CA2178833A1 - Phenylthiophenyl cycloalkenyl hydroxyureas as lipoxygenase inhibitors - Google Patents

Abstract

Certain novel phenylthiophenylcycloalkenyl hydroxyurea compounds having the ability to inhibit the 5-lipoxygenase enzyme and having formula (I) and the pharmaceutically acceptable salts thereof, wherein A and B, independently, are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halo-substituted alkyl or C1-C4 halo-substituted alkoxy; R1 and R2, independently, are hydrogen or C1-C3 alkyl; X is S, SO or SO2; and Z is methylene or ethylene. These compounds are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.

Description

~1/095/17379 2 1 7 8 8 3 3 F~1~J,, I.~n~
PHENYLTHIOPHENYL CYCLOAKENYL HYDROXYUREAS ~S LIPOXYGENASE INHIiiITORS
TPrhn;r~l Field This invention relates to novel N-hydroxyurea rnmrmlnri~ The compounds of the present invention inhibit the actlon of l;~uu,~y~ enzyme and are useful in the 5 treatment or aileviation of ;~n~""~ y diseases, ailergy and cardiovascular diseases in mammais. This invention aiso relates to ~ul~cu~l~a~c~L;~di compositinn~ comprising such compounds.
Back~7roiiLnd Art Arachidonic acid is k,nown to be the biologicai precursor of severai groups of 10 tlldu,5t,--ou~ mPt~hnli~P5, ,ul~ Ao~ including prostacyclins, thromboxanes and leukotrienes. The first step of the ~r~rhifinnir acid mPt~ho1i~m is the release of ~r~nhi~innic acid and related unsaturated fatty acids from membrane phospholipids, via he action of phnsrhnlir~P ~2. Free fatty acids are then mP-~hnli7--d either by uyclou~ ,e to produce the yl~ gl~.lli;ll~ and 1II1UIIIOU~ t ~ or by li~u~y"~.,a~ to 15 generate hydroperoxy fatty acids which may be further metabolized to the leuk~otrienes.
TP~lkntnPnps have been implicated in the pathophysiology of infiammatory diseases, including rheumatoid arthritis, gout, aslhma, ischemia reperfusion injury, psoriasis and ;"n~",,.,~,l,,y bowel diseases. Any drug thal inhibits lilJu~y~c,l~ is expected to provide significant new therapy for both acute and chronic ;..f~ llAlllly conditions.
Recently severai review articles on lipoxygenase inhibilors have been reported.
(See H.Masamune and L.S.Melvin, Sr., Annuai Reports in Medicinai Chemistry: 24 (1989) pp71-80 (Academic) and B.J.Fit_simmons and J.Roi~ach, TPllkntriPnP~ and LiUu~ g~.lG,~s (19~9) pp427-502 (Elsevier)).
More particulariy, Int~",~tiu"dl Patent Publication No. WO 92/9566 and U.S.
Patent No. 5,187,192, disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.
Brief Discln~--re ûf the In~entign - -=
The present invention pro~ides novel N-hydroxyurea compounds of the following chemical formula I:

WO 9~/17379 2 1 7 8 8 3 3 PCT/JP9J,102032 ~X~ o Rl N/~ NHR2 OH
and the ~ LllI~LLGULiLdily acceptable saits thereof, wherein A and B, inri.~r~nri-ntly, are hydrogen, haiogen, Cl-C4 aii;yl, Cl-C4 aii;oxy, Cl-C4 haio-S subshtuted ailcyl or Cl-C4 haio-substituted aikoxy;
Rl and R2, ;".i~ Li Itly~ are hydrogen or Cl-C4 aii;yl;
X is S, SO or S~2; and Z is methylene or ethylene.
The compounds of the formula I inhibit the S~ JU~yo~ L~G en~yme. Ther~Fore 10 the ~omrollnriC are- useful for treating a medicai condihon for which a S-lilJo~y,~
inhibitor is needed, in a m:~mm~ n subject, e.g., a human subject. The compoundsare especiaily useful for treating ailergic and ;"n,.""",,l",y conditions. This invention aiso Gmbraces ,,II~L ,l,~L-~uLi.~i ~ o~ which comprise a compound of the formulaI and a pll~LLlll~LC~ULi~Lily acceptable carrier.
1~ A preferred group of compounds of the invention consists of the compounds of the formula I, wherein Rl and R2 are each hydrogen and X is S. Within this preferred group, particularly preferred, ~ u~ are those wherein Rl and R2 are each hydrogen, X is S, A is 4-fiuoro, B is hydrogen and Z is ethyiene.
Particularly preferred individuai compounds of the invention are:
20 N-r3-[3-(4-Fluorophenylthio)phenyl~ 2--y-lu~ .lL-I-yl]-N-hydroxyurea, (+)-N-[3-[3-(4-FliLulu,~ ylLiliu)phenyl]-2-CyCIOpenten-l-yl]-N-Ilytllu,~yuLG~Land O 95117379 2 1 7 8 8 3 3 PCTlJPs1/02032 (-)-N-[3-[3-(4-Flllulu~ ylLllio)phenyl]-2-~;y~lu~ll~Jl-l-y~-N
Detailed Descri~tion of the In~ention In t}us application, the term "halo" is used to mean radicals denved from the elem~nts fluorine. chlorine and bromine.
The term ~p~ y acceptable salts" refers to salt ;Il-,ulpuldLillg non-toxic cations, including, but not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, m~gnl~ci~lm, and the lilce, as well as non-toxic ~mmnnillm, substituted ammonium and quaternary ammonium cations, includin~, but not limited to, ~mmnnil~m tetramethylA"",~ """,, L~ .llyl~ J~ l, methyl-lû ~ mmnnil lm ~ ylA l ~ l l l lul l i l l ~ trimeth~ " and ~ ylA ~ lm The compounds of formula I may be prepared by a number of synthetic methods. In the following formulae, Q is ~x~
wherein A and B are as previously defined.
In one rll-lloll;lll. "l, compounds of the formula I are prepared according to scheme 1:
Scheme I
Rl NH Fl N~ NHFI2 OH OH
II l In Scheme 1, the hydroxylamine II is treated with a suitable trialky~silyl wogs/l7379 21 78833 r~llJ. lA7n~ ~
isocyanate or lower alkyl isocyanale of the formula R2NCO~ in a reaction-inert solvent, usually at ambient through to refiux ~ d~ul~. Preferably the reaction ~tl~lyCldlUlt is from 20 to 100 CC. Suitable solvents which do not react with reactants and/orproducts are, for example, ~Lldl~ydluruldu~, dioxane, méthylene chloride or benzene.
5 An altemative procedure employs trQtment of the llyllUAyld~llille II with gaseous hydrogen chloride in reaction-inert solvent such as benzene or toluene arld thensubsequent treatment with phosgene. Reaction t~ d~U~ are usually in the range of ambient L~ ld~ul~ Lhrough to boiling point of solvent, preferably 25 to 80 C.
The illL~lllv8idLt carbamoyl chlonde is not isolated but subjected to (i.e. in si~) 10 reaction with aqueous ammonia or amine F~2N~I2. As a mr,tl;f;~t;nn of this procedure the acid addition salt of the llydlu~yldll~ II may be reacted with an equimolar amount of alkali meta~ cyanate, such as poLassium cyanate, in water. The product of formula I thus obtained is isolated by standard methods and ~ ir,l can be achieved by ~ull~lLiulldl means, such as recrystallization and ulll~ ly The aforpml~ntinn~rl hydlu~ylGlllille II may be prepared by standard synthetic procedures from ~w~ ulldi~, cyrl~ nl~n~ of the formula III or cycloalkenol of the formula IV.
R~O R OH
m n For example, suitable cyr'r,~'k~nrmr is converted to iLs ûxime and then reduced to the requisite hydroxylamine n with a suiLable reducing agent (for example, see R.
F. Bûrch et al, J. Am. Chem. Soc., 22, 2897, 1~71). Reducin~ agents of choice are, but not limited to, sodium uyd~ lJùlullydlidc and boron-complexes such as borane-pyridine, borane-tnethylamine and borane-dimeLhylsulfide, however triethylsilane in trifluoroacetic acid may also be employed.
The suiLable carbonyl compound m, (i.e. y~lùbuL~ "c"~ or u yl ll,~l~ ,llrlll, rc~, O 9S/17379 2 1 7 8 8 PCT/JP9~/02032 can be preparcd by a number of different methods (see WO 92/9566). The eyclo-butenones may be prepared by Ihe [2+2] eycloaddihon of Ihe LU~ JUllU;ll~, ethylenes and dichloroketene followed by reductive ~i~rhinrinAtinn (for example, see R. L
Danheiser et al., Tell~h~ u-- Lett., _~i, 3299,1987). The cyrl/~r"lr"~"~.; may be 5 prepared by the intr~mnl~cl~lAr aldol eyelization of 1,4-diketones, read;ly accessible from the Lull~lJullLlillg aldehydes and methyl vinyl ketone by the Stetter reaction (for example, see L. Novak et al., Liebigs Annalen Chemie, 509, 1986). Alternatively,the cyrlnAlkpnnn~c m can be prepared by the cross coupling reaction of, for example, the LUll~L~L llLiil~g aryl halides or triflates with the cycloalk~l.yl~ or vice versa lû in the presence of suitable catalyst such as Pd(PPh3)4, PdCI2(PPh3)2 and the like (for example, see J.~;. Stil~e: Angew. Chem. Int. Ed. Engl., -2, Sû8, 19863.
Alternatively, the arulr", ~ llyLllu~yl~u~lillc II can easily be prepared by treating the corresponding cycloalkenol IV with N,O-bis(rert-butylu~yL~ubu.,yl)-I~yLilu~yl~lllille under Mitsunobu-type reaction eonditions followed by aeid eatalyzed 15 hydrolysis (for example, employing Llilluulu~ ic aeid) of the N,O-proteeted ;lllrllll..i;AIr produet. The requisite eyeloalkenoi IV is readily prepared by the 1,2-reduetion of the Lullc~,uùlld;llg cyrloAli~nnn~ III using a suitable redueing agent sueh as sodium bLlullyLlli~ or sodium borohydride-eerium triehloride The hydroxylamine of formula II Ihus obtained by Ihe abov~m~ntinnr~i ~0 I~L,lr~ll~Live proeedures is isolated by standard methods and purification can be aehieved by conventional mcans, sueh as reerystallization and LI~ r~ lY
In another e,lll,odi"l~,lt, romro~ln~C of the formula I are prepared as illustrated in Seheme 2. R3 is phenyl, and R4 is phenyl or lower alkyl:
Sch~mc 2 C~ ~1~ OR~ NHR2 ~ OF(~ OH
V

