AU725122B2 - Endothelin antagonists - Google Patents

Endothelin antagonists Download PDF

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Publication number
AU725122B2
AU725122B2 AU20344/99A AU2034499A AU725122B2 AU 725122 B2 AU725122 B2 AU 725122B2 AU 20344/99 A AU20344/99 A AU 20344/99A AU 2034499 A AU2034499 A AU 2034499A AU 725122 B2 AU725122 B2 AU 725122B2
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Prior art keywords
trans
carboxylic acid
benzodioxol
acid
ethyl
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AU20344/99A
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AU2034499A (en
Inventor
Steven A. Boyd
Charles W Hutchins
Hwan-Soo Jae
Jeffrey A. Kester
Bryan K Sorensen
Andrew S. Tasker
Thomas W. Von Geldern
Martin Winn
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Abbott Laboratories
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Abbott Laboratories
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Priority claimed from AU32137/95A external-priority patent/AU711832B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

S F Ref: 362557D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIRCATION FOR A STANDARD PATENT
ORIGINAL
Name and Address of Applicant: Actual Inventor(s): Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 UNITED STATES OF AMERICA Martin Winn, Steven A. Boyd, Charles W. Hutchlns, Hwan-Soo Jae, Andrew S. Tasker, Thomas W. VonGeldern, Jeffrey A. Kester and Bryan K. Sorensen Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Endothelln Antagonists Address for Service: Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 o. Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates 20 employed in these processes and methods and compositions for antagonizing endothelin.
Background of the Invention Endothelin (ET) is a 21 amino acid peptide that is produced by 25 endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility jn vitro, stimulate mitogenesis in vascular smooth muscle cells in .itr., contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance jin yiQ, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in yjjt and in yio, increase plasma levels of -2vasopressin, aldosterone and catecholamines, inhibit release of renin in vitr and stimulate release of gonadotropins in vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. .Z 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrbage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S.ltoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. 15: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic 25 benefit in the indicated disease states.
Disclosure of the Invention In accordance with the present invention there are compounds of the formula R2 Z R 3
(CH
2 )n
R
wherein Z is -C(R, 8 )(Ricg)- or wherein R 1 ,4 and Rig are independently selected from hiydrogen and loweralkyl; nis I; kis -C-)-Wwherein rn is an integer from 0 to 6 and W is
-C(O)
2 -G wherein G is hiydrogen or a carboxy protecting group.
-1303H,, -P1(0)(01-l)E wherein E is hydrogen, loweralkyl or arylalkyl.
-CN,
C(0)NHR 17 wherein R 17 is loweralkyl, alkylaminocarbonyl, ialkylaminocarbonyl, (hi) tetrazolyl, hiydroxy, alkoxy, sulfonarnido, -C(0)NHS(0) 2
R
1 6 wherein R 1 is loweralkyl, hialoalkyl, phenyl or clialkN'Ianiin-o, (11n) -S(0) 2 N1-IC(0)R,6, HO 0
HO
OH
0 tR:\LIBXXIO2364.dIoc:aak 0 (s)H H 0 o 5 (N% 1 n R aeineenenl slctd rm yroen owrlkl N. alenl Hlyyakxakl loycroyakl yrxak aloyakxyly, hoakxaloyakl ccoakl .:amiocabonlalytalklamnocrboylakyl othe th a eidpnetyeetdfo hydrogen oeakl V. alkenyl, a whereinal R5xisl(i) akxcalebondl, (ii) alk lyl *~loylkxakl (iii) alk ylene k(i) -NR 20
-R
8 c lor al N()R wherein R 8 lakyl alyamn care ndependnly ee dfo lmio alkoylaen l d Ris yd nroge n lealkeyl, aknl (Raa(Rb)N-cycoaheeikisayl or cylol ylalkyl r hydrge or aR wherein Rg and R9a are independently selected from alkylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2 1 )-RlO- wherein RIO is alkylene and R 2 1 is hydrogen or loweralkyl; R4 and R6 are independently selected from the group consisting of (Ri 1
)(R
12 wherein R11 and R 12 are independently selected from hydrogen, toweralkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, (10) arylalkyl, and (11) (heterocyclic) alkyl1, (ii) leweralkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyt, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl and (Ai) alkoxyalkyl; R2 6 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyt, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, 9. 9 9 9999 9* 9 9** 9 9 9999 (hecterocyclic)alkyl, (xi) alkoxyalkyt or (xii) alkoxy-substitted haloalkyl; mid R27 is alkylcue or alkenylene;
R
2 2
O-C(O)-R
2 3 wherein R2 is a carboxy protecting goupJ or heterocyclic Mid R2 3 is a covalent bond, (ii) alkylenec, (Iii) alkeniylenei or (iv) 4
)-R
2 5 wherein is alkylenie anid R 24 is hydrogeni or loweralkNIl, loweralkyl, alkeniyl, alkyniyl, it(1) cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, IS(k) heterocyclic, (hicterocyclIic)al kyl1, alkoxyalkyl, (ii) alkoxyalkoxyalkyl. or
R]
3
-C(O)-CH-(R
1 4 P-cri I, is aminio, alkylaminio or dialkylaniio anid R 14 is aryl or R 15 \.hereinl R1 is arrinio. alkylamnino or dialkylainio; or a pharmaceutically acceptable salt thereo" and with the furthier proviso that the comp1Iound of' forl1a I is not I -mlethyl-' 3 -cyanio-pyrriolidinie, I -propyl-2-inethyl-3- [cltox\;-pyrruI ioidinie, I -ethiyl-'3fO-0lroyrro CI idinie. I -mcthy l-3-chi loromethyl Ipyrrol iclie.
1 -d 1; .i-iiy 1'-3)-aicetyI-pyrr-ol idinle, I -pe\l3\iyproidinle, I .2-diinethyl-3cvanopyrrol idine., I-benizyl acetoxypyrri-iol id ie. I-exl'ciiitl)Iiiio) odlc or' 1 -CI1lhy-3 -mIethIYLul tbnyl-pyrrol idinle.
I R\L I 3XX 102364.docaak A preferred emnbodiment of the invention is a compound of formula (I1) R2 Z11 ,R 3
N
R
H
2 )n wvherein the substituents -R2, -R and -RI exist ini a Iracn.icns relationship and Z, ni, R, RI, and R3 are as defined above.
Disclosed herein is a Compound of formula or (11) wherein n is 0 and Z is -CH 2 Another preferred embodiment of the invention is a compound of formul1,1a or (11) wherein n is I and Z is -CH- 2 Disclosed herein is a compound of formula or (11) wherein n is o, Z is and RK is RI-C(O)-R5-, R 6
-S(O)
2 or R 96 9 7 as defined above.
Also disclosed herein is a compound of formutla or (11) wherein n is 0, Z is I 3 ad R3 IS alkoxyalkyl or alkoxyalkoxyalkyl.
*Furthier disclosed herein is a compou~nd Of formul1-1a Or (11) Wherein 11 IS 0, Z is :-Clb-.and R3 is RI-C(O)-R 5 wherein R4 is (R 1
)(R
12 as defined above and R5 is *.alkylen e or R3 is R 6
-S(O)
2
-R
7 Or R- 26
-S(O)-R
2 wherCIein R 7 is alkylene. R27 is alkylene and R 6 and R26 are defined as above.
21)A-lso disclosed herein is a compound of fbrmul1,1a or (11) wherein 1n IS 0. Z is -CI4 2 :and RK Is R -C(O)-N(R 2 0 or R S() 2 1 \vherein RK and R 10 are alkylene :11( :Z1 ad K R 2 1 1 and are defined as above.
SIn addition there is disclosed hierein IS a c01)oond of formu1lak Or (11) where-in n1 0. R is tetrazolyl Or -C(O) 2 -G wherein G is hlydro-gen or a carboxy protecting 01-o-up Or 23R is -C(O)-NH-S(O) 2
R
16 wherein is loweralkyl or aryl. Z is R, and R- are independently selected from loweralkyf. (ii) cylcoalkyl. (Ini) substituted aryl wherin arl-\ I Shny 17CI1 Substituted with one Or twVo substituients idpnetyselected from Ioweralkvl. alkoxy. halo. alkoxyalkoxy and carboxyalkoxy and (iv) su~bstittted or 1101-1 BXX 102364.doc:aak UlnSLIbStituted heterocyclic, and R 3 is R_ 4 5 wherein R 4 is (RI 1 2 wherein R, an-d R I, are independently selected fromn loweralkyl, aryl and arylalkyl and R~ is alkylene; iS R 4
-C(O)-N(R
20 8 or R 6 1 wherein R, is loweralkyl, aryl, alkoxy, alkylamrino, aryloxy or arylalkoxy and R 6 IS loweralky!, haloalkyl, alkoxyalkyl, aryl or- arylalkyl, R8 and R 10 are alkylene and R 2 and R 21 l are loweralkyl; Or R 3 is R6- S0)- 7 -or Rm-)-S(O)-R-2 7 wherein R6 IS loweralkyl, R 7 is alkylenle, R-) 6 IS loweralkyl and R!7 is alkylene.
Fuirther there is disclosed herein is a compounrd of formula or- (11) wherein n is 0, R is -C(Oy wherein G is hydrogen or a carboxy protecting group, Z is R, is (i) I loweralkyl, (ii) cycloalkyl, (111) phenyl, (iv) pyridyl, furanyl or (vi) substituted or unllSubsti tuted 4-rnethoxyphenyl, 4-fluorophenyl, 3)-fluoropheniyl, 2-lorophenyl, 4 -inethoxyrnethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, I -benzodioxolyl, I .4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent Is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, is 1 ,'-benzodioxolyl, I ,4-benzodioxanyl, di hy\drobenzoturanyl, 4-mnethoxyphenyl, dimrethoxyphenyl, f0 uorophienyl or di1 flu11Oopheny)l and R3 is R 4 0
)-R
8 or R 6 -S(O)2-N(R? 1
)-R
10 wherein Rg and Ru() are alkvlene, and R 21 l are loweralkyl. R4 is lowveralkyl, aryl, alkoxy, alkylamino, ~*arv Ioxy or arylalkoxy and R6i loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
:Inl addition there is disclosed herein is a COmTpounid of formu11Lla or (11) wherein n 01 0 I2() R is-C(O>2-G whereini G ishydrogen or- a carboxy protecting group. Z is-CH?-I-, R, is Io\.eralkyl, (1i) cycloalkyl, (1i1) phenyl, (iv) pyridyl, furanyl or (vi) Substituted or '00000 uIHSuLbSIituted 4-nuethoxyphenyl. 4 -lluiorophenyl, 3-flu11OrphlI. 2-fluorophienyl, 000' 4 -imcthioxvniiethoxyph)Ieiyl. 4-hydroxypheiiyl. 4-t-butylphenyl)'. I .3-benzodioxolyl, 1.4-beuzodioxanyl or dihyclrobenizof'uranyl wherein the Sub.stitueICIl IS Selected Croln alkoxyalkoxy and carboxyaloy R I is13brzdoo. I .4-hernzocaoxan\ 1 '09.di hvcrobenizof'Uranyl, 4-rnethoxyphern/l. chlmethoxyphenlyl, IlUOrophenyl1 Or di fluo1rophenyl and R 3 is R 4 wherein R5 is alkylene anid R- is (Ri 2
)N-
he~reini R I I anid R 12 are independently selected from~ loweralkYl. aryl and arylalkyl.
IR\LiI13X X 102364.doc~aak Also disclosed herein is a Compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 R, is (i) phen~yl Or (11) Substituted or unsubstituted 4-mnethoxyphienyl, 4-fluorophienyl, 3-li uro1-pheny I, 2-fluorophenyl, 4-methoxymethioxyphieny I, 4 -hydroxyphentyl, 4-t-hUtylphenyl, I ,3-benizodioxolyl, I ,4-bcnizodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, is I .3 -henzod ioxoly I, I .4-benzodioxanyl, d ihydrobenzot furanyl, 4-mnethoxyphenyl, cli methoxyphenyl, fi uorophcnyl or dif[1uorophenyl and R 3 is RO-S(O) 2 -N (R 2 1 wherein R 1 is alkylene, R6, is loweralkyl, aryl or arylalkyl and R 21 I is loweralkyl, aryl or ii arylalkyl.
Further disclosed herein is a compound of formrula or (I1) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is R, is sub st ituted Or LInsuibstituted 4-miethoxyphenyl, 4-1LI orophienyl. 3-1fl uorophentyl, 2-ti uo0rophenty 4-mnethoxyrnethoxyphenyl, 4-hydroxypheny I, 4-t-buty Ipheny I, 513 I,'-benizodioxolyl, I ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected fromn alkoxy, alkoxyalkoxy and carboxyalkoxy, R? is I ,'-benzodioxolyl, I ,4-benzodioxanyl, dihydrobenzofu-ranyl, 4-methoxyphienyl, dimiethoxyphenyl, 1lLIOrophienyl or difluorophenyl and R 3 is R 4
-C(O)-R
5 wherein Ri is a lkylene and R 4 is (R I)(R 1 2)N- wVherein R, and R 12 are independently selected from lo\.eralkyl, aryl and ii ii" IIAlso disclosed herein is a compound Of formul1,1a or (11) wherein n Is 0. R is wherein G is hydrogen or a carboxy lprotectng rou 71OI) ZIS -Cl-I 2 RI is Substituted or- un1substituted 4-mnethoxyphenyl, 4-fluorophenyl, 3-Iiuo1rophenyl, 2- 111Ii uorophenyL1. 4-rnethoxymethoxyphenyl. 4-hydroxyphienylI, 4-t-bUtylphentyl, z~s henodixoll. ,-benzodioxanyl or dihydrobenizofuLraniyl wherin tesbtteti :skcected fr-om alkoxy. alkoxyalkoxy and carboxyalkoxy. R, is I.3-beuzoclioxolyl1. I .4heuzod uxanyl. dilhydroberizofuranyl., 4-m-ethoxy1phenIy1 l. dimetho0XN/phcnv\. 1..Ii pley or d~ Iluorophienyl and R 3 is R 4 -C(0)-R 5 wherein R Is ailkylene aind is (R ,R1)N \vhcirein RK and R 12 are independently selected front lowerailkyl.
Also disclosed heriIn is a Coound of fruaI)o(I)weennIs0 is 2 -G wherein G is hydrogen or a car-boxy protectingl group11. Z Is -Cl-I 2 R, IS Substituted Or Unsubstituted 4-mnethoxyphentyl. 4-fiUOr-ophenyl. 3- Iluorophenlyl, 2-li1 uIorophenIyl. 4 -inethoxyrrethioxyphenyl., 4-hydroxypheni-yl. 4-t-butylphlI, I .3)-enzod ioxolyl, I ,4-benizodioxan-yl or dihydi-obenizoftirayl Wherein the substituent is IR:\LIBXX 102364.doc:aak selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 is 1.3-benzodioxolyl, 1.4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, Fluorophenyl or difluorophenyl and R 3 is R 6 2
-N(R
2 1)-R 1 0- wherein RIo is alkylene,
R
6 is loweralkyl and R 2 1 is loweralkyl.
The present invention also relates to processes for preparing the compounds of formula and (11) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the marmmal a therapeutically effective amount of a compound of formula or (LI).
in The invention further relates to endothelin antagonizin" compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula or (I1).
Or se 1:\II 3XX j02364.docaak -11- The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used 20 in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", 25 edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C 1 to Ca loweralkyl methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl.and substituted derivatives thereof, for -12example, 5-indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, vale ryloxymethyl, i sob utyry loxym ethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1ethyl, 1 -(pivaloyloxyl)-1 -ethyl, 1 -methyl-i -(propionyloxy)-l -ethyl, pivaloyloxymethyl, propionyloxymnethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarboloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentycarboflyloxymethYl, cyclohexylCarbolylOXYmethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbo nylmethyl, 1 -methoxycarbonyl-1 ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbo nyloxymethyl, 1 -ethoxycarbo nyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylamifloalkyi, such as t-butyloxycarbonylaminomethyl and the like; alkylami nocarbonylaminoalkyl, such as methylami nocarbo nylami nomnethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyI and the like; dialkylaminocarbonylalkyl, such as dimethylamifocarboflylmethyl, 20 diethylamiflocarbonylmethyl and the like; (5-(loweralkyl)-2-oxO-1 ,3-dioxolen-4yl)alkyl, such as (5-t-butyl-2-oxO-1 ,3-dioxolen-4-yl)rfethyI and the like; and *hnl2oo13dooe--lakl uha 5pey--x-,-ixln4 phny-2ox- ,3dooe--laklsc s(-hnl2-x-1,-iln4 yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-ch lo robe nzoyl, -13- 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamnate forming groups such as benzyloxycarbonyl, p-ch lo robe nzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nit robe nzyloxycarbon yl p-bromobenzyloxycarbonyl, 3,4-di methoxybenzyloxycarbonyl, 2,4-di met hoxybe nzyloxycarbo nyl,, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, c,a- di met hy1-3 ,5-d imet hoxybe nzyloxycarbo nyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -t rich lo roet hoxycarbo nyl1, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenyithiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; too: and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The terms "loweralkyl" or "alkyl" as used herein refer to straight or to: branched. chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, to a t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2- :1.00. 25 dimethylpropyl, n-hexyl and the like.
The term "alkylamino" as used herein refers to R51 NH- wherein R 51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
eve* The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylami nocarbonyl, isopropylaminocarbonyl and the like.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 group.
-14- The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl'(NH 2 group.
The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylaminoalkyl" as used herein refers to
R
40
-C(O)-NH-R
41 wherein R 4 o is an alkylamino group and R 41 is an alkylene group.
The term "dialkylamino" as used herein refers to R 56
R
57 N- wherein R 5 6 and R 5 7 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkyl" as used herein refers to
R
5 o-C(O)-R51- wherein R 50 is a dialkylamino group and R 51 is an alkylene group.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino 2 group. Examples of alkylsulfonylamino include 25 methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44wherein R 4 3 is an alkanoyl group and R44 is an alkylene group.
The term "alkanoyloxyalkyl" as used herein refers to R 30 -O-R31- wherein
R
30 is an alkanoyl group and R 31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example -CH 2
-CH
2
CH
2
-CH(CH
3
-HCH
2
CH
2
-CH
2
C(CH
3 2
CH
2 and the like.
The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH 2 CH=CH-, -C(CH 3
-CH
2
CH=CHCH
2 and the 20 like.
The term "alkoxy" as used herein refers to R 41 0- wherein R 4 1 is a loweralkyl group, as defined above. Examples of alkoxy include, but are not o limited to, ethoxy, tert-butoxy, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as 25 previously defined appended to an alkyl radical as previously defined.
Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term "alkoxyalkoxy" as used herein refers to R 80 0-R 81 0- wherein
R
80 is loweralkyl as defined above and R 81 is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, tbutoxymethoxy and the like.
S* The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative -16examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylaminoalkyl" as used herein refers to
R
38 -C(O)-NH-R39- wherein R 3 8 is an alkoxy group and R39 is an alkylene group.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical.
Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to R 34 wherein R 3 4 is an alkoxy group and R 3 5 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
The term "alkoxycarbonyloxyalkyl" as used herein refers to
R
36 -C(O)-O-R37- wherein R36 is an alkoxy group and R 3 7 is an alkylene group.
20 The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term "alkynyl" as used herein refers to a straight or branched chain 25 hydrocarbon radical containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -C=C-H,
H-C=C-CH
2
H-C=C-CH(CH
3 and the like.
The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 10 carbon atoms and also containing a carboncarbon triple bond. Examples of alkynylene include -CEC-CH 2
-C=C-
CH(CH
3 and the like.
The term "aminocarbonyl" as used herein refers to H 2 -17- The term "aminocarbonylalkoxy" as used herein refers to H2N-C(O)appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkoxy" as used herein refers to R420- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "aryloxy" as used herein refers to R450- wherein R45 is an aryl group, for example, phenoxy, and the like.
The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "aroyloxyalkyl" as used herein refers to R 32
-C(O)-O-R
33 wherein R 32 is an aryl group and R 33 is an alkylene group. Examples of S. aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde radical, -C(O)H.
-18- The term "carboxy" as used herein refers to a carboxylic acid radical,
-C(O)OH.
The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined.
Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined.
Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-l-ethenyl and the like.
The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano group. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, 20 carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.
The term "haloalkyl" as used herein refers to a lower alkyl radical, as 25 defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
The term "haloalkoxy" as used herein refers to a lower alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2fluoroethoxy, 2,2,2-trifluoroethoxy and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one -19nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in nonadjacent positions; or two sulfur atoms in non-adjacent positions. The membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized.
The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloherane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothidzolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Heterocyclics also include SS. X.
*0
Y
S 20 compounds of the formula o where X* is -CH2- or and Y* is or where R" is hydrogen or C 1 -C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted 25 with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S0 3 H and loweralkyl. In addition, nitrogen containing heterocycles can be Nprotected.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term "(heterocyclic)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term "heterocycliccarbonyloxyalkyl" as used herein refers to
R
46
-C(O)-O-R
4 7- wherein R46 is a heterocyclic group and R 4 7 is an alkylene group.
The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "mercapto" as used herein refers to -SH.
The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl 4 *0 0 radical. Ethylenedioxy substituted on a phenyl ring results in the ga.
O
formation of a benzodioxanyl radical SThe term "tetrazolyl" as used herein refers to a radical of the formula 0 N- N 25 or a tautomer thereof.
21 I'lie term "tetrazolylalkoxy" as used herein refercis to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examnples of' tetrazolylalkoxy, nclude tetrazolylmethoxy, tetrazolylethioxy and the like.
Thle term "thiioalkoxy" as used hierein refers to R 7 0 S- wherein R 70 is loweralkyl.
Examrples of thiioalkoxy include, but are not limited. to. mnethiylthio, ethiylthiio and the like.
'he term "Irans, trans" as used hierein refers to the orientation Of S~bstitUentS (RI zid relative to the central substituent R aIS sh1own R
H
2 )n Thie term "Irans,cis" as used herein refers to thec orientation Of substituents (RI and I R) relative to the central substituent R as shown R21-.. Z R 3 R 1 R N N or Th1is definition encompasses 1)th the case whiere R and are cis and R and RI are trans and the case where R? and R are Irns and R and R, areL'is.
TheC term 'cisi''as used herein refers to theC orientatIon of' substituents (RI and 1 rlative to the central substitUenlt R aIS sho0wn R 2 R 3: D isclosed hierein are the fol1lowingi compIIoundIs: I 1' 17A I I'MI (4-Nlethoxypheln)1l) 4- (I.3-benzodioxol-5-vlI)- I pr-opy\laiinocai'bony llriethiyl)-1-)- I -rI'o idI ie-3-Car-bo\yl Ic ICcid: I R U.IBXX 102364.tloc:aak -22trans, trans-2-(4-MethoxyphelY)4(l,3-benzodioxol-5-yI)-1 (aminocarbonylmethy)-pyrrolidifle3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4(l,3-benzodioxol-5-yI)- 1 fluorobenzyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4- (1 ,3-benzodioxol-5-y)-1 ethoxyethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4-(1 ,3-benzodioxol-5-yI -1 propoxyethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)- 1 methoxyethoxy)ethyl]-pyrrolidifle-3carboxylic acid; trans, trans-2-(4-Methoxyphelyl)- 4 ,3-benzodioxol-5-yI)- 1 pyridyl)ethyl]-pyrrolidile-3-carboxyic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxol-5-yi)- 1 morpholinylcarbonyl)-pyrrolidile-3-carboxylic acid; trans, trans-2- Methoxyphefnl)- 4 ,3-be nzodioxole-5-yI)- 1 (butytaminocarbonyl)-pyrro Iidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphel)- 4 ,3-benzodioxol-5-yI)-1 methoxyphenylami nocarbonyl)-3-pyrrolidile-3-carboxyic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-be nzodioxot-5-yI)-1 acetylpyrroidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4-(1 ,3-benzodioxol-5-yl)-1 -(2-fu royl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphel)-4-(1 ,3-be nzodioxol-5-yI)-1 (phenylaminoCarboflyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4-(l ,3-benzodioxol-5-y)-1 (allylami nocarbonylmethy)-pyrrolidifle-3carboxylic acid; trans, trans-2-(4-MethoxyphelY)4-(l,3-benzodioxol-5-y)-1 :0.buty lam inocarbonyfl methyI)-pyrrol idifle-3-carboxyli c acid; trans, trans-2-(4-Methoxyphel)- 4 ,3-benzodioxol-5-yi)-1 -(N-n-butyt- N -met hylamiflocarbofnlylmethyI)-pyrrolidifle- 3 -carboxylic acid; *00trans, trans- 2- (4-Meth oxyphefnlY) 4 ,3-be nzodi oxol-5-y 1 -(pyrrolidin- 1 -ylcarbonylmethy)-pyrrolidifle-3carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l,3-benzodioxol-5-yI)-1 (isobutylaminocarbolylmlthyl)-pyrrolidile-3carboxyic acid; -23trans, trans-2(4-Methoxyphefl) 4 (,3-benzodioxoI-5-Y)l (cyclopentylamiflocarboflylmethYl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-MethoxypheflY)4dl,3-benzodioxol-5-yI)-l (morpholin-4-ylamiflocarbonylmethyl)pyrroidine3carboxylic acid; trans, trans-2- Meth oxyp hefnl)- 4 (1 benzo di oxol-5-y 1)-l1 phenoxyethy)-pyrroidile-3-carboxylic acid; trans, trans-2- Meth oxyp henlYl)-4- (1 ,3 -ben zodi oxol-5-yi)-l1 methoxyethylam in ocarboflyl met hYl)PYrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4- (1 ,3-benzodioxol-5-yI)-l butoxyethy)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxo-5-yI)-4-(4-methoxyphel)-l (propylaminocarbolylme'thy)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(1 ,3-BenzodioxoI-5-yl)-4-(4-methoxyphelY)l pro poxyethy)-py rro idi ne-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxol-5-yi)-4-(4-methoxyphel)-l methoxyethoxy)ethy)-pyrrolidifle-3carboxylic acid; trans, trans-2- (1 Befzodi oxoI-5-yi)4- met hoxyphe nyI)-l1 butoxyethy)-pyrrolidifle-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)Y4-(l,4-benzodioxan-6-yI)-1 (propylaminocarbolylmethyl)-PYrrolidie-3-carboxylic acid; *trans, trans-2-(4-MethoxypheflYl) 4 -(l,4-benzodioxal-6-y)-1 -(N-methyl- N- pro py lami no carbonlyfl ethyI)-pyrroli dife3carboxylic acid; ::25 trans, trans-2-(4-Methoxyphefl)- 4 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-butylaminocarbonyflmethyi)-pyrrolidifle3-carboxylic acid; trans, trans-2-(4-Methoxy-2-methoxymfethoxyphenyl) 4 dl ,3benzodioxol-5-yI)-1 -(N-methyI-N-butylamiflocarboflmethyI)- ::::*pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)- 4 -(l,3-benzodioxot-5-yI)-1 ethoxypropyI)-pyrrolidifl5-ofe3-carboxylic acid; trans, trans-2-(4-Methoxypheflt)-4-(l ,3-benzodioxol-5-yl)-l methoxybenzyl)-pyrrolidifl-5ofe3-carboxylic acid; -24trans, trans-2-(4-Methoxyphel)-4-( 1,3-benzodioxol-5-y)-1
,N-
diisoamylaminocarbonylmethyl)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4-(1 ,3-benzodioxo-5-yI)-1
,N-
dipentylaminocarbonylmethyl)-pyrrolidie-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N-di(2methoxyethyl)aminocarbonylmethyl)-pYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 hexynyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)-1 cyclopropylmethyl-N-propylaminocarbonylethyl)-pyrrolidifle-3carboxylic acid; trans, trans-2- Met hoxyp he ny1) (1 be nzodi oxo 1-5-yI1)- 1 -(N-methyl- N-pentylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,Ndilsobutylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4- Methoxyp he ny1)-4- (1,3-be nzodi oxol-5-y1)- 1 (N -met hylI- N- pro py nyl) am inocarbon ylmeth yl)-pyrroidiG -3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (N-methyl- N-(n-hexyl)aminocarbonylmethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-di(nbutyl)ami nocarbonylmethyl)-pyrrolidine-3-carbOXYlic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,Ndiethylaminocarbonylmethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-phenylaminocarbonylmethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-cyclohexylaminocarbonylmethyl)-pyrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-di(n- *pro pyl) ami nocarbon yl methyl) -pyrro lidie-3-carbo xylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yl)-1 -(N-methyl- N-isobutylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-MethoxyPheflY) 4 (l,3-benzodioxol-5-yI)-l butyloxycarbonylmethy)-pyrrolidifle3-carboxyiic acid; trans, trans-2-(4-MethoxypheflY) 4 (l -naphthyl)-1 -(N-methyl-Npropyl)ami nocarbonylmethyl)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4(2,3-di hydrobenzofural-5-yi)-l methyl- N-pro py1) ami no carbo nyl methy) -pyrro lidile-3-carboxyi c acid; trans, trans-2 ,4-Bis(4-me~thoxyphelyl)-1 -(N-methyl-Npropyl)aminocarbonylmethyl)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(3 ,4-dimethoxyphelyl)-1 -(N-methyl- N- pro py 1) ani nocarboflylflmethyt)-pyr roli dife3-carboxy li c acid; trans, trans-2-(4- Methoxypheflyl)-4-(3-methoxyphenyl)l -(N-methyl-Npro pyl)ami nocarbo nyl methyl)-pyrrolidifle-3carboxylic acid; trans, trans-2- (4-Methoxyphefl)-4-(2-flaphthyI)l -(N-methyl-Npropyl)ami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxol-5-y)-1 (ethylsulfiny)ethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxol-5-y)-1 (isopropyIsulfonylamilo)ethy)-pyrrolidifle-3.'carboxylic acid; trans, trans-2-(4-Methoxypheflyl)4(1 ,3-benzodioxol-5-yl)-1 (isobutoxy)ethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(l ,3-benzodioxol-5-yl)-1 (butylsulfonyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l,3-benzodioxol-5-y)-1 met hyl- N-i sobutyrylami no) ethyl)-pyrrolidifnle-3 -carboxyli c acid; trans, trans-2-(4-Methoxyphefl)-4-(l,3-benzodioxol-5-yl)-1 *methyl N -pro pion ylam ino)ethyI)-pyrro lidinle-3-carboxyli c acid; trans, trans-2-(4-MethoxyPhelyl)- 4 ,3-be nzodioxol-5-yl)- 1 -(N-methyl- N-benzylaminocarboflylmethyl)-pyrrolidifle-3-carboxylic acid; trans, trans-2-(4-MethoxypheflYl)- 4 ,3-benzodioxol-5-y)-1 -(N-ethyl-Nbutylami nocarbonylmethyl) -PYrrolidifle-3carboxylic acid; trans, trans-2-(4-Methoxypheflyl)- 4 -(l,3-benzodioxol-5-yI)-1 -(N-methyl- N-(2 ,2-di methylpropyl)amilocarboflYlmethyl)-PYrrolidine- 3 carboxylic acid; -26trans, trans-2-(4-Methoxyphefl) 4 3-benzodioxol-5-yI)-1 methyl-N-butylsu Ifonylami no)ethy)-pyrrolidifle-3-carboxyic acid; trans, trans-2- (4-Meth oxyPhenly) 4 (l,3-be nzodioxo 1-5-yi)- 1 (N methy-N-propylsufolamli no)ethy)-pyrroidifle-3-arboxylic acid; trans, trans-2-(4-MethoxyphelY) 4 (l,3-benzodioxot-5-yI)-1 (propylsulfonyI)ethyl)-pyrrolidifle-3carboxylic acid; trans, trans- 2- Met hoxyphe nyl)-4- (1 ,3-be nzodioxo 1-5 -yt) -1 methylhex-2-enyl)-pyrrolidile-3-carboxylic acid; trans, trans- 2- (4-Met hoxyphenflY) 4 (l,3-be nzodioxoI1-5- yl)- 1 -N (trans- 3 ,5-di methyIhex-2-enyI)-pyrrolidile-3-carboxylic acid; trans, trans-2- (4-methoxypheflyl)-4-( 1,3-benzodioxol-5-yI)-1 hepty Icarbo ny Imet hyl)- pyrro li di ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphefl)- 4 (l,3-be nzodioxol-5-yI)-l (vale rylmethy)-pyrrolidifle-3-carbOXYic acid; trans, trans-2-(4-MethoxypheflY) 4 (l,3-benzodioxol-5-yI)-1 ,4di methoxybenzy)-N-methylamilocarbonylmethyI)pyrrolidine- 3 carboxylic acid; trans, trans-2-(4-MethoxypheflY) 4 (l,3.benzodioxol-5-yI)-1 ,4dimethoxybenzyl)amilocarboflylmethyl)pyrroidine 3 carboxylic acid; (2R,3R,4S)-2-(4-Methoxyphel) 4 ,3-benzodioxol-5-y)-1 R)-1 (N ,N-dipropylami nocarbonyl)-l -butyI)pyrrOlidifle-3-carboxylic acid; o. o 25 (2S,3S,4R)-2-(4-Methoxyphefl)- 4 ,3-benzodioxol-5-y)-1 R)-1 (N ,N-dipropylaminocarboflYl)-l -butyl)pyrrolidifle-3-carboxyic acid; o' (2S ,3S ,4R)-2-(4-Methoxyphefl)-4-( 1,3-benzodioxoI-5-yl)-1 S)-1 (N ,N-dipropylamiflocarbol)-l -butyl)pyrrolidine-3-Carboxylic acid, oo*e (2R ,3 R,4S)-2- (4-Methoxypheflyl)-4-(l ,3-benzodioxol-5-yi)-1
S)-H
.oo~o:(N ,N-dipropylamiflocarbol)-l -butyl)pyrrolidine-3-carboxylic acid; -27trans,trans-2-(4-MethoxyphelY) 4 -(l,3-benzodioxol-5-yI)-1 ,N-di(ntrans, trans-2- Fluo ropheflyl)Adl -ben zodioxol1-5-yl)- 1 ,N-di(nbutyl)aminocarbonylmethYl)PYrrolidi ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)- 1 ,N-di (nbutyl)aminomethylcarbolyl)pyrrolidifle3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)- 4 (1,3-be nzodioxol1-5-yI)- 1 -(N-n-butyl)- N-(n-propyl)aminocarbolyflmethyl)pyrrotidile-3-carboxylic acid; trans, trans-2- Met hoxypheflyl)- 4 (l,3-be nzodi oxOl-5-yl1) -1 ,Ndi pro pyl)ami nocarbon yl)eth yl]py rro i dile-3-carboxyli c acid; trans,trans-2-(4-Methoxypheflyl)- 4 ,3-benzodioxol-5-y)-1 ,N-di(nbutyl)aminocarbonyl)pyrrolidile-3-carboxylic acid; trans, trans-2- (4-Methoxypheflyl)-4-(l ,3-benzodi oxol-5-yl)-1 ,N-di(nbutyl)aminocarbonylmethyl)pyrrolidile-3-carboxylic acid sodium salt; trans, trans-2- (4-Methoxyphefl)-4- (l,3-benzodioxol-5-yl)-1
,N-
di(n-butyl)aminocarbonyl)thy]pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxol1-5-yI)- 1 ,Ndi (n-butyl)ami nocarbonyl)-N-methYlamilo]ethyl)pyrrolidifle- 3 carboxylic acid; trans, trans-2- (4-Methoxypheflyl)-4-(l,3.benzodioxol-5-yl)- 1 ,N-di(nbutyl)ami nocarbonyl) methyl) pyrroIi dife 3
(N-
methanesulfonyl)carboxamide; trans,trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 ,N-di(nbutyl)amino carbonyl)methyl)pyrrolidife 3
(N-
benzenesulfonyl)carboxamihde; trans, trans-2-(4-Methoxypheflyl)- 4 ,3-benzodioxol-5-yl)-1 ,N-di(nbutyl) aminosulfonylmethyll-pyrrolidile-3carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(1 ,3-benzodioxol-5-yI)-1
N-
dibutylamiflo)carbofl- RS)-ethyl]pyrrolidifle-3-carboxylic acid; trans, trans-2- (Pe ntyl)- 4 ,3-be nzodioxo 1-5-yl)- 1 dibutylamino)carbonylm ethyl] pyrro Iidife3-carboxylic acid; trans, trans- 2- (Pentyl)-4- (l,3-be nzodioxo 1 -[2-(N-propyl-Npro pylsuIto ny lahi no)et hyI]pyrro lid ine-3 -carboxylic acid; -28trans, trans-2-(PropyI)- 4 ,3-benzodioxoI-5-yi):l
,N-
dibutylamino)carboflylmethYl]pyrroidine-3carboxylic acid; trans, trans-2-(4-MethoxyphelY) 4 1 ,3-benzodioxol-5-yl)-l (tertbutyloxycarbolyl-ami nocarbonylmethyl)-pyrroidifl63-carboxylic acid; trans, trans-2-(4-Methoxyphenfl)- 4 -O ,3-benzodioxol-5-yl)-1 pro pyl- N buty rylami no)eth yUpyrro lidi ne3 carboxy i acid; trans, trans- 2-(4-Methoxyphefnl)- 4 ,3-benzodioxo1-5'Yl)- 1 (Npropyl-N-(ethyamilocarbofl)amino)ethylUpyrrolidi ne-3carboxylic acid; trans, trans- 2- Met hoxyphefnlY) 4 ,3-be nzod ioxol-5-Y)l -[2-(N-butyl- N-butyrylamino)ethyl]pyrrl'Oidifle3-carboxylic acid; trans, trans- 2-(4-Methoxyphefnly) 4 (l ,3-benzodioxol-5-yl)- 1 pro py I-N- eth oxycarbo nlamino) ethyl]pyrroi di ne 3 carboxylic acid; trans, trans-2-(4-Methoxyphefl)- 4 ,3-benzodioxol-5-yI)- 1 methyl-N-(2-ethylbutyryl)amiflo)ethyl]pyrroidine- 3 -carboxylic acid; trans'. trgns-2-(4-MethoxyphelY) 4 (l,3-benzodioxol-5-yt)- 1 methy-N-(2-propylvaleryl)ami no)ethyllpyrrolidifle3-carboxyic acid; trans, tra ns- 2- Met hoxyphefnlY) 4 ben zo dioxo1-5-yI1)- 1 (N pro py I-N- (te rt-butyloxycarbo n lYmethy)ami no) ethyl] pyrro idin e- 3 carboxytic acid; trans, trans- 2-(4-Methoxyphefnl)- 4 ben zo dioxoI- 5-yl)-l1 .propyl-N-(n-propyl amiflocarbonylmethyl)amino)ethyI]pyrrolidine- 3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)- 4 -O ,3-benzodioxol-5-yI)-1 pr opyl-N-( 4 -methoxyphefloxycarbony)amino)ethyl]pyrroidine- 3 carboxylic acid; trans, trans-2-(4-MethoxypheflY) 4 (l,3-benzodioxol-5-yI)-1 propy-N-(4-methoxybeflzoyl)amino)ethyl]pyrroidine- 3 *carboxylic acid; -29trans, trans-2- Met hoxyphefnl)- 4 ben zodioxoI- 5-yi)- 1 propyI-N-benzoylamilo)ethyI]pyrrolidi ne-3-carboxyliC acid; trans, trans- 2- (4-MethoxyphelyI1)-4- (1 ben zodioxoI- 5-yI1)- 1 (N propyI-N-benzyIoxycarbolamio)ethylUpyrrolidi ne-3-carboxylic acid; trans, trans- 2- Met ho xyphenl)-4- (1 be nzodioxoI- 5-yI1)- 1 (N propyI-N-(4-methoxybenzyoxycarbofl)ami no)ethyl]pyrrolidi ne- 3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4-(1 ,3-benzodioxol-5-yl)-1 -(2-(N-butyt- N-ethoxycarbonylami no)ethy]pyrrolidine-3-carboxyic acid; trans, trans-2-(4-Methoxyphel)-4-(1 ,3-benzodioxol-5-y)-1 -[2-(N-butyl- N-propoxycarbonlyaino) ethy] pyrro lidi ne-3-carboxylic acid;) trans, trans-2-(4-Methoxyphefl)-4-(1 ,3-benzodioxoI-5-yi)-1 pro pyI-N-propoxycarbonylam ino)ethylUpyrrolidi ne3carboxylic acid; trans, trans-i -(NN-Di(n-buty)aminocarbofl)methyI- 2 4 -di (1 ,3benzodioxo-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i -(-N(-uy)Npoysloyaioehl--4 methoxyphenyl)-4-(1 ,4-benzodioxan-6-yI)pyrrolidifle-3carboxylic acid; trans, trans-i ,N-Di(n-butyl)ami nocarbonylmethyl)-2-(4methoxyphe nyl)-4-( 1,3-benzodioxo-5-y)pyrrolidi ne-3-carboxylic acid; trans, trans-i -(2-(N-Propy-N-propyisu Ifonyiamino)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxoI5-y)pyrrolidifle-3-carboxyic acid; trans,trafls-1 -(2-(N-Buty-N-butylsulfonylamino)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxoI-5-yl)pyrrolidifle-3-carboxylic acid; 30 trans, trans-i ,N-Dibutylaminocarboflmethyl)- 2 4 methoxymeth oxyphely 1) -4-(l1,3 -ben zodioxo 1-5 -y)pyrro lid ine-3 carboxylic acid; trans, trans-i N -D ibutylami nocarbo nyl met hyl)-2-( 4 hydroxypheflyl)-4-(l ,3-be nzodioxo l-5-yl)pyrrolidifle-3-carboxylic acid hydrochloride salt; trans, trans-i -(-NIoutlNpoylu nlmno)ethyl)-2-(4methoxypheflyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidifle3-carboxylic acid; trans,trans-1 -(-NBneeufnlNpoyaioehl--4 methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)pyrrolidifle3-carboxytic acid; trans, trans-i (4-Methoxybelzelesulofnl)-N-pro pyami no) ethyl)- 2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl) pyrrolidine-3carboxylic acid; trans, trans-i ,N-Di(n-butyl)ami nocarbonylmethyl)-2-( 2 methoxyethoxy-4-methoxyPhelt)- 4 yl)pyrrolidine-3-carboxylic acid; trans,trans- 1 (N-P ropyl-N-(2 ,4-dimethylbenzelesulfoflYl)aliflo)ethyl)-2-(4-methoxypheflyl)- 4 -(l,3-benzodioxol-5-yI)PYrrolidi ne- 3- carboxylic acid; trans,trans- 1 ropyl-N-(3-chloropropylsulflyl)amiflo)ethyl) 2 4 methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidifle3-carboxylic acid; trans, trans-i1 (N -P r opyl-N-(2-methoxyethyIsulfoflyl)amiflo)ethyl) 2 4 methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; 25 trans, trans-i -(2-(N-Propyl-N-(2-ethoxyethylsu lfonyl)amino)ethyl)-2-(4methoxypheflyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidifle3-carboxylic acid; :trans, trans- 1 (N -P ropy I-N- (5-d imethylamifno-1 30naphthyisulfonyl)amiflo)ethyl)2-4methoxyphenyI) 4 d( 1 3benzodioxol-5-yl)pyrrolidifle-3carboxylic acid; trans, trans-i 1 (2-(N-Propyl-N-(ethylsulfoflyl)amiflo)ethyl) 2 4 methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidifle-3-carboxylic acid: 31trans, trans-i P ropyI N- (4m ethy lbelzeflesu Io nyl)amino) ethyl)- 2 (4-methoxypheflyl)-4-(l 3 carboxylic acid; trans, trans-i1 ,N-Di(nbuty)aminocarboflYmethy)2-(3pyridy) 4 benzodioxoI-5-yI)pyrrolidifle-3-carboxylic acid; trans, trans-i -(-NPoy--n-uysloy mno)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxo-5-yI)pyrrolidifl93-carboxylic acid; trans, trans-i -(-NPoylN(-hoIbneeufonyl)ami no)ethyl)-2- (4-methoxyphelyl)-4-(1 3 carboxylic acid; trans, trans-i1 P ropyl-N-(be nzylsu If onyl)ami no)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxo-5-yI)pyrrolidile-3-carboxylic acid; trans,trans-1 Propyl-N-(4-f Iuorobehnelfonyl)amino)ethyt)-2- (4-methoxyphelyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidifle- 3 carboxylic acid; trans,trans-1 -(N-Methyl-NpropyamiflocarboflYmethyl)- 2 4 methoxypheny)-4-(4-belzofuraflY)pyrroidine3carboxylic acid; trans, trans-i (N-M ethyl- N-propylamiflocarbofnl methyl)- 2 4 methoxyphel)-4-(6-belzofuraflY)pyrroidine3-carboxylic acid; trans,trans-1 -(N-MethyI-N-propylamiflocarboflYmethyl) 2 4 methoxyphefl)-4-(6-belzo-2,3-dihydrofurany)pyrrolidi ne-3carboxylic acid; trans, trans-i Dibutylaminocarboflmethyt)-2-(4-methoxyphenyl)- 4-(4-be nzof uranyl) pyrrolidi ne-3-carboxylic acid; trans,trans-1 DibutylaminocarboflYlmethYl)2(4-methoxYPhenYl)- 4-(4-benzofuralyl) pyrrolidi ne-3-carboxyli c acid; ***trans,trans-1 -(N,N-DibutyaminocarboflYmethy)2(4-methoxyphenyI)- 4-(6-be nzof uranyt)pyrrolidi ne-3-carboxylic acid; trans, trans-i -(N,N-DibutyaminocarboflYmethyl)2(4-methoxyphenyl)- 4 6 -benzo-2,3-dihydroiuraflyrrolidine 3 carboxylic acid; trans,trans- 1 Methyl- N propy am iflocarbofnlY methyl) 2 4 met ho xyph eny)-4- (5-ifldaly 1) pyrro lidi ne 3 -carboxyli c acid; -32trans, trans-i -(N-Methyl-N-propylami nocarbonylmethyl)-2-(4methoxypheny)-4-(6-illY)pyrrolidi ne-3-carboxylic acid; trans, trans-i 1 (N-MethyI-N-propylamiflocarboflYmethy) 2 4 methoxyphenyl)-4-(3 ,4-difluorophelyrrolidile-3-carboxylic acid; trans, trans-i 1 (N-Methyl-N-propylamiflocarboflYmethy)- 2 4 met hoxypheny)-4-(p hel) pyrroli dife3-carboxyli c acid; trans, trans-i 1 (N-Methyl.N-propylamiflocarboflmethyl).
