US 3821301 A
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United States Patent 11 1 Klingler SUBSTITUTED AMINOALKYL GUANIDINES  Inventor: Karl Heinz Klingler, Langen,
Germany [73 Assignee: Deutsche Gold-und Silber-Scheideanstalt vormals Roessler, Frankfurt, Germany  Filed: Oct. 31, 1972 ] Appl. No.: 302,411
 Foreign Application Priority Data Nov. 8, 1971 Austria 9606/71  US. Cl 260/564 A, 260/50l.-l4, 260/570.6,
424/316, 424/326  Int. Cl. C07c 129/08  Field of Search 260/564 A, 501.14
[5 6] I References Cited UNlTED STATES PATENTS 4/1968 Fielder et al.. 260/564 A X 4/1968 Langis 260/564 A June 28, 1974 Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwart Attorney, Agent, or Firm-Cushman, Darby & Cushman  ABSTRACT Compounds are prepared of the formula:
R1 NH 8 Claims, N0 Drawings 1 SUBSTITUTED AMINOALKYL GUANIDINFS The invention concerns compounds of the general formula:
R1 NH where R, is hydrogen or hydroxy, R is hydroxy, hydroxymethyl or alkyl or one to six carbon atoms, R is hydrogen or alkylof one to four carbon atoms and Alk is a straight or branched chain alkylene group of two to six carbon atoms and their acid addition salts, e.g., the acid addition salts with pharmacologically acceptable acids, i.e., pharmaceutically acceptable acids.
The compounds of the inventionare pharmacologically active. They especially have high broncholytical activity as well as favorable circulatory effects (for example coronary widening activity, positive inotropic activity). H
The substituent R is preferably in the 3 or 4 position of the phenyl nucleus. If there are two substituents they are preferably in the 3,4 or 3,5 positions of the, phenyl nucleus. ln the case where the R residue is an alkyl group, preferably it has one to four carbon atoms, such as for example methyl, ethyl, propyl, butyl, isopropyl or t-butyl. In the case where R is an alkyl group, it is pref erably methyl or ethyl. Alk is for example ethylene, propylene or butylene which can be substituted with the same or different carbon atoms, especially methyl or ethyl. Preferably Alk is propylene (trimethylene) which in a given case can have a methyl substituent. Most preferably R and R areboth hydroxy.
As salts of the substituted aminoalkyl guanidines there can be prepared and employed salts of any nontoxic pharmacologically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric'acid, acetic acid, p-toluene sulfonic acid, propionic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid and citric acid.
Examples of compounds within the invention include 2-[2-(3,4-dihydroxyphenyl) -2-hydroxyethylamino] ethyl guanidine, 3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethylamino] -propyl guanidine, 2-[ l-methyl-Z- 3 ,4-dihydroxyphenyl )-2hydroxyethylamino] -ethyl guanidine, 3-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino1-propyl guanidine, l-methyl- 3-[2 -(3,5- dihydroxyphenyl) -2-hydroxy-ethylamino]-propyl guanidine, 3-[2-(4-hydroxyphenyl) -2- hydroxyethylamino] -propyl guanidine, 3-[2-(3- hydroxy-4-hydroxymethyl) -2-hydroxyethylamino] l-ethyl propyl guanidine, 3-[2-(3-hydroxy4-methylphenyl) -2-hydroxy-ethylamino] -propyl guanidine, 4-[2-(4-hydroxy-methylphenyl) -2- hydroxyethylamino] -butyl guanidine, 3-[2-( 3- hydroxy-4-butyl-phenyl) Z-hyd'roxyethylamino] propyl guanidine, 3-[2-(3-hydroxy-5-ethyl-phenyl) -2- hydroxy-ethylamino]. propyl guanidine, 3-[2-(4-tbutylphenyl) -2-hydroxyethylamino] propyl guanidine 3-[2-(3 -hydroxy-4-hexyl-phenyl) -2 hydroxyethylamino] l-ethylpropyl guanidine, 2-[l-ethyl-2-(3,4- dihydroxyphenyl) -2-hydroxy-ethylamino] -ethyl guanidine, 3-.[ 1-butyl-2-(3,5-dihydroxyphenyl) -2- hydroxyethyl-amino1 propyl guanidine, 2-[2-(2,6-
where R R and R as well as Alk are as defined above 7 with a reagent which converts the amino group into a guanidine group, or
b. by reacting a compound of the formula R, OH 5 where R R and R are as defined above and X is a halogen atom (e.g., chlorine or bromine) or else X forms an epoxide ringwith the secondary hydroxy group with an aminoalkylguanidine of the formula:
where Alk is'as definedabove, or
c. reducing a compound of formula I which has a keto group in place of the secondary hydroxy group or instead of the secondary amino group contains an imino group to form a compound of formula I.
