NO126368B - - Google Patents

Description

The compounds produced according to the invention can exist as cis- and trans-isomers and the production of these forms also falls within the scope of the invention. As the compounds also contain asymmetric carbon atoms, they can exist in optically active forms, and these forms also come within the scope of the invention.

The term "lower alkyl" shall here mean alkyl groups which

contains 1 to 6 carbon atoms.

The method for preparing the compounds of the formula (I) involves adding a pyrrolidine alkylamine of the formula (II):

where R, R^ and have the same meaning as mentioned above, or a salt thereof, is reacted with an S-alkylisothiourea substance, an O-alkylisothiourea substance or an acid addition salt thereof, cyanamide or a substituted cyanamide or an alkali metal salt thereof, a salt of 1 -guanylpyrazole or an alkylated guanylpyrazole, as guanylating agent.

Preferably, the guanylating agent is an S-alkylisothiourea or an acid addition salt thereof, and this is heated with the amine or salt thereof in an inert solvent to give the compound of formula (I).

It should be noted that in British patent 933 686 a method is described which can be said to be analogous to the method according to the present invention, and further that the compounds produced according to the present method also have a somewhat similar structure to the compounds according to said patent. However, it should be noted that the compounds produced according to the British patent comprise a /3,/3-disubstituted pyrrolidine and such compounds are quite difficult to produce, while the compounds according to the method according to the invention do not comprise any such tertiary carbon atoms and the is therefore much easier to produce.

The starting pyrrolidine alkylamines can be prepared by catalytic hydrogenation in solution of a corresponding pyrrole of the formula (III):

e.g. by using a rhodium/alumina catalyst or 5 or 10% Pd/c catalyst. When R or R^ is something other than a hydrogen atom, this reaction can form mixtures of cis-trans isomers.

Several methods can be used to prepare the pyrrole-alkylamines of the formula (III), and in particular:

(1) reaction of an acetylenic chlorocarbinol

C1CHR. CR2(0H) . CSC^ or ClCHR . CR2 (0H) . CH2.C<=>CH

with an amine NH2.(CH2)n. NH2.

(2) Reaction of an acetylenic epoxide of the formula:

with an amine NH2. (CH2)n. NH2.

(3) By converting a pyrrole alkanol of the formula:

to a reactive derivative of the formula:

where X is a halogen atom or the residue of a sulphonic acid, especially toluene-p-sulphonic acid, and this compound is reacted with an amine R^N<I>^.

The pyrrolidine alkylamines of formula (II) are also new compounds, as are a number of the other intermediates described here.

The following examples shall serve to clarify the invention:

Example 1

4-Chloromethylpent-1-yn-4-ol (57 g), anhydrous ethylenediamine (150 g, 166 ml) and ethanol (150 ml) were heated under reflux for 17 hours. The solvent and excess ethylenediamine were removed in vacuo and 40% aqueous sodium hydroxide (50 ml) was added. After removal of water from the mixture by azeotropic distillation with benzene, and removal of the solvent, an oil was obtained which was distilled to give 1-(3-(aminoethyl)-2,4-dimethylpyrrole (26.9 g, 45% ), cf. 72°C at 0.9 mm, n<*7>,<5>= 1.51.40.

This pyrrole (13.96 g) was hydrogenated at room temperature and 35 kg/cm 2 pressure in ethanol (250 ml) and 5N hydrochloric acid (45 ml) in the presence of 5% rhodium/alumina (5.0 g) as. catalyst. After 60 hours, the catalyst was filtered off and the solvent removed in vacuo. The residue was dissolved in water, basified with dilute sodium hydroxide solution, and the solution was continuously extracted with ether to give an oil which on distillation gave 1-(/3 -aminoethyl)-2,4-dimethylpyrrolidine (6.98 g, 48%) b.p. 71°C at 14 mm, n<*7>= 1.4578.

[Alternatively, the hydrogenation can be carried out using glacial acetic acid or aqueous acetic acid as solvent instead of ethanol - 5N hydrochloric acid. Likewise, the catalyst can be changed from 5% rhodium/alumina to 5% palladium on bone charcoal or 10% palladium on bone charcoal. The yields in the hydrogenation vary from 40-60%.]