2 -4 methoxypheny)4(4hydroxyphelyI)pyrrolidi ne-3-carboxylic acid; trans, trans-i 1 (N-Methyt-N-propylamiflocarboflYmethyl)- 2 4 rnethoxyphenyl)-4-(2 ,4-dimethoxyphel)pyrrolidile-3-carboxyic acid; trans, trans-i ,N-DibutytaminocarboflmethyI)-2-(4-methoxyphel)- 4-(5-benzo2,3dihydrofural)pyrroidile-3-carboxylic acid; trans, trans-i1 ,N-Di butytami nocarbofnlmethyI)-2- (4-methoxyphenyl)- 4-(4-methoxypheny)pyrroidile-3-carboxyic acid; trans, trans-i1 ,NDibutylami nocarbolyl methyl)-2- (4-methoxyphel)tans.4-(3 ,4-difluoropheny)pyrroidile-3-carboxyic acid; tanstrans-i1 ,NDibutylami nocarboflmethyI)-2- (4-methoxyphenyl)- 4-(2 ,4-dimethoxyphel)pyrrolidifle-3-carboxyic acid; trans, trans-1 ,N-Dibutyami no carboly Im et hy)-2-phef lYI 4 -(i13benzodioxo-5-y)pyrrolidifle-3-carboxylic acid; trans. trans-i ,N-Dibutylaminocarboflmethyl)-2-phefl-4-(5-benzo- 2,3-dihydrofurany)pyrroidile-3-carboxyic acid; trans. trans-i ,N-DibutylaminocarboflyimethyI)-2-(4-tbutyIphe nyl)-4- (5-benzo-2,3-dihydrofurafl)pyrrolidife3carboxylic acid; :'**trans, trans-2-(N,N- DibutyamiflocarbofylYmethy)2(4-methoxyphenyI)- 4-(4-fluoropheny)pyrroidil6-3-carboxyic acid; trans, trans-i ,N-Dibutylaminocarboflmlethyl)-2-(3-fury) 4 -(i13benzodioxol-5-yl)pyrrolidifle-3carboxylic acid; trans, trans-1 -(N,N-Dibutylamiflocarboflmethyt)-2-(isopropy) 4 -(i13benzodioxo-5-yI)pyrrolidifle-3carboxylic acid; -33trans, trans-i ,N-DibutylaminocarbonyIrnethyI)-2-(4-t-butyIPhefl)4- (1 ,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; trans, trans-i1 N- Di butylam inocarbo nylmethyl)-2-(4-t-butyIphelyl)- 4 (5-benzo-2,3-di hydrofuranyl)pyrrolidile-3-carboxyliC acid; trans, trans-i ,N-Dibutylaminocarbonylmethyl)-2-(alti- 4 methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidifle-3carboxylic acid; trans, trans-i ,N-Dibutylaminocarbonylmethy)-2-(syfl-47 methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidine-3carboxylic acid; trans, trans-i (N,N-Dibutylaminocarbonylmethyl)-2,4-di (5-benzo-2,3di hydrofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 ,N-Dibutylami nocarbonylmethyl)-2- (3-f 2,3-dihydrofu ranyl)pyrrotidine-3-carboxylic acid; trans, trans-i1 Dibutylami nocarbonylmethyl)-2-(4-methoxyphelYl)- 4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-i Dibutylami nocarbonylmethyl)-2-(4-methoxyphelyl)- 4-(3-pyridyl)pyrrolidine-3-carboxylic acid; trans,trans- 1 ,N-Dibutylaminocarbonylmethyl)-2-(2-fluorophefl)-4- (1 ,3-benzodioxol-5-y)pyrrolidile-3-carboxylic acid; 0 trans,trans-i ,N-Dibutylaminocarbonylmethyl)-2-(3-fIuorophel)-4- (1 ,3-benzodioxol-5-y)pyrrolidile-3-carbOXylic acid; trans. trans-i ,N-Dibutylaminophenyl)-2-(4-methoxyphelyl)-4-(1 ,3benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans,trans-i -(2-N,N-Dibutylaminopyri midi n-4-yi)-2-(4-methoxyphenyl)- 4-(1 ,3-benzodioxol-5-yl)pyrrolidile-3-carboxylic acid; *trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (p ropylaminocarbonylmethyl)-piPeridile-4-carboxylic acid; ****trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 ''30 (aminocarbonymhethyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)- 1 09999*fluorobenzyl)-piperidine-4-carboxylic acid; O 9 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)-1 eth oxyethyl) -piperidine-4-carboxylic acid; -34trans, trans-3-(4-Methoxyphefl)-5-( I,3-benzodioxol-5-yI)- 1 propoxyethyl)-piperidile-4-carboxylic acid; trans, trans-3- Met hoxyp he nyl)-5- (1 ,3-be nzod io xo 1-5-y 1 (2methoxyethoxy)ethyl]-piperidile-4-carboxyic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)- 1 pyridyl)ethyl]-piperidine-4-carboxyic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-be nzodioxol-5-yI)-1 (mo rpholi n-4-ylcarbonyl)- pipe ridile-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5- (1 ,3-benzodioxole-5-yI)- 1 (butytaminocarbonyl)-piperidi ne-4-carboxylic acid; trans, trans-3- Meth oxyp hen yl)-5 ben zodioxo1-5-yI1)- 1 (4met hoxyp he nylami n ocarbonyl)-3-pi pe ridi ne-4-carboxYic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-be nzodioxol-5-yI)-1 acetylpiperidine-3-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yI)- 1 -(2-furoyt)piperidine-3-carboxylic acid; trans, trans-3-(4-Methoxyphelyl)-5-(1 ,3-benzodioxol-5-yl)-1 (phenylaminocarbonyl)-piperidile-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxo-5-y)-.1 (allylaminocarbonylmethyl)-PiPeridi ne-4-carboxylic acid; :%see ~trans, trans Meth oxyp henyl)-5- (1 ben zodioxo 1-5-yi)- 1 butylaminocarbonylmethyl)-piperidile-4-carboxylic acid; trans~, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 -(N-n-butyl- Nmet hylam inocarbo nylmet hyI)-pi perdile-4-carboxyic acid; 25 trans, trans-3-(4-Methoxypheflyl)-5- (1 ,3-benzodioxol-5-yI)- 1 -(pyrrotidi n- *1 -ytcarbonyImethy)-piperidiO-4-carboxyic acid; trans, trans-3-(4-Methoxyphelyl)-5-(1 ,3-benzodioxol-5-yI)-1 S(i sobutylami nocarbo nyImet hyl)-pi pe ridile-4-carboxyi c acid; trans, trans-3- Methoxyp henlyl)-5- (1 ,3-be nzodioxol-5-yi)- 1 (cyclopentylamilocarboflylmlethyl)-PiPeridifle-4carboxylic acid;, trans, trans-3-(4-Methoxyphefl)-5-(l ,3-benzodioxol-5-y)-1 (mo rpho li n-4-ylan i nocarbonyl mth y) -pipe ridile-4-carboxyti c acid; trans, trans-3-(4-Methoxyphefl)-5-(l,3-benzodioxol-5-yI)-1 phenoxyethy)-piperidile-4-carboxylic acid; trans, trans-3-(4-Methoxyphefl)-5-(l ,3-benzodioxol-5-yi)- 1 methoxyethylami nocarbonylmethyl)-piPeridi ne-4-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (isopropylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (et hy lam i nocarbo nyl meth yl)-pyrrolIid i ne-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 met hylpro pylami nocarboflyIm et hy)-pyrro lidinle-3-carboxy i c acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (phenylaminocarbonylmethy)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4-(1 ,3-benzodioxo-5-y)-1 (piperidi nylcarbonylmethy)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (propyl ami n ocarbo nyl) ethyl) -pyrro li di ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphelyl)-4-(1 ,3-benzodioxo-5-yi)- 1 -(ar- (propylam in ocarbo nyl) bezy)-pyrrolid ie- 3- carboxy i c acid; trans, trans-2- (4-Methoxyphelyl)-4-(1 ,3-be nzodioxol-5-yI)- 1 -(bis- (propy lam i nocarbo ny1) methyl) -pyrroli di ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyph~nfly)-4-(1 ,3-benzodioxol-5-yI)-. 1 (pro py lam in ocarbofnlyt)ethy)-pyrrol idi ne-3-carboxy li c acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)- 1- (propylaminosulfonylmethyl)-pyrrolidile-3-carboxyic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yI)-1 phenethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)-1 (pentanoylmethyl)-pyrroidile-3-carboxyiC acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 (benzoylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(hexyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphe nyl)-4-(1 ,3-be nzodioxol-5-yt)-1 -(2-hexynyl)pyrrolidine-3-carboxylic acid; -36trans, trans-2-(4-Methoxyphefl)-4-(l ,3-benzodioxol-5-yI)-1 (pro poxymet hycarbon yl-pyrro i d ie-3-Carboxy iC acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxo1-5-y)- 1 -(phenacyt)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (anili nylcarbonyl)-pyrrolidine-3-carboxyic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-,enzodioxol-5-y)-1 acetylami noethyl)-pyrrolidile-3-Carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 phenoxyethy)-pyrrolidine-3-carboxyic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-y)-1 benzodioxanymethyl)-pyrrolidile-3-Carboxylic acid;, trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 tetrahydrofuranylmethyl)-pyrrolidile-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (propylami nocarbonylamino)ethenyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (propylaminocarbolylamilo)ethyl)-pyrrolidifle-3carboxyic acid; trans, trans-2- Met hoxyphelyl)-4- (1 ,3-be nzodioxo1-5-yl)- 1 -(3-oxohex- 1 -enyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (2 Di met hoxyph enyl1)-4- (1 ,3-be nzodi oxoI- 5-yI1)- 1 ropy lami nocarbo nyl methyl)- PYrroli di ne-3-carboxy Iic acid; trans, trans-2-(2-Carboxy-4-methoxyphelYl)- 4 ,3-benzodioxol-5-yI)- 1- (propylaminocarboflmethyl)-pyrrolidifle-3carboxytic acid; trans, trans-2-(2-Carboxamido-4-methoxypheflYl) 4 -(l,3-be yI)-l -(propylaminocarbolymethYl)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(2-Methanesuf ofamido-4-methoxyphefl)- 4 ,3be nzodioxol- 5-yI)- 1 (p ropylamni nocarbonyl methyl)- pyrro lidi ne- 3carboxylic acid; trans, trans-2- (2-Carbamoylmethoxy-4methoxyphelY) 4 1 -(propylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; -37trans, trans-2-(2- Methoxyethoxy-4-methoxyphefl) 4 {(,3-benzodioxo
I-
.(propylaminocarboflylmethyl)pyrrolidine3carboxylic acid; trans, trans-2-(2-Carboxymethoxy-4methoxyphenyl) 4 benzodioxol-5-y)-1 (propylaminocarboflylmethYl)-pyrrolidi ne-3carboxylic acid; trans, trn--4Mtoy2ttaoy mehxpey)4(,3be nzodioxol- 1 (pro pylami n ocarbo nyl methYt)-PYrro lidi ne- 3carboxytic acid; trans, trans-2-(2-Ayoxy-4- methoxyphefnl)- 4 1 ,3-beflzodioxo-5yI)-1 (propylaminocarbonyimethy)-pyrrotidifle3-carboxylic acid; trans, trans 2,4-Bis(4-methoxyphel)-1 -(propylamiflocarboflyimethyI)pyrrolidine-3-carboxylic acid; transtrans 2,4-Bis(1 ,3-benzodioxol-5-y)-1 (propylaminocarboflmthyl)-pyrrolidie3-carboxylic acid; trans, trans-2-(4-Methoxyphel)- 4 ,3-benzodioxol-5-yI)-1 -(N-methyl- N-propylaminocarboflmethyl)pyrrolidine3carboxylic acid; trans, trans-2-(4-MethOxyphelyl)-4-(l ,3-benzodioxole-5-yl)-1 -(N-methyl- N-butylaminocarbonyl)pyrrolidile-3carboxylic acid; trans, trans-2-(4-Methoxyphel)-4-(l ,3-benzodioxol-5-yl)-1 -(N-methyl- N-(4-methoxyphenyl)amiflocarboflyl)3-pyrrolidine 3 carboxylic acid; -trans, trans-2-(4-MethoxypheflYl)- 4 ,3-benzodioxol-5-yt)-1 -(N-methyl- N-phenylaminocarboflyl)-pyrrolidife3carboxylic acid; trans, trans-2-(4-Methoxyphefl)- 4 ,3-benzodioxol-5-yl)-1 -(N-methyl- N- al lylami nocarbofly fl ethyl) -pyrrolidife-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)- 4 ,3-benzodioxol-5-YI)-1 -(N-methyl- N-isobutylaminocarboflylmethyl)-pyrrolidife 3 carboxylic acid; trans, trans-2-(4-MethoxypheflYl) 4 (l,3-benzodioxol-5-yl)-1 (N-methyl- N-cyclopefltylamiflocarboflylmethyl)pyrrolidine 3 carboxylic acid; trans, trans-2-(4-Methoxyphefl)-4dl ,3-benzodioxol-5-yl)-1 -(N-methyl- N- met hoxyet hylainlocarboflyl)-pyrroli di ne 3 carboxyui c acid; -36trans, trans-2-(4-Methoxyphefnl)h 4 -(l,3-benzodioxol-5-y)- 1 -(N-methyl- N-butoxyethylaminocarbofl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(l ,3-Benzodioxol-5-yl)-4-(4-me1thoxyphel)- 1 -(N-methyl- N- pro py lam inocarbo nylmethy)- PYrro lidie-3-carboxyli c acid; trans, trans-2-(4- Met ho xyphe ny (1 ,4-be nzo di oxan-6-y1) -1 -(N-methyl- N- propy lam ino carbo ny I rnethy)-pyrroli difle3-carboxyl ic acid; trans, trans-2- Met hoxyphe ny1) ,3-be nzodi oxo1-5-yl)- 1 -(N-methyl- N- iso pro pylami nocarbo nyl methy)- pyrroli dinle-3-carboxy li c acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-be nzodioxol-5-yl)-1 (N-methyl- N-ethylami nocarbonylmethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxot-5-yl)-1 (N-methyl- N-(1 -methylpropyl)ami nocarbonylmethyl)-pyrrolidifle-3carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-be nzodioxol-5-yl)-1 (N-methyl- N-phenylaminocarboflylmethyl)-pyrrolidifle-3carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)-1 methyl-N-propylami nocarbonyl)ethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)- 1 methyl-N-propylaminocarboflyl)belzyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-ethyl-Npro pylami nocarbo ny Imethyl)-pyrroli die-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxole-5-yl)- 1 -(N-ethyl- N-butylami nocarbo nyl)-pyrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-N- (4-methoxypheny)amilocarboflyl)-3-pyrrolidifle3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxo-5-y)-1 -(N-ethyl-Nphenylaminocarboflyl)-pyrrolidifle3-carbOXYlic acid; trans, trans-2-(4-Methoxypheflyl)-4-(l ,3-benzodioxol-5-yl)-1 -(N-ethyl-NallylaminocarbonylmethYl)-PYrrOlidife3carboxYlic acid; trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-ethyl-N- (n-butyl)aminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; -39trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-y)-1 -(N-ethyl-Ni sob utylamnin ocarbo nyl methyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)-1 -(N-ethyl-Ncyclopentylaminocarbo nylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- Meth oxyph eny1)-4- (1 ,3-be nzod ioxo 1-5-y1) -1 (N -ethyl-N methoxyethylaminocarbonyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1 -(N-ethyl-Nbutoxyethylaminocarbonyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1 -(N-ethyl-Npro pylami no carbo nyl met hy1) -pyrrolIidi ne-3- carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4- (1 ,4-benzodioxan-6-yl)- 1 -(N-ethyl-Npro pylami nocarbonyl methyl)-pyrro lidi ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-Nisopropylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyphe ny1)-4- (1 ,3-be nzo di oxoI- 5-yI)- 1 ,Ndiethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-ethyl-N- (1 -methylpropyl)aminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 20 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-Nph enylaminocarbonylm ethyl) -pyrrolidi ne-3-carboxylic acid; :trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-be nzodioxol-5-yl)- 1 -(N-ethyl- N- pro pylami no carbo nylI)ethyl)-pyrro lidi ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(a-(N-ethyl- ~25 N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- *N-isobutylaminocarbonylmethyl)-pyrrolI dine-3-carboxylic acid; trans, trans-2-(4- Met hoxyphe ny1) (1 ,3-be nzodi oxo1-5-y)- 1 (N -methylI- N-cyclohexylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 30 trans, trans-2-(4- Met hoxyphe nyl)-4- (1 ,3-be nzo di oxo1-5-yl)- 1 ,Ndipropylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyp hen yl)-4- (1 ,3-be nzo di oxo1-5-y)- 1 (isobutyloxyethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-MethoxypheflY) 4 O (butylsulfofl)-pyrrolidife3-carboxylic acid; trans, trans-2-(4-MethoxyphelY) 4 -(l,3-benzodioxol-5-YI)-l (isopropytsu Ifonylaminoethy)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-MethoxyphelY) 4 -(l,3-benzodioxol-5-yt)- 1 (ethoxymethylcarboflylmethyl)-PYrrolidine-3carboxYlic acid; trans, trans-2-(4-MethoxypheflY) 4 (l,3-benzodioxol-5-yI)-1 ethylbutyrylmethy)-pyrrolidifle3-carboxylic acid; trans, trans-2-(4-Methoxyphefl)- 4 "(l,3-benzodioxol-5-YI)-1 -(N-methyl- N- (3 ,4-dimethoxybe nzyl)aminocarbonylmethYt)-pyrrolidifle- 3 carboxylic acid; trans, trans-2-(4-MethoxypheflY) 4 (l,3-benzodi oxol-5-yl)-l1 R)-1 methyl-N-propylami nocarbonyl)buty]-pyrrolidile-3carboxylic acid; trans, trans-2-(4-MethoxyphelY)4-(l,3-benzodioxol-5-y)-1 S)-1 methy I-N- pro py lam ilocarboflyl) buty]-pyrroli di ne3carboxyli c acid; trans, trans-2-(4-Methoxyphefl)- 4 -(l,3-benzodioxol-5-yl)-1 i isop ropoxyp ropyl)-py rro lidin e-3 -carboxylic acid; trans, trans-2-(4-Methoxyphel)- 4 ,3-benzodioxol-5-yI)-1 methylhexyl)-pyrrolidipe-3carboxylic acid; trans, trans-2-(4-Methoxypheflyl)4(l,3-benzodioxol-5-yi)-1 2- hexenyl)-pyrrolidifle-3-carboxylic acid; trans, trans-2-(4-MethoxypheflYl)- 4 -(l,3-benzodioxol-5-yl)-1 4- hexenyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-MethoxypheflYl)- 4 -(l,3-benzodioxol-5-yl)-1 dimethyl-2-hexeflyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxypheflyl) 4 -(l,3-benzodioxol-5-yI)-1 methyl-N-isobutyrylamiflo)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Metho~xyphelyl) 4 -(l,3-benzodioxol-5-Yl)-1 -(N-methyl- N-(2 2 -dimethylpropyl)amilocarboflylmethyl)pyrrolidine- 3 carboxylic acid; trans, trans-2-(4-MethoxyphelYl) 4 (l,3-benzod ioxol-5-Yl)-1 -(N-methyl- N-benzylaminocarbonlmethyl)-pyrrolidife3carboxylic acid; -41 trans, trans-2- Met hoxyp he nyl)-4- (5-i ndan yl)- 1 -(N-methyl-Npro pylam inocarbo nyl met hylI)-pyrroIi din e-3-carboxyli c acid; trans, trans-2- Metho xyp he nyl)-4- (2,3-di hyd robe nzofu ran 1 methyl-N-propylaminocarbo nylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyp hen yl)-4- (1 -methylindol-5-yi)-1 -(N-methyl-Npro pylam i no carbonyl methyl) -pyrro lidi ne-3-carboxyl ic acid; trans, trans-2- (4-Methoxyphe nyl)-4-(2- naphthyl)- 1 -(N-methyl-Npropylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyph e nyl)-4- (1 ,3-ben zo dioxolI-5-yt)- 1 -(N-butyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphe nyl)-4- (1 ,2-di met hoxy-4-p hen yl)- 1 methyl-N-propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 -methoxy-3-phenyl)- 1 -(N-methyl- N-propylaminocarbonylmethyl)-pyrrotidine-3-carboxylic acid; trans-trans-2- Met hoxyp henyl1)-4- (1 be nzodi oxol-5-yI)- 1 20[decahydroisoquinolin-2- carbon yl met hyl]-py rro li di ne-3-carboxylic acid; 20trans-trans-2-(4-Methoxyphe nyl)-4-( 1,3-benzodioxol-5-yl)- 1 di methylpipe ridinyl- carbo nyl methyI]- pyrroi di ne-3-carboxy li c acid; trans-trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)-1 -[2-(N-propyl-N-isobutoxycarbonylamino)ethyl]-pyrrolidi ne-3-carboxylic acid trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-l ,2,3 ,4tetrahydroisoquinoli n-2- carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-y)-1 -[2-(N-propyl-N dimethylami nocarbonylamino)ethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (N-propyl-N-(4nitrobenzenesulfonyl)am ino)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4- Met hoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(2-(N-propyl-N-npentanesu lfonylamino)ethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(4-Methoxyphenyl)-4-(1 ,37benzodioxol-5-yl) -1 -(2-(N-propyl-N-(4trifluoromethoxybenze nesu lfonyl)amino)ethyl)-pyrrolidi ne-3-carboxylic acid; -42trans, trans-2- Met hoxyp he ny1) (1 ,3-be nzodioxoI- 5-yl)- 1 (N-propyl- N-(2methyl-2-propenesulfonyl)amino)ethyl)-pyrrolidile-3-carboxyic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 -[2-ethylpipe ridinylcarbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yl)- 1 -(2-(N-propyl-N-(2methylpropanesulfonyl)amio)ethyl)-pyrrolidile-3-carboxyic acid; trans, trans-2-(4- Methoxyph enyl)-4- (1 ,3-benzodioxol-5-yi)- 1 -(2-(N-propyl-Nheptanesu Ifonytamino)ethyl)-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 -[2-(N-propyI-Nethoxycarbonylami no)ethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 -(2-(N-propyl-Nhexanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Ethylphenyl)-4-( 1,3-benzodioxo-5-y)-1 ,N-di (nbutyl)ami nocarbonylmethyl]-pyrro Iidine-3-carboxylic acid; trans-trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N-propyl-N-(2ch Ioroethoxy)carbonylamino)ethyl]-pyrrolidine-3-carboxylic acid; trans-trans-2-(2-Methoxyethyl)-4-(1 ,3-benzodioxol-5-yI)-1 ,N-di (nbutyl)ami no carbo nyl met hyl]-pyrroIi din e-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(2-(N-ethyl-N-npentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 ,Ndicyclohexylamino carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -[2-(N-propyl-N-tertbutoxycarbonylamino)ethyl]-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxy-3-fluorophenyl)-4-( 1,3-benzodioxol-5-yi)-1 N-di (nbutyl)ami no carbo nyl methyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-4- (1 ,3-benzodioxol-5-y)-2-(Propyl)-1 -(2-(N-propylpentanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxol-5-yi)- 1 -(2-(N-propyl-Ndimethylsulfamoylamino)ethyl)-pyrrolidile-3-carboxylic acid trans-trans-2-(4-Methoxphenyl)-4-( 1,3-benzodioxol-5-yi)- 1 -[2-(N-propyt-N-[4met h oxyphe nyl]suIo nyla mi no) propy]-pyro idie-3-carboxyic acid; trans-trans-2- Met hoxp he nyl) (1,3-be nzodioxoI- 5-yI1) -1 -[2-(N-propyl-Npro pylsu Ifonylamnin o)propyl]-pyrrolidi ne-3-carboxytic acid; -43trans, trans--2-(3- Flu oro-4-methoxyphe nyl)-4-(1 ,3-be nzodioxol-5-yl) 1 pro pyl-N-pe ntanesulIfo nylamni no)ethyl)-pyrro lidi ne-3-carboxylic acid; trans-trans-2-(4- Pyridinyl)-4-(1 ,3-benzodioxol-5-yl)-l1-[N, N-di (n-butyl)ami no carbon yl met hyl]-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N-propyl-Ndiethylaminocarbonylamino)ethyl].pyrrolidine-3-carboxylic acid; trans-trans- 2 -(4-Met hoxyphe nyl)-4- (1 be nzodi oxo1-5-yl1).-1 dimethylpiperidinyl- carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,N-di (sbutyl)ami no carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 Methylphenyl)-N-butylamino carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)- 1 M ethyl phe nyl)- N-butylami no carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-4- (1 ,3-Be nzodioxo 1-5-yl)-2-(be nzyloxymethyl)- 1 dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid; trans, trans-4-(1 ,3-Benzodioxo1-5-yI)-2-(hydroxymethyl)- 1 ,Ndibutylamino)carbonyl)methylpyrrolidine-3-carboxylic acid; trans, trans--4- (1 Ben zodio xol -5-yI1)-2- methyl pro pen amid-3 -yl) -1 Ndibutylamino)carbonyl)methyl)pyrrolidine.3carboxyic acid; trans, trans--4-(1 ,3-Benzodioxol-5-yI)-2-(1 -hyd rox-2-propen-3-y)- 1 :di butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid; trans, trans--4-(1 ,3-Benzodioxol-5-yI)-2-(N-benzylaminomethyl)- 1 ,Ndi buty lami no)carbo ny1) methy1) pyrro lid in e-3-carboxyli c acid; trans, trans--4- (1 3-Be nzodi oxol1-5-yl)-2- (N-acetylI- N-be nzylami n o m et hyl1)- 1 ,N-dibutylamino)carbonyl) methyl)pyrrolidine-3-carboxylic acid; trans, trans--4-(1 ,3-Benzodioxol-5-yl)-2-(ethynyl)-1
,N-
dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid; trans, trans--4-(1 ,3-Benzodioxol-5-yl)-2-(1 -pentynyl)-1 ,Ndibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxphe nyl)-4-(1 ,3-benzodioxol-5-y)-1 dioxopiperidinyl) ethyl}-pyrrolidine-3-carboxylic acid; trans-trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)-1
,N-
diphenylaminocarbonylmethy]- yrrolidine-3-carboxylic acid; -44trans-trans-2-(4-MethoxypheflY) 4 O ,3-benzodiOXOl-5-y)l1
,N-
diisopropylaminocarboflylmethyl]kPYrroldine3carboxylic acid; and trans, trans-2-(3-Fluoro-4-nmethoxypheflY) 4 dl,3-benzodioxOl-5-yl)-1 N-propyl-N-butaflesulfoflylamiflo)ethyl)pyrrolidine3carboxylic acid; or a pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are selected from the group consisting of: trans, trans- 2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethy)-PYrrolidine-3carboxylic acid; trans, trans-2-(4-MethoxyphenYl)-4-(l ,3-benzodioxol-5-yt)-1 pro poxyethy )-py rro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-1 propyl)-N-methylaminocarbonylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-Methoxyphenyl) 4 (l ,3-benzodioxo-5-y)-1 (isobutylaminocarbOnylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-MethoxyphenYl) 4 dl ,3-benzodioxol-5-yl)-1 (cyclopentylaminocarboflylmethYl)-PYrrolidine- 3 -carboxYlic acid; trns tas2(-ehx--ehxmtoyhnl(1,3- 1 (N-methyl-N-butylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; :*trans, trans-2-(4-MethOXyphenyl) 4 (l ,3-benzodioxol-5-yl)-1
,N-
diisoamytaminocarbonylmethyl)-pyrrolidine-3carboxYlic acid; trans, trans-2-(4-Methoxyphenyl)- 4 -(l,3-benzodioxol-5-yI)-1
,N-
.*dipentylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxypheny)4(l,3-benzodioxol-5-yI)-1 ,N-di(2methoxyethy)aminocarbonYlmethYl)-PYrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4{t ,3-benzodioxol-5-y)-1 cyclopropylmethyl-N-propylaminocarbonylmethyl)hpyrrolidineo 3 carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4(l,3-benzodioxol-5-yl)-1
,N-
di iso butylami nocarbo nylmet hyI)-pyrrolidi ne 3 carboxylic acid; trans, trans-2- Met hoxyphelyl1) (1 ,3 -be nzodi oxo1-5-yI1)- 1 -(N-methyl- N-(2-propynyl)aminocarboflyflethyI)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyphe n yl) (1 ,3 -be nzo dioxo 1 -(N-methyl- N-(n-hexyl)ami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 ,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidi ne-3-carboxyl.c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 ,Ndiethylaminocarbonylmethyl)-pyrrolidie-3-carboxyic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-cyclo hexylami nocarbo nylmnethyl) -pyrro lidine-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N,N-di(npropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyt)-4-(1 ,3-be nzodioxol-5-yI)-1 -(N-methyl- N-isobutylaminocarbonylmethyl)-pyrrolidile-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (ethylsulfi nyl)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yt)-1 methyl- N-i sop ropylcarbo nylami no)ethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yl)-1 methyl- N-pro pi onylaio)ethy)- PYrro lidie-3-carboxyi c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- :N-benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-Nbuty lam i nocarbo nyl meth yl) -pyrro lidi ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 methyl- N-pro pylIsulfo nylami no) ethyl) -pyrro lidi ne-3 -carbo xy lic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,4di methoxybe nzyl)-N- met hylami nocarboflylmethyl)pyrroidi ne-3carboxylic acid; -46trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 dimethoxybenzyl)ami nocarbonylmethyl)pyrrolidine-3-carboxylic acid; (2R,3R,4S)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 R)-1 (N ,N-dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid; (2S ,3S ,4R)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 R)-1 (N ,N-dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyp henyl)-4-(1 ,3-benzodioxol-5-y)- 1 ,N-di(nne; trans, trans-2-(4-Fluorophenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 -(N,N-di(nbutyl)aminocarbonylmethyl)pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-.Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-n-butyl)- N-(n-propyl)aminocarbonylmethyl)pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4- Met hoxyp hen yl)-4- (1 ,3-be nzodioxo1-5-y 1 ,Ndi(n-propyl)aminocarbonyl)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,N-di(nbutyl)aminocarbonyl)methyl)pyrrolidine-3-(Nmethanesulfonyl)carboxamide; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,N-di(nbutyl)aminocarbonyl)methyl)pyrrolidine-3-(Nbenzenesu Ifonyl)carboxamide; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yI)-1 dibutylamino)carbonyl-1 RS)-ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(Pentyl)-4-(1 ,3-benzodioxo-5-yI)-1 dibutylamino)carbonylmethyl]pyrrolidine-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 pro pyl-N -butyrylami no)eth yl]pyrroidin e-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yI)- 1 propyI- N- (ethy lam i nocarbo nyl)ami no)ethyl] pyrro lidi ne-3carboxylic acid; trans, trans-2-(4- Met hoxyphe nyl)-4- (1 ,3-be nzod ioxo1-5-y)-1I -[2-(N-butyl- N-butyrylamino)ethyl]pyrrolidine-3-carboxylic acid; -47trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 pro pyI- N-eth oxycarbo nylami no)ethYl]PYrro li di ne-3-carbo xylIic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo 1-5-yI)-l met hyl- N- (2-p ropylva le ry) ami no)ethyl] py rro i di ne-3-carboxy li c acid; trans, trans-2- Methoxyphe ny1) (1 ben zo dioxo I- 5-yl)- 1 propyl-N-(4-methoxyphenoxycarbonyl)amino)ethyllpyrrolidi ne-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)- 1 propyl-N-(4-methoxybe nzoyl)ami no)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2- Met hoxyphe nyl1)-4- (1 ben zo dioxo I- 5-yl) 1 pro pyt-N-benzoylami no)ethyl]pyrrolidi ne-3-carboxyli c acid; trans, trans- 2- (4-Met hoxyp heny1)-4- (1 ben zodioxoI- 5-yI1)- 1 propyl-N-benzyloxycarbonylami no)ethyl]pyrrolidi ne-3-carboxylic acid; -:68 trans, trans-2- Met hoxyphe nyl)-4- (1 ,3-benzodioxol-5-y)-1 -[2-(N-butyl- N-ethoxycarbonylamino)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -[2-(N-butyl- N- pro poxycarbo ny lami no) et hy] pyrro lidi ne-3-carboxyl ic acid; trans, trans- 2- Met hoxyphe nyl1)-4- (1 ,3-be nzo dioxoI- 5-y 1 *pro pyl-N-propo xycarbo nylamni no) ethyl] py rro lid ine- 3-carboxyli c acid; trans, trans-i ,N-Di(n-butyl)aminocarbonyl)methyl-2,4-di (1 ,3benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i Butyl)-N -pro pyl sulIfony lamiflo)ethyl)-2- (4methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; *sea, 30 trans, trans-i ,N-Di(n-butyl)aminocarbonylmethyl)-2-(4methoxyphenyl)-4-( 1,3-benzodioxo-5-y)pyrrolidi ne-3-carboxylic acid; -48trans,trans-1 -(-NPoy--rpluloyaioehl--4 methoxypheflyl)-4-( 1,3-benzodioxoI-5-yl)pyrrolidifle-3-carboxylic acid; trans, trans-i -(-NBtlNbtlutoyaioehl--4 methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidifle-3-carboxylic acid; trans, trans-i ,N-Dibutylami nocarbonylmethyl)-2-( 4 methoxymethoxypheflyl)- 4 ,3-benzodioxol-5-yl)pyrrolidi ne-3carboxylic acid; trans, trans-i ,N-Dibutylaminocarboflylmfethyl)-2-( 4 hydroxyphenyl)-4-(1 ,3-benzodioxol-5-y)pyrrOlidi ne-3-carboxylic acid hydrochloride salt; trans, trans-i lsobutyl-N-propylsulfonylailo)ethYl)-2-( 4 methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)pyrrolidile-3-carboxylic acid; trans, trans-i -(2-(N-Benzenesulfoflyl-N-propylamiflo)ethyl)- 2 4 methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrroidile-3-carboxylic see: acid; :0,09trans, trans-i -(-N(-ehxbneeutnl--rplmn~ty) 2-(4-methoxypheflyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidile-3carboxylic acid; trans. trans-i ,N-Di(n-butyl)amiflocarboflylmethyt)- 2 2 met hoxyethoxy-4-methoxypheflyl) 4 (,3-be 41 yl)pyrrolidine-3-carboxylic acid; trans,trans-1 -(2-(N-Propyl-N-(2 ,4-dimethylbenzenesulfoflYl)amilo)- .*,ethyl)-2-(4-methoxypheflyl)4dl 3-carboxylic acid; trans,trans-1 -(-NPoy--3clrpoylufnlaioehl--4 rethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidifle-3carboxylic acid; trans, trans-i -(-NPoy--2mtoytylufnlaioehl--4 methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidile-3-carboxylic acid; -49trans, trans-i -(2-(N-Propy-N-(2-ethoxyethysulfofl)amiflo)ethy)- 2 (4methoxyphenyl)-4-(l1,3-benzodioxo-5-y)pyrrolidifle-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N- (5-dimethylamino-1 n aphthylsuIfo ny1) ami no)ethyl)-2- met hoxyphefly) 4 benzodioxol-5y)pyrrolidile-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(ethylsulfonyl)ami no)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidile-3-carboxyic acid; trans,trans-1 -(2-(N-Propyl-N-(4-methylbenzelesufofl)amli no)ethyl)-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yt)pyrrolidifle-3carboxylic acid; trans, trans-i ,N-Di(n-butyl)ami nocarbonylmethyl)-2-(3-pyridyI)-4-( 1,3ne-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(n-butylsu Ifonyl)ami no)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidine-3-carboxyic acid; trans,trans-1 -(2-(N-Propyl-N-(4-chlorobelzelesulfoflyl)ami no)ethyl)-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidifle-3- 20 carboxylic acid;' trans, trans-i -(2-(N-Propy-N-(benzyIsutofl)aio)ethyI)-2-( 4 0. methoxyphenyl)-4-( 1,3-benzodioxol-5-y)pyrrolidile-3-carboxylic acid; ~trans, trans-i -(2-(N-PropyI-N-(4-fluorobelzeeleUfofl)amiflo)ethyI)-2- (4.methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidifle-3carboxylic acid; o otrans,trans-1 -(N-Methyl-N-propylailocarboflmlethyl)-2-(4- 0 0methoxyphnyl)-4-(6-benzofurayl)pyrrolidile-3-carboxylic acid; 0 trans, trans-i ,N.Dibutylami nocarbonylmethyl)-2-(4-methoxyphelyl)o 30 4-(4-benzofuranyl)pyrrolidile-3-Carboxylic acid; OV0. trans, trans-i1 N- Dibuty lami nocarbo nyl methyl)-2- m eth oxyphenlY)- 4-(4-be nzofuranyl)pyrrolidi ne- 3-carboxylic acid; trans, trans1-iN,N-Dibutylaminocarbonylmethyl)-2- (4-methoxyphenyl)- S4-(6-benzofuranyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i N- Dibutylami nocarbonylmethyl)-2-(4-methoxyphenyl)- 4-(6-benzo-2,3-dihydrofuranyl)pyrro lidi ne-3-carboxylic acid; trans, trans-i N-Dibutylami nocarbonylmethyl)-2-(4-methoxyphenyl)- 4-(5-benzo-2,3-dihydrofuranyl)pyrro lidi ne-3-carboxylic acid; trans, trans-i1 N- Dibutylami nocarbo nylmethyl)-2- (4-methoxyphenyl)- 4-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 N-Dibutylaminocarbonylmethyl)-2-(4-methoxyphenyl)- 4-(3,4-difluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans- 1 N- Dibutylami nocarbo nylmethyl)-2- (4-methoxyp henyl)- 4-(2 ,4-di methoxyphenyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i N-Dibutylami nocarbonylmethyl)-2-phenyl-4-(1 13be nzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; trans,trans-1 N-Dibutylami nocarbo nylmethyl)-2-phenyl-4- 2,3-di hyd rofu ran yl)pyrro lid in e-3 -carbo xylic acid; trans, trans-i1 N- Di butylamnin ocarbo nylm ethyl)-2-(4-t-butylphe nyl)-4- (5-benzo-2,3-di hydrofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(N ,N-Dibutylami nocarbonylmethyl)-2-(4-methoxyphenyl)- 4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid; trans. trans-i N-Dibutylami nocarbonylmethyl)-2-(3-furyl)-4-( 1,3- .20 benzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; tra ns, trans-i1 N- Di buty lami n ocarbo ny Im ethyl) (i sopropy1) (1 ,3benzodioxo-5:yI)pyrrolidine-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethyl)-2-(4-t-butylphenyl)-4- (1 ,3-benzodioxol-5-y)pyrrolidi ne-3-carboxylic acid; 25 trans, trans-i ,N-Dibutylaminocarbonylmethyl)-2-(4-t-butylphenyl)-4- (5-benzo-2,3-dihydrofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 (N ,N-Dibutylaminocarbonylmethyl)-2-(anti-4methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans, trans-i1 N-Dibutylami nocarbonylmethyl)-2-(syn-4methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans, trans-i N-Dibutylami nocarbonylmethyl)-2 ,4-di (5-benzo-2,3di hydrofu ran yl)pyrro lidi n -3-carboxylic acid; 51 Irans, trans- I -(N,N-Dibutylarninocarbonyimethyl)-2 -furyl)-4-(5 -benzo- -dilhydrofuranyl)pyrrolidine-3-carboxylic acid; 11rans, tr'ans- 1 -(N,N-Dibutylarninocarbon'ylmethy1)-2-(4-i-nethoxypheny1)- 4-(3)-fluorophenyl)pyrrolidine-3-carboxylic acid; ir~ans, itnsY-2-(4-Methoxyphenyl)-4-( I,-3 -benzodioxol-5-yi)- 1 -(N-butyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3 -carboxy lie acid; trany, tracny-i -(N,N-Dibutylarninocarbonylmethy1)-2-(2 -fluorophenyl)-4- (I ,3 -benzodioxol-5-yl)pyrrolidine-3 -carboxylic acid; fracns, trans-I ,N-Dibutylaminocarbonylmethyl)-2-(3 -fluorophenyl)-4- ,3 -benzodioxol-5-yl)pyrrolidine-3 -carboxylic acid; tranis, Irans- I -(N,N-Dibutylaminocarbonylmethyl)-2-(4-ethylphenyl)-4- (I ,'-benizodioxol-5-yl)pyrrolidine-3)-carboxylic acid; trans, trans- 1 -(N,N-Dibuitylaminocarbonylm ethyl)-2-(3 II Uoro-4-mnethoxyphenyl)-4- -benzodioxol-5 -yl)pyrrol i dine-3 -carboxylic acid; Ircins- I-(2-(N-Propyl-N-(n-pentysul foniyl)amino)ethyl)-2-(3 -fluoro-4imet hox yphenyl)-4-(, 1,3 -benzodioxolI- 5 -yl)pyrrolIi dine-3 -carboxy lic acid; (2 R,3 R,4S)-(+)-2-(4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1-(N,Ndi (i-butyl)amiinocarbonylrnethyl)-pyrrolidine-3 -carboxyl ic acid; and t,'anIS, tran/S- I Dibutylarninocarbonylmiethyl)-2-(3 -fluorophenyl)-4- 20 (1 ,3-benzodioxol-5-yl)pyrrolidine-3)-carboxylic acid; or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of., the invention are shown in Schemes 1-XIV.
