DK156562B - NAPHTHALENDER DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF PHARMACEUTICAL ACTIVE NAPHTHALENDER DERIVATIVES - Google Patents

Description

DK 156562 B

The present invention relates to novel naphthalene derivatives for use as intermediates in the preparation of pharmaceutically active naphthalene derivatives of the general formula ^^ X ^ / ^^ ch2-ch2-co-ch3

wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms, which derivatives are characterized in that they have the general formula IX

yv ^ CH = CH-CO-CH, ΧΧΎ 10 where X has the meaning given above.

Certain naphthalene derivatives are known to have valuable anti-inflammatory effects and to be suitable for use in the treatment of various rheumatic and arthritic conditions. A particularly effective naphthalene derivative which has found clinical use is naproxen (Naprosync®), which has the formula I

Γ3 I C02H 1 ch30

This compound and certain related compounds are disclosed in British Patent Nos. 1,271,132, 1,274,271, 1,274,272, 1,274,273, 1,291,386, 1,211,134, 1,297,306, 1,276,261, 1,216,882, 2

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1,289,041, 1,321,347 and 1,296,493. This pharmacological effect of such compounds is also described in J. Med. Chem., 13, 203 (1970) and J. Pharm. Exp. Thera., 179, 114 (1971).

Related compounds having anti-inflammatory effect are those compounds disclosed in Norwegian Patent Specification No. 125,971, compounds CH3 (wherein Z 2 is hydroxy or acetoxy, and Û- is CH 3 O, CH 3 or CH 3 S) and those described in Danish patent application no. 1861/70 described compounds yH3, jXT '(where Z represents methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoro-methoxy, methylthio, methoxymethylthio or difluoromethylthio).

Unfortunately, the compound of formula I can cause severe digestive tract irritation in some patients at doses that do not greatly exceed the therapeutic dose.

It has now been found that other naphthalene derivatives have good anti-inflammatory effect while also improving therapeutic conditions with respect to gastrointestinal irritation. Such compounds have the general formula II

CH2 'ch2' 00 'CH3

20 | T T II

3

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wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms.

In such compounds, X is especially a methoxy group.

A particularly preferred compound is 4- (6'-methoxy-2'-naphthyl) butane-2-one.

The compound mentioned has pronounced anti-inflammatory effect when tested at a dose of 100 mg / kg / day by the rat carrageenan anti-inflammatory test, but does not irritate the stomach at a three-fold dose.

4- (6'-methoxy-2 '-naphthyl) butan-2-one (A) has a more favorable therapeutic relationship (anti-inflammatory effect to gastric irritation) than naproxen. The anti-inflammatory effect (Π ^) was determined by graphical reading as a dose that caused 25% inhibition, while gastric irritation (GTD ^ q) was determined by that of Hitchens, JT et al., Pharmacologists, 9, 1969, p. 242, method indicated. The results are expressed as therapeutic relationship.

Naproxen A

GTD50 20 _ 1.95> 18.18 id25

By testing 4- (6'-methoxy-2'-naphthyl) butan-2-one (A) and 4- (6'-chloro-2'-naphthyl) butan-2-one (C) in a test with carageenin-induced edema (anti-inflammatory effect) and with gastric irritation in overnight fasted rats, the following results expressed as ED ^ q (mg / kg, perorite) and GTD ^ q (mg / kg, respectively) were obtained. , perorit), where the GTD ^ Q value was calculated by Litchfield and Wilcoxan's method. The results are compared to the 30 results obtained with naproxen.

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4

Anti-inflammatory Gastric irritation GTD, risk effect, tation, GTD

Compound EDcn EDcri

5U 5U

5 A 12.0 255 21.25 C 35.0 172 4.9

Naproxen 2.5 7.0 2.8

The above-mentioned compound (A) (Nabumetone) and the most similar aldehyde, 2- (6'-methoxy-2'-naphthyl) propanal, prepared according to the description of Danish patent application 1861/70, have been combined. similar to direct, partly for anti-inflammatory action against carrageenin-induced edema in rat paws and partly for gastric irritation.

