FR2731704A1 - Tetra:hydro naphthalene derivs. having 5-lipoxygenase inhibiting activity - Google Patents

Abstract

Tetrahydro-naphthalene derivs of formula (I) and their optical isomers and mixtures are new. R1 = (CH2)nAr; n = 0-4; Ar = phenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, quinolyl, isoquinolyl, 2-oxo1Hquinolyl, indolyl, isoindolyl, benzofuryl or benzothienyl, all opt. substd; and either A: R2 = OH or opt. substd. alkoxy; R3 = H or opt. substd. alkyl; or R2+R3 = O-CO- or O-CH2-, and so complete a ring; R4, R5 = H; or opt. substd. alkyl, alkenyl, aralkyl, or heteroaryl-alkyl; and R6, R7 = H; or B: R2+R3 = CH2-CH2-, and so complete a ring; R4 = H, OH, or opt. substd. alkoxy; R5 = H; or opt. substd. alkyl, alkenyl, aralkyl, or heteroaryl-alkyl; or R4+R5 = an oxo group; R6, R7 = H; or opt. substd. alkyl, alkenyl, aralkyl, or heteroaryl-alkyl; with the provisos that: optional substituents are selected from halo, OH, alkyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxy, alkoxycarbonyl, acyl, cyano, alkylthio, and CF3; optional substituents on Ar may further be tetrahydropyranyl, alkoxy-tetrahydropyranyl, and morpholinyl; alkyl, alkoxy, acyl, alkenyl = up to 6C; the aryl portion of aralkyl is phenyl or naphthyl; and heteroaryl is pyridyl, quinolyl, isoquinolyl, indolyl, and isoindolyl.

Description

The present invention relates to new tetrahydronaphthalene derivatives, inhibitors of the 5-lipoxygenase (5-LO) enzyme, their preparation process and the pharmaceutical compositions which contain them.

5-lipoxygenase is the enzyme of the first stage of the metabolism of arachidonic acid leading to the synthesis of leukotrienes. This first step results in the synthesis of 5-hydroxyperoxy-eicosatétraénOique (5 (S) -HPETE) which is converted into unstable epoxide, leukotriene A4. This is converted, by enzymatic hydrogenation, to leukotriene B4, or, by conjugation to glutathione, to leukotriene C4. The latter leads, by successive proteolytic cleavages, to the formation of leukotrienes D4 and E4. (B. Samuelsson and C.D.

Funk, The Journal of Biochemistry, 264 (33), (1989), 19469-19472).

The aforementioned leukotrienes are powerfully pro-inflammatory and spasmogenic lipid substances which play an important role in the pathophysiology of various diseases.

Indeed, changes in the metabolism of leukotrienes have been reported in various pathologies such as asthma, allergic rhinitis, rheumatoid arthritis, psoriasis, acute respiratory distress syndrome in adults, inflammatory bowel diseases,
Atherosclerosis, myocardial ischemia and endotoxin shock. (SD Brain and TJ

Williams, Phannac. Ther., 46, (1990), 57-66; A.W. Ford-Hutchinson, Crit. Rev. Immunol., 10, (1990), 1-12; R.A. Lewis et al., The New England Journal of Medicine, 323 (10), (1990), 645-665; K.P. Hui and N.C. Barnes, Pulmona Phamiacology, 6, (1993), 3-9).

The literature describes 5-LO inhibitors, in particular in patents EP-A-581464 and US
A-5,268,379.

The Applicant has now discovered new 5-LO inhibitors having an original structure characterized by the presence of a tetrahydronaphthalene nucleus, and which are more active, more powerful and better tolerated than those described in the prior art.

dans laquelle
R1 représente le groupement -(CH2)n-Ar, dans lequel n est choisi parmi 0, l, 2, 3 et 4 et
Ar est choisi parmi les radicaux phényle, naphtyle, thiényle, furyle, pyrrolyle, imidazolyle,
pyrrazolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, thiadazolyle, oxadiazolyle,
pyridyle, quinolyle, isoquinolyle, 2-oxo[lHlquinolyle, indolyle, isoindolyle, benzofuryle et
benzothiényle, chacun de ces radicaux pouvant être éventuellement substitué, et soit:
A.More particularly, the subject of the present invention is the compounds of general formula (I):

in which
R1 represents the group - (CH2) n-Ar, in which n is chosen from 0, 1, 2, 3 and 4 and
Ar is chosen from phenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl,
pyrrazolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, thiadazolyle, oxadiazolyle,
pyridyle, quinolyle, isoquinolyle, 2-oxo [1Hlquinolyle, indolyle, isoindolyle, benzofuryle and
benzothienyl, each of these radicals possibly being substituted, and either:
AT.

R2 is chosen from the hydroxyl radical and an alkoxy radical, optionally substituted,
R3 is chosen from hydrogen and an optionally substituted alkyl radical,
or
R2 and R3 together form a cycle with the respective carbon atoms which carry them
and with a bivalent radical chosen from -O-CO- and -O-CH2-, and
R4 and Rg, independently of one another, are chosen from hydrogen, an alkyl radical
optionally substituted, an akenyl radical, optionally substituted, an arall :: yl radical,
optionally substituted and an optionally substituted heteroarylalkyl radical, and
R6 and R7 each represent hydrogen, or:
B.

R2 and R3 together form a cycle with the respective carbon atoms which carry them
and with the bivalent radical -CH2-CH2-, and
R4 is chosen from hydrogen, the hydroxy group and an alkoxy radical,
possibly substituted,
R5 is chosen from hydrogen, an optionally substituted alkyl radical, a radical
alkenyl, optionally substituted, an arall ::: yl radical, optionally substituted, and a
optionally substituted heteroarylalkyl radical,
or
R4 and R5 together form an oxo group carried by the carbon atom to which R4 and
R5 are connected, and
R6 and R7, independently of one another, are chosen from hydrogen, a radical
alkyl, optionally substituted, an akenyl radical, optionally substituted, a radical
aralkyl, optionally substituted, and a heteroarylalkyl radical, optionally substituted, as well as their optical isomers in pure form or as a mixture, it being understood that:
- the term "possibly substituted" means that the radicals thus qualified
may be substituted by one or more groups or radicals chosen from
halogen, hydroxy, aikyle, alkoxy, amino, alkylamino, dialkylamino, nitro,
carboxy, alkoxycarbonyl, acyl, cyano, alkylthio and trifluoromethyl,
- in addition to the possible substituents listed above, the radical Ar defined in R1
may also be substituted by a radical chosen from tetrahydropyranyl,
alkoxytetrahydropyranyl and morpholinyl,
- the terms "alkyl", "alkoxy", "alkylamino", "dialkylamino", "aralkyle",
"heteroarylalkyl", "alkoxycarbonyl", "alkylthio" and "acyl" refer to
radicals with the saturated hydrocarbon chain, optionally substituted,
contains from 1 to 6 carbon atoms in a straight or branched chain,
- the term "alkenyl" denotes an optionally substituted radical containing 2
with 6 carbon atoms in a straight or branched chain, and one or more
unsaturations in the form of double bonds,
the term "aralkyl" denotes a radical, the aromatic part of which, optionally
substituted, is chosen from phenyl and naphthyl radicals,
- and that the term "heteroarylalkyl" denotes a radical, the part of which
optionally substituted heterocyclic, is chosen from pyridyl radicals,
quinolyle, isoquinolyle, indolyle et isoindolyle.

à une déméthylation, par exemple à l'aide d'acide bromhydrique, afin d'obtenir le composé de formule (III):

qui, soumis à l'action d'un halogénure de formule (mA) R1-X (VIA)
dans laquelle R1 est tel que défini pour les composés de formule (I) et X
représente un atome d'halogène, conduit au composé de formule (IVA):

The present invention also extends to the process for the preparation of the compounds of formula (I) characterized in that the methoxy-3,4-dihydro [2H] naphthalen-l-one of formula (II) is subjected:

demethylation, for example using hydrobromic acid, in order to obtain the compound of formula (III):

which, subjected to the action of a halide of formula (mA) R1-X (VIA)
in which R1 is as defined for the compounds of formula (I) and X
represents a halogen atom, resulting in the compound of formula (IVA):

dans laquelle R1 et R'8 sont tels que définis précédemment, puis éventuellement soumis, dans les mêmes conditions, à l'action d'un halogénure de formule (V')
R'9-X (V')
dans laquelle X représente un atome d'halogène et R'g est choisi parmi
un radical alkyle, alkényle, aralkyle et hétéroarylalkyle, chacun étant
éventuellement substitué, de façon à obtenir le composé de formule (IVC)::

in which R1 is as defined above, it can be subjected to the action of a halide of formula (V)::
R'8-X (V)
in which X represents a halogen atom and R'8 is chosen from
an aikyl, alkenyl, aralkyl and heteroarylalkyl radical, each being
optionally substituted, in the presence of a strong base, potassium hydride for example, in order to yield the compound of formula (IVB):

in which R1 and R'8 are as defined above, then optionally subjected, under the same conditions, to the action of a halide of formula (V ')
R'9-X (V ')
in which X represents a halogen atom and R'g is chosen from
an alkyl, alkenyl, aralkyl and heteroarylalkyl radical, each being
optionally substituted, so as to obtain the compound of formula (IVC):

