CA2178634A1 - Diphenyl-2-propenoates and homologs thereof useful for treating diseases associated with leukotriene b4 - Google Patents

Abstract

This invention relates to a compound of formula (I), where the several groups are defined herein. These compounds are leukotriene antagonists an as such can be used in treating various diseases associated with leucotrienes.

Description

Wo 95115752 2 1 7 8 6 3 ~ PCTIUS94/13966 Diphenyl-Z-~, u,et:l-o~ and hû" . 1~ _ th~reof useful for treating diseases ~ witn leukotrien~ B4.
Scor)e or the lnvention The field of Ihis invenlion is ~hat of certain substituted diphenyl-2-~
and homologs thereof, which have been found w be useful for treating diseases arising from or related w I ' ' . 1~ leukotriene B4. As such the e utility lies in ' ' ,, the affects of ' ~- 'nf'- I
T~te family of bioactive lipids known as the I ' ' exert ~ ' -- . - -- . .l. ,~, _l effects on respiratory. ~L~,v~ul~ and O - ' syStems. The I ' are 0 generally divided into two sub-classes, the I 1 ' ' ' (I ' C4, D4 snd E4) and the dihJJ~ ' ' (1 ' ' B4). This inventioQ is primarily concerned with the hJ~ ' ' (LTB) but is not limited to this specific group of " ' The l . ' ' ' ' ' are implicated in the biological response associated with the "Slow Reacting Substance of Anaphyla~tis" (SRS-A). This response is expressed fn - vivo as prolonged ~ ' ' - in ,~Luv ' effects such as coronary artery ' and numerous other biological responses. The ~ of the l l include smooth muscle ' myocardial depression, incteased vascular 1~ .dJ;Lly and increased mueous produerdon.
By cnn~p~icnn LTB4 exerts its biological effects through stimulation of leukocyte and Iy~phocyte funetions. It stimulates ch~mn qYic~ ,~ ' and agOregation of ~ . ' ' leukocytes fPMNs).
~ ~ ' ' are dtieally involved in mediating many types of ~ - l; v~
pulmonary, ~ - 1, renal, allergic, and " y diseases ineluding astbma, adult respiraw~y distress syndrome, cystic fibrosis, psoriasis, and ;~. n- I, . ~ y bowel disease.
I ' ' - B4 (LTB4) was fitst described by Borgeat and ~m~ lccnn in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z FE,Z)-6,~,10,14-' ' scid OH ~--COOH
~~ Flg. l It is a product of the :~rhirinnir acid cascade that results from the enzytnatic hydrolysis of LTA4. It has been found to be produced by mast eells, ~1~ , ' leukocytes, monocytes and ~ LTB4 has been shown to be a potent stimulus ~ v~vo for PMN leukocy~s, causing increased ~ h ~ and; ' ' ' migratiOD, 35 adherence,aggregation. ~" ' ' superoxideproduetionand~,yLuw.~d,;Ly. The effects of LTB4 rtre mediated through distinct recepwr sites on the leukocyte cell Wo 95/15752 2 t 7 8 63 4 PCr/US94/13966 ~
surface that exhibit a high degree of st~ ,u~ pl, ~ u~ studies on human blooTi PMN leukocytes indicale the presence of two classes of LTB4-specific receptors thal are separdte from receplors specific for the pep~ide ~ fac1ors, Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte 5 functions. Calcium .". l ;l;~ , is inYolved in both ll l~
LTB4 has been established as an ~ ~ mediator in vivo. k has also been associated With airway hyper~ u..~ ,~ in the dog as well as being found in increased levels in lung lavages from humans v~ith severe pulmonary d; ~ ' By ~ ~ the effects of LTB4, or u~ L' ~ active 0 mediators at the end organ, for example airway smooth muscle, the compounds attd L~T -- - I ' -- ;- _1 c~ - of this invention are valuable in the trt atment of diseases in subjects, including human or animals, in which ~ are a factor.
