IE45456B1 - Aminoalkyl furan derivatives - Google Patents

Abstract

Novel aminoalkylfuran derivatives of the general formula I: in which the symbols have the meaning given in claim 1, are prepared by reacting a compound of the formula (II) or (III) with a compound of the formula . The aminoalkylfuran derivative may be used in the form of the free base or in the form of a physiologically acceptable salt or a hydrate. These novel aminoalkylfuran derivatives inhibit gastric acid secretion when this secretion is stimulated by way of histamine H2 receptors.

Description

This invention relates to new aminoalkyl furan derivatives having a selective action on histamine receptors, to processes for the preparation thereof and pharmaceutical compositions containing them, as well as their use in therapeutics A subdivision of histamine receptors (E-receptors) into two groups designated Ej~ and Hg- receptors has been proposed by Ash and Schild (Brit. J. Pharmacol, Chemother, 1966, 27, 42?) snd Black et al (Nature 1972, 256. 385). Stimulation of bronchial and gastrointestinal smooth muscle is mediated through Bj-reeeptors and these effects can be prevented by conventional histamine antagonists such as mepyramine.

Stimulation of gastric acid secretion and heart rate is mediated through Hg-receptors5 these effects are not modified by mepyramine but are. prevented or abolished by Eg-antagonists such as metiamide. Histamine stimulates Hj- and Hg-receptors.

We have found that certain novel aminoalkyl furan derivatives are selective Hg-antagonists, that is they show inhibition of the secretion of gastric acid when this is stimulated via histamine Hg-receptors (Ash and Schild loc. cit,). 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 -2Black ot al (Nuture l'J72 230 3^5). The compounds according to the invention do not modify histamine induced contractions of isolated gastrointestinal smooth muscle.

Compounds with histamine Hg-hlocking activity may he used in the treatment of conditions where there is a hypersecretion of gastrij 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 invention therefore provides compounds of general formula (I): and physiologically acceptable salts and N-oxides and hydrates thereof, in which R^ and Rg whioh may he the same or different represent hydrogen, lower alkyl, cyeloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted hy an oxygen atom or a group -N-, in which R^ represents hydrogen or lower alkyl or Rj and R^ Rg may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and -N-; -3, 4 Β 4 5 β R3 is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is -CHg-fO or S; Y represents = S, = 0, = NRj. or = CHRg? Alk denotes a straight of branched alkylene chain or 1 to 6 carbon atoms; Rg is H, nitro, cyano, lower alkyl, aryl, alkylsulphonyl, or arylsulphonyl; Rg represents nitro, arylsulphonyl or alklsulphonyl; m is an integer from 2 to 4; and n is 1 or 2; or when X = S, or -dig-, n is sero, or 2.

Loweralkyl groups are those containing from 1 to 8 carbon atoms. Lower alkenyl groups are those containing from 3 to 6 carbon atoms. Preferred meanings for 1 aryl1 as a group or part of a group are phenyl, or phenyl substituted, for example, with alkyl, alkoxy or halogen. Particularly preferred meanings for the group R^ and R2 are hydrogen or alkyl containing from 1 to 4 carbon atoms.

The compounds according to the invention have the advantage that they are readily preparable from readily accessible starting materials.

All 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 diastereo-4»3456 Isomers and optical enantiomers.

In a preferred class of compounds according to the invention the following groups have the meanings indicated: Rj and Rg independently represent hydrogen, alkyl, phenylalkyl, dialkylaminoalkyl or together with the nitrogen at.5 form a 5- or 6-membered saturated heterocyclic ring e.g. morpholine, piperidino, pyrrolidino, and N-alkylpiperazino.

Alk represents a straight alkylene chain of 1 to 4 earbon atoms. ϊ is = S, = 0, =CHN0o or = NR^ where R„ is hydrogen, nitro, cyano, lower alkyl, alkylsulphonyl or benzenesulphonyl.

X, m, n, and R^ have the meanings given above.

In a particularly preferred class of compounds according to the invention the following groups have the meanings indicated: Rj and Rg independently represent hydrogen, alkyl of 1 to 3 carbon atoms or phenethyl or together with the nitrogen atom form a pyrrolidine ring.

Alk represents an alkylene chain of 1 to 3 carbon atoms.

Y is = S, = CHNOg, or = NR,., where R^ is nitro, cyano, methylsulphonyl or benzenesulphonyl.

If represents hydrogen, alkyl of 1 to 3 carbon -54345® atoms, propenyl or alkoxyalkyl of 3 carbon atoms, n + π is 3 or 4, and X is as defined above.

In another preferred class of compounds according to the invention the following groups have the meanings indicated: Rj_ and Rg independently represent H, alkyl of 1 to 3 carbon atoms, phenethyl or together with the nitrogen atom form a pyrrolidine ring.

Alk represents an alkylene group of 1 to 3 carbon atoms.

Y is = S, sCElJOg, or = NRg, where Rg is nitro, cyano, methylsulphonyl or benzenesulphonyl.

X is S or -CHg-.

Rg is hydrogen, methyl or methoxyethyl, a is 1 and a is 2 or 3.

In another particularly preferred class of compounds according to the invention the following groups have the meanings indicated: is hydrogen, methyl or ethyl.

Rg is mnfchvl or ethyl.

Alk represents a methylene group.

Y is =NCN, =NNOg, or sCBNQg.

Rg is hydrogen or methyl.

X is S or -CHg-. · n is 1 and m is 2. -6Particularly preferred specific compounds are: N-[2-[t[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N’-methylthiourea N-Cyano-N·-[2-[[[5-(dimethylamino)methyl-2-furanylJmethyl)thio]ethyl]-Nn-methylguanidine N~[2-[ [ [5-(Dimethylamino)methyl-2-furanyl]methyl]thio)ethyl]N*-methy1-2-ni fcro-1,1-ethenediamine N-Cyano-N’-[2-[[[5-(methylamino)methyl-2-furanylJmethyl]thio)ethyl ]-N'*-methylguanidine N— L~—[[[5-(Diethylamino)methyl-2-furanyl)methyl)thio]ethyl)N’-methyl-2-nitro-l,1-ethenediamine Ν-[2—[[L 5—(Dimothylamino)methyl-2-furanylJmethyl)thio)ethyl)N *-(2-methoxyethyl)-2-nitro-l,1-ethenediamine N-[2-[[[5-(Methylamino)methyl-2-furanyl]methyl)thio)ethyl)N’-methyl-2-nitro-l,1-ethenediamine N-[5-[[5-(Dimethylamino)methyl-2-furanyl)thio)propyl)-N·methyl-2-nitro-l,1-ethenediamine N-[2-[LL5-(Ethylmethylamino)methyl-2-furanyl]methyl)thio)ethyl]-N1-methyl-2-nitro-l,1-ethenediamine N- [2-[[(5-(Dimethylamino)methyl-2-furanyl]methyl)thio]ethyl)N1-nitroguanidine N-[,2-1. [[5-(Dimethylamino)methyl-2-furanyl)methyl)thio]ethyl)N·-methanesulphonyl-N-methylguanidine N-[4-[5-(Dimethylamino)methyl-2-furanyl]hutyl)-N1-methylthiourea -74!54ΰό N-Benzonesulphonyl-N’-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N-methylguanidine N-[5"[5-(Dimethylamino)methyl-2-furanyl]pentyl]-N’-methyl-2nitro-l,1-ethenediamine N-Cyano-N!-[5-[5-(dimethylamino)methyl-2-furanyljpentyl]-N *methyl guanidine N-[4-[5-(Dimethylamino)methyl-2-furanyl]butyl]-N*-methyl-2nitro-l,1-ethenediamine N-Cyano~N’-[4-[5-(dimethylamino)methyl-2-£uranyl]butyl]-N10 methylguanidine N-[2-[[ [S-MDimethylamino ]propyl 1-2-f uranyl Jmethyl ]thio ]ethyl]-M·-methyl-2-nitro-1,l-ethenediamine N-[2-[[[5-[[2™(dimethylamine)ethyl]amino]methyl-2-furanyl]methyl]thio]ethyl]-N *-aethyl-2-nitro-l,1-ethenediamine The compounds according to the invention readily form physiologically acceptable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulphates. Particularly useful salts of organic acids are formed with aliphatic mono- or di-carboxylic acids. Examples go · of such salts are acetates, maleates and fumarates. The compounds may also form hydrates. As indicated the compounds of the invention also include N-oxides, where R^ and Rg are both other than hydrogen.

The compounds according to the invention can be administered orally, topically or parenterally or by suppository, -8*5458 of which the preferred route is the oral route. They may he used in the form of the base or as a physiologically acceptable salt. They will in general he associated with a pharmaceutically acceptable carrier or diluent, to provide a pharmaceutical composition.

The compounds according to the invention can he administered in combination with other active ingredients, e.g. conventional antihistamines if required. For oral administration the pharmaceutical composition can most conveniently he 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 he in syrup form. Suitable topical preparations include ointments, lotions, creams, powders and sprays.

A convenient daily dose by the oral route would he of the order of 100 mg to 1.2 g per day, in the form of dosage units containing from 20 to 200 mg per dosage unit. A convenient regimen in the case of a slow release tablet would be twice or three times a day.

Parenteral administration may be by injections at intervals or as a continuous infusion. Injection solutions may contain from 10 to 100 mg/ml of active ingredient.

For topical application a spray, ointment, cream or lotion may be used. These compositions may contain an effective amount of the active ingredient, for example of the order of -9If to 2$ by weight of the total composition.

The compounds of the present invention may be made from a primary amine of the formula: ,/ N-Alfe (CH2)nX(CH2)mNH2 (II) in which Bj, Rg, η, X and m have the meanings given herein with a compound capable of introducing the group -CNHR^ in which R„ and Y have the meanings given herein. The amine may be used as the free base or in the form of a salt with a weak aeid e.g. acetic acid. Compounds which are capable of introducing the group are, isocyanates R^NCO, isothioΪΓ cyanates R^NCS, or compounds of the formula R^NHC - P or nr5 R,NKC - P where P is a leaving group. The reaction with the 5 Ii CHRg isocyanate or isothiocyanate may be carried out by allowing the amine and isocyanate or isothiocyanate fo stand in a solvent such as acetonitrile. The reaction with R-NHC - P 3 II nr5 or BjNHC - P can be carried out by fusing the reactants at CKRg an elevated temperature e.g. 100-120°C. Alternatively the -1010 i545S ◄ reaction between the amine (ll) and R^NHC - P may be carried nr5 out in a solvent e.g. acetonitrile at elevated temperatures in the presence of silver nitrate. Alternatively again the amine (ll) and the compound R-NHC - P may be stirred in aqueous I cbr6 solution at room temperature. Where R^ represents hydrogen alkali metal cyanates and thiocyanates are used. Examples of leaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl. The introduction of the group -CNHR^ "ay also &e effected by first reacting the amine Y (ll) with a compound of the formula: P P P P X/ o, X/ L 11 Cbr6 NR5 in which P is a leaving group as defined above. This reaction may be effected in a solvent, e.g. ether or acetonitrile at a temperature from ambient to reflux. Treatment of the resulting compound of formula (ill): \ I I ^N-Alk -<θ >- (CH^iCH^NHC-P (III) R2 Q -114345® where Q represents =NRg or =ΟΗΚθ with a primary amine RgNHg at a temperature from ambient to reflux gives the desired end product.

In an alternative procedure for the production of products in which Y is sulphur, the amine (II) can be heated with carbon disulphide and then reacted with a chloroformate ester, e.g. ethyl ehloroformate to form an isothiocyanate (IV) which is then reacted with an amine R-rlHg preferably in an alkanol as solvent e.g. ethanol. 1© N-Alk (0H2)nX(CH2)mNCS (IV) In another process, compounds wherein X is sulphur and n is 1, and when and Eg are both hydrogen Y is other than sGHKTOg, can be prepared from a starting material of formulae (V) or (Vi): go fi fi H-Alk—U >-CHo0R'0^ 7 (V) N-Alk· CH„C1 (VI) (Ry may be hydrogen or an acyl group such as acetyl or p-ni trob ensoyl) If R-, and Rg in the products are both hydrogen, they may be -124 5 4 5 8 protected in a compound of formula (V) as, for example a phthalimido group. The above compounds may be reacted with a thiol of formula (Vll): HStCH^NHCNHR^ Y (VII) with subsequent de;;rot6ction where appropriate. When the compound of formula (v) is used the reaction is preferably carried out at 0eC in concentrated hydrochloric acid. When a compound of formula (VI) is used the reaction may be carried out at room temperature in an organic solvent e.g. dimethylformamide. The chloromethyl compound (VI) may be prepared from the corresponding alcohol using for example, thionyl chloride or concentrated hydrochloric acid.

