GB1582944A - Benzamide derivatives - Google Patents

Description

PATENT SPECIFICATION

( 11) 1 582 944 ( 21) Application No's 22879/76 3474/77 ( 22) Filed 3 Jun 1976 28 Jan 1977

Complete Specification Filed 30 May 1977

Complete Specification Published 21 Jan 1981

INT CL 3 C 07 C 109/06 ( 52) Index at Acceptance C 2 C 1626 1745 20 ' 250 252 25 Y 313 31 Y 321 339 342 34 Y Y 57 Y 603 63 X 650 660 743 776 800 LY MU NG A 5 B 180 190 327 421 425 42 Y 480 482 483 49 Y 500 502 566 567 56 Y 671 67 Y H ( 72) Y 220 226 22 Y 247 280 281 29 X 29 Y 323 327 32 Y 333 351 354 364 36 Y 620 624 62 X 630 662 670 699 725 7 802 80 Y AA KH K NT 32 Y 380 38 Y 392 430 43 X 43 Y 440 48 Y 490 491 493 4 Y 542 543 54 Y 586 58 Y 661 666 Inventor: ERIC ALFRED WATTS ( 54) BENZAMIDE DERIVATIVES ( 71) We, BEECHAM GROUP LIMITED, a British Company of Beecham House, Great West Road, Brentford, Middlesex, England, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:

This invention relates to novel substituted benzamides having useful pharmacological properties, to pharmaceutical compositions containing them, and to a process for their preparation.

N-( 2-Diethylaminoethyl)-2-methoxy-4-amino -5-chlorobenzamide and 1-ethyl2( 2-methoxy-5-sulphamoylbenzamidomethyl)pyrrolidone are commercially available products having useful pharmacological activity such as the ability to regulate the gastrointestinal function and anti-emetic activity.

Surprisingly it has now been found that a class of substituted benzamides containing a hydrazine linkage possess useful pharmacological activity, and in particular are dopamine antagonists.

Accordingly the present invention provides a compound of the formula (I) and hydrates and pharmaceutically acceptable salts therof:

/(CH 2)a CO -NH-N N-R 4 (CH 2 b R 3 (I) wherein:

R, is a Ci-6 alkoxy group; R 2 and R 3 are the same or different and are hydrogen halogen CF 3 hydroxy Ci-6 alkoxy, C 2-7 acyl amino, amino substituted by one or two C,-6 alkyl groups C 2-7 acyl amino, aminosulphonyl aminosulphonyl substituted by one or two C -6 alkyl groups C,-6 alkylsulphonyl or nitro groups; ( 23) ( 44) ( 51) ( 19) Y 338 455 634 729 :Z 420 44 Y 49 X 565 66 Y 1,582,944 a and b are each 2 or 3; R 4-is a CL-6 alkyl group, or a phenyl-CL-3 alkyl group or a thienyl-CL-3 alkyl group in which the phenyl or thienyl moiety is optionally substituted by halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, amino, amino substituted by one or two CL-6 alkyl groups, or CF 3.

Suitable examples of the group RI include methoxy, ethoxy and n and isopropoxy.

Preferably R is a methoxy group.

Suitable examples of the groups R 2 and R 3 include the following groups: hydrogen, chlorine, bromine, CF 3, hydroxy, methoxy, ethoxy, n and iso-propoxy, n and sec and tert-butoxy, acetyl, propionyl, butyryl, amino, amino substituted by one or two methyl, ethyl, n or iso-propyl, n-, sec or tert-butyl groups, acetylamino, propionylamino, butyramino; aminosulphonyl aminosulphonyl substituted by one or two methyl, ethyl,n oriso-propyl,n-, sec or tert-butyl groups, and methyl, ethyl and n and iso-propylsulphonyl and nitro.

Particularly suitable R 2 and R 3 groups include hydrogen, halogen, amino and substituted amino as defined.

It is generally preferred that R 2 is in the 4-position relative to the amido side chain for greater activity in the resultant compound of the formula (I) For the same reason it is generally preferred that R 3 is in the 5 position relative to the amido side chain.

Particularly preferred R 2 groups include 4-amino and 4-(substituted amino) as defined.

Preferably R 2 is 4-amino Particularly preferred R 3 groups include 5halo, such as 5-chloro.

Preferably a and b are each 2 in formula (I).

