IE46886B1 - Aminoalkyl-benzene derivatives - Google Patents

Abstract

As intermediates for the preparation of aminoalkylbenzene derivatives, compounds of the general formula II in which the substituents attached to the benzene ring are in the ortho, para or meta position with respect to one another, and in which R1 and R2, which may be identical or different, represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups, or lower alkyl groups which are interrupted by an oxygen atom or a group in which R4 has the meaning hydrogen or lower alkyl, or R1 and R2 form, together with the nitrogen atom to which they are attached, a heterocyclic ring which may contain the hetero functions -O- and , represents -O-, -S-, -CH2- or , in which R5 has the meaning hydrogen or lower alkyl, m is an integer from 2 to 4, n has the value 0, 1 or 2 and Alk represents a straight-chain or branched alkylene chain having from 1 to 6 carbon atoms, and their acid addition salts with inorganic and organic acids.

Description

This invention relates to new aminoalkylbenzene derivatives having a selective action on histamine receptors, to processes for the preparation thereof, to pharmaceutical compositions containing them , as well as to their use in therapeutics. It also relates to novel intermediates of use in the processes referred to.

We have found that certain novel aminoalkylbenzene derivatives are selective Hg-antagonists that is they show inhibition of the secretion of gastric acid when XO this is stimulated via histamine Hg-receptors {Ash and Schild - Brit. J. Pharmacol. Chemother. 1966 27. 427).

Their ability to prevent the secretion of gastric juice when it is stimulated via histamine Hg-receptors can be demonstrated in the perfused rat stomach, using the method described by Ghosh and Schild - Brit. J. Pharmacol. 1958, 13. 54, modified as hereinafter described and in conscious dogs equipped with Heidenhain pouches using the same method as Black et al - Nature 1972 256, 385. The compounds, according to the invention do not modify histamine induced contractions of isolated gastrointestinal smooth muscle.

Compounds with histamine Hg-blooking activity may be used in the treatment of conditions where there is a hypersecretion of gastric acid e.g. in gastric and peptic ulceration, and in the treatment of allergic conditions where histamine is a known mediator. They may he used, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions such as urticaria.

The present invention provides compounds of the general formula (I): NAlk· (CH2)nX(CH9)MNHCNHR 2'm (I) and physiologically acceptable salts and hydrates, of such compounds and such «alts . in which the substituents attached to the benzene ring are ortho, meta or para to one another and R3 and R2 which may be the same or different represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups or lower alkyl groups interrupted by an oxygen atom or a group -N- in which Rh represents hydrogen or lower alkyl, or Rjand Rg together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain the hetero functions -0- and -N-; R_ > h represents hydrogen, lower alkyl, lower alkenyl or 25 alkoxyalkyl; 6 8 8 5 X is -0-, -S-, -CHO- or -N- where Rr is hydrogen or lower " ι J R5 alkyl; Y represents =S, =O,=NRg or =CHR„ in which R^ is hydrogen, nitro, cyano, lower alkyl, aryl, arylsulphonyl or lower alkylsulphonyl and R? is nitro, lower alkylsulphonyl or arylsulphonyl; m is an integer from 2 to 4 inclusive; n is zero, 1 or 2; and Alk denotes a straight or branched alkylene chain of 1 to 10 6 carbon atoms.

His term 'lower' as applied to 'alkyl' means that the group has 1 to 6 carbon stems,' and in particular 1 to 4 carbon atons and when applied to ’alkenyl’ that the group has 3 to 6 carbon atoms. The term '’aryl' preferably means phenyl or substituted phenyl for example phenyl substituted with one or,more alkyl or alkoxy groups or halogen atoms.

The compounds of formula (l) can exhibit tautomerism and the formula is intended to cover all tautomers. Where Alk denotes a branched chain alkylene group, optical isomers may exist, and the formula is intended to cover all diastereoisomers and optical enantiomers.

The preferred compounds are those in which R-^ and Rg independently represent hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 6 8 8 6 or 6-membered heterocyclic ring; Alk represents a straight alkylene chain of 1 to 3 carbon atoms; n is zero or 1; Y is =S, =0, =CHNO2 or =NRg where Rg is hydrogen, nitro, cyano or lower alkylsulphonyl; R^ ic hydrogen, lower alkyl or alkoxyalkyl; and in and x have the meanings given above.

Particularly preferred are the compounds where the side chains are in a meta position to one another.

In a preferred class of compounds R^ and R2 independently represent hydrogen or methyl or together with the nitrogen atom to which they are attached form a pyrrolidinering; Alk represents a methylene group; n is zero; Y is =CHN02 or =NRg where Rg is nitro, cyano or methylsulphonyl; R3 is hydrogen or methyl; m is 3 and x is oxygen.

In another preferred class according to the invention there are provided compounds of the general formula (la)s R-^ CHNO2 in which R represents hydrogen or methyl, and physiologically acceptable salts thereof, as well as hydrates of such compounds and such salts. 6886 Particularly preferred specific compounds are: N-Methyl-N1-Z7~ZZ?_W,N-dimethylaminomethyl)phenyl/methylthio7etfiyl-2-nitro-l,1-ethenediamine N-Methyl-N'-/2-//3-(N-methylaminomethyl)phenyl7methylthig7 5 ethy17-2-nitro-l,1-ethenediamine N-Methyl-N'-/β-/T-(Ν,Ν-dimethylaminomethyl)phenoxy7propyl7 2-nitro-1,1-ethenediamine N-Methyl-N'-/3-/7-(N-methylaminomethyl)phenoxy7propy17-2nitro-l , 1-ethenediamine 10 N-Methyl-N'-/7-/3-(1-pyrrolidinyImethyl)phenoxy7ProPyI7-2nitro-1,1-ethenediamine N-Nitro-N'-/7-/7-(Ν,Ν-dimethylaminomethyl)phenoxy7propylguanidine N-Cyano-N' -methy l-N-/7-/7- (Ν,Ν-dimethylaminomethy) phenoxy I·5 propyl/ guanidine N-Methyl-N’ -/5-/1- (H, N-dimethyl-2-aminoethyl)phenox^7propyI7-2nitro-1,1-ethenediamine N-Methanesulphonyl-Ν'-methyl-N*'-[3-[3-(N,N-dimethylaminomethyl) phenoxy]propyl]guanidine The compounds of formula (I) form physiologically acceptable salts with inorganic and organic acids. Particularly useful salts include hydrochlorides, hydrobromides and sulphates; acetates, maleates and fumarates. The compounds may also fen?, hydrates.

The compounds according to the invention can be administered orally, topically or parenterally or by suppository, of which the preferred route is the oral route.

They may be used in the form of a base or as a physiologically acceptable salt. They will in general be associated with a pharmaceutically acceptable carrier or diluent, to provide a pharmaceutical composition.

The compounds according to the invention can be administered in combination with other active ingredients, e.g. conventional anti-histamines if required. Por oral administration thejharmaceutioal composition can be most conveniently in the form of capsules or tablets, which may be slow release tablets.

The composition may also take the form of a dragee or may be in eyrup form. Suitable topical preparations include ointments, lotions, creams, powders and sprays.

A convenient daily dose by the oral route would be of the order of 10 mg to 2 g per day, in the form of dosage units containing from 2 mg to 200 mg per dosage unit.

Parenteral administration may be by injections at intervals or as a continuous infusion. Injection solutions may contain from 1 to 100 mg/ml of active ingredient.

For topical application a spray, ointment, cream or lotion may be used. The compositions may contain an effective amount of the active ingredient, for example of the order of 1¾ to 2% by weight of the total composition.

The above compositions may be suitable for either human or veterinary use.

In accordance with a further embodiment of the invention there is a method of treating a condition mediated through histamine Hg-receptors which comprises administering to a non-human patient an effective amount of a compound according to the invention to relieve said condition, which may, for example, be peptic ulceration or an allergic skin condition.

The compounds of formula (I) may be made by reacting a primary amine of the formula (II) (in which R^, Rg, Alk, n, x and m have the meanings previously defined) with a compound capable of introducing the group -CNHR. in which R, and Y have the meanings given herein with II 3 y the proviso that when X is -CHg-, n is zero and m is 2, or m + n is 3 and that X is NRg only when n is zero and Alk is methylene; and further that Rg only represents hydrogen. 6 8 8 6 Compounds which are capahie of introducing the group -CNHR, include isocyanates R-NCO, isothiocyanates R,NCS or H J -J J Y compounds of the formula (III): II Q (III) wherein Q represents a group =NRg or =CHR^ and P is a leaving group such as halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, hut is preferably thiomethyl.

The reaction with the isocyanate or isothiocyanate may be carried out by allowing the amine (II) and isocyanate or isothiocyanate to stand in a solvent such as acetonitrile. The reaction of the amine (ll) with a compound of formula (III) can be carried out by fusing the reactants at an elevated temperature,e.g. 100-120°C. Where Q is =NRg, the reaction between the amine (II) and the compound (III) may also be carried out in a solvent, e.g. acetonitrile or ethanol at elevated temperatures. Where Q is =CHRy, the amine (II) and the compound (ill) may be stirred in aqueous solution at room temperature.

Where R^ represents hydrogen, alkali metal cyanates and thiocyanates may be used, the reaction being effected at elevated temperature. Alternatively, organic isocyanates and isothiocyanates may be used,e.g. ethyl caxbonJ^othiocyanatidate which has the formula CH^CHgCCtOjECS,) followed by basic hydrolysis.

