US3098066A

US3098066A - Diaza-heterocyclic guanidine compounds

Info

Publication number: US3098066A
Application number: US12681A
Authority: US
Inventors: Mull Robert Paul
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1960-03-04
Filing date: 1960-03-04
Publication date: 1963-07-16
Anticipated expiration: 1980-07-16

Description

United States Patent Ofi 3,098,066 Patented July 16, 1963 ice 3,098,066 DIAZA-HETEROCYCLIC GUANIDINE COMPOUNDS Robert Paul Mull, Florham Park, NJ., assignor to Clba Corporation, a corporation of Delaware No Drawing. Filed Mar. 4, 1960, Ser. No. 12,681 12 Claims. (Cl. 260-439) The present invention concerns guanidino derivatives. More particularly, it relates to [1-N,N-(N-R,-aza-alkylene)-imino]-lower alkyl-guanidines, in which aza-alkylene 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 radical, as well as an acyl radical, salts or quaternary ammonium compounds thereof, as well as process for manufacturing such compounds.

The N,N-aza-alkylene-imino group, in which the azanitrogen is substituted by R represents primarily a hexacyclic, a heptacyclic or an octacyciic radical, as well as a pentacyclic, a nonacyclic or a decacyclic group. The ring carbon atoms are preferably unsubstituted or may contain, for example, hydrocarbon radicals, particularly lower alkyl, e.g. methyl, ethyl and the like, as substituents. The N,N-(N-R -aza-alkylene)-imino group is represented primarily by the group of the formula:

(can.

(cHn.,

in which each of the symbols n, and n represents one of the numbers 2, 3 and 4, with the proviso that the total of n +n represents one of the numbers 4, 5 and 6, and R has the previously given meaning. A more preferred group of N,N-(N-R -aza-alkylene)-imino radicals may be represented by the formula:

R1-N N- (com -on,

in which each of the symbols m and m represents one of the numbers 1 and 2, and R has the previously given meaning.

The N,N-(N-R -aza-a.lkylene)-irnino radical may be represented, for example, by 4-R -i-piperazino, 1-N,N-(3- R -3-aza-L6-hexylene) -imino, and l-N,N- (4-R;-4-aza-l,7- heptylene)-imino, in which R, has the previously given meaning, as well as by l-N,N-(3-R -3-aza-l,7heptylene)- imino and the like, and similar radicals, in which the carbon atoms of the :aza-alkylene portion may contain lower alkyl, e.g. methyl, ethyl and the like, as substituents, such as, for example, 4-R -2-methyl-l-piperazino, 4-R -2, o-dimethyl-l-piperazino, 4-R -2,2,6,6 tetramethyl-l-piperazino, 1-N,N-(3-R -3-aza-l,1,6,6-tetramethyl 1,6 hexylene)-imino and the like, in which R, has the previously given meaning.

An aliphatic hydrocarbon radical R comprising also a carbocyclic aliphatic hydrocarbon radical, is primarily an aliphatic hydrocarbon 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, 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-tetrarnethyl-butyl, 5,5-dimethyl-hexyl, n-nonyl, ndecyl and the like. Other aliphatic hydrocarbon radicals are, for example, lower alkenyl, e.g. ethenyl, 2-propenyl, Z-methyI-Z-propenyl, Z-butenyl and the like, lower alkynyl,

eg ethynyl, l-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-cyclopentenyl, 3- cyclohexenyl and the like, or any other suitable aliphatic hydrocarbon radical.

The above-mentioned aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted, for example, by'other aliphatic hydrocarbon radicals, primarily by cycloalkyl containing from three to seven, especially from live to six, ring carbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl and the like, cycloalkenyl containing from five to seven ring carbon atoms, eg. Z-cyclohexenyl, 3-cyclohexenyl and the like. The resulting radicals may be represented by cycloalkyl-lower alkyl, in which cycloalkyl contains from five to six ring carbon atoms and lower alkyl contains from one to four carbon atoms, e.g. cyclopentylmethyl, cyclohexylmethyl, l-cyclopentylethyl, Z-cyclohexylethyl, 3-cyclopentylpropyl and the like, or cycloalkenyl-lower alkyl, in which cycloalkenyl contains from five to six ting carbon atoms and lower alkyl contains from one to four carbon atoms, e.g. Z-cyclopentenylmethyl, 3-cyclohexenylmethyl, 2-(3-cycloheXenyl)-ethyl and the like.

Or, cycloaliphatic hydrocarbon radicals, such as the previously mentioned cycloalkyl and cycloalkenyl radicals, may also be substituted by other aliphatic hydrocarbon ridicals, such as lower alkyl, cg. methyl, ethyl and the li e.

An aliphatic hydrocarbon radical R; may also be substituted by carbocyclic aryl, particularly, monoc'yclic or bicyclic carbocyclic aryl, e.g. phenyl, l-naphthyl or 2 naphthyl, as well as substituted phenyl, substituted 1- naphthyl or substituted Z-naphthyl. Substituents attached to these carbocyclic aryl radicals are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. imethylenedioxy, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particnlarly N,N-di-substituted amino, such as N,N-di-lower alkylamino, cg. N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e. g. fiuoro, chloro, bromo and the like, or halogenolowcr alkyl, e.g. trifiuoromethyl. Substituents attached to carbocyclic aryl, particularly monocyclic carbocyclic aryl, portions may be in any of the available positions, whereby one or more than one of the same or of different subs-tituents may be present. The above aliphatic hydrocarbon radicals containing carbocyclic aryl substituents may be represented, for example, by carbocyclic aryl-lower aliphatic radicals, primarily monocyclic carbocyclic aryl-lower alkyl, such as phenyllower alkyl, e.g. benzyl, diphenylrnethyl, l-phenyl-ethyl, 2-phenyl-ethyl, 3-phenyhpropyl and the like, bicyclic car-bocyclic aryl-lower alkyl radicals, such as naphthyllower alkyl, e.g. l-naphthyl-methyl, Z-naphthyhmethyl and the like, monocyclic carbocyclic aryllower alkenyl, eg. phcnylethenyl, El-phenyl-Z-propenyl and the like, or bicyclic carbocyclic aryl-lower alkenyl, e.g. I-(Z-naphthyl)-ethenyl and the like. The carbocyclic portions of these radicals may be unsubstituted or may contain substituents, such as those mentioned hereinabove.

Another group of substituted aliphatic hydrocarbon radicals are those containing heterocyclic aryl radicals, such as monocyclic azacyclic aryl, for example, pyridyl, cg. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, bicyclic monocyclic aryl, for example, quinolyl, e.g. Z-quinolyl, 4-quinolyl and the like, monocyclic diazacyclic aryl, e.g. 3-pyridazinyl, 2-pyrimidyl, 4-pyrimidyl, Z-pyrazinyl and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g. 2-thicnyl and the like, monocyclic oxacyclic aryl, for

example, furyl, e.g. Z-furyl and the like. These hetero cyclic aryl radicals may also contain additional substituents such as, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like. The aliphatic hydrocarbon radicals substituted by heterocyclic aryl groups may, therefore, be represented by heterocyclic aryl-lower aliphatic hydrocarbon radicals, such as monocyclic or bicyclic heterocyclic aryl-lower alkyl radicals, particularly pyridyklower alkyl, e.g. 2- pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(4- pyridyU-ethyl and the like, pyridazinyl-lower alkyl, e.g. 4-pyridazinyl-methyl and the like, pyrimidyl-lower lalkyl, e.g. 2-pyrimidyl-methyl, 4-pyrimidyl-methy1 and the like, pyrazinyl-lower alkyl, e.g. iZ-pyrazinylmethyl and the like, thienyl-lower alkyl, e.g. Z-thenyl and the like, or furyl-lower alkyl, e.g. Z-furyl-methyl and the like.

The aliphatic radicals may also be substituted by functional groups, whereby one or more of the same or of different groups may be present; functional groups substitute primarily the above-mentioned lower alkyl radicals.

Functional groups are, for example, oxygen-containing groups, such 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 portions and may have a free terminal hydro-xy group or an etherified terminal hydroxy group, such as terminal lower alkoxy, e.g. methoxy, ethoxy and the like, group, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenylo-xy and the like, or carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, e.g. benzyloxy, diphenyl-methoxy, (4-chlorophenyl)-phenylmetihoxy and the like, or esterified hydroxy, such as lower alkoxycarbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, carbamyloxy, such as carbamyloxy, N-lower alkyl-carbamyloxy, e.g. N-methyl-carbamyloxy and the like, N,N-di-lower alkyl-carbamyloxy, e.g. N,N-dimethylcarbaimyloxy and the like, or N-carbocyclic aryl-carbamyloxy, particularly N-monocyclic carbocyclic arylcarbamyloxy, e.g. N-phenyl-carbiamyloxy 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 groups, such as amino groups, for example, unsubstituted amino, N-monosubstituted amino, for example, N-lower alkylamino, e.g. N-methylamino, N-ethylamino and the like, N-carbocyclic aryl-amino, particularly N-monocyclic carbocyclic aryl-amino, e.g. N-phenyl-amilo and the like, N-carbocyclic aryl-lower aliphatic hydrocarbon-amino, particularly N-monocyclic carbocyclic-lower alkyl-amino, such as N-phenyl-lower alkyl-amino, e.g. N-benzyl-amino, N-(2-phenyl-ethyl)-amino and the like, or primarily N,N- disubstituted amino, such as N,N-di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methyl-arnino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, N-cycloalkyl-N-lower alkylamino, e.g. N-cyclopentyl-N-methyl-amino, N-cyclohexyl- N-ethyl-amino, N-lower alkyl-Nrnonocyclic carbocyclic aryl-amino, particularly N-lower alkyl-N-phenyl-lower alkyl-amino, e.g. N-benzyl-N-methyl-amino, N-methyl-N (2-phenylethyl)-amino and the like, or N,Nalkylene-imino,N,N-oxa-alkylene-imino, or N,N-aza-alkylene-imin0, in which alkylene contains from four to six carbon atoms as ring members, such as, for example, l-pyrrolidino radicals, e.g. l-pyrrolidino, Z-methyl-l-pyrrolidino and the like, 1- piperidino radicals, e.g. l-piperidino, 2-methyl-1-piperidino, 3-methyl-1-piperidino, 4-methyl-l-piperidino, 3- hydroxy-l-piperidino, 3-acetoxy-1-piperidino, 3-hydroxymethyl-l-piperidino and the like, 1-N,N-(l,6-hexylene)- imino, l-morpholino, or l-piperazino radicals, e.g. 4- methyl-l-piperazino, 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl-l-piperazino, 4-(2-polyethylenedioxy-ethyl)-lpiperazino and the like.

Sulfur containing substituents of lower aliphatic radicals are primarily mercapto or etherificd mercapto groups attached to lower alkyl; etherified mercapto may be represented by lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like.

Also included as substituents 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.

The group R may also be represented by carbocyclic aryl radicals, which are primarily monocyclic carbocyclic aryl radicals, e.g. phenyl, or bicyclic carbocyclic aryl radicals, e.g. l-naphthyl or Z-naphthyl. Such radicals may be unsubstituted or may contain substituents; one or 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. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy and the like, or lower alkylenedioxy, e.g. methylenedioxy, esterified hydroxy, such as lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, or lower alkanoyloxy, e.g. acetyloxy, n-propionyloxy and the like, mercapto, etherified rnercapto, 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 amino, for example, N-lower alkyl-amino, e.g. N-methylamino, Nethylamino and the like, or particularly N,N-disubstituted amino, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or halogeno-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 hexacyclic heterocyclic radicals. Such radicals are represented, for example, by monocyclic mono-azacyclic aryl, for example, pyridyl, e.g. 2-pyridyl, S-pyridyl, 4-pyridyl and the like, bicyclic mono-azacyclic aryl, for example, quinolyl, e.g. Z-quinolyl, 4-quinolyl and the like, monocyclic di-azacyclic aryl, for example, pyridazinyl, e.g. 3- pyridazinyl and the like, pyrimidyl, e.g. Z-pyrimidyl, 4- pyrimidyl and the like, pyrazinyl, e.g. Z-pyrazinyl, pyrryl, e.g. 2-pyrry1 and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g. 2-thienyl and the like, or monocyclic 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.g. methylmercapto, ethyl-mercapto and the like, or halogeno, e.g. fiuoro, chloro, bromo and the like.

Acyl radicals representing the group R may be those of lower aliphatic carboxylic acids, such as lower alkoxycarbonic acids, e.g. methoxy-carbonic, ethoxy-carbonic acid and the like, amino-carbonic acids (or carbamic acids), such as carbamic, N-lower alkyl-carbamic acid, e.g. N-methyl-carbamic and the like, N,N-di-lower alkylcarbamic acid, e.g. N,N-dimethyl-carbamic and the like, N-carbocyclic aryl-carbamic acid, such as N-monocyclic or N-bicyclic carbocyclic aryl-carbamic acid, e.g. N-phenyl carbamic, 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-butenoic acid and the like, or lower alkynoic acids, e.g. propiolic acid and the like. Acyl radicals may also be those of substituted lower alkanoic acids, such as, for example, cycloalkyl-lower alkanoic acid, e.g. S-cyclopentyl-propionic acid and the like, halogeno-lower alkanoic acids, e.g. chloroacetic, dichioroacetic, trifluoroacetic, 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 amino-lower alkanoic acids, particularly N,N-di-lower alkyl-amino-lower alkanoic acids, e.g. N,N-dimethyl-amino-acetic, 3-N,N-diethylamino-propionic acid and the like, or N,N-alkyleneimino-lower alkanoic acids, e.g. 3-(l-piperidino)-propionic acid and the like. Other acyl radicals may be those of carbocyclic aryl carboxylic acids, especially monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic, 4- rnethyl-benzoic, 4-methoxy-benzoic, 3,4,5-trimethoxy-benzoic, 4-O-ethoxy-carbonyl-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. l-naphthoic, 2-naphthoic acid and the like, carbocyclic aryllower 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. cinnamic, 4-chloro-cinnamic, 3,4,5-trimethoxy-cinnarnic acid and the like, heterocyclic aryl carboxylic acids, such as monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic, 2-furoic, 2-thienoic acid and the like, or heterocyclic aryl-lower aliphatic carboxylic acids, such as monocyclic heterocyclic aryllower alkanoic acids, e.g. 2-pyridyl-acetic, Z-thienyl-acetic acid and the like.

The lower alkyl radical, linking the l-N,N-(N-R -azaalkyIene)-imino portion with the guanidino group, is represented by lower alkylene containng from one to seven carbon atoms. Preferably, lower alkylene contains from two to three carbon atoms, which separate the 1-N,N- (N-R -aza-alkylene)-imino portion from the guanidino group by the same number of carbon atoms; such radicals are 1,2-ethylene, l-methyl-LZ-ethylene, 2-methyl-l,2- ethylene or 1,3-propylene. Other lower alkylene radicals are, for example, methylene, 1,1-etbylene, 2,3-butylene, 1,3-butylene, 1,4-butylene, 1,4-pentylene or 1,5-pentylene and the like.