Products in which Y is a group NCN may be prepared from compounds of formula I where ϊ 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.

Compounds according to the invention in which Y is =NRg and Alk is a methylene group or branched alkylene chain can also be prepared from compounds of the formula (VIIl): (CH2)nX(CH2)aNHCNHR3 (VIII) nr5 -15by a Mannich reaction using an appropriate aldehyde and secondary amine or a salt of a primary amine or a secondary amine. For example, the (CH-J^NCE^- group can be introduced using dimethylamine and formaldehyde. The prooess may be carried out by reacting the amine salt with aqueous formaldehyde and the compound of formula (VIII) or by refluxing the amine salt with paraformaldehyde and the compound of formula (VIII).

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 hut are not included in the present invention. These intermediates may be made by a number of processes which are described below.

Amines of formula (ll) wherein X is S and n is 1 may be prepared from the furfurylthiol of formula (IX): (ix) go by reaction with an ω-bromoalhylphthalimide (X): -1410 The group compound *1**» N-Alk may he introduced ihto x—* of formula (XI): the resulting by for example a Mannich reaction.

Removal of tho protecting group by reaction with, for example, hydrazine hydrate gives an amine of formula (11), In an alternative process to amines of formula (XI) wherein X is S and n is 1, 2-furfuryl chloride may toe used as starting material. The reaction between furfuryl chloride and an ω-aminoalkylthiol in which the amine group ls protected, for example as a phthalimido (XII): gives an intermediate of formula (XI). This is treated as described above to give an amine of formula (ll), A further process to the amines (II) wherein X is S and n is 1 uses a starting material of formula (XIII): (XIII) 15ύ·. δ «4 3 S This compound may he treated under acid conditions, with an ω-aminoalkylthiol, in which the amine group may he protected ii desired. Alternatively, the compound of formula (XXIX) may he converted into the corresponding aeetate prior to reaction, under ba'sic conditions with the ω-aminoalkylthiol.

Primary amines of formula II (except those in which X = S and n = aero) may be prepared by reacting furan with butyl lithium, to produce a lithio derivative (XIV): (XIV) which is then reacted sequentially with (i) an a, dJ-dihalocompound Hal(CH2)nX(CH2)mHal (where Hal is chlorine, bromine or iodine), and (ii) potassium phthalimide. The product of the reaction of formula (XV): (CH2)nX(CH2)mN (XV) is then subjected to, for example, a Mannich reaction and deprotected by reaction with, for example, hydrazine hydrate.

Intermediates where X is S and n is zero can be made from a furan of formula (XVI): (XVI) X -16in which neither nor Ro are hydrogen by reacting it with lithium and elemental sulphur followed by reaction with an W-bromoalkylphthalimide (X). The resulting product of formula (XVII): may then be reacted with hydrazine hydrate to remove the protecting group.

The production of an intermediate in which X is an oxygen atom and n is 1 involves reacting an alcohol of the formula (XIII) in a solvent such as dimethylformamide with a compound Hal(CHg)mNH2 where Hal represents a halogen atom, preferably chlorine, in th® presence of a base, particularly potassium tertiary butoxide.

Intermediates of formula II where m is 2 and X is S or 0 way also be prepared by using ethylene imine. This compound is reacted with a compound of formula XIII or the isosterio thiol.

Amines of formula II may also be prepared by starting with a compound of formula (XVIII): CN (XVIII) -17' *345® In which n, m and X have the above stated meanings. A Mannich reaction is carried out on this nitrile compound followed by reduction with lithium aluminium hydride, to give a compound of formula II.

When a Mannich reaction is used, the group N-Alk may V be introduced at any convenient stage but the reaction is preferably carried out on compounds of formula (XIX) or (XX) (XIX) (CH2)nX{CH2)mN^ (xx) 0 The Mannich reaction, using an appropriate aldehyde and amine, is used to prepare compounds in which Alk represents a methylene group or a branched chain alkylene group. Where Alk represents methylene, formaldehyde is used.

An alternative process to compounds wherein Alk is methylene uses fursn-2-earboxylic acid as starting material. This is reacted with an amine of formula R-^RgNH to give an amide of formula (XXI) which is then reduced with, for example, lithium aluminium hydride to give a compound of formula (XXII): \c li ./) (XXl) R2 (XXII) In order to convert a compound of formula XXII into a -18. compound of formula XIII the hydroxymethyl group may he Introduced using formaldehyde and acetic acid. If Rj and Rg are both hydrogen, the amino group is protected during hydroxymethylation as a phthalimide. Deprotection is subsequently effected using hydrazine hydrate.

Alternatively, ’.here neither R^ nor Rg are hydrogen, hydroxymethylation may be effected using butyl lithium, followed by formaldehyde.

Where Alk is a straight chain alkylene group containing 2 or more carbon atoms, the following two methods are applicable.

A convenient method used for ethylene derivatives analogous to that above for methylene derivatives using the carboxylic acid (XXIII): HOOCCHg (XXIII) in place of furan-2-carboxylic acid.

Where the alkylene chain, Alk, is longer than 2 carbon atoms the lithio derivative of formula (XIV) may be treated sequentially with (i) a dihalo alkane of formula Hal Alk Hal where Hal is chlorine, bromine or iodine and (ii) an amine RjRgNH to give a compound of formula (XVI) wherein Alk contains 3 to 6 carbon atoms.

Where R^ and R(, are hydrogen, potassium phthalimide replaces the amine R^RgNII in both the above reactions. The -19· ΪΟ -3 ΰ -3 Β 6 product of both reactions is hydroxymethylated as described above, followed by deprotection where appropriate to give a compound of formula (XIII).

If compounds where Rj and Rg are other than hydrogen are required, the free amino compounds can be converted into suitable substituted amino groups, for example, by the use of formaldehyde and formic acid by the Eschweiler-Clarke procedure to give the dimethylamino compounds but it is preferable to use the substituted amine at the appropriate stage in the reaction.

Amines of formula XI where n is 2 may be made by utilizing as starting material a compound of the formula XXIV (XXIV) in which Z is a leaving group, e.g. tosyloxy, mesyloxy or bromine. This compound is reacted with an uJ-phthalimidoalkylthiol of the formula (XII). The resultant compound is then subjected to a Mannich reaction and subsequently deprotected to produce the desired amine of formula II.

In producing the compounds of the invention one may react a compound of formula V with a thiol of formula VII in which Y may inter alia be =CHNQ,j. Compounds of formula and m is 2 VII in which Y is =CHN0g/may be made from a thiazolidine intermediate of the formula: -20a r\ δγΝΗ (XXV) CHNOg by reaction with an amine K^NHg. The thiazolidine XXV may be made from cysteamire and a bis methylthio compound XXVI: CH-SCSCH3 || 3 (xxvi) CHNOg The thiols of formula VII wherein Y is =CHNOg and m is 2 are novel compounds but are not included in tha.present invention. -21In order that the invention may he more fully understood, the following Examples are given hy way of illustration only.

Preceding the Examples are Preparations 1 to 4 which describe the production of starting materials. Examples A to L and related intermediates, exemplify the preparation of amines of formula II/and Examples 1-32 of compounds of formula I. Example 33 exemplifies pharmaceutical compositions.

Preparation 1 (a) 5-(Methylamino)iaethyl-2-furanmethanol A mixture of 2-furanmethaaol (49 g), methylamine hydrochloride (51.5 g) end 36$ formaldehyde solution (50 ml) was stirred at 0-3° for 3 hr and allowed to stand for 16 hr.

Excess sodium carbonate was added and the slurry extracted with ethyl acetate. After removal of solvent the residue was distilled to give 5-(methylamino)methyl-2-furanmethanol (36.2 g) b.p. 111-113’ (0,2 mm).

Similarly prepared from 2-furanmethanol and the corresponding amine hydrochloride were: (b) 5"[(2-Phenylethyl)anino]methyl-2-furanmethanol. Oil Rf 0.45 (silica/acetone). NMR (CCl^) 7.29, br.s (4H); 6.8 s (2H); 6.40 s (2H); 5.62 s (2H); 4.0 br (2H); 2.87 s (5H). (c) 5-[(l"Meihylethyl)emino]methyl-2-furawnethanol. Oil Rf 0.55 (silica/methanol). Analysis Pound C, 63.35; -22Η, 8.78; N, 8,09. C^Hj^NOg requires C, 63.88; H, 8.94? N, 8.285(. (d) 5-(Ethylmethylamino)methyl-2-furanmethanol. Rf 0,32 (silica/acetone). NMR (CDC13) 8.93 t (3H); 7.80 s (3H); 7.55 q (2H); 6.50 s (2H); 6.33 br.s (IH); .47 S (2H); 3.80 m (2H). (e) 5-t[2-(Dimethylamino)ethyljamino]methyl-2-furanmethanol his maleate salt m.p. 119-121°.

Preparation 2 -[2-(N.N-Dimethylamino)ethyl]-2-furanmethanol N,N-Dimethyl-2-furanethanamine (9.8 g), 30½ aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated at 70° for 5 hr. The reaction was cooled, basified with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil b.p. 90-100° (0.5 mm).

Found: C, 64,0; H, 8.9; N, 8.0. CgH^NOg requires: C, 63.9; H, 8.95 N, 8.2½.

Preparation 3 2[l-(4-Bromobutyl)jfuran n-Butyl lithium (l,6M in hexane, 375 ml) was added to a solution of furan (40.8 g) in dry tetrahydrofuren (375 ml) and the mixture was stirred at 40° for 3 hr. 1,4-Dibromohutane (129.6 g) was then added at -30° and the reaction stirred at room temperature for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Distillation -23of the extract gave a clear colourless liquid b.p. 60-62°, 0.5 mm Hg.

N.N-Dimethyl-4-(2-furanyl)batanamine Dimethylamine (56 g) was added to a solution of 2-[l-(4bromobutyl)]furan (82 g) in toluene (500 ml). The resultant solution was stirred at room temperature for 2 days, and then acidified with hydrochloric aeid. The acid layer was separated, washed with ether, basified with sodium hydroxide and extracted with ether. The ethereal extract was distilled to give a clear colourless oil b.p. 55-53°, 0.8 mm Hg. Hydrochloride salt m.p. 133-136°. Found; C, 59.01; H, 9.02; H, 6.87. Calc, for C1OH17HO.HC1; C, 58.96; Hs 8.91; N, 6.880. °[4-(Dimethylamino)butyl]-2-furanmethanol (a) n-Butyl lithium (1.6M in n-hexane, 125 ®l) was added to an ice-cooled solution of N,N-dimethyl-4-(2-furanyl)butanamine (33.4 g) in dry tetrahydrofuran (125 ml). The mixture was stirred at room temperature for 4 hr. Paraformaldehyde (6.0 g) was then added and the mixture stirred for a further 1 hr.

The reaction was quenched with water and extracted with chloroform. The organic extracts were distilled to give a clear colourless oil b.p. 100-105°, 0.1 mm Hg, m.p. 26-28.5°. Found; C, 67.09; H, 10.01; N, 7.06. Calc, for C-^H^NOg: C, 66.97; H, 9.71; N, 7.100.

Similarly prepared was: (b) 5-[-3-(Dimethylamino)propyl]-2-furanmethanol, b.p. -24*ΰ45ο16O°/O.O8 mmHg, m.p. ca. 24°. Pound: C, 64.66; H, 9.36; N, 7.39. Calc, for C1()H17N02.5H20: C, 64.28; H, 9.39; N, 7.50#.

Preparation 4 [5- [4-[N,N-Dimethylamino jbutyl]-2-furanylImethyl ethanoate A mixture of 5«[4-(dimethylamino)hutyl]-2-furanmethanol (4.9 g), acetic anhydride (25 g) and fused and powdered sodium acetate (10 g) in benzene (25 ml) was stirred at room temperature for 24 hr. The reaction was diluted with water (100 ml) and extracted with ethyl acetate. The combined extracts were distilled to afford a clear colourless oil b.p. 100°, 0.5 mm Hg. Found: C, 65.62; H, 9.03; N, 5.95.

Calc, for C13H21NO5: C, 65.24; H, 8.85; N, 5.85#.

