CA1277332C - Phenyl nonatetraenoic acid derivatives - Google Patents

Abstract

Abstract 9-phenyl-3,7-dimethyl-2,4,6,8 nonatetraenoic acids wherein the phenyl group is substituted with an alkyl, aminoalkyl, hydroxyalkyl, alkoxy, hydroxyalkylamino, and a hydroxy alkoxy group, and derivatives thereof can be used as anti-rheumatic and immunosuppresive agents.

Description

~ 2~7332 . The present invention relates to compounds of the formula:

~7 R8 ~0 ~2~ ~ ~H=CR-C=CH-CH=CH-C=CH-R5 3 ~ 7 6 S 4 3 2 l wherein n i~ an integer selected from 6 or 7; Rl is hydrogen, loweralkyl, chlorine, fluorine or t~i~luoromethyl: R2 is hydrogen, lowe~ alkoxy, trifluoromethylloweralkoxy, hydro~y, lower alkyl, chlorine, trifluoromethyl, or fluorine; R3 i8 hydrogen, loweralkyl, chlorine or fluorine; R4 is alkyl contai~ing from 4 to lO carbon atoms or -CH2~CH2)nCH20H; X is -CH o-, Rlo -CH-, ,-C=CH- ,-0-. or ~N~; R5 is -I-OR9;
Rlo Rlo Rlo : and R7, R~ ~9 and Rlo are individually lower alkyl or hydrogen:
and salts thereof where R9 is hydroge~ to a process for their ~repacation and to ~harmaceutical compositions containing them.

Figures 1, 2, 3, 4, 5, 6 and 7 represent~ s~hematic ~rocess stee~ for ~re~aring the compounds of formula I above.
Grn/11.6.85 ~ r,~ j~

In the compound6 of this invention the term "halogen"
includes all four halogens, i.e. chlorine, bromine, iodine and fluoeine with chlorine and bromine being preferred. The term "lower alkyl" as used herein designates both straight and beanched chain lower alkyl grou~ containing from 1 to 7 carbon atoms. Among the pre~e;cred lower alkyl groups are methyl, ethyl, iso~ropyl, n-butyl, etc., with methyl and ethyl being especially preferred. The term "lower alkoxy"
de~ignates lower alkoxy groups containing ~rom 1 to 7 carbon atom~ such as methoxy, ethoxy, isopro~oxy, isobutyoxy, etc.
The term trifluoromethyl lower alkoxy de~ignates a trifluoromethyl substituted lower alkoxy ~ubstituent where lower alkoxy is defined as above. The term alkyliden~
designates a aliphatic saturated hydrocarbon group where the teLminal carbon atoms i5 divalent.

The term ~larylll designates mononuclear aromatic hydrocarbon groups which can be un~ubstituted or ~ubstitutad in one or more po6itions with a lower alkyl groups, ~uch a~
phenyl or tolyl, etc. and polynuclear aromatic groups which can be un6ubstituted or sub~tituted in ona or more po6itions with a lower alkyl group and a napthyl, phenanthryl or a~thryl. The preferred aryl group is phenyl.

In one of the embodiments of the com~ounds of Formula I, O- and R7 and R8 are lower alkyl preferably methyl. In another ereferred embodimen~, R4 is -(CH2)y H
with y being 6 to 9, more particularly 8 to 9 with 9 being especially preferred. In this embodiment of the invention, 30 Rl, R2 and ~3 are ere~erably hydrogen or Rl and R3 can be hydrogen and R2 can be lower alkoxy such as methoxy or ethoxy. On the other hand in ~his embodiment R2 and R3 can be hydrogen with Rl being chlorine or fluorine or Rl and R2 can be hydrogen with R3 being chlorine or 35 fluorine.

In still another embodiment of the compounds of formula ~.

.

'77332 I~ R4 is -CH2~CH2)nCH~OH. In this embodiment of the compounds of Eormula I, Rl, R2 and R3 are hydrogen, or Rl i8 chlorine or f luorine with R2 and R3 being hydrogen. On the other hand in this embodiment of the compounds of formula I, R1 and R3 are hydrogen and R2 is lower alkoxy preferably methoxy or ethoxy. Also preferred are those compounds of this embodiment o~ the compound of formula I where Rl and R2 are hydrogen and R3 i8 chlorine or fluorine.
Also included in this invention are salts of the compound of formula r above with pharmacautically acceptable, non-toxic, inorganic or organic bases, e.g.
alkali metal and alkaline earth metal salts. Among the preferred salt5 are the sodium, potassium, magnesium or calcium salts, as well as salts with ammonia or suitable non~toxic amines, such as lower alkyl amines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-~ hydroxyethyl~amine or zo tris-~2-hydroxyethyl~-amine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, ~or example N,N'-dibenzyl-ethylenediamine, and dibenzylamine. These salts can be prepared by treating the compounds of formula I, where Rg is hyd~ogen wi~h inorganic or organic ~ases by conventional mea~s well known in the a~t.

The compounds of formula I as well a6 salts thereof are effective as disease modi~iers Eor treating cheumatoid arthritis as well as related disorder~ such as 30 osteo-arthritis.

The compounds of formula I can be utilized to treat patients suffering from rheumatoid arthritis and related disorders. In such ca~es, the compounds modify the effects 35 of these diseases by reducing destruction of ~he bone joints - caused by this disease as well as reducing inflammation, heat and pain of the bone joints which results from .

~D,2t7''73~

rheumatoid arthriti6 and related disorder6. The compounds of formulae I and salts thereof are also useful fo~ treating diseases resulting from immune hyperactivi~y such as trans-plantation autoimmunity, autoimmune disease and graft versus host di6ease. The unexpected lack of toxicity of the compounds of this invention can be seen by the ~act that the compound ~all-E)-9-[2-(nonyloxy)-phenyl]-3,7-dimethyl--2,4-6,8-nonatetraenoic acid has a LD50 in mice of grea~er than 1,000 mg/kg both i.p. and p.o.

That the compounds of this invention are effec~ive ~nti-arthritic agents can be seen from the results obtained when these compound~ are admini~tered to rats in accordance with the chronlc adjuvant arthritis te~t system disclosed in Billingham and Davies "Handbook of ~xperimental Pharmacology" (editors J.R. Vane and S.H. Ferreira) Vol.
50/II, pg. 108-144, Springer-Verlag, Berlin, 1979).
~ ' ' In this procedure, adjuvant arthritls was induced by the subplantar injection on day O of 0.05 ml o~ adjuvant ~a suspension of heat-killed, dessicated Mvcobacterium butYricum! 0.5% (w/v), in heavy mineral oil containing 0.2 digitonin] into the right hind paw of male Charles River Lewis rats (120-140g) that were hou6ed individually and z5 given food and water ad lib. Paw volumes (both hind paws) were measured immediately after injection of the adjuvant.
Paw Volumes were also measured, to follow the development of inflammation-induced ~welling in the ar~hritic paws, at inteLvals of 3 to 7 days by immer~ion of the paw to the level sf the lateral malleolus in a mercury plethysmograph.

Drugs were adminis~ered once a day tstarting on the day ~ of adjuvan~ in}ection) by incubation using Tween*80 ;~ (polyoxyethylene ~orbitan mono-oleate~ at a do6e of 0.25 35 ml~100 g body weight as the vehicle. Arthritic control rats received daily dose6 of the vehicle only. On day 23-25, the rats were sacrificed, plasma collected and plasma fibrinogen * trade mark.

:' ~2 ;~733r~d levels determined (ammonium sulfate turbidimetric method) as described by Exner et al., Amer. J. Clin Path~ 71:521-527 (1979). Anti-inflammatory activity of the test drugs were determined by comparing the extent of paw swelli~g (paw volume on a particular day, i.e. day four to day twenty-five, minus the paw volume on day 0) in drug-treated arthritic rats with the extent of paw swelling in the vehicle-treated arthritic rats. Drug induced decreases in the level of plasma fibrinogen,, an acute phase protein tha~
0 i8 elevated in the plasma of rats with adjuvant-induced arthritis, were also used to guantitate the anti-inflammatory activity.

The results of various compounds of thi6 invention when compared to Indomethacin and 13-cis-vitamin A acid are given in the following table (TABLE I)~

,7--_~_ . _._ ~ __ __ . ~ - ~ 1 ^ 1 ^ 1 ~ 1 I ~r .' _ _ , _ ~ .~. _ E ~ ~ C~ _ n ~ . ,., _ _ _ _ _ . _ _ __ : ,OE~ I ~, ~.S3 .cl~ e~ ~ 1~ ~t O,~ T
uo~ _ _ ,_ _ ~_ ~ ~ .......... _ _ ~ ~ ~o ~ ~ ~ ~7 q,7 ~ ~

m _ _ ~ _ : _ . . . . . _ :~ ~ OQ ~ O ~o I~ n .u~ ~n ~

~277;~3~

In the above Table I the ~ercent reduc~ion in paw volume demonstrates the effectiveness of the compounds o~ this invention to reduce swelling caused by adjuvant arthritis.
As seen from the results in this Table, the compounds o~
this invention e~fectively reduce the swelling caused by the adjuvant. Furthermore the compounds of this in~ention were ef~ective in reducing the plasma fibrinogen generally associated with rheumatoid arthritis. Furtharmore as seen from the weight gain of the animals, the compounds of this L0 invention at the dosage tested produced no ~ubstantial reduction in the weight gain o~ the animals. This indicates the lack of toxicity exhibited by the compounds of this invention.

The compounds of formula I and their pharmaceutically acceetable salts can be used in a variety of pharmaceutical preparations. In these preparations, the~e compounds are administrable in the fo~m of oral unit dosage forms such as tablets, pills~ powders, ca~ules, as well a~ in such forms as injectables, solu~iong, suppositories, emulsion6, dispersions, and in other suitable forms. The pharmaceu-tical pre~arations which contain the com~ounds of formula I
are conveniently formed by admixing with a non-toxic ~harmaceutical organic carrier or a non-toxic pharmaceu~ical inorganic carrier. Typical of pharmaceuti- cally acceptable carriers are, foc example, water, gelatin, lactose, starche6, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ~etroleum jelly and other conventio-nally em~loyed pharmaceutically acceptable carriers. The pharmaceutical pce~arations may al60 contain non-toxic auxiliary subs~ances such as emulsifying, preserving and wetting agents and the like, as for exam~le, socbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfosuccinata and the like.

The daily dose administered for the com~ounds will, of course, vary with the ~articular novel compound employed, ~7733~

the chosen eoute of administration and the size of ~he recipient. The dosage administerQd is not subject to definite bounds but it will usually be in ef~ective amoun~s of the pharmacologically function of the compound~ of this invention. Reeresentative of a typical method for administering the comeounds of formula I or their 6alts is by oral administration. By this route, the compounds o~
formula I or their salts can be administered at a dosage of O.S mgtkg per day p.o. to lOO mg/kg per day p.o. Preferably these com~ound8 can be administ:ered daily to ~atient~ i~
unit oral dosage forms at daily dosages of ~rom l to 30 mg/kg of body weight, with dosages o~ ~rom l to lO mg/kg being especially ereferred.

The compound of Pormula I where X is -O- can be prepared from compounds of the formula ~

R2~CH(:) I O ~
~ OH

wherein Rl, R2 and R3 are as above, via the reaction scheme in Figure l.
2~
In the reaction scheme of Figure l, n. Rl, R2, R3, R7 and R8 are as above and R'g is lower alkyl, Z i8 a ; leaving grou~; Y is aryl preferably phenyl; Z' is halo.

The compound of formula III is converted to the compound of formula IV via reaction step (a) by reducing the aldehyde group to the alcohol. This reaction i~ carried out utillzing a conventional reducing agent which converts aldehyde~ to alcohols. Any conventional reducing agent for 35 this pur~ose can be utilized in the reaction of step (a).
- In carrying out this reaction it is generally pre~ereed to utilize an alkali metal borohydride such as sodium ~LZ7733~

g borohydride as the reducing agent. Any of the conditions conventional in such reduction ceactions can be utilized to carry out the reaction of step (a). If R2 is hydroxy it - is generally preferred to protect the hydroxy designated by R2 during the reduction of the compound of formula III and its subsequent conversion to the compound of formula II-~.
Any conventional hydrolizable hydroxy erotecting group such as a lower alkanoyl group may be utilized to protect the hydrox~ group when R2 i8 hydroxy. This e~ter protecting L0 group can be cleaved by con~entional ester hydrolysi~ after the focmation of the Wittig salts o~ formulae XIII and XVI
or after the formation of the ether of formula X.

The com~ound oi i'ormula IV is converted to the compound of formula VI via reaction step (b) by treating the compound of formula IV with a triarylphosphine hydrohalide. In this manner the phosphoniu~ ~alt of formula VI ifi produced. ~ny conven~ional method o~ reacting an allylic alcohol with a triarylphosphine hydrohalide can be used to carry out this ~, 20 reaction~ The phosphonium salt o~ formula V~ is reacted via a Wittig reaction with the compound of ~ormula VII in ~tep (c) to ~orm the compound of formula VIII. ~ny of the conditions conventionally used in Wittig Leactions can be utilized to carry out the reaction of ~tep (c~.
2s On the other hand the compound of formula III may be directly conver~ed to ~he compound of formula VIII via ~he ~eaction with the phosphonium salt of the compound of formula IX as in reaction step (e). The Leaction of the phosphonium salt of formula I~ with the compound of formula III to produce the compound of formula VIII is carried out utilizing the same conditions as described in connection with reaction step (c).

