Nova Patents
AU525927B2

Pharmacologically active compounds

Abstract

This record has no abstract on file.

AU525927B2, drawing sheet 1
Sheet 1 of 73

Term

Term ended

Expired 20 December 1998, 27.8 years ago.

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  2. Filed
  3. Granted
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  5. Today

5 claims: 3 independent, 2 dependent

  1. 1
    THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:7.7 m (6H);6.4-7.0 br, 6.63 s (6H) ;6.28 s (2H);6.18 s (2H);5.95 tr (2H);3.5-4.5 br (1H) ;3.0- 3.5 m (6H);2.78 tr (1H) ;-0.5 br (1H). (xvi) N-[2-([5-((Dimethylamino)methyl]-2-furanyl- 5 j?methyl] tiiio]ethyl] -2-nitro-N·-Γ2-Γ[5-((1- , pyrrolidinyl) methyl]-2-^ri '' hyi] thio] ethyl] 1,1-ethenediamine (1.03 g) as a hydrate from N,N 42 73½ dimethyl-5-[[[2-((1-methylthio-2-nitroethenyl) amino] ethyl] thio]methyl]-2-furanmethana_mine (1.0 g) and 210 [(5 - ((1-pyrrolidinyl)methyl] - 2 -^'i oph<^yl-me thy-1 ] thio] ethanamine (0.85 g) at 98-100° for 4 hours. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.34. NMR (CDC1 3 ) 't/ : 8 · 28 m ( 4H ) 7.80 s (6H) ;7.52 m, 7.30 tr (8H);6.70 br, 6.64 s (6H);6.30 s (4H);6.20 s 15 (2H);3.95 AB (2H) ;3.52 s + tr (2H) ;3.30 AB (2H) ;-0.5 br (1H)i ’ (xvii) N-(2-[(5-((Dimethylamino)methyl]-2-furanylmethyl] thio]ethyl]-2-nitro-N'-[3-[3-[(1-pyrrolidinyl)methyl] phenoxy]propyl]-1,1-ethenediamine (0.7 g) from 20 N,N-dimethy1-5-(([2-[(1-methylthio-2-nitroethenyl) amino] ethyl] thio] methyl]-2-furtiimethanamine (1.0 g) and 3-[3-[(1-pyrrolidinyl)methyl]phenoxy]propanamine (0.77 g) at 100° for 4 hours. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.21. 25 NMR (CDC1 3 )'V : 8.22 m(4H);7.90m, 7.77 s (8H);7.52 m, 7.32 tr (6H);6.4-7.0 br, 6.60 s (6H);6.45 s (2H) ;6.32 s (2H) ;5.98 tr (2H) f 3.88 s (2H) ;3.45 s (1H) ;3.0-3.3 m (3H) ;2.78 tr (1H) ;-0.5 br (1H) . (xviii) N*'-Cyano-N-[3-(5-((dimethylamino)methyl] - 30 2-furanylmethoxy]propyl]-N’-[3-[3-[(dimethylamino) methyl]phenoxy]propyl]guanidine (0.48 g) as a hydrate from Ν'-cyano-N-[3-(3-((dimethylamino)methyl] phenoxy]propyl]carbamimidothioic acid, methyl ester (1.0 g) and 5-((3-aminopropoxy)methyl]-N,N-dimethyl -2-furanmethanamine (0.76 g) at 100° for 4 hours. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.34. Found: C,61.8;H,8.0;N,17.0;5 α 25 Η 38 Ν 6 Ο 3’ Η 2° re( I uires: C,61.5;H,8.3;N,17.2% yj (xix) Ν''-Cyano-N-(3-(5-((dimethylamino)methyl]-2φ furanylmethoxy]propyl] -N'-[2-([5-((dimethylamino) • ’methyl]-2-furanylmethyl] thio]ethyl]guanidine (0.81 g) as a hydrate from N'-cyano-N-[2-[[5-[(dimethylamino) 10 methyl]-2-furanylmethyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.0 g) and 5-((3-aminopropoxy) methyl]-N,N-dimethyl-2-furanmethanamine (0.75 g) at 100° for 4 hours. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.43. 15 NMR (CDC1 3 )Ύ : 8.2m (2H);7.74 s (12H);7.38 tr (2H);6.71 q, 6.56 s (8H);6.40 tr (2H);6.30 s (2H) ;5.57 s (2H) -, 4.06 2xtr (2H) ;3.7-3.9 2AB (4H) . (xx) Ν' , -Cyano-N-[2-[[5-[(dimethylamino)methyl]-2furanylmethyl]thio]ethyl]-N'-[2-[[5-[(methylamino) 20 methyl]-2-furanylmethyl]thio]ethyl]guanidine .(1.23 g) > as a hydrate from N'-cyano-N-[2-[[5-[(dimethylamino) methyl]-2-furanylmethyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.0 g) and 5-[[(2-aminoethyl) thio]methyl]-N,N-dimethyl-2-furanmethanamine (0.71 g) 25 at 98-100° for 4 hours. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.4. NMR (CDC1 3 ) Ω7: 7.8 m, 7.73 s (7H);7.58 s (3H);7.28 tr (4H);6.70 m, 6.57 s (6H);6.28 s, 6.27 s (6H);3.4-4.3 br ni, 3.86 s (6H).. ' 30 Exam Pl e 13 (i) Ν,Ν 1 -bis-[3~[3-((Dimethylamino)methyl]phenoxy] P r °Pyl]~2~nitro~l,l-ethenediamino - 54a 2. Compounds of the general formula (II) v I ·* ft ft® U ft 9 «ft» »W ft OU- « «* V « ψ 9 ft ft a * » y & 6 hr Hr fe fe t U ft fe ft h v 3-(3-aminopropoxy)-N,Ν-dimethylbenzenemethanamine (1.09 g) and 1,1-bis(methylthio)-2-nitroethene (413 mg) were heated as an intimate mixture on a steam bath for 90 minutes. The resulting oil was 5g2 washed with ether and purified by column chromatography y^dn'silica using 2 % 0.88 