In the above recited processes, it is frequently expedient to protect the phenolic hydroxyl groups as well as the amino groups by a known protective group. Frequently such protective groups are already required for the starting compounds. These protective groups are easily splittable from the end products. It is either a matter of easily solvolytic splittable acyl groups or bydrogenating splittable groups as for example the benzyl group. The solvolytic splittable protective groups are split off for example by saponification with dilute acids at room temperature or by a short boiling. According to the type of protective group, however, the splitting also takes place during the reaction process. For example, the latter is the case if the amino group as well as, ina given case, the phenolic hydroxyl group also are protected by a benzyl group or a'carbobenzoxy group and. for example a keto group is hydrogenated. If the protective group is not split off during the reaction, a simple after treatment of the reaction product is necessary wherein then the splitting. off of the protective groups takes place, for example under the conditions given above. I
As protective groups for the amino groups there can be used, for example: the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus such as, for example, the p-bromo or pnitrobenzyl group,v the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the phthalyl group, the trityl group, the p-toluenesulfonyl group and similar groups. These same protective groups can be used for the phenolic hydroxyl groups; additionally there can be used simple acyl groups, as, for example, the acetyl group.
, Process (a) can be carried out in solution or as a molten mixture at temperatures between 20 and 150C, in a given case under elevated pressure. As solvents there can be used, for example, water or organic solvents such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, or butanol, benzene, toluene, xylene, dioxane, alcohol water mixtures. As reagents which convert an amino group into the guanidine group there can be used especially S-alkylisothioureas wherein the alkyl is preferably a straight or branched chain alkyl group having one to six carbon atoms, e.g., S-methyl isothiourea, S-ethyl isothiourea, S-propyl isothiourea,
S-butyl isothiourea, Sf-t-b'utyl isothiourea and S-hexyl isothiourea, cyanamide or guanidine. These compounds can be employed as the free base or in the form of the usual acid addition salts, e.g., sulfates, hydrochlorides, etc.
Process (b) canbe carried out with or without solvents, for example at temperatures between to -l00C. As solvents here can be used organic solvents such as alcohols, e.g., propyl alcohol or the otheralcohols set forth above, aromatic liquid hydrocarbons such as benzene, toluene and xylene, or dimethyl formamide, etc.
Process (c) is carried out suitably in a solvent or in suspension at temperatures between 0 and 100C. As solvents or suspending agents there can be used water, lower aliphatic alcohols, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol, propyl alcohol or butyl alcohol, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, e.g., diethyl ether, dimethyl formamide, etc., as well as mixtures of the agents with each other. Preferably the reduction takes place through catalytic hydrogenation. As catalysts there can be used the customary finely divided metal catalysts such as, for
example, noble metal catalysts (platinum, palladium) or nickel. The catalysts can be added with or without carriers. There can be employed normal pressure or elevated pressure. If the phenolic hydroxyl groups or the secondary amino groups contain hydrogenolytically splittable groups as for example benzyl groups, then these protective groups are simultaneouslysplit off in the catalytic hydrogenation, if, for example, there ,is used a palladium catalyst.
The reduction of the keto group can also take place through other known reducing agents which reduce a keto group to the hydroxy group. These types of reducing agents are for example: nascent hydrogen (zinc/acid such as zincglacial acetic acid or zinc-hydrochloric acid-aluminum amalgam), metal hydrides or complex metal hydrides (such as Lil-l, Li Al H alkali borohydrides, e.g., sodium borohydride, sodium triethoxy aluminum hydride), aluminum alcoholates such as aluminum isopropylate/isopropanol (Meerwein Ponndorf process), etc. lfR is the hydroxymethyl group under mild conditionsthere is obtained the end product of formula I where R is CH OH and by stronger conditions the end product where R is CH To obtain the CH OH group it is suitable towork at low or only slightly elevated temperature as well as at normal pressure and starting compounds employed as the base. An-
other possibility is to reduce the ketone with a reducing agent that only attacks the keto group, especially complex metal hydride (such as sodium borohydride or lithium aluminum hydride) and in a given case subsequently splitting off the protective groups by catalystic hydrogenation under mild conditions.
