US3178433A

US3178433A - 3-amino-1-diazacycloalkyl-alkyl-guanidines

Info

Publication number: US3178433A
Application number: US278750A
Authority: US
Inventors: Mull Robert Paul
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1963-05-07
Filing date: 1963-05-07
Publication date: 1965-04-13
Anticipated expiration: 1982-04-13

Description

United States Patent 3,178,433 S-AMHNO-l-DIAZACYCLOALKYL-ALKYL- GUANlDlNES Robert Paul Mull, Florham Park, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 7, 1963, Ser. No. 273,750

8 Claims. (Cl. 260268) The present invention concerns amino-guanidines. More especially, it relates to l-R-lower alkyl-S-amino guanidines, in which R represents N,N-(N-R -aza-alkylene)-imino having from four to six carbon atoms as chain members, and R representing an organic radical, salts or acyl derivatives of such compounds, as well as to process for the preparation of these compounds.

An N,N-(N-R -aza-alkylene)-imino group may be represented by the formula:

cnnm cin in which each of the letters m and m represents one of the numbers 1 and 2, and R has the previously-given meaning. Such N,N-(N-R -aza-alkylene)-irnino radical are represented, for example, by 4-R -1-piperazino, l- N,N(3-R -3-aza-1,6-hexylene)imino, l-N,N-(4-R -4-aza- 1,7-heptylene -imino, l-N,N-(3-R -3-aza-1,7-heptylene) imino and the like, in which R has the previously-given meaning, and analogous radicals.

Attached to the aza-nitrogen atom of an N,N-(N-Rraza-alkylene)-imino group, is an organic radical R which represents primarily an aliphatic radical, and especially lower alkyl having from one to seven, preferably from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and the like, as well as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl and the like, as well as lower alkenyl, preferably allylic lower alkenyl having from three to five carbon atoms, e.g. Z-propenyl (or allyl), 2-methyl-2-propenyl (or 2-methyl-allyl), Z-butenyl (or 3-methyl-allyl) and the like, lower alkynyl, e.g. ethynyl, l-propynyl and the like, a cycloaliphatic radical, particularly cycloalkyl having from three to seven, particularly from five to six, ring carbon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, cycloalkenyl having from five to seven ring carbon atoms, eg. 2-cyclopentenyl, 3-cyclohexenyl and the like, or any other suitable aliphatic radical.

The above-mentioned aliphatic, particularly lower al kyl, groups representing R in the above formulae may be substituted, for example, by other aliphatic radicals, such as cycloaliphatic groups, primarily by cycloalkyl and cycloalkenyl as defined hereinabove, carboxylic aryl, particularly monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, l-naphthyl or Z-naphthyl, as well as substituted phenyl, substituted l-naphthyl or substituted Z-naphthyl. substituents attached to the carbocyelic radicals are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower aikoxy, e.g. methoxy, ethoxy andthe like, lower alkylenedioxy, e.g. methylenedioxy and the like, lower 3,178,433 Patented Apr. 13, 1965 alkylmercapto, e.g. methylmercapto, ethyl-mercapto and the like, nitro, amino, particularly N,N-di-substituted amino, such as 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, trifluoromethyl or any other suitable substituent. Groups attached to carbocyclic portions may be in any of the available positions, whereby one or more than one of the same or of diiferent substituents may be present. Other substituents attached to an aliphatic, particularly a lower alkyl, group are heterocyclic aryl radicals, such as monocyclic azacyclic aryl, for example, pyridyl, e.g. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, bicyclic monocyclic azacyclic aryl, for example, quinolyl, e.g. 2-quinolyl and the like, monocyclic diazacyclic aryl, e.g. 3-pyridazinyl, Z-pyrimidyl, 4- pyrimidyl, Z-pyrazinyl and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g. 2-thienyl and the like, monocyclic oxacyclic aryl, for example, furyl, e.g. 2- furyl and the like. These heterocyclic aryl radicals may also have additional substituents, such as, for example, those attached to the above-described carbocyclic radicals.

