CA2195758A1 - Phenoxyphenylacetic acid derivatives - Google Patents

Abstract

Phenoxyphenylacetic acids and derivatives of general structural formula (I) have endothelin antagonist activity and are useful in treating cardiovascular disorders, such as hypertension, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, endotoxic shock, benign prostatic hyperplasia, inflammatory diseases including Raynaud's disease and asthma.

Description

2 ~ 95758 ~ W0 96104905 ~ . P~

TITLE OF THE INVENTION
PHENOXYPHENYLACETIC ACID DERIVATIVES

RELATED APPLICATIONS
The present application is a continuation in part application of Case 1~8g31B, U.S. Serial Number 08/287,374 iiled August ~, 1994 which is a continuation in part application of IJ.S. Serial Number 0~/197,467 filed February 24, 1994, which is a continuation in part application of U.S. Serial Number 0~31034,455 filed on March 19, 1 993(abandoned).

SUMh~ARY OF THE IN~rENTION
This invention is concemed with non-peptidic endotlleli receptor antagonists represented by the compound of Fc rmula I.
pharmaceutical compositions containing these compound.s, as well as combination therapies which inclucde a compoulId of the present invention. The compounds of the present invelItion are therapeutic agelIts particularly useful ior the treatment of asthma, hypertension, pulmonary hypertension. arteriosclerosis. congestive heart failure. renal failure, particularly post-ischemic renal failure, cyclosporin nephrotoxicity, vasospasm, vascular restenosis. cerebral and cardiac i.schemia and other i.schemic states, myocardial infarction, Raynaud's disease, benign prostatic hyperplasia. infl~mm ltory bowel diseases, including Crohn's disease and ulcerative colitis, as well as other inil~mm~ltory diseases, or endoto~ic shock caused by C~l associated with endc~tllelin.
This invention further constitutes a method for antagonizilIg endothelin receptors in a mamulIal, including humans, r which compri.ses administering to a mammal in need of such treatnlent an ei'i'ective amount of a compoulld of l'ormula I

~ i 9 5 7 5 ~ P~

BACKGROUN~) DF THF. ~FENTI(:)N
F.n~lothf~lin is a 21-amino acid peptide produced by endothelial cells ~The peptide is secreted not o:n]y by endothelia:l cell.s but also by tracheal epithelial cells or from kidney cells. End(lthelin (ET-1) has a potent vasoconstrictor effect. The vasocon.stricting effect is cau.sed by the binding of endothelin to its receptor on the va.scular smooth muscle ceDs.1-3 Endothelin~l ~ET-l) is one of three recently identified potent ~asoconstricting peptides which also includes endothelm-2 (ET-2) and endothelin-3 ~F,T-33 whose sequences dil'fer from ET-I by two and six amino acids. respectively.4 Incre;~.sed levels of endothelin are folmd in the blood of' patients with essential hypertension, acute myocardial infarction, pulmonary hypertens:io:n, Raynaudts disease or atherosclerosis or in the washing fluids of the ~ hdl~ly tract of patients with asthma compared to normal levels.S~~
An experimental model of cerebral vasospa~ln and a seccllld model of acute renal failure have led to the conclusion that endothelin is one of the mediators causing cerebral va.sospasm following a subarachnoid hemorrhage~ and renal failure.9-l(~
Endothelin was also found to control the release of many physiological s-lh~ nces such a.s renin, atrial natriuretic peptide, endothelium-derived relaxing factor IE~DRF~, thrclmboxalle A2,14-prclstacyclin, norepinephrine, angiotensin Il and substance p.~
Further, endothelin causes contract:ion of the smoot.h muscle oiF tbe gastrointestinal tract and the uterine smooth muscle.l~-T~) Endothelin has also been shown to promote the growth of rat ~ascular smooth muscle cells which would suggest a possible relev;mce to arterial hypertrophy.20 F.nflolTlf~lin receptors are present in high concentration in the peripheral tissues and also in the central nervous systeln, and cerebral ~(I",i"i~ rion of endothelin has been shown to induce behavioral changes in animals, suggesting that endothel:in may play an important role in controlling neural functions.2~

~ wo96104g0S ~ /L~.

Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelill is an import~mt ., mediator for endotoxin-induced diseases.2~-23 A study has shown that cyclosporin added to a renal cell culture. increased endothelin secretion.24 Another study has shown that ad".illi~l~dlion of cyclosporin to rats, led to a decrease in the glomerular filtration rate and all increase in the blood pressure, in association with a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the admillistration of anti-elldothelin antibody.25 These studies suggest that endothelin is ~ig;nific:lntly involved in the pathogene.si.s of cyclosporin-induced renal disease.
A recent study in patients with conge.stive heart failure demonstrated a good correlation between the elevated levels of endothelin in the plasma and the severity of the disease.26 Endothelin is an endogenous substance which direct:ly or indirectly (through the controlled release of various other endogenous substances) induce.s sustained contraction of vascular o r noll-vascular smooth muscles. Its excess production or excess secretion is believed to 2 be one of the factors responsible for hypertensioll, pulmonary hypertension, Raynaud's disease, bronchicll astllma. acute renal failure, myocardia] infarction. angina pectoris, arteriosclerosis, cerebral vasospasm and cerebral infarction. ~ A. M. Doherty, Endothelin: A
Nçw Challen~e. J. Med. Chem., 35, 1493-150~ (1992).
Subst~mces which specifically inhibit the binding of endothelin to its receptor are believed to block the physiological effects of endothelin and are useful in treating patiellts with endothelin related disorders.
The novel compounds of the present inventioll are useful as a non-peptidic endothelin antagonists, ~md have not been disclosed in any ,, issued patents or published patent applications. Among the published patent applications disclosing linear ~md cyclic peptidic compounds as endothelin antagonists are the following: Fujisawa in European Patent Application EP-457,195 and Patent Cooperation Treat:y (PCT) wO96/049r5 . ~>1~9~7s8 r~ 7 --International Application No. WO 93/10144, Banyu in EP-436,189 and 460,679, Imrnunopharmaceutics Inc. in WO 93/~225580, W'arner Lambert Co. WO g2/20706 and Takeda Chemical Ind. in EP-528,312 EP-543,425, EP-547,317 and WO 91/1308g .
Fujisawa has also disclosed hh~o nonpeptidic endothelin antagonist compounds: anthraquinone derivatives produced hy a ferrnentation process u.sing Streptomyces sp. No. 8gO09 in EP-405,421 and U.S. Patent No. 5,187,195; and a 4-phenoxyphel1ol derivative produced by a fermentation process using Penicillium citreonigrum F-12880 in a UK Patent Application GB 2259450. Shionogi and Co. has also disclosed nonpeptidic endothelin antagonist triterpene compounds whicl1 were produced by a f~rm~nt~ion process USillg Mvrica cerifera in WC) 9V12991.
Arnon~ the non-peptidic endothelin antagonist compounds which are known in the patent literature are: 1) a series of substituted (1.4-quinolinoxy~l11ethylbiphenylcarboxylic acids disclosed by Roussel-UcL~f in F P-498,723; 2) a series of of N-~4-pyrimidinyl)benzene-sulfonamides with different substitution patterns from Hoffm~mn-l,a Roche. published in EP-510,526, EP-526,708 and EP-601,386; 3) a series of naphthalenesulfonamides and benzenesulfonarnides disclo~sed by E.R. Sc~uibb & Sons in EP-558,2~ and EP-5~9,193, respectively; 4) a series of compounds represented by 3-~3-indolylmethyl~-1,4-diaz.t-2,5-dioxobicyclo[4.3.0]nonane-9-carboxylic acid irom ImrnunoPh:lrm~l çlitins Inc. in WO 93i23401; 53 a series of fused ~1,2.4]thiadiazoles substituted with an irminosulfonyl bUb~titU~ frOnl Takeda Chemical Ind. has been disclosed in EP-562,599; and 6~ a series of indane and indene derivatives from SmithKline Beechanl Corp.
disclosed in WO 93fO~779; and a series of related phenylal'kyl derivatives from ~rmithKline Beecb~rn disclosed in WO 94102474, 3~

~ W0 96t04905 . ~ ~ ~ i ' ' 2 l 9 ~ 7 5 ~ 5,~7 " REFERENCES

~- I Nature, 332, 411-415 (1988).
2 FEBS Letters, 231, 440-444 (]988~.
3 Biochem. Biophys. Res. Commun. 154, 86S-875 (1988~.

4 TiPS, 13, 103-108, March 1992.

5 Japan J. Hypenensioll 12, 79 (1989).

6 J. Vascular Mledicille Biology, ?, 207 (1990).

7 J. Arn. Med. Association, 264, 2868 (1990).
o 8 The Lancet, ii. 207 (1990) and The Lancet, ii, 747-748 (1989).
9 Japan. Soc. Cereb. Blood Flow & Metahol. 1, 73 (1989).
10 J. Clin. Invest., 83, 1762-1767 (1989).
I l Biochem. Biophys. Res. Comm. 157, 1164-1168 (1988).
12 Biochem. Biophys. Res; Comm. 155, 167-172 (1989).
13 Proc. Natl. Acad. Sci. USA, 85, 9797-9800 (1989).
14 J. Cardiovasc. Pharmacol., 13, 589-592 (1989).
Japam J. Hypertension 12, 76 (1989).
16 Neuroscience Letters. ]02? 179-]84 (1989).
17 FEBS Letters, 247, 337-340 (1989).
2 18 Fur. J. Pharmacol. 154, 227-228 (1988).
19 Biochern. Biophys. Res. Commun., 159, 317-323 (1989).
Atherosclerosis, Z~, 225-228 (1989).
21 Neuroscience Letter.s, 97, 276-279 (1989'~.
22 Biochem. Biophys. Res. Commull. 161, 1220-1227 (1989).
23 Acta. Physiol. Scand., 137, 317-318 (1989).
24 F.ur.J. Pharmaccl., ]80. 191-192 (1990).
Kidney lnt. 37, 1487-1491 (1990).
26 Mayo Clinic Proc., 67, 719-724 (1992).

2~ 9~7~8 W0 96~1)4905 ~ . r~ u,.,~

DETAILED DF~CCRIPTION OF Ti IE l:NVE:NTION. ~f This in~ention is collcerlled with nove:l compounds of structural formula 1:

~12 ~/~
~
X~,Z

R 3~--~ R 1 or a pharm i~ellticsilly acc~ptable salt thereof~ wherein:
R 1, R2 R3a and R3b are independently:
(a~ H, (b) F, Cl, Br, or 1, (c) -N02.
(d) -NH2~
(e ) -NH(C I -C4)-alkyl, (f) -N[(C I ~C4)-alkyl]2, (~ -So2NHR7, (h~ -CF3, :30 ~i) (Cl-C6)-alkyl, (.i ) -oR7, (k) -s(o)n-(cl-c4)-alk (1) -NHCO-~C I -C4)-alkyl, (m ) -N~ ICO-O(C 1 -C~-alkyl, (n) -CH~O-(Cl-C4)-alkyl, . ! . ' ,! ;l i, a-~7rQ
~ WOg6/04905 ~ L ~ 7 J ~ ~u r~ '7 (O) -o-(CH2)m-oR7 (P) -CoNR7R ] 1, (q) -CooR7, or (r) -phenyl;

K l and R2 on adjacent carboll atoms can he joined together to fonn a ring structure:

~
;

A Ir~lt;,~ S:
a) -Y-C(R4)=C(R5)-.
b) -Y-C(R4)=N-, c) -Y-N=C(R4)-, d) -Y-l C(R6)(R6)1 s -Y-, e) -Y-C(R6)(R6)-C(R6)(R6)-, f) -C(R4)=C(R5)-Y-, g) -N=C(R4)-Y-, h) -C(R6)(R6j-C(R6)(R6) -Y-, or i) -C(R4)=C(R5)-C(R4)=C~(R5)-;

n isO, I or2;

m is 2~ 3 or 4;
. I ".
s IS or, Y is -O-, -S(O)n- and NR7;

wo s6~04sos R4 and R5 are independently:
(a) H7 (b~ ~Cl-C6)-.llkyl or (C2-C6)-alkenyl each of which iS unsubstituted or substituted with one or twcl substituents selected from the group consisting of:
i) -OH, ii ) -O-(C I -C4)-alkyl, iii) -S(O)n-~C'l-C4)-alky!, iv) -NR7-(CI-C4)-alkyl, v) -NHR77 vi) -cooR7 vii) -CoNHR7~
viii) -oCoRI 1, or ix) -CoNR7R l l ~
~c~) (C3-C7)-cycloalkyl, (d~ F, Cl. Br, 1, le) CF3, (f) -CooR7, (~) -CoNR7R 11, (h) -NR7RI 1.
(i) -NR7CoNR7R 11, (i) -NR7Coo:Rl I
(k) -S02NR7RI 1, (1) -O-(CI-C4)-alkyl, (m) -S(O)n-lCI-C4)-alkyl~ or (n) -NHSO2Rl l;

R6 is:
(a) H~
(b~ (C]-C4~-alkyl unsubstituted or substitu~ed with clle of the following substituents.
i) -OH, ii) -NR7Rl I
iii) -cooR77 , 1 9~75~
~ ~VO 96104905 ~ .. .'C,. 7 iv) -CoNHR7, or v) -CoNR7R1 1, or (c) Cl, or F;

R7 is:
(a) H, (b) (C I -C~ alkyl, (c) phenyl, o (d) (Cl-C6)-alkylp~henyl, or (e) (C3-C7)-cycloalkyl;

R8 is:
(a) H, (b) ~CI-C6)-alkyl, unsubstituted or substituted with a subitituent .selected from the group consisting of:
phenyl, (ii) -(C3-C7 j-cycloalkyl, (iii) -NR7R1 1 (iv) -morpholin-4-yl, (v~ -01 1.
(vi) -Co2R7, or (vii~ -C'oN(R7)2, (c~ phenyh unsubstit:uted or sub.stituted with a substituent selected from the group consisting of:
;~ (Cl-C4)-a~
ii ~ -O-(C I -C4)-alkyl iii) -CoNR7R1 1, iv~ F, Cl, Br or 1, or ~ 30 v) -CooR7;

J R9 and R 10 are indepelldently:
(a~ H, (b) (Cl-C6)-al~yl, unsubstituted or sllhsliluted with (C3 -C7~-cycloalkyl or-CO2R, 7 ~ 9~ 75~
W096/04905 i~ r.,~l.. ,'.'{,~67 - ]O -(c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl~
(e) Cl, Br, F, 1, (f) (Cl-C6)-alkoxy, (g) perfluoro-(CI-C6)-alkyl, (h) (C3-C7~-cycloalkyl, unsubstituted or substituted with (Cl-C6)-alkyl.
(i ) phenyl (j) {cl-c6)-al}~yl-s(o)n-(cM2)n lC (k) hydroxy-(C1-C6)-alkyl.
(I) -CF3, (m) -Co2R7, (n) -0~, (~) -NR7RI 1~
(p) -I(Cl-C6)-alkyllNR7R1 1, (q) -N02, (r) -(cH2)n-so2-N~R7)2~
(.c) -NR7C'O-(CI-C4)-alkyl, c~r 2~ (t) -CoN(R7)2;

R9 and RIV 0n adjacent carbons can joic togethel to form a fu.sed phenyl ring, unsubstituted or .substituted with a substituent seleoted from the group consisting of: (Cl-C6)-alkyl, (Cl-2s C~-alkoxy, (C3-C7)-cycloalkyl and ~CI-C6)-aLkyl-(C3-C7)-eycloalkyl, Rll is (a) (C l -C6)-alkyl, unsubstituted or substituted with a .substituent selected from the group consisting of:
i) -oR7, 4 ii ) -N[R7~2.
NH2.
iv ) -CooR7, , ~j,7 ~ ~
, . ~ .
~ W0 96/04905 ~ ~ 2 1 9 5 7 5 ~ 'C,~67 v) -NLCH2CH2:]2 vi) -CF3. or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsllb~lilut~d c~r substituted with one or two substituents selected from the group consisting of:
i) (Cl-C4)-alkyl, ii) -O-(C I -C4)-alky h iii) -Co[NR7]2~
iv) E~, Cl~ Br or 1, v ~ -CooR7, vi) -NE-12, viil -NHL~CI -C4)-alkyl]~
viii) -NL(CI-C4)-aLkyl~2~ or ix) -CON[CE 12cl 1212Q;
(c) -(Cl-C4)-alkylaryl~ wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, ~,N~"N
(e~ N , or (f) CF3, R7 and Rl I on the same nitrogen atom they ccm join together to form a ring .se}ected from the group consisting of:
morpholinyl, piperazinyl~ or pyrrolyl, or QisO,Sor-NR7;

R12 iS
(a) H

W09610490~ ' ; 7'A 21~:~75~ F~ 7 (b) (Cl-C6)-alkyl, un~substituted or substituted with one or two substituents selecte;l from the group con~ in~ of i) -OH, ii) -O-(C I -C4)-alkyl, iii) -O-(C I -C4)-cycloalkyl .
iv~ -SIO)n-(Cl -C4)-alkyl, v) -NR7R
vi) -cooR7~
o vii) -CoN~R7-viii) -OCOR
i~) -CoNR7Rl l ~
x) -NR7CoNR7R I 1 7 xi) -NR7cooRl 1~
xii) -C(R6)(oH)-C(R6)(R7)(oH), xiii) -So2NR7R1 1, or R~
N~N
xiv) N--N;

(c) (C3-C7)-cycloalkyl~
(d) -oR7, (e) -CooR7 (f) -CONI 12 (g) -CONR160H, (h) -CoNR7R 11, (i) -CoNR7Co2R7, (j ) -NH2, (k) -NR7RI 1, ~1) -NR:7CoNR7RI I, (m) -NR7C~ooR1 1, (n~ -C(R6)(oH)-C(R6)(R7)(oH~, (o) -S021~R7RI 1, (p) -s(o)2NR7coRl 1, t ~ I; 7 !~ n W0 9611~4gO5 ~ 7 J ~ 'J ~ P~,lr~ 7 (q~ -S(0)2NR7Co2Rl I, (r) -S(0)2NR7cONR7Rl 1 ' (s) -NHS02RI 1~
(t) -NR7So2NR7Rl 1 (u) -CONHSO~RI 1~
(v) -CO-amino acid~ wherein amino acid is defined a~
an L-or D- amillo acid selected from the group con.sisting of Ala~ lle. Phe~ Asp, Pro and Val and which can be further substituted as a (Cl-C6~-alkyl ester or an amide~ or N~N

~ N
xis (a) -O, (b) -S(~)n-(c) -NR7 ~
(d) -CH2O-, (e) -cH2s(o)n (f~ -CH2NR7-~
(g) -ocH2 (h) -N(R7)CH2 ~
(i) -S(O)nCH2-, or (j) -single bond;

Z is:
(a) -C~2~
(b) -CO2R 13.
(c) -CONH-(tetrazol-5 -yl)~
(d) -CONHSO2OR 11 (e) -CoNHSo2NR7R 11 W0$16~04905 ~ ~2t 95758 F._~ s~ l ~

(f) -CONHSO2-a~l, wherein aryl is defined as phenyl or naphthyl which is unsubsfituted or substituted with one. two or three sllhititnl~n selected frorn the group consisting of:
i) (Cl -C4)-alkyl, ii) -O-(C I -C4)-alkyl, iii) -CoNR7Rl I
iv) F, Cl, Br or 1, ) -cool~7, v j) -NH2.
vii) -NHI(CI -C4)-alkyl'l, vii i) -N [(C 1 -C4)-alkyl] 2, ix) -phenyl, x ) -OH, ~ OCH2CH20H, xii) -CF3;
(g) -CONHS02-(CI-C~)-alkyl, wherein the alkyl group is unsubstituted or ~ilhstitllt.od as defined in K4(b), (tl) -CONE-lS02-~Cl-C4)-perfluoroalk~
(i) -tetrazol-5-yl, (.1~ -CONHSO2-heterc)aryl, wtlereill heteroaryl is defined as carbazolyl, furyl. thiellyl, pyrrolyl, isothiazolyl, imidazolyl, isox~olyl. thiazolyl.
oxazolyl, pyrazolyl, pyrdzinyl, pyridyl, pyrimidyl, purillyl or quinolillyl, which is nn~llhititllt~d or substituted Wittl on~, two clr three ~nh~tifll.ont~ selected from the ~sroup consi~fing of:
i) (Cl -C4)-alkyl, ii) -O-(C I -C4)-alkyl, iii) -CoNR7R~
iv~ F, Cl, Br or 1, v) -CooR7, vi ) -NR7CoNR7R 11 , and ~ WO 96/D4905 ~ 9 5 7 5 8 PCT~US95/09967 ~ vii~ -NR7CooR I l;
(k) -S02NHCO-aryl. wherein aryl is defined in Z(dl above, (I) -SO2NHCO-(CI-Cg~-alkyl, wherein the alkyl group is unsub.stituted or substituted as defined in R4(b).
(m~ -SO2NHCO-(CI -C4)-perfluoroalkyl, (n~ -SO2NI ICO-heteroaryl, wherein heteroaryl is as defined in Z(g) above, (o) -SO2NHCON(R1 1)2 wherein the Rl I groups are the same or different, (p) -Po(oR7)2, wherein the R7groups are the same or different, or (q~ -PO(R l I )oR7;

R13 is:
i ~) (C I -C4)-a Ikyl, (b) CHR I 4-o-coR 15, (c) Cl l2cH2-N~(c] -c2)-alkyl]
2Q (d) CH2cH2-N[cll2c}l2l2o (e~ (CH2CI-12O~y-o-l(cl-c~)-alkyll~ whelein y is I or 2 (~) phenyl, naphthyl, CH2-phenvl or C}12-naphthyl, where phenyl or naphthyl is substituted or un.substituted with CO2-(CI-C4~-alk .. ~ 2~ 957~8 wo sclo4sos ~ ru.~ 7 'g' 0)=(0 ~ , ~h) ~o, (j) 5sS~3, or (j) -CH2 ~ O; and i R 14 and R IS independently are ~Cl -C6)-alkyl or phenyl: ~md R 16 i~ H, ~Cl-C6)-alkyl or (Cl-C6)-alkylphenyl.

r ~ wO 96/049(l5 ~ ? ~i 8 ~ 7 ~ An embodiment of the invention is the compound of structural formula II:

R9--~--R lo X.~Z
R3 \
R3b ~ R
R3a ~ R2 or a pharmaceutically acceptable salt thereof, wherein:
Rl, R2, R3a and R3b are independently:
(a) 1-1, (b) F, Cl, Br, or 1, (c) -NO2, (d) -NH2, (e) -Nl l(Cl -C4)-alkyl, (f} -N[(C I -C4)-alkYl]2 (g) -S02NHR7, (h) -CF3, (i) (Cl-C6)-alkyl, ~i ) -oR7, (k) -S(O)Il-(Cl -C4~-alkyl, 3 o (1) -NHCO-(C I -C4 )-alkyl !
(m) -NHCO-O(CI -C4)-alkyl, (n~ -CH~O-(C I -C4)-alkyl, (O) -o-(CH2)rn-oR7 (P) -CON R7R I I . or (q) -CooR7;

WO 961049Ol . ~ = , 2 ~ ~ 5 7 5 8 T ~

R l and R2 on adjacent carbon atoms can be joined together to i:'orrn a ring structure-~

~ ;

A represents:
a) -Y-C(R4~=C(R5)-, b) -Y-C(R4~=N~, c) -Y -N=C(R4~-, d) -~r-LC~R6)(R6)]S-Y-, e) -Y-C(R6)(R6)-C(R6)(R6)-, f) -C~(R4')=C(R5~ Y, g) -N=c(R4)-y-~
h) ~ R6)(R6)-C(R6)~R6) -Y-, or i) -C(R4)=CIR5)-C(R4)=C(R5)-;

m is 2, 3 or 4, n is0, 1 o:r2, sis I or2, Y is -O~ (~)n- and NR7;

R4 and R5 are independently:
(a) H, ~ WO 96/04~05 ~ 2 ~ 9 5 7 5 8 ~ (b) (Cl-C6)-alkyl or (c2-c6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OI~I, ii) -0-(C1 -C4)-alkyl, iii) -S(O)n-(C I -C4)-alkyl, iv) -NR7-(C'1 -C4)-alkyl, v) -Nl IR7, vi) -cooR7 o vii ) -CoNHR7~
viii) -oCOR 11, or i~) -CoNR7R 11, (c) (C3-C7)-cycloalkyl.
(d) F, Cl, Br, I, (e) CF3, (f) -CooR7, (g) -CoNR7R] 1, (Il) -NlR7R1 1, (i) -NR7CoNR7Rl 1 (J) -NR7CooR1 I
(k) -S02NR7Rl 1, (I) -0-(C1 -C4)-alkyl, (m) -S(O)n-(Cl-C4)-alkyl, or (n) -NHS02Rl l;

R6 is:
(a) H, (b) (Cl-C4)-alkyl un.substituted clr substituted with one or two substituents selected from the group consisting of:
i) -01 ~, ii) -NR7RI 1, iii) -cooR7 ~
iv) -CoNHR7~ or W0 g6104905 ~ 2 1 ~ 5 7 5 ~

v) -CoNR7R 1 l, or (c) Cl, or F;

5R7 is:
(a) E~, (b) (Cl-C6)-alkyl, (c) phenyl, (d) ~C I -C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;

R2 is:
(a) H, (b) (Cl-C6~-alkyl, unsubstituted or substituted with one or two sub.stituents selected from the group consisting of:
(i) -phenyl.
(ii) -(C3-C7)-cycloalkyl.
(iii) -NR7R 1 l, (iv) -morpholin-4-yl, (v~ -OH, (vi) -Co2R7, or (vii) -CoN(R7)2, or (c) phenyl;

R9 ancl R 10 are independently:
~a) I 1, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3 -C7)-cycloalkyl or -C02R7, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, 1, (f) (C I -C6)-alko~y, (g) perfluoro-(Cl-C6)-alkyl, ~ WO96/0490!; ~ t' r~'. 2 1 9 5 7 5 ~} r~ ~/ L.~

(h) (C3-C7)-cycloalkyl, unsubstituted or substituted v~ith (Cl-C6~-alkyl, (i3 phenyl, (j) (cl-c6)-alkyl-s(o)n-(cH2) (k) hydroxy-(Cl-C6)-alkyl, (I ) -CF3, (In) -Co2R7, (Il) -OH, (o) -NR7Rl I, (p) -[(Cl-C6)-alkyl]NR R, (q) -N02.
(r) -(CH2)1l-So2-N(R7)2~
(s) -NR7CO-(CI-C4)-alkyl, or (t) -CoN(R7)2;

R9 and R10 on adjacent carbons can join together to i'olm a fu.sed phenyl ring, unsubstituted or substituted with a ,substituent selected from the group consistillg of: (Cl-C6)-alkyl, (Cl-C6)-alkoxy~ (C3-C7)-cycloalkyl cmd (Cl-C6)-alkyl-(C3-C7)-cycloalkyl, Rll iS
(a) (Cl -C6)-alkyl, unsubstituted c r substituted Wit}l a subst:ituent selected from the group consisting of:
i) -oR7, ii) -N[:R7 12, iii) -NH2, iv) -CooR7, 3() v) -N[CH2CH212Q, vi) -CF3, or vi i) -CCIN(R7)2;
(b) aryl, whereill aryl is defined as phenyl or naphthyl which is unsubstituted or substituted Wittl wo s6/0490~ 7 ~ 7 ~ 9 ~ s7 5 8 F~ u.......... .'~

- 2~ -one or tw{) substituents select:ed frum the group ~ consisting of:
i) (Cl-C4)-alkyl, ii) -O-(C 1 -C4)-alkyl, S iii) -Co[NR7 12.
iv) P, Cl, Br or 1, v) -CooR7.
vi) -NH~, vii) -NHI(Cl-C4)-aLkyl], viii) -N[(C;-C4)-aL~cyll2, ix~ -CONrCH2CH21~Q;
(c) -(C-l-C4)-alkylaryl, wherein aryl is as de~med above, (d) (C3-C7)-cycloalkyl, N~N
(e) N- N, or (f) CF3;

R7 and Rl I on the same nitrogen atom they can Join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrol~yl, or Q is O, S or -NR7;

R12 is (a) H
(b) (Cl -C6)-alkyl, unsub.stituted or substituted ~,vith one or two sub~stituent~. selected fronl the group eonsisting of:
i) -OH7 ii) -O-(C I -C4)-alkyl, iii) -O-(C I -C4)-cycloalkyl, iv) -S(O)n-{Cl -C4)-alkyl, ~ wo 96~90~ 1 9 5 7 5 ~ I ~ " ~ ~ 9~ 57 v) -NR7R 11 vi) -cooR7 vi~ CoNHR7 viii) -OCORI l~
ix) -CoNR7RI 1, x) NR7CoNR7RI 1 xi~ -NR7CooRl 1~
xii) -C(R6)(oH)-C~R6)(R7)(oH), xiii) -So2NR7Rl 1, or ~N'"N
xiv) N--N;

(c) (C3-C7)-cycloalkyl, (d) -oR7, (e) -CooR7 (f) -CONH2 (g) -CONR 16OH~
(h) -CoNR7RI 1 (i) -CoNR7Co2R7 (j) -Nl 12~
(k) -NR7Rl 1, (I) -NR7CoNR7R1 1~
(m) -NR7CooRl 1, (n) -C(R6)(oH)-C(R6)(R7)(oH), (o) -So2NR7Rl I, (p~ -S(0)2NR7CoRI I, (~I) -S(0)2NR7Co2R I I, 3~ (r) -S(0)2NR7CoNR7RI 1, (s) -NHS02RI 1, (t) -NR7So2NR7R~ 1, (u) -CONHS02R1 1, W0 9611)4905 ~ 2 1 ~ ~ 7 5 ~ J --(v) -CO-amino acid, wherein amino acid i.5 defined as an L-or D- arnino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro ~md Val and whicll can be further substituted as a (C'l-C6)-alkyl ester or an amide, or o (w) N-N;
X is (a) o, (b~ -S(O)n, (c~ -NR7-, (d) -CH2O, (e) -cH2s(o)n ~f) -CH2NR7-, (g) -ocH2 (h) -N(R7)CH2-~
(i) -S(O)nCH2-, or ~') -single bond;

Z is:
(a) -CO2H, (b) -Co2R 1 3, (c) -CONH-(tetrazol-S-yl), (d) -CONHSO2ORI I
(e) -CoNHSo2NR7R1 1 (:f) -CONH~O2-aryl. wherein a~l is deit'ined as phenyl or naphthyi which is l",~"I,.~ lt d or substituted with one, two or three substituents selected from the group cc nsistillg ol':
i) (Cl-C4)-alkyl, ii) -O-{CI -C4)-alkyl, t, ,~ ~
W0 96/04905 '~ 2 t 9 5 7 5 8 iii) -CoNR7R 11, iv) F, Cl, Br or 1, v) -CooR7, vi) -NH2, vii) -NH[(CI -C4)-alkyl]~
viii) -N[(C I -C4)-alkyl]2, ix) -phenyl, x) -OH, xi) -OCH2CH2OH, xii) -CF3;
~g) -CONHSO2-(Cl-Cg)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in R4(b), (h) -CONllS02-~Cl-C4)-perfluoroalkyl, (i) -tetrazc~ -yl, (j) -CONHS02-heteroaryl, wherein heteroaryl is defined as c~rb~olyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl~ isoxazolyl, thiazolyl, oxa~olyl. pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl, which is unsubstituted or substituted v~ith one, tu,o or three substituents selected from the grc)up cclllsisting of:
i) (Cl -C4)-alkyl, ii) -O-(C I -C4)-alkyl, 2s iii) -CoNR7RI 1, iv) F, Cl, Br or 1, v) -CooR7, vi) -NR7CoNR7R l l, and vii) -NR7CooR~ I;
(k) -SO2Nl~CO-aryl, wherein aryl is defined in Z(d) above, (I) -SO2NHCO-(C;l-C'~)-alkyl, wherein the alkyl group i.s lln~llh~titl1t~d or substituted as defined in R4(b), ~0 ~6/04sos ~ 1 9 5 7 5 8 r~ 67--(m) -SO2NHco-(c I -C4)-perfluoroalkyl, (n) -SO2NHCO-heteroaryl. wherein heteroaryl is a.s defined in Z~g) above, (o) -SO2NI ICON(R I 1 )2 wherein the R I I groups are the same or different, (p) -Po(oR7)2~ ~rherein the R7groups are the 6ame or different? or (q) -PO(R I ] )oR7;

R13 is:
(a) ~cl-c4)-alkyl~
(b) Cl IR14-O-COR] ~, (c) CH2CH2-N[(CI-C2)-alkyll2, (d~ CH2CH2-N[cH2cH2]2O~
(e) (CH2CH2Ojy~O-[(CI-C4)-alkyl:], wherein y is I or 2, (f) phenyl, naphthyl, CH2-phenyl or CH2-naphthyl, where phenyl or naphthyl i.s .substituted or ull~u~;.LiLuL~d with C O2-(C'I-C4)-alk -CH~ ~CH ~

(9) o~fO ' (h) ~o, (i~ ~3 . or U) -CH2 O~o; and \

~ W0 96/04905 ~ ! 2 1 q 5 7 5 8 R 14 and R 15 independently are (Cl -C6)-alkyl or phenyl; and R16 is H, (Cl-C6)-alkyl, or (Cl-C~)-alkylphenyl.

An embodiment of the compounds of Forrnula II are the compounds of Forrnula 111:

X Z
R3b--a~

lll or a pharmaceutically acceptable salt theleof, wherein:
Rl~ R2, R3a and R3b are independently:
(a) H, (b) F, Cl, Br~ or 1, 2~ (C) -N02, (d) (C I -C~,)-alkyl, (e) -oR7, (f) -NHC0-(C I -C~)-alkyl, (g) -NHC0-O(C I -C4)-alkyl, o (h) -C)-(CH2)m-OR7, (i) CoNR7Rl 1, or Ci) -C001~7;

R1 and R2 on adjacent carbon atoms can be joined together to form a ring structure:

2~gr758 ~o s6~04sos ~ 7 A l~plese~
a~ -Y-C(R4)=C(R5)-, b) -Y-C~R4)=N -~
c) -Y-N=C(R4)-, d) -Y-[C~R6)(R6)]s -Y-, e) -~-C'(R6)(R6)-C'(R6)(R6)-, f) -C~R4~=C(R5)-Y-~
g) -N=C(R4)-Y-, h) -~:'(R6)(R6)-C(R6)(R6) -Y-, or i) -C(R4)=C'(R5)-C(R4~=C(R5)-;
m is 2, 3 or 4, n is1), 1 or2, sis I or2, 2s Y is -O-, -S- and NR7 R4 and R5 are independently:
(a) H, (b): (Cl-C6)-alkyl, (c) (C3-C7)-cyc]oalkyl, (d) F, Cl, Br, 1, (e) -NR7CooR I I .
(f~ -So2NR7Rl I

WO 96/04905 ' 2 ~ ~ r 7 ~ o PCT/US95/09967 - (g) -O-(C I -C4)-alkyl, (h) -S(O)n-(C1-C4)-alkyl, or (i) -NHS02R l l, R6 is:
(a) H, or (b) (C I -C4)-alkyl. or (c) Cl, or F:
oR7 is:
(a) H, (b) (C I -C6)-alkyl, (c) phenyl, or (d) benzyl;

R8 is:
(a) H, (b) (C I -C6)-alkyl, or (c) phenyl;
R9 and R10 are independently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3 -C7)-cycloalkyl, (c) Cl, Br, F, 1, (d~ (C I -C6)-alkoxy, or (e) hydroxy-(CI-C6)-alkyl;

Rll is (a) (Cl -C6)-alkyl, unsubstituted or sub.stituted with a .substituent selected from the group consisting of:
i) -oR7, -N[R7]2, iii j -NH2, W0 96/~W905 ~ 9 5 7 5 8 . ~ r ~ _7 --iY) -CooR7.
v) -NICH2cH2]2Q, vi) -CF3. or vii) -CoNiR7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl whic:h is un.substitllted or s~ fitlltt~d vvith one or two snhsrjtllenls selected from the group g of:
i) ~Cl-C4~-alkyl, o ii) -O-(CI-C4)-alkyh iii ) -Co[NR7]2.
iv) P, Cl, Br or 1, v ) -CooR7, ~/ i) -NH2~
Vii) -NHI(Cl-C4)-alkyl], viii) -N[(cl-c4l-alkyl]2~
ix) -CON[CH2CH2]2Q,or ~c) -(Cl-C4)-aL~ylaryl, wherein aryl is a.s defined above, ~d) (C3-C7)-cycloalkyl, N~N
~11 ~e) N , or (f) CF3;

R7 and R 1 l on the sarne nitrogen atom they cun jOill together to forrn a ring selected from the group consistulg of.
morplloli:nyl, piperazinyk or ~pyrrolyl, or QisO,Sor-NR7;

12 is (~1) H, . , .

~ W096/04905 . . i~ 2! 9 5 758 r~ 7 ~1 ~ (b) (Cl-C6)-alkyl. whereill alkyl is defined as unsubstituted or substituted with one or two substituent.s selected from the group consisting of:
i) -OH, ii) -O-(C I -C4)-alkyl, iii) -O-(CI -C4)-cycloalkyl, iv) -S(O)n-(CI -C4)-alkyl, iv) -NR7-(C I -C4)-alkyl, v) -NR7R 11, Vi) -cooK7 vii) -CoNHR7 viii) -OCORI 1, ix) -CoNR7R l l, ~) -NR7coNR7R 11, xi) -NR7cooRl 1, xii) -C'(R6)(oH)-C(R6)(R7)(oH), xiii) -So2NR7Rl 1, or ~N~N
xiv) N--N, (C) -CooR7 (d) -CONH2~
(e) -CONR 1 6OH, 2 5 (f) -CoNR7Rll~
(g) -CoNR7Co2R7, (h) -C(R6)(OH)-C(R6)(R7)(OII), or (i) -CONHS02RI 1, (j) -S02NR7R1 1, (k) -NR7So2NR7Rl 1, (I) -CO-amino acid, wherein amino acid is de:t'ined as an L-or D- amino acid selected from the group consi.sting of Ala, lle, Phe, Asp, Pro and Val and which can be turther substituted as a (Cl-C6)-alkyl ester or an amide, or w0 96/0490~ ? 1 ~ ~; 7 5 8 ~ f~

(m ~ N- N ;

is (a) -O, (b) -NR7-, or (c) -single bond;

Z is:
(a) -CO2H, (b) -CO2R 13 ~
(C) -CONI-l(tetrazol-5-yl), (d) -CoNHSo2NR7R 11, (e) -CONIlS02-aryl. wherein aryl is defined a~
phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from rhe group consisting of:
i) (Cl-C4)-alkyl, ii~ -O-(CI-C4)-alkyl.
iii) -CoNR7RI I, iv) F, Cl, Br or 1, v) -CooR7, vi) -NH2, vii) -NH[(CI -C4)-alkyl], viii) -N[(cl-c4)-alkyl]2 ix) -phenyl;
(f~f -CONHSO2-(CI-Cg)-alkyl, wherein alkyl is unsubstituted or substituted as defined in R4(b~, (g~f -CONHSO2-heteroaryh wherein heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isot~hiazolyl~ imidazolyl, isoxazolyl, thiazolyl, oxazolyl. pyrazolyl, pyrazinyl, pyridyl, ~ WO 96/04905 ~ , 2 ~ 9 ~ 7 5 ~

~ pyrimidyl, purinyk or quinolinyl~ wh:ich is unsubstituted or .substituted with one, two or three b~iiiue~ki selected from the group consisting of:
i) (C l -C4)-alkyl, ii~ -O-(Cl-C4)-alkyl~
iii) -CoNR7RI 1, iv) F, Cl. Br or 1, V) -CooR7, vi) -NR7CoNR7R l l, and Vii) -NR7CooRI l;
~h) -tet:razol-5-yl;

R13 is (Cl-C4)-alkyl; and Rl6 is H, (C1-C6)-alkyl, or (Cl-C6)-alkylphenyl.

A subclas.s of the compounds of Formula III are the compounds of Formula IV:

Rg~
Xl, R3rd J~l R

IV

or a ph~nn u-ellti~,llly acceptable salt thereof, wherein:

R l and R2 taken together form the ring structure:

2 7 ~ 5~ ~ --W0 9610'19aS ~ ,.,. C,,.~7 ;

A

~ ; ~

A repre.sents:
a) -Y-lC(R6)(R6)],s -Y-. or b) -C(R4)=C(R5)-C~R43=C(R5)-;
sis l or2;

Y i~ -0-;

R3a is:
(a) H.
(b~ F, C1, Br, or I, (c) (C'l-C'6)-alkyl, (d) -oR7~
(e) -0-(Cl-12)m-OR7, (f) -CoNR7Rl 1, or (g) -CooR7;
mis2,30r4;

R4 and RS are independently:
(a) H, (b) (Cl-c6)-alkyl~
(cl (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) -NR7CooR1 1, (f) -S02NR7R l 1 (g) -0-(C l -C4)-alkyl, (h) -S(O)n-(Cl-C4)-alkyl, or (i ) -NHS02R 11;

~ W0 96/0490~ 2 1 9 5 7 5 ~ '05 :7 nisO, 1 or2, R6 is:
(a) H, or (b~ (Cl-C4)-all~yl, or (c) Cl, or F;

R7 is:
(a) H, o (b) (C'l-C6)-alkyl, (c) phenyl, or (d) benzyl;

R~ is:
~a) H.
(b) (Cl-C6)-alkyl, or (c) phenyl;

R9 is:
(a) H, (b) (Cl-C6)-alkyl, unsubstit:utecl Ol substituted witl (C3 -C7)-cycloalkyl, (c) Cl, Br, F, I, (d) (C I -C6)-alkoxy, or (ei hydroxy-(CI-C6)-alkyl;

Rll is (a) (Cl-C6)-alkyl, unsubstituted or substitwted with a - substituent select:ed from the group consisting of:
3 o i) -oR7~
ii) -N[R7]2, iii~ -NH2, iv) -CooR7, v) -N[CI{2CH2]2Q.

wo ~go~ ~ ~ 2 ~ 9 ~ 7 5 ~

vi) -CF3, or vii) -CoN(R7)2;
~b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group Coll.si.st~ g of:
i) ~CI-C4)-aLkyl, ii) -O-(C I -C4)-alkyl, iii) -CO[NR7 12.
iv) F. C]~ Br or 1, V) -CooR7, vi) -NH2, vii) -NH[(Cl -C4)-alkyl], ~viii) -N[(CI-C4)-alkyl]2, or ix) -CON~CI ~2CE-12]2Q;
(c3 -~CI-C~)-alkylalyl, wherein a:ryl is as det'ined ahove, (d) (C'3-C7)~cycloalkyl, N
'"N
~e) N , or (f) CF3;

R7 and R I I on the s~ne nitrogen atom they c.m jo;n tc~gether to.
form a ring selected from the group consisting of:
morpholinyl7 piperazinyl, or pyrrolyl, or Q is O, S or -NR7;
R12 is ~a~ El, (b) (C1-C6)-alkyl, wherein alkyl is defined as unsubstituted or substituted with one or two substituents selected from the group collsisting of:

~ w096~04go5 ;; ; ~ 2i 9575~ P~ 7 ~ i) -OH, ii) -O-(C 1 -C4)-alkyl, iii) -O-(CI -C4)-cycloalkyl, iv) -S(O )n-(C I-C 4)-alkyl, iv) -NR7-(Cl-C4)-alkyl, v) -NR7Rl 1, vi) -cooR7 ~
vii) -CoNHR7 viii) -oCORl 1 iX) -CoNR7R1 1 x) -N-R7coN-R7R 1 xi) -NR7CooR 11~
xii) -C(R6)(oH)-C(R6)(R7)(oH), or xiii) -So2NR7Rl 1, N'N
xiv) N--N
(C) -cooR7 (d) -CONH2~
(e) -CONR I 6OH, (f) -CoNR7R1 1, (g) -CoNR7Co2R7, (h) -C'(R6)(oH)-C(R6)(R7)(oH), or Z5 (i) -CONllSO,RI 1, (j) -so2NR7Rl 1, (k) -NR7So2NR7Rl I, (I) -CO-amino acid, wherein amino acid is defined as an L-or D- amillcl acid selecled from the group consisting of Ala, lle, Phe. Asp. Pro and Val and whicll can be furthel substitut:ed as a (Cl-C6)-alkyl ester or an amide, or wo s6~04sos ~ t Y ~ 7 ~ ~ r~

N~N
(ro ~ N

xi~
(a) -O-, (b) -NR7-~ or (c~ -single bond;

Z is:
(al -C'02H, (b) -Co2R13, (c) -CONH-(tetrazol-~ -yl j, (d~ -CONllSO2NR7Rl l, (e) -CONl-ISO2-aryh wherein aryl is def~:ned as phenyl or naphthyl which is u~ b~liluled or substituted v~ith one, two or three .substituent.s selected from the group consisting of:
i ~ (C I -C4)-alkyl, ii) -O-(C l -C4)-alkyl, iii) -CoNR7R l l, iv) F~ Cl, Br or I~
v ) -CooR7, vi) -NH2~
C I -C4)-~lkyl], viii) -N~Cl -C4)-alkyl]2, ix) -phenyl;
(f) -CONHSO~-(C1-Cgj-alkyl, wherein alkyl is unsubstituted or substituted as defined ill R4~b), (gi -CONHSO~-heteroaryl, wherein heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolylt thiazolyl, oxazolyl, pyrazolyh pyrazinyl, pyridylt ~ wo 96io490~ 2 1 9 r 7 c ~3 ~ pyr:imidyl~ purinyl, or quinolinyl, ~hich is Imsllhstitl~t~d or substituted with one, two, or three substituents selected from the group consisting of:
i) (Cl-C4)-alkyl, ii) -O-(C I -C4)-alkyl, iii) -CoNR7R1 1, iv) F, Cl, Br or 1, v ) -CooR7 .
vi) ~1R7CoNR7RI 1, and vii) -NR7CooRI l;
(h) -tetrazol-5-y l;
R13 is (Cl-C4)-alkyl; and R16 is H~ (Cl-C~)-all;yl, or (Cl-C6)-alkylphenyl.

