NZ184759A

NZ184759A - Aminoalkyl-furan derivatives and pharmaceutical compositions

Info

Publication number: NZ184759A
Application number: NZ184759A
Authority: NZ
Inventors: J W Clitherow; B J Price; J Bradshaw
Original assignee: Allen & Hanburys Ltd
Priority date: 1976-08-04
Filing date: 1977-07-27
Publication date: 1980-09-12
Also published as: HK55780A; DK416384D0; PH13540A; FI72318C; AT375931B; CH642072A5; DK148258C; DK337977A; PT66874A; DK416384A; DK149952B; SE7708521L; SE454883B; CH641176A5; YU40088B; IT1126759B; NZ191383A; PT66874B; CY1077A; DK148258B

Abstract

Novel aminoalkylfuran derivatives of the general formula I: in which the symbols have the meaning indicated in Claim 1, are prepared by reaction of a compound of the formula with a compound of the formula R3NZZ'. A, B, Z and Z' have the meaning indicated in Claim 1. The aminoalkylfuran derivative can 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 exhibit inhibition of gastric acid secretion if they are stimulated via histamine H2 receptors.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 84759 AMENDED under Section .,.- of the Patents Act 1953 from jCSSltTAMT COMMISSIONED OF PATENTS 1 84759 CO^D3D?-C07D405 C07D4-13 Priority tMtt3:A*}£,*n:.#;..l.l*..-77 Complcio C;;:c';;c CI <iss 9.p/fXr.9. Publication Cats: BL2- P.O. Journal, No. o? No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION PHARMACOLOGICALLY ACTIVE COMPOUNDS xM We, ALLEN & HANBURYS LIMITED, a British Company of Three Colts Lane, Bethnal Green, London E2 6LA., England hereby declare the invention for which^ix/ we pray that a patent may be granted to jg}&/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - 1 8 47 5 9 \ This invention relates to new aminoalkyl furan derivatives having a selective action on histumine receptors, to processes for the preparation thereof and pharmaceutical compositions containing them, as well as their use in therapeutics. A subdivision of histamine receptors (H-receptors) into two groups designated and H^- receptors has been proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27t 427) and Black et al (Nature 1972, 236. 385). Stimulation of bronchial and gastrointestinal smooth muscle is mediated through H^-receptors &nd these effects can be prevented by conventional histamine antagonists such as mepyramine. Stimulation of gastric acid secretion and heart rate is mediated through Hg-receptors; these effects are not modified by mepyramine but are prevented or abolished by Hg-antagonists such as metiamide. Histamine stimulates H^- 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 1^ 5^0» modified as hereinafter described and in conscious dogs equipped with Heidenhain pouches using the same method as 184759 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 he used in the treatment of conditions where there is a hypersecretion of gastric acid e.g. in gastric and peptic ulceration, and in the treatment of allergic conditions where histamine is a known mediator. They may he used, either alone, or in combination with other active ingredients in the treatment of allergic and inflammatory conditions such as urticaria. The invention therefore provides compounds of general formula (i): and physiologically acceptable salts thereof and N-oxides and hydrates, in which and R2 which may be the same o?: different represent hydrogen, lower alkyl having 1 to 8 carbon atoms, cycloalkyl, lower alkenyl having 3 to 6 carbon atoms, aralkyl or lower alkyl having 1 to 8 carbon atoms interrupted by an oxygen atom or a group or and R2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and - ; R4 184759 R3 is hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having. 3 to 6 carbon atoms or alkoxyalkyl X is -CH2~, 0 or S; Y represents = S, = 0, = NR5 or = CHRg; Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms; R4 is hydrogen or lower alkyl having 1 to 8 carbon atoms; R5 is H, nitro, cyano, lower alkyl having 1 to 8 carbon atoms, aryl, alkylsulphonyl or arylsulphonyl; R5 represents nitro, arylsulphonyl or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 or 2; or when X is -S-, or -CH2-, n is zero, 1 or 2. The term 'aryl* as a group or part of a group preferably means phenyl or phenyl substituted, for example, with alkyl, alkoxy or halogen. 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- 18475? isomers and optical enantiomers. In a preferred class of compounds according to the invention the following groups have the meanings indicated: and Rg independently represent hydrogen, alkyl, phenylalkyl, dialkylaminoalkyl or together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic ring e.g. morpholino, piperidino, pyrrolidine, and N-alkylpiperazino. Alk represents a straight alkylene chain of 1 to k carbon atoms. Y is = S, = 0, =CHN0p or = NR^ where R^ is hydrogen, nitro, cyano,, lower alkyl having 1 to 8 carbon atoms, alkylsulphonyl or benzenesulphonyl. X, m, n, and R^ hava 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, = CENOg, or = NR^, where R^ is nitro, cyano, methylsulphonyl or benzenesulphonyl. R^ represents hydrogen, alkyl of 1 to 3 carbon -5- TTroryica: 3 - oct 1979 I 184759 atoms, propenyl or alkoxyalkyl of 3 carbon atoms, n + m 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: R^ and R^ 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, =CHN02, or = NR^, 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 • In another particularly preferred class of compounds according to the invention the following groups have the meanings indicated: Rj is hydrogen, methyl or ethyl. Rg is methyl or ethyl. Alk represents a methylene group. Y is =NCN, =NN02, or =CHN02. R^ is hydrogen or methyl. X is S or -CH2-. n is 1 and m is 2. 18 47 Particularly preferred specific compounds axe: N- [2- [ [ [5-(Dimethylamino)methyl-2-furanyl ]methyl]thio ]-ethyl]-N'-methylthiourea N-Cyano-N'- [2- [ [ [5- (dimethylamino )methyl-2-f uranyl ]methyl ]-thio]ethyl]-N"-methylguanidine N- [2- [ [ [5- (Dimethylamino )methyl-2-f uranyl ]methyl]thio ]ethyl]-N' -methyl-2-ni tro-1, l-ethenediamine N-Cyano-N[2- [ [ [5- (methylamino )methyl-2-furanyl ]methyl ]thio ] ethyl]-N"-methylguanidine N— [2— [ [ [5-(Diethylamino)methyl-2-furanyl]metliyl]thio]ethyl]-Nt -methyl-2-ni tro-1, l-ethenediamine N- [2-[ [ [5- (Dimethylamino )methyl-2-furanyl ]methyl]thio ]ethyl]-N1-(2-methoxyethyl )-2-nitro-1, l-ethenediamine N- [2- [ [ [5- (Methylamino )me thy 1-2-f uranyl ]methyl ]thio ]ethyl ]-N •-me thyl-2-ni tro-1, l-ethenediamine N- [3- [ [5- (Dimethylamino )methyl-2-furanyl ]thio ]propyl ]-N' -methyl-2-nitro-l,l-ethenediamine N— [2- [ [ [5-(Ethylmethylamino)methyl-2-furanyl]methyl jthio ]-ethyl ]-N,-methyl-2-ni tro-1, l-ethenediamine N- [2- [ [ [5- (Dimethylamino )methyl-2-f uranyl ]methyl ]thio ]ethyl ]• N'-nitroguanidine N- [2- [ [ [5- (Dimethylamino )methyl-2-furanyl ]methyl ]thio ]ethyl ] Nf -methanesulphonyl—N"-methylguanidine N- [4- [5- (Dimethylamino )methyl-2-f uranyl ] "butyl ]-N '-methyl-thiourea 1 84759 N-Benzenesulphonyl-N*-[2-[ [ [5-(dimethylamino)methyl-2-furanyl ]-methyl ]thio Jethyl ]-N"-methylguanidine N-[5-[5-(Dimethylamino)methy1-2-furanyl]pentyl]-N'-methyl-2-nitro-1,l-ethenediamine N-Cyano-N* - [5- [5- (dimethylamino )methyl-2-furanyl ]pentyl ]-N' -methyl guanidine N- [4- [5- (Dimethylamino )methyl-2-f uranyl ]butyl ]-N'-methyl-2-nitro-1,1-ethenediamin e N-Cyano-N'-[4-[ 5-(dimethylamino )methyl-2-f uranyl ]butyl]-N"-methylguanidine N- [2— [ [ [5-(>{Dimethylamino ]propyl ]-2-furanyl ]methyl ]thio ]-ethyl ]-N '-methyl-2-ni tro-1, l-ethenediamine N-[2- [ [[5-[[2-(dimethylamino)ethyljamino]methyl-2—furanyl]-methyl]thio]ethyl ]-N f-methyl-2—nitro-1,1-etlienediamine The compounds according to the invention readily form physiologically acceptable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, iff hydrobromides and sulphates. Particularly useful salt^/are formed with aliphatic mono- or di-carboxylic acids. Examples 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,- 18 47 5 9 of which the preferred route is the oral route. They may be used in the form of the base or as a physiologically acceptable salt. They will in general be associated with a pharmaceutic ally acceptable carrier or diluent, to provide a pharmaceutical composition. The compounds according to the invention can be administered in combination with other active ingredients, e.g. conventional antihistamines if required. For oral administration the pharmaceutical composition can most conveniently be 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 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 18i/jp to 2% "by weight of the total composition. The compounds of the present invention may toe made from a primary amine of the formula: R (0H2)nx(CH2)mNH2 (XX) Rn in which R^, R^, n, X and si have the meanings given herein with a compound capable of introducing the group -CNHR^ in 10 Y 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 acid e.g. acetic acid. Compounds which are capable of introducing the group -CNHR, are selected from alkali metal i cyanates or thiocyanates or isocyanates of the formula R^NCO, or isothiocyanates of the formula R^NCS, or compounds of the formula RnNHC - P or R3NHC - P where P is a leaving 1 1 NR5 CHR6 group. The reaction with the isocyanate or isothiocyanate may be carried out by allowing the amine and isocyanate or isothiocyanate to stand in a solvent such as acetonitrile. The reaction with R^NHC - p or R^NHC - P can be carried 1 IR5 Chr6 out by fusing the reactants at an elevated temperature e.g. 100-120°C. Alternatively the •- '-A-r.Ca _10- 3 - oct 1979 f?£CSVED 1 847 5 9 reaction between the amine (II) and R-NHC - P may be carried 3 li nr5 out in a solvent e.g. acetonitrile at elevated temperatures in the presence of silver nitrate. Alternatively again the 5 amine (II) and the compound R^NHC - P may be stirred in aqueous CHR^ solution at room temperature. Where represents hydrogen alkali metal cyanates and thiocyanates axe used. Examples of leaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl 10 or alkoxy, preferably thiomethyl. The introduction of the group -CNHR^ may also be effected by first reacting the amine Y (II) with a compound of the formula: P P P P or N,/ I HR^ 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): R N-Alk JL0JJ- (CH2)nX(CH2)mNHC-P (III) r2 -G& -11- 1 84759 where Q represents =NR^ or =CHRg with a primary amine R^NHg a*t 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 (il) can be heated with carbon disulphide and then reacted with a chloroformate ester, e.g. ethyl chloroformate to form an isothiocyanate (IV) which is then reacted with an amine R^NHg preferably in an alkanol as solvent e.g. ethanol. | | Alk-l!^ o JL (CH2)nX(CH2)mNCS (XV) v In another process, compounds wherein x is sulphur and 15 n is 1, and when R^ and R2 are both hydrogen Y is other than =CHN02, can be prepared from a starting material of formulae (v) or (vi): 10 R Alk r2 (v) ch2ci (Ry may be hydrogen or an acyl group such as acetyl or p-nitrobenzoyl) If R^ and Rg in the products are both hydrogen, they may be •GB- -12- 18 4 7 5 9 protected in a compound of formula (V) as, for example a phthalimido group. The above compounds may be reacted with a thiol of formula (VII): with subsequent deprotection where appropriate. When the compound of formula (V) is used the reaction is preferably carried out at 0°C in concentrated hydrochloric acid. When a compound c£ formula (Vl) is used the reaction may be carried out at room temperature in an organic solvent e.g. dimethyl-formamide. 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 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. Compounds according to the invention in which Y is =NR^ and Alk is a methylene group or branched alkylene chain can also be prepared from compounds of the formula (VIII): HS(CH2)mNHCNHR3 Y (VII) (VIII) NR. '5 -13- 1 84759 by 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^gNCHg- group can be introduced using dimethylamine and formaldehyde. The process may be 5 carried out by reacting the amine salt with aqueous formalde hyde 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 10 the production of the compounds according to the invention reference has been made to primary amines of formula II. These amines are novel compounds and the invention includes such compounds. These intermediates may be made by a number of processes which are described below. 