ticularly a lower alkyl radical may also be substituted by functional groups, such as, for example, hydroxyl, 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 polyalkyleneoxy radicals may have from two to twenty lower alkyleneoxy portions and may have a free terminal hydroxyl group or an etherified terminal hydroxyl group, such as a terminal lower alkoxy, e.g. methoxy, ethoxy and the like, group, carbocyclic aryloxy, such as monocyclic earbocyclic aryloxy, e.g. phenyloxy and the like, or carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, e.g. benzyloxy, diphenylmethoxy, (4-chlorophenyl)-phenyl-methoxy and the like, or esterified hydroxyl, such as lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, carbamyloxy, such as carbamyloxy, or N- lower alkyl-carbamyloxy, e.g. N-methyl-carbamyloxy and the like, N,N-di-lower alkyl-carbomyloxy, e.g. N,N-dimethyl-carbamyloxy and the like, or N-carbocyclic arylcarbamyloxy, particularly N-monocyclic carbocyclic aryl-carbamyloxy, e.g. N-phenyl-carbamyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, or acyl groups, such as lower alkanoyl, e.g. acetyl and the like, amino, for example, unsubstituted amino, N-mono-substituted amino, for example, N-lower alkylamino, e.g. N-methylamino, N-ethylarnino and the like, N-carbocyclic aryl-amino, particularly N-monocyclic carbocyclic aryl-amino, e.g. N-phenylamino and the like, N-carbocyclic aryl-lower aliphatic hydrocarbon amino, particularly N-rnonocyclic carbocyclic-lower alkyl-amino, such as N-phenyl-lower alkyl-amino, e.g. N-ben'zyl-amino, N-(2-phenylethyl)-amino and the like, or primarily N,N-disubstituted amino, such as N,N-di lower alkyl-amino, in which lower alkyl has from one to four carbon atoms, e.g. N,N-dimethylamino, N-ethyl N-methyl-amino, 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-methylamino, N-cyclohexyl-N-ethylamino and the like, N-lower alkyl- N-monocyclic carbocyclic aryl-amino, particularly N- lower alkyl-N-phenyl-lower alkylamino, e.g. N-benzyl-N- methylamino, N-methyl-N-(Z-phenylethyl)-amiuo and the like, or N,N-alkyleneimino, N,N-oxa-alkyleneimino or N,N-aZa-alkyleneimino, in which alkylene has from four to six carbon atoms as ring members, such as, for example, 1-pyrrolidino groups, e.g. l-pyrrolidino, 2- methyl-l-pyrrolidino and the like, l-piperidino radicals,

An aliphatic radical R in the above formulae, parawe ass e.g. l-piperidino, 2-methyl-l-piperidino, 3-methyl-l-piperidino, 4-methyl-l-piperidino, B-hydroxy-l-piperidino, 3-acetoxy-l-piperidino, 3-hydroxymethyl-l-piperidino and the like, 1-N,N-(l,6-hexylene)-imino, 4-morpholino, or l-piperazino radicals, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4-ethyl-l-piperazino, 4-(2-hydroxyethyl)-1-piperazino, 4-(2 acetoxyethyl)-1- piperazino, 4-[2-(w-rnethoxy-polyethyleneoxy)-ethyl]-1- piperazino and the like, mercapto, etherified mercapto, especially lower alkyl-mcrcapto, e.g. methyl-mercapto, ethyl-mercapto and the like, halogeno atoms, e.g. fiuoro, chloro, bromo and the like, whereby one or more than one functional group may be attached to one or more than one carbon atom of an aliphatic, particularly lower alkyl, radical.

The group R in the above formulae may also represent carbocyclic aryl, primarily monocyclic carbocyclic aryl, e.g. phenyl, or bicyclic carbocyclic aryl, e.g. lnaphthyl or Z-naphthyl, which radicals may have one or more than one of the same or different substituents attached to any of the available carbon atoms; substituents are, for example, those previously-described as being attached to a carbocyclic aryl radical. It also represents heterocyclic aryl, primarily monocyclic or bicyclic heterocyclic aryl, which have one or more than one sulfur, oxygen and/or nitrogen atom as a ring member, such as, for example, monocyclic mono-azacyclic aryl, for example, pyridyl, e.g. Z-pyridyl, 3-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. 2-pyrazinyl and the like, pyrryl, e.g. 2-pyrryl and the like, monocyelic thiacyclic aryl, for example, thienyl, e.g. Z-thienyl and the like, or monocyclic oxacyclic aryl, for example, furyl, e.g. Z-furyl and the like, and these heterocyclic radicals substituted by substituents, such as, for example, those mentioned hereinbetore.

