LU82448A1 - ESTERS OF 2- (6-METHOXY-2-NAPHTYL) -1-PROPANOL, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

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The present invention relates to esters of a carboxylic acid and a 2-substituted propanol and more particularly relates to a; propanol substituted with a 6-methoxy-2-naphthyl group of formula (I)

- I

\ if 7 I 2 II:! CH, 0 i A 3 i - .. (I).

In which R represents the alkyl residue of a carboxylic acid containing from 1 to 20 carbon atoms.

. »The compounds of formula (I) have been found to exhibit properties | particularly remarkable, especially anti-inflammatory, anti-rheumatic, analgesic and anti-pyretic, comparable to the properties of a known substance f namely Naproxen, which is the most active enantiomer of the acid I 2- (6 -methoxy-2-naphthy ^.) propionic. However, when comparing the compounds 1 according to the invention with Naproxen, we. finds that the former are less toxic, exhibit significantly more activity, and cause only significantly less significant gastric damage.

The present invention aims to provide compounds of formula (I); on the other hand, it provides pharmaceutical compositions endowed with anti-inflammatory, anti-rheumatic, analgesic and anti-pyretic properties and containing, as active principle, at least one of the compounds of formula 25 (I).

The invention also aims to provide a process for the preparation of the compounds of formula (I), process according to which the 2- (6-methoxy-2-naphthyl) -l-propanol (II) is reacted with a carboxylic acid of formula R-COOH in which R is as defined above, in the presence of an acid catalyst.

According to an embodiment of the invention, the preparation can be carried out from the same alcohol substituted with an active derivative of the same carboxylic acid, in accordance with the reaction scheme below.

OE

i H I '^ CH + K-COX -> (I) 35 3 CH ^ O. '(II) (III) / / 2

In this scheme, X represents OH or one. group activating, for example, a halogen atom or an alkoxycarbonyloxy residue, such as the group C_H 0- C0-0-.

The following examples, in which all the proportions are by weight, serve to illustrate the invention without in any way limiting its scope.

EXAMPLE 1. 2- (6-methoxy-2-naphthyl) propyl acetate a) 2- (6-methoxy-2-naphthyl-1-propanol).

300 ml of THF, 53.5 g of 2- (6-nethoxy-2-naphthyl) propionaldehyde and 25 ml are placed in a three-necked flask fitted with a mechanical stirrer, a condenser 10 and a funnel. of water containing 2.5 g of NaOH.

With stirring, 2 g of NaBH 4 are slowly introduced while maintaining the temperature at 40 ° C. The mixture was stirred for one hour at room temperature and then acetic acid was added slowly with stirring and cooling to destroy the excess NaBH ^. Most of the solvent is evaporated in vacuo, then water is added and the material is extracted three times with ether, using a 100 ml portion each time. The ethereal extracts are combined, evaporated in vacuo and the oily residue is crystallized from a 50:50 mixture of petroleum ether and ethyl ether.

The yield is 49.9 g (93.3%); M.p. 82-84 ° C.

b) 2- (6-Methoxy-2-naphthyl) propyl acetate

500 ml of ethyl ether, 58.9 g (0.725 mole) of pyridine are introduced into a three-necked flask fitted with a mechanical stirrer, a condenser and a funnel and then slowly with stirring 58.8 g (0.725 mole) of acetyl chloride.

The solution is cooled to 0 ° C. and then 108 g (0.5 mole) of 2- (6-methoxy-2-naphthyl) propyl alcohol dissolved in 200 ml of ethyl ether are introduced slowly through the funnel. The temperature rises to around 40 ° C.

Stirring is continued for 5 hours at room temperature and the solution is then poured into 250 ml of water. The mixture is stirred and the organic phase is separated, washed with a 0.1 K HCl solution, then the organic phase thus washed is dried over anhydrous sodium sulfate, the solvent is evaporated in vacuo and the oily residue is distilled . The pure ester is distilled at 175-178 ° C under a pressure of 0.01 mm of mercury.