In an alternative process, the amine of formula (II) is reacted with a compound of formula (IV): V |j (IV) Q where P and Q are as defined above and P’ may have the same meanings as P or may, when Q represents =CHN02, be a group -S-A wherein A represents a lower alkyl group, e.g. tl methyl. 0 The resulting compound of formula (V) may then be reacted with an amine R-NHg to give a compound of formula (l). Both steps of the reaction may be effected in a solvent,e.g. ethanol or acetonitrile,at a temperature from ambient to reflux.

Compounds of the invention in which n is 1, X is sulphur and the other symbols hava the meanings given except that when R^ and R2 are both hydrogen, Y is other than=CIIR^ may also be prepared from compounds of formulae (vi) or (VII) using a thiol of formula (VIII): R.

R, -2 [Alk R, (VII, (VI) HS(CH2)mRHCNHRj (VIII) In the above formula (VI) L represents a leaving group e.g. halogen, e.g. bromine, or an acyloxy e.g. acetoxy group. Where one is producing compounds in which R^ and Rg are hydrogen, the amino group NRjRg is protected in compounds of formula (VI) and (VII) &e, in the case of a primary amine, for example, a phthalimido group, file protecting group may be removed at an appropriate stage in the-reaction using for example a primary amine or a hydrazine, e.g. methylamine or hydrazine hydrate, in the case where it is protected by phthalimido group formation.

The reaction between a thiol (VIII) and a compound of formula (VI) is preferably carried out in the presence of a strong base,e.g. sodium hydride,at room temperature in an organic solvent,e.g. dimethylformamide. The reaction I I between a thiol (VIII) and a compound of formula (VII) is preferably carried out at 0°C in a mineral acid e.g. concentrated hydrochloric acid. The starting materials of formula (Vi) may be prepared from alcohols of formula (VII) by conventional means.

Another process for preparing compounds according to the invention where Y is sulphur and and Rg are other than hydrogen involves treatment of the amine (ll) with carbon disulphide followed by reaction with a chloroformate ester e.g.,ethyl ohloroformate, to give an isothiocyanate of formula (ix) When the resulting compound of formula (IX) is reacted with an amine R^MHg, preferably in a solvent such as acetonitrile, the product is a compound of formula (i) wherein Y is sulphur and R^ and Rg are other than hydrogen.

Compounds of formula (I) where γ is a group =NCN may be prepared from compounds Of formula (I) wherein Y is sulphur by heating the latter compounds with a heavy metal cyanamide such as that of silver, lead, cadmium or mercury, preferably in aqueous solution.

When the groups R^ and Rg in compounds of formula (i) in which Y is other than =S are hydrogen they may be converted into alkyl or aralkyl groups by reaction with, for example, an alkyl or aralkyl halide. If compounds in which R^ and/or Rg are methyl groups are desired an alternative would be to use formic acid and formaldehyde as in the Eschweiler-Clarke reaction.

In the above discussion of the processes available for the production of the compounds according to the invention, reference has been made to primary amines of formula (II). These amines are novel compounds and the invention includes such compounds and acid addition salts thereof with inorganic and organic acids. These intermediates may be made hy a number of processes which are described below.

Amines of formula (il) wherein X is oxygen or sulphur may be prepared from compounds of formula (X) wherein X is oxygen or sulphur and Rg is the group RjRgNAlk or a group convertible thereto as appropriate, as herein described,and n has the meanings given above, by reaction in the presence of a base,e.g, sodium hydride •3 with compounds of formula (XI) (XI) in which L* has the meanings given for L or in addition may he a sulphonyloxy group e.g. mesyloxy or tosyloxy, m is as defined above and W is a group -NH, or a protected amino group, e.g. phthalimido, which protecting group may subsequently be removed by means described above.

By the term convertible thereto as applied to groups convertible to the group R^RjWAlK we mean aldehyde, carboxylic acid or-amidfe groups. For example, the group -CHO may he converted by reductive amination using an amine RjRgNH. Similarly, a carboxylic acid group may be converted into the corresponding acid halide or ester which may then he reacted with an amine R^R^NH, followed hy reduction of the amide so formed with, for example, lithium aluminium hydride to give a group R^RgNCHgAmines of formula (II) wherein n is 1 and X is oxygen or sulphur may he prepared by reaction of a compound of formula (VI) or (VII) with a compound capable of introducing the group -X(CHg)mNfl^wherein X is oxygen or sulphur and m has the meanings given herein. When a compound of formula (VI) is used, the presence of a base is desirable. Wien a compound of formula (VII) is used, the reaction, is done under acidic conditions.

Amines of formula (II) in which n is 1, m is 2 and X is oxygen or sulphur can be obtained by treating a compound of formula (X) in which n is 1 and X is oxygen or sulphur with ethylene imine.

Amines of formula (II) in which n is zero, m is 3 and X is oxygen may be obtained from the corresponding nitrile of formula (XII) V O^CH2^2CN (XII) by catalytic hydrogenation, for example using rhodium on aluminium oxide.

A compound of formula (XII) may be prepared from a phenol of formula (XIII) where is a group convertible to R^RgNAlk e.g, an aldehyde, by reaction with acrylonitrile in the presence of a base e.g. methanolic benzyl trimethylammonium hydroxide.

Amines of formula (II) wherein X is a methylene group, n is zero and ra is 2, may be prepared from compounds of formula (XIV) in which Rg is,for example,a group RjR9NAlk or a carboxamide or nitrile group, by standard methods. For example, reaction of the derived acid chloride or ester of a compound of formula (XIV) with ammonia, followed by reduction of the resulting amide yields an amine of formula (IX) in which X is -CHg-, n is zero and m is 2.

Alternatively reduction of a compound of formula (XIV) wherein Rg is, for example, a group R^RgNAlk or a carboxamide or nitrile group with, for example, lithium . aluminium hydride would yield an alcohol of formula (XV) which may be converted into a compound of formula (XVI) R, wherein R^ is R^R.^NAlk and L* has the meanings given above. Compounds of formula (XVI) may then be reacted with ammonia to give an amine of formula (II) in which X is -CHg-, n is zero and m is 2. Reaction of a r} compound of formula (XVI) with an alkali metal cyanide, e.g. potassium cyanide,would yield a compound of formula (XVII) (XVII) CHgCHgCHgCN which may then be reduced with, for example, lithium aluminium hydride to yield an amine of formula (II) in which X is -CHg- and the sum of m + n is 5.

Alternatively, a compound of formula (XVII) may be hydrolysed to a compound of formula (XVIII) RS\ (XVIII) CHgCHgCHgCOOH which may then be converted into an amine of formula (il) wherein X is -CHg- and the sum of m + n is 3,for example by reaction of ammonia with the derived acid chloride, followed by reduction as described above.

Amines of formula (II) in which n is zero and X is i7 886 a group -NH- and Alk is methylene may be prepared from starting materials of formula (XIX) R, '9 (XXX) where Rg is , ir . e.g. Rj-RgNC-, hy reaction with a compound of formula (XI) with subsequent removal of any protecting groups and reduction of the amide function.

The starting materials of formula (XIV) may be obtained for example by catalytic reduction of compounds of formula (XX) with attendant or subsequent modification of the aldehyde function.

OCH For example, where the reduction is performed in the presence of an amine, RjRgNH, the aldehyde may be converted into a group R^RgNCHp, In the reactions described above for preparing amines of formula (II) it is usually preferable to use intermediates containing the desired RjRgNAlk group, or a protected form thereof e.g, phthalimido. However, one may take intermediates containing a group convertible to said SjRgNAlk and convert such a group into R^RgNAlk at any suitable stage in the overall preparation.

Where and Rg are both hydrogen in intermediates to amines oi formula (II), the primary amino function may be protected, for example as a phthalimido group, in any of the above reactions, the protecting group being removed at a suitable stage by means described herein.

Where Rj and/or Ro are hydrogen in intermediates to amines of formula (II), they may be converted,where appropriate,into alkyl or aralkyl groups using, for example an alkyl or aralkyl halide. Where Rj and/or Rg are methyl, a reaction with formaldehyde and formic acid in the Eschweiler-Clarke procedure may be suitable.

In order that the invention may be more fully understood the following exemplification is provided by way of illustration only. Preparations 1 to 6 describe the preparation of starting materials, Examples A to P the preparation of intermediates of formula (II), and Examples 1 to 8 the preparation of compounds of formula (V) and of formula (I). In this exemplification:i) TLC measurements were carried out on silica gel plates of thickness 0,25 mm mounted on a plastic support. 11) NMR data Is recorded in values.

Ill) Distillation pressures were measured in millimetres of mercury. iV) All temperatures are in °C. 6 8 8 6 Preparation 1. 3-(1-Pyrrolidlnylmethyl)phenol Sodium borohydride (15.2 g) was added to a solution of -hydroxybenzaldehyde (48.8 g) and pyrrolidine (ϋϋ.ύ ml) in ethanol. After 18 hours the ethanol was removed and the residual oil was acidified with hydrochloric acid and washed with ethyl acetate. The aqueous solution was then basified with ammonia and extracted with ethyl acetate. Evaporation of the organic extracts yielded the title compound as an off-white solid (21.4 g), m.p. 100-102°. TLC Silica; methanol; 0.88 ammonia (80:l)Rf 0.48.