A second embodiment of the cc~mpounds of Formula n are the compounds of Forrnula V:

R~ Rl~
X~z R3b--~--R3a or a pharmaceutically acceptable salt thereof, wherein:
Rl, R~, R3a and R3b are independently:
(a) H, q ~ 7 5 ~
W09~v~04905 ~ C3~vl (b) F, Cl, Br, or 1, (c) -NO2, (d) (cl-c6)-alk (e) -oR7, (f) -NHCO-(C I -C4)-alkyl, (g) -NHCO-O(C 1 -C4)-alkyl, (h) -(:~ -(CH2)m-oR7, (i) CoNR7Rl 1, or (j) -CooR7;
m is 2, 3 or4, R4 and R5 are independently:
(a) H, (b) (Cl-C6)-alkyl, (c~ (C3-C7)-cycloalkyl, (d) F. Cl, Br, 1, (e) -~R7CooRl I, (f3 -So2NR7Rl 1, 2 0 (g) -0-(C I -C4)-alkyl, (h) -S(O)n-(C1-C43-aLiyl, or (i) -NHSO~RI l;
n is (), I or~, 2~
R~ is:
(a3 H, (b) (C I -C4~-alkyl,or (c i Cl or F, ~ W096/04905 ~ 9~758 1_1lu.. '~,3,_ - R7 is:
(a) H, (b) (C I -C6)-alkyl, (c) phenyl, or (d) benzyl;

R~ is:
(a) I 1, (b) (C I -C6)-alkyl, or (c) phenyl;

R9 and RIQ are indepelldently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cyClOalkyl~
(c) Cl, Br, F, 1, (d) (C 1 -C6)-alkoxy, or (e) hydroxy-(Cl-C6)-alkyl;

R 11 i~i (a) (Cl-C6)-alkyl, unsubstituted or suhstituted with a substituent selected from the group consisting of:
i) -oR7, ii) -Nl R7]2, 2s iii) -NH2, i', ) -CooR7, v) -N[ CH2CH2] 2Q.
vi) -CF3. or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defïned as phenyl or naphthyl which is unsubstituted or substituted with one or two .substituents selected from the group consisting of:
i ) (C 1 -C ~ )-alkyl, WO 96/r4905 ' ~ '. 2 ~ q 5 ? 5 8 r~ 3 l--ii) -O-(C I -C4)-alliyl.
iii) -CO[NR712, iv) F. Cl, Br or I~
v) -CooR7, vi) -NH2 vii) -NH[(C 1 -C4)-alkyll, viii) -N[~CI-C4)-alkyl]2~ or ix) -CONl CH2CH212Q;
(c) -(C1-C4~-alkylaryl, wherein aryl is as defined o above, (d) (C3-C7)-cycloalkyl, ~N~N
(e) N , or (f~ CF3, R7 and R11 on the same nitrogen atom they can join together to forrrl a ring selected from the group consisting of morphc linyl, pipera~ yl. or pyrrolyl, or Q is O, S or -NR7;

R12 is 2s (a) H, (b) (Cl-C~)-alkyl, wherein alkyl is defmed ias unsubstihuted or~substituted with one or two sllb~tihlents selected from the group consisting of:
i) -OH, ii) -O-(Cl-C4)-alkyl, iii) -O-(C 1 -C4)-cycloalkyl, i~i ) -S~O)n-(C I -C4)-alkyl, iv) -NR7-(CI -C4)-alkyl, v) -NR7R
vi ) -cooR7 ~ WO g6104905 . ! ~ ~ ~ 2 ~ 9 ~ 7 5 8 ~ S ~

vii) -CoNHR7 viii) -OCOR 11, ix) -CoNR7R 11 x) -NR7CoNR7R
s xi) -NR7CooRl 1~
xii) -C(R6)(oH)-C'(R6~(R7)(oHj, or xiii) -So2NR7RI I, or <N'N
xiv) N-N;
(C) -cooR7 (d) -CONH2~
(e) -CONR I 6OH, (f) -CoNR7R 11, (g) -CoNR7Co2R7, (h) -C(R6)(OII)-ClR6)(R7)(O}-I), or (i) -CONHS02RI 1, (j) -so2NR7R1 1, (k) -NR7So2NR7Rl 1, (I) -CO-amino acid, wherein amino acid i~ defined as ~Ul L-or D- amino acid selected from the group consi.sting of Ala. Ile, Phe, Asp, Pro and Val and which can be further substituted as a (Cl-C6)-alkyl ester or an amide, or ~,N'"N

- (m) N-N;

xis (a) -O, ~b) -NR7-, or (c) -single bond;

W096f04905 ~ 2195758 r~ o. I--Z is:
C02H, (b) -CO2R13, (c) -CONH-(tetrazol-5-yl), (d) -CoNHSo2NR7R I I
(e) -CONHSO2-aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or .substituted with one. two or three substiluents .selected from the group consistillg of:
i) (Cl -c4~-alky~l~
ii) -O-(CI -C4)-alkyl, iii) -CoNR7R1 1, iv) F, Ch Br or 1, v) -Coo'R7, vi) -NH2, vii) -NH[~CI -C4)-alkyl j, viii) -N[(C I -C4)-alkyll2, ix) -phenyl:
(f) -CONllSO2-(Cl-C~)-alkyl, wherein alkyl is un.substituted or substituted as defined in R4~b), (g) -CONHS02-heteroaryl, wherein heteroaryl is deFuled as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, iso~:azolyl, th:iazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridylt pyrimidyl, purinyl, or quinolinyl, which is msllhstitllted or substituted with one, two or three suhstihl~nts selected from the group consisting of:
i) (Cl-C4)-alkyl, ii) -O-~CI -C4)-alkyl, iii) -CoNR7R I I ~ r iv) F, Cl, Br or I, v ) -CooR7, vi) -NR7CoNR7Rl 1, and ~ W096104905 .: : ,,'; 2t95758 1~1,1 ,~, vii) -NR7CooRI l;
~h) -tetrazol-5-yl;

R l 3 is: (C l -C4~-alkyl; and Rl6 is H, (Cl-C6)-alkyl, or (C'l-C'6)-alkylphenyl.

A third embodiment of compounds of Forrnula II are the compounds of Fonnula VI

R9J¢l R10 X~Z

R3~ R2 v or a pharmaceuticall~ acceptable salt thereof. wherein:

Rl and R2 are represented by the iollowing ring structure:

~-~;

A represents:
a) -Y-LC(R6)(R6)]~ -Y-. or b) -C(R4)=C(R5)-C(R4)=C(R5)-;
sis l or2, 2 ~ 9 5 7 5 8 ~
WO9C104905 ~,II~Jw.,.~, 7 Y is -O-, -S- and NR7;

R3~1 and R3b are independentlS~:
(a) H, (b) P, Cl, Br, or 1, (C) -N02, (d) I C I -C,~)-alkyl, (e) -oR7, (f) -NHCO-(Cl-C4)-alkyl, (g) -NHC'O-O(C1-C4)-alkyl, ~h) -o-(cH2im-oR7 (i) c'oNR7Rll~ or (i ) -CooR7;
m i~ 2, 3 or4, R4 and R5 are independently:
(a) 1-1, (b) (C1-C~)-alkyl, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, 1, (e) -NR7cooRl I, (f) -S02NR7R 11, (g) -O-(C l-C4)-alkyl, (h) -S(O~n-(CI -C4)-alkyl, or (i) -NHSO2RI l;
nis0, 1 or2, 33 R6 is (a) H, or (b) (Cl-C4)-alkyl, or (c) Cl or F;

9 5 7 5 ~
WO 96/0490S l _ " "~, -/,.. , R7 is:
(a) H, (b) (Cl-C6)-alkyl, (c) phenyl, or (d) benzyl;

R8 i.s:
(a) H, (b) (C I -C6)-alkyl, or 1 o (c) phen~T l;

R9 and R10 are independently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituled or substituted with (C3 -C7 i-cycloalkyl, (c) Cl, Br, F, 1, (d) (C I -C6)-alkoxy, or (e) hydroxy-(CI-C6)-alkyl:
Rl I is (a) (C I -C~)-alkyl, unsubstituted or substituted with a subslituent selectecl from the group consisting of:
i) -oR7, ii) -Nl R7 12.
iii) -NH2.
iv) -CooR7, v) -N[CH2CH2 12Q.
vi) -CF3, or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or ~ naphthyl which is llncilb~titlltt~-l or substituted with one or two ~ub~lilu~ selected from the group consisting of:
i) (C I -C4)-alkyl, 2 1 ~ 5 7 5~ --W0 96/1~4905 1 ii) -O-(C l-C~-alkyl~
iii) -Co~NR7]2 iv) F, Cl, Br or 1, v ) -CooR7, vi) -NH2, vii) -2~H[(CI -C4)-alkyl], viii) -N[(Cl-C4)-alkyl~2, or ix) -CON[CH2CH2]2Q;
(c) -(Cl -C4)-alkylaryl, wherein aryl is as de.fined above, (d) (C3-C7)-cycloalkyl, ~N~"N
~e) N--N or (f) CF3;

K7 and Rl 1 on the .sarme nitrogen atom they can join together ~o i'c~rm a ring selected from the group consist:ing of:
morpholinyl, piperazinyl, or pyrro:lyl, or Q is O, S ar -NR7;

R12 is 2s (~) H, (b) (C'l-C6)-alkyl, whereill alkyl is defined a.s unsubstituted or substituted with one or t vo substituents selected from the group consisting of:
i) -OH, ii) -O-(CI-C4)-alkyl, ii i) -O-(C I -C4)-cycloalkyl, -S(OJn-(cl -C4)-alkyl, iv) -NR7-(C'1 -C4)-alkyl, v) -NR7R 11, vi) -cooR7 ~

2 ~ 9575B
W0 96104905 ~ F~ ,. C7 vii ) -CoNHR7 viii) -OCOR] 1, ix) -CoNR7RI 1~
x) -NR7CoNR7R1 1, S xi) -NR7CooK l l ~
xii) -C(R6)(oH)-C(R6)(R7)(oH), xiii) -So2NR7Rll~ or 1 0 ~N~N
xiv) N-;
(C) -cooR7 (d) -CONH2~
(e) -CONR 16OH, (f) -CoNR7R1 1, (g) -CoNR7Co2R7, (h) -C(R6)(oH)-C(R6)(R7~(oH), or (i) -CONHS02RI 1, (j) -SC)2NR7R1 1, (k) -NR7So2NR7Rl 1, (I) -CO-amino acid, wherein amino acid is defined as an L-or D- amino acid selected from the group consisting of Ala, lle, Phe, Asp, Pro and Val and which can be filrther substituted as a (C I -C6)-2s alkyl ester or an amide, or N~N
~ N

xis (a) -O, (b) -NR7-, or (c) -single bond;

WO 9G/04905 ~ 9 :~ ~ 5 8 ~ 7--Z is:
(a) -CO2H, (b) -CO2R 13, (c) -CONH-~tetraz.ol-~-yl), (d) -CoNHSo2NR7R 11, (e) -CONHSO~-aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted witll one, two or tllree substituen~s selected from the group consisting of:
i ~ (C l -C4)-alkyl, ii) -O-(C I -C4)-alkyl, iii) -CoNR7R 11, iv) F, Cl. Br or 1, v) -CooR7, v i ) -NH2, vii) -NH[(C I -C4)-alkyl], viii) -Nl(cl -C4)-alkyl]2, ix) -phenyl, (f) -CONHSO2-(CI-C~)-alkyl, whereill alkyl is unsubstituted or substituted as defined in R4(b), (g i -CONHSO2-heteroaryl, whereill heteroaryl is defined as carbazolyl, furyh thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, o~;azolyl, pyrazolyl, pyrazinyl, pyridyl, pyrim:idyl, purinyl, or quinolinyl, which is unsubstituted or sub.stituted with one, two or three substituents selected from the group consisting of:
i) (C1 -C4)-alkyl, 3 ~ -O-(C l ~C4)-alkyl, iii) -CoNR7Rl I
iv~ F~Cl,Brorl, V) -CooR7, vi) -NR7CoNR7R 1 l, and ~ wo96/0490~ ; 2 t 957S 8 ~IIL~ ' 7 vii) -NR7CooR 11;
(h) -tetrazol-5-yl;

R13 is (Cl-C4)-alkyl; and R16 is H~ (Cl-C6)-alkyl, or (Cl-C6)-all;ylphenyl.

An embodiment of the compoullds of Forrnula I are:

2-1(2~6-dipropyl-4-hydroxymethyl)pilenoxy]-2-(3-methyl!lhenyl)acetic acid;

2-[(2~6-dipropyl-4-hydroxymethyl)pherloxy]-2-(4-pllenoxypllenyl)-acetic acid;
2-[(2,6-dipropyl-4-hydroxymethyl)p}lenoxyl-2-(4-phenylpllenyl)acetic acid;

2-[(2,6-dipropyl-4-hydroxymethyl)phenoxyl-2-(3-carboxyphenyl)acetic 20 acid;
2-[(2,6-dipropyl-4-hydroxymethyl)pllenoxy j-2-(3,4-ethylenedioxy phenyl)acetic acid;

2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4,5-trimethoxy-25 phenyl)acetic acid;

2-~(2,6-dipropyl-4-llydroxymethyl)phenoxy]-2-(3~4-methylelledioxy-phenyl)acetic acid;
30 2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy~-2-(3,4-dimethoxy-phenyl)acetic acid;

2-[ (2~6-dipropyl-4-hydroxymethyl)phenoxy] -2-(3 ~5-dimethoxy-phenyl)acetic acid;

... . . .. . . .

W0 ~6/04905 ~ 9 5 7 5 ~ r~ , 7--2-((2,6-dipropyl-4-tetrazol-5-yl)phenoxy)-2-(3-bromophenyl):lcetic acid ~-1 (2,6-dipropyl-4-hydroxymethyl)phenoxyl -2-(3-bromophenyl ~acetic acid;
2-L(2,6-dipropyl-4-hydroxymethyllphenoxyl-2-~2-napllthyl)acetic acid;

2-[(2,6-dipropyl-4-~2-hydrnx~ethyl)phenoxy~-2-(2-naphthyl~acetic acid;

2-1 (2,6-dipropyl-4-(2-hydroxyethyl)phenoxy]-2-(3,4-1nethylelleclioxy-phenyl)acetic acid;

2-[(2,6-dipropyl-4-(2-hydroxyethyl)phenoxy]-2-(3-methox~phenyl~-15 acetic acid;

2-L(2,6-dipropyl-4~1 .2-dihydroxyethyl)phenoxy)l-2-~-naphthyl).~cetic acid;
2o 2-~(2~6-dipropyl-4-(1-hydroxypentyl)phenoxy]-2-( -naplltllyllacetic acid;

2-1~4-carboxy-2~6-dipropyl)phelloxy~-2-phenylacetic acid;

2-[(4-carboxy-2,6-dipropyl)phenoxyJ-2-(3,4-dichlurophenyl)acetic acid;

2-[(4-carhoxy-2,6-dipropyl)phenoxy]-2-(3-bromophenyl)acetic acid:

2-1(4-carboxy-2~6-dipropyl)phenoxyl-2-~3,4-methylenedioxyphenyl]
30 acetic acid;
2-[i4-carboxy-2,6-dipropyl)phenoxy]-2-(3-methoxyphenyl)acetic acid;

(N-ben~enesulfony 1~-2-[(4-(N -b~n7rnesl 1lfonyl~carboxam:ido-2,6-dipropylphenoxyl-2-(3-bromophellyl)acetamide;

~ W096/0~9US ~ ~ 2 ~ 95758 (N-4-t-butylbenze[lesulfonyl)-2-(4-methoxycarbonyl-2-propylphelloxy)-2-(3~4-methylenedioxyphenyl)acetamide;

5N-(benzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylene,dioxyphenyl),-rel~ltni~P;

N-(4-phenylbenzenesulfonyl)-2-(4-methoxyc.lrbonyl-2-propyl-phenoxy)-2-(3,4-methylenedioxyphenyl)acetamide;

N-(4-chlorobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propyl-phenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

N-(4-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propyl-5phenoxy)-2-(3 ,4-methylenedioxyphenyl~;tcer tmi~iP

N-(5-iso-butylthien-2-ylsulfonyl)-2-(4-methoxycarbonyl -2-propylphenoxy)-2-(3 .4-methylenedioxyphenyl),~ret~mirl,~;

20N-(4-methoxybenzenesulfonyl)-2-(4-methoxycarbcnyl-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

N-(4-dimethylan~ obenzenesulfonyl)-2-(4-methoxycclrbonyl-2-propylpllenoxy)-2-(3 ,4-methylenellioxypllenyl)acetamide;

N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphen) I)~tf et -rni~le;

N-(2-methoxycarbc~l~ylbel~zenesulf nyl)-2-(4-methoxycarbollvl-2-30propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetalnide;

N-(2-chlorobPnzP,IlP~nlfollyl)-2-(4-methoxyc~lrbonyl-2-propylphenoxy)-2-(3,4-metllylenedioxyphenyl),l~et llni(l~, W0 96/04905 ~ 7 !~ 9 5 7 5 3 r ~

N-(3-chloroben~.eneslllt'~ nyl)-2-(4-mett~ ycarb~ yl-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

N-~phenylme,tl-~lnP,slllfonyl)-2-(4-methoxycarbonyl-2-p:ropylphelloxy)-5 2-(3,4-methylenedioxypllenyl~acetarrlide;

N-(dansylsulfonyl)-2-14-methoxycarbonyl-2-propylphenoxy 1-2-(3,4-methylelledioxypllellyl')acetanlide~

N-(8-quinolinesulfonyl)-2-(4-methoxycnrbonyl-2-propylp}lelloxy)-2-(3,4-methylenediox~phenylacetamide;

N -(4-t-butylbenzerlesulfonyl)-2-(4-carboxy-2-propylphelloxy)-2-(3,4-methylenedioxyphenyl)~rel:~mi-~P

N-(benzenesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylelledioxyphenyl)acetLqmide, N -(4-phenylbenzcllesulfonyl)-2-(4-carboxy-2-propylphenoxy~-7-(3 ,4-20 methylenedioxyphenyl)acetamide;

N-~4-chlorobenzenesulfonyl7-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide;

N-(4-methylh~n7!~nP~ fonyl)-2-(4-carboxy-2-propylphenoxy)-2-(374-metilylenedioxyphenyl)a~etamide, N-(5-isobutylthien-2-ylsulfonyl)-2-(4-carboxy-2-propylphenoxy7-2-(3 ,4-methylenedioxyphenyl)acetamide;
3~
N-(4-methoxybenzellesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-( 3 74-methylenedioxyphenyl)~lcet~mi~P;

N-(4 -dimethylaminobe:nzenesulfonyl)-2-(4-carboxy-2-propylphenoxyJ-3 ,4-methylene.dioxyphenyl)acetamide;

~ W0 96/04905 ' ; r~ . 67 2t,~575~

N-(2-meth~ Ibcll~cllcsulfonyl)-2-(4-carboxy-2-propylphelloxy)-2-(3,4-met:hylenedillxyphenyl).lcetamide;

N-(2-methoxycarbonylbenzenesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxypllenyl)acetamide;

N-(2-chlorobc.lzcl.esulfonyl)-2-(4-carboxy-2-propylphelloxy)-2-(3,4-methylenedioxyphenyl)acetamide;
N-(3-chlorobenzenesulfonyl)-2-(4-carboxy-2-propylphenc)xy)-2-(3 ,4-methylenedioxyphellyl)acetamide;

N-(phenylmethanesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

N-(dansyl~ulfonyl)-2-(4-carboxy-2-propylphenoxy)-3,4-methylene-dioxyphenyl)acetamide;
N-(~-quinolinesulfonyl ~-2-(4-carhoxy-2-propylphenoxy )-2-(3 ,4-methylenedioxyphenyklcetamide;

N-(~-quinolinesull'(myl)-2-(4-carboxamidc)-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide;

a-(4-carbomethoxy-2-n-propylphenoxy)-3,4-methylenedioxy-phenylacetic acid;

N-(4-iso-propylbenzenesulfollyl)-a-(4-carbomethoxy-2-/l-propyl-phenoxy)-3~4-methylenedioxyphellylacetamide;

N-(4-i.~o-propylbenzenesLIlfonyl)-a-(4-carboxy-2-n-propylphen(lxy)-3,4-methylenedioxyphenylacetamide dipotassium salt;

- 2~9575û
W0 96/04905 r ~ u., a~,57--a-(2-iso-butyl-4-carbomethoxyphenox!, )-3~4-methylenedioxy-phenylacetic acid;

/\'-(4-iso-propylbenzenesulforlyl}-a-(2-iso-butyl-4-carbomethoxy-5 phenoxy)-3,4-methylenedioxyphenylacetamide;

/~,'-(4-i.s~o-propylbell7en~sll1fo1lyl)-a-(2-iso-butyl-4-carboxypheno.Yy)-3,4-methylenedioxyphe,nyklcet,lmide;

~ N-(4-iso-propylbenzenesulfonyl~-a-~2-/t-propyl-4-methoxycarbonyl-phenoxy)-a-met~lyl-3~4-rlletllylenedioxyphellyl ~ret/mli~ir.;

N-(4-is(~-propylbrn7~nf~slilfonyl)-a-(2-n-propyl-4-carboxyphenoxy)-a-rmethyl-3~4-metllylenedioxyphenyl~retslmi-lr dipotassium salt;

(4-i~o-propylb~n7l~nt~lllfonyl~-a-(2-n-prop~l-4-carhoxamid phenoxy)-3.4-methylenedioxyphe.nylacet;lmide;

IV-(4-lso-propylber~enesulfonyl~-a-(2-ll-propyl-4-hydroxymethyl-20 pllenoxy)-3,4-meth~ enedioxyphenyl~ t:~mi(l~, N-(4-isd-propylken7PnP~Il If onyl)-a-(4-forrnyl-~-n-propylphenoxy)-3,4-methylenedioxyphenyl~ret~mide, 25 a-(4-acetyl-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetic acid;

N-(4-isv-propylbenzenesulfonyl~-oc-(4-acetyl-2-/l-propylphenoxy ~-3 ,4-methyleneclioxyphenyl:~retslmitlr~;

3~ a-(2-n-propylphenoxy)-3,4-methylenedioxyphenylacetic acid N-(4-iso-propyJben7rnrs-llfonyl)-a-(2-n-propylphenoxy)-3,4-n~etllylelledioxypheny]acetamide;

~ wog~gos ~ 2~9~758 ~ .r..; 7 (3-methoxyphenoxy)-3,4-methylenedioxyphenylacetic acid:
a-(2-(2-hydroxyethyl)phenoxy)-3,4-methylenedioxyphenylacetic acid;

5 a,-(2-(2-carbomethoxyethyl)phenoxy)-3,4-methylenedioxyphenylacetic acid;

a -(4-hydroxymethyl-2-n-propylphenoxy)-3 ~4-methylenedioxyphenyl-acetic acid;

a-(4-(2-hydroxyethyl )-2-n-propylpllelloxy)-3 ,4-methylenedioxyphenyl -acetic acid;

N-(4-i,so-propylbenzenesulfonyl)-a.-(2-(2-carbomethoxyethyl)phenoxy)-3,4-rmethylenedioxyphenyl ~ret,lmi~l.o;

N-(4-isv-propylbenzenesulfonyl)-a-(2-(2-carboxyethyl)phenoxy)-3 .4-methylenedic~xyphenylacet~mide;

20 o-(2-(2-carboxyetllyl)phenoxy)-3,4-methylelledioxyphenylacetic acid;

N-(4-isO-propylbenzenesulfonyl)-2-(4-carbomethoxy-2-n-propyl-phenoxy)-2-(5-methoxy-3,4-methylenedioxyphenyl)~cet~mi~;

25 N-(4-isO-propylbenzenesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(5-methoxy-3 ,4-methylenedioxypllellyl)acetalllide;

N-(4-is0-propylbenzenesult'onyl)-2-(4-(N-(4-isv-propylbel~ene-sulfonyl)carboxamido)-2-propylphenoxy)-2-(5-methoxy-3,4-1nethylene-3~) dioxyphenyl)acetamide;

N-(4-iso-propylbenzenesull'onyl)-2-(4-carboxamido-2-propylphenoxy)-2-(5 -methoxy-3,4-methylenedioxyphenyl)acetamide;

~: ~ ? ~ ~ ~ O ~ --WO 96/04905 ~ 7 7 5 8 . ~ ~ " . ~

N-(4-iso-propylbenzenesulfonyl~-2-(4-(N-methylcarbox~nido)-2-propylphe,noxy)-2-(5-methclxy-3 ,4-methylenedioxyphenyl~ace.~slmi~

N-(4-iso-propylbenzellesulfonyl)-2-~4-(N-2-hydroxyethylcarhl)x.~ ido)-2-propvlplle:noxy~-2-(5-methoxy-3.4-methylelledioxyphenyl)acetan1ide;

N-(4-iso-propylb ~n7e.n~sll1fonyl~-2-(4-(N-morpholinylcarhclxam jdo)-2 propylphenoxy)-2-(5-methoxy-3,4-methylenedioxyphenyl)acetamide;

N-(4-i.so-propylben7enesulfonyl)-2-(4-(N-3-methylbutylc.lrbo.~amido)-2-propylphenoxy~-2-(5-methoxy-3 ,4-methylenedioxyphenyl)acelarl-ide:

:N-(4-i.so-propyl:benzenesulfonyl)-2-~4-(N-carboxymethylcarboxamido)-2-propylphenoxy)-2-(5-1llethoxy-3 ,4-methylenedioAYyphellyl)acetamide;

N-(4-iso-propyl~en7f,n~ l1fonyl)-2-(4-~N-(L-Ala-OEt)carboxamido)-2-propylphenoxy~-2-(~i-methoxy-3,4-methylenedioxyphenyl)ac.etamide;

N -(4-i.~o-propylbenzenesulfonyl)-2-~4-(N-2-ethoxycarbonylethyl-carboxamido)-2-propylphenoxy~-2-(5-methoxy-3,4-methylelledioxy-phenyl )acetamide;

N-(4-isv-propylbenzenesulfonyl)-2-(4-(N-~L-Ala)carbox.lmido)-2-propylphenoxy)-2-(5-methoxy-3.4-methylenedioxypllenyl )acetamide:

N-(4-iso-propylbenzenesulfonyl)-2-~4-(N-2-carboxyethylcarboxamido)-2-propylphenoxy)-2-(5-methoxy-3 ,4-methylenedivxyphenyl)acet~lnli(le:

N-(4-isv-propylbPn7.~n~sll1fonyl)-2-(4-(N-3-hydroxyprclpyl-3~ carb{)x~ id{))-2-propylphenoxy)-2-(5-metho~xy-3.4-methylenedioxy-phenyl)a cetamide;

~ W096/04905 ~ 219~75~3 r~ .J.,S/~ ~

- N-(4-iso-propylbenzenesulfonyl)-2-(4-(N-t:etra7.ol-S-ylcarbox,lmido)-2-propylphenoxy)-2-(5-metho~y-3,4-methylenedioxyphellyl)acetamide;

N-(4-iso-propylben7.l~nP.slllfonyl)-2-(4-(N-3-(morpholin-4-yl)propyl-carboxamido)-2-propylphenoxy)-2-(5-metlloxy-3.4-1llethylenedioxy-phenyl)acetamide;

N-(4-i.so-propylbenzenesulfonyl)-2-(4-~N-(D-Ala-O~Ie)carboxamido)-2-propylphenoxy)-2-(5 -methoxy-3 .4-methylenedioxyphenyl).lcetamide;

N-(4-isf.~-propylbenzenesulfonyl)-2-(4-(N-(D-Ala)carboxamido)-2-propylphenoxy)-2-(5 -methoxy-3 ,4-methylened ioxyphenyl)acetamide;

N-(4-iso-propylbenzenesulfonyl)-2-(4-(N-(3-carboxymetllylpropyl)-CarbOX.lmidO)-2-prOpylphenOXy)-2-(5-nlettlOXy-3~4-methylenedi phenyl)acetamide;

N-(4-i.so-propylbenzerlesuli'onyl)-2-(4-(N-(3-carboxypropyl)-carboxamido)-2-7t-propylphenoxy)-2-15-methoxy-3 .4-methylenedioxy-phellyl)acetarllide;

N-(4-isz~-propylbenzenesulfonyl)-2-(4-(N-iso-propylcarballloyl).lmillo-2-n-propylphenoxy)-2-(3~4-nletbylenedioxypilenyl)a(~e~mir1 a-(2-)1-prOpyl-4-nlethylanlillOSUlfOllylphenoxy)-374-methylenedi phenylacetic acid;

N-(4-iso-propylbenzenesuli'onyl)-a-(2-n-propyl-4-methylamino-suli'onylphenoxy)-3,4-methylenedioxyphenylacetamide pc tassium salt;
3~
N-(4-iso-propylbellzenesulf onyl)-~-[4-('cyanomethyl)-2-/1-propylphenoxy)~l-3 ,4-methylenedioxyphenylacetamide,;

N-(4-i.so-propylbPn7.~.nPslllfonyl)-cY.-[4-(tetrllz.ol-5-ylmethyl)-2-n-propylphenoxy)]-3 ,4-methyle,nedioxyphenylacetamide;

~1957 Wo g6/0490s ~ r ~- 5 ~ u~

N-(4-i.fo-propylben~enesulfollyl)~ N-(4-carbomethoxyphenylamillo)l-3 ,4-methylenedioxyphenylacet:amide;

5 N-(4-i.so-propyl'ben~enesulfonyl)-G~-[N-(4-carboxyp}lenylclmillt))]-3,4-methyle.nedioxyphenylllcP~:Imi~1P;
N -(3-pyridi:nesul~onyl)-2-(4-carboxy-~-propylphenoxy)-2-(3 .4-methylenedioxypllenyl)acetatmide.;

N-(2-metllyl-3-quinolineslllfc~nyl)-2-(4-carboxy-2-propylphelloxy)-2-(3 74-methylenedioxyphenyl)acet:amide;

N-(3 -quinoline~ulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-15 methylenedioxyphenyl)~( et~mi~

N-~4-bydro~;y-~ pyridinesulfonyl)-2-(4-cLIrboxy-2-plopylphetloxy)-2-(3,4-tnetllylelledioxyphenyl)acetamide;

20 N-(4-ethoxybPn7~l-Pslllfonyl)-2-(4-carboxy-'~-propylpllel:loxy)-2-l3,4-methylenedioxyp}lenyl~ Pf:,mirl~;

N -(4-carboxamidobenzenesulfonyl)-2-(4-carboxy-2-propylpheIloxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

5 N-14-(N,:N-dilrletllylcarboxamido)benzenesulfollyl]-2-(4-carboxy-2-propylphenoxy3-2-(3 .4-methylenedioxyphenyl,l~cet~mifl.o;

N-(4-ethyltlli~:~-3-pyridinesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-13 ,4-methylenedioxypllenyl)acetamide:
N-(4-ethoxy-3-pyrid:inesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl~acetarnide;

N-1 (4-amino-2,5-dimethoxy)ben~.enesulf'ollyl]-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl)acetLImide;

21 9~75~
W0 96/04905 ' ~ ; F~ JO7~ ~1S~S7 - 61 ~

N-[(2.5-dimethoxy)benzenesulfonyl] -2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide;

N-[(3,4-dimethoxy)benzenesulfonyl]-2-(4-carboxy-2-propylphenoxy)-2-(3 .4-methylenedioxyphenyl)acetamide;

N-[2-1'5-(morpholin-4-yl)benzothiophene]sulfonyl]-2-(4-carboxy-2-propylphenoxy)-2-(3 .4-methylened ioxyphenyl )acetamide;
1~
N-[[2-(4-methoxy)benzothiophenel.sult'ollyl]-2-(4-carboxy-2-propylphenoxy)-2-(3?4-methylenediox~phenyl)"~et,lmirl~:

N-[4-[2-(benzyloxycarbonylamino)ethyl]benzenesulfonyl ] -2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxyphellyl)acetamide;

N-[12,5-dimethoxy-4-((N-i.~o-propylcarbamoyl)amirlo)]benzene-sulfonyl] -2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxy-phenyl)acetamide, N-1~(2.4-dimethoxy)benzene.sulfonyl]-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphellyl)acetami(ie;

N-[(2,4,6-trimethoxy)benzenesulf(myl l-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxyphenyl )acetamide;
N-(8-~uinolinesulfonyl)-2-(4-carboxy-2-propylphelloxy)-2-(3,4-methylenedioxyphenyl~acetamide;

N-(3-quinolinesulfonyl)-2-(4-carboxy-2-propyll)helloxy)-2-(3.4-3 ~ methylenedioxyphenyl)acetamide;

N-(8-4uinolinesulfonyl)-2-(4-carboxamido-2-propylphenoxy)-2-(5-methoxy-3,4-n~ethylenedioxyphenyl): ce~mi~

WO 96/04905 2 ~ 9 5 7 5 ~

N-(4-rerf-hutylb~nzenesulfonyl)-2-~4-carboxamido-2-1-ropylp}lello~y)-2-(5-methoxy-374-methylenediox!,phenyl)acetamide;

N-(4-amino-2,5-dimetho~yl enz~.lesulfonyl3-2-(4-carboxamido-2-propylphenoxy 1-2-(~-methoxy-3,4-methylenediox$~phellyl)acetamide:

N-[4-r.sci-propylhen7P,nf~.slllfonyl]-2-(4-carboxy-2-propylphenoxy)-2-(3 ~4-methylenedioxyphenyl)acelamide;

N-(4-iso-propylber~ nP.~Illfonyl)-2-[l4-[N-[2-(c~arbethox$')ethyl 1-carbamoyll~-2-propylphenoxy]-2-(3.4-methylenedioxypi~ellyl)acetamide, N-(4-iso-propylbe:nzeneslllfollyl)-2-[ L4-[N-(2-ca:rboxyethyl )carbamoyl] 1-2-propylphenoxy] -2-(3 ,4-methylenedioxyptlenyl)acet.tlnide;

N-(4-iso-propylbenzenesulfonyl)-2-[[4-[N-(2-carbamoylethyl~-carbamoyll j-2-prop$~1phenoxyI-2-t3,4-methylenedioxyphenyl)acetamide;

N-(4-;s~)-propylbell7,ellesulfonyl3-2-[4-lN-(2,2,2-trifluoroethyl)-20 carbamoyl]-2-pr~ 1~ylphe~ y~-2-(3~4-methyletledioxyl~tle~ acetalllide;

A perferred embodiment of the compounds of this in~ention are:
25 N-(4-isO-prOpylbelll:elleSUlfOllyl)-o(-(4-carboxy-2-n-prop~rlphenoxy)-3,4-methylenedioxyphe:nylacetamide dipotassium salt;

N -(~-quinolinesulfc~rlyl~-2-(4-carboxy-2-propylphenoxy)-2-(3 ,4-methylenedioxy~ phenyl)acetamicle;

N-(4-dimethylaminobenzenesulfonyl~-2-~4-carboxy-2-n-p}opyl-phenoxy)-2-(3 ,4-methylenedioxyphenyl)acetamide .

~ ~ 219~758 ~ WO 96/0490~ J5,_7 The alkyl substituents recited above denote straight and branched chain hydrocarbon.s of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl-substituents denote al~yl groups as 5 described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes rings Goml70sed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon sub.stituents. and include for e~ample cyclopropyl, o cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
The heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, o~azolyl, 5 pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
Although the reaction schemes described below are reasonably general, it will be understood by those .skilled in the art of organic synthesis that one or more functional groups present in a given compound of FormuLI I may render the molecule 2Q incompatible ~vith a particular synthetic sequence. ln such a case an alternative synthetic route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagellts, solvent, U~Id~ and time, should be chosen so that tlley are consistent 25 witll the nature of the functionality present in the molecule.
The compounds of Formula I and specifically compounds c f Formula III can be synthesized using the reactions and techniques de.scribed t'or the synthesis of the non-heterocyclic components in the patent application W091/11999 ~Merck & Co.;
30 published on August 22,1991 under the Patent Cooperation Treaty), US Patent 5,177.095 (Merck & Co.; January 5, 1993), and also US
Patent 5,240,938 (Merck & Co.: August 31, 1993).
The reaction .schemes desclibed below have been generalized for simplicity. It is further to be understood that in the 2 1 ~ 5 7 ~ 8 generalized schemes below, unless specified more narrowly in the text~ the alkyl and aryl groups rrpresent unfamctionalized or functionalized derivatives as described before. The leaving group Q
present in lhe alkyiating agents is either chloro, bromo, iodc), 5 methanesulfonate, p-toluenesulfonate or triflate.
Scheme I

~S Q R9--~, Rto R9-- _ R10 + 1 zl Base.

XH Ar ~r ~r Ar = R -~--R1 R3b_~ or ~,~,~ R12 R3a R2 R a ~ Rl3--~ Rl~

2 5 R3b_ ~3a X~ Z
Q = Cl, Br, 1, OMs, OTs or OTf Ar ~, Y or Vl Zl = a precursor IO Z

;. 2 1 q J 7 ~ ~
WO 9~/04'70S P~, I Iv~., '0~ _ /

More specifically, the compounds of Formula 111, V or ~,'1 (where X is oxygen. sulphur or appropriately substituted nitrogen) Catl be synthesized as outlined in Scheme I . The substituted compound 1 may be reacted with the alkylating agent ~ in an d~ riate solvent 5 such ~1S alcohols (methanoh ethanol, isopropanol and liice), dimethylformamide ~DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) ~md acetone in the presence of an alkali metal salt such as alkoxides. carbonates, hydroxides and hydrides, or organic bases such as trialkylamines or alk;yl lithiums to provide comp(7und ~.
The zl group present in compound 3 may then be further transt'ormed to provide the appropriate compounds of Fonnula 111, ~/' or Vl.
In general, the alicylating agent ,~ can be prepared using methods and fP-hni(lllPs outlined in US Patent 5,177.09~. More specifically, compound 2 (where Zl is COOR and Q is Br) can be syntilesized from the substituted arylacetic acids 4 as outlined in Scheme The substituted arylacetic acid 4 is com~erted to the correspollding ester either by refluxing the acid in an appropliate alcohol in the presence of ~1 catalytic amount of conc. sulfuric acid, or using other conventional methods of esterificatiotl. 'I'he resulting ester is then 20 refluxed in carbon tetrachloride ~vith N-bromosuccinimide and a catalytic amount of a radical initiator (e.g., AII3N or ben7,0yll7eroxide~
to provide the 2-bromo-arylacetic acid ester ~.

Sclleme 2 1. ROH, H~ Br 2. NBS, AIBN
Ar/~COOH CC4 > Ar COOR

- Alternatively, the ester ~ may alsc be prepared from appropriate aryl aldehydes (Scheme 3). T-he aldehyde 6 can be reacted with trimethylsilyl cy~mide and catalytic amounts of KCN and 18-crown-6 to provide the corresponding trimethylsilyl cyanohydrin 7, i i 2 1 ~5~58 1~ 7--which upon further treatment with the gaseous llCl and alcotlol affords the, 2-hydroxy e~ster 3~. The ester 8 is treated with triphenylphc~spllirle and carbon tetrabrorllide in methylene chloride to give the 2-bromoarylacetate derivatives 5 .

Scheme 3 a OTMS b OH c Br Ar--CHO 1 1 1 0 Ar CNAr COOEt Ar COOEt a. TMSCN, Clat. KCN, CH2CI~, IS-Crown-6; b. HCl(g), F,tOH, 5 c. CBr4, Ph3P, CH2cl2 Scheme 4 illustrate~ a typical synthesi~ of an alk~lating agent ~ where Ar ,~ ,..t~ a heterocycle SUCtl as ~all indole). The appropriately su~stituted cyanoindole ~ (for ~ gener.ll ~ynthesis of 20 suh~tituted indoles refer to, R. K. Brown, Indole~u Part Orle. Ed. W. J.
Houli}~an~ ~fol. ?57 Chapter Il~ ~iley-lnterscience, New York. 1972) is reduced witll DIBAL-I I to provide the corresponding aldetlyde, whictl i~
then converte,d into the N-Boc derivative l~ . Reaction of l0 with the trichlorometllide anion Igenerated from KOH and CHCl3: J. ~1. Wyvratt 25 et. al., J. Org. Chem.. ~, 944-94S ~l9~7)~1 followed hy t,reatmellt with aqueous NaOH ;n D~F provides the alcohol LL Treatment of ~, with diazomethane followed by the reaction with CBr4/Ph3P yields the alkylating agent 12.

wo 96/0490~ 2 1 ~ ~ 7 5 ~ P~,lrL ,~7 Scheme 4 R3b R3b ~CN a ¢~,~3~CHO b N N
H R3a ' R3a 2 Boc R3b OH R3b Br ~\~COOH c <~-\~COOMe N~\ 3 NJ~\R3a Boc 11 Boc a. (i~ DIBALH, Toluene; (ii) Boc2O, DMAP, CH2CI2 b. (i) CHCb, KOH, DMF, 0~C; (ii) NaOH, DME / H2O
c. (il CH2N2; (ii) CBr4/Ph3P. CH2CI2 A t~pical .synthe.sis of alkylatin~ agents bearing a substituted 20 benzoxazole or b~n7thi~7l)1e ring is outlined in Scheme 5. The substituted benzoxazole 14 is prepared from the corresponding o-aminophellol 13 by the reaction of an appropriate orthoester under refluxing conditions (for other methods of synthesis of benzoxazoles see, S. A. Lang and Y. Lin, Comprehensive lleterocyclic Chemistry, 2s Vol. G, 1-130, Ed. C. \~'. Rees; and references cited therein). Reduction of 14 with NaBH4 provides the alcohol 15 which is then subjected to pyridinium dichromate (PDC) oxidation to yield the corlesponding aldehyde 16. Further elaboration of 16 as outlined provides the key intermediate 17. Similarly~ the benzothia7.01e 19 can also be prepared 30 form the appropriately substituted o-amincthiophenol 18.

W0 96104905 ' ~ . 2 1 9 ~; 7 5 ~ r~In . n )s.. ~--R3b R3b NH2 ~ ,COOH < ~
H O ~ \ 3~ R3a R3b </ ~,~ C <~

N~-,\s~GOOMe a. C H(O Et~3. EtO H.reflux < ~ ~
~. (i) ClC O OEt, Et3N, THF;~ii) NaBH4, THF-H2 ~ ~R3a c. Pyridiniurn dichrom ate, C H2C12 17 d. (i) C H Cl3, KO H, D M F,0~C;(ii) NaO H, D M E / H20:
(iii1 H Cli MeO H;(iv~ C Br~P~3P, C H2C12 R3b R3b Br NH2 ~\~COOH <N ~ COOll,Ae H S ~ \R3a S R~a 18 1~2 ~ ~; 2 ~ W0 96/04905 ~ 9 5 7 5 g r~

Scheme 6 illustrates the synthesis of benzofuran and dihydrobenzofuran alkylating agents ~ and 2~. The benzofuran ~.L can be prepared from the (x-phenoxy carbonyl compound 20 via a ring closure reaction [Stoermer and Wehtn, Chem. Ber., 35, 3549 (190~) 5 (for general methods of synthesis of benzofurans and dihyd-u~ ufuld~ls see, R. C. Elderfield and V. B. Meyer, Heterocyclic Compounds. Vol. 2, Chapter 1, Ed. R. C. Elderfield. Wiley; and references cited therein). The ester ~ is reduced to provide the aldehyde 22 which is then transfonned into the corresponding alkylating agent 23. The dihydrobenzofurall ester 2~, obtained by catalytic reduction of 21, can also be tr~msfomled into the corresponding atkylating agelIt 2~ using the sequence of reactions outlined in Scheme 6.
Benzothiophene ~ may be s~nthesized from the 5 corresponding aldehyde ~ in a manner similar to that outlined in Scheme 6 for benzofuran ~. Benzothiophene ~k can be prepared by the oxidative cyclization (using an alkaline solution of potassium ferricyanide) of a~l,.u~-ialely substituted o-mercaptocinnamic acid ~~~
~C. Ctlmelewsliy and P. Friedlander, Chem. Ber., 46, 1903 (1913)1.
20 (For general methods of synthesis of benzothiophene, ~ E.
Champaigne in Comprehensive Heterocyclic Chemistry. vol. 4~ Chapter 3-]5~ Eds. A. Katritzky and C.W. Rees.) Scheme 7 outlines a typical synthesis of oc-bromoaryl-acetates, 30 and 32,bearing appropriately substituted methylenedioxy or 25 1~4-dioxane rings. The substituted catechol derivative ~ is treated with ~m appropriate dibromide (wllere m is I or 2) in the presence of cesium carbonate in dimethyli'ormamide to provide 28. Treatment of 28 witl DIBALH yields the aldehyde ~2 which is then transformed into the desired alkyl bromide as described.

2 ~ 9 ' 75 8 W0 96/~490~ 7 Scheme 6 (EtO~2HC~0~,,;3~COOMe R3a 20 a o R COOMer~ R3b ~'~R3a R3a S ¦ d R3b I c Br o R~COOMe ~,~ COOMe R3a R3a 2;~
2~
¦ b,c a. ZnCi2 b. DIBALH, toluene Br c. (i) CHCI3, KOH, DMF, 0~C;
R3b 1 (li) NaOH, DME / H20, \s~COOMe ~iii) HCI / MeOH;
\~l ~J j~ (Iv) CBr4~h3P. CH~C12;
R3a d. Ra-NI I H2 R3b ~ COOMe R3b Br HOOC~R ~6~3~L

f t 8 ~ Wo s6/04905 ~ ~ ~ 9 ~:) 7 ~ P~ 7 Scheme 7 R3b 0 R3b COOM
a (CH2~mJ~"J b R3b (CH2)m~f ~
~0~\ 3a Ic p R3bCH2COOMe R3b Br 15(CH2)m~f ~ d O~,\s~COOMe ~ R3a oJ~\R3a 31 ~Q
a. Br-(CH2)m-Br, Cs2CO3, DMF
b. DIBALH, toluene c. (i) CHC13~ KOH. DMF, O~C; (ii) NaOH, DME I H20;
(iii) HCI / MeOH; (iv) CBr4/Ph3P, CH2C12;
d. NBS, AIBN, CC14 Br X ~r ~COOMe R12 0~\R3a 32 W096~04905 ~ 9 5 ~5~ 7--Fcolk~ing the synthetic route outlined in Scheme ~ below N-(4-iso-propylhPn~PnPslllfollyl)-a-(4-carhoxy-2-n-propylphenoxy~-3,4-methylenedioxyphenylacetamide dipotassium salt, 4~ i.s prepared.

Scheme 8 Methyl 4-hydroxy-3-1,1u~)yllJe-~ùal~. 36:

Br~ ~ 1 60-5~C
~/ K2CO3, acetone ~ ~,CI

OH reflux 0 ~ W'CI
33 3~

CO2CH3 co2CH3 1~1 H2,PdiC
MeOH
OH OH
~5 36 ~ W0 96104905 ~ 7 5 ~ u~ . ~

Ethyl a-bromo-3,4-methylenedioxyphenylacetate, 39:

OH
5 <o~CHO 1)TMSCN <O ~CO2C2Hs O 2) EtOH o 38 10PBr3, Et20, <~~CO2C2Hs 3g 4-is~l-propylbenzenesull'onate, 41:

SO2CI ~, SO2NH2 ~ NH~OH
H3C~ ' H3C~/ \~

WO 9v/~v~4905 ~ 5 7 5 ~ l/L~

N-~4-iso-propyll~ ,..1lfonyl)-a-(4-carboxy-2-n-propyl-phenoxy)-3.4-methylenedioxypherlylacetamide dipotassium salt. 45:

H3CO2C~ <O~CO2CH2CH3 aC2et~ e oJ~ref~ux H3CO2C~¢~ H3CC~2C~

N~OH.
15~f CO2C2Hs ~1eOH~,~~~3--CO2H

H3CO2C~ ~ CH3 20cr)l. DBU. THF ~oK+ ~CH3 Ctl3<~ ~Jb- N~S ~J
~CH3 O~ ~ ~ ~

H2N~S~ 41 O O 44Crystalline K 02C ~¢~[~~ CH3 I) NaOH, MeOI~, ~ K~ ~CH3 O /~
2) KO~I < ~ 1I S~

CrYstalline, pK Il = 5.4, pK~ .8, MW = 615.~, logP 2.7, Aqueou.s solubilitv > 1;0 mg/mL

21 ~75~
~ W0 91;104905 . ..... , , Similarly, compounds of Fomlula IV wherein -A- is represented by -OCH2- and X is ~ d by -NH- can be prel~ared using the route described below ~ ~ } ~ 1 ~7~&
WOg6/04g05 . ~,9JI J r.l.