S of the Inv.~T~ti~
In a first aspect, this invenrion covers a compound of formula I

R ~1 R~ I R2 Z--(CH 2~m formula I
or a ~ acceptable salt, where A is CH2 and Z is S(O)q where q is û, I or 2, CH2, CHOH, C=O, or NRX, or O;
20or A is C=O and Z is NRX;
misû -5;
Rx is hydT;ogen or lower alkyl;
R is CI to C2û-aliphaic, l ~ or substituted five-membered heteroaryl-25 Cl to Clû-aliphatic-O-, ' or substituted phenyl-CI to Clû-a1iphatdc whae substituted phenyl has one or more radicals selected from t~te group consisting of lower alkoxy, lowa aTkyl, ' ' yl, and halo, or R is Cl to C2û-aliphatic-O-, or R is ' or substituted phenyl-CI to Clû-aliphatic-O- where substituted phenyl has one or more radicals selected from t'TtC group consisting of lower alkoxy, lower allyl, 30 i ' ' ' ~1, and halo;
Rl is R4, -(Cl to Cs :~lipT~ ^)P 1, -(Cl to C5 aliphatic)CHO, -(Cl to Cs aTiphatic)CH20Rs;
R2 and R3 are ;~ .y halo, lower alkoxy, CF3, CN, or lower allyl;
R4 is ter azol-5-yl or COOH or an ester or amide thaeof; and 2 ~ 1 7 8 6 3 4 PCTIUS94/13966 Rs is H. Iower aikyl, CH3(CH2)0 6CO or phenyl(CH2)0 3CO.
In a further aspect, this invention relates to ~ ;G~ comprising a compound of fommula 1, or a salt thereof, in admixture with a carrier. Included in these are those suitable for ~ use and comprising a 5 ~ y acceptable excipient or ca~ier and a compound of formula I which may be in Lhe fotm of a y~ II y acceptable salL
These compounds can also be used for treating diseases, particularly psoriasis arld ~ '' ~ bowel disease.
Processes for making these compounds are also ircluded in Lle scope of this 10 inverltion, which processes compris~
a) forrning a salt, or b) forming an ester;
c) oxidizing a thio eLher to the su~foxide or sulfone; or d) forming a compound of formula I by treating a 6-halo~ lpJ.;~I
compound with the appropriate mercapttm, hydroxy, or amino compound, Gener~ll E ' ' The foi iowing '~ ~ used in describing this invention.
"Aliphatic" is intended to include saturat~d and unsaturated radicals. This includes notmal and branched chains, saturated or mono or poly unsaturated chairls where both double and triple bor~ds may be present in any ~ ' ' The phrase "lower aikyl" -means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normai or linear form. "Lower aikoxy" means the group lower aikyl-O-.
"Acyl-lower aikyl" refers to Lhe group (O)C-lower aikyl where Lhe carbonyl carbon is counted as one of the carbons of the I to 6 carbons noted under the definition of lower aikyl. "Halo" refers to and means fiuoro, chloro, bromo or iodo. The phenyl ring rttay be substituted with one or more of these radicais. Multipie substituents may be Lhe same or different, such as where there are three chloro groups, or a . ~ of chioro and aikyl groups and further where this latter ~ may have different aikyl radicais in the chloro/aikyl pattern.
The phrase ''I ' ' or substituted five-membered heteroaryl" means a five-membered aromatic ring which has one or more hetero atoms which are oxygen,suifur or nitrogen. Examples of such rings are furyl, thienyl, tettazolyl, thiazolyl, isoti~iazolyl, ttiazolyl, oxazolyi, isoxazolyl, thiadiazolyl, pyrrolyl, imidazolyl or pyrazolyl.
35 Rings may be substituted with one or more lower alkyl groups, preferably methyl.
The phrase "a ~ lly accepLable ester-forming group" covers ail esters which can be made from the acid function(s) which may be present in Lhese The resuitant esters wili be ones which are acceptable in their application to a Wo 95/15752 PCT/US94/13966 2 ~ 78634 use. By that il is meant that the esters will retain the biological activity of the parent compound and will not have an untowan~ or deletenous effect in their application and use in treating diseases.
Amides may be formed from acid groups. The most preferred arnides those 5 where the nitrogen is substituted by hydrogen or alkyl of 1 to 6 carbons. The d;~ ..Ic is particularly preferred.
rl ~ 'y acceptable salts of the instant compounds are also intended to be covered by this invenrion. These salts will be ones which are acceptable in their applicsion to a 1~ I use. By that it is meant that the salt will retain the 0 biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating disea.,es.
rl -- . . . - '. ..lly acceptable salts are prepared in a standard manner. The parent compound, dissolved in a suitable solvent, is treated with an e~eess of an organie or ir~organic acid, in the case of acid addition salts of a base, or an excess of organic or 15 inorganic base where R4 is COOH for example.
Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illuslrated herein. These are to be considered part of the invention.
If by some . ~ - Of c~hctin~n~c -a chiral center is ereated or another form of an isomeric eenter is ereated in a eompound of this invenlion, all forms of sueh 20 isomer(s) are intended to be covered herein. Cor~pounds with a chiral eenter may be L ' ' as a raeemic mixture or the racemates may be separated and the individual enanriomer used alone.