in which R1, R'8 and R'g are as defined above,
All of the compounds of formulas (IVA), (reg) and (IVC) forming all of the compounds of formula (1V)

in which R1 is as defined above, R8 is chosen from
hydrogen and R'g, and Rg is chosen from hydrogen and R'g, which, subjected to the action of allylmagnesium bromide, lead after ozonolysis to the compound of formula (VIA):

in which R1, R8 and Rg are as defined above, possibly being mono- or di-etherified, depending on the operating conditions, as a compound of formula (VIB):

in which R1, R8 and Rg are as defined above, R'2
represents an optionally substituted alkoxy radical and R'3 represents
an alkyl radical optionally substituted, or else subjected to the action of phosgene or dibromomethane in order to obtain the compounds of formula (VIC) and (VID) respectively

in which R1, R8 and Rg are as defined above, the compound of formula (IVA) can also be reduced then dehydrated so as to obtain the compound of formula (V1I):

in which R1 is as defined above, then oxidized, by osmium tetroxide for example, and again dehydrated to obtain the compound of formula (VIII):

in which R1 is as defined above, which subjected to the action of an alkylating agent, such as diiododiethylether, in the presence of a strong base, sodium hydride for example, as an appropriate solvent, such as tetrahydrofuran , leads to the compound of formula (VIE1):

in which R1 is as defined above, it being able to be subjected to the action of an alkylating agent of formula (IX):
R'6-X (IX)
in which X represents a halogen and R'6 has the same meaning
that R'8 in formula (V) above defined, so as to obtain the compound of formula (VIE2)

in which R1 and R'6 are as defined above, which can also be subjected to a second alkylation with a compound of formula (X):
R'7-X (X)
in which X represents a halogen and R'7 has the same meaning
as R'8 in the formula (V) above defined, so as to obtain the compound of formula (VIE3):

in which R1, R'6 and R'7 are as defined above, the set of compounds of formulas (VIE1), (VIE2) and (VIE3) forming the set of compounds of formula (VIE):

in which R1 is as defined above, R6 is chosen from
hydrogen and R'6 and R7 is chosen from hydrogen and R'7, compounds of formula (VIE) which can be subjected to the compound of formula (XI): R's-Mg-X (M)
in which X represents a halogen and R'5 has the same meaning
as R'8 in the formula (V) defined above, to obtain the compound of formula (VIF)

dans laquelle R1, R'4, R'5, R6 et R7 sont tels que définis précédemment, le composé de formule (VIE) pouvant également être réduit simplement en alcool selon des techniques classiques de réduction, puis éventuellement éthérifié, de façon à obtenir les composés de formules respectives (VIH) et (VIT) :

in which R1, R's, R6 and R7 are as defined above, the alcohol function of which can be etherified, according to conventional methods, by means of a halide of formula (XII):
R'4-X (XII)
in which X represents a halogen and R'4 represents a radical
optionally substituted alkyl, so as to obtain the compound of formula (VIG):

in which R1, R'4, R'5, R6 and R7 are as defined above, the compound of formula (VIE) can also be reduced simply to alcohol according to conventional reduction techniques, then optionally etherified, so as to obtain the compounds of respective formulas (HIV) and (VIT):

in which R1, R'4, R6 and R7 are as defined above,
All of the compounds of formulas (VIA) to (VII) forming all of the compounds of formula (I) which are optionally purified according to a conventional purification technique, and from which the isomers are separated, if desired optics according to a conventional separation technique.

The compounds of formula (I) for which the group R1 represents a radical which can be degraded during the various stages of synthesis listed above, can advantageously be obtained from the compound of formula (IX):

wherein R2, R3, R4, Rg, R6, and R7 are as defined
previously, which, subjected to de-O-alkylation, using for example palladium on carbon, leads to the compound of formula (X):

cas particulier des composés de formule (I) dans laquelle R'1 est tel que défini pour R1, le radical naphtylméthyle excepté.wherein R2, R3, R4, Rg, R6, and R7 are as defined
previously, then again O-alkylated, in order to obtain the compounds of formula (I '):

special case of the compounds of formula (I) in which R'1 is as defined for R1, the naphthylmethyl radical excepted.

The compounds of formula (I) have quite interesting pharmacological properties. Indeed, these compounds are powerful inhibitors of 5-lipoxygenase (5-LO).

The inhibition of 5-LO, the first step leading to the synthesis of leukotrienes, constitutes a very relevant therapeutic approach aimed at limiting the effects of these proinflammatory lipids, which are leukotrienes. The compounds of the invention having an inhibitory activity of 5-LO are therefore useful in the treatment of diseases in which the role of leukotrienes is recognized.

Thus, the compounds according to the invention find a therapeutic application in the prevention and treatment of pulmonary pathologies, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult acute respiratory distress syndrome, in the prevention and treatment of ENT, ophthalmological or cutaneous manifestations, inflammatory intestinal or systemic diseases such as arthritis, in particular rheumatoid arthritis, cardiovascular pathologies such as atherosclerosis, myocardial ischemia, endotoxin shock, as well as in the prevention and treatment of dermatological pathologies such as eczema and psoriasis.

The present invention also relates to pharmaceutical compositions containing the compounds of formula (I) or their possible optical isomers, alone or in combination with one or more inert and non-toxic excipients or vehicles.

Among the pharmaceutical compositions according to the invention, particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perlingual, transdermal, ocular or respiratory administration, and in particular simple or coated tablets, sublingual tablets, capsules, suppositories, creams, ointments, dermal gels, patches, injectable or drinkable preparations, aerosols, eye or nasal drops.

The useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges from 0.001 mg to 25 mg per kg of body weight intravenously. and between 0.01 mg and 100 mg per kg of body weight orally, and in one or more daily administrations.

The following examples illustrate the invention without, however, limiting it in any way. The starting materials are known or prepared from known procedures.

Example 1: 1- (2-Hydroxy-ethyl). 7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro-
naphthalen-1-ol
Step A: 7-hydroxy-3,4-dihydro [2! Fnnaphthalen-1 -one 32.00 g (182 mmol) of 7-methoxy-3,4-dihydro [2H] naphthalen-l-one are dissolved in 400 ml of a 48% aqueous hydrobromic acid solution. The whole is placed under stirring for 20 minutes at reflux and then cooled before the addition of 400 ml of a saturated solution of sodium chloride. The reaction mixture is diluted with ethyl acetate (600 ml) and the aqueous phase is reextracted twice with ethyl acetate. After concentrating the organic phase to approximately 200 ml, the expected product precipitates and 26.60 g (164 mmol) are isolated after filtration.

Efficiency: 90%
Step B: 7- (naphthalen-2-ylmethoxy) -3,4-dihydro [2H] naphthalen- 1 -one 13.00 g (80 mmol) of the compound obtained in Step A, 21.27 g (96 mmol ) of bromomethyl-2naphthalene and 27.64 g (200 mmol) of potassium carbonate and then 390 ml of anhydrous dimethylformamide are introduced into a flask under a nitrogen atmosphere. After 60 hours at room temperature with stirring, the precipitate obtained is filtered. The filtrate is evaporated in vacuo and the residual oil is taken up in dichloromethane. After usual treatment of the organic phase and purification of the product by chromatography on silica gel (eluent: dichloromethane / pentane, 1: 1), 19.10 g (63 mmol) of the expected compound are obtained.

Efficiency: 79%
Step C: 1 -allyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalen-1 -ol
To a solution of 10.40 g (34 mmol) of the compound obtained in Step B in 200 ml of anhydrous tetrahydrofuran cooled to -50 C are added dropwise and under a nitrogen atmosphere, 41 ml (41 mmol) of a molar solution of allylmagnesium bromide in anhydrous ether. After 24 hours at room temperature, 50 ml of a saturated solution of ammonium chloride are added. The whole is left under stirring for 10 minutes then diluted with ethyl ether (500 ml) and the reaction mixture is extracted. After usual treatment of the organic phase and purification by chromatography on silica gel (eluent: toluene / acetate) ethyl, 95: 5 then 9: 1), 8.00 g (23 mmol) of the expected product are obtained.

Yield: 68%
Step D: i - (2-hydroxy-ethyl) -7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro-
naphthalen- 1 -ol
A solution of 2.00 g (5.8 mmol) of the compound obtained in Step C in 100 ml of a 1: 1 dichloromethane / methanol mixture is subjected to ozonolysis for 10 minutes at -50 C.

The whole is placed under stirring at -50 ° C. under a nitrogen atmosphere for 30 minutes before the addition of 0.40 g (10.6 mmol) of sodium borohydride. After 30 minutes at -50 ° C., the reaction mixture is kept under stirring for 2 hours while allowing the temperature to progressively change to room temperature. 20 ml of a saturated solution of ammonium chloride are then added and the aqueous phase is extracted with dichloromethane. After the usual treatment of the organic phase and purification by chromatography on silica gel (eluent: dichloromethane / ethyl ether, 1: 1), 1.64 g (4.7 mmol) of the expected compound are obtained in the form of a foam.