The pyrrolidine (6.59 g) with S-methylisothiouronium sulfate (6.45 g) in ethanol (50 mL) and water (30 mL) was refluxed for 3 1/2 hours. After cooling, the solution was filtered, neutralized with 5N sulfuric acid (10 mL) and evaporated in vacuo to give an oil which on boiling with ethanol gave a colorless solid. Recrystallization from acetone/water gave 1-([3-guanidineethyl)-2,4-dimethyl-pyrrolidine sulfate hydrate (6.46 g, 50%), m.p. 291-292°C. (fission).

Example 2

4-Chloromethylhex-1-yn-4-ol (52.2 g), anhydrous ethylenediamine (122.0 g, 136 mL) and ethanol (200 mL) were heated under reflux for 30 h. Workup as described in Example 1 gave 1-((3-aminoethyl)-4-ethyl-2-methylpyrrole (36.7 g, 68%), b.p. 82-87°C/1.3-1.8 mm, nj° = 1.5087

Found : 71.0% C 10.5% H 18.3% n

<C>19<H>16N2requires : 71.1% C 10.5% H 18.4% N.

Hydrogenation of the pyrrole (33.1 g) under the same conditions as described in Example 1 gave 1-(β-aminoethyl)-4-ethyl-2-methylpyrrolidine (12.2 g, 36%), b.p. 88-89.5°C/15 mm, n^<6>,<5>= 1.4598, characterized as the di-toluene-p-sulfonate, m.p. 157-158°c.

Found: 54.4% C 7.2% H 5.6% N 13.2% S

C23H36<N>2<S>2°6requires: 55.2% C 7.2% H 5.6% N 12.8% S

Treatment of the pyrrolidine (6.0 g) with S-methylisothiouronium sulfate (5.4 g) in aqueous ethanol under reflux for 3 hours, followed by work-up as described in Example 1,

gave 1-(n3-guanidineethyl)'-4-ethyl-2-methylpyrroidine sulfate (8.0 g, 70%)

m.p. 248-250.5°C (decomposition ex-ethanol/water.)

Found : 40.7% C 8.2% H 18.8% N 11.2% S

C10H24N4S04requires : 40.6% C 8.1% H 18.9% N 10.8% S

Example 3

3-bromopropyne (71.5 g, 45 mL) was dissolved in ether (200 mL)

and a 10 ml portion of the solution was added to magnesium

shavings (14.65 g) covered with ether (200 ml). Once the reaction had started,

the mixture was cooled to -10°C and the remainder of the 3-bromopropyne solution was added dropwise at -10°C. l-chloro-3,3-dimethylbutane-

2-one (55.7 g) in benzene (200 mL) was then added dropwise and the mixture was stirred for a further 4 hours at -10°C. 5N sulfuric acid.

(250 mL) was then added, followed by water (250 mL). After filtration, the product was extracted in ether and the ether portion was

with water, saturated sodium bicarbonate solution, and finally

body of water. After drying over magnesium sulfate, the ether was removed under reduced pressure. Careful fractionation of the crude oil (65.3 g) led to the separation of 4-chloromethyl-5,5-dimethylhex-l-yn-4-ol (4.2 g, 6%) bp. 65-68°C/3.6 mm, n£<4>,<5>= 1.4828, and 4-t-butyl-4,5-epoxypent-1-yne (7.9 g, 14%) kp. 36-38.5°C/3.5 mm, n^<7>= 1.4482.

4-chloromethyl-5,5-dimethylhex-l-yn-4-ol (3.0 g), anhydrous ethylenediamine (6.2 g, 6.7 mL) and ethanol (100 mL) were heated under reflux for 24 h . Preparation as described in example 1

gave 1-(O-aminoethyl)-4-t-butyl-2-methylpyrrole (2.2 g, 71%), m.p. 60-62°C/0.05 mm, n^<7>1.5007.