Example A (a) 2-[[[5-(Dimethylamino)methyl-2-furanylImethyl]thio]ethanamine -(Dimethylamino)methyl-2-furanmetha»ol (15.5 g) was added dropwise to a stirred, ice-cold solution of cysteamine hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ml). After standing at 0° for 18 hr, excess anhydrous sodium carbonate was added and the resultant solid extracted with diethyl ether. Removal of solvent followed by distillation of the residue gave 2-[[[5-(dimethylamino)methyl-25 furanyljmethyl]thiojethanamine (11,6 g) b.p. 104-106° (0.1 mm). vs -25' • ,4543® Plcrate salt m.p. 142-144°.

Similarly prepared from the corresponding furanmethanols and cysteamine hydrochloride were: (b) 2- [ [[5-(Methylamino)methyl-2-furanyl]methyljthio]ethanamine. Monopicrate salt m.p. 116-118°. (c) 2-[[[5-[(1-Me thyl ethyl)aminojmethyl-2-furanyljmethyljthiojethanamine. Oil Rf 0.4 (silioa/methanoli0.880 ammonia 79:1). (fi) 2-[[[5-(Diethylaminomethyl)-2-furanyljmethyljthio]ethanamine b.p. 134-135° (l mm). (e) 2-[[[5-(1-Piperidinyl)methyl-2-furanyljmethyljthio jethanamine. Oil Rf 0.37 (silica/methanol:0.880 ammonia 79:1). (f) 2-[[[5-(Aminomethyl)-2-furanyljmethyljthio jethanamine, dihydrochloride m.p. 222-224° (dec.). (g) N-[5-[[[(2-Am£aoethyl)thiojmethylj-2-furanyljmethyljbensene ethanamine. Oil Rf 0.33 (silica/methanol:0.880 ammonia 79:1). (h) 2-[[[5-[2-(Dimethylamino)ethylj-2-furanyljmethyljthio jethanamine b.p. 150-155° (0.04 mm). (i) 2-[[[5-[3-(Dimethylamino)propylj-2-furanyljmethyljthio jethanamine b.p. 150° (0.05 mm). (j) 2-[[[5-(Ethylmethylamino)methyl-2-furanyljmethy^ thiojethanamine Rf 0.34 (silica/methanol:0.880 ammonia 79:l). ( k) 2-[[[5-[(2-Dimethylaminoethyl)aminojmethyl-2-furanylj-264 3 4 5 8 methyl) thio]ethanamine. Tris maleate salt m.p. 132-135°. (1) 2- [ [[5-(l-Pyrrolidino)methyl-2-furanyl]methyl]thio]ethanamine. Bis oxalate salt m.p. 136.5-138.5°.

Example B 2-[|[5-Γ4-(Dimethylamino)hutyl1-2-furanylImethyl]thio]ethanamine Cy3teamine hydrochloride (4.5 g) was added to a cooled solution oi potassium-fr-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9,6 g) was added. Tho reaction was heated at 90° for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 14O°/O,O5 mm Hg. Found: C, 60.81; II, 9.86; N, 10.44. Calc, for CjjHg^NgOS: C, 60.91; H, 9.44; N, 10.93,4.

Example C 2-[[2-(2-Furanyl)ethyl1thio1ethyl-lH-isoindole-l,5(2H)dione 80# Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethylformamide at 0°. After 20 mins a solution of 2-furanethanol, 4-methylbenzenesulphonate (1.33 g) in dry dimethylformamide was added dropwise and the solution stirred overnight at room -274 2 4 5 θ temperature. The mixture was poured into ice-water and 2-[[2-(2~furanyl)ethyl]thio]ethyl-lH-isoindole-l,j(2K)-dione isolated as a white solid (1.3 g) m.p. 53-55°.

Example D (a) 2-[2-[[)2~Furanyl)methyllthio jethyl]-lH-isoindole-l,3 (2E)-dione 80?£ Sodium hydride (1.58 g) was added in portions to a solution of furfuryl mercaptan (6 g) in dry dimethylformamide (50 ml). After 30 mins a solution of 2-bromoethylphthalimide (16.71 g) was added in dry dimethylformamide (65 ml) and the solution heated at 110° for 2 days. After removal of solvents the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent removed and the residue recrystallised from cyclohexane to give 2-[2-[[(2-£uranyl)methyl]thio]ethyl]-lHiSoindole-ls3(2H)-dione m.p. 62-63° (7.8 g).

Similarly prepared from the W-bromoalkylphthalimide and furfuryl mercaptan were: (b) 2-[3-[[(2-Puranyl)methyl]thio jpropyl]-lH-isoindole-l,3 (2K)-diones NMR (CDCI„) 7.7-8.3m (2H); 7.2-7.7m (2H); 6„29 s (2H); 6.23 ΐ (2H); 3.7 m (2H); 2.7 m (IB); 2.4m (4H). (c) 2-[4-[[(2-Furanyl)methyl]thio]butyl]-lH-isoindole-l,3 (2H)-dione, NMR (CDC1„) 8-8.5 m (4H); 7.49 t (2H); J? 6.33 m (4H); 3.7 n (2H); 2.7 m (lH); 2.3 m (4H). -28Example Ε (a) 2-[2-Γ Γ[5-(Dimethylamlno)methyl-2-furanylImethyl]thio]ethyl]-lH-isoittdole-l,3(2H)-dione A mixture of 2-[2-[[(2-furanyl)methyl]thio]ethyl]-lHfsoindole-l,3(2H)-dione (10 g), dimethylammonium chloride (5.1 g) and 36½ formaldehyde solution (3 ml) in acetic acid (50 ml) was heated on a steam hath for 9 hr, The solution was cooled and solvent removed in vacuo. The residue was basified with 5N sodium hydroxide and extracted with ethyl acetate. The organic phase w«3 treated with charcoal, dried and evaporated to give an oil which was purified by column chromatography (silica/ethanol:ethyl acetate 1:1) (5.7 g) Bf 0.4. NMR (CDC15/DMSO) 7.71 s (6H); 7.22 t (2H); 6.52 s (2H); 6.2 s (2H); 6.1 t (2H); 3.8 m (2H); 2.2 m (4H).

Similarly prepared from 2-£*)«.[[(2-furanyl)methyl]thio]alkyl]-lH-isoindole-l,3(2H)-dione, the corresponding amine, and formaldehyde were: (b) 2-1.2-[[[5-[(l-Pyrrolidinyl)methyl]-2-furanyl]methyl]thio]ethyl]-lH-lsoindole-l,3(2H)-dione. NMR (CDCl-j) 8-8.4 m (4K); 7-7.6 a (6H); 6-6.5 m (6H); 3.7-4.0 m (2H); 2-2.4 m (4H). (c) 2-[3-[t[5-(Dimethylamino)methyl-2-furanyl]methyl]thio.]propyl]-lH-isoindole-l,3(2H)-dione. Rf 0.45 (silica/ methanol). -29· 3 436 (d) 2-[4-[ [[5-(Dimethylamino)methyl-2-£uranyljmethyljthio]butyl]-lH-isoindole-l,3(2H)-dlone. Rf '0.26 (silica/ methanol). NMR (CDCl^) 8.85 m (4H); 7.7 s (6ll); 7.42 t (2H); 6.52 s (2H); 6.29 m (4H); 3.9 m (2H); 2-2.4 m (4H). (e) 2-[2-[[[5-[(4-Methyl-l-piperazinyl)methyl]-2-furanyl]methyl]thio]ethyi]-lH-isoinfiole-i,3(2H)-dione. NMR (CDC13) 7.75 s (3H); 7.52 s (8H); 7=7.5 a (2H); 6.5 s (2H); 6-6.3 a (4H); 3.85 a (2H); 2-2.4 m (4H). (f) 2-[2-[[[5-[(4-Morpholinyl)methyl]-2-furanyl]methyl]thio]ethyl]-lH-isoindole-l,3(2H)-dione. NMR (CDCl^ 7.54 m (4H); 7.24 m (2H); 6.50 s (2S); 6.22 m (8H); 3.8 m (2tt); 2.0-2.4 m (4H).

Example F 2-[2-[[2-[5-(Dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]IH-isoindole-l,3(2B)-dione 2-[[2-(2-Furanyl)ethylJthio]ethyl-lH-isoindole-l,3(2H)dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together under reflux in ethanol. After 5 hr further dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added and the heating continued for a further 16 hr. Solvent was removed, the residue basified and extracted with ethyl acetate to give an oil which after column chromatography (silica/methanol) gave 2-[2-[[2-[5-(dimethylamino)methyl-2-furanylJethylJthio]-30ethyl ]-lii-isoindole-J.,3(2H)dlone as a pale oil (t».43 g). Analysis Pound: C, 61.48; H, 6.13; N, 7.63; Cl9H22NT2033.5/4H20 requires: C, 61.35; H, 6.37; S, 7.53#.

Example G 2-[ Ϊ5-(Dimethylamino)me thyl-2-furanyl)methoxy]ethanamine Route (i) Tc· a solution of 5-(dimeihylamino)methyl-2-iurtininethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydr.ofuran was added a solution of methanesulphonic acid (11.6 g) in Ιθ tetrahydrofuran (40 ml). The solution wa3 evaporated and the oily residue heated at 98-100° for 10 mins. After 18 hr, 5N sodium hydroxide (60 ml) was added andithe solution evaporated to dryness. Anhydrous sodium sulphate and ethyl * acetate (150 ml) were added and after 2 hr the suspension ! was filtered,- treated with decolourising charcoal and evaporated. The resulting oil was chromatographed on silica, firstly with methanol-ammonia 0.88 79:1, and the eluate discarded, and secondly with methanol-ammonia 0.88 19:1.

This eluate was evaporated tc give an oil 'from which-the bis20 oxalate salt of 2-[[5-(dioethylamino)methyl-2-furanyl]methoxy]ethanamine (from ethanol) 0,2 g, m.p. 125-128°, was obtained. Route (ii) A solution of 2-chloroethylamine hydrochloride (6,25 g) in dry dimethylformamide was added dropwise to a stirred, cooled ΐ solution of potassium tert-butoxide (8.9b g) and 5-(dimethyl-31· 3 -15 6 amino)methy1-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue hasified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid.

The crystalline salt was recrystallised from ethanol to give 2=[[5~(dimethylasino 'iSethyl-2-furanyljmethoxy]ethanamine, bis oxalate, m.p. 130=135° (3.05 g).

Similarly prepared by route (ii) was: (b) 2-[[5-(Methylamino)methyl-2-furan]methoxy]ethanamine, bis oxalate m.p. 162=164°. (a) 2-[4=(2-Furanyl)butylΙ-ΙΞ-i soindole-1,3(2H)-dione 2[l-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature in dry dimethylformamide overnight. The solution was poured into ice-water and the resulting white solid filtered, dried and recrystallised from chloroform/petroleum ether (b.p. 60-80°) to give 2=[4-(2=Furanyl)butyl]-lH-isoindole-i,3(2H)dione as white microcrystals (430 mg) m.p. 61=63°.

In a similar manner was prepared: (b) 2-[5-(2-Furanyl)pentyl]-lH~isoindole-l,3(2H)-dione, m.p. 54-56°.

Example 1 (a) 2 •2-f uranyl ]butyl ]-lH-322-[4-(2-Furanyl)butyl]-lH-isoindole-l,3(2H)-dione (5.38 g), paraformaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) were refluxed In absolute ethanol (100 ml). After 6 hr further paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for a further 20 hr. The solvent was removed, the residue made strongly basic with 5N sodium hydroxide, extracted with ethyl acetate and the organic layer evaporated. The crude product was purified by column chromatography to give an amber oil (3.25 g) Rf 0.4 silica/ methanol. NMR (CDCl^) 8-8.6 ffi (4F); 7.75 s (bH); 7.3 m (2H); 6,55 s (2H); 6.3 m (2H); 4.0 m (2H); 1.9-2.4 m (4H).

In a similar manner was prepared: (b) 2-[5-[5-(Dimethylamino)methyl-2-furanyl]pentyl]-lHisoindole-l,3(2H)-dione. TLC Rf 0.4 silica/methanol.

NMR 8.0-8.8 m (6H); 7.70 m (6H); 7.37 t (2H); 6.52 s (211); 6.30 t (£H); 4.0 m (2H); 2.2 m (4H).

Example J -(Pimethylamino)methyl-2-furanpropanamine Furanpropionitrile (1.21 g), dimethylamine hydrochloride (1.62 g) and paraformaldehyde (0.7 g) in ethanol (20 ml) were heated under reflux for 24 hr. Solvents were removed, the residue basified to pH 12 and extracted with ethyl acetate.