Scheme I illustrates the general procedure for preparing the compounds when n and im are 0, Z is -CH 2 and W is -CO 2 H. A 13-ketoester 1, where E is loweralkyl or a carboxy protecting group and R, is aryl or heterocyclic, is reacted with a nitro vinyl compound 2, *\,vlere R? is aryl or heterocyclic, in the presence of a base (for example, I ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like.
The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4.
Reduction of 4 (for example, sodiumn cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine I A4 1 comIpouind 5 as a Mixture of cis-cis, trans, trans and cis, trans products. Chromatographic separation removes the cis-cis isomer leaving a m1-ixture of the trans, trans and cis, trans [R:\L1BXX]02364.doc:aak 52 isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, usine sodium ethoxide in ethanol) to give the Irans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R 3 -X (R 3 is RZl-C(0)- or R 6 -S(0) 2 and X is a leaving group such as a halide (Cl is preferred) or X taken together with R 4 or R 6
-S(O)
2 forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, Nhydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, CI, Br or 1) or In X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 6 which is still a mixture of /rans,/rcans and cis,rvians isomers. H-ydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the Irans,trans ester to give a mixture of 1 7 and 8. which are readily separated.
Scheme 11 illustrates a general procedure for preparing the compounds of the invention when n is 1, mi is 0, Z is -CH-2- and W is -COH-l. A substituted benzyl chloride S9 is reacted with a lithio dithiane 10 in an inert solvent such as THI-IF or dimethoxyethane to ,ive the alkylated adduct 11. The anion of compound 11 is formed using a base such n as n-butyllithium and then reacted with RI-Ci-l-X' wherein X' is a leaving group such as a halide or sulfonate to give compound 12. 'The dithiane protecting group is cleaved (for examsple. using a mercuric salt in water) to give the keto compound 13. Reaction of e.t Ikelone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14.
*I I Creatlment of compound 14 \with an activated nitriIle such as trimethylsilyl cyanide S: WI ollwed by a dehydrating agent such as phosphorous oxychlorice provides the isomeric ene nitriles 15. Reduction of the clouble bond (for examp)le. uLsing sodium borohydride) affords the piperidinyl nitrile 16. Hlydrolysis of the nitrile usine hydrochloric acid in the presenice of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (\vwhere I is a carboxy protecting group). Debenzylation by catalytic hydrogenation under u cidic conditions affords the free pipericine compound 18. Compound 18 is further clahorated by the procedures described in Scheme I for compound 5 to give the Final product compound 19.
Scheme Ill illustrates a general procedure for preparing the compounds whe n m and ly n are 0, Z is and W is -COH. B-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an c-haloester 21 (where J is lower alkyl or a I R:\Li 13XX 102364.doc:aak 53 carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or lithium diisopropylamide in an inert solvent such as -TIIF or dimethoxycthane to give diester 22. Treating compound 22 with R;-NHl2 and heating in acetic acid gives the cyclic compound 23. The double bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to give the desired (rans,(rans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,rans carboxylic acid Scheme IV illustrates a general procedure for preparing the compounds when n is 0, i m is 1, Z is and W is -CO2H. The 1rans,runs compound 7, prepared in Scheme 1, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is Cl). Compound 52 is treated with diazomethane to give the diazo ketone 53. Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid 1 )compound 54 or an ester which may be hydrolyzed. Compounds where m is from 2 to 6 so*: canL be obtained by repetition of the above described process.
In Schemes V and VI. A benzoyl acetate 26 is reacted with a nitro vinyl 20 benzodioxolyl compound 27 using 1,8-diazabicyclo5 .4.01undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to ICCreduction of the nitro group to an amine and subsequent cyclization to give the di hVclropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidne compound 30 as a mixture of cis-cis, irans. (uns and ci, 1 tr1ns isomers.
Chbrolliatography separates out the cis-cis isomer. leavine a inixture of the lransra ns and so.* cis, IrIn.s isomers (3 1).
Go Scheme VI illustrates the Fiurther elaboration of the r11ns. 11*1ns isomer. The mixture (31) of irns,rans and cis,lruns pyrrolidines described in Scheme IV is reacted with Npropyl bromoacetamide in acetonitrile in the presence of ethylcliisopropylamine to give 1i the alkylated pyrrolidine compound 32, still as a mixture of Irns,(rans and cis.(rans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the nrns'. rans c0mn)(oundi but leaves the ethyl ester of the ciC,1ns compound untouched, thus allowin separation of the trans. rans carboxylic acid 33 from the cis, rans ester 34.
RA Scheme VII illustrates the preparation of a specific pipericdinyl compound.
S Benzodioxolyl methyl chloride 35 is reacted with lithio dithiane 36 to give the alkylated I R\I113XX 102364.docaak 54 Comp11oLnd 37. Trreatment of compound 37 with 4-niethoxybenzyl chloride in the presence of lithium diisopropylamidc gives Compound 38. Cleavage oF the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 w.ith benzylamine and formaldehyde gIves the keto pipericline 40. Treatml-ent of conmpound 40 with too* I RAI 13XX 102364.doc:aak trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 4a (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48. Treating compound 48 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 5. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid i1.
Scheme IX illustrates the preparation of compounds where n is 0, Z is
-CH
2 and W is other than carboxylic acid. Compound 5, which can be 20 prepared by the procedures described in Scheme IV, is converted (for example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 5Z. Nitrile 5Z under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 5. Alternatively nitrile Z is reacted with hydroxylamine hydrochloride in the presence of a base S'(for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or 30 dimethylacetamide to give amidoxime 59. The amidoxime U is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the -56- O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in cyclization to compound 60. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61.
Scheme X illustrates the preparation of compounds in which R 3 is an acylmethylene group. A carboxylic acid 62 (where R 4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N-dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone 6. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 6 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 6.
Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5, prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is 20 a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 66. Treatment of 6 with an amine (R 2 oNH 2 affords secondary amine Z. This amine (6Z) can be reacted with an activated acyl compound (for example, R 4 and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively 25 amine 67 can be reacted with an activated sulfonyl compound (for example,
R
6 -S(0) 2 -CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69.
Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures 30 such as compound ZQ are known to add to unsaturated esters such as Z1 to provide pyrrolidines such as compound ZZ2 Tsuge, S. Kanemasa, K.
Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S. Kanemasa, T. Yamada, K.
Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O.
Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also -57shown in Scheme XII. Silylimine 7a is reacted with acrylate 24 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine Z5 as a mixture of isomers. This method can be modified to provide the N-acetamido derivatives directly by reacting 7 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound Z6.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 8Q, which can be further elaborated on the pyrrolidine nitrogen.
Intermediate racemic pyrrolidine ester ZZ (for example, prepared by the procedure described in Scheme V) is Boc-nitrogen protected (for example, by treatment with Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 20 Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81.
The use of (-)-cinchonine will give the opposite enantiomer.
25 Scheme XIV describes another procedure for preparation of pyrrolidines.
Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. et.al., J.
Chem. Soc., Perkin Trans. 1, 5:1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R55 is hydrogen or methyl) is condensed with a substituted .o 30 acrylate 8. (wherein R 2 is as described herein and R 56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to -58provide the N-substituted pyrrolidine REl. Standard ester hydrolysis of produces the desired pyrrolidine carboxylic acid.Z.
0000 0.06 -59.
Scheme I 0 Rl C0 2
E
~1
[H]
H
C0 2
E
Mixture of Cis-Cis Trans-Trans Cis-Trans
IX-R
3 /R 3
N
2 E C0 2
E
C0 2
E
4
R
3
R
2 R 60 2
H
Trans-Tranls
R
3 C0 2
E
Ctis-Trans
H
2 01 Mixture of Trans-Trants Cis-Trans Scheme II i S R2,, S 0
R
2
R
Xa
S
R2 Ri N
R
Rl R2 6J02E 17
R
QI ;NR2 Rl
I
ISOMER
Cr N R2 y CN
RI
R3 Nq R2 C0 2
H
0 -61- Scheme '111 Halo 21.
Halo CI, Br, or I J0 2 C R 2 C0 2
E
R
3 C0 2
H
Trans-Trans -62- Scheme IV C0 2
H
0 4%lL KI-1 ~C0 2
H
I H 2
N
2 opR 3 0 CHN 2 -63- ,~Scheme V C 0N 0 2 H 0Et 2 C 3 _O H2I COOEt
H
3 NaCNBH 3 C H 3 COOPt Mixture of Cis-Cis Trans-Trans Cis-Tranis Crmatographic separation 9 *9*9 9*9* 9 Cis-Cis Mixture of Trans-Trans and Cis-Trans -64- Scheme VI
H
0-b 91 -a OCH 3 COOEt Cis-Trans and 21 BrCH 2 CONHC3-1 7 6OOEt Trans-Trans r2NEt COQEt Trans-Trans and Cis-Trans NaOH H 2 0, EtOH 0 K" N HC 3
H
7 H C 3
H
7 a.
a Trans-Trans Cis-Trans a a.
a. a. a a a *aa.
a a Scheme Vil x O Q as Iz 0 OMe 0 N u 0
SC
MeO 3a
I>
N 0
CN
ISOMER
r r OMe OMe -66- Scheme VII cont.
()Yo N 0 r C CN OMe o 41 HN N 0
N
C0 2 Et H::OMe \1 0 a.
N
aCO 2
H
-CN
e -C0 2 Et -67- Scheme VIII 0 C02 C02E H3 E02 r 0 0 0 S ocH 3 r,0 00/
H
rb Trdns-Trar -68- Scheme IX
CO
2
H
(CH
2
)M
CONH
2 a a a. a a a a a a
R
3
N
R2
R
(CH
2 m
HNI
t0 R2' so
(CH
2
)M
CN
I N
R
3
R
2 -0R
H
2 N NQ R3 (0H 2 )m
HN'
I
0 -69- Scheme X
R
4 r OH 0 0
R
4 Y' c Il 0
.CO
2
E
R4
C
2
H
0 S.
S*
S.
S*
S
S
S
S
555*SS Scheme X1
N"
C0 2
E
/R
8
-X
C0 2
E
R
8
-NHR
2 0 R 2 C0 2
E
R- N N
H
C0 2
H
9..
99 99 9 9 9 9 *9*9 9. 9 9* 99 919 *9 99 9 9**9 .9 99 9&
C
9 9 9 0~ /R 6
"S'
P
-71- Scheme XII
CH
2 (COEt
I
CO2Et +8 Me3&., N' OCH3 0 6000 0* #0 a. a a 0000 0S S 09
S.
C S a a. 0*S*
SO
S. 00 0 9
S
0505 0 0*0e
S..
I
*0S0 0 0
OCH
3
OCH
3
BU
2
N
'CO
2 Et -72- Scheme XAII 1. BOC 2 0 2. NaOH, EtOH
H
2 0 9 W± 22 M± Za 1. (+)-cinchanine 2. recrystallize frorri EtOAc/hexane 3. Na 2
CO
3
HOI
EtOH 0C?
U.
W+ 7.2
BU
2
NC(O)CH
2 Br EtNiPr 2
CH
3
CN
W+ 11 -73- SCHEME XIV
R
55 Ph N Oe Me 3 Si.
H
2 Pd(OH) 2
/C
R3, NQ C0 2
R
56 R1 2 N' OC 2
R
56 TEA, CH 2
CI
2 H NQ_ C0 2
R
56 NaOH or LICH EtOH, H 2 0
R
5 N C0 2
R
56
R
3 Br
BU
4 N I or Nal CH 3 CN t
R
3 02 74 Compounds which are useful as intermediates are: (C H 2 1 III iS 0 to 6:; is (a)
(C)
(d) s 0 Or I; -C(0O2-G where G is hydrogen or a carboxy protecting grouIp, P0 3 112, -P(O)(OHl)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)N-R
1 where R 17 is loweralkyl, al kylaminocarbonyl, d ialkylarninocarbonyl.
teti-azolyl, hydroxy.
alkoxy, sI-lfoniamido,
-C(O)NHS(O)
2 1 6, where- RI 6 is loweralkYl, haloalkyl, phenyl or a *006 0000 0 0*eS *0 SO e 5 0 **ea 0 0 0@ S S 54 *5e0 6 a 0000 5*55 00 a S aS 0 *5 @005 0 a *55* @0 0 0 S S 0*
-S(O)
2 N l-lC(O)R 16, HO
INH
x RA\I A BX X]02364.doc:aak HO 0
OH
(p) 0
NH
0 (q) N
NHSO
2
CF
3 and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alke nyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 10 alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyi, cycloalkyl, amninocarbonylalkyl, alkylamninocarbonylalkyl, dialkylamninocarbonylalkyl, amninocarbonylalkenyl, alkylamninocarbonylalkenyl, dialkylaminocarbonylakenyl, ***hydroxyalkenyl, aryl, arytalkoxyalkyl, heterocyclic and -76- (Raa)(Rbb)NRcd- wherein R aa is aryl or aryl alkyl, Rbb is hydrogen or alkanoyl and Rec is alkylene, with the proviso that one of R, and R 2 is other than hydrogen; or a salt thereof; and a compound of the formula: R2 (C X~NH (C 2 m NH W (CH 2 )n
(CH
2 )n W RI ~or w R (IV) (V wherein nis 0ori1; m is 0 to 6; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or aryllkyl,
-CN,
-C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyt, tetrazolyl, 20 hydroxy, (alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R 1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6,
HO
(n) -77- HOD0
OH
(p) 00
NH
H
I 9. (t)H ,o 9**9
NSO
2
CN
u) an
R
1 adR 2 aeineedetyseetd rmhyrgnlwrak0 N- 9.
S a0eyaknl loylyakxcroyakl yrxakl 994f A 10akxakxakN holkxakxakl ylak am n(aroyS) kl aH yaioaroyak 9* 9N dalklamnocrboylaky, ainoarbnyllkeyl hyadRyareinpnenyt r loyalkyec te roc ydrogec and rlkl 78 (KW(RIL)N-RC-wherein is aryl or arylalkyl, Rjj is hydrogen or alkanoyl and R, Is alkylene, with the proviso that one of R, and is other than hydrogen; or a salt thereof.
Disclosed intermediates include compounds of formula (IV) and wherein m i is zero or 1, W is -C0 2 -G wherein G is hydrogen or a carboxy protecting grouIp, I10 and R, and R2 are Uts del'ined above.
ilso disclosed intermediates are comp)oundCs oft formul.a (IV) andI where-inl n and mi are both 0;, W is -C0?-G wherein G is hydrogen or a carboxy protecting group11; and R, is (i) loweralkyl, (ii) cycloalkyl, (1ii) phenyl, (iv) pyridyl, furanyl or (vi) Substituted or unllsubsti kited 4-methoxyphenyl, 4-fluorophenyl, 3- iluorophenyl, 2-171luorophenlyl, 4-methoxymnethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphienyl, 3 -benzodioxoly I, I .4-benizodioxanyl or dihydrobenzoftiranyl wherein the substituent is selected from 13 alkoxy, alkoxyalkoxy and carboxyalkoxy and is 1,3-benzodioxolyl, 1,4-benizodioxanyl, ci hydrobenizofudranyl, 4-rnethoxyphenyl, dimecthoxyphenyl. I-Luorophenyl or diHuor1-ophenlyl.
TFhe following abbreviations are used: Boc f'or tert-bu-tyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1, ,8-diazabi1cyclIo [5.4.O0]1-1ndec- 7-e ne, EDCI for- 0) I-(3 -ci miethylamiinopropyl-'3-etlhylcarbodiimide hydrochloride, EtOAc for ethyl acetate, FLtOl- for ethanol, lIOBt for I -hydroxybenzoti-iazole, EtN for triethylamnine and TFi-IF for Itc t ra hyd ro0 Ilt ra n.
I RA\I I XX 102364.doc:aak -79- Example 1 trans.trans- 2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-l)-1- (oropylaminocarbonvlmethyl)-pvrrolidine-3-carboxvlic acid Example 1A Ethyl 2-(4-methoxvbenzoyl)-4-nitromethyl-3-(1.3-benzcdioxole-5-vyIbutvrate To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2-nitrovinyl)-1,3benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to OC was added 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved.
The solution was stirred without heating for 30 minutes and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI solution.
The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g. of recovered ethyl (4-methoxybenzoyl)acetate.
Example 1B Ethyl 2-(4-methoxvphenyl)-4-(1.3-benzodioxol-5-yl)-4.5-dihydro-3H-vprrole-3carboxviate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (The Raney nickel was washed with ethanol three 30 times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
Example 1C Ethyl 2-(4-methoxvphenvl-4-(1.3-benzodioxol-5-yl)-Dvrrolidine-3-carboxylate) as a mixture of cis-cis: trans.trans: and cis.trans-isomers The compound resulting from Example 1B (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1:2 concentrated HCI in ethanol at such a rate that the color was kept at light yellow-green. After the yellow color persisted without additional HCI, the solution was stirred an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% trans,trans-compound and 34% cis,transcompound. Further elution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.
Example 1D trans. trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 (propvlaminocarbonvlmethvl)-pyrrolidine-3-carboxvlic acid The mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting from Example 1C) (5.72 g, 15.50 mmol), ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by the method of Weaver, W.E. and Whaley, J. Amer. Chem. Soc., 9: 515 (1947), in 30 mL of acetonitrile was heated at 50 OC for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis,trans- ethyl esters.
This mixture was dissolved in a solution of 50 mL of ethanol and 15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and 60 mL of water -81 added. The mixture was extracted with ether to remove the unreacted cis,transethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-1 53 OC.
1 H NMR (CD 3 OD, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.49 'sextet, J 7 Hz, 2H), 2.84 J 16 Hz, 1 2.95-3.20 (in, 4H), 3.20 J 16 Hz, 1 3.34-3.42 (in, 1 3.58-3.66 (in, 1 3.78 3H), 3.88 J 10 Hz, 1 5.92 2H), 6.75 (d,J 8Hz, 1H), 6.86 (dd, J= 8Hz, J =1 Hz, 1H), 6.90 J =9Hz, 2H), 7.02 J =1 Hz, 1 7.40 J =9Hz, 2H).
trans. trans-2-(4-Methoxvphenyl)-4- (1 .3-benzodioxol-5-yfL-1- (ami nocarbo nylm ethyl)-pyrro lid in e-3-carboxylic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 1 220 mng of diisopropylethylamine and 184 mng iodoacetamide were reacted at 45 0 C in 1 mL acetonitrile to give 291 mg of a mixture of 0:00 20 trans,trans- and cis,trans- N-alkylated esters. A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a ~:chloroform extraction was used to remove the unreacted cis,trans- ethyl ester.
The isolation and purification procedures described in Example 1 D were used :to give 134 mg of the title compound. m.p. 246-248 1C. 1 H NMVR (DMVSO-d, 300 MHz) 52.61 J= 16 Hz, 1 2.71 J= 9 Hz, 1 2.90 J 9Hz, 1 H), OV, 2.98 J 16 Hz, 1 H),3.25-3.35 (in, 1 3.45-3.55 (in, 1 3.71 3.75 J 10 Hz, 1 6.00 2 6.81 2 6.90 J 8 Hz, 2 7.10 1 H), 7.17 1 7.34 1 7.38 J 8 Hz, 2H).
3 trans. trans-2-(4-Methoxyphenyl)-4-(1 3-benzodioxol-5-yl)-1 -(4-fluoroben zyl)pvrrolidone-3-carboxvlic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from -82- Example 1 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans,trans- and cis, trans- N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 1 NMR (COCl 3 300 MHz) 8 2.74 J 9 Hz, 1 2.95 J 7 Hz, 1 2.98 J =14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 (in, 1 3.70 J 9 Hz, 1 3.78 J 14, 1 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1 6.77 (dd, J 8 Hz, 1 Hz, 1 6.91 J 9 Hz, 6.94 -7.00 (mn, 3H), 7.20 7.25 1 7.44 J 9 Hz, 2H).
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -(2-ethoxyethyl)pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 1 220 mg of di iso pro pylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for 3 hours (bath temperature at IC) to give 346 mg of a mixture of trans,trans- and cis,trans-esters.
Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 140 mg of the title compound. m.p. 88 90 1 H NMR (COCl 3 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21 -2.32 (in, 1 2.70-2.80 (in, 1 2.85-2,94 (in, 2H), 3.38-3.55 (mn, 6H), 3.67 J 10 Hz, 1 3.79 5.94 2H), 6.72 J= 8 Hz, 1 6.84 (mn, 1 6.84 J 9 Hz, 2H), 7.08 J 1 Hz, 1 7.33 J Hz, 2H).
30 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-ben zodioxol-5-yl)-1 (2-propoxyethyl)pyrrolidine-3-carboxylic acid Using the method described. in Example 1D, 520 mg of the mixture resulting from Example 1 C, 364 mng of diisopropylethylainine, 50 mng potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 TC in 0.5 mL -83acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,transesters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mg of the title compound as an amorphous powder. I NMR (CDCI 3 300 MHz) 5 0.87 J 7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 (in, 1 2.71-2.83 (in, 1 2.92-3.08 (in, 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 (in, 4H), 3.72-3.83 (in, 1 3.76 3H), 5.92 2H), 6.71 J 8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J =9Hz, 2H), 7.07 J 9 Hz, 2H), 7.73 J 9 Hz, 2H).
10Exml6 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxo 1-5-yi)- 1 methoxyethoxy)ethyll-pyrrolid n e-3-carboxylic acid Eampl A Ethyl trans.trans-2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-YI) pvrrolidine-3- To the pure cis,cis-compound resulting from Example 1 C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21 sodium ethoxide in ethanol. T he reaction mixture was ref luxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaQEt was neutralized with HCI in ethanol, and the solution was *too concentrated in vacua. The residue was taken up in toluene and extracted with s*.
:potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).
trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 -12-(2methoxyethoxy)ethyll-pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 250 mng of the compound *0ee resulting from Example 6A, 150 mng of 2-(2-methoxyethoxy)ethyl bromide and 175 mng diisopropyl-ethylainine in 1 mL acetonitrile were heated at 100 0 C for 3 hours to give 229 mng of the trans, trans-este r. A portion (200 mng) was -84hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 1 H NMR (CD 3 OD, 300 MHz) 5 2.9-3.9 13H), 3.81 3H), 4.49 J 10 Hz, 1 5.94 2H), 6.79 J 8 Hz, 1 6.89 (dd, J 8 Hz, 1 Hz, 1H), 7.00 J 9 Hz, 2H), 7.05 J =1 Hz, 1H), 7.49 J 9 Hz, 2H).
Example 7 trans.trans-2-(4-Methoxyohenvl)-4-(1.3-benzodioxol-5-vl)-1 -2-(2-Dvridvl)ethvl- Dvrrolidine-3-carboxvlic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, and stirred at 100 OC for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 202 mg of the title compound as the dihydrate. m.p. 77- 20 80 1 H NMR (CD 3 OD, 300 MHz) 5 2.8- 3.3 6H), 3.55-3.70 2H), 3.76 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1H), 6.80 (dd, J 8 Hz, 1 Hz), 6.85 J 9 Hz, 2H), 6.92 J 1 Hz, 1 7.20 J 9 Hz, 2H), 7.20-7.32 2H), 7.70-7.80 2H), 8.40 J 4 Hz, 1H).
Example 8 t' trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl-1 -(morpholin-4- Sylcarbonvl-pyrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by-the method described in Example 1D to give 288 mg of the title compound.
m.p. 244-246 0 C. 1 H- NMR (DMSO-d6, 300 MHz) 8 2.96 (dd, J 12,Hz, 13 Hz, 1 3.03-3.13 (in, 2H), 3.20-3.30 (in, 3.40-3.60 (in, 5H), 3.74 3H), 3.70- 3.85 (in, 3 5.10 J 10 Hz, 1 5.99 J 1 Hz, 2 6.80-6.90 (in, 2 H), 6.87 J 9 Hz, 7.07 1 7.25 J 9 Hz, 2H-).
trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodivxole-5-yl)-1 (butylaminocarbonyl)-pyrro lidine-3-carboxylic acid To the compound resulting from Example 6A (300 mng) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl isocyanate.
After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacua to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 232 mg of the title compound.
m.p. 220-221 OC. 1 H NMR (DMSO-d6, 300 MHz) 8 0.78 J 7 Hz, 3H), 1.10 (sextet, J 7 Hz, 1.22 (quintet, J 7 Hz, 2H), 2.78-3.05 (in, 3H), 3.40-3.56 (in, 3.74 3H), 3.95-4.05 (in, 1 4.93 J 9 Hz, 1 5.80 broad, J= 7 Hz, 1 5.99 2H), 6.78-6.86 (in, 6.88 J 9 Hz, 7.00 J 1 Hz, 1 7.12 J 9 Hz, 2H).
Example JQ trans, trans-2-(4- Mahoxyphe nyl)-4-(1 .3-be nzodioxol-5-yl)- 1 methoxyphenylaninocarbonyl)-3-pyrrolidi ne-3-carboxvlic acid The compound resulting from Example 6A (300 mg) was treated with 133 mg of 4-inethoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example 1 D to give 279 mg of the title compound. in.p. 185-187 OC. 1 NMR (CDCI 3 300 MHz) 8 3.23 (dd, J 12 Hz, 13 Hz, 1 3.55-3.68 (in, 2H), 3.72 3 3.83 3 4.50-4.65 (in, 1 5.06 J 10 Hz, 1 5.90 1 5.95 1 6.72 J 9 Hz, 6.7-6.8 (mn, 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H-).
Exmple-A -86trans. trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vl)-1 -acetvlpvrrolidine-3carboxvlic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1D to give 211 mg of the title compound. m.p. 248-250 OC.
Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d 6 300 MHz) 5 1.55 and 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28'(dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).
Example 12 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)-1 -(2-furoyl)pyrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example 1D to give 269 mg of the title compound as an amorphous powder. 'H NMR (DMSO-d 6 300 MHz) 6 3.06 (dd, J 12 Hz, 13 25 Hz, 1 3.3-3.6 2H), 4.25 1 5.19 d,J 10Hz, 1H), 6.67.4 8H), 7.8-7.9 1 H).
SExample 13 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1- 30 (phenvlaminocarbonvl)-pyrrolidine-3-carboxvlic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 OC. 1 H NMR (DMSO-d 6 300 MHz) 5 3.03 (dd, 1H), -87- 3.55 (in, 1 3.70 (in, 1 3.72 3H), 4.15 (in, 1 5.13 1 6.00 2H), 6.88 (in, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1 H).
Example 1 trans, trans-2-(4-Methoxypheny)-4-(1 .3-benzodioxol-5-yl-1- (allylami nocarbonylmethyl)-pyrroli dine-3-carboxylic acid[ Using the procedures described in Example 1 the "Stle compound was prepared. m.p. 138-1 40 1 H NMR (ODC1 3 300 MHz) 852.84 1 2.90- 3.10 (dt, 2H), 3.28 1 3.35 (dd, 1 3.62 (in, 1 3.72-3.97 (in, 3H), 3.80.
3H), 5.13 (bd, 2H), 5.50 (in, 1 5.97 6.74-6.97 (in, 5H), 7.38 2H).
Example trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 butylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 0C. 1 H NMR (ODC1 3 300 MHz) 5 0.90 3H), 1.30 (in, 2H), 1.45 (in, 2H), 2.80 1 2.87-3.35 (in, 6H), 3.62 (mn, 1 3.80 3H), 5.97 2H), 6.75-6.92 (in, 5H), 7.28 2H-).
trans. trans-2-(4-Methoxyphenyj)-4- (1 .3-ben zodioxol-5-yl)-1 -(N-(n-pro~yl)-Ninethylaininocarbonylmethyl)-pyrroldi ne-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous'solid. Rotational isomers are seen in the NMR. 1 NMR (ODCd 3 300 MHz) 5 0.73, 0.54 (2t, 3H), 1.49 (in, 2H), 2.80 (dd, 1 2.85 (2s, 3H), 2.95-3.20 (mn, bH), 3.20-3.40 (in, 1 3.40 1 3.60 (in, 1 3.79 3H), 5.93 2H), 6.73 1 6.56 (in, 7.03 (in, 1 7.32 2H).
-88trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(pyrrolidi n-i ylcarbonylmethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (C0013,300 MHz) 8 1.40-1.70 (in, 6H), 2.50 1 3.00 (in, 2H), 3.24-3.43 (in, 51H), 3.60 (in, 2H), 3.73 1 H), 3.80 3H), 5.95 2H), 6.74 1 6.80-6.90 (in, 3H), 7.04 1 7.30 (d, 2H).
10Exml1a trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y)-1 (isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 175-17700C 1 H NMR (CD 3 0D, 300 MHz) 850.87 (dd, 6H), 1.75 (septet, 1 2.85 1 2.90-3.10 (in, 4H), 3.23 1 3.40 (in, I1H), 3.58- 3.67 (rm, 1 3.78 3H), 3.89 1 5.92 2H), 6.76 1 6.86 (dd, 1 H), 6.91 2H), 7.02 1 7.40 2H).
ExampleJq trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yl)-1 (cyclopentylainocarbo nylmethyl)-pyrro lid*ine-3-carboxyli c acid Using the procedures described in Example 1 the title compound was prepared. in.p. 137-139 00. I H NMR (00013,300 MHz) 851.34 (in, 2H), 1.62 (in, 4H), 1.90 (in, 2H), 2.76 1 2.90 1 3.04 (dd, 1 3.22 1 3.28 (dd, 1 3.40 (in, 1 3.80 3H), 4.15 (in, 1 5.97 2H), 6.75-6.95 (in, 5H), 7.27 (in, 2H).
V, trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-yl)- 1 -(morpholi n-4- 30 ylaininocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 NMR (CDCl 3 300 MHz) 8 2.82 1 H), 3.00 (in, 2H), 3.24 (in, 1 3.30-3.52 (in, 4H), 3.52-3.75 (mn, 8H), 3.80 3H), 5.95 2H), 6.75 1 6.84 3H), 7.00 1 7.28 2H).
-89- Exmple21 trans, trans-2-(.4-Methoxyphenyl)-4-(1 .3-be nzodioxol-5-vfl- 1 -(2-QhenoxYethyjL'pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMR (CD 3 OD, 300 MHz) 8 2.82 (in, 1 H), 2.96 (dd, 1 3.13 (in, 1 3.32 (in, 1 3.51-3.70 (mn, 2H), 3.77 3H), 4.00 1 4.07 (mn, 2H), 5.91 2H), 6.72 1 6.80-6.95 (in, 6H), 7.03 1 H), 7.22 (ad, 2H), 7.39 2H).
Example22 trans. trans-2-(4- Methoxyphe nyl)-4-(1 .3-benzodioxol-5-yF- 1 ineth oxyethyl am inocarbonyl met hyl)-pyrrolid' ne- 3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 107-1090 1 C IH NMR (CD 3 OD, 300 MHz) 582.52 1 2.97 2H), 3.21 1 3.38 (in, 1 3.32 3H), 3.44 (in, 4H), 3.62 (in, 1 3.79 3H), 3.86 1 5.93 2H), 6.76 1 6.85 (dd, 1 6.91 2H), 7.01 1 7.38 2H).
Eape2 trans. trans-2-(4-Methoxyphenyl)-4- (1 .3-be nzodioxol-5-yl)-1 -(2-butoxyethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. in.p. 53-55 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.88 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz, 6Hz, 1 H), 2.92 J=1lOHz, 2H), 3.35 J=7Hz, 2H), 3.42-3.56 (mn, 4H), 3.68 J=1lOHz, 1 3.78 3H), 5.94 2H), 6.73 J=8Hz, 1 6.83 J=9Hz, 2H), 6.82- 6.87 (in, 1 7.06 J=2Hz, 1 7.32 J=9Hz, 2H). MS Wne 442 Example24 trans, trans-2-(1 .3-Benzodioxol-5-vl)-4-(4-methoxyphenyl)-1 (propylami nocarbonylmethyl-pyrroli dine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1,3ben zod ioxo l-5-ylcarbo nyl) acetate for ethyl (4-methoxybe nzoyl) acetate and 4- (2-nitrovinyl)anisole for 5-(2-nitrovinyl)-1 ,3-benzodioxol-5yI afforded the title compound. m.p. 97-99 00. I H NMR (CDCI 3 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 J=1l6Hz, 1 2.74 J=1lOHz, 1 2.80-3.10 (in, 4H), 3.26-338 (in, 1 3.53 (in, 1 3.73 3H), 3.80 J=1 0Hz, 2H), 7.80 J=6Hz, 1 MS (DCI/NH3) m/e 441 trans. trans-2-(l .3-Benzodioxol-5-yl)-4-(4-methoxyphelyl)-1 -(2-propoxyethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1,3be nzod ioxol1-5-ylcarbo nyl) acetate for ethyl meth oxybe nzoy1) acetate and 4nitrovinyl)ani sole for 5- nit rovi nyl)- 1 ,3-be nzodioxo1-5yl afforded the title compound. m.p. 67-69 00. I H NMR (ODC1 3 300 MHz) 8 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (in, 1 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45-3.57 (in, 4H), 3.73 (in, 1 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1 H), 6.85 J=8Hz, 3H), 6.98 1 7.37 J=8Hz, 2H). MS (001/NH 3 mWe 428 trans. trans-2-(1 .3-Be nzodioxol-5-yl)-4-(4-inethoxyphenyl)-1 inethoxyethoxy)ethyl)l-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 00. 1H NMR (CD 3 OD, 300 MHz) 5 3.18-3.90 (in, 3.79 3H), 4.57 J=1l0Hz, 1 6.02 2H), 6.91 J=8Hz, I1H), 6.95 J=9Hz, 2H), 7.06 (dd, J=8Hz, 1 7.12 (dd, J=1 Hz, 1 7.37 J=9Hz, 2H).
':MS (DCI/NH 3 m/e 444 .Example 27 trans. trans-2- (1 Be nzo di oxo 1-5-yl) met hoxyphe n yl) -1 -(butoxyethyl)pyrrofidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbromide to alkylate -91 the pyrrolidine nitrogen afforded the title compound. m.p. 54-56 00. 1H NMR (ODC1 3 300 MHz) 8 0.89 J-7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (in, 1 2.74-2.98 (in, 3H), 3.46 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=1l0Hz, 1 3.80 3H), 5.93 (dd, J=6Hz, 1 Hz, 2H), 6.72 (d, J=8Hz, 1 6.74 (dd, J=9Hz, 3H), 6.96 1 7.36 J=9Hz, 2H).
trans. trans-2-(4- Met hoxyphe nyl)-4- 1.4-be nzodioxan 1 (propvylami nocarbonylmethyl)-pyrrolidine-3-carboxvlic acid Using the procedures described in Example 1 and substituting 6-(2nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)- 1,3-benzodioxole afforded the title compound. in.p. 80-81 00. 1 H NMR (ODC1 3 300 MHz) 8 0.89 J-7Hz, 3H), 1.49 (sextet, J=7 Hz, 2H), 2.78 J=1 6Hz, 1 2.92 J=1 0Hz, 1 3.05- 3.43 (in, 5H), 3.24 J=1l6Hz, 1 3.52-3.62 (in, 1 3.80 3H), 3.80 (t, J=1 0Hz, 1 4.27 4H), 6.74-6.93 (mn, 5H), 7.29 J=9Hz, 2H). MS
(DCI/NH
3 m/e 455 tranis. trans-2-(4-M ethoxyphe nyl)-4-(1 .4-be nzodioxan-6-yi)- 1 -(N-methyl-N- 20 propylami nocarbonylmethyfl-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 1, substituting 6-(2nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound. in.p. 74-76 0C. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) 8 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 1 2.85 (2s, 3H), 2.96-3.15 (in, 3H), 3.27-3.42 (mn, 3H), 3.52-3.60 (in, 1 3.75 1 3.78 3H), 4.22 4H), 6.80-6.98 (in, 5H), 7.32 2H). MS
-(DCI/NH
3 m/e 469 -92- Exampl 3 trans, trans-2-(4-Methoxypheflyl)-4-( 1.3-benzodoxol-5-yl)-1 -(N-methyl-Nbutylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMVR. 1 NMR (CD 3 OD, 300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 4H), 3.40 (in, 2H), 3.52 (dd, 1 3.60 (in, 1 3.80 3H), 3.85 (in, 1 5.91 2H), 6.74 1 6.83-6.95 (in, 3H), 7.03 (dd, 1 7.35 (dd, 2H).