To recover end products of formula I in which R is CH in the case where the starting material has a CH OH group as R the material is hydrogenated until the calculated amount of hydrogen is taken up for the reduction of the keto group and the hydroxymethyl group as well as in a given case for the splitting off of the protective groups (acid' pH range and elevated pressure are favorable for this).
In the case that an imino group is reduced, process (0) can also be carried out by directly hydrogenating the reaction product (Schiffs base) from a compound of the formula without previous isolation of the Schiffs base. This reaction of a compound of formula V with a compound of formula V1 is generally carried out in a solvent such as water, lower aliphatic alcohols such as those specified above, e.g., ethyl alcohol, isopropyl alcohol, cyclic ethers such as dioxane, dimethyl formamide, etc. or mixtures of these agents at temperatures between 0 to C. This condensation can be carried out from the beginning under the hydrogenation conditions.
The compounds can be converted in known manner into salts. As anions for the salts there can be used those previously known and therapeutically usable acids such as those set forth above, e.g., hydrochloric acid, hydrogen peroxide, sulfuric acid, acetic acid, ptoluene sulfonic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid, etc.
The free bases can be produced again from the salts of the compounds in customary manner, for example, by treatment of a solution in an organic solvent such as alcohols (e.g., methanol, ethanol, butanol) with soda or soda lye.
Those compounds which containasymmetric carbon atoms and which as a rule are obtained as racemates can be split in known manner, for example, by means of optically active isomers, into optically active acid. However, it is also possible from the outset to employ optically active or diastereometric starting materials whereby there isobtained as the final product a corresponding pure optically active form or a diastereomer configuration. There can also occur stereoisomer racemates since they are present in the compounds produced two or more asymmetrical carbon atoms. Separation is possible in the customary manner, for example, by recrystallization.
As stated previously the compounds of the invention are useful in the production of pharmaceutical compositions. The pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of these with other pharmaceutically active materials. For the production of pharmaceutical preparations there can be used the customary pharmaceutical carriers and assistants. The medicines can be used enterally, parenterally, orally or perlingually. Dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, ointments, powders, liquids or aerosols. As liquids there can be used oily or aqueous solutions or suspensions, emulsions, injectable aqueous and oily solutions or suspensions.
Those starting materials which are not known can be obtained by the following procedures:
Process (a) Compounds of formula 11 can be formed by reaction of a halohydrine of the formula R54 H Ra where X is chlorine or bromine with excess diamine of the formula H N-Alk N11 Process (c) Starting materials in which the secondary hydroxyl group of formula 1 is formed from a keto group which starting materials have the formula:
can be prepared for example byreaction of haloketones of the formula:
where X is chlorine or bromine with aminoalkyl guanidines of the formula Preferably the primary amino group connected to the alkylene group is protected by a benzyl group. This reaction can be carried out, for example, in a solvent such as a lower aliphatic alcohol, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol or propyl alcohol, or an aromatic hydrocarbon such as benzene, toluene or xylene, or in dioxane at a temperature between 0 and C. Unless otherwise indicated all parts and percentages are by weight.
EXAMPLE 1 2-[ 2-( 3,4-dihydroxyphenyl )-2-hydroxycthyl-amino l ethyl guanidinc hydroxyethyl]- l ,2-diaminoethane dihydrochloride were dissolved in water, made alkaline with soda lye and'shaken with chloroform. The base remaining after drying and distilling ofiof the chloroform was dissolved in 240 ml of ethanol and treated with a solution of 18.6 grams of S-methyl isothiourea sulfate. The mixture was heated at reflux with stirring for 12 hours, after cooling there were added 8 ml of 2 normal sulfuric acid and filtered with suction on the dext day. For purification the product was recrystallized from a dimethyl formamide water mixture. There were obtained 18.8 grams of 2-[2-(3,4-dibenzyloxyphenyl) -2 hydroxy-ethylamino]- ethyl guanidine sulfate having a melting point of 210 215C.