After removal of solvents the residual oil was purified by column chromatography (silica/methanol) and 5-(dimethylamino)methyl-2~furanpropionitrile isolated (0.6 g) Rf 0.55 (silica/ methanol). -334 S 4 5 ΰ The nitrile (6.0 g) in dry ether (40 ml) was added dropwise with stirring to lithium aluminium hydride (2.0 g) in ether at 0°. Addition of water, followed by removal of solvents, gave, after column chromatography, 5-(dimethylamino)methyl-2-furanpropanamine as a pale oil (3.53 g). NMR (CDCl^) 8.2 a (2H); 7.6 br (2K); 7.75 s (6H); 7.30 m (4H); 6.60 s (2H); 4.0 m (2H).

Example K 2-[3- [[[5-(Pimethylamino)iaethyl-2-furanyl]thio jpropyl]]-lHisoindole-l,5(2H)-dione Sulphur (1.9 g) was added in portions to a solution of the lithio derivative of ΚΓ,Ν-dimethylfuranmethanamine (7.5 g) at -40°. The mixture was stirred at -10° for 20 mins and 2-(3broEopropyl)lH-isoindole-l,j(2H)-dione (16 g) added. The mixture was left at 0° overnight, solvent removed in vacuo and the residue in ethyl acetate filtered and extracted with 2N sulphuric acid. The aqueous layer was basified, re-extracted with ethyl acetate and the organic phase dried. Removal of the solvent gave a crystalline solid, which recrystallised from ethanol (charcoal) to give 2-[3-[[[5-(dimethylamino)methyl-2-furanyl]thio jpropyl]]—IH—isoindole-1,3(2H)-dione (7.59 g) m.p. 64-65°.

Example L (a) 4-[g-(Bimethylamino)methyl-2-furanyl]butanamine 2-[[4~(5-Dimethylamino)methyl-2-furanyl]butyl]-lH-344 04 isoindole-l,3(2H)-dione (2.9 g) and hydrazine hydrate (0.55 ml) were refluxed in ethanol for 6 hr. Solvent was removed and the crystalline residue dissolved in 5N sodium hydroxide solution. This was extracted with ethyl acetate which on removal of solvent gave the product as a mobile yellow oil (1.68 g), TLC Silica'methanol single spot Rf 0.15. NMR (ODClj) S.0-8.8 m (4H); 7.7 s (6H); 7.6 br (2H); 7.3 m (4H); 6.58 s (2H); 4.0 m (2H).

In a similar manner were prepared from the corresponding 10 phthalimide: (b) 5-[5-(Dimethylamino)methyl-2-furanyl]pentanamine. NMR (CDCip 8.0-8.8 m (6H)j 7.75 s (6H); 7.0-7.6 m (4H); 6.60 9 (2H); 4.0 m (2H). (c) 5-[[(3-Arainopropyl) thio jmethyl]-N,N-dimethylfuran-215 methanamine. NMR (CdClj) 8-8.5 m (2H); 7.75 s (6h); 7.42 t (2H); 7.25 m (2H); 6.58 s (2H); 6.3 s (2H); 3.88 s (2H). -354 S 4 5 3 Example 1 (a) N- [2- [ [ [5-(Diiaethylaaino)methyl-2-f uranyl ]methyl ]thi o ]ethyl1-N’-methylthiourea 2-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl-lH-isoindole-l,3(2H)-dione (5.5 g) and hydrazine hydrate (0.85 g) were refluxed in ethanol for 30 hr. Evaporation of the solvent gave the phthalhydrazide salt of 2- [ [[5-(dimethylamino)methyl-2-£uranyl]methyl]thio]ethanamine.

Thia salt (l g) was suspended in acetonitrile and mothylisothiocyanate (0.21 g) added. The suspension was stirred at room temperature for 5 hr and at 60° for 2 hr, filtered and evaporated to give an oil which was purified hy column chromatography (siliea/methanol). N-[2-[[[5(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N’methylthiourea was isolated as a pale oil (0.3 g). Analysis Found: C, 49.68; H, 7.52; 14.22; ci2H21N30S2 re9uires: C, 30.14; H, 7.57? N, 14.62,4.

Similarly prepared were: (b) N-Methyl-N'1 - [2- [ [ [5- (1-pyrrolidinyl )methyl-2-furanyl ] methyl]thio]ethyl]thiourea. Analysis Found: C, 52.33; H, 7.12; N, 13.17. Cj^HgjNjOSg.fHjjO requires: C, 52.14; II, 7.50; N, 13.03#. -36484 8Q (c) N-[4-[[[5-(Dimethylamino)methyl-2-furanyljmethyljthio] butylj-N’-methylthiourea. Analysis Found: C, 51.69; H, 8.53, N, 12.83; C-^HggNgOSg requires: C, 51.82; H, 8.08; N, 12.9554. (d) ϊί-[3-[[5-(Dimethylamino )methyl-2-furanyl jthio jpropyljN’-methylthiourea. Analysis Found: C, 49.71; H, 7.33; N, 14.35. ®ΐ2Ν2ΐΝ3θδ2 re(luires: C, 50.10; H, 7.30; N, 14.62$. iO (e) N-Methyl-N’-[2-[[5-(4-morpholinyl)methyl]-2-furanyljmethyljthiojethyljthiourea. Analysis Found: C, 51.26; H, 7.08; N, 12.51. C-^HggNgOg^ re9uires! c, 51.03? H, 7.04; N, 12.75$. (f) N-Methyl-N’-[2~[[[5-[(4-methyl-piperazlnyl)methylj2-iuranyljmethyljthiojethyljthiourea. Analysis Found: C, 50.93; H, 7.74; N, 15.82. C^Hg-N^OSg requires: c, 51.25; H, 8.03; N, 15.94$. (g) N-[2-[[2-[5-(Dimethylamino)methyl-2-£uranyljethyljthiojethylj-N’-methylthiourea. Analysis Found: C, 50.19; H, 7.20; N, 13.18. requires: C, 50.32; H, 7.74; X, 13.54$. -37ΰ 4 « 6 Example 2 (a) Ν- (5- [^-(DiisethylaElnojEethyl-B-furaHyllnantyll-K1methylthiourea -[5-(Dimethylamino)methyl-2-furanyljpentanamine 5 (0.5 g) and raethylisothioeysnate (0.25 g) were stirred in acetonitrile at room temperature for 2¾ hr. Solvent was removed and the product purified by column chromatography (silica/methanol) to give after trituration with ether N-[5-(5-(dimethylsmino}isetliyX-2-furanyl]pentyl]-N'-methyl10 thiourea as off-white crystals m.p. 66-69°.

Similarly prepared from the corresponding amine and methylisothioeyanate were: (b) N- [3- [ [[5-(®imethylai2ino Jmethyl-2-furanyl]methyl]thio]propyl]-N8-methylthiourea. Analysis Found: C, 51.38; H, 7.93; N, 13.41. ^131¾¾0¾ requires: C, 51.79; H, 7.69? Ν, 13.940. (c) M-[4-[5-(Dimethylamino)raethyl-2-furanyl]butyl]-N·methylthiourea. NI-fflT(CDCl^) 8-8.6 ra (4H); 7.72 s gO (SH); 7.35 t (2H); 6.98 d (3H); 6.2-6.8 m (4H); 4.0 d (2H); 3-3.8 m (2H). (d) M-[2-[[5"(Disethylaaino)aethyl-2-£uranyljmethoxy]ethyl] N’-methylthiourea. Analysis Found: G, 51.91; H, 8.14; Ν» 14.98. C12H21N302S.|H20 requires: C, 51.40; H, 7.91; K, 14.990. -38t* ΰ ·1 β ΰ Example 3 (a) Ν-[2-Γ[Γ5-(Dimethylamino)me thyl-2-furanylJmethyl ]thio ]e thyl1-N1-(2-me thoxyethyl)thiourea l-(lsothiocyanato)-2-methoxyethane (1.17 g) and 2[[[5-(dimethylami5 a)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) in acetonitrile were stood overnight. Solvent was removed and the residual oil chromatographed (siliea/methanol) to give N-[2-[[[?-(dimethylamino)methyl2-furanylJmethyl]thio]ethyl]-N’-(2-methoxyethyl)thiourea as a pale oil Rf 0.45. Analysis Pound: C, 50.64; H, 7.51; N, 12.58. Cl4H25N3O2S2 requires: C, 50.75; H, 7.55; N, 12.69#.

Similarly prepared from the corresponding isothiocyanate and 2—[[[5-(dimethylamiiia)methyl-2-furanylJmethyl]thio]15 ethanamine were: (h) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N’-(2-propenyl)thiourea. Found: C, 52.68; H, 7.58; N, 13.16. C1J^H23N30S2.iH20 requires: C, 52.14; H, 7.50; Ν» 13.03#. (c) N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N-(l-methylethyl)thiourea. Analysis Found: G, 51.84; H, 7.88; N, 13.00. requires: C, 51.90; H, 8.09; N, 12.97#. -39' fi 3 4 3 ό Example 4 Μ- [2- [ [ [g- (Methylamino )methyl-2-furarayl Imethyl jthio jethyl ]N’-methylurea To a stirred solution of 2-[[[5-(sethylamino)metliyl-2furanyl jme thyl jthio jethanataine (1.5 g) in acetonitrile (24 ml) was added dropwise a solution of methylisocyanate (0.45 g) in acetonitrile (15 ml). After 30 mins the solution was evaporated to dryness to give an oil which was column chromatographed firstly on silica/methanol: 0.88 ammonia 79:1 then aiumina/methanol to give an oil consisting of N-[2-[[[5-(taethylamino)methyl-2-furanyljmethyljthiojethylj-N‘-methylurea (0.25 g). Analysis Found: C, 51.00; H, 7.38; Ν» 15.91. Ο^Ν^Ν^Ο^ requires: C, 51.335 H, 7.44; N, 16.53½. (a) [2-[[[g-(Bimethylamino)methyl-2-furanyljmethyljthio]Methylisocyenate (0,33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyljmethyljthiojethanasiineo phthalhydraside complex (2 g) in acetonitrile (50 ml). After 2 hr the solution was filtered and the filtrate evaporated to give an oil which was purified by column chromatography (silica/methanol) to give N-[2-[([520 -40* 3 -J 5 ΰ (dimethylaminoJmethyl-2-furanylJmethylJthio]ethylJ-N·methylurea. Analysis Found: C, 52.38; H, 7.61; N, 15.25.

C12H21N3°2S-|H2° re1uires* c> 52.24; H, 7.76; N, 15.32%. Similarly prepared was: (b) N-Methyl-N'-[2~r[[5"(l"Pyrrolidinyl)i»ethyl-2-furanyl]met-hyiJthioJethylJuea. Analysis Found: C, 54.70; H, 7·33; N, 14.07. C^HgyNyigS.iHgO requires: C, 54.87; H, 7.89; N, 13.71%.

Example 6 (a) Ν-Γ2-Γ[r5-(Diaethylaaiino)gethyl-2-furanyl1methyl]" thio1e thyl~1 —N1 — f1-methylethyl)urea 2-EEC 5-(Dimethylamino)methyl-2-furanylJmethyl]thioJethanamine (2.14 g) and isopropylisoeyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. Solvents were removed and the residue recrystallised from methanol:ether to give N-[2-[[[5-(dimethylamino)methyl2-furanylJmethylJthioJethyl-N’-(l-methylethyl)urea as crystals m.p. 65-67° (2.8 g).

Similarly prepared were: (b) N-[3-[[[5-(DimethylaminoJmethyl-2-furanylJmethylJthioJpropylJ-N'-methylurea m.p. 69-69.50.

Example 7 N~[2-[[[5-(Dimethylamino)methyl-2-furanylJmethyl]thio]ethylJurea A solution of 2-[[[5-(dimethylamino)methyl-2-furanylJ-414 5 4 5 3 methyl]thio]ethanamine dihydrochloride (2.8 g) and potassium cyanate (3,75 g) in water (50 ml) was heated on a steam hath for 8 hr. Excess solid sodium carbonate was added and organic material continually extracted with diethyl ether. The extracts were evaporated and the residue after column chromatography yielded N-[2-[[[5-(diraethylam±no)methyl-2-fura»yl]methyl]thio]ethyljurea as a waxy solid (1.28 g). Analysis Pound: C, 48.22; H, 7.50; N, 15.61. (L^&j^NjOgS.HgO requires: C, 48.00; H, 7.65; N, 15.27#.

