CA2078126A1 - 5-lipoxygenase inhibitors - Google Patents

Abstract

Hydroxyurea compounds comprising substituted and unsubstituted 1,2,3,4-tetrahydronaphthalene, indane, dihydrobenzofuran, 4H-2,3-dihydrobenzopyran, dihydrobenzothiophene, and indoline derivatives, pharmaceutical compositions containing said compounds, and their use as analgesics and 5-lipoxygenase pathway inhibitors.

Description

WO 91/14674 P~/US91/02010 2~126 FIELD QF I~V~I~lON
1 5 This invention relates to novel compounds, pharmaceutical compositions and methods for inhibiting oxygenated polyunsaturatecd fatty acid metabolism and disease s~ates caused thereby. Specifically inhibited is the lipoxygenase enzyme pathway of arachidonic acid melabolism in an animal.
BAC~KGROUN~ QF ~1NV~NTIQ~
2 0 The metabolism of arachidonic acid occurs by many pathways. One routç of metabolism is via the cyclooxygenase (CO) mecliated pathway which produces PGH2 which is in turn rnetabolized to the prostanoids (PGE2, TXA2~ and prostacyclin). These products are produced by various cells including polyrnolphonuclear leukocytes, mast cclls and monocytes. Anotner route is 'oy the lipoxygenase mecliated pathway which oxidizes 2 5 arachidonic acid initially lo 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is further meta'oolized to LTA4, the precursor to the pepticloleukotrienes (LTC4, LTD4, and LTE4) and LTB4. Acdditionally 5-HPETE is converted to 5-hyc'~oxyeicosatetraenoic acid (5-HE~).
Lipoxygenases are classified according to the position in the arachidQnic acid 3 0 which is oxygenated. Plntelets metabolize arachidonic acid to 12-HETE, whilepolyrnorphonuclear leukocytes (PMNs) contain S and 15 lipoxygenases. It is known that 12-HETE and 5,12-diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflamma~ion process. 5-HPETE is known to be a precursor to the peptidylleukotrienes, forrnerly known as slow reacLing substance of anaphylaxis (SRS-A) 3 5 and LTB4. The SRS family of molecules, such as leuko~ienes C~ ~nd D~, have been shown ~o l~e potent bronchoconstrictors. LTB4 has been shown to be a potent chernotatic for PMNs. The products of the ~-lipoxygenase pathway are believed to play an import~nt role in initiating and mnintaining the inflammatory response of asthma, allergy, ~hritis.

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4 P~/US91/020~0 ps~asis, and inflarnmatory bowel disease. It is believed that blockage of this enzyrne will interrupt the various pathways in~olved In these disease states and as such inhibitors should be useful in trea~ng a variety of inflammatory diseases, such as those inumerated above.
The absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase, which 5 are active in vivo has prevented adequate investigation of the role of leukotrienes in inflarnrnation.
The arachidonic acid oxygenated products, as noted above, have been identifie(i as mediators of various inflammatory conditions. The various inflarnmatory disease states caused by these mediators and rnany other conditions, as discussed herein, are all conditions I O in which an oxygenated polyunsaturated fatty acid metabolite inhibitor, such as a 5-LO
inhibitor, would be indicated.
There remains a need for treatrnent, in this field, for compounds which are capable of inhibiting the oxygenation of arachidonic acid by inhibition of enzymes such as lipoxygenase, specifically 5-lipoxygenase (5-LO) thereby preventing the forrnation of 1 5 various leukotnenes and prostaglandins.
The compounds of Forrnula (I) have been found to be not only be selective 5-lipoxygenase inhibitors but also, unexpectantly, to possess analgesic activity, not norrnally associated with compounds having lipoxygenase inhibition.

2 0 SU~MARY QF T~E lNVENTION
This invention relates to a compound of the Forrnula (I) ( R2)q R ~ (R3) FORMUL~
2 5 wherein \ ,C~
~2 andR3 are ~N R4 R is hydrogen, a pha~naceutically acceptable cation, aroyl or a C 1-1~ allcoyl;
B is oxygen or sulfur;
R4 is N~sR6, alkyl 1-6. halosubstituted alkyl 1-6. hydroxy subs~i~uted alkyl 1-6. alkenyl 3 2-6. aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl 1~6. hydroxyl, or alkoxy 1-6;
Rs is H or alkyll-6;
R6 is H, alkyll 6, aryl, arylalkyl 1-6. heteroaryl, alkyl substituted by halogen or hydro~yl, aryl or heteroaryl optionally substituted by a member selec~ed from the group .~
~: ,. . :
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WO 91/14~74 PCr/US~1/û2010 ~3~ 2~78~ 26 consis~ing of halo, nitro, cyano, alkyll l2, alkoxy 1-6~ halosubstituted alkY11-6.
alkoxycarbonyl, arrunocarbonyl, aLkylarniwcarbonyl, dialkylarninocarbonyl, alkylthio, alkylsulphonyl, or alkylsulfinyl; or Rs and R6 rslay together form a ring having S to 7 members, which members may be optionally replaced by a hetero:lton selected from oxygen, sulfur or nitrogen;
W is CH2(CH2)S, O(cH2)s~ S(cH2)s~ or NR7(CH2)s;
R7 is hydrogen, Cl 4 aL~cyl, phenyl, C1 6 alkoyl, or aroyl;
s is a number having a value of 0 to 3; provided that when 1 is 1 and W is O(CH2)s, S(CH2)S, then s is 1 to 3; and when W is NR7(CH2)s then s is 1 to 3 and q is 1;
1 0 q is a number having a value of 0 or 1;
1 is a number having a value of 0 or 1;
provided that when q is 0 then 1 is 1 and R2 is hydrogen; and when q is 1 then I is 0 and R3 is hydrogen;
R1 is a member selected from the group consisting of hydrogen, aL~cyl1-10~ alkoxy1-10.
1 5 naphthyl, (CH2)m-Ar-(X)v, (CH2)m(C=C)n(CH2)p-Ar-(X)v~ O(CH2)mAr-(~)v.
S(CH2)m-Ar-(X)v, or N~CH2)m-Ar-(X)v;
p is a number having a value of 0 to 3;
m is a number having a value of 0 to 3;
n is a number having a value of 0 to 3;
2 0 v is a number having a value of 0 to 3;
Ar is a member selected from the group consisting of phenyl, naphthyl, quinolyl,isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;
X is a member selected from the group consisting of hydrogen, halogen, alkyl 1-10~
2 5 cycloalkyl 5-8, aLlcenyl ~-10, hydroxy, (cHy)tcarboxy~ O-alkyl 1-10~ S()r alkyl l 10, aryloxy, arylalkyll-6 oxy, halosubstituted alkyl1 6, hydroxy substituted alkyll 6, (CHY)tN(R5)2, or cyano; provided that if v is a number greater than 1 then one substituent must be selected from alkyl, O-alkyl 1-10~ or halo;
r is 0 to 2; Y is hydrogen or alkyl 1-3;
3 0 t is 0 or 1; provided that when q is 1, R4 is NR4Rs, W is CH2(CH2)~, and s is 1, then Rl i~
other than hydrogen, alkyll 10. or alkoxy l-lo;
and the pha~maceutically acceptable salts ~ereof.

This invention also relates tO a ph~rmaceutical composition comprising a 3 5 pharrnaceutically acceptable carrier or diluent and an effective, non-toxic ~ lipoxy_enase pathway inhibiting amount of a compound of the Forrnula (I) as defined above, or a pha~naceutically acceptable salt thereof.

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WO 91/14674 P~r/US91/02010 This invention also relates to a method of treating an oxygena~ed polyunsaturated fatty acid (hereinafter OPUFA) mediated disease in an animal in need thereof which comprises administering to suc~ animal, an effective amoun~ of a compound of Formula (I) or pharmaceutically acceptable salts thereof.
S More specifically this invention relates to a method of treating a lipoxygenase pathway mediated disease in an anirnal in need thereof which comprises administering to such animal an effective, non-toxic lipoxygenase pathway inhibiting arnount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
This invention further relates to a method of treating algesia in an animal in 1 0 need thereof which comprises administering to such ar~mal an effective, analgesic amount of a compound of Forrnula (I), or a pharrnaceutically acceptable salt thereof.

DETAILED I:)E~CRlP~lON QF THE I~NTJON
This invention relates to compounds of Formula (I) as described above, 1 5 pharrnaceutical compositions comprising a pharmaceutically acceptable carrier or diluent alld a compound of Formula (I) ahd pharmaceutically acceptable salt thereof, methods of treating an OPUFA mediated disease, specifically a 5-lipoxygenase pathway mediated disease comprising administration of a compound of Formula (I) and salts thereof, and methods o~
treating algesia comprising administration of a compound of Formula (I?, and salts thereof.
2 0 The compounds of Formula ~1) have been found to be useful in inhibiting the enzymes involved in the oxygenated polyunsaturated fatty acid pathway which includes the metabolism of arachidonic acid, in an animal, including humans, in need thereof. The compounds of Formula (I) have oral activity and are therefore useful for the treatment of various inflarnmatory disease states. The compounds of Formula (I), particularly the 2 5 hydroxyurea derivatives, also possess unexpectedly, a superior analgesic activily, thus providing a method of treatment for algesia in an animal in need thereof. The genus of conl-pounds of Formula (I) useful in the treatment of algesia and as inhibitors of the OPFUA
pathway does include compounds wherein q is 1, E~4 is NE~4Rs, W is CH2(CH2)s, s is 1, and Rl is hydrogen, alkyl1 10. or alkoxy 1-10-3 0 A preferred embodiment of the present invention is where R1 is selected ~rom O(CH2)m-Ar-(X)v, (CH2)m-Ar-(X)v, or S(CH~)m-Ar-(X)v; m is a number having ;value of 0 to 3; and v is a number having a value of l to 2. Preferred X groups are hydrogen, alkoxy, halo, and CF3, preferrably in the 4-position. When X is (CHY)tN(Rs)~
the Rs group is independently selected from hydrogen or an alkyl of 1-6 carbons yielding ;m 3 5 unsubstituted, mon~ or di-substituted amine component.
Specific Rl groups of interest are alkoxy, phenethyl, benzyloxy, arvloxv, and substitu~ed derivatives thereof. Specifically such groups are methoxy, phenoxv, benzyloxy, 4-methoxybenzyloxy, 4-chlorobenzyloxy, 4-flurophenoxy, ~-phenylethyl, ~-,~
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WO 91/14674 5 ~ ~ ~ 3 1 2 ~! 1/0 ~0]0 quinoylmethoxy, and 2-naphthylmethoxy. A more preferred embodiment of this in~enlion is where W is CH2(CH2)s or O(CH2)s ;md s is a number having a value of 0 or I .
A further preferred embodiment of the present invenliOn is ~ here B i~
oxy~en. Preferred R4 substituent groups are NRsR6 and the al~yl hvdroxan~ c S derivatives. Preferred R6 substitutions when R6 is ~l or arylalkyl are phenyl or benzyl.
A more preferred embodiment is where Rs and R~ are independently hydrogen or all~
Mo.st preferred is where q is 1 and I is 0 for all R ) alld R3 substitutent ~roups and W lerm~
A preferred ring placement when W is CH ~(CHa)s and s is I is on the 5- or 6-position of the benzene ring and when s is 0 the preferred position is the 4- or S-posi~ion;
1 0 applicable substitution patterns are also preferred when W is O(CH~)S, i.e., when s is 1, the 7- or ~- position, and when s is 0 the 6- or 7- position.
When 1?~, is other than a NRsl?fi moiely yielding a hydroxamate derivati~e~
R~ is preferrably alky], more preferably Cl-6, Such as methvl, ethyh n-propyl, isopropyl or t-butvl all optionally substituted; B is oxygen ;tnd q i~ ] . More preferred i~ u~here W i~;
I S CH~(CH~)~ or O(CH2)s and s is 0 or 1. For all comr)o~ d~i hcrein, R' is prefer;l~ Iy hydrooen or a pharrn;tceutically acceptable cation.
Some preferred hydroxyurea compounds of Formula (I) compounds which are themselves within the scope of the present invention include the following:
N- ] -(S-Benzyloxy- I ,2,3,4-tetrahydronaphthyl)-NI-hydroxyurea;
2 0 N- I -(5-Phenoxy- I ,2,3,4-tetrahydronaphthyl)-N-hydroxyurea:
N-l -[5-(4-Fluorophenoxy)-1 ,2,3,4-~etrahydronaph~hyl]-1~'-hydroxyurea;
N- I -(6-Benzyloxy- 1 ,2,3,4-tetrahydronaph~hyl)-N-hydroxyurea;
N - I - (6-Phenoxy- 1 ,2,3,4-~etrahydronaph~hyl)-N-hydroxyurea:
N-1-(6-(4-Fluorophenoxy)-1,~,3,4-tetrahydron:lphthyll-N-llydroxyllrea;
'~ 5 N-l -(6-Me~hoxy-1,2,3,4-~etrahydronaph~hyl)-N-hydroxvurea;
N- I -( I ,2,3,4-Tetrahydronaph~hyl)-N-hydroxyurea:
N- I -L6-(4-Methoxybenzyloxy)-1,2,3,4-tetrahydronaphthyl~ -hydroxyurea;
N-l -[6-(4-Chlorobenzyloxy)-1,2,3,4-tetrahydronaphthyll-N-hydroxyurea:
N-l -l6-(2-Naphthylmethoxy)-1,2,3,4-~etrahydronaphthyl~-N-hydroxyurea;
3 0 N-1-l6-(2-Phenethyl)-1,2,3,4-tetrahydronapthyll-N-hydroxyurea;
N-1-16-(2-Quiriolinylme~hoxy)-1,2,3,4-~etrahydrondphtllyll-1\'-hvdroxvurea;
N- I -[6-(2-Pyridinylmethoxy)- 1 ,2,3,4-~etrahvdronaphthyll-N-hydroxyure;l;
N- 1 -l 6-(2-Benzimidazolylmethoxy)-(1 ,2,3,4-tetrahydronaphthyl)]-N-hydroxyure;l;
N-2-(7-Methoxy-1,2,3,4-tetrahydronaphthyl)-~ hvdrox~ure;l;
3 5 lN l-(7-Benzyloxy-1,2,3,4-tetrdhydronapllthyl)-~ ydroxyllrc:l;
N-l -(fi-Phenyl-1,2,3,4-telrahydronapthyl)-1`~-hydroxyure;l;
N- ] -(5-Benzyloxyindanyl)-N-hydroxyurea; 1\ - ] -(5-Phenoxvindanyl)-N-hydroxyure;l;
N- ] -(5-(4-Flurophenoxvilldanyl)-l\'-hydroxyllrc;l:

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WO 91/14674 PCr/US9~/~2010 _ t" ~` -6- :

N- 1-(4-Benzyloxyindanyl)-N-hydroxyurea;
N-1-(4-Phenoxyind tnyl)-N-hydroxyurea;
N- I -(4-(4-Flurophenoxyindanyl)- N'-hydroxyure,t:
N-1-~5-(4-methoxvbenzyloxy)-ind tnyll-N-hydroxyure;t;
5 N- I -(7-Phenoxyindanyl)-N-hydroxyure,t;
N-3-(7-Phenoxy- ',3-dihydrobenzofuranyl)-N-hydroxyurea;
N-3-17-(4-Flurophenoxy)-2~3-dihvdrobenzofurany]~-N-hydroxyurea;
N-3-(7 -Benzyloxv-~ ~3-dihydrobenzofuranyl)-N-hydroxyurea;
N-3-(6-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyurea;
1 0 N-3-~6-(4-Flurophenoxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea;
N-3-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyurea; or N-3-16-(4-Melhoxybenzyloxy)-2.3-dihydrobenzofuranyl]-N-hydroxyurea.
Preferred hydrox:~ll;lte deriva~ives of Formul t (I) compounds wllich are ~ithill the scope of the present invention are I S N-Hydroxy-N- I -l6-(~-pllenylctilvl)- 1 ,~,3,4-tetrahydronaphthyllacet tmide;
N-Hvdroxy-l~ l-(fi-benzvloxv- I ,~,3,4-tetrahydronaphthyl)] tcetamide;
IN-Hydroxy-N-~ 1 -(S-benzyloxyindanyl)Jacetamide;
N-Hydroxy-N- I -(6-metiloxy- 1 ,2,3,4-tetrahydronaphthyl) tcetamide;
N-Hydroxy-N-1-(1,2,3,4-tetrahydronaphthyl)acetamide;
2 0 N-Hydroxy-~T- I -~6-(4-methoxybenzyl)oxy- 1 ,2,3,4-tetrahydronaphthyl]acetamide;
.'~'-Hvdroxy-N-1-16-(4-chlorobenzyloxy)-1,2,3,4-tetrahydronaphthyl]acelamide;
N-Hvdroxy-N-1-16-(2-naphthvlmethoxy)-1,2,3,4 tetrahydronaphthyl]acetamide;
N-llydroxv-N-3-(6-benzyloxy-2,3-dihydrobenzofuranyl)acetarnide;
N-Hydroxv-l~T- 1 -l 6-(2-4uinolinylmeth! loxy)- 1 ,2,3,4-~etrahydronaphthyl]acetamide;
2 ~ ~T-Hydroxy-N-2-(7-methoxy-1,2,3,4-tetrahydron tph~hyl)acetamide;
N-Hydroxy-N- I -(7-benzvloxy- 1 ,2,3,4-~etrahydronaphthyl)acetamide;
N-Hydroxy-N-I 1-(6-phellyl- 1 ,2,3,4-tetrahydronaphthyl)]acetamide;
N-Hydroxy-N- 1 -l 5-(4-methoxvbenzyloxy)indanyllacetamide;
N-Hydroxy-N-3-16-(4-meliloxvbenzyloxy)-'>,3-dihydrobenzofur;lnyl]acet-amide;
3 () N-Hvdroxy-N- I -(5-benzvloxy- 1 ,2,3,4-tetr:lhydronaphthyl)acet tmide;
N-Hydroxy-N- I -(6-phenoxv- 1 ,2,3,4-te~rahydronaphthyl))acetamide;
N-Hydroxy-N- I -(6-benzvloxy- 1 ,2,3,4-tetrahydronaphthyl)propionamide;
N-Hydroxy-N- I -(6-benzyloxy- 1 ,2,3,4-tetrahydronaphthylbenzamide;
N-Hydroxv-N-] -l6-(2-pllenethyl)-1 ,2,3,4-tetrahydronaphthylJ-2,2-dimethylpropion;lnlide 3 ~ As the hvdrox;lZll:ltes ;md hvdroxyureas disclosed herein are made thru a common intermedi tte, a hvdroxylamirle deriviatives of Fortnula (Il), ;tny N-hydrzxy acet;~mide derivatives of the correspol-ding hydroxy;tmines made herein are also considered ~ preferred eml)odimc:nt oi this hlventioll . , ~ ;. :
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WO 91/14674 PCr~US91/02010 ~7~ 2~78~2~

P~tricularly preferred hydroxyamines of Forrnula ~11) are 1\1 1-(5-Benzyloxy-1.2,3,4-tetrahvdronaphLhyl)-N-hydroxyamine;
N- 1 -(5-Phenoxy- I ,2,3,4-tetr;lhydronaphthyl)-N-hydroxyamine;
5-(4-Flurophenoxy)-1,2,3,4-tetrahydronaphthyll-N-hydroxyamine;
N- 1 -(6-Benzyloxy-1 ,2,3,4-tetrahydronaph~hyl)-N-hydroxyamine;
N- ] -(6-Phenoxy- I ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N- I -~6-(4-Fluorophenoxy)- 1,2,3,4-tetrahydronaphthyl]-N-hydroxyamine: or N- 1 -(6-Methoxy-1 72,3,4-tetrahydronaphlhyl)-N-hydroxyan-ine;
N- 1-( I ,2,~,4-Tetrahydronaphthyl)-N-hydroxyarnine;
1 0 N-1-~6-(4-Methoxybenzyloxy)-1,~,3,~tetrahydronaphthyl]-N-hydroxyamine;
1`~'- ] -[6-(4-Chlorobenzyloxy)- 1 .'~,3,4-tetrahydronaphthyl]-N-hydroxyamine;
N-1-16-(~-Naphthylmethoxy)-1,,3,4-tetrahydronaphthyl]-N-hydroxy~mine; ~ .
N 1 -l 6-(2-Phenethyl)- 1,2,3,4-tetrahydronapthyl]-N-hydroxyamine;
N- I ~6-(2-Quinolinylmethoxy)-1,~,3,4-tetrahydronaphthyl]-N-hydroxyamine;
1 5 1~'-1-16-(2-Pyridinylmethoxy)-1,~,3,4-tetrahydronaphthyl]-N-hydroxyamille;
i~-1-[6-(~-Benzimidazolylmethoxy)-(1~ 4-teu;lhydronaphthyl)]-1~'-hydrox~v;lmine;N-'~-(7-Methoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N- I -(7-Benzyloxy- 1 .2,3,4,-tetrahydronaphthyl)-N-hydroxyamine;
I~IT- I -(6-Phenyl- 1,2,3,4-tetrahydronapthyl)-N-hydroxyamine;
2 0 N-1-(5-Benzyloxyindanyl)-N-hydroxyamine; N-1-(5-Phenoxyindanyl)-N-hydroxyamine;
N- I -(5-(4-Flurophenoxyindany})-N-hydroxyamine;
N- I -(4-Benzyloxyindanyl)-N-hydroxyamine; N- I -(4-Phenoxyindanyl)-N-hydroxyamine;
I~i-I-( 1-(4-Flurophenoxyindanyl)-N-hydroxyamine;
N- I -15-(4-methoxybenzyloxy)-indanyl]-N-hydroxy~mine;
2 5 N-1-(7-Phenoxyindanyl)-N-hydroxyarnine;
N-3-(7-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
1`.'-3-17-(4-nurophenoxy)-2,3-dihydrobenzofuranyl]-N-hydroxyamine;
~;-3-(7-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
I\T-3-(6-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
3 () N-3- 1 6-(4-Flurophenoxy)-2,3-dihydrobenzofuranyll-N-hydroxyamine; or N-3-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyarnine;
N-~-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
N-3-~6-(4-Methoxybenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyamine; or NT-~-(7-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine.
Tlle terms "aryl" or "heleroaryl" are used herein at all occurrences 20 mean substiluted and unsubstituted aroma~ic ring(s) or ring sysTems con~ailling from S to 1 fi carbon aloms, which may include bi- or tri-cvclic syslems and may inelud~ but are nol ,. ~
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WO 91/14674~ pcr~ussl/o2olo limited to heteroatoms selected from O, N, or S. Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, and furanyl.
The terrns "lower alkyl" or "alkyl" are used herein at all occurrerlces to mean st aight or branched chain radical of 1 to 10 carbqn atoms, unless the chain length is limited thereto.
5 including, but not lirnited to methyl, ethyi, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The te~n "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including, but not lirnited to ethenyl, 1-propenyl, 2-propenyl, 2-rnethyl-1-propenyl, l-butenyl, 2-butenyl 1 0 and the like.
The term "aralkyl" is used herein to mean C1 4 Ar, wherein Ar is as defined in Forrnula (I).
The term "aroyl" is used herein to mean - C(O) Ar, wherein Ar is as defined in Forrnula (I), including, but not limited to benzyl, 1- or 2-naphthyl and the like.
1 5 The term "alkoyl" is used herein to mean -C(O)Cl lo, wherein alkyl is as defined above, including but not limited to methyl, ethyl, isopropyl, n-butyl, t-butyl, and the like.
The terrn "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The te~m "halo" or "halogen" are used interchangeably herein to mean radicals 2 0 derived from tne elements fluorine, chlorine, bromine, and iodine.
The terrn "lipoxygenase" is used herein to mean 5-, 12-, or 15- lipoxygenase, preferably 5-lipoxygenase.
By the terrn "OPUFA mediated disease or disease state" is meant any disease state which is mediated (or modulated) by oxidized polyunsaturated fatty acids, specifically the 2 5 a:rachidonic acid metabolic pathway. The oxidation of arachidonic acid by such enzymes as the lipoxygenase enzymes is specifically targeted by the present invention. Such enzymes include, but are not li nited to, 5-LO, 12-LO, and 15-LO; which produce the following mediators, including but not limited to, LTB4, LTC4, LTD4, 5,12-diHETE, S-HPETE, 1~-HPETE, 15-HPETE, 5-HETE,12-HETE and I5-HETE.
3 0 By the te~nn "OPUFA inteffering annount" is rneant an effective arnount of a compound of Formula (I) or (II) which shows a reduction of the ~n ~Q levels of an oxgyenated polyunsaturated fatty acid, preferably an arzchidonic acid me~bolite.The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racennic and optic31ly active forms. All of these compounds 3 5 are contemplated to be within the scope of the present invention. Specifically exemplified compounds are the pairs, (+)-N-1-(6-Benzyloxy-1,2,3,4-tetrahydron;lphthvl)-N-hydroxyurea, and (-)-N-1-(6-Ben2yloxy-1,~,3,4-tetrahydronaph~hyl)-N-hydro:cyurea: an(i .. . ..
.; . ~ , :': : ' , : . .
~ - ...... . .. .

WO 91/14674 PC~/I:JS91/02010 -9- 2~7~2S
(+)-N-3-(~Benzyloxy-2,3-dihydrobenzofuryl)-N-hydroxyurea and (-)-N-3-(6-Benzyloxy-2,3-dihydroben ofuryl)-N-hydroxyurea.

Useful interrnediates of the present invention are the novel hydroxylarnine derivatives of Formula (II) as represented by the forrnula below. The compounds of Folmula (II) have also been found to be compounds useful for inhibition of the OPUFA
pathway and in the treatment of algesia. The genus of compounds of Forrnula (II) useful as OPUFA inhibitors or in the treatrnent of algesia include compounds wherein ~ is hydrogen, W is CH2(CH2)S and s is O or 1, and compounds wherein B is hydrogen, W is S(CH2)s l O andsis l".

The compounds of Formula (II) are represented by the structure:
(R2)q I~R3)1 R~ W
FORMULA (II) -N--OB' l 5 whereinR2 andR3 are 1 ; -B' is hydrogen, benzyl, optionally substituted benzyl, Si(RX)3, C(O)Rs, C(O)ORs~, CH20CH2CH2Si(CH3)3, C1alkyl-C1 3alkoxy, C1alkylC2alkoxyC1 3alkoxy, or tetrahydropyranyl;
A is hydrogen or C(O)ORz;
2 0 Rz is benzyl, Si(Rx)3, t-butyl, or CH20CH2CH2Si(Rx)3;
Rs~ is C1 6 alkyl, aryl, or aralkyl;
Rx is independently selected from alkyl or aryl; and the remaining variables R l, W, Ar, X, Yi Rs, R7, m, n, p, S9 t, q; l, and v are as defined above for Forrnula (I); provided that when B is hydrogen, W is other than CH2(CH2)s, and s is O or 1, and B is hydrogen, W is 2 5 other than S(CH2)S and s is l.

Preferred B substituent groups are tetTahydropyranyl; CH20CH3 when B is ClalkylCl 3alkoxy; CH20CH~CH2Si(CH3)3, CH20CH2CH20CH3 when B is ClalkylC?alkoxyC1 3alkoxy; C(O)Rs~ and C(O)ORs~ with Rs as a Cl ~ alkyl, 3 0 specifically methyl, t-butyl, or phenyl.group and benzyl when Rs is an aralkyl group.
When B is an optionally substituted benzyl the substituent groups ~re selected from Cl-6 alkoxy or C1 6 alkyl.

The hydroxylarnine derivatives of Formula II are easily converted to the cornpounds 3 5 of Formula (I) wherein R4 is NHRsR6 or a hydroxamate derivative using art known ,, ! ` ~ ~ ~ - ; .

" ' '' ~ " ' ' ' ':' WO 91/14674 ~ 6 PCI/US91J02010 proceedures. Various illustrative methods to prepare compounds of Formula (I) are given in U.S. Patent Sumrners et al., 4,873,259, issued October l0, 1989, pages 7-ll whose disclosure is incorporated by reference herein.

The present compounds of Formula (I) can be prepared by art-recognized procedures from known compounds. Several different synthetic schemes can be used to prepare the compounds of this inven~ion and are described in greater detail below. Although the schemes when illustrated uti]ize only one particular compound, the 1,2,3,4-tetrahydronaphthalene derivative, it will be seen from the working exar.nples that other 1 0 compounds of this invention can be prepared in the sarne manner using the appropriate starting materials, such as ~methoxy-l-tetralone, 6-methoxy-2-tetralone, 5-hydroxy-2-tetralone, 7-methoxy-2-tetralone, 5-methoxy-indan-l-one, or 7-methoxybenzo-cycloheptan-l-one. Many additional starting materials are readily available to one skilled in the art, including but not limited to, the various mono- and di-substitu~ed 3-chromanones or 4-1 5 chromoanones or 3-hydroxybenzofuranones, as disclosed in Ileterocvclic Comvounds;
Chromenes. Chromanones. and Chromones. Chapters 3 and 4, Ellis Ed., IntersciencePublication, Wiley & Sons, New York, or in The Chemist~ Qf ~IerQcy~l~ (;;QDQ~lnds, Weissberger, A. and Taylor, E., Editors, Intersciene Publication, Wiley & Sons, New York, Mustafa, A., Chapter V. Benzofuranones.
As a general sumrnary of the synthetic pathways described in greater detail below the compounds of Forrmula (I) and (II) can be produced by the following means:
The compoun~s of Formula (I) can be produced by a process which comprises A. reacting a compound of Forrnula (II) as described above, wherein B is 2 5 hydrogen, (i) with trimethylsilyl isocyanate (TMSNCC)}, followed by work up with ammoniurn chloride to yield a hydroxyurea derivative of a Formula (I) compound wherein R4 is NH2; or (ii) with sodium or potassium cyanate in an acidic solution to yield a 3 0 hydroxyurea deriva~ve of a FoImula (I) compound wherein R4 is NH2; or (iii) with gaseous HCI, followed by treatment with phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroforrnate, such as ethyl chloroformate, resulting in the corresponding c~rbamate;
which is reacted with aqueous amrnonia, or a substituted amine to yield an optionally 3 ~ substituted hydroxyurea derivative of a Formula (I) compound; or (iv) with acetyl chloride and organic solvent, such as triethylamine, to y iel~ithe N,O-diacetate derivative followed by hydrolysis with an alkali hydroxide, such as li~hium hydroxide, to yield a compound of Fonnula (I) wherein R~ is other Ihan NRs~6; or ., . ~

. . .: . . . .