Efficiency: 81%
Elementary analysis: (Raw formula: C23H2403)
CH
% found 79.51 6.95
% calculated 79.28 6.94
Example 2: 1-Methoxy- 1- (2-methoxy-ethyl) -7. (Naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydro-naphthalene
2.23 g (55.7 mmol) of a 60% suspension are added to a solution of 3.86 g (11 mmol) of the compound obtained in Example 1 in 170 ml of anhydrous dimethylformamide under nitrogen atmosphere. % in sodium hydride oil then, after 5 minutes with stirring, 42 ml (690 mmol) of methyl iodide. After 20 hours with stirring at room temperature, the reaction mixture is diluted with ethyl ether and added with ice water then hydrochloric acid iN. The usual treatment of the organic phase followed by purification by chromatography on silica gel (eluent: pentane / ethyl acetate, 4: 1) leads to 2.90 g (7.7 mmol) of the expected compound.

Yield: 70%
Melting point: 82 "C
Elementary analysis: (Gross formula: C25H2803)
CH
% found 79.84 7.36
% calculated 79.76 7.50
Example 3: Spîro - [(1 ', 3'-dioxan-2'-one) -6', 1- (7- (naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydronaphthalene)]
To a solution of 0.300 g (0.86 mmol) of the compound obtained in Example 1 in 15 ml of an anhydrous dichloromethane / anhydrous pyridine mixture 2: 1 under a nitrogen atmosphere, 0.5 ml are added dropwise (0.965 mmol) of a 1.93M solution of phosgene in toluene. After
I overnight with stirring at room temperature, 5 ml of a saturated sodium bicarbonate solution are added. After usual treatment of the organic phase, the reaction medium is taken up in toluene and then evaporated. Purification by two chromatographies on silica gel (eluents: pentane / methyl acetate, 2: 1 and ethyl ether / dichloromethane, 1: 1) leads to 0.100 g (0.267 mmol) of the expected compound.

Yield: 31%
Melting point: 133 "C
Elementary analysis: (Gross formula: C24H2204)
CH
% found 76.59 6.00
% calculated 76.99 5.92
Example 4: Spiro - [(1 ', 3'-dioxane) -6', 1- (7- (naphthalen-2-ylmethoxy) -1,2,3,4-tetra-
hydronaphthalene)]
To a suspension of 0.335 g (8.4 mmol) of 60% sodium hydride in 20 ml of anhydrous dimethylformamide under nitrogen atmosphere, is added a solution of 0.500 g (1.4 mmol) of compound obtained with 1 'Example 1 in 30 ml of anhydrous dimethylformamide. After one hour with stirring at room temperature, 0.12 ml (1.7 mmol) of dibromomethane is added dropwise and the reaction mixture is left stirring for 48 hours. 10 ml of a saturated ammonium chloride solution are then added, the medium is evaporated to dryness and then taken up in 250 ml of dichloromethane. After filtration of the insoluble material, the filtrate is evaporated under vacuum. The residue is chromatographed on silica gel (eluent: toluene / ethyl acetate, 98: 2) and leads to 0.025 g (0.07 mmol) of the expected compound in the form of a foam.

Elementary analysis: (Raw formula: C24H2403)
CH
% found 79.79 6.80
% calculated 79.97 6.71
Example 5: 1- (2-Hydroxy-ethyl) -2,2-dimethyl-7- (naphthalen-2-ylmethoxy) -1,2,3,4- tetrahydronaphthalen - 1 -ol
Step A: 2,2-dimethyl-7- (naphthalen-2-ylmethoxy) -3,4-dihydro [2H]
naphthalen- I -one 8.30 g (72 mmol) of a suspension of potassium hydride in mineral oil are suspended in 50 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. A solution of 5.00 g (16.5 mmol) of the compound obtained in Step B of Example I in 50 ml of anhydrous tetrahydrofuran is then added dropwise at 0 C. After 5 minutes with stirring, 4.5 ml (72 mmol) methyl iodide are added dropwise at 0 C and the whole is stirred at 0 C for 1 hour 30 minutes before the addition of 50 ml of water and 250 ml of ethyl ether. After the usual treatment of the organic phase and purification by chromatography on silica gel (eluent: pentane / methyl acetate, 4: 1), 5.40 g (16.3 mmol) of the expected compound are obtained.

Efficiency: 99%
Step B: 1-allyl-2,2-dimethyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4
tetrahydronaphthalen- l-ol
To a solution of 2.70 g (8.17 mmol) of the product obtained in Step A in 50 ml of anhydrous tetrahydrofuran cooled to -50 ° C. are added dropwise and under a nitrogen atmosphere, 32.7 ml (32.7 mmol) of a molar solution of allylmagnesium bromide in anhydrous ether. The mixture is kept for 1 hour at -50 ° C. before the addition of 25 ml of a saturated ammonium chloride solution. After 10 minutes with stirring, the reaction medium is diluted with ethyl ether (250 ml). The usual treatment of the organic phase followed by purification by chromatography on silica gel (eluent: hexane / ethyl acetate, 9: 1) leads to 2.44 g (6.55 mmol) of the expected compound.

Efficiency: 80%
Step C: 1- (2-hydroxy-ethyl) -2,2-dimethyl-7- (naphthalen-2-ylmethoxy) -l 2,3,4-
tetrahydronaphthalen- l-ol
By proceeding according to the procedure described in Step D of Example 1, starting from 2.44 g (6.55 mmol) of the compound obtained in the previous step and 0.455 g (12 mmol) of borohydride from sodium, then purification by chromatography on silica gel (eluent: toluene / ethyl acetate, 9: 1), 1.11 g (2.95 mmol) of the expected product are obtained.

Yield: 45%
Melting point: 138 "C
Elementary analysis: (Gross formula: C25H2803)
CH
% found 79.55 7.39
% calculated 79.76 7.50
Example 6: 1-Methoxy- 1- (2-methoxy-ethyl) -2,2-dimethyl-7- (naphthalen-2-ylmethoxy) -
1,2,3,4-tetrahydronaphthalene 0.160 g (4 mmol) of a suspension of 60% sodium hydride in mineral oil are suspended in 5 ml of anhydrous dimethylformamide. A solution of 0.250 g (0.665 mmol) of the product obtained in Example 5 in 7 ml of anhydrous dimethylformamide is then added. After 5 minutes with stirring, 3.1 ml (49.8 mmol) of methyl iodide are added dropwise and the whole is kept stirring at room temperature for 4 hours. The reaction medium is diluted with ether ethyl and added with ice water. The usual treatment of the organic phase, then the purification by chromatography on silica gel (eluent: pentane / ethyl acetate, 9: 1) lead, after recrystallization from ethyl acetate, to 0.075 g (0.185 mmol) of product expected as an oil.

Efficiency: 28%
Elementary analysis: (Gross formula: C27H3203)
CH
% found 80.32 8.16
% calculated 80.16 7.97
Example 7: Spiro - [(1 ', 3'-dioxan-2'-one) -6', 1- (2,2-dimethyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4 -tetrahydronaphthalene)]
By proceeding according to the procedure described in Example 3, starting from 0.300 g (0.797 mmol) of compound obtained in Example 5, from 0.46 ml (0.888 mmol) of a 1.93 M solution of phosgene in toluene and 0.100 g (0.8 mmol) of Sdimethylaminopyridine, 0.075 g (0.186 mmol) of the expected product are obtained after chromatography on silica gel (eluent: toluene / ethyl acetate, 95: 5) and crystallization from l 'ethyl acetate.

Yield: 23%
Melting point: 136 "C
Elementary analysis: (Gross formula: C26H2604)
CH
% found 77.57 6.64
% calculated 77.58 6.48
Example 8 1- (2-Methoxy-ethyl) -7- (naphthalen-2-ylmethoxy) -1,2,3,4-tetrahydro-naphthalen-1 -ol
To a suspension of 0.038 g (0.95 mmol) of a suspension of 60% sodium hydride in 5 ml of anhydrous dimethylformamide are added, under a nitrogen atmosphere and at room temperature, a solution of 0.300 g (0 , 86 mmol) of product obtained in Example 1 in 10 ml of anhydrous dimethylformamide then, dropwise, 0.065 ml (1.04 mmol) of methyl iodide.

After one hour with stirring at room temperature, the reaction medium is diluted with water and ethyl ether. After usual treatment of the organic phase and purification by two chromatographies on silica gel (eluents: pentane / ethyl acetate, 9: 1 and toluene / methyl acetate, 9: 1) 0.063 g (0.174 mmol) of the expected compound are obtained .

Yield: 20%
Melting point: 74 "C
Elementary analysis: (Gross formula: C24H2603)
CH
% found 79.23 7.39
% calculated 79.53 7.23
Example 9: Spiro - [(1 ', 3'-dioxan-2'-one) -6', 1- (5- (naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydronaphthalene) 1
Step A: 5- (naphthalen-2-ylmethoxy) -3,4-dihydro [2H] naphthalen- 1 -one
By proceeding according to the procedure described in Step B of Example 1, starting at 7.80 g (48 mmol) of 5-hydroxy-3,4-dihydro [2H] naphthalen-1-one, from 10 , 61 g (48 mmol) of bromomethyl-2-naphthalene and 16.54 g (119 mmol) of potassium carbonate, 11.70 g (38.7 mmol) of the expected product are obtained.

