CA2236773A1 - Biphenyl hydroxamate inhibitors of matrix metalloproteinases - Google Patents

Abstract

Compounds of formula (I), or a pharmaceutically acceptable salt thereof inhibit matrix metalloproteinases and TNF.alpha. secretion and are useful in the treatment of inflammatory disease states. Also disclosed are matrix metalloproteinases and TNF.alpha. secretion inhibiting compositions and a method for inhibiting matrix metalloproteinases and TNF.alpha. secretion.

Description

CA 02236773 1998-0~-0~

BIPHENYL HYDROXAM~T~ INHIBITORS OF MATRIX
METALLOPROTEINASES

Technical Field ~ 5 This invention relates to compounds having ~ctivity to inhibit matrix metalloproteinases and TNFa secretion, to pharmaceutical compositions comprising these compounds, and to a medical method of Ll~a~ t. More particularly, this invention concerns biphenyl hydroxamate compounds which inhibit matrix metalloproteinases and TNFoc secretion, to pharm~ce~ltic~l compositions comprising these compounds and to a method of inhibiting matrix metalloproteinases and TNFa secretion.
Background of the Invention The matrix metalloproteinases (MMP's) are a class of extr~cellul~r enzymes including collagenase, stromelysin, and gelatinase which are believed to be involved in the tissue destr. ction which accompanies a large number of disease states varying from arthritis to cancer.
Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycopio~iIls. In healthy tissue, there is a continual and delicately-b~l~n~ed series of processes which include cell division, matrix synthesis, and matrix degradation. In certain pathological conditions, an imbalance of these three processes can lead to improper tissue restructuring. For example, in arthritis, joint mobility can be lost when there is improper remodelling of load-bearing joint cartilage. In the case of cancer, lack of coordination of cell division and the two processes of matrix synthesis and degradation can lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries leading to subsequent metastasis.
There has been hightened interest in discovering therapeutic agents which bind to and inhibit MMP's. The discovery of new therapeutic agents possessing this activity will lead to new drugs having a novel me~h~ni~m of action for combatting disease states involving tissue degenerative processes including, for example, rheumatoid arthritis, o~steoarthritis, o.steopenias such as osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration, and tumor metastasis or invasion.
Tumor Necrosis Factor a (TNFa) is a potent proinflammatory mediator which has been implicated in inflammatory conditions including arthritis, asthma, septic shock, and inflammatory bowel disease. TNFa is originally expressed as a membrane-bound protein of about 26 kD, which is proteolytically cleaved to release a soluble 17 kD fragment (TNFa processing) which combines with two other secreted TNFa molecules to form a circulating 51 kD homotrimer. Recently, several MMP inhibitors were found to inhibit TNFoc processing (see Mohler, et al., Nature, 1994, 370, 218; Gearing, et al., Natu~, 1994, 37(~, 555; and McGeehan, et al., Nature, l9g4, 370, 558), leading to the hypothesis that TNFoc processing is caused by an as yet uncharacteri~ed metalloproteinase residing in the plasma membrane of cells _ CA 02236773 1998-0~-0~

proAucing TNFa. Inhibitors of this metalloproteinase would therefore be useful as therapeutics to treat disease states involving TN~a secretion.
Certain aryl-substituted hydroxamic acid derivatives which inhibit lipoxygenase and/or cyclooxygenase are described in U.S. Pat. No. 5,036,157. United States Pat. No. 3,75S,603 5 discloses certain biphenyloxyacetohydroxamic acids which are claimed to have antiinflammatory ~r~,~c. Lies.

Summary of the Invention In its principal embodiment, the present invention provides a compound of formula o ~N R3 HO~N J~ X~
or a pharmaceutically acceptable salt thereof where m and n are independently 0 or I and p is 0-6, provided that m, n, and p cannot all be 0.
R1 is selected from the group consisting of (a) hydrogen; (b) alkyl of one to six carbon atoms; (c) alkenyl of two to six carbon atoms; (d) hydroxy; (e) --(alkylene)~ R6 where the alkylene portion is of one to six carbon atoms, and R6 is selected from the group consisting of alkyl of one to six carbon atoms, haloallcyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and hydroxy; (f) --(alkylene)--S(O)q~ R6 wherein q is ~), 1 or 2, the alkylene portion is of one to six carbon atoms, and R6 is defined above, (g) -(alkylene)-co2R7 wherein the alkylene portion is 20 of one to six carbon atoms, and R7 is hydrogen or alkyl of one to six carbon atoms.

R2 and R3 are independently selected from the group consisting of (a) hydrogen; (b) alkyl of one to six carbon atom~; (c) phenyl; (d) phenyl substituted with halogen, alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, allcoxy of one to six carbon atoms, 25 or hydroxy; (e) pyridyl, and (f) pyridyl substituted with halogen, aL~cyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms.
Alternatively, R2 and R3 taken together with the nitrogen atom to which they areattached define a ~- or 6-1-le-llbe-ecl saturated heterocyclic ring in which the heterocyclic ring optionally contains an additional heteroatom selected from the group consisting of -NRX
~o wherein R8 is hydrogen or alkyl of one to six carbon atoms, -O-, -S-, or ~S(O)r~ wherein r is I
or 2.

_ CA 02236773 1998-0=.-0=.

X is absent or is selected from the group consisting of (a) -O-; (b) -NH-; and (c) -S-;
with the provisos that (a) when X is oxygen, and m and n are zero, p is an integer of two to six, inclusive, and (b) when X is oxygen and m is one and n is zero; then p is an integer of one to six, inclusive.
~4 and RS are independently se1ected from the group consisting of (a) hydrogen; (b) alkyl of one to six carbon atoms; (c) halogen; (d) cyano; (e) cyanoalkyl of one to six carbon atoms; (f) haloalkyl of one to six carbon atoms, (g) hydroxy, and (h) alkoxy of one to six carbon atoms.
The present invention also provides pharmaceutical compositions which comprise a10 therapeutically effective amount of compound of Claim I in combination with a pharn ~f~elltically acceptable carrier.
The invention further relates to a method of inhibiting matrix metalloproteinases and/or TNFa ~ecretion in a host man~ al in need of such treatment compri.sing administering to a mal~---al in need of such ll~;at-llenl a therapeutically effective amount of a con-poulld of Ciaim 1.

D~ tz~iled Des~ tion As used throughout this specification and the appended claims, the following terms have the me~ning~ specified.
The term alkyl refers to a monovalent group derived from a straight or branched chain 20 saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, ~l-, sec-, iso- and tert-butyl, and the like.
The terms alkoxy and alkoxyl denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. ~epresentative alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the like.
The term alkenyl as used herein refer to monovalent straight or branched chain groups of 2 to 6 carbon atoms containing a carbon-carbon double bond, derived from an alkene by the removal of one hydrogen atom and include, but are not limited to groups such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl- l-propenyl, I -butenyl, 2-butenyl and the like.
The term a~cylene denotes a saturated divalent hydrocarbon group derived from a 30 straight or branched chain saturated hydrocarbon containing by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH(CH3)CH2- and the like.
The term alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon cont~ining at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, and the like.
The terms alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group Cont~ining ae least one carbon-carbon triple bond. Examples of alkynylene include -CH-CH-, -CH=C-CH2-, -CH--CH-CH(CH3)- and the like.

CA 02236773 1998-0~-0~

The terrn aryl as used herein refers to a monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
The term cycloalkyl as used herein refer to a monovalent saturated cyclic hydrocarbon 5 group. R~.Gse..~tive cycloaL~cyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclor2.2.1]heptane and the like.
Cycloalkylene denotes a divalent radical derived from a cycloalkane by the removal of two hydrogen atoms.
The term cyanoalkyl denotes an alkyl group, as defined above, substituted by a cyano 10 group and includes, for example, cyanomethyl, cyanoethyl, cyanopropyl and the like.
The term haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromeIl.yl, bromoethyl, trifluoromethyl, and the like.
By pharmaceutically acceptable salt is meant those salt,s which are, within the scope of 15 sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art . For example, S. M Berge, et a~. describe pharmaceutically acceptable salts in detail in ./.
Pharmacelltical Sciences, 1977, 60':l - 19 . The salts can be prepared in situ during the final 20 isolation and purification of the compounds of the invention, or se~ualal~ly by reacting the free base function with a suitable organic acid. RepIese.,~live acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, eth~rleslllfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, 25 hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.
30 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, lel~ametl-ylammonium~ tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
Asymmetric centers may exist in the compounds of the present invention. The present 35 invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisome}s of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by pl~p~dlion of Il~ihc~es of enantiomeric products follwed by separation as, for example, by conversion to a mixture of diastereomers followed by CA 02236773 l998-0~-0~

separation by recrystallization or chromatographic techni~ue~, or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry ~re either comrnercially available or are made by the methods detailed ~elow and resolved by techniques well known in the organic chemical arts.
Compounds contemplated as falling within the scope of this invention include, but are not limited to:
4-(4-phenylphenoxy)butanohydroxamic acid, 4-(3-phenylphenoxy)butanohydroxamic acid, 4-[4-(4-cyanophenyl)phenoxy]butanohydroxamic acid, 10 4-[4-(3-cyanophenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-cyanomethylphenyl)phenoxy]butanohydroxamic acid, 4-~4-(3-cyanomethylphenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-chlorophenyl)phenoxy3butanohydroxamic acid, 4-[4-(4-propylphenyl)phenoxy]butanohydroxamic acid, 15 4-[4-(4-methoxyphenyl)phenoxy]butanohydroxamic acid, 7-(4-phenylphenoxy)heptanohydroxamic acid, 7-[4-(4-cyanophenyl)phenoxy]heptanohydroxamic acid, 5-[3-(4-fluo~vphellyl)phenoxy]pentanohydroxamic acid, 5-[3-(3-cyanophenyl~phenoxy]pentanohydroxamic acid, 20 5-[3-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 4-[3-(4-fluorophenyl)phenoxy]butanohydroxamic acid, 4-[3-(4-cyanophenyl)phenoxy]butanohydroxamic acid, 4-[3-(3-cyanophenyl)phenoxy]butanohydroxamic acid, 5-[3-phenylphenoxy]pentanohydroxarnic acid, 25 5-[4-phenylphenoxy]pentanohydroxamic acid, 5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 6-[4-phenylphenoxy]hexanohydroxamic acid, 6-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 3-(4-phenylphenoxy)propanohydroxamic acid, 30 3-(3-phenylphenoxy)propanohydroxamic acid, 3-[4-(4-cyanophenyl)phenoxylpropanohydroxamic acid, 3-[4-(4-methoxyphenyl)phenoxy]propanohydroxamic acid, 3-[4-(4-fluorophenyl)phenoxy]propanohydroxamic acid, (S) 2-methyl-3-(4-phenylphenoxy)propanohydroxamic acid, 35 3-(N-methylcarboxamido)-5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 3-(4-biphenylthio)propanohydroxamic acid, 2-(4-biphenylthio)ethanohydroxamic acid, 3-(4-biphenylamino)propanohydroxamic acid, 2-(4-biphenyl3ethanohydroxamic acid, 4-(4-biphenyl)butanohydroxamie acid, 4-[4-(4-cyanophenyl)phenyl]butanohydroxamic acid, 3-(4-biphenyl)propanohydroxamic acid, 6 5-(4-biphenyl)pentanohydroxamic acid, 5-[4-(4-fluorophenyl)phenoxy]pentanohydroxamic acid, 4-(2-hydroxy-4-phenylphenoxy)butanohydroxamic acid, 4-(2-hydroxy-5-phenylphenoxy)butanohydroxamic acid, 3-~(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid, 10 2-tert-butyloxycarbonylmethyl~[4-(4-cyanophenyl)phenoxy]butanohydroxamic acid, 3-[4-(4-cyanonletl~ Jhenyl)phenoxy]propanohydroxamic acid, and 2-hydroxy-3-[(4-phenyl)phenoxy]propanohydroxamic acid or a pharmaceutically acceptable salt thereof.
Preferred compounds of the present invention have formula 1~

HO. N~X~ ~

wherein p is 0-6; and Rl, R2, R3, R4, R5 and X are defined above.
More ~lcr~ d compounds of the present invention have formula N~'X~R5 wherein p is 1-6; and Rl, R4, R5 and X are defined above.
The most ylGr~lled compounds of the present invention have the formula immediately 25 above wherein X is -O-.

DtilGI-llil.a~ion of Stromelysin Inh;bition The inhibition of stromelysin by the compounds of this invention was de~llllilled as follows: Recombinant truncated stromelysin (human sequence) produced in E. coli was 30 plG~>al~,d by expression and purification of the protein as described by Ye et al., Biochemistry, 1992, 31, 11231-11235. The enzyme was assayed by its cleavage of the thiopeptide ester substratG Ac-Pro-Leu-Gly-[2-n~GIc~to-4-methyl-pentanoyl]-Leu-Gly-OEt described by Weingarten and Feder, Anal. Biochem., 1985, 147, 437-440 (1985), as a substrate of vt;.~bl~t; collagenase. The reported conditions were modified to allow assays to be carried out in a rr~icrotiter plate. Upon hydrolysis of the thioester bond, the released thiol group reacts rapidly with 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB), producing a yellow color which is measured by a microtiter plate reader set at 405 nm. The rates of cleavage of the subs~ate by stromelysin in the ~ sel-ce or absence of inhibitors are measured in a 30 min assay at ambient temperature. Solutions of the compounds in DMSO are prepared, and these are diluted at various concentrations into the assay buffer (50 mM MES/NaOH pH 6.5 with 10 mM CaC12 and Q.2% Pluronic F-68), which is also used for dilution of the enzyme and substrate. The potency of the compounds [~C~o] are calculated from the inhibition/inhibitor concentration data.
10 The compounds of this invention inhibit stromelysin as shown by the data for representative examples in Table 1.

Table I
Inhibitory Potencies against Stromelysin of Rc;~"eselllative Compounds ExampleIC~o (~LM) or % inhibition 2 5% @ 100 ~M
3 3.5 6 1.9 7 47%@ 100~M

8 1() 45%@ 100~M
Il 2.3 12 20% @ 100 ~M
13 24% @ 100 ~M

~ 16 24 17 2.5 ~ 18 74 19 38%@ 100,uM
3.5 22 ~ 7 230.31 2414%@ IO~M
250.025 26O.Q79 270.19 2~0.15 290.35 30 2.1 310.88 32 4.6 3314% @ 100 ~M

35 8.3 38 1.0 3947% @ 100 ~M
4039% @ 100 ~M
4136% @ 100 ~M
420.015 430.49 440.19 45 2.3 TNFoc secretion Inhibition The inhibition of TNFa secretion by the compounds of this invention was determined using a H1~60 TNFo~ Release Assay. HL-60 cells were cultured in RPMI 1640 with 10% fetai bovine serum and penicillin/streptomycin. HL-60 cells (150,000 ceils/well) were placed in 96 well culture plates in RPMI 1640 with 10% fetal bovine serum and pen/strep cont~inin~ 4n nM
phorbol myristate acetate and test compound in DMSO (final DMSO 0.1%). HL-60 cells were then cultured for 2() hr at 37 "C (95% humidity) after which cell supernatants were collected for analysis of TNFoc by ELISA. The compounds of this invention inhibit TNFa seeretion as shown by the data for representative examples in Table 2.