WO 91/14674 2 ~ 7 8 ~ PC~/US9l/0~01~

(v) with an acylating agent, such as acetic anhydride in the presence of a base, such as pyridine, followed by hydrolysis with an aL~cali hydroxide, such as lithium hydroxide, to yield a compound of Formula (I) wherein R4 is a hydroxamic acid derivative;
or S B. reacting a compound of Formula tII) as described above, wherein B is benzyl, substituted benzyl or a benzyl carbonate protecting group, with (i) acetyl chloride in an organic solvent to yield a protected hydroxarnic acid derivative of Formula (I) compounds, which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of alum~nium ~ichloride, to yield a 1 0 compound of Formula (I) wherein R4 is other than NRsR6; or (ii) trimethylsilyl isocyanate as in step A above, to yield protected hydroxyurea derivatives of Formula (I) compounds which is then deprotected, optionally by hydrogenated with ethane thiol in the presence of alurninium trichloride, to yield a compound of Formula (I); or l 5 (iii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate, resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted arnine; which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium ~ichloride, to yield a compound of Formula (I); or 2 0 (iv) sodium or potassium cyanate in an acidic solu~on which is then deprotected, optionally by hydrogenation or wi~h ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or C. reacting a compound of Formula (II) as described above, wherein B is is Si(RX)3, or CH20CH2CH2Si(Rx)3 with 2 5 (i) sodium or potassium cyanate in an acidic solution and deprotected by use of anhydrous fluoride (R4N+)F-, or under mildly acidic conditions, to yield the corresponding compounds of Forrnula (I); or (ii) ~hosgene or a phosgene equivalent, resulting in the correspondin"
carbamoyl chloride interrnediate; or an allcylchloroformate, such as ethyl chloroformate, 3 0 resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or a substituted amine; which is deprotected by use of anhydrous fluoride (R4N+)F-, or under mildly acidic conditions; to yield the corresponding compounds of Formula (I); or (iii) trimethylsilyl isocyanate and deprotected by use of anhydrous fluoride )F-, or under mildly acidic conditions; to yield the corresponding compounds of 3 5 Formula (I); or (iv) acetyl chloride in organic solvent which is then deprotecled by use of anhydrous fluoride ((R4N+)F-, or under mildly acidic conditions, ~o yield the correspondi compounds of Forrnula (I); or .~ - : , ' : . . .
. ~ . . .;
;.- ~ . . .: ..

WO 91/14674 ~ 5 -12- PCr/US91/02010 D. reacting a cornpound of Formula (II) as described above, wherein B is ., tetrahydropyranyl, Clalkyl-C1 3alkoxy, or C1alkylC2alkoxyC1 3alkoxy, with (i) sodium or potassium cyanate in an acidic solution, and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCI to S yield the corresponding compounds of Fo~nula (I); or (ii) phosgene or a phosgene equivalent, resulting in the corresponding carbarnoyl chloride intelmediate; or an alkylchlorofolmate, such as ethyl chloroformate, resulting in the corresponding carbarnate, which is reacted with aqueous ammonia, or a substituted arninc; and deprotec~ed by a rnild acid treatment, such as pyndinium para-1 0 toulenesulphonate in methanol or dilute HCI; to yield the corresponding compounds ofFormula (I); or (ii) with trimethylsilyl isocyanate, then deprotected by a mild acid trea~ment, such as pyridinium para-toulenesulphonate in methanol or dilute HCI; to yield the corresponding compounds of Formula (I); or 1 5 (iii) with acetyl chloride in organic solvent which is then deprotected by a mild acid treatement, such as pyridinium para-toulenesulphonate in methanol or dilute HCI
to yield the corresponding compounds of Formula (I); or E. reacting a compound of Formula (II) as described above, wherein B is t-butyloxycarbonyl with 2 0 (i) sodium or potassium cyanate in an acidic solution, and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-luidine, or with anhydrous etherHCI; or (ii) phosgene or a phosgene equivalent, resulting in the corresponding carbamoyl chloride interrnediate; or an aL~cylchlorofoZmate, such as ethyl chlorofo}mate, 2 5 resulting in the corresponding carbarnate, which is reacted with aqueous ammonia, or a substituted amine; and deprotected by treatment with trifluroracetic acid, tnmethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HCI; to yield the corresponding compounds of Formula (I); or (iii) with trimethylsilyl isocyanate and then deprotected, optionally with 3 0 ethane thiol in the presence of aluminium trichloride by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HCI; to yield the correspondin~r compounds of Formula (I); or (iv) with acetyl chloride in organic solvent which is then deprotected, optionally with ethane thiol in the presence of alurninium trichloride; or by treatment wi~h 3 5 trifluroracetic acid, trimethylsilyltrifilale with 2,~1utidine, or anhydrous elher HCI to viel~l the corresponding compounds of Formula (I~; or F. reacting a compound of Forrnula ~II) as described above~ wherein B is a alkoyl or aroyl with .... ..

.-. .
, ., , ~ , :
, ,, ,, . ~ , : -:. .: . : !
~ ~ :' . ',' ' ' WO 91/14674 PCr/US91/02010 (i) sodium or potassium cyanate in an acidic solution and deprotected wilh :
suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I); or (ii) with trimethylsilyl isocy~mate and deprotectecl with a suitable base, such 5 as potassium carbonate; to yield the corresponding compounds of Forrnula (I); or (iii) with acetyl chloride in organic solvent which is then deprotected by treatment with a suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I).
The compounds of Formula (Il) can be produced by a process which comprises 1 0 A process for producing a compound of the Formula (II) as defined above, whicn process comprises A. reacting a compound of Formula (m) (R2~q ~(R3) R~ (III) wherein R2 and R3 are =O;
1 5 W, Rl, R7, s, q, l, m, v, Ar, S, t, and Y are as defined for Forrnula (II);
with hydroxylamine in solvent to yield the corresponding oxime derivative of Formula (IV) (R2)q ~ (R3) /~ W
R~
wherein R2 and R3 are =N-OH;
W, Rl, R7, s, q, l, m, v, Ar, S, t, and Y are as defined for Formula (II);
2 0 which is then reduced with borane pyridine complex, borane trime~hylarnine, or borane ~etrahydrofuran or other borane complexes, to yield the hydroxylamine derviatives of Formula (II); or B. reacting a compound of Fomnyla (TV) as defined above with sodium cyanoborohydride or phenyldimethylsilane in anhydride in trifluroacetic acid lo yield the 2 5 hydroxylamine derviatives of Fonnula (II); or C. reacting a compound of Formula (V) (Rz)q ~(R3)l R~ (V) wherein R2 and R3 are X;
X is a leaving group, such as a halogen, tosylate, mesylale or a ~iflate moiety;3 0 W, Rl, R7, s, q, 1, m, v, Ar, S, t, and Y are as defined for Forrnula (II);

' '` .' , -WO ~IJ14674 ~ ,6 14 P~/US91/~010 with Z-fur~ulaldehyde oxirne and base to yield the corresponding nitrone of Forrnul~ (VI) which is hydroylzed ~o yield the corresponding hydroxylamine derviatives of Forrnula (11);
D. reacting a compound of Forrnula (V) as described above, with a protected hydroxylarnine to yield the coIresponding protected hydroxylarnine of Forrnula 5 (TT); or E. reacting a compound of the Forrnula (VI) (R2)q ~(R3) /~ - w ~1 (VI) wherein R2 and R3 are OH;
W, Rl, R7, s~ q, 1, m, v, Ar, S, t, and Y are as defined for Forrnula (II) as described above;
1 0 with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylarnine) or bisbenzyloxycarbonyl, and triphenylphosophine/ diethyldia~odicarboxylate to produce ~n intermediate which is treated with acid to yield the hydroxylamines of Forrnula (II).

The homochiral compounds of Formula (T), as well as the homochiral interrnedi~tes 1 5 of Fonr.ula (TI) can be prepared by a process which comprises A. (i) reacting a homochiral oxazolidione of Forrnula (A) O N
\_J"
R (A) wherein R is an optionally substituted aryl, arylmethyl, heteroaTyl, or heteroarylmethyl:
with phosgene or a phosgene equivalent and a base in anhydrous solvent to yield to fonn the 2 0 corresponding acid chloride intemtediate of Forrnula (VTI) O O
O N ~CI
R (VII) (ii) reacting tne Formula (VII) adduct with a chloron~ted hydroc3rbon or e~heralsolvent and base to yield the cor~esponding (+) and (-) cornpound of Forrnula ~II);
2 5 (iii) cleaving the adducts under basic conditions to yield the individual entantiomers of the Fomtula (II) compounds; or B. reacting an optically active alcohol of Fonnula (VT) as defined ~bove, with N,O- :
bis(t-butyloxycarbonyl}hydroxylamine) and triphenylphosophine/ diethyldinzodic~rboxylate to produce an intermediate which is tre lted with ncid lo yield the hydroxylamines of Forrnula 3 0 (IT); or reacting the corresponding opticallv active h;llo or sulfonates of Forrnula (Vl),whictt ,. . ~ . ~ :., . - :

': ; ' ' ' . ~

WO 9l/14674 2 0 7 81 ~/US91/0~010 may be optionally protected with a base, such as triethylamine, or pyridine; are then optionally deprotected to yield the forrnula (II) compounds, which are optionally reacted under any of the various pathways described herein to yield optically active fin31 compounds of Formula (I); or C (i) reacting an optically active amine of Forrnula (Vl~l) (R2~q (R3)l R, (VI~) wherein R2 and R3 are NH2;
W, Rl, R7, s, q, 1, m, v, Ar, S, t, and Y are as defilned for Forrnula (II);
with 4-methoxybenzaldehyde in trimethylarnine;
1 0 (ii) oxidizing the interrnediate of step (i) to yield the corresponding oxaziridine;
(iii) reacting the oxa~iridine of step (ii) under acid conditions to yield the hy-droxylarnine salts of Formula (II) compounds; and then optionally reacting under the various pathways dçscribed herein to yield optically active final compounds of Forrnula (I); or D. reacting the. optically active amine of Formula (VIII) as described above with 1 5 dimethyldioxirane or a peracid anhydride, such as benzoyl peroxide, to yield the protected chiral hydroxylamine of Formula (II) compounds; which may be optionally deprotected to yield the final compounds of Formula (II); and optionally reacted by the various pathways described herein to yield optically active final cornpounds of Forrnula (I); or E. reacting the optically active alcohol of Formula (VI) as described above with2 0 diphenylphosphoryl azide and triphenylphosphine l diethyldiazodicarboxylate (DEAD) producing the optically active azide intermediate which can be reduced to produce the optically active amine used in Step C, parts ~i) and (ii) above; and optionally reacted by the various pathways described herein to yield optically active final compounds of Formula (1).
.....
2 5 The compounds of Formula (I) can be prepared according to the following synthetic route, as displayed in Scherne I below:

., ~ . . .

.

. . .
. . . . ..

WO 91/14674 ~ 1~ PCI/llS9lt02010 o o ~ EtS~ 1)KH ~DMF
MsO~J DMFHO~J 2) l~nzylbromide o N~O
~1 NH20H/ HCI ~ B~b in PhCHz--O ~ PhCH2--O~V 6N HCI

H~OHOH ~C~

~ 1 ) TMS N,C=O ~
PhCH2-O~J 2) aq, wor~p PhCH2--O~J

SCHEME I

In scheme I, compound 1 or any other suitable alkoxy derivative may be treated by a known means to remove the alkyl portion of the alkoxy group, such as using a S solution of sodium ethanethio}ate in a solvent, such as dry DMF, to which the alkoxy derivative is added and heated. Following concentration of the reaction and addition of an organic solvent, such as ethyl acesase, an aqueous acidic workup yields the corresponding hydroxy derivative 2. The hydroxy compound 2 is then ~reated with a metal hydride, such as potassium hydride, and after the gas evolution subsides, a benzylhalide or phenylethyl 1 0 halide, such benzylbrorn~de, is added. After stirring and concentrating, the residue is dissolved in an organic solvent, such as ethyl acetate, and washed with acid, preferably hydrochloric, to yield after a s~ndard aqueous workup the benzyloxy denvative 3.Compound 3 is then converted to the corresponding oxime 4 by addition of hydroxylarnil-e hydrochlonde in a solvent, such as pyridine ~d heated for about 30 minutes ~o about '~
1 5 hours. The oxime 4 is reduced to the corresponding hydroxylamine i by addition of a borane/pyridine c~mplex to which is added, after stirring an acidic solution, preferably 6N
HCI. Borane dimethylsulfide in tetrahydrofuran may also be used. Addition of an alkali metal hydroxide, such as NaOH, and extraction into an organic solven~, for example ethyl ether or CH2C12, yields the hydroxylamine 5. The hydroxylamine is converted to the 2 0 corresponding hydroxyurea 6 by addition of trimethysilylisocyanate and heating followed by an aqueous/organic workup.

" ... ,~. . . . . ..

: : . . ~.
... ... ...
. : . ~ . ,, . , . , ~ ,. ..

Wo 91/14674 PCr/l:lS91/02010 -17- 2~7~126 The hydroxamates can also be produced in a similar manner from the same interrnediate 5 which is then converted to a diacetate interrnediate by addition of an acylatin!
agent, such as acetyl chloride (about 2 equivalents), with triethylamine ~about 3 equivalent~) in methylene chloride for about 30 minutes. Acetic anhydride in the presence of other b;lse~
5 such as pyridine will also work. The O-acetate moiety is removed by hydrolysis with an alkali metal hydroxide, such as lithium hydroxide, to yield the corresponding hydroxamic acid of Formula (1). The oxime 4 or O-protected derivatives, such as the acetate, may also be reduced by borane-trimethylamine, borane-tetrahydrofuran, sodium cyanoborohydride in methanol, or other borane compounds.
1 0 Another synthetic route to prepare the compounds of Formula (I) is described in Scheme II, illustrated below.
o o ~1) N-Ph~nyltrifluromethane- ~ B(CH2CH2Ph)3 ll suHonimide, base OH--~ ~~ ~ --~ TfO~ ~ Pd / Ptphh OH
~~ 1) NH20H NH

8 H~N)~NH ~TMS-N2C.O
2) aqueous workup SCHEME II

1 5 The hydroxytetralone derivative 2 is modified to contain an active le~ving group, such as the triflate indicated in 7. Other acceptable leaving groups are the bromides, chlorides, iodides, tosylates, and mesylates. Using a bidentate Pd (II) cat31yst, such as PdC12 (dppf) or Pd(PPh3)4, or any other acceptable coupling agent, and a tris(phenethyl)-borane derivative, using the method of Sukuki (A. Suzuki et. al. J.A.C.S., 111, pgs.314-2 0 321, 1989) results in the addition of the appropriate Rl group to yield the co~Tesponding tetralone compound 8. The above cited procedure is especially useful for the prepar3~ion of compounds in which Rl is an alkyl group. The use of other organometallics, such as alkylzinc, -lithium, -tin or -aluminum reagents may also be useful when R I is an alkyl group (see references cited in Suzuki paper). Additional w~ys of coupling using a 2 5 palladium catalysis and organoborane (A. Suzuki, Pure_& Appl. Chem., 57, pgs. 1749-, WO 91/14674 ca~ Pcr/us9l/o2o~o 1758, 1985), organozinc (R. Keenan et. al., ~L Qmrr~uL, 19, pgs.793-798, 1989), or organotin (J. K. Stille, An~ew~ Chem. lnt, Ed., 25, pgs. 508-524, 1986) compounds ma~
also be useful in this process step when Rl is an ~ryl or olefinic group. Also po~endally useful when Rl is an alkyl, a~yl, or olefinic group is the copper mediated coupting of aryl trifaltes, such as 7, using the procedure~of McMurry (J. E. McMurry et. al., Tett. Lett., ~, pgs~ 2723-2726, 1983). The ketone 8 is converted to the hydroxylarnine 9 by reaction w ith hydroxylamine, and subsequently reduced with borane in pyridine and hydrochloric acid.
The hydroxylamine 9 is converted into the corresponding hydroxyurea 10 by the method outlined in Scheme I. The hydroxylamine 9 is also converted into the corresponding 1 0 hydroxamate by the method outlined above for Scheme I.
Alternatively, the hydroxyureas of Forrnula (I) wherein R4 is NRsR6 is a substitu~ed amine or cyclic amine can be prepared by reaction of the appropria~ely subsdeuted hydroxylamine hydrochloride of Formula ~I) wi~h phosgene to yield the acyl chloride inte~nediate which is reacted with the appropriate arnine to yield the compounds of 1 5 Formula (I).
An additional alternative to the use of phosgene is an alkyl chloroformate, such as ethyl chlorofortnate, in which case the resulting R4 term of Formula (I) will determine the reaction time and temperature needed for the ~eaction to proceed, i.e. at O C or below or, if slow at an elevated temperatures of 100-200 C in the appropriate solvent.
2 0 The preparation of the hydroxyureas of Fonnula (I) when -OB is a protecting group, as opposed to ~he free hydroxyl proceeds in a similiar manner. The protected hydroxylamine is reacted wi~h phosgene or a phosgene equivalent, such as carbonyl diimidazole or phosgene trimer yielding a protected hydroxylamine interrnediate which is reacted with an appropriate amine component (NHRsR6) ~o yield the protected hydroxyure~
2 ~ of Formula (I). Alternatively, the reaction of the protected hydroxylamine with trirnethylsil)~l isocyante or with sodium or potasium cyanate in an acidic solution as discussed above m~y be employed to prepare the protected hydroxyurea of Formula (I). This is followed by any means appropriate for the deprotection of the -OB group. Deprotection of the hydroxyl M~IV
be by hydrogenation with H2/Pd/C when B is benzyl, by mild acid treatrnent, such3 0 pyridinium para-toluenesulphonate in refluxing methanol or dilute HCI when B is tetrahydropyranyl, by a suitable base, such as potassium c~rbonate when B is an alkoyl or aroyl, by use of anhydrous fluoride (R4N~)F- when B is Si(RX)3, or by treatmen~ wi~h ~ifluoroacetic acid, t;imethylsilyltrifilate with 2,~1utidine, or anhydrous ether HCI when B
is t-butyloxycarbonyl. In general, suitable protecting groups ~nd methods for their remov;ll -3 5 will be found in T.W. Greene~ Protective Groups in Orp~anic Svnthesis. Wiley, New Yor~
lg81.
A hydroxyl lmine which is protected, such as O-benzylhydroxvlamine or O-tetrahydropyranyl hydroxylamine, or other O-protected hydroxylamines can also be used tV

. ,', .`
~, , ';~

Wo 9l/14674 PCr/US9l/02010 -l9- 207812~
pr~duce the hydroxyureas of Formula (I) using as a starting material a compound having ;ln active leaving group X ( in structure 11, Scheme III replace OH with X), such as Cl, Br, OMs, or OTs by ~eaction with the hydroxylamine (NH2-OB) with heating in an appropria~e solvent to yield a protected intermediate of Formula (II). The protected intermediate may then be deprotected using the standard removal conditions for the protecting group employed to yield the free hydroxylamines of Formula (II), or the protected intermediate may used as outlined above to prepare the ~protected hydroxyurea and then deprotected tO
yield the final compounds of Formula (I). Similarly, the above noted process can be used to make the s~arting amine compounds, chiral or not, as so desired, by use of NH3, or N3 and 1 Q suitable reduction step, all well known to those skilled in the art.
The starting compound, a halo compound can readily be prepared from the mesylate or toyslate derivatives (benzylic sulfonates are highly reactive and thus in most cases are used as non-isolated intermediates~ or can be produced directly by a number of art known procedures from the corresponding alcohol. The mesylates or tosylate derivatives 1 5 can be prepared from the ketone derivatives by reduc~on to the corresponding alcohol by any number of readily available agents, such as sodium borohydride, or lithium aluminum hydride. The alcohol is then reacted with mesyl or tosyl chloride in the presence of an appropriate base, for example pyridine or triethylarnine, with or without additional solvent to form the mesylate or tosylate derivatives which are in turn displaced, for exarnple either 2 0 by in situ reaction or in a subsequent reaction with lithium chloride or bromide in acetone, ~o form the corresponding halogenated derivatives.
Selected examples of protected compounds of Formula (II) may also prepared by reaction of the alcohol 11 with a protected hydroxylamine, such as O-benzyl hydroxylarnine or O-t-butyldiphenylsilyl hydroxylarnine under solvolytic conditions, for 2 5 example in the presence of trifluoroacetic acid. The protected interrnediate may then be deprotected using the standard removal conditions for the protecting group employed to yield the free hydroxylamines of Formula (II), or the protected interrnediate may be converted first to the protected urea and then to the final compounds of Forrnula (I) as discussed above.
3 0 Another synthetic pathway which will produce the hydroxylamines of Forrnula (ll) and may also used to prepare the optically active inte~nediates, if the optically active alcohol derivative is used as a starting material is illustrated in Scheme III below. The alcoholic star~ing material 11 is treated with N,O-bis(t-butyloxycarbonyl)hydroxylamine and triphenylphosphine / diethyldiazodicarboxylate (DEAD) producing the intermediate 12 3 5 which is then treated with an appropriate acid, such as trifluroacetic acid or hydrochloric acid, eo produce the free hydroxylamines of Forrnula (II). The op~ically active alcohol 11 may be prepared by enantioselective reduction of the corresponding ~etone precursor with an appropriate reducing agent (M. Kawasaki et. al., Chem. Pharm. Bull., 33, pgs 5~-60, .

, WO 9]/14~74 ~ 6 PCr/US9l/02010 20- ^

1985 or D. Mathre et. al., J~Qr~. ~he~" 56, pgs 751-762 and references cited therein).
The thus obtained optically active alcohol may also be converted to the corresponding optically active halo or sulfonate compound (see D. Mathre, compounds of Formula (II).
Such steps as noted above are obviously useful as well to make the racemic mixture.
The alcoholic starting material llL is treated with diphenylphosphoryl azide andtriphenylphosphine / diethyldiazodicarboxylate (DEAD) producing the optically active azide which can be reduced to the optically active amine 13.
o o Rl~C/ E~O~CN NCD~ Ph3P ~CO/\N_o o 1 1 Mr~3CO N-O Rl ~/ritluroacetic acid or hydrochloric acid S C H E M E I I I Fommula (Il) hydroxylamine compounds 1 0 An additional route for preparation of the optically active compounds of Formula (I) is detailed in Scheme IV below. The sequence st~ts with optically active arnines, obtained through a variety of methods including the classical methods of preparing salts with chiral acids, such as carnphor sulfonic acids, such techniques being readily apparent to those r skilled in the art. The requisite racemic amine can be prepared from the alcohol 11 or 1 5 activated derivatives thereof, by the methods previously outlined above, substituting ammonia for (un)substituted hydroxylamines. One available review for resolving racemic compounds is by R.M. Secor, Chern. Rev., 63, 197 (1963). The starting materia113 is either the pure "R" or a pure "S" configuration which is then reacted to forrn the intermedi;lle 14 with ~methoxybenzaldehdye in triethylamine. The intermediate 14 is then oxidized by 2 0 a variety of agents, such as MCPBA (metachloroperbenzoic acid), MPP
(monoperoxyphthalate) or MMPP (magnesium monoperoxyphthalate) to yield the oxaziridine derivative 15 which under acidic conditions then yields the hydroxylamine sal~
16. The general procedure can be found in Polanski et al., Tetrahedron Letters., 28, ~453-2456 (1974). Alternatively, the optically active arnine 13 may be conver~ed directly to the 2 5 chiral hydroxylamine 16 using dimethyldioxirane (Danishesky, et.al. J. Or~. Chem., vol .
55, pl981-1983, 1990) or a peracid anhydride, such as benzoyl peroxide (R.M. Coates et.al., J. OrE. ~hem., vol. 55, 3464-3474, 1990).

. . --. - -: . ~ . . ..

WO 91/14674 PC~/US~1/02010 -21- 2~7~12~
o R ~ ~ R~ 1 ~

id~ on H~,OH ~ HCI O
2,2-dimethyldioxaran~ ~ H' H N~
or b6n~oyl p~roxid~; basi~~ U
hydrolysis R /~ W R ,~ W ~OM~

SCHEME I V
An additional method for obtaining the homochiral hydroxyureas of formul;
II is to forrn diastereomeric adducts of the racemic hydroxyureas or hydroxarnates which may then be separated by a variety of commonly used techniques, including flash 5 chromatography and HPLC. This approach is illustrated in Scheme V. Reaction with a homochiral oxazolidinone, for example 4-(phenylmethyl)-2-oxazolidinone (see Ore. Svn., John Wiley & Sons, Inc., vol.68, p77 for preparation), with phosgene or a phosgene equivalent, such as phosgene trimer or carbonyl diimidazole, and a base in an anhydrous solvent, preferrably with NaH in toluene at reflux and then adding to this cooled solution at 1 0 about -70C to about 20 C, preferably about -30 to about 0C for use with phosgene.
Should a phosgene equivalent be used to temperature lange will be from about 20C to about 200 C. The thus formed interrnediate, for earnple, when phosgene is used, a chloro c~rbamate may be isolated.
Addi~onal 4-substituted chiral oxazolidinones which may also be used are 1 5 optionally substihlted (R groups) aryl, arylmethyl, heteroaryl, or heteroarylmethyl wherein the substituents include, but are not limited to, mono or disubstituted alkyl, halo, alkoxy, cyano, or any other protected amino, alcohol, carboxy, or sulfur (regardless of oxidation stat~). Additionally R can be an alkyl moiety of greater than 2 carbons, preferably longer, such as t-butyl or isopropyl, which may be optionally substituted as well. Representative 2 0 examples of the aryl and heteroaryl groups include, but not lirnited to phenyl, naphthyl, pyrrolyl, thienyl, thiazinyl and furanyl. These oxæolidinones are prepared from the chiral amino alcohols which are readily available from reduction of the chiral arnino acids by the general procedure of Evans fOr~Svn., John Wiley & Sons, Inc. Vol. 68, p77 and references cited therein~ which are incorporated by reference herein.
2 5 Addition of this adduct to a solution containing the hydroxyurea in a chloronated hydrocarbon or etheral solvent, preferably CH2CI2 and a base (either an amille base such as ~rialkylarnine or pyridine or a solid allcali metal carbonale, such ~s potassium or calcium, but most preferably triethylarnine) affords the diastereomeric adducts, 17A and - , , . . :, - ~
, . . . .
..
, , . - :

WO 9ltl4674 ' 6 Pcr/us9l/o2o1o 22- `

17B. Chromatography or other physical methods are employed to separate these adducts which are then cleaved under basic conditions, for example using an alkali metalhydroperoxide, such as lithium, in an-aqueous-etheral solvent tl~ , glyme, digylme, ethyl ether ) at about -20 to about 50C, preferably from about -5C to about room temperature, 5 more preferably from about OC to about 15C to yield the individual enantiomers of the hydroxyurea .

o o R'~ ~ ~ ' O j ~ plus O
HO`N W h_N~,o~N~,. oh~ ~ ~
O Nl-t2 NH2 0 NH2 17rl (S,S)-diasterr~ornor 17b-(S,R)diasleraorner 1.) soparate diastoroornors by chrornalography or rocrystalllzalion .
2.) hydrolyze to yeild individuai ~ onantiorners using aqueous basa H~RN~W HO N~W
O~NH2 O~NH2 (S) isomar (Rj-isorner SCHEME V
For the preparation of compounds in which W contains nitrogen a synthetic 1 0 sequence sirnilar to that outlined in Scheme I is employed tillustrated in Scheme VI). The starting materials 18 shown in Scheme VI can be prepared by the method of Kano et al ( J.C.S. Perkin I, pgs 2105-2111, 1980 and references therein) or when R1 = OMe by dealkylation/ refunc~onalization as described in previous examples (Schemes I and II).
When R2 is alkyl or substituted alkyl, this group is attached by reaction of 18 using the 1 5 appropriate base catalysis and alkylating reagent. When R2 in the final product 20 is to be hydrogen, then protection of 18 by forrnation of the carbamate 19 is required (R ~ =
CO2R3). Following transformation to the protected hydroxyurea 20, the nitrogen is depro~ected, for example with acid or fluoride when R3 is t-butyl or trimethylsilylethyl respec~ively. Enantiomerically pure compounds can be prep~red from 19 using the 2 0 procedures outlined above (Schemes III and IV plus text) or from 20 (R3 = alkyl or substituted alkyl or COR3) by resolution (Scheme V).

. ; . . ..

: . . . ::

WO 91/14674 . P~/US91/02û~0 -23- 2l~78126 R~ 1) NaH ~DMF

1~ ~9 NH~O~U HCI \~ BH3 in i I - ~ li I ~
~N ~ ~ ~N~ 6N HCI `' Il , , H~OH OH /C~

R1~ 1) TMS N=C=O ~
N 2) dsprotect NH (R2) R2 = alkyl, substitut6 d alkyl or CO2R3 whe~c R3 is t-butyl or trin~thylsilyl~thyl SCHEME V I
Compounds in which q= 0 and I = 1 (Forrnula (I)) can be prepared by the 1,2 carbonyl transposition of tlle ketone intermediates used to prepare compounds in which 5 q= 1 and I = O (Scheme VII). Many such 1,2 carbonyl transposition procedures are kno~ n (see Tetrahedron, 39, p345, 1983 for review). A particularly useful and general procedure is the reduction, dehydration, hydroboration-oxidation sequence ( see Kirlciacharian, B.S.et. al., SYnthesis. p815, 1990 for hydroboration-oxida~ion). When W containsnitrogen, suitable protection is required to effect this transformation. Protecting groups 1 0 such as those previously outlined are applicable. When W is sulfur the oxidation of the borane to the ketone may afford sulfur oxidation products, sulfoxide or sulphones. In eases where selective reduction of the oxidized sulfur is not possible alternative routes are employed.
R~ R~Q R~o Scheme Vll . ~' , ' ' ' ' .. .

: ~ '' ' ~ ' ~ "' "" ; : -WO 91/1~674 ~ PCr/US91/02010 Pharmaceutically acceptable base addition salts and their preparation are well known to those skilled in pharrnaceuticals. Pharmaceutically acceptable bases (cations) of the compounds of Folmula (I) which are useful in the present invention include, but are no~
lirnited to nontoxic organic and inorganic bases, such as ammonium hydroxide, arginine, 5 organic amines such as triethylamine, butylamine, piperazine and (trihydroxy)methylamine, nontoxic aL'kali metal and aL~caline earth metal bases, such as potassiurn, sodiurn and c~lcium hydroxides~ Pharmaceutically acceptable acid addition salts of the compounds of Formula (I) which are useful in the present invention include, but are not limited to, maleate, fumarate, lactate, oxalate, methanesulfonate, ethane-sulfonate, benzenesulfonate, tartrate, 1 0 citrate, hydrochloride, hydrobrornide, sulfate and phosphate salts and such salts can be readily repared by known techniques to those skilled in the art.

