DK156395B - ANALOGY PROCEDURE FOR PREPARING A (3-PYRROLIDINOPROPYL) -KETONE DERIVATIVE - Google Patents

Description

DK 156395 B

The present invention relates to an analogous process for the preparation of novel derivatives of phloroglucine or their acid addition salts or quaternary ammonia salts.

It is known that chlorohydrate of (2,4,6-trimethoxyphenyl) - (3-pyrrolidinopropyl) ketone, soin has been disclosed in British Patent No. 1,325,192 and which has the code number LL 1656, is a peripheral vasodilator agent currently available in the trade under the name Fonzylane (International Common Designation-10: Buflomedil Chlorohydrate) and whose pharmacological properties are the subject of an article: Debray et al., Thérapie (1975), 30, p. 259- 266th

It has now surprisingly been found that the compounds of the invention (which have a structure similar to the structure of LL 1656) are less toxic and have a longer lasting effect than LL 1656, while their closest homologue from a structural point of view (especially CRL 40.633 and CRL 40.634, which is examined below), lacks vasodilatory effect.

20

The novel compounds of the invention are: (hydroxyphenyl) - (3-pyrrolidinopropyl) ketones of the formula:

OR

R0 * (3-CO-CH2-CH2-CH2-K3) (I)

30H

wherein the two R's are the same and are H or CH 3, or their acid addition salts or quaternary ammonium salts.

35 Acid addition salts can be obtained in a manner known per se, e.g. by reaction of the free base with an inorganic or organic acid. Among the acids which can be used for this purpose are especially hydrochloric, hydrobromic,

DK 156395 B

2 acid, sulfuric acid, phosphoric acid, formic acid, oxalic acid, malic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, benzoic acid, glutamic acid, aspartic acid, methanesulfonic acid, paratoluosulfonic acid. Among the possible quaternary ammonium salts are the 5 salts obtained from the free base and JCH3 and CICH3. The preferred salts prepared according to the invention are the carbohydrates, tartrates and citrates.

The compounds of formula I are prepared by the process 10 of the invention by leaving a compound of formula I

/ OR

"-Q

OH

wherein the 2 R's are the same and are H or CH 3 react with 4-pyrro-1 idino-butyronitrile of the formula

20 NC - CH2 - CH2 - CH2 - N

in an anhydrous solvent in the presence of ZnCl2 or AlC13, optionally reacting the thus obtained compound with an inorganic or organic acid to form the corresponding acid addition salt or with a quaternizing compound such as ICH3 or C1CH3 to form of the corresponding quaternary ammonium salt.

The reaction proceeds according to the scheme:

OR OR

RO-jfAt HC- (CH ^ rH -ί · Κ0-

OH .OH

wherein R has the above meaning, the reaction being optionally completed with isolation and purification operations.

3

DK 156395 B

The compounds of formula I and their salts, in particular the chlorohydrates, citrates and tartrates, are peripheral vasodilatory agents and are used therapeutically for the treatment of arterial circulatory insufficiency in the limbs and in particular for the treatment of Raynaud's syndrome and ulcer.

The process of the invention is further illustrated by the following Examples 1-2, while Examples 3-5 illustrate the preparation of the comparative compounds used in the pharmacological samples.

Table 1 lists the products prepared according to the invention (Examples 1 and 2), their homologs (Comparative Examples 3 to 5), and a reference product already known in the therapy (LL 1656).

Example 1

Chloride of (2,4,6-trihydroxyphenyl) - (3-pyrrolidinopropyl) -20 ketone.

OH

'Hci

26 0H

Code number CRL 40.598 In 500 ml of anhydrous diethyl ether dried on CaCl2 dissolve 38.30 g (0.304 mole) of anhydrous phloroglucine and 41.95 g (0.304 mole) of 4-pyrrolidinobutyronitrile. 7.28 g of zinc chloride are added and HCl gas is bubbled through the reaction medium until saturation. One is left to stand for one night and water is added to the reaction medium.

