Патент USA US3055887код для вставки
35,655,882 Patented Sept. 25, 1962 ll 2 formed with organic acids, particularly with carboxylic' 3,055,882 acids, such as lower aliphatic carboxylic acids, for ex; REDUCTIUN PRUCESS FUR PREPARATION OF CYCLE? NETRQGEN COMPOUNDS ample, lower alkanoic acids, e.g. acetic, propionic or? pivalic acid and the like,’ substituted‘ lower alkanoic Robert Paul Mull, Florham Park, N.J., assignor to Cilia acids, e.g. trichloroacetic, hydroxyacetic or cyclopentyl~* propionic acid and the like, or lower alkenoic acids, e.g'. acrylic acid and the like, with aromatic carboxylic acids; for example, monocyclic aromatic carboxylic acids, e.g.~ The present invention concerns a process for the benzoic, hydroxybenzoic or aminobenzoic‘ acid; and the" preparation of guanidino compounds. More particu 10 like, or bicyclic aromatic carboxylic acids, e.g. l-naphe larly, the procedure of the invention relates to the man thoic or Z-naphthoic acid and the like, with carbocyclic‘ (Torporation, a corporation of Delaware No Drawing. Filed June llll, 1959, Ser. No. 819,209 11 Claims. (Cl. Mil-239) ufacture of (N,N-alkylene-imino)-lower alkyl-guani aryl-lower aliphatic acids, such as monocyclic carbocyclic dines, in which alkylene contains from four to ten car aryl-lower alkanoic acids, e.g. phenylacetic acid or [3 bon atoms as ring members, and the salts thereof. Also phenylpropionic acid and the like, or with heterocyclic anticipated are quaternary ammonium compounds and 15 carboxylic acids, for example, monocyclic heterocyclic acyl derivatives of these compounds, whenever prepared carboxylic acids, e.g. nicotinic, isonicotinic or 2-furoic according to the procedure of the invention. acid and the like. N,N-alkylene-imino radicals, containing from four to The above-mentioned derivatives and salts thereof have ten carbon atoms, primarily from six to eight carbon antihypertensive properties and can be used as antihyper atoms, are unsubstituted, or may contain as further sub tensive agents to relieve hypertensive conditions, par stituents of carbon atoms lower hydrocarbon radicals, such as lower alkyl, e.g. methyl or ethyl. They may be ticularly neurogenic or renal hypertension. A particular characteristic of this antihypertensive effect is its long represented by N,N-tetramethylene~imino (l-pyrrolidino), duration, which property is especially desirable in the N,N-pentamethylene-imino (l-piperidino), N,N-hexa treatment of chronic hypertensive states. Particularly methylene-imino (l-hexahydro-azepino), N,N-hepta 25 valuable with respect to their long-lasting antihyperten methylene-imino (l-octahydroazocino), N,N-octamethyl sive activity are the (N,N-alkylene-imino)-lower alkyl ene-imino (l~octahydro - azonino), N,N-nonamethylene guanidines, in which the N,N-alkyleneimino iportion con imino (l-decahydro-azecino) or N,N-decamethylene tains from six to eight, primarily seven, carbon atoms, imino radicals. _ and carries no additional substituents or only methyl The lower alkyl radical, linking the alkylene-imino groups, and in which lower alkyl, containing from two to three carbon atoms, separates the N,N-alkylene-imino portion from the guanidino group by two to three car bon atoms, and their salts with inorganic acids, such as mineral acids, e.g. hydrochloric or sulfuric acid, or with ring with the guanidino group, contains from two to seven carbon atoms and is represented by a lower alkyl ene radical, which may also be branched. Such alkyl ene radicals contain preferably from two to three carbon atoms and are represented, for example, by 1,2-ethylene, 1-methyl-l,2 ethylene, 2-methyl-l,2-ethylene or 1,3-propyl organic acids, such as hydroxy-substituted aliphatic acids, e.g. tartaric or citric acid, or unsaturated aliphatic acids, e.g. maleic acid. This group is represented by the (N,N ene; additional alkylene radicals are, for example, 2,3 butylene, 1,3-butylene, 1,4-butylene, 1,4-pentylene, 1,5 heptamethylene-imino)-lower alkyl guanidines, particu pentylene and the like. larly the guanidine compound of the formula: The guanidino group is preferably unsubstituted. 