GB1604674A

GB1604674A - Aminoalkyl-benzene derivatives

Info

Publication number: GB1604674A
Application number: GB20660/77A
Authority: GB
Original assignee: Allen and Hanburys Ltd
Current assignee: Allen and Hanburys Ltd
Priority date: 1977-05-17
Filing date: 1977-05-17
Publication date: 1981-12-16
Also published as: JPS6354343A; ZA782649B; JPH0153862B2; BE867106A

Description

(54) AMINOALKYL-BENZENE DERIVATIVES (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 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 H2antagonists, 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. The compounds according to the invention 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 present invention provides compounds of the general formula (I):

and physiologically acceptable salts and hydrates, of such compounds and such salts 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 -0- and

R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is -O-, -S-, -CH2-, or

where R5 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; Y is =S, =O, =CHNO2 or =NR6 where R6 is hydrogen, nitro, cyano or lower alkylsulphonyl; R3 is hydrogen, lower alkyl or alkoxyalkyl; and m 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 pyrrolidine ring; Alk represents a methylene group; n is zero; Y is =CHNO2 or =NR6 where R6 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 (Ia):

in which R represents hydrogen or methyl, and physiologically acceptable salts thereof, as well as hydrates of such comPounds and such salts.

Particularly preferred specific compounds are: N-Methyl-N'-[2-[[3-N,N-dimethylaminomethyl)phenyl]methylthio]ethyl-2-nitro-1,1 ethenediamine NMethylN'[2[[3methylaminomethyl)phenyljmethylthioJethyl]-2-nitro-l ,1- ethenediamine N-Methyl-N'-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl]-2-nitro-1 ,1 ethenediamine N-Methyl-N' - 3- 3-(N-methylaminomethyl)phenoxy]propl]-2-nitro- 1, 1-ethenediamine N-Methyl-N' - 3- 3-( 1-pyrrolidinylmethyl)phenoxy]propyl-2-nitro-1 ,1-ethenediamine N-Nitro-N'-[3-[3-(N,N-dimethylaminomethyl)phenoxyjpropyl-guanidine N-Cyano-N'-methyl-N"-[3-[3-(N,N-dimethylaminomethyl)phenoxylpropyl]guanidine N-Methyl-N'-[3-[3-(N,N-dimethyl-2-aminoethyl)phenoxy propyl -2-nitro-1 1- ethenediamine N-Methanesulphonyl-N'-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 form 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 pharmaceutic al composition.

The compounds according to the invention can be adminstered in combination with other active ingredients, e.g. conventional anti-histamines, if required. For oral administration the pharmaceutical 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 syrup 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 composition may contain an effective amount of the active ingredient, for example of the order of 1 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 H2-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 Rl, 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.

Compounds which are capable of introducing the group

include isocyanates R3NCO, isothiocyanates R3NCS or compounds of the formula (III):

where Q represents a group =NR6 or =CHR7 and P is a leaving group such as halogen, thiomethyl, 3,5-dimethyl-pyrazolyl or alkoxy, but 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 (II) 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 =NR6, 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 = CHR,, the amine (II) and the compound (III) may be stirred in aqueous solution at room temperature.

Where R3 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 carbonisothiocyanatidate, (which has the formula CH3CH2OC(=O)NCS, followed by basic hydrolysis.

In an alternative process, the amine of formula (II) is reacted with a compound of formula (IV):

where P and Q are as defined above and P' may have the same meanings as P or may, when Q represents =CHO2, be a group

wherein A represents a lower alkyl group, e.g. methyl.

The resulting compound of formula (V)

may then be reacted with an amine R3NH2 to give a compound of formula (I). 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 have the meanings given except that when R1 and R2 are both hydrogen, Y is other than=CHR7 may also be prepared from compounds of formulae (VI) or (VII) using a thiol of formula (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 R1 and R2 are hydrogen, the amino group NRIR2 is protected in compounds of formula (VI) and (VII) as, in the case of a primary amine, for example, a phthalimido group. The 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 the 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 between a thiol (VIII) and a compound of formula (VII) is preferably carried out at OOC 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 R1 and R2 are other than hydrogen involves treatment of the amine (II) with carbon disulphide followed by reaction with a chloroformate ester e.g., ethyl chloroformate, to give an isothiocyanate of formula (IX)

When the resulting compound of formula (IX) is reacted with an amine R3NH2, preferably in a solvent such as acetonitrile, the product is a compound of formula (I) wherein Y is sulphur and R1 and R2 are other than hydrogen.

Compounds of formula (I) where Y 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 R1 and R2 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 R1 and/or R2 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).