You get an aqueous phase and an ether phase. The ether phase 35 is washed with water and then the aqueous phase and the wash water are collected and the resulting mixture is heated to reflux for one hour. It is cooled, neutralized with sodium bicarbonate and filtered off the base. The base is dissolved in a minimal amount of dime.

DK 156395 B

4 thylformamide in the heat and acidify with 45 ml of 7 N ethanol is hydrogen chloride. The dimethylformamide is evaporated in vacuo without going to dryness and ether is added to facilitate the precipitation of the desired chlorohydrate. By recrystallizing the mixture of 5 equal volumes of methanol and acetone, 15 g (yield 16%) of chlorohydrate of (2,4,6-trihydroxyphenyl) - (3-pyrrolidinopropyl) ketone are obtained.

Melting point 260 ° C.

10

Analysis:% N measured = 4.52%% N theoretical = 4.64%.

The purity of CRL 40598 is checked by thin layer chromatography (eluent: CH3OH-CH3COCH3-NH4OH (50: 50: 2) v / v, plate: Silica gel (MERCK F 254) preparation: U.V. plus Draggendorf).

Example 2 Chlorohydrate of (2,4-dimethoxy-6-hydroxyphenyl) - (3-pyrrolidinopropyl 1) ketone.

CCH,

A

E3 CO-A m-CO-CCH2) 3-hQ, HCl

OH

Code number CRL 40.635 30 In a 2 liter 3 neck flask, 69 g (0.5 mole) of 4-pyrrolidinobutyronitrile is dissolved in 0.5 liter of chlorobenzene. 67 g (0.5 mole) of Ald.3 and then 77 g (0.5 mole) of 3,5-dimethoxyphenol are slowly added. A stream of HCl is then fed into the reaction medium (maintained at 25 to 30 ° C) for 2 hours (a duration necessary to saturate the reaction medium), and then allowed to stand at ambient temperature (15 ° C). 20 ° C) and one night. 0.5 liters of water are slowly added (to hydrolyze 5)

DK 156395 B

re the ketimine formed) and decant the aqueous phase which is collected. The aqueous phase is heated to reflux for 1 hour. Charcoal is formed and a precipitate P is formed, which is separated by filtration (the precipitate P, which is mainly constituted by the 5 isomeric 2,6-dimethoxy-4-hydroxyphenyl compound, is isolated as shown in Comparative Example 5). The filtrate is extracted with chloroform and the chloroform solution is evaporated to dryness under reduced pressure. The evaporation residue is dissolved in a minimal amount of water and the free base is formed with sodium carbonate.

10 Insoluble matter is filtered off and the base is extracted with chloroform. The new chloroform solution is evaporated to dryness under reduced pressure. The oil thus obtained is taken up in isopropanol and the HCl is bubbled up to pH 2. The desired chlorohydrate is crystallized. By filtration, 25 g (yield 15¾) of chlorohydrate of (2,4-dimethoxy-6-hydroxyphenyl) - (3-pyrrolidinopropyl) ketone are obtained.

Melting point 170 ° C.

Analysis:% CI "measured = 10.68%% CI" theoretical = 10.74%

Example 3 (Comparison) Chlorinated of (2,4,6-trihydroxyphenyl) - (3-diethylaminopropyl) ketone.

Code number CRL 40.624 30 From 12.6 g of phloroglucine (0.10 mole), 14.0 g of 4-diethylamino-butyronitrile (0.10 mole), 2.4 g of ZnCl 2 and 125 ml of diethyl ether were obtained ( as in Example 1), 8 g (yield 27%) of chlorohydrate of (2,4,6-trihydroxytophenyl) - (3-diethylaminopropyl) ketone.

35

Melting point 260 ° C,

Analysis:% Cl = 11.46%

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6

Notice; CRL 40.624 is not particularly soluble in water and physiologically specific at ambient temperature. At 60 ° C, its solubility in physiological semen (water containing 4 to 9 grams of NaCl per liter is less than 6 g per liter. The tartrate and citrate are no more soluble than the chlorohydrate.