ammonia in methanol to give t— CM $n 'silica the title compound as a pale yellow oil (0.74 g) . Rf 0.30, silica/2 % 0.88 ammonia in methanol. Similarly prepared were: (ii) 2-Nitro-N,N 1 -bis-[2-[[5-[(l-pyrrolidinyl)methyl]2-furanylmethyl]thio]ethyl]-1,1-ethenediamine (0.54 g) as a hydrate from 1,1-bis(methylthio)-2-nitroethene (0.21 g) and 2-[[5-[ (1-pyrrolidinyl)methyl]— 2-furanylmethyl]thio] ethanamine (0.66 g) at 98-100° TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.24. NMR (CDC1 3 )T : 8.0-8.4 m 6.7m (4H);6.38 s 6.29 3.48 s (1H). (iii) N,N'-bis[3-[5-Γ(Dimethylamino)methyl]-2-furanylmethoxy]propyl]-2-nitro-l,1-ethenediamine (0.83 g) as a hydrate from 5-[(3-aminopropoxy) methyl]-N,N-dimethyl 2-furanmethanamine (1.4 g)
  2. 2
    2-nitroethene (0.54 g) at 98-100° for 4 hr. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.43. NMR (CDC1 3 ) T : 8.2 m (4H);7.80 s (4H);6.61 s, 6.48 m (8H);5.61 s (4H) ;3.7-4.0 AB and br (5H) ;3.48 s- (1H) ;-0.3 br (iv) N,N'-bis-[2-[[5-[(Dimethylamino)methyl]-2- thi-ephen-ySne-thy 1 ] thio] ethyl] -2-nitro-l, l-et'nenediamine (8H);7.0-7.7 m s (8H) ;for 2 hr. (12H) ;
  3. 3
    86·s (4H); and. 1,1-bis(methylthio) (12H); 6.82 q (1H) . (0.56 g) from 5-[[(2-aminoethyl)thio]methyl]-N,Ndimethyl-2-thiophenemethanamine (0.9 g) and 1,1-bis(methylthio)-2-nitroethene (0.31 g) at 98-100° for 10 hr . aamine s ography give - 44 TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.52. Found: C,49.8;H,6.5;N,13.1;C 22 H 35 N 5°2 9 4 re< J uires: 0,49.9;H,6.7;N,13.2% (v) Ν''-Cyano-N,Ν'-bis[3-[3-[(dimethylamino)methyl] phenoxy]propyl] guanidine (1.1 g) as a hydrate from kO 3- (3-aminopropoxy)-N,N-dimethylbenzenemethanamine CO (1.71 g) and cyanocarbonimidodithioic acid, dimethyl ester (0.6 g) at 98-100° for 16 hr. thyl]• 54 g) iene anylhr. ft » eft * fe * * to •φ TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.33. ,ranylg) as methylo)— fe *« fe « t* ft *. to to ft to to ft to fe fe AB iamine bisor ft β fl * « w « ft* ft to » o a ft w * to to fe to- ft * ft to fe ft to to fe to fe fe k· NMR (CDC1 3 ) Ύ : 8.0 m, 7.80 s (16H);6.63 m and s (8H.) ;5.99 tr (4H) ;4.18 tr (2H) ;3-3.4 m (6H) ;2.79 m (2H). (vi) Ν''-Cyano-N,N'-bis-[2-[[5-[(1-pyrrolidinyl)methyl] -2-furanylmethyl]thio]ethyl]guanidine (0.53 g) as a hydrate from 2-[ [5-[(1-pyrrolidinyl)methyl] ~2furanylmethyl]thio]ethanamine (1.5 g) and cyanocarbonimidodithioic acid, dimethyl ester (0.45 g) as 98-100° for 8 hr. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.39. NMR (CDC1 3 ) 7/ : 8.22 m (8H);7.48 m, 7.30 tr (12H);6.70 q (4H);6.41 s (4H);6.28 s (4H);4.07 tr (2H);3.9 AB (4H). (vii) 2-Nitro-N,N'-bis-[3-[3- [ (1-pyrrolidinyl)methyl] phenoxy]propyl]-1,1-ethenediamine (0.9 g) as a hydrate from 3-[3-(1-pyrrolidinylmethyl)phenoxy] propanamine (2.34 g) and 1,1-bis-(methylthio)-2nitroethene (0.82 g) at 100° for 3 hr. TLC (silica/methanol-0.88 ammonia 20:1) Rf 0.38. NMR (CDC1 3 ) 7/: o.2 8 in, 7.99 br 6.68 brm, 6.48 s (8H);6.00 tr 3-3.4 m (6H);2.85 m (2H);3.84 (1H) ;m (12H);7.55 m (4H);3.43 s (1H) brs (1H);-0.40 (8H) ;I brs 42 735 ΐκ 42 735 Λ» - 45 (viii) Ν''-Cyano-N,N'-bis-[3-[5-[(dimethylamino) methyl]-2-furanylmethoxy]propyl]guanidine (0.66 g) as a hydrate from 5-[(3-aminopropoxy)methyl]-N,Ndimethyl-2-furanmethanamine (1.5 g) and cyano’carbonimidodithioic acid, dimethyl ester (0.45 g) at 98-100° for 6 hr. TLC (silica/methanol-O.88 ammonia 79:1) Rf 0.43. NMR (CDClg) Τ' = 8.28 m (4H);7.80 s (12H);6.82 q (4H);6.60 s (4H);6.50 tr (4H);5.62 s (4H);4.20 10 brt (2H) ;3.91 (2H) ;3.80 AB (2H). Example 14 2-Nitro-N,N*-bis-[2-[[5-[[(2,2,2-trifluoroethyl)amino] methyl]-2-furanylmethyl]thio] ethyl]-1,l-ethenediamine A. 5-[[(2-Aminoethyl)thio]methyl]-N-(2,2,2-tri15 fluoroethyl)-2-furanmethanamine Aqueous foimaldehyde (37 %, 2.8 ml) was slowly added to a mixture of 2-furanmethanol (3.05 g) and 2,2,2~trifluoroethanamine hydrochloride (4.55 g) cooled in ice. The mixture was kept at room 20 temperature for 18 hr, ethyl acetate (200 ml) and excess anhydrous sodium carbonate were added and after 3 hr the suspension was filtered. The filtrate was treated with