3,098tO66 column 21, lines 70 tb 75, the formula should appear as shown below instead of as in the patent: (CH ) ------CH (lower alkyl)-N 2 ml N-A'-C-NH--- C4@/ NH U2)M @@C.H2 2 2 column 22, lines 2 to 5, the formula should app6ar as shown below instead of as in the patent, (,CH ------ CH NH 2 rfli Ae 1001/ (lower alkyl)-N N-,I -A - NH--C \ (CH --CH x NH 2 m2 p 2 column 22, lines 32 and 33, for "groupings" read--- grouping column 23, line 55, for "foreging" rea@d -- foregoing --; column 24,, line 40, for "ocid" read -- acid - .-; line 47, for 'IN-N-l' rbad ---N,N- column 27, line 6, for "sulfonates.11 read -- sulfonates, line 59, for "centigrade" read -- Centigrade column 28, line 74, for "4methyl" read -- 4- methyl --; column 29, line 30, for "isothiourear" read -- isothiourea --; line 34, for "ethylamine prepared" read -- ethylamine (prepared - -; column 30, line 44, for "yields and the" read -- yields the column 36, line 47, for 111810",read.-- 1910 --; column 37, line 16, for "imino]propylgUanidine" read -- imino]-propyl-quadidine column 39, lines 4 to 7, the formula should appear as shown below instead of as in the patent, (CH ) Nq 2 n, C4 @v R'-N N-ANH(CH ) \NH-R' 2 n2 2 Signed and sealed this 25th day af February 1964. (SEAL) Attest: FDWIN L. REYNOLDS ERNEST W. SV@IDER Attesting Officer Acting Commissioner of Patents

United States Patent Office 3@0-98,0@66 3,098,066 DIAZA-HETEROCYCLIC GUANIDINE COMPOUNDS Robert Paul Miill, Florham Park, N.J., assignor to Ciba Corporation, a corporation of Delaware No Drawing. FUed Mar. 4, 1960, Ser. No. 12,681 12 Claims. (Cl. 260-239) The present invention concerns guanidino derivatives. More particularly, it relates to El-N,N-( N-RI-aza-alkyllo ene) -iminol -lower alkyl-guanidines, in which azaalkylene contains from three to eight, more particularly from four to six, carbon atoms, and R, stands for an aliphatic hydrocarbon radical, a substituted aliphatic hydrocarbon -radical, a carbocyclic aryl radical or a heterocyclic aryl 15 Tadical, as well as an acyl radical, salts or quaternary ammonium compounds thereof, as well as process for manufacturin- such com-poutids. The N,N-aza-alkylene-imino group, in which the aza-nitrogen is substituted by Rl, represents primarily a hexa2o cyclic, a heptacyclic or an octacyclic radical, as well ias a pentacyclic, a nonacyclic or a decacyclic group. The Ting carbon atoms are preferably unsubstituted or may contain, for example, hydrocarbon radicals, particularly lower alkyl, e.g. methyl, ethyl and the like, as stibstituents. 25 The N,N-(N-RI-aza-alkylene)-imino group is represented primarily by the group of the formula: (CH2) .1 RI-N N- 30 \(CH2).2 in which each of the symbols n, and n,_, represents o-@ie of the numbers 2, 3 and 4, with the proviso that the total C)f nl+n2 represents one of the numbers 4, 5 and 6, and RI 35 h,is the previolisly given meaning. A more preferred group of N,N- (NRi-aza-alkylene) -imino radicals may be represented by the formula: 40 Ri-N / N(OH2).@- CH2 in which each of the symbols ml and M2 represents one of the numbers I and 2, and R, has tha previously given 45 meaning. The N,N-(N-Rl-aza-alkylene)-imino radical may be repres-,nted, for example, by 4-RI-1-piperazino, 1-N,N(3- RI-3-aza-1,6-hexylene)-ir.-Ano, and 1-N,N-(4-RI-4-aza1,7- hep'Lylene)-imino, in which RI has the previously given 50 meanin.@, as well as by 1-N,N-(3-P,1-3-aza-1,7- heptylone) - inuno and the like, and similar Eradicals, in which the car,bon atoms of th@- aza-alkylene portion may contain lower alkyl, e.g. methyl, ethyl and the like, as substituents, si-ich as, for example, 4-RI-2-methyl-l-piperazino, 4-RI2, 55 6-di @methyl-l-piperaz;no, 4-RI.-2,2,6,6-tetra methyl-l-piperazino, 1-N,N-(3-R,-3-aza-1,1,6,6-tetra@me thyl-1,6-hexylene)-imino and the like, in which RI has the - previously given meaning. An -,iliphatic hydrocarbon radical RI, comprising also C)O a carbocyclic aliphatic hydrocarbon radical, is primarily an aliphatic hydrocarbo@n radical containing from one to ten carbon atoms, such as, for example, -alkyl, - containing from one to ten carbon atoms, especially lower alkyl containing from one to seven carbon atoms, e.g. methyl, 65 ethyl, n-propyl, isopropyl, n-butyl, isobutyl, - @secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, nhexyl, isohexyl, n-heptyl and the @like, as well as n-octyl, 2,2,3,3-tetramethyl-butyl, 5,5-dimethyl-he,@yl, n-nonyl, ndecyl and the like. Other aliphatic hydrocarbon radicals 70 are, for example, lower alkenyl, e.g. ethenyl, 2-propenyl, 2-methyl-2-propenyl, 2-buteriyl and the like, lower alkynyll Patented July 16, 1963 2 e.g. ethynyl, I-propynyl and the like, cycloalkyl containing from three to seven, particularly from five to six ring carbon atoms, e.g' cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, cycloalkenyl containing from five to seven ring carbon atoms, e.g. 2-cycIopentenyl, 3cyclohexenyl and the like, or any other suitable aliphatic hydroc-arbon radical. The above-mentioned aliphatic hydrocafbon, particularly lower alkyl, radicals may be slibstituted, for example, by other aliphatic hydrocarbon Tadicals, primarily by cycloa]kyl coiltaining from three to seven, esp.-cially from five to six, ring ca-rbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl and the like, cycloalkenyl containi-@ig from five to seven ring carbon @atoms, e.g. 2- cyclohexenyl, 3-cyclohexenyl and the like. The resultinp, - radicals may be represented by cycloalkyl-lower alkyl, 'n which cycloalkyl contains from five to six ring carbon atoms and lower alkyl contains from one to four carbon atorqs, e.g. cyclopentylmethyl, cyclohexylmethyl, I-eyelopentylethyl, 2- cyclohexylethyl, 3-cyclopentylpropyl and the like, or cycloal",enyl-lower alkyl, in which cycloalkenyl contains from five to six ring carbon atoms and lower alkyl contains f-rom one to folr carbon atoms, e.g. 2-cyclopentenylmethyl, 3- cyclohexenylm@ ethyl, 2-(3-cyclohexenyl)-ethyl and the like. Or, cycloaliphatic hydrocarb(yn radicals, such as the previouslymentioned cycloalkyl and cycloaikenyl radicals, may so be substituted by other aliphatic hydrocarbori radicals, such as lower alkyl, e.g. methyl, ethyl and the like. An ialiphatic hydrocarbon radical R, may also be substi-tuted by carbocyclic aryl, particularly. @m@onocyclic or bicyclic carbocyclic laryl, e.g. phenyl, 1-naphthyl or 2naphthyl, as well as substituted phenyl, substituted 1liaphthyl or substitu',ed 2-naphthyl. Substituents attached to these carbocyclic aryl radicals are, for example, lower ialkYL e.,-. Tnethyl, ethyl and the like, lower alkox@y, e.g. mothoxy, ethoxy and the lil@e, lowf@,r alkylenedioxy, e.g. methylonedioxy, lower alkyl-inereapto, e.g. methylmercapto, ethylmereapto and the like, nitro, aniino, par;ticularly NN-di-substituted iamino, such as N,N-di4ower alkylamino, e.g. NN-dimethylamino, N,N-diethylamino and the likt, halogeno, e.g. fluoro, chloro, bromo and the like, or halogeno-lower alkyl, e.g. triffuorom,cthyl. Substituents attached to carbocyclir, aryl, particularly monocyclic carboryclic aryl, portio,.qs may be in any of the available positions, whereby one or more than one of the s,-,rne or of different substituents rnay be present. The @-bove aliphatic hydrorarbon radicals containing carbocyclic aryl substituents maybe represented, for example, by carbocyclic axyl-lower aliphatic radicals, prifnarily monocyclic carbocyclic aryl-lower alkyl, such as phenyllower !alkyl, e.g. benzyl, diphenylmethyl, I-phenyl-ethyl, 2-phenyl-ethyl, 3- phenyl-propyl and the lilce, bicyclic carbocyclic aryl-lower alkyl radicals, such as naphthyllower alk@yl, e.g. 1-naphthyl-rnethyl, 2- nal@,ithylmethyl and the like, monocyclic carbocyclic aryl-loiver alkenyl, e.g. phenylethenyl, 3-phenyl-2-propenyl and the like, or bicyclic carboeyclic aryl-lo,,@,er alkenyl, e.g. 1-(2-naphthyl)- ethenyl and the like. T-be carbocyclic portions of these radicals may be unsubstituted or may contain slibstituents, such as those mentioned bereinabove. Another group of substituted aliphatic hydrocarbon radicals are those containing heterocyclic aryl radicals, such as monocyclic azacyclic aryl, for example, pyridyl, e.g. 2-pyridyl, 3-pyridyl, 4- p@yridyl and the like, bicyclic rionocyclic aryl, for exarnple, quinolyl, e.g. 2-quinolyl, 4-quinolyl and the like, monocyclic diazacyclic laryl, e@g. 3-pyridazinyl, 2-pyrimidyl, 4-pyrimidyl, 2- pyrazinyl and ithe like, monoeyelicthiacycl-.c aryl, for example, thienyl, e.@g. 2@tbienyl and the like, monocyclic oxacyclic @aryl, for

exar@iple, furyl, e.g. 2-furyl and the like. These heteroeyel-'@C aryl Tadicals may also contain additional substituents siieh as, for example, lower alkyl, eg. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo land tl-ie like. T-he ialiphatic hydrocarbon radicals slibstituted by heterocyclic aryl groups may, therefore, be represented by he,eroc,yelic aryl-lower aliphatic hydrocarban radicals, such as monocyclic or bicycli-- heterocyclic -aryl-lower alkyl radirals, particularly pyridyl-l(>wer alkyl, e.g. 2pyridylmethyl, 3,pyridylmethyl, 4- pyridylmethyl, 2-(4pyridyl)-ethyl and the, like, py ridazinyl-lower alkyl, e..@. 4- pyridazinyl-methyl and the like, pyrimidyl-lower talkyl, e.g. 2-pyrimidyl-,methyl, 4- pyrimidyl-me-thyl,and t-he like, pyrazinyl-lower all@.yl, e.g. 2-pyrazinylmethyl ;and the like, thienyl-lower alkyl, e.g. 2-thenyl and the like, or furyl-lower alkyl, e.g. 2-furyl-methyl and the like. The aliphatic radicals may also be substituted by functio-iial groups, whereby one or more of the same or of different groups may be present;- if-anctignal grout,)s stibstitute primarily the above-mentioned lower allcyl radi(,als. Functional groups are, for example, oxygen-containing groups, isuch as hydroxy, etherified hydroxy, such as lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n@butyloxy, isobutyloxy,and the like, polyalkylenedioxy, e.g. polyethylenedioxy, polypropylenedioxy and the like, which polyalkylenedioxy radicals may contain from two to twenty lower alkylenedioxy por-tions and may have a,free terminal hydroxy group or an etherified terminal hydroxy group, sticli as terminal lower alkoxy, e.g. methoxy, ethoxy and the like, group, carbocyclic aryloxy, such as monocyclic carbocyclir, iaryloxy, e.g. phenyloxy ;and the like, or carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic; aryl-lower alkoxy, e.g. benzyloxy, diphenylmethoxy, (4-chlorophenyl)-phenylmethoxy and the like, or esterified ihydroxy, such as lower alkoxycarbonyloxy, e.g. methoxy-earbonytoxy, ethoxy-earbonylor ' v and the like, carb-,unyloxy, such as carbamyloxy, N4ower ialkyl-carbamyloxy, e.g. Nmothyl-carbamyloxy and the like, N,N-di-lower alkyl-carbamyloxy, e.g, N,N-dimethyl_ carbamyloxy and tihe like, or N-carbocyclic aryl-car_ bam,yloxy, particularly Nmonocyclic carbocyclic arylcarbamyloxy, e.g. N-phenyl-carbamyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and,the like, or acyl groups, such as lower alkanoyl, e.g. acetyl and the like. Functional substituents of lower aliphatic, particularly lower alkyl, radicals are -also nitrogen-containing -roups, such as amino groups, for example, unsubstituted amino Nmonosubstituted amino, for example, N-lower alkyl' amino, e.g. N-methylamino, Nethylamino and the like, N-carbocyclic aryl-amino, particularly N-monocyclic carbocyclic aryl-amino, e.g. N-phenyl-amixo and the like, N-carbocyclic aryl4ower alipha@tir, hydrocarbon-amino, particularly N-monocyclic carbocyclic-lower alkylamino, such as N-phenyl-lower alkyl-amino, e.g. N-benzyl-amino, N-(2-phenyl-ethyl) - amino and the like, or primarily N,Ndisubstituted amino, stich as N,N-di-lower alkylamino, in which lower alkyl contains from one to four carbon atoms, e.g. N,Ndimethylamino, N-ethyl-N-methyl-aminol, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, N-cycloalkyl-N4oweralkylamino, e.g. Neyelopentyl-N-methyl-aAiilio, N-cyclohexvlN-othyl-amino, N-lo-%ver alkyl-Nmonocyclic carb6cyclic aryl-arm'no, partictilarly N-lower alkyl-N-phenyl-lower allcylamino, e.g. N-benzyl-N-methyl-amino, N-methyl-N(2-p henyletliyl)-amino and tl-ie like, o.- N,N-alkylene-;Mino,N,N-oxa-alkylene-imino, or N ,N-aza-alkylene-imi@Tio, in which alkylene contains from four to six carbon atoms as ring members, such as, for example, 1-pyrrolidino radicals, e.g. I-pyrrolidino, 2-metbyl-l-pyrrolidino and the like, 1piperidino radicals, e.g. I-pip-@ridino, 2-methyl-l-p@13eridino, 3-methyl-l-piperidino, 4- methyl-l-piperidino, 3hydroxy-l-piperidino, 3-aceto xy-l-piperidino, 3-hydroxy-methyl-lpiperidino and the like, 1-N,N-(1,6-hexylene)- 3,098,066 4 imino, 1-morpholino, or I-piperazino radicals, e.g. 4- methyl-l-piperazino, 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl-l-piperazino, 4-(2-polyethylen edioxy@ethyl),lpiperazino and the like. 5 Sulfur containing substituents of lower aliphatic radicals are primarily mercapto or etherified mercapto groups attached to lower alkyl; etherified rnercapto may be represented by lower alkyl-r@ierrapto, eig. methy-Imercapto, ethylmercapto and the like. 1( Also included as substiltuents of lower aliphatic, particularly of lower alkyl, radicals are halogeno atoms, e.g. fluoro, chloro, bromo and the like, whereby one or more than one halogeno atom may be attached to one or more than one carbon atom of a lower alkyl radical. 15 The group RI may also be represented by carboryclic aryl radicals, which are primarily monocyclic - carbocyclic aryl radicals, e.g. phenyl, or bicyclic carbocyclic aryl radicals, e.g. 1-naphthyl or 2-naphthyl. Such radicals may be unsubstituted or may contain substituents; one or 20 more than one of the same or different substituents may be attached to any of the available carbon atoms. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and the like, hydroxy, etherified hydroxy, such as lower alkoxy, e.g. 25 methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy and the like, or lower alkylenedioxy, e..-. methylenedioxy, esterified hydroxy, such as lower alkoxycarbonyloxy, e.g' methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, or lower alkanoyloxy, e.g. acetyloxy, n-propionyloxy and 30 the like, mercapto, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, carboxy, esterified carboxy, such as carbo-lower alkoxy, e.g. carbomethoxy,,carbethoxy and the like, nitro, amino, such as N-unsubstituted amino, N-monosubstituted 35 amino, for example, N-lower alkyl-amino, e.g. N-methylammo, N-ethylamino and the like, or particularly N,N-disubstituted amino, for example, N,N-di-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or halo40 geno-lower alkyl, e.g. trifluoromethyl and the like. Heterocyclic aryl radicals R, are primarily monocyclic or bicyclic heterocyclic aryl radicals, which contain one or more than one sulfur, oxygen and/or nitrogen atom as ring members, and which are preferably pentacyclic or 45 hexacyclic heterocyclic radicals. Such radicals arerepresented, for example, by monocyclic mono-azacyclic aryl, for example, pyridyl, e.g. 2-pyridyl, 3-pyridyl, 4- pyridyl and the like, bicyclic mono-azacyclic aryl, for example, quinalyl, e.g. 2- quinolyl, 4-quinolyl and the like, mono5( cyrlic di-azacyclic aryl, for example, pyridazinyl, e.g. 3pyridazinyl and the like, pyrirnidyl, e.g. 2-pyrimidyl, 4pyrimidyl and the like, pyrazinyl, e.g. 2-pyrazinyl, pyrryl, e.g. 2-pyrryl and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g. 2-thienyl and the like, or mono55 cyclic oxacyclic aryl, for example, furyl, e.g. 2-furyl and the like. The above described heterocyclic radicals are unsubstituted or may contain as substituents lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, e.a. methylGo mercapto, ethyl-mercapto and the like, or halogeno, e.g. fluoro, chloro, bromd and the like@ Acyl radicals representing the group R, tnay be those of lower aliphatic carboxylic acids, such as lower alkoxycarbonic acids, e.g. methoxy-earbonir,, ethoxy-earbonic r, 5 acid and the like, amino-carbonic acids (or carbamic acids), such as carbamic, Nlower alkyl-carbamic acid, e.g. N-methyl-carbamic and the like, N,N-di-lower alkylcarbamic acid, e.g. NN-dimethyl-carbamic and the like, N-carbocyclic arylcarbamic acid, such as ,N-monocyclic 70 or N-bicyclic carbocyclic aryl-carbaniic acid, e..-. N-phenyl carbaniic, N-2- naphthyl-carbamic acid and the like, lower alkanoic acids, e.g. acetic, propionic, butyric, pivalic acid and the like, lower alkenoic acids, e.g. 3-bi-itenoic, acid and the like, or lower alkynoic acids, e.g. propiolic acid 75 and the like. Acyl radicals may also be those of sub-