15 .Amines of formula (il) wherein X is S and n is 1 may be prepared from the furfurylthiol of formula (IX): c CH2SH (IX) by reaction with an ti»-bromoalkylphthalimide (X) U) 6B- -14- 1 847 5 The group N-Alk may he introduced into the resulting V compound of formula (XI): 0 (XI) 0 by for example a Mannich reaction. Removal of the protecting group by reaction with, for example, hydrazine hydrate gives an amine of formula (II). In an alternative process to amines of formula (il) wherein X is S and n is 1, 2-furfuryl chloride may be used as starting material. The reaction between furfuryl chloride and an uJ-aminoalkylthiol in which the amine group is protected, for example as a phthalimide (XII): gives an intermediate of formula (XI). This is treated as described above to give an amine of formula (il). A further process to the amines (il) wherein X is S and n is 1 uses a starting material of formula (XIII): (XII) 0 R (XIII) R, '2 <1847 59 This compound may he treated under acid conditions, with an uuaminoalkylthiol, in which the amine group may he protected if desired. Alternatively, the compound of formula (XIII) may be converted into the corresponding acetate prior to reaction, under basic conditions with the oJ-aminoalkylthiol. Primary amines of formula II (except those in which X = S and n = zero) may be prepared by reacting furan with butyl lithium, to produce a lithio derivative (XIV): which is then reacted sequentially with (i) an a, UJ-dihalo-compound Hal(CHg) XfCBg^Bal (where Hal is chlorine, bromine or iodine), and (ii) potassium phthalimi.de. The product of the reaction of formula (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): (XIV) 0 0 R (XVI) R, •2 1 847 in which neither R^ nor Rg are hydrogen hy reacting it with lithium and elemental sulphur followed hy reaction with an CO-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(CH2)mNHg where Hal represents a halogen atom, preferably chlorine, in the presence of a base, particularly potassium tertiary butoxide. Intermediates of formula II where m is 2 and X is S or 0 may also be prepared by using ethylene imine. This compound is reacted with a compound of formula XIII or the isosteric thiol. Amines of formula II may also be prepared by starting with a compound of formula (XVIII): 0 0 (XVII) (XVIII) -17- 1 84759 10 in which n, m and X have tha 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 be introduced at any convenient stage but the reaction is preferably carried out on compounds of formula (XIX) or (XX) UUoH ^0jhCH2>nX<CH2>,.N' (XIX) (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 l!> Alk represents methylene, formaldehyde is used. An alternative process to compounds wherein Alk is methylene uses furan-2-carboxylic 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, ?n lithium aluminium hydride to give a compound of formula (XXII): Rl\ J i Rl\ J i] /f-^0^ yCH2 0 ^ r2 0 (XXI) R2 (XXII) 25 GB- In order to convert a compound of formula XXII into a -18- 18 4759 10 compound of formula XIII the hyclroxymethyl group may he introduced using formaldehyde and acetic acid. If Rj and R2 are both hydrogen, the amino group is protected during hydroxymethylation as a phthalimide. Deprotection is subsequently effected using hydrazine hydrate. Alternatively, where 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): in place of furan-2-carboxylic acid. Where the alkylene chain, Alk, it, 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 R-jRgNH to give a compound of formula (XVI) wherein Alk contains 3 to 6 carbon atoms,. Where R^ and Rg are hydrogen, potassium phthalimide replaces the amine R-^RgNH in both the above reactions. The (XXIII) m- -19- product of both reactions is hydroxymethylated as described above, followed by deprotection where appropriate to give a compound of formula (XIII). If compounds where R^ 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 II where n is 2 may be made by utilizing as starting material a compound of the formula XXIV: PLCH2CH2Z (XXIV) in which Z is a leaving group, e.g. tosyloxy, mesyloxy or bromine. This compound is reacted with an uJ-phthalimido-alkylthiol 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 =CHNOg. Compounds of formula and m is 2 VII in which Y is =CHNO^may be made from a thiazolidine intermediate of the formula: -20- 18475? s nh (xxv) i ciinog by reaction with an amine R^NHg. The thiazolidine XXV may be made from cysteamine and a bis methyl thio compound XXVI: CH-SCSCH, 5 || 3 (XXVI) CHNOg The thiols of formula VII wherein Y is =CHNOg and m is ~2 are novel compounds which are described and claimed in our New Zealand Patent Specification No. 191383. -21- \ 8 47 5-9 In order that the invention may he more fully understood, the following Examples are given by 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 Il/and Examples 1-32 of compounds of formula I. Example 33 exemplifies pharmaceutical compositions. Preparation 1 (a) 5-(Methylamino)methyl-2-furanmethanol A mixture of 2-furanmethanol (49 g), methylamine hydrochloride (51.5 g) and 3696 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. 111-1139 (0.2 mm). Similarly prepared from 2-furanmethanol and the corresponding amine hydrochloride were: (b) 5- [(2-Phenyl ethyl) amino ]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-Methyl ethyl) amino ]methyl-2-furanmethanol. Oil Rf 0.55 (silica/methanol). Analysis Found C, 63.35; -22- 1 8 4759 of the extract gave a clear colourless liquid b.p. 60-62°, 0.5 mm Hg. N.N-Dimethyl-4- (2-f uranyl )butanamine Dimethylamine (56 g) was added to a solution of 2-[l-(4-bromobutyl)]furan (82 g) in toluene (500 ml). The resultant solution was stirred at room temperature for 2 days, and then acidified with hydrochloric acid. 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. 55-58°, 0.8 mm Hg. Hydrochloride salt m.p. 133-136°. Found: C, 59.01; H, 9.02; H, 6.87. Calc. for C10H17N0.HC1: C, 58.96; H, 8.91; N, 6.88$. 5- f 4- (Dimethylamino )butyl 1-2-f uranmethanol (a) n-Butyl lithium (1.6M in n-hexane, 125 ml) was added to an ice-cooled solution of N,N-dime thyl-4-(2-furanyl)butanamine (33.4 g) in dry tetrahydrofuran (125 ml). The mixture was stirred at room temperature for 4 hr. Paraformaldehyde (6.0 g) was then added and the mixture stirred for a further 1 hr. The reaction was quenched with water and extracted with chloroform. The organic extracts were distilled to give a clear colourless oil b.p. 100-105°, 0.1 mm Hg, m.p. 26-28.5°. Found: C, 67.09; H, 10.01; N, 7.06. Calc. for C1;,HigN02: c, 66.97; H, 9,71; N, 7.1096. Similarly prepared was: (b) 5-[-3-(Dimethylamino)propyl]-2-furanmethanol, b.p. -24- 1 S 47 5 H, 8.78; N, 8.09. C^H^NOg requires C, 63.88; H, 8.94; N, 8.28$. (d) 5-(Ethylmethylamino)methyl-2-furanmethanol. Rf 0.32 (silica/acetone). NMR (CDCl^) 8.93 t (5H); 7.80 s (3H); 7.55 q (2H); 6.50 s (2H); 6.33 br.s (1H); 5.47 s (2H); 3.80 m (2H). (e) 5-[[2-(Dimethylamino)ethyl]amino]methyl-2-furanmethanol bis maleate salt m.p. 119-121°. Preparation 2 5-f2-(N,N-Dimethylamino)ethyl]-2-furanmethanol N,N-Dimethyl-2-furanethanamine (9.8 g), 30$ 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. C^H^NOg requires: C, 63.9; H, 8.9; N, 8.2$. Preparation 3 2fl-(4-Bromobutyl)]furan n-Butyl lithium (1.6M in hexane, 375 ml) was added to a solution of furein (40.8 g) in dry tetrahydro furan (375 ml) and the mixture was stirred at 40° for 3 hr. 1,4-Dibromo-butane (129.6 g) was then added at -30° and the reaction stirred at room temperature for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Distillation -23- 1 8 4 7 5 l60°/0.08 mm Hg, m.p. ca. 24°. Pound: C, 64.66; H, 9.36; 1 N, 7.39. Calc. for C10H17N02.5H20: C, 64.28; H, 9.39; N, 7.50$. Preparation 4 [5- T4- fN,N-Dimethylamino Ibutyl 1-2-furanyl Imethyl ethanoate A mixture of 5-[4-(dimethylamino)butyl]-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 C13H21N03: C, 65.24; H, 8.85; N, 5.85$. Example A (a) 2- [ [ f5-(Dimethylamino)methyl-2-furanyl Imethyl ]thio ]-ethanamine 5-(Dimethylamino)methyl-2-furanmethanol (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-2-furanyl]methyl]thio]ethanamine (11.6 g) b.p. 104-106° (0.1 mm) 1 8 47 5 Picrate salt m.p. 142-144°. Similarly prepared from the corresponding furanmethanols and cysteamine hydrochloride were: (b) 2-[[[5-(Methylamino)methyl-2-furanyl]methyl]thio]-ethanamine. Monopicrate salt m.p. 116-118°. (c) 2-[[[5-[(1-Methylethyl) amino]methyl-2-furanyl]methyl]-thio]ethanamine. Oil Rf 0.4 (silica/methanol:0.880 ammonia 79:l). (d) 2-[[[5-(Diethylaminomethyl)-2-furanyl]methyl]thio]-ethanamine b.p. 134-135° (l mm). (e) 2-[[[5-(1-Piperidinyl )methyl-2-furanylJmethyl]thio]-ethanamine. Oil Rf 0.37 (silica/methanol:0.880 ammonia 79:1). (f) 2- [ [ [5-(Aminomethyl)-2-furanylJmethyl]thio]ethanamine, dihydrochloride m.p. 222-224° (dec.). (g) N- [5- [ [ [(2-Aminoethyl)thio]methyl ]-2-furanyl]methyl]-benzene ethanamine. .Oil Rf 0.33 (silica/methanol:0.880 ammonia 79:1). (h) 2-[[[5-[2-(Dimethylamino)ethyl]-2-furanyl]methyljthio]-ethanamine b.p. 150-155° (0.04 mm). (i) 2-[[ [5-[3-(Dimethylamino)propyl]-2-furanyljmethyl]thio]-ethanamine b.p. 150° (0.05 mm). n,i> 1 (3 ) 2~ [ [ [5-(Ethylmethylamino)methyl-2-furanyl]thio]mcthyl]-ethanamine Rf 0.34 (silica/methanol:0.880 ammonia 79:1). (k) 2- [[ [5-[(2-Dimethylaminoethyl)amino]methyl-2-furanyl]- -26- 1 84759 thioJnathyl]ethanamine. Tris maleate salt m.p. 132-135°. (1) 2-[[[5-(l-Pyrrolidino)methyl-2-furanyljmethyl]thio]- ethanamine. Bis oxalate salt m.p. 136.5-138.5°. Example B 2-rff5-f4-(Dimethylamino)butyl1-2-furanylImethyllthio]-ethanamine Cysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-jt-butoxide (8.98 g) in dry dimethyl-formamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino )bu tyl]-2-f uranyl ]me thy 1 ethanoate (9.6 g) was added. The 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;l) as eluent, and a further distillation afforded a colourless oil b.p. 140°/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44. Cal'c. for C^H^NgOS: C, 60.91; H, 9.44; N, 10.93$. Example C 2-f f2-(2-Furanyl)ethyllthio1ethyl-lH-isoindole-l,3(2H)dione 80$ Sodium hydride (0.155 g) was added portionwise to a solution of 2-phthalimido-ethanethiol (1.03 g) in dry dimethyl-formamide 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 -27- ^ 847 59 temperature. The mixture was poured into ice-water and 2-[[2-(2-furanyl)ethyl]thio]ethyl-lH-isoindole-l,3(2H)-dione isolated as a white solid (1.3 g) m.p. 53-55°. Example D (a) 2-[2-f[)2-Furanyl)methyl]thio]ethyl]-lH-isoindole-l.3 (2H)-dione 80$ Sodium hydride (1.58 g) was added in portions to a solution of furfuryl mereaptan (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 cyclo-hexane to give 2-[2-[[(2-furanyl)methyl]thio]ethyl]-lH-isoindole-1,3(2H)-dione m.p. 62-63° (7.8 g). Similarly prepared from the W-bromoalkylphthalimide and furfuryl mereaptan were: (b) 2- [3- [ [ ( 2-Puranyl) methyl ]thio jpropyl ]-lH-isoindole-l, 3 (2H)-dione, NMR (CDClj) 7.7-8.3m (2H); 7.2-7.7m (2H); 6.29 s (2H); 6.23 t (2H); 3.7 m (2K); 2.7 m (1H); 2.km (4H). (c) 2-[4-[[(2-FUranyl)methyl]thio]butyl]-lH-isoindole-l,3 (2H)-dione, NMR (CDC13) 8-8.5 m (4H); 7.^9 t (2H); 6.33 m (4H); 3.7 n (2H); 2.7 m (1H); 2.3 m (4H). -28- 184759 Example E (a) 2-[2-f f f5-(Dimethylamino)methyl-2-furanylImethyl]thio"1-ethyl1-lH-isoindole-l,3(2H)-dione A mixture of 2-[2-[[(2-furanyl)methyl]thio]ethyl]-lH-isoindole-1,3(2H)-dione (10 g), dimethylammonium chloride (3.1 g) and 36$ formaldehyde solution (3 ml) in acetic acid (50 ml) was heated on a steam "bath 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 was treated with charcoal, dried and evaporated to give an oil which was purified hy column chromatography (silica/ethanol:ethyl acetate 1:1) (5.7 g) Rf 0.4. NMR (CDC13/DMS0) 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-[2-[[[5-[(l-Pyrrolidinyl)methyl]-2-furanyl]methyl]thio]-ethyl]-lH-isoindole-l,3(2H)-dione. NMR (CDC13) 8-8.4 m (4h); 7-7.6 m (6h); 6-6.5 m (6h); 3.7-4.0 m (2h); 2-2.4 m (4H). (c) 2- [3- [ [ [5 - (Dime thy 1 amino ) me thyl-2-furanyl jmethyl ]thio ]-propyl]-lH-isoindole-l,3(2H)-dione. Rf 0.45 (silica/ methanol). 