Note: Descriptions are shown in the official language in which they were submitted.
~AN 4060/67
1050~42
The present invention r~lates to polye~e compound~,
More particularly, the inventio~ concerned with pol;~ene
compou~ds, a process for the manufacture thereof ~nd
pharmaceutical prepRration~ containing same.
. ~
The polyene compourld~ provided by the present invention
are compound~ o~ the general ~or~ula.
R3 ~R6 ( I
R~
R5
, wherein one of the ~ymbols Rl and R2
rQpr~8entB 8 halo~;en ~tom or 8 lower
al3~rl e;roup a~d the other s ymbol repre-
Bents 6 halogen ato~ or a lower ~lkoxy
group, the symbol~ R3 and R5 each r~pre-
sent a h;~roge2~ or ~sloge~ atom ~r a
low~r alk;srl group with the proYisD tha~
on~ o~ the symbols R3 ~d R5 reprefient~
other than a h~logen atom, the s; rmbol R4
represents a lower alkoxy qrol~p and the
symbol ~6 represents a
-- 2 --
~s/l. 8. 1975
~1
io~sao42
carboxyl, lower alkoxycar~onyl,
or mono(lower alkyl)carb~moyl group,
and salt8 thereof.
The afo~ementioned lower ~lkyl groups prefer~bly
. ~
contain up to 6 carbon atoms such a8 the methyl, ethyl,
propyl, isopropyl or 2-methylpropyl group. The lower
alkoxy groups likewi~e prefersbly contain up to 6 carbon
atoms such as the methoxy, etho~ or isopropo~y group.
Of the halogen ~toms, rluorine and chlorine are
preferred.
. ~he amino group can be mo~osubstituted or di-
substituted by straight-chai~ or br~nched-chai~ lower ~lkyl'
groups~ e.g, by ~eth~l, ethyl or isopropyl. ~.
The alkox~methyl and alkoxycarbonyl groups prefer~bly
contain alkoxy groups ~aving up to 6 carbon atoms. The6e
csn be straight-chain or branched-chain such ~s, ~or ex~mple.
the methoxy, ethoxy or isopropoxy group. However, the
alkoxy groupR c~n also be higher ~lkoxy group~ containin~
from 7 to 20 carbon ~toms. e6peci~11y ~he ce~yloxy group.
The ~ia alkox~ ~roup~ can be substituted b~ functionsl
groupE; for exA~ple. by nitrog~n-cont~inin~ group~ 6uch
a~ a~ optionally al~yl-substituted ~ino or morpholino ~roup.
or b~ 2 piperidyl or pyridyl group.
5~ ~ ~2
~ he alkenoxycarbonyl and alkynoxycarbonyl groups
also pre~erably contain alkenoxy and alkynoxy groups con-
taining up to 6 carbon atoms such a~, for ex~mple, the
allyloxy or propargyloxy ~roup.
~he alkanoylgroups present in the ~lk~noyloxymethyl
groupR are prefer~bly deri~ed from lower alka~ecarbox~lic
acid~ containing from 1 to 6 carbo~ atoms (e,~, acetic acid,
propionic acid or pi~lic acid),but they m~ al30 be asrived
from higher alkanecsrboxylic acids containing from 7 to 20
carbon atoms (e,g. p~lmitic acid or ~te~ric acid).
~he carbamoyl group can be mono~ubstituted or di-
substituted by ~trai~ht-chain or branched-chain lower alkyl
groups (e.g. meth~l, ethyl or isopropyl). Example~ of such
substituted carb~moyl groups are the meth~lcarbamo~l, dimethyl-
carbamo~l ~nd diethylcarb~moyl ~roups.
~he N-heterocyclyl portion of the ~-heteroc~cl~lcar-
bonyl ~roups i~ pre~er~bly a 5-membered or 6-m~mbered
heterocyclic group wh~ch, in addition to the nitrogen ~tom,
may al80 contain an oxy~sn or sulphur atom or a further
nitroge~ atom. ~xamples thereof are the piperldi~o,
morpholinos thiomor~holino or pyrrolidino group,
Examplss o~ compound~ of formula I ~r~:
9-(6-chloro-4-methoxy-2,3-dimethyl-phenyl)-3,7-dimethyl-
-nona-2,4~6,8-tetraen-1-oic acid ethyl ester,
9-(~-chloro-4-methoxy-2,5-dimethyl-phenyl~-3,7-dimethyl-
-nona-2,~.6,8-tetraen-1-oic acid ethyl ester,
~ 05004Z
9-(2-chloro-4-methoxy-~,5,6-trimethyl-phenyl)-3,7-dimethyl-
-rlona-2,4,6,8-tetraen-1-oic acid et~yl ester,
9-(5-chloro-2,4-dimethoxy-6-methyl-phenyl)-3,7-dim~thyl-
-nona-2,4,6,8-tetraen-1-oic acid ethyl ester,
9-(2,6-dichloro-4-methoxy-phen~1)-3,7-dimethyl-nona-
-2,4,6,8-tetr3en-l-oic acid ethyl ester,
9-(2,5,6-trichloro-4-methoxy-phen~ 3,7-dlmethyl-nona-
-2,4,6,8-tetraen-1-oic acid ethyl e9ter D
9-(6-methyl-2,4-dimethoxy-phenyl)-3,7-dimethyl-~ona-
-2,4,6,8 tetraen-1-oic acid ethyl ester and
9-(2,4-dimethox~-3,6-dimethyl-phen~ 3,7-dime~hyl-
-nona-2,4,6,8-tetr~en-1-oic ~cîd ethyl ester.
According to the process provided by the pre~ent
invention, the compounds of formula I hereinbefore and
their 8alt8 are ma~u~actured by reacting a compound of the
ge~eral ~ormula
R3 ~ A
R~ ~Rl
~ II
with a co~pound of the ge~eral formula
5~
~ ~ III
wherein thc s~mbol m standc for zcro
and the symbol n stands for 1, or the
symbol m stands for 1 and the sgmbol n
stands for zero 7 one of the symbols A
and B repre~ents the for~yl group and
the other symbol repres~nts eithe~ a
triarylpho~phoniummethyl group of the
formul~ -CH2-Pt~3
, in which the symbol X represe~ts an
aryl group and the symbol Y repres~nt~
th~ anion of an or~a~ic or inorganic
~cid, or a dialkoxyphosphinyl~ethyl group
of the formula -CH2-~Z]2-
o
in which the symbol Z represents an
al~oxy group; or one of the symbols A
a~d B represents a halomethyl~ alkyl-
~sulphonylox~methyl or arylsulphonyloxy-
methyl group and the other symbol repre~
sents a sulphonylmethyl group of the
formula -CH2~ ~ , in which the symbol
repre~ents an aryl or aralkenyl group
which may carry one or more electron-
-repelling to electron-weakly attracting
lalSO~Z
substituents; the symbol~ Rl, R2,
R3 9 R4, and R5 have the significance
given earlier; and the symbol R7
represents a carboxyl, alkoxycarbonyl,
alXenoxycarbon~yl, alkynoxycarbonyl,
di(lower alkyl)carbamoyl or N-hetero~
cyclylcarbonyl group; or the symbol
R7 also represent~ ~n alkoxymethyl or
alkanoyloxyme~h~l group when the ~ymbol B
represents the formyl group; or the
cymbol R7 also represen~s a for~yl,
alkox~m~t~yl or alkanoyloxymethyl group
when the symbol B repr~sents ~ halomethyl.