When R 4 is a Cl-6 alkyl group, or an optionally substituted phenyl-CI-3 alkyl group or thienyl-CI-3 alkyl group as defined, suitable examples of the groups include methyl, ethyl, nand iso-propyl and n-butyl; and benzyl, phenyl-ethyl, and phenyl-n and iso-propyl groups.

Preferred groups R 4 include Cl-6 alkyl groups such as methyl or n-butyl; and optionally substituted phenyl CI-3 alkyl groups such as benzyl.

From the aforesaid it will be realised that certain particularly suitable compounds of the formula (I) will be of the following formula:

Cl H 2 N CO-NH -N N R 4 v-I(I OCH 3 (D In formula (IT), R 4 is suitably C,-6 alkyl, such as methyl or ethyl; or benzyl.

Other suitable compounds are of formula (II) as defined but wherein the 4amino is substituted as hereinbefore defined.

The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic phosphoric, sulphuric citric tartaric lactic and acetic acid.

The pharmaceutically acceptable salts of the compounds of the formula (I) also include quaternary ammonium salts Examples of such salts include salts with compounds such as R 5 X wherein R 6 is CI-6 alkyl phenyl Ci-6 alkyl or C 5-7 cycloalkyl, and X is an anion of an acid.

Suitable examples of R 5 include methyl, ethyl and n and iso-propyl; and benzyl and phenyl ethyl Suitable examples of X include the halides such as chloride, bromide and iodide.

The invention also provides a process for the preparation of a compound of the formula (I), which process comprises reacting an acid of formula (III), or a reactive derivative thereof:

COOH R 3 R 1 i {R ( 1 T) 2 (I) 2 t i1,582,944 wherein R,, R 2 and R 3 are as defined in formula (I) with a compound of formula (IV):

C 2)a\ 5 H 2 N-N N-R 4 (CH 2 Ab 10 wherein, a, b, and R 4 are as defined in formula (I), and thereafter if desired or necessary converting a group R 2 or R 3 in the thus formed compound of the formula (I) to another group R 2 or R 3 15 The acid addition salts of compounds of the formula (I) may be prepared in entirely conventional manner by reacting the thus formed compound of the formula (I) in base form with the chosen acid.

The quaternary ammonium salts of the compounds of the formula (I) may be prepared in conventional manner for such salts, such as by reaction of the chosen compound of the 20 formula ( 1) with a compound Rs X as defined This reaction is suitably carried out in an appropriate solvent such as acetone, methanol, or ethanol, at ambient or raised temperature and pressure.

Reactive derivative' means a derivative of the compound (III) which can be reacted with the compound (IV) to form an amido linkage between the acid group of the compound (III) 25 and the -NH 2 amino group of the compound (IV).

Often this reactive derivative will be the acid halide, such as the acid chloride, of the acid (III) In such cases, the reaction will normally be carried out in an inert solvent, preferably in the presence of an acid acceptor The inert solvent can be any solvent inert to both reactants such as benzene, toluene, or diethylether The acid acceptor is normally an organic base such 30 as a tertiary amine e g, triethylamine, trimethylamine, pyridine picoline It may also be any inorganic acid acceptor, such as calcium carbonate and sodium carbonate It should also be noted that it is possible to use certain acid acceptors as the inert solvent as well, for example organic bases.

Another useful reactive derivative of the acid (III) that may be used is an acid ester, such as 35 methyl, ethyl, propyl or butyl ester, in which case the reaction is normally carried out by heating the reactants together in an inert solvent such as ethylene glycol.

The reaction may also be carried out by forming an anhydride of the acid (III) in the usual manner, and reacting that with the compound (IV)-normally a conventional mixed anhydride will be used; or by reacting the acid (III) and the compound (IV) in the presence of a 40 dehydrating catalyst such as a carbodiimide, for example dicyclohexyl carbodiimide.

The interconversion of suitable groups R 2 and R 3 after formation of a compound of the formula (I) may be carried out by conventional methods By way of example, nitro groups may be reduced to amino groups in the normal manner, and acylamino groups may be converted to amino also by conventional methods Also a compound of the formula (I) 45 wherein R 2 or R 3 is halogen can be prepared by a conventional halogenation The acids of formula (III) and the compounds 50 (CH 2)a H 2 N-N 7 N R 4 55 (CH 2)b 60 are either known compounds or can be prepared by analogous processes to known compounds By way of example a process for preparing compounds 65 4 1,582,944 4 (CH 2)a H 2 N N ' N R 4 (CH 2)b is reacting H b with a nitrosating agent such as HNO 2, to give a compound and then reducing that compound with a reducing agent, such as zinc/acetic acid or lithium 35 aluminium hydride to give a compound 1 1 /(CH 2)a H 2 N NC 2/ NR 4 (CH 2)b The compounds of the formula (I) have useful pharmacological properties As hereinbefore stated the compounds of the formula (I) are dopamine antagonists Depending on their balance between peripheral and central action, the compounds of the formula (I) may be used in the treatment of disorders related to improved gastro-intestinal motility, such as retarded gastric emptying, dyspesia, flatulence, oesophagal reflux, peptic ulcer and emesis, and/or is the treatment of disorders of the central nervous system, for example as neuroleptics.

