose-oxidase method of G~D~Perid.
Control group~ (given doses of unmedicated tragacanth mucilage) were included with each t~t.
The perc~ntage reduction in the concentration of blood glucose was calculated by c~mr~ri~on with th~
simultaneous control~, for each of the te~t compounds used.
The results obt~;ne~ are ~hown in th~ following Table Io ~- 9 -, TA:E~LE

CompolJnd mg/k~ body % cha~1ge iIl blood glucose weight p~~ day compared with control A 200 ; 1 û0 ; 30 -67 -6 1; -49 ; -13 ~ 200 4~
Y V 200 _53 W 200 -~8 W500j 200; 100; 30, 10; 5 -46; -62; -50; -58; -29, -25 hydrochlorlde X ~00 -58 200 -5 ~
00 200 ~35 H~po~lycaemic Activity in Diabetic Mice Group3 of diabe~ic ~ice (strain C 57g black, ~RI d~ri~ed Obese/Obese) of male s~x of mean weight b~tw~en 43 and 46 g were given the ~e5t compound W hydrochloride 5 orally in tragacanth mucilage at a dose of 2, 5 or 100 mg/kg body weight per day or 8 days~ Three hours after the last dose the animals were bled from the tail vein.
The blood glucose levels were assessed by the 10 glucose-oxidase method of GoD-Perid.
Control groups (given doses of unmedicated tragacanth mucilage) were included with each test.
The pereentage reduction in the concentration of hlood glucose was calculated by comparison with the simultaneous controls.
The results obtained are shown in the followiDg Table IA.

TABLE IA

Dsse ~ ehange in mglkg body blood glucosc weight per day eompared with control 2 w25 -2~
10~ -50 ~lypoglycaemis Ac~ivi~:y in ~'a~ted Rats Rats (Sprague-Dawley) of male sex e~ch wei~hing between 171 and ].74 g were ~iven the test compound W hydrochloride orally in tragacanth mucilage at a dose of 100 mg/kg body weight per day for 4 days. Four hours after t~he third dose ~he animals were kept without food up bD and beyond ~be ourth dose. Three hours after the last dose the animals were bled from the taii veill~
The blood glucose levels w~re assessed by the glucose-oxidase method of GOD-Pe~id, Con~rol groups (given doses of unmedica~ed tragacanth mucilage) were included wi~h each tc~t.
The percentage reduction in the 15 concentration of blood glucose was calculated by comparison with the simultaneous controls.
The results obtained are shown in the followi.ng Table~B.

TABLE ~B

Dose ~ change in mg/kg body blood gluco~e weight per day ~ompared w~h con~gol ~L''3~

~y~olipidaemic Activity in Ra~s - Male Wi3tar rats ~ach weighing between 120 and 150 e wer~
ca~ed in gl`OUp3 of eig;ht and fed a p~lleted diet incorporating 0.5% w/w cholesterol and 0.2~' w/w cholic acid for 10 days. For S th~ la3t ~ days of th~t ~eriod the test co~nound ~ras administered or~lly at a dose of 30~ 100 or 200 mg/kg bod~r weight per day ~n ~g~nth I r~7~ge~
At noon on d2y 10 the anim~ls t~ere killed by inhalation of carbon dio~ide fxom solid carbon dioxide. A sa~le of blooQ W2S removed by cardiac puncture and the serum cholesterol and seru~ triglycerides were 10 ,~nalysed by means of an auto-2naly~er.
Control groups (receiving only doses of ~nm~dicated tragacanth mucill~g~ were included with each testO
- 'rhe percenta~e reductions in the concsntrations of seru~ cholesterol and .sexum tr~glycerides were calculated by comp~rison ~it~ the ~imult~neous 15 controls, for each concentration of the test compound ~sed.
The results obtained are shown in 'r2ble II hereafterO

T ~ LE II
e. ,~ ~ ~ % ~ ~ ~
~ d ~ ~tr~l ~ .
h~o~tarol trigl~o~rid~

A200 ~82, -82, -83 -85,-89,~75 100 -35 ~36 0 -~3 ~7 D200 ~63 ~59 E200 -31 ~55 ~200 ~72 60 ~he lltility of the coD~pou~ds i~ ~nhan~ed by the f~ct 1:hat t:heg - are of only v~y low to~icit;;y,, as der30nstrzted in the followirlg t~st:--Oral ~oxic~r ln Mice S Groups of mice were dosed orally with g~zdeà dos~ of th~
te~t compound (in a 0~ w/v aqueous 3u~pension o~ ~ra~acanth ~clla~e) and ob~ ed for ~ days thereafter. ~he percenta&e of ~im&l.s ~hich died durin~ that period at each dose level were u~ed to oonstruc~ a graph2 from which ~he LD 5l that is to ~a~ ~he dose in mg/kg azlimzl body wei~ht necessa~y tc kill 50~o of the ~ice9 was salculated.
Cor~pou~ds of the present invention were tested and the IJ) 50 of each compound was ~reater than 1000 ~g~k~ animal body wei~htl, 5~3 c~ ~ oX ~e~ or~ula I ~3s b~ ;prepa~d ppl~catioa o~ a~ptRtlo~ ~ 1eno~ t~odo 0 ~*~Oa~ h~ o~or~ b~d o~ airt~r ~La~n~
5 (A3 Ao~o~ to a :~atn~ o~ e ~r0~t ~t~
OC t~ a ~ C~ o~U i.a I may, as ir~icated a ~ e, be prep~ned ky the reac~ion o~ a c~mrolm~ of ~e general formula:-C~
~2 a~a p ~ h~ b~ra d~ d)h ~ r~mP~n~ a~n~ Q~ ~h~ ~n~rpl ~

~ _ S ~ Hal ~II
(~ ~
wher~in Rl an~ m ar~ a3 h~re;n~for~ defin~d an~ Hal r~pre~ent~ a halogen, pr~ferably chlorine, atom.

~5~

9~11y c:ar~ d t~:e' 0~ t?r~Pn~ 10~ 0~
ba~ ~oæ . ,1~ a tr~k;ylaml~5 ~O ~rle~l~", or ~ld~n0~ ~ a taap~a~'b~t ~ O~C ~d lt~0 :r~us 5 ~ 7~ D~ lo~ b~

o~ o ~o~e~ g~a~0 o~ ~t $~r~ti~ ~
o~ u ~ ~o~la I ma~ be ~L~I by ~ reaction of a o~ O~.

~: ~OOil 10 (~

g~
.~2 2 ~ e~~ d~0~¢d~

ti~ d~r~at~ O~ a O or acid e~t~r) thereof ~opt;or~ y p~epared in ~itu) w:Lth a co;npound of the general :ormula :-~5 /~< (~3~

4 ~d ~ h~r~inbe~or~ 1sea~

5~3~3 -- :L6 --T~e :~aotio~ abo~e ;~ e~ally ~a3~led out i~i~t org~ 801~ex~1t e~., di~e~l~srm~iae or di~xaa~ and p~s~Lbly ln the pre~0~c~ o~ ;ia 'biaalr~ ~t9 ~or "~e a trial~l?.~ e" e~,~-, ~iL~!lt~l.ami~lQ9 al; a ~ ~.ata~ h ~ ba ~ator ~an a~ble~t 1t'3rl,~r~tll~
Xor ~ a15 b~e0~ ~¢ ~nd 50~0 ~ h~ a4ld ~h1 o~ e ma;y b~ ~L~ o~ ~a.ta1;io~
o~ a c, l oi e~n~ o~la IV ~ith thi~rl ~orid~ b~ t~e appllcati~ or adap1;~tio~ o~ ~ow~ ~e~od~9 10T13~ o~ o~ o~nla II m~r be p~ Lred by r~a~t;~ a ~ D, ~1 ~ 0~ al formaL:la Y wlth a cc ~ - a * ~ ~r~

Il (~ ~2S~ ~ ~d ~ nb~or~ d~ E~) 02 1~

ff ~2 (~iDL ~5 ~3 ~d ~ axe ~ h~ei~So~ ds3~ed) or a rea~ti~ der~vatl~ e,9gO E~d ~loxid~ hereof Lla a ~;m;l;:~r ~a~e to ~a!t harsl~e~ore ~e~xib~dL ~ ~).
~i~67 c ~ o~ ae:Psl 5~o~ula IV m~y b~ p~bp~d by reac~i~ a cc ~ oS ~ner~ ox~:l.~lL III sil~h a GC o~ula ~II ~ a to ~a~ her~e~o~ de00~ib0d ~ (A~, The C~01,~ 3 o:lE g~neral forml~l~IxI, V, VI
and VII are lcno~ co~pound3 or may be prepared by the application or adaptation of known method3.