Example 4 {Comparison) 10

Chlorohydrate of (2,6-dihydroxy-4-methoxyphenyl) - (3-pyrrolidino-propyl) -ketone or chlorohydrate of (2,4-dihydroxy-6-methoxy-phenyl) - (3-pyrrolidinopropyl) -ketone.

In a 2 liter three-neck flask, 69 g (0.5 mole) of 4-pyrrolidino-butyronitrile are dissolved in 1 liter of diethyl ether and 13.6 g (0.1 mole) of ZnCl 0.5 mole) of 1,3-dihydroxy-5-methoxybenzene. A stream of HCl is then passed through the reaction medium, maintained at 25 to 30 ° C for 2¾ hours, and then allowed to stand overnight. It is evaporated to dryness under reduced pressure and the evaporation residue is taken up in 1 liter of water, heated to reflux for 1 hour and then cooled down. The product crystallizes and is isolated by filtration and then recrystallization from a mixture of methanol and water (3: 1) v / v. 69 g (yield 44%) of CRL 40.633 are obtained.

Melting point 270 ° C.

30

Analysis:% CI measured = 11.35%% CI "theoretical = 11.22%

Notes: 35 1. Due to lack of peripheral vasodilatory effect of CRL 40.633, determination of the exact position of the methoxy group is not made. It is also possible that both of the isomers are present in the isolated product.

7

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2. CRL 40.633 is not very soluble in water and physiologically specific at ambient temperature. At 60 ° C, the maximum solubility in physiological serum (water containing 4 to 9 grams of NaCl per liter) is 10 grams per liter. liter. The tartrate and citrate 5 are no more soluble than the chlorohydrate.

Example 5 (Comparison)

Chlorohydrate of (2,6-dimethoxy-4-hydroxyphenyl) - (3-pyrrolidinopropyl) ketone.

Code Number CRL 40.634

The precipitate P, obtained in Example 2, is recrystallized from a mixture of equal volumes of acetone and ethanol to give 49.5 grams (yield 30%) of chlorohydrate of (2,6-dimethoxy-4-hydroxyphenyl) - (3-pyrrolidinopropyl) ) ketone.

Melting point 177 ° C.

20

Analysis:% Cl "measured = 10.72%% Cl" theoretical = 10.74%.

Marketing: 25

The position of the 4-hydroxy group in CRL 40.634 and of the 6-hydroxy group in CRL 40.635 (product of Example 2) is determined by analysis.

The following is summarized the results of samples taken with the products of Examples 1 (CRL 40,598) and 2 (CRL 40,635), the products of Comparative Examples 3 (CRL 40,624), 4 (CRL 40,633) and 5 (CRL 40,634). ) and a reference product known as peripheral vasodilatory agent (LL 35 1656).

1 · Acute toxicity.

DK 156395B

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By oral route in male mice (the products studied are administered in aqueous solution), the DL-50 values are as follows: CRL 40.598: DL-50 = 1400 ± 112 mg / kg 5 CRL 40.635: DL-50 = 800 ± 76 mg / kg LL 1656 : DL-50 = 280 ± 25 mg / kg 2. Vasodilatory effect.

The vasodilatory effect was examined on male dogs anesthetized with nembutal (6 animals per dose and per product). The products to be compared are administered in solution in physiological semen at a volume of 6 ml per ml. by intravenous route (perfusion of 1 ml per minute) (6 to 9 ml per animal at a per-fusion of 1.5 to 2 ml per minute for CRL 40,624 due to its poor solubility) and in a volume of 10 ml per animals by intraduodenal route (the solutions of CRL 40.633 are stored in a water bath). In relation to the control (the same animal receiving only physiological semen), 3 parameters are measured: at the arterial pressure 20 (expressed in mm Hg) heart rate (expressed in beats per minute) and the arterial flow (expressed in ml per minute). The variations in these parameters, expressed as a percentage of control, are listed in Tables II (intravenous administration) and III (in intraduodenal administration).

