AU8592198A - Endothelin antagonists - Google Patents

Endothelin antagonists Download PDF

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Publication number
AU8592198A
AU8592198A AU85921/98A AU8592198A AU8592198A AU 8592198 A AU8592198 A AU 8592198A AU 85921/98 A AU85921/98 A AU 85921/98A AU 8592198 A AU8592198 A AU 8592198A AU 8592198 A AU8592198 A AU 8592198A
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loweralkyl
trans
hydrogen
aryl
methoxyphenyl
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AU748469B2 (en
Inventor
Steven A. Boyd
Kenneth J. Henry
Charles W Hutchins
Hwan-Soo Jae
Jeffrey A. Kester
Steven A. King
Gang Liu
Bryan K Sorensen
Bruce G. Szczepankiewicz
Andrew S. Tasker
Thomas W. Von Geldern
Martin Winn
Steven J. Wittenberger
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Abbott Laboratories
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Abbott Laboratories
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    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
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    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • 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
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Description

WO 99/06397 PCT/US98/15479 ENDOTHELIN ANTAGONISTS This is continuation-in-part application of U.S. patent application 5 Serial No. 08/905,913, filed August 4, 1997 which is a continuation-in part of U.S. patent application Serial No. 08/794,506, filed February 4, 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/600,625, filed February 13, 1996, which is a continuation-in part of U.S. patent application Serial No. 08/497,998, filed August 2, 10 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/334,717, filed November 4, 1994, which is a continuation-in-part of U.S. patent application Serial No. 08/293,349, filed August 19, 1994. 15 Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and 20 compositions for antagonizing endothelin. Background of the Invention Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val 25 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 ji vitro, stimulate mitogenesis in vascular smooth muscle cells invitro, 30 contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus invitro, increase airway resistance .inj~y., induce formation of gastric ulcers, stimulate release of atrial natriuretic factor jnvitro and invivyo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release 35 of renin in vitro 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 WO 99/06397 - 2- PCT/US98/15479 (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 5 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 1o effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 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 15 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (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 20 after SAH has also been recently reported (S.Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states. 25 Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease. For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 3Q9, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have 30 demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51,12-27). 35 Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate WO 99/06397 - 3- PCT/US98/15479 cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role of endothelin in the pathophysiology of these diseases. Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists bind tightly to plasma 5 proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners. 10 Disclosure of the Invention In accordance with the present invention there are compounds of the formula (1): R2 Z N R 3
(CH
2 )n R 15 wherein Z is -C(R 18
)(R
19 )- or -C(O)- wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is 20 (a) -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, 25 (e) -C(O)NHR 17 wherein R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, 30 (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2
R
1 6 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, WO 99/06397 ~4- PCT/US98/15479 (M) -S(O) 2
NHC(O)R
16 wherein R 16 is defined as above, HO (n) 0 (o) HO 0 OH I N (p) 0 0 (X'NH 5 (q) 0, N 0 ( ) 0 , (s) H N L~CF3 N0 ()H ,or " -& NHS0 2 CF 3 (u) NS~~ 10 R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 15 aminocarbonylalkenyl, alkylaminocarbonylalkenyl, . dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, WO 99/06397 - 5- PCT/US98/15479 aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Roc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and 5 R 2 is other than hydrogen;
R
3 is (a) R 4
-C(O)-R
5 - , R4-R5a- , R 4 -C(O)- R 5
-N(R
6 )- , R 6
-S(O)
2
-R
7 or R 2 6-S(O)-R 27 wherein R 5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20
)-R
8 - or -R8a-N(R20)-R8 10 wherein R 8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-Re- or -R 9 a-O-R 9 - wherein R 9 and R9a are 15 independently selected from alkylene; R5a is (i) alkylene or (ii) alkenylene; R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 1
)-R
10 - or -RlOa-N(R21)-R1o- wherein R 10 and R10a are independently selected from the group 20 consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R 6 are independently selected from the group consisting of 25 (i) (R 11
)(R
12 )N- wherein R 11 and R 12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, 30 (4) -alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, 35 (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, WO 99/06397 - 6- PCTIUS98/15479 (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, 5 (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, (19) dialkylaminoalkyl, and (20) carboxyalkyl, 10 (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, 15 (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, 20 (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, 25 (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and 30 H
(CH
2 )z N N R 7 a (xxi) 0 wherein z is 0-5 and R7a is alkylene;
R
26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, WO 99/06397 -7~ PCT/US98/15479 (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and
R
27 is alkylene or alkenylene; (b) R 22 -0-C(O)-R 23 - wherein R 22 is a carboxy protecting 5 group or heterocyclic and R 23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24
)-R
2 5 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, (c) loweralkyl, 10 (d) alkenyl, (e) alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, 15 (i) arylalkyl, (j) aryloxyalkyl, (k) heterocyclic, (1) (heterocyclic)alkyl, (m) alkoxyalkyl, 20 (n) alkoxyalkoxyalkyl, or (o) R 13
-C(O)-CH(R
1 4
)
wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R 15 -C(O)- wherein R 15 is amino, alkylamino or dialkylamino; 25 or a pharmaceutically acceptable salt thereof. A preferred embodiment of the invention is a compound of formula (II) R2 Z N R 3 N
(CH
2 )n 30 R1
(II)
WO 99/06397 - 8- PCT/US98/15479 wherein the substituents -R 2 , -R and -R1 exist in a trans,trans relationship and Z, n, R, R 1 , R 2 , and R 3 are as defined above. Another preferred embodiment of the invention is a compound of 5 formula (1) or (II) wherein n is 0 and Z is -CH 2 -. Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH 2 -. 10 Another preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, and R 3 is R 4
-C(O)-R
5 - , R6-S(O)2-R7- or R2 6
-S(O)-R
27 - wherein R 4 , R 5 , R 6 , R 7 , R 26 and R 27 are as defined above. 15 Another preferred embodiment of the invention is a compound of formula (1) or (11) wherein n is 0, Z is -CH 2 -, and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl. A more preferred embodiment of the invention is a compound of 20 formula (I) or (11) wherein n is 0, Z is -CH 2 -, and R 3 is R 4
-C(O)-R
5 wherein R 4 is (R 11
)(R
12 )N- as defined above and R 5 is alkylene or R 3 is Re-S(O)2-R7- or R 26
-S(O)-R
27 - wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are defined as above. 25 Another more preferred embodiment of the invention is a compound of formula (1) or (11) wherein n is 0, Z is -CH 2 - and R 3 is R4-C(O)-N(R 20
)-R
8 - or R6-S(O) 2
-N(R
2 1)-R1 0 - wherein R 8 and R 10 are alkylene and R 4 , R6, R 20 and R 21 are defined as above. 30 An even more preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is
-C(O)-NHS(O)
2
R
1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is 35
-CH
2 -,
R
1 and R 2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substituted WO 99/06397 -9~ PCT/US98/15479 with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N 5 alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R 3 is R 4
-C(O)-R
5 wherein R 4 is (R11)(R12)N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R 5 is alkylene; or R 3 is R4-C(O)-N(R 20
)-R
8 - or 10 R6-S(O) 2
-N(R
21
)-R
10 - wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and R 10 are alkylene and R 20 and R 21 are loweralkyl; or R 3 is R 6
-S(O)
2
-R
7 - or R26-S(O)-R27 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 26 is loweralkyl 15 and R 27 is alkylene. A yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2
R
16 wherein 20 R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 25 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4 methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, 30 alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl,
R
2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 35 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and
R
3 is R4-C(O)-N(R 2 0
)-R
8 - or R6-S(O) 2
-N(R
2 1)-R1 0 - wherein R 8 and R 10 are alkylene, R 20 and R 2 1 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, WO 99/06397 - 10- PCT/US98/15479 alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl. Another yet more preferred embodiment of the invention is a 5 compound of formula (1) or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O) NHS(0) 2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, 10 (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4 methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 15 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl,
R
2 is substituted or unsubstituted 20 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and
R
3 is R 4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R 1 1
)(R
12
)N
wherein R 1 1 and R 1 2 are independently selected from loweralkyl, 25 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl. Another yet more preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is -C(O) 2 -G wherein G 30 is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)
NHS(O)
2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl,
R
2 is substituted or 35 unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4 benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or WO 99/06397 - 11 - PCTIUS98/15479 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R 4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R11)(R12)N- wherein R 11 is loweralkyl and R 12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic. 5 Another yet more preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O) NHS(0) 2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 10 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 fluorophenyl, 15 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3 benzodioxolyl, 20 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R6-S(O) 2
-N(R
21
)-R
10 - wherein R 10 is alkylene, R 6 is loweralkyl, 25 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl. Another yet more preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is -C(O) 2 -G wherein G 30 is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)
NHS(O)
2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl 35 or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) WO 99/06397 - 1 2- PcTIUs98/15479 heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 5 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R6-S(O) 2
-N(R
21
)-R
10 - wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is 10 loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl. Another yet more preferred embodiment of the invention is a = compound of formula (I) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O) 15 NHS(O) 2
R
16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl,, or alkylsulfonylamidoalkyl, and R 3 is
R
4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R 11
)(R
12 )N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, 20 alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. A still more preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0) 2
R
1 6 wherein 25 R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4 methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the 30 substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 35 methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N- wherein WO 99/06397 - 13- PCTIUS98/15479
R
11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic. Another still more preferred embodiment of the invention is a 5 compound of formula (I) or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O) NHS(0) 2
R
16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or 10 alkoxyalkyl,
R
2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R11)(R 12 )N- wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, 15 aminoalkyl, trialkylaminoalkyl, or heterocyclic. A most highly preferred embodiment of the invention is a compound of formula (I) or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted 20 or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4 methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 25 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N- wherein R 11 and R 12 are independently selected from loweralkyl. 30 Another most highly preferred embodiment of the invention is a compound of formula (1) or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 35 4-methylphenyl, 4-trifluoromethylphenyl, 4 -pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the WO 99/06397 - 1 4- PCTIUS98/15479 substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene and R 4 is 5 (R 11
)(R
12 )N- wherein R 11 is loweralkyl and R 1 2 is aryl. Another most highly preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted 10 or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3 fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4 methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 is 15 substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is 20 R6-S(O) 2
-N(R
21 )-R10- wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 2 1 is loweralkyl, haloalkyl or alkoxyalkyl. Another most highly preferred embodiment of the invention is a 25 compound of formula (1) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or 30 dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl 35 or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene and R 4 WO 99/06397 - 15- PCT/US98/15479 is (R 1 1)(R 1 2 )N- wherein R 11 is alkyl and R 12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic. Another most highly preferred embodiment of the invention is a 5 compound of formula (I) or (II) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is
R
4
-C(O)-R
5 - wherein R 5 is alkylene and R 4 is (R 11
)(R
12 )N- wherein R 11 10 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 1 1 and R 1 2 is alkyl. Another most highly preferred embodiment of the invention is a 15 compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, and R 3 is R4-C(O)-R 5 - wherein R 4 is (R11)(R12)N- as defined therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a 20 compound of formula (1) or (11) wherein n is 0, Z is -CH 2 -, R1 is loweralkyl, and R 3 is R4-C(O)-R 5 - wherein R 4 is (R11)(R12)N- as defined therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a 25 compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, R1 is alkenyl, and R 3 is R 4
-C(O)-R
5 - wherein R4 is (R11)(R 1 2 )N- as defined therein and
R
5 is alkylene. Another most highly preferred embodiment of the invention is a 30 compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, R1 is heterocyclic (alkyl), and R 3 is R4-C(O)-R 5 - wherein R 4 is (R11)(R 12
)N
as defined therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a 35 compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, R1 is aryloxyalkyl, and R 3 is R4-C(O)-R 5 - wherein R 4 is (R11)(R 1 2 )N- as defined therein and R 5 is alkylene.
WO 99/06397 - 1 6- PCT/US98/15479 Another most highly preferred embodiment of the invention is a compound of formula (1) or (11) wherein n is 0, Z is -CH 2 -, R1 is arylalkyl, and R 3 is R4-C(O)-R 5 - wherein R 4 is (R 11
)(R
12 )N- as defined 5 therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, R1 is aryl, and
R
3 is R 4
-C(O)-R
5 - wherein R 4 is (R 11
)(R
12 )N- as defined therein and R 5 10 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula (1) or (II) wherein n is 0, Z is -CH 2 -, R1 is (N alkanoyl-N-alkyl)aminoalkyl, and R 3 is R 4
-C(O)-R
5 - wherein R 4 is 15 (R11)(R 1 2 )N- as defined therein and R 5 is alkylene. Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH 2 -, R1 is alkylsulfonylamidoalkyl, and R 3 is R 4
-C(O)-R
5 - wherein R 4 is 20 (R 11
)(R
12 )N- as defined therein and R 5 is alkylene. The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes. 25 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 mammal a therapeutically effective amount of a compound of formula (1) or (11). 30 The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (11). 35 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 WO 99/06397 -1 PCT/US98/15479 of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Apple. Chem. (1976) 45, 13 - 30. 5 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" 10 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 15 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 in the protection of carboxyl groups in the penicillin and cephalosporin 20 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", edited by E.B. Roche, Pergamon 25 Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C 1 to C 8 alkyl (e.g., 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 30 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 example, 5-indanyl and the like; 35 dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- WO 99/06397 - 1 8 PCTIUS98/15479 (propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1 -ethyl, 1-methyl-1 (propionyloxy)-1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, 5 cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2 benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 10 methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and 15 the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4 -methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, 20 diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3 dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4 yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like. The term "N-protecting group" or "N-protected" as used herein 25 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 30 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-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; 35 sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, WO 99/06397 - 19- PCT/US98/15479 p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 5 2 -nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, 10 ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, 15 triphenylmethyl, benzyloxymethyl and the like; 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 term "alkanoyl" as used herein refers to an alkyl group as 20 previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) 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 25 alkanoylamino include acetamido, propionylamido and the like. The term "alkanoylaminoalkyl" as used herein refers to
R
43
-NH-R
44 - wherein R 43 is an alkanoyl group and R 44 is an alkylene group. The term "alkanoyloxyalkyl" as used herein refers to R 30
-O-R
3 1 30 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 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups 35 include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 methyl-2-buten-1-yl and the like.
WO 99/06397 - 20- PCTIUS98/15479 The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 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-, 5 CH2CH=CHCH 2 -, 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 (-0-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. 10 The term "alkoxy" as used herein refers to R 41 0- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, 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 8 1 is alkylene. 15 Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include 20 methoxyethoxyethyl, methoxymethoxymethyl, and the like. The term "alkoxyalkyl" as used herein refers to an alkoxy group as 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. 25 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 "alkoxycarbonylalkenyl" as used herein refers to an 30 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
-C(O)-R
35 - wherein R 34 is an alkoxy group and R 35 is an alkylene 35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
WO 99/06397 - 21 - PCT/US98/15479 The term "alkoxycarbonylaminoalkyl" as used herein refers to
R
38
-C(O)-NH-R
39 - wherein R 38 is an alkoxy group and R 39 is an alkylene group. The term "alkoxycarbonyloxyalkyl" as used herein refers to 5 R 36
-C(O)-O-R
37 - wherein R 36 is an alkoxy group and R 37 is an alkylene group. 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 10 methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like. The term "alkoxyhaloalkyl" as used herein refers to a haloalkyl radical to which is appended an alkoxy group. The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms 15 including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2 dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "(N-alkanoyl-N-alkyl)aminoalkyl" as used herein refers 20 to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene. The term "alkylamino" as used herein refers to R 51 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like. 25 The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group. The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of 30 alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like. The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group. The term "alkylaminocarbonylalkyl" as used herein refers to a 35 loweralkyl radical to which is appended an alkylaminocarbonyl group.
WO 99/06397 - 22- PCTIUS98/15479 The term "alkylaminocarbonylaminoalkyl" as used herein refers to
R
40
-C(O)-NH-R
41 - wherein R 40 is an alkylamino group and R 41 is an alkylene group. The term "alkylene" denotes a divalent group derived from a 5 straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example
-CH
2 -,
-CH
2
CH
2 -, -CH(CH 3 )-, -CH 2
CH
2
CH
2 -, -CH 2
C(CH
3
)
2
CH
2 - and the like. The term "alkylsulfonylamidoalkyl" as used herein refers R88S(O)2NHR89- wherein R88 is loweralkyl and R89 is alkylene. 10 The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(O) 2 -NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like. 15 The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -CEC-H, H-CC-CH 2 -, H-C=C-CH(CH 3 )- and the like. The term "alkynylene" refers to a divalent group derived by the 20 removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -CC-, -CEC-CH 2 -, -CEC-CH(CH 3 )- and the like. The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, 25 or dialkylamino group appended to the parent molecular moiety through an alkylene. The term "aminocarbonyl" as used herein refers to H 2
N-C(O)
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl
(NH
2 C(O)-) group. 30 The term "aminocarbonylalkoxy" as used herein refers to
H
2 N-C(O)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like. The term "aminocarbonylalkyl" as used herein refers to a 35 loweralkyl radical to which is appended an aminocarbonyl
(NH
2 C(O)-) group.
WO 99/06397 - 23 PCT/US98/15479 The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R 93 )- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene. The term "aroyloxyalkyl" as used herein refers to R 32
-C(O)-O-R
33 5 wherein R 3 2 is an aryl group and R 33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl 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 10 and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, 15 trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl 20 groups include tetrafluorophenyl and pentafluorophenyl. The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like. The term "arylalkoxy" as used herein refers to R 42 0- wherein R 4 2 25 is an arylalkyl group, for example, benzyloxy, 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 "arylalkyl" as used herein refers to an aryl group as 30 previously defined, appended to a loweralkyl radical, for example, benzyl and the like. The term "aryloxy" as used herein refers to R 4 5 0- wherein R 45 is an aryl group, for example, phenoxy, and the like. The term "arylalkylcarbonyloxyalkyl" as used herein refers to a 35 loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R 62 C(O)O- wherein R 62 is an arylalkyl group).
WO 99/06397 - 24- PCT/US98/15479 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 "carboxaldehyde" as used herein refers to a formaldehyde 5 radical, -C(O)H. The term "carboxy" as used herein refers to a carboxylic acid radical, -C(O)OH. The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously 10 defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3 carboxy-1-ethenyl and the like. 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, 15 carboxyethoxy and the like. The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like. 20 The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e.,
R
60 -C(O)-O- wherein R 60 is a cycloalkyl group). 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 25 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, carboxaldehyde, carboxy, alkoxycarbonyl and 30 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 "dialkylamino" as used herein refers to R 56
R
57
N
35 wherein R 56 and R 57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
WO 99/06397 - 25- PCT/US98/15479 The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group. The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent 5 molecular moiety through a carbonyl (-C(O)-) linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like. The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group. 10 The term "dialkylaminocarbonylalkyl" as used herein refers to
R
50
-C(O)-R
51 - wherein R 50 is a dialkylamino group and R 51 is an alkylene group. The term "halo" or "halogen" as used herein refers to I, Br, Cl or F. The term "haloalkenyl" as used herein refers to an alkenyl radical 15 to which is appended at least one halogen substituent. The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2, 2 ,3,3,3-pentafluoropropoxy and the like. 20 The term "haloalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group. The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or 25 pentafluoroethyl 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 5-, 6- or 7 membered ring containing one, two or three nitrogen atoms; one oxygen 30 atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The 35 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 cyclohexane ring or WO 99/06397 - 26- PCTIUS98/15479 another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, 5 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, 10 isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. ~X. oY* Heterocyclics also include compounds of the formula 0 15 where X* is -CH 2 - or -0- and Y* is -C(O)- or [-C(R") 2 -]v where R" is hydrogen or C1-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 20 disubstituted with substituents independently selected from hydroxy, halo, oxo (=0), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3 H, alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen 25 containing heterocycles can be N-protected. 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. 30 The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
WO 99/06397 - 27- PCT/US98/15479 The term "heterocycliccarbonyloxyalkyl" as used herein refers to R4 6
-C(O)-O-R
47 - wherein R 4 6 is a heterocyclic group and R 47 is an alkylene group. The term "hydroxy" as used herein refers to -OH. 5 The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group. The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4 10 hydroxybutoxy and the like. The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group. The term "leaving group" as used herein refers to a halide (for example, Cl, Br or 1) or a sulfonate (for example, mesylate, tosylate, 15 triflate and the like). 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 20 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 radical. . Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl radical O 25 The term "substantially pure" as used herein means 95% or more of the specified compound. The term "tetrazolyl" as used herein refers to a radical of the formula H, N- N N' or a tautomer thereof.
WO 99/06397 -28- PCT/US98/15479 The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like. 5 The term "thioalkoxy" as used herein refers to R 70 S- wherein
R
7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. The term "thioalkoxyalkoxy" as used herein refers to R 8 oS-R 81 0 wherein R 80 is loweralkyl as defined above and R 8 1 is alkylene. 10 Representative examples of alkoxyalkoxy groups include
CH
3
SCH
2 0-, EtSCH 2 0-, t-BuSCH 2 0- and the like. The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include
CH
3
SCH
2
CH
2 0CH 2
CH
2 -, 15 CH 3
SCH
2 0CH 2 -, and the like. The term "trans,trans" as used herein refers to the orientation of substituents
(R
1 and R 2 ) relative to the central substituent R as shown R2 ZN -R 3
(CH
2 )n R1 20 The term "trans,cis" as used herein refers to the orientation of substituents
(R
1 and R 2 ) relative to the central substituent R as shown
R
2 /,, Z N R 3
R
2 Z N R 3 N N R . (CH2)n R . H2)n R R1 1 or . This definition encompasses both the case where R and R 2 are cis and R and R 1 are trans and the case where R 2 and R are trans and R and R 1 are cis. 25 The term "cis,cis" as used herein refers to the orientation of substituents
(R
1 and R 2 ) relative to the central substituent R as shown WO 99/06397 - 29- PCT/US98/15479 R 2/ Z,,N R3 (CH) R H2)n R1 Preferred compounds of the invention are selected from the group consisting of: 5 trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3-(N propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3 carboxylic acid; trans,trans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-
(
2 -(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3 10 carboxylic acid; trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol
-
5 -yl)-1-[2 (N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2 15 (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; trans,trans-2-(4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; 20 trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1
-(NN
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N propyl-N-n-pentanesu Ifonylamino)ethyl]pyrrolidi ne-3-carboxylic acid; 25 trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yi) 1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-( 2 -(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl) 30 pyrrolidine-3-carboxylic acid; trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-y;) 1-(2-(N-isobutyl-N-(3 chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; WO 99/06397 - 30- PCT/US98/1 5479 trans, trans-2-(3-F Iuoro-4-methoxypheny I) 4-(1 ,3-benzodioxolI-5-y
I)
1 -[2-(N-propyl-N-(4 methylbutanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxy-3-fi uorophenyl)-4(7-methoxy-1 ,3 5 benzodioxol-5-yI)-l -[2-(N-propyl-N-(n pentanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -12-(N-propyl-N-(2,2,3,3 ,3-pentafluoropropoxyethanesufonyy. amino)ethyl]pyrrolidine-3-carboxyljc acid; 10 trans, trans-2-(1 ,4-Benzodioxan-e-yl)-4-(7-methoxy.1 ,3-benzodioxol 5-yI)-l1-[2-(N-propyl-N-(n pentanesulfonyi)amino)ethyflpyrrolidine3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yi) 1 -( 2 -(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3 15 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyI>.4-(1 ,3-benzodioxol-5-yI) 1 -( 2
-(N-(
2 -methoxyethyl)-N-(3-chloropropanesu Ifonyt)amino) ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.(1 ,3-benzodioxoi-5-yI) 20 1-(2-(N-(2-methoxyethyl)-N (pentanesuifonyl)amino)ethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxypheny)-4(1 ,3-benzodioxol-5-yl) 1 -[ 2 -(N-propyl-N-((2,2,2-trifluoroethoxyethane)su Ifonyl)amino) ethyl]pyrrolidine-3-carboxylic acid; 25 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -( 2
-(N-(
2 -methoxyethyl)-N-(butanesulfonylamino)ethyy.
pyrrolidine-3-carboxylic acid; trans, trans-2- (3- Fl uo ro-4-met hoxyp henyl)-4.(1 ,3-be nzodioxol1-5 yl)-1 -[2-(N-propyl-N-(2 30 methylpropanesulfonyl)amino)ethyl]pyrroidine3carboxylic acid; trans, trans-2-(3-Fluoro-4-.methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -( 2 -(N-isobutyl-N-(butanesuifonylamino))ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(2-Methylpentyl)-4(1 ,3-benzodioxol-5-yI)-1 -(N,N-di(n 35 butyl)aminocarbonylmethyl)pyrrolidine-3carboxyic acid; trans, trans-2-(2,2Dimethylpentyl)-4(1 ,3-benzodioxol-5-yI)-1
-(N,N
di(n-butyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid, WO 99/06397 - 31 - PCTIUS98/1 5479 trans, trans-2-(2-(l ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yt)-1 (N, N-d i(n -buty I)am ino carbo nyl methy I) -py rro Iidin e3carboxy Iic acid; trans, trans-2-(2-(2-Tetrahydro-2H..pyran)ethy I) 4(1 ,3-benzodioxolI 5 5 -y)-l -(NN-di(n-buty)aminocarbonymethy)pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,4-Trimethyl-3pentenyl)-4(1 ,3-benzodioxol-5-yl) 1 -(N, N-di(n-butyl)aminocarbonylmethyl).pyrrolidine-3-.carboxylic acid; 10 trans, trans-2-(2,2,-Dimethyl.2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3 benzodioxoi-5-yI)-1 -(N,N-di(n-butyl)aminocarbonymethyl). pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 [[N-4-heptyi-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl] 15 pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (1, 3 -Dioxo-2-y) ethyl) -4- (7-meth oxy-1 ,3 benzodioxol-5-yl)-l -(NN-di(n-butyl)aminocarbonylmethyly.. pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)4.(1 ,3-be nzodioxol1-5-yi) 20 1 -(NN-di(n-buty)aminocarbonymethy)pyrroidine3carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4(1 ,3-benzodioxol-5-yI)-1 -(N-4 heptyI-N-( 4 -fluoro-3-methylphenyl))aminocarbonyjmethyl) pyrrolidine-3-carboxylic acid; 25 trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5 yI)-1 -(N,N-di(n-buty)aminocarbonylmethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1
,
3 -Dioxol-2-yl)ethy)-4-(7-methoxy-1 3 benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluo ro-3 30 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethypenty)4(7-methoxy-1 ,3-benzodioxol-5 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyj>.pyrrolidine-3 carboxylic acid; 35 trans, trans- 2
(
2
,
2 dimethypenty)4(23dihydro-benzof uran- 5 -yl) 1 -(NN-di(n-butyl)aminocarbonylmethyl).pyrrolidine3carboxyjic acid; WO 99/06397 - 32- PCT/US98/15479 trans, trans-2-(2,2,-Di met hyl-2-(1 ,3-dioxolIan -2-y I) ethy1) -4-(7 met hoxy-1 ,3- be nzodioxol-5-y1) -1 -(N,N-di(n butyi)aminocarbonylmethyl)-pyrrolidne3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4(1 ,3-benzodioxol.-5-yl) 5 1 -(NN-di(n-buty)aminocarbonylmethy)-pyrroidine3carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)penteny)4(7-methoxy-1,3 benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; 10 trans, trans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxoi-5-yI)-1
-(N,N
di(n-butyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; (25, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxoi-5 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 15 (28, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5 yI)- - (N-4-heptyl-N-(4-fI uoro-3 methylphenyl))aminocarbonylmethyl).pyrrolidine-3..carboxylic acid; trans, trans-2- (2-(1 -pyrazo ly1) ethyl) -4- (1 ,3-be nzod ioxoi1-5-yI)- 1 -(N, N 20 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxypheny)-4(1 ,3-benzodioxol-5-yI)- 1 -[(N butyi-N-(4-dimethylaminobutyl)amino)carbonymethyl]. pyrrolidine-3-carboxylic acid;
(
2 R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI)1 25
(
2 -(N-propyl-N-pentanesulfonylamino)ethy)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4(1 ,3-benzodioxol-5-y!)-1
-((N
butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; 30 trans, trans-2-(2,2-Dimethylpenty)-4-(7-methoxy-1 ,3-benzodioxol-5 yI)-l1-(N-4-heptyl-N-(4-fI uoro-3 methylphenyl))aminocarbonymethy..pyrrolidine-3-.carboxyl ic acid; trans, trans-2-(2,2-Dimethylpenty)-4-(7-methoxy-1 ,3-benzodioxol-5 35 yI)-1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl) pyrroiidine-3-carboxylic acid; WO 99/06397 -33 PCTIUS98/1 5479 trans, trans-2-(2,2-Dimethy Ipent 3-enyl1)-4-(1 ,3- ben zodioxol-5-y1) -1 ( N-4-h eptylI-N-(4-f I uo ro-3-methyIph heny I)) am ino ca rbo ny Imet hy I) pyrroiidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent3enyl)-4(1 ,3-benzodioxol-5-yI)-1 5 ((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3eny)4-(7-.methoxy-1,3 benzodioxol-5-yI)-1 -(N, N-di(n-butyl)aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; 10 trans, trans-2-(2,2-Dimethypent3eny)4(7-methoxy-1,3 benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3 methylphenyl))aminocarbonylmethyl)-pyrrolidine..3-carboxylic acid; trans, trans-2-(2,2-Dimethypent-3enyl)-4(7-.methoxy-1,3 15 benzodioxol-5-yI)-l -((N-butyl-N-(4 dimethylamino)butyi)aminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl)-4(1 ,3-benzodioxol-5-yI) 1 -(N-4-heptyl-N-(4-fluoro-3 20 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl)-4-( ,3-benzodioxol-5-yl) 1 -((N-butyl-N-( 4 -dimethylamino)butyl)aminocarbonylme'thy) pyrroiidine-3-carboxylic acid; 25 trans, trans- 2 -(2,2,4-Trimethylpent3enyl)4(7-methoxy-1,3 benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyly.. pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethypent3enyI)-4-.(7-methoxy-1 3 benzodioxol-5-yI)- 1 -(N-4-heptyl-N-(4-fluoro-3 30 methylphenyi))aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans,trans-2-(2,2,4-Trimethypent3eny)4(7-methoxy1 ,3 benzodioxol-5-yI)-l -((N-butyl-N-(4 dimethyiamino)butyl)aminocarbonylmethyl)-pyrrolidine-3 35 carboxylic acid; WO 99/06397 -34- PCTIUS9815479 trans, trans-2-(2-(1 ,3-Dioxol-2-y I) ethy1) -4-(1 ,3- ben zodioxoi-5-y1) -1 [(N-butyl-N- (4-di met hylIam ino butyI) am ino) carbo nyl methy I] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3 5 benzodioxol-5-yl)-l -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethylpyrrolidine-3 carboxylic acid; benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluoro-3 10 methylphe nyl))am inocarbo nyl methy) py rro lid in e-3carboxyl ic acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3 benzodioxol-5-yI)-1 -[(N'-butyl-N-(4 dimethylaminobutyl)am ino)carbonylmethyl]-pyrrolidine-3. 15 carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7 methoxy-1 ,3-benzodioxol-5-yI)-1 -(N-4-heptyi-N--(4-fluoro-3 methylphenyl))aminocarbonylmethyl)pyrrolidine-3-.carboxylic acid; 20 trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxoian-2-yI)ethyl)-4-(7 methoxy-1 ,3-benzodioxol-5-yI)-1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl].pyrroidine-3. carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)ethyl)-4(1 ,3-benzodioxol-5-yi) 25 1 -(N-4-heptyl-N-(4-fluoro-3 methylphenyl))amino)carbonylmethyl]-pyrrolidine-.3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)ethy)4(1 ,3-benzodioxol-5-yI) 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] 30 pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-Met hoxyphe ny I)ethy )4(7-met hoxy-1 ,3 benzodioxol-5-yI)-1 - (N,N-di(n-butyl)aminocarbonylmethyl). pyrrolidine-3-carboxyiic acid; trans, trans-2-(2-(2-Methoxypheny)ethy)4(7-methoxy-1 3 35 benzodioxol-5-yI)-1 -(N-4-heptyi-N-(4-fluoro-3 methylphenyl))amino)carbonymethyl]pyrrolidine-3-.carboxylic acid; WO 99/06397 - 35- PCTIUS98/15479 trans, trans-2-(2-(2-Methoxyphenyl)ethyl)4(7-methcxy1 ,3 benzodioxol-5-yI)-l -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3. carboxylic acid; 5 trans, trans-2-((2-Methoxyphenoxy)methyl)-4(1 ,3-benzodioxol-5-yI) 1 -(N-4-heptyl-N-(4-fluoro-3 methylphenyl))amino)carbonylmethyl..pyrrolidine..3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)methyl)-4(1 ,3-benzodioxol-5-yI) 10 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] pyrroiidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)methy)4(7-methoxy-1,3 benzodioxol-5-yI)-1 - (NN-di(n-butyi)aminocarbonyimethyl). pyrrolidine-3-carboxylic acid; 15 trans, trans-2-((2-Methoxyphenoxy-methy)4(7-methoxy-1,3 benzodioxol-5-yl)-l1-(N-4-heptyl-N-(4-fluoro-3 methy Iphefl )) am in o)carbonfl methyl]ppyrro lid ine-3-carboxyl ic acid; trans, trans-2-(2-(2-Methoxyphenoxy)methyl)4(7-methoxy-1 ,3 20 benzodioxol-5-yl)-l -[(N-butyl-N..(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-1 -yl)-ethyl)-4-(1 ,3 benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl). 25 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yl)-ethyi)-4-(1 ,3-benzodioxol-5 yI)-l1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl].pyrrolidine-3..carboxyiic acid; 30 trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(1 ,3-benzodioxol-5 yl)- 1 -[(N-butyl-N-(4-di methylaminobuty!)amino)carbonylmethyl.. pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-Oxo pyrid in-..1 -y1) -ethyl1)-4- (7-meth oxy- 1 ,3 benzodioxol-5-yI)-l1-(N ,N-di(N-butyI)aminocarbonylmethyly.. 35 pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-Oxo py rid in- 1 -y1) -ethyl1)-4- (7-meth oxy- 1 ,3 benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3- WO 99/06397 - 36- PCTIUS98/15479 methyl I phe nyI)am ino) carbonyl methylp..pyrro Iid ine3-c.arboxy I c acid; trans, trans-2-(2-(2-Oxopyridin-1 -y I) -ethyI) -4-(7-methoxy-1 ,3 benzodioxol-5-yI)- 1 -[(N-butyl-N-(4 5 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2- (2 (-2-Oxo pipe rid in-1 -yt)-ethyl)-4- (1 ,3-be nzodioxol1-5 yl)-1 -(NN-di(N-buty)aminocarbonyjmethyly..pyrrolidine-3 carboxylic acid; 10 trans, trans-2- (2- (2-Oxopipe ridi n - 1 -yI) -ethyl) -4- (1 ,3-be nzodioxol1-5 yI)-l1-[(N-4-heptyl-N-(4-fluoro-3 methyiphenyl)amino)carbonylmethyl]-.pyrrolidine3carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -y)-ethyl)-4-(7-methoxy-1 ,3 15 benzodioxol-5-yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin.1 -yi)-ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)-l1-(N ,N-di(N-buty)aminocarbonylmethy). pyrrolidine-3-carboxylic acid; 20 trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]-pyrrolidine-.3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin.1 -yI)-ethyl)-4-(7-methoxy-1 ,3 25 benzodioxol-5-yI)-l -[(N-buty-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine- 3 carboxyiic acid; trans, trans-2-(2-(2-Oxopyrro Iid in-1 -y1) ethyl) -4- (1 ,3-be nzodioxol1-5 yI)-1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonymethyl]-. 30 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5 yI)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl].pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyi)-4-(1 ,3-benzodioxol-5 35 yI)-1-[(N-butyi-N-(4 dimethylaminobutyl)amino)carbonylmethyl]j pyrrolidine-3-carboxylic acid; WO 99/06397 -37- PCTIUS98/15479 trans, trans-2-(2-(2-Oxopyrro idin.1 -y I) ethy1) -4-(1 ,3- be nzodioxol-5 y 1)-1 -[(N-butylI-N-(4 tri met hylIam mo niobutyI) am in o)carbo ny Imet hy I-py rro Iid ine-3 carboxylic acid; 5 trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yi)-l -(N,N-di(N-butyl)aminocarbonylmethyl.. pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin.1 -yI)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)-l -[(N-butyl-N-(3 10 hydroxypropyl)amino)carbonylmethyl]pyrrolidine3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)- 1 -[(N-4-heptyl-N-(4-fluoro-3.. methylphenyl)amino)carbonylmethyl]-pyrrolidmne-3..carboxylic 15 acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)-l -[(N-butyl-N (propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy- 1 3 20 benzodioxol-5-y)-l -[(N-butyl..N-(4 dimethylaminobutyl)amino)carbonylmethyy..pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrojidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yI)-l -I(N-butyl-N-(4 25 trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydro benzofuran-5-yI)-1 -(N, N-di(N-butyl)aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; 30 trans, trans-2-(2-(2-Oxopyrrolidin-1 -yi)ethyl)-4-(2,3-dihydro benzofuran-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyi)amino)carbonylmethyl]-pyrroidine3-carboylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yi)ethyl)-4-(2,3-dihydro-. 35 benzofuran-5-yI)-l-[(N-buty-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine- 3 carboxylic acid; WO 99/06397 - 38- PCT[US98/1 5479 trans, trans-2-(2-(3,3-Dimethy-2-oxopyrro Iidin.1 -yI) ethy1) -4-(1 ,3 benzodioxol-5-yI)- 1 -(N,N-di(N-butyl)aminocarbonylmethyl). yrrolidine-3-carboxylic acid; trans, trans-2-(2-(3,3-DimethyI2oxopyrroidin-1 -yI)ethyl)-4-(1 ,3 5 benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]ppyrroidine-3-carboxylic acid; trans, trans-2-(2-(3,3-Dimethy-2-oxopyrrolidin- 1 -yI)ethyl)-4-(1 ,3 benzodioxol-5-yi)-l -[(N-butyl-N-(4 10 dimethytaminobutyl)amino)carbonylmethy]pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(4,4-DimethyI2oxopyrroidin..1 -yt)ethyl)-4-(1 ,3 benzodioxol-5-yI)-l1-(N ,N-di(N-butyl)aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; 15 trans, trans-2-(2-(4,4-DimethyI2oxopyrroidin..1 -yi)ethyl)-4-(1 ,3 benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-.3 methylphenyl)amino)carbonylmethyl]-pyrroidine.3-carboxylic acid; trans, trans-2-(2-(4,4-Dimethy-2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3 20 benzodioxol-5-y)-1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethy]-.pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4(1 ,3-benzodioxol-5-yI) 1 -(N, N-dibutylaminocarbonyl methyl-pyrro lid ine3carboxylic 25 acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4(1 ,3-benzodioxol-5-yI) 1 -[(N-4-heptyl-N-(4-fI uoro-3 methy Iphenyi)amino)carbonylmethyl]-pyrrolidi ne-3-carboxyiic acid; 30 trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4(1 ,3-benzodioxoi-5-yI) 1 -[(N-butyl-N-(3-hydroxypropyi)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4(1 ,3-benzodioxol-5-yI) 1 -[(N-butyl-N-(propoxy)amino)carbonymethyl]pyrrolidine-3 35 carboxylic acid; WO 99/06397 - 39- PCT/US98/15479 trans,trans-2-(2-(1 -propanesuItamyl)ethyl)-4-(1,3-benzodioxol-5-yl) 1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy-1,3 5 benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; trans,trans-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy-1 ,3 benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic 10 acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy-1,3 benzodioxol-5-yl)-1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; 15 trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydro benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(2,3-dihydro benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3 20 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(2,3-dihydro benzofuran-5-yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 25 carboxylic acid; trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1
-[(N
4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1
-[(N
30 butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1
-(N
butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; 35 trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1
-[(N
butyl-N-( 4 -dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; WO 99/06397 - 40- PCTIUS98/15479 trans, trans-2-(2-(1 -pyrazo IyI) ethyI) -4-(7-methoxy1 ,3-benzodioxo I 5-y1) -1 -(N, N-dibuty Iam inocarbony Imet hy I) pyrro Iidine-3 carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(7-methoxy..1 ,3-benzodioxol 5 5-yI)-l-[(N-4-heptyl-N-(4-fluoro-3 methy lphe nyl) ami no) carbonyl methyl]-pyrro lid i ne-3-carboxyl ic acid; trans, trans-2-(2- (1 -pyrazo lyl) ethyl) -4-(7-methoxy- 1,3-be nzod ioxol 5-yl)- 1-[(N-butyi-N-(4 10 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyI)ethyI)-4-(2,3-dihydro-benzofuran-.5-yi) 1 -(N, N-dibutylam inocarbonymethyl)pyrro lid ine-3carboxylic acid; 15 trans, trans-2-(2- (1 -pyrazoly I)ethy 1)-4(2,3d ihyd robenzof uran 5-yl>. 1 -[(N-4-heptyl-N-(4-fI uoro-3 methylphenyl)amino)carbonylmethyl]pyrrolidine-3.carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyI)ethy)-4-(2,3dihydrobenzofuran-5-yly 20 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-oxazolyl)ethyl)-4(1 ,3-benzodioxol-5-yI)-1
-(N,N
di(n-butyl)aminocarbonytmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2- (2-(OxazoI1-2-yI) ethyl)-4-(1 ,3-be nzodioxol1-5-yI1) -1 -[(N 25 4 -heptyI-N-( 4 -fluoro-3-methylphenyl)amino)carbonylmethyl] pyrrolidine-3-carboxyiic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4(1 ,3-benzodioxol-5-yI)-1
-[(N
butyl-N-( 3 -hydroxypropyl)amino)carbonylmethy]pyrrolidine-3 carboxylic acid; 30 trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1
-[(N
butyl-N-(propoxy)amino)carbonylmethyl]-pyrroidine-3-.carboxyijc acid; trans, trans-2-(2-(Oxazoi2y)ethyl)4(1 ,3-benzodioxo-5-y)-1
-[(N
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] 35 pyrrolidine-3-carboxylic acid; WO 99/06397 - 41 - PCTIUS98/15479 trans, trans-2- (2- (Oxazo -2-y) ethyl) -4- (7-.met hoxy 1 ,3-benzodioxol 5-yI1) -1 -(N, N-di(n-butyI) am inocarbony Imet hy I) pyrro idine-3. carboxylic acid; trans, trans-2 -(2- (Oxazo 1-2-y1) ethy1)-4(7-met hoxy.1, 3-be nzod ioxol 5 5-yI)-1-[(N-4-heptyl-N-.(4..fluoro-3 methy lp henyl) ami no)carbo nylmethyl].pyrro lid ine-3..carboxylic acid; trans, trans-2-(2-(Oxazol-2-y)ethy-4(7-methoxy-1,3-benzodioxol 5-yI)- 1-[(N-butyl-N-(4 10 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidmne-3 carboxylic acid; trans, trans-2- (2- (5-M ethyl oxazo -2-y)ethy)-4(1 ,3-be nzod ioxo 1-5 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 15 trans, trans-2-(2-(5-Methyloxazol2yl)ethyl)-4(1 ,3-benzodioxol-5 yl)-l1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(5-Methyloxazol2yl)ethyl)-4(1 ,3-benzodioxol-5 20 yI)-1 -[(N-butyl-N-(4-dimethyiaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrroidin..1 -yl)ethyl)-4-(1 ,3-benzodioxol 5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyj)-pyrrolidine-3 carboxylic acid; 25 trans, trans-2-(2-(2,5-D ioxopyrro lid in-..1 -y1) ethyl) -4- (1 ,3-be nzodioxolI 5-yi)-l1-[(N-4-heptyl-N- (4-fl uoro-3 methylphenyI)amino)carbonyimethyp-pyrrolidine-3-carboxyijc acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin..1 -yl)ethyl)-4-(1 ,3-benzodioxol 30 5-yI)-1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyi] pyrrolidine-3-carboxylic acid; trans, trans-2- (2-(2,5- Dioxopyrro lid in-..1 -yI) ethyl)-4- (1 ,3-be nzodioxolI 5 -yI)-1 -[(N-butyl-N-(propoxy) am ino) carbo nyl methyy]-pyrro lid ine 3-carboxylic acid; 35 trans, trans-2-(2-(2,5-.Dioxopyrrolidin- -yl)ethyl)-4-(1 ,3-benzodioxol 5 -yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidne3carboxylic acid; WO 99/06397 -42- PCTIUS98/15479 trans, trans-2-(2-(2,5-Dioxopyrro idin.1 -y I) ethyI) -4-(7-methoxy-1 ,3 benzodioxol-5-yi)-1 -(N, N-di(n-butyl)aminocarbonyimethyl) pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1-yI)ethyl)-4-(7-methoxy-1 ,3 5 benzodioxoi-5-yI)-1 -[(N-4-heptyi-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl].pyrrolidine.3-.carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4(1 ,3-benzodioxol-5-yI)- 1 -[(N 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonymethyl]. 10 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yi)ethyl)-4-(1 ,3-benzodioxol-5-yt)-1
-[(N
butyl-N-( 3 -hydroxypropyl)amino)carbonylmethyl]..pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxoi-5-yI)-1
-[(N
15 butyl-N-(propoxy)amino)carbonymethyl]pyrroldine3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4(1 ,3-benzodioxol-5-yI)-1
-[(N
butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; 20 trans, trans-2- (2- (Pyrid in-2-y) ethyl) 4(7-methoxy- 1,3-benzodioxol 5-yI)-1 -(N, N-di(n-butyl)aminocarbonylmethyj>.pyrrolidine-3 carboxylic acid; trans, trans-2- (2- (Py rid in -2-y) ethyl) 4(7-meth oxyl 1,3-benzodioxol 5-yI)- 1 -[(N-4-heptyl-N-(4-fI uoro-3 25 methylphenyl)amino)carbonylmethyl]..pyrrolidine3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4(7-methoxy.1 ,3-benzodioxol 5-yI)- 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3. 30 carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-y)ethyl)-4(1 ,3-benzodioxol-5-yI)-1 (N ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-.carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-y1)ethyl)-4(1 ,3-benzodioxol-5-yi)-1 35
[(N-
4 -heptyl-N-( 4 -fluoro3methylphenyl)amino)carbonylmethyl]l pyrrolidine-3-carboxylic acid; WO 99/06397 - 43- PCT/US98/15479 trans, trans-2-(2-(Pyrimidin-2-yI)ethyl)-4-(1,3-benzodioxol-5-yl)-1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5 5 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol- 5 yl)-1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic 10 acid; and trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5 yl)-l-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yI)-1
-(N,N
15 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl) 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3 20 benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid;
(
2 S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl) 1 -(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 25 ( 2 S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1 (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt. 30 Most preferred compounds of the invention are selected from the group consisting of: trans, trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic 35 acid; WO 99/06397 -44 PCTIUS98/15479 trans, trans-2-(2,2,-Dimethy 2-(1 ,3-dioxo Ian -2-y I) ethy1) -4-(1 ,3 benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyl) pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-DioxoI-2-yI)ethyi)-4-(1 ,3-benzodioxol-5-yI) 5 -1 -[[N-4-heptyl-N-(2-methylk3-luorophenyl)] aminocarbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1
,
3 -Dioxol-2-yI)ethyl)-4-(7-methoxyl ,3 benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonymethyl.. pyrrolidine-3-carboxylic acid; 10 trans, trans-2-((2-Methoxyphenoxy)-methyl).4.(1 ,3-benzodioxot-5-yI) 1 -(N,N-di(n-butyl)aminocarbonylmethyl).pyrrolidine3carboxylic acid; trans, trans-2-(2-(2-Oxopyrroidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5 yi)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 15 carboxylic acid; benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluoro-3 methylphe nyl))am inocarbo nyl methyl)-pyrro lid ine-3-.carboxyl ic acid; 20 trans, trans-2-(2,2-Dimethylpentyl)4(7-methoxy 1 ,3-benzodioxol-5 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyly..pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,-Dimethy-2-(l ,3-dioxolan-2-yl)ethyl)-4-(7 methoxy-1 ,3-benzodioxol-5-y!)-1 -(N,N-di(n 25 butyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)ethy)4.(1,3-benzodioxol-5-yl) 1 -(N,N-di(n-butyl)aminocarbonylmethyl-pyrrolidine3carboxylic acid; trans, trans-2-(2,2-Dimethy3(E)pentenyl)4(7-methoxy-1,3 30 benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyl)> pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4(1 ,3-benzodioxol-5-yi)-1 -(N, N di(n-butyl)aminocarbonylmethyl)-pyrrojidine-3carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrro id in-..1 -yI)ethyl)-4-(1 ,3-be nzodioxol1-5 35 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 -45- PCT/US98/15479 (2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S, 3R, 4 S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5 5 yl)-1-(N-4-heptyl-N-(4-fluoro-3 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1
-(N,N
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 10 (2R, 3R, 4 S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1 -[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 15 ( 2
S,
3 R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl) 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(
2
S,
3
R,
4
S)-
2 -(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3 benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) 20 pyrrolidine-3-carboxylic acid;
(
2
S,
3 R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl) 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; and
(
2 S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1 25 (NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 30 Methods for preparing the compounds of the invention are shown in Schemes I-XV. 35 Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH 2 - and W is WO 99/06397 - 46- PCTIUS98/15479
-CO
2 H. A p-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as 5 toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product a 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, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic 10 solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5- as a mixture of cis-cis, trans,trans and cis,trans products. Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using 15 sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is (1) acylated or sulfonylated with R 3 -X (R 3 is R 4 -C(O)- or R 6
-S(O)
2 - and X is a leaving group such as a halide (Cl is preferred) or X taken together with
R
4 -C(O)- or R 6
-S(O)
2 - forms an activated ester including esters or 20 anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R 3 -X where X is a leaving group (for example, X is a halide (for example, Cl, Br or 1) or X 25 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 a which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester E (for example, using a base such a 30 sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and j, which are readily separated. Scheme I illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH 2 - and W is
-CO
2 H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 35 I_Q in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct L1. The anion of compound 1.1 is formed using a base such as n-butyllithium and then reacted with R 1
-CH
2 -X' wherein X' is a WO 99/06397 -7 PCT/US98/15479 leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound .1_4. 5 Treatment of compound 1_4 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles 15. Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile using 10 hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 1Z (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 1 8. Compound 18 is further elaborated by the procedures described in Scheme I for 15 compound 5 to give the final product compound 19. Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -C0 2 H. p-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an a-haloester 2_1 (where J is lower 20 alkyl or a 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 THF or dimethoxyethane to give diester 22. Treating compound 22 with R 3
-NH
2 and heating in acetic acid gives the cyclic compound 23. The double 25 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 trans,trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,trans 30 carboxylic acid 25. Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is -CH 2 - and W is
-CO
2 H. The trans,trans compound Z, prepared in Scheme 1, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is 35 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 WO 99/06397 - 48- PCT/US98/15479 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 compound 54 or an ester which may be 5 hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process. A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to 10 give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 30 as a mixture of cis-cis, trans,trans and cis,trans isomers. Chromatography separates 15 out the cis-cis isomer, leaving a mixture of the trans,trans and cis,trans isomers (31). Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (Lj) of trans,trans and cis,trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in 20 acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32, still as a mixture of trans,trans and cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans,trans compound but leaves the ethyl ester of the cis,trans compound untouched, thus allowing separation of the 25 trans,trans carboxylic acid 33 from the cis,trans ester 34. Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 35 is reacted with lithio dithiane 36 to give the alkylated compound 37. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium 30 diisopropylamide gives compound 38. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 3. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40. Treatment of compound 40 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture 35 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 WO 99/06397 - 49 PCT/US98/15479 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 45. 5 A preferred embodiment of the process shown in Scheme IlIl is shown in Scheme VIII. 4-Methoxybenzoylacetate 46 (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. 10 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 50. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide 15 hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51. Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH 2 -, and W is other than carboxylic acid. Compound 55, which can be prepared by the procedures described in Scheme IV, is converted (for 20 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 57. Nitrile 57 under standard tetrazole forming conditions (sodium azide 25 and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, 30 DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime 59 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 35 carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in WO 99/06397 - 50- PCT/US98/15479 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 6 1. 5 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 10 chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCl in dioxane gives the a-chloroketone L. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 63 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, 15 hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 65. 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 20 alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6. Treatment of 66 with an amine (R 2 0NH 2 ) affords secondary amine 67. This amine (&Z) can be reacted with an activated acyl compound (for example, R 4 -C(O)-Cl) and then carboxy deprotected (for example, hydrolysis of an ester or 25 hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R6-S(O) 2 -Cl) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69. 30 Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound Z0 are known to add to unsaturated esters such as 7L to provide pyrrolidines such as compound 72 (0. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S. 35 Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, 0. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 WO 99/06397 -51- PCT/US98/15479 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the N acetamido derivatives directly by reacting 73 and 74 with the 5 appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76. Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 80, which can be further elaborated 10 on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Boc nitrogen protected (for example, by treatment with Boc 2 0) 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 15 Z8. 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 20 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 80. 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, 25 by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 8_1. The use of (-)-cinchonine will give the opposite enantiomer. Scheme XIV describes another procedure for preparation of 30 pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R 55 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R 2 is as 35 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 WO 99/06397 - 52- PCT/US98/15479 U5, which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 86. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87. A preferred process is shown in Scheme XV. Nitro vinyl compound 5 (L8) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a 10 temperature of from about 00 C to about 1000 C for a period of time from about 15 minutes to overnight to give compound 90. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day 15 of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium 20 on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91_a or a mixture of nitrone 91_a and imine 91 b. The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, 25 and the hydrogenation is continued to give pyrrolidine compound 92 as the cis,cis-isomer. Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the 30 like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -20' C to about 1200 C to give the trans, trans compound 93. Compound 9_3 itself can optionally be resolved into enantiomers prior to reacting with X-R 3 . The substantially pure 35 (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or WO 99/06397 - 53- PCTIUS98/15479 D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+)-isomer of 93 selectively crystallizes as the salt, leaving the (-)-isomer of 93 in solution. Alternatively, the substantially pure (i.e., 5 at least 95% of the desired isomer) optically active (-)-isomer of compound 93 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired 10 (+)-isomer of compound 93 in solution. Compound j (racemic or optically active) is reacted with X-R 3 (where X is a leaving group (for example, a halide or a sulfonate) and R 3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like 15 in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 00 C to about 1000 C to give the intermediate ester 94. The ester can be isolated or converted in situ to the carboxylic acid (af) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide 20 and the like in a solvent such as ethanol-water or THF-ethanol and the like. A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic p-ketoesters (Scheme XVI) may be prepared by copper-catalyzed addition of a 25 Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding p-ketoester, for example by activation using 30 carbonyldiimidazole and condensation with magnesio-ethoxymalonate. Alternatively, olefinic p-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired p-ketoester. N-alkyl,O-alkyl bromohydroxamates are prepared according to 35 Scheme XVII. N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium WO 99/06397 - 54- PCTIUS98/15479 catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide. The P-ketoesters described in Scheme XVI may be converted to 5 pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under 10 controlled pH. A mixture of isomers are generated, in which the trans trans is generally preferred. Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can 15 be further enriched through recrystallization. The salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid. 20 Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns 25 an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product. 30 Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4 heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-(92 hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, 35 for example using sodium hydroxide in aqueous alcohol, provides the product.
WO 99/06397 - 55- PCT/US98/15479 For one particular class of electrophile, N-(Q-hydroxyalkyl)-N alkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, followed by displacement with 5 halogen (for example, using lithium bromide) provides the corresponding halide. Displacement of halide with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.
WO 99/06397 PCT/US98/15479 -56 Scheme I R1 CO2E + RI1 C2 2R2
NO
2 [H] H - 5 R2 -I -R1 R2 L R1
CO
2 E
CO
2 E Mixture of 4 Cis-Cis Trans-Trans Cis-Trans
X-R
3 R 3 ,R3 CO 2 H R2 R Trans-Trans
[H
2 0] S CO 2 E +
R
3 Mixture of Trans-Trans R2"" R1 Cis-Trans C0 2 E 8 Cis-Trans WO 99/06397 PCTIUS98/15479 -57 Scheme 11
R
2 ,,,.Cl + LI3-i S~%% 9 10 13 12 0 - - . R2 0- CN R 15 14 Ri R, + ISOMER 0 C0C 2 E do L", CN 17 R, R 18 19 WO 99/06397 PCT/US98/15479 -58 Scheme III Halo R1 CO2E + 0 R2 OR1
JO
2 C R 2 Halo = Cl, Br, or I 1 RO N
CO
2 E R1 CO2 E O R 3 R2 i 2 CO2 H Trans-Trans WO 99/06397 PCT/US98/1 5479 -59 Scheme IV R3 RN R2 RR2RR C0 2 H 0 L 7 52
ICH
2
N
2 ~C0 2 H O10,CHN 2 53 WO 99/06397 PCT/US98/15479 -60 Scheme V 0H 3 N 02 0 C H30 + O OB( COOPt Et02C Oc 3 CH3O OO~ 27-
NO
2 O 26 2IM 0 H2 0 H 0 0 N OCH3 0 -- O1CH3 COOEt COOP NaCNBH 3 Mixture of 2 Cis-Cis Trans-Trans Chromatographic separation Cis-Trans Cis-Cis + Mixture of Trans-Trans and Cis-Trans 31 WO 99/06397 PCT/US98/15479 -61 Scheme VI O COOEt N H C3H7 Cis-Trans N and BrCH 2
CONHC
7 0
OCH
3 O H iPr 2 NEt OQEt OCH3 Trans-Trans and Cis-Trans 6OO~tO N H C O NHC3H7
OCH
3 OCH3 0HCOO TasTasCsTrans-rnanCi-as Tran Trans NaOH ,H 2 O, EtOH
SNHC
3
H
7 O CH 3 + O. O ~.&- CH 3 COOH COOEt Trans-Trans Cis-Trans WO 99/06397 PCT/US98/15479 -62 Scheme Vil C l + Li S o OMe 0 S -~ M O s8 MeO 0 0-O N O 0 N ''C 0 + ISOMER OMe OMe 41 WO 99/06397 PCT/US98/15479 -63 Scheme Vil cont. ~10 > 0 0 N C O N CN OMe - OMe 41 0% >~ 0 > HN O N O
CO
2 Et CO2Et 0 1 44 4 43 OMe OMe 0 R3-.N 0I r "C0 2 H opI l 45 OMe WO 99/06397 PCTIUS98/15479 -64 Scheme Vill
CH
3 O- -- CO2E CO2E SCH30 E02C Br 4 0_ O OE O E O C H0C2EC H 0 00CH 3 5' Trans-Trans WO 99/06397 PCTIUS98/1 5479 -65 Scheme IX N R 3 N/R (CHi 2 )m
(CH
2 )M I I
CO
2 Hl
CONH
2 N H ,RR (CH2m6
(CH
2 )m(H) % N H N=N1 WO 99/06397 PCT/US98/15479 -66 Scheme X
R
4 OH + c0l R4 C HN - A C0 2 E 0O +
R
2 R1 R4 N
CO
2 H R4 O N CO 2 E R2 O R2 E6 WO 99/06397 PCT/US98/1 5479 -67 Scheme X1 H
R
C0 2 E C0 2 E -R4I ,R8-
,R
8
-NHR
2 0 C0 2 H C0 2 E 67 C0 2
H
WO 99/06397 PCT/US98/1 5479 -68 Scheme X11 R3 Ri
CO
2 Et R N+~ 10 R3 R2
CQ
2 Et
CH
2
R
2 22 ~ 71 7 Me 3 S N < CO 2 Et
~OCH
3 0 73 74
OCH
3
OCH
3 HN O 2 N CO 2 Et 00 76~0 WO 99/06397 PCT/US98/1 5479 -69 Scheme XIII
OCH
3 OCH 3 1. BOC 2 0
CO
2 Et 2. NaOH, EtCH BN -C0 2 H
H
2 0 0~0 1. (+)-cinchonine 2. recrystallize I ronj EtOAc/hexane 3. Na 2
CO
3
OCH
3
OCH
3 HCI EtCH 0 0 0-i 0-i I Ett'iPr 2 , CH 3 CN
OCH
3 0
CO
2 (+) c WO 99/06397 PCT/US98/1 5479 -70 Scheme XIV 83 R R s N Ph ,N l-N, ~e 3 Ph Q -0 2
R
56 Me 3 Si TEA, CH 2
CI
2 2
H
2
R
3 Br Pd(OH) 2 /C H Nq C0 2
R
56
BU
4 NI or Nal
CH
3 CN R3, ~ NaOH or LIOHR3 N _C0 2
R
56 EtOH, H 2 0 N C0 2
H
WO 99/06397 PCTIUS98/1 5479 -71 Scheme XV R2 020 0 R~N2+ EQ ~0
R
2 Wi , R i0 2 N 0 C0 2 E + C0 2 E
R
2
P
1 91 b C0 2 E 90 R20- 1 RR R, C0 2 E C 0 2 E 92 93 3 3
R
2
R
1 R2--- R, C0 2 H C0 2 E 94 WO 99/06397 PCTIUS98/1 5479 -72 SCHEME XVI -COO~t nIU5IIgLJ NaOH CDI 0:Kt OEt -. ------------
-------
Da cat CuCI HOOC0 EtOOC OEt rmg OEt NaOH CDIQt H+, heat HOOC EtOOC SCHEME XVII -OHN NaH H2 BoN.-11- TFA BrCH 2 COBr 0t R-X Pd-C er, N'1 SCHEME XVIII 0 2 N ~ ~ o DBU H 2 NaBH 3 CN HN 0 + - - -------ip .iCOODt 0 or cat. KOtBu Ra-Ni pH4-5 EtOOC R R 0 WO 99/06397 PCT/US98/15479 -73 SCHEME XIX R (s)-(+). R HN mandelic HN COE HN *-COOEt acid recrystallization neutralization HN -COOEt 0 o/ \ O- R= (racemic) (single enantiomer) 1. EDAC, R 2. F-pheno6 R HN -k 1. NaOMe, H HN -. COOEt 1. Boc 2 0 0 MeOH HN ,iCOOMe 2. NaOH 3. separate 2. TFA / \ diastereomers 0I
CH
3 O 0 1
CH
3 0 (racemic) R = (single enantiomer) -N 1. EDAC, HOOBt -N HN B cOH 1. HCI, heat HN -COOt 2. NaOH 3. separate 2. HCI, EtOH diastereomers O O (racemic) (single enantiomer) WO 99/06397 PCTIUS98/15479 -74 SCHEME XX 0 R B R1 2 R HN NaOH R1' N -4COEt ___ '"iCOOH o0 0 OR0-O - O
NR
1
R
2 'R 0 F
,
SCHEME XXI 0 R cROR HN -nIcooEt 1. MsCi , r NR 1COOEt 2. LiBr N 00 00 'R 0
(CH
3
)
2 NH R RNaOH
'R
WO 99/06397 PCTIUS98/15479 -75 Compounds which are useful as intermediates for the preparation of compounds of the invention are: R2 NH
(CH
2 )n
(CH
2 )m W R1 wherein n is 0 or 1; m is 0 to 6; W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R 1 7 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O) 2 R16 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2 NHC(O)R16, HO - NH (n) 0 ( J)o (o) HO 0 WO 99/06397 PCT/US98/15479 -76 OH N (p) 0 0 - NH (q) 0, N (r) , ~0 Ns -C)~S N (s) H N
CF
3 N (t) H, or (u) .- \ NHSO 2
CF
3 and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and
R
2 is other than hydrogen; or a salt thereof; or a compound of the formula: WO 99/06397 PCT/US98/15479 -77
R
2 NH R2 NH (C V (CH2)n (C %. (H2)n
(CH
2 )m
(CH
2 )m W R1 or W R1 (IV) (V) wherein n is 0 or 1; m is 0 to 6; W is (a) -C(O) 2 -G where G is hydrogen or a carb6xy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2 R16 where R1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2 NHC(O)R16, HO O / NH (n) 0 .Jso (o) HO 0 OH (p) WO 99/06397 PCT/US98/15479 -78 0 (q) 0 , (r) N ( ) ,5= (s) H N iL CF 3 N (t) H
NHSO
2
CF
3 (uM and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R 1 and
R
2 is other than hydrogen; or a salt thereof. Preferred intermediates include compounds of formula (lII), (IV) and (V) wherein m is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
WO 99/06397 PCT/US98/15479 -79 Particularly preferred intermediates are compounds of formula (Ill), (IV) and (V) wherein n and m are both 0; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4 methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4 methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4 methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof. Other compounds which are useful as intermediates for the preparation of compounds of the invention are: R2 N-- Rsb- 0
(CH
2 )n
(CH
2 )m ( R 1
(VI)
WO 99/06397 PCT/US98/15479 -80 wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; Q is a leaving group; W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O) 2
R
1 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2
NHC(O)R
16 , HO / NH (n) , .JO (O) 0 OH N I (p) 0 0 (I NH (q)0, WO 99/06397 PCTIUS98/15479 -81 N -C (r) 0, N, S= O (S) , )-CF3 (t) H or (u) - NHS2CF3; and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Roc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R 1 and
R
2 is other than hydrogen; or a salt thereof; or a compound of the formula: R2 N'Rsb - Q
R
2 '- N'Rsb -Q
(CH
2 )n
H
2 )n
(CH
2 )m
(CH
2 )m W R or w R1 (VI) (Vill) wherein n is 0 or 1; m is 0 to 6; WO 99/06397 PCT/US98/15479 -82 R5b is alkylene; Q is a leaving group; W is (a) -C(0) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O) 2
R
1 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2
NHC(O)R
1 6 , HO NH (n) (o) HO 0 OH (p) 0 - --NH O (q) 0 N O (r) , WO 99/06397 PCT/US98/15479 -83 N-O A-I N (S) H ~, N tZ -CF3 N (t) H ,or ( . -\
NHSO
2
CF
3 and R1 and R2 are independently selected from hydrOgen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rec is alkylene, with the proviso that one or both of R 1 and
R
2 is other than hydrogen; or a salt thereof. Preferred intermediates include compounds of formula (VI), (VII) and (Vill) wherein m is zero or 1; R5b is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof. Particularly preferred intermediates are compounds of formula (VI), (Vil) and (VIII) wherein n and m are both 0; R5b is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; WO 99/06397 PCT/US98/15479 -84 and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4 methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4 methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent -is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof. Other compounds which are useful as intermediates for the preparation of compounds of the invention are: 2 N...
R
5 b-NHR 2 Oa
(CH
2 )n
(CH
2 )m H W R (IX) wherein n is 0 or 1; m is 0 to 6; R5b is alkylene;
R
20 a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C(0) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2
,
WO 99/06397 PCT/US98/15479 -85 (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2 R16 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2 NHC(O)R16, HO 0 NH (n) 0 0 (o) HO 0 OH \N (p) ~NH (q) 0, (r), 0 N O -C N (s) WO 99/06397 PCT/US98/15479 -86 ..- N CF3 N (t) H ,or
NHSO
2
CF
3 (u) ; and Ri and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R 1 and
R
2 is other than hydrogen; or a salt thereof; or a compound of the formula:
R
2 R5b - NHR 2 oa R5b - NHR 2 oa N N I I
(CH
2 )n
(CH
2 )n
(CH
2 )m (CH 2 )m : I I W R1 or W R1 (x) (XI) wherein n is 0 or 1; m is 0 to 6; R5b is alkylene;
R
2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C(0) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, WO 99/06397 PCT/US98/15479 -87 (e) -C(O)NHR1 7 where R 1 7 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(0) 2 NHC(O)R16, HO / -NH (n) , O
(
0 ) HO 0 OH N (p) 0, 0 NH (q) H 0,N O s (r) , N (S) H
CF
3 (t) H ,or WO 99/06397 PCT/US98/15479 -88 (u . -a
NHSO
2
CF
3 and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rec is alkylene, with the proviso that one or both of R 1 and
R
2 is other than hydrogen; or a salt thereof. Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof. Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0; R5b is alkylene;
R
20 a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- WO 99/06397 PCT/US98/15479 -89 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxy alkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof. The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept. The following abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1,8-diazabicyclo(5.4.0]undec- 7 -ene, EDCI for 1-(3 dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et 3 N for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran. Example 1 transtrans- 2-(4-Methoxvohenvl)-4-(1.3-benzodioxol-5-yl-1 (propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 1A Ethyl 2-(4-methoxbenzovi)-4-nitromethvl- 3 -(1.3-benzodiyoxoe-5-vYlbutvrate 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)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 0C 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 (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer WO 99/06397 PCT/US98/15479 -90 chromatography (5% 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 NaCl 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-methoxyphenyl)-4- (1.3-benzodioxol-5-yll-4,5-dihydro-3H-pyrrole-3 carboxylate 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 g). (The Raney nickel was washed with ethanol three 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-methoxyphenyl-4- (1.3-benzodioxol-5-yl)-pyrrolidine-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 HCl, 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, trans-compound. Further elution WO 99/06397 PCT/US98/15479 -91 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-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- 1 (propylaminocarbonlmethyl)-yrrolidine-3-carboxyliC 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, W.M., J. Amer. Chem. Soc., 69: 515 (1947), in 30 mL of acetonitrile was heated at 50 0C 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 added. The mixture was extracted with ether to remove the unreacted cis,trans- ethyl 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. 151-153 *C. 1 H NMR (CD 3 0D, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J = 7 Hz, 2H), 2.84 ( d, J = 16 Hz, 1H), 2.95-3.20 (m, 4H), 3.20 (d, J = 16 Hz, 1H), 3.34-3.42 (m, 1H), 3.58-3.66 (m, 1H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, 1H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J = 1 Hz, 1H), 6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1H), 7.40 (d, J = 9 Hz, 2H). Example 2 trans.,trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yl)-1 -(aminocarbonylmethyl) pyrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture WO 99/06397 PCTIUS98/15479 -92 resulting from Example 1C), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 *C in 1 mL acetonitrile to give 291 mg of a mixture of 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 ID were used to give 134 mg of the title compound. m.p. 246-248 0C. 'H NMR (DMSO-d 6 , 300 MHz) 8 2.61 (d, J = 16 Hz, 1H), 2.71 (t, J = 9 Hz, 1H), 2.90 (t, J = 9 Hz, 1H), 2.98 (d, J = 16 Hz, 1H),3.25-3.35 (m, 1H), 3.45-3.55 (m, 1H), 3-71 (s, 3H), 3.75 (d, J = 10 Hz, 1H), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J = 8 Hz, 2H), 7.10 (s, 1H), 7.17 (s, 1H), 7.34 (s, 1H), 7.38 (d, J = 8 Hz, 2H). Example 3 trans. trans-2-(4-Methoxyohenyl)-4-(1,3-ben zodioxol-5-yl)-1 -(4-fluorobenzyl) pyrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from Example 1C), 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 H NMR (CDCl 3 , 300 MHz) 8 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J = 7 Hz, 1H), 2.98 (d, J = 14, 1H), 3.07 (dd, J = 9 Hz, 1 Hz, 1H), 3.42-3.53 (m, 1H), 3.70 (d, J = 9 Hz, 1H), 3.78 (d, J = 14, 1H), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, 1H), 6.77 (dd, J = 8 Hz, 1 Hz, 1H), 6.91 (d, J = 9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20 - 7.25 (M, 1H), 7.44 (d, J = 9 Hz, 2H). Example 4 trans, trans-2-(4-Methoxypheny)-4-(1,3-ben zodioxol-5-yl)- 1 -(2-ethoxyethyl) pvrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for WO 99/06397 PCT/US98/15479 -93 3 hours (bath temperature at 95 *C) 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 *C. 1 H NMR (CDC1 3 , 300 MHz) 8 1.25 (t, J = 7 Hz, 3H), 2.21 2.32 (m, 1H), 2.70-2.80 (m, 1H), 2.85-2,94 (m, 2H), 3.38-3.55 (m, 6H), 3.67 (d, J = 10 Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.84 (m, 1H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J = 1 Hz, 1H), 7.33 (d, J = 9 Hz, 2H). Example 5 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -(2-propoxyethyl) oyrrolidine-3-carboxylic acid Using the method described in Example 1D, 520 mg of the mixture resulting from Example 1C, 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 0C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,trans-esters. 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. 1 H NMR (CDCl 3 , 300 MHz) 6 0.87 (t, J = 7 Hz, 3H), 1.53 (sextet, J = 7 Hz, 2H), 2.28-2.41 (m, 1H), 2.71-2.83 (m, 1H), 2.92-3.08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 (m, 1H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H), 7.07 (d, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H). Example 6 trans, trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)-1-22 methoxyethoxy)ethyll-pyrrolidine-3-carboxylic acid Example 6A Ethyl trans. trans-2-(4-methoxyohenvl)-4-(1.3-benzodioxol-5-vI) ovrrolidine-3 carboxylate To the pure cis,cis-compound resulting from Example 1C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutralized WO 99/06397 PCT/US98/15479 -94 with HCI in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with 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). Example 6B trans, trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)-1-[2-(2 methoxyethoxy)ethyll-pyrrolidine-3-carboxylic acid Using the method described in Example 1D, -250 mg of the compound resulting from Example 6A, 150 mg of 2-(2 methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 0 C for 3 hours to give 229 mg of the trans, trans-ester. A portion (200 mg) was hydrolyzed 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 0D, 300 MHz) 5 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1H), 5.94 (s, 2H), 6.79 (d, J = 8 Hz, 1H), 6.89 (dd, J = 8 Hz, 1 Hz, 1H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J = 1 Hz, 1H), 7.49 (d, J = 9 Hz, 2H). Example 7 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(2-pvridyl)ethyll pyrrolidine-3-carboxylic 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 1D to give 202 mg of the title compound as the dihydrate. m.p. 77-80 0 C. 1 H NMR (CD 3 0D, 300 MHz) 5 2.8 - 3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H), 3.99 (d, J = 10 Hz, 1H), 5.92 (d, J = 1 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), s AP (dd. J = 8 Hz. 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1H), WO 99/06397 PCT/US98/15479 - 95 7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, 1H). Example 8 trans.trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(morpholin-4 ylcarbonyl)-pyrrolidine-3-carboxylic 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, 1H), 3.03-3.13 (m, 2H), 3.20 3.30 (m, 2H), 3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J = 10 Hz, 1H), 5.99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz, 2H), 7.07 (s, 1H), 7.25 (d, J = 9 Hz, 2H). Example 9 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxole-5-yl)- 1 -(butylaminocarbonyl) pyrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) 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 vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 232 mg of the title compound. m.p. 220-221 0C. 1 H NMR (DMSO d6, 300 MHz) 8 0.78 (t, J = 7 Hz, 3H), 1.10 (sextet, J = 7 Hz, 2H), 1.22 (quintet, J = 7 Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, 1H), 4.93 (d, J = 9 Hz, 1H), 5.80 (t, broad, J = 7 Hz, 1H), 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz, 2H), 7.00 (d, J = 1 Hz, 1H), 7.12 (d, J = 9 Hz, 2H).
WO 99/06397 PCT/US98/15479 -96 Example 10 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(4 methoxyphenylaminocarbonyl)-3-pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (300 mg) was treated 5 with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example 1D to give 279 mg of the title compound. m.p. 185-187 *C. 1 H NMR (CDCl 3 , 300 MHz) 8 3.23 (dd, J = 12 Hz, 13 Hz, 1H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1H), 5.06 (d, J = 10 Hz, 1H), 5.90 (s, 1H), 5.95 (s, 1H), 6.72 (d, J = 9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H). Example 11 5 trans. trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yl)-1 -acetyloyrrolidine-3 carboxylic 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 o 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 *C. Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d 6 , 300 MHz) 8 1.55 and 2.00 (s, 3H), 5 2.94 and 3.03 (dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1H), 4.95 and 5.04 (d, J = 10Hz, 1H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz, 2H), 7.18 and 7.32 (d, J = 9 Hz, 2H). 3o Example 12 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-furoyl)-pyrrolidine-3 carboxylic 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 35 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 WO 99/06397 PCTIUS98/15479 -97 hydrolyzed by the procedure described in Example 1D to give 269 mg of the title compound as an amorphous powder. 1 H NMR (DMSO-d6, 300 MHz) 5 3.06 (dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 4.25 (m, 1H), 5.19 ( d, J = 10 Hz, 1H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1H). Example 13 trans, trans-2-(4-Methoxyhenyl)-4-(1,3-benzodioxol-5-yl)- 1 (phenylaminocarbonyl)-pyrrolidine-3-carboxylic 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 0C. 1 H NMR (DMSO-d 6 , 300 MHz) 8 3.03 (dd, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 3.72 (s, 3H), 4.15 (m, 1H), 5.13 (d, 1H), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, 1H). Example 14 trans. trans-2-(4-Methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl)- 1 (allylaminocarbonvlmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 *C. IH NMR (CDCl 3 , 300 MHz) 8 2.84 (d, 1H), 2.90-3.10 (dt, 2H), 3.28 (d, 1H), 3.35 (dd, 1H), 3.62 (m, 1H), 3.72 3.97 (m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, 1H), 5.97 (s, 2H), 6.74 6.97 (m, 5H), 7.38 (d, 2H). Example 15 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(n butylaminocarbonylmethyl)-pyrroidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 *C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.90 (t, 3H), 0 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1H), 2.87-3.35 (m, 6H), 3.62 (m, 1H), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H). Example 16 trans.trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yll-1-(N-(n-propyl)-N 5 methylaminocarbonylmethyl)-pyrrolidine-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 WO 99/06397 PCT/US98/15479 -98 NMR. 'H NMR (CDC13, 300 MHz) 5 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd, 1H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1H), 3.40 (d, 1H), 3.60 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1H), 6.86 (m, 2H), 7.03 (m, 1H), 7.32 (d, 2H). Example 17 transtrans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(pyrrolidin-1 ylcarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (CDCI 3 , 300 MHz) 5 1.40 1.70 (m, 6H), 2.80 (d, 1H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1H), 6.80-6.90 (m, 3H), 7.04 (d, 1H), 7.30 (d, 2H). Example 18 trans.trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 (isobutylaminocarbonylm ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 -C. 1 H NMR (CD30D, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, 1H), 2.85 (d, 1H), 2.90-3.10 (m, 4H), 3.23 (d, 1H), 3.40 (m, 1H), 3.58-3.67 (m, 1H), 3.78 (s, 3H), 3.89 (d, 1H), 5.92 (s, 2H), 6.76 (d, 1H), 6.86 (dd, 1H), 6.91 (d, 2H), 7.02 (d, 1H), 7.40 (d, 2H). Example 19 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y)- 1 (cyclooentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 -C. 1 H NMR (CDC13, 300 MHz) 8 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1H), 2.90 (t, 1H), 3.04 (dd, 1H), 3.22 (d, 1H), 3.28 (dd, 1H), 3.40 (m, 1H), 3.80 (s, 3H), 4.15 (m, 1H), 5.97 (d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H).
