NL8002737A - NAFTYL PROPANOL ESTERS. - Google Patents

Description

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Title: Naphthylpropanol esters.

The invention "relates to esters of an acid with a 2-substituted propanol and more particularly with propanol substituted by a 6-methoxy-2-naphthyl group of the formula I, wherein R is an alkyl group of 1- 20 carbon atoms.

It has been found that compounds of the formula I have particularly favorable properties, especially anti-inflammatory, anti-rheumatic, analgesic and antipyretic properties, comparable to that of a known substance, naproxen, the most active enandomer of 2- (6-methoxy-2 -naphthyl) propionic acid. Compared to naproxen, the compounds of the invention are less toxic and exhibit markedly stronger activity, while being less aggressive to the stomach. In addition to the compounds of the formula I, the invention relates to medicaments containing these substances and having the indicated activities. The invention also relates to processes for preparing the compounds of the formula 1, wherein a carboxylic acid of the formula R-C00H is reacted in the presence of an acid catalyst with 2- (6-methoxy-2-naphthyl) -1-propanol . According to a preparation form, the substituted alcohol is reacted with an active derivative of the carboxylic acid according to scheme A of the formula sheet, in which scheme represents 20 X hydroxyl or an activating group, e.g. a halogen atom or an alkoxycarbonyloxy group, such as C 8 H 2 O-CO-O-.

The invention is further illustrated by the following examples.

Example I; 2- (6-methoxy-2-naphthyl) propyl acetate a) 2- (6-methoxy-2-naphthyl-1-uronanol).

In a three-necked flask, equipped with a stirrer, a reflux condenser

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and a dropping funnel, 300 car THF, 53.5 g 2- (6-methoxy-2-

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naphthyl) propionaldehyde and 25 cm of water containing 2.5 g of RaOH.

While stirring, 2 g of alaBH4 was slowly added while the temperature was kept at Ho ° C. The mixture was stirred at room temperature for 1 hour and then slowly added acetic acid with stirring and cooling to decompose excess HaBH4. Most of the solvent was distilled off in vacuo, then water was added and the material extracted three times with 100 cm ether each.

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The ether extracts were then combined, evaporated in vacuo and the oily residue crystallized from a 50:50 mixture of petroleum ether and ethyl ether. Obtained U9.9 g (93> 3%), mp 82-8L + ° C.

5 h) 2- (6-methoxy-2-naphthyl) propyl acetate

In a three-necked flask equipped with a stirrer, a reflux condenser

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and a dropping funnel, 500 cm3 of ethyl ether, 58.9 g (0.725 mole) of pyridine and slowly added 58.8 g (0.725 mole) of acetyl chloride with stirring.

The solution was cooled to 0 ° C and then slowly fed 108 g (0.5 mol) of 2- (6-methoxy-2-naphthyl) propyl alcohol dissolved in 200 ml of ethyl ether through the funnel. The temperature thereby rose to approximately ko ° C.

Ha 1 more; stir for an hour at room temperature and dilute the solution with 250 ml water. This mixture was stirred and the organic phase separated, washed with 0.1 H hydrochloric acid and the organic phase dried with sodium sulfate. The solvent was distilled off in vacuo and the oily residue distilled. The pure ester distilled at 175-178 ° C and a pressure of 0.01 mm Hg. The yield was 102 g (75 $). The following compounds were also prepared according to the procedure described above: 2- (6-methoxy-2-naphthyl) propyl propionate at bp, 178-183 ° C at 0.01 mm Hg 2- (6-methoxy-2-naphthyl) propyl hexanoate with bpt. 188-190 ° C at a pressure of 0.01 mm Hg.

Example II: Preparation of 2- (6-methoxy-2-naphthyl-ronyloenanthate)

In a three-necked flask with a stirrer, reflux condenser and dripping

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peel funnel then 500 ml of ethyl ether, 58.9 g of pyridine and 107.1+ g (0.725 mol) of oenanthyl chloride were slowly introduced with stirring. The solution was cooled to 0 ° C. 108 g (0.5 mole) of 2- (6-methcocy-2- through the funnel

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30 naphthyl) propyl alcohol, dissolved in 200 ml of ethyl ether, is added. The temperature thereby rose to 1 + 0 ° C. After stirring for another hour at room temperature, the solution is poured out with 250 cm of water. This mixture was stirred, the organic phase separated, washed with a 0.1 N hydrochloric acid solution and the organic phase dried with anhydrous sodium sulfate.