25

The peripheral vasodilation is characterized here by an increase in femoral artery flow, and the other two parameters (medial arterial pressure and heart rate) are used to illustrate the appearance of the products in the organism. According to the present examination conditions, a product is said to be a peripheral vasodilatory agent if the femoral artery flow is at least 30% by intravenous administration and intraduodenal administration.

35 By intravenous route (see Table II), on anesthetized dogs, CRL 40.598 and CRL 40.635 are observed to slightly increase the mean arterial pressure, to be virtually unaffected by heart rate, and to increase 1 year artery flow much more.

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than LL 1656. Among other things, it is found that the vasodilatation induced by CRL 40,598 and CRL 40,635 lasts approx. 10 minutes for all the doses examined and this is longer than that of LL 1656. Table II shows that the products of Comparative Examples (CRL 40.624, CRL 40.633 and CRL 40.634) have no vasodilatory effect, and that this finding, if shown (at a dose of 3 mg per kg for CRL 40,634 and at a dose of 6 mg per kg for CRL 40,624) is of short duration volatility.

10

By intraduodenal route on anesthetized dog, LL 1656 was administered at doses corresponding to 1/40, 1/20 and 1/10 of DL-50, respectively, for mice by oral route, and CRL 40,598 and CRL 40,634 were administered at relatively weaker doses. corresponding to 1/70 of 15 DL-50 for the former and 1/44 of DL-50 for the latter. It is found that after intraduodenal administration, the duration of the peripheral vasodilatory effect of CRL 40,598 and CRL 40,635 is longer than that of LL 1656, the kinetics of the vasodilatory effect being as follows:

For LL 1656, the effect appears 5 minutes after administration and this effect reaches its maximum of 15 minutes and the maximum duration is 60 to 90 minutes.

25 For CRL 40.598, the vasodilatory effect appears more slowly, showing 30 minutes after injection and this effect reaches its maximum 2 to 4 hours after injection and its maximum duration is 5 hours.

30 For CRL 40,635, the vasodilatory effect begins 20 minutes after injection, reaching its maximum of 30 to 60 minutes and lasting more than 2 hours.

The results in Table III show that the intraduodenal route is CRL

35 40,598, CRL 40,635 and LL 1656 are active, while the other products (CRL 40,624, CRL 40,633 and CRL 40,634) lack vasodilatory effect, because the variation in arterial flow that they induce is very weak. I © observes 10

DK 156395 B

CRL 40.598 and CRL 40.635 do not induce any change in skin color (ears, tongue, pads) even with the strongest vasodilation.

In summary, the comparative results show that: (a) The products prepared according to the invention are peripheral vasodi 1 atoric agents which are equally as therapeutic as the reference product, LL 1656, and they differ from this 10 by a weaker toxicity and a peripheral vasodilatory effect. longer duration, and (b) the compounds prepared according to the comparative examples which are very close to the compounds prepared according to the invention in terms of structure lack peripheral vasodilatory effect.

3. Antioxidant effect.

It has also been found that the compounds prepared according to the invention have a beneficial anti-aggregating effect on the platelets. Thus, CRL 40,598 changes platelet aggregation according to ADP (adenosine diphosphate) samples at a dose of 50 mg per day. kg per day for four days in the rat (mean inhibition 44%).

25 4. Clinical Trials.

Clinical tests performed with the compounds of the invention have produced good results in humans in 30 medical treatments, where a vasodilation of the blood vessels is said. CRL 40,598 administered in the form of tablets or gelatinosis pills (each containing 100 mg to 200 mg CRL 40,598) in an amount of 2 to 3 tablets or pills per day. day has thus enabled effective treatment of Raynaud's disease and administered by intravenous route (injectable ampoule containing 50 mg to 100 mg CRL 40,598) in an amount of 2 to 3 injections per day. day has enabled a cérébral vasodilatory treatment.