The compou~d of formula VIII is conveLted to the compound of formula X by etherifying or alkylating the compound of f.ormula VIII with a compou~d of formula V as in ~;27733?, reaction step (d). In the compound of formula V, Z can be any conventional leaving group such as mesyloxy, tosyloxy OL
a halide. ~ny conventional method of etherification of a hydroxy group though reaction with a halide or a leaving group can be utilized to carry out ~he reaction of step (d).

In accordance with another embodiment of thi~ invention ~he compound of formula X, ~here when R2 iB hyd~oxy, the hydroxy group is protected ~ia a hydrolizable ester, can be ~o produced from the com~ound of the ~ormula III by alkylation or etherification of the compound o~ formula III with the compound of formula V to produce the comeound o~ XI. This reaction i8 carried by alkylating the compound of formula III with the compound of formula V as in step ~d). In the reaction of step6 (f) and (d) where R4 iB a hydroxy alkyl group, the hydroxy contained in a~ need not be protected.
This is true since under the conditions used in this reaction s~ep, the compound of formula V will react with either the compound of formula III or the compound of formula VIII to produce the compound of formula XI or the compound o~ ~ormula X without the neces6ity for protecting ~ ~he hydroxy grou~ contained on the ~lkyl chain. Alkylation :~ or etharifi~ation will occur direc~ly with the ~h~nyl - hydroxy moiety o~ either the compound of formula III or the compound of formula VIII and there will be little, if any ~ reaction with the hydroxy group contained on the alkyl chain :~ designated by R4. The compound of formula XI is converted to the compound of formula ~II, via reaction step (g) by reduction. The same;conditions described in connection with 30 reaction ste~ (aj can be utilized to convert the com~ound o ~: ~ormula XI to the compound of formula XII~
:;
The compound of formula ~II is converted, via reaction step (h), to the compound of formula XIII by treating the 35 compound of formula XII with a triaryIphosphine hydro-;- halide in ~he manner described hereinbefore in connection with step (bj. The compound of formula XIII is converted to ~Z7733~, the compound of formula X by reacting the compound of formula XIII with the com~ound of formula VII via reaction step (i). This reaction step is carried out in the same manner as described hereinbefore in connection with reaction step (c).

In accordance with another embodiment of this invention the compound of formula X is p~oduced by first convert~ng the compound of formula XI to the compound of formula XIV.
L0 The compound of formula XI is converted to the compound of formula XIV by aldol condensation with the compound of formula XX. Any conventional method o~ aldol condensation can be utilized to react the compound of formula XI with the compound of formula XX to form the compound of formula XIV.
L5 In the next ~tep the compound of fo~mula XIV is condensed via either a Grignard reaction with vinyl magnesium halide or a lithium condeFLsation reaction with vinyl lithium to produce the compound of formula XV. The reac~ion of step (k) can be carried ou~ by utilizing any of the conditions conventional in lithium condensation6 or Grignard condensation reactions. The compound of formula XV is converted to the compound of formula XVI by reacting the compound of formula XV with a triarylpho&phine hydrohalide ~: in the manner described hereinbefore in connection with the :~ 25 reaction of step ~b~. The compound of formula XVI i6 thereafter converted to the compound of formula ~, via reaction step (m). by reaction with the compound of formula XVIl. The reaction of step (m~ is carried out utilizing a standard ~ittig reaction as described in connection with the 30 reaction o~ step (c). The compound of formula XVI by the reaction with ~he compound of formula XVII produces the com2ound of formula X. The compound of formula X can be converted to the free acid i.e. the compound of formula I
where R5 is COOH by ester hydrolysis. Any co~entional 35 method of ester hydrolysis will produce the compound of the formula I where R5 is COOH.

~2~33~
~ 12 -The compounds of formula I where X is -N- a~e prepared Rlo from the compounds oE the formula R
R2 ~ C1~20T~
L J XXII
y~ NH2 wherein Rl, R~ and R3 are as above via the reaction scheme in Figure 2.

L5In Figur~ 2- Rl, R2, R3. ~4~ 7 8 9 Zl and Y are a~ above. In Figure 2, R13 is the same as R4 with one less carbon than the alkyl group contained ~y R4. Therefore R13 is an alkyl group containing from 3 o 9 carbon atoms or -C~2(CH2)mCH~OH where m is a ~o number one less than n, i.e. m is an integer of from 5 to S. In ~igure 2, Rlo i~ hydrogen or lower ~Ikyl containing from 1 to 7 carbon atoms and Rlo' is a lower alkyl group containing from 1 to 7 carbon atoms. In this embodiment Rlo" i~ a lower alkyl group having one carbon atom le s zs the alkyl group de~ignatad by Rlo'.

In Figure 2 the compound of formula XXII is reacted with acid ~hloride of formula XIX where Z' is halogen tG produce the compound of formula XXIII ~hich is later conv~rted either to the compound of formula ~XVI or the compound o~
; ~XXI. ~here R13 in the compound of for~ula XIX is : -CH2-(CH2)mCH20H where m is an in~eger of from 5 to 6 carbon atoms, the pesence of the hydLoxy group on the substituent of R13 will not effect the reaction to produce the compound of formula XXVI or the compound of formula XXXI. It has been found that this hydroxy groue remains una~fected throughout the series of reaction~ set forth in - :

r~
~ 13 --Figure 2.

On the other hand this hydroxy group can be erotected by mean~ of forming a hydrolyzable ether functional gcoup which protects the hydroxy group throughout these reactions. ~ny conventional ether protecting grou~ can be utilized to protect the hydroxy group throughout these reactions. Among the preferred ether pro~ecting groups, are included:
tetrahydropyranyloxy, t-butoxy, triloweralkylsilyloxy i.e.
trimethylsllyloxy, etc. Any conven~ional ether erotacting group can be utili~ed to protect the terminal hydroxy groue which may be present as Rl3. On the other hand, the reactions set forth in Figure 2 can be carried out without any protection of the terminal hydroxy gcoup.
In the first ste~ of the reaction, the compound of ~ormula XXII is reacted wi~h the compound of formula XIX to p}oduce the compound of formula ~XIII. Any conventional ~ method of condensing an amine with an acid halide can be ; 20 utili2ed to carry out this reaction. In the next step the compound of formula XXIII is converted to the compound o~
formula XXIV, via reaction step (n), by treating the compound of formula XXIII with a reducing agent. ~ny conventional alkali metal aluminum hydride reducing agent can be utilized to caIry out this reaction with the preferred reducing agent being lithium alum;num hydride.
Any of the conditions conventional in reducing with an alkali metal aluminum hydride reducing agent can be utilized to cacry out this reaction.

The compound of ~ocmula XXIV can be converted to ~he com~ound of formula XXVI via the intermedia~e XXV. In the first step of this procedure, step (o), the compound of formula XXIV is converted into the phosphonium salt of 35 formula XXV by reac~ion wi~h a ~ciacylehosphine hydro-halide as described hereinbefore in connection with the reaction of s~e~ (b). The compound of formula XXV is .

~ , .

127733,?~

converted to the compound of formula XXVI Yia reaction step (p), by reaction with the aldehyde of formula VII. (See Figure 1). The reaction of step (p) to produce the com~ound of formula XXVI is carried by a Wittig reaction in ~he same manner as described in reaction step (c) hereinbefore. The compound of formula XXVI where R9 is lower alkyl can, if desired, be converted into the Eree acid by conventional ba~ic hydroly6is. Any conventional method of basic hydroly~i~ to hydrolize esters can be utilized to convert lo the compound of formula ~XVI to the free acid. On the other hand, the compound of formula XXVI where R4 contain~ a terminal hydroxy group etherified with a conventional ether ~rotecting group can be converted into the free alcohol by acid hydrolysis. Any of the conventional methods of L5 hydrolyzing ethers can be utilized to carry out this reaction. Tho ether hydroly6is of the com~ound of formula XXVI can be carried out either befoLe or after the acid hydrolysis used to hydrolize the ester protecting Rg'. On the other hand if R4 in the compound o~ formula X in zo Figure 1 contains an etheri~iPd hydroxy group, the compound o~ formula X can be hydrolyzed in the same manner ~s is the compound Oe formula XXVI.

On thç other hand, the compound of formula XXIV can be zs converted to th~ tertiary amine compound of formula XXXI.
In this reaction, the com~ound oE formula XXIV is reacted, via reaction step (q), with the acid halide of formula ~IX-A, to produce the compound of formula XXVII in the same manner de~cribed hareinbefore in connection with the 30 reaction to convert the compound of formula XXII to the compound of formula XXIII.

The compound o~ formula XXVII i5 converted to the formula XXIX, via reaction ste~ (r), by treating the 35 comeound of Eormula XXVII with a lithium aluminum hydride reducing agent as described in connection with reaction o~

~;~77~33%

step (n).

In the next step of this reaction scheme, the compound of formula XXIX is converted to the compound of formula XXX, via reaction step ~5), by treating with a triarylpho6~hine hydrohalide. This reaction is carried out in the same manner as described in connection with reaction step (b) described hereinbefore. The compound of formula XXX is converted to the compound of formula XXXI, via reaction ste~
(t), by reaction wîth the compound of foemula VII (Figure 1). In carrying out the reaction of ~tep (t) a Wittig reaction iæ utilized. The reaction of stey (t) can be carried out in the same manner as described hereinbefore in connection with the reaction of step (c). The compound of ; LS formula XXXI where Rg' is a lower alkyl grsup can be converted, if desired, to the corresponding compound of the formula XXXI containing the free acid group by basic hydrolysis. 0~ the other hand, if R4 contains a terminal hydroxy group protected through the Pormation of a ; 20 hydrolizable ethe~, the compound of formula XXXI can be converted to the corresponding compound where R4 is a free hydroxy group by conventional ether hydrolysis. This ether hydroly~is can be carried out before or after hydrolysis of the e~er group denoted by R
; In the reac~ion scheme of Figure 2, when R2 i8 h~droxy, it i8 preferred that this hydroxy group be ~ protected via the formation of an ester protecting group.
; The e~ter protecting group can be removed after the ~ 30 formation o~ the Wittig ~alts oE formula XXX.
.

The compounds oE formula I where X is -CH-P~10 are prepared from a compound of the formula:

~27733~'?J

I
R2 ~ zH XXXV
~l - r 17 Rlo wherein Z" i~ ether bromo or iodo: Rl, R2, and R3 are as above: and Rlo is hydrogen or lower alkyl lo as set forth in Figure 3. In Figure 3, Rl, R2, R3, 4~ R7~ R3, ~ 9~ Rlo~ ~13.~ Y~ Z', and Z" are a~
above.

In Figure 3, the compound of formula XXXV is ~irst reacted with the compound of formula ~X%IV via reactio~ ste~
(u) to eroduce the compound of formula XXXVI. This reaction is carried out via a Wittig reaction. In the compound of formula XXXVI R13 can be, if desired, -CH2-(CH2)m -~:~ 0H where the free hydroxy grou~ can, i~ desired, be protected through the formation of any of the aforementionedco~ventional ether group~. On the other hand it has been~
found that thi~ OH group can be a P~ee hydrsxy group a~d ~:~ need not be protected by means o~ an ether protecting group. In carrying out ~he reactions o~ Figure 3 this free . ~ 25 hydroxy grou2 i$ not af~ected by the reaction~ which convert : ~he compound of formula XXXVI to the compound of ~ormula X~XXI. However for best yield~ it is generally preferred to ~rotect this hydroxy group via ~he formation o~ a hydrolizable ether.
T~e reaction of stee (u) is carried out via a Wittig . ~ reaction between the compound~ of formula XXXV and the compound o~ foemula XXXIV utilizing the same reaction conditions as described hereinbelow in connection with 35 reaction ste~ (c).

The comDDund of formula XXXVI ~n be converted to the :

~ ' .

~t7733~

compound of formula XXXVII via a reaction step (v) by hydrogenation. Any conventional method of hydLogenation can be utilized to carry out this reaction. ~mong the conventional method of hydrogenation are included treating the compound of formula XXXVI, in an inert organic solvent medium, with hydrogen gas in the presence of a catalyst.
~ny conventional hydrogenation catalyst can be utilized in carrying out this reaction. Among the preferred catalysts are included ealladi1lm. In carrying out this reaction any ~o conventional inert organic solvent can be utilized.
Furthermore, any of the conditions conventional in catalytic hydrogenation can be utilized in reaction step (v~.