The guanidino group may be represented by in which each of the radicals R R R and R stands primarily for hydrogen. They may also represent an aliphatic hydrocarbon radical, particularly lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, with the proviso that at least one of the radicals R R and R, stands for hydrogen. One of the radicals R and R may also be an acyl radical; such acyl radical may be identical with one of those which can represent R attached to the nitrogen atom of the l-N,N-(N-R aza-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, cyclopentylpropionic acid and 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, eg. benzoic, hydroxybenzoic, 4- methoxy-bcnzoic, 3,4-dimethoxy-benzoic, 3,4,5-trimethoxy-benzoic, 4-O-ethoxycarbonyl-syringic, 3,4-dichlorobenzoic, 3-N,N-dimethylaminobenzoic, 4-nitrobenzoic acid and the like, or bicyclic carbocyclic aryl carboxylic acids, e.g. Lnaphthoic, Z-naphthoic acid and the like, or heterocyclic aryl carboxylic acids, for example, monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic, Z-furoic acid and the like.

Salts of the new compounds of this invention are particularly therapeutically acceptable, non-toxic acid addition salts, such as those with inorganic acids, for example, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or those with organic acids, such as organic carboxylic acids, erg. acetic, propionic, glycolic, lactic, pyrnvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, pheny-lacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, Z-acetoxy-benzoic and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, 2-l1ydroxyethane sulfonic, p-toluene sulfonic acid and the like. Monoor poly-salts may be formed.

The new guanidino derivatives of this invention and the salts thereof are characterized by antihypertensive properties and can, therefore, be used as antihypertensive agents to relieve hypertensive conditions, particularly those of neurogenic, renal or essential nature. In addition, they cause an increase in the peripheral blood flow and can, therefore, be used in functional peripheral vascular diseases, such as Raynauds disease. These pharmacological properties are of relatively long duration and are coupled with a remarkably low degree of toxicity.

The compounds of this invention may also be employed as intermediates in the manufacture of other useful compounds.

A preferred group of compounds of this invention may be represented by the formula:

( M, NH

(OH2)n in which R stands for lower alkyl, containing from one to seven, particularly from one to four, carbon atoms, cycloalkyl containing from five to six ring carbon atoms, cycloalkyl-lower alkyl, in which cycloalkyl contains from five to six ring carbon atoms and lower alkyl contains from one to four carbon atoms, or monocyclic carbocyclic aryl, particularly phenyl, lower alkyl-substituted phenyl, in which lower alkyl contains from one to four carbon atoms, lower alkoxy-substitutcd phenyl, in which lower alkoxy contains from one to four carbon atoms, or halogeno-phenyl, in which halogeno has an atomic weight below 80, each of the symbols n and n stands for one of the numbers 2, 3 and 4, with the proviso that the total of n +n represents one of the numbers 4, 5 and 6, A represents lower alkylene, containing from two to three carbon atoms and separating the guanidino group from the ring nitrogen atom by from two to three carbon atoms, and R represents hydrogen, the acyl radical of a lower alkanoic acid containing from two to seven carbon atoms or the acyl radical of a monocyclic carbocyclie aryl carhoxylic acid, particularly the acyl radical of 'benzoic acid, the acyl radical of a lower alkyl-substituted 'benzoic acid, in which lower alkyl contains from one to four carbon atoms, the acyl radical of a lower alkoxy-substituted benzoic acid, in which lower alkoxy contains from one to four carbon atoms, or the acyl radical of a halogeno-substituted benzoic acid in which halogeno represents a halogeno atom with an atomic weight below 80, and therapeutically acceptable acid addition salts of such compounds.

Particularly valuable with respect to their pharmacological propcrties are the compounds of the formula:

in which lower alkyl contains from one to seven, particularly from one to four, carbon atoms, e.g. methyl, ethyl, n-propy], isopropyl, n'butyl or isobutyl, as well as secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and the like, each of the symbols m and m stands for one of the numbers 1 and 2, and A represents lower alkylene containing from two to three carbon atoms and separating the guanidino group from the ring nitrogen atom by from two to three carbon atoms, eg. 1,2-ethylene, 1-methyl-l,2-ethylene, 2-methyl-l,2-ethylene, 1,3-propylene, and therapeutically acceptable acid addition salts thereof. 2-(4-methyl-l-piperazino) ethylguanidine, 3-(4-methyl-l-piperazino) propyl guanidine, 2-(4-methyl-1-piperazino)-2-methyl-ethyl-guanidine, 2-(4- ethyl-l-piperazino)-ethyl guanidine, 2 (4 isopropyl lpiperazino)-ethyl-guanidine, 2-[l-N,N-(3-aza 3 methyl 1,6-hexylene)-imino]-ethyl-guanidine, 2-[l-N,N-(3 aza- 3-ethyl-1,6-hexylene)-imino]-ethyl-guanidine, 2-[1 N,N- (4-aza-4-methyl-1,7-heptylene)-imino1 ethyl guanidine, 2-[ l-N,N-(4-aza 4 ethyl 1,7 heptylcne) -imino] -ethylguanidine, and their therapeutically acceptable salts with mineral acids, represent this group of compounds.

Another group of valuable compounds are those of the formula:

( QM CIII Nir (earbocyclic aryl) -N N-A-NIIC (CH1) -CH2 Nils in which carboxylic aryl represents primarily monoeyclic chloro, bromo and the like, or phenyl substituted by halogeno-lower alkyl, e.g. trilluoromethyl, or bieyclic carbocyclic aryl, e.g. l-naphthyl, 2-naphthyl, or these radicals substituted by the above-described substituents, each or the L symbols m and m represents one of the numbers 1 and 2, and A represents lower alkylene, containing from two to three carbon atoms, which separate the guanidino group from the ring nitrogen atom by the same number of carbon atoms, e.g. 1,2-ethy1ene, 2-methyl-l,2-ethylene, 1,3-propylene and the like, and therapeutically acceptable acid addition salts thereof. One or more than one of the same or different substituents may be attached to any of the positions available in the carbocyclic aryl nucleus; substituted phenyl radicals are, for example, lower alkylphenyl, e.g. 4-methyl-phenyl and the like, lower alkoxyphenyl, e.g. 4-methoxy-phenyl, 2,5-dimethoxy-phenyl, 3,4- dlmethoxy-phenyl, 3,4,5 trimethoxy-phenyl, 4 ethoxyphenyl and the like, lower alkylenedioxy-phenyl, e.g., 3,4- methylenedio-xyaphenyl, N,N-lower a1kylaminophenyl, e.g. 3-N,N-dimethylamino-phenyl, 4-N,N-dimethylaminophenyl and the like, halogenO-phenyl, eg. 4-chloro-phenyl, 3,4-dichloro-phenyl, 3-iluoro-phenyl, 4-bromo-pheny1 and the like, or polyhalogeno-lower alkyl-phenyl, e.g. 3-trifiuoromethyl-phenyl and the like. Representing this group are, for example,

2-(4-phenyl-1-piperazino)-ethyl-guanidine,

3 (4-pheny'l- 1 -piperazino) -propyl-gu anidine,

2-rnethyl-2- 4-phenyl- 1 -piperazino) -ethyl-guanidine,

2- 4- 4-methyl-phenyl l-piperazino] -ethyl-gu anidine,

2- 4- 4-methoxy-phenyl) l -piperazino] ethyl-guanidine,

2- [4- 3 ,4-dimethoxy-phenyl l piperazino] -ethylguanidine,

2- [4-( 3 ,4, 5 -trimethoxy-pheny1) 1 -piperazino] -ethylguanidine,

2- 4- 3 ,4-methylenedioxy-phenyl -l-piperazino] -ethy1- guanidine,

2-[4-(4-dimethylarnino-phenyl)-1-piperazino]-etl1ylguanidine,

2- 4- 4-bromo-phenyl l-piperazino] -ethyl-guanidine,

in which halogeno represents a halogen atom with an atomic weight below 89, e.g. fluoro,

2- [4- 3,4-dichloro-phenyl)- l -piperazino] -ethylguanidine,

3- [4- 3 -tritluoromethyl-phenyl) -1-piperazino]-propylguanidine,

2- l-N,N-(3-aza-3-phenyl-1,6-hexylene -imino] -ethylguanidine,

3-[ l-N,N-(3-aza-3-phenyl-l ,6 hexylene)-imino] propylguanidine,

2-[ l-N,N (4-aza-4-phenyl-l ,7-heptylene) -irnino] -ethylguanidine,

and their therapeutically acceptable acid addition salts thereof.

The guanidino derivatives of this invention may also be represented by the compounds of the formula:

in which lower alkyl contains from one to seven carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and the like, each of the symbols m and m represents one of the numbers 1 and 2, A stands for a lower alkylene radical containing from two to three carbon atoms and separating the guanidino group from the ring nitrogen atom by from two to three carbon atoms, e.g. 1,2-ethylene, 2-methyl-1,2-cthylene, 1,3-propylene and the like, and R represents the acyl radical of a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, the acyl radical of benzoic acid, the acyl radical of a lower alkyl-substituted benzoic acid, e.g. 3-methyl-benzoic, 4-ethyl-benzoic acid and the like, the acyl radical of a lower alkoxysubstituted benzoic acid, e.g. Z-methoxy-benzoic, S-methoxy-benzoic, 4-ethoxy-benzoic, 3,4 dimethoxy benzoic, 3,4,5-trimethoxy-benzoic acid and the like, or the acyl radical of a halogeno-substituted benzoic acid, e.g. 4-fiuoro-benzoic, 2,5-dichloro-benzoic, 4-bromo-benzoic acid and the like, and the therapeutically acceptable acid addition salts thereof. This group may be represented by 3-acetyll [2- (4-rnethyll-piperazino) -ethyl} -guanidine,

3-benzoyl-l- [2-(4-methyl-l-piperazino)-ethyl]-guanidine,

1- 3 (4-ethyl-1-piperazino) -propyl] -3-propionylguanidine,

1- [2- 4-isopropyl-l-piperazino -ethyl] -3- (4-rnethoxybenZQyD-guanidine,

1-{2- l-N,N-(4-aza-4-methyl-1,7-heptylene -imino] ethyl}-3-(El-methyl-benzoyl -guanidine,

and therapeutically acceptable acid addition salts thereof.

Therapeutically acceptable acid addition salts of the described guanidino compounds are primarily those with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, as well as those with lower aliphatic polycarboxylic acids, such as lower alkene dicarboxylic aicds, e.g. maleic, citraconic acid and the like, hydroxy-lower alkane dicarboxylic acids, e.g. tartaric acid and the like, or hydroxy-lower alkane tricarboxylic acids, e.g. citric acid and the like.

The new guanidino derivatives may be used as medicarnents in the form of pharmaceutical preparations, which contains the new compounds or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols, petroleum jelly or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as tablets, such as scored tablets, dragees, capsules and the like, or in liquid form,

for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers and the like. They also may contain, in combination, other therapeutically useful substances.

The new guanidino compounds of this invention may be prepared, for example, by converting in a [l-N,N-(N- R -aza-alkylene)-imino]-lower alkyl-amine, in which R and aza-alkylene have the above-given meaning, or a salt thereof, the amino group into a guanidino group and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into its acyl derivative, and/or, if desired, converting a free compound into a salt or a quaternary ammonium compound thereof.

The reagents of choice for the conversion of an amino group into a guanidino group are S-lower alkyl-isothioureas, in which lower alkyl may stand primarily for methyl, as well as ethyl, n-propyl, isopropyl and the like, or acid addition salts thereof. Salts, which are employed in preference over the free base, are primarily those with mineral acids, such as hydrochloric, hydrobromic, or particularly sulfuric acid and the like. The isothiourea reagents used in the reaction may be depicted by the formula:

in which R R and R have the previously given meaning, and R stands for lower alkyl, particularly methyl, and mineral acid addition salts thereof. The preferred reagents for the conversion of an amino group into a guanidino group is S-methyl-isothiourea and its mineral acid addition salts; S-methyl-isothiourea sulfate is primarily used to form guanidino compounds, which contain an unsubstituted guanidino group. The [1-N,N-(N- R -aza-alkylene)imino}-lower alkyl-arnine starting material, in which the amino group is above all a primary amino group, but may also represent a secondary amino group, such as an N-lower alkyl-amino group, e.g. N- methylamino, N-ethylamino and the like, is generally used in the form of the free base.

The reaction is carried out by contacting the starting material with the reagent, preferably in the presence of a solvent, the choice of which depends primarily on the solubility of the reactants. Water or water-miscible orgnnic solvents, such as water-miscible lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, water-miscible cyclic others, e.g. p-dioxane, tetrahydrofuran and the like, ketones, e.g. acetone, ethyl methyl ketone and the like, lower alkanoic acids, e.g. acetic acid and the like, formamides, e.g. formamide, N,N-dimethylformamide and the like, or aqueous mixtures of such solvents may be used as diluents. The reaction may be carried out at room temperature, or, if necessary, at an elevated temperature, for example, at the boiling temperature of the solvent. An absence of oxygen may be achieved by performing the reaction in the atmosphere of an inert gas, e.g. nitrogen, and, if necessary, it may be carried out under pressure in a closed vessel.

This procedure is particularly suitable for the preparation of mineral acid addition salts of compounds of the formula:

curin -om NH;

(lower alityl) N in which m m and A have the previously given mean- 10 ing; such compounds may be obtained, for example, by contacting an amine of the formula:

(CH2) -CH1 (lower alkyl) N NAN Us (Gua -c112 in which m m and A have the previously given meaning, with a mineral acid addition salt of an S-lower alkylisothiourea, particularly the S-methyl-isothiourea sulfate, preferably at an elevated temperature.

Similar reagents capable of converting an amino into a guanidino group are O-lower alkyl-isoureas of the formula:

in which R R R and R have the previously given meaning, or their salts with mineral acids. These isourea derivatives are used in the same way as the above-described, corresponding isothiourea reagents; O-methylisourea sulfate represents a preferred reagent.

The above-described reagents are known, or, if new, may be prepared according to procedures described in the prior art and used for the manufacture of known analogs. For example, the S-lower alkyl-isothioureas or O-lower alkyl-isoureas may be prepared by alkylating thioureas or ureas, in which at least one of the nitrogen atoms 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. dirnethyl sulfate, diethylsulfate and the like.

Other reagents capable of transforming the amino group of a [l-N,N-(N-R -aza-alkylene)-imino]-lower alkylamine, in which R; and aza-alkylene have the previously given meaning, particularly of an acid addition salt thereof, are cyanimides having the formula:

in which R and R have the previously given meaning. The reaction may be carried out, for example, by heating the mixture of a il-N,N-(N-R -aza-alkylene)-imino]-lower alkyl-amine compound, particularly a salt thereof, such as a mineral acid addition salt, e.g. the hydrochloride, hydrobromide, sulfate and the like, thereof and the cyanamide. The resulting melt may then be dissolved in a solvent, such a lower alkanoic acid, e.g. acetic acid and the like, and the desired product may be isolated, for example, by crystallization and 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 salt of a free base used as the 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 cyanarnide reagent may also be formed in situ; for example, 1-nitroso-3-methyl-guanidine furnishes the N-methyl-cyanamide, which then reacts with the amine to form the desired guanidino compound. The reaction may proceed exothermically, and, if necessary, may be maintained by heating, for example, to from about to about 200; an atmosphere of an inert gas, e.g. nitrogen may be advantageous.