Table 2 Inhibitory Potencies against TNFoc secretion of Representative Compounds Example'% inhibiti~n ~? 16 ~M
27%
4 64%
82%
6 40%
7 35%
8 35%
Il 77%
12 62%
1 3 67%
14 64%
lS 63%
I ~s 62%
19 61%
5()%
24 59%
34 52%
38 65%

Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the' present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharrn:3~euti~z-l compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal o administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracis~ernally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The tenn "parenteral" administration as used herein refers to modes of ~lministration which include 15 intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

CA 02236773 1998-0~-0~
WO 97/18188 PCT/I~S96/18172 Pharm~e~tic~l compositions of this invention for p~cnt~ injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, 5 solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include i.sotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable 15 pharm~ceutiç~l form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may beaccomplished by the use of a liquid suspension of crystalline or amorphous material with poor 20 water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a ~uell~eldlly administered drug form is accomplhshed by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in 2~ biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and 35 granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium pho.sphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, CA 02236773 1998-0~-0~

polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium c~bulla~, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and rnixtures thereof. ln the case of capsules, tablets and pills, the dosage form may also comprise burfeIi~lg agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-10 filled gelatin capsules using such excipients as lactose or milk sugar as well as high mole-;ular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings and other coatings well known in the pharrn~-~eutic~l form~ ting art. They may optionally contain opacifying agents and can also be 15 of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene 25 glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and pc~Iru~ g agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitall estens, microcrystalline ceUulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can 35 be ~I~pa~ed by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room te~pt;I~ule but liquid at body tt;ml)eI~ule and therefore melt in the rectum or vaginal cavity and release the active compound.

CA 02236773 1998-0~-0~

Compounds of the present invention can also be administered in the form of liposomes.
As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipient~s, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,~o Methods in Cell Biolo~y. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical acl"Lini~.Ll~tion of a compound of this invention include powders, sprays, ointment,s and inhalants. The active compound i,s mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or 15 propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that i.s effeceive to achieve the desired therapeutic response for a particular patient, compositions, and mode of 20 administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a marnmalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

Preparation of Comyounds of this Invention The compounds of this invention may be prepared by a variety of synthetic routes.
Re,~)~t;se,lL~ti~e procedures are outlined in the following Schemes 1-4.
The p~e~ Lion of compounds of formula 5, wherein p is 2-6 and X, R4, R~, and Rl are defined above is described in Scheme 1. Reaction of I with haloester 2 (wherein Y is Br, 35 Cl, or 1) in the presence of base provides ester 3. Basic hydrolysis of the ester, for example using LiOH or NaOH in an aqueous solvent system such as aqueous dioxane or aqueous methanol, or acidic hydrolysis using, for example, trifluoroacetic acid provides acid 4.
Conversion of 4 to the desired hydroxamic acid 5 is accomplished by conversion to the acid chloride using, for example, thionyl chloride or oxalyl chloride, followed by ll~atmellt with hydroxylamine or a hydroxylamine e~uivalent such a~ O-tert-butyldimethylsilylhydroxylamine.

Scheme 1 X~o R1 4: R = H

R4~

\ R5 The preparation of the compounds of the invention of formula 7 is outlined in Scheme 2. Reaction of 1, wherein X is O, S, or NH, with ,B-propiolactone provides acid 6. When X is 10 O or S, a base such as potassium tert-butoxide is required for the lactone opening. Conversion of 6 to the hydroxamic acid 7 i~ then accomplished as described in Scheme I above.

Scheme 2 ~,XH X ~OH

\ R5 Alt~ tive routes to the compounds of this invention are outlined in Schemes 3 and 4.
According to Scheme 3, iodophenyl derivative 8, wherein X is O, S, or NH, is converted to ester ~ as described in Scheme I above. The palladium(0)-catalyzed coupling of 9 with phenyl derivative 11, wherein Y is B(OH)3 or trialkyltin, provides the desired biphenyl compound 13.

WO 97/18188 PCT/USg6/18172 ~iphenyl 1;~ is also obtained by conversion to 9 to the alkyltin compound 10, preferably by reaction with hexamethylditin and palladium(O), followed by coupling with halophenyl compound 1~, wherein Y is Br, trifluoromethanesulfonyl, or 1, in the presence of palladium(n).
A plerelled palladium(O) catalyst is tetrakis(triphenylphosphine)palladium(O). Ester 13 is then 5 converted to the hydroxamic acid 5 as described in Scheme I above.

WO 9711~188 PCT/US96118172 Scheme 3 . R" ~

, Pd(o) ~ R/S~~

Y = B(OH)3 or SnR3 R~

i~
~\R5 13 ~\Rs ~

Hydroxamic acid 5, is also ~,rep~ed from ester 9 as shown in Scheme 4. The ester is hydro}yzed and converted to the O-protected hydroxamic acid 1~ as described in Scheme I
above, except using H2NOP, wherein P is a suitable oxygen protecting group, instead of hydroxylamine. A particularly p.er~.led protecting group is benzyl. Conversion of IS to the biphenyl derivative 16 is then accomplished by the Pd(O)-catalyzed coupling with10 phenylboronic acid 11, or by conversion of 1~ to the trialkyltin derivative and coupling with halophenyl compound 12 in the presence of Pd(O) as described in Scheme 3 above. Removal of the protecting group, using, for example, catalytic hydrogenolysis when P = benzyl, provides the desired hydroxamic acid 5.

WO 97/~8188 PCT/US96/18172 Scheme 4 ~/~ X ~ NHOP

Rl R1 ~R5 t6 I~IR5 5 The preparation of compounds of this invention wherein m and n both are I and p>2 is outlined in Scheme 5. Ester 17, pn,pal~,d as described in Schemes 1, 3, or 4 above is deprotonated with a base, and the resulting anion is reacted with a haloester 18 to form diester 19. A ~ sentative base useful in this step of the process is lithium hexamethyldisilazide. The groups R and R' are selected such that R can by hydrolyzed in the presence of R'. Preferred 10 groups are ethyl and tert-butyl for R and R' respectively. Selective hydrolysis of 1~, for example using aqueous lithium hydroxide when R is ethyl, provides 20, which is then treated with 2 equivalents of a base as defined above followed by addition of alkyl halide RIX. This material is then converted to amide 21 by methods well-known in the art, for example using HNR2R3 hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 4-1~ methylmorpholine. Hydroxamic acid 22 is then prepared by hydrolysis of monoester 21, followed by reaction with hydroxylamine as described in Scheme 1.

Scheme 5 H~,, CO2R' base]

CO2R' ~ 19 ~,C02R' R~,CO2R' R4--~ ~P~ 1 a) [base] r~ ~ ~ NR2R3 ~R5 2) HNR2R3 ~Rs 2. H2NOH

R~N

R4 ~ ~P o ~3 22 \Rs The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept.

Example I
Preparation of 4-~4-phenylphenox~r)butanohydroxamic acid.
Step 1: 4-(4-phenylphenoxy)butanoic acid ethyl ester.
To a suspension in dry DMF of 4-phenylphenol (4.99 g,.29.4 mmol) and cesium carbonate (14.35 g, 44.0 mmol) was added ethyl-4-bromobutyrate (8.85 g, 45.3 mmol) in a single portion and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl ether and extracted with pH 7 buffer. The organic pha~.e was washed twice with brine, dried over MgSO4, filtered, and concentrated in vac~l~7 to give 4-(4-phenylphenoxy)butanoic acid ethyl ester ( I n.48 g) as a white solid.

Step 2: 4-(4-phenylphenoxy)butanoic acid.
A suspension in 1:1 dioxane/water (70 mL) of 4-(4-phenylphenoxy)butanoic acid ethyl ester (10.29 g, 36 mmol), prepared as in step 1, and lithium hydroxide hydrate (2.05 g, 49 20 mmol) was heated at reflux for I X hours. Dioxane (35 mL) was then added and an additional CA 02236773 1998-0~-0~

i8 2.0 equivalents of lithium hydroxide hydrate was added four hours later. The reaction mixture was heated at reflux for two more hours, then was cooled to ambient tell,pel~ture and concentrated in vacuo. The resulting white solids were shaken with ethyl ether and aqueous I M
NaOH and the residual solid (4-(4-phenylphenoxy)butyric acid, 3.53 g) was filtered off. The 6 organic phase was discarded and the aqueous phase was acidified with concentrated HCI. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract,s were dried over MgSO4, filtered, and concentrated in vacuo to give an additional 6.25 g of 4-(4-phenylphenoxy)butanoic acid.

10 Stev 3: 4-(~phenylphenoxy)butanohydroxamic acid.
A suspension of 4-(4-phenylphenoxy)butanoic acid (2.42 g, 9.45 mmol) in thionyl chloride (25 mL) was heated at reflux for 90 rninutes, during which time the mixture became homogenous. The reaction mixture was cooled to ambient te.-~p~.dture and concentrated in vacuo. The residue was taken up in 1: I methylene chloride/THF. In a separate flask, 4-methylmorpholine (3.5 mL, 32 mmol) was added to a solution of hydroxylamine hydrochloride (2.1 g, 30 mmol) in water (10 mL). THF (20 mL) was then added and the hydroxylamine solution was d~-c~nte~l into the acid chloride solution, and the reaction mixture was vigorously stirred for 2 hours. The reaction Illhclul~ was partitioned between saturated aqueous NH4CI
and methylene chloride. The organic phase was dried over MgSO4, filtered, and concentrated 20 i~t vacunto give 4-(4-phenylphenoxy)butanohydroxamic acid (1.45 g) as a white solid. IH
NMR (DMSO-d6) o 1.94 (m, 2H), 2.14 (t, 2H, J = 7 Hz), 4.01 (t, 2H, J = 6 Hz), 7.02 (d, 2H, J = 8 Hz), 7.29 (t, IH, J = 6 Hz), 7.43 (t, 2H, J = 6 Hz), 7.62 (m, 4H), 8.71 (s, IH), 10.44 (s, IH) . MS (DCItNH3) 289 (M+NH4+, 100), 272 (M~H+, 35), 255 (30). Anal.
Calcd for: Cl6HI7NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 64.81; H, 6.65; N, 5.82.
Example 2 Preparation of 4-(3-phenyl~henoxy)butanohydroxamic acid.

Step 1: 4-(3-phenylphenoxy)butanoic acid ethyl ester.
The desired compound was ~r.,pa-cd according to the method of Example 1, step 1,except sub~lilulillg 3-phenylphenol for 4-phenylphenol.

Step 1: 4-(3-phenylphenoxy)butanoic acid.
To a solution in 2: I dioxane/water (36 mL) of 4-(3-phenylphenoxy~butanoic acid ethyl ester (3.42 g, 12 mmol), prepared as in step I, was added lithium hydroxide hydrate (1.42 g, 33.8 mmol) and the reaction mixture was stirred overnight at ambient l~ lule. The reaction mixture was concentrated in vacuo and the resulting solid was mostly dissolved in aqueous Na2CO3. The aqueous solution was decanted from a small amount of residual solid and extracted with ethyl ether. The ether extract was discarded and the aqueous phase was taken to pH 2 with HCI and extracted with ethyl acetate. The ethyl acetate extract was dried over MgS04, filtered, and concentrated in vacuo to give 4-(3-phenylphenoxy)butanoic acid (3.17 g).

Ste" 3: 4-t3-~henylyhenoxy)butanohydroxamic acid.
The desired compound was prepared according to the method of Example 1, step 3, except sub~.lilulil-g 4-(3-phenylphenoxy)butanoic acid, prepared as in step 2, for 4-(~
phenylphenoxy)butanoic acid. IH NMR (DMSO-d6) o 1.93 (m, 2H), 2.11 (t, 2H, J = 7 Hz~, 4.01 (t, 2H, J = 6 Hz), 6.92 (d, lH, J = 4 Hz), 6.97 (dd, IH, J = 4, 9 Hz), 7.44 (m, 7H), 10 10.41 (s, lH).

~x~m~)le 3 PlGva".t;on of 4-r4-(4-cyano~henyl)phenoxylbutanohydroxarnic acid.
The desired compound was prepared according to the method of Example 2, except 15 ~ul):ililuling 4'-hydroxy-4-biphenylcarbonitrile for 3-phenylphenol. mp 170-172 ~C. IH NMR
(DMSO-d6) o 1.93 (m, 2H), 2.14 (t, 2H, J = 7 Hz), 4.02 (t, 2H, J = 6 Hz), 7.04 (d, 2H, J =
8 Hz), 7.71 (d, 2H, J = 8 Hz), 7.86 (m, 4H), 8.64 (s, lH), 10.40 (s, lH) . IR (KBr~ 3310, 2960, 2220, 1680, 1600, 1490, 1245 cm-l. MS (DCVNH3) 314 (M+NH4+, 100), 297 (M+H+, 40), 253 (70) . Anal. Calcd for 20 C17H16N2O3-0.25 H20: C, 67.87; H, 5.53; N, 9.31. Found: C, 68.00; H, 5.41; N, 9.08.

Example 4 Preparation of 4-r4-(3-cyano~henyl)phenoxylbutanohvdroxamic acid.

Ste~ 4-(4-iodophenoxy~butanoic acid ethyl ester.
The desired compound was ,~)r~ c;d according to the method of Example 1, step 1,except substituting 4-iodophenol for 4-phenylphenol.

30 Ste~ 2: 4-(4-ttimethylstannylphenoxy)butanoic acid ethyl ester.
To a solution in toluene (120 mL) under argon of 4-(~iodophenoxy)butanoic acid ethyl ester (2.00 g, 5.98 mmol) and hexamethylditin (2.35 g, 7.17 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol). The reaction mixture was stirred for 15 . . ~ rs at ambient lr~ ture and 30 minutes at reflux. The reaction mixture 35 was cooled to ambient lr,---pel~ture, diluted with ethyl acetate, and filtered. The filtrate was washed with pH 7 buffer (NaOH-KH2PO4) and brine, dried over Na2SO4, filtered, and conce"ildled in vacuo. Cl-rolllalography on silica gel (40: 1, then 20: 1, then 10: I hexane/ethyl acetate) gave 4-(4-trimethylstannylphenoxy)butanoic acid ethyl ester (1.14 g, 51 %) as a clear, colorless oil.

Step 3: 4-r4-(3-cyanophenyl)~henoxylbutanoic acid ethyl ester.
To a solution in toluene (27 rnL) under argon of 4-(4-trimethylstannylphenoxy~butanoic acid ethyl ester (0.50 g, 1.35 mmol) and 3-iodobenzonitrile (0.46 g, 2.0 rnmol) was added tetrakis(triphenylphosphine)palladium(0) (75 mg, 65 llmmol). The reaction mixture was stirred for 10 minutes at arnbient L~ cl ~Lul e and then for 24 hours at reflux. The reaction mixture was cooled to arnbient Lt;lll~u~"alur~ and di}uted with ethyl acetate. The organic solution was decanted away from a fine black ~ cil,i~te, washed with pH 7 buffer (NaOH-KH2P04) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10: 1, then 5: 1, then 3: I hexane/ethyl acetate) gave 4-14-(3-cyanophenyl)phenoxylbutanoie acid ethyl ester (0.31 g, 74%) as small white opaque rosettes.

Step4: 4-r4-(3-cyano~henyl)phenoxylbutarlohydroxarr~icacid.
The desired compound was plep~d according to the method of Exarnple 2, steps 2 and 3, except sub~Li~ul~llg ~[4-(3-cyanophenyl)phenoxy]butanoic acid ethyl ester, prepared as in step 3, for 4-~3-phenylphenoxy)butanoic acid ethyl ester. Pure 4-[4-(3-cyanophenyl)phenoxylbutanohydroxamic acid was isolated by trituration of the crude reaction product with acetonitnle cont~linin~ 1% trifluoroacetic acid. mp 130-133 ~C. IH NMR
2~ (DMSO-d6) o 1.95 (dt, 2H, J = 6.9, 13.8 Hz), 2.15 (t, 2H, J = 7.4 Hz), 4.02 (t, 2H, J = 6.2 Hz), 7.04 (d, 2H, J = 8.8 Hz), 7.63 (t, IH, J = 7.7 Hz), 7.70 (d, 2H, J = 8.8 Hz), 7.76 (d, IH, J = 7.7 Hz), 7.98 (d, IH, J = 7.7 Hz), 8.10 (~, IH), 8.73 (s, IH), 10.44 (s, IH). MS
(DCI/NH3) 297 (M+H)+, 314 (M+NH4)+. Anal. Calcd for: C17H16N2O3-0.10H2O C~ 68.49;
H, 5.48; N, 9.40. Found: C, 68.37; H, 5.41; N, 9.57 Example 5 Prc;l~al~lion of 4-r4-(4-cyanometl~yl~henyl)phenoxylbutanohydroxamIc acid.
The desired compound was prepared according to the method of Example 4, ~;teps 3 and 4, except sub~liluli~-g 4-iodophenylacetonitrile for 3-iodobenzonitrile. IH NMR (CD30D) 2.09 (dt, 2H, J = 7.4, 14 Hz), 2.30 (t, 2H, J = 7.7 Hz), 3.91 (s, 2H), 4.04 (t, 2H, J = 6.0 Hz), 7.0() (d, 2H, J = 8.X Hz), 7.40 (d, 2H, J = X. l Hz), 7.54 (d, 2H, J = X.8 Hz), 7.5X (d, 2H, J = 8.1 Hz) . MS (DCUNH3) 311 (M+H)+, 328 (M+NH4)+ . Anal. Calcd for:
C18H18N2O3-0.25H2O: C, 68.66; H, 5.92; N, 8.90. Found: C, 68.40; H, 5.58; N, 8.70.