In the next ste~ o~ this reaction, the compound o~
formula XXXVII is converted to the compound of ~ormula XXXIX
via reaction step (w), by treating com~ound o~ formula XXXVII with formaldehyde or a formaldehyde libera~ing compound. In carrying out this reaction the co~pound o~
formula XXXVII is first metalated with an alkali metal alkyl zo e.g. n-butyllithium. Generally this reaction is carried out in an inert organic solvent such a6 an ether solvent. ~mong the ~referred solvents are diethyl ether and tetrahydrofuran. In carrying out this reaction temperature and pressure are not critical. This reaction can be carried out at room tem~erature and atmospheric pressure. If desired, higher and lower tem~eratures can be utilized.
~fter treating the compound of formula XXXVIII with an al~ali metal alkyl, formaldehyde or a ~ormaldehyde liberating compound is added to the reaction medium. ~ny co~ventional compound capable of l~berating ~ormaldehyde such as paraformaldehyde can be utilized in carrying out this reaction. This reaction i8 carried out in the same reaction medium and utilizing ~he same conditions as the metalation of the compound o formula XXXVIII was carried out.

The com~ound of formula XXXIX is converted to the ~ll27733?,, compound of formula XXXX, via reaction step (x), by treating the compound of foemula XXXIX with triarylphosphine hydrohalide. This reaction is carried out in the same manner as described in connection with reaction step (b) as described hereinbefore. The compound of formula XXXX is converted, via reaction step (y), to the compound of formula XXXXI by reac~ion with the compound of formula VII. (See Figure 1). This reaction of step (y) is carried out via a Wittig reaction utilizing the same conditions described in L0 connection with reaction step (c). The compound of formula XXXXI may be converted to corresponding compound containing the free carboxyl group instead of Rg'. This reaction is carried out by conventional ester hydrolysis in the manner hereinbefore described. Any conventional method of ester hydrolysis can be utilized. If R4 contains terminal hydroxy group protected through the use of an ether protecting group, this ether group can be hydrolixed to yield the ~ree hydroxy group by conventional ether hydrolys;6 ~uch as by utilizing an aqueous inorganic acid.
Any conventional method of ether hydrolysis can be utilized. The protected ether hyd~oxy group can be hydrolized either prior to or after hyd~olysis of the ester grou~ to form the free acid of the compound of focmula XXXXI.

If it is desi~ed to produce compounds of the formulae I
and where X is -C=CH-, the com~ound of ~ormula XXXV in ~0 Figu~e 3 is reacted, via reaction step (u), with the comeound of formula XXXIV where R13 is R4 to produce the 0 compound of formula XXXVI where R13 is R4. This co~pound of formula XXXVI where ~4 is R13 ls then subjected to the same series of reactions as the compound of formula XXXVII, i.e. the reaction steps (w), ~x) and ~y), to produce the compounds of formulae I where X is 35 -C=C~-.
Rlo 1277;33?~
-- 19 ~

In the reaction scheme in Figure 3 where R2 in the compound of formula XXXV is a hydroxy group, it is preferred to protect this hydroxy group via esterifica~ion with a lower alkanoic acid. This ester protecting group can be cleaved after formation of the Wittig salt of formula XXXX.

The compound of formula I and II where X is -CH-0 ~ 10 can be erepared from a compoun-l of the formula ~0 ~-F~Z' 3 ~
l ~ L
~3 wherein Rl, R2, R3 and Z" as above by the reaction scheme of Figure 4. In Figure 4, Rl, ~ R R R R R ' Y d Zll b and ~15 is R4 wherein a hydroxy group contained in R15 is protected in the form of a hydrolizable ether group such a~ tetrahydropyranyl as well a6 the ether groups mentioned hereinbefore.

: 25 The compound of ~ormula L is co~verted to the compound of formula LI by reaction with the alkali metal alkoxide of formula L-A. This reaction i8 carried out by reacting the : compound sf formula L with the compound of formula L-A
utilizing the conditions conventional in reacting an alkali 30 metal alkoxide with a halide.
:
In the ste~, the compound of formula LI is converted to the compound of formula LII by first treating the compound of formula L[ with an alkyl lithium such as n-butyl lithium to metalate the compound of formula 1I. The metalated compound of formula LI i6 thereafter reacted with ; formaldehyde or a formaldehyde liberating compound. In 773~

converting the compound of formula LI to the compound of formula LII, the same reaction conditions as described in connection with reaction step (w) are used in this conver~ion. The compound of formula LII is converted to ~he phosphonium salt of ~ormula LIII treating the compound of formula LII with a triarylphosl?hine hydrohalide in the mannar set for~h in reaction step (b) above. The phosphonium salt of formula LIII is eeacted via a Wittig reaction with the compound of formula VII (see Figure 1) to L0 form a compound of formula LIV. This reaction to form the compound o~ fo~mula LIV i~ carriad out in the same manner as described in connection with step (c~ hereinbafore.

When R15 in the compound of formula LIV contains a protected hydroxy substituant said substituent can be hydrolized to form the free hydroxy compound by conventional methods for hydrolizing easily remo~able ether groups. Any conventional method for hydrolizing ether protecting groups can be utilized. The conditions conventional for zo hydrolizing ether protacting groups will not affect the other ether group contained within the compound of formula LIV. The com2ound o~ ~ormula LIV can be convarted to the ~rea acid by conventional ester hydrolysis.

Z5 If R2 in the compounds of formulae L, LI, LII and LIII
is hydroxy, it is peeferable that the hydroxy group be protec~ed via a hydrolyæable ester grou~ such as lower alkanoylvxy. The hydrolyzable ester ~rotecting group can be cleaved after forming the Wittig salt of formula LIII.
If desired, the double bonds within the comeound of formula I at positions 2-3, 4-5, 6-7 and 8-9 can be either in the ci~ or trans configuration. On the other hand, these compounds can be a mixture of the various cis and trans 35 isomers. In the compou~d of formula VII, the double bonds contained therein can be either in the cis or trans con~iguratioll de~ending upon tùe desired ~tereo ~;277331~:
- Zl -configuration of the double bonds within the compounds of formula I. The Wittig reaction carried out in producing the compounds of formula I and II such as in steps ~c), (e), (i), etc. produces the double bond at the 8-9 po6ition as a mixture o~ the 8-9 cis and trans isomers. These cis and tran~ i~omers can be separated by conventional means such as fractional crys~allization, etc.

In addition, where the compound6 o~ formula I have a L0 double bond in the trans configuration at the 2-3 position, this isomer can be converted to the corresponding Ci8 double bond with conventional methods of isomeriæation known in the art. bmong these ~rocedures are included treating the compound of either formula I with iodine in an inert organic L5 solvent. I60merization with iodine produces the compound o~
formula I with a 2-3 double bond in the cis position.

The comeounds of ormula I include all of its geometric isomers including mixtures of these geometric isomer5.
The eompound o~ formula XI where Rl is fluoro is a new compound and can be prepared from a comeound of the formula ~ F
~ 25 ~ ~ LV

where R2 and R3 are above via the reaction scheme given of Figure 5. In Figure 5, R2. R3 and R4 are as above.

In Figure 5, ~he compound o~ formula LV i6 alkylated by reaction with an allyl bromide. If the compound where R2 ~ i6 hydroxy is desired, the compound of formula LV where the :

~7733~

hydroxy group designated by R2 is protected by esterification is used as the starting material, i.e. the compound of formula LV where R2 is a protected hyroxy group. Any conventional method of alkylating a hydroxy group with an allyl bromide can be utilized to carry out the reaction o~ converting the com~?ound o LV to the compound of formula LVI. The compound of ormula LVI i8 rearranged to the compound of formula LVII by heating the compound of formula LVI to a temperature from 190 degrees to 230 degrees L0 centigrade. This rearrangement can take place without the use of any solvent or in the ~resence of a high boiliny hydrocarbon solvent. If R3 is hydrogen, the com~ound of fo~mula LVII i8 formed as a mixture with the isomer of the compound of formula LVII where the allyl group i6 para to the ~luorine substituent on the benzyl ring. This isomer can be separated or utilized in the subsequent reactions and separated from the reaction mixture at a later ~tage.

The compound of formula LVII i8 thereafter converted to zo the compound of formula LVIII by reaction with the compound of formula V (Figure 1) as set orth in reaction s~ep (d) hereinbefore. In the next step o~ this reaction scheme, ~he compound of formula LVIII is converted to the compound o~
formula LIX by isomerization with a strong base such as an alkali metal al~o~ide in the presence of an inert organic sol~ent preferably pota~sium tertiary butoxida in dimethyl sulfoxide. The compound of formula LIX i5 converted to the compound of formula LX by treating the compound of formula LIX with ozone gas. In carrying out this reaction, 30 temperature of from minu~ 70 de~rees centigrade to minus 20 degrees centigrade are utilized. Furthermore thi~ reaction is carried out in an iner~ organic solvent. Any conventional inert organic solvent can be utilized, ~re~erably halogenated hydrocarbons such as methylene 35 chloride.

A compound of formula LX is the com~ound of focmula XI

~7733,~

wherein Rl is fluoro. This compound can be converted to the compound of formula X in accordance with the reaction scheme set forth in Figure 1.

Where R2 is hydroxy in the compound of formula III
there are two hydroxy groups. Therefore, it i8 generally preferred to prepare the compound of formula XI where R2 is a protected hydroxy group from a compound of the formula LXI as shown in Figure 6. In this manner, compounds of L0 formula I can be prepared where X i8 -0-; R2 iS hydroxy and R3 and R4 are as above. In Fig. 6, Rl and R15 taken with its attached oxygen atom, is hydroxy protected by a conventional hydrol~zable protecting group preferably a lower alkanoyl.
In Figure 6, the compound of Formula LXI is converted to the compound of formula LXII utilizing the same reaction as described in ~onnection with the conver6ion of a compound of ~ormula LV ~o a compound o~ the Formula LVI. (See Fig. 8) The compound of Formula LXII is next converted to a com~ound of Formula LXIII by utilizing the same procedure described in connection with the conversion of the compound of Formula LVI to LVII. In the next 6tep6 the compound o Formula LXIII is converted to the compound LXIV ~y the ~ame zs procedure described in connection with step (g') in Figure 5 and then to the compound of Formula ~XV by the procedure described in connection with step (h') in ~igure 5. The conver~ion of bromobenzene compound of Formula LXV to the ~henol compound of Formula LXVI takes place by erocedures 30 well known in the art such as disclosed by Kidwell and Darling, Tetrahedron Letters, (1966) pgs. 531-535.

: In ~he next step of preparing the in~ermediate of formula XI where R2 is a protected hydroxy group, i.e. the 35 compound of Formula XI~ he hydroxy group is protec~ed on the compound of formula LXVI through esterification with any conventional hydrolyzable ester group to form the compound ~.~Z7733.~, of Formula LXVII where Rl5 taken together is attached oxygen forms a hydrolyzable ester group. Any conventional method of esterifying a hydroxy groups with an organic acid such as a lower alkanoic acid containing from 1 to 7 carbon atoms can be used to prepare the compound of Formula LXVII.
The com~ound of Formula XI-~ is formed from the compound of Formula LXVII by the reaction described hereinbefore with reseect to the conversion of a compound of the Formula LIX
to LX (See Pig. 5).
In carrying out the convQrsion of a compound of Formula XI-A, to a compound of Formula XVII, as in Figure 1, it ;8 generally prefe~red to hydrolyzs the ester substituent which forms R2 aftec the formation of the Wittig salt of Formula XIII or Formula XVI.

In accordance with another embodiment of this invention the compound of formula XI where Rl is CF3 (the compound of formula XI-B) can be formed by the reaction outlined in 2Q Figure 7 from a compound of Formula LXX~ In the fir6t ~te~
of this reaction the compound of Formula LXX is converted to a compound of Formula LXXI utili~ing the ~ame procedule dascribed hereinbefore in connection with the reaction. via step (d) where the compound of Formula VIII is reacted with a compound of the Formula V to produce a compound of the Formula X. In this reaction where R2 i5 OH, alkylation ~ occurs very slowly on the hydroxy group ortho to the CF3 ; group. Therefore, erotection of this group may no~ be neces6ary since alkylation eroceeds ~refeeably with the meta 0 h~droxy ~roup. Any mixtures of alkylated products obtained from this rea~tion can be separated by conventional separation procedures. The compound of formula LX~I is converted to the compound of formula XII-B by conventional procedures of formylating a benzene Ling such as by 35 treatment with an alkyl lithium and dimethylformamide.

The following examples are illus~rative but limitative ~2>7733?J

o~ the invention. In the exam~les the ether is diethylether and the solvents were removed in vacuo.

Example 1 [[(2-tNonyloxy~DhenYllmethYlltriPhenYlPhosPhonium bromide 2-Hydroxybenzaldehyde (110 g). was alkylated by mixing this compound with l-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80C ~or 14 hours. Hexane and watec were then added and the hexane extract was concentrated and the residue was distilled to yîeld the 2-nonyloxybenzaldehyde ~210 g). be 121C (0.3mm Hg).
solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10C was reduced by treating wi~h an L5 excess of sodium borohydride (6 g) and after 6tirring the mixture for a further 15-20 min. at room te~perature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile t500 mL) and the resultant solution wa~ heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the re~idue from a tetrahydrofuran/ethyl ether mixture gave the pure ~2-tnonylox~)phenylJmethyl]triphen phosphonium bromide (208 g3.