~S~t'3~

~ cor~ to a ~aature o~ the prese~t ~entlox~ the c .~n ~ o~ ~neral ~on~la I are ~o~ve,~d to ~eiæ
r~ oeuticall~ acce~t~le ~alta~ ~a ~ice ~rerca"
by t~ appl~eatio~ Qr ~pt~ion o~ k~o~ ~eth~d~v IL~ w~ bel~ ~ee~l i~ lt~ proosd~
or ~e pu~ifi~atio~L o~ C~ r fl~ Eene~
fo~la I a~ lt~ b~ t~ia~ ~tage o~ f~re~ce~
i~ ~o~u~lllt3r 1~ water ~a ~ io~ ~5Pn~C~ B91~e~11te 0~
C~ lV~ 1 ~d ll;helr ~ tE~ a~d C9f a~y ~pla~it:Le0 p:Eese~l;" by 10 IQea~s oP kno~ ~t~odo ~ eys~~ tlo~"
(1) C~ n~ or~la ~ w~
te ~ rbo~ ou~ D~ b~ c~ ed ~c ~heir saltla ~ lE~sCefutia~ ~cep~able basea5, ~o~ e~1e~, b~
reaot~on ~ o~ ate ba~ for c ,~10 ~he a~ ia~ c ~ 9~ o~ula~

~110~

(1,ihexe~ M~ px~a~ e~gO ~odlu~h or ~ 6 ~ o 4 ~oon ~,~
~ ato~ a ~raita~ble EU91Y~lt3 IE~g~ ffle~l310l 0 a~oli or a ~l~t~e o~ Y~ter a~ to~eoy ~ollowed i~ ".C~CQ8'^~ b~ ~o~tlon o~ t o:~ ~ll o~ ~he ~olv0alt ~55~3 ~olleo~o~ of the ~ol;ld ~alt.
~ee salt~ ~y be c~nv~lLed to ~ ~arent o~ g~ral ~or~ula I9 ~or ~ ,,le by 3~aCtiO~L wi~
a, ~l~le ~.g. gla~ial a~etic a~ld~ 3oluti~1a a 8~ Q~g1~ wat0r or e~ol~ follo~r~a ~C~?~po~at~io~ os~ psrt ox all o~ th~ ~ol~t"
~oll~on o~Olla ~ 0~ ~3ral ~rzn~l~L I~, (~) C~ 0~ o~mula I ~r b~ G~h~ ~ to th~ tioal~ aooep~ble a:~id addltlo~ ~-9, 10 ~or ~- ~19,, by reactio~ ~il;h the ~yloy ~ata acld ~
~l~tlo~ or snape~~l.on ~ itable ~ol~e~t9 e~0 a¢~aton07 m~ol or et~ll3l9 ~oll~ed 1~ ~eoa~ ~5 b;y ~por~tio~ of pa3~ or all D~ ~he ~ol~e~t,, a3ld ~olleotio~ o~ sol1d ~alt.
~e a~id additio~ 3slt~ r be ~o~rled t9 the p~rent ~ le ~ ~nesal ~o~la I" ~or e~ple by xeactio~ wl~h aqn~o~; ~ t~e I~xe~e~oe 0:~ a a~
~3ol~e~, e~50 ~3t~01t follo~d by ~a~t llfilth a ~alc aola~, ~or axamp3e gl~ ào~ltiG a¢id,, -- 20 ~
It will be und~ratood by thog0 ~killed in the srt tha'e 1~ th~ p~ro~rqnce Or ~hs pro~s~e~ d~xlbed aboYe o~ the pr~a6~t l~ntlon it may b~ desirable to ln~.od.~e ~ lcal proteoti~3 group~ ~nto th~ reaotant~ 1~ or~er to a~oidl s~oo~d~ry 5 r~actlon~ talt:i~g pl~:e,, ~or exa~pl~ the ~e~hoas s)î pr1,pa~tloa o~ der~qat~e~ her~lnb~or~ d~ribed hydro:3~y sub~ t(~ with~s ~h~ d~lnltion o~ th~ R1 ~d R3 ~ do~tix~a l~ atlo~ l;o ge~eral ~on~ula I ~ h~ b~n co~r~d into ~DeT2æ~lo~ ~ p~
befor~ rea~tion a~ a~aoribea w~th ~uba~quent re~o~al o~ ~9 0 prot~oti~g b~nzyl ~OUpA, to b~ u~de~tood that ~ o" ~lkyl~Q~rlog oar~ox~
~a h~ ps which are pr~aen~ c~rta~n r~a~te mag~
b~ pro~ct~d by any ~te~ti~ gro~p8 ~hloh ar~ uall~ ~mplo~e~
~or p~J6eotiD~ e~9 cæ~oxylic aeld~ or aloohol~ d ~fho~e 5 ~e do~ not ~d~r~ly ~ ot th~ ~ 1n~er o~ ~he ~olac~e.
3~ wa~ o~ ea~ plesD
~h~ amlno and al~yl~aiEao gro~p~ eaLn be pxot~eted by radical~;
~¢~ a~ te~ tu~rc6,~v~ylv 2l292 trio~loro~tbo~Ga~o~ l"
trlobloro~¢e~yl 9 tr~t;yl~ ~benzyl, dibenzyl, lban~ h"yl D
20 ~itrobe~zylo~ o~l, ~ho~ osy~arbon~l~ ohlor~ao~t3~19 or trl~luo~oa~et~l, th~ o~o~. æxoupo ~ b~ prot~t~l by r~di~ suo~ as ~thoxy~rl" t~rt~ yl" b~n~dryl0 p~ob~l or ~matho~ r~yl, ~d ~e ~yd~xy g~o~apB ~a~l b~ y~ ctcd. by radlo~l~ 0~0h a~ zyl9 t~ o~r~ r 2~ O~r~p-2-~lD