Efficiency: 81%
Step B: 1 - (2-hydroxy-ethyl) -5- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalen. i -ol
By proceeding according to the procedures described in Steps C and D of Example 1, starting from 1.00 g (3 mmol) of compound obtained in Step A, 0.467 g (1.34 mmol) of expected product are obtained.

Yield: 45% (2 steps)
Step C: spiro - [(1 ', 3'-dioxan-2'-one) -6', 1 - (5- (naphthalen-2-ylmethoxy) - 1,2,3,4-
tetrahydronaphthalene)]
By proceeding according to the procedure described in Example 3, starting from 0.300 g (0.86 mmol) of compound obtained in step B and 0.5 ml (0.965 mmol) of a 1.93 M solution of phosgene in toluene, 0.100 g (0.267 mmol) of the expected product are obtained in the form of a foam.

Yield: 31%
Elementary analysis: (Gross formula: C24H2204)
CH
% found 76.68 6.14
% calculated 76.99 5.92
Example 10: 1 -Methoxy-1. (2.methoxy-ethyl) -5- (naphthalen-2-ylmethoxy) -î, 2,3,4-
tetrahydro-naphthalene
To a solution of 0.450 g (1 mmol) of the compound obtained in Step B of Example 9 in 20 ml of anhydrous dimethylformamide, 0.280 g (7 mmol) of 60% sodium hydride are added and then, after 10 minutes with stirring at room temperature, 5 ml (80 mmol) of methyl iodide. After overnight at room temperature, 8 ml of a saturated ammonium chloride solution are added and the reaction mixture is evaporated. The residue is taken up in dichloromethane and, after the usual treatment of the organic phase, two gel chromatographies of silica (eluents dichloromethane / ethyl ether, 4: 1 and hexane / ethyl ether, 3: 2) lead to 0.160 g (0.42 mmol) of the expected product in the form of an oil.

Yield: 42%
Elementary analysis: (Gross formula: C25H2803)
CH
% found 79.76 7.76
% calculated 79.76 7.50
Example 11: Spgro - [(1 ', 3'-dioxane) -6', 1- (5- (naphthalen-2-ylmethoxy) -1,2,3,4-tetra-
hydronaphthalene)]
By proceeding according to the procedure described in Example 4, starting from 0.450 g (1.3 mmol) of product obtained in Step B of Example 9, from 0.300 g (7.5 mmol) of hydride 60% sodium and 0.1 ml (1.4 mmol) dibromomethane, 0.042 g (0.12 mmol) of the expected compound are obtained in the form of a foam.

Elementary analysis: (Gross formula: C24H2403)
CH
% found 79.46 6.82
% calculated 79.97 6.71
Example 12: Spiro-1 (1 ', 3'-dioxan-2'-one) -6', 1- (2,2-dimethyl-5- (naphthalen-2-ylmethoxy) -
1,2,3,4-tetrahydronaphthalene)]
Step A: 1- (2.hydroxyethyl) -2,2-dimethyl-5- (naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydronaphthalen- 1 -ol
By proceeding according to the procedure described in Example 5, 5.00 g (16.5 mmol) of the compound obtained in Step A of Example 9 lead to 1.52 g (4 mmol) of the expected product.

Yield: 24% (3 steps)
Step B: spiro - [(l ', 3'-dioxan-2'-one) -6', 1 - (2,2-dimethyl-5- (naphthalen-2-yl-
methoxy) - 1,2,3,4-tetrahydronaphthalene)]
By proceeding according to the procedure described in Example 3, starting from 0.300 g (0.797 mmol) of compound obtained in Step A and 0.44 ml (0.85 mmol) of a 1.93 M solution of phosgene in toluene, 0.050 g (0.127 mmol) of the expected product are obtained.

Yield: 16%
Melting point: 1200C
Elementary analysis: (Gross formula: C26H2604)
CH
% found 77.46 6.67
% calculated 77.59 6.51 Example 13: 13: 1- (2-Methoxy-ethyl) -2,2-dimethyl-5. (naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydronaphthalen- 1 -ol
By proceeding according to the procedure described in Example 6, 0.187 g (0.497 mmol) of compound obtained in Step A of Example 12 leads to 0.075 g (0.0192 mmol) of the expected product.

Efficiency: 39%
Melting point: 100 "C
Elementary analysis: (Gross formula: C26H3003)
CH
% found 80.31 7.84
% calculated 79.97 7.74
Example 14: 1- (2-Methoxy-ethyl) -2,2-dimethyl-7- (naphthalen-2-ylmethoxy) -1,2,3,4-
tetrahydronaphthalen- 1 -ol
By proceeding according to the procedure described in Example 6, starting from 0.300 g (0.796 mmol) of product obtained in Example 5, 0.035 g (0.875 mmol) of 60% sodium hydride suspension and 0.055 ml (0.875 mmol) of methyl iodide, 0.050 g (0.128 mmol) of the expected compound are obtained.

Yield: 16%
Melting point: 93 "C
Elementary analysis: (Gross formula: C26H3003)
CH
% found 79.67 7.57
% calculated 79.97 7.74
Example 15: 1- (2-Methoxy.ethyl) .2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3 ,;
tetrahydronaphthalen-1-ol (diastereoisomer B)
Step A: 2-methyl-7- (naphthalen-2-ylmethoxy) -3,4-dihydro [2H] naphthalen-1-one
To a solution of 5.8 ml (41.3 mmol) of N, N-diisopropylamine in 50 ml of anhydrous tetrahydrofuran under nitrogen, are added dropwise and at -78 ° C., 16.5 ml (41 , 3 mmol) of a 2.5M solution of n-butyllithium in hexane. After 20 minutes with stirring, 2.50 g (8.27 mmol) of compound obtained in Step B of Example 1 in solution in 50 ml of anhydrous tetrahydrofuran are added dropwise and the reaction mixture is stirred at -78 C for 30 minutes before the addition of 5.15 ml (82.7 mmol) of methyl iodide, 1, 44 ml (8.27 mmol) of hexamethylphosphoramide and 50 ml of anhydrous tetrahydrofuran. After 30 minutes at -78 ° C. and overnight at room temperature, 50 ml of a saturated ammonium chloride solution are added and the reaction medium is diluted with dichloromethane. The usual treatment of the organic phase and two purifications by chromatography on silica gel (eluents: toluene / ethyl acetate, 9: 1 and toluene / pentane, 4: 1) lead to 1.50 g (4.7 mmol) of the expected compound in the form of a mixture of two diastereoisomers.

Yield: 57% (mixture of the two diastereoisomers)
Step B: 1 -allyl-7- (naphthalen-2 -ylmethoxy) -2-methyl- 1,2,3,4-tetrahydro-
naphthalen- 1 -ol
By proceeding according to the procedure described in Step C of Example 1, starting from 3.30 g (10.43 mmol) of the mixture of diastereoisomers obtained in the previous Step and from 15 ml (15 mmol) d '' a molar solution of allylmagnesium bromide in anhydrous ether, 2.53 g (7.07 mmol) of the expected diastereoisomeric mixture are obtained.

Yield: 68% (mixture of the two diastereoisomers)
Step C: 1- (2-hydroxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-
tetrahydronaphthalen- 1 -ol
By proceeding according to the procedure described in Step D of Example 1, starting from 2.00 g (5.58 mmol) of the mixture of diastereoisomers obtained in the previous Step and from 0.600 g (15.86 mmol ) of sodium borohydride, then purification by chromatography on silica gel (eluent: hexane / ethyl acetate, 4: 1), 0.145 g (0.4 mmol) of diastereoisomer A as well as 0.420 g (1.16 mmol) of diastereoisomer B are obtained.

Yield: diastereoisomer A: 7% diastereoisomer B: 21%
Step D: 1 - (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-
tetrahydronaphthalen- l-ol (diastereoisomer B)
By proceeding according to the procedure described in Example 6, starting from 0.300 g (0.83 mmol) of diastereoisomer B obtained in the preceding step, then purification by chromatography on silica gel (eluent: pentane / acetate ethyl, 4: 1), 0.140 g (0.37 mmol) of the diastereoisomer
Expected B are obtained.

Yield: 45%
Melting point: 86 "C
Rf: 0.21 (Eluent: pentane / ethyl acetate, 4: 1)
Elementary analysis: (Gross formula: C25H2803)
CH
% found 79.39 7.36
% calculated 79.76 7.50
Example 16: 1 -Methoxy- 1 - (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) -
1,2,3,4-tetrahydronaphthalene (diastereoisomer B)
To a solution of 0.078 g (0.2 mmol) of compound obtained in Example 15 in 0.5 ml of anhydrous dimethylformamide, are added 0.050 g (1.25 mmol) of a suspension of sodium hydride at 60 %. After 45 minutes at 50 "C, 2 ml (32 mmol) of methyl iodide are added and, after one hour at 50" C, the whole is cooled before the addition of a saturated solution of chloride d 'ammonium. The reaction mixture is diluted with ethyl ether and, after usual treatment of the organic phase, then purification by chromatography on silica gel (eluent toluene / methyl acetate, 98: 2), 0.070 g (0.179 mmol) of the expected diastereomer B are obtained.