1 34759 (d) 2- [4- [ [ [5-(Dimethylamino )methyl-2-furanyl Jmethyl ]thio ]-butyl]-lH-isoindole-l,3(2H)-dione. Rf 0.26 (silica/ methanol). NMR (CDCl-j) 8.85 m (4H); 7.7 s (6h); 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]ethyl]-lH-isoindole-l,3(2H)-dione. NMR (CDC13) 7.75 s (3H); 7.52 s (8H); 7-7.5 m (2H); 6.5 s (2H); 6-6.3 m (4H); 3.85 m (2H); 2-2.4 m (4H). (f) 2- [2- [ [ [5- [(4-Morpholinyl)methyl ]-2-f uranyl ]methyl]thio ]-ethyl]-lH-isoindole-l,3(2H)-dione. NMR (CDC13) 7.54 m (4H); 7.24 m (2H); 6.50 s (2H); 6.22 m (8H); 3.8 m (2H); 2.0-2.4 m (4H). Example F 2- f2- f [2- f5-(Dimethylamino )methyl-2-furanyl lethyl lthio ]ethyl ]-lH-isoindole-1,3(2H)-dione 2- [ [2- (2-Furanyl) ethyl ]thio ]ethyl- 1H-i soindo 1 e-1, 3 ( 2H) -dione (0.5 g), dime thyl amine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together under reflux in ethanol. After 5 hr further dimethyl<amine 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-furanyl ]ethyl ]thio ]- -30- 18 4759 ethyl]-lH-isoindole-l,3(2H)dione as a pale oil (0.43 g). Analysis Found: C, 61.48; H, 6.13; N, 7.63; C19H22N203S.3/4H20 requires: C, 61.35; H, 6.37; N, 7.53$. Example G 2- rr5-(Dimethylamino)methyl-2-furanyl Imethoxylethanamine Route (i) To a solution of 5-(dimethylamino)methyl-2-furanmethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulphonic acid (11.6 g) in tetrahydro furan (40 ml). The solution was evaporated and the . oily residue heated at 98-100° for 10 mins. After 18 hr, 5N sodium hydroxide (60 ml) was added and the 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 to give an oil from which the bis-oxalate salt of 2-[[5-(dimethylamino)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 solution of potassium tert-butoxide (8.96 g) and 5-(<limethyl- I 8 47 5 9 amino)mGthyl-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue basified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid. 5 The crystalline salt was recrystallised from ethanol to give 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine, bis oxalate, m.p. 130-133° (3.05 g). Similarly prepared by route (ii) was: (b) 2- [[5-(Methylamino )methyl-2-furan]methoxy]ethanamine, 10 bis oxalate m.p. 162-164°. Example H (a) 2-r4-(2-Furanyl)butyl1-lH-isoindole-l13(2H)-dione 2[l-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature 15 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-l,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 I (a) 2- [4-f5-(Dimethylamino)methyl-2-furanyl Ibutyl 1-1H-25 isoindole-1.3(2H)-dione -32- 1 g4-7 5 9 2-[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 (CDC1-) 8-8.6 m (4H); 7.75 s (6H); 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 ]-lH-isoindole-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 (2H); 6.30 t (2H); 4.0 m (2H); 2.2 m (4H). Example J 5-(Dimethylamino)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). -33- The nitrile (6.0 g) in dry ether (40 ml) was added drop-wise with stirring to lithium aluminium hydride (2.0 g) in ether at 0°. Addition of water, followed hy removal of solvents, gave, after column chromatography, 5-(dimethylamino)-methyl-2-furanpropanamine as a pale oil (3.33 g). NMR (CDCl^) 8.2 m (2H); 7.6 br (2H); 7.75 s (6H); 7.30 m (4H); 6.60 s (2H); 4.0 m (2H). Example K 2- [3- [ [ [5-(Dimethylamino)methyl-2-furanyl ]thio ]propyl ] ]-lH.~ isoinclole-l 13(2H)-dione Sulphur (1.9 g) was added in portions to a solution of the lithio derivative of N,N-dimethylfuranmethanamine (7.5 g) at -40°. The mixture was stirred at -10° for 20 mins and 2-(3~ bromopropyl)lH-isoindole-l,3(211)-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 ]propyl] ]—1H—isoindole-1,3(2H)-dione (7.59 g) m.p. 64-65°. Example L (a) 4- [5- (Dimethylamino )methyl-2-f uranyl Ibutanamine 2- [ [4- ( 5-Mmethylamino )me thy 1-2-f uranyl ]butyl ]-lH- -34- 1 8 4 7 5 9 isoindole-1,3(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 (CDC13) 8.0-8.8 m (4H); 7.7 s (6H); 7.6 br (2H); 7.3 ra (4H); 6.58 s (2H); 4.0 m (2H). In a similar manner were prepared from the corresponding phthalimide: (b) 5-[5-(Dimethylamino )methyl-2-furanyl ]pentanamine. NMR (CPC13) 8.0-8.8 m (6H); 7.75 s (6H); 7.0-7.6 m (4h); 6.60 s (2H); 4.0 m (2H). (c) 5- L [ (3-Aminopropyl) thio ]me thyl ]-n, n- dimethyl f uran-2-methanamine. NMR (CDCl3) 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). -35- \8 47 5 9 Example 1 (a) N- [~2- T f f5-(Dimethylamino )methyl-2-furanyl Imethyl jthio ]- ethyl]-N1-methylthiourea 2-[2- [[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]~ ethyl-lH-isoindole-l#3(2H)-dione (5»3 g) and hydrazine hydrate (0„8|5 g) were refluxed in ethanol for 30 hr. Evaporation of the solvent gave the phthalhydrazide salt of 2- [ [[5-{dimethylainino)methyl~2-furenyl ]methyl jthio j-ethanamine. This 5) a It. (1 g) was suspended in acetonitrile and methyl isothiocyanate (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 (silica/methanol). N-[2-[[[5-(Dimethylamino)methyl-2-furanyl jmethyl jthio jethylj-N1-•nethyl thiourea was isolated as a pale oil (0.3 g). Analysis Found: C, 49.68; H, 7.52; 14.22; C^gHg^N^OSg requires: C, 50.14; H, 7.37; N, 14.62$. Similarly prepared were: (h) N-Methyl-N1-[2-[[[5-(l-pyrrolidinyl)methyl-2-furanyl] methyljthiojethyl]thiourea. Analysis Found: C, 52.33; H, 7.12; N, 13.17. ci4H23N30S2.^HgO requires: C, 52.14; H, 7.50; N, 13.03$. -36- 'I 847 5 9 ( c ) N- [4- [ [ [5- (Dimethylamino ) me thy 1-2-furanyl ]methyl ] thio ] butyl ]-N'-methylthiourea. Analysis Found: C, 51.69; H, 8.53, N, 12.83; C14H25N3OS2 requires: C, 51.82; H, 8.08; N, 12.95$. (d) N- [3- [ [5-(Dimethylamino )methy1-2-furanyl ] thio ]propyl ]-N'-methylthiourea. Analysis Found: C, 49.71; H, 7.33; N, 14.35. ci2N21N30S2 re3uires: c» 50.10; H, 7.30; N, 14.62$. (e) N-Methyl-N'- [2- [ [5-(4-morpho1inyl)methyl ]-2-furanyl ]-methyl]thio]ethyl]thiourea. Analysis Found: C, 51.26; H, 7.08; N, 12.51. ci4H23N3°2S2 retluires: C, 51.03; H, 7.04; N, 12.75$. (f ) N-Methyl-N* - [2- [ [ [5- [ ( 4-methyl-piperazinyl )methyl ]-2-furanyl]methyl]thio]ethyl]thiourea. Analysis Found: C, 50.93; H, 7.74; N, 15.82. ci5H26N40S2 re(luires: c, 51.25; H, 8.03; N, 15.94$. ( g ) N- [2- [ [2- [5-(Dimethylamino )methyl-2-furanyl ]ethyl ]-thio]ethyl]-N,-methylthio\irea. Analysis Found: C, 50.19; H, 7.20; N, 13.18. C^H^N^O.^HgO requires: C, 50.32; H, 7.74; N, 13.54$. 184759 Example 2 (a) N- f5- f 5-( Dimethylamino )methyl-2- furanyl Ipentyl ]-N' -methylthiourea 5- [5-(Dimethylamino )methyl-2-furanyl ]pei:tanamine (0.5 g) and methylisothiocyanate (0.25 g) were stirred in acetonitrile at room temperature for 24 hr. Solvent was removed and the product purified "by column chromatography (silica/methanol) to give after trituration with ether N- [5- ( 5 - (di me thyl amino ) me thy 1- 2 - furanyl ]pen tyl ]-N1 -me thyl-thiourea as off-white crystals m.p. 66-69°. Similarly prepared from the corresponding amine and methylisothiocyanate were: (h) N- [3- [ [ [5-(Dimethylamino )methyl-2-f uranyl ]methyl ]thio ]-propyl]-N*-methylthiourea. Analysis Found: C, 51.38; H, 7.93; N, 13.41. C13H23N20S2 requires: C, 51.79; H, 7.69; N, 13.94$. (c) ht- [4- [5-(Dimethylamino )methyl-2-furanyl Jbutyl ]-N'-methylthiourea. NMRt(CDCl3) 8-8.6 m (4h); 7.72 s (6h); 7.35 t (2h); 6.98 d (3h); 6.2-6.8 m (4h); 4.0 d (2h); 3-3.8 m (2h). (d) N-[2-[[5-(Dimethylamino)methyl-2-furanyl]methoxy]ethyl ] Nf-methylthiourea. Analysis Found: C, 51.91; H, 8.14; N, 14.98. Cj^gHgiNjOgS.-^HgO requires: C, 51.40; H, 7.91; N, 14.99$. Example 3 (a) N- f2— T [ f5—CDimethylamino)aiethyl-2-furanyl Imethyl ]thio ]-ethyl l-N'-( 2-methoxyethyl) thiourea l-(lsothiocyanato)-2-methoxyethane (1.17 s) 2" [ [ [5-( dimethylamino )methyl-2-furanyl ]methyl ]thio ]-ethanamine (2.14 g) in acetonitrile were stood overnight. Solvent was removed and the residual oil chromatographed (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-f uranyl ]methyl ] thio ]ethyl ]-N * - (2-methoxyethyl) thiourea as a pale oil Rf 0.45. Analysis Pound: C, 50.64; H, 7.51; N, 12.58. ClitH25N302S2 requires: C, 50.75; H, 7.55; N, 12.69$. Similarly prepared from the corresponding isothiocyanate and 2- [ [[5-(dimethylamino )methyl-2-furanyl ]methyl ]thio ]-ethanamine were: (h) N- [2- [ [ [5-(Dimethylamino )methyl-2-furanyl ]methyl ]thio ]-ethyl]-N'-(2-propenyl)thiourea. Found: C, 52.68; H, 7.58; N, 13.16. Cjj^HgjN^OS2.'i'HjjO requires: C, 52.14; H, 7.50; N, 13.03$. ( c) N- [2- [ [ [5- (Dimethylamino )methyl-2-furanyl jmethyl ] thio ]-ethyl]-N-(l-methylethyl)thiourea. Analysis Found: C, 51.84; H, 7.88; N, 13.00. C^Bg^OSg.^HgO requires: C, 51.90; H, 8.09; N, 12.97$. "T! — N, ✓ '.vi' ^ £ Example 4 N— f2— f T f5-(Methylamino )methyl-2«-furanyl Imethyl ]thio ]ethyl 1-N'-methylurea To a stirred solution of 2-[[[5-(methylamino)methyl-2-furajjyl jmethyl jthio ]ethanamine (1.5 g) in acetonitrile (24 ir).' was added dropwise a solution of me thyl isocyanate (O.'i''j g) in acetonitrile (15 ml). After 30 mins the solution was evaporated to dryness to give an oil which was column chromatographed firstly on^oilioo/methanol: 0.88 ammonia 79:1 then alumina/methanol to give an oil consisting of N-[2-[[[5-(methylamino)methyl-2-furanyl]-methyljthio]ethyl]-Nf-methylurea (0.25 g). Analysis Found: C, 51.00; H, 7.38; N, 15.91. cnNi9N3°2S re(lu:i-res! C, 51.33; H, 7.44; N, 16.3396. Example 5 (a) N- f2- T f f5-(Dimethylaniino)methyl-2-furanyl jmethyl jthio j-ethyl j-N1 -methylurea Methylisocyanate (0.33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyljmethyljthio]-ethanamine, phthalhydrazide 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-[[[5- -40 , 8^7 5 9 (dimethylamino )methyl-2-furanyl ]methyl ] thio ] ethyl ] -N' -methylurea. Analysis Pound: C, 52.38; H, 7.61; N, 15.25. C12H21N3°2S,¥H2° r^quires: c> 52.24; H, 7.76; N, 15.3296. Similarly prepared was: (b) N-Methyl-N,-[2-[[[5-(l-pyrrolidinyl)methyl-2-furanyl]-methyl]thio]ethyl]urea. Analysis Found: C, 54.70; H, 7.33; N, 14.07. C^HgjN^OgS.^HgO requires: C, 54.87; H, 7.89; N, 13.71%. Example 6 (a) N-f2-rrr5-(Dimethylamino)methyl-2-furanylImethyl1-thiolethyl1-N1-(1-methylethyl)nrea 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]-ethanamine (2.14 g) and isopropylisocyanate (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)methyl-2-furanyl]methyl ]thio]ethyl-N' - (1-methylethyl )urea as crystals m.p. 65-67° (2.8 g). Similarly prepared were: (b) N- [ 3- [ [ [5- (Dimethylamino )me thy 1-2-f uranyl ]methyl]-thio]propyl]-N'-methylurea m.p. 69-69.5°. Example 7 N-[2-[[[5-(Dimethylamino)methyl-2-furanylImethyl]thio]-ethyl]urea A solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]- 8 47 5 9 methyl]thio]ethanamine dihydrochloride (2.8 g) and potassium cyanate (3.75 g) in water (50 ml) was heated on a steam bath for 8 hr. Excess solid sodium carbonate was added and organic material continually extracted with diethyl 5 ether. The extracts were evaporated and the residue after column chromatography yielded N-[2-[[[5-(dimethyl-amino)methyl-2-furanyl]methyl]thio]ethyl]urea as a waxy solid (1.28 g). Analysis Found: C, 48.22; H, 7.50; N, 15.61. C^Hj^N^OgS.HgO requires: C, 48.00; H, 7.63; 10 N, 15.2796. Example 8 N— f 2— f f r 5-(Dimethylamino )methyl-2-furanyl Imethyl 1 thiol -ethyl1-N*-nitroguanidine A solution of 2-[[[5-(dimethylamino)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)methy 1-2-furany 1 ]methyl]-20 thio]ethyl]-N'-nitroguanidine m.p. 103-104°. Example 9 (a) N-Cyano-N1 - [2- [ [ [5- (methylamino )me thy 1-2-furanyl ]methyl ]-thio]ethyl]-N' '-methylguanidine A mixture of 2-[[£5-(methylamino)methyl-2-furanyl]-25 methyl]thio]ethanamine (2.0 g) and N-cyano-N'-methylcarbamimido- -42- thioic 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 crudp product was purified "by column chromatography Rf O.65 (silica/methanol:ammonia 79:1) to give N-cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio ]ethyl]-N'1 -methylguanidine (1.05 g) m.p. 81-85°. In a similar manner were prepared from the corresponding amine and N-cyano-N'-methylcarbamimidothioic acid, methyl ester: (b) N-Cyano-N'- [2- [[[5- (1-methylethyl) amino ]me thyl-2-furanyl jmethyl jthio jethylj-N' '-methylguanidine. Analysis Found: C, 54.73; H, 7.82; N, 22.31. C-^Hg^N^OS requires: C, 54.34; H, 7.49; N, 22.64#. (c) N-Cyano-N1- [2- [[ [5-(diethylamino ) me thyl-2-f uranyl j-methyljthiojethylj-N' '-methylguanidine. Analysis Found: C, 53.54; H, 7.82; N, 20.65. C^Hg^OS.