M~OD QF TREATMEl~T :
It has now been discovered that the compounds of Formula (I) are useful for treating 1 5 disease states mediated by the 5-lipoxygenase pathway of arachidonic acid metabolism in ;~n animal, including mamrnals, in need thereof. The discovery that the compounds of Formul:
(I) are inhibitors of the 5-lipoxygenase pathway is based on the effects of the compounds ol`
Forrnula (I) on the production of 5-lipoxygenase products in blood ~. vivo and on the 5-lipoxygenase m vitro assays, some of which are described hereinafter. The 5-lipoxygenase 2 0 pathway inhibitory action of the compounds of Forrnula ~I) was confirmed by showing that they impaired the production of 5-lipoxygenase products such as leukotriene B4 production by RBL-1 cell supernatants. It has also been found, unexpectedly that the compounds of Formula (I) possess analgesic activity, using the phenylbenzoquinone writhing test. It has further been found that the compounds of Forrnula (I) do not appear to inhibit prostagl~ndin 2 5 production l!L vitro and are therefore selective S-?ipoxygenase inhibitors. Test data presented in this specification is consistent with the premise that the mechanism of analgesic activity of the compounds of this invention is distinct and independent of the mechanism of action commonly associated with cyclooxygenase inhibitors.
The pathophysiological role of arachidonic acid rnetabolites has been the 3 0 focus of recent intensive studies. In addition to the well-described phlogistic activity (i.e.
general inflammatory activity) of prostaglandins, the more recent description of similar activity for other eicosanoids, including the leukotrienes, has broadened the interest in these products as mediators of inflammation [See, O'Flaherty, Lab. ~nvest., 47, 314-329 (1982)]. The repor~ed discovery of potent chemotactic and algesic activity for LTB4 [see, 3 5 Smith, Gen. PhannacoL, 12, 211-216 (1981) and Levine et al., $cience, 225, 743-745 (1984)J, together with known LTC4 and L11)4-mediated increase in capillary permeabili~v [see, Simmons et al., Bi~chem. Pharrnacol., 32, 1353-1359 (1983), Vane et ~1., ~g~, 21, 637-647 (1981), ~nd Camp et al., Br. J. Ph;lrrn~col., ~(), 497-502 ~ . ~ . .. .

.: . . .., ~
, : :, . .

Wo 91/14~74 ` PCr/US9l/02010 2~78l2~
(1983)], has led to their consideration as targets for pharmacological intervention in both the fluid and cellular phases of inflarntnatory diseases.
The pharrnacology of several inflamrnatory model systems has attested to th~
effectiveness of corticosteroids in reducing the cellular infiltration. These results, and the ;
observation th~. corticosteroids inhibit the generation of both cyclooxygenase and lipoxygenase products, suggest that such dual inhibitors may effectively reduce both the flllid and cellular phases of the inllammatory response since selective cyclooxygenase inhibitors do not reliably inhibit cell influx into inflarnmatory sites [See, Vinegar et al., Fe~.
Proc~, 35, 2447-2456 (1976), Higgs et al., ~rit. Bull., ~, 265-270 (1983), and ~iggs et 1 0 al., Prostag!andins. I.~eukotriençs lld Medicin~, ~, 89-92 (1984)]. Under optimal conditions, it is likely that an agent with preferential lipoxygenase inhibitory activity would not share the ulcerogenic liability of cyclooxygenase inhibitors or the toxicity of corticosteroids. This may suggest that the compounds of the present invention could be useful in treating diseases, such as osteoarthritis, where it is beneficial to limit ulcerogenic 1 5 activity or steroidal side effects. [See Palmoski et al., "Benoxaprofen Stimulates Proteoglycan Synthesis in Norrnal Canine Knee Cartiledge in Vitro," e~rthritls and Rheumatisrr~ 26, 771-774 (1983) and Rainsford, IC.D., A~ents ans~cttons 21, 316-319 (1987).]
Clinical data supports the enthusiasm for inhibitors of the 5-lipoxygenase 2 0 pathway in a variety of inflarnmatory diseases in which granulocyte and/or monocyte infiltration is prominent. The reported demonstra~ion of elevated levels of LTB4 in rheumatoid arthritic join~ fluid [See, Davidson et al., Ann. Rheum. Dis~, 42, 677-679 (1983)] also suggests a contributing role for arachidonic acid metabolites in rheumatoid arthritis. Sulfasalazine, which is used for treatment of ulcerative colitis, has been reported 2 5 to inhibit LTB4 and 5-HETE production in vitro [See, Stenson et al., l. Clin. Invest., 69, 49~497 (1982)]. The recently reported preliminary observation of efficacy, including remission, reported with sulfasalazine treatrnent of rheumatoid arthritic patients [See Neumann et al., Brit. Me~. J~, ~, 1099-1102 (1983)] illustrates the utility of inhibitors of the S-lipoxygenase pathway in Fheumatoid anhritis.
3 0 Additionally it has been reported that inflamed gastrointestinal mucosa ~rom inflarnmatory bowel disease patients showed increased production of LTB4 [See, Sharon et al., Gastroenterol~, 84, 1306 (1983)1, which suggests that sulfasalazine can be effective b!~
virtue of inhibition of production of chemotactic eicosanoids (such as the 5-lipoxygenase pathway product known as LTB4). The observations serve to underscore utility of 3 5 inhibitors of the 5-lipoxygenase pathway in inflamrrlatory bQwçl disease.
Another area of utility for an inhibitor of the 5-lipoxygenase p~thway is in the treatment of psoriasis. It was demonstrated th~t involved psoriatic skin h~d elev~ted levels of LTB4 [See, Brain et al., Lancet, 19, February 19, 1983]. The promising effect of .
.. . .. . ... .
, ,. ~ ." ,, .
- - , . . .. ...

WO91/14674 ~ 26- PCl/US91/02010 , benoxaprofen on psoriasis [See, Allen et al., Bri~. 1 ~matol., 1~9, 126-129 (1983)], a compound with in ~_ lipoxygenase inhibitory activity lends support to the concept that inhibitors of the 5-lipoxygenase pathway can be useful in the treatment of psoriasis.
Lipoxygenase products have been identified in exudate fluids from gouty patients. This disorder is characterized by massive neutrophil infiltration during the acute inflammatory phases of the disease. Since a major 5-lipoxygenase product, LTB4, is produced by neutrophils, it follows that inhibition of the synthesis of LTB4 may block an arnplification mechanism in gout.
Another area in which inhibitors of the 5-lipoxygenase product can have 1 0 utility is in myocardial infarction. Studies in dogs with the dual inhibitor, BW755-C, demonstrated that the area of infarction following coronary occlusion was reduced, and such reduction was at~ibuted to inhibition of leukocyte infiltration into the ischaemic tissue [See, Mull~ne et al., ~, ~, 510-522 (1984)].
Yet another area in which inhibitors of lipid peroxidation involved in the 1 5 OPUFA mediated can have utility is that generally refered as degenerative neurological disorders, such as P~rkinson's disease. Another area is that of traumatic or ischemic injuries, such as stroke, brain or spinal cord il~juries and inflarnmatory disease of the brain and spinal column. More specicially preferred disease states are the mycardial induced ischemic injuries and/or reperfusion injuries. [See, Braughler et al., Jour~ Biol. ~hem., 2 0 Vol. 262, No. 22, pplO438-40 (1987), see also Xu et al., ~. Neuro~hemistrv"~, 907-91 (1990); Asano et al., ~_ 10:101-133 (1989) and Bracken et al., NE. J. Med., 322: 1405-1411 tl990)]
Yet another area of utility for inhibitors of the 5-lipoxygenase pathway is in the area of prevention of rejection of organ transplants. [See, e.g., Foegh et al., Adv.
2 5 Prosta~landin~Throm~Q~anç. and l,euk~trier~e~earch, 13, 209-217 (1983).]
Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of tissue trauma. [See, e.g., Denzlinger et al. Science, 230 (4723), 330-332 (1985)].
Furthermore, another area of utility for inhibitors of the 5-lipoxygenase 3 0 pathway is in the treatment of inflammatorv reactiQn in the cen~Lnervous svs~m, includin~T, multiple sclerosis. [See, e.g., Mackay et al., Clin. Exp. Immunolo~y,15, 471-482 (1973)].
Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the treatment of ~h~. [See, e.g., Ford-Hutchinson, J~A~le~$y ~lin. Immunol., ~, 437-44() (1984)]. Additionally another utility for inhibitors of the 5-lipoxygense pathway is in the 3 5 ~reatment of Adult Respitory Distress Syndrome. [ See, e.g., Pacitti et. al., ~ Shnck, 21. 155-168 (1987)~. Yet another utility for inhibitors of the 5-lipoxygen.~se pathw~y is in the treament of allergic rhinitis.

WO 91/14674 PCr/US91/0201t) 207812~ 1 Another area of utility for inhibitors of the S-lipoxygenase pathway is in the treatment of vasculi~is, glomerulonephritis, and immune complex disease. [See Kadison e~ "
al., "Vasculitis: Mechanism of Vessel Darnage" in 1~_ (~liniçal l:~orrelate~, 703-718, Ed. Gallin et al., Raven Press, N.Y., N.Y. (19~8).]
Another area of utility for irlhibitors of the S-lipoxygenase pathway is in the treatrnent of dermatitis. [See Pye et al., "Systemic Therapy" in ~ tbook Qf De~na~lQ~, Vol. III, 2501-2528, Ed. Rook et al., Blackwell Scientific Publications, Oxford, England (1986).]
Another area of utility for inhibitors of the S-lipoxygenase pathway is in the 1 0 treatment of atherosclerosis. Recent studies have shown that inhibition of oxida~ive modification of low density lipoprotein slows progression of atherosclerosis, and ~hat inhibitors of lipoxygenase effectively inhibit cell-induced oxidative modification. [See Carew et al., Proç. Natl. Acad. Sci. U~, ~4, 7725-7729, Novem~er 1987; and Steinber,!, D., Cholesterol and Cardi~vascularDisease~76, 3, 508-514 (1987).]
l S An additional area of utility for inhibitors of the S-lipoxygenase pathway is in the opthamalogic area, in par~cular general inflammation of the corneal anterior and posterior segments due to disease or surgery such as in post surgical inflarnmation, uveitis, and allergic conjuntivitis. [See Rao N. et al. Ar~h~hathmal. l0~ (3) 413-419 (1987);
Chiou, l,. and Chiou, G. I. Q~L~r Pharmacol. 1, 383-390 tl985~; Bazan H., I,Q~
2 0 Phannal 4, 43-49 (1988); and Verbey N.L. et al., ~rent Eye Resçarch l. 361-368 (1988).]

FORM~TION OF P}~ARMACEU~ÇAI. COM~O~ITION~
The pharrnaceutically effective compounds of this invention are adrninistered 2 5 in conventional dosage fotms prepared by combining a compound of Forrnula (I) or (Il) ("active ingredient") in an amount sufficient to produce S-lipoxygenase pathway inhibiting activity with standard pharTnaceutical carriers or diluents according to conventional procedures. These procedures may involve rnixing, g!ranulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
3 0 The phalrnaceutical carrier employed may be, ~or example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesiurn stearate, stearic acid and the like. Exemplary of liquid carriers are 53TUp, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl monoste~ate or glyceryl 3 5 distearate alone or with a wax.
A wide variety of pharmaceutical forrns can be employed. Thus, if n solid ca~rier is used, the preparalion can be tableted, placed in a hnrd gelatin c~psule in powder or pellet forrn or in the form of a troche or lozenge. The amount of solid c~Tier will vary :.
.
,~ ~ ., .. - :.
' .,:,., " . . . '~`
.. .
:

WO91/14674 ~ ~ P~r/US91/02010 widely but preferably will be from about 25 m~. to about 1 g. When a liquid carrier is useLI, the preparation will be in the forrn of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an arnpule or nonaqueous liquid suspension.
Preferably, each parenteral dosage uni~ will contain the active ingredient [i.e., the compound of Formula (I)] in an amount of from about 30 mg. to abou~ 300 mg.
Preferably, each oral dosage will contain the active ingredient in an arnoLmt of from about 50 mg to about lO00 mg.
The compounds of Formula (I) may also be administered topically to a mammal m need of the inhibition of the 5-lipoxygenase pathway of arachidonic acid 1 0 metabolism. Thus, the compounds of Formula (1) may be administered topically in the treatment or prophylaxis of inflarnrnation in an animal, including man and other matnmals, and may be used in the relief or prophylaxis of 5-lipoxygenase pathway mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other a~hritic conditions, inflarned joints, eczema, psoriasis or other inflammatory skin conditions 1 5 such as sunbum; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
The amount of a compound of Formula (I) (hereinafter referred to as the active ingredient) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the inflammatory condition and 2 0 the ar~irnal undergoing treatment, and is ultimately at the discretion of the physician. A
suitable anti-inflammatory dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being l mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
By topical administration is meant non-systemic adrninistration and includes 2 5 the application of a compound of Formula (I) externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, in~aperitoneal and intramusculat administration.
While it is possible for an active ingredient to be adrninistered alone as the 3 0 raw chemical, it is preferable to present it as a pharrnaceutical formulation. The active ingredient may comprise, for topical adrninistration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weigh~ of the fo~mulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the fo~nulation.
3 5 .The topical forrnulations of the present invention, both for veterin~ry and for human medical use, comprise an active ingredien~ together with one or more acceptable caIrier(s) therefor and optionally any other therapeutic ingredient(s). The c~Tier(s) musl b~

, ,, ''' '' ~' WO 91/14674 -29- 2 ~ 7 8 1 2~us9l~o20l0 'acceptable' in the sense of being compatible with the other ingredients of the forrnulation and not deleterious to the recipient thereof.
Forrnulations suitable for topical adrninistration include liquid ar semi-liquidpreparations suitable for penetration through the skin to the site of inflammation such as:
S liniments, lotions, creams, ointrnents or pastes, and drops suitable for adrninistration to th~
eye, ear or nose.
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcholic solution of a bactericidal and/or fungici~al agent and/or any 1 0 other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-lOO~C. for half an hour.
Altematively, the solution may be steriliæd by filtration and transferred to the container by an aseptic technique. Exarnples of bactericidal and fungicidal agents suitable for inclusion h 1 5 the drops are phenylrnercuric nitrate or acetate (0.002%), benzalkonium chloride ~0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Lotions according to the present invendon include those suitable for applicadon to the skin or eye. An eye lodon may comprise a sterile aqueous solution 2 0 optionally containing a bac~ericide and may be prepared by methods similar tO those for the preparation of dsops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointrnents or pastes according to the present invention are semi-2 5 solid forrnulations of the acdve ingredient for external application. llley may be made bymixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such 3 0 as almond, corn, arac31is, castor or olive oil; wool fat or its derivatives, or a fat~y acid such as steric or oleic acid together with an alcohol such as propylene glycol. The forrnulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous 3 5 silicas, and other ingredients such as lanolin, may also be included.
The compounds of Formula (I) may also be administered by inhal~tion. Bv "inhalation" is meant intranasal and oral inhalaeion adrninistration. Appropriaee dosage forrns for such adrninistr~tion, such as an aerosol forrnulation or a meeered dose inhaler, WO 91/14674 ~, PCI~/US91/02010 30- ;

may be prepared by conventional techniques. The daily dosage amount of a compound of Formula (I) administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
This invention relates to a method of treating a disease state which is 5 mediated by the 5-lipoxygenase pathway in an animal in need thereof, including humans ~nd other marnmals, which comprises adrninistering to such animal an effective, S-lipoxygenase pathway inhibiting arnount of a Foronula (I) compound. This invention further relates tO ;l method of treating analgesia in an animal in need thereof, which comprisies administering ~o such animal an effective, analgesia inhibiting amount of a compound of Formula (I).
1 0 13y the te~n "treating" is meant eith~r prophylactic or therapeutic therapy. Bv the term "mediated" is meant caused by or exacerbated by. Such Formula (I) compound C;
be administered to such mammal in a conventional dosage form prepared by combining the Formula (I) compound with a conventional pha~naceutically acceptable caTrier or diluent according to known techniques. It will ~e recognized by one of skill in the art that the fom 1 5 and character of the phalTnaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of adrninistration and other well-known variables. The Formula tI) compound is administered to an animal in need of inhibition of the 5-lipoxygenase pathway in an arnount sufficient to inhibit the 5-lipoxygenase pathway. The route of administration may be oral, parenteral, by inhalation or 2 0 topical.
The terrn parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, in~ravaginal or intraperitoneal administration. The subcutaneous and inharnuscular forrns of parenteral adrninistration are generally preferred. The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day.
2 5 The daily oral dosage regir,nen will preferably be from about 100 mg to about 2000 mg per day for both 5-lipoxygenase and algesia treatment.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a Forrnula (I) or (II) compound will be determined by the nature and extent of the condition being treated, the forrn, route and site of administration, 3 0 and the particular animal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the Formula (I) compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
EXAMPLES
Without further elaboration, it is believed that one skilled in the ar~ can~ Usil1"
the preceding description, utilize the present invention to its fullest extent. The following .
. ~, ~ ''': ' ;' ' ' , .. ..

WO 91/14674 -31- 7 ~12 6 pcr/us91/o2o1o examples further illustrate the synthesis and use of the compounds of this inven~ion. The following examples are, therefore, to be construed as merely illustrative and not a limita~ion of the scope of the present invention in any way.
S
E~m~
~hydroxyurea ~ ~Hvdroxv-l-te~lone To a solution of ethanethiol (17 rnL, 230 mmol) in dry DMF (150 1 0 mL) was added slowly NaH t4.5 g of 80% suspension in mineral oil, 150 mmol). When the evolution of gas subsided, 6-rnethoxy-1-tetralone (10 g, 56.8 mmol) was added. The resulting mixture was heated at 150C for 3 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with 3N
HCI, H20 and saturated aqueous NaCI. The solvent was removed in vacuol and the crude 1 5 product ~9.2 g, 100%) was used without further purification.
~1Hz.1H ~1~ (CDC13): ~ 7.98 (d, lH); 6.78 (dd, lH); 6.72 (d, IH); 2.91 (t, 2H); 2.64 (t, 2H); 2.12 (m, 2H).

3enzvloxv-1-tetralQne To a solution of 6-hydroxy-1-tetralone (9.2 g, ~6.8 mmol) in 2 0 DMF (150 mL) was added potassium hydride (2.49 g, 62 mmol). When the evolution of gas subsided, benzyl bromide (10.6 g, 62 mmol) was added. After stirring for 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with 3N HCI, H20 and saturated aqueous NaCI. Removal of the solvent in vacuo and purification by flash chromatography eluting 2 5 with a gradient of 0 - 100% CH2C12/ hexanes yielded the desired product (9.7 g, 73%).
The infrared spectrum of the product indicated a conjugated ketone at 1665 - 1685 cm- l.
The NMR spectrum indicated the presenre of the benzyl methylene at ~ 5 and aromatic benzyl protons at ~ 7.4.

3 0 c~-Benzvloxv-l-tetralQnç oxime To a solution of ~benzyloxy-l-tetralone (9.7 g, 38 mmol) in dry pyndine (100 rnL) was added hydroxylamine hydrochloride (5.3 g, 76 mmol). rhe resulting mixture was heated a~ 50C for 30 min, then was allowed to cool and concentrated under reduced pressure. The residue was cr,vstallized from ethanol to yield the desired oxime (7.3 g, 71%).
d) N-l-f6-BenzvlQxv-l~2~4-tetrahvdrQnaphthvll-N-hv~roxx~minç. To a solution of the oxime prepared above (4.7 g, 17.6 mmol) in 2:1 Et20: MeOH (400 mL) at 0C was added BH3 pyridine complex (7.8 mL, 77 mmol). After warming to room temper~ture and .

, . . , ; . ~

WO 91/14674 ~ 32- Pt~/US91/02010 stirring for 1 h, 6N HCI (10 mL) was added, and the reaction mixture was stirred an additional 2 h. Thin layer analysis indicated that the reaction was incomplete, so additional BH3-pyridine (2 rnL, 20 rnmol) was added, and the rnixture was stirred for 3 h. At this time, more BH3 pyridine (2 rnL, 20 mmol) was added, followed by 6N HCI (30 rnL), and S the reaction was allowed to stir overnight. The reaction rnixture was adjusted to pH 10 with 10% NaOH and extracted with Et2O. The organic extract was washed successively with H20 and saturated aqueous NaCl and concentrated in vacuo to yield the hydroxyamine (4 3 g, 92%), which was used without further purification.

1 0 e) N ~-BenzvLQ2~y-L~3.4-~etrahYdrQn~htbvl)l:~-hyd~oxvu~a To a solution of the hydroxyatnine prepared a~ove (4.3 g, lS.9 rnmol) in dry THF (120 mL) was added trimethy}silyl isocyanate (4.3 mL, 31.8 mmol). After heating at 60C for 1 h, the reaction mixture was concentrated in va~uQ. The residue was dissolved in EtOAc, washed successively with H2O, saturated aqueous NaCI and dried (MgS04). Removal of the 1 5 solvent under reduced pressure and trituration with Et2O (60 mL) provided the desired hydroxyurea (4.0 g, 87%); m.p. 160 - 162C.
.z 1H NM~ (CDC13): ~ 7.36 (m, 5H); 7.2û (d, lH); 6.80 (dd, lH); 6.70 (d, lH);
5.45 (br t, lH); 5.04 (s, 2H); 2.71 (m, 2H); 2.00 (m, 3H); 1.75 (m, lH).
CTMS (isobutane); m/e (rel. int.): 313 [(M+H)+,2), 252 (19), 238 (17), 237 (100).
2 0 ~nal., calc. for C18H20N2o3: C 69.23, H 6.41, N 8.97; found: C 69.19, H 6.46, N

9.03.

Exam~le 2 (5-Benzvloxyindanyl)-N-hvdroxvurea a~ ~-Hvdroxy-1-indanone. To a solution of ethanethiol (35 rnL, 0.473 mol) in dry DMF
(300 rnL) under an argon atmosphere was added slowly sodium hydride (8.47 g of 80%
suspension in mineral oil, 0.308 mol). After the evolution of hydrogen ceased, S-methoxy-1-indanone (20.0 g, 0.123 mol) was added, ancl the resulting mixture was heated at 135C.
3 0 After heating for 1 I/2 h, thin layer chrornatographic analysis indicated that the reaction was complete, and excess ethanethiol was removed by distillation at atmospheric pressure. The reaction was then concentrated under reduced pressure. The residue was dissolved in EtOAc and extlacted with 1: 1 10% HCI/ saturated aqueous NaCI (500 mL). The organic ex~act was washed with saturated aqueous NaCI and dried (MgSO4). The mixture was3 5 filtered and allowed to stand at 0C for several d. The solid which formed was collected b~
filtration and washed with 1: I EtOAc/ hexanes to afford the title compound as a cr,vstalline solid (12.44 g, 68%).

.. . .
,.
..
.. :, . .. ~ ,: :
: . - . ~ :.

WO 91/14674 33 2 0 7 ~12 b~Cr/US91/02010 1Ql $-Benzyloxy-l-indanQne. To a solution of 5-hydroxy-1-indanone (8.02 g, 54.2 mmol) in dry DM~; (120 mL) under an argon atmosphere was added slowly sodium hydride (1.6 g of 80% suspension in mineral oil, 59.6 mmol). After the evolution of hydrogen ceased, benzyl chloride (7.12 rnL, 60.0 mmol) was added, and the resulting mixture was stirred for S lS rnin. The reaction mixtu~ was concentrated under reduced pressure and the residue was partitioned between EtOAc and 1: 1 saturated aqueous NaCV 3 N HCI. The organic extract was washe~ with saturated aqueous NaCI and dried (MgSC)4). ~e solvent was removed i vacuo, and the r~sidue was used without further purification.

1 0 c) S-Ben2vl0xv-l-indanone oxime. To a solution of 5-benzyloxy-1-indanone, prepared above, in dry pyridine (100 rnL) was added hydroxy}amine hydrochloride (7.7 g, 110 rnmol). The resulting rnixture was heated at 60C for 1 h. The solvent was removed in vacuo, and the residue was recrystallized from EtO~V H20 to provide the desired oxime as an off-white powder (10.43 g, 76% for two steps).

d) N-~ BenzylQ~Yl~-~-~LdrQx~ine. To a solution of S-benzyloxy-1-indanone oxime (7.5 g, 29.6 mmol) in 2: 1 THF/ EtOH (360 mL) at 5C was added BH3 pyridine (lS mL, 149 mmol), maintaining the temperature at 5 - 8C. To the resulting mixture was added 3 N HCl (150 mL) dropwise over 20 min. The resulting rnixture was allowed to 2 0 warm to room temperature and stand overnight. Ether (500 rnL) was added, followed by solid Na2CO3 and the mixture was poured into a mixture of 2N NaOH and saturated aqueous NaCI. The layers were separated, and the organic phase was dried (K2CO3). The solvent was removed in vacuo, and the solid residue was dissolved in CH2C12 (40 mL).
The mixture was concentrated on a stearn bath, and Et20 (50 - 100 mL) was added. This 2 5 was further concentrated and hexanes (Sû rnL) were added, followed by a seed crystal. The mixture was allowed to cool, and the solid which formed was collected by filtration and dried in vac~o to afford the title compound t4.55 g, 60%).
~$0 M~ JMF~, (CDC13): ~ 7.40 (m, 6H); 6.83 (m, 2H); 5.52 (br s, 2H); 5.05 (s,2H); 4.50 (dd, lH); 3.02 (m, lH); 2.83 (m, lH); 2.30 (m, lH); 2.14 (m, lH).
e~ Benzvloxvindan~ -N-hvdroxv~rea. To a solution of N- 1 -(S-benzyloxyindanyl)-N-hydroxyamine (4.55 g, 17.8 mmol) in dry THF (100 mL) under an argon atmospherewas added ~imethylsilyl isocyanate (S rnL, 32 rnrnol). The resulting mixture was heated at reflux for 4.5 h, then allowed to cool to room temperature and stand overnight. The solvent 3 S was removed under reduced pressure, and the solid residue was rec~ystallized from MeOH/
CHC13 to afford a white crystalline solid (2.5 g). The mother liquor was purified by flash chromatography, eluting with a solvent gr~dient of 5 - 10 % MeOH/ CHC13. The combined . . .

~ . :- ~ . . :
,: "

WO 91/14674 ~ 34 PCT/IJS91/02010 solid malerial was further recrystallized from EtOH, washed with Et20 and dried under reduced pressure to afford the title compound (2.62 g, 49%). m.p. 167C (dec) L Calc. for Cl7Hl8N2o3: C 68.44, H 6.08, N 9.39; found C 68.64, H 6.39, N
9.4~
250 MHz l~B (CDC13/ MeOH-d4): ~ 7.46 - 7.16 (m, 6H); 6.82 (m, 2H); 5.78 (dd,lH~; 5.04 (s, 2H); 3.03 (m, lH); 2.84 (m, lH); 2.45 ~ 2.13 (m, 2H).
E~am~

~Methoxv-l-tetralonç oxime To a solution of ~methoxy-l-tetralone (5.19 g, 29.0 mmol) in dry pyridine (50 mL) was added hydroxylamine hydrochloride ~4.41 g, 58.0 rnmol). The resulting mixture was heated at 50C ~or 40 min and allowed to cool to r~om temperature. The solvent was removed in vacuo, and the residue was Tecrystallized from 1 5 EtOH/ H2O to provide 5.08 g of the oxime (92% yield).
2~) MHz 1H ~MR (CDC13): ~7.82 (d, lH); 6.76 (dd, lH); 6.66 (d, lH); 3.80 (s, 3H); 2.78 (t, 2H); 2.73 (t, 2H); 1.85 (m, 2H).

b) N~ MethQxv-1.2.3.4-tetrahYdrQn~l~thyl~-lY-hvdrQxvarnine To a solution of 6-2 0 methoxy-1-tetralone oxime (568 mg, 2 96 mmol) in 1: 2 MeOHI Et2O (5 rnL), was added BH3-pyridine (0.9 rnL, 9.0 mmol), followed by the dropwise addition of 3 N HCI. The resulting mixture was stilTed at room temperature for 1 h, and additional BH3 pyIidine (0.25 mL, 2.5 mmol) was added followed by the dropwise addition of 3 N HCI. After stirring at room temperature for S h, sodium carbonate was added, and the rnixture was 2 5 extracted with CH2C12. The organic extrac~ was washed with H20 and saturated aqueous NaCI. The solvent was removed in vacuo. The residue was dissolved in ethanol, and 3 N
HCI was added dropwise with cooling. Sodium carbona~e was added, and the mixture was extracted with Et20. The organic extract was washed with H20 and saturated aqueous NaCI. Removal of the solvent in vacuo provided a white solid (391 mg, 69% yield) which 3 0 was used without further purification.

c) N~ 6-Methoxy-!~2.3.4-tetrahydron~phthvllN-h~rQ~y~rea.
To a solution of N-1-(6-methoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (339 mg, 1.76 mmol) in THF (5 mL) was added trimethylsilyl isocyanate (0.40 rnL, 2.96 mmol).
3 5 The resulting mixture was heated to 60C for 1-1/2 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H20 and saturated aqueous NaCI. The solvent was removed in vacuo, and Ihe residue was triturated wilh ,, : . ~, , :. .
..
. . : . : , . . : .
, ~ , .. ,. : , . ...
, - . .

WO 91~14674 35 2 0 7 ~12 6 Pcr/usslla2o1o .

Et20 (10 rnL) and recrystallized with CH2C12 to provide a white crystalline solid (149 mg~
39% yield). m.p. 164 C.
25QMH~1~MR (CDC13): ~ 7.25 (d, lH); 6.76 (dd, lH); 6.65 (d, lH); 5.50 (br t, lH); S.37 (br s, lH); 5.24 (br s, 2H); 3.78 (s, 3H); 2.77 (m, 2H); 2.05 (m, 3H); 1.78 5 (m, lH).
IB (cm~1): 3470, 3320, 3180, 2940, 2900, 1650.
!;~I~J NH3 (m/e, rel. int.): 237 (M+H+, 12); 221 (9); 176 (16); 161 (100).
Anal. Calc. for C12H16N2O3: C 61.00~ H 6.83, N 11.86; found C 60.21, H 6.77, N
11.7~.
1 0 ~
~- 1 -(1.2.~ ~4-Te~ahvdron~phthvl)-N-h~droxvurea a! I-Te~alone oxime To a solution of 1-tetralone (4.97 g,34.0 mmol) in dry pyridine (30 mL) was added hydroxylarnine hydrochloride (3.62g, 52.0 mmol). The resulting mixture 1 5 was heated at 50C for 1 h and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recrystallized from ethanol to provide 5.42 g of the oxime (99% yietd).
2SQ MHz 1~1 NMR (CDC13): ~ 7.90 (br d, lH); 7.21 (m, 3H); 2.80 (t, 2H); 2.75 (t,2H), 1.90 (m, 2H); 1.65 (br, lH).
b! N-1-(1.2~3.4-TctrahydrQn~hthvl)-N-hYdroxvamirL~ To a solution of 1-tetralone oxime (488 mg, 3.0 mmol) in CH2C12 (5 mL) was added BH3 pyridine (0.9 mL, 9.0 mmol) followed by glacial acetic acid (3 rnL). The resulting mixture was heated to reflux for 4 h, and the solvent was removed in vac~o. The residue was treated with 3N HCI (20 mL) an(i 2 5 stirred overnight. Sodium carbonate was added and the rnixture extracted with CH2C12.
The organic extract was washed with H2O and saturated aqueous NaCI. Removal of the solvent in vacuo provided a white solid (368 mg, 77% yield).