Rxample 6 P~ lion of 4-r~(3-cyanom~ ylphenyl)phenoxylbutanohydroxarnic acid.
The desired compound was prepared according to the method of Example 4, steps 3 and 4, except su~l;L~ ng 3-iodophenylacetonitrile for 3-iodobenzonitrile. mp 140-144 ~C. IH

WO 97/t8188 PC~/US96/18172 NMR (CD30D) o 2.10 (dt, 2H, J = 7, 14 Hz), 2.31 (t, 2H, J = 7.4 Hz), 3.95 (s, 2H), 4.04 (t, 2H, J = 6.0 Hz), 7.00 (d, 2H, J = 8.5 Hz), 7.28 (d, IH, J = 7.4 Hz), 7.42 (t, IH, J--7.4 Hz), 7.51-7.58 ~c, 4H). MS (DCI/NH3) 328 (M+NH4~+ . Anal. Calcd for:
ClgHIgN2O3-0.2o H20 C, 68.86; H, 5.91; N, 8.92. Found: C, 68.92; H, 5.78; N, X.72 Example 7 Preparation of 4-r4-(~chlorophenyl)phenoxylbutanohydroxamic acid.
The desired compound was prepared according to the method of Example 4, steps 3 and 4, except substituting 1-chloro-4-iodobenzene for 3-iodobenzonitrile. mp 168-170 ~C. IH
~o NMR (DMSO-d6) o 1.95 (dt, 2H, J = 7, 13 Hz), 2.14 (t, 2H, ~ = 7.7 Hz), 4.00 (t, 2H, J = 7 Hz), 7.02 (d, 2H, J = 7.7 Hz), 7.47 (d, 2H, J = 7.4 Hz), 7.61 (d, 2H, J = 9 Hz), 7.~4 (d, 2H, J = 7.7 Hz), ~.72 (s, IH), 10.43 (s, lH) . IR Microscope 3279 (m), 3064 (br), 2960 (w), 2804 (br), 1665 (s), 1626 (s), 1607 (s), 1485 (s), 1253 (s), 1200 (m), 811 (s) cm-l. MS
(DCI/NH3) 306, 308 (M+H)+, 323, 325 (M+NH4)~. Anal. Calcd for:
C16~l6NO3CI-0.40~2O: C, 61.40; H, 5.41; N, 4.48. Found: C, 61.46; H, 5.28; N, 4.33.

Example 8 Preparation of 4-14-(4-propylphenyl)phenoxylbutanohYdroxamic acid.
The desired compound was prepared according to the method of ~xample 4, steps 3 and 4, except substituting 4-iodo-1-propylbenzene for 3-iodobenzonitrile. IH NMR (DMSO-d6) o 0.91 (t, 3H, J = 7.4 Hz), 1.61 (dq, 2H, J = 7.2, 14.7 Hz), 1.95 (dt, 2H, J = 7, 14 Hz), 2.14 (t, 2H, J = 7.4 Hz), 2.57 (t, 2H, J = 7.t~ Hz), 3.99 (t, 2H, J = 6.0 Hz), 6.99 (d, 2H, J = X.4 Hz), 7.24 (d, 2H, J = 8.1 Hz), 7.52 (d, 2H, J = ~.1 Hz), 7.56 (d, 2H, J = 8.5 Hz), 8.71 (s, IH), 10.43 (s, lH) . MS (DCl/NH3) 313 (M+NH4-H20)+, 314 (M+H)+, 331 (M+NH4)+ .
Anal. Calcd for C1gH23NO3-0.50H2O-0.25NaCI: C, 67.7}; H, 7.18; N, 4.16. Found: C, 68.06; H, 6.94; N, 4.08.
I~xample 9 Preparation of 4-r4-(4-methoxyphenyl)phenoxy1butanohydroxamic acid.
~tep 1: 4-14-(4-methoxyphenyl)phenoxvlbutanoic acid ethyl ester.
To a solution in ethylene glycol dimethyl ether (30 mL) of ~(4-iodophenoxy)butyric acid ethyl ester (0.50 g, 1.5 mmol), prepared as in Example 5, step 1, was addedtetrakis(triphenylphosphine)palladium(0) (87 mg,75 ~M), and the mixture was stirred for 15 - minutes. A solution in ethanol (9.~ mL) of 4-methoxyphenylboronic acid (0.25 g, 1.~4 mmol) was then added. Saturated aqueous NaHCO3 (15 mL) was then poured in quickly and the reaction mixture was warmed to reflux and heated for one hour. The reaction mixture was cooled to ambient l~m~ ture and concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3. The organic phase was washed with 10% aqueous Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography 2:~
silica gel (20: 1, then 10: 1, then 5: I hexane/ethyl acetate) gave 4-[4-(4-methoxyphenyl)phenoxy]butanoic acid ethyl ester (0.27 g, 57%) as white feathery needles.

Step 2: 4-14-(4-methoxyphenyl~henoxvlbutanohydroxamic acid.
The desired compound was prepared according to the method of Example 2, steps 2 and 3, except substituting 4-r~(4-methoxyphenyl)phenoxy]butanoic acid ethyl ester, prepared as in step 1, for 4-(3-phenylphenoxy)butanoic acid ethyl ester. lH NMR (CD30D) ~ 2.08 (dt, 2H, J
= 6.8, 13.6 Hz), 2.30 (t, 2H, J--7.4 Hz), 3.80 (s, 3H), 4.01 (t, 2H, J = 6.0 Hz), 6.94 (d, 4H, J = 8.8 Hz),7.46 (d, 2H, 3 = 8.5 Hz), 7.46 (d, 2H, J = 8.8 Hz). MS (DCI/NH3) 302 (M+H)+, 319 (M+NH4)+ . Anal. Calcd for Cl7HlsNo4-o.4oH2o-o.6oNH4cl: C, 59.94; H,6.57; N, 6.58. I~ound: C, 60.28; H, 6.50; N, 6.60.

Example 10 Preparatlon of 7-(4-~henyl~henoxy)he~tanohydroxamic acid.
The desired compound was prepared according to the method of Example 2, except substituting 4-phenylphenol for 3-phenylphenol, and substitu~ing ethyl 7-bromoheptanoate for ethyl 4-bromobutyrate. mp 147-14g ~C. IH NMR (DMSO-d6) o 1.32 (m, 2H), 1.41 (m, 2H), 1.52 (p, 2H, J = 7 Hz), 1.71 (p, 2H, J = 7 Hz), l .96 (t, 2H, J - 7 Hz), 3.99 (t, 2H, J = f Hz), 7.01 (d, 2H, J = 9 Hz), 7.30 (m, lH), 7.42 (m, 2H), 7.59 (m, 4H), 8.66 (s, IH), 10.34 (S, IH). IR (KBr) 3250, 2920, 2845, 1620, 1600, 1520, 1485, 1250 cm~l. MS (DCI/NH3) 331 (M+NH4+, 100), 314 (M+Hf, 20) . Anal. Calcd for ClgH23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.52; H, 7.34; N, 4.64.

Example 11 2~i Pre~aration of 7-14-~4-cyanophenyl~phenoxylheptanohydroxamic acid.
The desired compound was prepared according to the method of F.xample 2, except ~ul~liLuLing 4'-hydroxy-4-biphenylcarbonitrile for 3-phenylphenol, and substituting ethyl 7-bromoheptanoate for ethyl 4-bromobutyrate. mp 79-82 ~C. IH NMR (DMSO-d6) o 1.31 (m, 2H), 1.42 (m, 2H), 1.54 (m, 2H), 1.73 (p, 2H, J = 7 Hz), 1.96 (t, 2H, J = 7 Hz), 4.()2 (t, 2H, J = 6 Hz), 7.06 (d, 2H, J = 9 Hz), 7.70 (d, 2H, J--9 Hz), 7.87 (dd, 4H, J = 9, 14 Hz), 8.67 (bds, IH), 10.36 (s, IH). IR (KBr) 3280 (br), 2925, 2850, 2230, 1600, 149(1, 1250 cm~l. MS (APCI (+)) 356 (M+NH4+, 15), 339 (M+H+, 60), 295 (100) . Anal. Calcd for C2oH22N2o3: C, 70.99, H, 6.55; N, 8.28. Found: C, 71.08; H, 6.72; N, 6.95.

Example 12 Preparation of S-r3-~4-fluorophenyl)~henoxylpentanohydroxarnic acid.
The desired compound was ple~ed according to the method of Example 4, except substituting methyl 5-bromovalerate for ethyl 4-bromobutyrate, substituting 3-iodophenol for 4-5 iodophenol, and sub~liLulillg 1-fluoro-4-iodobenzene for 3-iodobenzonitrile. IH NMR
~DMSO-d6) o 1.71 (m, 4H), 2.04 (t, 2H, 3 - 7 Hz), 4.03 (t, 2H, J = 7 Hz), 6.93 (dd, lH, J =
2, 10 Hz), 7.15 ~m, lH), 7.19 (d, lH, J = 8 Hz), 7.27 (t, 2H, J = 8 Hz), 7.36 (t, IH, ~ = X
Hz), 7.71 (dd, 2H, J = 6, 9 Hz), 8.70 (s, lH), 10.39 (s, IH) . MS (DCI/NH3) 321 (M+NH4+, 100) . Anal. Calcd for: Cl7HlgFNo3-o.33H2o: C, 66.02; H, 6.08; N, 4.53. Found: C, 65.73; H, 5.76; N, 4.3X.
ExampIe 13 Prepa d~ion of 5-r3-(3-cyanophenyl~phenoxylpentanohydroxarr~ic acid.
The desired compound was prepared according to the method of Example 4, except substituting methyl 5-bromopentanoate for ethyl 4-bromobutyrate, substituting 3-iodophenol for 4-iodophenol, and sul)~litu~ g 3-bromobenzonitrile for 3-iodobenzonitrile. IH NMR
(DMSO-d6) o 1.75 (m, 4H), 2.56 ~m, 2H), 4.07 (m, 2H), 6.98 ~dd, IH, J = 2, 8 Hz), 7.29 (m, 2,H), 7.39 (t, IH, J =7 Hz), 7.66 ~dt, lH, J = 1, 7 Hz), 7.83 (dd, lH, J = 1, 8 Hz), 8.03 (d, IH, J = 8 Hz), X.l9 (s, IH), X.70 (s, IH), 1()3iX (s, IH) . MS (APCI) 32X (M+NH4+, 100), 311 (M+H+, 90) . Anal. Calcd for: C~gHIgN2o3-l .25H2o: C, 64.95; H, 6.21; N, 8.42. Found: C, 65.09; H, 5.61; N, 8.14.

Example 14 Preparation of 5-r3-(4-cyano~henyl)phenoxylpentanohydroxamic acid.
The desired compound was prepared according to the method of Example 4, except 25 substituting methyl 5-bromopentanoate for ethyl 4-bromobutyrate, substieuting 3-iodophenol for 4-iodophenol, and substituting 4-bromobenzonitrile for 3-iodobenzonitrile. IH NMR
(DMSO-d63 o 1.71 (m, 4H), 2.04 (m, 2H), 4.06 (m, 2H), 7.01 ~m, lH), 7.28 (m, 2H), 7.41 (m, IH), 7.90 ~bds, 4H), 8.70 (s, IH3, 10.42 (s, IH). MS (FAB) 311 (M+H+, 60), 185 (100) . Anal. Calcd for ClgHlgN2O3-2H2O: C, 62.42; H, 6.40; N, 8.09. Found: C, 62.47;
30 H, 5.33; N, 7.60.

Example 15 Pre~aration of 4-r3-(4-fluorophenyl)phenoxylbutanohydroxamic acid.
Ste~ 1: 4-(3-iodophenoxy)butanoic acid.
The desired compound was prepared according to the method of Example 1, steps I and 2, except substituting 3-iodophenol for 4-phenylphenol.

Ste~,~ 2: O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid.
To a solution in dichlolume~llane (20 mL3 COnt~inirlg a few drops of DMF of 4-(3-iodophenoxy)butanoic acid (2.26 g, 7.38 mmol) was added oxalyl chloride (0.60 mL, 6.9 mmol) slowly via syringe. The reaction mixture was stirred for 30 minutes at ambient Lemp~laLul~ and then was dec ~nted into a dichlv~ el~lane solution of O-benzylhydroxylamine (3.5 g, 22 mmol; pltp~cd by shaking O-benzylhydroxylarnine in a mixture of dichloromethane and saturated a~ueous Na~CO3, separating the layers, and drying the organic phase over MgSO4). The reaction rnixture was stirred for 3.5 hours at ambient temperature and then was extracted with water and sa~ul~ted aqueous Na2co3. The organic phase was dried over 10 MgSO4, filtered, and concentrated in vacuo to give a white solid. The solid was dissolved in dichloromethane and the organic solution was washed with aqueous lM HCI, dried over MgSO4, filtered, and concentrated in vacuo to give O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid (3.12 g) as a fluffy white solid.

Step 3: O-benzyl-4-r3-(4-fluorophenyl)phenoxylbutanohydroxamic acid.
The desired compound was prepared according to the method of Example 9, step 1, except substituting O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid, prepared as in step 2, for 4-(4-iodophenoxy)butanoic acid ethyl ester and sub.stituting toluene for DME.

20 Step 4: 4-r3-(4-fluoroI~henyl)phenoxylbutanohydroxamic acid.
To a solution in T~F (15 ~,nL) of O-benzyl-4-[3-(4-fluorophenyl)phenoxy~butanohydroxarnic acid (0.29 g, 0.77 mmol), prepared as in step 3, was added 10% palladium on carbon (0.107 g) and the mixture was stirred overnight under a positive H2 pressure. Purification by reverse phase high perfo,rnance liquid chromatography 25 gave 4-[3-(4-1'luorophenyl)phenoxy]butanohydroxamic acid (57 mg) as a white solid. IH
NMR (DMSO-d6) o 1.94 (m, 2H), 2.16 (t, 2H, J = 7 Hz), 4.03 (t, 2H, J = 6 Hz), 6.92 (dd, IH, J = 2, 8 Hz), 7.16 (m, IH), 7.20 (d, lH, J = 7 Hz), 7.28 (t, 2H, J = 9 Hz), 7.37 (t, lH, J
= 8 Hz), 7.71 (dd, 2H, J = 5, 8 Hz), 8.71 (s, lH), 10.42 (s, lH) . MS (D~l/NH3) 307 (M+NH4+, 100), 290 (M+H+, 30) . Anal. Calcd for: C16H16FNO3: C, 66.43; H, 5.57; N, 30 4.84. Found: C, 66.04; H, 5.48; N, 4.78.