wo 95/17379 2 1 7 8 8 3 3 1 l/J

In this process, compound of formula V is prepared from the LUllC~pUIILIillg alcohol ~f and a bis-carboxyhydroxylamine, preferably N,O-bis~phenoxycarbonyl)-I~YLIIU~YI~IIIiIIe~ and ~h~ y converted to formula I by treatment with ammonia, ammonium hydroxide, or an amine of structure R2NH2 (A. O. Stewart and D. W.
Brooks., J. Org. Chem., ~7, 5020, 1992). Suitable reaction solvents for reactionwith ammonia, ammonium hydroxide or the amine of ~ormula R2NH2 are, for example, water, methanol, ethanol, tetrahydrofuran, benzene and the like, thoughreaction may be run in the absence of co-sûlvent, that is, in requisite amine alone.
Reaction Lr~ ulcs are typically in the range of ambient ~r~ Lule through to boiling point of solvent, preferably 25 to ~30 ~C. The product of formula I thusobtaincd is isolatcd by standard methods and purification can be achieved by Lull~.lltiol1al mcans, such as recrystallization and chromatography.
The compounds of this invention can exist in ~ U;~Ulll~L;C forms by virtue of the presence of one or IS~re chiral centers. The present invention ~ Irl I ~rl.Ur all such st~.~isulll~L,, including ~ iOIll~, did~t~.~rUI~ , and mixtures. The individual isomers of compounds of the formula of this invention can be pr~parcd by a number of methods known to those s};illed in the art. For instance, tney can be prepared by derivatization of a compound of formula I with a chiral auxiliary foilowed by separation of the resulting di~,Lr-,un,c.ic mixture and removal of the auxiliary group to provide the desired isomer, or by separation employing a chiral stationary phase.
The pi~Ul~ LLiL~Ily acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a ~1.,;r11;n",~ 1, ;r amount of a non-toxic cationl that is, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent. The salt may then be obtained by l~ Li~iLaLiL~il or by evaporation of the solvent.
The compounds of the prcsent invention inhibit the activity of li,uu~yr,.~ r enzyme. This inhibition can be rlf ,~ in ~ ro by an assay using l,.~i"i~
Human Whole Blood (HWB) cells, according to the method described in British Jû~lrnal of Pharfnacology: 99, 113-118 (1990), which determincs the effcct of said compounds on the metabolism of ~r~rhitionic acid. The compounds of examples 1 to ~VO95/17379 21 78833 ,~IIJI I~?n~

