United States Patent bffice 3,055,882

Patented Sept. 25, 1962 2 3,055,882 formed with organic acids, particularly with carboxylic REDUCTION PROCESS FOR PREPARATION OF acids, Such as lower aliphatic carboxylic acids, for ex CYCLEC NETRO GEN COMPOUNDS ample, lower alkanoic acids, e.g. acetic, propionic or Robert Paul Mull, Florham Park, N.Y., assignor to Ciba piyalic acid and the like, substituted lower alkanoic Corporation, a corporation of Delaware acids, e.g. trichloroacetic, hydroxyacetic or cyclopentyl No Drawing. Fied June 10, 1959, Ser, No. 89,209 propionic acid and the like, or lower alkenoic acids, e.g. (Cais. (C. 260-239) 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 O like, or bicyclic aromatic carboxylic acids, e.g. 1-naph larly, the procedure of the invention relates to the man thoic or 2-naphthoic acid and the like, with carbocyclic ufacture of (N,N-alkylene-imino)-lower alkyl-guani ary-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 g bon atoms as ring members, and the salts thereof. Also phenylpropionic acid and the like, or with heterocyclic anticipated are quaternary ammonium compounds and 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 20 tensive agents to relieve hypertensive conditions, par stituents of carbon atoms lower hydrocarbon radicals, ticularly neurogenic or renal hypertension. A particular such as lower alkyl, e.g. methyl or ethyl. They may be characteristic of this antihypertensive effect is its long represented by N,N-tetramethylene-imino (1-pyrrolidino), duration, which property is especially desirable in the N,N-pentamethylene-imino (1-piperidino), N,N-hexa treatment of chronic hypertensive states. Particularly methylene-imino (1-hexahydro-azepino), N,N- hepta 25 valuable with respect to their long-lasting antihyperten methylene-imino (1-octahydroazocino), N,N-octamethyl sive activity are the (N,N-alkylene-imino)-lower alkyl ene-imino (1-octahydro - azonino), N,N-nonamethylene guanidines, in which the N,N-alkyleneimino portion con imino (1-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 30 groups, and in which lower alkyl, containing from two ring with the guanidino group, contains from two to to three carbon atoms, separates the N,N-alkylene-imino seven carbon atoms and is represented by a lower alkyl portion from the guanidino group by two to three car ene radical, which may also be branched. Such alkyl bon atoms, and their salts with inorganic acids, such as ene radicals contain preferably from two to three carbon mineral acids, e.g. hydrochloric or sulfuric acid, or with atoms and are represented, for example, by 1,2-ethylene, organic acids, such as hydroxy-substituted aliphatic acids, 1-methyl-1,2 ethylene, 2-methyl-1,2-ethylene or 1,3-propyl e.g. tartaric or citric acid, or unsaturated aliphatic acids, ene; additional alkylene radicals are, for example, 2,3- e.g. maleic acid. This group is represented by the (N,N- 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 NH However, the amino, as well as the imino groups of the 2 guanidino portion may be substituted by lower hydro N-CH2C-N-C H. N. carbon radicals, such as lower alkyl, e.g. methyl or ethyl, NE Such Substituted guanidino groups are, for example, N monomethyl-, N-polymethyl-, N-monoethyl- or N-poly ethyl-guanidino groups. 45 and their therapeutically useful inorganic acid addition Salts of the compounds prepared according to the Salts, particularly their sulfates. process of this invention are particularly therapeutically The process of this invention comprises converting in useful acid addition salts, such as those with inorganic (N,N-alkylene-imino)-lower alkyl carboxylic acid gua acids, for example, hydrohalic acids, e.g. hydrochloric 50 nides or guanidino-lower alkyl carboxylic acid N,N-lower or hydrobromic acid, sulfuric or phosphoric acids, or alkylene-imides, the carbonyl group of the amide por those with organic acids, such as formic, acetic, propi tion to a methylene group, and, if desired, converting a onic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, resulting salt into the free compound, and/or, if de maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxy sired, converting the free compound into a salt, an acyl maleic, dihydroxymaleic, benzoic, phenylacetic, 4-amino 55 OT a quaternary ammonium derivative thereof. benzoic, 4-hydroxybenzoic, anthranilic, cinnamic, man The reduction of the carbonyl portion of the amide delic, salicylic, 4- aminosalicylic, 2-phenoxybenzoic, 2 groups may be carried out by treatment with an aluminum acetoxy-benzoic, methane Sulfonic, ethane Sulfonic, hy hydride, particularly an alkali metal aluminum hydride, droxyethane sulfonic