40 However, the amino, as well as the irnino groups of the guanidino portion may be substituted by lower hydro carbon radicals, such as lower alkyl, e.g. methyl or ethyl. Such substituted guanidino groups are, for example, N U NH2 monomethyl-, N-polymethyl-, N-monoethyl— or N~poly 45 ethyl-guanidino groups. and their therapeutically useful inorganic acid addition Salts of the compounds prepared according to the salts, particularly their sulfates. The process of this invention comprises converting in process of this invention are particularly therapeutically (N,N-alkylene-imino)-lower alkyl carboxylic acid gua useful acid addition salts, such as ‘those with inorganic acids, for example, hydrohalic acids, e.g. hydrochloric 50 nides or guanidino-lower alkyl carboxylic acid N,N-lower alkylene-imides, the carbonyl group of the amide por tion to a methylene group, and, if desired, converting a or hydrobromic acid, sulfuric or phosphoric acids, or those with organic acids, such as formic, acetic, propi_ onic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxy maleic, dihydroxymaleic, benzoic, phenylacetic, 4-amino resulting salt into the free compound, and/or, if de sired, converting the free compound into a salt, an acyl 55 or a quaternary ammonium derivative thereof. The reduction of the carbonyl portion of the amide‘ benzoic, 4-hydroxybenzoic, anthranilic, cinnamic, man delic, salicylic, 4- aminosalicylic, Z-phenoxybenzoic, 2 acetoxy-benzoic, methane sulfonic, ethane sulfonic, hy groups may be carried out by treatment with an aluminum hydride, particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride or sodium aluminum hy droxyethane sulfonic acid and the like. The guanidine compounds may also form quaternary 60 dride, or an earth alkaline metal aluminum hydride, e.g. magnesium aluminum hydride, or aluminum hydride. ammonium compounds, particularly those with lower The reduction with these reagents is preferably performed alkyl halides, e.gl methyl, ethyl, propyl or isopropyl chlo in the presence of a solvent, particularly an ether, such ride, bromide or iodide, or lower alkyl lower alkane as a di-lower alkyl ether, e.g. diethyl ether, a lower alkyl sulfonates, e.g. methyl or ethyl methane or ethane sul fonate, as well as the corresponding quaternary am monium hydroxides and the salts which may be formed from the quaternary ammonium hydroxides by the reac 65 carbocyclic aryl ether, e.g. anisole, a di-carbocyclic aryl ether, e.g. diphenyl ether, or a cyclic ether, e.g. tetra hydrofurane or p-dioxane, and, if desired, at an elevated tion with inorganic acids other than hydrohalic acids temperature and/or in the atmosphere of an inert gas, e.g. nitrogen. or with orgahic acids, such as those outlined above for the preparation of the acid addition salts. The desired conversion may also be carried out by 70 Acyl derivatives of the guanidine compounds prepared electrolytically reducing the amide derivatives on a cath according to the procedure of this invention are those ode of a high overpotential such as a cadmium, zinc, 3,055,882 4 alkylene-imine with a cyano-lower alkyl-halide, e.g. chlo ride, and reducing in a resulting (2-oxo-l-l\I,N-alkylene mercury, lead amalgam or lead. The catholyte used in such a reduction is preferably a mixture of water, sul imino)-lower alkyl nitrile the nitrile group to a methyl eneamino group, which may be accomplished, for ex ample, by treatment with a hydride, such as an aluminum furic acid and a lower alkanoic acid, e.g. acetic or pro pionic acid. A platinum, carbon, lead or stainless steel anode may be used; the anolyte is preferably sulfuric acid. The starting materials used in the above reduction pro cedure may be prepared, for example, by treating a re hydride, e.g. lithium aluminum hydride. The 2-0240-1 N,N-alkylene-imine may also be reacted with a lower alkene-nitrile, e.g. acrylonitrile, to yield the (2-oxo-1-N,N alkylene-imino)-lower alkyl nitrile, which is then re active functional derivative of an (N,N-alkylene-imino) lower alkyl carboxylic acid or of a guanidino-lower alkyl duced to the desired amino compound as shown herein carboxylic acid with a guanidino or an N,N-alkylene above. The thus obtained (2-ox0-1-N,N-alkylene-imi imine, respectively, to form the desired amide com pounds. Reactive derivatives of carboxylic acids are, for example, esters, such as lower alkyl, e.g. methyl or ethyl, esters of activated esters, which are particularly no)-lower alkyl-amine may then be converted to the cor responding guanidine, for example, by treatment with a salt of an S-lower alkyl-isothiourea, such as the S methyl-isothiourea sulfate. useful for the formation of amide bonds, such as esters A resulting (2-oxo-1-N,N-alkylene-imino)-lower alkyl with reactive mercaptan compounds, e.g. mercapto-acetic guanidine compound may be converted to the (Z-thiono l-N,N-alkylene-imino)-lower alkyl-guanidine, for exam ple, by treatment with phosphorus trisul?de or phosphorus ing to procedures which are known for the manufacture of analogous esters. Other reactive functional deriva~ 20 pentasul?de as shown hereinbefore. acid, or with reactive hydroxyl compounds, e.g. hy droxy-acetonitrile. Such esters may be prepared accord tives of acids are the acid addition salts of acid halides, particularly the hydrochloride of an acid chloride, which maybe prepared according to standard methods. The reaction of these reactive functional derivatives of carboxylic acids with the amino compounds may be 25 carried out, for example, by treating a salt of an acid The above-described starting materials are new and are intended to be included within the scope of this inven tion. Such compounds are, for example, (N,N-alkylene imino)-lowcr alkyl carboxylic acid guanides, in which alkylene has the above-given meaning, and salts thereof. A preferred group of compounds are (N,N~alkylene imino)-lower alkyl carboxylic acid guanides, in which halide, particularly the hydrochloride of an acid chloride with the amine, preferably in a polar, but non-hydrox ylated solvent, such as, for example, dimethylformamide, alkylene contains from six to eight carbon atoms, the lower alkyl carboxylic acid portion contains from two to three carbon atoms, separating the N,N-alkylene-imino diethyleneglycol dimethylether, dioxane, tetrahydrofuran portion from the guanidino group by two to three car and the like. A modi?cation of the above procedure comprises the bon atoms, and the guanidino group ,is otherwise unsub stituted. This preferred group may be represented by converting in (N,N-alkylene-imino)-lower alkyl thiocar the (l-N,N-heptamethylene-imino)-acetic acid guanide. boxylic acid guanides or guanidino-lower alkyl thiocar boxylic acid N,N-alkylene-imides, the thiocarbonyl group 35 These amide compounds may also be prepared by treating a reactive ester, formed by a hydroxy-lower alkyl car of the thioarnide portion into a methylene group, and, if boxylic acid guanide with a strong acid, for example, a desired, carrying out the optional steps. hydrohalic acid, e.g. hydrochloric acid, with the N,N The replacement of the sulfur in the above-mentioned thioamides may be carried out by desulfurization, for example, with a freshly prepared hydrogenation catalyst, alkylene-imine, if desired, in the form of a salt, such as Such reactive esters are, 40 an alkali metal salt thereof. for example, chloro-lower alkyl carboxylic acid guanides. such as Raney nickel, in an alcoholic solvent, e.g. meth Another group of valuable intermediates are the (N,N anol or ethanol, if desired, in the presence of hydrogen, alkylene-imino)-lower alkyl thiocarboxylic acid guanides, or electrolytically according to the procedure outlined in which alkylene has the above-given meaning, and salts hereinabove for the reduction of the amides. The thioamides used as the starting materials in this 45 thereof. These compounds are represented by the group modi?cation may be prepared from the corresponding amides previously mentioned, for example, by treatment with phosphorus trisul?de or phosphorus pentasul?de. A modi?cation may consist in electrolytically reducing of (N,N-alkylene-imino)-lower alkyl thiocarboxylic acid guanides, in which alkylene contains from six to eight carbon atoms, the lower alkyl thiocarboxylic acid portion contains from two to three carbon atoms, and separates the amide in the presence of an alkali metal sul?de, e.g. 50 the N,N-alkylene-imino portion ‘from the guanidino group by two to three carbon atoms, and the guanidino sodium sul?de, thereby forming the thioamide as a non group is otherwise unsubstituted; the (1-N,N-heptameth isolated intermediate. ylene-imino)-thioacetic acid guanide illustrates this pre Another method to prepare the above described guani ferred group. dino compounds comprises replacing in (2-R-l-N,N alkylene-imino)-lower alkyl-guanidines, in which R rep 55 resents an oxo group of the formula =0 or a thiono group of the formula :8, such group by two hydrogen atoms, and, if desired, carrying out the optional steps. The above-mentioned oxo and thiono groups form to Also included are the guanidino-lower alkyl carboxylic acid