N-(4-iso-propylben~;enesulfonyl~ -[N-(4-carboxyanilinyl) 1-3,4-methylenedioxyphenyl~(~et:lmi~ dipotassillm salt, 50:

Br S H3CO2C~3~ + < ~ X5~C
46 ~AIdrich) 39 H3CO2C~'NH H3C02C~3'NH
KOH ~ I
<~ ~3--CO2C2H5 MeOH' ~~ ~ CO2H

H3CO2C~ CH3 DMAP. EDC~ ~ , NH ~, ~CH3 - CH3 o~,l~, 2 S~ ~CH3 <o~J ~ ~ ~

HO2C ~3~ '~H3 I) KOH. I leOH , I H
reflux <~~~ "S~
o~ ~

, ,,,:,3< ~9 7 ~
~ ~0 96~0490~ J ~ .,u~ .9,67 HO~\/ CH3 H l~CH3 o~ N ~S ~J

¦ PBr3/Et20/0~C

0 Br/\~/ CH3 ~ H ~ CH3 < ~ ~,5~' ¦ KCN/DMSO
I room temperature NC ~¢~/ CH3 H ~CH3 o~ N 'S~) (cH3)3snN3 Toluene,120~C

N,N~ CH3 - H O ~ C
3Q I H l ll H3 o~ N 'S J~

W09610490~ ~ 2 ~ 95;~58 1~ 7--Scheme 8 illustrates the, synthetic route to cc~mpoullds bearing N-acylsulfamides (~) (Z=-CONHS02NH-R). The c.lrboxylic acid 33 tZI=-C~OOH: Scheme I ) is reacted with 1,1'-carbonyl-liimi-1~7c-1e (CDI) to provide the acylimidazole which is thell 5 reacted with an appropriate sulfamide (~L) in the prexeuce c~f DBU. 'I'he sulfamides (R-NI-ISO2N112) can be prepared from ~ .,u~ primary amilles using the literature procedures [W. L. Matie,r~ ~hh T. Comer and D. Deitchman, J. Med. Chem.. 15, 538-~;41(1972); J. D. Calt and W. 1,.
Maiter, J. Or~. Chelll.. 3c3, 566-568(19~4)l.

Scheme ~

R9--~ R1o 1)Cd~ y'" ~ ul~ R9 ~ 0 2) R-NHSO2NH2 (34), DBU ~
X~,COOH X~CONHSO2NH-R
Ar Ar 2~

~ W0 96/04905 ' ~ 2 J 9 5 7 5 ~ P~

The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the tran.sformatiorl being eft'ected. It is under.stood by those skilied in the art of organic synthesis that the functionality present on the heterocycle and in the reactants being employed should be consistent with the chemical transformations being conducted. L)epending upon the reactions and techni4ues employed, optimal yields may require changing the order of synthetic steps or use of protecth1g groups follo~ved by deprotection.
The compounds useful in the novel method treatment of this invention forl11 salts with various inorganic and organic acids and ba.ses whictl are .tlso withirl the scope of the invel1tion. Such salts include ammonium salts, alkali metal salts like sodium and potassium .salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic base.s; e.g., dicyclohexylamine .salts, N-rnethyl-D-ghlcamine salts, salts with amino acids like arginine~ Iysine, and the like.
Also, salt.s with organic and inorganic acids may be prepared; e.g.~ HCI, I lBr, i-12SO4, H3PO4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
The salts can be fonned by convel1tion.tl means, such as by reacting the free acid or free ba~e forms oi' the product with one or more equivalel1ts of the ;~ u~liale base or acid in a .solvent or medium in which the salt is iusoluble, or in a solvel1t such as water wtlicrl is then removed i~l uaclu~ or by freeze-drying or by exch~nging the cations of an existing salt for another cation on a suitable ion exchange resin.
It will be ;~ .;ial~d that the compounds of general Formula I in this invelltiol1 may be derivatised at functional group.s to provide prodrug derivatives which are capable of conversion b~ck to the parent compounds i~ vi~o. The concept of prodrug administration has been extensively reviewed (e.g. A.A. Sinkula h1 Annual Reports in Medicil1al Chemistry. Vol 10, K.V. Heinzelman, Ed., Academic Press, New York London, 1975, Ch. 31, pp- 306-326, H. Ferres, Dmgs of TodaY, Vol 19, 499-538 (1983) .md J. Med. Chem.~ 18, 172 (1975)).
Examples of such prodnugs include the physiologically acceptable and metabolically labile ester deriv.ttives~ such as lower alkyl (e.g. methyl Wo 9h/~l4gl~5 :~ ~ ; 2 . 9 5 7 5 8 F.~

or ethyl e.sters), aryl (e.g. ~-indanyl esters~. alkenyl (e.g. vinyl ester.s), alkoxyalkyl (e.g. methoxymethyl esters), alkylthioalkyl ~e.g.
methylthiomethyl esters~, alkanoyloxyaLkyl (e.g. pivaloyloxymetllyl esters), and sub.stituted or lln.illh~tihl~d aminoethyl esters (e.g. 2-dimethyl:~mino~thyl esters). Additionally, any physiologically acceptable equivalent.s of the compounds of general Formula 1, similar to the metabolically labile esters, which are capable of produchlg the paretlt compclullcls of general Fonnula I in vil!o, are within the scope clf this invention.
It will be t'urther appreciated that the majority of compounds of general Formula I claimed herein are a.syrrmletlic and are produced as racemic mixtures of enalltiomer~s and that bc~th the racenlic compo~mds and the resolved indivi(lual enantiomers are considered to be witllirl the scope of this invention. The racemic compounds of this invelltion may be resolved to pro-dde individual enantiomers utilizing methods known to those skilled in the art of organic synthesis. For example, diastereoisonleric salts, e.sters or imides may be obtained from a racemic compound of general Formula I and a suitable optically active amine, amino acid, alcohol or the like. The dia.stereoisomeric .salts, ester.s or imides are separated and purified, the optically active enantiomers are regenerated and the preferred enantiolller is the rmore pc~tellt isomer. ~'he resolved en~ln~ m~rs c f the coml-ounds of general Formula 1, their ph~rmSIrellrir,llly acceptable salts and their prodrug forms are also included within the scope of this invention.
2s Endothelin (ET-I~, and two closely related bioactive peptides, E~7'-2 ~und E'I'-3, are widely distributed in mSImm~ n tissues.
and they can induce numerous biologioal respon.ses in non-vascular as well as vascular tissues by bindnng to at least two distinct endothelhl receptor subtypes. In addition to cardiovascular smooth muscle, neural 30 and atrial sites~ endothelin receptors may also be iiound in brain, gastroilltestinal, kidney, Iung, urogenital, uteral and placental tissues.
Endothelin is a potent ~asoconstrictor peptide and thus prays a role in vivo in arterial pressure-volume homeostasis. Not only peripheral, bul c-oronary vascular resistance as well, is increased by _ . . . . . . . . . . . . .. . . . ...

~ W0 96/04905 , ~ 9 ~ 7 5 ~ r~ ,3~s7 .

endotheiin; cardiac output is decreased, while plasrna renin activity i.s increased. There is a reduction in renal blood flow and glomerular filtration rate, while levels of atrial natriuretic factor, vasopressin! and aldosterone become elevated.
It is also considered, in accordance with the present invention, that antagoni.st.s for the endothelin receptor may be useful in preventing or reducing restenosis subsequent to denudation following angioplasty. Such denudation results in myointimal thickening following angioplasty~ due to increased endothelin release. Endothelin o acts as a growth factor with respect to smooth muscle and fibroblastic cells, and possibly other types of cells, as well.
F,ndothelin is also a neuropeptide, acting on the posterior pituitary, where it modulates the release of the neurosecretory hormones vasopressin and oxytocin. Endothelin released from the posterior pituitary al.so acts as a circulating hormone, ha~ing a wide range of actions as discussed further above. This includes effects on the endocrine system, especially the adrenal glands. Endothelin increases plasma levels c f epinephrine.
Consequently, the novel compounds of the present invention, which are receptor antagonists of endothelin, have therapeutic usefulness in preventing, decreasing or modulatillg the various physiological effects of endothelin discus.sed above, bv wholly or partially blocking access of endothelin to its receptor.
Endothelin Receptor Bindin~ Assays The binding of the novel compounds of this invention tv the endotllelin receptor was detertnined in accord~unce with the assay describecl in detail immef~ tt~ly below. It is similar to the assay described in .~mbar et al. (1989) Biochem. Biopllys, Res. Commun.
158, 195-201; and Khoog et al. (1989) FEBS Letters~ ~53, 199-202.
The endothelins (ETs) ha\le a number of potent effects on a variety of cells, and exert their action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as antagonists of ET at the receptors. In order to wO 96rO490S ~ ~ - 2 1 9 5 7 5 8 identif~ ET antagonist.s and (1etl~rmin~. their eftïcacy irl ~r'tr v, the fclllowirlg three llgand receptor assays were established.
Receptor bindin.~ ~ssay usin~ cow aorta membrane preparatio:n:
Thoracic aortae u~ere obtained from freshl~ slallg.htered calves and brought to the lab on wet ice. The adventitia were removed, and the aorta was opened up lengthwise. The lumenal surface of the tissue was scrubbed with cheesecloth to remove the endothelial layer.
The tissue was ~round in a meat grinder, and .suspended in ice-cc~ld ().2~5 M .sucrose, 5 mll1 tris-~CI, pH 7.4, containing 0.5 mglmL leupeptin and 7 mg/mL pepstatin A. Tissue was homogenized twice and then centrifuged for lO minutes at 750 x g at 4~C. The supernatant was filtered through cheesecloth and centrifuged again for 30 minutes at 4~,000 x g at 4"C. The pellet thus obtained was resuspended in the buffer solution described above (i:ncluding the protea.se inhibitors). and aliquots were quick-frozen and stored at -70~C until use. Membranes wele d:iluted into 50 rnM pota.ssium phosphate (K:Pi), 5 m:M EDTA E~H
7.5 containing 0.01 q~c human serum albumin. Assays were done in triplicate. Test compound.s and lOOpM [1251]-endothelin-1 (2(:)0(:)-22(:)0 2(1 Ci/mmole, obtained from New Englalld Nuclear or .Amersham) were placed in a tube containing this buffer, and the membranes prepared above were added la.st. The .sarnple.s were incubated for 60 rmin at 37'~C.
At Ihe end of th:i.s incubation~ sarnples were filtered onto prewetted (with Z~; BSA in water) glass fiber filter pads and wa.shed wit:h 150 rnA~/
2~ NaCI, O.l~o BS~. The filter.s were assayed for IZSI radioactivity in a gamma counter. Nondisplaceable binding of [l251]-endothelin-1 is measured in the presence of 100 nM unlabelled endothelin-l [Endothelin-l ~ET-I~ was purchased from Peptide.s Intematiollal (Louisville, KYl. 125T-ET-1 (2000 Ci/m~lol~ w~s pur~hased from Amersham ~Arlington lleights, L)l. Specific binding is total binding mhlus nondisplaceable binding. The inhibitory c.oncentration (ICso) YY'hiCh gives 509to displacement of the total specifically bound [ I ~Sl~-endothelin-l was presented as a measure of the efficacy of such compounds as ET antagonists.

~ W0 96/04905 Receptor bindin~ assay usin~ rat hippocampal membrane preparation:
Rat hippocampi were obtained from freshly sacrificed male Sprague-Dawley rats and placed in ice cold 0.25 M sucrose, 5 mM tris-HCI, pH 7.4 containing 0.5 mg/mL leupeptin, ~ mg/mL pepstatin A.
5 lIippocampi were weighed and placed in a Dounce homogenizer with 25 volumes (wet weight to volume) ice-cold sucrose buffer in the presence of protease inhibitors. I~ippocampi were homogenized using a Dounce (glass-glass) homogenizer with t~Tpe A pestle, with homogenizer in ice.
Tissue homoge.nate was centrifuged at 750 x ,~,~ for l O min at 4~C.
o Supennatant was filtered through dampened cheesecloth, and centrifuged again at 48,000 x g l'or 30 min at 4~C. Pellets were resuspended in sucrose buft'er with protease inhibitors. Aliquots of this preparation wele quick frozen and stored at -70~C ulltil use. Membranes were diluted into 50 rrlll~ KPi, 5 mM EDTA pH 7.5 containing 0.01% human 5 serum albumin. Assays were done in triplicate. Test compounds and 25 pM [1251]-endothelin-l (200()-2200 Ci/mmole, obtained from New England Nuclear or Amersham) were placed in a tube containing this buft'er, and the membranes prepared above were added last. The samples were incubated for 60 min at 37~C. At the end of this 20 incubatiorl, samples were filtered onto prewetted (Witll 2~o BSA in watel ) glass fiber itilter pads and washed with 150 m,P!~ NaCl, 0. l ~o BSA. l'he filters were assayed ~or 1~51 radioactivity in a gamma counter. Nondisplaceable binding of [l251]-endothelin-l is measured in the presence of l O0 ~?M unlabelled endothelin- I [Endothelin- l (ET- l ) 25 was purchased from Peptides lntemational (Louisville, KY). 1251-ET-l (2000 Ci/mMol) was purchased t'rom Amersham (Arlingtoll Heights, IL,~]. Specific binding is total binding minus nondisplaceable binding.
The inhibitory concentration (IC~ol WlliCIl gi~,es 50% displacement of the total specifically bound 1~l~5ll-elldothelill-l was presented as a 30 measure of the efficacy of such compounds as endothelin antagonists.
Receptor b:inding assay using cloned hum~m ET receptors expressed in Chinese Hamste.r Ovarv Cells:
Both endc)the]ill receptor subtypes were cloned from a human cDNA library and were individually expresseci in Chinese _ . .. _ . . . _ . . .. . ... . ... ... . . .. .. . ..

wo s6/049~5 ~ ~ 2 1 ~ ~ 7 5 ~

Halnster Ovary cell.s. Cells were harvested hy addition of 126 mM
NaCI, 5 mll1 KCI, 2 ml~ EDTA, I mM NaH2PO~, 15 mM gluco.se~ 10 171Aq tris/HEPES pH 7.4 Cells were centrifuged at 250 .~ g for 5 minutes. The ~u~e~ ~nt was aspirated off, and the cell.s were resuspended in the 50 mM KPi, 5 mM EDTA pH 7.5 containing ().01~c.
human serurn albumin. Assays were done in triplicate. Test compounds and 25-100 pM 1 1 25ll-endothelin- 1 (2000-2200 Cilmmole, obtained from New England Nuclear or Amersham) were placed in a tube co:ntaining 50 mM KPi, 5 mM EDTA pH 7.5 containing 0,01~! human serum albumin, and the cells prepared above were added last The .samples were incubated for 60 m:in at 37~C. At the end of thi.s incubatiol1, sarnples were filtered onto prewetted (witl~ 2~o 13SA in water) glass fiber t'ilter pads and wa.shed with 150 mM NaCI, 0.19'~
BSA.
The filters were assayed for 1251 radioactivity in d gamma counter. Nondisplaceable binding of [1251]-endothelin-1 is measLIred in the presence of 100 nM unlabelled endothelin-] [:Endottlelir~ ET-I) was purchased frorn Peptides Interllational ~Louisville, KY~. 125I-ET-I (2(:)00 Ci/mMol) was purchased from Amersham (Arlington l-leights, IL)~. Specific binding is total binding minus nondisplaceable bi:nding.
The inhibitory c.oncentration (ICso) which gives 50~ di.splacernellt of the total specifically ~und ~1251]-endothelin-1 wa.s presented as a measure of the efficacy af such compounds as endothelin antagonists.
The binding assays described above were used to evaluate the pote:ncy of interaction of ~ s~l.L~ltive compounds of the invention with enduthelin receptors. To fl~t~rrnin~- ~vhether these cormpoLInds were endothelin antagonists, assays which measure the ability of the.
compounds to inhibit endothelin-~tim~ tpd phosphatidylinositol hydrolysis were established. Rat uterus contains predominantly one of the knowll end(lt.heli:n receptor subt~pes (F,l'A).

Phospl]atidylinositol hydrolysis assays using rat uterine slices:
Diethylstilbestrol primed femlle Sprague-Dawley rats were .sacrificed and their uteri were collected, dissected of fat and colmecti~e ti.ssue and minced. ~1ince-d tissue was added to oxygenated (95~o ~2~

2 ~ 9575~
~W0 96/04905 ~ 5, _ /

5'io CO2) 127 mM NaCI, 25 mll1 NallC03, 10 mM Glucose, 2.5 ntM
KCI, 1.2 mM KH2PO4, ~ .2 mM MgSO4, ] .~ mM CaC12. To the tissue ~ mince, 1.2 mM myo-[3H]~ ositol (.D.mersham) was added. 'I'he mincewas incubated 90 min at 37~C, with constant oxygenation. After incubation, the loaded tissue mince was washed five times with t:he same oxygenated buffer to remove excess radiolabelled inositol. The tissue mince was resuspended in the aboie buffer, containing 10 m~l LiCI, aliquotted into tubes, and 3 nM endothelin-l wit:h and without test compounds was added to start the assay. Assays were done in quadruplicate. Samples were incubated at 37~C under blowin~ ~2 in a hooded water bath for 30 minutes. Reaction ~as stopped by addition of trichloroacetic acid to 6~o concentration. Samples were sonicated for 10 min, centrifuged .'~.0 min, then trichloroacetic acid was extracted with 5 water-saturated ethyl ether. An ali~uot of eacll sample was neutralized and diluted by addition of 50 mM tris-HCI pH 7.4. A 100 mL aliquot of this solution was assayed for radioactivity in .l beta counter. The diluted neutralized sample was applied to Dowex I x ~-formate columns, washed with water, then washed with 60 mM ammonium formate, 5 20 mM sodium tetraborate. Samples were eluted with 200 mlll ammonium formate, 5 mM sodium tetraborate. The radioactivity of each eluted .sample was measured in a beta counter. Radioactivity was normalized by dividing r~ldioactivity in post column sample by radioactivity in precolumn sample. Control values (100% stim~ t~d) are values in the presence of endt t~ minus the values in the absence of endothelin (basal). Test sample values are the values in the presence of endothelin and test sample minus basal. Inhibitory concentrLItion ~ICso) is the concentration of test compound required to give a sample activity of 50~c, of control value.
~Sarafotl)xin S6c is a member of the endothelin family which bhlds preferentially to one of the known endothelin receptor subtypes (ETg).
Phosphatidvlinositol hydrolysis a.s.says usin~ rat lun~ slices:
Male Sprague-Dawley rat:s were sacrificed and their lungs were collected. dis.sected of fat and connective tissue and minced.

WO 96~04905 ' ~

Minced tissue was added to oxygenated (95% O~, 5~ CO2) 1~7 r NaCI~ 25 mA1 NaHCO3, lû mM glucose, 2.5 mM KCI, l.. mM
KH2PO47 1.2 rflM MgSO4, 1.8 mM CaC12. To the tissue mince, 1.2 ,~1 myo-~3H]-inositol wa.s added. The mince vdas incubated 60 min ,It 37~C, with con~tant oxygenation. After incubation, loaded tissue mince was wa.shed five times with the salne oxygenated buffer to remove excess radiolabelled illOSitOh Tissue mince was resuspended in the above buffer, colltaining 10 m~M LiC1, aliquotted into tubes, ancl 3 n~l .sarafotoxin S6c with and without test compounds was added to start the assay. As.says were done in quadruplicate. Sarmples were. incubated at 37~C under blov~ing ~2 in a hooded water bath for 30 minutes.
Reaction was stopped by addition of 0.5 rmL 18~ trichloroacetic acid to 69to concentration. Samples were sonicated for lO min, centrifuged 20 minl then trichloroacetic acid was extracted with water-saturated ethyl ether. An aliquot of each sample was neutralized and diluted by addition of 50 rnM tris-HCI pH 7.4. A 100 mL aliquot of this solution wa.s assayed for radic7activity in a beta counter. The diluted neutra]i~ed sample was applied to Dowex l x 8-formate columns, washed wit~h water, then washed with 60 mM ammonium formate, 5 mlll sodhlm tetraborate. Samples were eluted witll 200 mM amJnonium forrnate. 5 mM sodium tetraborate. The radic~activity of each eluted sample was measllred in a beta counter. Radioactivity was normalized by dividing radioacti~ity in post column sample by radioactiYity in precolumn sample. Control values (lûO% stimulated~ are values in the presence of sarafotoxin minus the values in the absence of sarafotoxin (hasal). l'est sample values are the values in the presence of sarLIfotoxin and test sample minus basal. Inhibitory concentration (ICso~ is the concentration of test compound required to give a sample activity of 50~7c of control value.

Phosphatidylinositol hydrolysis assayx using cloned hum~m endothelin receptors expressed in Chinese Hal~ster Ovary cells:
Endotllelin receptors of both receptor subtype.s were cloned from a human cDNA library and were indii/idually expressed in ~ W09~049~ qrJ75~ r .IIU~

Chinese Hamster Ovary cells. (~ells were loaded ovennight by the addition of 1.2 ~M myo-l3~1]-ino.sitol to their growtl1 medium. Cells were harvested by addition of 126 mM NaCI, ~5 mM KCI, 2 fnM EDTA, I mM NaH2P04, 15 mM glucose, 10 rnM tris,/HEPES pH 7.4. Cells were washed five times by centrifugation at 250 x g for 5 minutes to remove excess radiolabelled inositol. The supernatant was aspirated off, and the cells were resuspended in the same o~ygenated (95% ~2~ 5%
CO2) buffer containing 10 mM l iCI. aliquotted into tubes, and 0.3 nM
endothelin-l with and without test compounds was added to start the a.ssay. Assays were done in quadruplicate. ~amples were incubated at 37~C under blowing ~2 in a hooded water bath tor 30 minute.s~
Reaction was stopped by addition of 0.5 mL 18~o trichloroacetic ;~cid to 6% concentration. Samples were sonicated for 10 min, centril'uged 20 min, then trichloroacetic acid was extracted with water-saturated ethyl ether. An aliquot of each .sarnple was neutralized and diluted by addition of 50 l7~M tris-~lCI pll 7.4. A 100 mL aliqllot of this solution was assayed for radioactivity in a beta counter. The diluted neutralized .sample was applied to Dowe~ X-formate colunltls, washed with water, then washe(l with 60 ~nM .Immnninm formate, 5 ~7lM sodium tetraborate. Samples were eluted with 2()0 ~nM ammonium f'onmate, 5 n~JM sodium tetraborate. The radioactivity of each eluted sample was measured in a beta counter. Radioactivity ~as nclntlalized by dividing radioactivity in poit column sample by radioactivity in precolumn sample. Control values (100~,'o stimulated) are values in the presence of endothelin mil1u.s the values in the absence of endothelin ~basal). Test sample vahles are the values hl the presence of endothelill and test sample minus basal. Inhibitory concentration (ICso) is the concentration of test compound required to give a sample activity of 50% of control value.
Using the methodology described above, representative compounds of the inventio~ ere evaluated and found to exhibit ICso values of at least <50 ~1 thereby demonstrating and confirming the utility of the compounds of the inventiol1 as effective endothelin ~untagonists.

WO 961049115 ~ 19 5 75 8 Intravenuus Effect of Endothel:in-l Antagonist, IV-(4-iso-proT-ylbellzerle~
sulfonyl~-a-(4-carbc~xy-2-n-prol3ylphenox,y)-3~4-illethylenedioxyphenyl-~3~et:ut~ dipotassiunl .sult [Example 58~ on Endothelin l -lnducc d (:~hanges i:n Diastol;c and Urethral Pre.ssures in the Anesthetized Male Dog Methodology for rlpfl~rminin~ whether an ET-1 .selective antagonist could inhibit the ET-I mediated prostatic urethral contractions in a mongrel dog nlodel:
On separate days, two f:dsted male mongrel dog.s (HRP.
Inc.) weighing 11.0 and 12.4 kg, were anestheti~ed with Sodium Pentobarbital ~Steri.s Laboratorie.s, Inc.) at 35 mg~kg (i.-iu) to effect, followed by 4 mg/kg/hr ~i.v.) infusioll. A cuffed endotracheal tube was 5 inserted and each animal ~h~a.s ventilated with room air using ~ positive displacement large animal ventilator (Harvard Apparatus) at a rate of 1~ breaths/minute and an average tidal volume. of 18 mlJkg body weight. Body temperature was ma~ntained with a heatinsg pad and heat k!mp using a te~nlperature controller (YSI) and esophageal probe. Tu,o catheters (PE 2~31)) were placed in the aorta via the femor.ll arteries (one in each artery) for admini.stration of endothelirl or phenylephrille iand for continuous direct monitoring of blood pressure and heart rate u.sing a Statham blood pressure transducer ~Spectrarned) and a compllter system ~Modular In.strument~s, Inc.). Two other catheters (PE 260~
25 were placed in the vena cava via the femoral veins (one catheter in each vein) for administration of pentobarbital and N-~4-isc3-propylberlzene-sulionyl)-a-(4-carboxy-2-rl-propylptlenoxy)-3,4-1rlethylelledic)xyphellyl-acetamide dipotassium salt ['Exarnple 5X] . A supra-pubic ;ncision approxirnately one-half inch lateral to the penis was made to expose the 30 ureters, urinary bladder, pro.state, and urethra. The dome of the bladder was retracted to facilitate dissec.tion of the ureters. The ureters were cannulated with PE 90 and tied off to the bladder. Umbilical tape was passed beneath the uret:hra at the bladder neck and another piece of tape was placed approximately l-2 cm. distal to the prostate. l'he ~ wos6l04so~ r~.,.a,,...~ 7 bladder dome was incised and a l~icro-tip~ catheter transducer (Millar In~lrullle~ , Inc.) was advanced into the urethra. The neck of the bladder was ligated with the umbilical tape to hold the trall.sducer. The bladder incision was sutured with 3-0 sili~ (purse string suture). The transducer was withdrawn until it was positioned in the prostatic urethra. The position of the ~licro-tip~ catheter was verified by gently squeezing the prostate and noting the large change in urethral pressure prior to ligating the distal urethra.
o Experimental Protocol:
Phenylephrine (PE) ~l0 llg/kg, intra-atterial) was administered and pressor effects on diastolic blood pressure (DBP) and intra-urethral pressure (IUP) were noted. When blood pressure returned to baseline, endothelin-l (ET-I) (I nmole/kg, intra-arterial) was ~(lmini~t~red. Changes in DBP and IUP were monitored for one hour and an ET-1 selective endothelin antagonist~ such as the compound of Example 58, N-(4-iso-plopylbenzene-sulfonyl)-o~-(4-carboxy-2-n-propylphenoxy)-3,4-methyienedioxyphenyl-acetamide dipotassium salt (30 mg/kg, intra-venous) was admil1istered. l'en to fifteen minutes later when blood pressure had stabilized, ET-I was administered again.
and inhibition of ET-I induced effects were noted. PE was administered at the end of the experiment to verify specificity for E'l'-l blockade. The dogs were e-ltll~li7.~d with .LIl overdose of pentobalbit,ll followed by saturated KCI.
The drugs utilized in the experiment described above were:
I ) Phenylephrine, HCI (PE) (Sigma Chemical, Co.) was given at a volume of 0.05 ml./kg;
2) Endothelin-l (ET-I) (:Eluman, Porcine, Canine, Rat, Mouse, Bovine) (Peninsula Laboratories, iilC.) was given at a volllme of 3 c 0 05 mLllcg;
3) ET-l selective antagonist, SUCil as the compound of Example 58, N-(4-iso-propylbellzene-sulfonyl)-~-(4-carboxy-2-n-propylphenoxy)-3 ,4-methylenedioxyphellylacetamide dipotassium salt, was given at a volume of 0.3 ml,lkg.
All drugs were dissolved in isotonic saline solution.

W0 96/U~05 2 sl 9 5 7 5 8 r~ J--Re.sults:
ET-I elicited an initial depre.ssor effect followed by a longer pressor effect. In one dog, the pressor effect wa.s bipllasic. The decrease :in DBP in hot'h dog.s aver.iged 13 rmnHg, while the peali 5 pressor efl'ect averaged 26 mrnHg. 'l~e average ET-I induced increa.se in IUP was 15 mmHg. Ten to 14 minutes after administration of hl'-(4-isa-propylbenzene-sulfonyl3-t.lG-(4-carboxy-2-n-propylpllenoxy~)-3,4-methylenedioxy{3henyl-Sl~elSlrni-lP dipotassium salt IExarnple 5~. the dogs we.re challenged with ET-I again and the depressor and pressor effec.ts on DBP were. inhibited 69% and ~6%, respectively. The pressor effect on IUP s~as inhibited 930i~G (T-able I ~. Intra-arterial :PP.i-induced increases in DBP and IUP did not change ~ignitlrs~ntly after adm:illistration C13' N-(4-is~3-propyll3enzene-.sullonyl i-o~-(4-carboxy-2-n-propylphenoxy)-3.4-methylenedio~yphenyl-S~netSImide dipotassilun s alt [Exarllple 5~] in the one dog studied. Increases in DBP and IU:P were inhibited 35 and 13~.ro, re.spectively ~Table 2).

~ W09C1049~5 ~ 9~75,~ P~l/~J~. 5~1,rc7 Table 1. Eff'ects of ET-1 Antagonist, N-(4-i.so-propylbenzene-sulfonyl)~ 4-carboxy-2-n-prop~!lphenoxy)-374-methylenedioxyphenyl-acetamide dipotassium salt [Example 581, on ET-I Induced Changes in DBP and IUP in Anestheti~.ed Male Do~ (n=2) CHANGE
Cl-IANGE IN DBP IN IUP
(mmHg) (mmH~) DOG # DEPRF,SSOR ¦ PRESSOR PRESSOR
ET- I (i.a.) SEh/l 3 7 4 ET-I + Example 58 HG F'MJC -3 8 ~) INH131TION

~ HG FMHK 67 g4 91 SEM 2 18 2 , W096104905 ~ ' a ~95758 r~ sn--_ 9~ _ Table 2. Effects of ET-I Antagonist, N-~4-iso-propylbenzene-sulfonyl)-o~-(4-carboxy-2-n-propylphenoxy)-3 ,4-methylenedioxyphenylacetamide dipotassiunl salt [Exarmple 5~1, On PE-lnduced Changes ;n Di3~P and I~TP iu An~Clllp~i7~ Male Dog # H~ FMJC~

TREA1'MENT INCREASE IN DBP INCREASE 11~ IUP
(mm~
Phenylellhrille 17 31 Phenylephrine 1 i 27 Example 5~
% inhibitio:n of Control 3~ ]3 Conclusions:
ET- I causes constriction of the prostatic urethra, a.s well as a complex hemodynarriic re,sponse comprised of an initial depre.s.sor and 20 subsequent pressor response in anestheti~ed dog.s. rhe hemodynamic ~nd prostatic urethrai respons~ to ET-I were .speciilcall~, inhibited b~
IV-~ 4-i~<~-propylb~n~ne~ulf'onyl)-a-~4-carboxy-~ prop~ lphello~y )-3,4-methylelled:ioxyphe:nylacetam:ide dipotassium salt. The efficacy o~' the N-(4-iso-propylbellzenesulfonyl)-o~-~4-carboxy-2-n-propyl-25 phenoxy)-3,4-methylenedioxyphenyl~iret~mi;e dipotassium .salt Ul inhibiting the prostat:ic urethral pressor effect of ET- I suggests that seiective antagonists of E1'-1 will be usefui in the treatment of urin~
ob.struction in benign prostatic hyperplasia.

30 1~ Sifli Rat Pro,~tate:
Male Sprague-Dawley rats (Taconic Farms) weighin~ 300-400 grams were anesthetized with urethane (1.75 gll~g, ip). a tractleal canmlla was inserted, and the femoral arter~,~ was cslrin~ t~ri Core body temperature ~h'a.S maintained at 37 + 0.5 ~CI. A 4-5 cm midline ,lhdolnin ll incision was made to expose the bladder and prostate. Ttle 1 9~75~
~ WO 96104905 ' r~

- g3 -prostate was .separated from the bladder and surrounding capsule by blunt dissection with a iorcep. A length of surgical silk was gently secured around the anterior tips of the prostate lobes. A second length of surgical silk attached to an atraumatic needle was passed through and tied to the base of the prostate approxilIlately 10-] 2 mm posterior to the first tie. The posterior ligature was secured to an anchor post whereas the anterior ligature was connected to a Grass FT03 tran.sducer ~Grass Instruments, Quincy, MA) and m~int~in~d at a tension of I g. Signals from the transducer were amplified and recorded on a polygraph (Hewlett-Packard ~0:i13 amplifiers and 775~A recorder, Palo Alto.
CA). After equilibrating for approximately 15 min, the rats were administered pretreatment drugs (atropine I mg/kg, (+) propranolol I
mg/kg) lO min apart through the intra-arterial (IA) cannula. Thirty minutes later, ET-I (0.3 nmoles/kg) was injected intra-arterial every thirty minutes for a total of three times. Five minutes before the third injection of ET-I, vehicle ~ith or without an endothelin antagonist was injected IA. The response of the prostate to ET-l was qu.mtified by mea.suring the change (~) from baseline tension to the peak of the response during the 5-minute period after the third ET- I injection.
The in .Sitll rat postate protocol has been utilized to deterrnine the antagonist activity and potency of compounds of this invention to block the direct contractile effects of ET-I on the rat prostate in vivo. in this protocol, N-(4-is~i-propylbenzene-sulfollyl)-o~-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyptlenylacetamide dipotassium salt was dernonstrdted to cause a specific inllibitioll of F,T-I
to contract the prostate and will be useful in the treatment of urinary obstruction itl benign prostatic hyperplasia.

Accordingly the novel compounds of the present invention are useful in humall therapy for treating asthma. hypertension, renal failure particularly post-ischemic renal ~:ailure, cyclospcrin nephrotoxicity, vasospasm, cerebral and cardiac ischemia, myocardial infarction, or endotoxin shock caused by or associated ~vith endothelin, . . 2 ~ 9 5 7 5 ~
WO 9611~4905 , ~ "

hy admin.stration to a patient in need of such treatmelIt of a therapeutically ei'fective amount thereof In the manageme:nt of hypertension and the cl:inical conclitiolls noted above, the cc~rllpoll:nds of this invent:ion may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be ~1mini~ red to patients (an:imals and human) in need of such treatment in dosages that will provide optimal ph~rm ~ ellti-~l efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diet.s then be:ing followed by a patiellt, concurrellt medic.ltion, and other factc rs which those skilled in the art will recognize7 the dosage r~mge will gene.rally be. about 0.~ mg 5 to l.0 ~. per patient per day which can be sl~mini~t~red in single or multiple doses. :Peri'erably, the dosage range will be about 0.5 mg to 500 mg. per patient per day; l:nc~re preferably at~out 0.5 mg t(J 20() m~.
per patient per day.
The compound.s of this i:nvention can also be adlIlinistered 20 ill combination ~,vi~h A2-adrenosine receptoragonists, a-adrenergic antagonists, angioten.sin II antagonists7 angiotensin converting enzyme inhibitors, ~-adrenergic antagonists, atriopeptidase inhibitors~alone or with ANP), calcium channel blockers7 diuretics, potassium chamlel agonists7 renin inhibitors, sertonin antagonists, sympathol~tic ~gents7 as 25 well as otber antihypertensive agents. For example7 the compc~unds oi this invention c.~m be given in combination with such compound.s as A-69729, FK 906, FK 744, UK-739007 CSG 22492C7 amiloride, atenolol~
atriopeptin. bendroflumetlliazide7 chlorothalidone, chlorc~tlliazide, clonidine, cromakalin, cryptenamine acetates and cryptenamine talmates, 30 deserpidine, diazox:ide, doxazosin7 guanabenz, gua:nethidine, guanethidine sulfate, h~dral,lzine hydroctlloride7 hydrochlorothiazide, isradipirle7 ketan.serin7 losartan7 metolazone, metoprolol7 met:oprolol tartate, rmetllyc:lott1iazide, methyldopa. methyldopate hydrochlor:ide, minoxidil, nadolol, pargyline hydroclllc ride, pinacidil, pindolol7 2 t ~ 5 7 ~ Q
wo 96/0490~ -~ V I ~ l/lJ". ...,v, - 95 ~
polythiazide, prazosim propranolol, rauwolfia serpentina. rescilmamine, reserpine, sodium nitroprusside, spironol.lctcme, terazosin, timolol maleate, trichlormethiazide, trimethophan cam.sylate, verapamil.
benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, S aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril~ enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril, quinapril hydrochloride, ramapril~ teprot:ide, zofenopril, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nilïlodipine, nisoldipine~
nitrendipine, and the like, a.s well as admixtures and combinations thereof. Combinations useful in the management of congestive heart failure include, in addition, compounds of this invention with cardiac stimulants such as dohllt~mi~ and xamoterol and phosphodiesterase 5 inhibitors including amrinone and milrinone.
Typically, the individu.ll daily dosages for the.se combinations can range from about one-fifth of the minimllm recnmmPn(~Pd clinical dosages to the maximum recommended levels for those entities given singly. To illustrate these c.ombinations, one of the 20 endotheliIl antagonists of this invention effective clinically at a given dail~ dose range can be effectively combined, at levels wtlicll are less than that daily dose range, with the following compounds at the indicated per day dose range: hydrochlorothiazide (6-lO0 mg), chlorothiazide (125-S()0 mg), furclsemide(S-80 mg), ethacrynic acid (5-25 200 mg), amiloride (5-20 mg), diltiazem(30-540 mg), felodipine( l -20 mg), nifedipine(5- 120 mg), nitrendipine(S-60 mg), timolol maleate (1-20 mg), propanolol (10-480 mg), and methyldopa(l25-2000 mg). In addition triple drug combinations of hydrochlorothiazide(6-100 mg) plus amiloride (S-20 mg) plus endothelin antagonists of this invention, 30 or hydrochlorothiazide(6-lO0 mg) plus timolol maleate (I-20 mg) plus - endothelin antagonists of this inventiol, or hydrochlorothiazide(6-lO0 mg) plus nifedipine (5-60 mg) plus endothelin ant.lgonists of this invention are effective combilIati- ns to control blood pressure in hypertensive patients. Naturally, these dose ranges can be adjusted on a 2 1 ~75~
WO 46~04905 i r~.,. . Y.. _7--unit basi.s a.s necessary to permit divided daily dosage and the dose will vary depending on the nature and severity of thc disease. weigllt of the patient. special diets and other factors.
The present invention also relates to pharmaceutical 5 compositions t'or treating asthma, hypertension, renal failure, particularly post-ischemic renal failure, cyclosporin nephroto~icity, vasospasm, cerebral and cardiac ischem:ia, benign prostatic hyperplasia, myocardial infarct:ion, or endotoxin shock caused by or as~sociated with endothelin, comprising a therapeutically effective amount of the novel compound of this invention together with a ph~m~ elltic ~lly acceptahle carrier therefor.
About 0.~ mg to 1.0 g. of compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable Yehicle, carrier, 5 excipient, binder, pre.servative, stabilizer, flavor, etc., in a Ullit dosage form as called for by accepted pharrnaceutical practice. The arnoullt of acti~e substance in these cc~mpositiolls or preparations i.s such that a suitable dosage in the range indicated :i.s obtained.
Illu.strative of the adju~ants whicll can be incorporated in 20 ta:blets, capsules and the like are the following: a binder .such as gum tragacanth, acacia, corn starch or gelatin: an excipient such as microcry.stalline cellulose; a disintegratillg agent such as com starch, pregelatini~ed starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or 25 saccharin; a flavoring agent such as p~,pe,..lil.~, oil of wintergreen or cherry. Whe.n the dosage unitform is a capsule, it may contain, in addition to materia:ls of the above type, a liquid carrier such a5 fatty oil.
Variolls other rnaterials may be present as coatings or to otherwise modify the physical form of the dosage unit. Fclr inst~mce, tablets mày 30 be coated with .shellac, .sugar or both. A .syrup or elixir may cc~ntain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as pre.servatives, a dye and a flavoring such as cherry or orange flavor.

~ wos6/04sos ~ " ' ' 2 ~ 35 75~ P~

Sterile compositions for injection can be fonmulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut 5 oil, cottonseed oil, etc.. or a synthetic fatty vehicle like ethyl oleate or the lilce. Buffers, preservatives, antioxidants and the like can be incorporated as required.
The following examples illustrate the preparation of the compounds of Formula I and their incorpor~ltion into pharmaceutical o compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLE l 5 2-(2,6-Dipropyl-4-hydroxymethyl)phelloxyphenylacetic acids Step A: Preparation of Alliyl 2-bromo-2-phenvlacetate.s Method A:
Substituted phenylacetic acid is convered to the 20 corresponding methyl ester by refluxing the acid in methanol in the presence of a catalytic amount of conc. sulfuric acid. The e.ster thu~s obtained is then refluxed in carbon tetrachloride with N-bromosuccinimide (1.1 equiv) and AIBN (0.0~-O.l equiv). Upon completion of the reaction, the resulting product is purified by flash 25 column chromatography using silica gel and ethyl acetate in hexane as eluent to provide the desired al~yl bronlide.
Method B:
An arylaldeh~de is reacted ovemight with trimethylsilyl cyanide in the presence of catalytic amounts of KCN and l~-croivn-6 30 in methylene chloride. The reaction mixture is quenched with water and extracted with CH2Cl2f ethyl acetate/ether (l/2/2) mixture. The organic phase is washed with saturated aq. NaHC03 solutioll. After dryhlg and concentration of the organic phase, the resulting trimethyisilyl cyanohydrin is hydrolyzed to give the corresponding hydroxy acid. 1'reatment wit}l gaseous l lCl in methanol or ethanol at WO 96104905 r / ~ ~; 2 1 ~ 5 7 5 ~ ~ " Ll ~ i. c ~ hC7 ~ 98 ~
O"C for 0.5 h and then overrLight at room t~mrerltl~re alfords the crude 2-hydroxy ester. The ester is then treated with triphellylphosplline and carbon tetrabromide in methylene chloride at O'~'C o~ernight. Methylene chloride is removed and flash column 5 chromatography of the crude product using silica gel and ethyl acetate/lLexane as eluent gives the desired 2-bromophenylacetates.

StepB: Alkykltion of the ptlenol (2j6-Dipropyl-4-hydroxymethyl)phenol (prepared as described in patent application WO 91/11999) is alkylated with 2-bromo-2-aryl e.iters in DMF u.sing either cesium carbonate (Cs2C03), or polassium carbonate (K2C03). or sodium hydride (NaH~. The aL~ylated product is purified by flash column chromatograph~ using silica gel and ethyl acetate/hexane mixtlJre as 5 eluent to provide the desired sl-hstih-l~d 2-phenoxy-2-phenylacetic ',1 ~
acl~l es.ers.

Step C: (~ener~l pro~P~ re for ester hvdrolv.si.~
Th~ product of Step C is dissolved in methanol or e~Tlanol 20 and reacted with aqueous l~aOH or L.iOH, or E~OH solution at room temperature for 1- 6 hours, neutralized to pH 7 with I N HCI and then c.-nni~ntr~tPd in vacuo. The residue i.s purified 011 'd silica gel i1ash chromatography column to afford the corresponding carbo~ylic acid.
l'he follc~wil1g phenoxyphenylacetic acid derivatives were prepared using the general procedures mltlil1ed in Example 1.

2-[~2,6-Dipropyl-4-hydroxymethyl)phenoxy]-2-(3-methylphenyl)acetic acid IH NMR (400 Ml-lz, CD30D, ppm): o 7.15 - 6.95 (m, 4H), 6.86 (s, 2H), 4.92 (br s. IH), 4.5 (~s, 2H), 2.3-2.1 ~m, 4H3, 2.2 (s. 3lr)~ 1.5-1.35 (m. 2H), 1.32-1.lX (m, 2H), 0.7 (t, GH).

~ W0961049(15 ~ ' 2 ~ 9 57 5~ T.,I/L . 3 .................... ~7 _ 99 _ 2-[(2,6-Dipropyl-4-hydroxymethyl)phenoxyl-2-(4-p}lenoxyphenyl)-5 acetic acid IH NMR (400 MlIz, CD30D,ppm):o7.42 (d~ 2H,J=8.4 Hz),7.33 (dd,2H,J=7.4 Hz.,8.5),7.09(t,1H,J=7.411z),6.97-6.g5(m,4H), 6.91 (d, 2H,J=8.4 Hz),4.85(s,IH),4.47(s,2H),2.38(t~4H,J=8.0 o Hz),1.56(sx.2H,J=7.11Iz),1.42(sx,2H,J=7.1 Hz),0.85(t,6H, J=7.3 H7)-FAB-MS m/e = 435 (M+ I ) 2-1 (2,6-Dipropyl-4-hydroxymethyl)phenoxyl-2-(4-phenylphenyl)acetic acid IH NMR(400 MHz,CD30D,ppm):~7.62-7.60 (m, 4H),7.51(br, 20 2H),7.44(t,2H,J=7.5 Hz),7.34(t,111,J=7.4 Hzj,6.99(s,2Hj,4.83 (s,llI),2.40(br,4H),1.53(br,2H),1.42(br,211),0.82(t,6H, J=6.2 Hz).
FAB-MS m/e = 419 (M+l) 2s FXAMPI,E 5 2-[(2,6-Dipropyl-4-hydroxymethyl)phenoxy]-2-(3-carboxyphenyl)-acetic acid 30 IH NMR(400 MHz,CD30D, ppm): ~ 8.18(s,1H)8.04(d,111, J=7.5 Hz),7.70 (d, 111, J=7.4 Hz),7.51(d,1H~J=7.6)Hz,6.99(s, 2H),5.]5(s,1H),4.48(s,21-1),2.37(m,4H),1.52(m,2H),1.44(m, 2H),0.80(t,6H,J=7.3 Hz).
FAB-MS m/e = 387(M+I) - 2~ ~5753 ~0 96104gOS P~

EXAIVIPI ~ 6 2-[(2,6-l:)ipropyl-4-hydroxymet}lyl)phenoxy]-2-~3 74-ethylenedioxy-5 phenyl)acetic acid IH NMR ~200 MHz, CD3OD7 ppm~: ~ 6.g5 (m7 3H)7 6.85 (dd7 IH7 J=8.37 2.0 Hz~7 6.72 (d7 IH7 J=8.3 Hz~7 4.76 (s7 lH)7 4.46 (S7 2H)7 4.201s7 4H)7 2.37 (t7 4H7 J=7.9 llz)7 1.44 (m7 411), 0.83 (t. 6H. J=7.3 o Hz).
FAB-MS m/e = 401 (M+l) 2-[(276-Dipropyl-4-hydroxymethyljphenoxy1-2-(374~5-trimethoxy-phenyl)acetio acid 111 NMR (4()~3 MHz7 CD30D, ppm): ~ 6.97 (s, 2H), 6.80 (s, 2H), 4.88 (s. IH), 4.48 (s, 2H). 3.81 (s, 6H), 3.7~; (s~ 3H), 2.39 (t, 3H, J=8.1 Hz)7 1.~5~ (m7 2H)7 1.41 ~m7 211)7 0.82 (t7 6H, J-7.3 I{z).
FAB-MS mle = 433 (M+l) EXA~IPI,E 8 2-[2,6-Dipropyl-4-hydroxymethyl)phenoxy1-2-(3,4-methylenedioxy-phenyl)acetic acid lH NM~R (20Q lvlHz7 CD30D? ppm): o 7.03 (S7 11~1)7 6.97 (S7 211), 6.83 (d7 IH7 J=7.7 llz)7 6.73 (d, 2H7 J= 7.7 Hz), 5.94 (s, ~H)7 4.~4 (S7 3~ IH), 4.48 (s. ~H), 2.38 ~t7 4H7 J=~.0 Hz), 1.46 lm7 4H)7 0.85 ~t7 6H7 J=7.4 Hz).
PAB-MS m/e = 387 (M+l~

-- W096/0490S ~ . 9 7 5~ F~.IIL_. !i. ~5~7 2-[ (2,6-Dipropyl -4-hydroxymethyl)phenoxy] -2-(3,4-dimethoxy-phellyl)acetic~ acid lH NMR (400 MHz, CD30D, ppm): o 7.15 (d, IEI), 6.95 (d~ 2H), 6.~5 (dd, 2H), 4.8 (br s, IH), 4.46 (br s, 2H), 3.84 (s, 3H)~ 3.8 (s.
3H), 2.35 (t. 4H), 1.62-1.47 (m, 211), 1.45-1.3 (m, 2H), 0.85 (t, 6H).