As leukotriene _ these compounds ean be used in treaing a variety of diseases associated with or attributing their origin or affect to I , pardeularly 2s LTB4. T--rl --.. ~ ~y diseases sueh as psoriasis and; -~ y bowel disease may be treated by applying or ' - ~ the eompounds deseribed herein. It is also expeeted that these compounds ean be used to treat allergic diseases including those of a pulmonary and non-pulmonary nature. For example these compounds will be useful in ,~. ' ' anaphylaxis. They are useful in tteaing asthma, allergic rhinitis and 30 irritable bowel disease. Ocular diseases such as uveitis, and allergic, ; vl~;s ean also be trealed by these .
These eompounds show oral activily. that is they are absorbed in the gut and areactive in vivo in test models. This is a unique feature as compared with other compounds of similar structure which are leukotriene - ~, ' While other such 35 compounds may be absorbed in the gut they do not c' - a therapeuic response in the target organ or disease state, in particular as relates to treaing topical diseases such as psoriasis and the like.
Preferred compounds are those where R is C8 to C~o alkoxy, thienYI-Clt C10 2 ~ 78634 WO 9S/15752 PCrlUS94/13966 aikoxy, ~ ' or substituted thiazolyl-CI to Clo aikoxy, phenyi-CI to Clo aikoxyorsubstituted-phenylCI toCI()alkoxy;Rl is-(CI-c3alkyl)R4~or-(c2-C3aikenyl)R4 and R2 and R3, are both halo. The more preferred compounds are those where R is ' ' or substituted phenyl-C I to Clo aikoxy, particularly the , ' ' phenyl(CH2)2 8-0- group, or the p-fluoro- orp .f ~,.hvAylJh-l-J I~CH2)2-8-- group, or CH3(CH2)7-9--; m is 0 - 5, most preferably 0, 1, or 2; Rl is HO2C-CH~i-, or HO2C-CH2CH2- or a sait, ester or amide derivative thereof. As regards A, the CH2 group is preferred. As regards ~, S(O)q and O are preferred, and in S(O)q q is 1, 2 vr 3. Anotiter sui~grvup of preferred . , ' are those where R2 and R3 0 are haio; methyl or methoxy, particularly where both are haio, methyl or methoxy. The 2,6-dichloro is a preferred compound. Speciftc preferred compounds are:
(E)-3-[5-[[(2,6~'-'' ~i' ~I)~;v]~ ,Li~yl]-2-a-pl-~ y)yh~ ]-2-prvpenoic acid, (E)-3-[5-[[(2,6~ I)sulfinyl]methyl]-2-(2-~l,.,.. ~l.,l.uAy)p~ 1]-2-15 prvpenoic acid, (E)-3-[5-[[(2,6 1: hl vlu'- /I)suifonyl]methyl]-2-(2-~ L, i~vAy)l~ 1]-2-prvpenoic acid, 3-[5-[[(2,6~ ' yl]-2-(2-1' Jl~.Li.vAy)phenyl]-2-prvpanoic acid, (E)-3-[[[[3-(2~O1VV~Y~ JI) 1 [[8-(4-u-~ hvAy~ I)ocyl]oxy]-pheltyl]methyl' ' ' ' .~I]benzoic acid, (E)-3-[[[[3-(2~LvAy~lh.",JI) -i [[8-(4-~ Li-u~JI ' .~I)ocyl]oxy]--phenyl]methyl]suifinyl]methyl]benzoic acid, (E)-3-[[[[3-(2-_~LvAy~.Li-~ 4-[[8 (~1 - h ~yl Jl)OCyl]OXY]-25phenyl]methyl]suifonyl]methyl]ben-~oic acid 3-[[[[3-(2~LUA.~ 1)-4-[[8 (~ y. ' .~I)ocyl]-oxy]phenyl]methyll ' ' -' ;I]Llenzoic acid (E)-3-[5-[(phenylthio)methyl]-2-(2-1 ' jl-,d~uAy)lJll~r;]-2-propenoic acid, or (E)-3-[5-[[(2,6- 1: ~ 1, ]~ ,L~1~1]-2-(2-(4-30 fluulul,h~,,,.~l)-,.l-uAy)~,1.~,..~1]-2-propenoic acid, or a free acid thereof or another ~ , acceptable sait.
