DE1811832A1 - Pyrrolidine derivs hypotensive - Google Patents

Abstract

(A) Method for cmpds. (I):- and salts of (I), including all optical and geometrical stereoisomers. (B) The cpds. (II) and some (III) where R, R1 and R3 = H or (1-6C) alkyl R2 = (1-6C) alkyl or cycloalkyl R4 and R5 = H or (1-6C) alkyl, one of them may be NH2 or NO2 or R4 + R5 together may be -CH2CH2- n = 2-8 Hypotensives with low side effects. (a) 3-Chloromethylbut-1-yne-3-ol (11.85 g.), ethylenediamine hydrate (63.4 ml.), and EtOH (40 ml.), were refluxed 17 hrs., evapd. in vac., 40% NaOH (10 ml.) added, H2O removed by azeotropic distn. with PhH, evapd., and distilled, giving the pyrrol (III) (5.82 g.), b.p. 65.5-66 deg./2 mm. (b) This (12.4 g.) was hydrog. at 25 deg. and 35 kg/cm2 in EtOH (250 ml.) and 5N-HCl (40 ml.), over a 5% Rh.-Al2O3 catalyst (5.0 g.), for 60 hrs. The mixture was filtered, evapd., basified (d.NaOH), extd. with Et2O, and distilled, giving the pyrrolidine (II) (8.72 g.), b.p. 66 deg./14 mm. (c) This (3.84 g.), S-methylisothiouronium sulphate (4.17 g.), EtOH (40 ml.), and H2O (20 ml.), were refluxed 3.5 hrs., cooled, filtered, neutralised with 5N H2SO4 (6.0 ml.), evapd. in vac., and the residue refluxed with EtOH, giving (I) (7.31 g., 91%), m.p. 233-7 deg. (dec.).

Description

"New pyrrolidinoguanidines and their manufacturing process" Priority: December 7, 1967, United Kingdom Application No .: 55,708 The present invention concerns new pyrrolidinoguanidines, which have marked properties regarding lower blood pressure without undesirable side effects.

The novel pyrrolidinoguanidines which can be prepared according to the invention have the following general formula I: in which R, R1 and R3 each represent a hydrogen atom or a lower alkyl group with 1 - 6 carbon atoms, a lower alkyl group with 1 - 6 carbon atoms or a lower cycloalkyl group with 1 - 6 carbon atoms, R4 and R5 each represent a hydrogen atom or a lower alkyl ..

represent a group with 1 - 6 carbon atoms or one of the substituents R4 and R5 is an amino or nitro group, where R4 and R5 together also form an ethylene bridge -CE2CH2- and n has a value from 2 to 8 hats The invention relates also non-toxic acid addition salts of these compounds.

The compounds that can be prepared according to the invention do exist as cis and trans isomers. Also contain the new compounds asymmetric carbon atoms, and they can therefore be converted into optically active. to shape exist.

The process according to the invention for the preparation of compounds of the formula I and their non-toxic acid addition salts is characterized in that a pyrrolidinoalkylamine of the following formula in which R, R1, and R3 each represent a hydrogen atom or a lower alkyl group with 1-6 carbon atoms and R2 is a lower altyl or cycloalkyl group with 1-6 carbon atoms, or a salt of such a compound with a guanidine group-forming agent for Reaction is brewed.

Particularly suitable as agents forming the guanidine group are 1) an O- or S-alkylisothiourea or an acid addition salt thereof; 2) a Cyanamide or a substituted cyanamide or alkali metal salts of these cyanamides; 3) a salt of 1-guanylpyrazole or an alkylated 1-gaunylpyrazole, for example 1-guanyl-3,5-dimethylpyrazole or 1-guanyl-3,4-dimethylpyrazole; 4) an S-alkylisothiosemicarbazide, if either R4 or R5 is an amino group; 5) an N-alkyl-N'-nitro-N-nitrosoguanidine, if one of the substituents R4 or R5 is a nitro group; 6) a 2-nitroaminoimidazoline, if R4 and R5 together form an ethylene bridge.

Preferably, as the guanidine group forming agent, an S-alkylisothiourea is used or an acid addition salt thereof is used, and the reaction components are used together in an inert solvent to form a compound of the formula I heated.

The pyrrolidinoalkylamines used as starting material can be obtained by catalytic hydrogenation of a corresponding dissolved pyrool of the following general formula III: for example using a rhodium / aluminum oxide catalyst or an activated carbon catalyst, which is 5 or

Contains 10% palladium. If R or R1 do not represent a hydrogen atom, mixtures of ois and trans isomers are obtained in this reaction.

A wide variety of processes can be used to prepare pyrrolealkylamines of the formula III, for example the following 1) Reaction of an aoetylenically unsaturated chloroarbinol of the formula ClCHR.CR2 (OH) .ClCR1 or ClCHR.CR2 (OH) .CH2.ClCH with an amine of the formula NH2. (CH2) n .NH2; 2) Implementation of an aoetylenisoh unsaturated epoxy of the formula below with an amine NH2. (CH2) n.NH2 h) Conversion of a pyrrolealkanol of the formula below into a reactive derivative of the formula below in which X represents a halogen atom or the residue of a sulfonic acid, in particular toluene-p-sulfonic acid, and reaction of this reactive product with an amine R3NH2.

The above-described pyrrolidone alkylamines of the general Formula II are also new compounds.

The novel pyrrolidinoguanidines of the formula can confectioned with suitable carrier materials to form pharmaceutical preparations Suitable carrier materials are, for example, excipients, fillers, Binding agent and sterilized water, making preparations for oral parenteral and other forms of application.

Example 1 11.85 g 3-chloromethylbut-1-yn-3-ol, 60.8 g, (63.4 ml) ethylenediamine hydrate and 40 ml of ethanol are refluxed for 17 hours. Then become solvents and excess ethylenediamine removed in vacuo and there are 10 ml of a 40% aqueous sodium hydroxide solution added. After removing the water from the mixture azeotropic distillation with benzene also removes the solvent, and 9.67 g of one are obtained as which is again distilled.

In this way, 5.82 g (yield: 47%) of the compound 1- (β-aminoethyl) -3-methylpyrrole are obtained with a boiling point of 65.5 to 66 ° C / 2 mm Hg and a refractive index nD22.5 = 1.5115 The analysis gives the following result: Found: C = 67.75% H = 9.7%; N = 22.6% theory for C7H12N2; C = 68.0%; H = 10.2%; N = 22.9%.