Example 8 Ν-[2-ΓΓί5-(Dimethylamino)methyI-2-furanylImethyl1thio1ethyl]-N8-nitroRuamidine A solution of 2-[[[5-(fiimethylamino)methyl-2-furanyl]15 methyl]thio]ethanamine (2.14 g) and S-methyl-N-nitroisothiourea (1.5 g) in ethanol (10 ml) was heated to 40° for 5 mins.

The resulting precipitate was filtered and recrystallised from ethyl acetate and petroleum ether b.p. 80-100° to give N-[2-[[[5-(dimethylamino)aethyl-2-furanyl]methyl]20 thio]ethyl]-N’-nitroguanidine m.p. 103-104°.

Example 9 (a) N-Oyano-N1-[2-[[[5-(methylamino)methyl-2-furanyljmethyljthio]ethyl]-N11-aethylguaaidine A mixture of 2-[[[5-(methylamino)methyl-2-iuranyl]25 methyl]thio]ethanamine (2.0 g) and N-cyano-N’-methylcarbamimido -42thioic acid, methyl ester (1,25 g) was heated on a steam hath for 6.5 hr. Vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography Rf 0.65 (silica/methanol:ammonia 79:1) tc give N-cyanc-N'-[2-[[[5-(methylamino)methyl-2furftnyl]methyl]thic.ethyl]-N'’-methylguanidine (1,05 g) m.p. 81-85°.

In a similar manner were prepared from the corresponding amine and N-cyana-N’-raethylcarbamimidothioic acid, methyl ester: (b) N-Cyano-N1-[2-[[[5-(l-metfcylethyl)amino]methyl-2furanylJmethylJthioJethyl]-N*'-methylguanidine. Analysis Found: C, 54.73; H, 7.82; N, 22.31. Cj^H^N^OS requires: C, 54.34; H, 7.49; N, 22.64%. i5 (e) N-0yano-N'-[2-[[[5-(diethylamino)methyl-2-furanylJmethylJthioJethyl]-N-methylguanidine. Analysis Found: C, 53.54; H, 7.82; N, 20.65, Cj^Hg-NjOS.^O requires: C, 53.46; H, 7.70; N, 20.78%. (d) N-Cyano-N'-[2-[[[5-(l-pyrrolidinyl)methyl-2-furanyl]methyl Jthio Jethyl J-N-raethylguanidine. Analysis Found: C, 53.97; H, 6.875 N, 21.06. CjgHg^OS.^IgO requires: C, 53.79; H, 7.37} N, 20.91%. -434 S 4 6 6 (e) N-Cyano-N'-[3-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thioJpropyl]-N'•-methylguanidine. Analysis Found: C, 52.86; H, 7.49; N, 20.64; ci4H25N50S,"H2° requires: C, 52.80; H, 7.59; N, 21.200.

Example 10 N-Cyano-N*-[2-[[[5-(dimethylamino)methyl-2-furanyl]methylj•thloletfayll-.N1 '-me thyl guanidine To a stirred suspension of potassium carbonate (20.7 g) in a solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyljthio]ethanamine (10.7 g) end N-cyano-N'-methylcarbamiaidothioie acid methyl ester (7.1 g) in acetonitrile (107 ml) at 70° was added a solution of silver nitrate (9.35 g) in acetonitrile (20 ml) during 1 hr. The mixture was stirred for 16 hr, the solid filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml). A portion of this (10.5 ml) was washed with water (6 ml), the ethyl acetate layer evaporated to give a solid which was crystallised from isopropylacetate (1.75 ml) giving N! ’-cyano-N- [2- [[[5-= (dimethylaminoiaethyl)-2-furanyl ]methylJthiojethylj-N'-methylguanidine (0.35 g) m.p. 79-81.5°.

To a further portion (225 ml) was added a solution of sehacic acid (9.09 g) in ethanol (30 ml), the filtered solution giving the sehaeate salt (13.74 g) m.p. 92.5-94°. Analysis Found: C, 54.91; K, 7.94; N, 14.02. C-^Hg^OS. C10H18°4 re«uires: G> 55.51; H, 7.90; N, 14.070. -44,,3 4 b ό Example 11 N-Cyano-N(2-methoxyethyl )cax'bamimjdothioic acid, methyl ester Powdered cyanamide (4.2 g) was added to a stirred solution of sodium (2.3 g) in absolute ethanol. After 30 mins a solution of methoxyethyl isothiocyanate (11.7 g) in absolute ethanol was added V the cooled solution. After a further hour at room temperature dimethyl sulphate (12. 66g) was added over 30 mins and the mixture stirred overnight.

The solvent was removed and remaining solid washed well with water to give N-cyano-Ji'-2(methoxyethyl)earbamimidothioic acid, methyl ester as a white crystalline solid (12.37 g) m.p. 94.5-95.5°.

Similarly prepared was: N-Cyano-N'-(2-propenyl)carbamimidothioic aeid, methyl ester, m.p. 100-110°. (d) K-Cyano-H*-[2f;j 5-(dimet,hylamino)methyl-2-furanyl1methyljthlolethyl]-N>'-(gxnethoxyethyl)guanidine A mixture of 2-[[[5-(dimethylamino)methyl-2~furanyl]methyl]thio]ethanamine (2.14 g) and N-cyano-N'-(2-methoxyethyl)carbamimidothioic acid, methyl ester (1.73 g) was heated on a steam bath for 6.5 hr. Vacuum was applied occasionally to remove methanethiol. The crude product was purified by chromatography (silica gel/methanoj) to give N-cyano-N’[2-ί[[5-(dimethylamino)methyl~2"furanyi]methyl]thio]ethyl]-N, (2-methoxyethyl)guanidine (l.4 g). Analysis Found; G, 50.51; -454 G 4 Β 6 Η, 7.20; Ν, 19.41, CjgHg^N^OgS.HgO requires: C, 50.42; Η, 7.50; Ν, 19.600.

In a similar manner were prepared from 2-[[[5-(dimethylamino)-methyl-2-furanyl]methyl]thio]ethanamine and the corresponding N-alkyl-N’-cyanocarhamimidothioic acid, methyl ester: (h) N-Cyano-N·-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio ]ethyl]-N'*-(2-propenyl)guanidine.

Analysis Found: C, 53.33; H, 7-01; N, 20.70, C^H^N^OS.HgO requires: C, 53.θ9; H, 7.37j N, 20.640. (e) N-Cyano-N’-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-Ν’'-(l-Eethylethyl)guanidine.

Analysis Found: C, 52.97; H, 7.70; N, 20.57.

C15H25N50S H20 requires: C, 52.78; H, 7.91; N, 20.520. Example 12 (a) N-[2-[[[5-(Dimethylamino)methyl-2-furanylImethyl1thio]ethyl]-N1-methylguanidine A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethansHine (2.14 g) and N,S-dimethylisothiouronium iodide was heated on a steam hath for 3 hr. The residue in methanol was eluted from an Amherlyst A26 (Amberlyst is a Registered Trademark) ion exchange resin to give N-^/7/5(dimethylamino)methyl-2-furanyl/-methyl/thio7ethyl7-N'methylguanidine as an amber oil -46·» 3 ·3 ΰ ό (1.5 g). Analysis Found: C, 50.92; Η, 8.23; Ν, 19.90. Cl2H22N40S,liI20 reQulres: C, 50.76; Η, 8.34; N, 19.74%.

Similarly prepared were: (h) N-[2-C[[5—(Dimethylamino)methyl-2-furanylJmethylJthio J5 ethyl]~N’,N·*-dimethylguanidine. NMR (CDCl^) 7.75 s (6h); 6.8-7.3 m (8H); 6.5 m (4H); 6.22 s (2H); 3.80 m (2H); 2.0-3.5 hr (2H).

Example 13 N-Methyl-l-methylthio-2-nitroethenamine A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 33% ethanolic metliylamine in 0.8 litres of ethylene diehloride; 0.9 4 mole) was added over 5i hr at 70° to a stirre.d solution of l,l-hismethylthio-2-nitroethene (99.0 g, 0.6 mole) in ethylene diehloride (1.5 litres). The solution was heated to boiling and 0.7 litres of solvent were distilled off. The cooled solution was washed with 2N hydrochloric acid (0.25 litres), then with brine (0.25 litres), The solvent was removed and the residue crystallised from isopropyl acetate (0.5 litres), treating the hot solution with charcoal (10.0 g). The product (35.0 g) formed yellow prisms, m.p. 114°.

N- [2-[ [ [5-(Methyl amino)methy1-2-furanylJmethylJthio JethylJN*-methyl-2-nitro-l,l-ethenediamine hydrochloride A solution of 2-[[[5-(methylamino)methyl-2-furanylJ25 methylJthioJethanamine (10 g, 0.05 mole) and N-methyl-1-474 3 4 5 3 methylthio-2-nitroethanamina {7.4 g) in water (25 ml) was stirred at 50° for 2 hr. Acetone (350 ml) was added and the solvent was removed by distillation at atmospheric pressure until 275 ml of distillate had been collected.

Ethanolic hydrogen chloride (2M; 27.5 ml) was added to the residue and the solution was stirred overnight at room temperature. The product (11.0 g) m.p. 161°, was collected and recrystalUsed from ethanol as a colourless microcrystalline solid (10.1 g) m.p. 162°. Analysis Pound: C, 42.6; H, 6.3; N, 16.4. Ο,ρΐ^θΝ^Ο^β.ΗΟΙ requires: C, 42.8; H, 6.2; N, 16.6#.

Example 14 (a) N-1~2- [ [ f 5-(Methylamino)saethyl-2-f uranyljmethyl3thiojethyl 3-N,-aethyl-2-nitro-l., 1-ethenediaaine A mixture of 2·· [[[5- (methylamino )methy 1-2-furanyl ]methyl]thio]ethanamine (0.9 g) and N-methyl-l-methylthio2-nitro-etheneamine was heated at 100-120° for 30 mins under water pump pressure. The residue was purified by column chromatography (silica/nethanol:0.88 ammonia) to give N-[2-[[[5°· (methylamino)Eethyl-2-furanyl]methyl]thio]ethyl3-N·-methyl-2-nitro-l,1-ethenediamine whi ch was crystallised from acetonitrile m.p. 106-108° (Ο.65 g).

In a similar manner were prepared: (b) M-[2-[[[5-[(l-Methylethyl)amino]methyl-2-furanyl]25 methyl]thio jethyl]-N’-Eiethyl-2-nitro-l,1-ethenediamine. -48- . 1 . -.U,·, /- ,.0t _;* ( xy no j 2 requires: C, 57.12; ti, 6,81; N, 14.02%. (dj N-Methyl-2-nitro-N’-[2-[[[5-[(1-piperidinylJmethylJ-2furanylJmethylJthio JethylJ-l,1- ethenediamine. Analysis Found: C, 53.36; H, 7.51; N, 14.23. ^26^3^5¾0 requires: C, 53.33; H, 7.44; N, 15.61%. (e) N-[2-[[[5-[2-[Dimethylamino JethylJ-2-furanylJmethylJthio JothylJ-N'-methyl-2-nitro-1,1-ethenediamine, m.p. 95.5-96°. (f) N-[2-[[[5-[3-[DimethylaminoJpropyl]-2-furanylJmethylJthioJethylJ-N’-methyl-2-nitro-1,1-ethenediamine. NMRT (CDCl^J, 8.1-7.1 m (6H); 7.65 s (6hJ; 7.1 s (3H); 6.5 m (2H); 6.28s (2H); 4.0 m (SH); 3.38 s (lHj. (gj N-[2-[[[5-[4-[Dimothylamino]butylJ-2-furanylJmethylJthioJethylJ-N-methyl-S-nitro-1,1-ethenediamine. Waxy solid analysis found: C, 53.90; H, 7.95; N, 15.64. C^H^N^S requires: C, 53.91; H, 7.92; N, 15.72%. -494 S 4 5 ϋ (h) N-[2-[[[5-(Ethylmethylamino)methyl-2-furanyljmethyl ]thio]ethylj-Ν'-methyl-2-nitro-l,l-ethenediamine.