~0 ~a~ i74~ G~ l b~
or ~ cc~ el~b ~5~3 ~ w~ ~ ampl~
be r~mo~ral OI l;he prot~otivo ~rOtlp8 0~ a~ins~ 1a e~aot~d a~ follo~:
1~ th~ ~a~e o~ ~ I;ert~1tv~ o~,yl~ trltyl o~
~met,h~ a~bongl r~ al,t ~r trea~rlt in an aoid ~n~c $~0r~blyO tr~luoroa~tl¢ ae~d $~ used ~sd th0 p~C13DI~ ~FI o~rled o~t at a tQ~p~ra~ o~ b~ O ~ 20~ lr ~ e oæ a~eou~ fo~i¢ ~ld,, or par&tolu~n~sulpho~l~ or m~a~ulpho~i~ ~id3 1~ d ln aeetone or ~oetonltril~ at a te22peratur~ botwe~D. 20 a and th~ r~Plux t~ratur~ of th~
~ogi~n ~ixt~. ~d~ e ~d~oF~ x ~ Q~
ge~ o~ula I osn b~ obta~0~ 1~ ~e ~:rsE o~ th~s tri~lnor~-~¢~tat0p th~ ~ol~at~ ~i~ formio aoid~ th~ m~t~ phonat~ or 1;~e ~ara~tolu~ulpllona~O a~ ~rom th~ th~ amin~ ~np e~ b~
llb~rated by a~ m~thod whl¢h is ~x~ ltsel~ 2~ob~n ~or ob~p~n~g amin~ f'roD~ o~ o~ 1t~ 8~t~ wlthout ~ot1~ th~ n~er o~ the ~ le. In partic~la;r, th~ ~oc~ oa~led ol:at b~
~rta~ h~ to ~ontaet ~lth ~ i~n e~oh~rgo r0~ln or ~y tho ~ion o~ a~ o~nl~ ba8~o I~ th~ oa~o o~ ~ 29292-tri~hloro~Lo~ b-~,yl or p-~3i~0b~2yîv~ v~}~l }r~cal~ e~O~ (0~p~ially b~
-treatn~t with 2~nc ln acet~ ~sid~)o X3~ tha o ~ ~ o~ ~ ¢hloro80etyl o~ toie~lo~oao~tyl radlc~ , by applyi~ Ith~ ~eth~d ae~oslb~d in thQ Briti~h Patent ' pu~ h~d under ~o,. 1 " 454, 589 0 ~h~ nzyl~ d~b~næ~ r b~ lu,.~ lo~
o~t~ ti(~fio 5~

In the case of a trifluoroacetyl r~;c~ll by trea~ment in a ba~ic medium.
2r The removal of the protective group~ from the carbo~y radical i~ effected as follow~o in the case of a tert-butyl, ~metho~ybenzyl or ~enzhydxyl radical, by trea~ment in an acid medium, under the condi~ion~ ~e~cribed above ~or the r~moval of ~he pxotective trityl radical from an amino group. In the ~a~e of the benzhydryl radical, the proce~s can be carried out in the presence o~ ~nisol~.
In the case of a metho~ymethyl group~ by tre tment in a dilute acid medium.
In the ca~e of a ~-nitrobenzyl group, by reduction ~especially by treatment with zinr in acetic acid, or by hydrogenolysis).
3. The remDval of the protective groups from the hydroxy xadical~ i~ effected a2 follow~o in the case of a benzyl, trityl or tetrahydropyranyl group, by acidoly3i~, for example with trif~uoroacetic acid, aqueou~ or non-aquPous formic acid or para-toluene~-pho~;C acid.
In the ca~e o~ the 2-methoxy-prGp-2-yl-group, in accordance with the method described in Briti~h Patent 2021561~
It will be under~tood that it may b desirable to change the nature of one or m~re of the ~ubs~ituentQ at an appropriate stage during the 3ynthe~i~ o~ the compound~

3~3 _ ~3 -of the invention, for exampl~, the ~ompoundz o~ ral formula I wherein R~ ox R3 repre3ent3 an amino group may be alte~natively prepared fxom the corre3ponding compound~
of general ~or~ula I wherein Rl or R3 r~pre~n~ a m ~ro 5 group ~y the application or adaptation of ~nown methods for su~h conversion. Co~pound~ of g~nexal formula I
wherein R or R3 repre~nt~ an amino group may b2 tran~formed tQ diazonium ~alts, w~ich are u~eful ln ~yn~hesi~ a~ de~cri~d in Morri~on and Boyd'~ "Organic 10 ~hP~;~try" ~1959), and ~hence to, a halogen atom, for example, an iodine atom.

The following Examples and Reference Ex~mples illustrate the preparation of the compound~ of the present invention.

E~PLE 1 Compound A

2-Amino~ 3~imidazol-l~ylpropyl)benzamide (3~.9g) was dissolved in pyridine(l65ml~ and 4~chlorobenzene-sulphonyl chloride(4l.2g) was added in portionsO The temperature of the reaction mixture rose to 5~C. The \
~olution was stirred a~ room temperature for 4 hours and poured into wa~er ~1.5 1) to precipitate an oil which slowly solidified on ~tanding. The solid was collected, washed with water and recrystallised from ethanol to give 2~4-chlorobenæ~nesulphonam..~ - -(3 imidazol l yl~ropyl)-benzamide (24~4g), in the form of a white solid, m.p. 175-177C.
(i) 2-Amino-M-(3-imidazol-1-ylpropyl)b~nzamide used as starting material abvve was prepared as follows-Isatoic anhydride (2200g~ was added in portions to a stirred solution of 3-imida~ol-1-ylpropylamine tl702g~
in dioxan (lOOml) over a period of 15 minute~0 Stirring was continued for 40 minute~ before the solution was evaporated in vacuo to give 2 amino-N-(3~imidazol-1-ylpro~
pyl3b~n7.~m;de a~ a buff coloured solid, used without further purification.

By proceeding in a ~imilar manner to that de~cribed in Example 1 for the preparation of 2-(4-chlorobenzene-sulp~onamido)~N-(3~imidazol-1-ylpropyl)benæamide but replacing 4-chlorobenzenesulphonyl chloride or 2-amino-N-(3-imidazol-1-ylpropyl~benzamide by the indicated starting materials, the following compounds of general formula I
were prepared (the compound letter is given in parenthe~is):

2 (B): 2-(3-chlorobenzenesulphonamido)-N-[3-imidazol-1-ylpropyl~benzamide (white solid, m.p. 139-142C) starting material, 3-chloro~enzenesulphonyl chloride 3 (C): 2-(2~chlorobenzenesulphonamido)-N~(3-imidazol l-yl~
propyl)benzamide (off-white solid, mOp~ 154-158C~
starting material, 2-chlorobenzenesulphonyl chloride 4 (D~: 2-(4-bromoben2enesulphonamido~-N-(3-imidazol~l-yl propyl)benzamide (white solid, m.p~ 178-1~0C~^
starting material, 4-bromobenzenesulphonyl chloride 5 (E): 2-(benzenesulphonamido)~ 3-imidaæol-1-ylpropyl)-benzamide (off-white solid, mup. 112 llltC~
starting material,benzenesu~phon~l chloxide

6 (F~: 2-(4~methylbenzene8ulphonamido)~rN- (3-imidazol-1 yl-propyl)benzamide (off-white solid, m.p. 147 149JC~o starting material, 4~methylbenzenesulphonyl chloride

7 (G~ 2~(3~Lt-dimethylbenæenesulphonamido~N-(3 imidazol-l-ylpropyl)benzamide (white solid, m,p. 172-174C~:
starting material, 3 ,4~dimethylb~ene~ulphonyl chloride (H3: 2-(4-nitroben2enesulphonamido)-N~ ( 3-imidazol-l~yl~
propyl~benzamide (fawn coloured solid, m.p~ 8-150C3. starting material, 4~nitrobenzene3ulphonyl chloride 9 (I): 5-chloro 2~(4-chlorobenzenesulphonamido)-M-(3-imidazol-l-ylpropyl)benzamide (white solid, m~p~
125 128C)o starting material, 5-chloro-2-amino-~w (3-imidazol-1-ylpxopyl ~benzamide 10 ~J): 2-(2,5-dichlorobenzenesulphonamido) ~-(3-imidazol-0 ].-ylpropyl)benzamide (pale brown solid, m.p~ 198-200C): ~tarting material, 2,5-dichlorobenzene-sulphonyl chloride 11 (K~: 2-(2-nitrobenzene~ulphonamido3 N~(3-imidazol-1-ylpropyl~benzamide (pale brown solid, m.p. 145-147C):
starting matexial, 2 nitrdbenzenesulphon~l chloride 12 (L): 2-~4 fluorobenzenesulphonamido)-E-~3-imidaæol-1-ylpropyl~benzamide (white solid, m.p. 117-118C):
starting material, 4-fluordbenzenesulphonyl chloride EXAMPI~: 1 3 COmPound M
2-Amino-~-[3-~2-m~thylimidazol-1-yl)propyl~ben~mide (10.5g) was di~olved in pyridine (50ml) and 4-chloro-benzenesulphonyl chloride (12035g) wa~ added in portion~
during five minute~. ~he t~mperature of the reaction mixture rose to 45C. The solution was stirr~d at room temper ture for 4 hours and the pyridine was evaporated in vacuo ~ give a ~rown oil~ ~he oil wa~ chromatographed on silica gel, eluting with a mixture of chlorofoxm and methanol (19:1) to give 2-(4-chlorobenzene~ulphonamido)-N-~3-(2-methylimi azol-l-yl)propyl~benzamide in the fonm of a white solid (7g), mOp. 122~123C.
2-~mino-N-[3-(2-methylimidazol l-yl)propyl]benzamide used as startin~ material above waS prepared by proceeding in a similar manner to that hereinbefore described in Exarnple ~i~ for the preparation of 2-amino-N-~3-i7nidazol-l-ylpropyl)benzamide but replacing 3-imidazol-1-ylpropyl-amina by 3-(2-methylimidazol-1-yl)propylamine.
2-Amino-N-[3-(2-methylLmidazol-l~yl~propyl]benzamide was recovered in the fo~n of an oil which was used without further purificationO

