CH642257A5 - 2- (6-METHOXY-2-NAFTYL) PROPYL ESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The invention relates to esters of 2- (6-methoxy-2-naphthyl) -pro-piles of formula (I)

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wherein R represents an alkyl residue bearing from 1 to 20 carbon atoms.

The compounds (I) have proved to possess strong anti-inflammatory, antirheumatic, analgesic and 40 antipyretic properties, comparable to those of the more active enantiomer of 2- (6-methoxy-2-naphthyl) propionic acid, known by the name of Naproxene.

Compared to the latter, however, the compounds according to the invention are less toxic, have a considerably more prolonged activity and a much less pronounced gastrolesivity.

Therefore, the subject of the invention are also pharmaceutical compositions with anti-inflammatory, antirheumatic, analgesic and antipyretic activity, containing, in quality of the active principle, one or more compounds of general formula (I).

Finally, the invention relates to a process for the preparation of compounds (I), characterized in that 2- (6-methoxy-2-naphthyl) propanol-1 (II) is treated with ss carboxylic acids R-COOH (where R has the above indicated meanings) in the presence of acid catalysts, or with activated derivatives of the aforementioned carboxylic acids, according to the scheme shown below:

CD

10

15

20

25

0

(III)

I

i 3

642257

doxe X represents OH or an activating group, for example a halogen atom (preferably chlorine), or an alkoxycarbonyloxy residue, preferably the group C2HB-0 - C0-0-.

The process according to the invention is illustrated, but not limited, by the following examples.

Example 1 2- (6-methoxy-2-naphthyl) propyl a) 2- (6-methoxy-2-naphthyl) -propanol-1 acetate. 300 ml of THF, 53.5 g of 2- (6 - methoxy-2-naphthyl) propionaldehyde and 25 ml of water containing 2 are transferred into a 3-necked flask equipped with stirrer, reflux refrigerant and charging funnel. 5 g of NaOH. Under stirring, they are slowly added

2 g of NaBH4, keeping the temperature at 40 ° C. The mixture is stirred for one hour at room temperature and acetic acid is slowly added under stirring and cooling to destroy the excess of NaBH4. Under vacuum, most of the solvent is removed, then water is added and extracted three times with portions of 100 ml of ether.

The combined ether extracts are evaporated under vacuum and the oily residue crystallizes from petroleum ether / ethyl ether (50/50).

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 moles) of pyridine are introduced into a three-necked flask equipped with agitator, reflux coolant and dripping funnel and, slowly, under stirring, 58.8 g (0.725 moles) ) of acetyl chloride.

The solution is cooled to 0 ° C and 108 g (0.5 mol) of 2- (6-methoxy-2-naphthyl) propyl alcohol dissolved in 200 ml of ethyl ether are slowly introduced through the loading funnel. The temperature rises to about 40 ° C; stirring is continued for 4 hours at room temperature and then the solution is poured into 250 ml of water. The organic phase is stirred and recovered and washed with 0.1N HCl solution. The washed organic phase is anhydrified with anhydrous sodium sulphate. The solvent is evaporated with the aid of the vacuum and the oily residue is distilled. The pure ester distils at 175-178 at 0.01 mm Hg.

The yield is 102 g (75% yield).

By operating in the same way, the following compounds are also obtained:

2- (6-methoxy-2-naphthyl) propyl propionate, e.g. "01 = 178-183 ° C;

2- (6-methoxy-2-naphthyl) propyl hexanoate, e.g. 0 01 = 188-190 ° C.

Example 2 2- (6-methoxy-2-naphthyl) propyl enanthate

500 ml of ethyl ether are introduced into a three-necked flask equipped with agitator, reflux coolant and dripping funnel, 58.9 g (0.725 mol) of pyridine are charged and slowly, under stirring, 107.4 g (0.725 moles) of enanthic acid chloride. The solution is cooled to 0 ° C and -108 g (0.5 mol) of 2- (6-methoxy-2-naphthyl) propyl alcohol dissolved in 200 ml of ethyl ether are slowly introduced through the loading funnel.

