DK156642B - ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES - Google Patents

Description

DK 156642 B

The present invention relates to an analogous process for the preparation of novel naphthalene derivatives of the kind set forth in claim 1.

Certain naphthalene derivatives are known to have valuable anti-inflammatory action 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 (Napro-syn®), which has the formula I

COH 2 I

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, 1,289,041, 1,321,347 and 1,291,347. 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 with anti-inflammatory effect are the compounds described in Norwegian publication no. 125,971

CH .J

l 3 in Z1 2

Z

(where ί) - is hydroxy or acetoxy, and is CH 3 O, CH 3 or CH 3 S) and the compounds described in Danish Patent Application No. 1861/70 described in the description

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2 (where Z represents methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoro-methoxy, methylthio, methoxymethylthio or difluoromethylthio).

Unfortunately, the blending of the formula I can cause severe irritation in the alimentary canal 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 providing improved therapeutic conditions for gastrointestinal irritation. There are 10 such compounds having the general formula II

) rrrrr: CH-CO-CH3 | wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms, R 2 represents hydrogen or methyl, and the dotted union represents an additional bond or hydrogen on each of the 15 carbon atoms connected.

In such compounds, X is especially a methoxy group.

In such compounds, R 6 is suitably hydrogen.

Thus, particularly suitable compounds of formula II are those having the general formula III

(R1) -.-.---- CH- CO-CH,

20 1 ^ .1 Λ III

CH 3 (5 where R 1 and the dotted union have the meaning given in the formula II).

3

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From the foregoing it can be deduced that preferred groups of compounds which are within the general formula III are such that the general formulas IV and V have

.CH (R1) -CH2 -CO-CH, ΟΓΤ ch3o) = CH-CO-CH3

5 V

wherein Ro is hydrogen or methyl.

Compounds of formula II, where R · * · is not hydrogen, tend to have estrogenic effects at high doses, whereas those where R · * · is hydrogen are less likely to exhibit such effects. Preferred compounds are 4- (6'-methoxy-2'-naphthyl) butan-2-one and 4- (6'-methoxy-2'-naphthyl) but-3-en-2-one.

The two compounds and analogs thereto, in which the α-carbon atom carries a methyl substituent, exhibit anti-inflammatory action when tested at a dose of 100 mg / kg / day by the rat carrageenan anti-inflammatory test, but do not irritate the stomach at a dose three times the size.

4- (6'-methoxy-2'-naphthyl) butan-2-one (A) and 4- (6'-methoxy-2'-naphthyl) but-3-en-2-one (B) have a more favorable therapeutic ratio (antiinflammatory action against gastric irritation) than naproxen. The anti-inflammatory effect (ΠΠ) was determined by graphical reading as a dose that caused 25% inhibition, while gastric irritation (GTD, ^ ^) was determined by that of Hitchens, JT et al., Pharmacologists, 9, 1969 , page 242, method indicated. The results are expressed as therapeutic relationship.

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... ___ 4_______

Naproxen A B

GTD50 _ 1.95> 18.18> 23.4 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 carrageenin-induced breath (anti-inflammatory effect) and with gastric irritation 10 in rats who had fasted overnight, the following results expressed as respectively (mg / kg, perorhea) and GTD ^ q (mg / kg, perorhea) were obtained. , where the GTD ^ Q value was calculated by Litchfield and Wilcoxan's method. The results are compared with the results obtained with naproxen.

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

Compound ED ^ q ED₂ q A 12.0 255 21.25 20 C 35.0 172 4.9

Naproxen 2.5 7.0 2.8

The above-mentioned compound (A) (Nabumetone) and the closely related aldehyde, 2- (6'-methoxy-2'-naphthyl) propanai, have been compared directly, partly for anti-inflammatory action against carrageenin-induced breath. on rat paws and partly for gastric irritation.

At the carrageenin test, the rats were injected with 0.5% carrageenin in saline in the hind paw, and the resulting breath was measured 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 breath and the irradiation induced by the test compounds.