Compound ~
By proceeding in a similar manner to that her~inbefore described in ~mrle 1 for the preparation of 2-(4-chloro-benzenesulphon~mido)- -(3-imidazol-1-ylpropyl)benzamide but replacing 2-~nino-N-(3-imidazol-1-ylpropyl~benzami~e by 2~amino-N-~ 3- ( 4-methylimidazol-1-yl )propyl]benzamide there was prepared 2-(4-chlorobenzene~ulphon~nido)-~-[3-(4;methylimidazol-1-yl~propyl]benzamide in the form of a white ~olid, m.p. 123-125C.
2-Amino-N-[3-(4-methylimidazol-1-yl 3propyl~benzamide used as skarting material above was pxepared by proceeding in a similax manner to that hereinbe~ore described in Example 1(i) ~or the preparation of 2-amino-N-(3-imidaæol-~s~a3 l-ylpropyl)benzamide but replacing 3-imidazol~ ylpropyl-amine by 3-(4-methylimidazol-l~yl)propylamine.
2-Am~no-N-~3-(4 methylimidazol-l-yl)propyl~benzamide was recovered in the ~orm of an oil which was used without further purificationO

EX~MPL~ 15 Compound 0 By proceeding in a similar manner to that hereinbefore described in Example lh for th preparation of 2-(4-chloro-10 benzenesulphonamido)-N-~3-(4-methylimidazol-1-yl3propyl]-benz~mide but replacing 4-chlorob~næenesulphonyl chloride by 4-nitrobenze.nesulphonyl c~loride, there was prepared 2-(4-nitrobenzenesulphon ~m i do)-N ~3-(4-methylimidazol-l-yl) propyl~benzamide in the form of a yellow solid, m.p. 153 15 155Co Compound P
2-(4-~itrobenzenesulphonamidQ~~N-(3-imidazol-l ylpro-pyl)benzamide (38.4g) was dissolved in ~lacial acetic acid (30ml) and 5% w/w palladium-on-charcoal(8~0g) W2S added.
The mixture was stirred under an atmosphere of hydrogen for 4 hours, filtered free of catalyst and evaporated.
The ~olid re3idue wa~ dissolved in water and the solution was adju~ted to p~ 9 by the addition of aqueouq ammonia.
The solid w~ich had precipitated was collect~d and recrystallised from ethanol to give 2 (4-aminoben7ene-sulphonamido)-N-(3-imidazol-l ylpropyl)benzamide (26.7g) ~a5~3 in the fonm of a white solid, m~p~ 171-175C~
~ (4~Nitrobenzenesulphonamido)~N-(3-imidazol l~ylpropyl benzamide used above was prepared a~ hereinbefore described in ~xample 80 EX~MPLE 17 Compound A
4-Chlorobenzenesulphonyl chloride (lq56g~ was added in portions over 2 minutes to a solution of 2-amino-N
(3-imidazol-l~ylpropyl)benæamide (1.8g3 in water (50 ml3 at 80C on a steam batha The mixtura was stirred at 80~90C
for 3 hour~ cooled to room temperature and brought to pH
7 with saturated aqueou~ sodium bicarbonate solution. I~e crude product which had precipitated was extracted into dichloromethane (2 x lOOml), the resulting solution was dried over magnesium sulphate and evapor ted to give a solid. The ~olid was recrystallised rom ethanol to give 2-~4-chlorobenzenesulphonamldo3-N-(3-imidazol-1-ylpropyl)-benzamide (1~4g), in the form of a white solid, m.pO
174-176~C.

E~C~5PLS3 1 B
~ompound A
2~(4 ~hlorobenzenesulphonamido)benzoyl chloride (3.40g~
wa~ added in portions to a stirred mixture of 3-imidaæol-1 ylpropylamine (1~29g), triethylamine (1.04g~ and dimethyl-formamide (25ml3 at room temperature, The temperature of the mixture rose to 33C, the mixture wa3 then ~tirred at room temperature for 4 hour~ b~fore pouring into water ( SOOml ) ,. The aqueous solution was decanted from the crude product which had precipitated as a g~n. Thi3 gllI~tly material was dissolved in dichloromethane ( 50ml ), the solution was dried over magnesium sulphate and the solution was evaporated. The crude product was recry~talli~ed from ethyl acetate to give 2-(4-chlorobenzenesulphon~mido)-~-(3-imidazol-1-ylpropyl)benzamide) in the form of a white solid, m.p. 175-177C (yield D 2.1g)~

EX~MPLES 19 - 50 By proceeding in a similar manner to that described in Example 1 for the preparation of 2-(4-chlorobenzene-sulphonamido)-N-(3-imidazol-1-ylpropyl~benzamide but replacing 4 chlorobenzenesulphonyl chloride and/or 2~amino-~-( 3~imidaxol-1-ylpropyl)benz~mide by the indicated starting material, the following compounds of gen~ral formula I were preparad (the compound letter is given in parenthesis) 19 (Q) ~ 2~(4-methoxybenzenesulphonamido) ~ ( 3-imidaæol-1-ylpropyl)b~n7.~;de (white solid, m.p. 179-181C~
starting material~ 4-methoxy~enzenesulphonyl chloride 20 (R): 2-(4-acetamidobenzene~ulphonamido)~N~(3-imidaæol-l-ylpropyl~benzamide (white solid, m~p~ 192-194C)-~tarting material, 4-acetamidobenzenesulphonyl chlor.ide 25 21 (S)o 2-(4~isopropylben2enesulphonamido)-~ (3-imidazol-l ylpropyl )ben~m; de ~white solid, m.p~ 160-162C~
starting material, 4-isopropylbenz~nesulphonyl chloride 22 tT)o 2-(4-t-butylbenzenesulphonamido3-N--(3-imidazol-1-yl~
propyl)benzamide (white solid, m.p. 163~166C):
~tarting material, 4-t-butylbenzenesulphonyl chloride 23 (U3 2-(4-octylbenzene~ulphonamido~-N-(3-imidazol-1-yl-propyl~benzamide (white solid, m.p. 109-111C):
starting mat~rial, 4 octylbenzenesulphonyl chloride 24 (V): 2-(4-ethoxycarbonylbenzenesulphonamido)-N-[3~
imidazol-l-ylpropyl)b2nzamide (off-white solid, mOpo 156-158C3: starting material, 4-ethoxy-carbonylbenzenesulphonyl chlorid~
25 (W): 2-(3~trifluoromethylbenzenesulphonamido) N;~3-imidazol-l~ylpropyl~benzamide ~white solid, m.p~
~5 133-137~C)3 starting material, 3-trifluoromethyl-benzenesulphonyl chloride 26 (X)~ 2-~3,4-dichlorobenzene~ulphonamido3-N-(3-imi~azol-l-ylpropyl)benzamide ~white solid, m.p. 164-167C)~
s~arting material, 3,4~ dichlorobenzenesulphonyl chls~ride 27 (Y): 2-(2,4-dichlorobenzenesulphonamido~-N-(3-imidazol~
l-ylpropyl)benzamide (off white solid, m.p~ 152-155C): ~taxting material, 2,4-dichlorob~nzene-sulphonyl chloride 5 28 (Z): 2-(2,6-dichlorobe~zenesulphonamido3~N-~3-imidazol-l-~lpropyl)b~n2amid~ (off-whit~ sol:idt m.p~ 203-205C): ~tarting ~atexial, 2,6-dichlorobenzene~
~ulphonyl chloride s~