charcoal, filtered and evaporated to give a brown oil (5.53 g). To a solution of 25 this in 2N hydrochloric acid (1' ml) at 0° was slowly added a solution of 2-am ethanethiol ' hydrochloride (3 g) in concentrated hydrochloric acid (15 ml). The solution was kept at 0° for 16 hr and at room temperature for 24 hr. To the 30 solution was added excess anhydrous sodium caibonate and the solid residue extracted with isopropanol. Evaporation of the extract gave a brown oil which was chromatographed (silica/methanOl-O.88 ammonia 79:1). - 46 The appropriate eluate was evaporated to dryness to give the title compound (3.3 g) as an oil. TLC (s.ilica/methanol-0.88 ammonia 79:1) Rf 0.48. B. 2-Nitro-N,N l -bis-[2~r[5-Γ (2 ,2,2-trifluoroethyl) 5 framing]methyl]-2-furanylmethyl]thio]ethylj-1,142 735 A mixture of 5-[[(2-aminoethyl)thio]methyl]-N(2,2,2-trifluoroethyl)-2-furanmethanamine (0.83 g) and 1,1-bis-(methylthio)-2-nitroethene (0.25 g) 10 was heated at 9.8-100° for 3 hr. The gummy residue was chromatographed (silica/ethyl acetate then ethyl ac-tate/ethanol 9:1) and the appropriate eluate evapor'·.. . 1 to dryness to give the title compound (0.2 g) as an oil. 15 TLC (silica/ethyl acetate) Rf 0.39. Found: C,44.1;H,4.9;N,11.2;C 22 H 29 F 6 N 5°4 S 2 rec 3 uires: C,43.6;H,4.8;N,11.6% Example 15 N,N'-bis-[2-[[5-[(Cyclopropylamino)methyl]-2-furanyl20 methyl]thio]ethyl]-2-nitro-l,1-ethenediamine A. 5-[(Cyclopropylamino)methyl]-2-furanmethanol, oxalate salt Aqueous formaldehyde (36 %, 15 ml) was added slowly to a-cooled mixture of cyclopropylamine hydro25 chloride (16 g) and 2-furanmethanol (15 g). After 2 days at room temperature the solution was basified and dried with anhydrous sodium carbonate. The solid was extracted with isopropanol and the solvent evaporated to give an oil which was chromato30 graphed (silica/ethyl acetate-ethanol 9:1). The appropriate eluate was evaporated to dryness and a solution of the oily residue in ethanol was acidified with a solution of Oxalic acid in ethanol to give the title compound (11.17 g) as a crystalline - 47 solid. TLC (silica/ethyl acetate-ethanol 9:1) Rf 0.4. B. 5-[ [(2-Aminoethyl)thio]methyl]*-N-cyclopropyl'co 2-^furanmethanamine, bis oxalate salt A solution of 5-[ (cyclopropylamino)methyl]-2furanmethancil r oxalate salt (3.1 g) in water (5 ml) t*· was added slowly to a solution of 2-aminoetnanethiol ’<?4 hydrochloride (1.5 g) in concentrated hydrochloric acid below 10°. After 3 days at room temperature 10 the solution was basified and dried with excess anhydrous sodium carbonate. The solid was extracted with isopropanol and evaporation of the extracts ‘ yielded a brown oil. A solution of this in ethanol ivas acidified with a solation of oxalic 15 acid in ethanol to give the title - compound (2.32 g) as a crystalline solid. „ J TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.41. ' * c · N,N'-bis-[2-[[5-[(Cyclopropylamino)methyl]-2furanylmethyl]thio]ethyl]-2-nitro-l,1-ethenediamine 20 a mixture of 5-[[(2-aminoethyl)thio]methyl]N-cyclopropyl~2-furanmethanamine (1.67 g) and 1,1-bis- (methylthio) -2-nitroethene (0.61 g) was heated at 98-100° for 3 hr. The oily residue was ' '*· chromatographed (silica/methanol-0.88 ammonia 79:1) » v » 25 and the appropriate eluate evaporated to dryness % t a , . to give the title compound (1.07 g) as an oil. «, i .: b to· ft . . ' inr 11 1 ' · Γ ' ' ' · ’ ’ ' TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.61. . NMR (CDCljJTT: 8.6-9.2 m (8H);7.95 m (2H) ;7.0' 7.5 brs (4H) ;7.25 tr (4H) ;6.65 brm, 6.26 s, 6.20 s .30 (12H) ;3.75-4.0 m (4H) ;3.45 s (1H) . Example 16 ’ N f N‘-bis-[2-[[5-[[Hydroxy(methyl)amino]methyl]-2. ' · · ,- ....... .' i · .......... . > . ..... ...... furanylmethyl] thio] ethyl] -2-nitro-l, 1-e.thenedlamine * οι 42 735/78 A. 5-[[Hydroxy(methyl)amino]methyl]-2-furanmethanol A mixture of 2-furanmethanol (14.7 g) , N.methylhydroxylamine hydrochloride (13.8 g) and aqueous formaldehyde (36 %, 18 ml) was stirred at 0° for 1 hr and at room temperature for 4 hr. The solution was diluted with water (100 ml), excess sodium bicarbonate added and the solution