IE53275B1 - Chemical intermediates derived from cyclobutene - Google Patents

Description

The present Application has been divided out of Patent Application No. z/69/δώ t referred to belcw as our primary Application.

As disclosed in our primary Application, certain substituted 1,2-diaminocyclobutene-3,4-diones of the formula Z \2 wherein A is substituted phenyl, furyl, thienyl or pyridyl, Z is sulfur, oxygen or methylene, ns is 0-2, 2 n is 2-5 ar.d R and R are as defined below, are 10 potent histamine Hg-antagonists, inhibit gastric acid secretion and are useful in the treatment of peptic ulcers. 3urimamide (Ila) was the first clinically effective K^-receptor antagonist. It inhibits gastric secretion in animals, including man, but oral absorption is poor. Β Ila; R=H, Z»CH2, X-S b; R«CH3, Z-S, X=S c; R=CH3, 2=S, X-NCN Burinamide Metiamide Cimetidine Metiamide (lib), a subsequently evaluated Hj-antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (lie) is as.effective an Hjantagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug.

Reviews on the development of Hj-qntagcnists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924. (1976), in Drugs of the Future, 1, 13 (1976) and in references cited therein.

D.S. Patent 4,062,863 discloses histamine ^-antagonists of the formula V-/ HET-CH2Z(CH2)2NH NHR wherein R is hydrogen, (lower)alkyl or (CHjJjZ'CHj-EET*; Z and Z1 each are sulfur or methylene; and HET and HET* each are an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothia20le ring, and pharmaceutically acceptable acid addition salts thereof. U.S. Patents 4,120,968, 4,120,973 and 4,166,857 are divisionals thereof which have substantially the sane disclosure.

U.K. Published Patent Application 2,023,133 discloses histamine H2-antagonists of the formula R^N-Alk-Q- (CH^X N wherein R^ and K? are-independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cyclo5 alkyl, or R^ and r2, taken together with the nitrogen to which they are attached, may be a 5- to 10-membered alicyclic heterocyclic ring which may be saturated or may contain at least one double bond, which may be substituted ly one or more alkyl groups or a hydroxy group and/or which may contain another heteroatom; Aik is a straight or branched alkylene chain of 1-6 carbon atoms; Q is a furan or thiophene ring incorporated into the molecule via the 2- and 5-positions, the furan ring optionally bearing a further substituent R? adjacent the . R^R2N-Alk- group, or Q is a benzene ring incorporated into the molecule via its 1- and 3- or 1- and 4-positions; R? is halogen, alkyl (which may be substituted by hydroxy or alkoxy); X is methylene, oxygen, sulfur or ^>N-R6 in which R6 is hydrogen or methyl; n is 0, 1 or 2; m is 2, 3 or 4; Rj is hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl having at least two independently hydrogen, alkyl, alkyl substituted by hydroxy or C3_3 alkoxy, alkenyl, aralkyl or heteroaralkyl, or R^ and Rj taken together with the nitrogen to which they are attached, may be a 5- to 7-membered saturated heterocyclic ring which may contain another heteroatom or the group , or R^ and Rg taken together may be the group CRgRg wherein Rg is aryl or heteroaryl and Rg is hydrogen or alkyl; and physiologically acceptable salts and hydrates thereof.

Patent Specification No. £359/^ discloses histamine H?antagonists of the formula s J* r * R2 C-lf-r X 7“ 2 )b-Y- (CH2 )n-NH-R3 H2N' in which R1 and R2 are hydrogen or optionally halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl, provided that at least one 1 2 of R and R is halogen-substituted alkyl, cycloalkyl or cycloalkylalkvl; X is a phenyl ring with 1 or 2 optional substituents or a 5- or 6membered heterocyclic aromatic ring containing 1, 2 or 3 heterolo atoms selected from Ο, N and S, the heterocyclic ring, where possible, having 1 optional substituent, which optional substituents are halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy and amino; Y is 0, 5, a direct bond, methylene, cis or trans vinylene, 4 ——— sulfinyl or NR in which S is H or alkyl; m is 0 to 4 and n is 1 to 5; R3 is inter alia AB in which A is inter alia a 3,4-dioxocyclobuten-1,2-diyl radical and B is inter alia the radical NR7R8 in which R7 and R8 are inter alia hydrogen, alkyl, haloalkyl, alkoxycarbonyl, alkenyl, alkynyl, (primary hydroxy)alkyl or (primary amino)alkyl, or R® and R9, together with the nitrogen atom to which they are attached, may be a 5- or 6-membered ring which optionally contains 0 or NR in which R is H or alkyl.