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5 0em 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 *** 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 15 ***) p <0.001

Nabumetone = 16.0 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 stretched out. Bleeding erosions in the mucosa were assessed on a scale 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 erosion 5 erosions

Nabumetone 320 mg / kg 2/8 0.4 "160" 1/8 0.1 "80" 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

It is clear from the above results that the aldehyde in an amount of 20 mg / kg seems more irritating than Nabumetone in an amount of 320 15 mg / kg (potency 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 Formulas II-V may be formulated for anti-inflammatory and / or analgesic preparations suitable for oral administration to humans. Such preparations may be in any conventional form, for example as tablets or capsules.

The compounds of formula II are novel and the process for their preparation is characterized in that:

(A) compounds of general formula VI

OUCH

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7

Union has the meaning given above, is reacted with a methyl metal derivative of the general formula VII

CH3-Y2 VII

where Y2 is a metal, or with LiCu ((^ 3) 2, or

B) for the preparation of compounds of formula II where the double bond is absent and where R - * - is hydrogen, compounds of general formula IX

/ CH = CH-CO-CH3 / OC · X ^

where X has the meaning given above, or c) compounds of the general formula X are reduced

/ CR I 3

Π Π CO „H

AJU

wherein X, R 2 and the dotted union have the meaning given above, or a site thereof is decarboxylated, or

d) for the preparation of compounds of formula II where the double bond is absent, compounds of general formula XIII

1 3

^ CHR-Y

! </ Νγ XIII

X

where Y3 represents a replaceable unit, especially chlorine, bromine or iodine, and X and r! has the above meaning, reacted with an anion derived from acetylacetone, or

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8

e) compounds of general formula XV

wherein X, R 2 and the dotted line have the meaning set forth above, oxidized, or

F) for the preparation of compounds of formula II wherein X represents OCH3, compounds of general formula XVI

/ CR] -Rrr: CH-CO-CH., 3 xvi where R R and the dotted line have the meaning given above, are methylated, or 10 g) to prepare compounds of formula II wherein

the bond occurs and R 1 is hydrogen, compounds of general formula XVII

wherein X is as defined above, is reacted with a Wittig reagent of the formula Q = CH-CO-CH 3 wherein Q represents a trisubstituted phosphorus atom, or

h) for the preparation of compounds of formula II wherein the double bond occurs and R R is hydrogen, compounds of general formula XVIII

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9 CH (OH) -CH2-CO-CH3 XVI11 where X has the meaning given above is dehydrated.

With regard to progress variant (a):

The usual and preferred compound of formula VII is methyl-lithium, LiCHg.

As is common in chain extension reactions using alkyl metal derivatives, the reaction is preferably carried out in an inert, aprotic solvent at low temperature and preferably under an inert atmosphere. For example, the reaction may be carried out at a temperature of 10 below 40 ° C in diethyl ether.

Normally, cuprous iodide is added to the reaction mixture so that the alkylating agent in question is LiCu (CH3) 2 ·

With regard to method variant (b):

The reduction can be carried out 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 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 overpressure of hydrogen.

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

With respect to process variant c): Decarboxylation can be carried out in the usual way for β-keto acids, for example by heating, optionally in an acidic environment.

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10

Acids of formula X are novel and can be freely added by hydrolysis of their ethyl esters, which in turn can be prepared by reacting the compound of formula XIX

CH3.C0.CHNa.C02Et XIX

5 having compounds of general formula XIII

1 3

.. .CHR-Y

J XIII

wherein Y3 represents a replaceable purity and X and bA are as defined above or with compounds of general formula XX

R1

XX

X

10 where X and R 2 are as defined above, followed by dehydration. Such turnover takes place under usual conditions.

With regard to method variant d):

The formation of an anion derived from acetylacetone can take place prior to the introduction of compounds of formula XIII or in situ.

The reaction is usually carried out in an aprotic solvent such as ethyl acetate. All non-extreme temperatures can be used, but generally room temperature or preheated temperature is preferred, for example temperatures between 20 and 120 ° C. Turnover can take a long time to complete 20. If the anion is depleted in situ, at least one equivalent of a non-nucleophilic base must be present, e.g., sodium hydride, sodium carbonate or potassium carbonate.