stituted lower alkanoic acids, such as, for example, cycloalkyl-lower alkanoic acid, e.g. 3- cyclopentyl-propionic acid and the like, halogeno-low,-r alkanoic acids, e.g. chloroacetic, dichloroacetic, triluoroacetic, trichloroacetic, bromoacetic acid and the like, lower alkoxy-lower alkanoic acids, e.g. methoxy-acetic acid and the like, or aminolower alkanoic acids, such as tertiary imino-lower alkano.@@. acids, particularly N,N-di-lower alkyl-amitio-lower alkanoic acids, e.g. N,N-dimethy l-amino-acetic, 3-N,,N-diethylaminopropionic acid and the like, or NN-alkyleneimino-lower alkanoic acids, e.g. 3-(Ipii)eridino)-propionic acid and the like. Other acyl radicalstnay be those of carbocyclic aryl carboxylic acids, especially monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic, 4mothyl-benzoic, 4-methoxy-benzoic, 3,4,5- trimethoxy-benzoic, 4-0-ethoxycarbonyl-syringic, 3,4-dichloro-benzoic, 3-nitro-benzoic, 3,N,N-dimethyl-amino-benzoic acid and the like, or bicyclic aryl carboxylic acids, e.g. 1-naphthoic, 2-naphthoic acid and the like, carbocyclic aryllo,wer aliphatic carboxylic acids, such as monocyclic carbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, diphenylacetic, 3-phenyl-propionic, 4- methoxy-phenylacetic acid and the like, or monocyclic carbocyclic aryl-lower alkenoic acids, e.g. einnamic, 4-chloro-einnamic, 3,4,5-tr.; methoxy-cinnamic acid and the like, h&lerocyclic aryl carboxylic acids, such as monocyclic heterocyclic aryl carboxylic acids, e.g. iiicotinic, isonicotinic, 2-furoic, 2-thienoic acid and the like, or heterocyclic aryl4ower aliphatic carboxylic acids, such as monocyclic heterocyclic aryllower alkanoic acids, e.g. 2-pyridyl-acetic, 2-thienyl-acetic acid and the like. The lower alkyl radical, linking the 1-NIN-(N-Ri-az aalkylene)-imino portion with the guanidino group, is represented by lower alkylone containng from one to seven carbon atoms. Preferably, lower alkylene co7itains from two to three carbon atoms, which separate the I-N,N(N-RI-aza-alkylene)-imino portion from the guanidino group by the same number of carbon atoms; such radicals are 1,2-ethylene, 1-mothyl-1,2-ethylene, 2- niethyl-1,2ethylene or 1,3-propylene. Other lower alkylene radicals are, for example, methylene, 1,1-ethylene, 2,3-butylene, 1,3-butylene, 1,4-butylene, 1,4-pentylene or 1,5- pentylene and the lilce. The guanidino group may be represented by N-R4 -N-C R3 R2 in which each of the radicals R2, R3, IZ4 and R5 stands primarily for hydrogen. They may also represent an aliphatic hydrocarbo-ii radical, particularly lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, with the proviso that at least one of the radicals R2, R3 and R4 stands for hydro,-en. One of the radicals R2 and R4 MaY also be an acyl radical; such acyl radical may be identical with one of those wh@.ch can represent RI attached to the nitrogen atom of the I-N,N-(N-RI-az a-alkylene)-imino portion. Acyl radicals may, therefore, be, for example, those of lower aliphatic carboxylic acids, for example, lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, substituted lower alkanoic acids, e.g. chloroacetic, dichloroacetic, hydroxyacetic, methoxyacetic, eyclopentylpropionic acid ond the like, or lower alkenoic acids, e.g. 3-butenoic acid and the like, carbocyclic aryl carboxylic acids, for example, monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic, hydroxybenzoic, 4methoxy-benzoic, 3,4-dimethoxybenzoic, 3,4,5-trim.-thoxy-benzoic, 4-0-etho,@ycarbonyl-syringic, 3,4-dichlorobenzoic, 3-N,N-dimethylaminobenzoic, 4-nitrobenzoic acid and the like, or bicyclic carbocyclic aryl carboxylic acids, e.g. 1-naphthoic, 2-napbthoic acid and the like, or heterocyclic aryl carbocylic acids, for example, monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic, 2-furoic acid and the like. 3,098,066 6 Salts of the new compounds of this invention are particularly thertpeutically acceptable, non-toxic acid addition salts, such as those with iiaor,-anic acids, for example, mineral iacids, e.-. hydrocbloric, hydrobromic, sulfuric, r) phosphoric -,icids and the like, or those with organic acids, such as organir, carboxylic acids, e.1g. acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, suceinic, maleic, fumaric, malic, tartaric, citric, ascorbic, h3rdroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 10 4@hydroyybenzoic,, anthranilic, einnamic, m.andelic,- salicylic, 4-aminosalicylic, 2- phenoxybenzoic, 2-acetoxy-benzoic and the like, or or.-anic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, 2-hydroxyetb.aiie sulfonic, ptoluene sulfonic acid and the like. Mono- or poly-salts 15 may be formed. The new guanidino derivatives of this invention and the salts thereo'L are characterized by antibyperten@sive properties and can, therefore, be used as @antihypertensive agents to relieve hypertensive conditions, particularly 20 those of neurogenic,, renal or essential nature. In addition, they cause an increase in the pe,-ipharal blood flow and c-@n, therefore, be used in functional peripheral vascular diseases, -sur-h as Raynaud's disease. The-sepharmacolo@ical properties,are of relatively long duration and 25 are coiipled witli a rlmarkably low degree of toxicity. The compounds Gf this inventioii may also be employed is inlermediates in the manufacture of other useful compounds. A preferred group of compounds of this invention may 30 I)erepresented by the forinula: (OH2)., NI-I Ri--N N-A-NH-0 \ (CH9). / \ Nff-R2' 35 in which RI' stands for2lower alkyl, containing from one to seven, particularly from one to four, carbon atoris,- cycloallcyl containing from five to six ring carbon atoms, cyclo,,ilkyl-lower alkyl, in which cycloalkyl contains from 40 five to six r-ng catbo-@i atoms and lower alkyl co-@itains @from one to four carbon atoms, or monocyclic Garbocyclic aryl, particr-iarly phenyl, lower alkylsubstituted phenyl, in whicli lower alkyl co@itains f-rom one to four carbon atoms, lower alkoxy-substituted phenyl, in which -lower alkoxy contaiiis from one to ToLir carbon atoms, -orha!lo45 geno-phenyl in which ha:logeno has an atomic weight below 80, ea@@ of the symbols n, and n2 stands for one of the numbers 2, 3 and 4, with the proviso that the total of nl+n2 represents one of the ntimbers 4, 5 and 6, A represents lower alkylene, contai-,iing from two to three car60 bon @afoms and separating the guaiiidino grotip from the ring nitrogen ato@n by from two to t-hre.- varbon atoms, and R2' repres-@nts hydrogen, the acyl. radical of a lower alkanoic arid cor@taining froni twb to seven carbon atoms or the acyl TadiGal of a monocyclic carbocyclic aryl car55 boxylicacid, pirticularly the acyl radical of benzoic acid, t@he acyl radical of a lower alkyl-slbstituted benzoic icid, in which lower alkyl contains from one tc) four carbon atonis, the qcyl radical of a lower alkoxy-sTjbstitut-,d benzoic acid, in which lo@,ver a]-koxy contains from one to four 60 carbon atoms, or the a-.yl @radical of a halo.-c io-substituted benzoic acid in which balogeno represents a lial o,,eno atom with an atomic wei,-ht below 80, and therapeutically acceptable acid addition salts of such compotinds. Particularly valuabie with respect to their phari-,naco65 logical properties are the compounds of the formula: (CH2) .,-CH2 I\T H @-I (lower alkyl) -N N-A-NH-C.' (CH2).@-CH2 NII2 70 in wbich lower alkyl contains from oneto seven, particularly from one to four, carbon atons, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, as well as secondary butyl, tertiary butyl,.n-pentyl, isopentyl, neop@,ntyl, 75 nhexyl, n-heptyl indthe like, each of the symbols in, and

7 m2 stands for one of the n-umbers I and 2, iand A represents lower alkylene containing from two to three carbon -atoms and separating the @,-Uanidino goup, from the Ting nitrogen atom by @.Lromtwo to t-hree carbon atoms, e.g.- 1,2-ethylene, 1-methyl-1,2- ethylene, 2-methyl-1,2-ethylene, 1,3-propylene, and tlierapeuti--ally @acceptable acid addition salts thereof. 2-(4-methyl-i-pip-.razino) - ethylguanidine, 3-(4-mothyl-l-piperazino) - propyl - guanidine, 2-(4-methyl-l-piperazino)-2-methyl-ethyl-guaiiidine, 2-(4ethyl-l-pipe,razino)- et,hyl - guanidine, 2 - (4 - isopropyl - 1piperazin o)-ethyl-guanidine, 2-[I-N,N-(3-aza - 3 - metliyl1,6-- he,xylene)-imino]-ethyl-guanidine, 2-[I-N,N-(3-aza3-ethyl-1,6-hexylene)-imino]-ethylguanidine, 2-[I-N,N(4-aza-4-meth yl-1,7-heptylene)-iminol -ethyl - guanidine, 2-[I-N,N-(4- aza-4-ethyl- 1,7 - hepLyleie)-iminol-ethylglianidine, and their tl-iera@peutically,ace@-ptable - salts with mineral acids, represent tnis group ol' compounds. Another group of valuable compguncls are those of the form,ula: (CH2),@l-CH2 NII 51-@- (carbocyclic aryl)-N N-A-NII-C \1 N112 in which carboxylic aryl represents priniarily mo-@ioc-ycllc ca,rbocyclic aryl, pa@rticularly phenyl, as well as phenyl substituted by lower alky-1, containing from one to four carbon atoms, e,g. methyl, ethyl, n-propyl, isopropyl, n-buty@l and the ilike, phenyl 8ubstituted by lo,,ver alkoxy, containin@ from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-,outyloxy, and the like, phenyl substituted by NN-di-lower alkyl-amino, in ivhirh lower alkyl contains from one to four carbon atoms, e.g. N,N-dimet,hylamino, N,N-diethylaminoand the like, phenyl substituted by halogeno, iii which halogeno represents a haloge,n atom with an atomio weight below 80, e.g. fluoro, chloro, bromo and the like, or phenyl substituted by halogeno-lower alkyl, e.g. trifluoromethyl, or bicyclic carbocyclic aryl, e.g. 1-naphthyl, 2-naphthyl, orthese radicals substituted by the above-described substituents, each of tlle symbols ml and m2 represents one of the numbers I and 2, and A represents lower alkylene, containing from two to three carbon atoms, which separate the guanidi-.io gridup from the ring nitrogen atom by the samenumber <)fcarbon atoms, e.g. 1,2-ethylene,, 2-mothyl-1,2-ethylene, 1,3-propylene and the like, and therapeutically acceptable acid addition salts thereof. One or n-iore than one of the same or @different substituents may be attached to any of tlie positions available in the carbocyclig aiyl nucleus; substituted phenyl radicals are, for exam-ple, lower alkylphenyl, e.g. 4-methyl-phenyl and the like, lower ialkoxyphenyl, e.g. 4- methoxy-phenyl, 2,5-dimethoxy-phenyl, 3,4,dimet,hoxy-phenyl, 3,4,5 - trimethoxyphenyl, 4 - ethoxyphenyl and the like, lower;a;lkylenedioxy-phenyl, e.g., 3,4methylenedioxy,phenyl, N,N-lower alkyl-amino - phenyl, e.g. 3-N,N-dimethylamino-phenyl, 4-N,N-dimethylaminophenyl and the like, halogeno-phenyl,,e.g. 4-chloro@phenyl, 3, 4-dic,hloro-phenyl, 3-fluorophenyl, 4ilironiophenyl and the like, or polyhalogeno-lower alkyl-phenyl, e.g. 3-trifluoTomethyl-phenyl @and the like. Representing this group are, for example, 2-(4-phenyl-l-piperazino) -ethyl-guanidine, 3-(4-ph enyl-l-piperazino)-propyl-guanidine, 2-methyl-2-(4-phenyl-l-piperazino)-ethyl-guanidine, 2-[4-(4-methyl-phenyl)-i-piperazinol-ethyl-guanidine, 2-[4-(4-met,hoxy-phenyl)-l-piperazinol-ethyl-guanidine, 2-[4-(3,4-dimethoxy-phenyl)-l-piperazinol-ethylguanidine, 2-[4-(3,4,5-triinethoxy-phenyl)-l-piperazinol-ethylguanidine, 2-[4@(3,4-methylenedioxy-phenyl)-l-piperazino]-ethyl. guanidine, 2-[4-(4-dimethylamino@phenyl)-l-piperazino] -ethylguanidine, 2-[4-(4@bromo-phonyl) -1-piperazino] -ethyl-gtianidine, 3,098,066 8 2-[4-(3,4-dichloro-phenyl)-l-piperazinol-ethylguanidine, 3-[4-(3-tri'@luorometh3rl-phenyl)-l-piperazinol-propylguanidine, 2-[l-N,N-(3-aza-3-phenyl-1,6-hexylene)-imino]-ethylguanidine, 3-[l-N,N-(3-aza-3-phenyl-1,6-hexylene)-in-i:,nol-propylguanidine, 2-El-N,N-(4-aza-4-phenyl-1,7-heptylene)-i-@nino]-ethyl10 giianidine, and t@icir therapeutically acceptable a(@id addition salts thereof. The guanidino derivatives @of t-his invention may also be Tepresented by the compounds of the foimula: 15 (CH2)@i-CH2 NH (lower aldyl)-N N-A-NH-C (C)I-I2)@i-CH1 NH-R2, 20 in whirh lower alkyl contains from one to seven carbon atoms, e.g. met@hyl, ethyl, n-propyl, isopropyl, n-biityl, isobutyl, secondary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and the like, each 4of the symbols m@l and m2 represents one of the numbers I and 2, A stands for a lowcr alkylene 25 radical containing from two to three carbon @atoms and separating the ,-tialiidino groupi from the ring nitrogen atom by fr<)ni two to three carbon atoms, e.g. 1,2-ethylene 2-inetl-iyl-1,2-ethylene, 1,3-pTopylene and the like, and R2 represents the aCY1 Tadical of a lower -alkanoic acid, e.g. 30 acelic, pro@I)ionic, pivalic iac;d;and the like, the acyl radica:l of benzoic acid, the acyl radical of a lower alkyl-substituted @benzoic acid, e.g. 3-mothyl-benzoic, 4-ethyl-benzoic acid and the like, the, acyl radical of a loweralkoxysLibstituted benzoic -acid, e.g. 2-mathoxy--benzoic, 3-meth35 oxy-benzoic, 4-ethoxy-,b--nzoic, 3,4 - dimethoxy - benzoic, 3,4,5-trimethoxy-benzoic acid and the !like, or the acyl @iadical of a halogeno-substituted benzoic acid, e.g. 4-fluoro-benzoic, 2,5-dichiloro-benzoic, 4-bromo-benzoic acid a . nd the like, and the therapeutically acceptable acid addi40 tion salts thereof. This group may bi-, represented by 3-aceyl-l-[2-(4-methyl-l-piperazino)-ethyli@guanidine, 3-benzoyl-l-[2-(4-methyl-l-piperazino)-othyl]-guanidine, 1- [3-(4-ethyl-l-piperazino) -propyl] -3-propionyl45 guanidine, 1- [2-(4-isopropyl-l-piperazino) -ethyl] -3-(4-meth oxybenzoyl)-guanidine, 1- f2- E 1-N,N- (3-aza-3-n-et'@iyl- 1,6-,hexylen-.) -imino] et'nyll-3- (3,4-dicliloro-ib-- nzoyl) -guanidine, 1-f2- [ I-N,N-(4-aza-4-methyl-1,7-heptylene) - imino]- ethyl)-3-(3-methyl-benzoyl) -guanid@@'ne, and therapeutically acceptable acid addition salts thereof. Therapeutically acceptable acid addition salts of the described glianidiro compounds are primarily those with 55 mineral acids, e.g. hydrorhloric, hydrobromic, sulfuric, phosphoric acids and the like, as well as those with lower aliphatic polycar@boxylic acids, such as lower alkene dicarboxylic aicds, e.g. maleic, citraconic acid,and the like, -hydroxy-lower alkane dicarboxylic acids, e.g. tartaric acid 60 and the like, or hydroxy-lower alkane tricarboxylic acids, e.g. citric acid and the like. The new guanidino,derivatives may be used as medicaments in the form of phaxmaceutical preparations, which contains the new compounds or salts thereof in admixture 6,@) w-ith a pharmaceutical organic or inorganir,, solid or liquid car@rier suitable for enteral or parenteral administration. For maldng up the preparations t-here, can bD employed stibstances @w@hirh do not r,-act with the new compounds, sucli as water, gelatine, lactos,e, starches, stearic acid, i'O magnesium stearate, stearyl alcohol, tale, vegetable oils, benzyl alcohols, gums, propylena glycol, polyalkylene glycols, petroleu-m jelly or any other known caxrier for medicaments. The pharmaccutical preparations may be iii solid forri, for example, @as tablets, such as scored 75 tablets, dragees, capsules and the l@ike, or in liquid form,

3,098,066 9 for example, as sollitio@is, suspensions, emulsions and the lil-,e. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotir, pressure or buffers ,ind the like. They also may contain, in combination, 5 other th,-rapeutically useftil substances. The new guanidino compounds of this invention may be prepared, for example, by cor.,vertin.- in a [I-N,N-(NRI-aza-allcyle@-le)-imino]-lower alkyl-amine, in -whirh RI and aza-alkylene h-,t-ve the,above-given meaning, oy a salt 10 thereof, the amino @roiip into a giianidino -roup and, if desired, converting a resiilting salt into the @free conipound, and/or, if desired, converting a resulting compound into its acyl derivative, ind/or, if desired, converting a free compoii,id into a salt or a quaternary ammonium com- 15 pound thereof. The rea.-ents of choice for the conversion of an amino group into a guanidino -roup are S-lower alkyl-isothioureas, in which lower alkyl may stand primanly for inetbyl, as well as ethyl, n-propyl, isoprc)pyl and the like, 20 or acid addition salts thereof. Sal-ts, which are employed in preferenee over the free base, are primarily those with ,rnineral acids, such as hydrochlor.@c, hydrobromic, or particul.arly sulfliric acid and the like. The isothiourea reagents used in the reaction rnay be depicted by the for- 25 mula: N-R4 RO-S-C R3 10 inc,y; such compoiinds may be obtained, for example, bycontacting an amine of the formula: ( C I - 1 2 ) . , 7 C T T 2 (I o v7 er al ky l)- X / N - A - N I12 ( C H 2) @ iC II 2 inwhicli ml, ra2 and A have the previously given meaning, with a n-iineral acidaddition salt of an Slower alkylisothiourea, partiralarly the 8-methyl-isothiourea sulfate, preferably at an elevated @temperatlire. Similar reagents capable of convertiiig an amino into agiianidino grotip are 0-lower alkyl-isourea,s of the formula: N - R 4 R o - - O - c R 3 N R g in which R2, R3, R4 atid Ro have the previously given meaning, or their salts with mineral acids. These isourea derivatives are used in the same way as the above-described, correspording isothioiirea reag@-nts; 0-methylisourea sulfate represents a preferred reagen-t. The above-described reagents are known, or, if now, 1-nay be prepared according to proccdures described in the prior art and used for the manufacture of known analogs. For example, the S-lower alkyl-isothioureas or 0-lower alkyl-isoureas may be prepared by alkylating thioureas or N so ureas, in which at least one of tle nirogen a,toms carries a hydrogen atom, with a lower alkyl halide, e..g. methyl or ethyl chloride, bromide or iodide and the like, or with a di-lower alkyl-sulfate, e.g. diinethyl sulfate, diethylsulfate and the l,'ke. Other reagents capable of transforming the amino group of a [1-1,@1,N-(N-RI-aza-all@ylelie)- imino]4ower alkylamine, in Nvhich R, a,.id aza-,ilkyleric have the previously given meaning, particularly of aii acid additic,n salt thereof, are cyanimides having the forinula: N c R 3 N R 2 in Nvhich R2 and R3 have the previously given meaning. The reaction may be carried out, for ex,)mple, by heating the mixture of a [I-N,N-(N-RI-aza-alkylo ne)-imino]-lowor alkyl-aiiiine compoiind, partictilarly a salt thereof, such as a mineral acid addition salt, e.g. the hydrochloride, hydrobromide, sulfate and the l@,ke, thereof and the cyananlide. Therestilting rnelt rnay then be dissolved in a solvent, such a lower alkanole acid, e.g. acetic acid and the like, and the desired product rriay be isolated, for example, by crystallization aiid the like. The reaction may also be carried out in the presence of a solvent, such as a lower alkanol, e,g. ethanol and the like. The sqlt of a free base r@sed as tL-. starting material may also be formed at the site of the reaction by performing the latter in the presence of an acid, particularly a concentrated aqueous mineral acid, e.g. hydrochloric acid and the like. The cyanamide reagent i-nay also be formed in situ; for example, 1-nitroso-3-methyl-guanidine furnishes the N-inethyl-cyanamide, Nvhich then reacts with the amine to form the desired guanidino compound. The reaction may proceed exotherniically, and, if necessary, may be maintained by heating, for example, to from about 80' to abotit 200'; an atmosphere of an inert gas, e.g. nitrogen inay be advantageous. A third modification of the procedure for the manufacture of the products of this invention comprises reactirig the [I-N,N-(N-RI-aza - allylene) - iminol - lower alkylamine, in which RI and az-talkylene have the; previously given meaning, with a salt of a 1-guanyl-pyrazole. A salt in which t?il, M2 and A liave the previgiisly given -mean- 75 of a 1-gtianyl-pyrazole is primarily a salt with a mineral R2 in which R2, R3 and R4 have the previously @,iven meaning, and Ro stands for lower alkyl, particularly methyl, S5 and mine,-al acid addition salts -thereof. T-he preferred r,,agents -for t@e conversion of an amino groiip into a guanidino -rotip is S-methyl-isothiotixea a-@id its n-iineral acid addition salts; S-metliyl-isothiourea sullate is pri-marily tised to forri glianidino compounds, which con- 40 t,-.in an unsubstituted @uanidino -roup. The [I-N,N-(NRI-aza-alkylene)-imino]-lowe,r alkyl-amine starting material, in which the amino group is above all a primaxy amino grotip, @but may also represent a secondary amino groi-ip, such as an N-lower alkyl-amino group, e.g. N- 45 niethyl,imi@-,o, N-ethyl,-,mino and the like, is genc@rally used in the form of Viie free base. The reaction is carrled out by cortacting the starting Tnaterial with the rea-ent, preferably in the presence of a solvent, the choice of v,,Tiieh depends primarily on the 50 solubility of the reactaiits. Water or -vvater-rniscible @organic solvents, such as water-,niscible lower alkanols, e.g. methanol, elhp-nol, propanol, isopropanol, tertiary butanol and the like, water-miscible cyclic ethers, e.g. p-dioxane, tetrahydrofura--q and the lilce, ketones, e.g. acetone, 65 ethyl methyl ketone and the like, lower alkanoic acids, e.g. acetic acid and th-- like, formamides, c..-. formamide, N,N-dimethylforrnamide and the like, or aqueous mLxtures of sugh SOIVCDTS may be used as diluents. The reaction @may be caxried out at room temperature, or, if nec- 60 essary, at an elevated teniperature, for exam-ple, at the boil@in.- temperature of the solvent. An -absence of oxynn may,be achieved by peri.Orniing the reaction in @the atniosphere of an inert gas, e.g. nitrogen, and, if necessary, it may be carried olit under pressure in a closed @vessel. 65 This procedure is particularly suitable for the preparation of riiineral acid addition galts of compounds Df the formula: (CII2)m@- CH2 NH 70 (ION,ver alkyl)-N / N-A-NH-0 (C II2) .@- C II2 NH2