The temperature rises to 40 ° C, stirring continues for 4 hours at room temperature and then the solution is poured into 250 ml of water. The organic phase is stirred and recovered and washed with 0.1N HCl solution.

The washed organic phase is anhydrified with anhydrous sodium sulphate.

The solvent is evaporated with the aid of the vacuum and the oily residue is distilled. The pure ester distills at 191-193 at 0.01 mm Hg. The yield is 125.3 g (73.2% yield). U.V .: an ethanolic solution (25 mcg / ml) has two maxima at 5 260 ± 1 - 270 ± 1 and at 316 ± 1 - 331 ± 1.

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

By operating in a similar way the other esters of 2- (6-methoxy-2-naphthyl) propyl are obtained, of which table 1 shows the physical and analytical characteristics.

TABLE 1,

calculated C

found H

o ìli

M

175-78 / 0.01

74.42 to 74.10

6.98-6.96

QH5

178-83 / 0.01

75.00 to 74.84

7.35- 7.31

C4H9

183-87 / 0.01

76.00 to 75.80

8.00-7.95

C5Hn

188-89 / 0.01

76.43 to 76.20

8.28- 8.31

C6Hi3

191-93 / 0.01

76.82 to 76.80

8.54- 8.50

c, h15

193-95 / 0.01

77.19 to 77.00

8.77- 8.80

C8H17

194-98 / 0.01

77.53 to 77.40

8.98-8.95

CgHjg

198-200 / 0.01

77.84 to 77.81

9,19- 9,10

CioH2I

181-83 / 0.005

78.12 to 78.10

9.37- 9.31

CnH ^

185-87 / 0.005

78.39 to 78.43

9.55- 9.56

C12H25

188-89 / 0.005

78.64 to 78.60

9.70- 9.76

C14H29

191-93 / 0.005

79.00 to 79.00

10.00 to 10.20

C15H31

192-94 / 0.005

79.29 to 79.16

10.13 to 10.00

Qi6H33

195-97 / 0.005

79.50 to 79.61

10.26 to 10.15

Q1.7H35

199200 / 0.005

79.66 to 79.58

10.37 to 10.41

Ci8H37

201-202 / 0.005

79.84 to 79.77

10.48 to 10.44

The pharmaco-toxicological characteristics of the compounds according to the invention are illustrated, by way of example, by the results obtained with the 2- (6-methoxy-2 - naphthyl) propyl enanthate henceforth defined for brevity with the acronym ENA.

55 Anti-inflammatory activity a) acute test: carrageenan plantar edema [Winter C.A. et al., Proc. Soc. Exp. Biol. Med., Ili, 544 (1962)].

The two drugs were administered orally in equimolecular doses: ENA 60 mg / kg, naproxen 40 60 mg / kg, in CMC 1% at 20 ml / kg, immediately after the provocation of the edema by subplantar injection of carrageenan 1%, 0.05 ml / paw.

The results of this test are reported succinctly in Table 2.

65 b) subacute test: plantar edema from nystatin [Arrigoni-Martelli E .e coll., Pharmacology, 5, 215 (1971)].

The two drugs were administered orally in equimolecular doses for two consecutive days: the 1st

642257

4

day ENA 30 mg / kg, naproxen 20 mg / kg, in CMC 1% at 10 ml / kg; on the 2nd day ENA 60 mg / kg, naproxen 40 mg / kg, in CMC at 20 ml / kg. The provocation of the edema was carried out the evening before the 1st treatment with the drugs by subplantar injection of nystatin 300,000 U / ml, 0.1 ml / paw.

The results of this test are reported succinctly in Table 3.

TABLE 2

Anti-inflammatory activity - Acute test

Each figure is the average of 10 legs

Treatment

% Edema inhibition after:

2 hours

4 hours

6 hours

8 hours

ENA

62

49

61

85

Naproxen

60

31

30

36

Equal comparison

ENA more

ENA more

ENA more

statistical activity

active active active

p N.S.

P <0.025

P <0.01

P <0.05

As can be seen, the ENA is equivalent to naproxen at the second hour, but becomes more active in the following hours and at the eighth hour it maintains considerable activity.