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11

With regard to method variant (e):

In general, any usual mild oxidative method known to oxidize secondary alcohols to form ketones can be used. Such reactions are carried out under usual conditions.

5 With respect to method variant f):

Reaction of compounds of formula XVI with methylating agents is preferably carried out under usual conditions. Suitable methylating agents are, for example, methyl bromide, methyl iodide, dimethyl sulfate, methyl methanesulfonate, methyl p-toluenesulfonate and diazomethane. Except for reaction with diazomethane, the compound of formula XVI is preferably in the form of the anion or at least one equivalent of a non-nucleophilic base is present. Such reactions can generally take place under conditions whereby phenol is converted to anisole.

With respect to process variant (g): 15 Such reactions usually take place in an inert organic solvent. Suitable groups Q, which generally provide acceptable yields, are (Cgl 3 P, (0113) 3? And (02115) 3 ?. These reactions may be unsatisfactory.

With respect to process variant h): The starting compound of formula XVIII can be prepared by reacting a compound of formula XVII with acetone in 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. Such turnovers are very easy.

The process of the invention is illustrated in more detail by the following examples, the preparation of some starting materials being described in Examples 1-4.

Ethyl 3- (6'-methoxy-2'-naphthyl) -2-bututenate EXAMPLE 1

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10.8 g of sodium hydride (60% dispersion in mineral oil) is washed three times with cyclohexane and inflated with a nitrogen stream. 150 ml of tort 5 1,2-dimethoxyethane are added and the slurry is stirred at room temperature. 54 g of triethylphosphonoacetate are added dropwise and the mixture is stirred at room temperature for 1 hour under a nitrogen atmosphere. A solution of 30 g of 2-acetyl-6-methoxynaphthalene in 300 ml of 1,2-dimethoxyethane is added to the lobe and the solution is refluxed overnight under a nitrogen atmosphere.

The reaction mixture is diluted with water, acidified and extracted with ether. The ether phase is washed with sodium carbonate solution and with water, triturated over anhydrous magnesium sulfate and evaporated to give ethyl 3- (6'-methoxy-2'-naphthyl) -2-butenoate in the form of a yellow solid in quantitative yield. The product is shown by NMR spectrometry to be predominantly the trans isomer.

NMR Spectrum: Trans-vinylic proton 3.69r, cis-vinylic proton 4.0r.

-CO2CH2GH3: Triplet (3 protons) at 8.62r, 20 J = 11.5 cps.

quart (2 protons) at 5.71τ, J = 11.5 cps.

-CH3: Two peaks very close to each other at -7.28r, corresponding to ait 3 protons.

IR Spectrum: Garbonyl absorption at 1708 cm -1.

EXAMPLE 2

Ethyl 3- (6'-methoxy-2'-naphthyl) butyrate 24 g of ethyl 3- (6'-methoxy-2'-naphthyl) -2-butenoate is taken up in 100 ml of ethyl acetate and 2 is added. 4 g of 10% palladium / coal. The mixture is hydrogenated at room temperature and a pressure of 3.5 kg / cm 2 for two hours.

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The catalyst is removed by filtration and the filtrate is evaporated to give ethyl 3- (6'-methoxy-2'-naphthyl) butyrate in the form of a colorless solid in quantitative yield.

IR Spectrum: Saturated ester carbonyl absorption at 1730 cm "·.

5 NMR Spectrum: CH3-CH: 3 proton doubled at 8.68r, J = 11 cps.

Absence of vinylic protons.

EXAMPLE 3 3- (6'-Methoxy-2'-naphthyl) butyrate 14.4 g of ethyl 3- (6'-methoxy-2'-naphthyl) butyrate is taken up in 300 ml of methanol and 150 ml of 10% sodium hydroxide solution. , and the mixture is refluxed for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The aqueous phase is acidified and extracted with ethyl acetate. The acidic extract is washed with water, quenched over anhydrous magnesium sulfate and evaporated to give 11.9 g (92% of theory) of 3- (6'-methoxy-2'-naphthyl) formic acid as a white solid mp 126-129 ° C.