acid, such as, for example, nitric acid; a 1-guanyl-pyrazole may contain additional substituents in the pyrazole nucleus, particularly lower allcyl, e.-.. metl-iyl, ethyl and the like. Salts of 1-guanyl-3,5-diinethyl-pyrazole, particularly the salt with Pitrir, acid, represent the preferred reagents. The reaction may be carried ovt in the absence of a solvent, for example, by fusing the two reactants, or in the presence of a dituent, such as, for example, a lower alkanol, e.g. ethanol and the like, and advantageously, by exr,luding t!ie presene.- of carbon dioxide, for example, bY p-@rf-orming the reaction in the atmosphere of an inert gas, e.g. nitrogen. The reaction mixture'is preferably heated, for example, to the melting point of the mixture or to the boiling point of the solvent. The [1-N,N-(N-RI-aza-alkylene)-iminol-lower alkylamines, in which RI and azaallylene have 'Lhe previously given meaning, and the salts thereof, are known, or, if new, may be, prepared according to known procedures. They may, for example, be prepared by treating an N,N(N-Rl-aza-alkylene)-imine with a halogeno-lower alkanonitrile, in which halogeno represents, for example, chloro, bromo and the like, or with a lower alkeno-nitrile, in which the double bond is activated by the nitrile grolip in such fashion, that it adds to the imino group. In a [I -N, N-(N-RI-az a-alkylene)-i.minol-lower alkano-nitrile, resulting from one of these procedures, the nitrile group is then converted to a methylenearfiino groiip by reduction, for example, by catalytic hydrogenation, such as, treatment with hydrogen in the presence of a catalyst containing a metal of the eighth grojp of the periodic system, e.g. Palladium on charcoal, Raney -iiiclcel and the like, or, preferably, by treatment with a light metal hydride capable of converting a nitrile group to a methyleneamino group, for example, an aluminum hydride, such as lithium aluminum hydride, sodium aluminum e, magnes aluminum hydride, aluminum borohydride, aluminum hydride and the lil.-C, vihich hydrides rr@ay be used, if desired, in the presence ol' an activator, sucli as aluminum chloride. A gtoup of very important in,-,rmediates of the above type are new and are intended to be included within the scope of the present invention. They may be described by the formula: / (CH2)@f-CH2 HAC-N N-CH2-CH2-NI-12 in which each ol. the sy@nbols ml and in2 represe nts one of the numbers I nnd 2, and acid addition salts with mineral acids thereof. This group may be illustrated by 2-(4- methyl-l-piperazino)-ethylamine, 2- El-N,N-(3-methyl-3-aza-1,6-hexylene)-iminolethylaniine, 2-fl-NN-(4. methyl-4- aza-1,7-heptylene)-iinino] - ethylamine and the like, as well as their riiineral acid addition salts. The above compounds may be prepared, for example, by reacting a compound of the formula: (CI12).,-OH2 H3c-N \ / NH (CH2).@-CH2 in which ml and 1172 have the previously given meaning, or a salt thereof, with a halo.-enoacetonitrile, e.g. chloroacetonitrile and the like, and reduci-iig in a resulting compound of the formula: (CH2).,-Clfl H3C-N N-CH2--CN (CH2)@,7-CII2 in which tni and m2, have the previously given meaning, the nitrile group to a methylencamine group; these reactions may be carried out as previously shown. Com_Dounds of the preferred group of intermediates may also be ob3,098,066 12 tained, for example, by reacting a compound of the formiila: CH2-CH2--Xi .5 H3C-N CH2-01-12-X2 in which each oil the groups XI and X2 stands for a reactive esterified hydroxyl group, or a salt thereof, with ethylenediarnine and, if desired, converting a resulting com10 pound into a salt thereof. Reactive esterified hydroxy groups iii the starting material are, for e,,@ample, halogeno atoiis, e.g. chloro, bromo and the like, or monocyclic carbocyclic aryl stilfonyloxy groups, e.g. p-toluene sulfonyloxy and the like. Th@- starting material may react 15 with ethylenediam@.ne to form the desired 2-(4-m ethyl-lpiperazino)-ethylamine in the presence of an inert solvent, and, if desired, of an acid adsorbent; the reaction may be carried otit accordin.@ to standard niethods. The compounds of the present invention can also be 20 pre-!3ared by convert@.ng in a [I-N,N-(N-Ri-azaalkylene)imi@ol-lower alkylamine, ii which R, and aza-alkylene have the previously given meaning, and in which the amino group carries a substiluent capalol-, of being converted into an amidino group, or a salt of such compou-.id, such 25 substituent into an amidino grolip, and, if desired, carrying otit the ol)tional steps. Depending on the character of the substituent, which is capable of being converted into an am-ldino group and attached to the amino ,roup of the [IN,N-(N-Ri-aza-alkyl30 one)-iminol-lower alkyl-amine, th-@ procedure outlined hereinabove may be carried out according to different modificatioii.-. For example, the subs' itue-@l-t of the amino group of the [I-N,N-(N-Ri-azaal@'cylene)-imino] -lower alkyl-amine 35 may comprise a carbon -@tom, which s attached to the amino group. To such carbon atom t'here niay be conrected at least one nitrog@,.i atom. The carbon atom may also carry an add@.tional nitrogen a@,Om, as well as other hetero atoms, such as, for example, oxygen or sulfur, or 40 oth,-r substituents. Such groups mpy be, for example, cyano of the formula -C=-N, carbamyl of the formula -CONH-R4, thiocarbamyl of the formula -CSNH-R, 45 lower alkoxy-(imino)methyl of the formula -C(=NH)-OR, in which Ro represents lower alkyl, primarily methyl, as well as ethyl, n-propyl, isopropyl and the like, lower alkyl50 mereapto-(imino)methyl of the formula -C=(NR4)-SRO in which Ro has the above-given meaning, cyanoamidino of the forr.-iula - C(=NR4)-NH-C-N, guanidino55 (imino)methyl of the formula -C(@NR4)-[NH-C(==NH)-NH2] isocyano-(imino)methyl of the formula Go -C(=NR4)-N=C=O or isothiocyano-(in-tino)methyl of the formula -C(==NR4)-N==C=S and the like, in which R4 has the previously given meaning, but stands particularly ior hydrogen. 65 Together with the [ I -N N- (N-Ri-aza-alkylene) -ir-riino] lower alkyl-amino portioii, the,,e substittients form cyanamide, urea, thiourea, 04ower alkyl-isothiourea, eya-,iaguanidine, biguanide, eyanourea or cyanothiourea derivatives and the like. All of these compounds have the 70 above-,-iven common characteristic, i.e. to the amino group is attached a carbon atom, which carries at least a nitro-gen atom. The greater part of these starting materials may be converted into the desired guanidino derivatives by am75 mo-nolysis oraminolysis.

13 For example, a cyanamide may be converted into a guanidino derivative by treatment with @ammonia or an amir.onia-furnishin,- reagent, as well as with an amine, such as an N-lower alkyl-amine. This reaction may be carried out, for example, by treating the cyanamide com- 5 pound with liquid ammoiiia Linder pressure and at an elevated temp,-ratur,-, if desired, in the presence of an anion capable of forming a stable salt with a resulting gu@-nidine; am-moniur.,i acetate, ammonium sulfate, ammonium chloride and the like may be iised as an anion source. 10 Ammonia may be replaced by amr@ionia furnishin.- ammonilim salts; such salts are, for example, ammoi2ium ,nionoh)tdro.-en phospliate, which may be used under presslire and at an elevated ternperature or ammonium nitrate, wi'iereby a salt, stich as, for example, an alkaline earth 15 @nietal, e.g. calcium and the like, salt or an alkali metal, e.,-. sodium, potassitim and the like, salt of the cyanamide is preferably used, which may be reacted with the ammonitim nitrate in the presence of catalytic amounts of water. 20 The cyanamide compounds, used as the starting material and liavi-iig th@ formula: fl-l\',N-(NI-R,-aza-alkylene)-iininol-lower alkyl-N-C-=N I 5 R 25 in w' Iicli R5 stands prin-iarily for hydrogen, but may also be lower alkyl, and RI and aza-alkylene have the previously give-.i mea@iing, and salts thereof, may be prepared, for example, by treating the El-N ,N-(N-RI-aza-alkyle-ne) - 30 imino]-lower alkyl-aniine, in which RI and alky-lene have the praviously given meaning, with a cyanogen halide, such as cyanogen chloride, cyanogen bromide, and the like, advanta-eously in equivalent amounts and preferably in ap. inert solvent, suc,@ as, for example, dietliyl ether. The starting materials of t@he above formula arenew and 35 are intended to be included withiii the scope of this invention. Particularly useful as intermediates are the conipounds of the formula: (CH2).i-CI12 4(1 (I c)w@r alkyl) -N N-A-NH-C=-N (CH2).i--CH2 in whiell lower alkyl contains fr@oni one to seven carbon 45 atoi-ns, each of the symbols ml and n72 represents one of the numbers I and 2, and A stands for alkylene containing from two to three carbon atoms and separating the cyanamino grotip from th@e imino-nitrogen byfrom two to three carbon atoms; 2- (4-inethyl-l-piperazino) -,-thylcyanamide, 5 0 2 - (4-ethyl-l-piperazino)-ethyl-cyanamide, 2-[I-N,N-(3- aza-3-metbyl-1,6-hexylene)-imino]-ethyl-eyanarnide, 2-[lN,N-(4-aza-4-methyl-1,7-heptylene) - imino)-ethyl-eyanamide rep.-esent this -roup of intermediates. A carbamyl group attached to the amino group of the [I-N,N-(N-RI-aza-alkylene)-imiiio]-lo,wer allyl-arnine, in which RI and aza-alkylene have the previously given meaning, may be converted into the desired amidino group by treatment with amn-ionia, preferably, in the presence of a dehydrating agent, such as, for example, phosphorous pentoxide. This reaction r@iay be carried out at an elevated co temperature in a closed vessel; temperature and pressure may be reduced by the presence of a non-aqueoas solvent and/or of a reaction accelerator, such as finely dispersed nickel, alumintim, aluminum oxide and the like. Animonia may be replaced by an amine, such as an Nlower 65 ;alkyl-amine, and [1 - N,N-(N-R l-aza-alkylene)-iminollower alkyl-,-u,anidino compounds with substituted guanidino @groups can be obtained. Furthermore, a thiocarbamyl ,-roup, which together with the amino group of a [I-N ,N-(N-Rl-aza-alkylene)- 70 imino]-lower alkyl-amine, in which R, and aza-alkylene have the previously given meaning, forms a thiourea group, may be converted into an amidino group by treatment -,vith ammonia, for example, in the presence of water, and/or of a nonbydrolytic solvent, such,as, for ex75 3,098,066 14 ample, toluenc and the like, and in the presence of a desulfuriziii- a-,e-@it. The latter is selected advantageously from basic oxides, basic carbonates and the Iilie, of beavy metals, such as lead, zinc, cadmium, tin, mercury ai-id the )ike; such compounds are, for example, lead oxide, merr-uric oxide, lead liydrogen carbonate and the like. Mercuric chloride @inay also be used. This iammonolysis procedure is preferably carried otit at an elevated te@mper@ature, and, if necessary, in a closed vessel, primarily to avoid loss of ammonia. An,amine, such as an N-lower alkyl-ami-.ie, may replace animonia, and Nsubstituted guanidino derivatives niay be formed. Ureas and thioureas, used as the starting material in the above-mentioned modification of the procedure and having the formula: [I-N,N-(N-R,-aza-alkylone,-imino]-lower all@yl-N-C-NI-I-R, I 11 R5 x in which Rl, R4, R5 and aza-alkylene have the previously given iii.,anin,@, R4 and 1.@1,5 representin.- priniarily hydrogen, iand X stqnds for oxygen or sulfur, and salts thereof may be obtained, for exan-iple, from [I-N,N-(N-RI-aza., Ikylene)-iminol-lower alkyl-amines, in which RI and azaalkylene have the previously -iven rneanir@g, by treating tlie. latter with ammoniuni or rietal cyanates: or thiocyanates, such as alkali metal, e.-g. sodium, potassium and Lqe Iilce, cyaiiales or thiocyanates. These reagents are preferably used -in the - presence Df a solvent, for example, water, if desired, co@itaining a small amount of an acid, sueh as a mineral acid, c.@g. hydrochloric, sulfuric acid and the like. This procedure furnishes ureas or thioureas of the above-E-iven forniula, in which Rl stands for hydro,-Cn. A lower alkyl isocyanate or alo@ver alkyl isothiocyanate, when reacted with the [I-N,N-(NR,7azaalkylcne)-irninol-lower alkyl-amine coinpou-iid, yields a urea or a tliiourea, in which R4 represents lower allcyl. '-Fhe lower alkyl isocyariates and isothiocyanates are 'Lised in the presendt- of an organicsolvent, such qs, for exainple, a lower alkanol, n-icthanol, ethanol and th.e like. The above-mentioned urea or thiourea compounds used as the starting inaterials n-iay also be obtained by an ammonolysis or aminolysis procedure from reactive functional derivatives of N-[I-N,N(N-Rl-aza-alkylene)-iminollower ialkape carbamic acids or N-LIN,N-(N-RI-az,,,-a-lkylene)-iminol-lower alkane tliiocarbamic acids having the ge-,ieral formula: li-N,N-(N-Ri-aza-alkylene)-iminol-lower allcyl-N-O-XH @ 11 5 x iii which RI, R5, X, and aza-alkylene have the previously given meaning. Reactive functional derivatives of such acids are primarily esters, for example, lower alkyl, e.g. mothyl, etliyl and the like, esters or halides, e.g. chlorides and the like. Upon aniironol)lsis, for exami)le, by treatment with amomnia, if necessary, at an elevated temperature a-@i a closed vess-,I, these carbamic and thiocarbamic acid derivitives may yield the desired urea or tliiourea derivatives, respectively. Ammonia inay also be replaced by an amine, such ias an N-lower alkylamine. The above described starting materials are new and are intended to be included within the scope of this invention. Particularly useful are compounds of the formula: (lower alkyl)-N N-A-NI-1-c-Nir2 ii x in which lovver alkyl contains from one to seven carbon atonis, each of the symbols m,,, and M2 stands for one of the nuinbers I and 2, A represents alkylene containing from two to three carbon @atoms and separating the urea and t-@ @iourea,,group, respectively, from the iniino-nitrogen qtom by from t@wo to three carbon atoms, and X represents oxygen or sulflir, and salts t@hereof; 1- [2- (4-methyl- I pi perazino)-ethyll-2-urea, I - [2-(4 - ethyl-IViperazino)ethyl]-2-tirea, 1-{2-[l-N,N-(3-a za-3-nietbyl-1,6-hexylone)-