~(2-HYdroxYPhenyl?methylLtriPhen~l~--sphonium bromide 2-Hydroxybenzyl ~lcohol was treated with t~iphenyl-phosphine hydrobromide in acetonitrile as described in Example 1 to yield [(2-Hydroxyphenyl)methyl~riphenyl-phosphonium bromide.

ExamPle 3 ALL(EL-9-(2-Hydroxyphen~1)-3,7-dime hYl-2,4,6,8-nona-tetraenoic ac_d ethyl ester ~.2~7733~

A 601ution of ~t2-hydroxyphenyl)methyl]triphenyl-phosphonium bromide (1 mol~ in tetrahydrofuran was converted to the ylide at -35 with a solution of n-butyllithium in hexane (2.1 mol equiv.) and then exposed to 7-formyl-3-5 methyl-2,4,6-octatrienoic acid ethyl ester (1 mol) and then stirred at -70 for a fuether 15 min. Isolation of the organic products with a hexane~ethyl acetate mixture (4:1 parts by volume~ and dilute mineral acid (2M aqueous HCl) gave the pure all(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid eth~l eeter (90% yield) a~ter chromatography followed by crystallization from a dichloromethane/hexane mixture.

Example 4 ALL(E~-9=~2-HvdroxvphenrlL-3~7-dimethyl-2~ J8-nona tetraenoic acid ethyl_ester mixture of 2-hydroxybenzaldenyde (0.5 mol), (7-carboxy-2,6-dimethyl-2,4,6-heptatrien-1-yl)triphenylphos-phonium bromide (0.6 mol) in 1,2-epoxybutane (750 mL) was heated at re1ux for 30 ~in. cooled, poured into an ether/hexane mixture (1:1 ~arts by volume) fileered and concentrated. The residue was then crystallized from a hexane/ether mixture to yield all(E)-9-(2-hydroxyphenyl)-3, 7-dimathyl-2,4,6,~-nonatetraenoic acid ethyl ester (38 yield), mp 143-1~5.

Example 5 E)-9-~2~-(Nonyloxy)phenY11-3,7-di~ yl-2 4,6~8-nona-tetraenoic acid A solution of ~[2-(nonyloxy)ehenyl]methrl]triphenyl-~hosphonium bromide (150 g3 in tetrahyd~ofuran (1100 mL) was cooled to -50C to yield a fine suspension of the solid 8alt. To this mixture was added a solution o~
n-butyllithium in hexane (180 mL, a 1.6 molaL) to yield a solution of the ylide. The mixture was then stirred a further 15 min at -40C, cooled to -70~ and tLeated with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (65 g) , , .

Z7;733~?J
- 27 _ dissolved in tetrahyd~ofuran (250 mL). Addition o~ hexane and aqueous methanol (40~) to the reaction mixture followed by concentration of the hexane extract yielded All(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid ethyl ester (64 g, 58% yield), mp52-53C. This ester was then hydrolized by foeming a solution of ~his ester (70 g) in ethanol (1000 mL). This solution was trea~ed with aqueous potassium hydroxide (80 g in 400 m1 water) and heated at reflux for 1 h. Watar and L0 aqueous mineral acid was then added and the solids were extracted into chloroform. Concentration of this o~ganic extract and crystallization of the residue from an ethyl acetate hexane mixture yielded All(E)-9-E2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,B-nonatetLaenoic acid (38 g), mp lOZ-1~3C.

ExamPle_6 (All_E) 2~2-(NonYloxY)~henYl~,7-dimethvl-2,4,6l8-nona-tetrae~oic acid ; 20 A mixture o~ sodium hydride (24 g, 50~ by weight in mineral oil) and dimethylformamide (1000 mL) at 10C was treated with All(E~-9-t2-hydroxyphenyl3-3,7-dimethyl-2,4, 6,8-nonatetraenoic acid ethyl ester (0.4 equiv.). The ~esulting mixture was then stirLed at room temperature until all hydrogen evolution had stoeped to produce the sodium salt o~ All(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. ~ solution of l-nonyl tosylate (O.S equiv.) in dimethyl~ormamide (200 mL) was ~hen added to this salt solution and the reaction mixture ~as stirred at 45 for 14 h. Hexane/water was then carefully added and the hexane extract was concentLated and the residue was purified by chromatography over silica geI.
Crystalli2ation from hexane then yielded the puee All(E)-9-~2-(nonyloxy)ehenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid ethyl ester. Hydrolysis of this ester as in Examele 5 gave (All-E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-:~2773~

2,4,6~8-nonatetraenoic acid.

~ xample 7 ~ll-E2-3,7-DimethYl-9-r2-t~2 2-dimethYl-octYl)oxYlPhen s 2,4,5,8-nonatetraenoic acid 2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane to yield 7- (2,2-dimethyl octyloxy) benzaldehyde which was reduced to 2-(2,2-dimethyl, octyloxy)benzyl alcohol and ~hen converted to 10 ~2-(Z,2-dimethyloctyloxy~ehenyllmethyl]t~iphenylphosphonium bromide a~ in Example 1. Condensatîon of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-~2-t(2,2-L5 dimathyl-octyl)oxy]phenylJ-2,4,5,8-non-atetraenoic acid mp 113-117 (from dichloromethane/hexane mixture).

Examele 8 (All-E?-3,7-Dimethyl-,9-[2-L~octylox~)-methYllDhenyll-Z,4L6,8-nonatetraenoic a~id Lithium octanoate, prepared from oc~anol and ~-butyllithium, in a mixture of tetrahydrofuran/hexane dimethyl foemamide was condensed with 2-bromobenzyl bromide to yield 2(octyloxy)methylbromobenzene. This material was treated with n-but~llithium in ether/hexane mixtu~e and subsequently treated with para~ormaldehyde to yield 2-(octyloxy)methylbenzyl alcohol. This material was then treated wi~h ~riphenyl phosphonine bromide to yield ~[Z-[(octyloxy~-methylJphenyl~me~hyl3triphenyl pho~phonium bromide. Co~dansation of this material with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl estee, as in Example 3, ~ollowed by hydrolysis, as in Example 5, gave the (~ll-E)-3,7-Dimethyl-9-~2-~(octyloxy)-methyl~phenyl]-2,4,6,8-nonatetraenoic acid, mp 120-121 (from dichloro 35 methane/hexane mixture).

:

;

3LZ~7~3~i~

Exam~le 9.
(All-E)-9-r2-chloro-6-(nQnyloxy)PhenY11-3,7-dimethyl-2,4,6, 8-nonatet~aenoic acid _ 2-chloro-6-hyd~oxy-benzaldehyde was alkylated with l-b~omononane as in Example 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzyl alcohol which on treatment with triphenylphosphine hydrobcomide in acetonitrile as in Example 1 yielded ~[2-chloro-6-nonyl-oxy]-L0 phenyl]methyl~triphenyl phosphonium bromide. Condensationwith 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 produced (All E)-9~~2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. The ester was subjected to hydrolysis, as ~s in Example 5, to ~roduce (All-E)-9-~2-chloro-6-~nonyloxy)~
phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid mp 129-131 (from ethyl acetate~hexane mixtu~e).
' Exam~le 10 (All-E)-9-(5-Methoxy~2-nonYloxyehenyl)-3~7-dimethvl-?~4~6 8-nonatetraenoic acid 5-Methoxy-2-hydroxybenzaldehyde was alkylated with nonylbromide and reduced with sodium borohydride, as in Example 1, to yield 5-methoxy-2-nonyloxy-benzyl alcohol which on exposu~e to triphenylphosphine hydrobromide gave ~5-methoxy-2-nonyloxyphenyl)methyl]~riphenyl phosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-oc~atrienoic acid ethyl ester, as in Example 3 followed by hydrolysis, as in Example 5, gave (All-E)-9-(5-Methoxy-2-nonyloxyphenyl)-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid mp 125-126 (from methanol).

ExamPle 11 All(E)-g-~2-(8-H~droxyoctYl)oxy]pheny~-3L7-dimethyl-2~4~6 8-nonatetcaenoic acid The sodium æalt of All(E)-9-(2-hydroxyphenyl)-3,7-dime~hyl-2,4,6,3-nonatetraenoic acid ethyl ester in ~t7733;~

dimethylformamide ~repared as described in Example 6 was treated with l,8-dihydroxyoctane monotosylate as desceibed previously in Example 6 and gave ~ll(E)-9-~2-~8-hydroxy-o~tyl)oxy]phenyl-3,7-diethyl-2,4,6,8-nonatetraenoic acid ethyl ester after chromatog~aphy over 6ilica gel.
Hydrolysis as in Example 5 yielded All(E)-9-[2-[(8-hydroxy-octyl)oxy]phenyl]-3,7-dimethyl-phenyl]-3,7-dimethyl-Z,4,6,8-nonatetraenoic acid, mp 122-123 (from ethyl acetate).

ExamPle 12 ~ll(E)-rS-(2-NonyloxyphenYl)-3-methyl-2,4-1?entadienYlltri-PhenYlPhosphonium bromide 2-(nonyloxy)benzaldehyde (62 g) di6solved in acetone (500 mL) was treated with aqueous sodium hydroxide (100 mL, lM) at coom temperature for 18 h. Brine and ethyl acetate/hexane (1:1 parts by volume) wa~ then added.
Concentration of the organic phase followed by cystalliza-tion from ~exane gave 4-(2-nonyloxyphenyl)-3-~utene-2-one (53 g).

A solution of 4-(2-nonyloxyphe~yl)-3-butene-2-one (58 g) in tetrahydrofuran (200 mL) was added to a solution of vinylmagnesium bromide in tetrahydrofuran (200 mL, 1.6M
diluted to lL with more tetrahydro~uran) at -30C. ~fter com~lete addition, the mixture was stirred at 0 C for 30 min, quenched wi~h saturated aqueou~ ammonium chloride (100 mL) and ether (2L) and filtered free o~ solids.
Concentration of the organic extract and purifica~ion by 30 chromatography over silica gel yielded (E)-5-(2-nonyloxy-phenyl)-3-hydro~y-3-methyl-1,4-pentadiene (40 g) as an oil.

~ solution of (E)-5-(2-nonyloxyphenyl)-3-hydroxy-3-me~hyl-1,4-~entadiene (66 g) in acetonitrile (250 mL) was 35 added to a slurry of triphenylphosphine hydrobromide (66 g) in more acetoni~rile (300 mL) at 10C. After warming to room temperature, ~he mixture was stirred at ~his 33.V~, temperatuee ~or 2h to yield a solution. This solution was then extracted with hexane (2 x 250 mL) and the acetonitrile layer was concentrated (ca. 400 mL) and cooled to -10.
The solids were ~iltered o~f, washed with acetonitrile, hexane, and dried to give pure All(E)-[5~(2-nonyloxyphenyl)-3-methyl-Z,4-pentadienyl]triphenylphosphonium bromide (21 g).

Exam~

L0 Starting with All(E)-[$-(2-nonyloxyphenyl)~3-methyl 2,4-pentadienyl]triphenylphosphonium bromide and utilizing the proceduce of Examele 5, the ylide was reacted with 3-~ormyl-2-butenoic acid ethyl ester to yield ~ll(E)-9-(2-nonyloxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid after purification by chromatography over Bilica gel and hydrolysis with aqueous ethanolic potas6ium hydroxide ; solution as in Example 5.

Example 14 (Z,EI~E3-9-~2=(NonYloxy)phenyll-3,7-dimethyl-2,4,6~8-non-~ ~ll(E)-9-t2-~nonyloxy)phenyl]-3,7-dimethyl 2,4,6,8-;~ nonatetraenoic acid ethyl ester S10 g) was dissolved in ~b hexane (200 mL) containing iodine (0.5 g) and ctirred at room temperature for 30 min. ~he he~ane was washed ~ree o~
iodine with an aqueous sodium thiosulfate solution ~10~ by weight), dLied and concentra~ed to give a mixture of double bond isomers. Separation, by chro~atography on silica gel, yielded pure (Z~E,E,E)-9-~2-(nonyloxy)phenyl]-3,7-dimethyl-30 2,4,6,8-nonatetraenoic acid ethyl ester (1.5 g~. Hydrolysis with aqueous ethanolic potassium hydroxide at re~lux gave the pure ~Z,E,~,E)-9-~2-(nonyloxy)phenyl]-3,7-dimethyl-~,4,6,8-nonatetraenoic acid: mp 135-136C.

, .

~7733~
_ 32 -ExamPle 15 (E,E,E,Z)-9-[2-(NonYloxY)PhenY11-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid The mother liquor material resulting from the crystallization of All(E)-9-~2--(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester in Example 5 was a mixture containing various isomers. Pu~ification by chromatography yielded an 80% pure ethyl ester which after hydroly6is as in Example 5 yielded pure (E,E,E,Z)-9~2(nonyloxy)phenyl~-3,7-dimethyl-2,4,6,~-nonatetraenoic acld: mp 105-109.

Example 16 2-DecYl-l-bromgben ene Nonylmethyltriphenyl phosphonium bromide (0.1 mol) in tetrahydrofuran (200 mL) was converted to the ylide with n-Butyllithium (0.1 mol equiv: 1.6M in hexane) at -10C.