WO 99/06397 PCT/US98/15479 -99 Example 20 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -(morpholin-4 ylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 2.82 (d, 1H), 3.00 (m, 2H), 3.24 (m, 1H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H), 6.84 (d, 3H), 7.00 (s, 1H), 7.28 (d, 2H). Example 21 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2-phenoxyethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMR (CD30D, 300 MHz) 8 2.82 (m, 1H), 2.96 (dd, 1H), 3.13 (m, 1H), 3.32 (m, 1H), 3.51-3.70 (m, 2H), 3.77 (s, 3H), 4.00 (d, 1H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1H), 6.80-6.95 (m, 6H), 7.03 (d, 1H), 7.22 (dd, 2H), 7.39 (d, 2H). Example 22 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2 methoxyethylaminocarbonvlmethyl)-pvrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-109 *C. 1 H NMR (CD30D, 300 MHz) 8 2.82 (d, 1H), 2.97 (q, 2H), 3.21 (d, 1H), 3.38 (m, 1H), 3.32 (s, 3H), 3.44 (m, 4H), 5 3.62 (m, 1H), 3.79 (s, 3H), 3.86 (d, 1H), 5.93 (s, 2H), 6.76 (d, 1H), 6.85 (dd, 1H), 6.91 (d, 2H), 7.01 (d, 1H), 7.38 (d, 2H). Example 23 trans.trans-2-(4-Methoxyhenvl)-4-(1,3-benzodioxol-5-yi)-1-(2-butoxyethvl pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 *C. 1 H NMR (CDC13, 300 MHz) 8 0.88 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J=6Hz, 6Hz, 1H), 2.92 (q, J=lOHz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 5 3.68 (d, J=lOHz, 1H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.83 (d, J=9Hz, 2H), 6.82-6.87 (m, 1H), 7.06 (d, J=2Hz, 1H), 7.32 (d, J=9Hz, 2H). MS m/e 442 (M+H)+.
WO 99/06397 PCT/US98/15479 -100 Example 24 trans, trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1 (progylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1,3-benzodioxol-5-ylcarbofnyl)acetate for ethyl (4 methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2 nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound. m.p. 97 99*C. 1 H NMR (CDC3, 300 MHz) 5 0.78 (t, J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 (d, J=16Hz, 1H), 2.74 (t, J=lOHz- 1H), 2.80-3.10 (m, 4H), 3.26-3.38 (m, 1H), 3.53 (m, 1H), 3.73 (s, 3H), 3.80 (d, J=lHz, 2H), 7.80 (t, J=6Hz, 1H). MS (DCI/NH 3 ) m/e 441 (M+H)+. Example 25 transtrans-2-(1.3-Benzodioxol-5-yi)-4-(4-m ethoxyohenyl)-1 -(2-propoxyethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4 methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2 nitrovinyl)-1,3-benzodioxol-5yi afforded the title compound. m.p. 67 69 C. 1 H NMR (CDCl3, 300 MHz) 5 0.89 (t, J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (m, 1H), 2.78-3.00 (m, 3H), 3.32 (t, J=7Hz, 2H), 3.45 3.57 (m, 4H), 3.73 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.22 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 3H), 6.98 (s, 1H), 7.37 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 428 (M+H)+. Example 26 trans, trans-2-(1.3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-{2-(2 methoxyethoxyethyl)1-yrrolidine-3-carboxylic acid 0 Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2 methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 -C. 1 H NMR (CD 3 0D, 300 MHz) 6 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=lOHz, 1H), 6.02 (s, 2H), 6.91 5 (d, J=8Hz, 1H), 6.95 (d, J=9Hz, 2H), 7.06 (dd, J=8Hz, 1H), 7.12 (dd, J=lHz, 1H), 7.37 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 444 (M+H)+.
WO 99/06397 PCT/US98/15479 -101 Example 27 trans. trans-2- (1.3-Benzodioxol-5-vl)-4-(4- methoxyohenyl)-1 -(butoxvethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2 ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 54-56 *C. 1 H NMR (CDCl 3 , 300 MHz) 5 0.89 (t, J 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m, 1H), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H), 3.68 (d, J=lOHz, 1H), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 (s, 1H), 7.36 (d, J=9Hz, 2H). Example 28 trans, trans-2-(4-Methoxyphenyl)-4-(1 .4-benzodioxan-6-yll- 1 (propylaminocarbonylmethyl)-pyrrolidine-3-carboxylig acid Using the procedures described in Example 1 and substituting 6 (2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxole afforded the title compound. m.p. 80-81 *C. 1 H NMR (CDCl 3 , 300 MHz) S 0.89 (t, J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, 1H), 2.92 (t, J=lOHz, 1H), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, 1H), 3.52-3.62 (m, 1H), 3.80 (s, 3H), 3.80 (t, J=lOHz, 1H), 4.27 (s, 4H), 6.74-6.93 (m, 5H), 7.29 (d, J=9Hz, 2H). MS (DCI/NH 3 ) m/e 455 (M+H)+. Example 29 trans. trans-2-(4-Methoxyohenyl)-4-(1,4-benzodioxan-6-yi)-1 -(N-methyl-N prooylaminocarbonylmethyl-ovrrolidine-3-carboxylic acid Using the procedures described in Example 1, substituting 6-(2 nitrovinyl)-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. m.p. 74-76 *C. Rotational isomers are seen in the NMR. 1 H NMR (CDC1 3 , 300 MHz) S 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, 1H), 3.75 (d, 1H), 3.78 (s,-3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H). MS (DCI/NH 3 ) m/e 469 (M+H).+ WO 99/06397 PCT/US98/15479 -102 Example 30 trans. trans-2-(4-Methoxyohenyl)-4- (1.3-benzodioxol-5-yl- 1 -(N-methyl-N butylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 1 H NMR (CD 3 OD, 300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, 1H), 3.60 (m, 1H), 3.80 (s, 3H), 3.85 (m, 1H), 5.91 (s, 2H), 6.74 (d, 1H), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.35 (dd, 2H). Example 31 trans. trans-2-(4-Methoxy-2-methoxymethoxyhenyl)- 4 -(1.3-benzodioxol-5-yl- 1 -(N methyl-N-butylaminocarbonylmethyl)-yrrolidine-3-carboXylic acid Example 31A Ethyl 2-(4-methoxv-2-methoxymethoxyohenyl-4-(1.3-benzodioxol-5-yl)-oyrrolidine 3-carboxylate) Using the procedures described in Examples 1A and 1B and substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2 methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H pyrrole-3-carboxylate. The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in 20 mL of methanol, treated with 500 mg 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. Example 31B trans, trans-2-(4-Methoxv-2-methoxvmethoxvohenvl-4-(1.3-benzodioxol-5-vi)- 1 -(N methyl-N-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The compound resulting from Example 31A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in 5 Example 1D substituting N-methyl-N-butyl bromoacetamide for N propyl bromoacetamide to give the title compound (75 mg, 62%). m.p. 65-67 *C. Rotational isomers are seen in the NMR. 1 H NMR (CDCI3, 300 WO 99/06397 PCTIUS98/15479 -103 MHz) 5 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40 1.48 (m, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43 3.65 (m, 2H), 3.78 (s, 3H), 4.30 (t, J=7Hz, 1H), 5.09 (q, J=7Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J=3Hz, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 6.85 (2t, J=1Hz, 1H), 7.04 (t, J=1Hz, 1H), 7.42 (dd, J=3Hz, 1H). Example 32 trans. trans-2-(4-Methoxvphenl)-4-(1.3-benzodioxol-5-yl)- 1-(3-ethoxvoroovl pyrrolidin-5-one-3-carboxylic acid Example 32A Ethyl 2-(4-methoxybenzov)-3-carbomethoxy-1.3-benzodioxole-5-propionate To ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 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 (1,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added. 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-ethoxvpropvi)-2-(4-methoxvohenvi)-4-(1.3-benzodioxol-5-yl)-4.5-dihvdro 5-oxo-1H-pyrrole-3-carboxylate 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 0C. 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 obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg (42%) of the title compound.
WO 99/06397 PCTIUS98/15479 -104 Example 320 Ethyl 1-(3-ethoxvorooyl-2-4-methoxyphenyl)- 4 -(1.3-benzodioxol-5-yl)-pyrrolidin-5 one-3-carboxylate The compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 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-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(3-ethoxvoropvl pyrrolidin-5-one-3-carboxylic 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 OC 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, 64%). m.p. 134-140 *C. 1 H NMR (DMSO-d6, 300 MHz) 8 1.04 (t, J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 (m, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 (t, 5 J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1H), 3.78 (s, 3H), 3.88 (d, J=lOHz, 1H), 4.72 (d, J=lOHz, 1H), 6.02 (s, 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 (d, J=8Hz, 2H), 6.98 (d, J=8Hz, 2H), 7.38 (d, J=8Hz, 2H). MS
(DCI/NH
3 ) m/e 442 (M+H)+. Example 33 trans, trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxo-5-yl)- 1 -(3-methoxybenzyl) pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded 5 the title compound (123 mg, 65%). m.p. 150-152 0 C. 1 H NMR (CD 3 0D, 300 MHz) 8 2.96 (dd, J=8Hz, 10Hz, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 4.06 (d, J-.1IHz,... 1H A.5 ( ... =AH I 1H). 4.92 (o, J=16Hz, 2H), 5.92 (s, 2H), WO 99/06397 PCT/US98/15479 -105 6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), 6.94 (d, J=8Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI/NH 3 ) m/e 475 (M+H)+. Examl e 34 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-(N.N diisoamylaminocarbonvylmethl)-pyrrolidine-3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDC13, 300 MHz) 8 0.70 0.90 (m, 12H), 1.10-1.60 (m, 10H), 2.75 (d, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=1OHz, 1H), 3.40 - 3.52 (m, 2H), 3.55 - 3.62 (m, 1H), 3.75 (d, J=12 Hz, 1H), 3.79 (s, 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Example 35 trans.trans-2-(4-Methoxyphenyl)- 4 -(1.3-benzodioxol-5-yl)-1
-(N.N
dipentylam inocarbonyim ethyl)-pyrrolid ine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI3, 300 MHz) 5 0.82 (t, J = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, J=13Hz, 1H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d, J=13Hz, 1H), 3.52-3,60 (m, 1H), 3.70 ( J=1OHz, 1H), 3.75 (s, 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Example 36 trans. trans-2-(4-Methoxyohenvil-4-(1.3-benzodioxol-5-yil- 1 -(N.N-di(2 methoxyethyl)aminocarbonvlm ethyl-pyrrolidine-3-carboxYiic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 *C. 1 H NMR (CDCl 3 , 300 MHz) 6 2.82 (d, J=13, 1H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H), 3.73 (d, J=1OHz, 1H), 3.79 (s, 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
WO 99/06397 PCTIUS98/15479 - 106 Example 37 trans. trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yi)-1 -(2-hexynyl-pyrrolidine 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, prepared by the method described in Perkin I, , 2004 (1987), for 1 hour at 55 0C, 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. 1 H NMR (CDC1 3 , 300 MHz) 8 1.00-(t, J=7Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, 1H), 3.07 (dd, J=18Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 (t, J=9Hz, 1H), 3.36 (dd, J = 18 Hz, 2Hz, 1H), 3.47-3.55 (m, 1H), 3.79 (s, 3H), 3.88 (d, J=9Hz, 1H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.22 (d, J=9Hz, 2H). Example 38 trans. trans-2-(4-M ethoxyheny)-4- (1.3-benzodioxol-5-vi)- 1- (N-cyclooropvlmethyl N-orooylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 0C. Rotational isomers were seen in the NMR. 'H NMR (CDC13, 300 MHz) 5 -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32 0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 (d, J=13Hz, 1H), 2.85--3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, 1H), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, 1H), 3.78 (s, 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H). Example 39 trans. trans-2-(4-Methoxyheny)-4-(1.3-benzodioxol-5-yi)-1 -(N-methyl-N pentylaminocarbonylmethyl)-oyrrolidine-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 (CDC13, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 1.00-1.08 (m), 1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, J=13Hz, 1H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52 3.62 (1, IN1), 3.72 (2 dub!ets, IH). '.75 and 3.76 (2 singlets, 3H), 5.92 WO 99/06397 PCT/US98/15479 -107 (2 singlets, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Example 40 trans.trans-2-(4-Methoxyhenyl-4-(1.3-benzodioxol-5-vl)-1-(N.N diisobutylaminocarbonylmethyl-pyrrolidifne-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 *C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.54 (d, J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (m, 1H), 1.90 2.02 (m, 1H), 2.67 (d, J=13Hz, 1H), 2.70 (d, J=13Hz, 1H), 2.84 (dd, J=6Hz, 15Hz, 1H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, J=9Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.31 (d, J=9Hz, 2H). Example 41 trans. trans-2-(4-Methoxyohenvl)-4-(1.3-benzod ioxol-5-yl)- 1 -(N-methyl-N-(2 prooynyl)am inocarbonylmethyl)-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) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1H), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, 1H), 3.78 (s, 3H), 4.03 (d, J=13Hz, 1H), 4.00-4.30 (m, 3H), 5.93 (s, 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 and 7.11 (2 doublets, J = 2Hz, 1H), 7.30 (2 doublets, J=9Hz, 2H). Example 42 trans. trans-2-(4-Methoxyphenl)-4- (1.3-benzodioxol-5-y)- 1 -(N-methyl-N-(n hexvl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDC1 3 , 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=13Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1H), 7.30 (d, J=9Hz, 1H).
WO 99/06397 PCT/US98/15479 -108 Example 43 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-v)- 1 -(N. N-di~n butvl)aminocarbon ylmethy/)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 123-125 "C. 1 H NMR (CDCl 3 , 300 MHz) 8 0.79 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J=13Hz, 1H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13Hz, 1H), 3.52-3.62 (m, 1H), 3.75 (d, J=10 Hz, 1H), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 (d, J=8Hz, 1H), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH 3 ) m/e 511 (M+H)+. Anal calcd for C 29
H
38
N
2 0 6 : C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40. Example 44 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1
-(N.N
diethylam inocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 0C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.98 (t, J=7Hz, 3H), 1.06 (t, J=7Hz, 3H), 2.78 (d, J=13 Hz, 1H), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.76 (d, J=12 Hz, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.32 (d, J=9Hz, 2H). Example 45 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -(N-methyl-N phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD 3 0D, 300 MHz) 8 2.75 2.85 (m, 2H), 3.05-3.13 (m, 1H), 3.18 (s, 3H), 3.40-3.58 (m, 2H), 3.78 (s, 3H), 3.88 (d, J=12Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.75 6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H). Example 46 trans, trans-2-(4-Methoxyphenyll-4-(1 .3-benzodioxol-5-yl)- 1 -(N-methyl-N cyclohexylaminocarbonylmethyl)-yrrolidine-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 ANM. 1H NMR (CD30D. 300 MHz) 8 1.00-1.85 (m, 10H), 2.72 and 2.78 (2 WO 99/06397 PCT/US98/15479 -109 singlets, 3H), 2.75-2.82 (2 doublets, J=12Hz, 1H), 2.96-3.22 (m, 3H), 3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=lOHz, 1H), 3.77 and 3.78 (2 singlets, 3H), 5.92 (s, 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.30-7.40 (2 doublets, J=9Hz, 2H). Example 47 trans. trans-2-(4-Methoxvhenvl)-4-(1.3-benzodioxol-5-yi)-1 -(N.N-di(n proDyl)aminOcarbOnvlImethvl)-Drrolidine-3-carboxylic acid The title compound was prepared using the-procedures described in Example 1. m.p. 170-172 *C. 1 H NMR (CDCI3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1H), 3.72 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Example 48 trans. trans-2-(4-Methoxyh enyl-4-(1.3-benzodioxo-5-yl)- 1 -(N-methyl-N isobutylaminocarbonylimethvl-pyrrolidine-3-carboxuic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. '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 (m, 4H), 3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=10Hz, 1H), 5.93 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.80-7.90 (2 doublets, J=9Hz, 2H). Example 49 Alternate Prepration of Ethyl 2-(4-methoxybenzoyl-4-nitromethyl-3-( zo'A-'-rate Example 49A E-2-(3.4-Methylenedioxypheny)-l-nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol (120 mL) at 10 0C 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 WO 99/06397 PCTIUS98/15479 -110 maintaining the temperature between 10-15 *C. 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 *C, 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-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1 H NMR (300MHz, CDC 3 ) 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, s). MS (DCI/NH 3 ) m/e 194 (M+H)+, 211
(M+H+NH
3 )+. Example 49B Ethyl 2-(4-m eth oxvhenvloxo-4-nitro-3-(3,4-methylenedioxvphenvl)butvrate To a stirred solution of the nitrostyrene 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 (4-methoxybenzoyl)acetate (11.5 g, 51.7 mmol) in THF (50 mL) followed by 1,8-diazabicyclo[5,4,O]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 20% ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents were removed 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, CDC1 3 ,) 5 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1H, dd, J=9Hz,3Hz), 6.73 (1H, d, J=9Hz), 6.65 (1H, d, J=3Hz), 5.95 (2H, s), 5.89 (1H, d, J=4Hz), 5.88 (1H, d, J=4Hz), 4.90-4.60 (3H, m), 4.39 (1H, m), 4.18 (2H, q, J=7Hz), 3.94 (2H, WO 99/06397 PCT/US98/15479 -111 m), 3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS
(DCI/NH
3 ) m/e 416 (M+H)+, 433 (M+H+NH 3 )+. Example 50 trans. trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)- 1 -(t butyloxycarbonylmethyl)-pyrrolidine-3-carboxylic acid To a stirred solution of the compound resulting from Example 1C (100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively diisopropylethylamine (70 4L, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 gL, 0.29 mmol, 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 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 jL-), and then extracted with ethyl acetate (2x). The combined organic extracts were dried (Na 2 SO4), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid. 1 H NMR (300 MHz, CDCI 3 ) 8 7.36 (2H, d, J=8Hz), 7.13 (1H, d, J=3Hz), 6.90 (1H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1H, d, J=8Hz), 5.96 (2H, s), 3.96 (1H, d, J=9Hz), 3.81 (3H, s), 3.58 (1H, ddd, J=12, 1OHz,3Hz), 3.52 (1H, dd, J=9Hz,3Hz), 3.32 (1H, d, J=17Hz), 3.08 (1H, t, J=lOHz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=17Hz). MS (DCI/NH3) m/e 456 (M+H)+. Anal calc for C 29
H
29 NO7 - 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93. Example 51 trans. trans-2-(4-Methoxyohenyl)-4-(1 -nachthyl)-1 -(N-methyl-N propyllam inocarbonylmethvl-pyrrolidine-3-carboxlic 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. 1H NMR (300 MHz, CDCI3) 5 8.29 (1H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1H, d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (1H, m), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, s), 3.65 WO 99/06397 PCT/US98/15479 -112 (1H, m), 3.49 (1H, d, J=14Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH3) m/e 461 (M+H)+. Anal calcd for C 29
H
29 NO7 - 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: C, 70.95; H, 7.00; N, 5.46. Example 52 trans. trans2-(4-Methoxyphe ny)-4-(2.3-dihdrobenzofuran-5-yI)- 1 -(N-methyl-N propyl)am inocarbonylmethyl-prrolid ine-3-carboxylic acid Example 52A 2.3-Dihydrobenzofuran-5-carboxaldehyde 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 0C. The mixture was warmed to 0 0C, 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 OC at 0.3 mm Hg. Example 52B trans.trans-2-(4-Methoxvohenvl)-4-(2.3-dihvdrobenzofuran-5-yl)-1-(N-methyl-N propyl)aminocarbonylmethyl)-pyrrolidine-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. 1 H NMR (300 MHz, CDCI 3 ) 5 7.33 (1H, d, J=8Hz), 7.28 (1H, m), 7.19 (1H, m), 6.87 (1H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 4.56 (1H, t, J=8Hz), 3.83 (1H, d, J=lOHz), 3.80 (3H, s), 3.63 (1H, m), 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 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 2 6
H
32
N
2 05 - 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
WO 99/06397 PCT/US98/15479 -113 Example 53 trans. trans-2.4-Bis(4-methoxyhenyl-1 -(N-methyl-N-orooyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) 8 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m), 3.83 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C 25 l 32
N
2 0s - 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00. Example 54 trans.trans-2-(4-MethoxvDhenyl)-4-(3.4-dimethoxYhenyl)-1 -(N-methyl-N propyl)am inocarbonylmethyl)-pyrrolidin e-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. 1H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1H, m), 6.85 (1H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (1H, m), 3.79 (3H, s), 3.64 (1H, m), 3.50-2.95 (6H, m), 2.87 (1H, m), 2.85, 2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS
(DCI/NH
3 ) m/e 471 (M+H)+. Anal calc for C 26
H
34 N206 - 0.5 H 2 0: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59. Example 55 trans. trans-2-(4-Methoxyphenyl)-4-(3-methoxyphenYl)- 1 -(N-methyl-N proylaiminocarbonylmethyl)-pyrrolidine-3-carboxylic 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 NMR. 1 H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.05 (2H, m), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1H, m), 3.83 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 5 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 ) m/e 441 (M+H)+.
WO 99/06397 PCT/US98/15479 -114 Anal calc for C 25
H
32
N
2 0 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. Example 56 trans, trans-2-(4-Methoxyphenyl)-4-(2-naphthyl)-1 -(N-methyl-N propyl)am inocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCl 3 ) 8 7.82 (4H, m), 7.69 (1H, m}, 7.47 (2H, m), 7.37 (2H, dd, J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78 (3H, s), 3.57 (1H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1H, m), 1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH 3 ) m/e 461 (M+H)+. Anal calc for C 2 8
H
3 2
N
2 0 4 -0.5 H 2 0: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01. Examl e 57 trans. trans-2-(4-Methoxvpheny)-4-(1.3-benzodioxol-5-yi)-1 -(2-(ethylsulfinyllethyl) pyrrolidine-3-carboxylic 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 (75%) of the ethylthioethyl compound. To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2 Cl 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 10% 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 10% MeOH in
CH
2
CI
2 to afford the sulfoxide (62 mg, 65%). The ethyl ester was hydrolyzed by the procedure described in F'nmnip. 1D to afford the title compound as a diastereomeric mixture.
WO 99/06397 PCT/US98/15479 -115 m.p. 61-63 *C. MS (DCt/NH 3 ) m/e 446 (M+H)+. 1H NMR (CDC13, 300 MHz) 8 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02 3.08 (m, 1H), 3.32, 3.36 (d, J=3Hz, 1H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, J=7.5Hz, 1H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 3.84 3.89 (m, 3H), 7.02 (d, J=6Hz, 1H), 7.30, 7.34 (d, J=7.5Hz, 2H). Example 58 trans. trans-2-(4-Methoxyhenyl)- 4 -(1.3-benzod ioxol-5-yl)- 1 -(2 (isoDropvlsulfonylaminolethyl)-Dvrrolidine-3-carboXvlic acid To 2-bromoethylamine hydrobromide (1 mm-61) suspended in anhydrous
CH
3 CN was added 1 equivalent of Et 3 N. The mixture was stirred for 30 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 s 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 0C 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 o chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg (75%) 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, 88%). m.p. 94-96 0C. 1 H NMR (CD 3 0D, 300 MHz) 8 1.26 (d, J=6Hz, 6H), 1.97 (s, 1H), 2.38 (m, 1H), 2.77 (m, 1H), 2.88 5 (t, J=9Hz, 1H), 3.04 (m, 1H), 3.14 (t, J=7.5Hz, 2H), 3.35 (m, 2H), 3.46 (m, 1H), 3.58 (m, 1H), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, J=9Hz, 1H), 6.86 (dd, J=9Hz,3Hz, 1H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1H), 7.36 (d, J=9Hz, 2H). MS (DCI/NH3) m/e (M+H)+. 0 Example 59 trans.trans-2-(4-MethoxyDhenyl)- 4 -(1.3-benzodioxol-5-yl)-1 -(2-(isobutoxy)ethyl) pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 1C and 2 3s (isobutoxy)ethyl bromide. m.p. 68-70 0C. 1 H NMR (CDCI3, 300 MHz) 5 0.88 (d, J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1H), 2.22 (m, 2H), 2.72-2.79 WO 99/06397 PCT/US98/15479 - 116 (m, 1H), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 (s, 1H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH 3 ) m/e 442 (M+H)+. Examl e 60 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(butylsulfonyl) pyrrolidine-3-carboxylic 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 (90%) 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 5 (60 mg, 53%) as a white solid. m.p. 67-69 0C. 1 H NMR (CDCI3, 300 MHz) 5 0.82 (t, J=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J=9Hz, 1H), 3.49 (t, J=12Hz, 1H), 3.65 (dd, J=12Hz, 1H), 3.82 (s, 3H), 4.32 (dd, J=12Hz, 1H), 5.17 (d, J=9Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCI/NH 3 ) 0 m/e 462 (M+H)+. Example 61 trans. trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N isocroylcarbonylaminoethyl)-ovrrolidine-3-carboxlic acid 5 WO 99/06397 PCTIUS98/15479 -117 Example 61A trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)-1 -(2-bromoethyl) 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 0C 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 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-Methoxyphenl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(methylamino)ethyl) pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 61A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 0C 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 61C trans. trans-2-(4-Methoxyohenyl- 4 -(1.3-benzodioxol-5-yl)-1 -(2-(N-methyl-N isobutyrylamino)ethyll-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61B (-150 mg) dissolved in 5 mL of 1,2-dichloroethane was added 0.3 mL of D diisopropylethylamine. The solution was cooled to -40 0C, 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 5 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.
WO 99/06397 PCT/US98/15479 -118 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 s aqueous phase was acidified with 1 N H 3 PO4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2SO4. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 1 H NMR (CDC1 3 , 300 MHz) of the major rotamer 8 1.06 (d, 3H, 3 J=lOHz), 1.12 (d, 3H, J=10Hz), 2.15 (m, 1H), 2.5-3-.0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, 1H, J=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1H, J=2Hz), 7.29 (m, 1H). MS
(DCI/NH
3 ) m/z 469 (M+H)+. Analysis calcd for C 26
H
32
N
2 0 6 - 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24. 5 Example 62 transtrans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N propionylamino)ethyl)-pyrrolidine-3-carboylic acid The title compound was prepared by the procedures described in 0 Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1 H NMR (CDC1 3 , 300 MHz) of the major rotamer 5 1.13 (t, 3H, J=8Hz), 2.19 (m, 1H), 2.30 (m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8Hz), 6.75-6.9 (m, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DCI/NH 3 ) 5 m/z 455 (M+H)+. 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. Example 63 trans. trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yl)-1 -(N-methyl-N o benzylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCl3, 300 MHz) of the major rotamer 8 2.79 (s, 3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, 1H), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 (m, 4H), 7.00 (m, 1H), 5 7.15-7.35 (m, 7H). MS (FAB/NBA) m/z 503 (M+H)+. Anal calcd for
C
29
H
30
N
2 0 6 -0.5 H 2 0: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74; N. 5.36 .
WO 99/06397 PCTIUS98/15479 -119 Example 64 trans.trans-2-(4-Methoxhenvl)- 4 -(1.3-benzodioxol-5-yl)-1 -(N-ethyl-N butvlaminocarbonylmethyl)-yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCl3, 300 MHz) of the major rotamer 8 0.88 (t, .3H, J=7Hz), 1.06 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11H), 3.79 (s,3H), 3.80 (m, 1H), 5.92 (bd s, 2H), 6.75 (d, 1H, J=8Hz), 6.85 (d, 1H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (s, 1H), 7.33 (d, 1H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+. Anal calcd for C 27 H3 4 N206 - 0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.
Exampole 65 trans. trans-2-(4-Methoxvphenyl-4- (1.3-benzodioxol-5-yl) -1- (N-methyl-N-(2.2 dimethylorooylam inocarbonylimethyl-yrrolidine-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 0.90 (s, 9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1H), 3.80 (s, 3H), 3.82 (m, 1H), 5.94 (bd s, 2H), 6.74 (d, 1H, J=8Hz), 6.86 (d, 2H, J=8Hz), 6.87 (m, 1H), 7.03 (d, 1H, J=2Hz), 7.33 (d, 2H, J=8Hz). MS
(DCI/NH
3 ) m/z 483 (M+H)+. Example 66 trans. trans-2-(4-Methoxyphenyl-4- (1.3-benzodioxol-5-yl)- 1 -(2-(N-methyl-N butylsulfonylaminoethl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61B (60 mg, 0.13 mmol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mg (0.143 mmol, 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 (90%) of the ester. Ester hydrolysis by the procedure described in Example 1D afforded the title compound. m.p. 64-66 *C. 1 H NMR (CDCI3, 300 MHz) 8 0.92 (t, J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1H), 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, 1H), 3.25-3.34 (m, 1H), 3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, 1H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, WO 99/06397 PCTIUS98/15479 -120 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz,3Hz, 1H), 6.86 (d, J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH 3 ) m/e 519 (M+H)+. Example 67 trans. trans-2-(4-Methoxvohenvl-4-(1.3-benzodioxol-5-yl)-1-(2-(N-methyl-N propylsulfonylamino)ethyl)-pyrrolidine-3-carboxlic acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1 butanesulfonyl chloride. m.p. 69-70 0C. 1H NMR (CDC13, 300 MHz) S 1.02 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2'26 (m, 1H), 2.72 (s, 3H), 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47-3.58 (m, 2H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J=7.5Hz, 1H), 6.84 (d,d, J=7.5Hz, 3Hz, 1H), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, 1H), 7.43 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 505 (M+H)+. Example 68 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2 (propylsulfonylethyl)-pyrrolidine-3-carboXyiic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 0C for 1 hours. To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 mmol) in 2 mL THF. Heating was continued at 60-70 0C 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 mg (95%). To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H 2 0 was added a solution of osmium tetroxide (10 mg) in 0.3 mL of t-butanol. 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 over Na2SO4 and concentrated in vacuo. Flash chromatography afforded 177 mg (98%) of the ethyl ester which was hydrolyzed by the procedures described in Example 1D to afford the title WO 99/06397 PCT/US98/15479 -121 compound. m.p. 73-75 *C. 1 H NMR (CDC13, 300 MHz) 8 1.04 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 (m, 1H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 (m, 1H), 3.68 (d, J=9Hz, 1H),. 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 (d, J=9Hz, 2H), 6.99 (d, J=3Hz, 1H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 476 (M+H)+. Example 69 trans. trans-2-(4-Methoxyphenl)-4-(1.3-benzodioxol-5-yl)-1 -N-(trans-5-methylhex 2-enyl)-pyrrolidine-3-carboxylic icid 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 0C. Diisopropyl(ethoxycarbonylm ethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 *C. 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 Na2SO4, and evaporated to give a colorless oil which was purified by flash chromatography on silica gel eluting with hexanes. The title compound was isolated as a 5 colorless oil (2.1 g). Example 69B trans-5-Methylhex-2-en-1-ol The compound resulting from Example 69A (2.0 g) was dissolved in 0 toluene and cooled to 0 0C in an ice bath. Diisobutylaluminum hydride (1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 0C 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. Diethyl ether (50 mL) was added, the solids 5 removed by filtration and washed with additional ether (2 x 25 mL). The filtrate was extracted with ether (2 x 25 mL). The ether rrt wnqhinas were combined, dried, and evaported to give a WO 99/06397 PCTIUS98/15479 - 122 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-methylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 0C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 0C 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-Methoxyheny)-4- (1.3-benzodioxol-5-yl)- 1- N- (trans-5-m ethylhex 2-enyl-ovrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. 1 H NMR (CDCl 3 , 300 MHz) S 0.84 (d, 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,14Hz), 2.86 (t, 1H, J=lOHz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, 1H, J= 5Hz,14Hz), 3.29 (dd, 1H, J=3Hz,lOHz), 3.50 (m, 1H), 3.70 (d, 1H, J=1OHz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1H, J=8Hz), 6.83 (d, 3H, J=9Hz), 7.05 (s, 1H), 7.32 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C 2 6H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17. Example 70 trans. trans-2-(4-Methoxyoheny)-4- (1.3-benzodioxol-5-yl)-1 -N-(trans-3.5 dimethylhex-2-enyl)-oyrrolidine-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 s olefins. The crude product was purified by preparative HPLC (Vydac ptC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The Jtii-ed fraction e e re iny hili7rd tn nive, the product (and its WO 99/06397 PCT/US98/15479 -123 diastereomer) as a white solid. 1 H NMR of the major (trans) isomer: (CDCI3, 300 MHz) S 0.83 (d, 6H, J=8Hz), 1.56 (s,3H), 1.74 (m, 1H), 1.92 (d, 2H, J=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (m,4H), 3.78 (s, 3H), 3.9-4.0 (m, 1H), 5.22 (m, 1H), 5.90 (d, 2H, J=12Hz), 6.63 (m, 1H), 6.78 (m, 3H), 6.95 (s, 1H), 7.45 (d, 3H, J=8Hz). MS (DCI/NH 3 ) m/e 438 (M+H)+. Anal calcd for
C
27
H
33 NOs - 1.0 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-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)- 1 -(4 heptylcarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 71A 1 -Chloro-3-propyl-2-hexanone To 2-propylpentanoic acid (156.6 p1, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 pL, 4 mole %), and the solution was cooled to 0 0C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 gL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 0C 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 concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 0C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 4L, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. 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-methoxypheny)-4-(1.3-benzodioxol-5-Yi)-1 -(4 heptylcarbonvlmethyl-pvrrolidine3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans WO 99/06397 PCT/US98/15479 -124 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 *C 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 (46%) of the title -compound as a yellow oil. Example 710 trans trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(4 heptylcarbonylmethy)-pyrrolidine-3-carboxylic 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 (50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the pH to -5. 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 mg (39%) of the title compound as an off white powder. 1 H NMR (CDC1 3 , 300 MHz) 8 0.73-0.97 (m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1H), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.75 (d, 1H), 6.86 (d, 2H), 6.92 (d, 1H), 7.12 (s, 1H), 7.32 (d, 2H). MS (FAB) m/e 482 (M+H)+. Anal calcd for C 28
H
35
NO
6 : C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.
WO 99/06397 PCTIUS98/15479 -125 Example 72 trans.trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1 -(valerylmethyl) pyrrolidine-3-carboxylic acid Example 72A 1-Chloro-2-hexanone Using the procedure described in Example 71A 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. Example 72B trans.-trans-Ethyl 2-(4-methoxyphenYl)-4-(1.3-benzodioxole-5-yl)-1 (valeryl methyl)-pyrrolidine-3-carboxyl ate Substituting the compound resulting from Example 72A for 1 chloro-3-propyl-2-hexanone and using the procedure described in Example 71B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil. Example 72C trans. trans-2-(4-MethoxyphenlY)- 4 -(1.3-benzodioxol-5-yl)-1 (valerylmethyl-pyrrolidine-3-carboxylic acid By substituting the compound resulting from Example 72B for trans, trans-Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-l-(4 heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the procedure described in Example 71C, 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 (46%) was obtained as an off white powder. 1 H NMR (CDC1 3 , 300 MHz) 8 0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31 3.49 (m, 2H), 3.56 (m, 1H), 3.77, 3.79 (d,s, 4H), 5.94 (s, 2H), 6.75 (d, 1H), 6.81-6.93 (m, 3H), 7.09 (d, 1H), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+. Anal. calcd for C 25
H
29 NO6: C, 68.32; H, 6.65; N, 3.19. Found: C. 67.95: H. 6.64; N, 3.05.
WO 99/06397 PCT/US98/15479 -126 Exampole 73 trans. trans-2-(4-MethoxyphenYl)-4-(1.3-benzodioxol-5-yl)- 1 -(N-(3.4 dimethoxybenzyvl-N-methylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 73A trans.trans- and cis.trans-2-(4-Methoxyphenvl)- 4 -(1.3-benzodioxol-5 yl)-1 -((3.4-dimethoxybenzylaminocarbonvlimethyl)pyrroIidine- 3 carboxylic acid ethyl ester Using the procedure of Example 1 D, paragraph 1, substituting 3,4 dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield. Example 73B trans.trans- and cis.trans-2-(4-Methoxyphenyl)- 4 -(1.3-benzodioxol-5 yl)-1-(N-(3.4-dimethoxybenzyl)-N methylaminocarbonylmethylbpyrrolidine-3-carboxylic acid ethyl ester The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 0C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 0C for 1 hour, then methyl iodide (28 1 iL, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 0C for 45 minutes. TLC (Et 2 O) indicated 5 incomplete reaction. An additional portion of methyl iodide (28 iL, 64 mg, 0.45 mmol) and dry 1,3-dimethyl-3,4,5,6-tetrahydro 2(1H)pyrimidinone (50 p.L, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 o x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na 2 SO4), filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et 2 O gave the title compounds as an inseparable mixture in 43% yield. 1H 5 NMR (CDCl 3 , 300 MHz) 5 2.79 (s) and 2.81 (s), for the N-CH 3 signals. MS m/z 591 (M+H)+.
WO 99/06397 PCTIUS98/15479 -127 Example 730 trans.trans-2-(4-Methoxyhenyll-4-(1,.3-benzodioxoI-5-yI)-1 -(N-(3.4 dimethoxybenzvl-N-methylamin ocarbonvlimethyl)pyrrolidine- 3 carboxylic acid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 0C 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 Et20, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCl and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na 2 SO4), then filtered and concentrated in vacuo to give 40 mg (42%) of the title compound as a white foam. 1 H NMR
(CD
3 0D, 300 MHz, two rotameric forms) 5 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1H), 6.67 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for
C
31
H
35
N
2 0 8 (M+H)+: 563.2393. Found: 563.2385. Example 74 trans. trans-2-(4-Methoxvhenvl-4-( 1.3-benzodioxol-5-yl)-1 -(N-(3.4 dimethoxybenzyliaminocarbonylmethylyrrolidine-3-carboxylic acid 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 0D, 300 MHz) 8 2.85 (d, J=16Hz, 1H), 2.92 (br t, J=9Hz, 1H), 2.98 (br t, J=1OHz, 1H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1H), 3.67 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1H), 4.21 (d, J=15Hz, 1H), 4.41 (d, J = 15Hz, 1H), 5.91 (s, 2H), 6.67 (d, J=8Hz, 1H), 6.75-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS calcd for C 3 0
H
3 2
N
2 0 (M+H)+: 549.2237. Found: 549.2224.
WO 99/06397 PCT/US98/15479 -128 Example 75 (2R.3R.4R)-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-YI)-1-((1R)-1-(N.N diprooylaminocarbonyl)-1-butylopyrrolidine-3-carboxYlic acid Example 75A trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -((1 R)- 1 (benzyloxcarbonylibutl)yrrolidine-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 mg, 0.35 mmol) and (2S)-benzyl 2 bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na 2 CO3 and 25 mL of CH 2 Cl 2 . The aqueous phase was 5 extracted with 2 x 10 mL CH 2
CI
2 , and the combined organic phases were washed with 15 mL brine, dried (Na 2 SO4), 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
CI
2 -hexane to produce 106 mg (68%) of the title compound as a waxy o solid. 1 H NMR indicated the presence of two diastereomeric products. Example 75B trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -((1 R)-1 -(N.N dipropylaminocarbonl)-l-butyl)pyrrolidine-3-carboxvlic acid ethyl ester 5 The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H 2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to 30 give 81.4 mg (96%) 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 IC, then 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 35 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 WO 99/06397 PCT/US98/15479 -129 was partitioned between 20 mL EtOAc and 10 mL of 1 _M aqueous Na2CO3. The organic phase was washed with 10 mL of brine, dried (Na2SO4), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et 2 O-hexane. Further purification of overlap fractions by preparative TLC eluting with 1:2 Et 2 0-hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%) of a more polar product. Example 75C (2R.3R.4R)-2-(4-Methoxyphenyl)-4-(1.3-benzod-ioxol-5-yl)-l-((1R)-1 (N.N-dipropylaminocarbonyl)l vbutyl)pyrrolidine-3-carboxylic 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. [M]D = 520 (c=0.235,
CH
3 0H). 1H NMR (CD 3 0D, 300 MHz) S 0.55 (t, J=7Hz, 3H), 0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25 1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (m, overlapping with CD 2 HOD signal), 3.40-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1H), 6.92-6.98 (br m, 3H), 7.29-7.39 (m, 2H). MS m/z 525 (M+H)+. Example 76 (2S.3S,4S)-2-(4-Methoxyphenyl)-4-(13-benzodioxol-5-yl)-1 -((1 R)-1 (N.N-diproolaminocarbonyl)-l-butylpyrrolidine-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. [CID = +580 (c=0.37, CH 3 0H). 1 H NMR (CD30D, 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 (m, 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 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 (M+H)+.
WO 99/06397 PCT/US98/15479 -130 Example 77 (2S.3S.4S)-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1-((1 S)-1-(N.N dipropylaminocarbonyl)-1-butvl'pyrrolidine-3-carboxylic acid Example 77A trans.-trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -((1 S)-1 (N.N-dipropylaminocarbonyl)-1-butyl)pyrrolidine-3-carboxylic acid ethvl 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 solution was cooled to -20 *C. Trifluoromethanesulfonic anhydride (95 iL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 0C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 *C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 piL, 75 mg, 0.58 mmol) in 3 mL of CH 2 C2 was added. The reaction was stirred at 0 0C for 3 hours and for an additional 2 days at room temperature. TLC (Et 2 0-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 Na2CO3. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2SO4), filtered and concentrated in vacuo to a yellowish oil. Purification by flash chromatography on silica gel eluting with 1:2 Et 2 0-hexane gave 19.9 mg (7%) of a less polar product and 20.1 mg (7%) 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-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)--((1S)-l-(N.N diorooylaminocarbonyl)-1-butyl)oyrrolidine-3-carboxylic 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 73B, to provide the title compound in 100% yield. 1 H NMR
(CD
3 0D, 300 MHz) and MS identical to those of Example 75C.
WO 99/06397 PCT/US98/15479 -131 Example 78 (2R.3R.4R)-2-(4-MethoxYohenfl)l 4 -(l .3-benzodioxol-5--yF)1-l -((1S)-1 -(N.N diorooylaminocarbonyl)-l-butvl'pyrrolidine-3-carboxylic 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 73B, to provide the title compound in 88% yield. 1 H NMR
(CD
3 0D, 300 MHz) and MS identical to those of Example 76. Examole 79 trans. trans-2-(4-Methoxyphenyl)-4-(1-.3-benzodioxol-5-yil- 1- N.N-di(n butvl)aminocarbonvlmethvI)-3-(5-tetrazolyloyrroidine Carbonydiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 "C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound. m.p. 194-196 *C. 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 was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) 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 (62%) of the title compound. m.p. 165-167 *C. 1 H NMR (CDC13, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 0.87 WO 99/06397 PCT/US98/15479 - 132 (t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, 1H), 3.90 (t, J=9Hz, 1H), 4.37 (d, J=9Hz, 1H), 5.86 (s, 2H), 6.62 (d, J=8Hz, 1H), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, 1H), 7.11 (d, J=9Hz, 2H). Example 80 trans. trans-2-(4-Fluorophenyl-4-(1.3-benzodioxol-5-yi)-1-(N. N-di(n butv/)aminocarbonvLmeth/)pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole using the procedures described in Examples 1 and .43. 1H NMR (CDCI3, 300 MHz) S 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d, J=13 Hz, 1H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1H), 3.32-3.45 (m, 3H), 3.55-3.65 (m, 1H), 3.86 (d, J=lOHz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.86 (d, J= 8 Hz, 1H), 6.95-7.07 (m, 3H), 7.32 7.45 (m, 2H). Example 81 trans.trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-y)-1 -(NN-di(n butyl)aminocarbonyl methyl)yrrolidine-3-carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., 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 *C. After cooling to room temperature, 250 mg (0.678 mmol) of ethyl trans,trans-2-(4-methoxyphenyl)-4-(1,3 benzodioxo-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 0C 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 (CDC13, 300 MHz) 8 rotational isomers - 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.65-3.20 (m, 6H) 3.43-3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, 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 (m, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 (d, J=9Hz, 2H).
WO 99/06397 PCTIUS98/15479 -133 Example 82 trans. trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1 -(N-n-butyl)-N-(n propyl)am inocarbonymethyl) pyrrolidine-3-ca rboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 *C. 1 H NMR (CDCI 3 , 300 MHz) rotational isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.23 3.61 (m, 5H), 3.71 and 3.75 (two doublets, J=l0Hz, 1H), 3.78 (s, 3H), 5.92-5.96 (m, 2H), 6.72 (d, J=8Hz, 1H), 6.83-6.89 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.81 (d, J=9Hz, 2H). Example 83 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[2-(N.N-di(n prooyllaminocarbonylethylloyrrolidine-3-carboxylic 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 0 C in 0.75 mL of methoxyethanol for one hour. Toluene was 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 (80%) 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 removed 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 1D in 83% yield. 1 H NMR (CDCI3, 300 MHz) 5 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, 1H), 3.51-3.61 (m, 1H), 3.73 (d, J=12H, 1H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, 1H), 6.79-6.85 (m, 3H), 7.04 (d, J=2Hz, 1H)< 7.32 (d, J=9Hz, 2H).
WO 99/06397 PCTIUS98/15479 -134 Example 84 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-v)- 1 -(N.N-di(n butylam inocarbonyl) 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 al., Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1 H NMR (CDC1 3 , 300 MHz) 5 0.86 (t, J=7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J=12Hz, 1H), 3.30 3.41 (m, 2H), 3.59-3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, 1H), 5.81 (d, J=9Hz, 1H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9Hz, 2H). Example 85 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N-di(n butvl)aminocarbonvlmethv)yrrolidine-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 *C to yield 627.5 mg of the title compound. Example 86 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -[2-(N.N-di(n butyl)amino)ethyl]pyrrolidine-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 0C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2SO4 and concentrated. More toluene was added, and the solution was again concentrated to get rid-of excess dibutylamine. The residue was dissolved in warrfM heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg (87%) 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) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1H), 2.80-3.08 (m, 8H), 3.14-3.25 (m, 1H), 3.31-3.38 (m, 1H), 3.59-3.60 (m, WO 99/06397 PCT/US98/15479 - 135 1H), 3.74 (s, 3H), 3.75 (d, J=lOHz, 1H), 5.89 (s, 2H), 6.71 (d, J=9Hz, 1H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 (d, J=lOHz, 2H), 6.96 (d, J=2Hz, 1H), 7.37 (d, J=lOHz, 2H). Example 87 trans. trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -(2-fN-(N.N-di(n butylaminocarbonvil-N-methylaminolethyllpyrrolidine-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, and the solution was washed with potassium bicarbonate solution, dried over Na 2 SO4 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 of the title compound. 1 H NMR (CD 3 0D, 300 MHz) 5 0.92 (t, J=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.76 (m, 1H), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1H), 3.62-3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, J=12 Hz, 1H), 5.93 (s, 2H), 6.75 (d, J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1H), 7.40 (d, J=lOHz, 2H). Example 88 trans. trans-2-(4-Methoxyohenyl)-4- (1.3-benzodioxol-5-Yl')- 1- (N. N-di(n butylaminocarbonylmethlp)yrrolidine-3-(N-methanesulfony)carboxamide Carbonyldiimidazole (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 *C 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 *C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%) of the title compound. m.p. 170-173 C. 1 H NMR (CDC3, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.51 (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50 (m, 3H), 3.70-3.78 (m, 1H), 3.80 (s, 3H), 3.87 (d, J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, WO 99/06397 PCT/US98/15479 -136 J=9Hz, 1H), 6.84 (dd, J=9Hz, 2Hz, 1H), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.34 (d, J=lOHz, 2H). Example 89 trans.trans-2-(4-Methoxyohenyl-4-(1.3-benzodioxol-5-yl-1-(N.N-di(n butylaminocarbonylmethylpyrrolidine-3-(N-benzenesulfonyl'carboxamide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 0C for a sample recrystallized from acetonitrile. 1 H NMR LCDC13, 300 MHz) 8 0.81(t, J=7 Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.02-1.50 (m, 8H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1H), 3.65 (d, J=lOHz, 1H), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, J=lOHz, 2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7Hz, 1H), 8.95 (d, J=7Hz, 2H). Example 90 trans. trans-2-(4-Methoxvohenyl)-4-(1.3-benzodioxol-5-vil-1 -N.N-di(n-butyl) am inosulf onylm ethyl]-pyrrolidin e-3-carboxyl ic acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. 85: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide 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(n butyl)aminosulfenylimethyl]-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. _2: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
WO 99/06397 PCT/US98/15479 -137 Example 91 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -[(N. N-di(n butyl)aminocarbonyl-1-(RS)-ethyllpyrrolidine-3-carboxylic acid Example 91A (f)-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
C
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 "C, dibutylamjne (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 *C 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. 1 H NMR (CDCl 3 , 300 MHz) 8 0.93 (t, J=7Hz) and 0.97 (t, J=7.5Hz, 6H total), 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1H), 1.82 (d, J=6Hz, 3H), 3.04-3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J=7H, 1H). MS (DCI/NH 3 ) m/e 264 and 266 (M+H)+. Example 91B trans.trans- and cis. trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-yl)- 1 -((N.N di(n-butyl)amino)carbonyl-1-(RS)-ethyl)pyrrolidine-3-carboxylic 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 Et 2 0 and 10 mL of 1 M aqueous Na 2 CO3 solution. The organic phase was washed with 20 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 (70%) of the title compounds as a mixture of 4 diastereomers. 1 H NMR (CDCl 3 , 300 MHz) 5 0.66-1.55 (several m, 19H), 2.63 3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 WO 99/06397 PCT/US98/15479 -138 (m, 2.6H), 4.38 (d, J=10.5Hz, 0.2H) and 4.58 (d, J=10.5Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m, 2H). MS (DCI/NH 3 ) m/e 553 (M+H)+. Example 91C trans. trans-2-(4-Methoxyphenyll-4- (1.3-benzodioxol-5-yl-1 -((N. N dibutylam ino)carbonyl- 1 -(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield. 1 H NMR (CD 3 0D, 300 MHz) S 0.70-1.05 (several m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.03jm, 3.5H), 3.20-3.65 (br m, 4.6H plus CD 2 HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J=8Hz, 0.6H), 4.06 (t, J=7.5Hz, 0.4H), 4.25 (d, J=8Hz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d, J=2.5Hz) and 6.75 (d, J=3Hz, 1H total), 6.78-6.85 (m, 1H), 6.91-7.00 (m, 3H), 7.30 7.38 (m, 2H). MS (DCI/NH 3 ) m/e 525 (M+H)+. Anal calcd for C 3 oH 4 0N 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-(Pentyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N-di(n butyl' aminocarbonylmethyl)pyrrolidine-3-carboxyl ic acid Example 92A Methyl 2-(4-hexenoyl)-4-nitro-3-(1.3-benzodioxole-5-yl)butyrate 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 mLTHF, then DBU (22 jtL, 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. 1 H NMR (CDC1 3 , 300 MHz) 8 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J =8Hz, 0.5H), 4.10-4.20 (m, 1H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 (m, 1H), 6.68 (br s, 1H), 6.75 (d, 7.5Hz, 1H). MS (DCI/NH 3 ) m/e 381 (M+NH 4 )+. Anal calcd for C 18
H
21 N0 7 : C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.
WO 99/06397 PCTIUS98/15479 -139 Example 92B Methyl trans. trans-2-(pentyl)-4- (1.3-benzodioxol-5-vloyrrolid ine-3-carboxvlate The procedures of Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example 1 B, 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, 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 NaHCO3 diluted with 10 mL water and 30 mL of CH 2
C
2 . The aqueous phase was extracted (2 x 30 mL CH 2 Cl 2 ), then the combined organic phases were washed with 20 mL brine, dried over Na 2 SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH 2
CI
2 gave 336 mg (57%) the title compound as a yellow oil. 1H NMR (CDCl 3 , 300 MHz) 8 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 (m, 2H), 3.53 (q, J=9Hz, 1H), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H). MS
(DCI/NH
3 ) m/e 320 (M+H)+. Anal calcd for C 18
H
25 N0 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-(Pentyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N-di(n butylUaminocarbonylmethyl)oyrrolidine-3-carboxylic acid The procedures of Example 11B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam. 1H NMR (CDCI 3 , 300 MHz) 8 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43 1.78 (br m, 6H), 2.76 (t, J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=14Hz, 1H), 5.98 (AB, 2H), 6.70 (d, J=7Hz, 1H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCI/NH3) m/e 475 (M+H)+. Anal calcd for C 27
H
42
N
2 0 5 -0.5H 2 0: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
WO 99/06397 PCTIUS98/15479 -140 Example 93 trans. trans-2-(Pentyl)-4- (1.3-benzodioxol-5-yl)- 1-2- (N-propyl-N propyisulfonylamino)ethyllpyrrolidine-3-carboxylic acid Example 93A Methyl trans. trans-2-(pentyl)-4-(1.3-benzodioxol-5-yl)-1-(2-bromoethyl)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 (CDCl 3 , 300 MHz) 8 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 (m, 2H), 2.76 2.91 (m, 2H), 3.10-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69 6.77 (m, 2H), 6.90-6.94 (m, 1H). MS (DCI/NH 3 ) m/e 426, 428 (M+H)+. Example 93B Methyl trans. trans-2-(Pentyl-4-(1.3-benzodioxol-5-yl)- 1 -[2-(N-Dropyl-N propylsulfonylamino)ethylpyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 imol) in 1 mL EtOH was treated with propylamine (60 4L, 0.73 mmol). The solution was warmed to 80 0C 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 of 1 M aqueous Na 2
CO
3 . The organic phase was washed with 15 mL brine, then dried over Na 2
SO
4 , 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 Cl 2 , diiosopropylethylamine (65 p.L, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 pL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 x 3 mL CH 2 Cl 2 . The combined organic extracts were washed with 2 mL brine, then dried over Na 2
SO
4 , filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg (53%) of the title compound as a waxy solid. Rf = 0.17 (20%EtOAc-hexane). MS (DCI/NH 3 ) m/e 511 (M+H)+.
WO 99/06397 PCT/US98/15479 -141 Example 93C trans. trans-2-(Pentyl)-4-(1.3-benzodioxol-5-yl)- 1 -{2-(N-propyl-N Dropylsulfonylamino)ethyllpyrrolidine-3-carboxylic acid The procedure of Example 71C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71B, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14 (5%MeOH-CH 2
CI
2 ). 1 H NMR (CDCl 3 , 300 MHz) 8 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 (m, 2H), 3.05 (br t, J=9Hz, 1H), 3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J=8Hz, 1H), 6.77 (dd, J=1.5,8Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCI/NH 3 ) m/e 497 (M+H)+. Example 94 trans.trans-2-(Propyl)-4-(1.3-benzodioxol-5-yl)-1-(N.N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 94A Ethyl 2-(4-butanoyl)-4-nitro-3-(1.3-benzodioxole-5-yl)butyrate 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, 80%), Rf = 0.28 (25%EtOAc-hexane). 1 H NMR (CDCl 3 , 300 MHz) 8 0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 (t, J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 (t, J=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m, 1H), 2.60 (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-4.20 (br m, 1H), 4.23 (q, J=7Hz, 1H), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m, 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. Example 94B Ethyl trans. trans-2-(Dropyl)-4-(1.3-benzodioxol-5-yl)oyrrolidine-3-carboxylate 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. MS (DCI/NH 3 ) m/e 306 (M+H)+.
WO 99/06397 PCT/US98/15479 -142 Example 94C trans. trans-2-(Propyl)-4-(1.3-benzodioxol-5-y)- 1 -((N. N-di(n butylam inocarbonylm ethyl)-pyrrolidine-3-carboxylic acid The procedure of Example 92C 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 (CDCl 3 , 300 MHz) 8 0.89 (t, J=7.5Hz), 0.92 (t, J=7.5Hz), and 0.97 (t, J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 (t, J=7.5Hz, 1H), 3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1H), 3.78 (d, J=15Hz, 1H), 5.92 (q, J=1 Hz, 2H), 6.70 (d, J=8Hz, 1H), 6.79 (dd, J=1Hz,8Hz, 1H), 6.90 (d, J=1 Hz, H). MS (DCI/NH 3 ) m/e 447 (M+H)+. Anal calcd for C 25
H
38
N
2 0 5 -0.5 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94. Example 95 (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl-1-(tert butyloxycarbonyl-aminocarbonylmethyl)-pyrrolidine-3-carboxlic acid Example 95A trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(rtert butyloxycarbonylaminocarbonylmethyllpyrrolidine-3-carboxylic acid The resulting mixture of 64% trans,trans- and cis,trans pyrrolidines resulting from Example 1C (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 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 H NMR
(CDCL
3 , 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m, 1H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J=7 Hz, 1H), 4.14-4.28 (br m, 1H), 4.89-5.24 (br m, 1H), 5.94 (d, J=3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH 3 ) m/e 470 (M+H)+. 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 WO 99/06397 PCT/US98/15479 -143 250 mL of ether. The organic phase acidified to slight cloudiness (pH -7) with 1 h[ 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 (Na2SO4), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 %). 1 H NMR (CDCl 3 , 300 MHz) 5 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50 3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH 3 ) m/e 442 (M+H)+. Example 95B (2R.3R.4S)-(+)-2-(4-Methoxvohenyl-4-(1.3-benzodioxol-5-vl)-1-(tert butyloxycarbonvlaminocarbonvimethyl)-oyrrolidine-3-carboxylic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-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 by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate. The pure (2R,3R,4S)-(+)- 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). 1 H NMR (CDCl 3 , 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, 1H), 4.96 (br m, 1H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J=9 Hz, 2H), 7.19.(d, J=9 Hz, 2H). MS (DCI/NH 3 ) m/e 442 (M+H)+.
WO 99/06397 PCT/US98/15479 -144 Example 95C (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-y)-pyrrolidine-3 carboxvlate 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 0C. 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 SO4), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 69%). 1H NMR (CDCl 3 , 300MHz) 5 1.11 (t, J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 (t, J= 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q, J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH 3 ) m/e 370 (M+H)+. Example 95D (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y)-1-(tert butyloxycarbonyl-aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 .L, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 0C. 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. 1 H NMR (CDCl 3 , 300MHz) 8 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m, 8H), 2.78 (d, J=14 Hz, 1H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 (d, J=9 Hz, 1H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 (d, J=9 Hz, 1H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH 3 ) m/e 539 (M+H)+. 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 WO 99/06397 PCTIUS98/15479 -145 slowly to 40 *C. over 2.5 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, 83%). 1 H NMR (CDCI 3 , 300MHz) 8 0.80 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz, 1H), 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 (M+H)+. [a] 2 2 = +74.420. Anal calcd for C 2 9
H
3 8
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. Example 95E Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methoxyhenyl)-4-(1,3-benzodioxol-5 yl)-l-(tert-butyloxycarbonvlaminocarbonylmethyl)-oyrrolidine-3-carboxYlic 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 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 were 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. 164-168*. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-1100. (HPLC of this showed 20%of 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 WO 99/06397 PCTIUS98/15479 -146 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-Methoxvpheny)-4-(1.3-benzodioxol-5-yl-1 -r2-(N-oroolv-N butvrylaminolethylloyrrolidine-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 solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 (t, 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 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1H, J=lHz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 497 (M+H)+. Anal calcd for
C
28
H
36
N
2 0 6 - 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-Methoxyoheny)-4-(1.3-benzodioxol-5-vi)- 1 -[2-(N-orooyl-N (ethylaminocarbonylamino)ethyllpyrrolidine-3-carboxylic 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. 1 H NMR (CDCl 3 , 300 MHz) mixture of rotamers 8 0.80 (t, J=8Hz) and 1.05 (t, J=8Hz) and 1.20 (m) and 1.42 (m) total of 8H for the four peaks, 2.35 (br s, 1H), 2.70 (m, 1H), 3.0 (m, 3H), 3.2 (m, 3H), 3.25 (dq, 1H, J=1,8Hz), 3.42 (m, 1H), 3.6 (m, 1H), 3.75 (m, 1H), 3.78 (s, 3H), 4.8 (br s, 1H), 5.95 (s, 2H), 6.74 (d, 1H, J=8Hz), 6.85 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 498 (M+H)+.
WO 99/06397 PCT/US98/15479 -147 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. Example 98 transtrans-2-(4-Methoxphenyl)-4-(1.3-benzodioxol-5-yl)-1-[2-(N-butyl-N butyrylamino)ethyl]pyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:4 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 (CDCl 3 , 300 MHz) 8 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1H, J=lHz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 511 (M+H)+. HRMS calcd for C 29
H
38
N
2 0 6 : 511.2808. Found: 511.2809 E xample 99 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -{2-(N-Droyl-N ethoxycarbonylamino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl chloroformate 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. 1H NMR (CDCI 3 , 300 MHz) 5 0.80 (t, 3H, J=8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1H), 2.75 (m, 1H), 2.88 (br q, 2H, J=8Hz), 3.08 (br m, 2H), 3.27 (br m, 2H), 3.44 (m, 1H), 3.54 (dt, 1H, J=1,8Hz), 3.63 (d, 1H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.81 (dd, 1H, J=1,8Hz), 6.85 (d, 2H, J=8Hz), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS
(DCI/NH
3 ) m/e 499 (M+H)+. Anal calcd for C 27
H
34
N
2 0 7 -0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, -6.71; N, 5.30.
WO 99/06397 PCTIUS98/15479 -148 Example 100 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yi)- 1 -r2-(N-methvl-N-(2 ethylbutyryl)amino)ethylpyrrolidine-3-carboxylic 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 pL), 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 hi H 3
PO
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. 1H NMR (CDCl 3 , 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, 1H), 2.32 (m, 1H), 2.45 (m, 1H), 2.70 (m, 1H), 2.86, 2.94 (s, total 3H), 2.95 (m, 1H), 3.35 (m, 1H), 3.52 (m, 2H), 3.65 (m, 1H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), 6.73 (m, 1H), 6.84 (m, 3H), 6.97 (m, 1H), 7.30 (m, 2H). MS (DCI/NH 3 ) m/e 497 (M+H)+. 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-Methoxyohenyl)-4-(1.3-benzodioxol-5-I)- 1 -r2-(N-m ethyl-N-(2 proylvaleryl)amino)ethylloyrrolidine-3-carboxylic acid The 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 4C18) 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 (CDC1 3 , 300 MHz) 8 0.79 (t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10 (m, 4H), 1.2-1.5 (m, 4H), 2.55 (m, 1H), 2.96 (s, 3H), 3.15 (br m, 1H), 3.32 (br m, 1H), 3.56 (m, 2H), 3.68 (m, 1H) 3.68 (s, 3H), 3.70 (m, 1H), 3.80 (m, 2H), 4.65 (br d, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 525 WO 99/06397 PCTIUS98/15479 -149 (M+H)+. Anal calcd for C 30
H
40
N
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 102 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -2-(N-propyl-N-(tert butyloxycarbonylmethylam ino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and t-butyl bromoacetate 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. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1H), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1H, J=2,8Hz), 3.50 (dt, 1H, J=2,8Hz), 3.62 (d, 1H, J=8Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1H), 7.16 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 541 (M+H)+. Anal calcd for
C
30 H4 0
N
2 07 - 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 103 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yll- 1 -[2-(N-prooyl-N-(n prooylam inocarbonylimethyl)am ino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and N-propyl bromoacetamide for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac 4C18) 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. 1H NMR (CDC13, 300 MHz) 8 0.78 (t, 3H, J=8Hz), 0.88 (t, 3H, J=8Hz), 1.45 (m, 2H), 1.48 (m, 3H, J=8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1H), 3.04 (m, 1H), 3.15 (m, 3H), 3.28 (t, 1H, J=8Hz), 3.45 (t, 1H, J=8Hz), 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75 (m, 1H), 3.80 (s, 3H), 4.25 (d, 1H, J=8Hz), 5.95 (s, 2H), 6.75(d, 1H, J=8Hz), 6.86 (dt, 1H, J=1,8Hz), 6.88 (d, 2H, J=8Hz), 7.04 (d, 1H, J=lHz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 526 (M+H)+. Anal calcd for C 29
H
39
N
3 06 - 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
WO 99/06397 PCT/US98/15479 -150 Example 104 trans. trans-2-(4-Methoxvohenyl)-4-(1.3-benzodioxol-5-yl)- 1-2-(N-propvl-N-(4 methoxyhenoxvcarbonvl)amino)ethylovrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and 4-methoxyphenylchloroformate 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. 1H NMR (CD3OD, 300 MHz) mixture of rotamers 8 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, total of 1H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 (m, total of 1H), 5.95 (s) and 5.98 (s, total of 2H), 6.63(m, 1H), 6.72 (d, 1H, J=8Hz), 6.81 (m, 2H), 6.93 (m, 5H), 7.40 (m, 2H). MS (DCI/NH 3 ) m/e 577 (M+H)+. Anal calcd for
C
32
H
36
N
2 0 8 - 1.0 H 2 0: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63. Example 105 trans. trans-2-(4-Methoxyheny)-4-(1.3-benzodioxol-5-yl)-1 -[2-(N-propIYl-N-(4 methoxvbenzoyl)aminoethylloyrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and anisoyl chloride 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. 1 H NMR (CDCI3, 300 MHz) mixture of rotamers 8 0.78 (m) and 0.98 (t, J=8Hz) total of 3H, 1.47 (m) and 1.52 (q, J=8Hz) total of 2H, 2.25 (br s, 1H), 2.78 (br s, 1H), 2.90 (br t, 2H), 3.12 3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1H, J=8Hz), 6.83 (m, 5H), 6.94 (m, 1H), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. 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.
WO 99/06397 PCT/US98/15479 -151 Example 106 trans. trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yl)- 1 -12-(N-D roPYI-N benzoylaminoethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and benzoyl chloride 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. 1 H NMR (CDC13, 300 MHz) mixture of rotamers 5 0.65 and 0.9 (m, total of 3H) , 1.4 and 1.55 (m, total of 2H), 2.05 and 2.15 (m, total of 1H), 2.6 - 3.6 (m, 8H), 5.92 (s, 2H), 6.70(d, 1H, J=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH 3 ) m/e 531 (M+H)+. Anal calcd for C31H 3 4N206 -0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84. Example 107 trans. trans-2-(4-Methoxyohenyl)-4- (1.3-benzodioxol-5-vl)- 1 -12-(N-orooy-N benzyloxycarbonyla ino)ethyllpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and benzyl chloroformate for isobutyryl chloride in Example 61C. 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 (CDC1 3 , 300 MHz) 8 0.8 (m, 3H) 1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m, 1H), 2.93 (m, 1H), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1H), 3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s, 2H), 6.72(d, 1H, J=8Hz), 6.82 (m, 3H), 7.0 (br d, 1H, J= 15Hz), 7.2 (s, 4H), 7.30 (m, 3H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C 32
H
3 6N207 - 1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found: C, 60.66; H, 5.34; N, 4.28. Example 108 trans. trans-2-(4-Methoxvohenyl)- 4 -(13-benzodioxol-5-y)- 1 -[2-(N-orooyl-N-(4 methoxvbenzvloxvcarbonvlaminol)ethylloyrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61B WO 99/06397 PCT/US98/15479 -152 and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61C. ExamDle 109 trans. trans-2-(4-Methoxvphenyl)-4- (1.3-benzodioxol-5-vil- 1 -[2-(N-butyl-N ethoycarbonlaminoethylpyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac pC18) 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 (CDCI3, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, 1H), 5.94 (s, 2H), 6.76 (d, 1H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). MS (FAB) m/e 513 (M+H)+. Anal calcd for C 28
H
36
N
2 07 0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Found: C, 60.99; H, 6.80; N, 4.93. Example 110 trans. trans-2-(4-Methoxyhenyl)- 4 -(1.3-benzodioxol-5-vl)-1-f2-(N-butyl-N propoxycarbonylamino)ethyllpyrrolidine-3-carboxylic acid, The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and propyl chloroformate 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 (CDCI3, 300 MHz) 8 0.80 (br s, 1H), 0.85 (t, 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, 1H), 2.15 (br s, 1H), 2.72 (m, 1H), 2.87 (m, 1H), 3.1-3.45 (m, 5H), 3.55 (m, 1H), 3.64 (d, 1H, J=8Hz), 3.79 (s, 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 (s, 2H), 6.73(d, 1H, J=8Hz), 6.85 (m, 3H, 7.0 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for
C
29
H
38
N
2 07- 0.15 H 2 0: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21.
WO 99/06397 PCT/US98/15479 -153 Example 111 trans. trans-2-(4- Methoxyhenyl)-4- (1.3-benzodioxol-5-yI)- 1 42-(N-Droy proooxycarbonylamino)ethylloyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and propyl chloroformate 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. 1H NMR (CDCI 3 , 300 MHz) 8 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m,,3H), 1.62 (m, 1H), 2.15 (br s, 1H), 2.68-3.45 (m, 8H), 3.54 (m, 1H), 3.66 (m, 1H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.82 (m, 1H), 6.84 (d, 2H, J=8Hz), 7.00 (br s, 1H), 7.33 (m, 2H). MS (DCI/NH 3 ) m/e 513 (M+H)+. Anal calcd for C 28
H
36
N
2 07 -0.15 H 2 0: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06. Example 112 trans.trans-1 -(N.N-Di(n-butvilaminocarbonliethyl)-2.
4 -di(1.3-benzodioxol-5 ylloyrrolidine-3-carboxylic acid Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method of Krapcho et a/., Org. Syn. 47, 20 (1967) starting with 3,4 methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 *C. 'H NMR (CDCI3, 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J=13Hz, 1H), 2.94-3.12 (m, 4H), 3.28-3.50 (m, 4H), 3.58-3.62 (m, 1H), 3.78 (d, J=9Hz, 1H), 5.95 (s, 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, J=1Hz, 1H), 7.01 (d, H=1Hz, 1H). MS
(DCI/NH
3 ) m/e 525 (M+H)+. Example 113 trans. trans-1 -(2-(N- (n-Butvl-N-roovisulfon (1.3-benzodioxol-5-yl)vrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 0C. 1 H NMR (CDC 3 , 300 MHz) 5 0.83 (t, J=7Hz, 3H), 0.98 (t, J=7Hz, 3H), 1.12-1.25 (m, 2H), 1.32-1.41 (m, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H), WO 99/06397 PCT/US98/15479 -154 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.59 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.83 (dd, J=8Hz, 1Hz, 1H), 6.88 (d, J=9Hz, 2H), 7.02 (d, J=1Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH 3 ) m/e 547 (M+H)+. Example 114 trans. trans-1 -(N. N-Di(n-buty)am inocarbonylmethyl)-2-(4-m ethoxvohenl)- 4 -(1.3 benzodioxol-5-yl) pyrrolidine-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74-76 0C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, J=6Hz, 3H), 0.88 (t, J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (m, 6H), 2.75 (d, J=12Hz, 1H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, 1H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, J=9Hz, 1H), 6.85 (d, J=9Hz, 2H), 6.91 (d,d, J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 525 (M+H)+. Example 115 trans. trans-1 -(2-(N-Propvl-N-propvlsulfonylam inolethy)-2-(4-methoxyhenvl)-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. 72-73 *C. 1 H NMR (CDCl3, 300 MHz) 8 0.79 (t, J=8Hz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (m, 1H), 2.69-3.32 (m, 9H), 3.42 (dd, J=3Hz, 12Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=12Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=llHz, 1H), 6.83 (dd, J=lHz, 11Hz, 1H), 6.87 (d, J=11Hz, 2H), 7.0 (d, J=2Hz, 1H), 7.32 (d, J=11Hz, 2H). MS (DCI/NH3) m/e 533 (M+H)+. Example 116 trans, trans-1 -(2-(N-Butyl-N-butylsulfonylam ino)ethyl)-2-(4-methoxyrhenyl) 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 0C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.82 (t, J=6Hz, 3H), 0.91 )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33 1.42 (m, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (m, 1H), 2.70-3.28 (m, 9H), 3.41 (d, J=8Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J=8Hz, 1H), 3.79 (s, WO 99/06397 PCT/US98/15479 -155 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.01 (s, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 561 (M+H)+. Example 117 trans. trans-1 -(2-(N.N-Di(n-butylaminocarbonylmethyl)-2-(4 methoxymethoxyphenyl)-4-(1.3-benzodioxol-5-ylloyrrolidine-3-carboxylic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4 methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compotmd as a white solid. m.p. 48-49 0C. 1H NMR (CDCl 3 , 300 MHz) 5 0.81 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d, J=12Hz, 1H), 2.94-3.10 (m, 4H), 3.25-3.35 (m, 1H), 3.40 (d, J=12Hz, 1H), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, 1H), 3.77 (d, J=9Hz, 1H), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, 1H), 6.86 (dd, J=lHz, 8Hz, 1H), 7.0 (d, J=8Hz, 2H), 7.04 (d, J=lHz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 541 (M+H)+. Examiple 118 trans, trans-1 -(2-(N.N-Di(n-butyllaminocarbonylmethyl-2-(4-hydroxohenyl)-4-(1.3 benzodioxol-5-yllpyrrolidine-3-carboxylic acid hydrochloride salt The compound resulting from Example 116 was treated with concentrated HCI in 1:1 THF-isopropanol to give the title compound as a white solid. m.p. 211-212 *C. 1H NMR (CD 3 0D, 300 MHz) 8 0.90 (t, J=8Hz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1H), 3.14 3.35 (t, J=9Hz, 1H), 3.90 (bs, 3H), 4.17 (d, J=15Hz, 1H), 5.96 (s, 2H), 6.82-6.93 (m, 4H), 7.03 (d, J=lHz, 1H), 7.42 (bs, 2H). MS (DCI/NH 3 ) m/e 497 (M+H)+. Example 119 trans. trans-1 -(2- (N-1 sobutyl- N-prooylsu If onylam ino)ethyl)-2-(4-m ethoxyohenyl)-4 (1.3-benzodioxol-5-ylo'yrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 0C. 1 H NMR (CDCl 3 , 300 MHz) 8 0.80 (d, J=6Hz, 6H), 0.98 (t, J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, J=8Hz, 2H), 2.23-2:34 (m, 1H), 2.68-2.98 (m, 7H), 3.08-3.18 (m, WO 99/06397 PCT/US98/15479 -156 1H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.86 (d, J=8Hz, 2H), 6.98 (d, J=1Hz, 1H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 547 (M+H)+. Example 120 trans, trans-1 -(2-(N-Benzenesulfonyl-N-propylamino)ethyl)-2-(4-methoxyphenyl)-4 (1.3-benzodioxol-5-yl)pvrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 "C. 1 H-NMR (CDCl 3 , 300 MHz) 8 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (m, 1H), 2.62 2.72 (m, 1H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1H), 3.38 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.84 (dd, J=lHz, 8Hz, 1H), 6.85 (d, J=9Hz, 2H), 7.02 (d, J=lHz, 1H), 7.28 (d, J=9Hz, 2H), 7.39-7.54 (m, 3H), 7.70 (d, J=7Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+. Example 121 trans. trans-1 -(2-(N-(4-Methoxybenzenesulfonvl)-N-orooylam ino)ethyl)-2-(4 methoxyohenyl)-4-(1.3-benzodioxol-5-ylpvrrolid ine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 0C. 1 H NMR (CDCI 3 , 300 MHz) S 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1H), 2.62 2.71 (m, 1H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz, 1H), 3.48-3.56 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.81 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.81-6.89 (m, 5H), 7.01 (d, J=lHz, 1H), 7.28 (d, J=8Hz, 2H), 7.62 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 597 (M+H)+. Example 122 trans.trans-1 -(N.N-Di(n-butylaminocarbonylimethyl)-2-(2-methoxyethox-4 methoxyphenyl)-4-(1.3-benzodioxol-5-l)yrrolidine-3-carboxylic acid 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 OC to provide ethyl 2 methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 63-65 *C. 1 H NMR (CDC13, 300 MHz) 8 0.84 (t, J=7Hz, WO 99/06397 PCT/US98/15479 -157 3H), 0.89 (t, J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, 1H), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, 1H), 5.92 (s, 2H), 6.40 (d, J=2Hz, 1H), 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 (d, J=8Hz, 1H), 6.83 (dd, J=lHz, 8Hz, 1H), 5.98 (d, J=2Hz, 1H), 7.53 (d, J=9Hz, 1H). MS
(DCI/NH
3 ) m/e 585 (M+H)+. Example 123 trans. trans-1 -(2-(N-Propyl-N-(2.4-dimethylbenzenesulfonvylamino)ethyl)-2-(4 methoxyphenyll-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. 88-90 *C. 'H NMR (CDCl3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1H), 2.32 (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1H), 2.78 (t, J=9Hz, 1H), 2.89 (dd, J=8Hz, 1H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m, 1H), 3.60 (d, J=9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1H), 6.80 (dd, J=1Hz, 9Hz, 1H), 6.86 (d, J=9Hz, 2H), 6.97 (d, J=lHz, 1H), 7.03 (bs, 2H), 7.29 (d, J=9Hz, 1H). MS (DCI/NH 3 ) m/e 595 (M+H)+. Example 124 trans. trans-1 -(2-(N-Prooyl-N-(3-ch lorooroovlsulfonvl)am ino)ethyll-2-(4 methoxyhenvl)-4-(1.3-benzodioxol-5-yl'oyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 *C. 1H NMR (CDC3, 300 MHz) 5 0.80 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70 2.80 (m, 1H), 2.85-3.10 (m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.86 (d, J=8Hz, 2H), 7.00 (s, 1H), 7.33 (d, J=8Hz, 2H). MS
(DCI/NH
3 ) m/e 567 (M+H)+. Example 125 trans, trans-1 -(2-(N-Propvi-N-(2-methoxethvisulfonvlaminolethyl)-2-(4 methoxyphenyl-4-(1.3-benzodioxol-5-yl)oyrrolidine-3-carboxylic acid Using the procedures described in Example 66, trans,trans-1 -(2 (N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3- WO 99/06397 PCT/US98/15479 -158 benzodioxol-5-yl)pyrrolidine-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 *C. 1 H NMR (CDCl3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, 1H), 2.72-2.79 (m, 1H), 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.58 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.69 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=lHz, 8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.02 (d, J=lHz, 1H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 549 (M+H)+. Example 126 trans.trans-1 -(2-(N-Proovi-N-(2-ethoxvethvsulfonvlaminolethyl)-2-(4 methoxyphenyl)-4-(1.3-benzodioxol-5-y)pyrrolidine-3-carboxlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 58-60 0C. 1 H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.18 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24 2.33 (m, 1H), 2.70-2.80 (m, 1H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.46 (q, J=7Hz, 2H), 3.52 3.58 (m, 1H), 3.65 (d J=9Hz, 1H), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.83 (dd, J=lHz, 7Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.00 (d, J=lHz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 563 (M+H)+. Example 127 trans. trans-1 -(2-(N-Proyl-N-(5-dimethylamino-1 -naphthylsulfonyl)amino)ethyl)-2 (4-methoxyhenyl)-4-(1.3-benzodioxol-5-vl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 *C. 1 H NMR (CDC13, 300 MHz) 5 0.62 (t, J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1H), 2.78 (t, J=9Hz, 1H), 2.88 (s, 6H), 2.72-2.89 (m, 1H), 3.05-3.12 (m, 2H), 3.26-3.45 (m, 3H), 3.45-3.52 (m, 1H), 3.58 (d, J=9Hz, 1H), 6.97 (d, J=lHz, 1H), 7.13 (d, J=7Hz, 1H), 7.26 (d, J=8Hz, 1H), 7.42-7.50 (m, 2H), 8.08 (dd, J=lHz, 7Hz, 1H), 8.20 (d, J=8Hz, 1H), 8.48 (d, J=8Hz, 1H). MS (DCI/NH 3 ) m/e 660 (M+H)+.
