GB1604675A - Aminoalkylbenzenes - Google Patents

Description

(54) AMINOALKYLBENZENES (71) We, ALLEN & HANBURYS LIMITED a British company of Three Colts Lane, Bethnal Green, London E2 6LA 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 new primary amines of particular use as intermediates for compounds having a selective action on histamine receptors, in the production of new aminoalkyl benzene derivatives which are disclosed and claimed in the complete specification of cognate copending Applications Nos. 20660/77, 40129/77 and 17444/78 (Serial No. 1604674 from which cognate applications the present cognate applications have been divided.

In the said complete specification of the cognate copending applications Nos. 20660/77, 40129/77 and 17444/78 (Serial No. 1604674) are disclosed certain novel aminoalkylbenzene derivatives which are selective H2-antagonists, that is they show inhibition of the secretion of gastric acid when this is stimulated via histamine H2-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 H2-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 236, 385. These compounds do not modify histamine induced contractions of isolated gastrointestinal smooth muscle.

Compounds with histamine H2-blocking 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 be used, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions such as urticaria.

The compounds of said complete specification are of the general formula (I):

and include physiologically acceptable salts and hydrates thereof, in which the substituents attached to the benzene ring are ortho, meta or para to one another and Rl 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

in which R4 represents hydrogen or lower alkyl, or Rl and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain the hetero functions

R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl;

where Rs is hydrogen or lower alkyl; Y represents =S, =O, =NR6 or =CHR7 in which R6 is hydrogen, nitro, cyano, lower alkyl, aryl arylsulphonyl or lower alkylsulphonyl and R7 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 6 carbon atoms.

The term 'lower' as applied to 'alkyl' means that the group has 1 to 6 carbon atoms, and in particular 1 to 4 carbon atoms, 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 (I) 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 R1 and R2 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; Alk represents a straight alkylene chain of 1 to 3 carbon atoms; n is zero or 1.

In a preferred class of compounds Rl R2 N- forms a 5- or 6-membered heterocyclic ring; Alk represents a methylene group; n is zero; m is 3 and X is oxygen.

The compounds of formula (I) may be made by reacting a primary amine of the formula (II)

(in which R1, R2, Alk, n, X and m have the meanings previously defined) with a compound capable of introducing the group

in which R3 and Y have the meanings given herein.

The present invention provides as new compounds, the compounds of general formula II in which the symbols are as defined above, provided that when Xis methylene, n is zero and m is 2 or m + n is 3; R5 is not lower alkyl; and X is -NR- only when n is zero and Alk is methylene, and acid addition salts thereof with inorganic or organic acids and processes for the production thereof. These intermediates may be made by a number of processes which are described below.

Amines of formula (II) where X is oxygen or sulphur may be prepared from compounds of formula (III)

wherein X is oxygen or sulphur and R8 is the group R,R2NAlk 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, with compounds of formula (IV) L'(CH2),W (IV) is which L' is a leaving group, e.g. halogen e.g. bromine, or acyloxy, e.g. acetoxy, or in addition may be an organic 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 RIR2NAlk we mean aldehyde, carboxylic acid, amide group or phthalimido group. For example, the group -CR0 may be converted by reductive amination using an amine R1R2NH. Similarly, a carboxylic acid group may be converted into the corresponding acid halide or ester which may then be reacted with an amine RIR,NH, followed by reduction of the amide so formed with, for example, lithium aluminium hydride to give a group R1 R2NCH2-.

Amines of formula (II) wherein n is 1 and X is oxygen or sulphur may be prepared by reaction of a compound of formula (V) or (VI)

with a compound capable of introducing the group -X(CH2)mNH2 wherein X is oxygen or sulphur and m has the meanings given herein.