Severai methods, variations on the same process, have been used for preparing these; . ' In generai, the apprvach taken was to first make the 35 needed to make the R group, then to prepare a S ' ' ' J'L ' ' ' .~iu compound, coupiing it with a thiophenol or a I~ ,..yl l'~yl mercaptan, then I ~, _' - ~ the 2 position aidehyde or the 3 position hydroxyl group, the sequence is not criticai to making the funai producL Position 2 aikyl cllh~h~ n-c are derived from the , .

WO 95tlS752 2 ~ 7 ~ 6 3 4 PCTIUS94113966 ~
~,U~ v..~ g acrylate by catalytic h,1~Lvc.,~aliull. or some other form of reduction.
Once the groups a~ positions 2 and 3 are prepared, sa1ts, free acids, amides, altemative esters and the like can be prepared by ~.vll~/CIlliv--~l means.
Using the precursors prepared as per the noted PCI' ~1,1,1,. ~ ,.."~ or which have 5 been purchased from a commercial sourcc, and the steps outlined in Scheme I, carl bc used to prepare compounds of formula I.
~h~
SH
¢~ HCI (g) ~ D~ll, HO ~ Cl Ph~OT
OHC ~ KiCOJ
Cl ~ DMF

~ C Ph3P_CHCO 2Me OHC J~ toiuene, 50 C
Cl ~3 ~ Cl u~ooni~icsUon MoO 2C ~--~

~ WO95/15752 2~ 18~4 PCr/US94/13966 Ho 2C ~S~
Cl ~MeOC6i~4(cH2)4~ aq NaOH
MeO2G~N J~
SPh s The ~ ,yl~ yle is conYerted to the 5~hlv ul-~l-y" ' ' ' ,~ by combining the aldehyde with aqueous ' ' ' ' ydt, (37%) and hydt~chloric acid, at a reduced ~ L~ . in the range of -10 LO +10 C or ~h~ tc Gaseous HCI is then bubbled through the solution to saturate with HCI
after which the solution is stirred for a period sufficient to effect Lhe reaction at a 0 reduced t~ L~IIG, one which is about that ûf the i , at which the reactants werecombinedinitially. Theproduct,the5-~ 1)-2~ ~u~.y~ de, should be formed as a white precipitate which can be recovered by c~ ~.L;~,..al means.
The 5 (~ JI)-2-~ Lcl~.y~ h can then be coupled with any one of a num jer of thiophenols or I ' ' r ' " yl mercaptans in the next step. A numoer of 5 Lhiophenolsand ' ",~lph~,llylcompoundsusefulformakingtherighthandpoitionof formula I can be purchased fiom ".. ;l sources. A list, not intended to be exhaustive, is as follows: 2,5-~ `hl ' ' )r ~ 1, 2,6-L~ r' ' ' I ' 1~ 2,4-dichl~ 2-chloro-6--~.1-y~ 1, 2-chloro-4-'' . 1, 2,1 H' ' ' ' yl thioL 2-chloio-6-'' ' ~1 mercaptan, and 2,4.1 n, ....1~ -yl thiol.
Otber thiols can be made by published chemistry; that chemistiy involves converting a haloaUcylphcnyl (the bromo form is preferred) compound to Lhe ~-- --r .~
mercaptan by tteating the bt~mo compound with thiourea followed by base hydrolysis.
Alternatively tbc thiophenols can be prepared by thermal ~ of the ~~ ' ,, i' ' followed by hydrolysis.
2s Coupling the thiol with 5-(~ yl)-2-llyL~.yLcll~Ll~,hJ~ is . ' ' ' herein by using 1,8-J;r~l,;.,y-,lu[5.4.0]undec-7-ene (DBU) and am aprotic solvent, for exainple acetonitiile or acetonitiile and toluene. A slight molar excess of the thiol is used relative to the aldehyde. Moisture is excluded from the system and an inert gas is used, for example argon. The reaction can be carried out at room t "1" ' '1 " ' ~ or 30 there about. The reaction is run until aU of the I ' ' ' ~de is consumed; it can be Wo 95/15752 . PCr/US9 i/13966 2 l 7g634: --monilored by thin layer ' v . ' ~-Once the thiol is coupied wi~h the chloride, the aldehyde and the hydroxyl grvupat posi~ions ~ and 3 can be nn:~nir~ A IO provide the desired prvducl as per formula 1.
The chemistry for , ' _ these two posirions can be found in pubiished PCr ~ PCT/US91103398, PCTIUS91/037.72, PCT/US911nv3940~ and PCI~/lJS91/03399.