12.4 g of this pyrrole are at room temperature and a pressure of 35 pieces in 250 ml of ethanol and 40 ml of 5N "hydrochloric acid in the presence of 520 g of a catalyst hydrogenated which contains 5% rhodium on an aluminum support Contains oxide. After 60 hours the catalyst is filtered off and the solvent removed in vacuo. The residue is dissolved in water with dilute sodium hydroxide solution adjusted to basic and then the solution is extracted continuously with ether. In this way 11.6 g of one is obtained Oil from which bef the distillation 8.72 g (yield: 68%) of the compound 1- (β-aminoethyl) -3-methylpyrrolidine were obtained will.

The boiling point is 66 ° C / 14 mm Hg, the refractive index nD16 = 1.4631.

Analysis: found C r 65.8%; R - 12.6 g; N = 22.1% theory for C7H16N2 a = 65.5%; H = 12.5%; N = 21.9%.

3.84 g of this pyrrolidine are added together with 4.17 g of S-methylisothiochourea sulfa, Heated 30 ml of ethanol and 20 ml of water under reflux for 3/2 hours. After this Cooling, the solution is filtered, neutralized with 6.0 ml of 5N sulfuric acid and evaporated in a vacuum. Nan receives a very viscous liquid, which when cooked separates a colorless solid with ethanol, (7.31 g, yield = 91%), the has a melting point (with decomposition) of 233 to 237 ° C.

Recrystallization from an ethanol / water mixture gives 5.4 g (yield: 68%) of the compound 1- (ß-guanidinoethyl) -3-methylpyrrolidine sulfate with a melting point (with decomposition) of 243.5 to 245.5 ° C. The connection forms colorless crystal flakes.

Analysis: found: C = 35.4%; H = 7.9%; N = 21.2%, S = 12.2%; theory for the compound C8H20N4SO4: C = 35.8%, H = 7.5%; N = 20.9%, S = 11.9%.

Example 2 48.15 g 3-chloromethylhept-1-yn-3-ol, 182.4 g (190.2 ml) Ethylenediamine hydrate and 120 ml of ethanol are refluxed for 20 hours. The work-up of the reaction mixture is done in the same way as in Example 1 described.

In this catfish, 24.1 g (yield: 490) of the compound are obtained 1- (ß-Aminoethyl) -3-n-butylpyrrole with a boiling point of 106 to 107 ° C / 3 mm Hg and a refractive index nD21 = 1.4982.

Analysis: found: C = 72.2%; H = 11.1%; N = 17.1% theory for C10H18N2; C = 72.3%; H = 10.8%; N = 16.9%.

12.4 g of this pyrrole are for 48 hours at room tempera ture and a pressure of 49 at in 250 ml of ethanol and 30 ml of 5N hydrochloric acid in Presence of 4.0 g of a catalyst hydrogenated, which 5% rhodium on a Contains aluminum oxide carrier. 7.91 g (yield: 62%) of the compound are obtained in this way 1- (ß-Aminoethyl) -3-n-butylpyrrolidine with a boiling point of 90 - 92 ° C / 1 am Eg and a Breoh sindex nD20 = 1.4650.

7.66 g of the pyrrolidine together with 6.28 g of S-methylisothiochourea sulfate, Heated 50 ml of ethanol and 30 ml of water under reflux for 3 1/2 hours. The work-up is carried out according to Example 1 and 10.4 g (yield: 73%) of 1- (β-guanidinoethyl) -3-n-butylpyrrolidine sulfate are obtained with a melting point (with decomposition) of 194 - 197 ° C in the form of colorless Crystal plates.

Analysis: found: C = 42.2%; H = 8.5%; H = 18.15%, s = 10.6%; theory for C11H26N4SO4: C = 42.5%; H = 8.4%; N = 18.0%, S = 10.3%.

Example 3 57 g of 4-chloromethylpent-1-yn-4-ol, 150 g (166 ml) anhydrous Ethylenediamine and 150 ml of ethanol are refluxed for 17 hours. When working up according to Example 1, 26.9 g (yield: 45%) of the compound are obtained 1- (ß-Aminoethyl) -2,4-dimethylpyrrole with a boiling point of 72 ° C / 0.9 mm Hg a Refractive index nD17.5 = 1.5140.

Analysis: found: C = 69.6%; H = 10.1 %%; N = 20.2%; Theory for C8H14N2: C - 69.6; H - 10.15%; N - 20.3% ..

13.96 g of this pyrrole are under the conditions of Example 1 hydrogenated and this gives 6.98 g (yield: 48%) of the compound 1- (β-aminoethyl) -2-, 4-dimethylpyrrolidine with a boiling point of 71 ° C / 14 mm Hg and a refractive index nD17 = 1.4578.

Analysis: found: C = 67.2%; H = 13.2%; N = 19.7% theory for C8H18N2; C = 67.6%; H = 12.7%; N = 19.7%.

The hydrogenation can also be carried out using acetic or aqueous Basic acid as the solvent instead of the mixture of ethanol and 5N hydrochloric acid be performed.

A catalyst can also be used instead of the rhodium catalyst will the; Contains 5 or 10% palladium on a carrier material made of activated carbon. The yield in the hydrogenation stage is between 40 and 60%.

6.59 g of the pyrrolidine are added together with 6.45 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 3 1/2 hours. The work-up the reaction mixture is carried out as described in Example 1. That way it gets one 66.46 g (yield: 50%) of the compound 1- (S-guanidinoethyl) -2,4-dimethylpyrolidine sulfate hydrate with a melting point of 291 to 292 ° C (with decomposition) from an acetone-water mixture.

Analysis found: C = 36.1%; H = 8b3%; N = 18.9%, S = 10.8% theory for C9H22N4SO4H2O: C = 36.0%; H = 8.0%; N = 18.7%, S = 10.7%.

Example 4 15.8 g of 3-chloromethylhex-1-yn-3-ol together with 39 g (43.5 ml) of anhydrous ethylenediamine and 50 ml of ethanol under reflux for 21 hours heated. The reaction mixture is worked up as described in Example 1.

In this way, 10.8 g (yield: 66%) of the compound are obtained 1- (ß-Aminoethyl) -3-n-propylpyrrole with a boiling point of 58 - 60 ° C / 0.1 mm Hg and a refractive index nD18.5 = 1.4990.

Analysis: found: C = 71.0%; H = 10.7%; N = 18.3% theory for C9H16N2: C = 71m1%; H = 10.5%; N = 18.4% 9.4 g of the pyrrole are among those in Example 1 hydrogenated conditions described. 7.2 g (yield: 74% (of the compound 1- (ß-Aminoethyl) -3-n-propylpyrrolidn with a boiling point of 59.5 - 60 ° C / 0.7 mm Hg and a refractive index nD17.5 = 1.4641 Analysis: found: C = 69.3%; H = 13%; N = 16.9% theory for C9H20N2: C = 69.25%; H = 12.8%; N = 17.9%.