Example 16 P~cp~lion of 4-r3-(4-cyanophenyl~phenoxylbutanohydroxamic acid.
ste~ O-benzyl-4-r3-(4-cyanophenyl~phenoxylbutanohyf~roxamic acid.
The desired compound was prepared according to the method of Example 4, steps 2 and 3, except slll <,~ g O-benzyl-4-(3-iodophenoxy)butanohydroxamic acid, p~cpalcd as in Example 15, step 2, for 4-(4-iodophenoxy)butanoic acid ethyl ester, and substituting 4-bromobenzonitrile for 3-iodobenzonitrile.

WO 97/18188 PCT/US96/18r7~!
2~

Step 2: 4-r3-(~cvanophenvl)phenoxylbutanohydroxamic acid.
The desired compound was prepared according to the method of Example 15, step 4,except substituting O-benzyl-4-[3-(~cyanophenyl)phenoxylbutanohydroxamic acid, plG~aled as in step 1, forN-benzyloxy-4-[3-(4-fluorophenyl)phenoxy3butyramide. IH NMR (DMSO-d6) ~ 1.97 ~m, 2H), 2.15 ~t, 2H, J = 7.3 Hz), 4.05 (t, 2H, J = 6.2 Hz), 7.01 ~m, IH), 7.29 (m, 2H), 7.42 (t, IH, J = 8.1 Hz), 7.91 (m, 4H), 8.72 (s, IH), 10.42 (s, IH) . MS (FAB(+)) 297 (M+H+, 95), 264 (80), 102 (100);
(FAB(-)) 295 (M-H-, 20), 194 (100). Anal. Calcd for C17H16N3O3: C, 68.91; H, 5.44; N, 10 9.45. Found: C, 57.96; H, 4.66; N, 7.41.

Example 117 Prep~ration of 4-r3-(3-cyanophenyl)phenoxylbutanohydroxamic acid.
The desired compound was ~lcl~an,d according to the method of Example 16, except15 substituting 3-bromobenzonitrile for 4-bromobenzonitrile. IH NMR (DMSO-d6) o 1.97 (m, 2H), 2.15 (t, 2H, J = 7.3 Hz), 4.06 (t, 2H, J = 6.5 Hz), 6.99 (m, lH), 7.29 (s, IH), 7.31 (d, lH, J = 7.7 Hz), 7.40 ~t, lH, J = 7.8 Hz), 7.66 (t, lH, J = 7.~ Hz), 7.83 (d, IH, J = 7.7 Hz), 8.03 (d, IH, J = 8.1 Hz), 8.1~ (s, IH), X.XI (s, IH), 1().43 (s, IH) . MS (FAB(+)) 31~
(M+Na+, 10), 297 (M+H+, 70), 185 (100); (FA~(-)) 295 (M-H-, 25), 194 (100). Anal. Calcd 20 for C17~16N3O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 59.61; H, 4.94; N, 7.70.

I~xample IX
PreDaration of 5-~3-phenylphenoxylpentanohydroxamic acid.

25 Ste~ 1: 5-(3-phenylphenoxy)pentanoic acid methyl ester.
The desired compound was prepared according to the method of Example 1, step 1, except substitllting 3-phenylphenol for 4-phenylphenol, and substituting methyl 5-bromovalerate for ethyl 4-bromobutyrate.

30 Step 2~ 5-(3-phenylphenoxy~pentanoic acid.
To a solution in methanol (7.5 mL) of 5-(3-phenylphenoxy)pentanoic acid methyl ester (1.42 g, 5.0 mmol), prepared as in step 1, was added water (3.75 mL) and aqueous 4N sodium hydroxide (3.75 mL). The reaction mixture was stirred for 3.5 hours and then wasconcentrated in vacuo. The residue was partitioned between waier and ethyl ether. The 35 aqueous phase was taken to pH 2 with concentrated HCI and extracted twice with ethyl acetate.
The combined ethyl acetate extracts were dried over Na2SO4, ~lltered, and concentrated i~t vacuo to give a white solid. Trituration of the solid with 1: 1 ethyl ether-hexanes gave 5-(3-phenylphenoxy)pentanoic acid (1.21 g) as a white powder.

WO 97/18188 I'CT/US96/18172 Step 3: 5-13-phenylphenoxylpentanohydroxamic acid.
To a solution in dichlolo"lell,ane (10 mL) and DMF (10 drops) of 5-(3-phenylphenoxy)pentanoic acid (0.541 g, 2.0 mmol), prepared as in step 2, was added oxalyl chloride (192 }~L, 2.2 mmol) over 3 minutes and the yellow solution was stirred for 3 hours and then was cooled in an ice-water bath. A solution in aqueous THF (2.0 mL THP, 0.2 mL
H2O) of hydroxylamine (4.0 mmol; ple~ed by adding triethylamine to a 0 ~C solution in aqueous THF of hydroxylamine hydrochloride) was added and the reaction mixture was stirred for 5 minutes in the ice bath and then warmed to ambient temperature for 3 hours. The reaction I 0 mixture was conce,~ t~d in vacuo and the residue was partitioned between ether and aqueous I N NaOH. The aqueous phase was extracted twice with dichl~ ,etllane. The combined organic layers were concentrated in vacuo to give a yellow oil (5()7 mg). Chromatography on silica gel (1%, then 5% methanol/dichloromethane), then reverse phase high p~ lmance liquid chromatography (gradient from 30% to 95% acetonitrile/water) and trituration with ethyl ether gave 5-[3-and 4-phenylphenoxy~pentanohydroxamic acid (29 mg) as a 83:17 mixture. mp 113.1-118.0 ~C. 1H NMR (DMSO-d6) o 1.58-1.80 (c, 4H), 1.99-2.08 (c, 2H), 3.98-4.09 (c, 2H), 6.90-6.96 (c, 0.83H), 6.99-7.04 ~c, 0.17H), 7.15-7.24 (c, 2H), 7.33-7.40 (c, 2H), 7.42-7.52 (c, 3H), 7.57-7.63 (c, ().34H), 7.~4-7.70 (c, I.f)~H), X.~fi (s, lH), 1().35 (s, lH).
IR (KBr) 3200, 3040, 2960, 1630, 1600, 1520, 1480, 1470, 1420, 1300, 1290, 1220, 1070, 980, 780, 700 cm-l. MS (DCI/NH3) 269 (M-16), 286 (M~H)+, 303 (M+NH4)+.

Example 19 Preparation of S-r~phenylphenoxylpentanohydroxamic acid.

2~ Step 1: 5-(4-phenylphenoxv)pentanoic acid methyl ester.
A ~ ule in acetone of 4-phenylphenol (0.85 g, 5.0 mmol) and potassium carbonate (0.76 g, 5.5 mmol) was stirred for 30 minutes. Neat methyl S-bromovalerate (0.78 mL, 5.5 mmol) was added dropwise via syringe and the reaction mixture was stirred for 2 hours at ambient temperature and overnight at reflux. Catalytic Kl was then added and the reaction 30 mixture was heated overnight at reflux. An additional 10 drops of methyl 5-bromovalerate was then added and reflux was continued for 8 hours. The reaction mixture was cooled to ambient ~lll,ueldt~u~ and filtered. The collected solid was washed with acetone and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between ethyl ether and water. The aqueous phase was extracted with ethyl ether. The combined organic layers were 35 dried over Na2SO4, filtered, and concentrated in vacu~7 to give 5-(~phenylphenoxy)pentanoic acid methyl ester (1.66 g) as a white powder.

Ste~ 2: 5-r4-phenyl~henoxylpentanohydroxamic acid.
The desired compound was prepared according to the method of Example I 8, steps 2 and 3, except substituting 5-14-phenylphenoxy)pentanoic acid methyl ester, prepared as in step 1, for 5-(3-phenylphenoxy)pentanoic acid methyl ester. mp 151.5-153.5 ~C. IH NMR(DMSO-d6) ~ 10.36 (S, IH), 8.66 (d, IH, J--1.5 Hz), 7.65-7.55 (c, 4H), 7.46-7.39 (c, 2H), 7.34-7.26 (c, 2H), 4.00 (t, 2H, J = 6 Hz), 2.03 (t, 2H, J = 6 Hz), 1.80-1.58 (c, 4H). IR
(KBr) 3200, 3040, 2920, 2860, 1660, 1640, 1620, 1610, 1520, 1490, 1470, 1290, 1270, 12~0, 1200, 1180, 1030, 840, 780, 690 cm~l. MS (DCI/NH3) 269 (M-16), 286 (M+H)+, 303 (M+NH4)+. Anal. Calcd for: Cl7HlsNo3-o.25 H2O: C, 70.44; H, 6.78; N, 4.83. Found: C, 70.71; H, 6.82; N, 4.98.
Example 20 Prepara~on of 5-r4-(4-cyanophenyl)phenoxylpentanohydroxarnic acid~

Step 1: 5-(4-(4-cyano~henyl)~henoxy)~entanoicacid.
The desired compound was prepared according to the method of Example 2, steps I and 2, except sub~.l ;n ~ g 4'-hydroxy-4-biphenylcarbonitrile for 3-phenylphenol.

Ste~ 2: 5-r4-(4-cyano~?henyl)phenoxyl~entanohydroxamic acid.
To a solution in THF (13 mL) of 5-(4-(4-cyanophenyl)phenoxy)pentanoic acid (0.50 g, 1.7 mmol), prepared as in step 1, was added DMF (10 IlL, 0.13 mmol), and oxalyl chloride (0.16 mL, 1.9 mmol) and the reaction mixture was stirred for 2 hours. A solution in THF (2 mL) of O-tert-bu~ldimethylsilylhydroxylamine (0.30 g, 2.0 mmol) and ~iethylamine (0.25 mL, 1.8 mmol) was added dropwise via syringe and the reaction mixture was stirred for 3.5 hours. The reaction ~ e was quenched with methanol and concentrated in vacuo. The residue was partitioned between aqueous 1 M NaOH and ethyl ether, and the aqueous phase was extracted with ethyl ether. The aqueous phase was taken to pH 2 with concentrated HCl and extracted three t~mes with dichl~ ne. The combined dichloromethane extract~s were dried over Na2S04, ~lltered, and concen~ated in vacuo to give a white solid. ~ecrystallization from ethyl acetate gave 5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid (0.24 g) as a white solid. mp 141.8-142.6 ~C. IH NMR (DMSO-d6) o 1.59-1.84 (c, 4H), 2.03 (t, 2H, J = 7.5 Hz), 4.03 (t, 2H, J = 6 Hz), 7.06 (d, 2H, J--9 Hz), 7.69 (s, IH), 7.72 (s, IH), 7.XI-7.92 (c, 4H), 8.71 (s, lH), 10.39 (s, lH). IR (KBr) 3200, 3030, 3010, 2860, 2240, 1630, 1600, 1540, 1520, 1490, 1470, 1460, 1390, 1290, 1250, 1 180, 1 1 1(), 980, gS0, 820, 630, 580, 530 cm-l. MS (DCI/NH3) 294 (M-16), 311 (M+H)+, 328 (M+NH4)+. Anal. Calcd for C18~18N2O3: C, 69.66; H, 5.85; N, 9.03. E~ound: C, 69.54; H, 5.73; N, 8.99.

Example 21 Preparation of 6-r4-phenylphenoxylhexanohydroxamic acid.
The desired compound was prepared according to the method of Example 20, except substituting 4-phenylphenol for 4'-hydroxy-4-biphenylcarbonitrile, and substituting e~hy 6-6 bromohexanoate for methyl S-bromovalerate. mp 151.1-151.8 ~C. IH NMR (DMSO-d6) o 1.34-1.49 (c, 2H), 1.57 (m, 2H, J = 7.5 Hz), 1.73 (m, 2H, J = 7.5 Hz), 1.98 (t, 2H, J = 7.5 Hz), 3.99 (t, 2H, J = 7.5 Hz), 6.99 (s, lH), 7.02 (s, lH), 7.16-7.25 (c, lH), 7.42 (t, 2H, J =
7.5 Hz), 7.54-7.65 (c, 4H), 8.65 (s, lH), 10.33 (s, IH). IR (KBr) 3280, 3060, 3040, 2960, 2860, 1660, 1610, 1520, 1490, 1470, 1450, 1400, 1280, 1270, 1250, 1200, 10~0, 1040, Io 830, 780, 690 cm-1. MS (DCI/NH3) 283 (M+H)+, 317 (M+NH4)+. Anal. Calcd for C18H21NO3: C, 72.21; H, 7.07: N, 4.68. Found: C, 71.85; H, 7.29; N, 4.65.

Example 22 Prep~ration of 6-r4-~4-cyanophenyl)phenoxylhexanohydroxamic acid.
The desired compound was prepared according to the method of Example 21, except sub~Lilulillg 4'-hydroxy-4-biphenylcarbonitrile for 4-phenylphenol. mp 129.4-131.4 ~C. IH
NMR (DMSO-d6) ~ 1.33-1.48 (c, 2H), 1.57 (m, 2H, J = 7.5 Hz), 1.73 (m, 2H, J = 7.5 Hz), 1.99 (t, 2H, J = 7.5 Hz), 4.02 (t, 2H, J = 6 Hz), 7.05 (d, 2H, J = 12 Hz), 7.68 (.s, IH), 7.71 (s, IH), 7.80-7.91 (c, 4H). IR (KBr) 3300, 3050, 2950, 2850, 2200, 1660, 16(~0, 1560, 1530, 1500, 1470, 1400, 127~, 1250, 1170, 1120, 1090, 1050, 1000, 840, 830, 570, 550 cm~l. MS (DCI/NH3) 308 (M-16), 325 (M+H)+, 342 (M+NH4)~. Anal. Calcd for ClgH2oN2o3-o.25 H2O: C, 69.38; H, 6.28; N, 8.52. Found: C, 69.61; H, 6.11; N, 8.1X.

Example 23 P~al~lion of 3-(4-phenylphenoxy)propanohydroxamic acid.

Step 1: 3-(4-phenylphenoxy)propionic acid.
To a solution in THF of 4-phenylphenol (1.86 g, 10.9 mmol) was added potassium tert-butoxide (1.22 g, 10.9 mmol). Neat ,13-propiolactone (0.68 mL, 10.9 mmol) was added dropwise. The resulting white suspension was stirred overnight at ambient temperature and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic phase was discarded and the aqueous phase was acidified and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over MgS04, filtered, and concentrated in vacuo to give 3-(4-phenylphenoxy)propionic acid (0.86 g) as a white solid.

WO 97/18188 PCT/US96/18~ 72 ~;te~ 2: 3-(4-phenyl~henoxy)Dro~anohydroxamic acid.
The desired compound was plG~ltid according to the method of Example 1, step 3, except substituting 3-(4-phenylphenoxy)propionic acid, prepared as in step I, for 3-(4-phenylphenoxy)butanoic acid. lH NME~ (DMSO-d6) ~ 2.44 (t, 2H, J = 7 Hz), 4.22 (t, 2H, J
= 7 Hz), 7.01 (d, 2H, J = 6 Hz), 7.31 (t, lH, J = 5 Hz), 7.42 (t, 2H, J = 5 Hz), 7.61 (m, 4H), 8.88 (bds, lH), 10.53 (s, IH). MS (DCI/NE~) 275 (M+NH4+,100). Anal. Calcd for ClsHIsNO3-0.25 H2O: C, 68.82; H, 5.36; N, 5.70. Found: C, 68.78; H, 5.27; N, 5.18.

Example 24 P~ ion of 3-(3-phenylphenoxy)propanohydroxamic acid.

Step 1: 3-(3-phenylphenoxy~propionic acid.
The desired compound was prepared according to the method of Example 23, step 1,except subs~tuting 3-phenylphenol ~or 4-phenylphenol.