In the above formula (V) 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 Rl and R2 are hydrogen, the amino group NR1R2 is protected in compounds of formula (V) and (VI) as, in the case of a primary amine, for examine, a phthalimido group, in which case the protecting group may be removed at an appropriate stage in the reaction using a primary amine or a hydrazine, e.g. methylamine or hydrazine hydrate. When a compound of formula (V) is used, the presence of a base is desirable. When a compound of formula (VI) 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 (III) 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 (VII)

by catalytic hydrogenation, for example using rhodium on aluminium oxide. A compound of formula (VII) may be prepared from a phenol of formula (VIII)

where Rg is a group convertible to RlR2NAlk, 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 m is 2, may be prepared from compounds of formula (IX)

in which R8 is, for example, a group RlR2NAlk or a carboxamide or nitrile group, by standard methods. For example, reaction of the derived acid chloride or ester of a compound of formula (IX) with ammonia, followed by reduction of the resulting amide yields an amine of formula (II) in which X is -CH2-, n is zero and m is 2.

Alternatively reduction of a compound of formula (IX) wherein R8 is, for example, a group RIR2NAlk or a carboxamide or nitrile group with, for example, lithium aluminium hydride would yield an alcohol of formula (X)

which may be converted into a compound of formula (XI)

wherein R8 is RlR2NAlk and L' has the meanings given above.

Compounds of formula (XI) may then be reacted with ammonia to give an amine of formula (II) in which X is -CH2-, n is zero and m is 2. Reaction of a compound of formula (XI) with an alkali metal cyanide, e.g. potassium cyanide, would yield a compound of formula (XII)

which may then be reduced with, for example, lithium aluminium hydride to yield an amine of formula (II) in which X is -CH2- and the sum of m + n is 3. Alternatively a compound of formula (XII) may be hydrolyzed to a compound of formula (XIII)

which may then be converted into an amine of formula (II) wherein X is -CR2- 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, X is a group -NH- and Alk is methylene may be prepared from starting materials of formula (XIV)

where R9 is,

by reaction with a compound of formula (IV) with subsequent removal of any protecting groups and reduction of the amide function.

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

For example, where the reduction is performed in the presence of an amine, RlR.NH, the aldehyde may be converted into a group RlR2NCH2.

In the reactions described above for preparing amines of formula (II) it is usually preferable to use intermediates containing the desired RlR2NAlk group, or a protected form thereof, e.g. phthalimido. However, one may take intermediates containing a group convertible to said R,R2NAlk and convert such a group into RlR2Alk at any suitable stage in the overall preparation.

Where R1 and R2 are both hydrogen in intermediates to amines of 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 R1 and/or R2 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 R1 and/or R2 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 and Examples 1 to 7 the preparation of intermediates of formula (II) according to the invention.

In this exemplification: i) TLC measurements were carried out on silica gel plates of thickness 0.25 mm mounted on a plastic support.

ii) NMR data pressure is recorded in millimetres T values.

iii) Distillation pressures were measured in millimetres of mercury.

iv) All Temperatures are in C.

PREPARATION 1 3-(1-Pyrrolidinylmethyl)phenol Sodium borohydride (15.2 g) was added to a solution of 3-hydroxybenzaldehyde (48.8 g) and pyrrolidine (66.4 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 (80:1)Rf 0.48.

PREPARATION 2 3- (N, N-Dimethylaminomethyl) benzenemethanol (a) 3-(N, N-dimethylaminocarbonyl)benzoic acid, methyl ester A mixture of thionyl chloride (88 g) and benzene-1 ,3-dicarboxylic 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 the ester as an oil (36 g). TLC silica; ethyl acetate, Rf 0.8. NMR (CDCl3) 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 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-dimethylaminocarbonyl)benzoic acid, methyl ester prepared as in (a) above (36 g) in dry tetrahydrofuran was added to lithium aluminium hydride (16.6 g) in dry tetrahydrofuran. The reaction mixture was heated at 600 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 3-(N,N-dimethylaminomethyl)benzene methanol as an oil (16 g) b.p. 95-100 (0.1 mm). TLC silica/methanol Rf 0.57.