ç) N-1-(1~2.3~4-Tetrahvdronaphthvl)-N-hvdroxvurea To a solution of N-1-(1,2,3,4-3 0 tetrahydronaphthyl)-N-hydroxyamine (313 mg, 1.9 mmol) in THF (5 mL) was added tnmethylsilyl isocyanate (0.31 mL, 2.3 mmol). The resulting rnixture was heated to 60C
for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtQAc and washed with H20 and saturated aqueous NaCI. The solvent was removed in vacuo, and the residue was triturated with Et20 (5 rnL) and recrystallized with CH2C12 to provid~
3 5 white crystalline solid (154 mg, 39% yield). m.p. 168 - 169C.
250 MHz 1~IM~ (CDC13/ MeOD): ~ 7.25 (m, 4H); 5.53 (br t, lH); 2.84 (m, 2H);
2.10 (m, 3H), 1.86 (m. lH).
IB (cm~1): 3470, 3320, 3200, 2920, 1660.

.. ~ . . :

WO91/14674 ~ ,6 3~ PCI/US91/02010 ~~ / CH4 (m/e, rel. int.): 207 (M~H~, 7); 146 ~22); 131 (100).
~nal. Calc. for Cl IH14N2O2 1/8 H2O: C 63.37, H 6.89, N 13.44; found C 63.37, H
6.75, N 13.39.

lLN-hvs~r~xvurea ~_ To a solution of 6-hydroxy-1-tetralone (see 1 0 exarnple 1; 3.05 g, 18.8 mmol) in DMF (30 snL) was added sodium hydride (0.60 g of 80 suspension in mineral oil, 18.8 mmol). After the evolu~on of hydrogen, 4-methoxybenz~ l chlonde (2.84 g, 20.0 mrnol) was added, and the resulting mixture was heated at 50C for 1 h, followed by heating at 9ûC for 1 h. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 5 3 N HCl, and the organic extract was washed with H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with CH2Cl2 to provide 4.13 g (78% yield) of the desired product.
2~Q M~z l~B (CDC13): ~ 8.0~ (d, lH); 7.34 (d, 2H); 6.98 - 6.86 (m, 3H); 6.78 (d, lH); 5.04 (s, 2H); 3.82 (s, 3H); 2.92 (t, 2H); 2.63 (t, 2H); 2.12 (rn, 2H).
b? 6-f4-Me~h~enzvlQ~-1-te~ral~ne_~si~ To a solution of 6-(4-methoxybenzyloxy)~
tetralone (469 mg, 1.7 mmol) in d~y pyridine (4 mL) was added hydroxylarnine hydrochloride (0.27 g, 3.9 mmol). l he resulting mixture was heated at ~0C for 1 h and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue 2 5 was reclystallized from EtOH to provide 440 mg of the oxime (87% yield).
2~Q~l~MR ~CDCl3): ~ 7.82 (d, lH); 7.35 (d, 2H); 6.91 (d, 2H); 6.82 (dd, lH); 6.72 (d, lH); 5.00 (s, 2H); 3.82 (s, 3H); 2.80 (t, 2H); 2.74 (t, 2H); 1.86 (m, 2H); 1.64 (br s, l~I).
.

3 c~ ,(4-Methoxvbenzvloxv~-1.~3.4-tetrahvdr~n~,~hyll-N-hvdroxvarnine Toa solution of 6-(~methoxybenzyloxy)-1-tetralone oxime (713 mg, 2.4 mmol) in 1: 2 EtO~V
1~ (20 rmL) was added BH3 pyridine (0.48 mL, 4.8 mmol). The resulting mixture w~s stirred at room temperature for 2 h, at which time 3N HC1 was added dropwise. The reaction mixture was stirred at room temperature overnight. Sodium c3rbonate was added 3 5 and the tnixture extracted with CH2C12. The organic ex~act was washed with H20 and saturated aqueous NaCI and dried (MgSO4). Removal of the solvent in vacuo provided a white solid (489 mg, 68% yield).

~: : ': '':, : . , ., . .

Wo 91/14674 PCr/US9l/02010 ~37~ 2 ~
~ Y~ To a solution of N- 1 - [6-(4-methoxybenzyloxy)- 1,2,3,4-tetrahydronaphthyl] -N-hydroxyamine (160 mg, 0.54 mmol) in ~ (8 mL) was added trimethylsilyl isocyanate (0.16 rnL, l.
mrnol). The resultlng mixture was heated at 60C for 2 h and then concentrated under 5 reduced pressure. The residue was dissolved in EtOAc and washed with H2O and saturate~
aqueous NaCl. The solvent was removed in vacuo, and the residue was triturated with Et20 and purified by flash chromatography, eluting with CH2C12. Recrystallization from CH2C12 provided 65 mg (3S% yield) of the hydroxyurea. m.p. 165 - 166C.
O MHz l~B (CDC13/ MeOH-d4): ~ 7.32 (d, 2H); 7.19 ~d, lH); 6.90 (d, 2H);
1 0 6.80 (dd, lH); 6.71 (d, lH); 5.45 (br t, lH); 4.96 (s, lH); 3.83 (s, 3H); 2.73 (m, 2H);
2.03 (m, 3H); 1.78 (m, lH).
TR (cm~1): 3480, 3240, 2930, 1660, 1645.
~I~S/ NH3 (mle, rel. int.): 342 (M+H+, 2); 282 (45); 267 (100); 147 (20); 121 (50).
e~Dal~ Calc. for C19H22N2O4-1/4 H2O: C 65.79, H 6.54, N 8.08; found C 65.89, H
1 5 6.41, N 8.07.

F~x~rn~le 6 N~ -(4-Chloro~enzYloxvl- I ~2.3.4-tetrahvdronaphthyll-N-hvdroxYurça 2 0 a~ 6-(~ChlQrQb~n;~Qxy)-l-tetralone To a solution of 6-hydroxy-1-tetralone (see example 1, 489 mg, 3.0 mmol) in DMF (10 mL) was added sodium hydride (105 mg of 80%
suspension in mineral oil, 3.5 mmol). After the evolution of hydrogen, ~chlorobenzyl chloride (576 mg, 3.6 mmol) was added, and the resulting mixture was stirred at room tempera~ure for 2 h, followed by heating at 60C for 2 h. The reaction mixture was allowed 2, 5 to cool and was concentrated under reduced pressure. The residue was panitioned between E~OAc and 3 N HCI, and the organic extract was washed wi~h H2O and saturated aqueous NaCI. The solvent was removed in vaC~o, and the residue was purified by flash chromatography, eluting with CH2C12 to provide 600 mg (70% yield) of the desiredproduct.
3 0 2$0 MHz lH NMR (CDC13): ~ 8.01 (d, lH); 7.35 (s, 4H); 6.90 (dd, lH); 6.80 (d, lH); 5.09 (s, 2H); 2.91 (t, 2H); 2.64 (t, 2H); 2.13 (m, 2H).

b) ~(4 Chloro~enzyloxv)-l-tetralone Qxim~ To a solution of 6-(4-chlorobenz,vloxy)-l-te~alone (286 rng, 1.0 mmol) in dry pyridine (3 mL) was added hydroxyl~mine 3 5 hydrochloride (140 mg, 2.0 mmol). The resulting mixture was heated at 50C for 30 min and allowed to cool tO room temperature. The solvent was removed in vacuo, ~nd the residue was recrystallized from ethanol to provide 248 mg of the oxime (81 % yield).

.. ..

WO 91/1467~ PCr/lJS91/02010 ~Q~1H ~MR (CDC13): ~ 7.84 (d, lH); 7.36 (s, 4H); 6.82 (dd, lH); 6.72 (d, lH); 5.04 ~s, 2H); 2.80 (t, 2H), 2.73 (t, 2H); 1.88 (m, 2H~, 1.65 (br, lH).

6-~hloro~nzYlQ~ ,~ h~na~hthvlL-N-hv~m~ To a S solution of 6-(4-chlorobenzyloxy)-1-tetralone oxime (2.20 g,7.31 mmol) in 1: 2 EtOHl THF (15 rnL) was added BH3-pyridine (1.46 rnL, 14.6 rnmol). The resulting mixture was stiITed at room temperature for 1 h, at which time 3N HCl (50 ml,) was added dropwise.
The reaction mixnlre was st~red at room temperature for 1 h. Sodium carbonate was adde~
and the mixture ex~acted with CH2C12 (3x). The organic extract was washed with H20 1 0 and saturated aqueous NaCl and dried (MgSO4). Removal of the solvent in vacuo pr~vide~l the desired hydroxyarnine (2.02 g, 91 % yield).

d~ -L~-~4-(~hlorobenzvloxy)-1.2~4-tet~hy~ronaph~hvll-N-h--~droxv~ea Toasolution of N- 1 - [6-(4-chlorobenzyloxy)- 1,2,3,4-tetrahydronaphthyl] -N-hydroxyamine (180 mg, 1 5 0.60 mmol) in THF (3 mL) was added trimethylsilyl isocyanate (0.16 mL, 1.2 mmol). The resulting mixture was hea~ed at 60C for I h and then concentrated under reduced pressure.
The residue was dissolved in EtOAc and washed with H2O and saturated agueous NaCI.
The solvent was removed ln vac~o, and the residue was triturated with Et20 and recrystallized from CH2C12 to provide 71 mg (34% yield) of the hydroxyurea. m.p.166C.
250 ~Hz 1 NMR (CDC13/ MeOH-d4): ~ 7.36 (s, 4H); 7.20 (d, lH); 6.78 (dd, lH);
6.70 (d, lH); 5.43 (br t, lH); 5.00 (s, 2H); 2.74 (m, 2H); 2.00 tm, 3H); 1.77 (m, lH).
IR (cm~13: 3460, 3320 - 3100, 2920, 2860, 1640.
CIMS / NH3 (m/e, rel. int.): 347 (M+H+, 10); 331 (17); 286 (52); 271 (100).
2 5 ~L Calc. for Cl8HlgN2o3cl: C 62.34, H 5.52, N 8.08; found C 61.94, H 5.54, N
8.05.

~am~
)~- 1 - L6-(2-Naph thvlmethoxvLL2.~ 4-tetrahvdron aphchvll-N-h~droxv-lrea a) ~(2-Naphthvlmethoxy)-l-tetralone To a solution of 6-hydroxy-1-tetralone (see example 1, 1.65 g, 9.4 mmol~ in DMF (20 rnL) was added sodium hyd~ide (0.30 g of 80%
suspension in mineral oil, 9.4 mrnol). After the evolution of hydrogen ceased, ~-(chloromethyl)naphthalene (1.77 g, 10.0 mmol) was added, and the resulting mixture was 3 5 stirred at room tempera~ure for 1 h. The solvent was concentrated under reduced pressure and the residue par~ilioned between EtOAc and 3N HCI. The organic extr~ct was washed with H20 and saturated aqueous NaCI. The solvent was removed in vacuo, and the residue ~ ~ ;
;. ,-WO 91/14674 PCI`/US91~02010 -39- t 2 0 7 ~ 1 2 ~ !
was purifled by flash chromatography eluting with CH2C12 to provide 1.92 g (68% yield) of the alkylated tetralone.
250 MHz lH ~?. (CDC13): S 8.05 - 7.85 (m, 4H); 7.52 (m, 4H); 6.96 (dd, lH);
6.86 (d, lH); 5.53 (s, 2H); 2.93 (t, 2H); 2.61 (t, 2H); 2.10 (m, 2H).
~ To a solution of ~(2-naphthylmethoxy)- l-tetralone (1.80 g, 6.0 mrnol) in dry pyridine (50 mL) was added hydroxylamine hydrochloride (0.83 g, 11.9 mmol). The resulting mixture was heated at 50C for 15 min and ailowed to cool to room temperature. The solvent was removed in vac~o, and the 1 0 residue was recrystalliæd from EtOH to provide 1.67 g of the oxirne (88% yield).
250~1Hz 1H~MR (CDC13): ~ 8.05 (m, lH); 7.92 (m, 3H); 7.65 - 7.45 (m, 4H); 6.9 (dd, lH); 6.84 (d, lH); 5.50 (s, 2H); 2.83 (t, 2H); 2.78 (t, 2H); 1.88 (m, 2H).

c~ Na~hthy!~çthoxv~ ,34-1ç~rahydr~?n~2hthyl]-N-hy~oxYamine Toa 1 5 solution of 6-(2-naphthylmethoxy)-1-tetralone oxime (1.67 g, 5.3 mmol) in 1: 2 EtO~V
THF (30 mL) was added BH3 pyridine (1.6 rnL, 15.8 mmol). The resulting mixture w~s st~rred at room temperature overnight, at which time 3N HCl (18 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 4 h. Sodium carbonate was added and the mixture extracted with (',H2C12. The organic extract was washed with H20 and 2 0 saturated aqueous NaCI. Removal of the solvent in vacuo provided the desired hydroxyarnine (1.54 g, 92% yield).

d) N-l-r6-(2-l~ayhthvlmethoxv)-1.2.3.4-tetrahvdrona~h~vll-N-hydroxvure~
To a solution of N-1-[6-~2-naphthylmethoxy)-1,2,3,~etrahydronaphthyl]-N-2 5 hydroxyamine (1.50 g, 4.7 mmol) in THF (20 rnL) was added ~imethylsilyl isocyanate (1.27 mL, 9.4 mmol). The resulting mixture was heated at 60C and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H~O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was tntur~ted with Et2O to provide 584 mg (34% yield) of the hydroxyurea. m.p. 169 - 170C.
3 0 2~0 MHz l~T~B (CDC13, MeOH-d4): ~ 8.08 (m, lH); 7.90 (m, 2H); 7.53 (m, 4H);7.23 (d, lH); 6.90 (dd, lH); 6.81 (br s, IH); 5.48 (s, 2H); 5.45 (br t, lH); 2.78 (m, 2H); 2.05 (m, 3H); 1.80 (m, lH).
~R (cm~1): 3490, 3460, 3320 - 3160, 2900, 1650.
~/ NH3 (m/e, rel. int.): 347 (26); 302 (25); 287 (76); 158 (26); 147 (100).

, : ,,' ,:

.

WO 91/14674 ~ 6 40 PCT/US9~/02û10 E~

a) 6-~1-TetraIonvl~ trifl~lorQmethYl~llfon~.t~ To a solution of 6-hydroxy-1 tetralone (see example 1, 324 mg, 2.0 mmol) in CH2C12 at -30C was added trifluoromethanesulfonic anhydride (282 mg, 2.0 mrnol), 2,6-lutidine (278 mg, 2.6 rnmol) and dimethylarninopyridine (60 mg, 0.5 mmol). The resulting solution was allowed to warm ~o room temperature and stirred overnigh~. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and filtered. llle filtrate was washed successively with 10% HCI
1 0 and H20. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with a gradient of EtOAcI hexanes (0.5 2%) to provide the desired product (490 mg, B3%).
~Q~1H ~MR (CDC13): d 8.12 (m, lH); 7.20 (m, 2H); 3.00 (m, 2H); 2.68 (m, 2H); 2.15 (m, 2H).

b~ 6-(2-Phenv~ethy1~-1-tetralolle To a solution of 6-(l-tetralonyl) trifluoromethylsulfonate (447 mg, l.S mrnol) in THF/ DMF (20 mL) was added a solution of triphenylethylborane (5.8 mL of 0.3 M solution, 1.7 mmol; prepared from styrene and borane-T~ complex in 1~;), followed by K2C03 (714 mg, S.1 mmol) and HMPA (1 rnL). The reaction mixture 2 0 was deoxygenated, and tetralcis(triphenylphosphine)palladium (111 mg, 0.1 mmol) was added. The reacdon mixture was again deoxygenated and heated at 50C overnight. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H20 and satura~ed aqueous NaCI.
The solvent was removed in vacuo, and the residue was purified by flash chromatographv, 2 5 eluting with a ~radient of EtOAc/ hexanes (0.8 - 3%) to provide the desired product (274 mg, 73%)-250 MHz 1H ~MR (CDC13): ~ 7.94 (d, lH); 7.30 - 7.02 (m, 7H); 2.93 (s, 4H); ~.9 (t, 2H); 2.63 (t, 2H); 2.05 (m, 2H).

3 0 ç) ~(2-Pb~nvl~thvl~-l-tetralo~ne oxime To a solution of 6-(2-phenylethyl)-1-tetralone (5.01 g, 20.1 rnmol) in dry pyridine (40 rnL) was added hydroxylamine hydrochloride ( 79 ~,, 40.2 mrnol). The resul~ing mixture was heated at 50C for 30 rnin and allowed to cool to room ~emperature. The solvent was removed in vac~o, and the residue was recrystallized from ethanol to provide 5.26 g of the oxime (99% yield).
3 5 250 M~z~ (CDC13): o 7.81 td, lH), 7.24 (m, SH); 7.04 (dd, IH); 6.99 (br s.
lH); 2.90 (s, 4H); 2.83 (t, 2H); 2.73 (t, 2H); 1.88 (m, 2H).

..

.

WO 91/l4674 PCr/US91/020l0 2~78126 d) N-l-L6-(2-phenylethy~ 2~3~4-tetra~ ron~Lhth~ -hvdroxvamine To ~ solution Or 6-(2-phenylethyl)- 1-tetralone oxime (4.63 g, 17.5 mmol) in 1: 2 EtOH/ THF (35 mL) wa~
added BH3 pyridine (1.10 rnL, 11.0 rnrnol) at 0C, followed by the dropwise addition of 3N HCl (12 mL). The reaction mixture was s~irred at room tempe rature overnight. Thin 5 layer chromatographic analysis indicated an incomplete reaction, and additional BH3-pyridine (1.1 mL, 11.0 rnmol) was added, followed by 3N ]HCl (12 rnL). The reaction mixture was stiIred at room temperature for 1 h, and additional BH3-pyridine w~s added (1.1 mL, 11 mmol), followed by 3 N HCI (15 mL). The mixture was stirred anadditional S h at room temperature. The solvent was removed under reduced pressure; 3N
1 0 HCI was added (40 tnL), and the reaction rnixture was stirred at room temperature for 1 h.
Sodium carbonate was added and the mixture extracted with CH2C12. The organic extract was washed with H20 and saturated aqueous NaCI. Removal of the solvent in vacuo provided the hydroxyamine (4.30 g, 92% yield).

1 5 2N-I-r~2-Phen~lethvl)-1.2.3.4-tetrahvdrona~h~hy~-hyd~xvurea To a solution of N-1-[6-(2-phenylethyl)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyamine (3.]
g, 11.6 rnrnol) in T~ (30 rnL) was added trimethylsilyl isocyanate (3.1 rnL, 23.2 rnmol).
The resulting mixture was heated at 50C for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H2O and saturated 2 0 aqueous NaCl. The solvent was removed in vac~o, and the residue was triturated with Et2O and recrystallized from CH2C12 tO provide 1.30 g (36% yield) of ehe hydroxyurea.
m.p. 162- 163C.
250 M~z ~ IR (CDC13): d 7.24 (m, 6H); 7.03 (dd, lH); 6.95 (s, lH); 5.49 (br t, lH); 5.40 (s, lH); 5.27 (br s, 2H); 2.89 (m, 4H); 2.74 (m, 2H); ~.05 (m, 3H); 1.79 (m, lH).
IR (cm-1): 3480, 3330 - 3100, 2920, 2860, 1660.
~I~i/ NH3 (m/e, rel. int.): 311 (M+H+, 15); 250 (40); 235 (100).
Anal. Calc. for C19H22N2O2-3/8 H2O: C 71.96, H 7.23, N 8.83; found C 71.87, H
7.01, N 8.97.
Examp]e 9 a)~-(2-QuinolinYlmçthvloxY)-l-tetr~lone To a solution of 6-hydroxy-1-tetralone (see 3 5 example 1; 3.21 g, 19.8 rnmol) in DMF (50 ~rL) was added sodium hydride (0.75 g of 80~,~
suspension in mineral oil, 25.0 mmol). After the evolution of hydrogen, 2-(chloromethyl)quinoline monohydrochloride (5.08 g, 23.7 mmol) which had previouslv been treated with saturated aqueous K2CO3 was added. and the resulting mixture u as . .
.
: . . : .. . ~ , WO 9l/14674 ~ 42- PCl/US9l/02010 heated at 50C for 2 h. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The residue was partitioned between EtOAc and 3 N HCI, and the organic extract was washed with H20 and saturated aqueous NaCI. The solvent was removed in vacuo, and the residue was purif}ed by flash chromatography, eluting with CH2Cl2 to provide the desired product (3.03 g, 51%).

~o) 6-(2-QuinolinYlmetkvloxv~1-t~alo~e oxime To a solution of 6-(2-quinolinylmethyloxy)-l-tetralone (3.00 g, 9.9 mmol) in dry p,vridine was added hydroxylamine hydrochloride (1.37 g, 19.7 mmol). The resulting mixture was heated a 1 0 50C for 30 min and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recr,vstallized from EtOH to provide the oxime (950 mg, 30%).
250I\~lz lH NMR (CDC13): ~ 8.30(d, lH); 8.08 (d, lH); 7.92 - 7.56 (m, SH); 6.89 (dd, lH); 6.81 (d, lH); 5.38 (s, 2H); 2.75 (m, 4H); 1.85 (m, 2H).

1 5 c~ r6-(2-O~inolinvlmethyloxv)-1.2.3.4-tetr~ vdrona~hthvll-N-hvdroxvamine To a solution of ~(2-quinolinylmethyloxy) 1-tetra}one oxime (0.95 g, 3.0 mmol) in CH2CI ~
was added BH3-pyridine (1.0 mL, 10.0 mmol), followed by glacial acetic acid (3 mL). The resulting rn~xture was heated at reflux for 5 h and allowed to cool. The solvent was removed under reduced pressure, 3 N HCI was added (10 rnL) and the mixture was stirred 2 0 at room temperature overnight. Sodium carbonate was added and thç mixture extracted with CH2C12 (4x). The organic ex~act was washed with H2O and saturated aqueous NaCl.
The solvent was removed in vacuo to provide the desired hydroxyamine (0.92 g, 96%), which was used without further purification.

d) N~ 6-(2-OuinolinvlmethY!oxv)-1 2~3~tetrahvdrQnaphthvll-N-hvdroxyuTea To a solution of N-1-[6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyamine (0.90g, 2.8 mmol) in I~ (20 mL) was added trimethylsilyl isocyanate (0.76 mL, 5.6 mmol). The resulting mixture was heated at 60C for 1 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H20 and saturatetl 3 0 aqueous NaCI. The solvent was removed in vacuo, and the residue was tTiturated with Et2O and purified by flash chromatography, eluting with CH2Cl~ to afiord the desired hydroxyurea (0.31 g, 30%). m.p. 180.5 - 182.0C.
2~MHz l~l NMR (CDC13, MeOH-d4): ~ 8.30 (d, lH); 8.08 (d, lH); 7.88 (d, lH);
7.72 - 7.50 ~m, 3H); 7.20 (d, lH); 6.85 (dd, lH); 6.77 (d, lH); 5.40 (br t, lH); 5.3 3 5 (s, 2H); 2.73 (m, 2H); 2.02 (m, 3H); 1.80 (m, lH).
IR (cm~1): 3480, 3330, 3200, 2960 - 2870, 1660.
CIMS (NH3), rnJe (rel. int.): 364 ~(M+H~+, 17]; 305 (75); 288 (85); 144 (100).

~,'': . : ,:
.... .
t ~ ~ ~

WO 91/14674 2 0 7 8 1P~;tU~9l/02010 ,~ calc. for C21H21N3O3-1/2 H2O: C 67.72, H 5.~5, N 11.28; found C 67.9~, H
5.84, N 11.04.

- ~-3~L~-BçnzvlQxv-2~3-dihvdro)benzQfuranyl-N-hy~

a) 2~ oro-l-~4-dih~rox~enyll-l-ethanimine~ hvdrochlond~. To a solution of resorcinol (250 g, 2.27 mol) in Et20 (1 L) was added chloroacetonitrile (208 g, 2.75 mol) and ZnC12 (172 g, 1.26 mol). To the resulting mixture was passed dry HCI gas over 40 1 0 min, maintaining the temperature at 25C. The resulting cloudy rrlixture was then cooled tO
15C, with stin~ng, and a pinkish precipitate formed. The mixture was allowed to w~unn to room temperature and stirred for 18 h. The white solid which formed was collected by f~ltration and washed with Et20 (2 L) and dried to provide the title compound (602 g, 100%).
b) 2-Chloro-1-(2~4-dihydroxyphenvl)-1-ethanone 2-Chloro-1-(2,4-dihydroxyphenyl)-l-ethanimine, hydrochloride (504 g, 2.27 mol) was placed in H20 (5 L), and heated at reflux for 1 h, then allowed to cool to room temperature. A seed crystal was added, and the mixture was st*ed overnight. The solid which forrned was collected by filtration, washed 2 0 with H2O (3 L) and dried to afford the title compound (280 g, 66%) as a pale orange solid.

c) 2.3-Dih~vdro-6-hvdroxv-3-oxobenzQfuran. To a solution of 2-chloro-1-(2,4-dihydroxyphenyl)-1-ethanone (11.0 g, 0.059 mol) in absolute EtOH (150 mL) was added sodium acetate (7.5 g, 0.092 mol), and the resulting mixture was heated at reflux for I h.
2 5 The mixture was allowed to cool to 5C, and the solid which formed was collected by filtration and washed with EtOH (25 rnL). The solid was suspended in H20 (lû0 mL), sDrred for 20 rnin and filtered. The solid was dried at 40C tO afford the title compound (7.0 g, 79%)-25t) M~z 1H ~MR, (CDC13): o 7.50 (d, lH); 6.57 (dd, IH~; 6.50 (d, lH); 4.62 (s, 3 0 2H); 4.15 (br s, lH).

d) ~-Benzvloxv-3-oxo-2.3-dihvdro-benzofuran. To a solution of 2,3-dihydro-6-hydroxy- ~-oxo~enzofuran (363 g, 2.42 mol) in DMF (4 L) was added anhydrous potassium carbonate (668 g, 4.84 mol). After stirring for S min at room temperan~re, benzyl bromide (58~ g, 3 5 3.4û mol) was added to the mixture dropwise over 15 min. The resulting mixture was stilTed at room temperature for l 8 h, at which time the potassium carbonate was removed b~
~lltr~non and washed with DMF. llle combined organic m~erial was poured into cold H~(!

... ~ , ., - , , : , ,: ~

WO91/1467~ ~ PCI/U591/02010 (12 L) and stirred. The solid which formed was collected by filtration, washed with H2O (~
L) and dried to provide the title compound (5S4 g, 100%).

enzyloxY-3-oximino-2~3-dihY~f.~ran. Toasolutionof~benzyloxy-3-oxo-2,3-dihydrobenzofuran (5.8 g, 25 mmol) in dsy pyridine (38 mL) was added hydroxylarnine hydrochloride (3.5 g, 50 rnrnol). The resulting rnixture was heated at 50C
for 1 h, then allowed to cool to room ternperature and poured into cold H2O (100 mL). The resulting suspension was stirred for 15 rnin. The solid which formed was collected by filtration, washed with cold H20 (30 rnL) and dried to afford the oxime as a yellow solid 1 0 (5.~ g, 92%).
250MHz l~(CDC13): ~ 7.45 (d, lH); 7.40 (m, 5H); 6.64 (dd, lH); 6.55 (d, lH); 5.17 (s, 2H); 5.07 (s, 2H); 4.07 (br s, lH).

f~ N-3-f6-Benzvloxy-2~-~ro)benzofur~nyl-N-hvdroxyamine. To a solution of 6-1 5 benzyloxy-3-oxirnino-2,3-dihydrobenzofuran (505 g, 1.98 mol) in 1: 1 MeOH/ CH2Cl~
(10 L) was added BH~ pyridine (80~ g, 8.69 mol). To the resulting mixture was added dropwise over 1.25 h, 6 N HCI (1.5 L~, and the solution which resulted was allowed to s~ir for 18 h at room temperature. Activated carbon (100 g) was added, and the rnixture was stirred for 1 h, filtered and concen~ated under reduced pressure. The concentrate was 2 0 cooled to 10C, and 3 N HCl (2 L) was added cautiously. The resulting suspension was stirred for 1 h at room temperature, then cooled to 5C. The solid which forrned was collected by filtration and suspended in cold H2O. The pH was adjusted to pH 10.~, and the mixture was st*ed ~or 1 h. The mixture was filtered and the solid was washed wi1h H2O and dried to afford the title compound (440 g, 86%).
3-(6-Benzvloxv-2.3-dihydro)benzofuranYl-l~-hv~roxvurç~. To a solution of N-3-(6-benzyloxy-2,3-dihydro)benzofuranyl-N-hydroxyamine (100 g, 0.39 mol) in THF (2.3 L) was added decolorizing activated carbon (Norit A, 10 g), and the resulting mixture was stirred for 15 min. The mixture was filtered, and to the filtrate was added in one portion 3 0 under an argon atmosphere trimethylsilylisocyanate (77 mL, 0.S7 mol). The resulung mixture was heated at 55C for 1 h, at which time HPLC analysis indicated that the reactio was incomplete. Additional t;imethylsilylisocyanate was added (~3 mL, 0.17 mol), and heating at 55C was continued for an additional 30 min. The reac~on mixture was allowed to cool to room temperature. After stirring overnight, the mixture was cooled to 5C. The 3 5 solid which formed was collected by filtration9 washed with THF (250 mL) and dried at 40C to afford the title compound as a white powder (62 g, 53%). rn.p. 174.5 - 175.5C
250 M~z lH NMR (CDC13, MeOH-d~): d 7.45 - 7.25 (m, SH); 7.14 (d, lH); 6.51 (dd, lH); 6.41 (d, lH); 5.87 (t, lH); 5.03 (s, 2H); 4.53 (d, IH). ;

....