Preparation 2. 3-(N,N-Dimethylaminomethyl)benzeneaiethano1 (a) 5-(N,N-dimethylaminocarbonyl)benzoic acid, methyl ester A mixture of thionyl chloride (88 g) and benzene-1,3dicarboxylic acid monomethyl ester (33 g) was heated at 100° for 1.5 hours. The excess thionyl chloride was removed by distillation to leave an oil which was used without further purification. The oil in dioxan was added to a cold solution of aqueous dimethylamine (40$; 56 ml) in dioxan, and stirred at 5° for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The organic phase was dried and evaporated to give an oil (36 g).

TLC silica; ethyl acetate, Rf 0.8. NMR (CDClj) 1.8 m (2H); 2.2-2,7 m (2H); 6.1 s (3H); 6.95 s (6H).

If (a) is repeated using 70 g of the ester starting material and 25% aqueous methylamine (118 ml) 3-(N-methylaminocarbonyl)benzoic acid methyl ester (54 g) m.p. 128-130° was obtained. TLC silica; ethyl acetate Rf 0.57. (b) 3-(N,N-Dimethylaminomethyl)benzenemethanol 3-(N,N~Dimethylamino carbonyl)benzoic acid, methyl ester prepared as above (36 g) in dry tetrahydrofuran was added to lithium aluminium hydride (16.6 g) in dry tetrahydrofuran. The reaction mixture was heated at 60° for 3 hours, cooled and treated with water. The solvent was removed and the residue treated with dilute hydrochloric acid. The mixture was basified with sodium hydroxide and extracted with chloroform. The organic extracts were dried and distilled to give an oil (16 g) b.p. 95-100° (0.1 mm). TLC silica/methanol Rf 0.57.

If (b) is repeated using 25g of 3-(N-methylaminocarbonyl)benzoic acid methyl ester, prepared as above 3(N-methylaminomethyl)benzenemethanol (9.2 g) b.p. 110-115° (0.02 mm) was obtained. TLC silica; methanol. RF 036 Preparation 3 (a) 2-ZT-ZJ-(N,N-Dlmethylaminomethyl)phenoxy7propy](7-lHlsoindole-1,3(2H)-dione A mixture of 80% sodium hydride (2.2g) and 3-(N,Ndimethylaminomethyl)phenol (6.95 g) in dry dimethylformamide was stirred at 5° for 2 hr. N-(3-Bromopropyl)phthalimide (12.2 g) was then added and after 16 hours the reaction mixture was treated with water and extracted with ethyl L. acetate. Evaporation of the dried organic extracts gave the title compound as a yellow oil (13 g). HC silica; ethyl acetate; Rf 0.35. m.p. (oxalate salt) 204-207°.

The following compounds were prepared similarly from the corresponding phenol (A) and appropriate bromoalkylphthalimide (B). (b) A(l4 g) + B (21.5 g) gave 2-[3-[3-(1-pyrroIidinylmethyl) phenoxy]propyl]-ΙΠ-isoindolo-1,3(2H)-dione (21.4 g) .

TLC silica; methanol:0.g80 ammonia (80:1) Rf 0.46. m.p.(oxalate salt) 167-9°. (c) A (5 g) + B (9.5 g) gave 2-f4-f3-(N,N-dimethylaminomethyl) phenoxyjbutyl]-lH-isoindole-l,3(2H)-dione (8.7 g). TLC silica; methanol:O.88 ammonia (80;l) Rf 0.56, m.p. (oxalate salt) 169-70°. (d) A (5 g) '+ B (8.1 g) gave 2-[3-[ 3-(N,N-dimethylamino ethyl)phenoxy]propyl]-lH-isoindole-l,3(2H)-dione (5 g) ' m.p. 59-60°. TLC silica; ethyl acetate:isopropanol: wateriO.88 ammonia (25:15:8:2) Rf 0.45. (e) A (2.0 g) + B (3.4 g) gave 2-[4-f3-(N,N-dimethylamino ethyl)phenoxy]butyl]-lH-isoindole-l,3(2H)-dione (2.8 g) m.p. 52-3°. TLC silica; ethyl acetate:isopropanol: waier:0.88 ammonia (25:15:8:2) Rf 0.55. (f) A (2.2 g) + B (3.2 g) gave 2-[_3-F_3-(N,N-dimethylaminopropyl)phenoxy]propyl]-ill—isoindo1e-1,3(2H)-di one (2.5 g) b.p.250° (0.1 mm). TLC silica:ethyl acetate: isopropanol :wat,er: ammoni a (25:15:*:-!) Ill' 0.5. (g) A (2.2 g) + B (3.4 g) gave 2-f 4-[ 5-(N,N-ilimethylaminopropvl)phenoxy’ butylj-lH-isoindole-l,3(2H)-dione (2.6 g) b.p.225° (0.04 mm). TLC silica; ethyl acetate: isopropanol:water;0.88 ammonia, 111' 0.5. (h) A (7.0 g) + B (14.1 g) gave 2-[_4-Q4-(h',fi-dimethylaminome thy1) phenoxy ! buty 1 ] -1II-i so i ndo I «4,3(211) -di one, oxalate salt (3.8 g). TLC silica; methano1:0.88 ammonia (80:1) Rf 0.5. (i) A (5 g) + B (9.7 g) gave 2-( 5-f 4-(N,\-dimethylaminomethyl)phenoxy]propyl]-lH-isoindole-l,5(2H)-dione (7.1 g) TLC silica; methano1:0.88 ammonia (80:1) Rf 0.5, m.p. (oxalate salt) 166-70°.

Preparation 4, (a) 2-f 2-f 3-(N,N-Dimethylaminomethyl)phenoxy)ethyl)-lHi soindole-l,3-(2H)-dione 3-(N,N-Dimethylaminoraethyl)pheno1 (5.0 g), 80$ sodium hydride (l.2g) and 2-[2-(4~raethylbenzenesulphonyl)ethyl’]-lHisoindole-1,3(2H)-dione (13 g) were heated at 9o° in dimethylformamide. After 12 hours the reaction mixture was cooled, poured onto ice-water and extracted with ether. Evaporation of the organic solvent gave the product as a viscous yellow oil (3.2 g). TLC silica; methanol:ethyl acetate (1:1) Rf 0.37. m.p. (oxalate salt) 166-7°.

The following compounds were similarly prepared from the corresponding phenol (A) and 2-[2~(4~methylbenzenesulphonyl) ethyl]-ΙΙΙ-i soindole-l, 3(2H)-dione (c). (l>) A (5 e) + Ο (ii.7 g) gave 2-[, 2-;_5-(N,N-ib mol hyl ami noethyl) phenoxy J ethylί-ΙΗ-isoindole-l,3(2H)-di one (2.4 g) m.p. 84-5°. TLC silica; ethyl acetate:isopropanol: water:0.88 ammonia, Rf 0.45. (e) A (2.2 g) + C (4.2 g) gave 2-[.2-[5-(N,N-dimethylaminopropyl)phenoxy! ethyl]-lH-isoindole-1,3(2H)-dione (0.5 g). TLC silica; ethyl acetate:isopropanol:waler:0.sS0 ammonia (25:15:8:2) Rf 0.45.

Preparation 5 2-f 5-f 5-(N,N-Dimothylan:tnoinethy I)phenoxy]propyl!-IHisolndole-1,5(2H)-dione (a) 2-[5-Γ 5-(Formyl)phenoxyl propylf-lH-isoindole-1,5(2H)-dione -Hydroxybenzaldehyde (0.61 g), 3-hromopropylphthalimide (1.51 g) and potassium carbonate were stirred in dimethylformamide for 16 hours at room temperature. The reaction mixture was poured into water to precipitate 2-/3-/3-(formyl)phenoxy/propy1/lH-isoindole-1,3(2H)-dione (1.37 g) which was filtered off and dried m.p. 102-4°. TLC silica: methanol: toluene (1:9) Rf 0.65.

The following compoundswere prepared similarly. 4-hydroxybenzaldehyde (5 g) and the appropriate phthalimide (10. 4g) gave 2-f,2-|_4-( formyl )phenoxy] ethyl]-lH-isoindole-l,3(2H)-dione (1.5 g) m.p.131.5133.5°. TLC methanol:chloroform (1:100) Rf 0.5. 2-hydroxybenzaldehyde (6.1 g) and the appropriate phthalimide (12 g) gave 2-[4-[2-(formyl)phenoxy] butyl]-lH-isoindole-l,3-(2H)dionn (12.2 g) m.p. 99.5-101°. TLC silica; methanol:0.88 ammonia (80:1) Rf 0.8. (b) 2-Γ3-Γ 3-(N,N-Pimethylaminomethyl)phenoxy]propyl]-1H5 isoindole-l,3(2H)-dione, 2-(.3-(.3-(Formyl) phenoxy] propyl]-IH-isoindole-l,3(2H) dione (132 g) and 33% ethanolic dimethylamine (30Ό ml) were hydrogenated at room temperature and atmospheric pressure in ethanol over 10% palladium on charcoal. The catalyst was filtered off and the filtrate evaporated to give the title compound as a yellow oil (142 g), TLC silica (ethyl acetate) Rf 0.35, m.p. (oxalate salt) 204-207°.

The following were similarly prepared from 33% ethanolic dimethylamine and the corresponding phthalimide (P) prepared in (a) P (1.2 g) + 33% ethanolic dimethylamine (20 mi) gave 2-£2-(.4-(N,N-dimethylaminomethyl)phenoxy]ethyl] lH-isolndole-l,3(2H)-dione (1.3 g). TLC silica; methanol:0.88 ammonia (80:1) Rf 0.3.

P (10 g) + 33% ethanolic dimethylamine (50 ml) gave 2-£4-£2-(N,N-dimethylaminomethyl)phenoxy]butyl]lH-isoindole-l,3(2H)-dione (7 g). TLC silica; methanol: 0.8Θ ammonia (80:1) Rf 0.55, m.p. (oxalate salt) 162-3°.