2-Bromobenzaldehyde (0.09 ~ol) was then added in tetrahydLofuran (25 mL) and after the mixture had been stirred for a further 30 min at 0C hexane and aqueous me~hanol (40:60) was added. The hexane extract was conce~tLa~ed and the re6idue was di~tilled to yield 2-(1-decenyl)-l~bromobenzene (90%).
This material was dissolved in hexane containing a palladium on carbon catalyst (10%) and hydrogenated at eoom temperature and pres ure until the olefinic link was saturated. The ~olids wera filtered o~f and removal of the hexane and distillation o~ the residue gave pure 2-decyl-1-b~omobenzene (80~): bp 120 (.001 mm Hg).

~3 ?-Decvl-l-hydroxymethylbenzene 2-Decyl-L-bromobenzene (0.1 mol) dissolved in ether (lS0 mL) was treated with n-butyllithium (0.11 eq. 1.6M in hexane) and the mixture was stirred at room temperature for ~Z~33 ~

2 hours.

Dry paraformaldehyde (0.2 mol eq) was then added and the mixture was stir~ed for a further 18h at room temperature.

Water and move ether wa~ then added and the ether extract~ were dried and concentrated. The residue after chromatography yielded pure 2-decyl-1-hydroxy methyl benzene (75% yield).

Example 18 All(El-9-(DecYlPhenyl)-3,7-dimethy~-214~6~8-nonatetraenoic acid 2-Decyl-l-hydroxymethylbenzene was converted to the L5 ~hosphonium salt with triphenylphosphonium hydrobromide in acetonitrile by the ~rocedure of Example 1. This salt was then ex~osed to n-butyllithium in tetrahydrofuran as be~ore and then treated with 7-formyl-3-methyl-2,4,6-he~ta-trienoic acid methyl e~tar as be~ore.
Purification of the crude condensation product by chromatography on silica gel ~ollowed by basic hydrolysi6 yielded pure All(E)-9-(decyl~henyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid: mp 107-108 tfrom hexane-ether).
Example L9 ~ll(E~-9-L~octYlaminophenYl)-3,7-dimethvl-2,4,6,8-nona-tetraenoic ac d ethvl ester 2-Aminobenzyl alcohol ~1 mol) was treated with 30 octanoylchloride (2.2 mol) in a mixture of dichloromethane-triethylamine at 0C. After 30 min at 10C the mixture was washed with water and ~he ether was distilled off. The crude residue was dissoIved in tetrahydrofuran ~2000 ml), treated wi~h aqueous sodium 35 hydroxide (lN, 1500 mL) and stirred a~ room temperature for 3h.

31 2~7~3~

Addition of water and ether yielded the crude hydroxymethyl octylamide. Purification by chromatography yielded the pure octyamide (~5%).

This material (100 g~ was dis~olved in tetrahydrofuran (500 mL) and added to a slurry of Lithium aluminum hydride (2 mol equiv) in tetrahydrofuran ~1000 mL). Th~ mixture was then heated at reflux for 8h cooled to 0 C and quenched with aqueous sodium ~ulfate solution (100 mL).
~0 The solids were filtered off, the solvents were removed in vacuo and the residue wa~ puri~ied by chromatography on silica gel to yield ~ure 2-hydroxymethyl-N-octylamaline ; (75g)-~5 This material was dis601ved in acetonitrile (300 mL) containing triphenyl pho~2hine hydrobromide (1.1 eq) and the mixture was heated at ceflux for 24h and then concentrated.
The residue was digested with ether to give the phosphonium salt as a white solid.

This material was converted to the coLresponding ylide with n-butyllithium (1.5 mol eq) and stirred at 0 for lh. Excess 7-formyl-3-methyl-2,4,6-heptatrienoic acid ~ zs ethyl ester (1.6 mol eq) was then added in tetrahydrofuran -~ and the mixture was stirred at ~0C for lh.

Addition of hexane and aqueou~ methanol (2:3) and removal of the hexane in vacuo gave the crude coupled 0 product. Purification by chromatography on silica gel and crystallization from hexane gave pure ALL(E)-9-(2-octyl amino phenyl)-3,7-dimethyl-2.4,6,8-nonatetraenoic acid ethyl ester (25%): mp 38-40C.

~2~7~3~
_ 35 -Example 20 2-Fluoro-6-nonyloxybenz~l alcohol A solution of 3-fluoro phenol (100 g) in dimethyl-formamide (1000 mL) containing potassium carbona~e (165 g) was treated with allyl bromide (lL5 g) and heated at 80 for 18 hours.

Water and hexane were then added and the hexane extract was washed with aqueou~; sodium hydroxide solution L0 (5%). saturated brine solution and concentrated to yield the allyl ether (155 g). This material (134 g) was heated at 220 for 16 hours to yield a mixture of 3-fluoro-2-(2-butenyl)phenol and 5 fluoro-2-(Z-butenyl)~henol. This mixture was di~solved in dimethyl formamide (2000 mL) containing l-bromononane (170 g) and ~otassium carbomate (150 g) and heated at 80 for 16 hours. Dilution with water and extraction with hexane yielded a mixture of ~roducts on concentration. Distillation gave a mixture of 3-~(2-fluoro-6-nonyloxy)phenyl]-butene and 3-~(3-fluoro-2-nonyloxy)phenyl]-butene (186 g) bp. 120-125 @ O.lmm.

This mixture of isomers (185 g) in dimethyl~ulfoxide (1000 mL) containing potassium tert-butoxide (1.5 g) was left at room temperature for 6 hours. Addition of water and extraction ~ith hexane gave the mixture of 1-~(2-fluoro-6-nonyloxy)phenyl]-butene and 1-~(3-fluoro-2-nonyloxy)phenyl]butPne.

This mixture of isomers (175 g) was dissolved in a mixture of dichloromethane and methanol (9:1, Z000 mL) and exposed to a stream of ozone at -40 f or 8h. ~fter this time the reaction mixture ~as pouLed into a mixture of water, hexane and dimethylsulfide ~100 mL) and s~irrad at room temperature for L hour.
The hexane extract was washed (water), dried rMgS04), treated with more dimethyl sulfide (50 mL) and left at room .

733~

temeerature for 16 hours. `

Removal of the solvents yielded the mixture of aldehydes 2-fluoro-6-nonyloxybenzaldehyde and 4-fluoro-2-nonyloxy-benzaldehyde (155 g).

This mixture of aldehydes (150 g) in ethanol (2000 mL) was exposed to sodium borohydride (15 g) at 5 and then stirred at room temperature for 30 min. ~ater (1500 mL), brine (500 mL) were then added and the mixture of alcohols was extracted into hexane. Remo~al of the solvents and chromatography of the residue over sili~a gel (5~
ethylacetate-hexane mixture) yielded pure Z-~luoro-6-nonyloxy-benzyl alcohol (76 g).
Example 21 (~ll-E~-9-2-Fluoro-6-tnonyloxY~PhenYll-3,7=dimethyl-2,4,6 e~e~ id A mixture of 2-fluoro-6-nonyloxyben2yl alcohol (19 g) and triphenylphosphine hydrobromide~(26 ~) in acetonitrile (250 mL) was heated at reflux for 14 hour6 and then concentrated to drynes~ to yield ~[(2-~luoro-6-~ nonyloxy)phenyl]methyl]triphenyl phosphonium bromide (42 :~ g). Thi~ phosphonium salt was dissolved in tetrahydrofuran (600 mL) cooled to -50 and treated with n-butyllithium (45 mL, 1.6M in hexane). After stirring a further 15 min at -50 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (8.4 g) was added and the reaction mixture was warmed ~o room temperature and stirred for a further 15 min. Hexane ~ 30 wa~ then added and the mixture wa~ washed with water, 40%
:~ aqueous methanol and dried (MgS04). Concentration of the hexa~e extract and purification by chromatography (5%
ether-hexane) ga~e the pure trans i60mer (11 g).

Cry tallization from hexane-ethyl acetate gave (A11-E)-9-~2-fluoro 6-(nonyloxy)-phenyl]-3,7-dimethyl-204,6,8-.
~.

733;2 nonate~raenoic acid ethyl ester (9.5 g).

A solution of the ester ~6.5 g) in ethanol (150 mL) was treated with a solution of potassium hydroxide (7 g) in water (40 mL) and heated at reflux for 1 hour. ~he cooled reaction mixture was ~oured into cold aqueous hydrochloric acid and the acid was extracted into chloroform. Removal of the solvents and crystallization from hexane-ethyl acetate gave pure (all-~)-9-~2-fluoro-6-(nonyloxy)phenyl]-3,7-dimeth~l-2,4,6,8-nonatetraenoic acid mp 107-109.

:
: 25 `

~ 27733;~

Exam~le 2 ?

CAPSULE FORMUL~TIONS:

5 Item Inqredients mq/caPsule ~g~3p~ule mq/capsule 1. (All E)-9- 15 30 60 [2-(nonyloxy) ~henyl]-3,7-dimethyl-2,4~6, 8-nonatetraenoic acid ~5 2. Lactose 239 224 194 3. Starch 30 30 30 .
~. . .

4. Talc 15 15 15 ~ 20 -~ 5. Magnesium ____ _____ _____ Capsule fill weight 300mg 300 mg 300 ~g PROCEDURE:

1) Mix items 1-3 in a suitable mixer.
2) Add talc and magnesium stearate and mix for a short period of time.
3~ Encapsulate on an appropria~e encaesulation machine.

~D ~ ~
~.~77~3~
- 39 ~

ExamPle 23 Capsules are prepa~ed by the procedure of Example 22 except that the active ingredient (item 1) wa~ (All E)-9-[2-fluoro-6[nonyloxy)~henyl]-3,7-d}methyl-3,4,6,8-nona-tetraenoic acid.

ExamPle 24 ~o TABLET FORMULATION (Wet geanulation) Item Inaredients mq~tablet mq~tablet mq~_ablet : 1. (All E)-9- 100 250 500 L5 [2-(nonylo~y) phenyl]-3,7-dimethyl-20g, 6,8-nonatetrae-noic acid 20 2. Lactose 98.5 147.5 170 3. Polyvinyl 15 30 40 pyrrolidone (PVP) 4. Modified sta~ch 15 30 40 5. Corn starch 15 30 40 25 6. Magnesium 1.5 2.5 5 : ~ stearate Weight of tablet 245 mg 490 mg 7g5 mg : 30 .,~

: 3s '~
, .

:. , ~ ~773~`~
-- ~o --Procedure:

1. Mix i~ems 1, 2. 4 and 5 in a suitable mixer, granulate with PVP and dissolve in water/alcohol. Dry the gra~ulation. Mill the dry granulation through a suitable mill.
2. Add magnesium stearate and compre66 on a suitable ~ress.

ExamPle 25 ~0 Tablet are prepared in the same manner as Exam~le 24 except that the active inyredient (item 1) was (~11 E)-9-[2-fluoro-6(nonyloxy)~henyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid.
Exam~le 26 T~BLET FORMULATIONS: (DiLect Compre~sion) 20 Item Ingredientmq~tablet mg~ mq/tablet 1. ~All E)-9- 15 30 60 ~2-(nonyloyl~
phenyl]-3,7-dimethyl-2,4, 6,8-nonate~rae-noic acid 2. Lactose 207 192 162 3. Avicel~ 45 45 45 4. Direct 30 30 30 Compression StaLch 5. Magnesium 3 3 3 ; 35 ---- -___ ____ ~eight o~ tablet 300 mg300 mg 300 mg * trade mark.

~'73~

PROCEDURE:

1. Mix Item 1 with equal amount oP lacto~e. Mix well.
2. Mix with Item 3, 4, and remaining amount of Item 2. Mix well.
3. Add magnesium stearate and mix for 3 minutes.
4. Compre6s on a 6uitable punch.

Exam~
LO CAPSULE FORMUL~TION8~

Item Inqrsdients m~/caPsule m~/capsule mq/caP~ule 1. (~11 E)-(3,7- 15 30 60 ~s dimethyl)-9-~2~(8-hydroxy-octyl)oxy]phenyl]-Z,4,6,8-nonatetraenoic]
acid.
20 2. Lactose Z39 224 194 3. Starch 30 30 30 4. Talc 15 15 15 5. Magnesium , 25 Capsule fill weight 300 mg 300 mg 300 mg PROCEDU~E:

1) Mix items 1-3 in a suitable mixer.
30 2) Add talc and magnesium stearate and mix for a short period of time.
3) Encapsulate on an appropriate encapsulation machine.

~1 27733~

Example 28 TABLET FORMULATIONS (Wet granulation) Item Inqredient mq/tablet ma/tablet ma/tablet 1. (All E)-3,7- 100 250 500 ~ - dimethyl-9-- [2,~(octyloxy) methyl~phenyl]-2,4,6,8-nona-tetraenoic acid 2. Lactose 98.5 147.5 liO
3. Polyvinyl 15 30 40 L5 pyrrolidone 4. Modified starch 15 30 40 5. Co~n starch 15 30 40 6. Magnesium 1.5 2.5 5 - stearate ~~~~~ ~~~~-~ ~~~~~
Weight of tablet 245 mg490 mg 795 mg Procedure:

1. Mix items 1, 2, 4 and 5 in a suitable mixer, granulate with PVP and dissolve in water/alcohol. Dry the granulation. Mill the dry granulation th~ough a suitable mill.
2. Add magnesium stearate and compress on a suitable press.