Efficiency: 89%
Melting point: 94 "C Rf: 0.33 (Eluent: pentane / ethyl acetate, 4: 1)
Elementary analysis: (Gross formula: C26H3003)
CH
% found 79.86 7.69
% calculated 79.97 7.74 Example 17: 1-Methoxy-1- (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) -
1,2,3,4-tetrahydronaphthalene (diastereoisomer A)
By proceeding according to the procedure described in Example 6, 0.180 g (0.497 mmol) of the diastereomer A obtained in Step C of Example 15 leads to 0.015 g (0.04 mmol) of the expected diastereomer.

Rf: 0.37 (Eluent: pentane / ethyl acetate, 4: 1)
Melting point: 63 "C
Elementary analysis: (Gross formula: C26H3003)
CH
% found 79.92 7.75
% calculated 79.97 7.74
Example 18: Spiro. [(1 ', 3'-dioxan-2'-one) -6', 1- (2-methyl-7- (naphthalen.2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalene )]
By proceeding according to the procedure described in Example 3, starting from 0.280 g (0.77 mmol) of the diastereoisomer B of the compound obtained in Step C of Example 15, 0.160 g (0.41 mmol) of the expected compound are obtained.

Efficiency: 53%
Melting point: 129 "C
Elementary analysis: (Gross formula: C25H2404)
CH
% found 76.86 6.18
% calculated 77.30 6.23
Example 19: Spiro - [(7- (naphthalen-2-ylmethoxy) -3,4-dihydro [lBlnaphthalen-2-one) -1,4'-
tetrahydropyran]
Step A: 7- (naphthalen-2-ylmethoxy) -3,4-dihydronaphthalene
To a suspension of 18.14 g (60 mmol) of compound obtained in Step B of Example 1 in 150 ml of 95 "ethanol, are added, at 40" C and in small fractions, 1.40 g (37 mmol) sodium borohydride. The whole is brought to reflux for 30 minutes, then cooled before the addition of 150 ml of water. After concentration of the medium, the crystals obtained after filtration are dissolved in dichloromethane and the whole is dried over magnesium sulphate. The residue obtained after evaporation is taken up in 300 ml of toluene. 0.060 g (0.3 mmol) of paratoluenesulfonic acid monohydrate are added and the reaction mixture is brought to reflux for 1 hour 15 minutes, then cooled. The usual treatment of the organic phase leads, after evaporation, to 16.50 g (57.6 mmol) of the expected product.

Efficiency: 96%
Step B: 2-hydroxy-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalen-1 -ol
To a solution of 7.90 g (67.5 mmol) of N-methylmorpholine N-oxide in a water (40 ml) / acetone (25 ml) / t-butanol (25 ml) mixture, are added 3.7 ml (0.31 mmol) of a 2.5% osmium tetroxide solution in t-butanol, then 17.18 g (60 mmol) of compound obtained in Step A in solution in 320 ml d 'acetone. After 30 minutes with stirring at room temperature, 190 ml of water are added before concentration of the reaction medium. The whole is extracted with ethyl acetate and the organic phase is then washed successively with a solution of sodium bisulfite, sodium bicarbonate, then with water. After concentration in vacuo of the organic phase, the resulting solid is recrystallized from toluene and, after filtration, 16.50 g (51.5 mmol) of the expected compound are obtained.

Efficiency: 85%
Step C: 7- (naphthalen-2-ylmethoxy) -3,4-dihydro [1 Hlnaphthalen-2-one 3.20 g (10 mmol) of the compound obtained in Step B are dissolved hot in 100 ml of benzene before the addition of 0.400 g (2.1 mmol) of paratoluenesulfonic acid monohydrate.

The whole is brought to reflux for 15 minutes, then cooled before the usual treatment of the organic phase. Purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 4: 1) leads to 2.10 g (6.95 mmol) of the expected product.

Yield: 69% Step D: spiro - [(7- (naphthalen-2-ylmethoxy) -3,4-dihydrof l Hlnaphthalen-2-one) -
1, 4'-tetrahydropyran] 2.00 g (48.5 mmol) of a 60% sodium hydride suspension are suspended in 50 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. A solution of 5.88 g (19.4 mmol) of compound obtained in Step C in 30 ml of anhydrous tetrahydrofuran is added dropwise to the reaction medium before the rapid addition of a solution of 7.20 g ( 22 mmol) of diiododiethylether in 20 ml of anhydrous tetrahydrofuran. After 2 hours at reflux, the whole is cooled and 50 ml of water are added slowly. After extraction with pentane, then with dichloromethane, the vacuum concentration of the organic phase leads, after purification by chromatography on silica gel (eluent : heptane / ethyl acetate, 4: 1) to 5.85 g (15.7 mmol) of the expected product in the form of a foam.

Efficiency: 80%
Elementary analysis: (Gross formula: C25H2403)
CH
% found 80.26 6.53
% calculated 80.62 6.49
Example 20: Spiro - [(7- (1 methyl [1Blquinolin-2-one-6-ylmethoxy) -3,4-dihydro [1H naphthalen-2-one) - 1,4 '-tetrahydropyran]
Step A :: spiro - [(7- (hydroxy) -3,4-dihydro [ÎH] naphthalen-2-one) - 1,4 '
tetrahydropyran]
After dissolving 1.50 g (4 mmol) of the compound obtained in Example 19 in 15 ml of dimethylformamide, 1.50 g of 10% palladium on carbon, 6 ml of absolute ethanol are added, then 1.9 ml (20 mmol) of 1,4-cyclohexadiene. The whole is heated at 60 ° C. for 2 hours 30 minutes, then cooled before filtration of palladium on carbon. Evaporation of the filtrate leads, after filtration on silica gel (eluent: heptane / ethyl acetate, 1: 1) 0.850 g (3.66 mmol) of the expected compound.

Yield: 91%
Step B: spiro - [(7- (1-methyl [1H] quinolin-2-one-6-ylmethoxy) -3,4-
dihydro [1 H] naphthalen-2-one) - 1,4'-tetrahydropyran] 0.500 g (2.15 mmol) of product obtained in Step A, 0.650 g (2.5 mmol) of l-methyl [iH ] 6-bromomethylquinolin-2-one, 0.476 g (3.5 mmol) of potassium carbonate and then 20 ml of anhydrous dimethylformamide are introduced into a flask under a nitrogen atmosphere. After overnight at room temperature, the precipitate obtained is filtered and the filtrate is evaporated in vacuo.

The medium is then taken up in dichloromethane and, after usual treatment of the organic phase, purification by chromatography on silica gel (eluent: ethyl acetate / heptane, 2: 1 then 4: 1) leads to 0.770 g (1 , 91 mmol) of the expected compound in the form of a foam.

Efficiency: 88%
Elementary analysis: (Gross formula: C25H25N04)
CHN
% found 74.78 6.32 3.48
% calculated 74.42 6.25 3.47
Example 21: Spiro - [(5- (naphthalen-2-ylmethoxy) -3,4-dihydro [1H] naphthalen-2-one) -1,4'-
tetrahydropyran]
By proceeding according to the procedure described in Example 19, starting from 3.02 g (10 mmol) of compound obtained in Step A of Example 9, 0.756 g (2.03 mmol) of expected product are obtained in the form of foam.

Yield: 20% (4 steps)
Elementary analysis: (Gross formula: C25H2403)
CH
% found 80.39 6.51
% calculated 80.62 6.49 Example 22: 1-Methoxy-1- (2-methoxy-ethyl) -7- (1-methyl [1 Blquinolin-2-one-6-
ylmethoxy) -1,2,3,4-tetrahydronaphthalene
By proceeding according to the procedure described in Example 20, starting from 0.500 g (1.33 mmol) of product obtained in Example 2 then purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 1: 1), 0.463 g (1.37 mmol) of the expected compound are obtained in the form of a foam.

Efficiency: 85% (2 steps)
Elementary analysis: (Raw formula: C25H29NO4)
CHN
% found 73.61 7.27 3.38
% calculated 73.69 7.17 3.44
Example 23: Spiro - [(7- (naphthalen-2-ylmethoxy) -2-benzyl-1,2,3,4-tetrahydronaphthalen-
2-ol) -1,4'-tetrahydropyran]
To a solution of 0.500 g (1.34 mmol) of compound obtained in Example 19 in 10 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, are added dropwise and at -500C, 5.36 ml (5, 36 mmol) of a 1M solution of benzylmagnesium chloride in ethyl ether. After one hour at -50 ° C. and one hour at room temperature, 5 ml of a saturated ammonium chloride solution are added and the reaction mixture is extracted with ethyl ether. The usual treatment of the organic phase and purification by chromatography on silica gel give 0.525 g (1.13 mmol) of the expected product in the form of a foam.

Efficiency: 84%
Elementary analysis: (Gross formula: C32H3203)
CH
% found 81.97 6.85
% calculated 82.73 6.94 Example 24: Spiro - [(7- (naphthalen-2-ylmethoxy) -2-allyl-1,2,3,4-tetrahydronaphthalen-
2-ol) -1,4'-tetrahydropyran]
By proceeding according to the procedure described in Example 23, starting from 0.500 g (1.34 mmol) of product obtained in Example 19 and 5.36 ml (5.36 mmol) of a 1M solution of allylmagnesium bromide in ethyl ether, 0.500 g (1.21 mmmol) of the expected compound are obtained in the form of a foam.