4.0 g of this pyrrolidine are added together with 3.6 g of S-methylisothiourea sulfate heated under reflux in aqueous ethanol for 3 1/2 hours. The work-up of the reaction mixture is carried out according to Example 14. In this way, 2.4 is obtained g (Yield: 32% of the compound 1- (ß-guanidine ethyl) -3-n-propylpyrrolidine sulfate hemihydrate with a melting point of over 300 ° C from an ethanol / water mixture.

Analysis: found: C = 39.2%; H = 8.0%; N = 18.2%, S = 11.1% theory for C10H24N4SO4 1/2 H2O: C = 39.4%; H = 8.2%; N = 18.3%; S = 10.5%, example 5 60.2 g of 4-chloro-3-phenylbut-1-yn-3-01 together with 108.0 g (120 ml) of anhydrous Ethylenediamine and 200 ml of ethanol heated under reflux for 24 hours. The work-up of the reaction mixture is carried out as in Example 1. This gives 33.1 g (yield: 54%) 1- (ß-aminoethyl) -3-phenyopyrrole with a boiling point of 116 to 122 00 / 0.06 mm Eg and a refractive index nD19 = 1.6195. The hydrochloride of pyrrole has a melting point (with decomposition) of 204 to 207 ° C.

Analysis: found for the hydrochloride: C = 64.67%; H = 7.0%; N = 12.5%; Cl = 16.3% theory for C12H14N2.HCl: C = 64.67%; H = 6.7%; N = 12.6 %; Cl = 16.0%.

10 g of this pyrrole are among those described in Example 1 Hydrogenated conditions, and so 4.2 g (yield 41%) of the compound 1- (ß-aminoethyl) -3-cyclohexypyrrilidine are obtained with a boiling point of 90 - 91 ° C / 0.4 mm Hg and a refractive index nD18 = 1.4938.

Analysis: found: C = 73.75%; H = 12.5%; N = 13.85% theory for C12H24N2 C = 73.5%; H = 12.2%; N = 14.3%.

9.8 g of this pyrrolidine together with 6.7 g of S-methylisothiourea sulfate Refluxed in aqueous ethanol for 3/1 hours. The reaction mixture is according to Example 1 worked up, and 14.4 g are obtained (yield: 81%) of the compound 1- (ß-Guandinoäthyl) -3-cyclohexylpyrrolidinsulfatsesquihydrat with a melting point (with decomposition) of 208-211 ° C from an ethanol / water mixture.

Analysis: found: C = 43.1%; H = 8.25%; N = 15.2%; 5 = 9.2% o Theory for C13H28N4SO4.3 / 2H2O: C = 43.0%; H = 8.55%; N = 15.4%; 5 = 8.8%.

Example 6 22.4 g of 3-chloromethylpent-1-yn-3-ol are mixed with 60.1 g (67 ml) of anhydrous ethylenediamine and 100 ml of ethanol for 24 hours Heated to reflux. The reaction mixture is worked up according to Example t, and 14.4 g (yield: 62%) of the compound 1- (β-aminoethyl) -3-ethylpyrrole are obtained in this way with a boiling point of 64.5 - 65 ° C / 9 mm Hg and a Breohunge index nD20 = 1.5067.

Analysis: found: C = 69.2%; H = 10.3%; N = 20.1% theory for C8H14N2: C = 69.6%; H = 10.1%; N = 20.3%.

12.3 g of this pyrrole are among those described in Example 1 Conditions hydrogenated. 7.3 g (yield: 57%) of the compound 1- (β-aminoethyl) -3-ethylpyrrolidine are obtained in this way with a boiling point of 79 - 81 ° C / 14 mm Hg and a refractive index nD18.5 = 1.4633.

Analysis: found: C = 67.3%; H = 12.7%; N = 19.65; Theory for C8H18N2 C = 67.6%; H = 12.7%; N = 19.7%, 5.0 g of this pyrrolidine are combined with 4.9 g of S-methylisothiourea sulfate in aqueous ethanol for 3 1/2 hours heated under reflux. The reaction mixture is worked up according to Example 1. 7.5 g (yield: 74%) of the compound 1- (ß-guanidinoethyl) -3-ethylpyrrolidine sulfate are obtained in this way with a melting point (with decomposition) of 259 - 261 ° C from an ethanol / water mixture.

Analysis: found: «= 38.0%; H = 7.9%; = i9.4%, S-11.3%; theory for C9H22N4SO4: C = 38.3%; H = 7.8%; N = 19.85%, S = 11.35%.

Example 7 52.2 g of 4-chloromethylhex-1-yn-4-ol together with 122 g (136 ml) of anhydrous ethylenediamine and 200 ml of ethanol for 30 hours Heated to reflux. The reaction mixture is worked up according to Example 1. Man thus receives 36.7 g (yield 68 5 ') of the compound 1- (β-aminoethyl) -4-ethyl-2-methylpyrrole with a boiling point of 82 - 87 ° C / 1.3 - 1.8 mm Hg and a refractive index nD20 = 1.5087.

Analysis: found: C = 71.0%; H = 10.5%; N = 18.3% theory for C19H16N2: C = 71.1%; H = 10.5%; N = 18.4%.

33.1 g of this pyrrole are among those described in Example 1 Hydrogenated conditions and 12.2 g (yield 36%) of the compound 1- (β-aminoethyl) -4-ethyl-2-methylpyrrolidine are obtained with a boiling point of 88 - 89.5 ° C / 15 mm Hg and a refractive index nD16.5 = 1.4598.

The di-toluene-p-sulfonic acid salt of this compound has a melting point from 157 - 158 ° C.

Analysis of the sulfonic acid salt: found: C = 54.4%; H = 7.2%; N = 5.6%, S = 13.2% theory for C23H36N2S2O6 o = 55.2%; H = 7.2%; B ~ 5.6%, S. = 12.8%.

6.0 g of the pyrrolidine are added together with 5.4 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 3 hours. The reaction mixture is worked up according to the example and 8.0 g (yield: 70%) of the compound are obtained 1- (ß-guanidine ethyl) -4-ethyl-2-methylpyrrolidine sulfate with a melting point (below Decomposition) from 248 - 250.5 ° C from an ethanol / water mixture.