NMR X (CDCL3) 8.90 t (3H); 7.76 s (3H); 6.8-7.5 m (7H); 6.5 hr (2H); 6.42 s (2H); 6.25 s (2H); 3.77 s (2H); 3.35 s (IH). (i) N-[2-[[[5-[[2-(dimethylamino)ethyljaminojmethyl-2furanyljmethyljthiojethylj-N’-methyl-2-nitro-l,l-ethenediainine. NMR-ciCBCl^) 7.79 s (6h); 7-7.6 m (lOH); 6.6 m (2H); 6.26 s (2H); 6.22 s (2H); 3-85 m (2H); 3.37 s (IH); 2-3.2 hr (IH); 0,8-0.2 hr (lH). (j) N-[2-[5-(Dimethylamino)methyl-2-furanylmethoxyjetl5rljN,-Enethyl-2-nitro-l,l-etheaeaiamine5 m.p. 110-112°.

Example 15 N-1.2-Γ Γ Γ 5-(Dimethylamino)methyl-2-furanyljmethyl1thio1ethyl1N1-methyl-2-nitro-l„1-ethenediamine N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45-50°. 2-[[[5-(Dimethylamino) methyl-2-furanyljmethyljthio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 3a hr. The solution was then heated at reflux for | hr, cooled to 70° and 4-methylpentan-2-one (2 litres) added. The water lias removed hy azeotropic distillation under reduced pressure (260 torr) -50434: and the resultant solution treated with charcoal (10 g) at 50°. The solution was filtered and cooled to 10°.

N-[2-[[[5-(dimethylamino)methyl-2-furanylJmethylJthio]ethylJ-Ν’-methyl-2-nitro~l,1-ethenediamine (380 g) was filtered off and dried m.p. 69-70°.

Example 16 ji-Methyl-2-ni tro-N* -[2-[[[5-[(l-pyrrolidinyl)methyl]-2furanylJmethylJthio JethylJ-l,1-ethenediamine A mixture of 2-[[[5-(l-pyrrolidino)methyl-2-furanylJmcthylJthioJethanamine his oxalate salt (2.1 g), potassium hydroxide (1.12 g) and N-methyl-(l-methylthio)-2-nitroethenamine (0.9 g) in water (9 ml) was stirred at room temperature for 18 hours. The water was removed by evaporation under reduced pressure and the residue extracted with i ethyl acetate in the presence of excess anhydrous sodium carbonate. Evaporation of the solvent gave a residue which was crystallised from isopropyl acetate as a white crystalline ( solid (0.9 g) m.p. 79-82°. Analysis Found: C, 52.78; 1 H, 7.05; N, 16.57. C15H24N403S requires:’ C, 52.92; H, 7.11; N, 16.46$. ' ‘ 1 Example 17 · N-[2-[[[5-(Methylaaino)methyl-2-furanylJmethylJthio Jethyl]i N'-methylurea To a stirred solution of N-[2-mercaptoethyl3-N'-me,thylΪ urea (2,0 g) in concentrated hydrochloric aeid at 0° was . i -51Δ a 4 5 ΰ ΙΟ added dropwise a solution of 5-(methylaiaiiio)methyl-2-furanmethanol (2.0 g) in water (3 ml). After 24 hr, ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added.

The suspension was filtered, the filtrate evaporated to dryness and the oily residue column chromatographed (silica/ methanol;0.88 ammor.'.a 79:1). Ths relevant eluate was evaporated, to dryness to give an oil identical to product of Example 4 (0.42 g).

Example 18 N-Cyano-N1- [2- [ [ [5-(diiaethylamino)methyl-2-furanyl Imethyl ]thio]ethyl]-N·*-methylgaanidine To a stirred solution of N-cyano-N·-{2-mercaptoethyl)N!’-methylguanidine (l g) in concentrated hydrochloric acid at 0° was added 5-(dimethylaHino)-2-furanmethanol (0.98 g) dropwise Suring 10 Eins. After 3 hr, at room temperature, the solution was neutralized with excess anhydrous sodium carbonate and the resultant solid extracted with ethyl acetate. Evaporation of the solvent gave an oil, which after column chromatography yielded a product identical with the compound of Example 10.

Example 19 N-(2-[[5-(Aminomethyl)-2-furanylnethyl]thio]ethyl]-N'»2-(5-GhloroEethyl-2-furanyImethyl)-lH-isoindole-l,5-(2H)-dione 2-(5-Hydroxymethyl-2-furanyImethyl)-IH-isoindole-l,3(26)52.43 4 Β 6 dione (10 g) was dissolved in thionyl chloride (15 ml) with the aid of gentle heat. The solution was evaporated to dryness and the solid residue re-evaporated with cyclohexanebenzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-ehloromethyl~£-furanylmethyl)-lH-isoindole-l,3(2H)dione (10.1 g) m.p. 119-122° (dec,). Analysis Found: C, 61.32; H, 3.71; N, 5.00. 014Ηχθ01Ν0^ requires: C, 60.99; H, 3.66; N, 5.08%. iC N1*-Cyano-N-[2-[[5-ί(1,3-dioxo~2H-isoindol-2-yl)methyl1-2furanylmethyl}thio jethylJ-N'-methylguanidine To a stirred solution of N1’-cyano-N-(2-mercaptoethyl)N'-methylguanidine (1.0 g) and sodium hydride (0.152 g) in dry dimethylformamide (4 ml) at room temperature was added slowly a solution of 2-(5-chloromethyl-2-furanylmethyl)-lHisoindole-l,3(2H)-dione (1.74 g) in dry dimethylformamide (8 ml). After stirring for 2 hr in the solution was evaporated to dryness and the oily residue suspended in an ethyl acetate (25 ml)-water (20 ml) mixture. The solid residue was filtered and crystallised from methanol to give the title compound (1.4 g) m.p, 179-182°.

N-[2-f[5-(Aminomethyl)-2-furanylaethylJthio]ethylJ-N1'cyano-Ν'-methylguanidine A suspension of Ν»»-cyano-N-[2-[[5-[(l,3-dioxo-2H25 isoindol-2-yl)methylJ-2-furanylmethylJthioJethylJ-N'-methyl-534S456 guanidine (4.45 s) an& hydrazine hydrate (0.6 g) in methanol (35 ml) was heated under reflux for 4 hr. The suspension was evaporated to dryness, the residue dissolved in water (15 ml) at 0° and neutralised with 5N hydrochloric aeid.

The suspension was filtered, excess anhydrous sodium carbonate added.,and the solution evaporated to dryness. The residue was mixed with anhydrous sodium sulphate and the solid mass extracted with ethanol. Evaporation of the extract gave a semi-solid which was mixed with anhydrous sodium sulphate and extracted with ethyl acetate to give an oil (2.12 g) which was column chromatographed (silica/raethanol:0.88 ammonia 79:1). Evaporation, of the relevant eluate yielded an oil which slowly solidified consisting of the title compound (1.8S g) m.p. 80=82°. Analysis Pound: C, 49.57; H, 6.66; N, 25.93. requires: C, 49.41; H, 6.41; N, 26.200.

Example 20 N-[2-[j~[5-(Dimethylamino)methyl-2°furanyljmsthyl]thio]etfayl]N1-methyl-2-nitro-l„1-ethanediaaine 2-Nftromstfrylene thlaaolidirie A mixture of oysteamine hydrochloride (H.36 g), potassium hydroxide (5.61 g) and l,l-bis(methylthio)-2-nitroethene (16.52 g) in water (30 ml) and ethanol (100 ml) was heated -54. 4S453 under reflux for 1 hr. The suspension was evaporated to dryness, the residue suspended in water, filtered and the residue crystallised from methanol to give 2-nitromethylene thiazolidine (9.2 g) m.p. 141-142°. Analysis Pound; C, 32,91; H, 4.13; N, 19.10. C^HgNgOgS requires: C, 32.87; H, 4.14; N, 19,17#.

N-(2-Mercaptoethyl)-N1-methyl-2-nitro-l,1-ethenediamine A solution of 2-nithromethylene·thiazolidine (5 g) in a solution of methylaaine 33# in ethanol (40 ml) was kept at room temperature for 65 hr. The solid which separated was filtered, washed with ethanol and dried to give N-(2-mercaptoethyl)-N'-methyl-2-nitro-l,l’-ethenediamine (4.98 g), m.p. 174-175°, decomp. 209-211°.

Analysis Found: C, 34.05; H, 5.87; N, 23.85. C5HiiN3°2S require C, 33.88; H, 5.26; N, 23.71%.

N-[2-Π Γ5-(Dimethylamino)methyl-2-furanyljmethyljthio]ethyl]N1-methyl-2-nltro-1,1-ethenedlamine N-(2-Mercaptoethyl)-N’-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (2 ml) was added dropwise to 5-(dimethylamino)methyl-2-furanmethanol (428 mg) at 0°. After standing at 0° for 7 days the reaction was diluted with water (3 ml), excess potassium carbonate was added and the solid extracted with ethyl acetate (50 ml).

The solvent was evaporated and the residue purified by preparative layer chromatography to give the title compound >55— 4S156 (100 mg) as Example 15.

Example 21 N-[2-f[[5-(Dimethylamino)methyl-2-furanyljaethyl]thio]ethyl]N8-methyl-2-nitro-1,1-ethenediamine N,N-Dimethyl-2-furanmethanamine (125 mg) was dissolved in glacial acetic acid (l ml) and paraformaldehyde (30 mg) added. A solution of N-(2-mercaptoethyl)-N'-methyl-2-nitro151-ethenediamine (354 mg) in concentrated hydrochloric acid (l ml) and glacial acetic acid (1 ml) was added dropwise and 3.0 the mixture left to stand, at roam temperature for 5 days.

The solution was diluted with water (30 ml), saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were purified by preparative layer chromatography to give the title compound as Example 15 (89 mg).

Example 22 N-0yano-Na-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethylj-Ν''-methylguanidine N-Cyano-N!-Γ2-Γ Γ Γ5-(dimethylataino)methyl-2-furanyl]methyl ]ithio]ethyl]carbamlmidothioic acid, methyl ester 2-[[[5-(Diaethyiamino)methyl-2-furanyljmethyl]thio]ethanamine (1.07 g) was added to a solution of N-cyanoimidocarhamodithioic acid, dimethyl ester (0.75 g) in ether, and stirred overnight. The crystalline solid which formed was filtered, washed with ether and dried to give N-cyano-N'25 [2-[[[5-(dimethylamino)aethyl-2-furanyljmethyl]thio]ethyl]-56»S456 earbamimidothioic acid, methyl ester (1.14 g) m.p. 78-79°. N-Cyano-N1-[2-f[[5-(dimethylamino)methyl-2-furanylJmethyl]thio JethylJ-N11-methylguanidine A solution of N’-cyano-N-[2-[[[5-(dimethylamino)methyl-2furanylJmethylJthioJsthylJcarhamimidothioic acid, methyl ester (1.06 g) in ethanolio Diethylamine 33% (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetatelight petroleum (b.p. 80-100°) to give the title compound m.p. 77-80°.

Example 25 N-Cyano-N1-[2-[ f [5 — (dimethylamino)methyl-2-furanylJmethylJthioJethylJ-N1'-heptylguaaidine A mixture of heptylamine (1.15 g) and N-cyano-N'-[2[t[5-(dimethylamino}reethyl-2-furanylJmethylJthio JethylJcarbamimidothioic acid (3.12 g) was heated on an oil bath for 12 hr at 100°. The product was chromatographed (silica/ methanol) to give N-cyano-N'-[2-[[[5-dimethylamino)methyl2-furanylJmethylJthioJethylJ-N"-heptylguanidine hydrate (2.31g) Rf 0.49. Analysis Found: C, 56.99; H, 8.32; N, 17.53.

C19H33N50S.H20 requires: C, 57.43; H, 8.81; N, 17.63%.

Example 24 W-[2-[[[5-(Dimethylamino)methyl-2-furanylJmethylJthio Jethyl]N1-methyl-2-nitro-1,1-ethenediamine 2-[[[5-(Dimethylamino Jmethyl-2-furanylJmethylJthio J-57ethanamine (4.25 g) anti l,l-bis(methylthio)-2-niiroethene (5.3 g) were refluxed in acetonitrile (5θ ml) for 14 hr. Solvent was removed and the residue dissolved in 36$ methanolic methylamine (50 ml) and the solution refluxed for 8 hr. Solvents were removed and the residue in methanol treated with charco -.1, Filtration and evaporation of the solvent gave the title compound as Example 15 (5.0 g). (a) N-[2-[[[5-(Dimethylamino)methyl-2-furanylJmethylJthio110 ethylJ-N8~(2-methoxyethyl)-2-ni tro-'l „ 1-ethenediamine 2-[[[5-(Dimethylamino)mothyl-2-furanylJmethylJthio]ethanamine (2.14 g) and l,l-bis(methylthio)-2-nitroethene (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine X5 (Ο.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2furanylJmethylJthio JethylJ-U8=(2-methoxyethyl)-2-nitro-l,1ethenediamine (1.0 g). NMRT(CDCl^) 7.73 s (6H); 7-7.5 m 20 (2H); 6.2-7 m (UH); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).