Efficiency: 90%
Elementary analysis: (Gross formula: C28H3003)
CH
% found 80.91 7.24
% calculated 81.13 7.29
Example 25: Spiro - [(5- (naphthalen-2-ylmethoxy) -2-allyl-1,2,3,4-tetrahydronaphthalen-
2-ol) -1,4'-tetrahydropyran]
By proceeding according to the procedure described in Example 23, starting from 0.500 g (1.34 mmol) of compound obtained in Example 21 and 5.36 ml (5.36 mmol) of a 1M solution of allylmagnesium bromide in ethyl ether, 0.530 g (1.28 mmol) of the expected product are obtained in the form of a foam.

Yield: 95%
Elementary analysis: (Gross formula: C28H3003)
CH
% found 81.11 7.24
% calculated 81.13 7.29
Example 26: Spfro - [(5- (1-methyl [1H] quinolin-2-one-6-ylmethoxy) -3,4-dihydro [[1 H
naphthalen-2-one) -1,4'-tetrahydropyran]
By proceeding according to the procedure described in Example 20, 0.500 g (1.34 mmol) of product obtained in Example 21 leads to 0.380 g (0.94 mmol) of the expected compound in the form of a foam.

Yield: 70% (2 steps)
Elementary analysis: (Raw formula: C25H25N04)
CHN
% found 73.91 6.34 3.35
% calculated 74.42 6.25 3.47
Example 27: Spiro - [(6- (naphthalen-2-ylmethoxy) -3,4-dihydro [1H] naphthalen-2-one) -1,4'-
tetrahydropyran]
By proceeding according to the procedures described in steps A and B of Example 1 then in Example 19, starting from 32.00 g (182 mmol) of 6-methoxy-3,4-dihydro [2H] naphthalen- l-one, 13.18 g (35 mmol) of the expected compound are obtained in the form of a foam.

Yield: 19% (6 steps)
Elementary analysis: (Gross formula: C25H2403)
CH
% found 80.78 6.56
% calculated 80.62 6.49 Example 28 Spire SpUo - [(6- (naphthaien-2-ylmethoxy) -2-allyl 1,2,3,4-tetrahydronaphthalen-
2-ol) -1,4'-tetrahydropyran]
By proceeding according to the procedure described in Example 23, starting from 0.370 g (1 mmol) of compound obtained in Example 27 and from 4 ml (4 mmol) of a 1M solution of allylmagnesium bromide in 1 ethyl ether, 0.350 g (0.84 mmol) of the expected product are obtained in the form of a foam.

Efficiency: 84%
Elementary analysis: (Gross formula: C28H3003)
CH
% found 80.71 7.36
% calculated 81.13 7.29
Example 29: Spiro - [(6- (1-methyl [1Blquinolin-2-one-6-ylmethoxy) -3,4-dihydro [1H naphthalen-2-one) - 1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 20, 0.750 g (2 mmol) of product obtained in Example 27 lead to 0.621 g (1.54 mmol) of the expected compound in the form of a foam.

Yield: 77% (2 steps)
Elementary analysis: (Gross formula: C25H25N04)
CHN
% found 74.08 6.20 3.68
% calculated 74.42 6.25 3.47
Example 30: Spiro - [(7- (quinolin-2-ylmethoxy) -3,4-dihydro [1H] naphthalen-2-one) -1,4'-
tetrahydropyran] 0.200 g (0.86 mmol) of compound obtained in Step A of Example 20, 0.200 g (0.95 mmol) of 2-chloromethylquinoline hydrochloride, 0.380 g (2.75 mmol) of carbonate potassium, 0.025 g (0.15 mmol) of potassium iodide and 10 ml of anhydrous dimethylformamide are introduced into a flask under a nitrogen atmosphere. After one night with stirring at 60 "C,
The whole is cooled before concentration under vacuum of the solvent. The residue is taken up in dichloromethane and, after usual treatment of the organic phase, purification by chromatography on silica gel (eluent: heptane / methyl acetate, 2: 1) leads to 0.090 g (0.24 mmol) of the expected product in the form of a foam.

Efficiency: 28%
Elementary analysis: (Raw formula: C24H23NO3)
CHN
% found 76.80 6.24 3.57
% calculated 77.19 6.21 3.75
Example 31: Spiro - [(6- (quinolin-2.ylmethoxy) -3,4-dihydro [1H] naphthalen-2-one) -1,4'-
tetrahydropyran]
By proceeding according to the procedures described in Step A of Example 20 and then in Example 30, 0.345 g (0.926 mmol) of compound obtained in Example 27 lead to 0.090 g (0.24 mmol) of compound expected in the form of foam.

0,420 g (1,46 mmol) de bromure de 3'-(4-méthoxytétrahydropyrane4-yl)-benzyle, préparé suivant le mode opératoire décrit par Ducharme Y. et al (J. Med. Chem., 37, (1994), 512-518), 0,200 g (0,86 mmol) de composé préparé selon le mode opératoire décrit à l'Etape A de l'Exemple 20 à partir de 0,345 g (0,925 mmol) de composé obtenu à l'Exemple 27, 0,310 g (2,24 mmol) de carbonate de potassium et 6 ml de diméthylformamide anhydre sont introduits dans un ballon sous atmosphère d'azote.Après 2 heures 30 sous agitation à température ambiante, le mélange réactionnel est versé sur 20 ml d'eau puis extrait à l'acétate d'éthyle. Le traitement habituel de la phase organique suivi d'une purification par chromatographie sur gel de silice (éluant : heptane/acétate d'éthyle, 2:1 puis 1:1) conduit à 0,360 g (0,825 mmol) de produit attendu sous forme de gomme.Yield: 26% (2 steps)
Elementary analysis: (Raw formula: C24H23NO3)
CHN
% found 76.83 6.26 3.85
% calculated 77.19 6.21 3.75 Example 32: Spiro - [(6- (3 '- (4methoxytetrahydropyran-4-yl) -benzyloxy) -3,4-dihydro
[1H] naphthalen-2-one) -1,4'-tetrahydropyran]

0.420 g (1.46 mmol) of 3 '- (4-methoxytetrahydropyran4-yl) -benzyl bromide, prepared according to the procedure described by Ducharme Y. et al (J. Med. Chem., 37, (1994), 512-518), 0.200 g (0.86 mmol) of compound prepared according to the procedure described in Step A of Example 20 from 0.345 g (0.925 mmol) of compound obtained in Example 27, 0.310 g (2.24 mmol) of potassium carbonate and 6 ml of anhydrous dimethylformamide are introduced into a flask under a nitrogen atmosphere. After 2 hours 30 minutes with stirring at room temperature, the reaction mixture is poured into 20 ml of water and then extract with ethyl acetate. The usual treatment of the organic phase followed by purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 2: 1 then 1: 1) leads to 0.360 g (0.825 mmol) of the expected product in the form of rubber.

Efficiency: 96%
Elementary analysis: (Raw formula: C27H32O5)
CH
% found 74.56 7.54
% calculated 74.29 7.39
Example 33: Spiro - [(7- (3- (4-methoxytetrahydropyran-4-yl) -benzyloxy) -3,4-dihydro [1H] naphthalen-2-one) -1,4'-tee trahydropyran]
By proceeding according to the procedure described in Example 32, from 0.353 g (0.948 mmol) of compound obtained in Example 19, 0.360 g (0.825 mmol) of the expected product are obtained in the form of a gum.

Yield: 87% (2 steps)
Elementary analysis: (Gross formula: C27H32O5)
CH
% found 74.01 7.41
% calculated 74.29 7.39
Example 34: Spiro - [(S- (3- (4-methoxytetrahydropyran-4.yl) -benzyloxy) -3,4-dihydro [IHnaphthalen-2-one) -1,4'-tetrahydropyran]
By proceeding according to the procedure described in Example 32, from 0.384 g (1.03 mmol) of compound obtained in Example 21, 0.360 g (0.825 mmol) of the expected product are obtained in the form of a foam.

Yield: 80% (2 steps)
Elementary analysis: (Raw formula: C27M32O5)
CH
% found 74.23 7.67
% calculated 74.29 7.39
Example 35: Spiro - [(7- (naphthalen-2-ylmethoxy) -1, 2,3,4-tetrahydronaphthalen-2-ol) -1,4 '-
tetrahydropyranel
To a solution of 0.370 g (1 mmol) of the compound obtained in Example 19 in 16 ml of a dichloromethane / methanol mixture 1: 1, 0.038 g (1 mmol) of sodium borohydride are added at room temperature. After 1 hour with stirring, 5 ml of a saturated ammonium chloride solution are added and the aqueous phase is then extracted with dichloromethane. After the usual treatment of the organic phase and purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 1: 1), 0.360 g (0.96 mmol) of the expected product are obtained in the form of a foam.