Preparation 6, 2-Γ 3-i(3-(N.N-pimethylaminomethyl)phenyl]thio]propyl]-1H25 isoindole-1.3(2H)dlone. (1) Di thio bi s-3.31-N,Ν-dimethylbenzenecarboxamide Dimethylamine (57 ml) in toluene was added at 5° to 46886 3,3,-dithio(chlorocarbonyl)benzene (46 g) in toluene. After 4 hours water was added and the solution was extracted with ethyl acetate. Evaporation of the extracts gave the product as an orange oil (49 g). NMR (CDCl^) 2.4-2.8 m (8H); 7.05 br (12H). (2) Dithio bis-5,5l-N,N-dimethylbenzeneiaethanamine. 3j3’-Dithio Ν,Ν-dimethylbenzeneearboxamide (48 g) in dry ether was added to lithium aluminium hydride (20 g) in dry ether. The reaction mixture was stirred at room temperature, cooled, treated with water and filtered. The filtrate was extracted with ethyl acetate and the extracts were dried and distilled to give a colourless oil (8.8 g) b.p. 250° (0.1 mm).

NMR (CDClj) 2.5-2.9 m (8H); 6.66 s (4H); 7.8 s (6H). (3) 2-f 3-ΓΓ 3-(N^H)imethylaminomethyl )phenyl1thio)propyl)-1Hisoindole-l,3(2H)dione 80* Sodium hydride (2.3 g) and dithio bis-3,3'-N,Ndimethylbenzenemethanamine (7.8 g) were stirred at room temperature in dry dimethylformamide for 24 hr. N-(3-Bromopropyl) phthalimide (12.6 g) was then added. After 24 hr the reaction mixture was treated with water and extracted with ethyl acetate. The organic extracts were evaporated and the residue purified by column chromatography on silica with ethyl acetate/methanol to give the title compound as a pale orange oil (ll.3g). NMR (CDClj) 2.0-2.4 m (4H);2.6-2.9 Ο (4H)} 6.15 t (2H); 6.59 3 (2H); 7.02 t (2H); 7.75 s (6H); 7.98 m (2H).

ZO Example A 3-(3-Aminopropoxy)-N-methylbenzenemethanamine dioxalate (1) 5-Γ5-(Formyl)phenoxy1propionitrile A solution of m-hydroxybenzaldehyde (30.5 g) in acrylonitrile (265 ml) and 40$ methanolic benzyl trimethylammonium hydroxide (5 ml) was heated under reflux for 20 hr.

The mixture was diluted with ether (5θθ ml) and the solution was washed with 5$ sodium hydroxide solution and water.

The ethereal solution was dried over magnesium sulphate, filtered and evaporated In vacuo to give a clear colourless oil (32 g). TLC silica, chloroform, Rf 0.4. (2) 5-(2-Cyanoethoxy)-N-methylbenzenemethanamine, hydrochloride A solution of 3-£3-(iormyl)phenoxy]propionitrile (8.75 g) in a mixture of 33$ ethanolic methylamine (50 ml) and ethanol (200 ml) was stirred at room temperature with 5$ palladium oxide on charcoal (0.8 g) under hydrogen at 1 atmosphere. After uptake of hydrogen had ceased the mixture was filtered and the residues were washed with ethanol. The ethanolic filtrate and washings were combined, reduced in volume and treated with excess ethereal hydrogen chloride.

The precipitated hydrochloride was recrystallised from a mixture of ethanol and ether as colourless plates (7.9 g) m.p. 125-128°.

Assay Found! C, 58.1; H, 6.5: N, 12.3; CUH15C1N2O requires: C, 58.3; H, 6.5; N, 12.35$ 4688 6 (3) 5-(5-Aminopropoxy)-N-methylbenzenemethanamine, di oxalate A solution of N-methyl-f3-(2-eyanoethoxy)benzenemethanamine hydrochloride (5·39 g) in methanol (50 ml) was eluted through a basic ion-exchange column (Amberlyst Registered Trade Mark A-26) and tte .eluate was.evaporated to give the' free base as a colourless oil. The free base was dissolved in ethanol (500 ml) and 0.88 ammonia (25 ml) and shaken with 5% rhodium on alumina (2.5 g) at room temperature and under a pressure of 40 psi of hydrogen for 6 hr. The resulting suspension was filtered, evaporated in vacuo and the residue was dissolved in ethanol and treated with excess ethanolic oxalic acid. The precipitated dioxalate salt (6.56 g) was filtered off and dried,m.p. 196-198°. TLC silica; methanol:0.88 ammonia (99:1) Rf 0.1.

Example B -(3-Aminopropoxy)-N-methylbenzenemethanamine dioxalate 2-f3-f3-(Formyl)phenoxy]propyl]-ΙΗ-isoindole-l,3(2H)dione (8.5 g) was stirred in 33% ethanolic methylamine (300 ml) for 1 hr and then hydrogenated at room temperature and atmospheric pressure in ethanol over· 10# palladium on charcoal. The solution was filtered, evaporated to dryness in vacuo, and dissolved in ethanol (50 ml). The ethanolic solution was treated with excess ethanolic oxalic acid and the resulting precipitate was recrystallised from ethanol/water to give the title compound as colourless grains (3.9 g) m.p,196-198°.

TLC silica; methanol:0.88 ammonia (20:1) Rf 0.1.

Example C (a) 3-(3-Aminopropoxy)-N.N-dimethylbenzenemethanamine a-Li-Li-CNjN-DimethylaminoraethylJphenoxy]propyl]lH-isoindole-l,3(2H)-dione (25 g) was treated with 30# ethanolic methylamine (150 ml). After 24 hr at room temperature ether (100 ml) was added and a solid was filtered off. The filtrate was distilled to give the title compound as a yellow oil (12.3 g) b.p. 102-112° (0.2 mm). TLC silica; ethyl acetate!isopropanol;water:0.88 ammonia Rf 0.25.

The following compounds were similarly prepared frcr. the corresponding phthalimide (c). (b) C (5.¾ g) gave 3-(2-aminoethoxy)~N,N-dimethylbenzene~ methanamine (0.45 g). TLC silica; methanol/ammonia (80:1) Rf 0.04. NMR (CDClj) 2.8-3.1 m (4H); 6.05 t (2H); 6.55 s (2H); 6.98 t (2H); 7.80 s (6H); 8.4 hr.s (2H). (c) C (2.9 g)gave 4-(4-aminobutoxy)-Ν,Ν-dimethylbenzenemethanamine bis-oxalate salt (0.8 g). TLC silica; methanol;0.88 ammonia Rf 0.17. NMR (DgO) 2.5-2.9 m (4H); 5.7 s (2Η);^δ%® m^H); 7.12 s (6H); 8.09 m (4H). (d) C (6.6 g) gave 4-(3-aminopropoxy)-N,N-dimethylhenzenemethanamine bis-oxalate salt (1.2 g). NMR (D20)2.52.87 m (4H); 5.72 s (2H); 5.75 t (2H); 6.7 t (2H); 7.13 s (6H); 7.78 m (2H).

Example P (a) 3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine, 2-[,3-[.3-(N,N-Dimethylaminomethyl )phenoxy] propyl] lH-isoindole-l,3(2H)-dione (90 g) and 30$ aqueous methylamine (209 ml) were heated at 80°, After 4 hours the reaction mixture was cooled, basified with 5N sodium hydroxide solution and extracted with toluene. The toluene extract was distilled to give the title compound as a pale yellow oil (43.1 g) b.p. 102-112° (0.2 mm). TLC silica; ethyl acetate:isopropanol:water: 0.88 ammonia (25:15:8:2) Rf 0.25.

The following compounds were similarly prepared from the corresponding phthalimide (C). (b) 0-(6.7 g) gave 3-(4-aminobutoxy)-N,N-dimethylbenzenemethanamine (1.2 g). TLC silica; methano1:0,88 ammonia (80:1) Rf 0.24. (c) C (2.6 g) gave 3-[.3-(l-pyrrolidinylmethyl)phenoxy] propylamine isolated as the bis-oxalate salt (1.3 g) m.p. 184-5°. TLC silica; methanol:0.88 ammonia (l9:l) Rf 0.3.

Example E. (a) 3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine 2-£.3-[_3-(N,iT-Diinethylaminomethyl )phenoxy] propyl] lH-isoindole-l,3(2H)-dione (12.2 g) and hydrazine hydrate (2.1 ml) were heated at reflux in ethanol for 3 hr. The reaction mixture was cooled, filtered and the filtrate was distilled to give the product as a colourless oil (2 g), b.p. 127° (0.6 mm),m.p. (Hydrochloride salt) 212-215°.

The following compounds were similarly prepared from the corresponding phthalimide (C). 40886 (b) (c) (a) (e) (f) (6) (h) C (2.8 g) gave 3-(2~aminoethoxy)-N,N-dimethylbenzene ethanamine (1.7 g) b.p. 135° (O.O3mm). TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.3.

C (4.2 g) gave 3-(3-aminopropoxy)-N,N-dimethylbenzene ethanamine (2 g) b.p. 95° (0.03mm). TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.3.

C (2.5 g) gave 3-(4-aminobutoxy)-N,N-dimethylbenzeiie ethanamine (0.9 g)b.p. 150° (0.04 mm) TLC silica, ethyl acetate:isopropanol:watei-;0.88 ammonia Rf 0.3.