WO 99/06397 PCT/US98/15479 -159 Example 128 trans. trans-1 -(2-(N-Proov-N-(ethylsulfonyllaminolethyl)-2-(4-methoxvohenvi)-4 (1.3-benzodioxol-5-ylpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 0C. 1H NMR (CDCI 3 , 300 MHz) 8 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H), 1.43 (q, J=8Hz, 2H), 2.22-2.30 (m, 1H), 2.71-2.80 (m, 1H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.60 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.82 (dd, J=lHz, 7Hz, 1H), 6.88 (d, J=8Hz, 2H), 7.00 (d, J=lHz, 1H),. 7.32 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 519 (M+H)+. Example 129 trans, trans-1 -(2-(N-Prool-N-(4-methvlbenzenesulfonvilamino)ethyl)-2-4 methoxyhenvl)-4-(1.3-benzodioxo-5-vlovrrolidine-3-carboxyiic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 0C. 1 H NMR (CDCl 3 , 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.81 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.00 (s, 1H), 7.21 (d, J=8Hz, 2H), 7.29 (d, J=8Hz, 2H), 7.57 (d, J=8Hz, 2H). MS (DCI/NH 3 ) m/e 581 (M+H)+. Examle 130 trans. trans-1 -(N. N-Di(n-butylam inocarbonvlmethyl)-2-(3-yridyl- 4 -(1.3 benzodioxol-5-vl) oyrrol id ine-3-carboxylic 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 1 to provide the title compound as a white solid. m.p. 167-168 *C. 1 H NMR (CDCl3, 300 MHz) 5 0.82 (t, J-7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, 6H), 3.34-3.43 (m, 2H), 3.57 (dd, J=3Hz, 9Hz, 1H), 3.75-3.83 (m, 1H), 4.08 (d, J=9Hz, 1H), 5.93 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.90 (dd, J=2Hz, 8Hz, 1H), 7.03 (d, J=2Hz, 1H), 7.38 (dd, J=4Hz, 8Hz, 1H), 8.04 (d, J=8Hz, 1H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCI/NH 3 ) m/e 482 (M+H)+.
WO 99/06397 PCTIUS98/15479 -160 Example 131 trans.trans-1 -(2-(N-Prooyl-N-(n-butylsulfonyl)amino)ethyl)-2-(4-methoxyhenyl)-4 (1.3-benzodioxol-5-yl)pvrrolidine-3-carboXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 *C. 1H NMR (CDCI 3 , 300 MHz) 5 0.78 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.31-1.46 (m, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.12-3.23 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1H), 6.83-(dd, J=lHz, 7Hz, 1H), 6.86 (d, J=8Hz, 2H), 7.00 (d, J=lHz, 1H), 7.32 (d, J=8Hz, 2H). MS
(DCI/NH
3 ) m/e 547 (M+H)+. Example 132 trans. trans-1-(2-(N-Propvi-N-(4-chlorobenzenesulf onlam inolethyil-2-(4 methoxyphenyl-4-(1.3-benzodioxol-5-ylpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 *C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.72 (t, J=17Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (m, 1H), 2.78-2.86 (m, 1H), 2.96-3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, J=5Hz, 9Hz, 1H), 3.62-3.68 (m, 1H), 3.80 (s, 3H), 3.94 (d, J=9Hz, 1H), 5.92 (s, 2H), 6.75 (d, J=8Hz, 1H), 6.84 (dd, J=2Hz, 8Hz, 1H), 6.94 (d, J=8Hz, 2H), 6.98 (d, J=2Hz, 1H), 7.36 (d, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.68 (d, J=8Hz, 1H). MS (DCI/NH 3 ) m/e 601 (M+H)+. Example 133 trans, trans-1 -(2-(N-PropyI-N-(benzysulfony (1,3-benzodioxol-5-yl)yrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 *C. 1 H NMR (CDCI3, 300 MHz) 8 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, 1H), 2.56 2.67 (m, 1H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2Hz, 9Hz, 1H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.80 (dd, J=lHz, 7Hz, 1H), 6.86 (d, J=8Hz, 2H), 6.97 (d, J=lHz, 1H), 7.27-7.35 (m, 7H). MS (DCI/NH 3 ) m/e 581 (M+H)+.
WO 99/06397 PCT/US98/15479 -161 Example134 trans. trans-1 -(2-(N-Proov-N-(4-fluorobenzenesulfonvi)aminolethyl)-2-(4 methoxyhenyl)-4-(1.3-benzodioxol-5-yl)Dyrrolidinie-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 *C. 1 H NMR (CDC1 3 , 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1H), 2.56 2.67 (m, 1H), 2.78-2.87 (m, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (m, 2H), 3.33 (dd, J=2Hz, 9Hz, 1H), 3.43-3.50 (m, 1H), 3.57 (d, J=9Hz, 1H), 3.78 (s, 3H), 7.08 (t, J=8Hz, 2H), 7.24 (d, J=8Hz, 2H), 7.69 (dd, J=5Hz, 8Hz, 2H). MS (DCI/NH 3 ) m/e 585 (M+H)+. Example 135 trans.trans-1 -(N-Methyl-N-orooylam in ocarbonylmethyl)-2-(4-methoxyhenyl)- 4
-(
4 benzofuranyl)pyrrolid ine-3-carboxylic acid Example 135A Benzofu ran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 mmol, 1.25 eq) in DMF (60 mL) at 0 0C was added a solution of 3 bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 0C 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, 74%). b.p. 160-163 0C 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, 70%). b.p. 62-72 0C at 0.6 mm Hg. To a solution of the above compounds (8.11 g, 41.5 mmol) in ether (80 mL) at -78 *C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 0C. After stirring for 15 minutes, P nhution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) WO 99/06397 PCT/US98/15479 - 1 62 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 MgSO4 and concentated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 g), both as colorless oils. Example 135B trans. trans-1 -(N-Methyl-N-propylam inocarbonvlmethyl)-2-(4-methoxyohenvl)-4-(4 benzofuranylloyrrolidine-3-carboxylic 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 (1H, t, J=3Hz), 7.4-7.2 (6H, m), 6.8 (2H, d, J=8Hz), 4.03 (1H, m), 3.94 (1H, dd, J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (1H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=llHz, 5Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H, s), 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 C 2 6
H
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 Example 136 trans. trans-1 -(N-Methyl-N-prooylaminocarbonylmethyl)-2-(4-methoxyhenvl)-4-( 6 benzofuranyl)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, CDC1 3 ) (minor rotamer) 8 7.65 (1H, bd), 7.60 (1H, d, J=2Hz), 7.55 (1H, d, J=8Hz), 7.35 (3H, m), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1H, dd, J=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS
(DCI/NH
3 ) m/e 451 (M+H)+. Anal.calc. for C 26
H
3 0
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.
WO 99/06397 PCT/US98/15479 -163 Example 137 trans. trans- 1-(N-Methyl-N-oroolaminocarbonylmethyl-2-(4-methoxyhenl)-4-( 6 benzo-2.3-dihydrofuranyl)lyrrolidine-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, CDCl 3 ) (minor rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, m), 7.82 (3H, m), 5.40 (1H, dd, J=llHz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1H, m), 4.10 (1H, m), 3.88 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.35 (1H, m), 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40) (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 N205 - 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70. Example 138 trans. trans- 1-(N.N-Di(n-butvl)aminocarbonyimethyl-2-(4-methoxyhenyl)-4-(4 benzofuranylpvrrolidine-3-carboxlic 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-N-propyl bromoacetamide. 1 H NMR. (300 MHz, CDC13) 8 7.62 (1 H, d, J=3Hz), 7.39 (1H, dt, J=8Hz, 2Hz), 7.34 (3H, m), 7.26 (1H, d, J=2Hz), 7.23 (1H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1H, ddd, J=8, 6Hz,4Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.67 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C 3 oH 38
N
2 0s: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24. Example 139 trans. trans-1 -(N.N-Di(n-butyllaminocarbonylmethyl)-2-(4-methoxyphenyl)-4-(4 benzofuranyl)pyrrolidine-3-carboxylic 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 135A substituted 4 bromophenol for 3-bromophenol, in Example 49A for piperonal and susmiiiuiny N-dibUty! brom2cetamidP for N-methvl-N-propvl WO 99/06397 PCTIUS98/15479 -164 bromoacetamide. 1H NMR (300 MHz, CDCI 3 ) 8 7.64 (1H, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, m), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=11Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.82 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 507 (M+H)+. Anal.calc. for C 3 0H 38
N
2 05: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29. Example 140 trans. trans-1 -(N. N-Di(n-butyllaminocarbonylmethyl)-2-(4-methoxyohenyl)-4-(6 benzofuranylpyrrolidine-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-N-propyl bromoacetamide. 1 H NMR (300 MHz, CDCl 3 ) 6 7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, m), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=11Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.80 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS
(DCI/NH
3 ) m/e 507 (M+H)+. Anal.calc. for C 3 0
H
38
N
2 0 5 -0.75 H 2 0: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32. Example 141 trans, trans-1 -(NN-Di(n-butvlaminocarbonylmethyl)-2-(4-m ethoxyPhenl) - 4
-(
6 benzo-2.3-dihydrofuranyl)pyrrolidine-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 hp!c). 1 H NMR (300 MHz, CDCl 3 ) 8 7.40 (2H, d, J=8Hz), 7.16 (1H, d, J=8Hz), 6.97 (1H, dd, J=8Hz, 2Hz), 6.89 (3H, m), 5.90 (1H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58 (2H, m), 3.40 (1H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29 (3H, m), 1.08 (2H, m), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 509 (M+H)+. Anal.calc. for C 3 0
H
40 N205 -0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
WO 99/06397 PCT/US98/15479 -165 Example 142 trans.trans-1 -(N-Methyl-N-1roylaminocarbonylmethyl)-2-(4-methoxyhenl)-4-(5 indanyl)Dyrrolidine-3-carboxylic acid Example 142A Indane-5-carboxaldehyde indane-5-carboxaldehyde was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran 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 indane-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 4 N 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 MgSO4, filtered, 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 0C at 0.9 mm Hg. Example 142B trans. trans-1 -(N-Methyl-N-orogylaminocarbonylmethyl-2-(4-methOxYhenYl- 4 -(5 indanyloyrrolidine-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, CDCI3) (minor rotamer) 8 7.25-7.1 (5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, s), 3.50 2.90 (6H, m), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 451 (M+H)+, 473 (M+Na)+. Anal.calc. for C 27
H
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.
WO 99/06397 PCTIUS98/15479 -166 Example 143 trans. trans-1 -(N-Methyl-N-proylaminocarbonylmethyl)-2-(4-methoxyphenyl)- 4
-(
6 indolyl)pyrrolidine-3-carboxylic 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, CDCI3) (minor rotamer) S 8.43 (1H, brs), 7.57 (1H, d, J=8Hz), 7.43 (1H, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (1H, d, J=8Hz), 7.1 (1H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1H, m), 3.93 (1H, dd, J=6Hz, 3Hz), 3.80 (1H, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86 (2.82) (3H, s), 1.47 (2H, septet, J=7Hz), 0.83 (0.73)1 (3H, t, J=7Hz). MS (DCI/NH3) m/e 450 (M+H)+. Anal.calc. for C 26
H
31
N
3 04 -0.75 H20: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91. Example 144 trans.trans-1 -(N-Methyl-N-proplaminocarbonylmethyl-2-(4-methoxhenvl)- 4 (3.4-difluoroohenylovrrolidine-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 ) (minor rotamer) 8 7.60-7.3 (4H, m), 7.13 (1H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1H, m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 447 (M+H)+. Anal.calc. for
C
24
H
2 8F 2 N204 - 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 145 trans. trans-1 -(N-Methvi-N-oroylaminocarbonvimethyl)-2-(4-methoxvohenvl)-4 (phenylloyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) 5 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, J=8Hz), 3.90 (1H, m), 3.79 (3H, s), 3.70 2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH3) m/e 411 (M+H)+. Anal.calc. for C 24
H
3 oN2O4 2.00 H 2 0: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
WO 99/06397 PCTIUS98/15479 -167 Example 146 trans. trans-1 -(N-Methyl-N-propylaminocarbonylmethyl)-2-(4-methoxYohenvl)- 4
-(
4 hydroxyhenyl)pyrrolidine-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. 1H NMR (300 MHz, CDC1 3
-CD
3 0D) (minor rotamer) 8 7.35 (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, s), 3.65 (1H, d, J=8Hz), 3.70-3.00 (8H, m), 2.92 (2.83) (3H, s), 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS
(DCI/NH
3 ) m/e 427 (M+H)+. Anal.calc. for C 24
H
30 N205 - 1.00 H 2 0: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46. Example 147 trans.trans-1 -(N-Methvl-N -rooviaminocarbonvmethvl)-2-(4-methoxvohenvl)-4 (2.4-dimethoxohenlvrrolidine-3-carboxvlic 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 NMR (300 MHz, CDCl 3
-CD
3 0D) (minor rotamer) 8 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1H, d, J=8Hz), 6.45 (1H, d, J=3Hz), 3.90 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 (3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 471 (M+H)+. Anal.calc. for C 26
H
34 N206 -0.75 H20: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75. Example 148 trans.trans-1 -(N.N-Di(n-butyl)aminocarbonlmethl)-2-(4-methoxyhenyl)-4-(5 benzo-2.3-dihyd rofuranylpyrrolidine-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, CDC13) 8 7.31 (2H, d, J=8Hz), 7.27 (1H, d, J=2Hz), 7.18 (1H, dd, J=7Hz, 3Hz), 6.86 (2H, d, J=8Hz), 6.72 (1H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, s), 3.62 (1H, m), 3.50-3.25 (4H, m), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, m), 2.79 (1H, d, J=14Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, WO 99/06397 PCTIUS98/15479 -168 t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 509 (M+H)+. Anal.calc. for C 30
H
40
N
2 05 -0.25 H 2 0: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36. Example 149 trans.trans-1 -(N. N-Di(n-butyl)am inocarbonylmethyl)-2-(4-methoxvohenyl)- 4 -(4 methoxyphenyilpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 ) S 7.38 (219, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1H, m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=14Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal.calc. for C 29
H
40
N
2 0s: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54. Example 150 trans.trans-1 -(N.N-Di(n-butylaminocarbonylmethyl)-2-(4-methoxyphenyl-4-(3.4 difluoroohenvl)pyrrolid ine-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, CDC13) 8 7.35 (1H, m), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78 (3H, s), 3.79 (1H, m), 3.62 (1H, m), 3.50-3.30 (3H, m), 3.23 (1H, m), 3.15-2.90 (4H, m), 2.78 (1H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 503 (M+H)+. Anal.calc. for C 28
H
36
F
2 N204- - 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35. Example 151 trans.trans-1-(N,N-Di(n-butyl)aminocarbonylmethyl)2(4methoxyrhenyl) 4
(
2
.
4 dimethoxyphenyll)pyrrolidine-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 NMR (300 MHz, CDC13) 8 7.37 (2H, d, J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), WO 99/06397 PCT/US98/15479 -169 6.49 (1H, dd, J=6Hz, 2Hz), 5.35 (1H, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 527 (M+H)+. Anal.calc. for C 30
H
42
N
2 0 6 - 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07. Example 152 trans. trans-1 -(N. N-Di(n-butyllaminocarbonylmethyl)-2-phenyl-4-(1.3-benzodioxol-5 yl)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, CDCI 3 ) 8 7.50-7.25 (5H, m), 7.04 (1H, d, J=3Hz), 6.87 (1H, dd, J=7Hz, 3Hz), 6.74 (1H, d, J=8Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.85 (1H, d, J=8Hz), 3.64 (1H, m), 3.42 (3H, m), 3.27 (2H, m), 3.20-2.90 (5H, m), 2.81 (1H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 481 (M+H)+. Anal.calc. for C 28
H
36
N
2 05: C, 69.98; H, 7.55; N, 5.83. Found: C, 69.69; H, 7.63; N, 5.71. Example 153 trans, trans-1 -(N.N-Di(n-butvlaminocarbonylmethvl)-2-Dhenyl-4-(5-benzo- 2
.
3 dihydrofuranylo)yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.53 (2H, m), 7.40 (4H, m), 7.13 (1H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t, J=8Hz), 4.18 (1H, d, J=14Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (1H, d, J=14Hz), 3.35 (1H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS
(DCI/NH
3 ) m/e 479 (M+H)+. Anal.calc. for C 29
H
38
N
2
O
4 - 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.
WO 99/06397 PCTIUS98/15479 -170 Example 154 trans.trans-1-(N.N-Di(n-butyl)aminocarbonylmethyl) 2-(4-t-butylphenyl)- 4 (Sbenzo 2.3-dihydrofuranipyrrolidine-3-carboxylic 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 498 and 2,3-dihydrobenzofuran-5 carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCl 3 ) 8 7.60-7.30 (6H, m), 6.90 (1H, m), 4.50 (2H, m), 3.95 (1H, m), 3.85-2.95 (11H, m), 2.90 (1H, d, J=14Hz), 1..58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) m/e 535 (M+H)+. Anal.calc. for C 33
H
4 6
N
2 04 -0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14. Example 155 trans. trans-2-(N. N-Di(n-butylam inocarbonvimethyl)-2- (4-methoxyphenyl)-4- (4 fluoroohenvl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC13) 8 7.50 (1H, m), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=8Hz), 3.83 (1H, m), 3.8 (3H, s), 3.67 (1H, m), 3.47 (3H, m), 3.30-2.90 (5H, m), 2.82 (1H, d, J=14Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 485 (M+H)+. Anal.calc. for C 28
H
37
FN
2 04: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74. Example 156 trans. trans- 1 -(N.bN-Di(n-butylminorbonvImeth 5-yl)pyrrolidine-3-carboxvic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting p-oxo-3-furanpropionate in Example 498. 1 H NMR (300 MHz, CDC3) 5 7.41 (2H, m), 6.97 (1H, d, J=3Hz), 6.85 (1H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 6.42 (1H, s), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.90 (1H, m), 3.70-3.25 (5H, m), 3.20-2.90 (4H, m), 2.85 (1H, d, J=14Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, WO 99/06397 PCT/US98/15479 -171 m). MS (DCI/NH3) m/e 471 (M+H)+. Anal.calc. for C 26 H34N 2 06: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87. Example 157 trans. trans-1 -(N.N-Di (n-butyl'am in ocarbonylmethyl)-2-(isoproY)-4-(1.3 benzodioxo-5-lp)yrroidine-3-carboXylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 6.85 (1H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=8Hz), 5.92 (2H, s), 3.75 (1H, d, J=14Hz), 3.66 (1H, q, J=7Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H,m), 2.83 (1H, t, J=7Hz), 1.88 (1H, m), 1.55 (4H, m), 1.32 (4H, m), 0.92 (12H, m). MS (DCI/NH 3 ) m/e 447 (M+H)+. Anal.calc. for C 25
H
38
N
2 0 5 -0.50 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03. Example 158 trans. trans-1 -(N. N-Di(n-butyl)aminocarbonylmethyl)-2-(4-t-butYlphenl)-4-( 1.3 benzodioxol-5-yl)pyrrolidine-3-carboxlic 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 t-butylacetophenone), in Example 49B. 1 H NMR (300 MHz, CDC1 3 ) 5 7.32 (4H, d, J=3Hz), 7.04 (1H, d, J=2Hz), 6.87 (1H, dd, J=8Hz, 3Hz), 6.74 (1H, d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=14Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1H, d, J=14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS
(DCI/NH
3 ) m/e 537 (M+H)+. Anal.calc. for C 32
H
44
N
2 0s: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11. Example 159 trans. trans-1 -(N. N-Di(n-butvlam inocarbonylmethyl-2-(4-t-butvlohenyl)-4-(5-benzo 2.3-dihydrofuranyloyrrolidine-3-carboxylic 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, CDCI3) 8 7.30 (1H, s), 7.13 (1H, dd, J=7Hz, 2Hz), WO 99/06397 PCT/US98/15479 -172 6.82 (1H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1H, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 (2H, m), 3.3 (5H, m), 2.41 (1H, m), 1.65 (4H, m), 1.44 (4H, m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH 3 ) m/e 445 (M+H)+. Anal.calc. for C 26
H
4
ON
2 04 - 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-Di(n-butyl)am inocarbonylmethyl)-2-(anti-4-methoxycyclohexYl 4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Example 160A syn and anti Ethyl 4-methoxycyclohexanoylacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and 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 *C. 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 5% 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 D-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl s-keto ester (914 mg) as a colorless oil and the cis 4 methoxycyclohexyl D keto ester (1.07 g) as a colorless oil. Example 160B trans. trans- 1 -(N. N-Di(n-butylam inocarbonylmethyl)-2-(anti-4-methoxvcyclohex)l 4-(1.3-benzodioxol-5-ylpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Fxamoles 1 and 49 substituting the anti-compound resulting from WO 99/06397 PCTIUS98/15479 -173 Example 160A in Example 49B. 1 H NMR (300 MHz, CDC1 3 ) 5 6.84 (1H, d, J=2Hz), 6.76 (1H, dd, J=7Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1H, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 517 (M+H)+. Anal.calc. for C 29
H
4 4
N
2 06 -0.50 H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13. E example 161 trans. trans-1 -(N. N-Di(n-butvlaminocarbonlmethyl)-2-(syn- 4 -methoxycyclohexvl 4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxyic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCl3) 5 6.84 (1H, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, s), 3.65 (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1H, m), 2.10 (2H, m), 1.83 (2H, m), 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 517 (M+H)+. Anal.calc. for C 2 9
H
4 4
N
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. Example 162 transtrans-1 -(N. N-Di(n-butyl)aminocarbonylmethyl)-2.4-di(5-benzo- 2
,
3 dihydrofu ranyl)pyrrolidine-3-carboxylic acid Example 162A 5-Acetyl-2.3-dihydrobenzofuran To a 0 *C 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 *C. The solution was stirred 15 minutes at 0 *C, 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 *C. The dark red solution was stirred 1 hour at 2 0C 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 WO 99/06397 PCTIUS98/15479 -174 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-Di(n-butyl)aminocarbonvlmethyl-2.4-di(5-benzo-2.3 dihydrofuranylpvrrolidin e-3-carboxyic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.43 (1H, s), 7.38 (1H, s), 7.06 (2H, m), 6.75 (1H, d, J=6Hz), 6.70 (1H, d, J=6Hz), 5.40 (1H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, m), 3.82 (2H, m), 3.57 (1H, d, J=14Hz), 3.38 (1H, m), 3.30-3.05 (6H, m), 2.95 (2H, q, J=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 521 (M+H)+. Anal.calc. for C31 H 40 N205 - 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13. Example 163 trans. trans-1 -(N.N-Di(n-butyl)aminocarbonylimethyl)-2-(3-furyl)- 4 -(5-benzo- 2
.
3 dihydrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl p-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCl 3 ) 8 7.42 (1H, m), 7.38 (1H, m), 7.13 (1H, s), 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, m), 4.57 (2H, t, J=7Hz), 3.95 (1H, d, J=8Hz), 3.63 (1H, m), 3.55 (1H, d, J=14), 3.50-3.25 (4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, m), 2.87 (1H, d, J=14Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH 3 ) m/e 469 (M+H)+. Anal.calc. for C 2 7H 3 6N205 . 0.25 H 2 0: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
WO 99/06397 PCT/US98/15479 -175 Example 164 trans. trans-1 -(N.N-Di(n-butylaminocarbonylmethyl)-2-(4-methoxyhenvl)- 4
-(
3 fluoroohenyl pyrrolidine-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. 1H NMR (300 MHz, CDCI3) 8 7.30 (2H, d, J=8Hz), 7.22 (2H, m), 6.91 (1H, m), 6.86 (2H, d, J=8Hz), 3.79 (1H, m), 3.78 (3H, s), 3.68 (1H, m), 3.55-3.37 (3H, m), 3.29 (1H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=14Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal.calc. for C 2 8H 37 FN204 -0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67. Example 165 trans. trans-1 -(N.N-Di(n-butvlaminocarbonvimethyl)-2-(4-m ethoxvohenvl)-4-( 3 pyridyl)prrolidine-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 al., Can. J. Chem. 63: 2354 (1985). 1 H NMR (300 MHz, CDC1 3 ) 8 8.82 (1H, bs), 8.73 (1H, bd, J=9Hz), 8.62 (1H, bd, J=7Hz), 7.78 (1H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=1OHz), 6.90 (2H, d, J=lOHz), 4.39 (1H, d, J=12Hz), 3.95 (1H, m), 3.80 (3H, s), 3.79 (1H, m), 3.68 (1H, d, J=18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) m/e 468 (M+H)+. Anal.calc. for C 27
H
3 7N304 - 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27. Example 166 trans. trans- 1 -(N.N-Di(n-butyl)aminocarbonyimethyl)-2-(2-fluorophenyl)-4-(1.3 benzodioxol-5-yl)pvrrolidine-3-carboxlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 7.52 (1H, dt, J=7Hz, 3Hz), 7.25 (1H, m), 7.13 (1H, dt, J=7Hz, 3Hz), 7.02 (2H, m), 6.88 (1H, dd, J=7Hz, 3Hz), 6.73 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 4.25 (1H, d, J=9Hz), 3.68 (1H, m), 3.42 (3H, m), 3.39 (1H, m), 3.20-2.95 (4H, WO 99/06397 PCT/US98/15479 -176 m), 2.91 (1H, d, J=14Hz), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 499 (M+H)+. 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. Example 167 trans. trans-1 -(N. N-Di(n-butyl)am inocarbonyim ethyl)-2-(3-fluorophenyl.-4-(1.3 benzodioxo-5-y)pyrroidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-fluorobenzoylacetate in Example 49B. 1 H NMR (300 MHz, CDC 3 ) 8 7.38 (1H, m), 7.18 (1H, d, J=7Hz), 7.15 (1H, m), 7.00 (1H, d, J=2Hz), 6.95 (1H, m), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.94 (1H, d, J=14Hz), 3.63 (1H, m), 3.42 (3H, m),. 3.35-2.95 (5H, m), 2.87 (1H, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 ) m/e 499 (M+H)+. Anal.calc. for C 28
H
35
FN
2 05: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40. Example 168 trans. trans-1 -(4-N.N-Di(n-butylaminochenyl)-2-(4-methoxvohenYl)- 4 -(1.3 benzodioxol-5-ilyrrolidine-3-carboxylic acid 4-Nitro- 1 -fluorobenzene, ethyl trans, trans-2-(4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-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-nitrophenyl)-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 1D affords the title compound.
WO 99/06397 PCTIUS98/15479 -177 Example 169 trans. trans-1 -(2-N. N-Dibutylaminooyrim idin-4-yl)-2-(4-methoxyphenyl)-4-(1.3 benzodioxol-5-ylv)prrolidine-3-carboxylic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4 dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans,trans-2-(4 methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-pyrrolidifne-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 methoji of Example 1D 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 170 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 (isopropyl am inocarbonyl methyl) -pyrrolid in e-3 carboxylic acid; 171 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(ethylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid; 172 trans,trans-2-(4-Methoxyphenyl)- 4 -(1,3 benzodioxol-5-yl)-1 -(1 methylpropylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 173 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(phenylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid; 174 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(piperidinylcarbonylmethyl) pyrrolidine-3-carboxylic acid; WO 99/06397 PCTIUS98/15479 -178 175 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(1 (propylaminocarbonyl)ethyl)-pyrrolidine-3 carboxylic acid; 176 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(a (propylaminocarbonyl)benzyl)-pyrrolidine-3 carboxylic acid; 177 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(bis- (propylaminocarbonyl)methyl)-pyrrolidine-3 carboxylic acid; 178 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(2 (propylaminocarbonyl)ethyl)-pyrrolidine-3 carboxylic acid; 179 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(propylaminosulfonylmethyl) pyrrolidine-3-carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-phenethyl)-pyrrolidine-3 carboxylic acid; 181 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(pentanoylm ethyl) pyrrolidine-3-carboxylic acid; 182 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(benzoylmethyl)-pyrrolidine 3-carboxylic acid; 183 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(hexyl)-pyrrolidine-3 carboxylic acid; 184 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-hexynyl)-pyrrolidine-3 carboxylic acid; 185 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(propoxymethylcarbonyl pyrrolidine-3-carboxylic acid; WO 99/06397 PCTIUS98/15479 -179 186 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(phenylacetyl)-pyrrolidine-3 carboxylic acid; 187 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(anilinylcarbonyl) pyrrolidine-3-carboxylic acid; 188 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)-1 -(2-acetylaminoethyl) pyrrolidine-3-carboxylic acid; 189 trans,trans-2-(4-Methoxyphenyl)-4-(1 ,3 benzodioxol-5-yl)-1 -(2-phenoxyethyl)-pyrrolidine 3-carboxylic acid; 190 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)-1 -(2-benzodioxanylmethyl) pyrrolidine-3-carboxylic acid; 191 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-tetrahydrofuranylmethyl) pyrrolidine-3-carboxylic acid; 192 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2 (propylaminocarbonylamino)ethenyl)-pyrrolidine-3 carboxylic acid; 193 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)-1 -(2 (propylaminocarbonylamino)ethyl)-pyrrolidine-3 carboxylic acid; 194 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yI)-1-(3-oxohex-1-enyl) pyrrolidine-3-carboxylic acid; 195 trans,trans-2-(2,4-Dimethoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(propylaminocarbonyl methyl) pyrrolidine-3-carboxylic acid; 196 trans, trans-2-(2-Carboxy-4-methoxyphenyl)-4 (1,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidifne-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -180 197 trans,trans-2-(2-Aminocarbonyl-4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 (propylaminocarbonyl methyl)-pyrrolidine-3 carboxylic acid; 198 trans,trans-2-(2-Methanesulfonamido-4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 199 trans, trans-2-(2-Aminocarbonylmethoxy-4 methoxyphenyl)-4-(1,3-benzodioxol-5-,yl)-1 (propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 200 trans,trans-2-(2-Methoxyethoxy-4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 (propylaminocarbonylm ethyl)-pyrrolidine-3 carboxylic acid; 201 trans, trans-2-(2-Carboxymethoxy-4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 202 trans,trans-2-(4-Methoxy-2 tetrazolylmethoxyphenyl)-4-(1,3-benzodioxol-5 yl)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 203 trans,trans-2-(2-Allyloxy-4-methoxyphenyl)-4 (1,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 204 trans,trans 2,4-Bis(4-methoxyphenyl)-1 (propylaminocarbonyl methyl)-pyrrolidine-3 carboxylic acid; 205 trans,trans 2,4-Bis(1 ,3-benzodioxol-5-yl)-1 (propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCTIUS98/15479 -181 206 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-methyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxole-5-yl)-1-(N-methyl-N butylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 208 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-methyl-N-(4 methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3 carboxylic acid; 209 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 210 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N allylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 211 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-methyl-N-(n butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 212 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N isobutylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 213 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N cyclopentylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 214 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-methyl-N-(2 methoxyethyl)aminocarbonyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -182 215 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-methyl-N butoxyethylaminocarbonyl)-pyrrolidine-3 carboxylic acid; 216 trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4 methoxyphenyl)- 1 -(N-methyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 217 trans,trans-2-(4-Methoxyphenyl)-4-(1,4 benzodioxan-6-yl)-1-(N-methyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 218 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-methyl-N isopropylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 219 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-m ethyl-N ethylaminocarbonylm ethyl)-pyrrol idine-3 carboxylic acid; 220 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-methyl-N-(1 methylpropyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 221 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N phenylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 222 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(1-(N-methyl-N propylaminocarbonyl)ethyl)-pyrrolidine-3 carboxylic acid; 223 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(a-(N-methyl-N propylaminocarbonyl)benzyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -183 224 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 225 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxole-5-yl)-1 -(N-ethyl-N butylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 226 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-ethyl-N-(4 methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3 carboxylic acid; 227 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)-1 -(N-ethyl-N phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 228 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N allylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 229 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N isobutylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 230 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N cyclopentylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 231 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N methoxyethylaminocarbonyl)-pyrrolidine-3 carboxylic acid; 232 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(N-ethyl-N butoxyethylaminocarbonyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -184 233 trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4 methoxyphenyl)- 1 -(N-ethyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 234 trans,trans-2-(4-Methoxyphenyl)-4-(1,4 benzodioxan-6-yl)-1 -(N-ethyl-N propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 235 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N isopropylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 236 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N,N diethylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 237 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N-( 1 methylpropyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 238 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-ethyl-N phenylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 239 trans, trans -2-(4-Met ho xyphe nyl)-4-(1,3 benzodioxol-5-yl)-1-(1-(N-ethyl-N propylaminocarbonyl)ethyl)-pyrrolidine-3 carboxylic acid; 240 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(a-(N-ethyl-N propylaminocarbonyl)benzyl)-pyrrolidine-3 carboxylic acid; 241 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N isobutylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -185 242 trans,trans-2-(4-Methoxyphenyl)-4-(1, 3 benzodioxol-5-yl)-1 -(N-methyl-N cyclohexylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 243 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N,N dipropylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 244 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(isobutyloxyethyl) pyrrolidine-3-carboxylic acid; 245 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yI)-1-(butylsulfonyl)-pyrrolidine-3 carboxylic acid; 246 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)- 1 (isopropylsulfonylaminoethyl)-pyrrolidine-3 carboxylic acid; 247 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 (ethoxymethylcarbonylmethy)-pyrrolidine-3 carboxylic acid; 248 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-ethylbutyrylmethyl) pyrrolidine-3-carboxylic acid; 249 trans,trans-2-(4-Methoxyphenyl)- 4 -(1, 3 benzodioxol-5-yl)-1 -(N-methyl-N-(3,4 dimethoxybenzyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; 250 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yi)-1 -[(1 R)-1 -(N-methyl-N propylaminocarbonyl)butyl]-pyrrolidine- 3 carboxylic acid; 251 trans,trans-2-(4-Methoxyphenyl)- 4 -(1, 3 benzodioxol-5-yl)-1-[(1S)-1-(N-methyl-N propylaminocarbonyl)butyl]-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 -186 252 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(3-isopropoxypropyl) pyrrolidine-3-carboxylic acid; 253 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(5-methylhexyl)-pyrrolidine 3-carboxylic acid; 254 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1-(5-methyl-2-hexenyl) pyrrolidine-3-carboxylic acid; 255 trans,trans-2-(4-Methoxyphenyl)-4-(1, benzodioxol-5-yl)- 1 -(5-methyl-4-hexenyl) pyrrolidine-3-carboxylic acid; 256 trans, trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(3,5-dimethyl-2-hexenyl) pyrrolidine-3-carboxylic acid; 257 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-(N-methyl-N isobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid; 258 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-methyl-N-(2,2 dimethylpropyl)aminocarbonylmethyl)-pyrrolidine 3-carboxylic acid; 259 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(N-ethyl-N butyl ami nocarbonyl m ethyl) -pyrrolidi ne-3 carboxylic acid; 260 trans,trans-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)- 1 -(N-methyl-N benzylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 262 trans, trans-2-(4-Methoxyphenyl)-4-(5-indanyl)-1 (N-methyl-N-propylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid; WO 99/06397 PCTIUS98/15479 -187 262 trans,trans-2-(4-Methoxyphenyl)-4-( 2
,
3 dihydrobenzofuran-5-yl)-1 -(N-methyl-N propylaminocarbonylmethyl)-pyrrolidifne-3 carboxylic acid; 263 trans,trans-2-(4-Methoxyphenyl)-4-( 1 methylindol-5-yl)- 1 -(N-rn ethyl-N propylaminocarbonylmethyl)-pyrrolidifne-3 carboxylic acid; 264 trans,trans-2-(4-Methoxyphenyl)-4-(2-naphthyl) 1 -(N-methyl-N-propylaminocarbonylmethyl) pyrrolidine-3-carboxylic acid; 265 trans,trans-2-(4-Methoxyphenyl)-4-(1,2 dimethoxy-4-phenyl)-1 -(N-methyl-N propylaminocarbonylmethyl)-pyrrolidifne-3 carboxylic acid; 266 trans,trans-2-(4-Methoxyphenyl)-4-(1 -methoxy-3 phenyl)- 1 -(N-methyl-N propyl aminocarbonylm ethyl) - pyrrol i dine-3 carboxylic acid; Examples 267-288 Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared. 267 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)- 1 -(propylaminocarbonylmethyl) piperidine-4-carboxylic acid; 268 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)- 1 -(aminocarbonylmethyl) piperidine-4-carboxylic acid; 269 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1-(4-fluorobenzyl)-piperidine 4-carboxylic acid; 270 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-l -(2-ethoxyethyl)-piperidine-4 carboxylic acid; WO 99/06397 PCT/US98/15479 -188 271 trans, trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yi)-1 -(2-propoxyethyl)-piperidine 4-carboxylic acid; 272 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 -[2-(2-methoxyethoxy)ethyl] piperidine-4-carboxylic acid; 273 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yi)-1 -[2-(2-pyridyl)ethyl] piperidine-4-carboxylic acid; 274 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yi)-1 -(morpholin-4-ylcarbonyl) piperidine-4-carboxylic acid; 275 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxole-5-yl)-1-(butylaminocarbonyl) piperidine-4-carboxylic acid; 276 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 -(4 methoxyphenylaminocarbonyl)-3-piperidine-4 carboxylic acid; 277 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yI)- 1 -acetylpiperidine-3-carboxylic acid; 278 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3 carboxylic acid; 279 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 -(phenylaminocarbonyl) piperidine-4-carboxylic acid; 280 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yi)-1 -(allylaminocarbonylmethyl) piperidine-4-carboxylic acid; 281 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yI)-1-(n butylaminocarbonylmethyl)-piperidine-4-carboxylic acid; WO 99/06397 PCT/US98/15479 -189 282 trans, trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 -(N-n-butyl-N methylaminocarbonylmethyl)-piperidine- 4 carboxylic acid; 283 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1-(pyrrolidin-1 ylcarbonylmethyl)-piperidine-4-carboxylic acid; 284 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)- 1 (isobutylaminocarbonylmethyl)-piperidfne-4 carboxylic acid; 285 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 (cyclopentylaminocarbonylmethyl)-piperidine-4 carboxylic acid; 286 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1-(morpholin-4 ylaminocarbonymethyl)-piperidine-4-carboxylic acid; 287 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1 -(2-phenoxyethyl)-piperidine 4-carboxylic acid; 288 trans,trans-3-(4-Methoxyphenyl)-5-(1,3 benzodioxol-5-yl)-1-(methoxyethylaminocarbonyl) piperidine-4-carboxylic acid. Example 289 trans.trans- 2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1- (4 dibutylaminophenyl)-pyrrolidine-3-carboxylic acid 4-Nitro-fluorobenzene, ethyl trans, trans-2-(4-methoxyphenyl)-4 (1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di isopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2 (4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-nitrophenyl) pyrrolidine-3-carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This 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- WO 99/06397 PCT/US98/15479 -190 dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1D to give the title compound. Example 290 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2 dibutylamino-pyrimidine-4-vl)-pyrrolidine-3-carboxylic acid 2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4 dichloropyrimidine according to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4 methoxyphenyl)-4-(1,3-benzodioxol-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 1D to give the title compound. Example 291 trans.trans-2-(4-Methoxyohenyl)-4-(1.3-benzodioxol-5-yi)-1 -(N-butyl-N phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. 1 H NMR (CD 3 0D) : 8 0.87 (t,3H,J=8); 1.2-1.35 (m,2H); 1.35-1.5 (m,2H); 2.78 (m, 2H); 3.10 (t,1H, J=9); 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,1H); 3.78 (s,3H); 5.93 (s,2H); 6.7-6.9 (m,4H); 7.0-7.2 (m,5H); 7.4 (m,3H). MS (DCI/NH 3 ): m/e 531 (M+H)+. Anal calcd for C 31
H
34
N
2 0 6 : C, 70.17; H, 6.46; N, 5.28. Found: C,70.36; H, 6.52; N, 4.99. Example 292 Sodium trans, trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)-1 -(N. N-di(n butyl)aminocarbonylmeth y/)-pyrrolidine-3-carboxylate Example 292A Ethyl 3-(4-methoxyphenyl)-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 35 L 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 WO 99/06397 PCTIUS98/15479 -191 toluene was added, agitated for 5 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 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% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous sodium chloride . The organic 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-Methylenedioxy-1 -(2-nitroethenyl)-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*-20* C. The jacket temperature was set to -5* C and the reaction solution cooled to a temperature of +3.50 C. A 21* C solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10*-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 most of the solid. The reaction mixture was filtered through canvas and then a 27R1OSV 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 WO 99/06397 PCT/US98/15479 -192 dichloromethane. The combined organics were dried 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 (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air. Example 292C . Ethyl 2-(4-methoxybenzoyl)-3-(1.3-benzodioxol-5-yl)-4-nitro butanoate 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-(4 methoxyphenyl)-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. Example 292D Ethyl 2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yL)-4.5-dihydro-3H pyrrol-3-carboxyl ate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi # 28 (300 g). 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 crystals formed. The solution was cooled to 00 C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 C). The solids were dried in vacuo at 500 C to a constant weight of 193.4 g (21% yield, melting point 80-81* C) of the WO 99/06397 PCT/US98/15479 -193 title compound. A further 200 g (23% yield) of product was obtained from the mother liquors. Example 292E Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl-pyrrolidine 3 carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4 methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro- 3 H pyrrole-3-carboxylate (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, 0.5 L of 7% aq. NaHCO3 was added. The reaction mixture was concentrated and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHCO3 and once with 2.5 L of 23% aq. NaCl, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil. Example 292F Ethyl 2-(4-methoxypheny)-4-(1,3-benzodioxol-5-yl)-1-(N.N-di(n butyl)aminocarbonylmethyl) pyrrolidine 3-carboxylate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4 methylenedioxyphenyl)-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 dibutylamidomethyl 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 C). 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. NaCl nad dried over 0.399 kg MgSO4 and filtered.
WO 99/06397 PCTIUS98/15479 -194 Concentration as above provided 3.112 kg (96 % yield) of the title compound as a dark oil. Example 292G transtrans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-yl)-pyrrolidine 3-carboxylate and preparation of trans.trans 2-(4-methoxyhenyl)-4 (3.4-dioxyphenyl)-pyrrolidine-3-carboxylic acid ethyl ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl) 4-(3,4-methylenedioxyphenyl)-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 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. NaCl, dried with 0.298 kg MgSO4 , filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were 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 filtered. 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. Example 292H Sodium trans,trans-2-(4-methoxyphenyl)-4-(13-benzodioxol-5-yl)-1 (N.N-di(n-butyl)aminocarbonylmethyl) pyrrolidine 3-carboxylate Into a 20-L flask was charged trans,trans 2-(4-methoxyphenyl) 4-(3,4-methyledioxyphenyl)-1-(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3-carboxylic acia (0.927 Ky, 1.o1 mul). A so l in WO 99/06397 PCT/US98/15479 -195 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 vacuo at 50* C to a constant weight of 0.937 kg (97% yield) of the title compound. Example 293 trans-trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 [decahydroisoquinolin-2- carbonylmethyll-pyrrojidine-3-carboxlic The title compound was prepared using the procedures described in example 1. NMR (CDsOD, 300 MHz) shows a mixture of isomers. MS
(DCI/NH
3 ) m/z 521. Anal calcd for C 30
H
3 6N20 6 . 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 . Example 294 trans-trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-yl- 1-3.3 dimethylpiperidinyl- carbonylmethyll-prrolidine-3-carboxYlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD 3 0D, 300 MHz) indicates presence of rotamers. 8 0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, 1H, J=8), 6.90 (dd, 1H, J=1,8), 7.01 (d, 2H, J=9), 7.03 (s, 1H), 7.47 (d, 2H, J=9). MS (DCI/NH 3 ) m/z 495. Anal calcd for C 28
H
34
N
2 06 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 . Example 295 trans-trans-2-(4-Methoxyphenyl)-4-(1.3-ben zodi oxol-5-yl)- 1 -r2-(N proyi-N-iso-butoxycarbonylaminolethil-oyrrolidine-3-carboxylic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and isobutyl chloroformate 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. 1 H NMR (CDCl 3 , 300 MHz) 8 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m, 1H), 2.72 (m, 1H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1H), WO 99/06397 PCTIUS98/15479 -196 3.55 (m, 1H), 3.62 (m, 1H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J= 8Hz), 6.82 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 527 (M+H)+. Anal calcd for C 29
H
38
N
2 06 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95. Example 296 trans-trans-2-(4-Methoxyphenyl-4-(1.3-benzodiox ol-5-Yil-1 -1.2.3.4 tetrahydroisoquinolin-2- carbonylmethyll-oyrrolidine-3-carboxylic The title compound was prepared using the-procedures described in example 1. NMR (CD 3 0D, 300 MHz) indicates presence of rotamers. 8 2.97 (m, 2H), 4.68 (s, 3H), 5.97 (s, 2H), 6.83 (d, 1H, J=8), 6.9-7.0 (m, 3H), 7.03 (d, 1H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NH 3 ) m/z 515. Example 297 trans-trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-yl)-1 -r2-(N propyl-N-dimethyl aminocarbonylaminolethyll-pyrrolidine- 3 -carboxylic aclid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and dimethylcarbamyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac lC18) 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.' H NMR (CDC13, 300 MHz) S 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H), 3.1-3.45 (m, 4H), 3.70 (m, 1H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J= 8Hz), 6.87 (m, 3H), 7.05 (s, 1H), 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 498 (M+H)+. Anal calcd for C 27
H
3 5N 3 06 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, trans-2-(4-Methoxvphenyl)- 4 -(1.3-benzodioxol-5-y)-1 -(2-(N propyl-N-(4-nitrobenzenesulfonyl)aino)ethYlPpyrrolidine- 3 carboxylic acid Using the procedures described in Eample 66, the title compound w- prerared _s q yellow solid. m.o. 85-87*C. 1H NMR (CDC13, 300 MHz) WO 99/06397 PCTIUS98/15479 -197 5 0.77 (t, J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (m, 1H), 2.57-2.66 (m, 1H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, 1H), 3.49-3.57 (m, 1H), 3.59 (d, J=9Hz, 1H), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=lHz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 (d, J=lHz, 1H), 7.27 (d, J=9Hz, 2H), 7.82 (d, J=9Hz, 2H), 8.23 (d, J=9Hz,2H). MS (DCI/NH3) m/e 612 (M+H)+. Example 299 transtrans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-(N propyl-N-n-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 59-61*C 1 H NMR (CDC1 3 , 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 0.90 (t, J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (m, 1H), 3.63 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1H), 6.83 (dd, J=lHz,J=7.5Hz, 1H), 6.87(d, J=8Hz, 2H), 7.00 (d, J=lHz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+. Example 300 transtrans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 -(2-(N propyl-N-(4-trifluoromethoxybenzenesulfonyliaminolethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.122-124*C. 1 H NMR (CD30D, 300MHz) 5 0.75 (t, J=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J=lOHz, 1H), 3.81 (d, J=9Hz, 2H), 3.86 (s, 3H), 3.92 (t, J=9Hz, 1H), 4.63 (d, J=lOHz, 1H), 5.97 (s, 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 1H), 7.06-7.08 (m, 3H), 7.46 (d, J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, J=9Hz, 2H). MS (DCI/NH3), m/e 651 (M+H)+.
WO 99/06397 PCTIUS98/15479 -198 Example 301 trans, trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(N propyI-N-(2-methI-2-propenesulfonvliaminl)ethyl)-pyrrolidine-3 carboxviic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71OC.. 1 H NMR (CDCI3, 300MHz) S 0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 (s, 3H), 2.25-2.35 (m, 1H), 2.68-2.77 (m, 1H), 2.85-3.28 (m, 7H), 3.40 (d, J=9Hz, 1H), 3.52 3.68 (m, 2H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 4.92 (s, 1H), 5.07 (s, 1H), 5.97 (s, 2H), 6.74 (d, J=7Hz, 1H), 6.82-6.89 (m,3H), 7.01 (s,1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3), m/e 545 (M+H)+. Example 302 trans-trans-2-(4-Methoxyphenyl)-4- (1.3-benzodioxol-5-yl)-1-[2 ethylpiperidinyl-carbonylmethyll-yrrolidine-3-carboxYlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD 3 0D, 300 MHz) shows a mixture of isomers. S 0.75 (t, 3H, J=7), 1.4-1.7 (m, 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1H, J=8), 6.91 (d, 1H, J=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCI/NH 3 ) m/z 495. Anal calcd for C 28
H
34
N
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 . Example 303 trans.trans-2-(4-MethoxyphenYl-4-(1.3-benzodioxol-5-yl)-1 -(2-(N propyl-N-(2-methylpropanesulfonyl)aminolethyl)-pyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73*C. 1H NMR (CDC13, 300 MHz) 8 0.82 (t, J=7.5Hz, 3H),1.04 (d, J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, 1H), 3.23 3.45 (m, 1H), 3.43 (d, J=llHz, 1H), 3.55-3.62 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J=9Hz, 1H), 6.83 (dd, J=lHz,J=9Hz, 1H), 6.87(d, J=9Hz, 2H), 7.02 (d, J=lHz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 547 M+H)+.
WO 99/06397 PCT/US98/15479 -199 Example 304 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(N propyl-N-heptanesulfonylaminolethyl)-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 H NMR (CDCI3, 300MHz) 5 0.80(t, J=7.5Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.23-1.36 (m, 8H), 1.94 (q, J=7.5Hz, 2H), 1.71(quintet, J=7Hz, 2H), 2.23-2.32 (m, 1H), 2.70-3.09(m, 7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,J=9Hz, 1H), 3.52-3.58(m,1H), 3.65(d, J=9Hz, 1H), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, J=7Hz, 1H), 6.83 (dd, J=lHz, J=7Hz, 1H), 6.87(d, J=9Hz, 2H), 7.01(d' J=lHz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) m/e 589 M+H)+. Example 305 trans-trans-2-(4-Methoxyphenyl-4-(1,3-benzodioxol-5-YI)-1 -{2-(N ethyl-N-ethoxycarbonylaminolethvl-pyrrolidine-3-carboxYlic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude 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 solid. 1 H NMR (CDCI3, 300 MHz) 8 0.90 (t, 3H, J=7), 1.22 (m, 3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J=7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 (d, 1H, J= 8Hz), 6.84 (m, 3H), 7.00 (s, 1H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH 3 ) m/e 485 (M+H)+. Anal calcd for C 26
H
32
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. Example 306 transtrans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yi)-1 -(2-(N propyl-N-hexanesulfonylaminolethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60*C. 1H NMR (CDCI3, 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, 1H), 2.72-3.08(m, 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1H), 3.55-3.62(m, 1H), 3.65 (d, J=1OHz, 1H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1H), 6.82(d, WO 99/06397 PCT/US98/15479 -200 J=7.5Hz,1H), 6.87(d, J=9Hz, 2H), 7.01(s,1H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 (M+H)+. Example 307 trans-trans-2-(4-Ethylphenyl)-4-(1.3-benzodioxol-5-yl)-1 -rN.N-di(n butyl)aminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDC1 3 , 300 MHz) 5 7.31 (2H, d, J=8Hz), 7.16 (2H, d, J=8Hz), 7.03 (1H, d, J=3Hz), 6.86 (1H, dd, J=8&3Hz), 6.73 (1H, d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=9Hz), 3.60 (1H, m), 3.53-3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (1H, d, J=14Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, m), 1.40 1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCl, NH 3 ) 509 (MH+) Anal.calc. for C3 0
H
40
N
2 0 5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25 . Example 308 trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N propyl-N-(2-chloroethoxy)carbonylamino)ethyll-pyrrolidine-3 carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and 2-chloroethyl chloroformate 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. 1 H NMR (CDC1 3 , 300 MHz) 5 0.80 (t, 3H, J=7), 1.22 (m, 3H), 2.15 (m, 1H), 2.75 (m, 1H), 2.85 (m, 1H), 3.1 (m, 2H), 3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1H), 4.30 (m, 1H), 5.98 (s, 2H), 6.72 (m, 1H), 6.82 (m, 3H), 7.00 (m, 1H), 7.30(m, 2H). MS (DCI/NH 3 ) m/e 533 (M+H)+. Anal calcd for C 27
H
33
N
2 07CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
WO 99/06397 PCT/US98/15479 -201 Example 309 trans-trans-2-(2-Methoxyethyll- 4 -(1.3-benzodioxol-5-yl)-1-fN.N-di(n butylaminocarbonylmethyll-yrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4 methoxybenzoylacetate in Example 1A. The title compound is a yellow foam. 1 H NMR (CDCl 3 , 300 MHz) 8 0.91 (t, J=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1H), 3.30 (s) and 3.20-3.68 (br m, 11H total), 3.72-4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J=8.5Hz, 1H), 6.82 (dd, J=1.5, 8.5Hz, 1H), 6.91 (d, J=1.5Hz, 1H); MS (FAB) m/e 463 (M+H)+. Anal calcd for C 25
H
38
N
2 0 5
-H
2 0: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69. Example 310 trans.trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-yl)-1 -(2-(N ethyl-N-n-pentanesulfonylamino)ethyl)-pyrrolidine- 3 -carboxyic acid 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 (CDC13, 300MHz) 8 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,1H), 2.71-2.96(m,5H), 3.08-3.30(m,4H), 3.95(d, J=9Hz, 1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz,1H), 3.80(s, 1H), 5.97(s, 2H), 6.73(d, J=9Hz, 1H), 6.82(d, J=9Hz,1H), 6.88(d, J=9Hz, 2H),7.02(s,1H), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 (M+H)+. Example 311 trans-trans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-y)-1-fN.N dicyclohexylamino carbonylmethyll-prrolidine-3-carboxYlic acid. The title compound was prepared using the procedures described in example 1. - NMR (CD 3 OD, 300 MHz) 8 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H, J=8), 6.86 (dd, 1H, J=2,8), 6.95 (d, 2H, J=9), 7.04 (d, 1H, J=2), 7.38 (d, 2H, J=9). MS (DCI/NH3) m/z 563. Anal calcd for C 33
H
42
N
2 06 . 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 . Found: C, 69.42; H, 7.29; N, 4.78.
WO 99/06397 PCT/US98/15479 -202 Example 312 trans-trans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-yli)-1 -r2-(N propyl-N-tert-butoxycarbonylamino)ethyll-prrolidine-3-carboxylic The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61C. NMR (CD 3 0D, 300 MHz) suggests presence of rotamers 5 0.81 (t, 3H, J=7), 1.2-1.5 (m, 11H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1,2), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2,8), 6.92 (d, 2Hr J=9), 6.99 (bd s, 1H), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 527. Anal calcd for C 29
H
38
N
2 07: C, 66.14; H, 7.27; N, 5.32 . Found: C, 66.,05; H, 7.36; N, 5.15. Example 313 trans-trans-2-(4-Methoxy-3-fluoropheny)-4-(1.3-benzodioxol-5-yl' 1 -rN, N-di(n-butyl)aminocarbonylmethyll-pyrrolidine-3-carboxylic acid. The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. m.p. 142-143 *C. NMR (CDCl 3 , 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=13Hz, 1H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1H), 3.55-3.65 (m, 1H), 3.82 (d, J=lOHz, 1H), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, 1H), 7.06 (m, 2H). Anal calcd for C 29
H
37
N
2 0 6 F : C, 65.89; H, 7.06; N, 5.30 . Found: C, 65.82; H, 7.13; N, 5.29. Example 314 trans. trans-2-(Prooyl)-4-(1.3-benzodioxol-5-yl-1.-(2-(N-orooYl pentanesulfonvlamino)ethyllDyrrolidine-3-carboxylic acid Example 314A Propyl pentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL
CH
2
C
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 Cl 2 under a nitrogen atmosphere. The reaction was stirred at 0 0C for 30 min, then at 25 *C for 4 h. The soluilufl W~ arbki~e ont~c 2 mL^f 10 n A nunij NpH5qOflA nd 25 mL WO 99/06397 PCT/US98/15479 -203
CH
2 C2. The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na 2 SO4), 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 H NMR (CDC13, 300 MHz) 8 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H), 1.28 1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCI/NH 3 ) m/e 211 (M+NH 4 )+. Example 3149B Ethyl trans. trans--4-(1.3-benzodioxol-5-yl)-1 -(2-bromoethyl-2-proovlpyrrolidine-3 carboxylate The title compound was prepared according the procedure of Example 61A, substituting the compound of Example 94B for the pyrrolidine mixture. Example 3140 Ethyl trans. trans-2-(Propyl)-4-(1 .3-benzodioxol-5-v)-1-(2-(N-Droyi pentanesulfonylaminolethylopyrrolidine-3-carboxylate A solution of the compound of Example 314A (6.6 mg, 34 pLmol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 pimol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 imol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylammonium iodide. The reaction was sealed under argon and stirred at 60 0C 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 Na 2 SO4, 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 (73%) of the title compound as a wax. > .Example 314D trans.trans-4-(1.3-benzodioxol-5-l)-2-(Provlyi)-1 -(2-(N-propyl entanesulfonylamino)ethyl)oyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C. 1 H NMR (CDCI3, 300 MHz) 5 0.88-1.00 (m, 9H), 1.20-1.55 5 (br m, 6H), 1.55-1.68 (m, 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 (s, 2H), 6.76 (d, J=8Hz, WO 99/06397 PCT/US98/15479 -204 1H), 6.79 (m, 1H), 6.93 (br s, 1H); HRMS (FAB) calcd for C2sH 4 1N 2 06S (M+H)+ 497.2685, found 497.2679. Example 315 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(N propyl-N-dimethylsulfamoylamino)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*C. 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,1H), 2.65(s, 6H), 2.70-2.79(m, 1H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 (t, J=9Hz,1H), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1H), 6.83(d, J=9Hz, 1H), 6.88(d, J=9Hz, 2H), 7.02(s, 1H), 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 (M+H)+. Example 316 trans-trans-2-(4-Methoxphenyl)-4-(1.3-benzodioxol-5-yl)-1-r2-(N proyl-N-r4-methoxvhenyllsulfonylam ino) oroyll-pyrrolidine-3 carboxylic acid Example 316A Ethyl trans-trans and cis- trans 2-(4-Methoxyphenyl)-4-(1.3-benzodiox 5-yi) -1-(3-bromopropyl) prrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4 methoxyphenyl)-4-(1,3-benzodiox-5-yl) -pyrrolidine-3-carboxyl ate (4.00 g; prepared according to example IC), 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 (Na2SO4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 (98%) of the title compound.
WO 99/06397 PCT/US98/15479 -205 Example 316B Ethyl trans-trans and cis-trans 2-(4-Methoxyhenyl)-4-(1.3-benzodiox 5-yl) -1-(3-propylaminopropyl) oyrrolidine-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 (Na2SO4). 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. Example 3160 trans-trans-2-(4-Methoxphenyl)-4-(1.3-benzodioxol-5-yl)-1 -[2-(N propyl-N-4-methoxyphenyllsulfonylamino)propyll-pyrrolidine-3 carboxylic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1D. NMR (CDC13, 300 MHz) S 0.83 (t, J=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 (m, 2H), 2.00-2.11 (m, 1H), 2.40-2.51 (m, 1H), 2.69-2.78 (m, 1H), 2.84-3.03 (m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 3H), 6.93 (d, J=8Hz, 2H), 7.02 (d, J=2Hz, 1H), 7.29 (d, J=8Hz, 2H), 7.69 (d, J=8Hz, 2H). Anal calcd for C 32
H
3 8
N
2 08S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45. Example 317 trans-trans-2-(4-Methoxphenyfl-4-(1.3-benzodioxol-5-y)-1 -2-(N Dropyl-N-propylsulf onvamino)propvil-pvrrolidine-3-carboxviic acid Using the method described in example 66, the propylamino compound prepared in Example 316B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resuling product was chromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1D. NMR (CDC13, 300 MHz) 5 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60 WO 99/06397 PCTIUS98/15479 -206 (m, 2H), 1.65-1.85 (m, 4H), 2.04-2.16 (m, 1H), 2.42-2.57 (m, 1H), 2.72 3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72 .(d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C 28
H
38 N207S: C, 61.52; H, 7.01; N, 5.12 . Found: C, 61.32; H, 7.01; N, 5.01. Example 318 trans. trans--2-(3-Fluoro-4-methoxyphenvl)-4-(1.3-benzodioxol-5 yl)l-(2-(N-propvl-N-pentanesulfonyiaminolethyl)-pyrrolidine-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 (CDCI3, 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(m, 2H), 2.25-2.33(m, 1H), 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,1H), 3.53-3.60(m, 1H), 3.66(d, J=1OHz, 1H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(dd, J=lHz,J=8Hz,1 H), 6.92(t, J=8Hz,1H), 6.97(d, J=lHz, 1H), 7.12(d, J=8Hz, 1H), 7.18(dd, J=lHz,J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+. Example 319 trans-trans-2-(4-Pyridinyl)-4-(1.3-benzodioxol-5-yl)-1-rN,N-di(n butyl)aminocarbonylmethyll-pyrrolidine-3-arboxylic acid. The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am. Chem. Soc. 1993, 115, 11705) in place of ethyl (4 methoxybenzoyl)acetate. m.p. 131-132 *C. NMR (CDCI 3 , 300 MHz) 5 0.82 (t, J+7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.97*(d, J=13Hz, 1H), 3.00-3.25 (m, 4H), 3.32 (m, 1H), 3.39 (d, J=13Hz, 1H), 3.45-3.52 (m, 1H), 3.67-3.78 (m, 1H), 4.10 (d, J=9Hz, 1H), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H), 7.02 (d, J=2Hz, 1H), 7.45 (d, J=8Hz, 2H), 8.50 (d, J=8Hz, 2H). Anal calcd for C 27
H
35 N30 5 : C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39; H, 7.45; N, 8.61.
WO 99/06397 PCT/US98/15479 -207 Examile 320 trans-trans-2-(4-Methoxyhenyl-4-(1.3-benzodioxol-5-yl)- 1-2-(N propyl-N-diethylaminocarbonylaminoethyl-prrolidine-3-carboxylic The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and diethylcarbamyl chloride for isobutyryl chloride in Example 61C. NMR (CD 3 0D, 300 MHz) 8 0.74 (t, 3H, J=7), 1.09 (t, 6H, J=7), 1.33 (m, 2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1H), 5.93 (s, 2H), 6.86 (d, 1H, J=8), 7.06 (dd, 1H, J=2,8), 6.94 (d-, 2H, J=9), 7.04 (d, 1H, J=2), 7.40 (d, 2H, J=9). MS (DCI/NH 3 ) m/z 526. Anal calcd for
C
29
H
39
N
3 06 . 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43; N, 8.14. Example 321 trans-trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yil-1 -f3.5 dimethylpiperidinyl- carbonylimethyll-pyrrolidine-3-carboxYlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD 3 0D, 300 MHz) shows mixture of isomers. 8 0.88 (d, 3H, J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1H, J=8), 6.89 (dd, 1H, J=1,8), 7.00 d, 2H, J=9), 7.03 (m, 1H), 7.47 (d, 2H, J=9). MS (DCI/NH 3 ) m/z 495. Example 322 trans-trans-2-(4-Methoxyphenyl)- 4 -(1.3-benzodioxol-5-yl)-1 -rN.N di(s-butyl)aminocarbonylimethyl-pyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD 3 0D, 300 MHz) suggests a mixture of isomers. 8 0.83 (t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, 1H, J=8), 6.86 (d, 1H, J=8), 6.94 (d, 2H, J=9), 7.03 (d, 1H, J=2), 7.35 (d, 2H, J=9). MS (DCI/NH 3 ) m/z 511.
WO 99/06397 PCT/US98/15479 -208 Example 323 trans-trans-2-(4-Methoxvhenvl-4-(1.3-benzodioxol-5-y)-1-rN-(2 Methylphenyli-N-butylamino carbonylmethyll-oyrrolidine-3-carboxylic acid. The title compound was prepared using the procedures described in example 1. MS (DCI/NH3) 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. Example 324 trans-trans-2-(4-Methoxyphenyl)-4-(1.3-benz-odioxol-5-yli)-1 -rN-(3 Methylphenyl-N-butylamino carbonylmethyll-pyrrolidine-3-carboXylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD 3 0D, 300 MHz) d 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H), 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1H, J=10), 3.3 (m, 1H), 3.44 (dd, 1H, J=5,10), 3.53 (m, 1H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m, 1H), 5.93 (s, 2H), 6.74 (d, 1H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1H, J=2), 7.09 (d, 2H, J=9), 7.18 (d, 1H, J=7), 7.27 (t, 1H, J=7). MS (DCI/NH3) m/z 545. Anal calcd for C 32
H
36 N206 . 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 . Found: C, 68.70; H, 6.67; N, 4.85. Example 325 trans, trans-4- (1.3-Benzodioxo-5-yl)-2-(benzyloxymethyl)-1 -((N. N dibutylaminocarbonylmethyll)oyrrolidine-3-carboxylic acid Example 325A Ethyl trans. trans-4- (1.3-Benzodioxo-5-vl-2-(benzyloxymethyl)-1 -((N.N-di(n butyllam inocarbonylmethylloyrrolidine-3-carboxylate The procedures of Example 1A-1 D were followed, substituting ethyl 4 benzyloxy-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; 1H NMR (CDCl 3 , 300 MHz) 5 0.88 (t, J=7Hz, 6H), 1.17 (t, J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 (t, J=8Hz, 1H), 2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64 3.75 (m, 2H), 3.92 (d, J-14Hz, 1H), 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (m, 2H), 6.69 (d, J=9Hz, 1H), 6.77 (dd, J=1.5, 9Hz, 1H), 6.91 (d, J=1.5Hz, 1H); MS (DCI/NH 3 ) m/e 553 (M+H)+.
WO 99/06397 PCT/US98/15479 -209 Example 325B trans. trans-4- (1.3-Benzodioxol-5-yl)-2-(benzyloxymethyl)-1 -((N.N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71C, as a colorless glass. TLC (5% MeOH-CH2Cl2) Rf 0.13; 1 H NMR (CDCI3, 300 MHz) 8 0.86 (t, J=7Hz), and 0.90 (t, 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, 1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.84 (dd, J=1,8Hz, 1H), 6.93 (d, J=1Hz, 1H), 7.28-7.39 (m, 5H); MS (DCI/NH 3 ) m/e 524 (M+H)+. Example 326 trans.trans-4- (1.3-Benzodioxo-5-yl)-2-(hydroxymethyl)-1 -((N.N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 326A Ethyltrans.trans-4-(1.3-Benzodioxol-5-yl)-2-(hydroxymethyl-1 -((N.N-di(n butyl)am inocarbonylmethylpyrrolidine-3-carboxylate The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg of 20% Pd(OH) 2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes 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- (hydroxvmethyl)- 1 -((N. N di(butyllaminocarbonylmethylpyrrolidine-3-carboxviic 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-methyloropenamid-3-yl-1 -((N, N-di(n butyl)aminocarbonylmethylpyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -210 Example 327A Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(formyl)-1 -((N.N-di(n butyliaminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is made by selective oxidation (e.g. using the Swern 5 oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess Martin periodinane) of the compound of Example 326A. Example 327B Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(0-tert-butylpropenoat-3-yl)- 1- ((N. N o di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2
C
2 solution. Example 3270 I5 Ethyl trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(propenoic acid-3-yl)-1-(N.N-di(n butyl)am inocarbonylm ethyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2 Cl 2 (1:1). 20 Example 327D Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)- 1 -(N.N di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327C with methylamine hydrochloride in the presence of a carbodiimide (e.g. N 25 ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC). Example 327E trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(N-methylpropenamid-3-yl)-1 -(N. N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid 30 The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71C. Example 328 trans, trans--4-(1.3-Benzodioxol-5-yl)-2-(1 -hydroxy-2-propen-3-yl)-1 -(N, N-di(n 35 butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -211 Example 328A Ethyl trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(1 -hydroxy-2-propen-3-yl)-1 -(N. N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 327C 5 with borane methyl sulfide complex. Example 328B trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(1 -hydrox-2-propen-3-yl)-1 -(N. N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid o The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 71C. Example 329 transtrans--4-(1.3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1 -(N. N-di(n 5 butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 329A Ethyl trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(N-benzylaminomethyl)-1 -(N.N-di(n butyllam inocarbonylmethyl)pyrrolidine-3-carboxylate o 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-yI)-2-(N-benzylaminomethyl)- 1 -(N. N-di(n 5 butyl)am inocarbonylmethyl)pyrrolidine-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 o trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylam inomethyl)- 1 -(N.N di (n-butyl)am inocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 330A Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylam inomethyl)- 1 35 (N.N-di(n-butyl)aminocarbonylmethyl)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.
WO 99/06397 PCT/US98/15479 -212 Example 330B trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(N-acetyl-N-benzylaminomethyl)- 1 -(N.N di(n-butyl)am inocarbonylmethyl)pyrrolidine-3-carboxyic acid 5 The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71C. Example 331 trans. trans--4-(1.3-Benzodioxol-5-yI)-2-(ethynyl)-1 -(N. N-di(n o butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 331A Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(ethynyl)-1-(N. N-di(n 5 butyl)am inocarbonylmethyl)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 o trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(ethynyl)-1 -(N.N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 71C. 5 Example 332 trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(1 -pentynyl)-1 -(N. N-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 332A 0 Ethyl trans. trans--4-(1.3-Benzodioxol-5-yl)-2-(pentynyl)-1-(N.N-di(n butyl)aminocarbonyimethyl)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. (J. Org. Chem. 1989, 54(15), 3618-24). '5 WO 99/06397 PCT/US98/15479 -213 Example 332B trans.trans--4-(1.3-Benzodioxol-5-yl)-2-(1 -pentynyl)-1 -(N.N-di(n butyl)aminocarbonylmethyl)pyrrolidine-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. Example 333 trans-trans-2-(4-Methoxphenyl-4-(1.3-benzodioxol-5-yl)-1-[2-(2.6 dioxopiperidinyl) ethyl}-pyrrolidine-3-carboxylic acid The compound of example 61A 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 1 D. Example 334 trans-trans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-yl)-1 -fN.N diphenylaminocarbonylmethyll-pyrrolidine-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, 9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, J = 9.5), 3.49 (d, 1, J = 15.3), 3.51 (dd, 1, J = 4.6, 9.5), 3.57 (m, 1), 3.79 (s, 3), 3.85 (d, 1, J = 9.5), 5.90 (s, 2). 6.71 (d, 1, J = 8.0), 6.84 (m, 3), 7.04 (d, 1, J = 1.6), 7.14-7.16 (m, 6), 5 7.19-7.34 (m, 6); MS (DCI/NH 3 ) m/z 551; Anal Calcd for
C
33
H
3 oN 2 0 6 -0.65H 2 0.0.35C 2 H50COCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64. Example 335 o trans-trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1
-[N.N
diisopropylaminocarbonylmethyll-pyrrolidine-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 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J = 6.4), 1.30 (d, 6, J = 6.8), 2.85 (d, 1, J = 12.5), 3.04 (dd, 1, 5 J = 8.1, 9.8), 3.14 (t, 1, J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1), 5.92 (s, 2), 6.75 (d, 1, J = 8.1), 6.85 (dd, 1, J = 1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1, WO 99/06397 PCT/US98/15479 -214 J = 1.7), 7.35 (m, 2). MS (DCI/NH 3 ) m/z 483. Anal Calcd for C27H 34
N
2 0 6 .0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52. Example 336 5 transtrans-2-(3-Fluoro-4-methoxyphenyl)-4- (1.3-benzodioxol-5-yl) 1-(2-N-propyl-N-butanesulfonylamino)ethyl)-pyrrolidine-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 o (CDCl3, 300MHz) 8 0.82(t, J=7.5Hz, 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,1H), 2.72-2.94(m, 5H), 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1H), 3.53 3.60(m, '1H), 3.67(d, J=9Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 6.92(t, J=9Hz, 1H), 6.97(s, 1H), 7.12(d, J=9Hz, 5 1H), 7.18(d, J=12Hz, 1H). MS (DCI/NH3) m/e 565 (M+H)+. Example 337 Using methods described in the above examples, the compounds o disclosed in Table 1 can be prepared.
H
3 C fOOH Table 1 ?5 R R R 02 H2N%. 1. 2. 3.
WO 99/06397 PCTIUS98/15479 -215 Table 1 cont. R R R NN 4.5. 6. NdO H3CO'F2 N 7. 8. 9. N 30O 10. 11. 12.
H
3 CO C O 14. 15. 13. 16. 17. 18. 2 N Q r% 19' 620. 2 19. 20. 21.
WO 99/06397 PCT/US98/15479 -216 Table 1 cont. R R R O~ 00 00 C 22. 23. 24.
H
3 C H3CO OF3 io% 0 000 0 0 25. 26. 27. F3 FH 2 O FH 2 C 0 0 0 0 0 0 28. 29. 30. FH 2 C O FH 2 C 2 F 2 HCO
F
2 0 0 0 2 0 0 31. 32. 33. F2HC N F3C' ,.- F3C- C ,S -T "- -4- F2 O O F 2 O O F 2 O''O 34. 35. 36. O O3 'F38.,O 37. 38. 39.
WO 99/06397 PCT/US98/15479 -217 Table 1 cont. R R R 606 40. 41. 42. H3 H3C( . 43. 44. 45. 46. 47. 48. 49. 50. 51.
N~
00 52. 53. 54. 56. 57. 0 0 0 58. 59. 60.
WO 99/06397 PCT/US98/15479 -218 Table 1 cont. R R R rO ON OyN- o " QoyN" 61. 62. 63. N N 0 0 64. 65. 66. N(O O N 67. 68. 69. O Nor O N ON 70. 71. 72. ON 73. 74. 75. N7 76. 77. 78.
WO 99/06397 PCTIUS98/15479 -219 Table 1 cont. R R R
H
3 CO C Oo N C01 N1 79. 80. 81. 0 0 0 82. 83. 84. 85. 86. 87. O N,, , Of,
-
N Ci m O 88. 89. 90. N O O C o O 0 0 0 91. 92. 93. 0 0 0 94. 95. 96.
WO 99/06397 PCTIUS98/15479 -220 Table 1 cont. R R R 0 0 0 97. 98. -- Oy y 0 yu- fl OYKN 0 0 0 100. 101. 102. 103. 104. 105. H r H N NN NN N 000 106. 107. 108.
CH
3 CH 3 N N, Ok NN N N 0 0 109. 110. 111 rolN 112. 113. 114. 115. 116. 117.
WO 99/06397 PCTIUS98/15479 -221 Table 1 cont. R R R r 0Y 118. 119. 120. 121. 122. 123. F 124. 125. 126. Cl 127. 128. 129. OC HaCODa
OCH
3 130. 131. 132. 133. 134. 135.
WO 99/06397 PCT/US98/15479 -222 Table 1 cont. R R R 0 136. 137. 138. 139. 140. 141. 00 0 0o 142. 143. 144.
F
3 C S 145. 146. 147. 148. 149. 150. H3C 151. 152. 153.
WO 99/06397 PCTIUS98/15479 -223 Table 1 cont. R R R 154. 155. 156. yr&~ 0 157 0 0 157. 158. 159. 160. 161. 162. 163. 164. 165. 60 FF 0 00 166. 167. 168.
WO 99/06397 PCT/US98/15479 -224 Table 1 cont. R R R FYFY F 0 00 00 169. 170. 171. Y Y 0 0 0 0 0 172. 173. 174. Y3 FY y F 0 N F ,N0 175. 176. 177. FayOFa O F, 178. 179. 180. F F H3CO 181. 182. 183.
H
3 C0 H3CO H 184. 6 . 185. 186. H3CO
H
3 Ca
H
3 CO 007 00
FF
0 187. 188. 189.
WO 99/06397 PCT/US98/15479 -225 Table 1 cont. R R R
H
3 CO0* H 3 Cc(> HFJ aCO> 190. 191. 192. 193. 194. 195. 0 0 F 3 C' .AS 196. 197. 198. F 3 C - , "3 I I 0 1 1 S F F O Fa O 60 199. 200. 201. 202. C 203. 204. OCI%%QC% 205. 206. 207.
WO 99/06397 PCT/US98/15479 -226 Table 1 cont. R R R 208. 209. 210. y y 211. 212. 213. V HH 214. 215. 216. OH OH 217. 218. 219.
CF
3 CF 2.1N 220. 221. 222.
WO 99/06397 PCT/US98/15479 -227 Table 1 cont. R R R
F
3 9F3
F
3 223. 224. 225. 9F3 226. 227. 228. y y-l 229. 230. 231. 232. 233. 234. 235. 236. 237.
WO 99/06397 PCTIUS98/15479 -228 Table 1 cont. R R R 238. 239. 240. yK 241. 242. 243. 244. 245. 246. "o~ry K 247. 248. 249. F NC, N ,NCNr 250. 251. 252.
WO 99/06397 PCT/US98/15479 -229 Table 1 cont. R R R NCN & YNC N< 253. 254. 255. NC.,y.N.% .. 0 256. 257. 258. y Kr ~N 0N 259. 260. 261. ~* 0 0XN 262. 263. 264. y K ~XNO..N 0 N0 265. 266. 267.
WO 99/06397 PCTIUS98/15479 -230 Table 1 cont. R R R v H N9F3 268. 269. 270. N N- N 271. N 2 272. 273. NC% N x N 0 274. 275. F 276. N 0 N N 0 N 0 277. 278. 279. N2 280. 28.281. 282.
WO 99/06397 PCTIUS98/15479 -231 Table 1 cont. R R R .N 0 )--cN 0 283. 284. 285. 286. 287. 288. N 0 .N 0 289. 290. 291. 292. 293. 294. N N 0 295. 29. 29. 295.296. 297.
WO 99/06397 PCT/US98/15479 -232 Table 1 cont. R R 298. 299. 300. NIy y LANY ANA'r ,), 301. 302. 303. N-y
K.X
4 NYN 0 N 0 304. 305. 306. .N 0 307. 308. 309. y 31 N 0 310. 311. 312.
WO 99/06397 PCT/US98/15479 -233 Table 1 cont. R R R 313. 314. 315. 316. 317. 318. 0y 319. 320. 321. 322. 323. 324. 325. 326. 327.
WO 99/06397 PCT/US98/15479 -234 Table 1 cont. R R R Nyrl 328. 329. 330. )SY- 0 331. 332. 333. 0' 0 K 334. 335. 336. 0 0 337. 338. 339. 340. 341. 342.
WO 99/06397 PCTIUS98/15479 -235 Table 1 cont. R R R Ry 343. 344. 345. I NyX-A -N 346. 347. 348. N N~ 349. 350. 351. NL# FLX.-r 352. 353. 354. 355. 356. 357.
WO 99/06397 PCT/US98/15479 -236 Table 1 cont. R R R Nv 358. 359. 360. V I lN 361. 362. 363. 364. 365. 366. N NK N 367. 368. 368. 370. 371. 372.