Certain of these amines are claimed in our cognate copending applications Nos 8032729, 8032730 and 8032731 (Serial No. 1604674).

In order that the invention may be more fully understood the following exemplification is provided by way of illustration only. The preparation of starting materials and of intermediates of formula (II) are described in our cognate copending applications referred to above. The Examples which follow describe 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.

ii) NMR data is recorded in values.

iii) Distillation pressures were measured in millimetres of mercury.

iv) All temperatures are expressed in C.

EXAMPLE 1 (a) N-Methyl-N'-[3-[3-(N, N-dimethylaminomethyl)phenoxy]propyl]-2-nitro-1,1- ethenediamine.

A mixture of 3-(3-aminopropoxy)-N,N-dimethylbenzene-methanamine (1 g) and Nmethyl-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:isopropanol: 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 (1.4 g) gave N-methyl-N'-[2-[[3-(N methylaminomethyl)phenyl]methylthiorethyl]-2-nitro-1,1-ethenediamine (0.8 g).

TLC silica; methanol: ammonia (50:1) Rf 0.3, m.p. (fumarate salt) 163-5 .

(c) Diamine (1 g) + D (0.73 g) gave N-methyl-N'[3-[[3-(N,N- dimethylaminomethyl)phenyl]thio]propyl]-2-nitro-1,1-ethenediamine 25 g) NMR (CDCl3)-0.5-0.5 brm (1H); 2.5-3 m (4H); 3.4 s (1H); 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-[3-(N methylaminomethyl)phenoxylpropyl]-2-nitro-1,1-ethenediamine (0.35 g). TLC silica; methanol:0.88 ammonia (20:1) Rf 0.35. NMR (CDCl3) 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).

(e) Diamine (0.45 g) + D (0.24 g) gave N-methyl-N'-[3-[3-(1- pyrrolidinylmethyl)phenoxy]propyl]-2-nitro-1,1-ethenediamine (0.35 g). TLC silica; methanol:0.88 ammonia (80:1) Rf 0.35. NMR (CDCl3) 2.8 m (1H); 2.9-3.5 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-(N,N dimethylaminomethyl)phenoxy ethylj-2-nitro-1 , 1-ethenediamine 00.55 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-methyl-N'-[4-[3-(N,N- dimethylaminomethyl)phenoxyjbutylj-2-nitro- 1, 1-ethenediamine (0.38 g) TLC silica; methanol:0.88 ammonia (80:1) Rf 0.34. NMR (CDCl3) 0.3 br (1H); 2.82 t (111); 3.0-3.5 m (5H); 6.08 br (2H); 6.67 m (4H); 7.15 br (3H); 7.81 s (6H); 8.2 br (411).

(h) Diamine (0.6 g) + D (0.46 g) gave N-methyl-N'-[3-[3-(N,N-dimethyl-2 aminoethyl)phenoxy]propyl]-2-nitro-1 1-ethenediamine (0.58 g) m.p. 93-4 . TLC silica:ethyl acetate:isopropanol:water:0. 88 ammonia (25:15:8:2) Rf 0.45.

(i) Diamine (0.5 g) + D (0.36 g) gave N-methyl-N'-[4-[3-(N,N- dimethylaminoethyl)phenoxy]butyl]-2-nitro-1,1-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-nitro-1,1-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-N'-[3-[3-(N,N dimethylaminopropyl)phenoxyjpropylj-2-nitro-1 , 1-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 phenoxyjbutylj-2-nitro-1 1-ethenediamine (0.45 g) m.p. 79 80.5 . TLC silica; ethyl acetate:water:isoDropanol: 0.88 ammonia (25:8: 15:2) Rf 0.5.

(m) Diamine (0.28 g) + D (0.5g) gave N-methyl-N'-[2-[4-(N,N dimethylaminomethyl henoxyjethy-2-nitr1 ,lethenediainine (0.11 g) m.p. 141 142 . TLC silica; 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) henoxyjpropylj-2-nitro-1 , 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-[4-(N,N-dimethyl-2- aminoethyl)phenoxy]butyl]-2-nitro-1 , 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-(N,N dimethylaminomethyl)phenoxy]butyl]-2-nitro-1 ,1-ethenediamine (1.9 g) m.p. 98.5 100 . TCL silica; methanol: ammonia (80:1) Rf 0.45.