Step 2: 3-(3-phenylphenoxy)vropanohydroxamic acid.
A mixture of 3-(3-phenylphenoxy)propionic acid (0.27 g, 1.1 mmol) and excess thionyl chloricle was heaeed at reflux for ~() minutes. The mixture was coole(i to ~mbient temperatllre and concentrated in vacu(7. The residue was azeotroped three times with ethyl ether, and then was taken up in THF (3() mL). To the acid chloride solution was added aqueous hydroxylamine (3.34 mmol; prepared by adding 2.X mL of aqueous 50% NaOH to a ~olution in 5 mL water of hydroxylamine hydrochloride) and the reaction mixture was stirred for 4 hours.
The reaction mixture was quenched with 1: I dichloromethane-saturated aqueous NH4CI. The aqueous phase was washed with brine, dried over Na2S04, filtered, and concentrated i~ vacuo.
The residue was taken up in ethyl ether and left standing at -30 ~C for 3 days. The resulting crystals were collected to give 3-(3-phenylphenoxy)propanohydroxamic acid. mp 113-116 ~C.
IH NMR (DMSO-d6) ~ 10.58 (s, IH), ~.68-8.63 (d, lH, J = 1.5 Hz), 7.67-7.65 (d, 2H, J =
7 Hz)~ 7.48-7.43 (t, 2H, J--7.7 Hz), 7.38-7.34 (t, 2H, J = 7.7 Hz), 7.24-7.21 (d, IH, J =
7.4 Hz), 7.15 (m, lH), 6.94-6.90 (dd, IH, J = 3, 7 Hz), 4.28-4.24 (t, 2H, J = 6 Hz), 2.47-2.43 (t, 2H, J = 6 Hz). MS (DCI/NH3) 275 (M+NH4)+. Anal. Calcd for C1sHlsNO3-0.25 H2O: C, 68.82; H, 55.46; N, 5.35. Found: C, 68.92; H, 5.87; N, 5.33.

Example 25 Preparation of 3-r4-(4-cyanophenyl)phenoxylpropanohydroxamic acid.
3~i The desired compound was prepared according to the method of Example 23, except substituting 4'-hydroxy-4-biphenylcarbonitrile for 3-phenylphenol, and using a THF-DMF
solvent ~ lule. mp 114- 118 ~C. IH NMR (DMSO-d6) o 2.45 (t, 2H, J = 5.9 Hz), 4.25 (t, 2H, J = 5.9 Hz), 7.06 (d, 2H, J = 8.8 Hz), 7.72 (d, 2H, J = 8.X Hz), 7.~5 (d, 2H, J = 8.5 CA 02236773 l998-0~-0~

Hz~, 7.88 (d, 2H, J = 8.5 Hz), 8.87 (s, lH), 10.56 (s, lH). IR (microscope) 3241 (br), 2244 (w), 2235 (w), 1629 (s), 1606 (m), 1496 (m), 1257 (m), 815 (m) cm-l. MS (DCUNH3) 300 (M+NH4)+, 317 (M+NH4+NH3)+. Anal. Calcd for C16H14N2O3 ~0.60 H2O: C, 65.56; H, 5.23; N, 9.56. Found: C, 65.41; H, 4.85; N, 9.83.

E~ample 26 Preparation of 3-~4-(4-methoxy~henyl)~henoxylpro~anohydroxamic acid.
The desired compound was prepared according to the method of Example 24, except substituting 4-hydroxy-4'-methoxybiphenyl for 3-phenylphenol, and using a THF-DMF
10 solvent mixture for the lactone opening. IH NMR (DMSO-d6) o 2.44 (t, 2H, J = fi. I Hz), 3.78 (s, 3H), 4.21 (t, 2H, J = 6.1 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz), 7.52 (d, 2H, J = 8.8 Hz), 7.54 (d, 2H, J = 8.8 Hz), 8.83 (s, IH), 10.52 (s, IH). IR
(microscope) 3279 (br), 2948 (w), 1629 (s), 1503 (m), 1470 (m), 1275 (s), 1250 (m), 1052 (m), 815 (s) cm~1. MS (DCI/NH3) 305 (M+NH4)+. Anal. Calcd for C16H17NO4-().25 H20:
C, 65.85; H, 6.04; N, 4.79. Found: C, 65.80; H, 5.83; N, 4.50.

Example 27 P.t;v~lion of 3-r4-(4-fluoro~henyl)phenoxylpro~anohydroxamic acid.

20 Ste~ 1: 4-(4-fluoro~henyl)~henol.
A mixture under N2 in DMF (18 mL) of 4-iodophenol (2.00 g, 9.0~ mmol), 4-fluorophenylboronic acid (1.4() g, 10.0 mmol), cesium carbonate (4.44 g, 13.6 mmol), and te~akis(triphenylphosphine)palladium~0) (0.27 g, 0.23 mmol) was stirred for 10 minutes at ambient temperature and then overnight at reflux. The reaction mixture was cooled to ambient 25 temperature, diluted with ethyl acetate, and extracted twice with water. The organic phase wa.s washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10: 1, then 5: 1 hexanes-ethyl acetate) gave 4-(4-fluorophenyl)phenol (0.79 g, 46%) as a white powder.

30 Step 2: 3-r4-(4-fluoroDhenyl~henoxylpropanohydroxamic acid.
The desired compound was prepared according to the method of Example 26, except substituting 4-(4-fluorophenyl)phenol, prepared as in step 1, for 3-phenylphenol. IH NMR
(DMSO-d6) ~ 2.44 ~t, 2H, J = 6.0 Hz), 4.22 (t, 2H, J = 6.0 Hz), 7.00 (d, 2H, J = X.8 Hz), 7.25 (t, 2H, J (F-Hortho, Hortho-Hmeta~ = 9.0 Hz), 7.56 (d, 2H, J = 8.5 Hz), 7.~4 (dd, 2H, 35 J (F-Hmeta, Hortho-Hmeta) = 5.4, 8.8 Hz), 8.83 (d, IH, J = 1.7 Hz~, 10.52 (d, IH, J = 1.4 Hz) . IR (Microscope) 3146 (br), 3022 (br), 2920 (m), 1659 (s), 1626 (s), 1501 (s), 1288 (m), 1248 (s), 816 (s) cm-l. MS (DCI/NH3) 293 (M+NH4)~. Anal. Calcd for ClsH14NO3F:
C, t~5.44; H, 5.12; N, 5.08. Found: C, 65.21; H, 5.13; N, 4.83.

Example 28 Prep~ration of (S) 2-methyl-3-(4-~henyl~henoxy)propanohydrQxamic acid.

5 Step 1: tris(~biphenyl)bismuth.
To a -78 ~C solution in THF (325 mL) of 4-bromobiphenyl (7.51 g, 32.5 mmol) was added tert-butyllithium (1.7 M, 38 mL, 64.6 mmol) and the dark-green solution was stirred for 15 minutes. A solution in THF (30 mL) of bismuth trichloride (3.38 g, 10.7 mmol) was added via syringe, and the reaction mixture was warmed to ambient tel~,pe,~LulG over 3 hours. The 10 reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate.
The organic phase was dried over MgSO4, filtered, ~nd concentrated in vacuo to give tris(4-biphenyl)bismuth (6.53 g) as a yellow solid.

Step 2: (S) 2-methyl-3-(4-phenylphenoxy)propionic acid methyl ester.
To a suspension in 4:1 dichloromethane-THF (30 mL) of tris(4-biphenyl)bismuth ( I .9f~
g, 2.93 mmol) was added peracetic acid (32% in aqueous acetic acid, 0.73 g, 3.1 mmol). After 30 seconds, methyl (S)-(~)-3-hydroxy-2-methylpropionate (0.355 g, 3.00 mmol) and~:opper(lJ) acetate (0.515.g, 2.X4 mmol) were rinsed into the reaction flask with 4:1 dichloromethane-THF (10 mL). The reaction mixture was heated at reflux for 20 hours, then 20 was cooled to ambient ~e~l-pe~ture and quenched with saturated aqueous NaHS03 solution.
The mixture was partitioned between dichloromethane and pH 7 buffer. The organic pha.se was dried over Na2S04, filtered, and concentrated i~1 vacuf> to give a yellow brown solid (1.35 g).
Chromatography on silica gel (3:1, then 2:1, then 1:1 hexanes-dichloromethane, then dichloromethane) gave (S) 2-methyl-3-(4-phenylphenoxy)propionic acid methyl ester (().()~2 g) 25 as a pale yellow solid.

SteD 4: (S) ~-methyl-3-(4-phenylphenoxy~propionic acid.
To a solution in THF (4 mL) of (S) 2-methyl-3-(4-phenylphenoxy)propionic acid methyl ester (0.14 g, 0.52 mmol), prepal~;d as in step 2, was added aqueous lithium peroxide 30 (1.1 mmol; prepared by adding 0.047 g of lithium hydroxide hydrate to 0.135 g of 30%
aqueous H2~2 in 2 mL of H2O) and THF (4 mL). The reaction mixture was stirred for 7 hours and then was quenched with aqueous NaHS03, taken to pH5~ with saturated aqueous Na2CO~, and extracted with ethyl ether. The aqueous phase was taken to pH 2 with HCI and extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered, ~5 and concenhated in vacuo to give (S) 2-methyl-3-(4-phenylphenoxy)propionic acid (61 mg) as a white solid.

_ Ste~ 3: tS) 2-methyl-3-(4-phenylphenoxy)pro1~anohydroxamic acid.
The desired compound was prepared according to the method of Example 1, step 3, except substituting (S) 2-methyl-3-(4-phenylphenoxy)propionic acid, prepared as in step 2, for 4-(3-phenylphenoxy)butanoic acid. mp I ~s7- l 88 ~C. I H NMR (DMSO-d6) o 1.()9 (d, 3H, J =
7 Hz), 2.62 (m, IH), 3.90 (dd, IH, J = 5, 9 Hz), 4.13 (t, IH, J = 9 Hz), 7.00 (d, 2H, J = 9 Hz), 7.31 (m, IH), 7.42 (t, 2H, J = 8 Hz), 7.59 (m, 4H), 8.83 (d, IH, J = 2 Hz), 10.56 (d, lH, J = 2 Hz). MS (DCUNH3) 289 (M+NE~4+, 100) . Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.57; H, 6.22; N, 4.82.

~o Example 29 P~ a,a~ion of 3-(N-methylcarboxamido)-5-r4-(4-cyanophenyl)~henoxyl-~entanohydroxamic acid.

Step 1: 4-r4-(4-cyanophenyl~phenoxylbutanoic acid ethyl ester.
The desired compound was prepared according to the method of Example I, step I, except sub~ uling 4'-hydroxy-4-biphenylcarbonitrile for 4-phenylphenol.

Step 2: 3-carboethoxy-5-14-(4-cy~nophenyl)phenoxylpentatloic a~;id tert-butyl ester.
To a -78 ~C solution in THF (100 mL) of diisopropylamine (0.94 mL, 7.15 mmol) was added n-butyllithium (25 M in hexanes, 2.86 mL, 7.15 mmol) and the mixture was stirred for 15 minutes. A solution in THF (25 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid ethyl ester (2.01 g, 6.5 mmol), prepared as in step I, was added dropwise and the reaction mixture was stirred for 15 minutes. Neat t-butyl bromoacetate (1.03 mL, 6.~S mmol) was added rapidly and the reaction mixture was stirred at -78 ~C for 2 hours, then for 0.5 hours at ambient tel~lp~ . The reaction mixture was quenched with saturated aqueous NH4CI and extracted twice with ethyl ether. The combined organic layers were dried over MgSO4, ~lltered, and concentrated in vacuo. Successive cll,o,llalographies on silica gel (dichloromethane, then 1:3 ethyl acetate-hexanes) gave 3-carboethoxy-5-[4-(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.91 g, 33%).
Step 3: 3-carboxv-5-r4-(4-cvanophenyl)phenoxylpentanoi(; acid fert-butyl ester.
To a solution in 2-propanol (30 mL) of 4-carboethoxy-5-[4-(4-cyanophenyl)phenoxy]pentanoic acid te~-t-butyl ester (0.91 g), prepared in step 1, was added aqueous IM lithium hydroxide (8.6 mmol) and water (5 mL) to forrn a clear solution, and the 3~ reaction mixture was stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NH4CI and extracted twice with ethyl ether and once with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Chlo",alugraphy on silica gel (4% methanol-dichloluln~ ane) provided 3-carboxy-5-[4-(4-WO g7/18188 PCT/~S96J18~72 cyanophenyl~phenoxy]pentanoic acid tert-butyl ester (0.62 g).

Ste~ 4: 3-(N-methylcarboxamido)-s-r4-(4-cyanophenyl)7JhenQxyl7~?entanoic acid ~rt-butyl ~Ç~
To a solution in dry dichlu.unlel'flane (100 mL) of 4-carboxy-5-~4-(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.62 g, 1.57 mrnol) was added ~ methylamine hydrochloride ~0.159 g, 2.35 mmol) and 4-methylmorpholine (0.26 mL, 2.35 mmol). The reac~don mixture was cooled to 0 ~C and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.361 g, 1.88 rnmol) was added. The reaction mixture was warmed slowly to ambient temperature and stirred overnight. The reaction mixture was extracted with aqueous IN HCl, twice with dichloromethane, and once with ethyl acetate. The combined organic layers were dried over MgSO4, ~lltered, and concentrated irl vacuo.
Chromatography on silica gel (4% methanol-dichloromethane) provided 3-(N-methylcarboxamido)-5-[4-(4-cyanophenyl)phenoxyJpentanoic acid tert-butyl ester (0.24 g).
Ste~ 5: 3-(N-methylcarboxamido)-5-r4-(4-cyanophenyl)phenoxylpentanoic acid.
A mixture of 3-(N-methylcarboxamido)-5-[4-(4-cyanophenyl)phenoxy]pentanoic acid telt-butyl ester (0.22 g), preparecl a~ in step 4, and trifluoroacetic acid (1.0 mL~ was placed in the sonic bath until all of the solid dissolved and then was stirred for 15 rninutes at ambient ~e~ ture. The reaction mixture was concentrated in VaCU(7 and the residue was azeotroped with dichlorolllell-ane and ethyl ether to give 3-(N-methylcarboxamido)-5-~4-(4-cyanophenyl)phenoxy~pentanoic acid (0.22 g).

Ste~ 6: 3-(JV-methylcarboxamido)-5-r4-(4-cyano~henyl)phenoxylpentanohydroxamic acid.
The desired compound was prepared according to the method of Example 29, step 5,except su'v~ g 3-(N-methylcarboxamido)-5-~4-(4-cyanophenyl)phenoxy~pentanoic acid, prepared as in step 5, for 3-methyl-2-~(4-cyanophenyl)phenoxy~butanoic acid. mp 176 ~C.
IH NMR (DMSO-D6) ~i 1.75-1.97 (m, 2H), 2.11 (dd, lH, J = 7.5, 7.5 Hz), 2.26 (dd, IH, J
= 7.5, 7.5 Hz), 2.56 (d, 3H, J = 4.5 Hz), 2.77-2.88 (m, IH), 3.90-4.01 (m, 2H), 7.02 ~d, 2H, J = 9 Hz), 7.71 (d, 2H, J = 9 Hz), 7.81-7.91 (m, SH), 8.75 (s, lH), 10.42 (s, IH). MS
(DCI/NH3) 368 (M~H)+, 352. Anal. Calcd for C2oH21N3O4-0.25 H20: C, 64.59; H, 5.~S2;
N, 11.29. Found: C, 64.51; H, 5.62; N, 11.15.

Example 30 3~ Pl~pa~dlion of 3-(4-biphenvlthio)propanohydroxamic acid.

~tep 1: 2-~4-bromophenylthio)propanoic acid.
The desired compound was pltipal-ed according to the method of Example 23, step 1, CA 02236773 1998-0~-0~

except substituting 4-bromothiophenol for 4-phenylphenol, and using 10:2 THF-DMF as solvent.