Analysis: found: C r 40.7%; H = 8.2%; N = 18.8%, S = 11.2% theory for C10H24N4SO4: C = 40.6%; H = 8.1%; N = 18.9%, S = 10.8% o example 8 71.5 g (45 ml) of 3-bromopropine are dissolved in 200 ml of ether and 10 ml of this Solution are added to 14.65 g of magnesium turnings, which are covered by 200 ml of ether are. As soon as the reaction begins, the mixture is cooled to -10 ° C and the The remaining 3-bromopropion solution is added dropwise at -10 ° C. Afterward a solution of 55.7 g of 1-chloro-3,3-dimethylbutan-2-one in 200 ml is added dropwise Benzene is added and then the mixture is stirred for a further 4 hours at -10 ° C. Then 250 ml of 5N sulfuric acid and then 250 ml of water are added. After filtration, the reaction product is extracted into ether, which becomes ether washed with water and then with saturated sodium bicarbonate solution and finally another flood of water follows. After drying over magnesium sulfate, the Ether removed under reduced pressure. Through careful fractionation of the crude oil (65.3 g), 4.2 g (yield 6%) of the compound 4-chloromethyl-5,5-dimethylhex-1-yn-4-ol are obtained with a boiling point of 65 - 68 ° C / 3.6 mm Hg and a refractive index nD14.5 = 1.4828 and 7.9 g (yield: 14%) of the compound 4-tert-butyl-4,5-epoxypent-1-yn with a boiling point of 36 - 38.3 ° C / 3.5 Hg and a refractive index nD17 = 1.4482.

3.0 g of the compound 4-chloromethyl-5,5-dimethylhex-1-yn-4-ol become together with 6.2 g (6.7 ml) of anhydrous ethylenediamine and 100 ml of ethanol for 24 hours heated under reflux. The reaction mixture is worked up according to Example 1.

2.2 g (71% yield) of the compound 1- (β-aminoethyl) -4-tert-butyl-2-methylpyrrole are obtained in this way with a boiling point of 60 - 62 ° C / 0.05 mm Hg and a refractive index nD17 = 1.5007.

Analysis: found: C = 73.1%; H = 11.3%; N = 15.1%; Theory for C11H20N2: C = 73.3%; H = 11.1%; N = 15.6%.

Another procedure is that you 6.85 g of 4-tert-butyl-4,5-epoxypent-1-yn together with 17.75 g (19.4 ml) of anhydrous ethylenediamine and 100 ml of ethanol 24 Heated under reflux for hours. The solvent and excess material are then removed Ethylenediamine in vacuo and the water by azeotropic distillation with benzene. Obtained after removal of the solvent and another distillation 6.4 g (72% yield) of the compound 1- (ß-aminoethyl) -4-tert-butyl-2-methylpyrrole.

7.0 g of this pyrrole are among those described in Example 1 Conditions hydrogenated. 4.3 g (yield 60%) of the compound 1- (β-aminoethyl) -4-tert-butyl-2-methylpyrrolidine are obtained in this way with a boiling point of 105 - 109 ° C / 14 mm Hg and a refractive index nD21 = 1.4618.

Analysis: found: N = 14.8% theory for C11H24N2 t N = 15.2%.

3.3 g of this pyrrolidine are added together with 2.5 g of S-methylisothiourea sulfate heated to reflux in aqueous ethanol. The work-up of the reaction mixture is carried out according to Example 1. This gives 4.2 g (yield 70%) %) of the compound 1- (ß-Guandiniäthyl) -4-tert-butyl-2-methylpyrrolidine sulfate hemihydrate with a melting point (with decomposition) of 24 249 ° C from an ethanol / water mixture.

Analysis: found: C = 43.4%; H = 8.7%; N = 16.5%, S = 9.8 β theory for C12H28N4SO4.1 / 2H2O: C = 43.2%; H = 8.7%; N = 16.8% S = 9.6%.

Example 9 143.3 g of the compound 4-chloro-3-methylpent-1-yn-3-ol become together with 450 g (500 ml) of anhydrous ethylenediamine for 6 days under RUokfluss heated. The reaction mixture is worked up as in Example 1. Man thus obtained 60.0 g (yield 43%) of the compound 1- (β-aminoethyl) -2,3-dimethylpyrrole with a boiling point of 72 ° C / 0.9 mm Hg and a refractive index nD19 = 1.5162.

Analysis: found: C = 69.75%; H = 10.3%; N = 20.5% theory for C8H14N2: C = 69.6%; H = 10.15%; N = 20.3%.

27.6 g of this pyrrole are among those described in Example 1 Conditions hydrogenated. 16.0 g (yield t 56.5%) of the compound 1- (β-aminoethyl) -2,3-dimethylpyrrolidine are obtained with a boiling point of 81 - 83 ° C / 18 mm Hg and one Refractive index nD20 = 1.4640. This compound is converted into the dipicric acid salt, which has a melting point of 320 - 321 ° C.

Analysis of the dipinkric acid salt t found: C = 40.0%; H = 4.1%; N = 18.5% theory for C20H24N8O14: C = 40.0%; H = 4.0%; N = 18.7%.

8.0 g of this pyrrolidine are mixed with 7.8 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 5 hours. The reaction mixture is worked up according to Example 1. 13.6 (yield 86%) of the compound are obtained in this way 1- (ß-Guanidinoethyl) -2,3-dimethylpyrrolidinsulfathalbhydrat with a melting point (with decomposition) from 272 - 274 ° C.

Analysis: found: C = 37.35%; H = 7.8%; N = 19.6%, S = 11.2% Theory for C9H22N4SO4.1 / 2 H2O: C = 37.15%; H = 7.9%; N = 19.2%, s r 11.0%, The 1- (β-aminoethyl) -2,3-dimethylpyrrolidine obtained in the manner described above falls in the form of a solution in which the cis and transf isomers in one The ratio is 65:35. These isomers can be carried out on a laboratory scale Gas-liquid chromatography can be separated using a separation column, Which Contains 20% silicone oil on celite as an adsorbent, with nitrogen serving as the carrier gas.

Each of these pure isomers can be separated in the usual manner S-methylisothiourea sulfate reacted and described in Example 1 Way to be worked up. In this way, cis-2,3-dimethyl-1- (ß-guanidinoethyl) pyrrolidine sulfate is obtained with a melting point (with decomposition) of 292-295 ° C.

(Analysis: found: C = 38.6%; H = 8.0%; N = 20.0%, S = 11.4% theory for C9H22N4SO4: C = 38.3%; H = 7.8%; N = 19.9%, s - 11.35%.) In the same The compound trans-dimethyl-1- (ß-guanidinoethyl) pyrrolidine sulfate hemihydrate is obtained with a melting point (with decomposition) of 294 - 295 ° C.