(q) Diamine (0.7 g) + D (0.44 g) gave N-methyl-N'-[4-[3-(N,N-dimethylamino methyl)phenyljbutylj-2-nitro-1,1-ethenediamine (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!13-[3- (N, N-dimethylaminomethyl)phenoxy]propyl] guanidine N-nitrocarbamimidothioic acid methylester (0.77 g) and 3-(3-aminopropoxy)-N,Ndimethylbenzenemethanamine (1.0 g) were heated in ethanol at 40 for 20 mins. The solution was cooled to precipitate the title compound which was filtered off and recrytallised from ethyl acetate as a white solid (0.44 g) m.p. 114-115 . TLC silica; methanol:0.88 ammonia (80:1) Rf 0.48.

EXAMPLE 3 N-[3-[3- (N, N-Dimethylaminomethyl)phenoxy]propyl]guanidine dinitrate 3-(3-Aminopropxy)-N ,N-dimethylbenzenemethanamine (2 g) and 3,5-dimethylpyrazole1-carboxamidine 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-N"-[3-[3- (N, N-dimethylaminomethyl)phenoxyjpropyl]guanidine.

N-Cyano-N'-methylcarbamimidothioic acid methyl ester (0.8 g) and 3- [3-aminopropoxyj N,N-dimethylbenzenemethanamine (1.0 g) where heated together at 1000 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; C,5H23NsO requires: C, 62.28; H, 7.96; N, 24.22% Similarly prepared from the corresponding amine (5 g) and N-cyano-N'methylcarbamimidothioic acid methyl ester (2.8 g) were (b) N-cyano-N'-methyl-N"-f2-[[3-(N,N-dimethylaminomethyl)phenyl]methYlthio]- ethyl]guanidine (2.3 g). TLC silica; methanol, Rf 0.47. NMR (CDCl3) 2.5-3 m (4H); 6.25 s (2H); 6.5-6.9 m (4H); 7.18 d (3H); 7-7.5 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]methylthiojethyl] guanidine (1.1 g) m.p. 107-108.5".

EXAMPLE 5 N-Methyl-N' -[3-[3-(N, N-dimethylaminomethyl)phenoxy]propyl]urea Methyl isocyanate (0.27 ml) and 3-(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-[[2-(N, N-dimethylaminomethyl)phenyl]methylthio]ethyl]thiourea 2-[[2-(N,N-Dimethylaminomethyl) henyljmethylthiojethanamine (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 chromatographed on silica using a mixture of ethyl acetate and methanol as eluent to give the title compound as a white solid (1 g) m.p. 57~9O Assay Found: C, 56.2; H, 8.1; N, 13.8; C14H23N3S requires: C, 56.5; H, 7.8; N, 14.1% EXAMPLE 7 N-Methyl-N' -[2-[[3- (N, N- dimethylaminomethyl)phenyllmethylthio]ethyl]-2-nitro-1, 1- ethenediamine.

2-[[3-(N,N-Dimethylaminomethyl)phenyljmethylthio]ethanamine (3 g) and 1-nitro-2,2bis(methylthio)ethylene (2.2 g) where 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 (0.23 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 1-nitro-2,2bis(methylthio)ethylene (2-2 g) was N-methyl-N'-[2[[4-(N,N dimethylaminomethyl)phenyl]methylthiojethylj-2-nitro- 1, 1-ethenediamine (2.5 g) m.p.

98.5-100".

Assay Found: C, 55.45; H, 7.4; N, 17.1% C15H24N402S requires: C, 55.5; H, 7.45; N, 17.3% EXAMPLE 8 (a) N-[3-[3-N, N-D imethylaminomethyl) ph en oxy jpropyll -N' -(2-methoxyethyl) -2-nitro 1,1 -ethenediamine hydrochloride (1) N-l3-[3-(N,N-Dmethylaminomethyl)phenoxylpropyll-2-nitroimidothioic acid methyl ester 3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (10 g) and 1-nitro-2,2bis(methylthioethylene (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 Found: C, 54.95; H, 7.15; N, 12.95; C15H23N3O3S requires: C, 55.35; H, 7.05; N, 12.9% (2) N-[3-J3- (N, N-Dimethylaminomethyl)phenoxyjpropyl]-N'- (2-methoxyethyl) -2-nitro- l,l-ethenediamine hydrochloride.

A mixture of N-[3-(3-(N,N-dimethylaminomethyl)phenoxy]propyl]-2-nitroimidothioic acid methyl ester (0.8 g) and 2-methoxyethylamine (0.2g) 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 Found: C, 52.1; H, 7.7; N, 14.0; Cl,H28N404 requires: C, 52.5; H, 7.45; N, 14.4% The following compounds were similarly prepared from the ester and the corresponding amine: (6) Ester (0.8 g) and 70% aqueous ethylamine (3 ml) gave N-ethyl-N'-[3-[3-(N,N dimethylaminomethyl)phenoxyjpropyl]-2-nitro- 1, 1-ethenediamine hydrochloride (0.69 g) m.p. 144-145 . TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf (c) Ester (0.8g) and 0.88 ammonia (0.5 ml) gave N-[3-[3-(N,N dimethylaminomethyl)phenoxyjpropyl]-2-nitro-1 , 1-ethenediamine hydrochloride (0.6 g) m p. 100-102". TLC silica; ethyl acetate; isopropanol;water;0.88 ammonia (25:15:8:2) Rf 0.65.