IR Spectrum: Carbonyl absorption at 1700 cnT

EXAMPLE 4 Trans-3- (6'-methoxy-2'-naphthyl) crotonic acid 27.4 g of ethyl trans-3- (6'-methoxy-2'-naphthyl) -2-butenoate are taken up in 600 ml of methanol and 300 ml of 10% sodium hydroxide solution and the mixture is refluxed for 2 hours. The sodium salt of the single acid product crystallizes and is filtered off. The filtrate 25 is extracted with ethyl acetate and the aqueous phase is separated.

- - - 14

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The sodium salt of the acid is suspended in the aqueous phase and the mixture is simmered. Ethyl acetate is added and the mixture is heated until the solid is dissolved. The ethyl acetate phase is separated, washed with water, triturated over anhydrous magnesium sulfate and evaporated to give 5 g of 20.7 g of a pale yellow solid. The product is recrystallized from ethyl acetate to give 15.9 g (67.8% of theory) of trans 3- (6'-methoxy-2'-naphthyl) crotonic acid in the form of a colorless solid, m.p. 195-204 °. C.

IR Spectrum (Nujol): Carbonyl absorption at 1680 cm

EXAMPLE 5 4- (6'-Hethoxy-2'-naphthyl) pentan-2-one 8.15 ml of thionyl chloride is added dropwise to a solution of 19.0 g of 3- (6'-methoxy-2'-naphthyl) butyric acid in 200 ml of tort benzene and boil gently under reflux overnight. The solvent is evaporated to give the crude acid chloride in the form of a brown oil.

Dilute 253 ml of methyl lithium (2.18M in ether) to 2 liters with ether, cool to 0 ° G and stir under a nitrogen atmosphere. 48.6 g of cuprous iodide are added and stirring is continued for 10 minutes. The mixture is cooled to -70 ° C and a solution of the crude acid chloride in 250 ml of ether is added. The mixture is stirred under nitrogen atmosphere at -70 ° C for 15 minutes. 350 ml of methanol are added to stop the reaction and the mixture is diluted with water and simmered. Diatomaceous earth is added as a filtration aid and the reaction mixture is filtered through a pad of diatomaceous earth. The ether phase is washed with sodium carbonate solution and water, triturated over anhydrous magnesium sulfate and evaporated to give a brown oil. The product is purified by short column chromatography to give 4- (6'-methoxy-2'-naphthyl) -pentan-2-one in the form of a pale yellow oil which slowly solidifies on standing. Yield 10.7 g, which corresponds to 57% of theory.

IR Spectrum: Carbonyl Absorption at 1705 cm -1

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NMR Spectrum: CH3 CO-: 3 proton singlet at 8.01τ · CH3-CH-: 3 proton doubled at 8.12r, J = 1 cps.

EXAMPLE 6 Trans-4- (6'-methoxy-2'-naphthyl) pent-3-en-2-one 8.15 ml of thionyl chloride is added dropwise to a solution of 14.0 g of trans-3- (6'- methoxy-2'-naphthyl) crotonic acid in 140 ml of tort benzene and the mixture is gently refluxed for 4 hours. The solvent is evaporated to give the crude acid chloride as a brown oil.

Dilute 173.3 ml of methyl lithium (2.1 M in ether) to 1200 ml with ter ether, cool to 0 ° C and stir under a nitrogen atmosphere. 34.75 g of cuprous iodide are added and stirring is continued for 10 minutes. The mixture is cooled to -70 ° C and a solution of the crude acid chloride in 150 ml of ether is allowed to pass. The mixture is stirred under nitrogen atmosphere at 70 ° C for 15 minutes. 150 ml of methanol are added to stop the reaction and the mixture is diluted with water and acidified. Diatomaceous earth is added to aid filtration and the reaction mixture is filtered through a pad of diatomaceous earth. The ether phase is washed with sodium carbonate solution and with water, triturated over anhydrous magnesium sulfate and evaporated to give a yellow solid. The product is purified by chromatography on a short column and by recrystallization of petroleum ether with a boiling range of 60-80 ° C, 11.5 g (82, ¾¾ of the theoretic) trans-4- (6'-methoxy-2 ') is obtained. -naphthyl) pent-3-ene-2-one in the form of a pale yellow solid, mp 98-101 ° C.