The yield is 102 g (75%).

By the same process as above, the following substances are prepared: - 2- (6-methoxy-2-naphthyl) propyl propionate, boiling point 178-188 ° Γ. snnc 0 ^ 01 mm do fie ·? 3 'boiling point 188-190 ° C under 0.01 mm Hg.

EXAMPLE_2 | Preparation of 2- (6-methoxy-2-naphthyl) propyl enanthate | j In a three-necked flask fitted with a stirrer, a condenser and a

At the funnel, 500 ml of ethyl ether, 58.9 g (0.725 mole) of pyridine are introduced and slowly, with stirring, 107.4 g (0.725 mole) of chloride

Enanthyl.

] The solution is cooled to 0 ° C. 108 g are introduced through the funnel! (0.5 mole) 2- (6-methoxy-2-naphthyl) propyl alcohol dissolved in 200 ml; 10 ethyl ether. The temperature rises to 40 ° C. The agitation is continued for. 4 hours at room temperature and then the solution is poured into 250 ml of water. The mixture is stirred, the organic phase is separated, washed i! with a 0.1 N solution of HCl and the organic phase thus washed is dried over anhydrous sodium sulfate. The solvent is distilled in vacuo and the oily residue is distilled. The pure end ester at 191-193 ° C under 0.01 mm Hg.

L

: dement is 125.3 g (73.2%).

Ultraviolet spectrum: a solution of the substance in ethanol; (25 mcg / ml) has two maxima: 20 (1) at 260 + 1 -270 + 1 and (2) at 316 + 1 -331 + 1.

The substance is insoluble in water and it is soluble in chloroform, ethanol, acetone, hexane and also in oils.

! . .Applying the same process as above allows other | '25 esters of 2- (6-methoxy-2-naphthyl) propanol as can be seen in [Table I below, in which the properties f | , physical and analytical values, £ s obtained compounds.

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TABLE_I

h ίι> 2 1 '5 | J | J Cü3 0 j 3 - i

ANALYSIS

10 Pt. Eb. ° C / ram Hg C H

Calculation Found Calculated Found 15 C ^ 175-78 / 0.01 '74, 42 - 74.10 '6.98 - 6.96 C2H5 178-83 / 0.01 75.00 - 74.84 7.35 7, 31 C4H9 183-87 / 0.01 76.00 - 75.80 8.00 - · 7.95 C_5H1I 188_89 / °> 01 76.43 - 76.20 8.28 - 8.31 C, H ,. 191-93 / 0.01 76.82 - 75.80 8.54 - 8.50

20 b - IJ

C? H15 193-95 / 0.01 77.19 - 77.00 8.77 - 8.80

CgH17 194-98 / 0.01 77.53 - 77.40 8.98 - 8.95 CH '198-200 / 0.01 77.84 - 77.81 9.19 - 9.10 C10H21 18i_83 / ° » 005 78.12 - 78.10 9.37 - 9.31 CH .. 185-87 / 0.005 78.39 - 78.43 9.55 - .9.56 • 2c 1 I ^ -13 C12H25 188 “89 / ° »005 78.64 - 78.60 9.70 - 9.76 cj 4H29 191-93 / 0.005 79.00 - 79.00 10.00 - 10.20 C15H3] 192-94 / 0.005 79.29 - 79 , 16 10.13 - 10.00 C16H33 195 "97 / 0.005 79.50 - 79.61 10.26 - 10.15 CH 199-200 / 0.005 79.66 - 79.58 10.37 - 10.41 30 w ”

ClgH37 201-202 / 0.005 79.84 - 79.77 10.48 - 10.44 35 ^ '\! T j.

i * '5; For the study of the pharmaceutical properties of the compounds according to the invention, as well as for the determination of toxicological data, the compound enanthate of 2- (6-methoxy72-; naphthyl) propyl was used as an example. which is abbreviated below by ENA.