(Analysis: found: C = 37.4%; H = 7.8%; N = 18.7%, S = 11.0% Theory for C9H22N4SO4.1 / 2 H2O: C = 37.15%; H = 7.9%; N = 19.2%, S = 11.0%.) Example 10 210 g of 3-chlorobutan-2-one in 500 ml of benzene are added dropwise to a stirred solution of propargyl magnesium bromide in ether at -10 ° C added. These The solution is made according to Example 8 from 357 g (225 ml) of 3-bromopopine and 72 g of magnesium shavings obtain. The reaction mixture is worked up according to Example 8. 230.9 g (yield 80%) of the compound 5-chloro-4-methylhex-1-yn-4-ol are obtained in this way with a boiling point of 35 - 40 ° C / 0.7 - 1.0 mm Hg Analysis: found: Cl = 23.5 % Theory for C7H11C10: Cl = 24.2%.

146.5 g of the compound 5-chloro-4-methylhex-1-yn-4-ol and 360 g (400 ml) ethylenediamine are refluxed for 3 days. Working up the reaction mixture takes place according to Example 1. This gives 115.1 g (yield 76%) of the compound 1- (ß-Aminoethyl) -2,3,5-trimethylpyrrole with a boiling point of 60 - 65 ° C / 0.01 mm Hg and a refractive index nD21.5 = 1.5171.

Analysis: found: C = 70.3%; H = 10.6%; N = 18.1% theory for C9H16N2: C = 71.1%; H = 10.5%; N = 18.4%.

20 g of the pyrrole are hydrogenated under the conditions of Example 1, and 15.6 g (yield 77%) of the compound 1- (β-aminoethyl) -2,3,5-trimethylpyrrole are obtained in this way with a boiling point of 78.5 - 80 ° C / 11 mm Hg and a refractive index nD20 = 1.4995. The dipicric acid salt of pyrrolidine has a melting point of 227-228 ° C.

Analysis: found: C = 41.0%; H = 4.3%; N = 18.4% of the dipicric acid salt Theory for: C21H26N8O14: C = 41.05%; H = 4.2%; N = 18.25%.

7.1 g of pyrrolidine are added together with 6.5 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 4 hours. The reaction mixture is worked up according to Example 1, and 9.7 g (72% yield) of are obtained in this way Compound 1- (ß-guanidinoethyl) -2,3,5-trimethylpyrrolidine sulfate with a melting point (with decomposition) from 275 - 278 ° C from an ethanol / water mixture.

Analysis: found: C = 40.3%; H = 8.2%; N = 18.7%, S = 10.9% theory for C10H24N2SO4 C = 40.6%; H = 8.1%; X = 18.9%, S = 10.8%.

Example 11 From 164.0 g (113 ml) of ethyl bromide and 36.0 g of magnesium turnings Ethylmagnesiumbfromide made in ether becomes 700 in the course of an hour ml of ether was added, which is saturated with 1-butyne. During the addition, the The temperature of the reaction mixture is kept below 10 ° C. and at the same time leaves a stream of 1-butyne is continuously bubbled through the reaction mixture. The mixture is then cooled to a temperature of 5 ° C. and 93 g are added dropwise Chloroacetone too.

This mixture is stirred at room temperature overnight and then carefully add 250 ml of saturated ammonium chloride solution added. the inorganic precipitate which separates out is filtered off and washed with Ether. The filtrate is washed with water, dried over magnesium sulfate and evaporated in a vacuum. 136 g of an oil are obtained in this way. through careful fractionation 57.5 g (yield: 39%) of the compound 5-chloro-methylhex-3-yn-5-ol are obtained from the oil with a boiling point of 81 ° C / 11 mm Hg and a refractive index nD21 = 1.4710.

Analysis: found: C = 37.2%; H = 7.6%; Cl = 24.5% theory for C7H11C10: C = 57.3%; H = 7.5%; Cl = 24.2%.

As a result of the conversion between unconverted ethyl magnesium bromide and chloroacetone are also 24.0 g (yield 20%) of the compound chloromethyl-butan-2-ol isolated.

48.8 g of 5-chloromethylhex-3-yn-5-ol together with 108.0 g (120 ml) anhydrous ethylenediamine and 150 ml of ethanol for 24 hours under reflux heated. The reaction mixture is worked up according to Example 1. You get so 36.8 g (yield 73%) of the compound 1- (ß-aminoethyl) -2-ethyl-4-methylpyrrole with a boiling point of 79 - 80 ° C / 0.12 mm Hg and a refractive index nD21 = 1.58085.

Analysis: found: C = 70.4%; H = 10.8%; N = 18.0% theory for C9H16N2: C = 71.1%; H = 10.5%; N = 18.4%.

20 g of the pyrrole are obtained under the conditions described in Example 1 hydrogenated, and 18.1 g (yield 88%) of the compound 1- (β-aminoethyl) -2-ethyl-4-methylpyrrolidine are obtained with a boiling point of 82 ° C / 12 mm Hg and a refractive index nD21 = 1.4610. The pyrrolidine is characterized as dipicric acid salt and has a melting point from 180 - 181 ° C on analysis of the dipicric acid salt: found: C = 41.3%; H = 4.3%; N = 18.1% theory for C21H26N8O14: C = 41.05%; H = 4.2%; N = 18.25%.

7.6 g of the pyrrolidine are added together with 6.95 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 4 1/2 hours. The reaction mixture is worked up according to Example 1. 10.6 g (yield 71%) of the compound are obtained 1- (ß-guanidinoethyl) -2-ethyl-4-methylpyrrolidine sulfate with a melting point (below Decomposition) of 272-274 ° C (with decomposition) from an ethanol / water mixture.

Analysis: found: C = 40.05%; H = 8.2%; N = 18.6%, S = 11.4% Theory for C10H24N4SO4: C = 40.6%; H = 8.1%; N = 18.9%, 5 a 10.8%, example 12 23 g of 4-chloromethylpent-1.yn-4-ol together with 84.5 g (95 ml) 1,3-diaminopropane and 200 ml of ethanol heated under reflux for 23 hours. The solvent is then removed in vacuo and there are 18.9 ml of a 40% aqueous sodium hydroxide solution was added. Then the mixture is made with Chloroform extracted. The chloroform extracts are concentrated in vacuo and then the concentrated solution is extracted with petroleum ether (boiling range 60 - 80 ° C). after the extract has been dried over magnesium sulfate, the petroleum ether is reduced in vacuo evaporated to give 17.1 g of a crude oil.

14.1 g are obtained from this oil by distillation (yield: 50%) %) of the compound 1- (γ-aminopropyl) -2,4-dimethylpyrrole with a boiling point from 78 - 80 00/1 mm Hg and a refractive index nD20 = 1.58081.

Analysis: found: C = 71.55%; H = 10.6%; N = 18.4% theory for C9H16N2: C = 71.1%; H = 10.5%; N = 18.4%.