Efficiency: 96%
Elementary analysis: (Gross formula: C25H2603)
CH
% found 79.47 7.03
% calculated 80.18 7.00
Example 36: Spiro - [(5- (naphthalen-2-ylmethoxy) -1,2,3,4-tetrahydronaphthalen-2-ol) -1,4'-
tetrahydropyran]
By proceeding according to the procedure decnt in Example 35, from 0.370 g (1 mmol) of compound obtained in Example 21, 0.360 g (0.96 mmol) of the expected product are obtained in the form of a foam.

Efficiency: 96%
Elementary analysis: (Gross formula: C25H2603)
CH
% found 80.36 7.15
% calculated 80.18 7.00
Example 37: Spiro - [(6- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalen-2-ol) - 1,4'-
tetrahydropyran]
By proceeding according to the procedure described in Example 35, starting from 0.370 g (1 mmol) of compound obtained in Example 27, 0.330 g (0.88 mmol) of the expected product are obtained in the form of a foam.

Efficiency: 88%
Elementary analysis: (Gross formula: C25H2603)
CH
% found 80.32 7.22
% calculated 80.18 7.00
Example 38: Spiro - [(2-methoxy-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro
naphthalene) -1,4'-tetrahydropyran]
To a solution of 0.200 g (0.54 mmol) of compound obtained in Example 35 in 3 ml of anhydrous dimethylformamide under nitrogen atmosphere, are added, at 0 ° C., 0.080 g (2 mmol) of a suspension of '' 60% sodium hydride. After 1 hour 30 minutes with stirring at room temperature, 0.100 ml (1.61 mmol) of methyl iodide is added and the whole is left stirring overnight before being poured onto 15 ml of water. is then extracted with ethyl acetate and, after the usual treatment of the organic phase, purification by chromatography on silica gel (eluent: heptane / ethyl acetate, 2: 1) leads to 0.120 g (0, 31 mmol) of expected product in the form of foam.

Efficiency: 57%
Elementary analysis: (Gross formula: C26H28O3)
CH
% found 79.53 7.28
% calculated 80.38 7.26
Example 39: Spiro - [(2-methoxy-5- (naphthalen-2-ylmethoxy) -1,2,3,4-tetrahydro-
naphthalene) - 1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 38, 0.200 g (0.54 mmol) of compound obtained in Example 36 leads to 0.160 g (0.41 mmol) of the expected product in the form of a foam.

Efficiency: 76%
Elementary analysis: (Gross formula: C26H28O3)
CH
% found 79.71 7.25
% calculated 80.38 7.26
Example 40: Spiro - [(2-methoxy-6- (naphthalen-2-ylmethoxy) -1,2,3,4-tetrahydronaphthalene) - 1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 38, 0.200 g (0.54 mmol) of compound obtained in Example 37 leads to 0.180 g (0.463 mmol) of the expected product in the form of a foam.

Efficiency: 85%
Elementary analysis: (Gross formula: C26H28O3)
CH
% found 79.57 7.20
% calculated 80.38 7.26
Example 41: Spiro - [(5- (quinolin-2-ylmethoxy) -3,4-dihydro [lBlnaphthalen-2-one) -1,4'-
tetrahydropyran]
By proceeding according to the procedures described in Step A of Example 20 and then in Example 30, 0.384 g (1.03 mmol) of compound obtained in Example 21 leads to 0.2 g (0.535 mmol) of expected compound in the form of foam.

Yield: 51% (2 steps)
Elementary analysis: (Raw formula: C24H23NO3)
CHN
% found 76.55 5.97 3.70
% calculated 77.19 6.21 3.75
Example 42: S piro - [(3-allyl-7- (naphthalen-2-ylmethoxy) -3,4-dihydro [H] naphthalen-2- one) -1,4'-tetrahydropyran]
To a solution of 1.36 g (13.4 mmol) of diisopropylamine in anhydrous tetrahydrofuran, are added dropwise, at -78 ° C., 5.36 ml (13.4 mmol) of a 2.5M solution of nbutyllithium in hexane. After 20 minutes with stirring, a solution of 1 g (2.6 mmol) of compound obtained in Example 19 in anhydrous tetrahydrofuran is added and then, after 30 minutes at -78 C, are added slowly 1.16 ml (13.4 mmol) of allyl bromide then, quickly, 0.46 ml (2.6 mmol) of hexamethylphosphoramide. The whole is placed at room temperature and, after 2 hours with stirring, a saturated solution of ammonium chloride is added before extraction of the reaction mixture with ether. After usual treatment of the organic phase and then chromatography on silica gel (eluent: heptane / ethyl acetate, 9: 1), 0.23 g (0.56 mmol) of the expected compound is obtained in the form of a foam.

Yield: 21.5%
Elementary analysis: (Gross formula: C28H28O3)
CH
% found 81.19 6.80
% calculated 81.52 6.84
Example 43: Spiro - [(3,3-diallyl-7- (naphthalen-2-ylmethoxy) -3,4-dihyhydro [1B
naphthalen-2-one) - 1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 42, 0.23 g (0.51 mmol) of the expected product is obtained in the form of a foam.

Yield: 19.5%
Elementary analysis: (Gross formula: C3 lH3203)
CH
% found 82.15 7.20
% calculated 82.27 7.13 Example 44: Spiro - [(3-henzyl-7- (naphthalen-2-ylmethoxy) -3,4-dihybydro [1ho
naphthalen-2-one) - 1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 42, starting from 1.6 ml (13.4 mmol) of benzyl bromide, 0.200 g (0.43 mmol) of the expected compound are obtained in the form of a foam.

Yield: 16.5%
Elementary analysis: (Gross formula: C32H3003)
CH
% found 83.06 6.61
% calculated 83.09 6.54
Example 45: Spiro - [(3,3-dibenzyl-7- (naphthalen-2-ylmethoxy) -3,4-dihyhydrot 1B
naphthalen-2-one) -1,4 '-tetrahydropyran]
By proceeding according to the procedure described in Example 42, from 1.6 ml (13.4 mmol) of benzyl bromide, 0.240 g (0.43 mole) of the expected product are obtained in the form of a foam.

Yield: 16.5%
Elementary analysis: (Gross formula: C39H3603)
CH
% found 84.27 6.67
% calculated 84.75 6.57
PHARMACOLOGICAL STUDY
COMPOUNDS OF THE INVENTION
Example A: Determination of the inhibitory activity of 5-lipoxygenase in vitro
This study was carried out based on the work of ME Goldyne et al. (The Journal of
Biological Chemistry, 259 (4), (1984), 8815-8819) and C. New-Chang and Gin Wensu (Biochemical Pharmacology, 36 (8), (1987), 3033-3036).

The inhibitory activities of 5-lipoxygenase were determined on rat peritoneal leukocytes. Leukocytosis is induced in OFA male rats (IFFA CREDO) weighing 200 to 250 g, by intraperitoneal injection of sodium caseinate 12%. 18 hours after the injection, the cells are collected by washing the abdominal cavity. The number of cells is adjusted to 2.106 per ml.

The cell suspension is incubated in the presence of Ca ++ (5.104 M) and Mg ++ (2.10-3 M) and of different concentrations of the compounds of the invention, for 10 min. at 37 C. Controls are carried out by incubating the cells with the solvent for the 2% dimethyl sulfoxide products.

After stopping the reaction at + 4 ° C. and centrifuging, the amount of LTB4, expressed in ng per 2,106 cells in the supernatants, is determined by the EIA method (STALLERGENES
FRANCE). The results are expressed as% inhibition calculated according to the following formula
ng of LTB4 (solvent controls) - ng of LTB4 (for a product concentration)
% inhibition:
ng of LTB4 (solvent controls)
The majority of the compounds of the invention showed a percentage of inhibition of between 70 and 100% for a product concentration of 10-6 M.

Example B: Pharmaceutical composition: tablets
Preparation formula for 1000 tablets dosed at 50 mg.

Compound of Example 33: 50 g
Wheat starch :. 15g
Corn starch: . 15g
Lactose:. . . . 65g
Magnesium stearate :. 2 g
Silica:. . lg Hydroxypropylcellulose:. 2g

Claims (16)

AT.  optionally substituted, and either:  isoindolyl, benzofuryl and benzothienyl, each of these radicals can be  oxadiazolyle, pyridyle, quinolyle, isoquinolyle, 2-oxo [1H] quinolyle, indolyle,  imidazolyle, pyrrazolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, thiadazolyle,  and Ar is chosen from phenyl, naphthyl, thienyl, furyl, pyrrolyl,  R1 represents the group - (CH2) n-Ar, in which n is chosen from 0, 1, 2, 3 and 4  in which