-lHgO requires: C, 53.46; H, 7.70; N, 20.7896. (d) N-Cyano-N'- [2- [[ [5-(l-pyrrolidinyl)methyl-2-furanyl ]-methyl jthio jethylj-N''-methylguanidine. Analysis Found: C, 53.97; H, 6.87; N, 21.06. C^Hg^N^OS.^HgO requires: C, 53.79; H, 7.37; N, 20.9196. -43- (e) N-Cyano-N' - [3- [ [ [5-(dimethylamino )methyl-2-furanyl j- methyl jthio]propyl]-N''-methylguanidine. Analysis Pound: * C, 52.86; H, 7.^9; N, 20.64; C^Hg^NjjOS.^HgO re<luires: C, 52.80; H, 7.59; N, 21.20#. Example 10 N-Cyano-N' - f2- f f f5— ( dimethylamino )methyl-2-furanyl jmethyl ]-thiojethylj-N''-methylguanidine To a stirred suspension of potassium carbonate (20.7 g) in a solution of 2- [[ [5-(dimethylamino )methyl-2-furanyl ]-methyl jthio jethanamine (10.7 g) and N-cyano-N '-me thylcarbam-imidothioic 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-(dimethylaminomethyl)-2-furanyl j-methyljthiojethylj-N'-methylguanidine (0.35 g) m.p. 79-81.5°. To a further portion (225 ml) was added a solution of * sebacic acid (9.09 g) in ethanol (30 ml), the filtered solution giving the sebacate salt (13.74 g) m.p. 92.5-94°. Analysis Pound: C, 54.91; H, 7.94; N, 14.02. C^Hg^N^OS. C10H18°4 re(luires: c» 55.51; H, 7.90; N, 14.07#. -44- 184759 Example 11 N-Cyano-N1- (2-methoxyethyl)carbamimidothioic 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 5 solution of methoxyethylisothiocyanate (11.7 g) in absolute ethanol was added to 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 10 with water to give N-cyano-N'-2(methoxyethyl)carbamimido-thioic 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 acid, methyl ester, 15 m.p. 109-110°. (a) N-Cyano-N'-f 2-[ [" [5-(dimethylamino )methyl-2-:furanylImethyl 1-thiol ethyl 1-N' '-(a-nethoxyethyl )guanidine A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]thio]ethanamine (2.14 g) and N-cyano-N(2-methoxyethyl)-20 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/methanol) to give N-cyano-N'-[2—[[[5—(dimethylamino)methyl-2-furanyljmethyl]thio]ethyl]-N'*-25 (2-methoxyethyl)guanidine (1.4 g). Analysis Found: C, 50.51; -45- 1 £.47 5 9 H, 7.20; N, 19.41, C15H25N502S.H20 requires: C, 50.42; H, 7.50; N, 19.60#. In a similar manner were prepared from 2-[[[5-(dimethyl-amino)-methyl-2-furanyl]methyl]thio]ethanamine and the corresponding N-alkyl-N'-cyanocarbamimidothioic acid, methyl ester: (b) 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^^Hg^N^OS.HgO requires: C, 53.09; H, 7.37; N, 20.64#. (c) N-Cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]thio]ethyl]-N''-(l-methylethyl)guanidine. Analysis' Found: C, 52.97; H, 7.70; N, 20.57. C15H25N50S H20 requires: C, 52.78; H, 7.91; N, 20.52#. Example 12 (a) N-r2-f ff5-(Dimethylamino)methyl-2-furanyllmethyl]thiol-ethyll-N'-methylguanidine A mixture of 2-[[[5-(diinethylamino)methyl-2-furanyl]-methyl]thio]ethanamine (2.14 g) and N,S-dimethylisothiouronium iodide was heated on a steam bath for 3 hr. The residue in methanol was eluted from an Amberlyst A26 ion exchange resin to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]thio]ethyl]-N'-methylguanidine as an amber oil -46- • c, 9 t- ' L' ' V . * I (1.5 g). Analysis Pound: C, 50.92; H, 8.23; N, 19.90. C12H22N40S*^2° re<luires: C, 50.76; H, 8.34; N, 19.74#. Similarly prepared were: (b) N- [2- [ [ [5-(Dimethylamino )methyl-2-f uranyl Jmethyl ]thio ]-ethyl]-n',N'1-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 br (2h). Example 13 N-Methyl-l-methylthio-2-nitroethanamine A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 3356 ethanolic methylamine in 0.8 litres of ethylene dichloride; 0.9 4 mole) was added over hr at 70° to a stirred solution of 1,l-bismethylthio-2-nitro-ethene (99.0 g, 0.6 mole) in ethylene dichloride (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- f [ 1*5-(Methylamino)methyl-2-furanyl Imethyl ]thio ]ethyl ]-N1-methyl-2-nitro-1. l-ethenediamine hydrochloride A solution of 2- [[[5-(methylamino )methyl-2-furanyl ]-methyl]thio]ethanamine (10 g, 0.05 mole) and N-methyl-1- *r i / D methylthio-2-nitroetheneamine (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 recrystallised from ethanol as a colourless micro-crystalline solid (10.1 g) m.p. 162°. Analysis Found: C, 42.6; H, 6.3; N, 16.4. C-j^^qN^OjS.HCI requires: C, 42.8; H, 6.2; N, 16.6#. Example 14 (a) N- [2- [ f f5-(Methylamino )methyl-2-furanyl Imethyl lthio 1-e thyl ]-N' -me thyl-2-ni tro-1, l-ethenediamine A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]-methyl ]thio ]ethanamine (0.9 g) and N-methyl-1-methylthio-2-nitro-etheneamine was heated at 100-120° for 30 mins under water pump pressure. The residue was purified by column chromatography (silica/methanol:0.88 ammonia) to give N- [2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]-ethyl ]-N1-methyl-2-nitro-1, l-ethenediamine which was crystallised from acetonitrile m.p. 106-108° (0.65 g). In a similar manner were prepared: (b) N- [2- [ [ [5- [(1-Me thyl ethyl) amino ]methyl-2-furanyl]-methyl jthio ]ethyl ]-N'-methyl-2-nitro-1, l-ethenediamine. -48- 7 5 9 Analysis Found: C, 49.75; H, 7.21; N, 16.36. Cj^H^N^S.fcE^O requires: C, 49.83; H, 7.47; N, 16.60#. (c) N-Methyl-2-nitro-N'-[2-[[[5-[(2-phenylethyl)aminoj-methylj-2-furanyl]methyl]thio]ethyl]-l,l-ethenediamine. Analysis Found: C, 57.19; H, 6.53; N, 13.83. C^H^N^S.-friy) requires: C, 57.12; H, 6.81; N, 14.02#. (d) N-Methyl-2-nitro-N1-[2-[[[5-[(l-piperidinyl)methylj-2-furanyljmethyljthio jethylj-1,l-ethenediamine. Analysis Found: C, 53.36; H, 7.51; N, 14.23. CjgH^N^S.^O requires: C, 53.33; H, 7.44; N, 15.61#. (e) N-[2-[[[5-[2-[Dimethylamino jethylj-2-furanyljmethyljthio j-ethylj-N'-methyl-2-nitro-1,l-ethenediamine, m.p. 95.5-96°. (f) N-[2-[[[5-[3-[Dimethylamino jpropyl]-2-furanyljmethyl]-thiojethylj-N'-methyl-2-nitro-1,l-ethenediamine. NMR T (CDC13), 8.1-7.1 m (6H); 7.65 s (6H); 7.1 s (3H); 6.5 m (2H) ; 6.28s (2H); 4.0 m (2H); 3.38 s (1H). (g) N- [2- [ [ [5- [4- [Dimethylamino jbutyl j-2-furatiyl jmethyl ]-thiojethylj-N-methyl-2-nitro-1,l-ethenediamine. Waxy solid analysis found: C, 53.90; H, 7.95; N, 15.64. Ci6H2qN403S requires: C, 53.91; H, 7.92; N, 15.72#. -49- , ,47 59 (h ) N-[ 2- [ [ [5- (Ethylmethylami.no ) me thyl-2-furanyl ]me thyl ] -thio]ethyl]-N'-methyl-2-nitro-l,l-ethenediamine. NMR t;(CDCL3) 8.90 t (3H); 7.76 s (3H); 6.8-7.5 m (7H); 6.5 br (2H); 6.42 s (2H); 6.25 s (2H); 3.77 s (2H); 5 3.35 s (1H). (i) N—[2—[[[5—C[2-(dimethylamino)ethyljaminojmethyl-2-furanyljmethyl]thi o]ethyl]-N'-methyl-2-nitro-1,1-ethene-diamine. NMR~£(CDCl^) 7.79 s (6h); 7-7.6 m(lOH); 10 6.6 m (2H); 6.26 s (2H); 6.22 s (2H); 3.85 m (2H); 3.37 s (1H); 2-3.2 hr (1H); 0.8-0.2 hr (1H). (j) N-[2-[5-(Dimethylamino)methyl-2-furanylmethoxy]etlyl]-N1-methyl-2-nitro-1,l-ethenediamine, m.p. 110-112°. 15 Example 15 N- f 2- [ f T 5- (Dimethylamino )methyl-2-furanyl Imethyl 1 thio 1 ethyl 1 -N'-methyl-2-nitro-l.l-ethenediamine N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45-50°. 20 2-[[[5-(Dimethylamino) methyl-2-furanyljmethyljthio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 3i hr. The solution was then heated at reflux for £ hr, cooled to 70° and 4-methyl-pentan-2-one (2 litres) added. The water was removed hy 25 azeotropic distillation under reduced pressure (260 torr) 4* -50- ; ; 47 5 9 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-furanyljmethyljthioj-ethylj-N'-methyl-2-nitro-1,l-ethenediamine (380 g) was filtered off and dried m.p. 69-70°. Example 16 N-Methyl-2-nitro-Nt -\2- TI" f5- f (1-pyrrolidinyl )methyl ]-2-furanyl jmethyl jthio jethyl j-1, l-ethenediamine A mixture of 2-[[[5-(l-pyrrolidino)methyl-2-furanylj-methyljthiojethanamine his oxalate salt (2.1 g), potassium hydroxide (1.12 g) and N-methyl-(l-methylthio)-2-nitro-ethenamine (0.9 g) in water (9 ml) was stirred at room temperature for 18 hours. The water was removed hy evaporation under reduced pressure and the residue extracted with 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; H, 7.05; N, 16.57. ci5H24N4°3S requires: C, 52.92; H, 7.11; N, 16.46#. Example 17 N- \2- f [" f5-(Methylamino)methyl-2-furanyl jmethyl jthio jethyl 1-N'-methylurea To a stirred solution of N-[2-mercaptoethylj-N1-methyl-urea (2.0 g) in concentrated hydrochloric acid at 0° was -51- 475 added dropwise a solution of 5-(methylamino)methyl-2-furan-methanol (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 ammonia 79:1)* The relevant eluate was evaporated to dryness to give an oil identical to product of Example k (0.42 g). Example 18 N-Cyano-N1 - 1*2- [" T f5- (dimethylamino )methyl-2-furanyl Imethyl 1-thio lethyl ]-N'1 -methylguanidine To a stirred solution of N-cyano-N'-(2-mercaptoethyl)-N*'-methylguanidine (1 g) in concentrated hydrochloric acid at 0° was added 5-(dimethylamino)-2-furanmethanol (0.98 g) dropwise during 10 mins. 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-f[5-(Aminomethyl)-2-furanyImethyllthiolethyl1-N''-cyano-N' -methylguanidine 2-(5-Chloromethyl-2-furanylmethyl)-lH-isoindole-l.3-(2H)-dione 2-(5-Hydroxymethyl-2-furanyImethyl)-lH-i so indole-1,3(2H) - 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 cyclohexane-benzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-chloromothy1-2-fur anylmethy1)-1H-isoindo1e-1,3(2H)-dione (10.1 g) m.p. 119-122° (dec.). Analysis Found: C, 61.32; H, 3.71; N, 5.00. ClitH1()ClN04 requires: C, 60.99 H, 3.66; N, 5.08#. N*'-Cyauo-N-[2-175-f(1.3-dioxo-2H-isoindol-2-yl)methyl1-2-fur any Imethyl lthio lethyl 1-N1 -methylguanidine To a stirred solution of N1'-cyano-N-(2-mercaptoethyl)-Nf-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)-lH-isoindole-1,3(2H)-dione (1.74 g) in dry dimethylformamide (3 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 f5-(Aminomethyl)-2-furanyImethyllthiolethyl1-N*1-cyano-N'-methylguani dine A suspension of N''-cyano-N-[2-[[5-[(1,3-dioxo-2H-isoindol-2-yl)me thyl ]-2-furany Imethyl ]thio ]ethyl ]-N' -methyl- -53- "J "'■/ '7 5 9 guanidine (4.45 g) and 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 acid. 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/methanol:0.88 ammonia 79si). Evaporation of the relevant eluate yielded an oil which slowly solidified consisting of the title compound (1.88 g) m.p. 80-82". Analysis Found: C, 49.57; H, 6.66; N, 25.93. CjjH-j^NfjOS requires: C, 49.41; H, 6.41; N, 26.20#. Example 20 N— f 2— f f f 5-(Dimethylamino )methyl-2-f uranyl ]methyl ]thio ]ethyl ]-N1-me thyl-2-ni tro-1.1-ethanediamine 2-Nitroethylene thiazolidine A mixture of cysteamine hydrochloride (11.36 g), potassium hydroxide (5.61 g) and l,l-Ms(methylthio)-2-nitroethene (16.52 g) in water (30 ml) and ethanol (100 ml) was heated -54- 47 5 9 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-nitroethylene thiazolidine (9.2 g) m.p. 141-142°. Analysis Found: C, 32.91} H, 4.13; N, 19.10. C^HgNgOgS requires: C, 32.87; H, 4.14; N, 19.17#. N-(2~Mercaptoethyl)-Nt-methyl-2-nitro-1.l-ethenediamine A solution of 2-nitroethylene thiazolidine (5 g) in a solution of methylamine 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-mercapto-ethyl)-N'-methyl-2-nitro-1,l'-ethenediamine (4.98 g), m.p. 174-175° , decomp. 