3,098,066 iminol-ethylf-2-urea, 1-@2-[I-N,N-(4 - aza-4- methyl-1,7- heptylene)-imino]-ethyl'--2-i-iraa, 1-[2-(4-metliyl-lp,',Pcrazino)-ethyll-2-thiourea, 1-[2-(4-ethy l-l-piperazino)- ethyll-2-thiourea, 1-@2-El-N,N-(3 - aza-3-nietbyl-1,6- hexylene)-iminol-et,l-iyl} - 2 - thiourea, 1-{2-[I-N,N-4-aza4- 5 -metl-iyl-@1,7-heptylene)-iminol-ethyll-2-thiourea are specific examples of @such compounds. The,group of 0-low-@r alkyl-isoureas and S-lower alkylisothioureas of the formula: [1-N,N-)N-Ri-aza-alkylene)4minol-lower alkyl-N-C=NR4 10 i 1 IZ5 XRO in which RI, R4, R5, X and aza-alkylene have the previously ,-iven meaning, and Ro stands for lower alkyl, primarily methyl, as -well as ethyl, n-propyl, isopropyl and the like, 15 and salts thereof, are cornpounds containing the previously mentioned 0-lower alkoxy-(imino)methyl group of the formula -C(=NR@.)-ORO and S-lower alkylmercapto(imino)methyl grou-p of the, formula -C(=NR4)- SRO, respectively, in v@hich R4 and Ro have il@e previo,,isly given 20 meaning; these compounds are, therefore, useful as starting materials in the preparation of the compounds of this invention. They may be converted into the latter, for example, by a-inmonolysis or aminolysis. Ammoiiolysis may be, carried out by treatment with animonia, either in its 25 liquid form or as an,aqu,-ous solution thereof, whereby an elevated temp-,rature and/or a closed vessel, as well as the presence of an ammonium salt, such as animonium chloride and the like, may be r.-quired. If necessary, dehydratin.@ a.-ents or desulfurizing agents, such as those 30 previously described, may be prese-iit in the reaction medium, @de@pending on the type, of startin@, material @used. An amine, such @as an N-lower alkyl-ariline, may also be used for the conversion of the isoureas and isothioureas into guanidino @derivatives containin.- substittited giianidino 35 groups. The isourea and isothiourea conipounds used as the starting materials may be obtained, for example, from the previously mentioned urea iand thiourea derivatives by treatment @of the latter, or of ;a metal,sa:lt thereof, such 40 as all alkali metal, le.g. sodium, potassium and the like, salt thereof, with a lower alkyl halide, e.g. methyl or ethyl chloride, brorilide or iodide @and the like, or with a di-lower alkyl sulfate, e.g. diinethyl sul@fate, diethyl Sulfate @and the like. Stich reaction may be carried out in 45 the presence of a isolvent, the selection :of which depends on the type of reagents used; la free urea or t@hiourea compound may be -used in the presence @of water o@r a lower alkanol, e.g. methanol, ethanol and the like, whereas an alkali metal salt of a urea or thiourea compound 50 ,may be Teacted in the presence of a hyd@ocarbon, e.g. tolue,ne and the like, solution. The isourea and iscithiourea compounds used in the above-modific,ation of the general method are new and aTe intended to be iiicluded within the scope of the 55 present invention. A p,articularly useful group of such intermediates can be depicted by the formula: (OH2)@,-CHg (lower alkyl)-N N-A-NII-C=NH 60 I (CH;)M@-CII2 X-CTT3 in which lowet @alkyl contains from one to seven icarbon of the numbers I and 2, A represents alkylene containing from two to thTee carbon atoms and separating the isou.rea and isothiourea aroiip, respectively, from the iminonitrogen,atom by from two to three carbon atoms, and X stands for,oxygen or sulfur, or salts thereof. This 70 @roup of compounds may be represented by 1-[2-(4-methyl-l-piperazino)-ethyll-0-Tn&,hyl-2-isoure,a, 1-[2-(4-,ethyl-l-piperazino,)-ethyll-0-methyl-2-isourea, 1-t2-[I-N,N-(3-@aza-3-me,thyl-1,6-hexylene)-im,inolethyl)-Q-niethyl-2-isourea, 75 16 1-{2-[lN,N-(4- aza-4- metliyl-1,7- heptylene)- iminolethyl)-0- methyl-2- isourea, 1-[2-(4- metl-iyl-lpiperazino) -ethyl]-Smotliyl-2- isothiourea, 1-[2-(4- cithyl-lpiperazino) @ethyll-Smothyl-2- isotliiourea, 1-{2-LIN,N-(3- aza-3- mothyl-1,6- hexylene)- iininolethyll-S-niethyl-2- isothiourea, 1-@2-LIN,N(4,aza-4- methyl-1,7- heptylene,) -iminol@ethyl)-Smethyl-2- @isothiour ea are specific compounds of stich group. A eyanami dino group, which forms a eyanogu anidino group with ithe amino group of a ElN,N-(NRlazaalkyl ene)- imino]- lower alkylamine, in which R, and azaalkylene ,have the previousl y given meaning, may be convert ed into an iamidino group by ammono lysis or aminolys is. This reaction may be carried out by treatmeil t with ammoni a, as well as with an ammo.iium salt, e.g. - a,mmoni um chloride, ammoni um nitrate,;a mmoniu m sulfate land the like, whereby these salts may also pro@mo te ammono lysis with ammoni a itself. Aminolysis of the starting materials may be carried @out by treatme nt with an amine, such as an Nlower @alkyla mine, and Nstibtituted guanidin e derivativ es may be obtained. In the @animo nolysis PTOced ure of a cyano.- uanidino to a guaniclin o detivativ e as descr,@ bed hereinab ove, a biguanid o group may be formed intermed iarily, whiieh, upon further itreatme nt with the ammono lysis reagent, may be converte d to the desired guanidin o group. Such biguanid o derivativ es may be accessibl e through different procedu res (as @vill be shown hereinbe low) and lare, therefor e, also useful as starting material s for the formatio n of the desired guanidin o compou nds by treatme n-t with ione lof the ammono lysis or arninolys is reagents describe d here,@in before. A cyanoguanidin o derivativ e, as mention ed hc@rein @above, m!ay also be converte d into the desited gaanidin o @compo und by reductiv e cleavage of the cyano group. Such cleavage may be,carrie d out, for example, by electroly tic Teductio n on @a cathode, such as, for example, @a lead cathode. The eyanogu anidino derivativ es of the formula: N - R 4 @ - I [I-N,N-(NRi-azaalkylone)- iminolloweralkyliN-C R 5 N H - C = - N in which Rl, R4, R5 and azaalkylene have the previousl y given meaning, @and their salts, which compou nds represeil t the starting material s used in the above ammono lysis, aminolys is or reductio n ptocedur e, may bo prepar,- d, for example, by treatme nt;Df the Slower alkylcya noisothiour eas of the formula: [I-N,N-(N@-azaalkylene)- imino]- loweralkylN-C=NC=-N 11 I I R5 S-Ra in which Rl, R5, Ro and aza@alk ylene have the previousl y gi@ven meaning, with ammoni a in a lowet alkariol, e.g. ethanol and the like, or with an arnine, such las an Nlower alkylamine preferab ly in a sealed tube. The starting material s having the abovegiven meaning @are new and are in+,ende d to be dncluded within - the scope of the invention . Preferre d intermed iates are those of in which lower alkyl contains from one to sevenca rbon atoms, earh o-f the symbols ml and M2 stands fOT One of the numbers I and 2, @and A iepresent s alkylene containid .- from itwo to three carbon atoms and separati ng the cyanogu anidino group from the iminonitrogen atom atoms, each of the symbols ml and M2 stands for one 6,5 the formula: NH Cower alkyl)-N N-A-NH-0 (CH2).f-CH2 / Nl-I-C--N

17 by from two to three carbon atonis, @and salts thereof. This group may be represented by 1-[2-(4-inothyl-l-piperazino),-ethyll-3-cyano-guanidine, 1-[2-(4-ethyl-l-piperazino)-ethyll-3-eyano-,-uanidine, I-'k2- [ I -N,N- (3-aza-3 -mf-thyl- 1,6-hexylene) -imino I - 5 ethyll-3-eyano-gu,,inidine, 1-@2- L 1-N,N- (4-az-t,4-methyl- 1,7-@heptylene) -iminol - ethyl)-3@cyano-guanidine and thf like. Since the above-described cyano-guanidine, derivatives 10 are obtained by ammonolysis or aminolysis from S-lower alkyl-cyanoisothiourea compounds having the above-given formula, these cyanoisothiourea conipounds may, therefore, directly serve as startin-, materials for th-@ preparatio,n of the guanidino compounds of this inverition. The 15 ammonolysis or aminolysis of the eyanoisothiourea compounds to the latter is carried out by treat@meilt with ammonia of an amine in the presence of an anion of a strong acid, such as a halide, a nitrate, a sulfate io ' n and the like, for example, by the res@pective ammonium salts. 20 The S-lower @alkyl-cyanoisothiourea derivatives @of the above formlila or salts thereof may be obtained, for example, by treating a [ I -N,N-) N,RI-aza-alkylene) -iminol - lower alkyl-isothiocyanate, in which RI and aza-alkylene have the previously @iven meaning, with an alkali metal, 25 e.g. sodium and the like cyanamide and alkylating a resulting 1-f[I-N,N-(N-RI-aza-alk ylene)-iminol-lower lalkyll-3-cyano-2-thioure,a, preferably a salt thereof, with a lower alkyl halide, e.g. methyl or ethyl chloride, bromide, or particularly iodide and the like, or with a di- 30 lower alkyl sulfate, e.g. dimethyl sulfate, chothyl sulfate and the like, as previously shown in the preparation of S-lower alkyl-isothioureas used ;as startin.a niaterials in the ammonolysis to the desired guanidines. The above-described S-lower alkyl -cyanoisothiourea 35 derivatives used as starting materials are new and @are intended to be included within the scope of this invention. A preferred group of such intermediates are the compounds of the formula: 40 (lower alkyl)-N N-A-NI-I-C=N-C=-N (CH2).@-CH2 b -U -US in which lower alkyl contains from one to seven carbon 45 atoms, each of the symbols in, and M2 stands for ope of the numbers I and 2, and A stands for alkylene containing from two to three carbon ;atoms and separating the eyano-isothiourea group from the imino-nitrogea atom by frgm two to three carbon atoms, or salts thereof, which 50 may be represented by 1-eyano-S-met hyl-3-[2-(4-methylI-piperazine)-ethyll-2-isothiourea, 1-c yano-3-[2-(4-ethylI - piperazino) - ethyl]-S-methyl-2-isothiourea, I-eyano-Smethyl - 3 - f 2 - [I - N,N-(3-aza-3-me thyl-1,6-hoxylene)- imino] - ethyl) - 2 - isothiourea, 1-cy-ano-S-metliyl-3-f 2- [ 1- 55 N,N - (4-aza-4-methyl-1,7-heptylone)i minol-ethyl)-2-isothiourea and the Jike. As has been sho@vr., the ammonolysis of cyano-guanidine compounds may give rise to the formation of biguanido compounds of the formula: 60 N-R4 NH 11 11 [I-N,N-(N-R,-aza-alkyleno)-iininol-iower aiKyi-i-q-C-NH-C-NH2 I -LC5 in which RI, R4, R5 and aza-alkylene have the previOuslY 65 given meaning, and salts thereof. These compounds may also be prepared, for example, by reacting a El-N,N(NRI-aza-alkyl-@ne)-imino]-lower alkyl-amine compound, in which RI -and azaalkylene have the previously given meaning, with dicyanodiamide, preferably in the 7o presence of !a cornplex metal-forn-iing salt, e.g. copper sulfate and the like. A resulting bigiianido complex metal salt, such as the copper complex salt thereof, may be liberated to form the free compound by treatnient with an acid, such as a mineral acid, e.g. sulf-uric acid and 75 3,098,066 is the like, to form the free compound. As has been showil hereinbefore, ammonolysis and aminolysis of these biguanido derivatives give rise to the formation of the desired L 1 - N,N - (N - RI-aza-alkylene) -imino] -lower alkylguanidines of this invention. As nientioned here@nbefore, ammonolysis with amnionia or ammonia-furnishinreagents may be replaced by aminolysis with amines, particularly N4ower alkyl@ainines, e.g. N-methylamine, N-ethylamine and the like. Such aminolysis reactions provide for the formation of sub@stituted guanidino groups mentioned hereinabove. In addition to ammonolysis and aminolysis reactions, the guanidino compounds may also be obtained, for example, by hydrolysis of a [I-N,N -(N-RI-aza-alkylene)in-,Linol4ower alkylamine, in which R, and aza-alkylene have the previously given meaning, and in which the amino group contains a substituent capable of beinghydrolyzed to an amidino group. For example, such substituent forms together with the amipo grioup o,f the El-N,N-(N-Riaza-alkylene)-imino]-lower alkyl-amine ia cyaiiourea or a eyanotbioure,a group of the formulae -C(=NR4)-N=C=O and -C(=NR4)-N=C=S, respeclively, in which R4 has the previously given meaning,butsta ndsprimarilyforhydrogen. Compoundscontaining such groups yield tipon treatment with a hydrolytic reagent, particularly with dilute aqueoiis mineral acid, e.g. :aqueous sulfuric acid and the like, the desired guanidino compounds. In hydrolysis, the desired guanidino deriv@ative may be formed simultaneously with a ibiuret derivative as theby-product. A eyanourea or cyanothiotirea conipound of the formula: N-R4 fi-iN,N-(N-Ri-aza-alkylene)-iminol-loweralkyl-N-0 R, N=C=X in which Rl, R4, R5 and aza-@alkyle ' ne have the a,.bove,given meaning,:and X represents oxygen or sulfur, orsalts thereof, which compounds may be converted to the desired guanidino compounds by hydrolysis, may be obtained, for example, by reacting a [I-N,N-(N-RI-aza-alkylene)iminol-lower alkyl-cyanamide with an ammortium or a metal cyanate or thiocyanate, particularly an alkali metal, e'g. sodium or potassium cyanate or thiocyanate, in a neutral medium, particularly in the presence of water. The starting materials used in the above ireaction are new and are intended to be included v,,ithin the scope of the invenlion. P-referred eyanourea and th@iocyanourea compoL7nds are those of the formula: ( CH2).,- 0112 N H (l ower alkyl)- N N -A-NH-C ( CH2).@- CH2 N ,=C,=X in which lower alkyl contains from one to seiren carbon atoms, each of the symbols nil and M2 stands for one of the numbers I and 2, and A represents alkylene containing from two to three carboil atoms and separating the eyanourea and thiocyanourea group, respectively, by from two to three carbon ;atoms, or salts thereof; this group may be represented by I- [2-(4-methyl-l-piperazino) -ethyl] -cyanourea, 1- [2-(4-ethyl-l-piperazino) -ethyl] -cyanourea, 1-@2- E 1,N,N- (3-aza-3-methyl-1,6-hexylene) -imino] -ethyl)-eyano@,irea, 1-@2- E I-N,N- (4-aza-4-methyl-1,7-heptylene) -imlinol-ethyll-cyanourea, 1-[2-(4-methyl-l-piperazino)-ethyll-eyanothioure:a, 1-[2-(4-ctliyl-l-piperazino)-ethyljcyanothiourea, 1-f2-[I-N,N-(3-aza-3-metbyl-1,6-hexylene)-ii-ninol-ethyl)-cyanothioLirea, 1-{2-[l-N,N-(4-aza-4-methyl-1,7-lieptylene)-imi.nol-etliyll-cyanothiourea and the like. Apart frori [I-N,N-(N-RI-aza-alkyle ne)-imino]-lower

3,098,066 alkyl-amines, in which the amino group is subsl@ituted by a@carbon atom carrying at least one nitrogen atom, other LI-N,N-(N-RI-aza-alk ylene)-imino]-lower alkyl-amines, in which the amino g@roup carries a substituent convertible into @an amid-ino group, may be useful for a conversion into 5 t@lie des-ired El-N,N-(N-Rl-aza-alkylene)- imino]-lower alkyl-guanidines, in which Ri and aza-alkylene have tile above-given meaning. In such a conversion intermediates maybe formed, whicli may have the previously given characteristics, i.e. the aniino group carries a carbon with 10 at least one nitrogen atom iattached faereto. Such groups are ester groups formed by carboxyl, thionocarboxyl, thiolocarboxyl or dithiocarboxy grotips with loiver alkanols, as well as halogeno-carbonyl or balogeno-thionocarbonyl groups, inwhich halogeno represents prin-iarily 15 chloro. P;4rticularly useful starting materials are, for example, the re)active functional derivatives of carbamic and thiocarbamic acids, having the fotmula: 20 1-N,N@(N-Ri-aza-alkylene)-iijainol-lower alkyl-I\T-CXII I 11 RS x in which RI, RB and aza-alkylene have the previously given meaning, and X represents oxygen or sulfur, or 25 salts thereof. As shonvn hereinabove, esters, for examp,le, lower alkyl, e.g. inetllyl, ethyl and the like, esters or halides, e.g. chlorides and the like, ;of the -abovegiven acids yield upon ammonolysis the cortesponding urea and thiou.rea deri@iatives. However, if, for example, the am- 30 monolysis of @a carbamic acid ester is carried out in the presence of a dehydrating agent, such as, for example, previously shown in the conversion of a urea derivative to the,desired -uanidino con-ipound, an N-[l-N,N(N-Rllaza-alkylene) -imino] -lower ailkyl carb@amic acid ester may 35 be converted directly into the desired guanidino conipound. Or, an ester of an N -[I-N,N-(@,4-RIaza-alkylene)-iininol -lower alkyl thiocarbamic acid deri,,,ative may be su@bjected to ammonolysis to yield directly the desired guanidino &ompound, if such tammonolysis is carried out, 40 for example, in t@he presence of a ;desulfurizing revgent, such as one of those previously shown in the conversion of a thiourea derivative into the desired guanidino compounds, e.g. lead oxide and the like. The carbamic and thiocarbamic acid derivatives used 45 as the starling materials r@lay be prepared accordiiig to procedures used for the manufacture of known an-,tlogs. For example, upon treatment,ol' a [lN,N-(N-RIaza-alkylene)-iminol-lower al@kylamine, in Nvhich RI and azaa,lkylene have the previoiisly given meaning, with phos- 50 gene or thiophosgene, which reagents may be used dn a sli.-ht excess over the amines, the LI-N,N-(NRI-azaalkylene)-imino]-lower alkyl-isocyanate a-@id [1- N,N-(NRl-aza-@alkvlene)-iminol-lo,,ver alkyl-isothiocyanate, respect,ively, may be formed. Sucl-i cyanate and isotliio- 55 eyanate derivatives may then be converted into an ester of a carbamic acid or a thiocarbamic @acid - derivative by treatment with an alcohol, for example, with a low-.r alkanol, e.g. methanol, ethanol and the like, or to a thiolester, for example, by treatment with a mercaptan, such 60 as a lbwer!alkyl-mereaptan, e.g. m ethylmercaptan, ethylmereaptan and the like. The ab@ove derivatives may also be obtained by reacting a f l-N,N-(N-RI-azaalkylene)- ,imino]-lower alkyl-@amine with a lower alkyl carbonic acid ester, or, particularly, With a lower allcyl dith,.,Oc@Arbonic (35 acid ester, as well as with a lower alkyl ester of a halogeno-f6rmic acid, such as chloroformic acid, or, primarily, of a halogeno-thioformic acid, such as chlorothioformic acid. Or, a salt of a [,l-N,N-(N-RI-azaalkylene)imino]- 70 lower,alkyl-amine, particularly a hydrohalide, e.g. hydrochloride and the like, thereof, when reacted with phosgene ior thiophosgene at an elevated temperature, prefera,bly in a closed vessel, may yield the desired NLl-,N, N-(N-Rl-aza-alkylene)iminol-lower alkane carbamic @acid 75 chloride and N- [ 1-N,N- (N-RI-aza-alkylene) -in@no,] - lower alkane thiocarbarr@ic acid chloride. The reactive depivatives of tb@a carbamic and tlaiocarbamic acids of the above formula are new starting materials and are intended to be included -,Vithin the scope of the initention. Particularly useful are the co@npounds of the formula: (OH2)m,-CH2 (lower alkyl)-N N-A-NII-C-Y II (CH2)mf-CH2 x in which lower!alkyl contains from one to seven carbon 'atoms, each of the symbols ral and n72 stands for one of the ni-imbers I and 2, A Tepresents alkylene containing frorn two to thr-.e carbon atoms and s-,pa@rating the carbamyl and tbiocarb;amyl group, resp,-ctively, from the imino-nitrogen atom by from two to tliree carbon atoms, and Y represents lower alkoxy, e.g. methoxy, et@hoxy and ' he -like, Iower alkyl-riereapto, e.,-. methylmercapto, ethylmercapto land the like, or halogeno, particularly ch.oro, or salts thereof. Very useful intermediates are, for example, Tnetliyl N-[2-(4-methyl-l-piperazino)-ethyl]-carbamate, ethyl N-[2-(4-ethyl-lpiperazino)-ethyll-carbarnate, methyl N-[2-(4-methy l-l-piperazino)-ethyl]- thiocarbamate, N-[2-(4-methyl-l-pip-.raz ino)-ethy-11-carbamic acid chloride iand the like. The [1-N,N-(N-RI-aza-alkylene)-imino]-lower al-kylamines, in which R, and aza-alkylene have the previously given meaning, which are used in inany of the above instances for the m@ariufacttire of the above-describ(-d startin.- materials, may be prepared, for example, according to the previously shown procedure. A further procedure for the preparation of the compotinds of this invention comprises converting a El-N,N(N-RI@aza-alkylene)imino]-lower alkane carboxylic iacid guanide, in which RI and aza-alkyleiie have the previously giveii meaning, or in a guanidino-lower alkane carboxylic acid N,N-(N-RI-az a-alkyl@-ne)-i-@nide, in which R, iand aza-alkylenehave the previously gi@ien nicaning, or a salt th,,reof, the carbonyl rroup,of tl-le amido or imido portion to a @methy-lene group, and, if desired, carryiig out the optionat steps. The reduction of tne carbonyl portion -of the amido or irpido groups may be cariied out, for example, by treatment with an aluminum hydride capab-le of reducing such carbonyl group, pa@rticularly with an alkali metal aluminLm liydr@ide, e.g. lithium aluminuiii hydride, sodium aluminum hydride and the like, or an alkaline earth metal altiminum hydride, e.g. magnesiiim -aluniinum hydride and the like, or aluminiiin hydiide. If necessary, activators such as, for example, aluminum chloride, may be used togeth,-r with such hydride reducing reagent. Thereduet-ion with these reagents is preferably performed in the presence of a solvent, particularly of @an ether, su-@h as a -di-lower alkyl etl@er, e.g. diethyl ether, dipropyl ether iand the Eke, a lower alkyl carbocyclic aryl ether, e.g. anisole aiid the like, a di-carbocyclic aryl etlier, e.g. dipbenyl etiier and the like, or a cyclic ether, e.g. tetrahydrofuran, pdioxane and the like, land, if desired, at an elevated temperature and/or in the atmosphere iof an inert gas, e.g. nitrogen. Removal of the oxygen atom of a carbonyl group in an amide compourid may also be accomplished by trelatmerit with hydrogen in the presence of certain catalysts, such as, for example, a copper-chromium catalyst and t' ie like; hydrogenation inay be carried out iii the presence of an inert solvent and, if necessary, under inereased pressure. The desired conversion may also be carried out by e lectrolytically reducing the amido or imido derivatives on a cathode of a h-.gh overpotential such as, for example, mercury, 4ead amalgam, lead cathode and the like. The catholyte used in such a reduction is preferably a