11.6 g of this pyrrole are under the conditions of Example 1 hydrogenated and 8.0 g (yield 66%) of the compound 1- (γ-aminopropyl) -2,4-dimethylpyrrolidine are obtained with a boiling point of 82 - 86 ° C / 13 mm Mg and a refractive index = 1.4595. The pyrrolidine is known as dipicric acid salt with a melting point of 195-198 ° C characterized.

Analysis for dipicric acid salt 5 found: C = 41.0%; H = 4.4 %; N = 18.2% theory for C21H26N8O14: C = 41.05%; H = 4.2%; N = 18.25%.

1.32 g of the pyrroldine are added together with 1.18 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 3 1/2 hours. The reaction mixture is worked up according to Example 1. 1.4 g (yield 36%) of the compound are obtained 1- (γ-guanidinopropyl) -2,4-dimethylpyrrolidine sulfate hemihydrate with a melting point (with decomposition) of 292-294 ° C from an ethanol / water mixture.

Analysis: found: C = 39.8%; H = 8.2%; N = 18.3%, S = 10.6% theory for C10H24N4SO4.1 / 2 H2O: C = 39.4%; H = 8.2%; N = 18.3%, S = 10.5%.

Example 13 17 g of 4-chloromethylpent-1-yn-4-ol are together with 60 g of 1,8-diamino-n-octane and 150 ml of ethanol were heated under reflux for 24 hours. The reaction mixture is worked up according to Example 12 and 17.2 is obtained in this way g (yield: 60%) of the compound 1 - (# - Amino-n-octyl) -2,4-dimethylpyrrole with a Boiling point of 112 - 114 ° C / 0.02 mm and a refractive index nD20 = 1.4919.

Analysis: found: C = 75.7%; H = 12.0%; N = 12.4% theory for C14H26N2: C = 75.8%; H = 11.7%; N = 12.6%.

14.7 g of this pyrrole are among those described in Example 1 Conditions hydrogenated. 10.0 g are obtained (yield 50%) the connection 1 - (# - Amino-n-octyl) -2,4-dimethylpyrrolidine with a boiling point of 96 ° C / 0.35 mm Hg and a refractive index nD23 = 1.4620.

Analysis: found: C = 73.8%; H = 13.5%; N = 12.2% theory for C14H30N3: C = 74.3%; H = 13.3%; N = 12.4%.

4.0 g of the pyrrolidine are mixed with 2.5 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 3 1/2 hours. The reaction mixture is worked up according to Example 1. 6.5 g (yield 95%) of the compound are obtained in this way 1 - (# - Guanidino-n-octyl) -2,4-dimethylpyrrolidine sulfate hydrate in the form of a hydroscopic Rubbers.

Analysis: found: C = 47.1%; H = 9.75%; N = 14.5%, s ~ 8.7% theory for C15H32N4SO4.H2O: C = 46.9%; H = 9.4%; N = 14.6%, 5n 893%.

Example 14 To 14.2 g of a solution prepared according to Example 3 of 1- (ß-aminoethyl) -2,4-dimethylpyrrolidine in 100 ml of 50% aqueous ethanol 10.1 g of N-methyl-N1-nitro-N-nitrozoguanidine are added in small portions. The temperature of the reaction mixture is kept below 20 ° C. during this process. One stirs overnight and then filtered off the precipitated crystalline product. washes 50 % aqueous ethanol and dry about phosphorus pentoxide. By Recrystallization from ethyl acetate gives 7.45 g (yield 46%) of the compound N-ß- (2,4-Dimethyl-1-pyrrolydinyl) -ethyl-N1-nitroguanidine with a melting point of 121 ° C, the compound being obtained in the form of colorless crystal flakes.

Analysis: found: C = 47.3%; H = 8.4%; N = 30.9% theory for C9H19N5O2 : C t 47.2%; H = 8.3%; N - 30.6%.

6.9 g of this guanidine are dissolved in butanone and then passed running a stream of anhydrous hydrogen chloride through this solution, giving 7.95 g (yield 99%) of the corresponding monohydrochloride are precipitated. This Hydrochloride has a melting point of 158 ° C. By recrystallization from ethanol colorless crystal flakes with a melting point of 158 ° C. are obtained.

Analysis: found: C = 40.6%; H = 7.55%; N = 26.45%, Cl = 13.5 % Theory for C9H20N5ClO2: C = 40.7%; H = 7.5%; N = 26.4%, Cl - 13s4 as for example 15 7.1 g of the 1- (ß-aminoethyl) -2,4 dimethylpyrrolidine prepared according to Example 3 together with 8.2 g of S-methylisothiosemicarbazide hydroiodide in ethanol for 30 hours reacted for a long time at room temperature. The mixture is then send evaporated in vacuo and the oily residue is in the smallest possible amount Dissolved ethanol. After the addition of ether, 9.1 g (yield 79%) of a colorless precipitate Solid with a melting point of 110-111 ° C. By recrystallization 7.75 g (yield 75%) of the compound are obtained from an ethanol / ether mixture N-Amino-N1-ß- (2,4-dimethyl-1-pyrrolidinyl) -äthylguanidinhydidid in the form of colorless Crystal platelets with a melting point; from 113 - 114 ° C.

Analysis: found: C = 32.8%; H = 6.6%; N = 21.4%, J = 38.4% theory for C9H22N5J: C = 33.0%; H = 6.7%; N = 21.4% J = 38.8%.

Example 16 21.9 g of the 1- (β-aminoethyl) -2,4-dimethylpyrrolidine prepared according to Example 3 are mixed in a reagent flask with 4.4 g of 2-nitraminoimidazoline and added heated to 130 ° C. in an oil bath. The reaction, which initially started vigorously, is left subside somewhat and then the reaction mixture is slowly heated to 200 oC and Maintained at this temperature for 10 minutes. After cooling the reaction mixture excess ß-pyrrolidinylethylamine is removed in a water jet vacuum.

Distillation gives 6.35 g (yield 88%) of the compound 1- (ß-2'-imidazolinylethyl) -2,4-dimethylpyrrolidine with a boiling point of 147 - 149 ° C / 0.01 mm Hg as a colorless liquid, which turned to color when left to stand hygroscopic Solidified crystals with a melting point of 72 - 73 ° C.

6.3 g of the imidazoline are dissolved in ethanol and then set 12.1 ml of 5N sulfuric acid are added. By evaporating the neutral solution to dryness under reduced pressure and recrystallization of the solid residue from a Ethanol-ethyl acetate mixture gives 8.7 g (yield 88%) of the corresponding Sulphate hydrates with a melting point of 219-221 ° C in the form of colorless crystal flakes.