7 were tested in the aforementioned assay and they were shown to possess the efficacy of inhibiting IIIJU~,7elld~ activity. In this test, the compounds of Examples 1 to 7 show IC50 vaiues of 0.05 to 5 ~M in HWB assay, with respect to li~u~r,~ ~d~ activity.
The in vivo activ;ty after orai ~ l of compounds of the invention to ICR mice (maie) cdn be determined using PAF lethaiity assay in a simiiar manner as described by J. M. Young et ai. ( J. M. Young1 P. J. Maioney, S. N. Jubb1 and J. S.
Clark, Pros~aglandins, 30, 545(19~5). See aiso: M. Criscuoli and A. Subissi, Pr. ~.
Phar~nac., 90, 203(19~7); H. Tsunoda, S. Abe, Y. Salcuma, S. Katdyama, and K.
Katdyama, Prostaglandins ~.ellkorrienes ar/d ~ssential ~a~ry Acids, 3g, 291(1990)). In this test, the compounds of Examples I to 7 indicdte ED~o vaiues in the range of I to 20 mg/kg.
The ability of the compounds of the present invention to inhibit li~ùAyO~l~d~r enzyme makes them useful for controlling the symptoms induced by the e.ldùr~.,uu, metdbolites arising from ~rArhirlnnir acid in a m~mm~ n subject. The compounds are therefore valuable in the prevention and tredtment of such disedse stdtes in which the lAti~ll Of zlr~rhi(lnnir acid metdbolites are the causative factor; e.g. ailergic bronchiai asthma, skin disorders, rheumatoid arthritis and o"euduLl,lili,. Thus, the compounds of the present invention and their ~ " ,~ i, rlly acceptdble saits are of particular use in the treatment or aileviation of in~mm~t(lry disedses in a human subject.
For treatment of the various conditions described above, the compounds of the formula I of this invention can be ad~ ~i to a human subject either aione, or preferably in combination with pharmaceuticaily acceptdble carriers or diluents in a pl-d-l-ld~ o-,ll,~siLiu,~ according to standard ~hdulll~u~i~di practice. This ~ , can consist of about 0.1 to 909O, preferably about 10 to 60%, of the compound of formuld I or the sait in liquid or solid form of the unit use.
The compounds can be administered to human subjects by various conventionai routes of administration including ordl or parenterdl. When the compounds are administered orally, the dose range will be from about 0.1 to 20 mg/kg of body v~eight of the subject to be tredted per day, preferdbiy from about 0.5 to 15 mg/iig of body weightperday, insingieordivideddoses. If parenteral~l",i"i~ linn isdesired, then 2 1 7 8 8 3 3 1 ~IIJA, ~' ?1~?
_~_ an effecDive dose will be from about 0.05 to 10 mg/~g of body weight of the human subject to be treated per day. In some instances it may be necessary to use dosages outside these iimits, since the dosages will necessarily vary according to the age, weight and res~DOnSe of the individuai patient as well as the severity of the patient's symptoms and the potency of the particular compound being dd~ t~
For orai ~riminictr~inn, the compouDds of the invention and their acceptable saits can be adl"i,~ rd, for example, in the form of tablets, powders, lozenges, syrups or capsules or as an aqueous solution or suspension.
In the case of tablets for orai use, carriers which are commonly used include lactose and corn starch. Further lubncating agents such as magnesium stearate are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch. When aqueous ~ are required for orai use, the active ingredient is combined with emulsiflng and suspendlng agents. If desired, certain sweetning and~or flavoring agents can be added. For in~r~ml~rlll~r, i~ ubl,uL~ulcvu~ and illlld~.llOU~ use, sterile soiutions of the active ingredient are usuaily prepared and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the totai r~nr-nrr~ir,n of solute should be controlled to mal~e the preparation isotonic.
ExamDles The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Proton nucledr magnetic rcsonance spectra (NMR) were measured at 270 MH_ unless otherwise indicated and peal~ positions are expressed in parts per million (ppm) downfield from tG~Idl~ ilane. The peal; shapes are denoted as follows: s -singlet, d - doublet, t - triplel, m -multiplet and br - broad.
ExamDle I
~V-r3-r3-f4-i-1uDropherlvlthio~phenYl]-2-cvclobuten-l-yll-lv-hydroxvurea [A] I-Bromo-3-(4-fiuu~ u~ lll-io)benzene:
To a stirred solution of l-bromo-3-ir-~r,b~n7~n~ (143.5g; 0.507M) in EtOH
(1.5L~ ~as added 4-nuu-vLlliul~ lul (65g; û.5û7~I), NaO'Bu (~orj-sgi l.û14~I), and Pd(Ph3P)4 ~40g; 0.032M) at room Ltlll,u~.~d~U~ under argon. The mixture was refiuxed for 5 hr, and the mixture stirred over two days at room Itlll~,cldLul~:. The mixture was ~o 95/17379 2 1 7 8 8 3 3 1 "J ~, filtered through a pad of celite, and the filtrate was evapc~rated in vacuo. Water (400ml) was added to the residue, and the whole was extracted with Et20 (400mlx2).
The combined organic layers was washed with water (300ml), brine (200ml), dried over MgSO4, and ~UIl~llLLdlL-~I in vacuo. The residue was purified by flash column 5 ~ UllldLU~,ld~lly (SiO2) eluting with n-hcxane to give 113g (yield 7gL~) of subtitle compound as a pale yellow oil.
H-NMR (CDCI3) o; 7.46-7.23 (m, 4H), 7.13-6 99 (m, 4H).
~B] 2-r3-(4-Fluûl u~uh..-ylllLio~phenyl]-1-(trimethylsilyl)acetylene:
Tû a stirred solution of l-bromo-3-(4-fluorophenylthio)benzene (I 13g; 0.399M) in triethylamine (500ml) was added l-(trimethylsilyl)acetylene (62ml; 0.439M) and Pd(Ph3P)2CI2 (28g; 0.0399M) at room ~e,..~,~.dlu~. The mixture was refluxed for 2 hr, and then stirred ovemight at room ~Clll~ dLUI~. Water (700ml) was added, and the whole was extracted with Et20 (500ml). The organic layer was washed with saturated aqueous NH4CI (300ml), water (300mlx2), brine (300ml), dried over MgSO4, and 15 evaporated in vacuo. The residual oil was purified by flash column ~ UllldLUt,ld~lly (SiO2) eluting with n-hexane to give 130g (yield quant.) of subtitle compound as a pale yellow oil.
lH-NMR (CDCI3) o; 7.40-6.99 (m, 8H), 0.23 (s, 9H).
[C] 3-(4-FI ~ul-..lylLlliû)l~h_..yl.
To a stirred solution of 2-r3-(4-lluulu~ ylLlliO)phenyl]-l-(trimethylsilyl) acetylene (130g; 0 433M) in THF (200ml) was added a IM solution of n-Bu4NF in THF (600ml; 0.649M) at room t~",~..dtule under N2. After stirring overnight, volatiles were removed by L,vdJulcLLiù.,. Water (500ml) was added, and the whole was extracted with ethyl acetate-Et20-n-hexane (lOOml-lOOml-200ml). The organic layer was washed with water (150ml), brine (150ml), dried over MgSO4, and evapûrated in vacuo. The residue was pu~ified by flash column ullLu~ n~ ly (SiO2) eluting withn-hexane to give 78g (yield 79%) of subtitle compound as a pale yellow oil.
IH-NMR (CDCI3) ô; 7.44^7.18 (m, 6H), 7.05 (t, J=8.5Hz, 2H), 3.06 (s, lH).
rD] 3^r3-(~-Fluoropherlylthio)phen~1]-4,4-dichloro-7-c~rloh~tPr~ne To a stirred suspension of 3-(4-fLuorophenylthio)phenylacetylene (30g; 0~132M) -WO 9S117379 2 t 7 8 8 3 3 1 " , ~ f~