N,N-alkylene-imides, in which alkylene has the above-given meaning, and salts thereof. This series of intermediates is represented by the preferred group of guanidino-lower alkyl carboxylic acid N,N-alkylene gether with the nitrogen atom of the N,N-alkylene-imino 60 imides, in which alkylene contains from six to eight car bon atoms, the lower alkyl carboxylic acid portion con portion an amide or a thioamide group. Such groups tains from two to three carbon atoms, separating the N,N may be converted into the desired methyleneimino group alkylene-imino portion from the guanidino group by the by the previously described procedures; for example, an same number of carbon atoms, and the guanidino group oxo group of an amide grouping may be replaced by two hydrogen atoms by treatment with an aluminum 65 is otherwise unsubstituted. The guanidino-acetic acid hydride, such as lithium aluminum hydride, or a thiono group of a thioamide grouping may be exchanged for two hydrogen atoms by desulfurization with a freshly prepared hydrogenation catalyst, such as Raney nickel. These reactions are carried out as previously shown. The starting material used in this modi?cation may be prepared, for example, by introducing into a 2-oxo-1 N,N-alkylene-imine an amino-lower alkyl radical, which may be accomplished, for example, by reacting an alkali metal, e.g. lithium or sodium, salt of the 2~oxo-1-N,N 75 N,N-heptamethylene-imide represents this preferred group of compounds. These compounds may also be prepared, ‘for example, by treating a guanidine with a reactive ester, formed by a hydroxy-lower alkyl car boxylic acid N-N-alkylene-imide and a strong acid, such as a mineral acid, e.g. hydrochloric acid. Such reac tive esters are, for example, chloro-lower alkyl carboxylic acid N,N-lower alkylene-imides. Furthermore, the above-disclosed guanidino-lower al kyl thiocarboxylic acid N,N-alkylene-imides, in which 3,055,882‘ 5 alkylene has the previously given meaning, and their salts are also part of the present invention. The reaction is preferably carried out in an inert solvent, for example, in a hydrocarbon, such as an aliphatic hy They are rep resented by the preferred group of guanidino-lower alkyl drocarbon, e.g. hexane, or an aromatic hydrocarbon, thiocarboxylic acid N,N-alkylene-imides, in which alkyl e.g. benzene, toluene or xylene, or in a tertiary organic base, such as a liquid pyridine compound, e.g. pyridine ene contains from six to eight carbon atoms, the lower alkyl thiocarboxylic acid portion contains ‘from two to or collidine. three ‘carbon atoms, separating the N,N-alkylene-imino portion from the guanidino group by two to three carbon The guanidine compounds may be converted into the quaternary ammonium compounds by reacting the ter atoms, and the guanidino group is otherwise unsubsti tiary bases with an ester formed by a hydroxylated lower tuted, and illustrated, for example, by the guanidino-thio 10 hydrocarbon compound with a strong inorganic or or— acetic acid l-N,N-heptarnethylene-imide. ganic acid. Hydroxylated lower hydrocarbon compounds The (2-oxo-1-N,N-alkylene-imino)-lower alkyl-guani contain from one to seven carbon atoms and the esters dines, in which ‘alkylene has the previously given mean thereof are more especially those with mineral acids, e.g. ing, as well as their salts, represent a further group of valuable intermediates, which may be illustrated by the preferred group of (2-oxo-1-N,N~alkylene-imino)-lower alkyl-guanidines, in which alkylene contains from six to eight carbon atoms, lower alkyl contains from two to three carbon atoms separating the guanidino group from the alkylene-imino portion by two to three carbon atoms, and the guanidino group is otherwise unsubstituted. The hydrochloric, hydrobromic, hydriodic, or sulfuric acid. Such esters are speci?cally lower alkyl halides, e.g. methyl, ethyl or propyl chloride, bromide or iodide, or lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate. The quaternizing reaction may be performed in the presence or absence of a sol 20 vent; suitable solvents are more especially lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, tertiary 2 - (2~oxo-1-'N,N-heptamethylene-imino)-ethyl-guanidine butanol or pent-anol, lower alkanones, e.g. acetone or represents one of the preferred members. Also included are the (2-thiono-1-N,N-alkylene ethyl methyl ketone, or organic acid amides, e.g. form amide or