~ 32 -29 ~A~o 2-(2,3-dichlorobenzenesulphonamido)~-(3-imidazol-~l~ylpropyl)benzamide (o~f-white ~olid, m.p~
153-155C)- starting material, 2,3-dichloro-benzenesulphonyl chloride 30 (BB)o 2 (2-trifluoromethylbenzenesulphonami~o~-(3~
imidazol-l-ylpropyl)benzamide (fawn solidJ mOpO
173-175C~. ~tarting material, 2-tri~luoromethyl-benzenesulphonyl chloride 31 (CC): 2-~4-chloro-2-trifluoromethylbenzenesulphonamido~-~-(3-imidazol-1-ylpropyl3benzamide (off-white solid, m.p. 155~157C~ starting material, 4~chloro 2-trifluoromethylbenzenesulphonyl chloride 32 (DD)U 2-(3,5-bistrifluoromethylbenze~esulphonamido)-~(3~imidaæol~1~ylpropyl3benzamide (o~f-white solid, m~p. 109C~- starting material, 3~5-bi~trifluoromethylbenzenesulphonyl chloride 33 (EE): 2-t2,4,5-trichlorobenzenesulphonamido)-M (3-imidaæol-l-ylpropyl~bPn7.~mide (off-white solid, m.p. 190-200C~- ~tarting material, 2,4,5-trichlo robenzenesulphonyl ch~oride 34 (FF~ 2-(2,3,4-trichlorobenzene~ulphon~mid~3-~-(3-imidazol~ ylpropyl)benzamide (off-white solid, m.p. 195-1~7C). ~t~rting material~ 2,3,4-trichlorobenzene~ulphonyl chloride 35 (GG)~ 2 (4-chloro-3-trifluoromethylbenzene~ulphon~mido~-~-(3 imidazol~l ylpropyl)benzamide ~white solid, m~p. 148-ol51d: starting material~ 4-chloro 3-trifluoromethylbenzenesulphonyl chloride ~5~3~3~

36 (H~). 5-chloro-2-(3--trifluoxomethylbenzenesulp~onamido)-N~(3-imidaæol-1 ylpropyl)b~n7~mide ~white solid, m~p, 159-162C~ starting material~, 5~chloro-2 amino-N-(3-imidazol-1-ylpropyl~benzamide and 3-trifluoromethylbenzene~ulphonyl chloride 37 (II): 5-chloro-2 (3,5-bistrifluorom~thylbenzQnesulphon-amido)~ 3-imidazol l-ylpropyl~enzamide (white solid, mDpO 149 150C~: starting materials, 5~chloro-2-amino-N~ ( 3-imidazol-1-ylpropyl ) benzamide and 3, 5-bistrifluoromethyl~enzene sulphonyl chloride 38 ~JJ)~ 5-chloro-2-~3~chlorobenzenesulphonamido)~N-~3-i~nidazol l-ylpropyl )benzamide (white ss~lid, m~p. 124-126C): starting materials, 5-chloro-2-amino~ 3~imidazol-1-ylpropyl~ benæamide and 3-chlorobenzenesulphonyl chloride 39 (KK~: 2 (3 fluorobenzenesulphonamido)-N-(3 imidazol-l-ylpropyl)benzamide (white ~olid, mOp~ 147~149C~:
starting material, 3-fluorobenzenesulphonyl chloride 40 (LL~ 2-(3-fluoro-4-methylb~nzenesulphonamido~ (3-imidazol-l-ylpropyl)benzamide (of~whi~e solid~
m.pO 155 157~C)q ~tarting mat~rial/ 3~fluoxo~4 methylbenzenesulphonyl chloride 25 41 (MM)ô 2 (3-bromobenz~nesulphonamido~N~(3-imidazol-1=
ylpropyl~benzamide (white ~olidO m,p. :146-148~C)o ~tarting material, 3-bromobe~2enesulphonyl chloride e~ 3 4~ (NN): 2-(3-nitrobenzenesulphonamido)-N-t3 imidazol-l-ylpropyl)ben~mide (fawn solid, m..pG 160-162C~:
starting material, 3-nitrobenzene~ulphonyl chloride 43 (OO3 2-(2,4-difluorobenzenesulphonamido~- ~(3-imidazo~
l-ylpropyl)b~nzamide (cream-coloured solid, m~p~
122~124C) ~tarting matexial, 2,4-difluoro-benzene~ulphonyl chloride 44 (PP): 2-~3-methylbenzenesulphonAm;do).-N-(3~
imidazol-l-ylpropyl )benzamide ~off~white ~olid, m.p. 160-161QC): starting material,3-methyl-benzenesulphonyl chloride 4 5 ~ QQ ): 2- ( 2-methylbenz enesulphonamidc~ ( 3-imid~zol-1-ylpropyl )benzarnide (white solid, m.pO 139-141C):
starting material, 2-methylhenzenesulphonyl chlor.ide 46 ~RR)~ 2-(2-fluorobenzenesulphonamido~-N-(3~imidazol-1-ylpropyl)benzamide (off-white solid, m.p. llS-117~: starting material , 2~f:1uorobenæene~3ulphonyl chloxide 47 (SS)O 2-(2-chloro-5~trifluoromethylb~nzenesulp~onamido)-~-(3-imidazol-1-ylpropyl)b~n~m;de ~pale-brown solid, m.pO 181~1849C): ~tarting mat~rial, 2-chloro-5-trifluoromethylb~nzene~ulp~onyl chlorlde 5 48 ( W ~ 2 (4-chlorobenzenesulphonamido)-N~(4-imidazol~l~
ylbutyl)benzamide (off~white solid3 m.p. 131-133~C)o starting material, 2-amino~-(4~imidazol-l-ylbutyl)benzamid~

49 (W): 2-(4-chlorobenzerlesulphonamido~-N~ (2-imidazol-1 ylethyl)benzamide (white solid, m.pO 130-133C):
starting material, 2-amino-N-(2-imidazol-1-ylethyl~benzamide 5 50 (~W)~ 2-(4-chlorobenzene~ulphonamido~-N-(3~
imidazol l-ylbutyl)benzamide (w~nite solid, mOp.
150-lS3C3~ starting material, (~)-2 amino-N~
(3~imidazol-1-ylbutyl)benzamide EX~MoeLE 51 Comp~und IT
A solution o~ 2~(4-aminobenzenesulphonamido) N~(3-imidazol-l-ylpropyl)benzamide (ll.Og;hereinbefore prepared in Example 16) in a mixture of concentrated hydrochloric acid (905ml~ and water (50m1) was cooled to ~etwe~n 0C
and 5C whilst a solution of sodium nitrite (2.0gg) in water (15ml) was added dropwise over 15 minutes.
solution of potassium iodide (4.58g~ in water (lO~l) was then added over 30 minutes, maint~;n;ng a temperature between 0C and 10C~ The mixture was then heated at 95C fox 15 minutes. The resultant solutiQn was cooled and adjusted to pH 8 by dropwise addition of lO~o W/V aqueous sodium hydroxide ~olution. The sol.id precipitate was collected, washed with water and recrystallised from ethyl acetate to give 2-~4~iodobenzenesulphonamido3w~-(3-imida~ol l-ylpxopyl~ben2amide in the form of a pale~
yellow solid, m.pO 162~166C (yield 0 3~4~0 EXA~PLE 52 Compound W hydrochloride 2-(3-Trifluoromethylbenzenesulphon~nido ~-E- ( 3-imidazol-l-ylpropyl~benzamide (9.Og) was dis~olved in hot isopropanol ~9Oml). Concentrated aqueou~ hydrochloric acid (2~0ml) wa~ added. The resultant solution was evaporated to yield an oil which was recxystallised from ethyl acetate to give 2~(3-trifluoromethylbenzenesulphon-amido~ 3-imidAzol-l-ylpropyl)benzamide hydrochloride (9.3g) in the form of a white solid, mDpO 173-175C.