Similarly prepared was: (b) N-[2-[[[5-(Dimethylamino)methyl-2-furanylJmethylJthio JethylJ-2-nitro-l,1-ethenediamine, m.p. 100-101°. ,58j S 4 £> ΰ Example 26 (a) N-[4-[5-(Dimethylamino)methyl-2-furanyljbutyl3-K1-methyl2-nitro-l,1-ethenediamine 4-[5-(Dimethylamino)methyl-2-furanyl]hutanamine (0.7 g) and l,l-bis(thiomethyl)-2-nitroethene (0.6 g) in acetonitrile (12 ml) were refluxed for 22 hr. Solvent was removed and the residue in 330 ethanolie methylamine refluxed for 2 hr. Solvents were removed and the residue purified hy column chromatography (silica/methanol) to give N-[4-[5-(dimethylamino )methyl-2-furanyl]butyl]-N’-methy1-2-nitro-1,1-ethenediamine (310 mg). Analysis Found; C, 55.54; H, 8.23; H, 17.75. Cl4H2ftN403.iH20 requires; C, 55.26; H, 8.22; N, 18.420.

Similarly prepared were: (b) N-[5-[5-(Dimethylamino)methyl-2-furanyl]pentyl]-N’methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 56.76; H, 8.36; N, 17.37. ci5H26N4°3^H2° re4uircs: C, 56.43; H, 8.46; N, 17.550. (c) N-[3-t[5-(Dimethylamine)methyl-2-furanyl]thio]propyl]N’-methyl-2-nitro-1,1-ethenediamine. Analysis Found: G, 49.36; H, 7.19; N, 17.45. C13H22N403S requires: C, 49.66; H, 7.05; N, 17.840. (d) N-[3-[5-(Dimethylamino)methyl-2-furanyl]propyl]-N’-594 545 6 methyl-2-nitro-1,1-ethenediamine. Analysis Found: C, 55.09; H, 7.84; C^HggN^O^ requires: C, 55.31; H, 7.72#. (e) N- [2- [ [ [5-(Methylamino) methyl-2-furanyljmethyl2)thi5l-®thenediamine. Analysis Found: C, 51.58; H, 7.44; ΐί. 15.66. °igH26N4°3S'^H20 requires: C, 51.26; H, 7.74; N, 15.94#. (f) N"L3[[[5-(Dimethylamino)methyl-2-furanyljmethyl]thio]propyl]-N,=methyl-2-nitro-l,l-ethenedieaine. Analysis Found: C, 49.57; H, 7.20; Ν, X5.59. C^H^N^S.I^O requires: G, 49.86; H, 7.47; N, 16.61#.

Example 27 (a) N-Cyano-N8*-[4-[5-(dimsthylamino)methyl-2-furanyljbutylj;g 4-[5-(Dimethylamino)methyl-2-furanyljbutanamine (0.4 g) and N-cyanoimidocarbemodithioic acid, dimethyl ester (0.3 g) were stirred in ethanol at room temperature for 3 hr. A solution of 33# methylaaine in ethanol was then added and the mixture heated under reflux for 2 hr. Solvent was removed under reduced pressure and the product purified by column chromatography (siliea/methanol) to give the product as a pale yellow oil. HfaTiCDCl-) 8-8.5 br (4H); 7.77 s J (6H); 6.61-7.5 a (9H); 4.0 m (2H); 2.8-3.7 m (2H). -60ά ΰ 4 ΰ 6 In. a similar manner were prepared: (b) N-Cyano-N’-[5-[5-(dimethylamino Jmethyl-2-furanyljpentyl]Ν'-methyl guanidine. NMRt(CDCl5) 8.0-8.7 hr (6h); 7.68 s (6h); 7.32 t (2H); 7.10 d (3H); 6.7 q (2H); 6.48 s (2H); 3.8-4.3 m (4H).

Example 28 (a) N-[2-[[[5-(Dimethylamino)methyI-2-furanyljmethyljthio]ethyl j-N'-methanesulphonyl-N''-methylguanidine Methanesulphonyliminodithiocarhamie acid, dimethyl ester IG (1.9 g) and 2-[[[5-(dimethylamino)methyl-2-furanyljmethyljthioethanamine (2.14 g) were stirred in ethanol at room temperature for 3 hr. 33½ Ethanolie methylamine (20 ml) was added and the whole heated under reflux for 16 hr. The product was purified hy column chromatography (silica/methanol) to give N-[2-[[[515 (dimethylamino Jmethyl-2-furanyljmethyljthio jethyl]-N'methanesulphonyl-N''-methylguanidine as a pale oil (2.7 g). Found: C, 43.54; H, 7.05; N, 15.48. Ο^Η^Ν^Ο^.ΙΒ^Ο requires: C, 43.70; H, 7.00; {{,15.69½.

Similarly1prepared was: (h) N-Benzenesulphonyl-N'-[2-[[[5-(dimethylamino)methyl2-furanyljmethyljthio jethylj-Ν''-methylguanidine. Analysis Found: C, 50.30; H, 6.25; N, 12.93. C18H26N4°3S-H20 requires: C, 50.47; H, 6.54; N, 13.08½.

Example 29 N-Cyano-N*-[2-Γ Γ Γ5— (dimethylamino)methyl-2-furanyljmethyljthio jethyl]-N1'-methylguanidine -61A solution of silver nitrate (8.25 g) in dimethylformamide (50 ml) was added dropwise to a solution of N-cyano-N*-methylearbaminidothioie acid, methyl ester (6.1 g), triethylamine (4.8 g) and 2-[[[2-furanylJmethylJthioJethanamine (?»8 g) in methanol (150 ml). After 42 hr at 50° the mixture was filtered and th·. filtrate evaporated. The residue was partitioned between ethyl acetate and water. The organic layers were dried and evaporated to give an oil which yielded crystalline N-6yano-N1-[2-[[[2-furanylJmethylJthioJethylJ2,0 Ν'’-methylguanidine (3.9-g) m.p. 78-82°.

A solution of this amine (4.5 g), dimethylamine hydrochloride (3.1 g) and 36% aqueous formaldehyde (3.16 g) in ethanol (20 ml) was heated at 50° for 60 hr. The residue was partitioned between etSiyl acetate and aqueous base.

The organic extracts were combined, dried and evaporated to give an oil which on treatment with sebacic acid in isopropanol gave the sebacic acid salt of the title compound (2 g) m.p. 93-94°.

Example 30 N-[2-Γ Γ Γ5-(Dimethylamino)methyl-2-furanylJmethylJthio Jethyl]N> -methylthiourea Carbon disulphide (1.52 g) was added with stirring to a cooled solution of sodium hydroxide (0.8 g) in water (1.7 ml). 2-[[[5-(Dimethylamino)methyl-2-furanylJmethylJthio Jethanamine (4.28 g) was added slowly and when addition was complete the -62ά ΰ «1 ΰ 3 mixture heated at 100° for 2 hr. After cooling to below 40° ethyl chloroformate (1.94 ml) was added and stirring continued for a further 30 mins. The lower thick yellow oil was extracted with chloroform, dried and evaporated to give NjN-dimethyl-5-[[[2-iisothiocyanato)ethyljthio jmethyljfuranmethanamine as an oil RF 0.43 (siliea/methanol).

The crude isothiocyanate (0.46 g) was dissolved in 330 ethanolic methylamine (25 ml), left to stand overnight and N-[2-[C[5-(dimethylamino)methyl-2-furanyljmethyljthiojethyl]— N*-methylthiourea isolated as a pale oil (0.16 g) identical to material prepared from 2-[[[5-(dimethylamino)methyl-2furanyljmethyljthiojethanamine and methyl isothiocyanate.

Example 31 N-Cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methylj15 thio jethyll-N1'-metfry tguanidine A solution of N-[2-[[[5~(dimethylamino)methyl-2~furanyljmethyljthiojethyl]-N'-methylthiourea (1.3 g) was heated at reflux with lead cyanamide (1.5 g). The solution was filtered and the filtrate evaporated. Treatment of the residue with a solution of sebacie acid in isopropanol gave the title compound as its monosebacate salt (0.7 g) m.p. 90-92°.

Example 32 N-[2-[[f5"(Dimethylamino)methyl-2-furanyljmethyl]thiojethyljNt-methyl-2-nitro-l,l-ethenediamine hydrochloride N-[2-[[[5-(Dimethylamino)methyl-2-furanyljmethyl]thio jethyl -63¢,2436 N’-methyl-2-nitro-l,1-ethenediamine (50 g, 0.16 mole) was dissolved in industrial methylated spirit 74° o.p. (200 ml) containing 0.16 of an equivalent of hydrogen chloride. Ethyl acetate (200 ml) was added slowly to the solution. The hydro5 chloride crystallised and was filtered off, washed with a mixture of industrial methylated spirit 74° o.p. (50 ml) and ethyl acetate (50 sl) and was dried at 50°. The product (50 g) was obtained as an off-white solid m.p. 133-134°. -64' Vi ·5 Jt U Example 33 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(Registered Trademark) 1500 Starch* 300 g Magnesium Stearate B.P. 30 g The drug is sieved through a 250 jum sieve and then the four powders are intimately mixed in a blender and compressed between 8.5 mm diameter punches in a fcabietting machine.

* A form of directly compressible starch, supplied by A.E. Staley Mfg. Go. (London) Limited, Orpington, Kent. (b) Injection for Intravenous administration (200 mg in 2 ml) % w/w Active ingredient iO.O 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 Injections, 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 pm. 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. 6510 (c) Oral Sustained Release Tablets 150 mg for 10,000 tablets Active ingredient 1.50 kg CutinafRegistered Trademark) HR** 0.40 kg Anhydrous lactose H.S.P. 2.060 kg Magnesium Stearate BP 40g 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 sa 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. (fi) Oral Syrup % w/v Active ingredient 2.0 Dilute hydrochloric acid BP, as required Sorbitol Solution BPC 60 v/v Flavour as required Distilled water to 100 The drug is dissolved in some of the water with stirring -66by adding gradually hydrochloric acid until the pH has fallen to 5.0. The Sorbitol Solution, flavour and the rest of the water are added and the pH re-adjusted to 5.0. The syrup is clarified by filtration through suitable cellulosic filter pads, (e) Oral Capsules 50 tag tor 10,000 capsules Active ingredient 500 g Sta-itx 1500* 1700 g Magnesium Stearate BP 20 mg The drug is sieved through a 250 um mesh sieve and is ί then blended with the other powders. The powder is filled into No. 3 size hard gelatin capsules on a suitable filling machine. (f) Ointment % by weight !' Active ingredient 2,0 White Soft Paraffin BP to, 100 The drug is sieved through a 150 jum aperture sieve and is then uniformly blended with the White Soft Paraffin in a high shear mixer, (g) Cream % by weight Active ingredient 2,0 Cetomacrogoi Emulsifying Ointment BP 30.0 Chlorocresol 0.1 Distilled water t to 100 -67^45® The drug is passed through a 150 jum aperture sieve and is then blended intimately with the Cetomaerogol Emulsifying Ointment at 65°0. The ehlorocresol is dissolved in the water at 65°C and this solution is then mixed with the oily drug mixture and the resulting emulsion is stirred continuously during cooling to give a cream.

The active ingredient is a compound according to the invention. Particular examples are the compounds of Examples 10, 15 and 32. Other compounds according to the invention may also be used. -68The 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 80 sucrose in normal saline instead of drinking water.

The rats are anaesthetized by a single intraperitoneal 10 injection of 250 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 i« separated from the liver and spleen by cutting the connective tissue. A small opening if, is made in the fundic region of the stomach and the stomach washed with a 50 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 -69fluid 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 hy 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 1.3 ml/min. for each cannula. The effluent is passed over a micro-flow pH electrode and recorded via a pH meterand 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 'gastric1 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 aeid secretion, between basal output and the histamine stimulated plateau level is calculated as hydrogen -70ion concentration in mole/L. The reduction oi 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. ΕΏ^θ values for inhibition of acid secretion are determined by administering one dose of the test compound to one rat and repeating this in at least four rats for each of three or more dose levels. The results obtained are then used to calculate the value by the standard method of least squares, its used for any dose response line.