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The solvent was distilled off in vacuo and left oily residue distilled. The pure ester boiled at 191-193 ° C and 0.01 ma Hg. The yield was 125.3 g (73.2%).

Ultraviolet spectrum: A solution of this substance in ethanol 5 (25 mg / l) has two maxima: at 260 + 1 to 270 + 1 and at 316 + 1 to 331 + 1. This compound is insoluble in water, soluble in chloroform , ethanol, acetone, hexane and in addition in oils.

Using the same procedure yields all further esters of 2- (6-methoxy-2-naphthyl) propanol as shown in Table A, which also shows physical properties and analysis figures.

Table A

formula 1 Analysis

15 B_ student room. ° C / mm Hk | C.. I H

__I_ber. found. I ber. found CS3 175-78 / 0.01, 71.12-71.10. 6.98 - 6.96 C2H5 178-83 / 0.01] 75.00 - 71.81 y 7.35 - 7.31 183-87 / 0.01 y 76.00 - 75.80 | 8.00-7.95 20 '188-89 / 0.01; 76.13 - 76.20; 8.28 - 8.31 C6H13 191-93 / 0.01 y 76.82 - 76.80 8.5 l - 8.50

CtH15 193-95 / 0.01 y 77.19 - 77.00 '8.77 - 8.80 C8H1T 1911-98 / 0.01 I 77.53 - 77 .10 8.98 - .8.95

C9H19 198-200 / 0.01 77.81 - 77.81 9.19 - 9, IQ

25 C10H21 181-s3 / 0.005 5 78.12 - 78.10 9.37 - 9.31 C11H23 185-87 / 0.005 y 78.39 - 78.13 9.55 - 9.56 C12H25 | 188-89 / 0.005 1 78.6b- - 78.60. 9.70 -: 9.76

ClhS29 191-93 / 0.005! 79.00 - 79.00 10.00 - 10.30 C15H31 192-91 / 0.005; 79.29 - 79.16 -10.13 - 10, Q0 30 195-97 / 0.005 I 79.50 - 79.61. 10.26 - 10.15 C17H35 199-200 / 0.005! 79.66 - 79.58, 10.37 - 10.11

G18H3T | 201-202 / 0.005; 79.81 - 79.77 10.18 - IQ, H

I i 1

The pharmaceutical properties of the present compounds and their toxicological figures are detailed below with reference to 2- (6-800-2737-um-methoxy-2-naphthyl) propyloenanthate (ENA). Anti-inflammatory activity

This activity was determined compared to naproxen in equimolar dose. Male rats with an average weight of 150 g were used. Two tests, i.e. an acute and a subacute were performed.

Acute test: plantar edema caused by carrageenan according to Winter in Proc. Soc. Exp. Biol. Med. 111, 5 ^ (1962).

The two compounds to be tested were administered orally in 10 equimolar doses: MA 60 mg / kg, naproxen ^ 0 mg / kg in 1 ^ s

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carboxymethylcellulose (CMC) in an amount of 20 cnr / kg immediately after the appearance of the edema due to a subplantar

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injection of carrageenin in an amount of 1% and 0.05 cm per leg. The results of this test are shown in Table B.

Sub-acute test: plantar edema caused by nystatin according to Arrigoni-Martelli, Pharmacology, 215 (1971). The two compounds were administered orally in equimolar doses for two consecutive days as follows:

The first day EDA 30 mg / kg, naproxen 20 mg / kg in 1 $ CMC in a 3 amount of 10 cm / kg.

The second day ENA 60 mg / kg, naproxen Uo mg / kg in 1% CMC

in an amount of 20 mg / kg.

The edema was caused overnight before the first treatment by a subplantar injection of nystatin in an amount of 300,000 unit / cm 2 in an amount of 0.1 cm / leg.

The results of this test are shown in Table C.

Table B

Anti-inflammatory activity - acute.

Each figure is the average of 10 legs.

30 Treatment *% inhibition of edema after; > _; _ 2 hours_; Hrs_ \ 6 hours' 8 hours MA -62! ^ 9 j 6l 85

Naproxen _'_ 60 31_i 30_. 36

Statistical equal activity 1 MA active ^ ENA action- ENA activity comparison J activity P <^ 0.025 more active 35 P N.S. I Ρ ^ Ο, ΟΙ j P <fo, 05 __ t __ __ 1__ 800 2 7 37 ** * -5-

As these figures show, after 2 hours MA it is as active as after £ raxing, but more effective in the further course, while the activity is still very evident after 8 hours.