and zinc-copper couple (34.4g; 0.526M) irl Et20 *OOml) was added dropwise tri-chloroacetyl chloride (44ml; 0.395M) and ~UI~u~ ulu~ oxychloride (37ml; 0.395M) in ~t70 ~'300ml) at room t~llly~ldLul~ After completion of addition, th~ mixture was refluxed for 48 hours. After cooling, zinc-copper couple was filtered off. The filtrate was f~ nrll in Yacuo, and Et20-n-hexane (400ml-600ml) was added. The whole was washed wlth water (500mlx3), saturated aqueous NaHCO3 (350ml), water (350ml), brine (500ml), dried over MgSO4, and hltered Lhrough a short column of silica gel to afford 21g (yield 47%) of crude subtitle compound as yellow solids, which was used without further p~ltifir~Frln IH-NMR (CDCI3) ~; 7.70 (d.t, J= I.~-H~, 7.4Hz, IH), 7.6~ (t, J= 1.5Hz, IH), 7 54-7.38 ~m, 4H), 7.1~ (t, J=8.4Hz, 2H), 6.56 (s, lH).
[E~ 3-[3-~4-Fiuul uy~ o)phenyl]-2-cyrlnh~tf~n~nne To a stirred suspension of 3-~3-t4-fluorophenylthio)phenyl~-4,4-dichloro-2-cyclobutenone (21g; 0.062M) in acetic acid (lOOml) was added zinc dust (20.3g;
0.31M) at room l~lllyC~ld~UI~. After stirring for 1.5 hours, insolubles were filtered off.
The filtrate was evaporated in v~cuo. The residue was purified by f~ash column ~IllullldtoDlaylly (SiO2) eluting with ethyl acetate-n-hexane (1:10) to give 7.4g ~yield 44%) of subtitle compound.
IH-NMR (CDCI3) ~; 7.47-7.27 (m, 6~I), 7.08 (t, J=8.5Hz, 2H), 3.50 (s, 2H).
~F`i 3-[3-(1 Fluorophenylthio)phenyl]-2-cyriob~f-t~nf oxime:
To a stirred solution of cyrlnhl~tf-nnnf- (7.4g; ~7mM) in EtOH-pyridine(50ml-17ml) was added hydroxylamine hydrochlonde (2.48g; 35.6mM) at room L~lly~ldtul~.The mixture was stirred for 2 hours at 50C, and then stirred ovemlght at room t~lly~dtUI~. The solvent was removed by CV~yOldtiull, and the resulting oil dissolved ;n ethyl acetate (300ml). The organic phase was v~ashed with diluted aqueous HCI(lOOml), and the aqueous layer extracted with ethyl acetate (150ml), the combined organic layers v~ashed with water (lOOml), brine (lOOml), dried over MgSO4, and filtered through a short co~umn of silica gel to prûvide 8.3g (yield quant.) ûf subtitle compound .
[G] N-[3-[3-(4-Fluoropheny~thiû)phen~l]-~-cyclobuten-l-~l]-N-h~drox~l-amine:

~vo g~/17379 2 1 7 8 8 3 3 I'~l/J. Ir?l~?
To a stirred solution of 3-[3-(4-fluulu~ ylLl~io)phenyl]-2-uyulù~ r~ r (3.31g; 29mM) in acetic acid (50ml) was added Na~3H3CN (2.75g; 43.7mM) at loom Lr~ dLul~:. After stirring for 1.5 hours, the reaction mixture was poured into 10%
aqueous NaOH (500ml~. The whole was extracted with ethyl acetate (200mlx2), and the combined organic layer washed with water (200ml), brine (200ml), dried oYer MgSO4, and "-"- f ~ m vacuo. The residue was purified by flash column chrnm~tn~r~rhy (SiO~) eluting with CH~Cl2-~tOH (40:1) to give 1.55g (yield 19%) of subtitle compound.
IH-NMR (CDCl3) ô; 7 40-6.98 (m, 8H), 6.32 (s, lH), 4.14 (d, J=4.0Hz, lH), 2.97 ~d.d, J=4.4Hz, 13.6Hz, lH), 2.59 (d, J=13.6Hz, lH).
rH]N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclobuten-l-yl]-N-hyJlu~ulca To a stirred solution of N-[3-[3-(4-nuulu,uh.,lyllllio)phenyl]-2-cyclobuten- l-yl]-N-hydlu,.yldl,li,,e (1.55g; 5.4mM) in THF (20ml) was added tnmethylsilyl isocyanate (TMSNCO) (0.95g; 7.02mM) at room LtllllJ~ ld~ult~ under N2. The mixture was stirred overnight, and EtOH (lOml) was added. SolYent was removed in v~cuo, and the residue was recrystallized from i-PrOH to provide 0.4g (yield 22%) of title compound as colorless flakes.
m.p. 135-136C.
IH-NMR (DMSO-d6) ~; 9.07 (s,lH), 7.47-7.16 (m, 8H), 6.35 (s, 3H), 5.04 (br.s, IH), 2.92-2.75 (m, 2H).
Anal. Calcd. for Cl7HI5FN,O~S: C, 61.80, H, 4.58, N, 8.48, F, 5.75, S, 9.70;
found: C, 61.58, H, 4.55, N, 8.35, F, 5.68, S, 9.72.
EXamDle 7 N-r3-r3-(4-Fluûrophenvlthio~phenYl1-2-methvl-7-cvclûbuten- I-yll-N-hvdroxvurea [A] 1-[3-(~-Fluorophen~lthio)phen~l]-1-propyne:
To a cooled, slirred solution of 1.5M solution of lithium diisopropylamide in cyclohexane (51.3ml; 77mM avaulable from Aldnch) in THF (180ml) cooled to -78C
was added 3-(4-fluorophenylthio)phenylacetylene (16g; 70mM) in THF (45ml) dropwise under N,. Af~er stirring for 1.5 hours, CH31 (35g; 1~0mM) was added. The mixture was allowed to warm ~o room L. IllJ. dLul~, and stirred for a further 1 hour.