2-[(2,6-Dipropyl-4-hydroxymethyl)phenoxy]-2-(3,5-dimetlloxy-phenyl)acetic acid I H NMR (400 Ml lz, CD30D, ppm): o 6.954 (s, 2H), 6.66 (d, 2H), 6.39 (t, lH~, 4.747 (s, IH), 4.47 (s, 2H), 3.74 (s, 6H)~ 2.39 (t, 4H), 1.60-1.51 (m, 2H), 1.437-1.35 (m, 2H), 0.82 (t, 6H).

2-~(2,6-Dipropyl-4-tetrazol-5-yl)phenoxy)-2-(3-bromophenyl)acetic acid I H NMR (400 MHz, CD30D, ppm): ~ 7.73 (s, 2H), 7.67 (t, lH, J=l .X
Hz), 7.57 (m, IH), 7.46 (m, IH), 7.33 (t, lH, J=7.9 Hz), 5.X9 (ddd, lH, J=1.6, 10.1, 17.1 Hz), 5.41 (s, IH), 5.08 (dd, 11-1, J=10.1, 1.6 Hz), 5.01 (dd. IH, J= 1.7, 17.1 Hz), 4.93 ~s, 2H), 3.72 (s, 311), 3.36-3.30 (m, 2H).

FAB-MS mle = 470 (M+ l ) 2-[(2,6-Dipropyl-4-hydroxymethyl)phenoxyJ-2-(3-bromophellyl)acetic acid WO 96/0490S ~ , 2 1 9 5 --TT 5 8 I H NMR ~400 MHz. C'D~OD/CI:)C13,2/1, ppm): o 7.667 (s, I H~), 7.496 (d, IH), 7.3925 (d, 111)7 7.252 (t, 11-I), 6.9~ s~ 2H), 4.995 (s, 111), 4.~85 (s, 2H), 2.342 (t, 4E-1), 1.65-1.35 (m, 2H),0.803 (t,6H~.

2-[(2,6-Dipropyl-4-hydroxymethyl)phenoxyl-2-(2-naphthyl)acetic acid H NMR (400 MHz, CD30D, ppm): o S.56-~.52 (m, lH), 7.~¢6-7.79 o (m, 2H), 7.47-7.4~ ~m, 2H), 7.35-7.32 (m, I H), 6.91 (s, 2Tl), 5.36 (s, 111),4.44 (~, IH~, 1.46-1.41 (m, 2 1~). 1.2-1.16 (m, 2E~), 0.5~ (t, J
= 7.37, 6 H).

2-[(2,6-Dipropy]-4-(2-hydroxyethyl)phenoxy]-2-(2-naphthyl)acetic acid STEP A: t-ButvldimeLhvlsilvloxv-~.6-Diprop~TI- I-furm~lberlzerle To a solution of 5.03 g (1~.4 mmol~of t-butyl-dimethylsilylo~y-2,6-dipropyl-4-hydroxylnethyl benzene in 30 mL
of met:hylene chluride was aT~ded 8.7 g of pyridiniT~ dichrumale (PDC). The reaT~tion mixture w~s stirred for 3 houls and thell dilute.d with 30~3 ml, of ethyl ether. The sclluticm was then filtered 25 through a pad Qf a ifl mixture of florisil and celite. Concentration of the filtrate ga~e 4.~5 g of the title compound.
] H NMR ~400 MHz. CDC13, ppm): o 9.~ (s, IH),7.51 (s, 2H), ~.59-2.55 (m, 2Hi 1.59-1.55 ~m, 211), 0.99 (s, 9H T, 0.91 ~t, J = 7.2~ T.~Z~, 30 3H), ().20 (s,6H).

STEP B: t-l~utyldimethyl~silyloxy-2~6-flillropyl-4-vinyl benzene Tcl a .solution of 1.0 g (2.~0 mmol) of methyl triphenylphosphollium bromide in 5.0 mL of ether at 0 C was added 1.12 mL (2.51~,1, 2.~0 mmol) of butyllithium. The reaction mixture -- WO 9GlQ4gO5 ~ 2 1 9 5 7 5 8 ~ was stirred for 30 minute.s at 0 C and then 756 mg (2.33 mmol) oi the title compound from Example 14 (Step A) was added. After stirring for lh at room temperature. the reaction mixture was poured into ethyl acetate and washed with water and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash cll-ulllc~to~ld~lly (silica gel, hexane / ethyl acetate 97:3) gave 411 mg of the title compound.
IH NMR (400 MHz, CDC13, ppm): o 7.02 (s, 2H), 6.6 (dd, J = 17.6, J = 10.7 H~, IH~, 5.55 (d, J=17.6 E~z, IH), 5.0~ (d, J = 10.7 llz, 11:1), 2.53-2.50 (m, 4 H), 1.59-1.53 (m, 4H), 0.996 (s, 9 H), 0.90 (t, J =
7.33E-Iz,6H),0.16(s,6H).

STEP C: t-E3utyldimethylsilyloxy-2,6-dipropyl-4-(2-hydroxyethyl)-benzene To a solution of 475 mg (1.4~ mmol) of the product of Step B in 3 mL of THF at 0 C was added 1.6 mL (1.62 rnmol) of a I N borane / THF solution. After I houl Tl.C indicated th.lt the 2c starting material had been consullled. The reaction mixture was quenched Wit}l 3 drops of methanol and then 0.70 rmL (6.22 mmol) of 30 ~'~O sodium peroxide and 6.2 mL (6.2 n~nol) of I N sodium hydroxide were added. After two hours tlle reaction mixture was diluted with ethyl acetate and washed with water and brine. The 25 organic layer was then dried over sodium sulfate, filtered and concentrated. Flash chromatography (silica gel, hexane / ethyl acetate 4: 1) gave 265 mg of the title compound as a clear oil.
I EE Nh/IR (4()0 MHz, CDC13, ppm): ~ 6.79 (s, 2 H), 3.79 (m, 2 H), 30 2.75 - 2.72 (m, 2 EE), 2.51 - 2.4~ (m, 4 H), 1.5~ - 1.51 (m. 6 E-l), 0.99(s,9H),0.90(t,J=7.33,6H),0.16(s,6H).

STEP E>: 2~6-Dipropyl-4-(2-hydroxyethyl)phenol To a solution of 1.0 g (2.9~ mmol) of the product of Step C in 3.0 mL of THE~' was added 3.57 mL (3.57 mmol) of 1.0 N

WO 961049U5 ! ~ 2 t 9 ~ 7 5 8 I ~ I ~ ,115 .

- I ()4 -solution of tetrabutylammonium fluoride in ~HF. After 1~ minutes TLC indicated that the reaction was complete. The reaction mi~ture was ,.ol1cen~ d and then purified by flash ~ vl~ o~;ld~hy ~silica gel, hexane/eth~l acetate 3:1) to give 1.13 g of the title compound.
I H NMR (400 MHz~ C'DC13, ppm): o 6.8 (s. 2 H~, 3.78 (t . J = 6.5 Hz, 2 E-1), 2.73 ~t, J = 6.5 Hz., H~, 2.54 - 2.50 (m, 4H), 1.66 - 1.56 (m,4H),0.96(t,J=7.3Hz,6H).
STEP E: Methyl 2-[(2,6-d;propyl-4-(2-hydroxyethyl)phenoxy]-2-(2-n~phthvl )acetate The title compound was prepared from 2,6-dipropyl-4-(2-hydroxyetbyl)phenol (S~ep D) by alkylating with methyl 2-bromo-2-(2-naphthyl)acetate using cesium carbonate or pota.ssium carbonate in DMF. The reaction mixture was filtered through Celite and the filter cake was washed with methylene chloride. The filtrate was concentrated and the resultant material was purified by ~lash columll chromatograplly to yield the titled es~er.
I H NMR (400 MH7., C'DC13, ppm~: o 7.90 - 7.82 (m, 4 H~, 7.69 -7.67 tm. I H), 7.49 - 7.47 (m. 2H), 6.8 (s, 2 H), 2.74 (t~ J = 6.2 Hz, 2 H~. 2.36-2.3~ (m, 4 E-1~, 1.49 - 1.41 ~m, 4 H), 0.72 (t, J = 7.3, 6 El).

S'lEP E~: 2-[(2,6-Dipropyl-4-(2-hydroxyethyl,~phenoxy~-2-(2-naphthyllacetic acid 'I'lle title eoll1pound was prepared from the producl c)f Step E
by saponification with IN aque.ous KOM in med1anol as outlined in Step C of E~ample 1.
30 l E'l 'NMR (400 MHz, CD30D, ppm) o 7.84 - 7.7 (Irl, 4 H), 7.73 ~d, J = 6.8 Hz, I H~, 7.45-7.43 (rm, 2 H), 6.79 (s, 2 H), 5.01 (s, 2 H~, 3.66(t,J=7.2Elz,2H),2.68(t,J=7.2Hz,2H~,2.33-, 29(m~4 H), 1.55 - 1.4~i (m, 2H~, 1.40- 1.28 (M, 2 El), 0.69 (t,3 = 7.3, 6 El).
F.4.B- MS: mle = 445 (M + K), 429 (~1 + Na), 407 (M f 1).

~ W0 96104905 ~ 2 1 q 5 7 5 P~ P~ 7 The following phenoxyphenylacetic acid derivatives were prepared using the general procedures outlined in Example 14.

2-1 (2,6-Dipropyl -4-(2-hydroxyethyl)phenoxy 1-2-(3 ,4-methylenedioxy-phenyl)acetic acid NMR (200 MHz, CD30D, ppm): o 7.03 (s~ IH), 6.133 (m, 3H), 6.72 (d, lH, J=7.8 I-lz), 5.93 (s, 211)7 4.80 (s, IHJ, 3.68 (t, 2H, J=7.1 Hz), 2.69 (t, 2H, J=7.1 Hz), 2.35 (t, 4H, J=7.9 l~z), 1.42 (m, 4H), 0.~3 (t, 6H, J=7.3 Hz).
5 FAB-MS m/e = 401 (IM+I) 2-L(2,6-Dipropyl-4-~2-hydroxyethyl)pllelloxy]-2-(3-methoxyphenyl)-20 acetic acid IH NMR ~400 MHz, CD30D, ppm): o 7.28 (t, IH, J=7.9 Hz), 7.07 (m, IH), 7.15 (m~ IH), 6.g4 (m, IH), 6.8i4 (s, 2H), 4.99 (s, IH), 3.79 (s, 3H), 3.G8 (t, 2H, J=7.] Hz), 2.70 (t, 2H, J=7. I Hz), 2.34 (t, 4H, 25 J=8.0 Hz), 1.54-1.40 (m, 4H), 0.~0 (t, 31-1, J=7.3 H7).
FAB-MS m/e = 387 (M+l) EXAMPLE ]7 30 2-[(2,6-Dipr(lpyl-4(1,2-dillydroxyethyl)phelloxy~]-2-(2-llapllthyl)acetic acid STEP A: 2~6-dipropyl-4-vinylphenol WOg6~W9DS ~ 21 ~57~8 r~~

- io6-'Ille title compoulld was prepared from t-butyldimetllyl-silyloxy-2,6-dipropyl-4-vinylbenzene (Step B, Exarnple 14) by treatment with tetrabutyl~mmnnillm fluoride in THF for a few hours. It was poured into ether/ethyl acetate mixture and washed with brine. After removal of the solvent the crude product was purified by flash column chromatography using ethyl acetate/he.xalle as eluent.
IH NMR (400 MHz, CDCL3, ppm): o 7.01 (s, 2 H), 6.55 (dd, J =
o 17.6, J = l l.O Hz, lH). 555 (d, J = 17.6 Hz. l H), ~.06 (d, J = l l.O
Hz, I H), 2.64 ~t, J = 7.7 I{-z, 4 H~, 1.65 - 1.6() ~'m, 4 H), 0.96 (t, J =
7.2 Hz 6 H).

STEP ~B: Methyl 2-[~2,6-dipropyl-4-vinyl)phenoxyl-2-I2-naphthyl)-acetate The title compound was prepared by alkykatiorl of 2,6-dipropyl-4-vinyl phenol (Step A~ with methyl 2-bromo-2-(2-naphthyl)acetate using the procedure for alkylation described in Step B of F,xample 1.
~H NMR (400 MHz, CDC13~ ppm): o 7.9 - 7.~ (m, 411), 7.6R ~d, J =
6.7 llz, IH), 7.50 ~ 7.4~ ~m, 2 H), 7.02 (s, 2 H), 6.57 (dd J = 18.4, 10.8Hz, I H).5.61 (d.J=18.4, I E~).5.~6~s, 1 11),~.14~;d,J=
10.8, I H)~ 3.73 ~s, I H), 2.3~ - 2.34 (m, 4 H), 154 - 1.43 Im, 4 H~, 0-74 (t, J = 7.33 H~, 6 Hj.

ST~P (~: Methyl 2-[(2,6-dipropyl-4-(1 ,2-dihydroxyethyl)phenoxyl-2-(2-naphthyl)acer~rt~
To a solution of 6 mg (0.024 mmol) of OsO4 and 31 mg (0.263 mmol) of N-methylmorpholine-N-oxide ('NMO) in 3 ml, oi acetone and 2 drops of water was added 96 mg (0.239 mmol) of the prc~duct c)f Step 13. After 90 minutes the reaction mixture was poured intn a mixture of ether and water. The layers were separated aucl tbe aqueous layer was extracted twice with ether. The combined aqueous klyers were wa.stled ~ith saturated sodium chlnride, dried over ~ wO 96/049û5 ~ 19 5 7 5 ~ r~ , 7 ~ anhydrous magnesium sulfate, filtered and concentrated. Purification by flash chromatography (silica gel, hexane / ethyl acetate 1: 1) gave 63 mg of the title compound.
s 1H N~IR (400 MHz, CDCl3, ppm): o 7.89 - 7.80 (nl~ 4 H), 7.67 (d, J
=8.4Hz,lH),7.50-7.48(m,2H),6.9(s,2H),5.25(s,1H), 4.75-4.68 (m. I H), 3.72 (s, 3 H), 3.75 - 3.61 (m, 2 H), 2.38 - 2.34 (m, 4 H), 1.53 - 1.46 (m, 4 H), 0.75 - 0.71 (m, 6 H).

10 STEP D: 2-[(2,6-Dipropyl-4-(1,2-dihydroxyethyl)phenoxyl-2-(2-naphthyl)acetic acid The title compound was prepared from the product of Step C by saponificatiol1 with IN aqueous KOH solutiol1 as described above.
I l l NMR (400 MHz, CD30D, ppm): o 7.84 - 7.71 (m, 5 H), 7.46 -7.42(m,2H),6.96(s,2H),5.03(s, I H),4.55(t,J=7.2Hz, I H), 3.54(d,J=7.2Hz,2H),2.34(t,J=7.9Hz,4H), 1.51-1.30(m,4 H~,0.70(t,J=7.3Hz,6H).

~XAMPLE~ 1~

2-1 (2,6-Dipropyl-4-( 1 -hydroxypentyl)phenoxy] -2-(2-naphthyl~acetic acid STEP A: Methyl 2-l (2,6-dipropyl-4-lormyl)phenoxy]-2-(2-naphthylklcetateTo a solution of 262 mg (0.645 mmol) of methyl 2-[(2,6-dipropyl4-hydroxymethyl)pllenoxyl-2-(2-naptlthyl)acetate in 2 mL of methylene chloride wa.s added 4()4 mg (0.968 mmol) of PDC.
After 4 hours the reaction mixture was diluted with 20 mL of ether and filtered through a pad of florisil / celite and concentrated to give 235 mg of the title comllound.

wo96~90s ~ ~ ' . 2 ~ 9 5 7 5 8 1~I~ LL.. ~ '57 I H NMR (400 Ml lz. CDC13. ppm): ~ 9.S6 (s, Il), 7.89-7.S() (m. 4 H), 7.65 (m, 1 H), 7.5~ - 7.49 (m, 4 H), 5.35 (s. 1 H), 3.73 (s. 3 H), 2.47-~.43 (m, 4 ~), 1.54-1.43 (m, 4 H), 0.77 (t, J = 7.3 Hz, 6 H).

STEP B: Methyl 2-1(2,6-dipropyl-4-~1-hydrox~pentyl)pilelloxy]-2-(2-naphtllyl)acetate Tu a solution of 56 mg (0.143 mmol) of the product of Step A in 1 mL of THF at -78 C was added 0.075 mL (2.0 M in THF. 0.]50 mmol) of n-butyl magnesium chloride. TLC analysis showed that the starting material remained uncollsullled so ().020 nlL
of n-butyl magnesium chloride was added. After 1 h the reaction mi~ture wa,s diluted with saturated aqueous ~IllllllUIIiUIII chloride solution and thcn extracted twice with ethyl acetate. The organic layers were dried over anhydrous sodiurn sulfate, filtered and concentrated. 'Purification by Jla.sh colunm cluomalogrdpll~ (silica gel, hexane / ettlyl acetate 6: 1) gave 32 mg of the title cc~mpc und.
I H NMR (400 MHz, CDC13, ppm): ~ 7.~9-7.X2 (Itl, 4 H), 7.67 (m, I
I l), 7.49-7.47 ~;m, I 1), 6.9 (.s, 2 H), 5.26 (s, I H), ~.36 (t, J = 8.0 I-lz, 4 T-l). 1.75-1.2 (m, 8 1~), 0.86 (t, J = 7.2 Hz, 3 H). 0.72 (t, J =
7.3 Hz. 6 H).

STEP C: 2-L(2~6-Dipropyl-4-~1-hydroxypentyl)phenoxy)]-2-naphth~llacetic acid 2s The title compound was prepared from the product of Step B by saponification with aqueous lN KOH in methanol as described above.

11-1 NMR (400 MHz, C~D3OD, ppm): o 7.S4-7.72 (m, 5 I l), 7.45 -~.43 (m, 2 H), 6.91 {s, 2 H), 5.03 (s. 1 1-1)~ 4.45 (t. I 1-1), 2.36 - 2.32 (m, 4 H), 1.75 -1.45 (m, 4 H), 1.35 -1.29 (m, 4 H~, 0.S7 (t, J = 7.
Hz,3H),0.70(t,J=7.21-lz,6H).
FAB-MS: m/e = 487 (M+ K), 469 (M + Na).

~ W096/04905 . ~1 95758 r~"~ os c7 . ~ . i , 2-~(4-Carboxy-2.6-dipropyllphenoxyl-2-pbenylacetic acid 5 STEP A: t-Butyl 2-[(4-carbomethoxy-2,6-dipropyl~phenoxyl-2-phenylacetate Methyl 2,6-dipropyl-4-hydroxybenzoate (1.5 g, 6.383 mmol~ was refluxed with K2C03 (1.5 equiv) and t-butyl a-bromophenylacetate (2.4 g. 8.856 mmol) in acetone for 16 h. The o reaction mixture was filtered through Celite, the filter cake was wa.shed with acetone and the combined filtrate and washillgs were concentrated. The resulting crude oil was chromatographed (flash column) using silica gel and lO~'~o ethyl acetate in hexane to give the titled compound (2.7 g).
IH NMR (400 MHz, CD30D, pprn): o 7.665 (s, 2H), 7.443 (dd, 2Hj, 7.345 (dd, 3H), 5.019 ~s, IH), 3.851 (s~ 3H), 2.49-2.335 (m, 4H), 1.63- 1.4 (m, 4H), 1.364 (s, 9H), 0.803 (t, 6H).

20 STEP B: t-Butyl 2-[(4-carboxy-2,6-dipropyl)phenoxyl-2-phenyl acetate Saponification of the above t-butyl 2-[(4-carbomethoxy-2,6-dipropyl)phenoxy]-2-phenylacetate (200 mg, 0.47 mmol) with IN aqueou.s solution of LiOH in methanol gave the titled compound 2s (125 mg).
I H NMR ~400 MHz, CD30D, ppm~: ~ 7.66 (s. 2H), 7.5-7.4 (dd, 2H).
7.43-7.36 (dd, 3H) 4.88 (s, IH), 2.5-2.35 (m, 4H)~ 1.63-1.33 (m, 4H), 1.38 (t, 911). 0.83 (t, 61-1).

STEP C: 2-1(4-Carbomethoxy- ,6-dipropyl)phenoxyl-2-phenyl~lcetic acid t-Butyl 2-[(4-carbomethoxy-2,6-dipropyl)phenoxy]-2-phenylacetate (Step A) (125 mg, 0.293 mmol) was treated with 3 mL

WO 96/0490!i ;~ , P~
2 ' 95/758 of trifluoroacetic acid ~TFA) in methylene chloride for 2 h. 'llle volatiles were removed to give the titled compound ~90 mg~.
I H NMR ~400 ~IHz, CD30D, ppm): ~ 7.67 (s. 2H), 7.463-7.44 (m, 2H), 7.387-7.362 (m, 311), 5.177 ~s, lH), 3.856 ~s, 3H), 2.377 (t, 4H), l.tj -1.366 (m, 4H), 0.773 ~t, 6H).

STEP D: 2-r~-Carboxy-2.6-dipropyl)phenoxy1-2-phenyiacetic acid The product of Step C ~70 mg, O.lg mmol) WdS treated o with lN aqueous solution of LiOH in methanol. The reaction was monitored by TL,C. When the starting material was completely consumed, the mixture was acidified at 0~C to pH 5 by addition of IN HCI. 'rhe aqueous phase was extracted with ethyl acetate, dried over anhydrous magnesium sulfaie and filtered. The filtrdte was 15 ~oncerltrated to yield the titled compound (25 mg).
I H NMR (400 MHz, CD30D, ppm): ~ 7.68 (~, 2H), 7.52-7.45 (m, 2H), 7.43-7.365 (m, 3H), 5.175 (s, IH), 2.43 (t, 4H), 1.o4-1.4 (m, 4H), 0.83 (t, 6H).

2-l(4-Carboxy-2~6-dipropyl)phenoxyl-2-~314-dichlorophellyl'~acetic acid The titled compound was prepared using procedures similar to that described in Example 19.
IH NMR (20(1 MH7., CD30D, ppm): o 7.72 ~d, IH, J= 2.() H~) 7.6~:~
(s, 2H), 7.56 (d, IH, J=8.3 Hz), 7.43 (dd, lH, J=8.3, 1.9 Hz~, 5.18 (s, IH), 2.45 (111, 4H), I.S8-1.43 (m, 4H), 0.~4 (t, 6H, J=7.3 Hz).
FAB-MS m/e = 426 ~M+l ) ~ WO 96/04905 ~ , 9 5 7 5 8 2-[(4-Carboxy-2,6-dipropyl)phenoxy]-2-(3-bromophenyl)acetic acid The titled compound was prepared using procedures similar to that described in Example 19.
111 NMR (200 Mltlz, CD30D, ppm): o 7.73 (d, IH, J=l .8 Hzj, 7.69 (s, 2H), 7.56 (dd, lH, J=7.8, 1.9 Hz), 7.46 (d, Ill, J=7.9 Hz), 7.32 (t, o IH, J=7.8 Hz), 5.19 (s, IH), 2.44 (t, 4H. J=7.6 Hz), 1.70-1.34 (m, 4H), 0.~4 (t, 6H, J=7.3 Hz).
FAB-MS m/e = 436 (M+l ) 2-[(4-Carboxy-2,6-dipropyl)phenoxyl-2-[3,4-methylelledioxyphenyl' acetic acid The titled compound was prepared using procedures 20 similar to that described in Example 19.
IH NMR (200 MHz, CD30D, ppm): ~ 7.68 (s, 2H), 7.02 (d, IH, J=1.6 Hz), 6.84 (m, 2H), 5.98 (s, 2H), 5.08 (s, IH), 2.44 (t, 4H, J=7.9 Hz), 1.52 (m, 4H), 0.86 (t, 6H. J=7.3 Hz).
FAE~-MS m/e = 401 (M+l) 2-[(4-Carboxy-2,6-dipropyl)phenoxyl-2-(3-methoxyphenyl)acetic acid The titled cornpc~und was prepared using procedures similar to that described in Example 19.
IH NMR (200 MHz, CD30D, pprm) o 7.68 (s, 2H), 7.29 (t, I H, J=7.9 I-lz), 7.08 (d, 1 H, J= 2.3 l lz), 7.03 (d, lH, J=7.7 Hz), 6.95 (dd, I H, W0 96/~4~05 ~ 2 t 9 5 7 5 ~ b l --J=0.9, 8.3 Hz), 5.14 (s, lH), 3.79 (s,3H), 2.43 1t, 4H, J=7.9 Hz).
1.58-1.42 (m, 4H), 0.82 ~t, 6H, J=7.3 Hz).
FAB-MS mle - 387 ~M+I) (N-Benzenesulfonyl)-2-[(4-(N-ben~enesulfonyl)carboxarnido-2,6-dipropylpheno~y]-2-(3 -bromophenyl)acetamide .

Th~ titled compound was prepared using the procedure descrihed for the synthesis of N-sulfr m,~lcarboxamides in US Palellt 5,177,095. The diacid 2-1(4-carboxy-2,6-dipropyl)pheno.cy~-2-~3-bromophenyl)acetic acid (200 mg~ 0.46 rnmol; from Example 2i) was refluxed with carbonyldiimidazole (1.5 equiv) in THF for 3-4 h.
At room 1~ ",~ llre, a mixture of 1.5 equiv of benzelle.sulfollalllide and 1.5 e~luiv DBU in THF' was added to the abvve reaction mixture, and the mixture was stirred overnight. The reaction mixture W.IS
diluted with ethyl acetate and washed with 5'-;~, a4. solution of citric acid. The solvent wa.s removed and the crude product wa.s purified by flash column chromatography to provide 238 mg of the titled compc und.
IH NMR 140() M}lz, CD30D, ppm): ~ 8.07 (dd, 2H. J=1.4.7.2 Hz), 7.91-7.88 (m, 2H), 7.67-7.49 ~m,8H), 7.46 (s, 2H). 7.~8-7.2~ (m.
25 2H), ~.01 (s, IH~, 2.28-2.23 (m, 4H7, 1.49-1.2'9 (m, 4H7; 0.71 (t. 6H~
J=7.4 l lz').
FAB-MS mle = 713 ~M+1).
~0 l!~XAl~rlPLE 2~

N-(4-t-butylbenze:nesulfonyl)-2-(4-meihoxycarbonyl-2-propyl-phenoxy)-2-(3,4-methylenedioxyphenyl ~acetamide ~WO 96/04905 ~ 9 5 7 5 ~
; ;.

Step A: Preparation of 2-(~-carboll1ethoxy-2-propylpllenoxy)-3 4-methylenedioxyphel1ylacetic acid ~ To ethyl 2-(4-carbomethoxy-2-propylphenoxy)-3 4-methylenedioxyphenylacetate (Step A of Example 56) (2.04 g 5.10 mmol) in MeOH (40 mL) wa.s added 5 N NaOI-I (8 mL). The rapid reaction was fo]lowed immf~ t~ly by TLC to monitor mono deesterification. The reaction was quenched with 9 N HCI (4.5 mE) after loss of the ethyl ester and before methyl ester saponification. A
saturated solution of NaHCO~ was added to the reaction until it was basic and the ~leOH was removed in vacuo. The residue wa.s partitioned between Et20 and uater collecting the product in the aqueous phase and removin~ impurities with the organic phase. The aqueous phase was then acidified with 9 N HCI (pH = I ) and the product extracted into EtOAc. The solution was dried over ~IgSO4 filtered and the solvent removed. yield = 1.78 g (4.7~ mmol 94~o) rf = 0.16 (~O:10:1/CHCl~:MeOH:NH40H).

Step B: Preparation of the precursor sulfonamide To a dichloromethane solution of the sulfonyl chloride (~ leq) cooled to 0~C was added t-butylamine (3 eq). After 3-5 hrs the CH2CI2 was removed and replaced with EtOAc. The reaction solution was washed with I N HCI water~ 1 N NaOH and brine. The resulting .solution was dried over MgSO4 and filtered. The .solvent was removed.
To the resulting solid was added a couple of drops of anisole and then TI~A to remove the t-butyl group. After all of the sulfonamide had been deprotected. the TFA was removed in vacuo and the residue taken up in EtOAc/Et20. The solution ~vas ~vashed with saturated l~al-{CO3 solution to remove any residual TFA then with brine dried over - MgS04 filtered and the solvent removed.
The sulfonamide precursors used in the preparation of the compounds of Examples 28 29 31 32~ 37 38 and 39 were prepared from the corresponding sulf'onyl chlorides utilizing the procedure described above. The sulfonamide precursors used in the prepardtion W096104905 p~"~ ,57 2~ 9~75~

of the compound.s of Examples 26 and 33-36 are commercially available.
'I'he sult'onamide precursors used in Examples 27, 30 and 32, whose sulfonyl chlorides are not cornmercially availahle, were prepared using standard chemistry:

Preparation of precursor sulfo~mide for Example ~7 The t-buh~lsulfonamide of 4-bromobenzenesulfonyl chloride was prepared usin6 the procedure- described above. The t-butylsulfonalnide was then coupled to phenylboronic acid in a p~ll"~ rn catalyzed cross-coupling reaction with NaOH, EtO}I, toluene, and Pd(PPh3~4 at l()(~' C' to afiord the biphenylsulfonamide. Deprotection of the t-butylsulfonamide with TFA and anisole yielded the f'ree sulfonamide.

Preparation of precursor.sulfonamide for Fuuln~le 30 The t-butylsulfonamide of 2-thiophenesulfollyl chloride ~vas prepclred using the procedure described above. Treatmenl of the t-butyl.sulf'onamide with Bul,i then i.sobutyl iodide afforded the .1-20 isohutyl-2-thiophene-t-butylsulfonamide which was then deprutected Witil TFA and anisole to yield the free sulfonclmide.

Preparation of prec:ursor sulfonamide for Ex ~nu;~le 32 The ~-butylsulfonamide of p-nitrober~enesult'onyl chloride was prepared using the procedure described above. Reduction of the nitro group to the amine W'dS accomplished with hydrogen in MeC)H
over Pd-C. Treatment of the free arnine with LiBr and (MeOi~PO and then NaOH afforded the dimethylamine and the t-butylsulfonainide was deprotected with TFA and ani.sole to yield the free sulfonalllide.
31) ~ : ~ '' 2~q~7~8 W0 96/04905 Y~ 7 Step C: Preparation of N-(4-t-butylbenzenesulfonyl~-2-(4-carbo-methoxy-2-propylphenoxy)-3,4-methylenedio~yphenyl-acetamide To the product of Step A (57.2 mg. 0.154 mmol) in dry THF (0.75 mL~ was added CDI (76.0 mg, 0.469 mmol) and the reaction heated to 50~C for 2.5 hr. To this solution was added a solution of p-t-butylphenyl-sulfonamide (131.7 mg, 0.618 mmol) and DBU (92.1 ~lL, 0.594 mmol) in dry TIHF (0.75 mL). The reaction continued to be stirred at 50~C monitoring by thin layer chromatography until all of the mono-acid was con.sumed (approx. 3 hr). The reaction ~,vas concentrated in vacuo and the residue was taken up in 50:50/F,t20:EtOAc. The organic phase was washed with lO~o citric acid (2~), water and brine then dried over MgSO~, filtered and the solvent removed. Purifïcation was accomplished by radial chromatography 15 eluting with 3:2/He~:EtOAc. yield = 74.3 mg (0.131 mmol, 85~) rf =
0.32 (R0:10:1/CHCll:MeOH:NH4011) FAB mass spectrum, m/e 590.0 (M+Na calculated for C30H33NSO# 5903. See Drummond, J.T.;
Johnsoll, (G. Tetrahedron Lett., 1988, 29, 1653.

2~

W0 9G/04gO5 r~

Example.s 26 through 39 were prepared following the procedure.s de~cribed above in Example 25.

CO2Me ~
o~z 0~3 E ~ h,1as~ pe~ -um CON} S02Ph (M+ ;) 5 ~.. 0 -CONH 02-~p-phen~ )Ph (M+l~ a) l ~.0 CONrrlS02-(p-CI) ~ (~1+) 5--6.0 .,CO~-lSO2-(p-Me' ~1 coN-~c --(5-isu~ hio,~rlene (~I+~IJ ~6.4 C~ !~ û,-(p-:~/eO)Eh ,_CON~ 02-(p-N YIe ) 'h Y + ) : . .
'.,0.~- 02-(o- \~ +- ) - -2s -CC'N - -(o-CO2~ e,Ph ~ ~+~ . 7 .u ::C~~- 02-~o-C ):'h v +~: 4 .
02-lm-C ~h ~ +') 4 Cf~ ~ -I 02CH2 'h ( ~' + ~ ~h, C~ ~ ~-dansy ( v + ) COI~-. 02-~-quinoline 1':.~ + ) - ~. . ' 2 ~ 9 5 7 5 8 WO 96/0490~ 7 The proton NMR data for Example 29 is given below:

5 N-(4-methylben~enesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3.4-methylenedioxyphenyl)acetamide ~H NMR (400 MHz~ CD30D, ppm): o 0.89 (t, 3H), 1.59 (m, 2H), 2.34 (s, 3H), 2.63 (m, 2H), 3.85 (s, 3H), 5.49 (s, 11-~), 5.97 (s, 2H), 6.55 (d, 0 111), 6.79 (d, 11-1), 6.91 (d, 11-1), 6.96 (dd, 111), 7.26 (d, 2H), 7.58 (dd, IH), 7.70 (d, 2H), 7.74 (d, lH).

N-(4-t-butylbenzenesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide To the product of Example 25 (51.1 mg, 0.090 mmol) in MeOltl (2 mL) was added 5 N NaOH (0.5 mL). The reaction was 2c monitored by TLC. When the reaction was complete the MeOH was removed .md the residue partitioned between water .md Et20:EtOAc.
The water layer was acidified with HCI solution and the product extracted into the organic phase. The organic phase was washed with brine then dried over MgSO4, filtered and the ~olvent removed.
25 Trituration wittl Et20/Hex provided a wllite solid. yiekl = 25.8 mg (0.047 mmol, 52~,o) I~AB mass spectrum, m/e 554.2 (M+l calculated f'or C2~ NSOi 554).

75~
~ ' 21q5 WO9C/OJ90~ r~l,.u, EXAMPLES 41-~4 E~amples 41 through ~4 were prepared following the~ A
procedures described above in E~ample 40.
s ~~
o~z 0~
h'x. Z Mass Spectrum C~IN~ SOzPh ~'v1+1~ 4 CONH ~ 'p-phenyl)Ph ~ M+~
~C~ - S _7-(p-C~l)P} I 1~+) ~ ~.C
CO\ ~SC~2-(p-M~)P I (' vi+l~ 3, 3 ~'C()l~ iBu)-hor~ene ~'~+1~ ) 5 2.0 ~n C ~ ~.. O~-~p-~v ~ ~ h , ~/+ ~''Y.(l ON~S~2-(P-Nve.)'h ~,v+ M ~ .
C~ l O~-(o-h~ J~/ + ~,.
~C~ S~ O-c~2~ 1 ( V + . ' ,.
')~f-~ 3. ~2-(~-~ V+~
(_QI' O~-(m-Cl)r~ v + ' ", ~ iH o2CH2Ph (.v+ ' _.
T- -dansyl ( v+
~ CO1~1~07-8-quinoline (v+ )~

2 ~ 9 ~ 7 5 ~
WO 96/04905 : I _IlVv .l ,_ _ I

The proton NMR data for several of the Examples is given below:

N-(4-dimethylamillobenzenesulfonyl~-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acef:lmi~l~

H NMR(300 MHz,CD3OD,ppm):o0.89 (t. 3H),1.59(m,2H),2.62 (m,2H),3.03(s,6Hj,5.48(s,1H),5.96(s,2EI),6.43 (d, lH),6.64 (dd, 2H)~6.79 (d. IH),6.91 (m, 2H),7.55 (dd, lH),7.64 (dd. 2H),7.74 (d, IH).

lS
N-~2-carboxybenzenesulfonyl)-2-(4-carboxy-2-propylphenoxy)-2-(3,4-methylenedioxypheny l)acetamide IH NMR(400 MHz,CD30D, ppm): o0.92 ~t, 3H),1.62(m,2EI),2.67 (m,2H),5.66(s,1H),5.g5(s,2H),6.74 (d, 111), 6.77 (d, 11-1), 6.93 (d, IH),6.98 (dd. IH), 7.60(m,2H),7.69(m,1E~),7.75(m,2H),8.09(d, IE-I).

2s N-(dansylsulfonyl)-2-(4-carboxy-2-propylphelloxy)-2-(3,4-methylenedioxyphenyl)acetamide IEINMR(400 MHz, CD~OD, ppm): ~ 0.83(t,3H),1.51(m,2H),2.57 (m,2H),2.88(s,6H),5.40(.s,1H),5.95 (dd, 2H),6.26 (d, IH),6.65 (d, IH),6.79 (d, IH),6.85 (dd, lH),7.19 (dd, IH),7.25 (d, IH), 7.48(t, lH),7.54(t,IH),7.66 (d, IH),8.13 (d, IH), 8.30 (dd, IH), 8.53 (d, IH~.

q ~ 7 W0961U490~i 58 1~l" ~, N -(8-quinolinesulfonyl i-2-(4-carboxy-2-propylphelloxy)-2-(3,4-methylenedic~xyphenyl)~ e.l~lmi~

IH NMR (300 M11z, CD~OD, ppm): o 0.S5 ~t, 31{), 1.54 (m, 2H), 2.59 Im~ 2H), 5.57 ~s. IE-1), 5.94 (s~ 21H), 6.47 (d, IE-I), 6.66 (d, Il{), 6.71 ~d~
IH), 6.87 (dd, lH), 7.34 (dd, IH), 7.58 (dd, ]H~, 7.6~ (m, 2H)1 ~.20 (dcl, IH), 8.39 ~dd~ ]H), 8.47 (dd, lH), 8.~3 ~dd~ IH).

N-(8-quinoline~uli'onyl)-2-(4-carbo~amido-2~ Jyl~ o~y)-2-(3,4-methylenedioxyphenyl)~e~rni~f~

To N-~8-quinolinesulfonyl)-2-l4-carboxy-2-propyl-pheno~y l-2-(3 ,4-1nethylenedioxyphenyl)~ ei:lm i~, Example 54,125.X
mg, 0.047 mmol~ dry DMF (0.~ mL) was added 1-~3-dimethyk~ o-propyl)-3-ethylcarbodiimide hydrochloride, also referred to as EDC, 20 (18.4 mg, 0.0~ mmol), NH4CI ~6.7 m$, 0.125 mrnol), ;~d TEA (17.
mL, 0.125 mmol). Reaction was followed by thin layer chromatography ~100:15:1.5/CH2Cl,:MeOH:HOAc). When iiIe l~actioll was completed the DMF was remc ved in vacuo and the residue taken uy in Et~O/EtOAc. The solution was washed with 109~, citric acid, water 2s and brine then dried over MgSO4, filtered and the solvent removed.
The prodllct was purihed by chromatograplly eluting with 200:5:1.~1CH2Cl2:MeOH:HOAc. rf = 0.35 (100:5:1.5/CI12CI2:MeOr-l:HOAc) FAB mass spectrum. m/e :548.01~1+1 calculate(i fc~r C2~H25N3SO7 ~48).

~ WO 96104905 ~ 2 ~ 9 5 7 5 ~ p~,l/LI~_lb, j - a-(4-carbomethoxy-2-n-propylphenoxy)-3.4-methylenedioxy- phenyl)acetic acid Step A: Preparation of ethyl (x-(4-carbomethoxy-2-n-propyl-phenoxv)-3.4-methvlenedioxyphenylacetate To a 2 L three necked 24/40 round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a dropping funnel wa.s first added a solulion of 36.0 g (0.1 ~5 ItlOI) of methyl 4-hydroxy-3-n-propylben~oate dissolved in 700 mL of anhydr()us DMF followed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged wittl nitrogen and the reaction mixture was stirred at room temperature tor 2 hours. A solution of 58.5 g (0.204 mol) of ethyl o~-bromo-3,4-5 methylenedioxyphenylacetate dissohr7ed in 100 mL of DMF was theadded via ;m addition funnel over a 15 minute period. The reaction mixture was stirred an additional I hour at room temperature then quenched by addition to 5 I of a 5'Yc, aqueous citric acid .solution. The organic product was extracted into diethylether (2 x 4 L), the organic 20 layers were separated, wa.shed with saturated aqueous NaCI, dried (1\1gS04), filtered, and evaporated. The residue was applied to a .silica gel (2 kg; 70-230 mesh) column equillibrated in 1()~! C112Cl2-hexane.
The column was then eluted succes.sively with 12 L of 10~ Cl-12CI2-hexane, 12 L of 5'~c, EtOAc-hexane, 4 L of 7.5C~c ~tOAc-hexane, 12 L
25 of 10'~c EtOAc-hexane, and finally 8 L of 2()~o F,tOAc-hexane.
Combination of the purified fractions and evaporation in vacuo afforded 76.3 g (74.2 theoretical) of the title compound as ~l p~lle yellow oil which was used without further purification in the nexl step.

30 Step B: Preparation of a-~4-carbomethoxy-2-n-propylphenoxy)-3,4-methylenedioxyphenvlacetic acid A I L 3 necked 24/40 round bottom flask equippe.d with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0. l 85 mol) of the semi-purified product of ~V0 96/0491}5 2 1 9 5 7 5 8 ~ L . ~

Step A dissolved in 500 mL of methanol. The flask was purged witl nitrogen, the stirrer was started, and 37 mL of a 5.0 N aqueou~ .~iolutio:n of sodium hydroxide was added over a 30 minute period via an addition ~fu:lmel. The reaction mixture was stirred at room temperature for an add:itional 30 mimltes at which point TLC analysis (CH2C12-l\leOH-:NH4OH 90:10: 1) iodicated that the starting material had been con.sumed.
The reaction mixture was adjusted to pH=4 with 6 N HCI. and the bulk of the organic solvent was removed in vacuo. The precipitated or,gallic product and t:he ~queous layer were next partitioned between Cl-1~2CI1 ( I
L) and water (I L) which produced a copious emulsion. '1'he, react:ion mixture was then aged ovemight in ~I refridgerator which resulted ir crystallization of the organic product. The crystalline solid was se~larated from the two phase mixture by filtration and washed with CH2C12. The solid was slurried again in diethylether7 filtered, wa.shed with hexane, and then dried in a ~acuum to at'ford 65 g (94~o) of the title compound as a white crystalline .solid.
I E-l-NMR (400 MHz, CD30D, ppm): ~ ().93 (t, J=7.2() H~., 3H), 1.62-1.75 ~m, 21-1), 2.63-2.70 (m. lH), 2.77-2.81 (m, lH), 3.~4 (s~ 3H)~ 5.54 (s~ 1), 5.94 (~, 21-1), 6.~1 (d, J=7.60 Hz, IH)~ 6.89 (d, J=g.20 Hz, I ~iJ, 7 0~ ~d, J=1.60 1-1z, Il{), 7.11 ~br s, lH), 7.78-7.RI (m, 2H).

E~X~4MPLE 57 N-(4-iso-propylbenzenesulfonyl)-a-~4-carbomethoxy-2-n-propyl-phelloxy)-3~4-methylenedioxyphenyl~ret:~m~

Step A: Preparation of IV-(4-iso-propylben~enes~ onyl)-o~-(4-carbomelhoxy-2-rl-propylphenoxy i-3,4-methylenedioxy-phenylacetamide An oven dried three-necked 24/40 1 L round-bottom flask V~,'.lS eqllipped ~ith a mechanica:l stirrer, a nitrogen inlet, and a septum.
The flask was flushed with nit:rogen, then char~ed witll 20.06 g (53.9 mmol) of the product of Example ~6, 400 mL of anhydrous THF. and 9.76 mL ~70.0 nurlol) of triethylamine. The flask and its contents were ~ , 2~9~7~8 W0 96/04905 ~ - r~

stirred and cooled to -78~C with an extemal dry ice-acetone bath and then 7.30 mL (59.3 mmol) c~f trimethylacetyl chloride was added slowly via a syrin~,e. After the addition was complete, the dry ice-acetone bath was replaced with an ice-water bath and the reaction was stirred at 0'C
for 1 hour. A separate oven dried 3 necked 24/40 2 L round-bottom ilask was equipped with a mechanical stirrer, a septum and a nitrogen inlet. The flask was flushed with nitrogen then charged with 16.102 g (80.8 mmol) of 4-iso-propylbenzellesulfonamide and 300 mL of anhydrous methyl sulfoxide. The stirrer WLIS started and a 162 mL of a 1Q 1.0 M solution of lithium bis(trimethylsilylamide) in TIIF was .slowly ~mildly exothermic) added via a syringe through the .septum. After the addition was complete, the reaction nli~ture was stirred at room temperature for ;m additional 30 minutes. The contents of the first reaction mixture including a fine white precipitate that was suspended in the reaction mixture were then slowly transfered to the stirred solution of the deprotonated sulfonamide in the second flask via a wide diameter cannula. The combined reaction mixture was then stirred for an additional l4 hours under a nitrogen atmosphere. The reaction wlls the quenched ~,ith 1.0 N HCI llnd the majority of the volatile solvents \i,~ere 20 removed in vacuo. The residue wa.s partitioned bet~A~een E~tOAc and 1.0 N HCI. then organic layer wa.s separated. washed ~vith saturated a~lueous NaCI, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel (3 kg; 70-230 mesh) chromatography column (15 cm ~ 150 cm) eluted with (90:10:1 CH2C12-MeOII-25 NH40H). Combhlation of the purified fractions and evaporation hvacuo afforded 18.367 g (629'o) of the title cumpound.
IH-NMR (400 Mll~, CD30D, ppm): ~ 0.8X (t, J=7.60 Hz,3H),1.24 (d, J=7.00 Hz,3H)~ 1.25 (t. J=7.00 Hz,3H),1.55-1.60 (m,2H),2.59-2.66 - (m,2H),2.97 (.sept, J=7.00 Hz,111),3.83 (s,311),5.52 (s, IH),5.97 (s~
3~ 211),6.50 (d, .1=8.80 Hz~ I 1-1), 6.80 (d, J=8.00 Hz, IH),6.8~ (d, J=1.60 Hz, IH),6.~4 (dd, J=2.00, 8.00 Hz7 IH), 7.14 ~d, J=8.80 Hz,2H),7.59 (dd, J=2.20, 8.80 Hz, I }-1), 7.75 (d, J=2.20.1 H),7.79 (d, J=8.80 Hz, 2H).

W0 961~4905 ~C ~ / r~ u~

EXA~IPLE :58 N-~4-iso-propylh~n7.f n~.slllfonyl)-a-(4-carboxy-2-n-prc pyll)helloxy')-3,4-methylenedioxyphenylacetamide dipotassium salt ~; F~reparation of N-(4-iso-prc pylbenz,enesull'onyl)-a-(4-carboxy-2-/1-propylphenoxy)-3,4-methylenedioxyphenyl-~,t.~mi~lP dipota.ssium salt To a solution of 18.367 g (33.2 mmol') of the product of o Example 57 dissolved in 100 mL of methanol was added a solution of 6.56 g (116.9 mmol~ of potassium hydroxide in ?5 mL of water alld the reaction mixture was stirred at 60~C under a nitrogen atmosphere.
After 6 hours TLC analysis (80:15:1 CHC13-MeOH-NH4011) indicated that ester hydrolysis was complete. The reaction mi~ture ~vas cooled to 15 room temperatllre. diluted with 100 mL water7 filtered tllrou~h a 0.45 micron filter and then divided into two equal volume pc~rtions. '1'he fractions were indi~r~idually desalted and purified on a Waters Millipore Delta Prep 30QO liquid chromatograph equipped with an MIOQO Prep-Pak module containing a 47 x 300 mm Delta-Pa}c C18 1511m IOOA
20 column cartridge. Two solvent resevoirs were employed: solvent system A ~95-5 water-acetonitrile), and solvent .sy.stem B ~.'i-95 water-acetollitrile), and the column effluent was monitored sirnultaneously at 210 and 280 nm Wit'tl a Waters model 490 UV-visible detector. Each fraction was pump-injected onto the colurnn and desalted by elutioll 150 2s mL/min) with ~several column ~olumes of solvent system A. A gradient elution was then begun which had as initial cr~n~itir)n~ lOO~o solvent system A-O~o solvent system B and reached after 30 minutes 50~o solvent system A-50~~, solvent system B, and the ~fractions were collected u!ith an ISC~O Foxy 200 fractioll collector. The purified 30 fraction.s were combined in round bottom flasks, frozen in a -78~C dry ice-acetone bath. and Iyophilized. Combination of the purified product afforded 18.719 g (92%) of the title compound a.s a white Iyophili~ed powder.