In the carrageenin test, the rats were injected with 0.5% carrageenin in saline 15 into the right hind paw and the resulting edema was ground 3 hours later. Except for the control animals, the rats were administered the test compounds at various doses in 0.7% methylcellulose, as shown in the table below, indicating the induced edema and the irradiation induced by the test compounds.

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0dem induced by carrageenin 0dem ± s.e. % Inhibition A) Methyl cellulose 58.6 ± 2.7 B) Nabumetone 45 mg / kg 35.6 + 1.4 39 ** C) "15 mg / kg 42.8 ± 3.8 27 D)" 5 mg / kg 55.8 ± 2.2 5 irk-k 10 E) Aldehyde 18 mg / kg 32.7 + 2.7 44 *** F) 6 mg / kg 40.6 ± 2.9 31 G) "2 mg / kg 51.4 ± 2.9 12 (n = 8) **) p <0.01 *** *** p <0.001

Nabumetone = 16.6 mg / kg

Aldehyde = * 4.5 mg / kg

Strength ratio - 3.7

To assess the gastric irritation, the rats were starved for 18 hours for the test. The compounds were administered orally. Four hours later, the animals were killed and the stomach was washed with 0.9% saline and. tense out. Bleeding erosions in the mucosa were assessed on a scale whose skills were proportional to the eroded area. The quantities administered and the values measured are shown in the table below.

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Gastric irritation

Percentage of rats Average with gastric points for erosions erosion 5 _

Nabumetone 320 mg / kg 2/8 0.4 160 ”1/8 0.1 80 M 0/8 0

Aldehyde 80 "5/8 2.3 10" 40 "4/8 1.8" 20 "3/8 1.3

Methyl cellulose - 0/6 0

The above results show that the aldehyde in an amount of 20 15 mg / kg seems more irritating than Nabumetone in an amount of 320 mg / kg (strength ratio> 16).

It can be concluded from the two comparative experiments described above that Nabumetone has a clearly better therapeutic relationship than the nearest known compound.

The compounds of formula II are novel and the process for their preparation from the compounds of the invention assumes that compounds of general formula IX

CH = CH-CO-CH-

IX

X

where X has the meaning given above is reduced.

The reduction can be effected by hydrogenation in the presence of a transition metal catalyst such as palladium / coal. The reaction may be carried out at any suitable non-extreme temperature, but there

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7, room temperature is preferred. The reaction is usually carried out in an inert organic solvent such as ethyl acetate or ethanol using atmospheric pressure or a slight hydrogen overpressure.

Reduction with a complex metal hydride such as LÎA1H4 under usual reaction conditions for olefinic reduction of an α / β unsaturated ketone can also be used, but is sometimes less preferred as reduction of the carbonyl group can lead to undesired products.

Compounds of the invention of formula IX are important intermediates in the preparation of naphthalene derivatives of formula II.

Compounds of formula IX can be prepared by

(a) exchange of compounds of general formula XVII;

CHO

'S | ^ XVII

X

wherein X is as defined above, with a Wittig reagent of the general formula Q-CH-CO-CH 3 wherein Q represents a trisubstituted phosphorus atom, Such reactions usually taking place in an inert organic solvent; suitable groups Q which generally yield acceptable yields are (GβΗΗ) ΡΡ and (02115) 3?; these reactions may be unsatisfactory; or know

b) dehydrating compounds of general formula XVIII

. * CH (OH) -CH9-CO-CH

XVIII

,OUCH

where X has the meaning given above.

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The starting compound of formula XVIII is prepared by reacting a compound of formula XVII with acetone in the alkaline environment and the dehydration of the compound formed occurs spontaneously, for example under the influence of heat or a dehydration catalyst such as an acid, as illustrated by the following reaction scheme:

Il I Acetone Γ | J Me ° h „x \ Ay

H 2 O

10 Such transitions are very easy.

The preparation of compounds of the invention is illustrated in Examples 1 and 3-4 below, and the preparation of compounds of formula II from the compounds of the invention is illustrated in Example 2.