If (b) is repeated using 25 g of 3-(N-methylaminocarbonyl)benzoic acid methyl ester, prepared as above 3-(N-methylaminomethyl) benzene methanol (9.2 g) b.p. 110-115 (0.02 mm) was obtained. TLC silica; methanol. RF 036 PREPARATION 3 (a) 2-[3-[3- (N,N-Dimethylaminomethyl)phenoxy]propyl]-1H- isoin dole-i ,3 (2H) -dione A mixture of 80% sodium hydride (2.2 g) and 3-(N,N-dimethylaminomethyl)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 acetate. Evaporation of the dried organic extracts gave the title compound as a yellow oil (13 g). TLC 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(14 g) + B (21.5 g) gabve 2-[3-3-(1-pyrrolidinylmethyl)phenoxyjpropyl]-1H- isoindole-1,3(2H)-dione (21.4 g). TLC silica; methanol: 0.880 ammonia (80:1) Rf 0.46.

m.p. (oxalate salt) 167-9 .

(c) A (5 g) + B (9.3 g) gave 2- 4-[3-(N,N-dimethylaminometbyl phenoxy]butyl]-lH- isoindole-1,3(2H)-dione (8.7 g). TLC silica; methanol: 0.88 ammonia (80;1) 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]-lHisoindole-1,3(2H)-dione (5 g) m.p. 59-60 . TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.45.

(e) A (2.0 g) + B (3.4 g) gave 2-[4-[3-(N,N-dimethylaminoethyl)phenoxy]butyl]-1H- isoindole-1,3(2H)-dione (2.8 g) m.p. 52-3 . TLC silica: ethyl acetate: isopropanol: water: 0.88 ammonia (25:15:8:2) Rf 0.55.

(f) A (2.2 g) + B (3.2 g) gave 2-[3-[3-(N,N-dimethylaminopropyl)phenoxy]propyl]-1H- isoindole-1,3(2H)-dione (2.5 g) b.p. 250 (0.1 mm). TLC silica: ethyl acetate: isopropanol :water:ammonia (25:15:8:2) Rf 0.5.

(g) A (2.2 g) + B (3.4 g) gave 2-[4-[3-(N,N-dimethylaminopropyl)phenoxy]butyl]-1H- isoindole-1,3(2H)-dione (2.6 g) b.p. 225 (0.04 mm). TLC silica; ethyl acetate: isopropanol:water:0.88 ammonia, Rf 0.5.

(h) A (7.0 g) + B (14.1 g) 2-[4-[4-(N,N-dimethylaminomethyl)phenoxy]butyl -lH- isoindole-1,3(2H)-dione, oxalate salt (3.8 g). TLC silica; methanol:0.88 ammonia 80:1) Rf 0.5.

(i) A (5 g) + B (9.7 g) gave 2-[3-[4-(N,N-dimethylaminomethyl)phenoxy]propyl]-1H- isoindole-1,3(2H)-dione (7.1 g). TLC silica; methanol:0.88 ammonia (80.1) Rf 0.5, m.p.

(oxalate salt) 166-70".

PREPARATION 4 (a) 2-[2-[3-(N,N-Dimethylaminomethyl)phenoxy]ethyl]-1H-isoindole-1,3-(2H)-dione 3-(N,N-Dimethylaminomethyl)phenol (5.0 g), 80% sodium hydride (1.2 g) and 2-[2-(4 methylbenzenesulplionyl)etbyl-1H-isoindole-1,3J2R)-dione (13 g) were heated at 90 in dimethylformamide. After 12 hours the reaction mixture was cooled, poured into ice-water and extracted with ether. Evaporation of the organic solvent gave the product as a viscous yellow oil (5.2 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]-1H-isoindole-1,3(2H)-dione (C).

(b) A (5 g) + C (11.7 g) gave 2-[2-[3-(N,N-dimethylaminoethyl)phenoxy]ethyl]-1R- isoindole-1,3(2H)-dione (2.4 g) m.p. 84-5". TLC silica; ethyl acetate:isopropanol: water:0.88 ammonia, Rf 0.45.

(c) A (2.2 g) + C (4.2 g) gave 2-[2-[3-(N,N-dimethylaminopropyl)phenoxy]ethyl]-1H- isoindole-1,3(2H)-dione 00.5 g). TLC silica; ethyl acetate:isopropanol:water:0.880 ammonia (25:15:8:2) Rf 0.45.

PREPARATION 5 2-[3-[3-(N,N-Dimethylaminomethyl)phenoxy]propyl]-1H-isoindole-1,3(2H)-dione (a) 2-[3-[3-(Formyl))phenoxylpropyl]-1H-isoindole-1,3(2H) -dione 3-Hydroxybenzaldehyde (0.61 g), 3-bromopropylphthalimide (1.31 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]propyl]-1R- 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 compounds were prepared similarly.