Wo 95/17379 ~ 1 7 8 8 3 3 Pcr~JPs~/02032 Water (200ml) was added lo the mixture and solvent was removed in v~cuo. The whole was extracted with Et2O (200mlxl, 150mlxl)7 the combined organic layer washed with water (150ml), bnne (150ml), dried over MgSO4, and rnnrl~ntr~t~ri invaCuo Cll~u~ purification (S;02) of the residue eluting with n-hexane provided 12.08g (yield 71.3%) of the subtitle compound as a colorless oil IH-NM~ (CDCr3) 13; 7.42-7.35 (m, 2H), 7.27-7.12 (m1 4H), 7.01 (t, J=8.8Hz, 2H), 2.02 (s, 3H).
[B] N-[3-r3-(4-Fluorophenylthio)phenyl]-2-methyl-2-cyclobuten-1-yl]-~-IIJ~ AJ~
The title compound was prepared according to the procedure of Example I
using 1-[3-(4-nuuluul~c,~ylthio)phenyl]-l-propyne instead of 3-(4-lluuluul~ ylLilio)-phenylacetylene in step [D].
m.p. 149.5-150.5C (dec.).
IH-NMR (DM~O-d6) ~; 8.98 (s, IH), 7.50-1.12 (m, 8H), 6.39 (s, 2H), 4.92 ~br.s, 15 = lH), 2.70-2.60 (m, 2H), 1.80 (s, 3H).
Anal. Calcd. for Cl8HI7FN2O2S: C, 62.77, H, 4.98, N, ~.13, F, 5.52, S, 9.31;
found: C, 62.81, H, 5.06, N, 8.12, F, 5.10, S, 9.55.
ExamDle 3 IV-r3-r3-(4-Fluorophenvlthio)l~henY11-2-methvl-2-cyclobuteri- I-yll-l`l-hYdroxY-IV'-methvlurea - - ~
The title compound was prepared according to the procedure of Example I
using 1-[3-(4-lluu-uL~ y~ )phenyl3-l-propyne instead of 3-(4-lluuluul~c,~ylLl~io)-,uh..,yl~Lylene in step [D], using m~thyl isocyanate instead of TMSNCO in step [H].
m.p. 117.5-119.5C.
IH-NMR tDMSO-d6) ~; 8.90 (s, IH), 7.50-7.12 (m, 8H), o.95 (q, J=4.8Hz, lH), 4.90 (br. s, lH), 2.~1 (d, J=4.~3Hz, 3H)~ 2.72-2 55 tm, 2H), 1 79 (s, 3H) IR (nujol) cm l: 3370, 1745, 1630, 1590, 1530, 1490, 1220, 835, 785.
Anal. Calcd. for CL9HI9FN2O2S: C, 63.67, H, 5.34, N, 7.82, F, 5.30, S, 8.94;
found: C, 63.83, H, 5.47~N, 7.50, F, 4.98, S, 9.31.
ExamDle 4 ~YO 95/17379 2 1 7 8 8 3 3 P~IIJ., ~/n~n~