The " needed for forming those R groups, where the ' wvre not avaiiable .. : lly are prepared by the synthetic methods disclosed in noted PCT _l-~ All are . ' herein by reference. Forming the ethers of 0 position 3 is -. ~... l.li h .I by the chemistry recited in these PCT ~, ' i' ;i~ewise, g the 2 position aidehyde is done by the chemistries sel out in these seif-same s~rrli~ n~
Base, or acid, can be used to hydroiyze any ester group, if so desired. The fteeacid can be obtained from the sait by aci~vlifying a solution of the sait. i~sters and amides 5 can be prepared using standard reaction conditions and reagents. Tetrazoles are prepared from the, r v acid haiide, e-g-, the acid chloride, by literature methods.
rl- - ~ - of the present invention cornlJrise a I ' -' carrier or diluent and some arttount of a compound of the formula a). The compound 20 may be present in an atnount to effect a ~Jh,~..;vlvv;vrl response, or it may be present in a lesser amouM such that the user wiil need to tai~e two or more urtits of tbe ~
to effect the rreatment intended. These ~ - may be made up as a soiid, liquid v^r in a gaseous form. Or one of tbese three forrns may be i ~ ' to another at the time of being ' ' ' such as when a solid is delivered by aerosol means, or when a 25 iiquid is delivered as a spray or aerosol.
Included within the scope of this disclosure is the method of tneating a disetise mediated by LTB4 which comprises ~ v to a subject a ' ~ ~y effective amount of a compound of for~nuia I, preferably in the form of a l ' ' .. . For example, inhibiting the symptoms of an ailergic response resuiting 30 fr^m a mediator release by ' ' ' of an effective ar tount of a compound of fomtuia I is included witbin tbe scope of this disclosure. The ' ' may be carried out in dosage units at suitable intervals or in single doses as needed. Usualiy this method will be practiced when relief of symptoms is specificaily rvquired. Mowev, the method is aiso usefuiiy carried out as continuous or ~ ;.yl~Li~. treatment. It is within 35 the sicili of the art to determine by routine ~ the effective dosage to be . i from the dose range set forth above, tai~ing into ....~ l. ,a ;~ such factors as the degree of severity of the condition or disease being treated, and so forth.
The nature of the ~ .. ." and the l~ -l carrier or diiuent wiil, of WO 95115752 ;~ 1 7 8 ~ 3 4 PCINS94113966 course, depend upon the intended route of ~ - for example ~o~L lll.r.
topically, orally or by inhalation.
For lopical ~ 1 the ~ .,U~U,,II . ~ ;.,.1 will be in the form of 8 cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for 5 ' to the skin, eye, ear, or nose.
For parenteral r~ the ~ will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
For oral r ' ' ' ' thc ~ will be in the form of a 0 tablet, capsule, powder, pellet, attocho, lozenge, syrup, liquid, or ernulsion.
When the 1~ , - q ~ is employed in the forrn of a solution or suspension, cxamples of appropriate ~ catriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesamc oil, liquid parafins and mixtures thereof with 5 water, for solid systems, lactose, kaolin and mannitol; and for aerosol systerrts, L~,hlv.. --A ~ lu~ ' and~A,mr~rcc~carbondioxide. Also, in addition to the I ' ~ ' carrier or diluent, the insti~nt ~ ~ ~ . q ~ may include othor ingredients such as stabilizers, ~ , lubricants, suspending agenLs, viscosity modifiers and the likc, provided that the additional ingredienLs do not 20 have a deLrimental effect on thc therapeuLic acdon of thc instant ~ ~- `I ~ '; -The I ' ~ - thus describ~d are made following the ~U~ LiUII/II techniques of the 1 ~1 - ~ - - - ~ l ;- -I chemis~ as appropriale to the desired end product.
In these ~ the amt~unt of carrier or diluent will vary but preferably 25 will be the _aior proportion of a suspension or solution of the active ingredienL When thc diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingtedienL
Usually a compound of formuia I is ~ to a subject in a: , comprising a nontoxic amount sufficient to pro~uce an inhibition of the symptoms of a 30 disease in which 't ' are a factor. Topical ' ' will contain between about Q01 to 5.0% by weight of the active ingrcdient and will be applied as required as a IJI O ~ .,.I~Liv~: or curative agent to the affected area. When employed as an oral, or other ingested or injectt~d regimen, the dosage of the ~ is selected from the r~tnge of from 50 mg to 1000 mg of active ingredient for each ' For 35 ~ u..~. equal doses will be .1~ I I to S Limes daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
No, , ' ' ~ i -I effecLs are expected when these compounds are ' in accordance with the present invention.