WO 99/06397 PCT/US98/15479 -237 Table 1 cont. R R R y 373. 374. 375. 376. 377. 378. 379. 380. 381. LWNN 'L 382. 383. 384. 3.63 385. 386. 387.
WO 99/06397 PCT/US98/15479 -238 Table 1 cont. R R R 388. 39 389 . 390. 391. 392. 393. 394. 395. 396. 397. 398. 399 400. 401. 402.
WO 99/06397 PCT/US98/15479 -239 Table 1 cont. R R R NN 403. 404. 405 vN 406. 407. 408. 409. 410. 411. 412. 413. 414. 415. 416. 417.
WO 99/06397 PCT/US98/15479 -240 Table 1 cont. R R R V-^ N' COOEt COOEt 418. 419. 420. vN A,-'CO COOPt NO 2 421. 422. 423. - N 2
NO
2
NO
2 424. 425. 426. 427. 428. 429. 430. 431. 432.
WO 99/06397 PCT/US98/15479 -241 Table 1 cont. R R R 02W 02W 433. 434. 435. 0 436. 437. 438. 0y0 0A 439. 440. 441. 0 0 0 442. 443. 444. 446. 447.
WO 99/06397 PCT/US98/15479 -242 Table 1 cont. R R R F& 0 448. 449. 450. FJO yK FF ' F~a' 451. 452. 453. 454. 455. 456. MOO MeO1%'< s'o MO 00 457. 458. 459. MeO MO MeO MeO 0 4 4 460. 461. 462.
WO 99/06397 PCT/US98/15479 -243 Table 1 cont. R R R MeO M~oA 463. 464. 465. MeO MOO Meo 466. 467. 468. MOOIC Meo b2X%2VA 469. 470. 471. Y474 372. 473. 475. 476. 477.
WO 99/06397 PCTIUS98/15479 -244 Table 1 cont. R R R cI 478. 479 0c0 480. iLi CIcc CI~ r 481. 482. 483. 0 0 0 484. 485. 486. F F 487. 488. F 489. 0F F FO~IF FX 7 0 0 0 490. 491. 492.
WO 99/06397 PCT/US98/15479 -245 Table 1 cont. R R R F) IXX 493. 494 0 4950 0 496. 497. 498. 499. 500. 501. 0 0 502. 503. 504.
M
eO 505. 506. 50 507.
WO 99/06397 PCTIUS98/15479 -246 Table 1 cont. R R R Moo MoM GM. 0 GM. 0 GMO 0 508. 509. 510. Meo MeO MOo~N GMe GM. 0 GM. 511. 512. 513. MeOrMeO MeO OM. 0 OMe 0 OMe 0 514. 515. 516. OMo 0 OMe 0 GM. 517. 518. 519. MOO MeO meO GM. 0 GM. OMe 0 520. 521. 522.
WO 99/06397 PCT/US98/15479 -247 Table 1 cont. R R R MeO MeO H 523. 524. 525. BrBr -Nr 0 Orr,~ 526. 527. 528. Br Br Br 529. 530. 531. Br Br B 532. 533. 534. 535. 536. 537.
WO 99/06397 PCT/US98/15479 -248 Table 1 cont. R R R y yI 538. 539. 540. V 0 1)0~B~O 540. 542. 543. y 0 B, B 544. 545. 546. B)r' Ba r B~a~ 547- 548. 549. B 550 F51 552. 551. 552.
WO 99/06397 PCT/US98/15479 -249 Table 1 cont. R R R F F 553. 554. 555. 556. 557. 558. BrQN%(v4 Br K~y - Br 559. 560. 561. Bry yr KBryy Br F 0ry~ 562. 563. 564. Br. Br 566-K567 565. 566. 567.
WO 99/06397 PCT/US98/15479 -250 Table 1 cont. R R R F Y 568. 569. 570. F FY K, cY 571. 572. 573. 0 574 575 576. 08 578. 579. 577. 00o 580. 581. 582. 03 584. 5 0 58. 584. 58.
WO 99/06397 PCTIUS98/15479 -251 Table 1 cont. R R R 0 0 0 586. 587. 588. 591. 589. 590. y K 592. 593. 594. rY v Ar-T 595. 596. 597. 598. 599. 600. K2 601. 602. 603.
WO 99/06397 PCT/US98/15479 -252 Table 1 cont. R R R H H H Ny, 604. 605. 606. - 0 Nc 0 607. 608. 609. 610. 611. 612. 613. 614. 615. it0 - 0 - 0 616. 617. 618. 619. 620. 621.
WO 99/06397 PCT/US98/15479 -253 Table 1 cont. R R R H" 1 H N y , 622. 623. 624. HHH 625. 626. 627. H Ny-j N~- y 628. 629. 630. r 5rTn &Nr 631. 632. 633. 634. 635. 636. y K.3 637. 638. 639.
WO 99/06397 PCT/US98/15479 -254 Table 1 cont. R R R rV 0 640. 641. 642. 0 0 643. 644. 645. -646. 647. 648. 0A 649. 650. 651. c o ci c 652. 653. 654.
WO 99/06397 PCT/US98/15479 -255 Table 1 cont. R R R 655. 656. 657. 658. 659. 660. 661. 662. 663. 664. 665. 666. 667. 668. 669.
WO 99/06397 PCT/US98/15479 -256 Table 1 cont. R R R 670. 671. 672. VF 673. 674. 675. A)V 0C 0 F F F0 676. 677. 678. 679. 680. 681. 682. 683. 684.
WO 99/06397 PCT/US98/15479 -257 Table 1 cont. R R R 685. 686. 687. F F 688. 689. F 690. 691. 692. 693. F F F 694. 695. 696. M6O07 68 M O99 607. 698. 699.
WO 99/06397 PCTIUS98/15479 -258 Table 1 cont. R R R MOO MeO mo 700. 701. 702. 703. 704. 705. F0 F 706. 707. 708. 00 o 0 709. 710. 711. HH 712. 713. 714. 070 715.
WO 99/06397 - 259- PCT/US98/15479 Example 338 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. Table 2A F MOM
H
3 .COOH COOH -*COOH R OOH O \ 0 2. 3.
CH
3 MOM F ,pCOOH ,COOH COOH jO .COOH ,COOH COOH 0 8. 9. 7.
WO 99/06397 PCTIUS98/1 5479 -260 Table 2A cont, F MOMO
H
3 .COOH .COOH O.COOH F
I"OCH
3 10. F F1 12. OH F momF pr COOH F+- COOH R *.COOH
,NOCH
3
~"OCH
3 k
OCH
3 OCH 3 13. 14. 15.
CH
3 F ,PCOOH OCOOH ,COOHH 0 0 160OH 3
OCH
3 17. 18. mom CH 3 F flON 0COOH _lN .COOH f- CO 0 0> 21. 0> 19. OCH 3 20 0 WO 99/06397 PCT/US98/1 5479 -261 Table 2A cont.
CH
3 F MOM3 .COOH OCOOH R-MOCOOH R-
I
23. 0 24. -~0 22. 0 M MOCH 3 F ,,.COOH OCO R- FCOOH
R
I - 0 25. 0 26. 27
CH
3 F OICOOH IPCOOH R- #COOH R R- N.)( 28. 029. .0
MOMCH
3 F COH CO0H R -. C00H R- .OO0C R-N 31. 32. 33.
WO 99/06397 PCTIUS98/1 5479 -262 Table 2A cant. mom
CH
3 F MOM CH 3 COOH R- COOHCfl 40COOH 06N C38 OC 3 3. CH mom
CH
3 F .COOH f R- .COOH fl-N 0 4.* 38. OCH 39
OCH
3 OMOM OCH3 ~WCOOH .OCOH COH *..COO0 0 F' 43. O0H 3 4. 45. N42 WO 99/06397 PCTIUS98/1 5479 -263 Table 2A cont. MOMO CH 3 & , % COOH t COOH R- .CO 48. .#CO0HCOH.*.COOH ~..CR- R-,OO t.COOH 52 . F5. 5. ."COOH OCOH -ICOOH #COO R OC - , O C 55. 56. F OC7.
WO 99/06397 PCT/US98/1 5479 -264 Table 2A cont. R- .COOH F+- COOH R- OCOOH 58. 09 0 60. 0 Ff- CF+- -*COOH p ,COOH 61. 62. 63. R- 4COOH R- ICOOH F+- COOH 64. F 65. 00H 3 6. 0 _COOH .C00H
-ICOOH
\1 0 0 67. 0 68. '69.
WO 99/06397 PCT/US98/1 5479 -265 Table 2A cont. ~.C0H ,COOH __COOH 7 72. OCH, 70. -~oJ71. F72 c
CH
3
OCH
3
OCH
3 ~CI"- ECOOH ~COOH \N 0 73. 74. 0 75. 0 0OHCOHCO tCH 3 OCH 3 OCH 3 / 0 '~OOH / 0 ~C00 / 0 C0H *.COOH .ICOOH *.COOH CH CH 3
H
3
/
0 COOH
/
0 -- COOH /11* ICCOOH *COOH 4COOH F INOCH 3 81. 9 79. F 80. OCH 3 0 WO 99/06397 PCTIUS98/1 5479 -266 Table 2A cont.
CH
3
OCH
3
OCH
3 H OHOH OH ,cOOHH # COOH Rq83. ~o84. 82. 0
H
3 OCH 3
HCH
3 O OH OH F+ CO - .COOH R- fcooH
CH
3
OCH
3
OCH
3 OH / ,.1 OCH3 0 / 0 OCH3 ~~,COOH ~.eCOOH .CO 1
~OCH
3 0 88. OCH 3 89. 90.
OCH
3
OCH
3
OCH
3 OH OC OCH 0~OH 0.OO ,.COOH OCOOH CH + 91. 93.
WO 99/06397 PCTJUS98/1 5479 -267 Table 2A cont.
CH
3
OCH
3 F CHOCH R- COOH R+-N eCOOH r .C O ,%. OCH 3 0 94. F 95. OCR 3 96. 0 F F F
~OCH
3 /CH c(
OCH
3 *..COOH *COOH _COORC 97. 98. F F F
OCH
3
OCH
3
OCR
3 PC .COOH F+-~ #O*O ICOOH 100. .0O 101. a )102. F F CH 3 C0
H
3 CO F .COOH 111COOH OICOOH 1
NOCR
3 ,N0 103. OCR 3 104. 0>105. 0 WO 99/06397 PCT/US98/15479 -268 Table 2A cont.
H
3 F H 3 CO H3C F/ COOH .COOH #COOH **CO 106. o 107. 108.
H
3 C H 3 CO H 3 CO F COOH -%.COOH COO ,COOH
R
OCH
3 F11
OCH
3 109. 0 110. F R- COOHR- R- ,CH 112. 113. 114 R- -N -COOH COOH R- R OCOOH R- ,,, COOH .COOH R- R 118. 119. 120.
WO 99/06397 PCTIUS98/1 5479 -269 Table 2A cont. 0 0 0 R- COOH R- ..COOH R- ;COOH 121. 0 122. 123. 00H 3
OCH
3
OCH
3 -*COOH R *,COOH R ,COOH 124. 0>125. 126.
OOCH
3
OOCH
3 ,.COOH .*COOH IOCOOH 127. 0> 128. 0>129. 0>
H
3 C0 0CH 3 .. ~~~~COOH 0H.CO 130. 0131. 12 WO 99/06397 PCTIUS98/1 5479 -270 Table 2A cont. SC3H 3 CI. PH 3
OCH
3 R-lS~:)R COO COHR VOC00H 133. 134. 0o 135.
OCH
3
OH
3
OCH
3 R-OO ",COOH R- COOH 136. H3C -- H 3 138. 137.
H
3
OCH
3
OCH
3 I*COOH O-ICOOH .COOH 139. F 140. 0 141.
H
3
OCH
3
OCH
3 OPCOOH R- ICOOH R- OCOOH R-~~ 0-I HC 142. N 1 I 143. 144. 0-- WO 99/06397 PCT[US98/1 5479 -271 Table 2A cont.
OCH
3 F
OH
3 COH .COOH __COOH CH0 I
H
3 C0 - 146. CH 3 147. 145. F F F .COOH OICOOH OIC00H
H
3 00
OCH
3 148. 14.150. F F mom MOM OICOOH R- IVCOH R-- COH %- OCH F15.0 15. 315.
WO 99/06397 PCT/US98/15479 -272 Table 2A cont. MOM OCH 3 MOM -- - OCH 3 .COOH A *COOH ,reCOOH R-N *oo R~ 158. F 159. O 157. OCH3
OCH
3
OCH
3
CH
3
OCH
3 \ OCH 3 . '--- OCH COOH '*COOH ,COOH ,O
H
3 C -OCH % 160. 162. 161.
CH
3 OCH 3 H 3 C O OCH3 5 / OCH3 A OCOOH -N -COOH N COOH F 163. OCH 3 164. 165. OCH 3 HCF MOMO
H
3 C -om FH H \ \ N A O C O O H AN N R-N Co WN 11 O 166.
'OCH
3 167. O 68 WO 99/06397 PCT/US98/15479 -273 Table 2A cont. F MOM F H H H N N N N 169. 0 170. 171. 0 MO F MOMO H H H No N ,.N MFM MOMOO H H N N XN F- R-Fl 175.Z 178. 1797 . 180. HH H ., / N. ,, N N pN - OC- .,- OCr 17 . 1 77'1 8 0 WO 99/06397 PCT/US98/15479 -274 Table 2A cont. F MOMO H 3 C -N N >O R- R-N H 0 0) 181. 0 182. 183. 0
H
3 C F MOMO ''~ 'Wr 0 o VNSC s 3 sPCr NCH R- H H H 185. 186. 184. 0 185. 0 1 F MOMO F
RCH
3
CH
3
N-
3 N CH 3 H- H H 187. 0 188. O 189. O MOMO F MOMO p/ 0 0,2p H CH 3 R- H H 0 190. 191. 192.
WO 99/06397 PCT/US98/1 5479 -275 Table 2A cont. F F momO 00 R 'N CH 3 0.eCH "N-SCH 3 H R- N' R- H -. F 193. 194. 195. mom F MOMO E.1C H : 'CH3CH 3 H
NOH
3 RH 'k F
OCH
3 'k OCH 3 196. F 19.OCH 3 198. OCH 3 F MOMO H 3 C R- H PR H H 0% 0 0 199. 200. -~ 0 J 201. 0>
H
3 C H 3 C H 3 C /i )%Nes.cH 2 o N, CH 2
CF
3 RN ~L N(CH 3
)
2 R-H2H I H Rr H 0Nc 202. 0 203. 0 204. 0 WO 99/06397 PCT/US98/15479 -276 Table 2A cont. Pr %COOH ,i ICOOH #COOH O 0 0 ' 206. 207. 205. ?H3 OCH3 40COOH ,COOH ,,COOH 0 0 0 208. 209. 210.
H
3 C F
H
3 C /\ /\/ OCOOH ,COOH h COOH / O / O \O/ 0 140 0 211. OCH 3 212. OCH, 213. OCH 3
H
3 C
OCH
3 0h COOH JCOOH COO 2 0 0 O0H 214. OCR 3 215. OCR 3 216. OCR 3 WO 99/06397 PCTIUS98/15479 -277 Table 2A cont. EtO EtO F ,COOH \ *,COOH COOH 0 R-) R
OCH
3 217. 218. 219. EtO F EtO F EtO F .,COOH ,.COOH R C 220. 221. 222. EtO EtO F h0 EO OOCOOH /
OCH
3 223. 224. 225. OCO \ /\ \h ,COOH .COOH ,COOH A-t R- 0 R \. 2 O 228. 226. 227.
WO 99/06397 PCT/US98/I 5479 -278 Table 2A cont. 0 0 0 0 0 ,C00H ,,,OOH 0 Ft' 0 0 229. 230. C 231. OCH 3 HC OCH 3
H
3 C OCH 3
H
3 C OCH 3 HC OH oo h . ~COOH ,PO .COOH .OHFt 233. 234. 232.
H
3 C OCH 3
H
3 C OCH 3 HC OCH 3 .COOH eCOOH ,.COOH WlN R-f .0f 235. 236. 237.
H
3 C OCH 3 0,0 0,0 ,,CO0H *.COOH ,COOH 238. OCH 3 239. 240.
WO 99/06397 PCT[US98/1 5479 -279 Table 2A cont. 00%0 ,0 oo COOH ,QOOH OCOOH R N0 R- 0 241. 242. 243. 0 0
H
3 C .. COOH .. COOH k\ OOA 244. 245. 00H 3 246.
H
3
FH
3 C F H 3 C F I* A.COOH eCOOH 0,COOH..OHCH ft Fe-N -F R.A '4/0 /0 247. 248. 29 HC FH 3 C -H 3 -F
H
3 FCkF F F OOC0H F .. COOH0 ,COOH 0-rN 0 R-N 0 250. 251.25. O 3 WO 99/06397 PCT/US98/15479 -280 Table 2A cont. F% F F ,PCOOH OO0H *,COOH 0 '0 'o0 253. 254. 255. F F F ,COOH 4,C0OH .,COOH 256. 257. 258. F 1 C00H .C0H COH \ o 259. OCH3 260. 261, 262. 263. 264. F ,,,COOH J COOH \ A CO 265. 266. 0CH~3 267.
WO 99/06397 PCTJUS98/1 5479 -281 Table 2A cont. F ,COOH .COOH ,COOH 0 0 0 l 268. 269. 270. *COOH ,COOH -ICOOH 0 271. 272. 273.
OCH
3 ,COOH *.COOH CH ~,OI COO ..COOH 00 277. 278. 279.
WO 99/06397 PCT/US98/15479 -282 Table 2A cont. ,OOOH 00)0 Oo0 0 _/0 280. OCH 3 281. 282. .COOH I OCOH ,.COOH 283. 284. 285. C M COOH .,COOH 286. 287. OCH 3 288. 1 COOH OCOOH JCOOH 289. 290. 291. 0/
OCH
3 292. 293. 294.
WO 99/06397 PCT/US98/15479 -283 Table 2A cont. *COOH eCOOH .COOH R- R 295. 296. 297. O~COOH .COOH IOCOOH 298.2930 0 R -N JC N R. RN 300 30. 299 30. 30. ,*OO COOH COOH WN 0'0 N 0/ / 304. OC330. 306.
WO 99/06397 PCTIUS98/I 5479 -284. Table 2A cont. 4PCOOH ',COOH.CO 0 R '309. 307. 308. OCH 3 39 OO0H C0 CO 310. 311. 312. 1 .CO 0' / CO .COOH 4.COOH .COOH R- I rO - i OCH 3 313. 314. 315. .COOH .COOH CO R- R- R 316.'1 1301 317. 318. ,eCOOHCO #rOH R-R- 0O R 319. 320. 321.
WO 99/06397 PCT/US98/1 5479 -285 Table 2A cant. ,CO .COOH ,COOH 0 0. Ao 00 322. OCH 3 323. 324. COO ,c00H ~,COOH 325. 326. 37 I, COOH *COOH 328. 329. OCH 3 33. OCH 3 eCOOH .COOH CH 331. 332. 333. .,COOH .~COOH ,,COOH R- R- 0 /0 334. 335. 336.
WO 99/06397 PCT/US98/1 5479 -286 Table 2A cont. .4 1 eCO COOH .COOH 0 0~ 337. ~ 338. 39 .. COOH bCO 4 COOH ICOOH ,COO 00 0- 0 34. 347. 348. C, C00H 0 ,OH00COH 00 00 0 0 4 '0 34. OC 3 35. 35.
WO 99/06397 PCTIUS98/15479 -287 Table 2A cont.
H
3 C EtO 0 0 -- - 0 \ / 0 , C O CHa H
H
0 HH / O OCH 3
OCH
3 352. HC F EtO O k\ 00 \ /h 1N \ / 0 4-CH 3 \ NH H 0 0 / 356. 357. 355. OCH 3
H
3 C F EtO NH NH h NH 0 O R- - R-R
OCH
3
OCH
3 358. 359. 360. 0 0 H 3 C H - 0 N. \ 00 \/ 00* \ NH \ / O CH, H HN H 0 H 0 0 3 O6 I 361. OCH 3 362. 363.
WO 99/06397 PCT/US98/15479 -288 Table 2A cont.
H
3 C H 3 C HCS O-\/ O CH 3 .CH N H > O 0 364. 365. 366.
H
3 C H 3 C H 3 C -- \ N \ / 0 p-CHa N /NH F 367. 368. 369.
H
3 C H 3 C H 3 C \ / O /O 370. 371. 372.
H
3 C - 0O LNH \ / O OCH 3 H \/ F / O 373. 374. 375.
WO 99/06397 PCT/US98/15479 -289 Table 2A cont. - oS k -h OS0 \ 0 C4- \C/ 0 S-CH 3 \/ OCH3 3 376. 377. 378. - 09~ \/,9 NN \~~~\ h 0'..\/ jNH CH O S-CH 3 NH H HF O / F 379. 380. 381. \ / N \ / N NH \/ N LNN NHh 0 0 R_
R
382. 383. 384. \ / NH NH NH 0 F 3.63 385. 386. 387.
WO 99/06397 PCT/US98/15479 -290 Table 2A cont. 3 9 ,NH NCH CH N.' H 0 N N OH 00
H
0 0 0~ 388. 389. 390. FFa F 3 *NH1\h CONH .. COOH ,COOH 00 391. 392. 39.
F
3
F
3
F
3 .COOH .COOH ,COOH 0 0 p-N p-0 N 0 394. 395. 396.
F
3
F
3
-F
3
CF
2 p-NOO .COOH ,COOH0 /9'/00 p 397. 398. OCH 3 399.
WO 99/06397 PCT/US98/1 5479 -291 Table 2A cont.
F
2
CF
3
'F
2
CF
3
F
2
CF
3
~
1 C.. COOH __.COOH 0/0 ,0 400. 401. 402.
F
2
CF
3
F
2
CF
3 kF 2
CF
3 ... COOH A .COOH .COOH 0 0 403. 404. 405.
F
2
CF
3 0 h **C00H .COOH 'o 00 40.OCH 3 407. 408. ,,COOOH ,OC0OH R,0O ' 0 / 411. 409. 410. .,CO0H ,POOH .COOH 412. 413. 414.
WO 99/06397 PCTIUS98/15479 -292 Table 2A cont. 415. 41. 4. R--N CO\ H/C H 2. 42.423. 0 0> 0> R- %R 418. 41. 42. j COOH ~CO COOH0 RN 0) ,COOH OH OOR .o R -N C O \OHO 427 2N 429. /0 42. 42. 429.
WO 99/06397 PCT/US98/1 5479 -293 Table 2A cont. .. COOH .COO ~,COOH 0 A 0 430. 431. 42 '~0 ,.COOH J .COOH- .. O 0 f0 RN0 R- Rw 433. 434. 45 9 *COOH 14 4C0OHOH 436. 437. 438. .~COOH k C0HCOOH 0 0 0/ Rr ~ 0 439. 440. 441. 0 eCOOH ~COOH .COOH R- 00 R' *0 442. 443. 444.
WO 99/06397 PCT/US98/15479 -294 Table 2A cont. , C O O H H ,.C 0454476 448. 4496.0 IJ .COOH *COOH \ N 448. 4475. 451. 452. 453. COOH ,COOH O COOH IRO WN I 0 50 44. 455. 45.
WO 99/06397 PCT/US98/15479 -295 Table 2A cont. or .,COOH J COOH .COOH 0 0 0) 457. 458. 459. 0 COCOOH .COOH COOH 0 0) 0 0 460. 461. 462. 0 0 0 0 463. 464. 465.
WO 99/06397 PCTIUS98/15479 -296 Table 2B R R R 0 0 0 2. 3. 0 4 5. 6. 8. 9. 10. 11. 12. 0 0 0 13. 14. 15.
H
3 C
H
3 C 0 0 16. 17. 18. ,,' 0 0 ,,S' 19. 20. 21.
WO 99/06397 PCTIUS98/15479 -297 Table 2B cont. R R R H C O1, 0 H CO 60 0 do 60 22. 23. 24. HCH3CO,,,,N F3C ,-'N
H
3 C0,,-,,,czN 0' 0o' 25. 26. 27. F3 FH2S, FH2c,--N,^ 6o6~ 00( 0 28. 29. 30. FHCFH2CI F2HN
F
2 0 0 S F2O0 0 F 2 6 0 31. 32. 33. F2H FaC N F
F
2 6 2 0
F
2 0 0 F 2 6 34. 35. 36. 37. 38. 39. 0 0 40. 41. 42.
WO 99/06397 PCT/US98/15479 -298 Table 2B cont. R R R F3 OW 0 0 0,0 0 0 43. 44. 45. F3COL_ aOH3_ ae 0F0 6O o 46. 47. 48. 0N 0~ 49. 50. 51 52. 53. 54. 0F00 F 55. 56. 57. c0 58. ci59. 60.
WO 99/06397 PCT/US98/15479 -299 Table 2B cont. R R R O H3C& 61.
OCH
3 63. 62. cc Nh 64. 65. 66. ~jNN 67. 68. 69. YH 3 ' YH 70. 71. 72. N0 N 73. 74. 75. 7N O N N78 76. 77. 78.
WO 99/06397 PCTIUS98/15479 -300 Table 2B cont. R R R 0 0 0 6 79. 80. 81. 0 F F do 11 82. 83. 84. FF 00 0 000 85. 86. 87. Y 0 0 6 00 88. 89. 90. F F3 91. 92. 93.
F
3 C-. FF l -. " F0 F F 6 94. 95. 96. F F H3COI 0
F
3 u F0 . O
F
3 97. 98. 99.
WO 99/06397 PCTIUS98/15479 -301 Table 2B cont. R R R
H
3 C0~H 3 COc(Th H 3 C0 *00 0 0 .4 100. 101. 102. H3 ~H3C0Th)H3 F3C F 00 0 FF0 103. 104. 105.
H
3 C> H3COF FC F H 3 C> 000"') F3COO $ 106. 107. 108. 0 0 0 0 0 109. 110. F3C 000 00 112. 113. 114. FPa Fa O O 115. 116. 117.
WO 99/06397 PCT/US98/15479 -302 Table 2B cont. R R R F3C 118. 0Qc 119. 120. y 0 121. 122. 123. 124. 125. 126. y
K
c A 127. 128. 129. OH 1 130. 131. 132.
WO 99/06397 PCT/US98/15479 -303 Table 2B cont. R R R H OH 133. 134. 135. qF3 qF 3 N ~ O Nr O , Nr 136. 137. 138. CF3 CF3 CF 139. 140. 141. ?F3 A~yoy 144. 142. 143. yK 145.146. 147.
WO 99/06397 PCT/US98/15479 -304 Table 2B cont. R R R 148. 149. 150. y K C CI C N FVQ F 151. 152. 153. 154. 155. 156. yCK 157. 158. 159. 160. 161. 162.
WO 99/06397 PCT/US98/15479 -305 Table 2B cont. R R R 163. 164. 165. FN y 166. 167. 168. N O N NC 169. 170. 171. NCN .N0 172. 173. y K.7 0 Y. N 00 175. 176. 177.
WO 99/06397 PCT/US98/15479 -306 Table 2B cont. R R R F F' 178. 179. 180. y y F - 0 N0C 181. 182. 183. 184. 185. 186. CF 0F 187. 188. 189. NC,,aC .N 0 190. 191. F 192.
WO 99/06397 PCT/US98/I 5479 -307 Table 2B cont. R R R K y 193. 194. 195. 196. 197. 198. 199. 200. 201. K y NAI A 202. 203. 204. 5 N 2 205. 206. 207.
WO 99/06397 PCT/US98/15479 -308 Table 2B cont. R R R Nl Y 'N 0N0N0 208. 209. 210. y N % .J~ N 0 rN9 ~ 211. 212. 213. >1N 214. 215. 216. ucc-r- uc Ny~yIyNK K N0 &J(N 0N 217. 218. 219. 220. 221. 222.
WO 99/06397 PCT/US98/15479 -309 Table 2B cont. R R R 223. 224. 225. yK y 226. 227. 228. uN Nr 229. 230. 231. 232. 233. 234. 5 2 6 N 235. 236. 237.
WO 99/06397 PCT/US98/15479 -310 Table 2B cont. R R R 238. 239. 240. 241. 242. 243. V ' 244. 245. 246. 247. 248. 249. 250. 252. 252.
WO 99/06397 PCT/US98/15479 -311 Table 2B cont. R R R 253. 254. 255. 256. 257. 258. y CNN 259. 260. 261. 262. 263. 264. 265. 266. 267.
WO 99/06397 PCT/US98/15479 -312 Table 2B cont. R R R ,y K VA 268. 269. 270. NeK- y , .N IN 271. 272. 273. 274. 275. 276. 277. 278. 279. y8.2 y CI NNl -' 280. 281. 282.
WO 99/06397 PCT/US98/15479 -313 Table 2B cont. R R R ,N 283. 284. 285. NNy 286. 287. 288. y N~ 289. 290. 291. 292. 293. 294. N y N YN K' N 295. 296. 297.
WO 99/06397 PCTIUS98/15479 -314 Table 2B cont. R R R 7XN vy 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312.
WO 99/06397 PCT/US98/15479 -315 Table 2B cont. R R R 313. 314. 315. 316. 317. 318. T 319. 320. 321. 322. 323. 324. vN 325.326. 327.
WO 99/06397 PCT/US98/15479 -316 Table 2B cont. R R R 328. 329. 330. 331. 332. 333. COOEtCOt 334 335. 336. AiC- O ~ OOBt
NO
2 COOEt 337. 338. 339. N0 2
NO
2 NO 2 340. 341. 342.
WO 99/06397 PCT/US98/15479 -317 Table 2B cont. R R R O CN CNCN 343. 344. 345. 0 2 02 346. 347. 348. 02w , 02m 031 349. 350. e c 0 0 0 352. 353. 354. A 355. 356. 357.
WO 99/06397 PCT/US98/15479 -318 Table 2B cont. R R R 358. 359. 360. 361. 362. 363. 364. 365. 366. FK 367. 368. 369. F Me N MeO Mo F 00 0 370. 371. 372.
WO 99/06397 PCT/US98/15479 -319 Table 2B cont. R R R 373. 374. 375. M Mel mo 0 0 0 376. 377. 378. o 0 0 379. 380. 381. 1meo MeO 00 0 382. 383. 384. Meo uso A A 385. 386. 387. 0 3 0 388. 389. 390.
WO 99/06397 PCT/US98/15479 -320 Table 2B cont. R R R 391. 392. 393. 394. 395. 0 396. cici ci 0 397- 398. 399. C cc 400. 401. 402. F) 0 F 403. 404. 0 405. F F F 0 0 0 406. 407. 408.
WO 99/06397 PCTIUS98/15479 -321 Table 2B cont. R R R F Fx 409. 410. 411. 0 412. 413. 414. 0 00 415. 416. 417. o 0 0 418. 419. 420. A4 MOO 0 42.O OMO 0 421. 422. 423. MeOj MeOM4 OMS 0 OMe 0 OMO 0 424. 425. 426.
WO 99/06397 PCT/US98/15479 -322 Table 2B cont. R R R -10 MOMeoo'l MeO) 41 OMO 0 OMO OMe 0 427. 428. 429. MOMeo MeOO 0MG 0 OMe 0 CM. 0 430. 431. 432. Mo MeO MO OM. 0 OMO 0 CM. 0 433. 434. 435. OMeeO q Me CM. ~e M. 0 436. 437. 438. MeOMN 439. 440. 441. Me H 0 B 442. 443. 444.
WO 99/06397 PCT/US98/15479 -323 Table 2B cont. R R R *' ry Ky 445. 446. 447. B B B 448. 449- 450. nF 451. 452. 453. y K 454- 455. 456. F 0 457. 458. 459.
WO 99/06397 PCTIUS98/15479 -324 Table 2B cont. R R R y B B B VO 460. 461. 462. BB B 463. 464. 465. B): F F C 466. 467. 468. 469. 470. 47 4C7O 47.0 7CIO 472. 473. 474.
WO 99/06397 PCTIUS98/15479 -325 Table 2B cont. R R R Br Br Br 475. 476. 477. Br Br Br 478. 49 8 F 481. 482. 483. Fy FA F 484. 485. 486. 487. 488. 489.
WO 99/06397 PCT/US98/15479 -326 Table 2B cont. R R R F oO F' 0F 0 0 490. 491. 492. 0 Jj494. 495. 493. 496. 497. 498. 499. 500. 501. 0 50 0 502. 503. 504. 0 50 50 505. 506. 507.
WO 99/06397 PCT/US98/15479 -327 Table 2B cont. R R R y rKr 508. 509. 510. 511. 512. 513. y 514. 515, 516. Kyn r r0 r 517. 518. 519. 520. 521. 522.
WO 99/06397 PCT/US98/15479 -328 Table 2B cont. R R R H HH 0< .0 0 523. 524. 525. 526. 527. 528. 529. 530. 531. H H H 0 0 532. 533. 534. 535. 536. 537.
WO 99/06397 PCT/US98/15479 -329 Table 2B cont. R R R H H NO, 538. 539. 540. H ~ HH 541. 542. 543. HH & 0 544. 545. 546. r 0Q 547. 548. 549. 550. 551. 552.
WO 99/06397 PCT/US98/15479 -330 Table 2B cont. R R R y K-r 553. 554. 555. 556. 557 558. 559. 560. 561. 562. 563. 564. Jy~A A 565. 566. 567.
WO 99/06397 PCT/US98/15479 -331 Table 2B cont. R R R c cl ct 568. 569. 570. c Nc ,c r 0 0 571. 572. 573. 574. 575. 576. 577. 578. 579. 580. 581. 582.
WO 99/06397 PCT/US98/15479 -332 Table 2B cont. R R R 583. 584. 585. 586. 587. 588. F Fy 589. 590. 591. 592. 593. 594. 595. 596. 597.
WO 99/06397 PCT/US98/15479 -333 Table 2B cont. R R R F F
F
598. 599. 600. F y N F N 601. 602. 603. F N F 604. 605. 606. 607. 608. 609. 610. 611. 612.
WO 99/06397 PCT/US98/15479 -334 Table 2B cont. R R R
M
4 O meo 613. 614. 615. M.O MeO MeO 617. 618. 616. M.O 619. 620. 621. 622. 623. 624. V -Y, N l 2 4 00 0 0 625. 626. 627.
WO 99/06397 PCTIUS98/15479 -335 Table 2B cont. R R R H H N N F3 N O 0 / 00 628. 629. 630. 631. 632. 5 io 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. 15 WO 99/06397 PCT/US98/I 5479 -336 Table 3A F MOMO
F
6CO0H IeCOOH _U~COOH 1. 02. 3. 0
CH
3 CH 3 OCH 3 H3,OH ,COOH b.COOH R .COOH 0 0 7. 8. R- j~ 0 R-N COOH #COOH t R-N 0. 8.1)1. 0) 12.
WO 99/06397 PCT/US98/1 5479 -337 Table 3A cont. -N
H
3 0 I .PCOOH *.OI .COOH 13. 14. 0)15.
CH
3
H
3 C
H
3 C / H *,.COOH w CH 3 0I 16. 17. 18. & F 0 0 >0> 19. 20.21 WO 99/06397 PCT/US98/15479 -338 Table 3B R R R 1 2. 3. 4. 05. 06. 0 0. 0 7- 8. 9. 00 00o 10 11. 12. 0 0 0 13. 14. 15.
H
3 CQ H3C 0 0 0 16. 17. 18. 1 20 19. 20. 21.
WO 99/06397 PCTIUS98/15479 -339 Table 3B cont. R R R HC H0C1 OC S 60 0 00 22. 23. 24. HCH3C N,_ J FC 0,0 25. 26. 27. Fa o FH2C SN FH2C 28. 29. 30.
FH
2 C~.. FH 2 C F 2 HC. N
F
2 0F 2 60 F 2 6 0 31. 32. 33.
FF
3 2HC FF3
F
2 60 35. 36. 37. 38. 39. 00 00 40. 41. 42.
WO 99/06397 PCT/US98/15479 -340 Table 3B cont. R R R F 3 , F C ~ ,F 3 C O ~0 0 43. 44. 45.
F
3 C 0 ",(H3 H3 oo o00 o 0 0 0 46. 47. 48. 49- 50. 51. 52. 53. 54. F 55. 56. 57. 58. 59. 60.
WO 99/06397 PCT/US98/15479 -341 Table 3B cont. R R R Oc b H3C 0 61. OCH 3 63. 62. P, I IkN 1 64. 65. 66. 67. 68. 69. 9H 3 YH3 O OyNy 000 70. 71. 72. 73. 74. 75. 6. .0 0 76. 77. 78.
WO 99/06397 PCTIUS98/15479 -342 Table 3B cont. R R R 00 0 0 79. 80. 81. F Fa O d'f o~% FF 6- 6 l 82. 83. 84. FY 85. 86. 87. Y Y Y 0 0 6 0O 88. 89. 90. Fa F3 00 F F 0 00 91. 92. 93. FC-F, FC 00 6 *b F F 6 b 94. 95. 96. F F H 3 CO F3C-O11 , F3x O
O
7 0 .o 00 97. 98. 99.
WO 99/06397 PCT/US98/15479 -343 Table 3B cont. R R R
H
3 C0>**
H
3 Cc<>,*
H
3 C> 100. 101. 102.
F
3 F3N., -p 0 0F 0 F FF0o 103. 104. 105. - FCC0 O3CF* 0 0 106. 107. 108. 109. 110. 111 FC 0 O 112.' 113. 114. Fa F o 0 0 115. 116. 117.
WO 99/06397 PCTIUS98/15479 -344 Table 3B cont. R R R F3Y c.
118. 119. 0. 121. 122. 123. 124. 125. 126. y K 127. 128. 129. OH 1 .
1 130. 131. 132.
WO 99/06397 PCT/US98/15479 -345 Table 3B cont. R R R H" H H 133. 134. 135. OH VF3 136. 137. 138.
,F
3 3F CFO CF3 CF a OV r O N~r O CNr/ 139. 140. 141.
F
3 142. 143. 144. y 1 145. 146. 147.
WO 99/06397 PCT/US98/15479 -346 Table 3B cont. R R R I*Y - "IC rN Cl 148. 149. 150. c r N Cl Cl NCS y K 151. 152. 153. p0 154. 155. 156. y
K
Ci N ) 157. 158. 159. 160. 161. 162.
WO 99/06397 PCTIUS98/15479 -347 Table 3B cont. R R R 163. 164. 165. NC yN,.r NCyy Nr 166. 167 168. yK N O C N C NN 169. 170. 171. NC 4 172. 173. 174. y K.7 175. 176. 177.
WO 99/06397 PCT/US98/15479 -348 Table 3B cont. R R R A _JyYAYy 7 178. 179. 180. y K-l 181. 182. 183. 184. 185. 186. 187. 188. 189. NCy. 190. 191. 192.
WO 99/06397 PCT/US98/15479 -349 Table 3B cont. R R R _A K y 193. 194. 195. NNN N 196. 19.198. 199. 200. 201. y 202. l~N 203. 204. 2 26 27 205. 206. 207.
WO 99/06397 PCT/US98/15479 -350 Table 3B cont. R R R ~N 0 N 0 N 208. 209. 210. N ONN 211. 212. 213. Y N 0N0 214. 215. 216. K y 217. 218. 219. 220. 221. 222.
WO 99/06397 PCT/US98/15479 -351 Table 3B cont. R R R N N N % 223. 224. 225. yr y utNN N N 226. 227. 228. 1/ N r/NNr N N~r 229. 230. 231. 232. 233. 234. 235. 236. 237.
WO 99/06397 PCT/US98/15479 -352 Table 3B cont. R R R 238. 239. 240. 241. 242. 243. 244. 245. 246. rIi "y r N,,0A-) 0N,_0) 0 247. 248. 249. 0 250. 252. 252.
WO 99/06397 PCTIUS98/15479 -353 Table 3B cont. R R R N 253. 254. 255. N NN 256. 257. 258. y N -N -N 259. 260. 261. N FN 262. 263. 264. FXN N F N 265. 266. 267.
WO 99/06397 PCT/US98/15479 -354 Table 3B cont. R R R NN F 268. 269. 270. K y NN 271. 272. 273. NN N 274. 275. 276. 277. 278. 279. 20 2 YN~Z Ny N, 280. 281. 282.
WO 99/06397 PCTIUS98/15479 -355 Table 3B cont. R R R NI N 283. 284. 285. NN 286. 287. 288. y 289. 290. 291. 292. 293. 294. 9 2y 295. 296. 297.
WO 99/06397 PCT/US98/15479 -356 Table 3B cont. R R R 298. 299. 300. 301. 302. 303. 304. 305. 306. NL~ 307. 308. 309. 310. 311. 312.
WO 99/06397 PCT/US98/15479 -357 Table 3B cont. R R R 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 3 .2 WO 99/06397 PCT/US98/15479 -358 Table 3B cont. R R R
K
1 N 328. 329. 330. 331. 332. 333. CXOOEt COOPt 334. 335 336. Al COt C COOEt N0 2 COEt 337. 338. 339. N0 2 3.NO 2 NO 2 340. 341. 342.
WO 99/06397 PCT/US98/15479 -359 Table 3B cont. R R R >CN ( CN 0 ICN 343. 344. 345. 02 02 346. 347. 348. 02 349. 350. 351. QO O 0 0 352. 353. 354. 5 3 30 355. 356. 357.
WO 99/06397 PCT/US98/15479 -360 Table 3B cont. R R R y 358. 359. 360. 361. 362. 363. 364. 365. 366. y K-, F 367. 368. 369. MeO MO FMe N MeO (t 0.0 0 370. 371. 372.
WO 99/06397 PCT/US98/15479 -361 Table 3B cont. R R R 0 me 373. 374. 0375. M oo m e-wo~ 0 0 0 376. 377. 378. 379. 380. 381. MeO MeO MeO 0 0 0 382. 383. 384. 0o 385. 386. 387. 0 3 0 388. 389. 390.
WO 99/06397 PCT/US98/15479 -362 Table 3B cont. R R R 391. 392. 393. cl Ai IA~rC 396. II~~rl- CI)C 1 0 0 0l O 0 397. 398. 399. c c c 0 00 400. 401. 402. F F F 403. 404. 405. FC F F.F 0 A 0 406. 407. 408.
WO 99/06397 PCT/US98/15479 -363 Table 3B cont. R R R F)WN- A
A
00 409. 410. 411. 412.14. 412. 413. 414 yA 0 0 0 415. 416. 417. o 0 0 418. 419. 420. MeO 421. 422. 423. MeO MeO A OMe 0 OMe 0 OM. 0 424. 425. 426.
WO 99/06397 PCT/US98/15479 -364 Table 3B cont. R R R MeO MerI MMOOOX%: M0 -j OMe 0 OMe OM. 0 427. 428. 429. MeO Me MOo OM. 0 M. 0 MS 0 OMe 0 OMeO O 430. 431. 432. MeO Me q Me CMO 0 Oo 0 S 0 433. 434. 435. MeO MOO MOO CM.e 0~ 436. 437. MeO Mee 439. 440. 441. MeH N / 8 Br 442. 443. 444.
WO 99/06397 PCT/US98/15479 -365 Table 3B cont. R R R y Kr BBkl fr BF"a r 445. 446. 447. B- B~ r Bk, Kr 448. 449. 450. F F 451. 452. 453. yyN NOV~t 454. 455. 456. 4F 4F 459 457- 458. 459.
WO 99/06397 PCT/US98/15479 -366 Table 3B cont. R R R -, ry B BB 460. 461. 462. B B 8 2 B 463. 464. 465. B F F4 466. 467. 468. s~clo 1 0 a c F F 469. 470. 471. 472. F 473. F47 472. 473. 474.
WO 99/06397 PCT/US98/15479 -367 Table 3B cont. R R R B Br t r Br 475. 476. 477. SBr Br 478. 479. 480. Br Br C$c N 481. 482. 483. FF F 484. 485. 486. F~ F>F Izt )r 487. 488. 489.
WO 99/06397 PCTIUS98/15479 -368 Table 3B cont. R R R FVO F&00 0 490. 491. 492. A 0 0 494. 495. 493. 496. 497. 498. 499. 500. 501. 502. 503. 504. 505. 506. 507.
WO 99/06397 PCT/US98/15479 -369 Table 3B cont. R R R y K 508. 509. 510. 511. 512. 513. r-- rY rY 514. 515, 516. ~rY ~ NrYA 517. 518. 519. 520. 521. 522.
WO 99/06397 PCT/US98/15479 -370 Table 3B cont. R R R - 0 e 0 523. 524. 525. 526. 527. 528. H I~H 529. 530. 531. HHH 0 .- 0 0 532. 533. 534. 536. 537.
WO 99/06397 PCT/US98/15479 -371 Table 3B cont. R R R S H H N~r.y 538. 539. 540. H HH 0 0 0 541. 542. 543. rH H .4 0 544. 545. 546. H(&NH 0H 547. 548. 549. 550. 551. 552.
WO 99/06397 PCT/US98/15479 -372 Table 3B cont. R R R y
KI
553. 554. 555. 556. 557. 558. 559- 560. 561. 562. 563. 564. 565. 566. 567.
WO 99/06397 PCT/US98/15479 -373 Table 3B cont. R R R c cl c~ a r 569. 570. 571. 572. 573. 574. 575. 576. 577. 578. 579. 580. 581. 582.
WO 99/06397 PCT/US98/15479 -374 Table 3B cont. R R R 583. 584. 585. 586. 587. 588. 589. 590. 591. 592. 593. 594. 595. 5 V1596.
WO 99/06397 PCT/US98/15479 -375 Table 3B cont. R R R F N F F> N 598. 599. 600. F N4 F N0 601. 602. 603. FF 604. 605. F 606. FV F. N F N 607. 608. 609. 0V 610. 611. 612.
WO 99/06397 PCT/US98/15479 -376 Table 3B cont. R R R F M0 0e 613. 614. 615. MO 0mewMeOM 616. 617. 618. 619. 620. 621. 622. 623. 624. 0 O 625. 626. 627.
WO 99/06397 PCTIUS98/15479 -377 Table 3B cont. R R R H H N- FCM,,N -0 - 0 0 0 628. 629. 630. 631. 632. 5 Example 340 trans, trans-4- (1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(N-(3-methylbut- 1 -yl) N-phenyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 10 was prepared. 1 H NMR (300 MHz, CD 3 0D) s 0.85 (d, J=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (m, 1H), 3.43-3.85 (m, 9H), 3.88s (3), 5.95 (s, 2H), 6.80 (d, J=7 Hz, 1H), 6.86 (dd, J=9 Hz, 1H), 6.89-7.00 (m, 2H), 6.97 (d, J=1 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.40-7.47 (m, 3H). MS (C.I.) m/e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28). 15 WO 99/06397 PCT/US98/15479 -378 Example 341 trans, trans-4-(l.3-Benzodioxol-5-yl)-2-.(4-methoxyhenyl-1-(N butyl-N-(4-methylohenylaminocarbonylmethvl-pyrrolidine-3 carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 1.47 (m, 4H), 2.37 (s, 3H), 2.83 (q, J=7 Hz, 2H), 3.06-3.25 (m, 2H), 3.40 3.50 (m, 1H), 3.51-3.63 (m, 3H), 3.80 (s, 3H), 3.87 (d, J=9 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=8 Hz, 1H), 6.80-6.86 (m, 3H), 6.89 (d, J=8 Hz, 2H), 10 7.04 (d, J=2 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.19 (d, d=8 Hz, 2H). MS (DCI) m/e 545 (M+H)+. Analysis calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03. Example 342 is trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-propoxyphenyl-1
-(N.N
di(n-butylbamino)carbonlmethl)-yrrolidine-3-carboxYlic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3 ) 8 7.30 (2H, d, J=9), 7.03 (1H, d, J=2), 6.83 (3H, m), 6.72 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 20 3.88 (2H, t, J=7), 3.73 (1H, d, J=12), 3.58 (1H, m), 3.53-3.20 (4H, m), 3.10-2.90 (4H, m), 2.72 (1H, d, J=15), 1.79 (2H, q, J=8), 1.50-1.05 (8H, m), 1.02 (3H, t, J=7), 0.87 (3H, t, J=7), 0.80 (3H, t, J=7). MS (DCI/NH3) m/e 539 (M+H)+. Anal calcd for C31H42N206 - 0.5H20: C, 67.98; H ,7.91; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03. 25 Example 343 trans, trans-4-(1.3-Benzodioxol-5-yi)-2-(4-propylphenl)-1 -(NN-di(n butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 30 was prepared. 1 H (300MHz, CDC13 ) 8 7.31(2H, d, J=9), 7.13 (2H, d, J=9), 7.03 (1H, d, J=2), 6.84 (1H, dd, J=6, 2), 6.73 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 3.76 (1H, d, J=10), 3.60 (1H, m), 3.55-3.20 (4H, m), 3.13-2.88 (4H, m), 2.75 (1H, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q, J=8), 1.50-1.00 (8H, m), 0.92 (3H, t, J=7), 0.85 (3H, t, J=7), 0.78 (3H, t, 35 J=7). MS (DCI/NH3) m/e 523 (MH+). Anal calcd for C31 H42N2O5-0.25 H20 : C, 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.
WO 99/06397 PCT/US98/15479 -379 Example 344 trans-trans-2-(4-Metho xyphenyl)-4-(1.3-benzodio xol-5-yl)- 1-3-(N propyl-N-n-pentanesuIfonylamino)propyllpyrrolidine-3-carboxylic acid 5 Using the procedures described in Example 316, the title compound was prepared. 1 H NMR (300MHz, CDCl3) 5 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.3-1.4 (m, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (m, 4H), 2.05-2.15 (m, 1H), 2.43-2.56 (m, 1H), 2.72-3.1 (m, 7H), 3.27 3.4 (m, 2H), 3.5-3.6 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 10 1H), 6.8-6.9 (m, 1H), 6. 85 (d, J= 9Hz, 2H), 7.02 (6, J=2Hz, 1H), 7.80 (d, J=9Hz, 2H). Example 345 trans, trans-4-(1.2-Dihydrobenzofuran-5-yI)-2-(4-ethylphenyl)-1 15 (N.N-di(n-butyilaminocarbonylimethyli-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 ) 8 7.40 (3H, m), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 3), 6.72 (1H, d, J=9), 5.28 (1H, d, J=12), 4.55 (2H, t, J=9), 4.15 (1H, d, J=18), 4.03 (2H, m), 3.75 (2H, m), 3.40 (2H, m), 3.20 20 (2H, t, J=9), 3.15 (1H, m), 3.10-2.90 (2H, m), 2.63 (2H, q, J=9), 1.47 (2H, m), 1.31 (4H, m), 1.12 (3H, t, J=8), 1.10 (2H,m), 0.92 (3H, t, J=9), 0.80 (3H, t, J=9). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31 H42N204 1.0 TFA: C ,63.86 ; H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43. 25 Example 346 transtrans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(((N-(3 pentyl)-N-phenylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.93 (t, J=7.3 Hz, 3H), 0.94 30 (t, J=7.3 Hz, 3H), 1.33 (m, 4H), 2.72 (d, J=15.2 Hz, 1H), 2.81 (m, 1H), 3.11-3.23 (m, 2H), 3.45-3.57 (m, 2H), 3.79 (s, 3H), 3.83 (d, J=9.8 Hz, 1H), 4.54 (m, 1H), 5.92 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.83 (m, 3H), 6.98 (bs, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.07 (2), 7.37 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H33N206 . 0.35H20: C, 69.76; H, 6.71; N, 35 5.08. Found: C, 69.72; H, 6.66; N, 4.94.
WO 99/06397 PCT/US98/15479 -380 Example 347 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methxyphenyl)-1
-(((N
butyl)-N-(3-trifluoromethylphenyl)amino)carbonyl)methyl)pyrrolidine 3-carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=6.6 Hz, 3H), 1.17 1.45 (m, 4H), 2.65 (d, J=16.5 Hz, 1H), 2.72 (m, 1H), 3.10 (t, J=9.5 Hz, 1H), 3.21-3.27 (m, 1H), 3.40 (dd, J=4.1, 9.9 Hz, 1H), 3.54 (m, 1H), 3.61 3.74 (m, 3H), 3.77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m, 3H), 10 7.33 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.58 (t, J=7.8'Hz, 1H), 7.69 (d, J=7.5 Hz, 1H). MS (DCI) m/e 599 (M+H+). Anal calcd for C32H33F3N206: C, 64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57. Example 348 15 trans. trans-4-(1.3-Benzodioxol-5-yil-2-(4-methoxyvhenyl)-1-(N propyl-N-(4-morpholinilcarbonylI)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.78 (t, J=7 Hz, 3H), 1.43 (q, 20 J=7 Hz, 2H), 2.07-3.01 (m, 1H), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (m, 5H), 3.05 (3.70, J=m Hz, 11H), 3.76 (s, 3H), 5.88 (s, 2H), 6.67 (d, J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (m, 2H), 6.98 (d, J=2 Hz, 1H), 7.32 7.39 (m, 2H). MS m/e calc'd for (M+H) C29H39N307: (M+H) 540.2710,. Found (M+H) 540.2713. 25 Example 349 trans, trans-4-(1,3-Benzodioxol-5-yl)-2-(4-methoxyphenvi)-1-(cis 2.6-dimethylpiperidin-1 -vl)carbonylmethyI)-pyrrolidine-3-carboxylic acid 30 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 6 0.94 (d, J=7 Hz, 3H), 1.15d (7, 3H), 1.10-1.70 (m, 6H), 1.70-1.90 (m, 1H), 2.9. (d, J=13 Hz, 1H), 3.00-3.20 (m, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 (s, 3H), 3.80-4.00 (m, 1H), 4.10-4.65 (m, 2H), 5.95 (s, 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (m, 35 2H). MS m/e calc'd for (M+H)+ C28H35N206: (M+H) 495.2495. Found (M+H) 495.2493.
WO 99/06397 PCTIUS98/15479 -381 Examole 350 trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1.3-benzodioxol-5-y) 1-(2-(N-propyl-N-n-pentanesulfonylamino)ethyllpyrrolidine-3 5 carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 *C. 1 H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.28-1.36 (m, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 (t, J=7Hz, 2H), 2.20-2.32 (m, 1H), o 2.72-3.10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.48 (s, 3H), 3.52-3.59 (m, 1H), 3.68 (d, J=9Hz, 1H), 5.15 (s, 2H), 5.94 (s,2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=lHz, J=8Hz, 1H), 6.98-7.02 (m, 3H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 591 (M+H)+. 15 Example 351 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(((N-(2 butyl)-N-phenylamino)carbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.79-0.89 (m, 6H), 1.14-1.21 20 (m, 1H), 1.25-1.40 (m, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 (t, J=9.0 Hz, 1H), 3.05-3.13 (m, 2H), 3.37-3.49 (m, 2H), 3.70 (s, 3H), 3.80 (d, J=9.8 Hz, 1H), 4.53 (m, 1H), 5.83 (m, 2H), 6.65 (d, J=8.1 Hz, 1H), 6.72 ( 6.76, J=m Hz, 3H), 6.87 (m, 2H), 6.95 (d, J=1.7 Hz, 1H), 7.03 (m, 2H), 7.29 (m, 3H). MS (DCI) m/e 531 (M+H+). Anal calcd for C31 H34N206 ' 25 0.4H20: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03. Example 352 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(((N-(2 propyl)-N-phenylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid 30 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.99 (d, J=6.8 Hz, 6H), 2.71 (d, J=15.6 Hz, 1H), 2.84 (m, 1H), 3.13-3.18 (m, 2H), 3.45-3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, 1H), 4.80 (m, 1H), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.13 35 (m, 2H), 7.38 (m, 3H). MS (DCI) m/e 517 (M+H+). Anal calcd for WO 99/06397 PCT/US98/15479 -382 C30H32N206 - 0.4H20 - 0.08CH3CO2C2H5: C, 68.65; H, 6.28; N, 5.28. Found: C, 68.64; H, 6.35; N, 5.14. Example 353 5 trans. trans-4-(4-Propoxyphenvyl-2-(4-methoxvphenll-1 -(N.N-di(n butyllaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 ) 8 7.42 (2H, d, J=1OHz), 7.38 (2H, d, J=lOHz), 6.92 (2H, d, J=10Hz), 6.88 (2H, d, J=lHz), 5.13 (1H, bd, 10 J=12Hz), 4.02 (2H, m), 3.90 (2H, t, J=8Hz), 3.80 (3H, s), 3.71 (3H, m), 3.40 (2H, m), 3.19 (1H, m), 3.10-2.90 (2H, rn), 1.80 (2H, m), 1.48 (2H, m), 1.29 (4H, m), 1.13 (2H, m), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz). MS (DCI/NH3) m/e 525 (MH+). Anal calcd for C31H44N2O5- 1 TFA: C, 62.06 H 7.10; N, 4.39 . Found: C, 62.43; H, 7.28; 15 N, 4.39. Example 354 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenYl)-1 ((1.2.3.4-tetrahydroquinolin-1 -yl)carbonyllmethyl)pyrrolidifne-3 20 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 1.88 (quintet, J=6.5 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.87 (t, J=8.6 Hz, 1H), 3.14 (m, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1H), 3.53-3.70 (m, 3H), 3.72-3.78 (m, 1H), 3.77 (s, 3H), 25 3.86 (d, J=9.6 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.83 (m, 3H), 6.98 (d, J=1.1 Hz, 1H), 7.02-7.23 (m, 6H). MS (DCI) m/e 515 (M+H+). Anal calcd for C30H30N206 - 0.3H20 - 0.15 CH3CO2C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19. 30 Example 355 transit rans-2-(3.4-Dimethoxyphenyl)-4-(1.3-benzodioxol-5-yl)-l (N.N-di(n-butylaminocarbonylmethyl)-Oyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 64-65 *C. 1 H NMR 35 (CDCl3, 300MHz) 5 0.79 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H),1.07 (sextet, .1=7H7. 2H). 1.20-1.35 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, WO 99/06397 PCT/US98/15479 -383 J=13.5Hz, 1H), 2.94-3.17 (m, 4H), 3.22-3.42 (m, 1H), 3.40-3.48 (m, 3H), 3.58-3.65 (m, 1H), 3.82 (s, 3H), 3.85 (s, 4H),5.92 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.81 (d, J=8Hz, 1H), 6.86-6.96 (m, 3H), 7.07 (d, J=3Hz, 1H). MS (DCI/NH3) m/e 541 (M+H)+. 5 Example 356 trans. trans-2-(3.4-Dimethoxyphenyl)-4-(1.3-benzodioxol -5-yil-1-2 (N-propiy-N-n-pentanesulfonylaminolethylpyrrolidine-3-carboxylic o Using the procedures described in Example~1, the title compound was prepared and isolated as a white solid. m.p. 75-86 0C. 1 H NMR (CD30D, 300 MHz) 8 0.75 (t, J=7Hz, 3H), 0.82 (t, J=7Hz, 3H), 1.32-1.43 (m, 6H), 1.65-1.77 (m, 2H), 3.0-3.09 (m, 4H), 3.23-3.27 (m, 2H), 3.44 (t, J=6Hz, 1H), 3.47-3.56 (m, 2H), 3.78 (d, J=9Hz, 1H), 3.83-3.93 (m, 2H), 15 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J=13Hz, 1H), 5.97 (s, 2H), 6.82 (d, J=7Hz, 1H), 6.93 (d, J=7Hz, 1H), 7.06 (d, J=7Hz, 1H), 7.08 (d, J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, 1H), 7.27 (d, J=3Hz, 1H). MS (DCI/NH3) m/e 591 (M+H)+. 2o Example 357 transtrans-2-(3.4-Dimethoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -2 (N-propyl-N-r-hexanesulfonylamino)ethyll pyrrolidine-3-carboxylic Using the procedures described In Example 1, the title compound 25 was prepared and isolated as a white solid. m.p. 65-66 *C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.23-1.48 (m, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (m, 1H), 2.73-3.10 (m, 7H), 3.19-3.32 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.59 (m, 1H), 3.68 (d, J=9Hz, 1H),3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, 30 J=8Hz, 1H), 6.79-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, 1H). MS (DCI/NH3) m/e 605 (M+H)+.
WO 99/06397 PCT/US98/15479 -384 Example 358 trans, trans-2-(4-Methoxyphenl)- 4 -(1,3-benzodioxol-5-yi)- 1-2 (phthalimid )ethyll-pyrrolidine-3-aroxyligc acid The compound of Example 1C (250 mg), N-bromoethylphthalimide 5 (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitrile and heated for 2.5 hours at 95 *C. Toluene was added, and the mixture was washed with KHCO3 solution. The solution was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 10 mg of an intermediate ethyl ester which was hydrolyzed by the method of Example 1 D to give 130 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) S 3.12-3.26 (m, 2H), 3.60-3.75 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.55 (m, 1H), 4.69 (d, J=9Hz, 1H), 4.76 4.88 (m, 1H), 5.96 (s, 2H), 6.55 (d, J=8Hz, 1H), 6.60-6.70 (m, 3H), 6.79 15 (d, J=8Hz, 1H), 7.05-7.45 (m, 5H), 7.75 (d, J=7Hz, 1H). Example 359 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1 -(((N-(2 pentyl-N-1phenylamino) carbonvlfm ethylpvrrolidine-3-carboxylic acid 20 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.86-0.98 (m, 6H), 1.17-1.22 (m, 1H), 1.23-1.41 (m, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1H), 2.83 (m, 1H), 3.10-3.21 (m, 2H), 3.45-3.60 (m, 2H), 3.79 (s, 3H), 3.86 (m, 1H), 4.74 (m, 1H), 5.91 (m, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (m, 2H), 7.04 25 7.14 (m, 3H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N206 - 0.25 CH3CO2C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C, 70.03; H, 6.54; N, 4.78. Example 360 30 trans, trans-4-(1.3-Benzodioxoi-5yl2(4-ethoxyphenyl1(N butyl-N-(2-naphthyl)aminiocarbonyl methyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.83 (t, J=7 Hz, 3H), 1.23 35 1.39 (m, 4H), 1.40-1.55 (m, 3H), 2.60-2.72 (m, 2H), 3.00-3.80 (m, 5H), 3.66 (s, 3H), 5.87 (s, 2H), 6.39 (d, J=9 Hz, 2H), 6.74-6.85 (m, 3H), 7.17 WO 99/06397 PCTIUS98/15479 -385 (d, J=2 Hz, 1H), 7.40 (dd, J=8 Hz, 1H), 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1H), 7.90-8.00 (m, 2H). MS (DCI) m/e 581 (M+H)+. Analysis calcd for
C
35 H36N206 - 0.3 H20: C, 71.73; H, 6.29; N, 4.78. Found: C, 71.74; H, 6.26; N, 4.72. Example 361 trans.trans-2-( 4-Proooxyhenyl)-4-(1.3-benzodioxol-5-yl)-l-r2-(N propyl-N-n-pentanesulfonylaminolethyllpYrrolidine- 3 -carboxyic acid Using the procedures described in Example 66, the title compound o was prepared and isolated as a white solid. m.p. 53-54 *C. 1 H NMR (CDC13, 300MHz) S 0.79 (t, J=7Hz, 3H), 0.89 (t, J-7Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (m, 2H), 1.80 (sextet, 2H), 2.23-2.33 (m, 1H), 2.72-2.93 (m, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (m, 2H), 3.42 (d, J=9Hz, 1H), 3.54-3.62 5 (m, 1H), 3.67 (d, J=9Hz, 1H), 4.90 (t, J=7Hz, 2H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 2H), 7.02 (s, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 589 (M+H)+. Example 362 o trans.trans-4-(1.3-Benzodioxol-5-vil-2-(4-methoxyhenyl)-1 -((2 methylindolin-1 -yilcarbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 mixture of indole C2 diastereomers, 0.95 (m, 1.5 (CH3 )), 1.05 (d, 6.3H, 1.5 (CH3)), 2.62 (m, 5 1H), 3.01 (m, 2H), 3.14-3.25 (m, 1H), 3.37-3.52 (m, 1.5H), 3.56-3.80 (m, 2H), 3.65 (s, 1.5 (CH30)), 3.76 (s, 1.5 (CH30)), 3.93 (m, 0.5H), 4.05-4.13 (m, 0.5H,), 4.42 (m, 0.5H), 4.65-4.74 (m, 1H), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 0.5H), 6.75 (m, 0.5H), 6.85 (m, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.00-7.06 (m, 2H), 7.14 (t, J=7.7 Hz, 1H), 7.21 (t, J=6.6 Hz, 1H), 7.38 (m, 2H), 7.99 30 (m, 1H). MS (DCI) m/e 515 (M+H+). Anal calcd for C30H30N206 ' 0.35H20 -0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.
WO 99/06397 PCT/US98/15479 -386 Example 363 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(2 hydroxy-3-propylhex-1 -ylI)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CD30D) 8 1.06 (m, 6H), 1.26-1.60 (m, 9H), 3.16 (dd, J=10.9, 12.6 Hz, 1H), 3.18 (d, J=11 Hz, 1H), 3.44 (d, J=2.0 Hz, 1H), 3.61 (t, J=11 Hz, 1H), 3.73 (t, J=11.0 Hz, 1H), 3.85 (m, 1H), 3.96-4.17 (m, 2H), 4.02 (s, 1.5 (CH30 diastereomer)), 4.03 (s, 1.5 (CH30 diastereomer)), 6.15 (s, 2H), 7.01 (d, J=8.1 Hz, 0.5H), 7.00 (d, J=8.1 Hz, 10 0.5H), 7.10 (m, 1H), 7.23 (m, 3H), 7.77 (m, 2H). V5- (DCI.) m/e 484 (M+H+). Anal calcd for C28H37NO6 - 0.33 H3PO4: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60. Example 364 15 trans.trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1 -(((N-(4 heptyl)-N-(3.4-dimethoxybenzyl)amino)carbonilmethl)pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 81:1 mixture of rotamers, 0.61 20 (t, J=7.1 Hz, 1.5H), 0.72 (7.3, 1.5H), 0.76 (t, J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.5H), 1.05-1.60 (m, 8H), 2.84-3.10 (m, J=2.5, 3.18, t, 9.7 Hz, 0.5H), 3.41-3.52 (m, 2H), 3.47-3.69 (m, 2H), 3.66 (s, 1.5H), 3.73 (s, 1.5H), 3.77 (s, 1.5H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.86 (d, J=9.8 Hz, 0.5H), 4.19 (d, J=17.7 Hz, 0.5H), 4.29 (d, J=15.2 Hz, 0.5H), 4.40-4.49 (m, 0.5H), 4.47 (d, 25 J=15.3 Hz, 0.5H), 4.60 (d, J=17.6 Hz, 0.5H), 5.93 (m, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.5H), 6.52 (d, J=2.0 Hz, 0.5H), 6.74 (m, 2.5H), 6.80 (s, 1H), 6.83 6.88 (m, 1H), 6.92 (n, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (m, 1H), 7.36 (m, 1H). MS (DCI) m/e 647 (M+H+). Anal calcd for C37H46N208: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11. 30 Example 365 trans.trans-4-(1.3-Benzodioxol-5-yi)-2-(4-methoxyphenl-1 ((indolin-1 -yl)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 35 was prepared. 1 H NMR (300 MHz, CD30D) 82.97 (dd, J=8.1, 9.5 Hz, 1H), 3.10 (t, J=8.1 Hz, 2H), 3.16-3.22 (m, 2H), 3.51-3.68 (m, 3H), 3.73 (m, WO 99/06397 PCT/US98/15479 -387 3H), 3.83-4.05 (m, 3H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.86 (m, 3H), 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 (d, J=0.7 Hz, 1H), 7.11 (m, 1H), 7.18 (d, J=7.1 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 8.02 (8.1, 1H). MS (C.I.) m/e 501 (M+H+). Anal calcd for C29H28N206 - 0.5 H20 . 0.15 5 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25. Example 36 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1-(N 0o butyl-N-(2-chlorophenyl)aminocarbonylmethylpyrrolidine-3 carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 80.89 (dt, J=7 Hz, 3H), 1.23 1.51 (m, 4H), 2.52-4.00 (m, 8H), 3.78 (d, J=6 Hz, 3H), 5.92 (d, J=6 Hz, 15 2H), 6.70-6.87 (m, 4H), 7.02-7.21 (m, 4H), 7.27-7.52 (m, 3H). MS (DCI) m/e 565 (M+H)+. Analysis calcd for C31H32N206CI - 0.6H20: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64. Example 367 20 trans, trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yl)-1 (3.4.5-trimethoxybenzyl)pyrrolidine-3-carboxylic acid The compound resulting from Example 1C (0.25 g) was reacted with 0.169 g of 3,4,5-trimethoxybenzyl chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room 25 temperature. The resulting ester was isolated and then hydrolyzed by the method of Example 1D to give 0.193 g of the title compound. m.p. 108-110 "C. 1 H NMR (300 MHz, CDCI3) 82.75 (t, J=9Hz, 1H), 2.95-3.05 (m, 2H), 3.20 (d, J=11 Hz, 1H), 3.45-3.55 (m, 1H), 3.7-3.8 (m, 2H), 3.84 (s, 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 (s, 2H), 6.70 (d, J=8Hz, 1H), 30 6.30-6.35 (m, 1H), 6.90 (d, J=9Hz, 2H), 7.13 (d, J=2Hz, 1H), 7.43 (d, J=9Hz, 2H).
WO 99/06397 PCTIUS98/15479 -388 Example 368 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(N butyl-N-(3-chlorophenyllaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.89 (t, J=7 Hz, 3H), 1.20 1.42 (m, 4H), 3.42-3.87 (m, 9H), 3.9 (s, 3H), 5.96 (s, 2H), 6.75 (7.10, J=m Hz, 7H), 7.33-7.50 (m, 4H). MS (C.I.) m/e 565(M+H). Analysis calcd for C31H33N206CI-1.OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found: C, 10 58.41; H, 4.99; N, 4.08. Example 369 trans. trans-2-(4-Methoxphenyl)-4-(1.3-benzodioxol-5-yil-1 -{2-(di-n butylamino)pyrimidin-4-yllpyrrolidine-3-carboxylic acid 15 The compound resulting from Example 1C (0.25 g) was reacted with 0.11 g of 2,4-dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-methoxphenyl)-4-(1,3 benzodioxol-5-yl)-1 -(2-chloro-4-pyrimidyl)-pyrrolidine-3 20 carboxylate. This compound was reacted with 1 mL of dibutylamine in 2 mL of toluene at 125 *C for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example 1D to give 0.142 g of the title comopund as a white powder. 1 H NMR (300 MHz, CDCl3) S0.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (m, 1H), 3.3-3.5 25 (br, 2H), 3.55-3.67 (m, 2H), 3.75 (s, 3H), 4.6 (br, 1H), 5.2 (br, 1H), 5.45 (br, 1H), 5.87 (s, 2H), 6.3 (br, 1H), 6.67 (d, J=8Hz, 1H), 6.7-6.85 (m, 4H), 7.10 (d, J=9Hz, 2H). Example 370 30 trans.trans-4-(1.3-Benzodioxol-5-y)-2-(4-methoxphenyv)-1 -(((N-(2 methylbut-2-yl'-N-phenylaminoicarbonylmethyl)pyrrolidin e-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.90 (t, J=7.5 Hz, 3H), 1.12 35 (s, 3H), 1.14 (s, 3H), 2.06 (q, J=7.5 Hz, 2H), 2.73 (d, J=15.3 Hz, 1H), 2.91 (t, J=9.5 Hz, 1H), 3.11 (d, J=15.6 Hz, 1H), 3.21 (t, J=8.8 Hz, 1H), 3.50- WO 99/06397 PCT/US98/15479 -389 3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J=10.2 Hz, 1H), 5.91 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (m, 3H), 6.93 (m, 1H), 6.98 (m, 1H), 7.03 (d, J=1.7 Hz, 1H), 7.17 (m, 2H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 5 4.97. Example 371 trans. trans-2-(4- Ethylphenyll-4- (5-in danyl-1- (N. N-di(n butyl)aminocarbonylmethyl-pyrrolidine-3-carboxylic acid o Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3) 8 7.25 (3H, m), 7.21 (1H, d, 3Hz), 7.17 (3H, m), 3.80 (1H, d, 10Hz), 3.65 (1H, ddd, 6, 5, 3Hz), 3.4 (4H, m), 3.10 (2H, m), 2.98 (2H, m), 2.88 (5H, m), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, m), 1.42 (2H, m), 1.32 (1H, m), 1.21 (3H, t, 7Hz), 5 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) m/e 505 (M+H+). Anal calcd for C32H44N203: C, 76.15; H, 8.79; N 5.55. Found: C, 75.96; H, 8.75; N, 5.36. Example 372 20 trans, rans-2-(3.4-Difluorophenyl)-4-(1.3-benzodioxol-5-yl)-1-(N.N di(n-butylaminocarbonylmethvl-prrolidine-3-carboxIic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 62-63 *C. 1H NMR (CDCl3, 300 MHz), 8 0.83 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.13 25 (sextet, J=7Hz, 2H),1.20-1.32 (m,3H), 1.36-1.49 (m,3H), 2.85-2.93 (m,2H), 2.98-3.23 (m, 4H), 3.36-3.45 (m, 3H), 3.58-3.66 (m 1H), 3.94 (d, J=8Hz, 1H), 5.93 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 6.84 (dd, J=lHz, J=7.5Hz, 1H), 6.98 (d, J=7.5Hz, 1H), 7.08-7.15 (m, 2H), 7.22-7.28 (m, 1H). MS (CDI/NH3) m/e517 (M+H)+. 30 Example 373 transtrans-2-(3.4-Difluorophenyl)-4-(1.3-benzodioxol-5-yl)-1 -r2-(N propyl-N-n-pentanesulfonylamino)ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 35 was prepared and isolated as a white solid. m.p. 71-72 *C. 1H NMR (CDCI3, 300 MHz) 5 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.25-1.38 WO 99/06397 PCT/US98/15479 -390 (m, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (m, 1H), 2.72-2.95 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.34 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (m, 1H), 3.71 (d, J=9Hz, 1H), 5.96 (s, 2H), 6.75 (d, J=9Hz, 1H), 3.82 (dd,, J=2Hz, J=9Hz, 1H), 5.96 (d, J=2Hz, 1H), 7.09-7.18 (m, 2H), 7.23-7.34 (m, 1H). MS (CDI/NH3) m/e567 (M+H)+. Example 374 trans.trans-4- (1.3-Benzodioxol-5-yl)-2-(ethoxymethyl)-1 -(((N.N-di(n butylaminocarbonylmethyl)-pyrrolidine-3-::arboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf = 0.53. 1H NMR (CDCI3, 300 MHz, rotameric forms) 5 0.70 (t, J=7Hz), 0.80 (t, J=7Hz) and 0.96-1.04 (m, 6H total), 1.04-1.75 (m, 11H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 2.80-3.08 (m, 2H total), 3.10-3.82 (br m, 12H), 4.03 (m) and 4.22-4.45 (br m, 2H total), 5.90 (s) and 5.91 (s, 2H total), 6.65-6.84 (m) and 6.93 (m) and 6.99 (m, 3H total). MS (FAB) m/e 463 (M+H)+. Anal calcd for C25H38N206 - 1.5 H20: C, 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62. Example 375 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(n-ybutyl)-1 -(NN di(n-butylaminocarbonylmethyl)-prrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2Cl2) Rf = 0.37. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.71 (t, J=7Hz) and 0.77-1.05 (m, 9H total), 1.05-1.20 (m, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (m, 1H), 2.87-3.00 (m, 1H), 3.05-3.60 (m, 5H), 3.60-3.80 (br m, 2H), 3.88-4.05 (br m, 1H), 4.28 (br d, J=15Hz, 1H total), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.82 (m, 3H total). MS (FAB) m/e 461 (M+H)+. Anal calcd for C26H40N205 - 1.75 H20: C, 63.45; H, 8.90; N, 5.69. Found: C, 63.18; H, 8.22; N, 5.60.
WO 99/06397 PCTIUS98/15479 -391 Example 376 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(2-methylbutyll-1 -(N.N-di(n butyliaminocarbonylmethyl)-prrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless glass. TLC (10% MeOH CH2C2) Rf = 0.49. 1H NMR (CDC13, 300 MHz, rotameric forms and mixture of diastereomers) 8 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, 1H), 2.87-3.01 (br m, 1H), 3.06 3.82 (br m, 7H), 3.90-4.40 (br m, 2H), 5.90 (s) and 5.92 (s, 2H total), 6.67-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+. Example 377. trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(3-methylbutyl)-1 -(N.N-di(n butylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf = 0.41. 1H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.73 (t, J=7Hz) and 0.77-1.05 (m, 12H total), 1.07-1.75 (m, approx. 14H plus H20), 2.48-2.63 (m, 1H), 2.87-3.05 (m, 1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, J=15Hz, 1H), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+. Example 378 trans.trans-2-(4-Methoxyhenyl-4-(1.3-benzodioxol-5-yl-1 -r2-(N 5 propyl-N-((N-methyl-N-propylaminolsulfonyilamino)ethyllpyrrolidine 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 58-59 *C. 1H NMR (CDCI3, 300MHz) 8 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.27 (sextet, 0 J=7Hz, 2H), 1.48 (m, 4H), 2.22-2.30 (m, 1H), 2.62 (s, 3H), 2.68-2.78 (m, 1H), 2.84-3.03 (m, 5H), 3.08-3.31 (m, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (m, 1H), 3.63 (d, J=9Hz, 1H),3.79 (s, 3H), 5.95 (s, 2H), 3.73 (d, J=8Hz, 1H), 6.83 (dd, J=2Hz, J=8Hz, 1H), 3.87 (d, J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 576 (M+H)+. 5 WO 99/06397 PCT/US98/15479 -392 Example 379 trans, trans-2.4-Di(3.4-difluorophenyl)- 1 -(N.N-di(n butylaminocarbonlmethyli-yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300MHz, CDC13 ) 8 7.35 (2H, m), 7.18 (4H, m), 4.87 (1H, d, J=12), 4.00-3.60 (5H, m), 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 1.29 (4H, m), 1.15 (2H, m), 0.91 (3H, t, J=9), 0.83 (3H, t, J=9). MS (DCI/NH3) m/e 509 (M+H+). Anal calcd for C27H32F4N203 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66. 0 Example 380 trans. trans-4-(3.4-Dim ethylphenyl)-2-(4-methoxyhenvl)-1 -(N.N-di(n butyliaminocarbonylimethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.43 (2H, d, J=9), 7.25 (1H, bs), 7.18 (1H, dd, J=8, 3), 7.11 (1H, d, J=9), 6.90 (2H, d, J=10), 5.48 (1H, d, J=12), 4.26 (1H, d, J=18), 4.16 (2H, m), 3.83 (2H, m), 3.81 (3H, s), 3.56 (1H, bd, J=18), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 2.24 (3H, s), 2.22 (3H, s), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, o J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 495 (M+H+). Anal calcd for C30H42N204- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38. Example 381 5 trans. trans-2.4-Di(3-fluoro-4-methoxyphenyl- 1-(N.N-di(n butyllaminocarbony)imethyl)-oyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 ) 8 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (1H, m), 4.26 (1H, m), 4.16 (2H, m), 3.83 (2H, m), 3.87 30 (6H, s), 3.56 (1H, m), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 533 (M+H+). Anal calcd for C29H38F2N205- 0.75 H20: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99.
