CA1049039A - Aromatic ketones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Napthylene derivatives of the formula (II):

Description

The present lnvention relates to pharmaceuti-cally active naphthalene derivatives, to procesees for their preparatlon and to pharmaceutical composltions oontalnlng them.
Certain naphthalene derivatives are known to possess userul anti-inflammatory activity and to be sultable for use in the treatment Or various rheumatlc and arthritlc conditions. One particularly ef~ective , naphthalene derivati~e that hae ~ound ¢linlcal use is _ _ Naproxen ~hich is o~ the rormula (I):
.
~ 1 3 3 ~

This com~ound and certain related compounds have been descrlbea in British Patent Speci~ications Nos. 1,271,132;
1!274,271; 1,274,273 ; 1,291,386 ; 1,21 1,1 34; 1,297,306 ;
1,276,261; 1,216,882; 1,289,041; 1,321,347 and , 15 1,296,493; ln U.S.Patent Specirications Nos. 3,562,336;
i 3,663,584; 3,626,012; 3,683,015 and 3,651,106; ln J ' the Publishea ~peclrlcatlons Or Netherlande Patent i Applications ~08. 71/15159 and 71/12833 and ln the Published Speclricatlons o~ German Patent Appllcations l 20 ~OB. 2,007,177 and 2,014,030. The pharmacological : a¢tivities Or sNch compounds have also been descrlbed .` .. '' - '.

2-t .
.: - . , - . ': :'' : .- - ~ . ... ~. . ;.
: .

: :
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ln J,Med.Chem., 13, 203 (1970) and J. Pham,Exp.Thera., 179, 114 (1971).
Un~ortunntely, the compound of formula (I) can cause 6evere lrritation of the gastro-inte~tinal tract ln ~ome sub~ects at doses not greatly ln excess of the therapeutic dose.
It has no~ been discovered that other naphthalene derivatives have good anti-in~lammatory activity whlle having an improved therapeutlc ratio as based on gastro-intestinal irritancy. Accordingly, the present in-~ vention provides compounds of the ~ormula (II~:
U
x ~3 Y Z

wherein X is a chlorine or bromine atom or a methoxy,methylthio or alkyl group of 1-4 carbon atoms; Y ie 1 ~1(R2)~- -CHP~1-CO-, -GHR1-C(OH)R2- or -C(R )=
C(R2)- group where R1 and R2 are each a hydrogen atom or a methyl, ethyl grou~ or propyl group and Z i8 a R4, 2 n 4- (C~2)nCH(OH~R4 or (CH2)nC(CH3~(0H)R4 group where R4 18 an alkyl group of 1 to 4 carbon atoms and n is O, ~ or 2; with the proviso~that Y - Z contains at least one oxy~en atom and not more than one carbonyl group and when X is methoxy, Y - Z is not a -CH2-CH2-CO-CH3 group.
Most suitably X l~ methoxy or methylthio.

..,Y

.' .
. - ~ .

One especially ~uitable sub-group of com wunds of ~ormula (II) are those o~ rormula (III):

3 CH(R1)-CH(Rz) A1 4 wherein R1, R2 an~ R4 are derined in relatlon to formula (II) and l~1 is a CO or CHOH grouP. ~-In comr~ounds of formula (III) R1 18 preferably - ;
& hydrogen atom or methyl group, R2 i8 preferably a hydroeen atom and R4 18 prererably a methyl or propyl group. ~!ost suitably A1 is a CO group.
Such com~ounds include, for example, tho~e whereln the 6ide chain is a group selected from -~ ' ' `s ~ -CH( CH3 )-C:H2-00 CH3 3 ) CH2--CO-CH2-CH2-CH3 s or -CH2-C%~2-CHOH-CH3 `~ 15 The co~pounds of rormula (III) whereln R~ 18 a methyl group, R2 is a hydrogen atom, At is CO and R4 is a methyl group are particularly suitable, A further especiaily suitable sub-grou~ Or com~ounds of formula (II) are tho~e of formula (IV):
. C~ ,r (I.) ~ - 4 -`i .

~ .

: . .

wherein R1, R2, R4 and A1 are as de~lned in relatlon to formula (III).
In compounds of rormula (IV), R1 18 preferably a hydrogen atom or methyl grou~f R2 18 prererably a hydro~en atom and R4 18 ~rererably a methyl group.
Mogt Eultably A1 i8 a 00 grou~.
In a further a6pect, the present invention provides a process for the preparation of compounas o~
the rormula (V):
. .
,.~ ~ ",~ CH(R1 )-CH(R2 )-A2-R4 . '' X~~ (V) whereln ", R1, R2 and R4 sre as deflned ln relation to . rormula (II) and A2 ie a 00, CHOH or C(CH3)0H grou which process com~rises the reaction Or a compound o~
the rormula (VI):
.
"C~Rl )-al{(R2 )~

. . where Bl is a chlorlne or bromine atom; with a compound o~ the rormula (VII):
. ' . R4 - B2 (VII) YJhere R4B2 is an alkyl metal derlvative to yield a ¢ompound of the rormula (VIII):
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.3 ~ .

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- : ' -'; . . ' ' , '.
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) CH(R2 )--cO--R4 X ~ ~ ~ J (VIII) and therea~ter optlonally reduclng the compound (VIII) in conventlonal manner to yield a compound Or the rormula ~` (V) wherein A2 i8 a CHOH group or else optionally re-- acting the compound of the rormula (VIII) ~ith a con-,j 5 ventlonal methyl metal compound to produce a ¢ompound the ~ormula (V) wherein A2 is a C(GH3)0H group.
The conventional and prererred compound (VII) is an alkyl lithium compound.
,; As is common in chain extension reactions Usin~
' 10 ,metal aerivative~, the reaction is carried out in an ;~ inert, ~protic solvent at a depre6sed temperaturs and ~i ' pre~erably under an inert atmosphere. -For example, the reactlon may be carried out at below -40C ln dry ,~, .
dlethglether. ' ~, 15 Normally, an additive such a6 cuprous iodide 18 present durlng the rea¢tion.
It will be realized that compounds Or the formula (V) wherein A2 i8 a CO group are valuable materiale whl¢h ! (~uite independently Or the methoa Or their produ¢tlon) ;~ 20 can serve as intermediates in the production o~ the com-pounds o~ formula ~V) wherein A2 is a CHOH or C(CH3)0N
' group.
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~`- - 6 -~- - ,, - - .
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Th~ red~ction o~ oompound8 Or rormula (~) wh~rein A2 18 a carbonyl group to the correspondlng secondary alcohol may take place uslng conventional method~ Or reduction such ag hydrogenation in the pre-. 5 sence of a transltlon metal catalyst or by the use Or a hydrid~ such a~ ~aBH4, LiAlH4 or the like.
Slmilarly, the production o~ the tertiary alcohols Or rormula (V) rrOm tbe oorresponding Xotonos may utlllze conventional methods such as reaction ~ith a CH3MgCl, CH3~gBr, CH3~gI, CH3Il or the ll~o.
In another aspect Or the process o~ th~s ln-vention, it pro~ides a process ~or the preparation o~
compounds or the rormula (IX):

¦ X ~ ~ ~ (R~) C(R2) A2 ~
~herein X, ~1~ R2 and R4 are as derined in relation to rormula (II) and A2 is a CO, CHOH or C(CH3)0H group which pro¢os~ compri~os the reaotlon.or a compound Or the formula (X):

: ~ ~ X ~,C(Rl ) = C(R2)-co-B~

~here B1 i8 a chlorino or bromlne atom; ~ith a compound . ~ .

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.. . . .~ . . ~ .
.

of the formula (VII) a6 previously defined to yield a compound o~ the rormula (XI):

X'~ ~ C(R1) = C(R2) CO 4 ~nd therearter optionally reducing the com~ound of ~ormula (XI) in a manner which convert6 the CO group a CHOH group or optionally reacting the compound of formula (XI) with a conventional methyl metal com~ound to produce a compound o~ the formula (I~) ~hereln ~2 i8 a C(CH3)0H group: the later reaction i8 60metimes complicated by 1-4 additlon reactions which can reduce yields of the compound of the ~ormula ~XI)~l.
The conventional and preferred com~ound o~
~ormula (VII) i6 an alkyl lithlum compound.
The chain extension reaction may take place under the general condition~ outlined above.
It wlll be realised that compoundfi of the ~ormula (IX) wherein A2 i8 a CO group are valuable materials which (qulte lndependent o~ the method o~ their production) can serve as intermediates ln the production o~ co~pounds Or ~ormula (IX) ~herein A2 iB a CHO~ or C(CH3)0H group.
. In another aspect, the present invention provides a process ~or the preparation o~ a compound of the ~ormula (XII):

:

104~39 ~ ~ ~ 1 3 4 (XII) whereln X, R1 and R4 are as de~ined in relation to formula (II) and ~3 i~ a CO or C(OH)R2 where R2 i8 as de~ined ln relatlon to formula (II) which proces~ comprises the reaction of a compound of the rormula (YIII):

"~ 1 , ~ (XIII) X~

~here B1 is a chlorine or bromine atom; with a compound o~ the ~ormula (VII) as previously defined to yield a com~ound of the rormula (XIV):

X ~ ~ ~ CHR1_CO-R4 ~XIV) : and thereafter optionally reduclng the compouna (XIV) in conventlonal m~nner to yield a compound o~ the rormula (XII) wherein A3 is a CHOH group or else optionally reacting the compound Or rormula (~IV) with a conventional methyl metal or ethyl metal compound to produce a com-pound Or formula (XII) wherein A3 is a C(OH)CH3 or C(oH)c2H5 groUP.

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.: ' ' . ~ ' ~049039 The compound o~ formula (VII) 18 con~entionally and Pre~erabIy an alkyl lithium com~ound.
The chaln extention, reduction and addition reaction~ may be carried out under the previously described general condltions.
In a flurther aspect, this invention provides a proce~s ror the preparation or compounds ar the formula (XV):

C(a7)(~2)-A5-R4 wherein X, Rl, R2, and R4 are as defined in relation to : 10 ~ormula (II) and A5 is a CO, CHOH or C(CH3)0H group which proce~s comprises the hydration o~ a compound of the-~ormula (~VI):

_" ~ ~ CNR1-C(ON)R2-C - C-R5 ` , ~herein R5 i8 a hydrogen atom or an alkyl group o~ 2 to 3 c~rbon atoms in the presence o~ a mercuric 6alt to yield a compound Or the rormula (~

-C(OH)R2-CO-CH2R5 x ~ ~J (XVII) , .

.~

.
: . - , and therea~ter if desired, reducing the carbonyl group to a CHOH group in conventional manner or el~e reacting the carbonyl group ~ith an 81~y1 metal compound to form a terminal C(OH)(CH3)R4 group in conventional manner.
The preparation of comoounds of formula (XV) wherein A5 i8 a CHOH or C(CH3)0H group by the reduction or alkylation or the corre~ponaing compouna wherein A5 i8 a CO group, forms an aspect of this invention irrespective of the method of production of the keto compound.
The compound Or formula tYVI) may be prepared by the reaction of a compound of the formula (XVIII):

` CHR~-CO-R2 (XVIII~

where X, R1 and R2 as defined in relation to formula (II) With an ac~tylide lon or the formula ~ C - C.R5 whi¢h : 15 has been generated in conventional manner.
Compounds of the formula (II) wherein X is a methoxyl grou~ may be prepared by methylation under con-ventional reaction condition~ of the corre6pondlng com-. ~ pound of formula (II) wherein X i8 a hydroxyl group or ` 20 an anion thereof.
Com~ounds of the formula (II) wherein Y - Z is a .

.

CH=CH-C0-CH3 group may be prep~red rrom a compound of the formula (XVIX):

~ ~ ~ CH0 ~ (XVIX) by ba6e cataly6ed condensation with acetone.
Compounds Or the formula (II) wherein Y - Z is a CHR1-CH2-CO-R4 group may be prepared by the reduction ~~ ~
o~ a compound Or the ~ormula (xx):
b~ C~4 Such reduction reactions may be e~fected by hydrogenation u~ing a conventional transition metal catalygt such as palladium on charcoal. Such reactions are normally carrled out in an innert organic sol~ent at ambient .. temperature uslng an atmospheric or ~lightly super-atmo6pheric pre6~ure of hydrogen.
Compoundg Or the ~ormula (II)whereln Y - Z is a CHRl.CH2CO.CH3 group may be prepared by the reactlon of a . 15 compound o~ the formula (~YI):
CHR1-Br X ~ ~ ~ (XXI) .
. - 12 -`
-~ ' , .

with acetylacetone in the presence of a base. Su¢h reactions are generally carried out in an organic solvent ~uch a6 a lower alkanol at an elevated temperature, ror example, in ethanolic ~olution under reflux. Sultable ba~es are those which promote formation Or the anion of acetylacetone without causing expulsion of the bromine atom. A 6uitable base i8 potassium carbonate.
For such a reaction R1 is pre~erably hydrogen.
Compounds of ~ormula (II) often include assy-metric centres and therefore, exist in various optical forms. All such forms are included within thi~
in~ention.
Compounds o~ rormula (II) ha~e anti-inflammatory : and/or analgesic activity. Accordingly, pharmaceutical compositions are included within the scope o~ this invention which compositions comprise a compound Or ~ormula (II) together with a pharmaceutically acceptable carrier.
The compositions Or this invention may be in any conventlonal rOrm but in general, orally admini-strable unit dosage compositions such as tablets or capsules are preferred. Such dosage forms will normally contain ~rom 20 mg to 1000 mg and more usually rrom about 100 mg to 600 mg. Such dosage rorms may be taken one or more times a day (pre~erably 2 to 4 time8 a day) so that the dally do6e i6 normally between . ~ .

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300 mg and 3000 mg and more usually from 500 mg to 2000 mg, for example 600 mg to 1600 mg.
In the rollowing Examples, certaln new pharma-ceutically active compounds or this inventlon are prepared in Examples 4, 10, 12 and 14 to 20, and certa1n useful intermediates are prepared in Examples 1, 2, 3, 5 to 9, 11 and 13. Some detail~ of the pharmacalogical activity Or the compound~ o~ the in-vent10D nre e1vcn ln Example ~

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:i _____ -hy~ (6'=~J~b9U~=iC~ LL~ u~enoate ~ odium hydrlde (10.8g., 60~ dispersion ln mlneral oil) was washed three times wlth cyclohe~ane and blown dry ln a stream Or nitrogen. Dry 1,2-dl-methoxyethane (150 ml) was added and the slurry was stirred at room temperature. Trlethyl phosphonoacetate (54g.) was added dropwise and the mixture stirred at room temperature ror 1 hour under nitrogen. A solutlon o~ 2-acetyl-6-methoxynaphthalene (30~.) in 1,2-dlmethoxyethano (300 ml) was run in and the solutlon rerluxed overnlght under nltrogen.
The reaction mixture was dilute~ with ~ater, acldi~ied and extracted with ether. The ethereal layer was washed with ~odium carbonate solutlon and w~th wator, dried over anhydrous magnesium sulphate an~ eva~orated to giveethyl 3-(6'-methoxy-2'-naphthyl)-2-butenoate as a yollow sol~d ln quantltatlve yleld. The ~roduct ~as ehown by WMR to bo predomlnantly the trans lsomer.
.~ .
N~R : trans vlnyllc proton 3.69~-, c18 ~lnylic proton 4.0~.
- C02CH2CH3 : triplet (3 protons) at ô.62~, J = 11.5 Cp8.
~uarter (2 protons) or 5.71r, J = 11.5 cpe.
- CH3 : two peaks very close together at~ 7.28r, equivalent to 3 proton~ ln total.
IR ; Carbonyl absorption at 1708 cm '.

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'`' " ' ' '-, '' ' ' -, : I

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, ~ ,. :~ ' ''' .-'" ' ' '' " " '', . ' ' ' . 13XAMPLE 2 Eth~ ~ -me~h~ .2'-naE~h h~ by~ate Ethyl 3-(6'-methoxy-2'-naphthyl)-2-butenoate (24g.) was taken up ln ethyl acetate (100 ml) and 10%
Pd/C t2.4g.) addea. The mixture was hydrogenated at room temperature and 50 psi pressure ror two hours.
The catalyst was removed by filtration and the ~iltrate evaporated to give ethyl 3-(6'-methoxy-2'-naphthyl)-butyrate as a colourless solld in Qu~ntitatlve yield.
IR : Saturated ester carbonyl absorption at 1730 cm '.
NUR : C~ -CH : 3 proton doublet at 8.68t~ J = 11 Cp8.
Absence o~ vinyllc protons.
.
.

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6' _ hQ~L-~?'-na~hth~y~ b~t~ric_ac~d Ethyl 3-(6'-methoxy-2'-naphthyl)-butyrate (14.4g.) was taken u~ ln methanol (300 ml) and 10~ -sodlum hydroxide solution (150 ml) and the mixture was re~luxed ror 2 hours. The reactlon mi~ture was diluted with water and extracted wlth ethyl acetate. The agueous layer was acidlrled and extracted with ethyl acetate. ~he acid extract was washed wlth water, drled over anhydrous magnegium sulphate and evaporated-I to glve 3-(6'-methoxg-2'-na~hthyl)-butyric acid as a white solid (11.9g., 92~), mp. 126-129.

IR : carb _ ~ sosorptlon at 1700 c ;'.

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~049039 EXA~PLE 4

4-~6'-metho~-2,'-naphthylL-pe~ntan-~2~-vo~Q
Thlonyl chloride (8.15 ml) was added dropwise to a eolutlon Or 3-(6'-methoxy-2'-naphthyl)-butyric acid (19.0g) ln dry benzene (200 ml) and the mixture ~as gently refluxe~ overnight. The solvent was eva~orated to glve the crude acid chlorlde as a bro~n oll.
~!ethyl lithiuin (253 ml., 2.18 ~ ln ether) ~as dlluted to 2 lltres with dry ether, cooled to 0C and stirred under nitrogen. Cuprous lodide (48.6g) was ¦ added and stirrin, continued ror 10 minute~. The mixture was coole~ to -70C and a solution o~ the crude acid chloride in ether (250 ml~ was run in. The mixturo was stirred under nitrogen at -70C ror 15 minutes.
~ethanol (350 ml) was added to guench th~ reaction and the mlxture was diluted with water and acidiriod.
Kieselguhr was added to aid filtration and the reaction s mixture ~as ~iltered throueh a paa o~ Kiesel~uhr. Tho i ether layer was washed with sodium carbonate ~olution and ~ith ~ater~ dried over anhydrous ma~nesium sulphate and evaporated to give a brown oil. The product was purlfied by short column ¢hromatography to give 4-(6'-metho~y-2'-naphthyl)-pentan-2-one as a pale yellow oil, which solidiried slo~ly on ~tanding. Yield 10.7 g., 57~.
IR : Carbonyl absorptlon at 1705 cm NMR : CH3C0- 3proton singlet at 8.01~
CH3 - CH:3 proton doublet at 8.72~, J = 11 CpB-,~ .
;`. . .
- 18 ~

'~`'` ` '` '`- `" '- ' - .' `:
. .
, .. . .
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- .
. ' ' .; - .'' ' EXAMPLE ~
~5~ ' .
Powdered anhyarous aluminium chloride (100 g) was taken up ln dry nitrobenzene (600 ml) and the mixture stirred ln an lce-bath. 2-methoxynaphthaleno (96 g) was added and acetyl chloride (54.5 ml) was run ln drop-wise o~er a period of 15 mlnutes. The ice-bath wae removed arter ~ hour8 and the mixture was stirred rOr a rurther 3 days.
The reaction mixture was ~oured lnto a solutlon o~ crushed lce, concentrated hydrochlorlc acld (200 ml) and water (200 ml) and extracted wlth ether. The ethereal layer ~as washed with ~ater till neutral~ drled o~er anhydrous magnesium ~ulphate and evaporated. The residual nitrobenzene uas removed by vacuum distlllatlon and the dark-brown regidue which remained was rractlonally .
dlstilled to give ~acç~ty~ ~C~ 9 ~D~Ue~Li~ a8 a yello~
solld b.p. 155-160/0.4mm Hg as the ma~or rra¢tlon.
Thls ~as melted and poured lnto methanol (300 ml). Tho colourloss crystals t24.6 g mp. 109-110) whlch se~aratea wero colle¢ted by ~lltration, washed wlth methanol and dried ln a vacuum deslccator. Further amounts o~
produ¢t could be obtained by concentration Or the mother ll~uors.
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,: .. , ~ - ,, - .. , -, ~ , ¦ l04so3a EXAMPLE 6.

m~,t,ho,~y-,2'-E~ h~ æti5~sid A mixture of 2-acetyl-6-methoxynaphthalene , (213 g), sulphur (38.4 g) and morpholine (120 ml) was refluxea overnight. The ¢rude thlomorpholide lnter-- mediate was puri~led by tr~turation with ether, taken up ln ethanol (300 ml) and 10~ potassiu~ hydroxide '~-~''~~
solution (1000 ml) and re~luxed rOr 4 hours.
The product mlxture was riltered and extracted with ethyl acetate. The agueou6 layer was acidified and the precipitate riltered, washed wlth water and dried to ~lve ~ ~2~2 as a cream solid (107.2 g, 46.6~), mp. 158-162.
NMRs 2 ~roton singlet (-GH2-) at 6.23~r.

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- , - . ~: . ' Z~ ~l~-acetate 2-~6'-metho~Y-2'-napht~Yl)-acetic acid (26.89 g) was taken up in methanol (120 ml) and acetyl chloride (15.5 ml) and gently refluxed ~or 2 hours. The reaction mixture was diluted with water and extracted wlth ether.
The ethereal layer was washed with sodium carbonate solution and with water, dried over anhydrous magnesium sulphate and evaporated to gl~e methYl 2-(6'-metho~Y-2'-naPhthYl)-acetate as a pink solid (24.9 g, 87~) m.p. 75 N~R: 3 proton singlet (-C02CH3) at 6.29~;

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1~49039 X~
t~ox~-?'~aphth~ but~rrate Sodium (2.5 g) and a fe~ crystals Or rerrl¢
nltrate were ad~ed to li~uid ammonia (200 ml distilled ~rom sodlum) and the mixture was stlrred for 2 hours.
¦ ~'ethyl 2-(6'-methoxy-2'-naphthyl~-acetate (24.9 g) in ! snhydrous tetrahydrofur&n (60 ml) was added and ~tirring continued for 15 mlnutes. Ethyl iodide (7.9 ml) ln tetrahydro~uran (10 ml) was cautlously ad~ed and the mixture stirred for 2 hours. Ammonlum chloride (7 g) was added and the ammonia was allowed to evaporate over-nlght.
The reaction mixture was diluted with ~ater and extracted ~ith ether. The ethereal layer was washed with sodium bicarbonate ~olution, with sodium chlorido solution and with water, dried over anhydrous magnesium sulphate and evaporated to give met~hvl 2-(6'-metho~v-2'-bu~iYrate as a yellow solid (27.4 g, 98~), m p 69-71 NMR: 3 proton triplet (=CH3 - CH2-) at 9.09~; J = 12 cp~.
The ~periment was repeatefl using soaium (1.05 g), liguid ammonia (200 ml), methyl 2-(6'-methoxy-, 2'-naphthyl)-acetate (10.5 g) and methyl iodido ~2.8 ml).
~ork-up as above gave methyl 2-(6'-metho~y-2'-naphthyl)-.~
propionate as a yellow solid (10.3 g, 92.5,) N~R: 3 proton doublet ( ~3-CH-) at ô.41 , J = 12 cp~.

, ~ ,.

:. -:1 -`Z

~' ` ' . ' ' .
' . ' ' ' ` ~ ` ` ~ ' , 1 `-~049039 EXAMPLE 8 (continued) The e~periment was repeated using sodlum . (1.0 g), llguld ammonla (100 ml), methyl 2-(6'-metho~y-2'-naphthyl)-acetate (10 g) and 1-bromopropane (3.15 ml).
Work up as above gave a brown oll, p.urlrled by ohort column chromato~raphy to glve met~h~ 2-~6'-metho~Y-2'-na~hthvl)-vnlcr~ o a yollow oolld (6.49 g, 55~).

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--: - : , :; ' ' ' ' ', ' 1~349039 , EXA~PLE g I

Methyl 2-(6l-methoxy-2~-naphthyl)-butyrate (27.4 g) was taken up in methanol (300 ml) and 10~
sodium hydroxide solution (150 ml) ana refluxed ~or 2 houre.
The reaction mixture was diluted with water and extracted with ethyl acetate. The agueous layer ~ae acldified, extracted with et~Yl acetate and the organic layer washed with water, drie~ over anhydrou~ magnesium sulphate ana evaporated to give 2-(6'-methoxY-2'-na~hthvl)-bu~ric acid a~ an or~nge solid ~25.8 g, 99~), mp. 125-131.
The experiment ~ae repeated using methyl 2-(6'-methoxy-2'-naphthyl)-propionate (10.3 g), methanol (200 ml) and 1~; sodlum hydroxide solution (100 ml). ~ork up as above gave an orange solid t9.3 g, 96~) which was re-crystallisea ~rom ether to glve 2-(6'-methox~-?'-na~ht ~ro~lonlc acid as a yollow solld mp. 148-153.
The experiment was repeated using methyl 2-(6'-metho~y-2'-naphthyl)-valerate (6.49 g), methanol (90 ml) .and ~0~ sodium hydroxide solution (45 ml). ~ork up as above gave 2-(6'-methoxY-2'-na~hthYl)-valer~o acid as a cream solld (5.2 g, 84%).

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1049~)39 -(6~-me~oxY-2~-nap~ 2-~
?-(6~-metho~cy-2'-naphthyl)-butys'ic acld (23.9 g) was taken up in dry benzene (100 ml) and thlonyl chlorlde (11.5 ml) in benzene (10 ml) was added dropwlse. Th~
mlxture was gently rerluxea overn~ght. The solvents uere removed by evaporation to glve the crudo acid chlorlde.
llethyl l~thium (311 ml, 2.2M solution in other) tO ~as diluted to 1800 ml dth dry ether, cooled to 0 and stlrred under nitrogen. Cuprous iodide (59.5 g) wag added and stirrlng continued for 10 minutes.
The mixture was cooled to -70 and a solution or the acid chloride in arY ether (400 ml) l~as addod.
t5 The mi~eure was stirred at -70 under nltrogen for 15 minutes.
i, Methanol (250 ml) was added to guonch tho reactlon and the reaction mixture ~as allowed to com~ to room temporaturo diluted ~ith ~ater and acldiried ~ith '! ' 3 20 diluto hydrochloric acld. Kiesolguhr was addod and tho mi~cture r~as riltered. Tho ethereal layer Or the n~
; trate was soparatod, washod ~ith sodium carbonate solution and ~lth wster, driea ovor anhydroug magneslum sulphsto ana evaporated to a brown oil, whlch was puriried by ;i .
~3 25 short column chroa~atography to give ~-(6'-~etho~
;~ ~Laphth~ ~an-2-one as a pale yello~ so}id (14.2 g, 60%), `"' ' ' ~ , ........................... .
'~ ' ' ' ' '.

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';- :~ - : . ~ , - . . -.. ' ': :' ' ' . ' ~., - , E~CAPIIPLE 10 (contlnued) mp. 56-59. Infra red carbonyl absorption at 1705 cm .
NMR: 3 proton slnglet (CH3C0-) at 7.9r.
The experlment wa~ repeated using 2-(6'-methoxy-2'-naphthyl)-acetlc acld (5.0 g), thionyl chloride (2.4 ml) methyl lithium (60 ml, 1.95 m) and cuprous iodlde (12.1g).
'~ork up es above gave a brown solld (4.7 g, 95%), which ;~ was purified by short column chromatography to give 1-(6'-metho~v-2'-nahthYl)-Pro~an-2-on,e as a yellow solid mp. 69-72. NMR: 3 proton slnglet (CH3C0-) at 7.87 .
The experlment was repeated uglng 2-(6'-methoxy-2'-naphthyl)-propi acid (16.4 g), thionyl chloride (7.2 ml), methyl lithium (180 ml, 1.95m and cu3~nous lodlde (36.3 g). ~ork up as above gave a yellow oil (15.9 g, .
98%), which llas puriried by short column chromatography to give 3-t6'-methoxY-2'-na~hthYl)-butan-2-one as a yellow 80lia, mp. 68-69. NMR: 3 proton singlet (CH3C0-)at 7.94r.
The experiment was repeated using 2-(6'-methoxy-2'-naphthyl)-valerlc acld (5.2 g), thionyl chloride (2.1 ml), methyl lithium (66.6 ml, 2.18M) and cuprous iodide ~13.1 g). Kork up as above gave a yellow oil puri~ied by short column chromatography to glve ~-methoxv-2'-na~hthYl)-hexan-2-one as a pale yellow oil (4.5 g, ô7~ 5R: 3 proton slnglet (CH3C0-) at 8.0T.

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1~ 1049039 dro~Y-3-methYl-4-(6~-metho~v-2~-naDhthy~ ho~Yne Ethyl magnesium bromlde tO.24 mole) was pre-pared rrom ethyl bromlde (25.5 ml) and magneslum (6.15 g) ln dry tetrahydroruran (150 ml) under nltrogen.
Acetylene was bubbled through dry tetrahydro-ruran (100 ml) ror 30 mlnutes. Bubbling ~a8 contlnued ~hile th~ warm ethyl magne81um bromide 801ution ~as added dropwise. Acetylene was bubbled through for a ; 10 rurther 45 minutes after additlon ~as complete.
3-(6'-methoxy-2'-naphthyl)-pentan-2-ono ~9.19 g, 0.038 mole) in dry tetrahydrofuran (50 ml) was added dropwise at room temperature to the stlrred ~rignard reagent. Stlrrlng was continued overnlght.
The re~ction mixture ~as poured lnto 5~
ammonium chloride 801ution and extracted ~ith other.
The ethereal layer was ~a~hed ~lth water, arled o~or anhyarous magneslum sulphato and evaporated to a bro~n . ~ .
oll, which ~as purlried by short column chromatography to gl~o 3-hvdro~ met~Yl-4-(6'-methoxY-2'-na~hthvl)-l-hoxYne as a yellow oll (5.2 g, 51~). lnrra-rod:
absence Or carbonyl absorptlon, -C-CH Rbsorption at 3300 cm . (C-H stretch~ng), broad - OH absorptlon at 3500 cm~ .
The exporlment wag repeated uslng ethyl magnesium bromlde (0.24 mole) and 3-(6'-methoxy-2'-:

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.

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1~49039 EXAMPLE 11 (continued naphthyl)-hex~n-2-one (9.8 g). 'J~?ork up as above gave?
a brow?n oil purlfied by short column chromatography to glre ~ ~ -3-~th,vl~-(6'-methox.v-?'-na~hth.yl)-hePt.yne as a yellow resin (8.99 g, 83~^). Inrra-red:
absence o~ carbenyl absorption, -C~CH absorption at : 3300 cm~ , -OH absorption at 3500 C~

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, EXA~PLE 12 3-HYdroxy-3-methyl-4-~6'-methoxv-2'-na~hth~l)-hexan-2-Aone 3-Hydroxy-3-methyl-4-(6'-methoxy-2'-naphthyl)-1-hexyne (5,2 g) was taken up ~n tetrahYdrO~Uran (60 ml) and dllute ~ulphuric acid (40 ml) and mercuric sulphate (375 mg) was added. The mlxture was gently re~luxed for two hours.
The reaction m~xture ~as diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulphate and e~aporated to give 3-hYdrox~-3-methvl-4-~ (6'-methoxY-?'-napht~Yl)-hexan-2-onç as a yellow oll ; (5.34 g, 96~). Crystallisation rrom 60-80 petrol gave the product ag a colourless solld, mp. 94-97.
Infra-red: carbonyl absorptlon at 1705 cm , -OH
absorption at 3490 cm . N~R: 3 proton slnglet (CH3CO-) at 7.61~.
'l'he experlment ~as repeated using 3-hydrozy-3-methyl-4-(6'-methoxy-2'-naphthyl)-1-pentyne t5 g), tetrahydrofuran (60 ml), dilute sulphuri¢ acid (40 ml) and mercuric sulphate (250 mg). ~York-up as above ga~e a brown oll purlried by short column chromatography to glve 7-hYdroxry-3-methYl-4-(6'-methoxY-2~-napht~hvl)-... .
entan-2-one as a cream solid (2.18 g, 41~), mp 72-74.
~` 25 lnrra-red carbonyl absorption at 1690 cm ` , .
The experlment was repeated using 3-hydroxy-3-~1 .
., -~ - - 29 - -'' ' ' -, .

EXAk~LE 12 (contlnued) methyl-4-(6'-metho~y-2~-naphth,yl)-1-heptyne (7.5 g), tetrahydroruran (120 ml), dilute sulphurlc acld (80 ml) and mercurl¢ sulphate (750 mg). '~ork up as abovo gave a brown oil t7.7 g, 96~), which was puri~iod by short column chromatograph,Y to give ~-b~Ydro~ meth.vl-4-(6~-metho~Y-2~-naPhthyl)-hePtan-2-one as a yellow 60lid mp; 89-90. Inrra-red carbo~rl absorptlon at 1700 cm~ .

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EXAllPLE 1 3 ~rans-~-(6'-methoxY-2~-na~ht~Yl)-2-butenolO acid Ethyl trans-3(6'-methoxy-2'-naphthyl)-2-butenoate (27.4 g) was taken in methanol (600 ml) and 10~ sodlum hyaro~ide solution (300 ml) and the mi~turo refluxed ~or 2 hours. The sodlum salt Or the regulred acld product crystalllsed out and ~ae flltered Orr.
The rlltrate was e~tracted wlth ethyl acetste and the agueou~ layer was separated.
Tho sodium salt Or the acid ~as susponded ln __ _ _ the agueous layer and tho mi~ture was acldiried. Ethyl acetate was added and the mixture ~arme~ untll all the i solid had dissol~ed. The ethyl-acetate layer ~as ~' separated, ~ashed ~ith water, dried o~er anhydrous 9 15 magnesium sulphate and evaporated to gi~e a pale yello~
`' solid (20.7 g). The product was recrystalli~ed ~rom ethyl acetato to gl~e trans-3-(6'-methoxy-2'-naphthyl)-2-buteno~c a~id ae a colourloes solid (15.9 g, 67.8~), mp. 195 - 204.
IR (Nu301): Carbonyl abeorption at 1680 cm 1.
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EXA~PLE 14 Trans-4-(6'-methoxY-2'-na~ht~vl~-~ent-3-ene-2-one Thionyl chloride (8.15 ml) was added dropwlse to a solutlon of trans-3-(6'-methoxy-2'-naphthyl)2-butenoic acid (14.0 g) ln dry benzene (140 ml) and the mixture was gently re~luxed ror 4 hours. The solvent was evaporated to give the crude acid chloride as a brown oil.
Methyl lithium (173.3 ml, 2.1 Jl ln ether) was diluted to 1200 ml. with dry ether, cooled to 0C and stirred under nitrogen. Cuprous iodide (34.75 g) was added and gtirring continued ~or 10 minutes. The mixture was cooled to -?0~3 and a solution Or the c~ude acid chloride in ether (150 ml) was run in. The mixture ~las stirred under nitrogen at -70 ror 15 minutes. Ilethanol (150 ml) ~as added to quench the reaction and the mlxture was dlluted with water and acidi~ied. Kieselguhr was added to aid riltration and the reaction mixture was ril-tered through a pad Or ~iesel~uhr. The ether layer was washed wlth sodium carbcnate solution and ~lth ~ater, dried over anhydrous magnes~um sulphate and eraporated to give a yellow solid. The product was purlrled by short column chromatography and recrystallisation from 60-80" Petrol to give trans-4-(6'-methoxy-2'-naphthyl)-pent 3-ene-2-one as a pale yellow solid (11.5 g, ô2.ô~), mp. 98-101C.
IR (Nu~ol): Carbonyl absorption at 1680 cm 1 Vinyllc proton singlet at 3.30 CH3C0-: 3 proton singlet at 7.30 ~ ~ 32 ~
r- - ;

, . ~ ~ ;-' . . .
- 1' ' 4-~'-Methoxy-2'-na~hthvl)-~entan-2-ol To a solution of 4-(6'-methoxy-2'-naphthyl)-pentan-2-one (2 g) in methanol (tOO ml), cooled in ice, ~as added sodium borohyarlde (1 g). The solution was stlrred rOr 1 hour, acidi~ied with dil. HCl and ex-tracted wlth ether (100 ml x 3). The water-washea ether extracts were dried (anh. Na2S04) and evaporated, glving a clear coIourle~s oll (1.3 g).
IR 3400 ¢m 1 (OH). No C = O absorption apparent.

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4-~6'~ethoxv-2~-naphth.vl)-Pentan-2-o~

4-(6'-Metho~Y-2'-naphth~rl)-pentan-2-ono (2 g) ln ether (100 ml) was added to a ~rlgnard prepared rrom moth,Yl lodlde (1.0 ml) and magneslum (0.5 g) ln ether (100 ml). The mlxture wa~ re n uxea for 1 hour, - cooled and decompoeed ~lth eaturated ammonium chlorlde solutlon. Extractlon wlth ether and evaporatlon gavo a clear colourless oil (1.5 g).
1: 3~50 ~m 1 (o~). No 0 ~ O aboorptlon app~r-nt.

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EXAMPLE~

4-(2-~aDhthvl~e~tan~2-o~ç

Vslng a reaction procedure exactly analagous to that or Example 4, 3-(2-naphthyl)butyrlc acld ~as con~erted to 4-(2-naphthyl)pontan-2-one b.p. 156/
1.5 mm Hg. ~~~

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~-(2-Na~hthvl)hexane-2-one Using a reactlon procedure analagous to that o~ Example 4, 5-(2-naphthyl)hexane-2-one ~as prepared ~rom 4-(2-naphthyl)valeric acld.

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Uslng the procedure of Ex~mple 15, the compound o~ Example 18 ~as reduced to yleld the tltle compound a8 an oil.
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6-Methoxy-2-naphthaldehyde (30 g) wae etirred in acetone (500 ml) with sodlum hydroside (10 mls Or 10~ aqueous solutlon) for 3 hours.
The solution was acidiried and extracted with ether. The ether solution wae dried (~gS04) and evaporated under reduced pressure to yleld a solid (30 g). Thls impure material wag puriried on a sllica gel column using benzene as eluant to glve ... . .
S 4-(6-methoxy-2-naphthyl)-3-buten-2-one (15 g), mp. t20C.

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iO49039 Pharmacalo~ical dat3 Ucing a conventlonal Allen-Doisy Test, the Oe~trogenic activity Or certain compounds Or the invention was ascertalned. The resultc are shown ln Table 1. The antl-in~lammatory activity o~ certain compounds of the lnvention was ascertained by using a standard Rat Paw Carrageenin Test. These re6ults are also ehown ln Table 1.
These results show that compounds o~ this lnvention have a good level Or activity at a dosage where excessive oestrogenslty is not to be expected.
Further, it is believed that an absence Or brancing at the~-carbon atom reduces greatly any oestrogenicity ~Jhich ~igh~ be ~re~cnt ~hile not errecting the anti-lnflammatory activity o~ the compounds to any great extent.
It has further been observed that compounds or the rormula:

C _ CH-CO-CH3 t Y~herein Rl is H or CH3 and the dotted line represents a double bond optionally present, do not excessively .

:. :

EXAMPLE 23 (continued) lrritate the rat stomach at a dose of 300 mg/k ~day orally after 3 days while at the end of 1~ day~ oral .treat~ent wlth the compound of formula (I), very severe gastrlc lrrltation was noted at the same do6e level.

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Claims (69)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of naphthylene derivatives of the formula (II):
(II) wherein X is a chlorine or bromine atom, or a methoxy, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CH(R1)-CH(R2)-, -CH(R1)-CO-, -CH(R1)-C(CH)R2-or -C(R1) = C(R2)- group, wherein R1 and R2 are each a hydrogen atom or a methyl ethyl or propyl group and Z is a R4, -(CH2)nCOR4, -(CH2)nCH(OH)R4 or -(CH2)nC
(CH3)(OH)R4 group wherein R4 is an alkyl group of 1 to 4 carbon atoms and n is 0, 1 or 2; with the provisos that (1) Y - Z contains at least one oxygen atom and not more than one carbonyl group and (2) X is not methoxy when Y - Z is a -CH2CH2-CO-CH3 group, which comprise (i) preparing a compound of the formula (II) wherein Y - Z
is -CH(R1)-CH(R2)-A2-R4, wherein X, R1, R2 and R4 are as defined above and A2 is a-CO,-CHOH or-C(CH3)OH group, by reacting a compound of the formula (VI) (VI) wherein X, R1 and R2 are as defined above and B1 is a chlorine or bromine atom, with a compound of the Formula (VII) R4-B2 (VII) wherein R4 is as defined above and B2 is a metal cation, to yield a compound of the formula (VIII) (VIII) wherein X, R1, R2 and R4 are as defined above; reducing the compound of the formula (VIII) to yield a compound of the formula (II) wherein Y - Z is - CH(R1)-CH(R2)-A2-R4 wherein A2 is a -CHOH group; and reacting the compound of the formula (VIII) with a methyl metal compound to yield a compound of the formula (II) wherein Y - Z is a -CH(R1)-CH(R2)-A2-R4 wherein A2 is a -C(CH3)OH group and R1, R2 and R4 are as defined above; and (ii) preparing a compound of the formula (II) wherein Y - Z is -C(R1) = C(R2)-A2-R4 wherein X, R1, R2 and R4 are as defined above and A2 is a -CO, -CHOH or -C(CH3)OH group, by reacting a compound of the formula (X) wherein X, R1 and R2 are as defined above and B1 is a chlorine or bromine atom, with a compound of the formula (VII) as defined in (i) to yield a compound of the formula (XI) (XI) wherein X, R1, R2 and R4 are as defined above; reducing a compound of the formula (XI) to convert the -CO group to a -CHOH group; and reacting the compound of formula (XI) with a methyl metal compound to obtain a compound of the formula (II) wherein Y - Z is a -C(R1) = C(R2)-C(CH3)OH group, wherein R1 and R2 are as defined above; and (iii) preparing a compound of the formula (II) wherein Y - Z is a -CHR1-A3-R4 group wherein R1 and R4 are as defined above and A3 is a -CO or -C(OH)R2 group, wherein R2 is as defined above, by reacting a compound of the formula (XIII) (XIII) wherein X and R1 are as defined above and B1 is a chlorine or bromine atom, with a compound of the formula (VII) as defined in (i) to yield a compound of the formula (XIV) (XIV) wherein X, R1 and R4 are as defined above; reducing a compound of the formula (XIV) to convert the -CO group to a -CHOH group; and reacting a compound of the formula (XIV) with a methyl metal or ethyl metal compound to obtain a compound of the formula (II) wherein Y - Z is a -CHR1-C(OH)CH3-R4 or -CHR1-C(OH)C2H5 group, wherein X, R1 and R4 are as defined above; and (iv) preparing a compound of the formula (II) wherein Y - Z is -CH(R1)-C(OH)(R2)-A5-R4, wherein x, R1, R2 and R4 are as defined above and A5 is a -CO, -CHOH or -C(CH3)OH group, by hydrating a compound of the formula (XVI) (XVI) wherein X, R1 and R2 are as defined above and R5 is a hydrogen atom or an alkyl group of 2 to 3 carbon atoms in the presence of a mercuric salt to yield a compound of the formula (XVII) (XVII) wherein X, R1, R2 and R5 are as defined above; reducing the -CO
group to a -CHOH group; and reacting a compound of the formula (XVIII) with an alkyl metal compound to form a compound of the formula (II) wherein Y - Z is a -CH(R1)-C(OH)(R2)-C(OH)(CH3)R4 group, wherein R1, R2 and R4 are as defined above; and (v) preparing a compound of the formula (II) wherein X is a methoxyl group and Y - Z is as defined above, methylating a compound of the formula (II) wherein X is a hydroxyl group or an anion thereof to obtain the corresponding, methoxy derivative; and (vi) preparing a compound of the formula (II) wherein X
is as defined above and Y - Z is a -CH = CH -CO-CH3 group, by condensing by base catalysis with acetone, a compound of the formula (XVIX) (XVIX) wherein X is as defined above; and (vii) preparing a compound of the formula (II) wherein X is as defined above and Y - Z is a -CH(R1)-CH2-CO-R4 group, wherein R1 and R4 are as defined above, by reducing a compound of the formula (B) (XX) wherein x, R1 and R4 are as defined above; and (viii) preparing a compound of the formula (II) wherein Y - Z is a -CH(R1)CH2COCH3 group, wherein R1 is as defined above, by reacting a compound of the formula (XXI) (XXI) wherein X and R1 are as defined above, with acetylacetone in the presence of a base.

2. A process for the preparation of a compound of the formula (V) (V) wherein X, R1, R2 and R4 are as defined in relation to formula (II) given in Claim 1 and A2 is a -CO, -CHOH or -C(CH3)OH group, with the proviso that X is not methoxy when R1 is a hydrogen atom, R2 and R4 are each methyl groups and A2 is a -CO group, which comprises reacting a compound of the formula (VI) (VI) wherein X, R1 and R2 are as defined above and B1 is a chlorine or bromine atom, with a compound of the formula (VII) R4-B2 (VII) wherein R4 is as defined above and B2 is a metal cation to yield a compound of the formula (VIII) (VIII) wherein X, R1, R2 and R4 are as defined above; reducing the compound of the formula (VIII) to convert the-CO group to a-CHOH group; and reacting the compound of the formula(VIII) with a methyl metal compound to obtain a compound of the formula (V) wherein A2 is a-C(CH3)OH group.

3. A process for the preparation of a compound of the formula (IX) (IX) wherein X, R1, R2 and R4 are as defined in relation to formula (II) given in Claim 1 and A2 is a -CO, -CHOH or -C(CH3)OH group which comprises reacting a compound of the formula (X) (X) wherein X, R1 and R2 are as defined above and B1 is a chlorine or bromine atom, with a compound of the formula (VII) R4-B2 (VII) wherein R4 is as defined above and B2 is a metal cation to yield a compound of the formula (XI) (XI) wherein X, R1, R2 and R4 are as defined above; reducing the compound of the formula (XI) to convert the -CO group to a -CHOH group; and reacting the compound of the formula (XI) with a methyl metal compound to obtain a compound of the formula (V) wherein A2 is a -C(CH3)OH group.

4. A process for the preparation of a compound of the formula (XII) wherein X, R1 and R4 are as defined in relation to formula (II) given in Claim 1 and A3 is a -CO or -C(OH)R2 group, where R2 is as defined in relation to formula (II) given in Claim 1 which comprises reacting a compound of the formula (XIII) (XIII) wherein X and R1 are as defined above and B1 is a chlorine or bromine atom, with a compound of the formula (VII) R4-B2 (VII) wherein R4 is as defined above and B2 is a metal cation to yield a compound of the formula (XIV) (XIV) wherein X, R1 and R4 are as defined above; reducing the compound of the formula (XIV) to convert the -CO group to a -CHOH group; and reacting the compound of the formula (XIV) with a methyl metal or ethyl metal compound to obtain a compound of the formula (XII) wherein A3 is a -C(OH)CH3 or a -C(OH)C2H5 group.

5. A process for the preparation of a compound of the formula (XV) (XV) wherein X, R1, R2 and R4 are as defined in relation to formula (II) given in Claim 1 and A5 is a -CO, -CHOH or -C(CH3)OH group which comprises hydrating a compound of the formula (XVI) (XVI) wherein X, R1 and R2 are as defined above and R5 is a hydrogen atom or an alkyl group of 2 to 3 carbon atoms in the presence of a mercuric salt to yield a compound of the formula (XVII) (XVII) wherein X, R1, R2 and R5 are as defined above; reducing the compound of the formula (XVII) to convert the -CO group to a -CHOH group; and reacting the compound of the formula (XVII) with an alkyl metal compound to obtain a compound of the formula (XV) wherein A5 is a -C(OH)(CH3) group.

6. A process for the preparation of a compound of the formula (II) given in Claim 1 wherein X is a methoxy group and Y - Z is as defined therein which comprises methylating a corresponding compound of the formula (II) wherein X is a hydroxyl group or an anion thereof to obtain the corresponding methoxy derivative.

7. A process for the preparation of a compound of the formula (II) given in Claim 1 wherein X is as defined therein and Y - Z is a -CH = CH-CO-CH3 group, which comprises condensing by base catalysis with acetone, a compound of the formula (XVIX) (XVIX) wherein X is as defined above to obtain the required compound.

8. A process for the preparation of a compound of the formula (II) as given in Claim 1 wherein X is as defined therein and Y - Z is a -CHR1-CH2-CO-R4 group, wherein R1 and R4 are as defined therein, provided that X is not methoxy when Y - Z is a -CH2CH2-CO-CH3 group, which comprises reducing a compound of the formula (XX) (XX) wherein X, R1 and R4 are as defined above to obtain the required compound.

9. A process for the preparation of a compound of the formula (II) as given in Claim 1 wherein X is as defined therein and Y - Z is a -CH(R1)CH2 COCH3 group, wherein R1 is as defined in relation to formula (II), provided that X is not methoxy when Y - Z is a -CH2CH2-CO-CH3 group which comprises reacting a compound of the formula (XXI) (XXI) wherein X and R1 are as defined above, with acetylacetone in the presence of a base to obtain the required compound.

10. A process as claimed in Claim 1, reactions (i), (ii), and (iii), Claim 2 or 3 wherein the compound of formula (VII) is an alkyl lithium compound.

11. A process as claimed in Claim 4 wherein the compound of formula (VII) is an alkyl lithium compound.

12. A process as claimed in Claim l, reactions (i), (ii), (iii) and (iv), Claim 2 or 3 wherein the reduction is carried out by hydrogenation in the presence of a transition metal catalyst or in the presence of a hydride selected from NaBH4 and LiAlH4.

13. A process as claimed in Claim 4 or 5 wherein the reduction is carried out by hydrogenation in the presence of a transition metal catalyst or in the presence of a hydride selected from NaBH4 and LiAlH4.

14. A process as claimed in Claim 1, reactions (i), (ii), (iii) and (iv), Claim 2 or 3 wherein the convertion of the CO to the corresponding tertiary alcohol is carried out by reaction with a compound selected from CH3MgCl, CH3MgBr, CH3MgI and CH3Li.

15. A process as claimed in Claim 4 or 5 wherein the convertion of the CO to the corresponding tertiary alcohol is carried out by reaction with a compound selected from CH3MgCl, CH3MgBr, CH3MgI and CH3Li.

16. A process as claimed in Claim 1, reaction (iv) or claim 5 wherein the compound of the formula (XVI) is prepared by reacting a compound of the formula (XVIII) (XVIII) wherein X, R1 and R2 are as defined in Claim 1 with an acetylide ion of the formula ?C ? C.R5, wherein R5 is as defined in Claim 1.

17. A process as claimed in Claim 2 wherein X is methoxy or methyl-thio and R1, R2, R4, B1 and B2 are as defined in Claim 2.

18, A process as claimed in Claim 3 wherein X is methoxy or methylthio and R1, R2, R4, B1 and B2 are as defined in Claim 3.

19. A process as claimed in Claim 4 wherein X is methoxy or methyl-thio and R1, R2, R4, B1 and B2 are as defined in Claim 4.

20. A process as claimed in Claim 5 wherein X is methoxy or methyl-thio and R1, R2, R4 and R5 are as defined in Claim 5.

21. A process as claimed in Claim 7 wherein X is methoxy or methyl-thio and R1 and R4 are as defined in Claim 7.

22. A process as claimed in Claim 8 wherein X is methoxy or methyl-thio and R1 and R4 are as defined in Claim 8.

23. A process as claimed in Claim 2 wherein X is methoxy and R1, R2, R4, B1 and B2 and A2 are as defined in Claim 2.

24. A process as claimed in Claim 6 wherein Y - Z is -CH(R1)-CH(R2)-Al-R4 wherein R1 and R2 are each a hydrogen atom or a methyl, ethyl or propyl group, R4 is an alkyl group of 1 to 4 carbon atoms and Al is a CO, CH(OH) or C(OH)CH3 group.

25. A process as claimed in Claim 23 wherein X is methoxy, R1 is a hydrogen atom or a methyl group, R2 is a hydrogen atom and R4 is a methyl or propyl group, and A2, B1 and B2 are as defined in Claim 23.

26. A process as claimed in Claim 24 wherein R1 is a hydrogen atom or a methyl group, R2 is a hydrogen atom and R4 is a methyl or propyl group and Al is as defined in Claim 24.

27. A process as claimed in Claim 25 wherein X, R1, R2, R4, B1 and B2 are as defined therein and A2 is a CO group.

28. A process as claimed in Claim 25 wherein R1 and R2 are each hydrogen, R4 is methyl and X, B1, B2 and A2 are as defined in Claim 25.

29. A process as claimed in Claim 26 wherein R1 and R2 are each hydrogen, R4 is methyl and X and Al are as defined in Claim 26.

30. A process as claimed in Claim 25 wherein R1 is methyl, R2 is hydrogen, R4 is methyl and X, B1, B2 and A2 are as defined in Claim 25.

31. A process as claimed in Claim 26 wherein R1 is methyl, R2 is hydrogen, R4 is methyl and X and Al are as defined in Claim 26.

32. A process as claimed in Claim 25 wherein R1 is methyl, R2 is hydrogen, R4 is propyl and X, B1, B2 and A2 are as defined in Claim 25.

33. A process as claimed in Claim 26 wherein R1 is methyl, R2 is hydrogen, R4 is propyl and X and Al are as defined in Claim 26.

34. A process as claimed in Claim 25 wherein R1 and R2 are each hydrogen, A2 is CHOH and R4 is methyl, and X, B1 and B2 are as defined in Claim 25.

35. A process as claimed in Claim 26 wherein R1 and R2 are each hydrogen, Al is CHOH, R4 is methyl and X is as defined in Claim 26.

36. A process for the preparation of 4-(6'-methoxy-2'-naphthyl)-pentan-2-one which comprises reacting the acid chloride of 3-(6'-methoxy-2'-naphthyl)-butyric acid with methyl lithium and isolating the desired compound.

37. A process as claimed in Claim 9 wherein X is methoxy and R1 is a methyl, ethyl or a propyl group.

38. A process as claimed in Claim 37 wherein X is methoxy and R1 is a methyl group.

39. Naphthylene derivatives of the formula (II) as defined in Claim 1 whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

40. A naphthylene derivative of the formula (V) as defined in Claim 2 whenever prepared by the process of Claim 2 or an obvious chemical equivalent thereof.

41. A naphthylene derivative of the formula (IX) as defined in Claim 3 whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.

42. A naphthylene derivative of the formula (XII) as defined in Claim 4 whenever prepared by the process of Claim 4 or an obvious chemical equivalent thereof

43. A naphthylene derivative of the formula (XV) as defined in Claim 5 whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.

44. A naphthylene derivative of the formula (II) as defined in Claim 6 whenever prepared by the process of Claim 6 or an obvious chemical equivalent thereof.

45. A naphthylene derivative of the formula (II) as defined in Claim 7 whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.

46. A naphthylene derivative of the formula (II) as given in Claim 8 whenever prepared by the process of Claim 8 or an obvious chemical equivalent thereof.

47. A naphthylene derivative of the formula (II) as given in Claim 9 whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.

48. A naphthylene derivative of the formula (V) given in Claim 2 wherein X is methoxy or methylthio and R1, R2, R4 and A2 are as defined in Claim 2 whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.

49. A naphthylene derivative of the formula (IX) given in Claim 3 wherein X is methoxy or methylthio and R1, R2, R4 and A2 are as defined in Claim 3 whenever prepared by the process of Claim 18 or an obvious chemical equivalent thereof.

50. A naphthylene derivative of the formula (XII) given in Claim 4 wherein X is methoxy or methylthio and R1, R4 and A3 are as defined in Claim 4 whenever prepared by the process of Claim 19 or an obvious chemical equivalent thereof.

51. A naphthylene derivative of the formula (XV) as given in Claim 5 wherein X is methoxy or methylthio and R1, R2, R4 and A5 are as defined in Claim 5 whenever prepared by the process of Claim 20 or an obvious chemical equivalent thereof.

52. A naphthylene derivative of the formula (II) as given in Claim 1 wherein X is methoxy or methylthio and Y - Z is a CH = CH-CO-CH3 group whenever prepared by the process of Claim 21 or an obvious chemical equivalent thereof.

53. A naphthylene derivative of the formula (II) as given in Claim 1 wherein X is methoxy or methylthio and Y - Z is a CHR1CH2COCH3 group wherein R1 is a hydrogen atom or a methyl, ethyl or propyl group, provided that X is not methoxy when Y - Z is a -CH2CN2-COCH3 group whenever prepared by the process of Claim 22 or an obvious chemical equivalent thereof.

54. A naphthylene derivative of the formula (V) as given in Claim 2 wherein X is methoxy and R1, R2, R4 and A2 are as defined in Claim 2 whenever prepared by the process of Claim 23 or an obvious chemical equivalent thereof.

55. A naphthylene derivative of the formula (II) as given in Claim 1 wherein X is methoxy and Y - Z is as defined in Claim 24 whenever prepared by the process as claimed in Claim 24 or an obvious chemical equivalent thereof.

56. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein X, R1, R2 and R4 are as defined in Claim 25 and A2 is as defined in Claim 2 whenever prepared by the process of Claim 25 or an obvious chemical equivalent thereof.

57. A naphthylene derivative of the general formula (II) as given in Claim 6 wherein Al, X, R1, R2 and R4 are as defined in Claim 26 whenever prepared by the process of Claim 26 or an obvious chemical equivalent thereof.

58. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein X, R1, R2, R4 and A2 are as defined in Claim 27 whenever prepared by the process of Claim 27 or an obvious chemical equivalent thereof.

59. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein X, R1, R2, R4 and A2 are as defined in Claim 28 whenever prepared by the process of Claim 28 or an obvious chemical equivalent thereof.

60. A naphthylene derivative of the general formula (II) as given in Claim 6 wherein X, R1, R2, R4 and A1 are as defined in Claim 29 whenever prepared by the process of Claim 29 or an obvious chemical equivalent thereof.

61. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein X9 R1, R2, R4 and A2 are as defined in Claim 30 whenever prepared by the process of Claim 30 or an obvious chemical equivalent thereof.

62. A naphthylene derivative of the general formula (II) as given in Claim 6 wherein X, R1, R2, R4 and A1 are as defined in Claim 31 whenever prepared by the process of Claim 31 or an obvious chemical equivalent thereof.

63. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein R1, R2, R4, X and A2 are as defined in Claim 32 whenever prepared by the process of Claim 32 or an obvious chemical equivalent thereof.

64. A naphthylene derivative of the general formula (II) as given in Claim 6 wherein R1, R2, R4, X and A1 are as defined in Claim 33 whenever prepared by the process of Claim 33 or an obvious chemical equivalent thereof.

65. A naphthylene derivative of the general formula (V) as given in Claim 2 wherein X, R1, R2, R4 and A2 are as defined in Claim 34 whenever prepared by the process of Claim 34 or an obvious chemical equivalent thereof.

66. A naphthylene derivative of the general formula (II) as given in Claim 6 wherein X, R1, R2, R4 and A1 are as defined in Claim 35 whenever prepared by the process of Claim 35 or an obvious chemical equivalent thereof.

67. 4-(6'-methoxy-2'-naphthyl)-pentan-2-one whenever prepared by the process of Claim 36 or an obvious chemical equivalent thereof.

68. A naphthylene derivative of the general formula (II) as given in Claim 1 wherein X is methoxy and Y - Z is a CHR1CH2COCH3 group wherein R1 is a methyl, ethyl or propyl group whenever prepared by the process of Claim 37 or an obvious chemical equivalent thereof.

69. A naphthylene derivative of the general formula (II) as given in Claim 1 wherein X is methoxy and Y - Z is a CH(CH3)CH2-COCH3 group whenever prepared by the process of Claim 38 or an ob-vious chemical equivalent thereof.