209-211° . g u tJ O s Analysis Found: C, 34.05; H, 5.87; N, 23.85J C, 33.88; H, 6.26; N, 23.71#. N-[2-[f f5—(Dimethylamino)methyl-2-furanylImethyl]thiolethyl1-N*-methyl-2-nitro-1,l-ethenediamine N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,l-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 toy preparative layer chromatography to give the title compound 847 5 9 (100 mg) as Example 15. Example 21 N- [2- [175-1Dimethylamino )methyl-2-furanyl Imethyl ] thio lethyl ]-N'-methyl-2-nitro-1,l-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-nitro-1,l-ethenediamine (354 mg) in concentrated hydrochloric acid (l ml) and glacial acetic acid (1 ml) was added dropwise and the mixture left to stand at room 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-Cyano-N1 - f2- [ [ [5- (dimethylamino )methyl-2-furanyl Imethyl ]-thiolethyl1-Nf'-methylguanidine N-Cyano-N' - f2- f f f5-(dimethylamino)methyl-2-furanyl Imethyl 1-thio lethyl lcarbadmiiai do thioic acid, methyl ester 2- [ [ [5- (Dimethylamino ) me thyl-2-furanyl jmethyl ]thio ]-ethanamine (1.07 g) was added to a solution of N-cyanoimido-carbamodithioic acid, dimethyl ester (0.73 g) in ether, and stirred overnight. The crystalline solid which formed was filtered, washed with ether and dried to give N-cyano-N'-[2- [ [ [5-(dimethylamino)methyl-2-furanyl jmethyl jthio jethyl j- -56- ' p. & ~ 5 9 v. w * carbamimidothioic acid, methyl ester (1.14 g) m.p. 78-79°. N-Cyano-N' - [2- [ \ [5-(dimethylamino )methyl-2-f uranyl Imethyl ]-thiolethylj-N''-methylguanidine A solution of N'-cyano-N-[2-[[[5-(dimethylamino)methyl-2-furanylImethyl]thiojethyljcarbamimidothioic acid, methyl ester (1.06 g) in ethanolic methylamine 33# (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetate-light petroleum (b.p. 80-100°) to give the title compound m.p. 77-80°. Example 23 N-Cyano-N' - [2- [ f f 5-(dimethylamino ) me thy 1-2-furanyl jmethyl ]-thiolethyl1-N1'-heptylguanidine A mixture of heptylamine (1.15 g) and N-cyano-N'-[2-[ C [5- (dimethylamino )methyl-2-furanyl ]methyl jthio jethyl j-carbamimidothioic 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)methyl-2-f uranyl jmethyl jthio jethyl j-N' •-hep tylguani dine hydrate (2.31g) Rf 0.49. Analysis Found: C, 56.99; H, 8.32; N, 17.53. C19H33N5OS.H2O requires: C, 57.43; H, 8.81; N, 17.63#. Example 24 N- \2- f f f5-(Dimethylamino )methyl-2-furanyl jmethyl jthio jethyl ]-N1 -me thyl-2-ni tro-1. l-ethenediamine 2- [ [ [5-(Dimethylamino)methyl-2-furanyl jmethyl jthio ]- 1 84759 ethanamine (4.25 g) and 1,l-bis(methylthio)~2-nitroethene (3.3 g) were refluxed in acetonitrile (50 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 charcoal. Filtration and evaporation of the solvent gave the title compound as Example 15 (5.0 g). Example 25 (a) N- f2- [" [ T5-( Dimethylamino ) me thy 1-2-furanyl ]methyl jthio ]-ethyl 1-N' - (2-methoxyethyl) -2-ni tro-1, l-ethenediamine 2- [ [[5-(Dimethylamino)methyl-2-furanyl]methyljthio j-e than amine (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 (0.75 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-2-furanyljmethyljthio jethylj-N*-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (l.O g). NMRX(CDC13) 7.73 s (6h); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H). Similarly prepared was: (h) N-[2-[[[5-(Dimethylamino)methy1-2-furanyljmethyljthio]-ethylj-2-nitro-1,l-ethenediamine, m.p. 100-101°. 1847 59 Example 26 (a) N- ["4- f 5-(Dimethylamino ) me thyl-2-furanyl Ihutyl ]-N' -methyl-2-nitro-1.l-ethenediamine 4-[5-(Dimethylaraino)methyl-2-furanyl]butanamine (0.7 g) and l,l-t>is(thiomethyl)-2-nitroethene (0.6 g) in acetonitrile (12 ml) were refluxed for 22 hr. Solvent was removed and the residue in 33# ethanolic methylamine refluxed for 2 hr. Solvents were removed and the residue purified liy column chromatography (silica/methanol) to give N-[4-[5-(dimethylamino ) me thyl-2- furanyl Jbutyl]-N'-methyl-2-nitro-1,1-ethene-diamine (310 mg). Analysis Found? C, 55.54; H, 8.23; N, 17.75. C^Hg^N^O^.-jHgO requires: C, 55.26; H, 8.22; N, 18.42#. Similarly prepared were: (h) N-[5-[5-(Dimethylamino )methyl-2-furanyl ]pentyl]-N'-methyl-2-nitro-1,l-ethenediamine. Analysis Found: C, 56.76; H, 8.36; N, 17.37. Cj^Hg^N^O^.^HgO requires: C, 56.43; H, 8.46; N, 17.55#. ( c) N- [3- [ [5- (Dimethylamino )methyl-2-furanyl ]thio ]propyl ]-N*-methyl-2-nitro-1,l-ethenediamine. Analysis Found: C, 49.36; H, 7.19; N, 17.45. C^H^N^S requires: C, 49.66; H, 7.05; N, 17.84#. (d) N- [3- [5-(Dimethylamino )methyl-2-f uranyl jpropyl ]-Nf- j 8^-7 5 9 methyl-2-nitro-1,l-ethenediamine. Analysis Pound: C, 55.09; H, 7.84; C13H22N403 requires: C, 55.31; H, 7.72#. (e) N- [2- [ [ [5- (Dimethylamino )methyl-2-f uranyl ]methyl ]thio ]-ethyl]-N'-methyl-2-nitro-1,l-ethenediamine. Analysis Found: C, 51.38; H, 7.44; N, 15.66. C^HggN^O^S.iHgO requires: C, 51.26; H, 7.74; N, 15.94#. (f ) N- [3- [ [ [5- (Dimethylamino )methyl-2-furanyl ]methyl ]thio ]-propyl ]-N* -me thyl-2-ni tro-1,1-ethenediami ne. Analysis Found: C, 49.57; H, 7.20; N, 15.59. C^H^N^S.^O % requires: C, 49.86; H, 7.47; N, 16.61#. Example 27 (a) N- Cyano-NT — f 4— f 5— (dime thyl amino) me thy 1 -2- furanyl ]buty 1 ] N'*-methylguanidine 4-[5-(Dimethylamino)methyl-2-furanyl]butanamine (0.4 g) and N-cyanoimidocarhamodithioic acid, dimethyl ester (0.3 g) were stirred in ethanol at room temperature for 3 hr. A solution of 33# methylamine 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 (silica/methanol) to give the product as a pale yellow oil. NMR"C(CDC13) 8-8.5 br (4H); 7.77 s (6H); 6.61-7.5 m (9H); 4.0 m (2H); 2.8-3.7 m (2H). -60- I ? "■? 5 9 In a similar manner were prepared: (b) N-Cyano-N' - [5- [5- (dimethylamino )methyl-2-f uranyl ]pentyl ]-N»-methyl guanidine. NMRT(CDC13) 8.0-8.7 br (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— f2— f f f 5-(Dimethylamino )methyl-2-furanyl Imethyl lthio ]-ethyl 1-N' -me thane sulphonyl-N1 1 -methylguanidine Methanesulphonyliminodithiocarbamic acid, dimethyl ester (1.9 g) and 2- [ [[5—(dimethylamino)methyl-2-furanylImethyl]thio-ethanamine (2.14 g) were stirred in ethanol at room temperature for 3 br. 33# Ethanolic methylamine (20 ml) was added and the whole heated under reflux for 16 hr. The product was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino )methyl-2-f uranyl ]methyl ]thio ]ethyl ]-N'-methanesulphony1-N*'-methylguanidine as a pale oil (2.7 g). Pound: C, 43.54; H, 7.05; N, 15.48. C^H^N^Sg.^O requires: C, 43.70; H, 7.00; N,15.69#. Similarly prepared was: (b) N-Benzene sulphonyl-N1- [2- [ [ [5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N' '-methylguanidine. Analysis Pound: C, 50.30; H, 6.25; N, 12.93. ClgH26N403S.H20 requires: C, 50.47; H, 6.54; N, 13.08#. Example 29 N-Cyano-N'- [2- f [ f 5-(dime thyl ami no )me thyl-2-furanyl Imethyl 1-thiolethyl1-N''-methylguanidine -61- A solution of silver nitrate (8.25 g) in dimethylformamide (50 ml) -was added dropwise to a solution of N-cyano-N'-methylcarbamimidothioic acid, methyl ester (6.1 g), triethylamine (4.8 g) and 2- [[[2-furanyl]methyl]thio]ethanamine (7.8 g) in methanol (150 ml). After 42 hr at 50° the mixture was filtered and the 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-cyano-N1-[2-[[[2-furanyl]methyl]thio]ethyl]-N''-methylguanidine (3.9 g) m.p. /8-82°. 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 etliyl acetate and aqueous base. The organic extracts were combined, dried and evaporated to give an oil which on treatment with sebacic acid in iso-propanol gave the sebacic acid salt of the title compound (2 g) m.p. 93-94°. Example 30 N-f2-T f \5~(Dimethylamino)methyl-2-furanylImethyllthio]ethyl]-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-f uranyl ]methyl ] thio ]ethanamine (4.28 g) was added slowly and when addition was complete the -62- 184759 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 N,N-dimethyl-5-[[[2-(isothiocyanato)ethyl]thio]methyl]furan-methanamine as an oil RF 0.43 (silica/methanol). The crude isothiocyanate (0.46 g) was dissolved in 33# ethanolic methylamine (23 ml), left to stand overnight and N- [2- [ [ [5-( dimethylamino )methyl-2-f uranyl ]me thyl] thio ]ethyl ]-N1 -methylthiourea isolated as a pale oil (0.16 g) identical to material prepared from 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine and methyl isothiocyanate. Example 31 N-Cyano-N1- [2- f [ [5-(dimethylamino) me thyl-2-furanyl ]methyl ]-thio]ethyl ]-N' '-methylguanidine A solution of N-[2-[[[5-(dimethylamino)methyl-2-furanyl]-me thyl ] thio ] e thyl ]-N'-me thyl thiourea (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 sebacic acid in isopropanol gave the title compound as its monosebacate salt (0.7 g) m.p. 90-92°. Example 32 N- [2- r f f 5- (Dimethylamino )methyl-2-f uranyl ]methyl ]thio lethyl ]-N'-methyl-2-nitro-1.l-ethenediamine hydrochloride N- [2- [ [ [5-(Dimethylamino )methyl-2-f uranyl ]methyl ]thio ]ethyl ] -63- 1 £47 59 N'-methyl-2-nitro-1,l-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 hydrochloride crystallised and was filtered off, washed with a mixture of industrial methylated spirit 74° o.p. (50 ml) and ethyl acetate (50 ml) and was dried at 50°. The product (50 g) was obtained as an off-white solid m.p. 133-134°. -64- q a 7 S 9 Example 33 Pharmaceutical Compositlong (a) Oral Tablets 50 mg for 10,000 tablets Active ingredient 500 g 5 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 jm sieve and then the four powders are intimately mixed in a blender and compressed 10 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) In.jectlon for Intravenous administration (200 mg in 2 ml) °h w/w 15 Active ingredient 10.0 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 20 is 5*0. The sdlution is sparged with nitrogen and is then clarified by filtration through a membrane filter of pore size 1.35 ^un* 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 25 minutes. J&B- -65- 1847 59 (c) Oral Sustained Release Tablets 150 mg for 10.000 tablets Active ingredient Cutina HR** 1.50 kg 0.40 kg 2.060 kg 40g Anhydrous lactose U.S.P. Magnesium Stearate BP The active ingredient, Anhydrous lactose and most of the Cutina HR are intimately mixed and then the mixture is moistened by mixing with a 10# solution of the remainder of the Cutina HR in Industrial Methylated Spirit OP 74. The moistened mass is granulated through a 1.2 mm aperture sieve and dried at 50°C in a fluidised bed dryer. The granules are then passed through a 0.85 mm aperture sieve, blended with the magnesium stearate and compressed to a hardness of at least 10 kg (Schleuniger tester) on a tabletting machine with 12.5 mm diameter punches. ** Cutina HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Limited, London. (d) Oral 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 -66- 18 47 5 9 by adding gradually hydroohloric 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 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 jam 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. (f) Ointment # by weight Active ingredient 2.0 White Soft Paraffin BP to, 100 The drug is sieved through a 150 jam 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 Cetomacrogol Emulsifying Ointment BP 30.0 Chlorocresol 0.1 Distilled water to 100 -67- 1 •* 7 5 9 The drug is passed through a 150 jam aperture sieve and is then blended intimately with the Cetomacrogol Emulsifying Ointment at 65°C. The chlorocresol is dissolved in the water at 65°C and this solution is then mixed with the oily drug 5 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 Example 10 and Example 15. Other compounds according to the invention may 10 also he used. -68- 1 3 4-759 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 j 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 pferfusion i 84759 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. St ah wounds are made in the body wall and the cannulae passed through. The stomach is perfused through the oesophageal and pyloric cannulae with 5# dextrose solution at 39° C at a rate of 1.5 ml/min. for each cannula. The effluent is passed over a micro-flow pH electrode and recorded via a pH meter and flat bed recorder. The basal output of acid secretion from the stomach is monitored by measurement of the pH of the perfusion effluent and then increased acid secretion is induced by a continuous intravenous infusion of a sub-maximal dose of histamine; this produces a stable plateau of acid secretion and the pH of the perfusion effluent is determined when this condition is obtained. The test compound is then administered to the rat by an intravenous injection and the change in 'gastric' acid secretion is monitored by measuring the change in the pH of the perfusion effluent. From the change in pH.of the perfusion effluent, the difference in acid secretion between basal output and the histamine stimulated plateau level is calculated as hydrogen </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 1 84759 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. ED,-q 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 ED,-q value by the standard method of least squares, as used for any dose response line. Using the above procedure the following were obtained: Compound of Example No. ED50 2(c) 1.5 0.65 8 9(a) 2.30 10 1.39 14(a) 14(f) 14(h) 15 0.23 0.8 0.48 0.18 25(a) 26(a) 0.55 1.82 18475? MOW AMENDED WHAT WE CLAIM IS:

1. Compounds of the general formula I: R Rr N-Alk II \\ (cii2)nxyCII9)mN,ICN11 2'vx (I) and physiologically acceptable salts theneof and N-oxides and hydrates, in which R^ aim Rg which inay he the same or different represent hydrogen, lower al/yl having 1 to 8 carbon atoms, cycloalkyl/ lower alkerjyl having 3 to 6 carbon atoms, aralkyl 9fr lower alky^ having 1 to 8 carbon atoms interrupted byf an oxygen ajfom or a group -^1-, *4 or and R2 may, /together witjtf the nitrogen atom to which they are attached, forirt a heterocyclic ring which may contain other heteroat^ms selected from O and -N-; k4 R2 is hydrogen, lower alkyl having 1 to 8 carbon atoms, lpwer alkenyl/having 3 to 6 carbon atoms or alkoxyalkyl; or S; y represents = S, = 0, = NR5 or = CHRg; /Alk denotes a straight or branched alkylene chain of 1 yco 6 carbon atoms; R4 is Kydrogen or lower alkyl having 1 to 8 carbon atoms; Rcj Is H, nitro, cyano, lower alkyl having 1 to 8 carbon /atoms, aryl, alkylsulphonyl, or arylsulphonyl; represents nitro, arylsulphonyl or alkylsulphonyl; is an integer from 2 to 4; and -72- * M.Z. i GFflCS 3-OCT5979 NOW AMENDED 184759 n is 1 or 2; or when X is -S-, or -CH2~/ n is zero, 1 or 2. /