The lower alkyl radical, linking R with the aminoguanidino group, is represented by lower alkylene having from one to seven carbon atoms. Preferably, lower alkylene has from two to three carbon atoms, which separate the group R from the amino-guanidino group by the same number of carbon atoms; such radicals are l,2-eth ylene, l-methyl- 1 ,Z-ethylene, Z-methyll ,Z-ethylene or 1,3-propylene. Other lower alkylene radicals are, for example, 2,3-butylene, 1,3-butylene, 1,4-butylene, 1,4- pentylene, 1,5-pentylene and the like.

The 3-amino-guanidino group may be represented by the formula:

in which each of the groups R R R and R stands primarily for hydrogen, but may also represent an organic substituent, such as, for example, an aliphatic group, particularly lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, as well as a carbocyclic aryl radical, particularly monocyclic carbocyclic aryl, e.g. phenyl, 'or phenyl substituted by one of the previously-mentioned "substituents, or a carbocyclic aryl-aliphatic radical, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, Z-phenylethyl, diphenylmethyl and the like, and analogous radicals in which the phenyl portion is substituted by any or the previously-described substituents. One of the groups R and R may also represent an acyl radical, particularly the acyl radical of an organic carboxylic acid, such as a lower aliphatic carboxylic acid, for example, a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, a substituted lower alkanoic acid, e.g. chloroacetic, dichloroacetic, hydroxyacetic, methoxy-acetic, cyclopentyl-propionic acid and the like, or a lower alkanoic acid, e.g. 3-butenoic acid and the like, a carboxylic aryl carboxylic acid, for example, a monocyclic carbocyclic aryl carboxylic acid, e.g. benzoic, hydroxybenzoic, 4-methoxy-benzoic, 3,4-dimethoxy-benzoic, 3,4,S-trimethoxy-benzoic, 4 O ethoxycarboxylsyrnigic, 3,4-dichlorobenzoic, 3-N,N-dimethylamino-benzoic, 4-nitrobenzoic acid and the like, or a bicyclic carbocyclic aryl carboxylic acid, e.g. l-naphthoic, Z-naphthoic acid and the like, or a heterocyclic aryl carboxylic acid, for example, a monocyclic heterocyclic aryl carboxylic acid, e.g. nicotinic, isonicotinic, Z-furoic acid and the like. The amino-guanidino group is more especially the group of the formula:

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

The new compounds of this invention and the salts thereof cause in the anesthesized, normotensive dog an inhibition of the carotid occlusion reflex pressor response and antagonize the pressor responses elicited by high doses of amphetamine, and lower the arterial pressure in the unanesthesized renal or neurogenic hypertensive dog. These effects appear to be due to an inhibition of the release and/ or distribution of transmitter substances from sympathetic nerve terminals. In view of the fact that the compounds of this invention block the hypertensive effects of these pressor substances, they can, therefore, be used as antihypertensive agents to relieve hypertensive conditions, particularly those of neuroginic, renal or essential nature. In addition, compounds of this invention cause an increase in peripheral blood flow, and can, therefore, be used in functional peripheral vascular diseases, such as Raynauds disease and the like. The compounds are characterized by a fast onset of the pharmacological effects.

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

in which each of the letters m and M have the previously-given meaning, A represents lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the N,N-N-R -aza-alkyleneimino group by two to three carbon atoms, and R stands for lower alkyl having preferably from one to four carbon atoms, c.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, and pharmaceutically acceptable, non-toxic acid addition salts thereof. Specific compounds of this group are, for example,

3 -amino- 1 2- (4-methyll-piperazino) -ethyl] -guanidine,

3-amino-1 [3-(4-methyll-piperazino)-propyl] guanidine,

3-a1nino-1-[2-(4-ethyl-l-piperazino)-ethyl]-guanidine,

ene glycols or any other known carrier used in the manufacture of such preparations. The latter may be in solid form for example, as capsules, tablets, dragees 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, sfabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.