Table C

5 Anti-infmallmatic activity - subacute Each digit is the average of 10 legs.

Day No. 1

Treatment% inhibition of edema after: I ·. * 10 ___1 hours 1 2 hours 'U' hours_8 hours MA 12 i 8 i 10 11 naproxen__5__k_k_5

compare MA more active _ even MA EM

P (0.001! Active more active more active 1 P Bf.S. = Ρ ^ Ο, ΟΙ P <0.01 15 __ | __

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Treatment% inhibition of edema after:! . j ^ _! _ 1 hour 2 hours__4 hours j “hours 20 EKA I 6 12 12 17 naproxen 5_8__7 __—

statistical briefly briefly ENA

compare active active active i more active P H.S. P Bf.S. F ÏT.S. | From the above figures it can be seen that MA is therapeutically active against stable pre-induced edema, which activity is not only comparable to that of naproxen, but lasts even longer and is statistically very significant.

Analgesic Activity The analgesic activity was determined by comparison with naproxen at an equimolar dose. Two experiments were performed, one in female mice with an average weight of 25 g and one in male rats with an average weight of 100 g. a) test in mice: contortions caused by phenylquinone according to Hendershot in the J. Pham. Exp. Ther., 1251 237 (1959) o η n 9 7 37 f -6-

The two compounds were administered orally at substantially equimolar doses of up to MA 30 mg / kg, naproxen 20 mg / kg in 1% CMC solution at a dose of 20 cm / kg. The contortions were caused at various intervals after the administration of the compounds by an endoperitoneal injection of 0.02% phenylquinone in 5% alcohol at a dose of 10 cm / kg. The results of this test are shown in Table D.

b) Test in rats: This test was performed by pressure on an inflamed leg according to Randall in the Arch. Int. Fharmacodyn. 111.

10 U09 (1957) The two compounds were administered orally at doses that were equimolar, MA 60 mg / kg, naproxen ^ 0 mg / kg in a 1 cm CMC solution at 20 cm / kg immediately after causing the inflammation from a subplantar injection

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of $ 10 yeast in an amount of 10.1 cm / leg. The results of this test are shown in Table E.

Table D

Analgesic activity - mice

Each figure is the average of 8 mice.

20 Treatment% inhibition of contortions after: __1 hours 2 hours H hours__6 hours_ MA 27 57 Μ

Naproxen lU 68 30 13

25 Statistical momentary momentary ENA

compare active active active more active P N.S. P N.S. P N.S. P CO, 01

As the figures show, MA shows naproxen-like activity in the first few hours, but after the sixth hour, MA's activity increases, while napraxen activity slowly decreases.

Table E

Analgesic activity - rats

Each figure is the average of 10 legs.

35 8002737 -7- treatment% pain inhibition after: 'I * ί ______________________1 hour -2 hours 3 hours y ^ hours i 5 hours EHA _ 2 ^ 0! kOO. 152: 1 ^ 1 i 100

Naproxen__kj_ "79_. 67_I 6k_; 6h 5 statistical ECTA more active MA action; just take a moment. P 0.001 j more active active j active I P 0.001 P H.S. P H.S.j P N.S.

The figures show that MA is clearly more active than naproxen, especially in the beginning, and even more active after several hours, but this is not statistically significant.

Antipyretic activity

This activity was determined compared to naproxen in equimolar doses. The two animal species were used, i.e. male rats with an average weight of 250 g and female rabbits with an average weight of 2.5 kg.

a) Rats: The temperature increase was caused by yeast according to Teotino in <1. Med. Chem., 6, 2h8 (> 1963). The two compounds were administered orally in equimolar doses, i.e. FÏA 60 mg / kg, naproxen 1 + 0 mg / kg in 1% CMC; the dose was 10 cm / kg. The fever was caused the previous night by a 20% subcutaneous injection

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yeast suspension in a dose of 10 car / kg. The results are shown in Table F.

b) Rabbit test: fever was caused by yeast. The two compounds were administered orally in equimolar doses: ΕΝΑ 60 mg / kg, 25 naproxen Uo mg / kg in 1% CMC at a dose of 10 crn / kg immediately after the first fever induction with a 20% yeast suspension centrifuged, filtered, then the filtrate was administered intravenously at a dose of 1 cm 3 / kg. This treatment, causing fever, was repeated twice at 1h30 and 30min intervals. The results are shown in Table G.