REFERENCE EX~MPLE 1 2-Methylamino- -(3-imidazol-1-ylpropyl)ben~amide which may be used as starting material was prepared as ~ollows:-N-Methylisatoic anhydride (17.7g) was added in portions to a stirred solution of 3-imidazol l-ylpropyl-amine (12.5g) in dioxan (150ml~ over a period of 15 minutes.
Stirring was continued for 40 minutes before the solution was evaporated in vacuo ~o give 2-methylamino-N-~3-lmidazol-l~ylpropyl)benz~nide (18.0g3, in the form of a buff coloured solid, m.p~ 13~3 141C, after recrystallisation from isopropanol.
2-Me~hyl~nino N-~3~imidazol-1-ylpropyl~benzamide may be used to replace th~ 2-amino~ 3-imidazol-1-ylpropyl~
benz~nide u3ed as starting matexial in ~he foregoing ~XA~rle~ to prepare corre~ponding compounds o~ general formula I in which R2 repxesents a methyl groupO

- RE~k~ ~XAMPLE 2 5-Chloro~2-amino-N-(3-imidazol-1-ylpropyl)benzamide used as starting material in Example 9 was prep~red a~
follows:
5~Chloroi~atoic anhydride (26.7g) was added in portion~ to a stirred solutio~ of 3-imidazol-1-ylpropyl~
amine ~17.2g) in dioxan (1~0 ml~ over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 5~chloro-2 amino-N-(3-imidazol-1-ylpropyl)benzami~e as a buff coloured solid, used without further purificationO
2-Amino-N-(4-imidazol~l ylbutyl)benzamide used as starting material in Exampl~ 48 was prepared by pxoceeding in a similar manner to that herelnbefore described in Example 1 (i~ for the preparation of 2-amino~
N-(3-imidazol-1-ylpropyl)benzamide but replacing 3-imidazol-l~ylpropylamine by 4~imida~Dl-l-ylbuty~am~ne, 2-~mi~o-N- (4-imidazol-1-ylbutyl)benzamide was 20 recovered in the form of an oil which was used without ~urther purification.
2~mino-N-(2-imidazol-1-ylethyl)benzamide used as starting material in ~mrle 49 was prepared by proceeding in a sLmilar manner to thak hereinbefore described in Example l(i) for the preparation of 2-amlno-~-(3-imidazol-1 ylpropyl.)benzamide but replaci~g 3-imidazol-l-ylpropylamine by 2-imidazol l-ylethylamineO

2-Amino-~-(2-imidazol-l-ylethyl)b~n7Am-de was recovered in the form of an oil which was used without further puri~ication~
~ +)-2 mino- -(3-imidazol-1 yl~utyl)benz~mide used as starting material .in ~x~m~l e 50 was prepared by proceeding in a similar manner to that hereinbefore described in Ex~mple l~i) for the preparation of 2-amino-N- ~ 3-imidazol~l-ylpropyl)benzamide but replacing 3~imidazol-1-ylpropylamine by ( )-3-imidazol~l ylbutylamine.
(+)-2 mino-N-(3-imidazol~l-ylbutyl~benzamide was recovered in the fo.rm of an oil which was used without further purification.
The pre~ent invention includes within its scope phAr~ceutical compositions which comprise at least one of the compounds of general formula I or a ph~rm~ceutically acceptable salt thereof in association with a ph~rm~ceu~
tically ~cceptable earrier or coating. In clinical practice the compounds of the present invention may be administered parenterallyt but are prefexably administered rectally or, more prefera~ly, orally.
Solid compositions for oral administration include compres~ed ta~let~, pill~, powders and granules. In such ~olid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluant ~uch as starch, sucrose or lactose. The composition~ may also comprise, a~ i~ normal practice, additional sub~tances other than inert diluent~, e.g. lubricating agents, such as ~S~3 magnesium stearate.
Liquid compositions for oral admini~tration include phanmaceutically acceptable emulsions, ~olutions, ~uspen~ions, syrups and elixir~ containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants~
such as wetting, and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administ-xation also include capsules of absorbabl0 material such asgelatin, cont~;n;ng o ne or more of the active substances with or without the addition of diluents or excipients.
Preparations accor ;ng to the invention for parenteral ~in;S~ration include sterile aqueous, aqueous-organic, and organic solutions,su~pensions and emulsions. Examples of organic solvents or suspending media ~e propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stab~ising, preserving, wetting, emulsifying and dispersing agents.
They may be sterilized by, for example, filtration through a bacteria-ret~;n;ng filter, by ineo~poration in the compositions of sterilizing agents, by irradiation or by heating. They may also be manufactured in the form or sterile solid compo~itions, which can be dissolved in sterile water or some other sterile injectable medium immediately before u~eO

~L95~3 f Solid compositions for r~ctal administration include suppositories formulated in accordance with known methods and cont~;ning one or more of the compounds of formula I
or a pharmaceutically acceptable salt ~hereof.
The percentaye of active ingredient in the compositions of the invention may be varied, it being necessary that it ~hould constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the s~me time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient~ In the ad~lt, the doses are generally between 0.1 and 50 mgfkg body weight per day by oral administration~ For ~x~mrle, in the treatment of diabetes between 5 and 40 mg~kg body weig~t per day by oral ~m;n;stxation, and a~
hyroJ;p;d~emic agents between 10 and 50 mgfkg b~dy weig~t per day by oral ~m;n; s~xation~
The following ~x~mrle illustrates pharmaceutical compositions according to the present inventionO

~3S9~3 ~o, 2 size gelatin capsules each contA;n;ng:-2- (4-chlorobe3~zenesulphonamido ~ -N- ( 3-imidazol-l-ylpropyl )benzamide 20 mg lactose 100 rng s tarch 60 Ing dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the u~ual procedureO

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)-benzamide or a pharmaceutically acceptable salt thereof characterized in that 2-amino-N-(3-imidazol-l-ylpropyl)-benzamide is reacted with 4-chlorobenzenesulphonyl chloride to obtain 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-l-ylpropyl)benzamide and, if desired, the obtained 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)-benzamide is converted to a pharmaceutically acceptable salt thereof.

2. 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-l-ylpropyl)benzamide or a pharmaceutically acceptable salt thereof whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.

3. A process for the preparation of 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-l-ylpropyl)-benzamide or a pharmaceutically acceptable salt thereof characterized in that 2-(4-chlorobenzenesulphonamido)-benzoylchloride is reacted with 3-imidazol-1-ylpropylamine to obtain 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-l-ylpropyl)benzamide and, if desired, the obtained 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpxopyl)-benzamide is converted to a pharmaceutically acceptable salt thereof.

4. 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-l-ylpropyl)benzamide or a pharmaceutically accept-able salt thereof whenever obtained by a process as defined in claim 3 or an obvious chemical equivalent thereof.

5. A process for the preparation of 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide or a pharmaceutically acceptable salt thereof characterized in that 2-amino-N-(3-imidazol-1-ylpropyl)benzamide is reacted with 3-trifluoromethyl-benzenesulphonyl chloride to obtain 2-(3-trifluoromethyl-benzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide and, if desired, the obtained 2-(3-trifluoromethylbenzene-sulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide is con-verted to a pharmaceutically acceptable salt thereof.