Exmple 31 trans. trans-2-(4-Methoxy-2- methoxymethoxypheyl)-4-(1 .3-benzodioxo 1 (N -meth yl-N -butylamnin ocarbo nyl met hyl)-pyrrofidi n e-3-carboxyli c acid Examle31A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(1 pyrrolidi ne-3-carboxylate) Using the procedures described in Examples 1 A and 1 B and substituting ethyl methoxy-2-met hoxyinethoxybe nzoyl) acetate for ethyl (4methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2methoxymethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-4 ,5-di hydro-3 H-pyrrole-3carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in 20 mL of methanol, treated with 500 mng of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with ethyl acetate to afford-the title compound (1.9 g, 63%) as the cis-cis isomer.
Exml 31 B trans, trans-2- (4-Methoxy-2- methoxynethoxyphe nyl-4-(1 .3-benzodioxo 1 -(N-methyl-N-butylam i nocarbonyl met hvl)-pyrrolidine-3-carboxyli c acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mng, 0.23 minol) was then reacted by the prbcedures described in Example 1 D -93substituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, m.p. 65-67 OC. Rotational isomers are seen in the NMR. 1 H NMR (CDCI 3 300 MHz) 5 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40-1.48 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 3H), 3.43-3.65 2H), 3.78 3H), 4.30 J=7Hz, 1 5.09 (q, J=7Hz, 2H), 5.92 2H), 6.55 (dd, J=3Hz, 1H), 6.68 1H), 6.72 1H), 6.85 (2t, J=1 Hz, 1 7.04 J=1 Hz, 1 7.42 (dd, J=3Hz, 1 H).
Example 3 trans. trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vl-1 -(3-ethoxvDropylpyrrolidin-5-one-3-carboxvlic acid Example 32A Ethyl 2-(4-methoxvbenzovl)-3-carbomethoxv-1.3-benzodioxole-5-propionate To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1,3bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added.
20 The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.
Example 32B Ethyl 1 -(3-ethoxvoropyvl-2-(4-methoxvDhenvl-4-(1.3-benzodioxol-5-vyl-4.5dihvdro-5-oxo-1 H-oyrrole-3-carboxvlate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue -94obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg of the title compound.
Example 32C Ethyl 1-(3-ethoxvproDvnl-2-(4-methoxvohenvl)-4-(1.3-benzodioxol-5-yl)pyrrolidin-5-one-3-carboxvlate The compound resulting from Example 32B (300 mg, 0.64 mmol) in mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
Example 32D trans.trans-2-(4-Methoxyvhenvl-4-(l .3-benzodioxol-5-vl)-1-(3-ethoxvDropyl)pyrrolidin-5-one-3-carboxvlic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21% sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue which was washed with ether. The aqueous layer was neutralized with 3 M HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, m.p. 134-140 OC. 1 H NMR (DMSO-d6, 300 MHz) 8 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 1H), 2.93 (dd, J=9Hz, 1 3.25 (t, J=7Hz, 2H), 3.28-3.40 2H), 3.48-3.57 1H), 3.78 3H), 3.88 1H), 4.72 J=10Hz, 1H), 6.02 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 (d, J=8Hz, 2H), 6.98 J=8Hz, 2H), 7.38 J=8Hz, 2H). MS (DCI/NH3) m/e 442
(M+H)
trans, trans-2-(4-Methoxyphenyl)-4- (1 .3-benzodoxol-5-yl)- 1 -(3-methoxybenzylpyrrolodin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3methoxybenzylamnine for 3-ethoxypropylamine afforded the title compound (123 mg, m.p. 150-15200C 1 H NMR (CD 3 0D, 300 MHz) 582.96 (dd, J=8Hz, Hz, 1 3.72 3H), 3.80 3H), 4.06 J=1lOHz, 1 HI, 4.58 J=8Hz, 1 H), 4.92 J=l6Hz, 2H), 5.92 2H), 6.55-6.63 (in, 2H), 6.82 J=8Hz, 4H), 6.94 J=8Hz, 2H), 7.15-7.22 (in, 3H). MS (001/NH 3 m/e 475 trans.trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-vl)-1 .Ndiisoamylaminocarbonylmethyl)-pyrroldine-3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (ODC1 3 300 MHz) 8 0.70 -0.90 (in, 12H), 1.10-1.60 (in, 1 OH), 2.75 J=1l3Hz, 1 2.90-3.10 (in, 4H), 3.15 3.30 (in, 2H), 3.40 J=1 0Hz, 1 3.40 3.52 (in, 3.55 3.62 (in, 1 H), 3.75 J=1 2 Hz, 1 3.79 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=8Hz, 1 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1 7.30 J=9Hz, 2H).
Exmle3 trns trn--4-ehxp enh413b zd dietlmncroymt*)proiie3croyi aci (d 6rn .8-6.884(meH ),ph7y03(,.-b J=2z 1 7.30 d, (N 2N- -96trans, trans-2-(4-Methoxypheyl)- 4 .3-be nzodioxol-5-y)-1 .N-dli( met hoxyet hyl) ami norarbonylmethyl)-pyrrolidi ne-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 0 C. 1 H NMR (CDCI 3 300 MHz) 5 2.82 J=1 3, 1 H), 2.94-3.08 (in, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11 3.73 (d, J=1 0Hz, 1 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Hz, 1 H), 6.80-6.90 (in, 3H), 7.04 J=2Hz, 1 7.30 J=9Hz, 2H).
Exampl 3 trans. trans-2-(4-Methoxyphe nyl)-4-(1 .3-be nzodioxol-5-yl)-l -(2-hexynyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 4, 200 mg. of the pure trans,trans isomer, the compound resulting from Example 6A was reacted with 109 mg of 1 -bromo-2-hexyne, preparedby the method described in* Perkin 1,, 2004 (1987), for 1 hour at 55 0 C, to give 226 mg of the intermediate ester. The ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. 1H NMR (CDC1 3 300 MHz) 1.00 -J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 3.07 (dd, J=1 8Hz, 2Hz, 1 3.15 (dd, J=9Hz, 2Hz, 1 3.26 J=9Hz, 1 3.36 (dd, J 18 Hz, 2Hz, 1 3.47-3.55 (in, 1 3.79 3H), 3.88 (d, J=9Hz, 1 5.95 2H), 6.72 J=8Hz, I1H), 6.80-6.88 3H), 7.03 (d, J=2Hz, 1 7.22 J=9Hz, 2H).
Eape3 trans. trans-2- (4-Methoxyl;heny)-4-(1 .3-be nzodioxol-5-yl)- 1 cyclopropylmethyl-N-propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid The title compound was prepared using the procedures described in ~*Example 1. m.p. 167-169 OC. Rotational isomers were seen in the NMR. 1 H NMR (C~DC 3 300 MHz) 5 -0.1 0.05 0.12-0.25 0.32-0.51 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 1.20-1.55 2.72 J=1 3Hz, 1 H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3.52-3.62 (in, I1H), 3.65-3.73 (2 doublets, J=1lOHz, 2Hz, 1 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (in, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 21H).
-97trans. trans-2-(4-Methoxyphe nyl)-4-(1 .3-be nzodi oxol-5-yl)- 1 Met hyl-Nietylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (CDC1 3 300 MHz) 860.85 J=7Hz, 3H), 1.00-1.08 1.13-1.32 (in), 1.35-1,50 2.72-2.82 (2 doublets, J=1 3Hz, 1 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (mn, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (in, 1 3.72 (2 doublets, 1 3.75 and 3.76 (2 singlets, 3H), 5.92 (2 singlets, 2H), 6.72 J=8Hz, 1 H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 2H).
trans. trans-2-(4-Methoxyphenyll-4-(1 .3-benzodioxol-5-vl)- 1 diisobutylaminoarbonylrnethyl)-pyrrolidi ne-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 1 H NMR (CDC1 3 300 MHz) 860.54 J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1 .60-1 .75 (in, 1 1.90-2.02 (in, 1 H), 2.67 J=1 3Hz, 1 2.70 J=1 3Hz, 1 2.84 (dd, J=6Hz, 15Hz, 1 2.96- 3.06 (in, 2H), 3.20 (dd, J=9Hz, 15Hz, 1 3.35 (dd, J=2Hz, 10OHz, 1 3.44- 3.60 (mn, 4H), 3.70 J=9Hz, 1 3.79 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 0 0 6.72 J=9Hz, 1 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1 7.31 J=9Hz, 2H).
xmle4 *trans. trans-2-(4- Met hoxyphe nyl)-4-(1 .3-benzodioxo 1 -(N-inethyl-N-(2aboymehl)prrldie3-aboym acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (ODC1 3 300 MHz) 6 2.09 and 2.32 (2 triplets, J=2Hz, 1 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (in, 2H), 3.52-3.62 (in, 1 H), 3.78 3H), 4.03 J=1 3Hz,* 1 4.00-4.30 (in, 3H), 5.93 2H), 6.72 (2 doublets, J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 and 7.11 (2 doublets, J 2Hz, 1 7.30 (2 doublets, J=9Hz, 2H).
-98trans. rans-2-(4-Methoxyp he nl)l 4 (1 .3 -benzodioxol-5-yl)- 1 -(N-methyl-N- (n- ,hexyflami nocarbonylmethyl)-yrrolidle-3-carboxylc acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMVR (CDC13, 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50, (in, 8H), 2.72-2.82 (2 doublets, J=1 3Hz, 1 H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (in, 1 3.72 (2 doublets, 1 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 1 H).
trans. trans-2-(4- Methoxyg he nyl)-4-(1 .3-benzodioxol-5-yi)-l .N-di (nbutyflami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 123-125 0 C. I NMR (CDC1 3 300 MHz) 8 0.79 J=7 Hz, 3H), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 81H), 2.74 J=l3Hz, 1 2.90-3.09,(in, 4H), 3.23-3.50 (in, 3H), 3.38 J=1l3Hz, 1 3.52-3.62 1H), 3.75 J=1 0 Hz, 1 3.78 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 J=8Hz, 1 6.81-6.89 3H), 7.03 J=2Hz, 1 7.30 J=9 Hz, 2H). MS (DCIINH3) m/e 511 -Anal calcd for C 29 H38N206: C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Exampl44 ~trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-be nzodioxol-5-yl)-1
N-
diethylaminocarbonylm 'thl)-yrrolidi ne-3-carboxylic acid The title compound was prepared using the procedures described in .~.Example 1. m.p. 132-1 34 0 C. 1 .H NMR (CDCI3, 300 MHz) 8 0.98 J=7Hz, 3H), 1.06 J=7Hz, 3H), 2.78 J=1 3 Hz, 1 2.95-3.20 (in, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1 3.76 J= 12 Hz, 1 3.79 3H), 5.93 2H), 6.72 J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 7.32 J=9Hz, 2H).
-99trans. trans-2-(4-Methoxyohelyl)-4-(1 .3-benzodioxol-5-fl)-1 -(N-m-ethyl-Nphenylaminocarbonylmethyl)-pyrrolidile-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 'H NMR (CD 3 00, 300 MHz) 5 2.75-2.85 (in, 2H), 3.05-3.13 (in, 1 3.18 3H), 3.40-3.58 (in, 2H), 3.78 3H), 3.88 J=1 2Hz, 1 5.92 2H), 6.72 J=8Hz, 1 6.75-6.85 (in, 3H), 7.00- 7.12 (in, 5H), 7.82-7.92 (in, 3H).
Example a trans. trans-2-(4-M ethoxyphe nyl-4-(1 .3-be nzodi oxl-5-yfl)-1 met hyl-N cyclohexylami nocarbonylmethyl'-pyrro lidi ne-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (CD 3 00, 300 MHz) 5 1.00-1.85 (mn, 1 OH), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, J=1l2Hz, 1 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=1lOHz, 1 3.77 and 3.78 (2 singlets, 3H), 5.92 2H), 6.72 (2 doublets, J=8Hz, 1 6.82-6.88 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.30-7.40 (2 doublets, J=9Hz, 2H).
p2ropyl)ami nocarbonylinethyl)-pyrroIi dine-3-carboxylic acid Thetilecompound was prepared using the procedures described in Example 1. m.p. 170-172 I H NIMR (CDC1 3 300 MHz) 850.69 J=7Hz, 3H,0.85 J=7Hz, 3H), 1.20-1.55 (mn, 4H), 2.72 J=1l3Hz, 1 2.90-3.10 (in, 4H), 3.25-3.47 (in, 4H), 3.35-3.62 (mn, 1 3.72 J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 1 6.80-6.90 (mn, 3H), 7.02 J=2Hz, 1 H), 7.30 J=9Hz, 2H).
Exml 4.
-100trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl)-1 -(N-methyl-Nisobutvlaminocarbonvlmethyl-pyrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (CD 3 OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (m, 1H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 4H), 3.10-3.65 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=1OHz, 1 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 3H), 7.02 (2 doublets, J=2Hz, 1 7.80-7.90 (2 doublets, J=9Hz, 2H).
Example 49 Alternate Prepration of Ethyl 2-(4-methoxvbenzovl-4-nitromethvl-3-(1.3-benzodioxole-5-yl)butyrate Example 49A E-2-(3.4-Methvlenedioxyphenyl-1 -nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol (120 mL) at 10 OC was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while maintaining the temperature between 10-15 OC. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below 5 OC, until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4- 30 methylenedioxy)-nitrostyrene as yellow needles (53 g, 1H NMR (300MHz, CDCI) 8 7.94 (1H, d, J=13.5Hz), 7.47 (1H, d, J=13.5Hz), 7.09 (1H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, MS
(DCI/NH
3 m/e 194 (M+H) 211 (M+H+NH 3 -101- Ethyl 2 4 -methoxyphefyl)oxo-4nitrp-3(3.4meth-lenetixyohenvl)butyrat To a stirred solution of the nitrostyrefle resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 ml-) and tetrahydrofuran (175 ml) at room temperature was added successively a solution of ethyl methoxybe nzoyl) acetate (11.5 g, 51.7 mmol) in THF (50 ml-) followed by 1 ,8-diazabicyclo[5,4,]undec- 7 ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1'hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel,_eluting with ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents were remov ed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR. 1 H NMR (300 MHz, CDC13,) 5 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H1, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1 H, dd, J=9Hz,3Hz), 6.73 (1 H, d, J=9Hz), 6.65 (1 H, d, J=3Hz), 5.95 (2H, 5.89 (1 H, d, J=4H1z), 5.88 (1 H, d, J=4Hz), 4.90-4.60 (3H, in), 4.39 (1 H, in), 4.18 (2H, q, J=7Hz), 3.94 mn), 3.80 (3H, 3.78 s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) mn/e 416 433 (M+H+NH3)+.
tn. rn2(4MtOyhnl--(1 .3-enzodiox~o1-5-yl)- (tb-utyloxycarbon lmethyj))Pvrro lidine-3-carboxylic acid To a stirred solution of the compound resulting from Example 1 C (100 mg, 0.27 iniol) in acetonitrile (2 ml-) was added successively diisopropylethylalmne (70 i±L, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 30 0.29 iniol,'1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester. To a stirred solution of the diester In ethanol (1 inL) at room temperature was added 50% w/w sodium hydroxide (300 ing, 3.75min01) in water. The mixture was stirred 2 hours, then the volatiles, were removed in vacua. The residue was dissolved in water (5 mL), -102and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 and then extracted with ethyl acetate The combined organic extracts were dried (Na2SO4), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid. I NMR (300 MHz, CDC1 3 5 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90 (1 H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=BHz), 6.76 (1 H, d, J=8Hz), 5.96 (2H, 3.96 (1 H, d, J=9Hz), 3.81 (3H, 3.58 (1 H, ddd, J=1 2, 1lOHz,3Hz), 3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=1 7Hz), 3.05 (1 H, t, J=1 0Hz), 2.92 (1 H, dd, J=9Hz,7Hz), 2.83 (1 H, d, J=1l7Hz). MS (DCI/NH 3 m/e 456 Anal calc for C 29
H
29 N0 7 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
trans. trans-2 -(4-Met hoxyphenyl)-4.(1 -naphthyl)-1 -(N-methyl-Npropyl)ami nocarbo nyl methyl)-pyrro 1idin e-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene-1 -carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC1 3 8 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1 H, d, J=BHz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 dd, J=9Hz,2Hz), 4.50 (1 H, in), 3.94 (1 H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 (1 H, in), 3.49 (1 H, J=1 4Hz), 3.40-2.93 in), 2.91, 2.83 (3H, 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz).
MS (DCI/NH 3 m/e 461 Anal calcd for C 29
H
29 N0 7 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: C, 70.95; H, 7.00; N, 5.46.
Example :*.trans, trans-2 -(4-Met hoxyp he nyl-4- (2 .3-dihyd robe nzofu ran 1 (N -meth yl-N propylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid 2.-Di hyd robe n zofu ran-5-carboxalde hydg -103- To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH 2
CI
2 (5 mL) maintaining the temperature at or below -35 The mixture was warmed to 0 stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 °C at 0.3 mm Hg.
Example 52B trans.trans-2-(4-Methoxyphenyl)-4-(2.3-dihydrobenzofuran-5-l)-1 -(N-methyl-NproDvylaminocarbonvlmethyl)-Dvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI 3 5 7.33 (1 H, d, J=8Hz), 7.28 (1H, 7.19 (1 H, 6.87 (1 H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 4.56 (1H, t, J=8Hz), 3.83 (1H, d, J=10Hz), 3.80 20 (3H, 3.63 (1 H, 3.4-3.0 (9H, 2.87,2.84 (3H, 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 453 (M+H) Anal calc for
C
26
H
32
N
2 0 5 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
Example 53 trans.trans-2.4-Bis(4-methoxyphenvyl-1-(N-methyl-N- DropDvlaminocarbonvlmethvl)-pyrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in 30 Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC13) 5 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, 3.83 (1 H, 3.81 (3H, 3.79 (3H, 3.64 (1H, 3.48-2.97 (6H, 2.87, 2.83 (3H, s), 2.85 (1H, 1.45 (2H, 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 441 -104- Anal caic for C 25
H
32
N
2 05 .0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23.
Found: C, 67.15; H, 7.31; N, 6.00.
Exmple 54 trans. trans-2-(4-Methoxypheny)-4-(3 .4-di meth oxyphenyl)- 1 -(N-methyl-Npropyl~ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC1 3 5 7.33 (2H, d, J=7.5 Hz), 7.07 (1 H, d, J=2.0 Hz), 6.98 (1 H, in), 6.55 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (311, 3.86 (3H, 3.83 (1 H, in), 3.79 (3H, 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCt/NH 3 Wne 471 Anal calc for
C
26
H
34
N
2 0 6 -0.5 H 2 0: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
trans, trans-2-(4-Methoxyphenyl)-4-(3-methoxyphenylI-1 (N-methyl-Npro pyl)ami no ca rbonyl methyl)- pyrro lid in e-3-carboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde. for piperonal in *Example-49A. Rotational isomers are seen in the NMVR. 1 H NMR (300 MHz, ODC1 3 5 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t, J=7.5 Hz), 7.05 (2H, mn), 6.85 (2H, dd, J=7..5&2 Hz), 6.76 (1 H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1 H, in), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 in/e 441 Anal calc for C 25
H
32
N
2
O
5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
trans, trans-2-(4- Meth oxyphenyl)-4-(2-naphthyl)- 1 -(N-methyl-Np ropyl) ainocarbo nylimeth yl)-pyrro lidin ne-3-carboxyli c acid title compound was prepared by the procedures described in a:...:Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMVR. I H NMR (300 MHz, -105- CDCI3) 5 7.82 (4H, 7.69 (1 H, 7.47 (2H, 7.37 (2H, dd, J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1 H, d, J=8 Hz), 3.78 (3H, 3.57 (1 H, 3.52- 2.97 (6H, 2.93, 2.85 (3H, 2.90 (1 H, 1.52 (2H, 0.86, 0.76 (3H, t, Hz). MS (DCI/NH 3 m/e 461 (M+H) Anal calc for C 28
H
32
N
2 0 4
H
2 0: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.
Example 57 trans.trans-2-(4-Methoxvhenvl)- 4 .3-benzodioxol-5-yl)-1 (ethvlsulfinvlethvl)-ovrrolidine-3-carboxvlic acid To the compound resulting from Example 1C (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2
CI
2 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room temperature. A solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and MeOH in CH 2
CI
2 to afford the sulfoxide (62 mg, The ethyl ester was hydrolyzed by the procedure described in Example 1D to afford the title compound as a diastereomeric mixture. m.p. 61-63 oC.
MS (DCI/NH3) m/e 446 (M+H) 1 H NMR (CDCI3, 300 MHz) 51.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 4H), 2.84-2.96 3H), 3.02-3.08 1H), 3.32, 3.36 J=3Hz, 1H), 3.47-3.58 2H), 3.65, 3.68 J=7.5Hz, 1H), 3.76, 3.80 (s, 3H), 5.94 2H), 6.72 J=7.5Hz, 1 3.84-3.89 3H), 7.02 J=6Hz, 1 H), 30 7.30, 7.34 J=7.5Hz, 2H).
-106trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vyl-1-(2- (isopropvysulfonvlamino)ethyl)-pyrrolidine-3-carboxvlic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous
CH
3 CN was added 1 equivalent of Et 3 N. The mixture was stirred for minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et 3 N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 mmol) in 3 mL of CH 3 CN. The mixture was warmed at 50-60 °C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1D to afford the title compound (133 mg, m.p. 94-96 1 H NMR (CD 3 OD, 300 MHz) 8 1.26 J=6Hz, 6H), 1.97 1H), 2.38 1H), 2.77 1H), 2.88 J=9Hz, 1H), 3.04 1H), 3.14 J=7.5Hz, 2H), 3.35 2H), 3.46 1H), 3.58 1H), 3.78 3H), 5.92 (s, 2H), 6.74 J=9Hz, 1 6.86 (dd, J=9Hz,3Hz, 1 6.92 J=9Hz, 2H), 7.00 J=3Hz, 1 7.36 J=9Hz, 2H). MS (DCI/NH 3 m/e (M+H) Example 59 trans.trans-2-(4-Methoxvphenvyl-4-(1.3-benzodioxol-5-vyl-1 (isobutoxvyethyl)-pyrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 1C and 2- (isobutoxy)ethyl bromide. m.p. 68-70 1H NMR (CDCI, 300 MHz) 8 0.88 J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1 2.22 2H), 2.72-2.79 1 2.86- 2.95 2H), 3.13 J=6Hz, 2H), 3.45-3.56 4H), 3.68 J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 m/e 442 (M+H) ***oo *oooo -107trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vlI-1 -(butvlsulfonvl)pyrrolidine-3-carboxvlic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1C dissolved in 10 mL of THF was added 1-butanesulfonyl chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mg of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH~6 with acetic acid and then extracted with EtOAc (2 x 50 mL).
The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid. m.p. 67-69 OC. 1 H NMR (CDCI 3 300 MHz) 8 0.82 J=7.5Hz, 3H), 1.20-1.33 2H), 1.58-1.68 2H), 2.48- 2.69 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=12Hz, 1H), 3.65 (dd, J=12Hz, 1H), 3.82 3H), 4.32 (dd, J=12Hz, 1H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 3H), 6.92 J=9Hz, 2H), 7.35 J=9Hz, 2H). MS (DCI/NH 3 m/e 462 Example-61 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 -(2-(N-methyl-Nisooropylcarbonylamino)ethyl-pvrrolidine-3-carboxylic acid Examle 61 A trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl-1 -(2-bromoethyl)- 30 pyrrolidine-3-carboxylic acid ethyl ester To the mixture of cis,trans and trans,trans pyrrolidines resulting from Example 1C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7 .mL of diisopropylethylamine and 30 mg of sodium iodide.- The resultant mixture was heated at 100 OC for 1 hour, and then the solvents were removed in vacuo.
-108- The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.
Example 61B trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl- 1 (methylamino)ethyl)-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 61A (450 mg) dissolved in mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo.
The resultant product was carried on without further purification.
Example 61 C trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl- 1 -(2-(N-methyl-Nisobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61B (-150 mg) dissolved in mL of 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 OC, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours. The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAc-hexanes going to EtOAc and finally using 10% MeOH- EtOAc.
The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 N H 3 P04 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2SO4. The solvents were -109removed in vacuo to provide 82 mg of the title compound as a white foam.
Rotamers were seen in the NMR. 1H NMR (COC 13, 300 MHz) of the major rotamer 8 1.06 3H, J=1 0Hz), 1. 12 3H, J=1 0Hz), 2.15 (in, 2.5-3.0 (in, 3H), 2.91 3H), 3.32 (in, 2H), 3.50 (in, 3.65 (in, 2H), 3.77 3H), 5.92 (s, 2H), 6.73 1 H, J=8Hz), 6.75-6.9 (in, 4H), 6.96 1 H, J=2Hz), 7.29 (mn, 1 H).
MS (DC I/NH 3 m/z 469 Analysis calcd for C 26 H32N206 -0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.
trans, trans-2-(4-Methoxyphenyl)-4-(1 2-be nzodioxol-5-y)- 1 -(2-(N-methyI- Npropionylamino~ethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1 H NMR (CDCI 3 300 MHz) of the major rotamerB 1.13 3H, J=8Hz), 2.19 (in, 1 2.30 (in, 2H), 2.65-3.0 (mn, 3H), 2.85 3H), 3.25-3.4 (in, 2H), 3.7.(in, 3H), 3.79 3H), 5.92 2H), 6.74 1 H, J=8Hz), 6.75-6.9 (mn, 4H), 7.00 (bd s, 1 7.29 (bd s, 1 MS (DCI/N H 3 in/z 455 Analysis calcd for C 25
H
30
N
2 0 6 1.0 H 2 0: C, 63.55; H, 6.83; N, 5.93. Found: C, 63.55; H, 6.52; N, 5.73.
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -(N-methyl-Nben zylainnocarbo nyl methyl) -pyrrol' done-3 -carboxyli c acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI 3 300 MHz) of the major rotainer 8 2.79 3H), 2.8- 3.2 (in, 2H), 3.48 (in, 2H), 3.61 (in, 2H), 3.77 3H), 3.78 (in, 1 4.3-4.5 (in, 2H), 5.95 2H, J=2Hz), 6.7-6-9 (mn, 7.00 (in, 1 7.15-7.35 (in, 7H). MS 30 (FAB/NBA) in/z 503 Anal calcd for C 29
H
30 N206 0.5 H 2 0: C, 68.36; N, 5.50. Found: C,68.41; H, 5.74; N, 5.36.
-110trans. trans-2-(4-Methoxyghe nyj)-4-( 1.3-benzod oxol-5-yfl)-1 -(N-ethyl-Nbutylaminncarbonylethyfl-Yrrolidi ne-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI3. 300 MHz) of the major rotamer 8 0.88 3H, J=7Hz), 1.06 3H, J=7Hz), 1.27 (in, 21H), 1.45 (mn, 2H), 2.8-3.6 (in, 11 3.79 3.80 (in, 1 5.92 (bd s, 2H), 6.75 1 H, J=5Hz), 6.85 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 1 7.33 1 H, J=8Hz). MS (DCI/NH 3 m/z 483 Anal calcd for C 27
H
34 N206 0.5 HOAc: C, 65.61; H,7.08; N, 5.46.
Found: 0,65.51; H, 6.70; N, 5.66.
trans. trans-2-(4-Methoxyphenyfl- 4 .3-be nzodioxol-5-yi)l- -(N-methyl-N-(2.2dimethyloropylhainocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. I H NMR (CDCI3, 300 MHz) of the major rotamer 580.90 9H), 2.8- 3.1 (in, 4H), 2.94 3H), 3.3-3.5 (in, 3H), 3.61 (mn, 1 3.80 3H), 3.82 (mn, 1 5.94 (bd s, 2H), 6.74 1 H, J=8Hz), 6.86 2H, J=8Hz), 6.87 (in, I1H), 7.03 1 H, J=2Hz), 7.33 2H, J=BHz). IMS (DCl/NH3) in/z 483 25 trans. trans-2-(4-MethoxyghenyP)-4 4 l .3-benzodioxol-5-yl)-1 -(2-(N-methyl-
N-
butylsulfonylanino)ethyl)-Pyrrolidi ne-3-carboxylic acid To the compound resulting from Example 61B (60 mg, 0.13 inmol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mng (0.143 iniol, 1.1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc- **.*hexane to yield 64 mg of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. in.p. 64-66 00. 1 HNMR (CDC1 3 300 MHz) 8 0.92 J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (in, 2H), 2.16-2.25. (in, 1 2.72 3H), 2.75-2.92 (in, 5H), 3.12-3.20 (in, 1 H), 3.25-3.34 (in, 1 3.46-3.55 (in, 2H), 3.65 J=9Hz, 1 3.78 3H), 5.53 (s, 2H), 6.72 J=7.5Hz, 1 6.82 (dd, J=7.5Hz,3 Hz, 1 6.86 J=9Hz, 2H), 7.02 J=3Hz, 1 7.34 J=9Hz, 2H). MS (DCI/NH3) mle 519 Example 67 trans. trans-2-(4- Methoxyphenyl)-4- (1 .3-be nzodioxol-5-gl)- 1 -(2-(N-methyl-Npropylsulfonylamino)ethyl)-pyrro lidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1'-butanesulfonyl chloride. in.p. 69-70 0 C. I H NMR (CDCI 3 300 MHz) 8 1.02 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 (in, 1 2.72 3H), 2.75-2.95 (in, 6H), 3.13-3.22 (in, 1 3.25-3.35 (in, 1 3.47-3.58 (mn, 2H), 3.66 J=9Hz, 1 H), 3.80 3H), 5.96 2H), 6.74 J=7.5Hz, 1 6.84 J=7.5Hz, 3Hz, 1 H), 6.87 J=9Hz, 2H), 7.04 J=3Hz, 1 7.43 J=9Hz, 2H). MS (DCI/NH3) m/e 505 trans. trans-2-(4-Methoxyphe nyl)-4-(1 .3-benzodioxol-5-y)-1 (propy Isu If onyl~ethyl)-pyrro lid ine- 3-carboxyli c acid To 1 -propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THE was added 632 mng (26.32 minol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 0 C for 1 houis. To this mixture was added the compound resulting from Example 61 A (180 ing, 0.38 inmol) in 2 mL'THF. Heating was continued at 60-70 0 C for an additional 2 hours, and then the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to give 170 mng To a solution of 170 mng (0.36 minol) of the sulfide and 93 mg (0.8 minol) of N-methylmorpholine N-oxide (NMO) in a mixiure of 20 mL of acetone and mL of H 2 0 was added a solution of osmium tetroxide (10 mg) in 0.3 mL of tbutanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. the residue was partitioned between EtOAc and H 2 0. The organic phase was washed with brine, dried -112over Na 2
SO
4 and concentrated in vacuo. Flash chromatography afforded 177 mg of the ethyl ester which was hydrolyzed by the procedures described in Example 1D to afford the title compound. m.p. 73-75 OC. H NMR (CDCI3, 300 MHz) 8 1.04 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1H), 2.84-3.08 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1 3.68 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.75 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 J=9Hz, 2H), 6.99.(d, J=3Hz, 1 7.32 J=9Hz, 2H). MS
(DCI/NH
3 m/e 476 (M+H) Example 69 trans. trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl- 1 methvlhex-2-envyl-pvrrolidine-3-carboxvlic acid Example 69A trans-5-Methylhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 OC.
Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 OC. Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na2SO 4 and evaporated to give a colorless oil which was purified by flash chromatography 25 on silica gel eluting with hexanes. The title compound was isolated as a colorless oil (2.1 g).
Example 69B trans-5-Methvlhex-2-en-1 -ol 30 The compound resulting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 OC in an ice bath. Diisobutylaluminum hydride (1.5 t in toluene, 20 mL) was added dropwise and the solution stirred at 0 OC for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature.
-113- Diethyl ether (50 mL) was added, the solids removed by filtration and washed with additional ether (2 x 25 mL). The filtrate was extracted with ether (2 x mL). The ether extractions and washings were combined, dried, and evaported to give a colorless oil which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C trans-1 -Bromo-5-methvlhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 OC in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 OC for two hours.
The solution was poured onto ice, the layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).
Example 69D trans. trans-2-(4-Methoxvphenyl-4-(1.3-benzodioxol-5-vl-1 methvlhex-2-envl-ovrrolidine-3-carboxvlic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 69C for Npropyl bromoacetamide. 1 H NMR (CDCl 3 300 MHz) 5 0.84 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1 H, J=8Hz,14Hz), 2.86 25 1H, J=10Hz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, 1H, J= 5Hz,14Hz), 3.29 (dd, 1H, J=3Hz,10Hz), 3.50 1H), 3.70 1H, J=10Hz), 3.78 3H), 5.47 (m, 2H), 5.93 2H), 6.71 1H, J=8Hz), 6.83 3H, J=9Hz), 7.05 1 7.32 (d, 2H, J=9Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
*Example o -114trans. trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl)- 1 dimethylhex-2-envl)-ovrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olefins. The crude product was purified by preparative HPLC (Vydac uC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product (and its diastereomer) as a white solid. 'H NMR of the major (trans) isomer: (CDC13, 300 MHz) 8 0.83 6H, J=8Hz), 1.56 1.74 1H), 1.92 2H, J=6Hz), 3.3-3.5 3H), 3.6-3.8 3.78 3H), 3.9-4.0 1 H), 5.22 1 5.90 2H, J=12Hz), 6.63 1 6.78 3H), 6.95 1 7.45 3H, J=8Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C 2 7
H
3 3 NO5 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10; N, 2.34.
Example 71 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 heptvlcarbonvlmethvlf-pyrrolidine-3-carboxvlic acid Example 71A 1 -Chloro-3-proDvl-2-hexanone To 2-propylpentanoic acid (156.6 uIl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 gL, 4 mole and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 UL, 1.08 mmol) dropwise over a few minutes. The reaction 25 was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added.
The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and 30 concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 h solution in dioxane (275 gL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient ooo.o -115temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
Example 71B trans. trans-Ethyl 2-(4-methoxyvhenvyl-4-(1.3-benzodioxol-5-yl)-1-(4heptvlcarbonvlmethvl-ovyrrolidine-3-carboxylate To the compound resulting from Example 71 A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 gL, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole and the reaction mixture was stirred 18 hours under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 OC with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg of the title compound as a yellow oil.
Example 71C trans. trans-2-(4-Methoxvohenvl-4-( 1 .3-be nzodioxol-5-vln-1 heptvlcarbonvlmethvl'-pyrrolidine-3-carboxvlic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether mL). The aqueous layer was neutralized with 1 N hydrochloric acid to 30 cloudiness and then 10% aqueous citric acid was added to adjust the pH to This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL).
The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1:1 ethyl acetate-hexane to give 86 -116mg of the title compound as an off white powder. 1 HNMR (CDCI 3 300 MHz) 5 0.73-0.97 (in, 6H), 1.03-1.33 (in, 6H), 1.36-1.58 (in, 2H), 2.46 (in, 1 H), 2.80-2.98 (in, 3H), 3.38-3.64 (in, 3H), 3.75-3.90 (in, 1 3.79 3H), 5.94 (s, 2H), 6.75 1 6.86 2H), 6.92 1 7.12 1 7.32 2H). MS (FAB) m/e 482 Anal calcd for C 28
H
3 5NO 6 C, 69.83; H, 7.32; N, 2.91.
Found: C, 69.57; H, 7.41; N, 2.73.
trans. trans-2-(4-Methoxyphenyli-4-( 1.3-benzodioxol-5-yl)-1 -(valervlmethyl)pyrrolidine-3-carboxylic acid Example 2A 1 -Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
trans. trans-Ethyl 2-(4-methoxyphenfl)-4-( 1.3-benzodioxo Ie-5-yfl-1 (vale Eyl methyfl-pyrrolidi ne-3-carboxylate Substituting the compound resulting from Example 72A for 1 -chloro-3- 4 propyl-2-hexanone and using the procedure described in Example 71 B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient 99...temperature and purifying by -silica gel chromatography eluting with 3:17 ethyl 25 acetate-hexane, the title compound 305 mg was obtained as a yellow oil.
Example 2C *9 30 trans. trans-2- Methoxyph eny 1.3-be nzodioxo 1-5-v )1 -(valerLyl methy) yrrolidene-3-carboxylic acid By substituting the compound resulting from Example 72B for trans,trans- 9 Ethyl 2-(4-inethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 heptylcarbonylinethyl)-pyrrolidine-3-carboxylate and using the procedure -117described in Example 71 C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg was obtained as an off white powder. 1H NMR (CDC1 3 300 MHz) 8 0.87 3H), 1.26 (in, 2H), 1.49 (in, 2H), 2.37 (in, 2H), 2.79-2.98 (in, 3H), 3.31-3.49 (mn, 2H), 3.56 (in, 1 3.77, 3.79 4H), 5.94 (s, 2H), 6.75 1 6.81-6.93 (in, 3H), 7.09 1 7.33 2H). MS (FAB) m/e 440 Anal. calcd for C 2 5H- 29 N0 6 C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.
-Eape7 trans.trans-2-(4-Methioxyghenyl)-4-(1 .3-benodioxo-5-vfl)-1-(N-(3.4dim ethoxybe nzyl)- N-methy Iani nocarbo ny Imethyl~Dvrroli dine.3-carb xy li c acid trans.trpns- and cis. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl- 1 dimiethoxvbenzyflainocarbonylmethyl)oyrro lidine-3-carboxylic acid ethyl ester Using the procedure of Example 1 D, paragraph 1, substituting 3,4diinethoxybenzyl bromoacetamide for dipropyl bromoacetainide, the desired product mixture was obtained as a white foam in 81 yield.
trans.trans- and cis. trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-vfl- (3 .4-di iethoxybenzy)-N-methyjami nocarbonylmethylrprrolidine-3.carbpxvlic 25 The resultant product from Example 73A (220 mng, 0.404 iniol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 OC) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 minol) in 0.2 mL THF, under an argon atmosphere.
The resulting mixture was stirred at 0 'C for 1 hour, then methyl iodide (28 p.L, 30 64 ing, 0.45 iniol) was added. The reaction mixture was stirred at 0 0 C for .1I minutes. TLC (Et 2 O) indicated incomplete reaction. An additional portion of methyl iodide (28 jLa, 64 mng, 0.45 minol) and dry 1 ,3-dimethyl-3,4,5,6- '6400"tetrahydro-2(1 HMpyrimidinone (50 ILL, 0.41 inmol) were added. The reaction I mixture was stirred at ambient temperature for 2 days. The reaction was -118poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na 2
SO
4 filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et 2 0 gave the title compounds as an inseparable mixture in 43% yield. 1 H NMR (CDC13, 300 MHz) 5 2.79 and 2.81 for the
N-CH
3 signals. MS m/z 591 Example 73C tran.trans2(4-Methoxyphenvl), 4 (l 3-henz odioxol-y 5 N-(4dimethoxvbenryl)-Nmethyainoinarhbnnlmct yr o id To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 oC was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H 2 0. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL
H
2 0 and 15 mL Et 2 0. The aqueous phase was extracted with 5 mL Et 2 0, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc.
The EtOAc extracts were combined, dried (Na 2
SO
4 then filtered and concentrated in vacuo to give 40 mg of the title compound as a white i foam. 1 H NMR (CD 3 OD, 300 MHz, two rotameric forms) 5 2.85 3H), 2.94- 3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br 3.74 2 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 25 (AB, 1 5.91 and 5.93 2H total), 6.50-6.60 1 6.67-7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31 H35N 2 0 8 563.2393. Found: 563.2385.
Exampile 74 trans. trans-2- (4-Methoxvphenvl-4 (1.