Table F

Antipyretic activity - rat

Each figure is the average of 5 animals.

35 800 27 37 * <-8-

Treatment Fever reduction in ° C after:, _ 1 hour j 2 hours L hours! 8 hours_

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EM j 0.80 1 1.22 1.32 1.00

Naproxen_! 0,7 6__1,2¾__1,32__0,9¾_ 5 Statistical even equally even active active active active _ P N.S. P N.S. P N.S. P N.S.

In this test, the activity of the two substances was almost parallel, while "both still show high activity even after 8 hours.

Table Q

Antinyretic activity - rabbits Each digit is the average of U animals.

Treatment Reduction of the fever in ° G after: 15 __2 hours j U hours I 6 hours__8 hours_ EM 0.59 0.58 j 0, U8 0.51

Naproxen__1,0¾__0,6l j 0,28__0,25_

Statistical EM less equally ENA more active ENA more active comp. active active 20 P (0.05 P N.S. P \ 0.05 P <0.05

In this test, the antipyretic activity of EM was first less than that of naproxen, then it became equal and finally after 6-8 hours the activity of ENA remained constant, while the activity of naproxen gradually decreased. / 25 Acute toxicity

The acute toxicity of ENA was determined in two animals: mice of both sexes with an average weight of 20 g and rats of both sexes with an average weight of 200 g.

Four methods of administration were used: oral, intraperiodonal, intravenous and subcutaneous. In all these cases, the animals were kept without food overnight for the test. 10 animals each, 5 male and 5 female, were used. The LD 50 values expressed in cm 2 / kg were calculated according to the conventional method, observing applied 8 days after treatment.

The results are shown in Table H. These provide a comparison of the LD 50 of ENA with that of naproxen, which equation 800 2 7 37-9 is based partly on literature figures and partly on original experimental work.

Table 5

Acute toxicity -ID 50 in mg / kg 5 ---, ---- y-

Type of Route j LD 50; equivalent to LD 50 j ratio

• EHA i naproxen i naproxen i naproxen / ERA

> ί ï I

Mouse | oral j 1 * 200 j 2800 j 123l * X j 0.1A

i.p. j 5000! 3333 I 550] 0.17 10 i.v. : 1000! 66y! 1 * 35Χ ί j ί | t - η __s.c. 9000! 6000_) 1100 I * _

Rat oral j 3200 | 2133! 5 ^ 3X 0.25: x 0 26 i.p. 3330 2222; 575 9.

i.v. 1000 667 | 1 * 00 0> 6 ° 15 s.c. 3000 2000 1000 ° 5 °

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_____i__ (x) A.P. Roszkowski et al, J. Pharm. Exp. Ther., 179, 111 * (1971).

As the last column shows, EHA is markedly less toxic than naproxen, especially taking into account the difference in molecular weight.

Toxicity to a fetus

This type of toxicity was determined in rats and rabbits.

a) Rat: 10 female rats were fed in the first 20 days of the

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gestation treated orally with EHA at a dose of 20 cur / kg per day corresponding to 13.2 mg / kg naproxen. The animals were then sacrificed, the fetuses removed and the uterus examined. The traits looked at were: maternal growth, number of live fetuses, number of dead fetuses, average weight of the latter and number of reabsorptions and malformations.

30 Results: No toxic symptoms in pregnancy or in the fetuses were observed.

b) Rabbits: Five female rabbits were orally treated with EHA at a dose of 20 mg / kg / day corresponding to 13.2 mg / kg naproxen for the first 2b days of gestation. The animals were then killed, the fetuses removed and the uterus examined. The traits 97% 7-10 pen examined were: maternal growth, number of live fetuses, number of dead fetuses, average weight of the latter, number of reabsorptions and malformations. Results: No toxic symptoms were observed, neither he gestation nor he fetuses.

5 Suhacute toxicity by rectal administration.

Six rabbits, three male and three female with an average weight of 2 kg were treated. The daily treatment lasted 10 days and consisted of suppositories with 300 mg of active substance each, which was administered into the rectal cavity, while this cavity was kept closed for 30 minutes. This treatment did not change the general health, body weight, blood count, life function, glycemia, azotaemia, glycosuria, protein neururia and ematuria.