dimethylformamide. If necessary, an elevated temperature and/ or a closed vessel may be employed. imino)-lower alkyl guanidines, in which alkylene has the previously given meaning, and the salts thereof. A pre ferred group of these intermediates are the (Z-t-hiono-l The invention also comprises any modi?cation of the general process wherein a compound obtainable as an intermediate at any stage of the process is used as start TN,N-alkylene-imino)-lower alkyl-guanidines, in which al lkylene contains from six to eight carbon atoms and lower :alkyl from two to three carbon atoms separating the guanidino group‘ from the alkylene-imino portion by two to three carbon atoms, whereas the guanidino group is otherwise unsubstituted. This group may be represented by the 2-(2-thiono-1-N,N-heptamethylene-imino)-ethyl .guanidine. A combination of the two principal modi?cations of the process of the present invention may also be antic ipated. For example, upon treatment of a (Z-oxo-l ing material and the remaining steps(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 ?nal products men tioned in the beginning as preferred embodiments of the invention. 35 As used herein, the term “thiocarboxylic acid” (or derivative thereof) refers to a structure in which the sulfur is a thiono sulfur, i.e, double bonded to carbon. The following examples illustrate the invention and are ZN,N-alkylene-imino')-lower alkyl carboxylic acid guanide not to be construed as being limitations thereon. Tem or of a guanidino-lower alkyl-carboxylic acid 2-oxo-1 40 peratures are given in degrees centigrade. N,N-alkylene-imide, in which alkylene has the above given meaning, with one of the reduction reagents pre viously described, the desired (N,N-alkylene-imino) lower alkyl~guanidines described hereinbefore, may be Example 1 13.6 g. of chloroa-cetyl guanide is added while stirring to a solution of ‘22.6 g. of heptamethylene-imine in 200 formed. The starting materials used in such a procedure 45 ml. of benzene. After warming for one hour, and then may be prepared along the previously outline procedures cooling, the solution is ?ltered and the ?ltrate concen by selecting the appropriate intermediates. trated under reduced pressure. Likewise, (2-thiono-l-N,N-alkylene-imino)-lower alkyl The residue, containing the 2-('1-N,N-heptamethylene thiocarboxylic acid guanides or guanidino-lower alkyl imino)~acetic acid guanide, is suspended in tetrahydro thiocarboxylic acid 2-thiono-1-N,=N-alkylene-imides may 50 furane and added to a re?uxing solution ‘of 6 g. of lithium be converted to the desired (N,N-alkylene-imino)-lower aluminum hydride in tetrahydrofuran. After comple alkyl-guanidines, for example, by desulfurization as out tion of the reaction, the excess of lithium aluminum lined hereinabove. The above starting materials may be hydride is decomposed by adding water, then aqueous prepared according to the previously outline procedures sodium hydroxide. The solid material is ?ltered off, the by selecting the appropriate intermediates. 55 ?ltrate is acidi?ed with sulfuric acid and the 2-(1-N,N Depending on the conditions used, the guanidine com pounds are 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 an alkaline reagent, such as an aqueous 60 alkali metal hydroxide, e.g. lithium, sodium or potas sium hydroxide, an aqueous alkali metal carbonate, e.g. lithium, sodium or potassium carbonate or hydrogen heptarnethylene-imino)-ethyl-guanidine sulfate can be re covered and recrystallized from aqueous ethanol, M.P. 276-281 ° (with decomposition) . Example 2 16.6 g. of 3a(2-oxo-1-N,N-hexamethylene-imino) propionitrile is dissolved in absolute ethanol and hydro genated over 2 g. of Raney nickel ‘at a temperature of about 125° and under pressure. After the necessary transformed into its therapeutically useful acid addition 65 amount of hydrogen is taken up, the solution is cooled carbonate, or aqueous ammonia. A free base may be salts by reaction with an appropriate inorganic or organic acid, such as one of those outlined hereinabove, pref erably in the presence of a solvent, such as a lower al ‘and the catalyst removed by ?ltration. The ?ltrate is treated with 13.9 g. of S-methyl-isothiourea sulfate; the mixture is re?uxed until the evolution of methyl-mercap kanol, e.g. methanol, ethanol, propanol or isopropanol, tan ceases. The solution is concentrated under reduced or an ether, e.g. diethylether or