::

WO 91/14674 2 0 ~ pcr/us9l/o2o1o ~5~

IR (cm~l): 3460, 3320, 3180, 2880, 1650 - 1620.
A~l. calc. for C16H16N~O4-3/8 H20: C 62.58, H 5.50, N 9.12; found C 6'2.62, H 5.3~, N 9.24.

~-hvdrQxv~r.ea ~m~ To a solution of 7-me~hoxy-2-tetralone (499 mg, 2.83 nrnol~ in d.~ pyridine (2 mL) was added hydroxylarnine hydrochloride (399 mg, 5.80 1 0 rnmol). l'he resulting mixture was heated at 50C for 1 h. The solvent was concen~ated under reduced pressure, and t'ne solid residue was recr,vst~llized from ethanol to provide Ihe oxime (511 mg, 95%) which was used without further purifica~ion.

b) ~-2-(7-~lethoxv-l~2.~4-tçn~hvdrona~th~ -hvdroxvamine To a solution of 7-1 5 methoxy-2-te~alone oxime (500 mg, 2.6 mmol) in 1: 2 EtOH/ THF (15 rnL) at 0C was slowly added BH3 pyridine (0.52 rnL, 5.2 mmol), followed by 3 N HCI (1.5 rnL). The resulting rnixture was allowed to warrn to room temperature and stirred for 2 h. Sodium carbonate was added, and the mixture was extracted with CH2C12. The organic extract w~s washed with H2O and saturated aqueous NaCI, and dried (MgSO4). Removal of the 2 0 solvent in vacuo provided ~he desired hydroxyamine (171 mg, 34%) which was used without further purification.

c) ~l-2-t7-Melhoxv-l~2~3~4-t~trahvdron~Fhthvl)-N-hvdroxv~rea To a solution of N-2-(7-methoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (150 mg, 0.78 mmol) in dry THF
2 5 (5 mL) was added trimethylsilyl isocyanate (0.78 mL, 1.56 mmol), and the resulting mixture was heated at 50C for 1 h. The solvent was concentra~ed under reduced pressure.
The residue was dissolved in EtOAc and washed with H2O and saturated aqueous NaCI.
The solvent was removed in Yacuo, and the residue was triturated with Et20 and recrystallized from CH2C12 and MeOH to provide the hydroxyurea (88 mg, ~18% yield).
3 0 m.p. 152 - 53C.
250 MHz lH NMR (CDC13, MeOH~ 7.00 (d, lH); 6.69 (dd, lH); 6.64 (d, lH):
4.42 (m, lH); 3.10 (dd, lH); 2.85 (m, 3H); 1.96 (dd, 2H).
IR (cm~1): 350û, 3330, 3160, 2900, 1640.
CTM~/ NH3 (nlle~ rel. int.): 237 (M+H+, 49); 221 (15); 194 (65); 178 (100).

. . . ..
: ; , ; .
- . ., . ~ .. .
.. . ..

: . . ~
.. . . . ... .

WO 91~14674 ~r~ 46- PCT/US91/0~010 E~xam~le 12 ~-1-(7-Benzylo~-1 ~ ,~trahvdronaphthvlL-N-hvdrQxy~

a) 7-Hvdmxv-1-tetralone To a solution of ethanethiol (8.4 rnL, 0.114 mol) in d y DMF (75 S mL) was added slowly sodium hydride (1.6 g of 80% suspension in mineral oil, 57 mmol).
After the evolution of hydrogen ceased, 7-methoxy-1-tetralone (S. 14 g, 29 mmol) was added, and the resulting mixture was heated at 150C for 3 h. The mixture was allowed tO
cool and was concentrated under reduced pressure. The residue was partitioned between EtOAc and 3 N HCl, and the organic extraçt was washed with H20 and saturated aqueous 1 0 NaCI and dried ~MgSO4). Removal of the solvent in vacuo and trituration of the residue with CH2C12 provided the hydroxy tetralone (3.27 g, 69%) which was used without further purification.
25Q MHz lH NMR (CDC13): o 7.40 (d, lH); 7.15 (d, lH), 7.00 (dd, lH); 2.90 (t, 2H); 2.63 (t, 2H); 2.12 (m, 2H).
b~ 7-BenzYloxv-l-tetralone To a solution of 7-hydroxy-1-tetralone (2.01 g, 12.4 mmol) in dry DMF (50 mL) was added slowly sodium hydride (0.60 g of 80% suspension in miner;~l oil, 18.6 mmol). After the evolution of hydrogen ceased, benzyl chloride (2.47 g, 18.6 mmol) was added, and the resulting mixture was heated at 60C for 30 min. The rnixture 2 0 was allowed to cool and was partitioned between EtOAc and 3 N HCl. The organic extract was washed with H20 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2: 3 CH2C12/ hexanes to provide the desired tetralone as a white çrystalline solid (1.69 g, 54 7c).
250 M~z 1H NMR (CDC13): o 7.62 (d, lH); 7.46 - 7.10 (m, 7H); 5.10 (s, 2H); 2.90 2 5 (t, 2H); 2.64 (t, 2H); 2.10 (m, 2H).

ç) 7-Benzyh2~y-l-tetralone oxime To a soludon of 7-benzyloxy-1-tetralone (1.53 g, 6.1 rnmol) in dry pyridine (20 rnL) was added hydroxylamine hydrochloride (0.81 g, 12.1 mmol). The resulting mixture was sti~ed at room temperature for 1 h. The solvent was 3 0 removed in vac~o, and the residue was recIystallized from EtOH/ H20 to provide the desired oxime (1.52 g, 99%).
250M~z lH NMR (CDC13): ~ 7.53 (d, lH); 7.49 - 7.24 (m, 5H); 7.05 (d, lH); 6.92 (dd, llH); 5.06 (s, 2H); 2.80 (t, 2H); 2.70 (t, 2H); 1.85 (m, 2H). ~-3 5 d) N-1-(.7-Benzvloxy-1~2~.4-tetrahvdronaphthvl)-~-hvdroxvamine To a solution of 7-benzyloxy-1-te~alone oxime (107 mg, 0.42 mmol) in ethanol (5 mL) was added BH3 pyridine (0.14 mL, 1.4 mmol). The solution was cooled to 0C, and 3 N HCI (1.4 mL) was added dropwise. The resulling mixture was allowed to w~rm to room temper~ture '' . ~' ' ' ' . ' ~
, ~. .", .. . .

WO 91/14~.74 ~47- 2 ~ 7 8 1 2 6 Pcr/US9l/020l0 and stirred for 2 h. Sodium carbonate was added, and the mixtu;e was extractsd with CH2C12. The organic extract was washed with H20 and saturated aqueous NaCl and drie-l (MgSO4). The solvent was removed in vacuo to provide the desired hydroxyamine (100 mg, 95%), which was used without further purification.
~) N-1-(7-B~n~yloxy-1.2,3~4-tet~bvdro~hyD~-hy~oxvure~L To a solution of N-1-(7-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyanine (1.10 g, 4.3 mmol) in dry THF
(20 mL) was added tnmethylsilyl isocyanate (1.2 nL, 8.7 mmol). The resulting mixture was heated at 60C for 30 min, then allowed to cool to room temperature and stirred 1 0 overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with H20 and saturated aqueous NaCl. The solvent was removecl in vac~o, and the residue was triturated with Et20 to provide the desired hydroxyurea (858 mg, 64%). m.p. 158 - 161C.
250 MHz lH N~IR (CDC13, MeOH~ 7.47 - 7.30 (m, SH); 7.00 (d, IH); 6.95 (d, 1 5 lH); 6.82 (dd, lH); 5.43 (brt, lH); 5.02 (s, 2H); 2.72 (m, 2H); 2.00 (m, 3H); 1.78 (m, lH).
IR (cm~1): 3470, 3330 - 3100, 2930, 2870, 1670 - 1630.
CTl~S (CH4), m/e (rel. int.): 313 (M+, 3); 252 t34); 237 (100); 236 (38); 91 (86).
Anal. calc. for C18H20N2o3: C 59.21, H 6.45, N 8.97; found C 69.15, H 6.52, N 8.95.
Example 13 f6-Phenvl- I .2.~.4-tetrahvd~ona~2hthYl~-N-hvdroxvurea a~ ~-Phenvl- I-tetralone To a solution of zinc chloride (5.1 nL of 1.0 M solution, 5.1 2 5 mmol) in dry THF (20 rnL) was added phenyl lithium (2.6 rnL of 2.0 M solution, 5.1 mmol). The resulting mixture was stilTed at room temperature for 30 min and added to a solution containing 6-(1-tetr~lonyl) ~ifluoromethylsulfonate (1.09 g, 3.7 mmol, see example 8 for preparation), palladium acetate (7.6 mg, 0.03 mmol) and bis(1,3-diphenylphosphino)-propane (14 mg, 0.03 mmol) in dry THF (50 mL). The resulting 3 0 mixture was stirred at room temperature for 1 h, and then par~itioned between E~OAc and 3 N HCI. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4).
The solvent was removed in vacuo, and the residue was purified by flash chromatograph), eluting with 10% EtOAc/ hexanes to provide the desired product which was reclystallized from hexanes (0.42 g, 51%).
3 5 250MHz IH NMR (CDC13): ~ 8.10 (d, IH); 7.66- 7.35 (m, 7H); 3.03 (t, 2H); 2.70 (t, 2H); 2.20 (m, 2H).

, ' ' WO 91/14674 ~ 48- PCI`/US91~02010 b~ ~Phenvl-l-te~alone oxime To a solution of 6-phenyl-1-tetralone (99 mg, 0.4 rnmol) in dry pyridine (6 mL) was added hydroxylarnine hydrochloride (90 rng, 1.3 mmol). The resulting mixturc was stin~d at room temperature for 30 min. The solvent was removed ilt vacuo, and the residue was recrystallized from EtOH to provide the desired oxime (85 mL~, 5 81%)-~Q k~lH NMR (CDC13/ MeOH-d4): o 7.96 ~d, lH); 7.63 - 7.33 (m, 7H); 2.85 (~t, 4H); 1.92 (rn, 2H).

c) N-l-(~-Phenvl-1~2.~.~-tenahvdronaph~hyl).~-hydroxyamine To a solution of 6-phenyl-1 0 l-tetralone oxime (352 mg, 1.5 mmol) in CH2C12 (10 mL) was added BH3-pyridine (0.6 mL, 6.0 mmol), followed by glacial acetic acid (1.5 mL). The resulting mixture was heated at reflux for 2 h and allowed to cool. The solvent was removed under reduced pressure, 3 N HCI was added (5 mL) and the mixture was stirred at room temperature for 2 h. Sodiun~
carbonate was added and the mixture extracted with CH2C12 (4x). The organic extract w~s 1 5 washed with H2O and saturated aqueous NaCI. The solvent was removed in vacuo to provide the des*ed hy~roxyamine (270 mg, 75%), which was used without further punfication.
~Q~IHz lH NMR tCDC13): o 7.60 - 7.30 (m, 8H); 4.17 (t, lH); 2.85 (m, 2H); 2.25 (m, lH); 2.05 - 1.73 (m, 3H).
d~ N-l-f~pheny~L~ 4-tetrahydronaphthvl)-N hy.~roxvurea To a solution of N-1-(6-phenyl-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (270 mg, 1.1 mmol) in dry THF (10 mL) was added trimethylsilyl isocyanate (0.30 mL, 2.2 mmol). The resulting mixture w~s heated at 60C for 1 h and then concentrated under reduced pressure. The residue was 2 5 dissolved in EtOAc and washed with H20 and saturated aqueous NaCI and dried (MgSO4).
The solvent was removed in vacuo, and the residue was triturated with Et20 and recrystallized from CH2C12/ hexanes. Further purification by flash chromatography, eluting with a solvent gradient of MeOH/ CH2C12 provided the desired hydroxyurea (70 mg, 23%). m.p. 175 - 176C.
3 0 250 MHz lH N~ (CDC13, MeOH-d4): d 7.57 (d, 2H); 7.46 - 7.32 (m, 6H); 5.53 (br t.
lH); 2.85 (m, 2H); Z.07 (m, 3H); 1.84 (m, lH).
IR (cm~l): 3490, 3320 - 3160, 2930, 2860, 1640, 1630.
(NH3), m/e (rel. int.): 283 [(M+H)~, 12]; 267 (22); 222 (37); 207(100).
Anal. calc. for C17H18N2O2-1/4 H2Q: C 71.18, H 6.50, N 9.77; found C 71.06, H 6.4~.
3 5 N 9.74.

WO 91/14674 PCr/US91t02010 ~9~ 20~-~126 ~m~
S-~LMethoxvbenzvl~danvll-N-hv~3roxyurea a~ ~:(4-~lethQxv~en2~;v)-l-in~an~ne To a solution of 5-hydroxy-1-indanone (1.30 g, 8.8 mmol, see example 2 for preparation) in dry DMF (25 ml.) was added slowly sodium hydride (0.26 g of 80~o suspension in mineral oil, 8.8 mrnol). After the evolution of hydrogen ceased, 4-methoxybenzyl chloride (1.~0 g, 10.6 mmol) was added, and theresulting mixture was st~red at 60C for 1 h. The mixture was allowed to cool and was partidoned between EtOAc and 3 N HCI. The organic extract was washed with H2O and 1 0 saturated aqueous NaCI. The solvent was removed in vac~o, and the residue was purified by flash chromatography, eluting with CH ~C12 to provide the desired product ( 1.76 g, 75%)-2~0 ~IHz lH~MR~ (CDC13): ~ 7.70 (d, lH); 7.35 (d, 2H); 6.96 (m, 4H); 5.05 ~s, 2H); 3.82 (s, 3H); 3.10 ~dd, 2H); 2.69 (dd. 2H).

b~ $-!4-Methoxv~enzvloxv)- 1 -indanQn~ oxime To a solution of 5-(4-methoxybenzyloxy)-l-indanone (1.74 g, 6.5 mmol) in dry pyridine (40 mL) was added hydroxylamine hydrochloride (0.90 g, 13.0 mmol). The resulting mixture was heated at 60C for 1 h. The solvent was removed in vacuo, and the residue was recrystallized from EtOH/ H20 to 2 0 provide the desired oxime (1.32 g, 72%).

c) N-l [5-L4-Methoxvbenzvloxvlindanyll-N-hv~rQxv-amine To a solution of 5-(4-methoxybenzyloxy)-1-indanone oxime ~1.30 g, 4.6 mmol) in CH2C12 (25 mL) was added BH3 pyridine (1.84 mL, 18.4 mmol), followed by glacial acetic acid (4.6 mL). The2 5 resulting mixture was heated a~ reflux for 4 1/2 h and allowed to cool. The solvent was removed under reduced pressure, 3 N HCI was added ( 15 mL), and the mixture was stirred at room temperature ovemight Saturated aqueous sodium car~onate was added with cooling, and the mixture extracted with CH2CI~ (2x) and dried (Na2S04). The solvent W;lS
removed in vac~o and the residue was purified by flash chromatography, eluting with a 3 0 gradient of MeOH/ CH2C12 to provide the desired hydroxyamine (227 mg, 17%).
25Q M~z 1 NMR (CDC13): ~ 7.31 (m, 3H); 6.86 (m, 4H); 5.42 (br, IH); 4.98 (s, 2H3; 4.50 (dd, lH); 3.82 (s, 3H); 3.02 (m, lH); 2.81 (m, lH); 2.30 (m~ lH); 2.10 (m, lH~; 1.60 (br, lH).

3 5 d) N-l-r5-(4-Meth~xvb~ To a solution of N-1-[5-(4-methoxybenzyloxy)indanyl]-N-hydroxyamine (220 mg, 0.8 mmol) in dry THF (4 mL) was added trimethylsilyl isocyanate (0.'~1 mL, 1.5 mmol). The resulting mixture was heated ;It 60C for 1 h, then allowed tO cool to room temper:~ture and stirred overnight. The solvent , . .~ ,. . .

:

WO 91/14674 PCI`/US91/02010 so w?s removed under reduced pressure and the residue was triturated with Et20. Purificatiol-by flash chromatography eluting with a gradient of MeOH/ CH2C12 provided the desired hydroxyurea (154 mg, 61%). m.p. 166 - 167C.
2~QMElz lEI NMR (CDCl3, MeOH-d4): d 7.35 (d, 2H); 7.18 (d, lH); 6.92 (d, 2H);
6.82 (m, 2H); ~.78 (dd, llH); 4.97 (s, 2H); 3.04 (rn, lH); 2.82 (m, lH); 2.45 - 2.14 (m, 2H).
(cm~l): 3400, 3350, 3290, 3100, 2870, 1690, 1615.
(NH3), m/e (rel. int.): 346 (23); 330 (25); 284 (22); 268 (34); 253 (100); 133 (36);
121 (39).
1 0 ~ calc. for C1gH20N2o4: C 65.84, H 6.14, N 8.53; found C 65.54, H 6.15, N 8.5~.

~amP~
N-3-~Methoxvbenzvloxyl-2~3-dihvdrQbenzofuranYll-N-hvdroxYurea 1 5 a) 2,3-dihydro-6-hydroxy-3-oxobenzofuran (see Example 10, 1.93 g, 12.9 mmol) in DMF
(35 mL) was added sodium hydride (0.46 g of 80% suspension in mineral oil, 15.5 mmol).
After the evolution of hydrogen, 4-methoxybenzyl chloride (2.19 g, 15,5 mmol) was added, and the resulting mixture was stirred at rcom temperature for 2 h. The reaction mixture was partitioned between EtOAc and 3 N HCI, and the organic extract was washed 2 0 with H20 and sa~urated aqueous NaC1. The solvent was removed in vacuo, and the residue was purif-le~ by flash chromatography, eluting with 2% MeO~V CH2C12 to provide 2.46 g (69% yield) of the desired product.

b) ~-(4-M~thQxv~enzvloxv)-~-oximino-~,3-dihvdrobenzQfuran. To a solution of 6-(4-2 5 methoxybenzyloxy)-3-oxo-2,3-dihydrobenzofuran (2.46 g, 9.1 mmol) in dry pyridine (10 ~xlL) was added hydroxylamine hydrochloride (1.24 g, 18.0 mmol). The resulting mixture was heated at 50C for 2 h and allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was recrystallized first from EtOH/ H20 and a second time from CH2C12 tG provide 739 mg of the oxime (29% yield).
c)N-3-~6-(4-MethQ~vbenzv!oxv)-2.3-dihvdrQbenzofuranvll-N-hvdroxvamine. Toa solution of 6-(4-methoxyben~yloxy)-3-oxirnino-2,3-dihydrobenzofuran (739 mg, 2.6mmol) in CH2C12 (8 rnL~ was added BH3 pyridine (1.00 mL, 10.0 mmol) followed by glacial acetic acid (2.6 mL). The resulting mixture was heated at reflux for S h, allowed ~o 3 5 cool to room temperature and concentrated under reduced pressure. llle residue was treated with 3 N HCI (10 rnL), and the mixture was stilTed at room temperature for 2 h. Sodium carbonate was added, and the mixlure was extracted with CH2CI~. The organic extract was washed with H2O and saturated aqueous NaCI. The solvent was removed in vacllo, and the ' '' '., `

WO 91/14674 51 2 0 7 ~ PCr/US91/02010 residue was purified by flash chromatography, elutlng with 2% MeOH/ CH2C12 to provide the hydroxyamine (510 mg, 68%).

d) ~-3-~6-~4-Methoxy~enzYloxY~ 3-dihvdrokçn~ofuranvll-N-hvdroxvurea. To a solu~ion of N-3-[6-(~methoxybenzyloxy)-2,3-dihydrobenzofuranyl}-N-hydroxyamine ~510 mg, 1.78 mmol) in dry THF (10 mL) was added trimethylsilyl isocyanate (0.48 rnL, 3.5~
mmol). The resulting solution was heated at 60C for 1 h and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H2O and saturated aqueous NaCI. The solvent was removed in vacuo, and the resiclue was triturated with 1 0 Et2O and recrystallized from MeOHI CH2C12 to provide the hydroxyurea (92 mg, 16%).
~0 ~z1H ~MR tCDC13, MeOH-d4): ~ 7.35 (d, 2H); 7.20 (d, lH); 6.91 (d, 2H);
6.56 (dd, lH); 6.4B (d, lH); 5.92 (t, lH); 4.95 (s, 2H); 4.60 (d, 2H); 3.72 (s, 3H).
IR (cm~1): 3460, 3320, 3200- 3120, 2950- 2840, 1700 - 1610, 1600, 1580.
FAB MS, m/e (rel. int.): 331[(M+H)+, S8]; 330 (M+, 73); 329 ~(M-H)+, 95]; 313 (48);
1 ~ 255 (55); 137 (100), 121 (100).
. Calc. for C17H18N2Os 1/4 H2O: C 60.98, H 5.57, N 8.37; found C 60.88, H
5.41, N 8.31.

Example 16 2 0 ~Benzvloxv-1.2.3.4-~rahvdronaphthvl)-N-hvdroxvurea a) 5-BenzvlQxv-l-te~alone. To a mixture of potassium hydride (120 mg, 3.0 mmol) in DMF was added 5-hydroxy-1-tetralone (486 mg,3.0 mmol), and the resulting mixture was stirred at room temperature for 1 h. To this mixture was then added benzyl bromide (0.38 '~ S rnL" 3.2 mmol). After stirring at room temperature for an additional 1.5 h, the reaction mixture was concentra~ed under reduced pressure. The residue was dissolved in EtOAc ;lnd washed successively with acidic H2O and saturated aqueous NaCI and dried. The solvent r was removed in vacuo, and the material was used without further purification.

3 0 ~L5-Benzvloxv-l-t~ralone. oxime. To a solution of 5-benzyloxy-1-tetralone, prepared above, in 1: 1 EtOHl pyridine (25 mI,) was added hydroxylarnine hydrochloride (630 mg, 9.1 mmol), and the resulting mix~ure was allowed to stir overnight at room temperature.
The reaction mixture was concentrated under reduced pressure. The residue was purified bv flash chromatography, eluting with a solvent gradient of 0 - 20% EtOAc/ hexanes to affor(l 3 5 the title compound (444 mg, 55% for two steps).

c~ N-1-~(5-Be~Ll~xy-1~ 4-te~r~hydronaphthvl)~l-hvdroxvamine~ To a solution of 5-benzyloxy- I-tetralone, oxime (420 mg, 1.57 mmol) in EtOH was added BH3 pyridine ,1 ,: .. . .
~. .

WO 91/14674 ~ ' 6 -52- PCr/US91/0201û

( 1.20 mL, 11.9 rnmol). To ehis was added 3 N HCI until a slight effervescence was noted, and the reaction rnixture was stirred at room temperature for several h. To the mixture w~s added excess 3 N HCI until the effervescence ceased, and the pH was then adjusted to pH

- 10 with 3 N NaOH. Water (200 mL) was added, and the solid which formed was S collected by filtration and used without further purification. m.p. 108 - 110C
lH N~R (CDC13): o 7.49 - 7.28 (m, ~H); 7. 15 (t, lH); 6.99 (d, lH); 6.81 (d, lH);
5.07 (s, 2H); 4.12 (apparent t, lH); 2.99 - 2.84 (ddd, lH); 2.67 - 2.51 (ddd, lH); 2.
(m, lH); 1.99- 1.70 (m, 3H~.
~Ikl~ (NH3); rn/e (rel. int.): 270 [(M+H)+, 85], 254 (100), 237 (72).
1 0 ~. Calc. for C17H1gNO2: C 75.81, H 7.11, N 5.20; found: C 75.83, H 7.31, N 5.24.

N-l-(S-Benzvl~xy-1,2.3.4-tetrahydrQn~hthvl)-l~-hYdroxvurea. To a solution of N-l-(S-benzyloxy-1,2,3,4-tetrahydronaph~hyl)-N-hydroxyamine (350 mg, 1.49 mmol) in THF
1 5 was added trimelhylsilyl isocyanate (0.46 mL, 3.4 mmol). The resulting mixture was heated at reflux for 1 h and then allowed to cool. The solid which formed was collected by filtration and washed with Et20 to afford the title compound (130 mg). The combined mother liquor and Et20 washes were washed successively with dilute HCI, H20 and saturaeed aqueous NaCl and dried. The solvent was removed under reduced pressure to .-~
2 0 afford additional hydroxyurea (200 mg total, 43%) as a white crystaline solid. m.p. 187 -18~C
1~MR (CDC13, MeOH~ 7.39 - 7.20 (m, 5H); 7.04 (1, lH); 6.82 (d, lH); 6.70 (d, lH); 5.40 (br t, lH); 4.96 (s, 2H); 3.40 - 3.29 (m, 2H); 2.03 - 1.85 (m, 3H); 1.69 (m, lH).
2 5 CIM~ ~NH3); rn/e (rel. int.): 330 [(M-~NH4)+, 79J, 313 [(M+H)+, 71], 297 (39), 270 (55); 254 (100), 237 (85).
~1. Calc. for C18H20N2o3: C 69.21, H 6.45, N 8.97; found: C 68.93, H 6.55, N
8.99.
~xample 17 3 0 ~ -Phe~xy_1.2,3~4-t~trahyd~naphthvl)-N-hvdroxvurea S-PIIçnoxv-l-tenalQne. To a solution containing S-hydroxy-1-tetralone (970 mg, 6.0 mmol) and iodobenzene (4.0 rnL, 35.7 mmol) in DMF (12 rnL) was added slowly withcooling sodium hydride ~150 mg, 6.25 mmol). The resulting mixture was heated until 3 5 dissolution occurred, then allowed to cool. To ~he mixture was added slowly with cooling cuprous chloride (600 mg, 6.1 mmol), followed by tris[2-(2-methoxyethoxy)ethyl~am~ne (0.68 rnL, 2.1 mmol). The resulting mixture w~s heated at 145 - 150C overnight and then allowed to cool. The reaction mixture was partitioned between 3 N HCI and EtOAc and "
.

wo gl/lq674 2 ~ 7 8 1 2 ~ PCr/U~91/02010 filtered. The organic extract was washed successively with H?O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purifie~l by flash chromatography, eluting with a solvent gradient of 0 - 5% EtOAc/ hexanes to afford the title compound (300 mg, 21%).
lH NklR (CDC13): S 7.89 (dd, lH); 7.40 - 7.25 (m, 3H); 7.10 (m, 2H); 6.94 (m, 2H);
2.93 (apparent t, 2H); 2.67 (dd, 2H); 2.14 (apparent quin~et, 2H).

b! 5-Phenoxy~L~et~alon~ ae. To a solu~ion of S-phenoxy- l-tetralone (400 mg, 1.68 msnol) in 1: 1 EtO~V pyridine was added hydroxylarnine hydrochloride (352 mg, 5.1 1 0 mmol), and the resulting mLl~ture was allowed to s~r overnight at room temperature. The reaction rn~xture was concentrated under reduced pressure. The residue was suspended in H20 and the solid which formed was collected by filtration to afford the oxime (330 mg, 78%) which was used without further purification.

) N-1-(5-Pkenoxy-1.2~3 4-~e~rahvdronaphthYI~-N-hvdroxva~nine. To a solution of 5-phenoxy-l-tetralone, oxime (330 mg, 1.3 rnrnol) in EtOH was added BH3 pyridine (0.5~
mL, 1.3 7A'nmOI). To this was added 3 N HCI until a slight effervescence was no~ed, and the reaction ~nixture was s~irred at room temperature for several h. To the mixture was added excess 3 N HCI until the effervescence ceased, and the pH was then adjusted to pH 9 - 10 2 0 with 3 N NaOH. Water was added, and the solid which folmed was collected by filtr~tion and used without further purification (316 mg, 95%).
lH NM~ (CDC13): ~ 7.29 (m, 2H); 7.18 - 7.01 (m, 3H); 6.91 (m, 2H); 6.82 (dd, lH);
4.17 (m, lH); 2.90 - 2.78 (m, lH); 2.62 - 2.49 (m, lH); 2.27 - 2.15 (m, lH); 1.95 -1.71 (m, 3H).
CIMS tNH3); mle (rel. int.): 256 [(M+H)+, 100~, 240 (88); 238 (74), 223 (39).
Anal. Calc. for C16H17NO2: C 75.27, H 6.71, N 5.49; found: C 75.11, H 6.80, N
5.41.

d) N-l-f5-Phenoxv-1,2,3,4-tetrahvdronaphth~l)-N-hvdroxvure~. To a solution of N-1-(5-3 0 phenoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine (255 mg, 1.0 mmol) in THF w~s added ~imethylsilyl isocyanate (0.32 rnL, 1.0 mmol). The resulting mixture was he~ted reflux for 1 h and then allowed to cool. The reaction rnixture was concentrated under reduced pressure, and Et20 was added ~o the residue. The solid which formed w~s collected by filtration to afford the title compound (150 mg, 50%). m.p. 123 - l~SC
3 5 lH~MR (C:DC13, MeOH-d4): ~ 7.30 - 7.22 (m, 2H); 7.12 - 6.99 (m, 3H); 6.88 (m, 2H); 6.73 (m, lH); 5.46 (m, lH); 2.82 - 1.70 (m, 6H).
(NH3); m/e (re]. int.): 316 [(M+NH4)+, 46], 299 [(M+H)+, 100].

: , .. : , . ~.
' ,. ::

!
WO 9~/14674~S~ 6 PCr/US91/021~10 _~

,~. Calc. ~or C17H1SN2O3: C 68.44, H 6.08, N 9.39; found: C 68.18, H 6.04, N
9.54.

Exam~le 18 SN-I-!~-PhenQxvindanyl~-N h~drQx~wrea ~3,~. To a solution containing 3-phenoxybenzyl alcohol (5.0 g, 25.0 mmol) and mphenylphosphine (7.2 g, 27.5 rnmol) in CH2C12 (200 rnL) under anargon atmosphere at -30C was added, pornonwise, N-bromosuccinimide (4.4 g, 25.01 O rnmol). The resulting mixture was stirred at -30C for 1 h, and then concen~ated under reduced pressure. The residue was filtered through silica gel, eluting with hexanes to affonl the title compound as a colorless oil (4.73 g, 72%).

b? Diethvl 3-ph~oxvbenzYlmalQnate. To a suspension of sodium hydride (1.36 g of 60qo 1 5 dispersion in mineral oil, 33.9 mmol) in DMF ~30 mL) under an argon atmosphere at 0C
was added, over 10 min, a solution of diethyl malonate (5.42 mL, 35.7 mmol) in DMF ('~0 mL). The reaction mixture was stirred at 0C for 30 min, at which time a solunon of 3-phenoxybenzyl bromide (4.7 g, 17.9 mmol) in DMF (25 mL) was added. The resultingmixture was allowed to warrn to room temperature and stirred for 1 h. The mixture was 2 0 partitioned between Et20 and aqueous NH~CI, and the organic extract was washed successively with ~2 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10%
EtOAc/ hexanes to afford the title compound as a colorless oil (4.17 g, 68%).