WO 99/06397 PCT/US98/15479 -393 Example 382 transtrans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyhenyl-1 -(((N-(2 penty. N-(3-methylphenyl)amino)carbonyl)methyl)pyrrolidine-3 carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.90 (m, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.13-1.37 (m, 4H), 2.30 (s, 3H), 2.34 (s (CH3 rotamer)), 2.73 2.91 (m, 2H), 3.17-3.26 (m, 2H), 3.32-3.62 (m, 2H), 3.77-4.08 (m, 1H), 3.80 (s, 3H), 4.71 (m, 1H), 5.92 (m, 2H), 6.61-6.84 (m, 6H), 7.04-7.16 10 (m, 3H), 7.23-7.29 (m, 2H). MS (DCI) m/e 559 (M+H+). Anal calcd for C33H38N206 - 0.35 H20 - 0.05 CH3CO2C2H5: C, 70.03; H, 6.92; N, 4.92. Found: C, 70.08; H, 6.82; N, 4.95. Example 383 is trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1-(N butyl-N-(1-naphthyl)aminocarbonylmethylbpyrrolidine-3-carboxylic Agid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 20 1.40 (m, 2H), 1.40-1.60 (m, 2H), 2.42-2.80 (m, 2H), 2.85-4.00 (m, 6H), 3.77 (d, J=1.5 Hz, 3H), 4.05-4.20 (m, 1H), 5.94 (d, J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 (m, 4H), 6.95-7.02 (m, 2H), 7.17 (dd, 8H, 1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m, 4H), 7.87-8.00 (m, 2H). MS (E.S.I.) m/e (M+H) 581. Analysis calcd for C35H36N206 - 1.4 H20: C, 25 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41. Example 384 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -r2-(N phenyl-N-n-hexanesulfonylamino)ethyllpyrrolidine-3-carboxylic acid 30 Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. m.p. 67-68 *C. 1 H NMR (CD30D, 300 MHz) 8 0.88 (t, J=7Hz, 3H), 1.25-1.40 (m, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (m, 1H), 2.64-2.88 (m, 3H), 3.02 (sextet, J=8Hz, 2H), 3.44-3.53 (m, 2H), 3.58 (d, J=9Hz, 1H), 3.56-3.75 (m, 1H), 35 3.78 (s, 3H), 3.88-3.98 (m, 1H), 5.93 (s, 2H), 6.72 (d, J=9Hz, 1H), 5.78- WO 99/06397 PCTIUS98/15479 -394 5.84 (m, 3H), 6.96 (d, J=2Hz, 1H), 7.20 (d, J=9Hz, 2H), 7.27-7.36 (m, 5H). MS (DCI/NH3) m/e 609 (M+H)+. E xample 385 trans. trans-4-(1.3-Benzodioxol-5-yl-2-(4-methoxyphenvl- 1 -(2 methyl-1 .2.3.4-tetrahydrouinolin-1-yl)carbonlimethYI)DyrrOlidine- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 1.03 (m, 3H), 1.10-1.45 (m, 1H), 2.10-2.85 (m, 4H), 2.90-4.00 (m, 7H), 3.76 (s, 1.5H), 3.77 (s, 1.5H, isomer), 5.90 (m, 2H), 6.70-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31H32N206 - 0.3 H20: C, 69.73; H, 6.15; N, 5.25. Found: C, 69.74; H, 6.10; N, 5.01. Example 386 trans, trans-4-(1.3-Benzodioxol-5-vi)-2-(4-methoxvphenvl-1 -(3 butyl-hept-2-en-1-ylpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.86 (t, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.20-1.41 (m, 8H), 1.95-2.06 (m, 4H), 3.24 (d, J=11.0 Hz, 1H), 3.51-3.59 (m, 3H), 3.60-3.71 (m, 1H), 3.77-3.84 (m, 1H), 3.81 (s, 3H), 4.45 (d, J=11.0 Hz, 1H), 5.52 (t, J=7.4 Hz, 1H), 5.93 (s, 2H), 6.77 (d, J=8.1 Hz, 1H), 6.87 (dd, J=1.8, 8.1 Hz, 1H), 6.99 (m, 3H), 7.46 (m, 2H). MS (DCI) m/e 494 (M+H+). Anal calcd for C30H39NO5: C, 72.99; H, 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64. Example 387 trans, trans-2-(3-Flu-oro-4-methoxyphenvi)-4-(1,3-benzodio xoL-5-vi-l 1-[2-(N-p2ropv-N-n-hexanesulfonylamino)ethyllpyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-65 *C. 1 H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=6Hz, 3H), 1.23-1.47 (m, 6H), 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (m, 5 1H), 2.70-2.93 (m, 5H), 2.96-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J--3Hr7 .I=9Hz. 1H). 3.52-3.59 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.87 (s, 3H), WO 99/06397 PCT/US98/15479 -395 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.42 (t, J=8Hz, 1H), 6.96 (s, 1H), 7.12 (d, J=9Hz, 1H), 7.17 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+. 5 Example 388 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyhenyl)- 1 -((3 pyridyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 2.87 (m, 2H), 3.04 (dd, J=3.2, o 9.7 Hz, 1H), 3.21 (d, J=13.7 Hz, 1H), 3.51 (m, 1H)-,3.76-3.85 (m, 2H), 3.79 (s, 3H), 5.90 (m, 2H), 6.71 (m, 1H), 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, 1H), 8.39 (m, 1H), 8.46 (dd, J=1.4 Hz, 1H). Anal calcd for C25H24N205 - 0.70 H20 - 0.05 CH3CO2C2H5: C, 67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90. 5 Example 389 trans. trans- 2 - (n-Hexyl)-4-(1.3-benzodioxol-5-yi)-1 -(N.N-di(n butyliaminocarbonylmethyli-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound o was prepared. 1 H NMR (CDCI3, 300 MHz) 5 0.82-1.00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H), 1.70-1.90 (br m, 2H), 3.10-3.46 (m, 6H), 3.65 (t, J=10.8 Hz, 1H), 3.76 (t, J=11.0 Hz, 1H), 3.92-4.06 (m, 2H), 4.14 4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS(DCI/NH3) m/e 489 (M+H)+. Anal calcd S for C28H44N205 - 0.9 TFA: C, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N, 4.61. Example 390 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(((N-(2 .0 pent yl) -N- (4-fluo ro -3 methylphenylamino)carbonyl)methyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 6 0.92 (m, 3H), 0.97 (t, J=7.1 Hz, 3H), 1.13-1.40 (m, 4H), 2.22 (m, 3H), 2.58-2.74 (m, 1H), 2.78-2.87 (in, 1H), 3.09-3.25 (m, 2H), 3.39-3.60 (m, 2H), 3.70-3.90 (m, 1H), 3.80 (s, 3H), 4.70 (m, 1H), 5.93 (m, 2H), 6.70-6.76 (m, 1H), 6.75 (dd, J=1.4, WO 99/06397 PCT/US98/15479 -396 8.1 Hz, 1H), 6.80-6.94 (m, 4H), 6.96-7.13 (m, 4H). MS (DCL.) m/e 577 (M+H+). Anal calcd for C 33 H37FN206 - 0.25 H20: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74. 5 Example 391 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -((2 pyridylmethylpyrrolidine-3-carbxyiic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 2.97 (dd, J=7.9, 9.7 Hz, 1H), 0 3.04 (t, J=9.6 Hz, 1H), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 (d, J=14.0 Hz, 1H), 3.59 (m, 1H), 3.78 (s, 3H), 3.96 (d, J=9.9 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.83 (dd, J=1.7, 7.9 Hz, 1H), 6.92 (m, 2H), 6.96 (d, J=1.8 Hz, 1H), 7.28 (m, 1H), 7.44 (m, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.80 (dt, J=1.8, 7.7 Hz, 1H), 8.42 (m, 1H). MS (DCI) m/e 433 (M+H+). 5 Anal calcd for C25H24N205 - 0.35 H20: C, 68.43; H, 5.67; N, 6.38. Found: C, 68.44; H, 5.61; N, 6.24. Example 392 trans, trans-2-(3-Phenylpropyl)-4-(1,3-benzodioxol-5-yl)-l-(N.N o di(n-butyl)aminocarbonylmethyl)-prrolidine-3carboxyic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 5 0.89-0.97 (m, 6H), 1.22-1.36 (m, 4H), 1.41-1.55 (m, 4H), 1.63-1.95 (m, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (m, 7H), 3.53-3.60 (m, 2H), 3.65-3.76 (m, 1H), 3.82-3.90 5 (m, 1H), 3.96-4.10 (m, 1H), 5.92 (s, 2H), 6.71 (d, J=8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.5 Hz, 1H), 6.86(d, J=1.2 Hz, 1H), 7.10-7.28 (m, 5H). MS(DCI/NH3) m/e 523 (M+H)+. Anal calcd for C31H42N205 .0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50. 30 Example 393 3rans--rans-2-(4-Methoxy-3-fluorop benzodioxol-5-yl)-1 -(N.N-di(n-butylaminocarbonylmethy-I pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 35 was prepared and isolated as a white solid. m.p. 115-117 0C. 1 H NMR (300 MHz, CDCI3) 5 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.5 (m, WO 99/06397 PCT/US98/15479 -397 8H), 2.85 (d, J=13Hz, 1H), 2.90-3.17 (m, 5H), 3.20-3.35 (m, 1H), 3.35 3.50 (m, 3H), 3.55-3.65 (m, 1H), 3.84 (d, J=lOHz, 1H), 3.87 (s, 3H), 3.92 (s, 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.90 (t, J=8Hz, 1H), 7.05-7.20 (m, 2H). 5 Example 394 trans-trans-2-(1.4-Benzodioxan-6-yl)-4-(7-methoxy-1.3-benzodioxol 5-yl)-1-(N.N-di(n-butyllaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid o Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 107-110 *C. 1H NMR (300 MHz, CDCI3) 5 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.75 (d, J=13Hz, 1H), 2.90-3.12 (m, 4H), 3.32-3.60 (m, 5H), 3.69 (d, J= 8Hz, 1H), 3.90 (s, 3H), 4.23 (s, 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 5 (s, 1H), 6.70 (s, 1H), 6.78-6.93 (m ,3H). Example 395 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(3 butyl-2-fluoro-hept-2-en-1-yl)pyrrolidine-3-carboxylic acid 0 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.84 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H), 1.16-1.37 (m, 8H), 1.83 (t, J=8.5 Hz, 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, J=9.3 Hz, 1H), 3.32-3.42 (m, 2H), 3.50 (m, 1H), 3.71 (d, J=9.2 Hz, 1H), 3.78 (s, 3H), 5.91 (m, 2H), 6.72 (d, J=7.8 5 Hz, 1H), 6.83 (dd, J=1.7, 8.1 Hz, 1H), 6.90 (m, 2H), 7.02 (d, J=1.7 Hz, 1H), 7.34 (m, 2H). MS (DCI) rn/e 512 (M+H+). Anal calcd for C30H38FN05: C, 70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66. Example 396 3o transtrans-2-(3-Fluoro-4-ethoxyphenyl)-4-(1.3-benzodioxol-5-ylO-1 [2-(N-oropyl-N-n-pentanesulfonylaminolethyllpyrrolidine-3-carboxylic acoid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-66 *C. 1 H NMR 3E (CDCI3, 300 MHz) 6 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.26-1.36 (m, 4H), 1.41-1.52 (m, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (m, 1H), WO 99/06397 PCT/US98/15479 -398 2.69-2.96 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.37 (m, 2H), 3.43 (d, J=9Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J=9Hz, 1H), 4.08 (q, J=7Hz, 2H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (s, 1H), 7.07 (d, J=8Hz, 1H), 7.15 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+. Example 397 ns, t, trans- 2 -(4-Metho xv-3-fIuo rophenv)-4-(7-methoxv-1,3 benzodioxol-5-yl)-1 -f(N-buty-N propylamino)carbonylmethyllpyrrolidine-3-carboxiic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 0C. 1H NMR (300 MHz, CDCI3) 5 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (m, 8H), 2.80-3.50 (m, 9H), 3.55-3.65 (m, 1H), 3.82 (d, J= 10Hz, 1H), 3.85 (s, 3H), 3.92 (s, 3H), 5.96 (s, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.90 (t, J=8Hz, 1H), 7.08-7.22 (m, 2H). Example 398 trans, trans-4-(13 -benzodioxol-5-yl)-(N butyl-N-(4-chlorophenyl)aminocarbonylmethylpyrrolidife 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 1.50 (m, 4H), 2.66-4.00 (m, 9H), 3.81 (s, 3H), 5.95 (s, 2H), 6.77 (d, J=7 Hz, 1H), 6.85 (d, J=8 Hz, 3H), 7.05 (m, 5H), 7.33-7.42 (m, 2H). MS (C.1,) m/e 565 (M+H). Analysis calcd for C31H33N206CI - 0.25 H3PO4: C, 63.16; H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53. Example 399 trans. trans-4-(1.3-Be nzodioxol- -(4 methyl-1 .2.3.4-tetrahydroauifnolifn-1 -ylcarbonyl methyflpyrrolidine 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 1.27 (d, J=7 Hz, 1.5H), 1.28 5 (d, 7H, 1.5-diastereomer), 1.39-1.55 (m, 1H), 2.02-2.15 (m, 1H), 2.60 '1 9 (m 5H) 3.33-4.00 (m, 5H), 3.78 (s, 3H), 5.92 (d, J=3 Hz, 2''), 5.73 WO 99/06397 PCTIUS98/15479 -399 (dd, J=8 Hz, 1H), 6.75-6.90 (m, 3H), 6.91-7.35 (m, 7H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31H32N206: C, 70.44; H, 6.10; N, 5.30. Found: C, 70.16; H, 6.04; N, 5.04. 5 Examp2le 400 trans. trans-2-(3-Fluoro-4-methoxyphenylb-4-(1.3-benzodio xol-5-Yi 1-r2-(N-propyl-N-(2-(piperidin-1 yliethanesulfonylaminolethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 10 was prepared and isolated as a white solid. m.p. 9'5-96 *C. 1H NMR (CDCl3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 1.43-1.55 (m, 4H), 1.63-1.72 (m, 4H), 2.29-2.38 (m, 1H), 2.64-2.78 (m, 5H), 2.87 (t, J=8Hz, 1H), 2.95-3.04 (m, 5H), 3.20-3.30 (m, 1H), 3.32-3.43 (m, 4H), 3.54-3.63 (m, 1H), 3.78 (d, J=8Hz, 1H), 3.87 (s, 3H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.78 (dd, 15 J=2Hz, J=8Hz, 1H), 6.88 (t, J=8Hz, 1H), 6.94 (d, J=2Hz, 1H), 7.08-7.20 (m, 2H). MS (DCI/NH3) m/e 620 (M+H)+. Example 401 transtrans-2- (n-Heptyl)-4-(1.3-benzodioxol-5-yl)-1 -(NN-di(n 20 butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.83-0.98 (s, 9H), 1.18-1.40 (m, 14H), 1.44-1.60 (m, 4H), 1.72-1.96 (br m, 2H), 3.12-3.45 (m, 6H), 3.65 (t, J = 10.5 Hz, 1H), 3.76 (t, J = 11.2 1H), 3.90-4.06 (m, 2H), 4.13 25 4.33 (m, 2H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 7.8, 1.7 Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS(DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N205 - 0.75 TFA: C, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50. 30 Example 402 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyheny)-1 -(3 methyl-1,.2.3.4-tetrahydroquinolin-1 -yl)carbonylmethylipyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound 35 was prepared. 1H NMR (300 MHz, CD30D) 8 0.99 (d, 1.5H), 1.03 (d, J=6 Hz, 1.5H, second diastereomer), 2.60-4.00m (12), 3.78 (s, 1.5H), 3.79 (s, WO 99/06397 PCT/US98/15479 -400 1.5H, second diastereomer), 5.92 (s, 1H), 5.93 (s, 1H, diastereomer), 6.65-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31 H32N206 - 0.8 H20: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 6.10; N, 5.30. Example 403 trans. trans-4-(1.3-Benzodioxol-5-vl1-2-(4-methoxvphenvl- 1-(N butyl-N-(4-fluorophenyl)aminocarbonyimethylpyrrolidine- 3 carboxylic acid Using the procedures described in Example'1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.2-1.47 (m, 4H), 2.7 (d, J=12 Hz, 1H), 2.80 (t, J=9 Hz, 1H), 3.09 (t, J=9 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.47 (m, 1H), 3.49-3.65 (m, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 (s, 3H), 5.94 (s, 2H), 6.72-6.86 (m, 4H), 7.00-7.15 (m, 5 7H). MS (DCI) m/e 549 (M+H)+. Analysis calcd for C 3 1H33N206F - 0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99. Example 404 trans, trans-1 -(N -Butyl-N-(3-methylphenyl)amin nocarbonylmethyl)- 2 0 (4-methoxyphenyl)-4-(5-benzofuranyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDCI3) 5 7.66 (1H, bs), 7.60 (1H, d, J=3Hz), 7.45 (2H, s), 7.15 (4H, m), 6.75 (5H, m), 3.96 (1H, d, J=1OHz), 3.78 (3H, s), 3.74 (1H, m), 3.59 (3H, m), 3.21 (1H, t, J=9Hz), 3.19 (1H, 5 d, J=16Hz), 2.92 (1H, t, J=9Hz), 2.70 (1H, d, J=16Hz), 2.29 (3H, s), 1.41 (2H, m), 1.24 (2H, m), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) m/e 541 (M+H+). Anal. calcd for C33H34N20 - 1 H20: C, 71.21; H, 6.52; N 5.03. Found: C, 71.31; H, 6.30; N, 4.98. 0 Example 405 trans. trans--(N -Butvl-N-(3-methvlphen
(
4 -fluorophenyl)-4-(5-benzofuranvlorroidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 7.67 (1H, bs), 7.60 (1H, d, 35 J=3Hz), 7.45 (2H, m), 7.18 (3H, m), 7.12 (1H, d, J=7Hz), 6.93 (2H, m), 0.70 (1H, d, J-3Hz), 7n (7H. hd). 4.02 (1H, m), 3.77 (1H, m), 3.59 (3H, WO 99/06397 PCT/US98/15479 -401 m), 3.29 (1H, m), 3.19 (1H, m), 2.94 (1H, m), 2.71 (1H, m), 2.30 (3H, s), 1.45 (2H, m), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) m/e 529 (M+H+). Anal. calcd for C33H34N205 - 0.2 HOAc: C, 71.98; H, 6.30; N 5.18. Found : C, 71.68; H, 5.89; N, 5.25. Example 406 trans, trans-4-(1.3-Benzodioxol-5-yll-2-(4-methoxyphenvl)y-1 -((N. N (di-(3-methylphenyl)amino)carbonylimethyl)pyrrolidin e-3-carboxyliC 0 Using the procedures described in Example'1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 2.27 (s, 6H), 2.81 (dd, J=8.1, 9.5 Hz, 1H), 2.98 (d, J=15.3 Hz, 1H), 3.20 (t, J=16.6 Hz, 1H), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, J=9.5 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.85 (m, 3H), 6.95 (m, 4H), 7.05 (d, J=1.7 Hz, 1H), 7.06-7.24 (m, 5 6H). MS (DCI) n/e 579 (M+H+). Anal calcd for C35H34N206 - 0.15 H20 0.20 CH3CO2C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.51. Example 407 o transtrans-4-(1.2-D ihydrobenzofuran-5-yi)-2-(4-methoxyphenyl)-1 (((N-butyl-N-(3-methylphenyl)amino)carbonyl)methyl)pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 ) 8 7.73 (2H, m), 7.40-7.10 (4H, m), 5 6.92 (2H, m),.6.72 (2H, d, J=9), 6.63 (1H, m), 5.40 (1H, m), 4.55 (2H, t, J=9), 4.30-4.10 (3H, m), 3.84 (3H, s), 3.82 (1H, m), 3.65 (1H, m), 3.39 (1H, m), 3.21 (2H, t, J=9), 3.10-2.90 (2H, m), 2.26 (3H, s), 1.55 (2H, m), 1.45 (2H, m), 0.92 (3H, t, J=9). MS (DCI/NH3) m/e 543 (M+H+). Anal calcd for C33H38N205 - 0.65 H20: C, 71.50; H, 7.15; N, 5.05 . Found: C, o 71.47; H, 6.96; N, 4.83.
WO 99/06397 PCT/US98/15479 -402 Example 408 trans, trans-2-(3-Fluoro-4-met oxvphenvl)-4-(1.3-benzodioxol-5-yl 1-(2-(N-propyl-N-r2-(N.N dimethylaminol)lethanesulfnylamino)ethl)orrolidine-3-carboxyic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 *C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15 2.24 (m, 1H), 2.36 (s, 6H), 2.66-2.76 (m, 1H), 2.83-3.04 (m, 6H), 3.18 3.41 (m, 5H), 3.55-3.63 (m, 1H), 3.72 (d, J=8Hz, TH), 3.85 (s, 3H), 5.90 (d, J=6Hz, 2H), 6.67 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.84 (t, J=8Hz, 1H), 7.94 (d, J=2Hz, 1H), 7.09 (d, J=8Hz, 1H), 7.20 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 580 (M+H)+. Exmpxle 409 trans. trans-1-(N.N-Dibutyainminocarbonvimethvi-2-(4-luorophenyl 4-(5-benzofuranylpyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.88 (1H, bs), 7.80 (2H, m), o 7.61 (1H, d, J=3Hz), 7.55 (1H, bd, J=8Hz), 7.46 (1H, d, J=8Hz), 7.07 (2H, t, J=8Hz), 6.76 (1H, d, J=3Hz), 5.53 (1H, bd, J=11Hz), 4.18 (2H, m), 3.91 (3H, m), 3.55 (1H, d, J=16Hz), 3.30 (3H, m), 3.12 (1H, dd, J=10&9Hz), 2.95 (1H, m), 1.51 (2H, m), 1.31 (4H, m), 1.12 (2H, m), 0.92 (3H, m), 0.83 (3H, t, J=7Hz). MS m/e (DCI, NH3) 595 (M+H+). ?5 Example 410 trans.tranis- 4 -(1,2-Dihydrobenzofuran-5-yl)-2-(4-ethylohenyI)-1-(((N buy--(3- met hvl henvIa m i no c arb o nylm ethylpyr ro id:i ne -3 carboxylic acid 30 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.35 (2H, m), 7.20-7.00 (7H, m), 6.70 (2H, d, J=9), 5.38 (1H, m), 4.55 (2H, t, J=9), 4.05 (1H, m), 3.64 (2H, in), 3.45 (1H, m), 3.21 (2H, t, J=9), 2.95 (1H, m), 2.75 (1H, m), 2.63 (2H, q, J=8), 2.38 (2H, m), 2.27 (3H, s), 1.43 (2H, m), 1.30 (2H, m), 1.22 35 (3H, t, J=9), 0.89 (3H, t, J=9). MS (DCI/NH3) m/e 541 (M+H+). Anal WO 99/06397 PCTIUS98/15479 -403 calcd for C34H40N204 - 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80. Example 411 trans.trans-4-(1.2-Dihydrobenzofuran-5-ylb-2-(4-fluorophenyl)-1 (N.N-di(n-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.40 (2H, m), 7.28 (1H, bs), 7.18 (1H, dd, J=8, 3), 7.00 (2H, t, J=9), 6.72 (1H, d, J=9), 4.53 (2H, t, J=9), 3.92 (1H, m), 3.65 (1H, m), 3.42 (3H, m), 3.19 (2H, t, J=9), 3.15 2.90 (6H, m), 1.43 (3H, m), 1.25 (3H, m), 1.10 (2H, m), 0.90 (3H, t, J=8), 0.83 (3H, t, J=8). MS (DCI/NH3) m/e 497 (M+H+). Anal calcd for C29H37FN204 -0.25 H20: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44. ExamAle 412 trans.trans-4-(1.2-Dihydrobenzofuran-5-yil-2-(4-fluorophenyl)-1 (((N-butyl-N-(3-methylphenylamino)carbonyl)methyl)Dyrrolidine-3 carboxylic acid ) Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 ) S 7.28 (1H, bs), 7.25-7.00 (5H, m), 6.91 (2H, m), 6.72 (3H, d, J=9), 4.54 (2H, t, J=9), 4.00 (1H, m), 3.60 (3H, m), 3.45 (1H, m), 3.19 (2H, t, J=9), 3.11 (2H, m), 2.84 (1H, m), 2.67 (1H, bd, J=18), 2.26 (3H,s), 1.42 (2H, m), 1.25 (2H, m), 0.88 (3H, t, J=8). MS (DCI/NH3) m/e 531 (M+H+). Anal calcd for C32H35FN204 -0.25 H20: C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03. Example 413 trans. trans-4-(Indan-5-yl-2-(4-methoxyphenylb-1-(N.N-di(n ) butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.32 (3H, m), 7.18 (2H, m), 6.85 (2H, d, J=9), 3.83 (1H, m), 3.79 (3H, s), 3.67 (1H, m), 3.50-3.20 (4H, m), 3.20-2.92 (4H, m), 2.87 (5H, m), 2.79 (1H, bd, J=15), 2.06 (2H, m), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.88 (3H, t, J=8), 0.82 (3H, t, WO 99/06397 PCTIUS98/15479 -404 J=8). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N204: C, 73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17. Example 414 ns, t. rans2-(4-MethoXV henVI)-4-(3.4-dif luorophenV)-1-f(N-butyl N-(3-methylohenyl)amino)carboniylmethyll1yrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3) 8 0.86 (t, J=7Hz, 3H), 1.10-1.35 (m, 2H), 1.35-1.52 (m, 2H), 2.29 (s, 3H), 2.63 (d, J=13Hz, 1H), 2.76 (t, J=7Hz, 1H), 3.06-3.20 (m, 2H), 3.42-3.53 (m, 1H), 3.50-3.64 (m, 3H), 3.80 (s, 3H), 3.86 (d, J=9Hz, 1H), 6.66-6.82 (m, 4H), 7.02-7.22 (m, 6H), 7.30-7.40 (m, 1H). Example 415 trans. trans-1- (N-Butyl-N-(3-chIorophenylaminocarbonvlmethyl)-2 (4-fluorophenyl)-4-(5-benzofuranl)prrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.64 (1H, d, J=2Hz), 7.61 (1H, d, J=3Hz), 7.47 (1H, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1H, dt, J=8&2Hz), 7.21 (1H, d, J=8Hz), 7.19 (2H, m), 7.00 (1H, bs), 6.94 (2H, t, J=8Hz), 6.83 (1H, bd, J=8Hz), 6.74 (1H, dd, J=2&lHz), 3.96 (1H, d, J=lOHz), 3.75 (1H, ddd, 6, 5&3Hz), 3.59 (3H, m), 3.23 (1H, t, J=1OHz), 3.18 (1H, d, J=16Hz), 2.92 (1H, dd, J=10&9Hz), 2.69 (1H, d, J=16Hz), 5 1.41 (2H, m), 1.23 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCl, NH3) 549, 551 (M+H+). Anal. calcd for C31H30CIFN20: C, 67.82; H, 5.51; N, 5.10. Found: C, 67.43; H, 5.33; N, 4.78. Example 416 o trans.trans-4-(1,3-Benzodioxol-5-vl -2-(4-methoxvphenvl-1
-(((N
propyl-N-(4-ohenoxybenzylaminocarbonyl)methyl'tPvrrolidine- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 (rotamer) 7.40-7.20 (5H, m), 5 7.13 (2H, m), 6.98 (2H, m), 6.93-6.60 (7H, m), 5.93 (1H, d, J=2), 5.88 (5.85) (1H, a, J=2), 4.90 (45 )('A ,J 1) .10 (A .25) (1W'H, 11 ) WO 99/06397 PCTIUS98/15479 -405 3.77 (3.73) (3H, s), 3.72 (1 H, m), 3.60 (1 H, m), 3.53-3.20 (3H, m), 3.15 2.75 (4H, m), 1.60-1.20 (2H, m), 0.83 (0.64) (3H, t, J=8). MS (DCI/NH3) m/e 623 (M+H+). Anal calcd for C 3 7H38N207 -0.25 H20: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42. 5 Example 417 trans.trans-4-(1.2-Dihydrobenzofuran-5-Yl)-2(4-ethylphefl)-1
-(((N
(2-pentyl)-N-(4-fluoro-3 methylphenylamino)carbonYl)methyl)prrolidine-3-carboxyiic acid o Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.30 (1H, bs), 7.20-7.00 (5H, m), 6.87 (1H, m), 6.73 (2H, d, J=9), 6.57 (1H, m), 4.81 (1H, m), 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (1H, m), 3.43 (1H, m), 3.18 (2H, t, J=9), 3.17 (1H, m), 3.06 (1H, dd, J=15, 6), 2.88 (1H, dd, J=11, 9), 2.61 (2H, q, 5 J=8), 2.59 (1H, m), 2.18 (3H, m), 1.40-1.10 (4H ,m), 1.22 (3H, t, J=9), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 573 (M+H+). Anal calcd for C35H41FN204 -0.75 H20: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56; H, 7.33; N, 4.56. 0 E example 418 trans.trans-2-(4-Methoxphenl)- 4 -(1.3-benzodioxol-5-Yl)- 1 -2-(N propyl-N-f2-pyrimidinllamino)ethyllprrolidine-3-carboxylic acid Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-{2-(N propylamino)propylpyrrolidine-3-carboxylate, prepared by the 25 procedures of Example 61B (300 mg), 138 mg of 2-bromopyrimidine, and 150 mg of diisopropylethylamine were heated at 95 *C for 15 hours in 2 mL of acetonitrile. The resulting intermediate trans-trans ethyl ester was isolated by chromatography on silica gel eluting with 5-10% ETOAc in CH2CI2 and hydrolyzed with NaOH in ethanol/water to give 95 30 mg of the title compound. 1 H NMR (300 MHz, CDCl3) 5 0.82 (t, J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (m, 1H), 2.75-2.97 (m, 3H), 3.40-3.55 (m ,4H), 3.60-3.70 (m, 3H), 3.75 (s, 3H), 5.95 (s, 2H), 6.34 (t, J=4Hz, 1H), 6.65 (d, J=8Hz, 1H), 6.75-6.82 (m, 1H), 6.78 (d, J=9Hz, 2H), 6.96 (d, J=2Hz, 1H), 7.27 (d, J=9Hz, 2H), 8.20 (d, J=4Hz, 2H). 35 WO 99/06397 PCT/US98/15479 -406 Example 419 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyhenvl)-1-(3 butyl-2-chloro-hept-2-en-1-ylipyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.84 (t, J=6.8 Hz, 3H), 0.88 (t, J=6.7 Hz, 3H), 1.19-1.39 (m, 8H), 2.05-2.09 (m, 2H), 2.17-2.23 (m, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1H), 2.95 (t, J=9.2 Hz, 1H), 3.32-3.37 (m, 2H), 3.49 (m, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.77 (s, 3H), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 1H), 6.85 (dd, J=1.9, 8.1 Hz, 1H), 6.89 (m, 2H), 7.08 (d, J=1.5 Hz, 1H), 7.36 (m, 2H). MS (DCl) m/e 528 (M+H+). Anal calcd for C30H38CIN05 - 0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40. Example 420 5 trans. trans-4-(1.2-Dihydrobenzofuran-5-yll-2-(4-methoxyphenvl)-1 (((N-(2-pentyl-N-(4-fluoro-3 methylphenyilamino)carbonylmethyllDyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.28 (1H, bs), 7.15 (3H, m), o 6.90 (1H, m), 6.77 (2H, dd, J=9, 3), 6.71 (2H, d, J=9), 6.56 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J=9), 3.92 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.45 (1H, m), 3.19 (2H, t, J=9), 3.18 (1H, m), 3.03 (1H, dd, J=15, 6), 2.85 (1H, m), 2.55 (1H, m), 2.18 (3H, m), 1.40-1.05 (4H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C 3 4H39FN205 - 0.35 H20: C, 5 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30. Example 421 trans.trans-4-(1.2-Dihydrobenzofuran-5-yl-2-(4-methoxyphenyil -1 (((N-butyl-N-(3-chlorophenyl)amino)carbonyl)methyl)pyrrolidine-3 0 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 5 7.29 (1H, d, J=3), 7.25-7.05 (5H, m), 6.98 (1H, bs), 6.80 (2H, m), 6.72 (2H, d, J=9), 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 (3H, s), 3.58 (3H, m), 3.42 (1H, dd, J=10, 6), 3.18 35 (4H, m), 2.87 (1H, m), 2.66 (1H, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 (3H, WO 99/06397 PCTIUS98/15479 -407 t, J=9). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C32H35CIN205 0.25 H20: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55. Example 422 s trans.trans-4- (1.3-Benzodioxol-5-yi)-2-(5-ethylfuran-2-Y-1
-(N.N
di(n-butylaminocarbonylmethyl)-pyrrolidine-3-carboxyIic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.77 (1H, bs), 7.11 (1H, d, J=3), 7.02 (1H, dd, J=9, 3), 6.82 (1H, d, J=9), 6.52 (1H, d, J=4), 6.08 (1H, o d, J=4), 5.98 (2H, s), 5.80 (1H, d, J=6), 4.70 (1H, bd, J=15), 4.37 (2H, m), 3.70 (2H, m), 3.39 (2H, m), 3.20 (1H, m), 3.10-2.82 (2H, m), 2.76 (2H, q, J=8), 1.45 (2H, m), 1.32 (3H, t, J=9), 1.30-1.10 (6H, m), 0.87 (3H, t, J=9), 0.85 (3H, t, J=9). MS (DCI/NH3) m/e 499 (M+H+). Anal calcd for C28H38N206 - 1.75 HCI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, s 6.96; N, 4.88. Example 423 trans.trans-4-(1.2-Dihydrobenzofuran-5-ylb-2-(4-fluoroohenyll-1 (((N-(2-penty)-N-(4-fluoro-3 o rmethylphenylamino)carbonylmethyl)pyrrolidine- 3 -carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 5 7.30-7.10 (4H, m), 6.92 (3H, m), 6.73 (2H, d, J=9), 6.59 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J=9), 4.00 (1H, bd, J=10), 3.62 (1H, m), 3.45 (1H, m), 3.22 (1H, m), 3.21 (2H, t, 25 J=9), 3.02 (1H, dd, J=15, 6), 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 (3H, bs), 1.40-1.30 (3H, m), 1.15 (1H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C 3 3H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71. 30 Example 424 trans.trans-4-(1 .2-Dihydrobenzofuran-5-yl-2-(4-fluorophenYl-1 (((N-butyl-N-(3-chlorophenvl)amino)carbonvlbmethylloyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound 35 was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.30 (2H, m), 7.25-7.10 (4H, WO 99/06397 PCT/US98/15479 -408 n), 6.95 (3H, m), 6.82 (1H, bd, J=9), 6.73 (1H, d, J=9), 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (3H, m), 3.43 (1H, dd, J=9, 6), 3.21 (2H, t, J=9), 3.16 (2H, m), 2.87 (1H, m), 2.69 (1H, m), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=9). MS (DCI/NH3) m/e 551 (M+H+). Anal calcd for 5 C31H32CIFN204 -0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76. Example 425 trans.trans-4-(1.2-Dihvdrobenzofuran -5-vil-2-(4-ethylphenyl)-1
-(((N
D butyl-N-(3-chlorophenvl) amino)carbonyl)methylprrolidine- 3 carboxylic ac~id Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 7.30 (1H, m), 7.21 (1H, d, J=9), 7.15 (2H, m), 7.09 (4H, bs), 6.96 (1H, bs), 6.80 (1H, bd, J=9), 6.73 5 (1H, d, J=9), 4.54 (2H, t, J=9), 3.89 (1H, bd, J=11), 3.60 (3H, m), 3.43 (1H, m), 3.22 (2H, t, J=9), 3.18 (2H, m), 2.92 (1H, m), 2.72 (1H, m), 2.62 (2H, q, J=8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, J=9), 0.87 (3H, t, J=9). MS (DCI/NH3) m/e 561 (M+H+). Anal calcd for C33H37CIN2O4 0.25 H20: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65. 0 Example 426 trans.trans-1 -(N-Butyl-N-(3-chlorop methoxyphenvl-4-(5-benzofuranylprrolidine 3 carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1 H NMR (300 MHz, CDCl3) 5 7.67 (1H, bs), 7.60 (1H, d, J=3Hz), 7.48 (1H, d, J=8Hz), 7.42 (1H, dd, J=8&3Hz), 7.29 (1H, dt, J=8&3Hz), 7.21 (1H, d, J=8Hz), 7.14 (2H, m), 6.99 (1H, bs), 6.76 (4H, m), 3.88 (1H, d, J=lOHz), 3.75 (1H, ddd, J=6, 5&3Hz), 3.59 (2H, m), 3.53 (1H, dd, J=10&3Hz), 3.22 (1H, t, J=9Hz), 3.19 (1H, m), 2.96( 1H, 30 m), 2.70 (1H, d, J=16Hz), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) m/e 563, 561 (M+H+). Anal. calcd for C32H33CIN205 .0.5 H20: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68.
WO 99/06397 PCT/US98/15479 -409 E example 427 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphe nyl)-1 -(((N cyclohe xyl-N-butylamino)carbonyl)methyl)Dyrrolidine-3-carboxyl ic 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) (rotamer) 8 0.78 (0.86) (t, 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) (d, 1H, J=12Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) (s, 3H), 5.92 (s, 2H), 6.72 (d, 1H, J=9Hz) 6.86 (m, 3H) 7.03 (d, 1H, J=6Hz), 7.34 (m, 2H). MS (DCI/NH3) m/e 537 (M+H)+. Anal. calc'd for C31H40N206 - 1 H20: C, 67.13; H, 7.63; N, 5.05. Found: C, 67.09; H, 7.34; N, 4.92. Example 428 trans. trans-4-(1.3-Benzodioxol-5-yfl-2-(4-ethylpheny)- 1 -(((N-(3 15 methylohenvil-N-butylami no)icarbonyli)methylpyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 0.86 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, 3H), 2.6 (q, 2H, J=7Hz), 20 2.68 (d, 1H, J=12Hz), 2.86 (t, 1H, J=8Hz), 3.19 (q, 2H, J=7Hz), 3.44 (dd, 1H, J= 3Hz,lOHz), 3.59 (m, 3H), 3.94 (d, 1H, 9Hz), 5.92 (s, 2H), 6.75 (m, 3H), 6.86 (dd, 1H, J= 2Hz, 8Hz), 7.08 (m, 6H), 7.17 (t, 1H, J= 8Hz). MS (DCI/NH3) m/e 543 (M+H)+. Anal. calc'd for C33H38N205 . 0.60 H20: C, 71.61;.H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87. 25 Example 429 trans. trans-4-(Benzofuran-5-yl)-2-(4-ethylphenyl)-1 -((( N-(3 methylphenyl)-N-butylamino)carbonyl)methyl)pyrrolidine-3-carboxylic ad 30 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.90 (t, 3H, J=7Hz), 1.30 (t, 3H, J=7Hz), 1.31 (m, 2H), 1.43 (m, 2H), 2.27 (s, 3H), 2.73 (q, 2H, J=7Hz), 3.15 (d, 2H, J=17Hz), 3.61 (t, 2H, J= 8Hz), 3.82 (m, 2H), 4.00 (t, 1 H, 12Hz), 4.26 (m, 2H), 5.53 (br d, 1H), 6.54 (br s, 2H), 6.76 (d, 1H, J= 2Hz), 35 7.14 (m, 3H), 7.28 (s, 1H), 7.40 (m, 3H), 7.48 (d, 1H, J= 8Hz), 7.63 (d, 1H, WO 99/06397 PCTIUS98/15479 -410 J=2Hz), 7.73 (s, 1H). HRMS. calc'd for C34H39N204 (M+H)+: 539.2910. Found: 539.2891 E xample'430 trans. trans-4-(1.4-Benzodioxan-6-yl-2-(4-ethylphenyl)-1 -(((N-(3 methylphenyl-N-butyiamilno) carbonyl)methyl)pyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.87 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.24 (m, 2H), 1.42 (m, 2H), 2.30 (s, 3H), 2.61 (q, 2H, J=7Hz), 2.67 (d, 1H, J=14Hz), 2.86 (t, 1H, J= 8Hz), 3.18 (q, 2H, J=7Hz), 3.41 (dd, 1 H, J=4,lOHz), 3.59 (m, 3H), 3.93 (d, 1H, J=10Hz), 4.25 (m, 4H), 6.74 (br s, 2H), 6.80 (d, 1H, J=8Hz), 6.93 (dd, 1H, J=2Hz,8Hz), 6.99 (d, 1H, J=2Hz), 7.07 (m, 5H), 7.17 (t, 1H, J=8Hz). MS (DCI/NH3) m/e 557 (M+H)+. Anal. 5 calc'd for C34H40N205 - 0.40 H20: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62. E xample 431 trans.trans-2-(3-Fluoro-4-methoxyhenyl)- 4 -(1 .3-benzodioxol-5-yi) 3 1 -r2-(N-propvi-N-2-mesitvlenesulfonviaminolethvilpvrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 80-82 *C. 1H NMR (CDCI3, 300 MHz) 5 0.69 (t, J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09 5 2.17 (m, 1H), 2.24 (s, 3H), 2.53 (s, 6H), 2.54-2.64 (m, 1H), 2.73-2.86 (m, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (m, 3H)), 3.44-3.53 (m, 1H), 3.57 (d, J=9Hz, 1H), 3.89 (s, 31-1), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.85 (s, 2H), 6.92 (d, J=8Hz, 1H), 9.94 (d, J=2Hz, 1H), 7.06 (d, J=8Hz, 1H), 7.13 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) 0 m/e 627 (M+H)+. Example 432 trans. trans-2-(4-Methoxypheny)-4(3.4difluorohenyll -r(N-b.-tyl N-(3-chlorophenyl)amino)carbonylrnethyllpyrrolidine3carboxyLic aci 5 Using the procedures described in Example 1, the title compound .1HNP.A (3flfl M--A m ) S 0.86 (t. J=7Hz. 3H), 1.18-1.32 WO 99/06397 PCT/US98/15479 -411 (m, 2H), 1.35-1.48 (m, 2H), 2.64 (d, J=13Hz, 1H), 2.71 (t, J= 7Hz, 1H), 3.08-3.18 (m, 2H), 3.42-3.48 (m, 1H), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.80 (d, J=9Hz, 1H), 6.73-6.85 (m, 3H), 6.94 (s, 1H), 7.04-7.40 (m, 7H). 5 Example 433 ns, t.rans-2-(3-Fluoro-4-methoxyph ny -4-(1.3-benzodioxol-5-vi) 1-( 2 -(N-propyl-N-(3-chloroprooanesulfonyllaminolethylloyrrolidine-3 carboxylic aQCd Using the procedures described in Example 1, the title compound o was prepared. 1 H NMR (CD30D, 300 MHz) S 0.80(t, 3H, J=7), 1.47 (bd hex, 2H, J=8), 2.15 (pen, 2H, J=7), 2.32 (m, 1H), 2.7-3.2 (m, 9H), 3.46 (dd, 1H, J=4, 10), 3.57 (m, 1H), 3.64 (t, 2H, J=6), 3.67 (d, 1H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.96 (d, 1H, J=2), 7.06 (t, 1H, J=9), 7.18 (m, 2H). MS (DCI/NH3) m/e 585 (M+H; 15 3 5Cl)+; 587 (M+H; 3 7 Cl)+. Anal calcd for C 2 7H34N207CIFS: C, 55.43; H, 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70. Example 434 trans.trans-2-(3-Fluoro-4-methoxvPhenvl-4(1.3-benzodioxol-5-vl 20 .1-(2-(N-isobutvi-N-(3-chloropropanesulf onvlamino)ethyllpvrroidine 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD30D, 300 MHz) 8 0.79 (d, 3H, J=7), 0.84 (d, 3H, J=7),1.68 (hept, 1H, J=7), 2.18 (pen, 2H, J=7), 2.8-3.4 (m, 10H), 3.5-3.8 25 (m, 3H), 3.65 (t, 2H, J=6), 3.90 (s, 3H), 5.94 (s, 2H), 6.77 (d, 1H, J=8), 6.87 (dd, 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.13 (t, 1H, J=9), 7.27 (m, 2H). MS (DCI/NH3) m/e 599 (M+H)+. Anal calcd for C 2 8
H
3 6N207CIFS - 0.3 TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01. 30 Example 435 trans. trans-2-Propoxymethyl-4-(1.3-benzodioxol-5-yl-l-(N. N-di(n butyllaminocarbonvliethylP-prroiine acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDC13, 300 MHz) 8 0.87-0.98 (m, 9H), 1.21-1.39 3S (m, 4H), 1.43-1.57 (m, 4H), 1.58-1.70 (m, 2H), 3.13-3.29 (m, 4H), 3.34 3.43 (m, 3H), 3.45-3.55 (m, 3H), 3.69 (dd, J = 10.2, 4.5 Hz, 1H), 3.80- WO 99/06397 PCT/US98/15479 -412 4.20 (m, 4H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H). MS(DCI/NH3) m/e 477 (M+H)+. Anal calcd for C26H40N206-0.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22. 5 Example 436 trans. trans-2-(3-Fluoro-4-methoxyphenll)- 4 -(l.3-benzodioxol-5-yil 1-[2-(N-oroovi-N-(4-methylbutanesulf onv)aminolethyllovrrolidine-3 carboxylic acid 10 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-67 0C. 1 H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (d, J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (m, 3H), 2.24-2.33 (m, 1H), 2.68-2.93 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52 15 3.58 (, 1H), 3.65 (d, J=12Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 (d, J=9Hz, 1Hz) , 7.16 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+. 20 Example 437 trans, trans-2-(4-Methoxy-3-fluorophen.3 benzodioxol-5-yl)-1-r2-(N-propyl-N-(n pentanesulfonylaminolethylopyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 25 was prepared. 1H NMR (300MHz, CDCI3) 8 0.81 (t, J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (m, 4H), 1.44 (sextet, J=7Hz, 2H), 1.67-1.78 (m, 2H), 2.22-2.34 (m, 1H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.33 (m, 2H), 3.45 (dd, J=3Hz, 9Hz, 1H), 3.47-3.56 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 5.95 (s, 2H), 6.55 (s, 1H), 6.65 (s, 1H), 30 6.92 (t, J=7H, 1H), 7.11 (d, J=9Hz,1H), 7.17 (d, J=12Hz, 1H).
WO 99/06397 PCT/US98/15479 -413 Example 438 trans.trans-2-(3-Fluoro-4-methoXyphenyl)- 4 -(1.3-benzodioxol-5-ylb 1 -r2-(N-propyl-N-(2.2.3.3.3 pentafluoroprooxyethanesulfonl)aminolethyllpyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-64 *C. 1H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24 2.33 (m, 1H), 2.70-2.82 (m, 1H), 2.85-3.09 (m, 5H), 3.14-3.28 (m, 4H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (m, 1H), 3.15 (d, J=9Hz, 1H), 3.87 (s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 685 (M+H)+. 5 Example 439 trans.trans-2-( 1.4-Benzodioxan-6-yi)-4-(7-methoxY-1 3-benzodioxol 5-y)-1-[2-(N-roovi-N-(n-pentanesulfonyllaminolethvilpvrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound o was prepared. 1H NMR (CDC13) 8 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.23-1.36 (m, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (m, 2H), 2.20 2.30 (m, 1H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 (m, 1H), 3.59 (d, J=9Hz, 1H), 3.91 (s, 3H), 4.24 (s, 4H), 5.95 (s, 2H), 6.57 (s, 1H), 6.68 (s, 1H), 6.82 (d, 5 J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 (d, J=2Hz, 1H). Example 440 transtrans-4-(13- Ben zodioxol-5-v)-2-(4-methoxvohenvi)-1-(((N butvli-N-(4- meth oxvbenzvl) amino)cgarbonvil)methyl)lovrrol idi ne-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) S (rotamer) 7.32 (1H, d, J=10), 7.22 (1H, m), 7.10 (1H, d, J=9), 7.03 (6.98) (1H, d, J=3), 6.90-6.80 (4H, m), 6.79 (2H, d, J=9), 6.77 (1H, t, J=8), 5.85 (2H, s), 4.92 (4.10) (1H, d, 35 J=15), 4.42 (4.22) (1H, d, J=15), 3.81 (1H, m), 3.79 (3.78) (3H, s), 3.76 (3H, s), 3.62 (1H, m), 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 (1H, m), 1.23 WO 99/06397 PCT/US98/15479 -414 (2H, m), 1.01 (1H, m), 0.83 (0.75) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N207 - 0.5 H20: C, 67.91; H, 6.73; N, 4.80. Found: C, 67.78; H, 6.44; N, 4.55. 5 Example 441 trans. trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-ylF 1-(2-(N-isobutvi-N-(pentanesulfonviaminolethvilpvrrolidine-3 carboxviic acid Using the procedures described in Example 66, the title compound 0 owas prepared. 1 H NMR (CD30D, 300 MHz) 8 0.76 (d, 3H, J=7), 0.84 (d, 3H, J=7), 0.92 (t, 3H, J=7), 1.36 (m, 4H),1.70 (m, 3H), 2.90 (m, 2H), 3.02 (m, 2H), 3.1-3.8 (m, 7H), 3.84 (d, 2H, J=8), 3.91 (s, 3H), 5.96 (s, 2H), 6.80 (d, 1H, J=8), 6.88 (dd, 1H, J=2, 8), 7.00 (d, 1H, J=2), 7.19 (t, 1H, J=9), 7.35 (m, 2H). MS (DCI/NH3) m/e 593 (M+H)+. Anal calcd for C30H41N207F 15 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95. Example 442 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxypheniYl-1-(N butyl-N-(3-fluorophenylaminoicarbonliethYlyrrolidine- 3 20 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.87 (t, J=7 Hz, 3H), 1.10 1.30 (m, 4H), 2.70-2.90 (m, 2H), 3.13 (t, J=8 Hz, 1H), 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.80-7.20 (m, 9H), 7.40 25 (m, 1H). MS (DCI) m/e 549 (M+H)+. Anal calcd for C31H33N206F - 0.8 H20: C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84. Example 443 trans, trans-4-(1.3-Benzodioxol-5-yI)-2-(4-fluorophenyl)-1 -(N-butyl 30 N-(3-chlorophenylamino)carbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 1.50 (m, 4H), 2.65-2.85 (m, 2H), 3.05-3.85 (m, 7H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.85 (dd, J=8 Hz, 1H), 6.90-7.10 (m, 4H), 7.10-7.25 (m, 3H), 35 7.33-7.45 (m, 2H). MS (DCI) m/e 553 (M+H)+. Anal calcd for WO 99/06397 PCT/US98/15479 -415
C
3 0H30N205FCl: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98. Example 444 5 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1
-(((N
butyl-N-(3.4-dimethoxybenzyllamino)carbonylimethylpyrrolidine-3 carboxviic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 (rotamer) 7.33 (1H, d, J=10), 0 7.23 (1H, m), 7.03 (6.97) (1H, d, J=3), 6.90-6.60 (6H, m), 6.47 (1H, m), 5.93 (2H, m), 4.83 (4.09) (1H, d, J=15), 4.45 (4.22) (1H, d, J=15), 3.83 (3.86) (3H, s), 3.79 (1H, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (1H, m), 3.43 (2H, m), 3.28 (1H, m), 3.20-2.70 (4H, m), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 605 5 (M+H+). Anal calcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38. Example 445 transtrans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 -(((N 20 butyl-N-(2-methoxybenzyl)amino) carbonyl)methyl)pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 ) 8 (rotamer) 7.33 (1H, d, J=10), 7.11 (2H, m), 7.03 (1H, dd, J=8, 3), 6.90-6.60 (7H, m), 5.93 (2H, m), 4.83 25 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=15), 3.81 (1H, m), 3.78 (3.73) (3H, s), 3.72 (3H, s), 3.59 (1H, m), 3.43 (2H, m), 3.30 (1H, m), 3.20-2.70 (4H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 4.61. 30 WO 99/06397 PCTIUS98/15479 -416 Example 446 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxypheny)-1
-(((N
butyl-N-(3-methoxvbenzyl)aminoicarbonylmethylipyrrolidine-3 carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 ) 8 (rotamer) 7.31 (1H, d, J=10), 7.13 (1H, d, J=9), 7.16 (1H, dt, J=8, 3), 7.03 (1H, dd, J=10, 2), 6.90-6.60 (6H, m), 6.50 (1H, m), 5.94 (2H, m), 4.82 (4.19) (1H, d, J=15), 4.50 (4.23) (1H, d, J=15), 3.78 (3.76) (3H, s), 3.77 (1H, m), 3.75 (3.67) (3H, s)., 3.59 0 (1H, m), 3.57-3.35 (2H, m), 3.25 (1H, m), 3.20-2.70 (4H, m), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60. 15 E example 447 trans. trans-2-(3-Fluoro-4-methoxyphenyl-4-(1.3-benzodioxol-5-yli 1-(2-(N-(2-methoxyethyDl-N-(3 chloropropanesulfonylbaminolethlipyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound 20 was prepared. 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, J=7), 2.33 (m, 1H), 2.81 (m, 2H); 2.93 (t, 1H, J=9); 3.1-3.6 (m, 10H), 3.24 (s, 3H); 3.65 (t, 2H, J=6), 3.70 (d, 1H, J=9), 3.87 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.97 (d, 1H, J=2), 7.07 (t, 1H, J=9), 7.17 (m, 2H). MS (DCI/NH3) m/e 601 (M+H)+. Anal calcd for C27H34N208CIFS: 25 C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26. Example 448 trans. trans-2-(3-Fluoro-4-methoxyphenyli-4-(1.3-benzodioxol-5-yl 1-(2-(N-(2-methoxyethyl)-N-(pentaneulfonyl)aminl)ethyl)pyrrolidine 30 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD30D, 300 MHz) 8 0.93 (m, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.33 (m, 1H), 2.75-3.1 (m, 7H), 3.23 (s, 3H), 3.3-3.6 (m, 6H), 3.70 (d, 1H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 35 (dd, 1H, J=2, 8), 6.97 (d, 1H, J=2), 7.07 (t, 1H, J=9), 7.18 (m, 2H). MS WO 99/06397 PCTIUS98/15479 -417 (DCI/NH3) m/e 595 (M+H)+. Anal calcd for C29H39N208FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29. Example 449 5 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)- 1 -(((N-4 heptyl)-N-(4-fluoro-3 methylphenylaminoicarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.89 (m, 6H), 1.18-1.36 (m, 10 8H), 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=14.9 Hz, 1H), 2.82 (m, 1H), 3.07-3.29 (m, 2H), 3.32-3.41 (m, 1H), 3.53-3.60 (m, 1H), 3.70-3.79 (m, 1H), 3.79 (s, 3H), 4.68 (m, 1H), 5.92 (m, 2H), 6.69-6.90 (m, 6H), 6.93-7.07 (m, 4H). MS (DCI) m/e 605 (M+H+). Anal calcd for C35H41FN206: C, 69.52; H, 6.83; N, 4.63. Found: C, 15 69.31; H, 6.78; N, 4.35. Example 450 transtrans-4-(1.3-Benzodioxol-5-yil-2-(4-methoxyheny)-1 -(((N-(5 nonyl)-N-(4-fluoro-3 20 methylphenyllamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) S 0.81-0.90 (m, 6H), 1.30 (m, 12H), 2.14 (s, 1.5 (CH3 rotamer)), 2.30 (s, 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz, 1H), 2.80 (m, 1H), 3.09-3.24 (m, 2H), 3.33-3.42 (m, 1H), 25 3.50-3.55 (m, 1H), 3.65-3.77 (m, 1H), 3.79 (s, 3H), 4.64 (m, 1H), 5.93 (m, 2H), 6.70-6.84 (m, 5H), 6.91-7.13 (m, 5H). MS (DCI) m/e 633 (M+H+). Anal calcd for C37H45FN206: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19. 30 Example 451 trans, trans-4-(1.3-Benzodioxol-5-yil-2-(4-methoxyphenyl)-1 -((N-(5 nonylamino)carbonylmethylloyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.80 (t, J=7.0 Hz, 3H), 0.84 35 (t, J=7.1 Hz, 3H), 1.15-1.55 (m, 12H), 2.88 (d, J=15.9 Hz, 1H), 3.07 (m, 2H), 3.26 (d, J=16.3 Hz, 1H), 3.36 (dd, J=4.4, 9.8 Hz, 1H), 3.64 (m, 1H), WO 99/06397 PCT/US98/15479 -418 3.76 (m, 1H), 3.79 (s, 3H), 3.98 (d, J=9.5 Hz, 1H), 5.93 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.85 (dd, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 6.99 (d, J=1.7 Hz, 1H), 7.39 (m, 2H). MS (DCI) m/e 525 (M+H+). Anal calcd for C30H46N206 - 0.35 H20: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11. Example 452 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxvphenvll-l-((N butyl-N-(2-fluorop~henvil)amino)carbonvimethyllpvrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (dt, J=7 Hz, 3H), 1.15 1.32 (m, 4H), 3.77 (d, J=2 Hz, 3H), 2.65-5.92 (m, 9H), 5.93 (d, J=4 Hz, 2H), 6.70-6.90 (m, 4H), 7.00-7.45 (m, 7H). MS (DCI) m/e 549 (M+H)+. 5 Anal calcd for C31H33N206 - 0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68. Example 453 trans, trans-2-(4-Methoxphenl)- 4 -(1.3-benzodioxol-5-y)-1 -[2-(N 0 prooyl-N-(2-benzothiazolyl)amino)ethyilpyrrolidine-3-carboxylic acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-bromopyrimidine. 1 H NMR (300 MHz, CDCI3) 8 0.88 (t, J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25 2.37 (m, 1 H), 2.85-2.97 (m, 3H), 3.28-3.36 (m, 2H), 3.50-3.58 (m, 3H), s 3.60-3.65 (m, 1H), 3.67 (d, J=9Hz, 1H),3.71 (s, 3H), 5.87 (d, J=2Hz, 1H), 5.91 (d, J=2Hz, 1H), 6.57 (d, J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, 1H), 6.76 (d, J=8 Hz, 2H), 6.91 (d, J=2Hz, 1H), 7.01 (t, J=8Hz, 1H), 7.22 (t, J=8Hz, 1H), 7.29 (d, J=8Hz, 2H), 7.40 (d, J=7Hz, 1H), 7.55 (d, J=7Hz, 1H). 0 Example 454 trans, trans-2-(2-Ethoxyethyl)- 4 -(1,3-benzodioxol-5-yjl-1 -(N N-dil( butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.91 (t, J = 7.4 Hz, 3K), 0.94 35 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 5H), 1.46-1.60 (m, 4H), 2.03-2.12 (m, 2H), 3.07 (t, J = 8.0 Hz, 1H), 3.07-3.34 (m, 6H), WO 99/06397 PCT/US98/15479 -419 3.43-3.52 (m, 3H), 3.59-3.74 (m, 3H), 3.80-4.01 (m, 2H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS(DCI/NH3) m/e 477 (M+H)+. Anal calcd for C26H40N206 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29. 5 Example 455 trans.trans-2-(4-Methoxy-3-fluorophenyl-4-(1.3-benzodioxol-5-vi> 1-[2-(N-Drpv-N-(2-(morphoin-4 ylethylsulfonylaminlO'ethyllrrolidine-3-carboxylic acid 10 Ethyl 2
-(
4 -methoxy-3-fluorophenyl)-4-(13-benzodioxol-5-yl) 1-[2- (N-propyl-N-[2-vinylsulfonyl]amino)ethylpyrrolidine-3 carboxylic acid, prepared. by the procedures of Example 125, was reacted with excess morpholine for 4 hours at room temperature. Chromatography on silica gel eluting with EtOAc gave a 65% yield of an 15 intermediate ethyl ester which was hydrolyzed to the title compound with NaOH in ethanol/water. IH NMR (300 MHz, CDCI3) 8 0.81 (t, J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (m, 1H), 3.62 3.70 (m, 5H), 3.88 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.70 (dd, 20 J=2Hz, 8Hz, 1H), 6.90 (t, J=9Hz, 1H), 6.96 (d, J=2Hz, 1H), 7.10 (d, J=8Hz, 1H), 7.18 (dd, J=2Hz, 12Hz, 1H). Examiple 456 trans. trans- 2-(3-Fluoro-4-methoxvphenvl-4-(1.3-ben zodioxol-5-Yi 25 1 -I2-(N-propyl-N-((2.2.2 trifluoroethoxyethanelsulfonvlaminolethvilpvrrolidine-3-carbxvho Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 95-96 *C. 1 H NMR 30 (CD30D, 300MHz) 8 0.80 (t, J=7Hz, 3H), 1.35-1.48 (m, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (m, 8H), 3.80-3.87 (m, 2H), 3.93 (s, 3H), 3.94 4.02 (m, 4H), 4.66 (d, J=12Hz, 1H), 5.96 (s, 2H), 6.83 (d, J=8Hz, 1H), 6.94 (d, J=8Hz, 1H),7.06 (d, J=2Hz, 1H), 7.23 (t, J=9Hz, 1H), 7.43 (d, J=9Hz, 1H), 7.49 (dd, J=2Hz,J=12Hz, 1H). MS (DCI/NH3) m/e 635 (M+H)+. 35 WO 99/06397 PCT/US98/15479 -420 Example 457 trans. trans-4-(1.3-Benzodioxol-5-vl-2-(4-fluo rohenv)-1 -(N-butvl
N-(
3 -methyl1henylami nocarbonylmethyl) pyrroidine 3 carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CD30D) S 0.87 (t, J=7 Hz, 3H), 1.20 1.50 (m, 4H), 2.31 (s, 3H), 2.65-2.80 (m, 2H), 3.19 (t, J=7 Hz, 1H), 3.25 (d, J=10 Hz, 1H), 3.35-3.65 (m, 4H), 3.79 (d, J=10 Hz, 1H), 5.93 (s, 2H), 6.74 (d, J=7 Hz, 1H), 6.80-6.90 (m, 3H), 6.91-7.09 (m, 3H), 7.10-7.35 (m, 4H). MS (DCI) m/e 533 (M+H)+. Anal calcd for C 3 1H33N205F: C, 69.91; o H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23. Example 458 trans. trans-2-(3-Fluoro-4-methoxyphenvl)- 4 -(1.3-benzodioxol-5-yiW 1-(2-(N-(2-methoxethyl)-N-(butan Is 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.94 (m, 3H), 1.23 (hex, 2H, J=8), 1.69 (m, 2H), 3.08 (m,2H), 3.20 (s, 3H), 3.3-3.5 (m, 10H), 3.77 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5.96 (s, 2H), 6.81 (d, 1H, J=8), 6.88 (dd, 20 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.22 (t, 1H, J=9), 7.38 (m, 2H). MS (APCI) m/e 581 (M+H)+. Anal calcd for C 2 8 H37N208FS - 1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11. Example 459 25 trans. n--(3-Fluoo-4-ethoxyphenyl)-4-( .3-benzodioxol-5I 1-2-(N-proovl-N -(2-methvlpropanesulf onvlaminolethyl'ipyrrolidine 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 77-78 *C. 1 H NMR 30 (CDCI3, 300MHz) 8 0.83 (t, J=7Hz, 3H),1.06 (d, J=6Hz, 6H),1.45 (q, J=7HZ, 2H), 2.20 (septet, J=6Hz, -1H), 2.26-2.36 (m, 1H), 2.62-2.78 (m, 3H), 2.85-2.95 (m, 2H), 2.97-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.62 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, 35 J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.12 (d, J=9Hz, 1H), 7.18 (dd, J=2Hz, .1=12Hz. 1H). MS (DCI/NH3) m/e 565 (M+H)+.
WO 99/06397 PCTIUS98/15479 -421 Example 460 trans, trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1
-(((N
butyl-N-(4-nitrobenzylamino)carbonylmethylpyrrolidine-3 5 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 ) 8 (rotamer) 8.11 (2H, m),7.32 (3H, dd, J=9, 2), 7.16 (7.07) (1H, bd, J=10), 6.98 (6.94) (1H, d, J=2), 6.85 (2H, d,.J=9), 6.83-6.70 (2H, m), 5.99 (5.97) (2H, d, J=2), 5.02 (4.18) (1H, o d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) (3H' s), 3.72 (1H, d, J=10), 3.61 (1H, m), 3.48 (1H, bd, J=15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (1H, m), 3.79 (1H, bd, J=14), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 5 6.85. Example 461 trans. trans-2-(4-Ethylphenyl)-4-(3.4-difluorophenyl- 1 -(N. N-di(n butylaminocarbonylmethyl-pyrrolidine-3-carboxylic acid o Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD30D, 300 MHz) 8 0.78 (t, 3H, J=7), 0.87 (t, 3H, J=7), 1.02 (hex, 2H, J=7), 1.22 (t, 3H, J=7), 1.27 (m, 2H), 1.45 (m, 2H, J=7), 2.63 (q, 2H, J=7), 2.77 (d, 1H, J=14), 2.94 (dd, 1H, J=7, 9), 3.05 (m, 3H), 3.3-3.5 m, 3H), 3.44 (d, 1H, J=14), 3.66 (m, 1H), 3.75 (d, 1H, J=10), 5 7.20 (td, 2H, J=1,8), 7.22 (m, 2H), 7.32 (td, 2H, J=1,8), 7.43 (ddd, 1H, J=2,8,12). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H38N203F2 - 0.6 H20: C, 68.11; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37. 0 Example 462 trans.trans-4-(1.3-Benzodioxol-5-yil-2-(4-methoxypheny)-1-(N butyl-N-(4-fluoro-3-methylphenyl)aminocarbonylmethyl)pyrrolidine 3-carboxylic acid Using the procedures described in Example 1, the title compound is was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 1.50 (m, 4H), 2.21 (d, J=2 Hz, 3H), 2.64 (d, J=14 Hz, 1H), 2.75 (dd, J=10 WO 99/06397 PCT/US98/15479 -422 Hz, 1H), 3.05 (t, J=7 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.35-3.70 (m, 5H), 3.77 (s, 3H), 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-7.10 (m, 4H). MS (DCI) m/e 563 (M+H)+. Anal calcd for C 3 2H35N206F - 0.5 H20: C, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81. 5 Example 463 trans.trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl-1-(N butyl-N-((3-isopropyl)phenylamino) carbonvlimethyl)-prrolidine-3 carboxylic aci-d 0 Using the procedures described in Example'1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, 3H), 1.17 (d, J=7 Hz, 6H), 1.20-1.50 (m, 4H), 2.63 (d, J=15 Hz, 1H), 2.75 (t, J=7 Hz, 1H), 2.85 (m, 1H), 3.00 (t, J=7 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.70 (m, 5H), 3.75 (s, 3H), 5.90 (s, 2H), 6.65-6.80 (m, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 5 (m, 3H), 7.20-7.35 (m, 2H). MS (DCI) m/e 573 (M+H)+. Anal calcd for C34H40N206 - 0.15 H3PO4: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43. Example 464 20 trans, trans-4-(1,3-Benzodio xol-5-y()-2-(4-methoxyphenyt)-1-(N butyl-N-( 3 -ethylphenyl)aminocarbonylmethyl)Drrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (m, J=7 Hz, 3H), 1.16 (t, 25 J=7 Hz, 3H), 1.20-1.47 (m, 4H), 2.50 (q, J=7 Hz, 2H), 2.70-2.85 (m, 2H), 3.13 (t, J=7 Hz, 1H), 3.20-4.5 (m, 6H), 3.78 (s, 3H), 3.83 (d, J=8 Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.90 (m, 5H), 7.02-7.13 (m, 3H), 7.15-7.25 (m, 2H). MS (DCI) m/e 559 (M+H)+. Anal calcd for C33H38N206 .0.3 H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H, 30 6.63; N, 4.60.
WO 99/06397 PCT/US98/15479 -423 Example 465 transtrans-4-(1.3-Benzodioxol-5-yl)-2-(4-ethylohenyl)-1 -(((N-(3 chlorophenylI)-N-butylamino)carbonylmethyl)pyrrolidine-3-carboxylic 5 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 0.87 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.41 (m, 2H), 2.63 (q, 2H, J=7Hz), 2.67 (m, 1H), 2.92 (rn, 1H), 3.20 (m, 2H), 3.42 (m, 1 H), 3.60 (q, 2H, J=7Hz), 3.93 (m, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 3H), 6.95 (br s, 1H), 7.02 10 (s, 1H), 7.10 (br s, 3H), 7.25 (m, 2H). MS (APCI) rfi/e 563 (M+H)+. Anal. calc'd for C32H35N205CI - 0.80 H3PO4: C, 59.92; H, 5.88; N, 4.37. Found: C, 59.90; H, 5.83; N, 4.07. Example 466 15 trans.trans-4-(1.4-Benzodioxan-6-yil-2-(4-ethylphenly)-1-(((N-(3 chloropheny)-N-butylamino)carbonyl)methyl)oyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) S 0.86 (t, 3H, J=7Hz), 1.23 (t, 20 3H, J=7Hz), 1.25 (m, 2H), 1.40 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.70 (m, 1H), 2.95 (m, 1H), 3.20 (m, 2H), 3.40 (m, 1 H), 3.57 (m, 3H), 3.90 (m, 1H), 4.25 (s, 4H), 6.80 (d, 1H, J=8Hz), 6.95 (d, 1H, J=2Hz), 6.95 (m, 2H), 7.07 (br s,.3H), 7.22 (m, 3H). MS (APCI) m/e 577. (M+H)+. Anal. calc'd for C33H37N205CI - 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; 25 H, 6.25; N, 4.36. Example 467 trans. trans-4-(Benzof uran-5-yl)-2-(4-ethylphenyl)-1 -(((N-(3 chlorophenyl)-N-butylamino) carbonyl)methyl)pyrrolidine-3-carboxylic 30 aci Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 5 0.85 (t, 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (m, 2H), 1.40 (m, 2H), 2.60 (q, 2H, J=7Hz), 2.72 (m, 1H), 2.93 (m, 1H), 3.22 (m, 2H), 3.50 (m, 1H), 3.55 (m, 2H), 3.75 (m, 1H), 3.90 35 (br d, 1H), 6.75 (d, 1H, J=1 Hz), 6.80 (br d, 1H), 6.95 (br s, 1H), 7.08 (m, 4H). 7.20 (t, 1H, J=8Hz), 7.28 (t, 1H, J=8Hz), 7.42 (m, 2H), 7.58 (d, 1H, WO 99/06397 PCT/US98/15479 -424 J=1Hz), 7.63 (s, 1H). MS (APCI) m/e 559 (M+H)+. Anal. calc'd for C33H35N204C1 - 0.45 H20: C, 69.88; H, 6.38; N, 4.94. Found: C, 69.83; H, 6.04; N, 4.87. 5Example 46 trans. trans-2-(4-Methoxy-3-fluorophenv)-4-(7-methox-1 .3 benzodioxol-5-vl-1-r2-(N-butvi-N-phenviaminoethvliprrolidine-3 carboxvyic acid Ethyl 2 -(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1,3 o benzodioxol-5-yl)-1-[2-(bromoethyl]-pyrrolidine-3-carboxylate, prepared using the procedures of Example 61A (300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white 5 powder. 1 H NMR (300 MHz, CDCI3) 6 0.90 (t, J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (m, 1H), 2.68-2.77 (m, 1H), 2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m, 3H), 3.45-3.55 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.83 (s, 3H), 3.90 (s, 3H), 5.95 (s, 2H), 6.51 (d, J=7Hz, 2H), 6.55-6.62 (m, 2H), 6.69 (d, J=2Hz, 1H), 6.84 (t, J=8Hz, 20 1H), 7.02-7.15 (m, 3H), 7.19 (dd, J=2Hz, 12Hz, 1H). Example 469 trans, trans-4-(1 .4-Benzodioxan-6-yi)-2(4ethylphenyl)1
-(((N,.N
di(n-butylaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid 25 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.78 (t, 3H, J=7Hz), 0.88 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.78 (m, 1H), 2.9-3.2 (envelope, 4H), 3.30 (m, 1H), 3.40 (m, 3H), 3.60 (m, 1H), 3.80 (m, 1H), 4.25 (s, 4H), 6.80 (d, 30 1H, J=8Hz), 6.90 (m, 1H), 6.98 (d, 1H, J=2Hz), 7.17 (d, 2H, J=8Hz), 7.30 (m, 2H). MS (APCI) m/e 523 (M+H)+. Anal. calc'd for C31H42N205 ' 1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 7.55;.N, 4.48.
WO 99/06397 PCT/US98/15479 -425 Example 470 trans. trans-4-(1.4-Benzodioxan-6-yl)-2-(4-methoxyhenl)-1
-((N
butyl-N-(3-methylphenylamino)carbonylmethylp yrrolidine-3 carboxylic acid 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=7.1 Hz, 3H), 1.30 (m, 2H), 1.44 (m, 2H), 2.30 (s, 3H), 2.80 (d, J=15.2 Hz, 1H), 2.85 (t, J=9.3 Hz, 1H), 3.19 (t, J=9.3 Hz, 1H), 3.33 (d, J=10.2 Hz, 1H), 3.42-3.61 (m, 3H), 3.79 (s, 3H), 3.91 (d, J=9.8 Hz, 1H), 4.22 (m, 4H), 6.75-6.86 (m, 6H), 10 6.95 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 7.22 (d, J=10.2 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H). MS (DCI) m/e 559 (M+H+). Anal calcd for C33H38N206 - 0.4 CH3CO2C2H5: C, 69.97; H, 6.99; N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48. 15 Example 471 trans.trans-4-(1.4-Benzodioxan-6-yl)-2-(4-methoxyphenyl-1
-((N
butvi-N-(3-chlorophenviamino)carbonvlmethyllpvrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound 20 was prepared. 1 H NMR (300 MHz, CD30D) 5 0.87 (t, J=7.0 Hz, 3H), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d, J=14.6 Hz, 1H), 2.86 (t, J=9.0 Hz, 1H), 3.16 (t, J=9.5 Hz, 1H), 3.34-3.43 (m, 2H), 3.48-3.62 (m, 3H), 3.79 (s, 3H), 3.85 (d, J=9.5 Hz, 1H), 4.22 (m, 4H), 6.78 (d, J=8.5 Hz, 1H), 6.81 6.86 (m, 3H), 6.93-7.09 (m, 5H), 7.33-7.38 (m, 2H). MS (DCl) m/e 579 25 (M+H+). Anal calcd for C32H35CIN206 - 1.1 CH3CO2C2H5 - 0.15 H3PO4: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98. Example 472 trans.trans-4-(1.3-Benzodi oxol-5-yl)-2-(4-methoxphenvl- 1-(4 30 pyridylimethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 2.84 (t, J=9.6 Hz, 1H), 2.88 (dd, J=9.6, 7.3 Hz, 1H), 3.09 (dd, J=3.3, 9.6 Hz, 1H), 3.21 (d, J=14.3 Hz, 1H), 3.53 (m, 1H), 3.78 (s, 3H), 3.81 (m, 2H), 5.92 (m, 2H), 6.73 (d, J=8.1 35 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 1H), 6.93 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 7.43 (m. 4H). 8.44 (d, J=5.2 Hz, 2H). MS (DCI) m/e 433 (M+H+). Anal WO 99/06397 PCT/US98/15479 -426 calcd for C25H24N205 - 0.3 CH3CO2C2H5: C, 68.57; H, 5.80; N, 6.10. Found: C, 68.68; H, 5.60; N, 5.81. 'E xample 473 5 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenvl)- 1 -((N butyl-N-(3-te rt-butylohenylaminoicarbonylimethyl)pyrrolidine- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.88 (t, J=7.2 Hz, 3H), 1.23 o (s, 9H), 1.26-1.45 (m, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (m, 1H), 3.13 (t, J=9.0 Hz, 1H), 3.29 (d, J=15.1 Hz, 1H), 3.50-3.66 (m, 4H), 3.77 (s, 3H), 3.84 (d, J=9.6 Hz, 1H), .5.92 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.79-6.85 (m, 4H), 6.86-6.90 (m, 1H), 6.99 (t, J=1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.13 (m, 2H), 7.33 (t, J=7.7 Hz, 1H), 7.42 (m, 1H). MS (DCI) m/e 587 5 (M+H+). Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69. Example 474 trans.trans-4-(1 .3-Benzodioxol-5-yli-2-(4-methoxyphenyl--((N 20 butyl-N-(3-n-butylphenylamino)carbonvyl methy)Dyrrolidine- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 5 0.88 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 1.23-1.59 (m, 8H), 2.58 (t, J=7.6 Hz, 2H), 2.75 (d, 25 J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 1H), 3.12 (t, J=9.3 Hz, 1H), 3.29 (d, J=15.6 Hz, 1H), 3.46 (dd, J=4.9, 9.7 Hz, 1H), 3.52-3.64 (m, 3H), 3.78 (s, 3H), 3.83 (d, J=9.8 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.79 6.87 (m, 4H), 7.05 (d, J=1.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 (t, J=7.6 Hz, 1H). MS (DCI) m/e 587 (M+H+). Anal calcd for 30 C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.
WO 99/06397 PCTIUS98/15479 -427 Example 475 trans. trans-4-(3.4-Difluorochenyl-2-(4-ethylphenl)-1 -(N-(n-butyl) N-(3-methylohenyllaminocarbonylmethyl)pyrrolidine 3 carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (CD30D, 300 MHz) 5 0.87 (t, 3H, J=7), 1.19 (t, 3H, J=7), 1.28 (m, 2H), 1.43 (m, 2H), 2.28 (s, 3H), 2.60 (q, 2H, J=7), 2.66 (m, 2H), 3.06 (m, 1 H), 3.21 (d, 1H, J=15), 3.42 (dd, 1H, J=4,9), 3.58 (m, 3H), 3.71 (d, 1H, J=9), 6.80 (s, 2H), 7.06 (s, 4H), 7.18 (m, 4H), 7.45 (m, 1H). MS (APCI) m/e 535 (M+H)+. Anal calcd for C 3 2H36N203F2 - 1.3 HOAc: 10 C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70. Example 476 trans. trans-2-(4-Ethlhenl-4-(4 -(N-(n-butyl N-(3-chlorophenyllaminocarbonyimethyl'prrolidine-3-carboxylic acid 15 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD30D, 300 MHz) 8 0.82 (t, 3H, J=7), 1.16 (t, 3H, J=7), 1.23 (m, 2H), 1.35 (m, 2H), 2.55 (q, 2H, J=7), 2.66 (m, 2H), 3.01 (t, 1H, J=9), 3.16 (d, 1H, J=15), 3.32 (dd, 1H, J=4,9), 3.56 (m, 3H), 3.67 (d, 1H, J=9), 6.94 (d, 1H, J=7), 7.02 (m, 5H), 7.14 (m, 2H), 7.32 (m, 3H). MS 20 (APCI) m/e 555 (M+H)+. Anal calcd for C 3 1H33N203CIF2 - 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98. Example 477 trans.trans-4-(1.4-Benzodioxan-6-y)-2-(4Luorphenyl)l -(N-butyL 25 N-(3-chlorophenyllaminocarbonylimethyl)Pyrrolidine3carboxyic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.10 1.30 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (t, J=7 Hz, 1H), 3.15-3.75 (m, 6H), 4.02 (m; 4H), 6.75 (d, J=6 Hz, 1H), 6.85 (dd, J=7 Hz, 1H), 6.90 (7.19, J=m 30 Hz, 6H), 7.32-7.43 (m, 3H). MS (DCI) m/e 567 (M+H)+. Anal calcd for C31H32N205FCI - 1.6 H20: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H, 5.54; N, 4.42.
WO 99/06397 PCT/US98/15479 -428 Example 478 trans, trans-4-(Benzofuran-5-yl)-2-(4-ethylphenyl)- I -(N. N-di(n butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CDCI3) 5 0.78 (t, 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 1.21 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.45 (m, 2H), 2.62 (q, 2H, J=7Hz), 2.80.(d, 1H, J=13Hz), 3.0 (m, 2H), 3.15 (m, 2H), 3.35 (m, 1H), 3.43 (m, 2H), 3.52 (m, 1H), 4.40 (m, 2H), 6.73 (d, 1H, J=lHz), 7.14 (d, 2H, J=8Hz), 7.26 (s, 1H), 7.31 (d, 2H, J=8Hz), 7.44 (s, 0 2H), 7.60 (d, 1H, J=1 Hz), 7.65 (s, 1H). MS (APCI) W1/e 505 (M+H)+. Anal. calc'd for C31H40N204: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.21. Example 479 15 trans, trans-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-1.3 benzodioxol-5-yl)-1-r2-(N-propyl-N-(pyrrolidine-1 carbonylmethylaminoethyllpyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1,3 benzodioxol-5-yl)-1-[2-(N-propyl-aminoethyl]-pyrrolidine-3 20 carboxylate, prepared according to the procedures of Example 61B (300 mg), N-bromoacetyl pyrrrolidine (132 mg) and diisopropylethylamine (154 mg) were heated for 1 hour at 50 *C in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example 1D. 1 H NMR (300 MHz, CDCl3) 8 0.88 25 (t, J=7Hz, 3H), 1.30-1.45 (m, 2H), 1.75-1.92 (m, 4H), 2.30-2.40 (m, 1H), 2.47-2.58 (m, 2H), 2.70-3.00 (m, 5H), 3.24-3.45 (m, 6H), 3.50-3.70 (m, 2H), 3.83 (s, 3H), 3.86 (d, J=9Hz, 1H), 3.88 (s, 3H), 5.93 (s, 2H), 6.58 (d, J=2Hz, 1H), 6.70 (d, J=2Hz, 1H), 6.87 (t, J=8Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.21 (dd, J=2Hz, 12Hz, 1H). 30 Example 480 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzo-dioxol-5-yl)-1 -(2-((N (perhydroazeoinylcarbonyl)-(D)-leucyl)amino)lethyl)pyrrolidine-3 carboxylic acid 35 WO 99/06397 PCT/US98/15479 -429 Example 480A D-Leucine Q-benzyl ester Tosylate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 g). The 5 reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%). 10 Example 480B N-Perhydroazepinylcarbonyl-D-Leucine O-Benzyl ester To the compound resulting from Example 480A (1.0 g) dissolved in chloroform (20 mL) was added triethylamine (0.4 mL). The solution was cooled to 0 *C, and carbonyldiimidazole was added. After 1.5 15 hours, TLC indicated complete consumption of starting material, so hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 N H3PO4 (2 x 20 mL), 20 and brine (20 mL), dried over Na2SO4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 25 - 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%). 25 Example 480C N-Perhydroazepinylcarbonyl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% palladium on carbon (10 mg). After flushing the flask with nitrogen, the reaction was stirred 30 vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg).
WO 99/06397 PCT/US98/15479 -430 Example 480D trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y)-1 (cyanomethyl)-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 % wt. 5 solution in toluene) dissolved in acetonitrile (2.0 mL) was added diisopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 mL). After 2 hours, TLC indicated complete comsumption of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with 20 - 40% EtOAc in 10 hexanes to give the title compound as a colorless'oil (0.28 g, 99%). Example 480E transtrans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -(2 gminoethyl)-pyrrolidine-3-carboxylic acid ethyl ester 15 To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 g), and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) 20 and extracted with 1 M HCI (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 x 2 mL). The combined organic extracts were dried with MgSO4, filtered and evaporated to give the title compound as an unstable oil (0.14 g). 25 Example 480F trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-((N (perhvdroazepinylcarbonyl)leucyl)amino)ethyl)-pyrrolidine-3 carboxylic acid, ethyl ester The compound resulting from Example 480E (0.10 g) was 30 dissolved in methylene chloride (3.0 mL), and the compound resulting from Example 480C (0.07 g) was added. The solution was cooled to 0 *C, and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 mL), and EtOAc (10 mL). The orgainc solution was washed with water (1 mL) and brine (1 mL), 35 dried over MgSO4, filtered and evaporated. The residue was purified by WO 99/06397 PCT/US98/15479 -431 flash chromatography on silica gel eluting with 50 - 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%). Example 480G 5 transtrans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-y)-1 -(2-((N (perhydroazepinylcarbonyl)leucyl)amino)ethyl)pyrrolidine-3-carboxylic acid The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 mL) and 5 M NaOH (0.050 mL) was added. After 10 2 hours, additional 5 M NaOH (0.090 mL) was added. After an additional 3.5 hours, the reaction was evaporated. The residue was dissolved in water (5 mL) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 N H3PO4 to pH = 3. The solid which precipitated dissolved when the mixture was extracted with 15 chloroform (3 x 3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgSO4, filtered and evaporated to give the title compound as a tan solid (0.053 g). Purification by HPLC (Vydac mC18) eluting with a 10 - 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophilization of the desired 20 fractions. 1H NMR (CDC13, 300 MHz) 5 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J = 5.7, 5.7 Hz, 6H), 1.04-1.28 (m, 3H), 1.34-1.65 (m, 19H), 2.95 (br m, 2H), 3.15-3.40 (m, 14H), 3.40-3.55 (m, 4H), 3.58-3.68 (m, 2H), 3.70 3.76 (br m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93 (s, 3H), 5.95 (s, 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (br m, 3H), 25 8.2 (br s, 1H), 8.5 (br s, 1H). MS(DCI/NH3) m/e 623 (M+H)+. Anal calcd for C34H46N407 - 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54. Example 481 30 transtrans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1
-(N.N
di (n-hexylaminocarbonylmethylipyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.80-0.95 (m, 6H), 1.0 (m, 2H), 1.07 (1.55, J=m Hz, 14H), 2.70 (d, J=13 Hz, 1H), 2.85-3.15 (m, 4H), 35 3.20-3.60 (m, 9H), 3.64 (d, J=10 Hz, 1H), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H), 1, 6.80-6.93 (m, 3H), 7.05 (2, 1H), 7.35 (d, J=10 Hz, 2H). Anal WO 99/06397 PCTIUS98/15479 * -432 calcd for C33H46N2O6 - 1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52. Example 482 5 trans. trans-4-(1.4-Benzodioxa-6vl-2-(4-fluorohenvl-1-(N-butvl
N-(
3 -methylphenyl)amin ocarbo nlmethyl) yrroidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 8 0.87 (t, J=7 Hz, 3H), 1.20 1.35 (m, 2H), 1.35-1.40 (m, 2H), 2.32 (s, 3H), 2.55-2.70 (m, 2H), 2.97 (t, 10 J=7 Hz, 1H), 3.22 (d, J=14 Hz, 1H), 3.25-3.70 (m, 5H), 4.20 (m, 4H), 6.97 (d, J=2 Hz, 1H), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCI) m/e 547 (M+H)+. Anal calcd for C 3 2H35N205F - 1.2 H20: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70. 15 Example 483 trans.trans-4-(1. 3 -Benzodioxol-5-Y)-2-(4-methoxyphenyil-1
-(((N
butvi-N-(3-nitrobenzvlIamino)carbmn th carboxylic acid Using the procedures described in Example 1, the title compound 20 was prepared. 1 H NMR (300 MHz, CDC13 ) 8 (rotamer) 8.14 (2H, m), 8.05 (7.83) (1H, m), 7.60-7.30 (3H, m), 7.13 (.1H, m), 7.10-6.70 (5H, m), 5.94 (2H, m), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, m), 4.10 (2H, m), 3.80 (3.76) (3H, s), 3.75-3.40 (3H, m), 3.20-2.80 (2H, m), 1.50 (1H, m), 1.30 (1H, m), 1.20-1.00 (2H, m), 0.91 (0.78) (3H, t, 25 J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C 3 2H35N308 - 2.1 TFA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71. Example 484 transtrans-4-(1.2- Dihydrobenzofuran-5-yl)-2-(4-ethylphenl 1 -(((N 30 butyl-N-(3,4-dimethoxybenzyllamino)carbonyl)me carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDC13 ) 8 (rotamer) 7.40 (2H, m), 7.30-7.10 (4H, m), 6.90-6.70 (3H, m), 6.48 (1H, m), 5.45 (1H, m), 4.65 (1H, d, 35 J=15), 4.57 (2H, dt, J=9, 3), 4.40-4.00 (5K, m), 3.87 (3.85) (3H, s), 3.84 (J, ), 3.E3 (3.79) (3 , , .2) ( , m). 2 0 (2H. t J=10). 2.90 (1H, WO 99/06397 PCTIUS98/15479 -433 m), 2.64 (2H, q, J=8), 1.52 (1H, m), 1.31 (2H, m), 1.22 (3H, dt, J=9, 2), 1.07 (1H, m), 0.92 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 601 (M+H+). Anal calcd.for C36H44N206 - 1.35 TFA: C, 61.59; H, 6.06; N, 3.71. Found: C, 61.69; H, 6.04; N, 3.63. 5 E xample 485 trans. trans-4-(1.3-Benzodioxol-5-yl)-2-(4-methoxyhenyl-1-(((N butyl-N-(4-heptylamino)carbonylmethyl)pyrrolidine-3-carbo xylic 10 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.71-1.04 (m, 11H), 1.07 1.35 (m, 6H), 1.73-1.53 (m, 4H), 2.79-3.25 (m, 5H), 3.35-3.44 (m, 1H), 3.51-3.68 (m, 3H), 3.78-3.89 (m, 1H), 3.79 (s, 3H), 5.92 (m, 2H), 6.74 (dd, J=1.7, 8.1 Hz, 1H), 6.85 (td, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 7.02 15 (dd, J=1.7, 9.5 Hz, 1H), 7.36 (m, 2H). MS (C.1.) m/e 553 (M+H+). Anal calcd for C32H44N206: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06. Example 486 20 trans, trans-2-(4-Methylcyclohexyl)-4-(1,3-benzodioxol-5-yl)-1 -(N.N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.88 (3H, d, J = 7Hz), 0.92 (3H, t, J = 7Hz), 0.96 (3H, t, J = 7Hz), 25 1.05 (1H, m), 1.22-1.40 (7H, m), 1.45-1.65 (6H, m), 1.67-1.84 (4H, m), 3.17-3.45 (6H, m), 3.70 (1H, brm), 3.82 (1H, dd, J = 9Hz, 15Hz), 3.86 (1H, d, J = 15Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H44N205 - 0.25 CF3CO2H : C, 66.96; H, 8.43; N, 5.29. Found: 30 C, 66.79; H, 8.60; N, 4.87.
WO 99/06397 PCT/US98/15479 -434 Example 487 trans, trans-2-(2-Propyloentyl)-4-(1.3-ben zodioxol-5-yl)-1 -(N N-di(n butylaminocarbonylmethyli-pvrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 5 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.12 1.40 (13H, m), 1.42-1.68 (6H, m), 2.90 (1H, m), 3.14-3.30 (2H, m), 3.33 (4H, m), 3.72 (1H, brm), 3.90 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS 0 (DCI/NH3) m/e 517 (M+H)+. Anal calcd for C30H4'8N205 0.35 CF3CO2H : C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98. Example 488 trans.trans-4-(1.4-Benzodioxan-6-yil-2-(4-fluorophenyl)-1 -(N.N-di(n 5 butyliaminocarbonylmethvl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.83 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.90-1.17 (m, 4H), 1.20-1.65 (m, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1H), 2.95-3.60 (m, 7H), 3.71 (d, J=9 Hz, 1H), 4.21 (s, 4H), o 6.72 (d, 1H), 6.91 (dd, J=8 Hz, 1H), 6.97 (d, J=2 Hz, 1H), 7.05 (t, J=7 Hz, 2H), 7.40-7.50 (m, 2H). MS (DCI) m/e 513 (M+H)+. Anal calcd for C29H37N205F - 1.2C F3COOH: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56. 5 Example 489 trans.trans-2-(3-Methylpentyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N-di(n butyl)aminocarbonylmethyl-prrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 o MHz) 5 0.83 (3H, t, J = 7Hz), 0.85 (3H, d, J= 7Hz), 0.91 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7H, m), 1.43-1.68 (5H, m), 1.89 (1H, m), 2.94 (1H, t, J = 6Hz), 3.15-3.27 (3H, m), 3.29-3.60 (5H, m), 3.72 (1H, brd, J = 6Hz), 3.92 (1H, brd, J = 13.5Hz), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, 35 d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N205 WO 99/06397 PCT/US98/15479 -435 -0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84. Example 490 5 trans.trans-2-(2-Ethylbutyl-4-(1.3-benzodioxol-5-yl)-1 -(N.N-di(n butylaminocarbonylmethyl)-oyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.13 10 1.41 (13H, m), 1.43-1.72 (6H, m), 2.96 (1H, brm), 3.12-3.52 (6H, m), 3.55-3.70 (1H, m), 3.70-3.86 (2H, m), 3.99 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N205 0.45 CF3CO2H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 15 5.08. Example 491 trans. trans-2-(3-Fluoro-4-m ethoxyphenyl-4-(1.3-benzodioxol-5-yl) 1 -(2-(N-isobutyl-N-(butanesufonylamino))ethyl)pyrrolidine-3 20 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD30D, 300 MHz) 8 0.74 (d, 3H, J=7), 0.83 (d, 3H, J=7), 0.94 (t, 3H, J=7), 1.44 (hex, 2H), 1.67 (m, 4H), 2.91 (d, 2H, J=8), 3.04 (dd, 2H, J=8,10), 3.1-3.6 (m, 5H), 3.78 (m, 2H), 3.92 (s, 3H), 4.60 25 (m, 1H), 5.97 (s, 2H), 6.82 (d, 1H, J=8), 6.89 (dd, 1H, J=2, 8), 7.01 (d, 1H, J=2), 7.22 (t, 1H, J=9), 7.39 (m, 2H). MS (ESI) m/e 579 (M+H)+. Example 492 trans. trans-2-(4-Methoxy-3-fluorophenyl)-4-(1.3-benzodioxol-5-yl 30 1-[2-(N-propyl-N-[4-ethvipyrimidin-2-yllaminolethyllpyrroLidine-3 carboxylic acid 1-Dimethylamino-1-pentene-3-one, prepared by the method described in Syn. Comm. 12 (1), 35 (1982), was converted to 2-amino 4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 35 (1964). This material was converted to 2-bromo-4-ethyl-pyrimidine with NaNO2 and HBr, using the method of Helv. Chim. Acta 75, 1629 WO 99/06397 PCTIUS98/15479 -436 (1992). This bromopyrimidine was reacted with ethyl 2-(4 methoxphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N-propylamino)propyl] pyrrolidine-3-carboxylate, prepared using the procedures of Example 61B, using the procedure for Example 418, to give the title compound as 5 a white powder. 1H NMR (300 MHz, CDCI3) 8 0.83 (t, J=7Hz, 3H), 1.11 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1H), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (m, 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (d, J=4Hz, 1H), 6.68 (d, J=8Hz, 1H), 6.79 (dd, J=2Hz, 8Hz, 1H), 6.82 (t, J=9Hz, 1H), 6.92 (d, J=2Hz, 1H), 7.05 (d, J=9Hz-r 1H), 7.15 (dd, J=2Hz, o 12Hz, 1H), 8.10 (d, J=4Hz, 1H). Example 493 trans.trans-4-(1.3-Benzodioxol-5-vil-2-(4-methoxyphenyl-1-((N buty-N-(3.4-dim ethylphenylaminocarbonylimethyl)pyrrolidine- 3 5 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 (t, J=7.3 Hz, 3H), 1.23 1.36 (m, 2H), 1.38-1.43 (m, 2H), 2.22 (s, 3H), 2.29 (s, 3H), 2.79 (d, J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 (t, J=9.5 Hz, 1H), 3.32 0 (d, J=15.3 Hz, 1H), 3.43-3.61 (m, 4H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, 1H), 5.93 (s, 2H), 6.74 (m, 3H), 6.83 (m, 3H), 7.04 (d, J=1.7 Hz, 1H), 7.11 (m, 3H). MS (C.I.) mle 559(MH+). Anal calcd for C33H38N206-0.3H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58. 25 Example 494 trans, trans-2 -(3- Me thyl pent-3-efn-1 -yl.-4-(1.3-benzodioxol-5- (N.N-di(n-butyllaminocarbonylimethyl)-pyrrolidie 3 carboxylic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 30 MHz) 8 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.22-1.40 (5H, m), 1.44-1.61 (8H, m), 1.82 (1H, brm), 2.02 (2H, m), 3.05-3.30 (4H, m), 3.3.8 (1H, m), 3.55 (1H, brm), 3.85 (2H, m), 4.12 (1H, brd, J = 15Hz), 5.11 (1H, dd, J = 6Hz, 12Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 487 (M+H)+. Anal 35 calcd for C28H42N205 - 0.7 CF3CO2H : C, 62.34; H, 7.60; N, 4.95. Found: C. 62.49: H, 7.43; N, 4.13.
WO 99/06397 PCT/US98/15479 -437 Example 495 1 -(N-Phenylaminocarbonylmethyl)-2-(4-methoxyphenvl- 4 -(l ,3 benzodioxol-5-ylipvrrolidine-3-carboxlic acid 5 Example 495A N-Phenylbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at -50 *C was added successively N,N-diisopropylethylamine 10 (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40 *C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether 15 (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title 20 compound. Example 495B trans. trans-1 -(N-Phenvaminocarbonvimethvl)-2-(4-methoxvohenvl) 4-(1.3-benzodioxol-5-yl pyrrolidine-3-carboxviic acid 25 Using the procedures described in Example 1 and the compound resulting from Exampe 495A, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.8 (bs, 1H) 7.49 (2H, d, J=8Hz), 7.38 (4H, m), 7.11 (1H, tt, J=8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 30 3.94 (1H, d, J=10Hz), 3.78 (3H, s), 3.70 (1H, ddd, J=6, 5&3Hz), 3.42 (1H, dd, J=10&3Hz), 3.41 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.01 (1H, t, J=1OHz), 2.93 (1H, d, J=16Hz). MS (DCI, NH3) m/e 475 (M+H+). Anal. Calc for C27H26N206 - 1 H20: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38. 35 WO 99/06397 PCT/US98/15479 -438 Example 496 trans. trans-1 -(N-(2.3-Dimethylpheny)aminocarbonylmethyl)-2-(4 methoxyhenyl)-4-(1.3-benzodioxol-5-yi)fyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CDCI3) 8 8.68 (1 H, bs), 7.64 (d, J=8Hz), 7.38, (2H, d, J=8Hz), 7.09 (1H, t, J=8Hz), 6.97, (1H, d, J=8Hz), 6.90 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.76 (1H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.95 (1H, d, J=lOHz), 3.80 (3H, s), 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.44 10 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.06 (1H, t, J=1OHz), 2.96 (1H, d, J=16Hz), 2.31 (3H, s), 2.16 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 - 0.5 H20: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29. 15 Example 497 trans. trans-1 -(N-(2.4-Dimethylpheny)am inocarbonylm ethyl- 2
-(
4 methoxyphenyl-4-(1,3-benzodioxol-5-ylpyrrolidine-3-carboxYlic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.60 (1H, bs), 7.78 (d, 20 J=8Hz), 7.38, (2H, d, J=8Hz), 6.99 (1H, m), 6.95, (1H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.92 (1H, d, J=1OHz), 3.79 (3H, s), 3.68 (1H, ddd,.J=6, 5&3Hz), 3.43 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, 25 J=lOHz), 2.95 (1H, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N206 - 0.75 H20: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13. Example 498 30 trans.trans-1 -(N-(2.5-Dimethylhenyl)aminocarbonlimethyl- 2
-(
4 methoxyhenyl)-4-(1.3-benzodioxol-5-Yl)PYrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.62 (1H, bs), 7.79 (1H, bs), 7.38, (2H, d, J=8Hz), 7.03 (1H, d, J=8Hz), 6.95, (1H, d, J=8Hz), 6.94 35 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, -, J=aHz), 5 07 (9H ) 3.92 (1H. d. J=1OHz), 3.78 (3H, s), 3.70 (1H, WO 99/06397 PCT/US98/15479 -439 ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=1OHz), 2.95 (1H, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N206 - 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5 5.89; N, 5.25. Example 499 trans. trans-1 -(N-(3.4-Dimethylphenyl)amino carb nyImethyl)- 2
-(
4 methoxyohenyl-4-(1.3-benzodioxol-5-yloDyrrolidine-3-carboxYlic acid 10 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 5 8.73 (1H, bs), 7.38 (2H, bd, J=8Hz), 7.30, (1H, d, J=3Hz), 7.20 (1H, bs), 7.08, (1H, d, J=8Hz), 7.01 (1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1H, bs), 6.80 (1H, d, J=8Hz), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=1OHz), 3.78 (3H, s), 15 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=1OHz), 2.95 (1H, d, J=16Hz), 2.25 (3H, s), 2.21 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N206 - 0.75 H20: C, 67.50; H, 6.15; N 5.43. Found: C, 67.24; H, 5.94; N, 5.20. 20 Example 500 trans, trans-1 -(N-(3.5-DimethyIphenylaminocarbonlmethyl)-2-( 4 methoxyphenyl)-4-(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 25 was prepared. 1 H NMR (300 MHz, CDCl3) 8 8.75 (1H, bs), 7.35, (2H, d, J=8Hz), 7.10 (2H, s), 7.02 (1H, d, J=3Hi), 6.90 (2H, d, J=8Hz), 6.84 (1H, d, J=2Hz), 6.80, (1H, d, J=8Hz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.79 (3H, s), 3.68 (1H, ddd, J=6, 5&3Hz), 3.40 (2H, m), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J=lOHz), 30 2.88 (1H, d, J=16Hz), 2.3 (6H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N206 - 0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.
WO 99/06397 PCTIUS98/15479 -440 Example 501 Alternate Preparation of (+)-trans. trans-1 -(N.N-Di(n-butyllaminocarbonylmethyl)-2-(4 methoxyhenyl)-4-(1.3-benzodioxol-5-ylpyrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A N. N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in D toluene (500 mL) cooled to 0 *C was added a soTution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 *C. Upon completion of the addition, the reaction mixture was stirred at 0 *C for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and 5 the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene. 0 Example 501B 5-(2-Nitrovinyl)-1.3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), 5 acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 *C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 0C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was o cooled to 10 0C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 0C for 2 days to afford 15.94 kg (80%) of the title compound as a bright yellow solid.
WO 99/06397 PCT/US98/15479 -441 Example 501C 4-Methoxybenzoyl acetate To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5 *C under mechanical stirring and under nitrogen 5 was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 0C. The reaction mixture was heated to 60 0C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 0C and quenched by D adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20 *C. The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 0C during the distillation. The 5 yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%). Example 501D Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl- 3 -(1,3-benzodioxol-5-yl) 0 butyrate To the compound resulting from Example 501B (7.5 kg, 37.9 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example C (8.4 kg, 37.9 mol). The mixture was cooled to 17 0C, sodium ethoxide (6.4 g, 0.095 mol) was 5 added, and the reaction was stirred for 30 minutes. After about 15 minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (6.4 g, 0.095 mol) was added, and the mixture was stirred at 25 *C until HPLC shows less than 1 area % ketoester remaining. The reaction was concentrated to 32.2 kg which was determined by HPLC assay to be 3o -14.9 kg (95%). Example 501E Ethyl cis, cis-2-(4-methoxyphenyl)-4-(13-benzodioxol-5-ylI pyrrolidine-3-carboxylate 35 Raney nickel (20.0 g), from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple.
WO 99/06397 PCT/US98/15479 -442 THF (20 mL), the crude compound resulting from Example 501D (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at 60 psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area % nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and chased with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 N NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g (73%) of the title compound. Example 501F Ethyl trans, trans-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate The solution of the compound resulting from Example 501E (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 *C. When HPLC shows <3% of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound.
WO 99/06397 PCT/US98/15479 -443 Example 501G Ethyl (2R,3R, 4S)-(+)-2-(4-methoxyphenyI)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate. (S)-(+) mandelate salt The solution resulting from Example 501F was chased with acetonitrile (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 *C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 *C to give 5.65 g (40%) of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexane ethanol-diethylamine; flow - 1 mL/min.; UV detection at 227 nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min. Example 501 H (2R.3 R.4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 -(N.N di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid The compound resulting from Example 501G (20.0 g, 0.0383 mol) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 *C. Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution (40%, 20 mL, 0.200 mol) was added, and the mixture was heated at 60 *C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH 5 with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.
WO 99/06397 PCT/US98/15479 -444 Example 5011 (2R.3R.4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yil-1-(N.N di(n-butylaminocarbonYlmethyll- pyrrolidine-3-carboxylic acid hydrochloride salt To a solution of the compound of Example 501H in ethyl acetate at room temperature in a mechanically stirred vessel equipped with a thermocouple, was added 39.4 mL of 1 N HCI in ethanol (0.0394 mol) The resultant solution was filtered to remove foreign matter, concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 *C to afford 17.6 g (90%) of the title compound. Example 502 trans, trans-2-(2-Methylpentyl-4-(1.3-benzodioxol-5-yl-1
-(N.N
di(n-butyl)aminocarbonylmethyl)-pyrrolidine- 3 -carboxylic acid Example 502A (±)-Ethyl 3-methylhexanoate To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of hexanes and 100mL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50mL of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the 5 solvent was removed under reduced pressure to give 3.Og of the title Cnmnond.
WO 99/06397 PCT/US98/15479 -445 Example 502B (±)-Ethyl 5-methyl-3-oxooctanoate To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas, Bul. Chem. Soc. Fr., 945 (1964). Example 502C trans, trans-2-(2-Methylpentyl)-4- (1.3-benzodioxoI-5-yl)-1 -(N, N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl 5-methyl-3-oxooctanoate for ethyl (4-methoxybenzoyl)acetate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. Note that the multiplicity of the signals in the aryl region of the NMR spectrum reflects a 1:1 mixture of diastereomers on the alkyl chain. 1H NMR (CDCl3, 300 MHz) 8 0.8-1.0 (m, 12H), 1.2-1.4 (m, 7H), 1.45-1.6 (m, 6H), 1.6-1.74 (m, 1H), 1.8-2.0 (m, 1H), 3.1-3.4 (m, 5H), 3.67-3.78 (m, 1H), 3.8-3.91 (m, 1H), 4.0-4.2 (m, 2H), 4.3-4.5 (m, 2H), 5.93 (d, J=1.5 Hz, 2H), 6.73 (dd, J=8.1, 1.2 Hz, 1H), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 6.86 (dd, J=3.9, 1.5 Hz, 1H). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N205-1.0 TFA- 0.5 H20: C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.
WO 99/06397 PCT/US98/15479 -446 Example 503 trans. trans-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl-1 -(N.N di(n-butyf)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3_1, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3 dimethylhexanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 'H NMR (CDCI3, 300 MHz) 8 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60 3.69 (m, 1H), 3.75-3.86 (m, 1H), 3.95-4.16 (m, 2H), 4.28-4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.8 (dd, J=8.1, 1.5 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 (M+H)+. Anal calcd for 5 C29H46N205-1.05 TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33. Example 504 trans. trans-2-(2-(1.3-Dioxo-2-yl)ethy)-4-(1.3-benzodioxol-5-yll-1 o (N.N-di(n-butylbaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 504A Ethyl 5-(1.3-dioxolyl-3-oxopentanoate 5 The title compound was synthesized from ethyl acetoacetate and 2-bromomethyl-1,3-dioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971). Sodium hydride 4.97 g (0.124 mol), as a 60% mineral oil dispersion, was weighed into a 250 mL flask, into which 80 ml of o tetrahydrofuran was directly added. The flask was capped with septum cap, flushed with nitrogen, and cooled in an ice bath. To above stirred slurry was added dropwise 15.0 mL (0.118 mol) ethyl acetoacetate. After the addition was complete, the resulting mixture was stirred at 0 *C for additional 10 min. To above mixture was then added 48.4 mL 35 (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise mannpr. The resulting orange color solution was stirred for 10 min WO 99/06397 PCT/US98/15479 -447 before 13.5 mL (0.130 mol) bromomethyl-1,3-dioxane was added in one portion. The reaction mixture was then allowed to warm to room temperature and stirred for additional 120 min before it was then quenched by slow addition of 9.8 ml (ca. 0.12 mol) concentrated 5 hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was extracted thoroughly with additional ethyl ether. The ethereal extracts were combined, washed with 2x50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced 0 pressure to give an brown oily residue. The crude product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g (20%) of b-keto ester as a light yellow oil. Example 504C 5 transtrans-2-(2-(1.3-Dioxo-2-yl)ethyl)-4-(1.3-benzodioxol-5-yl)-1 (N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate 20 afforded the title compound. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.38 (m, 4H), 1.52 (sextet, J = 7.9 Hz, 4H), 1.85-1.95 (m, 2H), 2.02-2.17 (m, 2H), 3.18 (dd, J = 6.0 Hz, 9.0 Hz, 2H), 3.30 (dd, J = 9.0 Hz, 18.0 Hz, 2H), 3.35 (m, 1H), 3.79 (dd, J = 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88 (m, 3H), 3.97 (dd, J = 4.8 Hz, 6.0 Hz, 1H), 4.05 2s (q, J = 9.6 Hz, 2H), 4.30-4.40 (m, 1H), 4.37 (s, 2H), 4.87 (t, J = 3.6 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (APCI) (M+H)+ at m/e 505. Anal calcd for C27H40N207-1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27. 30 Example 505 trans. trans-2-(2-(2-Tetrahydro-24pyran)ethyl)-4-(1.3-benzodioxol 5-yfl-1 -(N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid WO 99/06397 PCTIUS98/15479 -448 Example 505A Ethyl 5-(2-tetrahydro-2H-Dyran)-3-oxoDentanopte Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow oil. Example 505B trans, trans-2-(2-(2-Tetrahydro-2H-pyranlethyl)-4-(1.3-benzodioxol 5-yi)-1 -(N, N-di(n-butyliaminocarbonylmetfiyl)-pyrrolidine-3 carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2H-pyran)-2-oxopentanoate for ethyl 3 methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCl3, 300 MHz) as a mixture of two diastereoisomers: 8 0.89 (t, J = 8.1 Hz, 3H), 0.89 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 1.20-1.40 (m, 10H), 1.42-1.66 (m, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H), 3.10-3.29 (m. 8H), 3.29-3.52 (m, 6H), 3.54-3.81 (m, 6H), 4.01 (q, J = 9 Hz, 2H), 4.12-4.25 (m, 4H), 4.43 (d, J = 9 Hz, 2H), 4.50 (d, J = 2.7 Hz, 2H), 5.94 (s, 2H), 5.95 (s, 2H), 6.76 (s, 2H), 6.76 (s, 2H), 6.81 (s, 1H), 6.81 (s, 1H). MS (APCI) (M+H)+ at m/e 517. Anal calcd for C29H44N206.1.4 TFA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H, 6.99; N, 3.83. Example 506 trans. trans-2-(2.2.4-Trimethyl-3-pentenyl)-4-(1.3-benzodioxol-5 yl)-1-(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic Example 506A Methyl 3.3.5-trimethyl-4-hexenoate To a slurry of isopropyltripenylphosphonium iodide (20.5g, 47mmol) in 200mL of tetrahydrofuran was added n-butyllithium (27mL of a 1.6M solution in hexane, 43mmol), and the solution was briefly WO 99/06397 PCTIUS98/15479 -449 warmed to 00C. After recooling, a solution of methyl 3,3-dimethyl-4 oxobutenoate (5.7g, 40mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 1j 169 (1986) in 1OmL of tetrahydrofuran was added, and the reaction was warmed to 00C for 30min. The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1g (30%) of the title'compound. Example 506B trans, trans-2-(2.2.4-Trimethyl-3-pentenyl)-4-(1.3-benzodioxol-5 yl)-1-(N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDC13, 300 MHz) 5 0.92 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 1.11 (s, 3H), 1.13 (s, 3H), 1.24-1.37 (m, 4H), 1.46-1.59 (m, 4H), 1.61 (d, J=1.2 Hz, 3H), 1.69 (d, J=1.2 Hz, 3H), 2.04-2.11 (m, 2H), 3.10-3.20 (m, 2H), 3.30-3.39 (m, 3H), 3.67-3.82 (m, 2H), 3.95-4.08 (m, 1H), 4.32 (m, 2H), 4.37-4.47 (m, 1H), 4.99 (s, 1H), 5.95 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.78 (dd, J=8.4, 1.2 Hz, 1H), 6.84 (d, J=1.2 Hz, 1H). MS (DCI/NH3) m/e 515 (M+H)+. Anal calcd for C30H46N205-1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43. Example 507 trans. trans-2-(2.2.-Dimethyl-2-(1.3-dioxolan-2-yl)ethyl)-4-(1.3 benzodioxol-5-yl)-1 -(N.N-di(n-butyl)aminocarbonylimethyl) pyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -450 Example 507A Methyl 3.3-dimethyl-3-(1.3-dioxolan-2-y)propanoate Methyl 3,3-dimethyl-4-oxobutanoate (10g, 70mmol), prepared 5 according to the procedure of Hudlicky et al., Synth. Commun., 16 169 (1986), was dissolved in 40mL of benzene, followed by addition of ethylene glycol (20mL), and p-toluenesulfonic acid monohydrate (1.3g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200mL of ether, washed with saturated 0 sodium bicarbonate, water and brine, dried with linhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g (94%) of the title compound. Example 507B 5 trans, trans-2-(2.2.-Dimethyl-2-(1,3-dioxolan-2-yllethyl)-4-(1.3 benzodioxol-5-yl)-1-(N.N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting o methyl 3,3-dimethyl-3-(1,3-dioxolan-2-yl)propanoate for ethyl 3 methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.82-1.00 (m, 12H), 1.24-1.40 (m, 4H), 1.43-1.64 (m, 5H), 1.76 1.84 (m, 1H), 2.93-3.00 (m, 1H), 3.15-3.47 (m, 6H), 3.60-3.70 (m, 3H), 5 3.74-3.95 (m, 5H), 4.48 (s, 1H), 5.94 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H). MS (DCI/NH3) m/e 533 (M+H)+. Anal calcd for C29H44N207 -1.1 TFA-0.2 H20: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25. 0 Example 508 trans, trans-2-(2- (1.3-Dioxo-2-yl)ethyl)-4-(1, 3-benzodioxol-5-yl)-1 [rN-4-heptyl-N-(2-methyl-3-fluorophenylbl amino carbonylmethyl pyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -451 Example 508A 4-Heptanol To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 5 20 mL of diethyl ether was added 370 mg (10.0 mmol) of LiAlH4, in portions to keep ether reflux at a minimum. After 45 minutes, the reaction was quenched by sequential dropwise addition of 0.4 mL H20, 0.4 mL 15% (w/v) NaOH(aq), and 1.2 mL H20. After stirring another 45 minutes, MgSO4 was added until the salts were free flowing, then the 0 reaction was filtered. The salts were washed with diethyl ether (3 x 5 mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g (100%). Example 508B 5 4-Methanesulfonyloxyheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute. 0 The mixture was stirred at 0 *C for 30 minutes, then extracted with H20 (1 x 15 mL), 5% NH40H (2 x 15 mL), 1M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31g (94%). 1 H NMR (300 MHz, CDCI3) d 0.96 (t, 6, J = 9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J = 5). 5 Example 508C 4- Fluoro-3-methylani line To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 0 400 mL of ethanol was added 2g of 10% Pd-C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.
WO 99/06397 PCT/US98/15479 -452 Example 508D N-Heptyl-4-fluoro-3-methylaniline To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline 5 in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4 methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H20 and extracted with diethyl ether (2 x 30 mL). The combined ether layers were back extracted with brine (1 x 30 mL), dried over MgSO4, 0 filtered, and concentrated to an oil. This was puirified via silica gel chromatography, eluting with 97.5: 2.5 hexanes: ethyl acetate, to give 2.56g (35%) of a pale yellow oil. Example 508E 5 NN(4-Heptyl)-(4-fluoro-3-methyl)phenylbromoacetamide To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4 fluoro-3-methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl 20 bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 0C, then extracted with 1M HCI (1 x 100 mL). The aqueous layer was back extracted with diethyl ether (1 x 50 mL), then the combined organic layers were washed with H20 (2 x 50 mL), saturated NaHCO3(aq) (2 x 50 mL), and brine (1 x 50 mL), dried over 25 MgSO4, filtered, and concentrated in vacuo to an oil. This was purified via silica gel chromatography, eluting with 90:10 hexanes: ethyl acetate to give 7.48g (99%) of a light yellow oil. 1 H NMR (300 MHz, CDCl3) d 0.94 (t, 6, J = 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.31 (s, 1.5), 3.54 (s, 2), 4.72 (quintet, 1, J = 5), 6.96-7.04 (m, 2), 7.07(d, 1, J = 30 7).
WO 99/06397 PCT/US98/15479 -453 Example 508F transtrans-2-(2-(1.3-Dioxol-2-yl)ethyl)-4-(1.3-benzodioxol-5-yl)-1 rrN-4-heptyl-N-(2-methyl-3-fluoroohenyll amino carbonylmethyll pyrrolidine-3-carboxylic acid 5 Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and N,N-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N dibutylbromoacetamide afforded the title compound as an amorphous o solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (brt, 6H)' 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9.0 Hz, 1H), 3.52-3.67 (brm, 2H), 3.73 (t, J = 9.0 Hz, 1H), 3.81-4.02 (m, 6H), 4.13 (brm, 1H), 4.72 (quintet, J = 6.9 Hz, 1H), 4.86 (t, J = 4.0 Hz, 1H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 5 6.96 (m, 2H), 7.08 (t, J = 9.0 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 599. Anal Calcd for C33H43N207F-0.8 TFA: C, 60.24; H, 6.40; N, 4.06. Found: C, 60.21; H, 6.14; N, 3.86. Example 509 o trans.trans-2-(2-(1.3-Dioxol-2-yl)ethyl-4-(1.3-benzodioxol-5-yl)-1 (N.N-di(n-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5 (1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6 5 methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1H NMR (CDCl3, 300 MHz) 8 0.93 (t, J = 7.8 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H), 1.31 (m, 4H), 1.53 (m, 4H), 1.90 (m, 2H), 2.09 (m, 2H), 3.19 (dd, J = 8.4 Hz, 8.4 Hz, 2H), 3.30 (q, J = 9.6 Hz, 2H), 3.25-3.42 (m, 1H), 3.73 (q, J = 10.5 Hz, 1H), 3.78-3.94 (m, 4H), 3.88 (s, 3H), 3.96 so (dd, J = 5.1 Hz, 6.0 Hz, 1H), 4.03 (dd, J = 3.0 Hz, 6.3 Hz, 2H), 4.33 (m, 3H), 4.87 (t, J = 3.6 Hz, 1H), 5.94 (s, 2H), 6.53 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 535. Anal calcd for C28H42N208-1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N, 4.26. 35 WO 99/06397 PCTIUS98/15479 -454 ExamDle 510 trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(1.3-benzodioxol-5-yfl 1-(N.N-di(n-butylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Using the procedures described in Example 502, substituting o methoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.15-1.35 (m, 4H), 1.40 1.55 (m, 4H), 3.05-3.25 (m, 4H), 3.28-3.55 (m, 4H), 3.58-3.68 (m, 1H), 0 3.75-3.80 (m, 1H), 3.82 (s, 3H), 3.91 (d, J=14Hz, 1H), 4.05-4.15 (m, 1H), 4.23-4.33 (m, 1H),5.91 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.82-6.95 (m, 5H), 7.03 (s, 1H). MS (DCI/NH3) (M+H)+ at m/e 541. Anal calcd for C30H40N207: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09. 5 Example 511 (2S.3R.4S)-2-(2.2-Dimethylpentyl-4-(1.3-benzodioxol-5-yfl-1 -(N-4 heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethvl) pyrrolidine-3-carboxylic acid 0 Example 511A trans. trans- N -tert-Butoxycarbonyl-2-(2.2-dimethylpentyll-4-(1.3 benzodioxol-5-yl)-pyrrolidine-3-carboxylic acid 5 Ethyl trans, trans-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5 yl)-pyrrolidine-3-carboxylate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 50mL of methylene chloride and di-tert butyldicarbonate (1.5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the o residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 50mL of ethanol followed by addition of sodium hydroxide (10mL of a 5M aqueous solution). After stirring for 20 hours at room temperature, the solvent 5 was removed under reduced pressure, and the residue was dissolved in 150mL of water, and acidified with concentrated phosphoric acid. The WO 99/06397 PCT/US98/15479 -455 mixture was extracted with chloroform (3X5OmL), and the organic layers were washed wiith brine, dried over .anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam. 5 Example 511 B Methyl trans, trans-2-(2.2-dimethylpentyl-4-(1.3-benzodioxol-5-yli 1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl) pyrrolidine-3-carboxylate: As a single enantiomer 0 The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to OC, followed by addition of DMF (0.017mL, 5%), and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at O*C under a stream of nitrogen. The residue 5 was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazolidinone (1.2g, 6.8mmol) was dissolved in 30mL of THF followed by addition of n-butyllithium (4.OmL of a 1.6M solution in hexanes) at 0*C, and the slurry was stirred for 15min. The acid chloride was dissolved in 20mL of THF and cooled to 0*C, followed by 0 dropwise addition of the lithium oxazolide suspension via cannula. After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash 5 chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, 43%), then elution with 20% ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%). The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of o trifluoroacetic acid was added. After 30min, the volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure. The TFA salt was stirred with 4mL of acetonitrile followed by addition of diisopropylethyl amine (1.0mL, 5.7mmol), and N-4-heptyl 5 N-(4-fluoro-3-methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was WO 99/06397 PCT/US98/15479 -456 warmed to 50*C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oil. 5 The above amide (200mg, 0.26mmol) was dissolved in 2.OmL of THF and 0.7mL of water. Solid lithium hydroxide monohydrate (22mg, 0.53mmol) was added at 0*C, followed by 30% hydrogen peroxide (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room temperature. After an additional hour, the reaction was partitioned 0 between 1:1 ethyl acetate:hexanes and water, 0.15g of sodium thiosulfate was added and the mixture was mixed thoroughly. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was dissolved in 2mL of ether, and 5 1mL of methanol. A solution of (trimethylsilyl)diazomethane in hexanes was added dropwise until the yellow color remained. The reaction was quenched by addition of 2 drops of glacial acetic acid, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on 10g of silica gel eluting with 15 ?o 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5 0 C). Example 511C (2S,3R,4S)- trans. trans-2-(2,2-Dimethylpentyl)-4-(1.3-benzodioxol-5 25 yl)-l-(N-4-heptyl-N-(4-fluoro-3 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylate The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.OmL of methanol and sodium hydroxide (O.1mL of a 5M aqueous 30 solution) was added. After 2 hours, the reaction was warmed to reflux. After 6 hours, the reaction was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in water and acidified with concentrated phosphoric acid. The aqueous solution was washed with chloroform (3X5mL), which was then washed with brine, 35 dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization WO 99/06397 PCT/US98/15479 -457 from dilute aqueous TFA/CH3CN. 1 H NMR (CDCl3, 300 MHz) d 0.78-0.95 (n, 15H), 1.04-1.46 (m, 12H), 1.76-2.95 (m, 2H), 2.31 (s, 3H), 3.23-3.33 (n, 1H), 3.47-3.58 (m, 1H), 3.6-3.75 (m, 2H), 3.80-3.95 (m, 2H), 4.05 4.15 (m, 1H), 4.73 (m, 1H), 5.94 (s, 2H), 6.70-6.80 (m, 2H), 6.82-6.93 (m, 2H), 6.96-7.14 (m, 2H). MS (DCI/NH3) m/e 597 (M+H)+. Anal calcd for C35H49N2FO5 *0.05H20 e0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: 21 C, 63.84; H, 7.18; N, 3.94. [a]D =+46* (c 2.7g/L, CHCI3) E xample 512 trans. trans-2-(2-(2-Oxopyrrolidin-1 -ylethyl-4-(1.3-benzodioxol-5 yl)-1-(N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic Example 512A 2-Oxopyrrolidin-1-ylpropionic acid To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin-1 ylpropionitrile in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 *C over night. The reaction mixture was then allowed to cool to room temperature, extracted with methylene chloride three times. The extracts were combined and washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g (25%) of acid as a brown oil. Example 512B Ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Brain and Vilkas, Bul. Chem. Soc. Fr., 945 (1964).
WO 99/06397 PCT/US98/15479 -458 Example 5120 trans. trans-2-(2-(2-Oxopyrrolidin-1 -yllethyl)-4-(1.3-ben zodioxol-5 yl)-1 -(N. N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxy lic acid 5 Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl 3 methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 0 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t,'J = 6.9 Hz, 2H), 2.12 2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, 1H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H), 3.66 (t, J = 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 5 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N306-1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14. Example 513 0 trans, trans-2-(2-(1.3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1.3 benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3 methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate, N-4 heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCl3, 300 MHz) 5 0.93 (br t, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 0 9 Hz, 1H), 3.60-4.03 (m, 8H), 3.88 (s, 3H), 4.21 (brs, 1H), 4.72 (quintet, J = 6.6 Hz, 1H), 4.86 (t, J = 3.6 Hz, 1H), 5.93 (s, 2H), 6.49 (s, 1H), 6.61 (s, 1H), 6.96 (m, 2H), 7.08 (t, J = 9 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 629. Anal calcd for C34H45N208F-1.0 TFA: C, 58.21; H, 6.24; N, 3.77. Found: C, 58.11; H, 6.11; N, 3.58. 5 WO 99/06397 PCT/US98/15479 -459 Example 514 trans, trans-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3-benzodioxol-5 yi)-1-(N.N-di(n-buty)aminocarbonylmethyl)-pyrroidine-3-carboxylic acid 5 Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3-methylhexanoate and 6 methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.81 (s, 3H), 0.84 (s, 3H), 0 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0'96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1H), 4.12 (d, J = 16.8 Hz, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J 5 = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 533. Anal calcd for C30H48N206-0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33. Example 515 trans.trans-2-(2.2-dimethyientyl)-4-(2.3-dihydro-benzofuran-5-yl) 1-(N.N-di(n-butvl)aminocarbonyimethyl)-prrolidine-3-carboxylic acid Using the procedures described. in Example 502, substituting ethyl 3,3-dimethylhexanoate for ethyl 3-methylhexanoate and 2,3-dihydro benzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H20. 1H NMR (300 MHz, CDCI3) 8 0.83 (s, 3H), 0.85 (s, 3H), 0.86 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.09-1.39 (m, 8H), 1.44-1.59 (m, 4H), 1.88 (dd, J=15.0, 7.2 Hz, 1H), 2.00 (d, J=15.0 Hz, 1H), 3.09 (m, 2H), 3.18 (t, J=9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 (q, J=10.0 Hz, 1H), 4.18 (d, J=16.8 Hz, 1H), 4.30-4.45 (m, 2H), 4.55 (t, J=9.0 Hz, 2H), 6.70 (d, J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DCI/NH3) at m/e 501 (M+H)+. Anal calc'd for C30H48N 2 0 4 -1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, 62.19; H, 8.00; N, 4.43.
WO 99/06397 PCT/US98/15479 -460 Example 516 transtrans-2-(2.2.-Dimethyl-2-(1.3-dioxolan-2-yl)ethyl)-4-(1 methoxy-1.3-benzodioxol-5-yl)-1 -(NN-di(n butyliaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3-(1,3-dioxolan-2-yl)propanoate for ethyl 3 methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophylization with 0 CH3CNITFA/H20. 1 H NMR (CDCI3, 300 MHz) 5 0.93 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (m, 4H), 1.93 (dd, J=15.9, 6.0 Hz, 1H), 2.13 (d, J=15.9 Hz, 1H), 3.20 (dd, J=7.7, 7.7 Hz, 1H), 3.26-3.40 (m, 3H), 3.60 (m, 1H), 3.75-3.86 (m, 3H), 3.88 (s, 3H), 3.93-4.01 (m, 3H), 4.00-4.11 (m, 1H), 4.23 (d, J=15.9 5 Hz, 1H), 4.37-4.48 (m, 2H), 4.49 (s, 1H), 5.94 (s, 2H), 6.51 (d, J=2.1 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H). MS (DCI/NH3) at m/e 563 (M+H)+. Anal calcd for C30H46N208-0.9 TFA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05. 20 Example 517 transtrans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1.3-benzodioxol-5-yl) 1 -(N, N-di(n-butyl)ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting o 25 methoxyphenylpropionic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 0.91 (t, J=7Hz, 3H), 1.10-1.27 (m, 4H), 1.42 1.60 (m, 4H), 1.72-1.89 (m, 1H), 1.91-2.02 (m, 1H), 2.55-2.77 (m, 2H), 2.94 (t, J=6Hz, 1H), 3.05-330 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, 30 J=14Hz, 1H), 3.77 (s, 3H), 5.91 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.78-6.88 (m, 3H),6.92 (d, J=2Hz, 1H), 7.08-7.19 (m, 2H). MS (DCI/NH3) (M+H)+ at m/e 539. Anal calcd for C31H42N206: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99. 35 WO 99/06397 PCT/US98/15479 -461 Example 518 trans, trans-2-(2.2-Dimethyl-3-(E)-pentenyl)-4-(1 -methoxy-L .3 benzodioxol-5-yi)-1--(N. N-di(n-butyl)aminocarbonylmethyl)_ pyrrolidine-3-carboxylic acid Example 518A 4-Methyl-3-penten-2-ol To a stirred solution of 3-methyl-2-butenal (8.7g, 103mmol) in 100mL of tetrahydrofuran under N2 at 0 OC was added methylmagnesium bromide (38mL of a 3.OM solution in ethyl ether, 114mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g (81%) of alcohol as a colorless oil. Example 518B trans-Ethyl 3.3-dimethyl-4-pentenoate A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) was heated at 150 0C for 7 hours. The product was then distilled under normal pressure (200-220 *C) to give 5.Og of crude ester as a colorless oil. Example 518C trans, trans-2-(2.2-Dimethyl-3-(E)-pentenyl)-4-(1-methoxy-1.3 benzodioxol-5-yl)-1-(N.N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting trans-ethyl 3,3-dimethyl-4-pentenoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an WO 99/06397 PCT/US98/15479 -462 amorphous solid by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) S 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, J=7.2 Hz, 4H), 1.58 (d, J=5.4 Hz, 3H), 1.92 (dd, J=15.0, 6.6 Hz, 1H), 2.04 5 (d, J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 (m, 3H), 3.75 (m, 2H), 3.87 (s, 3H), 3.99 (q, J=9 Hz, 2H), 4.11-4.30 (m, 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 (s, 2H), 6.50 (d, J=1.8 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H). MS (DCI/NH3) at m/e 531 (M+H)+. Analysis calc'd for C30H46N206-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; 0 found: C, 60.00; H, 7.33; N, 4.35. Example 519 trans, trans-2-(3-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Example 519A 3-(2-Pyridyl)-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was o placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 *C. After the addition was completed, the mixture was held at 50 *C until the 5 color of the reaction mixture turned brown, then heated at 80 *C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for 5 o min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, 78%).
WO 99/06397 PCT/US98/15479 -463 Example 519B trans, trans-2-(3-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-y)-1
-(N.N
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 8.65 (d, J=6.0 Hz, 1H), 8.06 (t, J=6.91 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.51 (t, J=6.91 Hz, 1H), 6.82 6.66 (m, 3H), 5.91 (s, 2H), 4.45 (s, 2H), 4.29-4.18 (m, 1H), 4.04 (dd, J=20.1, 10.5 Hz, 1 H), 3.84 (t, J=12.6 Hz, 1 H), 3.62 (dd, J=13.8, 9.6 Hz, 1H), 3.46-3.13 (m, 7H), 2.51 (broad s, 2H), 1.60-1.43 (m, 4H), 1.37-1.22 (m, 4H), 0.91 (t, J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 (M+H)+. Anal calcd for C29H39N305-1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81. Example 520 (2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1.3-benzodioxol-5 yl)-1-(NN-di(n-butyllaminocarbonylmethyl)-pyrrolidine-3-carboxylic Example 520A (2S. 3R. 4S)-Ethyl-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1.3 benzo dioxo I-5-yli pyrro lid in e-3-ca rb oxyl ate-(S-Mandelate The racemic amino ester from Example 512 (3.45g, 8.98mmol) in 10mL of ethyl acetate was treated with (S)-(+)-mandelic acid (0.75g, 4.93mmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring till the solution became light cloudy. The solution was left stirred at room temperature over night. The D crystals was then collected by filtration, recrystalized from ethyl acetate/hexane twice to give a yield of 800 mg (17%) of pure salt.
WO 99/06397 PCTIUS98/15479 -464 Example 520B (2S, 3R. 4S)-Ethyl-2-(2-(2-oxopyrrolidin-1 -ylethyl)-4-(1.3 benzodioxol-5-yl)- 1 -(N. N-di(n-buty)aminocarbonylmethyll pyrrolidine-3-carboxylate 5 To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added NN-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed 0 under reduced pressure and the .crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound. Example 520C (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1.3-benzodioxol-5 s yil-1-(N.N-di(n-butylaminocarbonylmethyl)-oyrrolidine-3-carboxylic acid Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with .0 CH3CN/TFA/H20. 1H NMR (CDCl3, 300 MHz) 8 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J = 6.9 Hz, 2H), 2.12-2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47 2.61 (m, 1H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H), 3.66 (t, J = ?s 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N306-0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84. 30 WO 99/06397 PCTIUS98/15479 -465 Example 521 (2S, 3R. 4S-2-(2-(2-oxooyrrolidin-1-yI)ethyl)-4-(1.3 benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3 methylpheny))aminocarbonylmethyl)-oyrrolidine-3-carboxylic acid Using the procedures described in Example 520, substituting N,N (4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N dibutylbromoacetamide afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H20. 1H NMR (CDCI3, 300 MHz) 8 0.85-0.98 (m, 6H), 1.22-1.55 (m, 8H), 2.04 (quiritet, J=7.9 Hz, 4H), 2.32 (s, 3H), 2.36 (t, J=7.9 Hz, 2H), 2.61 (m, 1H), 3.14 (m, 1H), 3.25-3.61 (m, 5H), 3.66-3.77 (m, 1H), 3.79-3.90 (m, 2H), 3.92-4.03 (m, 1H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 (s, 2H), 6.71 (s, 2H), 6.78 (s, 1H), 6.93-7.13 (m, 3H); MS (DCI/NH3) at m/e 610 (M+H)+. Anal calc'd for C34H44N306F1-1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52. Example 522 trans, trans-2-(2-(1-pyrazolyliethyl)-4-(1.3-benzodioxol-5-yl)-1 (N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 522A 3-(1-Pyrazolyl-propionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.
WO 99/06397 PCTIUS98/15479 -466 Example 522B trans. trans-2-(2-(1 -oyrazoly)ethyl)-4-(1.3-benzodioxol-5-yil-1 (N.N-di(n-buty)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid 1 H NMR (CDCI3, 300 MHz) S 7.56 (d, J=3.0 Hz, 1 H), 7.50 (d, J=3 Hz, 1H), 6.83-6.66 (m, 3H), 6.28 (t, J=3 Hz, 1H), 5.91 (s, 2H), 4.55-3.98 (m, 6H), 3.83-3.72 (t, J=10.5 Hz, 1H), 3.61-3.40 (t, J=10.5 Hz, 0 1 H), 3.36-3.12 (m, 5H), 2.69-2.43 (m, 2H), 1.59-1.42 (m, 4H), 1.38-1.21 (m, 4H), 0.91 (t, J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 (M+H)+. Anal calcd for C27H38N405-0.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67. 5 Example 523 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-(N butyl-N-(3-hydroxyproyilamino)carbonylmethyll-pyrrolidine-3 carboxylic acid 20 Example 523A N-Butyl-N-(3-hydroxyropyil-amine To a solution of 15.9g (100 mmol) of methyl 3-N-(n butyl)aminopropionate in 150 mL of diethyl ether at 0 'C was added 50 25 mL (0.35 mmol) of 1.OM LiAlH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 'C for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 mL 15%w/v NaOH(aq), and 5.7 mL H20. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was 30 concentrated to 11.3 g (86%) of a light yellow oil. Example 523B N-Butyl-N-(3-hydroxypropyl)-chloroacetamide 35 To an ice cooled solution of 1.31g (10.0 mmol) of N-butyl,N-(3 hydroxypropyl)amine in 20 mL of ethyl acetate was added a solution of WO 99/06397 PCTIUS98/15479 -467 1.71g (10.0 mmol) of chloroacetic anhydride in 10mL of ethyl acetate. The mixture was stirred, and gradually warmed to room termperature over 18 hours. The reaction was extracted with H20 (1 x 50 mL), saturated- NaHCO3 (aq) (2 x 50 mL), and brine (1 x 50 mL), dried over 5 MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate to give 723 mg (35%) of a light yellow oil. Example 523C 0 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-beniodioxol-5-yl-1-r(N butyl-N-(3-hydroxyrooyl)amino)carbonyimethyll-pyrrolidine-3 carboxylic acid Using the procedures described in Example 1D, substituting N 5 butyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMSO as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CD30D, 300 MHz) 8 0.78-0.95 (m, 3H), 1.00-1.80 (m, 4H), 2.80-3.65 (m, 15H), 3.80 (d, J=1.5 Hz, 2H), 5.93 (s, 2H), 6.72 0 7.05 (m, 5H), 7.33-7.40 (m, 2H). MS (DCI/NH3) at m/e 513 (M+H)+. Anal calc'd for C28H36N207-1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.21; N, 4.88. 5 Example 524 trans, trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-vyl)-1-(N propyl-N-ropoxyamino)carbonylmethyll-prrolidine-3-carboxylic acid Example 524A N-Boc-0-allylhydroxylamine O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 00C in an ice bath. Diisopropylethylamine (8mL) and di-t-butyldicarbonate (10.0g) were 5 added. The mixture was stirred at 00C for 1 hour at which point the bath was removed and the reaction allowed to warm to room WO 99/06397 PCT/US98/15479 -468 temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried 5 with sodium sulfate and evaporated to give a light yellow oil (6.5g) which was used without any further purification. Example 524B N-Boc-N-propyl-O-allylhydroxylamine 0 N-Boc-O-allylhydroxylamine (6.5g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 00C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min 5 at 0*C. 1-lodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 00C for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1 N phosphoric acid (3 x 50 mL), and o brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0g). 5 Example 524C N-Boc-N-propyl-N- propoxyamine N-Boc-N-propyl-O-allylhydroxylamine (6.0g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5g) was added, and the o mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8g).
WO 99/06397 PCT/US98/15479 -469 Example 524D N-Propyl-N-propoxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCI/dioxane (10mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1g) was collected by filtration and washed with diethyl ether. Example 524E N-propyl-N-propoxy-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20 0 C. Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -20 0 C for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35g). The product is a mixture of chloro and bromoacetamides in a ratio of -3:1. Example 524F trans, trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(3-hydroxypropyl)amino)carbonylmethyl-pyrrolidine-3 carboxylic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl) 4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was purified by preparative HPLC (Vydac mC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was lyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) 8 0.87 (m, 6H, J=8Hz), 1.49 (m, 2H, J=8Hz), 1.61 (m, 2H, J=8Hz), 3.55 (m, 6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.00 (m, 2H), 4.13 (d, 2H, WO 99/06397 PCTIUS98/15479 -470 J=17Hz), 5.96 (s, 2H), 6.77 (d, 1H, J=9Hz), 6.90 (m, 3H), 7.05 (d, 1H, J=1Hz), 7.44 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C27H34N207 . 1.20 TFA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55. 5 Example 525 trans. trans-2-(4-Methoxyhenyl-4-(1.3-benzodioxol-5-yil-1-[(N butyl-N-propoxyamino)carbonylmethyll-pyrrolidine-3-carboxylic acid 10 Example 525A N-butyl-N-(2-hydroxyethyl)-amine In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide was condensed at -78'C. To this12.5 ml (120 mmol) of butylamine 15 was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50'C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound. Example 525B 20 N-Butyl-N-(2-azidoethyl)-chloroacetamide To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oil. Diethyl 25 ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and 1.0g (16 mmol) of sodium azide was added. The reaction was stirred at 75 *C for 2 hours, then poured into 50 mL of 0.6M NaHCO3(aq.) and extracted with diethyl ether (3 x 15 mL). The combined ether layers were back 30 extracted with brine (1 x 15 mL), dried over MgSO4, and filtered. To the ether solution was added 850 mg (4.97 mmol) of chloroacetic anhydride. The reaction was stirred for 10 min, then concentrated to an oil. This was taken up in 10 mL of saturated NaHCO3(aq.) and extracted with diethyl ether (3 x 5 mL). The combined ether layers 35 were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel WO 99/06397 PCT/US98/15479 -471 chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg (17%) of an oil. Example 5250 5 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(2-aminoethyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid According to the procedure of Example 523C, N-butyl-N-(2 o azidoethyl)-chloroacetamide was coupled with 6thyl 2-(4 Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room 5 temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To 100 mg (0.10 mmol) of the azide was added 1mL of 1M HCI(aq.), 0.5 mL of dioxane, to and 5 mg of 10% Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1 H NMR (CD30D, 300 MHz) 8 0.92 (t, J=7.0 Hz, 3H), 0.96 (t, rotamer), 1.23 .5 (m, 2H), 1.41 (m, 2H), 3.06 (m, 4H), 3.39 (m, 2H), 3.69 (m, 2H), 3.84 (s, 3H), 3.94 (m, 3H), 4.18 (m, 2H), 5.05 (bd, J=10.7 Hz, 1H), 5.98 (s, 2H), 6.84 (d, J=7.7 Hz, 1H), 6.93 (dd, J=1.8, 8.1 Hz, 1H), 7.05 (m, 3H), 7.56 (m, 2H). MS (DCI/NH3) at m/e 498 (M+H)+. Anal calcd for C27H35N306-3.15 TFA: C, 46.68. H, 4.49. N, 4.90. Found: C, 46.61; H, 4.73; N, 4.79. 30 WO 99/06397 PCT/US98/15479 -472 Example 526 trans. trans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-yl-1-[(N butyl-N-(3-aminopropyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid 5 To and ice-cold solution of the compound of Example 523C (100 mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of methanesulfonyl chloride, and 39 mL of triethylamine. The mixture was stirred for 20 min, then diluted with 1.5 mL of dichloromethane o and extracted once with 5mL of water to which ha-d been added 1 drop of 85% H3PO4, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x 2.5 mL), dried over MgSO4, filtered, and concentrated to an oil. To a solution of 81 mg (0.13 mmol) of the mesylate in 1mL of DMF was added 65 mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour 5 at 50 'C, then poured into 10 mL of water and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 60:40 hexanes: ethyl acetate to give 57 mg of a colorless oil. The product o was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with 5 brine and dried over Na2SO4. To this azide was added 1mL of 1M HCI(aq.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as so its TFA salt. 1 H NMR (D6-DMSO, 300 MHz) 8 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 (m, 2H), 1.30 (m, 2H), 1.67 (m, 2H), 2.71 (m, 2H), 3.04 (m, 1H), 3.21 (m, 3H), 3.45 (m, 1H), 3.75 (m, 3H), 3.97 (s, 3H), 3.85-4.80 (broad m, 3H), 6.03 (m, 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.01 (m, 2H), 7.16 (m, 1H), 7.55 (m, 2H), 7.72 (m, 2H), 7.85 (m, 1H); MS 35 (DCI/NH3) (M+H)+ at m/e 512. Anal calcd for C28H37N306-3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.
WO 99/06397 PCT/US98/15479 -473 Example 527 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N butyl-N-(3-dimethylaminopropyl)amino) carbonylmethyll-pyrrolidine-3 5 carboxylic acid Example 527A N-butyl-N-(3-bromopropyl)bromoacetamide 10 To 1.50g (11.4 mmol) of N-butyl-N-(3-hydroxy)propylamine was added 3 mL of 48% HBr(aq.), and 1.5 mL of conc. H2SO4. The reaction was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured over 50 mL of ice, and the solution was treated with 50 mL of 2M NaOH(aq.). The basic is solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x 25 mL), dried, and filtered. To the ice cooled ethyl acetate solution was added 3mL of triethylamine, then 1.5 mL of bromoacetyl bromide as a solution in 3.5 mL of ethyl acetate. The reaction was stirred at 0 'C 20 for 30 min, then extracted with 1M HCI(aq.) (2 x 25 mL) saturated NaHCO3(aq.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1.47g of a colorless oil. 25 Example 527B Ethyl trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 [(N-butyl-N-(3-bromopropyl)amino)carbonylmethyll-pyrrolidine-3 carboxylate 30 According to the procedure of Example 523C, N-butyl-N-(3 bromopropyl-bromoacetamide was coupled with ethyl 2-(4 Methoxyphenyl)-4- (1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica, using 40% EtOAc in 35 hexanes to elute.
WO 99/06397 PCT/US98/15479 -474 Example 5270 trans, trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(3-dimethylaminooropyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid 5 To 400 mg (0.663 mmol) of the compound of Example 527B in 4 mL of absolute EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 'C for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from o CH3CN to remove most of the trimethylamine. The product was purified via silica gel chromatography, eluting with 9:1 CH2CI2: MeOH over about 20 mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in 5 vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4, and the product was purified by preparative HPLC. 1H NMR (CD30D, 300 MHz) S 0.92 (t, J=7.0 Hz, 3H), 1.22 (m, 2H), 1.39 (m, 2H), 1.90 (m, 2H), 2.87 (s, 6H), 3.07 (m, 4H), 3.24 (m, 1H), 3.43 (m, 1H), 3.62 (m, 1H), 3.84 (s, 3H), 3.88 (m, 0 3H), 4.07 (m, 1H), 4.17 (m, 1H), 4.97 (M, 1H), 5.97 (s, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.93 (dd, J=1.7, 8.1 Hz, 1H), 7.05 (m, 3H), 7.53 (m, 2H). MS (DCI/NH3) at m/e 540 (M+H)+. Anal calcd for C30H41 N306-2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62. 25 Example 528 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(3-trimethylammoniopropyl)amino)carbonvliethll pyrrolidine-3-carboxylic acid 30 Prepared according to the procedures of Example 527C, substituting aqueous Me3N for Me2NH. 1 H NMR (CD30D, 300 MHz) 8 0.91 (m, 3H), 1.24 (m, 2H), 1.40 (m, 2H), 1.99 (m, 2H), 3.13 (s, 9H), 3.18 (s, rotamer), 3.20 (m, 3H), 3.39 (m, 4H), 3.72 (m, 1H), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, 1H), 5.19 (m, 1H), 5.97 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.96 35 (dd, J=1.7, 7.9 Hz, 1H), 7.10 (m, 3H), 7.62 (m, 2H). MS (DCI/NH3) at m/e WO 99/06397 PCT/US98/15479 -475 554 (M+H)+. Anal calcd for C31H44N306-0.1 H20-1.65 TFA: C, 47.25. H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75. Example 529 5 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N butyl-N-(4-aminobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid Example 529A o N-butyl-N-(4-hydroxybutyl)-amine A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To 5 a solution of 3.18 gm (20 mmol) of the resultant N-butyl -4 hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DIBAL(25%W). The solution was heated with stirring at 70 'C for 18 hours. After cooling to O'C, the reaction was quenched with methanol (1/3 amount of DIBAL solution was used) followed by addition of t0 saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4. Example 529B .5 N-butyl-N-(4-hydroxybutyl)-chloroacetamide Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in 30 small portions. The reaction mixture was allowed to stir for 5 hours at O'C, and then was allowed to warm to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography. 35 WO 99/06397 PCT/US98/15479 -476 Example 529C Ethyl trans, trans-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-Yil-1 [(N-butyl-N-(4-hydroxybutylamino)carbonylmethyll-pyrrolidine-3 carboxylate 5 According to the procedure of Example 523C, N-butyl-N-(4 hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4 Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica gel. 0 Example 529D Ethyl trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 {(N-butl-N-(4-bromobutyl amino)carbonylmethyll-pyrrolidine-3 carboxylate 5 To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at O'C for 2 hours and was slowly-warmed to room 2o temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography. Example 529E 25 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-U(N butyl-N-(4-aminobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid To a solution of 0.135 gm (0.21 mmol) of the compound of 30 Example 529D in 2 ml DMF was added 0.1 gm of sodium azide. Reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. After addition of water, the product was extracted into EtOAc. The crude product (117 mg) was dissolved in 10 ml ethanol under nitrogen atmosphere. To this 45 mgs of 10% Pd/C catalyst was 35 added, the nitrogen from the reaction flask was evacuated and was flushed with hydrogen by placing a balloon filled with hydrogen.
WO 99/06397 PCTIUS98/15479 -477 The reaction was allowed to stir for 4 hours under hydrogen atmosphere, and was worked up by filtering through a Celite pad. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution 5 was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4, and the product was purified by preparative HPLC. 1H NMR (CD30D, 300 MHz) 8 0.90 (t, J=7 Hz, 3H), 1.10-1.65 (m, 6H), 2.85-2.95 (m, 2H), 3.00 4.10 (m, 14H), 5.50 (d, J=3 Hz, 2H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, 1H), o 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 (m, 3H), 7.45-7.55(m, 2H). MS (DCI/NH3) at m/e 526 (M+H)+. Anal calc'd for C29H39N306.2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Found: C, 51.75; H, 5.31; N, 5.30. Example 530 5 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yi)-1-f(N butyl-N-(4-dimethylaminobutyl)amino)carbonimethyll-pyrrolidine-3 carboxylic acid The title compound was prepared from the compound of Example o 529D, employing the procedures of Example 527C. 1 H NMR (CD30D, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (m, 8H), 2.75 (d, J=7 Hz, 6H), 3.0 4.25 (m, 16H), 5.97 (s, 2H), 6.83 (d, J=8 Hz, 1H), 6.93 (dd, J=8 Hz, 1H), 7.02-7.08 (m, 3H), 7.49-7.56 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+. Anal calc'd for C31H43N306-2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: 5 C, 53.50; H, 5.38; N, 5.34. Example 531 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N butyl-N-(3-pyridyllamino)carbonylimethyll-pyrrolidine-3-carboxylic Example 531A N-butyl-N-(3-pyridyl)-amine 35 To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic WO 99/06397 PCTIUS98/15479 -478 acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture 5 was poured into 300 mL of 0.67M NaOH(aq.), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted with brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18g (79%) of a colorless solid. 10 ExampDle 531 B trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(3-pyridyl)amino)carbonylmethyll-pyrrolidine-3-carboxylic acid 15 The compound of Example 531A was reacted according to the procedures of Example 523, to give the title compound. 1 H NMR (D6 DMSO, 300 MHz) 8 0.80 (t, J=6.4 Hz, 3H), 1.15-1.99 (m, 4H), 2.59 (m, 1H), 3.05 (m, 2H), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (t, J=7.1 Hz, 2H), 3.73 (s, 20 3H), 6.00 (s, 2H), 6.80 (m, 3H), 6.85 (d, J=8.1 Hz, 1H), 6.98 (m, 2H), 7.04 (m, 1H), 7.41 (dd, J=1, 4.7 Hz, 8.1H), 7.58 (m, 1H), 8.36 (bs, 1H), 8.54 (bs, 1H), 12.24 (bs, 1H). MS (DCI/NH3) at m/e 532 (M+H)+. Anal calcd for C30H33N306-0.1 H3PO4: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60. 25 Example 532 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yb)-1-f(N butyl-N-(3-aminomethylphenyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid 30 Example 532A N-butyl-N-(3-hydroxymethylphenyl)-amine To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 35 ml DMSO was added 3.78 g (45 mmol) solid NaHCO3 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 'C for WO 99/06397 PCT/US98/15479 -479 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. Example 532B N-butyl-N-(3-hy<droxymethylphenyl)-bromoacetamide To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to O'C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at O'C and then was allowed to warm to room temperature. Saturated potassium 5 carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3PO4, water, and brine. Example 532C 3 Ethyl trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 r(N-butyl-N-(3-chloromethylphenyl)amino)carbonylmethyll-pyrrolidine 3-carboxylate According to the procedure of Example 523C, N-butyl-N-(3 5 hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4 Methoxyphe-nyl)-4- (1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 00C; 19 mg of LiCI was added, followed by 85 pl of thionyl chloride. The mixture was allowed to stir for 30 min; water was added, and the D mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.
WO 99/06397 PCT/US98/15479 -480 Example 532D trans. trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-1-r(N butyl-N-(3-aminomethylphenyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, 6.5 eq) of sodium azide. The resultant solution was heated at 115 *C for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with waiter and brine, and dried over Na2SO4. Example 532E trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N butyl-N-(3-aminomethylphenyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid In a 50 ml round bottom flask 0.090 gm Tin (11) chloride was suspended in 1 ml acetonitrile. Triethylamine (0.2 mL) was added, followed by 0.19 ml of thiophenol ; the reaction mixture turned yellow. Reaction flask was cooled to O'C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI . The aqueous extract was 5 basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted o with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4, and the product was purified by preparative HPLC. 1H NMR (CD30D, 300 MHz) 8 0.88 (t, J=7 Hz, 3H), 1.15-1.45 (m, 4H), 3.40-4.20 (m, 14H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, 1H), 6.88 (dd, J=8 Hz, 1H), 6.97-7.20 (m, 5H), 7.40 (d, J=9 Hz, 2H), 7.56 (d, J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 5 (M+H)+. Anal calcd for C32H37N306-4.2 TFA: C, 46.72; H, 4.00; N, 4.05. Found: C, 46.66; H, 4.06; N, 4.00.
WO 99/06397 PCT/US98/15479 -481 Example 533 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yil-1-r(N butyl-N- (3-t ri methylammoni om ethyl phenylI amino) carbonylm ethyll s pyrrolidine-3-carboxylic acid To a stirred solution of 0.128 gm of the compound of Example 532C in 0.5 ml methanol, 0.25 ml of an aqueous solution of trimethylamine was added. The mixture was allowed to stir at room o temperature under nitrogen atmosphere for 4 hours. IN HCI was added; the aqueous was washed with ether to extract organic impurities. The aqueous layer was dried azeotropically with toluene, and the residue was dried under high vacuum. Yield 0.115 gm. 1 H NMR (300 MHz, D6 DMSO) 8 0.83 (t, J=7 Hz, 3H), 1.15-1.40 (m, 4H), 2.62 (s, 2H), 3.35 (s, 5 9H), 3.40-3.80 (m, 10H), 4.47 (s, 2H), 6.00 (s, J=3 Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.37 (m, 2H), 7.45-7.60 (m, 3H). MS (DCI/NH3) at m/e 602 (M+H)+. Example 534 0 (2R.3R,.4,)2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)l (2-(N-propyl- N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid Example 534A 5 Ethyl (3-fluoro-4-methoxy)benzoylacetate Sodium hydride (17g of a 60% suspension in mineral oil) is washed three times with toluene. The powder is suspended in 138 mL of toluene, and 35 mL of diethyl carbonate is added. The mixture is )o heated to 90 *C, and a solution of 25 g of 3-fluoro-4 methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then the reaction is cooled to room temperature. A solution of 50- ml of concentrated HCI in 75 ml of ice water is added slowly, and the mixture 35 is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product WO 99/06397 PCT/US98/15479 -482 is dried over Na2SO4 and decolorized with charcoal to give 34.5 g (97%) of the title compound. Example 534B Ethyl 2-(3-Fluoro-4-methoxyhenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxyl ate The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3 benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 min. An additional 0.1 g of DBU was added, and the solution was stirred for 1 hour. The solvents were removed in vacuo; toluene was added, along with brine containing 3 ml of concentrated HCt. The mixture was extracted twice with toluene; the organics were dried over MgSO4. The residue was flashed on silica, using CH2CI2 to elute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2C2. Yield 10.13 g = 66%. The product is combined with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN are added, along with a trace of bromcresol green as indicator. A solution of 1:2 concentrated HCI/EtOH is added dropwise to maintain pH at green yellow; after color persists, the reaction mixture is stirred for an 5 additional 20 min. The solvents are removed in vacuo; the residue is stirred with mixture of toluene and KHCO3 solution. The organic phase is washed with water and brine, and dried over MgSO4. The crude product is purified by flash chromatography on silica, eluting with 2:1 EtOAc/hexanes. Yield 5.92 g (58%) of a 2:1 mixture of trans-trans and 0 cis-trans isomers.
WO 99/06397 PCT/US98/15479 -483 Example 5340 Ethyl (2R.3R.4)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol 5-yl)-pyrrolidine-3-carboxylate 5 To the racemic amino ester above (15.0 g, 38.8 mmol), dissolved in 75 ml methylene chloride and cooled in an ice bath, was added Boc anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room temperature, the solution was concentrated in vacuo ; the residue was dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium 0 hyroxide in 19 ml water. The solution was warmed until all was soluble. After stirring for 2 hours at room temperature, the solution was concentrated and redissolved in 200 ml of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The combined aqueous phases were acidified with 5 7.5 g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1:1 ether:hexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was o suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-methylbenzylamine. After heating to dissolve the acid, 80 ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum 5 recovery) of salt, m.p. 165-168*C. After one recrystallization, chiral HPLC analysis, using a Regis Whelk-O column, indicated >99.5 % e.e. The salt was dissolved in 500 ml of 36% HCI in ethanol; a white solid forms. The resultant suspension was heated for 16 hours at 520C. After concentrating in vacuo, the residue was combined with toluene o and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate to get 6.9 g (99%) of the resolved amino ester.
WO 99/06397 PCTIUS98/15479 -484 Example 534D Ethyl {2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)- 4 -(1.3-benzodioxol 5-yl) 1 -(2-(N-oropylamino)ethyl)-pyrrolidi ne-3-carboxylate 5 The compound of Example 534C was dissolved in 1,2 dibromoethane ( 10 mL per 1 g of starting material ); diisopropylethylamine (1 mL per 1 g of starting material ) and Nal ( 100 mg per 1 g of starting material) were added, and the mixture was stirred at 1000C for 1 hour. Toluene was added, and the mixture was o washed with bicarbonate. The solvents were concentrated, and the resultant black residue was chromatographed on silica gel, eluting with 4:1 hexane-EtOAc to give the N-(2-bromoethyl)pyrrolidine (85-92%). This compound was combined with n-propylamine (3.5 eq.) and Nal (10% by weight of bromide) in ethanol ( 5 mL per 1 g of bromide), and was 5 heated at 800C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2SO4), and concentrated. More toluene was added, and removed in vacuo, to get rid of the primary amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the 0o desired product (86-93% yield), which was used for the next step without further purification. Example 534E 1-Pentanesulfonyl chloride 25 1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60 0C for 3 hours. The solvents are removed in 30 vacuo; toluene is added and removed in vacuo to remove residue of SOC12. The residue is partitioned between CH2CI2 and ice water; the organic layer is dried over Na2SO4 . The crude product is purified by distillation (bp 54-56 *C @ 0.5 mm Hg) to give a clear oil, 61% yield.