C (0.5 g) gave 3-(2-aminoethoxy)-N,N-dimethylbenzene propanamine (0.26 g) h.p. 130° (0.03 mm). TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia (25:8:15:2) Rf 0.45.

C ( 2 g) gave 3-(3-aminopropoxy)-N,N-dimethylbenzene propanamine (0.95 g) b.p. 160° (0.04 mm) TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia (25:8:15:2) Rf 0.3.

C (2 g) gave 3-(4-aminobutoxy)-N,N-dimethylbenzene propanamine (1.05 g) b.p. 130° (0.04 mm). TLC silica; ethyl acetatezwater:isopropanol:0.88 ammonia (25:8:15:2) Rf 0.25.

C (ll. 3 g), gave 3-(,(3-atainopropyl)thio]-Ν,Ν-dimethylbenzene methanamine (2.3 g) h.p.142° (0.1 mm) NMR (CDCl^) 2.5-3 m (4H); 6.6 s (2H); 6.99 t (3H); 7.17 t (2H); 7.76 s (6H); 8.22 m(2H); 8.58 brs (2H). (i) C (1.3 g) gave 4-[_2-aminoethoxy]-N,N-dimethylbenzenemethanamine (0.28 g) b.p. 90° (0.04 mm). TLC silica; methanol:0.88 ammonia (80.1) Rf 0.2. (j) C (7 g) gave 2-(4-aminobutoxy)-N,N-dimethylbenzenemethanamine (2.7 g) b.p.90° (0.07 mm). TLC silica; methanol:0.88 ammonia (80:1) Hi 0.2.

Example F (a) 2-fΓ5-(N,N-Pimethylaminomethyl)phenyi]methylthio]ethanamine 3-(N,N-Dimethylaminomethyl)benzenemethanol (17.4 g) and oysteamine hydrochloride (12 g) in concentrated hydrochloric acid were heated at 100° for 4 hr. The cooled reaction mixture was treated with solid sodium carbonate and extracted with ether. The organic extracts were distilled to give the product as an oil (21.5 g) b.p.154-158° (1.5 mm), m.p. (hydrochloride salt) 180-182°. TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.37· (b) From 3-(N~methylaminomethyI)benzene methanol (10.1 g) and cysteamine hydrochloride (7.7 g) was similarly prepared 2~LL3-(N-methylaminomethyl)phenyl)methylthiolethanamine (6.5 g) b.p.140-145° (0.01 mm). TLC silica; ethyl acetate:isopropanol: water:0.88 ammonia Rf 0.28. (o) From 2-(N,N-dimethylaminomethyl)benzenemethanol (0.8g) and cysteamine hydrochloride (0.57 g) was similarly prepared 2-CL2-(Ν,Ν-dimethylaminomethyl)phenyl]methylthio]ethanamine (0,38 g) b.p. 100-105° (0.01 mm). TLC silica; ethyl acetate methanol:0.88 ammonia (10:10:1) Rf 0.22. (d) From 4-(N,N-Dimethylaminomethyl)benzenemethanol (4 g) and cysteamine hydrochloride (2.8 g) was similarly prepared 2-CL4-(U,N-dimethylaminomethyl)phenyl]methylthio]ethanamine (3.6 g) b.p. 148-50°(0.01 mm).

Assay Found: C, 63.8; H, 9.2; N, 12.1; C12H20N2S re4ulred! c> 6^·2; H» 9.0; N, 12.5* Example G (N,NDimethylafflinomethyl)berizeng7butanamine 3-/37(H,N-Dlmethvlamlnomethyl)benzenepropanoic acid, ethyl’ ether 3*-Formyl cinnamic acid (5.5 g) was heated at 60° in * ethanolic dimethylamine (45 ml) for 30 min and then stirred at room temperature with 10* palladium oxide on charcoal (1.5g) under hydrogen at 1 atmosphere. After uptake of hydrogen had ceased, the mixture was filtered and the filtrate evaporated.

The residue was heated under reflux in ethanol and concentrated sulphuric acid for 4 hr. The solution was neutralised with sodium carbonate and distilled to give the product as a colourless liquid (4.2 g) b.p. 130° (0.05 mm).

TLC (silica; ethyl acetate:isopropanol;water:0.88 ammonia (25:15:8:2) Rf 0.75.

-(N,N-Dimethylamlnomethyl)benzenepropan-l-ol (N,N-Dimethylaminomefchyl>benzene7propanoic acid, ethyl ester (0.5 g) and lithium aluminium hydride (0.2 g) were stirred at room temperature in dry tetrahydrofuran for 2 hr, treated with water and filtered. The filtrate was evaporated to give the product as a colourless liquid (0.34 g).

TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.7. NMR (CDCl^) 2.81 m (4H); 6.33 tr (2H); 6.59 s (2H); 7.28 m (2H); 7.75 s (7H); 7.7-8.4 m (2H). 4-/T- (N,N-Pimethylaniinoiii.ethyl)benzene7butanenitrile 3- (N,N-Dimethylaminomethyl)benzenepropan-l-ol (0.9 g) and p-toluene sulphonyl chloride (0.9 g) were stirred in pyridine for 2 hr. The solvent was evaporated and the residue treated with potassium cyanide (0.7 g) in dimethyl10 formamide at 45° for 16 hr. Water was added and the mixture extracted with ethyl acetate. The extract was distilled to give the product as a colourless liquid (0.3 g) h.p.110° (0.02mm) TLC silica: ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2)Rf 0.75. 4-/3- 4- /3=- (Ν,Ν-Dimethylaminomethyl)benzene/butanenitrile (0.9 g) and lithium aluminium hydride (0.35 g) in tetrahydrofuran were stirred at room temperature for 2 hr. Water was added > and the suspension was filtered. The filtrate was evaporated to give the product as a colourless oil (0.8 g).

TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.1 m.p. (oxalate salt) 125-7°.

Example 1 (a) N-Methyl-N'-Γ 3-Γ 5-(N,N-dimethylaminomethyl)phenoxy] propyl]-2-nitro-1,1-ethenediamine.

A mixture of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (l g) and N-methyl-2-nitroimidothioic acid methyl ester (0.78 g) in water ( 4 ml) was stirred at room temperature for 4 hr. The resultant solution was acidified using glacial acetic acid, then washed with ethyl acetate. The acidic solution was basified with sodium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulphate, filtered and evaporated to an oil which crystallised from ethereal solution to give the title compound as a white solid (0.6 g), m.p. 81-3°, TLC silica; ethyl acetate:isopropanolί water:0.88 ammonia (25:15:8:2) Rf 0.6.