1 | 5 Anti-inflammatory activity

This activity is estimated by comparison with Naproxen, at equimolar doses. Male rats weighing on average about 150g are used. Two tests are performed, an acute test and a subacute test.

a) Acute test: plantar edema caused by carrageenan according to 13. IT. Rinse et al, Proc. Soc- Exp. Biol, lied-, 111, 544 (1962).

The two substances tested are administered orally at equimolar doses: ENA + 60 mg / kg, Naproxen = 40 mg / kg in an I · „1% solution of carboxymethylcellulose (CMC), at a rate of 20 ml / kg immediately after the onset of edema following the sub-plantar injection of carrageenan in an amount of 1% and at a dosage of 0.05 ml / paw. The results of this test are shown in Table II.

| b) Subacute test: the plantar edema is caused by nystatin I according to E. Arrigoni-Martelli et al, Pharmacology, _5, 215 (1971). We administer | the two substances orally at equimolar doses for two successive days, as follows: i On the first day, ENA = 30 mg / kg, Naproxen = 20 mg / kg in a 1% solution of CMC, at a rate of 10 ml / kg.

I On the second day, ENA »60 mg / kg, Naproxen = 40 mg / kg in a solution! at 1% CMC, at a rate of 20 mg / kg.

The edema was caused overnight preceding the first treatment I by a sub-plantar injection of nystatin in an amount of 300,000 j U / ml at a rate of 0.1 ml / leg. The results of this test are shown in Table III.

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Anti-inflammatory activity ~ acute test.

Each value is the average for 10 legs.

TABLE_II

% inhibition of 1 * edema after: 5 Treatment 2 hours 4 hours 6 hours 8 hours \ ENA 62 49 61 85:

Naproxen 60 31 30 36:

Comparison of equal activity ENA more active ENA more active- · ENA more statistical p N.S. p £ 0.0025 tif P <[0.01 active P4: 0.05 10 ______— 1

As can be seen from this table, the ENA is as active as Napro-xene during the second hour but becomes more active during the following hours and after eight hours its activity is still considerable.

TABLE III

Anti-inflammatory activity - subacute test Each value is the average for 10 legs.

1st day_. ________% inhibition of edema after: treatment] hour 2 hours 4 hours 8 hours 20 ENA 12 8 10 11

Naproxen 5 4 4 5 _. ENA plus activity equal to ENA plus ENA plus active

Comparison tifP ^ 0j00] p N.S. active Ρ <Ό, Ό: vk. 0.01 25 ______ 2nd day „% inhibition of edema after:

Treatment 1 hour 2 hours 4 hours 8 hours 30___ ENA 6 I 12 12 17

Naproxen -5 8 7 11

Comparison of activity equals activity ENA activity more statistically p N.S. equals P N.S. equals P N.S. tif P £ 0.005. 7 'It is clear from these data, that EKA shows therapeutic activity against previously induced stable edema,' activity which is not only comparable to that of Naproxen but is, especially for very prolonged periods, more important and statistically I 5 very significant.

Analgesic activity

This analgesic activity is estimated by comparison with Na-proxene at an equimolar dose. Two tests are carried out: the first on female mice weighing on average about 25 g and 1 other on male rats weighing on average 100 g; a) Test on female mice contortions caused by! phenylquinone according to L.C. Hendershot et al., J. Pharm. Exp. Ther., 125, 237 (1959).

The two compounds are administered orally at approximately equal doses: ENA: 30 mg / kg, Naproxin: 20 mg / kg, in a 1% CMC solution, in a dosage of 20 ml / kg. Contortions are caused at different time intervals after administration of the compounds by endo injection! peritoneal phenylquinone 0.02 2 in 5% alcohol has a dose of! 10 ml / kg. The results of this test are given in Table IV.

B) Test on male rats: this test is carried out by exerting pressure on an inflamed leg according to L.O. Randall et al, Arch. Int. Pharmacodyn., 111, 409 (1957).