TABLE 3 Anti-inflammatory activity - Subacute test

Each figure is the average of 10 legs

1st day

Treatment

% Edema inhibition after:

1 hour

2 hours

4 hours

8 hours

ENA

12

8

10

11

Naproxen

5

4

4

5

Comparison

ENA more

same

ENA more

ENA more

active activity

active active

P <0.001

P N.S.

P <0.01

P <0.01

2nd day

Treatment

% Edema inhibition after:

1 hour

2 hours

4 hours

8 hours

ENA

6

12

12

17

Naproxen

5

8

7

11

Equal comparison equal equal

ENA more

statistical activity

activities

activities

active

P N.S.

P N.S.

P N.S.

P <0.005

As can be seen, the ENA carries out a curative activity of a pre-established and stable edema that is not only comparable to that of naproxen, but, especially at longer times, even greater and with high statistical significance.

Analgesic activity It was evaluated in comparison with equi-molecular dose naproxen. Two tests were carried out: one in the female mouse weighing approximately 25 g and one in the male rat weighing approximately 100 g.

a) mouse test: contortion from phenylquinone [Hender-shot L.C. et al., J. Pharm. Exp. Ther., 125, 237 (1959)].

The two drugs were administered orally in doses equimolecular to each other: ENA 30 mg / kg, naproxen 20 mg / kg, in CMC 1% at 20 ml / kg. The provocation of the contortions was carried out at different intervals after the administration of the drugs by endoperi-tonal injection of phenylquinone 0.02% in alcohol 5%, 10 ml / kg. The results of this test are reported succinctly in Table 4.

b) "rat test: pressure on the inflamed paw [Randall L.O. and coll., Arch. Int. Pharmacodyn., Ili, 409 (1957)].

The two drugs were administered orally in doses equimolecular to each other: ENA 60 mg / kg, naproxen 40 mg / kg, in CMC 1% at 20 ml / kg, immediately after the provocation of the inflammation: subplantar injection of yeast 10%. 0.1 ml / paw.

The results of this test are reported succinctly in Table 5.

TABLE 4 Analgesic activity - Mouse test Each data is the average of 8 mice

Treatment

Inhibition of contortions after:

1 hour

2 hours

4 hours

6 hours

ENA

27

57

44

46

Naproxen

14

68

30

13

Equal comparison equal equal

ENA more

statistical activity

activities

activities

active

P N.S.

P N.S.

P N.S.

P <0.01

As can be seen, the ENA performs an activity comparable to that of naproxen in the early hours, but still keeps it elevated at the sixth hour while naproxen significantly reduces them.

TABLE 5 Analgesic activity - Test in the rat Each datum is the average of 10 legs

Treats - Inhibition% of tenderness after:

chin 1 hour 2 hours 3 hours 4 hours 5 hours

ENA

240

400

152

131

100

NAPRO

xen

47

79

67

64

64

With

ENA

ENA

equal equal equal front plus

more

activities

activities

activities

active active

P N.S.

P N.S.

P N.S.

stico

P <0.001

P <0.001

As can be seen, in this test the ENA performs greater analgesic activity than naproxen significantly in the first hours and apparently but not statistically significant in the following hours.

5

I

microsecond

20

25

30

35

40

45

50

55

60

65

5

642 257

Antipyretic activity

It has been evaluated in comparison to equi-molecular dose naproxen. Two animal species were used: male rats weighing about 250 g and female rabbits weighing about 2.6 kg.

a) rat test: yeast pyresis [Teotino. U.M. and coli. J. Med. Chem., 6, 248 (1963)].

The two drugs were administered orally in doses equimolecular to each other: ENA 60 mg / kg, naproxen 40 mg / kg, in CMC 1%, 10 ml / kg. The provocation of the fever was carried out the previous evening by subcutaneous injection of 20% beer yeast suspension, 10 ml / kg.

The results are reported succinctly in Table 6.

b) rabbit test: yeast pyresis.