A third modification of the procedure for the manufacture of the products of this invention comprises reacting the [1-N,N-(N-R -aza alkylene) irnino] -lower alkylamine, in which R, and aza-alkylenc have the previously given meaning, with a salt of a l-guanyl-pyrazole. A salt of a l-guanyl-pyrazole is primarily a salt with a mineral acid, such as, for example, nitric acid; a l-guanyl-pyrazole may contain additional substituents in the pyrazole nucleus, particularly lower alkyl, e.g. methyl, ethyl and the like. Salts of l-guanyl-3,S-dimethyl-pyrazole, particularly the salt with nitric acid, represent the preferred reagents. The reaction may be carried out in the absence of a solvent, for example, by fusing the two reactants, or in the presence of a diluent, such as, for example, a lower alkanol, e.g. ethanol and the like, and advantageously, by excluding the presence of carbon dioxide, for example, by performing 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 [l-N,N-(N-R -aza-alkylene)-imino]-lower alkylamines, in which R and aza-alkylene have the 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 R -aza-alkylene)-imine with a halogeno-lower alkano nitrile, 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 group in such fashion, that it adds to the imino group. In a [l-N, N-(N-R -aza-alkylene) -imino] -lower alkano-nitrile, resulting from one of these procedures, the nitrile group is then converted to a methyleneamino group by reduction, for example, by catalytic hydrogenation, such as, treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the periodic system, e.g. palladium on charcoal, Raney nickel and the like, or, preferably, by treatment with a light metal hydride capable of converting a nitrite group to a methyleneamino group, for example, an aluminum hydride, such as lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, aluminum borohydride, aluminum hydride and the like, which hydrides may be used, if desired, in the presence of an activator, such as aluminum chloride.

A group of very important intermediates 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:

in which each of the symbols in, and m represents one of the numbers 1 and 2, and acid addition salts with mineral acids thereof. This group may be illustrated by 2-( 4-methyl-l-piperazino) -ethylamine, 2-[1-N,N-(3-methyl-3-aza-l,6-hexylene)-imino]-ethylamine, 2 [1-N,N (4- methyl-4-aza-1,7-heptylene)-imino] -ethylamine and the like, as well as their mineral acid addition salts.

The above compounds may be prepared, for example, by reacting a compound of the formula:

Gua -c in caro -om in which 111 and m have the previously given meaning, or a salt thereof, with a halogenoacetonitrile, e.g. chloroacetonitrile and the like, and reducing in a resulting compound of the formula:

crmm -cm NCITT-CN Gua -c11 in which m and m have the previously given meaning, the nitrile group to a methylencamine group; these reactions may be carried out as previously shown. Compounds of the preferred group of intermediates may also be obtained, for example, by reacting a compound of the formula:

in which each of the groups X and X stands for a reactive esterified hydroxyl group, or a salt thereof, with ethylenediamine and, if desired, converting a resulting compound into a salt thereof. Reactive esterified hydroxy groups in the starting material are, for example, halogeno atoms, e.g. chloro, bromo and the like, or monocyclic carbocyclic aryl sulfonyloxy groups, e.g. p-toluene sulfonyloxy and the like. The starting material may react with ethylenediarninc to form the desired 2-(4-rnethyl-lpiperazino)-ethylaminc in the presence of an inert solvent, and, if desired, of an acid adsorbent; the reaction may be carried out according to standard methods.

The compounds of the present invention can also be prepared by converting in a [l-N,N-(N-R -aza-alkylene)- iminoI-lower alkyl-amine, in which R and aza-alkylene have the previously given meaning, and in which the amino group carries a substituent capable of being converted into an amidino group, or a salt of such compound, such substituent into an amidino group, and, if desired, carrying out the optional steps.

Depending on the character of the substituent, which is capable of being converted into an amidino group and attached to the amino group of the [l-N,N-(N R aza-alkylenc)-imino]-iovrer alkyl-amine, the procedure outlined hercinabove may be carried out according to different modifications.

For example, the substituent of the amino group of the [l-N,N-(N-R,-aza-alkylene)-imino] lower alkyl amine may comprise a carbon atom, which is attached to the amino group. To such carbon atom there may be connected at least one nitrogen atom. The carbon atom may also carry an additional nitrogen atom, as well as other hetero atoms, such as, for example, oxygen or sulfur, or other substituents. Such groups may be, for example, cyano of the formula CEN, carbamyl of the formula -CONHR thiocarbamyl of the formula CSNH-R lower alkoxy-(imino)methyl of the formula -C(=NH)-OR in which R represents lower alkyl, primarily methyl, as well as ethyl, n-propyl, isopropyl and the like, lower alkylmercapto-(imino)rnethyl of the formula in which R has the above-given meaning, cyanoamidino of the formula C(:NR4)NHCEN, guanidino- (imino)methyl of the formula isocyano-(imino)methyl of the formula C(=NR )-N:C:O

or isothiocyano-(imino)methyl of the formula C(=NR )N=C=S and the like, in which R, has the previously given meaning,

but stands particularly for hydrogen.

Together with the [l-N,N-(N-R -aza-alkylcne)-imino]- lower alkyl-amino portion, these substituents form cyanamide, urea, thiourea, O-lower alkyl-isothiourea, cyana guanidine, biguanide, cyanourea or cyanothiourea derivatives and the like. All of these compounds have the above-given common characteristic, i.e. to the amino group is attached a carbon atom, which carries at least a nitrogen atom.

The greater part of these starting materials may be converted into the desired guanidino derivatives by ammonolysis or aminolysis.

For example, a cyanamide may be converted into a guanidino derivative by treatment with ammonia or an ammonia-furnishing 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 compound with liquid ammonia under pressure and at an elevated temperature, if desired, in the presence of an anion capable of forming a stable salt with a resulting guanidine; ammonium acetate, ammonium sulfate, ammonium chloride and the like may be used as an anion source. Ammonia may be replaced by ammonia furnishing am monium salts; such salts are, for example, ammonium rnonohydrogen phosphate, which may be used under pressure and at an elevated temperature or ammonium nitrate, whereby a salt, such as, for example, an alkaline earth metal, e. g. calcium and the like, salt or an alkali metal, e.g. sodium, potassium and the like, salt of the cyanamide is preferably used, which may be reacted with the ammonium nitrate in the presence of catalytic amounts of water.

The cyanamide compounds, used as the starting material and having the formula:

in which R stands primarily for hydrogen, but may also be lower alkyl, and R and aza-alkylene have the previously given meaning, and salts thereof, may be prepared, for example, by treating the [l-N,N-(N-R -aza-alkylene)- iminoJ-lower alkyl-amine, in which R; and alkylene have the previously given meaning, with a cyanogen halide, such as cyanogen chloride, cyanogen bromide and the like, advantageously in equivalent amounts and preferably in an inert solvent, such as, for example, diethyl ether.

The starting materials of the above formula are new and are intended to be included within the scope of this invention. Particularly useful as intermediates are the compounds of the formula:

(lower alkyl) N in which lower alkyl contains from one to seven carbon atoms, each of the symbols m; and 111 represents one of the numbers 1 and 2, and A stands for alkylene containing from two to three carbon atoms and separating the cyanamine group from the imino-nitrogen by from two to three carbon atoms; 2-(4-methyl-l-piperazino)-ethyl-cyanamide, 2 (4-etl1yl-1-piperazino)-ethyl-cyanamide, 2-[l-N,N-(3- aza-3-methyl-1,6-hexyiene) -im ino]-cthyl-cyana.mide, 2- l- N,N-(4-aza-4-methyl-1,7-heptylene) iminoJ-ethyl-oyanarnide represent this group of intermediates.

A carbamyl group attached to the amino group of the l-N,N-(N-R -aza-alkylene)-imino]-lower alkyl-amine, in which R and aza-alkylene have the previously given meaning, may be converted into the desired amidino group by treatment with ammonia, preferably, in the presence of a dehydrating agent, such as, for example, phosphorous pentoxide. This reaction may be carried out at an elevated temperature in a closed vessel; temperature and pressure may be reduced by the presence of a non-aqueous solvent and/or of a reaction accelerator, such as finely dispersed nickel, aluminum, aluminum oxide and the like. Ammonia may be replaced by an amine, such as an N-lower alkyl-amine, and [1 N,N-(N-R -aza-alkylene)-imino]- lower alkyl-guanidino compounds with substituted guanidino groups can be obtained.

Furthermore, a thiocarbamyl group, which together with the amino group of a [l-N,N-(N-k -aza-alkylene)- iminoj-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 with ammonia, for example, in the presence of water, and/or of a nonhydrolytic solvent, such as, for example, toluene and the like, and in the presence of a desulfurizing agent. The latter is selected advantageously from basic oxides, basic carbonates and the like, of heavy metals, such as lead, zinc, cadmium, tin, mercury and the like; such compounds are, for example, lead oxide, mercuric oxide, lead hydrogen carbonate and the like. Mcrcuric chloride may also be used. This ammonolysis procedure is preferably carried out at an elevated temperature, and, if necessary, in a closed vessel, primarily to avoid loss of ammonia. An amine, such as an N-lowcr alkyl-amine, may replace ammonia, and N-substituted guanidino derivatives may be formed.

Ureas and thioureas, used as the starting material in the above-mentioned modification of the procedure and having the formula:

in which R R R and aza-alkylene have the previously given meaning, R and R representing primarily hydrogen, and X stands for oxygen or sulfur, and salts thereof may be obtained, for example, from [l-N,N-(N-R -azanlkyIene)-imino]-lower alkyl-amines, in which R and azaalkylcne have the previously given meaning, by treating the latter with ammonium or metal cyanates or thiocyanates, such as alkali metal, e.g. sodium, potassium and the like, cyanates or thiocyanates. These reagents are preferably used in the presence of a solvent, for example, water, if desired, containing a small amount of an acid, such as a mineral acid, c.g. hydrochloric, sulfuric acid and the like. This procedure furnishes ureas or thioureas of the above-given formula, in which R, stands for hydrogen. A lower alkyl isocyanate or a lower alkyl isothiocyanate, when reacted with the {l-N,N-(N-R -azaalkylene)-imino]-lower alkyl-amine compound, yields a urea or a thiourea, in which R represents lower alkyl. The lower alkyl isocyanates and isothiocyanates are used in the presence of an organic solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like.

The above-mentioned urea or thiourea compounds used as the starting materials may also be obtained by an ammonolysis or aminolysis procedure from reactive functional derivatives of -[l-N,N(N-R -aZa-alkylene)-imino]- lower alkane carbamic acids or N-[l-N,N-(N-R -aza-alkylene)-imino]-lower alkane thiocarbamic acids having the general formula:

in which R;, R X, and aza-alkylene have the previously given meaning. Reactive functional derivatives of such acids are primarily esters, for example, lower alkyl, e.g. methyl, ethyl and the like, esters or halides, e.g. chlorides and the like. Upon ammonolysis, for example, by treatment with amomnia, if necessary, at an elevated temperature in a closed vessel, these carbamic and thiocarbamic acid derivatives may yield the desired urea or thiourea derivatives, respectively. Ammonia may also be replaced by an amine, such as 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:

w -011K in which lower alkyl contains from one to seven carbon atoms, each of the symbols in; and m stands for one of the numbers 1 and 2, A represents alkylene containing from two to three carbon atoms and separating the urea and thiourea group, respectively, from the imino-nitrogen atom by from two to three carbon atoms, and X represents oxygen or sulfur, and salts thereof; 1-[2-(4-methyl-1- piperazino)-ethyl]-2-urea, 1 [2-(4 ethyl-l-piperazino)- ethyll-Z-urea, 1-{2-[1-N,N-(3-aza-3-methyl-l,6-hcxylene)- imino]-ethyl{-2-urea, 1-{2-Ll-N,N-(4 aza-4-methyl-l,7- heptylene)-imin]-ethyl}-2-urea, ll2-(4-methyl-l-piperazino)-ethyl]-2-thiourea, 1-[2-(4-ethyl-1piperazino)-ethylJ-2-thiourea, l-{2-[1-N,N-(3 aza-3-methyl-l,6-hexylene)-imino]-ethy1} 2 thiourea, 1-{2-[l-N,N-4-aza-4- methyl-1,7-heptylene)-imino]-ethyl}-2-thiourea are specific examples of such compounds.

The group of O-lower alkyl-isoureas and S-lower alkylisothioureas of the formula:

in which R R R X and aza-alkylene have the previously given meaning, and R stands for lower alkyl, primarily methyl, as well as ethyl, npropyl, isopropyl and the like, and salts thereof, are compounds containing the previously mentioned O-lower allcoxy-(imino)methyl group of the formula -C(=NR )OR and S-lower alkyl-mercapto- (imino)methyl group of the formula C( NR )SR respectively, in which R and R have the previously given 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 ammonolysis or aminolysis. Ammonolysis may be carried out by treatment with ammonia, either in its liquid form or as an aqueous solution thereof, whereby an elevated temperature and/ or a closed vessel, as well as the presence of an ammonium salt, such as ammonium chloride and the like, may be required. If necessary, dehydrating agents or desulfurizing agents, such as those previously described, may be present in the reaction medium, depending on the type of starting material used. An amine, such as an N-lower alkyl-amine, may also be used for the conversion of the isoureas and isothioureas into guanidino derivatives containing substituted guanidino groups.

The isourea and isothiourea compounds used as the starting materials may he obtained, for example, from the previously mentioned urea and thiourea derivatives by treatment of the latter, or of a metal salt thereof, such as an alkali metal, e.g. sodium, potassium and the like, salt thereof, with a lower alkyl halide, cg. methyl or ethyl chloride, bromide or iodide and the like, or with a di-lovver alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like. Such reaction may be carried out in the presence of a solvent, the selection of which depends on the type of reagents used; a free urea or thiourea compound may be used in the presence of water or a lower alkanol, e.g. methanol, ethanol and the like, whereas an alkali metal salt of a urea or may be reacted in the presence of a hydrocarbon, e.g. toluene and the like, solution.

The isourea and isothiourea above-modification of the general method are new and are intended to be included within the scope of the present invention. A particularly useful group of such intermediates can be depicted by the formula:

compounds used in the (lower alkyl) -N (CH3) ,-GII2 1- [2- 4-methyl-1-piperazino) -ethyl] -Ornethyl-2-isourea,

1- 2- (4ethyl-1-piperazino) -ethyl] -O-methyl-2-isourea,

1-{2-[ l-N,N- 3 aza-3-rnetbyl- 1 ,6hexylene)-imino] ethyl}'O methyl-2-isourea,

thiourea compound 1-{2-[ l N,N(4-aza4-rnethyl-1,7-heptylene) -imino]- ethyl}-O-methyl-2-isourea,

l- [2- 4-methyl-l-piperazino) -ethyl] -S-methyl-2- isothiourea,

l-[2-(4-ethyl-l-piperazino) -ethyl] -S-methyl-2-isothiourea,

1-{2-[ l-N,N-(3-aza-3-methyl-1,6-hexylene)-imino] ethyl}-S-methyl-2-isothiourea,

1-{2-[1-N,N-(4-aza-4-methyl-1,7-heptylene)-imino]- ethyl}-S-methyl-2-isothiourea are specific compounds of such group.