The two compounds are administered orally at mutually equimolar doses: ENA: 60 mg / kg, Naproxen: 40 mg / kg in solution | 25 to 1% of CMC, at a rate of 20 ml / kg, immediately after the inflammation caused: i ί subplantar injection of yeast at 10% at a rate of 0.1 ml / leg. The results of this test are shown in Table V.

TABLE IV

Analgesic activity - Mouse test 30 Each figure is the average for 8 mice.

. „. Z contortion inhibition after:

Treatment 1 hour 2 hours 4 hours 6 hours ENA 27 57 44 46. ^ Naproxen__14__68__30__13_

Comparison of activity equal activity equals equal activity ENA plus statistics P N.S. 'P N.S. P N.S. active P <* 0.0l 8

As can be seen from these data, the activity of ENA is comparable to that of Naproxen for the first few hours, but this activity always remains at a high level during the sixth hour, whereas Naproxen undergoes a strong reduction at this time. 'activity.

5 TABLE_V

Analgesic activity - Rat test Each figure is the average of 10 legs.

Pain inhibition treatment Z: after; z'- ‘-] Q 1 hour 2 hours 3 hours 4 hours 5 hours ENA 240 400 152 131 100

Naproxen 47 79 67 64 64

ENA plus ENA plus ac comparison activity activity activity

] 5 active statistic Ρ ^ Ο, ΟΟΙ tif P ^ 0.001 equal P equal P equal P

N.S. N.S. N.S.

9

These data show that ENA has a greater analgesic activity than Naproxen to a significant degree during the first few hours. After the first few hours, stronger activity is apparent but is not statistically significant.

Anti-pyretic activity

This activity is determined by comparison with Naproxen in equimolar doses. We use two animal species; male rats weighing approximately 250 g and rabbits weighing approximately 2.6 kg.

a) Test in rats: pyrexia caused by yeast according to U.M.

Teotino et al, J. Med. Chem., J6, 248 (1963). The two compounds are administered orally at mutually equimolar doses: ENA: 60 mg / kg, Naproxen: 40 mg / kg, in 1% CMC, at a dose of 10 ml / kg.

The fever was caused the previous night by a subcutaneous injection of a 20% yeast suspension at a dose of 10 ml / kg. The results are shown in Table VI.

b) Test in rabbits: pyrexia caused by yeast. The two compounds are administered orally at equimolar doses: ENA: • 60 mg / kg, Naproxen: 40 mg / kg, in CMC at 1 Z, at a dose of 10 ml / kg im immediately after the first induction fever using a 20% yeast suspension, which is centrifuged, filtered and injected (the - filtrate) endovenously in a dose of 1 ml / kg. This is repeated twice; I repeat this treatment which causes the fever at 90 minute intervals.

The results appear in Table VII.

J - TABLEAU_VI

Antipyretic activity - Test in rats The data are averages for 5 animals.

5 _ · _j_ „. Fever reduction in ° C after:. Treatment 1 hour 2 hours 4 hours 8 hours i p— p '; ENA 0.80 1.22 1.32 1.00 11® Naproxen 0.76 1.24 1.32 0.94

Comparison of activity activity equal activity equal activity equal statistical activity P N.S. P N.S. P N.S. P N.S.

i 15 * | In this test the activity of the two substances is roughly parallel.

and both maintain high activity during the eighth day.

'TABLE VII

20 • - Antipyretic activity - Test in rabbits 1 The data are averages for 4 animals.

i m # · Fever reduction in ° C after:; · Treatment ί 2 hours 4 hours 6 hours 8 hours 25 ------ | * ENA 0.59 0.58 0.48 0.51 d Naproxen 1.04 1.04 0.61 0.28. 0.25

Comparison ENA minus equal activity ENA plus active ENA plus ac-30 statistical tif P ^ _0.05 P N.S. P £ 0.05 tif P £ 0.05

In this test, the antipyretic activity of ENA is first of all weaker than that of Naproxen, then it becomes equal to the latter and during the sixth and eighth hours, the activity remains constant | 35 whereas that of Naproxen decreases in a statistically significant fashion.