21 mixture of water, sulfuric acid and a lower alkanoic geid, e.@, acetic, propionic acid and t@.e like or any equivalent and suitable ineditim. A p'@atinum, oarbon, lead anode and the like rnay be used; the anolyte is - preferably sulfuric,acid or any olher suitable anolyte. 5 The starting materials used in the above reduction procedure may be prepared, for -exaniple, by treating a reactive functional derivative of a [1-NN-(N-RI-aza,alkylene)-iminol-lower alko@ne carboxylic acid, in which RI and aza-,Llkylene have the previously given meanin@ 10 or of a g-uanidino-lower alkane carboxylic acid with a ,-uanidine or with a I-N,N-(N-RI -aza-alkylene)-imiiie, in which RI and aza-alkylene have the previotisly given meaning, respectively, to form the desired amido or imido compounds. Reactive derivatives of carboxylic 15 acids are, for example, esters, stich as lower alkyl, e.g. mothyl, ethyl and the like, esters, or activated esters, which are particularly useful for the for-mation of amide bonds, such as esters with reactive morcaptan compounds, e.g. mercapto-acetic acid and the like, or with reactive 20 hydroxy compounds, e.g. liydroxy-acetonitrile and the Re. These esters mty be prepared @according to procedures which are known for the, manufacture of analogous esters. Other reactive functional derivatives of acids are, for example, the qcid addition salts of acid balides, 25 particularly the hydrochloride of an acid chloride, which may be prepared according to standard methods. The reaction of the abgve-mentioned reactive f-unctional derivatives of carboxylic acids with the iamino compounds may be carried out, for example, by treating 30 a salt of an acid halide, particularly the hydrochloride of an acid chloride with the an-dne, prefera@bly in a polar, but non-hydroxylated solvent, such as, for example, N,Ndimethylformamide, diethylen-,glycol dimetliylether, p- 3,5 dioxane, tetrahydrofuran and the like. A modification of the above procedure comprises converting in a [I-N,N-(N-RI-azaalkylene)-iminol-lower alkane thiocarboxylic acid giianide, in which RI and,azaalkylene have the previously given rneaning, or in a 40 guanidino-lower alkane thiocarboxylic acid N,N-(N-Rl-,za-alkylene)-imide, in which RI and aza-alkylene have the previotisly given meanin.-, or a salt thereof, the -thiocarbonyl group of the thioarrjjdo or tbioimido portion into a methylene group, and, if desired, carrying out the 15 optional steps. The replacement of sulfur in the above-mentioned thioamides and thioimides may be carried out by desulfurization, for example, with a freshly prepared hydrogenation 50 catalyst, such as Raney nickel, in a lower alkanol, e.g. methanol, e,hanol and the like, and if desired, in the prese@ice of hydrogen, or with an electrolytic reduction procedure, for exarnple, according to the rnettod outlined hereinabove for the reduction of the amides. 55 The thioamides and thio-imid,-s, used as the starting materials in this modification may be prepared, for example, -from the corresponding amides and imides previously mentioned, for example, by treatment with phosphorous trisulfide, phosphorus trisulfide, phosphorus 60 pf,ntasulfide and the like. A modification may consist in electrolyti--ally reducing the amide in the presence of an ,alkali n-iotal sulfide, e.g. sodi-Lim s-alfide and the like, thereby formina the thioaniide or the thioimide as a nonisolated intermediate. r,5 Ttic starting mliterials tised in the above reaction are new and are intended to be included within the scope of the present invention. Partictilarly useful as intermediates are the compounds of the forniulac: 70 (OH2).i-CH2 NH 00WOT alk-yi)-N N-Al-C-NH-0 11 (CI-12).,- CI12 x NH2 75 3,098,066 22 and (OH2).,7-CH2 NU (lower alkyl)-N/ N-C-Al-NH-0 \ (CH2).@--CH2 / @l \ NH2 in which lower alkyl contains from one to seven carbon atoms, each of the symbols nil aiid in2 represents ore of the numbers I and 2, A' stands for alkylene containing from one to two carbon atoins @and separating the caro u p f r bonyl gr om the imino-nitrogen atom and the guanidino group, respectively, by from one to two carboi atoms and X stands for oxygen or sulfur, or salts thereof. Spec@ific compounds of this group are, for example, (4@methyl-l-piperazino)-acetic, acid guanide, 1- (guanidinoacetyl)-4-niethyl-piperazine and the lilce. Another method useful @for the preparation of the above-described guanidino compounds comprises replacing in a [I-N,N-(N-RI-aza -alkylene)-imino]4ower alkylguanidine, in which RI and aza-alkylene have the previously given meanin@ and in which at least one of the O' two carbon atoms of the aza-alkylene portion, which are located adjacent to the iminonitro,-ei atom,, carries a doubly bound oxygen or sulfur :atom, or a salt thereof, such oxyge-ii or sulfur atom by two hydrogen atoms, and, if desired, carrying out the optional steps. The above-mentioned oxygen or sulfur atoms form together ivith the carboff 'atom, to which they are aftached, and with the imino-nitrogen atom of the I-N,N(N-RI-azaalkylene)-imino portion imido or thio-imido groups. Such groups may be converted into the desired metliylencimino group by the previously described procedures; for example, the oxygen atom of an imido group. ings may be replaced by tw-o hydrogen atom.s by treat=,with an aluminum hydride, such as lithium altimihydride, or the sulfur atom of a thioamide groupirfg rnay be exchanged for two hydro,@en atoms b3i desulfurization with a freshly prepared hydrogenation catalyst, such as Raney nickel. These re-actions lare carried out as previously shown; in case two of the saine or of dif@ferent imide-oxygen and/or thio-imide-sulfur atoms are present, such atoms may be re-placed simultaneously or in succession. The starting material used iiy this modification may be prepared, for example, by introducing into an N,N- (NRi-aza-alkylone)-imine, in which at least o'ne of the carboit atoms of the aza-alkylene radical, which are located @adjacent to the imino-nitrogen atom, carries a doublybound oxygen atom, an amino-lower alkyl radical, which may be iaccomplis'@ied, for example, by reacting an alkali metal, e.g. lithium sodium and the like, salt of the N,N(N-Rl.@aza-alkylene)-irriine, in which at least one of the carbon atoms of the aza-alkylene radical, which are located adjacent to the imino-nitrogen atom, carries a !doubly-bound oxygen atom, with a halogeno-lower alkano-nitrile, e.g. chloroacetonitrile and the like, and reducin@ in a resulting [I-N,N-(N -RI-aza-alkylene)imilqo]-lower alkanonitrile, in which at least one of the carbon atoms of the aza-alkylene radical, which are located adjacent to the imino-nitrogen atom, carries a do-ably-bound oxygen atom, the nitrile group, tc) a methyleneamino group, wbich may beaccomplished, for example' by treatment with @a hydride reducing agent, such as m alkali metal aluminum hydride, e.g. lithium @aluminum h@Tdride and the like. The N,N-( N-Rl-aza-alkylene)-iinine, in which at least one of the carbon atoms of the aza-alkylene radical, which are located adjacent to the imino-nitrogen atom, carries a doubly-bound oxygen atom, may also be reacted with a lower alkenonitrile, e.,g. iacrylonitrile and the like, to yield the r 1 -N,N(N-RI-azaalkylene) -inuno] 4ower alkano-nitrile, in which at least one of the carbon atoms of the aza-alkylene radical, which are located adjacent to theimino-nitrogen atom, carries a doubly-bound oxygen atom, and which is then reduced to the idesired amino compound as shown

23 hereijqabove. The resulting [1-N,N-(N-RI-aza-alkyl cne)-imino]-lower alkyl-amine, in which,at least one of the two carbon atoms of the aza-alky@lene radical, which are located adjacent to the imine-nitro.-en atom, carries adoubly-bound oxygen atom, may then be converted to the corresponding guanidine compound, for example, by treatment with a salt of an S-16wer ialkyl-isothiour6a, such as the S-methylisothiourea sulfate. In a resulting [I-N,N-(N-RI-aza-alkylene)-irninollower @ailkyl-guanidine compound, in which at least one of the carbon atoms of the -aza-alkylene portion, -,vhich are 16cated @adjacent to the imitio-nitragen atom, carries a,doubly-bound oxygen atom, such oxy,- en may be exchanged by sulfur, for ex'ample, by treatment of the above guanidiiio compound miith phosphorus trisulfide, phosphoi-us pentasulfide -and the like, as shown - hereinbefore. The above used starting materials @are new,and are intended to be included within the scope of the present invention. A pieferred -group of such intermediates may be represented by the compounds of the formulaX' 11 (CH@,mf-c \ ;:-, NH (lower al@kyl)-fi \ / N-A-NH-b \ (CH2).f- C NH2 11 X" in winich lower alkyl contains from one to seven carbon atoms, each &f the symbols ml and m2' istands for one of the numberg 1 and 2, A represents alkylene cbntaining fromtwo to three catbon atoins and separating the guani,din6 group from the imino and thioimido group, respectively, by from two to three carbon atolhs, and at least one of the gr6,ups X' and X" represents oxygen or sulfur, aiid the other stands for two hydrogen atoms or a dou'oly-bbund oxy.-en or sulfur atom, or salts thereof. The@e cgmpounds may be represented by 2-(4-methyl-2oxo - I - piperazino) - ethyl-guanidine, 2-[I-N,N-(3- aza-3niethyl-l-oxo-1,6-hexylene)-iminol-ethyl-guanidine, 2-[lN,N- (4-aza-4-methyl - I - oxo - 1,7 - heptylene) - iminol ethyl-guaiiidine, 2 - (2,6 - dioxo - 4 - @methyl-lpiperazino)ethyl - guaqidine, 2 - (4 - methyl - 2 - oxo - 6 . thion6 - 1piperazino)-ethylguanidine and the like, A doubly bound oxygen or sulfur -atom may also be attached to at least one of @the carbon atoms of the azaalkylene portion in a [ 1-N, N-(i@T-Rl-aza-alkylene) - iminollower -alkyl--,Uanidine, in which Rl,a@nd aza-alkylene have the previously given meaning, or a salt thereof, whirh carbon atoms are lorated adjacent to the aza-nitrogen atom; such oxygen or sul-fur atoms may be replaced by two hydrogen atotns arcording to previously shown procedures, e.,g. reduction, desulfurization and t@he like, to form the desired [I - ll;,N-(N-RI-azp--alkylene) - in-iinol lower alkyl-guanidines of this invention. The intermedia,tes used in the foreging procedure are prepare , example@ ;accordin.@ to previously described proredures, for example, by introducing the guanidino-lower alkyl chain @in@to a I-N,N-(N-RI-az a-alkylene)@imine compound, in -which at elast one of the carbon atoms of the azaalkylene portion, which are located @adj.acent to the azanit,rogen aton-is carries a doubly-bound oxygen or sulfur atom; the intr@duction may be carried out according to previously described mothods. The @above starting materials are new land are intended to be included within the scope of the present invention. A preferred group of such intermediates have the forniula: X' 11 C(CH2)@l\ 5;- NII (lower alkyl)-N/ NA-NH-C C(CH2).2 NH2 11 X" in which lower alkyl contains from one to seven carbon atoms, each of the symbols nil and M2 stands for one of 3,098,066 24 the numbers I and 2, A represeiits alkylene containing from two to three carbon atoms and separating the guanidinb group from -the imino and thioimido group, respeetively, by from two to three oarbon atoms, aiid at least one of the groups X' and X" represents,oxygen or sulfur, and the other stands for two hydro-,en a@,oms or a doublybound oxygen @or sulfur atom, or salts tliereof. These compounds may be represented, for example, by 2-(4mothyl-3-axo-l-pip@razino)-ethyl-guanidine, 2-(3,5-dioxo1( 4-methyl-l-piper@azino)-ethyl-guanidine, - 2-LI-N,N-(3aza-3-methyl-4-oxo1,6-hexylene)-iminol - ethyl - guanidine and the like. A combination of the iabove-showri modifications may also be carricd out. For example, upon treatment of a 15 El-N,N-(N-Rl-aza - alkylene) - in-iinol - lower alkyl carboxylic aoid guanide or of a guanidino4ower alkyl-carboxylic acid N,N-(N-Rl aza-alkylene)-imide, in which RI and aza-atkylene havethe previoil-sly given meaning, and in which -at least one of the carbon atoms of the 20 aza-alkylene por-tion adjacent to the imino- or inlidonitrogen @atom con,@ains a doubly-bound oxygen or sulfur atom, with one of the reducing reagents previously described, the desired [1-N,N-(N-RI-aza-alkylene)-imino]lower alkyl-guanidines of this invention can be fornied. 25 T@he st-arting materials used in such a procedure may be prepared along the previously @outlined procedures by selecting the appropriate intermediates. Compounds of this invention may also be prepared by treating an NIN-(N-Rlaza-a'@kylene)-imine, in wliieh RI 30 and aza-alkylene have the above-given meaning, or a salt thereaf, with a reactive ester of a igiianidino-lower alkanoll in which the lower alkanol portion contains at leasttw6 carbon atoms, which separate the hydroxyl from the guanidino group by at least two carbon atonis, or a salt 35 thereof, and, if desired, carrying out the option@al steps. A reactive este@r ;of a,guanidino-lower alkanol is particul@arly an ester with -a strong inor,,-,anic acid, such @as a mineral acid, particularly a hydrohalic acid, e.g. hydrochloric, hyd@robromic, hydriodic, suli'uric acid and the like, 10 or with a strong otganic ocid, particularly an organic s-alfonic @acid, sup-h as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-tolene sulfo@iie acid and the Ue. These esters are, therefore, primarily guanidino4ower alkyl halides, e.g. chlorides, br-omides and the like, or salts 45 thereof with @hydrohalic acids, e.g. hydrochlotic, hydrobromic acld @and the lilce, which, upon reaction with the N-N-(N-RI-aza-@alkylene)-imines, or salts thereof, yield the desired [I-N,N-(N-Rl-aza-alkylene - iniinol - lower alkyl-guanidines@ 50 This Tleaction may be carried out, for example, bytreatin,@ the N,N- (N - RI - aza - alkylene) -imine, in which RI and aza-@alkylene have the above-given meaning, or a salt thereof, wit'nthe ester of the giianidino-lower alkanol or@asalt-Liereof. Asaltof-theN,N-(N-Rlaza-alkylene)- 55 imine is particularly an alkali metal, e.g. sodiurn, potassium and the like, s@alt, which may be prepared, for example, by trealment with an alkali metal, e.g. sodium, potassium and the like, or an alkalli metal hydride or amide, 6 e.g. sodium or potassium hydride or amide;and the like, in the presence of an ineit solvent, such as, for example, toluene, p-dioxane and the like. Such salt is thentreated with the reactive ester of the guanidino-lower alkanol. Or, the re@action of the N,N-(N-RI-aza-alkylene)-imine wit@h the latter may be performed in the presence of a salt65 formirig reagent, such as, for example, an alkali metal, e.g. sodium or potassium, in liquid amonnia, or an alkal@i metal, e.g. sodium or potassium, carbonate. The Teactive ester of @a guanidino-lower alkanol may be used in the 70 fgrm of 4a salt thereof, @or as the free compotind, wbich may also be liberated at the site of the reaction by treating the salt With the necessary iamount of an alkaline reagent. The reaction is preferably carried out in the presence of a solvent, which is selected depending on 75 the properties of the reagen-ts; a lower alkanol, e.g. meth-