A cyanamidino group, which forms a cyanoguanidino group with the amino group of a [l-N,N-(N-R -azaalkylene)-imino]-lower alkyl-amine, in which R and aza-alkylene have the previously given meaning, may be converted into an .amidino group by ammonolysis or aminolysis. This reaction may be carried out by treatment with ammonia, as well as with an ammonium salt, eg. ammonium chloride, ammonium nitrate, ammonium sulfate and the like, whereby these salts may also promote ammonolysis with ammonia itself. Aminolysis of the starting materials may be carried out by treatment with an amine, such as an N-lower alkylamine, and N- substituted guanidine derivatives may be obtained.

In the ammonolysis procedure of a cyanoguanidino to a guanidlino derivative as described hereinabove, a biguanido group may be formed intermediarily, which, upon further treatment with the ammonolysis reagent, may be converted to the desired guanidino group. Such biguanido derivatives may be accessible through different procedures (as will be shown hereinbelow) and are, therefore, also useful as starting materials for the formation of the desired guanidino compounds by treatment with one of the ammonolysis or aminolysis reagents described hereinbefore.

A cyano-guanidino derivative, as mentioned hereinabove, may also be converted into the desired guanidino compound, by reductive cleavage of the cyano group. Such cleavage may be carried out, for example, by electrolytic reduction on a cathode, such as, for example, a lead cathode.

The cyanoguanidino derivatives of the formula:

N-R [l-.\l,N-(N R -aza-alkylcnel-iminollowcr alkyhN- 0 R5 Nil-GEN in which R R R and aza-alkylene have the previously given meaning, and their salts, which compounds represent the starting materials used in the above ammonolysis, aminolysis or reduction procedure, may be prepared, for example, by treatment of the S-lower alkylcyano-isothioureas of the formula:

(lower alkyl) -N NH- 0 EN in which lower alkyl contains from one to seven carbon atoms, each of the symbols m and m; stands for one of the numbers 1 and 2, and A represents alkylene containing from two to three carbon atoms and separating the cyanoguanidino group from the imino-nitrogen atom 17 by from two to three carbon atoms, and salts thereof. This group may be represented by 1- [2- 4-methyll -piperazino) ethyl] -3-cyano-guanidine,

1- 2- (4-ethyl-l-piperazino) -ethyl 3 -3-cyano-guanidine,

1-{2-[ l-N,N- 4-aza-4-methyl- 1 ,7-heptylene) -imino] ethyl}-3-cyanoguanidine and the like.

Since the above-described cyano-guanidine derivatives are obtained by ammonolysis or aminolysis from S-lower alkyl-cyanoisothiourea compounds having the above-given formula, these cyanoisothiourea compounds may, therefore, directly serve as starting materials for the preparation of the guanidino compounds of this invention. The annnonolysis or aminolysis of the cyanoisothiourea compounds to the latter is carried out by treatment with ammonia of an amine in the presence of an anion of a strong acid, such as a halide, a nitrate, a sulfate ion and the like, for example, by the respective ammonium salts.

The S-lower alkyl-cyanoisothiourea derivatives of the above formula or salts thereof may be obtained, for example, by treating a [l-N,N-)N,R -aza-alkylene)-imino]- lower alkyI-isothiocyanate, in which R, and aza-alkylene have the previously given meaning, with an alkali metal, e.g. sodium and the like cyanamide and alkylating a resulting l {[1 N,N (N-R -aza-alkylene)-imino]-lovver alkyl}-3-cyano-2-thiourea, 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 dilower alkyl sulfate, eg. dimethyl sulfate, cliethyl sulfate and the like, as previously shown in the preparation of S-lower alkyl-isothioureas used as starting materials in the ammonolysis to the desired guanidines.

The above-described S-lower alkyl-cyanoisothiourea derivatives used as starting materials are new and are intended to be included within the scope of this invention. A preferred group of such intermediate-s are the compounds of the formula:

in which lower alkyl contains from one to seven carbon atoms, each of the symbols m and m stands for one of the numbers 1 and 2, and A stands for alkylene containing from two to three carbon atoms and separating the cyano-isothiourea group from the imino-nitrogen atom by from two to three carbon atoms, or salts thereof, which may be represented by 1-cyano-S-methyl-3-[2-(4-methyll-piperazine)-ethyl -2-isothiourea, l-cyano-3- {2-(4-ethyl- 1 piperazino) ethyl]-S-methyl-2-isothiourea, l-cyano-S- methyl 3 {2 [1 N,N-(3-aza-3-methyl-l,6-hexylene)- imino] ethyl} 2 i-sothiourea, l-cyano-S-methyl-3-{2-[1- N,N (4-aza-4-methyll ,7-heptylene) imino] -ethyl}-2-isothiourea and the like.

As has been shown, the .ammonolysis of cyanoguanidine compounds may give rise to the formation of biguanido compounds of the formula:

N-R4 NH [l-N,N-(N-Ri-aza-a.lkylene) -in1ino]-lowcr alkyl-N%NH d--NII,

6 in which R R R and aza-alkylene have the previously given meaning, and salts thereof. These compounds may also be prepared, for example, by reacting a {l-N,N- (N R aza alkylene) -imino]-lower alkyl-amine compound, in which R, and aza-alkylene have the previously given meaning, with dicyanodiamide, preferably in the presence of a complex metal-forming salt, e.g. copper sulfate and the like. A resulting biguanido complex metal salt, such as the copper complex salt thereof, may be liberated to form the free compound by treatment with an acid, such as a mineral acid, eg. sulfuric acid and 18 the like, to form the free compound. As has been shown hereinbefore, 'ammonolysis and aminolysis of these biguanido derivatives give rise to the formation of the desired [1 N,N (N R -aza-alkylene)-imino]-lower alkylguanidines of this invention.

As mentioned hereinbefore, ammonolysis with ammonia or ammonia-furnishing reagents may be replaced by aminolysis with amines, particularly N-lower alkyl-amines, e.g. N-methylamine, N-ethylarnine and the like. Such aminolysis reactions provide for the formation of substituted guanidino groups mentioned hereinabove.

In addition to ammonolysis and aminolysis reactions, the guanidino compounds may also be obtained, for example, by hydrolysis of a ll-N,N-(N-R -aza-alkylene)- iminoJ-lower alkylamine, in which R and azaalkylene have the previously given meaning, and in which the amino group contains a substituent capable of being hydrolyzed to an amidino group. For example, such substituent forms together with the amino group of the [1-N,N-(N-R aza-all(ylene)-imino]-lower alkyhamine a cyan-ourea or a cyanothiourea group of the formulae C(=NR )-N=C=O and -C(=NR.,)N=C=S, respectively, in which R, has the previously given meaning, but stands primarily for hydrogen. Compounds containing such groups yield upon treatment with a hydrolytic reagent, particularly with dilute aqueous mineral acid, e.g. aqueous sulfuric acid and the like, the desired guanidino compounds. In hydrolysis, the desired guanidino derivative may be formed simultaneously with a biuret derivative as the by-product.

A cyanourea or cyanothiourea compound of the formula:

in Which R R R and aza alkylene have the above-given meaning, and X represents oxygen or sulfur, or salts thereof, which compounds may be converted to the desired guanidino compounds by hydrolysis, may be obtained, for example, by reacting a [1-N,N-(N-R -aza-alkylene)- iminol-lower alkyl-cyanamide with an ammonium or a metal cyanate 0r thiocyanate, particularly an alkali metal, eg. sodium or potassium cyanate or thiocyanate, in a neutral medium, particularly in the presence of Water.

The starting materials used in the above reaction are new and are intended to be included within the scope of the invention. Preferred cyanourea and thiocyanourea compounds are those of the formula:

(c nt es, N=O=X in which lower alkyl contains from one to seven carbon atoms, each of the symbols m, and m stands for one of the numbers 1 and 2, and A represents alkylene containing from two to three carbon atoms and separating the cyanourea and thiocyanourea group, respectively, by from two to three carbon atoms, or salts thereof; this group may be represented by l- [2-( 4-methyll -piperazino -ethyl -cyanourea,

l- [2- (4-ethyll -piperazino) -ethyl] -cyanourea,

1-{2- l -N, N- 4aza-4-methyll ,7-heptylene -imino] -ethy1}-cyanourea,

1- I 2- 4-methyll-pipcrazino -ethyl -cyanothiourea,

l- 2-( 4-ethyll -pipcrazino -cthyl cyanothiou rea,

l-{2-[ I-N,N- 3-aza-3-methyll ,6-hexylene -imino] -ethyi}-cyanothiourea,

l-{2-{ l-N,N- (4-aza-4-methyll ,7-heptylene)-imino] -cthyl}-cyanothiourea and the like.

Apart from [1-N,N-(N-R -aza-alkylene)-imino]-lower alkyl-amines, in which the amino group is substituted by a carbon atom carrying at least one nitrogen atom, other [1-N,N-(N-R -aza-alkylene)-imino]-lower alkyl-amines, in which the amino group carries a substituent convertible into an amidino group, may be useful for a conversion into the desired [1-N,N-(N-R -aza-alkylene)-imino]-lower alkyl-guanidines, in which R, and aza-alkylene have the above-given meaning. In such a conversion intermediates may be formed, which may have the previously given characteristics, i.e. the amino group carries a carbon with at least one nitrogen atom attached thereto. Such groups are ester groups formed by carboxyl, thionocarboxyl, thiolocarboxyl or dithiocarboxy groups with lower alkanols, as well as halogeno-carbonyl or halogeno-thionocarbonyl groups, in which halogeno represents primarily chloro.

Particularly useful starting materials are, for example, the reactive functional derivatives of carbarnic and thiocarbamic acids, having the formula:

in which R R and aza-alkylene have the previously given meaning, and X represents oxygen or sulfur, or salts thereof. As shown hereinabove, esters, for example, lower alkyl, e.g. methyl, ethyl and the like, esters or halides, e.g. chlorides and the like, of the above-given acids yield upon ammonolysis the corresponding urea and thiourea derivatives. However, if, for example, the ammonolysis 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 guan'idino compound, an N-[l-N,N-(N-R,- iaza-alkylene)-imino]-lower alkyl carbamic acid ester may be converted directly into the desired guanidino compound. Or, an ester of an N-[1-N,N-(N-R -a2a-alkylene)-imino]-lower alkyl thiocarbamic acid derivative may be subjected to ammonolysis to yield directly the desired guanidino compound, if such ammonolysis is carried out, for example, in the presence of a desulfurizing reagent, 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 as the starting materials may be prepared according to procedures used for the manufacture of known analogs. For example, upon treatment of a [lN,N-(N-R,-aza-alkylene)-imino]-lower alkylamine, in which R, and azaalkylene have the previously given meaning, with phosgene or thiophosgene, which reagents may be used in a slight excess over the amines, the [l-N,N-(N-R -azaalkylene)-imino]-lower alkyl-isocyanate and [l-N,N-(N R -aza-alkylene)-imino]-lower alkyl-isothiocyanatc, respectively, may be formed. Such cyanate and isothiocyanate 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 lower alkanol, e.g. methanol, ethanol and the like, or to a thiolester, for example, by treatment with a mercaptan, such as a lower alkyl-mercaptan, e.g. methylmercaptan, ethylmercaptan and the like. The above derivatives may also be obtained by reacting a [l-N,N-(N-R -aza-alkylene)- imino]-lower alkyl-amine with a lower alkyl carbonic acid ester, or, particularly, with a lower alkyl dithiocarbonic acid ester, as well as with a lower alkyl ester of a halogeno-formic acid, such as chloroformic acid, or, primarily, of a halogeno-thioforrnic acid, such as chloro-thiOformic acid.

Or, a salt of a l-N,N-(N-R -aza-alkylene)imino1- lower alkyl-amine, particularly a hydrohalide, e.g. hydrochloride and the like, thereof, when reacted with phosgene or thiophosgene at an elevated temperature, preferably in a closed vessel, may yield the desired N-[l-,N, N-(N-R -aza-alkylene)iminol-lower alkane carbamic acid 20 chloride and N-[l-N,N-(N-R -aza-alkylene)-imino]- lower alkane thiocarbamic acid chloride.

The reactive derivatives of the carbamic and thiocarbamic acids of the above formula are new starting materials and are intended to be included within the scope of the invention. Particularly useful are the compounds of the formula:

( 2) in -OH:

(lower alkyl)N (C H .,,,G 112 in which lower alkyl contains from one to seven carbon atoms, each of the symbols in, and m stands for one of the numbers 1 and 2, A represents alkylene containing from two to three carbon atoms and separating the carbamyl and thiocarb-amyl group, respectively, from the imino-nitrogen atom by from two to three carbon atoms, and Y represents lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or halogeno, particularly chloro, or salts thereof. Very useful intermediates are, for example, methyl N-[2-(4-methyl-l-piperazino)-ethyl]-carbamate, ethyl N-["-(4-ethyl-l-piperazino)-ethyl1-carbamate, methyl N-[2-(4-rnethyl-1-piperazino)-ethyl]-thiocarbamate, N- 2-(4-mcthyll-piperazino)ethyl1-carbamic acid chloride and the like.

The i1-N,N-(N-R -aza-alkylene)-imino]-lower alkylamines, in which R and aza-alkylene have the previously given meaning, which are used in many of the above instances for the manufacture of the above-described starting materials, may be prepared, for example, according to the previously shown procedure.

A further procedure for the preparation of the compounds of this invention comprises converting a []-N,N- (N-R aZa-alkylene)imino]-lower alkane carboxylic acid guanide, in which R; and aza-alkylcne have the previously given meaning, or in a guanidino-lower alkane carboxylic cid N,N-(N-R -aza-alkylene)-imide, in which R and aza-alkylene have the previously given meaning, or a salt thereof, the carbonyl group of the amide or imido portion to a methylene group, and, if desired, carrying out the optional steps.

The reduction of the carbonyl portion of the amide or irnido groups may be carried out, for example, by treatment with an aluminum hydride capable of reducing such carbonyl group, particularly with an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g. magnesium aluminum hydride and the like, or aluminum hydride. If necessary, activators such as, for example, aluminum chloride, may be used together with such hydride reducing reagent. The reduction with these reagents is preferably performed in the presence of a solvent, particularly of an ether, such as a di-lower alkyl ether, e.g. diethyl ether, dipropyi ether and the like, a lower alkyl carbocyclic aryl ether, e.g. anisole and the like, a di-carbocyclic aryl ether, e.g. diphenyl ether and the like, or a cyclic ether, e.g. tetrahydrofuran, p-dioxane and the like, and, if desired, at an elevated temperature and/or in the atmosphere of an inert gas, e.g. nitrogen.

Removal of the oxygen atom of a carbonyl group in an amide compound may also be accomplished by treatment with hydrogen in the presence of certain catalysts, such as, for example, a copper-chromium catalyst and the like; hydrogenation may be carried out in the presence of an inert solvent and, if necessary, under increased pressure.