IR Spectrum (Nujol): Carbonyl absorption at 1680 cm.

NMR Spectrum: Vinyl proton singlet at 3.30 CH 3 CO-: 3 proton singlet at 7.30.

4- (6'-Methoxy-2'-naphthyl) -3-buen-2-one EXAMPLE 7 16

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In this process variant, spontaneous dehydration occurs, which can be illustrated by the following reaction scheme.

MeO MeO

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 under reduced pressure 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 ° C.

Example 8 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 under hydrogen at atmospheric pressure until no additional hydrogen is obtained to give 22.5 g of 4- (6'-methoxy-2'-naphthyl) butane-2 on melting point 78.5 ° C.

EXAMPLE 9 4- (6'-Methoxy-2'-naphthyl) butan-2-one 17

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A mixture of 0.1 mole of 6-methoxy-2-bromomethyl-naphthalene, 0.1 mole of acetylacetone and 0.1 mole of potassium carbonate in 125 ml of ethanol is boiled under reflux for 16 hours. The ethanol is evaporated under reduced pressure and the residue is shaken with 400 ml of water / ether mixture in a 1: 1 ratio. The ether phase is triturated over magnesium sulfate and evaporated in vacuo to give a clear oil which after purification gives 4- (6'-methoxy-2'-naphthyl) butan-2-one.

EXAMPLE 10 4- (6'-Methoxy-2'-naphthyl) butan-2-one 0.45 mole of 3-ethoxycarbonyl-4- (6'-methoxy-2'-naphthyl) butan-2-one in ethanol ( total volume (1200 ml) and 470 ml of 5N HCl are refluxed for 7 hours, after which thin layer chromatography shows complete reaction. The ethanol is evaporated under reduced pressure to give off a skin-colored solid. This is read in 1.0 liter of ethyl acetate and the aqueous acid phase is separated and washed with an additional 100 ml of ethyl acetate. The co-poured organic solutions are washed with saturated sodium hydrogen carbonate solution to pH 8 (800 ml in 20 several portions) and water and triturated over sodium sulfate.

Evaporation of the solvent under reduced pressure gives 103.6 g (101% of theoretical) light brown colored fat, solid which according to glc contains 70% of the title compound.

Crystallization of 588 ml of 80% ethanol / O with subsequent cooling 25 afforded 56.0 g (54.6% of theory) of cream-colored microcrystals of the title compound, mp 78.5-79.5 ° C with 96% purity according to glc.

Evaporation of the solvent and crystallization of the mark residue (46.6 g) of 70 ml of ethanol on cooling gives an additional 18

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9.2 g (9.0% of theory) crystals of the title compound, m.p. 78-79.50 ° C which, according to glc, have 94% ripeness.

The substance is crystallized again by 275 ml of ethanol upon cooling to give 55.9 g (54.5% of theory) of the title compound, m.p. 80.5-81 ° C, in the form of pale cream-colored microns, as a result glc has a purity of 97.7%. The NMR spectrum is consistent with the structure.

EXAMPLE 11

Preparation of 4- (6'-methoxy-2'-naphthyl) butan-2-one by oxidation of an alcohol 500 mg of 4- (6'-methoxy-2'-naphthyl) butan-2-ol in 100 ml of acetone oxidized using CrÛ3 in water / sulfuric acid (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, p. 142). The oxidizing agent is added dropwise until the orange color disappears. At 15 thin layer chromatography (silica gel plates / toluene), the reaction is shown to be complete. By filtration of the solution, evaporation of the solvent and crystallization of the residue of ethanol / water, 330 mg of 4- (6'-methoxy-2'-naphthyl) butan-2-one were obtained, m.p. 79 ° C.