The amino-guanidine compounds of this invention may be prepared, for example, by converting in an R-lower alkyl-amine, in which R has the above-given meaning, or a salt thereof, the amino group into an amino-guanidino group and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting compound into a salt or an acyl derivative thereof.

The reagents of choice for the conversion of an amino group into an amino-guanidino group are S-lower alkyl- 2-isothiosemicarbazides, particularly those of the formula:

in which R R and R have the previously-given meaning, and R stands for lower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like, and acid addition salts thereof. The salts, which are employed in preference over the free base, are primarily those with mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like. The preferred reagents are acid addition salts of S-methyl-Z-isothiosemicarbazide with mineral acids, such as the hydrochloride, hydriodide, sulfate and the like. The starting material, in which the amino group is above all an unsubstituted amino group, but may also represent a substituted amino group having R as the substituent, is generally used in the form of its free base.

The reaction is carried out by contacting the starting material with the reagent, preferably in the presence of an inert solvent, the choice of which depends primarily on the solubility of the reactants. Water or water-miscible organic solvents, such as lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, ethers, e.g. diethyleneglycol dimethyl-ether, 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 represent the preferred diluents.

The reaction may be carried out at room temperature, or, if necessary, at an elevated temperature. Furthermore, it may be performed in the atmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel.

Analogous reagents capable of converting an amino group into an amino-guanidino group are the O-lower alkyl-2-isosemicarbazides, particularly those of the formula:

in which R R R and R have the previously-given meaning, or salts thereof with mineral acids. These semicarbazide derivatives are used in the same way as the above-described, corresponding l-amino-Z-isothiourea reagents; an acid addition salt of O-methyl-Z-isosemicarbazide with a mineral acid, e.g. hydriodic, sulfuric acid and the like, 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-2-isothiosemicarbazides or O-lower alkyl-Z-isosemicarbazides may be manufactured by alkylating thiosernicarbazides or semicarbazides with a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide and the like or with a dilower alkyl-sulfate e.g. dimethyl sulfate, diethyl sulfate and the like.

The starting materials, i.e. the R-lower alkyl-arnines, in which R has the previously-given meaning, are known or may be prepared according to known procedures. They may be obtained, for example, by treating a compound of the formula R--H, in which R has the previously-given meaning, with a halogeno-lower alkanonitrile, in which halogeno represents, for example, chloro, bromo, and the like, or with a lower alkeno-nitrile, in which the double bond is activated by the nitrile group. In a resulting R-lower alkano-nitrile compound, the cyano group is then converted into an aminornethyl 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 suitable light metal hydride, for example, an aluminum hydride, e.g. lithium aluminum hydride, sodium aluminium hydride, magnesium aluminum hydride, aluminium borohydride, aluminum hydride and the like, which hydrides may be used, if necessary, in the presence of an activator, such as aluminum chloride and the like.

The compounds of the present invention may also be prepared, for example, by converting in a l-R-lower alkyl-S-X-guanidine, in which R has the previously-given meaning, and X stands for nitro or nitroso, or a salt thereof, the group X into an amino group, and, if desired, carrying out the optional steps.

The conversion of a nitro or a nitroso group into an amino group may be carried out by per se conventional reduction methods. For example, reduction may be achieved by treatment with nascent hydrogen; the latter may be generated by contacting a suitable metal or metal compound with a hydrogen donor, for example, zinc or any other analogous metal, with acetic acid and the like, zinc acetate or any analogous metal compound with water or a moist solvent, or any other equivalent metalhydrogen donor combination, such as, for example, an alkali metal, e.g. sodium and the like, in the presence of liquid ammonia, a lower alkanol and the like. Treatment with hydrogen in the presence of a catalyst, e.g. nickel and the like, may also be employed in the above conversion of a nitro or a nitroso group into an amino group; reduction of a nitro-guanidino group in neutral or basic medium may first lead to the formation of a nitroso-guanidino group, whereas reduction in an acidic medium yields directly the desired amino-guanidino group. The reduction procedure may also be carried out electrolytically.