2. Compounds as claimed in claim 1 in wifiLch and independently represent hydrogen, alkyl/ phenylalkyl/, dialkylamino alkyl or together with trie nitrogen atom form a 5- or 6-membered saturated heterocyclic ring,/Alk represents a straight alkylene chain of 1 toy^ carbon at9<hs, Y is = S, = 0, = CHNO2 or =NRg where R5 iaf hydrogen, nitro, cyano, lower alkyl having 1 to 8 cartton atoms, alkylsulphonyl or benzenesulphonyl, and X, m,Ai, and R3 have the meanings given in claim 1.

3. Compounds as claimed in either/fclaim 1 or 2, in which aryl as a group or pain: of a groups represents phenyl or phenyl substituted/with alkyl,yalkoxy or halogen.

4. Compounds asyfclaimed in ^tny of claims 1 to 3 in which n + m is 3 or 4/

5. Compound^ 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 Rl is Ji/or alWl and R2 is alkyl.

7. Compounds as/claimed in any of claims 1 to 6 in which amd/or Rg ar/ methyl or ethyl, -73- I'J. PATffi/T" 18475? SOW M«tN0W

8. Compounds as claimed in any of claim/ 1 to 7 in >&hich X is a sulphur atom.

9. Compounds as claimed in any of claims 1 to 8/ in which X represents a group -CHg-.

10. Compounds as claimed in clainr 1 in which/ft^ and Rg independently represent hydrogen^, alkyl of y to 3 carbon atoms or phenethyl or togethei/with the ni/trogen atom form , where R^ a pyrrolidine ring; Alk represents an alkylene chain of 1 to 3 carbon atoms; Y if' = S, = CHNQ^, or = NR^, is nitro, cyano, methylsCilphonyl or /benzenesulphonyl; represents hydrogen, alkyl of 1 to'3 carbon atoms, propenyl or alkoxyalkyl of 3/carbon atoms'{ n + m is 3 or k. and X / is as defined in claim 1. /

11. Compounds d claimed ir^claim 1 in which R^ and Rg independently/represent H,/alkyl of 1 to 3 carbon atoms, phenethyl oy together with the nitrogen atom form a pyrrolidine ring; Alk^epresents an alkylene group of 1 to 3 carbon atoms;/ Y is = S, = CHN0o, or = NR,_, where / / 5 R^ is/fiitro, cyanc/, methyl sulphonyl or benzene sulphonyl; X xj S or -CHg-j/ R^ is hydrogen, methyl or methoxyethyl; n/xs 1 and m is 2 or 3. ■'i.2. 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 = NCN, = NNOg, or = CHNOg; is hydrogen or methyl; X is S or -CHg-; and n is 1 and m is 2 N.Z. PATSF'rr G7?ICE 3-oct 1979 1 847/9 MOW AMENDS'

13. A compound as claimed in claim 1 which jug N-[2-[[[5-(dimethylamino)methyl-2-furanyl jmethyljthiq^ethyI methylthiourea.

14. A compound as claimed in claim 1 wrfich is N-c/ano-N1-[2-[ [ [5-(dimethylamino)methy1-2-furanylJmethyl]thiomethylj-N"-me thylguani dine.

15. a compound as claimed in clafm 1 which iA N-[2-[[[5-( dimethylamino )methyl-2-furany^me thyl jthiq/jethyl j-N'-methyl-2-nitro-l,l-ethenediamine.

16. A compound as claimed An claim 1 which is N-cyano-N'-[2- [ [ [5-(methylamino )metl,)yl-2-furany}/jmethyl ]thio ]ethyl j-N"-methylguanidine.