Acute toxicity

The acute toxicity of ENA was determined on two animal species: 10 mice of both sexes weighing on average 20 g and rats of both sexes weighing on average 200 g.

, Four routes of administration are used: oral, endoperitoneal, endovenous and subcutaneous. In each case, the animals are deprived of food during the night preceding the test. Ten animals, five males and five females, are used for each dose of treatment. The LD 50 values, expressed in ml / kg, are calculated according to the probit method: on the basis of the mortality detected during an eight-day treatment period.

• The results are given in table VIXI. This table indicates] 0 the comparison between the LD 50 of ENA and the LD 50 of Naproxen, a comparison which is partly based on data published in the literature and partly on original experimental work.

TABLE VIII

Acute toxicity - LD 50 in mg / kg 15 ______: _: _: -. . DL 50 equivalence DL 50

11113 016 ^ Napro- Naproxen / ENA report

ENA Naproxen ^ ^ r xene

Oral mouse 4,200 2,800 1,234 3E 0.44 20 i.p. 5,000 3,333,550 0.17 i.v. 1,000,667,435 3E 0.65 s.c.> 9,000,000 1,100 <0.18

Oral rat 3,200 2,133,543 3Ê 0.25 * 25 ip- 3,330 2,222,575 3E 0.26 iv 1,000,667 400 0.60 sc y-3,000> 2,000 1,000 ^ 0.50 (X) AP Roszkowski et al, J. Pharm. Exp. Ther., 179, 114 (1971).

30 As can be seen from the reports in the last column of the table, the ENA is much less toxic, about 1/2 to 1/5 compared to Naproxen, also bearing in mind the difference between molecular weights .

Toxicity to the fetus For this type of toxicity test, two animal species are used: rats and rabbits.

a) Test in rats: 10 rats are treated during the first 20 innre Λρ opcl-ptinn r »ar irrvî o nralû atmp flo T * KNA fl 1IT1P fîOSP dp 9Π τη! / ΐτο * / Ί ΠΤΙΤ! . Π! which corresponds to 13.2 mg / kg of Naproxen. Then we sacrifice the animals I to extract the fetuses and observe the uteri. The characteristics examined are: growth of the mother, number of living fetuses, number of dead fetuses, average litter weight, number of reabsorptions and deformities.

** Results: There are no toxic symptoms on gestation and on the fetuses.

b) Test in rabbits: 5 rabbits are treated during the first 24 days of gestation by administering oral ENA at a rate of 20 mg / kg / day, which corresponds to 13.2 mg / kg of Naproxen . The aliens are then sacrificed to remove the fetuses and examine the uteri. The characteristics examined are: growth of the mother, number! of live fetuses, number of dead fetuses, average litter weight, number of reabsorptions and deformities.

Results, there are no toxic symptoms on gestation or ^ on the fetuses.

Subacute rectal toxicity

We treat six rabbits, namely three males and three females, weighing! on average about 2 kg. Daily treatment for a period of 10 days I consists of the administration of suppositories containing 300 mg of | 20 active ingredient and which is introduced deep into the orifice of the rectum while holding this orifice closed for 30 minutes using Check forceps. This treatment does not cause a noticeable change in the general state of health of body weight, hemocrasis, liver function, blood sugar, azotemia, glycosuria, proteinuria and 25 l ematuria.- i | Subacute oral toxicity (ULCEROGENESE) i j * The comparison is carried out using an amount of ENA which is i equimolar to the dose of Naproxen known to be ulcerogenic. Male rats weighing on average about 150 g are used, keeping them under partial young (for only one night), the number of rats being five in total. The daily treatment is carried out by introducing into the esophagus: ENA at a rate of 150 mg / kg / day, Naproxen at a rate of 100 mg / kg / day, in solution in CMC at 1%, at a dose of 5 ml / kg

A few hours after the fifth administration, one of the animals dies between treatments with Naproxen and it is decided to sacrifice all the animals to examine them. The results of observations during f-ρΗ-ρ nprinilp dp * ï înitrs pf anrp "Ta Tnrvrf · annaraTSRP.nt scbématinnpriprit dan <; 12 Table IX.