The desired conversion may also be carried out by electrolytically reducing the amide or imido derivatives on a cathode of a high overpotential such as, for example, mercury, lead amalgam, lead cathode and the like. The catholyte used in such a reduction is preferably a mixture of water, sulfuric acid and a lower alkanoic acid, e.g. acetic, propionic acid and the like or any equivalent and suitable medium. A platinum, carbon, lead anode and the like may be used; the anolyte is preferably sulfuric acid or any other suitable anolyte.

The starting materials used in the above reduction procedure may be prepared, for example, by treating a reactive functional derivative of a [1-N,N-(N-R,-azaalkylene)-imino]-lower alkane carboxylic acid, in which R and aza-alkylene have the previously given meaning, or of a guanidino-lower alkane carboxylic acid with a guanidine or with a 1-N,N-(N-R -aza-alkylene)-imine, in which R, and aza-alkylene have the previously given meaning, respectively, to form the desired amido or imido compounds. Reactive derivatives of carboxylic acids are, for example, esters, such as lower alkyl, e.g. methyl, ethyl and the like, esters, or activated esters, which are particularly useful for the formation of amide bonds, such as esters with reactive mcrcaptan compounds, e.g. mercapto-acetic acid and the like, or with reactive hydroxy compounds, e.g. hydroxy-acetonitrile and the like, These esters may be prepared according to procedures which are known for the manufacture of analogous esters. Other reactive functional derivatives of acids are, for example, the acid addition salts of acid halides, particularly the hydrochloride of an acid chloride, which may be prepared according to standard methods.

The reaction of the above-mentioned reactive functional derivatives of carboxylic acids with the amino compounds may be carried out, for example, by treating a salt of an acid halide, particularly the hydrochloride of an acid chloride with the amine, preferably in a polar, but non-hydroxylated solvent, such as, for example, N,N- dimethylformamide, diethyleneglycol dimethylether, pdioxane, tetrahydrofuran and the like.

A modification of the above procedure comprises converting in a [l-N,N-(N-R -aza-alkylene)-imino]-lower alkane thiocarboxylic acid guanide, in which R, and azaalkylene have the previously given meaning, or in a guanidino-lower alkane thiocarboxylic acid N,N-(N-R aza-alkylene)-imide, in which R and aza-alkylene have the previously given meaning, or a salt thereof, the thiocarbonyl group of the thioamido or thioimido portion into a methylene group, and, if desired, carrying out the 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 catalyst, such as Raney nickel, in a lower alkanol, e.g. methanol, ethanol and the like, and if desired, in the presence of hydrogen, or with an electrolytic reduction procedure, for example, according to the method outlined hereinabove for the reduction of the amides.

The thioamides and thio-imides, used as the starting materials in this modification may be prepared, for example, irom the corresponding amides and imides previously mentioned, for example, by treatment with phosphorous trisuliide, phosphorus trisulfide, phosphorus pentasulfide and the like. A modification may consist in electrolytically reducing the amide in the presence of an alkali metal sulfide, e.g. sodium sulfide and the like, thereby forming the thioamide or the thioimide as a nonisolated intermediate.

The starting materials used in the above reaction are new and are intended to be included within the scope of the present invention. Particularly useful as intermediates are the compounds of the formulae:

ii Gua -om NH:

and

Gua -0H2 NH (lower alkyD-N /NCA'NIIC (CHsh-ihOHn NH:

in which lower alkyl contains from one to seven carbon atoms, each of the symbols m; and m represents one of the numbers 1 and 2, A stands for alkylene containing from one to two carbon atoms and separating the carbonyl group from the imino-nitrogen atom and the guanidino group, respectively, by from one to two carbon atoms and X stands for oxygen or sulfur, or salts thereof. Specific compounds of this group are, for example, (4- methyl-l-piperazino)-acetic acid guanide, l-(guanidinoacetyl} 4-methyl-piperazine and the like.

Another method useful for the preparation of the above-described guanidino compounds comprises replacing in a [l-N,N-(N-R -aza-alkylene)-imino]-lower alkylguanidine, in which R, and aza-alkylene have the previously given meaning, and in which at least one of the two carbon atoms of the aza-alkylene portion, which are located adjacent to the imino-nitrogen atom, carries a doubly bound oxygen or sulfur atom, or a salt thereof, such oxygen or sulfur atom by two hydrogen atoms, and, if desired, carrying out the optional steps.

The above-mentioned oxygen or sulfur atoms form together with the carbon atom, to which they are at tached, and with the imino-nitrogen atom of the l-N,N- (N-R -aza-alkylene)-itnino portion imido or thio-imido groups. Such groups may be converted into the desired methyleneimino group by the previously described procedures; for example, the oxygen atom of an imido group ings may be replaced by two hydrogen atoms by treatrnent with an aluminum hydride, such as lithium aluminum hydride, or the sulfur atom of a thioamide grouping may be exchanged for two hydrogen atoms by desult'urization with a freshly prepared hydrogenation catalyst, such as Raney nickel. These reactions are carried out as previously shown; in case two of the same or of different imide-oxygen and/or thio-imide-sulfur atoms are present, such atoms may be replaced simultaneously or in succession.

The starting material used in this modification may be prepared, for example, by introducing into an N,N-(N- R -aza-alkylene)-imine, 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 doublybound oxygen atom, an amino-lower alkyl radical, which may be accomplished, for example, by reacting an alkali metal, e.g. lithium, sodium and the like, salt of the N,N- (N-R -aza-alkylene)-imine, 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 reducing in a resulting [l-N,N-(N-R -aza-alkylene)- irninoJ-lower alkano-nitrile, 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, the nitrile group to a methyleneamino group, which may be accomplished, for example, by treatment with a hydride reducing agent, such as an alkali metal aluminum hydride, e.g. lithium aluminum hydride and the like. The N,N-(N-R -aza-alkylene)-imine, 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. acrylonitrile and the like, to yield the [l-N,N (N-R -aza-alkylene)-imino1-lower alkano-nitn'le, 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, and which is then reduced to the desired amino compound as shown hereinabove. The resulting [1-N,N-(N-R -aza-alkylenel-iminoHower alky l-amine, in which at least one of the two carbon atoms of the aza-alkylene radical, which are located adjacent to the imine-nitrogen atom, carries a doubly-bound oxygen atom, may then be converted to the corresponding guanidine compound, for example, by treatment with a salt of an S-lower alkyl-isothiourea, such as the S-methylisothiourea sulfate.

In a resulting [l-N,N-(N-R -aza-alkylene)-imino]- lower a lkyl-guanidine compound, in which at least one of the carbon atoms of the aza-alkylene portion, which are located adjacent to the imine-nitrogen atom, carries a doubly-bound oxygen atom, such oxygen may be exchanged by sulfur, for example, by treatment of the above guanidino compound with phosphorus trisulfide, phosphorus pentasulfide and the like as shown hercinbefore.

The above used starting materials are new and are intended to be included within the scope of the present invention. A preferred groupof such intermediates may be represented by the compounds of the formula:

(lower alkyl) -N in which lower alkyl contains from one to seven carbon atoms, each of the symbols m and m stands for one of the numbers 1 and 2, A represents alkylene containing from two to three carbon atoms and separating the guanidino group from the imino and thio-imido group, respectively, by from two to three carbon atoms, and at least one of the groups X and X represents oxygen or sulfur, and the other stands for two hydrogen atoms or a doublybound oxygen or sulfur atom, or salts thereof. These compounds may be represented by 2-(4-methyl-2- oxo l piperazino) ethyl-guanidine, 2[1-N,N-(3-aza-3- methyl-l-oxo-1,6-hexylene)-imino]-ethyl-guanidine, 2-[1- N,N-(4 aza-4-methyl l oxo 1,7 heptylene) imino1- 4 ethyl-guanidine, 2 (2,6 dioxo 4 methyl-l-piperazino)- ethyl guanidine, 2 (4 methyl 2 oxo 6 thiono lpiperazino)-ethyl-guanidine and the like.

A doubly bound oxygen or sulfur atom may also be attachecl to at least one of the carbon atoms of the azaalkylene portion in a [l-N,N-(N-R -aza-alkylene)-imino]- lower alkyl-guanidine, in which R and aza-alkylene have the previously given meaning, or a salt thereof, which carbon atoms are located adjacent to the aza-nitrogen atom; such oxygen or sulfur atoms may be replaced by 0 two hydrogen atoms according to previously shown procedures, e.g. reduction, desulfurization and the like, to form the desired [1 -N.N-(N-R,-aza-alkylene) imino]- lower alkyl-guanidines of this invention. The intermediates used in the foreging procedure are prepared, for example, according to previously described procedures, for example, by introducing the guanidino-lower alkyl chain into a l-N,N-(N-R -aza-alkylene)-imine compound, in which at elast one of the carbon atoms of the azaalkylene portion, which are located adjacent to the azanitrogen atoms, carries a doubly-bound oxygen or sulfur atom; the introduction may be carried out according to previously described methods.

The above starting materials are new and are intended to be included within the scope of the present invention. A preferred group of such intermediates have the formula:

in which lower alkyl contains from one to seven carbon atoms, each of the symbols m and m stands for one of the numbers 1 and 2, A represents alkylene containing from two to three carbon atoms and separating the guanidino group from the imino and thioimido group, respectively, by from two to three carbon atoms, and at least one of the groups X and X" represents oxygen or sulfur, and the other stands for two hydrogen atoms or a doublybound oxygen or sulfur atom, or salts thereof. These compounds may be represented, for example, by 2-(4- methyl-3-oxo-l-piperazino)-ethyl guanidine, 2-(3,5-dioxo- 4-methyl-1-piperazino)-ethyl-guanidine, 2 [1 N,N (3- aza-3-methy1-4-oxo-1,6-hexylene)-' ino] ethyl guanidine and the like.

A combination of the above-shown modifications may also be carried out. For example, upon treatment of a [1-N,N-(N-R -aza alkylene) imino] lower alkyl carboxylic acid guanide or of a guanidino-lower alkyl-carboxylic acid N,N-(N-R -ana-alkylene)-imide, in which R and aaa-alkylene have the previously given meaning, and in which at least one of the carbon atoms of the aza-alkylene portion adjacent to the iminoor irnidonitrogen atom contains a doubly-bound oxygen or sulfur atom, with one of the reducing reagents previously de scribed, the desired [l-N,N-(N-R -aza-alkylene)-imino]- lower alkyl-guanidines of this invention can be formed. The starting 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 N,N-(N-R -aZa-alkylene)-i mine, in which R and aza-alkylene have the above-given meaning, or a salt thereof, with a reactive ester of aguanidino-lower alkanol, in which the lower alkanol portion contains at least two carbon atoms, which separate the hydroxyl from the guanidino group by at least two carbon atoms, or a salt thereof, and, if desired, carrying out the optional steps.

A reactive ester of a guanidino-lower alkanol is particularly an ester with a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with a strong organic ocid, particularly an organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-tolene sulfonic acid and the like. These esters are, therefore, primarily guanidino-lower alkyl halides, e.g. chlorides, bromides and the like, or salts thereof with hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, which, upon reaction with the N-N-(N-R,-aza-alkylene)-'mines. or salts thereof, yield the desired [l-N,N-(N-R -aza-alkylene imino] lower alkyl-guanidines.

This reaction may be carried out, for example, by treating the N,N-(N R 12a alkylene)-imine, in which R, and aza-alkylene have the above-given meaning, or a salt thereof, with the ester of the guanidino-lower alkanol or a salt thereof. A salt of the N,N-(N-R -a2a-alkylene)- imine is particularly an alkali metal, e.g. sodium, potassium and the like, salt, which may be prepared, for example, by treatment with an alkali metal, e.g. sodium, potassium and the like, or an alkali metal hydride or amide, e.g. sodium or potassium hydride or amide and the like, in the presence of an inert solvent, such as, for example, toluene, p-dioxane and the like. Such salt is then treated with the reactive ester of the guanidinodower alkanol. Or, the reaction of the N,N-(N-R -aza-alkylene)-imine with the latter may be performed in the presence of a saltforming reagent, such as, for example, an alkali metal, eg. sodium or potassium, in liquid amonnia, or an alkali metal, e.g. sodium or potassium, carbonate. The reactive ester of a guanidino-lower alkanol may be used in the form of a salt thereof, or as the free compound, which may also be liberated at the site of the reaction by treating the salt with the necessary amount of an alkaline reagent. The reaction is preferably carried out in the presence of a solvent, which is selected depending on the properties of the reagents; a lower alkanol, e.g. methanol, ethanol and the like, may be used with the salt of an ester of the guanidino-lower alkanol, whereas the free base may be reacted in the presence of a non-hydroxylic solvent, such as, for example, an ether, e.g. p-dioxane and the like, or a hydrocarbon, such as a monocyclic carbo cyclic aryl hydrocarbon, e.g. benzene, toluene and the like. It may be performed under cooling, or more preferably, at an elevated temperature, if desired, in a closed vessel under pressure, or in the atmosphere of an inert gas.

The reactive esters of guanidino-lower alkanols, in which the lower alkanol portion contains at least two carbon atoms and separates the guanidino group from the hydroxyl group by at least two carbon atoms, or salts thereof, which reagents are used as the starting materials in the above reaction, may be prepared by esterifying guanidino-lower alkanols. For example, a guanidinolower alkanol may be converted into a guanidino-lower alkyl halide by treatment with a ithionyl halide, particularly thionyl chloride; such reaction may be carried out in the presence of an inert solvent, for example, a hydrocarbon, such as a monoeyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, or in any other suitable solvent. Such procedure yields preferably the acid addition salt with a hydrohalic, e.g. hydrochloric, hydrobromic acid and the like. A guanidinodower alkyl sulfonate, particularly a p-toluene-sulfon-ate, may be prepared, for example, by treatment of the guanidino-lower alkanol with a sulfonyl halide, such as p-toluene-sulfonyl chloride, in the presence of a solvent, such as pyridine and the like.

A modification of the above procedure comprises treating a reactive ester of a [l-N,N-(N-R -aza-alkylene)- imino]-lower alkanol, in which R, and aza-alkylene has the above-given meaning, or a salt thereof with a guanidine, and, if desired, carrying out the optional steps.

A reactive ester of a [l-N,N-(N-R -aza-aikylene)- iminoJ-lower alkanol is, as has been hereinabove shown, formed with a strong inorganic or organic acid; the {l- N,N-(N-R,-aza-alkylene)-imino]-lower alkyl halides, e.g. chlorides, bromides and the like, and the [l-N,N-(N-R aza-alkylene)-imin] -lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. p-toluene sulfonates, are the preferred reagents. The guanidines, such as guanidine itself, as well as guanidines with additional substituents, which do not interfere with the reaction, may also be used in the form of their salts. The reaction is performed along the general procedure outlined hereinbefore.

The starting material, i.e. the reactive esters of a [l- N,N-(N-R -aza-alkylene)-imino]-l0wer alkanol, in which R, and aza-alkylene have the previously given meaning, may be prepared according to known methods, used for analogous compounds. For example, an N,N-(N-R -azaalkylene)-iimine may be reacted with a halogenohydrin, such as a chlorohydrin, e.g. ethylenechlorohydrin and the like, or a bromolhydrin, e.g. ethylenebromohydrin and the like, or with an epoxide, e.g. ethylene oxide and the like, and the resulting [l N,N-(N-R -aza-alkyiene)- imino]-lower alkanol may then be converted to the halide by treatment with a thionyl halide, e.g. thionyl chloride and the like.