extracted with ethyl acetate (4 x 100 ml). The combined ethyl acetate extracts were dried (sodium sulphate), 1q filtered and the filtrate evaporated to give an oil which was distilled (6 x 10 mm/200-210°) to give the title compound (9.1 g). TLC (silica/ether) Rf 0.2. B. 5-[[(2-Aminoethyl)thio]methyl]-N-hydroxy-N- 15 methyl-2-furanmethanamine, dihydrochloride 5-[[Hydroxy(methyl)amino]methyl]-2-furanmethanol * (7.85 g) was added to a stirred solution of 2aminoethanethiol hydrochloride (5.68 g) in concentrated * hydrochloric acid (15 ml) at 0° during 45 mins. 2Q After 48 hr at 0° the crystalline solid which separated was mixed with isopropanol (40 ml), * filtered and crystallised from ethanol to give the title compound (9.1 g) m.p. 164-165° dec. C· N,N 1 -bis-[2-[[5-[[Hydroxy(methyl)amino]methyl]25 2-furanylmethyl]thio]ethyl]-2-nitro-l,l-ethenediamine A mixture of 5-[[(2-aminoethyl)thio]methyl]-Nhydroxy-N-met)\yl-2--furanmethanamine base (1.48 g) and 1,1-bis-(methylthio)-2-nitroethene (0.57 g) was heated at 98-100^ for 3 hr. The oily residue was 30 chromatographed (silica/acetone) and the appropriate eluate evaporated to give the title compound (0.78 g) as an amber oil. TLC (silica/acetone) Rf 0.35. k - 49 Found: C,47.9;H,6.5;N,13.7;C 20 H 31 N 5°6 S 2 squires: C,47.9;H,6.2;N,14.0% Example 17 Γ3-[3-[(Dimethylamino)methyl]phenoxy]propyl]5 -[2-[[5-[(methylamino)methyl]-2-furanylmethyl] thio]ethyl]-2-nitro-l,1-ethenediamine fS? A. N-Methyl-5-[[[2-[(l-methylthio-2-nitroethenyl) amino]ethyl]thio]methyl]-2-furanmethanamine, oxalate salt A solution of 2-[[5-[(methylamino)methyl]-2furanylmethyl]thio]ethanamine (6.0 g) and 1,1-bis(methylthio)-2-nitroethene (19.8 g) in dry dimethylformamide (150 ml) was stirred for 1 hour at 0° and for 5 hours at room temperature. A solution of oxalic acid (4.0 g) in dry dimethylformamide (16 ml) was added and the solid which formed during 18 hours was filtered, washed with dimethylformamide, ethanol and ether and dried. The solid was suspended in water (200 ml) at 55° and on cooling was filtered, washed with water and dried to give the title compound (3.25 g) m p. 158160° dec. B. N-[3-[3-{(Dimethylamino/methyl]phenoxy]propyl] -N'-[2-[[5-[(methylamino)methyl]-2-furanylmethyl] thio]ethyl]-2-nitrO-l,1-ethenediamine tf A mixture of N-methyl-5-[[[2-[(l-methylthio2-nitroethenyl)amino]ethyl]thio]methyl]-2furanmethanamine (1.6 g) (prepared from the oxalate salt) and 3-(3-aminopropoxy)~N,N-dimethylbenzenemethanamine (1,15 g) was heated at 98-100° for 3 hours. The oily product was chromatographed (silica/ methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound <r - 59a i (V) 42735m as a hydrate as an amberoil (2.12 g). TLC (siliea/methanol-O.88 ammonia 79:1) Rf 0.22. NMR (CDC)l 3 )T : 8.18 br (1H) ;7.85 m (2H) ;7.75 s (6H) ;7.58 s (3H);7.30 tr (2H);6.5-7.0 m, 6.60 s (6H);6.31 s (4H) ;5.94 tr (2H) ;3.90 AB (2H) ;3.46 s (1H) ;3.0-3.3 m (3H) ;2.80 tr (1H);-0.5 br (1H). Example 18 Ν-[2~Γ[5-[(Dimethylamino)methyl]-2-furanylmethyl] thio]ethyl] -N 1 -[3-[3-[(dimethylamino)methyl]phenoxy] 10 propyl]thiourea A. 5-[[[2-(Isothiocyanato)ethyl]thio]methyl]-N,N~ dimethyl-2-furanmethanamine A solution of carbon disulphide (4.2 g) in dry acetone (8 ml) was added dropwise to a solution of 515 [[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2furanmethanamine (10.71 g) in dry acetone (30 ml) during 15 minutes at -10° to 0°. To the stirred solution at -15° was added dropwise a solution of mercuric chloride (13..6 g) in dry acetone (20 ml) 20 during 45 minutes. The solution was warmed to 0° and triethylamine (1 Ί .5 g) was added dropwise with stirring during 15 mii utes. The mixture was refluxed for 45 minutes, the suspension filtered and the filtrate evaporated to dryness. The oily residue 25 was dissolved in ether (150 ml), decolourising charcoal and excess anhydrous sodium sulphate were added and the suspension filtered after 2 hours. The filtrate was evaporated to dryness, the oily residue dissolved in ether and the solution 30 chromatographed (alumina deactivated with water, 72.5 ml/kg/ether). The appropriate eluate was evaporated to give the title compound (5.05 g) as a brown oil. TLC (alumina/ether) Rf 0.9. --w « .