2 7 ~5~5~
-- W096N~491}5 r~ J,,.;h,, 7 - i25-IH-NMR (400 MHz, ~D30D, ppm): o 0.88 (t, J=7.20 Hz, 3H), 1.21 (d, J=7.00 Hz, 3H), 1.22 (d, J=7.00 Hz, 3H~, 1.56-1.63 (m, 2H), 2.52-259 ~ (m, lHj, 2.67-2.74 (m, lH), 2.91 (sept, J=7.00 Hz, lH), 5.33 (s, IH), 5.92 (d, J=1.20 Hz, I H), 5.93 (d, J=1.20 Hz, IH), 6.72 (d7 J=8.50 Hz, IH), 6.76 (d, J=8.50 llz, IH~, 7.04 (d, .1=7.50 I-lz, IH), 7.05 (s, IH), 7.21 (d, J=8.50 Hz, 2}{), 7.64 (dd, J=2.00, 8.50 Hz, 111), 7.67 (d, J=~.50 Elz, 2H), 7.73 (d, J=2.00 Hz, IH).
Microanalysis for C28H27Nso8K2-H2o~
0 Calc'd: C = 53.06; H = 4.61; N = 2.21; K = 12.34.
Found: C = 52.81; H = 4.56; N = 2.17; K = 12.02.

a-(2-iso-butyl-4-carbomethoxyphenoxy)-3.4-1nethylelledioxy-phenylacetic acid Step A: Yreparation of ethyl a-(2-i~v-butyl-4-carbometlloxy-phenoxv)-3.4-methYlenedio.~ypheny1acetate To a solution of 1.008 g (4.84 mmol) c~f methyl 3-isz~-butyl-4-hydloxyberlzoate and 1.737 g (6.05 mmol) of ethyl oc-bromc~-3,4-methylenedioxyphenylacetate in 10 mI of acetone W.ls added 1.33 g (10 mmol) of finely powdered potassium carbonate. The reaction mixture was m~gn~lically stirred and refluxed fclr 4 hours, then cooled 2 to room temperature, filtered and evaporated. The residue was purified on a silica gel fla.sh chromatography column eluted with 10% EtOAc-hexane; combination of the purified fractions and drying in vacuo afforded 1.518 g (76~/o) of the title cormpound as an amorphous powder.
1 H-NMR (400 l~lE-lz, CDC13, ppm): o 0.90 (d. J=6.60 Hz, 3H), 0.94 (d, - J=6.60 Hz, 3H), 1.17 (t, .J=7.20 llz. 3H), 2.02-2.08 (m, IH), 2.55 (dd, J=7.20, 13.20 Elz, IH)~ 2.64 (dd, J=7.20, 13.20 llz., 11-~), 3.~ (s, 3H), 4.11-4.19 (m, 2H), 5.56 ~s. 111), 5.96 (s, 2H), 6.70 (d,J=9.20 Hz, lH), 6.6~ (d, J=7.60 Hz, lE~), 7.02 (dd, J=1.60, 8.00 Hz, lH), 7.05 (d, .1=2.00 Hz, IH). 7.78-7.81 (m, 2H~.

2 ' q 5 7 ~ ~
WO ~C/~4905 r~

Step B: Preparation of u-(2-iso-butyl-4-carborlletl1oxyphenoxy) 3~4-methylenedioxyphenylacetic acid To a solution of 1.518 g ( 3.66 mmol) of the product vf Step A dissolved in 8.0 mL of methanol was added 1.0 mL of a 5.0 M
5 solution of aqueous sodium hydroxide. The reaction was stirred at room temperature and monitored by TLC (80:15:1 C~HC13-MeOll-NH4OH). After 1.5 hours the reaction was ;judged to be complete and the reaction mixture was adjusted to pH=5 with 1.0 N HCI. 'l~he reaction mixture ~h~as then partitioned between EtOAc and water, separated~ dried (MgSO4)~ filtered, and evaporated. The residue wa.s purified on a silica gel flash chromatography cc~lumn eluted with CHC13-MeOEI-NH4OH (80:15:1); evaporation of the purified f}actions and drying in vacuo afforded the title compound as an amorphous foam.
I H-NMR (400 MH~.. CD30D, ppm): o 0.86 (d, J=6.R0 H~, 3EI), 0.89 15 (d,./=6.80 llz, 3E-1), 1.96-2.04 (m, IH). 2.4'~ (dd,J=7.20, 12.~0 llz, 11-1 2.69 (dd,.l=7.20, 12.80 E-lz, 1~1), 3.84 (s, 3H), 5.49 (s, lH), 5.92 (d, .l=1.2() H~, lH), S.g3 (d,.l=1.20 ~Iz, IH~, 6.79 (d,J=~.OO l-lz, IH'~, 6.89 id, J=8.~0 Elz, 11-1), 7.08 (dd, J=1.60, 8.00 Hz, IHj, 7.11 (d, .l=1.60 Hz.
I El j, 7.74 (d, .r=2.40 Hz, IH). 7.7X (dd, J=2.40, X.80 Hz. 11-1).
20 Cl-MS mle = 386.2 (M+)-EX~MP!.~. 60 N-(4-iso-propylhPn7,P,nPsulfonyl)-a-(2-iso-butyl-4-ca}bomethoxy-25 plletlox,r~)-3,4-rlleth!,~lenedioxyp~lenylacetaLlIide Step A: Preparation of 1~,'-(4-iso-propylbeiIzenesulfonyl)-cx-(2-iso-butyl-4-carhomethoxyphenoxy)-3,4-mettlylenedio,Yypllellyl-a~etaltlide, To a solution of U.727 g ~ 8 mmol) of the product of Step B in Example 58 dissol~ed in 4 mL of ~mbyrdmus THF was added 0.458 g (2.82 mmol) of 1,1 ~ -carbonyldiimidazole and the mixtun~ \~'ilS
ma~netically s~irred and refluxed for 2 hours. Tlle reaction mixture was then cooled to room temperature, and 0.56~ g (2.82 mmol) of 4 .

~ wo 96/W905 ~ ; 2 1 9 ~ 7 5 8 ~",, .~ , iso-propylbenzenesulfonamide and 0.42 mL (2.~2 mmol) of l,S-diazabicyclo[5.4.0]undec-7-ene were added. The reaction mixture was stirred an additional 3 hours at room temperdture, then was evaporated in vacuo. The residue was partitioned betweell EtC)Ac and 1.0 N HCI
and extracted. The organic layer was separated, dried (MgSO4), filtered, and evaporated and the residue was purified on a silica gel flash chromatography column eluted with CHC13-MeOH-NH4011 (S0:15:1).
Evaporation of the purified fractions and drying in vacuo afforded 0.666 g (63~o) of the title compound.
1 I-NMR (400 MHz, CD30D, ppm): ~ 0.R I (d, J=6.80 HZ! 3H), 0.S4 (d, J=6.S0 Hz, 3H). 1.23 (d, J=6.80 llz, 311), 1.24 (d, J=6.S0 HZ! 3H), I.S8-1.94 (m, 111~, 2.45 (dd, J=7.00, 13.00 Hz, 111), 2.~S (dd, ~=7.00, 13.00 H~, lH), 2.95 (sept, J=6.80 Hz, IH), 3.S4 (s, 31-1), 5.46 (s, IH), 5.95 (d, J=l .20 H~, I H). 5.96 (d, J= 1.20 II~, IH), 6.59 (d, J=8.60 Hz, IH), 6.79 (d, .1=S.00 1 Iz, 11-1), 6.98 (br s, I H), 6.99 (dd, J=I .60, S.00 Hz, 1 H), 7.30 (d, J=8.40 Hz, 211), 7.60 (dd, J=2.00, S.60 I Lz, 11-1)~ 7.70 (d, .1=2.00 Hz, IH), 7.72 (d, J=8.40 H~., 2H).

N-(4-i.s(l-propylbenzenesulfollyl)-a-(2-iso-butyl-4-carboxyphenoxy)-3 ,4-methylenedioxypllenylacetdmide Step A: Preparatioll of N-(4-iso-prc pylbell~enesulfonyl)-a-(2-iso-butyl-4-carboxyphenoxy)-3,4-rmethylenedioxyphenyl-acetamide To a solutiolI of 0.294 g (0.52 mmol) of the product of Example 60 dissolved in 3.0 mL of methanol was added 1.0 mL of a 5.0 - N a~lueous .solution of .sodium hydroxide. The reaction mixture was maglletically stirred at 60~C. After 3 hours TI.C analysis (CHC13-MeOH-NH40H S0:15:1) indicated complete hydrolysis of the ester. The reaction was cooled to room t~ peld1ul~, adjusted to pl 1=5 with dropwise addition of 1.0 N HCI, then partitioned behveen EtOAc and water. The organic layer was separated, washed witb .saturated a~ueous 2 1 Y ~ ~5 ,~ --W0 ~6/04905 ~ r~

NaCI, dried ~MgSO4~ filltered and evapor.lted. The residue was driecl in vacucl to afford 0.238 g (X3~70) Of the title compound a.s an amorphous po~der.
I H-NMR (400 MHz. CD30D, ppm): o 0.82 ~d, J=6.80 l lz, 3H), 0.85 (d, J=6.80 Hz, 31 i), 1.24 (d, J=7.20 Hz, 3H), i.75 (d, ~=7.~0 Hz., 3H), 1.91 (.sept, J=~ 0 Hz, I 1-1), 2.48 ~dd, J=7.20, 13.2û Hz~ IH), 2.~6 ~dd, J=7.20~ 13.20 Hz, IHj, 2.97 (sept,J=7.20 Hz, IH), ~.51 (s, IH~, 5.97 (s, 111),6.50(d,J=8.4011z, IH),6.81 (d,J=8.00Hz, IH),6.91 (d,J=1.6(1 Hz, IH), 6.9:5 ~dd, J=1.60, 8.00 Hz, IH~, 7.36 (d, J=S.40 TIz, 2H~, 7.62 (dd. J~2.20, 8.40 Hz, I H), 7.72 (d, J=2.20 l lz, IH), 7.79 (d, J=8.40 Itlz~
2E-1).
FAB-MS nlle = 554 (M + 1).

/~-(4~ o-propy3henzenesulfonyl)-o~-(2-n-propyl-4-methoxycarbonyl-~henoxy~-o~-methyl-3 ,4-met~lylenedioxyphenyl~et,lmi-l~

Step A: Preparation of N-~4-iso-propylbell~enesulfonvl~l-(x ~7-n-propyl-~-methoxycarbonylphenoxy~ methyl-3,4 m~thylenedioxvphenvlacetamide To a sohltioll of 0.516 ~ ( 0.93 rnrnol) of the producl of Example 57 dissolved in 1.0 mL of anhydrous THF was added ~ 80 mL
(2.80 mmol) ol a 1.0 M solution of lithium bis~trimeth~isilylami(ie) in 25 THF at -78~C under ~a nitrogen atmosphere. The reaction mixture was magnetically stirred at -78~C for I hour, then 174 !lL (2.80 mmol~ of ioclometllane was added ~/ia syringe. The reaction was allowed to wa to room temperah~re and was stirred an additional 14 hours. The reaction was next quenched with excess 10~c aqueous NaHSO4 and 30 partitiolled between EtOAc and water. The organic Ltyer was washed with saturated aqueou.s NaCI, dried (MgSO4), filtered ~md evapotaled.
The residue was purified on a silica gel flasiI chlomatography column eluted with Cl-lC13-MeOH-NH40H (90: 10~ . Evaporation of the W096~04905 ~ r~ . .. 7 purified fractions and drying in vacuo afforded 0.293 g (55~o) of the title compound as an amorphous solid.
I I l-NMR (400 MH~, CD30I:), ppm): o 0.g9 (t, J=7.20 Hz,3H~, 1.31 (d, J=6.80 Hz, 6H), 1.64-1.72 (m, 2H), 1.66 (s, 3H), 2.64-2.73 (m, IH), 2.81-2.88 (m, lH), 3.02 ~sept, J=6.~0 llz, ll-l), 3.85 (s, 3H), 5.96 (s, 2H)~ 6.36 (d, J=8.40. 11-1), 6.77 (d, J=8.40 Hz, 2H), 6.99 (m, I H), 7.05 (br s, IH), 7.37 (d, J=7.60 Hz, IH), 7.43 (dd, J=2.40, 8.60 Hz, IH), 7.76 (d, J=8.40 Hz, 2H), 7.81 (br s, I H).
FAB-MS mlc = 568 (M + 1).

N-(4-i.s()-propylbenzetlesulfonyl)-c~-(2-n-propyl-4-carboxyptlenoxy)-oc-methyl-3,4-methylenedioxyphenyl~cets mi~ dipotassium salt Step A: Preparation of N-(4-iso-propylbenzenesulfollyl)-oc-(2-n-propyl-4-clrboxyphenoxy)-(x-methyl-3,4-methy lenedioxy-phenylacetamide dipotassium salt To a solution of 0.293 g (0.52 mmol) of the product of 20 F.xample 62 dissolved in 2.0 mL of methallol was added a solution of 0.143 g (2.54 mmol) of potassiurll hydroxide dissolved in 1.0 mL of water. The reaction mixture was ms~n~tic~lly stirred at 60~C for 4 hours until TLC anlysi~ (CHC13-MeOH-NH4OH 80:15:1) indicated complete hydrolysili of the .starting material. The reaction mixture was 2s then cooled to room temperature, dilwted with 5.0 mL of water and filtered through a 0.45 micron filter. The filtrate was then purified a Waters l~lillipore Delta Prep 3000 liquid chromatograph equipped with two DuPont Zorbax(~ 21.2 mm x 25 cm ODS reversed phase HPLC columns connected in series. Tivo solvent resevoirs were 3c employed: solvellt system A (95-5 wclter-acetonitrile), and solvent systetm B (5-95 water-acetollitrilej, and the column effluent was mc~llitored sirnlllt:~neously at 210 and 2~0 nm with a Waters model 490 UV-visible detector. The reaction mixture was injected onto the colurnn and desalted by elution (50 ml /min) with approximately IL of .solvent W0 96/049U5 2 1 5~ 5 ~ ~7 8 T ~

system A. A gradient elution was tl~e~n begun whiuh had as initial conditions 100~ solYent system A-O~ro solvent sy.stem B and reached after 30 Inillutes 50~Y~7 solvent system A-50% s01veIlt system B, and the fractions were collected with an ISCO l:~oxy 200 fractioll collector. The purified fractions were combined in round bottom flaslis, fro7en in a -7~'C dry ice ac~tone bath, ~md lyophilized. Combination of the purified product afforded 0.273 g (~4~o) of the title compound as a white lyophili_ed powder.
lH-NMR (400 Mllz, CD30D, ppm): ~ 0.96 (t, J=~.20 l lz, 3Hj, 1. - 5 (d.
J=7.20 }-Iz, 3H~ 6 (d, J=7.20 Hz, 3H), 1.64- 1.71 (m, 2H j, 1.67 (s, 3H~ 2.58-2.65 (m, 11-1~, ~.74-2.82 (m, lH), 2.96 (sept, J=7.~0 Hz, lHh 5.91 (d, .1=1.20 11_, 1II), 5.92 (d, J=1.20 Hz, I H), 6.52 (d, J=8.40 llz, lH), 6.72 (d, .J=~.00 Hz, IH), 7.12 (dd, J=l .80, 8.00 Hz, 11~), 7.17 ~d, J=2.00 H_. IH), 7.2~ (cl, J=~.80 Hz, 211), 7.50 (dd, J=2.2(), 8.40 H.z., L 5 l H), 7.72 (d, J=8.80 H~, 2H~, 7.74 (d, J=2.00 Hz, 111).
E~AB-MS m/f' = ~91.6 (M + K+~.

EXAl~PLE 64 N-(4-lso-prop~lbenzelleslllfonyl)-a-(2-n-propyl-4-carboxami(l{)-phenoxy)-3 ,4-methylenedioxyphenylacetamide Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o-(2-rl-pr~pyl-4-c.Lrboxamidophenoxy3-3,4-methylenedioxy-s phenylacetamide Tu a sOIUt:iOtl of 0.162 g (0.30 mmol) of N-(4-iscJ-propylben7.en~sll1fc)llyl)-a-(4-carboxy-2-n-propylphenoxy~-3,4-methylenedio~yphenylacetamide (free acidic form of the product Or Exampie 5~) di.ssolved in 1.5 rnL of anhydruus THF was added 0.0~3 ~
(045 mmol~ of l,l'-citrbonyl~iimid~i7O1e and the resulting mixtule was magnetically stirred and refluxed for 50 rm~r:iutes. The reaction mixture was cooled to room lc,l,L,elalul~, and then addecl at O~C to e~cess TH}-~
that had been preYiously saturated with anhydrous ga.seous ~Ininloni~
The reaction mixture was se.aled and then stirred at room ~ -,alu ~ W096104905 /~ - ' '. 219575~ .~"~ cg~ ~

for 14 hours. The reaction mixture was then poured into water (70 mL) and extracted with EtOAc (150 mL). The organic layer was separated, washed with saturated aqueous NaCI. dried (MgSO4), filtered, and evaporated in vacuo to afford the title compound as an 5 amorphous solid.
I I-I-NMR (400 MHz, CD30D, ppm): o 0.X8 (t, J=7.60 lHz, 311), 1.21 (d, J=6.80 Hz, 6H), 1.55-1.66 (m, 2H)~ 2.54-2.62 (m, IH), 2.70-2.77 (m, lH), 2.89 (sept, J=6.80 l lz, III), 5.36 (s, 111), 5.93 (d, ~=1.20 Hz. IH), 5.94 (d, J=1.20 ~Iz, III), 6.75 (d, .1=~.40 ~-Iz, 11 ~), 6.78 (d, J=8.80 Hz, IH), 7.02-7.04 (nl, 2H), 7.06 (br s, 2H), 7.20 (d, J=8.40 Hz, 2H), 7.55 (dd, J=2.20, 8.60 Hz, I H), 7.62-7.66 (m, 2H), 7.71 (s, I H).
FAB-MS mle = 539 (M + 1).

N-(4-iso-propylbenzenesulfonyl)-o!-(2-n-propyl-4-hydroxymethyl-phenoxy~-3,4-metlIylenedioxyphenylacetamide 20 ~tep A: Preparation of methyl a-(4-hydroxymethyl-2-/t-propyl-phenoxv)-3,4-methvlenedioxyphenylacetate To a solution of 3.~4 g (23.13 mmol) of 4-hydroxy-3-t1-propylbenzyl alcohol dissolved in 70 mL of anhydrou.s DMF was added 9.04 g (27.7 mmol) of cesium carbonate and the reaction mixture was 25 magnetically stirred at room temperature i'or 15 minutes. Methyl a-bromo-3,4-methylenedioxyphenylacetate (7.58 g, 27.7 mmol) was added and the reaction mixture wa.s then stirred for an additional 14 hours at room temperature under a nitrogen atmosphere. The reaction W.IS t}lell - partitioned between 5% a~lueolls citric acid (700 mL) and EtOAc (100 30 mL) and extracted. The organic Iayer was separated, washed with saturated aquec us NaCI, dried (MgSO4), filtered and evaporated. The residue WLIS PUr;f;ed On ;I silica gel ilash chrolIlcltography column eluted with 40% EtOAc-hexane. The purified fractions were combined, WO 96/04905 ~ 2 ? ~ 5 ~ 5 8 r ~"~

evaporated~ and dried in vacuo to afford 6.74 g (81 ~G) of the title compound as a yellow oil.
I H-NMR (200 I\IHz~ CDC13, ppm): o 0.97 (t7 J=7.60 1 L 3~). 2.55-2.75 ~m, 2H), 2.71 ~t, J=7.20 Hz, 2H), 3.71 (s, 3H), 4.59 (s, 2H), 5.55 (s, 111). 5.97 (,s, '2ll), 6.69 (d, J=8.20 Hz. lH), 6.82 (d, l=7.80 Hz. IH), 7.02-7.28 ~m~ 4~1).
FAB-MS mle = 359 (M + 1).

Step ~: Prepaiation of methyl a-(4-tcrt-butyldimethylsilyloxy-methyl-2-n-propylphenoxy)-3 ,4-methylenedioxyphenyl-acetate To a solution of 2.50 g (6.g8 mmol) of the product of Step A dissolved in 20 mL of dichloromethane was added 1.95 mL (14.0 mmol) of triethylamine, 1.26 g (8.38 mmol) of ~ert-l S butyldimeth~lchlorosilane, 85 mg (0.1 eq) of 4-dimethylaminopyridine and the reaction mixture was stirred at room te.l.pelalu,e for 30 minute.s under a nitrogen abnosphere. The reactic~ll was thell dilute(l with I00 nlI. E~tOAc, washed ~ith water~ 1.0 N HCI, saturated aqueous NaHCO3, .satulated NaCI, dried (M~,SO4). filtered and evaporated in vacuo to affi3rd 3.2() g (97~o) of the title compolmd.
El-MS m~e = 472 (M+).

Step (:~: Prep;3ration af o~-(4-tert-butyldimethylsilyloxymetl~yl-2 propylphenoxy)-3~4-methylerlediQxyphenylacetic acid To a solution of 3.20 g (6.7~ n~nol) of the product of Step B dissolved in IV mL of methanol and 3 mL of dichloromethane ~,vas added 1.42 mL ~7.17 mmol) of a 5.0 N aquec~ll.s solution of sodium hydroxide and the reaction mixture wa.s magnetically stirred at room temperature. After 4 hours TLC analysis (CHC13-MeOH-NH4O~I
3~ 80:15:1 j indicated complete hydrolysis and the reaction mixttlre was adjusted to pH=4 with 1.0 N ~Cl. The reaction mixture was then compl(,tely evapDIated and dried in vacuo to afford the Grude product which was used directly in the next step.
FAB-MS nllc = 48I (M + Na+).

~ WO96/04905 ~ . . 2 f q575~ L .,c7 Step D: Preparation of N-(4-iso-propylben_ene.sulfonyl)-c;~-(4-tert-butyldimethylsilyloxymethyl-2-~i-propylphenoxy)-3 ,4-methylenedioxyphenvlacetamide To a solution of 3.30 g (7.21 mmol~ of the crude produc~
from Step C dissolved in 40 mL of anhydrous THF was added 1.75 g (10.8 mmol) of l,1'-carbonyldiimidazole and the reaction mixture was magnetically stirred and heated at reflux for 10 minutes. The reaction was then cooled to room le~ ure, 2.15 g (10.R mmol) of 4-iso-propylben_enesulfonamide and 1.61 mL (10.8 mrnol) of 1,~-diazabicyclol5.4.01undec-7-ene were added and the reaction was stirred for an additional 30 minutes at room temperature. The mixture was then diluted with EtOAc (80 mL), washed with 10% aqueous citric acid, saturated aqueous NaCI, dried (MgSO4), filtered and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with (:IHC13-MeOH-NH4OH (92:8:0.5). The semi-purified material was combined and repurified on a second silica gel flash chromatograplly collmm eluted initially with 35% EtOAc-hexane, later witll 50% EtOAc-hex~me, and finally with 70~70 EtO,t~C-heXalle.
2Q Combination of the purified fractions and evaporatic)n afforded 3.20 g (69C~o) of the title comE~ound as a yellou, oil.
FAB-MS mi~ = 67Rs (M + K+).

Step E: Preparation of N-(4-rso-propylllen7enf slllfollyl) o~ (4 2s hydroxymethyl-2-n-propylphenoxy)-3,4-methylenedioxy-phenylacetamide To a solution of 3.20 g (5.01 mmol) of the product of Step D disscllved in 5.0 mL of anhydrous THF \~v~lS added 5 06 mL (5.06 - mmol) of a 1.0 ~1 solution of tetrabutylammonium fluclride in THF and the reaction mixture was stirred at room ternperature under a nitroge atmosphere. After 2.5 hours 1.0 mL additional tetrabutylammonium fluoride in THF was added and the reaction mixture was stirred for a additional 14 hours. The reaction mixture was then concentrated in vacuo and applied to a silica gel flash chromatograplly column and W096/WgO5 ~ 5 75~ r~ D;. /--eluted with 60~~to EtOAc-he~ane. Comhin~tinn of the purified fractions and drying in vacuo afforded 0.691 g (26%) of the title compound dS an amorphous powder.
I hl-Nl~R (400 MHz, CD30D. ppm): ~ 0.87 (t, J=7.60 Hz, 3H~, 1.26 (d.
J=6.80 Hz, 3H). 1.27 (d, J=6.80 Hz, 3H), 1.51-1 63 (m, 2H), 2.54-2.68 m, 2H~ 2.98 ~sept. J=6.~0 Hz, IH), 4.46 (s, 2H), 5.37 Q~ 1), 5.95 ~s.
1 H), 6.51 ~d, J=8.40 Hz, IH), 6.77 (d, J=8.00 Hz, lH), 6.8X-6.95 (m, 3H), 7.10 (d, J=2.00 Hz, l H), 7.36 (d, J=8.4() Hz. 2H), 7.77 (d, J=8.40 Hz, 2H).
FAB-MS ~??le = 548 (M + Na+).

F.XAMPLE 66 N-(4-iso-propylbenzenesulfonyl)-a-(4-formyl-2-n-propylphenoxy)-3,4-methylenedioxyphenyl:~ret~mi~

Step A: Preparation of N-(4-i.so-propylbenzenesulfonyl)-a-(4-formyl -2-n-propylphenoxy)-3,4-metllylenedioxyphenyl-acetamide 2c To a solution of 0.573 g (].09 mmvl~ of tl~e product vf Ex;{mple 65 dis~vlved in 5.0 mL of dichloromethane W~IS added 2.8(~ r (32.9 mmol) of m~ng~n~.~e dioxide and 1.15 ~ of finely powdered 3A
mc)lecular sieves alld the reaction mixture was magnetically stirred at room temperature for 14 hours. The reaction mixture wa.s thell filtered 25 through a bed of celite and MgSO4 and the filtratç was evaporated in vacuo. The residue was dissolved in dichloromethane ~md applied to a silica gel flash chromatography column and then eluted with 3~ MeC)H-CH2C12. Ev.lpvrdtion of the purified fractions and drying in vacu afforded 0.149 ~ (26~o) of the title compound.
3~ IH-NM:R ~400 ~Hz, CD30D, ppm): ~ 0.89 (t, ~=7.60 H7, 3H), 1.24 (d.
J=7.2U Hz, 3H). 1.25 (d,.J=7.20 Hz, 3H), 1.57-1.68 (nl, 2H), 2.63-2.74 (m, 2H~, 2.96 lsept, J=7.20 Hz, IH), 556 (s, 1~L), 5.97 (s, 2H)~ 6.70 (d, J=8.40 H7, lH~, 6.80 (d, J=8.00 11~, IH), 6.91 (d,J=1.60 Hz, lH), 6.96 (dd, J=1.60. 8.Q() Hz, lH), 7.34 (d, .J=8.40 Hz, 2H~, 7.53 (dd, ~=2.()0, , ~ ~ t ~, 2 ~ ~5753 ~ WO 96/04905 : ~ ~ ' P~ '115 8.40 Hz, lH), 7.66 (d, J=2.00 Elz, lH), 7.76 (d, .1=8.40 Hz, 2H), 9.77 (s, 111).
FAB-MS mle = 546 (M + Na+).

a-(4-acetyl-2-n-propylphenogy)-3,4-methyienedioxyphenylacetic acid Step A: Preparation of 4-hydroxy-2-n-propylacetophellone 0 A Parr hydrogenation apparatus flask was charged with a soluticln of 2.00 g (11.36 mmol) of 3-allyl-4-hydroxyacetophenone dissolved in 10 mL of ethanol and 200 mg of a 10~~'c palladium on carbon catalyst. The nask was mounted in the Parr apparatus and shaken under a 46 psig hydrogen atmosphere for 15 minutes. At the 5 end of this period TLC analysis (15~o EtOAc-hexane) indicated that the starting material had been completely consumed, and the reaction mixture was filtered ~und evaporated. The residue was purified on a silica gel flash chromatography column eluted with 25% EtOAc-llexane.
Evaporation of the purified fractions and drying in vacuo afforded 1.83 20 g (91%) of the title compound.
II-I-NMR (200 MHz. CDC13, ppm): oO.98 (t,J=7.40 Hz, 3H). 1.56-1.78 (m. 2H), 2.57 (s, 3H), 2.63 (t, J=7.20 Hz, 2H), 6.08 (br s, IH), 6.84 (d, J=8.20 Hz, IH), 7.74 (dd, ./=2.20, X.20 Hz, IH), 7.79 (d, J=2.20 Hz, IH).
25 FAB-MS m~e = 178 (M+)-Step B: Preparation of methyl o~-(4-acetyl-2-n-propylphenoxy)-3,4-methylelledio~yphenylacetate - To a solution of 0.250 g (1.40 mmol) of the product of 3~ Step A dissol~ed in 3.0 mL of DMF was added 0.504 g (1.54 mmol) of cesium carbonate and the reaction mixture was magnetically stirred at room temperature under a nitrogen atmosphere for 15 minutes. Methyl o~-bromo-3,4-methylenedioxypherlylacetate (0.422 g, 1.54 mmol) was then added and the resulting mixture was stirred at room temperature wog6,049~ i ~ i 2 ~ q5 7~8 . ~ 7--for an additional 24 hours. The reaction mixture WdS then partilioned between 105'o aqueous citric acid and EtOAG. The organic layer was washed with saturated aqueous NaHCO3, saturated aqueous NaCI, dried (MgSO4). filtered and evaporated in vacuo to afford the title compound.
IH-NMR (300 MHz~ DC13, ppm~: o 0.96 (t, .1=7.50 Hz. 3H), 1.ti2-1.74 (m, 2H), 2.52 (s, 3H), 2~68-2.75 (m, 2H), 3.71 (s. 3H)~ 5.61 ~s, I H), 5.98 (s. 2H~, 6.71 ~d, ./=8.60 Hz, lH'), 6.81 ~d, J= 8.20 Hz. lH~
7.02 (dd, J=l .80, 8.20 Hz, IH), 7.04 (d, J=l .80 Hz, ] H), 7.73 (dcl, J=2.20, 8.60 Hz, lI-i), 7.79 (d, J=2.20 Hz7 lH).
FAB-MS mie = 371 (M + ]).

Step C: Preparatiotl of cx-(4-acet~ 2-n-propylpl1eno~y)-3,4-me:thylenedio~yphenylacetic acid To a solutioll of 0.556 g ~1.50 rnmol) of the product of Step R dissol~ed in 4.0 mL of methanol WdS added 0.45 mL (2.15 mrllol) of a 5.0 N ayueous solution of sodium hydro~ide. The reactio mi~ture was stirred at room lell-pe~ and monitored by TLC
(CHCl3-MeOH-NH4OH 80:15:l). After4 hour.s the reaetion was judged to be complete and the reaction mixture was adjusted to pH=7 Wit}l 6.0 N I ICI. The mixture was then evapo~ated in vacuo and the residue was purified on a silica gel flash chromatography eolulrll1 eluted with ClIC13-MeOH-NH4OH (80:15:1). Evaporation of the puril~ied fraction6 and drying in ~acuo afforded 0.416 g ~78~o'J of the title compoulld.
I I I-NMR (400 ~ lz~ CD30D, ppm): o 0.94 ~t, J=7.60 Hz, 3H), 1.62-1.70 (m, 2H), 2.53 (s, 3H), 2.61-2.69 (m, IH), 2.80-2.88 9m, IH), ~i.39 (s, 11~1), 5.93 (d, J=1.20 Hz, IH), 5.94 (d, J=1.20 Hz, lH), 6.79 ~d.
./=8.00 Hz, lH), 6.91 (d,.l=8.80 Hz, lH), 7.10 ~dd,J=1.60, 8.00 lIz.
111~, 7.15 (d~ J=l .60 Hz. I H~), 7.78 Id, J=2.40 Hz, 1 H), 7.81 ~dd, J=2.4(), 3~ 8~01-Iz IH) ~ WO 96104905 ~ 2 1 9 5 75 ~ I ~",J~

- ]37 -N-(4-iso-propylbenzenesulfonyl)-a-(4-acetyl-2-n-propylphenox~ )-3 ,4-methylenedioxyphenylacet~mide Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-a-(4-acetyl -2-n-propylphenoxy)-3,4-metllylenedioxyphenyl-acetamide To a solution of 0.181 g (0.51 mmol) of the product of 0 Example 67 dissolved in 2.5 mL of anhydrous DMF was added 0.248 g (1.53 mmol) of l,l'-c.lrbonyldiimidazole and the reaction mixture was magnetically stirred and heated at X0'C under a nitrcgen atmosphere in an oil bath. After 20 minutes the reaction mixture was cooled to room temperature and 0.152 g (0.77 mmol) of 4-~.s(J-propylbenzene-15 sulfonamide and 381 ,uL (2.55 mmol) was added. The reaction mixturewa.s heated at ~0~C for an additional 10 minutes then cooled again to room temperature and partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with saturated aqueous NaHCO3, saturated aqueous NaCI, dried (MgSO4)~ filtered and 20 evaporated. The residue was purifïed on a silica gel flash chronnatography column eluted with CHC13-MeOH-NE14OII (80:15:1);
evaporation of the purified fractions and drying in v~cuo afforded 0.128 g (47C~!) of the title compound as an amorphous solid.
I H-NMR (400 MHz, CD30D, ppm): o 0.88 (t, J=7.60 l lz, 3H), 1.21 (d, 25 .l=6.~0 Hz, 3H), 1.22 (d,./=6.$0 Hz, 3H), 1.55-1.65 (m, 2H), 2.51 (s, 3H), 2.54-2.64 (m, IH), 2.67-2.75 (m, IH), 2.92 (sept,J=6.80 Hz, lH), 5.43 (s, I H), 5.94 (s, 2H), 6.75 (d, J=8.80 Hz" I H), 6.77 (d, J=8.40 Hz, IH), 7.01-7.03 (m, 2H), 7.23 (d, J=8.40 1 Iz, 2Hj, 7.66 (dd, J=2.40, 8.80 - Hz, I H), 7.67 (d, ~=8.40 Hz, 2H), 7.73 (d7 J=2.40 Hz, 1 H).
30 FAB-MS m/e = 538 ~M + 1).

EXAMPI~E 69 a-(2-n-propylpheno~y)-3,4-methylenedioxyphenylacetic acid , " . : ! ' ~
W096tOJ905 ~ 2~9575~ r~

EAB-MS for C1~H1 8~5: mle = 337 (:M + Na+).

s N-(4-i.s~o-propyl'bellzenesulfonyl)-o -~2-n-propylphelloxy)-3,4-methylenedioxyphenylacetamide FAB-MS for C27H29NS06: mle = 534 (M + K+~.

(x-(3-methoxyphenoxy)-3,4-methylenedioxyphenylacetic acid El-MS for C16:H1406: n~le = 30~ (M+).

0!-(2-(2-h~ oxyr,lllylJphenoxy)-3,4-methylenedioxyphenyl~lcetic acid FAB-MS for C17H1606: ~?tle = 317 (M + 1).

25 c~ 2-(2-carbomethoxyethyl)phenoxy)-3,4-methylenedioxyphenytacetic acid Cl-MS l'or C'19H18~7: lille = 3~9 (M + I).

~-(4-hydroxymethyl-2-/1-propylphenoxy)-3 ,4-methylenedioxyptlenyl-acetic acid Cl-MS for C19112006: mle = 326 (M+ - H20~.

~ W0 96/049~5 ~ .' 2 ! 9 5 7 5 8 r~l~u~. . . c~

a-(4-(2-hydroxyethyl)-2-n-propylpllenoxy)-3,4-methylelledioxyphenyl-acetic acid Cl-MS for C20H22o6: mle = 359 (M + 1~.

N-(4-iso-propylhe,n7.t~nt~cl~1fonyl)-a-~2-(2-carbomethoxyetllyl)phenoxy)-3 ,4-methylenedioxyphenylacetamide ESI-MS for C2gH29NSOg: m/e = 540 (M + 1).

N-(4-i.so-propylbenzenesulfonyl)-ol-(2-(2-carboxyethyl)phenoxy)-3,4-methylenedioxyphenylacetamide Cl-MS for C27H27NSOX: mle = 526 (M + 1).

:EXAMPLE 78 ~ 2-(2-carboxyethyl)pllerloxy)-3,4-1llethylenedioxyphenylacetic acid Cl-MS for ClXH16O7: mle = 345 (M + 1).

N-(4-~so-propylbenzenesulfonyl)-2-(4-carbomethoxy-2-n-propyl-phenoxy)-2-(5-methoxy-3 ,4-methylenedioxyphenyl)acetamide W0961D4905 ~ ~ 2195758 ~ .7--Step A: Ethyl 2-(4-carbomethoxy-2-/1 -propylphenoxy)-2-( 5 -methoxy-~ ~4-methylenedioxvphenyl)acetate To a mixutre of methyl 4-hydroxy-3-n-propylbenzoate (3.0 g. 15.46 mmol3 and C.s2C03 (5.1 g, 16 mmol) in dry dhnethylfcl~namide (50 mL) was added ethyl 2-bromo-2-(5-methoxy-3,4-methylenedioxy)phenylacetate (4.3 g, 15.56 mrnol~, and the resulting mixture was stirred at room temperature for 6 h. At the end Or this period~ the reaction mixture was diluted with ice water (300 mL) ;md extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed with water and brine, and then dried over anhydrous MgS04, filtered and solvent removed to give the crude~ product.
Purification of the crude product by silica-gel flash column chromatograplly using ethyl acetate-llexane (1:9) aiforded the titled pr)duct as an oil (5.1 g).
lll NMR (200 MHz, CDC13. ppm) ~ 7.82 ~m, 2H). 6.75 (m, 3H); 6.61 (d, 111, J = 1.5 Hz); 5.93 (~s, 2Hl; S.~S4 ~s, IH); ~ (m, 21-1); 3.84 (s.
3H); 3.~3 ~.s, 3H); 2.68 (m, 2~1~; 1.69 (ln. 2H~ 0 ~t, 311, J = 7.4 llz?;
0.90 (t, 3H, J = 7.4 1 Iz).

Step B: 2-(4-carbomethoxy-~-n-propylphenoxy)-2-(5-methoxy-3.4-m~tll~ylenediQxyphel1y])acetic acid To a sclluti(ll1 of the product of Step A (4.3 g, 12 rmnol) in methanol (25 mL) was added aqueous 2N NaOH (10 rmL) and the reaction mixture was stirred at room ~ e~ u~. The rapid progress 2s of mono-deesterification was monitored by TL-C analy.sis Usillg CHC13-MeOH-NH40H:(80~ 1). After 1~ min, the reaction nlixture was cooled to 0~C and neutralized with aqueous 2N i ICI. l~,Iethanol was rellloved in vacuo and the resulting mixture was acidified with aqueous 2N HCI. The oily product which precipitated was extracted hltc~ -30 methylene chloride (l3 x 40 mL~ and the combined organic phase was wa.shed with water, brine and then dried over MgS04. Removal of' the solvent in vacuo afforded the crude product which was then purified by fla.sh-chromato~raphy on silica gel using CHC13-~,leOH-Nl 1401-1:(80:10:1 ) to give desired product as the arnmonium salt. The 2~9~7~8 ~ W096/0490~ r~,l/Liv....................................... .,~7 - salt was treated with aqueous I N HCI (20 mL) to provide the titled compound as a white solid (3.4 g).
I H NMR (200 MHz, CD30D, ppm) o 7.78 (m, 21-1~, 6.77 (m, 3H), 6.61 (d, lH, J = 1.5 Hz), 5.93 (s, 2H), 5.54 (s, IH), 3.84 (s, 3H), 3.83 (s, 3H), 2.68 (m, 2H), 1.69 (m, 2H)~ 0.90 (t, 3H, J = 7.4 Hz).

Step C: N-(4-isc/-Propylbenzenesulfonyl)-2-(4-carbomethoxy-2-n-propylphenoxy)-2-(5-metho~y-3 ,4-1nethylelledioxyphenyl )-acetamide To the product of Step B (0.12 g, 0.30 mmol) in d~ THF
(1.5 mL) was added l,l'-carbonyl-liimid i7nle (0.1 g, 0.61 mmol) and the reaction stirred at 50QC fc r 3 hr. To this solution was added a solution of 4-is~o-plulJyl~r-lr7enesl~1fonamide (0.17 g, 0.9 mmol) and DBU (0.14 mL, 0.94 mmol) in dry THF (1.5 mL), and the reaGtion 5 continued at 50~C for 4 hr. The reaction was diluted with ice water and acidified with aqueous IN HCI. The precipitated material was taken up in EtOAc and the organic phase was washed with water, brine, and then dried over MgSO4, filtered and the sol~{ent removed. The product was purified by flash-chromatography on silica-gel USillg 20 CHCI3:MeOH:NH40H (80:10:1) as the eluting solvent to ~/ielcl the titled product as the ammonium salt. Acidificatio n of the anmlonium salt afforded the titled product as a white solid (0.14 g).
11-1 NMR (400 Ml~z, CD30D, ppm): o 7.78 (d, 2H, J = 8.4 Hz),7.76 (d, ll-I,J=2.3Hz),7.62(dd, IH,J=8.6,2.21-lz),7.37(d,2H,J=8.4Hz), 6.70 (d, lH, J = 1.4 llz), 6.61 (d, IH, J = 1.5 Hz), 5.97 (s, 211),5.49 (.s, IH), 3.84 (s, 3H), 3.853 (s, 3H), 2.98 (sept. 111. J = 6.9 Hz), 2.65 (m, 2H), 1.59 (m, 2H), 1.25 (dd, 6H, J = 7.0, 2.5 Hz), 0.90 (t, 3H, J = 7.4 ~) C3"H3~NO~)N: Calc: C 59.50 ll 5.33 N 2.31. Found: C 59.60 H 5.34 N
30 2.59 ;; 2t957 W0 96/0490S r~

EXAMPLE ~0 N -(4-i~o-propylben7,enesll1fonyl)-2-(4-carboxy-2-propylphelloxy)-2-(5-methoxy-3,4-methylenedioxyphenyl)~et~m i~L~

To tlle product of Example 79 (0.6 g, 1.02 mlmol~ in MeOH
~15 mL) was added aqueous 2N NaOH (5 mL) and the reaction was stirred at 60~C ~or 3 h. When the reaction was complete the MeOH was removed in vacuo and the aqueous phase was acidified with 2N HCI.
Ti1e product precipitated was e~;tracted il1tO methylene chloride (3 X 50 mL) ~md the comhined org~mic phase vvas wa.shed with brine tllen dried o~er MgSO4, filtered and the solvent removed. The residue upo n trituration with ether provided the titled product as a white solid (0.45 O) IH NMR (400 MHz" DM~SO-d~, ppm): o 12.67 (br, IH), 12.63 (br~ IH~, 7.70 Id, 2H, J = 8.4 Hz), 7.66 (d, IH, J = 2.1 Hz)~ 7.5B (dd, IH, J = 8.5, 2.2 Hz), 7.40 (d, 2EI, J = ~s.4 Hz), 6.78 (d, IH, J = 1.2 Hz}, 6.66 (d, IH, J = 1.2 Hz), 6.51 l~d, 1 EI, J = B.5 Hz), 6.02 (d, 2EI. J = ~.1 Hz), 5.69 (s, 111)~ 3.79 (s, 31-13, 2.93 (.sept, IH, J = 6.9 Hz)~ 2.56 Im. 2H1, 1.53 (m, 2'~ 21-1), 1.17(d,6H,J=6.9Hz),0.B3(t,3H,J=7.4Hz).
FAB mass .spectrurrl: m/e 570 (M+l).
C~qH3lNOgS: Calc: C 61.15 11 5.49 N 2.46 Found: C 60.X6 H 5.64 N
2.71.
2s N-~4-;so-propyrl~nzenesult'onyl)-2-(4-(N-(4-iso-propylbenzene-sulfonyl)carboxalllido)-2-propylphenoxy)-2-(5-n1ethox~ -3 ~4-methylene-dioxyphenyl~,~ref~ltlid~

The titled compound was prepared from N-(4-iso-prc~pyll~en7.~nt-slllfonyl)-2-(4-carboxy-2-prop,vlpheno~y)-5~ ethoxy-W0 96/04905 ,. .~ = 2 t 9 ~7 58 r~ .._7 - 3,4-methylenedioxyphenyl)acetaniide (Example 80) using a procedure similar to that de.scribed in Step C of Example 79.
FAB mass spectrum: m/e 751 (M+l).
C3gH42N2O~oS2 ~0.5 H2O: Calc.: C 60.06; 1-15.70, N 3.69.
Found. C 60.15; H 5.73; N 3.58.

N-(4-lso-propylbenzellesulfonyl)-2-(4-carboxamido-2-prc)pylphenoxy)-2-(5 -methoxy-3.4-methylenedioxyphenyl)acetamide To N-(4-i.so-propylbenzenesulfonyl)-2-(4-carboxy-2-propylphenoxy~-2-(5-methoxy-3,4-methylenedioxyphen~Yl)~l~et~m i(l~
(Exaniple 80) (0.12 g, 0.21 mmol) in dry THF (1.5 rnl.~ was added l,l'-carbonyldiimidazole (0.1 g, 0.61 mmol) and the mixture was stirred at 50~C for 21h The reaction wa.s cooled to room le,~ e~,ltu~e and was .saturated with dry NH3 The reaction mixture was stirred at room temperature for Ih and then acidified. The crude product isolated was purified by silica-gel flash column chromatography usin~ CHCI3-MeOH-NH40H: (40:10:1 i to give the product as the ammonium salt.
Acidification provided tlle desired titled product as a white solid (0.06 g)-IH NMR (300 MHz, [:~MSO-d6, ppm): o 7.76 (br, IH), 7.68 (d, 2H, J =
8 4 llz), 7.64 (d, lH, J = 2.1 Hz), 7.55 (dd, lH, J = 8.6, 2.3 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.16 (br, IH), 6.76 (s, IH), 6.65 (d, IH, J = 1.2 Hz), 6.53 (d, 111, J = 8.7 Hz), 6.01 (d, 2H, J = 2.9 Hz), 5.67 (s. 111), 3.78 (s, 3H), 2.93 (sept, I iH, J = 6.8 Hz~, 2.55 (m, 2H), 1.54 (m, 2H~, 1.17 (d, 6H, J = 6.9 Hz), 0.84 (t, 31-I, J = 7.3 llz).
FAB mas.s spectrum: m/e 569 (M+l).

W0 96t04905 ' ~ 2 ~ 9 5 7 5 8 . ~

N-(4-is~J-propylhP,Il7,~nt~s-~lfollyl)-2-(4-~N-metllyl)carbQxamido-2-propylphenoxy3-2-(5-met~hoxy-3,4-methylenedioxypherlyl~ 3~er ~m;~
s The titled compound was prepared using procedures similar to those described in Example 82.
IH NMR (3~0 hIHz, DMSO-d~, ppm): o 8.21 ~q. 111, J = 4.7 Hz)~ 7~68 (d,2H,J=8.4Hz),7.59(d, lH,J= 1.9Hz),7.49(dd, IH,J=8.6,2.1 o Hz), 7.40 (d, 2H. J = 8.4 Hz3, 6.77 (s, IH), 6.65 (s, lH), 6.53 (d. IE-I, :I =
8.7 Hz), 6.01 (d. 2H, J = 2.9 Hz), 5.67 ~s, 11-1~, 3.78 (s, 3H), 2.93 (sept.
lH, J = 6.8 Elz), 2.73 (d, 3H, J = 4.4 Hz3, 2.56 (m, 2EI), 1.54 (m, 21-I~, 1.16 (d, 6H, J = 6.9 Hz), 0.84 (t, 3H, 7.3 Hz).
C3(,H34N20~S: Calc: C 61.84; H 5.88; N 4.81.
Found: C 61.84; H 6.03; N 4.5g.

20 N-(4-i~ J-prOpylbenZeneSUIf(~nyl)-2-(4-(N-2-tl~drOXyet:h~lcarbo~ ido) 2-propylpherlo~y)-~-(5-methc xy-3,4-methylenedio~yphellyl)acetamide The titled compound was prepared USillg procectures 25 .simiLIr to those described in Example 82.
I H NMR (4()0 MHz, CD30D, ppm): o 7.77 (d, 2H, J = 8.4 Hz), 7.64 (d, IH, J = 2.3 E-lz), 7.51 (dcd, lH, J = 8.5, 2.4 Hz), 7.36 (d, 2H, J = X.5 Hz), 6.68 (d, IH, J = 1.4 Hz), 6.60 ~m, 2H), 5.96 ts, 211), 5.41~ (s, IH~, 3.82 (s, 3H), 3.68 (t, 2H, J = 5.9 Hz). 3.46 (t. 2H. J = 5.9 Hz), 2.97 Isept~ IE-I, 30 J = 6.9 Hz), 2.66 (m, 2H), 1.62 (m, 2H), 1.25 ~cld, 6H, J = 6.9, 1.2 1 Iz), 0.90 (t, 3H, J = 7.4 Hz).
C3~ 6N20~S: Calc: C 60.77; H 5.92; N 4.57.
Found: C 60.49; H 6.04; N 4.45 ~ W0 96/04905 ' 2 1 9 ~ 7 5 ~

- EXAI~,IPLE 85 N-(4-i.sO-propylbenzenesulfonyl~-2-(4-(N-morpholinylcarboxamido)-2-propylphenoxy)-2-(5-methoxy-3.4-methylenedioxyphenyl)acetamide The titled compound was prepared using procedures similar to those described in Example 82.
I H NMR (400 MHz, CD3OD. ppm): o 7.77 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.4 Hz), 7.22 (d, lH. J = 2.1 ~Lzj, 7.09 (dd, IH, J = ~.4, 2.2 Hz), o 6.66(d, IH,J= 1.5Hz),6.62(d, 1~-I,J=8.5Hz),6.57(d, lH,J= 1.5 Hz), 5.95 (s, 2H). 5.46 (s, IH), 3.81 (s~ 3H), 3.65 (m, 81~), 2.98 (m, IH), 2.66 (m, 2H), 1.60 (m, 2H), 1.26 (d, 6H, J = 7.1 llz), 0.90 (t, 311, J
= 7.4 Hz).
C331-13~N20c~S: Calc: C 62.05; H 6.00; N 4.39.
Found: C 61.96; H 5.98; N 4.55.

EXAMPLF, 86 N-(4-i.~o-prclpylbenzeneslllf'onyl)-2-(4-(N-3-methylbutylcarboxamido)-2-propylphenoxy)-2-(5-methoxy-3,4-methylelledioxyphenyl)acetarllide The titled compound was prepared using procedures similar to those described in Example 82.

I H NMR (400 MHz, CD30D7 ppm): ~ 7.77 (d, 2H, J = 8.5 Hz,), 7.60 (d, IH, J = 2.3 Hz), 7.47 (dd, 111, .1 = 2.3, X.S llz), 7.36 (d, 2H, J = 8.5 Hz), 6.68 (d, IH, J = 1.5 Hz), 6.59 (d, IH, J = 1.4 Hz), 6.58 (d, IH, J = 8.6 ~ Hz), 5.96 (s. 2H), 5.48 (s, IH), 3.82 (s, 3H), 3.36 (t, 2H, J = 7.5 Hz)~
2.97 (m, IH), 2.66 (m, 2H), 1.62 (m, 3H), 1.49 (q, 2H, J = 7.2 Hz), 1.25(cld,2H.J= 1.2,6.9Hz),0.95(d,6H,J=6.6Hz),0.9(J(t,311,J=
7.4 Hz).
C3~H~2N2O~S: Calc: C 63.93; H 6.63; N 4.39.
Found: C 63.81; H 6.73; N 4.44.

2~ 95~5~
W096104905 ~ 3 ~ 5~3~7 ~

5 N-(4-i.~ u,uyl~-r~ culfonyl)-2-(4-(N-carboxymethylcarbo,~ i 2-propylplle,rloxy)-2-(5-metlloxy-3,4-mettlylenedioxvphellyl)~ mi ~tep A: N-[4-is~i-propylbel1zenesulfonyl)-2-~4-(N-t-butoxy-carbonylmethylcarboxarllido)-2-propylphenoxy)-2-(5-m~thoxy-3.4-methylelledioxyphen~l lacetalnide The titled compound wa.s prepared u.sing procedare.s .similar to those described in Example 827 where ~Iycine-t-butyl ester was the amine .starting material.
111 NMR (300 M13z, CDC13 ppm): o 7.70 (d~ 2E-I, J = X.2 llz), 7.66 (d, Il~,J= 1.3H~,7.56(m, IH),7.41 (d,2H,J=~.2Hz3,6.79(s. IH), 6.67 (.s, IH), 6.59 (d~ IH, J = 8.5 Hz), 6.03 (s, 2H), 5.71 (s, lH). 3.X8 (d, 21-1, J = 5.5 Hz), 3.R0 (s. 3H), 2.95 (sept, IH, J = 6.9 Hz), 2.78 (m~
2H), 1.56 (m, 2H), 1.32 (s, 91-1'~, 1.17 (d, 6H, J = 6.~ Hz'), 0.86 (t, 3}-1, J
=7.3Hz).

Step B: N-(4-iso-propylbellzenesulfonyl)-2-(4-~N-c~arboxymethyl-carboxamido)-2-propylphenoxy)-2-(5-methoxy-3,4-m~lh~ylerledioxyphenvl)acetamide 2s A solution of the product of Step A (0.069 g, 0.1 mmol~ in anhydrou.s trifluoroacetic acid (1.5 mL) was stirred at room temperature for 4h. 'I'he excess reagent was evaporated in vacuo ialld the resulting residue was triturated with dry ether to give the titled product as white solid (0.6 g~.
IH NMR (300 MHz, DMSO-d~, ppm): o 7.70 (d, 2H~ J = 8.2 Hz~, 7.66 (d, 11-1, J = 1.3 llz), 7.56 (m, IH), 7.41 (d, 2H, J = 8.2 Hz), 6.79 (s, 11-1~, 6.67 (5, lH), 6.59 (d, lH, J = 8.5 Hz), 6.03 (~, 2H), 5.71 (~t IH), 3.88 (d, 2H, J = 5.5 Hz), 3.80 (~, 311), 2.95 (sept, IH, J = 6.9 Hz), 58 (m, 2H), 1.56 (m, 21-1), 1.17 (d, 6H, J = 6.8 Hz), 0.86 (t, 3H, J = 7.3 llz).

f i 21 957~g W0 96104~05 ~ r~ )s - C3lH34N2OloS Ø4 H2O: Calc.: C 58.74; H 5.53, N 4.42.
Found: C 58.79; lH 5.83; N 4.37.

N-(4-i.so-propylbenzenesulfonyl)-2-t4-(N-(L-Ala-OEt)carboxamido)-2-propylphenoxy)-2-(5-methoxy-3,4-methylenedioxyphenyl)~eet~mide The titled compound was prepared using procedures o similar to those described in Example 82, where l.-aklnine ethyl ester was the amine starting material.
I H NMR (400 MHz, DMSO-d6, ppm): ~ 8.55 (d, I H, J = 6.1 Hz), 7.69 (m,3H),7.57(q, IH,J=9.2Hz),7.40(m,21[),6.78(d, IE~,J=3.8 Hz), 6.63 (s, IH), 6.55 (m, lH), 6.02 (s, 2H), 5.70 (s, IH), 4.39 (m, 5 lH), 4.08 (q, 2H, J = 6.8 Hz), 3.79 (d, 3H, J = 2.9 Hz), 2.93 (sept, IH, J
= 6.9 Hz), 2.57 (m, 2H), 1.55 (nl, 2H), 1.37 (d, 3H, J = 5.5 Hz), 1.16 (m, 9H), 0.~¢5 (t, 3H, J = 7.5 Hz).

N-(4-is~l-propylbenzenes~ onyl)-2-(4-(N-2-ethoxycarbonylethyl-carboxamido)-2-propylphenoxy)-2-(5 -methoxy-3,4-methylenedioxy-phenyl)acetamide 'I'he tiLled compound was prepared using procedures similar to those described in Example 82, where ~-aLmine ethyl ester was the amine starting material.
I H NMR (400 MHz, DMSO-d(j, ppm): o 8.34 (t, I H, J = 5.4 Hz), 7.68 (d,2H,J=8.3Hz),7.58(d, lH,J=2.2Hz),7.49(dd, IH,J=8.6,2.3 3~ Hz), 7.39 (d, 2H, J = 8.4 Hz), 6.77 (d, IE~, J = 1.4 Elz), 6.65 (d, 111, J =
1.3 Hz), 6.53 (d, IH, J = 8.8 llz), 6.01 (s, 2EI), 5.67 (s, IE-I), 4-05 ('1, 2H, J = 7.1 Hz), 3.78 (s, 3H), 3.44 (m, 2H), 2.92 (sept, IH, J = 6.9 Elz), 2.53 (m, 2H), 1.54 (m, 2H), 1.16 (111, 9H), 0.84 (t, 3H, J = 7.4 Hz).

W0 96/04905 ~ 2 ~ 9 ~ 7 5 8 ~ L /~t l ~

EXAMPLE gO

N-~4-i.so-prop), 11~el~ellesultonyl)-2-(4-(N-(L-Ala)carboxamido)-2-propylphenoxy)-2-~5 -methoxy-3,4-methyle.nedioxyphenyl~acetalllide The product from Example 8R was saponifiled to give the tit]ed product.
IH NMR (400 MHz, DMSO-d6, ppm): ~ 12.64 (br. IH), 12.51 (br, IHi, 8.44 ~dd, IH, J = 7.1, 2.7 Hz), 7.69 (m, 3H~, 736 ~m, lH), 7.40 (ro, 211), 6.77 (d, IH, J = 1.6 Hz), 6.66 (d, IH, J = 1.7 Hz), 6.55 (m, 11~1), 6.01 ~d, 2H, J = 2.6 lIz), 5.69 (s, lH), 4.37 (pn, lE~, J = 7.4 Hz~, 3.79 (d, 3H, J = 1.9 Hz), 2.93 ~sept, IH, J = 6.9 Hz), 2.57 ~m, 211), 1.54 (m, 2H), 1.36 ~dd, 3H, J = 7.3, 2.7 Hz), 1.16 (d, 6H, J = 6.X Hz), ().85 ~t, 3H,J=7.2Hz).

N-(4-iso-propylbenzenesulfonyl)-2-(4-(N-2-carbclxyei:hylcarboxalnido3-2-propvlphenoxy)-2-~5-metlloxy-3 ,4-methylenedioxypllel3yl'~acetalllide Tile product fiom Example ~9 was .saponified to give the titled product.
IH NMR (400 MHz, D~I~O-d~, ppm): ~ 12.64 ~br, Il{), 12. 21 (br, IH). 8.32 ~t, IH, J = 5.5 lHz), 7.68 (d, 2H, J = 8.4 Hz), 7.~9 (d, I H, J =
1.9 Hz), 7.49 (dd, IH, J = 8.5, 2.1 Hz), 7.40 (d, 2H, J = 8.4 Hz), 6.77 (s, lli), 6.65 (d, 111, J = 1.2 Hz), 6.01 (d, 2H, J = 2.9 Hz), 5.68 (s, 11:1), 3.79 Is, 3H), 3.:?tg ~Ill, 2H), 2.93 (sept, IH, J = 6.B Hz), 2.55 (m, 2H).
1.5~1 (m, 211), 1.16 (d, 6H, J = 6.9 Hz), 0.84 ~t, 3H, J = 7.3 llz).
30 C32H36N2OI(~S: ('alc: C 59.g9; H 5.66; N 4.37.
Found: C 59.72; H 5.77; N 4.49.

W096/04905 ~ 2 ~ 95758 r~"~ 3 1 EXAI\/IPLE 92 N-(4-iso-propylbenzenesulfonyl)-2-(4-(N-3-hydroxypropyl-carboxamido)-2-propylphenoxy)-2-(5 -methoxy-3,4-methylenedioxy-5 phenyljacetamide The titled cc~mpound was prepared using procedures similar to those described in Example 82, where 3-aminopropanol was the amine starting material.

IH NMR (400 MHz, C'D30D, ppm): o 8.33 (m, 11-1), 7.77 (d, 2H, J =
8.5 Hz), 7.60 (d, IH, J = 2.3 Hz), 7.48 (dd, IH, J = 8.5, 2.3 Hz), 7.36 (d, 2H, J = 8.4 Hz), 6.68 (d, lH, J = 1.5 Hz), 6.60 (d, 111, J = 1.4 Hz), 6.59 (d, llI, J = 8.6 Hz), 5.96 (s, 2H), 5.48 (s, IH), 3.82 (.c, 3H), 3.63 (t, 2H, J = 6.3 1 Iz), 3.43 (t, 2H, J = 5.8 Hz), 2.97 (sept, I H, J = 7.0 Hz), 2.66 ~m, 2H), 1.80 (pn, 2H, J = 6.7 Hz~, 1.61 (m~ 21~), 1.25 (dd, 6H, J =
6.9, 1.3 l lz), 0.90 (t, 3H, J = 7.4 Hz).
C32H3gN2O~)S: Calc: C 61.33; H 6.11, N 4.47.
Found: C 61.07, H 6.09: N 4.48.

N-(4-i.so-propylben7,t~.nPslllfollyl)-2-(4-(N-tetrazol-S-ylcarboxamido)-2-propylphenoxy)-2-(5 -methoxy-3 ,4-methylene.dioxyphenyl)acetamide The titled compound was prepared using procedures simiklr to those described in Example 82, where 5-aminotetrazole was the amine starting material.

30 FAE~-MS m/e = 640 (M+l) WO96104905 2 1 ~5758 1~1~ 7 --N-(4-i.s o-propylbenzenesulfonyl)-2-(4-(N -3 -(~morpholin-4-yl)propyl-carboxamido)-2-propylphenoxy)-2-(5-methoxy-3 ,4-meihylenedioxy-phenyl)~-~el,lmifli~

The titled compound was prepared using procedures similar to those described in Example 82, where 3-(N-morpholinyl)-aminopropane was the amine starting material.
o IH NMR (400 MHz~ CD30D, ppltl) ~ 7.65 ~d, 2~, J = 8.3 Hz), 7.65 (s, lH~, 7.58 (dd, IH. J = 2.4, 8.6 Hz), 7.24 (d, 2H, J = R.4 Hz), 6.~1 (d, lH~ J = 8.6 Hz~, 6.78 Sd, lH, J = 1.4 Elz). 6.69 (d, 111, J = 1.4 Hz~, .Ci.9 l (s~ 2EI), 5.40 ~s, lHj, 3.132 (s, 7H), 3.54 (m, 2H), 3.12 (m, 6 H), 2.9'~
(sept, lH, J = 6.9 Hz), 2.66 (m, 2H), 1.62 (m, 2H), 1.22 (d, 6E{, J = 6.9 1 IZ) 0.90 (t, 3H, J = 7.4 Hz).
C3sH43N3OgS Ø75 H2O: Calc.: C 60.46: H 6.45; N 6.C)4.
l~ound: C 60.39; E-l 6.43. N cj 93 N-(4-is~-propylbellzellesulfollyl)-2-(~ N-(D-Ala-OMe)c~rboxamido i-2-propylphenoxy)-2-(:5-methoxy-3,4-methylenedioxyphenyl)acel "m i~

The titled compound was prepared using procedures 2s similar to those described in Example 82, where D-alanine methyl ester W.lS tlie amine .s~tarting material.

lH NMR (400 MH~, CD3OD, ppm): o 854 (d, lH, J = 6.8 Hz); 7.77 (d, 2}1, J = 8.3 Hz), 7.66 (.s, IH), 7.53 (m~ lH)~ 7.36 (d, 21{, J = ~.3 Ikl, 30 6.68 (s~ IH~, 6.60 (m, 2EI), 5.96 (s, 2H), 5.49 (s. IH), 4.57 (Ill, IH), 3.82 (s~ 3H), 3.i3 (s, 3H), 2.97 (sept, IEI, J = 6.8 Hz), 2.67 (m, 2H), 1.62 (m, 2H),. 1.47 ~d, 3H, J = 7.4 Hz), 1.24 (d, 6EI, J = 7.0 llz), 0.91 (t, 3~-1, J = 7.4 Hz).

2~9~7~8 W0 96104905 ' ~ , f7 N-(4-iso-propylbenzenesulfonyl)-2-(4-(N-(D-Ala)carboxamido)-2-5 propylphenoxy)-2-(5-methoxy-3,4-methylenedioxyphenyl)acetamide The product from Example 95 was saponified to give the titled product.

0 IH NMR (40û MHz, DMSO-d~" ppm) o 12.64 (br7 IH), 12.48 (br7 IH)7 ~.44 (dd7 lH7 J = 7.3, 2.6 Hz), 7.68 (m, 3H), 7.56 (m, lH)7 7.40 (dd, 2H7 J = 4.0, X.4 llz), 6.77 (d, IEI7 J = 2.3 Hz)7 6.66 (m7 lH)7 6.55 (dd, IH,J=21.0~8.~Hz),6.01 (d,2H,J=3.6Hz),5.70(d,111,J=3.8Hz), 4.37 (pn, IH, J = 7.3 Hz), 3.78 (d, 3H, J = 1.8 Hz), 2.93 (sept, IH, J =
7.0 Hz), 2.57 (m, 2H), 1.55 (m, 2H), 1.36 (dd, 3H, J = 7.3, 2.7 Hz), 1.16(d,6H,J=6.9Hz),0.85(t73H7J=7.3Hz).

N-(4-is~J-propylbenzenesulfonyl)-2-(4-(N-(3-carbc xymethylpropyl)-carboxamido)-2-propylphenoxy)-2-(5 -methoxy -3 ,4-methylenedioxypllenyl)~( et lmi~lP

The titled compound was prepared using procedures 2s similar to those described in Example 82, where methyl ~-aminobutyrate was the amine starting material.

IH NMR (400 MHz, CD30D7 ppm): ~ 7.77 (d, 2H7 J = 8.5 Hz), 7.61 (d7 IH, J = 2.2 Hz), 7.48 (dd7 lH7 J = 8.5, 2.3 Hz)7 7.36 (d7 2H7 J = 8.5 Hz)7 6.68 (s, IH), 6.59 (s, IE-1), 6.59 (d. IH, J = 8.3 Hz). 5.95 (s. 2H)7 5.48 (S7 lH), 4.09 (q, 2H, J = 7.1 Hz), 3.X2 (.s, 3H), 3.37 (m, 2H), 2.97 (sept, I H, J = 6.9 Hz,), 2.66 (m, 2H), 2.38 (t, 2H, J = 7.4 Hz.), 1.89 (pn, 2H, J
= 7.1 Hz~, 1.61 (m, 2H), 1.23 (d, 6H, J = 6.9 Hz), 0.90 (t, 3H, J = 7.3 l~z).

WO 96104905 2 1 9 5 7 5 8 r~ . Js 7 ~

E:XAMPLF 9~

N-(4-is~)-prc~pylbellzelIesulfonyl)-2-(4-(N-(3 -carboxypropyl~-5 carboxamido~)-2-n-propylphenoxy)-2-(5-methoxy-3.4-methylenedioxy-phenyl)acetamide The product f rclm Example 97 was saponified to give the tilled product.

lH NMR (400 MHz, DM-SO-d6, ppm): o 12.fi3 (br, lH;, 12.06 (br, IH)~
8.27(t, IH,J=5.5Hz),7.68(d,2H,J=8.4Hz).7.60(d, IH,J=2.2 Hz), 7.50 (dd, I H, J = 8.5, 2.2 Hz), 7.40 (d, 2H. J = 8.4 Hz), 6.77 (d, IH,J=1.211z),6.66(d,1H,J=1.3Hz),6.52(d,1H,J=g.8Hz),6.01 (d, 2H, J = 2.9 Hz), 5.68 (s, IH), 3.7g (s, 3H), 3.22 (q, 2H, J = 6.5 H~.), 2.92 (sept, 6.B llz~, 2.54 (m, 2H), 2.2.S (t, 2H, J = 7.4 Hz), 1.71 (pn, 7.1 ~izj, 1.~4 (m, 211), 1.16 (d, 6H, J = 6.8 H~l, 0.84 (t, 3H, J = 7.3 11z).
C33H~xN~OIl~S: Calc: C 60.54; H ~ ; N 4.28.
Found: C 60.26; H 6.17; N 4.0~.

N-(4-i.s(l-propylbenzenesulfonyl)-2-(4-(N-iso-propylcar~a:moyl)a~ o-25 2-n-propylphenoxy)-2-~3,4-1Ilethylelledic xyphenyl)acetamide Step A: 4-Nitro-2-(propen-3-yl)phenol A mixture of 4-nitrophenoxyallyl ether ~4.0 g, 22.35 mmol) and 1,2-dichl-,lube~ e (15 mL) was heated to reflux for 6h.
3~ The reaction mixture was cooled and purified by silica-gel tlash column cllromatography using hexanes and EtOAc-hexanes ( 1 6) as eluents, respectively. 1'he pure product was obtained as an yellow oil ~2.6 g).
I H NMR (200 l\~Hz~ CDC13, ppm): o 8.05 (d, 2H~. 6.92 (d, I H)7 6.0 i (m. lH), 5.18 (111, 2H), 3.42 (d, 2H, J = 7.3 Hz).

~ W096/r4905 ~ ' r~"............................... ~., c7 Step B: Methyl 2-(4-nitro-2-(propen-3-yl)phenoxy)-2-(3,4-methylenedioxyphenyl)acetate The titled compound was prepared using the procedures 5 similar to that described in Step A of Example 79. Methyl 2-bromo-2-(3,4-methylenedioxyphenyl)acetate was used as the alkylating agent.
Purification of the crude product was accomplished by silica-gel flash column chromatography USillg ethyl acetate-hexane (l:S).
IH NMR (200 MHz, CDC13, ppm): o 8.05 (m, 2H), 7.02 (m. 2H), 6.78 (m, 2H), 5.96 (s, 2H), 5.6 (s, IH). 5.15 (m, 2H), 4.15 ~m, 2H), 3.75 (s, 3H), 3.47 (m, 2H).

Step C: 2-(4-(N-iso-propylcarbamoyl)amino-2-n-propylph~noxy)-2-(3~4-methylenedio?~yphenvl)acetic acid To a solution of the product c f Step B (0.5 g) in methanol (6 mL) was added Pd-C(10%)(0.05g), and the reaction mixture was stirred at room temperature for 6h under an atmosphere of hydrogen gas. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the desired methyl a-(4-amilIo-2-ll-propylphenoxy)-2-(3.4-methylenedioxyphenyl)acetate (0.5 g) as a solid. This material without further purification was dissolved in dry THF (S mL) and reacted with N-is~-propylisocyanate (0. I mL) at room temperature f'clr 12h. Purification of the crude product by flash chromatclgraphy using EtOAc-hexanes (I :2) gave the titled compound as white solid (0.36 g).
I H NMR (300 MHz, CDC13, ppm): o 7.1-6.77 (m. 611), 6.61 (d, lH, J =
1.5 I-lz), 5.93 (s, 2H), 5.54 (s, IH), 3.98 (m, IH), 3.78 (s, 3H), 3.63 (m, IH) 2.6~ lm. 2H), 1.69 (m, 211), 1.]5 ~dd~ 611, J = 7.0, 2.5 Hz~, 0.90 (t, 3H, J = 7.4 Hz).

WO 96/04905 2 1 9 5 7 5 8 P~

SteF D: N-~4-iso-propylbenzenesulfonyl)-2-(4-(N-i~o-propyl-carbanloyl~amino-2-n-propylpheno~y)-2-~3 ,4-methylene-dioh~lphenyl~acetamide The titled product ~-.IS prepared frotn the prodllct obtail1eci 5 in Step C usin~ procedures similar to those described in Steps B and C' of Example 79.
I H N~IR (300 MHz, CD30D, ppm): ~ 7.78 (d, 2H. J = 8.4 H~), 7.76 (m. IH), ~.52 ~rll. lH), 7.32 ~d, 2H, J = 8.4 Hz~, 7.07 (d, IHJ = 1.4 Hz), 6.75-6.90 (m, 2H), 6.75 ~d, lH, J = 8.2 Hz), 6.42 (d, IH, J = 8.2 Hz~, 5.97 ~s. 21-1), 5.21 ~.s. IH), 3.8~ (m, IH1, 2.82 (m, IH), 2.54 (m, 2H), 1.69 (m, ~H), 1.26 (dd, 6H, J = 7.0, 2.5 liz), 1.15 Idd, 61-1. J = 7.0, 2.5 11z), 0.90 ~t. 3H, J = 7.4 Hz).
FAB-MS- rn/e ~96 (M+1).

c~-(, -n -propyl -4-methylaminosulfollylphelloxy)-~ ,4-methylenedioxy-phenylacetic ac~id ~0 Step A: Preparation of 3-allyl-4-hydroxybenzenesult'onamide TD a solut;on of 5.00 g (28.9 rnmol) of 4-hydroxybenzellesulfonamide dissolved in 30 mL of anhydrous DMF was added 10.36 g (31.8 mmol) of cesium carbonate and the reactic~l1 mixture was magnetically stirred at room lellll~,.<ltUlC'- under a nitrogen 2s at1llospl1e~l-e for 10 minutes. Allyl brornide ~2.75 mL. 31.8 mmol) was added and the reaction mixture was then slirred For an additional 14 hours. The reaction mixture wa.s then partitioned between EtC)Ac (6(1 mL) and 10% aqueous citric acid (200 mL) and extracted. The organic layer was separated, washed with saturated aqueous N?aHCO3, saturated 3~ aLIueolls NaCI, dried ~MgSO4~, filtered, evaporated and dried in ~acuo to afiord 5.40 g (8~%) of a yellow solid. The crude O-allyl ether (5.36, 25.~ mmol) WLIS then dissolved in 10 ml. of 1,2-dichloroben7elle in a 50 mL round bottom fla.ck and magnetically stirred at reflux under a nitrogen ~llno~llhPre for 15 hours. The reaction mixture WaS then cooled to room temperature and diluted with methanol. ~ e 1,2-1 9 ~ 7 5 8 ~ , .. ~ , WO 96/0490S - ' ~ r .l,lJ..,...~., ~7 - dichlorobenzene was removed by extraction of the rmethanol layer with hexane, the methanol layer was separated, thell evaporated. The residue was then purifed on a silica gel flash chromatography colurnn eluted with 5% MeOH-CE~2C12. Combination of the purified fractions, 5 evaporation and drying in vacuo afforded 3.04 g (57~o) of the title compound.
IH-NMR (400 MHz, CD30D. ppm~: o 3.38 (d, J=6.40 Hz.2H), 5.02-5.10 (m, 2H), 5.94-6.04 (m, lH). 6.84 (d, J=8.40 Hz, IEI), 7.58 (dd~
.J=2.40,8.40 Hz, IH),7.61 (d, J=2.40 I-lz, lH).
o cl-Ms l~lle = 213 (M+) Step B: Preparation of 4-hydroxy-3-~?-propvlbenzellesulfollamide A Parr hydrogenation flask was charged with a solution of 3.04 g (14.30 mmol) of the product of Step A di.ssolved in 25 mL of 5 ethanol and 0.300 g of a 10~ palladium on carbon catalyst was added.
The flask was mounted in the hydrogelIatioll apparatus, freed of air, pressurized with hydrogen (40 psig) and shaken for 15 minutes. At the end of this period TLC analysis (3C~o MeOH-CH2C12, 2 elutions) indicated that the reaction was complete and the reaction mixture was 20 filtered and evaporated. The product was dried in vacuo to afford 3.06 g (99~c,) of the title compolmd.
IH-NMR (400 MHz, CD30D, ppm): ~ 0.94 (t, J=7.20 Hz, 3Hh 1.58-1.68 (m, 2H), 2.01 -2.62 (rn, 2EI). 6.82 (d, J=8.40 E~z, IH), 7.55 (dd, J=2.40, ~.40 E Iz, 111), 7.60 (d, J=2.40 Hz, IH).
25 FAB-MS mle = 216 (M + 1).

Step C: Preparation of methyl o~-(2-n-propyl-4-amillosulfolIyl-pheno~v)-3,4-methvlenedi(IxvpllellY lacetate To a solution of 3.06 g (14.23 rnmol) of the product of 3 ~ Step B dissolved in 25 mL of anhydrous DMF was added 4.~7 g (1 :; .0 mmol) of ce.sium carbonate and the reaction mixture was magnetically stirred under a nitrogen atmosphere at room temperature for 15 minutes. Methyl a-bromo-3,4-1Ilethylelledioxyphenylacetate (4.08g, 15.0 mmol) was then added and the reaction mixture was stirred t'or an additional 3 hours. The reaction mixture was then partitioned between ~ ~1 q57~ --W0 96/04905 -- ~ ~ S ~

EtOAc (80 mL~ and 1(11~6 aqueous citric acid (300 mL). The organic layer was ~separated. washed with saturated aqueous NaHCO3, satual-ated aqueous NaCI. dried (MgSO4), filtered and evaporated. Th~ residue wa.s driecl in VclCllO to afford 5.90 g (5.79 theoretical) of the t;tle 5 compound which was used in the next step without further purifilcation.
H-NMR (400 MHz, CD30D, ppm): ~ 0.97 (t, J=7.20 Elz, 3H), 1.64-1.76 (m, 2H), 2.74 (t, J=7.20 Hz, 2H), 3.70 ~s, 311), 5.87 (s, lH), 5.97 (.s, 2H), 6.8~ ~d, J=8.1)0 Hz, IH), 6.93 (d, .l=8.40 Hz. 11-1;, 7.03 ~d, J=1.60 Hz, IH~ 7.06 (dd, J=1.60, R.00 E-lz, 1~1). 7.65 (dd7 J=2.40, ~.40 HZ. IH), 7.69 ~d, J=2.40 Hz, IH).
FAB-MS nll~ = 408 (M + 1).

Step ~: Preparation of rmethyl o-(2-n-propyl-4-methylamino-sul~onylphenoxy)-3.4-methylenediQItypher~lacetate To a so!ution of 2.19 g (5.38 mmol~ of ~e product of Step 15 C dissolved in ~0 mL of anhydrous THF was added 2.4l mL (16.1 mrnol) of 1,8-diazilbicyclol5.4.0-1undec-7-ene and the reaction mixture was magnetically stirred under a nitrogen atmosphere for 2~ minutes at room temperature. Iodomethane (1.00 mL; 16.1 mlnol) was added ial)d the reaction mixture was stirred an aclditional 15 hours at room 20 temperature. The reaction mixture wa.s diluted with EtOAc alld a precipitate formed which was redissolved by additioll of' metharlc)l. The mixture was furthel diluted with warm EtOAc (150 mL total), rel'ridgerated overnight and a solid separated whiGh was removed by filtratioiu The fi!trate was evaporated in vacuo and the residue v~as 25 purified on a silica gel flash chromatography collumn eluted with 5~6 EtOAc-CHCl3. Combinatioll of the purified fractions and evaporation in vacuo afforded 0.164 g of the title compound and a number of iml)ure fractions whictl were reserved l~or repurification.
IH-NMR (400 ~IHz, Cl)3OD, ppm): ~ 0.97 ~t, J=7.20 Hz, 3E~), 1.65-30 1.77 (m, 2H)~ 2.48 (s. 3H~, 2.74 (t, J=7.20 Hz, 2H), 3.71 (s, 3H), 5.87 (s, IH), 5.98 (s, 2H), 6.85 ~d, ./=X.00 Hz, lH~ 6.96 (d, J=8.80 Hz, I E~
7.04 (d, J=1.60 Hz, 1~, 7.07 (dd, J=1.60, 8.00 Hz, 111), 7.58-7.61 (m, 2H).
ESI-MS mle = 421 (M+).

2 1 ~ 5 7 ~ 8 ~. WO 96/04905 ~ ~ Preparation of o -(2-n-propyl-4-1llethylaminosulfonyl-phenoxy)-3~4-methylenedioxyphenylacetic acid To a solution of 0.372 g (0.884 mrnol) of the product of Step D dissolved in 3.0 mL of methanol was added 212111, (1.06 mmol) 5 of a 5.0 N aqueous sodium hydroxide solution which resulted in a cloudy suspension. The reaction wa.s warmed to assist solution, methanol (1 mL) was added followed by dichloromethane (0.5 mL), however a clear solution was not obtained. Additional 5 N sodium hydroxide solution was added (212 IlL), and finally 0.5 mL of THF was added which resulted in a clear solution. After stirring an additional 15 hours at room temperature, Tl.C analysis (CHC13-MeOH-N1140H
80: 15: 1) indicated complete hydrolysis of the starting material and the reaction ivas adjusted to pH=7 with 6 N HCI. The reaction mixture was then concentrated in vacuo and the residue was purified on a silica gel 5 flash chromatography column eluted with CHC13-MeOII-HOAc (92:7:1). Combination of the purified fractions ~md drying in vacuo afforded 0.335 g (93~) of the title compound as an amorphous solid.
IH-N~R ~400 MHz, Cr~3OD, ppm): ~ 0.96 (t, J=7.20 Hz. 3}-1), 1.66-1.78 (m, 2H), 2.48 ~s. 3H), 2.73-2.77 (m, 2H), 5.74 ~s, 11-1), 5.97 (s, 20 2H), 6.85 (d, J=7.60 H~, 111), 6.98 (d, J=9.20 Hz, IH), 7.07-7.10 ~m, 2H), 7.59-7.62 (m, 2H).
ESI-MS m~e = 407 (M+).

N-(4-isr~-propylbenzeneslllfonyl)-f~-(2-17-propyl-4-methylarnino-.sulfonylphenoxy)-3,4-methylenedioxyphenylacetamide potassium salt To a solutiotl of 0.298 g (0.73 mmol) of the product of Example 100 dissolved in 4.() mL of anhydrous THF was added 0.237 g 30 (1.46 mrnol) of l,l'-carbonylfliimifl~7r)1e and the reaction mixture was magnetically stirred and refluxed l'or 2 hours under a nitrogen atmosphere. The reactioll mixture was then cooled to room temperature, 0.219 g (1.10 mmol) 4-iso-propylhf n7f neslllfonamide and 16411L (1.10 mrllol) 1,8-diazahicyclo[5.4.0]undec-7-ene were added auld 2 ~ 9 5 7 ~ 8 W0 96/04905 r~

the reaction w~s stirred and heated at reflux for an additional l 0 minutes. The reaction mixture was then ccloled to room temperature.
partitioned between 105'o aqueous citric acid and EtOAc and extracted.
The organic layer u,hich separated was washed with saturated aqueous NaCI, dried ~MgSO4l, filtered and e~ aporated. The residue was redis.solved in 1.0 mL of methanol and treated with 2.2C~ mL (3 e~l) of a 1.1 hl aqueous solution of potassium hydroxide. The mixture was then diluted with ~ mL of water and filtered through a 0.45 micron filter.
The filtrate w-as desalted and purified on a VVater.s Millipore Delta Prep 3000 liquid chrt)lllatograph equipped witll an M1000 Prep-Pak module containing a 47 x 300 mm Delta-Pak C18 ISIlm 100A colunm cartridge.
Two solvent resevoirs were employed: solvent system A (95-5 water-acetonitrile), and .solvent system B (5-95 water-acetonitrile), .uld the column et'fluent was monitored ~irnlllf:ln?ously at 210 and 280 mn with a Waters model 490 UV-visible detector. The column was preequillibrated with solvent system A and the filtrate wa.c injected.
The product wa.s desalted by elution with 0.5 L of solvent system A (50 mLfmin) then a gradient elution was be~un wllich had .I.S illitial conditions 100~ sol~ent system A-0% solvent systelII B arlcl reached after 1~ minute~ 60~, solvent ~ystem A-40~i sol~ent sy.stern B, ~md the f'rdctions were collected with an ISCO ~oxy 2()0 fr~ction collectl~r. Thoe purified frac~tions were combined in round bottom flasks, fro7en in a -7~C dly ice-acetone bath. and Iyophilized. Combination of the purified product afforded 0.284 g (62%) of the title compound as a white lyophilized powder.
I H-NMR (400 MHz, CD30D, ppm): o 0.89 (t, J=7.60 llz, 3H), 1.21 (d.
.l=6.80 Hz. 3H), 1.22 (d, .J=6.80 Hz. 3H), 1.57-1.64 (m, 2H), 2.45 ~s, 3H), 2.56-2.63 (m, IH), 2.70-2.76 (m, IH), 5.37 (s, IH), 5.93 (d, J=l .?0 H z, III), 5.94 ~d, .J=1.20 lIz, IEE), 6.76 ~d, J=8.40 H7., II-IJ. 6.85 (d, J=8.80 Hz, I H), 7.02-7.04 (m, 2H), 7.21 (d, .J=S.40 llz, 2H), 7.47 (dd, J=2.40, 8.80 Hz, lH), 7.52 (d. J=2.40 Hz, IH), 7.65 (d, J=8.40 Hz, 211).
ESI-MS mle = 627 (I\I + 1).

21 9~7~Q
W096/049~ /C~

N-(4-iso-propylbenzenesuli'onyl)-c~-L4-(cyanomethyl)-2-n-propylphenoxy)]-3 ,4-methylenedioxyphenylacetamide 5 Step A: Preparation of ~T-(4-i.so-propylben~enesulfonyl)-o~-(4-bromomethyl-2-~?-propylphenoxy)-3 ,4-methylenedioxy-phenvlacetamide To a solution of 0.200 g ~.381 mmole) of the product of Example 65 dissolved in l.:'j mL of diethyl ether was added 0.837 mL
(.837 mmole) of 1.0 M phosphorus tribromide in methylene chloride solution under nitrogen at 0~C. The reaction mixture was stirred at 0~C for 2 hours when TLC analysis (~():15:1 CHC13-~feOH-NI-14OI-I) indicated that the reaction was nearly complete. The reaction was quenched at 0~C with water and then partiLioned with EtOAc. The 5 aqueous portion was separated and the EtOAc portion was washed with brine (2 X 10 mL). The EtOAc portion was then dried over MgSO4, filtered, evaporated to a residue, and then used in the next step of the reaction scheme.

Step B: Preparation of N-(4-i.so-propylbt n 7~n~s- 11fonyl)-a-(4-cyanomethyl-2-n-propylphelloxy)-3 ,4-methylenedioxy-phenylacetamide To a solution of the crude product of Step A dissolved in 1.5 mL of methyl sulfoxide was added 0.050 g (.762 mmole) of potassium cyanide at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour when TLC analysis (80:15:1 CHC13-MeOI l-NI-1401-1) indicated that the reaction had gone to completion. The reaction mixture was diluted with EtOAc and 10 NaHSO4 aqueous solution. The aqueous phase was separated and the EtOAc portion was washed with brine (2 X 10 mL). The EtOAc portion was then dried ov er MgSO4, filtered, evaporated to a residue.
and purifled. Purification was done by reversed phase HPLC (Waters Millipore Delta Prep 4000 with Delta-Pal~ C18 15 llm 100 A column cartridge) with a solvent system of 30:70 water-acetonitrile and 0.1 ~!
TFA buffer. The purified fractions collected were combined in a round ~ ~ 2 1 ~57 WO961D4905 - 58 .~ lu~ ,,'7 bottom flask, freeze in a -78~C dry ice-acetone bath, and Iyopbilized.
The resulting Iyophilized powder afforded 0.071 g (35 ~c~ 2-step yield~.
I l-l-NMR (400 MHz, CD3OD. ppm): S 0.8R (t, J=7.37 Hz, 3H), I .25 (d, J=6.92 Hz, 3HI, 1.27 (d, .1=6.97 Hz, 3H), 1.~5 Im.2H)~ 2.60 ~m, 2H), 2.99 (m, IH), 3.75 (s, 2H), 5.40 (s, IH), 5.96 (s, 2H), 6.~3 (d, J=8.39 Hz. lH), 6.78 (d? J=8.03 Hz, lH), 6.86-6.96 (m, 3EI), 7.10 (s, lH), 7.37 (d, J=6.h4 Hz, 2H), 7.7R (d, J=8.48 Hz, 2H).
MS ~ESI): C29H30N206S 534.63 Foulld: [535.1, M+l].

N-(4-i.s~o-propylhPn7e~ sulfollyl)-(x-l4-(tetraz(71-~-ylmethyl~-2-/1-propylpheno~y)l-3,4-methylenedioxyphenylsl- et:lmi~
A solution of 0.120 g (.224 mmole~ of the produet of Example 102 and 0.139 g (.673 mmole) of trimethyltin azide dissolved in 1.5 mL of toluene was heated in sealed pressure reaction tube and .stirrecl for 5 hours at 120~C. Analytical HP~C analysis (30:70 water-acetollitrile with 0.1 ~~ TFA) ;ndicated that the reaction had gone to 20 ec)mpletioD. The reaction mixture was cooled to room temperature when 2 M 11C l solution was added. The reaction mixture wa.s piartitioned with EtOAc and the aqueous ponion was separated. ~he EtC)Ac portion was washed with brine (2 X 10 ml,). dried over r~lgSO4 . filtered~ e~raporated to a residue, and purified. Purification was done 25 by reverse(l phase HP1,C (Waters Millipore Delta Prep 400Q rwitll Delta-Pak ClR 15 ,~m 100 A column cartridgre) with a solvent system of 30:70 watel Acetl)nitrile and 0.1 % TFA buffer. The purified fractions collected were combined in a round bottom flask, freeze in a -7~~C' dry ice-acetone bath. and Iyophilized. The resulting Iyophilized powder 30 affordeo 0.0306 g (24 ~,10 yield).
IH-NMR (40Q MHz, CD30D, ppm): ~ 0.B6 ~t, J=7.47 lIz, 311), 1.25 (d7 J=6.82 Hz, 6H), 1.~4 (m, 2H), 258 (m, 2H), 2.96 (m, lHI, 4.19 ~s, 2H), 5.38 (.s, IH~, ~.96 (s, 2H), 6.51 (d, J=R.30 Hz, 111), 6.76 (d, J=8.~3 Hz, III), 6.84-6.89 ~m, 3H), 7.04 (.s, lH~, 7.3~ (d, J=8.30 Hz, 2H), 7.76 (d, J=8.3~ Hz, 2H).

~ WO9G10490S ~t 95758 r~l,~J M~l ............................ -, ~ MS (ESI~: C29H31N506S 577.66 Found: j578.2~ M+l].

N-(4-iso-propylbenzenesulfonyl)-a-[N-(4-carbomethoxyphen~lamino)l-3 ,4-methylenedioxypilenylacetamide ~: Preparation of ethyl a-[N-(4-carbomethoxyphenylamino)l-3 ~4-methylenedioxyplletlvlacetate o To a .solution of 5.034 g (33.4 mmoles) of methyl 4-aminobel~oate dissolved in 50.0 mL of DMF was added 10.526 g (36.7 mmoles) of ethyl a-bromo-3,4-methylenedioxyphenylacetate. The reaction mixture was heated to 85~C and stirred in a sealed pressure reaction tube for 16 hours. TLC analysis (25~o EtOAc:Hexanes) 5 indicated that the reaction had gone to completion. The reaction mixture was transferred to a sep. funnel and partitioned between EtOAc and water. The aqueous portion was separated and the organic portion was washed with brine (2X25 mL), dried over MgS01, filtered, and evaporated to a residue. Purification was done by flash 20 chromafography eluting with 20~rO EtOAc:EEexanes. The purified fractions collected were combined and evaporated to afford 7.90 g of the titled product.
MS (ESI): C19H19N06 357.36 E~ound: [357.9. M+l].

Step B: Preparation of a-[N-(4-carbomethoxyphenylamino)]-3~4-methvlenedioxyphenykacetic acid To a solution of 2.12 g (5.93 mmoles) of the product of Step A dissolved in 10 mL of methanol was added 6.52 mL (6.52 30 mmoles) of 1.0 N KOH solution in methanol. The reaction mixture vvas stirred at room t~.l.pe.atul~ for I hour. TLC analysi.s (25~7o EtOAc:Hexanes) at that time indicated that there was no more starting material present in the reaction mixture. The reaction mixture was diluted with EtOAc and quenched witlI 10~~ NaHS04 aqueous solution.

t ~ 5 7 5 8 W096/04905 ~ ~ P~~ 13.::7--The aqueous phase was separated and the organic portion wa.s washed with brine (2 X t5 mL), and evaporated to a residue. Purificatioll ~as done by reversed phase HPLC (Waters Millipore Delta Prep 400() witll Delta-Pak C18 1~ llm lû0 A column cartridge) with a solvent system of 50:50 water-acetonitrile and 0.1 % TFA bufter. The purified fractic)ns collected were combilIed in a round bottom flask, freeze in a -7~~C dry ice-acetone bath. and Iyc)philized. The resulting Iyophili~ed powder afforded 1.11 ~ (57O,lo yield) of the titled product.
MS (C~l): C17Hl~NO6 329.13 Found: [330-5, M+11.

Step C: Preparation of N-(4-i.so-propylbenzelIesulfonyl)-a-[N-(4-c~arbomethox),phenylarllirlo)~-3,4-1nethylenedioxyllhenyl-acetarnide l'o a solutiolI of 0.180 g ~.~47 mmole) of the product of 5 Step B di.ssolved in 1.5 ml, of methylene chloride wa.s added 0.080 g (.656 mmole) of 4-dimethylaminopyridine, 0.147 g (.766 mmole'~ clf 1-ethyl-3-(3-dimethylamilIo-propyl3carbodiimide hydrochloride, and ().121:) g (,60? mmole) of the sulfonalnide respectively. The reaction mixture was .stirred at room te"-pe,dLu,~ under nitrogen i-or ~4 hours.
20 TLC analysis ~0:15:1 CHC13-CI-1301-1-NH40H) indicated that the reaction had ~one to completion after 24 hours of stirring. The reaction mixture was diluted with E~tOAc and transferred to a sep.
funnel. The organic pclrtion was washed with 2 N HC~I (2X 10 mL) and brine (IX10 mL). dried over MgSO4, filtered. and evaporated to a 2s residue. Purification was done by reversed phase HPLC (Waters Millipore Delta l'rep 4000 with Delta-Pak CIR 15 ~lm 100 A colulIm cartridge3 with a solvent .system of 40:60 water-acetonitrile and 0.1 ~,fo 1'FA buffer. ~he purified fractions collected were combined in a round bclttom flask, t'reeze in a -78~C dry ice-acetone bath~ and Iyophilized.
30 The resulting Iyophilized powder afforded 0.060 g (21C~c yieldj of titled product.
I H-NMR (40Q MHz, CD30D, pprm3: o 1.25 (d. J=6.96 llz, 3H). 1.2t~
id, J=6.~7 Hz~ 3H~, 2.97 (sept., J=7.06 Hz. 1~31 3.~0 (s, 311), 1.86 (.s~

2? 9~758 ~ WO 96/04905 ~ i7 ~ lH), 5.g4(s, 2H), 6.45 (d, J=8.81 Hz, 211), 6.87-6.75 (m, 3H~, 7.36 (d, J=8.39 Hz, 2H), 7.65 (d, J=8.85 Hz, 2H), 7.78 (d, J=8.48 Hz, 2H).
MS (ESI): C261T26N207S 510.57 Found: [511.0, M+ll.

N-(4-iso-~ pylbel~e-lesulfolly1)-a-[N-(4-carboxyphenylamino)~-3 ,4-methylenedioxyphenylacetamide Following the hydrolysis procedure described in Example 58 the titled compound is prepared from N-(4-iso-propylbenzene-sulfonyl)-a-[N-(4-carbomethoxyphenylamino)] -3 .4-methylenedioxy-phenyl~re~milt~

~ r ~ 2 1 ~ 5 jr 5 8 WO 9610490!; ~ I ~,11-!~. '. ............................ _ I _ EXAI~PLES 106-121 Ex~mple~ 106 throu~h 121 were prepared follovving the 5 procedures de~cribed i:n E~ample 40.

~
O~Z

0~

~x. # Z Ma~s Spectrum 1~+1) 2~ 106 C.ONHS~,-3-pyridyl fM+I~ 513 107 CONHSO2-(2-Me)-3-4uininolinyl (M+l) 563 1~)8 CoN~so2-3~ui~ yl (M+l) 54~, 109 CONHS02-~4-OH)-3-pyridyl ~M+1) 529 1 10 CONHS02-(4-OEt)Ph (M+NH4+) 559 111 CONHS02-(4-CONH2)Ph (M+l) 542 1 12 CONHS02-[4-CO(NiMej2)]Ph (M+:l ) 569 113 coNHso2-(4- SEt~- 3-pyridyl 1 M+ I ) 5 5 114 CONllS02-(4-OEt)-3-pyndyl (M+l i 543 3~ 115 CONHS02-(4-~rnine, 2,5-di-OMe~Ph (M+:l~ 573 116 CONHS02-(2~5-di-OMe)Ph (M+l) 558 1]7 CONHSO2-i3,4-di-OMelPh (M+l) 558 118 CONHS02-[5-(4- , ~ ~ yl~l-2-~Li~J~J~ +l) 639 I 1~} CONI'lSO2-(4-O~ e!-2-bl-n~ f+l ) 585 120 coNHso2-~4-(fcH2)2NHcsz))]ph ~M+ l 1 675 2 ~ 9 5 7 5 8 ~ WO 96/0490S P~, I /LI.~ 'T,'O,.l 7 121 CoNHso2-(2~s-di-oMe~4-NHcoNTHipr!ph (M+l) 658 122 CoNHso2-(2~4-di-oMe)ph 123 CoNHso2-(2~4~6-tri-oMe)ph ~

o)~ R

Ex # R 12 R3a Z Ma~
Spectrum (M+l ) 124 CO2H H CoNHso2-x-quininolinyl 579 125 CO2H H CoNHso2-3-quininolinyl 579 126 CON112 OMe CONHSO2-8-quininolinyl 57 127 CONH2 OMe CONHSO2-(4-t-butyl)Ph 553 12~ CON112 OMe CoNHso2-(4-amine~2~s-di-oMe)ph 572 129 CO2H H CONHSO2NH-(4-iPr)Ph 5~5 9 ~ 7 ~ 8 W0 96104905 - - r~ . , 7'--N-IN'-(4-iso-propylbenzene)aminosulfonyl~cx-[(4-c,lrboxy-2-n-propyl)phenoxy]-3,4-methylenedioxyphenyl~oetsimi~lP

Step A: Preparation of N-~4-isopropylbenzene)-N'-tert-hsutyl-sulfamide To a solution of p-isopropylaniline (1.69 g, 11.77 mmol) in CH2C12 (0.5 ml~ was added N,N-diisopropylethylamine (2 ml) followed by the dropwise addition of a solution of N-t-butylsulfamoyl chloride (1.01 g. 5.88 mmol) [prepared according to the procedure described b~
W.L. Matier and W.T. Comer, J. I~ied. Chem., 15:5~ 538 (1972)~ in CH2C12 (0.4 ml~ via a ~yringe at 0~C. The reaction mixture was then maglletical}y stirred at room temperature for i8 hrs. The reactioll was diluted with C1~2C12 smd quenched with aqueouslN HCI. The organic phase was separated~ washed with water, saturated aqueous NaCI. dried (MgS04)~ filtered~ evaporated and dried in vacuo to yield an impure solid. The residue was puri~led bv trituratin~ with Hex:EtOAc (4:1) fo yield 930 mg (58~~c,) of the titled product as a white solid.
Il-i-NMR (300 MHz, CD30C), ppm~: ~ 1.1-1.3 (m, 15H), 2.7-2.9 ~m~
IH). 6.9-7.2 (IU, 4H).
ESI-MS mle = 271 (M + 1~.

Step B: Preparatic n of N -4-isopropvlht~n7~n~culfamide 2s A solution of 0.9 g (3.32 mmol) of the product of Step A in tritluoroacetic acid (15 ml) was mslgn~ticiqlly stirred at ruom temper.lture ullt;l TLC indicated the reaction was collIplete. The solvent was removed in vacuo, washed with cold Et20, smd filtered to y;eld 553 mg (78 ~~i) of the titled product as a white solid.
IH-NMR (300 MHz, CD30D, ppm): ~ 1.1-1.3 (d. 6EI), 1.7-1.9 (m, IH). 7.1 (s~ 4H).
Cl-MS, mle = 232 (M ~ NH4+).

9 J 7 5 ~
~ WO 96/~4905 ' ' ~ J ~ 5/~

Step C: Preparation of N-[N'-(4-iso-propylbenzene)aminosulfonyll-a-l (4-carbomethoxy-2-n-propyl)pllenoxy]-3 ,4-methylene-dioxyphenylacetamide The compound from Step B was reacted with the carboxylic acid, obtained in Step B of F.xample 56, according to the procedure de.scribed in Step C of Example 25 to provide the titlted compound.
IH-NMR (300 MHz~ CD30D, ppm): o O.X-0.9 (t, 3H), 1.1-1.3 (d. 6H), 1.4-1.7 (m, 2H), 2.5-2.9 (m, 2H), 2.7-2.9 (m, lH), 3.~ (s. 3H), 5.3 (s, IH), 5.9 (s, 2H). 6.5-6.7 (dd, 2H), 6.8-7.1 (m, 6H), 7.5-7.6 (dd, IH), 7.7 (s, 111).
ESI-MS, m/~ = 659 (M+l).

Step D: Preparation of N-[N'-(4-iso-propylbenzene~aminosulfonyl]-a-l(4-CarbOXy-2-tl-prOpyl)phenOXyl-3.4-lllethylenedioxy-phenylacetamide The titled compound was prepared following the procedure described in Example 40.
IH-NMR (300 MHz, CD30D, ppm): ~ O.X-0.9 (t, 3H), 1.1-1.3 (d. 6H), 1.4-1.7 (m, 2H), 2.5-2.9 (m, 2H), 2.7-2.9 lm, IH), 5.3 (s, IH), 5.9 (s, 2H), 6.5-6.7 (dd, 2H), 6.8-7.1 (Ul, 6H), 7.5-7.6 (dd, IH), 7.7 o;, 11-1).

N-(4-i..~o-propylbenzenesulfollyll-o -[4-methanesulfonylamino-2-n-propylphenoxyl-3,4-methylenedioxyphenyl~ et lmide o-(4-Amino-2-n-propylphenoxy)-3,4-rnethylenedioxy-phenylacetate (Product of Step C Example 99) was reacted with methanesulfonyl chloride in ~ mixture of pyridine and methylene chloride to pro~ide o~-[4-(N-methanesulfonyl)amino-2-n-propyl-phenoxy]-3,4-methylenedioxy- phenylaeetate. which upon further 2~ 957C;~ ~' WO ~610~905 J u I ~

elaboration following the procedures described in Example 99 provided the titled compoulld.
I H-NMR ~300 I~lHz, CDC13, ppm): ~ 0.8-O.g (t, 3H), 1.1-1.3 (d, 611)~
1.4-1.7 (m, 2H), 2.4-2.69 (m, 2H), 2.72 (s, 3H), 2.75-Z.9 (m, lH), 5.3 (s, IE-I), 5.85 (s. 2H), 6.6-6.7 (dd, ,H), 6.8-7.1 (m, 6H), 7.6-7.75 (dd, IH~, 7.9 (s, 111).

EXAMPLE~ 132 N-(4-i.~o-propylben~enesulfonyl)-cc-l(4-(N,N-dilnetilylcarh3Jnclyl)-amino-2-n-propylphenoxy l-3 ,4-methylenedioxy-phenylacetamide The title compound '~Y.LS prepared by reacting the amine from Example 99 (Step C) with N,N-dimethylcarbamoyl chloride.
1 H-NMR (300 MHz, CDC13, ppm): o U.95 (t, 3H), 1.1-1.3 (d, 6H).
].45-1.8 (Itl, 2H), 2.5-2.7 ~m, 2H), 2.75-2.9 (m, 11-1)~ 3.0 l~s. 61-1), 5.3 (s,IH), 5.85 (s, 2H), 6.6-6.7 (dd, 2H~, 6.8-7.1 (m, 6H), 7.6-7.75 (dd. 11-1), 7.9 (d, 2H).

N-(4-i~o-propylhenzenesulfonyl)-~x-[4-methoxycarbonylaminu-2-1l-propylphenoxy]-3.4-methylenedic~xy-pllenyl i~e~:lmiflP
2s 1 he title compound was prepared by reacting the amine from Example 99 (Step C) with ethylchlorc)iorlll~te.
H-NMR (300 MHz, CDC13, ppm)- o 0.9 (t, 3H), I .I -1.3 lm, 9H), 1.45-1.7 (m, 2H). 2.45-2.7 (m, 2E-1), 2.8-3.0 ~m, IH), 4.1-4.25 (Ll, 2}1), 5.3 ~s, IH), 5.9 (s, 2H), 6.5-6.75 (m, 2H), 6.8-7.0 (m, 6H~, 7.6-7.75 30 (dd, IH), 7.8 (d, 211)-2 1 q ~i 7 5 PJ
~ W096/04905 ,~"~

Methyl 3-allyl-4-hydroxybenzoate 5 Step A: Preparation of methyl 4-allyloxybenzoate To a nitrogen flushed 5 L three neck round bottom flask fitted wilh a mech~llir 1l stirrer, condenser, and a nitrogen inlet was charged 60~ g ~4 mol~ of methyl 4-hydoxybenzoate, 520 ml ( 727 g, 6.00 mol, 1.5 eq) of allyl bromide, 663 g (9.6 mol of anhydrous 0 potassium carbonate, and 2.3 L of acetone. The mixture was refluxed with vigorous stirring for ~0 min. Additional potassium carb~mate, (50 g) was added, and 25 g added again after an additional 50 min. At'ter ~0 min (total reaction time of 160 min), the suspension was allowed to cool to ambient t~-llL)el~lule and stirred overnight. The mixture was 5 filtered and the cake washed with 3 L of acetone. The solution was concentrated to obtain 7~8.6 g (theoretical yield 76~.9 g) of a pale yellow, almost colorless oil which was used without purification in the next step. The product was a single spot on TLC (silica-l:l EtOAc/Hex) and the MNR was consistent with methyl 4-20 allyloxybenzoate.

Step B: Preparation of methyl 3-allyl-4-hydroxybenzclllte To a nitrogen flushed magnetically stirred 3 L single neck round bottom flask fitted with a condenser, and a nitrogen inlet was 25 charged the methyl 4-allyloxybenzoate, 4()0 mL of 1.2-dichlolol,~ elle, and 10 g of BEIT. The solution was heated and distillate collected untill the head temperature reached tl~at c~f 1,2-dichlorobenzene (1~0~C). The solution was then refluxed for 6.5 hr, then cooled to 140~C and aged ovemight. The hot solution was then poured into 2.5 L of hexanes and 30 the re.sulting suspension aged overnight with stirring. The suspension was filtered, ~md the cake waslle(l with hex~mes. The solid wa.s air dried affording 747.7g (~7.3~ yield) as a white solid haYing a faint odor of' o-dichlorobenzene.

7 1 0 ~ 7 ~ 0 ;, ~ L I ~ J I J U j~
W096/04905 ' I ~ Jv rr; _ ~ _ I :H-I~MR (3(1() ~IHz7 CDC13. ppm): ~ 3.42 (dt .J=6.4,1.4 Hz, 2L~), 3.~7 (~s, 311), ~.11-~.18 (m, 2H~, S.X7 (hs, IH), 5.93-6.06 ~m,lll), 6.R3 (d, J=7.9 Hz~ lH), 7.79-7.85 ~m, 21-1).

Methyl 4-hydoxy-3-n-propylbenzoate o Step A: Preparation of methyl 4-hvdoxy-3-n-propvlbenzoate A solutioll of 3~3 g of methyl 3-allyl-4-hydoxybenzoate in 1.5 L of methallol was hydrogellated for I hr in a ParrR type shaker at 40 psi and ambient temperature using 1.5 g c~f 10~ p~lladium on carbon as the catalyst. The reaction was filterd through Sulka-FlocR and the caL e washed with I L of methanol. The combined filtrate was concentrated and the oil tlushed with ether. Hexanes (1.5 L~ were added and the resulting suspension cooled to 0~C. The product was collected by filtrati(m, washecl with hexanes ancl dried affolding 176.6 g of methyl 4-hydoxy-3-1l-propylbenzoate. A secc~lld crop of 166.4 g was obt;lilled hy c(JIlcentratin~; tile filtrate, cliluting with hexan~s ;md filtelillg, bringillg the total to 343 g (94.3% yield).
I H-NMR (3()0 MHz, C'DC13, ppm): ~ 0.94 (t .1=7.4 Hz; 3H), 1.63 ~m, 2H)t 2.59 (t .1=7.7 Hz, 2H), 3.86 (s, 3H), ~.87 (s, IH), 6.~4 ~d J=8.4 Hz, 111~. 7.76 (dd 1=8.4. 2.2 Hz, IH~, 7.81 (d ./=2.2 Hz, ] H).
~XAMPLE 136 Ethyl 3,4-methylenedioxy-d,l-mandelate Step A: a-1'rimethylsilvloxy-3.4 methylenedioxyphenvl~lcetorlitrile To a nitrogen fTushed magnetically stirred 3 L single neck rou1ld bc~ttom fla.sk fitted with a nitrogen inlet was charged 2RSg (1.9 mol) of piperonal, 200g (2.0 mol) of trrmethylsilylyc.yanide, 0.2 g of potassium cyanide, 0.2 g of 1~-crown-6 and 500 mL of methylene chloride. The mixture was stirred at amhient temperature for 75 min, 2 ~ ~ 5 7 5 ~
W0 96/1~4905 r~ ,3;7 _ during which time the reaction exothermed to 35~C. A second charge of 5 g of piperonal was added and the reaction stirred an additional 75 min. The reaction mixture was diluted with ether and 250 mL of saturated sodiuim biGarbonate solution u!as added. The mixture wa.s stirred for 20 min before partitioning. The organic Llyer was washed with another 250 ml, portion of saturated sodiuim bicarbonate, twice with brine (300 mL)~ dried with sodiurm .sulfate, filtered and concentrated leaving 48g.6 g (481.4 g theoretical yield) of the title compound as a pale yellow oil. This was used as is without purification in the next step.

Step B: Preparation of ethyl 3~4-meth~/lenediox~-dd-mandelate To a nitrogen flushed magnetically stirred 3 L single necl;
round bottom flask fitted with a gas inlet was charged the product obtained from the previous step and I L of absolute ethanol. The solution was cooled to 0~C and HCI gas gentiy bubbled through the solution for 1 hr. After a few minutes the reaction solidified to a white mass which was aged at room temperature ovemight. I L of methylene chloride, and I L of water were added. The mixture wa.s shaken for ca 5 min dis.solving some of the white solid. l'he mixture wa.s deccmted and the procedure repeated several more time.s until all of the .solid had been dissolved. The layers were separated and the aqueous Iayer back extracted once with methylene chloride. The combined organic layer was washed with brine, dried with magnesium sulfate and filtered through a pad of .silica . The solution wa.s concentrated, flu.shed witl ether and diluted with hexanes. The white slurry was cooled to 0~C
then filtered. The cake was wa.shed with 1:2 ether/tlexalles followed by hexanes. The product was dried affording 347.2 g of the title compound as a white solid. A second crop of 24 g was obtained by 3 concentrating the mother liquors, bringing the total to 371.4 g (85.8~, yield).
IH-NMK (300 MHz, Cl:)C13, ppm): ~ 1.22 (t, J=7.2 Hz, 3H), 3.41.(d, J=5.6 1 Iz, IH), 4.10-4.31 (nl, 2H), 5.03 (d, J=5.6 Hz, IH), 5.94 (s, 2H), 6.77 (d, J=8.5 Hz, IH), 6.8~S-6.gO (m, 2H).

W0961049U~ 2 t 9 5758 . ~

F.XAMPLE 137 Ethyl o~-bromo-3,4-methylenedioxyphenylacetate Step A Ple~ lati~ of ethyl o-bronlo-3,4-rllethylenedioxypilellyl-acetate To a nitrogen flushed 5 L three neck round botlc~nl fla.sk fitted with a mechanical stirrer, a dropping funnel and a nitrogen inlet was charged 433.8g (1.93 mol) of ethyl 3,4-methylenedioxy-d,l-mandelate and 3.51, o f ether. The suspellsion ~lla.s caoled to 0-5~C and a solution of 179~ ~0.66 mol) of PBr3 in 500 mL of ether was added over a period of 30 min. The reaction was aged for ~.5 hr at 0-5~C
during which time, an additional 24.2 g (0.09 mol) of PBr3 wa~s added.
15 The solid initially plesent slowly dissolved leaving a clear yellow solutioll. The reaction was quencl~ed by careful addition of 800 mL of saturated sodiuim bicarbonate solution and 200 nlL o~ water. The layers were separated and the aqueous layer e~itracted once witll ether.
The combined organic phase was washed once with satumted sodiuim 20 bicarbonate solution, lO~o sodium bisulfite solution. brinel dried with magnesium sul~'ate, and filtered throu~h a pad of silica. The solution was concentrdted to 507.6 g (91.4~~to ) of a pale yellow oil. Es.sentially a single spot on TLC (silica-l:l Et2O/Hex)~ NMR indic~tei a small annount of ether is present. This was used as is without purification in 5 the next step.
lH-NMR (300 l\lHz, CDC13, ppm)- ~ 1.27 (t, .I=7.2 Hz, 3H~. 4.1( -4.35 (m, 2H), 5.26 (s, lH), 5.96 (s, 2H~, 6.72 (d, J=8. Hz, IE-13, 6.94 (~dd, J=8.0, 1.8 I-lz, IH). 7.11 (d,J=1.8 Hz, IH~.
3~ EXAMPLE 138 cc-(4-Carbometlloxy-2-~1-propylpheno1i;y)-3 ,4-methylenedioxy-phenyl)acetic acid sodium salt ~ WO 96tO4!~05 ~ ~2 1 9 5 7 5 8 r~ e ~7 Step A: Preparation of ethyl oc-(4-carbomethoxy-2-n-propyl-phenoxy)-3.4-methylenedioxyphenylacetate To a 2 L three necked 24/40 round bottom flask e4uipped with a mechanical stirrer, a nitrogen inlet and a dropping furmel was first added a solution of 36.0 g (0.1~5 mol) of methyl 4-hydroxy-3~
propylben~oate dissolved in 700 ml. of anhydrous DMF follo~ed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged with nitrogen and the reaction mixture was stirred at room te~ eld~ul~ ~or 2 hours. A solution of .~i8.5 g (0.204 mol) of ethyl (x-bromo-3.4-methylenedioxyphenylacetate clissolved in 100 mL of DMF wa.s then added via an addition i'unnel over a 15 minute period. The reaction rmixture W.ls stirred an additional I hour at room telulu~.dtulc then quenched by addition to 5 L of a 5% aqueous citric acid solution. The organic product wa.s extracted into diethylether (2 x 4 L). the organic layers were separated, wa.shed with saturated aqueous NaCI, dried (MgSO4), filtered, .und evaporated. The residue was applied to a silica gel (2 kg; 70-230 mesh) column equillibrated in 10% CH2C12-hexane.
The column was then eluted successively with 12 1. of lO~o CH2C12-hexane, 12 L of 5~ EtOAc-hexane, 4 L of 7.5~o EtOAc-hexane, 12 1, Of 1O~! FtOAc-hexane, and finally X L of 20~i' F.tOAc-hexane.
Combination of the purified fractions and evaporation in vacu(i afforded 76.3 g (74.2 theoretical) of the title compound as a pale yellow oil which wa~s used without further purification in the next step.

Step B: Preparation of o~-(4-carbomethoxy-2-n-propylphenoxy)-3~4-metnylenedioxvphenvlacetic acid .sodium salt A I L 3 necked 24/40 round bottom flask e~uipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0.1X5 mol) of the semi-puriried product of Step A dissolved in 500 mL of methanol. The flask was purged with nitrogen, the stirrer was started. and 37 mL of a 5.0 N aqueous .solution of sodium hydroxide was added over a 30 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 30 minutes at W}liCh point TLC analysis (CH2C12-h,leOH-WO 9610490~ .' . 2 1 ~ 5 7 5 8 , ~

NH40H 90:10 1 ) indicated that the starting material had been consumed.
The reaction mixture was adjusted to pH=4 with 6 N HCI, and the bull~
of the organic solvent was removed in vacuo. The precipitated c7rgallic product and the aqueous layer were next partitioned betweell CH~CI ( I
L) and water (I L) which producecl a copious emulsion. Tbe reaclion mixture was th~n aged overnight in a refridgerator which resulted in crystallization of the organic product The eïystalline solid was separated from the two phase mixture by filtration and washed with CH2C12. The solid was slurried again in diethylether. filtered, waslled ~~ vvith hexane, and then dried in a vacuum to afford 65 g (85 3~to) of Ihe title compound as a white crystallhle solid I l Z-NMR (40Q l~,lHz, CD30D, ppm): ~ 0.~3 (t, J=7.2 Hz, 3H3, 1.62-1.75 (m~ 2H), 2h3-2.70 (m, IH), 2.77-2.81 ~m, IH), 3 ~s4 (s, 3H3, :5.54 (s. I H~, 5.94 (s, 2H)~ 6.81 (d, J=7 6 Hz, lH), 6.89 ~d, J=9.2 Hz. I H), 7 O~i ~d, J=l .6 1 Iz, lH)~ 7.11 (hr s, IH3, 7.78-7 81 (m. 2H).
Microanalysis for C20H20o7Nao~7~-L25 H20.
Calc'd. C = 58 29; H = 5.~0: Na = 4.1 Found: C = 58.19; I-l = 5.17; Na = 3.93 I~XAMPLE 139 N-(4-is(~-propylbellzellesulfonyl)-a-(4-carbomethoxy-2-n-propyl-phenoxy)-3 t4-methylenedioxyphenyl :~cet~ln~

25 Step A: Preparation of ethyl a-(4-~ u~ Ll.oxy-2-il-propyl-phenoxy~-3.4-methylenedic xyphenylacetate To a nitrogen flushed 5 L three neck round bottom flasli fittecl witll a mecllanical stirrer, condenser, and a nitrogen inlet was Ghargecl 326g (1.68 mol) of methyl 4-hydoxy-3-n-propvlbenzoate, 30 ~(}7.6 g (1.73 mol3 of ethyl o~-bromo-3,4-methyleneclioxyphenylacetate from abo~ie. 23~g ( 1.70 mol) of anhydrous potassium carbonate, and 1.7 L of acetone. The mixture was refluxed with vigorous stirring f'c~r 9 hr The suspension was allowed to cool to ambient temperdture aod stirred overnight. The mixture diluted with ~ L of ether, cooled to 0~C

W0 96/OJ905 2i } 9 ~i 7 5 8 T ~ 7 - 17~ -and filtered through Super-CelR. The cake washed with ether and the combined filtrate concentrated. l'he residue was redissolved in ether and the organic layer washed with ollce with I N HCI~ saturated sodiuim bicarbonate solution. lO~o sodium bisulfite solution, brine, dried with magnesium sulfate, treated with charcoal ~md filtered through a plug of silica. The pale yellov.~ solution was concentrated to 697.3 g (theoretical 678 g) of a thick yellow oil which was used without purification in the next step. NMR was ccnsistent with the title compound.
I H-NMR (300 I\IHz, CDC13, ppm): ~ 0.95 (t, J=7.3 Hz, 311), 1.17 (t, J=7.1 Hz, 3H), 1.61-1.81 (m, 2H)j 2.63-2.80 (m, 2H), 3.85 (s, 3H~, 4.07-4.23 (rm, 2H), 5.58 ~s. lH), ~.96 (s, 2H), 6.71 (d, J=8.5 Hz, IH), 6.76 (d, J=8.0 1 Iz, IH), 7.02 (d,d, J=8.0, 1.7 Hz. I H), 7.05 (d, J=l .7 Hz, I H), 7.79 (d,d, J=8.5. 2.2 1 Iz, IH), 7.~4 ~d, J=2.2 Hz, IH).

Step B: Preparation of a-(4-carbolIlethoxy-2-n-propyipheno7sy)-3.4-methylenedioxyphenylacetic acid To a nitrogen flushed 5 L 3 neck round bottom fklsk e~luipped with a mPch,lni~sll stirrer, a dropping fulmel, and a nitrogen inlet was charged with 697.3 g ( 1.68 mol) of the crude product of Step A and 2 L of methanol. 500 mL of 5.0 N (1.5 eq) aqueous sodium hydroxide was added over a 20 minute period via an addition funnel.
The reaction mixture was stirred at room temperature for an additional I hr at which point TLC ~malysis (CH2C12-MeOH-NH4OH 90:1():1 ) indicated that the starting material had been consumed. The reaction mixture neutralized with 420 mL of 6 N HCI, and the bulk of the organic solvent was removed in vacuo. The residue was dissolved in ether and extracted with a ~u~ ation of aqueous NaOH and NaHCO3 The aqueous layer was extracted with ether and the combined organic layer was washed with aqueous Nal-lCO3 ~e aqueous klyer was acidified with HCI and extracted with ether. The ether solution was dried with magnesium sulfate, filtered, and concentrated tc afford 708.9g ~theoretical 62~ gi of the title compound as a viscous orange oil.

WO96/04905 . ~ 2 1 9 5 7 ~8 NMR rndicated that it was ca 85'~o product by weight (I~'~rc ether) thus pro~iding a corrected yield of 602.6 g (96.4~ yield) I H-NMR (300 MHz, CD30D, ppm): ~ 0.93 ~t, J=7.4 1{~, 3H), 1.56-1.77 (m, 2~ .6~ (t, 2H), 3.84 (s, 311), ~.57 (s, IH~, 5.95 (s. 2H)~ 6.4 (bs, lH), 6.71 ~d, J=8.5 Hz, lH), 6.79 (d, J=7.9 Hz, III), 6.99-7.05 (m, 2H~ 7.78 (d,d, J= 8.5, 2.2 Hz, IH), 7.82 (d, J=2.2, lH).

Step C: Plep,aratioll of N-(4-is~-propylbenzenesulfonyl~-a-(4-carbomethoxy-2-~-propylphenoxy3-3 ,4-methylenedioxy-phenylacetamide pota~siulll salt.
To~ a nitrogen ilu.shed S L 3 neck round bc1ttOm flas~
equiped with a mechanical stirrer, a dropping funnel, a condenser and a nitrogen inlet was charged I L of THF and 3~û g (2.16 mol, 1.~2 eql c f carbonyl diimidazole (CDI~. The mixture was heated to reflux and a solution of 663.6 g ( 1.52 mol) c f acid trom Step B an~d I L of THF was added dropwise over a period of 30 min. The reaction was monitored for coversic)ll of the acid to the acyl imidazolidc bv NrMR. An additional S5 g of COI was added over 45 min. 11le solutioll W.IS cooled and 291 g (1.4~ mol~ 4-isl)-propylbenzenesulfonamide was ~Idcled as a solid in one portion and the solutioll aged 20 min. DBli 2~0 mL (?34g, 1.54 moll W;iS added drop~;vise over 10 min resulting in an exotherm to 45~C. The reaction ~a.s aged at room temperatyurc for 3 hr then concentraEed in vacuc . The residue was partitioned between ~.751, oi' 2.5 N I~CI and 3 L of ether. The aqueous layer was extracted with I L
25 of ether, and the combined organic layer washed with 2 N HCI ;md saturated potassillm bicarbonate solution. The etherial layer was l-d~ e,lt;d to a ~ L 3 neck round bottom flask equipped with a mechanical stirrer. I L of aqueous pOtaSSiUIll bicarbonate solution was added and the mixture stirred overnight at room te~ GIdlul~. The 30 resulting thick suspension wa,r; filtered and the cake ~h~ashed with 500 mL
of water followed by 1 L of ether. l'he product was then slurried in the fulmel with additional ether and sucked dry yielding 741g of a tan .solicl The scllid was recharged to a ~ L 3 neck round hottorn flask equipped with rl mechanical st;rrer to which WEIS added I L of ethyl acetate alld ~¦ W0 96104905 ~ ' 2 ? 9 5 7 5 8 ~ . _., '7 500 mL of saturated potassium bicarbonate .solution. The slurry was ,stirred at room lC~ JCld~Ul~ for I hr, diluted with 3 L of ether, and the ,~ slurried stirred at room temperature overnight. The yroduct was filtered, washed with 500 mL of water and I L of ether and dried in 5 vacuo. The yield was 592 g of the title compound as a white crystalline solid. A second crop of 47.6 g was obtained frc m the mother liqours bringing the total to 639.6 g (74% of theory) IH-NMR (300 ~IHz, CD30D, ppm): o 0.88 (t, J=7.4 El-, 3H),1.21 (d, J=6.~ Hz, 6H), 1.52-1.66 (m, 2H), 2.50-2.76 lrll, 21-1), 2.90 (sept, J=6.9 llz, IH~, 3.X4 (s~ 3H),5.35 (s. IE~ .94 (s, 2H), 6.69 (d, J=8.6 Hz, 111)?
6.76 (d, J=85 Hz. l H), 7.()4 (m, 2H), 7.20 (d, J=, 8.4 Hz, 2H), 7.61 (dd, J=8.5, 2.20, Hz, 111), 7.67 (d, J=~.4, 2H), 7.71 (d, J=2.1 Hz, 111).

N-(4-i.sc~-propylbenzeneslllfollyl)-a-(4-carboxy-2-n-propylphelloxy)-3,4-methylelledioxyphenylacetamide dipotassium salL

Method A:
20 ~tep A: Preparation of N-(4-i~c~-propylbellzenesulfonyl)-o~
carboxy-2-/7-propylphenoxy)-3,4-methylelledioxyphenyl-acetamide dipotassium salt A mixture of 204 g (0.345 mol) of the product of Example 139, 420 mL of 1.0 N KOH in methanol and 500 mL of water was 25 .stirred at 60~C under a nitrogen atmo.sphere. After 3 hours TLC
analysis (90:10: I CH2C12-MeOH-NH4OH) indic,lted that ester hydroly.si.s wa.s complete. The reaction mixture was cool ~slightly, then concentrated on a rotary evapc~rator to a weight of 500 g. 2.5 L of isopropanol was added alld the solution re-oncentrated to an oil. The 3() residue was flushed with an additional 2-3 L of isoprc~panol until crystallizatioll began. The slurry wa.s concentrated to ca 1.5 L and cooled to 30~C, filtered and wasllecl with 300 mL of IPA and 500 mL, of ether. The product was dried affording 185 g of semi-pure title compound a.s a white crystalline solid. A second crop of 17 g was WO g61049U5 ~ ' ' 2 ~ 9 5 7 ~ 8 P~

obt~ined from the filtrate after cooling. The material was recrystallized as follows: 16~ g was dissolved in 3 L of absolute etharlol at retlux, filtered hot, and the flask and funnel rinse~ with an additiollal 50() mL
of ethanol. 70 rnL of ~vater was added and the solution cooled to 0~C
5 over 2 hr then aged at 0~C ior 6 hr. The product was collected by filtration, washed with ethanol, then air. The yield was 1~0.8 g of the title compound as a white crystalline solid.
I H-NMR ~400 MHz, CD30D, ppm): o 0.88 (t, J=7.2 Hz. 3H~, 1. 2 I (d, J=7.0 Hz, 3H), 1.22 ~d~ J=7.0 Hz, 3H). 1.56-1.63 (m, 2H), 2.52-2.59 ~m, IH), 2.67-2.74 (m, lH), 2.91 ~sept, J=7.0 Hz, IH), 5.33 (s, I H), 5.92 (d, J=l .2 H~, I H!t 5.93 (d, J=1.2 Hz, I H), 6.~2 (d, J=R.5 Hz. 11-1~, 6.7h (d, J=X.5 l-lz, lH), 7.04 (d, J=7.5 Hz, lH), 7.05 (s, I H). 7.21 (d, J=R.5 1 Iz, 211), 7.64 (dd. J=2.0, 8.5 Hz~ IH), 7.67 (d, .1=8.5 Hz, 21-1), 7.73 (d, J=2.0 Hz, lH).
5 Microanalysis for C2~H27NSO~K2-3.4 H20.
KF = 9.00 (calc for 3.4 H20 = 9.04) Calc'd: C = ~J,9.67; H = 5.03; N = 2.07; K = i 1.55; S = 4.74.
Found: C = 49.30, H = 4.95; N = 2.06; K = I I.g5; S = 4.~2 20 ~lethod B:
Step A Preparat;on of N-(4-i.s~v-propyl~-~n7en~ iollyl)-o~-{4-carboxy-2-n-propylp'ileno~y)-3 ,4-methylenedioxyptlenyl-ace~.amide A mi~ture of 20~ g (0.345 mol i of the product clf E~ample 25 139, 425 mL of 1.0 N KOH in methanol and 500 mL Cli' water wasstirred at 60~C under a nitrc~gell atmosphere. After 1.75 hours l'LC~
analy.sis (90:1~:1 CH2C12-MeOH-NH4O}I) indicated that ester hydrolysis was cormplete. The reaction mixture wa.q cooled slightly, then cc~ncentrated on a rotary evaporator. The concentrate was 30 acidified with 400 mL of 2 ~ HCI and extracted first with 6 L oi ether-EtOAc-CI-12C12 4:1:1, then with 3 L of 1 :2 EtOAc-CH2CI The organic layers were washed with 250 mL of 2N HCI, then with 3 X 500 mL of water, dried with magnesium sulfate, filtered, and concentrated, during whicll~ the product began to crystallize. The solution ~IS

~ WO 96104905 ' P~

concentrated to a white sluury of ca 750 mL, diluted with I L of hexanes, cooled to 0CC, aged I hr then filtered. The product wa.s air dried affording 170.0 g (919~ yield) of the title compound as a white crystalline solid.
IH-NMR (400 MHz, CD30D, ppm): o 0.8~ (t, J=7.2 Hz, 3H), 1.21 (d, J=7.00H7" 3H), 1.22 (d, J=7.0 Hz, 3H), 1.56-] .63 (m, 211), 2.52-2.59 (m, IH), 2.67-2.74 (m, IH), 2.91 (sept, J=7.0 Hz, lH), ~.33 (s, IH), 5.92 (d, J=1.2 Hz, I H), 5.93 (d, J=1.2 Hz, lH), 6.72 (d, J=8.5 Hz5 IH~), 6.76 (d, J=R.5 Hz, I H), 7.04 (d, J=7.5 ~z, I H), 7.05 (s, I H), 7.21 (d, 0 J=8.5 ~tz, 2H~, 7.64 (dd, J=2.0~ ~.5 Hz, I H), 7.67 (d, J=~.5 Hz, 2H), 7.73 (d, J=2.0 Hz, lH).
Microanalysis i'or C28H29N08S
Calc'd: C = 62.33; H = 5.42; N = 2.60; S = 5.94.
Found: C = 62.15; H = 5.4~; N = 2.54; S = 5.99 Step B: Preparation of N-(4-iso-propylbenzenesuifonyl)-a-(4-carbox y-2-n-propylphenoxy)-3,4-methylenedioxyphenyl-acetamide dipota.ssium salt 15g.7 g (0.296 mol) of acid fro~n Step A was suspended in 20 3 L of absolute ethanol. To this was added 590 mL of 1.0 N KOH in metha[lol over 20 min while simultaneously warming the mixture to 50~C. The clear and colorless solution was cooled to 0~C during wllicl it wa.s seeded with 20 mg of the title compound. The suspension was stirred for 2 hr at 0~C, I L of ether was added and the suspension 25 filtered. 1~e .solid was dried affording 16~.4g of the title compound as a white crystalline solid. A second crop Or 22.3 g of comparable quality material was obtained by concentrating the ML to ca. I L, diluting with I L of ether, filtering, and recrystallizing the solid (27 g) so obtained from 200 mL of 98C~'C! ethanol. Thus affording after drying a total of 30 190.7 g (96.8~ yield corr!d for water content) of the title compound.
Microanalysis for C2XH27K2No8s-2.75 H O.
KF = 7.45 (calc for 2.75 H2O = 7-44) Calc'd: C = 50.55; H = 4.92; N = 2.11; K = 11.75;
Found: C = 50.69; H = 4.56; N = 2.05; K = 11.20; S = 4.71 7 5 8 ; ~
WO 96/04905 , ~ , . P~

EXAMPLE 1~i3 1~-14-iso-propylb~ e~ulfonyl)-a-(4-carboxy-2-n-prc)pylphenoxy)-3.4-methylenedioxyphenyl.~et~mi~f~ dipotassium salt Step A: Preparatio:n of N-(~-iscj-propylbenzenesulfonyl~-a-(4-carbc~xy-2-n-propylphenoxy)-3,4--nettlyleIlediox~ phenyl -acetamide di-S-(-)-a-methvlbe.nzylamine~ salt 32.4 g of the acid from Example 139 wa.s dis.solved in 50() nlL c~f isop:ropallol, and 15.5 mL of S -(-)-cx-meti-~ Ibenzyl amine was added. The solution was allowed to stand at room ~emperature overnight. The mixture was filtered and the cake washed with a small amount of isopropanol. The solid was recryastallized 4 more times from i.sopropanol affording 45 of the title compound.

Step 1~: Preparation of hl-(4-iso-propylbe:nzenesulfollyl j-a-~4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenyl-acetamide d;potassium salt 'I:'he c~-metl1ylbellzylamirle salt :from step A wa.s partitiol1ed between ethyl acetate and NaHSO~i, dried with h~gSO~, filtered .ind concf~ntr~t~-l The residue was dissolved in methanol-water at roc)m )ela~ul~, and basicified with ca. 12 mL of 1 N NaOII iu methanol, diluted with water and filtered through a 0.45 micron. The solution was desalted and purified on a Waters Millipore Delta Prep 3000 liquid chromatograph equipped with an MlOVO Prep-Pak module cont:ai~ g a 47 x 300 nm1 Delta-Pak Cl~ 1511m IOOA colurnu cartridge. Two solvent resevoirs were en-ployed: solvent system A (95-5 water-acetonitrile), and sol~ent system B (5-95 water-acetol1itrile), arld the column effluent was monitored simultaneously at 210 and 2RO nm with a Waters model 490 W-visible detector. Each fraction was pump-injected onto the c.olumn and desalted by elution (50 mL/mill) witll several colun1n volumes of solvent system A. A gradient elution wa.s then begun which llad as initial conditions lOO~o solvel1t sy~stem A~

W096/04905 "~ 21~758 r~", ~ ~

solvent sy.stem B and reached after 30 minutes 50% solvent system A-50% solvent system B, and the fractions were collected with an ISCO
Foxy 200 fraction collector. The purified fractions were combined in round bottom flasks, frozen in a -78~C dry ice-acetone bath, and 5 Iyophilized. Combination of the purified product afforded _ of the title compound as a white Iyophilized powder.
IH-NMR (400 MHz, CD30D, ppm): o 0.88 ~t,J=7.2 Elz, 3H), 1.21 (d, J=7.0 Hz, 3H), 1.72 (d, J=7.0 Hz, 3H), 1.56-1.63 (m~ 2H), 2.52-2.59 (m, IH j, 2.67-2.74 (m, IE-I), 2.91 (sept, J=7. Hz, I H), 5.33 (s, I H), 5.92 (d, o J= 1.2 Hz, I H), 5.93 (d, J= 1.2 Hz, IH), 6.72 (d, J=8.50}-lz, 111), 6.76 (d, .1=8.5 Hz, IH), 7.04 (d, J=7.5 Hz, IEI), 7.05 (s, IH), 7.21 (d, J=8.5 Hz, 2H), 7.64 (dd, J=2.0, 8.5 Hz, IH), 7.67 (d,./=8.5 Hz, 2H), 7.73 (d,.l=2.0 Hz, IH).
Microanalysis for C28H27Nso8K2-H2o~
Calc'd: C = 53.06; H = 4.61; N = 2.21; K = 12.34.
Found: C = 52.81; El = 4.56; N = 2.17; K = 12.02.

20 N-(4-i~so-plopylbenzelles~llton~ 2-[[4-[N-[2-(carbethoxy)et carbamoyl l]-2-propylphenoxy]-2-(3 ,4-metllylenedioxyphenyl)zl~ e The titled compound was prepared using procedures similar to those de.scribed in Example 82 except that ,B-alanine ethyl 25 ester (liberated from the corresponding hydrochloride in situ) was the amine .starting material. The crude product was flash chromatographed o~,~er silica gel ~gradient elution, 1-5~, Meolllcl-l2cl2) Eo give the desired product as a white foam in 78~o yield; homogeneous by TLC
(10190 MeOH/CH2C12); mp 167- 168~C; MS (ESI) 639 (M+H)+.
30 Analysis (C33}13~N2OgS-0.75H2O):
Calcd: C, 60.78; H, 6.10; N, 4.30 Found: C, 60.69 H,5.88 N, 4.30 I H NMR (400 MHz, CD30D, ppm): ~ 8.36 (t, 111~ J = 5 Hz), 7.72 (d, 2H, J = 8.4 Elz), 7.58 (d, lEI, J = 2.3 Hz)~ 7.46 (dd, IH, .1 = 8.5, 2.3 Hz), WO96/04905 .~ t ~ 575~ ,s~l ~
~, ~ ,. .,;, 7.30 (cd, 211 J = R.4 Hz), 6.93-6.98 (m, 211), 6.77 (d. 11~, J = 7.9 }Iz), F
6.65 (d, IH, J = 8.7 Hz), 5.95 (s, 2H), 5.47 (s, IH), 4.13 (q, 2H, J = 7.1 Hz), 3.57-3.63 ~m, 2H), 2.g3-2.98 (m, IH), 2.68 ~m, 2H), 2.62 (t, 2H, J
= 6.9 Hz), 1.60 ~m, 2H), 1.21-1.25 (m, 6H), 0.88 (t, 3H. J = 7.4 llz).

N-(4-iso-propylh.on~n~ lfonyl)-2-[14-[N-(2-carboxyethyl)carbamoyl] 1-2-propylphenoxyl-2-(3,4-methylenedioxyphenyl)acetamide The product from Example 142 was saponifïe{l (e~cess NaO1 i in MeOl-1, 60~C, 4 h) to give the titled product as a white solid in quantitative yield; mp Ig9-201~C, MS (ES1) 611 (I\l+M)~.
Analysis (C311134N2O95 0.4M20):
Calcd: C, 60.25; M, 5.67, N, 4.55 Found: C, 60.49 H, 5.48 N, 4.18 I H NMR (400 MHz, CD3OD, pprm): ~ 7.76 ~dd, 2M, J = 1.8, 8.5 1-17.), 7.5R (d, lH, J = 2.3 Hz), 7.46 (dd. IH, .1 = 2.4, 8.6 HY.), 7.3~ (d, ~H J =
8 4 Hz), 6.~2 I'dd, IH, J = 1.7. 8.0 Hz), 6.R7 (d, IH, J = 1.6 llz), 6.7R
(d~ IH, J = 8.0 H~). 6.56 (d, 11-1, J = ~.7 Hz)? 5.g6 (s, 2H), 5.51 ~s, IH), 3.~R (m~ 211), 2.95 (m, IH), ~.68 (m, 2H), 2.61 ~t, ?H, J = 7.'' Hz (m, 21-1~), 1.21-1.25 (-m, 6M), 0.88 (t, 3H, J = 7.4 llz).
2 s EXAMPLE 144 N -(4-iso-propylbenzenesulf'onyl)-2-[ [4-~N-(2-carbamoy]ethyl)-cal bamoyl] ] -2-propylphenoxy~ -2-~3,4-methylenedioxyphenyl)acetamide The titled compound wa.s prepared using procedllres similar tc those described in Example 82. The crude product ~hras fla.sh chromatographecl over silica gel (gradient elution, 2-10~o ~leO~llCH2C12) to yield the desired product as a white foam in 42 ~ W0 96~04905 ~ 219 5 7 5 8 r~

~ yield;homogeneousbyTLC(10190MeOII/CH2C12~,mp 110-112~C;
MS (ESI) 610 ~M+H)+.
Analysi~ (C31 H35N3O8S 0.75H20 i:
Calcd: C, 59.73; H, 5.90; N, 6.76 Found: C, 59.74 H, 5.61 N, 6.62 I H NMR (400 MI-lz, CD30D, ppm): o 7.77 (d, 2H~ J = 8.3 Hz),7.59 ~d, IEI, J = 2.3 Elz),7.46 (dd, IH, J = 2.4, 8.6 Hz), 7.36 (d, 2H J = 8.7 Hz), 6.92 (dd, IEI, J = 1.5, 8.0 Hz), 6.87 (d, IH, J = 1.6 Elz), 6.78 (d, IH, J =
o 8.1 Hz), 6.58 (d, IH, J = $.6 }Iz),5.97 (s, 2H),5.50 (s, IH), 3.. S9 (t,21-I~
J = 7.0 Hz), 2.98 (m, IH), 2.68 (m, 2H), 2.51 (t, 2H, J = 6.9 Hz), 1.60 (m, 2H), 1.21-1.28 (m, 6H), 0.89 (t, 3H, J = 7.4 H~).

N-(4-iso-propylbenzenesulfonyl)-2-~4-1N-~2,2,2-trifluoroethyl)-carbamoyll-2-propylphenoxy]-2-(3,4-methylenedioxyphenyl)acet:alllide The titled compound wa.s prepared using procedures similar to those descrihed in Example 82 except that trifluoroettlylamine was used as the amine starting material. The crude product was flash chromatographed over silica gel (gradient elution, 1-4~i~o MeOH/CI-12Cl2) to give the desired product as a white foam in 79~k, yield; homogeneous by Tl,C (5195 MeOH/CH2C12), mp I lU-112~C; MS
(ESI) 621 (M+H)+.
Analysis (C30H31 F3N2o7s 0~5H20):
Calcd: C, 57.22; H, 5.12; N, 4.46 Foulld: C, 57.33 H,4.87 N, 4.52 3c I H NMR (400 MHz, CD30D, ppm): o 7.71 (d, 2}I, J = 8.3 l lz),7.63 (d, IH~J=2.4Elz),7.52(dd, lH.J=2.2,8.4Hz),7.29(d,211J=8.3Hz).
6.97 (m, 2H), 6.77 (d, I H, J = 7.9 Hz), 6.68 (d, lH, J = 8.7 Hz), 5.96 (s, 2H), 5.47 (s, IH), 4.05 (dq, 2H, J = 3.0, 9.2 Hz), 2.92 (m, III), 2.6R (m, 2EI), 1.6] (m, 2H), 1.19-1.30 ~m, 6H~, 0.89 (t, 3H, J = 7.3 Mz).