Compounds of the present invention may also be manufactured by converting in a [l-N,N-(N-R -aza-alkylene)- imino1-lower alkyl-guanidine, in which aza-alkylene has the previously given meaning, and R stands for a substituent capable of being converted into R having the previously given meaning, or a salt thereof, the radical R into the desired group R and, if desired, carrying out the optional steps.

The radical R 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 representing the group R R may also stand for the acyl radical of a thionocarboxylic acid, such as, for ex* ample, a lower alkane thionocarboxylic acid, e.g. thiono- 26 acetic, thionopropionic acid and the like, or any other suitable thionocarboxylic acid. The carbonyl group and the thiocarbonyl group of the acyl radical form together with the aza-nitrogen atom of the aza-alkylene radical in [l-N,N-(N-R -aza-alkylene)-imino] -lower alkyl-guanidine compound an imido and a tbio-imido group, respectively. The oxygen and sulfur atoms of such groups may, therefore, be replaced by two hydrogen atoms according to previously described procedures, such as, for example, by treatment with an aluminum hydride, e.g. lithium aluminum hydride and the like, by hydrogenation in the presence of certain catalysts, e.g. a copper-chromium catalyst and the like, or by electrolytic reduction, and by desulfurization, for example, in the presence of a metal catalyst, e.g. Raney nickel and the like, respectively; these procedures have been described in detail hereinbefore.

The starting materials used in the above procedure may be prepared according to one of the previously described methods.

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:

NR4 [l-N,N-(N-Ri-aza alkylenel-iminollower alkyl-NC Rs NH-Rs may be acylated to form compounds of the formula:

N-Ri [1N,N-(N R i-aza-alkylene)-imincl-lower a1ky1-l\ C\ R3 in which formulae R R R R and aza-alkylene have the previously given meaning, and R represents an acyl radical. Such reaction may be carried out, for example, by treating the guanidine compound with the reactive derivative of a carboxylic acid, for example, with the halide, e.g. chloride and the like, or the anhydride thereof. It may be performed in the presence of an inert solvent, for example, in a hydrocarbon, such as a lower alkane, e.g. pentane, hexane and the like, or a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene, xylene and the like, or in a tertiary organic base, such as a liquid pyridine compound, e.g. pyridine, collidine and the like. Acylation may also be achieved in the absence of a solvent, for example, by heating the guanidine compound or a salt thereof with the acylating reagent, for example, acetic acid anhydride in a sealed tube.

The new guanidine compounds may be obtained in the form of the free compounds or as the salts thereof. A salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reagent, such as aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or a strong quaternary ammonium anion (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 inorganic or organic acid, such as one of those outlined hereinabove; such reaction may be carried out advantageously in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, an ether, e.g. diethyle'ther, p-dioxane and the like, a lower alkyl lower alkanoate, e.g. ethyl acetate and the like, or a mixture of such solvents, and isolating the desired salt. Salts of the polybasic compounds of this invention 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 part in the salt formation.

The new guanidine compounds or salts thereof may also form 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 sulfate and the like, lower alkyl lower alkane sulfonates. e. g. methyl or ethyl methane or ethane sulfonate, or lower alkyl m-onocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate, and the like, as well as the corresponding quaternary ammonium hydroxides and the salts, which may be formed from the quaternary ammonium hydroxides by the reaction with inorganic acids other than the 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 obtained by reacting a free base or a salt thereof with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl chloride, bromide or iodide and the like, a di-lower alkyl-sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane or ethane sulfonate and the like, or a lower alkyl monocyclic carbocyclie aryl sulfonate, e.g. methyl p-toluene sulfonate and the like. The quaternizing reac tion may be performed in the presence of a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, ethyl methyl ketone and the like, or an organic acid amide, e.g. formamide, N,N-dimethylforrnamide and the like. Resulting quaternary ammonium compounds may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting resulting quaternary ammonium halides with silver oxide, by treating quaternary ammonium sulfates with barium hydroxide, or quaternary ammonium salts with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be formed therapeutically suitable quaternary ammonium salts by treating the quaternary ammonium hydroxide with acids, for example, with those outlined hereinbeforc as being useful for the preparation of acid addition salts.

The invention also comprises any modification of the general process wherein a compound obtainable 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 intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No. 848,559, tiled October 26, 1959, now abandoned, which in turn is a continuation-in-part application of my application Serial No. 816,669, filed May 29, 1959, now abandoned, which in turn is a continuation-in part application of my application Serial No. 813,349, filed May 15, 1959, now abandoned.

The following examples illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees oentigrade.

Example 1 A solution of 3 g. of 2-(4-methyl-1-pipera2ino)-cthylamine and 2.92 g. of S-methyl-isothiourea sulfate in 5 ml. of Water is refluxed for 4 hours. The solid, which separates on concentration, is recrystallized from a mixture of ethanol and water to yield the desired 2-(4-methyl-1- piperazino)-ethyl-guanidine sulfate, M.P. 191-200 (with decomposition). The resulting salt contains two mols of the base per one mol of sulfuric acid.

Other therapeutically acceptable acid addition salts of 2-(4-methyl-l-piperazino)-ethyl-guanidine may be prepared as follows: The sulfate may be dissolved in a minimum amount of water, the solution filtered through a column containing a strong quaternary ammonium (hydroxyl ion) exchange resin, and the solution of the free 228 base may be treated with hydrochloric acid and a 2-(4- methyl-l-piperazino) ethyl-guanidine polyhydrochloride may be obtained.

The starting material may be prepared as follows: 50.4 g. of chloroaeetonitrile is added dropwise to a solution of 133 g. of 4-mcthyl-piperazine in ml. of ethanol. The mixture is refluxed and stirred for two hours and allowed to stand overnight. The solution is concentrated under reduced pressure, the residue is treated with 270 ml. of 30 percent aqueous sodium hydroxide while cooling and then extracted with ether. The ether phase is dried over solid sodium hydroxide, the solvent is removed and the residue fractionated to yield the 4-mcthyl-l-piperazinoacetonitrile, Bl. -l25/l2 mm. The product solidifies upon standing, M.P. 5356.

A solution of 50 of 4-methyl-l-piperazino-acetonitrile in 403 ml. of anhydrous ether is added to 1000 ml. of anhydrous ether containing 19 g. of lithium aluminum hydride while cooling and stirring. The reaction mixture is then reliuxed for 6 hours, allowed to stand overnight and decomposed by successive addition of 17 ml. of water, 20 ml. of 20 percent aqueous sodium hydroxide and 53 ml. of water. The mixture is filtered, the filtrate is evaporated and the residue is distilled to yield the desired 2-(4-methyll-piperazino)-ethylamine, Bl. 9092/l6 mm.

Other 2-(4-lower alkyl-l-piperazino)-ethyl-guanidines and salts thereof may be prepared according to the above procedure by selecting the appropriate starting materials, which may be obtained, for example, by using the above procedure. Such compounds are, for example, 2-(4npropyl-lpiperazino) ethyl-guanidine, 2(4-isopropyl-lpiperazino) cthyl--guanidine, 2-(4-n-hutyl-l-piperazino)- ethyl-guanidine, 2-(4-isobutyl-1-pipcrazino)-ethyl-guanidine. 2-(4-secondary butyl-l-piperazino)-ethyl-guanidine, 2-(4-tertiary hutyl-l-piperazino)-ethyl-guanidine, 2-(4npentyl-lpiperazino) -ethyl-guanidine, 2-(4-n-hexyl-1-piperazino) ethyl-guanidine, 2-[4-nheptyll-piperazino)- ethyl-guanidine and the like; these compounds are isolated preferably in the form of acid addition, particularly of therapeutically 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-piperazino)ethylamine and 2.78 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. The reaction mixture is concentrated under reduced pressure and the 2-(4-ethyl-l-piperazino)-ethyl-guanidine sulfate is recrystallized from a mixture of ethanol and diethyl ether, M.P. 201-2tl3.

The starting material may be prepared by treating 13.2 g. of l-ethylpipcrazine with 13.2 g. of chloroacetonitrile in the presence of 37.1 g. of sodium carbonate in ml. of toluene and reducing 17.0 g. of the resulting (4- ethyl-l-pipera2ino)-acetonitrile (13.1. l171l8/13 mm, yield: 19.4 g.) with 6.33 g. of lithium aluminum hydride in diethyl ether to the desired 2(4-ethyl-l-pip-erazino)- ethylamine (9798/13 1nm.; yield: 9.7 g); the above reactions are carried out as shown in Example 1.

Example 3 A solution of 3-( l'methyl-l-piperazino)-propylamine and 1.77 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. The reaction mixture is concentrated under reduced pressure and the residue is recrystallized from a mixture of ethanol and water. The 3-(4-rnethyl-l-pipcrazino)propyl-guanidine sulfate melts at 99100.

The starting material may be prepared by reacting 1- methyl-piperazine with acrylonitrile in the presence of benzyltrimethylammonium hydroxide and reducing the csulting S-( i-methyl-l pipcrazino)-propionitrile with lithium aluminum hydride to the desired 3-(4methyl-l-piperazino)-propylaminc.

29 Example 4 To a solution of 2.34 g. of 2-(4-methyl-l-piperazino)- ethylguanidine sulfate in 10 ml. of methanol is added 3 ml. of 8 N aqueous hydrochloric acid; the mixture is heated to form a complete solution. Upon cooling and filtering, 2.96 g. of a solid material is obtained, which is dried at 50-55 under reduced pressure (28 mm.) and which represents the 2-(4-rnethyl-l piperazino)ethyl-guanidine dihydrochloride sulfate hydrate, M.P. 198.8- 200.0".

Example 5 A mixture of 2-[4-(2-meth0xyethyl)-l-piperazino]-ethylamine and S-rnethyl-isothiourea sulfate in water is refluxed and the desired 2-[4-(2-rnethoxyethyl)-l-piperazinoLethyl-guanidine sulfate can be received upon concentration of the resulting solution.

The starting material may be prepared as shown in Example 1 by selecting the appropriate reagents.

Example 6 The 2 {4 {2 (w methyl) nona ethylenedioxyethyl]-l-piperazino}-ethyl-guanidine sulfate may be ob tained by reacting 1-{2-(w-methyl)-nona-ethylenedioxyethyl]-piperazine with chloroacetonitrile, reducing the nitrile group in the resulting 4-[2-(w-methyD-nona-ethylenedioxy-ethylj-l-piperazino-acetonitrile to a methylene amino group and reacting the 2-{4-[2-(w-rnethyU-nonaethylenedioxy ethyl] l-piperazino}-ethylamine with S- iethyl-isothiourear sulfate; all these reactions are carried out according to the methods given in Example 1.

Example 7 2 i4 (2 diphenylmethoxy ethyl) l piperazinoJ- cthylamine prepared from l-(Z-diphenylmethoxy-ethyl)- piperazine by treatment with chloroacetonitrile and reduction of the resulting 4-(Z-diphenylmethoxy-ethyl)-1- piperazino-acctonitrile with lithium aluminum hydride), when refluxed with S-methyl-isothiourea sulfate in the presence of water, yields the 2-[4-(2-diphenyl-rnethoxyethyl) -l-piperazino] -ethy1-guanidine sulfate.

Example 8 A mixture of 2-[4-(2-N,N-dimethylaminoethyl)-1-piperazinol-ethylamine and Smethyl-isothiourea sulfate in water is refluxed and concentrated; the desired 2-{4-(2-N, N-dimethylaminoethyl I -piperazino] -ethyl-guanidine can be recovered as its sulfate.

The starting material may be prepared according to the procedure disclosed in Example 1; l-(2-N,N-dimethylaminoethyl)-piperazine serves as the intermediate and is reacted with the chloroacetonitrile to form the [4-(2-N,N- dimethylaminoethyl)-l-piperazino]-acetonitrile, which is converted to the starting material by treatment with lithium aluminum hydride.

Example 9 A mixture of 2-{4-[2-(4-methyllpiperazino)-ethyl]- l-piperazino}-ethylamine and S-methyl-isothiourea sulfate in water yields the desired 2-{4-[2-(4-methyl-l-piperazino)-ethyl]-1-piperazino}-ethyl guanidine sulfate upon refiuxing and concentrating the solution.

The reaction of l-[2-(4-methyl-piperazino)-ethyl]'piperazine with chloroacetonitrile and the reduction of the resulting 4-[2-(4-rnethyl-piperanno)-ethyl]-l-piperazinoacetonitrile with lithium aluminum hydride according to the procedure of Example 1 furnishes the desired starting material.

Example 10 A solution of 2.05 g. of 2-(4-phenyl-l-piperazino)-ethylamine and 1.39 g. of S methyl-isothiourea sulfate in 5 ml. of water is refluxed for 4 hours. Upon cooling a solid material separates, which is filtered off and recrystallized from Water to yield the 2-(4-phenyl-l-piperazino)- ethyl-guanidine sulfate, M.P. 256-258 (with decomposition).

30 Example 11 A A mixture of 2-{4-(4-rnethyl-phenyl)-I-piperazino]- ethylamine and S-ethyl-isothiourea sulfate in water, when refluxed, yields the desired 2-{4-(4-methyl-phenyl)-1- piperazino]-ethyl-guanidine sulfate, recovered after concentrating the solution.

The starting material may be prepared according to the procedure given in Example 1 by using l-(4-methylphenyl)-piperazine as the intermediate.

Example 12 A solution of 2-[4-(3,4-dichloropheny1)-l-piperazino]- ethylamine and Smethyl-isothiourea sulfate in water is refluxed and then concentrated to yield the desired 2-[4- (3,4-dichlorophenyl)-l-piperazino}-ethyl guanidine sulfate.

The starting material may be prepared by reacting 1- 3,4dichlorophenyl -piperazine with chloroacetonitrile and reducing the resulting acetonitrile compound with lithium aluminum hydride as shown in Example 1.

Example 13 5.0 g. of 2-(4-benzyl-l-piperazino)-ethylamine and 3.17 g. of S-rnethyl-isothiourea sulfate are dissolved in 5 ml. of water, the solution is refluxed for four hours and concentrated under reduced pressure. The 2-(4-benzyll-piperazino) ethyl-guanidine sulfate is recrystallized from ethanol, M.P. 185-190.

The starting material may be prepared by reacting 50 g. l-benzyl-piperazine with 10.72 g. of chloroacetonitrile according to the procedure given in Example 1, and treating a solution of 20 g. of the resulting (4-benzyl-1-piperazino)-acetonitrile (B.P. 152-155 70.3 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-l-piperazino}ethylamio: can be obtained, M.P. 180l87/l3 mm.

Example 14 2-(4-diphenylmethyl-l-piperazino) cthylamine, when refluxed with S-rncthyl-isothiourea sulfate in the presence of water, yields and the desired 2-(4-diphenylmethyl-lpiperazino)-ethyl-guanidine sulfate.

The starting material may be prepared according to the procedure described in Example 1 by replacing l-rnethylpiperazine by 1-diphenylmethyI-piperazine.