6. 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide or a pharmaceutically acceptable salt thereof whenever obtained by a process as defined in claim 5 or an obvious chemical equivalent there-of.

7. A process for the preparation of 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide or the hydrochloride salt thereof characterized in that 2-amino-N-(3-imidazol-1-ylpropyl)-benzamide is reacted with 3-trifluoromethylbenzenesulphonyl chloride to obtain 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide and, if desired, the obtained 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide is converted to the hydrochloride salt thereof.

8. 2-(3-trifluoromethylbenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide or the hydrochloride salt thereof whenever obtained by a process as defined in claim 7 or an obvious chemical equivalent thereof.

9. A process for the preparation of a benzamide derivative of the general formula (I):

(I) wherein A represents an ethylene, trimethylene or 3-methyl-trimethylene group and R1 represents a halogen atom, tri-fluoromethyl group, or a C1-4 alkyl group and m represents the integer 1 or 2, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-4 alkyl group in the 4-position and p represents zero or the integer 1, characterized in that a compound of the general formula (II):

(II) wherein A, R3 , R4, n and p are as defined above is reacted with a sulphonating agent of the general formula (III):

(III) wherein R1 and m are as defined above, and Hal represents a halogen atom, to obtain a compound of the general formula (I) as defined above, and if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof.

10. A process according to claim 9, wherein R1 and R4 are methyl and R3 represents a chlorine atom.

11. A process according to claim 9, wherein m is the integer 1 and the group R1 is in the 2, 3 or 4-position when R1 represents a halogen atom or a C1-4 alkyl group, or in the 3-position when R1 represents a trifluoromethyl group.

12. A process according to claim 9, wherein m is the integer 2 and the groups R1 are the same, are halogen or methyl and are in positions 2,4; 3,4 or 2,5 when R1 represents halogen and in positions 3,4 when R1 represents methyl.

13. A process according to claim 9, wherein A
represents a trimethylene group.

14. A process according to claim 10, wherein m is the integer 1.

15. A process according to claim 10, wherein m is the integer 2 and the groups R1 are in positions 3,4.

16. A process according to claim 14, wherein A
represents a trimethylene group.

17. A process according to claim 15, wherein A
represents a trimethylene group.

18. A benzamide derivative of the general formula (I) (I) wherein A represents an ethylene, trimethylene or 3-emthyltrimethylene group and R1 represents a halogen atom, trifluoromethyl group, or a C1-4 alkyl group and m repre-sents the integer 1 or 2, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-4 alkyl group in the 4-position and p represents zero or the integer 1, or a pharmaceutically acceptable salt thereof, whenever obtained by a process as defined in claim 9 or an obvious chemical equivalent thereof.

19. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl and R3 represents a chlorine atom, whenever obtained by a pro-cess as defined in claim 10 or an obvious chemical equiva-lent thereof.

20. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein m is the integer 1 and the group R1 is in the 2, 3 or 4 position when R1 represents a halogen atom or a C1-4 alky1 group or is in the 3-position when R1 represents a trifluoromethyl group, whenever obtained by a process as defined in claim 11 or an obvious chemical equivalent thereof.

21. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein m is the integer 2 and the groups R1 are the same, are halogen or methyl and are in positions 2,4-, 3,4- or 2,5- when R1 represents halogen and in positions 3,4- when R1 represents methyl, whenever obtained by a process as defined in claim 12 or an obvious chemical equivalent thereof.

22. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, whenever obtained by a process as defined in claim 13 or an obvious chemical equivalent thereof.

23. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl, R3 represents a chlorine atom and m is the integer 1, whenever obtained by a process as defined in claim 14 or an obvious chemical equivalent thereof.

24. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl, R3 represents a chlorine atom, m is the integer 2 and the groups R1 are in positions 3,4-, whenever obtained by a process as defined in claim 15 or an obvious chemical equivalent thereof.

25. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, R1 and R4 are methyl, R3 represents a chlorine atom and m is the integer 1, whenever obtained by a process according to claim 16 or an obvious chemical equivalent thereof.

26. A benzamide derivative of the general formula (I) according to claim 18 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, R1 and R4 are methyl, R3 represents a chlorine atom, m is the integer 2 and the groups R1 are in positions 3,4-, whenever obtained by a process as defined in claim 17 or an obvious chemical equivalent thereof.

27. A process for the preparation of a benzamide derivative of the general formula (I):

(I) wherein A represents an ethylene, trimethylene or 3-methyltrimethylene group and R1 represents a halogen atom, trifluoromethyl group, or a C1-4 alkyl group and m represents the integer 1 or 2, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-4 alkyl group in the 4-position and p represents zero or the integer 1, characterized in that a compound of the general formula (IV):

(IV) wherein R1, R3, m and n are as defined above, or a suitable reactive derivative thereof, is reacted with a compound of the general formula (V):

(V) wherein A, R4 and p are as defined above, to obtain a compound of the general formula (I) as defined above, and, if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof.

28. A process according to claim 27, wherein R1 and R4 are methyl and R3 represents a chlorine atom.

29. A process according to claim 27, wherein m is the integer 1 and the group R1 is in the 2, 3 or 4-position when R1 represents a halogen atom or a C1-4 alkyl group, or in the 3-position when R1 represents a trifluoro-methyl group.

30. A process according to claim 27, wherein m is the integer 2 and the groups R1 are the same, are halogen or methyl and are in positions 2,4; 3,4 or 2,5 when R1 represents halogen and in positions 3,4 when R1 represents methyl.

31. A process according to claim 27, wherein A
represents a trimethylene group.

32. A process according to claim 28, wherein m is the integer 1.

33. A process according to claim 28, wherein m is the integer 2 and the groups R1 are in positions 3,4.

34. A process according to claim 32, wherein A
represents a trimethylene group.

35. A process according to claim 33, wherein A
represents a trimethylene group.

36. A benzamide derivative of the general formula (I):

wherein A represents an ethylene, trimethylene or 3-methyltrimethylene group and R1 represents a halogen atom, trifluoromethyl group, or a C1-4 alkyl group and m represents the integer 1 or 2, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-4 alkyl group in the 4-position and p represents zero or the integer 1, whenever obtained by a process as defined in claim 27 or an obvious chemical equivalent thereof.

37. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl and R3 represents a chlorine atom, whenever obtained by a process as defined in claim 28 or an obvious chemical equivalent thereof.

38. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein m is the integer 1 and the group R1 is in the 2, 3 or 4 position when R1 represents a halogen atom or a C1-4 alkyl group or is in the 3-position when R1 represents a trifluoromethyl group, whenever obtained by a process as defined in claim 29 or an obvious chemical equivalent thereof.

39. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein m is the integer 2 and the groups R1 are the same, are halogen or methyl and are in positions 2,4-, 3,4- or 2,5- when R1 represents halogen and in positions 3,4- when R1 represents methyl, whenever obtained by a process as defined in claim 30 or an obvious chemical equivalent thereof.

40. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, whenever obtained by a process as defined in claim 31 or an obvious chemical equivalent thereof.

41. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl, R3 represents a chlorine atom and m is the integer 1, whenever obtained by a process as defined in claim 32 or an obvious chemical equivalent thereof.

42. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl, R3 represents a chlorine atom, m is the integer 2 and the groups R1 are in positions 3,4-, whenever obtained by a process as defined in claim 33 or an obvious chemical equivalent thereof.

43. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, R1 and R4 are methyl, R3 represents a chlorine atom and m is the integer 1, whenever obtained by a process according to claim 34 or an obvious chemical equivalent thereof.

44. A benzamide derivative of the general formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, R1 and R4 are methyl, R3 represents a chlorine atom, m is the integer 2 and the groups R1 are in positions 3,4- , whenever obtained by a process as defined in claim 35 or an obvious chemical equivalent thereof.