The starting materials, which are new and intended to be included within the scope of this invention, may be prepared, for example, by reacting an R-lower alkyl-amine with an S-lower alkyl-1-nitro-2-isothiourea or an S-lower alkyl-l-nitroso-Z-isothiourea or an acid addition salt of such reagents; the reaction may be carried out according to the previously-described treatment of an amine with a 1-amino-S-lower aikyl-2-isothiourea. The coiresponding O-lower alkyl-l-nitro-Z-isoureas or O-lower alkyl-l-nitroso-2-isoureas may be substituted for the 2-isothiourea reagents.

Preferred l-(R-lower alkyl)-3-nitro-guanidines and 1- (R-lower alkyl)-3-nitroso-guanidines used as the starting materials are, for example, those of the formulae:

oilin -H NHN0 in which R A and the letters m and m have the previously given meaning, and the acid addition salts thereof. Specific starting materials of that type are, for example,

1- [2- (4-methyl1-piperazino -ethyl] -3-nitro-guanidine,

1- 3- 4-methyll -piperazino -propyl] -3-nitro-guanidine,

1- 2- 4-ethyll- *iperazino -ethyl] -3-nitro-guanidine,

1- 2- 4-isopropyll-piperazino) -ethyl] -3-nitro-guanidine,

1-{2- l-N,N-( 3-aza-3-methyl-hexamethylene -imino] ethyl}-3-nitro-guanidine,

l-{2-[1-N,N-(4-aza-4-methyl-heptamethylene)-imino]- ethy1}-3-nitro-guanidine and the like, and

l- [2- (4-1nethyll-piperazino -ethyl] -3-nitr-oso-gu anidine,

1- 3- (4-methyll -piperazino -propyl] -3-nitroso-g1anidine,

1- 2- (4-ethyll-piperazino -ethyl] -3-nitroso-guanidine,

1- [2- 4-isopropyll-piperazino) -ethyl] -3-nitro soguanidine,

1-{2-[1-N,N-(3-aza-3-methyl-hexarnethylene)-imino]- ethyl}-3-nitroso-guanidine,

1-{2-[ 1-N,N- (4-aza-4-methyl-heptamethylene -imino] ethyl}-3-nitroso-guanidine and the like, and

acid addition salts of such compounds.

The new 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 an acid addition salt thereof by reacting the latter with an appropriate inorganic or organic acid, such as one of those outlined hereinabove; such reaction may be carried out, for example, by treating a solution of the base in a suitable solvent or solvent mixture with the acid or a solution thereof 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 then 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 t-formation.

Acyl derivatives of the compound of this invention, i.e. compounds of the previous formula, in which one of the groups R and R represents an acyl radical as defined hereinabove, may be prepared, for example, by treating the amino-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. Such reaction may be performed in the presence of an inert solvent, -f-or 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 a tertiary organic base, such as a liquid pyridine compound, e.g. pyridine, oollidine and the like. Acylation may also be achieved in the absence of a solvent, for example, by treating the amino-guanidine compound or a salt thereof with the acylating reagent, for example, acetic acid anhydride in a sealed tube.

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. 116,246, filed June 12, 1961, which in turn is a continuation-in-part application of my application Serial No. 76,480, filed December 19, 1960, and now abandoned.

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

Example 1 A mixture of 10 g. of 2-(4-methyl-1-piperazino)-ethylamine and 16.3 g. of S-methyl-Z-isothiosemicarbazide hydriodide in ml. of water is refluxed for four hours and then concentrated to dryness. The residue, recrystallized from a mixture of ethanol and diethyl ether, yields the 3-amino-l-[2-(4-methyl-1-piperazino)-ethyl] guanidine hydriodide of the formula:

Ego-N HI which melts at 169-172.

The starting material may be prepared as follows: f 0.4 g. of chloroacetonitrile is added dropwise to a solutron of 133 g. of 4-methyl-piperazine in 100 ml. of ethanol. The mixture is refluxed, stirred for two hours and allowed to stand overnight. The solution is concentrated under reduced pressure, the residue is treated with 270 ml. of 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-methyl-piperazinoacetonitrile, B.P. 120-125 12 mm. The product solidifies upon standing, M.P. 53-56.

A solution of g. of 4-methyl-piperazino-acetonitrile in 400 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 refluxed for 6 hours, allowed to stand overnight and decomposed by successive addition of 17 ml. of water, 20 of 30 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, B.P. 92/ 16 mm.