- - ’TP'* „1 ait- r.~;Ο--·/ - 51 Β. N-[2-[[5-Γ(Dimethylamino)methyl]-2-furanylmethyl] thio]ethyl]-N 1 -[3-[3-[(dimethylamino)methyl]phenoxy] propyl]thiourea ' To a solution of 5-[[[2-(isothiocyanato)ethyl] 5 l^thio]methyl]-N,N-dimethyl-2-furanmethanamine (0.77 g) VS>i n dry acetonitrile (3 ml) was added a solution of ^3- (3-aminopropoxy) -N ,Ν-dimethylbenzenemethanamine ¢^(0.63 g) in dry acetonitrile (3 ml). After 1 hour ^the solution was evaporated to dryness to give an 10 oil which was chromatographed (silica/metnanol-0.88 ammonia 79:1). The appropriate eluate was evaporated to dryness to give the title compound (1.25 g) as an oil. TLC (silica/methanol-0.88 ammonia 79:1) Rf 0.45. 15 Found: . C,59.2;H,7.9;N,12.0;S,13.5;C 23 H 36 N 4°2 S 2 rec 3 uires: C,59.5;H,7.8;N,12.1;S,13.8% EXAMPLE 19 Pharmaceutical Compositions (a) Oral Tablets 50 mg 20 Active ingredient Anhydrous lactose U.S.P. Sta-Rx 1500 Starch* Magnesium Stearate B.P. for 10,000 tablet's 500 g 2.17 kg 300 g 30 g The drug is sieved through a 250 pm sieve and then the four powders are intimately mixed in a blender and compressed between 8.5 mm diameter punches in a tabletting machine. * A form of directly compressible . starch, supplied by A.E. Staley Mfg. Co. (London) Limited, Orpington, 30 Kent. '' (b) Injection for Intraveneous administration (50 mg in. 2 ml) , % Active ingredient2.5 Water for injections BP to100.0 Dilute hydrochloric acid BP to pH 5.0 The active ingredient is dissolved with mixing in Water for Injection, adding the acid slowly until pH is 5.0. The solution is sparged with nitrogen is then clarified by filtration through a membrane It is packed into 2 ml the the and ^filter of pore size 1.35 pm. u^glass ampoules (2.2 ml in each) and each ampoule sealed under an atmosphere of nitrogen. The ampoules are _ sterilised in an autoclave at 121° for thirty minutes. (c) Oral Sustained Release Tablets 150 mg for 10,000 tablets Active ingredient 1,.50 kg Cutina HR** 0.40 kg Anhydrous lactose U.S.P. 2.060 kg Magnesium Stearate BP 40 g The active ingredient, anhydrous lactose and most of the Cutina HR are intimately mixed and then the mixture is moistened by mixing with a 10 % solution of the remainder of the Cutina HR in. Industrial Methylated Spirit OP 74. The moistened mass is 20 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 th magnesium stearate and compressed to a hardness of at least 10 kg (schleuniger tester) on a tabletting 25· machine with 12.5 mm diameter punches. ** Cutina HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Limited, London. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS;1. Compounds of the general formula (I) ‘•^N-Alk-Q- (CH 2 ) X (CH 2 ) ^NHCNH (CH 2 ) E(CH 2 ) -Z(I) Ό II· K 2Y 5 and physiologically acceptable salts, N-oxides, and hydrates thereof, in which Y represents =0, -S, =CHNO 2 or =NR 3 where R 3 represents hydrogen, nitro, cyano, lower alkyl, aryl, lower alkyl ’Ulphonyl or arylsulphonyi;and R 2 , which may be 10 the same or different, each represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, hydroxy, lower trifluoroalkyl, lower alkyl substituted by hydroxy, lower alkoxy, amino, lower alkylamino or lower dialkylamino, ur R^ and R 2 together with the nitrogen atom to which they are attached 15 form a saturated 5 to 7 membered heterocyclic ring which may contain oxygen as another heteroatom or the group -N- where R R^ represents hydrogen or lower alkyl;4 Q represent t -furan or thiophen ring in which incorporation .. · tie rest of the molecule is through 20 bonds at the 2- ann 5-positions, or a benzene ring in which incorporation into the rest of the molecule is through bonds at the 1- and 3- or 1- and 4-positions;X represents -CH 2 ~, -0- or -S-;n represents zero, 1 or 2;m represents 2, 3 or 4;Aik represents a straight chain alkylene group of 1 to 3 carbon atoms;(except that n is not zero when X is oxygen and Q is a furan, or thiophen ring system);q represents 2, 3 or 4 or can additionally