The two drugs were administered orally at doses between equimolecular V-ro: ENA 60 mg / kg, naproxen 40 mg / kg, in CMC 1%, 10 ml / kg, immediately after the first provocation of fever: suspension 20% brewer's yeast, centrifugation, filtration, injection of this intravenous filtrate at 1 ml / kg; this pyretogenic treatment was repeated twice at 1 hour and 30 minute intervals.

The results are reported succinctly in Table 7.

TABLE 6 Antipyretic activity - Test in rats Each data is the average of the 5 animals

Treatment Fever reduction in ° C after:

1 hour 2 hours 4 hours 8 hours

ENA

0.80

1.22

1.32

1.00

Naproxen

0.76

1.24

1.32

0.94

Comparison equal equal equal equal statistical activity

activities

activities

activities

P N.S.

P N.S.

P N.S.

P N.S.

In this test a parallel trend of activity of the two drugs is observed. Both retain high activity in the eighth hour.

Acute toxicity The acute toxicity of the ENA was determined on two animal species: mice of both sexes with an average weight of about 20 g and rats of both sexes with an average weight of approximately 5 g 200.

There were four routes of administration: oral, endoperitoneal, intravenous and subcutaneous. All animals were removed from the food the evening before the experiment. 10 animals (5 male and 5 female) were used for each treatment dose. The DL 50 values, expressed in mg / kg, were calculated using the probits method based on the mortalities found within 8 days of treatment.

The results briefly reported in table 8 compare the ENA DL 50 with the corresponding i5 DL 50 of naproxen, partly known from the literature and partly original.

TABLE 8

Acute toxicity - DL 50 in mg / kg

Species

Street

DL 50

equiva

NAPRO

RELA

ENA

xenon lens

NAPRO

DL 50

NAPRO

xen

xen /

25

ENA

Mouse

OS

4200

2800

1 2 3 4*

0.44

intraperitoneal

5000

3333

550

0.17

30

fully paid

1000

667

435 *

0.65

S.C.

> 9000

> 6000

1100

<0.18

Rat

OS

3200

2133

543 *

0.25

intraperitoneal

3330

2222

575 *

0.26

35

I.V.

1000

667

400

0.60

S.C.

> 3000

> 2000

1000

<0.50

(*) Roszkowski A.P. et al., J. Pharm. Exp. Ther., 179, 114 (1971).

As can be seen from the reports shown in the last column, the ENA is much less toxic, from about half to about a fifth, than naproxen even taking into account the different «molecular weight.

TABLE 7 Antipyretic activity - Test in the rabbit Each data is the average of 4 animals

Treatment Fever reduction in ° C after:

2 hours

4 hours

6 hours

8 hours

ENA

0.59

0.58

0.48

0.51

Naproxen

1.04

0.61

0.28

0.25

Comparison

ENA

same

ENA

ENA

statistical less activity

more

more

active

P N.S.

active active

P <0.05

P <0.05

P <0.05

In this test the antipyretic effect of ENA is initially lower than that in naproxen, then it is the same, then, at the sixth and eighth hour, it remains constant while that of naproxen becomes significantly lower.

Fetal toxicity Two animal species were investigated: rat and rabbit, I know a) rat test: 10 rats were treated for the first 20 days of oral gestation with ENA at 20 mg / kg / day equal to 13.2 mg / kg of naproxen. After that, they were sacrificed to take the fetuses and observe the womb.

Observed parameters: growth of mothers, N ° 55 fetuses alive, N ° dead fetuses, average weight of broods, N ° of resorption, malformations.

Results: no toxic effects on gestation and fetuses.

b) rabbit test: 5 rabbits were treated for 60 the first 24 days of gestation orally with ENA at 20 mg / kg / day equal to 13.2 mg / kg of naproxen. After that, they were sacrificed to take the fetuses and observe the womb.

Observed parameters: growth of mothers, N ° 65 live fetuses, N ° dead fetuses, average weight of broods, N ° of resorption, malformations.

Results: no toxic effects on gestation and its fetuses.

642257

6

Subacute rectal toxicity 6 rabbits (3 males and 3 females) with an average weight of approximately 2 kg were treated. The daily treatment for 10 days consisted of a suppository containing 300 mg of active ingredient which was introduced deeply into the rectal ampoule which was kept tight for 30 minutes with cocher forceps.