alkyl~ulphonylsx~methyl or arylsulphonyl-
o~methyl group; or the symbol R7 also
represents a formyl group when the symbol
` B represents a triarylphosphoniummethyl
group, a dial~ox~phosphinylmeth~l group or
a sulphonylmethyl group,
and clea~ing off a sulphone group which may be pre~ent in
the reaction product to form an ~dditional carbon-carbon
bo~d, a~d, if desired, converting an acid obtained or sn
amine obtainsd into a salt, or converting a carboxylic acid
of formula I into a carbo~ylic acid ester of formula I or
into an amide of formula I, or converting a carbox~lic acid
ester of formula I into a carboxylic acid of formula I or
i~to ~n amide of formula I, or r~ducing a carboxylic acid
of formul~ I or a carboxylic acid ester of formula I to
the corresponding alcohol of formula I and if d0sired
ethcrifying or esterifying said alcohol, or saponifying a~
lOS~O~Z
alcohol ester of formula I, or oxidising ~n ~lcohol or
alcohol ester of fo~mula I to the corresponding carbo~ylic
acid.
~he aryl groups denoted by the ~ymbol X in the
triarylphosphoniummethyl groups formulated earlier include all
generally known aryl group~. How~verf the aryl group~ are
preferably mononuclear aryl groups such as phenyl or (lower
alXyl)- or (lower alkoxy)-fiub~tituted phenyl groups
(e~g. tolyl, xylyl. mesityl and p-methoxgphe~yl). Of the
inorganic acid anions denoted by the symbol Y, th~ chlorine,
bromine or iodine ion or the hydrosulphate ion is preferred.
Of the organic acid anio~s, the to~yloxy ion i~ preferred.
~he alkoxy groups denoted by the ~gmbol Z in the
dialkoxypho~phinylmethyl ~roups formulated ~arlier are
preferably lower alkoxy groups containing from 1 to 6 carbon
atoms, especially methoxy and ethoxy group~.
Example~ of aryl or aralkenyl groups, which ma~
carry one or more electron-repelling to electron-weakly
attr~cting ~ubstitue~ts, denoted by the symbol E i~ the
~0 sulphon~lmethyl group~ formulated earlier are phenyl and
styryl, both of which may be ~ubstituted in the o-, m- or
p-position by
methoxy, phenoxy, acetoxy;
dimethylamino, phenylmethylamino, scetylamino;
thiomethyl, thiophenyl, thioacetyl,
chloro, bromo;
cyano; or
nitro in th~ m-position.
-- 8 --
0 5~ 0 ~ 2
~ he starting materi~ls of formula II are, in part,
novel and such novel starting materials al~o form par~ of
this invention. The~ can be prepared. far example, i~
the followlng manner:
Compounds of formula II in which the ~mbol m stands
for zero and the s~mbol A representa a triar~lpho~pho~ium-
meth;yl group [ IIaJ or a dialkoxyphosphinylmethyl group
~IIc] can be prepared, for example, by treating a corre~pon-
ding (Rl-R5)-benzene with formaldeh~de in the presence of a
h;~rdrohalic acid (e.~;. in the prosence of concentr~tea hyaro-
chloric acia optionally in a solvent, e~peci~lly in a glacial
acetic acid) and reacting the resulting (Rl-R5)-benzyl halide
~a halide of formula II in which the ~ymbol m stand~ for zero
and the symbol A represent~ a halomethyl group (IIi)] in a
manner known per ~e with a triarylphosphine in a sol~ent,
preferabl~ with triphenylphosphine in toluene or benzene, or
with trlalkylpho~phite, e~peci~lly with triethylpho~phite.
A~ alkoxy group can be introduced into the ~fore-
D~ontioned (Rl-R5)-benzene b r, for example, alkyl~tion of a
h~dro~y group alroaay pre~ent. For ex~mple, the corresponding
ph~nol, preferAbly in a sol~ent (e.g. an al~anol) and in the
presence of a base (e.g. potas~ium carbonate) can be r~acted
with an alkyl halide (e.g. meth~l iodide) or dimsth~lsulphate.
Compounds of the formula II in which the sgmbol m
6ta~d6 for 1 and the s;s~mbol R repre~ents a triar;ylpho~phonium-
-methyl group ~IIb~ or a di~lkoxypho~phinylmethyl group (IId)
can be prepared, for example, in the following msnner: A
corro6ponding (Rl-R5)-benze~e is fir~t subaected to
~ 05004Z
formylation; for example, by allowi~g a form~lating age~t
to act on said (Rl-R5)-benzene~ This can be carried out,
for example, by carrying out the form~lation in the prese~ce
of a Lewis acid. As fo~mylating agents, there ma~ be
mentioned, in particular, orthoformic acid esters, ~ormyl
chloride ana dimethylform~mide. Especîall~ ~uitable l~wi8
acid~ are the halides o~ zinc. ~luminium, tit~nium, ti~ and
iron, such as zinc chloride, aluminium trichlorid~, titanium
tetr~chloride, tin tetrachloride ~nd ion trichloride, as well
as the h~lides of inorganic and or~an~c acids such as, for
example, phosphoruc oxychloride a~d metha~e~ulphon~l chloride.
If the form~lati~g agent i~ pre~ent in exces~, the
form~lation ma~ be carried out without the addition of a
furt~er solvent. Howe~2r, it i~ generally recommended to
carry out the formylstion in an inert solvent (e.g.nitroben.ene
or ~ chl~rinated hydrocarbo~ such as methyle~e chloride~. The
formylation can be carried out at temperature between 0C and
the boiling point of the for2ylatio~ ~ixture,
The (~l-R5)-benzaldeh~de obtAi~ed can be subsequently
con~erted in a manner known per ~e by condensation with ace-
tone in the cold (i.e. ~t ~ temper~ture of Rbout 0-30~ in
the pre~ence o~ alk~ .g. dilute aqueous sodium h~droxide)
into ~ (Rl-R5)-phen~l-but-3-en-2-one which can be cQnverted
into a corresponding (Rl-R5)-phenyl~3-methyl-3-hydroxy-penta-
-4-en-1-yne in a ma~ner known per ~e by means of ~n organo-
metallic reaction (e,g, a Grignard reaction with the addition
of acetylene), The reeultin~ tertiary acetylenic carbinol is
subs~quentl~ partially hydrogenated in a manner ~nown per se
uaing ~ partl~ deactivated noble metal catalyst (Lindlar
-- 10 --
~ os~
cataly~t). The resulting tertiary ethylenic carbinol c~n
subsequently be converted into the desired phosphonium salt
of formula IIb in which the symbol m stands for 1 under
allylic rearr~ngement ~y treatment with a triarylphosphine,
especially triphenylpho~phine, in the presence of a mineral
acid (e,g. a hydrogen halide ~uch a~ hydrogen chloride or
hydrogen bromide or sulphuric acid) in a solvent (e,g.bonzene),
~he tertiary ethylenic carbinol can also be halogenated to
give a halide of the formula II i~ which the symbol m stand~
for 1 and the symbol A repre~ents a halomethyl group (IIk)
a~d the halide can be converted with a tri~lkylphosphite
(e.g. triethylpho~phite) into a corresponding phosphonate of
the formul~ IId.