represent zero or 1 when E is a -CH 2 - group;p represents zero, 1 or 2;E represents -CH 2 -, -0- or -S-;and Z represents a monocyclic 5 or 6 membered carbocyclic or heterocyclic aromatic ring;the carbocyclic aromatic ring may be substituted by one or more of lower alkyl, optionally substituted by hydroxy, or hydroxy, amino, lower alkoxy or halogen and the heterocyclic aromatic ring may be substituted by lower alkyl optionally substituted by hydroxy or halogen, or Z represents the group where Q* represents any of the rings defined for Q;Aik’ represents any of the groups defined for Aik;and Rg and Rg, which may be the same or different, each represent any of the groups defined for R^ and R 2 ;(except that p is not zero when E is oxygen and Q’ or Z is a furan or thiophen ring system). ’ i - 54a - 2, Compounds of the general formula (II) / R 5 -Alk-Q-(CH O ) X(CH„) NHCNH (CH_) E(CH 0 ) -Q'-Alk-N^ 2 n 2m u 2q 2p \ *£ Y R 6 and physiologically acceptable salts, N-oxides, and io ♦ hydrates and •b-i-opreeu'g-oogu thereof, in which Y represents =0, =S, =CHNO 2 or =NR 3 where R 3 represents hydrogen, nitro, cyano, lower alkyl, aryl, lower alkylsulphonyl or arylsulphonyl;5 Rj,, R 2 , R 5 and R g , which may be the same or different, FS each represent hydrogen, lower alkyl, cycloalkyl, kq lower alkenyl, aralkyl, lower alkyl interrupted by an oxygen atom, or lower alkyl interrupted by a group -N- where R. represents hydrogen or lower alkyl or 04 i 4 Xfi R 4 10 R^ and R 2 together with the nitrogen atom to which they are attached or R g and R g together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic ring which may contain another heterofunction selected from oxygen or the group -N-;*4 15 Q and Q', which may be the same or different, each represents a furan or thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5-positions, or a benzene ring in which incorporation into the rest of the molecule 2q is through bonds at the 1- and 3-positions;X and E, which may be the same or different, each represent -CH 2 ~, -0- or -S-;n and p, which may be the same or different, each represent zero, 1 or 2;25 m and q, which may be the same or different, each represent 2, 3 or 4;Aik and Aik', which may be the same or different, each represent a straight chain alkylene group of ] to 3 carbon atoms;30 (except that n is not zero when X is oxygen and Q is a furan or thiophen ring system and p is not zero when 42 735/78 φ E is oxygen and Q' is a furan or thiophen ring system). 3. Compounds of the general formula (III) R1 \ N-Alk-Q-(CH 2 ) n X(CH 2 ) m NHCNH(CH 2 ) q E(CH 2 ) p -Z·(III) V * and physiologically acceptable salts, N-oxides, hydrates and· 'bioprccur-sere thereof, in which Y represents =0, =S, =CHNO 2 or -NR^ where R^ represents hydrogen, nitro, cyano, lower alkyl, aryl, lower alkylsulphonyl or arylsulphonyl;R^ and R 2 , which may be the same or different, each represent hydrogen, lower alkyl, cycloalkyl, lower 10 alkenyl, aralkyl, .lower alkyl interrupted by an oxygen atom, lower alkyl interrupted by -N- in which R 4 represents hydrogen or lower alkyl;or R^ and R 2 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic ring whi-h 15 may contain the further heterofunction oxygen or -N-;Q represents a furan or thiophen ring in which incorporation into the rest of the molecule is through bonds at the 2- and 5-positions, or a benzene ring in which incorporation into the rest of the molecule is 20 through bonds at the 1- and 3- or 1- and 4-positions;X represents -CH 2 -, -0- or -S’-;n represents zero or 1;m represents 2, 3 or 4;Aik represents a straight chain alkylene group of 1 25 to 3 carbon atoms;(except that n is not zero when X is oxygen and Q is a furan or thiophen ring system);X represents -Ο- or -S-;η represents zero or 1;m represents 2 or 3;- 57a q represents zero, 1, 2 or 3;p represents zero, 1 or 2;E represents -CE^-r -0- or -S-;and Z represents furyl, lower alkyl substituted imidazolyl, 5 phenyl, hydroxyalkyl substituted furyl, pyridyl, hydroxy/ R 5 alkyl substituted phenyl or -Q'-Alk'-N. R 6 where Q represents a furan or thiophen ring