PhosPhonium bromide mixture of a,~.~-tri~luoro-m-cresol (51 g)~
l-bromononane ~70 g), potassium carbonate (100 g) in dimethylformamide was heated a~ 85C for 48 h. Addition of water and hexane gave pure (3-trifluoromethyl) phenyl .

~Z7733.~

nonyl ether (89 g): b.p. lL5C at 0.1 mmHg. This product (89 g) in ether (1.5 L) at -20 C was mixed with n-butyllithium (1.5 M in hexane: 233 mL) and then sti~red for 2h at room temperature. This mixture was then cooled to -40, treated with an excess o~ dry dimethyl~ormamide (40 m~) in ether (100 mL), warmed to 0 and then treated with water. Extraction with hexane and chromatography on si.lica (5% ether-hexane) gave (2-trifluoromethyl-6-nonyloxy)-benxaldehyde (35 g). Reduction of this ~roduct with L0 ~odiumborohydride i~ ethanol by the pcocedure set ~orth in Example 1 gave (2-trifluoromethyl-6-nonyloxy)benzenemethanol (32 g) after cheomatography over 8ilic~. This material (31 g) was converted into Ct2-trifluoromethyl-6(nonyloxy)phenyl]-methyl]triphenyl~hosphoniu~ beomide by reaction with triphenylphosphine hydrobromide by the procedure given in Example 1.

Example 30 (All-E)-9-L~=(Tri~luoromethyl)-6-(nonYIoxy)ph ~ ll-3~7 dimethyl-2,4,6,8-nonatetraenoic acid ~ 2-trifluoromethyl 6-(nonyloxy)phenyl]methyl]triphanyl-phosphonium bromide (97 mmol) in tetrahydro~uran (600 mL) wa~ converted by ~eaction with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester to (All-E)-9-~2-(trifluoro-methyl)-6-(nonyloxy)phenyl~-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid e~hyl ester by the procedure given in Example 3. Purification by chromatography and crystallization from hexane gave the pure ethyl ester (41%). Hydrolysis (5.2 g) a~ in example 5 gave eure (All-E~-9-~2-(t~ifluoromethyl)-6-(nonyloxy)phenyl]-3~7-dimethyl-2,4,6,8-nonatetraenoic acid (3 g): mp 135-136 (from ethyl acetate hexane).

Example 31 (All-E~-9-~2=~hexyloxY~henyll-3~7-dimeth~1-2~4~6~8-nona-tetra no acid t[2-(hexyloxy)phenyl]methyl]triphenylphos~honium ~L2773~
- 4~ -bromide, prepared by the procedure of Example 1 by reacting 2-hydroxybenzaldehyde and l-bromohexane, was converted to (All-E)-9-~2-(hexyloxy)phenyl]-3,7-diethyl-2,4,6,3-nona-tetraenoic acid, m~ 137-138 (fLom ethanol) by the procedure of Exam~le 3.

Exam~
r ~ 2-(Non~loxY)-5-(h~droxv)Dheny-llmethylltriphenvlphosphonium bromide A solution of 4-bromophenol (1 mol) in tetrahydro~ura~
(500 mL) was added to a Rlurry of sodium hydride (1.17 mol) in dimethylformamide (1.2 L) at 25 C. ~fter complete ~eaction allylchloride (1.32 mol) wa~ added and after stirring for a ~uLther 3 h at 45 the product was isolated L5 with water and hexane. Di~tillation gave allyl-(4-bromo-phenyl)ether. bp. 65-67 at 0.1 mm (82%). This material was heated at 195 with dimethylanaline for 4 hours and ~hen di tilled to yield 2-allyl-4-bromophenol (0.81 mol). A
solution of this material (0.81 mol) in tetrahydrofuran (200 mL) was added to a mixture of l-bromononane (0.8 mol), sodium hydride (0.92 mol) potassium iodide (1 g) in dimethylformamide (lL) at 2SC. After hydrogen evaluation was complete the mixture was heated at 50 for 14 h, cooled, added to an exces~ of water and extracted with hexane. Distillation furnished nonyl-(2-allyl-4-bromo-phenyl)ether (256 g): b.p. 147-156 at 0.1 mm. This material (255 g) in dimethylsulfoxide (1 L) and tetrahydrofuran (0.5 L) was heated at 35-40 with ~otassium tert. bu~oxide (2 g) for 2 h and then quenched 30 with acetic acid (5 mL) and water. Isolation o~ the reaction products with hexane yielded eure l-r2-(nonyloxy)-5-(bromo)~henyl]eropene (234 g~: b.p.
145-155 at 0.1 mm. ~ solution of the above material (0.56 mol~ in tetrahydrofuran (600 mL) was converted to the 35 Grignard reagent wi~h magnesium (1 mol) at 55C for 3 h.
After complete reaction ~he mixture was cooled to 0C and ~reated with trimethylborate (0.75 mol) in ether (200 mL).

~ ;~t7~73~

Af~er stirring for a further 30 min. at 25 C the mixture was cooled to 0 and exposed to a mixture of ammonium chloride (10%) and hydro~en peroxide (10%, 500 mL) and stirred ~or a further lh at 25 C. Addition of water and hexane gave the crude material after removal of the hexane in vacuo. The crude product was passed through a plug of silica gel to yield para [2-(1-propenyl 4-(nonyloxy)-phenyl]phenol (73 g). Acetylation of this material (0.8 g) with acetylchloride and trieth~ylamine in dichloromethane lo gave the [2-(l-proeenyl)-4-(nol~yloxy)-l-(acetoxy)]benzene (89%). This material (99 g) was dissolved in a mixture of methanol (150 mL) and dichloromethane (1.5 L) and treated with ozone at -40C until all the starting material had been consumed. Dimethylsulfide (50 mL) and water (500 mL) ~5 were then added and after vigorous stirring for 30 min. a~
the organic phase was dried (MgS04~ and concentrated to yield [2-(nonyloxy)-5-(acetoxy)~benxaldehyde (83 g).
Reduction of this material (80 g) with sodium borohydride (6 g) in ethanol (~Lj at 20 C for 2 h gave the crude ~2~(nonylo~y)-5-(acetoxy)]benzanemethanol which was immediately exposed to aqueous potassium hydroxide (300 mL, 40%) in ethanol (lL) for 30 min at 60C. Acidification with aqueous acid (6 Molar hydrogen chloride) and extraction with chloroform yielded the crude p~oduct on concentration.
25 Digestion of the residue with hexane gave ~ure ~3-(hydroxymethyl)-4-~onyloxy)]phenol ~63 g) as a solid. A
solution of this matecial (62 g) in a mixture of acetonitrile (0.5 L) and trihenylphosphine hydrobromide (86 g) was heated at reflux f OL L4 h and concen~rated to dryness 30 at 50C ts yield [[2-(nonylsxy)-5~h~droxy)phenyl]methyl]-triphenylphosphonium bromide as a glass.

ExamPle 33 (~ll-E)-9-~S-Hydroxv-2-(nonYloxy)phenyl]-3,7-dimethYl-2,4,6,8-35 nsnatetraensic acid The ~2 ~nonyloxy)-5-~hydroxy)ehenyl]methyl~triphenyl-phosphonium bromide (0.23 mol) in tetrahydrsfuran (1.5 L) at 33~
- ~6 --70C was treated with n-butyllithium ~1.6M in hexane: 315 mL) and then treated with ethyl 8-formyl-3,7-dimethyl-2,4,6-oc~atrienoate (59 g) in tetrahydrofuran-. The mixture was then warmed to -15C acidified with acetic acid and extracted into ether and aqueous methanol (40%).
Purificatio~ by chromatography over silica gel gave pure (All-E)-9-[5-hydroxy-2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. Hydrolysis of this ester (6 g) by the procadure given in Example S gave L0 (All-E)-9-~5-hydroxy-2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid (3.5 g): mp 170-173 (from ethylacetate).

Example 34 ~All-E)-9-[2-(nonYloxY)-5-(2,2,2-triflUoroethoxy)phenvll-3~7 dimethYl-2 4,6,8-nona~etraenoic acid (All-E~-9-~5-hydroxy-2-(nonyloxy)phenyl]-3,7-dimethyl-2,4, 6,8-nonatetraenoic acid ethyl ester (4.4 g) was heated at 90 C for 72 h with eota~sium carbonate (7 g), 2,2,2-tri~luoroethyl-p-toluensulphonate (6 g) in dimethylformamide (Z00 mL~. ~ork up with water and hexane followed by purification over silica gave the pure ethyl ester (0.75 g). Hydroly~is o~ this ester ~0.9 g) by ~he procedure of Example 5 gave pure (All-E)-9~2-(nonyloxy)-5(2,~,2-trifluoroethoxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetra enoic acid (0.6 g) after crystalli~ation from a mixture o~
tetrahydro~uran and hexane: mp 121C.

Ex ple 35 (z2-~[2-tl-Decenyl)phenyllmethyll-triphenylphosp4onium bromide and ~E)-~r2(1-Decenyl)PhenYllmethylltriphenY
phosPhonium bromide An (E,Z) mixture of 2-(1-decenyl)-1-bromobenzene as prepared in Example 16 (1:4) was con~erted to a (E,Z) 35 mixture of 2-(1-decenyl)-1-hydroxymethyl benzene by the : procedure of Example 17. This mixture was separated by chromatography on silica gel to yield ths pure (E) and (Z) ~27'7332 - 47 _ alcohols. Reaction of each of these isomers with triphenylphosphine hydrobcomide as in exam~le 1 gave the corresponding phosphonium salts i.e. (Z)~2-(1-decenyl)-~henyl]methyl]-triphenylphosphonium bromide and (E~2-(1-decenyl)phenyl]methyl]triphenylphosphonium bromide.

ExamPle 36 tAll-E)-9-~2-(1-DecenVl~PhenYl.1-3.7-dimethYl-2,4,6,,8-nona-tetraenoic acid L0 The (E)-~2-(1-decenyl)phenyl]methyl]-triphenyl-phosphonium bromide was converted into the ethyl ester of (All E)-9-[2-(decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid by the procedure given in Example 1.
Hydrolysis with base as in Exam~le 1 and crystallization of the crude acid ~rom acetonitrile gave tAll-E)-9-[2-tl-decenyl)phenyl]-3,7- dimethyl-2,4,6,8-nonatetraenoic acid, mp 10S-107.

ExamPle 37 (E~E~E~E~)-9-c2-(l-pecenyl)phenyl]-3~7-dimethvl-2L~ 8 nonatetraenoic acid The title com~ound was pre~ared in the same manner as in Example 36 employing the (Z)-C[2-~l-decenyl)phenyl~methyl~-; triphenyl phosphonium bromide. Hydrolysis of the ethyl - zs ester and crystallization of the crude acid from ether yielded ~ure (E,E,E,E,Z~-9-~2-(1-decenyl)ehenyl]-3,7 ~; ~ dimethyl-2,4,6,8-nonatetLaenoic acid, mp 103-105.

In the following examples, Compound A is All(E)-9-[2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. In the following examples, Compound ~ was tested by various ~ests for its anti-inflammatory activi~y in animal models of inflammation and in certain chronic models foc adjuvant arthritis.
In all tests, Compound A and the other retinoids tested concurrently were formulated in arachis oil containing 0.05%

`- ~.27~

propylgallate as anti-oxidant. The dose volumes used were 5 ml.kg for rats and 10 ml.kg for mice. Controls were dosed with the appropriate volume of arachis oil vehicle.

ExamP le 38 Effect of ComPound A on delaYed hYpersensitivity to methYlated bovine serum albumin (MBSA) LO Animals Male and femall~ MFI mice substrain E33.
Initial weight approximately 25 gm.

Materials Methylated bovine seeum albumin (MBSA) (Sigma) Freunds comelete adjuvant (Difco) Method Grou~s of 10 mice were sensitized (day 0) by injecting intradermally a~ two abdominal.
sites 0.05 ml. of a water i~ oil emulsion of MBSA and Freunds complete adjuvant. On day 9 the mice were challenged by injecting 20 1 of a 1~ MBS~ solution to one pa~ and 20 1 of water into the contralateral paw.
Paw volumes were measured 24 hours later by mercury displacement plethy~mography. The mean percentage increase in eaw volume of the MBSA-challenged paw compared with the water challenged paw was calculated for each treatmen~ group. Dosing with vehicle a~d ~etinoid commenced on day O and finished on day 9.

Results The result~ are given in the following table (Table II~

.

.