p-dioxane, and the like. 70 pressure, the residue is taken into water, aqueous sodium Acyl derivatives of the guanidine compounds of the present invention may be prepared, for example, by treat— ing a resulting guanidine compound with the reactive derivative of a carboxylic acid, for example, with \a halide, hydroxide is added, and the aqueous layer is extracted with ether. The ether solution is dried and then added to a solution of 5 g. of lithium aluminum hydride in 500 ml. of ether. e.g. chloride, or with the anhydride of a carboxylic acid. 75 The reaction mixture is re?uxed overnight, the excess of 3,055,882 7 3 and the lower alkyl thiocarboxylic acid portion has from lithium aluminum hydride is decomposed by adding water two to three carbon atoms and separates the N,N-alkyl ene-imino portion from the guanidino group by two to and the reaction mixture is ?ltered. The solvent is evap orated, and the residue, containing the 3-(N,N-hexameth ylene-imino)-propyl-guanidine, is converted to the sul fate by adding dilute sulfuric acid and concentrating the three carbon atoms, and acid-addition salts thereof. 5. (1-N,N-heptamethylene-imino)-acetic acid guanide. 6. (1~N,N-heptamethylene-imino)thioacetic acid gua aqueous solution. nide. The starting material may be prepared by slowlyv add 7. Guanidino acetic acid N,N-heptamethylene-imide. ing to a solution of 56.5 g. of caprolactam in 150 ml. 8. Guam'dino - thioacetic acid N,N - heptamethylene of p-dioxane, 28 g. of acrylonitrile while stirring and cooling. A few drops of a strong base, such as benzyl trimethylammonium hydroxide, are added to initiate the reaction, and the temperature is maintained between 30 35° for one-half hour. The mixture is allowed to stand for several days at room temperature, and is then acidi?ed imide. 9. A member selected from the group consisting of imino)-propionitrile by distillation, B.P. l33-l36°/ 0.3 the 2-R-l-N,N-alkylene-imino portion from the guanidino (2-R-1—N,N-alkylene~imino)-lower alkyl-guanidine, in which alkylene has six to eight carbon atoms, R is a member selected from the group consisting of 0x0 of the with hydrochloric acid. The residue, after evaporating 15 formula =0 and thiono of the formula :8, and lower alkyl has from two to three carbon atoms and separates the solvent, yields the desired 3-(l-N,N-hexamethylene group by two to three carbon atoms, and addition salts thereof. What is claimed is: 10. 2 - (2 - oxo - 1 - N,N - heptamethylene - imino) 1. A member selected from the group consisting of 20 mm. ethyl-guanidine. (N,N-alkylene-imino)-lower alkyl carboxylic acid gua 11. 2 - (2 - thiono - 1 - N,N - heptamethylene - imino) nide, in which alkylene has six to eight carbon atoms, and the lower alkyl carboxylic acid portion has from two to three carbon atoms and separates the N,N-alkylene imino portion from the guanidino group by two to three carbon atoms, and acid addition salts thereof 2. A member selected from the group consisting of ethyl-guanidine. References Cited in the ?le of this patent UNITED STATES PATENTS 2,846,382 2,852,510 2,852,528 2,909,523 2,957,867 (N,N-alkylene-imino)-lower alkyl thiocarboxylic acid guanide, in which alkylene has six to eight carbon atoms, and the lower alkyl thiocarboxylic acid portion has from two to three carbon atoms and separates the N,N-alkyl ene-imino portion from the guanidino group by two to three carbon atoms, and acid-addition salts thereof. guanidino-lower alkyl carboxylic acid N,N-alkylene 1958 1958 1958 1959 1960 FOREIGN PATENTS 3. A member selected from the group consisting of imide, in which alkylene has six to eight carbon atoms, and the lower alkyl carboxylic acid portion has from Allen _________________ __ Aug. 5, Hoffmann et al ________ __ Sept. 16, Ho?mann et al ________ .. Sept. 16, Bach et al. ___________ __ Oct. 20, Werner _____________ __ Oct. 25, 35 874,447 Germany ____________ __ Apr. 23, 1953 OTHER REFERENCES Cook et al.: J. 'Phys. Chem., vol. 36, pp. 2383-89 two to three carbon atoms and separates the N,N-alkyl ene-imino portion from the guanidino group by two to (1932). Sidgwick: Organic Chemistary of Nitrogen (1937), 40 three carbon atoms, and acid-addition salts thereof. pp. 297-298. 4. A member selected from the group consisting of guanidino-lower alkyl thiocarboxylic acid N,N-alkylene imide, in which alkylene has six to eight carbon atoms, Migrdichian: Organic Synthesis, v01. 1, pp. 176-186 (1957).