EXAMPLE 9 N-Methanesulphonyl-N' -methyl-N' -[3-[3- (N, N-dimethylaminomethyl) phenoxy]propyl]- guanidine.

N-Methanesulphonylcarbonimidodithioic acid dimethyl ester (which has the structure

(3 g) and 3-[3-aminopropoxy]-N,N-dimethylbenzenemethanamine (2.5 g) were heated reflux in ethanol for 4 hours. Methylamine was then added and the reflux continued for 1l/2 hours. The solvent was removed and the residue was purified by column chromatography 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 (CDCl3) 2.85 m (1H); 2.9-3.3 m (3H); 3.0-4.3 brs (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 500 g Anhydrous lactose U.S.P. 2.17 kg Sta-Rx 1500 Starch* 300 g Magnesium Stearate B.P. 30 g The drug is sieved through a 250 m 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) % wiw 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 1.35 Fm. 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 1.50 kg Cutina (Registered Trade Mark) HR** 0.40 kg Anhydrous lactose U.S.P. 2.060 kg Magnesium Stearate BP 40 g 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 500C 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 iim 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 and provided with 8% sucrose in normal saline instead of drinking water.

The rats are anaesthetized by a single intraperitoneal 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 by 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 cumin. 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.

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

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

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 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 iim 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 and provided with 8% sucrose in normal saline instead of drinking water. The rats are anaesthetized by a single intraperitoneal 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 by 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 cumin. 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. WHAT WE CLAIM IS:

1. Compounds of the general formula:

and physiologically acceptable salts and hydrates of such compounds and such salts in which the substituents attache to the benzene ring are ortho, meta or para to one another and in which 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 R1 and R2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain the hetero functions - 0 - and

R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X represents -O-, -S- or -CH2- or

where R5 is hydrogen or lower alkyl; Y represents =S, =O, =NR6 or =CHR7; in which R6 represents hydrogen, nitro, cyano, lower alkyl, aryl, arylsulphonyl or lower alkylsulphonyl; and R7 represents 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.

2. Compounds as claimed in claim 1 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- membere heterocyclic ring.

3. Compounds as claimed in claim 1 or claim 2 in which Alk 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, =O, =CHNO2 or =NR6 where R6 is hydrogen, nitro, cyano or lower alkylsulphonyl.

6. Compounds as claimed in any of claims 1 to 5 in which R3 is hydrogen, lower alkyl or alkoxyalkyl.

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.

8. Compounds as claimed in claims 1 to 7 in which Rl and R2 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 =CHNO2 or =NR6, where R6 is nitro, cyano or methylsulphonyl; R3 is hydrogen or methyl; m is 3 and X is oxygen.

9. Compounds of the general formula (Ia):

in which R represents hydrogen or methyl, and physiologically acceptable salts and hydrates of such compounds and such salts.

10. N-Methyl-N'-f2-[[3-(N,N-dimethylaminomethyl)phenyl]methylthio] ethyl] 2-nitro-1 ,l-ethenediamme.

11. N-Methyl-N'-[2-[[3-(N-methylaminomethyl)phenyl]methylthio]ethyl]-2-nitro-1, 1-ethendiamine.

12. N-Methyl-N'-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propylj.2.nitro-1 1- ethenediamine.

13. N-Methyl-N![3-[3-(N-methylaminomethyl)phenoxy]propyl]-2-nitro-1,1- ethenediamine.

14. N-Methyl-N'-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-nitro-1,1- ethenediamine.

15. N-Nitro-N' -[3-[3-(N ,N-dimethylaminomethyl)phenoxyjpropyl]guanidine.

16. N-Cyano-N'-methyl-N' '-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propylj guanidine.

17. N-Methyl-N' [3- [3-(N ,N-dimethyl-2-aminoethyl)phenoxy]propylj-2-nitro- 1,1- ethenediamine.

18. A compound as claimed in claim 1 which is N-Methanesulphonyl-N'-methyl-N"-[3 [(N,N-dimethylaminomethyl)phenoxy]propyl]guanidine.