Example 2 A mixture of 8.55 g. of 2-(4-methyl-l-piperazino)- ethylamine and 8.32 g. of S-methyl-Z-isothiosemicarbazide hydrochloride in 25 ml. of water is refluxed for 4 /2 hours. After the strong evolution of methyl-mercaptan subsides, the solution is concentrated under reduced pressure and the residual oil crystallizes on cooling. The 3- amino-l-[2-(4-methyl-I-piperazino) ethyl] guani-dine hydrochloride of the formula is purified by recrystallization from a mixture of ethanol and acetonitrile, M.P. 156-159; yield: 10.0 g.

Example 3 5.7 g. of 1-[2-(4-methyl-1-piperazino)-ethyl1-3-nitroguanidine and 8.5 g. of zinc dust are mixed in a mortar with water to form a thick paste, which is then added to 2.5 ml. of acetic acid while stirring. The temperature is held between and during the mixing of the reagents and is then allowed to slowly rise to room temperature. The reaction mixture is warmed to 40 on the steam bath and held at that temperature for fifteen minutes. The solid material is filtered off, the filtrate is concentrated under reduced pressure to yield an acetate salt of 3 amino 1-[2-(4-methyl-1-piperazino)-ethyl]-guani dine, which is converted to the product of the procedure described in Example 2 by treatment with 6 N hydrochloric acid.

The starting material is prepared as follows: A mixture of 4.75 g. of 2-(4-methyl-1-piperazino)-ethy1-amine and 3.6 g. of S-methyl-l-nitro-Z-isothiourea in 100 ml. of ethanol is refluxed for four hours. After cooling, the 1 [2 (4-methyl-1-piperazino)-ethyl]-3-nitro-guanidine is filtered off and recrystallized from ethanol.

In the above example, the 1-[2-(4-methyl-1-piperazine)- ethyl] 3 nitro-guanidine may be replaced by 1-[2-(4- methyl l-piperazino)-ethyl]-3-nitroso-guanidine which upon reduction with zinc in acetic acid is converted into the 3 amino 1 [2-(4-methyl-1-piperazino)-ethyl]- guani-dine.

What is claimed is:

1. A member selected from the group consisting of a l-R-lower alkyl-S-amino-guanidine, in which R is N,N- (N-R -aza-alkylene)-imino of the formula:

in which each of the letters m and m represents one of the numbers 1 and 2, and R stands for lower .alkyl, and in which the amino-guanidino group has the formula:

NHNH2 and a pharmaceutically acceptable acid addition salt thereof.

2. A compound of the formula:

ennu -on, NH

mar e in which R is lower alkyl, each of the letters m and m stands for 1, and A is lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the ring-nitrogen atom by two to three carbon atoms.

3. A pharmaceutically acceptable acid addition salt of a compound of the formula:

2)m 2 NH-NHg in which R is lower alkyl, each of the letters m and m stands for 1, and A is lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the ring-nitrogen atom by two to three carbon atoms.

4. 3 amino 1 [2-(4-methyl-1-piperazino)-ethyl]- guanidine hydriodide.

5. 3 amino 1 [2 (4-methyl-1-piperazino)-ethyl]- guanidine hydrochloride.

6. A member selected from the group consisting of a compound having one of the formulae:

in which R stands for lower alkyl, each of the letters m and 111 stands for one of the numbers 1 and 2, and A is lower alkylene having from two to three carbon atoms and separating the nitroguanidino and the nitrosoguanidino group EfI'OIXl the ring-nitrogen atom by two to three carbon atoms, and an acid addition salt thereof.

7. 1 [2 (4 methyl-1-piperazino)ethyl]-3-nitroguanidine.

8. 1 [2 (4 methyl-l-piperazino)-ethyl]-3-nitrosoguanidine.

References Cited by the Examiner UNITED STATES PATENTS 3,055,882 9/62 Mull 260-239 3,055,883 9/62 Mull 260239 3,098,066 7/63 Mull 260-268 X 3,101,336 8/63 James et al. 260268 IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners.

Claims

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 1-R-LOWER ALKYL-3-AMINO-GUANIDINE, IN WHICH R IS N,N(N-R1-AZA-ALKYLENE)-IMINO OF THE FORMULA: