Note: Descriptions are shown in the official language in which they were submitted.
1049039
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 .
.: - . , - . ': :''
: .- - ~ . ... ~. . ;.
: .
: :
~ .
1049039
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
.'
.
. - ~ .
1049039
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 .
~ .
: . .
1049039
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):
_`5 _ .
.3 ~ .
`,. , ~ , , :'
:. ' - : .
- : '
-
'; . . ' ' , '.
. ` ~ ' ~ :- ':: - - ..
.
1049039
) 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.
~ .
.~` ,~ ,, , '.
~`- - 6 -
~- - ,, - - .
, . . ~ - :
'- , - : -.-
,. . ~ : . ~ .
.. ~ , . .
1049039
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
. ~ .
7 --
;i .
, . - - . .
.. . . .~ . . ~ .
.
1049039
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):
CHR1-CO-B
"~ 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.
_ g _
.~ ~
~ ' .
: . , .
.: ' ' . ~ '
~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)
-- 10 --
, .
.~
.
: . - ,
1049039
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
.
.
-- 11 --
1049039
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 -
`
-
~ ' , .
1049039
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
. ~ .
:.
~ : - -
', '. ' . , '' .
'
., ' ' ' ' . :
I~
1049039
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 ~
. ~ .
~ `
,--
. .
, ,
~; .
:i
-- 14 --
1049039
EXAMPLE 1
_____
-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 '.
_
:7`
'`' " ' ' '-, '' ' ' -, : I
;' , ' " ' ' ' ': ' ,'
. .
, ~ ,. :~ ' ''' .-'" ' ' '' " " '', . ' ' '
- 1049039
. 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.
.
.
- 16 -
,' . ' "- ' ':~
.
1049039
PIE~
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 ;'.
~, ' ''' ; ':
. ~ .
'': ' ' ~ '
''',, ' , ' .
.~ ' ' .
- 17 -
,~; . .
.~ .
,:,. . ., .... ' . : .
- . , .
.. ,
.~ . .
''' ' ` .. . :
..
.. .
~ - ~
~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 ~
'~`'` ` '` '`- `" '- ' - .' `:
. .
, .. . .
.
- .
. ' '
.; - .'' '
1049039
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.
.
.~ . ..
. ......... . ..
, .
- 19 -
. , ' '
. , .
,:,~.. , .- . , . . . .; . .
. - , . . -
..
,: . - : :- . . :
,: , . .
. ~ . . , ... ... ~ ..... ..
,: .. , ~ - ,, - .. , -, ~ ,
¦ 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.
~ . ..
.. . ~ , .
~ . .
:j ~ ', . . . - -
' '
20 - -
' ::
. . - . . : . . .- : : . :
- ,
- . ~: . '
1049039
EXAMPLE 7
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~;
.' . '
.,
;, .
;` , ". , ' .
.
... . .
:; . . . .
~, .
- 21 -
.
:., : - . ~ . ,
.
- . ~
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 -
- 22 -
`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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.
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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%).
.
'. ':
- 24 -
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. .
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.:
1049~)39
EXAMPLE 10
-(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%),
`"' ' ' ~ , ........................... .
'~ ' ' '
' '.
-- 25 --
: ~, ' - -
. . -
. - -
.. . . -
.. - . :
. ~. . .. . . .
-.- .- . . .. .
';- :~ - : . ~ , - . . -
.. ' ': :' ' ' . ' ~., - ,
1049039
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.
.j .
-- 26 --
.. .
.
.. ~ .
- .
'
`' -, : ,
- . . .
:.. - .
1~ 1049039
EXAMPLE 11
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'-
:
-~ - 27 -
... . . . .
.
, .
- ~ .
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~
- ' ~
.. . .
.~ . .
! -- 2B --
~_, . ..
~. . . .
' ~. -'" -''':. ,,
. ` .
.
1049039
, 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 - -
'' ' ' -
, .
1049039
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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.
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1049039
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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1049039
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' '
1049039
EXAMPIE 15
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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1049039
: .
EXAMPLE 16
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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1049039
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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. .' .'' ' ' ':
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- - - 35-
l ' ' - . .
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... . . .
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..
1049039
EXAMPLE 18
~-(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.
. . .
i .~ . . . .
.
.. ~ , .
., .
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~.
.. ..
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.
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1049039
`;
- EXAKPLE 19
^ ~
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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1049039
EXAMPLE 20
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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, ..... . . . . . . , - -
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iO49039
EXAMPLE 21
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
CH30
Y~herein Rl is H or CH3 and the dotted line represents
a double bond optionally present, do not excessively
.
:. :
1049039
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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1049039
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--41--
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