5 an(yi, ethanol ind the like, may be used with the salt of an ester of the -Uariidino-lower alkanol, whereas the free base may be re-,icted in th-- presence of -t noii-hydroxylic solvent, such,as, for exaniple, an ether, e.-. p-dioxane aiid the like,, or a hydrocarboii, sucli as a monocyclic carbocyclic iryl hydrocatbon, e.g. benzene, toluene and the like. It may be perforined tirder cooling, or more preferably, it an elevated temperattire, if desired, in a closed vessel under pressure, or in the -atmospher-- of in inert gas. The reactive esters of guanidino4ower alkanols, in w,hich the lower ,ilkinol portion contains ,it least two carbon atoms and separatp-s the guanidiio groi,-p from the hydroxyl group by at least two carbon atoms, or silts thereof, which reagents are used jas flic starting materials in the abov.- reaction, may be prep,,ired by esterifyiii.guanidin,o-lower alkanols. For e-,@ample, a giianidinolower alk-,inot may be converted into a guanidino-lower alkyl halide by treatment with athicnyl halide, particularly thionyl chloride; such re-,Lction may be carried Out in the presence of an inert solvent, for ex-,zmple, a hydroc-,trbon, such as a rnonoeyelic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, or in any other suitable solvent. Sticll procedure yields preferably the acid addition salt with a hydrohalic, e.g. liydroel)-loric, hydrobroinic acid and the like. A guanidino-lower alkyl sulfonate, particularly a ptoluene-sulfoiiate, may be prepa,red, for example, by treal-nent of the giianidino-lower alkanol with ,L sulfonyl b@alide, such as p-talliene-sulfoilyl chloride, in the presence of a solvent, sucli as pyridiiie and the like. A modification of the above procedure comprises fre,,Lting a rea--tive ester of a [IN,N-(N-RI-aza-alkylene)imino]-lower alkanol, in whieb R, and aza-alkylene lias the above-given meaning, or a salt thereof with a gua-@iidine, and, if desired, carrying otit the optional steps. A reactive es'Ler of a r.1-N,N-(N-RI-aza-pdkylene)iminol-lower alkanol is, as has been bcreinabove shown, formed witli a strorig inorg,,mic or organic acid; the [1N,N-(N-RIaza-alkylene)-iminol-lower alkyl halides, e.g. chlorides, brom@ides and tlie like, and the [I-N,N-(N-Rlaza-alky@lene)-in-iino]-lower alkyl monocyclic c,,irbocyclic aryl sulfonates, e.g. p-toluene sulfonates, are the preferred rea.-ents. The guanidines, such is guanidine itself, as Nvell,as guanidines with additional substituents, Nvhich dO not i-- titerfere with the reaction, m,,iy also be tised in the form of their salts. The reaction is perforined along the general procedure outlined hereinbefore. The starting material, i.e. the reactive esters of a [1N,N-(N-Rl-aza-alkylene)- irnino]4ower alka@iol, in which R, and aza-alkylene have the previGLisly given nieaning, may be prepared according to known metl,,ods, used for analo-ous compounds. For example, an N,N-(N-RI-azaalkylene)-imine r@aay be reacted with la halogenohydrin, such as a chlorohydrin, e.,a. ethyl enecblorol-iydrin and the like, or a bromohydrin, e.g. othylenebromohydrin and the like, or with an epoxide, e.g. ethylene oxide and tlae like, a.,id the resulting [I-N,N-(NRI-aza-alkylene)iminol -lower 7,,ilkanol may then be converted to the halide by treatment with a tliionyl halide, e.g. thlonyl chlorije and the like. Compounds of the pr,-se-nt invention mLy also be mantifaotured by converting in -@L [@l-N,N-(N-R,'-aza-alkylene)imino] -lower alkyl-guanidine, in whic@@ aza-alkylene has the previously given meaning, and RI' stands for a substiti-lent captble of being converted into RI hav@ing the previously given meaning, or a salt thei7eGf, -th-@ radical RI' into the desired group RI, @and, if d,-sired, carrying out @the optional steps. T'he radical RI' may be, for example, the, acyl radical of a carboxylic acid, such as, for example, the acyl radical of one of the carboxylic acids mentioned hereinbefore as re,preserting ithe group Rl. RI' may also stand for the acyl radical of a thionocarboxylic acid, such as, for example, a lower alkane thionocarboxy'lic acid, e.g. thiono3,098,066 26 acetic, thionopropionic acid and the like, or any other suitable thionocarboxylic acid. The carbonyl grotip and the thiocarbonyl group of th-- acyl radical form together with the aza-nitrogen atom of the aza-alkyleneradical in fl-N,N-(N-R,'-aza-alkylene)-iminol-lower alkyl-glianidine compound an imido and a thio-imido group, respec@tively. The oxygen and sulfur atoms of such groups may, there@'Ore, be replaced by t,,vo hydrogen atoms according to previously described procedures, such as, for example, 10 by treatment with an aluminuni hydride, e.g. lithium aluminum hydride and the like, by hydrogenation in the presence of certain catalysts, e.g. a copper-chremium catalyst and the like, or by electrolytic reduction, ;and by desulfiirization, for example, in the presence of a metal 15 catalyst, e.g. Raney nickel and the like, respectively; these procedures have been described in detail hereinbefore. The start,' ng materials used in the above procedure may be prepared according to one of the previously descnbed methods. 20 In products obtained according to the above-described methods, additional groups may be introduced or groups may be exchanged for other substituents. For example, resulting guanidines, such as, for example, those of the formula: 25 'Nl- R 4 [I-N,N-(N-Ri-aza-alkyleiie)-iminol-lower alkyl-N-0 I \ R, iN'H-R3 30 may be acylated to form compounds of the formula: N-R4 fl-N,N(N-Ri-aza-alkyleie)-imino]-lower alkyl-NI-C R3 I R5 N 35 R2 in which formulae Rl, R3, R4, R5 and aza-alkylene have the previously given ineaning, and R2 represents an acyl radical. Such reaction may be carried out, for example, 40 by treating the guanidine compound with the reactivederivative of a carboxylic acid, for example, with the halide, e.,-. chloride and the like, or the anhydride thereof. It may be performed in the presence of an inert s-olvent, for exaniple, in a hydrocarbon, such as a lower alkane, e.g. 45 pentane, hexane and the like, or a monocyclic carbocycl@ic aryl hydrocarbon, e.g. benze-.ie, toluene, xylene and the lilce, or in a tertiary organic basd, such as a liquid pyridine compolind, e.g. pyridine, collidine and the like. Acylation may also be achieved in the absence of a solvent, for 50 exapiple, by heating the guanidine compound or a salt @thereof with the @acylating reagent, for exainple, acetic acid anhydride in a sealed tube. The new guanidine compounds may be obtai-ned in the form of the free compounds or as the salts thereof. A li5 salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reag,-nt, such as aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the 19@e, or a strong quaternary ammonium anion 60 (hydroxy ion) exchange resin and the like. A free base may be transformed into its therapeutically useful acid addition salts by reacting the latter with an appropriate inorgal-iie or organic acid, such as one of those outlined hereinabove; such reaction may be carried out advanta,-e(35 ously in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol an.d the like, an ether, e.g. diethylether, p-dioxane and the like, a lower falkyl lower alkanoate, e.g. ethyl acetate and the like, or a mixture of such solvents, and isolating the desired salt. 7o Salts of the polybasic compounds of tliis inventon may be obtained, in which not all of the salt-forming basic groups participate in the salt formation. Such salts may be treated with an acid in order to form compounds in which all or a greater number of the basic groups take 75 partin the salt formation.

2'1 The new guanidine compounds or salts thereof niay also f6rm quaternary ammonium compounds, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl,or isopropyl chloride bromide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sul.feit,e and the like, lower alkyl lower alkaric sulfonates. e.g. methyl or ethyl methane,or ethane sulfonate, or 10wer alkyl mbnocyclic carbocyclic;aryl sulfonates, e.g. methyl p-toluene sulfonate, and the like, as well as the corresponding quaternary ammonium hydroxides andtl-le salts, wwch may be foxmed from @the quaternary ammonium hydroxides by the reaction with inorganic acids other than tl-ie hydrohalic acids or with organic acids, such;as those outlined above for the preparation of the acid addition salts. The quaternary ammonium compounds may be ob. tained by reacting a free base or a salt thereof with a lower alkyl halide, e.,-. methyl, et-hyl, n-propyl, isopropyl ciiioride, bromide or iodide and the lil@e, a di-lower alkyl-sulfate e.g. dimethyl sulfate, diethyl sulfate and the like, a lower alkyl lower alkane sixlfonate, e.,-. niethyl or ethyl methane or ethane sulfonate, @and the like, or a lower alkyl monocyclic carboryclic aryl sulfonate, e..-. metli@'I P-tolu6ne sulfonate and the like. The quaternizirg reaction may be perfor-med in the presence of a solvent, such as, for example, a loaver alkanol, e.g. methanol, ethan,l, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, ethyl methyl ketone and tl-,e like, or an organic acid amide, e.g. formamide, N,N-dimethylformamide and the like. Resulting quaternary ammonium icompounds may be converted into the corresponding quateriiary aminonium hydroxides, for exaniple, by reacting resultin,@ qtiaternary a@iunonium halides with silver oxide, by treating quateriiary amnionium sulfates with barium hydtoxide, or quaternary ammonium salts with an anion exchanger, or by electrod,'alysis. Fo,, a resulting quaternary ammonitim hydrox@de there may be for@med therapeutically suitableqiiaternary ami-@ionium salts by treatin,@ the quaternary ar@imoniurn hydroxide witii acids, for example, with those otitlined hereinbefore as being useful for the p@-eparation of acid addition salts. The invention also comprises any modificatio-ii of the general process wherein a compouiid obtaiiaable as an intermediate at any stage of the process is used as starting material -and the remaining step(s) of the process is(are) carried out, as well as any new interi-nediates. In the process of this invention such startin.- materials are preferably used which lead to final products n-ientioned in the beginning as preferred embodiments of the invention. T@his is a continuation-in-part application of my application Serial No. 848,559, filed Octobet 26, 1959, now abandoned, which in turn is a continuation-in-part application of rny application Serial No. 816,669, filed May 29, 1959, now abandoned, which in turn is a continuatioii-inpatt application of my application Serial No. 813,349, filed May 15, 1959, now abandoned. The following examples illustrate the inveiition and are not to be construed as being lir@iitations thereon. Temperatures,are given in degrees centi.-rade. Example 1 A solution of 3 g. of 2-(4-methyl-l-piperazino)-ethylamine and 2.92 g. of S-methylisothiourea sulfate in 5 ml. of water is refluxed for 4 hours. The solid, which separates on concentration, is recrystallized from a m@xlure of ethanol and water to yield the desired 2-(4-rnethyl-lpiperazino)-ethyl-guanidine sulfate, M.P. 191-200' (with decomposition). The resulting salt conlains two mols of the base per one mol of sulfuric acid. Other therapeutically acceptable acid addition salls of2-(4@met@hyl-i-piperazino)- ethyl-guanidine -may be preparedasfollows: Thesulfatemaybedissolvedinaminimum amount of water, th@- solution filtered through a column containing a strong quaternary ammonium (hydroxyl ion) exchange resin, and the solution of the free 3,098,066 23 base niay be treated with hydrochloric acid and a 2 -(4methyl-l-pip-.razino) - ethylguanidine polyhydrochloride may be obt@iined. The starlin.@ material may be prepared as follows: 50.4 g. of chloroacetonitrile is added dropwise to a solution of 133 g. of 4-methylpiperazine in 100 ml. of ethanol. The mixture is refluxed and stirred for two hours alid allowed to stand overni.-ht. The solutioti is coiicentrated under reduced pressure, the residue is treated with 270 ml. 10 of 30 pere@-nt aqueous sodium hydroxide while cooling and then extracted with ether. The ether phase is dried over sohd sodiiin-Y hydroxide, the solvent is removed and the residue fractionated to yield the 4-methyl-f-piperazinoacetonitrile, B.P. 120-125'/12 mm. The product solid15 ifies upon stinding, M.P. 53-56'. A solut-'@on oll 50 g. !of 4-i-nethyl-l-piperazino-acetonitrile in 4 00 ml. of anhydroiis ether is added to 1 000 ml. of anhydrous eth-.r containin.- 19 g. of lithium aluminum hydride while cooling and stirring. The reaction mixture 20 Is then reftuyed for 6 hours, allowed to stand ovemight and decomposed by successive addition of 17 ml. of water, 20 inl. of 20 percent iqueous sodium hydroxide and 5 3 ml. of water. The mixttire is filtered, the filtrate is evaporated and the residue is distilled to yield the desired 2- (4-rnethyl25 1-piperazino)-et-hylamine, B.P. 90-92'/16 mm. Other 2-(4-lower alkyl-l-pip,-razino)-ethyl-guanidines and,salts thereof may be prepared according to the above procedure by s,-Iecting 'Lhe appropriate starting materials, whir-h m,@Ly be obtained, for exa-inple, by using the above 30 procedure. Such compounds are, for example, 2-(4-npropyl-lpiperazino) - ethylguanidine, 2-(4-isopropyl-lpiperazino) - ethyl-guanidine, 2-(4-n-bLityl-l-piperazino)- ethyl-giianidiie, 2-(4-isobutyl-l-pipera zino)-ethyl-guanidine, 2-(4-secondary butyl-l-piperazitio)-ethyl-,-Uar@idine, 35 2-(4-t-,rtiary butyl-l-pip,,razino)-ethyl-guanidine,- 2-(4-npentyl-l-piperazino) -ethylguanidine, 2-(4-n-hexyl-l-piperazino) - ethyl-guadidine, 2-(4-n-heptyl-l-pip--razino)- ethyl-guanidine and the lilce; these cornpounds are isolated preferably in the forrq of lacid addit-lon, particularly of 40 therap-@utically acceptable acid, e.g. mineral acid,- addition salts, such as the sulfates and the like. Example 2 A mixture of 3.14 g. of 2-(4-ethyl-l-pip erazino)-ethyl45 amine and 2.78 g. of S-methyl-isothioLirea slilfate in 5 n-ii. of water is refluxed for folir hours, The, reaction n-j-ixtur-, is concentrated under redliced pressure and the 2-(4-ethyl-l-piperazino)- ethyl-guonidine sulfate is recrystallized from a mixture of ethanol and diethyl ether, 50 M.P. 201-203 0. The staitin,@ material may be prepared by treating 13.2 of I-ethyl-piperazine with 13.2 a. of chloroaceto@iitrile iii the presence cf 37.1 g. of sod'ium carbonate in 150 ml. of toluene and reduging 17 0 g. of tl-ie resulting (4- 55 ethYl-l-piperazino)-acetonitrile '(B.P. 117-118'/13 mm., yield: 19.4 g.) with 6.33 g. of litl-jium aluminum hy&ide iii diethyl ether to the desired 2-(4-ethyl-i-piperazino)etliylaniine (97-98'/13 mrn.; yield: 9.7 g.); the above 60 reictions are ca@iried oiit las shown in Example 1. Exa7i?ple 3 A solution of 3-(4-rnethyl-l-piperazino)-propylamine and 1.77 of S-methyl-isothiourea sulfate in 5 ml. of 0 rs 65 water is efflixed for four h u . The reaction mixture is concentrated ui-ider Teduced pressure and the residue is recrystallized from a mixture of etliancl and water. The 3-(4-methyl-i-piperazino)-propyl-gLianidine -sulfate melts at 99-100'. 70 The startiiip n-iaterial may be prepared by reacting1methyl-Diperazine with acrylonitrile in the presence of benzylt.@imethylammoiiium hydroxide and reducing the rosultin.- 3-(4-methyl-l-piperazino)-prop;onitrile with lithium alumiiium hy(lride to the desired 3-(4methyl-i-piper75 azino) -propylaniine.

3io9s,068 29 E.vaiiiple 4 @fo a solutioil of 2.34 g. of 2-(4-methyl -l-piperazino)- ethyl-guanidi@ie sulfate i,,i 0 ml. of methanol is added 3 ml. of 8 N aqLicoLis hydrochloric acid; the mi ixlure is heated to foi-m a complete solution. Upoii cooling and 5 filterin,, 2.96 g. of a solid material is obtaiiied, which is dri.-d at 50-55' under reduc-ed pTeSSUrC (20 mm.) and which reprcsents the 2-(4-mathyl-i-piper azino)-ethyl-guanidine dihydrochloride sulfate hydrate, M.P. 198.8- 200.0'. 10 Exaniple 5 A mixture of 2-[4-(2,methoxyethyl)-l-p iperazino]-ethylamine and S-rnethyl-isc)thiourea sulfate in water is refluxed and th.- desired 2-[4-(2-methoxy ethyl)-l-p@ipera- 1 zino]-ethyl-,-Lianidine sulfate can be r,@,ceived Lipon con- 5 centratio-i of the resulting solution. The startin.@ materi@-tl may be prepared as shown in Exarf@ple I by selectin@ the appropria,e reagents. E,vai;7ple 6 20 The 2 - @4 - [2 - (w - mechyl) - nona - ethylenedioxyethyll-l-piperazinol-ethyl-guanidine sulfate may be obtained by reactiig 1-[2-((,j-methyl),-no na-ethylenedioyyethyl]-piperaziiie with chloroacetonitrile, reducing the nitrile grolip in 'he resulting 4-[2-(w-meth yl)-noiia-etllyl- 25 e.nedioxy-el,hyll-l-piperazi-.o-acetonit,rile to n, mothyleneamino -roLip and reactl'ng the 2-@4-L2- (w-methyl),iionaethyleiiedioxy - ethyl] - 1-piperazinol-ethylaynire witli Si,aethyl-isothicurcai, si,,Ifate; all these reactions are carried otit accordin.- to the methods -,ivei in Exal-nple 1. 30 Exan7ple 7 2 - [ 4 - (2 - diph.-nylmcthoxy - ethyl) - 1 - pipeirazino I - ethylainine prepared frorii 1-(2-diph--nyl metlioxy-etliyl)- 35 piperaziric by treitmeiit 'with chloroaceloiiitrile and reduction of the res,,ilting 4-(2-diphenyl metloxy-ethyl)-tpiperazino-acetonitr:tle w;th lithiuni al-Liminum hydride), when refluxed with S-n-iethyl-isothiourea sulfate, in the p,reseilce of water, yields the 2-[4-(2-d iphenyl-niethoxy- 4@0 ethyl)-l-pipci@azino]-ethyl-guanidine sulfate. E,Yample 8 A mixture of 2-[4-(2-N,N-diiilethylam inoethyl)-l-piperazinol-ethylamine and S-methyl-isothiourea si-ilfate in wo,ter is refluxed and conc--ntrated; the@ desired 2-[4-(2-N, 45 N-dimethyla,minoethyl)-l-piperazino]-ethyl-guanidine can be recovered as its sulfate. The starting material may be prepared according to the procedure dis-,Iosed in Example 1; 1 -(2-N,N-dimethylaminoethyl)-piperazine sci-ves as the intermediate and is 50 reacted with the chloroacetonitrile tc) form the [4-(2-N,Ndimethylaxninoethyl)-l-piperazino]-ace-'Onitrile, which is converted to the starting inaterial by treatment with lithiun-1 alurninlm hydride. Exaniple 9 55 A mixtlire k)f 2-@4-[2-(4-methyl-l-pipe razino)-ethyll1-piperazinol-ethylamine and S-,tnethyl-isothiourea sulfate in water yields the desired 2-f4-[2-(4- methyl-l-piperazino)-ethyll-l-piperazinol-ethyl guanidine su'@fate upon re- C,( R-Lixing and concentrating the solution. The reaction of 1-[2-(4-methyl-piperaz ino)-ethyll-piperaziiie with chloroacetonitrile and the reduction of the resulting 4-[2-(4-methyl-piperazino)-eth yll-l-piperazinoacetonitrile with lithium alum;num hydride acr-ording to C, the procedure of Ex,,impla I fu@r-kiiq-hes th.- desi@red startin,@ material. E.Tan7ple 10 A solution of 2.05 g. o't 2-(4-pheqyl-l-pip,-razino)-ethylamine aiad 1.39 g. of S-methylisothioLirea stilfate in 5 70 ml. of water is refluxed for 4 hours. Upon cooling a solid material separates, whic.a is filtered off alid recrystallized from waler to yield the 2-(4- phenyl-l-piperazino)ethyl-guanidine sulfa'Le, M.P. 256-258' (with deconiposition). 75 @10 Exatnple 11 A Amixtureof2-[4-(4-methyl-phenyl)-l -piperazinolethylamine and S-ethylisothiour.-a sulfate in water, when refluxed, yields the desired 2-IL4-(4-metliyl-phenyl)- lpiperazino]-ethyl-guanidi@ic sulfate, recovered after concentratin,, the solution. The starting material may be prepared according to the procedure given in Example I by using 1-(4-methyl-phenyl)-piperazine as tiie intermediate. Example 12 A solution c>f 2-[4-(3,4-dichlorophenyl)-l-piperazinolethylamine and S-mothylisothiourea sulfate in water is ref.uxed and then concentrated to yield the :desired 2- [4(3,4-dichlorophenyl)-l-piperazinol-ethyl-guanidine sulfate. 'I'he starting r@laterial may be prepared by reactin.@ 1(3,4-dicWorophenyl)- piperazine with chloroacetonitrile and redticing the resulting acetonitrile compound with lithium alumin-om hydride as shown in Example 1. Exaniple 13 5.0 g. of 2-(4-benzyl-l-piperazil-io)-etliylamine and 3.17 g, of S-methyl-isothiourea sulfate are dissolved in 5 rnl. of water, the solution is refluxed for four hours and concentrated tinder reduced pressure. The 2-(4-ben zyl1-piperazino) ethyl-guanidine stilfate is recrysta7ilized from ethanol, M.P. 185-190'. The starting material may be prepared by reacting 50 g. 1-benzyl-piperazine with 10.72 g. of chloro,acetonitrile according to the procedure given in Example 1, and treating a solution of 20 g. of the resulting (4-be nzyl-l-piperazino)-acetonitrile (B.P. 152- 155'/0.3 mm.) in ether with 5.28 g. of lithium aluminum hydride. Upon decomposing the complex with 6 mL of water, 8 ml. of 20 percent aqueous sodium hydroxide and 18 ml. of water, evaporating the solvents and distilling the residue, the desired 2-(4-benzyl-lpiperazino)-ethylamine can be obtained, M.P. 180-187'/13 inm. Exainple 14 2-(4-diphenylmethyl-l-piperazino) -ethylamine, when refluxed with S-methylisothiourea sulfate in the presence of water, yields and the desired 2-(4- diphen3,,Imethyl-lpiperazino)-ethyl-gua-nidine sulfate. The starting @material may be prepared according to the procedure described in Example I by replacing 1-methylpiperazine by 1-diph enylmethyl-piperazine. Example 15 A mixture of 2-[4-(3,4,5-trimethoxy-benzyl)-l-piper azino]-ethylamine and S-methylisothiourea sulfate in water, when refluxed and theii concentrated, yields the desired 2- [4-(3,4,5-trimethoxy-benzyl) - 1 - _piperazino]ethyl-guanidine sulfate. The starting material is obtained by reactin.- 1-(3,4,5- trilvethoxy-,benzyl)-piperazine with and treating the resulting 4-(3,4,5-trimethoxy-benzyl)- l@piperaziic-aceto-nitrile with lithiuin aluminum hydride. Example 16 A solution of 5.0 g. of 2-[4-(2-phenylethyl)-l-pipe razino]-ethylanaine and 2.97 g. of iSMethyl-isothiourea sulfate in 5 inl. ofwater is reffuxed until the evolution of methylmereaptan ceases and the solid material is filtered off. The resulting 2-[4-(2- phenylethyl)-l-piperazinolethyl-guanidine sulfate is recrystarized from a mixture of ethanol and water, M.P. 266- 271'. The starting riiaterial may be prepared by reacting 37 g. of 1-(2-phenylethyl)- piperazine and 7.32,g. of chloroacetonitrite according to the procedure of Example I to form the [4-(2-phenylethyl)-l-piperazinol-aectonitrile, which is purified by distiflation, B.P. 170-172'/13 mm. 12 @. of the latter is dissolved in ether, 2.9 g. of lith@ium aluminum hydride is added and the mixture is refluxed