All the compounds of the formula (I) may be used in the treatment of emesis.

Examples of compounds of formula (I) which are of particular interest for their motility enhancing activity are those wherein R 4 is Cl-4 alkyl.

The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier Such compositions may be adapted for oral or parenteral administration and as such may be in the form of tablets capsules, syrups, reconstitutable powders injectable and infusable solutions or suspensions The compositions may also be in the form of suppositories Normally orally administrable compositions are preferred.

It has been found that compounds of the formula (I) have the ability ot potentiate the effect of conventional analgesics in migraine treatment when administered concurrently with the analgesic Thus the invention provides a pharmaceutical composition comprising a compound of the formula (I) and an analgesic.

The compound of the formula (I) anid the analgesic such as aspirin or paracetamol, will be i so i 1,582,944 1,582,944 present in the composition in amounts generally similar to their usual effective dose.

The composition can be a combination product, for example a tablet or capsule containing both a compound of the formula (I) and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.

The following Examples illustrate the invention 5 EXAMPLE 1

4-amino-5-chloro-2-methoxy-N l 4-benzyl 1-piperazinyllbenzamide 4-acetylamino-5-chloro-2-methoxybenzoic acid ( 3 50 g, 0 144 mole) was treated with thionyl chloride ( 25 ml) at 50 for A hour The mixture was evaporated in vacuo and the residue azeotroped twice with anhydrous benzene ( 100 ml) and redissolved in anhydrous 10 benzene ( 100 ml) Triethylamine ( 1 45 g) was added followed by Iamino-4-benzylpiperazine ( 2 75 g 0 144 mole) and the reaction left for 6 hours at room temperature The mixture was evaporated in vacuo, taken up in water ( 50 ml) basified with dilute sodium hydroxide ( 10 %o) and extracted with chloroform Evaporation of the dried (Mg SO 4) chloroform extract gave 4-acetylamino-5-chloro -2-methoxy-N lbenzyl-l 15 piperazinyllbenzamide ( 3 50 g; 58 %o) as colourless microcrystalsm p 211213 C A sample recrystallised from benzene gave m p 212 C.

Treatment of the above with 85 % potassium hydroxide ( 3 O g) in aqueous ethanol ( 50 ml) for 6 hours at reflux gave on cooling 4-amino-5-chloro-2 methoxy-N-l 4benzyl 1piperazinyllbenzamide ( 1 90 g; 70 %) as colourless microcrystals m p 185 C (ex ethylace 20 tate/light petroleum 40 60 ) lCompound 1 l.

A solution in ethanol of the above when treated with ethereal hydrogen chloride gave a hydrochloride salt as colourless crystals m p 177 178 C.

C 19 H 23 CIN 402 Requires: C = 60 88 H = 6 14 N = 14 95 25 Cl = 9 48 Found: C = 61 24 H = 6 41 N = 15 32 Cl = 9 29 EXAMPLE 2 30

4-amino-5-chloro-2 methoxy-N l 4-methyl 1 l-piperazinyllbenzamide 4-acetylamino-5-chloro-2-methoxy benzoyl chloride ( 2 70 g 0 0103 mole) in anhydrous benzene ( 100 ml) in the presence of triethylamine ( 1 lg) was treated with 4-methyl l-amino piperazine ( 1 18 g) After 6 hours the reaction mixture was basified with dilute sodium hydroxide and extracted with hot ethyl acetate On cooling the extracts yielded 35 4-acetylamino-5-chloro-2-meihoxy-N-l 4 methyl-1-piperazinyllbenzamide ( 1 72 g) m p.

198-200 C.