18.0 grams of the compound obtained were hydrogenated in a mixture of 400 ml of distilled water, 400 ml of ethanol and 200 ml of methanol with addition of 3 grams of 10% palladium-activated carbon catalyst at 60C. The product was worked up by filtering, evaporating under nitrogen and triturating the residue with ethanol. Yield 9.8 grams. Production of the Starting Material:
41 grams of l-(3,4-dibenzyloxy-phenyl)-l-hydroxy- 2-bromoethane were introduced into 20 ml of ethylene diamine inside an hour with stirring. Subsequently it was heated for another hour at 60C., the excess ethylene diamine distilled off in the vacuum and the residue dissolved in benzene. It was extracted twice with water, dried with potassium carbonate, filtered and the benzene distilled off. The base remaining behind was dissolved in ml of isopropanol and treated with alcohol hydrochloric acid until it reacted acid. The precipitated salt was filtered off with suction,'heated with stirring with ethanol and again filtered with suction. After the drying there were obtained 38.8 grams of N-[2- (3 ,4-dibenzyloxyphenyl )-2-hydroxyethyl l ,2- diaminoethane dihydrochloride. Melting Point 1984- 99Cz propyl guanidine This compound was prepared in a manner analogous to example 1 from 3-[2-(3,4-dibenzyloxyphenyl)-2- hydroxy-ethylamino]-propyl guanidine sulfate (MP. 240 244C.)
The sulfate of the title compound melted at 206-20- 8C. and contained a molecule of water of crystallization. Yield about 10 grams. Production fo the Starting Material:
Analogous to example 1 there were obtained 28.5 grams of N- 2-( 3 ,4-dibenzyloxyphenyl )-2- hydroxyethyl] -l,3-diaminopropane dihydrochloride M.P. 164-170C. by reaction of 41 grams of 1-(3,4- dibenzyl-oxyphenyl l -hydroxy-2-bromoethane with 200 ml of 1,3-diaminopropane.
EXAMPLE 3 2-[ 1,-methyl-2-( 3,4-dihydroxyphenyl )-2- hydroxyethylamino]-ethyl guanidine W ,W, m
The free base was made from N-[1-methyl-2-(3,4- dibenzyloxyphenyl )-2-hydroxyethyl] -1 ,2- diaminoethane dihydrochloride in a manner analogous to example 1. grams of the free base were dissolved in 195 ml of ethanol and there was added a solution of 15.2 grams of S-methyl isothiourea sulfate in 39 m1 of water and the reaction solution heated at reflux for 16 hours. The mixture was acidified with 10 ml of 10% sulfuric acid, filtered with suction, washed with ethanol and crystallized from dimethyl formamide with addition of activated carbon. The product filtered off was heated again with ethanol, again filtered with suction and dried. There were obtained 11.5 grams of 2-[1- methyl-2-( 3,4-dibenzyloxyphenyl )-2- hydroxyethylaminol-ethyl guanidine sulfate having a melting point of 206 208C.
10.3 grams of the compound obtained were catalytically hydrogenated at 80C. in a mixture of 200 ml of dimethyl formamide and 200 ml of distilled water with addition of 2.0 grams of 5% palladium-activated carbon catalyst. The mixture was filtered, the solvent distilled off in a vacuum and the residue taken up in ethanol. The substance crystallized out after several days was filtered with suction and dried in the vacuum chest at 50C. There were obtained 7.6 grams of the sulfate having a melting point of 20l203C. Production of the Starting Material:
90 grams of l-(3,4-dibenzyloxy-phenyl)-l-hydroxy- Z-bromopropane were-introduced inside of an hour with stirring into 450 ml of ethylene diamine. The mixture was heated for 3 hours at 60C., the excess diamine distilled off in a vacuum and the. residue dissolved in benzene. The benzene solution was extracted twice with water, dried with potassium carbonate, evaporated and the residue dissolved in ether. The mixture was filtered, acidified with alcoholic hydrochloric acid, filtered with suction on the next day and recrystallized from ethanol. There were obtained 33 grams of N-[ 1- methyl-2-( 3,4-dibenzyloxy-phenyl )-2-hydroxyethy1]- 1,2-diamino-ethane dihydrochloride having a melting point of l87-l88C.