Step 2: O-tert-butyl-3-(4-bromophenylthio~propanohydroxamic acid.
To a solution in THF (100 mL) of 3-(4-bromophenylthio)propanoic acid (6.8~ g, 26.~
mmol) was added 4-methylmorpholine (2.94 g, 29.2 mmol) and isobutyl chloroformate (3.6 g, 29.2 mmol) and the reaction mixture was stirred for I hour. To the reaction mi~ul e was added aqueous O-tert-butylhydroxylamine (39.8 mmol; prepared by dissolving the hydrochloride in water and adding 3 M NaOH to give the free base) and the reaction mixture was sti~ed 10 overnignt at ambient lenlp~,dlulc;. The reaction mixture was poured into a mixture of ethyl ether and saturated aqueous N~4CI. The aqueous phase was extracted with ethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (30% ethyl acetate-hexanes) gave O-tert-butyl-2-(4-bromophenylthio)propanohydroxamic acid (5.36 g, 60%).
~tep 3: O-tert-butyl-2-(4-biphenylphenylthio)propanohydroxamic acid.
The desired compound was prepared according to the method of Example 9, step I, except sub~ u~ing N-tert-butoxy-2-(4-bromophenylthio)propanohydroxamic acid, prepared a~
in step 2, for 4-(4-iodophenoxy)butyric acid ethyl ester.
Step 4: 2-(4-biphenylthio)propanohydroxamic acid.
To a 0 ~C solution in dichloromethane (2 ml,) of N-tert-butoxy-2-(4-biphenylphenylthio)propanohydroxamic acid (0.27 g, 0.~2 mmol), prepared as in step 3, was added trifluoroacetic acid (10 mL), and the reaction mixture was warmed slowly to ambient 25 temperature and stilTed overnight. The reaction mixture was concentrated in vacuo. Trituration of the residue with ac~lonil-ile containing 1 % trifluoroacetic acid gave 2-(4-biphenylthio)propanohydroxamic acid (113 mg) as a white solid. mp 156-158 ~C. IH NMR
(DMSO-d6) o 10.47 (s, IH), 7.67-7.62 (m, 4H), 7.48-7.33 (m, SH), 3.21-3.17 (t, 2~3, J = 7 Hz), 2.32-2.31 (t, 2H, J = 7.4 Hz). MS (DCI/NH3) 291 (M+NH4)+. Anal. Calcd for 30 ClsHl~NO2S: C, 65.91; H, 5.53; N, 5.12. Found: C, 65.26; H, 5.52; N, 4.73.

Ex~mple 31 P~ dlion of 2-(4-biphenylthio)ethanohydroxamic acid.

35 Step 1: 2-(4-bromophenylthio)ethanoic acid tert-butylester.
The desired compound was prepared according to the method of Example 1, step 1, except substituting 4-bromothiophenol for 4-phenylphenol, and :iubslilulillg tert-butyl bromoacetate for ethyl-4-bromobutyrate.

CA 02236773 l998-05-05 WO 97/18188 PCT/US96/28l72 Step 2: 2-(~biphenylthio)ethanoic acid tert-but~l esteî.
The desired compound was prepared according to the method of Example 9, step 1, except substituting 2-(4-bromophenylthio)ethanoic acid t~rt-butyl ester, prepared as in step 1, 5 for 4-~4-iodophenoxy)butyric acid ethyl ester.

Ste~ 3: 2-(4-bi~henvlthio)ethanoic acid.
The desired compound was prepared according to the method of Example 31, step 4.except substituting 2-(4-biphenylthio)ethanoic acid tert-butyl ester, prepared as in step 2, for N-10 tert-butoxy-2-(4-biphenylphenylthio)propanohydroxamic acid.

Ste~ 4: 2-(4-biphenylthio)ethanQhydroxamic acid.
The desired compound was prepared according to the method of Example 31, step 2,except substituting 2-(4-biphenylthio)ethanoic acid, prepared as in step 3, for 3-(4-15 bromophenylthio)propanoic acid, and substituting aqueous hydroxylamine for aqueous O-tert-butylhydroxylamine. mp 156-158 ~C. 1H NMR (DMSO-d6) o 10.72 (s, lH), 9.01 (s, lH), 7.67-7.61 (m, 4H), 7.48-7.43 (m, 4H), 7.38-7.33 (t, IH, J = 8.0 Hz), 3.58 (s, 2H). MS
(DCI/NH3) 277 (M+NH4)+.

Z0 Example 32 Preparation of 3-(4-biphenylamino)~ropanohydroxamic acid.

Step 1: 3-(4-biphenylamino)propanoic acid.
To a solution in THF (30 ml,) of 4-aminobiphenyl (2.89 g, 17.1 mmol) was added ,B-propiolactone (1.60 g, 22.3 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours, at reflux for 5 hours, and at ambient temperature for 48 hours. The reaction mixture was quenched with aqueous 1N sodium carbonate and the THF was evaporated in vacuo. The aqueous solution was extracted twice with ethyl acetate and acidi~led with conce~ dtt;d HCI. The acidic mixture was extracted three times with dichloromethane. The combined dichlc~ro,~ ane extracts were dried over MgSO4, filtered, and concentrated in vacu~
to give 3-(4-biphenylamino)propanoic acid.

Step 2: 3-(4-biphenylamino)propanohvdroxamic acid.
The desired compound was prepared according to the method of Example 31, step 2.~5 except substituting 3-(4-biphenylamino)propanoic acid, prepared as in step 1, for 3-(4-l~u~-lophenylthio)propanoic acid, and substituting aqueous hydroxylamine for aqueous O-tert-butylhydroxylarnine. 160 ~C (dec). lH NMR (DMSO-d6) o 7.56-7.~3 (d, 2H, J = X.4 Hz), 7.45-7.42 (d, 2H, J = 8.1 Hz), 7.40-7.35 (t, lH, J = 7.4 Hz), 7.24-7.21 (t, IH, J = 7.1 Hz), 6.72-6.68 (d, 2H, J = 7.2 Hz), 3.31-3.27 (t, 2H, J = 7 Hz), 2.29-2.25 (t, 2H, J = 7 Hz). MS
(DCI/NH3) 257 (M+H)+.

Example 33 5 Plc;~d~iorl of 2-(4-biphenyl~ethanohydroxamic acid.
The desired compound was prepared according to the method of Example 1, step 3, except substituting 4-bipheny}acetic acid for 4-(4-phenylphenoxy)butanoic acid. mp 200-201 ~C. IH NMR (DMSO-d6) o 3.37 (s, 2H), 7.36 (m, 3H), 7.46 (t, 2H, J = 8 Hz), 7.63 (m, 4H), 8.88 (s, IH), 10.75 (s, lH). IR (KBr) 3400 (br), 3200, 3030, 2900, 1625, 14X5 cm~l.
10 MS (DCI/NH3) 245 (MfNH4+, 100). Anal. Calcd for C14H13N02-0.66 H20: C, 68.44; H, 6.77; N, 6.14. Found: C,68.55; H, 6.68; N, 5.87.

Fy~ml-le 34 Preparation of 4-(4-biphenyl)butanohy-lroxamic acid.
~5 Step 1: N-benzyloxy~4-(4-biphenyl)butyramide.
A suspension of 4-iodophenylbutyric acid (2.0 g, 6.9 mmol) in thionyl chloride (4 mL) was heated at reflux for 2() minutes. The rea~tion mixture wa~ cooled to ambient temper~ture, concentrated in vacuo, and the residue was taken up in dichloromethane and decanted into a 20 dichlul omt;lllane solution of O-benzylhydroxylamine (26 mmol; prepared by shaking O-benzylhydroxylarnine in a mixture of dichl~lu~lleLl~ane and saturated aqueous Na2C03, sepaldLillg the layers, and drying the organic phase over MgSO4). The reaction mixture was stirred for 3.5 hours at ambient len~ dlu~c; and then wa,s partitioned between dichloromethane and water. The organic phase was washed with aqueous I M HCI and saturated aqueous 25 sodium carbonate, dried over MgSO4, filtered, and concentrated in vacuo to give N-benzyloxy-4-(4-biphenyl)butyramide (2.47 g) as a tan solid.
Step 2: 4-(4-biphenyl)butanohydroxamic acid.
The desired compound was prepared according to the method of Example 15, steps 3and 4, except suhstit~lting N-benzyloxy-4-(3-iodophenyl)butyramide, prepared as in step 1, for 30 N-benzyloxy-4-(3-iodophenoxy)butyramide. mp 168-170 ~C. IH NMR (DMSO-d6) ~ 1.84 (m, 2H), 1.99 (t, 2H, J = 7.4 Hz), 2.60 (t, 2H, J = 7.7 Hz), 7.28 (d, 2H, J = 8.1 Hz), 7.35 (d, IH, J = 7.0 Hz), 7.45 (t, 2H, J = 7.4 Hz), 7.58 (d, 2H, J = 7.7 Hz), 7.64 (d, 2H, J = 7.0 Hz), 8.70 (s, IH), 10.38 (s, IH). MS (DCI/NH3) 273 (M+NH4+, 100~, 256 (M+H+, 10).
Anal. Calcd for C16Hl7NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.12; H, 6.72; N, 35 5.47.

Example 35 P~ )~alion of 4-14-(4-cyanophenyl)~henyllbutanohydroxamic acid.

~tep 1: N-benzvloxv-4-r4-(4-cyanophenyl)phenyllbutyramide~
The desired compound was ~ pal~d according to the method of Example 4, steps 2 and 3, except substituting N-benzyloxy-4-(3-iodophenyl)butyramide, prepared as in Example 43, step I, for ~(4-iodophenoxy)butanoic acid ethyl ester, and substituting 4-bromobenzonitrile for 3-iodobenzonitrile.

~tep 2: 4-14-(4-cyanophenyl)~henyllbutanohydroxamic acid.
The desired compound was prepared according to the method of Example 15, step 4,except sub~ u~ g N-benzyloxy-~1~(4-cyanophenyl)phenyl]butyramide, prepared as in step 1, forN-benzyloxy-4-[3-(4-fluorophenyl)phenoxy]butyramide. IH NMR (DMSO-d6) ~ 1.82 (m, 2H), 1.99 (t, 2H, J = 8 Hz), 2.62 (t, 2H, J = 7 Hz), 7.33 (d, 2H, J = 9 Hz), 7.69 (d, 2H, J = 9 Hz), 7.89 (m, 4H), 8.6~ (s, IH), 10.38 (~s, IH). MS (DCI/NH3) 298 (M+NH4+, X()), 2X0 (M+H+, 75), 236 (100).

Example 36 Pl~pa-~lion of trans 3-(4-biphenyl)propenohydroxamic acid.
To a suspension in dichloromethane of 4-phenylcinnamic ac;d (2.18 g, 9.75 mmol) was added oxalyl chloride (0.85 mL, 9.8 mmol) and the reaction mixture was stirred for 1() minutes.
In a separate flask, hydroxylamine hydrochloride ( 1.98 g, 28.5 mmol) was dissolved in water (15 mL) and 4-methylmorpholine (3.3 mL, 30 mmol) and THF (30 mL) were added. Thesolution of hydroxylamine in aqueous THF was then added to the acid chloride solution and the 2~ mixture was stirred for 2 hours. The reaction mixture was then shaken with adichloromethane/saturated aqueous NH4CI mixture. The resulting precipitate was filtered off and rinsed with water. The dichloromethane was separated, dried over MgSO4, filtered, and concentrated in vacllo to give trans 3-(4-bipenyl)propenohydroxamic acid (0.78 g) as a peach-colored solid. mp 160-163 ~C. IH NMR (DMSO-d6) o 6.51 ~d, lH, J = 15 Hz), 7.42 (m, IH), 7.29 (m, 3H), 7.73 (m, 6H), 9.01 (s, IH), 10.75 (s, IH). IR (KBr) 3450 (br), 3250, 3040, 1660, 1630, 1605, 1570, 14~5 cm~l. MS (DCI/NH3) 257 (M+NH4+, 20), 240 (M~H+, 10), 196 (70), 102 (100) . Anal. Calcd for: ClsH13NO2: C, 75.30; H, 5.48; N, 5.85. Found:
C, 74.72; H, 5.62; N, 5.56.

WO 97/18188 PCT/lJS96/18172 Example 37 Preparation of 3-~4-biphenyl~pro~anohydroxamic acid.

Step 1: 3-(4-bi,~henyl)propanoic acid.
Hyd;ogenation of 4-phenylcinnamic acid (ethyl acetate, 10% Pd/C, 4 atm H2) provided 3-(4-biphenyl)propanoic acid.

Step 2: 3-(4-biphenyl)propanohydroxamic acid.
The desired compound was prepared according to the method of Example 37, except lo substituting 3-(4-biphenyl)propanoic acid, pl~paled as in step 1, for 4-phenylcinnamic acid.
IH NMR (DMSO-d6) â 2.29 (t, 2H, J = 7 Hz), 2.~4 (t, 2H, ~ = 7 Hz), 7.29 (d, 2H, J = 6 Hz), 7.34 (d, IH, J = 5 Hz), 7.46 (t, 2H, J = 5 Hz), 7.57 (d, 2H, J = 6 Hz), 7.63 (d, 2H, J =
5 Hz), 8.72 (s, lH), 10.39 (s, IH). MS (DCI/NH3) 259 (M+NH4+, 100), 242 (M+H+, S).
Anal. Calcd for CIsHl~No2-o~25 H2O: C, 73.30; H, 6.36; N, 5.70. Found: C, 72.~7; H, 6.05; N, 5.25.
Example 3X
Preparation of 5-(4-biphenyl)pentanohydroxamic acid.

Ste~ 1: 4-pentynoic acid benzyl ester.
To a solution in dichlo,o~ llane (25 mL) containing a few drops DMF of 4-pentynoic acid (2.49 g, 23.4 mmol) was added oxalyl chloride (2.2 mL, 25 mmol). The reaction mixture was stirred for 1.5 hours and benzyl alcohol (3.9 mL, 38 mmol) was added via syringe. The reaction mixture was stirred for 6 hours and then was extracted with saturated aqueous sodium carbonate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-pentynoic acid benzyl ester (5.'~4 g) as a yellow liquid.

Step 2: 5-(4-biphenyl~pentynoic acid benzyl ester.
To a mixture in triethylamine (125 mL) of 4-pentynoic acid benzyl ester (4.70 g, 25 mmol), 4-bromobiphenyl (5.80 g, 24.9 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.97 g, 1.4 mmol) was added phenothiazine (10 mg) and the mixture was warmed to reflux. The reaction mixture was heated at reflux for 4 hours, and then was cooled to ambient temperature, filtered, and concentrated in vacuo. Chromatography on silica gel (30%
dichloromethane/hexanes) gave 5-(4-biphenyl)pentynoic acid benzyl ester (0.70 g) as a white solid.
Step 3: 5-(4-biphenyl)"entanoic acid.
Hydrogenation of 5-(4-biphenyl)pentynoic acid benzyl ester (ethyl acetate, 10% Pd/C, 4 atm H2) provided 5-(4-biphenyl)pentanoic acid.

WO 97/18188 PCT/US96tl8172 Ste~ 4: 5-~4-biphenyl)pentanohydroxarnic acid~
The desired compound was prepared according to the method of Example 37, except ~ub~Li~u~ g 5-(4-biphenyl)pentanohydroxamic acid"~lepa~d as in step 3, for 4-phenylcinnamic acid. mp 158-159 ~C. IH NMR (DMSO-d6) o 1.54 (m, 4H), 1.97 (t, 2H, J =
7 Hz), 2.59 (t, 2H, J = 7 Hz), 7.27 (d, 23~, ~ = 7 Hz), 7.37 (m, lH), 7.44 (t, 2H, J = 7 Hz), 7.57 (d, 2H, J = 7 Hz), 7.64 (d, 2H, J = 7 Hz), 8.68 (s, lH), 10.36 (s, lH). IR (KBr) 3280, 3050, 3030, 2920, 2850, 16G0, 1620, 1485 cm~l. MS (DCI/NH3) 287 (M+NH4+, 100), 270 (M+H+, 15). Anal. Calcd for Cl7HlgNo2-o~s H2O: C, 73.36; H, 7.24; N, 5.03. Found: C, to 73.70; H, 7.11; N, 5.20.