Without purification the acetylamino compound ( 1 72 g) was hydrolysed in aqueous alcoholic potassium hydroxide ( 10 mis) at 80 for 1 hour to give 4amino-5-chloro-2-methoxy -N-l 4-methyl-1-piperazinyllbenzamide ( 1 67 'g, 56 %o) as the monohydrate, m p 159-160 , 40 (softening at 112 C) (Compound 2).

EXAMPLE 3

4-acetylamino-5-chloro -2-methoxy-N l 4-methyl l-piperazinyllbenzamide ( 1 31 g) was dissolved in ethanol and treated with anhydrous ethereal hydrogen chloride to give the monohydrochloride ( 970 mg), recrystallised from ethanol/anhydrous ether to m p 224 45 230 .

EXAMPLE 4

4-amino-5-chloro-2 methoxy-N-l 4-methyl-l piperazinyllbenzamide ( 700 mg) gives the monohydrochloride hemihydrate (m p 237-239 C) when treated as in Example 3.

EXAMPLES 5 50

Ethyl iodide ( 8 13 g 0 052 mole) was added to acetone ( 80 ml) containing N-nitroso piperazine ( 6 0 g 0 052 mole) (prepared as described in U S Patent 2,907, 767) and anhydrous potassium carbonate ( 7 3 g 0 052 mole) The mixture was heated under reflux for 24 hours, cooled treated with water ( 50 ml) evaporated to 1/2 volume and extracted with ether ( 3 x 150 ml) The combined extracts were dried (K 2 CO 3) filtered and evaporated in 55 vacuo to yield N-ethyl-N'-nitrosopiperazine ( 7 71 g 98 %) as a straw coloured oil.

A solution of N-ethyl-N'-nitrosopiperazine ( 4 0 g 0 028 mole) in anhydrous freshly distilled tetrahydrofuran ( 80 ml) was added dropwise to a stirred suspension of lithium aluminium hydride ( 1 5 g excess) under nitrogen in anhydrous tetrahydrofuran ( 160 ml) at 20-25 C After addition stirring was continued for a further 8 hours Work up via controlled 60 addition of water ( 1 5 ml) 10 % sodium hydroxide ( 2 25 ml) and water ( 3 75 ml) gave N-amino-N'-ethyl piperazine ( 2 26 g 63 %o) as a pale straw coloured oil.

Subsequent treatment with 4-acetylamino-5-chloro-2-methoxy benzoic acid ( 4 27 g.

0.0175 mole) as an acid chloride in anhydrous benzene ( 100 ml) containing triethylamine ( 2 O g) gave 4-acetylamino-5-chloro -2-methoxy-N-ll-ethyl -4piperazinyllbenzamide ( 4 16 65 1,582,944 g, 67 %) as a foam (ex, ethyl acetate).

Hydrolysis in aqueous alcoholic potassium hydroxide ( 1 5 g in ethanol ( 10 ml) containing water ( 4 ml)) at 80 C for 1 hour gave 4-amino-5-chloro-2-methoxy -N-llethyl4-piperazinyllbenzamide ( 2 3 g; 65 % as colourless microcrystals, m p 177-178 5 C (ex.

Et O Ac) 5 EXAMPLE 6

Reaction between 4-acetylamino-5-chloro-2-methoxy benzoic acid ( 3 2 g, 0 013 mole), triethylamine ( 1 3 g) and N-n-butyl-N'-amino piperazine ( 2 06 g) (prepared in similar manner to that described in Example 5) and hydrolysis as described in Example I gave 10 4-amino-5-chloro-2 methoxy-N-l 1 -n-butyl-4-piperazinyllbenzamide ( 2 80 g, 63 %) as colourless microcrystals, m p 173 5-174 C (ex Et O Ac/light petrol 40-60 ).

EXAMPLE 7

Reaction between 4-acetylamino-5-chloro-2 methoxy benzoic acid ( 3 0 g, 0 0123 mole) triethylamine ( 1 3 g) and N-amino-N'-4-chloro benzyl piperazine ( 2 8 g) and hydrolysis as 15 described in Example 1 gave 4-amino-5-chloro-2-methoxy-N l 1-( 4-chloro benzyl)l4-piperazinyl benzamide ( 1 96 g, 44 %) as colourless microcrystals, m p 196-197 C (ex.

Et O Ac/light petrol 40-60 ).

EXAMPLE 8

Reaction between 4-acetylamino-5-chloro 2-methoxy benzoic acid ( 3 0 g, 0 012 mole) 20 tri-ethylamine ( 1 3 g) and N-amino-N'-( 4 methoxy benzyl) piperazine ( 2 72 g, 0 012 mole) and hydrolysis as described in Example 1 gave 4-amino-5-chloro-2-methoxy -N-l 1-( 4-methoxybenzyl) -4-piperazinyll benzamide ( 3 93 g, 81 %) as colourless microcrystals, m p 154-156 C(ex Et O Ac).