4-hydroxybenzaldehyde (5 g) and the appropriate phthalimide (10. 4 g) gave 2-[2-[4 (formyl)phenoxyjethyl -lH4soindole-1,3(2H)- ione (1.3 g) m.p. 131.5-133.5 . TLC methanol:chloroform (1:100) Rf 0.5.

2-hydroxybenzaldehyde (6.1 g) and the appropriate phthalimide (12 g) gave 2-[4-[2 (formyl)phenoxyjbutyl-1H-isoindole-1,3-(2H dione (12.2 g) m.p. 99.5-101". TLC silica; methanol:0.88 ammonia (80:1) Rf 0.8.

(b)2-3-[3- (N, (N,N-Dimethylaminomethyl)phenoxy jpropyll-l ,3(2H)-dione.

2-[3-3-(Form l)phenoxyjpropylj-1R-isoindole-1,3(2R) dione (132 g) and 33% ethanolic dimethylamine ()00 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 as in (a).

P (1.2 g) + 33% ethanolic dimethylamine (20 ml) gave 2-[2-[4-(N,N dimethylaminomethyl)phenoxyjethyl -lH-isoindole-1,3(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)phenox jbutylj-1H-isoindole-1,3(2H)-dione (7 g). TLC silica; methanol:0.88 ammonia (80:1) Rf 0.55, m.p. (oxalate salt) 162-3 .

PREPARATION 6 2-[3 -[3- (N, N-Dimethylaminomethyl)phenyl]thiojpropylj-lH-isoindole-1,3 (2H) dione (1) Dithio-bis-3,3' -N, N-dimethylbenzenecarboxamide Dimethylamine (57 ml) in toluene was added at 5 to 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 (CD Cl3) 2.4-2.8 m (8H); 7.05 br (12H).

(2) Dithio-bis-3,3'-N, N-dimethylbenzenemethanamine 3,3'-Dithio-N,N-dimethylbenzenecarboxamide (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 (CDCl3) 2.5-2.9 m (8H); 6.66 s (4H); 7.8 s (6H).

(3) 2-[3-[[3- (N, N-Dimethylaminomethyl)phenyljthio]propyU-lH-isoindole4,3 (2H) dione 80% Sodium hydride (2.3 g) and dithio-bis-3,3'-N,N-dimethylbenzenemethanamine (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 (11.3 g). NMR (CDCl3) 2.0-2.4 m (4H); 2.6-2.9 m (4H); 6.15 t (2H); 6.59 s (2H); 7.02 t (2H); 7.75 s (6H); 7.98 m (2H).

EXAMPLE 1 3-(3-Aminopropoxy)-N-methylbenzenemethanamine dioxalate (1) 3-[3- (Formyl)phenoxy]propionitrile A solution of m-hydroxybenzaldehyde (30.5 g) in acrylonitrile (265 ml) and 40% methanolic benzyl trimethyl-ammonium hydroxide (5 ml) was heated under reflux for 20 hr. The mixture was diluted with ether (500 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) 3-(2-Cyanoethoxy)-N-methylbenzenemethanamine, hydrochloride A solution of 3-[3-(formyl)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; C11R15ClN2O requires: C, 58.3; H, 6.5; N, 12.35% (3) 3- (3-Aminopropoxy) -N-methylbenzenemethanamine, dioxalate A solution of N-methyl-[3-(2-cyanoethoxy)benzenemethanamine hydrochloride (5.39 g) in methanol (50 ml) was eluted through a basic ion-exchange column (Amberlyst (Registered Trade Mark) A-26) and the 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 2 3- (3-Aminopropoxy) -N-methylbenzenemethanamine dioxalate 2-[3-[3-(Formyl)phenoxy)propyl-lH-isoindole-1,3(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 grain (3.9 g) m.p. 196-198 .