~m33z Table II The effects of Compound ~ in the M~3S~
delaYed hYpersensitivit~ test Treatment Dose % increase %reduction Mean body mg.kg paw volume ~cf. arachis weight change ~ oil control~ (q) Arachis Oil lO9 + 11 M 3.8 LO E' 0.2 E~retinate lO 59 + 9** 46 M -0.8 F -2.0 Compound A lO 102 + lZ 6 M 3.3 F -0.2 15 COmpound A 30 50 + 7*** 5 M 2.8 0.~
Com~ound A lOO 40 ~ 5*** 63 M 3.3 - F -0.2 20 . _ _ _ :~;
Each group consisted of 4 male and 6 female mice (separately ~ caged). Drugs were dosed orally at a dose volume of 10 :~ z~ ml.kg l tlO doses).

ns. Not significant **p < O.Ol ***p <0.001 com~ared with ~ehicle control u6ing Student's two-tailed t ~est.

.

Example 39 Effect of ComPond A on developinq ad3uvant arthritis in ~he rat.
Animals AHH/R Female rats (PVG derived with an initial weight range of 110 to 1~0 g.
were used.

Materials Adjuvant for injection. An homogenized suspension of hea~ killed M. tuberculosis L0 (Human strains C, DT and PN), 5 mg.M1 L
in liquid paraffin wa~ prepared.

Method Rats were randomly 8plit into groups of five and adjuvant arthritis was induced L5 by the sub-plantar injection of 0.1 ml of adjuvant suspension into the right hind paw of each rat. Tes~ compounds were administered by intubation each morning commencing the day of adjuvant injection. Two group~ of control rats WeLe dosed with the vehicle as was a group of three normal rats included for comparative purposes. Dosing wa~ carried out daily until the end of the te~t on day 15 exce~t foL the fir~t weekend (day~
S ~ 6). Tre~ment groups are shown in Table III and include etretinate as ~tandard re~inoid.

~;2 77;~2 - 51 ~

Measurements of right hind paw volume were made initially and on days 2 and 4 after and adjufant injection (pLimary phase). Right and left hind paw volume were then measured. on day 8 and every two or three days until the end of the experiment on day 15 (secondary ~hase).
At this time the mobility of each ankle joint and the incidence and severity of seaondary lesions on nose, ears, ~orepaws, left hind paw and tail were also a6sessed in terms of degrees o~ flexion ~ossible and L5 by using an arbitrary scoring system, respectively.

Asse6smen~ of refiults The time course curves for the injec~ed paws were in~egrated from days 0 to 4 to reflect primary swelling and ~rom days 8 to 15 (secondary swelling). The secondary swelling in the non-injected paw was ; 25 integrated similarly f rom days 8 to 15 Calculations were carried out using a specific computer program which computed mean + se for each lntegrated area. The significance of differences from controls was determined by Student's t tast (2 ta;led) and percentage reductions from control areas were calculated.
Percen~age improvements in joint mobility and percentage redu~tions in lesion score were also determined. In the lattar case the Wilcoxo~ rank ~um test (2 tailed) was used ~o express the difference ~rom the .

control score using raw data. Mean body weiyht change in each group was recoeded.

Results The results are given in the following table (Tablle III) ~ LO

: ~5 , ~ 25 ; 30 :~ :
~ 35 : ~ :

.

12~332 5 ~ ~

~ ~`' l l ~0 ~D O
~ . O ~ ~ ~ ------ b ~ 5 H . 5 = ~ _ __ u~ _ ~

. 3 ~0 . . _ ~O N ~
2 0 L ~ ~-- . * . O
Cl O O ~ l l t ~ ~1 1~ L V
`' i~ OU~- _ _ _ _ ~0~
~ ~ ~ ~~O ~D ~ ~ O ~
2 5 ~ . : G ~1 _ _ _ ~ D O

o O .. . _ ~.' ~:1 .' o!C ___ r~ ~ r/ 1: ~ -3 0 ' ~--L~ '1:1 -- ~ ~ ~' ~ ,~V ~ E _ v v ~L2~'733~

Example 40 E~fect of Compound A on established t~Pe II collaqen arthritis Animals Male and female Alderley Park Strain 1 rats.

Materials Type 2 collagen (prepared ~rom bovine nasal septum cartilage), Freunds incomplete adjuvant ~Di~co).

Method Rats were sen6itized to type 2 collagen by injecting them intradermally with 1 ml.
lS of a water in oil emulsion consisting of equal parts of a 1 mg.ml~l solution of type 2 collagen in 0.45M NaCl, 0.02M
Tris, pH 7.4 and Freunds incomplete adjuvant. ~ats developing arthritis were allocated on day 15 post sensitization to a control arachis oil treated group (6 male, 4 female~ or to the Compound A
treated group (6 male, 5 female). Hind paw volume measurement6 were ~aken to ensure even dis~ribu~ion of rats between groups. An overnight collection of urine was made on days 15/16 and dosing commenced on day 16. These urine sam~les were analyzed for glycosaminoglycans (GAG3. Compound A was dosed at 100 mg.kg 1 p.O. On days 19/20 a second overnight collection of urine was made.
These urine samples were analyzed ~or glycosaminoglycans (GAG). on day 20 a second hind paw measurement was taken.
Rats were then anaesthetised with sodium ' ' .

1~77~32 ~ 55 -: pentobarbitone, bled, killed and X-ray~
; taken o~ hind and forepaws. Rats were do~ed on days 16-19 inclu6ive (4 do~e~).
;

5 Results The results are ~iven in the following table tTable IV).

:

; L5 ', ~ ~ :

` ~: :
~ 35 ~ ~

.

~: ' -' :-'` ' ' ' . ' . - ' .

~.27733%

+ I + I
~: S 3 ~ ~

~ ~ ~1 +1 0 L 0 h ~, : ~ +1 ~
:. v 3 L5 hc ~ ~ o G

ZO _, U,~ ~ _ o ~ o ~ O
C
~ 6 0 3 ~
4.~ ~ ~ 6 O
u ~ ~9 o ~ 4 Ei O

`: : 35 ~: :

:, .

.

3L~Z~733~:

Example 41 Effect of Compound A on non-immune in1_mmation Animals Female Alderley Park Strain 1 rats weighing 170-205 g. at the start of the experiment were used.

Materials Lambda -carrageenan. Pre~ared as a solution in saline and sterilized by LO autoclaving.

Method Compound ~ was administered orally to grou~s of 8 rats once daily for 10 day~
at doses o~ 10, 30 and 100 mg.kg 1.
lS Control animals received the vehicle.
one hour after the last dose the animals wece anesthetised with methohexitone (Brietal, 50 mg.kg ~) and 0.2 ml of 1%
}ambda carrageenan was injected into the ~leural cavity. Four hours later the animals were killed with an overdose of pentobarbitone (Sagatal), the pleural exudate was collected and the pleural cavity was washed out with 2 ml o~
phosphate-buffered saline (PBS-A, Oxoid~.
The exuda~0 volume was recorded and cell count were detarmined using an automatic cell counter (Coulter). ~i~ferential cell coun~s were ~erformed on exudate 0 smear~ stained with Giem6a stain in order to determine separately the numbers o~
polymor~honucIear leucocytes (PMN) and mononuclear cells (M~).

Immedia~ely aftsr recovery of the pleural exudates the tibiae of the animals wece ~27733~

excised and theiL breaking strains were determined.

The body weights of the animals were recorded daily. Stati~tical analyses were perfor~med using Student's two-tailed t te~t.

10 Resul~s The results are given in the following table (Tablle V). In the following table : ~he dose iB in mg ~er kg ~er day.

:: ~5 .

' .

~ :
2~

:: 30 , ~

.
~ 35 ' :;
~ .
: :

~ : ' , : .

1 73~:

~_ ~ s l o m ~ ~ . . .
r~ U~ ~ ~n ~n u :~ 0 ~ ~ ^ ~Z; -l Z ~ Z ~
_ ~ ~ r O, O, O, O
~ 1~ _ ~ _ ~ 1 ~O I ~ ~ ~1 ': _ ~ r~ ~ ~
L0 ~ ~ ~ ~ NO) Z 1:~ r~ ~ _~ ~1 ,- c O ,,, O O 'r O~ ~ O ul ~1 E~ ~ _1 I I a: +1 r~ ~1 r~ ~1 O
_ . _ ~ . 3 ',' l ~ ~ 0 l ~ C
`:: 1.5 ~, ' ~0 c~ U . .~, ~d 01 I e~ c~ ~ Z~ r ~ ~o ~ .C
~ -'~1 I -'+1 +l `~ ~ O : _ _ __ ' ~' ,CI g . ~11 1~ ~:
20 ~ ~ ~u c ~ u ~ ' = ~
:: O : O X 11 Z
C E~ ~ ~ -~ ~ r~ ~ O ~ r1 ~ : N + I N ~ ~ _1 + ¦ O ~ U

__ _ ~ S
~: ` S ~1 C~ 0 0~ N _~
o b3 3~ ;: la ~ II ~D t-~
~ ~:; ~ ~ ~0 0~~ 00 O ;~

. : :
. ~ ~ d ~1 tJI ~ ~1 O
~: : : Cl 0 ~It~ O E o V l I
~ 8~ : ~ ~; ~o u : ~
: : ~ : :
; -~ ~o,~ ¢~C: ~:: ~
: ~ ~ ~ o ~ ~ C:
: : U ~ 3 ' ~ : a. :
3 5 ~ ~ ~ o U, o: u z : .:
, ` ~ ~ : ,: :

~ ~ .
"~
`:-.;, , ` . , i :, : .
.~
:

~: ~ " .:

`: : . . `
~::

~27733~

Example 42 Effect of ComPound A on the impreqnate,d sPonqe qranuloma test in_the rat.

5 Animals ~HH/R female rats (PVG derived) with an initial weight range of 120-140 g. were used.

Materials Sponge prep,aration. Pelle~s (6.5 mm lo diameter) w~ere punched from cellulose sponge cloth ("~ettex") and 0.1 ml. of a suspension containi~g 0.5 mg.ml~l of heat killed M. tuberculosis (human strains C, DT and PN) in ~terile saline L5 wa~ applied to each pellet. The eellets were dried, weighed and autoclaved.

-Method Rats were randomly divided into groups of ` ' five and daily dosinq with test compounds zo was commenced. After the fifth dose the rats were anaesthetised with Sagatal (45 mg. kg 1 i . p . ) the back~ were shaved and two pellets weLe implanted subcutaneously (one each side) into each rat through a small dor~al midline incision. The incision was closed and the rats allowed to recover from the anaesthetic.

Seven days after implantation the rats 0 were killed and the pellets were removed, ; dissected free of extraneous tissue and weighed. Each pellet wa~ then placed in a 4 ml aliquot of distilled water, chopped with fine scissors and sonicated. ~fter centrifugation ~he Na and K content of the supeLnatant :~2~7332 was determined by flame photometry. In addition the adrenal and thumus glands from each rat were dis6ected out and weighed and the lower hind limbs were removed for measurement o~ tibial bone breaking strain. Body weights we~e also recorded throughout the teæt period~

Results The re~ultE, are given in the ~ollowing ~able (Table VI).

As essment of results The mean + S~ for each of the parameters was calculated and L5 differences from the control values were determined by Student's t test (2-tailed). Percentage reductions of granuloma weight, Na and K~ content and percentage changes of adrenal and thymus, weight and tibial breaking strain were de~ermined.

~ .
.

~ ' .

lZ~7~

v r~ O ~ ~1 + I O

~S ~ c 1 ~ ~ ~

0 3 ~ ~

OO~ a~ ~ ~ ~ .

30 ~ o,~ '' '' '' ` :
~V ~o j~ V

:

~7733Z

~nimals Male Lewis rats from Charle~ River were used for these experiments.

Materials Heat-killed, dessicated Mycobacteriam butvricum.

Method Adjuvant art:hritis was induced by the injection of 0.1 ml of adjuvant ~a su6pension of hea~-killed, dessicated MYcobacterillm but~ricum, 0.5% CW/V) in heavy mineral oil containing 0.2~
digitonin] into the base of the tail.
The arthritis wag allowed to develop for 21 days and then the volume of both hind t5 paws were measured using a mercury plethysmograph. The rats were divided : into groups of 8 with equal mean paw volumes and then the rats were treated with Compound A, indomethacin (as a : 20 control drug), or vehicle for 7 days at : the end of the treatment period, the : volumes of both hind paws were again measured to assess antii~flammatory effect~. Body weight changes were also followed and, at the end of the ex~eriment, ela6ma wa6 collected for determina~ion of plasma fibrinogen ~Exner et. al., Amer. J. Clin. Path, 71:
521-527).
Results: The results are given in the following Table (Table VII).

. .