The following compounds were similarly prepared from the corresponding diamine and N-methyl-2-nitroimidothioic acid methyl ester (D). (b) Diamine (2 g) and D (l.4 g) gave N-methyl-N'-f2-ff3(N-methylaminomethyl)phenyl]methylthio]ethyl]-2nitro-1,1-ethenediamine (0.8 g). TLC silica; methanol: ammonia (50:1) Rf 0.3, m.p, (fumarate salt) 163-5°. (c) Diamine (l g) + D (0.73 g) gave N-methyl-N'-r3-[75(Ν,Ν-dimethyleminomethyl)phenyl] thio]propyl]-2-nitro1,1-ethenediamine (0.25 g) NMR (CDC1^)-O.5-O,5 bra (lH); 2.5-3 m (4H); 3.4 s (IH); 6.2-6.8 m (4H)$ 6.8-7.4 m (5H); 7.72 s (6H); 8.02 m (2H). (d) Diamine (2.5 g) + D (1.8 g) gave N-methyl-N'-[]3-L3(N-methylaminomethyl)phenoxy]propyl]-2-nitro-1,1ethenediamine (0.35 g). TLC silica; methanol:0.88 ammonia (20:l) Rf 0.35. NMR (CDCl^) 2.68 m (2H); 2.9-3.4 m(3H); 5-9 t (2H); 6.29 s(2H); 6.53 t (2H); 7.12 br.s (3H); 7.58 s (3H); 7.62-8.2 m (2H). (θ) Diamine (0.45 g) + D (0.24 g) gave N-methyl-N1-L.5[_3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-nitro1,1-ethenediaraine (0.35 g). TLC silica; methanol:0.88 ammonia (80:1) Rf 0.35. NMR (CDCl^) 2.8 m (1H); 2.93.5 m (4H); 5.90 t (2H); 6.4 s (2H); 6.50 m (2H); 7.1 br (4h); 7.5-8.3 m (7H). (f) Diamine (0.8 g) + D (0.78 g) gave N-methyl-N'-[2-[3(Ν,Ν-dimethylaminomethyl)phenoxy]ethyl]-2-nitro-1,1ethenediaraine (0.55 g) m.p. 130-1°. TLC silica; methanol:0.88 ammonia (80:1) Rf 0.3. (g) Diamine (0.7 g) + D (0.52 g) gave N-methyI-N'-L4-[3(Ν,Ν-dimethylaminomethyI)phenoxy]butyl]-2-nitro-1,1ethenediamine (0.38 g) TLC silica; methanol:0.88 ammonia (80:1) Rf 0.34. NMR (CDCl^) 0.3 br (lH); 2.82 t (1H); 3.0-3.5 m (5H); 6.08 br (2H); 6.67 m (4H); 7.15 br (3H); 7.81 s (6l?); 8.2 br (4H). (h) Diamine (0.6 g) + D (0.46 g) gave N-methyl-N'-[3-(,3(N,N-dimethylaminoethyl)phenoxy]propyl]-2-nitro-1,1ethenediamine (0.58 g) m.p. 95-4°. TLC silica:ethyl 6 8 8 6 acetate:isopropanol:water:0,88 ammonia (25:15:8:2) Rf 0.45. (i) Diamine (0.5 g) + D (θ.3ό g) gave N-raethyl-N'-[4-(3(Ν,Ν-dimethylaminoethyl)phenoxy]butyl]-2-nitro-l,15 ethenediamine (0.12 g) m.p. 59-63°. TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.4. (j) Diamine (0.26 g) and D (0.22 g) gave N-methyl-N’-(.2-(.3(N,N-dimethylaminopropyl)phenoxy]ethyl]-2-ni tro-1,110 ethene diamine (0.2 g) m.p. 82-83.5°. TLC silica; ethyl acetate;water:isopropanol: 0.88 ammonia (25:8:15:2) Rf 0.4. (k) Diamine (0.2 g) + D (0.15 g) gave N-methyl-Ν'-(3-(3(Ν,Ν-dimethylaminopropyl)phenoxy]propyl]-2-nitro-l,115 ethenediamine (0.14 g) m.p. 59.5-61°. TLC silica; ethyl acetate:water:isopropanol: 0.88 ammonia (25:8:15:2) Rf 0.35. (l) Diamine (0.5 g) + D (0.36 g) gave N-methyl-N'-[_4-(3(N,N-dimethylaminopropyl)phenoxy]butyl]-2-ni tro-1,ΙΒΟ ethenediamine (0.45 g) m.p. 79-80.5°. TLC silica; ethyl acetate:water:isopropanol: 0.88 ammonia (25:8:15:2) Rf 0.5. (ffl) Diamine (0.28 g) + D (0.5g) gave N-methyl-N'-[2-(4(Ν,Ν-dimethylaminomethyl)phenoxy]ethyl]-2-nitro-l,125 ethenediamine (0.11 g) m.p.141-142°. TLC silica; *»10 methanol:0.88 ammonia (50:1) Rf 0.39. (n) Diamine (0.56 g) and D (1.19 g) gave N-methyl-N'-[_3[,4-(N,N-dimethylaminomethyl)phenoxy]propyl]-2-nitro1,1-ethenediamine (0.12 g) m.p. 133-136°. TLC silica; methanol;0.88 ammonia (19:1) Rf 0.5. (o) Diamine (0.45 g) + D (0.3 g) gave N-methyl-N’-[4/5-(N,N-dimefchyl-2-aminoet'hyl)phenoxy/buty!7-2-nitro-l,1 ethenediamine (0.25 g) m.p. 98-100°. TLC silica; methanol:0-.88 ammonia (80:1) Rf 0.45. (p) Diamine (2.5 g) + D (2.0 g) gave N-methyl-N*-[_4-[ 2(Ν,Ν-dimethylaminomethyl)phenoxy]butyl] -2-nitro-1,1ethenediamine (1.9 g) m.p. 98.5-100°. TLC silica; methanol: ammonia (80:l) Rf 0.45. (q) Diamine (0.7 g) + D (0.44 g) gave N-methyl-N'—L4—[_3(N,N-dimethylaminomethyl)phenyllbutyl]-2-nitro-1,1ethenediamine (0.4 g) m.p. (dihydrochloride) 137-9°.

TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.5· Example 2.

N-Nitro-N'-Γ 3-Γ 3-(N,N-dimethylaminomethyl)phenoxy]propyl] guanidine N-nitrocarbamimidothioio acid methylester (0,77 g) and 3-(3-aminopropoxy)-N,N-dimethylhenzenemethanamine (l.Og) were heated in ethanol at 40° for 20 mins. The solution was cooled to precipitate the title compound which was filtered 46880 off and recrystallised from ethyl acetate as a white solid (0.44 g) m.p. 114-115°. TLC silica; methanol:0.8« ammonia (80:1) Rf 0.48.

Example 5 N-Γ 3-(. 5-(N,N-Dlmethylaminomethyl)phenoxy1 propyl] guanidine dinitrate 3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (2 g) and 3,5-dimethylpyrazole-l-earboxamidine nitrate (2.1 g) were heated at reflux in ethanol for 16 hr.· The solvent was removed and the residue was washed with boiling ethyl acetate before it was crystallised from ethanol to give the title compound as a white solid (1 g) m.p. 123-4°.

TLC silica; ethyl acetate;isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.34.

Example 4 (a) N-Cyano-N'-methyl-N1'-f3-Γ 3-(N,N-dimethylaminomethyl) phenoxy]propyl]guanidine.

N-Cyano-N'-methylcarbaraimidothioic acid methyl ester (0.8 g) and 3-[.3-aminopropoxy]-N,N-dimethylbenzenemethanamine (1.0 g) were heated together at 100° for 12 hours. The melt was cooled, dissolved in methanol, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica with methanol to give the title compound as a clear yellow oil (0.54 g), TLC silica; methanol:0.88 ammonia (80:1) Rf 0.51.

Assay Found: C, 62.54; H, 8.31; N, 23.93; C15H25N5Q requires: C, 62.28; H, 7.96; N, 24.22$ Similarly prepared from the corresponding amine (5 g) and N-cyano-N'-methylcarhamimidothioie acid methyl ester (2,8 g) were (h) N-cyano-N'-methyl-Ν''-(_2-[L3"(N,N-dimethylaminomethyl) phenyl]methylthio]ethyl]guanidine (2.3 g). TLC silica; methanol, Rf 0.47. NMR (CDCLj) 2.5-3 m (4H); 6.25 s (2H); 6.5-6.9 m (4H); 7.18 d (3H)^.5 m (2H); 7.73 s (6H). (c) Amine (1.5 g) and ester (0.86 g) gave N-cyano-N'methyl-N' '-[_2-[[_2-(N,N-dimethylaminomethyl)phenyl] methylthio] ethyl] guanidine (l.l g) m.p. 107-108.5°.

Example 5 N-Methyl-N'-[~ 5-Γ5-(N,N-dimethylaminomethyl)phenoxy]propyllurea Methyl isocyanate (0.27 ml) and 5-(3-aminopropoxy)-N,Ndimethylbenzenemethanamine (0.97 g) were stirred at room temperature in acetonitrile for 2 hours. The title compound was filtered off, washed with acetonitrile and recrystallised from ethyl acetate as colourless prisms (0.49 g) m.p. 79.5-80°. TLC silica; methanol;0.88 ammonia (80:1) Rf 0.45.

Example 6 N-Methyl-N-[ 2—ΓΓ2-(N,N-dimethylaminomethyl)phenyl]methylthio] ethyl]thiourea 2-L[2-(N,N-Dimethylaminomethyl)phenyl]methylthio] ethanamine (1.5 g) and methyl isothiocyanate (0.5 ml) were stirred at room temperature in acetonitrile for 6 hr. The solvent was removed and the residue was column cliiomatographed on silica using a mixture of ethyl acetate and methanol as eluent to give the title compound as a white solid (l g) m.p. 57-9°.

Assay Found: C, 56.2; H, 8.1; N, 13.8; C14H23N5S requires: C, 56.5; H, 7.8; N, 14.1# Example 7 N-Methyl-N2-f[5-(N,N-diniethylaminomethyl)phenyl]methylthio] ethyl]-2-nitro-1,1-ethenediamine. 2-f L.3"(N,N-Dimethylamin)methyl) phenyl]methyl thio] ethanamine (3 g) and l-nitro-2,2-bis(methylthio)ethylene (2.2 g) were heated under reflux in acetonitrile for 7 hours. The solvent was removed and the residual oil used without further purification. The oil was treated with ethanolic methylamine (33#» 34ml) and heated under reflux for 3 hours.

The solvent was removed and the residual oil was purified by column chromatography on silica with methanol. The resultant orange oil was triturated with ether to give the title compound as a white crystalline solid (0.25 g) m.p.62-4°. TLC silica; ethyl acetate:isopropanol:water:0,88 ammonia (25:15:8:2) Rf 0.36.

Similarly prepared from the corresponding amine (3 g) and l-nitro-2,2-bis(methylthio)ethylene (2.2 g) was N-methylN'-f2-[f,4-(N,N-dimethylaminomethyl)phenyl]methylthio] ethyl] 2-nitro-l,l-ethenediamine (2.5 g) m.p. 98.5-100°.

Assay Found: C, 55.45; II, 7.4; N, 17.1# c15H24n4°2s squires: C, 55.5 ; H, 7.45; N, 17.3# 4) Example 8 (a) N-[5-Γ 3-(N,N-Dimethylaminomethyl)phenoxy]propyl]-N1(2-methoxyethyl)-2-nitro-1,1-ethenediamine hydrochloride (1) Ν-Γ 5-Γ 5-(N,N-Dimethylaminomethyl)phenoxy]propyl]-2nitroimidothioic acid methyl ester -(3-Aminopropoxy)-N,Ν-dimethylhenzenemethanamine (10 g) and l-nitro-2,2-bis(methylthio)ethylene (16 g) were heated under reflux in tetrahydrofuran for 19 hours. Oxalic acid dihydrate (1.3 g) was added and the resulting precipitate was discarded. The solvent was removed to leave the title compound as a crystalline solid (10 g) m.p. 59-63°.