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

EXAMPLE 3 (a) 3-(3-Aminopropoxy)-N, N-dimethylbenzenemethanamine 2-[3-[3-(N,N-Dimethylaminomethyl)phenoxy propyl]-lH-isoindole-1 ,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 from the corresponding phthalimide (b) C (5.4 g) gave 3-(2-aminoethoxy)-N,N-dimethylbenzenemethanamine (0.45 g). TLC silica; methanol/ammonia (80:1) Rf 0.04. NMR (CDCl3) 2.8-3.1 m (4H); 6.05 t (2H); 6.55 s (2H); 6.98 t (2H); 7.80 s (6H); 8.4 br. s (2H).

(c) C (2.98) gave 4-(4-aminobutoxy)-N ,N-dimethylbenzenemethanamine bis-oxalate salt (0.8 g). TLC sllica; methanol: 0.88 ammonia Rf 0.17. NMR (D2O) 2.5-2.9 m (4H): 5.7 s 2H); 5.8 m (2H) 6.85 m (2H); 7.12 s (6H); 8.09 m (4H).

(d) C (6.6 g) gave 4-(3-aminopropoxy)-N ,N-dimethylbenzenemethanamine bis-oxalate salt (1. 2).NMR (DsO) 2.5-2.87 m (4H); 5.72 s (2H); 5.75 t (2H); 6.7 t (2H); 7.13 s (6H); 7.78 m2H).

EXAMPLE 4 (a) 3- (3-Aminopropoxy)-N, N-dimethylbenzenemethanamine 2-[3-3-(N,N-Dimethylaminomethyl)phenoxyjpropyl]-1H-isoindole-1 ,3(2H)-dione (90 g) and 30% aqueous methylamine (200 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 C (6.7 g) gave 3-(4-aminobutoxy)-N,N-dimethylbenzenemethanamine (1.2 g). TLC silica; methanol: 0.88 ammonia (80:1) Rf 0.24.

(c) C (2.6 g) gave 3-[3-(1-pyrrolidinylmethyl)phenoxy]proplamine isolated as the bis-oxalate salt (1.3 g) m.p. 184-5". TLC silica; methanol: 0.88 ammonia (19:1) Rf 0.3.

EXAMPLE S (a) 3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine 2-[3-[3-(N,N-Dimethylaminomethyl)phenoxy]propyl]-1H-isoindole-1 ,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 coo 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. 1300 (0.05 mm).

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

3- (N, N-Dimethylaminomethyl)benzeneprnpan-1-ol 3-[3-(N,N-Dimethylaminomethyl)benzene]propanoic 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 (CDCl3) 2.81 m (4H); 6.33 (2H); 6.59 s (2H); 7.28 m (2H); 7.75 s (7H); 7.7-8.4 m (2H).

4-[3- (N, N-Dimethylaminomethyl) benzenejbutanenitrile 3-(N,N-Dimethylaminomethyl)benzenepropan-1-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 created with potassium cyanide (0.7 g) in dimethylformamide at 450 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) b.p. 110 (0.02 mm).

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

4-[3- (N, N-Dimethylaminomethyl) benzene]butanamine 4-[3-(N,N-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 .

WHAT WE CLAIM IS: 1. Compounds of the general formula II

and salts thereof with organic or inorganic acids, in which the substituents attached to the benzene ring are ortho, meta or para to one another and in which R, 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

in which R4 represents hydrogen or lower alkyl; or -Al and R2 may, together with the nitrogen atom to which they are attached, form a heter)cyclic ring which may contain the hetero functions -0- and

X represents -0-, -S- or -CR2- or

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (13)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   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. 1300 (0.05 mm).

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

   3- (N, N-Dimethylaminomethyl)benzeneprnpan-1-ol 3-[3-(N,N-Dimethylaminomethyl)benzene]propanoic 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 (CDCl3) 2.81 m (4H); 6.33 (2H); 6.59 s (2H); 7.28 m (2H); 7.75 s (7H); 7.7-8.4 m (2H).

   4-[3- (N, N-Dimethylaminomethyl) benzenejbutanenitrile

   3-(N,N-Dimethylaminomethyl)benzenepropan-1-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 created with potassium cyanide (0.7 g) in dimethylformamide at 450 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) b.p. 110 (0.02 mm).

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

   4-[3- (N, N-Dimethylaminomethyl) benzene]butanamine 4-[3-(N,N-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 .