WO95/1575~ ~2 1;78~4 PCr/'vS94/13966 The specifici~y of Ihe antagonisl aclivity of a number of Ihe compounds of Ihis invemion is ~' ' by relalively low levels of anlagonism toward agonisls such as potassium chloride, carbachol, histamine and PGF2.
Thc receptor binding affinity of the compounds used in the method of this itlvention is measured by the ability of the compounds to bind to [3H]-LTB4 binding sites on human U937 cell ' The LTB4 antagonist activiy of the compounds used in the method of this invention is measured by their abiliy to antagonize in a dosc dependent mznner the LTB4 elicited calcium transieM measured with fura-2, the fluorescent calcium prrv~be. The methods employed have been disclosed in prior published i?CT application PCT/US91/03772 which was flied 31 May 1991. The assays disclosed there are r I herein by reference.
,~;nr,~rifir F ' Tbe following examples are given to iiiustrate how lo make and use the compounds of this inventdon. These Examples are just thzt, examples. and are notintended to ~ or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors.
Exa.mele l Prrr~r~hnnof(F)-3-r5-rr(7~,l;~h'~ h vl~ lm~ttv11-2-(2- ' ' ' ~, 1-2-rm~7rnr~ir ~, i,i l(a) 5-(~~ vl~-2 ~V~LuAr~ ' 1. h~.l-S~d;~,~ ' ' ' ' J Je (8.7 mL. 65.6 mmol~ was added to a solution of aciueous rul~idvll r~ (14 mL, 37%) and conc. HCi (42 mL) at 0 C The reaction solution wæthen sahlrated with HCI gas and stirred at 10 C An off-white precipitate was formed 25 which was coi iected and washed with cold water. The solid was dissolved in CH2ci2 and dried over MgSO4. Evaporation of solvent provided 8.73 g of product. Mp 76-79 C.
I(b) s-rrl7 6-D- ~.I...."h vlllhiolmrthyil-2 ~I~.LuAyl~ ..,,.I.i. h"~
Ch ioride from Fvxample I (a) (4.32 g, 25.4 mmol), 2, 6- ' ' ' ' . ' ' (5.0 g,279 mmol), and DBU (4A8 mi_, 30 mmol) were stirred together st room: , in a 1:2 solution of ' " ' - (72 mL) untii complete , ' of chioride was indicated (TLC v) The reaction solution was parLitioned v~vtween EtOAc and water. The organic iayer was separated and washed with water and drivd (MgSO4).
JUlr~iu,l of solvent pmvvided a dark ydlow solid which was t iturated witil coldEtOAc-hexane(1:8). ~ryinggaveS.04gofproduct. Mp 114-117C.
l(c) 1-(4-T~ ' '' 1-2- ' ' ' Phenethyl alcohol (3.0 g, 24.6 mmol) was dissolved in ttiethyl amine (7 mL) atldCH2a2 (30 mL). The solution was cooled to 0 C and tosyl chloride (5.15 g, 27.1 ~ WO 9~15752 2 ~ 7 8 6 3 ~ PCT/US94/13966 mmol) was added. The reaction was stir ed at r~70m L,~ ul~ for 16 h. Reacdon solution was diluled with EtOAc and Ihe organic layer washed wilh 5% HCI, aq.
NaHC03, and brine and dried (MgSO4) E~, tl ..liul, gave 6.84 g of product. NMR
(250 MHz, CDC13) ~ 7.69 (d, 2H, aryl), 7.37 (m, 5H, aryl), 7.11 (d, 2H, aryl), 4.21 (t, J
= 6.86 Hz, 2H, OCH2), 2.96 (t, J = 6.80 Hz, 2H, benzylic), 2.42 (s, 3H, Me).
l(d) 5-rr(7 ~' ' ' ' '~ ' ' ' ~, 'l-2-(2-~,~h ~ vb.~ ..,,.1.1, hV,1, Phenol from Example I (b) (500 mg, 1.6 mmol), tosylate from Example I (c) (401 mg, 1.45 mmol), and powdered K2CO3 (276 mg, 2 mmol) were sti~red togedher at ro~7m i , irl DMF (10 mL) for 48 h. The reaction solution was partitioned ~0 between EtOAc and water. The orgarlic layer was separated and washed widl water arid dried (MgS04). The pi-oduct was purified by flash column ' ' y (silica, 4:1 hexane-EtOAc) to give 388 mg of product. Mp 54-58 C.