This treatment did not show significant changes in the general state of health, the trend of the body weight of the blood crasis, liver function,

blood sugar, blood sugar, glycosuria, protein-nuria, hematuria.

Oral subacute toxicity (Ulcerogenesis) The comparison was made in equimolarity with a notoriously ulcerative dose of naproxen. Male rats with an average weight of approximately 150 g were used with partial fasting (only at night), N ° 5 per treatment. Daily treatment was carried out using an esophageal probe: ENA 150mg / kg / day, naproxen 100 mg / kg / day, in 1% CMC, 5 ml / kg. A few hours after the fifth administration there was a death among naproxen treated and it was decided to sacrifice and observe all the other animals.

The results of the observations made during the five days and of the conclusive necropsy are schematically reported in table 9.

TABLE 9 Gastro-enteric ulcerogenic effect in the rat

Reliefs before the killings

ENA Naproxen animals animals n% n. %

Marked pallor

0

0

2

40

Weight reduction> 15% on day 0

0

0

3

60

Growth failure between 4th and 5th day

0

0

4

80

Blood in the stool

P

0

2

40

Diarrhea

0

0

2

40

Death1 (from peritonitis)

0

0

1

20

Necropsy findings

Power failure

0

0

2

40

Anemic digestive tract

0

0

5

100

Gastro-intestinal ulcers

0

0

1

20

As can be seen, the daily dose of naproxen used is very harmful, even lethal, for the gastrointestinal tract, while the equimolecular dose of ENA does not show signs of intolerance, nor of gastroenterolesivity 5 even after 5 days.

Example 3

Soft gelatin capsules.

Each capsule contains:

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

350

Example 4

Suppositories.

Each suppository contains:

15 2- (6-methoxy-2-naphthyl) propyl mg enanthate

300

Miglyol '

mg

50

Witepsol E 85

mg

460

Witepsol W 35 q.b. to gr

2.2

20 Example 5

Suppositories.

Each suppository contains:

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

600

Miglyol mg

10

25 Witepsol E 85

mg

370

Witepsol W 35 q.b. to gr

2.3

Example 6

5% cream.

30 100 gr of cream contain:

2- (6-methoxy-2-naphthyl) propyl enanthate gr

5

Cetylstearyl alcohol gr

5

Isopropyl myristate gr

7

Vaseline oil gr

5

35 Spermaceti gr

7

Stearic acid gr

2

Monolaurate polysorbitan 60

gr

0.5

Triethanolaminic carboxyvinylpolymer gr

1

Benzoic acid gr

2

40 Distilled water gr

100

Example 7

300 mg ampoules.

Each 2 ampoule contains:

45 2- (6-methoxy-2-naphthyl) propyl mg enanthate

300

Lidocaine base mg

10

Benzyl alcohol mg

50

Ethyl oleate (or FU olive oil) to taste do you love

3

50

Claims (7)

642257 2. As the compound according to claim 1, the 2- (6-methoxy-2-naphthyl) propyl enanthate. 2 CLAIMS 1. Esters of 2- (6-methoxy-2-naphthyl) propyl of formula wherein R represents an alkyl residue bearing from 1 to 20 carbon atoms. 3. Pharmaceutical compositions with anti-inflammatory, antirheumatic, analgesic and antipyretic activity, characterized in that as an active principle they contain one or more compounds according to claim 1. Pharmaceutical compositions according to claim 3, characterized in that as an active principle they contain 2- (6-methoxy-2-naphthyl) propyl enanthate. 5. Process for the preparation of 2- (6-methoxy-2-naphthyl) propyl (I) esters, characterized in that 2- (6-methoxy-2-naphthyl) propanol-1 (II) is reacted ) with a compound of formula (III), according to the scheme: GH-CH20H CH ^ O: (II) where R has the above meanings, while X represents OH, a halogen atom, or an alkoxy - carbonyloxy residue. 6. Process according to claim 5, characterized in that X represents chlorine. 7. Process according to claim 5, characterized in that X represents the residue C2H5-0-C0-0-.