' Complete Disclosure This application relates to intermediates useful for preparing certain histamine H^-antagonists which are effective inhibitors of gastric acid secretion in animals, including man, which are useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity, and which have the foxmula x1 A- (CH, )Z (CH- LNHa-N 2 wherein R and R each are independently hydrogen or (lower)1 2 alkyl, and, when R is hydrogen, R also Day be allyl, propargyl, cyclo(lower)alkyl(lower}alkyl, cyclo(lower)alkyl, cyano (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, hydroxy, 2,3-dihydroxypropyl, or in which p is an integer of from 1 to 6 , q Is an 4 io integer of from 1 to 6, R and R each are independently hydrogen, (lower)alkyl, hydroxy, (lower)alkoxy or halogen, and, when R3 is hydrogen, R4 also may be trifluoromethyl, or R3 and R4, taken together, may be methylenedioxy, R5 is hydrogen, (lower)alkyl, (lower)alkoxy, hydroxy, amino or halogen; m is an integer of from 0 to 2 ; n is an integer of from 2 to 5 ; Z is sulfur, oxygen or methylene; and A is in which R6 is hydrogen, (lower)alkyl, (lower)alkoxy or halogen; r is an integer of from 1 to 4; and 9 R and R each axe independently hydrogen, (lower)alkyl, allyl, propargyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo (lower)alkyl, or phenyl (lower)alkyl, provided that R® and R9 may not both be cyclo (lower)alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)nonane; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

The foregoing definition of the compounds which may be prepared from the intermediates of the present invention, the said compounds being the compounds of the Formula I initially set forth herein, is to be understood tc include within its scope all possible tautomeric·forms, geometric isomers, optical isomers and zwitterionic forms of the compounds of Formula I, as well as mixtures thereof. As used herein and in the claims, the terms ” (lower)alkyl and (lower)alkoxy· mean straight or branched chain alkyl or alkoxy groups containing from 1 to 6 carbon atoms. Preferably these groups contain from 1 to 4 carbon atoms and, most preferably, they contain 1 or 2 carbon atoms. The term cyclo (lower)alkyl, as used herein and in the claims, means a cycloalkyl ring containing from 3 to 7 carbon atoms and preferably from 3 to 6 carbon atoms. Unless otherwise specified in the particular instance, the tern halogen” as used herein and in the claims is intended to include chloride, fluorine, bromine and iodine. The term nontoxic pharmaceutically acceptable salts* is intended to include salts of the compounds of Formula Z with any nontoxic pharmaceutically acceptable acid. Such acids are well-known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, tartaric, citric, camphorsulfonic, and levulinic. The salts are made by methods known in the art.

The compounds of Formula I may be prepared by certain procedures utilizing as a starting material a compound of the formula R12 R12 II in which R is a good leaving group such as halogen, phenoxy, substituted phenoxy, or alkoxy. Suitable leaving groups are well-known to those skilled in the art. Preferably, R12 is (lower)alkoxy, and especially methoxy and ethoxy.

Of the two routes from a compound of the R>rmula II to a compound of the Formula I which are represented in the Reaction Scheme set forth below, that which is of interest in connection with the present Application is the route passing through a compound of the Formula III.

Reaction Scheme Compound (CH2)nKH2^ Λ (0^8(0¾ ^12 II || «ΛΑ III ,2/ NH NH Ψ /r1 e“ Z '-'S’ AtCH2)mZ(CH2)nNH2 A(CH-) Z(CH-) NH n' -2· m 2 n \ /^r2 AA IV I The reactions are conducted in an inert organic solvent; we find methanol to be a convenient and readily available solvent. The reaction temperature is not critical. Most starting materials are quite reactive and we prefer to conduct the reaction at a temperature below room temperature, e.g. 0-10’C.