Example 15 A mixture of 2-[4(3,4,S-trimethoxy-benzyl)-l-piperazinoJ-ethylamine and S-methyl-isothiourea sulfate in water, when refluxed and then concentrated, yields the desired 2-[4-(3,4,5-trimethoxy-benzyl) -1 piperazinoJ- ethyl-guanidine sulfate.

The starting material is obtained by reacting l-(3,4,5- trimethoxy-benzyl)-piperazine with chloroacetonitrile and treating the resulting 4-(3,4,5-trimethoxy-benzyl)-l-piperazine-aceto-nitrile with lithium aluminum hydride.

Example 16 A solution of 5.0 g. of 2-[4-(Z-phenylethyl)-1-piperazino]-ethylan1ine and 2.97 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed until the evolution of rnethylmercaptan ceases and the solid material is filtered off. The resulting 2-[4-(2-phenylethyl)-l-piperazinoJ- ethyl-guanidine sulfate is recrystallized from a mixture of ethanol and water, M.P. 266-271".

The starting material may be prepared by reacting 37 g. of I-{Z-phenylethyl)-piperazine and 7.32 g. of chloroacetonitrile according to the procedure of Example 1 to form the {4- Z-phenylethyl l -piperazino] -acetonitrile, which is purified by distillation, B.P. -l72/l3 mm. 12 g. of the latter is dissolved in ether, 2.9 g. of lithium aluminum hydride is added and the mixture is refluxed for six hours. The complex is decomposed by adding 3 ml. of water, 2 ml. of 20 percent aqueous sodium hydroxide and 10 m1. of water, and the free base is extracted and then purified by distillation, to yield the 2- [4-(2-phenyl-ethyl)-1-piperazino]-ethylamine, B.P. 157 159"/ 14 mm.

Example 17 Example 18 A solution of 4.17 g. of 2-[4(2-pyridyl)-l-piperazinolethylamine and 2.81 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. The desired 2-[4-(2-pyridyl)-1-piperazino]-ethyl-guanidine sulfate is obtained by concentrating the reaction mixture under reduced pressure and recrystallizin g the residue from a mixture of ethanol and water, M.P. 272 (decomposition).

The starting material may be prepared as usual; the [4-(2-pyridyl)-l-piperazino]-acetonitrile, obtained from 40 g. of 1-(2-pyridyl)-1-piperazine and 7.47 g. of chloroacetonitrile, is purified by distillation, B.P. 120122/0.5 mm. and converted to the 2-[4-(2-pyridyl)-l-piperazino1- ethylamine (B.P. l12-115/0.05 mm.) by treating a solution of the nitrile in ether with 5.42 g. of lithium aluminum hydride as shown in Example 1.

Example 19 A mixture of 5 g. of 4-[4-(Z-pyridyl)-l-piperazino]- butylamine and 2.96 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed until methylmercaptan is no longer evolved. The solvent is evaporated under reduced pressure and the residue is recrystallized from a mixture of ethanol and water to yield the 4-[4-(2- pyridy1)-l-piperazino]-butyl-guanidine 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 to the procedure given in Example 1 yields the 4-[4-(2- pyridyl)-1-piperazino]-butyronitrile, purified by distiliation, B.P. 14l-l43/1 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 hours. The resulting complex is decomposed with 4 ml. of water, 5 ml. of 20 percent aqueous sodium hydroxide and 12 ml. of water, the mixture is concentrated and the desired 4-[4-(2-pyridyl)-l-pipcrazino]butylamine is isolated and purified by distillation, B.P. 113-1 l5/0.05 mm.

Example 20 3 g. of 2[l-N,N-(4-aza-4-methyl-1,7-heptylene)-imin]-ethylamine and 2.44 g. of S-methyl-isothiourea sulfate are dissolved in ml. of water, and the solution is refluxed for four hours and then concentrated under reduced pressure. The residue is recrystallized from a mixture of methanol and ether to yield the 2-[l-N,N-(4-aza- 4 methyl 1,7 heptylene) imino] ethyl guanidine sulfate, M.P. 198215.

The starting material may be prepared as follows: To a solution of 10.01 g. of 1,2-trimethylene-pyrazolidine in 200 ml. of dry acetone is added 15 ml. of methyl bromide while cooling with ice. After standing at room temperature for a few hours, the mixture is cooled to 12 and the resulting crystalline precipitate is filtered off rapidly and washed with a small amount of dry acetone. The hygroscopic 1 methyl 1,2 trimethylene pyrazolidinium bromide is dried and melts at 264267.

The above-described quaternary ammonium compounds is added to aluminum amalgam (obtained from 4 g. of aluminum shavings) in ml. of ether, 10 ml. of water is added in portions while cooling with ice, and the mixture is allowed to stand overnight at 0. An excess of solid potassium 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)-im- A solution of 8.5 g. of N,N-(4-aza-4-methyl-l,7- heptylene)-irnine in 160 ml. of toluene is added while stirring to a solution of 5.02 g. of acetonitriie in 50 ml. of toluene containing 15 g. of sodium carbonate. The reaction mixture is refluxed for six hours, filtered hot, and the filtrate is concentrated to a small volume. The residue is distilled; the desired [l-N,N-(4-aza-4-methyi- 1,7-heptylene)-imino]-acetonitriie boils at 83-85/0.4

5.44 g. of the [l-N,N-(4-aza-4-methyl-l,7-heptylene)- imino]-acetonitrile in 30 ml. of ether is added to 2 g. of lithium aluminum hydride in ml. of ether. The reaction 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 filtrate is concentrated under reduced pressure and the residue is distilled. The desired 2-[N.N- (4-aza-4-methyl-l,7-heptylene)-imino]-ethylamine boils at 112ll7/l3 mm.

Example 21 A mixture of N-methyl-N-[2-(4- nethyl-l-piperazino)- ethyH-amine and S-methyl-isothiourea sulfate in Water yields the desired N-methyl-N-[Z-( i-methyll -piperazino)- ethyll-guanidinc sulfate upon refluxing and then concentrating the solution.

The starting material may be prepared by treating l-methyl-piperazine with 2-brornoethanol, reacting the resulting 2-(4-mcthyl-lpiperaZino)-ethanol with thionyl chloride and exchanging the chlorine atom in 2-(4' methyl-l-piperazino)-ethyl chloride with methylamine.

Example 22 A mixture of 20 g. of 2-(4-methyl-l-piperazino)-ethylamine and 15 g. of cyanogen bromine in ether yields the 2 (4 methyl 1 piperazino) ethyl cyanamide hydrobromide, which 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 ammonia.

16.8 g. of 2-(4-methyl-l-piperazino)-ethy1-cyanamide 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 while agitating. Upon cooling the reaction mixture yields the 2-(4-methy'll-piperazino)-ethyl-guanidine sulfate, M.P. 193198.

Example 23 A solution of 14.3 g. of 2-(4-methyl-l-piperazino)- ethylarnine 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-methyl-l-piperazino)-ethyl]-2-thiourea is obtained upon concentrating the solution under reduced pressure.

A solution of the above 1-[2(4-methyl-1-piperazino)- ethyl]-2-thiourea in aqueous ammonium hydroxide is heated while stirring in the presence of a suspension of freshly precipitated mercuric oxide as a desulfurizing reagent. The reaction mixture is filtered, the filtrate is made actidic with sulfuric acid, whereupon the 2-(4-methyl-1-piperazino)-ethyl-guanidine sulfate precipitates and is recrystallized from a mixture of ethanol and water. The compound is identical with the product obtained according to the procedure of Example 1.

Example 24 40.0 g. of the 1-[2-(4-rnethyl-l-piperazino)-ethyl] 2- thiourea described in Example 23 is dissolved in Water and treated with 13.6 g. of dimethyl sulfate. The reaction mixture is allowed to proceed spontaneously, with occasional cooling to control the reaction. The desired S methyl 1-[2-(4 methyl-l-piperazino)-ethyl]-2-isoth.iourea sulfate precipitates from the cold solution.

26.5 g. of S-methyi-1-[2-(4-methyl-l-piperazino)-eth yIJ-Z-isothiourea in aqueous methanol is treated with ammonia and mercuric chloride. After several hours the solution is filtered to remove the metallic precipitate. The filtrate is made acidic with sulfuric acid and the desired 2-(4-methyl-l-piperazino)-ethyl-guanidine sulfate can be recovered.

Example 25 16.8 g. of the 2-(4-methyl-l-piperazino)-ethy1-cyanamide, described in Example 22, and 16.2 g. of potassium cyanate are dissolved in water, and the solution is allowed to stand for twenty-four hours. The excess cyanate is destroyed with nitric acid and the silver salt of the resulting 1-[2-(4-methyl-l-piperazino)-ethyl]-3-cyano-urea is precipitated by treatment with silver nitrate. The silver salt is suspended in warm water, decomposed with hydrochloric acid, and the precipitated silver chloride is filtered oil.

The resulting l-[2-(4-methyl-l-piperazino)-ethyl]ll-cyano-urea is heated for three hours to about 50 to 80 with 6 N aqueous sulfuric acid; after cooling the crystalline 2-(4-methyl-l-piperazino)ethyl-guanidine sulfate can be recovered and recrystallized from aqueous ethanol.

Example 26 To 20.0 g. of l-methyl-piperazine in 75 ml. of ethanol is added 15.8 g. of Z-guanidino-ethyl chloride hydrochloride in an ethanol solution. After the addition is complete, the reaction mixture is refluxed for several hours, then cooled, filtered and concentrated under reduced pressure. The residue is dissolved in water, the solution is made alkaline with dilute sodium hydroxide, and the resulting base converted to the 2-(4-methyl-1-piperazino)- ethyl-guanidine sulfate, M.P. 193l98.

The 1-methyi-piperazine may also be converted into the sodium salt, for example, by treatment with sodium, sodium amide or sodium hydride in toluene; such sodium salt is then reacted with the guanidino-ethyl chloride, freshly prepared from its hydrochloride salt, to form the desired 2*(4-methyl-1-piperazino)-ethyl-guanidine, which may be characterized as its sulfate.

The starting material may be prepared as follows: To 10.5 g. of Z-guanidino-ethanol hydrochloride in 500 ml. of toluene is added while stirring 16.9 g. of thionyl chloride. After standing overnight, the mixture is warmed for about 30 minutes and the toluene is decanted, any excess of thionyl chloride is evaporated with the remaining toluene and the residue, representing the Z-guanidino-ethyl ohloride hydrochloride, is recrystallized from a mixture of ethanol and ether. The free base may be formed by treating a mixture of the salt in ether with the stoichiometric amount of ammonia.

By substituting in the above reaction 3-guanidino-propanel for the Z-guanidino-ethanol, the B-guanidino-propyl chloride hydrochloride may be obtained.

Example 27 A solution of 19.9 g. of 2-(4methyl-1-piperazino)- ethyl chloride hydrochloride and 21.6 g. of guanidine sulfate in water is neutralized and made slightly alkaline with aqueous sodium hydroxide. The reaction mixture is heated on the steam bath and additional sodium hydroxide solution is added to neutralize generated acid. After cooling and acidifying with sulfuric acid, the resulting solution is concentrated under reduced pressure and the 2-(4-methyl 1 piperazino)-ethyl-guanidine sulfate 34 separates; it is recrystallized from a mixture of ethanol and water.

The starting material may be prepared as follows: 20 g. of l-methyl-piperazine is added to a solution of 25 g. 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 pressure. The 2-(4-methyl-1-piperazino)-ethanol is recovered by distilling the residue.

To a solution of 5.72 g. of 2-(4-methyl-1-piperazino)- ethanol in 50 ml. of benzene is added dropwise while stirring a solution of 5.15 g. of thionyl chloride in ml. of benzene. The reaction mixture is then stirred and refluxed for two hours, then cooled, the solid material is filtered oil and recrystallized from a mixture of methanol and ether to yield the 2-(4+methyl-1-piperazino)-ethyl chloride hydrochloride.

By reacting I-phenyl-piperazine with ethylene bromohydrin and treating the resulting 2-(4-phenyl-1-piperazino)-ethanol with thionyl chloride as shown hereinabove, the desired 2-(4-phenyl-l-piperazino)-ethyl chloride hydrochloride may be obtained, which, upon treatment with guanidine sulfate according to the previously given procedure, yields the desired 2-(4-phenyl-l-piperazino)-ethyl-guanidine, which may be characterized as its sulfate, M.P. 256-258 (with decomposition).

Example 28 iguanide is added while stirring to a solution of 20.0 g. of l-methyi piperazine in 200 ml. of benzene. After warming for one hour, and then cooling, the solution is filtered and the filtrate concentrated under reduced pressure.

The residue, containing the 2-(4-methyl-1-piperazino)- acetic acid guanide, is suspended in tetrahydrofurane and added to a refluxing solution of 6 g. of lithium aluminum hydride in tetrahydrofuran. After completion of the reaction, the excess of lithium aluminum hydride is decomposed by adding water, then aqueous sodium hydroxide. The solid material is filtered oil", the filtrate is acidified with sulfuric acid and the 2-(4-methyl-1-piperazino)- eLhyl-guanidine sulfate can be recovered and recrystallized from aqueous ethanol, M.P. 193-198" (with decomposition).

13.6 g. of chloroacetyl Example 29 To a mixture of 1.46 g. of benzoyl-cyanarnide and 1.50 g. of 2-(4-methyl-1-piperazino)-ethylamine is added a small amount of concentrated aqueous hydrochloric acid; the mixture is heated on the steam bath for ten to fifteen minutes, then cooled and diluted with ethanol. Ether is added to precipitate the l-benzoyl-3-[2-(4-meth yl-l-piperazino)-ethyl} guanidine hydrochloride, which is separated by filtration. It shows a band at about 1678 cm. (in chloroform) in the infrared absorption spectrum.

Benzoyl-cyanamide may be replaced by (4-rnethoxybenzoyl) cyanamide, (3,4,5trimethoxy-benzoyl)-cyunamide and the like; when treated with 2-(4-rnethyl-lpiperazino) ethylamine as shown in the above example, these reagents yield the 3-{2-(4-n1etbyl-1-piperazino)- ethyl]-1-(4-methoxybenzoyl) guanidine hydrochloride, 3-[2-(4-methyl-l-piperazino)-ethyl] l (3,4,5-trimethoxy-benzoyU-guanidine hydrochloride and the like.

A mixture of 2.01 g. of 1-guanyl-3,S-dimethyI-pyrazole nitrate and 14.3 g. of 2-(4-methyl-1-piperazino)-ethylamine is heated for 2% hours while stirring. The excess amine is removed by distillation under reduced pressure, the residue is dissolved in water and converted to the desired 2-(4-methyl-l-piperazino)ethyl-guanidine sulfate by treatment with a strong anion (sulfate) exchange resin, such as, for example, as described in US. Patent No. 2,591,573. The solution is evaporated 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-(41nethyl-1-piperazino)- ethylamine trihydrochloride and 3.15 g. of cyanamide in 100 ml. of ethanol is refluxed for six hours. The solvent is removed under reduced pressure, the residue dissolved in water and converted to the 2-(4-methyl-1-piperazino)- ethyl-guanidine sulfate with the help of a strong anion (sulfate) exchange resin as shown in Example 31.