acid and the like. e.g. lithium aluminum hydride or sodium aluminum hy. The guanidine compounds may also form quaternary 60 dride, or an earth alkaline metal aluminum hydride, e.g. ammonium compounds, particularly those with lower magnesium aluminum hydride, or aluminum hydride. alkyl halides, e.g. methyl, ethyl, propyl or isopropyl chlo The reduction with these reagents is preferably performed ride, bromide or iodide, or lower alkyl lower alkane in the presence of a solvent, particularly an ether, such sulfonates, e.g. methyl or ethyl methane or ethane sul as a di-lower alkyl ether, e.g. diethyl ether, a lower alkyl fonate, as well as the corresponding quaternary am 65 carbocyclic aryl ether, e.g. anisole, a di-carbocyclic aryl monium hydroxides and the salts which may be formed ether, e.g. diphenyl ether, or a cyclic ether, e.g. tetra from the quaternary ammonium hydroxides by the reac 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, or with organic acids, such as those outlined above for e.g. nitrogen. the preparation of the acid addition salts. The desired conversion may also be carried out by Acyl derivatives of the guanidine compounds prepared 70 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 3 4. mercury, lead amalgam or lead. The catholyte used in alkylene-imine with a cyano-lower alkyl-halide, e.g. chlo such a reduction is preferably a mixture of water, sul ride, and reducing in a resulting (2-oxo-1-N,N-alkylene furic acid and a lower alkanoic acid, e.g. acetic or pro imino)-lower alkyl nitrile the nitrile group to a methyl pionic acid. A platinum, carbon, lead or stainless steel eneamino group, which may be accomplished, for ex anode may be used; the anolyte is preferably sulfuric acid. ample, by treatment with a hydride, such as an aluminum The starting materials used in the above reduction pro hydride, e.g. lithium aluminum hydride. The 2-oxo-1- cedure may be prepared, for example, by treating a re N,N-alkylene-imine may also be reacted with a lower active functional derivative of an (N,N-alkylene-imino)- alkene-nitrile, e.g. acrylonitrile, to yield the (2-oxo-1-N,N- lower alkyl carboxylic acid or of a guanidino-lower alkyl alkylene-innino)-lower alkyl nitrile, which is then re carboxylic acid with a guanidine or an N,N-alkylene 0. duced to the desired amino compound as shown herein imine, respectively, to form the desired amide com above. The thus obtained (2-oxo-1-N,N-alkylene-imi pounds. Reactive derivatives of carboxylic acids are, no)-lower alkyl-amine may then be converted to the cor for example, esters, such as lower alkyl, e.g. methyl or responding guanidine, for example, by treatment with ethyl, esters of activated esters, which are particularly a salt of an S-ower alkyl-isothiourea, such as the S useful for the formation of amide bonds, such as esters 5 methyl-isothiourea sulfate. with reactive mercaptain compounds, e.g. mercapto-acetic A resulting (2-oxo-1-N,N-alkylene-imino)-lower alkyl acid, or with reactive hydroxyl compounds, e.g. hy guanidine compound may be converted to the (2-thiono droxy-acetonitrile. Such esters may be prepared accord 1-N,N-alkylene-imino)-lower alkyl-guanidine, for exam ing to procedures which are known for the manufacture ple, by treatment with phosphorus trisulfide or phosphorus of analogous esters. Other reactive functional deriva 20 pentasulfide as shown hereinbefore. tives of acids are the acid addition salts of acid halides, The above-described starting materials are new and are particularly the hydrochloride of an acid chloride, which intended to be included within the scope of this inven may be prepared according to standard methods. tion. Such compounds are, for example, (N,N-alkylene The reaction of these reactive functional derivatives imino)-lower alkyl carboxylic acid guanides, in which of carboxylic acids with the amino compounds may be 25 alkylene has the above-given meaning, and salts thereof. carried out, for example, by treating a salt of an acid A preferred group of compounds are (N,N-alkylene halide, particularly the hydrochloride of an acid chloride imino)-lower alkyl carboxylic acid guanides, in which with the amine, preferably in a polar, but non-hydrox alkylene contains from six to eight carbon atoms, the ylated solvent, such as, for example, dimethylformamide, lower alkyl carboxylic acid portion contains from two to diethyleneglycol dimethylether, dioxane, tetrahydrofuran 30 three carbon atoms, separating the N,N-alkylene-imino and the like. portion from the guanidino group by two to three car A modification of the above procedure comprises the bon atoms, and the guanidino group is otherwise unsub converting in (N,N-alkylene-imino)-lower alkyl thiocar stituted. This preferred group may be represented by boxylic acid guanides or guanidino-lower alkyl thiocar the (1-N,N-heptamethylene-imino)-acetic acid guaihide. boxylic acid N,N-alkylene-imides, the thiocarbonyl group 35 These amide compounds may also be prepared by treating of the thioamide portion into a methylene group, and, if a reactive ester, formed by a hydroxy-lower alkyl car desired, carrying out the optional steps. boxylic acid guanide with a strong acid, for example, a The replacement of the sulfur in the above-mentioned hydrohalic acid, e.g. hydrochloric acid, with the N,N- thioamides may be carried out by desulfurization, for alkylene-imine, if desired, in the form of a salt, such as example, with a freshly prepared hydrogenation catalyst, 40 an alkali metal salt thereof. Such reactive esters are, such as Raney nickel, in an alcoholic solvent, e.g. meth for example, chloro-lower alkyl carboxylic acid guanides. anol or ethanol, if desired, in the presence of hydrogen, Another group of valuable intermediates are the (N,N- or electrolytically according to the procedure outlined alkylene-imino)-lower alkyl thiocarboxylic acid guanides, hereinabove for the reduction of the amides. in which alkylene has the above-given meaning, and salts The thioamides used as the starting materials in this 45 thereof. These compounds are represented by the group modification may be prepared from the corresponding of (N,N-alkylene-imino)-lower alkyl thiocarboxylic acid amides previously mentioned, for example, by treatment guanides, in which alkylene contains from six to eight with phosphorus trisulfide or phosphorus pentasulfide. carbon atoms, the lower alkyl thiocarboxylic acid portion A modification may consist in electrolytically reducing contains from two to three carbon atoms, and separates the amide in the presence of an alkali metal sulfide, e.g. 50 the N,N-alkylene-imino portion from the guanidino sodium sulfide, thereby forming the thioamide as a non group by two to three carbon atoms, and the guanidino isolated intermediate. group is otherwise unsubstituted; the (1-N,N-heptameth Another method to prepare the above described guani ylene-imino)-thioacetic acid guanide illustrates this pre dino compounds comprises replacing in (2-R-1-N,N- ferred group. alkylene-imino)-lower alkyl-guanidines, in which R rep 55 Also included are the guanidino-lower alkyl carboxylic resents an oxo group of the formula =O or a thiono group acid N,N-alkylene-imides, in which alkylene has the of the formula FS, such group by two hydrogen atoms, above-given meaning, and salts thereof. This series of and, if desired, carrying out the optional steps. intermediates is represented by the preferred group of The above-mentioned oxo and thiono groups form to 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 portion an amide or a thioamide group. Such groups bon atoms, the lower alkyl carboxylic acid portion con may be converted into the desired methyleneimino group tains from two to three carbon atoms, separating the N,N- by the previously described procedures; for example, an alkylene-imino portion from the guanidino group by the oxo group of an amide grouping may be replaced by same number of carbon atoms, and the guanidino group 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 N,N-heptamethylene-imide represents this preferred group of a thioamide grouping may be exchanged for group of compounds. These compounds may also be two hydrogen atoms by desulfurization with a freshly prepared, for example, by treating a guanidine with a prepared hydrogenation catalyst, such as Raney nickel. reactive ester, formed by a hydroxy-lower alkyl car These reactions are carried out as previously shown. 70 boxylic acid N-N-alkylene-imide and a strong acid, such The starting material used in this modification may be as a mineral acid, e.g. hydrochloric acid. Such reac prepared, for example, by introducing into a 2-oxo-1- tive esters are, for example, chloro-lower alkyl carboxylic N,N-alkylene-imine an amino-lower alkyl radical, which acid N,N-lower alkylene-imides. may be accomplished, for example, by reacting an alkali Furthermore, the above-disclosed guanidino-lower al metal, e.g. lithium or sodium, salt of the 2-oxo-1-N,N- 75 kyl thiocarboxylic acid N,N-alkylene-imides, in which 8,055,882 S 6 alkylene has the previously given meaning, and their salts The reaction is preferably carried out in an inert solvent, are also part of the present invention. They are rep for example, in a hydrocarbon, such as an aliphatic hy 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 ene contains from six to eight