DK168072B1 - 5-(2-pyrrolidin-1-yl)ethoxy)-p-cymene derivatives, a process for preparing them, and medicaments which comprise them - Google Patents

Description

in DK 168072 Bl

The present invention relates to 5- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene derivatives, processes for the preparation of these derivatives and drugs in which these derivatives are present.

GB Patent No. 1,325,795 discloses phenoxyethylamines which are stated to have vasodilatory and antifibrillatory effects.

U.S. Patent No. 3,906,030 discloses amino-ethers of the p-system which are said to be useful as diuretics, respiratory analgesics, skull vasodilators and peripheral vasodilators, antiarrhythmics and antispasmodics. These compounds, in contrast to the compounds of the invention, do not specifically have a 2- (pyrrolidin-1-yl) ethoxy group at the 5-position of the p-cymer ring, and furthermore, unlike the compounds of the invention, a -COOR group of the 6-position of the cymene ring.

There is no indication in the above-mentioned patents that the known compounds can be used in the urological field.

The 5- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene derivatives are novel compounds of the formula: <jH3 / (I)

CH

wherein R is selected from H, OH, OCOCH3 (acetoxy) and OCO (CH2) nCH3, wherein n is between 1 and 8 (wherein 1 and 8 are included in the definition of n) and the salts of the compounds of formula (I) with pharmaceutically acceptable acids.

2 DK 168072 B1

The process for preparing the compound of formula (I) wherein R is H is characterized by reaction of thymol with N- (2-chloroethyl) pyrrolidine hydrochloride. The reaction can be carried out by phase transfer in a liquid-liquid system in the vicinity of a catalyst (triethylbenzylammonium chloride). This gives the compound of formula (I) wherein R is H.

The process for preparing a compound of formula (X) wherein R is -O-COCH 3 is characterized by reacting a compound of formula (I) wherein R is -COCH 3 obtainable by reacting the compound of formula (X) I) wherein R is H, with acetic anhydride, in the presence of perchloric acid, with an oxidizing agent such as m-chlorobenzoic acid, in the presence of an acid.

Thus, the compound of formula (I) wherein the group R is acetyl can be prepared in a solvent such as toluene and in the presence of 70% perchloric acid by reacting the compound where R = H with acetic anhydride.

The compound of formula (I) wherein the group R is acetoxy is prepared by reacting an oxidizing agent such as m-chloroperperbenzoic acid with the derivative of the compound of formula (I) wherein R is acetyl, said reaction being carried out in a solvent (toluene) in the presence of an acid (trichloroacetic acid).

The compound of formula (I) wherein the group R is a hydroxyl group is prepared by a process which is characterized by reacting a compound in which R is the acetoxy group with a solution of sodium hydroxide.

Finally, those compounds of formula (I) wherein the group R is OCO (CH2) nCH3 are prepared by esterification of the compound of formula I wherein R is OH with an acid chloride of formula

RC

N1 is wherein CH is CH3 - (CH2), where n is between 1 and 8.

The salts, e.g. the hydrochlorides are obtained in a known manner by contacting a solution of the compound of formula (I) with the acid in question (for example, by bubbling hydrogen chloride 5 into a solution of the compound of formula (I)).

The present invention also relates to drugs having in particular α-blocking effect and containing at least one compound of formula (I) or a salt of said compound as the active compound. Said drugs may be useful, especially in the field of urology.

The following examples illustrate the methods of preparing the compounds of the invention.

Example 1

Synthesis of 3- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene hydrochloride (B 1007) 1. Preparation of 3- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene.

. The following is added a 4 liter, three-neck flask equipped with a cooler, a pneumatic stirrer and a thermometer: 150.2 g (1 mole) of thymol 20 16.68 g of triethylbenzyl ammonium chloride and 751 ml of sodium hydroxide solution.

1495 ml of methylene chloride is added. The medium is stirred very vigorously.

The addition of 212.76 g of N- (2-chloroethyl) pyrrole in dinohydrochloride (1.25 mol) in 70.9 ml of water causes the temperature to rise to 25 ° C.

4 DK 168072 B1

The mixture is heated under reflux for 4 hours with vigorous stirring.

After cooling to room temperature, the mixture is allowed to separate the organic phase and the sodium phase is extracted with 2 x 42 5 ml of methylene chloride.

The combined organic phases are washed successively with 2 x 350 ml of acidified water (0.25¾ acetic acid) and then with 2 x 700 ml of a saturated aqueous solution of sodium chloride until neutral. Then, dry over sodium sulfate.

After filtration, the solvent is evaporated under vacuum.

This gives 259.57 g of an orange oil.

The crude product is purified by fraction distillation in vacuo (under nitrogen).

184.7 g of a colorless oil are isolated. Boiling point below 0.1 mm Hg: 155-160 ° C; perchloric acid / CH 3 COH titre: 102.1¾.

2. Preparation of the hydrochloride.

Dissolve 24.73 g of this oil (0.1 mole) in 400 ml of anhydrous ethyl ether. The solution is then saturated with a stream of dry HCl gas in an ice bath. The crystals formed are filtered off on a 25 ml glass frit washed with anhydrous ethyl ether and then dried over potassium hydroxide at 70 ° C.

This gives 25.12 g of beige crystals (the crude product yield = 88.6¾).

30

After the recrystallization from ethyl acetate, 22.22 g of slightly beige crystals are isolated.

The crystals obtained are subjected to elemental analysis (empirical formula C 15 H 2 gClNO), giving the following results: 35 5 DK 168072 B1

Calcd. Found C 67.70 67.69 H 9.23 9.25 N 4.93 4.83 5 Cl 12.48 12.65 0 5.63 5.76

The crystals have a melting point m.p. <RTI ID = 0.0> B P & 157-158 ° C and their IR and NMR spectra are consistent with the assumed structure.

10

Example 2

Synthesis of the intermediate product 2-acetyl -5- [2- (pyrrolidin-1-yl) ethoxy] -β-cymene.

The 3- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene obtained according to Method 1 of Example 1 is used as starting material, this product being pre-purified.

247.38 g (1 mole) of this product are dissolved in 1600 ml of toluene and 863 ml of acetic anhydride in a 4 liter three-neck flask equipped with a condenser equipped with an H2SO4 trap, a thermometer and a dropping funnel. The mixture is stirred and 225.2 ml of 70% perchloric acid is then added dropwise, keeping the temperature below 45 ° C.

The mixture is stirred for one hour at room temperature and then poured into 760 ml of a saturated aqueous solution of NaCl.

After cooling by an ice bath and after mixing the mixture with sodium hydroxide solution (pH 12), the organic phase is separated and extraction with 2 x 300 ml of methylene chloride. The organic phases are combined and washed with acidified water and a saturated aqueous solution of NaCl until neutrality. Then, it is dried over sodium sulfate and filtered and the solvent is evaporated in vacuo. This gives 297.3 g of a brown oil with a GC purity of 97% (crude product yield 35> 100%).

The crude product is then purified by fraction distillation in vacuo (under nitrogen).

6 DK 168072 B1

196.14 g of a yellow oil are isolated.

The product obtained has a boiling point (below 0.4 mm Hg) of 149-153 ° C and a perchloric acid titer of 98.6% and the product's IR-g and NMR spectra are consistent with the assumed structure.

Example 3

Synthesis of 2-acetoxy-5- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene-10 hydrochloride (B 1024).

1. Synthesis of 2-acetoxy-5- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene.

The purified oil obtained in Example 2 is used as the starting material.

15 289.42 g (1 mole) of this product and 1650 ml of toluene are introduced into a 4 liter, three-neck flask equipped with a cooler equipped with an H2SO4 trap, a thermometer and a pneumatic stirrer.

20 392.13 g (2.4 mol) of tr in hydrofluoroacetic acid are added portionwise keeping the temperature below 15 ° C. Then, 258.84 g (1.2 moles) of 80% chlorobenzoic acid are introduced.

The mixture is kept at 15 ° C for 24 hours with stirring. The mixture is then poured into 2130 ml of 5% ammonia in ac.

The organic phase is separated by decantation. The aqueous phase is extracted with 2 times 890 ml of toluene. The organic phases are combined and washed with 890 acidified water and then with 1180 ml of a saturated aqueous solution of NaCl until neutrality. They are then dried over sodium sulfate and filtered and the solvent is evaporated in vacuo.

266.3 g of a brown oil are obtained with a GC purity of 97.2% 3g (crude product yield = 87.2%).

2. Synthesis of the hydrochloride.

30.54 g (0.1 mole) is this crude oil dissolved in 210 ml of anhydrous ethyl ether. A stream of dry HCl gas is bubbled into the solution in an ice bath. The crystals formed are filtered off on a glass frit, washed with anhydrous ethyl ether and then dried over potassium carbonate at 50 ° C in vacuo.

g 16.74 g of beige crystals are isolated (crude product yield = 49%).

After recrystallization from a 20/1 AcOEt / EtOH mixture, 11.31 g of light beige crystals were obtained.

The said crystals have a melting point m.p. of 182-183 ° C and a perchloric acid titer of 100.8% and the crystals IR and NMR spectra are consistent with the assumed structure.

Example 4 15

Synthesis of 2-hydroxy-5- [2- (pyrrolidin-1-yl) ethoxy] -p-cymene hydrochloride (B 1058).

The purified oil obtained after the first step of Example 3 is used as the starting material.

20.5 g (0.1 mole) of this oil and 110 ml of ethanol are introduced into a 500 ml erlenmeyer coupler equipped with a cooler and a magnetic stirrer.

110 ml of 1 N sodium hydroxide solution (0.11 mol) is added to this solution and the mixture is stirred for 24 hours at room temperature. The ethanol is evaporated in vacuo, the residue is taken up with 150 ml of water and extracted with 3 x 180 ml of methylene chloride.

The combined organic phases are washed with a saturated aqueous solution of sodium chloride until neutrality. Then, dry over sodium sulfate and evaporate the solvent in vacuo. This gives 25.28% of an orange oil {crude product yield = 96%).

After crystallization from hot pentane and recrystallization from hexane, 21.54 g of white crystals having a melting point m.p. of 86-87 ° C are isolated.

The obtained product was converted to a salt (hydrochloride) by the following procedure: 13.16 g (0.05 mole) of purified base was dissolved in 200 ml of anhydrous ethyl ether with stirring. After a stream of dry HCl gas has been bubbled in, the crystals formed are isolated by filtration on a frit.

5

After washing with ethyl ether and drying in vacuo at 50 ° C, 14.54 g of beige crystals (crude product yield = 97%) were obtained.

After recrystallization from an AcOEt / EtOH mixture (2/1), 11.1 g of white crystals were isolated.

10

Said crystals have a melting point m.p. g of 147-148 ° C and their IR and NMR spectra are consistent with the assumed structure. Elemental analysis of these crystals (empirical formula C1gH26clN02) 9 of the following results: 15

Calculated Found C 64.09 64.08 H 8.74 8.78 N 4.67 4.65 Cl 2 11.82 11.96 O 10.67 10.86

Example 5

Preparation of an ester and its hydrochloride.

25 - Synthesis of 2-butyryloxy-5- [2- (pyrrolidin-1-yl) -ethoxy] -p-cymene (R = CH 3 - (CH 2) 2-CO-0-).

The following materials are introduced with stirring into a 500 ml three-neck coupler equipped with a condenser, a pneumatic stirrer and a thermometer: 26.3 g (0.1 mole) of 2-hydroxy-5- [2- ly 1) ethoxy] -p-cymene 200 ml benzene and 10.6 g triethylamine (0.105 mol)

11.2 g (0.105 mole) of butyryl chloride are added to this solution.

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The reaction medium is heated at 50 ° C for 20 hours.

The progress of the reaction is monitored by gas chromatography analysis of the medium.

5

After cooling to room temperature, the reaction mixture is poured into 350 ml of water.

The benzene phase is decanted and countercurrent extraction is carried out on the aqueous phase with 3 x 250 ml benzene.

10

The combined benzene phases are washed with water until the washings are neutral and dried over sodium sulfate.

After filtration, the solvent is evaporated in vacuo.

This gives 31.5 g of a brown oil.

Raw product yield = 94.5% GC purity = 99.5%

Perchloric acid titer = 94.3% 2Q TLC = single spot B - Synthesis of 2-butyryloxy-5- [2- (pyrrolidin-1-yl) -ethoxy] -p-cymene hydrochloride (B 1132).

16.67 g (0.05 mole) of this oil is dissolved in 180 ml of anhydrous ethyl ether. The solution is saturated with a stream of dry HCl gas (in an ice bath). The crystals formed are filtered off, washed with anhydrous ethyl ether and then dried over phosphoric anhydride at 50 ° C.

This gives 12.18 g of beige crystals (crude product yield = 65.8%).

After recrystallization from isopropanol, 10.04 g of slightly beige crystals are isolated.

35 10 DK 168072 B1

Yield after recrystallization = 54.3%

Mp = 189-190 ° C

TBAH time = 97.8%

AgNO 3 ~ titer = 97% 5 GC purity = 99.8% IR = in accordance with the assumed structure NMR = in accordance with the assumed structure Karl Fischer (water determination) = 0.2% TLC = single spot 10

The hydrochlorides mentioned in the summary table below were prepared following the same procedure as described in Example 5:

SUMMARY TABLE

15

Code No. n Empirical Formula Yield- ^ 'KB C

(target weight) tea S staltoaticcap solvent) 20 B 1125 1 C19H30C1N03 51.2 177-178 (355.91) B 1132 2 C20H32C1N03 54.3 189-190 25 (369.94) (IPA) B 1131 4 C22H36C1N03 50 156-157 (397.99) 30 B 1134 8 C ", H., ClNOo 45.4 148-149 26 44 3 (454.10) (IPA) 35 The products of the invention were tested for their toxicity and their pharmacological properties.

11 DK 168072 B1 1. Toxicity

The following 50% lethal doses were obtained following oral administration (p.o.) and intravenous administration (i.v.) of the drug cabs to mice.

ISLAND

The results obtained are summarized in Table (I).

Table I

LD - mg / kg 10 Compound __ p.o. i.v.

B 1007 330 75 B 1024 100 18 B 1058 80 17 15 B 1125 300 ND * B 1131 550 ND * B 1132 i * 500 ND * B 1134 2 = 5 400 36

Thymoxamine 300 72.5 20 ____ * ND: not determined 2. Pharmacological properties 2.1. - In vitro α-adrenolytic activity.

25

This was investigated on ductus deferens in rats and on urethra in rabbits.

Principle of measurement: Norepinephrine causes contractions of the 20 isolated ductus deferens in rats and the isolated urethra in rabbits. The presence of α-blocking agents in a bath containing the body antagonizes these contractions. The use of increasing concentrations of α-blocking agents makes it possible to calculate: pA2 for the compounds on ductus deferens in rats, with pA2 being the negative logarithm of the molar concentration of the compound in the presence of the concentration of norepinephrine, 3 5 DK 168072 B1 1 -2- must be doubled to obtain the same effect as in the absence of the compound, and pD'2 sf the compounds on the urethra of rabbits, pD'2 being the negative logarithm of the molar concentration of the compound in the presence of the contraction-inducing agent. the effect of norepinephrine is halved.

results:

The results obtained are summarized in Table II

α-blocking effect against norepinic

Connecting _Grin_- ______ else E® insulated ductus on insulated, deferens urethra 15 PA2 pD * 2 B 1007 6.74 6.88 B 1024 6.98 6.38 B 1058 7.18 6.69 20 B 1125 7.14 6.25 B Π31 6.98 6.12 B 1132 7.35 6.0 B 1134 6.57 6.23

Thymoxamine 7.25 7.03 25 --——-—--

These results show an interesting α-blocking effect of the compounds studied.

2.2. - In vivo adrenolytic action.

2.2.1. In rats Measurement Principle: Norepinephrine is injected intravenously at high doses, causing 100% of animals to die within 15 35 minutes. after they have been injected.

The cause of death is pulmonary edema due to the arterial hypertension caused by stimulation of the adrenergic receptors. The oral administration of α-adrenolytic substances in advance makes it possible to reduce the toxicity of norepinephri n. The compounds are administered orally at times, varying between 30 min. and 6 hours before the intravenous injection 5 (i.v.) of norepinephrine (0.4 mg / kg.).

Results: The results obtained are listed in Table III.

TABLE III

10 I ^ Γ I

Compound Dose p.o. % protection The time interval between ad-ή t, administration of the pre-mg / kg mocl death of the bonds and i.v.

I-I --- ^ -! B 1007 50 60 30 min! B 1024 25 70 30 min 15 I B 1058 50 90 30 min I B 1125 25 60 30 min

J

I B 1131 50 60 30 min B 1132 50 90 30 min B 1134 100 100 4 h '20

Thymoxamine 50 80 30 min

These results show that the compounds studied provide effective protection against norepinephrine toxicity.

2.2.2. In anesthetized rabbits.

"In vivo" α-blocking activity, expressed as the urethral and vascular pressures in anesthetized rabbits, was studied by intravenous administration of compounds B 1007, B 1024, B 1058, B 1125 and B 1134.

Principle of measurement: oc The intravenous injection of norepinephrine causes dose-

ISLAND ISLAND

dependent increase in the arterial and urethral pressure of rabbits. α-blocking agents injected intravenously antagonize these pressure increases as a function of dose. The dose, inhibiting 50¾ (ID50), defined as being the dose of the compound causing a 50% decrease in the effects of norepinephrine on the arterial and urethral pressures is calculated.

5

results:

The results obtained are listed in Table IV.

TABLE IV

ID50 (mg / kg)

Compound T TT 77i Arterial Cell Urethral Hypertension ~ Hypertension 15 B 1007 7.63 0.34 B 1024 4.14 0.23 B 1058 1.22 0.13 B 1125 5.95 0.36 B 1134 6.17 0.48 20 Thymoxamine 2.72 '0.5

These results show that the tested compounds antagonize the increase in urethral pressure, at much lower doses than those necessary to antagonize the increase in arterial pressure.

2.2.3. Lethral specificity in anesthetized dogs.

The effect of compounds B 1007, B 1024, B 1125 and B 1134 injected intravenously on neurogenic urethral hypertension and arterial pressure was investigated on anesthetized dogs.

Measuring principle:

Electrical stimulation of the hypogastric nerve causes an increase in urethral pressure by releasing norepinephrine from the sympathetic fibers of the nerve.

B1 α-blocking agents antagonize these increases in urethral pressure as a function of dose, causing arterial hypotension through a blocking effect on the vascular receptors.

5

The dose that causes a 50% inhibition of the effects of the hypogastric nerve stimulation on urethral pressure (ΪΟ50) and the dose that causes a 20% arterial hypotension (ED20) are calculated.

10

Result tater:

The results obtained are listed in Table V.

TABLE V

15 ---; ---

Arterial hypotension Neurogenic urethral

Compound ED20 "g / kg hypertension 20 ID_Q - weight / kg B 1007 2 0.35 20 B 1024 8 0.07 B 1125 12 0.09 B 1134 30 · 0.11

Thymoxamine 0.27 0.09 2 5

These results show that the tested compounds antagonize the increases in urethral pressure induced by stimulation of the hypogastric nerve at doses much smaller than those which cause hypotensive vascular action.

The toxicological and pharmacological experiments show that the compounds of the invention can be administered orally or by injection, as drugs in functional urethral pathologies, depending on a sympathetic mechanism.

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Claims (6)

Compounds according to claim 1, characterized in that n is selected from 1, 4 and 8. A process for preparing the compound of formula (I) according to claim 1, wherein RerH, characterized in that thymol is reacted with N- (2-chloroethylpyrrolidine hydrochloride). Process for the preparation of a compound of formula (I) according to claim 1, wherein R is -O-COCH 3, characterized in that the compound of formula (I) wherein R is -COCH 3 obtainable by reaction of the compound of formula (I) wherein R is H, with acetic anhydride in the presence of perchloric acid, is reacted with an oxidizing agent such as m-chloroperbenzoic acid in the presence of an acid. Process for the preparation of the compound of formula (I) according to claim 1, wherein R is OH, characterized in that the compound of formula (I) wherein R is -O-COCH 3 is reacted with a solution of sodium hydroxide. DK 168072 B1 Process for the preparation of esters of the formula (I) according to claim 1, wherein R is -CO (C ^), characterized in that 2-hydroxy-5- [2-pyrrolidin-1-yl) -ethoxy ] -p-cymene is reacted with an acid chloride of formula ./. X 1 wherein R is CH 3 - (CH 2) n / where n is between 1 and 8. A drug having in particular an α-blocking effect, characterized in that it contains at least one compound of formula (I) as defined in claim 1 or a salt of said compound. 10