Assay Pound: C, 54.95; H, 7.15; N, 12.95; C15H25N3O3S requires: C, 55.35; H, 7.05; N, 12.9$ (2) N-f 3-Γ 5-(N.N-Dimethylaminomethyl)phenoxy]propyl]-Nl(2-methoxyethyl)-2-nitro-1,1-ethenediamine hydrochloride, A mixture of N-[.5-l3-(N,N-dimethylaminomethyl) phenoxy]propyl]-2-nitroimidothioic acid methyl ester (0.8g) and 2-methoxyethylamine (0.2 g) was stirred at room temperature in ethanol for 24 hours. The solvent was removed to leave an orange oil which was treated with ethanolic hydrogen chloride to give the title compound (0.4 g) m.p, 109-112°.

Assay Pound: C, 52.1; H, 7.7; N, 14.0; C17H28N4°4 re Example 9 phenoxy]propyl]guanidine N-Metlianesulpiionylcarbonimidodithioic acid dimethyl ester (which has the structure (3 g) and 3-/3-aminoprqpaxyyfa,N-dimethylbenzenemethanamine (2.5 g) were heated at reflux in ethanol for 4 hours. Methylamine was then added and the reflux continued for 1¾ hours. The-solvent was removed and the residue was purified by column chranatography on silica 'with methanol to yield the title compound as a yellow gum (1.9 g). TLC methanol:0.88 ammonia (80:1) Rf 0.65. NMR (CDCl-j) 2.85 m (IH); 2.9-5.3 m (3H); 3.0-4.3 hrs (2H); 5.90 t (2H); 6,5 q (2H); 6.6 s (2H); 7.1 s (6H); 7.75 s (6H); 7.9 m (2H).

Example 10 Pharmaceutical Compositions (a) Oral Tablets 50 mg for 10,000 tablets Active ingredient Anhydrous lactose U.S.P. Sta-Rx 1500 Starch* Magnesium Stearate B.P. 500 g 2.17 kg 300 g 30 g The drug is sieved through a 250 /im sieve and then the four powders are intimately mixed in a blender and compressed between 8.5 mm diameter punches in a tabletting machine.

* A form of directly compressible starch, supplied by A.E.

Staley Mfg. Co. (London) Limited, Orpington, Kent. (b) Injection for Intravenous administration (50 mg in 2 ml) # w/w Active ingredient 2.5 Water for Injections BP to 100.0 Dilute Hydrochloric acid BP to pH 5.0 The active ingredient· is dissolved with mixing in the Water for Injection, adding the acid slowly until the pH is 5.0. The solution is sparged with nitrogen and is then clarified by filtration through a membrane filter of pore size 1.3571m. It is packed into 2 ml glass ampoules (2.2 ml in each) and each ampoule sealed under an atmosphere of nitrogen. The ampoules are sterilised in an autoclave at 121° for thirty minutes. (c) Oral Sustained Release Tablets 150 mg for 10,000 tablets Active ingredient I.50 kg Cutina Registered Trade Mark HR** 0.40 kg Anhydrous lactose U.S.P. 2.O60 kg Magnesium Stearate BP 40g 6886 The active ingredient, anhydrous lactose and most of the Cutina HR are intimately mixed and then the mixture is moistened by mixing with a 10* solution of the remainder of the Cutina HR in Industrial Methylated Spirit OP 74.

The moistened mass is granulated through a 1.2 mm aperture sieve and dried at 50°C in a fluidised bed dryer. The granules are then passed through a 0.85 mm aperture sieve, blended with the magnesium stearate and compressed to a hardness of at least 10 kg (Schleuniger tester) on a tabletting machine with 12.5 mm diameter punches.

** Cutina HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Limited, London. (d) Oral Capsules 50 mg for 10,000 capsules Active ingredient 500 g Sta-Rx 1500* 1700 g Magnesium Stearate BP 20 mg The drug is sieved through a 250 jim mesh sieve and is then blended with the other powders. The powder is filled into No. 3 size hard gelatin capsules on a suitable filling machine.

The compounds of the formula (i) have been found to be inhibitors of gastric acid secretion induced by histamine. This has been shown in rats using a modification of the procedure described by M.N. Ghosh and H.O. Schild in the British Journal of Pharmacology 1958, Vol. 13, page 54.

Female rats weighing about 150 g are starved overnight 6 886 and provided with 8# sucrose in normal saline instead of drinking water.

The rats are anaesthetized hy a single intraporitoneal injection of 25# w/v urethane solution (0.5 ml/100 g) and the trachea and jugular veins cannulated.

A mid-line incision in the abdomen wall is made to expose the stomach which is separated from the liver and spleen hy cutting the connective tissue. A small opening is made in the fundic region of the stomach and the stomach washed with a 5# dextrose solution. The oesophagus is cannulated with rubber tubing and the oesophagus and vagi are then cut above the cannula.

A small opening is then made in the pyloric region of the stomach. A large perspex cannula is then placed in the stomach via the opening in the fundic region in such a manner that the inlet end of the cannula passes out of the stomach through the opening in the pyloric region. The cannula is of such a shape so as to reduce the effective volume of the stomach and to provide a turbulent flow of the perfusion fluid over the mucosal surface. A drainage cannula is then inserted through the opening in the fundic region of the stomach. Both cannulae are tied in place by ligatures around the stomach, positioned to avoid the main blood vessels. Stab wounds are made in the body wall and the cannulae passed through. The stomach is perfused through the oesophageal and pyloric cannulae with 5* dextrose solution at 39°C at a rate of 1.5 ml/min. for each cannula. The effluent is passed over a micro-flow pH electrode and recorded via a pH meter and flat bed recorder.

The basal output of acid secretion from the stomach is monitored by measurement of the pH of the perfusion effluent and then increased acid secretion is induced by a continuous intravenous infusion of a sub-maximal dose of histamine; this produces a stable plateau of acid secretion and the pH of the perfusion effluent is determined when this condition is obtained.

The test compound is then administered to the rat by an intravenous injection and the change in 'gastric' acid secretion is monitored by measuring the change in the pH of the perfusion effluent.

From the change in pH of the perfusion effluent, the difference in acid secretion between basal output and the histamine stimulated plateau level is calculated as hydrogen ion concentration in mole/l. The reduction of acid secretion caused by the administration of the test compound is also calculated as the change in hydrogen ion concentration in mole/l from the difference in the pH of the perfusion effluent. The percentage reduction in acid secretion caused by the administration of the test compound may then be calculated from the two figures obtained.

Claims (36)

1. CLAIMS; Compounds of the general formula; RR< (CE 2 ) n X(CH 2 ) m NHCNHR 3 (I) and physiologically acceptable salts and hydrates 5 of such compounds and such salts in which the substituents attached to the benzene ring are ortho, meta or para to one another and,. in which Rj and Rg, which may be the same or different, represent hydrogen or lower alkyl, eycloalkyl, aralkyl or lower alkenyl groups, or lower alkyl groups interrupted by an oxygen atom or a group - , in which R^ represents hydrogen or lower alkyl; or R£ and Rg may, together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain the hetero functions -0- and R 3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyaikyl; X represents -0-, -S- or -CHg- or -N- where Rg is hydrogen or lower alkyl; Y represents =S, =0, =NRg or =CHR^; in which Rg represents hydrogen, nitro, cyano, lower alkyl, aryl, arylsulphonyl or lower alkyl sulphonyl; and R? represents nitro, lower alkylsulphonyl or arylsulphonyl; a is an integer from 2 to 4 inclusive; n is zero, 1 or 2; and Aik denotes a straight or branched alkylene chain of 1 to 6 carbon atoms,

2. Compounds as claimed in claim 1 in which R^ and R,, independently represent hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5or 6- membered heterocyclic ring.

3. Compounds as claimed in claim 1 or claim 2 in which Aik represents a straight alkylene chain of 1 to 3 carbon atoms.

4. Compounds as claimed in claim 1, 2 or 3 in which n is zero or 1.

5. Compounds as claimed in any of claims 1 to 4 In which Y is =S, =0, =CHN0 2 or =NRg where Rg is hydrogen, nitrq cyano or lower alkylsulphonyl.

6. Compounds as claimed in any of claims 1 to 5 in which R^ is hydrogen, lower alkyl or alkoxyalkyl. 4 68 8 6

7. Compounds as claimed in any one of claims 1 to 6 in which the substituents attached to the benzene ring are meta to one another. to 7

8. Compounds as claimed in olains 1/in which R^ and R 2 independently represent hydrogen or methyl or together with the nitrogen atom to which they are attached form a pyrrolidine ring; Alk represents a methylene group; n is zero; Y is =CHN0 2 or =NRg, where Rg is nitro, cyano or methylsulphonyl; R^ is hydrogen or methyl; a is j and X is oxygen.

9. Compounds of the general formula (la): 0(CH o ),NHCNHCH„ - J It · ·> CHNOg in which R represents hydrogen or methyl, and physiologically acceptable salts and hydrates of such compounds and such salts

10. N-Methyl-N '-^-//3- (N, N-dimethylaminoethyl) phenyl/ methylthig7ethyl7-2-nitro-l,1-ethenediamine.

11. N-Methyl-N' -/§-/23- (N-wthylaminamethyl) phenyl/tethylthio/ethy17-2nitro-l, 1-ethenediamine.

12. N-Methyl-N' -/3-/7- (N ,N-dimethylaminanethyl) phsnoxjy'propyl/' 2-nitro-1,1-ethenediamine. 5

13. N-Methyl-N 1 -/3^/3^ (N-mthylatninaiiethyl)£teK»^propy37-2-iii'tro-l,lethenediamine.

14. N-Methyl-N' -/3-/3-( i-pyrrolidinylmethyl) phenax^prcpyl/2-nitro-l, ethenediamine.

15. N-Nitro-N' -/3-/7 1 (N, N-dimethylaminonethyl) phenox^propyi? lo guanidine.

16. N-cyano-N 1 -methyl-N'' -/7-/7 1 (N ,N-dimethylaminonethyl) phenaxy7 propyl] guanidine.

17. N-Methyl-N' -/7-/7- (N ,N-dimethylaminoethyl) phenoxy/propyl/ 2-nitro-1,1-ethenediamine.

18. A compound as claimed in claim 1 which is N-Methanesulphonyl-N’-metbyl-N* ’- [3- [(N,N-dimefchylaminomethyl) phenoxy]nropyl]guanidxne.