With some less reactive compounds it is convenient to conduct the reaction at room temperature. Sometimes it is desirable to subsequently raise the temperature of the reaction mixture (e.g. to 50-60*C) to complete the reaction. ;o According to the present invention, there are provided intermediates of the formula A-{CH2,mZ{CH2)nNH· .12 III wherein R is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and alkoxy; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene; and A is in which E6 is (lower)alkyl, (lower)alkoxy cr halogen, provided that, in the second, third or fourth of the four values of A specified above, R® may alternatively be hydrogen; r is an integer of from 1 to 4; and 9 R and R each are independently hydrogen, (lower)alkyl, allyl, propargyl, (lower) alkoxydower)alkyl in which the I 532 75 (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo(lower)alkyl, or phenyl(lower)alkyl, B 9 provided that R and R may not both be cyclo (lower) alkyl, or R8 and R9 * *, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperarino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]10 nor.ane.

A preferred embodiment of the intermediates of Formula III are those having the structure Ό- (CHp^iCHPaira-rrzj\c „12 Ilia wherein R12 is a conventional leaving group selected from 15 halogen, phenoxy, substituted phenoxy and (lower)alkoxy; m is an integer of from 0 to 2 ; n is an integer of from 2 to 5 ; is sulfur, oxygen or methylene; R8 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 . and 9 ’ R and R each are independently hydrogen or (lower)8 9 alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, wethylpiperidino, N25 methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclol3.2.2]nonane. ί2 Another preferred embodiment of the intermediates of Formula III are those having the structure {CH2)n2(cH2)nNH »12 Illb wherein R is a conventional leaving group selected from 5 halogen, phenoxy, substituted phenoxy and (lower)alkoxy; m is an integer of from 0 to 2 ; n is an integer of from 2 to 5 ; is sulfur, oxygen or methylene; R6 is (lower)alkyl; o r is an integer of from 1 to 4; and e 9 R and R each are independently hydrogen or (lower)B 9 alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N.5 methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)nonane.

Another preferred embodiment of the intermediates of Formula III are those having the structure wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower)alkoxy; m is an integer of from 0 to 2; n is an integer of from 2 to 5: Z is sulfur, oxygen or methylene; R^ is hydrogen or (lower)alkyl; r is an integer of from 1 to 4; and 9 R and R each are independently hydrogen or (lower)8 9 alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)nonane.

Another preferred embodiment of the intermediates of 10 Formula III are those having the structure R6 „8 (CH2)r ,12 XI Id wherein R11 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower)alkoxy; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4; and 9 R and R each are independently hydrogen or (lower)BQ . . alkyl; or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, hmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo(3.2.2)nonane.

As presently envisaged, the most preferred intermediates of Formula III are ι4 a) l-Methoxy-2-[3-(3-piperidinomethylphenoxy)propylamino}cyclobutene-3,4-dione. b) l-Methoxy-2-{2-( (5-dimethylaainomethy 1-3-thienyl)methylthio] ethylamino}cyclobutene-3,4-dione. c) l-Methoxy-2-{ 2-[ (5-piperidinomethyl-3-thienyl )methylthio]ethylamino}cyclobutene-3,4-dione. d) l-Methoxy-2- [3- (3-dimethylaminomethylphenoxy)propylamino] cyclobutene-3,4-dione. e ) l-Methoxy-2-[3-(3-pyrrolidinomethylphenoxy)propylamino]10 cyclobutene-3,4-dione. f ) l-Methoxy-2-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}cyclobutene-3,4-dione. g) l-Methoxy-2-13- (3-hexamethyleneiminomethylphenoxy) propylamino] cyclobutene-3,4-dione. h) l-Methoxy-2-I3-(3-piperidinomethylthiophenoxy)propylamino] cyclobutene-3,4-dione. i) l-Methoxy-2-13- (3-heptamethyleneiminomethylphenoxy)propylamino] cyclobutene-3,4-dione. j) l-Methoxy-2-[3- (3-octaiaethyleneiminomethylphenoxy)propylamino] cyclobutene-3,4-dione. 5327 The invention is illustrated by the following enables, in which all temperatures are given in degrees Centigrade, and in which the word Celite is a Trade Mark and refers to a diatomaceous earth.

Exanples dealing with additional preparations of conpoinds of the formula I set forth above, frat intermediates of the Formula III, are to be seen in the specification of our primary Application.