3 -benodioxol.-5-) -N .4dimethoxybenzyl)aminocrbonyimethva)vrroidine..3-crnoviic aidi The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound. 1 H NMR (CD 3 OD, 300 MHz) -119- 2.85 J=1l6Hz, 1 2.92 (br t, J=9Hz, 1 2.98 (br t, J=1lOHz, 1 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 3.67 3H), 3.78 3H), 3.80 3H), 3.85 (d, J=1 0 Hz, 1 4.21 J=1l5Hz, 1 4.41 J 1 5Hz, 1 5.91 2H), 6.67 (d, J=8Hz, 1 6.75-6.95 (in, 7H), 7.33-7.40 (in, 2H). HRMS calcd for 0 30
H-
32
N
2 0 8 549.2237. Found: 549.2224.
(2R.3R .4R)-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-y)-1 R)-1 .Ndipropylaminocarbonyl)-l -butylpyrrolidine-3-carboxvlic acid trans, trans-2-(4- Methoxyphenyl)-4(1 .3-be nzodoxol-5-yF)- 1 R).L (be nzvloxycarbonyl)butyl'ipyrrolidine-3-carboxylic acid ethyl ester The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H 2 0, and ammonium carbonate (34 mng, 0.35 mmol) and (2S)-benzyl 2-bro mope ntanoate (78 mg, 0.30 inmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na2003 and 25 mL of CH 2 01I2.
The aqueous phase was extracted with 2 x 10 mL CH2CI2, and the combined organic phases were washed with 15 mL brine, dried (Na2SO 4 then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3:1 CH 2 01 2 hexane to produce 106 mg of the title compound as a waxy solid. H NMR indicated the presence of two diastereomeric products.
trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-yl)-1 R)-1 dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid ethyl ester The resultant compound from Example 75A (101 mg, 0. 180 minol) and mg of 10% palladium on charco al were stirred in 2 mL EtOAc under 1 **.*atmosphere of H 2 for 4 hours. The reaction mixcture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst. The combined filtrate and -120wash were concentrated in vacuo to give 81.4 mg of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 then 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na 2
CO
3 The organic phase was washed with 10 mL of brine, dried (Na 2
SO
4 then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et 2 0hexane. Further purification of overlap fractions by preparative TLC eluting with 1:2 Et20-hexane yielded 32 mg of a less polar product, and 44 mg (46%) of a more polar product.
Example (2R.3R.4R)-2-(4-Methoxyphenvl-4-(1 .3-benzodioxol-5-vl)-1 dioroDvlaminocarbonvl-1 -butyl)Dyrrolidine-3-carboxvlic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield. [aMD -520 (c=0.235, H NMR (CD 3 OD, 300 MHz)5 0.55 J=7Hz, 3H), 0.87 J=7Hz) and 0.87-0.94 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 25 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 overlapping with
CD
2 HOD signal), 3.40-3.60 (br m, 2H), 3.79 3H), 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1H), 6.92- 6.98 (br m, 3H), 7.29-7.39 2H). MS m/z 525 Example 76 -121- (2S.3S.4S)-2-(4-Methoxyphenylv-4-(1.3-benzodioxol-5-vl)-1-((1 R-1-(N.NdioroDylaminocarbonvl-l -butyl)vyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [a]D +580 (c=0.37, 1H NMR (CD 3 OD, 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 6H), 1.08- 1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 (br m, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 3.69 3H), 4.03-4.16 (br m, 2H), 5.91 2H), 6.71-6.83 2H), 6.86-6.97 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 Example 77 (2S.3S.4S)-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 S)-1 dipropylaminocarbonyl-1 -butvl)pyrrolidine-3-carboxvlic acid Example 77A trans. trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1 dioropylaminocarbonvyl)--butvlvpyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon atmosphere, diisopropylethylamine (75 mg, 0.58 mmol) was added, then the :i solution was cooled to -20 oC. Trifluoromethanesulfonic anhydride (95 pL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and at room temperature for an 25 additional 1 hour. The resulting slurry was recooled to 0 OC, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 gIL, 75 mg, 0.58 mmol) in 3 mL of CH2C12 was added. The reaction was stirred at 0 OC for 3 hours and for an additional 2 days at room temperature. TLC (Et 2 O-hexane 1:2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na 2
CO
3 The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na 2 SO4), filtered and concentrated in vacuo to a yellowish oil. Purification by flash -122chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg of a less polar product and 20.1 mg of a more polar product. 1 H NMR spectra and MS were the same as those of Example 76B.
Example 77B (2S.3S.4S)-2-(4-Methoxvohenvl)-4-(1.3-benzodioxol-5-vl)-1 S-1-(N.Ndiorovylaminocarbonvl-1 -butvlovrrolidine-3-carboxlic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 738, to provide the title compound in 100% yield. 1 H NMR (CD 3 0D, 300 MHz) and MS identical to those of Example Example 78 (2R.3R.4R-2-(4-MethoxyDhenvyl-4-(1.3-benzodioxol-5-vl)-1 diDroDvlaminocarbonvl-1 -butvl)pyrrolidine-3-carboxvlic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 738, to provide the title compound in 88% yield. 1 H NMR (CD30D, 300 MHz) and MS identical to those of Example 76.
SExample 79 trans. trans-2-(4-Methoxvphenvyl-4-l .3-benzodioxol-5-yl-1 -(N.N-di(n- Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 25 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg of the 3-carboxamide compound. m.p.
30 194-196 0C.
Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature.
Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over'sodium sulfate, and concentrated. The residue -123was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg of the 3-carbonitrile compound.
To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid to get 532 mg of the title compound. m.p. 165- 167 oC. 1 H NMR (CDCI 3 300 MHz) 5 0.85 J=7Hz, 3H), 0.87 J=7Hz, 3H), 1.10-1.50 8H), 3.0-3.6 8H), 3.70 3H), 3.7-3.8 1H), 3.90 J=9Hz, 1H), 4.37 J=9Hz, 1H), 5.86 2H), 6.62 J=8Hz, 1H), 6.65-6.73 3H), 6.95 J=2Hz, 1 7.11 J=9Hz, 2H).
Examole trans.trans-2-(4-Fluorophenvl--4-(1.3-benzodioxol-5-vl- 1 -(N.N-di(nbutvlaminocarbonvlmethvl)ovrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid from methyl (4flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole using the procedures described in Examples 1 and 43. 1 H NMR (CDCI 3 300 MHz) 6 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.0-1.55 8H), 2.81 J=13 Hz, 1H), 25 2.90-3.10 4H), 3.15-3.30 1 3.32-3.45 3H), 3.55-3.65 1 3.86 J=10Hz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 1 6.95-7.07 3H), 7.32-7.45 2H).
Example 81 trans.trans-2-(4-Methoxyvhenvl)-4-1 .3-benzodioxol-5-vl)-1 -(N.N-di(nbutvlaminomethvlcarbonvlDpvrrolidine-3-carboxvlic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 OC.
-124- After cooling to room temperature, 250 mg (0.678 mmol) of ethyl trans,trans-2- (4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 OC for 30 minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.
The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. 1H NMR (CDCl3, 300 MHz) 8 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 8H), 2.65-3.20 6H) 3.43-3.70 3H), 3.72 3H), 3.87 J=15Hz, 1H), 4.49 (dd, J=12Hz, 6Hz) and 5.23 (dd, J=12Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 3H), 6.86 and 7.04 J=9Hz, 2H), 7.22 J=9Hz, 2H).
Example 82 trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1 -(N-n-butvl)-N-(npropyl)aminocarbonylmethvl)oyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 OC. 1 H NMR (CDCl 3 300 MHz) rotational isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1H), 2.90-3.10 4H), 3.23-3.61 5H), 3.71 and 3.75 (two doublets, J=1OHz, 1H),.3.78 3H), 5.92-5.96 2H), 6.72 J=8Hz, 1H), 6.83-6.89 3H), 7.03 J=2Hz, 1 7.81 J=9Hz, 2H).
.Example 83 25 trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl)-1-[2-(N.N-di(nprovpylaminocarbonyl)ethvl]pyrrolidine-3-carboxvlic acid The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 OC in 0.75 mL of methoxyethanol for one hour. Toluene was 30 added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mg of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was -125removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydrolyzed to the title compound by the method of Example 1 D in 83% yield. 1 HNMR (COCl 3 300 MHz) 5 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (in, 4H), 2.35-2.60 (in, 3H), 2.80-3.07 (in, 3.14-3.21 (in, 2H), 3.31-3.38 (in, 1 3.51-3.61 (in, 1 3.73 J=1 2H, 1 H), 3.75 3H), 5.94 2H), 6,71 J=9Hz, 1 6.79-6.85 In, 3H), 7.04 (d, J=2Hz, 1 7.32 J=9Hz, 2H).
Example 4 trans.trans-2-(4-Methoxyohenyl-4-(1 .3-benzodioxol-5-yl)-1 .N-di(nbutyflaminocarbonyl~pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino et Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1
H
NMR (C~DC 3 300 MHz) 8 0.86 J=7Hz, 6H), 1. 14-1.28 (in, 4H), 1.35-1.48 (in, 4H), 2.81-2.94 (mn, 2H), 3.11 J=1l2Hz, 1 3.30-3.41 (in, 2H), 3.59-3.68 (in, 2H), 3.76 3H), 3.78-3.85 (in, 1 5.81 J=9Hz, 1 5.94 2H), 6.73-6.86 (mn, 5H), 7.24 J=9Hz, 2H).
trans. trans-2(4- Methoxyhe nyP)-4-(1 .3-benzodioxol-5-yl'- 1 .N-di(nbutyl)arninocarbonvlinethylhpyrroldi ne-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 minol) in 2 mL of 25 MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 minol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacua to give a powder which was dried in the vacuum oven for 2 hours at 0 C to yield 627.5 mng of the title compound.
-126trans.trans-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-vl)- -1[2-(N.N-di(nbutvl)aminocarbonvylethvllpyrrolidine-3-carboxylic acid A solution of the bromoethyl compound resulting from Example 61A (150 mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 oC for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2
SO
4 and concentrated. More toluene was added, and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1D to give the title compound as a white powder. 1 H NMR (CD 3 0D, 300 MHz) 5 0.89 J=7Hz, 6H), 1.16-1.30 4H), 1.44-1.56 4H), 2.48-2.57 1H), 2.80-3.08 8H), 3.14-3.25 1H), 3.31-3.38 1H), 3.59-3.60 1H), 3.74 3H), 3.75 (d, 1H), 5.89 2H), 6.71 J=9Hz, 1H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 J=1 OHz, 2H), 6.96 J=2Hz, 1 7.37 J=1 Hz, 2H).
Example 87 trans.trans-2-(4-MethoxyDhenvl)-4-(1.3-benzodioxol-5-vl-1 -{2-fN-(N.N-di(nbutvl)aminocarbonvl-N-methvlaminolethvlipyrrolidine-3-carboxylic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, 25 and the solution was washed with potassium bicarbonate solution, dried over Na 2
SO
4 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.
The ester was hydrolyzed by the method of Example 1D to afford 141 mg 30 of the title compound. 1H NMR (CD 3 OD, 300 MHz) 8 0.92 J=7Hz, 6H), 1.21too*. 1.32 4H), 1.42-1.53 4H), 2.62 3H), 2.65-2.76 1H), 3.00-3.20 (m, 8H), 3.44-3.55 1H), 3.62-3.78 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 2H), 6.75 J=9Hz, 1 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 J=10 Hz, 2H); 7.04 J=2Hz, 1H), 7.40 J=10Hz, 2H).
-127trans. trans-2-(4-Methoxvohenyl)-4-(1 .3-benzodioxol-5-y)-1 .N-di(nbutyflami nocarbonyl)methyl)pyrrolidi ne-3-(N-methanesulfonvl)carboxamide Carbonyldlimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 0 IC for 2 hours. After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 00 for 2 hours. The solvents were removed in vacua, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg of the title compound. m.p. 170-173 00. 1 H NMR (CDC1 3 300 MHz) 6 0.82 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.05-1.51 (in, 8H), 2.75-2.86 (in, 2H), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-3.50 3H), 3.70-3.78 (in, 1 3.80 3H), 3.87 (d, J=1lOHz, 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 J=9Hz, 1 6.84 (dd, J=9Hz, 2Hz, 1 6.90 J=1 0 Hz, 2H), 7.01 J=2Hz, 1 7.34 J=1 0Hz, 2H).
trans. trans-2 -(4-Met hoxyphenyl)-4-(1 .3-benzodioxol-5yl-1 .N-di(nbutyl)aminocarbonyl)methyl)pyrroli din e-3-(N-benzenesulfonyl)carboxamide The compound resulting from Example 43 was converted to the title 0 11 compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. in.p. 169-171 00 for a sample recrystallized from *860 acetonitrile. 1 H NMR (CDC1 3 300 MHz) 8 0.81 J=7 Hz, 3H), 0.89 J=7Hz, 25 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (in, 1 3.65 J=lOHz, 1 3.81 3H), 5.94 2H), 6.70 2H), 6.81-6.90 (in, 3H), 7.17 J=lOHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, :1 8.95 J=7Hz, 2H).
soot; woo* 0.6 -128trans. trans-2-(4-Methoxyphenvyl)-4-(1.3-benzodioxol-5-yl)- 1 N-di(n-buty) aminosulfonvyl methyll-pyrrolidine-3-carboxylic acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et.
al., Chem. Ber. 5: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,Ndibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with Nchlorosuccinimide to give chloromethyl sulfenyl chloride by the method of E.
Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,trans-2-(4- Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[N,N-di(nbutyl)aminosulfenylmethyl]pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. U: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
Example 91 trans.trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-yl-1 dibutvylamino)carbonvyl- 1-(RS)-ethyl pyrrolidine-3-carboxylic acid .Example 91 A (+)-Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH 2
CI
2 the solution was cooled to 0 0C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL 3.5 mmol). After 10 minutes at 0 OC, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 OC for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na 2
CO
3 solution, then the organic phase was **washed sequentially with 25 mL of 1 M aqueous NaHSO 4 and 25 mL brine, dried (Na 2
SO
4 filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 1H NMR -129- (CDCla, 300 MHz) 5 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 7H), 1.60-1.78 1H), 1.82 J=6Hz, 3H), 3.04-3.27 2H), 3.42-3.64 2H), 4.54 J=7H, 1H). MS (DCI/NH 3 m/e 264 and 266 Example 91 B trans.trans- and cis.trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5-yl)-1- ((N.N-dibutylamino)carbonvl-1 -(RS-ethylDpyrrolidine-3-carboxvlic acid ethyl ester A solution of the resultant mixture of trans,trans and cis,trans compounds from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example 91A (183 mg, 0.693 mmol) in 2 mL of CH 3 CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C under a N 2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et20 and 10 mL of 1 M aqueous Na 2
CO
3 solution. The organic phase was washed with mL water and 20 mL brine, dried over Na 2
SO
4 filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude). The product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg of the title compounds as a mixture of 4 diastereomers. 1 H NMR (CDCI 3 300 MHz) 0.66-1.55 (several m, 19H), 2.63-3.00 3H), 3.05-3.39 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 2.6H), 4.38 J=10.5Hz, 0.2H) and 4.58 J=10.5Hz, 0.2H), 5.90-5.97 2H), 6.68-6.96 5H), 7.38-7.43 2H).
MS (DCI/NH 3 m/e 553 Example 91C trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 dibutylamino)carbonyl-1-(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 91B for the resultant compound from Example 73B to give the title compound in 61% yield. 1 H NMR (CDsOD, 300 MHz) 5 0.70-1.05 (several m, 8H), 1.14 J=6Hz, 2H), 1.17-1.55 6H), 2.79-3.03 3.20-3.65 (br m, 4.6H plus CD 2 HOD), 3.70-3.78 0.4H), 3.79 3H), 3.98 (d, J=8Hz, 0.6H), 4.06 J=7.5Hz, 0.4H), 4.25 J=8Hz, 0.4H), 5.92 and 5.94 -130- 2H total 6H), 6.73 J=2.5Hz) and 6.75 J=3Hz, 1 H total), 6.78-6.85 (m, 1 6.91-7.00 3H), 7.30-7.38 2H). MS (DCI/NH 3 m/e 525 Anal calcd for C 30
H
40
N
2 0 6 -0.5H 2 0: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
Example 92 trans.trans-2-(Pentvl)-4-(1.3-benzodioxol-5-yl)-i dibutvlaminolcarbonvlmethyvllprrolidine-3-carboxvlic acid Example 92A Methyl 2-(4-hexenovy)-4-nitro-3-(1 A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 g.L, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture of diastereomers in a 1:1 ratio. 1H NMR (CDCI3, 300 MHz) 6 1.55-1.66 3H), 2.02-2.17 (br m, 1 2.20-2.37 (m, 2.49-2.76 1.5H), 3.57 1.5H), 3.74 1.5H), 3.97 J=7.5H, and 4.05 J =8Hz, 0.5H), 4.10-4.20 1 4.68-4.82 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 1 6.68 (br s, 1 6.75 7.5Hz, 1 MS
(DCI/NH
3 m/e 381 (M+NH 4 Anal calcd for C 18
H
2 1 N0 7 C, 59.50; H, 5.82; N, 25 3.85. Found: C, 59.32; H, 5.71; N, 3.72.
S. Example 92B Methyl trans.trans-2-(Dentvl)-4-(1.3-benzodioxol-5-vyl)vrrolidine-3-carboxvlate The procedures of Example 1B and Example 1C were followed, with the 30 substitution of the resultant compound from Example 92A for the resultant compound from Example 1A, and the substitution of the this resultant compound for the resultant compound from Example 1B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions. A solution of the crude compound (660 mg, -131- 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO 3 diluted with 10 mL water and mL of CH 2 C1 2 The aqueous phase was extracted (2 x 30 mL CH 2
CI
2 then the combined organic phases were washed with 20 mL brine, dried over Na 2
SO
4 filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with methanol in CH 2 CI2 gave 336 mg the title compound as a yellow oil. 1H NMR (CDCI3, 300 MHz) 5 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1H), 3.34-3.45 2H), 3.53 J=9Hz, 1 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS (DCI/NH 3 m/e 320 Anal calcd for C 1 8
H
2 5N0 4 C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.
Example 92C trans.trans-2-(Pentvl)-4-(1.3-benzodioxol-5-vl-1 dibutvlamino)carbonvlmethyl]pyrrolidine-3-carboxvlic acid The procedures of Example 1B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from 2 Example 1B, to provide the title compound as a white foam. 1H NMR (CDCI3, 300 MHz) 6 0.87 (br t) and 0.89 (br t, 6H total), 0.97 J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40- 3.60 3H), 3.73 J=14Hz, 1 5.98 (AB, 2H), 6.70 J=7Hz, 1 6.77 (dd, J=1.5,7Hz, 1 6.89 J=1.5Hz, 1H). MS (DCI/NH 3 m/e 475 (M+H) Anal calcd for C 27
H
42
N
2 05-0.5H 2 0: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
Example 93 -132trans.trans-2-(Pentyl)-4-(1.3-benzodioxol-5-vl)-1-[2-(N-proDvl-Npropvlsulfonylamino)ethyllyvrrolidine-3-carboxvlic acid Example 93A Methyl trans.trans-2-(Dentyl-4-(1 .3-benzodioxol-5-vl)-1-(2bromoethyl)pyrrolidine-3-carboxylate The procedure of Example 61A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example 1C, to provide the title compound as a yellow oil. 1 H NMR (CDCI 3 300 MHz) 5 0.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 2H), 2.76-2.91 2H), 3.10-3.22 2H), 3.36-3.47 2H), 3.68 3H), 5.92 2H), 6.69-6.77 2H), 6.90-6.94 1H). MS (DCI/NH 3 m/e 426, 428 Example 93B Methyl trans.trans-2-(Pentyl-4-(1.3-benzodioxol-5-vl)-1 -[2-(N-propyl-NproDylsulfonylaminolethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 limol) in 1 mL EtOH was treated with propylamine (60 glL, 0.73 mmol). The solution was warmed to °C for 4 hours. The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL S 25 of 1 M aqueous Na 2
CO
3 The organic phase was washed with 15 mL brine, then dried over Na2SO4, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL of CH 2
CI
2 diiosopropylethylamine (65 0.373 mmol) was added, followed by propylsulfonyl chloride (29 LL, 0.26 mmol). The 30 solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH and the mixture was extracted with 2 x 3 mL CH 2
CI
2 The combined organic extracts were washed with 2 mL brine, then dried over Na2SO4, filtered, concentrated in vacuo.
Purification by flash chromatography eluting with 20% ethyl acetate in hexane l*e -133provided 65.0 mg of the title compound as a waxy solid. Rf 0.17 MVS (DCI/NH 3 m/e 511 trans. trans- 2-(Pentyl)-4-(1 .3-be nzod oxol-5-yi)- 1 -r2-(N-propyl-Npropylsulfonylamino)ethyllpyrrolI dine-3-carboxylic acid The procedure of Example 71 C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71 B, to provide the title compound as a white foam (47 mg, Rf= 0.14 (5%MeOH-CH 2
CI
2 1 H NMVR (CDCI 3 300 MHz) 5 0.88 (br t) and 0.92 (t, J=7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (in, 2H), 3.05 (br t, J=9Hz, 1 3.10-3.30 (in, 3H), 3.30-3.80 (br mn, 7H), 5.94 2H), 6.71 J=8Hz, 1 6.77 (dd, J=1.5,8Hz, 1 6.89 (d, J=1 .5 Hz, 1 MVS (DCI/NH 3 m/e 497 trans.trans-2-(Propyl)-4-(1 .3-benzodioxol-5-y)-l1-fJN
.N-
dibutylainino)carbonylmethylloyrrolidine-3-carboxylic acid Exalmple 9A Ethyl 2-(4-butanoyl-4-nitro-3-( 1.3-benzodioxole-5-yflbutyrate The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, Rf 0.28 hexane). 1 H NMR (CDCI 3 300 MHz) 850.74 J=7.5Hz) and 0.91 3H total), 1.08 J=7Hz) and 1.28 J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2.24 J=7Hz, total)2.40-2.54 (in, 1 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5H total), 3.93-4.09 (in, 2H), 4.10-4.20 (br in, 1 4.23 J=7Hz, 1 4.67-4.85 9mn, 2H), 30 5.94 2H), 6.62-6.75 3H). MS (DCI/NH 3 m/e 369 (M+NH 4 Anal calcd for C 17
H
2 1 N0 7 C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.
Ethyl trans. trns-2- (propyl)-4-( 1.3-ben zodioxol-5-yl)pyrrolidi ne-3- carboxylate, -134- The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MVS (DCI/NH 3 m/e 306 5Exml94 trans. trans-2-(Propvl)-4-(1 .3-benzodoxol-5-yl-1 Ndibutylamino)carbonyflmetbylpyrrolidine-3-carboxylic acid The procedure of Example 920 was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. 1 H NMR (ODC1 3 300 MHz) 50.89 0.92 J=7.5Hz), and 0.97 J=7.5H, 9H total), 1.22-1 .80 (br m, 1 2H), 2.83 (t, 1 3.40-3.55 (br m, 2H), 3.55-3.68 (in, 1 3.78 J=1 5Hz, 1 H), 5.92 J=1 Hz, 2H), 6.70 J=8Hz, 1 6.79 (dd, J=1 Hzj5Hz, 1 6.90 (d, J=1 Hz, MS (DCI/NH 3 m/e 447 Anal calcd for C 2 5H 38
N
2 0 5
H
2 0: 0, 65.91; H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94.
(2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-yl)-1 -(tertbutyloxycarbonyl-aminocarbonylmethyl-pyrrolidine-3-carboxylic acid trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-be nzodioxoL-5-yl)-1 -([tertbutvloxycarbonylami nocarbonylmethylipyrroldi ne-3-carboxylic acid The resulting mixture of 64% trans,trans- and cis,trans- pyrrolidines resulting from Example 10C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1) indicated that all of the starting material was .006. 30 consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. 1 HNMR
(CDCL
3 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 0 .5(r ,1H ,34 -135- 4.28 (br m, 1 4.89-5.24 (br m, 1 5.94 J=3 Hz, 2H), 6.69-6.90 7.06-7.20 2H). MS (DCI/NH 3 m/e 470 To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water. The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH with 1 N hydrochloric acid, then to pH 4 with 10 citric acid and extracted with 5 ethanol in methylene chloride (3 x 100 mL).
The combined organic layers dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 1
H
NMR (CDCI 3 300 MHz) 5 1.16 (v br s, 9H), 3.11 (br m, 1 3.50-3.64 2H), 3.81 3H), 4.24 (br m, 1 4.96 (br m, 1H), 5.94 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 Example (2R.3R.4S-(+)-2-(4-Methoxvphenvyl-4-(1.3-benzodioxol-5-vl)-1 -(tertbutyloxvcarbonvlaminocarbonvlmethvl)-pyrrolidine-3-carboxvlic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and 20 cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam. This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated 25 by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1 H NMR and chiral HPLC. The amount of enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved Swhen the enantiomer could no longer be detected in the filtrate.
The pure enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether. The aqueous layer was further extracted twice with 100 mL of ether. The combined ether layers were washed with brine, dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum, >99.5 ee). 1H -136- NMR (CDCla, 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 (m, 2H), 3.81 3H), 4.24 1 4.96 (br m, 1 5.95 2H), 6.70-6.79 3H), 6.86 J=9 Hz, 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 Example (2R.3R.4S)-(+)-Ethyl 2-(4-methoxvyhenvl)-4-(1.3-benzodioxol-5-vl)-Dvrrolidine- 3-carboxylate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 with stirring for 18 hours at which point all of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2
SO
4 filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 1 H NMR (CDCl, 300MHz) 8 1.11 J=7 Hz, 3H), 2.18 (v br s, 1 2.93 J= 9 Hz, 1 3.19,3.22 (dd, J=7 Hz, 1 3.50-3.69 2H), 3.80 3H), 4.07 J=7 Hz, 2H), 4.49 J=9 Hz, 1H), 5.94 2H), 6.73 J=2 Hz, 2H), 6.81- S 20 6.92 3H), 7.34-7.41 2H). MS (DCI/NH 3 m/e 370 *Example (2R.3R.4S)-(+-2-(4-Methoxyphenyv-4- (1.3-benzodioxol-5-vl)-1-(tertbutvloxvcarbonvl-aminocarbonvlmethyl)-pyrrolidine-3-carboxylic acid 25 To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 gL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oil. 1H NMR (CDC13, 300MHz) 60.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H),.1.10 J=7 Hz,.3H), 1.00-1.52 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 4H), 3.23-3.61 5H), 3.71 J=9 Hz, 1H), 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, -137- Hz, 2H), 6.74 J=9 Hz, 1 6.83-6.90 3H), 7.03 J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH 3 m/e 539 To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40 OC. over hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous hydrochloric acid until cloudy, and the pH was then adjusted to -4-5 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol-methylene chloride (3 x 50 mL). The combined extracts were dried (Na 2
SO
4 filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 1H NMR (CDCl 3 300MHz) 8 0.80 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.08 2H), 1.28 3H), 1.44 3H), 2.70-3.77 (svr br m, 12H), 3.79 3H), 5.95 2H), 6.75 J=8 Hz, 1 6.87 (br d, J=8 Hz, 3H), 7.05 (br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH 3 m/e 511 [a] 22 +74.420. Anal calcd for C 29
H
38
N
2 0 6 -0.5 H 2 0: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.
20 Example Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1.3benzodioxol-5-vl-1 -(tert-butvloxvcarbonvlaminocarbonvlmethyl)-pvrrolidine-3carboxvlic acid The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The S:ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals 0were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 1670. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-1680. The filtrate was concentrated again and put in the refrigerator and let stand -138overnight giving 1.6906 g, m.p. 102-1100. (HPLC of this showed the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
Example 96 trans. trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vl)-1 -[2-(N-propvl-Nbutvrylamino)ethvllDvrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The product was purified by preparative HPLC (Vydac iC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white 20 solid. 1 H NMR (CDCI 3 300 MHz) 8 0.80 3H), 0.90 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1H), 5.95 2H), 6.75 1 H, J=8Hz), 6.84 1 6.85 2H, J=8Hz), 7.04 1 H, J=1Hz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 497 Anal calcd for C 28
H
36
N
2 06 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.
Example 97 trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl 1-f2-(N-oropvl-N- (ethvlaminocarbonvylamino)ethyl]pvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid.- H NMR (CDC13, 300 MHz) mixture of rotamers 8 0.80 J=8Hz) and 1.05 -139- J=8Hz) and 1.20 (in) and 1.42 (in) total of 8H for the four peaks, 2.35 (br s, 1 2.70 (in, 1 3.0 (in, 3H), 3.2 (in, 3H), 3.25 (dq, 1 H, J=1 .8Hz), 3.42 (in, 1 H), 3.6 (in, 1 3.75 (in, 1 3.78 3H), 4.8 (br s, 1 5.95 2H), 6.74 1 H, J=8H-z), 6.85 (in, 3H), 7.00 1 7.30 2H, J=8Hz). MS (DCI/NH 3 m/e 498 Anal calcd for C 27
H
35
N
3 0 6 -0.75 H 2 0: C, 63.45; H, 7.20; N, 8.22.
Found: C, 63.38; H, 7.29; N, 8.44.
trans. trans-2-(4-Methoxypheny'-4- (1 .3-be nzodioxol-5-y)- 1 -[2-(N-butyl-Nbutyrylamino~ethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylainine for inethylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. 1 H NMR
(CDCI
3 300 MHz) 5 0.80 (in, 3H), 0.90 3H-, J=8Hz), 1.45 (in, 4H), 1.6 (in, 2H), 2.20 3H, J=8Hz), 2.94 (br in, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br mn, 2H), 3.82 3H), 4.30 (br s, 1 5.95 6.75 1 H, J=8 Hz), 6.84 (in, 1 H), 6.85 2H, J=8Hz), 7.04 1 H, J=1 Hz), 7.40 2H-, J=5Hz). MS (DCI/NH 3 in/e 511 HRMS calcd for C 29
H
38
N
2 0 6 511.2808. Found: 511.2809 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yb)-1 -12-(N-n2ropyl-Nw ethoxycarbonylain o'ethvllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 850.80 3H, J=8Hz), 1.05 (in, 2H), 1.22 (in, 3H), 1.45 (in, 3H), 2.08 (br s, 1 2.75 (in, 1 2.88 (br q, 2H, J=8Hz), 3.08 (br mn, 2H), 3.27 (br in, 2H), 3.44 (in, 1 3:54 (dt, 1 H, J=1 ,8Hz), 3.63 1 H, J=8Hz), 3.78 3H), 4.02 (br d, 2H), 5.93 2H), 6.72 1 H, J=8Hz), 6.81 (dd, 1 H, -J=1 ,8Hz), 6.85 2H, J=8Hz), 7.00 1 7.30 2H, J=8Hz). MVS -140-
(DCI/NH
3 m/e 499 Anal calcd for C27H34N207 0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.
Example 1QQ trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)-1-12-(N-methyl-N-(2ethvlbutvryvlamino)ethylpyrrolidine-3-carboxvlic acid To the compound resulting from Example 61B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N-methylmorpholine (50 iiL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 h H 3P 0 4 and brine, dried with Na 2
SO
4 and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61C. The crude product was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 'H NMR (CDCI3, 300 MHz) (mixture of rotamers) 6 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 2H), 1.25-1.75 (m, 2.16 1 2.32 1 2.45 1H), 2.70 1 2.86, 2.94 total 20 3H), 2.95 1 3.35 1 3.52 2H), 3.65 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 1H), 6.84 3H), 6.97 1 7.30 2H). MS
(DCI/NH
3 m/e 497 Anal calcd for C 28
H
36
N
2 0 6 0.25 H 2 0: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 trans.trans-2-(4-Methoxyphenvl-4-(1.3-benzodioxol-5-vl)-1 -12-(N-methyl-N-(2propvlvale ryl)aminoethyl]vprrolidine-3-carboxylic acid SThe title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid.
The crude product was purified by preparative HPLC (Vydac p.C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.
1 H NMR (CDCl 3 300 MHz) 6 0.79 3H, J=8Hz), 0.82 3H, J=8Hz), 1.10 (m, 4H); 1.2-1.5 4H), 2.55 1 2.96 3H), 3.15 (br m, 1 3.32 (br m, 1 H), -141- 3.56 (in, 2H), 3.68 (in, 1 H) 3.68 3H), 3.70 (in, 1 3.80 (in, 2H), 4.65 (br d, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.05 (s, 1 7.42 2H, J=8Hz). MS (OCI/NH 3 m/e 525 Anal calcd for
C
30
H
4
ON
2 0 6 1.25 TFA: C, 58.51; H, 6.23; N, 4.20. Found: C, 58.52; H, 6.28; N, 4.33.
Example JDZ trans. trans-2- (4-M eth oxyphen yl 4-(1 ben zodioxo r1 f2- pro pyl-N- (tert-butyloxycarbonylmethyl)ami no~ethyl~joyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and t-butyi bromoacetate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (ODC1 3 300 MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 2H), 1.19 (s, 9H), 2.12 (mn, 1 2.46 (in, 2H), 2.70 (in, 2.85 (in, 2H), 3.20 2H), 3.40 (dd, 1 H, J=2,8Hz), 3.50 (dt, 1 H, J=2,8Hz), 3.62 1 H, J=8Hz), 3.78 3H), 5.95 2H), 6.72 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.05 1 7.16 2H, J=8Hz). MS (DCI/NH 3 m/e 541 Anal calcd for C 3 oH 4 oN 2
O
7 1.0 H 2 0: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.
Example trans. trans -2-(4-Methioxyphenyl)-4-(1 .3-benzodioxol-5-vl)-l1-12-(N-propyl-N-(n-- :propylaminocarbonylinethyt~amino)ethyllpyrrolidine3carboxylic acid The title compound was prepared by the methods described in Example C 61, but substituting propylamine for inethylamine in Example 61 B and N-propyt bromoacetainide for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac gCl 8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the ego.* 30 product as a white solid. 1 H NMR (C~DC 3 300 MHz) 8 0.78 3H, J=8Hz), 0.88 3H, J=8Hz), 1.45 (in, 2H), 1.48 (in, 3H, J=BHz), 2.55-2.7 (in, 2H), 2.90 (in, 1 3.04 (in, 1 3.15 (in, 3H), 3.28 1 H, J=8Hz), 3.45 1 H, J=8Hz), 3.60 (in, 2H), 3.70 2H, J=8Hz), 3.75 (in, 1 3.80 3H), 4.25 1 H, J=8Hz), -142- 5.95 2H), 6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1 ,8Hz), 6.88 2H, 7.04 1 H, J=1 Hz), 7.40 2H, J=8Hz). MVS (DCI/NH 3 m/e 526 Anal calcd for C 29
H
39
N
3
O
6 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
trans. trans- Meth oxyph enyl)-4-(1 .3 -be nZod oxol-5-yI- -[2-(N-propyl-N-(4methoxyphenoxycarbonylpmino~ethyllpyrrolidineappcrboxyi-c acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61iB and 4methoxyphenylchloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMVR (CD 3 OD, 300 MHz) mixture of rotamers; 8 '0.58 1.57 (in, 2H), 2.45 (br s) and 2.60 (br s, total of 1 2.90-3.15 (in, 4H), 3.42-3.7 (in, 5H), 3.78 3H), 3.80 3.85 (in) and 4.0 (mn, total of 1 5.95 and 5.98 total of 2H), 6.63(m, 1 6.72 1 H, J=8Hz), 6.81 (in, 2H), 6.93 (in, 5H), 7.40 (in, 2H). MS (DCI/NH 3 mWe 577 Anal calcd for C32H 36
N
2 OS -1.0 H 2 0: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N,.
4.63.
trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 -[2-(N-propyl-N- (4methoxybenzoyl)ainino)ethyllpyrrolidi ne-3-carboxylic acd The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified *.by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. 'H NMR (CDC1 3 300 MHz) mixture of rotainers 5 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1.52 J=8Hz) total of 2H, 2.25 (br s, 1 2.78 (br s, 1 2.90 (br t, 2H), 3.12-3.68 (in, 7H), 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 1 H, J=8Hz), 6.83 (in, 5H), 6.94 (in, 1 7.22 (in, 4H). MS (FAB) m/e 561 -143- Anal calcd for C 32
H
36
N
2 0 7 -0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6:38; N, 4.59.
Eam~L~e106 trans. trans-2-(4-Methoxyphenyli-4-(1 .3-benzodioxol-5-yl)-1 4[2-(N-p2ropyl-Nben zoylami no) ethyll pyrro lid*ine-3-carboxvli c acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamnine in Example 618B and benzoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. 1 H NMR
(CDCI
3 300 MHz) mixture of rotamers 5 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (in, total of 1 2.6 3.6 (in, 8H), 5.92 (s, 2H), 6.70(d, 1 H, J=8Hz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH 3 m/e 531 Anal calcd for C 3 1
H
34
N
2 0 6 -0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23.
Found, C, 69.48; H, 6.19; N, 4.84.
Exmple 1QZ trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-yl)-1 -f2-(N-propyl-Nben zyloxycarbo nylami noethvll pyrro li din e-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamnine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac jiCi8) eluting with a 10-70% gradient of
CH
3 CN in 0.1 TEA. The desired fractions were lyophilized to give the product 0 OV.as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.8 (mn, 3H) 1.45 (mn, 2H), 2.20 (br m, 1 2.75 (in, 1 2.93 (in, 1 3.15 (in, 3.32 (in, 3H), 3.52 (in, 2H), 3.66 (in, 1 3.78 3H), 5.00 (in, 2H), 5.94 2H), 6.72(d, 1 H, J=8Hz), 6.82 (in, 7.0 (br d, 1 H, 15Hz), 7.2 7.30 (mn, 3H). MS (FAB) m/e 561 Anal calcd for C3 2 H36N 2 0 7 -1.0 TFA: C, 60.53; H, 5.53; N, 4.15.
Found: C, 60.66; H, 5.34; N, 4.28.
-144trans. trans-2-(4-Methoxvphenyl)-4-(1 .3-benzdoxol-5-yi)-1 -r2-(N-nroPYl-N-(4methoxybenzyloxycarbonyl~amino)ethylljpyrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61 B and 4methoxybenzyl chioroformate for isobutyryl chloride in Example 610C.
Exml 0 trans.trans-2-(4-Methoxyphenyl)-4-(1 .3-be nzodioxol-5-yf)l--[2-(N-butyl-Nethoxycarbonylamino)ethylljpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61 B and ethyl chioroformate for isobutyryl chloride in Example 610C. The crude product was purified by preparative HPLC (Vydac 1±018) eluting with a 10-70% gradient of
CH
3 CN in 0.1 TFA. The desired fractions were lyophilized to give the product as a white solid. I H NMR (CDCl 3 300 MHz) 5 0.82 3H, J=8Hz), 1.20 (in, 1.34 (in, 2H), 3.08 (in, 2H), 3.17 (in, 3.52 (in, 2H), 3.75 (in, 2H), 3.78 (s, 3H), 4.06 2H, J=8Hz), 4.35 (br s, 1 5.94 2H), 6.76 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 (br s, 1 7.17 (br s, 1 7.7 (br s, 2H). MVS (FAB) m/e 513 .:Go Anal calcd for C 28
H
36
N
2
O
7 0.5 TFA: C, 61.15; H, 6.46; N, 4.92.
Found: C, 60.99; H, 6.80; N, 4.93.
ExmlC1 trn.tasC...ehxpeyl--13b zoixl5y)l 1-NbtlN pr oyabnya noehylpro1 d aboyicai isovdi CH3C and wat~tas2-4Mthxper n yop4-( t3bnoivextheprodut)as whi-(-b te 61,8 bt substituting7 byaefr mehyamn in Example,2H,6.3d,1HJ8 6 8 m and p 7opy sld 1 H NMR0 (Od 3 302H)~08 bs H,08 t H, J=8Hz), 0.9 (br nlcac o -145- C29H 38
N
2 0 7 0.15 H 2 0: C, 65.80; H, 7.29; N, -5.29. Found: C, 65.79; H, 7.30; N, 5.21.
Exmg~le 111 trans, trans-2-(4-Methoxvnhenyl)-4.(-1.3-benzodioxol-5-yl)-1 -1 2-(N-prpl lPro 1oxyca rbo nylamin p)ethyll pyrro lid' ne-3-carboxyl' c acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamnine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 31-, J=8Hz), 093 (in, 3H), 1.43 (in, 3H), 1.62 (in, 1 2.15 (br s, 1 2.68-3.45 (in, 3.54 (in, 1 3.66 (in, 1 H), 3.78 3H), 3.94 (in, 2H), 5.94 2H), 6.72 1 H, J=8Hz), 6.82 (mn, 1 6.84 2H, J=8Hz), 7.00 (br s, 1 7.33 (in, 2H). MS (DCI/NH 3 m/e 513 Anal calcd for C28H 36
N
2 0 7 -0.15 H 2 0: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.
Os. 20 trans, trans-i 1-(N=-Di (n-butyflainocabonyl)methyl..4di( .3-benodioxoI-.ylpyrrolidine-3-carhoxvlic aci-d a.**Ethyl (3 4 met hyle nedioxybe nzoy1) acetate, prepared by the method of Krapcho et al, Org. Syn. A.Z, 20 (1967) starting with 3,4a. methylenedioxyacetophenone instead of 4 -methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. in.p. 58-60 1 H NMR (ODC1 3 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (in, 6H), 2.80 J=1 3Hz, 1 H), 2.94-3.12 (in, 4H), 3.28-3.50 (mn, 4H), 3.58-3.62 (in, 1 3.78 J=9Hz, 1 H), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (in, 2H), 6.92 J=1 Hz, 1 H), 7.01 H=1 Hz, 1 MS (DCI/NH 3 in/e 525 Example11 -146trans. trans-i- (N-(n-ButyI)-N -pro pylsu If onylami no~lethyI)-2-(4methoxyohenyl)-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title Compound was prepared as a white solid. mn.p. 64-65 0C. 1 H NMR (CDC1 3 300 MHz) 6 0.83 (t, J=7Hz, 3H), 0.98 J=7Hz, 3H), 1.12-1.25 (in, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2H), 2.72-3.32 (in, 8H), 3.43 (dd, J=9Hz, 3Hz, 1 3.53-3.59 (in, 1 3.65 J=9Hz, 1 3.80 3H). 5.95 2H), 6.73 (d, J=8Hz, 1 6.83 (dd, J=8Hz, 1 Hz, 1 6.88 J=9Hz, 2H), 7.02 J=1 Hz, 1 7.33 J=9Hz, MS (DCI/NH 3 m/e 547 (M+H) 4 trans trans-1 n-butyflaminocarbonylmethyl)-2-(4-methoxvlphenyl)-4- (1 .3-benzodioxol-5-yflpyrrolidine-3-carboxylic acid Using the procedures described in Examples 25 and 43, the title compound was prepared as a white solid. m.p. 74-76 0 C. 1 H NMR (ODC1 3 300 MHz) 860.50 J=6Hz, 3H), 0.88 J=8 Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=1l2Hz, 1 2.95-3.09 (in, 3.26-3.59 (in, 3.75 J=9Hz, 1 3.79 3H), 4.28 6.78 J=9Hz, 1 6.85 (d, J=9Hz, 2H), 6.91 J=3Hz, 9Hz, 1 6.98 J=3Hz, 1 7.32 J=9Hz, 2H). MS (DCI/NH 3 m/e 525 tran s. tra ns- 1 (N -P ropyl- N-p ropl su lfon y Iam in o)et hyQ)-2- meth oxYp2h e n Yr- 1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was 0 V prepared as a white solid. mn.p. 72-73 00. IH NMR (CDCI 3 300 MHz) 6 0.79 (t, J=8Hz, 3H), 0.98 J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, 2H), 2.22-2.32 (in, 1 2.69-3.32 (in, 9H), 3.42 (dd, J=3Hz, 12Hz, 1 3.52- 3.58 (mn, 1 3.64 J=1l2Hz, 1 3.80 3H), 5.95 2H), 6.73 J=1llHz, 1 6.83 (dd, J=1 Hz, 11 Hz, 1 6.87 J=1l1Hz, 2H), 7.0 J=2Hz, 1 H),-7.32 J=1 1 Hz, 2H). MS (DCI/NH 3 mn/e 533 Exml 1 -147trans.trans-i -(2-(N-Butyl-N-butylsulfonvlami no)ethyl)-2-(4-methoxyphenyln-4- (1 .3-benzodioxol-5-yl)pyrrolidine-3-Carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 00. 1 H NMR (CDC1 3 300 MHz) 5 0.82 (t, J=6Hz, 3H), 0.91 J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-1.42 (in, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (in, 1 2.70-3.28 (in, 9H), 3.41 J=8Hz, 1 3.52-3.58 (in, 1 3.65 J=8Hz, 1 3.79 3H), 5.95 2H), 6.72 (d, J=8Hz, 1 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.01 1 7.32 (d, J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Example 117 trans.tranis-1 -(2-(N.N-Dibutylaminocarbonylmethyl)-2-(4methoxymethoxyphenyl)-4-(1 .3-benzodioxol-5-y)pyrrolidine-3-carboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THIF at room temperature to give ethyl 4methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid. m.p. 48- 49 0C. 1 H NMR (C6C1 3 300 MHz) 5 0.81 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 41H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d, J=1l2Hz, 1 H) 2.94-3.10 (in, 4H), 3.25-3.35 (in, 1 3.40 J=1l2Hz, 1 3.43- 3.52 (in, 2H), 3.47 3H), 3.55-3.62 (in, 1 3.77 J=9Hz, 1 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1 6.86 (dd, J=1 Hz, 8Hz, 1 7.0 J=8Hz, 2H), 7.04 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 541 Examnie118 trans. trans-i .N-Dibutylamninocarbonylmethyl)-2-4- ydroxyphenyl)-4-( 1.3- *...benzodioxol-5-yl)pyrrolidine-3-carboxylic acid -hydrochloride sat The compound resulting from Example 116 was treated with concentrated HCl in 1:1 THE-isopropanol to give the title compound as a white solid. m.p. 211-212 00. 1 H NMR (0D 3 00, 300 MHz) 8 0.90 J=8Hz, 6H), 1. 12-1.27 (in, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 1 3.14-3.35 J=9Hz, 1 H), 3.90 (bs, 3H), 4.17 J=1l5Hz, 1 5.96 21H), 6.82-6.93 (in, 4H), 7.03 (d, J=1 Hz, 1 7.42 (bs, 2H). MS (DCI/N H 3 m/e 497 -148trans. trans-l 2 -(N-Isobutyl-N-oropylsulfonylamino)ethyl-2-'4-methoxphenl-.
4-(1 .3-benzodoxol-5-y)pvrrolidine--3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. mn.p. 73-74 0 C. 1 NMVR (CDCI 3 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1 1.74 (sextet, J=8Hz, 2H), 2.23-2.34 (in, 1 2.68-2.98 (in, 7H), 3.08-3.18 (in, 1 3.26-3.42 (in, 2H), 3.52-3.58 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.90 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.86 J=8Hz, 2H), 6.98 J=1 Hz, 1 H), 7.33 J=8Hz, 2H). MS (DCI/N H 3 m/e 547 Example 12trpns.trans-1 -(2-(N-Benzenesulfonyl-N-proylamino~ethyl)2(4.
ineth oxyphe ny)-4-(1 .3-be nzodi oxo -5-vl) pyrro lid' ne-3-carboxylc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 00. 1 HNMR (CDC1 3 300 MHz) 6 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (in, 1 2.62-2.72 (in, 1 H), 2.85-3.05 (in, 4H), 3.12-3.22 (in, 1 3.38 (dd, J=3Hz, 9Hz, 1 3.49-3.57 (in, 1 3.62 J=9Hz, 1 3.82 3H), 5.96 2H), 6.73 J=8Hz, 1 6.84 (dd, J=1 Hz, 8Hz, 1 6.85 J=9Hz, 2H), 7.02 J=1 Hz, 1 7.28 J=9Hz, 2H), 7.39-7.54 (mn, 3H), 7.70 J=7Hz, MS (DCI/NH 3 m/e 567 ExamUle 121 trans, trans-i1 2 (N Meth oxybe nze nesuf on yl)- N -roy Iamin o) et hy h- 25 inethoxyphenyl)-4-(1 .3-benzodioxol-5-ylprrolidne-3--carboxylic acid OV. Using the procedures described in Example 66, the title compound was I prepared as a white solid. mn.p. 96-97 CC. 'H NMR (CDC1 3 300 MHz) 5 0.73 (t, 0..J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1 2.62-2.7 1 (in, 1 H), V....2.82-3.03 (mn, 4H), 3.08-3.18 (mn, 2H), 3.38 (dd, J=3Hz, 9Hz, 1 3.48-3.56 (in, 0 0 30 1 3.62 J=9Hz, 1 3.81 3H), 3.86 3H), 5.95 2H), 6.73 1 6.81 -6.89 (mn, 5H), 7.01 J=1 Hz, 1 7.28 J=8Hz, 2H), 7.62 (d, J=8Hz, 2H). MS (DCI/NH 3 m/e 597 -149trans. trzns-i N- Di (n-butyl) ami nocarbo nylImet hYfl-2-(2-mehO~ethoxy-4methox yphenyl)-4-(1 .3-benzodioxol-5-yl) pyrrolidine-3-carboxylic acid was treated with sodium hydride and bromoethyl methyl ether in THF at 70 00C to provide ethyl 2m ethoxyet hoxy-4- methoxybe nzoyl acetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 63- 1 H NMR (ODC1 3 .300 MHz) 8 0.84 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (in, 3H), 3.26-3.36 (in, 3.43 3H), 3.47-3.54 (mn, 3H), 3.66-3.72 (in, 2H), 3.78 3H), 3.76-3.84 (in, 1 4.02-4.10 (in, 2H), 4.25 (d, J=9Hz, 1 5.92 2H), 6.40 J=2Hz, 1 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 J=8Hz, 1 6.83 (dd, J=1 Hz, 8Hz, 1 5.98 J=2Hz, 1 7.53 J=9Hz, 1 MS (DCI/N H 3 m/e 585 Examole 1 trans. -trans-1 -(2-(N-Propyl-N-(2.4-dimethylbenzenesulfonyl)aninoethyl)-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yflpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 I1 NMR (CDC1 3 300 MHz) 8 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1 2.32 3H), 2.47 (s, 3H), 2.62-2.69 (in, 1 2.78 J=9Hz, 1 2.89 (dd, J=8Hz, 1 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (mn, 1 3.60 J=9Hz, 1 3.82 (s, 3H), 5.96 2H), 6.72 J=7Hz, 1 6.80 (dd, J=1 Hz, 9Hz, 1 6.86 (d, J=9Hz, 2H), 6.97 J=1 Hz, 1 7.03 (bs, 2H), 7.29 J=9.Hz, 1 MS (DCI/N H 3 m/e 595 (M+H) 4 trans. trans-i -(2-(N-Propyl-N-(3-chloro prgpylsulfo~yflamino)ethyl)-2-(4methoxyphenyfl-4-(1 .3-benzodioxol-5-vl)pyrrolidine-3-ciarboxylic acid 30 Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 00. 1 HNMVR (CDC1 3 300 MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (in, 3H), 2.70-2.80 (in, 1 H), 2.85-3.10 (in, 6H), 3.23-3.31 (mn, 2H), 3.43 (bd, J=9Hz, 1 3.55-3.66 (in, 4H), -150- 3.51 5.94 6.73 J=8Hz, 1 6.82 J=8Hz, 1 6.86 (d, J=8Hz, 2H), 7.00 1 7.33 J=8Hz, 2H). MS (DCI/NH 3 m/e 567 Exml 2 trans. trans-l1 Propyl-N- methoxyethylsulfonyl)ami no)ethy)-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-y)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, trans,trans-l Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1 ,3-benzodioxolne-3-carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid. m.p. 62-64 0 C. 1 NMR (ODC1 3 300 MHz) 8 0.78 J=7Hz, 1 .42 (sextet, J=7Hz, 2.23-2.32 (in, 1 2.72-2.79 (in,l 2.56-3.05 (in, 4H), 3.10-3.27 (in, 3.32 3.43 (dd, J=3Hz, 9Hz, 1 3.53-3.58 (in, 1 H), 3.65 J=9Hz, 1 3.69 J=6Hz, 3.80 5.94 2H), 6.73 (d, J=8Hz, 1 6.82 (dd, J=1 Hz, 8Hz, 1 6.87 J=5Hz, 7.02 J=1 Hz, 1 7.33 J=8Hz, 2H). MS (DCI/NH 3 m/e 549 Exmple 26 trans, trans-i1 -(2-(N-Propyl-N-(2-ethoxyethylsulfonyl~amino~ethyl)-2-(4methoxyphe nyl)-4-(1 .3 -be nzodioxo 1-5-YI)pyrro lid*ine-3-carboxyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 58-60 T0. 1 H NMR (ODC1 3 ,300 MHz) 860.78 (t, J=7Hz, 3H), 1. 18 J=7Hz, 1.43 (sextet, J=7Hz, 2H), 2.24-2.33 (mn, 1 H), 2.70-2.80 (in, 1 2.87-3.05 (nm, 4H), 3.13-3.20 (mn, 3.22-3.32 (in, 3.42 (dd, J=2Hz, 9Hz, 1 3.46 J=7Hz, 2H), 3.52-3.58 (in, 1 3.65 (d J=9Hz, 1 3.72 J=6Hz, 2H), 3.80 3H), 5.95 2H), 6.73 J=7Hz, 1 6.83 (dd, J=1 Hz, 7Hz, 1 6.87 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H).
MS (DCI/NH 3 m/e 563 -151- ExampIl 27 trans.trans-l -(2-(N-Propyl-N-(5-dimethylamilo-1 naphthylsulfonyI~amino~ethyl)-2-(4-methoxyrhel)- 4 yl)pyrroli di ne-3-carboxylic acid Using the procedures. described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 0 C. 1 NMR (CDC1 3 300 MHz) 0.62 J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2.12-2.20 (in, 1 2.78 J=9Hz, 1 2.88 6H), 2.72-2.89 (in, 1 3.05-3.12 (in, 2H), 3.26-3.45 (in, 3H), 3.45- 3.52 (in, 1 3.58 J=9Hz, 1 6.97 J=1 Hz, 1 7.13 J=7Hz, 1 7.26 J=8Hz, 1 7.42-7.50 (in, 2H), 8.08 (dd, J=1 Hz, 7Hz, 1 8.20 J=8Hz, 1 8.48 J=8Hz, 1 MS (DCI/NH 3 m/e 660 Exawml~l1 trans.trans-1 Pro pyl- N-(ethyl suIfo nyl) ami n oethyfl-2- (4-methoxyphe naf- 4-(1 .3-benzodioxol-5--yl'pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 00. 1 HNMVR (CDC1 3 300 MHz) 6 0.79 (t, J=8Hz, 3H), 1.28 J=7Hz, 3H), 1.43 J=5Hz, 2.22-2.30 (in, 1 2.71 2.80 (in, 1 2.82-3.10 (in, 6H), 3.18-3.32 (in, 2H), 3.43 (dcf, J=3Hz, 9Hz, 1 H), 3.53-3.60 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.96 2H), 6.73 (d, J=7Hz, 1 6.82 (dd, J=1 Hz, 7Hz, 1 6.88 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (DCt/NH 3 m/e 519 trans.trans-1 -(2-(N-Plropyl-N-(4-methylbenzenesulfonyl)ainino)ethyfl-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yflpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared'as a white solid. m.p. 78-79 00. 1 HNMR (ODC1 3 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1 2.40 3H), 2.61-2.72 (mn, 1 2.83-3.05 (in, 4H), 3.08-3.19 (mn 2H), 3.48 (dd, J=3Hz, 9Hz, 1 3.49- 1 3.57 (in, 1 3.62 J=9Hz, 1 3.81 3H), 5.95 2H), 6.73 J=8Hz, 1 H), -152- 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.00 1 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Hz, MIS (DCI/NH 3 m/e 581 trans. trans-1 -N-Di(n-butvl)aminocarbonylmethyl).2.(3pyridyI) 4 (l 3.
benzodioxol-5.yflpyrlidine3carboxylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by -the procedures described in Example i to provide the title compound as a white solid. m.p. 167-1 68 0
C.
1 H NMR (ODC1 3 300 MHz) 5 0.82 J-7Hz, 3H), 0.89 J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (in, 6H), 2.86-3.20 (in, 6H), 3.34-3.43 (mn, 2H), 3.57 (dd, J=3Hz, 9Hz, 1 3.75-3.83 (mn, 1 4.08 J=9Hz, 1 5.93 2H), 6.73 J=8Hz, 1 6.90 (dd, J=2Hz, 8Hz, 1 7.03 J=2Hz, 1 7.38 (dd, J=4Hz, 8Hz, 1 8.04 J=8Hz, 1 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCI/N H 3 m/e 482 trans. trans- 1 2 -(N-Propyl-N-(n-butylsuIf ony1)ainino)ethylV-2-( 4 inethoxyphenyl)-4-(11.
3 -benzodioxol-5-y)pyrrolidine.3-crboxlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 OC. 1 H NMR (C0013, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.31-1.46 (in, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (mn, 1 2.70-3.08 (mn, 7H), 3.12-3.23 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 3.52-3.58 (in, 1 3.64 J=9Hz, 1 3.50 3H), 5.96 2H), 6.72 (d, J=7Hz, 1 6.83 (dd, J=1 Hz, 7Hz, 1 6.86 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (001/NH 3 m/e 547 .trans. trans-i1 2 Propyl-N- (4-ch lo robe nzene su fonyllani no)et hvl) 30 inethoxyphenyl)-4-(1 3 -benzodioxol-5-yl pyrroldine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106'-C.
I
1 H NMR (CDCl 3 300 MHz) 8 0.72 J=7Hz, 3H), 1.34 (sextet, J=7Hzin 2H), 2.56-2.62 (in, 1 2.78-2.86 (in, 1 2.96-3.03 (in, 3H), 3.1 3-3.26 (in, 3H), 3.51 (dd, J=5Hz, 9Hz, 1 3.62-3.68 -153- (in, 1 3.80 3H), 3.94 J=9Hz, 1 5.92 2H), 6.75 J=8Hz, 1 6.84 (dd, J=2Hz, 8Hz, 1 6.94 J=8Hz, 6.98 J=2Hz, 1 7.36 J=8 Hz, 1 7.49 J=8Hz, 1 7.68 J=8Hz, 1 MS (DCI/NH3) m/e 601 Eall 3 trans.trans-l -(2-(N-Pro~yl-N-(benzylsulfonvl)amino)ethyl)-2-(4meth oxyphe nfl)-4(1 .3 -benzod ioxol--l pyrro 1lidin e- 3-carboxylic -acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 00. 1 H NMR (CDCI 3 300 MHz) 8 0.72 (t, J=7 Hz, 3 1.32 (sextet, J=7 Hz, 2 2.06-2.16 (in, 1 2.56-2.67 (in, 1 H), 2.75-3.10 (in, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 5.95 2H), 6.73 J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 7Hz, 1 6.86 J=8Hz, 6.97 J=1 Hz, 1 7.27-7.35 (in, 7H). MS (DCI/NH 3 m/e 581 Example 13 trans.trans-1 -(2-(N-Propyl-N-(4-fluorobenzenesulfonylamno~ethyl)-2-(4methoxyphe nyl)-4-(1 .3-benzodioxol-5-yI) pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 00. I H NMR (CDCI 3 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2.18-2.27 (in, 1 2.56-2.67 (in, 1 H), 2.78-2.87 (mn, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (mn, 2H), 3.33 (dd, J=2Hz, 9Hz, 1 3.43-3.50 (in, 1 3.57 J=9Hz, 1 3.78 3H), 7.08 J=8Hz, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, J=5Hz, 8Hz, MS (DCI/NH 3 in/e 585 frans.trans-l -(N-Methyl-N-propylaminocarbonylmethyfl-2-(4-methoxyphenyl)-4- (4-benzofuranyl)pyrrolidine-3-carboxylic acid Ben zofu ran-4-carboxald ehyde a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 minol, 1.25 eq) in DMF (60 inL) at 0 OC was added a solution of 3-bromophenol (13.8 g, 80 inmol) in DMF (5 mL). After 10 minutes, broinoacetaldehyde diethyl -154acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO 4 filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, b.p. 160-163 OC at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yield a colorless liquid (8.13 g, b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether mL) at -78 OC was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 After stirring for 15 minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated. The organic solution was dried over MgSO 4 and concentated in vacuo. The residue was purified by flash 20 chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 both as colorless oils.
Example 135B trans. trans-1 -(N-Methvl-N-Drovylaminocarbonvlmethvl-2-(4-methoxvphenvl)-4- (4-benzofuranvl)pyrrolidine-3-carboxvlic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49A for piperonal. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 5 7.59 30 (1H, t, J=3Hz), 7.4-7.2 (6H, 6.8 (2H, d, J=8Hz), 4.03 (1H, 3.94 (1H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1H, dd, J=8Hz, 7 3Hz), 3.42 (1 H, dd, J=11 Hz, 5Hz), 3.40-2.90 (5H, 2.82 (2.81) (3H, 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 (M+H) Anal.calc. for -155-
C
2 6H 3 0
N
2 0 5 -AcOH: C, 65.87; H, 6.71; N ,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s trans. trans- 1 Methyl-N-propylamni nocarbo nylImet hyl)-2-(4-mehoxYph-enl.4.
(6-benzofuranvl)pyrrolidine-3-carboxylic- acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal. 1 H NMR (300 MHz, ODC1 3 (minor rotamer) 8 7.65 (1 H, bd), 7.60 (11 H, d, J=2Hz), 7.55 (1 H, d, J=8Hz), 7.35 (3H, in), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1 H, dd, J=3Hz, 2Hz) 1 3.83 (2H, in), 3.79 (3H, 3.60-3.0 (7H, in), 2.91 (2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.53 (0.78) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 AnaI.calc. for C 2 6H 30
N
2 0 5 0.5 H 2 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
Example 13 trans. trans-i1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-ineth oxyPhe nyl-4 -(6-benzo-2.3-dihydrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H 2 in. AcOH, followed by preparative hplc) of the compound *...resulting from Example 136 1 H NMR (300 MHz, CDCI 3 (minor rotainer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (11 H, d, J=8Hz), 7.00 (11 H, in), 7.82 (3H, in), 5.40 (1 H, dd, J=1 1 Hz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (11 H, in), 4.10 (11 H, in), 3.88 (1 H, in), 3.79 (3H, 3.60 (11 H, in), 3.35 (11 H, in), 3.19 (2H, t, J=8Hz), 3.00 (4H, in), 2.91 (2.78) 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7 Hz). MS (DC I/NH 3 in/e 453 Anal.calc. for C26H 32
N
2 0 5 -1.25 ~.TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.
9 9 -156trans. trans- 1 -(.-~uyaioabnlrehl--4mtoyhnl--4 benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-Npropyl bromoacetamidle. 1 H NMR (300 MHz, CDC1 3 5 7.92 (1 H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 (3H, in), 7.26 (11 H, d, J=2Hz), 7.23 (1 H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8, 6Hz,4Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, 3.67 (1H, dd, J=1l0Hz, 31Hz), 3.44 (2H, in), 3.35-3.15 (3H, in), 3.00 (2H, in), 2.84 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MVS (DCI/NH 3 m/e 507 (M+tH) 4 Anal.calc. for C 30
H
38
N
2 0 5 C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
trans. trans- 1 .N-Dibutylaminocarbonylmethyl)-2-(4-inethoxyphenyl)-4-(4.
ben zofu ranvl)pyrrolidi ne-3-ca rboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 1 35A substituted 4-broinophenol for 3bromophenol, in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 H NMR (300 MHz,
DC
3 8 7.64 (1 H, bd), 7.59 (1 H, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, dl, J=8Hz), 6.85 (2H, dl, J=8Hz), 6.73 (11 H, dd, J=3Hz, 1 Hz), 3.82 (11 H, d, J=1 1 Hz), 3.89 (1 H, d, J=9 Hz) 3.79 (3 H, 3.53 (1 H, dd, J=1 0 Hz, 3 Hz), 3.44 (2 H, in), 3.30 (1 H, in), 3.20-2.95 (5H, in), '2.82 (1 H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (31H, t, J=7Hz). MVS (DCIINH 3 in/e 507
(M+H)
4 Anal.calc. for C30H3 8
N
2 05: C, 71 .12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
Exmple 14 -157trans. trans-i1 N- D'butylami nocarbo nylm ethyl)-2-(4- methoxyphenyl) ben zofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-Npropyl bromoacetamide. 1 H NMR (300 MHz, CDCI 3 5 7.63 (1 H, bd), 7.59 (1 H, d, J=2Hz), 7.53 (1 H, d, J=8Hz), 7.36 (3H, in), 6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=1 1 Hz), 3.89 (1 H, d, J=9Hz) 3.79 3.53 (1 H, dd, J=1lOHz, 3H-z), 3.44 (2H, in), 3.30 (1 H, in), 3.20-2.95 (5H, in), 2.80 (1 H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 t, J=7Hz), 0.82 (3H, t, MS (DCI/NH 3 m/e 507 Anal.calc. for
C
30
H
38
N
2 0 5 -0.75 H 2 0: 0, 69.25; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.
Exmpe 41 tran's.trpns-1 N -Di butylam in ocarbo nyl methyl)-2-(4-inethoxyph enyl)-4- (6be nzo-? .3-dihydrofuranyl)pyrrolidi ne-3-carboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H 2 in AcOH, followed by preparative hplc). 1 H NMR (300 MHz, ODC1 3 5 7.40 (2H, d, J=8Hz), 7.16 (1 H, d, J=8Hz), 6.97 (1 H, dd, J=8Hz, 2Hz), 6.89 (3H, in), 5.90 (1 H, bs) 4.57 (21H, t, J=9Hz), 4.93 (2H, in), 3.80 (3H, 3.70-3.58 mn), 3.40 (1 H, in), 3.30-2.90 (8H, in), 1.40 (2H, in), 1.29 (3H, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCIINH 3 in/e 509 Anal.calc. for *25 C 30
H
4
ON
2 0 5 .0.85 TEA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
trans. trans- 1 (N-Methyl- N-propylamin ocarbo nylmethyl)-2-(4-meth oxyp hen YU-4 30 (5-indanyl)o2yrrolidine-3-carboxylic acid *V 0.
-158- Example1AA was prepared by formylation of indane under the conditions described for 2,3-di hydrobenzof uran in Example 52A. The resultant mixture of 4- and 5-carboxaldehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indlane-5-carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystallized from hot acetonitrile to yield the 5-aldimine as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 41h1 hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether. The organic solution was dried over MgSO 4 fiftered, and concentated in vacuo.
Vacuum distillation of the residue afforded indane-5-carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 00 at 0.9 mm Hg.
trans. trans-i1 Methyl- N-propylam inocarbo nyl methvI)-2(4- metoxyD henvl)- 4 (5-indanvlpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 (minor rotamer) 8 7.25-7.1 (5H, in), 6.78 (2H, d, J=8Hz), 3.89 (1 H, d, J=8Hz), 3.75 (3H, 3.50-2.90 (6H, in), 2.88 (6H, t, J=GHz), 2.82 (2.80) (3H, 2.04 t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 473 25 Anal.calc. for C27H 34
N
2 0 4 -2.5 H 2 0 C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.
trans. trans-i1 Methyl-N-propylaminocarbonylmethyl)2.(4..methoxyhe nyl)-4- 30 (6-indolyl) pyrro lodene-3-carboxyloc acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 8 8.43 (1 H, brs), 7.57 (1 H, d, -159- J=8Hz), 7.43 (1 H, 7.31 (2H, dd, J=6Hz, 3H-z), 7.22 (1 H, d, J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1 H, in), 3.93 (1 H, dd, J=6Hz, 3Hz), 3.80 (1 H, in), 3.73 (3H, 3.60-2.90 in), 2.86 (2.82) (3H, 1.47 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MVS (DCI/NH 3 m/e 450. Anal-calc. for C 26
H
31
N
3 0 4 0.75 H 2 0: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
Example14 trans. trans-i1 Met hyl- N-propyl amin ocarbony Imet hyfl-2-(4-meth oxyP hen yl)-.4- (3.4-difluorophenyl)pvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dif luo robe nzaldlehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 567.60-7.3 (4H, in), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=BHz), 3.90 (1 H, mn), 3.79 (3H, 3.60-2.95 (6H, in), 2.92 (2.78) (3H, 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz).
MS (DCI/NH 3 m/e 447 Anal.calc. for C 24
H
28
F
2
N
2
O
4 -1 .80 H 2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
Example 14 tra ns. trans- 1 -M et hyI- N-p ropyl am in ocarbon y Imet hyl) meth ox Yoh e nyl ***(phenyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 25 Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A.
1 H NMR (300 MHz, CDCI 3 (minor rotamer) 6 7.53 d, J=6Hz), 7.40-7.20 (3H, in), 6.88 (2H, d, J=8Hz), 3.90 (1 H, in), 3.79 (3H, 3.70-2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 411 Anal.calc. for C2 4
H
30
N
2 04 .2.00 H20: C, 64.55; H, 7.67; N, v 30 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
Exml- 46 -1 trans. trans-i1 -(N-Methyl-N-propylaminocarbo nvlmethfl)-2-(4-methoxypfhenv,-4.
(4-hvdroxyp~henylhpyrrolidine--3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3
-CD
3 OD) (minor rotamer) 67.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89 (2H, d, J=8Hz), 3.81 (3H, 3.65 (1 H, d, J=8Hz), 3.70-3.00 in), 2.92 (2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 427 Analcaic. for 0 24
H
30
N
2 0 5 -1 .00 H 2 0: C, 64.85; H, 7.26; N, 6.30.
Found: C, 64.82; H, 7.39; N, 6.46.
Exampl 47 trans, trans-i1 Met hyI- N-gropyvlamnin ocarbo nyl rnethyl) methoxyp2hen l-4- 2 .4-dimethoxyphenvfloyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1 H IMR (300 MHz, CDC1 3 -C D 3 OD) (minor rotamer) 8 7.61 (1 H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 (1 H, in), 3.81 (3H, 3.79 (3H, 3.77.(3H, 3.70-2.90 (8H, in), 2.85 (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/N H 3 m/e 471 AnaI.calc. for C 2 6
H
34
N
2 0 6 0.75 H 2 0: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
E xample _4.
25 trans. trans-i1 .N-Dibutylaminocarbonylmethyl)-2-(4-methoxylheny).4-(5-.
be nzo-2 .3-di hyd rofu ran yl) pyrro I*di ne-3-carboxylic acid :The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 567.31 (2H, d, J=8Hz), 7.27 (1 H, d, J=2Hz), 7.18 (1 H, dd, J=7Hz, 3Hz),'6.86 (2H, d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, 3.62 (1 H, in), 3.50-3.25 (4H, mn), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, in), 2.79 (1 H, d, J=1l4Hz), 1.43 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 -161m/e 509 Anal.calc. for C 30
H
40
N
2 0 5 -0.25 H 2 0: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.
Exmle 149 trans, trans- 1 N-Di butylam in ocarbonyl met hyl)-2-(4- met hoxypheny (4methoxylhenyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedu.res described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 5 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 (3H, 3.63 (1 H, in), 3.50-3.20 (4H, in), 3.15-2.90 (5H, in), 2.78 (1 H, d, J=1 4Hz), 1.43 (3H, in), 1.27 (3H, in), 1.09 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 497 Anal.calc. for C 29
H
4 0
N
2 0 5 C, 70.13; H, 8.12; N, 5.64.
Found: C, 69.78; H, 8.10; N, 5.54.
Exml trans. trans-i1 .N-Dibutylaminocarbonylmethyfl-2-(4-methoxyphenyl)-4-(3 .4difluorophe nyl~pyrrolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 6 7.35 (1 H, in), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, in), 6.87 (2H, d, J=8Hz), 3.78 3.79 (1 H, in), 3.62 (1 H, in), 3.50-3.30 (3H, in), 3.23 (1 H, mn), 3.15-2.90 (4H, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz).
25 MS (DCI/NH 3 m/e 503 Anal.calc. for C 28
H
36
F
2
N
2 0 4 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
trans. trans-i1 N- D4butylamni nocarbo nyl methyl)-2- (4-inethoxyphe ny (2.4diimet hoxyph enyl~pyrro lidi ne-3 -carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-diinet hoxybenzaldehyde for piperonal in Example 49A. 1 HNMR (300 MHz, CDCI 3 8 7.37 (2H, d, J=8Hz), 7.20 (1 H, d, 6.92 (2H, d, J=8Hz), 6.60 (1 H, d, J=3Hz), 6.49 (1 H, dd, J=6Hz, 2Hz), -162- 5.35 (1 H, d, J=8Hz), 4.20 (3H, in), 4.10 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, in), 1.07 (4H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=71Hz). IMS (DCI/NH 3 m/e 527 AnaI.calc. for C 30
H
42
N
2 0 6 1.30 TFA: 0, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
Example 152 trans, trans-i1 N- D*butylami nocarbonyl methyl-2-pheny;-4-(1 .3-benzodioxo I- 5-yI)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B. 1 H NMR (300 MHz, ODC1 3 8 7.50-7.25 (5H, in), 7.04 (1 H, d, J=3Hz), 6.87 (1 H, dd, J=7Hz, 3Hz), 6.74 (1 H, d, J=8Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.85 (1 H, d, J=8Hz), 3.64 (1 H, in), 3.42 (3H, in), 3.27 in), 3.20-2.90 (5H, in), 2.81 (1 H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DOIINH 3 m/e 481 Anal.calc. for
C
28
H
36
N
2 0 5 C, 69.98; H, 7.55; N, 5.83. Found: 0, 69.69; H, 7.63; N, 5.71.
trans. trans- 1 Dibutylainocarbo ny Imet hyl-2-p2henyl-4- ben zo- .3 3.
di hydrofuranyl)pyrrolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in so 00Examples 1 and 49 substituting ethyl benzoylacetate in Example 498 and 2,3for piperonal in Example 49A. 1 HNMR 25 (300 MHz, C~DC 3 6 7.53 (2H, in), 7.40 (4H, in), 7.13 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 5.40 (1 H, d, J=1lOHz), 4.56 (2H, t, J=8Hz), 4.18 (1 H, d, J=1l4Hz), 4.07 (2H, in), 3.79 (2H, in), 3.48 (1 H, d, J=1l4H-z), 3.35 (1 H, in), 3.28 (3H, in), 2.95 (2H, mn), 1.47 (2H, in), 1.28 (4H, in), 1. 10 (2H, in), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS (001/NH 3 mle 479 Anal.calc. for
C
29
H
38
N
2 0 4 1.10 TEA: C, 62.04; H, 6.52; N, 4.64. Found: 0, 61.89; H, 6.44; N, 4.57.
-163- Exmle 14 trans. trans-i1 N- Di butylami nocarbo nyl methyl)-2-(4-t-butyl phe nyl)-4- be nzo-2 .3-di hyd rofu ran ylkgyrro lid* ne-3-carboxyli c acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967) starting from 4-t-butylacetophenone, in Example 49B and 2,3-di hyd robe nzof uran-5-carboxaldehyde for piperonal in Example 49A. I H NMR (300 MHz, CDC1 3 5 7.60-7.30 (6H, in), 6.90 (1 H, in), 4.50 (2H, mn), 3.95 (1 H, in), 3.85-2.95 (11 H, in), 2.90 (1 H, d, J=1l4Hz), 1-.58 (2H, in), 1.50 (7H, in), 1.41 (6H, 1.10 (2H, in), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 535 Anal.calc. for C 33
H
46
N
2 0 4 0.25
H
2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
trans.trans-2-(N .N-Dibutylaininocarbonylnethyl)-2-('4-methoxylhenyl)-4-(4fluorophenyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures descitbed in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 57.50 (11H,mi), 7.42 (1 H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1 H, d, J=8Hz), 3.83 (1 H, in), 3.8 a be:(3H, 3.67 (1 H, in), 3.47 (3H, in), 3.30-2.90 (5H, in), 2.82 (1 H, d, J=1 4Hz), 101.43 (2H, in), 1.28 (4H, in), 1.08 (2H, in), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 485 Anal.calc. for C 2 8H 3 7FN 2 0 4
C,
69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.
trans.trans-1 .N-Dibutylaminocarbonylmethy)-2-(3-furl)-4-(1 .3-benzodioxol- 5-yl)pyrrolidine-3-carboxyloc acid The title compound was prepared by the procedures described in 30 Examples 1 and 49 substituting 0-oxo-3-furanpropionate in Example 498. 1
H
*NMR (300 MHz, CDCI 3 8 7.41 (2H, in), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, in), 3.70-3.25 (5H, in), 3.20-2.90 (4H, in), 2.85 (1 H, d, J=l4Hz), 1.43 (2H, in), 1.40-1.05 (6H, in), 0.90 (6H, in). MS (DCI/NH 3 in/e 471 -164- Anal.calc. for C 26
H
34
N
2 0r 6 C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Exml trans, trans- 1 N- Dibutylami nocarbo nyl methyl)-2- (i sop ropvl)-4- (1 .3- Dyrrolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B. 1H NMR (300 MHz, CDCI 3 8 6.85 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=6Hz, 2Hz), 6.71 (1 H, d, J=8Hz), 5.92 (2H, 3.75 (1 H, d, J=1l4Hz), 3.66 (1 H, q, J=7Hz), 3.42 (3H, in), 3.25 (3H, in), 3.11 2.83 (1 H, t, J=7Hz), 1.88 (1 H, mn), 1.55 (4H, in), 1.32 (4H, in), 0.92 (12H, in). MS (001/NH 3 mle 447 Anal.calc. for
C
25
H
38
N
2 0 5 -0.50 H 2 0: 0, 65.91; H, 8.63; N, 6.15. Found: 0, 66.07; H, 6.10; N, 6.03.
Exml trans, trans-i1 N- Dibutylam i nocarbonyl methyl)-2-(4-t-butylp hen yl)-4- (1 .3benzodioxol-5-yflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4-tbutylacetophe none), in Example 49B. I H NMR (300 MHz, ODC1 3 587.32 (4H, d, J=3Hz), 7.04 (11 H, d, J=2Hz), 6.87 (1 H, dd, J=8Hz, 3Hz), 6.74 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 J=4Hz), 3.77 (1 H, d, J=1l4Hz), 3.65-3.25 25 in), 3.15-2.85 (4H, in), 2.73 (1 H, d, J=l4Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, in), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MVS (DCI/NH 3 m/e 537 Anal.calc. for C 32 H44N 2
O
5 C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
-165trans.trans-1 -(N.N-Dibutylaminocarbonvlmethyl)-2-(4-t-butvlhenyl)-4-(5benzo-2.3-dihvdrofuranyl)pyrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1
H
NMR (300 MHz, CDCI 3 5 7.30 (1 H, 7.13 (1 H, dd, J=7Hz, 2Hz), 6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, 3.19 (3H, 3.80 (3H, 3.48 (2H, 3.3 (5H, 2.41 (1H, 1.65 (4H, 1.44 (4H, 1.21 (3H, d, 1.17 (3H, d, J=5Hz), 1.05 (6H, MS (DCI/NH 3 m/e 445 (M+H) Anal.calc.
for C26H40N 2 0 4 1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Example 160 trans.trans-1 -(N.N-Dibutvlaminocarbonvlmethvl)-2-(anti-4-methoxvcyclohexyll- 4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Example 160A syn and anti Ethyl 4-methoxvcvclohexanovlacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and 20 carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature. At the same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature. The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with 20% ethyl acetate in hexanes.
Pure fractions of the syn and anti methoxycyclohexyl p-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl p-keto ester (914 mg) as a colorless oil and the cis 4-methoxycyclohexyl P keto ester (1.07 g) as a colorless oil.
-166trans. rans- 1 N-Dibutylami nocarbonyl methyfl-2-(anti-4-methoxycyclo hexyl)- 4(1.3 -benzodioxol-5-yflpyrroldine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the anti-compound resulting from Example 160A in Example 496. 1 H NMVR (300 MHz, ODC1 3 866.54 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 3.69 (2H, in), 3.50-3.27 in), 3.26 (3H, 3.25-3.00 (3H, mn), 2.88 (1H, mn), 1.95 (2H, in), 1.62 (7H, in), 1.33 (9H, in), 0.97 (3H, t, J=7Hz), 0.92 t, J=7Hz). MVS (DCI/NH 3 in/e 517 Anal.calc. for C 2 gH44N 2
O
6 0.50 H 2 0: 0, 66.26; H, 8.63; N, 5.33.
Found: 0, 66.27; H, 8.50; N, 5.13.
Examle161 1 trans. trans- 1 .N-Dibutylami nocarbonyl methyl-2-(syrn-4-methoxycQyclohexyL)..
4-(1 .3-benzodioxol-5-yl)pvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A i n Example 49B. 1 H NMVR (300 MHz, CDCI 3 6 6.84 (1 H, d, J=2Hz), 6.77 (1 H, dd, J=6Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 3.65 (2H, mn), 3.42 (2H, mn), 3.32 (3H, 3.30-3.00 (6H, in), 2.82 (1 H, in), 2.10 (2H, in), 1.83 (2H, in), 1.52 (6H, in), 1.33 (4H, in), 1.20-1.00 (4H, in), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MVS (DCI/NH 3 in/e 517 Anal.calc. for C2 9 H44N 2 0 6 0.30
H
2 0: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.
*trans, trans-i1 N-Dibutylami nocarbonyl methyl)-2.4-di (5-enzp-..23 dihydrofuranyl)pyrroldi ne-3-carboxylic acid 5-Acetyl-2 .3-dihyiJrobe nzof uran -167- To a 0 OC solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 The solution was stirred 15 minutes at 0 and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 OC. The dark red solution was stirred 1 hour at 2 OC and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Example 162B trans.trans-1 -(N.N-Dibutylaminocarbonvlmethyl)-2.4-di(5-benzo-2.3dihvdrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in S 20 Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC13) 6 7.43 (1H, 7.38 (1H, 7.06 (2H, 6.75 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, 3.82 (2H, 3.57 (1H, d, J=14Hz), 3.38 (1H, 3.30-3.05 (6H, 2.95 (2H, q, J=6Hz), 1.50 (2H, 1.30 (4H, m), 1.15 (2H, 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 521 (M+H) Anal.calc. for C31H4 0
N
2 0 5 1.25 TFA: C, 60.67; H, 6.27; N, 4.22.