19. Compounds as claimed in claim 1, the production of which is specifically described in the Examples, other than those claimed in claims 10 to 18.

20. A process for the preparation of compounds as claimed in claim 1 which comprises (a) reacting a primary amine of formula II in which Rj, Rg, Alk, X, n and m have the meanings given in claim 1, with a compound capable of introducing a group -CNHR^ in which R^ and Y have the meanings given in claim 1; or (h) reacting a compound of formula (v) in which Rj, Rg, Alk, X, n and m have the meanings given in claim 1, and Q represents a group =NR^ or =CHR? (where R, and R? have the meanings given in claim l) and P represents a leaving group, with an amine of the formula R^NH O , wherein R^ has the meaning given 5 in claim 1; or (c) for the production of compounds of formula I in which n is 1, X is sulphur and the other symbols have the meanings given in claim 1, except that when R^ and R o are both hydrogen Y cannot he CHR?, where R? has the meaning given in claim 1, reacting a compound ,,, of formula VI: NAlk, ch 2 l (VI) (in which Rj, R 2 and Alk have the meanings and L is a leaving group) or a compound of given in claim 1 formula (VII) (VII) (in which R|, and have the meanings given in claim l) with a thiol of the formula (VIII): HS(CHJ NHCNHR, 2'm „ 3 Y (VIII) in which m, Y and have the meanings given in claim 1, with protection of the amino group -NR^Rg when the product is to he a compound in which R^ and are both hydrogen with subsequent deprotection at an appropriate stage; or (d) for the production of compounds of formula (1) in which Y is sulphur and and Rg are other.than.hydrogen, reaction of an isothiocyanate of formula IX; NAlk w— (CH 2 ) n X(CH 2 ) m NCS (IX) in which R^ and Rg are other than hydrogen and Alk, 10 Q»

21. and x have the meaning given in claim 1, with an amine of the formula R^NHg in which R^ has the meaning given in claim 1, or (e) for the production of compounds of formula I in which Y is a group =NCN heating a compound of formula I in which Y is sulphur with a heavy metal 15 cyanamide; or (f) for the production of compounds of formula I in Which Y is other than =S and R x and Rg represent alkyl or aralkyl groups,reacting a compound of formula I in which Rj and Rg are hydrogen with an alkyl or aralkyl halide; or (g) for the production of compounds of formula I in 2o which R^ and/or R 2 are methyl groups., reacting a compound of formula I in which Rj and/or Rg are hydrogen with formic 4 6 8 8 6 acid and formaldehyde; the compound of formula I in each case being isolated as the base or in the form of a physiologically acceptable salt, or as a hydrate or N-oxide thereof. 5 21. A process as claimed in claim 20 (a) in which the compound capable of introducing the group -CNHR, is II J Y selected from isocyanates of formula R^NCO, isothiocyanates of formula R^NCS, or compounds of the formula C tt Q in which Q represents a group =NRg or =CHR^ where Rg and R? have the meanings given in claim 1, and P represents a leaving group.

22. A process as claimed in claim 20 substantially as herein described with reference to the Examples.

23. Compounds as claimed in claim 1 when prepared hy a process as claimed in any of claiBm20 to 22. 4 68 8 6

24. Compounds of the general formula II R. z NA1K R. (II) and salts thereof with organic or inorganic acids, in which 5 the substituents attached to the benzene ring are ortho, meta or para to one another and in which R^ and R 2 , which may be the same or different, represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups, or lower alkyl groups interrupted by 10 an oxygen atom or a group in which R^ represents hydrogen or lower alkyl; or R^ and R 2 may, together with the nitrogen atom to which they are 15 attached, form a heterocyclic ring which may contain the hetero functions -0- and R, X represents -0-, -S- or Cfig- or -ΪΙR, ‘5 - 56 46886 where Rg is hydrogen; in is an integer from 2 to 4 inclusive; n is zero, 1 or 2; and Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms, with the proviso that, when X is -CHgn is zero and m is 2 or m + n is 3; and further X is -NRg - only when n is zero and Alk is methylene.

25. 3- (3-aminopropoxy) -N,N-dimethylbenzenemet'nanamine.

26. Compounds of the general formula Alk. -<αι 2 ) η χ(αφ Λ in which R^ and R 2 , may be the same or different, represent hydrogen, lower alkyl, cycloalkyl or lower alkenyl groups, or lower alkyl groups interrupted by an oxygen atom or a group -Nί *4 in which R^ represents hydrogen or lower alkyl, or R^ and R 2 together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain the hetero functions 0 and -N57 46 886 X represents 0,S “CHg- or -NI K 5 where R g is hydrogen; 5 m is an integer from 2 to 4 inclusive; n is zero, 1 or 2; and Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms, with the proviso that, when X is -CHg-, 10 n is zero and in is 2 or m + n is 3; and further X is -NR^- only when n is zero and Alk is methylene.

27. Compounds of the general formula: in which R represents hydrogen or methyl.

28. Compounds of the general formula: (ID 20 in which the substituents attached to the benzene ring are ortho or para to one another and in which Rj and Rg, which may be the same or different, 4 6 8 8 6 represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups or lower alkyl groups interrupted by an oxygen atom or a group -NI I R 4 in which represents hydrogen or lower alkyl, or R^ and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain the hetero functions -0- and -NI *4 X represents -0-, -S-, or -NI R 5 where R g is hydrogen? m is an integer from 2 to 4 inclusive; n is zero, 1 or 2; and Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms, with the proviso that, when X is -CH 2 ~, n is zero and m is 2 or m + n is 3; and further X is -NR g - only when n is zero and Alk is methylene.

29. Compounds as claimed in any one of claims 24, 26 and 28 in which R^ and R 2 independently represent hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring.

30. Compounds as claimed in any of claims 24, 26, 28 and 29 in which Alk represents a straight alkylene chain of 1 to 3 carbon atoms.

31. Compounds as claimed in any of claims 24, 26 and 28-30 in which n is zero or 1. 5

32. Compounds as claimed in any of claims 24, 26 and 28 in which R^R^N- forms a 5- or 6-membered heterocyclic ring, Alk represents methylene, n is zero, m is 3 and X is oxygen.

33. Compounds as defined in any of claims 24, 26, 27 or 28 10 the preparation of which is specifically described in any one of Examples A-G.

34. A process for the preparation of compounds as claimed in any of claims 24 and 26-32 which comprises a) for the preparation of compounds in which X is oxygen 15 or sulphur, reacting a compound of the formula /~(CH 2 ) n XH (X) wherein X is oxygen or sulphur and R g is a group R^gNAlk or a group convertible thereto as herein defined and n has the 20 meaning given in claim 1, in the presence of a base with a compound of the formula L' (CHg)mW (XI) in which L' represents a leaving group or an organic sulphonyloxy group, m has the meaning given in claim 24 and - 60 4 6386 W is a group -NH 2 or a protected amino group, which may subsequently be converted to such group by deprotection,. and with subsequent conversion as herein described of the group Rg to a group R-^NAlk- where necessary; b) for the preparation of compounds in which n is 1 and X is oxygen or sulphur, reaction of a compound of the formula D in which an ^ h ave meanings given in claim 24 and L is a leaving group, with a compound capable of introducing the group - X(CH 2 ) m NH 2 wherein X is oxygen or sulphur and m has the meaning given in claim 24. c) for the production of compounds in which n is 1, m is 2 and X is oxygen or sulphur, treatment of the compound X defined in (a) above in which n is 1 and X is 0 or S with ethylene imine; d) for the production of compounds in which n is zero, m is 3 and X is oxygen, catalytic hydrogenation of the corresponding nitrile of the formula (XII) (XII) wherein R g has the meaning given in (a) hereof; e) for the preparation of compounds in which X is a methylene group, n is zero and m is 2, reduction of the amide (-CONH ? ) derived fron an acid of the formula CHgCHgCOOH (XIV) wherein R g has the meaning given in (a) hereof with sunsequent conversion as herein described of the group R g to a group RjRgNAlk, if necessary; f) for the preparation of compounds in which X is - CHg-, n is zero and m is 2, reaction of a compound of the formula (XVI) CHgCH 2 CH 2 L' (XVI) (in which R 8 and L' have the meanings given in (a) hereof) with ammonia; g) for the preparation of compounds in which X is “CHg- and 20 the sum of m + n is 3, reduction of a compound of formula XVII in which R g has the meaning given in (a) hereof; or -CHgCHgCHgCN (XVII) 4 6 S 8 6 h) for the preparation of compounds in which X is -CH^- and the sum of m + n is 3, reduction of the amide corresponding to the acid of the formula XVIII wherein Rg has the meaning given in (a) hereof, with subsequent conversion as herein described of the group Rg to a group R^RjNAlk if necessary.

35. A process as claimed in claim 34 substantially as 10 herein described with reference to the Examples .

36. Compounds as claimed in any of claims 24 to 33 when prepared by a process as claimed in either of claims 34 or 35.