2 5 ~D~. To a solution of diethyl 3-phenoxybenzylmalonate (4.17 g, 12.2 mmol) in EtOH (100 mL) was added 1 M NaOH (61 rnL, 60.9 mmol), andthe resulting mixture was heated at reflux overnight. The mixture was allowed to cool, and the pH was adjusted to pH 4 by the addition of 1 M HCI. The mixture was diluted with CH2C12, and the organic layer was washed successively with H2O and saturated aqueous 3 0 NaCI and dried (MgSO4). The solvent was removed in vacuo, and the residue was dissolved in acetic acid and heated at reflux overnight. The reaction mixture was allowed to cool and was par~tioned between CH~C12 and H20. The aqueous phase was extracted with CH2C12 (2 x 100 mL) and the combined organic extracts were washed successively with H20 and sa~urated aqueous NaCI and dried (MgSO4). The solven~ was removed in 3 5 vacuo to afford the title compound as a pale yellow oil (2.67 g, 90%).

d) 5-Phenoxv-l-in~anone and ?-phçnoxv-l-indanone. To a round-bottomed flask fitted with a mechanical stirrer was added polyphosphoric acid (600 g). To this was added over I

. . , .
. . .
. . . . ...
,. .. . . ..... . .
- . ,: , ., .

WO 91/14674 2 ~ 7 ~ US91~02010 h, 3-(3-phenoxyphenyl)propanoic acid (49 g, 0.202 rnol), main~aining the ternpera~ure at 75C. Upon completion oî the addition, the resulting mixture was stirred for 1 h at 80C, ~hen cooled to 0C and diluted with ice cold H2O. Ether was adcled, and the mixture was stirred for 30 min. The layers were separated, and the aqueous phase was ex~acted with Et20 (2 x 200 mL). The combined organic extracts were washed successively with H20, saturated K2CO3, H20 and saturated aqueous NaCI and dried (K.~CO3). The solvent was removed ~n vacuo, and the residue was purified in portions by flash chromatography, eluting with 10~o EtOAcl hexanes. The major component which was isolated was recrystallized from cyclohexane to afford 5-phenoxy-1-indanone (4.63 g, 10%). m.p. 67 -~R. (CDC13): ~7.72 (d, lH); 7.42 (t, 2H); 7.22 (m, lH); 7.10 (d, lH); 6.98 (d, lH); 6.93 (s, lH); 3.06 (dd, 2H); 2.71 (dd, 2H).
A minor component was also isolated and recrystallized from cyclohexane lo afford 7-phenoxy-1-indanone (548 mg, 1%). m.p. 102 - 103C
el 5-Phçnoxv-l-indanonç. oxirne. To a solution of 5-phenoxy-1-indanone (4.5 g, 19.9 mmol) in pyridine (30 mL) was added hydroxylamine hydrochloride (2.78 g, 39.9 mmol).
The resulting mixture was heated at 50C for 30 min and then allowed to cool. The mixture was concentrated under reduced pressure, and the residue was treated with H2O (100 mL) 2 0 and stirred for 1 h. The solid wh*h formed was collected by filtranon, washed with H2O
and dried underreduced pressure to afford the oxime (4.48 g, 94%) as a solid. m.p. 107 -f~ N~l-rS-Phenoxvindanvl)-r~J-hydroxvamine. To a solution of S-phenoxy-l-indanone, 2 5 oxime (6.38 g, 26.6 rnmol) in 2: 1 Et2O/ MeOH (120 mL) under an argon atmosphere at 0C was added BH3-pyridine (11.78 mL, 116.6 mmol). The resulting mixture was allowed to wann to room temperature, and 2 N HCI (42 mL, 84.3 rnmol) was added dropwise over 30 min. Upon completion of the addition, thin layer chromatographic analysis indicated that the reaction was incomplete, so additional BH3-pyridine (3 mL, 30 3 0 mmol) was added. Stirring was continued for 30 rnin more, at which time 2 N HCI (25 rnL, 50 mmol) was added dropwise. The pH was adjusted to pH 12 by the addition of 3 N
NaOH. The mixture was extracted with CH2C12 (4 x ~S0 mL), and the combined organic extracts were washed successively with H2O and saturated aqueous and dried (Na2SO4).
The solvent was removed in vacuo, and the residue was purified by flash chromatography, 3 5 eluting with ~5~ EtOAc/ hexanes to afford the title compound as a white solid (5.1 g, 79%). m.p. 99 -100C

,, :;
~, -:.: ~

WO gl/14674 ~ PCr/US9l/02010 ~ N- l -(S-PhenQxyindany~ -hvd~oxvurça. To a solution of N- I-(S-phenoxyindanyl)~
hydroxyamine (4.9 g, 20.3 mmol) in THF (100 rnL) under an argon atmosphere was add~3 trimethylsilyl isocyanate (2.75 mL, 4~,.6 mrnol). The resulting mixture was heated to 60C
for 1.5 h, and then allowed to CQOL The rnixture was concent~ated under reduced pressure, 5 and the solid residue was recrystallized ~rom EtOH to afford the ti,~e compound as a white solid (3.0~ g, 53%). m.p. 172 - 173C
~kl~. (NH3); m/e (rel. int.): 302 [(M+N~4)+, 9], 285 [(M+H)+,10], 209 (100).
. Calc. for Cl6Hl6N2o3: C 67.59, H 5.67, N 9.85; found: C 67.51, H 5.72, N
9.90. .;

~ ,:
N-1-r5-(4-FluoLoDIIenoxvLlæ~ 4-tetrahvdrQn~2hthvll-l~-hv~roxvurea a~ 5-~4-nuorophennxv!- I -tep alone. To a solution containing S-hydroxy- I -te~alone ( 1.0 ~, 1 5 6.1 mmol) and p-difluorobenzene (4.4 mL, 42.4 mmol) in DMF (13 ml.) was added slo~ly with cooling sodium hydride (160 mg, 6.67 mmol). The resulting mixture was heated until dissolution occurred, then allowed to cool. To the mixnlre was added slowly with cooling cuprous chloride (585 mg, 6.1 tnmol), followed by tris[2-(2-methoxyethoxy)ethyl]amine (0.68 mL, 2.1 mmol). The resuldng mixture was heated at 145 - 150C overnight and then 2 ~ allowed to cool. The reaction mixture was par~i~oned betw~een 3 N HCI and EtOAc and filtered. The organic extract was washed successively with H20 and saturated aqueous NaCI and dried (MgSO4). The solvent was removed in vacuc, to afford the title compound (250 mg, 16%).
IR (CDC13): ,~, 7.83 (cl, lH); 7.26 (t, lH); 7.03 (m, 3H); 6.91 (m, 2H); 2.94 (t, 2 5 2H); 2.66 (dd, 2H); 2.12 (apparent quintet, 2H).
(~IM,~ (NH3), rn/'e (rel. int.): 274 [(M+NH4)+, 100], 257 [(M+H)+, 42].

bl 5l4~ orophenoxY)-l-tetralvne, oxim~. To a solution of 5-(4-fluorophenoxy)-1-tetralone (250 mg, 1.0 mmol) in 1: 1 EtO~V pylidine (4 mL) was added hydroxyl~mine 3 0 hydrochloride ~210 mg, 3.0 mmol), and the resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended in H20 and the solid which formed was collected by filtration to a~ford the oxime (160 mg, 62%) which was used without further purification.

3 5 ~ ~ C ~ . To a solution of 5-(4-fluorophenoxy)-1-tetralone, oxime (150 mg, 0.SS mmol) in E~OH was added BH3 pyridine (0.4û mL, 4.0 mmol). To this was added 3 N HCI until a slight effervescence was noted, and the reaction mixture was stirred at room temperature for WO 91/14674 -57- 2 0 7 ~ 1 2 6 several h. To the rnixtu.~ was added excess 3 N HCl until the effervescence ceased, and th~
pH was then adjusted to pH g - 10 w~th 3 N NaOH. Water was added, and the solid which formed was collected by filtration and used without further purification (79 mg, 53%).

S ~=_Q~. Toasolution of N- 1-[5-(4-fluorophenoxy)- 1 ,2,3,4-tetrahydronaphthyl]-N-hydroxyamine (79 mg, 0.29 rmTlol) in THF was added trimethylsilyl isocyanate (0.10 mL, 0.74 mmol). The resulting rnixturc was heated at reflux for 1 h and then allowed to cool. The reaction rnixture was concentrated under reduced pressure, and EtzO was added to the residue. The solid which 1 0 formed was collected by filtration to afford the title compound (40 mg, 44%).
(CDCl3, MeOH-d~ 7.08 (m, 2}I); 6.97 (m, 2H); 6.84 (m, 2H); 6.68 (dd, IH); 5.49 (m, lH); 2.84 - 2.50 (m, 2H); 2.00 (m, 3H); 1.74 (br m, lH).
~k~ (NH3), m/e (rel. int.): 334 [(M+NH4)~, 41], 317 E(M+H)+, 100].
An~. Calc. for C17H17FN2O3: C 64.55, H 5.42, N 8.86; ~ound: C 62.15, H S.Sl, I`~1 5 9.17.

E~arnple 20 aL6-(2-p~ dinvlmeIhQxv~ t~tralone~ To a solu~on containing ~hydroxy-1-tehalone (500 mg, 3.08 mmol) and 2-picolyl chlonde, hydrochloride (556 mg, 3.39 mmol) in dry DMF
(lS mL) under an argon atmosphere was added potassium carbonate (1.28 g, 9.24 mmol).
The resulting mixture was allowed to stir at room temperature for 24 h, thèn diluted with 2 5 EtOAc and filtered. The fil~ate was washed successively with H20 and saturated aqueous NaCl and dried (MgS04). The solvent was removed in vacuo, and the residue was pu;ifie~
by flash ch~omatography, eluting with 2: 1 hexanes/ EtOAc to afford the title compound (578 mg, 74%) as a colorless oil which solidified upon standing. m.p. 58 - 59C
1~MR (CDC13): ~ 8.6(~ (m, lH); 8.00 (d, lH); 7.72 (m, lH); 7.50 (m, lH); 7~21 (m, lH); 6.90 (dd, lH); 6.80 (d, lH); 5.25 (s, 2H); 2.91 (t, 2H); 2.60 (t, 2H); 2.10 (m, 2H).
~!kl~ (NH3), m/~: 271 [(M+NH4)~], 254 [(M+H)+].
Anal. Calc. for C16H1SNO2: C 75.87, H 5.97, N 5.53; found: C 75.95, H 5.99, N
5.61.
b~ f2-Pyridiny!methQxy2:L-tetralone oxime. To a solution of 6-(2-pyridinylmelhoxy)- l-te~alone (56û mg, 2.21 minol) in dry pyridine (6 mL) under an ~rgon ~tmosphere w~s added hydroxylarnine hydrochloride (307 mg, 4.42 mmol). The resulting mixture W;1S

.. . .

:

WO 9l/14674 ~ 58- PCI/U59~/02010 heated at 50C for 0.5 h, then allowed to cool to room ternperature and concentrated under reduced pressure. The residue was cTystallized from EtOH to afford the title compound as ;
white solid (468 mg, 79%). m.p. 164 - 165C
l~NM~ (CDC13): o 8.60 (br d, lH); 7.86 (d, lH); 7.72 (m, lH); 7.55 (apparent d, lH); 7.26 (m, lH); 6.B6 (dd, lH); 6.79 (d, lH); 5.30 (s, 2H); 2.85 - 2.70 (overlapping t and m, 4H); 1.90 (m, 2H).
(: IklS (NH3), m/e: 286 [(M~NH4)~], 269 [(M+H)+].
l. Calc. for Cl6Hl6N2o2: C 71.62, H 6.01, N 10.44; ~ound: C 71.61, H 5.95, N
10.~4.

c~ -r6-!2~pvridinylm~ k7oxv)-l.2~3-~4--te~r-ahvdronaDhthv~ -hydroxvamine. Toa solution of ~(2-pyridinylmethoxy)-1-tetralone, oxime (335 mg, 1.25 mmol) in 2: 1 E12O/
MeOH (65 rnL) under an argon atmosphere at 0C was added BH3-pyridine (0.55 nL, 5.49 mmol). The reaction mixture was allowed to warm to room temperature. After stirring 1 5 for 1 h, 2 N HCI (2 mL, 4.0 mmol) was added dropwise over 10 min. The mixture was stirred an additional 5 h, at which time 1 N HCl was added, and stirring was continued until the effervescence ceased. The pH was then adjusted to pH 9 - 10 by the addition of 3 N
NaOH. The rnixture was extracted with CH2C12 ~4x), and the combined organic extracts were washed successively with H20 and saturated aqueous NaCl and dried (MgSO4). The 2 0 solvent was removed in vaCuo, and the residue was purified by flash chromatography, eluting with 2% MeOH/ CH2C12 to afford the hydroxyamine as a white solid (216 mg, 64%). m.p. 1 14 -1 15C
lH ~IR (CDCl3): ~ 8.58 (br d, lH); 7.70 (apparent t, lH); 7.50 (d, lH); 7.22 (m,2H); 6.79 (dd, lH); 6.71 (br s, lH); 5.14 (s, 2H); 4.06 (m, IH); 2.72 (m, 2H); 2.20 2 S (m, lH); 1.97 - 1.65 (m, 3H).
CTMS (NH3)9 m/e: 271 [(M~H)+], 253.
Anal. Calc. for Cl6Hl8N2O2-0.25 H2O: C 69.92, H 6.78, N 10.19; found: C 70.24, H 6.86, N 10.30.

3 0 dl N-1-~6-(2-Pvn~y!methoxv?-1.2~3.4-tetrahvdronaphthvll-N-hv~ oxvurea. To asolution of N-1-[6-(2-pyridinylmethoxy)-1,2,3,~tetrahydronaphthyl]-N-hydroxyamine (260 mg, û.96 mmol) in dry THF (15 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.26 mL, 1.92 rnmol). The resulting mixture was heated at 60C
for 1 h, then allowed to cool to room temperature and stilTed an additional 1 h. The re~ction 3 5 mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H20 and saturated aqueous NaCI and dried tMgS04). The solvent was removed in vacuo, and the solid residue was recrystallized from E~O~V Et~O to afford the title compound as an off-white solid (117 mg, 39%). m.p. 175 - 176C

.
..: : ~ '. ' :
.
; . , WO 9~ 674 PCr/US91/02010 ~59~ ~ 7~1 2:6' ' ' lH ~IR (DMSO-d6): o 8.88 (s, lH); 8.56 (d, lH); 7.80 (t, lH); 7.49 (d, lH); 7.32(m, lH); 7.06 (d, lH); 6.79 (dd, lH); 6.71 (d, lH); 6.30 (s, 2H); 5.2~ (m, IH); 5.12 (s, 2H); 2.54 (m, 2H); 2.00 - 1.57 (m, 4H).
IB (KBr): 1675 cm~1.
S ~I~ (NH3), m/e: 331 [(M+NH4)+], 314 [(M+H)~].
~l. Calc. for Cl7Hl9N3o3: C 65.16, H 6.11, N 13.41; found: C 65.16, H 6.18, N
13.04.

~mv.
N-l-r6-(2-~çn~in~idazo~ n~hQxv),~ .4-tçtrahYdrQna~hthv~L-N-hvdroxy7~re~

~! ~(2-B~elIzirnidazolylmethoxyl-l-tetralone~ To a solution containing 6-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and 2-(chloromet'nyl)benzirnidazole (2.26 g, 13.6 mmol) in dry DMF (61) mL) under an argon atmosphere was added potassium carbonate (5.1 1 g, 37.() I S mmol). The resulting mixture was allowed to stir at roorn temperature for 24 h, then diluted with EtOAc and filtere~ e filtrate was washed successively with H20 and saturated aqu¢ous NaCl and dned (MgS04). The solvent was removed in vacuo, and the residue w~s purified by flash chromatography, eluting with 1: 1 EtOAc/ hexanes to provide the ~itle compound as a pale yellow solid (507 mg, 14%). m.p. 165 - 166C
lH NMR (CDC13): o 7.95 (d, lH); 7.75 (brs, lH); 7.45 (brs, lH); 7.28 (m, 2H);
6.85 (dd, lH); 6.75 (d, lH); 5.40 (s, 2H); 2.88 (m, 2H); 2.60 (m, 2H); 2.10 (m, 2H).
. Calc. for C1gH16N2O2: C 73.95, H 5.52, N 9.58; found: C 73.48~ H 5.51, N
9.55.

2 5 bL6-(2-Benzimidazolvlmethoxv)-l-te~Qne.gxim~. To a solution of 6-(2-benzimidazolyl-methoxy)-1-te~alone (375 mg, 1.28 mmol) in pyridine (4 mL) was added hyd;oxylarnine hydrochloride (178 mg, 2.56 mmol). The resulting mixture was hea~ed at 50C for 30 rnin, then allowed to cool to room temperat~re and concentrated under reduced pressure. The residue was clystallized from EtOH to provide the title compound as a white solid (278 mg, 3 0 71%). m.p. >210C (dec) 1~1 NMR (CDC13, MeOH-d~ 7.69 (d, lH); 7.53 (m, 2H); 7.35 (m, 2H); 6.73 (m, 2H); 5.40 (s, 2H); 2.57 (m, 4H); 1.6S (m, 2H), ~1. Calc. for Cl8Hl7N3o2 HCI: C 62.88, H 5.28, N 12.22; found: C 62.63, H
5.31, N 12.10 c~N~ (2:BenzimidazQlylmethQxy)-(1.2.~.4-~,etrahvdronaphthvI)~-N-hvdroxvamine. Toa solu~on of 6-(2-benzimidazolylmethoxy)- 1 -tetralone, oxime (262 mg, 0.85 mmol) in 1:
MeOHJ Et20 (50 mL) at 0C under an argon atmosphere was added BH3 pyridine (0.38 ....

WO 91/14~74 P~/lJS91/02010 2 0 7 ~ '1 2 ~ 60-mL, 3.75 mmol). The reaction mixture was allowed to warrn lo room temperature and stirred for 1 h, at which time 2 N HCI (1.36 rnL, 2.73 mmol) was added dropwise over 10 r min. The resulting mixture was allowed to stir at room temperature overnight. To the rnixture was added 1 N HCI, and stirring was continued until the effervescence ceased. The S pH was adjusted to pH 9 - 10 by the addition of 3N NaOH, and the mixture was extracted with CH2Cl2 (4x). The combined organic extracts were washed successively with H20 and saturated aqueous NaCI and dried (MgSO4). The solvent was removed in vacuo, and the solid residue was recrystallized from CH2C12 to afford the title compound ( 129 m~, 49%). m.p. 157-159C
1 Q lH NMR (DMSO-d6): o 7.60 (m, lH); 7.47 (m, lH); 7.32 - 7.12 (m, 3H); 6.83 (m, 2H); 5.22 ~s, 2H); 3.80 (m, lH); 2.65 (m, 2H); 2.04 (m, 2H); 1.88 (m, lH); 1.60 (m, 2H).

d) N-l-r~(2-Benzimidazolvlmethoxy)-(1.2.3.4-tetrahvdronar)hthYl~l-N hvdroxvure~. To a 1 5 solution of N-1-[6-(2-benzimidazolylmethoxy)-(1,2,3,4-tetrahydronaphthyl)]-N-hydroxyamine (115 mg, 0.37 mmol) in dry THF (7 rnL) under an argon atrnosphere W;1S
added tnmethylsilyl isocyanate (0.10 mL, 0.74 mmol). The resulting mixture was heated at 60C for 2 h, then allowed to cool to room temperature and concentrated under reduced pressure. The solid residue was purified by flash chromatography, eluting with 1: l 2 0 MeO~V CH2C12 to afford the title compound as a whits solid (64 mg, 49%). m.p. 158 -lH NklR. (DMSO-d6): ~ 8.88 (br s, lH); 7.60 (m, lH); 7.50 (m, lH); 7.19 (m, 2H);7.10 (br d, lH); 6.85 (br dd, lH); 6.78 (br d, lH); 6.31 (br s, 2H); 5.23 (overlapping s and m, 3H); 2.63 (m, 2H); 2.00 - 1.77 (two overlapping m, 3H); 1.65 (m, lH).
2 5 FAB M~, rnJe: 391 [(M+K)+], 375 [(M+~a)+~, 353 [(M+H)~].
Anal. Calc. for C1gH20N4o3-H2o: C 61.61, H 5.99, N 15.13; found: C 61.71, H
5.98, N 14.84.

3 Example 22 N- I -t7-Phenoxyindanvl)-N-hyslroxvurea a) 7-Phenoxy-1-1ndanQne, oxime. To a solution of 7-phenoxy-1-indanone (485 mg, 7.16 mmol, see example 18 for preparation) in pyridine (20 rnL) was added hydroxyl~rnine 3 5 hydrochloride (300 mg, 4.32 mrnol). The resulting mixture was heated at 50C for 1 h ~nd then allowed to cool. The mixture was concentrated under reduced pressure, and the residue was triturated with H2O. The solid which formed was collected by filtration, :

- . : , , WO ~1/14674 -61- 2~ ~/US91/02010 washed with H20 and dried under reduced pressure to afford the oxime (460 mg, 89%) as :
yellow solid. m.p. ~200C (dec) b! N-1-(7-~he~cvindanvlL~-hvdroxvamin~. To a solution of 7-phenoxy-1-indanone, oxime (450 mg, 1.88 mmol) in 2: 1 Et2O/ MeOH (100 rnL) uncler an argon atmosphere was added BH3-pyridine (0.83 mL, 8.27 tnmol), followed by the dropwise addition of 2 N
HCl (3 mL, 6 tnrnol). The resulting mixhlre was allowed to stir at room temperature for ~
h, at which time 2 N HCI (20 rr~) was added dropwise. The pH was adjusted to pH 9 - 10 by the addition of 3 N NaOH. The mixture was extracted with CH2Cl2 (4 x 100 rnL), and 1 0 the combined organic extracts were washed successively with H2O and saturated aqueous and dried (Na2S04). The solvent was removed in vacu~, and the residue was purified by flash chromatography, eluting with 25% EtOAc/ hexanes to afford the title compound as a light brown oil which solidified upon standing (341 mg, 75%). The oil was triturated with cyclohexane providing a light tan solid.

cl l'J-1-(7-PhenoxvindanYI)-~-hv roxvurea. To a solution of N-1-(7-phenoxyindanyl)-N-hydroxyarnine (315 mg, 1.30 mmol) in THF (20 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.35 mL, 2.60 mmol). The resulting mixture was heated to 60C for 2 h, and then allowed to cool. The mixture was concent~ated under reduced 2 0 pressure, and the solid residue was recrystallized from EtOH to afford a tan solid. This was further purified by flash chromatography, eluting with 1: 1 EtOAc/ hexanes to afford the title compound as a white solid (168 mg, 45%). m.p. 161 - 162C
FAE~ M[S, rn/e: 285 [(M~H)+].
l. Calc. for Cl6Hl6N2(:)3 1/8 H2O: C 67.06, H 5.70, N 9.79; found: C 67.02, H
2 5 5.62, N g.60.

~-~v~roxv-N-l -r6-(2^phenvlethvl~-1 .2~3~4-tetrahvdronaphthvllacetamide 30 a) N-Ace~Qxv-N~ (2-phenvle~hvl)-1~2~tetrahydr~naphthvllacetamide. Toasolutionof N-hydroxy-N-1-[6-(2-phenylethyl)-1,2,3,4-tetrahydronaphthyl]amine (0.63 g, 2.4 mmol) in ~I2C12 (12 mL) prepared in Example 8, Step (c) was added triethylarnine (0.99 rnL, 7.08 rnmol) and acetyl chloride (0.37 mL, 5.19 mmol). The resulting rnixture was stiITed at room temperature for 30 min, then poured into dilute aqueous HCl and washed 3 5 successively with H2O and saturated aqueous NaCl. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting wi~h CH2C12 to provide the desired product (0.59 g, 72%).

WO 9l/l4674 ~ PCr/US~1/02010 ~
2,078~2b " " - -62- , ~
b) I~-Hvdrox~N-l-r~-(2-~hçnvlethyl~ 3.4-tetrahvdronaphthvlLacet~mide. Toa solution of N-acetoxy-N-1-[6-t2-phenylethyl)-1,2,3,4-te~ahydronaphthyl]acetarnide (5~0 mg, l .7 mmol) in 2: 1 isopropanoV H2O (6 mL) was added LiOH (204 mg, 8.5 mmol).The resulting n~ixture was stirred at room temperature for 30 min, then poured into CH2C12, washed successively with H20 and saturated aqueous NaCI and dried (Na2SO~,).
The solvent was removed in vacuo, and the residue was recrystallized from CH2C12/
hexanes. The residue was further purified by flash chromatography, eluting with 25%
EtOAc/ hexanes to provide the desised acetamide ~67 mg, 13%).
~1}1~ ~IR (CDC13): o 5.80 and 5.10 (br t and dd, lH); 2.87 (s, 4H); 2.76 (m, 1 0 2H); 2.25 (s, 3H); 2.06 (m, 3H); 1.81 (m, IH).
IR (cm~1): 3090 - 3010, 2960- 2780, 1620 - 157û.
. (NH3), m/e (rel. int.): 310 [(M~H)+, 4]; 294 (40), 235 (100).
~. Calc. for C20H23NO2: C 77.64, H 7.49, N 4.53; found: C 77.55, H 7.34, N
4.51.

Example 24 N-~vdroxv-N-Ll~benzvloxv-1~2~3~4 tetrahvdronaphthyl)laçetamide N-~ydroxy-N- I -(6-benzvloxv- 1 ~2.~,~-tetrahYdrona~h~hvl~laçetam;de. The desired 2 0 compound is prepared according to the method of Exarnple 23, steps (a) and (b) exçept using a solution of N- 1-(6-benzyloxy- 1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 1, step (d).

~m~Z~
2 5 N-Hydroxv-N-~1-(5-benzvloxYin~anvl)lacetarnide N-Hvdroxv-N-l-(5-benzvloxvindanvl~açetamide. The desired compound is prepared according to the method of Example 23 steps (a) and (b) except using a solution of N- 1 -(5-ben~yloxyindanyl)-N-hydroxyamine as prepared in Example 2, step (d).
Ex~m~le 2~
N-~lvdroxv-N I-(6-me~hoxy~ etrabvdrQnaphthvl)acetamide N-~vdrQxv-N- 1 -(~-methoxv- l .2,~tetrahvdronaphthvl~acetamide 3 5 The desired compound is prepared according to the method of Example 23, steps (~) and (b) except using a solution of N-1-(6-methoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 3, s~ep ('o).

:`

..

WO 9]/1467q ~ 7 8 1 2 6 ~Pcr/US91/020~0 ~xam~le 27 N-Hvdroxv-N~ 3,4-tetra~hy~rQn~ph~hyl)~

N-Hydroxv-N-1-!1.2~3.4-tetrah~dron~bthyl)a~tamide. Thedesiredcompoundis prepared according to the method of Exarnple 23, steps (a) and (b) except using a solution of N-1-(1,2,3,4-tetrahydronaph~hyl~-N-hydroxyamine as prepared in Example 4, step (b).

~amvl~
N-Hvdroxv~6-(~--methoxybenzyl`Lo--xy-l ~2~4-~etrahvdronaphthvllacet~ide ~ . The desired compound is prepared according to the method of Example 23, steps (a) and ~b) except using a solution of N-1-[6-(4-methoxybenzyloxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyarnine as prepared in Example 5, step (c).
~m~L~2 N-Hydroxv-N- I -~-(4-~hlorobenzyloxv)- 1 .23~4-tetrahvdrQnaphthyllacetamide N-Hvdroxv-N-l~L~4 chLorobenzvloxv)- 1 .~.3.4-fetrahvdrQn~Yll~ce~amide. The 2 0 desired compound is prepared according to the method of Example 23, steps ~a) and (b) except using a soludon of N-1-[6-(4-chlorobenzyloxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyarnine as prepared in Example 6, step (c).

2 5 N-HvdrQxy-l~-l-L~-~2-na~hthYlmethQxY)-L2.~-tetr~hvdrQnaphthvllacetamide ~Hvdroxv-~-l-r~-(2-naphthyLmetho~ l~2~ hy~na~hthy!la~mi~.
The desired compound is prepared according to the method of Examp}e 23, steps (a) and (b) except using a solution of N-1-[6-(2-naphthylmethoxy)-1,2,3,4-tetrahydronaphthyl]-~-3 0 hydroxyamine as prepared in Exarnple 7, step (c).

Exampl~l N-Hydrox v-N-~-(6-benzvloxy-2.3-dihvdro~nzofuranvl~acetamide 3 5 N-Hvdroxy-N-3-(~benzvloxv-2 ~ihy~Qbenzofuranvllacetamide. The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-3-(~benzyloxy-2,3-dihydrobenzo~uranyl)-N-hydroxy~mille as prepared in Example 10, step (e~.

:: , ";:, .
: ::

WO 91/14674 P~/US91/02010 2~ ?'G
Exam~le 32 ~-Hvdroxv-N-1-~6-('~-quinolin~lmethvlo~~ 4-tetrahvdronaphthvlla,çetamide _ ~bIhyl~l~ The desired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-1-[6-~2-quinolinylmethyloxy)-1,2,3,4-tetrahydronaphthyll-N-hydroxyamine as prepared in Exarnple 9, step (c).

~
N-Hvdroxv-N-2-f7-methoxv-1 ~2~3,4-te~rahvdronaphthvl~Lceramide N-HydroxY-N-2-(7-methox~L2.~4-~etrahYdrQn~hthvl)acetamide. The desired compoun(lis prepared according to the method of Example 23, steps (a) and (b) except using a solution 1 5 of N-2-(7-methoxy- 1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 11, step (b).

Exam~le ~
N-~1ydrQxv-~- I -r7-bçnzvlQxv- 1~2.3 ~çtrahYdronaphthvl~acetamide -Hvd~oxv-~-1-(7-b~nzyloxy-1~2~3~4-tetrahvdrona~hthvl)acetamide. Thedesired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-1-(7-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Exannple 12, step (d).
~xam.~le 35 N-~lvdroxY-~- ~1 -(6-phenvl- I ~2~ -tetrahvdrQnaphthvl)l~cç~mide -Hvdroxv-N-tl-(6-phenvl-1,2~3~4-tetrahydronaphthYl)lacetamide. Thedesired 3 0 compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-1-(6-phenyl-1,2,3,~tetrahydron~phthyl)-N-hydroxyamine as prepared in Example 13, step (c).

Example 36 3 5 . N-~vdroxv-N-l-rS-(~me~ Y~enzvloxv~indanvllacçtamide N-~vdroxy-N-1-~5-(4-methox~benzvl~xy~indanvllacet~T~e The desired compound is prepared according to the method of Ex~nple 23, steps (a) and (b) except using a solutio ., , .. ,, ~ ~ . . .:, , .