Found : 73.1% C 11.3% H 15.1% N

C11H20N2 requires : 7 3.3% C 11.1% H 15.6% N

Alternatively, 4-t-butyl-4,5-epoxypent-1-yne (6.85 g), anhydrous ethylenediamine (17475 g, 19.4 mL) and ethanol (100 mL) were heated under reflux for 24 hours. Solvent and excess ethylenediamine were removed in vacuo and water was removed by azeotropic treatment with benzene. Removal of solvent and distillation gave 1-(/3-aminoethyl)-4-t-butyl-2-methylpyrrole (6.4 g, 72%) o

Hydrogenation of the pyrrole (7.0g) under the same conditions as described in Example 1 gave 1-((3-aminoethyl)-4-t-butyl-2-methylpyrrolidine (4.3g, 60%), bp . 105-109°C/14 mm, n^<1>= 1.4618.

Found : 14.8% N

<C>11<H>24<N>2 requires:15.2% N

Treatment of the pyrrolidine (3.3 g) with S-methylisothiouronium sulfate (2.5 g) in aqueous ethanol under reflux for 3 1/2 hours followed by work-up as described in Example 1 gave 1-(/3-guanidineethyl)-4 -t-butyl-2-methylpyrrolidine sulfate hemihydrate (4.2 g, 70%), m.p. 246-249°C (decomposition) ex-ethanol/water.

Found s 43.4% C 8.7% H 16.5% N 9.8% S<C>12<H>28N4S04ol//2H2° requires: 43.2% C 8.7% H 16.8% N 9.6% S

Example 4

4-chloro-3-methylpent-l-yn-3-ol (143.3 g) and anhydrous ethylenediamine (450 g, 500 ml) were heated under reflux for 6 days. Workup as described in example 1 gave 1-(/ 3-aminoethyl)-2,3-dimethylpyrrole (60.0 g, 43%), b.p. 72°C/0.9 mm, n<*9>= 1.5162.

Found : 69.75% C 10.3% H 20.5% N C8H14N2 requires : 69.6% C 10.15% H 20.3% N

Hydrogenation of the pyrrole (27.6 g) under the same conditions as described in Example 1 gave 1-(β-aminoethyl)-2,3-dimethylpyrrolidine (16.0 g, 56.5%), b.p. 81-83°C/18 mm, n20 = 1.4640, characterized as the dipicrate, m.p. 320-321°C.

Found : 40.0% C 4.1% H 18.5% N

<C>20<H>24<N>8°14requires : 40.0% C 4.0% H 18.7% N

Treatment of the pyrrolidine (8.0) with S-methylisothiouronium sulfate (7^8 g) in aqueous ethanol under reflux for 5 hours, followed by work-up as described in Example 1, gave 1-(/3-guanidineethyl)-2,3- Dimethylpyrrolidine sulfate hemihydrate (13.6 g, 86%), m.p. 272-274°C (decomposition).

Found : 37.35% C 7.8% H 19.6% N 11.2% S CgH22N4S04.l/2H20 requires : 37.15% C 7.9% H 19.2% N 11.0% S

1-(/3-aminoethyl)-2,3-dimethylpyrrolidine prepared as described is obtained as a mixture of cis and. trans isomers in the respective ratio 65:35. These isomers can be separated by gas-liquid chromatography using a column of 20% silicone

oil DC 550 on "Celite" and nitrogen as carrier gas.

Treatment of each of the pure isomers separately with S-methylisothiouronium sulfate in the usual way, followed by working up

divide as described in Example 1, gave cis-2,3-dimethyl-1-(β-guanidineethyl)-pyrrolidine sulfate, m.p. 292-295°C (decomposition).

Found : 38.6% C 8.0% H 20.0%N 11.4% S<C>9<H>22N4S04 required : 38.3% C 7.8% H 19.9% N 11.35% S

respectively trans-2,3-dimethyl-1-(/3-guanidineethyl)-pyrrole in din sulfate hemi-hydrate, m.p. 294-295°C (decomposition).