Example 39 Preparation of 5-r4-(4-fluorophenyl)phenoxylpentanohydroxarnic acid.

1~ Step 1: ~-(4-iodophenoxy)pentanoicacid.
The desired compound wa.s prepared according to the method of Example 2, step.s I and 2, except sub:jliLu~ g 4-iodophenol for 3-phenylphenol, and substituting methyl 5-bromovalerate for ethyl 4-bromobutyrate.

20 Ste~ 2: O-tert-butyl 5-(4-iodovhenoxy)pentanohydroxamic acid.
A mixture of 5-~4-iodophenoxy)pentanoic acid (6.00 g, 18.8 mmol) and excess thionyl chloride was heated at reflux for 30 minute.s. The reaction mixture was cooled to ambient l~,npelature and concentrated in vacuo. The residue was azeotroped three times with ethyl ether and then was taken up in THF. To the acid chloride solution was added an aqueous solution of 25 O-tert-butylhydroxylamine (24 mmol; prepared by adding aqueous 3M NaOH to an aqueous solution of O-tert-butylhydroxylamine hydrochloride) and the cloudy solution was stirred for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous NH4Cl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give O-t~rt-butyl 5-(4-iodophenoxy)pentanohydroxamic acid (t~.52 g).
3~
Step 3: O-tert-butyl 5-r4-(4-fluorophenyl)phenoxylpentanohydroxamic acid. The desired compound was prepared according to the method of Example 9, step 1, except substituting O-t~rt-butyl 5-(4-iodophenoxy)pentanohydroxamic acid, prepared as in step 2, for 4-(4-iodophenoxy)butanoic acid ethyl ester and substituting toluene for DME.
3~;
Step 4: 5-r4-(4-fluorophenvl)phenoxylpentanohydroxamic acid.
A solution in trifluoroacetic acid of O-tert-butyl 5-[4-(4-fluorophenyl)phenoxy]pentanohydroxamic acid (0.41 g, 1.1 mmol) was stirred overnight. The CA 02236773 1998-0~-0~

reaction mixture was concentrated in vacuo and the residue was suspended in acetonitrile anc~
stir~ed for 30 minutes. The solid was filtered and dried in vacun to give 5-[4-(4-fluorophenyl~phenoxy]pentanohydroxamic acid (12X mg) as a white solid. mp 160-162 ~C.
IH NMR (DMSO-d6) o 10.378 (s, IH)~ ~.69 (s, IH), 7.66-7.63 (m, 2H), 7.57-7.55 (d, 2H, J = 8.8 Hz), 7.27-7.21 (t, 2H, J = 8.8 Hz), 7.02-6.99 (d, 2H, J = 8.8 Hz), 4.02-3.98 (t, 2H, J = 5.9 Hz), 2.04-2.00 (t, 2H, J = 7 Hz), 1.68-1.66 (m, 4H). 13C NMR (DMSO-d6) o 21.76, 28.15, 31.87, 67.11, 114.85, 115.38, 115.66, 118.34, 127.6~, 127.94, 128.03, 131.04, 136.20, 136.33, 158.18, 159.76, 162.98, 168.87. MS (DCI/NH3) 304 (M+H)+, 321 (M~NH4)+. Anal. Calcd for C17H1gNO3F: C, 67.31; H, 5.98; N, 4.61. Found: C, 67.19; H, o 6.03; N, 4.40.
Example 40 Prep~ration of 4-~2-hydroxy-4-phenylphenoxy~butanohydroxamic acid.

Stçp 1: 4-(2-hydroxy-4-phenylphenoxy)butanoic acid.
1 ~ The desired compound wa~ prepared as a 1: I mixture with 4-(2-hydroxy-5-phenylphenoxy)butanoic acid, as described in Example 1, steps I and 2, except substituting 1,2-dihydroxy-4-biphenyl for 4-phenylphenol.

SteD 2: 4-~2-hydroxy-4-~henyl~henoxy)butanohydroxamic acid.
A suspension of the 4-(2-hydroxy-4-phenylphenoxy)butanoic acid and 4-(2-hydroxy-5-phenylphenoxy)butanoic acid mixture prepared in step I (0.5Q7 g, 1.86 mmol) in trifluoroacetic anhydride (10 mL) was stirred for 15 minutes at 0 ~C and sn minutes at arnbient l~ tUI~.
The reaction mixture was concentrated in v~cuo and the residue was dissolved in THF ( I U mL).
In a separate flask, 4-methylmorpholine (1.2 mL, 1 I mmol) was added to a solution of hydroxylamine hydrochloride (0.70 g, 10 mmol) in water (4 mL). The aqueous hydroxylamine solution was flec~nt~d into the mixed anhydride solution and followed with a THF rinse (15 mL). The reaction mixture was stirred for 3 hours and then was partitioned between saturated aqueous NH4CI and ethyl acetate. The organic phase was dned over Na2S04, ~lltered, and concentrated in vacuo to give an off-white foam (0.52 g). The 1: 1 mixture of 4-(2-hydroxy-4-phenylphenoxy)butanohydroxamic acid and 4-(2-hydroxy-5-phenylphenoxy)butanohydroxamic acid was punfied by high performance liquid chromatography. The fractions enriched in 4-(2-hydroxy-4phenylphenoxy)butanohydroxamic acid were combined to give 82 mg of a 2: 1 mixture. mp I IX-122 ~C. IH NMR (DMSO-d~) o l.9t~ (p, 2H, J = 7 Hz), 2.15 (t, 2H, J = 7 Hz), 4.04 (t, 2H, J = 7 Hz), 6.86 (d, IH, J = 7 Hz), 7.07 (dd, IH, J = 3, 7 Hz), 7.16 (d, IH, J = 3 Hz), 7.28 (m, IH), 7.39 (t, 2H, J = 7 Hz), 7.59 (d, 2H, J = 7 Hz), 9.0 (bds, 2H), 10.42 (s, IH) . 13C NMR (DMSO-d6) o 24.98, 28.83, 67.92, 112.36, 116.00, 119.38, 12~S.11, 126.41, 128.70, 131.49, 140.31, 146.68, 147.00, 168.87 . MS (DCI/NH3) 305 (M+NH4+, 45), 289 (M+NH4-O+, 20), 288 (M+H+, 15), 287 (M+NH4-H2O+, 10), 244 (100). Anal.

Calcd for Cl6HI7NO4-H2O: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.17; H, 5.74; N, 4.55.

Example 41 Preparation of 4-(2-hydroxv-5-phenylphenoxy)butanohydroxamic acid.
The fractions enriched in 4-(2-hydroxy-5-phenylphenoxy)butanohydroxamic acid from the chromatography in Example 46 were combined to give 10 mg of a 3:1 mixture. mp 148-152 ~C. IH NMR (DMSO-d6) o 1.94 (p, 2H, J = 7 Hz~, 2.18 (t, 2H, J = 7 Hz), 3.98 (t, 2H, J
= 7 Hz), 6.97 (d, lH, J = 7 Hz), 7.02 (d, IH, J = 3 Hz), 7.08 (d, lH, J = 3 Hz), 7.29 (d, IH, J = 7 Hz), 7.41 (t, 2H, J = 7 H~), 7.53 (d, 2H, J = 7 Hz), 8.71 (s, lH), 8.99 (s, lH), 10.41 10 (s, I H) 13C NMR (DMSO-d6) o 24.93, 2~S.76, t~7.85, 113.90, 114.11, 118.34, 126.09, 126.63, 128.74, 133.27, 140.07, 146.44, 147.08, 16~3.84 . MS (D(~T/NH3) 305 (M+NH4+, 100), 288 (M~H+, 25) . Anal. Calcd for C16H17NO4-2/3 H2O: C, 64.21; H, 6.17; N, 4.68.
Found: C, 64.34; H, 5.97; N, 4.72.

Example 42 Preparation of 3-r4-(3-cyanomethylphenyl)phenoxylpropanohydroxarnic acid.

Step 1: 3-(4-iodo~henoxy)pro~anoic acid.
The desired compound was prepared according to the method of Example 23, step 1,20 except substituting 4-iodophenol for 4-phenylphenol.

Step 2: O-tert-butyl 3-(4-iodovhenoxy)propanohydroxamic acid.
A suspension of 3-(4-iodophenoxy)propanoic acid (I.ûO g, 3.42 mmol) in thionyl chloride (6.0 mL) was heated at reflux for 30 minutes. The reaction mixture was cooled to 26 ambient temperature, diluted with ethyl ether, and concentrated in ~acuo. The residue was azeotroped three times with ethyl ether, dried under high vacuum, and taken up in dichloromethane (7 mL) under N2. To the solution was added a solution in dichloromethane of O-tert-butylhydroxylamine (8.60 mmol; prepared by dissolving O-tert-butylhydroxylarnine hydrochloride in water, making the free base with aqueous 10% Na2CO3, and extracting the 30 solution with dichloromethane, and drying the organic solution over MgSO4), and the reaction mixture was stirred for two hours. The reaction mixture was washed with saturated a~ueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated fn vacuo to give a yellow oil which crystallized on standing to give O-tert-butyl 3-(4-iodophenoxy)propanohydroxamic acid (1.22 g, 98%).

Step 3: O-tert-butyl 3-~4-(3-cyanomethylphenyl)phenoxylpropanohydroxarnic acid.
The desired compound was prepared according to the method of Example 4, steps 2 and 3,- except substituting O-tert-butyl 3-(4-iodophenoxy)propanohydroxarnic acid, prepared as in CA 02236773 1998-0~-0~

st~p 2, for 4-(4-iodophenoxy)butanoic acid ethyl ester, and substituting 3-iodophenylacetonitrile for 3-iodobenzonitrile.

Step 4: 3-r4-(3-cyanomet~ylphenyl)phenoxylpro~anohydroxamic acid.
A solution of O-tert-butyl 3-[4-(3-cyanomethylphenyl)pheonxy]propanohydroxamic acid (0.043 g, 0.12 mmol) in 1: I trifluoroacetic acid-dichloromethane was stirred overnight at ambient temperature. The reaction mixture was filtered, concentrated in vacuo, and azeotroped with dichlo~ elllane and dichloromethane-ethyl ether. Chromatography on silica gel (40: 1, then 20: I dichloromethane-methanol, both containing 0.25% acetic acid) gave 3-[4-(3-10 cyanomethylphenyl)pheonxy]propanohydroxamic acid (16 mg, 44%). IH NMR (DMSO-d6t o 2.45 (t, 2H, J = 6.0 Hz), 4.08 (s, 2H), 4.23 (t, 2H, J = ~.0 Hz), 7.02 (d, 2H, J = X.8 Hz), 7.29 (d, IH, J = 7.5 Hz), 7.46 (t, lH, J = 8.0 Hz), 7.57 (d, lH, J = 6 Hz), 7.58 (s, lH), 7.60 (d, 2H, J = 8.8 Hz), 8.84 (br s, IH), 10.53 (br s, IH). TR (microscope) 3245 (br), 2924 (m), 2251 (w), I~43 (s), 16()8 (s), 1518 (s), 1483 (m), 1244 (s), 7X4 (m) cm~1. MS
15 (DCI/NH3) 314 (M+NH4)~ . Anal. Calcd ~or C17H16N203-û.70 H20-0.20 t~uOH: C, fi~.04;
H, 6.04; N, 8.65. Found: C, 65.93; H, 5.64; N, 8.30.

Example 43 Ple~)al~ion of 2-tert-butyloxycarbonylmethyl-4-f4-(4-cyanophenyl)phenoxyl-20 butanohydroxamic acid.

Step 1: N-r4-(4-(4-cyanophenyl)phenoxv)butanoyll-(S)-(-~-4-benzyl-2-oxazolidinone.
To a -70 ~C solution in THF (100 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid (1.00 g, 3.66 mmol), prepared a~ in Example 3, was added triethylamine (0.64 mL, 4.62 2~ mmol) and pivaloyl chloride (0.4g mL, 3.91 mmol). The reaction mixture was stirred for 15 minutes at -70 ~C, 45 minutes at 0 ~C, and then was cooled back to -70 ~C. In a separate flask, n-butyllithium (2.5 M in hexanes, 2.56 mL, 6.40 mmol) was added via syringe to a -7X ~C a solution in THF (50 mL) of (S)-(-)-4-benzyl-2-oxazolidinone. The oxazolidinone anion solution was then added to the mixed anhydlride solution via cannula. The reaction mixture was 30 then warmed slowly to ambient temperature and stirred overnight. The reaction mixture was quenched with aqueous I M HCl and extracted with ethyl ether. The organic pha~e was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting white solid was a~euL-uped with ethyl ether and purified by chromatography on silica gel ~2% methanol-dichlo-umethane) to give N-[4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-35 oxazolidinone (1.30 g, 82%).

Step 2: N-r2-tert-butylûxycarbonylmethyl-4-(4-(4-cyanophenyl)phenoxy)butanoyll-(S)-(-)-4-benzyl-2-oxazolidinone.

To a -78 ~C solution in THF (50 mL) of N-14-((4-cyanophenyl)phenoxy)butanoylI-(S)-(-)-4-benzyl-2-oxazolidinone (1.30 g, 2.95 mmol), prepared as in step 1, was added sodium bis(trimethylsilyl)amide (1.0 M, 3.25 mL, 3.25 mmol) and the reaction mixture was stirred for 20 minutes. Neat tert-butyl bromoacetate (0.50 mL, 3.25 mmol) was added quickly dropwise and the reaction mixture was stirred for 20 minutes at -78 ~C and then was walmed to -50 ~C
over 3 hours. The reaction mixture was quenced with acetic acid (5 mL) in ethyl et'ner (40 nL), warmed to ambient temperature, and extracted with brine. The organic phase was concentrated in vacuo to give a viscous oil. The oil was crystalli~d fro~m ethyl acetate-ethyl ether to give a solid (10 g). C~umat()graphy on silica gel (1 :3 ethyl acetate-hexanes) gave N-1 2-tert-10 butyloxycarbonylmethyl-4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (7.18 g).

Step 3: 2-tert-butyloxycarbonylmethyl-4-r4-¢4-cyanophenyl)phenoxylbutanoic acid.To a 0 ~C solution in THF (200 mL) of N-~2-tert-butyloxycarbonylmethyl-4-(4-(4-1~ cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (7.05 g, 12.7 mmol) was added 30% aqueous H20~ (3.0 mL, 50.8 mmol) and 1 M aqueous LiOH (20.3 mL, 20.3 mmol) and the reaction mixture was stirred for one hour. The reaction mixture was quenched with saturated aqueous NaHSO3 and diluted with dichloromethane. The aqueous phase was made basic with aqueous 2N NaOH and extracted twice with dichloromethane. The organic extracts 20 were discarded and the aqueous phase was cooled to 0 ~C and acidified with aqueous 2N HCI.
The aqueous phase was extracted with dichlolulnt;lIlane and THFldichloromethane. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo.
C~loma~ography on silica gel (dichloromethane/10% THF/I % methanol) gave 2-tert-butyloxycarbonylmethyl-4-r4-(4-cyanophenyl)phenoxyIbutanoic acid (2.6 g, 52%).