WO 91/14674 2 0 ~ 31~ 6 ~ ~

of N-1-[5-(4-methoxybenzyloxy)indanyl]-N-hydroxyamine as prepared in Example 14, st~
(c).

ExarnDle 37 S -Hvdmxv-~-3-~6-(4-methoxy~en~lQx~ 3-dihydrQbenzQ5~yL

~-HvdrQxv-N-~ (4-methoxvhenzvloxv)-2~-dihv~robenzofuranvllacetamide. The desired compound is prepared according to the method of ~xample 23, steps ~a) and (b) except using a solution of N-3-[6-t4-rnethoxybenzyloxy)-2,3-dihydrobenzofuranyl]-N-1 0 hydroxyamine as prepared in Fxample 15, step (c)~

Example ~
~-Hys~"o,xy-N-I-fS-benzvloxY-l~ ~tetrahydrQnaphthvl)acetamide ~I:Hvdroxv-N-l-t~-benzvloxy-l~2~3~4-tetrahvdro~aphthyl~amide~ Thedesired compound is prepared according to the method of Example 23, steps (a) and (b) except using a solution of N-1-(5-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 16, step (c)~
Example 39 ~-~vd~oxv-N-I-f6-phenoxv-1~2~3~4-~e.~ahvd.ron~hthvl~acetamide a) -Phenoxv-l-te~a]one. A solution of 6-(1-tetralonyl) trifluoromethylsulfonate (4~7 mOt 2 5 1.5 rnmol; see exarnple 1 for preparation) and phenol ( 300mg, 3~2 mmol) in dry collidine (3 mL) con~aining Cu20 (107 mg,0.75 mmol) is heated at 170 C for 72 h. The resultin~J
solution is diluted with ether, washed with 6N HCI and brine and then concentrated in vacuo to yield the desired bialyl ether.

3 0 b) ~he~oxv-l-tetT~lone oxime. To a solution of 6-phenoxy-1-tetralone (2.4 g, 10.7 mmol) in dry pyridine (25 mL) is added hydroxylamine hydrochloride ( 1.4 g, 24 mmol).
The resulting rnixture is heated at 50C for 30 min, then allowed to cool and concen~ted under reduced pressure to afford the oxime.

C! N-1-(6-Phenoxv-1.'7~.4-tetrahydronapht~-N-hvdroxvamine. Toasolutionofthe oxime prepared above (2.39 g, 10 rr~nol) in 2:1 Et~O: M OH (200 mL) at 0C is added BH3-pyridine complex (3.9 mL, 38 mmol). After wa~ing to room temperature and StilTing ~or I h, 6N HCI (S mL) is added, and the reaction n~ixture is stirred an additional ' ,, . ~ .: . ;. . ~

, ' . ~ , , ., ' . . !
. ~ ' ' ' ' 1. .
' ' . ' , . ' . . .

2~ 66- PCI/USgl/02010 h. At this time, more BH3-pyridine (2 rnL, 20 mmol) is added, followed by 6N HCI (30 mL~ and the reaction is allowed to stir overnight. The reaction mixture is adjusted to pH 10 with 10% NaOH and extracted with ~t2O. The organic extract is washed successively whh H20 and saturated aqueous NaCI and concentrated in vacuo to yield the hydroxyamine S which is used without further purification.

.dl I~-HydrQxv-~ -(6-phçnoxv-~ 3~4-tet~hydron~hthy~ Let~ Thedesired compound is prepared according to the method of Example 23, steps (a) and ~b) except using a solution of N-1-(6-phenoxy-1,2,3,4-te~rahydronaphthyl)-N-hydroxyamine as1 0 prepared in step ~c) above.
Example 40 N-Hvdrox~-N- I -f6-~enzvloxY- 1~2.~4-~etrahvdrona~hthvl)pro~ionamide N-E~vdrQxv-N-1-l6-benzYloxv-1.2~3~4-tetrahydmnaphthvl)pro~ionamide. Thedesired 1 5 compound is prepared according ~o the method of Example 23, steps (a) and (b) except using a solution of propionyl chloride and a solution of N-1-(6-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine as prepared in Example 1, step (d).

E~ml~l 2 0 N-~vdroxv-N- I -(6-benzvloxY- 1.~4-tetra~hvdrona~hIhvl~enzamidç

l~-Hydroxv-~- 1 -(6-benzylQxv- I ~2.3~4-tetrahYdronaphthvl~r zamide. The desiredcompound is prepared according to the method of Example 23, steps (a) and (b) except using a solu~ion of benzyl chloride and a solution of N-1-(6-benzyloxy-1,2,3,4-2 5 tetrahydronaphthyl) -N-hydroxyamineas prepared in Example 1, step (c).
~x~
N-HY~rQxY-N- 1 -r6-(2-FhenethYl~- I .2~3~4-tetrahydrQnaDhlhyll-2~2-~imeth~lpropiQnamide 3 0 a) 1-HvdroxY-6-(2-phene~hvl)-1~2~3~4-tetrahvdrona~hthalene~ To a solution of 6-(2 phenethyl)-1-tetralone (see Example 8, step (b), 2.50 g, 10.0 mmol) in THF under an ~rgon atmosphere is added lithium aluminum hydride (190 mg, 5.0 mmol). The resulting mixlure is stined at room temperature for several h and quenched by the successive dropwise addition of H20 (0~19 rnL), 15% NaOH (0~19 mL) and H20 (0.57 mL). The alcohol is3 5 obtained by filtralion and removal of the solvent in vacuo.

k) I-~hloro-6-f2-phçnYlethyl)-1~2~4-tçtTahydrona~hthalene. To a solutionof 1-hydrox~-6-~2-phenethyl)-1,2,3,4-telrahydronaphthalene (2~52 g, 10~0 mmol) in CH2C12 (15 mL) is ,~,: ";"~,'', ;`, .. .

WO 91/14674 2 ~ 7 ~312;6 ,PCl/llS91/02010 added CC14 (1.21 mL, 12.5 mmol). Triphenylphosphine (3.93 g, 15.0 mmol) is addedportionwise with cooling, and the resulting rnixture is allowed to warm to roorn temperatur~
and stirred for 30 m~n. The solvent is removed in vacuo. Ether is added to the residue, which is washed with H20 and dried. The desired product is obtained by removal of the solvent in vacuo.

~ N-BenzvLoxy ~l-f~f2-~henvlethvl)- 1.2~4 ~etrahydr~na~htby~m~. To a suspension of O-benzylhydroxylarnine hydrochloride (4.79 g, 30.0 mmol) in THF (150 rnL) is added triethylamine (4~20 rnLl 30.0 rmslol). After stining for 1 h, at room 1 0 temperature, the rnixture is filtered and is concentrated under reduced pressure. The residue is dissolved in benzene (15 mL) and is added to a solution of l-chloro-6-(2-phenyle~hyl)-1,2,3,4-tetrahydronaphthalene (2~71 g, 10~0 rnmol). The resulting rnixture is stirred at room temperature for 48 h. The alkylated ~benzylhydroxylarnine is obtained after removal of the solvent under reduced pressure and purification by flash chromatography.

Benzvloxv-N- I -~-(2-phenvlethvl)-1 ~3~4-te~rahvdrona~hthvll-2.2-dimethvl~roDionamide. To a solution of N-benzyloxy-N-1-[6-(2 phenylethyl?-1,2,3,4-tetrahydronaphthyl]amine (3.57 g, 10.0 mmol) in THF is added triethylamine (1.72 rnL, 12.5 rnmol), followed by trimethylacetyl chloride (1.54 mL, 12.5 mmol). The resulting 2 0 mixture is stirred at room temperature for 2 h and is filtered. The desired produc~ is obtained by removal of the solvent in vacuo.

e) I~-~vdroxv-1~ 6-~2-phenvlethvl)-1.2.~4-tctrahvdrQna~hthvll-2~2-dimethv!~ropionamide. To a solution of N-benzyloxy-N-1-[6-(2-phenylethyl)-1,2,3,4-2 5 tetlahydronaphthyl]-2,2-dimethylpropionamide (4.41 g, 10.0 rnmol) in absolute EtOH is added 5% palladium on activated carbon (0.25 mmol), and the mixture is hydrogenated at 25 psi H2 for 24 h. The rnixture is filtered, and the solvent is removed in vacuo to provide the N-hydroxyamide which is purified by flash chromatography.

Exam~l~ 4~
(+)-N- I -(6-Benzvloxv- 1 .2.3.4-~etrahvdronaphthvl)-N-hvdroxvurea ~n~
(-)-N- I -(fi-Benzvloxv- I ~2~.4-tetrahvdronaphthvl~-N-hvdroxyurea 3 5 (S~-4-Benz~l-~ oxazolid~none~-car~oxvliç acid chloride. A dispersion of 60% sodium hydride in mineral oil (0.82 g of, 20.3 mmol) was washed with pentane. The pentane w;ls replaced wilh dry toluene (70 rnL), and to the resulting suspension was added (S)-4-benz~ l-2-oxazolidinone (3.00 g, 16.9 mmol). The mixture was heated a~ reflux oven~ight, then - - .
-, : ~ :'' . ` ~;, , . : : ., WO 9l/14674 PCr/US91/~2~10 ~.
68- `

allowed to cool to -17C and added slowly to a pre-cooled (-17C) solution of phosgene (110 mL of 20% solution in toluene, 22.1 mmol). The resulting mixture was stirred at -17C for 1 h, and then filtered and concentrated under reduced pressure. The residue w~s washed with hexanes to afford the titte compound (2.91 g, 72%).
I~I~IB (CDC13): ~ 7.34 - 7.17 (m, 5H); 4.68 (rn, lH); 4.22 ~m, 2H); 3.32 (dd, lH);
2.91 (dd, lH).
IR: 2150, 1830, 1800, 1725 cm~l.

~1 ~S ~ 4SL-N- 1 -f6-Benzv]Qxv- 1~2.3 ~4-tetrahv~lronaphth~l)-N-(N'-4-benzvl-3-1 0 ça~ox~!oxazolidin-2-Qnyl)ur~a. To a solution of N-1-(6-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea (2.00 g, 6.4 mmol) in CH2C12 (300 mL) was added triethylarnine (1.7 rnL, 12.8 rnmol), followed by (S)-4-benzyl-2-oxazolidinone-N-3-carboxylic acid chloride (2.30 g, 9.6 mmol). The resulting mixture was stL~red at room temperature for 1 h, then poured into CHCl3 and washed successively with H2O and1 5 saturated aqueous NaCI and dried (Na2S04). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2% MeOEV CH2Ct2 to af'ford the title compound as a mixture of diastereomers (2.77 g, 84%). The diastereomers were separated by semi-preparative, reverse-phase HPLC (Ultrasphere column, 30 mL;l min ftow rate, 280 nm UV detector), eluting with 7: 3 DMF/H2O.
N-l-f6-Benzvloxy-l.2~3~rahydronaphthvl)-N-hvdroxvurea. To a solulion of one ol`
the diastereomers obtained from the separation of (lRS, 4S)-N-I-(~benzyloxy-1,2,3,4-tet~ahydronaphthyl)-N-(N'-4-benzyl-3-carboxyloxazolidin-2-onyl)urea in 4: 1 THF/ H2O
(21 mL) at 0C was added hydrogen peroxide ~40 mL of 30% aqueous solution), followed 2 5 by lithium hydroxide (0.40 g, 9.5 mmol). The resulting mixture was allowed to warrn to room temperature and stirred for 1 h. The mixture was then cooled to 0C, and saturated aqueous NaHSO3 (50 rnL) was slowly added. The mixture was extracted with EtOAc, and the organic extract was washed suçcessively with H20 and saturated aqueous NaCI and dried (Na2S04). The solvent was removed in vacuo, and the residue was purified by flash 3 0 chromatography, eluhng with 2% MeOH/ CHC13 to afford the title compound. This isomer was determined by HPLC analysis (eluting with 2: 8 isopropanoV hexanes, chiraeelcolumn, 254 nm uv detector) to consist of 98% enantiomeTic excess. m.p. 146 - 147C.
[a]D = -1.53.
IH NMR (MeOH-d4): ~ 7.48 (m, 5H); 7.18 (d, lH); 6.80 (dd, lH); 6.71 (d, lH); 5.~' 3 5 (apparent t, lH); 5.04 (s, 2H); 2.90 - 2.63 (m, 2H); 2.02 (m, 3H); 1.78 (m, lH).

(+)-N-l-(~Benzvloxv-l.2~3.4-tetrahv~ronaphthvl)-N-hvdroxvurea. The (+)-enantiomer was prepared in a similar fashion, except using the other diastereomer obtained frorn the ` .' ,.` `~, .

.,. . :.:

WO 91/14674 pcr/ussl/o2o1o -69- ~ 2 ~

separation of (lRS, 4S)-N-1-(6-benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-(N'-4-benzyl-~-carboxyloxazolidin-2-onyl)urea The (+) isomer was determined by HPLC (eluting with ~:
8 isopropanoV hexanes, chiracel column, 254 mn uv detector) analysis tO consist of 88%
enantiomeric excess. m.p. 154.5 - 155.5C. [a]D = ~2.98.
l~MR (MeOH-d4): ~7.37 (m, 5H); 7.20 (d, lH); 6.80 (ddl, lH); 6.71 (d, lH); 5 4tapparent t, lH); 5.05 (s, 2H); 2.90 - 2.63 (m, 2H); 2.00 (m, '3H); 1.78 (m, lH).
IB: 3500, 3460, 3360, 3180 - 3100, 2940, 2880, 1650, 1635 cm-l.

1 0 f+,)-N-3-~Benz~lQxv-~,~ihydrobenzQfuryl)-N-hydrnxvur~a f-)-N-~-(6-Benzvloxv-2~-dihvdro~enzofurvl)-N-hvdrox~llrea ~3RS~ 4$)-N-3-(6-Benzvloxv-2.3-dih~drobenzQfurvl)-N-(?~'-4-benzyl-3-carbox~!-1 5 oxazolidin-2-onyl)urea. To a solution of N-3-(6-benzyloxy-2,3-dihydrobenzofuryl)-N-hydroxyurea (2.01 g, ~.41 mmol) in CH2C12 (50 mL~ was added triethylamine (1.7 rnL, 12.8 r~Lrnol), followed by (S)-4-benzyl-2-oxazolidinone-N-3-carboxylic acid chloride (2.3() g, 9.6 tnmol). The resulting mixture was stirred at room temperature for 1 h, then washed successively with H20 and saturated aqueous NaC1. The solvent was removed in vacuo, 2 0 and the residue was purified by flash chrotnatography, eluting with 1 % MeOH/ CH2Cl2 t afford the title compound as a mixture of diastereomers (1.67 g, 6~%). The diastereomers were separated by no~mal-phase HPLC (porasil column, 400 mL/ min flow rate, R.I.detector), eluting with 60: 40: 1 hexanes/ EtOAc/ HCO2H.

2 5 (+)~ -(6-Benzvloxv-2~-dihydrobenzof~vl)-N~hYdroxvurea. To a solution of one of the diastereomers obtained from the separation of (3RS, 4S)-N-3-(6-benzyloxy-2,3-dihydrobenzofuryl)-N-(N'-4-benzyl-3-carboxy-oxazolidin-2-onyl)urea in 3: I THF/ H2O
(12 mL) at 0C was added hydrogen peroxide (6.6 mL of 30% aqueous solution), followed by lithium hydroxide (0.07 g, 1.68 mmol). The resulting rnixture was allowed to warrn to 3 0 room temperature and stirred for 1 h. The mixture was then cooled to 0C, and saturated aqueous NaHS03 was slowly added. The mixture was concentrated under reduced pressure, and the residue was extracted with CH2C12. The organic extr~ct was concentrate~
in vacuo, and the residue was purified by flash chromatography, eluting wilh 5% MeOH/
CHCl3 to af~ord the title compound. This isomer was determined by HPLC ~nalysis 3 5 (eluting with 2: 8 isopropanoV hexanes, chiracel col~mn, 254 nm uv detector) to consist of 97% enantiomeric excess. m.p. 189 - 190C. [a]D = ~10.1 (DMSO).
IH NMR (DMSO-d6): o9.12 (s, IH); 7.40 (m, 5H); 7.05 (d, IH); 6.50 (m. 4H); 5.78 (dd, lH); S.05 (s, 2H); 4.~6 (apparen~ t, IH); 4.45 (dd, IH).

... . . .

. ., .. . . ..

.. ~ : : ~

WO 91/14674 PC!-~US91/02010 _ IR: 3480, 3340, 3200 - 3160, 2920 - 2880, 1650, 1635 cm-l.
(:IM~ (NH3), snJz (rel. int.): 318 [(M+NH4)+, 11], 225 (100).
Anal. Calc. for C16Hl6N2O4: C 63.9g, H 5.37, N 9.33; found: C 62.68, H 5.~3, N
8.73.
5 (- 1:~3-(~enzvlQxv-2.3-dih~robenzQfur~ -h~rQxv~rea. The (-)-enantiomer was prepared in a sirnilar fashion, except using the other diastereomer obtained from the separation of (3RS, 4S)-N-3-(6-benzyloxy-2,3-dihydrobenzofuryl)-N-(N'-4-benzyl-3-carboxy^oxazolidin-2-onyl)urea. m.p. 188 - 189C. [a]D ~ -10.7 (DMSO).
1~MR (DMSO-d6): ~ 9.12 (s, lH); 7.40 (m, SH); 7.06 (d, lH); 6.49 (m, 4H); 5.78 1 0 (dd, lH); 5.05 (s, 2H); 4.56 (apparent t, lH); 4.46 (dd, lH).
~: 3480, 3340, 3180, 2880, 1650, 1635 cm-l.
CIM$ (NH3), rnlz (rel. int.): 318 [(M+NH4)+, 11], 225 (100).
~1. Calc. for Cl6Hl6N~o4: C 63.99, H 5.37, N 9.33; found: C 63.76, H 5.24, N
9.20.

~XAMPLE 45 - CAPSIII~E COMPQSI~I
A pharmaceutical composition of this invention in the form of a capsule is prepared by filling a standard two-piece hard gelatin capsule with 50 mg. of a compound of Formula (I), in powdered forrn, 1 lQ mg. of lactose, 32 mg. of talc and 8 mg. of magnesium 2 0 stearate.

EXAMPLE 46 - OIN-I MENT (: OMPOSITION
Compound of Formula (I) 1.0 g White soft paraffin to 100.0 g 2 5 The compound of Formula (I) is dispersed in a small volume of the vehicle and this dispersion is gradually incorporated into the bulk to produce a smooth,homogeneous product which is filled into collapsible metal tubes.

EXAMPLE 47 - T~)P~CAI, CREAM COMPOSITTON
3 0 Compound of Formula (I) 1.0 g Carbowax 200 20.0 g Lanolin Anhydrous 2.0 g White Beeswax 2.5 g Methyl hydroxybenzoate 0.1 g 3 5 Distilled Water to 100.0 g The carbowax, beeswax and lano}in are heated together at 60C ~nd added lo a solution of methyl hydroxybenzoate. Homogenization is achieved using high spPed stining and ~he temperature is allowed to ~all to 50C. The compound of Formula (I) is . . : .

W~ 91/14674 PCr~US91/02010 _ -71-2078~26 added and dispersed throughout, and the composition is allowed to cool wilh slow speed stirring.

~AkIPLE~ 48- TOPIC~ LQTION COMPOSmON
Compound of Forrnula (I) 1.0 g Sorbitan Monolaurate 0.6 g Polysorbate 20 0.6 g Cetostearyl Alcohol 1.2 g Glycerin 6.0 g l 0 Methyl Hydroxybenzoale 0.2 g Purified Water B.P. to 100.00 ml The methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the waler at 75QC. The sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75C and added to the aqueous solution. The resulting emulsion is l 5 homogenized, allowed to cool with continuous stirring and the compound of Forrnula (I) is added as a suspension in the remaining water. The whole suspension is stirred until homogenized.

EXAMPLE42- C C~IPOSI~I~ FQR AE2~11NTSl~QN BY IN~ALATION
2 0 For an aerosol cont~iner with a capacity of 15-20 rnl: Mix 10 mg of a compound of Forrnula (I) w;th 0.1-0.2% of a lubricating agent, such as Span 85 or oleic acid, and disperse such rnixture in a propellant (c.a.), such as freon, preferably a combination of freon 114 and freon 12, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation adrninistration.
2 ~ E~MPl~E ~Q - COMPQSlllO~ FO~DM~NISTRAT~C)N BY IN~IALATIQN
For an aerosol container with a capacity of 15-20 ml: Dissolve l0 mg of a compound of Formula (I) in ethanol (6-8 rnl), add 0.1-0.2% of a lubricating agent, such as Span 85 or oleic acid, and disperse such in a propellant (c.a.), such as freon, preferably a combination of freon 144 and freon 12, and put into an appropriate aerosol container 3 0 adap~ed for either intranasal or oral inhalation administration.

IlllLITY EXAMPLES
I. METHODS
For the in vitro experiments, compounds were dissolved at appropria~e 3 5 concentrations in ethanol or DMSO (dimethylsulfoxide) having a final concentration of less than or equal to l .0%, and then diluted ~o their respective concentrations using the buffers indicated in the text.

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WO 91/14674 PCr/~lS91/02010 In experiments when mice were used they were CDI mice obtained frorn Charles River Breeding Laboratories, and within a single experimen~ the rnice were age-matched. Their weight range was from 25 ~o 42 g. The test groups generally contained 3-6 animals.
s 5~ GEl~ASE ACllV~
The 5-lipoxygenase (5-LO) was isolated from extracts of RBL-1 cells. The assay for assessing inhibition of the 5-LO activity was a continuous assay which monitored the cornsumption of oxygen (2)- The cell extsact (100 ug) was preincubated with the 1 0 inhibitor or its vehicle in 25 mM BisTris buffer (pH 7.0) that ~ontained 1 mM EDTA, 1 rnM ATP, 150 mM NaCI and 5% ethylene glycol for 2 minutes at 20C (total volume 2.99 ml). Arachidonic acid (10 uM) and CaC12 (2 mM) were added to start the reaction, and the decrease in 2 concentration followed with time using a Clark-type electrode and the Yellow Spring 2 monitor (type 53) (Yellow Spnngs, OH). The optimum velocity was 1 5 calculated from the progress curves. All compounds were dissolved in ethano] with the final concentration of ethanol being 1% in the assay.
Drug-induced effects on enzyme activities are described as the concentration of drug causing a 50% inhibition of oxy~en consumption (ICso).

21) ETCO~NOID PROD~ICT~ON FP~QM ~ AN ~Q~JC)ÇYTES ~N VITRO
Human monocytes were prepared from leukosource packs supplied by the American Red Cross. The leukosource packs were fractionated by a two-step procedure described by F. Colatta et al. (J. Immunology 132:936, 1984) that uses sedimentation on Ficoll followed by sedimenta~ion on Percoll. The monocyte fraction that results from this 2 5 technique was composed of 80-90% monocytes with the remainder being neutrophils and Iymphocytes. In addition, significant number of platelets are present.
The monocytes (106 cells) were placed into polypropylene tubes and used ,lS
a suspended culture. The assay buffer consisted of RPMI 1640 buffer, 2 mM glutamine, 2.~ mM H~PES and 2 mM CaC12 (~otal volume 0.475 ml). Compounds (0.005 ml) 3 0 were added in DMSO, and thè cells were preincubated for 10 minutes at 37C with consta agitation. A23187 (2 uM) was used to stimula~e the cells. After an addi~ional 10 minutes, the buffer was collected by centlifugation (2500 xg for 15 minutes), and stored at -70C
until assayed. LTE~,4 production was measured by radioimmunassay which was performe~
according to the manufacnlrer's (Advanced Magnetics, Boston, MA) ins~uctions. PGE~
3 5 was detennined using an RIA kit supplied by New England Nuclear (Boslon, MA).

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WO 91/14674 PCl`/US91/û2010 -- 7~
- - 2~)78~12 E~ V~VQ MQUSp~LQS)D l~ Q~
Mice were pre-treated per os with vehicle or a ~est compound (dissolved in dirnethylacetanude and diluted 1 to 10 with sesame oil) 30 minutes prior to removal of blood. The 5-lipoxygenase product LTB4, was extracted ~rom whole blood followingA23187 stimulation. Aliquots of pooled heparinized rnouse bloocl (1 ml each aliquot) from male CDl mice (Charles River) were placed into 4 rnl polypropylene tubes. The tubes wer~
preincubated for about fiYe minutes at 37C. A23187 ~60 uM) was added to stimulate eicosanoid production. Several aliquo~s of blood were no~ stimulated and, thus, provided background levels ~or eicosanoid production. All tubes were incubated for about 30 1 0 minutes at 37C. The blood samples were centrifuged at 400 xg for about 15 minutes, and the plasrna recovered for extraction. One volume of chilled acetonitrile was added to ~ t 5C. The supernatants were recovered and diluted with 1% fortnic acid:1% tTiethylamine to achieve a final concentration of 20% acetonitrile. These supernatants were then loaded onto the extraction cartndge that had been conditioned according to the Manufacturer's 1 5 instructions tSolid Phase Extraction Columns, J. T. Baker, C18 3 ml size). The samples were washed with 3 ml of 1% formic acid: 1% tAethylamine, a~r dried, and then washed with 3 ml of petroleum ether. After cur drying again, the samples were eluted with methyl forrnate. The eluents were concentrated under vacuum. The concentrates were resuspended in 30% acetonitrile buffered with 50 mM arnmonium aceta~e (200 ul~. The recovery of 2 0 LTB4 was 60%. The 300 ul concentrates were assayed by radioreceptor assay for LTB4 by Iabortatory protocol-PMENYLBENZ:~;)OUrNONE-TNDU~ED ABDQMT~AL (~ONSTR~ C)N ASSAY
Phenylbenzo4uinone (PBQ, Eastman Kodak Co., Rochester, NY) was 2 5 dissolved in warrn (50C) ethanol and diluted with distilled water to a final concentralion of 0.2 mg/rnl. The solution which was protected from light by a foil wrap was administered intraperitoneally at a dose volume of 0.01 mUgm.
Mice were pre-treated with vehicle or test compound (dissolved or suspended in 25% PES:i 200) for about 15 minutes and then injected with PBQ, following 3 0 which each mouse was placed into individual 4 liter beakers. CD1 rnice show a characteristic abdorninal contraction/stretching response which consists of extending one or both of the hind limbs. These responses which occur at a variable frequency (not less than 1-2 seconds apart) were counted on a hand counter. The counting period was for 10 minutes following a 5 minute acclimation period. Results are based on the total number o~`
3 5 constTictions observed during the 10 rninute period.

.

WO 91/14674 ~?~6 74 PC~/US91/û2010 _ DATA A~ALYSIS A~ STATISTIC~
Mean values for groups were calculated and percent inhibition was detennined between the vehicle control rnean and test group. The EDso was determined using linear regression analysis and was taken as the dose which resulted in a 50%
S inhibition of the vehicle control constriction response. Statistical analysis was done using Student's "t" test and a p~O.05 was considered statistically significant.

B~
The effect of hydroxyurea compounds as inhibitors of 5-LO is shown in Table I.
1 0 The comps)unds tested displayed a range of inhibitoIy activity both in vitro and in vivo. On the RBL-1 supernatant 5-LO enzyme assay several compounds showed activity in andaround 1.0 uM ICso. A second group of compounds had activity in the range of -3 uM
ICso and a third group had appreciably less activity (15-48 uM ICso), which can be seen from a review of Table 1. Examination of the activity of the first two groups of compounds 1 5 on human monocyte production of LTB4 corroborated the 5-LO inhibitory activity. All the compounds tested were less than 1 uM IC50 In contrastt none of the compounds showe~
potent inhibition of cyclooxygenase activity as indicated by production of the prostaglandin, PGE2.
Evaluation of the in vivo 5-LO inhibitory activity of these compounds was done 2-0 using mouse whole blood stimulated with calcium ionophore (A23187) ex vivo. As seen in Table II, with the exception of three cornpounds (3, 7 and 12) all of the others tested were shown to inhibit 5-LO activity ex vivo as well as in vi~o. Several of these compounds also showed dose-related inhibition of LTB4 production (ED50~s ranged from 1-10 mg/kg, p.o.).
2 5 N-Acetoxy-N-1-[6-(2-phenylethyl)-1,2,3,4-tetrahydronaphthyl]acetarnide, showed a 6~ percent inhibition of LTB4 in mouse blood ex vivo at a dose of lOmg/kg, or an ICso of 5.8. Compounds of Formula (II): N-1-(5-Benzyloxyindanyl)-N-hydroxyamine, N-1-(5-Benzyloxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine, N- 1 -(5-Phenoxy- 1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine, N-1-(5-Phenoxyindanyl)-N-hydroxyamine all 3 0 inhibited LTB4 at a dose of 1 Omg/kg.
The analgetic activity of these compounds was tested using the phenylbenzoquinone-induced abdominal constriction assay. As seen in Table II, several of these cvmpounds ( I, 2, 5, 6,7, 8 and 10) possessed signi~lcant analgetic activity. Several of these compounds also showed a dose response (EDso 7.9 to 11.2 mg/kg, p.o.).
3 5 N-Acetoxy-N-1-[6-(2-phenylethyl)-1,2,3,~tetrahydronaphthyl~-acetamide, a hydroxamate of Formula (I) compounds yielded a s~tistically significant percent inhibition of PBQ writhing at a dose of lOmg/kg of 27G/o. Compounds of Folmul~ (Il): N-1-(5-Ben~yloxyindanyl)-N-hydroxyamine yielded a statistically significant percent inhibition of , , , , . . . .; ;
- .: .. : , .. ....
. ~ ..

WO 91/14674 75 2 ~ 7 ~ 1 2 ~ PCT/Us9l/02~l0 PBQ writhing at a dose of 10mg/kg; N-l-(S-Benzyloxy 1,2,3,4-~et;ahydronaphthyl)-N-hydroxyamine, N- 1 -(5-Phenoxy- 1 ,2,3,4-tetrahydronaphthyl)-N-hydroxyamine, N- 1~
Phenoxyindanyl)-N-hydroxyall~ine, yielded a sta~istically significant percent inhibition of PBQ writhing at a dose of 20mg/kg.

nf~s~
The compounds shown herein inhibited 5-LO enzyme activity using isolated enzyme, whole cells and mouse blood, ex vivo. This inhibition of fatty acid oxygenase activity did not extend to cyclooxygenase and therefore, these selective 5-LO inhibitors 1 0 would not be expected to have analgetic activity which is a property of cyclooxygenase inhibitors (Doherty, N.S. Mediators of the Pain of Inflammation. Annual Reports in Med.
Chem. 22: 24S-252, 1987). It was therefore surprising to find that many of these 5-LO
inhibitors had significant and potent analgetic activity. This property enhances the utility of these inhibitors in diseases such as osteoarthritis were the clinical endpoint is pain l 5 (Moskowitz, R.W. Treatment of Osteoarthritis. In: Arthritis and Allied Conditions. Ed. D.~.
McCarty. Lea and Febiger, Philadelphia., PA p. 1 181- I 189, 1979).