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 R1, R2, Alk, X, n and m have the meanings given in claim 1, with a compound capable of introducing a group

in which R3 and Y have the meanings given in claim 1; or (b) reacting a compound of formula (V)

in which R1, R2, Alk, X, n and m have the meanings given on claim 1, and Q represents a group =NR6 or =CHR7 (where R6 and R7 have the meanings given in claim 1) and P represents a leaving group, with an amine of the formula R3NH2, wherein R3 has the meaning given 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 R1 and R2 are both hydrogen Y cannot be =CHR7, where R7 has the meaning given in claim 1, reacting a compound of formula VI:

(in which Rl, R2 and Alk have the meanings given in claim 1 and L is a leaving group) or a compound of formula (VII)

Sin which Rl, R2 and Alk have the meanings given in claim 1) with a thiol of the formula (VIII):

in which m, Y and R3 have the meanings given in claim 1, with protection of the amino group -NRlR2 when the product is to be a compound in which Rl and R2 are both hydrogen with subsequent deprotection at an appropriate stage; or (d) for the production of compounds of formula (I) in which Y is sulphur and R1 and R2 are other than hydrogen, reaction of an isothiocyanate of formula IX:

in which R1 and R2 are other than h drogen and Alk, n m and X have the meaning given in claim 1, with an amine of the formula R3NH2 in which R3 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 cyanamide; of (f) for the production of compounds of formula I in which Y is other than S and Rl and R2 represent alkyl or aralkyl groups, reacting a compound formula I in which R1 and R2 are hydrogen with an alkyl or aralkyl halide; or (g) for the production of compounds of formula I in which R1 and/or R2 are methyl groups, reacting a compound of formula I in which R1 and/or R2 are hydrogen with formic 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.

21. A process as claimed in claim 20 (a) in which the compound capable of introducing the group

is selected from isocyanates of formula R3NCO, isothiocyanates of formula R3NCS, or compounds of the formula

in which Q represents a group =NR6 or =CHR7 where R6 and R7 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 by a process as claimed in any of claims 20 to 22.

24. Pharmaceutical compositions comprising a compound as claimed in claim 1 or claim 23, in association with a pharmaceutically acceptable carrier or diluent, and if desired, other active ingredients.

25. Compositions as claimed in claim 24 in a form suitable for oral, topical or parenteral administration or administration by suppository.

26. Compositions as claimed in claim 25 in oral form as tablets.

27. Compositions as claimed in claim 26 in the form of slow release tablets.

28. Compositions as claimed in claims 26 or 27 containing 2 to 200 mg of active ingredient per tablet.

29. Compositions as claimed in claim 25 in topical form as a spray, ointment or cream.

30. Compositions as claimed in claim 25 substantially as herein described with reference to the Examples.

31. A method of treating a condition mediated through histamine H2-receptors which comprises administering to a non-human patient an effective amount of a compound as claimed in claim 1 to relieve said condition.

32. A method as claimed in claim 31 in which the condition is peptic ulceration.

33. A method as claimed in claim 31 in which the condition is an allergic skin condition.

34. Compounds of the general formula

and physiologically acceptable salts thereof in which R, and R2, which may be the same or different, represent hydrogen, lower alkyl, cycloalkyl or lower alkenyl groups which alkyl groups may be 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 other hetero functions selected from 0 and

R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is O, S -CH2- or

where R5 is hydrogen or lower alkyl; Y represents S, O, =NR6 or

in which R6 is hydrogen, nitro, cyano, lower alkyl, lower alkylsulphonyl or aryl; R7 represents nitro, lower alkylsulphonyl or arylsulphonyl; m is an integer from 2 to 4 inclusive; n is 0, 1 or 2; and Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms.

35. Pharmaceutical compositions comprising a compound as claimed in claim 34 in association with a pharmaceutically acceptable carrier or diluent, and if desired, other active ingredients.

36. A method of treating a condition mediated through histamine H2-reactors which comprises administering to a non-human patient an effective amount of a compound as claimed in claim 34 to relieve said condition.

37. Compounds of the general formula

and physiologically acceptable salts and hydrates thereof in which the substituents attached to the benzene ring are ortho orpara to one another and R1 and R2 which may be the same of 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

Rs represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; Xis -O-, -S-, -CH2- or

where R5 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.

38. Pharmaceutical compositions comprising a compound as claimed in claim 37 in association with a pharmaceutically acceptable carrier or diluent, and if desired, other active ingredients.

39. A method of treating a condition mediated through histamine H2-receptors which comprises administering to a non-human patient an effective amount of a compound as claimed in claim 37 to relieve said condition.