EXAMPLE 9 25

1-methylhomopiperazine (prepared as described by A H Somers et al, in J Amer Chem.

Soc 76, 5805, 1954) ( 6 10 g, 0 0535 mole) was dissolved in concentrated hydrochloric acid ( 25 ml), cooled to O 5 C, stirred and treated dropwise with sodium nitrite ( 4 06 g) in water ( 10 ml) After addition the solution was allowed to come to room temperature, then heated for i hour at 70 C The solution was cooled was basified with solid KOH and extracted with 30 ether ( 3 x 100 ml) The dried (K 2 C 03) extracts yielded N-methyl-N'nitrosohomopiperazine ( 3.80 g, 50 %) as a pale yellow oil.

Lithium aluminium hydride reduction in anhydrous tetrahydrofuran as described in Example 5 gave N'-amino-N-methylhomopiperazine ( 1 8 g) as a colourless oil.

Subsequent reaction with 4-acetylamino-5-chloro -2-methoxy benzoic acid ( 3 5 g) and 35 triethylamine ( 1 5 g) and hydrolysis as described in Example I gave 4amino-5-chloro-2methoxy-N-l l-methyl-4 ( 1,4-diazacycloheptanyl) lbenzamide ( 520 mg) as colourless microcrystals, m p 141-143 C after purification by chromatography.

EXAMPLE 10

Reaction between 4-acetylamino-5-chloro-2-methoxybenzoic acid ( 3 75 g, 0 015 mole), 40 triethylamine ( 3 ml) and N-amino-N'-( 3-chlorobenzyl)piperazine ( 3 61 g 0 014 mole), followed by work up and hydrolysis as described in Example 1 gave 4-amino5-chloro-2methoxy-N l 1-( 3-chlorobenzyl) l-4-piperazinyl benzamide ( 2 49 g 48 %) as colourless microcrystals m p 211-213 C (ex Et O Ac).

Pharmacological Data 45 1 Compounds prepared in the Examples were tested for the following pharmacological activities in the rat:

(a) Increase in intragastric pressure Intragastric pressure changes were recorded from previously starved conscious but restrained rats using a saline filled catheter inserted into the lumen of the stomach via a 50 permanent gastric fistula The catheter was connected to a physiological pressure transducer and pressure changes recorded on a hot wire pen recorder In each animal a pre dose period of minutes was allowed to obtain a measure of spontaneous activity An index of activity was obtained by measuring the average height of pressure waves during 10 minute periods.

Values for 4 such periods were obtained during assessment of spontaneous activity and for 55 the 40 minute period after the subcutaneous administration of the Compounds Student "t" test was applied to the difference in average values obtained for spontaneous and post Compound activity.

(b) Increase in gastric emptying-reversal of apomorphine induced delay in gastric emptying of a test meal 60 Rats equipped with chronic gastric fistual were used and it was through this that 5 ml of a test meal ( 5 ml phosphate buffer at p H 9) was administered and recovered The %recovery of the standard meal after remaining in the stomach for 10 minutes was taken as an index of gastric emptying Delay in gastric emptying was induced by the administration of Apomorphine HCI ( 5 mg/kg subcutaneously) and was given 15 minutes prior to the subcutaneous 65 7 1,582,944 7 administration of the Compound The %recoveries of the test meal was determined at 15 25 and 45 55 minutes post dosing with the Compound and compared with vehicle only dosed animals set up simultaneously Six animals were used for each group.

(c) Inhibition of stereotype behavour induced by apomorphine This is indicative of dopamine receptor blockage in the central nervous system 5 The method of Ernst A M ( 1967) Pyschopharmocologia (Berl) 10 pp 316-323 was followed.

The Table shows active doses (mg/kg) in these tests either by the subcutaneous (s c) or oral (p o) route of administration.

None of the compounds tested showed any signs of toxicity at the active doses 10 (a) Increase in (b) Increase in (c) Inhibition Example Intra-Gastric Gastric of Sterotype No Pressure Emptying Behaviour 15 1 25 mg s c 0 625 mg s c.

2 1 mg s c Inactive mg p o 25 mg s c ( 100 mg s c) 4 10 mg p o 20 Inactive 50 mg s c 50 mg s c ( 50 mg s c.