carbon atoms, the lower base, such as a liquid pyridine compound, e.g. pyridine alkyl thiocarboxylic acid portion contains from two to or collidine. three carbon atoms, separating the N,N-alkylene-imino The guanidine compounds may be converted into the portion from the guanidino group by two to three carbon 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 O hydrocarbon compound with a strong inorganic or or acetic acid 1-N,N-heptamethylene-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 hydrochloric, hydrobromic, hydriodic, or sulfuric acid. valuable intermediates, which may be illustrated by the preferred group of (2-oxo-1-N,N-alkylene-imino)-lower Such esters are specifically lower alkyl halides, e.g. alkyl-guanidines, in which alkylene contains from six to methyl, ethyl or propyl chloride, bromide or iodide, or eight carbon atoms, lower alkyl contains from two to lower alkyl lower alkane sulfonates, e.g. methyl or ethyl three carbon atoms separating the guanidino group from methane or ethane sulfonate. The quaternizing reaction the alkylene-imino portion by two to three carbon atoms, may be performed in the presence or absence of a Sol and the guanidino group is otherwise unsubstituted. The 20 vent; suitable solvents are more especially lower alkanois, 2 - (2-oxo-1-N,N-heptamethylene-imino)-ethyl-guanidine e.g. methanol, ethanol, propanol, isopropanol, tertiary represents one of the preferred members. butanol or pentanol, lower alkanones, e.g. acetone or Also included are the (2-thiono-1-N,N-alkylene ethyl methyl ketone, or organic acid amides, e.g. form imino)-lower alkyl guanidines, in which alkylene has the amide or dimethylformamide. If necessary, an elevated previously given meaning, and the salts thereof. A pre 25 temperature and/or a closed vessel may be employed. ferred group of these intermediates are the (2-thiono-1- The invention also comprises any modification of the N,N-alkylene-imino)-lower alkyl-guanidines, in which al general process wherein a compound obtainable as an kylene contains from six to eight carbon atoms and lower intermediate at any stage of the process is used as start alky1 from two to three carbon atoms separating the ing material and the remaining steps(s) of the process guanidino group from the alkylene-imino portion by two is (are) carried out, as well as any new intermediates. to three carbon atoms, whereas the guanidino group is In the process of this invention such starting materials otherwise unsubstituted. This group may be represented are preferably used which lead to final products men by the 2-(2-thiono-1-N,N-heptamethylene-imino)-ethyl tioned in the beginning as preferred embodiments of the guanidine. invention. A combination of the two principal modifications of 35 As used herein, the term “thiocarboxylic acid' (or the process of the present invention may also be antic derivative thereof) refers to a structure in which the ipated. For example, upon treatment of a (2-oxo-1- sulfur is a thiono sulfur, i.e. double bonded to carbon. N,N-alkylene-imino)-lower alkyl carboxylic acid guanide The following examples illustrate the invention and are or of a guanidino-lower alkyl-carboxylic acid 2-oxo-1- not to be construed as being limitations thereon. Tem N,N-alkylene-imide, in which alkylene has the above 40 peratures are given in degrees centigrade. given meaning, with one of the reduction reagents pre Example 1 viously described, the desired (N,N-alkylene-imino)- 13.6 g. of chloroacetyl guanide is added while stirring lower alkyl-guanidines described hereinbefore, may be 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 filtered and the filtrate concen by selecting the appropriate intermediates. trated under reduced pressure. Likewise, (2-thiono-1-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 refluxing 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 filtered off, the by selecting the appropriate intermediates. 55 Depending on the conditions used, the guanidine com filtrate is acidified with sulfuric acid and the 2-(1-N,N- pounds are obtained in the form of the free compounds heptamethylene-imino)-ethyl-guanidine sulfate can be re or as the salts thereof. A salt may be converted into the covered and recrystallized from aqueous ethanol, M.P. free compound in the customary way, for example, by 276-281 (with decomposition). treatment with an alkaline reagent, such as an aqueous 60 Example 2 alkali metal hydroxide, e.g. lithium, sodium or potas 16.6 g. of 3-(2-oxo-1-N,N-hexamethylene-imino)- sium hydroxide, an aqueous alkali metal carbonate, e.g. propionitrile is dissolved in absolute ethanol and hydro lithium, sodium or potassium carbonate