11 DK 156395 B

TABLE I

A-CO- (CH2) 3-B, HCl

Product Code No. A B F

- - 0H - -

Example 1 CRL 40598 pyrrolidino 260 ° C

m.

. 0CH3

Example 2 CRL 40655 H₂CO₂-pyrrolidino 170 ° C

W _

Example 3 CRL 40624 βΕ N (C £H H) 2 260 ° C

(sighing) HO

(b) ^ "" OH

OH

Example 4 CRL 40633 H 2 CO- γ-pyrrolidino 270 ° C

(comparison) or 3h (b) (c) HO

OH

* Qqh ^

Example 5 CRL 40634 H0 ~ C4 pyrrolidino 177 ° C

(comparison) 3 (b) (d) ______ _PCH3

FONZYLANE LL 1656 H3ca ^ V- pyrrolidino 192 ° C

(reference) AND- (a)

Notes: (a) The product is active as a peripheral vasodilatory agent (b) The product is inactive as a peripheral vasodilatory agent, (c) The product whose structure has not been determined could be a mixture of the two isomers, (d) Isomer of the product from Example 2,

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TABLE II

Variation in parameters according to intraven0s administration = to anesthetized dog. .

Product Dose _ Variations in% _ mg / kg artery = thigh artery = heart ^ pressure flow rate CRL 40598 1.5 +9 +56 (a) +3 CRL 40635 1.5 +3 +38 (a) +2 CRL 40624 1, 5 -5 +3 -5 CRL 40633 1.5 0 +5 +1 CRL 40634 1.5 +2 +10 0 LL 1656 1.5 0 +33 (¾) +5 CRL 40598 3 +10 +63 (a) 0 CRL 40635 3. + 5 +40 (a) +1 CRL 40624 3 -7 +1 -6 CRL 40633 3 +1 +8 -2

CRL 40634 3 -1 +30 (c) 0

LL 1656 3 -2 +36 (b) +6 CRL 40598 6 +4 +63 (a) +3 CRL 40635 6 +2 +44 (a) +1 CRL 40624 6 -10 '+26 (d) -8 CRL 40633 6 +2 +7 +1 CRL 40634 6 +1 +7 +2 LL 1656 6 -2 +39 (b) 0

Notes: (a) Duration of effect: 10 minutes (b) Duration of action: 5 minutes (c) Duration of action: 3 minutes (d) Duration of effect: 1 minute

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TABLE III

Variation in parameters after intraduodenal administration to anesthetized iiund.

Product Dose Variations in% J

mg / kg artery = thigh artery = heart = pressure flow rate LL 1656 7 +2 +44 +7 LL 1656 14 -3.5 +73 + 4.5 LL 1656 28 -4.5 +100 +6 CRL 40598 20 -2 +60 -8 CRL 40624 2Q 0 + 2 +1 CRL 40633 20 +1 +3 +2 CRL 40634 20 -1 +5 -1 CRL 40635 20 -2 +60 -8

Claims (2)

DK 156395 B Patent claims. Analogous Process for the Preparation of a (3-Pyrrolidinopropyl) Ketone Derivative of the General Formula f -F 'RO' ROH ^Y-CO - CH₂ - CH₂ - CH₂ - _ '(1) 10 2 R's are the same and are H or CH 3 or its acid addition salts or quaternary ammonium salts, characterized in that a compound of the formula 15 / OR RO-O OH 20 wherein the 2 R's are the same and is H or CH 3, react with 4-pyrrolidino-butyronitrile of the formula NC - CH, - CH, - CH, - N 25 2 2 2 35 35 an anhydrous solvent in the presence of ZnCl 2 or Al The compound thus obtained reacts with an inorganic or organic acid to form the corresponding acid addition salt or with a quaternizing compound such as ICH3 or C1CH3 to form the corresponding quaternary ammonium salt.