Inactive 6 5 mg s c 25 mg s c ( 25 mg s c) 25 7 50 mg s c.

8 25 mg s c 3 mg s c.

Inactive 9 10 mg s c 25 mg s c ( 25 mg s c) 30 930 2 Anti-emetic activity in the dog At 0 25 mg/kg s c the Compound of Example I abolished the emetic response to apomorphine in the dog At 2 mg/kg s c the Compound of Example 2 partially abolished the response 35

Claims (1)

1. WHAT WE CLAIM IS:

   1 A compound of the formula ( 1) or a hydrate or a pharmaceutically acceptable salt thereof:

   40 (CH 2)a CO NH -NR 4 '1 (CH 2)b 45 R 3 R 3 N (I) R 2 50 wherein:

   R is a Cl-6 alkoxy group; R 2 and R 3 are the same or different and are hydrogen halogen CF 3 hydroxy C 1-6 alkoxy.

   C 2-7 acyl amino amino substituted by one or two Ci-6 alkyl groups C 2-7 acyl amino, aminosul 55 phonyl aminosulphonyl substituted by one or two Ci-6 alkyl groups Ci-6 alkylsulphonyl or nitro groups; a and b are each 2 or 3; R 4 is a Ci-6 alkyl group or a phenyl-Ci 3 alkyl group or a thienyl-CI-3 alkyl group in which the phenyl or thienyl moiety is optionally substituted by halogen Ci 6 alkyl C,-6 alkoxy hydroxy, 60 or CF 3.

   2 A compound as claimed in claim 1 wherein R 2 is 4-amino and R 3 is hydrogen or 5-halo.

   3 A compound as claimed in claim I or 2 wherein R 3 is 5-chloro.

   4 A compound as claimed in claim 12 or 3 wherein R, is methoxy 65 8 1,582,944 8 A compound as claimed in any one of the claims l to 4 wherein a and b are each 2.

   6 A compound as claimed in claim 5, wherein R 4 is a Ct-6 alkyl group.

   7 A compound as claimed in claim 5, wherein R 4 is a phenyl-CI 3 alkyl group in which the phenyl ring may be substituted 8 A compound as claimed in any one of the claims 2 to 7, wherein the R 24amino group 5 is acylated by a C 2 7 acyl group.

   9 A compound as claimed in claim 8, wherein R 2 is acetylamino.

   A compound as claimed in claim 1, of the formula (II):

   10 Cl H 2 N CO-NH-N N-R 4 15 OCH 3 20 wherein R 4 is as defined in claim 1.

   l A compound as claimed in claim 10, wherein R 4 is a phenyl CI-3 alkyl group optionally substituted in the phenyl ring.

   12 A compound as claimed in claim 1 1, wherein R 4 is benzyl 25 13 A compound as claimed in claim 10, wherein R 4 is C 1-6 alkyl.

   14 A compound as claimed in claim 13, wherein R 4 is methyl.

   A compound as claimed in claim 13, wherein R 4 is n-butyl.

   16 A pharmaceutical composition comprising a compound as defined in any one of the claims I to 15 together with a pharmaceutically acceptable carrier 30 17 A composition as claimed in claim 16, also comprising an analgesic.

   18 A composition according to claim 17 wherein the analgesic is aspirin or paracetamol.

   19 A process for the preparation of a compound as claimed in claim 1 which process comprises reacting an acid of formula (II), or a reactive derivative thereof:

   35 COOH R 1 40 1 (SL R 33 2 R 45 wherein Rl, R 2 and R 3 are as defined in claim I with a compound of formula (IV):

   50 (CH 2)ai H 2 N-N N R 4 55 (CH 2)b 60 wherein a b and R 4 are as defined in claim 1 and thereafter if desired or necessary converting a group R 2 or R 3 in the thus formed compound of the formula (I) to another group R 2 or R 3.

   A process as claimed in claim 19 substantially as hereinbefore described with reference to any one of the Examples.

   21 A compound as claimed in claim 1 substantially as hereinbefore described with 65 9 1,582,944 9 reference to any one of the Examples.

   22 A compound as claimed in claim 1, wherever prepared by a process as claimed in claim 19 or 20.

   For the Applicants 5 H.B DAWSON Chartered Patent Agent.

   Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980.

   Published by The Patent Office, 25 Southampton Buildings London, WC 2 A l AY,from which copies may be obtained.

   1 i