   WHAT WE CLAIM IS: 1. Compounds of the general formula II

   and salts thereof with organic or inorganic acids, in which the substituents attached to the benzene ring are ortho, meta or para to one another and in which R, 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

   in which R4 represents hydrogen or lower alkyl; or -Al and R2 may, together with the nitrogen atom to which they are attached, form a heter)cyclic ring which may contain the hetero functions -0- and

   X represents -0-, -S- or -CR2- or

   where R5 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 -CH2n is zero and m is 2 or m + n is 3; and further X is -NRS- only when n is zero and Alk is methylene.
2. 2. 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine.
3. 3. Compounds of the general formula

   in which R1 and R2, 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

   in which R4 represents hydrogen or lower alkyl, or R, and R2 together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain the hetero functions 0 and

   X represents 0, S -CH2- or

   where R5 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 -CH2-, n is zero and m is 2 or m +n is 3; and further X is -NR5- only when n is zero and Alk is methylene.
4. 4. Compounds of the general formula:

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

   in which the substituents attached to the benzene ring are ortho or para to one another and in which R1 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

   in which R4 represents hydrogen or lower alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain the hetero functions - 0 - and

   X represents -0-, -S-, -CH2- or

   where R5 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 -CH2-, n is zero and m is 2 or m + n is 3; and further X is -NRs- only when n is zero and Alk is methylene.
6. 6. Compounds as claimed in any of claims 1, 3 and 5 in which R1 and R2 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.
7. 7. Compounds as claimed in any of claims 1, 3, 5 and 6 in which Alk represents a straight alkylene chain of 1 to 3 carbon atoms.
8. 8. Compounds as claimed in any of claims 1, 3 and 5-7 in which n is zero or 1.
9. 9. Compounds as claimed in any of claims 1, 3 and 5 in which R,R2N- forms a 5- or 6-membered heterocyclic ring, Alk represents methylene, n is zero, m is 3 and X is oxygen.
10. 10. Compounds as defined in any of claims 1, 3, 4 or 5 the preparation of which is specifically described in any one of Examples 1 to 7.
11. 11. A process for the preparation of compounds as claimed in any of claims 1 and 3-9 which comprises (a) for the preparation of compounds in which X is oxygen or sulphur, reacting a compound of the formula

    wherein X is oxygen or sulphur and R8 is a group R1R2NAlk or a group convertible thereto as herein defined and n has the meaning given in claim 1, in the presence of a base with a compound of the formula L' (CH3,W in which L' represents a leaving group or an organic sulphonyloxy group, m has the meaning given in claim 1 and W is a group -NH2 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 R8 to a group R1R2NAlk- 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

    or of the formula

    in which R1, R2 and Alk have the meanings given in claim 1 and L is a leaving group, with a compound capable of introducing the group -X(CH2),NH2 wherein X is oxygen or sulphur and m has the meaning given in claim 1; (c) for the production of compounds in which n is 1, m is 2 and X is oxygen or sulphur, treatment of the compound III defined in (a) above in which n is 1 and X is O 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 (VII)

    wherein R8 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 (-CONH2) derived from an acid of the formula

    wherein R8 has the meaning given in (a) hereof with subsequent conversion as herein described of the group R8 to a group RlR2NAlk, if necessary; (f) for the preparation of compounds in which X is -CH2-, n is zero and m is 2, reaction of a compound of formula (XI)

    (in which R8 and L' have the meanings given in (a) hereof) with ammonia; (g) for the preparation of compounds in which X is -CH2- and the sum of m + n is 3, reduction of a compound of formula XII

    in which R8 has the meaning given in (a) hereof; or (h) for the preparation of compounds in which X is -CH2- and the sum of m + n is 3, reduction of the amide corresponding to the acid of the formula XIII

    wherein Rs has the meaning given in (a) hereof, with subsequent conversion as herein described of the group R5 to a group RlR2NAlk if necessary.
12. 12. A process as claimed in claim 11 substantially as herein described with reference to the Examples.
13. 13. Compounds as claimed in any of claims 1 to 10 when prepared by a process as claimed in either of claims 11 or 12.