3)098)066 31 for six hours. The complex is decomposed by adding 3 ml. of water, 2 ml. of 20 percent aqueotis sodium hydroxide and 10 ml. of water, and the free base is extracted and then purified by distillation, to yield the 2- [4-(2-phenyl-ethyl)-l-piperazinol-ethylamine, B.P. 157- 5 159'/14 mm. Example 17 The reaction of 2-[4-(I-naphthylmethyl) -l-piperazino]- ethylamine with S-methyl-isothiourea stil-'Late in tfic pres- 10 ence of water furnishes the 2-[4-(Inaphthylmethyl)-lpiperazinol-ethyl-guanidine sulfate upon refluxin,- and concentrating the reaction mixture. The starting material may be prepared as shown in Example I by using 1-(I-naphthylmethyl)-piperazine as the 15 intermediate instead of the 1-methyl-piperazine. Example 18 A solution of 4.17 g. of 2- F 4- (2-pyridyl) - I -pil)erazino I ethylamine and 2.81 g. of S-methyl-isothiourea suli@ate in 5 ml. of water is refluxed for fotir hoiirs' The desired 20 2-[4-(2-pyridyl)-t-piperazinol-ethyl-guanidine sulfate is obtained by concentrating the reaction mixture under reduced pressure and recrystallizing the residue from a Tnixture of ethanol and water, M.P. 272' ( decon-ipos,@tion). The starting material may be prepared as usi,-al; @@e 25 [4-(2-pyridyl)-l-piperazino]-acetonitrile, obtained from 40 g. of 1-(2-pyridyl)-l-piperazine and 7.47 g. of cliloroaectonitrile, is purified by idistillation, B.P. 120-122'/0.5 mm. and converted to the 2-[4-(2-pyrid yl)-l-piperazinolethylanii,ne (B.P. 112-115'/0.05 mm.) by treating a 30 ,solution of the nitrile in ether with 5.42 g. of litliium a-luminum hydride as shown in Example, 1. Example 19 A @mixture of 5 -g. of 4-[4-(2-pyridyl) -l-piperazinol- 35 butylamine and 2.96 g. of S-methyl-isothiourea stilfate in 5 ml. of water is refltixed until methylmereaptan is no ,longer evolved. The @solvent is evaporated under reduced pressure and the residue is rer-rystallized froin a mixture of ethailol and water to yield the 4-[4-(2_ 40 pyridy@l)-l-piperazinol-butyl-guaiiidine sulfate, M.P. 280- 283' (decomposition). The starting material may be prepared as follows: The reaction of 10.24 g. of y-bromo-butyronitrile and 40 g. of 1-(2-pyridyl)-piperazine, in ethanol according 45 to the procedure given in Example I yields the 4-[4-(2- pyridyl)-l-piperazino]-butyronitrile, purified by distil!ation, 13.P. 141-143'/l mm. 14 g. of the latter is dissolved in 350 ml. of ether, 3.47 g. of lithium -aluminum hydride is added and the mixture is refluxed for six 50 hours. The resulting,complex is decomposed with 4 ml. of water, 5 ml. of 20 percent aqueous sodiurn hydroxide and 12 ml. of kvater, the mixture is concentrated and the desired 4-[4-(2-pyridyl)-i-piperazinol-butylamine is isolated and purified by,distillation, B.P. II 3-115'10.05 mm. 55 Exatnple 20 3 g. of 2-[I-N,N-(4-aza-4@methyl-1,7 -heptylene)-imino]-ethyl,arnine and 2.44 g. of S-methyl-isothiourea sulfate are dissolved in 5 ml. of water, and the solution is 60 refluxed for four hours and then concentrated under reduced pressure. The residue is xecrystallized from a mixture of nietha@nol and ether to yield the 2-[l-N,N-(4-aza4 - methyl - 1,7 - heptylene) - iminol - ethyl - gua-@iidine sulfate, M.P. 198-215'. 65 T-he starting material may be prepared ias follows: To a solution of 10.01 g. of 1,2-trimethylene-pyrazolidine iii 200 ml. of dry acetone is added 15 ml. ofmethyl bromide while cooling with ice. After standing at room temperature for a few hours, the mixture is cooled to - 12' 70 ,and the resulting crystalline preripitate is filtered off rapidly and washed with @a small amount of dry acetone. The hygroscopic I - methyl - 1,2 - trimethylene - pyrazolidinium bromide is dried and melts at 264-267'. The above-described qtiaternary ammoniuni icom- 75 32 pounds is added to alun-iinlim amal.-am (obtained from 4 g. of aluminum shavings) in 80 ml. of ether, l@O ml. of water is added in portions while cooling with ice,,and the -mixture is allowed to stand overnight at O'. An excess of solid potassiiim hydroxide is added, the mixture is extracted with ether, the ether evaporated to yield the crude N,N-(4-aza-4-methyl-1,7-heptylene)-imine. A solution of 8.5 g. of NN-(4-aza-4-methyl-1,7heptylene)-imine in 160 ml. of toluene is added while stirring t6 a solution of 5.02 g. of :acetonitrile in 50 ml. of toluene containing 15 g. of sodium carbonate. The reaction mixture is refluxed for six hours, filtered hot, and 'Lhe filtrate is concentrated to a small volume. Tbe residue is distilled; the @desired [I-NT,N-(4-aza-4-methyl1,7- heptylene)-imino]-a@cetonitrile boils at 83-85'/0.4 MM. 5.44 g. of the [I-N,N-(4-aza-4-methyl-1,7-heptylen e)imino]-acetanilrile in 30 ml. of ether is added to 2 g. of lithitim ialuminum hydride in 100 ml. of ether. The Teaction mixture is heated to reflux for six hours and stirred overnight; the complex is decomposed with 2 -ml. of water, 2.6 ml. of 20 percent aqueous sodium hydroxide and 7 ml. of water. The reaction mixture is filtered, the fiItrate is concentrated under redticed pressure and the residue is distilled. The desi-red 2-[N,N(4- aza-4-methyl-1,7-heptylene) -iminol -ethylamine boils at 112-117'/13 mm. Exainple 21 A mixture of N-methyl-N-[2-(4-inethyl-l-piperazino)ethyl]-amine and S-methyl-isothiourea sulfate in water yields t@ie desired N-methyl-N- [2-(4-methyl-l-piperazino) elhyll-guanidine sulfate upon relltixipg and then concentrating the solution. The starting material may be prepared by treatin.1- methyl-piperazine with 2-bTOMOethan0l, Teacting the re@sultin@ 2-(4-methyl-l-piperazino)-ethanol with thionyl chloride -and exchanging the chlorine atom in 2-(4methyl-l-piperazino)-ethyl chloride with methylamine. Exainple 22 A nlixture of 20 g. of 2-(4-methyl-l-piperaziiio)-ethylamine and 15 g. of cyanogen bromine in ether yields the 2 - (4 - methyl - I - piperazino) - ethyl -,ryanamide hyrobromide, whirh is converted into the free compound by treatment with an equivalent amount of @aqueous sodium hydroxide. The salt may be used directly in the subsequent amonolysis by employing an excess of amnionia. 16.8 g. of 2-(4-methyl-l-pipera2@ino)-etliyl-ryanamide and 13.2 g. of ammonium sulfate are dissolved in 100 ml. of a 15 percent aqueous ammonium hydroxide solution. The solution is heated for about three hours in an autoclave to about 100' to about 150', while agitating. Upon cooling the reaction mixture yields the 2-(4-methyl1-piperazino )-ethyl-guanidine sulfate, M.P. 193-198'. Example 23 A soliit-ion of 14.3 g. of 2-(4-methyl-l-piperazino)ethylamine in water is treated with 8.1 g. of sodium thiocyanate; the reaction mixture is warmed up for about one hour. The crystalline 1-[2-(4- methyI-I-piperazino)-ethyl]-2-thiourea is obtained uponconcentrating the solution under reduced pressure. A solution of the above 1-[2-(4-mothyl-l-piperazino)ethyl] -2-thiourea in aqueous ammonlium hydroxide is heated while stirring in the presence of asuspension of freshly preeipitated mercuric oxide as a desulfurizing reagent. The reaction niixture is filtered, the filtrate is made aoidic with sulfuric acid, whereupon the 2-(4-methyl-l-piperazi no)-ethyl-guanidine sulfate precipitates and is recrystallized from a inixture of ethanol and water. The compound isidenticail with the product obtained according to the procedure of Example 1.

3,098,066 33 Exan7ple 24 40.0 g. of the 1-[2-(4-methyl-l-piperazino)-ethyll-2thiourea described in Example 23 is dissolved in water and treated with 13.6 g. of dimethyl sulfa@te. The reaction mixture is allowed to proceed spontaneously, with occasional cooling to control the reaction. The desired S - metbyl - 1-[2-1\4-methyl -l-piperazino)-ethyl]-2-isotluourea slilfate precipitates from the cold solution. 26.5 g. of S-rnethyl-l-[2-(4-metliyl-l-piperazino) -ethyll-2-isotiiiourea in aqlieous methanol is treated w,,ith ammonia apd rnercuric cliloride. After several hours the solution is filtered to remove the metallic precipitate. The filtrate is made acidic witii siilfuric acid and the desired 2-(4-metliyl-l-piper az,i.io)-ethyl-guanidine sulfate can be recovered, Example 25 16.8 g. of the 2-(4-methyl-l-piperazino)-etbyl-cyanamide, described in Exarnple 22, and 16.2 g. of potassium eyanate are dissolved in witer, and the solution is allowed to stand for twenty-four hours. The excess cyanate is destroyed with nitric acid and the silver sal-t of the resulting 1-[2-(4-metli yl-!-pipera7ino)-ethyll-3-cyano-urea is precip-'tated by treatmeit Nvith silver nitrate. The silver salt is suspended ii-i warm water, decomposed with hydrochloric acid, and the precipitated silver chloride is fikered off. The reslilting 1-[2-(4-methy@1-1-pipe razino)-ethyl]-3-cyano-urea is heated for Liree hours to about 50' to 80' with 6 N aqueous sulftiric acid; after cooling the crystalline 2-(4-mehyl-l-piperazino)-ethyl-guanidine sulfate can be recovered and recrystal@lized from aqlieous ethanol. Exainple 26 To 20.0 g. of 1-methyl-piperaziiie in 75 ml. of ethanol is added 15.8 -. of 2-,-Uan-idinoethyl chloride hydrochloride in an ethanol solution. After the addition is complete, the reaction mixture is refluxed for several hours, then cooled, filt--red -,ind concentrated under reduced pressure. The res:due is dissolved in water, the solution j, made alkaline witii diltite sodium hydroxide, and the resutting base converted to the 2-(4-methyl-lpiperazino)ethyl-gtianidine sulfate, M.P. 193-198'. The 1-m@-thyl-piperazi@ie w--,ly also be converted into the sodium salt, for example, by treatment with sodium, sodii,im am-ide or sodium hydride in toluene; such sodium sa,lt is then reacted with the guanidi,-io-othyl cbjoride, freshly prepared from its hydrochloride salt, to form the desired 2-(4-metbyl -l-piperazino)-ethyl-guanidine, which may be characterized as -its stilfate. The starting material may be prepared qs follows: To 10.5 g. of 2-guanidino-ethanol hydrochloride in 500 ml. of toluene is add-.d while stir@ing 16.9 g. of thionyl chlor@ide. After standing ove;-lii.-ht, the mixture is warined for about 30 n-linu-tes and the toluer-c is decanted, any excess of thionyl ch'@oride is evaporated w@.th the remaining toluene and the residue, representing the 2-guanidino-ethyl G-hlor,ide hydrochloride, is recrystallized -from a mixture of ethanol and ether. Th-. free base may be formed by treating a mixture oll the salt in ether w@ith the stoichiometric amount of ammonia. By substituting in @the above reactioii 3-guanidino-propanol for the 2-guan@ldiiioothanol, the 3-guanidino-propyl chloride hydrochjoride may be obtained. E,Yarnple 27 A solution of 19.9 g. of 2-(4-methyl-l-piperazino)ethyl chloride hydrochloride and 21.6 g. of guanidine sulfate in water is neutralized and @made slightly alkaline v,,ith aqueous sodium hydroxide. The reaction mixture is heated on the steam bath aiid additio-iial sodium hydroxide sollution is added to neiitralize generated acid. After cooling and acidifying with sulfurie acid, the resulting solution is concentre@.ted under reduced pressure and the 2-(4-methyl - I - piperazino)-ethyl-gLianidine sulfate 34 separates; it is recrystallized from a mixture of ethanol and water. The starting material may be prepared as; follows: 20 g. of 1-methyl-piperazine is added to a soliition of 25 ,-, of ethylene bromohydrin in 200 ml. of benzene, containing a suspension of 15 g. of anhydrous sodium carbonate. The mixture is stirred and refluxed overnight, then filtered and the, filtrate concentrated under reduced pressvre. Th,- 2-(4- methyl-l-piperazino)-ethanol is re10 covered by distilling thc@ residue. To a solution of 5.72 g. of 2-(4-niethyl-l-piperazino)ethanol in 50 ml. of benzene is added dropwise while stirrin.- a solution of 5.15 g. of thionyl chloride in 150 ml. of benzene. The reaction mixture is then stirred 15 and refltixed for two hours, then cooled, the solid material is filtered off and recrystallized from a mixture of ,methanol and ether to yield the 2-(4-mc:thyl-lpiperazino)lethyl chloride hydrochloride, By reacting 1-phenyl-,piperazine with ethylene bromo20 hydrin and treating the resulting 2-(4@phenyt-lpiperazino)-ethanol with thionyl chloride as shown hereinabove, the desired 2-(4-phe nyl-l-piperazino)-ethyl chloride hydrochloride may be obtained, which, upon treatment with -Uanidine sulfate according to thD previously 25 given procedure, yields the desired 2-(4-phenyt-f-piperazino) -ethyl-guanidine, which may be characterized as its sulfate, M.P. 256-258' (with decomposit@'.on). Exan7ple 28 30 13.6 g. of cliloroacetyl igtian@'.de is added NNhilestirrin.- to a solution of 20.0,g. of 1-inethyl-piperazine in 200 ml. of be@izene. After warrriing for one hour, an,d then cooling, the soltition is filtered aiid the filtrate concentrated under reduced pressure. 35 The residue, containing the 2-(4-methyl-l-piperazino)acetic acid guanide, is suspended in totrahydrofurane and added to a refluxin.- solution of 6 -- of lithium aluminum hydride in tetrahydrofuran. After completion of the reaction, the exc.-ss of lithium aluminum hydride is de40 composed by adding water, then aqueous sodium hydroxide,. The solid material is filtered off, the filtrate is acidifl.-d with sulfuric acid and the 2-(4-methyl-l-piperazino)- ethyl-guanidiiie sulfate can be recovered and recrystallized from aqueous ethanol, M.P. 193-198' (with decomposi45 tioll) - Example 29 To a mixtlire of 1.46 @g. of benzoyi-cyanamide and 1.50 g. of 2-(4-methyl-lpiperazino)-othylamine is added a small amount of concentrated aqucous h.ydrochloric '50 acid; the mixture is heated on the steam bath for ten to fifteen miniites, then cooled and diluted with ethanol. Ether is added to precipitate the 1-benzoyl-3-[2-(4-inethyl-l-piparazino)-ethyll-i,-,uanidine hy&ochloride, which is separated by filtration. It shows a band at ;about 1678 55 cm.-' (in chloroform) in the infrared absorption spectrum. Benzoyl-cyanamido, may be replaced by (4-methoxybenzoyl) - cyanamide, (3,4,5-trin-icthoxy-benzoyl)-cyanarnid-, and the like; -,vl-ien treated with 2-(4-methyl-l60 piparazino)-ethylamine as shown in the a-bove example, these reaaents yield the 3-[2-(4-methyl-l-p,iperazi no)et-hyl]-I-(4-methoxybenzoyl) - iguanidine hydrochloride, 3-[2-(4-methyl-l-piparazino)-othyll - I - (3,4,5-trimeth65 oxy--benzoyl)-guanidine hydrochloride and the like. Example 30 A mitxure of 2.30 g. of 2-(4-methyl-l-p@iperazino)e ithyl-guanidine hydxoohloride and 1 -g. of propionyl ch@loride is heated in a scaled tube at about 100' during sev70 ral ho-Lirs. The reaction mixture is cooled and then dissolved in iethanol and the 3-[2@(4-n-iethyl-l-piperazino)- ethyl] -1 -propionyl-guanidine hydrochloride is precipitated by addingether. Example 31 75 A mixture of 2.01 g. of 1-gtianyl-3,5-dimethyl-pyrazole