Example 33 14.3 g. of 2-(4-methyll -piperazino)-ethylamine is added to a suspension of 10.2 g. of 1-methyl-3-nitrosoguanidine in water. The mixture is allowed to stand at room temperature for several days until gas evolution has ceased. The solid material is filtered off, the l-metnyl-3-[2-(4-methyl-l-piperazino)-ethyl]-guanidine sulfate is obtained by adding aqueous sulfuric acid to the filtrate, concentrating the solution and adding ethanol. The compound is identical with the product obtained according to the procedure of Example 1.

Example 34 A mixture of N,N-diethyl-cyanamide, 13 g. of 2-(4- methyl-l-piperazino)-ethylamine trihydrochloride and ml. of 95 percent ethanol is heated in a sealed tube for twenty hours at 100. The reaction mixture is cooled, the solvent is removed under reduced pressure, excess N,N-diethyl-c'yanamide is removed by extraction with ether and the residue is treated with aqueous sulfuric acid. The solution is concentrated under reduced pressure and the desired 1,1-diethyl-3-[2-(4-methyl-1-piperazino)-ethyl]-guanidine sulfate is precipitated by adding ethanol.

Example 35 A mixture of 5.0 g. of 2-{4-(2-N,N-diethylaminoethyl)- l-piperazino]-ethylamine and 3.05 g. of S-rnethylisothiourea sulfate in 5 ml. of water is refluxed for six hours. The solution is then concentrated under reduced pressure and the residue is recrystallized from a mixture of ethanol and diethyl ether; the 2-[4-(2-N,N-diethylaminoethyl)-1- piperazino]-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. of anhydrous piperazine in 150 ml. of ethanol. An exothermic reaction occurs, the reaction mixture is stirred for an additional 18 hours and then chilled. The resulting solid material is filtered off, the filtrate is concentrate-d to dryness under reduced pressure and the residue is distilled. The 1-(2-N,N-diethylaminoethylhpiperazine boils at 120126/13 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 g. of chloro-acetonitrile in 100 ml. of toluene, in which 25.4 g. of anhydrous sodium carbonate is suspended. The mixture is refluxed for eight hours, then filtered hot and the filtrate is concentrated under reduced pressure. The [4-(2-N,N-diethylaminoethyl)-1-piperazino]acetonitrile obtained as the residue is distilled, B.P.115116/0.5 mm.

15.4 g. of [4-(2-N,N-diethylaminoethyl)-1-piperazino1- acetonitrile in 100 ml. of diethyl ether is added dropwise while cooling and stirring to a solution of 3.92 g. of

lithium aluminum hydride in 250 ml. of diethyl ether. After completion of the addition, the solution is refluxed overnight, then cooled and decomposed by successive addition of 5 ml. of water, 8 ml. of 20 percent aqueous sodium hydroxide and 13 ml. of water. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is distilled to yield the desired 2 [4-(2-N,N-diethylaminoethyl)-l'piperazino1- ethylamine, 13.1. 97/0.3 mm.

Example 36 A mixture of 2.45 g. of2-[4-(kl-chlorophcnyl)-l-pipcrazino]-ethylarnir|c and 1.42 g. of S-methyl-isothiourea sulfate in a mixture of ethanol and water is refluxed for four hours and then allowed to cool. The resulting 2-[4- (4-chlorophenyl l -piperazino] -ethylguanidine sulfate is filtered off and recrystallized from a mixture of ethanol and water, M.P. 250265 (with decomposition).

The starting material may be prepared as follows: A solution of 27.5 g. of l-(4-chlorophenyl)-piperazine in 400 ml. of toluene is added to a stirred solution of 10.6 g. of chloroacetonitrile in 300 ml. of toluene containing 30.0 g. of anhydrous sodium carbonate. The reaction mixture is refluxed for eight hours and filtered; the filtrate is concentrated under reduced pressure and the solid residue is recrystallized from n-heptane to yield the [4-(4- chloro-phenyl)-1-pipernzino]-acetonitrile, MP. 120-125".

A solution of 10.0 g. of [4-(4-chloro-phenyl)-1piperazino]-acetonitrile in 1000 ml. of diethyl ether is slowly added to a solution of 2.25 g. of lithium aluminum hydride in 500 ml. of diethyl ether while cooling. The solution is then refluxed overnight and allowed to stand for 2% days. 2.25 ml. of water, 3 ml. of 20 percent aqueous sodium hydroxide and 18 111i. of water are added in this order, the reaction mixture is filtered, the filtrate is concentrated and the residue is distilled; the desired 2-[4- (4-chloro-phenyl)-1-piperazino]-ethylamine is collected at 152158/O.3 mm. and solidifies on standing.

Exmnplc 37 A solution of 4.8 g. of 2-[1-N,N-(4-aza-4benzyl-L7- heptylene)-imino]-ethylamine and 2.7 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. The reaction mixture is concentrated under reduced pressure and the residue is recrystallized from ethanol; the dry 2-[ l-N,N-(4-aza-4-benzyl-1,7-heptylenc)- imino]-ethyl-guanidine sulfate melts at l88l81.

The starting material may be prepared as follows: To 36.2 g. of 1,5-diaza-cyclo-octane is dropwise added 402 g. of benzyl chloride while stirring and cooling. The reaction mixture is stirred for an additional 24 hours, the solid material is filtered ofl and the filtrate is concentrated under reduced pressure. The remaining yellow oil is combined with the solid material separated by filtration, 40 percent aqueous sodium hydroxide is added and the aqueous solution is extracted three times with diethyl ether. The ether solutions are dried over sodium sulfate, and concentrated under reduced pressure. The remaining yellow oil is distilled to yield the desired l-benzyl-l,S-diaza-cyclo-octane, B.P. 97100/0.25 mm.

20.4 g. of l-henzyl-l,S-diaza-cyclo-octane in 200 ml. of toluene is added dropwise to a mixture of 7.55 g. of chloroacetonitrile and 22.0 of sodium carbonate in 100 ml. of toluene while stirring. The reaction mixture is refluxed for eight hours, stirred overnight and filtered. The Solid material is washed with hot toluene, the wash logs are combined with the filtrate and the solution is evaporated to dryness. The remaining brown oil is distilled to yield 13.8 g. of the slightly yellow ll,N,N-(4- aza-4-benzyl-l,7-heptylene)-imino]acetonitrile, BP. 147- l49/0.25 mm.

A solution of 11.0 g. of [l-N,N-(4-aza-4-benzyl-l,7- hcptylene)-iminol-z\cctonitrile in 100 ml. of diethylcther is added dropwise to a mixture of 2.81 g. of lithium aluminum hydride in diethyl ether while stirring and cooling in an ice-bath. The reaction mixture is refluxed overnight, the excess lithium aluminum hydride is de stroyed by adding 3 ml. of water, ml. of 20 percent aqueous sodium hydroxide and ml. of water, and the reaction mixture is filtered. The solid material is washed with diethyl ether, the filtrate and the washings are combined, dried over sodium sulfate and evaporated to dryness to leave the desired 2-[l-N,N-(4-aza-4-benzyl-1,7- heptylene)-imino]-ethylamine, which is purified by distillation, B.P. 134137/0.3 mm.; yield: 6.8 g.

Other guanidino compounds, such as 2-{1-N,N-(4-aza- 4-phenyl-1 ,7-heptylene -irnin-o] -ethyl-guanidine, 2-{ l-N, N-[4-aza-4-(4-methoxy-phenyl) 1,7 heptylene]-imino}- ethyl-guanidine, 2-{1 N,N [4-aza-4-(4-methyl-phenyl)- 1,7 heptylene]-imino}-ethylguanidine, 3-[1-N,N-(4-aza- 4-phenyl-l,7heptylene)-imino]propylguanidine and the like, particularly the sulfates thereof, can he prepared according to the previously given procedure by selecting the appropriate starting materials.

Example 38 A mixture of 5.0 g. of 2-[1N,N-(3-aza-3-benzyl-l,6- hexylene)-imino]-ethylamine and 2.97 g. of S-rnethyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours and allowed to stand overnight. The solidified reaction product is recrystallized from a mixture of ethanol and ether and dried at 70 under high vacuum to yield the 2-[1-N,N-(3-aza-3-benzyl-1,61hexylene)-imino]- ethylguanidine sulfate, M.P. 205-207.

The starting material may be prepared as shown in Example 1; the 1-benzyl-1,3-diaza-cycloheptane boils at 91-101/0.3 mm. and is converted by treatment with chloracetonitrile to the [l-N,N-{3-aza3-benzyl-1,6-hexylene)-imino]-acetonitrile, B.P. 156158/1.2 mm.; yield: 20.1 g., which is reduced to the 2-[1-N,N-(3-aza-3- benzyl-1,6-hexylene)-imino]-ethylamine, B.P. 125-126/ 0.3 mm. with lithium aluminum hydride.

The 2 [l-N,N-(3-aza-3-phenyl-1,6-hexylene)-iminolethyl-guanidine sulfate, 2-{l-N,N-[3-aza-3-(3,4-dimethoxyphenyl)-1,fi-hexylene]-imino}-ethyl-guanidine sulfate and the like can be prepared according to the above procedure by using the appropriate starting materials.

Example 39 A mixture of 4.0 g. of 2-(4-methyl-2,6-cis-dimethyl-1- piperazino)-ethylamine and 3.25 g. of S-methyl-isothiourea sulfate in 5 ml. of water is refluxed for four hours. The reaction mixture is concentrated under reduced pressure and the residue is recrystallized from a mixture of ethanol and ether to yield the 2-(4-methyl-2,6-cis-dimethyl-l-piperazino)-ethyl-guanidine sulfate, M.P. 225 231 (with decomposition).

The starting material may be prepared as follows: A mixture of 85.5 g. of 2,6-cis-dirnethyl-piperazine and 40 g. of methyl formate is heated for five hours at 85. The reaction mixture is concentrated under reduced pressure and the residue is distilled to yield the 1'formyl-3,5- cis-dimethyl-piperazine, B.P. 112115/0.8 mm.; yield: 63 g.

A solution of 14.0 g. of l-formyl-S,S-cis-dimethybpiperazine 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 ice-bath for two hours, the excess reducing reagent is destroyed by adding 10 ml. of water, 5 ml. of 20 percent sodium hydroxide and ml. of water, and the separated organic layer is evaporated to dryness. The desired l-methyl-3,S-ciS-dimethyI-piperazine is purified by distillation, B.P. 114-l16/0.5 mm; yield: 5.9 g.

The l-methyl-3,S-cis-dimethyl-piperazine is converted into the (4-methyl-2,6-cis-dimethyl-1-piperazino)-acetonitrile, B.P. 125-126/ 13 mm., by treatment with chloroacetonitrile, and the resulting nitrile derivative is reduced 38 to the 2- (4-methyl-2,6-cis-dimethy1-1-piperazino)-ethyl amine, B.P. 102103/13 mm., with lithium aluminum hydride; these reactions are carried out according to the methods given in Example 1.

Example 40 A mixture of 5.0 g. of 2-[I-N,N-(3-aza-3-methy1-1,6- hexyleneyiiminol-ethylarnine and 4.42 g. of S-rnethylisothiourea sulfate in 5 ml. of water is refluxed for four hours and then concentrated under reduced pressure. The solid residue is recrystallized from a mixture of ethanol and water to yield the 2-[1-N,N-(3-aza-3-methyl-l,6- hexylene)-imino]-ethyl-guanidine sulfate, M.P. 137-140.

The starting material may be prepared by reacting 18.0 g. of I-rnethyl-1,4-diaza-cycloheptane with 11.91 g. of chloroacetonitrile in the presence of 33.0 g. of anhydrous sodium carbonate and reducing 8.6 g. of the resulting [1 N,N (3 aza-3-methyl-1,6-hexylene)-imino]-acetonitrile, B.P. 6872/0.2 mm. with 3.2 g. of lithium aluminum hydride to the desired 2-[1-N,N-(3-aza-3-methyl-1,6 hexylene)-imino]-ethylamine, B.P. 104/13 mm., yield: 6.7 g.; these reactions are carried out according to the procedures described in Example 1.

Example 41 The compounds of the present invention may be formulated into pharmacological preparations. Thus, 2-(4- methyl-I-piperazino)-ethyl-guani-dine dihydrochloride sulfate (of Example 4) may be made up into tablets containing from 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 dosage unit. For example, tablets containing 0.025 g. of 2-(4-methyl-1-piperazino)-ethyl-guanidine dihydrochloride sulfate are prepared as follows (for 10,000

tablets}.

Ingredients: G.

2 (4-methyl-1-piperazino)-ethyl-guanidine dihydnochloride sulfate 250.00

Lactose, spray dried 2062.50 Tragacanth 50.00 Corn starch 125.00 Magnesium stearate 12.50

Ingredients: G.

2-(4-methyl-1-piperazino)-ethyl-guanidine dihydrochloride sulfate 25.00

Citric acid, anhydrous 2.50

Sodium citrate 10.00

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- methyl-l-piperazino) ethyl-guanidine dihydrochloridesulfate is dissolved in the resulting solution and additional water is added to bring up the volume to 2500 ml. The solution is passed through a medium porosity sintered glass filter and 2.2 ml. of the filtrate is filled into ampules. The sealed ampules are sterilized at for 30 minutes.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula rem), NII

N-A-NII-o (H NH-Ra in which R stands for a member selected from the group consisting of lower alkyl, cycloalkyl having from five to six ring carbon atoms, cycloalkyl-lower alkyl, in which cycloalkyl has from five to six ring carbon atoms, phenyl, (lower alkyD-phenyl, (lower a1koxy)-pheny1 and (halogeno)-phenyl, each of the symbols in and n stands for an integer from the group consisting of 2, 3 and 4, with the proviso that the total of U i-n stands for an integer selected from the group 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 R is a member of the group consisting of hydrogen, lower alkanoyl, benzoyl, (lower alkyl)-benzoyl, (lower alkoxy)- benzoyl and (halogeno)-benzoyl, and pharmaceutically acceptable acid addition salts thereof.

2. Compounds of the formula:

ounm -cnt NII (lower alkyl) -N in which each of the symbols m and m 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 -C'Ilr NII 40 in which each of the symbols rm and m 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.

4. 2-(4-methyl-l-piperazino)-ethyl-guanidine. 5. The therapeutically acceptable acid addition salts of 2-(4-methyl-1-piperazino)-ethyl-guanidine.

6. 2-(4-methyl-l-piperazino)-ethyl-guanidine sulfate. 7. 2-(4-methyl-l-piperazino)-ethyl-guanidine dihydrochloride sulfate.

8. 2-(4-ethyl-1-piperazino)-ethyl-guanidine. 9. 2-[1-N,N-(3-aza-3-methyl 1,6 hexylene) iminolethyl-guanidine.

10. 2-[1-N,N-(4-aza-4-methyl-1,7-heptylene) iminolethyl-guanidine.

11. Compounds of the formula:

ctmm om N11 NANIIG Gua -cm NIL.

(phcnyl) N in which each of the symbols m and 111 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.

12. 2-(4-phenyl-l-piperazino)-ethyl-guanidine.

References Cited in the 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 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 676,812 Great Britain Aug. 6, 1952

Claims

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA