PT85269B - {(PYRROLIDINYL-1) -2-ETOXY} -5-PYENE DERIVATIVES, AND OF MEDICINES CONTAINING THE DERIVATIVES REFERRED TO - Google Patents

Abstract

Pyrrolidinyl p-cymene derivatives of formula (I) and their pharmaceutically-acceptable salts, are new R = H, acetyl, acetoxy, or hydroxy. In prepn. of (I), a thymol (II) is treated with N-(2-chloroethyl) pyrrolidine (III) in a liquid - liquid system in the presence of a phase transfer catalyst, esp. triethyl benzyl ammonium chloride. (I; R = acetyl) may be prepared by acetylation of (I; R = H) using acetic anhydride/percloric acid in toluene.

Description

Description of the object of the invention that

INSTITUT DE RECHERCHES CHIMIQUES ET BIOLOGIQUES AHtlQUÈES (i.R.C.

EBA), société a responsibility limitedé, French, industrial, headquartered at 62, Grande-Rue, 78490 VICQ, France, intends to obtain in Portugal, for: PROCESS FOR THE PREPARATION OF DERIVATIVES FROM / (PIR R0LIDINIL-1) -2- ETOXI7-5 p-CIMENO, AND OF DRUGS CONTAINING REFERRED DERIVATIVES.

Mod. 71 - 10,000 6x. 4-86 the present invention relates to Z (pyrrolidinyl-1) -2-ethoxy derivatives 17-5 p-cymene; It also concerns a process for the preparation of these derivatives and the drugs containing the said derivatives.

Derivatives of / (pyrrolidinyl — 1) -2-ethoxy7'-5 p — cymene are the new products of formula

where R is chosen from H, OCOCH ^ (acetoxy) and OCO (CH ₉ ) CEEC where n is between 1 and 8, (where 1 and 8 is within the definition of n) and the salts with pharma58 acids. 142

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Mod. 71 - 10,000 ex. - 4-86 ceutically acceptable products of formula (i).

The process for preparing the compounds of formula (i) consists of a first step, reacting the thymol with the N '- (chloro-2-ethyl) -pyrrolidine hydrochloride; the reaction is carried out by phase transfer in a liquid-liquid system in the presence of a catalyst (tri-ethyl benzylammonium chloride); this gives the product of formula (i) where R is Η. The preparation of the product of formula (i) in which the group R is acetyl, is carried out in a solvent such as toluene and in the presence of 70% perchloric acid by reacting the product in which R = H with acetic anhydride.

The preparation of the product of formula (i) in which the group R is acetoxy is carried out by acting on the derivative of formula (i) in which R is acetyl, of an oxidant such as m-chloroperbenzoic acid, the mentioned reaction being carried out in a solvent (toluene) in the presence of an acid (trichloroacetic acid).

The preparation of the product of formula (1) in which the group R is a hydroxy group is carried out by saponification, with the aid of a soda solution, of the product in which R is the acetoxy group.

Finally, the preparation of the product of formula (i) in which the group R is 000 (0 ^) ^ 0 ^ is carried out by performing the esterification of the product in which R is 0H with an acid chloride of formula

CL

Salts, for example hydrochlorides, are obtained in a known manner by contacting a solution of the product of formula (i) with the acid in question (for example by bubbling hydrochloric acid in a solution of the product of formula (i).

P

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The present invention also relates to the drug preparation process characterized in that said drugs contain, as an active product, by rng. a product of formula (i); The aforementioned drugs can be used in particular in the field of urology.

The following non-limiting examples illustrate the processes for preparing the products according to the invention.

EXAMPLE 1

Synthesis of [_ (pyrrolidinyl-1) -2ethoxy-7-3 p-cymene hydrochloride (B 1007).

1. Preparation of / _ (pyrrolidinyl-1) -2-ethoxy / -3 p-cymene

In a 3 liter 4-neck flask, equipped with a refrigerator, pneumatically stirred and thermometer, the following are introduced:

150.2 g (1 mole) of thymol

16.68 g of triethylbenzylammonium chloride; and

751 ml of bleach.

1 495 ml of methylene chloride is added and the medium is vigorously stirred.

The addition of 212.76 g of N- (chloro-2-ethyl) pyrrolidine hydrochloride (1.25 mol) in 70.9 ml of water leads to an increase in temperature up to 25 ^o C.

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

After cooling to room temperature, the organic phase is decanted, and the sodium phase is extracted with 2 x 425 ml of methylene chloride.

The combined organic phases are washed successively with 2 x 350 ml of acidulated water (acetic acid i

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0.25%), then with 2 x 700 ml of water saturated with sodium chloride until neutralization. Then they are dried over sodium sulfate.

After filtration, the solvent is removed in vacuo.

259.57 g of an orange oil are obtained. The crude product is purified by vacuum distillation (under nitrogen).

184.7 g of a colorless oil are isolated. Boiling temperature under 0.1 mmHg: 155-160 ° C; perchloric value / CH2 COOH: 102.1%.

2. Preparation of hydrochloride

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Dissolve 24.73 g of the said oil (0.1 mol) in 400 ml of anhydrous ethyl ether. The solution is saturated in a dry HCl gas stream over an ice bath. The crystals formed are filtered over calcined glass, washed with anhydrous ethyl ether and then dried over potash at 70 ° C.

25.12 g of beige crystals are obtained (crude yield = 88.6%).

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

The crystals obtained are subjected to the following elemental analysis25:

(C ^^ H ^^ CINO crude formula) gave the results

calculated found ç 67.70 67.69 H 9.23 9.25 N 4.93 4.83 CL 12.48 12.65 0 5.63 5.76

Crystals have a melting point:

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Mod. 71 - 10,000 ex. - 4-66 = 157-158 ° C and present the IV and MRI spectra according to the presented structure.

EXAMPLE 2

Synthesis of acetyl-2 (pyrrolidinyl-1) -2-ethoxy-7-5 p-cymene.

The / (pyrrolidinyl-1) -2-ethoxy / -3 p-cymene obtained according to process 1 of example 1 is used as the starting product;

this product was previously purified.

247.38 g (1 mol) of this product were dissolved in 1,600 ml of toluene and 863 ml of acetic anhydride in a 4-liter 3-neck flask equipped with a refrigerator equipped with an SO4 reservoir, a thermometer and an introduction ampoule. The mixture was stirred and then 225.2 ml of 70% perchloric acid was added dropwise, keeping the temperature below 45 ° C.

The mixture was stirred for 1 hour at room temperature and then poured into 760 ml of water saturated with NaCl.

After cooling in an ice bath and alkalinizing with soda bleach (pH: 12), the organic phase was separated, and extracted with 2 x 300 ml of methylene chloride. The organic phases are combined and washed with acidified water and water saturated with NaCl until neutralization. Dry over sodium sulfate, filter and remove the solvent under vacuum. 297.3 g of brown oil are obtained, with a CPV _O purity of 97% (gross yield> 100%).

the crude product is then purified by fractional distillation under vacuum (under nitrogen).

196.14 g of a yellow oil are isolated.

The obtained product presents an ebuition point (under 0.4 mmHg) of 149-153 ° C, a perchloric value of 98.6% and the IR and MRI spectra are in accordance with the presented structure.

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EXAMPLE 3

Synthesis of acetoxy-2 / (pyrrolidinyl-1) -2-ethoxyT-5 p-cymene hydrochloride. (B 1024).

1. Synthesis of acetoxy-2 / (pyrrolidinyl-1) -2-ethoxy7 ~ 5 p-cymene

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The purified oil obtained in example 2 is used as the starting product.

289.42 g (1 mol) of this product with 1 650 ml of toluene are introduced into a 4-liter 3-neck flask equipped with a refrigerator equipped with an I ^SO ^ reservoir, a thermometer and a pneumatic stirring .

Add 392.13 g (2.4 moles) of trifluoroacetic acid in portions, keeping the temperature below 15 ° C. Then 258.84 g (1.2 mol) of 80% m-chloroperbenzoic acid are introduced.

The mixture is kept for 24 h at 15 ° C with stirring and then poured into 2,130 ml of 5% ammonia.

The organic phase that separates is decanted. The aqueous phase is extracted with 890 ml of toluene twice. The organic phases are combined, washed with 890 ml of acidified water and then with 1180 ml of water saturated in NaCl until neutral. Dry over sodium sulfate, filter and remove the solvent under vacuum.

266.3 g of a brown oil of C.P.V. 97.2% (gross yield = 87.2%).

2 · Hydrochloride synthesis

Dissolve 30.54 g (0.1 mol) of this crude oil in 210 ml of anhydrous ethyl ether. A dry HCl gas stream is bubbled over an ice bath. The crystals formed are filtered over calcined glass, washed with anhydrous ethyl ether and then dried over potash at 50 ° C in a vacuum.

16.74 g of beige crystals are isolated (rendered.

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Mod. 71 - 10,000 ex. - 4-06 gross income = 49%).

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

Said crystals have a melting point Eg ^ · d® 182—183 ° C, a perchloric value of 100.8% and the IR and MRI spectra are in accordance with the presented structure.

EXAMPLE 4

Synthesis of hydroxy-2 ^ (pyrrolidinyl-1) -2-ethoxy ^ -5 p-cymene hydrochloride. (B 105θ).

The purified oil obtained after the first operation of example 3 is used as a starting product.

30.5 g (0.1 mol) of this oil are introduced and introduced with 110 ml of ethanol in a 500 ml conical flask equipped with a refrigerator and magnetic stirring.

110 ml of 1 N soda (θ, 11 mol) are added to this solution and the mixture is stirred 24 h at room temperature. The ethanol is removed under vacuum; the residue is taken up with 150 ml of water, extracted 3 times 180 ml of methylene chloride.

The combined organic phases are washed with water saturated with sodium chloride until neutralization. Dry over sodium sulfate and remove the solvent under vacuum. 25.28 g of an orange oil are obtained (crude yield = 96%).

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

obtained product was transformed into salt (hydrochloride) operating as follows:

13.16 g (0.05 mol) of purified base was dissolved in 200 ml of anhydrous ethyl ether with stirring. After bubbling from a dry HCl gas stream, the crystals formed by filtration over glass calci7 were isolated

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After washing with ethyl ether, drying under vacuum at 50 ° C, 14.54 g of beige crystals were obtained (crude yield = 97%)

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

These crystals have a melting point of 147-148 ° C and the IR and MRI spectra are in accordance with the structure shown; The elementary analysis of these crystals (crude formula 0 ^^ Η2 ^ 01Ν0 ₂ ) gave the following results:

calculated verified

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EXAMPLE 5

ç 64.09 64.08 H 8.74 8.78 N 4.67 4.65 CL 11.82 11.96 0 10.67 10.86

Preparation of an ester and its hydrochloride

A - Synthesis of butyryloxy-2-Ζ (pyrrolidinyl) -2-ethoxy ^ / - 5 P — cymene

R = CH ₃ - (CH ₂ ) ₂ In a 500 ml 3-neck flask, equipped with a refrigerator, pneumatically stirred and a thermometer, the following are introduced under agitation:

- 26.3 g (0.1 mol) of hydroxy-2 - / ^ (pyrrolidinyl-1) -2 — ethoxyJ / —5 p — cymene

- 200 ml of benzene

- 10.6 g of triethylamine (0.105 mol)

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To this solution, 11.2 g (0.105 mol) of butyric acid chloride are added.

reaction medium is heated to 50 ° C for 20 hours.

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

After cooling to room temperature, poured over 350 ^m l of water.

The benzene phase is decanted and the

Mod. 71 - 10,000 θχ. - 4-86 traction of the aqueous phase with 3 x 250 ml of benzene.

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

After filtration, the solvent is dissipated under vacuum.

31.5 g of a brown oil are obtained.

Gross income

Purity C.P.V.

Perchloric value = 94.5% = 99.5% = 94.3%

C.C.M.

= single spot

B - Synthesis of butyryloxy-2 ^ (pyrrolidinyl-1) —2-ethoxyT-5 p — cymene hydrochloride (B 1132)

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

12.18 g of beige crystals were obtained (crude yield - 65.8%).

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

Yield after recrystallization = 54.3% f _bk = 189 - 190 ° C

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58,142 Ref: 03 / AC / ACH / FRP H. 15252 / / Cas 100 + 100a T.B.A.H. = 97 , 8% AgNO value ^ = 97% Purity C.P.V, = 99 , 8% IV = According to the structure presented texture MRI = According to the structure presented texture Karl Fischer (from sa water) = 0, 2% C.C.Mo = Single spot Operating as at the example 5, prepared the hydrochlorides mentioned in the table summed up below indicates— of: SUMMARY TABLE No. n Crude formula Yield ^f bk ° ^c Code (PM) % (re-crystal solvent.) B 1125 1 θιΛο ⁰ - ^ (355.91) 51.2 177 - 178 B 1132 2 ^C 2O ^H 32 ^CL> ÍO 3 (369.94) 54.3 189 - 190 (i.P.A.) B 1131 4 022 ^ 6 ^^ 3 (397.99) 50 156 - 157 (i.p.a) B 1134 8 ^C 26 ^H 44 ^CLNO 3 45.4 148 - 149 (454.10) (I.P.A)

The products according to the invention were

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studied with regard to their toxicity and pharmacological properties.

1. Toxicity

The following 50 lethal doses were obtained after oral (P.O.) and intravenous (i.V.) administration of the substances in the rat.

The results obtained are mentioned in qua10

Mod. 71 - 10,000 ex. - 4-B6 dro I. Table 1

Substances DL 50-mg / kg ^-1 POWDER. I.v. B 1007 330 75 B 1024 100 18 B 1058 80 17 B 1125 300 ND * B 1131 550 ND * B 1132 500 ND * B 1134 400 36 Thymoxamine 300 72.5

not determined

2. Pharmacological properties

2.1 - Actividadec <-adrenolytic in vitro

It was studied in the descending canal of the rat and in the urethra of the rabbit.

Measurement principle:

Norepinephrine causes contractions of the isolated descending channel of the rat and the isolated urethra of rabbits. The presence in an organ bath, of substances ° (blocking antagonists these contractions: The use of

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increasing concentrations of oÇ-blocking substances makes it possible to calculate:

- The pA £ of the compounds on the descending channel of the rat; pA £ as the modified signal logarithm of the product's molar concentration in the presence of which the noradrenaline concentration must be multiplied by two to obtain the same effect as in the absence of the product;

- The pD'2 of the compounds on the rabbit urethra; pD'2 as the modified logarithm of signal indication of the molar concentration of the product in the presence of which the contracting activity of norepinephrine is divided by two.

Results: The results obtained are mentioned in table II.

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TABLE II

Products Norepinephrine-blocking action in face gives about 0 channel regarding the urethra isolated pendant P ^A 2 isolated PD ' ₂ B 1007 6.74 6.88 B 1024 6.98 6.38 B 1058 7.18 6.69 B 1125 7.14 6.25 B 1131 6.98 6.12 B 1132 7.35 6.0 B 1134 6.57 6.23 Thymoxamine 7.25 7.03

These results show an activity 12

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- interesting blocker for the tested products.

2.2. - Adrenolytic activity in vivo

2.21. in the mouse Principle of measurement

Norepinephrine injected in high doses intravenously causes the death of 100% of the animals within 15 minutes after their injection. Death comes from pulmonary edema due to arterial hypertension induced by stimulation of adrenergic receptors. The prior administration of substances —adrenolytic orally - reduces the toxicity of norepinephrine. The products are administered orally at times ranging from 30 minutes to 6 hours before intravenous (iV) injection of noradrenaline (0.4 mg / kg ^-1 ).

Results:

The results obtained are mentioned in the table

III

TABLE III

PRODUCTS Doses p.0. mg / kg ¹ % protection against death times traction before from adminis— of I.V. B 1007 50 60 30 min B 1024 25 70 30 min B 1058 50 90 30 min B 1125 25 60 30 min B 1131 50 60 30 min B 1132 50 90 30 min B 1134 100 100 4 H Thymoxamine 50 80 30 min

- 13 -REtyG3 / 1 '

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These results show that the tested products have an effective protection against the toxicity of noradrenaline.

2.2.2. in the anesthetized rabbit.

In vivo ¹¹ -blocking activity ¹¹ at urethral and vascular levels in the anesthetized rabbit was ordered by intravenous administration of products B 1007, B1O24, B 1058, B 1125 and B 1134.

Principle of measurement

Intravenous injection of norepinephrine causes a dose increase in the rabbit dependent on arterial and urethral pressures. The blocking substances injected intravenously antagonize depending on the doses of these pressure increases. The 50% inhibitory dose (DI 50) defined as the product dose that causes a 50% reduction in the effects of norepinephrine is calculated. on arterial and urethral pressures.

Results

The results obtained are mentioned in the TV table

TABLE IV

PRODUCTS D.I. 50 (mg / kg 1) due to hypertension arterial urethral 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 Thymoxamine 2.72 0.5

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These results show that the tested products antagonize the increase in urethral pressure at much lower doses than those needed to antagonize the increase in blood pressure.

2.2.3. Urethral specificity in the dog 's anesthesia.

The effect of products B 1007, B 1024, B 1125 and B 1134, injected intravenously on neurogenic urethral hyperpressure and blood pressure, was investigated in the anesthetized dog.

Principle of measurement

Electrical stimulation of the hypogastric nerve causes an increase in urethral pressure by releasing the nora-drainenin from the nerve's sympathetic fibers.

The blocking substances antagonize depending on the doses of these increases in urethral pressure and cause hypotension by blocking action at the level of vascular receptors.

The dose that inhibits the hypogastric nerve stimulation on urethral pressure is calculated by 50% (DI. 50) and the dose that causes a 20% arterial hypotension (DE. 20).

Results

The results obtained are shown in table Y.

TABLE V PRODUCTS Arterial hypotension DE.20 — mg / kg ¹ urethral hyperpressure neurogene DI. 50 -mg / kg ¹ B 1007 2 0.35

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JuL

TABLE V (continued)

PRODUCTS Arterial hypotension DE.20-mg / kg ^-1 neurogenic urethral hyperpressure DI _O 50 —mg / kg ^-1 B 1024 8 0.07 B 1125 12 0.09 B 1134 30 0.11 thymoxamine 0.27 0.09

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These results show that the tested products antagonize the increase in urethral pressure induced by stimulation of the hypogastric nerve at doses much lower than those that cause a hypotensive vascular effect.

Toxicological and pharmacological tests show that the products according to the invention are usable orally or injectable as a medicine in functional urethral pathologies dependent on a sympathetic mechanism.

Claims (5)

- CLAIMS1? - Process for the preparation of new products of formula (I) - 16 58.1 ^ 2 Ref: 03 / AC / ACH / FRP H. 15252 Cas 100 + 100a -è: z: .337 r, <. ·. ___- -, where R is chosen from H, OH, -OCOCH „and -O-CO-CH _n ) 3 2 'n between 1 and 8 and from the salts of the pharmaceutically acceptable acids-CH ^, where There are no products of formula (i) available, because the thymol is reacted with the characterized chloriposto N- (chloro-2-ethyl) -pyrrolidine to obtain a formula I when R is H. 2? - Process of agreement is -O-COCH ^, characterized in that R is -COCH de according to claim 1, Mod. 71 - 10,000 ex. - 4-86 where R duct of formula (i) in c reacting the product of formula (i), acetic hydroxide in the presence of perchloric acid, with m-chloroperbenzoic acid in the presence of an acid. 3- _ Previous process in which R is OH, characterized by the product of formula (i) in which R sodium. reacting the pro to be obtained which can in which R is H with the „z according to the claims if it is reacted is -O-COCH ^ with a solution the preparation of the esters if the hydroxy 20 is reacted 4? - Process of formula (i), characterized by do-2- / (pyrrolidinyl-1) -2 — ethoxy / —5 p — cene on an acid chloride of formula being n between 1 and 8. 5- - Process for the preparation of medicaments showing, inter alia, a blocking activity, characterized by mixing at least one product of formula (i) or a salt of said product with a vehicle