or hydrogen genated over 2 g of Raney nickel at a temperature of carbonate, or aqueous ammonia. A free base may be 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 salts by reaction with an appropriate inorganic or organic and the catalyst removed by filtration. The filtrate is acid, such as one of those outlined hereinabove, pref treated with 13.9 g, of S-methyl-isothiourea sulfate; the erably in the presence of a solvent, such as a lower al mixture is refluxed 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 hydroxide is added, and the aqueous layer is extracted present invention may be prepared, for example, by treat with ether. ing a resulting guanidine compound with the reactive The ether solution is dried and then added to a solution derivative of a carboxylic acid, for example, with a halide, 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 refluxed overnight, the excess of 8,055,882 7 3 lithium aluminum hydride is decomposed by adding water and the lower alkyl thiocarboxylic acid portion has from and the reaction mixture is filtered. The solvent is evap two to three carbon atoms and separates the N,N-alkyl orated, and the residue, containing the 3-(N,N-hexameth ene-imino portion from the guanidino group by two to ylene-imino)-propyl-guanidine, is converted to the sul three carbon atoms, and acid-addition salts thereof. fate by adding dilute sulfuric acid and concentrating the 5 5. (1-N,N-heptamethylene-imino)-acetic acid guanide. aqueous solution. 6. (1-N,N-heptamethylene-imino)thioacetic acid gua The starting material may be prepared by slowly add nide. ing to a solution of 56.5 g. of caprolactam in 150 ml. 7. Guanidino acetic acid N,N-heptamethylene-imide. of p-dioxane, 28 g. of acrylonitrile while stirring and 8. Guanidino - thioacetic acid N,N-heptamethylene cooling. A few drops of a strong base, such as benzyl O imide. trimethylammonium hydroxide, are added to initiate the 9. A member selected from the group consisting of reaction, and the temperature is maintained between 30 (2-R-1-N,N-alkylene-imino)-lower alkyl-guanidine, in 35 for one-half hour. The mixture is allowed to stand which alkylene has six to eight carbon atoms, R is a for several days at room temperature, and is then acidified member selected from the group consisting of oxo of the with hydrochloric acid. The residue, after evaporating 5 formula =O and thiono of the formula =S, and lower the solvent, yields the desired 3-(1-N,N-hexamethylene alkyl has from two to three carbon atoms and separates imino)-propionitrile by distillation, B.P. 133-136/0.3 the 2-R-1-N,N-alkylene-imino portion from the guanidino . group by two to three carbon atoms, and addition salts What is claimed is: thereof. 1. A member selected from the group consisting of 20 10. 2 - (2 - oxo - 1 - N,N- heptamethylene - imino)- (N,N-alkylene-imino)-lower alkyl carboxylic acid gua ethyl-guanidine. nide, in which alkylene has six to eight carbon atoms, 11. 2 - (2 - thiono - 1 - N,N- heptamethylene - imino)- and the lower alkyl carboxylic acid portion has from two ethyl-guanidine. to three carbon atoms and separates the N,N-alkylene imino portion from the guanidino group by two to three References Cited in the file of this patent carbon atoms, and acid addition salts thereof UNITED STATES PATENTS 2. A member selected from the group consisting of 2,846,382 Allen ------Aug. 5, 1958 (N,N-alkylene-imino)-lower alkyl thiocarboxylic acid 2,852,510 Hoffmann et al. ------Sept. 16, 1958 guanide, in which alkylene has six to eight carbon atoms, 2,852,528 Hoffmann et al. ------Sept. 16, 1958 and the lower alkyl thiocarboxylic acid portion has from 30 two to three carbon atoms and separates the N,N-alkyl 2,909,523 Bach et al. ------Oct. 20, 1959 ene-imino portion from the guanidino group by two to 2,957,867 Werner ------Oct. 25, 1960 three carbon atoms, and acid-addition salts thereof. FOREIGN PATENTS 3. A member selected from the group consisting of guanidino-lower alkyl carboxylic acid N,N-alkylene 35 874,447 Germany ------Apr. 23, 1953 imide, in which alkylene has six to eight carbon atoms, and the lower alkyl carboxylic acid portion has from OTHER REFERENCES two to three carbon atoms and separates the N,N-alkyl Cook et al.: J. Phys. Chem, vol. 36, pp. 2383-89 ene-imino portion from the guanidino group by two to (1932). three carbon atoms, and acid-addition salts thereof. 40 Sidgwick: Organic Chemistary of Nitrogen (1937), 4. A member selected from the group consisting of pp. 297-298. guanidino-lower alkyl thiocarboxylic acid N,N-alkylene Migrdichian: Organic Synthesis, vol. 1, pp. 176-186 imide, in which alkylene has six to eight carbon atoms, (1957).