17. A compound as claimed in claim 1 which is N-[2-[[[5-( diethylamino )methp^-2-furanyl^nethyl ]thio ]ethyl ]-N' -methyl- 2-nitro-l, 1-ethe/fediamine. /

18. a compoun/4 as claimed/in claim 1 which is N-[2-[[[5~ ( dimethylamino )methyl-2-furanyl jmethyl jthio ]ethyl j-N'-(2-methoxyetl]^l)-2-nitro-2/^l-ethenedi amine.

19. A Qi&npound as c^aimcd in claim 1 which is N-[2-[[[5-(dime'W(iylamino)metnyl-2—furanyl jmethyl j thio jethyl ]-N'-(2-9ethoxyethyl)/thiourea. 2(/. A compound as claimed in claim 1 which is N-[2-[[[5-4methyl£imint/)methyl-2-furanyl jmethyl jthio jethyl j-N'-methyl-2-ni tro-1 /l-ethenediamine. -75- w.r. , 5 - OCT 1979TS 1847b? uow

21. A compound as claimed in claim 1 which is^N-[3-[ [5-(dimethyiamino)methyl-2-furanyl ]thio jpropyl -methyl.^2-nitro-1,l-ethenediamine.

22. A compound as claimed in claim 1 wi/ich is N-[/-[[[5-(ethylmethylamino)methyl-2-furanyl jmeyt&yl jthio je-tynyl j-N'-methyl-2-nitro-1,l-ethenediamine.

23. a compound as claimed in cla^m 1 which N-[2-[[[5-(dime thyl amino )methyl-2-furanyJ/jme thyl jthio jethyl j-N' -nitroguanidine.

24. a compound as claime&nLn claim 1 ^nich is N-[2-[[[5-(dimethylamino)methyl-2-^uranyl jmethyljthio jethyl j-N' - / t inetlianesulphonyl-N" -methylguanidine. / /

25. a compound as olaimed in clctim 1 which is N-[4-[5- (dime thyl amino) me^nyl-2-furanyl jbuty1 ]-N' -methyl thiourea.

26. a compound/as claimcd in claim 1 which is N-bonzcnc-sulphonyl-N' r^2- [ [ [5-(dime/thylamino)mcthyl-2-furanyl jmethyl j- thio jethyl WtS"-methylguanidine . /

27. a compound as claimed in claim 1 which is N-[5-[5-(dimetjtylamino)met^iyl-2-f uranyl jpentyl j-N'-methyl-2-nitro-1, l-ethenediamine. 28/ a compouncL^as claimed in claim 1 which is N-cyano-N'-/ / [5- [5-(dimetiiylainino)methyl-2-furanyl jpentyl j-N'-methylguanidine/ 29• A/Compound as claimed in claim 1 which is N-[4-[5-(dimethylamino )methyl-2-iuranyl jbutyl j-N'-methyl-2-nitro- ill 1,1/etliene diamine. -76- 1847b9 SOW AMEND®

30. A compound as claimed in claim 1 which is if-cyano-N1-[4- [5-(dimethylamino )methyl-2-furanyl ]butyl ]7«"-methyl-guanidine.

31. A compound as claimed in claim 1 wh£ch is N-C2-E:LII5-C.3-Cdimethyl ami no] propyl] -2-f uranylj ni^thyl] thioj et^tfyl} -N1 • methyl-2-nitro-1,l-ethenediamine. .

32. a compound as claimed in cbum 1 which is N-[2-[[[5- [ [2 - (dime thyl amino ) ethyl ]amin^fme thy 1-2-furanyl ]methyl ]thio ]-ethyl ]-N'-methyl-2-nitro-l ,^£ethenedi amine.

33. Physiologically acceptable acid addition salts of the compounds of claims 13/to 32. /

34. Hydrochlorides^f the compounds of claims 13 to 32. 35- Compounds as/klaimed in claim 1 specifically herein described in Examples 1 to 3^ 01 claims 10 to/ik. »ther than those claimed in 36 r irises A process for the preparation of compounds as claimed in claip 1 which cor (a)^/reacting a cp^npound of formula II: / / / N-Alk (CH^XtCH^NH, 2'm (II) f in whfch R, , Rot Alk, n, X and m have the meanings givsn / in/claim 1 with a compound capable of introducing a group NOW AMENDED 1 p ) 'j 1 0 -CNHR3 m which R3 and Y have the meanings given in clai.iv 1/ J 7 said compound being selected from alkali metal cyanates or / thiocyanates or isocyanates of the formula RgNCO or isothiocyanates / of the formula R^NCS, or compounds of the formula R^NHC-P or/ 1R 5 / / RoNHC-P where P is a leaving group, and Ro , kc and Rc hav4 the | . 6 / CHRg / meanings given in claim 1; or (b) for the production of compounds in which Y is ^ group =NRjj or =CHRg, reacting a compound of formula II; R, X N-A3 k ^0jLt<5H2)nX(CHj^-P / « (HI) / / in which Q represents =NB^ or =CHRg,^4nd R^, R2, Alk, X, n, m, Rc, Rc. and P have th'e meanings given above, with a primary • . J amine of formula R3NH2 in which R^ has meaning given above; or (c) for the production of compounds in which X is sulphur ' / and n is 1 and when R^ and R^ are both hydrogen, Y is other than =CHN02, reacting a cojprfpound of the formula: / R, \ /ii" :| / J- Cj^()R7 / (V) or N-/VI k- 0 - CH„C1 IVI) / in/which R^, RVand Alk Have the meanings given above and R^ is rdrogen or an acyl group in which Ri and R9 when they are ' • / hydrogen may be protected, with a thiol of the formula VII: HS(CH2)mNHCNHR- (VII) v''r~C= in which Y, m and Rg have the meaning^ given above, if necessary with subsequent deprotection; or ^ OCTi979 -78" 181 NOW AMENDEO (d) for the production of compounds in which/Y is a group7 / •/ =NCN reacting a compound of formula I whereyY is sulphur^ ' with a heavy metal cyanamide; or (e) for the production of compounds in'which Y is ssNR,- and Alk is a methylene group, or a "branched alkylene /roup, / subjecting a compound of the formula VIII: (CH£)nX(CH2)mNHCNHR3 (VIII) 0^ > NRr in which X, n, m, and iCj have the meanings given above, to a Mannich reaction with an appropriate aldehyde and a / secondary amine or a sfelt of a primary amine or a secondary ' / amine; or / / / / (f) for the production of cojilpounds in which Y is sulphur, reacting a compound of IV: / / R, X(C!H2)mNCS (IV) c/ii wherein R, , RQ, /elk., X, m. and n have the meanings given / / above, with ay'amine of formula R^NHg wherein R^ has the meaning given above; in each carae the end-product if desired being isolated as a -79- N.2. ?: 1847b? * physiologically acceptable salt or being'converted from one such salt to another. ^

37. A process as claimed in claim 36(b) in which the compound of formula (III) is prepared by reacting the amine of formula ' (II) with a compound of the formula: or of the formula: / P / / / 5 / / I / in which R/and R., have the meaning given in claim 1 and /D O P is a leaving group.

38. iy'process as claimed in claim 36(f) for the production / of cpmpounds of formula (IV) in which a compound of formula (II) is reacted' with carbon disulphide and then with a .chloro formats ester. ./ / / / / "80" rf? N.Z.PAnv.TOT-":Cc ^ O-0CTH79 ReC£f-~ 184 NOW AMENDED J / /

39. A process as claimed in claim 36 substantially/as herein described with reference to Examples 1 to32.

40. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 36-39'. / '

41. compounds of formula II specified in clainv 36(a), that is ' / /' , / / \-A I k -1^ n jL ( CH2 ) „x( CH2)mKii2 (II) RZ ' / / / in which R^, R^, Alk, n, X and'm have the meanings given in any of claims 1 to 12. ^

42. Compounds as claimed/in claim 41, the production of / which is specifically described in Examples A to L.

43. Pharmaceutical cpmpositions comprising a compound as / claimed in claim 1 or claim 40, in association with a pharmaceutically^cceptable carrier or diluent, and if desired other active ingredients. -81- P J? 184/0

44. Compositions as claimed in claim 43 in'a form sui/able for oral, topical or parenteral administration or administration by suppository. /' /

45. Compositions as claimed in claim'44 in oral /form as . t tablets. /

46. Compositions as claimed in p/aim 45 in form of slow release tablets. /

47. Compositions as claimed .in claim 46 /containing 20 to 200 mg of active ingredienyper tablet./

48. Compositions as claimed in clainy/44 in topical form, as a spray, ointment on'cream.

49. Compositions as claimed in claim 48 substantially as wi tli / herein described/reference to Example 33.

50. a method of /treating a condition mediated through histamine H, >-re6e l2-^oeptors which comprises administering to a patient (oth^r than human^ an effective amount of a compound as claimed An claim 1 dhc relieve said condition.

51. A method as claimed in claim 50 in which the condition Ls peptic ulceratioii. ». / ^ L IS ,B.n method as^claimed in claim 50 in which the condition allergic/Skin condition. NOW AMENDED 18 i'/D? 53. r, Compounds of the general formula Is 'N-Alk- Y II 0 (ch0) x(ch~) nhcnhr-2. n z m 3 and physiologically acceptable salts thereof/? in which R^ and r2 which may be the same or different represent hydrogen, / / lower alkyl having 1 to 8 carbon.atoms ^or.alkenyl or lower- • alkyl having 1 to 8 carbon atoms interrupted by an' oxygen atom or a group -N~, or R^ and R2 may, together with the nitrogeii atom to which / / they are attached, form a heterocyclic riiig which may / / / J contain other heteroatoms/selected from O and -N-; * f * / t R4 is lower/alky1 having 1 to 8 carbon atoms; X is 0 or/S; /' / Y represents = S, = X), = NR^ or = CHRg; Alk y enotes a straight or branched alkylene chain of / to 6 carbon atoms; / 4 is hydrogen or lower alkyl having 1 to 8 carbon atoms R5 is nitr6, cyano, lower alkyl having 1 to 8 carbon atoms/&r aryl; Rg represents nitro; / ■ :"r m is an integer frqm 2 to 4; — ^ ■{rid n is 1-

54. / Pharmaceutical compositions comprising a compound as/fclaimecl in claim 53 in association with a pharmaceutically ^acceptable carrier or diluent. . *** -83- DATED this day of a. j. park & son per AGENTS FOR THE APPLICANTS AS AMENDED IS4-75? What we claim is:

1. The compound N-[2-[[[5-(dimethylamino)methyl-2-furanyl] methyl] thio] ethyl] -N' -methyl-2-nitro-1 , 1-ethenediamine hydrochloride.

2. Pharmaceutical compositions comprising the compound as claimed in claim 1, in association with a pharmaceutically acceptable carrier or diluent, and if desired other active ingredients. —l.i.qrvtan By the authorised agents0 ~ A J PARK & 80N Pw </div>