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically 2 0 disclosed herein are within the scope of the following claims. Wi~hout further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Exa nples herein are to be construed as merely illustrative and not a lirnitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are 2 5 defined as follows.

, WO Si1/14674 ~ ; . PCr/US91/02~10 -~

,6 ~Q, TABLE I
s (HQ~ Nffl X~l N Hl) Hum~n Uonocyl-~ ICso uM
~s-mpl- X q\l Y W U Z S LO ICs~ ui~ LTii, PG~, . . . - . _ . . . . ____~ _ 1 -OCH~Pb 1\0 H H H ~CH~h 1 2 0 1D ,30 2 OCH~Ph 1~0 H H H CH2 t 5 0 19 NT
3 OCH~ 1\0 H H H ~CH~)~ 48 0 NT NT
4 H IW H H H~CHIb 29 0 NT NT
6 OCH~4.0i4- Ph) 1\0 H ii ¦ H ~CHI), 0 5 0 15 NT
6 OCH7~4 Cl Ph) 1\0 H H H ~CHI)~ 2 2 0 32 NT
7 OCH~2 n-phlhyl) 110 H H H ~CH7jl 0 5 0 25 ~llm 3 ~Cill)~Ph 1\0 H H H (CH,)2 0 6 0 02 lim fi OCH~2 quln~1yl)1~0 H H H ICH2h 1 9 0 09 ~30 OCH~Ph1\0 H H H O 2 3 0 42 ~30 11 H 0\1oCH~ H H ~Ci~ 15 0 NT NT
12 H 1~0OCH7Pb H H ~Ci1~)~ 3 0 0 74 >30 13 Ph110 H H H ~CHIh 1 5 0 3- >30 14 OCH~4 OM- Ph) IW H H H CH3 1 4 0 33 , 30 OCH~4 OU--Ph) 1\0 H M H O 2 7 0 7s ~30 16 H 1~0 H OCH~Ph il ~CH~)~ 0 D1 0 16 ~30 17 H 1\0 H OPh H ~CH,i2 o.a4 0 12 ,30 18 OPh 1\0 H H H Cil~ o.as 0 33 >30 1f H 1\0 H 0~4 F-Ph) H~t H7)~ 0 61 0 ~5 ~30 20OCH~2 pyrlF2yl) 1\0 H H H~CHIh 10 NT NT
21OCH~9 ~-ndml~-~ol~) 1\0 H H ii (CH~)I 11 NT NT
22 H 1\0 H H OPh CH~ 5 6 NT NT
NT- not tested stim - s~imula~ed above con~ol values ,, ;.,, , .. . ~
, ~ ,, .

WO 91/14674 77 PCI/US91~02010 -~.

2~

s ~ .
TABIE II

O
( ~1N~ O
X~ t H ~ ~

lL hh.ol LT2t, roou~- bluo~ 1L Inh. PIIO w~hhlr o ~mDlo X ~~ .1 W U Z ~1~hlO ~10 mol~o tED~ ~ 10rno ho/ED~cl OCII~Ph 110 H H H(5H~ S7 ~0.9 ms~o) S9 (7.0) 2OCU~P~ 1\0 H H N CHt 5 ~-.0 mo/~) 52 t7.n 2OCN~ 1\0 H H H~CN,)~ NA UA
H N0 H H NtCN~)I 00 NA
OCN~.OLt~.rh) 1\0 N H N tCH~\I 01 t93 mo/~L7) U 110.2) OCH~t~-CI-Ph~ 1\0 H N HICH~I~ 70 1~.5 mo/~o) 72 t11.2) 7OCHttl-n~Phth~l) 1\0 H H H tCNJI 103 10 m~ho ~J
3~CHr~,~h IS0 H N HtCH ~ - 5- t-.D) 3OCH~t2-rtulnol1U) 110 H U H tCHh SS t10.2 mgh~) 11~ /~2 % ~ 2 0 h 3 20) 10OCH,Pb 110 H H H O 100 p.~) 20 t7.n 11 U 0~1OCH~ H H(CH~ UT NA
12 H 1~0OC11~Ph N tCH~)I 5Tl t tS0 100) ~ 20 ~;
15I t~ 1\0 H H HtCU~)~ S2 NA
1~OCH7t~-OY~ Ph)N0 rl H N CH~ 10 NT
1 OCH,t~t.OtY~.Ph) 1\0 H H N O 7~t9-') I.IA
1S N 1\0 NOCHlPh H tCHh ~ t~15) ~.U~ 3 20 moho 17 H 1\0 H OPh HtCH~)~ 5~ t~ t11~ 3 20 mol~o) 1- OPh 1\0 H N H CH~ ~ ) NA 1--- 3 ~0 13 H 1\0 HOt~ Ph) N tCHh 05 t2 % ~ 20 mo~0 20OCN~t~-p~rld~l) 1\0 H N H tCH~ NT NT
21OCN7t~ t bi\0 H U H tCN~)~ 117 !JT
22 H N0 H H;IPh CH~ UT hlT

1 0 NA - not ac~ve NT - not tested S~m - s~mulated above c~n~ols values given in parentheses represent the E~D~o in mg/kg .
, ;, , ,: .

Claims (36)

What is claimed is:

1. A compound of the formula wherein R2 and R3 are R is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1-12 alkoyl;
B is oxygen or sulfur;
R4 is NR5R6, alkyl 1-6, halosubstituted alkyl 1-6, hydroxy substituted alkyl 1-6, alkenyl 2-6, aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyll 6, hydroxyl, or alkoxy 1-6;
R5 is H or alkyl 1-6;
R6 is H, alkyl1-6, aryl, benzyl, heteroaryl, alkyl substituted by halogen or hydroxyl, or phenyl substituted by a member selected from the group consisting of halo, cyano, alkyl1-12, alkoxy 1-6, halosubstituted alkyl1-6, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R5 and R6 may together form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen;
W is CH2(CH2)s, O(CH2)s, S(CH2)s, or NR7(CH2)s;
R7 is hydrogen, C1-4 alkyl, phenyl, C1-6 alkoyl, or aroyl;
s is a number having a value of 0 to 3; provided that when 1 is one and W is O(CH2)s, S(CH2)S, then s is 1 to 3; and when W is NR7(CH2)S then s is 1 to 3 and q is 1;
q is a number having a value of 0 or 1;
l is a number having a value of 0 or 1;
provided that when q is 0 then I is l and R2 is hydrogen; and when q is 1 then l is 0 and R3 is hydrogen;
R1 is a member selected from the group consisting of hydrogen, alkyl1-10, alkoxy1-10, (CH2)m-Ar-(X)v, O(CH2)mAr-(X)v, or S(CH2)m-Ar-(X)v;
m is a number having a value of 0 to 3;
v is a number having a value of 0 to 3;
Ar is a member selected from the group consisting of phenyl, napthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;

X is a member selected from the group consisting of hydrogen, halogen, alkyl 1-5cycloalkyl 5-8, hydroxy, (CHY)tcarboxy, O-alkyl 1-5, S(O)r alkyl 1-5, halosubstituted alkyl1-6, (CHY)tN(R5)2 or cyano; provided that if v is a number greater than 1 then one substituent must be selected from alkyl, O-alkyl 1-5, or halo;
r is a number having a value of 0 to 2;
Y is hydrogen or alkyl1-3;
t is a number having a value of 0 or 1; provided that when q is 1, R4 is NR4R5, W is CH2(CH2)s, and s is 1, then R1 is other than hydrogen, alkyl1-10, or alkoxy 1-10;
and the pharmaceutically acceptable salts thereof.

2. The compound according to Claim 1 wherein W is CH2(CH2)s or O(CH2)s, and s is a number having a value of 0 or 1.

3. The compound according to Claim 2 wherein R4 is alkyl 1-6, halosubstituted alkyl 1-6, hydroxy substituted alkyl 1-6, alkenyl 2-6, aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl1-6, hydroxyl, or alkoxy 1-6.

4. The compound according to Claim 2 wherein R4 is NR5R6.

5. The compound according to Claim 3 wherein B is oxygen and q is 1.

6. The compound according to Claim 5 wherein R1 is O(CH2)m-Ar-(X)v, (CH2)m-Ar-(X)v, or S(CH2)m-Ar-(X)v; m is a number having a value of 0 to 2; and v is a number having a value of 1 to 2.

7. The compound according to Claim 6 wherein s is 1,W is CH2CH2, R1 is in the 5- or 6-position; and when W is OCH2, R1 is in the 7- or 8-position; and when s is 0, W is CH2, R1 is in the 4- or 5-position, and when W is O, R1 is in the 6- or 7-position.

8. The compound according to Claim 7 wherein R1 is benzyloxy, 4-methoxybenzyloxy, 4-chlorobenzyloxy, phenoxy, or 4-flurophenoxy.

9. The compound according to Claim 8 wherein R5 and R6 are independently selected from hydrogen or alkyl.

10. The compound according to Claim 1 wherein the compound and their pharmaceutically acceptable salts are selected from N-1-(6-Benzyloxy- 1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;

N-1- 5-Benzyloxyindanyl)-N-hydroxyurea;
N-1-(6-Methoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
N-1-(1,2,3,4-Tetrahydronaphthyl)-N-hydroxyurea;
N-1-[6-(4-Methoxybenzyloxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea;
N-1-[6-(4-Chlorobenzyloxy)-1,2,3,4-tetahydronaphthyl]-N-hydroxyurea;
N-1-[6-(2-Naphthylmethoxy)-1,2,3,4-tetrahydronaphthyl]-N-hyclroxyurea;
N-1-[6-(2-Phenethyl)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea;
N-1-[6-(2-Quinolinylmethoxy)-1 2,3,4-tetrahydronaphthyl]-N-hydroxyurea;
N-3-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyurea;
N-1-(7-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
N-1-(6-Phenyl-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
N-1-[5-(4-methoxybenzyloxy)-indanyl]-N-hydroxyurea;
N-3-[6(4-Methoxybenzyloxy)-2,3-dihydrobenzofuranyl]-N-hydroxyurea;
N-1-(5-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
N-1-(5-Phenoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea;
N-1-(5-Phenoxyindanyl)-N-hydroxyurea;
N-1-(4-Phenoxyindanyl)-N-hydroxyurea;
N-1-(5-(4-Flurophenoxyindanyl)-N-hydroxyurea;
N-1-(4-(4-Flurophenoxyindanyl)-N-hydroxyurea;
N-3-(7-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyurea;
N-1-[5-(4-Fluorophenoxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea;
N-1-[6-(2-Pyridinylmethoxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea;
N-1-[6(2-Benzimidazolylmethoxy)-(1,2,3,4-tetrahydronaphthyl)]-N-hydroxyurea; or N-1-(7-Phenoxyindanyl)-N-hydroxyurea.

11. The compound according to Claim 1 which is N-1-[(5-Phenyloxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea and the pharmaceutically acceptable salts thereof.

12. The compound according to Claim 1 which is N-1-(6-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea and the pharrnaceutically acceptable salts thereof.

13. The compound according to Claim 1 which is N-1-[5-(4-Flurophenoxy)1,2,3,4-tetrahydronaphthyl]-N-hydroxyurea and the pharmaceutically acceptable salts thereof.

14. The compound according to Claim 1 which is N-1-(5-Phenoxyindanyl)-N-hydroxyure:~
and the pharmaceutically acceptable salts thereof

15. The compound according to Claim 1 which is N-3-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyurea and the pharmaceutically acceptable salts thereof.

16. The compound according to Claim 1 which is (-)-N-1-(6-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyurea and pharmaceutically acceptable salts thereof.

17. The compound according to Claim 1 which is (+)-N-3-(6-Benzyloxy-2,3-dihydrobenzofuryl)-N-hydroxyurea and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and a compound of Claim 1 or a pharmaceutically acceptable salt thereof.

19. A method of treating an OPUFA mediated disease in a mammal in need thereof, which process comprises administering to such mammal an effective OPFUA inhibiting amount of a compound according to Claim 1, or pharmaceutical salt thereof .

20 . The method according to Claim 19 wherein the enzyme 5-lipoxygenase is inhibited.

21. The method according to Claim 20 wherein W is CH2(CH2)s or O(CH2)s, and s is a number having a value of 0 or 1.

22. The method according to Claim 21 wherein B is oxgyen and q is 1.

23. The method according to Claim 19 wherein the lipoxygenase mediated disease is arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, dermatitis, ischemic induced myocardial injury, reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclerosis, inflammatory bowel disease, stroke, spinal cord injury or traumatic brain injury.

24. A method of treating algesia in an animal in need thereof which comprises administering to said mammal an effective analgesic amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

25. A compound of the formula (II) wherein R2 and R3 are ;
B' is hydrogen, benzyl, optionally substituted benzyl, Si(RX)3, C(O)R5', C(O)OR5', CH2OCH2CH2Si(Rx3)3, C1alkylC1-3alkoxy, and C1alkylC2alkoxyC1-3alkoxy, or tetrahydropyranyl;
R5' is C1-6 alkyl, aryl, or aralkyl;
A is hydrogen or C(O)ORz;
Rz is benzyl, Si(Rx)3, t-butyl, CH2OCH2CH2Si(CH3)3;
Rx is independently selected from C1-6 alkyl or aryl;
W is CH2(CH2)s, O(CH2)s, S(CH2)s, or NR9(CH2)s;
R9 is hydrogen, C1-4 alkyl, C1-6 alkoyl, or aroyl;
s is a number having a value of 0 to 3;
q is a number having a value of 0 or 1;
l is a number having a value of 0 or 1;
provided that when q is 0 then l is 1 and R2 is hydrogen and when q is 1 then l is 0 and R3 is hydrogen;
R1 is a member selected from the group consisting of hydrogen, alkyl 1-10, alkoxy 1-10, (CH2)m-Ar-(X)v, O(CH2)mAr-(X)v, S(CH2)m-Ar-(X)v, or N(CH2)m-Ar-(x)v;
m is a number having a value of 0 to 3;
n is a number having a value of 0 to 3;
v is a number having a value of 1 to 3;
Ar is a member selected from the group consisting of phenyl, napthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;
X is a member selected from the group consisting of hydrogen, halogen, alkyl 1-10, cycloalkyl 5-8, alkenyl 2-10, hydroxy, (CHY)tcarboxy, O-alkyl 1-10, S-alkyl 1-10, SO-alkyl 1-10, SO2-alkyl 1-10, aryloxy, arylalkyl1-6 oxy, halosubstituted alkyl1-6, (CHY)tN(R5)2 or cyano; provided that if v is a number greater than 1 then one substituent must be selected from alkyl, O-alkyl 1-10, or halo;
Y is hydrogen or alkyl1-3;
t is 0 or 1; provided that when B is hydrogen, W is other than CH2(CH2)s, and s is 0 or 1, and B is hydrogen, W is other than S(CH2)s and s is 1;

and the pharmaceutically acceptable salts thereof.

26. The compound according to Claim 25 which is N-1-(5-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N-1-(5-Phenoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N-1-[5-(4-Flurophenoxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyamine;
N-1-(6-Benzyloxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N-1-(6-Phenoxy-1,2,3,4-tetrahydronaphthyl)-N-hydroxyamine;
N-1-[6-(4-Fluorophenoxy)-1,2,3,4-tetrahydronaphthyl]-N-hydroxyamine; or N-1-(5-Benzyloxyindanyl)-N-hydroxyamine;
N-1-(5-Phenoxyindanyl)-N-hydroxyamine;
N-1-(5-(4-Flurophenoxyindanyl)-N-hydroxyamine;
N-1-(4-Benzyloxyindanyl)-N-hydroxyamine;
N-1-(4-Phenoxyindanyl)-N-hydroxyamine;
N-1-(4-(4-Flurophenoxyindanyl)-N-hydroxyamine;
N-3-(7-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
N-3-[7-(4-Flurophenoxy)-2,3-dihydrobenzofuranyl]-N-hydroxyamine; or N-3-(7-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
N-3-(6-Phenoxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine;
N-3-[6-(4-Flurophenoxy)-2,3-dihydrobenzofuranyl]-N-hydroxyamine; or N-3-(6-Benzyloxy-2,3-dihydrobenzofuranyl)-N-hydroxyamine.

27. A method of treating an OPUFA mediated disease in a mammal in need of such treatment which comprises administering to said mammal an effective OPFUA inhibiting amount of a compound according to Claim 25 or a pharmaceutically acceptable salt thereof.

28. The method according to Claim 27 wherein the OPUFA mediated disease is ischemia induced myocardial injury, reperfusion injury, stroke, traumatic brain injury or spinal cord injury.

29. A process for producing a compound of the formula (I) wherein R2 and R3 are ;

R is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1-12 alkoyl;
B is oxygen or sulfur;
R4 is NR5R6, alkyl 1-6, halosubstituted alkyl 1-6, hydroxy substituted alkyl 1-6, alkenyl 2-6, aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl 1-6, hydroxyl, or alkoxy 1-6;
R5 is H or alkyl1-6;
R6 is H, alkyl1-6, aryl, benzyl, heteroaryl, alkyl substituted by halogen or hydroxyl, or phenyl substituted by a member selected from the group consisting of halo, cyano, alkyl1-12, alkoxy 1-6, halosubstituted alkyl1-6, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R5 and R6 may together form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen;
W is CH2(CH2)s, O(CH2)s, S(CH2)s, or NR7(CH2)s;
R7 is hydrogen, C1-4 alkyl, phenyl, C1-6 alkoyl, or aroyl;
s is a number having a value of 0 to 3; provided that when l is one and W is O(CH2)s, S(CH2)s, then s is 1 to 3; and when W is NR7(CH2)s then s is 1 to 3 and q is 1;
q is a number having a value of 0 or 1;
l is a number having a value of 0 or 1;
provided that when q is 0 then l is 1 and R2 is hydrogen; and when q is 1 then l is 0 and R3 is hydrogen;
R1 is a member selected from the group consisting of hydrogen, alkyl 1-10, alkoxy 1-10, (CH2)m-Ar-(X)v, O(CH2)mAr-(X)v, or S(CH2)m-Ar-(X)v;
m is a number having a value of 0 to 3;
v is a number-having a value of 0 to 3;
Ar is a member selected from the group consisting of phenyl, napthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;
X is a member selected from the group consisting of hydrogen, halogen, alkyl 1-5, cycloalkyl 5-8, hydroxy, (CHY)tcarboxy, O-alkyl 1-5,S(O)r alkyl 1-5, halosubstituted alkyl1-6, (CHY)tN(R5)2 or cyano; provided that if v is a number greater than 1 then one substituent must be selected from alkyl, O-alkyl 1-5, or halo:
r is a number having a value of 0 to 2;
Y is hydrogen or alkyl1-3;
t is a number having a value of 0 or 1;
and the pharmaceutically acceptable salts thereof which process comprises:

A. reacting a compound of Formula (II) as described above, wherein B is Hydrogen, (i) with trimethylsilyl isocyanate (TMSNCO), followed by work up with ammonium chloride to yield a hydroxyurea derivative of a Formula (I) compound wherein R4 is NH2; or (ii) with sodium or potassium cyanate in an acidic solution to yield a hydroxyurea derivative of a Formula (I) compound wherein R4 is NH2; or (iii) with gaseous HCI, followed by treatment with phosgene or phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate resulting in the corresponding carbamate;
which is reacted with aqueous ammonia, or substituted amine to yield an optionally substituted hydroxyurea derivative of a Formula (I) compound; or (iv) with acetyl chloride and organic solvent, such as triethylamine to yield the N,O-diacetate derivative followed by hydrolysis with an alkali hydroxide, such as lithium hydroxide, to yield a compound of Formula (I) wherein R4 is other than NR5R6; or (v) with an acylating agent, such as acetic anhydride in the presence of a base, such as pyridine, followed by hydrolysis with an alkali hydroxide, such as lithium hydroxide, to yield a compound of Formula (I) wherein R4 is a hydroxamic acid derivative;
or B. reacting a compound of Formula (II) as described above, wherein B is a benzyl, substituted benzyl or benzyl carbonate protecting group, with (i) acetyl chloride in organic solvent to yield a protected hydroxamic acid derivative of Formula (I) compounds, which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I) wherein R4 is other than NR5R6; or (ii) trimethylsilyl isocyanate as in step A above, to yield protected hydroxyurea derivatives of Formula (I) compounds which is then deprotected, optionally by hydrogenated with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (T); or (iii) phosgene or phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or substituted amine; which is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or (iv) sodium or potassium cyanate in an acidic solution and is then deprotected, optionally by hydrogenation or with ethane thiol in the presence of aluminium trichloride, to yield a compound of Formula (I); or C. reacting a compound of Formula (II) as described above, wherein B is is Si(RX)3, or CH2OCH2CH2Si(Rx)3 with (i) sodium or potassium cyanate in an acidic solution, as described in Step .-above and deprotected by use of anhydrous fluoride (R4N+)F-, or under mildly acidic conditions; or;
(ii) phosgene or phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or substituted amine; which is deprotected by use of anhydrous fluoride (R4N+)F-, or under mildly acidic conditions; or (iii) trimethylsilyl isocyanate as in step A above and then deprotected by use of anhydrous fluoride (R4N+)F-, or mildly acidic conditions; or (iv) acetyl chloride in organic solvent which is then deprotected by use of anhydrous fluoride ((R4N+)F-, or under mildly acidic conditions to yield the corresponding compounds of Formula (I); or D. reacting a compound of Formula (II) as described above, wherein B is tetrahydropyranyl, C1alkyl-C1-3alkoxy, or C1alkylC2alkoxyC1-3alkoxy, with (i) sodium or potassium cyanate in an acidic solution, as described in Step A
above and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCI; or (ii) phosgene or phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or substituted amine; and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCI; or (ii) with trimethylsilyl isocyanate as in step A above and deprotected by a mild acid treatment, such as pyridinium para-toulenesulphonate in methanol or dilute HCI;
or (iii) with acetyl chloride in organic solvent which is then deprotected by a mild acid treatement, such as pyridinium para-toulenesulphonate in methanol or dilute HCI
to yield the corresponding compounds of Formula (I); or E. reacting a compound of Formula (II) as described above, wherein B is t-butyloxycarbonyl with (i) sodium or potassium cyanate in an acidic solution, and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HCI; or (ii) phosgene or phosgene equivalent, resulting in the corresponding carbamoyl chloride intermediate; or an alkylchloroformate, such as ethyl chloroformate resulting in the corresponding carbamate, which is reacted with aqueous ammonia, or substituted amine; and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or with anhydrous ether HC1; or (iii) with trimethylsilyl isocyanate and then reacted with ethane thiol in the presence of aluminium trichloride as in step I.; and deprotected by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HC1; or (iv) with acetyl chloride in organic solvent which is then deprotected, optionally with ethane thiol in the presence of aluminium trichloride; or by treatment with trifluroracetic acid, trimethylsilyltrifilate with 2,6-lutidine, or anhydrous ether HC1 to yield the corresponding compounds of Formula (I); or F. reacting a compound of Formula (II) as described above, wherein B is an alkoyl or aroyl with (i) sodium or potassium cyanate in an acidic solution, as described in Step B
above; and deprotected with a suitable base, such as potassium carbonate; or (ii) with trimethylsilyl isocyanate as in step A above and deprotected with n suitable base, such as potassium carbonate; or (iii) with acetyl chloride in organic solvent which is then deprotected by treatment with a suitable base, such as potassium carbonate; to yield the corresponding compounds of Formula (I).

30. A process for producing a compound of the formula (II) wherein R2 and R3 are ;
B' is hydrogen, benzyl, optionally substituted benzyl, Si(RX)3, C(O)R5, C(O)OR5', CH2OCH2CH2Si(Rx3)3, C1alkyl-C1-3alkoxy, and C1alkylC2alkoxyC1-3alkoxy, or tetrahydropyranyl;
R5' is C1-6 alkyl, aryl, or aralkyl;
A is hydrogen or C(O)ORz;
Rz is benzyl, Si(RX)3, t-butyl, CH2OCH2CH2si(Rx)3;
Rx is independently selected from C1-6 alkyl or aryl;

W is CH2(CH2)s, O(CH2)s, S(CH2)s, or NR9(CH2)s;
R9 is hydrogen, C1-4 alkyl, C1-6 alkoyl, or aroyl;
s is a number having a value of 0 to 3;
q is a number having a value of 0 or 1;
I is a number having a value of 0 or l;
provided that when q is 0 then l is 1 and R2 is hydrogen and when q is 1 then l is 0 and R3 is hydrogen;
R1 is a member selected from the group consisting of hydrogen, alkyl 1-10, alkoxy 1-10, (CH2)m-Ar-(X)v, O(CH2)mAr-(X)v, S(CH2)m-Ar-(X)v, or N(CH2)m-Ar-(x)v;
m is a number having a value of 0 to 3;
n is a number having a value of 0 to 3;
v is a number having a value of 1 to 3;
Ar is a member selected from the group consisting of phenyl, napthyl, quinolyl, isoquinolyl, pyridyl, furanyl, imidazoyl, benzimidazoyl, triazolyl, oxazolyl, isoxazolyl, thiazole, or thienyl;
X is a member selected from the group consisting of hydrogen, halogen, alkyl 1-10, cycloalkyl 5-8, alkenyl 2-10, hydroxy, (CHY)tcarboxy, O-alkyl 1-10, S-alkyl 1-10, SO-alkyl 1-10, SO2 alkyl 1-10, aryloxy, arylalkyl1-6 oxy, halosubstituted alkyl1-6, (CHY)tN(R5)2, or cyano; provided that if v is a number greater than 1 then one substituent must be selected from alkyl, O-alkyl 1-10, or halo;
Y is hydrogen or alkyl1-3;
t is 0 or 1; provided that when B is hydrogen, W is other than CH2(CH2)s, and s is 0 or 1, and B is hydrogen, W is other than S(CH2)s and s is 1;
and the pharmaceutically acceptable salts thereof which process comprises A. reacting a compound of Formula (III) (III) wherein R2 and R3 are =O;
W, R1, R7, s, q, 1, m, v, Ar, S, t, and Y are as defined for Formula (II);
with hydroxylamine in solvent to yield the corresponding oxime derivative of Formula (IV) (IV) wherein R2 and R3 are =N-OH;
W, R1, R7, s, q, 1, m, v, Ar, S, t, and Y are as defined for Formula (II);
which is then reduced with borane pyridine complex, borane trimethylamine, or borane tetrahydrofuran or other borane complexes, to yield the hydroxylamine derviatives of Formula (II); or B. reacting a compound of Formula (IV) as defined above with sodium cyanoborohydride or phenyldimethylsilane in anhydride in trifluroacetic acid to yield the hydroxylamine derviatives of Formula (II); or C. reacting a compound of Formula (V) (V) wherein R2 and R3 are X;
X is a leaving group;
W, R1, R7, s, q, l, m, v, Ar, S, t, and Y are as defined for Formula (II);
with Z-furfulaldehyde oxime and base to yield the corresponding nitrone of Formula (VI) which is hydroylzed to yield the hydroxylamine derviatives of Formula (II);

D. reacting a compound of Formula (V) with a protected hydroxylamine to yield the corresponding protected hydroxylamine of Formula (II); or E. reacting a compound of the Formula (VI) (VI) wherein R2 and R3 are OH;
W, R1, R7, s, q, l, m, v, Ar, S, t, and Y are as defined for Formula (II) as described above:
with a protected hydroxylamine, such as N,O-bis(t-butyloxycarbonyl)-hydroxylamine) or bisbenzyloxycarbonyl, and triphenylphosophine/ diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II).

31. The process according to Claim 30, Step C. wherein the leaving group is halogen, tosylates, mesylates or a triflates moiety; and the hydrolysis is by hydroxylamine or under acidic conditions.

32. A process for making the chiral compounds of Formula (I) as described above which process comprises A. (i) reacting a homochiral oxazolidione of Formula (A) (A) wherein R is an optionally substituted aryl, arylmethyl, heteroaryl, or heteroarylmethyl;
with phosgene or a phosgene equivalent and base in anhydrous solvent to yield to form the corresponding acid chloride intermediate of Formula (VII) (VII) (ii) reacting the Formula (VII) adduct with a chloronated hydrocarbon or etheralsolvent and base to yield the corresponding (+) and (-) compound of Formula (II);
(iii) cleaving the adducts under basic conditions to yield the individual entantiomers of the Formula (II) compounds; or B. reacting (i) an optically active alcohol of Formula (VI) as defined above with N,O-bis(t-butyloxycarbonyl)hydroxylamine) and triphenylphosophine/
diethyldiazodicarboxylate to produce an intermediate which is treated with acid to yield the hydroxylamines of Formula (II); or (ii) reacting the corresponding optically active halo or sulfonate of Formula (VI), which may be optionally protected in a base, such as triethylamine, pyridine to yield the corresponding chiral Formula (II) compounds; or C. (i) reacting an optically active amine of Formula (VIII) (VIII) wherein R2 and R3 are NH2;
W, R1, R7, s, q, l, m, v, Ar, S, t, and Y are as defined for Formula (II);
with 4-methoxybenzaldehyde in trimethylamine;
(ii) oxidizing the intermediate of step (i) to yield the corresponding oxaziridine:
(iii) reacting the oxaziridine of step (ii) under acid conditions to yield the hydroxylamine salts of Formula (II) compounds; or D. reacting the optically active amine of Formula (VIII) as described above withdimethyldioxirane or a peracid anhydride, such as benzoyl peroxide, to yield the protected chiral hydroxylamine of Formula (II) compounds; which may be optionally deprotected to yield the final compounds of Formula (II).

33. The process according to Claim 32, Part A. (i) wherein the R is an optionally substitututed phenyl; the base in step (i) is NaH, the anhydrous solvent is toluene and the solution is cooled to about -70°C to about 20°C.

34. The process according to Claim 33 wherein base of step (ii) is an amine base, such as trialkylamine or pyridine, or is a solid alkali metal carbonate, such as calcium carbonate or potassium carbonate.

35. The process according to Claim 34 wherein the adduct is cleaved in step (c) by an alkali metal hydroperoxide, such as lithium hydroperoxide.

36. The process according to Claim 35 wherein the cleavage occurs in an aqueous-etheral solvent such as tetrahydrofuran, glyme, diglyme or ethyl ether, at a temperature of about -20°C to about 50°C.