I(e) ~th"yl (E~-3-rs-rr(7 ~ hl-~".~ thit lm~th~vll-2-(2-,~h 1"~ -2-A'idehyde from Example l(d) (388 mg, 0.93 mmol) and methyl (I ', ~li . , ~;.i `. ) ~ ~t tt~-~ (341 mg, 1.02 mmol) were heated together at 50 C in toluene (7 mL) for 1.5 h. The co~71ed reacion solution was applied direcdy to a flash ' ~ , ', column (silica) and eluted widh hexane followed by hexane-EtOAc (4:1) to yield 310 mg of product. Mp 80-84 C
I(f) Sl '' fF)-3-rs-rr( t~ hit,~ '~, '1-2-(2 ~ 1-2-~n~
Ester from Exlimple I (e) (200mg, 0.42 mmol) was dissolYed in MeOH (0.85 mL) and THF (255 mr ) and treated widh IN NaOH (0.84 mL, 0.84 mmol). Th~e reaction was sti'rred at ro.7m r for 18 h- The solvents were evaporated and dhe product purified by reversed phase MPLC (RP-18 silica, 0-80% MeOH-water). The product was isolated by 1~ ,h'l; ~ (133 mg). MS (ES) m~e 459 rM+H]+.
Proceeding in a similar fashion, but ' ' ' ~ dhe appropriate ' '' and substrates for the ones detailed in (a) through (f) the following compounds are made as dhe sodii~m salt.
(E)-3-[5-[[(2,6-~iirhl , ' ~,I)sulfinyl]methyl]-2-(2-~ .,Ay), ' ,,1]-2-pr~7penoic acid, (E)-3-[5-[[(2,6~ v~ ,I)sulfonyl]methyl]-2-(2-~' ,' ' y\~' ~,;]-2-propenoic acid, 3-[5-[[(2,6 1'' ~ ~ " ~,l` ' ' ' ' ~,1]-2-(2-1 ' yl~ ,.,Ay)phenyl]-2-propanoic 35 acid, ~E)--3--[[[[3--(2--~ULAJA~t~ tl)~[[8-(4--Ill~l.lluA~t, ,~I)OCtYI]OXY]-phenyl]methyl~ hjl]benzoicacid, (E)-3--[[[[3--(2~A~t~ tV i--[[8 ( i .. I~ tA~t, ~1l)octyl]oxy]
phenyl]methyl]sulfinyllmethyl]benzoic acid.

Wo 9S/15752 2 1 7 8 6 ~ ~ PCrlUS94/13966 (E)-3-[[[[3-(2~11~UA~ 4-[[8-(4-~ UAy~ yl)octyl]ûxy]-phenyl imeIhyl ISulfonyl Imethyl Ibenzoic acid, 3-1 1 1 1 3-(2-carboAyethanyl)-4-1 1 8-(4-,--~ uA~ l)octyl]-oxy~phenyllmethy!! ' ' yl~oenzoic acid, (E)-3-[5-[(phenylthiû)methyl]-2-(2-1,l.~ ,.1.uA~ yl]-2-propenoic acid, or (E)-3-[5-[[(2,o~ -lu-ul,l-~.. yl)ll,io]l,-~ 1]-2-(2-(4- , ~1)-ethoxy)phenyl]-2-propenoic acid.
EAam~le 2 o r. for ~ -I use . ~ _ compounds of the present invention carl be prepared in various forms and with numerous excipients. Means for making various r.. - ~ can be found in standard tcxts such as 1~ 's r ~ Sciences, and similar ~ ' " and compendia. Specific examples of are given below.
OrNTMENTS
U~ Petrolatum IEL~gi~û~ Amn~mt (~o ~'. .:~ th~
Cholesterol 30.0g Stearyl Alcohol 30.0g White Wax 78.0g Active Ingredient 2.0g White Petrolatum 800.0g The stearyl alcohol, white wax and white petrolatum are melted together (steam bath for example) and cholesterol and the actdYe ingredient are added. Stirring is 20 ~ ~ ~ 1 and continued until the solids disappear. The source of heat is removed and the mix allowed to congeal and pac~aged in metal or plastic mbes.

~WO 95/15752 2 1 7 8 6 3 4 PCT/US94/13966 Fnn~llcinn ~ )intrn~-n~
~i~ Amo~nt (% W/W) Methylparaben 0.25g l`rU~/J~ ~II 0.15 Sodium Lauryl Sulfate IQOg Active Ingredient 5.0g Propylene Glycol 12QOg Stearyl Alcohûl 25QOg White Petrolatum 250.0g Ptuified Water QS to lOOO.Og The stearyl alcohol and white petrolatum are combined over heat. Other ingrcdients are dissolved in water, then this solution is added to the warm (ca 50 to 1û0 5 C) alcohoUpetrolatum mixture and stilred until the mixtt~ congeals. It can then be packed in tubes or another ap~ropriate package form.