35 nitrate and 14.3 g. of 2-(4--inethyl-l-piperazino)-ethylamine is heated for 21/2 hours - ,vhile stirrin,-. The excess amine is removed by distillation under reduced pressure, the residue is dissolved in wate-r and converted to the desired 2-(4-methyl-l-piperazino)- ethyl-,,-iianidine slilfate by treat@ment with a strong anion (stilfate) exchange resin, such as, for exainiple, as described in U.S. Patent No.- 2,591,573. The solution is eva@porated 'under reduced pressure and the residue recrystallized from aqueous ethanol; the product is identical with the compound obtained according to the procedure of Example 1. Example 32 A solution of 12.6 g. of 2-(4-inethyl-l-piperazino)ethylamine trihydroghloride and 3.15 g. of cyanamide in 100 ml. of etlianol is refluxed for six hours. The solvent is removed under reduced pressure, -the residue -dissolved in water and converted to tl-ie 2-(4- methyl-l-piperazino)ethyl-guanidine sulfate with the help of @a strong ianion (sulfate) exchange resin as shown in Example 31. Example 33 14.3 g. of 2- (4-methyl - I - piperazino) -ethylamine is added to a suspension of 10.2 g. of 1-methyl-3-nitrosoguanidine in water. T@lie mixture is allowed to stand at room tempeTature for several days until gas evolution has ceased. The solid material is filtered off, the 1-methyl-3-[2,(4-methyl-l-piperaz ino)-ethy,l]-gLianidine sulfate is obtained by adding aqueous sulfuric acid tothe filtratp., concentrating the solution and adding efnanol. The compound is identical with the product obtained,according to -the procedtire of Example 1. Exai7iple 34 A mixture of N,N-diethyl-cyanamide, 13 g. of 2-(4me thyl-l-piperaziiio)-ethylamine trihydrochloride and 5 ml. of 95 percent et-hanol is heated in a scaled tube for twenty hours at 100'. The reaction mix@ture is cooled, the solvent is removed under reduced pre@,sure, excess N,N-diethyl-r,yan@amide is removed byextraction with e@ther and the residue is treated with aqueous sulfuric acid. The solution is colicentrated under reduced pressu,re and the desired 1,1-diethyl-3-[2- (4-motliyl-l-piperazino)-ethyl]- guanidine sulfate is precipitated by adding ethanol. Exan7ple 35 A mixture of 5.0 g. of 2- [4- (2-N,N-diethylaminoethyl)- I-piperazinol-e,thylamine and 3,05 g. of Smethyl-isothiourea sulfate in 5 ml. of water is refluxed for six bours. The isolation is then concentrated under reduced pressure and the residue is recrystallizedfrom @a mixture of ethanol and diethyl ether; the 2-[4-(2-N,Ndiethylaminoethyl)-lpiperazinol-ethyl-guanidine sulfate melts at 208-212' The starting material can be prepared,as follows: 67.75 g. of 2-N,N-diethylaminoethyl chloride is -added dropwise to a solution of 43.0 g. ofanhydrotis piperazine in 150 ml. of ethanol. An exothermic, reaction occurs, the reaction mixture is stirred for,an additic)nal 18 hours and then chilled. The resulting solid material is filtered off, the filtrate is concentrated to dryness under reduced pressure and the residue is distilled. The 1-(2-N,N-diethylaminoet@hyl)-pi,perazine boils at 120-126'/13 mm. A solution of 21.4 g. of 1-(2-N,N-diethylaminoethyl)piperazine in 200 ml. of toluene is added to a stirred solution of 8.73 @-. of chloro-acetonitrile in 100 ml. of toluene, in which 25.4 g. of anhydrous sodium carbonate is suspended. 'The niixture is Tefluxed for eight hours, then filtered hot and the filtrate is concentra-ted under reduced pressure. The [4-(2-N,N-diethylaminoethyl)-l-pipe razino],acetonitrile obtained as the residue is distifled, B.P. 115-116'/0.5 mm. 15.4 g. of [4-(2-N,N-diethylaminoetbyl)-l-piperazi nolacetonitrile in 100 ml. of diethyl ether is added dropwise whilq f ooling Iiid stirring to a solution of 3.92 g. of 3,098,066 36 lithiuni aluminuni hydride in 250 ml. of diethyl ether. After completion of the addition, the solution is refluxed overnight, then cooled and der-omposed by successive addition of 5 ml. of @water, 8 ml. of 20 percent aqueous sodium hydroxide @and 13 @ml. !of w,,Lter. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure and tlie Tesidtie is distilled to yield the desired 2 - [4-(2-N,N-diethylaminoethyl)-l-piperazi nolethyl-aiiiine, B.P. 95-97'/0.3 mm. 10 Exa77iple 3@6 A mixture of 2.45 g. of 2- [ 4- (4-cl-'iorophenyl) - I -piperazino]-ethylamine iand 1.42 g. of S-ii-iethyl-isothiourea sulfate in a i-nixture of ethanol and water is refluxed for 15 four hoi-irs,and -then allowed to cool. The resulting 2-14(4-chlorophenyl)-I-- oiperaziiiol-ethylgu7anidine sulfate is filtered off and rer-,rystallized from a mixttire of ethanol and water, M.P. 250-265' (with decompositign). Th.- starting material may b-- prepared as follows: A 20 solution of 27.5 g. of 1-(4-cl-ilorcphenyl)-piperazine in 400 ml. of toluene is added -to a stirred solution of 10.6 g. of c@loroacetonitrile in 300 ml. of toluene containing 30.0 g. of anhydrous sodium carbonat-.. The reaction mixture is refluxed for eight hours and filtered; the filtrate 25 is concentrated under reduced -pressure and the solid residue is recrystallized from n-heptane to yield the [4-(4- chloto-phenyl)-l-piperazinol-acetoni@Lrile, M.P. 120-125'. I A solu-tion of 10.0 g. of [4-(4-rhloro-phenyl)-lpiperazino]-acetoiitrile in 1000 ml. of diethyl ether is slowly 30 added to a solution of 2.25 g. of lithium aluminum hyd,@ide in 500 ml. of diethyl ether while coolin.a. The @solution is then refluxed overnight alid allowed to stand for 21/2 days. 2.25 ml. of water, 3 ml. of 20 percent aqueous sodium liydroxide and 18 ml. of water are added 35 i, this order, the react;on mixture is filtered, the filtrate is concentrated iapd the residue is distilled; the desired 2-[4- (4-cliloro-phenyl)-l-piperazinol-@-thylamine is collected at 152-158'/0.3 mm. and solidifies on standing. 40 Example 37 A solu-tioii of 4.8 g. of 2-[l-T,4,N-(4-aza-4-benzy l-1,7heptylene)-iminolethylaniine and 2.7 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. Thc reaction mixture is :concentrated Linder re45 duced pressure and the residue is recrystallized from ethanol; the dry 2-[I-N,N-(4- aza-4-benzyl-1,7-heptyleiie)i-Tninol-ethyl-guanidine sulfate melts a-t 188-181'. The starting materi,,ll may be prepared as follows: To 36.2 g. of 1,5-diaza-cyclo-octane is dropwise added 40.2 50 g. of benzyl chloride while stirring and cooling. The reaction mixture is stirred for an additional 24 hotirs, the solid material is filtered ofi- and the filtrate is concentrated under reduced pressure. The Temaining yellow oil is combined with the solid material separated by fil5,5 tration, 40 percent aqueous sodiiim hydroxide is added and the aqueous solution is extracted three times witli diethyl ether. 'Fhe ether solutions are dried over sodium sulfate, and concentrated under reduced pressure. The remaining yellow oil is dis@lilled to yield the desired (;O 1-benzyl-1,5-diaza-cyclo-octane, B.P. 97-100'/0.25 mm. 20.4 g. of 1-benzyl-1,5-diaza-cyelo-oc@tane in 200 ml. of toluene is added dropwise to a mixttire of 7.55 g. of chloroacetonitrile and 22.0 g. of sodium carbonate in 100 ml. of toltiene -,vhile stirring. The reaction mixture C,5 is refluxed for eight hotirs, stirred overni,-ht and filtered. The solidmaterial is washed with hot toluene, the washings are combined with the filtrate and the solution is tvaporated to dryness. The remainin,- brown oil is distilled to yield 13.8 @. of @tlie slightly yellow [1,N,N-(4- 70 aza-4-benzyl-1,7-heptylene)-iniino]-acetonitrile, B.P. 147149'/0.25 mm. A soliition of 11.0 g. of [I-N,N-(4-aza-4-benz3TI-1 ,7heptylene)-iminol,,icetonitrile in 100 ml. of diethylether is added dropwise to a inixture of 2.81 g. of lithiun-i 7,5 aluminum hydride in diethyl ether while stirring ancl

3,098,066 37 cooling in an ice-bath. The reaction mixture is refluxed overni,-ht, the excess lithitim alaminum hydride is destroyed by adding 3 ml. of water, 5 nil. of 20 percent aqueous sodium hydroxide and 10 ml. of water, and the reaction mixture is filtered. -i he solid material is washed with diethyl ether, the filtrate and the washings are combined, dried over sodium stilfate and evaporated to dryness to leave the desired 2-[l-N,N-(4-aza-4- benzyl-1,7heptylene)-imino]-ethylamine, which is purified by distillation, B.P. 134- 137'/0.3 mm.; yield: @6.8 g. Other -uanidino compounds, such as 2-fl-N,N-(4-aza4 -phenyl-1,7-heptylene)-imino]- ethyl-guanidine, 2-fl-N, N- [4-aza-4- (4-methoxy-phenyl) - 1,7 - heptylonel - imino)ethyl-guanidine, 2-@l-N,N-[4-az a-4-(4-methyl-phenyl)1,7-lieptylene]- iminol-ethyl-,-uanidilie, 3-[I-N,N-(4-aza4 -phenyl-1,7-heptylene)- iminolpropylguariidine and the like, particularly the sulfates thereof, can be prepared according to ttic previously given procedure by selecting Lbe appropriate starting matorials. Exa777ple 38 A mixture of 5.0 g. of 2-[I-N,N-(3-aza-3-benzyl-1,6 hexylene)-;Minol-ethylamine and 2.97 g. of Smethyl-isothiourea sulfate in 5 ml. iof water is refluxed for four hours and allowed to stand overnight. The solidified reaction product iS Tecrystallized from a mixture of ethanol and ether and dried at 70' under higii vacuum to yield the 2-[I-N,N-(3-aza-3-benzyl-1,6-hexylone)- iminojethylguanidine sulfate, M.P. 205-20,7'. 'ne starting material may be prepared as sbown in Example 1; the 1-benzyl-1,3-diaza-cycloheptane boils at 91-101'/0.3 mm. and is converted by treatment with ebloraectonitrile to the [I-N,N-(3-aza3-benzyl-1,6-hexylene)-iminol-acetonitrile, B.P. 156-158'/1.2 mm.; yield: 20.1 g., which is reduced to the 2-[I-N,N-(3-aza-3benzyl-1,6-hexylone)-iminol-ethylamine, B.P. 125-126'/ 0.3 n-im. with lithium alurninum hydride. The 2- [I-N,N-(3-aza-3-phonyl-1 ,6-hexylene)-iminolethyl-,-Lianidine sulfate, 2-flN,N-[3-aza-3-(3,4-dimethoxyphenyl)-1,6-hexylenel-im ino}-ethyl-guanidine sulfate a@-id the like can be prepared according to the above procedi-ire by usin.@ the appropriate starting materials. Exainple 39 A mixtlire of 4.0 of 2-(4-methyl-2,6- cis-dimethyl-lpiper,izino)-ethylai-nine and 3.25 g. of S-metnyl-isothiotirea sulfate in 5 ml. of water is refluxed for four hours. The reaction mixture is concentrated under reduced pressure and the residlie isrecrystallized from a rnixture of ethanol and etixer to yield the 2-(4-methyl-2,6-cis-dimethyl-lpiperazino)-ethyl-guanidine sulfate, M.P. 225231' (with decomposition). The starting material ii-iay be prepared as follows: A mixture of 85.5 g. of 2,6-cis-dimethylpiperazine and 40 g, o'L methyl formate is heated for five hours at 85'. The reaction n-iixture is concentrated under reduced presstire and the residue is distilled to yield the 1-formyl-3,5cisdimethyl-piperazine, B.P. 112-115'/0.8 mm.; yield: 63 g. A solution of 14.0 g. of 1-formyl-3,5-cis-dimethyl-piperazine in 50 ml, of diethyl ether is added to 5.7 g. of lithium aluminum hydride in 400 ml. of lithium aluminum hydride. After stirring in the icebath for two hours, the excess reducing reagent is destroyed by adding 10 ml. of water, 5 ml. of 20 percent sod@ium hydroxide and 15 ml. of water, and tiae separated organic layer is evaporated to dryness. The desired 1-methyl-3,5-cis-dimethyl-piperazine is purified by distillation, B.P. 114- 116'/0.5 mm.; yiel.d: 5.9 g. The 1-methyl-3,5-c-is-dimethyl-piperaz@ne is converted into the (4-methyl-2,6-cis-dimethyl-lpiperazino)-acetanitrile, B.P. 125-126'/ 13 mm., by treatment with chloroace38 to ;the 2 - (4-methyl-2,6-cis-dimethyl-l-pipeTazino)-ethylamine, B.P. 102-103'/13 mm., with lithium aluminum hydride; these reactions are c-arried out according to the methods given in Example 1. 5 Example 40 A mixture of 5.0 g. of 2-[I-N,N-(3-aza-3-methyl-1,6- hexylene)-imino]-ethylamine and 4.42 g. of S-mothyl isothiourea,sulfate in 5 ml. of water is refluxed for four 10 liours and then concentrated under reduced pressure. The solid residue iS Tecrystallized from a mixture of ethanol and water to yield the 2-LI-N,N-(3-aza-3- methyl-1,6hexylene) -imino] -ethyl-guanidine sulfate, M.P. 137-140'. The starting material may be prepared by reacting 18.0 15 g. of 1-methyl-1,4-diaza-cyeloheptane with 11.91 g. of chloroacetonitrile in the presence of 33.0 g. o-f anhydrous sodium carbonate and reducing 8.6 g. of the resulting [I - N,N - (3-laza-3-methyl-1,6-hexylene)-iminol-acetov-itrile, B.P. 68-72'/0,2 mm. with 3.2 g. of lithium alumi20 num hydride to the desired 2-[I-N,N-(3-aza-3-methyl-1,6- hexylene)-iminol-ethylamine, B.P. 104'/13 mm., yield: 6.7 g.; these Teactions are carried out according to the procedures described in Example 1. 25 Exainple 41 The co@-npouiids of the present invention may be formulated into pharmacological preparations. Thus, 2-(4methyl-i-piperazino)-ethyl-guanidine dihydrochloride sul30 fate (of Example 4) may be made up into tablets containing froni;about 0.001 g. to about 0.050 g., preferably from about 0.015 g. to,about 0.035 g. of the active substance per dos,,ge unit. For example, tablets containing 0.025 g. of 2-(4-methyl-l-piperazino)-ethyl-guanidine di35 hyd-rochloride sulfate are prepared as follows (for 10,000 tablets). In gredients: G. 2 - (4-methyl-l-piperazino)-ethyl-guanidine 40 dihydr ochloride sulfate --------------- 250.00 La@,to se, spray dried -------------------- 2062.5 0 Tragac anth -------------------------- 50.00 Corn starch --------------------------- 125.00 45 Magne sium stearate -------------------- 12.50 The 2-(4-@methyl-l-piperazino)-othyl-guanidine dihydrochloride sulfate is triturated with the corn starch and passed through a No. 40 screen. The other ingredients are passed through a No. 20 screen and thoroughly niixed 50 in a niixer with thetriturate. The resultin- niix is compressed into tablets (0.250 g. total weight) USing "I@2" standard concave punches. SolLitions, for example, of 2-(4-methyl-l-piperazin o)ethyl-guanidine dihydrochloride sulfate, may contain from 55 0.001 g. to about 0.025 g. per millifiter solution. A colution, containing 0.0lg.Iml. of 2-(4- methyl-l-piperazino)ethyl-guanidine dihydrochloride sulfate, can be prepared as follows (for 2,500 ml.). 60 Ingredients: G. 2-(4-mothyl,l-piperazino)-ethyl-guam,,dine dihydrochloride sulfate ------------------- 25.00 Citric acid, anhydrous -------------------- 2.50 Sodium citrate -------------------------- 10.00 65 Sodium chloride ------------------------- 15.00 Water for injection, q.s. 2500.00 ml. The citric acid, sodium citrate and sodium chloride are dissolved in 2000 ml. of water for injection. The 2-(4- 70 methyl-l-pip,-razino)-athyl-guanidine dihydrochloridesulfate is dissolved in the resulting solution and additional water is added to bring up the volume to 2500 ml. The solut@ion is passed through a medium porosity sintered glass filter and 2.2 ml. of the futrate is filled into ampules. tonitrile, and the resulting nitrile derivative is reduced 75 The sealed ampules are sterilized @at 115' for 30 nlinutes.

39 What is!claimed is: I ' A member iselected from the group consisting of a compound of the formula // (CH2).l \ / NH RL'-N N-A-NH-C (CH2).2 NH-R2' in whirh Rl' stands for a meniber selected from the group consisting of lower alkyl, cycloalkyl havinig from five to s@ix ring;carbon atoms,- cyoloalkyl-lower alkyl, in which cycloalkyl has from five to six ring carbon atoms, phenyl, (lower,alkyl)-phenyl, (lower alkoxy)-phenyl and (hal(Ygeno)-plienyl, each of the syrnbols n, @and n2 stands for an integer from the group consisting of 2, 3 and 4, with the proviso that the total of nl+n2 stands for an integer selected from the -roup consisting of 4, 5 and 6, A is lower alkylene, which has from -two to three carbon atoms and separates the guanidino group from the ring nitrogen atom by from two to three carbon atoms, and R2' is a member of the 'group Qonsisting of hydrogen, lower alkanoyl, benzoyl, (lower-alkyl)-benzoyl, (lowf,@r alkoxy)benzoyl and (halogeno)@benzoyl, and pharmaceutically acceptable acid addition salts thereof. 2. Compounds of the formula: (CH2)@iCH2 NT-T :@-I (lower alkyl)-N N-A-NIIC \ (CH2).@-CH2 / \ NH2 in which each of the symbols ml and m2 stands for one of the numbers 1 and 2, and A stands for lower alkylene, which contains from two to three carbon atoms and separates the guanidino group from the ring nitrogen atom by from two to three carbon atoms. 3. The therapeutically acceptable acid addition salts of compounds of the formula: (CH2)m,-CH2 NH (lower alkyl)-N / N-A-NU-C (CH2).,@-CH3 NH2 in which eacli of the symools nil and M2 stands for one of the numbers I and 2, and A stands forlower alkylene, which contains from tnvo to three carbon atoms and separates the guanidino group from tlle ring nitrogen atom .5 by from two to three carbon,atoms. 4. 2-(4-methyl-l-piperazino)-ethyl-guanidine. 5. The therapeutically acceptable acid addition salts of 2-(4-methyl-l-piperazino)-ethyl-guanidine. 6. 2-(4-methyl-l-piperazino)-ethyl-guanidine sulfate. 10 7. 2-(4-methyl-l-piperazino)-ethyl-guanidine dihydrochloride sulfate. @8. 2-(4-ethyl-l-piperazino)-ethyl-guanidine. 9. 2-El-N,N-(3-aza-3-methyl - 1,6 - hexylene) iminolethyl-guanidine. 15 10. 2-El-N,N-(4-aza-4-methyl-1,7-heptylene) iminolethylguanidine. 1 1. Compounds of the formula: (CI-12).,-CH2 NH (phenyl)-N N-A-Ni-i-C @-I 20 NH2 in which each of the symbol& ml and M2 stands for oiie of the numbers I and 2, and A stands for lower alkyl25 ene, which contains j'rom tnvo to three,carbon atoms and separates the glianidino group from the ring nitrogen atoni by from two to three carbon atoms. 12. 2-(4-phenyl-l-piperazino)-ethyl-guanidine. 30 References Cited in th-. file of this patent UNITED STATES PATENTS 2,655,498 Weston et al - ----------- Oct. 13, 1953 2,683,145 Lyle et al - ------------- July 6, 1954 35 2,945,860 Schmidt-Barbo et al. ---- July 19, 1960 2,946,793 Michaels et al - --------- July 26, 1960 2,951,078 Beil ------------------ Aug. 30, 1960 FOREIGN PATENTS 40 676,812 Great Britain ---------- Aug. 6, 1952

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,098,066 July 16, 1963 Robert Paul Mull It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. Column 8, lin6s 15 to 19, the formula should appear as shown below itis-tead of as in the patent: (CH @@CH NH 2 z@, (lower alkyl)-N (CH @@CH \NH-R' 2 m 2 2 lii,ie 58, for "aieds" read -- acids --; column 12, line 51, for "-C==(Nli,4)-SRO " read -- -C(==NR4)-SRO --; line 67, for "O-lower alkyl-i.sothiourea, eyana-" read --@ 0-lower alkyli.sourea, S-lower alkyl-isothiourea, eyaiio- --; column 14, line 43, for IIN,N(N" read -- N,N-(N --; line 54, for "amow-nia" read -- ammonia --; column 15, line 1, for "imino]-ethyl@-2urea" read -- iminol-ethyll-2-urea --; line 5, for IIN,N-4-aza" read -- N,@N-(4-aza --; same column 15, lines 58 to 63, in the .9 f ormUI6, f or "CH 11 read -- CH2 --; column 17, line 23, f or ")NR read (N-R, --; column 18, line 64, for "I,N,N" read -- I-N,N line 69, for Ilethyl]cyanothioureall read -- ethyl]- eyanothiourea column 19, lines 20 to 23, the formula should appear as Shown below instead of as in the patent: I-N, @,T-(N-Ri- aza-alkylene)-i.mino]-lower alkyl-N- @l -XH R 5 A line 48, for "lN,N" read -- I-N,N --; line 70, for "alkylene) i-mi 1, Lnov@ read -- alkylene)-imino --; same column 19i lin@es 74 and 75, for "N-[I-,N,Ni-(N-R,,- aza-alkylene)imino]" reacl -- N-.[I-N,N-.(N-B.,-,aza-alkylene)-imino] --; column 20, lin,e 36, for "converting a" read -- converting in a --; line 37, for "alkylene)imino" read -- alkylene)-imino