 CLAIMS 1. Compounds of general formula (I): B.  R6 and R7 each represent hydrogen, or:  optionally substituted, and  aralkyl radical, optionally substituted and a heteroarylalkyl radical,  optionally substituted alkyl, an optionally substituted akenyl radical, a  R4 and Rg, independently of one another, are chosen from hydrogen, a radical  bear and with a bivalent radical chosen from -O-CO- and -O-CH2-, and  R2 and R3 together form a ring with the respective carbon atoms which  or  R3 is chosen from hydrogen and an optionally substituted alkyl radical,  R2 is chosen from the hydroxyl radical and an alkoxy radical, optionally substituted,  quinolyle, isoquinolyle, indolyle et isoindolyle.  optionally substituted heterocyclic, is chosen from pyridyl radicals,  - and that the term "heteroarylalkyl" denotes a radical, the part of which  substituted, is chosen from phenyl and naphthyl radicals,  the term "aralkyl" denotes a radical, the aromatic part of which,  unsaturations in the form of double bonds,  with 6 carbon atoms in a straight or branched chain, and one or more  - the term "alkenyl" denotes an optionally substituted radical containing 2  contains from 1 to 6 carbon atoms in a straight or branched chain,  radicals with the saturated hydrocarbon chain, optionally substituted,  "heteroarylalkyl", "alkoxycarbonyl", "alkylthio" and "acyl" refer to  - the terms "alkyl", "alkoxy", "alkylamino", "dialkylamino", "aralkyle",  alkoxytetrahydropyranyl and morpholinyl,  may also be substituted by a radical chosen from tetrahydropyranyl,  - in addition to the possible substituents listed above, the radical Ar defined in R1  carboxy, alkoxycarbonyl, acyl, cyano, alkylthio and trifluoromethyl,  halogen, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, nitro,  may be substituted by one or more groups or radicals chosen from  - the term "possibly substituted" means that the radicals thus qualified  optionally substituted, as well as their optical isomers in pure form or as a mixture, it being understood that:  an araikyl radical, optionally substituted, and a heteroarylalkyl radical,  aikyle, optionally substituted, an alkenyl radical, optionally substituted, a  R6 and R7, independently of one another, are chosen from hydrogen, a radical  R4 and R5 are linked, and  R4 and R5 together form an oxo group carried by the carbon atom to which  or  optionally substituted heteroarylalkyl radical,  alkenyl, optionally substituted, an arakyl radical, optionally substituted, and a  R5 is chosen from hydrogen, an alkyl radical, optionally substituted, a radical  possibly substituted,  R4 is chosen from hydrogen, the hydroxy group and an alkoxy radical,  bear and with the bivalent radical -CH2-CH2-, and  R2 and R3 together form a ring with the respective carbon atoms which 2. Compounds according to claim 1, in which the radical -O-R1 substitutes the  tetrahydronaphthalene in position 5, 6 or 7,  as well as their optical isomers in pure form or as a mixture. 3. Compounds according to any one of claims 1 and 2, in which R1 represents  the naphthylmethyl radical,  as well as their optical isomers in pure form or as a mixture. 4. Compounds according to any one of claims 1 to 3, in which R3 represents the  methyl radical,  as well as their optical isomers in pure form or as a mixture. 5. Compound according to any one of claims 1 to 4 which is l- (2-methoxy-ethyl)  2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalen-l-ol,  as well as its optical isomers in pure form or as a mixture. 6. Compound according to any one of claims l to 4 which is l-methoxy-l- (2-  methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydronaphthalene  as well as its optical isomers in pure form or as a mixture. 7. Compound according to any one of claims 1, 2, 3, 4 and 6 which is (lR, 2R) -l-  methoxy- 1- (2-methoxy4thyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3 4-tetrahydro-  naphthalene, 8. A compound according to any one of claims l, 2, 3, 4 and 6 which is the (they, 2S) -l-  methoxy- i. (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro  naphthalene, 9. Compound according to any one of claims 1, 2, 3, 4 and 6 which is (lR, 2S) -l-  methoxy- l - (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro  naphthalene, 10. Compound according to any one of claims 1, 2, 3, 4 and 6 which is the (1S, 2R) -l-  methoxy- 1 - (2-methoxy-ethyl) -2-methyl-7- (naphthalen-2-ylmethoxy) - 1,2,3,4-tetrahydro-  naphthalene, 11. Compounds according to any one of claims 1 and 2, in which R1 represents  the 3- (4-methoxytetrahydropyran4-yl) phenyl radical,  as well as their optical isomers in pure form or as a mixture. 12. Compounds according to any one of claims 1 and 2, in which R2 and R3  together form a ring with the bivalent radical -CH2-CH2-,  as well as their optical isomers in pure form or as a mixture. 13. Compound according to any one of claims 1, 2, 11 and 12 which is the spiro - [(7- (3 '  (4-methoxytetrahydropyran4-yl) -benzyloxy) -3,4-dihydro [1 H] naphthalen-2-one) - 1,4 '  tetrahydropyran],  as well as its optical isomers in pure form or as a mixture. 14. Preparation process according to any one of claims 1 to 13, characterized in that  that the methoxy-3,4-dihydro [2H] naphthalen-1 -one of formula (II) is subjected:

 to demethylation, in order to obtain the compound of formula (leaked):

 which, subjected to the action of a halide of formula (mA)  R1-X (mA)  in which R1 is as defined for the compounds of formula (I) and X  represents a halogen atom, leads to the compound of formula (IVA):

 optionally substituted, in the presence of a strong base, in order to lead to the compound of formula (IVB):  an alkyl, akenyl, aralkyl and heteroarylalkyl radical, each being  in which X represents a halogen atom and R'8 is chosen from  R'8-X (V)  in which R1 is as defined above, it being able to be subjected to the action of a halide of formula (V)

 optionally substituted, so as to obtain the compound of formula (IVC):  an aikyl, akenenyl, aralkyl and heteroarylalkyl radical, each being  in which X represents a halogen atom and R'g is chosen from  R'9-X (V ')  in which R1 and R'8 are as defined above, then optionally subjected, under the same conditions, to the action of a halide of formula (V ')

 in which R1, R'8 and R'g are as defined above, the set of compounds of formulas (IVA), (IVg) and (IVC) forming the set of compounds of formula (IV):

 hydrogen and R'8, and Rg is chosen from hydrogen and R'g, which, subjected to the action of allylmagnesium bromide, lead after ozonolysis to the compound of formula (VIA):  in which R1 is as defined above, R8 is chosen from

 in which R1, R8 and Rg are as defined above, possibly being mono- or di-etherified, depending on the operating conditions, into a compound of formula (VIB):

 an alkyl radical optionally substituted, or else subjected to the action of phosgene or dibromomethane in order to obtain the compounds of formula (VIC) and (VID) respectively  represents an optionally substituted alkoxy radical and R'3 represents  in which Rl, R8 and Rg are as defined above, R'2

 in which R1, R8 and Rg are as defined above, the compound of formula (IVA) can also be reduced and then dehydrated so as to obtain the compound of formula (VII):

 in which R1 is as defined above, then oxidized, and dehydrated again to obtain the compound of formula (vm)

 in which R1 is as defined above, which subjected to the action of an alkylating agent, in the presence of a strong base, in an appropriate solvent, leads to the compound of formula (VIE 1):

 that R'8 in the formula (V) above defined, so as to obtain the compound of formula (VIE2):  in which X represents a halogen and R'6 has the same meaning  R'6-X (Ix)  in which R1 is as defined above, it can be subjected to the action of an alkylating agent of formula (IX):

All the compounds of formulas (VIEl), (VIE2) and (VIE3) forming the set of compounds of formula (VIE)  in which R1, R'6 and R'7 are as defined above,

 that R'8 in the formula (V) above defined, so as to obtain the compound of formula (VIE3)  in which X represents a halogen and R'7 has the same meaning  R'7-X (X)  in which R1 and R'6 are as defined above, which can also be subjected to a second alkylation with a compound of formula (X):

 as R'8 in the formula (V) above defined, to obtain the compound of formula (VIF):  in which X represents a halogen and R'5 has the same meaning  hydrogen and R'6 and R7 is chosen from hydrogen and R'7, compounds of formula (VIE) which can be subjected to the compound of formula (XI) R's-Mg-X (XI)  in which R1 is as defined above, R6 is chosen from

 in which R1, R'4, R'5, R6 and R7 are as defined above, the compound of formula (VIE) can also be reduced simply to alcohol according to conventional reduction techniques, then optionally etherified, so as to obtain the compounds of respective formulas (HIV) and (lives):

 optionally substituted alkyl, so as to obtain the compound of formula (VIG)  in which X represents a halogen and R'4 represents a radical  R'4-X (XII)  in which R1, R'5, R6 and R7 are as defined above, the alcohol function of which can be etherified, according to conventional methods, by means of a halide of formula (XII):  of seperation.  and from which, if desired, the optical isomers are separated according to a conventional technique  formula (I) which are optionally purified according to a conventional purification technique,  the set of compounds of formulas (VIA) to (VII) forming the set of compounds of  in which R1, R'4, R6 and R7 are as defined above,  several inert, non-toxic and pharmaceutically acceptable vehicles.  according to any one of claims 1 to 13, alone or in combination with one or 15 Pharmaceutical compositions containing as active ingredient at least one compound 16. Pharmaceutical compositions according to claim 15 exerting an inhibitory activity  of 5-lipoxygenase, and useful in the prevention and treatment of asthma,  chronic bronchitis, chronic obstructive pulmonary disease,  acute respiratory distress in adults, O.R.L., ophthalmologic or  skin, inflammatory bowel or systemic diseases, arthritis,  cardiovascular pathologies, atherosclerosis, myocardial ischemia, shock  endotoxin, eczema and psoriasis.