~o s6A74sns . ~ , 2 1 ~ 5 7 5 8 P~lll E~XAMPI r 146 N-(4-iso-propylbenzenesulfonyl~-a-(4-N-t-butyklxycarbonyl-aminosulfonyl-2-n-propylphenoxy)-3.4-methylenedioxvphenylacetamide Step A: Preparation of methyl o -(4-i'~ -butyloxycarbonylamino-sulfonyl-2-n-propylphenoxy)-3 ~4-rmethylenedioxyphenyl-acetate To a stirred solution of 76 mg tO.lP,7 mmol) of methyl a-(2-n-propy 1-4-~alrlillc)slllfonylpheno~y)-3 ,4-methylenedioxyphenylacetate (the product of Lxample 100 Step C), 29 uL (0.206 mmol) of triethylamine and 2.3 mg (0.0187 rnmol) of DMAP llydrocllloride inl ml, of methylene chloride was added 47 mg (0.215 mmol) of di-te.rt-butyl-dicarbor~te. After 1.5 hours, TLC analysis ~5~! methanol /
methylene chloride) indic ated that the couplillg vvas complete and the reaction mi~ture wa~ diluted with eth~ l acetale, p~rtitiollecl with water, washed another time with water, and wa.i}lcd Wil}l brine. The organic layer uas then driecl o~er magnesiulll ~ult'ate, fiitered, .uld the filtrate 2G concentrated in l~acuo and dried on vacuunl to afford 95 m~ (lOO''~o) of the titie compu~md as an amorphous solid.
1 H-NMR (400 MHz, CDC13,ppm) o 0.97 (tJ=7.40 1~z,3H~, 1.35 (~,9H), 1.62-1.75 (m,2H), 2.66-2.79 ~m,2H~, 3.71 (s,3H~, 5.60 (s,ll-l), 5.98 (s,2H), 6.75 ~d,J=9.2 Hz,lH), 6.81 (dJ=8.0 Hz,l l-l), 6.99-7.04 ~m,2H), 7.74-7.76 (m,2H).

Step B: Preparatioll of meth~l a-(4-/V-~-butyloxycarbollylamin(7-sulfonyl-2-n-propylpheno~y)-3,4-methylelledic)xy-p~henylacetic acid 3~7 To a stirred solution of 95 mg {0.187 mrnol) of the prclduct of Step A in 0.75 mL of methylene chloride and 0.75 mL of methanol wa.~ aclded 45 aL (0.225 mmol) of 5N sodiurn hydroxide. Afler S
hours, TL(~ analysis (5~ methanol / methylene chlc7ride) indicated slo~
ester hydrolysis and an additional 45 uL (0.225 mrnol) of 5N sodium W0 96~0490!i ~ 2 ~ 9 5 7 5 8 I ~r~ J

hydroxide was added. The reaction mixture stirred 2 days, at whic}
time TLC analysis (5% methanol / methylene chloride) indicated the ester hydrolysis was complete. The re.tction was extracted with ethy!
following acidification to pH4-5 with 10~~, citric acid and dilution with water. The extract was washed with brine, dried over m~gn~silln~
sulfate, filtered and the filtrate was evaporated in vacuo and dried to afford 75 mg (82%) of the title compound as an amorphous solid.
lH-NMR (400 MHz, CD30D,ppm) o 0.96 (t,~=7.40 Hz,3H), 1.34 (s,911), 1.62-1.75 (m,2H), 2.75 (t~/=7.40 H_,2H), 5.78 (s,lH), 5.97 o (s,2H), 6.~4 (dJ=8.00 H_,IH), 6.99 (d,J=9.20 Hz,lH), 7.06-7.10 (m,2H), 7.72-7.74 (m,2H).
APCI-MS 1721e = 51 1 (M+NH4).

Step C: Preparation of N-(4-i.io-propylbenzenesulfonyl)-lx-(4-N-f-butyloxycarbonyl-aminosulfonyl-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide A solution of 68 mg (0.138 mmol) of the product of Step B
and 34 mg (0.207 mmol) of carbonylfliirnid"7- 1e in 0.~ mL of dry tetrahydrofuran was refluxed using a heated oil bath. After 2 hours, 'I'LC analysis (20% methanol / methylene cl-loride) indicated the desired intermediate had formed. The reaction mixture was then cooled to room temperature and 41 mg (0.207 mmol) of dry 4-iso-propylbenzene.sulfonamide and 31 uL (0.207 mmol) of DBU were added. The reaction mixture was refluxed again for 25 minutes, allowed to cool, after which TLC analy.sis (20~,~o methanol I methylene chloride) indicated the desired product had been fonned. The reaction mixture was poured into 10% citric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by si]ica-gel flash chromatography eluting first with 3~r~c, methanol / methylene chloride .md then with 5'J~o methanol / methylene chloride. The mixed fractions cont,~ ing both the title compound and the des-~-butyloxycarbonyl version of the title compound were combined, evaporated and used in Example 147. The purified t'ractions were WO 9610490~? ? 9 5 7 5 ~ Jr 7 S

combined and evaporated to afford 11 mg ( l 29;'o) Of the title compound as an amorphous solid.
IH-MvlR (400 MHz, CD3OD,ppm) ~ 0.~8 (t,J=7.40 Hz,3H), 1.24 ,, (d,3=7.20 Hz,311)~ 1.25 (d?J=7.20 Hz,3H), 1.3~ (s,9H), 1.56-1.68 S (m,2H), 2.60-2.69 ~m,l I-I), 2.70-2.77 (m,lH), 2.95 (sept., J=7.20 Hz,lH), 5.46 ~s,lH). 5.95 (s,2H~, 6.77 (d,J=8.4Q Hz,lH), 6.81 (dJ=8.40 I-lz,l 1{), 7.00-7.03 (m,2H), 7.27 (drl=8.00 Hz,2H), 7.60 (dd,J=2.4(1, ~¢.4() Hz,lH), 7.64 (d?J=8.00 Hz,2H~, 7.6X (dJ-2.4 Hz.lll).
F,SI-MS m/c~ = 697 ~M+Na).

N-~4-iso-propylbenzenesulfonyl)-o~-~4-N-f-batylc~xycarbonylamino-sul fonyl-2-n-propylphenoxy)-3 ,4-rnethylenedioxyphenylacetamide A solution of 1~ m~, iO.û267 rnmoli of mixed fractions from Step C of Example 146 in 0.8 mL of dimeh1ylsultoxide Wah he~lted to reflux for ~ minutes ~mcl cooled to room temperature. After the 20 lleatin~. TLC analysis (205~o methanol I methylene chloride) indicated them1al deprotection was complete. The reactic~n was diluted with 6 mL of water and filtered through a 0.45 mrn filter disc. The filtrate was purified U.sil1g a Waters 600E HPLC system with a 9.4 ~ 250 n~n 5 mm Zorbax-RX C8 at 40~C eluting at 5.0 mL/min first usin~ 100'~
25 (95 5 water-acetonitrile) with 0.1 ~Yo TFA for 12 minutes and then switching 65~io A (95-5 acetonitrile-water) 35~o B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored simultaneously at ~10 and 277 nM with a Waters model 490 UV-visible detector. The purified fractions were cormbined in a round 30 bottom flasl~, frozen in a -78~C dry ice-acetone bath and lyophylized to affold 10.7 mg (7]'Yo) of the title comyound as a white lyophilized powder.
I l I-NMR (400 M~Hz, CD30D,ppm) ~ 0.90 (t,J=7.20 Hz,3H)? I .2G
(d,J=6.80 Hz.3H), 1.27 (dJ=6.80 Hz,3H), 1.54-1.6~ (m~2TI), 2.60-2.72 ~ WO96/04905 ~ . F~IJ~ ,; 7 2~9~75~

(m,21~ 3.00 (sept., J=6.80 Hz,IH), 5.54 (s,1Hj,5.97 (s,~H), 6.65 (dl=~.40 Hz,1H). 6.78 (dJ=8.00 Hz,lH),6.84 (d,J=1.60 Hz,lH),6.91 (dd,J=1.60, R.00 Hz,lH), 7.37 (d,J=8.40 Hz,2H), 7.53 (dd,J=2.40, 8.40 Hz,lI-l),7.66 (dJ=2.4 Hz,l~),7.76 (dJ=8.40 Hz,2H).
5 ESI-MS m/e = 575 (M~H).

N-(~-iso-propylbenzene.sulfonyl)-a-(4-(N-methylacetamido aminosulfonyl)-2-n-propylpheno~y)-3,4-methylenedioxyphenyl-acetarnide ~: Preparation of methyl a-(4-(N -methylacet~rnido-arninosulfonyl)-2-n-propylprlelloxy)-3,4-methylene-dioxvphenyla~;etate To a stirred solution Or 500 mg (1.23 mmol) of methyl o-(~4-aminosulfonyl-2-n-pr( pylphenoxy)-3,4-methylenedioxyphenylacetate 20 (the product of Example 100, Step C) in dry dimethylfclrmllmide (2 mL) wa.s added ~()ul. (1.35 mmol) of methyl isocyanate l'ollowed by 6 mg (0.06 mmc l) of cuprous chloride. The reaction mixture W;IS stirred overnight, after which TLC analysis (5 ~, methanol I methylene chloride) indicated the reaction had not proceeded to completion.
25 Subsequently, an additional 80 uL (1.35 mmol) of methyl isocyanate, 6 mg (0.06 mmol) of cuprous chloride as well as 342 uL (2.46 mmol) of triethylamine was added and the reaction mixture wa.s again stirred overnight. Tl.C analysis (5 ~Jc methanol / methylene chloride) indicated the reaction had proceede(i to completion. The reaction nlixture was 30 poured intc~lN IICI and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vaullo and dried to afford 57() mg (100%) of the title compound as an amorphous solid.

W096/(~ 2 1 95 758 1~ u~ 7--NMR (400 MHz, CD30I:),ppm) o 0.9fi ~tJ=7.20 Hz,3H). 1.64-1.77 ~m.2H), 2.65 (s,3H~ 2.74 (tJ=7.00 11z,2H3. 3.71 (s.3H3, 5.88 (5,11H).
5.98 ~s,21-1), 6.~5 (d~/=8.00 Hz,lH~, 6.95 (d,J=8.40 Hz,11~1), 7.04 (dd,J=1.60, 8.40 Hz,lH~. 7.07 (d~l=1.60 Hz,lH3, 7.72-7.76 (m,21-1~.
ESI-~IS m~e = 464 (M+13.

Step E~: Preparation of oc-(4-(h -methylacetamidoaminosulfonyl)-2-n-propylphenoxy)-3.4-methylenedioxvphenyhlcetic acid To a stirred solution of 570 mg (1.2~ mmol-l of the product of Step A in G mL of methanol was added 54Q uL (2.71 mmol) of 5N
sodium hydroxide. The reaction mi.xture was allowed to stir overrligllt after WlliCIl TLC analysis (90:10:1 c:hlc)rof'oml I medla1lol / acetic acid) indicated the saponification had proceeded to completioll. Ttle reaction mixtule was acidified to pH=2 using 6 N IICI, poured into water, and extracted with ethyl acetate. The e~tract was dried over rma~llesium sulfate, filtered Imd evaporated in l~acuo to give the crude product.
Purification of the cmde product by silica-~el f~ash chromatograpll.y U.sillg (92:7:1 chloroform / methanol I acetic acid) affcrdecl 3X4 mg (70%~ of the t;tle compc und as an amorphvus solid.
I E-1-NMR (400 MHz, CD3OD,ppm) ~ 0.96 (t,J=7.40 H~.3H), 1.62-1.77 (m,2H), ~.65 (~3H~, 2.74 (tJ=7.6V Hz,2H), ~.76 (s,lH~, 5.98 ~s,2H), 6.85 (d,J=8.()0 H~,11-1j, 6.95 (d,~=X.40 Hz,lH)~ 7.06 (dJ=1.60 Hz,ll-l), 7 .0~ (dd,J= 1.60, ~ .00 I-lz, ] H~, 7.72-7.75 (m,2H) .
Cl-MS m/~ = 538 (M+l ).

Step C: Preparation of N-i4-iso-propylbenze1lesulfollyl3-c)c-(4~
methylacetarnido-aminosulfonyl~-2-n-propylphenc xy)-3,4-methvlenedioxvpllellvlacetamide A solution of 384 mg (0.853 mmol3 of the product of Step B and 20~ mg (1.28 mmol) of carbonyldiim~ 7nle in 2 mL of dry tetrahydrofuran s~a.s refluxed 2 minutes by placing the reaction nlixture into a preheated oil bath. After brief refluxing and gas evollltion, TLC
analysis (90:1():1 chloroforrn / methanol I acetic acid) indicated that the desired intermediate had formecl. The reaction mixture was then cooled ~ W0 96/04905 ~ 2 ~ q ~ 7 5 ~ r~

to room le-l~pe~aLu/t; and 255 mg (1.28 mmol) of dry 4-i.so-propylbenzenesulfonamide, 10 mg (0.085 mmol) of DMAP followed by 191 uL (1.2R mmol) of DBU was added. The reaction mixture was refluxed for 3 minutes, allowed to cool and stir at room te,,,pc,dLu,~ I
hour after which TL,C analys;s ~96:3:1 chloroform / methanol / acetic acid) indicated the desired product had been formed. The reaction mixture was poured into 10% citric acid and extracted with ethyl acetate. The extract wa.s washed with brine, dried over m~nPiillm sulfate, and evaporated in vaclf o. The residue was partially purified by o silica-gel fla.sh chromatography eluting fir.st with ethyl acetate and then with (92:7:1 chlorofonrl I methanol / acetic acid). The purified fractions were combined to afford 48 mg (9~o) of the title compound.
Ilpon standing, material precipitated from the ethyl acetate fractions to afford an addition 55 mg (IO~?o) of the title compound. The remclinder of semi-purified material was combined and puril'ied using a Waters Delta Prep 3000 HPI.C by applying the residue in 6 ml total volume (4.5 mL methanol and 1.5 mL water) to an M1000 Prep-Pak module containing a 47 x 300 mm 15 uM DeltaPak Cl~ column and eluting~
isocratically at 50 mL/;nin using 60~o A (95-5 acetonitile-water) and 40~, B (95-5 waler-acetonitrile) each with 0.15~c! TFA. The colullm effluent ~.s monitored simultaneously at 210 and 277 nM with a Waters model 490 VV-visible detector and the purified fractiolls were combined in a round bottom flasl~, frozen in ;1 -78~C dry ice-acetone hath and Iyophylized. 'I'he HPLC purified Iyophylizatel55 mg (29%)~
the silica gel purilïed amorphous solid 48 mg (99~) and the precipitated amorphous solid 55 mg (105~o) were combined to afford 258 mg (48%'~
of the title ~ompound.
IH-NMR (400 MHz, CD3OD,ppm) o 0.89 (t,J=7.40 Hz,3H), 1.26 (d,J=6.80 Hz, 3H), 1.27 (d,J=6.80 Hz, 3H), 1.55-1.65 (m~2H), 2.63-2.70 (m,5H), 3.00 (sept.J=6.80 Hz, IH), 5.56 (s,lH), 5.97 (s,2h), 6.67 (d,J=~.40 Hz. IH)7 6.79 (d~l=7.60 Hz, 11-1), 6.84 (dJ=1.60 Hz, IH), 6.91 (dd~l=1.60. 7.60 Hz, 111), 7.38 (dJ=8.40 Hz~ 211), 7.62 (dd,J=2.40. 8.40 Hz, lH), 7.71 (d~l=2.40 Hz, IH), 7.77 (d~l=8.40 Hz. 211).
Cl-MS mle = 632 (M+1).

WO 96/0490~ ' 2 1 9 5 7 5 8 .

- IgO-Step D: Preparation of /\~-~4-iso-propylbenzene.sulfonyl)-a-(4-~N-m~thylacetamido-aminosult'onyl ~-2-n-propylphenoxy)-3,4-methylenedio7;vphenylacetamide dipotassium salt To a solution Or 250 mg (0.3~6 rnmol) of the product of Step C in 3 mL of methanol was added 1.~8 mL (1.58 mmol) of a IN
potassium hydloxide rn methanol solution. l~e reaction mixture was .stirred 15 mim~tes at RT, diluted with 7 mL of water and filtered through a 0.45 uM filter disc. The filtrate WtdS purif1ed using a Waters Delta ~Prep 3000 HPLC by applying the compound in a 15 ml total ~olume (R mL methanol and 7 mL water) to an MI000 Prep-Pak module containing a 47 x 300 mm 15 u~l DeltaPak C l ~ colun~n and elutin~ at 50 rnL/min first using lOO~o B (95-5 water-acetc~rlitrile) for 10 minutes and then a 30 minute linear gradient to 60~. A (95-5 acetonitile-water) and 40~ B (95-5 water-acetonitrile). The column effluent was monitored iimlllt:7ln~?ollsly at 210 and 277 nM with a Waters model 490 UY-vi.sible detector and the purified fr~ctions were combined in a round hottom flask, fro7el1 in a -7~~C' dry ice-acetoIle~
2~3 bath and Iyophylized to afford 221 Illg (79aro) of the title compound as a white Iyophillzed powder.
I H-NMR ~400 MHz, (:~D30D,ppm) ~ 0.89 (t~/=7.10 Hz~ 3H), 1.22 (d 1=6.80 Hz. 3H), 1.23 ~d,J=6.80 I-lz, 3H), 1.53-1.68 (m~211~, 2.54-2.6 (m,41-1), 2.67-2.74 (m,lH~, 2.91 (sept., J=6.8U Hz, lH~, 5.34 (s,ll-l), ~.92 (s,2H~, 6.73-6.79 (m,2H), 7.00-7.02 ~m~2H')~ 7.20 ~dl =8.00 llz, 2H), 7.57 (ddl=1.80, 8.60 Hz, lH3, 7.61-7.64 (m.3H).
F,SI-MS mic = 701 (M+l ).

EXAMP~E 14~

~IV-(4-i.s~/-propylbenzenesulfonyl j-oc-(4-(methylsul~onyklmino-1~'-oxo1nethyl)-2-~7-propylphenoxy)-3,4-meti1ylenedioxyphenylacetamide dipotassiurn salt ~ W096104905 ~- ' ' 21 ;~575~ 7 ~: Preparation of N-(4-i.so-propylbenzellesultonyl )-a-(4-(methyl~sulfonykLmino-N'- I -oxomethyl)-2-n-propyl-phenoxv)-3 .4-meth~ienedioxvphenylacetamide A solution of 146 mg (0.271 mmol) of N-(4-iso-5 propylbenzelle.sulfonyl)-ot-~4-carboxy-2-n-prc pylphenoxy)-3,4-methylenedioxyphenylacetamide (t'ree acidic form of the product of Example 58) and 66 mg (0.406 mmol) of carbonyldiimidazole in I mL
of dry tetrahydrofuran was refluxed t'or 1.5 hour.s. The reaction mixture was cooled to room temperature ancl 39 mg (0.406 mmol) of methallesulfonamide and 101 uL (0.667 mmol) oi' DBU were added and the mixture was reiluxed a~aill. The reaction progless was nlonitored by analytical HPLC analysis u.sin~ a Water.s 60()E HPLC' .systenl with a 4.6 x 250 mm Sum Zorbax-RX Cl~ at 40C~C ~nd eluting isocratically 1.5 mL/min using 60~? A (95-5 acetonitrile-water) 40~c B (95-5 water-5 acetonitrile) each with 0.1% TFA where tbe column effluent wasmonitored simultaneously at 210 and 277 nM with a Waters model 490 UV-visible detector. Al'ter 1.0 hour of additiollal refluxing, analvtic;il HPLC analysi.s indicated that the coupling was cc~mplete. The reaction mixture poured into lN HCI and extracted with ethyl acetate. washed 20 with hrine. dried o~er magne.sium sult'ate, filtere(l, and the filtrate evaporated ill l'~lC110 to ai'ford 160 mg (96%) of the title compound as an amorphous solid.
I l l-N~IR (400 MHz, CD3OD,ppin) o 0.90 (t,J=7.40 Hz. 3E-1). 1.25 (d,.J=6.80 Hz, 3H), 1.26 (dJ=6.~0 E~z, 3H), 1.53-1.66 (m,2H), 2.5~-2.63 25 (m,2H), 3.U0 (.sept., J=6.~0 Hz, IH), 3.33 (.s,3H), 5.54 (s,lH), 5.97 (s,211), 6.61 (d,.l=~.~0 Hz, IH), 6.79 (d~ .00 Hz, lH), 6.87 ~d~J=1.60 Hz. IH), 6.93 (dd~/=1.60, 8.80 llz, IEI), 7.36 (dJ=8.40 I-lz, 2H), 7.56 (d,.J=2.40, 8.2'30 Hz, IH), 7.70 (dl =2.40 E~z. IHI, 7.77 (dJ=~.40 Hz, 2H).
30 Cl-MS i721c' = 634 (M+NH4).

'Jl q5758 w0 96f049û~ .l .,C7 --- 19~-Step B Pr~paratiorl of N-(~-is(J-propylbenz,enesuli'orlyl)-~x-(4-(methylsulfonylamino-l~ oxomethyl~- -tl-propylphenoxy)-3,4-1llethylenedioxyphell3llacetamide~
~ otas~iium salt Tv a solution of 160 m~ (0.260 mmoll of the product of Step E~ in I mL of methanol wa~ added 1.04 mL ( 1.04 mmol~ of a I N
potassium hydroxide in melhal~ol solutioll. The reaction mixture. WilS
stirred ] 5 millutes at RT, diluted with 4 mL, of water and filtered through a 0.4.S uM filter disc. The filtrate was purified using a Water~
Delta Prep 3000 1 {PL,C by applying tlle compound in a 10 ml tok volume (6 mL methanol cmcl 4 nll, wateri to an tvf 1000 Prep-Pak module containil~g a 47 x 300 mrn 15 m:M I)eltaPal; C1~ column and eluting lat 50 mL/min first using 100% B (95-~ water-acetonitrile) i'or 10 minutes and then a 30 minute linear gradient to 60~, A (95-5 5 ~Icetonitile-water) and 4()~c B (95-~; water-acetonitrile). The column effluellt wa.s monitored simultaneously at 210 a:lld 277 nl\/l Witil a Water.i model 490 UV-visible detector and the purified fr.~ctions vvere corllbined in a rouncd bottom fla.ik. frozen in a -7S~C drs~ ice-acetolle bath and Iyophylized to afford 1 3S mg (77~,~ro 1 of the title colllpvund ;~
20 white Iyophilized powder.
II-I-NMK (40() IMHz, CD30D,ppm) o 0.~7 (t,J=7.40 Hz, 3~{), 1.21 (d~l=6 ~U Hz, 6H),1.52-1.67 ~m,2H), 2.~1-2.~ (m,lH), 2.67-2.74 (m,llH), 2.91 (~ept.~l=6.P~0 Hz, IH), 3.07 (s,3H~, 5.33 (:;,IH), ~.92 (s,21-1), 6~70 (drl=~3.S0 Hz, 11~. 6.74 (ddJ=2.20. 6.20 1Iz, 1 H),7.02-7~04 25 (m,2H), 7.21 (dJ=~.40 Hz"2H), 7.6~ (d,J=~.40 Hz,2H), 7.70 (ddJ
=2.20, ~.40 Hz. 111), 7.7~s ~d,J=2.()0 Hz, IH).
ESI-MS m/~ = 693 (M+l ).

EXA~IPLE 150 N-(4-isc~-propylbellzenesulfonyl~-a-(4-(aminosulfollylaminc~-N'-oxomethyl)-2-/l-propylphenoxy~-3,4-nlethylenedioxyphellylacetamide dipotassium s~lt W0~6/0490s ~ 2195753 ,~ 7 ~: Preparation of N-(4-iso-propylbenzenesuli'onyl)-~x-i4-(aminosulfonylarnino-N~-l -oxomethyl)-2-n-propvlphenoxv)-3 .4-methylenedioxyphenylacetarnide A solution of 158 mg (0.293 mmol) of N-(4-iso-S propylbenzellesulfonyl)-a-(4-carboxy-2-/1-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acidic form of the product of Example 5X) and 71 mg (0.440 mmol) of carbonykliimi~ 7ole in l mL
of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 tmmol) of 0 sulfamide and 110 ul (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600L I-IPLC system with a 4.6 x 250 mm 5um Zorbax-RX C8 at 40~C and eluting isocratically 1.5 mLlmin using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector.
After 2.0 hour of additional refiuxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diiuted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 550() HPLC by applying the compound in a 4.5 ml total volurrle (2.5 mL methanol and 2 mL water) onto two in series 21.2 x 250 mrn 7mm Zorbax ODS
columns and eluting at 15 mL/min with 60''fo acetonitrile and 40'~o watel both with 0,15to TFA. The column effiuent was monitored 25411M with a Kratos Spectrotlow 783 IJV detector. Combination and evaporltion of the purified fractions afforded 50 mg (28C~) of the title compound.
The mi~ed fractions were combined and sub,jected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65C~C water and 35C~o acetonitrile both with 0.1C~oTFA to 65~o acetonitrile and 35% water hoth ~ith 0.1 ~cTFA, holding all other conditions from the previous chromato~raph~;. The purified fractions were combined and concentrated to afford 57 mg (31 %) of the title compound, which was combined with the previollsly purified material WO96/04905 ~ 2l~575~ P~llu ~67--to provide a total of 107 mg (S9~o) of the title compound ax ar amorphous solid.
IH-NMR ~400 MHz, CD30D,ppm) o 0.89 (t,~=7.40 H~, 3H), 1.25 "~
(dl=6.80 Hz, 311), 1.26 (dJ=6.80 Hz, 3H), 1.53-1.66 (m,2H), 2.58-2.73 (m,2H), 2.9S (.sept.. J=6.80 I-lz, lH), 5.54 (s,lH), 5.97 (s,2H), 6.62 (d,J=8.80 Hz, 111), 6.79 (dJ=8.00 Hz, Il-I), 6.~6 (d,J=1.60 Hz, lH). 6.92 (dd,J=1.60, 8.00 Hz, lH), 7.36 (d~=8.50 Hz, 21-1), 7.56 (d.J=2.40, 8.R0 Hz. IH), 7.69 ~d,J =2.40 Hz, IH), 7.77 (d~l=8.50 Hz. 2H).
ESI-MS m/~ = 61R (1\1+1).

Step B: Preparation of N-~4-i~s(l-propyll:en7~ slllfony~ c-(4 (aminosulfonylarllin(l-N'- I -oxomethyl)-2-n-propyl-phenoxy)-3~4-methylenedioxyphenylacehlmide dipotassiu:m salt lS To a .solution of 107 mg (0.173 mmol) of the product of Step B in 1.5 mL of methanol wa.s added 0.691 mL (0.691 1I~llOI) of a I N potassium hydro~cide in methanol solution. The reactioll mi.~iure was stirred 15 millutes at R'l', diluled with 1 rmL of water .md filtered throllgh a 0.45 uM filter disc. The filtrate wa~s purii'ied Usillg a Varian 20 5500 HPLC by applying the compound in a 4.0 ml total ~olume (3 mL
methallol and I mL water') onto two in series 21.2 x 250 mm 7mm Zorbax ODS culumns and eluting at 15 ml,/min first llsing 95~1i water and ~o acetonitrile tor 10 minutes and therl a 30 minute linear gradiellt to 60ac acetonhrile and 40% water. The column effluent was 25 nlonitored 254 nM with a Kratos Spectroflow 783 W detector alld the purified fractions were combined in a round bottom flask, frozen in a -78~C dry ice-acetone bath and Iyophylized tc aff'ord 84 mg (73~/o) Qf the title compound as a white Iyophilized powder.
1H-NMR (4('K) MHz, CD30D,ppm) o 0.87 (tJ=7.40 Hz., 3H), 1.2(-) 30 ~dl=6.80 Hz, 3H), 1.21 (d,J=6.80 H7., 3H~? 1.53-1.66 (m,211), 2.51-2.59 fm,lH), 2.67-2.74 (m,lH), 2.91 (sept.J=6.R0 Hz~ IH). 3.07 (s,3H), 5.33 (s~lH)~ 5.g2 (s,~H), 6.71-6.75 (m,2H), 7.01-7.04 (m,2H), 7.19-7.22 (m,. H), 7.64-7.70 ~m,3EI), 7.77 (d,J=2.4 Hz, IH).
ESI-MS m/c = 694 (~M+I ).

~ Y~'09611~49~ 2 1 9~7 5~ P~

5 N-(4-iso-propylbenzenesulfonyl)-a-(4-cyarto-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetarnide potassium salt Step A: Preparation of 3-allyl-4-hydroxvbenzonitrile To a stirred solutioll of 25.00 g (210.1 mmol) of 4-o cyanophenol (Aldrich) in 100 nlL of acetone was added 30.49 g (220.6 mmol) of powdered potassium carbonate followed by 19.09 mL (220.6 mmol) of allyl bromide and the reaction mixture refluxed overnight.
TLC ~unalysis (15% ethyl acetate / hexane) indicated that the alkylation was complete and the reaction mixture was filtered, the filtrated 5 evaporated in vacuo to afford 33.20 g (99%) of a light yellow oil. The 33.20 (209 mmol) of crude O-allyl ether was dissolved in 100 ml of 1,2-dichlorobenzene and stirred at reflux for 56 hours until TI,C
analysis (15% ethyl acetate /hexane) indicated essentially no starting O-allyl ether remained. The reaction mixture was poured intO 300 mL of 20 hexane, cooled in a freezer overnight, and the precipitate was filtered on and dried on vacuum to provide 29.76 g (90~) of the title compound as a light tan amorphous solid. IH-NMR (300 MHz, C[~C13,ppm) d 3.36 (D,J=6.30 Hz,2H), 5.09-5.19 (m,2H), 5.79 (bs,lH), 5.~6-6.00 (m,lH), 6.82 (dd,J=1.80, 7.20 Hz,lJI), 7.3R-7.41 (m,2H).
25 El-MS mle = 159 (M+~

Step B: Preparation of 4-hYdroxy-3-n-propylbenzonitrile A Parr hydrogenation shaker was charged with a solution 30 of 29.76 8 (1~7 mmol) of the product of Step A in 100 mL of ethanol and 3.00 g of a lOS~o palladium on carbon cataly.st was added. The flask ~h~as mounted in the hydrogenation appartus, freed of air, pressurized with hydrogen (40 psig) ~md shaken 80 minutes. At the end of this preiod, TLC analysis (15C7O ethyl acetate / hexane) indicated that the reaction was complete and the reaction mixture was filtered and _ WO96104905 ~ ~ 219575~ ~ }~

5 ~

evaporated. The product was dried in vacllo to afford 30.01 g (99'Y~,) of the title compaund as a yellow oil.
IH-NMR (300 MHz, CDCl3,ppm~ ~ 0.92 (t,.l=7.40 H~,3EI), 1.53-1.~S5 (m,2H), 2.~4 (t,J=7.60 Hz,2EI), 6.77 (dJ=8.10 Hz"l H), 7.32-7.37 5 (m~2H)~
EI-MS m/e = 161 ~M+) Step C: Preparation of methyl o!-(?-n-propyl-4-cyanophel1t~xy)-3,4-meth vlel1edioxvphenylacetate 'I'o a stirred solution of 4.50 g (27.95 rrm1ol) of the product of Step B in 30 mL of acetone was added 4.64 g (33.~4 mmol) of powdered potassiurn carbonate and the reaction mixture ~A~as stirred fol 1() mil1utes. ~lethyl a-bromo-3,4-methylenedioxyphenylacetate (R.()l g;
29.35 lmnol) was then added and the reaction mi~ture refluxed 5 overnight. The reactiorl mixture was cooled, filtered. and the filtrate evaporated irl vacuo, dried on vacuum to a~fford 10.30 g (9.~7g theoretical) of the t;tle compound which waS used without purificatio in the next .step.
IEI-NIvlR (300 MHz, C'DC13,pprm) ~ 0.92 (tTI=7.40 Elz,31~), 1.S8-1.6 (m,2H)~ 2.60-2.71 (m,2H), ~.53 (s,lH~, 5.95 (s,~H), 6.68 (dJ=8.10 ll~,lH~, 6.7~ ~d?l=7.~0 lIz,lE-I), 6.95-6.9~ (m.2H), 7.35-7.39 (rm, H).
El-MS ml~ = 353 ~M+) Step D: Prepa~.ltion of methyl ~-~2-n-propyl-4-cyanophenoxy)-3,4-methvlenedioxyphenylacetic acid TQ a solution of 3.5 g (8.64 rnmol) of the product of Step C' in 30 mL of methanol v.~as added '7.07 mL (10.37 mmol) of 5.0 N
aqueou.s sodium hydroxide solution. After .stirring overnight, TLC
analysis ( ~0: 15:1 chloroform / methanol l ammonium hy(lloxide) indicated that the saponificatiou was complete. The reaction mixture wa.s acidified to pEI 3 with 6 N aqueous HCI and concentrated in vac~io.
With heating and sonnication, the residue was redissolved in ethyl acetate, washed with brine, dried over magnesium .sulfate, filtered, and tlle filtrate evaporated in vauJo to afford 2.92 g ~99~) of the title ~ WO 96/04905 r . ' ; ~ ,, 2 I q ~ 7 5 8 1 ~ - "~

compound as an amorphous solid which was used without further purification in the next step.
? IH-NMR (300 Mllz, CD3OD,ppm) ~ 0.90 ~t,J=7.40 Hz,3H), 1.58-1.68 (m,2H), 2.66 (tJ=7.60 Hz,2H), 5.72 (s,lH), 5.92 (s,2H), 6.60 (d,J=8.10 Hz,l~), 6.90-6.93 (m,lH), 7.00-7.04 (m,2H), 7.45-7.47 (m,2H).
El-MS mle = 339 (M+) Step E: Preparation of N-(4-iso-propylbenzene.sulfonyl)-a-(4-cyanc~-2-n-propylpheno.xy)-3,4-methylened:ioxypllenyl-acetamide 'I'o a stirred solution of 2.92 g (X.61 mmol) of the the product of Step D in 40 mL of methylene chloride was added 2.31 g (12.05 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 5 hydrochloride, 1.26 g (10.33 rnrnol) of 4-dimethylaminopyridine, and 1.8g g ((9.47 mmol) of 4-iso-propylbenzenesulfonamide. The reaction mixture was stirred overnight and after TLC analysis (80:15: 1 chlorofonn / methanol / ammonium hydroxide) was poured into I N
HCI and extracted with ethyl acetate. The extract was washed with 20 brine, dried over m; gn~sium sulfate, filtered. and evaporate(l irlV~fc uo.
The residue was partially purified with silica gel flash chromatography eluting first with 40% ethyl acetate-hexane and then with 3~7O methanol-methylene chloride to flush the column. All of the product product fractions were tainted with a con~minAnt and combined and 25 concentrated for a subsequent chromatography. The 3.86 g of semi-purified material was dissolved in 15 mL of acetonitrile and 15 mL of water and filtered through a 0.45 uM filter disc. The compound was purified using A Waters Delta Prep 3000 IIPLC by applying the filtered solution io an M 1000 Prep-Pak module containing a 47 x 30(i mm 15 30 mM DeltaPak C18 column and eluting at 50 mL/min first using 50% A
(95-5 acetonitile-water) and 50~o B (95-5 water-acetolIitrile) with O.l~
TFA for 15 minutes and then 70C~o A (95-5 acetoniti]e-water) and 30%
B ~95-5 water-acetonitrile) both with 0.1% TFA. The column effluellt was monitored simultaneously at 210 and 277 nM witll a Waters model W0 961~14905 ; ~ 2 1 q 5 7 5 ~ 7--- Ig8-490 UV-visible deLectar and the purified fractions were combined in a round bottom flask and concentiated in vacuv to afford 1.45 g (38%) ol the title compound as an amorphous solid.
IH-NMR (500 MHz. CD30D,ppm) ~ 0.8~) ~t~/=7.50 Hz,3H~), I.26 (d,J=7.00 Hz,3H3, 1.27 (dJ=7.00 Hz,3H), 1.53-1.61 ~m,2E{), 2.59-2.66 (m,2H?, 3.00 (sept.l=7.00 Hz,lH), 5.55 (s,lH~, 5.97 (s,2H), 6.60 ~d~/=7.50 llz,lHj, 6.7g (dJ=8.00 Hz~lH), 6.85 (d,~=2.50 Hz,lH), 6.92 (dd,J=2.00, 8.21:) Hz~lll), 7.31 (ddJ=2.50, 8.00 Hz,lH), 7.38 (d~=8.50 Hz~2H~, 7.45 ~d~J=2.00 Hz,lH), 7.78 (d,J=8.50 Hz,2H).

Step F: Preparation of N-(4-iso-propylbc~ le~ulfonyl)-a-~4-cyano-2-n-propylphenoxy)-3.4-methylenedioxy-pllenyLacetamide potassium salt To a stirred solution of 393 mg (0.756 mmol) of the the product of Step E in I ml of methanol was added 2.26 mL (2.27 mmol) of a I N potassium hydroxide solution in methanol. The reaction mixture was stirred 15 minutes, diluted with water and filtered through a 0.45 mm filter disc. The filtrate was purified usin~ a Varian .~500 20 HPLC by apply;ng the compound in a 4.0 ml tot~l volume (3 mL
methanol and I nlL water) onto two in series 21.2 x 250 mn1 7mm Zo}bax ODS columns and eluting at 15 m~/min first u.sin~ 85~i water and 15~c acetonitrile for 10 minutes and then a 30 minute linear gradient to 50% acetonitrile and 50% water. ~he column eflluent was 25 nnonitored 254 nM with a ~Kratos Spectroflow 783 UV detector and the purified fractians were combined in a roulld bottom flask. frozen in a -78~C dry ice-acetone bath and Iyophylized to afford 177 mg (42~o) of the title compound as a wllite Iyophilized powder.
IH-NMR (500 MHz? CD3OD,ppm) o 0.88 (tJ=7.50 Hz,31-I). 1.23 30 (s,3H)~ 1.24 (s,3H), 1.55-1.62 (m,2H~ 2.53-2.5~ (m~lH~ 2.67-2.73 (m~ 3.90-2.94 (m~lH)~ 5.37 (s,lH), 5.94 (:s,21-1~, 6.76-6.78 (m~2H)~
7.02-7.04 (m~2H1~ 7.21 (dJ=8.50 Hz,2H0~ 7.27 (dd~/=2.0()~ 8.50 Hz~lH), 7.38 (dJ=2.00 Hz,lH), 7.66 (d,J=8.50 Hz,2H~.
ESI-M,S m/e = 5~9 (M+l).

wo96104905 ~ , 2 1 9575~ r~

~XAMPLE 152 N-(4-iso-propylbenzenesulfonyl)-a-(4-tetrazo-5 -yl-2-r/-propyl-phenoxy)-3,4-methylenedioxyphenylacetamide dipotassium salt Step A: Preparation of N-(4-iso-propylben7~n~snlfollyl~ -(4-tetrazo-5-yl-2-n-propylphenoxy)-3,4-methylenedioxy-phenylacet~lmide A stirred solution of 600 mg ( I .15 mmol) of the product of Example 151, Step F and 284 mg (1.38 mmol) of trimethyltinazide in 2 mL of toluene was heated with an oil bath at reflux overnight. The reaction was evaporated in v~cuo~ purified by silica gel flash chromatography eluting with methylene chloride I methanol / acetic acid 100:3:1, and the purified fractions concentrated in VClCUo to afford 244 mg (38C~o) of the title compound as ,m amorphous solid.
Ill-NMR (500 MHz, CD30D,ppm) o 0.90-0.94 (rm,2H), 1.16-1.19 Im,6~1), 1.60-1.68 (m,2H), 2.64-2.75 (m,2H), 2.89-2.95 (m,lll), 5.56 (s,lH), 5.96 (~s,2Hi, 6.73 (d,J=8.50 Hz,lH), 6.79 (dJ=8.00 Hz,lH), 6.89 (d,.7= 2.00 Hz,lH), 6.94 (dd~/=2.00, 8.00 Hz,lH), 7.34 (ddJ=1.50, 8.50 Hz,211), 7.64 (dd,J=2.00, 8.50 Hz,lH), 7.76 (d,J=2.00 Hz,lll), (ddJ=2.00, 8.50 Hz,2H).
ESI-MS mie = 564 (M+l).

Step B: Preparation of N-(4-i.so-propylbenzenesulfonyl)-o~-(4-tetrazo-5 -yl-2-n-propylphe.noxy)-3 ,4-methy lenedioxy-phenylacetamide dipota.ssium salt To a stirred solution of 240 mg (0.426 rmmol) of the product of Step A in 3 ml of methanol was added 2.41 mL (2.41 mmol) of a I N potassium hydroxide solution in methanol. The reaction mixture was stirred 15 minutes, diluted with 4 mI, of water ~md filtered WO 96/~490~ 2 1 9 5 7 r; 8 ~ 7 ~~
;. ~, .
. ~ .i thlough a 0.45 mrn filter disc. The filtrate was purified using a Varian 5500 HPLC by applying the compound in a 8.0 ml total volume (4 ml methanol and 4 mL water) OlltO two in series 21.2 x 250 mm 7mrn Zorbax ODS columns and eluting at 15 mL/min first using 90~o water 5 and 10% acetonitrile for 5 minutes and then a 30 minutç linear gradiellt to 40~Vo acetonitrile and 60% water. The column ef~luent was monitored 254 nM with a Kratos Spectroflow 783 UV cletector and the purifiecl fractions were combined in a round bottom flask! frozen in a -7R~C dry ice-acetone bath and Iyophylized to afford 196 mg (72~o) of the title compoulld as a white Iyophilized powder.
NMR (500 Ml Iz, CD30D,ppm) o 0.91 (tJ=7.20 E~z,3H~, 1.15 (d,J=7.0 Hz,3H~, 1.16 (d~l=7.0 Hz,3~), 1.62-1.68 ~rll,2H), 2.58-2.64 (m,lH), 2.74-21~0 (m,lH~, 2.86 (sept.,J=7.00 Hz,lH), 5.36 (s,lH), 5.93 (d,.J=1.20 Hz,lH), 5.94 (drl=l .20 Hz,lH), 6.76 (d~l=7.50 Hz,ll~). 6.82 5 (d~ .50 Hz,lE~), 7.04-7.07 (m~2H), 7.20 (dJ=~3.50 Hz,211). 7.65-7.69 (m,3H), 7.78(dJ=2.()0 H~,lH).
LSI-MS mle = 640 (M+l~.

N-(4-iso-propylbenzenesulfonyl)-a-(4-N-tnethyl-l~i~-methc~xy-carboxamido-2-~-propylphenoxy)-3 ,4-methylenedioxyphenylacetamide Step A: N-~4-i~o-propylbenzenesulfollyl)-~-~4-,'V-methyl-A,1-methoxycarboxamido-2-n-propylphelloxy)-3,4-methylenedioxvphenylacetamide To a 0~ C suspension of 2.00 g (3.25 mmol~ of the product of Example 58 and 951 mg (9.75 mmol) N,O- dimetbylhydroxylamille hydrochloricle in 15 mL of methylene chloride and 1.36 mI, (9.75 30 ml:llOI) of triethylamine was added 1.49 g (9.75 mrllol~ of l-hydroxybenzotria~ole hydrate and 1.87 g (g.7~ mmol~ of 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred 16 hour and alklwed to wann to room temperature after which TLC analysis (10~ methanollmethylene ~i Wo g6l0490s ~ p~
7 5 ~

chloride) indicated that the couplihg reaction was complete. The reaction was diluted with ethyl acetate (30 mL) and partitioned with water (150 mL). The organic layer was washed with I N HCI (50 mL), brine (50 mL), dried over MgSO4, filtered, evaporated and dried in 5 vacuo affording 1.64 g ~7%) of the title compound as an amorphous powder.
IH-NMR(400 MHz, d6-DMSO,ppm): o 0.82 (t~=7.20 Hz,3H), 1.17 (d,~=7.20 Hz,6H), 1.43-1.58 (m,2H), 2.4~S-2.60 (m,2H), 2.93 (sept, J=7.20 Hz,lH), 3.19 (s,1}1), 3.51 (s,3H), 5.66 (s,lH), 6.03 (d,J=1.20 Hz,lH), 6.04 (drl=1~20 Hz,lH), 6.47 (d,J =8.40 lIz,lH), 6.91-6.9~S
(m,3H), 7.25 (dd,J= 2.00, S.40 H~, lH), 7.3~ (d,J= 2.00 Hz, lH), 7.41 (d,/= 8.40 ~Iz,2H), 7.69 ~d,J= 8.40 Hz,2H).
ESI-MS m/e = 5~3 (M+l).

N-(4-i.so-propylbenzenesulfonyl)-o~-(4-( 1 -oxoethyl)-2-n-propyl-phenoxy)-3,4-methylenedioxyphenylacetamide dipc tassium salt Step A: Yreparation of N-(4-i.so-propylbenzenesulfonyl)-oc-(4-(1-oxoethyl)-2-n -propylphenoxy)-3,4-methylenedioxy-pheny lacetamide To a 0~ C stirred suspension of 594 mg (1.02 mrnol) of the 25 product of Example 153 in 8 mL of dry tetrahydrofuran was added 1.19 mL (3.57 mmol) of methyln-~gn~sillm chloride as a 3.0 M solution in tetrahydrofuran. Following the grignard addition, a homogellous reaction mixture was achieved and tlhell allowed to uarm to room t~ dlUI~. After stirring 3 hour~, TLC analysis (10~, methanol /
30 methylene chloride) indicated that the couplillg reaction wa.s complete.
The reaction mixture was poured into 5'~o 6N HCI / ethanol (20 mL) and then partitioned between brine (6() ml,) and ethyl acetate (30 mL).
The extract was dried over m;l~n~siilm sulfate, filtered and the filtrate W096fO490~ '? ~ 9 57 ~8 concentrated in va~ uo affording 373 mg (68~o) of the title colllpoulld as an amorphou.s powder.
l l-I-NMR (400 MHz, CD30D,ppm) o 0.88 (tJ=7.20 E Iz,3H), 1.21 (d,J=6.80 Hz,611), 1.54-1.66 ~m,2H), 2.51 (s3H), 2.55-2.63~m,1H), 2.67-2.75 (m,lEI), 2.91 (.sept.,J=6.80 Hz,lM), 5.43 (s,lH~, 5.94 (d,J=1.20 1-lz,21-1), 6.74-6.77 (m,2H), 7.01-7.03 tm,2H), 7.23 ~d,J=8.40 Elz,2H~, 7.65-7.69 ~m,3H), 7.73 (d,J=2.40 Hz,lH).
Cl-MS mlc = 5~38 (M+l).

Step B: Preparation of N-(4-isO-propylbenzene6ulfotlyl)-a-(4-(l-oxoethyl)-2-n-propylphenoxy)-3,4-methylenedio~yphellyl-acetamide potas.sium salt 'rhe titled compound is prepared u6ing the product of Step A according to the procedure described in E~ample 152, Step 13.

Claims (4)

WHAT IS CLAIMED IS:

1. A compound which is: N-(4-iso-propylbenzene-sulfonyl)-.alpha.-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxy-phenylacetamide or a pharmaceutically acceptable salt thereof.

2. A compound which is: N-(4-iso-propylbenzene-sulfonyl)-.alpha.-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxy-phenylacetamide dipotassium salt.

3. A method of treating renal failure by administering to a mammal in need of such treatment with a therapeutically effective amount of the compound recited in Claim 1.

4. A pharmaceutical composition which comprises a pharmaceutically effective amount of the compound recited in Claim 1 and a pharmaceutically acceptable carrier.