Example 12 Preparation of 4- (6'-methoxy-2'-naphthyl) butan-2-one by methylation of a naphthol 4.35 g of 4- (6'-hydroxy-2'-naphthyl) butan-2-one Boil under reflux in 100 ml of methanol and 30 ml of concentrated sulfuric acid for 3 hours.

The mixture is poured into 500 ml of water and filtered to give 3.7 g of a light brown solid, mp 65 ° C. This is recrystallized from ethanol / water to give 2.15 g of 4- (6'-methoxy-2'-naphthyl) butan-2-one, m.p. 75.5 ° C.

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EXAMPLE 13 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 with 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 (boiling range 8O-10O ° C) melts at 120 ° C.

EXAMPLE 14 4- (6'-Chloro-2'-naphthyl) pentan-2-one 8.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid is boiled under reflux overnight in 250 ml of tort toluene containing 4.0 ml of thionyl chloride.

The toluene is evaporated to give 7.7 g of crude acid chloride in the form of a brown oil.

Reaction of the acid chloride with methyl lithium / cup iodide: under the conditions described in Example 5 followed by recrystallization of ether / pentane gives 2.0 g of pure 4- (6'-chloro-2 '-naphthyl) pententan-2-one, m.p. -54 ° C.

% NMR spectrum (CDCl3): δ = 7.9-7.15 (m, 6H); 3.36 (m, ΊΗ); 2.66 (d, 25 - J = 6Hz, 1H), 2.64 (d, J = 8Hz, 1H); 1.95 (s, 3H) and 2.29 (id, J = 7Hz, 3H).

The starting material is prepared as follows: 43.2 g of triethyl phosphonoacetate are added at room temperature over 1

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20 hours to a suspension of 6.48 g of sodium hydride in tort dimethoxyethane under nitrogen atmosphere and stir for an additional 1 hour.

24.1 g of 2-acetyl-6-chloro-naphthalene in 200 ml of tort dimethoxyethane are added and the reaction mixture is refluxed overnight. The mixture is diluted with 500 ml of water, sieved with 5N hydrochloric acid and extracted with ether. The ethereal extracts are washed with 1 N sodium carbonate solution, triturated with sodium sulfate and evaporated. The crude ester is chromatographed on silica using chloroform as eluant to give 16.54 g of 3- (6'-chloro-2'-naphthyl) but-2-enoic acid ethyl ester.

16.54 g of this ester is hydrogenated in ethyl acetate using 3.00 g of 10% palladium / carbon as catalyst to give 16.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid ethyl ester .

16.0 g of this saturated ester is hydrolyzed by boiling under reflux overnight in 300 ml of methanol containing 4.00 g of sodium hydroxide and 10 ml of water. The reaction mixture is diluted with water and extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic extract is triturated over sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gives 10.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid, mp 109-110 ° C.

Example 15 4- (6'-Methyl-2'-naphthyl) butan-2-one

A mixture of 78 g of 2-bromomethyl-6-methylnaphthalene, 15 g of acetyl-25 acetone and 21 g of potassium carbonate in 500 ml of ethanol is refluxed for 48 hours. The mixture is allowed to cool and filtered, and the solvent is removed by evaporation on a rotary evaporator. To the material obtained is added 500 ml of ether and 200 ml of water. After shaking, the ether phase is separated and the solvent removed on 30 rotary evaporators. The resulting crude oil is chromatographed on alumina using petroleum ether (boiling range 40-

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21 to 60 ° C) to give 10 g of pure 4- (6'-methyl-2'-naphthyl) butan-2-one, m.p. 55-57 ° C.

The intermediate is prepared by reacting 38 g of bromine and 82 g of 2,6-dimethyl naphthalene over a period of 3 hours in a refluxing 5 boiling solution in 200 ml of carbon tetrachloride containing some iodine crystals.