Subacute toxicity following oral administration (ulcerogenesis) A comparison was performed using an equimolar amount of ENA compared to an equimolar amount of naproxen, which is known to be ulcerogenic. 150 g male rats were used which were not fed overnight and the total number of 5 'was used. The daily treatment was carried out by administration in the esophagus: EEE in an amount of 150 mg / kg / day, naproxen in an amount of 100 mg / kg / day in a l # * s CMC solution at a dose of 5 car / kg: '. A few hours after the fifth administration, 1 animal died between naproxen treatments, after which it was decided to kill all animals to examine them. The results of the observations during the five daily periods and their deaths are shown schematically in Table J.

Table J

Ulcerogenic gastroenteritic effect in rats __. > »,,, ISAIA animals j naproxen animals

Observations for death _! _ _ ^ Significant pallor '0 0' '2 ^ 0 weight reduction 15 # starting; 0 0 3 60 on day 0 reduction in growth between the be and the 5th day j 0 0 h 80 (i

blood in the fetus 00 .2 bO

diarrhea 0 0 2 ^ 0 death from peritonitis__0 0__i_20_ 8002737 C- · "« -n-

Observations after death_j_J_ 1 i reduction in nutrition. j 0 0 2 Ho l anemia in the digestive tract 0 0 5 100 gastrointestinal tract 0 0 1 20 5 -; - ~ -------

These figures show that the daily dose of naproxen, which is very toxic, is at this point lethal via the gastrointestinal route, while the equimolar dose is ERA. had no symptoms, not even the slightest damage to the gastrointestinal tract after five days.

2o Example III-

Soft Gelatin Capsules: Each capsule contained 2- (6-methoxy-2-naphthyl) propyanthanthate 350 mg

Example 17:

Suppositories: Each suppository contained: 2- (6-methoxy-2-naphthyl) vropylphenanthate 300 mg

Miglyol 50 mg

Witepsol E 85 i «50 mg

Witepsol W 35 to 2.2 g

Example V: 2Q Suppositories: Each suppository contained: 2- (6-methoxy-2-naphthyl) propyl cenanthate 600 mg

Miglyol 10 mg

Witepsol E 85 370 mg

Witepsol W 35 to 2.3 g 25 Example VI: 5% cream: 100 g cream contained: 2- (6-methoxy-2-naphthyl} propyl cenanthate 5 g cetyl stearate alcohol 5 g opris opyl myri 7 g Vaseline oil 5 g spermaceti 7 g stearic acid 2 g polysorbitan monolaurate 60 0.5 g carboxyvinyl polymer with triethanolamine 1 g benzoic acid 2 g distilled water 100 g 8002737

Example VII: «3 -12-

300 mg vials: 2 cm ftial each contained: 2- (6-methoxy-2-naphthyl) propyloenanthate 300 mg lidocaeine base 10 mg 5 benzyl alcohol 50 mg

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ethyl oleate (or olive oil F ^) to 3 cm

This composition according to the invention can be used to combat inflammation, pain, fever and skin at a dose of 300-1200mg / day.

8002737

Claims (2)

1. Esters ran 2- (6-methoxy-2-NAF tyl) propanol met the Formule 1 van formuleblad, R -waarin been met alkylgroep 1-20 koolstofatomen voorstelt. 2. 2- and 6-meth, y-2-naftyl) propyloenanthaat. 5 3. Geneesmiddel met ontstekingsverende, antireumatische, analge- tische en antipyretische activiteiten, met het kenmerk, dot net tenminste been verbinding volgens Conclusio 1 bevat. T h. Geneesmiddel volgens CONCLUSION 3, met daarin 2- (6-methoxy 2-naftyl) propyloenanthaat. 10 · 5 Werkwijze voor het van bereiden ester Van 2- (6-METHOXY- 2-naftyl) met propanol of Formula 1, met het kenmerk, gives men 2- (6-methoxy-2-naftyl) prapanol permite reageren met een verbinding met the formula 3, R vaarbij been met alkylgroep 1-20 koolstofatcmen 10 is en hydroxyl, Halogen of een alkoxycarbonyloxygroep, gevolgd door 15 isolatio van verbinding met the formule 1 shipped net reactiemengsei. 3002737 CH-900-100-A Xkj CH3 2 2 2 2 0 CH3O scheme a CH-R-CH9OH cox- * if AAJ CH3 CH3 ° Milan Farmaceutica s.r.l. 8002737