EXAMPLE 4 3-[2-( 3,5-dihydroxyphenyl )-2-hydroxy-ethylamino] propyl guanidine In a manner analogous to example 1 there were prepared 16.1 grams of 3-[2-(3,5-dibenzylphenyl)-2- hydroxyethylamino]-propyl guanidine sulfate having a melting point of 262-265C. from 20.7 grams of N-[ 2-( 3,5dibenzyloxyphenyl) -2-hydroxyethyl ]-l ,3- diaminopropane dihydrochloride and 1 1.6 grams of S methyl isothiourea sulfate.
15 grams of this compound suspended in an ethanolmethanol-water mixture (4 4 2) were catalytically hydrogenated at 60C. in a manner analogous to Example 1. There were obtained 9.] grams of the sulfate having a melting point of 273276C. The compound contained 1 molecule of water of crystallization.
If it is desired to recover the dihydrochloride then, for example, the above described sulfate having a melting point of 262 to 265C. can be stirred with barium chloride in aqueous solution on the water bath, the precipitated BaSO filtered off and the solution evaporated in a vacuum. The residue was stirred with acetone and the precipitated dihydrochloride filtered off with suction.
This salt was hydrogenated in a mixture of two parts of ethanol and one part of water at 60C. with addition of palladium-activated carbon catalyst. The 3-[2-(3,5- dihydroxyphenyl)-2-hydroxyethylamino] propyl guanidine dihydrochloride obtained melted at 204 to 206C.
' The production of the starting material took place in a manner analogous to example 1 from 30 grams of 1- (3,5-dibenzyloxyphenyl 1 -hydroxy-2-bromoethane and 140 ml of 1,3-diaminopropane. Yield 20.9 grams of N-[2-( 3,5-dibenzyloxyphenyl)-2-hydroxyethyl] -l ,3- diaminopropane dihydrochloride M.P. 147150C.
EXAMPLE 5 1-methyl-3-[2-( 3,5-dihydroxyphenyl )-2-hydroxyethylaminol-propyl guanidine 19.9 grams of l-(3,5-dibenzyloxyphenyl)-l-hydroxy- 2-bromoethane were added to 17.0 grams of 1,3- diaminobutane. The mixture was stirred for 1% hours at C., dissolved in benzene, extracted twice with water, dried with potassium carbonate, filtered and the benzene distilled off. The base remaining behind was dissolved in ml of ethanol, 9.8 grams of S-methyl isothiourea sulfate in 25 ml of water added and the mixture heated at reflux with stirring for 10 hours. There was added 10% of sulfuric acid until a pH of about 4 was reached, the solution decanted from the oily precipitate and this residue taken up in acetone. There crystallized out 9.8 grams of l-methyl -3-[2-(3,5- benzyloxyphenyl)-2-hydroxyethylamino] propyl guanidine sulfate which was purified by boiling with dimethyl formamide and ethanol, MP. 254257C.
9.2 grams of the product obtained were hydrogenated in a mixture of 400 ml of dimethyl formamide and 400 ml of distilled water with addition of 1.5 grams of 5% palladium-activated carbon catalyst at 65C. After filtering and evaporating in a vacuum the product was taken up in ethanol and allowed to stand for several days. The product was filtered with suction, boiled with acetone, again filtered with suction and dried at 120C. in the vacuum drying chest. There were ob tained 4.2 grams of the sulfate having a melting point of 168C. The compound contained one molecule of water of crystallization.
The compounds of the invention are suited for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain as the active material one or several ofthe compounds of the invention, in a given case in-admixture with other pharmacologically or pharmaceutically effective materials. The production of the medicine can take place with the use of known and customary pharmaceutical carriers and diluents, as well as other customary assistants.
Such carriers and assistants are set forth for example in Ullmans Encyklopadie der technischen Chemie, Vol. 4 1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 et seq: H. v. Czetsch- Lindenwald, Hilfstoffe fur Pharmazie Lmd angrenzende Gebiete; Pharm. I Vol. 2 1961) pages 72 et seq.; Dr. H. P. Fiedler, Lexicon der Hilfsuyffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor Kg. Aulendorff in Wurtt (1971).