WO 99/06397 PCT/US98/15479 -485 Example 534F {2R.3R.4S)-2-(3-Fluoro-4-methoxyhenl)-4-(1.3-benzodioxol-5-yl) 1 (2-(N-ropyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N,N diisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHCO3 solution, 1N H3PO4, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with 40% s EtOAc/hexane to give 220 mg of product (85%). This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H20. This mixture was stirred for 3 hours at room temperature. The solution was -concentrated in vacuo using low (<400C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was o extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a 5 white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound. Example 534H (12R,3R,42-(3-Fluoro-4-meth oxyhenyl)-4-(1.3-benzodioxol-5-yl)1 0 (2-(N-propyl-N-pentanesulfonylamin acid, hydrochloride salt The free amine is dissolved in iPrOH; a slight excess of HCI in iPrOH is added, and the solution is concentrated in vacuo. More IPA is 5 added, and the solution is reconcentrated. The resultant sticky WO 99/06397 PCT/US98/15479 -486 material is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 0C. Yield 95%. E xample 535 The compounds in Table 3C may be prepared using methods presented in the above Examptes. Table 3C. 1 2 HO N N -- nCOOH ,O'N ' N -- oiCOOH O 0 0-i 0 3 4 *.,C0OHN N H2N N N .eCOOH H2N -- CO0'CO / \ / \i WO 99/06397 PCT/US98/15479 - 487 5 6 -j -0 7 8 H*N.uCOOH .06*1COOH 0 10 11 10 +rf-_j N t rN*.COOH .'ICOOH 0 0 0 0- WO 99/06397 PCT/US98/1 5479 - 488 13 14 UCOC *muCOOH ICOG 0.(' .COOH C 0 0 CH4 3 C CH b 17 18 .. COOHHtKN..N .CH 0 0
-
0
COH
3
CH
3
-
WO 99/06397 PCT/US98/15479 - 489 19 20 -COOH N CH 21 22 0 -, OOH 0 -*.COOH // \ 0 0 O - O CH CH 23 24 N COOH 0N COOH 0
CH
3
CH
3 0 WO 99/06397 PCTIUS98/1 5479 - 490 25 26 .N -TrN ~~..COOH 2 ICO -0
CH
3 CH 27 28 N* loCOOH -oCA)OH
CH
3 -: 29 30 F N0~ N <%r N -C N COOH -0 0 31 32 N ..iCOOH H2 N ',COOH 0 0 WO 99/06397 PCT[US98/I 5479 -491 33 34 N ..COOH N e4COOH 0 35 36 N-air lCOOH -uCOOH 37 38 39 'COOH 0 COOH rQ ~ -sCOOH 40 41 NC-- ." oCOOH H 2 NNjA~ *eCOOH WO 99/06397 PCT/US98/1 5479 - 492 42 43 >J+NNCOOH i ~COOH 44 45 -. vaCOOH N ... COOH 0 0 46 47 H 2 Ne,,,NyN .aCOOH *rN .mCOOH o 0 48 49 .. ,iCOH -'COOH 0 'Col00 n-i - 0 WO 99/06397 PCTIUS98/1 5479 - 493 50 51
H
2 N N~~N .. COOH I 8 *.COOH 0 52 53 - .'COOH ",ICOOH 54 55 oNCOOH r.,CO -3 56 57 N ... COH *.oCOOH 0 0'CO 0 0 0 CH 3 0
-J
WO 99/06397 PCT/US98/1 5479 - 494 58 59 0 0 C H C H 60 61 *YN) N .aCOOH H 2 N ,_N -(.N
..
"C00 0 0
CH
3
CH
3
-
62 63 0 .,COOH ,N0 r . C O H 0 0 Cl-I 3 CH3I 64 65 0 'CO 0 ""COOH 0 0
CH
3
CH
3 WO 99/06397 PCTIUS98/1 5479 - 495 66 67 0 *'COOH . -'COOH
CH
3 CH 68 69 C OH -- COO 0 0 CH CHI 70 71 .,COOH ~ .,COOH 0 0
CH
3 CH 3 72 73 I .1 C O O H *rN .. C O OH~ 0 WO 99/06397 PCTIUS98/1 5479 - 496 74 75 H , ...OcooH N .uCOOH 76 77
H
2 N~~r ..COOH N "OO 78 79 N *.,,COO-N .'iCOOH 80 81 H 2 W - , N .. IC O O HN .NtcT h WO 99/06397 PCTIUS98/1 5479 - 497 82 83 .ICOOH -iCOOH 84 85 ..COOH H~Njf. .. COOH 0 86 87 0 0COO .. COOH 0 00 88 89 N .. COOH *C00H 0 WO 99/06397 PCTIUS98/1 5479 - 498 90 91 2..,,.N H 2 Nj jN N *'OCOOH .CO 0 0 92 93
-
.
"COOH N. uCOOH 0 03 94 95 .C H i 0.C O 0 0 96 97 * N+ %. N>~N N~ ><N ~ ...1COOH -~ COOH 0 0 -1 0 1 WO 99/06397 PCT/US98/1 5479 -499 98 99 0 0 100 101 .COOH 0 I.< .s I~ 0 0
CH
3 102 103 0~C0 0 osC0 0 0
CH
3 CH 3 104 105 ..'uCOOH H 2 N~~N~ 0 0 COOH 00
CH
3 CH 3 WO 99/06397 PCTIUS98/1 5479 - 500 106 107 N ",COOH ... GOOH 0 0 9 0 CH CH 3 108 109 'I r N H 2N
-
'rf' N C 0 --coO 0 *CO 0 0 11011 -- - N NIN i.CCOH - *.CO0H I0 0 0 0
OH
3 J IH 3 n 112 113 N *.COOH ~ .uiCOOH 0 0 CHA 0 Oi H 3
D
WO 99/06397 PCT/US98/1 5479 -501 114 115 .COOH :"NCOH
CH
3 C H 3 116 117 LtH .1COOHFhIh 2 'N*sQQ 0 0 118 119 HO , *eCOOH N- N N CO0H 0 0 120 121
H
2 N~ ~~.% *sCOOH . *'sCO0H 0 0o WO 99/06397 PCT/US98/1 5479 - 502 122 123 *...COOH ~ N ~~. *COOH 124 125 H2-- N-N Nr N .. COO .sCOOH NuV~ ~ iCOOH 0"1 128 129 + N *ICOOH H 2N~ >~ N *. 00O WO 99/06397 PCTIUS98/1 5479 - 503 130 131 0 13213 *rCOOH P *.COOH 0 0-i b0 13413
H
2 N~ *'sCOOH H2N.N, , "COOH 136 137 0
..
aCOOH N .NIc I.C O 00 ... ,C3 O0 WO 99/06397 PCT/US98/15479 - 504 138 139 "ICOOH -{N "COOH 0 0 140 141 -*ICOOH N -COOH / \0 142 143 .,.NN -e'COOH
H
2 NC N *COOH o 0 144 145 -'r N -*COOH N N -COOH 0CH 0 C H 3 WO 99/06397 PCT/US98/115479 - 505 146 147 'Ir N "COOH0 'sCOOH 0 CH3O OH 3 148 149 's ,*.ma-N % o -,CO O H H 2 N ,,, N . ( N .SIo O O H 0 0r ~0 0
OH
3 CH 3 0 150 151 H2NN<.'IN N N .eCO 0 0c 0 0
OH
3 OH 152 153 .. 'C0OH H N -(N ."COOH 0 0
OH
3 -i H 3 WO 99/06397 PCTIUS98/1 5479 - 506 154 155 .. K0)0H*'iCOOH 0- 0 0 CH 3 C 3 157 159
H
2 NNf-lN 'sCOOH -j~r''~ .COO 0 CH3 03 H 160 161 {% .COOH 0 ICO WO 99/06397 PCT/US98/1 5479 - 507 162 163 *"COOH O 'N "'COOH 164 165 *emcooH H2.NN*COOH 166 167 .'iCOOH .. COOH 168 169 -COOH ..COOH WO 99/06397 PCTIUS98/1 5479 - 508 170 171 N N cOO NK~ %IN '.O ICOOH ."CJ *"OO -1:0 174 175 .',COOH *COOH 0 176 177 0 00 0 0 WO 99/06397 PCT/US98/15479 - 509 178 179 0 H N N 0 -- COOH 181 180 0 0 N -.. COOH H2N" N N -.COOH 182 183 O 0 -- ,COOH N N -- COOH .,O IO 184 185 0 .ICOOH s N N -'COOH / \0 WO 99/06397 PCTIUS98/1 5479 -510 186 187 12 N *'uH0 OOH -0 0 188 189 HO ~ ~ ,tsCOOH .'ICOOH OH 3 CH 3 190 191 Y .. ICOOH H2..,I~N *COOH 00
CH
3 0CH 192 193 00 OH 0H 3 WO 99/06397 PCT/US98/15479 - 511 194 195 H2N N -"COOH N -NOO 0 COOHH 0 0
CH
3 CH 3 196 197 ' "ICOOH I - COOH \ /0
CH
3 CH W 198 199 0 "COOH
H
2 N N -CO 0
OH
3 - H 200 201 N. N ."COOH -.nCOOH
OH
3 WO 99/06397 PCT/US98/15479 -512 202 203 F N -"ICOOH HON N 'COOH 204 205 0 ON ) N -n.ICOOH H2N,, N r N -miCOOH / \ / 206 207 / \ '/ \ O 208 209 o 0 -N N ..rOHH2N-' M N .CH -COOH -COOH /0 WO 99/06397 PCTJUS98/1 5479 -513 210 211 N~ N -- flN N-~ COO6 N' .COOH 212 213 0 N *'s"COO 214 215 H2N N 0 ICOOH 0~~i *COOH 216 217 N UCOOH HO , t N "COOH 0 0 WO 99/06397 PCT/US98/1 5479 -514 218 219 00 *'uCOO H 2 NNN{N *COO 220 221 00 ..rOOH -0 'I0 222 223 o 0 o 0 224 225 o 0 .uaCOOH N'-.IICOOH 0 0 WO 99/06397 PCT/US98/I 5479 -515 226 227 0 " 'CO H N - COH -0 0 0 230 231 0 0 232 233 0 0 -0 0
CH
3
OH
3 -c WO 99/06397 PCTIUS98/1 5479 -516 234 235 0 0.oCOOH .N *ICOOH CHI CH 3 236 237 .,COOH 0 *'nCOOH 238 239 IN N 0 -',COOH 0r "'ICOOH CH 3
CH
3 ."OO 240 241 0 "ICOOH >.N..N "C 00H
OH
3 5- CH 3
-J
WO 99/06397 PCT/US98/1 5479 -517 242 243 N %N N
H
2 N~'~f l*'COOH i>'-,f~N *iCOOH 0 0
OH
3 CH 3 244 245 -COOH -- O.-- 'COOH 0 0 248 249 0 0 N .CO0H
H
2 N,^,-N r .COOH WO 99/06397 PCT/US98/15479 -518 250 251 0 'I4COOH r .. iCOOH 252 253 00 0 254 255 0 0 *"tCOOH NK< *oCOOH 256 257
+N,~''
1 *'COOH H 2 )r~~(N .COOH WO 99/06397 PCTIUS98/1 5479 -519 258 259 0 4COOH *~r..COOH 0 260 261 H O ~ ~ ~ N .COOH .gCO H 0 262 263 H 2 N ~ N ~ N .ICOOH H 2 N .# ,Ni COOH 264 265 iiCOOH .iCOOH 09 -9o
.C
WO 99/06397 PCTIUS98/1 5479 - 520 266 267 N~TN .. aCOOH *'sCOOH 268 269 N~T .'ICOOH ..iCOOH 00 270 271 KJ~N .'aCOH *..COOH 00 272 278 *.m--iCOOH 0 **"COOH 00 CH3 WO 99/06397 PCTIUS98/1 5479 - 521 274 275 0'C O 0 ICOOH
CH
3 CH 276 277
..
TChO
H
2 N~N *.ICOOH 0 .COOH 0 0 0
CH
3
CH
3 278 279 0 0
CH
3 CH 280 281 fH 2 NO-"' CON ."COOH 00 0 0
CH
3
OH
3 WO 99/06397 PCTIUS98/1 5479 - 522 282 283 0
CH
3
CH
3 284 285 NK~"" .uCOOH + -sICOOH
CH
3
-CH
3 286 287 0 H 2 N~ N~ N .CO O *.iCOOH 0 0! II~ .'COOH N **'aCOOH WO 99/06397 PCT/US98/I 5479 - 523 290 291 0 0 HO, N{ N .. CN<. *..tCOOH 292 293
H
2 N N~N *uuIGOOH H2N,,N , N -. COOH 0 294 295 -' .sCOOH N: .ICOOH 296 297 0 H2-" r N .,COOH N <N .'COOH 00 WO 99/06397 PCT/US98/1 5479 - 524 298 299 Nr ueGOOH ueCOOH 300 301 .*0COOH H2N .eaCOOH eCOOH .. CO ) 304 305 N .COOH F YrN .. sCOOH 0 304 305 WO 99/06397 PCTIUS98/1 5479 - 525 306 307
CH
3 CH.: 30 30830
H
3 JH -,COOH ,sCOOH a0 31031 H OCH 3
H
2 N o'iCOOH *.uCOOH 312 31 N.->
OCH
3 N.rII1f'N 0.aC WO 99/06397 PCTIUS98/1 5479 - 526 314 315 z
CH
3 OH3 *..aCOOH .COOH ~0 316 317 H,3
OH
3 0_ 0
CH
3 318 319
CH
3 H: 0
CH
3 -~CH 320 321
H
3 H 3 0 0
OH
3
-H
3 -3 WO 99/06397 PCT/US98/1 5479 - 527 322 323 fliq *",COOH *"',COOH 00 0 0 CH CH 324 325
SH
3 CH 3
.
.COOH 2 N-*.'OOH CH6 CH3O0 326 327
CH
3 H3 0 Y'IOH~i .. sSCOOH 0 0
CH
3 CH 328 329 H H3 -lsCOOH -Nl-N .'COOH
OH
3
-CH
WO 99/06397 PCT/US98/15479 - 528 330 331 CH 3 --COOH N .N COOH
CH
3 CH 3 332 333
H
3
H
3 -enCOOH F N .nCOOH 334 335 CH: H3 a-COOH .. sCOOH 336 337 Ha CHt H 3 H H2N N N -.'COOH H2NN iCOOH 0
O
WO 99/06397 PCT/US98/1 5479 - 529 338 -339
H
3
H
3 ., N *uCOOOH N! NQ N .. saCQOH 340 341 Ha
CH
3
H
2 N ~ t r-s .C OOH -(N *mCOOH 342 343 H3 CH .. aaCQOH N-V -*.ICOOH 0 344 345 H 3 H 3 - .-COOH tr'COOH WO 99/06397 PCT/US98/1 5479 - 530 346 347 Qb H Q\ H 3 0 0 -4 r N."iCOOH ~ .0sCOOH 350 351 lpOCH: QP OCH 0'- 0 *.eiCOOH H 2 ~-~ .COOH 00 352 353 9 bCHI) 3 Q0 H .0.COOH -N-2{.N oCOOH co 0 O-j J WO 99/06397 PCT/US98/15479 - 531 354 355 ~bH O M O CH 3 H-COOH -,,eCOOH 356 357 ; OCH3 O N COOH NN C -05 358 359 QHCH3 00 N -. COOH H2 N-'COOH 00 360 361 P MH3 CH3 4 N N -- sCOOH -- fiCOOH j ~ CH3 - WO 99/06397 PCT/US98/15479 - 532 362 363 9%00H3 H3 F N .COOH H - iCOOH 0 CH3O CH 364 365 00 ~~0 C 366 367 N N NCH 3 0 -COOH HNN COOH - 00
CH
3 CH -. 368 369 H3 9'CH 0 H -"COOH H 2 N -*COOH 0 O.C 0-'C 00
CH
3
CH
3 H3 H, WO 99/06397 PCTJUS98/1 5479 - 533 370 371 90 H3 90H3 .. ICO*H ICOOH 00 0H 3 0 CH 372 373 N ~~N 9 b H 3 0" ~CH 3 .. 'iCOOH ~NKIaN .iC 00
CH
3 C H 3 374 375 0 0
H
2 N Nk A'gN .COOH -1 ' r N ..iCQOH 376 377 P - OCH3 H 3 00 -00O00 WO 99/06397 PCT/US98/15479 - 534 378 379 H HZ
QOCH
3 9 POCH3 -COOH N.OCOOH 380 381 bH3 H3 00
H
2 N, N -COOH -- nCOOH 382 383 Q;:0CH 3 Q'0H 3 0 0 N N -.mCOOH .nCOOH 384 385
QOCH
3 P OCH 3 0 0
H
2 Ne N N -. iCOOH -.. COOH /r \I \o'C
O
WO 99/06397 PCTIUS98/15479 -535 386 387 0 3 90 H3 0H N N --COOH 388 389 9 O CH 3 9 O CH3 N COOH
H
2 NN N -"COOH 390 391 0O
H
3 N -COOH "COOH / 0 392 393 QQ 0 0 .. COOH HO. N -. COOH / \ WO 99/06397 PCTUS98/1 5479 - 536 394 395 * A N .SiCOOH
H
2 N^ N )<N .'iCOOH 0 39639 ipC*..ICOOH 0 0 0J 398 399 N 0 0 N N N )rN .HCOOH .aCOOH 0 C 40401oJ 400 < N ~ ~ ~ ICO0 WO 99/06397 53-PCT/US98/1 5479 402 403 Q Q 0 N +.CO .. siCOOH 00 -C 404 405
H
2 N >if> .sCOOH ti~ eCOOH 406 407 a 0 Qo\ QN'CO 0'O*.CO 00 NN HO%~NyN.u.COOH *..COOH 0 44F0 0 0
CH
3
CH,
WO 99/06397 PCT/US98/15479 - 538' 410 411 H2N -- "COOH .sCOOH CH CH 412 413 o 0 "N -- COOH N .iCOOH 0 0 / \0 C K3 CH 3 414 415
H
2 N N N -- nCOOH -'COOH 00 O O
CH
3 C CHI a J 416 417 Q N"O O NN+"-">- 0 N~ 0+ -COOH N--COOH 0
OH
3 CHa WO 99/06397 PCTIUS98/15479 - 539 418 419 Q Q 00
CH
3
CH
3 420 421 Q N .. {COO* -ICOOH CH3 422 Q2 0 N-" 0 'r N 111OOHHO N N .aICOOH 42442 N IiCOOH H2*N.mCOOH 0ric ) 0 - o WO 99/06397 PCT/US98/15479 - 540 426 427 H2N ~N N .iCOOH N.uCOOH 428 429 O O .COOH
H
2 .NN .COOH 430 431 Qo 0 0 N -- nCOOH N0 -"PCOOH 432 433 Q Q 0 O NC N -COOH N ' N -COOH / \O\ WO 99/06397 PCTIUS98/1 5479 - 541 434 435 oCOH FCWO 43643 k N 43843 HO N..N iPOH -. O rN .. COOH 440 441 H N* N-rN .iCOOH H2~~%NN *'miCOOH 0 05 -C5 WO 99/06397 PCTIUS98/15479 - 542 442 443 N N N N N N -- COOH 00 I 0O o 0 444 445 Q Q 0 O H2 W__ N N -enCOOH N --CO ... iCOO -Tr .sCOOH 00 O-J 446 447 Q QO O O 448 449 .. N .COOH H 2 NN N ..tICOOH / \ -. O1)I WO 99/06397 PCTIUS98/15479 - 543 450 451 jN N .iCOOH CO 0 452 453 -"COOH 'ICOOH
CH-
3 CH 454 455 *% ' -V' N *'ICOOH
H
2 N,' N (rN *'a'COOH 0 0C 0 0
CH
3 CH 456 457 0 0" 0 0 CH -jC H WO 99/06397 PCT/US98/15479 -544 458 459 Q Q O U -COOH
H
2 N-- N$N .'aCOOH 0 0 0 0
CH
3 CH 3 460 461 Q NN -- nCOOH ~ N~N fN -- 'ICOOH IN 0 0 0 ON
CH-
3 CH 462 463 N-NCOH N N-COOH
CH
3 C H 3 464 465 Q 0 %. O 00 -00 H2 N N -- nCOOH Nr N -- COOH CHad b-- CH30'D WO 99/06397 PCT/US98/15479 - 545 466 467 N (N cOOHN -. iCOOH 468 469 HO N N -s COOH O N -usiCOOH 470 471 QOQ H2N N-COOH N -"COOH 472 473 w 0 N O N N+ -n:iCOOH N-ICOOH *.ICO 0 WO 99/06397 PCT/US98/15479 - 546 474 475 H.a -COOH -PCOOH 476 477 Q Q >f N N ..iCOH*N -COOH 478 479 N O .iCOOH H.2COOH / \ / \ 480 481 N -iCOOH N-NCOOH / \ / WO 99/06397 PCTIUS98/15479 - 547 482 483 *, N' N .COOH HON % N .COOH 0 486 487 N0 N40 488 O- 489 --. _ <>.oCOH .'COOH 00 '0 0 WO 99/06397 PCT/US98/15479 - 548 490 491 -W N .COOH N N -ICOOH 0 492 493 494 4954 H.2COOH -COOH 0 496 497 N -COOHF N N -COOH / \ -CH-a WO 99/06397 PCT/US98/15479 - 549 498 499 O COOH , O N *.sICOOH 0 0 9 0 CH
CH
3 500 501 H2N N N -COOH H2N N N -lICOOH 0 IC0 0 0
CH
3
CH
3 502 503 O4 O O -"COOH O *ICOOH 504 505 2u-COOH N N -.COOH 0 O
CH
3 CH0 WO 99/06397 PCTIUS98/1 5479 - 550 506 507 N0N ICOOH )N "'q'O 51 51 CH R 512 513 *,COOH HO-N-%. *'OOH 0-~0 WO 99/06397 PCT/US98/15479 - 551 514 515 0
NH
2 N N N -enCOOH 516 517
N
0N (N OO H NN N -COOH f iN .COOH 518 519 0 O -N COOH O ..nCOOH 0 520 521 O O 00 NICOOH N-sCOOH 0 0 WO 99/06397 PCT/US98/15479 - 552 522 523 -No N -COOH N -"COOH 524 525
(%N-
.COOH -.. iCOOH / \0 526 527 N40 -- N 0 N -. COOH F r N -. COOH OC 528 529 HO N N .. COOH O' N .iCOOH .0 0 WO 99/06397 PCTIUS98/15479 -553 530 531 0 0
H
2 N N N -. COOH H2NN --COOH 0 0 / J\/ 532 533 O O N ND -- nCOOH O -- iCOOH 00 534 535 S 0O 4 H2N - nCOOH NN---iCOOH O O 536 537 N4.QO N4j'g .'C 0 0 O O >o N-COOH N -- COOH \ "Co/ \ WO 99/06397 PCT/US98/15479 - 554 538 539 0 N N N -- iCOOH H2N--COOH 540 541 NO - aNCOOH N -- COOH 0 O CH3 542 543 0N-- o N' N.T F N -COOH HO N .N .COOH 0 0 0
CH
3
CH
3 544 545 O O NIN -- " COOH
H
2 N N N -. iCOOH 0 0
CH
3 J CH 3 WO 99/06397 PCT/US98/15479 - 555 546 547 N-' N'~ o 0 H2N N N O uCOOH O .iCOOH o 0
CH
3 CH 3 548 549 0 N
-
N -COOH H 2 N -COOH o 0 o 0
CH
3 CH 3 550 551 0 o 05 Y N -. ,COON -,COOH
CH
3 CH 3 552 553 N 40f~ NN 0N~ N -*"COOH + N N .'COOH - C C H 3 O H 3 - H WO 99/06397 PCT/US98/15479 - 556 554 555 00 -COOH -,iCOOH CH
CH
3 556 557 O COO 558 559 0-0 HO N N -..COOH N -- COOH 560 561 O O'
H
2 N-- N ' N -.
NCOOH H2 -- COOH 0 WO 99/06397 PCT/US98/15479 - 557 562 563 ,NN N
N
0 - COOH -iiCOOH 564 565 O O H2N -4iCOOH N N -COOH 566 567 0 N N COOH COOH 568 569 0 N N -. COOH HN-COOH / \ / \H WO 99/06397 PCT/US98/15479 - 558 570 571 arN4 , 'OO N -,CO 572 573 N -COOH H N N-COOH 00 0 574 577 O N N 576 577 O0 H2 N N .N OOH N uCOOH 00 / \o
'O
WO 99/06397 PCT/US98/15479 - 559 578 579 0 -"COOH H 2 N,-f N .'ICOOH 00 / \ C/O\ 580 581
N
N0 N --'COOH 0 ..COOH 0 582 583 0 00 --COOH .N COOH 584 585 NN' 0 N H 2 NNfJ { N .ICOOH0*.OH WO 99/06397 PCTIUS98/15479 - 560 586 587 rN' NO 0 O0 N -ACOOH FN -COOH CH CH 3 bj 588 589 HO N -- COOH O I N I.COOH 00
CH
3
CH
3
-
590 591 H N COOH H.2NCOOH
CH
3
CH
3 592 593 o N N .'ICOOH N -nCOOH ~ I ~ J
CH
3 O'' CH 3
J
WO 99/06397 PCTIUS98/15479 - 561 594 595 N' N 40 N 4 O H-iCOOH -ICOOH 0 0 CH. J
CH
3 596 597 N'N O O N, r N --COOH -mCOOH CH CH3 598 599 Q 0 0 +N N N
-
wCOOH H A I v
-
lCOOH
CH
3
OH
3 0 600 601 N' N N :: U.NN -COOH 0 -'COOH
CH
WO 99/06397 PCTIUS98/15479 - 562 602 603
N-
N0 N 4 F N N -- uCOOH HO N COOH 604 605 N (N 0 N N -oICOOH H2NI N -COOH 606 607 N' H2,N. N H N -nOH "COOH 0 608 609 O O 0 -iCOOH H 2 N "COOH 0 WO 99/06397 PCT/US98/15479 - 563 610 611 N OI NN N-COOH N N -iCOOH 612 613 N-N1 NC; N N m-COOH .N N N -ICOOH 614 615 H2N-- N.IO IHI -sI OH CO H2N--COOH -nNi COOgH 616 617 -S*ICOOH COOH 0 O /-,^,O \0\ WO 99/06397 PCT/US98/15479 - 564 618 619 -Hi COOH -"COOH 0 620 621 0 'alCOOH -"COOH 0 0 622 623 H2N N-nCOOH N--COOH 624 625
K>
0 N .ICOOH N--COOH 0-i WO 99/06397 PCTIUS98/15479 -565 626 627 0 0 J ICOOO 628 629 CO O1 - N COOH 0 N -COOH CH 630 631 F -COOH N .COOH
CH
3 CH ' 632 633 O Oh O -COOH H 2 N -COOH C0
CH
3
CH
3 WO 99/06397 PCT/US98/15479 -566 634 635 O Oh H . COOH o s I' O O H o 00
CH
3 CH 636 637 COOH H2 "COOH 0 O 0
CH
3 - CH3 O 638 639 aO O 0 0
CH
3 CH 640 641 N -<N COOH -.aCOOH 0 0 OH
OCH
3 -i WO 99/06397 PCT/US98/15479 - 567 642 643 OCIO H2NCOOH
-
O 0COOH 0 0
CH
3 CH 3 644 645 C O O N N -. aCOOH F $ ;J1COOH 646 647 clTh 0 HO, -"COOH O -"COOH 648 649 N O 0 H2N N .COOH
H
2 N,_ N -.COOH 0 0 /co \co\ WO 99/06397 PCT/US98/1 5479 - 568 650 651 0 652 653 il2I ~ gI-otgCOOHI6."COOH 654 655
NA
0
NA
0 *" tr N .iCOOH H2Ne-ICO0H 0 0 656 657 0 0 **'HO 2NN *.iCOOIH WO 99/06397 PCT/US98/15479 -569 658 659 NO rN 1 -- COOH NI -- COOH - 0 660 661 S.COOH H N.--COOH 0 0
/
662 663 O N COOH H2N -.COOH 0 0 \ /0 664 665 mt dm -. COOH N N -. ICOOH 0 O 00 / \0 WO 99/06397 PCT/US98/15479 - 570 666 667 .4COIHH2N -sCOOH 0 O 668 669 O O0 N -eCOH-*COOH 0 O /\ /\ 670 671 /. \\ o 0 09 0 672 673 H2N -*COOH NN -- OOH 0 0 WO 99/06397 PCTIUS98/1 5479 - 571 674 675 *rN .COOH -'COOH CH -
CH-.,.
676 677 HQ0 N<N 0N .COOH 0 .1COOH
CH
3 CH 3 678 679 NON, -'COOH HN ~.'COOH CH3 C H 680 681 0 'jCOOH 0 01COOH
H
3
H
3
-%
WO 99/06397 PCTIUS98/15479 - 572 682 683 H2 -COOH N -COOH
CH
3
CH
3 684 685 -. COOH N - COOH
CH
3
CH
3 a 686 687 A A 1 "COOH H 2 -.. COOH /2 \ IO/ \ 0 0 CH,
CH
3 688 689 A A N N -. COOH N COOH 0 0 0
OH
3 WO 99/06397 PCT/US98/15479 - 573 690 691 0 HOL~NrJ 0 -COOH HQ.COOH 692 693 0 O 0 -- COOH H2N 0 -COOH / \ 694 695 HN"OOH N g .'COOH 696 697 0 0 0 -. uCOOH H 2N .COOH 0 0 WO 99/06397 PCT/US98/15479 - 574 698 699 O O N -oCOOH )tN siCOOH 700 701 N -*'COOH + "COOH 0 702 703 H2N * f<N -*COOH N -"iCOOH 704 705 2 N IN .-oCOOH -.COOH 0F 0 0 WO 99/06397 PCT/US98/15479 - 575 706 707 0 tlO O Oh HQ <N -- COOH O -.COOH 00 //3 708 709 H2N- -1COOH H2N. -COOH -3 3 710 711 .COOH 0 -. mCOOH 712 713 0 HN-3 COO .OO WO 99/06397 PCTJUS98/1 5479 -576 714 715. ti~0 716 717 ifI'J~> *'mOOH"UiCOOH 718 719 N* I."OOOH *.COOH 0 CH 1 720 721 *s'COOH HO, *s'oCOOH 0 =0
CH
3 - CH 3
-
WO 99/06397 PCTIUS98/15479 - 577 722 723 Oa -COOH H2NCOOH
CH
3
CH
3 724 725 H2N,. -COOHCOOH CH3CH 3 726 727 -*.COOH H 2 N.COOH
CH
3
CH
3 WO 99/06397 PCT/US98/1 5479 - 578 728 729 *suCOH ... 1COOH CH,. CH.. -CO 'o OO 3H 3 734 735 0 0 .6COOH .COOH 0 .CO .CO CH3 H0 WO 99/06397 PCT/US98/15479 - 579 736 737 0 O-iCOOH -'COOH 738 739 *OH 00 H2N" -COOH -COOH O0 740 741 N"COOH -NiCOOH 742 743 H-eCOOH NIOO O O01 WO 99/06397 PCT/US98/15479 - 580 744 745 Ot O -sCOOH N-COOH 746 747 ~AO .iCOOH H--tCOOH 748 749 a 0 I .COOHN N -- CO 750 751 O O .ICOOH H--*sCOOH 0 \ -9 - WO 99/06397 PCT/US98/1 5479 - 581 752 753 N xo N" --CO(OH *..i -,COOH 754 755 *2, sPCOOH .ssiCOOH 756 757 0 -stCOOH *"'COOH 758 759 <"NN 00 0 0 J -0-I WO 99/06397 PCT/US98/15479 - 582 760 761 N -- COOH N-aCOOH 762 763 N O H2N N*--COOH Lu-ICOOH 764 765 -- COOHCOOH ~ f N INIC J COO 0 F OH - 0 CH C~ 766 767 00 HI .. COOH CO O O0 CH -
CH
3 WO 99/06397 PCTIUS98/15479 - 583 768 769 *wCOOH H N.N N *aCOOH 0 0 o0 0
CH
3
CH-
3 770 771 ON 0 NO SIIaCOOH 0i *"ICOOH 0 0 CH., ~ CH 3 772 773 ~N 0 -ovCOOH uOO
CH
3 j ~ C H 3 774 775 00 .uCOOH NK.II( ~C00H CH CH 3 0 0 WO 99/06397 PCT/US98/15479 - 584 776 777 0 -oCCK)H.11OOH
CH
3 CH 3 778 779 .. COOH *rN .COOH CH3 780 781 .4.COOH HO-1l{o.sCOOH 782 783 *.uCOOH YK *.COOH WO 99/06397 PCT/US98/15479 - 585 784 785 H 0 N -esCOOH -9*COOH 786 787 -eCOOH ->.COOH 788 789 NCN N< -{IICOOH -N.COOH 0 0 790 791 0 O N -COOH -COOH WO 99/06397 PCT/US98/15479 - 586.
792 793 794 795 "I1COOH ".COOH 796 797 HON %..N .iCOOH -41N 1sCOOH 798 799
H
2 N- 'w *mCOOH 0A.I *.'COOH 0 0 WO 99/06397 PCTIUS98/15479 - 587 800 801 ~ *.uCOOH ir .COOH 0 0 802 803
H
2 Nfl *.IICOOH 0 'sCOOH 0 0 804 805 0.ICO N N< N *''C NN iCOOH .'COOH 0 0 0J WO 99/06397 PCTIUS98/15479 - 588 808 809 -400COH ...- ,COOIH
CH
810 811 s ic *.ICOOH 0. COO CH O C H0, 812 813 o N .. oiCOOH HN.',COOH 0 ~0
CH
3
CH
3 814 815 N 0N H .tCOOH II" *,,OOH 0 00
OH
3 '
CH
3 -i WO 99/06397 PCTJUS98/15479 - 589 816 817 *.,COOH H 2 -,'IgIN .COOH 0 0 CH Oj H 3 C 818 819 .uCOOH 2j ~ ~ .. sCOOH
OCH
3 OH .cI 820 821 NN 1 N -COOH r I-,COOH
OH
3 - 0 3 822 823 'g~N *'IOOH I 4 N *COOH
CH
3 O H, 3 0 WO 99/06397 PCT/US98/15479 - 590 824 825 -- vCOOH F -COOH 826 827 "COOH O-COOH 828 829 O0 O H2N--COOH H20nCO / \ / O 830 831
,COO
WO 99/06397 PCTIUS98/15479 - 591 832 833 H2N22 < H - mCOOH -. 1ICOOH 0 O 0 O 834 835 N < -COOH VN N -*COOH '0 0 OC 0 836 837 N 0 0 N -eCOHH2W ---COOH 0 WO 838 839 rN" -.ICOOH N -COOH 0 0 WO 99/06397 PCTIUS98/15479 - 592 840 841 -COHO 0 0 hh J -- COOH --COOH 842 843 O-COOH H 2 NN .10COOH 844 845 O O 0 H2N -NCOOH *N-COOH 0 0 846 847 N 0 N ao **COOH H2N .. COOH / \ 09 WO 99/06397 PCTIUS98/15479 - 593 848 849 COOHCOOH 850 851 NnCOOH 0 O ,, 09 0 -0( 852 853 H2ltCOOH
..
1 1 CONr 854 855 .OCOON .- COOH N 0 CH13 -iCH 3
-
WO 99/06397 PCT/US98/15479 - 594 856 857 -COOHOH O O CH, CHa3
H
3
-
Hr- 858 859 OQ O H2N -ICOOH
H
2 N-,N -COOH O O 0 0 CH3 CH r 860 861 N0 N -. ICOOH N -ICOOH CH
CH
3 862 863 H2N - COOH - sCOOH 0 0 CH -i CH3 WO 99/06397 PCTIUS98/1 5479 - 595 864 865 0 0 -COOH -,'COOH SI0 *.ICOH0 0
OH.
3
-CH
3 866 867 0 N N .01 'COOH*.OH CHC 870 871 0H00 <ir *"COOH 0*COOH WO 99/06397 PCTIUS98/1 5479 - 596 872 873 0m N 0 -COOH H 2 {N iCOOH 874 875 "'1COOH *"'COOH 876 877 N N< ... COOH H."COOH 878 879 -N *1'CO0H -"COOH 0 WO 99/06397 PCT/US98/15479 - 597 880 881 NO aCOOH -COOH 882 883 H2N N -.COOH N - POOH 884 885 N N COOH N'COOH N 1IC 0A ~ o*sC O 00 886 887 H ,ICOOH C N -COOH 0 O 0 0
J-
WO 99/06397 PCTIUS98/1 5479 - 598 888 889 01 890 891 .1"C00H **'iCOOH 892 893 {N IC00H N .'oCOH 894 895 +" N N "'IOH :)N' N -COOH 0 0 .. I-J WO 99/06397 PCTIUS98II 5479 - 599 896 897 'o 0.' 0' "C0O 0 0 N~0 No F~~1~N "COOH HO NsN*COOH
CH
3
CH
3 902 903 *smCOOH *..iCOOH
OH
3
H
3
,
WO 99/06397 PCT/US98/1 5479 - 600 904 905 0 N-h 0 04000H .4'ICO0H
CH
3 CH I 906 907 (0 *4o 0 0 *".1COOH H 2 N-< N *COOH 0 o
OH.
3 CH, 908 909 (4o. -"1COOH 0- .aCOOH o 0 910 911 Nuf KN .'COOH + -COOH -30 CH30 OH 3 WO 99/06397 PCT/US98/15479 - 601 912 913 N~Th *0 * .NCOOH -- liCOOH - 0 0
CH
3
CH
3 914 915 ~Th=0 N N -. "COOH F N -.'COOH 916 917 Oa -iCOOH O, -'ICOOH 0 0 918 919 .s=O =C H2W -er N .ICOOH
-,,COOH
WO 99/06397 PCT/US98/1 5479 - 602 920 921 '0 .0O -111COOH .'COOH 922 923 H NN,_,% NN .'COOH N*.-stCOOH 924 925 .siCOOH
*."CCOOH
WO 99/06397 PCT/US98/15479 - 603 928 929 0 0 0 -SJ 930 931 OO N -"COOH -COOH 0 0 F.C) O O 932 933 -'COOH H2N - COOH 934 935 -COOH 0 -. 'COOH 0 0 WO 99/06397 PCTIUS98/15479 - 604 936 937 O0 M "COOH
H
2 N--,y 938 939 O N -ICOOH N -,,iCOOH 0 0 940 941 0 NK."COOH
-+
2 COOH -0J 942 943 H2N fCOOH .COOH 0 WO 99/06397 PCTIUS98/15479 - 605 944 945 N COOH F- .COOH
CH
3 CH 3 946 947 N o N O H Ok - COOH -"COOH 0 0
CH
3 CH 3 948 949 N O
H
2
N,-
2 - "COOH
H
2 N -. N -COOH 0 ' 0 0
CH
3 CH 950 951 N0
OH
3 " OOH
O
3 COOH CH3 CH3 WO 99/06397 PCT/US98/15479 -606 952 953 ON 0
H
2 N "COOH -.. COOH /\ /\ o CH, - CH 954 955 sN ON N -iCOOH N -'COOH 0 CH
CH
3 -CH 956 957 "COOH H2COOH 0 0
CH
3
CH
3 958 959 - COOH N N -COOH 0 CH3 WO 99/06397 PCT/US98/15479 - 607 960 961 O0 F"COOH HNCOOH F 0 \ / \C 962 963 0COOH
H
2 N'-' < 0 -COOH 964 965 0 ."ICOH 0 .1COOH COO 966 967 "COO H-ICOOH 130 WO 99/06397 PCT/US98/15479 - 608 968 969 0 "COOH -ICOOH 970 971 O O ~N N-COOH -'lCOOH 00 00 972 973 H 2 N N - C O a C O 974 975 N -IICOOH F-.1C OOH \0 WO 99/06397 PCT/US98/1 5479 - 609 976 977 0N *'COOH 0-'COOH ~0 0 978 979 ~Th 0 <NN H2'- 'ICO0H 0 *"COOH 980 981 ""ICOOH < 'CQ ~0 0 o.j
J-
982 983 -LO 40 0 0 WO 99/06397 PCTIUS98/15479 -610 984 985 ~-Th0 N-ko *O -.aCOO N -'COOH 986 987 -*ICOOH 2 -COOH 0 0 988 989 N-.COOH NN COOH 00
CH
3 990 991 F .COOH -COOH
CH
3 - CH 3 - I WO 99/06397 PCTIUS98/1 5479 -611 992 993 rN -COOH H2- .saCOOH
CH
3
OH
3 994, 995 .ICOOH *.I"OOOH 0 996 997 ~ .COOH H2I"-N .ICOOH
OH-
3
OH
3 998 999 I *suCOOH I *.'COOH CH3
C~H
3
C
WO 99/06397 PCTIUS98/15479 -612 1000 1001 NO Nm NC4OH -Qn*COOH
CH
3
CH
3 1002 1003 H0 . COOH COOH 0 0 00 CH3 CH3 o3 1004 1005 0 N -COOH F -- "COOH 0 1006 1007 -m 0 COOH 0 '"COOH \ / \r WO 99/06397 PCT/US98/15479 -613 1008 1009 H2N ) Y N 0 "COOH II..N~ COOH 1010 1011 N 0 1COOH '<N I'sCOOH 1012 1013 0 H2NOO .. COOH 1014 1015
N
0 o 'COOH N-eCOOH 0 WO 99/06397 PCT/US98/15479 -614 1016 1017 H2N N -COOHH -COOH 1018 1019 OOO .'NCOOH FCOOH 1020 1021 HO N N HO , N r l-N - COOH N - O, N ) N 'alCOOH 0 'IC OH"O O 0 0 O 1022 1023 H N N .. iCOOH N -"COOH 0 0 / i \ / \ ... ,CO
'O
WO 99/06397 PCTIUS98/15479 -615 1024 1025 NN N O -"COOH N COOH 0 0 1026 1027 H2-N N NI -"ICOOH -nICOOH \ /0 1028 1029 NN-N Nl. -COOH N eCOOH 0 0 1030 1031 4N N -- COO H2N N N -CO WO 99/06397 PCT/US98/15479 -616 1032 1033 -"COOH -COOH O0 0 C
CH
3 1034 1035 N -COOH HO N N COOH -- 0
CH
3
CH
3 1036 1037 NT N N N N -IICOOIH H2N N - COOHN 6 ."COOH ,COOH
CH
3 0
CH
3 0I 1038 1039 H2NN HNj N I O I N 2N N N ICO O ./N COOH / 0 CH CH, r WO 99/06397 PCTIUS98/1 5479 -617 1040 1041 0
CH
3 C HIt3 3 1042 1043 NN ~N N "CO COO . COOH
OH
3 3 OH 3 -0j 1046 1047 0. 3COOH I 'COOH 00 H - CH- WO 99/06397 PCTIUS98/15479 -618 1048 1049 N N -COOH F 0COOH 1050 1051 HO rN -*COOH .-iCOOH / 0 1052 1053
NN
H
2 N-- g N -.ICOOH HN N -COOH 1054 1055 NN' N N -gCOOH oN, N N -.COOH 0 0 WO 99/06397 PCT/US98/1 5479 -619 1056 1057 N~N-N H2~~ ~ ~ W-_-' N *"IOO r COOH 1058 1059 N N*-N .,CQOH N K g% *.mCOOH 1060 1061 *us#N
N
2 ~~rY CO N N-I )r N .1KWH *N .COOH WO 99/06397 PCT/US98/1 5479 - 620 1064 1065 $II r N "COOH 0 *"COOH 0 1066 1067 "'1*- -l*N .,COOH H2,,..iN--COOH 0 0 1 0 1068 1069 H2N rN N .. "tCOOH - N.-N .. mICOOH 1070 1071 J7i N .'uCOOH
H
2 N 'rf N -CO 0 0 WO 99/06397 PCTIUS98/1 5479 - 621 1072 1073 '~N N I *"COO1H IN -- oCOOlH 1074 1075 I 'ICOOH ""ICOOH 0 0 1076 1077
H
2 N Nzt N N "flCOOH ..11J~ COOH 1078 1079 0CO *.'COOH 00
CH
3 , CH - WO 99/06397 PCT/US98/1 5479 - 622 1080 1081 00
CH
3 -J3 1082 1083 Nm 0 HW 'r-N .',COOH H2" f~-N ..COOH 0 0 O )CHI -C 3 1084 1085 f7 N N N .. "COOH *."COOH 00
OH
3
-CH
3 0 1086 1087 N H 2 N - N Y , N . .IC O O - - . .'C O O H 0 0
OH
3 OH WO 99/06397 PCT/US98/1 5479 - 623 1088 1089 0 "CGOH **ICOOH 0
CH
3 3 CH 1090 1091 N~TN "'ICOOHHNN~N N "OH
OH
3 CH 1092 1093 N0 ~ N -gJoo'*-N OO %..%N C00H 0
CH
3 1094 1095 N N-I, N .. CO0H ~ ~lN ",COOH F 0 0 0 WO 99/06397 PCT/US98/1 5479 - 624 1096 1097 0 1098 1099 ".COOH0 ~'COO 1100 1101 9 9 N .mCOOH H 2 N Ng N ..iCOOH 1102 1103 N '- > N .'COOH olN .ICOOH 0 WO 99/06397 PCTIUS98/1 5479 - 625 1104 1105 NN *.sCOOH *..COOH 1106 1107 0 < *. C O H O Hjj j 00 1108 1109 -N "ICOOH F-Ir0sCOOH ,0 1110 11 -N -N .. "C0OH .N'. "ICOOH 0 C)0 0 0 WO 99/06397 PCT/US98/1 5479 - 626 1112 1113 -N -N
H
2 N-% < .0COOH - ..COOH 00 1114 1115 N -N ,N ~~y ICOOH > N .miCOOH 0 0 0 1116 1117 N -N
H
2 N-__N N .'iCOOH N -a *.COOH 1118 1119 -N .- t00H ."COOH 00 00 0 WO 99/06397 PCTIUS98/1 5479 - 627 1120 1121 -NN *.iCOOH
H
2 ~ r~%~ COOH 1122 1123 -N *"COOH C H 0 0 0_ 0 CH3 1124 1125 -NN N -N N CH3C 1126 1127
N
N 1 0 'N r .. ,COOHH 2 N oN,,N < N C 'IC 0O 0*C O ~0 0
OH
3 bJ
H
3 WO 99/06397 PCT/US98/1 5479 - 628 1128 1129 -N I ,N -N H2N.~N.<N .. COOH N o~N *sCOOH
CH
3 -3CH3 1130 1131 N -N IIC*.'iCOOH 0 0 0 0
H
3 0~ H 1132 1133 N N N-N 0 0 ~ C0 0 CH O3 H 3 1134 1135 -N *.'~0H N.N<%N .COOH CH 'jCH 3 O 0 WO 99/06397 PCT/US98/15479 - 629 1136 1137 -N -N H2N J *COOH NN -"COOH -9 0 CH
CH
3 1138 1139 -N r-"COOH FjN N -'COOH 1140 1141 Q-N NN O -COOH i -'COOH 0 0 1142 1143 N N
H
2 N N~N -- COOH H2N N N -.COOH WO 99/06397 PCTIUS98/1 5479 - 630 1144 1145 -N -N -spUCOOH N .,oCOcOH 0D 1146 1147 -N -N sCOOH *mCOOH 1148 1149 -N N N!-01COOH ... ICOOH 1150 1151 NN N .N, r~ .1COOH H2N'~j~ N..<-NCOOH 0 WO 99/06397 PCTIUS98/15479 - 631 1152 1153 -N -N -,COOH -- uCOOH 1154 1155 N -N F*N-eCOOH HO N .N -"'COOH 1156 1157 N O N -COOH H 2 N N N ."COOH F0 o 0 1158 1159 -N -N HN N ON -*COOH O . ICOOH 0 0 00 WO 99/06397 PCTIUS98/15479 - 632 1160 1161 -N N O*--COOH 0 0 0 \ 1162 1163 N - N -N N N -COOH N-ICOOH 0 1164 1165 N N 'rN NI -COOH N N -COOH /\o /-\ 1166 1167 -N -N H2 N N -tiCOOH N .'COOH / 11 o \ \ OO WO 99/06397 PCT/US98/1 5479 - 633 1168 1169 -N -sCOOH *."cooH F 0
CH
3 CH 1170 1171 N *h N - N 0 *'1COOH 0*sCOOH -0 0 00 OH30 b H 3 1174 1175 -NN OH
OH
3 WO 99/06397 PCT/US98/1 5479 -634 1176 1177 -N -N -NN .iCOOH 0Kf'I> *..aCOO q- 0 CH C 1178 1181
N
+N~~ ~ -*'sCOOH 0 .m~ C HA CHH ' 1182 1183 NN NN ~ - *.-OOH *..iCOOH C l WO 99/06397 PCT/US98/15479 - 635 1184 1185 N F N N -COOH HO N -aCOOH 1186 1187 -N .. N N -COOH
H
2 N N N -ICOOH 1188 1189 HNN NCO N N O -COOH -*ICOOH 1190 1191 -coN -,COOH --tCOOH 0 0 "OO WO 99/06397 PCTIUS98/15479 - 636 1192 1193 N :N -N ..COOH -"4COOH 1194 1195 1 -- N N ."IC N "COOH N -COOH 1196 1197 -N -N H COOH N N -COOH 1198 1199 NN -mCOOH F N N -. ICOOH 0 WO 99/06397 PCT/US98/15479 - 637 1200 1201 -N -N HO 0 - .0OH "COOH 1202 1203 - N1O 1 N 0
H
2 NN.~N H 2 ~~N~ .,COOH -3 0 1204 1205 0 -N 0 J"COOH NI ~0 0 1206 1207 ZN N .. IICOOH Nr N *.0O 0 0 WO 99/06397 PCTIUS98/15479 - 638., 1208 1209 7N 7 *"BCOOH "'COOH 1210 1211 ,N N N HN -N -N N 0 *.iCOOH "CO 1212 1213 N ~-N/-N NN N "@COOH 0 -C00H 0 CH3 1214 1215
N
-- sCOOH **"COOH
C
3 - 0H 0 WO 99/06397 PCTIUS98/15479 - 639 1216 1217 ZN -N O N N -enCOOH
H
2 N N N -' OOH 00
CH
3 1 CH 3 0 1218 1219 N NN
O
1 N - COOH Ot -'IOOOH 0O 0 O 0 0 CH
OH
3 CI 1220 1221 -N -N N X, N rN H2N"' NIN, O COOH O -COOH 0_ 0
CH
3 CH 1222 1223
N
N~-N 1 N -.COOH N N -COOH CH C OH
OCH
WO 99/06397 PCT/US98/15479 - 640 1224 1225 N -"COOH N -"COOH 'o 0 CH -CH 3 1226 1227 -N -N H2N N .COHN N -OH "COOH ...COOH 0 0 CH -' CH 1228 1229 -N -- &COOH N -. nCOOH 00 1230 1231 N -N HQ,,- N -nCOOH O'N N -..COOH 0 O WO 99/06397 PCT/US98/15479 - 641 1232 1233 -N -N H2N,, N N H2N N N -ICOOH -.. COOH 1234 1235 N-N N N N O "ICOOH -'COOH 0 1236 1237 -N -N H 2N ,- N N N -gN COOH -*.COOH 1238 1239 -N --ICOOH -*COOH WO 99/06397 PCT/US98/15479 - 642 1240 1241 N -COOH HN COOH 1242 1243 -N -i !N Ng" -COOH -.'COOH -N F O -COOH >O -COOH o 0 0-J 1246 1247 N ICOOH
H
2 N N I N -*oCOOH 0 0O 0 0+ -i9 WO 99/06397 PCT/US98/15479 - 643 1248 1249 -. COOH O .COOH 0 0 0 1250 1251 N N -. "COOH H2 W-, N N - CO - ~ *..COOH ."'COOH -j 0 1252 1253 -"'COOH 'IICOOH '0 0 1254 1255 -N N "COOH +N N -COOH 90 WO 99/06397 PCT/US98/1 5479 - 644 1256 1257
H
2 N<~N *'COOH .N+NN..%N 'COOH 0 0 1258 1259 -N 0.61C0H -"COOH
CH
3
CH
3 1260 1261 HC,..N r N .'COOH
N,
0 N{... N .. C00H 0 0 C H CH 3 1262 1263 -N
H
2
~
2 ~~N iCOOH HN N fN *COOH 0 0 CH 0, CH 3 WO 99/06397 PCT/US98/1 5479 - 645 1264 1265 .ICOOH N CO 0 0 0
CH
3 CH 1266 1267 0 I "COOH 00 CH -, CH 3 1268 1269 "'-COO - 1 N 'OH ICO"H
..
COOH 0o 0 C H CH ' 1270 1271 -N *COOH H 2 .N.N ICOOH 0~ 0 CH - CH WO 99/06397 PCT/US98/15479 - 646-. 1272 1273 N Y IN -COOH --. COOH
CH
3 1274 1275 F N -"COOH HO, N N aICOOH 1276 1277 -"COOH
H
2 N.NN -a:COOH 0 0 0 1278 1279 H 2N .O - C O O H ON -alN) r .C O O H 0 0 0 WO 99/06397 PCTUS98/1 5479 - 647 1280 1281 +N - N rN N "COcH
H
2
'~
1 'N *sCOOH 1282 1283 0 ..C C 1284 1285 Nk 2 N .4m'COOH N. ~NN N COOH 00 1286 1287
H
2 Nrr~JN~%(% *COOH N "COO WO 99/06397 PCT/US98/15479 - 648 1288 1289 O'0o 0 N FCH -COOH 1290 1291 H0 0 *..uCOOH O nCOOH -3 0 1292 1293
H
2 N M- 2 {C H2N N_, **COOH
-
3
-
3 1294 1295 0N -- COOH --1COOH 0 0
J-
WO 99/06397 PCT/US98/15479 - 649 1296 1297 O O=q ..iCOOH N.8-COOH 1298 1299 -"COOH N.ICOOH 0 1300 1301 +N2~N -'COOH H*ssNCOOH 1302 1303 00 N: -COOH N N -COOH CH33 WO 99/06397 PCTIUS98/15479 - 650 1304 1305 Fu-- COOH H COOH 00
CH
3 CH 3 1306 1307 O -aCOOH H2N-COOH 1308 1309 00 H2N N" O -nOOH-COOH 0 \ IC /I H3 CH3 1310 1311 0 O 'I OOH H 2 N- COOH \ /H \ CH3 CH3 WO 99/06397 PCTIUS98/1 5479 -651 1312 1313 ON~ 0 N ~ 0 2 yN N +1 0 "COOH -0 CH3
CH
3 1314 1315 0 0 0 ~ 0 CO .NJAfN **COOH ~~0
OH
3 0H1 H 3 1316 11 00 CH3 HI I3 1318 11 *"COOH
*CO
WO 99/06397 PCTIUS98/1 5479 - 652 1320 1321 0 "'COOH O-lN.COOH 0 COO 1322 1323 H2*" COOH r2,, *.iC0OH 1324 1325 N...N<% *.COOH -- #~NN *COOH 0 0 1326 1327 -IaCOOH I "'ICOOH WO 99/06397 PCTIUS98/1 5479 - 653 1328 1329 o= Q 1 0 =X'N ) N~~ % .N -COOH I k %~ -lCOOH
'COOHH
2 N~r ~<~ 1 N" 'COO H 000 1332 1333 0 1COOH H2"COI 1334 1335 0-Th H Q ~ ~ ,COO -. N.qN *ICOOH 0 0 1334 133 WO 99/06397 PCTIUS98/1 5479 - 654 1336 1337 ~ .saCOOH 0~~% *.ICOOH c 0 b 1338 1339 *COOH N i .COOH 00 1342 1343 ~ ~~ *sCOOH NKI'I~ .COOH 00 WO 99/06397 PCTIUS98/1 5479 - 655 1344. 1345 .. COOH .uCOOH 0 0 1346 1347 ~II~~ .6iCOOH --'iC0OH 00 C CH 3 1348 1349 *I N sICOOH H _ N -I N *.iICOOH c 0 0
CH
3 OH 3 1350 1351 0 *.COOH **'CaOH 0 0
CH
3 OH 3 WO 99/06397 PCT/US98/15479 -656 1352 1353 S .COOH O.'COOH 0 O CH3 CH 1354 1355 NN N
H
2 N '-,-N IrN COOH 0 o 0 0
OH
3 O CH,3 CH 1356 1357 - *.N-COOH N N--COOH 0 O 0
CH
3 CH 1358 1359 N I-t -COOH , N -COOH 0 0 OH C OC~ WO 99/06397 PCTIUS98/1 5479 - 657 1360 1361 N~>~~f .0N iCOOH 2~~Nf~ .'COOH CH CH 1362 1363 N~N N --- *"COOH r ~N *",COOH 1364 1365 N *..iCOON S*aCOOH .jCO 1366 1367 NN N " 1'COOH H 2 N ,_ -N~ N 'CO 00 00 WO 99/06397 PCT/US98/15479 - 658 1368 1369 N NN N .COOH -. COOH 1370 1371 H2 N N -enCOOH N N -- siCOOH 0//\ 1372 1373 N. NN -i -- COOH N --nCOOH oC I/COOH 1374 1375 NN N N -- mCOOH H 2 N N -"COOH WO 99/06397 PCTIUS98/I 5479 - 659 1376 1377 'K~~ ' *IICOOH O.'2 ~ .COOH C~c 0
-
J O 1378 1379 N\ *'.COOH N "CO 00 -jc 1380 1381 N C .COOH H 2 N N- N~~ % * C 00 IC 1382 1383 & N . "COOH N _,N " *"COOH 0oh WO 99/06397 PCTIUS98/I 5479 - 660 1384 1385 "'COOH
H
2 NNA %N 1~ 0 1386 1387 .. JC00H '-~ .COOH 0 C 00 1388 1389 N') *."COH I COOH 0- 0 1390 139 WO 99/06397 PCT/US98/1 5479 - 661 1392 1393 NN N N ~~NN 0 "COOH 0"Co0 0 -C 0
H
3 0H 139 139 N NnI 0 2 ~ 2 y~ "'COOH
H
2 N N "N *'ICO0H 00 3 -C
H
3 139 139 ~ >(,N *COOH NNN ~ "C O 0C -Hk 0 0 OH OCH3 WO 99/06397 PCTIUS98/15479 - 662 1400 1401 N Nn NN H2N NNN 0 ONCOO O -NCOO 0 0 CH O
CH
3 1402 1403 N N N-miCOOH N-yNiCOOH 0 0
CH
3 O CH3 1404 1405 N NN NN N -COOH H2W' N N -iOH . UJ I iC0H *"iCOOH' OH CH3 CH3 bO. 1406 1407 N N N+ N rN --lCOOH -ICOOH / \N CHo WO 99/06397 PCT1US98/15479 - 6638 1408 1409 *."COOH H O N1N 'COOH 0 1410 1411 Nn)) Nn/ *'a' N..COOH HNN, # N N *.zCOOH -00 1412 1413 N'N)N H2N~~N.N **"OOH 'N *'COOH 0 1414 1 415 NN
ICOH
2 NN(N 0 *.ICOOH 0 ~ C00H 0 0 WO 99/06397 PCT/US98/1 5479 - 664 1416 1417 C>, I *'.COOH 0I *'COOH 1418 1419 N *"I1COOH 0*.'ICOOH 0II 1420 1421 NN *COOH . * I'CH 0 0CO WO 99/06397 PCTIUS98/15479 - 665 1424 1425 HO~~.~ **COOH 0 *-ICOOH 00 1426 1427
H
2 N -,,N ..IO 2N r' 0 "IOH0 *"COOH 0 0 1428 1429 -N N N' *.iiC00H 'Ir *'.ICOIOH 00 0 0C 00 043 043 0- WO 99/06397 PCTJUS98/15479 - 666 1432 1433 N ~N 0~Y~ IC" COOH 0 0 -j 1434 1435 *mIICOOH H 2
N~N
0 ~~ ~C0 0 0 -J 1436 1437 N N NN 00 N< .. Ca "ICOO
OH
3 ICHw0 WO 99/06397 PCT/US98/1 5479 - 667 1440 1441 .0siO O O H H 2 , ,, , .. aC O O H 0 0 00
CH
3
-CH
3 1442 1443 N .iCOOH COO H 0
OH
3 Oj H 1444 1445 NN N N (N N o.aCOOH H 2 W-_N- .g N .. iCOOH 0 ~0
OH
3
-
H
3 1446 1447 N I *mIOOH iCH
OH
3 O H WO 99/06397 PCTIUS98/15479 - 668 1448 1449 N N NN N >-.sOO '.N.N - COOH -aCOOO CH,
CH
3 1450 1451 N N H2N N -gCOH N N -COOH CH -jCH3 1452 1453 N N 0--oCOOH F N N -COOH 1454 1455 N N HO, N NO' -rN .COOH N .COOH WO 99/06397 PCT/US98/15479 - 669 1456 1457 N ,N H2N N H2N*N N 0 .'COOH 1458 1459 N N - .COOH O -- nCOOH 1460 1461 N H2N-" N Nr 0 COOH N *"nCOOH 1462 1463 N N N -enCOOH N-enCOOH / \ /0 WO 99/06397 PCT/US98/1 5479 -670 1464 1465 N .a~COOH *.CO 1466 1467 N *..iCOOH *.aiCOOH -0 1 1468 1469 >j~j 2 .61suCOOH HN%. .'ICOOH 0/ 0 1470 1471 0 0 0 -o1 0 WO 99/06397 PCT/US98/1 5479 - 671 1472 1473 0 N .08COH N *s'COOH 1474 1475 NZ WN.-'N .. OH 2 N_. N -n$*N .COOH 0 0 00 00 1476 1477 NJT *siCOOH N 0 -CO 0 0 0 -3 -- I WO 99/06397 PCTIUS98/15479 - 672 1480 1481 0 N Nb N-eCOOH N N ICOOH 1482 1483 NJN N -'ICOOH F~N ..nCOOH 00
CH
3
CH
3 1484 1485 N '"COOH N N-COOH o 0 0 0 CHa 3 CH 3 1486 1487 0 b b H Ne,,,N N 2h, N b
H
2 N NgN -"COOH HN -- nCOOH C C0
OH
3 -i O H 3
-
WO 99/06397 - 673 - PCT/US98/I 5479 1488 1489 ---COOH .uiCOOH
CH
3 CH 3 1490 1491
H
2 N g N .ICOOH "sICOOH
CH
3 ~ CH 3 1492 1493 N, N Nk .aCOOH -ICOOH CH H j 1494 19 N3 0 "COOH 0~N N *sCO
OH
3
OH
WO 99/06397 PCT/US98/15479 - 674 1496 1497 Nb NN---COOH -e&KCOOH CH" 1498 1599 F*.N N .ICOOH HN -. ICOOH 1500 1501 O N _ N -iCOOH
H
2 N ,N )rN -. iCOOH 0 1502 1503 NN N ON -COOH -.COOH 0 WO 99/06397 PCT/US98/1 5479 - 675 1504 1505 r .,oCOHH 2 N~ - ~ N .'ICOOH 00 1506 1507 0 6 'sCOOH 0 *ICOOH 0 1508 1509 ... aICOH ."COOH 1510 1511 -. COOH I !J3I~ WO 99/06397 PCT/US98/15479 - 676 1512 1513 CH CH -'iCOOH F-COOH 1514 1515 CH
CH
3 ON *UCOOH O N ."COOH 0 0 0 ~0 1516 1517
CH
3 CH 3
H
2 NN~ N -- COOH N .. COOH 0 0 1518 1519 CH
CH
3 .N o- N 'I N N N .iCO O *.'ICOOH N--COOH 0 0 WO 99/06397 PCTIUS98/1 5479 .677 1520 1521
CH
3 CH 3 *..aCOOH .'COOH 0 0 1522 1523
CH
3 CH 3 ~~N+~ %~L .0 N1<1 sCOOH 0 1524 1525
CH
3 CH 3 1526 1527
CH
3 CH 3 tC'o 0 COOH 0.ICO 0 CH3 WO 99/06397 PCTIUS98/15479 - 678 1528 1529 CH
CH
3
CH
3
-CH
3 153 153
CH
3 CH 3
CH
3
-CH
3
CH
3 CH 3
H
2 . N~r N 2-1N ~fN .'COOH )rN "OO 0 ~0
CH
3 CH 3 1534 1534
CH
3
H
3 0 H 2 N,, N ,oNCON .COOH 0 CO 0 0
H
3 - H 3 WO 99/06397 PCT/US98/15479 - 679 1536 1537 CH CH 3 I *uICOOH O -'"COOH CH OCH 3 1538 1539 NCOOH rN0"COOH 0 0 0 CH3 CH3 1540 1541 CHQ CH H 2 N C O O H N 'C O O H / \0 OH CH 1542 1543
CH
3 CH3 N N -COOH F .COOH / \) / \
CHO
WO 99/06397 PCT[US98/1 5479 - 680 1544 1545 CH CH 3 HO %N0< *.4'OO .'gN *'COOH 1645 1647
CH
3 CH 3 N .'iCOOH ,'COOH 1548 1549
CH
3
CH
3 .., .N,'COOH 1 r N .ICO 0~~ 0.aCOO 1550 1551
CH
3 OH 3 L *'COOH j
I.COOH
WO 99/06397 PCT/US98/15479 -681 1552 1553
CH
3
CH
3 . COOH "COOH 1554 1555
CH
3 CH N N -IICOOH H2N N-COOH 1556 1557 c~u CH3 -* N N N COOH -ICOOH 1558 1559 Nu F N-COOH 0 -j 0 WO 99/06397 PCTIUS98/15479 - 682 1560 1561 0 N.COOH H2N..aN -COOH 1562 1563 0OY H N .nCOOH N N N -.COOH /. \ / 1\ 1564 1565 0 O N H2N COOH -.tCOOH 1566 1567
K
0
K
0 N -COOH N N .COOH / 1 .. O \ \ WO 99/06397 PCTIUS98/15479 - 683 1568 1569 O~ N .- iCOOH N -COOH 00 1570 1571
H
2 N .NN - sICOOH N N -I."COOH 1572 1573 N - COOH F -COOH 0
CH
3 CH 3 1574 1575 uC O H ,.N N -oCOOH
-
N fN -COOH 0 C CH,, OH 3
-
WO 99/06397 PCT/US98/15479 - 684 1576 1577 H2N N -ICOOH H "COOH 0 0
CH
3 CH 1578 1579 co N N O "COOH - COOH 0 0 0 0 0
CH
3 CHa, 1580 1581 0 0 2NN -COOH N -.COOH CH CH 1582 1583 -"COOH N->N ICOOH C C CH3~
CH
WO 99/06397 PCT/US98/15479 - 685 1584 1585 N " COOH
H
2 N N COOH .IO
CH
3
CH
3 1586 1587 C~Cf 1588 1589 O F N N COOH 0 N -COOH 0 1590 159 OO N N -nCOOH H2N N -COOH WO 99/06397 PCT/US98/1 5479 - 686 1592 1593 0 0 ..aiCOOH N ..COOH c r 1598 1599 *s'COOH 'NIr~~ .COOH W 'CO WO 99/06397 PCT/US98/15479 -687 1600 1601 H2N"COOH + N -'COOH / \ / \ 1602 1603
CH
3 O
CH
3 -. COOH F rN N -ICOOH 1604 1605
CH
3 CH 3 O HO N N O jr N.. N o O iCOOH 0 COOH 0 0 1606 1607
CH
3 O CHaO
H
2 N N N -. COOH H2N N N -. ICOOH 0 O 0 .
-
\
WO 99/06397 PCT/US98/15479 - 688 1608 1609 I &> N 3 CH NN .. *'uCO O H o C O
..
,C O 1O0 0 t3 ~- 1610 1611 N H 3 OH 3 H 2 N ~ 0 ~f N * OH >4 -"ICOOH 0 0 t~-J 1612 1613 N~Th CH30
CH
3 0 NI 0'IOOH 0.IC 00 00 1614 1615
CH
3 0 CH 3 0 .iCOOH ~"00 -9 0 WO 99/06397 PCT/US98/1 5479 - 689 1616 1617 .4000H --COOH
CH
3 1618 1619
OH
3 CH30 N .18ICOOH HO%,-, . N Ir-..N ..eiCOOH 0 ~0 1620 1621 -0, CH 3 0
CH
3 O 0 'C O O H
.
"C o O
OH
3 - H 3 J 1622 1623
CH
3 CH 3 0 0 0
CH
3 CH 0 WO 99/06397 PCTIUS98/1 5479 -690 1624 1625
CH
3 CH 3 0 N .. COOH
H
2 N- r N *.,"COOH
CH
3
CH
3 t 3 1626 1627 CH30
CH
3 0 N~BO~ - NIN~N *.COOH 0 0 CH CH 1628 1629
CH
3 00H30 + COOH -"COOH o 0
-
03 1630 1631 CH30
CH
3 0 H2*" .. COOH >-mNN<%. ~C00H C .H C -0
C
WO 99/06397 PCTIUS98/1 5479 - 691 1632 1633
CH
3
CH
3 O *.uCOOH "COOH 1634 1635 H ,CH3 0 i
CH
3 O 1636 1637 N-> CH 3 0
CH
3 0 H2N'' N 0 N _HCOOH H2N, *.uON 0"OO 0ICO 1638 1639 I ~~ CH30I ~N CH30 WO 99/06397 PCT/US98/15479 - 692 1640 1641 cH 3 CH 3 .COOH "COOH 1642 1643
CH
3 O CH 3 O NN -COOH N COOH 1644 1645
CH
3 O CH 3 0 S N COOH
H
2 N N N .COOH 1646 1647
CH
3 0 CH30 1 N- COOH -- COOH \.,/o\ WO 99/06397 PCT/US98/15479 - 693 1648 1649
CH
3 ON 1 CH3O F N N -niCOH HQ N -ICOOH 1650 1651
CH
3 O
CH
3 O N -ICOOH N2N N N .m'COOH 0 O 1652 1653 CH30
CH
3 0 H2N N N.ICO H NN r N 0 -*COOH -iCOOH 0 0 O-J 1654 1655
CH
3 O
CH
3 O N NCOOH
H
2 N N .. NCOOH 0 0 93 ' WO 99/06397 PCT/US98/15479 - 694 1656 1657
CH
3 O CH 3 0 -- NN NN N -"ICOOH | O--COOH 00 3 00J 1658 1659 CH30 CH30 0 - .ICOOH N N -.COOH 0 0 1660 1661 2Z
CH
3 0 CH30 H2N N rN -.
sOO N r N -COOH -300 1662 1663
CH
3 O
CH
3 0 -0 -iCOOH F N N ,-COOH 0 0 CH OHj -i WO 99/06397 PCTIUS98/15479 - 695 1664 1665
CH
3 O CH HQ N N -- nCOOH O -- sCOOH 0 o 0
CH
3 CH 3 1666 1667 CH2 CH3 H2N N N -COOH H2N . N ' N -*.COOH 0/ \
CH
3 CH 3 1668 1669 CH30 CHa5 O "ICOOH - .COOH "oN 0 O C H 3 0 C H 3 1670 1671 3Z
CH
3 CH a )
H
2 N %N ~ N -.. iCOOH N N .CO CH, CH " WO 99/06397 PCTIUS98/1 5479 - 696 1672 1673 N CHPONN CH30 CH CH._ N,0COOH N*.I.COOH Hi 3 CH 1676 1677
CH
3 CH30 'COOH 0CO 00 CH ."C 1678 1679 CH30 CH? N N *.uCOOH Hc-N%-,%N
"COOH
WO 99/06397 PCTIUS98/15479 - 697 1680 1681 CH3
CH
3 O sOiN N -- COOH
H
2 N N N -.. COOH 0 1682 1683 Oz 90 9
CH
3 O CH3O H2N ,,-,_N N ,NN N O -'COOH -.'iCOOH 0 1684 1685 PO0
CH
3 0 CH30 N -- nCOOH H2N N 'COOH o 0 1686 1687 CH30 CH30 Y^,N -- COOH N .ICOOH O O / \ /
\
WO 99/06397 PCTIUS98/1 5479 - 698 1688 1689 C 2p
CH
3 O H 3 0 Nf1( -COOH -ICOOH 00 ~ *.mIOOH *,COOH 1694 1695 H N N *..COOH - -N rCOOH WO 99/06397 PCTIUS98/1 5479 - 699 1696 1697 00 H2N'iCOOH N2J--NI H.N ..CrOOH 00 1698 1699 K ~zT 0 0 iCOOH iI -.jC00H Ci 0 0 0 1700 1701 00 CNCOOH % .sCOOH
-
s OO
-
.5C 1702 1703 .. ',COOH oCH 0 -0 WO 99/06397 PCT/US98/1 5479 - 700 1704 1705 -I 00 .,ICOCH le KXO 1708 1709 0) 0 -- ",CO O.COOH 00 CH H C 170 1711 0* ~C 0H 0.iCO 00 C0H 3
CH
3
-
WO 99/06397 PCT/US98/15479 -701 1712 1713 Oz 0 0 H2, N Y N N.O> rN -COOH 0 0
CH
3
CH
3 1714 1715 0 0 0)
H
2 N -n"COOH - COOH 0 O o 0
CH
3
CH
3 1716 1717 IN -OCOOH NN -*COOH
CH
3 3
CH
3 -3 1718 1719 O) 0 NK lN -COOH N .-.COOH
CH
3 CH 3 WO 99/06397 PCT/US98/1 5479 - 702 1720 1721 0N
H
2 NNrJJgN -.1CO L.J .uaCOOH
CH
3 OH 3 1722 1723 0 0 NCOOOO 1724 1725 0I) 0I HO, N N N.iQH~*aCO 1726 17207 0I~ 0
H
2 N,N 'rN *.eiCOOH
H
2 N,N,,-,,. N *.'COOH 0 0 WO 99/06397 PCT/US98/1 5479 - 703 1728 1729 00 ~N -*.sCOOH L -w.mCOOH 1730 1731 00 C .ICOOH *.COOH 1732 1733 00 *.COOH L .. aiCOOH WO 99/06397 PCT/US98/15479 - 704 1736 1737 O H +..tCOOH N -ICOOH 1738 1739 H HN N HQ,, *.sCOOH F I I--N C O O H C O O H 0 1740 1741 0 O r N -eniCOOH H2N N " N ...'COOH 0 00 1742 1743 ot HN HON 0 HN o 00 --3COOH -JCOOH O O / \ /0 rN C O WO 99/06397 PCTJUS98/1 5479 - 705 1744 1745
HN,
0 0 1COOH HN0 "',COOH 0 0 ~10-PO 1746 1747 1.0 H --o H "'o I 0 'COOH I 'COOH 0 -3 1748 1749 HNS1 H-. NC-1 LcNFt~ *ICOOH 'rNN -C<'N 0 0 1750 1751 H~~N{~ .. uCOOH -N*aCOOH -0 0 WO 99/06397 PCTIUS98/1 5479 - 706 1752 1753 H HN f 0 N .- loCOOH o OH CH ~ CH 3 -"ol 1754 1755 HNHN HN 0 00 0 ~~..COOH*sCO
CH
3 CH 3
-
1756 1757 H HNV
H
2 N~N.N "COOH
H
2 --N~ *sCOOH
CH
3 CH 1758 1759 1.0 I.0 HNIS H N - - N~-. <N .ICOOH ..ICOOH
CH
3 OH 3 WO 99/06397 PCTIUS98/15479 - 707 1760 1761 I ,0 1.0 HNS- NS' 011COOH %*N...{%N *iC00H 0 O H 3 CH 1762 1763 INS-o HW -' NN~ t ~ ~ ~.ICOOH -C>H N N 01 NCO"OH 0
CH
3 CH 1764 1765 H NN~ *.IOO H 2 N~Nj>N -CO
OH
3 OH 1766 1767 1.0I -N HNS?: N *~C 0
MH
3
'CO
WO 99/06397 PCT/US98/15479 - 708 1768 1769 H O HNRO 0 .- eCOOH HO N N -- COOH F 0 0 1770 1771 HN =0 HN =O 00 N N -- COOH H2N "N N -- COOH 0 O 1772 1773 H 0r HNAZ 0
H
2 N N < 0 -ICOOH .. ICOOH 0c 1774 1775 1.0 1.0 H 0 HN .O O -- nCOOH
-*ICOOH
WO 99/06397 PCTIUS98/1 5479 - 709 1776 1777 H 0 HNS.b 0 *4COOH .'aaCOOH 1778. 1779 1780 1781 NI .0 .. sIC 00H )N *-o *iCOOH WO 99/06397 PCT/US98/15479 -710 Example 536 [2S.3R.4SI-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3-benzodioxol-5 yl)-l-(N.N-di(n-butylaminocarbonylmethyll-pyrrolidine-3-carboxylic .RLid Example 536A Ethyl 5.5-dimethyl-3-oxooctanoate Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., A, 7425 (1990). To a solution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, cooled to 0*C, was added a solution of 30 g of NaOH in 150 mL of water. The resultant solution was warmed to ambient temperature and stirred overnight. Solvents were removed in vacuo; the residue was taken up in 700 mL of water, and extracted twice with 1:1 ether/hexanes. The aqueous layer was acidified to pH3 with 1N HCI and extracted twice with hexanes. The combined hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of the crude product is dissolved in 150 mL of THF; 27.3 g of 1,1'-carbonyldiimidazole is added portionwise, to control gas evolution. In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride are combined in 350 mL of THF (overhead mechanical stirring) and warmed to 50"C for 3 hrs. This mixture is cooled to ambient temperature, and the above acid imidazolide solution is added. The resultant slurry is stirred overnight. Ether (600 mL), hexanes (600 mL) and aqueous 1N phosphoric acid (500 mL) are added, and the mixture is sitrred for 30 min. The aqueous layer is separated; the organics are washed sequentially with bicarb (2X), water and brine. The organics are dried over sodium sulfate, filtered and concentrated to give 30.2 g (95% yield) of a colorless liquid. Example 536B 4-Methoxy-6-(2-nitrovinyl)-1.3-benzodioxole 3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is WO 99/06397 PCT/US98/15479 -711 added, and the mixture is heated to 50 0 C for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for 20 min. The solution is filtered; the filtrate is washed with water, then ether, to give'51.8 g of a yellow solid. Example 536C Ethyl trans. trans-2-(2.2-Dimethylentyl-4-(7-methoxy-1 .3 benzodioxol-5-yl)-pyrroli di ne-3-carboxylate The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 g of the compound of Example 536B in 40 mL of THF. DBU (0.5 mL) was added, and the mixture was stirred at ambient temperature for 6 hrs, during which time it turns reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with aqueous 1N phosphoric acid and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst (washed sequentially with water and ethanol) was added, followed by 10 mL of acetic acid. The resultant mixture was hydrogenated under 4 atmospheres of hydrogen until hydrogen uptake ceased (- 3 hrs). The catalyst was removed by filtration; solvents were removed in vacuo. The residue was dissolved in 90 mL of 2:1 ethanol/THF; 30 mg of bromcresol green indicator was added, followed by 30 mL of 1N sodium cyanoborohydride in THF. Concentrated HCI was added dropwise to maintain pH at the indicator point, over 1 hr. The resultant solution was stirred overnight at ambient temperature. Bicarb was added, and the solvents were removed in vacuo; the residue was partitioned between water and EtOAc. The organic material was washed with water (2X) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in 100 mL of acetonitrile; 10 mL of H~nig's base was added, and the solution was warmed to 400C overnight. Removal of solvents in vacuo provided 5.0 g of a yellowish oil.