45. A process for the preparation of a benzamide derivative of the general formula (I):

(I) wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and R1 represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkoxycarbonyl, dialkyl-amino, alkylcarbamoyl or alkanoylamino group and n repre-sents zero or the integer 1 or 2, R4 represents an alkyl radical and p represents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that either (i) a compound of general formula (II):

(II) wherein A, R2, R3, R4, n and p are as defined above, R3 when hydroxy, amino or carboxy being, if desired, protected by a suitable protecting group, is reacted with a sulphonating agent of the general formula (III):

(III) wherein R1 and m are as defined above, R1 when hydroxy, amino, carboxy or alkylamino, being, if desired, protected by a suitable protecting group, and Hal represents a halogen atom, any protecting group present being thereafter removed, to obtain a compound of the general formula (I) as defined above, and if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof, or (ii) a compound of the general formula (IV):

(IV) wherein R1, R2, R3, m and n are as defined above, R1 when hydroxy, amino, carboxy or alkylamino, being, if desired, protected by a suitable protecting group, R3 when hydroxy, amino or carboxy, being, if desired, protected by a suitable protecting group, or a suitable reactive derivative thereof, is reacted with a compound of the general formula (V):

(V) wherein A, R4 and p are as defined above, any protecting group present being there-after removed, to obtain a compound of the general formula (I) as defined above, and, if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof.

46. A process according to claim 45, wherein A
represents a divalent straight- or branched-chain alkyl group containing 2, 3 or 4 carbon atoms.

47. A process according to claim 45, wherein alkyl groups or moieties, alkoxy groups or moieties and alkanoyl groups or moieties contain from 1 to 4 carbon atoms.

48. A process according to claim 45, wherein A
represents an ethylene, trimethylene, 3-methyltrimethylene or tetramethylene group and R1 represents a halogen atom or an amino, nitro, trifluoromethyl or acetamido group or a C1-C4 alkyl, C2-C5 alkoxycarbonyl or C1-C4 alkoxy group and m represents zero or the integer 1, 2 or 3, R2 repre-sents a hydrogen atom, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-C4 alkyl group in the 2- or 4-position and p represents zero or the integer 1.

49. A process according to claim 45, wherein R1 and R4 are methyl and R3 represents a chlorine atom.

50. A process according to claim 45, wherein m is the integer 1.

51. A process according to claim 45, wherein m is the integer 2.

52. A process according to claim 45, wherein A

represents a trimethylene group.

53. A benzamide derivative of the general formula (I) wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and R1 represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkoxycarbonyl, dialkyl-amino, alkylcarbamoyl or alkanoylamino group and n repre-sents zero or the integer 1 or 2, R4 represents an alkyl radical and p represents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, whenever obtained by a process as defined in claim 45 or an obvious chemical equivalent thereof.

54. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein A represents a divalent straight- or branched-chain alkyl group containing 2, 3 or 4 carbon atoms, whenever obtained by a process as defined in claim 46 or an obvious chemical equivalent thereof.

55. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein alkyl groups or moieties, alkoxy groups or moieties and alkanoyl groups or moieties contain from 1 to 4 carbon atoms, whenever obtained by a process as defined in claim 47 or an obvious chemical equivalent thereof.

56. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein A represents an ethylene, trimethylene, 3-methyltrimethylene or tetramethylene group and R1 represents a halogen atom or an amino, nitro, trifluoromethyl or acetamido group or a C1-4 alkyl, C2-5 alkoxycarbonyl or C1-4 alkoxy group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom, R3 represents a halogen atom and n represents zero or the integer 1, and R4 represents a C1-4 alkyl group in the 2-or 4-position and p represents zero or the integer 1, whenever obtained by a process as defined in claim 48 or an obvious chemical equivalent thereof.

57. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein R1 and R4 are methyl and R3 represents a chlorine atom, whenever obtained by a process as defined in claim 49 or an obvious chemical equivalent thereof.

58. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein m is the integer 1, whenever obtained by a process as defined in claim 50 or an obvious chemical equivalent thereof.

59. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein m is the integer 2, when-ever obtained by a process as defined in claim 51 or an obvious chemical equivalent thereof.

60. A benzamide derivative of the general formula (I) according to claim 53 or a pharmaceutically acceptable salt thereof wherein A represents a trimethylene group, whenever obtained by a process as defined in claim 52 or an obvious chemical equivalent thereof.

61. A process for the preparation of a benzamide derivative of the general formula (I):

(I) wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and R1 represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkylthio, alkyl-sulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkoxycarbonyl, dialkylamino, alkylcarbamoyl or alkanoylamino group and n represents zero or the integer 1 or 2, R4 represents an alkyl radical and p represents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that either (i) a compound of the general formula (II):

(II) wherein A, R2, R3, R4 , n and p are as defined above, R3 when hydroxy, amino or carboxy being, if desired, protected by a suitable protecting group, is reacted with a sulphonating agent of the general formula (III):

(III) wherein R1 and m are as defined above, R1 when hydroxy, amino, carboxy or alkylamino, being, if desired, protected by a suitable protecting group, and Hal represents a halogen atom, and protecting group present being thereafter removed, to obtain a com-pound of the general formula (I) as defined above, and if desired, the obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof, (ii) a compound of the general formula (IV):

(IV) wherein R1, R2, R3, m and n are as defined above, R1 when hydroxy, amino, carboxy or alkylamino, being, if desired, protected by a suitable protecting group, R3 when hydroxy, amino or carboxy, being, if desired, protected by a suitable protecting group, or a suitable reactive derivative thereof, is reacted with a compound of the general formula (V):

(V) wherein A, R4 and p are as defined above, any protecting group present being thereafter removed, to obtain a compound of the general formula (I) as defined above, and, if desired, the obtained compound of the general formula (I) is converted into a pharmaceuti-cally acceptable salt thereof, (iii) a compound of the general formula (I) wherein R1, R3 or both R1 and R3 represent a nitro group, R1 when hydroxy, carboxy or alkylamino being, if desired, protected by a suitable protecting group, R3 when hydroxy or carboxy being protected by a suitable protecting group, is treated to convert said nitro group into an amino group, any protect-ing group present being thereafter removed, to obtain a compound of the general formula (I) as defined above wherein R1, R3 or both R1 and R3 represent an amino group and, if desired, the so obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof, or (iv) a compound of the general formula (I) wherein R1, R3 or both R1 and R3 represent an amino group, R1 when hydroxy, carboxy or alkylamino being, if desired, protected by a suitable protecting group, R3 when hydroxy or carboxy being protected by a suitable protecting group, is treated to convert said amino group into a halogen atom , any protecting group present being thereafter removed, to obtain a compound of the general formula (I) as defined above wherein R1 or R3 or both R1 and R3 represent a halogen atom and, if desired, the so obtained compound of the general formula (I) is converted into a pharmaceutically acceptable salt thereof.

62. A benzamide derivative of the general formula (I):

(I) wherein A represents a divalent straight- or branched-chain alkylene group containing from 1 to 6 carbon atoms and R1 represents a halogen atom or a hydroxy, mercapto, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkoxycarbonyl, alkylamino, dialkylamino, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, alkanoyloxy or alkanoylamino group and m represents zero or the integer 1, 2 or 3, R2 represents a hydrogen atom or an alkyl group, R3 represents a halogen atom or a hydroxy, amino, nitro, cyano, carboxy or carbamoyl group or an alkyl, fluorine-substituted alkyl, alkoxy, alkoxycarbonyl, dialkylamino, alkylcarbamoyl or alkanoylamino group and n represents zero or the integer 1 or 2, R4 represents an alkyl radical and p represents zero or the integer 1 or 2, or a pharmaceutically acceptable salt thereof, whenever obtained by a process as defined in claim 61 or an obvious chemical equivalent thereof.