I~,T-r3-r3-(4-Fluorovhenvlthio)phenyll-2-~,yL,luJc,,~ll-l-vll-l~'-hvdroxvurea ~A] 3-(4-nuu. v~ rl~llio)benzaldehyde:
To a stirred solution of l-bromo-3-(4-fluorophenylthio)benzene (28.3g; 0.1M) in THF (60ml) cooled to -75C v~as added dropwise a 1.6M solution of n-BuLi (56ml;
0.09M) under N2. After stirring for 0.5 hour at Ihe same L~ cldLu.L" DMF (7.9g;
0.108M) was added to the mixture. The reaction mixture was stirred for 0.5 hour at -75CC, and then ailowed to warm to room LCIIIUCldLU~C. After stirrino for 0.5 hour at room L.,~ JCIdLUIC, diluted aqueous HCI (80ml) was added to the mixture. The whole was extracted with Et2O (150mlx2), the combined organic layer washed with water (80ml)1 bnne (80ml), dried over M~SO4, and evaporated in vacuo. The residue was purified by hash column Llll~ U~ ,lly (SiOj!) to give 18.03g (86%) of the subtitle compound as a pale yellow oil.
IH-i~MR (CDCI3) ~i; 10.30 (s, lH), 7.82 (d.d, J=2.6Hz, 6.6Hz, IH), 7.53 (d.d.d, J=2.6Hz, 5. lHz, 8.8Hz, IH), 7.37-7.28 (m, 5H), 7.12 (d.d, J=8.8Hz, 9.9Hz, IH).
[B] 1-[3-(4-Fl~,v-u~ .-ylllliO)phenyl]-ll4-F ' -' To a stirred solution of 3-(4-fi~ulu~ul~ ylLll;O~benzaidehyde (18.03g; 77.72mM) in EtO~ (40ml) was added methyl vinyl ketone (5.2ml; 62.36mM), 3-benzyl-5-(2-hydroxyethyl)-4-,~ -yl~lli~ulium chloride (3.63g; 13.47mM), and triethylamine (17.76ml; 127.42mM) at room ~ .ld~UlL,. After stirrinV for 48 hours, volatiles were removed by ~vd,uu~L~ioll~ To the residue was added water (150ml), and the whole was extracted with ethyl acetate (120mlx3). The combined orlJanic layer washed with water (150ml), brine (200ml), dried over MgSO4, and ~ lrv in ~acuo. The residual oil was purihed by fiash column ~I.,o~ u~ ,l,y (SiO2) eluting with ethyl acetate-n-hexane (1:5) to give 19.3g (quant.) oFthe subtitle compound as a yeliow oil.
IH-NMR (CDCI~) ,'i; 7.86 (d.d, J=2.6Hz, 7.ûHz, IH), 7.45 (d.d.d, J=2.6Hz, 4.8Hz, 8.8Hz, IH), 7.33-7.27 (m, 5H), 7.0g (d.d, J=8.8Hz, 10.6Hz, IH), 3.26-3.20(m, 2H), 2.85 (t, J=6.2Hz, 2H), 2.24 (s, 3H).
~C] 3-[3-(4-nuoropheny~thio)phen~1]-2-c~clopentenone:
Asolutionofl-[3-(4-fiuorophenylthio)phenyl]-1,4-p~t~nf~ n~(19.3g;63.9mM) WO g~/17379 2 1 7 8 8 3 3 P~ ./J., IIA7n1? ~

in 0.43M aqueous NaOH soluuon (300ml) was refLuxed for 19 hours. After cooling, the whole extracted with ethyl acetate (150mlx1, lOOmlx2). The combined extract was washed with water (150ml), brine (150ml), dried over MgSO4, and filtered through a pad of silica gel. The filtrate was ~ in ~acuo to give 16.5g (yield 91f'O) of S the subLitle compound as a black oil.
IH-NMR (CDCI3) ~; 7.54 (d.d, J=2.2Hz, 7.0Hz, lH), 7 43-7.27 (m, 6H), 7.12 (d.d, J=8.4H~, ll.OHz, lH), 6.69 (d, J=~.~Hz, lH), 3.00 (d.d, J=2.9Hz, 5.1Hz, 2H), ~.SO (d.t, J=2.2Hz, 5.1Hz, 2H).
rD~ 3-r3-(4-Fluulu~h~ io)phenyl]-2-c~r~op.,nt.~no eoxime:
To a stirred solution of 3-[3-(4-fluorophenylthio)phenyl]-2--,y~lu~u~.,tc-lu"c (16.5g; 58.1mM) in EtOH-pyridine (120ml-30ml) was added hydroxylamine hydro-chloride (5.25g; 75.5mM) at room ~e"lL ~.dLu.~. Aher stirring overnight, solvent was removed by evaporation. To the residue was added diluted aqueous HCI (120ml), and the whole was extracted with ethyl acetate (2ûOmlx2). The combined organic ~ayer was washed with water (lSOml), brine (lSOml), dried over MgSO4, and ~ in vacllo to give 19.5g of crude subtitle compound as a brown oil, which was used without further purificatlon.
tE] N-[3-[3-(4-FI,,~I u~ ylLl~io)phenyl]-2-~,lol l-yl3-N-hydroxyl-amine:
To a stirred solution of 3-r3-(4-lluclu~,;,c"yl~llio)phenyl]-;~-cyrl~np,-nt~nnT~oxime (19.5g; 65.2mM) in acetic acid (120ml) was added NaBH3CN (6.15g; 97.8mM) at room I~ .ldLulC-. After stirring for 3 hours, acetic acid (30ml) and NaRH3CN
(1.5g; 24.5mM) were added. The mixture was stirred for an additional 3 hours, and then volatiles were removed by evaporation. The residue was dissolved in ethyl acetate ~5 (200ml), and the whole was washed with saturated aqueous NaHCO3 (80ml). Theaqueous layer was extracted with ethyl acetate (lOOml), and the combined organic layer washed with water (lOOml), brine (lOOml), dried over MgSO4, and ",",. ,.Il,u~ invacuo. Cl-lullldlu ,ld~hic-punflcation of the residue eluting with CH2Cll-EtOH (50:1) provided 8.7g (yield 44%~ of the subtitle compound as a yellow oil.
[11 N-r3-[3-(~-Fluorophenylthio)phen~lJ-7-cyclopenten-l-yl~-N-hydrox~-~YO95/17379 21 78833 P~ I/J~ r~
urea:
To a stirred solution of N- [3- [3- (4-nuul u~ y ~ io)phenyl] -2-~y~lu~l l k~ -yl]
N-l~ydlu~yl~ lt (8.7g; 28.9mM) in THF (80ml) was added TMSNCO (5.88g;
43.4mM) at room Lt:llluc~ ul~ unde} N2. After stirring for I hour, EtOH (50ml) was 5 added. Volatiles were removed by evaporation, and the resulting residue was recrystallized from ethyl acetate (lSOml) to prQvide 3.03g of the title compound as colorless solids.
m.p 159-160C (dec ).
IH-NMR (DMSO-d6) ~; 8.97 (s, IH), 7.43-7.23 (m, 8H), 6.34 (s, 2H), 6.17 (s, IH),5.34 (br.s, IH), 2.79-2.67 (m, 1~), 2.60-2.48 (m, lH), 2.12-2.00 (m, IH), 1.97-1.~2 (m, IH).
~nal. Calcd. for Cl8HlgFNzO2S: C, 62.77, ~, 4.98, N, 8.13, F, 5.52;
found: C, 62.76, H, 4.94, N, 8.17, F, S.SI.
E~amr~le ~
(+)-N-r3-r3-(4-Fluulu~ ylLllio)l~henvll-2-cvcloQenten- l-yll-N-hydroxYu~-a, The title d~L uluL~luly enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea. The racemate (650mg) was resolved by HPLC (eluent; n-hexane-i-PrOH ~70:30)) using a chiral pak AS column (DAICEL CHEM IND) to give 276mg of the more polar enantiomer as colorless crystals after recrystalli~ation from ethyl acetate-n-hexane.
m p. 156-156.5C (dec.); ~]D= +102 (c=0.08, EtOH).
E~amrJle 6 (-~-N-r3-r3-(4-Fl~Q~u~ vlLlliu)phenyll-2-cv~ u~ -yll-N
The title levorotatory enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-~3-(4-fluulupl~c"ylLiliu)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea. The racemate (650mg) was resolved by HPLC (eluent; n-hexane-i-PrOH (70:30)) using a chiral pal; AS column (DAICEL CHEM IND) to give 267mg of the less polar enantiomer as colorless crystals after recrystallizalion from ethyl acetate-n-hexane.

wo 95/17379 ~ 2 1 7 8 8 3 3 PCT/JP9~102032 ~

m.p. 157-157.5~ (dec.); [CY]D= -106.82 (c=0.088, EtOH).
~xamPle 7 ,~-r3-r2-~4-Fluolui~h~lyllllio)-4-iniuorophenvll-2-cvclopenten-l-v~ v-hvdroxvùrea The title compound was prepared accordin,g to the procedure of Example 4 using 2-(4-f,uorophenylthio)-4-llu~,1ul,~l,~,',dehyde instead of 3-(4-nuu~ "ylLl1iu)-benzaldehyde in step ,rB].
m.p. 138.2-139.6C.
IH-NMR (DMSO-d6) ,~; 8 98 (s, 1~), 7.52 (t, J=7.33H~, 2H), 7.38-7.29 (m, 3H), 7.05 (t, J=8.43Hz, IH~, 6.56 (d, J=9.53Hz, lH~, 6.33 (s, ~H), 5.81 (s, lH~, 5.33 ~or. s, lH), 2.76-2.64 (m, 2H), 2.11-1.95 (m, 2H).
IR (KBr~ cm~l: 3450, 3700, 1660, 1600, 1580, 1240, 1210, g00.
Ana',. Calcd. for Cl8HI6F2N;~02S: C, 59.66, H, 4.45, N, 7.73;
found: C, 59.50, H, 4.39, N, 7.91.

Claims (9)

-17-

1. A compound of the following chemical formula:

and the phamaceutically acceptable salts thereof, wherein A and B, independently, are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halo-substituted alkyl or C1-C4 halo-substituted alkoxy;
R1 and R2, independently, are hydrogen or C1-C4 alkyl;
X is S, SO or SO2; and Z is methylene or ethylene

2. A compound according to claim 1, wherein R1 and R are each hydrogen and X is S.

3. A compound according to claim 2, wherein A is 4-fluoro, B is hydrogen and Z is methylene

4. A compound according to claim 3, wherein the compound is N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclobuten-1-yl]-N-hydroxyurea.

5. A compound according to claim 2, wherein A is 4-fluoro, B is hydrogen and Z is ethylene.

6. A compound according to claim 5 wherein the compound is selected from:
N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea;
(+)-N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea; and (-)-N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-1-yl]-N-hydroxyurea.

7. A pharmaceutical composition for the treatment of an allergic or inflammatory condition in a mammalian subject which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A method for treatment of a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.

9. A method according to claim 8, wherein the medical condition is an allergic or inflammatory condition.