~ , 10 p a O O O
20 ~ ~ 3 ~

2 5 3 c ~ u ~ v ~ ~-1 q~ ~ 3 O ~ 3 ~ O L, ~

~ 30 ~ ô

- o ~ o u 3 g Z '-' ~: ~ .¢ ~ v

Claims (41)

1. A process for the preparation of compounds of the formula I

wherein R1 is hydrogen, lower alkyl, chlorine, fluorine or trifluoromethyl: R2 is chlorine, trifluoromethyl, lower alkyl, fluorine, hydroxy, loweralkoxy, trifluoromethylloweralkoxy, hydrogen;
is hydrogen, lower alkyl, chlorine, or fluorine; R4 is an alkyl group having a straight chain length of 4 to 9 carbon atoms, or -CH2(CH2)nCH2OH;
X is , , -O-, , or ; R5 is COOR9; and R7, R8, R9, and R10 are hydrogen or lower alkyl; n is 6 or 7; and pharmaceutically acceptable salts thereof where R9 is hydrogen, which comprises a) reacting a compound of formula II

with a compound of the formula VII
or b) reacting a compound of formula XVI

with a compound of formula XVII

or c) reacting a compound of formula VIII

with a compound of formula R4Z, wherein in the above formulae R1, R2, R3, R4, R7 and R8 a claim I; R9, is lower alkyl; Y is aryl, Z is a leaving group and Z' is a halogenide ion: and if desired, converting a carboxylic alkyl ester group -COOR9, contained in the reaction product to the free acid and if further desired converting the acid in a pharmaceutically acceptable salt.

2. A process as in Claim 1 wherein in the starting com-pounds R1 is hydrogen, chlorine or fluorine;
R2 is hydrogen, lower alkoxy, chlorine or fluorine;
R3 is hydrogen, lower alkyl, chlorine or fluorine;
R4 is alkyl containing from 8 to 10 carbon atoms with a straight chain length of 8 to 9 carbon atoms;
is -CH-O-, , -O- or ; R5 is COOR
and n, R7, R8, R9 and R10 are as in Claim 1.

3. A process as in Claim 2 wherein in the starting compounds R4 is an alkyl group as defined in Claim 2.

4. A process as in Claim 3 wherein in the starting compounds X is -O-.

5. A process as in Claim 4 wherein in the starting compounds R1 is chlorine or fluorine.

6. A process as in Claim 4 wherein in the starting compounds R2 is lower alkoxy.

7. A process as in Claim 1 for the preparation of 9-[2-Chloro-6-(nonyloxy)phenyl]-3,7,dimethyl-2,4,6,8-nonatetrae-noic acid wherein in the starting compounds R1 is chlorine, R2 and R3 are hydrogen, R4 is nonyl, R7 and R8 are methyl, R'9 is lower alkyl and X is -O- and the lower alkoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

8. A process as in Claim 1 for the preparation of (All-E)-9-[2-fluoro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetrae-noic acid wherein in the starting compounds R1 is fluorine, R2 and R3 are hydrogen, R4 is nonyl, R7 and R8 are methyl, R'9 is lower alkyl and X is -O- and the lower alkoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

9. A process as in Claim 1 for the preparation of 3,7-Dimethyl-9-(5-Methoxy-2-nonyloxyl-phenyl)-2,4,6,8-nonatetrae-noic acid wherein in the starting compounds R1 and R3 are hydrogen, R2 is methoxy, R4 is nonyl, R7 and R8 are methyl, R'9 is lower alkyl and X is -O- and the lower alkoxy carbony group in the reaction product of formula I is converted into a carboxy group.

10. A process as in Claim 1 for the preparation of 9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid wherein in the starting compounds R1, R2 and R3 are hydroge R4 is honyl, R7 and R8 are methyl, R'9 is lower alkyl and X is -O- and the lower alkoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

11. A process as in Claim 1 for the preparation of (All-E)-3,7-dimethyl-9-(2-octylaminophenyl)-2,4,6,8-nonatetraenoic acid wherein in the starting compounds R1, R2 and R3 are hydrogen, R4 is octyl, R7 and R8 are methyI, R'9 is lower alkyl, X is -NH- and the lower alkoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

12. A process as in Claim 1 for the preparation of (All-E)-3-7-dimethyl-9-[2-[(8-hydroxyoctyl)oxy]phenyl]-2,4,6,8-nona-tetraenoic acid wherein in the starting compounds R1, R2 and R3 are hydrogen, R4 hydroxyoctyl, R7 and R8 are methyl, R'9 is lower alkyl, X is - O - and the lower alkoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

13. A process as in claim 1 for the preparation of (All-E)-8-[2-(trifluoromethyl)-6-(nonyloxy)-phenyl]-3,7-di methyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9-[2--(octyloxy)phenyl]-2,4,6,8-nona-tetraenoic acid, 3,7-di-methyl-9-[2-(2,2-dimethyl-octyl)oxy]-phenyl]-2,4,6,8-nona-tetraenoic acid, 9-[2-(nonyloxylphenyl]-3,7-dimethyl--2,4,6,8-nonatetraenoic acid ethyl ester, (all-E)-9-[2--(hexyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid, (all-E)-9-[5-hydroxy-2-(nonyloxy)phenyl]-3,7-di-methyl-2,4,6,8-nonatetraenoic acid, (all-E)-9-[2-(nonyl-oxy)-5-(2,2,2-trifluoroethoxy)phenyl]-3,7-dimethyl--2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9[2-[(octyloxy)--methyl]-phenyl]-2,4,6,8-nonatetraanoic acid, 9-(decyl-phenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-di-methyl-9-(2-octylaminophenyl) 2,4,6,8-nonatetraenoic acid ethyl ester and (all-E)-9-[2-(1-Decenyl)phenyl]-3,7-di-methyl-2,4,6,8-nonatetraenoic acid, wherein in the starting compounds R1, R2, R3, R4, R7, R8, and X are appropriateiy selected, R'9 is ethyl and, if an acid is prepared, the ethoxy carbonyl group in the reaction product of formula I is converted into a carboxy group.

14. A compound selected from the group of phenyl derivatives of the formula:

I

wherein R1 is hydrogen, lower alkyl, chlorine, fluorine or trifluoromethyl; R2 is chlorine, trifluoromethyl, lower alkyl, fluorine hydroxy, loweralkoxy, trifluoromethylloweralkoxy, hydrogen;
R3 is hydrogen, lower alkyl, chlorine, or fluorine; R4 is an alkyl group having a straight chain length of 4 to 9 carbon atoms, or -CH2(CH2)nCH2OH;
X is , , -O-, , or ; R5 is COOR9; and R7, R8, R9, and R10 are hydrogen or lower alkyl; n is 6 or 7; and pharmaceutically acceptable salts thereof where R9 is hydrogen whenever prepared according to claim 1 or by an obvious chemical equivalent thereof.

15. Compounds of claim 14 wherein R1 is hydrogen, chlorine or fluorine; R2 is hydrogen, lower alkoxy, chlorine or fluorine; R3 is hydrogen, lower alkyl, chlorine or fluorine; R4 is alkyl containing from 8 to 10 carbon atoms with a straight chain length of 8 or 9 carbon atoms;
is , , -O- or ; R5 is COOR9 and n, R7, R8, R9 and R10 are as in claim 1; and salts thereof where R9 is hydrogen whenever prepared according to claim 2 or by an obvious chemical equivalent thereof.

16. The compounds of claim 15 wherein R4 is an alkyl group as defined in these claims whenever prepared according to claim 3 or by an obvious chemical equivalent thereof.

17. The compounds of claim 16 wherein X is -O- whenever prepared according to claim 4 or by an obvious chemical equivalent thereof.

18. The compounds of claim 17 wherein R1 is chlorine or fluorine whenever prepared according to claim or by an obvious chemical equivalent thereof.

19. The compounds of claim 17 wherein R2 is lower alkoxy whenever prepared according to claim 6 or by an obvious chemical equivalent thereof.

20. 9-[2-Chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 7 or by an obvious chemical equivalent thereof.

21. (All-E)-9-[2-fluoro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 8 or by an obvious chemical equivalent thereof.

22. 3,7-Dimethyl-9-(5-Methoxy-2-nonyloxyl-phenyl)-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 9 or by an obvious chemical equivalent thereof.

23. 9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 10 or by an obvious chemical equivalent thereof.

24. (All-E)-3,7-dimethyl-9-(2-octylaminophenyl)-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 11 or by an obvious chemical equivalent thereof.

25. (All-E)-3,7-dimethyl-9-[2-[(3-hydroxyoctyl) oxy]phenyl]-2,4,6,8-nonatetraenoic acid whenever prepared according to claim 12 or by an obvious chemical equivalent thereof.

26. (All-E)-8-[2-(trifluoromethyl)-6-(nonyloxy)-phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-di-methyl-9-[2-(octyloxy)phenyl]-2,4,6,8-nona-tetraenoic acid, 3,7-dimethyl-9-[2-(2,2-dimethyl-octyl)oxy]-phenyl]-2,4,6,8--nonatetraenoic acid, 9-[2-(nonyloxylphenyl]-3,7-dimethyl--2,4,6,8-nonatetraenoic acid ethyl ester, (all-E)-9-[2--(hexyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid, (all-E)-9-[5-hydroxy-2-(nonyloxy)phenyl]-3,7-di-methyl-2,4,6,8-nonatetraenoic acid, (all-E)-9-[2-(nonyl-oxy)-5-(2,2,2-trifluoroethoxy)phenyl]-3,7-dimethyl-2,4,6,8--nonatetraenoic acid, 3,7-dimethyl-9[2-[(octyloxy)-methyl]--phenyl] -2,4,6,8-nonatetraenoic acid, 9-(decylphenyl)-3,7--dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9-(2--octylaminophenyl)-2,4,6,8-nonatetraenoic acid ethyl ester and (all-E)-9-[2-(1-Decenyl)phenyl]-3,7-dimethyl-2,4,6,8--nonatetraenoic acid whenever prepared according to claim 13 or by an obvious chemical equivalent thereof.

27. A compound selected from the group of phenyl derivatives of the formula:

I

wherein R1 is hydrogen, lower alkyl. chlorine, fluorine or trifluoromethyl; R2 is chlorine, trifluoromethyl, lower alkyl, fluorine, hydroxy, loweralkoxy, trifluoromethylloweralkoxy, hydrogen:
R3 is hydrogen, lower alkyl, chlorine, or fluorine; R4 is an alkyl group having a straight chain length of 4 to 9 carbon atoms, or -CH2(CH2)nCH2OH;
X is , , -O-, , or ; R5 is COOR9; and R7, R8, R9, and R10 are hydrogen or lower alkyl; n is 6 or 7; and pharmaceutically acceptable salts thereof where R9 is hydrogen.

28. Compounds of claim 27 wherein R1 is hydrogen, chlorine or fluorine; R2 is hydrogen, lower alkoxy, chlorine or fluorine; R3 is hydrogen, lower alkyl, chlorine or fluorine; R4 is alkyl containing from 8 to 10 carbon atoms with a straight chain length of 8 or 9 carbon atoms:
X is , , -O- or ; R5 is COOR9 and n, R7, R8, R9 and R10 are as in claim 1; and salts thereof where R9 is hydrogen,

29. The compounds of claims 27 or 28 wherein R4 is an alkyl group as defined in these claims.

30. The compounds of claim 29 wherein X is -O-.

31. The compounds of claim 30 wherein R1 is chlorine or fluorine.

32. The compounds of claim 30 wherein R2 is lower alkoxy.

33. 9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

34. (A11-E)-9-[2-fluoro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

35, 3,7-Dimethyl-9-(5-Methoxy-2-nonyloxyl-phenyl)-2,4,6,8-nonatetraenoic acid.

36. 9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

37. (All-E)-3,7-dimethyl-9-(2-octylaminophenyl)-2,4,6,8-nonatetraenoic acid.

38. (All-E)-3,7-dimethyl-9-[2-[(8-hydroxyoctyl) oxy]phenyl]-2,4,6,8-nonatetraenoic acid.

39. (All-E)-8-[2-(trifluoromethyl)-6-(nonyloxy)-phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-di-methyl-9-[2-(octyloxy)phenyl]-2,4,6,8-nona-tetraenoic acid, 3,7-dimethyl-9-[2-(2,2-dimethyl-octyl)oxy]-phenyl]-2,4,6,8--nonatetraenoic acid, 9-[2-(nonyloxylphenyl]-3,7-dimethyl--2,4,6,8-nonatetraenoic acid ethyl ester, (all-E)-9-[2--(hexyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nona-tetraenoic acid, (all-E)-9-[5-hydroxy-2-(nonyloxy)phenyl]-3,7-di-methyl-2,4,6,8-nonatetraenoic acid, (all-E)-9-[2-(nonyl-oxy)-5-(2,2,2-trifluoroethoxy)phenyl]-3,7-dimethyl-2,4,6,8--nonatetraenoic acid, 3,7-dimethyl-9[2-[(octyloxy)-methyl]--phenyl] -2,4,6,8-nonatetraenoic acid, 9-(decylphenyl)-3,7--dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9-(2--octylaminophenyl)-2,4,6,8-nonatetraenoic acid ethyl ester and (all-E)-9-[2-(1-Decenyl)phenyl]-3,7-dimethyl-2,4,6,8--nonatetraenoic acid.

40. A pharmaceutical composition comprising a compound of formula I or a salt thereof as in claims 27 or 28, together with a pharmaceutically acceptable carrier.

41. Pharmaceutical compositions having anti-rheumatic, anti-arthritic or immunosuppressive properties, said composi-tions comprising a compound of formula I or a salt thereof, as set forth in claim 27 or 28, wherein R9 is hydrogen, together with a pharmaceutically acceptable carrier.