in which incorporation into the rest of the molecule is through •**10 bonds at the 2- and 5-positions or a benzene ring in which incorporation into the rest of the re r e a·« « » * * azolyl, hydroxywhich hrough g in which molecule is through bonds at the 1- and 3-positions;Aik' represents ~CH 2 -;and r_ and R r which may be the same or different, each □ 0 represent hydrogen or lower alkyl or R 5 and R g 5 together with the nitrogen atom to which they are LQ attached form a 5 to 7 membered heterocyclic ring. '°®5. Compounds as claimed in claim 1 which are (£*·« _ N-(2-( (5-( (dimethylamino)methyl] -2-furanylmethyl] thio]ethyl]-N'-((2-(furanylmethyl)-thio]ethyl]-2-nitro1 q 1 1 1-ethenediamine;N- [3- [5- ( (dimethylamino)methyl]-2-furanylmethoxy] propyl]-2-nitro-N'-[2-((3-pyridinylmethyl)thio]ethyl] J ί · -1,l-ethenediamine;ft © * N- [2- ( [5- [ (dimethylamino) methyl] -2-furanylmethyl] thio] - · ic ethyl]-Ν'-(3-[3-(hydroxymethyl)phenoxy]propyl]-2‘ nitro-1,1-ethenediamine;ii , N- (2- ( [5- ( (dimethylamino)methyl]-2-furanylmethyl] thio]ethyl]-2-nitro-N'-(2-((3-pyridinylmethyl)thio] ethyl]-1,1-ethenediamine;20 N,N’-bis(2-([5-((methylamir , methyl]-2-furanylmethyl] thio] ethyl] --2-nitro-l, 1-ethenediamine ;N''-cyano-N,N'-bis (3-(3-((dimethylamino) methyl] phenoxy]propyl]guanidine;2-nitro-N,N'-bis-(3-(3-((1-pyrrolidinyl)methyl] 25 phenoxy]propyl]-1,1-ethenediamine;N-(2-((5-[(dimethy1amino)methyl]-2-fur anyIme thy1]th io] ethyl]-N'-(3-(3-((dimethylamino)methyl]phenoxy]propyl]2-nitro-l,1-ethenediamine;N-(2-((5-((dimethylamino)methyl]-2-furanylmethyl]thio] 30 ethyl]-N'-(2-((5-((dimethylamino)methyl]-2—thienylmethyl] thio]ethyl]-2-nitro-l,1-ethenediamine;N-(2-((5-((dimethylamino)methyl]-2-furanylmethyl]thio] ethyl-N'-(2-((5-((methylamino)methyl]-2-furanylmethyl] 59 thio] ethyl] -2-nitrp-l, 1-ethenediamine;N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio] ethyl]-Ν’-[2-[[5-[[hydroxy(methyl)amino]methyl]-2 furanylmethyl]thio]ethyl]-2-nitro-lrl-ethenediamine;N-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-N’-[2 [ [5-[(methylamino)methyl]-2-furanylmethyl]thio]ethyl] -2-nitro-l,1-ethenediamine;N''-cyano-N-[3-[3-[(dimethylamino)methyl]phenoxy]propyl] -N’-[2-[[5-[(1-pyrrolidinyl)methyl]-2-furanyl-methyl]thio] ethyl]guanidine ;N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio] ethyl]-2-nitro-N’-[3-[3-[(1-pyrrolidinyl)methyl]phenoxy] propyl]-1,1-ethenediamine. 6. A process for the preparation of compounds as claimed in Claim 1 which comprises: (a) for the preparation of compounds in which q is is the same as X, p is the same as n and Z the same as m, E is -Q'-A.lk’-N^E ' with Q’ the same as Q, Alk r the same as * R 6 2G Aik, the same as R^amd Rg the same as R 2 , reacting a primary amine of formula (IV) N-Alk-Q-(CH-) X(CH-) NE_ 2 n 2 m 2 < (IV) in which R^, R 2 , Aik, Q, η, X and m are defined in Claim 1, with a. compound of formula (V) Ί& t in which P represents a leaving group, between the two amine residues derived from formula (IV);or (b) reacting an amine of formula (IV) in which R^, R 2 , χ. Aik, ¢), ί 1 X and m are ac defined in Claim 1 (and wherein, if R^ and R 2 a;?*: hydrogen, the group --NR^R 2 with a compound capable of converting t the group is protected), ί ~NH 2 into £. (. q, E, p and Z are as defined in Claim I or reac . ,g an amine of formula (VI) Z-(CII > E(CH ) »H, (VI) 2 q & q 2 in which Z, p, E and q are as defined in Claim l·, (and any primary amino group within the group Z is protected), with a ' uund capable of Converting the group -NH 2 into the ^up -HN-C-NH n Y (CH n ) A X(CH J -Q-Alk-N m 2 n ’ ' « t : * ’ 6 . fir ¢.4 ·. # <4 ' ' .. € t ¢. in which Y, m, X, n, Q, Aik, R^ and R^ are as defined in Claim 1, wherein the compound capable of converting the gro t p ^ nto S rou P -HN-C-NH(CH 0 ) E(CH,j -Zor „ 2 a 2 p Y‘ R. / 1 -HN-C-NH (CHJ X(CH_) -Q- YLk-N< z m z nx. R 2 where Ϋ is oxjgen or sulphur is an isocyanate or isothiocyanate ©f the formula (VII) or (VIII) όκ .