Compou~ds of formuls II in which the symbol m stands for
zero and the s~mbol A represents a sulphonylmethyl group E IIe
car. be pr~parcd, for example, by dissolving a (Rl-R5)-phenol
or a corresponding halobenæene in a polar solvent (e,g, a~
alka~ol such as metha~ol, ethanol or isopropanol, tetrahydro-
-furan, dimethylform~mide or gl~cial acetic acid) and treating
the solution at room temper~ture with a sulphinic acid of t~e
formula Ho~ -E~ in ~hich the symbol ~ has the significance
given earlier. or with an alkali salt of said sulphinic acid.
~he sulphone can be isolated from the reaction mixture by,
for example, making the re~ction mi~ture ~eutral by the
addition of an agueous sodium bicarbonate solution and ex-
tracting the ~ulphone with an organic solvent (e.g, ethyl
acetate or ether~,
Compou~ds of formula II in which the s;ymbol m stands
~ 0 50 ~ ~ Z
for 1 and the symbol A repre~ent~ a sulphonylmeth~l group
[IIf] can be prepared ln ~n ~nalogous mæ~ner b~ reactin~ a
(Rl-R5)-phenyl-3-meth~yl-pe~ta-2~4-dien-l-ol or ~ corre~ponding
halide with a previ~u~ly de~cribea sulphinic ~cia or with ~n
alkali metal salt thereof.
Compound6 of formula II in which the symbol m stands
for z~ro and the s~mbol A represents the formyl group ~II]
can be prepared, for example, by formylating a (Rl-R5)-benzene
in the ~annor prev_ously describ0d. I~ this m~n~er, there i~
obtained directly the (Rl-R5~-benzaldehyde,
Compound~ of formuld II i~ which the symbol m ~tands
for ~ ~d the ~ymbol A represents the form~l group ~IIh~ can
be prep~red~ for ex~mple, by reacting a (21-~5)-phenyl-~ut-
-3-en-2-one (de~cribed hereinbefore in connection with the
prepar~tion of compou~ds o~ formula IIb) under the conditions
of a Wittig rcaotio~ with ethoxycarbonyl-methylene-triphe~
-phosphorane or with diethyl-phosphonacetic acid ethyl e~ter~
Thé re~ulting (Rl-R5~-phen~1-3-methyl-penta-2,4-aie~-1-oic
acid eth~l ester i~ ~ub~equentl~ reduced in the cold by me~n~
of a mixed met~l hydride, especially lithium alumi~ium hydride,
in a~ organic 801ve~t (eOg. ether or tetrahydrofur~n) to give
a (Rl-R5)-phenyl-3-methyl-penta-2,4-dien-1-ol. This alcohol
i8 then oxidised by treatment with an oxidising agent (e,g.
m~ng~nese dioxide in an or~anic colverLt 3uch as acetone or
meth~lene chloride) at a temper~ture between 0C and the
boilin~ point of the oxidation mixture to gi~e the desired
(Rl-R5)-phe~yl-3-methyl-pentfl-2,4-dien-1-al of for~ula IIh,
- 12 -
~os~
~he co~pounds of the formula III are. in part, nov~l.
Compounds of formula III in which the symbol n stanas
for zero ~nd the sgmbol B r~presents a tri~rylphosphoni~m-
methyl group ~IIIa] or ~ dialkoxyphosphi~ylm~thyl group
tIIIc] csn be readily prepared by xescting a 4-halo-3-methyl-
-crotonic acid~ which ~ay be esterified, or an etheri~ied
4-h~10-3-meth;yl-crotyl alcohol with a triar;ylpho~phi~e i~ a
801v~nt~ pref~rably with triphe~ylpho~phine in toluene or
benzene, or with a trialkylpho~phit~,especiall~ with triethyl-
10 phosphite.
Compounds o~ formul~ III in which the symbol n ~t~nd~for 1 ~nd the sgmbol B rQpresents ~ triarylphosphoniummethyl
~roup ~IIIb3 or a dial~oxypho~phinylmethyl ~roup ~IIId~ can
be prep~red, for example, by reducing the for~yl group i~ an
aldehgde of formula III, in which the symbol ~ stands for 1
and the ~gmbol B repr~s~nts the formyl group ~IIIh3 to th~
hgdroxymethyl group using a mstal hydride such a~ ~odiu~
boro~ydride in an fil~nol (e.g. sthanol or i~opropa~ol).
th~ r~ulting ~lcohol c~n be halogenated using a cust~mary
h~logenating ~gent (e.g.pho~porous o~ychloride) and the
resulting 8-halo-3,7-dimethyl-oet~-2,4,6-triene-1-carboxylic
acid, ~ halide of formul~ III in which the ~mbol n st~nd~
for 1 a~d the symbol B represen~ 8 h~lomethyl group ~IIIi~,
or a deriv~tive thereof can be co~verted with a triarylphos-
-phi~e i~ a solvo~t, preferably triphenylpho~phine,in tolusne
or benzene, or wit~ a trialkylphosphite, especially
triethylphosphite, i~to a desired pho~pho~ium salt of for~ula
IIIb or pho~phonate of formula IIId.
~5~
Compounds of formula III in which the symbol n stand~
for zero and the symbol B represents a ~ulpho~lmethyl group
~IIIe3 ca~ be prepared, for exa~ple, by reacting 4-hydroxy
-3-mathyl-but-2-e~-1-al or the acetat~ thereof or the corre~-
po~di~g bromide in a polar 801~ent ( e.g, isoprop~nol orn-butanol) in the m~n~er pre~iou~ly describ~d with an ~ore
mentioned ~ulphinic Acid or wi~h an alkali met~l ~alt th~reof~
Compounds of formula III i~ which the symbol n ~tanas
for 1 and the ~ymbol B repre~ents 8 ~ulphon~lmethyl group
tIII~ can be prepared in a ma~ner analogous to th~t previousl~
described by the re~ction of, for example~ 8-hydroxy-3,?-
-dimethyl-octa_2,4,6-trien-l~oic acid or the acetate thereo~
or a corresponding bromide with a~ ~foremention~d sulphinic
acid.
Compounds o~ formula III in which the ~ymbol n ~tand~
for zero and the agmbol B r~present~ the form~l group [IIIg]
can be prepared, for oxa~ple, by oxidatively clea~ing an
optionally e~terified t~rtaric acid (e,g. uæing l~ad tetra
-acetate at room te~perature in an organic solvent such as
ben~ene), ~he ~lyoxalic ~cid deriv~tive obtainsd is 6ub-
eque~tly condeneed i~ a manner known per se. co~eniently
i~ th0 pre~enoe of an ami~e, wlth propio~aldeh~de a~ an
el~vated temperature ~e.g. a temper~ture betwee~ 60C a~d
llO~C) with 10~9 of water to ~ive a desired 3-formyl-crot~l
slcohol deri~ati~s.
Compound~ of for~ula III in which the ~mbol n stand6
for 1 and the symbol B represents the formyl group ~IIIh~
-- 1~
~500~2
c~n be prepared, for example, by allowing phosgene to aot on
4,4 dimethoxy-3-m~thyl-but-1-en-3-ol in the cold9 preferabl~
at -10C to -20C, i~ the pre~e~ce of a tertiary amine ~uch
a~ pyridi~e ~nd condensing the re~ulting 2-formyl-4-chloro-
-but-2-ene under the coud~tion~ o~ ~ Wittig reaction with
3-formyl-croto~ic acid, which ma~ be ssterified9 or with a
3-formyl-crotyl ~lcohol, which m~ be esterified, to give
the desired aldehyde of formula IIIh.
In accord~nce with the process provided by the pre~e~t
invention, a pho~pho~ium salt of formula IIa or IIb is
reacted with an alde~yde of formula IIIh or IIIg, or a
phosphonium ~alt of formula IIIa or IIIb is reacted with
an aldehyde of ~ormula IIh or IIg, or a phosphonate of
~ormula IIc or IId i8 reacted with an ~ldehyde of formula
IIIh or IIIg 9 or a phosphonate of formula IIIc or IIId is re-
acted. with an alaehyde of formula IIh or IIg, or a sulphone
of formul~ IIe or IIf i8 reacted with a halide o~ formula
IIIk or ITIi or a ~ulphone of formula IIIe or III~ is reacted
with a halide of for~ula IIk or IIi.
According to the Wittig procedure, the compo~ents are
reacted with one another iu the presence of an acid-binding
agent ~e.g, an alkali metal alc~hol~te 5uc~ as sodium methylate
or a~ alkylene oxide which may be alkyl-substituted, e~pecially
ethylene oxid~ or 1,2 but~lene oxide), or if desir~d in a
~olvent (e.g. a chlorinated h~drocarbon such as meth~lene
chloride~ or dimeth~lform~mide), at a temperature between
room temperature and the boil~ng point of the reaction mixture,
- 15 -
~S0042
According to th~ Horner procedure, the compo~ents are
reaeted to~3ether u~i~ag a ba~ and pr~f0rably in'the pr~er~ce
o~ an inert organic 801ve~nt9 ~or ex~mple sodium h;rdrid~ i~
benzene, toluene, dimeth;ylfornamide, t~trah;ydrofura~ or
1,2-dimethox;s~ethane, or alao sodium methylate in ~thanol,
at a temperature between 0C ~nd the boiling point of the
reaction mixtur¢.
According to l;he Julia procedure, th~ comporLents ~re
reacted ~ith o~e a~other u8i~g a cond~naation agc~t, con-
veniorltly in the pres~no~ of a polar solvent. ~u~table
solv~nts are, for e3~ample, dimeth~l~Grm~mide, dimct}~l
sulp}:loxide, dimethyl~cetamideg tetr~h~dro~ur~ a~d hexs-
-meth;~lpho~phoric acid triamid~ a~ well as ~lcohol~ ~uch a8
metha~ol, isopropano~ or terbutanol~, Of the stro~g b~0es
which are particul~rl~ use~ 18 the co~densatio~ ag~nts
there ca~ be mentioncd, for exam~le, allc~li mat~l and alkaline
~arth metal carbonate~, ~specially sodium carbonato. alkali
~etal hardroxides ~uch a~ pot~sium h~rdroxide or sodium
h;~rdroxide, alkali metal and ~lk~line earth metal alcohol~tes
8UCb a~l sodium Dleth~late and, eapeci~lly, potassium tert-
-butylete, alkali met~l hydrides such as sodium ~dride,
alkyl-magne~ium halides ~uch a~ methyl-magnesium bromide snd
~lkali metal amides ~uch ~8 ~od~um ~mide, The resction
USirlg this proeedure i~ pr~ferably carried out st a low
temper~ture, e~pecially at a temp~rature below the freezing
point (e,g, betwee~-5C)C and -80C).
It has boen ~ound to be con~Tenient in cert~in case~ to
carry out the aforementio~ed re~ctions in situ; th~t is to
-- 16 --
:1~50042
say, without i~olating the particular phoQphonium ~alt,
phosphonate or sulphone from the medium in which it i8
prepared .
A carboxylic ac~d of ~ormula I can be co~erted in a
mann~r known per ~e (e,æ, by treatment with thion~l chloridet
preferabl~ in pyridine3 into ~n acid chloride which c~n be
co~verted into an ester by resction with an alka~ol a~d into
an amide by re~ction with 8mmonia,
A carboxylic acid ester of formula I can be h~drolysed
to a c~rboxylic acid in a man~er known per se, for example,
by treatment with an alkali, especially uqueous-alcoholic
~odium h~droxide or potassium hydroxide at a temperature
betwee~ room temperature and th~ boiling point of the mixture,
- ~he re~ulting carbo~ylic ~cid c~ then be amidated via an
acid h~lide. Alternati~el~, a carboxylic acid ester ca~ be
directly amid~ted a~ de~cribed herein~fter.
A carbo~ylic acid ester o~ formula I c~n be converted
dir~ctly into a corresponding amide by treatment with lithium
amide. ~his treatment 1~ advanta~eously carried out at roo~
temper~ture.
A cfirboxylic ~cid or a carboxylic acia ester o~ formula
I can be reduced to a corresponding alcohol of formula 1 in a
manner X~own per se. ~he reducticn i~ advantageou~ly carried
out using a metal ~ydride or alkyl metal hydride in an inert
solvent. Examples of hydride~ which h~ve proved to be
particularly suitable are mixed metal hydride~ such A~ lithium
~ os~4~
aluminiu~ h~dride and bis-~methoxy-ethylenoxy~-sodium ~lu-
minium hydride. Suit~ble inert ~olven~ are, int~r alia 9
ether, tetrahydrofuran or dioxane when lithium aluminium
h~dride is used and ether, hexane~ benzene or toluene when
diisobutylaluminium hydride or bi~-~methoxy-ethyle~oxy~-
-sodium aluminium ~ydride is usedO
An alcohol of formula I can be etherified with an alkyl
h~lid~ (e,g. eth~l iodide), for example in the presence of a
ba~e, preferably ~odium hydride, in an organic solv~nt such
0 ~8 dioxane, tetrahydrofuran, 1,2-dimethsxyetha~or dimethyl-
formamide, or in the presence o~ an alkali metal alcoholate
in an alka~ol, at a temperature betwee~ 0C and room te~-
peratureS
An alcohol o~ formul~ I can ~180 be esterified b~
treatment with an alkano~l halide or anh~dride, expedientl~
in th~ prcssnce of e bas~ (e,g. pyr~dine or triethyl~mine)
at ~ t~mperhture betwee~ room temperature and the boili~g
point of the mixtur~.