Found: C, 60.49; H, 6.18; N, 4.13.
E 130 *..Exa e 163 Examole 163 -166trans-trans-1 -(N.N-Dibutylaminocarbonylmethyl)-2-(3-furyl)-4-(5-benzo-2.3dihydrofuranyl) oyrro lidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl fP-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A.
1 HNMR (300 MHz, CDCI 3 8 7.42 (1 H, in), 7.38 (1 H, in), 7.13 (1 H, 7.16 (1 H, dd, J=7Hz, 3Hz), 6.70 (1 H, d, J=8Hz), 6.41 (1 H, in), 4.57 (2H, t, J=7Hz), 3.95 (1 H, d, J=8Hz), 3.63 (1 H, in), 3.55 (1 H, d, J=1 3.50-3.5 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, in), 2.87 (1 H, d, J=l4Hz), 1.45 (4H, in), 1.35-1.10 (4H, in), 0.85 (6H, in). MS (DCt/NH 3 mn/e 469 Anal.calc. for C27H 36
N
2 0 5 0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
Exml 6 trans. trans-i1 .N-Dibutylaminocarbonytmethyfl-2-(4-methoxyphenyl)-4-(3fluorophenyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and.49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 5 7.30 (2H, d, J=8Hz), 7.22 (2H, in), 6.91 (1 H, in), 6.86 (2H, d, J=8Hz), 3.79 (1 H, in), 3.78 (3H, 3.68 (1 H, in), 3.55-3.37 (3H, in), 3.29 (1 H, in), 3.15-2.90 (5H, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.25 (4H, in), 1.07 (2H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz).
MS (DCI/NH 3 m/e 485 Anal.calc. for C 28
H
37
FN
2 0 4 -0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.
trans. trans- 1 .N-Dibutylaminocarbonylmethyl)-2-(4-inethoxyphenyl-4zpyridyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et at., Can. J. Chein. 63: 2354 (1985). 1 HNMR (300 MHz, CDC1 3 8 8.82 (1 H, 8.73 (1 H, bd, J=9 Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (1 H, bdd, J=9 Hz, 3 Hz), -169- 7.38 (2H, d, J=lOHz), 6.90 (2H, d, J=lOHz), 4.39 (1H, d, J=l2Hz), 3.95 (1H, in), 3.80 (3H, 3.79 (1 H, in), 3.68 (1 H, d, J=1 8Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, in), 1.31 (4H, in), 1.20 (2H, mn), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 468 AnaI.calc. for C27H 37
N
3
O
4 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
trans.trans-1 -(N.N-Dibutylaminocarbonlmethyl)-2-(2-fluorohenyl)-4-(1 .3benzodioxol-5-yl)p2yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B.
1 HNMR (300 MHz, ODC1 3 5 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25 (1 H, in), 7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H, in), 6.88 (1 H, dd, J=7Hz, 3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 4.25 (1 H, d, J=9Hz), 3.68 (1 H, in), 3.42 (3H, in), 3.39 (1 H, in), 3.20-2.95 (4H, in), 2.91 (1 H, d, J=1l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.57 t, J=7Hz), 0.81 (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 499 Anal.calc. for C 28
H
35
FN
2 0 5 0.25 H 2 0: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.
V trans. trans- 1 (N.N -D ibuty Iam in oc arb o ny Imet h y1)-2-Q -f Iu oro p he ny1)- 4- (1.3 benzodioxol-5-yl~pyrrodi ne-3-carboxylic acid The title compound was prepared by the procedures described in :Examples 1 and 49 substituting ethyl 3-fluorobenzoylacetate in Example 49B.
1H NMR (300 MHz, CDCI 3 5 7.38 (1 H, in), 7.18 (1 H, d, J=7Hz), 7.15 (1 H, in), 7.00 (1 H, d, J=2Hz), 6.95 (1 H, in), 6.86 (11 H, dd, J=7Hz, 2Hz), 6.75 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.94 (1 H, d, J=1 4Hz), 3.63 (1 H, in), 3.42 (3H, in), 3.35-2.95 (5H, in), 2.87 (1 H, d, J=1l4Hz), 1.44 (3H, in), 1.27 (3H, in), 1.10 (2H, in), 0.58 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS
(DCI/NH
3 Wne 499 Anal.calc. for C 28 H35FN 2 0 5 C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
-170- Exapl 16 trans.trans-1 N. N- Dibutylamni nophe nyfl-2- met hoxyph enyb)-4- (1 .3pyrrolidi ne-3-carboxylic acid 4-Nitro-1 -fluorobenzene, ethyl trans, trans-2- methoxyphe nyl)-4- (1 ,3benzodioxol-5-yl)-pyrrolidi ne ,3-carboxylate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl trans, trans-2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -(4-nitrophe nyl)pyrrolidine-3-carboxylate. The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N-dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1 D affords the title compound.
Example 16 trans. trans-i1 .N-Di butylaminopyrimi di n-4-yfl-2-(4-methoxyphenyl)-4- (1 3ne-3-carboxylic acid 2-(Di butylamino)-4-chloropyri midine is prepared from 2,4dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem.
24: 205 (1987) and reacted with ethyl trans, trans-2- methoxyp he nyl)-4- (1,3 ne-3-carboxylate (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example 1iD to the title compound.
Examples 170-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.
Ex. No. Name **17 0 trans, trans- 2-(4 -M eth oxyphe9n yl)-4- (1 ,3-be nzodi oxo1-5-y1)- 1 (isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -171- 171 trans, trans-2-(4-Meth oxyph enyl)-4-(1 ,3-benzodioxol-5-y)- 1 (ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 172 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)-1 methylpropylaminocarbonyl methyl)-pyrrolidi ne-3-carboxylic acid; 173 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-ben zodioxol-5-yI)- 1- (phe nylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 174 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yI)- 1 (piperidi nylcarbonylmethyl)-pyrrolidine-3-carboxylic acid; 175 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo I-5-yI)- 1 (propytaminocarbonyl)ethyl)-pyrrolid ne-3-carboxylic acid; 176 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (propylami nocarbonyl)benzyl)-pyrrolidine-3-carboxylic acid; 177 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)- 1 -(bi s- (pro pylami no carbo nyl1) met hyl)-pyrrolIidi ne-3-carboxyl ic acid; 178 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxo I-5-yI)- 1 (pro pylami nocarbo nylI)et hy1) -pyrrolid i ne-3-carboxy li c acid; 179 trans, trahs-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (propylaminosulfonylmethyl)-pyrrolidine.3carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 phenethyl)-pyrrolidine-3-carboxylic acid; 181 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (pentanoylmethyl)-pyrrolidine-3-carboxylic acid; 18 2 trans, trans- 2-(4-Meth oxyph enyl) ,3-benzodi oxol1-5-y 1 (benzoylmethyl)-pyrrolidine-3-carboxylic acid; 18 3 trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxo1-5-yi) -1 -(hexyl)pyrrolidine-3-carboxylic acid; *184 trans, trans-2- (4-Methoxyph enyl)-4- (1 ,3-be nzodioxoI- 5-y1) 1 (2hexynyl)-pyrrolidine-3-carboxylic acid; 185 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (phe nylacetyl)-pyrrolidi ne-3-carboxylic acid, -172- 187 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxoI1-5-yi)- (anilinylcarbonyl)-pyrrolidi ne-3-carboxylic acid; 188 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5y)-1 acetylaminoethyl)-pyrrolidine-3-carboxylic acid; 189 trans, trans-2-(4-Methoxyphenyl)4-(1 ,3-benzodioxol-5-y)-1 phenoxyethyl)-pyrrolidine-3-carboxylic acid; 190 trans, trans-2-(4-Methoxyphenyl)-4.(1 1 3-benzodioxol-5-yI)- 1 benzodioxanylmethyl)-pyrrolidi ne-3-carboxylic acid; 191 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 tetrahyd rofu ran yl methyl)-pyrro Ii di ne-3-carboxyl ic acid; 192 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonylamino)ethenyl).pyrrolidine.3carboxyic acid; 193 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (propylami nocarbonylamino)ethyl)-pyrrolidi ne-3-carboxylic acid; 194 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxoI-5-yI)-1 oxohex-1 -enyl)-pyrrolidine-3-carboxylic acid; 195 trans, trans-2-(2,4-Dimethoxyphenyl)-4(1 .3-benzodioxol-5-y)-1 (pro pylam inocarbo nyl met hyl) -pyrro i dmne.3-carboxylic acid; 1-96 trans, trans-2-(2- Carboxy-4- met hoxyphe nyl)-4- (1 ,3-be nzodi oxo 1- 06.0 -(propylami nocarbo nyl met hyl)pyrrolidi ne-3-carboxy li c acid; 197 trans, trans-2-(2-Ami nocarbonyl-4methoxyphe nyl)-4(1 ,3benzodioxol-5-yi)- 1 -(propylami nocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; .198 trans, trans-2- Met han esu Ifo namido-4.met hoxyphe ny)4-( 1,3 1 -(propylami nocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; *199 trans, rans-2-(2-Am inocarbonylmethoxy.4methoxyphenyl)- 4 (1 ,3- V, benzodioxol-5-yl)-1 -(propylaminocarbonylmethyl).pyrrolidi ne-3carboxylic acid; 200 trans, trans-2-(2-Methoxyethoxy-4-methoxyphenyl)4-(1,3be nzodioxol-5-yi)- 1 -(propylami nocarbonylmethyl)-pyrrotidine-3carboxylic acid; -173- 201 trans, trans-2-(2-Carboxymethoxy-4-methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 2 02 trans, trans-2-(4-Methoxy-2-tetrazolylmethoxyp henyl)-4- (1,3benzodioxol-5-yI)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 203 trans, trans-2-(2-AIlyloxy-4-methoxyphenyl)-4-(1 yI)-1 -(propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 204 trans, trans 2,4-Bis(4-methoxyphenyl)- 1- (pro pylami nocarbo nyImethyl)-py rro lidi ne- 3-carboxy li c acid; 205 trans,trans 2,4-Bis(1 ,3-benzodioxol-5-yI)-1 (pro pylami nocarbo nyl met hyl)-pyrrolidi ne-3-carboxyli c acid; 206 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)- 1 methyl-N-propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo le-5-y)- 1 (Nmethyl-N-butylaminocarbonyl)-pyrrolidine.3-carboxylic acid; 2 05 8trans, trans-2-(4- Methoxyphe ny1) (1 ,3-benzod ioxo -5-y1) -1 methyl-N-(4-methoxyphe nyl)ami nocarbonyl)-3-pyrrolidi ne-3carboxylic acid; 209 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yl)-1 methyl-N-phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 210 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I- 5 1 92 met hyI- N- allylami nocarbo nyl met hyI)-pyrro li di ne-3-carboxyl ic acid; 211 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yi) 1 :::.methyl-N-(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic ~:.acid; 212 trans, trans-2-(4- Methoxypheny)-4-(1 ,3-benzodioxo I-5-yI) 1 methyl-N-isobutylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 213 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 methyl-N-cyclope ntylami nocarbonylmethyt)-pyrrolidine-3-carboxylic acid; -174- 214 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-beflzodioxoI1-5-yI) 1 methyl-N-(2-methoxyethyl)aminocarbonyl)-pyrrolidne-3-carboxylic acid; 215 trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-be nzodioxo1-5-y) -1 methyl-N-butoxyethylami nocarbonyl)-pyrrolidine-3-carboxylic acid; 216 trans,trans-2 ,3-Be nzodioxol-5-yI)-4-(4-methoxyphenyl)-.1 methyI-N-propylaminocarbonylmethyl)-pyrrolidine3.carboxyic. acid; 217 trans, trans-2-(4-Met hoxyphenyl)-4- (1 ,4-be nzodioxan-6-y)- 1 methyl-N-propylami nocarbonylmethyl)-pyrrolidine-3-carboxylic adid; 218 trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxo 1-5-yI)- 1 methyl-N-isopropylaminocarbonylmethyl).pyrrolidine3carboxylic acid; 219 trans, trans-2 -(4-Met hoxyphenyl)-4- (1 ,3-be nzodioxoI- 5-y1)- 1 methyI-N-ethylaminocar bonylmethy)-pyrroidine.3carboxylic acid; 220 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo 1 methyl-N-(l1 methylpropyl) ami nocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; 221 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo1-5-y)- 1-(Nmethyl-N-phe nylami nocarbonylmethyl)-pyrrolidifle-3-carboxylic acid; 222 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-i1 methyl-N-propylami nocarbonyl)ethyl)-pyrrolidine..3-carboxylic acid; "foes*223 trans, trans-2-(4-Methoxyphe nyl)-4-( 1,3-be nzodioxol-5-y)- 1 (N- **methyl-N-propylamriinocarbonyl)benzyl)-pyrrolidine-3-carboxylic acid; ~2 24 trans, trans-2-(4-Met hoxyphenyl)-4-(1 ,3-benzodioxol1-5-yI)- 1 *r ethyl-N-propylaminocarbonylmethy)-pyrrolidi ne-3-carboxylic acid; 225 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodiaxole-5-yI)- 1 eth yl- N-butylami no carbon yl) -pyrro lid ine-3-carboxyl ic acid; sees226 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 ethyl- N- methoxyp he nyl)ami no carbo nylI)-3-py rrolIi di ne-3too% carboxylic acid; -175- 227 trans, trans-2 Met hoxyph enyl)-4- (1 ,3-be nzod ioxoI- 5-y) -1 ethyl-N-phe nylami nocarbonyl)-pyrrolidine-3-carboxylic acid; 228 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 ethyl-N-allylaminocarbonylmethy)-pyrrolidmne-3-carboxylic acid; 229 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-y)-1 ethyl- N-isobutylami nocarbo nylmethyl)-pyrrolidi ne-3-carboxylic acid; 230 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-y)-1 ethyl-N-cyclopentylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 231 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo1-5-y)- 1-(Nethyl-N-methoxyethylaminocarbonyl)-pyrrolidi ne-3-carboxylic acid; 232 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yI)- 1 ethyl- N-buto xyet hylam i nocarbo n yI)-pyrro lidi ne- 3-carboxyl ic acid; 233 trans, trans-2-(1 ,3-Benzodioxol-5-yI)-4-(4-methoxyphenyl)- 1 ethyl-N-propylaminocarbonyl methyl)-pyrrolidi ne-3-carboxylic acid; 234 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,4benzodioxan-6-y)- 1 ethyl-N-peopylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 235 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yI)-1 ethyl-N-isopropylaminocarbo nylmethyl)-pyrrolidi ne-3-carboxylic acid; 236 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo I-5-yl)- 1 Ndiethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; *237 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo1-5-y) -1 ethyl-N-(1 -methylpropyl)ami nocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; 238 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol1-5-yI)- 1 .*ethyl-N-phe nylami nocarbonyl met hyl)-pyrrolidi ne-3-carboxyli c acid; 239 trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-be nzodioxol-5-yI)- 1 (1 .ethyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid; 2* 240 trans, trans-2 Met hoxyph e n yl) (1 ,3-be nzodi oxol-5-y)- 1 (az-(N ethyl- N-propylami nocarbon yl) benzyl)-pyrrolidi ne-3-carboxyli c acid; -176- 241 trans, trans-2-(4-Methoxyph enyl)-4- (1 ,3-benzodioxo1-5-y) 1 methyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 242 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)-1 methyl-N-cyclohexylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 243 trans, trans-2-(4- Methoxyp henyl)-4-(1 ,3-benzodioxo 1-5-yI1)- 1 Ndipropylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 244 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (isobutyloxyethyl)-pyrrolidine-3-carboxylic acid; 245 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)- 1 (butylsu Ifonyl)-pyrrolidine-3-carboxylic acid; 246 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (isopropylsulfonylaminoethyl)-pyrrolidine.3-carboxylic acid; 247 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (ethoxymethylcarbonylmethyl)-pyrrolidine-3-carboxylic acid; 248 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 ethylbutyryl met hyl)-pyrro lidi ne-3-carboxylic acid; 249 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 methyl-N-(3 ,4-dimethoxybenzyl)aminocarbonylmethyl)-pyrro lidi ne- 3-carboxylic acid; 250 trans, trans-2-(4- Methoxyphe nyl) ,3-be nzo dioxol1-5-yi)- 1 1- (N-methyl-N-propylami nocarbonyl)butyl]-pyrrolidine-3-carboxylic acid; 251 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 1- N (-methyI- N -propy lamin nocarbo nyl)butyl]-pyrro lid ine-3-carboxy Iic acid; 252 trans, trans-2-(4-Methoxyphenyl)74-(1 ,3-benzodioxol-5-y)-1 isopropoxypropyl)-pyrrolidi ne-3-carboxylic acid; 253 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo1-5-yi)- 1 methylhexyl)-pyrrolidine-3-carboxylic acid; 2 54 trans, trans-2- Metho xyp heny (1 ,3-be nzodioxoI- 5-y1)- 1 methyl-2-hexenyl)-pyrfolidine-3-carboxy lic acid; -177- 255 trans, trans-2-(4-Methoxyph enyl)-4- (1 ,3-benzodioxo I-5-yl)- 1 methyl-4-hexenyl)-pyrrolidine-3-carboxylic acid; 256 trans, trans-2-(4- Methoxyphenyl)-4- (1 ,3-benzodioxo I-5-yl)- 1 dimethyl-2-hexe nyl)-pyrrolidine-3-carboxylic acid; 257 trans, trans-2- Met hoxyphe nyl) (1 ,3-be nzodi oxol1-5 1 m ethyl- N-i sobutyrylam i no)eth yl) -pyrro li dine -3-carboxyl ic acid; 258 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo1-5-yl)- 1 methyl-N-(2,2-dimethylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 259 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 ethyl-N-butylami nocarbonylmeth yl)-pyrrolidi ne-3-carboxylic acid; 260 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)- 1 methyl-N-benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 262 trans, trans-2- Meth oxyphe nyl)-4- (5-i ndanyl)- 1 -(N-methyl-Np ropylami noca rbo nylIm ethyl) -py rro lid ine-3-carboxyl ic acid; 262 trans, trans-2-(4- Methoxyphe ny1) (2,3-di hydrobe nzofu ran -5-yl1)- 1 (N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 263 trans, trans-2-(4-Metho xyphenylI)-4-(1 -methylindol-5-yl)-1 -(N-methyl- N -p ropylami no carbo nylImet hyl) -pyrro lid ine-3-carboxylic acid; 264 trans,trans-2-(4-Methoxyphenyl)-4-(2-naphthyl)-1 -(N-methyl-Npropylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; *265 trans, trans-2-(4- Methoxyphe nylI)-4-(1 ,2-di met hoxy-4-phe nyl1)- 1 methyl-N-propylami nocarbonyl methyl)-pyrrolidine-3-carboxylic acid; 266 trans, trans-2- Met h oxyphe nyl)-4-'(1 -methoxy-3-phenyl)- 1 methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; Examples 267-288 ****Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.
a -178- 267 trans, trans-3-(4-MethoxyphelY)5-(1 ,3-benzodioxol-5-yI)-1 (propylami nocarbonylmlethyl)-piPeridi ne-4-carboxylic acid; 268 trans, trans-3-(4-Methoxyphefl)-5-(1 ,3.benzodioxol-5-yI)-1 (ami nocarbonylmethyl)-piperidile-4-carboxylic acid; 269 trans, tranS-3-(4-Methoxyphenfl)-5 (1 ,3-benzodioxol-5-yI)-1 fluorobenzy)-pipeddile-4-carboxyic acid; 270 trans, trans-3-(4-Methoxypheflyl)-5-(1 ,3-benzodioxol-5-yI)-1 ethoxyethyl)pipeidile-4-carboxyic acid; 271 trans, trans-3-(4-Methoxyphel)-5-(1 ,3-benzodioxo I-5-yI)- 1 propoxyethyl)-piperidi ne-4-carboxylic acid; 272 trans, trans-3.-(4- Moth oxyp helyl)-5 (1,3-benzodioxo 1-5-yI1)- 1 methoxyethoxy)ethy1-piperidile4-carboxyic acid; 273 trans, trans-3-(4-Methoxyphef ly) 5 (l ,3-benzodioxol-5-yI)- 1 pyridyl)ethyllpiperidile-4-carboxylic acid; 274 trans, trans-3-(4-Methoxyphefl)-5-(l ,3-benzodioxol-5-yI)-1 (mo rph oli n-4-y Icarbo nyI)-pi pe rid ile-4-carboxyl ic acid; 275 trans, trans-3-(4-Methoxyphel)-5-(1,3-benzodioxole-5-yI)-1 (b utylami nocarbonyl) -pipe rid ie-4-carboxyli c acid; 276 trans, trans-3- (4 -Met hOXyph 9flyl)5-(1 ,3-benzod ioxoI- 5-y) -1 methoxyphenylami nocarbonyl)-3-piperidile-4-carboxylic acid; 277 trans, trans-3.(4-Methoxyphel)-5-( 1,3-benzodioxol-5-yI)-1 acetylpiperidine-3-carboxylic acid; 278 trans, trans-3.(4-Methoxyphefl)-5-(l ,3-benzodioxo I-5-yI)-l furoyl)-piperidine-3-caboxylic acid; 279 trans, trans-3-(4-Methoxypheflyl)-5-(l,3-benzodioxol-5-yl)-1 (ph eny Iamino carbonly)- piperidi e- 4-crboxyic acid; 280 trans, trans-3-(4-MethoxypheflY)5(l ,3-benzodioxol-5-yl)-1 (aIlylaminocarboflmethyI)-piperidifle-4-aboxylic acid; 281 trans, trans-3-(4.Methoxyphefl)Y5-(l,3-benzodioxol-5-yI)-1 butylaminocarboflylmfethyl)-piperidile-4caboxyIIC acid; trans, trans-.3-(4-MethoxyphelYl)-5-(l ,3-benzodioxol-5-y)-1 Z 0 butyI- N-methylaminocarboflmethyI)-piperidile-4-carboxyi~c acid; -179- 283 trans, trans-3-(4-Methoxyphenyl)-5- (1 ,3-benzodioxol-5-y)- 1 (pyrrolidin-1 -ylcarbonylmethyl)-piperidine-4-carboxylic acid; 254 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)- 1 (isobutylaminocarbonylmethyl)-pipe ridi ne-4-carboxylic acid; 285 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)- 1 (cyclo pe nty lam in ocarbo nyl meth y)-pipe ridi ne-4-carboxyli c acid; 286 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)- 1 (morpholin-4-ylami nocarbonylmethyl)-piperidine-4-carboxylic acid; 2 87 trans, trans-3-(4-Methoxyphenyl)-5- (1 ,3-benzodioxol-5-yl)- 1 phenoxyethyl)-piperidi ne-4-carboxylic acid; 288 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)- 1 (methoxyethylami nocarbonyl)-piperidi ne-4-carboxylic acid.
Example 289 trans. trans- 2-(4-Methoxvohenvl)-4-(1 .3-benzodioxol-5-vfl- 1- (4dibutvlaminolhenl)-Dvrrolidine-3-carboxylic acid 4-Nitro-fluorobenizene, ethyl trans, trans-2-(4-methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di-isopropyl ethylamine are heated in dioxane to give ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(4-nitrophenyl)-pyrrolidine-3carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch Am Chem. Soc., 93, :2897, 1971) to give the corresponding N,N-dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
Eample 290 trans. trans-2-(4-Methoxyghenyl)-4-(1 .3-benzocioxol-5-yl)-1 -(2-dibutylaminopyrimidine-4-vyi)v2rrolidi ne-3-carboxvlic acid 2-(Dibutylamino) 4-chloropyrimidine. is prepared from 2-4dichloropyrimidine according to the method of Gershon Heterocyclic Chem.
24, 205, 1987). This compound, ethyl trans, trans-2-(4-methoxyphenyl)-4-(1 ,3- -180benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
trans. trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl-1 -(N-butyl-Np 1henylaminocarbonylmethyl-pyrroidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1.
MS (DCI/NH 3 53.1 Anal calcd for C 31
H
34
N
2 0 6 70.17; H, 6.46; N, 5.28. Found: C, 70.36; H, 6.52; N, 4.99.
NMVR (CD 3 OD): 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 2H); 3.10 (t,1 H, 3.26 (d,1 H,J=15); 3.44 (dd,1 H,J=5,10); 3.5-3.7 3.77 (m,1 3.78 5.93 6.7-6.9 7.0-7.2 7.4 Sodiumi trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxdl-5-ylr- 1 N-di (nbutyflaminocarbonylmethyl)-pyrrolidine-3-carboxylate Exmple22A Ethyl 3-(4-methoxyphenyl)-3-oxopropionate .:Simultaneous reactions were run in both a 65-L reactor and a reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oil and 32 L toluene were charged into the ambient temperature reactors.
The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for minutes, allowed to settle and 28 L of the toluene solution was aspirated.
68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4-methoxyacetophenone in -181- 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 100 C and stirring continued for 16 hours. A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% aqueous sodium chloride The organinc solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Example 292B 3.4-Methvienedioxv-1 -(2-nitroethenvl)-benzene In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-200 C. The jacket temperature was set 20 to -5 0 C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium hydroxide diluted with 3.7 L water was pumped-in. The reaction temperature was maintained between 100-150 C. When addition was complete, the jacket temperature was reset to 10 C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve o* most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 210 C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 260 C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were -182dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 40 C.
Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg of a second crop. The yellow product darkened on standing in light and air.
Example 292C Ethyl 2-(4-methoxybenzovl)-3-(3.4-methvlenedioxv-phenvl-4-nitro-butanopat Into a 45-L stirred reactor at ambient .temperature were charged 5.819 kg (30.1 moles) 3, 4 -methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate A solution of 5.355 kg (24.1 moles) ethyl 3-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
20 Example 292D Ethyl 2-(4-methoxVDhenvl)-4-(3.4-methvlenedioxyVhenvl)-4.5-dihydro.3Hpyrrol-3-carboxylate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in 25 ethyl acetate) was added to a glass reactor containing RaNi 28 (300 The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until -183crystals formed. The solution was cooled to 00 C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 The solids were dried in vacuo at 500 C to a constant weight of 193.4 g (21% yield, melting point 80-810 C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Example 292 E Ethyl 2 -(4-methoxvDhenvl)-4-(3.4-methvlenedioxvphenvl)-yrrolidine 3carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H -pyrrole-3carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen.
Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCI was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, L of 7% aq. NaHCO3 was added. The reaction mixture was concentrated 20 and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHC03 and once with 2.5 L of 23% aq. NaCI, the dried over 190g MgS04, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
S: Example 292 F SEthyl 2 4 -methoxvhenv)4-(3.4-methvlenedioxvohenvl)- dibutvlaminocarbonvl methyl) pvrrolidine 3-carboxylate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol). The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg -184dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 780 C for 17 hrs. After the disappearance of starting material, the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (00 Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgSO4 and filtered. Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil.
Example 292G ethyl trans, trans 2-(4-methoxvphenvl)-4-(3.4-dioxvohenvyl-pyrrolidine 3carboxvlate and preparation of trans. trans 2-(4-methoxyphenvl)-4-(3.4dioxvphenvl)-pyrrolidine-3-carboxvlic acid Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)-4-(3,4methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol). 16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the 20 mixture was refluxed at 790 C for 1 hr. The mixture was cooled to 150 C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 150 C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether.
The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M HCI was added to the aqueous layer. The aqueous layer was extracted with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCI, dried with 0.298 kg MgSO4 filtered, and concentrated to give 2.132 kg of a dark S*oil. The oil was triturated with 18 L ether. The undesired solids were 30 filtered and saved for later use. The mother liquors were concentrated to obtain 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 650 C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 100 C and -185filtered. The crystals were washed with 2 L ether (00 C) and dried to constant weight in vacuo at 500 C to give 0.846 kg (43% yield, melting point 119-120) of crude product, which was further purified by normal phase silica gel chromatography.
Sodium trans.trans-2-(4-methoxyphenyl)-4-(3.4-methv'enedoxyhenyl)-1 (N .N-dibutylaminocarbo nyl methyl) pyrrolidine 3-carboxylate Into a 20-L flask was charged trans,trans 2-(4-methoxyphenyl)-4-(3,4methyledioxyphenyl)-1-(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3carboxylic acid (0.927 kg, 1.819 mol). A solution of 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried in vacua at 500 C to a constant wyeight of 0.937 kg (97% vield) of the title compound.
trans-trans-2- Met hogyphe nyl) (1 .3-be nzod ioxo 1 [decahydroisoguinolin-2- carbonyl met hyl-pyrro lidi ne-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. MVS
(DCI/NH
3 m/z 521. Anal calcd for C 30
H
36
N
2 0 6 1.3 TFA: C, 58.54; H, 6.62; N, 4.19. Found: C, 58.34; H, 5.58; N, 4.00.
Example 29 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -33 di methylpipe ridinyl- carbonylmethyl]-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CID 3 O1D, 300 MHz) indicates presence of rotamers. 8 0.84 (s, 0.86 1.35-1.6 (in, 3.83 5.96 6.81 1 H, J=8), 6.90 (dd, 1 H, J=1 7.01 2H-, 7.03 1 7.47 2H, MVS -186-
(DCI/NH
3 m/z 495. Anal calcd for C28H34N 2 O6. 1.4 TEA: C, 56.55; H, 5.45; N, 4.28. Found: C, 56.52; H, 5.83; N, 4.26.
Example295 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-yl-1 -[2-(N-p2ropyl-N-isobutoxycarbonvlamino)ethyl-jiyrrolidine-3-carboxylic acid The title compound was prepared by the methods dietailed in Example 61, but substituting propylamine for methylamine in Example 61 B and isobutyl chioroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMVR (CDCI 3 300 MHz) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1 2.72 (in, 1 2.90 (in, 2H), 3.10 (in, 2H), 3.25 (mn, 2H), 3.40 (in, 1 3.55 (in, 1 3.62 (in, 1 3.7-3.9 (mn, 2H) 3.78 3H), 5.95 (s, 2H), 6.72 1 H, J= 8Hz), 6.82 (in, 3H), 7.00 1 7.30 2H, J=8Hz). MS
(DCI/NH
3 mWe 527 Anal calcd for C 29
H
38
N
2 0 6 -0.5 H 2 0: C, 65.03; H, 7.34;.N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
trans-trans-2-(4-Methoxyphe nyfl-4-(1 .3-benzodioxol-5-yl)-l1-[1 .2.3.4tetrahydroisogui nolin-2-w carbonylnethyll-pvrro lidi ne-3-carboxylic acid.
title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 2.97 (in, 2H), 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1 H, 25 7.1-7.3 (mn, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH 3 in/z 515.
trans-trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-y)-1 -42-(N-propyl-Ndimethylami nocarbonylamino)ethyll-pyrrolidine-3-carboxylic acid The title compound was prepared by the methods detailed in Example but substituting propylamine for methylamine in Example 61 B and diinethylcarbamyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac g±C1 8) eluting with a 10-70% gradient of CH 3 CN in 0.1 TFA. The desired fractions were lyophilized to give -157the product as a white solid. 1 NMVR (CDCI 3 300 MHz) 8 0.70 3H, 1.28 (in, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (in, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 3H), 4.72 (in, 1 5.95 2H), 6.75 1 H, J= 8Hz), 6.87 (in, 3H), 7.05 1 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 498 Anal calcd for
C
27
H
35
N
3 0 6 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.
Example 298 trans. tran-2-(4-Metho-xyp~henyl)-4-(1 .3-benzodioxol-5fl)- 1 -(2-(N-Propyl-N- (4nitrobenzenesulfonynaminolethyl)ypyrrolidine-3crboxylic acid Using the procedures described in Eample 66, the title compound was prepared as a yellow solid. m.p. 85-870C. 1 H NMR (CDCI3, 300 MHz) 8 0.77 (t, 3H), 1.35 (sextet, J=7.5Hz, 2.20-2.29 (in, 1 2.57-2.66 (in, 1 H), 2.82-3.15 (in, 4H), 3.22 J=7.5Hz, 2H-) 3.38 (dd, J=3Hz,J=9Hz, 1 3.49-3.57 (in, 1 3.59 J=9Hz, 1 3.83 3H), 5.96 2H), 6.73 J=8Hz, 1 6.82 (dd, J=1 Hz,J=8Hz, 1 6.87 J=9Hz, 2H), 6.98 J=1 Hz, 1 7.27 (d.
J=9Hz, 2H), 7.82 =9Hz, 2H), 8.23 J=9Hz,2H). MS (DCI/NH3) nile 612 Eale29 trans. trans-2-(4-Methoxyphenyl).4(1 .3-benzodioxol-5-yfl-1 -(2-(N-propyl-N- npentanesu Ifonylami ng)ethyl-1yrrolidine-3-cprboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 59-61 OC 1 H NMR (CDCI 3 300MHz) 5 0.79 (t, 25 J=7.5Hz, 3H), 0.90 J=6Hz, 3H), 1.26-1.32 (in, 4H), 1.43 (sextet, J=7.5Hz, 2H-), 1.67-1.76 (in, 2H), 2.23-2.32 (in, 1 2.70-3.08 (in, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1 3.52-3.57 (in, 1 3.63 J=9Hz, 1 3.80 3H), 5.95 6.73 J=7.5Hz, 1 6.83 (dd, J=1 Hz,J=7.5Hz, 1 6.87(d, J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=BHz, 2H). MS (DCI/NH 3 in/e 561 188trans, trans-2-(4-M eth oxvo2henvl)-4- (1 .3-be nzodioxo 1-5-vl) -1 (N-Drogl- N trifluoromethoxvbenzenesulfo nyflami no)ethvl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.1I22-124 0 C. 1 NMVR (CD3OD, 300MHz) 8 0.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (mn, 2H), 3.23 (bs, 2H), 3.35-3.45 (in, 2H), 3.52 J=1 0Hz, 1 3.81 J=9Hz, 2H), 3.86 3H), 3.92 J=9Hz, 1 4.63 J=1 0Hz, 1 5.97 6.82 J=9Hz, 1 6.93 (dd, J=3Hz,J=9Hz, 1 7.06-7.08 (in, 3H), 7.46 J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MVS (DCI/NH3), in/e 651 Exmil31 trans, trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-yl)-1 -(2-(N-pro~yl-N-(2methyl-2-propenesu lfonyflamino)ethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71 0 1 H NMR (CDCI3, 300MHz) 5 0.79 (t, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 3H), 2.25-2.35 (mn, 1 2.68- 2.77 (in, 1 2.85-3.28 (in, 7H), 3.40 J=9Hz, 1 3.52-3.68 (in, 2H), 3.66 (d, J=9Hz, 1 3.80 3H), 4.92 1 5.07 1 5.97 2H), 6.74 J=7Hz, 1 6.82-6.89 7.01 (s,1 7.33 J=9Hz, 2H). MVSr (DCI/NH3), in/e 545 Examl 0 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5yl)-1 4f2-ethylgip~eridi nylcarbo nyl met hya-pyrro lidi ne-3-carboxyli c acid.
The title c ompound was prepared using the procedures described in example 1. NMVR (CD 3 QD, 300 MHz) shows a mixture of is omers. 5 0.75 (t, 3H, J=7),11.4-1.7 (in, 8H), 3.84 5.96 2H), 6.83 1 H, 6.91 (d, 1 H, 7.0-7.1 (in, 3H), 7.52 21-, MVS (DCI/NH 3 in/z 495. Anal calcd for C28H34N 2 0 6 1.6 TFA: C, 55.35; H, 5.30; N, 4.14. Found: C, 55.26; H, 5.37; N, 4.01.
-189trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yI)-1 -(2-(N-pQropyl-N- (2methvlpropanesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 0 C. 1 H NMVR (CDCI3, 300 MHz) 8 0.82 (t, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 2.57- 2.75 (in, 2H), 2.84-3.08 (mn, 3H), 3.12-3.21 (in, 1 3.23-3.45 (mn, 1 3.43 (d, J=-1 1 Hz, 1 3.55-3.62 (mn, 1 3.66 J=9Hz, 1 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1 6.83 (dd, J=1 Hz,J=9Hz, 1 6.87(d, J=9Hz, 2H), 7.02 (d; J=1 Hz, 1 7.33 J=9Hz, 2H). MS (DCI/NH3) Wne 547 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -(2-(N-D2ropyl-Nheptanesulfonylanino)ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59 0 C. 1 NMR (CDCI3, 300MHz) 8 0.80(t, 3H), 0.88 J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (in, 1 2.70-3.09(mn, 7H), 3.13-3.32 (in,2H), 3.43(dd, J=3Hz,J=9Hz, 1 3.52-3.58(m,1 3.65(d, J=9Hz, 1 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1 6.83 (dd, J=1 Hz, J=7Hz, 1 6.87(d, J=9Hz, 2H), 7.01(d, J=1 Hz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) Wne 589 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 4f2 (N-propyl-Nethoxycarbonylanino~ethyll-pyrroldine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting ethylainine for methylamine in Example 61 B and ethyl chloroforinate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac jiCl8) eluting with a 10-70% gradient of CH 3 CN in 0.1 TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.90 3H, 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (mn, 2H), 3.78 3H), 3.82 (mn, 4H), 4.10 2H, J=7HZ), 3.5 (br s, 1 H), 5.97 (dd, 2H, J=1 ,7Hz), 6.72 1 H, J= 8Hz), 6.84 (in, 3H), 7.00 1 7.42 (d, -190- 2H, J=8Hz). MS (DCI/NH3) m/e 485 Anal calcd for C26H3 2
N
2 0 7 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl-1 -(2-(N-propyl-NhexanesuIf onyla m ino)eth yl)-p2yrro lid ine-3-carboxyli c acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60 0 C. 1 H NMR (CDC13, 300MHz) 8 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, J=7.5Hz, 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1 2.72-3.08(m, 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1 3.55-3.62(m, 1 3.65 J=1lOHz, 1 3.80(s, 5.96(s, 2H), 6.74(d, J=7.5Hz,1 6.82(d, J=7.SHz,1 6.87(d, J=9Hz, 2H), 7.01 (s,1 H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 15Exml30 trans-trans-2-(4-Ethylphenyl)-4-(1 .3-benzodoxol-5-yl-1 .N-di(nbutyl)am inocarbo ny I met hyll]-pyrro 1idi ne-3-carboxyli c acid.
The title compound was prepared using the procedures described in 9% 0 examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 4Z, 20 (1967) starting with 4'ethylacetophe none) in proQedure 49B. NMR (ODC1 3 300 MHz) 5 7.31 (2H, d, J=BHz), 7.16 (2H, d, 4=5Hz), 7.03 (1 H, d, J=3Hz), 6.86 (1 H, dd, J=8&3Hz), 6.73 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1 H, in), 3.53-3.23 (5H, in), 3.13-2.90 (4H, mn), 2.73 (1 H, d, J=1l4H-z), 2.62 *25 (2H, q, J=9Hz), 1.45 (2H, in), 1.40-1.10 (6H, in), 1.02 (2H, in), 0.87 t, J=7Hz), 0.78 (3H, t, J=7Hz). in/e (DCl, NH 3 509 Anal.calc. for 4
ON
2 0 5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25 see* w* 00.0 -191trans-trans-2- (4-Methogxyph en yl)-4- (1 ben zodi oxo--y)1 -(2-(N-propyl.-(2 ch loroethoxy)carbo nylami no~ethyll-pyrrolidine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61 B and 2-chloroethyl chioroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether! hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. I H NMR (ODC1 3 300 MHz) 8 0.80 3H, 1.22 (in, 3H), 2.15 (in, 1 2.75 (mn, 1 H), 2.85 (in, 1 3.1 (in, 2H), 3.25 (in, 2H), 3.5 (in, 3H), 3.65 (in, 2H), 3.80 3H), 4.18 (in, 1 4.30 (in, 1 5.98 2H), 6.72 (in, 1 6.82 (in, 3H), 7.00 (in, 1 7.30(m, 2H). MS (DCI/NH 3 mn/e 533 Anal calcd for C27H 33
N
2 0 7 CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
trans-trans-2-(2-Methoxyethyl)-4-41 .3-benzodioxol-5-fl)-l1-[N. N-di(nbutyl)amino carbonylmethy-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1, substituting ethyl 5-inethoxy-3-oxopentanoate for ethyl 4methoxybenzoylacetate in Example 1 A. The title compound is a yellow foam.