-, ~ Z-CCH.JJUCHm) NCY (VII) A W A Q / 60a (VIII) or where Y is «CHNOg or «NR 3 '3 a compound of formula (IX) or (X) 2'p v 2'q (IX) (X) Where L is a leaving group;or (c) for the preparation of compounds in which n is 1 and X is sulphur, reacting a compound of formula (XV) or (XVI) (XV) (> Ί) in which r 2 , A‘„k and Q is . leaving group, with are as defined in Claim 1, and a thiol of formula (XVII) /) ο (XVII) HS(CH 2 ) m NHCNH(CH 2 ) q E(CH 2 ) p -Z Y g in which m, Y, q, E, p and S are as defined in claim CO 1» if Ri and R 2 are hydrogen the amino group in •t*· compounds of formula (XV) or (XVI) being protected, •y* or, for the preparation of compounds in which p is 1 5 and E is sulphur, reacting a compound of formula (XVIII) or (XIX) ft ft ft ft·· ft 9· ♦· • ft » • ft • ft • ft ft ft • 0 «9 V ft Z“CH 2 G (XV r .II) Z-CH 2 OH (XIX) in which Z is as defined in claim 1 and G is a leaving group, with a thiol of formula (XX) ft to a ft « * te * HS(CH 2 ) q NHCNH(CH 2 ) m X(CH 2 ) n ~Q-Alk-N Y (XX) in which q, Y, m, X, n, Q, Aik, R^ and R 2 are as iO defined in claim 1, any amino groups in the group Z within compounds (XVIII) or (XIX) bring protected;or . (d) for the preparation of compounds in which Q is a furan ring, Aik is methylene, z is other than 15 furyl and Y is -NR^, reacting a compound of formula (XXI) (XXI) in which η, X, m, q, E, ρ, Z am R 3 are as defined in claim 1, with formaldehyde and a secondary amine or a salt of a primary amine or a secondary amine or for the preparation of compounds in which Z is -Q’-Alk and Q* is a furan ring, Aik’ is methylene and Y is =NR 3 , reacting a compound of formula (XXII) • 0 p 6 Ί ft j Q a · o * • (CH 2 ) O E(CH 2 )qNHCNH(CH 2 ) m X(CH 2 ) n ~Q-AlkN nr 3 (XXII) Oft ft 0 ft <5 e ft · in which p, E, q, m ( X, n, Q f Aik, R^ and R 3 are as defined in claim 1, with formaldehyde and a 10 secondary amine or a salt of a primary amine or a secondary amine;or (e) for the preparation of compounds in which R^ and R 2 are both methyl, Q is a furan or thiophen ring, Y is other than =CHNO 2 and Z is other than furyl 15 or thienyl, treating a compound of formula (XXIII) (CH 2 ) n X(CH 2 ) ra NHC NH(CH 2 ) g E(CH 2 ) p -Z (XXIII) Ϋ in which η, X, m, Y, q, E, p and Z are as defined in claim 1 except that Y is other than =CHNO 2 and M represents oxygen or sulphur, with the reagent of the !r ft ft * ft ft ft Aft ft ftftft o ft ft ft ft. ft ft ft ft ft ft & « o ft » ft • ft ♦ ft OP • ft o • · wo·· « • e » ft » -4'to «8 ‘J ft ft to ft ft * • r « * ft * fe« to w to to * to to &» ft A » ft to ft ft t to it b to to r toft a < to u ti <·. I formula (XXIV) • V «9 • ft t>9© •4« • «
  4. 4
    4 » 4 • 0* •0 V #fio •0 0 we·· ft> ftneft
  5. 5
    9 T tt fid e a * * « * r a» · fe ft fe * ft V ft ft «4. ft ft» ft ft w « ft! V fc C. t e k </ L· v ··. fit· u # 4 ft. ft £> ft 'W ·* 1 , ft -X (CH 3 ) 2 N=CH 2 (XXIV) or for the preparation of compounds in which Z is -Q’-Alk’-N< R S , Re and Rz- are both methyl, Q' is . 6 e CQ Ο» a furan cr thiophen ring and Y is other than =CHNO 2t treating a compound of formula (XXV) / R 1 p E n X n -0-Mk-N</ Y R 2 in which p, E, q, Y, m, X, n, Q, Aik, and R^ are as defined in claim 1 except that Y is other than =CHNO 2 and M represents oxygen or sulphur, with a reagent of the formula (XXIV);with subsequent salt formation if desired. -J-,---A-preooss- as claimed in cJ aim-. 6(h) wherein the compound capable of converting the group -NH into the group or -HN-C-NH(CH 2 ) g E(CH 2 ) p -Z Ϋ .H N -C-NH(CH 2 ) m X(CH 2 ) n Y the formula (VII) or (VIII) ~(CH 2 ) p E (CHANCY (VII) 4 4 4 * 04 0 / '*l··· I -4>· j. s oo • OO ·.) • 0 9 9 9S 9 O Γ 9 « ·«(> 9>3 9 • · O • ·© »«·«·» « « « ···· «IT ' ·»*· 999 9 ·* 999 (VIII) Z-(CH 2 ) p E(CH o )„NHCX . 'n-A?J<-Q (CH 2 ) n X (CH 2 ) m NCY R 2 X . £~or where Y is =CHNO 2 or -NR. formula (IX) or (X) CO is a (X) pound of ving—group?-------------------—---------Compounds as claimed in claim 1 when prepared a process as claimed in either—of- claims -5-or- 6. A pharmaceutical composition comprising a compound claimed in any of claims 1 to 5 ory-8- together th least one pharmaceutically acceptable carrier or diluent, and optionally one qr more further active ingredients.
Independent claims5