F.xarnple rnh~ nn r A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired amount of dtug per use.

Claims (8)

1. What is claimed is:
   A compound of formula I
   formula 1 or a pharmaceutically acceptable salt, where A is CH2 and Z is S(O)q where q is 0, 1 or 2, CH2, CHOH, CO, NRX, or O, or A is C=O and Z is NRX;
   m is 0 -5;
   Rx is hydrogen or lower alkyl;
   R is C1 to C20-aliphatic, unsubstituted or substituted five-membered heteroaryl-C1 to C10-aliphatic-O-, unsubstituted or substituted phenyl-C1 to C10-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C1 to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-C1 to C10-aliphatic-O- where substituted phenyl bas one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
   R1 is R4, -(C1 to C5 aliphatic)R4, -(C1 to C5 aliphatic)CHO, -(C1 to C5 aliphatic)CH2OR5;
   R2 and R3 are independently, halo. lower alkoxy, CF3, CN. or lower alkyl;
   R4 is tetrazol-5-yl or COOH or an ester or amide thereof; and R5 is H, lower alkyl, CH3(CH2)0-6CO or phenyl(CH2)0-3CO.
2. 2. A compound of claim 1 where R is C8 to C20 alkoxy, thienyl-C1 to C10 alkoxy, substituted thiazolyl-C1 to C10 alkoxy, phenyl-C1 to C10 alkoxy or substituted-phenylC1 to C10 alkoxy; R1 is -(C1-C3alkyl)R4, or -(C2-C3alkenyl)R4.
3. 3 A compound of claim 2 where R is thien-2-ylethyloxy, thien-3-ylethyloxy, 3-methylthiazol-2-ylethyloxy, unsubstituted or substituted phenyl-C2 to C10 alkoxy or CH3(CH2)7-9-O-; m is 0, 1 or 2; R1 is HO2C-CH=CH-, or HO2C-CH2CH2-or a salt, ester or amide derivative thereof.
4. 4. A compound of claim 3 where R2 and R3 are both halo or both methyl.
5. 5. A compound of claim 4 which is (E)-3-[5-[[(2,6-dichlorophenyl)thio]methyl]-2-(2-phenylethoxy)phenyl]-2-propenoic acid, (E)-3-[5-[[(2,6-dichlorophenyl)sulfinyl]methyl]-2-(2-phenylethoxy)phenyl]-2-propenoic acid, (E)-3-[5-[[2,6-dichlorophenyl)sulfonyl]methyl]-2-(2-phenylethoxy)phenyl]-2-prpenoic acid, 3-[5-[[2,6-dichlorophenyl)thio[methyl]-2-(2-phenylethoxy)phenyl]-2-propanoic acid, (E)-3-[[[[3-(2-carboxyethenyl)-4-[[8-(4-methoxyphenyl)octyl]oxy]-phenyl]methyl]thio]methyl]benzoic acid, (E)-3-[[[[3-(2-carboxyethenyl)-4-[[8-(4-methoxyphenyl)octyl]oxy]-phenyl]methyl]sulfinyl]methyl]benzoic acid, (E)-3-[[[[[3-(2-carboxyethenyl)-4-[[8-(4-methoxyphenyl)octyl]oxy]-phenyl]methyl]sulfonyl]methyl]benzoic acid, 3-[[[[3-(2-carboxyethanyl)-4-[[8-(4-methoxyphenyl)octyl]-oxy]phenyl]methyl]thio]methyl]benzoic acid, (E)-3-[5-[(phenylthio)methyl]-2-(2-phenylethoxy)phenyl]-2-propenoic acid, or (E)-3-[5-[[(2,6-dichlorophenyl)thio]methyl]-2-(2-(4-fluorophenyl)ethoxy)phenyl]-2-propenoic acid, or a free acid thereof or another pharmaceutically acceptable salt.
6. 6. A method for treating psoriasis which comprises administering an effective amount of a compound of formula I according to claim 1 alone or admixed with a suitable carrier.
7. 7. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.
8. 8. A method for treating inflammatory bowel disease which comprises administering an effective amount of a compound of formula I according to claim 1 alone or admixed with a suitable carrier.