Example 16 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 10¾ 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 column using benzene 15 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 certain compounds prepared by the method of the invention is shown. The results are given in Table I. The anti-inflammatory effect of certain compounds is demonstrated using the standard rat paw carrageenin test. These results are also listed in Table I.

The results show that the compounds prepared according to the invention have a good level of activity at a dose where excessive estrogenicity should not be expected. It is further believed that the lack of branching at the α-carbon atom greatly reduces any possible estrogenicity, while not having any significant effect on the anti-inflammatory action of the compounds.

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Furthermore, it has been found that 6'-methoxy compounds of formula II do not particularly irritate the rat stomach at a dose of 300 mg / kg / day taken orally after 3 days while after 1 1/2 days oral treatment with the known compound naproxen can be observed severe gastric irritation at the same dose level.

By that of Meier, R.K. et al., Experimentia. 6, 1950, p. 469, described in Example 15 the cotton pellet granuloma test for anti-inflammatory action was found to be effective at a dose of 50 mg / kg per day / day administered from day 0 to day 5 and at the same dose neither be gastric irritant or estrogenic.

In the cotton pellet granuloma test, the compound prepared according to Example 14 was found to be anti-inflammatory at a dose of 10 mg / kg of perorheate, and in the same test, the compound prepared according to Example 8 was effective at a dose of 20 mg / kg of perorhea .

Claims (6)

An analogous process for the preparation of naphthalene compounds of general formula II) -rm CH-CO-CH3 x4XJ wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms, pA represents hydrogen or methyl, and the dotted line denotes an additional bond or hydrogen on each of the two bonded carbon atoms, characterized in that A) compounds of the general formula VI '* CH-CO-Y1 XXj wherein Y 2 represents bromine, chlorine or iodine, and X, rA and the dotted union bear the above meaning, are reacted with a methyl compound. 5 is a derivative of the general formula VII CH3-Y2 VII wherein Y2 is a metal, or with LiCu (CH3) 2, or b) for the preparation of compounds of formula II where the double bond is absent and R 1 is hydrogen; compounds of the general formula IX .. CH = CH-CO-CH 3 ^ 111 x where X has the meaning given above are reduced, or c) compounds of the general formula X _ rpî ·. "TTTC-CO-ChL èo2H wherein X, R - * - and the dotted union are as defined above, or a site thereof is decarboxylated, or d) for the preparation of compounds of formula II where the double bond does not occur , compounds of the general formula XIII DK-YY XIII x wherein Y bet represents a replaceable moiety, especially chlorine, bromine or iodine, and X and bA have the meaning given above, are reacted with an anion derived from acetylacetone, or e) compounds of general formula XV | XV X wherein X, rA and the dotted line have the meaning set forth above, are oxidized, or f) to produce compounds of formula II wherein X represents 10 OCH 3, compounds of the general formula XVI / CfO. TrrrtCH-GO-CH- / yv XVI wherein bA and the dotted union have the meaning set forth above, are methylated, or g) to prepare compounds of formula II wherein the double bond occurs , and rA is hydrogen, compounds of the general formula XVII DK 156642 B CH0 XVII where X has the meaning given above is reacted with a Wittig reagent of formula q = ch-co-ch3 where Q represents a trisubstituted phosphorus atom, or h) for free-setting compounds of formula II where double The bond occurs and kA is hydrogen, compounds of the general formula XVIII CH1OH) -ch2-co-ch3 XVIII where X has the meaning given above are dehydrated. Process according to claim 1, characterized in that compounds of the general formula III (R) (R1) ____ are prepared; * -rCH-CO-CH-, III where R 1 and the dotted line have the meaning given in the formula II in claim 1. DK 156642 B A process according to claim 1, characterized in that compounds of formula II are prepared, wherein R R represents hydrogen. Process according to claims 3, 5, characterized in that 4- (6'-methoxy-2'-naphthyl) butan-2-one is prepared. Process according to claim 4, characterized in that the compound obtained is isolated as a solid. Process according to claim 5, characterized in that the compound obtained is isolated as a solid with a melting point of 78.5 ° C.