Anylyse: found: C = 40.5%; H = 8.15%; N = 17.2%; S = 10.3% Theory for C11H24N4SO4.H2O: C = 40.5%; H = 8.0%; N = 17.35%, s = 10.4%.

Example 17 132.5 g of 4-chloromethylpent-1-yn-4-ol are used together with 366 g (360 ml) of ethanolamine and 200 ml of ethanol were heated under reflux for 24 hours. The reaction mixture is worked up according to Example 1. 68.6 g are obtained in this way (Yield 50%) of the compound 2, 4-dimethyl-1- (ß-hydroxyethyl) pyrrole with a Boiling point of 76 - 78 ° C / 0.4 mm Hg and a refractive index nD20 = 1.5094.

Analysis: found: C = 69.4%; H = 9.6%; N = 10.2% theory for C8H13NO : C = 69.1%; H = 9.35%; N = 10.1%.

30 g of toluene-p-sulfonyl chloride are at 0 ° C to a solution of 20 g of the ß-pyrrolylethanol in 100 ml of pyridine are added.

The mixture is left to stand for 4 days at 0 ° C. and then the reaction mixture is poured with vigorous stirring in 400 g of ice water.

The precipitate is filtered off, washed with ice water and im Vacuum dried at room temperature. By recrystallizing from a large one Volume fraction of petroleum ether (boiling range 40-60 ° C.) gives 32.7 g (yield 76%) of the salt of toluo-p-sulfonic acid with a melting point (with decomposition) from 93 - 94 ° C in the form of gray-colored crystal plates.

Analysis: found: c = 60.8%; H = 6.6%; N = 4.5%, 5 = 10.8% theory for C15H19NSO4: C = 61.4%; H = 6.5%; X - 4.8%, s = 10.9%.

28.2 g of this salt are added to 210 ml of a 33% solution of methylamine in ethanol and this mixture is left at room temperature for 7 days stand. Then the solvent and the excess methylamine are in vacuo removed. Then 10 ml of a 40% aqueous sodium hydroxide solution are used and carefully extract the solution with ether. The ether extract is made over magnesium sulfate dried and then the ether is evaporated and the residue is distilled 0 nanometers thus obtained 6.7 g (yield 46%) of the compound 2,4-dimethyl-1- (β-methylaminoethyl) pyrrole with a boiling point of 67 -69 ° C / 1.0 mm Hg and a refractive index nD20 = 1.4995. In the form of the picric acid salt, pyrrole has a melting point of 158 ° C.

Analysis: found: C = 47.4%; H = 5.1%; N = 18.3%; Theory for C15H19N5O7: C = 47.25%; H = 5.0%; N = 18.33%.

5.9 g of this pyrrole are among those described in Case 1 Hydrogenated conditions and 4.0 g (yield 66%) of the compound 2,4-dimethyl-1- (ß-methylamino) ethylpyrrolidine are obtained with a boiling point of 89 - 90 ° C / 25 mm Eg and a refractive index nD21 = 1.4490. The pyrrolidine is characterized in the form of the dipicric acid salt and has a Melting point (with decomposition) of 141-142 ° C.

Analysis for the dipicric acid salt: found: G = 41.0%; H = 4.4 %; 11-18.2% theory for C21H26N8O14 C = 41.05%; H S 4.2%; N = 18.25%.

3.2 g of the pyrrolidine are added together with 2.9 g of S-methylisothiourea sulfate refluxed in aqueous ethanol for 16 hours. The reaction mixture is worked up according to Example 1 and 2.6 g (yield 40%) of the are obtained in this way Compound N-methyl-N-ß- (2,4-dimethyl-1-pyrrolidinyl) ethylguanidine sulfate sesquihydrate with a melting point (with decomposition) of 254 - 256 oC from an ethanol / water mixture.

Analysis: found: C = 37.4%; H = 7.5%; N = 17.2%, S = 9.4% theory for C10H24N4SO4.3 / 2 H2O: C = 37.2%; H = 7.45%; N = 17.35%, S = 10.2%.

Example 18 50 g of 4-chloromethylpent-1-yn-4-ol together with 165 g (190 ml) 1,2-diamonopropane heated under reflux for 19 hours. The reaction mixture is worked up according to Example 1 and 26.9 g (yield 47%) of one are obtained Colorless oil with a boiling point of 60 - 65 ° C / 0.05 mm Hg and a refractive index nD21 = 1.5048. This oil contains a mixture of 1- (ß-aminopropyl) -2,4-dimethylpyrrole in a ratio of 65:35 and ß- (2,4-dimethyl-1-pyrroloyl) propylamine.

Analysis: found: C = 69.75%; H = 10.8%; N = 18.0% theory for C9H16N2: C = 71.1%; H = 10.5%; N = 18.4%.

15.2 g of this pyrrole mixture is made at room temperature and atmospheric Pressure in 100 ml of ethanol to which 40 ml of 5N hydrochloric acid has been added, hydrogenated in the presence of 4.0 g of a catalyst containing 5% rhodium on a Contains aluminum oxide carrier. After 24 hours, the reaction mixture is according to the example 1 worked up and 10.5 g (yield 67%) of a colorless oil are obtained with a Boiling point of 78 - 82 ° C / 14 mm Hg and a refractive index nD19 = 1.4526.

This oil contains the two compounds 1- (ß-aminopropyl) -2,4-dimethylpyrrolidine in a ratio of 63 s 37 and β- (2,4-dimethyl-1-pyrrolidinyl) propylamine.

Analysis: found: C = 69.0%; H = 13.1%; N = 17.9% theory for C9H20N2: C = 69.25%; H = 12.8%; N = 17.95%.

5.0 g of this pyrrolidine mixture are mixed with 4.4 g of S-methylisothiourea sulfate heated in aqueous ethanol for 3 hours under re-sulfate. The reaction mixture is worked up according to Example 1 and 9.5 g (100% yield) of one are obtained colorless crystal mixture consisting of 1- (ß-guannidinopropyl) -2,4-dimethylpyrrolidine sulfate and β- (2,4-dimethyl-1-pyrrolidinyl) propylguanidine sulfate. By recrystallization from ethanol, 2.25 g of colorless crystal flakes with a melting point are obtained (with decomposition) from 304 - 305 ° C.

Analysis: found: C = 39.4%; H = 8.15%; N = 18.35%, S = 10.65 % Theory for C10H24N4SO4.1 / 2 H20 t C = 39.4%; H = 8.2%; B = 18.3%, S = 1095 % o Example 19 A mixture of 1-guanyl-3,5-dimethylpyrrazole nitrate and according to Example 3 produced 1- (ß-aminoethyl) -2,4-dimethylpyrrolidine is stirred with stirring Heated for 2 1/2 hours. The excess amine is then removed in vacuo and the residue is dissolved in water. By treatment with a strong anion exchange resin (Sulate form) the desired 1- (ß-guanidinoethyl) -2,4-dimethylpyrrolidine sulfate is obtained.