Step 4: 2-tert-butyloxycarbonylmethyl-4-~4-(4-cyano~henyl)phenoxyl-butanohydroxamic acid.
The desired compound was prepared accordin~ to the method of Example 29, step 5,except substituting 2-tert-~outyloxycarbonylmethyl-4-[4-(4-cyanophenyl)phenoxy]butanoic acid, prepared as in step 3, for 3-methyl-2-~4-(4-cyanophenyl)phenoxy]butanoic acid. ~H NMR
30 (DMSO-d6) o 1.38 (s, 9H), 1.76-1.98 (m, 2H), 2.36 (dd, tH, J = 6, 15 Hz), 2.45-2.58 (m, IH), 2.58-2.70 (m, IH), 3.90-4.50 (m, 2H), 7.03 (d, 2H, J = 9 Hz), 7.72 (d, 2H, J = '~ Hz), 7.82-7.91 (m, 4H), 10.58 (s, IH). MS (DCI/NH3) 411 (M+H)+, 428 (M+NH4)+, 372, 354.
Anal Calcd. for C23H26N2Os 1.25 H2O: C, 63.80; H, 6.63; N, 6.46. Found: C, 63.67; H, 6.17; N, 6.41.
Example 44 PlGVd1aLiOn of 3-r4-~4-cyanomethylphenyl)phenoxyIpropanohydroxamic acid.
The desired compound was prepared according to the method of Example 43, except substituting 4-iodophenylacetonitrile for 3-iodophenylacetonitrile. lH NMR (DMSO-d6) o 2.44 CA 02236773 1998-0~-0~
WO 97/18188 PCT/US96/18~ 72 (t, 2H, J = 6.1 Hz), 4.05 (s, 2H), 4.23 (t, 2H, J = 6.0 Hz), 7.00 (d, 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.5 Hz), 7.60 (d, 2H, J--8.8 Hz), 7.64 (d, 2H, J = 8.1 Hz), 8.83 (s, l~I), 10.52 (s, IH). IR (microscope) 3218 (m), 3195 (m), 2252 (w), 1632 (s), 804 (m) cm~l. MS
(DCI/NH3) 298 (M+NH4-O)+, 314 (M+NH4)~ . Anal. Calcd for Cl7H16N2O3 5 ~0.60H20-0.20: CF3CO2H C, 63.34; H, 5.32; N, 8.49. Found: C, 63.33; H, 4.98; N, 8.52.

Example 45 Plt,p~dlion of 2-hydroxy-3-1(4-phenyl)phenoxylpropanohydroxamic acid.

Step 1~ Dimethoxy-2-~4-biphenyloxy)ethane.
4-Phenylphenol (1.70 g, 10 mmol) and cesium carbonate (3.91 g (12 mmol) were stirred at room l~ .cl,lt~lG under a nitrogen atmosphere in 20 mL of dimethylformarnide until it 1~ apl)eal~d that no more solid was dissolving. At that point, 1.42 mL (12 mmol~ of bromoacetaldehyde dimethyl acetal (2.03 g, 12 mmol) were added to the mixture via syringe and the resulting brown suspension was stirred at room k~ l dture overnight. The mixture was then heated under reflux for two hours and then stirred at room temperature overnight. At the end of this period, I nn mL of water and 20n mL of Aiethyl ether were added; the orL~anics 20 were extracted into the ether layer, which was sepala~ed, dried over anhydrous sodium sulfate and evaporated to yield 2.10 g (h 1% yield) of dimethoxy-2-(4-biphenyloxy)ethane.

Step 2: 4-B~henyloxyacetaldehyde.
The acetal from Step I (2.10 g) was dissolved in 10 mL of tetrahydrofuran and I mL of 25 distilled water was added to the yellow solution, followed by I mL of concentrated hydrochloric acid. This mixture was stirred rapidly overnight, then a small amount of saturated aqueous brine solution was added to the reaction mixture, followed by 50 mL of diethyl ether.
The organics were extracted into the ether layer and the aqueous layer was washed twice more with diethyl ether. The ether layers were combined, dried over anhydrous magnesium sulfate, 30 and evaporated. The residue was triturated with a 10% solution if isopropyl alcohol in chloroform, leaving a white solid. This solid was again triturated with a small amount of methanol in dichloromethane. The yield of filtrates from the above two triturations was I .X4 g (71 %) of 4-biphenyloxyacetaldehyde.

Step 3: 2-(4-phenylphenoxy)ethane cyanohydrin.
The aldehyde from Step 2 ( 1.84 g) was placed in a 250 rnL three-necked flask and 65 ml of toluene were added. The resulting mixture was stirred under nitrogen at room t~ d~urt; until a cloudy yellow suspension resulted. Diethylaluminum cyanide solution ( I M
in toluene, Aldrich Chemical Co., Milwaukee, Wl) (11.3 mL 11.3 mmol) was added to the 40 stirred rnixture in a dropwise manner over a period of six minutes. The resulting mixture was .
CA 02236773 1998-0~-0~
WO 97~t~8188 PCT/US96/18172 stirred at -15~C for one hour and then at room ~IIIp~dt~l~ for an additional thirty minutes. The mixture was cooled in an ice batn and 25 rnL of saturated aqueous Rochelle salt solution was added in a dropwise manner over eight minutes. At the end of this time, the mixture was allowed to warm to room temperature and was stirred at this temperature for thirty minutes. A
5 mixture of a~ueous Rochelle salt solution and 100 mL of ethyl acetate were added to the mixture. The organic layer was set aside and the aqueous layer extracted with ethyl acetate.
The ethyl acetate solutions were combined, dried over anhydrous sodium sulfate, filtered and evaporated to yield 1.70 g of light yellow residue.
This solid was taken up in a mixt~Ire of hexane, ethyl acetate and dichloromethane and 10 the resulting solution charged to a column of 50 g of silica. The mixture was eluted from the column (30 mL 15% ethyl acetate in hexane.s; 73n mL: sn% ethyl acetate in hexanes; and I liter, 100% isopropyl alcohol) to yield 1.43 g (68%3 2-(4-phenylphenoxy)ethane cyanohydrin as a white solid.

Ste~l~ 4: 2-hydroxy-3-1(4-phenyl)phenoxylpropanoic acid.
Anhydrous methanol (140 rnL, maintained at a temperature below 25~C) was sa~ ;d with hydrogen chloride gas in a l-liter, three-necked flask. This solution was then added in one portion to ~ solution of the cy~nohydrin obtained from Step 3.
The resulting mixture was m~int~inf d at about 0~C and stirred under nitrogen overnight. After 2n this time, the mixture was allowed to warm to about 2noc where it was stirred for several hours. Water (150 mL) was added and the resulting mixture was stirred for thrity minutes at 20~C.
After this time the mixture was heated under reflux for tnree hours. The mixture was cooled to room ~ dlulc; and evaporated to dryness under vacuum to yield a yellow, semi-25 solid residue. This material was partitioned between 1 M aqueous NaOH and dichloromethaneand the organic layer was set aside. The aqueous layer was acidified with aqueous HCI and extracted twice with dichl-.lolllelllane and once with a 10% solution of isopropyl alcohol in chlu~vrolll-. The aqueous layer was then extracted twice with ethyl acetate and these organic extracts combined with those described above. The overall yield of 2-hydroxy-3-[(4-phenyl)phenoxy]propanoic acid was 1.41 g (91%~.

Ste~ 5: 2-hydroxy-3-r(4-phenyl)~henoxyl~ropanohydroxamic acid.
2-hydroxy-3-[(4-phenyl)phenoxy]propanoic acid (517 mg, 2 mmol) from Step 4 was mixed with 740 mg (5.48 mmol) of hydroxybenzotriazole hydrate (Aldrich Chemical Co., 35 Milwaukee, Wl) and the solid mixture was dissolved in 20 mL of dichloromethane. This mixture was stirred under a nitrogen atmosphere at room lelllp~ldture and then S mL of dimethylformamide and 291.6 g, 2.9 mmol) of 4-methylmorpholine were added. This was followed by addition of 353 mg of O-tert-butyldimethylsilyl hydroxylamine (Aldrich Chemical Co., Milwaukee, ~;VI) dissolved in S mL of dichloromethane.
To the resulting cloudy yellow suspension was added, as a solid, ~53 mg (2.9 mmol~
of i-(3-dimethylaminopropyl)-3-ethylcarbodiimide ("EDCI," Aldrich Chemical Co., Milwaukee, WT). Upon addition of the ~DCI, the mixture became first, a clear yellow, then a 5 clear orange solution, and finally, a cloudy orange suspension. This mixture was stirred at room temperature for two hours and then diluted with 30 mL of saturated a~ueous arnmonium chloride solution. The organic layer was separated and set aside. The aqueous layer wa.s washed with dichlu-u~ ;lhane and the two organic solutions combined, dried over anhydrous magnesium sulfate and concentrated to yield 970 mg of solid residue.
This solid residue was taken up in a solution of I % methanol in dichlûromethane, and methanol carefully added until only a slight cloudiness remained. This mixture was loaded on a column of 110 g of silica and eluted (25 mL of 1% methanol in dichloromethane (fractions 1-32), 25 mL of 5% methanol in dichloromethane (fractions 33 99), and 700 mL of 10()%
isporpoyl alcohol (fraction 100). Fractions 54-69 were combined to yield 15.6 mg of 2-hydroxy-3-~(4-phenyl)phenoxy]propanohydroxamic acid as a white solid having a melting point of 138.7~C-140.5~C. 1H NMR (DMSO-d6): â 0.87 (s, IH), 4.03-4.28 (c, 2H), 5.79 (d, lH, J = 6 Hz), 7.00 (s, lH), 7.03 (s, lH), 7.30 (t, IH, J = 7.5 Hz), 7.43 (t, lH, J = 7.5 Hz), 7.57-7.65 (c, 4H), 8.35 (s, IH), 1().66 (s, lH); Infrared spectrum (KBrpellet) 342n, 326n, 1600, 1520, 1480, 1450, 1290, 1270, 1250, 1110, lOS0, 830, 780, 700 cm~l; Mass spectrum:
(DCl/NH3): 291 (M + NH4+), 274.1079.

The foregoing examples are merely illustrative of the invention and are not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which is 25 de~med in the appended claims.

Claims (14)

WE CLAIM:

1. A compound of formula or a pharmaceutically acceptable salt thereof where m and n are independently 0 or 1;
p is 0-6, with the proviso that m, n, and p cannot simultaneously be zero;
R1 is selected from the group consisting of (a) hydrogen;
(b) alkyl of one to six carbon atoms;
(c) alkenyl of two to six carbon atoms;
(d) hydroxy;
(e) where the alkylene portion is of one to six carbon atoms, and R6 is selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and hydroxy;
(f) wherein q is 0, 1 or 2, the alkylene portion is of one to six carbon atoms, and R6 is defined above;
(g) -(alkylene)-CO2R7 wherein the alkylene portion is of one to six carbon atoms, and R7 is hydrogen or alkyl of one to six carbon atoms;

R2 and R3 are independently selected from the group consisting of (a) hydrogen;
(b) alkyl of one to six carbon atoms;
(c) phenyl;
(d) phenyl substituted with halogen, alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or hydroxy;
(e) pyridyl, and (f) pyridyl substituted with halogen, alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; or R2 and R3 taken together with the nitrogen atom to which they are attached define a 5- or 6-membered saturated heterocyclic ring in which the heterocyclic ring optionally contains an additional heteroatom selected from the group consisting of -NR8 wherein R8 is hydrogen or alkyl of one to six carbon atoms, -O-, -S-, or -S(O)r wherein r is 1 or 2;

X is absent or is selected from the group consisting of (a) -0-;
(b) -NH-; and (c) -S -;
with the provisos that (a) when X is oxygen, and m and n are zero, p is an integer of two to six, inclusive, and (b) when X is oxygen and m is one and n is zero; then p is an integer of one to six, inclusive;

R4 and R5 are independently selected from the group consisting of (a) hydrogen;
(b) alkyl of one to six carbon atoms;
(c) halogen;
(d) cyano;
(e) cyanoalkyl of one to six carbon atoms;
(f) haloalkyl of one to six carbon atoms, (g) hydroxy, and (h) alkoxy of one to six carbon atoms.

2. A compound or pharmaceutically acceptable salt thereof as defined by Claim 1 of formula or a pharmaceutically acceptable salt thereof wherein p is an integer of 0-6, inclusive.

3. A compound as defined by Claim 1 or pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of (a) hydrogen, (b) alkyl of one to six carbon atoms, and (c) alkenyl of two to six carbon atoms.

4. A compound or pharmaceutically acceptable salt thereof as defined by Claim 3 wherein R2 and R3 are independently selected from hydrogen and alkyl of one to six carbon atoms.

5. A compound or pharmaceutically acceptable salt thereof as defined by Claim 4 wherein X is -O-.

6. A compound or pharmaceutically acceptable salt thereof as defined by Claim 1 having the formula wherein p is 1-6.

7. A compound or pharmaceutically acceptable salt thereof as defined by Claim 6 wherein R1 is selected from the group consisting of (a) hydrogen, (b) alkyl of one to six carbon atoms, and (c) alkenyl of two to six carbon atoms.

8. A compound or pharmaceutically acceptable salt thereof as defined by Claim 6 wherein X is absent.

9. A compound or pharmaceutically acceptable salt thereof as defined by Claim 6 wherein X is -O-.

10. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of 4-(4-phenylphenoxy)butanohydroxamic acid, 4-(3-phenylphenoxy)butanohydroxamic acid, 4-[4-(4-cyanophenyl)phenoxy]butanohydroxamic acid, 4-[4-(3-cyanophenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-cyanomethylphenyl)phenoxy]butanohydroxamic acid, 4-[4-(3-cyanomethylphenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-chlorophenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-propylphenyl)phenoxy]butanohydroxamic acid, 4-[4-(4-methoxyphenyl)phenoxy]butanohydroxamic acid, 7-(4-phenylphenoxy)heptanohydroxamic acid, 7-[4-(4-cyanophenyl)phenoxy]heptanohydroxamic acid, 5-[3-(4-fluorophenyl)phenoxy]pentanohydroxamic acid, 5-[3-(3-cyanophenyl)phenoxy]pentanohydroxamic acid, 5-[3-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 4-[3-(4-fluorophenyl)phenoxy]butanohydroxamic acid, 4-[3-(4-cyanophenyl)phenoxy]butanohydroxamic acid, 4-[3-(3-cyanophenyl)phenoxy]butanohydroxamic acid, 5-[3-phenylphenoxy]pentanohydroxamic acid, 5-[4-phenylphenoxy]pentanohydroxamic acid, 5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 6-[4-phenylphenoxy]hexanohydroxamic acid, 6-[4(4-cyanophenyl)phenoxy]hexanohydroxamic acid, 3-(4-phenylphenoxy)propanohydroxamic acid, 3-(3-phenylphenoxy)propanohydroxamic acid, 3-[4(4-cyanophenyl)phenoxy]propanohydroxamic acid, 3-[4-(4-methoxyphenyl)phenoxy]propanohydroxamic acid, 3-[4-(4-fluorophenyl)phenoxy]propanohydroxamic acid, (S) 2-methyl-3-(4-phenylphenoxy)propanohydroxamic acid, 3-(N-methylcarboxamido)-5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid, 3-(4-biphenylthio)propanohydroxamic acid, 2-(4-biphenylthio)ethanohydroxamic acid, 3-(4-biphenylamino)propanohydroxamic acid, 2-(4-biphenyl)ethanohydroxamic acid, 4-(4-biphenyl)butanohydroxamic acid, 4-[4-(4-cyanophenyl)phenyl]butanohydroxamic acid, 3-(4-biphenyl)propanohydroxamic acid, 5-(4-biphenyl)pentanohydroxamic acid, 5-[4-(4-fluorophenyl)phenoxy]pentanohydroxamic acid, 4-(2-hydroxy-4-phenylphenoxy)butanohydroxamic acid, 4-(2-hydroxy-5-phenylphenoxy)butanohydroxamic acid, 3-[4-(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid, 2-tert-butyloxycarbonylmethyl-4-[4-(4-cyanophenyl)phenoxy]butanohydroxamic acid,3-[4-(4-cyanomethylphenyl)phenoxy]propanohydroxamic acid, and 2-hydroxy-3-[(4-phenyl)phenoxy]propanohydroxamic acid.

11. A method for inhibiting matrix metalloproteinases in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.

12. An composition for inhibiting matrix metalloproteinases comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

13. A method for inhibiting TNF.alpha. secretion in a mammal in need of such treatment, comprising administering to the therapeutically effective amount of a compound of Claim 1.

14. A composition for inhibiting TNF.alpha. secretion comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.