Example I 1-Amino-2- f3-(3-piperidinomethylphenoxy)propylaniino]cycIobutene3,4-dione A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 4.46 g; 13.9 mmoles) (prepared according to published D.K. Patent Application 2,023,133] in 40 mL of methanol was added all at once to a solution of 1,2-dimethoxycyclobutene-3,4-dione (1.97 g; 13.9 nmoles) in 40 mL of nethanol that had been cooled to 5* in an ice-water bath. After 2 hours at ambient temperature, the solution was cooled to 5* and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then filtered to give 4.35 g of product.

The product (4.20 g; 12.2 mmoles) was suspended in 40 mLcf 95% aqueous ethanol and 6.11 mL (12.2 mmoles) of aqueous 2.0 N ECI was added with stirring. The solution was filtered through Celite, cooled at 0· for 17 hours, and then filtered to give 4.33 g of the title compound as its hydrochloride salt, mp 254-257*.

Anal. Calc'd. for C19R26C1N3°3: C' 6Ο’θ8; Η» 6·90' Μ» n·06? Cl, 9.33.

Found (corr. for 0.28% HjO): C, 59.73; H, 6.97; N, Cl, 9.36. 11.14 ιό Example 2 1-Amino-2- {2- (( 5-dimethylaminomethyl-2-thieny 1) methy Ithio] ethylaroino}cyclobutene-3,4-dione A solution of 2-(( 5-dimethylaminomethyl-2-thienyl) 5 methylthio]ethylamine (2.06 g; 8.94 mmoles) [prepared according to the procedure described in Belgian Patent 867,105] in 20 mi of methanol was added all at once to a cold (5°) solution of l,2-dimethoxyeyclobutene-3,4-dione (1.27 g; 8.94 mmoles) in 20 mL of methanol. After 3.5 hours at ambient temperature, lo the solution was cooled to 5° and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred for 18 hours at ambient temperature and then filtered to give 2.66 g of product. Recrystallization from 95% aqueous ethanol yielded the title compound, mp 240-243* (dec.).

Anal. Calc'd. for ci4Bi9H3°2S2: C, 51.67; H, 5.88; N, 12.91; S, 19.70.

Found: C, 51.60; B, 5.76; N, 12.97; S, 19.69. ϊ7 example 3 2-{ 2-[ (S-Dimethylaminomethyl-2-thienyl)methylthiol ethylamino)-1methylaminocyclobutene-3,4-dione A solution of 2-1 (5-diraethylaminomethyl-2-thienyl) methylthio]ethylamine (1,32 g; 5.73 mmoles) in 20 mL of methanol was added to a cold (5·) solution of 1,2-dimethoxycyclobutene3,4-dione (814 mg; 5.73 mmoles) in 15 mL of methanol. After 3.5 hours at ambient· temperature, the solution was cooled to 5* and excess anhydrous aethylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 70 hours at ambient temperature and then filtered to give 1.38 g of product. Recrystallization frcm ethanol yielded the title compound, m.p. 185-187*.

Anal. Calc'd for ci5H21N3°2S2s C, 53.07; H, 6.23; N, 12.38; S, 18.89 Found: C, 53.18; H, 6.21; N, 12.25; S, 18.94 Example 4 l-Methylamino-2- [ 3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3 ,4-dione A solution of 3-(3-piperidinomethylphenoxy) propylamine (from the dihydrochloride, 3.21 g; 10.0 mmoles) in 40 mL of methanol was added to a solution of 1,2-dimethoxycyclobutene3,4-dione (1.42 g; 10.0 mmoles) in 40 mL of methanol. After 1 hour at 10’ and 30 minutes at ambient temperature, the solution was cooled to 5* and excess anhydrous methylamine was bubbled o into the solution for 5 minutes. The mixture was stirred for 17 hours at ambient temperature and then filtered to give 2.77 g of product.

The product (2.77 g) was suspended in 40 mL of ethanol and 4.07 mL (8.1 mmoles) of agueous 2N HCl was added with stirring to yield the hydrochloride salt of the title compound, m.p. 194-198*.