The solution is evaporated under reduced pressure and the residue is recrystallized from aqueous ethanol. The product thus obtained is with the according to Example 3 obtained compound identical.

Example 20 A solution of 1- (ß-aminoethyl) obtained according to Example 3 -2,4-dimethylpyrrolidine in ethanol is neutralized with 5N sulfuric acid and then cyanamide is added and the mixture is refluxed for 6 hours. After removing the solvent in vacuo, the residue is crystallized out aqueous ethanol and receives 80 the compound 1- (ß-guanidinoethyl) -2, -dimethylpyrrolidinsulfathydrat, which corresponds to the compound obtained in Example 3.

Example 21 According to Example 3, 1- (β-aminoethyl) -2,4-dimethylpyrrolidine is used prepared and dissolved in water. This solution is neutralized with 5N sulfuric acid and then add an equivalent amount of monosodium dynamide. The mixture will Heated to reflux for 8 hours. Then the reaction mixture treated with an equivalent amount of 5N sulfuric acid and then evaporated in vacuo. Obtained by recrystallizing the residue from an ethanol / water mixture one the desired 1- (ß-guanidinoethyl) -2,4-dimethylpyrrolidinsulfathydrat. This The product is identical to the product obtained in Example 3.

Example 22 The 1- (β-aminoethyl) -2,4-dimethylpyrrolidine prepared according to Example 3 as well as o-Methylischarnstoffsulfat are dissolved in aqueous ethanol and this Mixing is 4 hours heated under reflux for a long time. Then neutralized the reaction mixture with 5N sulfuric acid and evaporated in vacuo.

By recrystallizing the residue from an ethanol / water mixture the desired 1- (ß-guanidinoethyl) -2,4-dimethylpyrrolydine sulfate hydrate is obtained, which is identical to the product obtained in Example 9.

Patent claims:

Claims (1)

Claims 1 Q. Pyrrolidineuanidine compounds of the formula below and their non-toxic acid addition salts, in which R, R1 and R3 each represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms; R2 is a lower alkyl or cycloalkyl group having 1-6 carbon atoms; R4 and R5 each represent a hydrogen atom or a lower alkyl group with 1-6 carbon atoms and R4 or R5 can also represent an amino or nitro group, or R and R5 together can form an ethylene bridge -CH2CH2-, and n has a value from 2 to 8 Has. 2. 1- (ß-Guanidinoethyl) -3-methylpyrrolidine and its non-toxic Acid addition salts. 3. 1- (ß-guanidinoethyl) -3-n-butylpyrrolidine and a non-toxic Acid addition salts. 4. 1- (ß-Guanidinoethyl) -2,4-dimethylpyrrolidine and its non-toxic Acid addition salts. 5. 1- (ß-Guanidinoethyl) -3-n-propylpyrrolidine and its non-toxic Acid addition salts. 6. 1- (ß-Guanidinoethyl) -3-cyclohexylpyrrolidine and its non-toxic Acid addition salts. 7. 1- (ß-Guanidinoethyl) -3-ethylpyrrolidine and its non-toxic Acid addition salts. 8. 1 - (13-guanidinoethyl) -4-ethyl-2-methylpyrrolidine and its non-toxic Acid addition salts. 9. 1- (ß-guanidinoethyl) -4-tert-butyl-2-methylpyrrolidine and its non-toxic acid addition salts. 10. 1- (ß-Guanidinoethyl) -3-dimethylpyrrolidine and its non-toxic Acid addition salts. 11. 1- (ß-Guanidinoethyl) -2,3,5-trimethylpyrrolidine and its non-toxic Acid addition salts 120 1- (ß-guanidinoethyl) -2-ethyl-4-methylpyrrolidine and its non-toxic acid addition salts. 13. 1- (γ-Guanidinopropyl) -2,4-dimethylpyrrolidine and its non-toxic Acid addition salts 0 1 4o 1 - (# - Guanidino-n-octyl) -2,4-dimethylpyrrolidine and its non-toxic acid addition salts. 15. N-ß- (2,4-Dimethyl-1-pyrrolidinyl) -ethyl-N1-nitroguanidine and its non-toxic acid addition salts. 16. N-Amino-N1-ß- (2,4-dimethyl-1-pyrrolodinyl) ethylguanidine and its non-toxic acid addition salts. 17. 1- (β-2'-Imidazolinylethyl) -2,4-dimethylpyrrolidine and its non-toxic Acid addition salts. 18. N-methyl-N-β- (2,4-dimethyl-1-pyrrolidinyl) ethylguanidine and its non-toxic acid addition sal.e0 19. 1 - (ß-guanidinopropyl) -2,4-dimethylpyrrolidine and its non-toxic acid addition salts. 20. ß- (2,4-Dimethyl-1-pyrrolidinyl) propylguanidine and its non-toxic Acid addition salts. 210 Process for the redellation of pyrrolidinoguanidine compounds represented by the following formula and their nontoxic acid addition salts in which R, R1 and R3 are each a hydrogen atom or a lower alkyl group having 1 - 6 carbon atoms, R2 is a lower alkyl or cycloalkyl group having 1 - 6 carbon atoms, R4 and R5 are each a hydrogen atom or a lower alkyl group with 1-6 carbon atoms and one of the S @@ tituenten R4 or R5 can also represent an amino or nitro group, or R4 and R5 together form an ethylene bridge -CH2CH2- and n has the value 2-8, characterized in that a Pyrrolydinoalkylamine of the general formula below in which R, R1, R2, R3 and n have the meaning given above, or a salt of such a pyrrolide alkylamine is reacted with an agent which forms the guanidine group. 22. The method according to claim 2, characterized in that for the Implementation of an O- or S-alkylisothiourea or an acid addition salt such a connection is used0 23. The method according to claim 21, characterized in, that for the implementation cyanamide or a substituted cyanamide or alkali metal salts Such compounds are used 0 240 method according to claim 21, characterized characterized in that a salt of 1-guanylpyrazole or an alkylated one for the reaction 1-guanylpyrazole is used. 25. The method according to claim 24, characterized in that 1-guanyl-3,5-dimethylpyrazole is used for the reaction 26o pyrrolidinoalkylamime of the following formula: and their non-toxic acid addition salts, in which R, R1 and R3 each represent a hydrogen atom or a lower alkyl group with 1-6 carbon atoms, R2 is a lower alkyl or cycloalkyl group with 1-6 carbon atoms and n has the value 2 to 8.