WO 99/06397 PCT/US98/15479 -712 Example 536D Ethyl 12S.3R.4S0-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3 benzodioxol-5-yl)-pyrrolidi ne-3-carboxylate 5 The crude compound of Example 536C (2.0 g) was combined with 4 mL of triethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate was added, and the mixture was stirred at ambient temperature for 5 hrs. Solvents were removed in vacuo, and the residue was taken up in 60 mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was 0 added, and the resultant solution was stirred overnight. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g 5 of a colorless oil. A sample of this material (0.734 g, 1.58 mmol) was combined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL of DMF. The resultant solution was stirred at ambient temperature for 1 hr, then was poured onto 50 mL of 0.6M sodium bicarbonate solution and extracted (3 X 15 mL) with ether. The combined ether extracts were !0 washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a foam, which was dissolved in 5 mL of THF and cooled to 00C. Simultaneously, 0.418 g (2.37 mmol) of R-4 benzyl-2-oxazolidinone was combined with -0.1 mg of pyreneacetic acid in 5 mL of THF and cooled to 0*C. N-butyllithium (1.6M in hexanes) was 25 added to a red endpoint (persists -10 sec), and the solution was stirred for 10 min. The solution was transferred into the solution of the pentafluorophenyl ester, and the resultant solution was stirred at 00C for 40 min. Solvents were removed in vacuo; the residue was taken up in bicarb and extracted with ether (3 X 10 mL). The combined ether 30 extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture of diasteromeric products was separated by flash chromatography on silica gel, eluting with a gradient from 4:1->3:1->2:1 hexanes/EtOAc, giving 423 mg of the faster-moving and 389 mg of the slower-moving diastereomer, 35 respectively. The faster-moving diastereomer was dissolved in 2 mL of a 2.OM solution of sodium methoxide in methanol (freshly prepared, WO 99/06397 PCT/US98/15479 -713 containing 5% methyl formate by volume) and stirred at ambient temperature for 16 hrs. Solvents were removed in vacuo, and the residue was partitioned between ether and aqueous 1N sodium hydroxide. The ether laypr was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 4:1 hexanes/EtOAc. The resultant material was dissolved in 5 mL of TFA and stirred at ambient temperature for 1 hr. Solvents were removed in vacuo; the residue was suspended in bicarb and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 98 mg of product. Example 536E {2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1 .3-benzodioxol-5 yl)-1 -(N.N-di(n-butyllaminocarbonylmethyl)-pyrrolidine-3-carboxylic The compound of Example 536D (48 mg) was combined with 35 mg of the compound of Example 501A in 3 mL of acetonitrile; 0.5 mL of D HOnig's base was added, and the solution was allowed to stir overnight at ambient temperature. Solvents were removed in vacuo; the residue was partitioned between EtOAc and aqueous 1N phosphoric acid. The organic layer was washed with bicarb. and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash 5 chromatography on silica gel, eluting with 2:1 hexanes/EtOAc. - The product was dissolved in 4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, and the resultant solution was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was 0 acidified to pH 3 with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a colorless oil. Lyophilization from acetonitrile/0.1% aqueous TFA gave 56 mg of a white solid. 1 H NMR (CDCI3, 300 MHz) d 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 35 3H), 0.93 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J = 6.9 Hz, 10.0 Hz, 2H), WO 99/06397 PCTIUS98/15479 -714 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1H), 4.12 (d, J = 16.8 Hz, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H). MS (ESI) (M+H)+ at m/e 533. Anal calcd for 5 C 3 oH 48
N
2 0 6 -0.7 TFA: C, 61.57; H, 8.01; N, 4.57. Found: C, 61.59; H, 8.20; N, 4.63. Example 537 r2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1
-(N.N
di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 0 Example 537A Ethyl trans. trans-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate 5 Prepared according to the procedures of Example 536C above, substituting the compound of Example 501B (5-(2-nitrovinyl)-1,3 benxodioxole) for 4-methoxy-6-(2-nitrovinyl)-1,3-benzodioxole. Example 537B .0 Ethyl [2S.3R.4S-2-(2.2-Dimethylpentyl)-4--(1 .3-benzodioxol-5-y) pyrrolidine-3-carboxylate The compound of Example 537A (6.8 g) was dissolved in 100 mL of ether; a solution of 1.6 g of (S)-(+)-mandelic acid in 60 mL of ether was 25 added, the total volume was made up to -200 mL, and the solution was seeded. The mixture was stirred slowly overnight. The resultant crystals were collected by filtration and recrystallized from ether/EtOAc to give 1.8 g of a white solid. Thsi material was partitioned between bicarb and ether; the ether layer was washed with 30 brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the enantiomerically pure product (>98% e.e.).
WO 99/06397 PCTIUS98/15479 -715 Example 537C [2S.3R.4S0-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1 -(N.N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 5 Prepared from the compound of Example 537B according to the procedures of Example 536E. 1H NMR (CDCI3, 300 MHz) d 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60-3.69 (m, 1H), 3.75-3.86 (m, 1H), 3.95-4.16 (m, 2H), 4.28 4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.8 (dd, J=8.1, 1.5 Hz, 0 1H), 6.87 (d, J=1.8 Hz, 1H). MS (APCI+) m/e 503 (M+H)+. Example 538 [2S.3R.4S2-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1 -((N proDoxy, N-(n-butyl)laminocarbonylmethyll-pyrrolidine-3-carboxylic 5 acid Example 538A N-Boc-N-butyl-O-allylhydroxylamine 0 O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 00C in an ice bath. Diisopropylethylamine (8mL) and di-t-butyldicarbonate (10.0g) were added. The mixture was stirred at 00C for one hour at which point the bath was removed and the reaction allowed to warm to room 5 temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil (6.5g). This 0 crude product was dissolved in dry THF (25 mL) and the solution cooled to 0*C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over five minutes. The resulting mixture was stirred for 30 minutes at 0*C. 1-lodobutane (4.1 mL) was added dropwise to the mixture. The reaction was stirred at 00C for one hour, then stirred 5 overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), WO 99/06397 PCTIUS98/15479 -716 saturated sodium bicarbonate solution (3 x 50 mL), IN phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% 5 EtOAc/hexanes to give the title compound as a colorless oil (6.0 g). Example 538B N-butyl-N-propoxyamine trifluoroacetate 0 The compound of Example 538A (6.0 g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5 g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite 5 and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give a colorless oil (5.8 g). A sample of the resultant material (1.15 g) was dissolved in CH 2 C1 2 (5 mL) and cooled in an ice bath. Trifluoroacetic acid (3mL) was added and the solution stirred cold 0 for two hours. The solvent was removed in vacuo , care being taken not to allow the solution to warm above room temperature. The residue contained considerable TFA and was used without further purification. Example 538C 5 N-butyl-N-propoxy-bromoacetamide The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL) and cooled to -20 0 C. Hjnig's base (5.5 mL) was added slowly. Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. 0 The solution was stirred at -20*C for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and 35 evaporated to give a dark orange oil (0.65 g) which was used without further purification.
WO 99/06397 PCT/US98/15479 -717 Example 538D (2S.3R.4SI-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)- 1 -((N propoxy. N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic The compound of Example 537B was reacted with the compound of Example 538C according to the procedures of Example 536E. Example 539 [2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1 -((N propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic E xample 539A N-propyl-N-propoxy bromoacetamide Prepared according to the procedures of Example 538A-C, substituting iodopropane for iodobutane in Example 538A. E xample 539B [2S.3R.4SI-2-(2.2-Dimethylpentyl)-4-(1.3-benzodioxol-5-yl)-1 -((N propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3-carboxvlic The compound of Example 537B was reacted with the compound of Example 539A according to the procedures of Example 536E.
WO 99/06397 PCT/US98/15479 -718 Example 540 [2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3-benzodioxol-5 yl)-1-((N-propoxy. N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid 5 The compound of Example 536D was reacted with the compound of Example 538C according to the procedures of Example 536E. Example 541 3 r2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3-benzodioxol-5 yl)-1-((N-propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid The compound of Example 536D was reacted with the compound of 5 Example 539A according to the procedures of Example 536E. Example 542 [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yi)-1 ((N-propoxy, N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3 0 carboxylic acid Example 542A trans-Ethyl 3.3-dimethyl-4-hexenoate 5 A mixture of 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74mmol) and propionic acid (0.28 mL, 3.7 mmol) was heated at 1500C for 7 hr. The product was then distilled under normal pressure (200-220 0C) to give 5.0 g of crude ester as a colorless oil. 0 Example 542B Ethyl trans.trans-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5 yl)-pyrrolidine-3-carboxylate 5 The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542A WO 99/06397 PCT/US98/15479 -719 for ethyl 3,3-dimethylhexanoate in Example 536A and the compound of Example 501B (5-(2-nitrovinyl)-1,3-benxodioxole) for 4-methoxy-6-(2 nitrovinyl)-1,3-benzodioxole in Example 536C. Example 542C Ethyl r2S.3R.4SZ-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5 yl)-pyrrolidine-3-carboxyl ate The compound of Example 542B was resolved according to the procedure described in Example 537B. Example 542D [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yl)-1 ((N-propoxy. N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid The compound of Example 542C was reacted with the compound of Example 538C according to the procedures of Example 536E. Example 543 [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yl)-1 ((N-propoxy. N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid The compound of Example 542C was reacted with the compound of Example 539A according to the procedures of Example 536E. Example 544 [2S.3R.4S]-2-(2.2-Dimethylpent-3-enyl)-4-(7-methoxy-1.3 benzodioxol-5-yl)-1-((N-propoxy. N-(n-butyl))aminocarbonylmethyl) pyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -720 Example 544A Ethyl trans. trans-2-(2.2-Dimethylpent-3-enyl)-4-(7-methoxy- 1, 3 benzodioxol-5-yl)-pyrrolidine-3-carboxylate The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542A for ethyl 3,3-dimethylhexanoate in Example 536A. E xample 544B Ethyl [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(7-methoxy- 1.3 benzodioxol-5-yl)-pyrrolidi ne-3-carbo xylate The compound of Example 544A was resolved according to the procedure described in Example 536D. Example 544C [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(7-methoxy-1, 3 benzodioxol-5-yl)-1-((N-propoxy. N-(n-butyl))aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E. Example 545 [2S.3R.4SI-2-(2.2-Dimethylpent-3-enyl)-4-(7-m ethoxy-1, 3 benzodioxol-5-yl)-1-((N-propoxy. N-(n-propyl))aminocarbonylmethyl) pyrrolidine-3-carboxylic acid The compound of Example 544B was reacted with the compound of Example 539A according to the procedures of Example 536E. Example 546 [2S.3R.4S-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl)-1 -f[N- 4 heptyI-N-(2-methyl-3-fluorophenyl)l amino carbonylmethyll pyrrolidine-3-carboxylic acid WO 99/06397 PCTIUS98/15479 -721 Example 546A Ethyl trans.trans-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 519A for 3,3-dimethylhexanoic acid in Example 536A. Example 546B Ethyl [2S.3R.4S-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-vl pyrrolidine-3-carboxylate The compound of Example 546A (1.5 g) was dissolved in CH2C2 (25 mL). Di-t-butyldicarbonate (0.9 g) was added and the solution 5 stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc (50 mL), washed with water (1x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL). The organic layer was dried with sodium sulfate and evaporated in vacuo to give an oil with was purified by flash 3 chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes to give a colorless oil (1.5 g). The oil was dissolved in EtOH (10 mL) and 50% NaOH solution (0.5 mL) and water (5 mL) were added. The mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo and the residue taken up in EtOAc (25 mL) and 5 acidified with 1 N H3PO4 (10 mL). The layers were separated and the organic layer dried with sodium sulfate and evaporated to give a white semi-solid (1.3 g). A sample of the resultant Boc-protected amino acid (0.9 g) was dissolved in DMF (5 mL). (S)-Phenylalaninol (0.32 g), HOOBt (0.33 g), and EDCI (0.40 g) were added and the solution sitrred overnight D at room temperature. Water (50 mL) was added and the mixture extracted with EtOAc (3x25 mL). The organic layers were combined, washed with water (2x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a yellow oil; tic indicated the presence of two diastereomeric products. The 5 diastereomeric amides were separated by flash chromatography on silica gel eluting with 1/12/12 EtOH/EtOAc/hexanes to give faster- WO 99/06397 PCTIUS98/15479 -722 (450 mg) and slower-moving isomers (400 mg). The faster-moving diastereomer (400 mg) was taken up in 6N HCI and heated at reflux overnight. The solvent was evaporated and the residue was taken up in toluene (75 rnL) and evaporated. This was repeated two additional times 5 to give a brown solid, which was dissolved in EtOH (50mL). 4N HCI/dioxane (10 mL) was added and the solution heated at reflux overnight. The EtOH was evaporated and the residue taken up in EtOAc which was treated with saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash ) chromatography on silica gel eluting with 30% EtOH/EtOAc gave a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional purification. 5 Example 546C [2S.3R.4S-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl)-1 -[N- 4 heptyl-N-(2-methyl-3-fluorophenyl)1 amino carbonylmethyll pyrrolidine-3-carboxylic acid 0 The compound of Example 546B was reacted with the compound of Example 508E according to the procedures of Example 536E. Example 547 [2S.3R.4S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 -f(N-buty 5 N-(4-dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid Example 547A N-butyl-4-hydroxybutyramide 0 To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 850C for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid. 5 WO 99/06397 PCTIUS98/15479 -723 Example 547B N-butyl-4-hydroxybutyl chloroacetamide To an ice cooled solution of 3.40 g (91.9 mmol) of LiAIH4 in 90 mL of THF was added 2.4 mL of 98% H2SO4, dropwise, with stirring. After bubbling had ceased, a solution of 4.7 g of the compound of Example 547A in 10mL of THF was added. The mixture was stirred at reflux for 24 hr, then cooled with an ice bath and quenched by sequential dropwise addition of 1.7 mL H20, and 17 mL of 25% w/v aqueous NaOH. The white precipitate was filtered, and washed with about 50 mL of THF. The combined filtrate and washings were concentrated to 3.85 g of an oil. To an ice cooled solution of this material in 35 mL of ethyl acetate was added a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mL of ethyl acetate. The solution was stirred at 00C for 30 min, then extracted with saturated aqueous NaHCO3 solution (1 x 25 mL), 2M NaOH (1 x 25 mL), 5% NH40H (1 x 25 mL), 1M HCI (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol, to give 1.52 g (31%) of a colorless oil. Example 547C Ethyl [2S.3R.4S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N butyl-N-(4-hydroxybutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylate To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl [2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3 benzodioxol-5-yl)-pyrrolidine-3-carboxylate (prepared by neutralization of the compound of Example 501G), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3 x 25 mL). The combined ether layers were washed with water (1 x 25 mL), 4% (v/v) H3PO4 (1 x 25 mL), saturated aqueous NaHCO3 solution (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel WO 99/06397 PCTIUS98/15479 -724 chromatography, eluting with 98:2 diethyl ether: methanol to give 3.Og (79%) of a colorless oil. Example 547D Ethyl [2S.3R.451-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yi)-1-r(N butyl-N-(4-bromobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylate To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0 0C for 20 min. The reaction was diluted with 75 mL of diethyl ether, then extracted with saturated aqueous NaHCO3 solution (2 x 25 mL), 5% NH40H (2 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to 3.0 g of a colorless oil. To this material in 45 mL of DMF was added 6.0 g (69 mmol) of LiBr. The reaction warmed to about 50 *C, then gradually cooled. The solution was stirred at ambient temperature for 4h, then poured into 450 mL of water, and extracted with diethyl ether (3 x 100 mL). The combined ether layers were back extracted with water (1 x 100 mL), and brine (1 x 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g (90%) of a colorless oil. Example 547E [2S.3R.4S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-f(N-butv1 N-(4-dimethylaminobutyl)amino)carbonyl methyll-pyrrolidi ne-3 carboxylic acid To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min. Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. he resultant maieriai was idke up in 5 L WO 99/06397 PCT/US98/15479 -725 of 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1M HCI (-7 mL required). The mixture was extracted with EtOAc (3X); the aqueous layer was concentrated in vacuo. The residue was washed 3X with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam. Example 548 [2S.3R.4S-2-(2.2-Dimethylpentyll-4-(1.3-benzodioxol-5-yl)-1-r(N butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3 carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 537B (ethyl [2S,3R,4S]-2-(2,2 Dimethy.lpentyl)-4-(1,3-benzodioxol-5-yl)-pyrroIidine-3-carboxylate) in Example 547C. Example 549 [2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1.3-benzodioxol-5 yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyll pyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 536D (ethyl [2S,3R,4S-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3 carboxylate) in Example 547C. Example 550 [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yl)-1 LN-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine 3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,3R,4S)-2-(2,2- WO 99/06397 PCTIUS98/15479 -726 Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3 carboxylate) in Example 547C. Example 551 5 r2S.3R.'4S -2-(2.2-Dimethypent-3-enyl-4-(7-methoxy-1.3 benzodioxol-5-yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)aminoicarbonylmethyll-prrolidine-3-carboxvlic 0 Prepared according to the procedures of Example 547, substituting the compound of Example 544A (ethyl [2S,3R,4S]-2-(2,2 Dimethylpent-3-enyl)-4-(7-methoxy- 1,3-benzodioxol-5-yl) pyrrolidine-3-carboxylate) in Example 547C. 5 Example 552 (2S.3R.4S0-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-benzodioxol-5-yl)-1 f(N.N-di(nbutyl)amino)carbonylmethyll-pyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 1, substituting the 0 compound of Example 541C (ethyl[2S, 3R,4S]-2-(2,2-Dimethylpent-3 enyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate). Example 553 [2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(7-m ethoxy-1.3 5 benzodioxol-5-yl)-1-[(N.N-di(n-butyl)amino)carbonylmethyll pyrrolidine-3-carboxylic acid Prepared according to the procesures of Example 1, substituting the compound of Example 544B (ethyl [2S,3R,4S]-2-(2,2-Dimethylpent-3 0 enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate). 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. 15 WO 99/06397 PCT/US98/15479 -727 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 Receptor 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 gg/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. [1 2 5 11ET-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 mM Tris, 100 mM NaCl, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 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 [ 12 5 1]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 0C. After incubation, unbound ligands were 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 pM ET-1. The data are shown in Table 4. The per cent inhibition at a concentration of 1 mM is shown. The data show that the compounds of the invention bind to the endothelin receptor.
WO 99/06397 PCT/US98/15479 -728 Table 4 Binding Data Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 sM sM 1D 96.4 34 95.5 2 58.4 35 91.8 3 42.2 36 94.5 4 78.2 37 47.9 5 95.1 38 100.0 6B 34.9 39 83.6 7 63.4 40 94.8 8 53.7 41 89.9 9 69.2 42 95.2 10 66.1 43 99.2 14 86.6 44 91.3 15 84.8 45 85.4 16 96.0 46 90.4 17 73.9 47 95.1 18 97.3 48 96.3 19 90.3 52 84.0 20 80.9 54 64.6 21 56.3 55 50.5 22 86.3 56 34.3 23 85.9 57 93.2 26 83.0 58 81.9 27 61.2 59 70.8 28 63.8 60 42.8 29 85.3 61C 90.6 30 80.0 62 94.1 31B 93.6 63 92.0 WO 99/06397 PCTIUS98/15479 -729 Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 M piM 64 95.0 98 86.8 65 82.8 99 92.1 66 87.7 100 76.8 67 96.3 101 89.2 68 84.6 102 75.2 69D 37.4 103 69.0 70 62.7 104 98.0 71 81.4 105 98.6 72C 80.7 106 90.0 73C 96.3 107 97.2 74 95.6 109 96.8 75C 95.3 110 94.4 76 93.1 111 101.8 79 100.4 112 94.9 80 89.4 113 94.3 82 90.3 114 86.2 83 85.0 115 88.4 84 65.3 116 79.3 86 52.6 117 95.2 87 62.4 118 93.2 88 84.3 119 86.6 89 84.6 120 99.5 91C 91.6 121 98.6 92C 107.4 122 95.3 93C 59.2 125 97.2 95D 82.1 126 91.7 96 86.1 127 91.4 97 89.0 128 95.4 WO 99/06397 PCT/US98/15479 -730 Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 pM gM 123 89.7 156 92.6 124 91.0 157 83.8 129 100.1 158 91.8 130 91.0 159 36.2 131 89.5 160B 80.3 132 90.0 161 93.6 133 88.6 162B 91.5 134 92.2 163 90.6 135B 77.7 164 98.6 136 79.4 165 54.1 138 83.0 166 91.6 139 98.6 167 94.4 140 106.3 291 100.0 141 92.8 293 89.8 142B 78.7 294 77.7 143 20.6 295 93.0 144 78.2 296 87.1 145 32.4 297 84.4 146 25.0 298 93.3 147 73.0 299 90.4 148 94.7 300 96.1 149 84.6 301 96.7 150 93.6 302 86.6 151 80.5 303 87.2 152 86.9 304 89.7 153 97.1 305 87.4 154 80.2 306 93.3 155 92.7 307 92.2 WO 99/06397 PCT/US98/15479 -731 Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 M M 308 93.0 351 99.0 309 80.7 352 96.2 310 87.1 353 73.7 311 92.3 354 79.3 312 88.2 355 100 313 96.3 356 93.5 314 86.0 357 96.3 315 82.7 358 62.7 316 74.0 359 94.7 317 68.5 360 93.7 318 79.0 361 92.8 319 79.0 362 94.1 320 82.2 363 82.3 322 95.6 365 59.2 323 91.3 366 91.5 324 95.0 367 71.0 334 88.0 368 94.6 335 84.1 370 84.3 340 94.0 371 97.2 341 87.4 372 91.6 342 89.9 373 92.9 343 98.7 374 91.4 344 95.6 375 97.8 345 86.6 376 90.2 346 88.9 377 85.6 348 91.3 378 91.1 349 73.0 379 90.7 350 92.1 380 99.0 WO 99/06397 PCT/US98/15479 -732 Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 RM pM 381 95.7 408 100 382 96.8 409 89.4 383 91.4 410 91.4 384 79.4 411 93.5 385 86.2 412 86.4 386 47.8 413 99.5 387 98.7 414 91.4 388 69.2 415 87.3 389 100 416 86.4 390 98.2 417 98.7 391 45.6 418 100 392 93.7 420 100 393 100 421 100 394 97.8 422 96.6 395 79.8 423 89.1 396 98.7 424 85.8 397 100 425 90.8 398 90.0 426 97.2 399 59.9 427 100 400 93.0 428 100 401 96.5 429 100 402 80.5 430 94.1 403 96.1 431 99.1 404 95.4 432 95.5 405 86.4 433 99.6 406 94.5 434 100 407 100 435 97.8 WO 99/06397 PCT/US98/15479 -733 Example % Inhibition Example % Inhibition of ETA at 1 of ETA at 1 jiM jM 436 100 459 97.4 437 100 460 91.6 438 94.3 461 99.6 439 94.3 462 98.3 440 100 463 96.1 441 98.3 464 97.1 442 100 465 95.1 443 100 466 94.2 444 100 467 93.6 445 98.1 468 88.7 446 97.8 469 98.7 447 96.9 470 100 448 97.4 471 100 449 100.0 475 91.6 450 99.7 476 82.3 451 100 477 80.1 452 100 479 96.5 453 94.4 495 95.9 454 96.8 496 92.7 455 99.1 497 83.7 456 95.3 498 81.6 457 88.9 499 68.5 458 93.4 500 55.7 WO 99/06397 PCT/US98/15479 -734 Example. % Inhibition of ETA at 1 502 95.7 503 97.0 504 97.1 505 95.8 506 99.7 507 99.3 508 97.6 509 100 510 100 511 99.2 512 98.9 513 98.0 514 100 515 99.1 516 99.7 517 94.1 518 96.3 519 99.1 520 97.4 521 100 523 99.0 524 99.2 525 100 526 100 527 96.6 528 98.3 529 98.1 531 99.8 532 100 533 97.9 536 100 537 97.2 WO 99/06397 PCT/US98/15479 -735 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 Phosphatidylinositol (PI) Hydrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 tCi/mL of
[
3 H]myo-inositol 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 1.5 mL of 1:2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 2Q 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 gL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1 X8 (Bio-Rad). The IC50 is the concentration of test compound required to inhibit the ET-induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.
WO 99/06397 PCTIUS98/15479 -736 Table 5 Phosphatidylinositol Hydrolysis Example IC50 4M ID 0.025 14 0.017 15 0.010 16 0.009 18 0.009 19 0.024 30 0.001 31B 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 534 0.05 553 0.0004 5 Table 6 ETA/ETB Selectivity MMQ cells, porcine cerebellar tissues (known to contain ETB receptors) and chinese hamster ovary cells (CHO) permanently 0 transfected with the human ETA or ETB receptor were homogenized in 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor (50 mM EDTA , 0.1 mM PMSF, 5 .ig/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disruptor. The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and 15 centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitor and centrifuged again. The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 WO 99/06397 PCTIUS98/15479 -737 containing protease inhibitors and stored at -80 *C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. 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 mM Tris, 100 mM NaCl, 10 mM MgCl2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 pg/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition binding studies, membranes (0.02 mg) were incubated with 0.1 nM of [1251]ET-1 (for ETA assay in MMQ or CHO cells transfected with human ETA receptor) or [1251]ET-3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETB receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 *C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence of 1 gM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors. Table 6 EXAMPLE rET-A rET-A pET-B Selectivity hET-A hET-B Selectivity NO. (%l @ 1C50 IC50 (rA/pB IC50 IC50 (hA/hB 1pgM) (nM) (nM) ratio) (nM) (nM) ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.92 52,000 56,000 504 97.1 3.1 >100,000 >32,000 4.6 >100,000 >21,000 505 95.8 2.0 60,000 30,000 5.7 68,000 12,000 506 99.7 3.2 >100,000 >31,000 3.0 61,000 20,000 WO 99/06397 PCT/US98/15479 -738 507 99.3 3.0 >100,000 >33,000 1.63 >100,000 >60,000 508 97.6 1.9 45,000 23,000 2.1 51,000 24,000 509 100 0.56 30,000 53,000 0.51 23,000 45,000 510 100 0.50 35,000 68,000 1.0 11,000 11,000 511 99.2 0.81 N.D. - - - - 0.60 15,000 25,000 512 98.9 0.42 >80,000 >190,000 0.58 60,000 >102,000 513 98.0 0.30 8,800 29,000 0.36 14,000 37,000 514 100 1.0 26,000 26,000 0.36 9,800 29,000 515 99.1 1.6 >62,000 >37,000 6.7 >100,000 >15,000 516 99.7 0.71 29,000 40,000 1.8 37,000 21,000 517 94.1 1.0 30,000 30,000 0.43 12,000 29,000 518 96.3 1.3 85,000 63,000 0.31 38,000 124,000 519 99.1 0.38 14,000 36,000 0.23 19,000 83,000 520 97.4 0.20 28,000 130,000 521 100 0.67 37,000 54,000 523 99.0 0.42 360 880 0.33 290 880 524 99.2 0.79 1,700 2,100 0.82 890 1,100 525 100 8.2 560 70 WO 99/06397 PCT/US98/15479 -739 526 100 42 - - 17 7,400 440 527 96.6 7.9 10,000 1,300 528 98.3 11 43,000 3.800 529 98.1 3.6 6,300 1,700 531 99.8 1.2 - - 0.71 870 1,200 532 100 5.1 3,200 630 533 97.9 76 7,900 100 40 22,000 560 534 0.12 0.36 3.0 0.08 0.28 3.5 536 100 0.52 17,000 33,000 0.92 52,000 56,000 537 97.2 0.96 5,900 6,200 0.23 1,900 8,200 552 97.3 0.78 7100,000 7125,000 1.0 >96,000 >96,000 553 100 0.26 42,400 160,000 0.29 39,500 136,000 Determination of Plasma Protein Binding A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 5 1OX into PBS. A 0.4 mL sample of this secondary stock solution was added to 3.6 mL of fresh plasma, and incubated at room temperature for 1 hour. A 1 mL sample of this incubation mixture was transferred to a Centrifree ultrafiltration tube. The sample was centrifuged in a fixed-bucket rotor for approximately 2 min and the filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 pL 10 sample of the ultrafiltrate was transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 pL sample was injected and the concentration of drug in the ultrafiltrate was determined by HPLC analysis compared against a standard sample prepared identically in the absence of plasma. Ultrafiltrate concentrations are calculated from a calibration curve. Protein binding is 15 calculated according to the equation: 739 WO 99/06397 PCT/US98/15479 - 740 %PB = [1-(Cu/Ci)] * 100% where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration. The percent of bound compound is listed in Table 7. Table 7. Example #43 > 99.5 % bound Example #530 78% bound Example #531 92% bound Example #532 96.8% bound Example #533 82.6% bound It has been demonstrated in the literature (Wu-Wong, et al., Life Sci. 1996, 58, 1839-1847, and references contained therein) that compounds which are highly protein bound show decreased potency in vitro in the presence of plasma proteins. A decrease in in vitro potency may correspondingly result in reduced in vivo potency. An endothelin antagonist which has reduced protein binding might be expected to be less susceptible to this effect, and thus be more potent as an in vivo agent. The ability of "reduced protein binding" endothelin antagonists to exhibit enhance activity in the presence of serum albumin has been demonstrated through the following study: A series of binding curves is recorded for a given antagonist, each experiment performed in the presence of increasing concentrations of serum albumin. Protocol for Albumin-induced binding shift studies: Binding assays were performed in 96-well microtiter plates precoated with 0.1 % BSA unless otherwise indicated. Membranes were diluted in Buffer B (20mM Tris, 100mM NaCl, 10mM MgCl2, pH 7.4, 0.1 mM PMSF, 5mg/mL Pepstatin A, 0.025% bacitracin and 3 mM EDTA) to a final concentration of 0.05 mg/ml of protein. Varying concentrations of human serum albumin (HSA) were added as indicated. In competition studies, membranes were incubated with 0.1 nM of [ 1 2 5 11ET in 740 WO 99/06397 PCTIUS98/15479 -741 Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25*C. After incubation, unbound ligands were separated from bound ligands by vacuum filtration using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., Watertown, MA), 5 followed by washing the filter strips with saline 11 ml) for three times. Nonspecific binding was determined in the presence of 1 pM ET-1. Figure 1A. 120 100 801 60 0 U 40 IC50 -0% HSP0.22 nM \ 20- -"-0.2% 0.85 nM \ f .1% 2.75 nM - 5% 6.72 nM -20 10" 1012 10'0 10" 10" 10' [Example 43], M >98% Protein Bound Figure 1B. Figure 1C. 120 120 100- 100 80 80 . 0 IC50 S-0-0%HS - 0 - -0% HSA 0.2 2. M2 0.2% 6.5 nM -.- 1% 3.1 nM . .. 1% 5.0 nM 0 -- 5% 5.5 nM 0 - 5 5.0 nM -20 1 -20 , 10"1 10,2 10'o 10' 10' 10' 10-" 10-" 101" 10" 10-' 101 r~ape531], M [Examp le 530], M 10 protein n bound 78% Protein Bound Figure 1 Inhibition of [ 12 s11ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either 0%, 0.2%, 1 %, or 5% HSA, and 741 WO 99/06397 PCT/US98/15479 - 742 assays were performed as described above. The results are expressed as % of control binding, with [ 125 lET-1 binding in the absence of antagonist defining 100%. Each point represents the mean (±S.D.) of three determinations. As observed in Figure 1 A, a compound which is highly protein bound (Example 4 >98% bound) shows a rightward shift of the binding curve (toward decreasing potency in the presence of increasing albumin levels. The compound of Example 531 (Figure 1 B in which protein binding is reduced to 92%, shows a substantial diminution of this rightward shift; the shift is completely eliminated with the compound of Example 530 (Figure 1 C), in which protein binding is reduced to 78%. This experiment demonstrates that a reduction in protein binding translates into increased potency in the presence of plasma proteins, and suggests that such compounds may exhibit enhanced in vivo activity. The observed reduction in protein binding, in compounds which retain high affinit for endothelin receptors, appears linked to the placement of "basic" functionality (group which carry a positive charge at physiological pH). Such compounds also exhibit improved solubility in aqueous solutions, as demonstrated below (Table 1) in an experiment in which maximum solubility was measured in aqueous media at varying pH at about 25 0 C. These results indicate that compounds that contain charged groups on the amide sidechain exhibit increased solubility over a significant range of pH. Such increased aqueous solubility, coupled wit the enhanced potency resulting from decreased protein binding, might make such compounds preferred for development as parenteral agents. Table 8 presents the pH Solubility profiles for representative compounds of the present invention. Table 8. pH [Example 43] (mg/m [Example 5311 (mg/ 5.1 0.08 >3.3 6.5 0.51 >3.4 7.1 0.99 3.54 7.6 1.14 3.55 742 WO 99/06397 -743- PCT/US98/15479 The present invention provides less protein bound compounds having improved in vitro and in vivo activity as pharmaceutical agents. The present invention also provides compounds that show that the affinity of hydrophobic acids for plasma protein may be reduced by attaching a counterbalanced charge at a biologically acceptab site. For example, protein binding is reduced by attaching a "basic" functionality (group which carry a positive charge at physiological pH) on the amide sidechain (see Formula wherein R. has an amide sidechain). The present invention covers compounds having the formula XII: R2 Z N R 3
(CH
2 )n R XII wherein Z is -C(R 18
)(R
1 9 )- or -C(O)- wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is (a) -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, (b) -P0 3
H
2 , (c) -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 wherein R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0) 2
R
1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, 743 WO 99/06397 PCT/US98/15479 - 744 (M) -S(0) 2
NHC(O)R
1 6 wherein R 16 is defined as above, HO O NH (n) 0 (o) HO 0 OH N (p) 0 0 NH 5 (q) 0 N 0 (r) H N (S) H N, N LZ L CF3 (u)
NHSO
2 CF 3 (U) 10 R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, 15 dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, 744 WO 99/06397 PCTIUS98/15479 - 745 heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen;
R
3 is (a)R 4
-C(O)-R
5 -, R 4
-C(O)-R
5 - N(R 6 )-, 5 wherein R 5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 0
)-R
8 - or
-R
8 a-N(R 20
)-R
8 - wherein R 8 and R 8 a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R 9 or -R 9 a-O-R 9 - wherein R 9 and R9a are independently selected from alkylene; 10 R 4 and R 6 are (R 11
)(R
1 2 )N- wherein R 1 1 and R 12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, 15 (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, 20 (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, 25 (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, 30 (19) dialkylaminoalkyl, (20) carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic)aminoalkyl, and 35 (24) (heterocyclic)aminoalkyl, with the proviso that at least one of R, and R, 2 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, 40 (heterocyclic)aminoalkyl, and (heterocyclic)alkylaminoalkyl; or a pharmaceutically acceptable salt thereof. 745 WO 99/06397 PCT/US98/15479 - 746 Preferred compounds having reduced protein binding are shown in Table SA wherein R may be selected from the substituents shown in Table 9B. Table 9A.
OCH
3 OCH 3 OCH 3 R. N R. N R.N ..N -COOH R . COOH R . COOH 0 0 5 1 O 2 0 3 O
OCH
3
-
ROH"OHN ----..... .....
............
COOH -~ ci - 0 4 ci 5 CH 3 O 6 01 RN R. R ---- COOH N "".COOH . ""COOH -.. 0 ci 7 0 8 O 9 c1 R. N R N R. N -"COOH ""COOH N .''"COOH - 0 -. 0 10 CH 3 0 a -1 12 0 746 WO 99/06397 PCTIUS98/1 5479 - 747 - 0 -.. ciN 0 R. N R. N ...
R . COOH "COQH 'COOH - 0 -l 0 16 oj 17 0l 18 H3 0) N0 N 0 N R. N R. N R N ... COOH ... COOH .... COOH 0 I- 0 190 -N2 C 3 ~ 2 R. N R.N R.N COOH .... COOH "CO0H -. 0 0 C 22 0l 23 CH0 0124 0C RN R-N R COOH "COOH 'COOH -~ 0 . 5 25 0 ~ 26 0j 27 0 747j WO 99/06397 PCTIUS98/15479 - 748 OCH 3 R.RR N "OR. N NN R.N NN NNH NNH . C 28 CI 29 0- 30 CH 3 O R.N NN R.N NN N.NH NNH 0 0 31 CH 3 0 J 32 0 5 Table 9B. H3CNH N H3CNH,_,,_ N H3CNH N 1 0 2 0 3 0 H
H
3 CNH - N N N,_,N,, 4 0 5 0 6 0 H NN, N N N o 8 09 H H H 0 1 1 12 0 H H N N N NN N H H 13 0 14 0 15 0 H H N N NN N 16 0 17 H 0 18 0 748 WO 99/06397 PCT/US98/15479 - 749 H N N, NN N 19 0 20 0 21 H 0 H +H N, N N, NN 22 0 23 0 24 0 H2N -,,N H2N _,- N Y^-H2NN 25 0 26 0 27 0
H
2 N N (H 3
C)
2 N N (H 3
C)
2 N N 28 0 29 0 30 0 + 0 (H3C)2N N (HC)2N,, _ N (CH3)3N -N' 5 31 0 32 0 33 0 + 0 0 (CH3)3N" N (CH 3
)
3 N (CH3)3NN 34 35 36 N N N NN 37 38 39 0 N 0 40 41 42 )N00 0 N NN NN N 43 44 45 0 o) 0K 0 10 460 47 480-) HN 0 0 HN 0 N NN N NNA 49 50HN, 51 0 CH 3 N 0 0 5 2 HN 53 5 4
CH
3 N 749 WO 99/06397 -750- PCTIUS98/15479
CH
3 N 0 0 H O 55 ,-..) 5 6
CH
3 NI) 57 58 H 59 60 H H~NQ 0 0 0 NOI_ Oa N N N0- r 610 62 H O 64 5 For the purposes of this disclosure, the term "(cycloalkyl)aminoalkyl" as used herein refers a cycloalkyl moiety attached to the parent compound through an aminoalkyl. Examples of (cycloalkyl)aminoalkyl include (cyclohexane)aminopropyl, (cyclohexane)aminoethyl, angi the like. 10 The term "(heterocyclic)aminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an aminoalkyl. Examples of (heterocyclic)aminoalkyl include (pyridine)aminopropyl, (benzofuran)aminopropyl, (tetrahydopyran)aminoethyl, and the like. The term "(cycloalkyl)alkylaminoalkyl" refers to a cycloalkyl moiety attached to 15 the parent compound through an alkylaminoalkyl. Examples of (cycloalkyl)alkylaminoalkyl include (cyclohexane)ethylaminomethyl, (cyclopentane)methylaminoisopropyl, and the like. The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an alkylaminoalkyl. 20 Examples of (heterocyclic)alkylaminoalkyl include (pyridine)ethylaminopropyl, (benzofuran)methylaminoisobutyl, (tetrahydopyran)methylaminoethyl, and the like. 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. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 10 131 25 (1983). The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990). 750 WO 99/06397 PCT/US98/15479 -751 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). The ability of the compounds of the invention to treat coronary angina can be 5 demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984). 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. 5 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991). 10 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 15 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 20 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 cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990). 25 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. 79 619 (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. 30 Physiol. and Pharmacol. 67 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 be 35 demonstrated according to the methods described in Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990). 751 WO 99/06397 PCTIUS98/15479 - 752 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). The ability of the compounds of the invention to treat proliferative diseases 5 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. 191 840-846 (1993); and Shichiri, et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress 10 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 15 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. 20 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. 87 25 1867 (1991). The ability of the compounds of the invention to treat IL-2 (and other 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). 30 The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol. Exp. Therap. 271 156 (1994). The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J. 35 Pharmacol. 1996, 309, 261-269). 752 WO 99/06397 PCTIUS98/15479 - 753 The ability of the compounds of the invention to treat ischemia-repurfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, 9, 201-207). The ability of the compounds of the invention to treat angina, pulmonary 5 hypertension, raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27). 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, 10 benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, 15 persulfate, 3-phenylpropionate, 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, 20 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, 25 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 (1), or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of 30 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 sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not 35 limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other 753 WO 99/06397 PCTIUS98/15479 - 754 representative organic amines 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 5 human or other mammal. In addition, the compounds of the present invention are useful (in a human or other mammal) for the treatment of hypertension, 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 10 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 15 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, especially treatment of bone pain associated with bone cancer. 20 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. 25 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 the specific 30 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 unit 35 formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use 754 WO 99/06397 PCTIUS98/15479 - 755 of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleagenous 5 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 10 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 prepared by mixing 15 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 20 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, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. 25 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 agents. 30 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 phospholipids or other lipid substances. Liposomes are formed by mono- or multi lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non toxic, physiologically aceptable and metabolizable lipid capable of forming liposomes 35 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 755 WO 99/06397 PCT/US98/15479 - 756 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), 5 p. 33etseq. A representative solid dosage form, for example, a tablet or a capsule, comprises: Compound of the invention: 35% w/w Starch, Pregelatinized, NF 50% w/w 10 Microcrystalline Cellulose, NF 10% w/w Talc, Powder, USP 5% w/w 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 5 agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin I antagonists, potassium channel activators and other cardiovascular agents. Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, 0 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 5 thereof. 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, 0 gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof. Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-1 34672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin 11 antagonists include DUP 753, A-81988 and the like. 5 Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof. 756 WO 99/06397 PCTIUS98/15479 -757 Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof. Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically 5 acceptable salt thereof. The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses. 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 route of 0 administration, severity of the disease and the response of the patient. The combination can be administered as separate 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 5 times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended 0 claims. 757

Claims (98)

1. A compound of the formula: R2 Z R3 (CH 2 )n R R1 5 wherein Z is -C(R 18 )(R 19 )- or -C(O)- wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is 10 (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, 15 (e) -C(O)NHR 17 wherein R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, 20 (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, (M) -S(O) 2 NHC(O)R 1 6 wherein R 16 is defined as above, HO NH 25 (n) 0 WO 99/06397 PCTIUS98/15479 -759 (o) HO 0 OH IN (p) , 0 -- NH (q) 0 N* (r) 0 0 NS AlI! N 30 (s) H CF 3 N (t) Hor NHSO 2 CF 3 (u); R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 35 haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, 40 aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Roc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; WO 99/06397 PCT/US98/15479 -760 45 R 3 is (a)R4-C(O)-R 5 -, R4-R5a-, R4-C(O)-R 5 - N(R 6 )- , R6-S(O) 2 -R 7 - or R26-S(O)-R27 wherein R 5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 - or -Rea-N(R20)-R8 wherein R 8 and R8a are independently selected from the group 50 consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R 9 - or -R 9 a-O-R 9 - wherein R 9 and R 9 a are independently selected from alkylene; R5a is (i) alkylene or (ii) alkenylene; 55 R 7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 1 )-R 10 - or -RlOa-N(R21)-Rlo- wherein R 10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R 2 1 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; 60 R 4 and R 6 are independently selected from the group consisting of (i) (R11)(R12)N- wherein R 11 and R 12 are independently selected from (1) hydrogen, (2) loweralkyl, 65 (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, 70 (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, 75 (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, 80 (18) alkylaminoalkyl, WO 99/06397 PCT/US98/15479 -761 (19) dialkylaminoalkyl, and (20) carboxyalkyl (ii) loweralkyl, (iii) alkenyl, 85 (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, 90 (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, 95 (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, 100 (xix) dialkylaminoalkyl, (xx) alkoxy, and H (CH2)z N N, -Cf~. R7a (xxi) 0 wherein z is 0-5 and R7a is alkylene; 105 R 26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy substituted haloalkyl; and R 27 is alkylene or alkenylene; 110 (b) R 22 -0-C(O)-R 23 - wherein R 22 is a carboxy protecting group or heterocyclic and R 23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24 )-R 25 - wherein R 25 is alkylene and R 2 4 is hydrogen or loweralkyl, (c) loweralkyl, WO 99/06397 PCT/US98/15479 -762 115 (d) alkenyl, (e) alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, (h) aryl, 120 (i) arylalkyl, (j) aryloxyalkyl, (k) heterocyclic, (1) (heterocyclic)alkyl, (m) alkoxyalkyl, 125 (n) alkoxyalkoxyalkyl, or (o) R1 3 -C(O)-CH(R1 4 ) wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R 1 5 -C(O)- wherein R 15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof. 130
2. The compound according to Claim 1 wherein n is 0 and Z is -CH 2 -
3. The compound according to Claim 1 wherein n is 1 and Z is -CH 2 -.
4. The compound according to Claim 1 wherein n is 0, Z is -CH 2 -, and R 3 is R 4 -C(O)-R 5 - , R 6 -SO 2 -R 7 - or R2 6 -S(O)-R 27 - wherein R 4 , R 5 , R 6 , R 7 , R 26 and R 27 are as defined therein.
5. The compound according to Claim 1 wherein n. is 0, Z is -CH 2 -, and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.
6. The compound according to Claim 1 wherein n is 0, Z is -CH 2 -, and R 3 is R 4 -C(O)-R 5 - wherein R 4 is (R 11 )(R 12 )N- as defined therein and R 5 is alkylene or R 3 is R6-S(O) 2 -R 7 - or R 26 -S(O)-R 27 wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are as defined 5 therein. WO 99/06397 PCTIUS98/15479 -763
7. The compound according to Claim 1 wherein n is 0, Z is -CH 2 - and R 3 -is R 4 -C(O)-N(R 2 0 )-R 8 - or R 6 -S(O) 2 -N(R 21 )-R 10 - wherein R 8 and R 10 are alkylene and R 4 , R 6 , R 20 and R 21 are as defined therein.
8. The compound according to Claim 1 wherein n is 0, R is tetrazolyl or -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 and R 2 are independently 5 selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) aryloxyalkyl, 10 (viii) arylalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 - wherein R 4 is (R11)(R 1 2 )N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyl 15 and R 5 is alkylene; or R 3 is R 4 -C(O)-N(R 20 )-R 8 - or R 6 -S(O) 2 -N(R 21 )-R 10 - wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and R 10 are alkylene and R 20 and R 2 1 are loweralkyl; or R 3 is Re-S(O) 2 -R 7 - or R 26 -S(O)-R 27 20 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 2 6 is loweralkyl and R 27 is alkylene.
9. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) 5 cycloalkyl,- (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 10 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl WO 99/06397 PCT/US98/15479 -764 or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3 15 benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8 methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R 3 is R4-C(O)-N(R 20 )-R 8 - or R6-S(O) 2 -N(R 2 1)-R10- wherein R 8 and R 1 0 are alkylene, R 20 and R 2 1 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, 20 alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
10. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) 5 cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 10 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3 15 benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8 methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 methoxyphenyl, dimethoxyphenyl, fluorophenyl, or difluorophenyl, and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N wherein R 11 and R 12 are independently selected from loweralkyl, 20 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
11. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, WO 99/06397 PCT/US98/15479 -765 tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl (ii) alkenyl, (iii) arylalkyl, (iv) 5 aryloxyalkyl, (v) heterocyclic, (vi) heterocyclic (alkyl), (vii) aryl, (viii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, 10 fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R1 2 )N- wherein R 11 is loweralkyl, and R 12 is aryl or arylalkyl.
12. The compound according to Claim 1 wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) phenyl or (ii) substituted or unsubstituted 4 5 methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy, and carboxyalkoxy, R 2 is substituted or unsubstituted 10 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R6-S(O) 2 -N(R 21 )-R 10 - wherein R 10 is alkylene, R 6 is loweralkyl, 15 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
13. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 5 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy WO 99/06397 PCT/US98/15479 -766 and alkoxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4 10 benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R-S(O) 2 -N(R 21 )-R 10 - wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is 15 loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
14. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4 5 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 10 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R1 2 )N- wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 15
15. The compound according to Claim 1 wherein n is 0, R is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is loweralkyl, 5 alkoxyalkyl, or alkenyl, R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N wherein R 11 and R 12 are independently selected from loweralkyl, aryl 10 hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyl. WO 99/06397 PCT/US98/15479 -767
16. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R1 is substituted or unsubstituted 4-methoxyphenyl, 4 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 5 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, 10 dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 12 )N- wherein R 11 and R 12 are independently selected from loweralkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
17. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R1 is substituted or unsubstituted 4-methoxyphenyl, 4 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 5 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, 10 dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 12 )N- wherein R 11 is loweralkyl and R 12 is aryl.
18. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro 4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4 5 ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4 benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7 methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4- WO 99/06397 PCT/US98/15479 -768 10 benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R1 2 )N- wherein R 1 1 is alkyl and R 12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, 15 and heterocyclic.
19. A compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, 20 aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R 12 )N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 25
20. A compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or 30 alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 1 1 and R 12 is alkyl.
21. The compound according to Claim 1 of the formula: R2 Z N R 3 N (CH 2 )n R1 5 wherein Z is -C(R 18 )(R 19 )- or -C(O)- wherein R18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; WO 99/06397 PCT/US98/15479 -769 R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is. 10 (a) -C(O)2-G wherein G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR17 wherein R 17 is loweralkyl, 15 (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, 20 (k) sulfonamido, (1) -C(O)NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, (M) -S(O) 2 NHC(O)R 1 6 wherein R1 6 is defined as above, HO (n) 0 25 (o) HO 0 OH IN (p) , NH (q) 0, N) (r) 0, WO 99/06397 PCT/US98/15479 -770 0 N-O AtjL N (s) H N-N CF 3 N 30 (t) H or ' -& NHS2cF3 (u) R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, 35 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, 40 alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Roc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; R 3 is (a) R4-C(O)-R 5 -, R4-R5a-, Re-S(O) 2 -R 7 - or R2 6 -S(O)-R 27 45 wherein R 5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 - or -R8a-N(R20)-R8 wherein R 8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or 50 cycloalkylalkyl or (v) -O-R 9 - or -R9a-O-R9 wherein R 9 and R9a are independently selected from alkylene; R5a is (i) alkylene or (ii) alkenylene; R 7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21)-R10- or -Rloa-N(R21)-Rl 55 wherein R 10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R 4 and R 6 are independently selected from the group consisting of WO 99/06397 PCTIUS98/15479 -771 (i) (R11)(R12)N- wherein R 11 and R12 are independently 60 selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, 65 (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, 70 (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, 75 (15) alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl, (ii) loweralkyl, (iii) alkenyl, 80 (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, 85 (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, 90 (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, WO 99/06397 PCTIUS98/15479 -772 95 (xix) dialkylaminoalkyl, (xx) alkoxy, and H (CH 2 )z N NR R7a (xxi) 0 1.00 wherein z is 0-5 and R7a is alkylene; R 26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy substituted haloalkyl; and 105 R 27 is alkylene or alkenylene; (b) R22-0-C(O)-R 23 - wherein R 22 is a carboxy protecting group or heterocyclic and R 23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24 )-R 25 - wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, 110 (c) loweralkyl, (d) alkenyl, (e) alkynyl, (f) cycloalkyl, (g) cycloalkylalkyl, 115 (h) aryl, (i) arylalkyl, (j) aryloxyalkyl, (k) heterocyclic, (I) (heterocyclic)alkyl, 20 (m) alkoxyalkyl, (n) alkoxyalkoxyalkyl, or (o) R13-C(O)-CH(R 1 4 ) wherein R 13 is amino, alkylamino or dialkylamino and R14 is aryl or R 15 -C(O)- wherein R 15 is amino, alkylamino or 25 dialkylamino; or a pharmaceutically acceptable salt thereof. WO 99/06397 PCTIUS98/15479 -773
22. The compound according to Claim 21 wherein n is 0 and Z is -CH 2 -.
23. The compound according to Claim 21 wherein n is 1 and Z is -CH 2 -.
24. The compound according to Claim 21 wherein n is 0, Z is -CH 2 -, and R 3 is R4-C(O)-R 5 - , R6-SO 2 -R 7 - or R2 6 -S(O)-R 27 - wherein R 4 , R 5 , R 6 , R 7 , R 2 6 and R 2 7 are as defined therein.
25. The compound according to Claim 21 wherein n is 0, Z is -CH 2 -, and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.
26. The compound according to Claim 21 wherein n is 0, Z is -CH 2 -, and R 3 is R 4 -C(O)-R 5 - wherein R 4 is (R11)(R 1 2 )N- as defined therein and R 5 is alkylene or R 3 is R 6 -S(O) 2 -R 7 - or R2 6 -S(O)-R 27 wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are as defined 5 therein.
27. The compound according to Claim 21 wherein n is 0, Z is -CH 2 - and R 3 is R4-C(O)-N(R 20 )-R 8 - or R6-S(O) 2 -N(R 21 )-R 10 - wherein R 8 and R 10 are alkylene and R 4 , R 6 , R 2 0 and R 2 1 are as defined therein.
28. The compound according to Claim 21 wherein n is 0, R is tetrazolyl or -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 and R 2 are independently 5 selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted and unsubstituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) 10 aryloxyalkyl, (viii) aryalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl, and (x) alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 4 is (R11)(R 12 )N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, WO 99/06397 PCTIUS98/15479 -774 heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl 15 and arylalkyl and R 5 is alkylene; or R 3 is R4-C(O)-N(R 20 )-R 8 - or R6-S(O) 2 -N(R 2 1 )-R1o wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and 20 R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and R 10 are alkylene and R 20 and R 2 1 are loweralkyl; or R 3 is R 6 -S(O) 2 -R 7 - or R 26 -S(O)-R 27 wherein R 6 is loweralkyl or haloalkyl, 25 R 7 is alkylene, R 26 is loweralkyl and R 27 is alkylene.
29. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) 5 cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 10 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3 15 benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8 methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-N(R 20 )-R 8 - or R 6 -S(O) 2 -N(R 21 )-R 1 o wherein R 8 and R 10 are alkylene, 20 R 20 and R 2 1 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and WO 99/06397 PCT/US98/15479 -775 R6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
30. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) 5 cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 10 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryoxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3 15 benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8 methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4 methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R 11 )(R 12 )N- wherein R11 and R 12 are independently selected from loweralkyl, haloalkyl, 20 alkoxyalkyl, haloalkoxyalkyl, aryl and arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
31. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) loweralkyl or (ii) alkenyl, (iii) aryalkyl, (iv) 5 aryoxyalkyl, (v) heterocyclic (alkyl), (vi) aryl, (vii) (N-alkanoyl-N alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl,R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4 benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or 10 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R 1 1 )(R 1 2 )N- wherein R 11 is loweralkyl and R 12 is aryl or arylalkyl. WO 99/06397 PCT/US98/15479 -776
32. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is (i) phenyl or (ii) substituted or unsubstituted 4 5 methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3 10 benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8 methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R6-S(O) 2 -N(R 2 1)-R 10 - wherein R 10 is alkylene, R 6 is loweralkyl, 15 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
33 The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 5 3 -fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4 -methoxymethoxyphenyl, 1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4 10 benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R6-S(O) 2 -N(R 2 1)-R 10 - wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is 5 loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
34. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, WO 99/06397 PCTIUS98/15479 -777 tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4 5 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 0 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N- wherein R 11 and R 12 are independently selected from loweralkyl, aryl arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 5
35. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2 -, R 1 is loweralkyl, alkoxyalkyl or alkenyl, R 2 is 1,3 5 benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene and R 4 is (R11)(R 1 2 )N wherein R 1 1 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and o heterocyclic.
36. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 5 4-pentafluoroethylphenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 12 )N- wherein R 11 and R 12 are independently selected from loweralkyl. WO 99/06397 PCT/US98/15479 -778
37. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4 fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 5 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1,3-benzodioxolyl, 1,4 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, 10 dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R12)N- wherein R 11 is loweralkyl and R 12 is aryl.
38. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro 4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4 5 ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4 benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7 methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4 0 benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is Re-S(O) 2 -N(R 2 1)-R1 0 - wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, 5 haloalkyl or alkoxyalkyl.
39. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, 0 aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 - wherein R 5 is alkylene WO 99/06397 PCTIUS98/15479 -779 and R 4 is (R11)(R1 2 )N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, and heterocyclic. 25
40. A compound according to Claim 21 wherein n is 0, R is -C(O).2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 -, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R 5 - wherein R 5 is alkylene 30 and R 4 is (Ri)(R12)N- wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 11 and R 12 is alkyl
41. A compound selected from the group consisting of trans-trans-2-(4-Methoxphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[3-(N propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3 carboxylic acid; 5 trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-( 2 -(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol -5-yl)-1-[2 (N- propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3 0 carboxylic acid; trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2 (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrroidine-3 carboxylic acid; trans,trans-2-( 4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yI)-1-[2-(N 5 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1 -(((N,N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N 0 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-[ 2 -(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; WO 99/06397 PCTIUS98/1 5479 -780 25 trans, trans-2-(3-F Iuo ro-4-methoxypheny1) -4-(1 ,3 -ben zodioxol-5-y I) 1 -( 2 -(N-propylI-N-(3-ch Io ropropanesuIf o nyI) am ino) ethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.(1 ,3-benzodioxol-5-yI) 1 -(2-(N-isobutyl-N-(3 30 chloropropanesulfonyl)amino)ethyl)pyrrolidine3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl) 1 -[2-(N-propyl-N-(4 methylbutanesulfonyl)amino)ethyl]pyrrolidine3carboxylic acid; trans, trans-2-(4-Methoxy-3-fluorophenyI)-4-(7-methoxy-1 3 35 benzodioxol-5-yi)-1 -[2-(N-propyl-N-(n pentanesulfonyl)amino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -[ 2 -(N-propyI-N-(2,2,3,3,3-pentafluoropropoxyethanesufonyl). amino)ethyl]pyrrolidine-3-carboxylic acid; 40 trans, trans-2-(1 ,4-Benzodioxan-6-yI)-4-(7-methoxy- 1,3-benzodioxol 5 -yI)-1 -[2-(N-propyl-N-(n pentanesulfonyl)amino)ethyllpyrrolidine3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -( 2 -(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3 1.5 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -( 2 -(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino). ethyl) pyrrol idine-3-carboxyl ic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 50 1-(2-(N-(2-methoxyethyl)-N (pentanesulfonyl)amino)ethyl)pyrrolidine3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -[ 2 -(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino). ethyl]pyrrolidine-3-carboxylic acid; 55 trans, trans-2-(3-Fiuoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -( 2 -(N- (2- methoxyethyl)-N- (butanes uIf onyl am ino) ethyl)-. pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI) 1 -[2-(N-propyl-N-(2- WO 99/06397 PCTUS9815479 -781 60 m ethylIpro panesu If onyl)am ino) ethyI] pyrro d ne3carboxylic acid; and trans, trans-2-(3-Fluoro-4-methoxypheny)-4-(1 ,3-benzodioxol-5-yI) 1 -( 2 -(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine.3 carboxylic acid; 65 trans, trans-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 -(N,N di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 -(N,N di(n-butyI)aminocarbonylmethyI)-pyrroidine3carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)-l 70 (NN-di(n-buty)aminocarbonylmethyI)-pyrrolidine-.3-carboxylic acid; trans, trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4(1 ,3-benzodioxol 5 -yI)-1 -(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 7'5 trans, trans-2-(2,2,4-TrimethyI-3-pentenyI)-4-(1 ,3-benzodioxol-5 yl)- 1 -(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3 benzodioxol-5-yI)-1 -(N, N-di(n-butyl)aminocarbonylmethyl) 30 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 [[N-4-heptyl-N-(2-methyl-3-fI uorophenyl)] aminocarbonylmethyII-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3 35 benzodioxol-5-yI)-1 -(NN-di(n-butyI)aminocarbonylmethy) pyrrolidine-3-carboxylic acid trans, trans-2-((2-Methoxyphenoxy)-methyl)4.(1 ,3-benzodioxol-5-yI) 1 -(N,N-di(n-butyI)aminocarbonyimethyl)-pyrrolidine-3 carboxylic acid; '0 (2S,3R,4S)-2-(2,2-Dimethypenty)-4.(1 ,3-benzodioxol-5-yI)-1 -(N-4 heptyl-N-(4-fluoro-3-methylphenyI))aminocarbonylmethy>. pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yi)ethyl)-4-(1 ,3-benzodioxol-5 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 5 carboxylic acid; WO 99/06397 PCTIUS98/1 5479 -782 (2S, 3R, 4S)-2-(2,2-Di methy'lpe ntyl)-4-(7-methoxy- 1 ,3-benzodioxol-5 yi)- 1 -(N,N-di(n-butyl)aminocarbonylmethyl).pyrrolidine-3 carboxylic acid trans, trans-2-(2-(l ,3-Dioxol-2-yI)ethyl)-4-(7-me thoxy-1 ,3 0 benzodioxol-5-yl)-l -(N-4-heptyl-N-(4-fluoro-3 meth ylp he nyl))am inocarbo nylmethyl) -py rro lid ne-3-.carboxyl ic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxyl ,3-benzodioxol-5 yI)-l1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 5. carboxylic acid; trans, trans-2- (2 ,2-di methylpe ntyl)-4-(2 ,3-d ihydro-benzofuran-5-yI) 1 -(N ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7 0 methoxy-1 ,3-benzodioxol-5-yi)-1 -(N,N-di(n butyl)aminocarbonylmethyl)-pyrrolidine-3-.carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)4(7-methoxy-1,3 benzodioxol-5-yi)-1 -(N, N-di(n-butyl)aminocarbonyl methyl) pyrrolidine-3-carboxylic acid; 5 trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3 benzodioxol-5-yl)-1 -(N, N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; trans, trans-2- (2- (2-pyridy1) ethyl) -4- (1 ,3-be nzod ioxol1-5-y1) -1 -(N,,N di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; 0 (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol-5 yI)- 1 -(N, N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5 yI)-l1-(N-4-heptyl-N-(4-fl uoro-3 5 methylphenyl))aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxoi-5- yl)-1 (N, N-di(n-butyl)aminocarbonylmethyl)..pyrrolidine-3-carboxylic acid; WO 99/06397 PCT/US98/15479 -783 10 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)-1 -[(N butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] pyrrolidine-3-carboxylic acid; (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3 5 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 o carboxylic acid; ( 2 S, 3 R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3 benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl) 5 1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4(1,3-benzodioxol-5-yl)-1 (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 0 or a pharmaceutically acceptable salt thereof.
42. A compound of the formula: R2 NH (CH 2 )n (CH2)m W R1 w 5 wherein n is 0 or 1; m is 0 to 6; W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, WO 99/06397 PCTIUS98/15479 -784 (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, 5 .(i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2 R1 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, :o- (M) -S(O)2NHC(O)Rl 6 , HO (n) 0 O (o) HO 0 OH IN (p) , <,NH O (q) 0 NO 5 (r) 0 ~y2s=o (s) H CF 3 (t) H or WO 99/06397 PCT/US98/15479 -785 (u) NHSO2cF3 and R 1 and R 2 are independently selected from hydrogen, loweralkyl, 30 alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, 35 dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and 10 R 2 is other than hydrogen; or a salt thereof.
43. The compound of Claim 42 wherein m is zero or 1; W is -C02-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof. 5
44. The compound of Claim 42 wherein n and m are both 0; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, 5 (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4 -pentafluoroethylphenyl, 3 -fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 0 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted 5 or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4 benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or WO 99/06397 PCT/US98/15479 -786 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or !o the substantially pure (+)- or (-)-isomer thereof.
45. The compound according to Claim 42 of the formula: NH NH I I S (CH2)n H2)n (CH2)m (CH2m W R1 or W R1 5 wherein n is 0 or 1; m is 0 to 6; W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, o (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, 5 (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O) 2 R 1 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, o (M) -S(O)2NHC(O)Rl6, HO NH (n) 0 (o) HO 0 , WO 99/06397 PCT/US98/15479 -787 OH (p) 0 NH (q) 0, N 0 N (s) H CF 3 A-N N1 N ca (t) H, or (u) - NHSO2cF3 and R 1 and R 2 are independently selected from hydrogen, loweralkyl, 30 alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, 35 dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Roc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and 40 R 2 is other than hydrogen; or a salt thereof.
46. The compound according to Claim 45 wherein m is zero or 1; WO 99/06397 PCT/US98/15479 -788 W is -CO2-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof. 5
47. The compound according to Claim 45 wherein n and m are both 0; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, 5 (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 0 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted 5 or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4 benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or 0 the substantially pure (+)- or (-)-isomer thereof.
48. The substantially pure compound (+)-trans,trans-2-(4 Methoxyphenyl)-4-(1, 3 -benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof. 5
49. The substantially pure compound (2S,3R,4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a salt or ester thereof. WO 99/06397 PCT/US98/15479 -789
50. A compound of the formula R2 N.R5bQ (CH 2 )n (CH2)m w 5 wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; Q is a leaving group; 10 W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, 15 (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, 20 (k) sulfonamido, (I) -C(O)NHS(O) 2 R 1 6 where R 1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2 NHC(O)R 16 , HO NH (n) 0 HO 0 25 (0) H WO 99/06397 PCT/US98/15479 -790 OH IN (p) NH (q) 0, N * (r) , 0 N-O . 'NS=O A-I- N 4 (s) H N -- N \i)- CF 3 N 30 (t) H ,or (U) NHSO 2 CF 3 and R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, 35 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, 40 alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof. 45 WO 99/06397 PCT/US98/15479 -791
51. The compound according to Claim 50 wherein m is zero or 1; R5b is alkylene; 5 Q is a leaving group; and W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
52. The compound according to Claim 50 wherein n and m are both 0; R5b is alkylene; Q is a leaving group; 5 W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 10 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R 2 is 15 substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, (x) aryloxyalkyl, (xi) 20 heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer thereof.
53. The compound according to Claim 50 of the formula R2 N R5b -Q R2 N ,R5b Q (CH 2 )m (CH 2 )m W R1 or W R1 WO 99/06397 PCT/US98/15479 -792 5 wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; Q is a leaving group; W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, 0 (b) -P0 3 H 2 , (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, 5 (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, 20 (1) -C(O)NHS(O) 2 R 1 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (M) -S(O) 2 NHC(O)R 1 6 , HO ~rHO (n) 0 (o) HO 0 OH N 0 ?5 (p)O , - <-NH 0 WO 99/06397 PCT/US98/15479 -793 N (r) (s) H N CF 3 (t) Ho NHSO 2 cF 3 30 (u) ; and R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, 35 alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and 40 (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; or a salt thereof.
54. The compound according to Claim 53 wherein m is zero or 1; R5b is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-) isomer thereof. 5
55. The compound according to Claim 53 wherein n and m are both 0; R5b is alkylene; Q is a leaving group; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, 5 (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- WO 99/06397 PCT/US98/15479 -794 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 10 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3 benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, 15 dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure (+)- or (-)-isomer 20 thereof. WO 99/06397 PCT/US98/15479 -795
56. A compound of the formula R2 N..R5b - NHR 2 oa (CH 2 )n (CH 2 )m W R1 5 wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , 0 (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, 5 (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(O)NHS(O) 2 R 1 6 where R 16 is loweralkyl, haloalkyl, phenyl or D dialkylamino, (M) -S(O) 2 NHC(O)R 1 6 , HO rH (n) 0 (0) HO 0 OH ( ) (p) 0 WO 99/06397 PCT/US98/15479 -796 0 5 (q) 0, N* (r) , 0 N O (s) H - CF 3 N- N (t) H , or (u) NHSO2CF3 and 30 R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 35 aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or wo alkanoyl and Roc is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof.
57. The compound according to Claim 56 wherein m is zero or 1; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, 5 haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and WO 99/06397 PCTIUS98/15479 -797 W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof.
58. The compound according to Claim 56 wherein n and m are both 0; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, 5 haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 10 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4 hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from 15 loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4 benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 20 benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
59. The compound according to Claim 56 of the formula R24N'R5b - NHR 2 oa R2 N'R 5 b - NHR 2 0a (CH2)m (CH 2 )m W R1 or W R1 WO 99/06397 PCTIUS98/15479 -798 5 wherein n is 0 or 1; m is 0 to 6; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C(O)2-G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , 0 (c) -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 where R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, 5 (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(O) 2 R 1 6 where R 1 6 is loweralkyl, haloalkyl, phenyl or 0 dialkylamino, (M) -S(O) 2 NHC(O)R 16 , HO -4rHO (n) 0 O (o) HO 0 OH N (p) 0 0 NH 5 (q) 0 -( 0 (r)0 , WO 99/06397 PCTIUS98/15479 -799 N" 0\ S=O -- N (S) H N NCF 3 (t) H ,or (u \ NHSO 2 CF 3 and R1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, 5 alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N 10 alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof.
60. The compound according to Claim 59 wherein m is zero or 1; R5b is alkylene; 5 R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; and W is -C02-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure (+)- or (-)-isomer thereof. WO 99/06397 PCT/US98/15479 -800
61. The compound according to Claim 58 wherein n and m are both 0; R5b is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is (i) loweralkyl, (ii) 5 alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4 ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4 pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2 fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3 10 benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3 benzodioxoyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4 15 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
62. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier.
63. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of the compound of Claim 21 and a pharmaceutically acceptable carrier. 5
64. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)- WO 99/06397 PCT/US98/15479 -801 4-(7-methoxy-1, 3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier. 10
65. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -( 2 -(N-propyl-N-pentanesulfonyl)ethyl) pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier.
66. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 5
67. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21. 5
68. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-y)-1 (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid. 0
69. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2 (N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
70. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, WO 99/06397 PCT/US98/15479 -802 pulmonary hypertension, migraine, cerebral or myocardial ischemia or 5 atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
71. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, 5 IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
72. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a 5 therapeutically effective amount of a compound of Claim 21.
73. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial 10 ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4 (7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl) pyrrolidine-3-carboxylic acid. 15
74. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, WO 99/06397 PCT/US98/15479 -803 pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4 20 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-pentanesulfonyl)ethyl) pyrrolidine-3-carboxylic acid.
75. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative 5 diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21. 10
76. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, 15 IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of ( 2 S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy 1,3-benzodioxol-5-y)-1-(N,N-di(n-butyl)aminocarbonymethyl)-pyrrolidine-3-carboxylic 20 acid.
77. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative WO 99/06397 PCT/US98/15479 -804 25 diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1,3 30 benzodioxol-5-yl)-1 -( 2 -(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid.
78. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a 5 therapeutically effective amount of a compound of Claim 1 in combination with one or more cardiovascular agents.
79. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents. 5
80. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl) 10 1-(N,N-di(n-butyl)aminocarbonymethyl)-pyrrolidine-3-carboxylic acid in combination with one or more cardiovascular agents. WO 99/06397 PCT/US98/15479 -805
81. A process for the preparation of a compound of the formula: R2 R1 CO 2 E 5 wherein E is a carboxy-protecting group and R 1 and R 2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyakyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 0 aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: 0 2 N 0 R2 )--i R1 5 CO 2 E wherein E, R, and R 2 are defined as above and b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids.
82. The process of Claim 71 wherein E is loweralkyl, R, is aryl and R 2 is heterocyclic.
83. The process of Claim 71 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid. WO 99/06397 PCT/US98/15479 -806
84. The process of Claim 71 wherein E is loweralkyl, R 1 is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl.
85. A process for the preparation of a compound of the formula: R2 R1 CO 2 E 5 wherein E is a carboxy-protecting group and R1 and R 2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, 10 arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: 0 2 N 0 R2 )--i R1 15 C0 2 E wherein E, R 1 and R 2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, and 20 c) epimerization of the product of step b) with a base. WO 99/06397 PCT/US98/15479 -807
86. The process of Claim 75 wherein E is loweralkyl, R 1 is aryl and R 2 is heterocyclic.
87. The process of Claim 75 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
88. The process of Claim 75 wherein E is loweralkyl, R 1 is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl.
89. A process for the preparation of a compound of the formula: R 3 R2M-C R1 CO 2 E 5 wherein E is a carboxy-protecting group, R 1 and R 2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, 10 arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R 11 )(R 1 2 )N- wherein R 11 and R1 2 are independently selected from (1) loweralkyl, 15 (2) haloalkyl, (3) alkoxyalkyl, (4) haloalkoxyalkyl, WO 99/06397 PCT/US98/15479 -808 (5) alkenyl, (6) alkynyl, 20 (7) cycloalkyl, (8) cycloalkylalkyl, (9) aryl, (10) heterocyclic, (1) arylalkyl and 25 (12) (heterocyclic)alkyl; (13) hydroxyalkyl, (14) alkoxy, (15) aminoalkyl, and (16) trialkylaminoalkyl, 30 or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: 0 2 N 0 R2 R1-T CO 2 E 35 wherein E, R, and R 2 are defined as above, b) catalytic hydrogenation of the product of step a) in the presence of an acid or a mixture of acids, c) epimerization of the product of step b) with a base and d) alkyation of the product of step c) with a compound of the formula R 3 -X wherein X 40 is a leaving group and R 3 is defined as above.
90. The process of Claim 79 wherein E is loweralkyl, R, is aryl, R 2 is heterocyclic and R 3 is -CH 2 C(O)NR 11 R 12 wherein R 11 and R 12 are independently selected from the group consisting of loweralkyl. WO 99/06397 PCT/US98/15479 -809
91. The process of Claim 79 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
92. The process of Claim 79 wherein E is loweralkyl, R 1 is 4-methoxyphenyl, R 2 is 1,3-benzodioxol-5-yl, R 3 is -CH 2 C(O)N(n-Bu) 2 and X is a halogen or sulfonate leaving group.
93. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula: R2 M-R1 CO 2 E wherein E is loweralkyl, R 1 is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl, or a salt thereof, comprising reacting a mixture of the (+) and (-) enantiomers of the compound of the formula: R2 R1 CO 2 E wherein E is loweralkyl, R, is 4-methoxyphenyl and R 2 is 1,3-benzodioxol-5-yl with S-(+)- mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer. WO 99/06397 PCT/US98/15479 -810
94. A compound of the formula: R2 Z R3 (CH 2 )n R wherein Z is -C(R 18 )(R 19 )- or -C(O)- wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is (a) -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 , (c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(O)NHR 17 wherein R 17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (1) -C(O)NHS(0) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, (M) -S(0) 2 NHC(O)R 1 6 wherein R 16 is defined as above, WO 99/06397 PCT/US98/15479 -811 HO H (n) (o) HO 0 OH N 0 NH 0 0 (q) ~0 N O /S=O JJ)~~CF3 N (s) H or (u) NHSO 2 CF 3 R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, WO 99/06397 PCT/US98/15479 -812 haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rec- wherein Raa is aryl or arylalkyl, Rbb is h ydrogen or alkanoyl and Roc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; R 3 is (a)R 4 -C(O)-R 5 -, R 4 -C(O)-R 5 - N(R 6 )-, wherein R 5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 - or -R 8 a-N(R 20 )-R 8 wherein R 8 and R 8 a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or (v) -O-R 9 - or -R 9 a-O R 9 - wherein R 9 and R9a are independently selected from alkylene; R 4 and R 6 are (R 11 )(R 1 2 )N- wherein R 1 1 and R 12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, WO 99/06397 PCTIUS98/15479 -813 (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl, (19) dialkylaminoalkyl, (20) carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic)aminoalkyl, and (24) (heterocyclic)aminoalkyl, with the proviso that at least one of Rjj and R 12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic)aminoalkyl, and (heterocyclic)alkylaminoalkyl; or a pharmaceutically acceptable salt thereof. WO 99/06397 PCT/US98/15479 -814
95. A compound selected from the group consisting of: OCH 3 OCH 3 OCH 3 R.N.N R. N R .. N -COOH .. N COOH R . COOH - 0 - 0 1 0 2 0 3 O , OCH 3 R. R. R N .coHN N N ..- COOH ""..COOH ---.. COOH -~0 ci CC 4 C , 5 CH 3 0 0 , 6 O , RN R.N R N R COOH R .N.-COOH .N.--COOH 0 O CH30 0 - 0 10 0HO 11 0- 12 0 WO 99/06397 PCTIUS98/15479 -815 ....COOH *N ....COOH *N .CO 0 -.. ci C- C 13 014 ci 15 0 3 R. R.R ... COH N ... CR N ... COOH - 0 - 0 16 0-1 17 0 18 0j N 0 -N0N 19. CC 20. CHO 92 NN N1 N N N R. N. COOH N . ROO COOH - 0 0 '0 25 0l 26 0 27 0 WO 99/06397 PCT/US98/15479 -816 OCH 3 R. R. R. N ""COO 'N NzN N N- N "COOH<\\ N'NH N'NH -.C 28 C , 29 O , 30 CH 3 O 30~ R.N NN R.N NaN N'NH NNH ~- 0 - 0 31 CH 3 0 O and 32 0- , wherein R is selected from the group consisting of: H3CNH ,_N Y--H3CNH _ N H3CNH N 1 0 2 0 3 0 H 3 CNH, N NN H 4 0 , 5 0 6 0 , H 4 0 8 0 , H H N N-N N 7 0 , 8 8 , 9 0 , H H N,_ N,,N N, N H H N AN NN 13 0 , 14 0 , 0 H H 16 N0, N N/ N 0 16 0 ,17 0 18 0 WO 99/06397 PCTIUS98/15479 -817 H N N NN 19 H, 20 0 , 21 0 H H 22 0, 23 H , 24 ' H 2 N NH2 NHN N 25 0 , 26 0 , 27 0 H2N _,,,,_N (H3C)2N _N (H3C)2N,, ,N 28 0, 29 0 , 30 0 + 0 (H3C)2N N (Hl3C)2N_-_,-_ N (CH3)3 N_, 31 0 , 32 0 33 0 + 0 0 (CHN N (CH3)3 N (H)3 34 35 , 36 N N NN 0 37 38 , 39 N N 0 40 41 42 0 0 0 -- 0 N N N N N NK 43 44 , 45 N N N Nr 460 , 47 , 480 HN 0 0 HN 0 N,- NAC lN '-NkN N 49 50HN_ 51 0 CH 3 N 0 0 52 HN,, 53 54 CH 3 N WO 99/06397 PCT/US98/15479 -818 CH 3 N 0 0 0 LN HNNN 55 , 5 6 CH 3 N,) 57 H) 58 H 59 60 H NH O NN 61 62 H O ,and 64 H
96. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia, atherosclerosis, coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising a therapeutically effective amount of a compound of claim 94, wherein said compound has an attached charged functionality which reduces the degree of plasma protein binding of the compound.
97. A method of improving the in vivo activity of compounds by reducing the amount of compound bound to protein by attaching a charged functionality to the compound. WO 99/06397 PCT/US98/15479 -819
98. A method of claim 97 wherein the charged functionality carries a positive charge at physiological pH.
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