1 HNMR (CDC1 3 300 MHz) 5 0.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28- 1.41 (br m, 4H), 1.45-1.63 (br in, 4H), 2.00-2.20 (br in, 2H), 3.06 (br t, J=9Hz, o 1 3.30 and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br m, 4H), 5.92 21-), 6.72 J=8.5Hz, 1 6.82 (dd, J=11.5, 8.5Hz, 1 6.91 J=1 .5Hz, 1 MS (FAB) in/e 463 Anal calcd for 025H38N20 5
-H
2 0: C, 62.48; H, 8.39; N, 25 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
trans. trans-2-(4-Methoxyphenl)-4-(1 .3-benzodoxl-5-y)-1 -(2-(N-ethyl-N-n- Soot of pentanesulfonylamino)ethyL)-pyrrolidine-3-carboxylic acid 30 Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 C. 1 H NMR (CDCI3, 300MHz) 5 0.89(t, J=7Hz, 3H), 1 .06(t, J=7.5Hz, 3H), 1.26-1 .37(m, 4H), 1 .72(quintet, J=7.5Hz, 2H), 2.22-2.32(m,1 2.71 -2.96(m,5H), 3.08-3.30(in,4H), 3.95(d, J=9Hz, 1 3.53- 3.60(in, 1 3.67(d, J=9Hz,1 3.80(s, 1 5.97(s, 2H), 6.73(d, J=9Hz, 1 H), wMNOEN -192- 6.82(d, J=9Hz,1 6.88(d, J=9Hz, 2H),7.02(s,1 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 Exmle31 trans-trans-2-(4-Methoxyphenyl)-4.(1 dicyclohexylami no carbo nylmethyll-pyrrolidine-3-carboxylic acid, The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) 5 1.0-2.0 (in, 20H), 3.0-3.1 (in, 2H), 3.80 3H), 5.95 2H), 6.75 1 H, 6.86 (dd, 1 H, 6.95 2H, J=9), 7.04 1 H, 7.38 2H, MS (DCI/NH 3 m/z 563. Anal calcd for
C
33
H
42
N
2 0 6 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90. Found: C, 69.42; H, 7.29; N, 4.78.
Example 32 trans-trans-2-(4- Met hoxyp hen nyl-4 (1 .3-be nzodi oxo 1-5-yl)- 1 -[2-(N-Propyl-N-tertbutoxycarbonyl ami no~ethyll-pyrro lid* ne-3-carboxyli c acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61C. NMR
(CD
3 OD, 300 MHz) suggests presence of rotamers 5 0.81 3H, 1.2-1.5 (in, 11 3.78 3H), 5.92 (dd, 2H, J=1 6.74 1 H, J=8B), 6.84 (dd, 1 H, 6.92 2H, 6.99 (bd s, 1 7.35 2H, MS (DCI/NH 3 m/z .527. Anal calcd for C29H 38
N
2 0 7 C, 66.14; H, 7.27; N, 5.32. Found: C, 66.,05; H, 7.36; N, 5.15.
trans-trans-2-(4-Methoxy-3-fluorophenyl)-4-(1 .3-benzodoxol-5-l)-1 .N-diUnbutyl)amino- carbonylmethyl-pyrroladine-3-carboxylic- acid, V, The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4methoxy acetophenone. m.p. 142-143 NMR (CDC1 3 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 1.03-1.50 (in, 8H), 2.82 J=l3Hz, 1 2.90- 3.13 (in, 4H), 3.20-3.50 (mn, 3.39 J=1 3H, 1 3.55-3.65 (in, 1 3.82 (d, J=1 0Hz, 1 3.87 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.83- -193- 6.91 (in, 2H), 6.99 J=2Hz, 1 7.06 (in, 2H). Anal calcd for C29H37N 2 0 6
F:
C, 65.89; H, 7.06; N, 5.30. Found: C, 65.82; H, 7.13; N, 5.29.
Eample 31 trans. trans-2-(Propyl)-4- (1 .3-benzodioxol-5-yfl- 1 -(2-(N-proPYL- 2e ntane sulfo nylame no) ethyl) pyrro li dine-3-carboxylic acid Exampl 34A Propyl pentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL 0H 2
CI
2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH 2
CI
2 under a nitrogen atmosphere. The reaction was stirred at 0 0 C for 30 min, then at 0 C for 4 h. The solution was partitioned between 20 mL of 1.0 M aqeous NaHSO 4 and 25 mL CH 2
CI
2 The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na 2
SO
4 filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1 HNMR (ODC1 3 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28-1.50 (br m, 20 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br mn, 2H), 2.98-3.06 (mn, 2H), 3.08 J=6Hz, 2H), 4.10-4.23 (br m, 1 MS (DCI/NH 3 Wne 211 (M+NH 4 Ex* ample 149 Ethyl trans, trans--4-(1 .3-benzodoxol-5-yl)- 1 -(2-bromoethyfl2.
propylpyrrolidi ne-3-carboxylate The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 948 for the pyrrolidine mixture.
pentanesu Ifonylami no)ethyl)pyrrolidine-3-carboxylate A solution of the compound of Example 314A (6.6 mg, 34 pgmol) in 0.1 mL OME was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 pinol). The resulting mixture was stirred at room temperature for -194min, then a solution of the compound of Example 1898 (9.0 mg, 22 .Lmol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra- n-butylammoni um iodide. The reaction was sealed under argon and stirred at 60 00 overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO3, 1 mL water and 5 mL EtOAc.
The organic phase was washed with 1 mL brine, dried by passing through a plug of Na2SO4, and the filtrate concentrated in vacuo to an oil. The crude_ product was purified by preparative TLC (silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg of the title compound as awax.
trans. trans-4-( 1.3-be nzodioxol-5-yfl-2-(Propyl)- 1 (N-proPYL pe ntanesu Ifo nvlami no)eth yl) pvrro lid ine-3-carboxyli c acid The title compound was prepared according to the procedure of Example 710C. 1 H NMR (CDC1 3 300 MHz) 5 0.88-1.00 (in, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (in, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 2H), 6.76 J=8Hz, 1 6.79 (in, 1 H), 6.93 (bjr s, 1 HRMS (FAB) calcd for C 25 H4jN 2 06S 497.2685, found 497.2679.
trans. trans-!2-(4-Methoxyphenvl)-4-(1 .3-benzodoxol-5-yl)-1 -(2-(N-proPYl-Ndimethylsulfamoylamino~ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61 00. 1 H NMR (CDCI3, 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1 2.65(s, 6H), 2.70- 2.79(m, 1 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1 H),3.55 (t, 3.65(d, J=9Hz,1 3.81 31H), 5.96(s,2H), 6.75(d, J=9Hz, 1 H), 6.83(d, J=9Hz, 1 6.88(d, J=9Hz, 2H), 7.02(s, 1 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 -195- Examl 16 trans-trans--2-(4-Methoxphenyrl-4-( 1.3-be nzodioxol-5-yl)-- 1 2-(N-propvl-N-[4methoxyphenyllsulfonylamino)propyl]-pvrrolidine-3-carboxylic acid Exmple 3 Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyl)-4-(1 .3-benzodiox-5-yl) -1 (3-bromooropyl) Dyrrolidi ne-3-carboxyiate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4-methoxyphenyl)-4- (1 ,3-benzodiox-5-yI) -pyrrolidine-3-carboxylate (4.00 g; prepared according to example 1iC), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 1000 for 1.25 hrs.-The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2SO 4 and the solution concentrated.
The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc.
yielding 5.22 of the title compound.
Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyl)-4-(1 .3-benzodiox-5-yl' -1 (3-propvlaminopropyl) pyrrolidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at 800 for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents-were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried (Na2SO 4 The soilution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without purification.
trans-trans-2-(4-Methoxohenyl)-4-( 1.3-benzodoxo-5-yl)- 1 -l2-(N-p2ropyl-N-14- *:methoxyphenylls ulfonylamino)propyl]-pyrrolidine-3-carboxylic acd Using the method described in example'66, the compound prepared in Example 31 6B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylarnine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1 D. NMVR (CDCI 3 300 MHz) 8 0.83 -196- J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (in, 2H), 2.00-2.11 (in, 1 2.40- 2.51 (in, 1 2.69-2.78 (in, 1 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1 6.55 (d, J=8Hz, 3H), 6.93 J=8Hz, 2H), 7.02 J=2Hz, 1 7.29 J=8Hz, 2H), 7.69 J=8Hz, 2H). Anal calcd fcr C 32
H
38
N
2 0 8 S: C, 62.93; H, 6.27; N, 4.59.
Found: 0, 62.97; H, 6.39; N, 4.45.
Exm~l 17 trans-trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -[2-(N-propyl-Npropvlsulfonylami no)propkll-pyrrolidine-3-carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 31 6B was reacted with propanesulfonyl chloride in acetonitri le containing dilsopropylethylainine. The resu ling product was chroinatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1 D. NMVR (CDC 13, 300 MHz) 8 0.85 J=7Hz, 3H),.1.02 J=7Hz, 3H), 1.47-1.60 (in, 2H), 1.65-1.85 (in, 4H), 2.04- 2.16 (in, 1 2.42-2.57 (in, 1 2.72-3.11 (in, 5H), 3.25-3.41 (in, 2H), 3.50-3.62 (in, 2H), 3.80 3H), 5.85 2H), 6.72 J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 7.30 J=9Hz, 2H). Anal calcd for C 28
H
38
N
2 0 7 S C, 61.52; H, 7.01; N, 5.12. Found: C, 61.32; H, 7.01; N, 5.01.
Example 18 trans, trans!!-2-(3- Flu oro-4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yl) 1 propyl-N-pentanesulfonylamino)ethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68 0 C. 1 H NMR (00013, 300MHz) 8 0.81 (t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1 .35(m, 4H), 1 .45(sextet, J=7.5Hz, 2H), 1.68-1 .76(mn, 2H), 2.25-2.33(mn, 1 2.72-2.92(mn, 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,1 3.53- 3.60(mn, I1H), 3.66(d, J=1lOHz, 1 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1 H), 6.82(dd, J=1 Hz,J=8Hz,1 6.92(t, J=8Hz,1 6.97(d, J=1 Hz, 1 7.1 2(d, J=8Hz, 1 7.18(dd, J=1lHz,J=l 2Hz, 1 MS (DCI/NH3) in/e 579 -197trans-trans-2-(4-Pyridinyl)-4-(l-.3-benzodioxol-5-y)- 1 N-di (n-bUtYl)ami no carbonvlmethyll-pyrrolidi ne-3-carboxylic acid.
The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-,(4-pyri dyl) pro pan oate Am. Chem.
Soc. 1993, 115, 11705) in place of ethyl methoxybe nzoyl) acetate. m.p.
131-1 32 0 C. NMR (CDC1 3 300 MHz) 580.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9Hz,. 1 2.97 J=1 3Hz, 1 3.00-3.25 (in, 4H), 3.32 (in, 1 3.39 J=1 3Hz, 1 3.45-3.52 (in, 1 3.67-3.78 (mn, 1 4.10 J=9Hz, 1 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 J=9Hz, 1 6.90 (dd, J=9Hz, 2Hz, 1 7.02 J=2Hz, 1 7.45 J=8Hz, 8.50 J=8Hz, 2H). Anal calcd for C 27
H
35
N
3 0 5 C, 67.34; H, 7.33; N, 8.73. Found: C, 67.39; H, 7.45; N, 8.61.
15Exml32 trans-trans-2-(4-Methoxyohenyl)-4-(1 .3-benzodoxol-5-yl)- 1 -(2-(N-propyl-Ndi ethyl amino carbony lam in o)eth yl -pyrroldi* ne-3-carbo xylic acid, The title compound was prepared using the procedures described in example 61, substituting propylainine for aqueous inethylamine in Example 61 B and diethylcarbamyl chloride for isobutyryl chloride in Example 61 C. NMR
(CD
3 OD, 300 MHz) 8 0.74 3H, 1.09 6H-, 1.33 (in, 2H), 3.17 (q, 4H, 3.78 3H), 4.04 (in, 1 5.93 6.86 1 H, 7.06 (dd, 1 H, 6.94 2H, 7.04 1 H, 7.40 2H, MS (DCI/N H 3 in/z 526. Anal calcd for C 29
H
39
N
3 0 6 0.1 TEA: C, 65.31; H, 7.34; N, 7.82.
Found: C, 65.33; H, 7.43; N, 8.14.
trans-trans-2-(4-Methoxyphenyl)-4- (1.3-be nzodioxol-5-yl)- 1 dimethylpeperidinyl- carbonylmethyl]-pyrrolidi ne-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows mixture of isomers. 8 0.88 3H, 0.93 3H, 3.82 3H), 5.95 6.82 1 H, 6.89 (dd, 1 H, J=1 7.00 d, 2H, 7.03 (mn, 1 7.47 2H, MS (DCI/NH 3 m/z 495.
-198trans-trans-2-(4-Methoxyohenfl)-4-( 1.3-benzodioxol-5-yl-1 N .N-di (sbutyl~amino carbonylmethyll-pyrrolidine-3-carboxylic aciOd.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) suggests a mixture of isomers. 8 0.83 (t, 6H, 1.27 6H, 1.6 (in, 3.79 3H), 5.93 2H), 6.75 1 H, 6.86 1 H, 6.94 2H, 7.03 1 H, 7.35 2H, J=9).
MS (DCI/NH 3 mn/z 511.
Exam23 trans-trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-l)-1 Methylphenyl)-N-butylamino carbonyl methyll-pyrro lid in e-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. MS (DCI/NH 3 m/z 545. Anal calcd for C 32
H
36
N
2 0 6 0.9 H 2 0: C, 68.53; H, 6.79; N, 4.99. Found: C, 68.56; H, 6.62; N, 4.71.
trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-y)-1 Methylphenyl)-N-butylami no carbonl met hyll-pyrro lid in e-3-carboxyli6c acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) d 0.88 3H, 1.2-1.5 (in, 4H), 2.31 3H), 2.8 (in, 2H), 3.14 1 H, J=1 3.3 (in, 1 3.44 (dd, 1 H, J=5,10), 3.53 (in, 1 3.60 2H, 3.79 3H), 3.82 (in, 1 5.93 2H), 6.74 1 H, 6.8-6.9 (in, 7.06 1 H, 7.09 2H-, 7.18 1 H, 7.27 1 H, MS (DCI/NH 3 m/z 545. Anal calcd for C32H 36
N
2 0 6 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 Found: C, 68.70; H, 6.67; N, 4.85.
ode 30 trans, trans-!4-( 1.3-Benzodoxol-5-yI)-2-(benzyloxymethyl)-1-(((N .Ndibutylamino~carbonyl) methyl)pyrrolidine-3-carboxylic Acid -199- Ethyl trans. transm4-(l .3-Be nzod oxo-5-yl)-2 (be nzy oxym ethyl) 1 N dibutylamino)carbonyl) methyl)pyrrolidi ne-3-carboxylate The procedures of Example 1 A-i D were followed, substituting ethyl 4benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0. 18; 1
H
NMR (C~DC 3 300 MHz) 8 0.88 J=7Hz, 6H), 1.17 J=7Hz, 3H), 1.20-1 .34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 J=BHz, 1 2.98-3.30 (in, 5H), 3.39-3.60 (in, 3H), 3.64-3.75 (mn, 2H), 3.92 J-1l4Hz, 1 4.10 (two overlapping q, 2H), 4.53 2H), 5.91 (in, 2H), 6.69 J=9Hz, 1 6.77 (dd, J=1 9Hz, 1 6.91 J=1 .5Hz, 1 MS (DCI/NH 3 m/e 553 Example325B trans, trans-4-(1 .3-Be nzodioxo 1-5-yr)-2-(benzyloxymethyl-1 Ndibutylainino~carbonyl)methyl)pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C, as a colorless glass. TLC MeOH-CH 2
CI
2 Rf 0.13; 1 H NMR (00013, 300 MHz) 8 0.86 J=7Hz), and 0.90 J=7Hz, 6H total), 1. 15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 1 H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 2H), 6.70 J=8Hz, 1 6.54 (dd, J=1 ,8Hz, 1 6.93 J=1 Hz, 1 7.28-7.39 (in, 5H); MS (001/NH 3 m/e 524 30 diuya. *abnlmtylproiie--abxl Th reutn rdcUrmEape35 18m,022mo)ad2 mgo 0 dO).o.hrol..7m tHwssire ne t hyroe fo 8hUh itr a itrd hog lgo ei n h caaytwswahdwt...1 LEOthntecmiedflrt n -200washes were concentrated under reduced pressure to afford the crude product.
Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Example 326B trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(hydroxymethyl)- 1 dibutylamno)carbonyl)methylpyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C.
Example 327 trans.trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-methylprooenamid-3-yi)-1
N-
dibutylamino~carbonylmethyl)pyrrolidne-3-carboxylic acid Example 327A Ethyl trans.trans--4-(1 .3-Benzodioxol-5-yl)-2-(formyl)-l dibutylaminocarbonylImethyl)pyrrolidine-3-carboxylate The title compound is made by selective oxidation using the Swern oxidation with DMSO, oxalyl chloride, ethyldilsopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.
:i Example 327B Ethyl trans. trans--4- (1.3-Benzodioxol-5-y1)-2-(O-tert-butylpropenoat-3-yl)- 1- (((N.N-dbutylamino)carbonyl)methyl)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2
CI
2 solution.
Example 327C= Ethyl trans.trans--4- (i .3-Benzodioxol-5-yl)-2-(propenoc acid-3-yl)-1-(((N.Ndibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2
CI
2 1- Ethyl trans. trans--4-( 1.3-Benzodioxol-5-y)-2-(N-methylpropenamd.3yl). 1- N-dibutylamino)carbonyl)methyl)pyrrolidinpe.3-carboxylate The title compound is produced by condensing the compound of Example 3270 with methylamine hydrochloride in the presence of a carbodiimide N-ethyl-N-(3-dimethylamino)propylcarbodiimide,
DCC).
trans. trans--4-(1 3 -Be-nzodi oxo l-5-fl)-2-(Nmn7ethylpro pen amid..3-YD-1 dibutylamino~arbonyti)methyl~nyrrolidi ne-3-carboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 710C.
trans, trans--4-(1 .3-Benzodioxol--yl2-(1 -hydroxy-2-propen-3-Yl)-1
-N-
dibutylamino~carbonyl~methvl)p2yrrolidine-3.crboxyic acid Ethyl trans. trans--4- (1 .3-Benzodioxol-5-vl)-2-(1 -hydroxv-2-propen-3-yl) Ndibutylami no)carbonvl)methylnyrrolidine.3-carboxylate The title compound is produced by reacting the compound of Example 327C with borane methyl sulfide complex.
25 trans. trans--4-(1 .3-Benzodioxol-5-yl)-2- 1 -hydrox-2-propen-3-yl-1
N-
dfibutylamino~carbonyl~ methyl)pyrrolidine-3-carboxylic acid The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 710C.
Exml 32 trans. trpns--4-(1 3 -Benzodioxol:5--yl)2(Nbenzylaminomethyl)-1
N-
dibutylamino)carbo nvl~methyl)pyrolidi ne-3-carboxylic acid -202- Examle 329A Ethyl trans.trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1 dibutylamino)carbonyllmethyl)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 329B trans. trans--4-(1 .3-Benzodioxol-5-ylW-2-(N-benzylaminomethyl- dibutylamino~carbony methyl)oyrrolidi ne-3-carboxylic acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C.
Example 330 transtrans--4-(1 .3-Benzodoxol-5-yl)-2-(N-acetyl-N-benzylaminomethy)- 1 (((N.N-dibutylamino)carbonyl)methFlpyrrolidine-3-carboxylic acid Example 330A Ethyl trans.trans--4-(1 .3-Benzodioxol-5-yI) -2-(N-acetyl-N-benzylaminomethyu- 1 -(((N.N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.
Example 330B rans. trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylami nomethyl)- 1- (((N.N-dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid OV. The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71 C.
Example 331 trans.trans--4-(1 .3-Benzodioxol-5-yl-2-(ethynyl)-1 dibutylamino~carbonyFl methvliycrrolidi ne-3-carboxlic acid -203- Examle A Ethyl trans.trans--4-(1 .3-Benzodioxol-5-ylr-2-(ethynyl)-1 1 N dibutylamino)carbonvl'methyl)pyrrolidine-3-carboxylate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.
Example 331B trans.trans--4-(1 .3-Benzodoxol-5-yl)-2-(ethynyl)-1 dibutylaminto~carbo nvl~methyl)pyrrolidi ne-3-carboxylicacidd The title compound is produced by reacting the compound of Example 331A with lithium hydroxide according to the procedure of Example 71C.
Example 332 trans.trans--4-(1 .3-Benzodioxol-5-yl)-2-(1 -pentynyl)-l dibutylamino)carbonyl)methylpyrolidine-3..carboxylic acid Examle 332A Ethyl trans. trans--4-(1 .3-Benzodioxol-5-y)r-2-(pentynyl)- 1 Ndibutylamino)carbonyj)methyl)pyrrolidine-3-carboxylate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. Org. Chem. 1989, 54(15), 3618-24).
25 Example trans. trans--4-(1 .3-Benzodoxol-5-yl)-2-(1 -oentynyl)-l .Ndibutylamino)carbonyl)methyl)pyrrolidi e-3-carboxylic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of Example 71C.
-204trans-trans-2- met hoxp hen yl)-4- (1 .3-be nzodoxo-5-y)- 14-2-(2.6dioxopiperodinyfl ethyll-pyrrol'dine-3-carboxylic acid The compound of example 61 A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of example Exm 34 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxol-5-ylU-1 diphenylaminocarbonylmethyl-nyrrolidine-3-carboxylic acid.
The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 0D) 8 2.83 (dd, 1, J 8.1, 2.99 (d, 1, J 15.4), 3.19 1, J 3.49 1, J= 15.3), 3.51 (dd, 1, J 4.6, 3.57 (in, 3.79 3.85 1, J 5.90 6.71 1, J 6.84 (in, 7.04 1, J 7.14-7.16 (in, 7.19-7.34 (mn, MS (DCI/NH 3 m/z 551; Anal Calcd for C 33
H
3 0
N
2
O
6 .0.65H 2 0.0.35C 2
H
5 0C0CH 3 C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
trans-trans-2-(4-Methoxyphenyr)-4-( 1.3-be nzodioxol- .Ndiisopropylaminocarbonylmethyll-pyrrolidine-3-carboxlc acid, The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 0D) 5 0.95 3, J 1.24 3, J 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, J 8.1, 3.14 (t, 1, J 3.32-3.55 (mn, 3.63 (in, 5.92 6.75 1, J 6.85 9. (dd, 1, J 1.7, 6.93 (in, 7.02 1, J 7.35 (in, MS (DCI/NH 3 m/z 483. Anal Calcd for C27H34N206.0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19.
Found: C, 5.74, H, 7.26, N, 5.52.
-205trans. trans-2-(3- Fluo ro-4- methoxyphe nyl)-4-(1 .3-be nzodio xol-5-yi)- 1 propyl-N-butanesulfo nylami no)ethyl)kpvrro lid'ine-3-carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66 0 C. 1 H NMR (CDCI3, 300MHz) 5 0.82(t, J=7.5 Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34-1 .52(m, 4H), 1 .72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1 2.72-2.94(m, 5H), 2.97-3.1 2(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1 3.53-3.60(m, 1 3.67(d, J=9Hz, 1 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J= 8Hz, 1 6.82(d, J=8Hz, 1 6.92(t, J=9Hz, 1 6.97(s, 1 7.1 2(d, J=9Hz, 1 7.1 8(d, J=1 2Hz, 1 MS (DCI/NH3) m/e 565 Using methods described in the above examples, the compounds :disclosed in Table 1 can be prepared.
9,
II
0 -206- TABLE I 4 13 00 H2~Q H3=N a -Th yK~~ a a a 14
H
3 CO i: 12 0 18 21 o 0~0 00
C
dlo 2 0023 6 24 00 22 0 -207- TABLE 1 (cont'd)
R
28 d 31 F 2 0 34
F
2
HC-.
00 00 27
F
3 0..
a31- 0 0C4 o 38T
F
2
HC%C
F
2 0%
F
2 0 S-Th 00 o.o.
0.0.
.:090: r0 42 60 oc 0 v 50 0 0 -208- TABLE 1 (cont'd
P"
52 0 pr fl
Q
5 4 Cx 0 0 56 a 58 0 610 64 "Y Oy" 67' 0 'DQr 76 0 0 0 60 0 63 ay 66 o
Q
0
Y"~
r oy" 00- 0 720om* 75
V'
74 0 0 0 -209- TABLE 1 (cont'd)
R
-0h 79;0 82 0 0 (k 88 0 91 0 94 0 97 100 103 0 0 0 0 ,rky 0 0 0
R
810 840 870 90 0 930 96 0 990 101 9 102 0 0 104 0 -210- TABLE I (cont'd) 106 109 112 115 0
CH,
67 p~ 107
R
H H r, c~ruy" 108 110 114 0 113St qH 3 0 0 H3 K 1175, 116 r 121 0 124U
F
1270&l yNy^ lig I-01 122 120 0 123 "0 126F 129c0 125 128 c1
S*..SS
-211- TABLE 1 (oont'd) a 130UOC$3 133O0 131 OCH 3 134,6 135 137 0 138~8 136 139 0 0 140 143 do 141 144 00O 142 00 145 -or 0 146 0 0"S',j 1474 r 0 0 148 CI 151 d H3 149 do o 150, 00 -212- TABLE 1 (cont'd) 152o 9 155 158 0 161(5 164 0
H
1 5 3 6,1 0 156 0 0 157 0 160 1636:: 159 1626: 1658.
0* 00 00 0000 d -213- Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.
S. OV
OO
-2 14- TABLE 2A
F
COOH
1 0 OH 3 COO H 4 0 mom
COOH
,COOH
0
OCH
3 R-
COOH
0
F
R- 0 0600 0 *00
I
0 6000 0 00 0 0 0~ I. 0*
MOM
FF
MOMO
R
,-OOH
SO lb
I
MOMO
F 12
OCH
3 00CH 3 -215- TABLE 2A (cont'd)
F
R-N
OC~b 14
F
R- OCOOH mom
.,COOH
H
3
VACOOH
0
OCH,
.COOH
omom
~.COOH
0
OCH
3
H
3
.COOH
0 21
,CDOH
R-ti .C0 0 2
F
R- ,COOH 0 -216- TABLE 2A (cont'd) mom H 3 CO HR COO H
R-O
0 26 o 27 0 O M H 3
F
C O C O O H C O 28 29 OM
H
3
F
*COOH. COOH COO H R-PCp -N N 31 N /32 33 0 0 00 o* M H3 ,COOH 4PCOOH OCOOH 34 35 36 N 0 00.0 -217- TABLE 2A (cont'd)
H
3 R- COOH R 110C P OC339
F
R- ~C0
OCH
3 R OM.C.COOH
OCH
3 41
H
3
*.COOH
R-
OCH 34 2
F
.COOH
OCH
3
M
R- %OCOOH.
OCH
3
MOOO
R-4 -218- TABLE 2A (cont'd) .OCOOHCOOH COOH
*.COOH
49 50 0 510 IeCOH ,rOOHCOOH R- C0HR-
R-OO
52 0 53 54 .COC)H ,OOOH.COOIH R- ,,OHR- E.OHR-N O 56 F 57 oc-b OCOOH OCOOH 00~COH 00COH.CO R- R- R- 58 0 59 0 60 0 -219- TABLE 2A (cont'd) R- ~.OHR-N 62 jeCOOH 64 F IOCOOH R- W H 63 0 R-N COOH 0C143 6 S S .55*
S
S
R OOOH '69
,CWOH
R-
OCOOH
71 R .COOH I OCI43 001b -F 72 -220- TABLE 2A (cont'd)
CR
3 cr'COOH R- COO
H
74 CR3 c'-COOH
COOH
oc~h
,COOH
R-kOO OCH3
-'O"-COOH
R-
COOH
OCF3 L/ 0
COOH
1 0 0H
OCR
3
,/COOH
F
'-COOH
R- ~CO
H
3
OH
O 84
H
3
O
COH
R- CO 0 -221- TABLE 2A-(cont'd) CH 3
X-,H
H
R-
COOH:
O0, H
.OCH
3 a a a. a.
a a a
.A.
a
F
R- 0COOH 0
H
3 96 0 -222- TABLE 2A (cont'd) 97 100 103 101 104 102 105
H
3 CO
F
.#COOH
0
H
3 CO
F
108 106 107 -223- TABLE 2A (coo='d
H.
110
.COOH
109 R-
COOH
COOH
R-
OCOOH
112 113 114
.COOH
115 116 R-
*COOH
117 R_
COOH
I 0 120 R-
COOH
R-
ICOOH
118 119 -224- TABLE 2A (cont'd) 121 124 122
H
3 R-
COOH
0 .0 0 123 O0H 3 R-
,COOH
ij~ 126
OOCH
3 R-
%COOH
0 129 R
COOH
CH
3 R-
/CO
OCH
3 I0) 0
S
127 130 125 128 131 132 -225- TABLE 2A (contMd (SCM3 0 0
H
3 C. PCH 3
*COOH
0 135 133 136 134
CH
3 .C00H
H
3 C 137 0 CH 31 3 8
CH
3 C0
S
S
S S *5 S. S S S. S S
S
**SS
139 140
H
3
"IN
CH
3
OCOOH
H
3 C 142 143 144 -226- TABLE 2A (cont'd) 145 148 146 147
.COOH-
149 150 S. S S 5 S.
SS
SS
S. S S S. S S. 55 S S
S
555S
S
S
S
F
COOH
ocoo
OCH
3 152 F 153 M omCOOH
R-
155 H 3 C 0CH 3 156 154 -227- TABLE 2A (cont'd /C 3
OCH
3
O.COOHC
157
OCH
3 158 159
OCH
3 R-
I.COOH
CH
3 161 H 3 C OCH 3 1 6 2 160 0..0.
0.000 60-6
H
3
OCOOH
OCH
3
H
2
,CQ
163 164 165 166 167 168 -228- TABLE 2A (cont'd) F MOMO F ,e N -N.
R- R-RN 169 .170 0 171 MOMO F MO R
R
Ij- R 172. 173 '174 F MO F
F
175 176 17 N N R R- R-N F CN 3 *178 F 179 Oc~ 180 -229- TABLE 2A (cont'd F mom R
-R
181 o 182 18
H
3 C
F
R- R- H '0) 184 185 o186 F MOMO R- R-1 **187 188 *MOMO
F
01 S.
I3 39 -230- TABLE 2A (cont'd)
F
R- H F 193 196 199 194 197 200 ~95
F
R )N N sCH3 R-N H I c 20
F
R-N H 0j H3C R- H 0
U.
U U a.
U. U U U
U.
U U U U. U UU .U U U
U
U
4~UUU
U
U
U
H
3C dNASC 4CH3 R- H 20~ 203 204 -231- TABLE 2A (cont'd) R \/,kCOOH
.ACQOH
R- RR 205 0 206 0 207 R- t O0H R-
.COOH
280 209 0 210 see Dow* YH3 -232- 0 100 13 0 IA; 0
R
11 0 14 0 a -Th 0
A
0 9 0 -Th 00 0 0 0 00C~a HCos_ s2: 22 0 25 0~on '0 27
FH
2 C,-e Z c5~o -Th 0 -233- TABLE 2B (conit'd)
R
31 34
F
2 H0~.
43o
R
32 FH20C.
35 F 2 38 41 44
F
33
F
2
HC..
36 F3C'o 39 42 00Qa F C ckalr, elo 48 ~Th 51o 54 57 Fzl -234- TABLE 2B (cont'd) 58 c
N**
I N
N
61 aeo oc$3 60 crO 63 H 3 00 0' 666 6 4 (o I 0 68 0 71 Qr 720(
YH
3 r$ Nl 00 rg -235- TABLE 2B (cont'd) 79 00
R
oT 81 a a a a. a a.
a a. a.
a a a -236- Example 339 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.
S. *o *o o 0 -237- TABLE 3A
F
.,COOH
2
MOMO
.,COOH
3
F
COOH
CH 3 R-
,.COOH
OCH
3 R- lmCOOH
CH
3
,.COOH
OOH
I-)
0
.COOH
0
COOH
0 0 -238- 'TABLE 3A (cont'd)
-N
R-
P.COOH
0
OCH
3
OCH
3 0 /0 0 0 -239- TABLE 3B
R
0 0
R
2 0 5 0 -ly 8 0 a 0 13 0 16 0 19 22 0 14 0 0 00c 12 0 15 0 18 0 21 0 24 27 0 00 26 28 0 -240- TABLE 3I(otd 31 p 2 00 34 F 2 0 0o 37 4 3. No
P
R
FH
2
C..
32 F 2 0 0
F
3 0.
35
F
38 00 41 0 0 44 00o
R
F
2 HC,.a- 33
F
39 42 o0 45 00 48 0 51 0 57 F6-
S.
S
SeS.
5555 *5S*
S
*e5~
S
0 0 47
,*TN
OYNc 0cZ H3',- 00o
O#NV
-241- TABLE 3B (cont'd)
H
58 U' 1'59
R
60 0r1 2 0 C 'Nlik Y- 61 e 08% 62 OCH 3 63 H 3
CO
64 0 )r 0 &N
N-
0j 990f99 .99 94 *see
IH
3 r 0 0 dr 0 9H3 7 1 72 74 75 Vr* 0' 0 R Do -242- TABLE 3B (Cont'd) 79 00 00 81 d -243- As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.
Binding Assay ETA Recept Preparation of membranes from MMQ cells: MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells)] cells from 150 mL culture flasks were collected by centrifugation (1000xg for 10 min) and then homogenized in 25 mL of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA 0.1 mM PMSF, and 5 g/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes).
The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 'C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.
125 1IET-1 binding to membranes: Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mMTris, 100 mM NaCI, 10 mM MgC12, pH 7.4, with 0.2% BSA, 0.1 25 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of [1251]ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 OC. After incubation, unbound ligands were S 30 separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times. Nonspecific binding was determined in the presence of 1 lM ET-1. The data are shown in -244- Table 4. The per cent inhibition at a concentration of 1 pM is shown. The data show that the compounds of the invention bind to the endothelin receptor.
Table 4 Binding Data Example 0**e 9 1D 2 3 4 6B 7 8 9 14 16 17 18 19 20 21 22 23 26 27 28 29 Inhibition of ETA at 1 IM 96.4 58.4 42.2 78.2 95.1 34.9 63.4 53.7 69.2 66.1 86.6 84.8 96.0 73.9 97.3 90.3 80.9 56.3 86.3 85.9 83.0 61.2 63.8 85.3 42.8 Inhibition of ETA at 1 lM Example 30 31B 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 52 54 55 56 57 58 59 3 80.0 93.6 95.5 91.8 94.5 47.9 100.0 83.6 94.8 89.9 95.2 99.2 91.3 85.4 90.4 95.1 96.3 84.0 64.6 50.5 34.3 93.2 81.9 70.8 59.2 93C -245- 610C 62 63 64 66 67 68 69D 71 72C 73C 74 750 76 79 82 83 84 86 87 88 89 910c 90.6 94.1 92.0 95.0 82.8 87.7 96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 65.3 52.6 62.4 84.3 84.6 91.6 95D 96 97 98 99 100 101 102 103 104 105 106 107 109 110 il1 112 113 114 115 116 117 118 119 120 121 82.1 86.1 89.0 86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6 I 92C 107.4 1122 95.3 123 124 125 126 127 128 89.7 91.0 97.2 91.7 91.4 95.4 146 147 148 149 150 151 *25.0 73.0 94.7 84.6 93.6 80.5 -246- 129 130 131 132 133 134 1 35B 136 138 139 140 141 1428 143 144 145 100.1f 91.0 89.5 90.0 88.6 92.2 77.7 79.4 83.0 98.6 106.3 92.8 78.7 20.6 78.2 32.4 152 153 154 155 156 157 158 159 160B 161 1628 163 164 165 166 167 291 86.9 97.1 80.2 92.7 92.6 83.8 91.8 36.2 80.3 93.6 91.5 90.6 98.6 54.1 91.6 94.4 100.0 *:Go 0.0 0 00&0* Example 293 295 297 299 301 303 305 307 Example 309 311 313 Inhibition of ETA at 1 9iM 89.8 93.0 84.4 90.4 96.7 87.2 87.4 92.2 Inhibition of ETA at 1pM 80.7 92.3 96.3 Example 294 296 298 300 302 304 306 308.
Example 310 312 314 Inhibition of ETAat 1 p.M 77.7 87.1 93.3 96.1 86.6 89.7 93.3 93.0 Inhibition of ETA at 1 p.M 87.1 88.2 86.0 -247- 315 82.7 316 74.0 317 68.5 318 79.0 319 79.0 320 82.2 322 95.6 323 91.3 324 95.0 334 88.0 335 84.1 As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the described compounds to inhibit ET-1-induced phosphatidylinositol hydrolysis was measured.
Determination of Phosphatidvlinositol (PI) Hvdrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 Ci/mL of 3 H]myoinositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and 10 mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of mL of 1:2 chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 chloroform-methanol-water of as described by Berridge (Biochem. J.
206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 IL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1-X8 (Bio- Rad). The ICso is the concentration of test compound required to inhibit the ET- S.induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.
3 S
S
o* 0 -248- Table Phosphatidylinositol Hydrolysis Example IC5o .M 1 D 0.025 14 0.017 0.010 16 0.009 18 0.009 19 0.024 0.001 31 B 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 15 103 (1990) and Takata, et al., Clin. Exp. Pharmacol.
Physiol. J 131 (1983).
The ability of the compounds of the invention to treat congestive heart 10 failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990).
The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990).
15 The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ.
Res. 54 711 (1984).
-249- The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J. Neurosurg. Ef 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991).
The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82, (1991).
The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin.
Invest. 83 1762 (1989).
The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am.
J. Physiol. 256 G661 (1989).
The ability of the compounds of the invention to treat cyclosporininduced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 3Z 1487 (1990).
The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. Z9 619 (1990).
The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J.
25 Physiol. and Pharmacol. 6Z 1213 (1989).
The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).
The ability of the compounds of the invention to treat atherosclerosis can 30 be demonstrated according to the methods described in Bobik, et al., Am. J.
Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 5. 327 (1990).
.•The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).
-250- The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 19 840-846 (1993); and Shichiri, et al., J. Clin. Invest. iZ 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).
The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin.
Invest. 81 1867 (1991).
The ability of the compounds of the invention to treat IL-2 (and other 25 cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat.
Acad. Sci. 92 2691 (1995).
The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J.
30 Pharmacol. Exp. Therap. 21 156 (1994).
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, -251benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as 25 sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines 30 useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of the present invention are useful (in a human or other mammal) for the treatment of lille -252hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of 25 the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage 30 unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes -253subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be The title compound was prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, lubricating agents such as fob magnesium stearate. In the case of capsules, tablets, and pills, the dosage f 25 forms may also comprise buffering agents. Tablets and pills can additionally be o prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming V, "agents.
*::The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from go• Slll -254phospholipids or other lipid substances. Uposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
25 Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
"Representative renin inhibitors include enalkiren, zankiren, ~RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof.
255 Representative angiotensin II antagonists include DUP 753, A-81988 and the like.
Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative potassiLum channel activators include pinacidil and the like or a fpharmlnaceutically acceptable salt thereofl.
Other representative cardiovascular agents include sympatholytic agents such as methyldopa. clonidcline, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
I The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower closes. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the I-route of administration, severity of the disease and the response of the patient. 'The combination can be administered as separate I compositions or as a single dosage form containing both agents.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the too: therapeutic agents can be given as a single composition.
a a a a a a e 1 1)2364. dow :aak

Claims (4)

  1. 3.The com1pound according to claim I or- 2 whierein n is I and Z is -Cl-I 2
  2. 4. A pharmaceutical compIIositionl for antagonizing endcothelin comprising a thera-,peutically effective amroun11t of' the c01Iompond of. claim I 2 or- 3 and a phiarmaceu-tically acceptable carrier. A- method for antagonizing endothelin comprising admlinistering to a mammal I I1( fnedof suIch treatment a therapeutically effective amoun,11t Of a compound of claim 1 2 o or- ol'a composition of claim 4.
  3. 7. A method for treating hy)pertension., conne1stive heart I'illure. restenlosis I0I loviog arterial inju1-ry, cerebral or- myocardial isehemia or- atherosclerosis compriSillg ani11stering to a mammal inl n'eed Of suIch treatment a thierapeuLtically effective amount ofi acomp)oundC of claim'1 I 2 o- 3) o- o a composition of' claim 4I obnton\ll n ant7.oizing ethod for treating hypertension. rai coe_,stiv heart failure. retenossll( arterial inju~ry, tetn cerebral oratm myocardial ieei rahrslrsscmr~n adinCi-eringof toan mammaosleoinse.o uhtetmn hrpuialyefcieaon Usres fopain a comlOound ofdeiedI clam I inill thprraainofadcet for siMbstILKtia as herein described \vi reference to the Examples. I RAI IiXX J02364.docmaak 261 1 0. A Compound of claim 1 when prepared by the process of claim 9.
  4. 11. A medicament when prepared by the use ot claim 8. Dated 8 August, 2000 Abbott Laboratories Patent Attorneys for the Applicant/NorninatedI Person SPRUSON FERGUSON I KA 1i 3XX 102364.doc:aak
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3342833A (en) * 1964-08-07 1967-09-19 Shell Oil Co Pyrrolidine production from aziridines and olefins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3342833A (en) * 1964-08-07 1967-09-19 Shell Oil Co Pyrrolidine production from aziridines and olefins

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