Found : 37.4% C 7.8% H 18.7% N 11.0% S C9<H>22N4S04.1/2H20 requires : 37.15%C 7.9% H 19.2% N 11, 0% S

Example 5

3-Chlorobutan-2-one (210 g) in benzene (500 mL) was added dropwise to a stirred solution of propargyl magnesium bromide (prepared from 3-bromopropyne (357 g, 225 mL) and magnesium shavings (72

g) as described in example 3) in ether at -10°C. Workup as described in example 3 gave 5-chloro-4-methylhex-1-yn-4-ol

(230.9 g," 80%) , b.p. 35-40°C/0.7-l .0 mm, n^<9>= 1.4702.

Found : 23.5% Cl

C7HllCl° requires: 24.2% Cl

5-chloro-4-methylhex-l-yn-4-ol (146.5 g) and ethylenediamine

(360 g, 400 mL) was heated under reflux for 3 days. Workup as described in Example 1 gave 1-((3-aminoethyl)-2,3,5-trimethylpyrrole (115.1 g, 76%) bp. 60-65°c/0.01mm, n£<1>,<5>= 1.5171.

Found : 70.3% C 10.6% H 18.1% N

•<C>9<H>16N2requires: 71.1% C 10.5% H 18.4% N

Hydrogenation of the pyrrole (20 g) under the same conditions

gels as described in Example 1 gave 1-(3-aminoethyl-2,3,5-trimethylpyrrolidine (15.6 g, 77%), b.p. 78.5-80°C/11 mm, n^° = 1.4995, characterized as the dipicrate, mp 227-228°C.

Found : 41.0% C 4.3% H 18.4% N

C21H26<N>8°14requires : 41.05%C 4.2% H 18.25% N

Treatment of the pyrrolidine (7.1 g) with S-methylisothiouronium sulfate (6.3 g) in aqueous ethanol under reflux for 4 h, followed by work-up as described in Example 1, gave l-(/3-guanidineethyl)- >2 , 3,5,-trimethylpyrrolidine sulfate (9.7 g, 72%), m.p. 275-278°C (decomposition') ex-ethanol/water.

Found : 40.3% C 8.2% H 18.7% N 10.9% S C10<H>24N4S04requires:40'6% c 8'1^ H 18/9% N 10.8% S

Example 6

Ethyl magnesium bromide (prepared from ethyl bromide [164.0 g, 113 mL] and magnesium shavings [36.0 g] in ether) was added over 1 hour to ether (700 mL) saturated with 1-butyne. During the addition, the internal temperature was below 10°C and a steady stream of 1-butyne was bubbled into the reaction mixture. The mixture was then cooled to 5°C and chloroacetone (93 g) was added dropwise. After stirring overnight at room temperature, ammonium chloride solution was saturated

(250 mL) was carefully added, and the resulting inorganic precipitate was filtered off and washed with ether. The filtrate was washed with water, dried over magnesium sulfate and evaporated in vacuo to give an oil (136 g). Careful fractionation gave 5-chloro-methylhex-3-yn-5-ol (57.5 g, 39%), b.p. 81°C/11 mm, n^<1>= 1.4710.

Found: 57.2% C, 7.6% H, 24.5% Cl

CyH^ClO requires : 57.3% C 7.5% H 24.2% Cl 2-Chloromethyl-butan-2-ol (24.0 g, 20%) was also isolated due to reaction between unchanged ethylmagnesium bromide and chloroacetone .

5-Chloromethylhex-3-yn-5-ol (48.8 g), anhydrous ethylenediamine (108.0 g, 120.0 mL) and ethanol (150 mL) were heated under reflux for 24 hours. Workup as described in Example 1 gave 1-(/3-aminoethyl)-2-ethyl-4-methylpyrrole (36.8 g, 73%), b.p. 79-80°C/ 0.12 mm, n^<1>1.5085.

Found : 70.4% C 10.8% H 18.0% N C9H16N2 kre,/er571 c 10.5% H 18.4% N

Hydrogenation of the pyrrole (20 g) under the same conditions as described in Example 1 gave 1-(β-aminoethyl)-2-ethyl-4-methyl-pyrrolidine (18.1 g, 88%), b.p. 82°c/12 mm, n^<1>= 1.4610, characterized as the dipicrate, m.p. 180-181°C.

Found : 41.3%C 4.3%H 18.1%N

<C>21<H>26<N>8°14requires : 41/05% C 4.2% H 18.25% N

Treatment of pyrrolidine (7.6 g) with S-methylisothiouronium sulfate (6.95 g) in aqueous ethanol under reflux for 4 1/2 hours, followed by work-up as described in Example 1, gave 1-O-guanidineethyl)-2- ethyl 4-methylpyrrolidine sulfate (10.6 g, 71%), m.p. 272-274°c (decomposition) ex-ethanol/water.

Found : 40.05% C 8.2% H 18.6% N 11.4% S C10H24N4S04 required : 40.6% C 8.1% H 18.9% N 10.8% S

Example 7

A mixture of 1-guanyl-3,5-dimethylpyrazole nitrate and 1-(/3-aminoethyl)-2,4-dimethylpyrrolidine (prepared as described in Example 1) was heated for 2 1/2 hours with stirring. Excess amine was removed in vacuo, and the residue was dissolved in water and re-

formed to the desired 1-(/3-guanidineethyl)-2,4-dimethylpyrrolidine sulfate hydrate by treatment with a strong anion (sulfate) exchange resin. The resulting solution was evaporated under redu-

pressure and the residue was recrystallized from aqueous ethanol.

The product was identical to that obtained according to ec-

simple 1.

Example 8

A solution of 1-(/3-aminoethanol)-2,4-dimethylpyrrolidine (prepared as described in Example 1) in ethanol was neutralized with 5N sulfuric acid, cyanamide was added and the mixture was heated under reflux for 6 hours. Removal of solvent and recrystallization of the residue from aqueous ethanol afforded 1-(/3-guanidineethyl)-2,4-dimethylpyrrolidine sulfate hydrate, identical to the compound obtained according to Example 1.

Example 9,

A solution of 1-(0-aminoethyl)-2,4-dimethylpyrrolidine (prepared as described in Example 1.) in water was neutralized with

.5N sulfuric acid, an equivalent amount of monosodium cyanamide was added, and the mixture was heated under reflux for 8 hours. The mixture was then treated with an equivalent amount of 5N sulfuric acid and evaporated in vacuo. Recrystallization of the residue from ethanol/water gave the desired 1-((3-guanidinemethyl)-2,4-dimethylpyrrolidine'-sulphate hydrate). The product was identical to the compound which

obtained in example 1.

Example 22

1-(/3-Aminoethyl)-2,4-dimethylpyrrolidine (prepared as described in Example 1) and O-methylisouronium sulfate were dissolved in aqueous ethanol and heated under reflux for 4 hours. After neutralization with 5N sulfuric acid, the mixture was evaporated in vacuo and crystallization of the residue from ethanol/water gave the desired 1-((3-guanidineethyl)-2,4-dimethylpyrrolidine sulfate hydrate). The product was identical to the compound obtained in example 1.

In the table below, the activity of certain compounds produced according to the present invention is compared with the antihypertensive activity of guanethidine, which is possibly the best antihypertensive agent currently available. Guanethidine has the formula:

which is the most active compound produced according to Norwegian patent 98 970.

The compounds produced according to the invention were examined subcutaneously and orally with regard to antihypertensive activity in hypertensive rats, and the doses which cause a 20% drop in blood pressure were determined. The activities are reproduced in relation to the activity of guanethidine, which is given the value 1.00.

Each compound was examined as the sulfate. The results are given for a 65:35 ratio of cis to trans isomers.

Claims (1)

Analogous process for the preparation of pyrrolidino-guanidine compounds with valuable pharmaceutical properties and with the formula (I): and non-toxic acid addition salts thereof, where R, R1 and R2 are each hydrogen or a lower alkyl group, with however at most one of these substituents being hydrogen, characterized in that a pyrrolidinoalkylamine of the formula (li): where R, R^ and R2 have the same meaning as mentioned above, or a salt thereof, is reacted with an S-alkylisothiourea, an O-alkylisourea or an acid addition salt thereof, cyanamide or a substituted cyanamide or an alkali metal salt thereof, a salt of 1-guanylpyrazole or an alkylated guanylpyrazole as guanylating agent.