Examples of such materials include gelatin, sucrose, pectin, starch. tylose, talc, lycopodium, silica, lactose, cellulose derivatives, micropulverized cellulose, stearates, e.g., methylstearate and glyceryl stearate, emulsifiers, vegetable oils, water, pharmaceutically compatible monoor polyvalent alcohols. and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, as well as derivatives of such alcohols and polyglycols, dimethyl sulfoxide, esters of saturated and unsaturated fatty acids with monoor polyvalent alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., e.g. glyceryl stearate, glyceryl palmitate, glyceryl oleate, ethylene glycol stearate; such esters of polyvalent alcohols can in a given case also be etherified, benzyl benzoate, dioxolane, glycerine formal, glycol furfural, dimethyl acetamide, lactamide, lactates. e.g., ethyl lactate, ethyl carbonate, etc.
Furthermore, there can be added preservatives, stabilizers, buffers, taste corr'ectives, antioxidants and complex formers (for example ethylenediaminotetraacetic acid) and the like.
As antioxidants there can be used for example sodium metal bisulfite and ascorbic acid, as preservatives there can be used for example sorbic acid, phydroxybenzoic acid esters, e.g., methyl phydroxybenzoate and ethyl p-hydroxybenzoate and similar materials.
The pharmacological and galenical treatment of the compounds of the invention takes place according to the usual standard methods.
The drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays.
The compounds of the invention have a good bronchospasmolytic activity as exhibited, for example, on the isolated tracheal spiral of the guinea pig.
The bronchospasmolytic activity is comparable to that of the known drug orciprerlaline.
The middle of the bronchospasm at 50-100 percent expectorant dosage in the above animal experiments expressed as EDSO, for example, at 10' to 10 gram/ml, especially 10' to l0 g/ml of solution. The dosage range for broncholytic activity is the same as for orciprenaline.
The compounds of the invention have utility in treating bronchial asthma, chronic asthmatic bronchitis, emphysema bronchitis with spasmic components and additional obstructive respiratory illnesses.
The compoundscan be delivered in the form of tablets, capsules, pills, dragees, liquids, dusts or aerosols.
As liquids there can be used oilyor aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions. The preferred forms of use are tablets which contain between 1 and 50 mg. of active material or solutions which contain between O.l and 5% of active material.
in individual closes the amount of active component of the invention can be used for example in an amount of 2 mg dispensed orally or 10 strokes of a 0.2% solution dispensed as an aerosol. These doses can be dispensed once or several times a day.
For example there is recommended the use of one tablet containing 2 mg of active ingredients 3 times daily or dispensed as an aerosol one to four times a day up to 10 strokes of the 0.2% solution.
The acute toxicity of the compounds of the invention in the mouse (expressed by the LD 50 mg/kg; method of Miller and Tainter, Proc. Soc. Exper. Biol. and Med., Vol. 57 (I944) pages 261 et seq.) in i.v. application is between 50 mg/kg and mg/kg.
The drugs can be used in human medicine or in veterinary medicine, e.g., to treat cats, dogs, horses, sheep, cattle, goats and pigs.
What is claimed is:
l. A compound having the formula R2 OH NH:
where R is hydrogen or hydroxy, R is hydroxy, hydroxymethyl or alkyl of one to six carbon atoms, R is hydrogen or alkyl of one tofour carbon atoms and Alk is an alkylene group of two to six carbon atoms or a salt thereof of a pharmaceutically acceptable acid.
2. A compound according to claim 1 wherein at least one of R and R is hydroxy.
3. A compound according to claim 2 wherein Alk is alkylene of 2 to 4 carbon atoms and R is hydrogen or methyl.
V the 3 position and R is in the 4 or 5 position.
4. A compound according to claim 1 wherein R, and 7. A compound according to claim 5 wherein Alk is R are both hydroxy. trimethylena A Compound according to Clam] 4 wherein m 8. A compound according to claim 5 wherein Alk is 6. A compound according to claim 5 wherein Alk is 5 methyl substituted trimethylena ethylene