Example in 4- (6'-Methoxy-2'-naphthyl) -3-buten-2-one

In this process, a spontaneous dehydration of 4- (6'-methoxy-2'-naphthyl) -4-hydroxy-butan-2-one occurs, which is formed by reaction between the aldehyde and acetone, which can be illustrated by the following reaction scheme 9.

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/ VV010 OH n I il | acetone

30 g of 6-methoxy-2-naphthaldehyde are stirred in 500 ml of acetone with 10 ml of 10% aqueous sodium hydroxide solution for 3 hours. The solution is acidified and extracted with ether. The ether solution is triturated over magnesium sulfate and evaporated to reduced uride to give 30 g of a solid. This crude material is purified on a silica gel gel using benzene as the eluent to give 15 g of 4- (6'-methoxy-2'-naphthyl) -3-buten-2-one having a melting point of 120 ° G.

EXAMPLE 2 4- (6'-Methoxy-2'-naphthyl) butan-2-one 32 g of 4- (6'-methoxy-2'-naphthyl) -3-buten-2-one in 500 ml of ethyl acetate is shaken room temperature over 3 g of 10% palladium / carbon hydrogen at atmospheric pressure until no further hydrogen is taken up to give 22.5 g of 4- (6'-methoxy-2'-naphthyl) butan-2-one with melting point 78.5 ° C.

EXAMPLE 3 1.5 g of 6-methoxy-2-naphthaldehyde, 4 g of triphenylacetonylphosphine and 200 ml of tetrahydrofuran are refluxed for 120 hours. 100 ml of 5N HCl is added to the mixture followed by 200 ml of ethyl acetate. The organic phase is separated, the aqueous phase is extracted twice

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two 200 ml of ethyl acetate each time and the combined organic phases are washed with water, triturated over anhydrous sodium sulfate and evaporated to give a light brown solid.

The solid is chromatographed on a silica gel column using benzene as the eluent to give 400 mg of the aldehyde and 1.15 g of 4- (6'-methoxy-2'-naphthyl) but-3-ene. 2-one which after crystallization of petroleum ether (ball range 80-100eC) melts at 120 ° C.

Example 4 4- (6'-Methyl-2'-naphthyl) but-3-en-2-one

A mixture of 11 g of 6-methyl-2-naphthaldehyde, 160 ml of acetone and 5 ml of 10% aqueous sodium hydroxide is stirred overnight at room temperature.

The resulting solution is evaporated and then extracted with ether. The ether solution is triturated over sodium sulfate and evaporated under reduced pressure to give a pale yellow solid. This crude material is purified on an alumina seal using benzene as eluant to give 3.5 g of 4- (6'-methyl-2'-naphthyl) but-3-en-2-one, m.p. 128-129 ° C .

Pharmacological Data Using a conventional Allen-Doisy test, the estrogenic activity of a compound prepared from a compound of the invention is shown. The results are presented in Table I. The anti-inflammatory effect of the same compound is demonstrated using the standard rat paw carrageenin test. These results are also listed in Table I.

The results show that compounds prepared from compounds of the invention have a good level of activity at a dose where excessive estrogenicity should not be expected.

Claims (2)

Table I Compound Estrogenicity Anti-inflammatory Allan-Doisy test rat carrageenin 4- (6'-methoxy-2'-naph-200 mg / kg orally 50 mg / kg orally, 15 thyl) butan-2-one inactive (rat) slightly active 100 mg / kg orally, active 1 hour after dosing * 20. Aspirin (300 mg / kg) gives similar activity 2 hours after dosing. Naphthalene derivatives for use as intermediates in the preparation of pharmaceutically active naphthalene derivatives of the general formula: wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms, characterized in that they have the general formula IX ^ \ ^ y ^ ch - ch-co-ch3 ix 5 where X has the meaning given above. Naphthalene derivative according to claim 1, characterized in that it is 4- (6'-methoxy-2 '-naphthyl) but-3-en-2-one.