An alcohol e~ter obtained can be saponified in a ~anner
kno~ per se; for example in the man~er previou~ly describcd
in connection with the saponification of a carbox~lic acid
ester,
An ~lcohol of formula I or ~n ester thereof can be
oxidised in a maDner known per ~e to give a corre~ponding
acid of formula I. The oxidation is ad~antageou~ly carried
out U8ihg ~ er ~I) oxide and an alkali in w~ter or in a
- 18 -
~05Q04'~
water-miscible organic 801vent st a temper6ture between room
temperature and the boiling point of the mixture.
An amine of formula I ~orms acid addition salts with
inorganic acids (e,g, hydrohalic acids, especially hydrochloric
acid or hydrobromic acid, and sulphuric acid) a~d with orga~ic
acids (e,g, benzoic acid, acetic acid. citric aoid ana l~ctic
acid), A carboxylic acid of formula I form~ ~alts with b~se~,
e~pecially with alkali met~l hydroxidc~ and particularly with
sodium h~droxide and pot~s3ium h~droxid~.
10The compounds of formul~ I can occur a~ a ci~/trans
mixture which m~y be ~eparated in a manner known per s~ into
the ci~ ~nd trans compone~t~ or isomeri~ed in a manner known
per se to the all-tran~ compounds.
~hc present polye~e compounds ~re pharmacod~namically
valuable. They can be usea for the topical ana 9y8temic:
therapy of benign and malignant neoplasia and of premalignant
lesions as well ~8 for the systemic and topical proph~laxis
of these conditionc. ~hey are al80 suit~ble for the topical
and ~y~temic therspy of acne, ~coriacis and other dermatoses
20 accompanied by an increased or patholo~ically altcred corni-
fication, and for the treatment of infl~mmatory and allergic
dermatological condition~, ~he present pol~ene compounds
ca~ al~o bs used for comb~ttin~ mucous membrane disea~es with
inflammatory or de~enerative or metaplastic alterations.
25The toxicity of the pre~ent polyene compounas is slight.
For example, when 9-(2-chloro-4-methoxy-3,5,6-trimethyl-
- 19 -
~os~04z
-phenyl)-3~7-dimethyl-~ona 2,4~6,8-tetrRen l-oic acia i~
adminiætered intraperitone~lly to mice weighing ~0 g i~ a
daily dosage of 200 mg/kgf then no indication OI an A-h~per-
vitaminosis become~ evident ~fter 14 days ~ total of 10 ~d-
ministration days~
~ he first indic~tio~s of a slight A-hypervitaminosis
in mice appears at a daily do~age of 400 mg/kg after 14 d~ys
Ztotal of 10 administratio~ dP~] This ma~ife~ts it6elf
in a weight decrease of 20~, a moderate h~ir loss and slight
flaking of the skin.
The tumour-inhibiting ~CtiYity of the pre68nt polyene
compound~ i8 significantr In the papilloma te~t, tumours
induced with di~ethylbenzanthracene and crot~n oil regreas.
~he dia~eter of the papilloma~ within 2 weeks after the
intraperitoneal administr~tion of 9-(2-chloro-4-methoxy-3,5,6-
-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic
acid eth~l ester decre~se3 by 61~ at a dos~ge of 400 ~g/kg/week
and by 45~ at a dosage of 200 mg/kg/week.
The polyene compounds of fo~mula I and their salts can
therefore be used as medicaments; or example, in the form of
pharmaceutical preparation~ which contain them in association
with a c~mpatible phar~aceutical carrier,
~ he pharmaceutical preparations for systemic adminis-
tratio~ can be prepar~d f for ~xample, by adding a polyene
compound as the active ingredient to no~-toxic inert solid or
liquid carriers which are usual in such preparations.
- 20 -
~ ~0 ~ ~ 2
The pharmaceutical preparations can be administered
enterally or parenterally. Suitable preparations for enteral
administration are, for example, tablets, csp~ules, dra~ées 9
8yrup~, suspensio~ olutions ~nd ~uppositories and suitsble
preparation~ for parenteral administrati~n are infusion and
in~ection solutions,
The aosage~ in which the polyene compound~ of this
invention are adminiRtered can b~ varied according to the mode
and route of admini~tration ~nd according to the requir~ments
of the patient,
~he polyene co~pound~ of this in~e~tion can be adminis-
tered in amount~ of from 5 mg to 200 mg daily i~ one or more
dosage~. Capsules containing ca 10 mg to ca 100 mg of a
polyene compound of thi~ inventio~ represent a proferred form
o~ administr~tion.
~he pharmaceutical preparations ca~ contain i~ert or
pharm~cod~namically acti~e additi~es, Tablet6 or granules,
for ex~mple, ccn conta~n a æerie~ of binders, fillers, c~rrier
materials or diluents, Liquid preparations can, for example,
take the form of a 8t9rile WBter-mi~Cible 801utio~. C~psule~
can co~t~ filler or thiekener, ~urthermore, flavour-
-improvi~g additi~es and ~ubstances commonly usea a~ pre~er~
~ative~, stabili6ers, moisture-retainers or emulsifier69
salts for var~ing the os20tic pressure ~ buffers aIld other
additives can al80 be present in the pharmaceutical prep~r&-
tions .
~soo~z
~ he aforementioned c~rrier ma~erial3 ~nd diluQnt~ ca~
be organic or inor~anic ~ubatances ~uch a~ wst6r, ~el~tin,
lactose, ~tarch, magnesium ~tearate, talc, gum arabic, poly-
alkylenegl~col~ and th~ like, It i~, of cource~ a pre-
requisite that Rll ad~uvants used in the preparation o~ thepharmaceutical preparations are no~-toxic.
For topic~l ~d~inistr~tio~, the pre~ent pol~ene com-
pounds are expedientl~ mede up in the form or ointment~,
tinctures, cream~, 801ution8 ~ lotion~, sprays, ~uspe~sion~
and the like. Ointm~t~, crssms and ~olutions sre pr~ferred.
These pharmaceutical preparation~ for topic~l ad~inistration
ca~ be prepared by mixing the pol~ne compou~dst a~ the active
ingredie~t, with no~ toxic insrt ~olid or liquid carriers
which are cuatomary i~ su~h prep~r~tions and which are suitable
for topic~l treatm~nt~
Expedient for topic~l ad~i~istration are ca 0.10% to
ca 003%, pre~erably O.OZ% to 0.1%~ solution~ ~nd ca 0.05% to
ca 5%, preferably ca 0.1% to ca 2.~%, ointments or creams.
An antioxiaant (e.~ tocopher~ metbyl-~-tocophera-
mine, butyl~ted hydroxy~nisole or but~latod hydroxytoluene)can ~180 be present in the pharmaceutic~l prepar~tion~,
- 22 -
~L050042
The following ~xamplas illu~tr~te the process provided
by the present invention:
9,9 g of 2-chloro-4-methox~-3,5,6-trimethyl-benzyl-
-tr~phenylphosphonium chlor~de sre dissolved in 50 ml of
d$meth~1formamide, A~ter the addition of 4~16 g of 7-formyl-
-3-methyl-octa-2,4,6-trien-1-oic acid cthyl ester. the
solution is treated dropwise at 20~ with 10 ml of ~ solution
of sodium ethylate frefi~ly prep~red from 0.460 g of sodium
and 10 ml of ab~olute ethanol, The mixture i~ stirred
~t room tomperature for 12 houra, then introduced into 100 ml
o~ w~ter and extracted with hexane. ~he hexane ~xtract is
shaken out three times with methanol/water, dried over soAium
sulphate and evaporated under rcduced pressure. ~he residue
i9 purifiad by ~bsorption on ~ilica gel using meth~lene
chloride/hex~ne (8:2) for the elution. The 9-(2-chloro-4-
-methoxy-3,5,6-trimethyl-phenyl)-3,7-dimet~yl-octa-2,4,6,8-
-tetraen-l-oic acid ethyl ester obt~ined from the eluate ~elts
at 90C ~fter recr~3t~11is~tion from hexane.
~he 2-chloro-4-methox~-3,5,6~trimeth~1-benzyl-
-triphenylphosphoniu~ chloride uced as the st~rting material
can b~ prepared, for examplQ, a~ follows:
189 g of 3-chloro-4,6-dimethyl-benzyl chloride are
introduced into 1500 ml of 5-~ sodium hydroxid~, ~he mixture
is treated while stirring with 195 g of zinc dust within 2
hours, The temperature of the reaction, which takes place
1C~S~04Z
exothermic~llg~ i8 maint~in~d at 70 C by cooling, ~he mixture
i~ stirred for a further 12 hours ~t 50~C end sub~quently
filtered. ~he filtrate i~ extractsd three time~ with 800 ml
of ethyle~e chloride, ~he meth~le~ chloride extract i8
washed neutral with water, dried o~er sodium ~ulphate and
evaporated. The re~ual 2-chloro-3~5,6-trimethyl-benzene
i~ purified by adsorpt~on on ~ilica gel u8ing hexane/m~th~l~ne
chloride ~9;1) for the elution. Th~ compound boils ~t 81~9
Torr~
70 g of 2-chloro-3,5~6-trimethyl-be~ene are ada~d
dropwi~e within 30 minutes wh~le Bt~rrin~ to 400 ml of nitric
acid t70% v~v] pr~-cooled to O~C. ~he mixture i8 ~tirred
for a ~urth~r 4 hours at a ~low}~ increasin4 te~peraturc up
to +20~G, then introduced ~n~o ic0-water a~d thoroughly
extract~d with ether. ~e ether extract i~ washed 8iX time~
wit~ 1000 ml of wat~r, dri~d over ~oaium ~ulphate and ev~porst0d
under reduced prec~ure. ~he r~cidual 2-chloro-4-nitro-3,5,6-
-trimethyl-be~zen~ i~ purifi~d b~ adsorption o~ ~ilica g21
u8ing hexan~/benze~e (3:7) ~or the elution. ~he co~po
~elts at 79-C after recrystalli~ation ~rom low-boil$ng
petroleum ethor.
114,5 g of 2-chloro-4-nitro-~,5,6-trimethyl-benzene
are di~olved in ~00 ml of ethyl ~cet~te. The 601ution i~
diluted with 300 ml of ethanol and, sfter the ~ddition o~
20 ml of Ra~ey-nickeli hydro~enated u~der no~mal con~it~ons.
~fter th~ uptak~ of 43 litr~s of hydrogen, the hydrogen~tion
is tarminated, ~he catel~ iB filtered off while gassing
with carbo~ dioxlde and washed with ~tha~ol, The combined
- 24 -
~os~o~z
filtrates are e~aporated under reduced pres~ure, ~he re~idual
4-amino-2-chloro-3,5,6-trimethyl-benze~e melt~ ~t 93~C after
recrystallisation from hexa~e.
65 g of 4-amino-2-chloro-3,5,6-trimethyl-ben~ene are
gradually introduced into 250 ml of concentrated sulphuric
acid while ~tirring a~d cooling. In ~o doi~g, the tempera-
ture ri~es to ~60C. ~he mixture i~ cooled to 0C by the
gr~dual addition of 75Q g of ice a~d then tre~ted dropwi~e
within 3 hours with a solution of 26.4 g of sodium ~itrite in
80 ml of water, The mixture is ~tirred for a further 90
minutes Qt 0C to +10C and sub~eQuently filtered, ~he
filtrat~ i8 ~ub~ect~d to a steam di~till~tio~ while adding
dropwi8e 600 ml of sulphuric ~cid ~50 vol %~, The aistill~te
i~ extracted threz tim~ with 1000 ml of methylene chloride,
The meth~lene chlorid~ extract i8 dried o~er ~odium sulphate
~n~ e~aporated, ~he re~idual 2-chloro-4-hydro~y 3,5 96-
-trim~thyl-benzene melts ~t 97-C after recryst~llisation from
hexane.
After t~e a~dition of 400 ml ~f methanol and 85,5 ~1
of dimeth~l sulphate, 76 g of 2-chloro-4-hydroxy-3,5,6-
-trimethyl-benzene are treated dropwise while stirring with
265,5 ml of potassium hydroxlde ~25~ g/v]~ The mixture,
which thereb~ heat~ to boiling, i8 stirred for ~ further 4
hour~ under reflux conditions and ~ubsequently evaporated.
~he residue i8 taken up in 600 ml of water. ~he aqueous
~olutio~ i8 extr~cted three time~ with 600 ml of ether. ~he
ether extract i~ wa~hed neutr~l with ~ater, dried over ~odium
~ulphate ~nd ev~por~ted under reduced preææure~ The re~idual
10~042
oily 2-chloro-4-methoxy-3,5,6-trimeth~l benzene boils ~t
77 -79 C/l ~orr~
65.35 g of 2-chloro-4-methoxy-3,5Y6-trimethyl-benzene
are mixed with 235 ml of acetic ac~d, 446 ml of hydrochloric
acid [37 g~v~ ~d 107 ml of formaldehyde ~35%), The mixture
is ~tirred at 70 C for ~ hour~ and, after cooli~g, i~troduced
into 2~00 ml of water~ The aqueous solution is extracted
three times with 1000 ml of meth~lene chloride. The meth~-
lene chloride extract i~ wa~hed three times with 1~00 ml of
water, dried over ~odium sulphate a~d evaporated. The
residual 2-chloro-4-methox~-3,5,6-trimethyl-ben~yl chloride
is purified ~yadsorption o~ 6ilica gel u~in~ low boiling
petroleum ether for the elutio~, The compound melt~ at
59-63C after recrystalli~ation from low boili~g petroleum
ether.
70.8 g of ~-chloro~4-methox~-3,5,6-trimethyl-benzyl
chloride are dis~olved in 500 ml of toluene. The solution
i8 treated with 77 g of triphenylpho~phinç a~d stirred at
100C for 18 hour~. The 2-chloro-4-methoxy-3.5,6-trimethyl-
-be~zyl-triphenylphospho~ium chloride which separate~ in the
form o~ white cr~tal~ ic washed with ether and dried in
vacuo. The phospho~ium ~alt m~lts at 215JC.
~he 7-formyl-3-methyl-oct~-2,~,6~trien-1-oic acid eth~l
ester u~ed as the starting material can be prepared, for
exampl~, as follows:
After the addition of a 6mall amount o:E ion ~ III)
-- 26 ~
nitrate, 2700 ml of liquid ammonia are treated portionwise
with 169.5 g of potassium ~hile stirring and cooling. A~
soon as the initially blue colour has di~app~ared (i,e. ~fter
about 30-45 minutes), ac~tylene gaa i~ introduced in a stream
of three litre~ per minute until th~ d~rk colour of tha mixture
becomes lighter. Thsn the ga~ ~tre~m i~ reduced to two litre~
per minuke ~nd the mixture treated aropwise with a solutio~ of
500 g of methylglyoxal dim~thylacetal in 425 ml of ab~olute
ether. ~he g~ing with acetylene i~ continu~d for a ~urther
1 hour while stirring. ~he ~ixture i8 su~sequently treated
portionwise with 425 g of ammonium chloride, gradua?l~ warmed
to 30~C within 12 hour~ wh~le evaporating the a~monia ~nd
extracted with 1600 ml of ether. The ether extract i~ dried
ov~r ~odium sulphate ~nd e~por~ted under r~duced pre~sure.
The residual 4,4-dimethox~-3-meth~l-but-1-yne-3-ol boils,
af~er rectification, ~t 33C/0.03 ~orr; ~ 5 ~ 1.4480.
198 g of 4,4-dimethox~-3-methyl-but-1-yne-3-ol ~re
di~sol~ed in 960 ml of high boiling petroleum ether and, Qfter
the additio~ of 19~3 g of 5% palladium cat~ly~t qnd 19.~ g of
quinoline, hydrogenated under normal condition~. After the
upta~e of 33.5 litres of hydrogen, the hydro~enation i~ ter-
minated, The catal~st i8 filtered off. ~he ~iltrate is
evaporated under reduced pres3ure. ~he residual 4,4-dimethoxg-
-3-meth~l-but-1-e~-3-ol boils, ~fter rectification, at
70-72~C~18 ~orr.
195 ml of pho~gene are introduced into 1570 ml of
carbon tetr~chloride st -10C, After the ~ddition of 213 g
of pyridine, the ~slution ia tre~ted dropwise with 327 g of
4,4-dimethoxy~3-methyl-but-1-en-~-ol at a temperature of -10C
- 27 -
10$0042
to -20C. The mixture i5 ~lowly warmed to 25 C while 3tirring,
stirred for a ~lrther 3 hours at room temp~rature 9 cooled to
15~C and trea~ed with 895 ml of water~ ~he aqueou~ pha~e i~
separated a~d discarded. After standing for 12 hour~ in the
cold, the orga~ic ph~e i9 treated with 448 ml of 5~ ~ulphuric
acid, stirrea for 5 hours, th~n w~hed with water, dried over
~odium ~ulphate and ev~porated u~der reduced pres~ure, ~he
re~idual 2-formyl-4-chloro-but-2-ene boils, ~fter rectif~cation,
at 37-40C/1.8 ~orr; n25 ~ 1,48950
lQ 165,7 g of 2-form~l-4-chl~ro-but-2-ene are dissolved in
84Q ml of benzene and treated with 367 g of triphenylpho~phine.
~he mixture i8 he~ted to boiling under reflux conditions for
12 hour~ while ga~ing with nltrogen Rna then cooled to 20C.
The precipitsted 2-formyl-but-2-ene-~-triphe~ylphosphonium
chloride melts at 250-252~C ~fter wa~hi~g with benzene and
dr~ing.
212.6 ~ of 2-form~ ut-2-ene-4-triphe~ylpho~phonium
chloride and 95 g of 3-formyl crotonic acid ethyl e3ter are
;ntroduced into 1100 ml of butanol ~nd tr~ated at 5C with ~
s~lu~ion of 57 g of triethylami~e in 60 ml of butanol. The
mixture i~ subsequently stirred for 6 hours ~t 25C, then
cooled, i~troduced into water and thoroughl~ extracted with
he~a~e. ~he hexane pha~e i~ ~ir~t wa~hed repeatedly with
metha~ol/water (6:4), then wanhed with water, dried o~er
sodium sulphate and ~ilterad, Th~ ~$1trate i~ i~omeri~ed b~
shaking with iodine for 12 hour~, The iodine is romo~ed b~
the addition of ~odium thiosulphate, The filtrate i~ washed
with w~ter again, dried and 0vaporated under reduced pre~ure.
- 28 -
04Z
~he residual 7-form~1-3-me~hyl-octa-2~4,6-trien-1-oic acid
ethyl ester c~n be used in the process without ~urther
purification~
39 ~ o~ 2 ,6-dichloro-4-methoxy-bellzyl-triphenylpho~-
phonium chloride a~d 16 g o$ 7-fo~myl-~-met~yl-octa-2,4,~-
-trien-l-oic acid ethyl ester are heated at 82~-85C under
reflux co~aitions while gtirring ~or 2 hours &f~er the addition
of 40 g of 1,2-butylene oxiae. The mixture i8 then thoroughly
extr~ctaa with h~xsna. ~he ~exa~e extract is washed several
times with meth~nol/wster (60:40), aried over sodium ~ulph~te
and e~por~ted und~r reducad pressure. ~he residue is puri-
fied b~ ~dsorption on silica gel u~in~ hexd~e for the elution.
~he 9-(2,6-dichloro-4-m~thox~ phen~l)-3,7-d~methyl-octa-2,4.6,8-
-tetr~e~-l oic acid ~hyl egter obtained from the eluate melts
at 117-118~C after recry~tallisation from hexane,
~he 2,6-dichloro-4-methoxy-benzyl-triphen~lphospho~ium
chloride used a~ the starting material can be prepQrea. for
example, a~ follow~:
77 g of 3,5-dich1oro-~nisole are di~sol~ed in 250 ml
o~ ether, After the addition of 70 ml of formaldehyde
r35% g/~], the ~olution i~ g~sscd with hydrogen chloride at
room t~mperature while ~tirring for 8 ~ours, ~he solu~ion
is subsequentl~ pourea on to ice and thoroughly ex*racted
with ether, The ether extract i8 washed neutral with water,
dried over ~odium ~ulph~te ~nd evaporsted under reduced
~ 29 -
~ 05~4Z
pressure, ~he residual oily 2,6-dichloro-4-methox~ benzyl
chloride has a refractive index of nD4 = 1.5730~
23,7 g of 2,6-dichloro-4-methoxy-benzyl chloride,
26.2 ~ of triphenylphosphine ~nd 150 ml o~ absolute benzene
are hested for 12 hours under reflux conditions. The
2,6-dichloro-4-m~thoxy benzyl-triphenylpho~phonium chloride
which precipitates on cooling is dried in vacuo be~ore beinK
u~ed in the process.
~.~,
In a m~nner anologouc to that described in ~xa~ples
1 and 2, by reacting 2-chloro-4-m~thoxy-5,6~dimethyl-benzyl-
-triphenylpho~phonium chloride with 7-f~rmyl-3-methyl-octa-
-2,~,6-trien-1-oic acid ethyl ester there is obtained 9 (2-
-chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7 dimethyl-nona-
2,4,6,8-tetraen-1-oic a~.id ethyl ester, a yellow-red oil.
~he 2-chloro-4-methoxy-5,6-dimeth~l-benz~l-triphenyl-
pho~phonium chlorido used a~ th~ startin$ ma~erial can be
preparea i~ a ma~ner a~alogou~ to that described in Ex~mple~
1 and 2 starting, for example 9 from 2,3-dimeth~1-aniline and
proceeding Tia 2,3-dimethy1-5-nitro-~niline, 2.3-dimothyl-5-
-nitro-phenol, 2,3-dimethyl-5-nitro~anisole, 2~3-dimethyl-5-
-amino-a~isole, 2,3-dimethy1-5-chloro-anisole ~nd 2 chloro-4-
-methoxy-5,6-dimethyl-benzyl chloride.
- 30 -
1~50042
In a m~nner analogous to that de3cribed in ~xamp~es 1
~nd 2, by reacting 2,3,6-trichloro-~-methoxy-benæyl-triphenyl
-pho~phonium chloride with 7-formyl-3-methyl-octa-?,4,6 trien-
-l-oic acid ethyl e~ter there i8 obtained 9-(2,3,6-trichloro-
~ -methoxy-phen~ 3,7-dimethyl-~ona-~,4~6,8-tetr~en-1-oic
acid ethyl ester o~ melting poin~ 126-128C.
The 2,3,6-trichloro-4-methoxy-benzyl-triphenylpho~pho-
nium chloride used as the starting material can be prepared
in a manner ~nalogous to th~t de~cribed in Example~ 1 asd 2
starting, for ex~mple, from ~,3,5-trichloro phenol and pro-
ceeding ~ia 2,3,5-trichloro-ani6010 and 2,3,6-trichloro-4-
-methoxy-benz~l chloride.
Example 5
15 I~ a manner analogous to that de~crib~d in Examples 1
~nd 2, by re~cting 2,4-aimethoxy-~,6-aimet~yl-benzyl-triphenyl-
-pho3pho~ium chloride with 7-formyl-3-methyl-octa-2,4,6-trien-
-l-oic ~cid ethyl ester there i~ obt~i~ed 9-(2~4-dimethoxy-
- 3 ~6-aimethyl-phen~ 3,7-dimethyl-~on~-2 14 9 6,8-tetr~en-1-oic
~cid eth~l estor,
~ he 9-(2,4-dimethoxy-3,6-dimethyl~phenyl)-3,7-dimethyl-
-nona-2,4,6,a-tetraen-1-oic-acid obtained by saponifying the
foregoi~g ester ~elts at 214-215G.
The 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphosphonium
- 31 -
chloride use as the stArting materi~l can be prepared in ~
m~nner ~n~logous to that described in Examples 1 and 2 starting,
for example, ~ro~ orcin (3,5 dih~drox~-tolu~n~ ~n~ proce~di
via 2-ace~ 3,5-dihydroxy-toluene, 2-~cetyl-3,5~dih~drox~-
-p-xylol, 2,6-dihydroxy-p-xylol, 2,6-dimethoxy-p-x~lol and
2,4-dimethoxy-3,6-dimethyl-benzyl chloride,
x~mple~j6
In ~ manner analogous to that de~cribed in Ex~mpl~ 1
and 2, by re~cting 6-chloro-4-methox~-2,5-dimeth~l-ben~
Dtriphenylphosphonium chloride with 7-for~yl-3-methyl-oct~-
2.4,6-trien-1-oic acid ethyl e~tsr there i~ obtained 9-(6-
-chloro-4-methoxy-2,5-dimeth~l-phenyl)-3,7-di~ethyl-nona-
-2,4,6,8-tetr~en-1-oic 8Ci~ ethyl ester o~ meltiDs point
106-107^C.
The 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenyl-
-phosphonium c~loride use~ as the stsr~ing materi~l can be
prep~rea in a manner analogous to th~t de~cribed in Examples
1 and 2 starting, for example, ~rom 3-chloro-2,5-dimethyl-
-~itrob~n~ene and ~roceedi~g ~a 3-chloro-2,5-di~ethyl-
-aniline, 3-chloro-?,5-dimethyl-phenol, 3-chloro-2,5-dimethyl-
-a~i~ole-a~d 6-chloro-4-methoxy-2,5-dimethyl-benzyl chloride,
~ea~Z
41 g of 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-
-3,7-dimethyl-nona-2,4,6,8-tetraen l-olc acid ethyl ester
are di~solved in 750 ml of ethanol, ~he 601ution i6 treated
with 41 g o~ potaææ~um hydroxide in 63 ml of water, heated
- ~2 -
1C~5004Z
to boiling for 30 minute~ under ~ nitrogen atmo~phere 9 cooled 9
introduced into water and ~cidified with h~drochloric acid,
The precipitated 9-(6-chloro-4-methox~-2,5-di~ethyl-phenyl)-
-3,7-dimeth71-nons-2,4,6,8-tetraen-1-oic acid melts at
231-234C.
15 g of 9-(6-chloro-~-methoxy-2,5-dimethyl-phenyl)-
-3,7-dimathyl-nona-2,4,6,8-tetraen-1-oic acid are di~olved
in 750 ml of tetrahydrofuran. ~he solution obtained i~
treated with 2,64 ml (0,7 mol) of phosphoru~ trichloride,
concentrated after 12 hours to half of its volume at 30C
under reduced pressure and added dropwiae at 0-5 C to a
tetrahgdrofuran solution containi~g 14.6 g of eth~lamine.
The mixture i8 stirrea for 1 hour at room temperature,
introduced into a ~sturated squeou~ sodium chloride solution
and extracted with methyl0ne chloride, ~he extr~ct is w~shed
with an aqueous sodium chloride solution, dried and ~vaporated
under reduced pressure. ~he residual 9-(6-chloro-4-methoxy-2,
5-dimethyl-phe~yl)-3,7-dimeth~l-nona-2,4,6,8-tetraen-1-oic
acid ethyl amide i8 purified by adsorption on ~ilica ~el
using methylene chloride/methanol (90:10) for the elution,
After recryst311is~tion from ethyl ~cetste, this ethyl amide
melts at ?o2o-2o~oc.
- ~3 -
4;~
: The following ~xamples illu3trate typical ph~rmaceutical
prepar~tions provided by this invention.
A capsule can contai~ the ~ollowing ingredient~:
9-(2-Chloro~-methoxy-3,5,6-
-trimethyl-phenyl~-3,7-dimethyl-
-non~-2l4,6,8-tetraen-1-oic ~cid 10 mg
ethyl ester
Wax mixture 41.5 mg
Vegetable oil 98,0 mg
~risodium ~alt of ethylenedi~ine-
tetraacetic acid 0.5 mg
Individual weight of a capsule150 mg
Active ingredient co~tent of a capcule 10 mg
Example B
A 6~1ve cont~ining 2~0% of Qctive ingredient can be
prepQred U6i~g the following ingredients:
9-(2-Chloro-4-methox~-3,5,6-
-trimeth~l-phenyl)-3,7-di~ethyl-
-~ona-2,4,6,8-tetraen-1-oic açid
eth~l ester 2.0 g
Cetyl alcohol 2. 7 g
L~nolin 6.0 ~
Petroleum ~elly 15.0 g
Distilled w~ter q.s ad 100 0 g
~ 34 --