Anal. Calc'd for C20H2?N3O3«HCl: C, 60.99; H, 7.16; N, 10.67 Found (corr. for 1.35% H20): C, 60.63; H, 6.96; II, 10.71

Claims (8)

1. ί9 λ compound of the formula A- (CH,) Z (CH,) NH-j=3- R A in 2 u HI wherdin R is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and alkoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; and A is in which R 6 is (lower)alkyl, (lower)alkoxy or halogen, provided that, in the second, third or fourth of the four values of A specified above, R 3 may alternatively be 5 hydrogen; . r is an integer of from 1 to 4 inclusive; and 8 9 R. and R each are independently hydrogen, (lower)alkyl, allyl, propargyl, (lower)alkoxy (lower)alkyl in which the (lower) alkoxy moiety is at least two carbon atoms removed from 10 the nitrogen atom, cyclo(lower)alkyl, or phenyl (lower)alkyl, 8 9 provided that R and R may not both be cyclo (lower)alkyl, or 8 9 R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrol idino, morpholino, thiomorpholino, piperidino, methyl15 piperidino, diraethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclol3.2.2Jnonane.

2. a compound of Claim 1 having the formula ^> 2>r45 jP< a b>»’ ,a, ! , »h==Ilia wherein R 12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lover)alkoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; 5 z is sulfur, oxygen or methylene; R 6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and 8 9 R and R each are independently hydrogen or (lower)8 9 alkyl, or R and R , taken together with the nitrogen atom to 10 which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,

3. ,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)nonane. 15 A compound of Claim 1 having the formula ,8 ΓΠ \ (CH 2 ) r -|J- J- (CH 2 ) n 2 (CH 2 ) n NH=12 Illb wherein R is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower)alkoxy; m is an integer of from 0 to 2 inclusive; 2c n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R 6 is (lower)alkyl; r is an integer of from 1 to 4 inclusive; and R 8 and R 9 each are independently hydrogen or (lower)25 alkyl, or R 8 and R 9 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, »methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)30 nonane S3275

4. a compound of Claim 1 having the formula (CH^lCH^l® »12 IIlc wherein R is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower)alkoxy;

5. M is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R 6 is hydrogen or (lower,alkyl; r is an integer of from 1 to 4 inclusive; and 8 9 lo R and R each are independently hydrogen or (lower)8 9 alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidj.no, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, 15 heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]nonane. A compound of Claim 1 having the formula I(CH 2 ) r (CH-) 2 (CH-) NH· £ ro * n »12 Hid wherein R is a conventional leaving group selected from 2o halogen, phenoxy, substituted phenoxy and (lower,alkoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R^ is hydrogen or (lower,alkyl; r is an integer of from 1 to 4 inclusive; end R 8 end R 9 each are independently hydrogen or (lower)alkyl; or R 8 and R 9 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, 5 morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicycloI3.2.2)nonane. 6 · l-Methoxy-2-I3- (3-piperidinomethylphenoxy) propylamino) 10 cyclobutene-3,4-dione. 7 · l-Methoxy-2-{2-[ (5-dimethylaminomethyl-3-thienyl)methylthio) ethylamino) cyclobutene-3,4-dione. K S- l-Methoxy-2-{2-( (5-piperidinomethyl-3-thienyl)methylthio) ethylamino}cyclobutene-3,4-dione. 15 9. 1-Me thoxy-2-[3- (3-dimethylaminomethylphenoxy) propylamino] cyclobutene-3,4-dione.

6. 10. l-Methoxy-2-f3- (3-pyrrolidinomethylphenoxy)propylamino]cyelobutene-3,4-dione. 11 · l-Methoxy-2-{3-[3- (3-methylpyrrolidino)methylphenoxy)20 propylamino)cyclobutene-3,4-dione. 12 · l-Methoxy-2- [3τ (3-hexamethyleneiminomethylphenoxy) propylamino) cyclobutene-3,4-dione. 13 · l-Methoxy-2-13- (3-piperidinomethylthiophenoxy) propylamino) cyelobutene-3 , 4-dione. 25 14. l-Methoxy-2-[ 3-(3-heptamethyleneiminomethylphenoxy )propylamino]cyclobutene-3,4-dione. S3275

7. 15. l-Methoxy-2- [,3-(3-octaraethyleneimino®ethylphenoxy)propylamino} cyclobutene-3,4-dione.

8. 16. A compound of the formula III given and defined in Claim 1, which is any one of those specifically herein5 before mentioned.