TABLE IX

Gastroenteric ulcerogenic effect in ENA rats Naproxen animal animals

Observations before death number -% number -% 5 Noticeable pallor 0 0 2 40 Weight reduction of 15%.

10 from day 0 0 0 3 60

Lack of growth between 4th and 5th day 00 4 80 blood in the fetus 0 0 2 40

Diarrhea '0 0 2 40 15 Death (caused by peritonitis) __ 0_0_1_20

Observations after death

Lack of food 0 0 2 40 20

Anemic digestive tract 0 0 5 100

Gastrointestinal ulcer 00 1 20

It appears from the above data that the daily dose of Naproxen 25 that was used is very toxic to the point of being lethal gastroenterically, while the equimolar dose of ENA gives no symptoms of intolerance and no symptom of gastroenteric lesions even after five days.

EXAMPLE 3 30 Soft gelatin capsules: each capsule contains:

2- (6-methoxy-2-naphthyl) propyl enanthate 350 mg EXAMPLE 4

Suppositories: each suppository contains:

2- (6-methoxy-2-naphthyl) propyl enanthate 300 mg ^ Miglyol 50 mg "Witepsol" E 85 460 mg "Witepsol" W 35 q.s.p. 2.2 g 13 *; j EXAMPLE 5

Suppositories: each suppository contains:

Enanthate 2- (6-methoxy-2-naphthyl) propyl 600 mg

Miglyol 10 mg "Witepsol" E 85 370 mg 5 "Witepsol" W 35 q.s.p. 2.3 g I EXAMPLE_6

5% cream: 100 g of cream contain: I Enanthate of 2- (6-methoxy-2-naphthyl) propyl 5 g

Cetylstearyl alcohol. 5g 10 Isopropyl myristate 7 g. Vaseline oil 5 g

Spermacetes 7 g i

Stearic acid 2 g

Polysorbitan monolaurate (60) 0.5 g 15 Carboxyvinyl polymer with triethanolamine 1 g

Benzoic acid 2 g

Distilled water 100 g EXAMPLE_7 20 Ampoules of 300 mg: each ampoule of 2 ml contains:

2- (6-methoxy-2-naphthyl) propyl enanthate 300 mg

Lidocaine base 10 mg

Benzyl alcohol 50 mg Ethyl IOleate (or olive oil F) q.s.p. 3 ml 25

The composition according to the invention can be used to relieve a living being I of inflammation, pain, fever, at dosages of 300 to 3,200 mg / day.

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Claims (4)

1. 2- (6-Methoxy-2-naphthyl) propanol ester, characterized in that it! meets the formula ".. x if ί 1 2" 5. CH,. 0 3 -..- (1) ôi o ·, in which R is an alkyl radical of 1 to 20 carbon atoms. '10 2. Ester according to claim 1, characterized in that it is 2- (6-methoxy-2-naphthyl) propyl enanthate. 3. Pharmaceutical composition, in particular with anti-inflammatory action, "anti-rheumatic, analgesic and anti-pyritic, characterized in that it includes, as active principle, at least one compound according to the claim! 15 tion 1 or 2. 4. Process for the preparation of an ester of formula (I), characterized in [that a 2- (6-methoxy-2-naphthyl) propanol of formula (II) is reacted with a compound of formula (III) , according to the equation: 20 ΛΎΡΗ, ΟΗ ..... CH + ECX - ** CH, U CB v 3 H CH, 0 ^ ^ 3 3 0 3 (II) (ΙΠ) (I) i | · -, I 25 I in which R is an alkyl radical of 1 to 20 carbon atoms, X 1 represents OH, a halogen atom or an alkoxycarbonyloxy radical and en | * that the compound of formula (I) is isolated from this reaction mixture. i j · *! ΐι ·%, 1 3! * ’\ F, i ΐ /. / Λ I *