Using the above procedure the following EDgQs were obtained: Compound of Example No. ®®50 "sAi? 2(c) 1.5 8 0.65 9(a) 2.30 10 1.39 14(a) Ο.23 14(f) 0.8 14(h) 0.48 15 0.18 25(a) 1.82 26(a) 0.55 -71ύ Cd S o

Claims (13)

1. CLADS; 1. Compounds of the general formula I: R. R, '1 (CH 2 ) n X(CH 2 ) m NHCNHR- (l) '2 and physiologically acceptable salts thereof and N-oxides and hydrates, in which R^ and Rg which may be the same or different, represent hydrogen, lower alkyl, cyeloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group -N~, in which R^ represents hydrogen or lower alkyl or Rj and R 2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and -N-: I *4 R_ is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is -CHg-, 0 or S; Y represents = S, = 0, = NRg or = CHRgj Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms; is H, nitro, cyano, lower alkyl, aryl, alkylsulphonyl, or arylsulphonyl; Rg represents nitro, arylsulphonyl or alkylsulphonyl; m is an integer from 2 to 4; and 72 η is 1 or 2; or when X = S, or -Cfl 2 “, n is zero, 1 or 2.

2. Compounds as claimed in claim 1 in which and R 2 independently represent hydrogen, alkyl, phenylalkyl, 5 dialkylamino alkyl or together with the nitrogen atom form a 5- or S-membered saturated heterocyclic ring, Alk represents a straight alkylene chain of 1 to 4 carbon atoms, Y is = 3, = O, = CHNO 2 or =NRj where R^ is hydrogen, nitro, cyano, lower alkyl, alkylsulphonyl or benzenesulphonyl, and X, m, 10 n, and R^ have the meanings given in claim 1.

3. Compounds as claimed in any of claims 1 and 2, in which aryl as a group or part of a group represents phenyl or substituted phenyl. '

4. Compounds as claimed in any of claims 1 to 3 in which n + m is 3 or 4.

5. Compounds as claimed in any of claims 1 to 4 in which Alk represents a methylene group.

6. Compounds as claimed in any of claims 1 to 5 in which R 1 is H or C 1-4 alkyl and R 2 is ^_ 4 alkyl.

7. Compounds as claimed in any of claims 1 to 6 in which R 1 and/ or R 2 are methyl or ethyl. -73Λ-S 4 ΰ a

8. Compounds as claimed in any of claims 1 to 7 in which X is a sulphur atom,

9. Compounds as claimed in any of claims 1 to 8 in which X represents a group -CH O „ 5

10. Compounds as claimed in claim 1 in which R^ and Rg independently represent hydrogen, alkyl of 1 to 3 carbon atoms or phenethyl or together with the nitrogen atom form a pyrrolidine ring; Alk represents an alkylene chain of 1 to 3 carbon atoms; Y is = S, = CHNOg, or = NRg, where Rg 10 is nitro, cyano, methylsulphonyl or benzenesulphonyl; Rg represents hydrogen, alkyl of 1 to 3 carbon atoms, propenyl or alkoxyalkyl of 3 carbon atoms; n + m is 3 or 4, and X is as defined in claim 1.

11. Compounds as claimed In claim 1 in whieh R^ and Rg 15 independently represent H, alkyl of 1 to 3 carbon atoms, phenethyl or together with the nitrogen atom form a pyrrolidine ring; Alk represents an alkylene group of 1 to 3 carbon atoms; Y is = S, = CHNOg, or = NRg, where R^ is nitro, cyano, methylsulphonyl or benzenesulphonyl; X is S or -CHg-; R^ is hydrogen, methyl or methoxyethyl; n is 1 and m is 2 or 3·

12. Compounds as claimed in claim 1 in which R^ is hydrogen, methyl or ethyl; Rg is methyl or ethyl; Alk represents a methylene group; Y is = NON, = NNOg, or = CHNOg; Rg is 25 hydrogen or methyl; X is S or -CHg-; and n is 1 and m is 2 - 74 Λ3Α8 3

13. Ν-Γ2-(Γ[5(dimethylamino)methyl-2-furanylJmethylJthio JethylJ-N’methylthiourea, 11. N-cyano-N'£2[ί[5-( dime thyiamino)me ^hyl-2-furanylJmethylJthio JethylJ-Nme fchylguanidine. 15. N-j2<[{5(dime thy I amino )methyl-2-i'uranyl JmethylJthioJethylJ-Ν'-methyl2-nitro-1,1-ethenediamine. lfi. N-cyano-N’!.——[[ [5-(methyl amino) me thy'l-2-f uranyl Jmethyl Jthio Jethyl J-N~ methylguanidine. 17. »-p-[[p(diethylamine)methyl-2-furanylJmethylJthio JethylJ-N'-methyl2-ni tro-1,1-ethenediamine, 18. N-P-IXC5(dime thylamino)me thyl-2-furanylJme thylJthio JethylJ-N' - (2methoxyethyl)-2-nitro-1,1-ethenediamine. i9 · «-e-cp(dimethylamino)methyl-2-furanylJmethylJthio JethylJ-N'(2-methoxyethyl) thiourea. 20. N-li-CCCs(methylamino Jmethyl-2-iuranylJmethylJthio JethylJ-N’-methyl2-nitro-1,1-ethenediamine. - 75 21. Ν-[3-Π5(dimethylamino)methyl-2-furanyljthio Jpropyl]-N’-methyl-2nitro-1,1-ethenediamine. 22. N-C2- CL 13“ (ethylmethylamino)methyl-2-furanyljmethyljthio jethylJ-Ν’ methyl-2-nitro-l,1-ethenediamine. 23. N-g-ne( dimethyl amiho)methyl-2-furanylJmethyljthio JethylJ-N ! nitroguanidine. 24. N-t2-tL]5(dimethylamino)methyl-2-furanyljmethyljthioJethylJ-N’methanesulphonyl-N-methylguanidine. 25. N-{4-{5(dimethylamino)methyl-2-iuranylJhutylJ-N’-methylthiourea. 26. N-benzenesulphonyl-N*-[2-[[[5-(dimethylamino)methyl-2-furanylJmethylJ thio JethylJ-N-methylguanidine, 27. Ν-β-β-(dimethylamino)methyl-2-furanyljpentylJ-N’-methyl-2-nitro1.1- ethenedi amine. 28. N-cyano-N’[5-[5-(dimethylamino)methyl-2-furanylJpentylJ-N’-methylguanidine. 29. N(dimethylamino)methyl-2-furanylJhutylJ-N'-methyl-2-nitro1.1- ethenediamine. - 76 30. N-cyano-N'[4-[5-(dimethylamino)methyl-2-furanyljbutyl]-N-metliylguanidine. 31. N[[dime thylamino]prepyi]-2-furanyl]methyl]thio]e thyl]-N’nn· thy 1-2-ni tro-1, (-ethenediamine. |!2-(dimethylamino)ethyI]amino]methyl-2-furanyl]me thyl]thio]ethylj-N'-methyl-d-nitro-l.1-ethenediamine. 33. Physiologically acceptable acid addition salts of the compounds of claims 13 to 32. 34. Hydrochlorides of the compounds of claims 13 to 32. 35. Compounds as claimed in claim 1 specifically herein described in Examples 1 to 32 other than those claimed in claims 13 to 32. 36. A process for the preparation of compounds as claimed in claim I which comprises (a) reacting a compound of formula II: It R, N-Alk (CH 2 ) n X(CH 2 ) m NH 2 (II) l 2 in which Rp R 2 , Alk, η, X and m have the meanings given in claim 1 with a compound capable of introducing a group - 77 &l34Sd -CNHR„ in which R_ and Y have the meanings given above; or II 3 3 γ (b) for the production of compounds in which Y is a group =NRg or =CHRg, reacting a compound of formula XII; (CH 2 ) n X(CH 2 ) ai NHC-P Q (in) in which Q represents =NRg or =CHRg, P is a leaving group and Rp Rg, Alk, X, n and m have the meanings given above, with a primary amine of formula RjNHg in which Rg has the meaning given in claim 1; or (c) for the production of compounds in which X is sulphur and n is 1 and when Rj and S g are both hydrogen, Y is other than =CHNO gs reacting a compound of the formulae; in which Rj and Rg have the meanings given above and R? is hydrogen or an acyl group in which R^ and Rg when they are hydrogen may be protected, Tilth a thiol of the formula VII: HS( c H 2 ) m NHCNHR 3 (VII) if necessary with subsequent deprotection; or - 78 physiologically acceptable salt or being converted from one such salt to another. 37. A process as claimed in claim 36 (a) in which the compound capable of introducing the group -CNHR^ is selected from Ii Y 5 alkali metal cyanate» or thiocyanates or isocyanates of the formula R^NCO or isothiocyanates of the formula R^NCS, or compounds of the formula R-NHC-P or R-NHC-P where P is 3 II 5 1 NR r CHR r 5 6 a leaving group. 38. A process as claimed in claim 36 (b) in which the compound O of iormula (III) is (Ii) with a compound prepared by reacting the amine of formula of the firmula: P P ZX om 6 or of the formula: NRin which R_ and Rg have the meaning given in claim 1. 39. A process as claimed in claim 36 (f) for the production of compounds of formula (IV) in which a compound of formula (II) is reacted with carbon disulphide and then with a chloroformate ester. - 80 -b'd (d) for the production of compounds in which Y is a group NON reacting a compound of formula X whore Y is sulphur with a heavy metal cyanamide; or (c) 1'or the production of compounds in which Y is =NRg and 5 A.Jk is a methylene group, or a branched alkylene group, subjecting a compound of the formula VIII: (®2>η Χ ( Ο Η 2 > Β ΝΗ ™3 (VIII) NR C to a Mannich reaction with an appropriate aldehyde and a secondary amine or a salt of a primary amine or a secondary 10 amine; or (I) for the production of compounds in which Y is sulphur, reacting a compound of IV: N-Alk / A, (CHo), t x (CH 2 ) a NCS (IV) wherein R^, Rg, Alk, X, m and n have the meanings given above, with an amine of formula R^NHg wherein Rg has the meaning given in claim 1; in each ease the end-product if desired being isolated as a - 79 40. A process as claimed in claim 36 substantially as herein described with reference to Examples 1 to 32. 41. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 36-40. 42. Pharmaceutical compositions comprising a compound as claimed in claim 1 or claim 41, in association with a pharmaceutically acceptable carrier or diluent, and If desired other active ingredients. 43. Ccrnpositians as claimed in claim 42 in a form suitable for oral, topical or parenteral administration or administration by suppository. 44. Compositions as claimed in claim 43 in oral form as tablets. 45. Ccnpositions as claimed in claim 44 in the form of slow release tablets. 46. Compositions as claimed in claim 44 or 45 containing 20 to 200 mg of active ingredient per tablet. 47. Compositions as claimed in claim 43 in topical form as a spray, ointment or cream. 48. Compositions as claimed in claim 42 substantially as herein described with reference to Example 33. 49. A method of treating non human animals for a condition mediated'through histamine H 2 ~receptors which comprises administering to a patient an effective amount of a compound as claimed in claim 1 to relieve said condition. 4. 5 4 Β ϋ 50. A method as claimed in claim 49 in which the condition is peptic ulceration. A method as claimed in claim 49 in which the condition is an allergic skin condition. 52. Compounds of the general formula I: N-Alk (CH 2 ) n X iCH 2 ) m HHCNHR 3 II ‘2 (I) and physiologically acceptable salts thereof, in which Rj and R 2 -which may be the same or different represent hydrogen, lower alkyl or alkenyl or lower alkyl interrupted by an oxygen atom or a group ' J? *4 in which represents hydrogen or lower alkyl or R^ and S 2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and -H-; Rj is lower alkyl; X is 0 or S? X represents = S, = 0, = MR^ or = CHRg; Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms; - 82 LO.J ί Rg is nitro, cyano, lower alkyl or aryl; Rg represents nitro; m is an Integer form 2 to 4; and n is 1. 5. 53. Pharmaceutical compositions comprising a compound as claimed in claim 52 in association with a pharmaceutically acceptable carrier or diluent. 54. N- [2~f [ [5- (Dimethylamino) methyl-2-furanyl] methyl] thio]ethyl] -N'-methy1-2-nitro-l,1-ethenediamine hydrochloride.