AU2984101A - Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists - Google Patents

Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists Download PDF

Info

Publication number
AU2984101A
AU2984101A AU29841/01A AU2984101A AU2984101A AU 2984101 A AU2984101 A AU 2984101A AU 29841/01 A AU29841/01 A AU 29841/01A AU 2984101 A AU2984101 A AU 2984101A AU 2984101 A AU2984101 A AU 2984101A
Authority
AU
Australia
Prior art keywords
trans
loweralkyl
aryl
alkylene
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
AU29841/01A
Other versions
AU781355B2 (en
Inventor
Steven A. Boyd
Kenneth J. Henry Jr.
Charles W Hutchins
Hwan-Soo Jae
Jeffrey A. Kester
Steven A. King
Gang Liu
Bryan K Sorensen
Bruce G. Szczepankiewicz
Andrew Tasker
Thomas W. Von Geldern
Martin Winn
Steven J. Wittenberger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU22620/97A external-priority patent/AU2262097A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to AU29841/01A priority Critical patent/AU781355B2/en
Publication of AU2984101A publication Critical patent/AU2984101A/en
Application granted granted Critical
Publication of AU781355B2 publication Critical patent/AU781355B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Description

S&F Ref: 425370D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
9 0 o 0 :.1 o o.
e. 5* l o
S.
Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 United States of America Martin Winn, Steven A. Boyd, Charles W. Hutchins, Hwan-Soo Jae, Andrew Tasker, Thomas W. von Geldern, Jeffrey A. Kester, Bryan K. Sorensen, Bruce G.
Szczepankiewicz, Kenneth J. Henry Jr., Gang Liu, Steven J. Wittenberger and Steven A. King Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 Novel Benzo-1,3-dioxolyl- and Benzofuranyl Substituted Pyrrolidine Derivatives as Endothelin Antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c NOVEL BENZO-1.3-DIOXOLYL- AND BENZOFURANYL SUBSTITUTED
PYRROLIDINE
DERIVATIVES AS ENDOTHELIN ANTAGONISTS 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 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 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 in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release 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 (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
I
-2binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 8I 1762 (1989)).
In addition, an anti-endothelin antibody attenuated the nephrotoxic 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- 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 after SAH has also been recently reported (S.ltoh, 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 i": ET/ET receptor binding will provide therapeutic benefit in the indicated disease states. 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, 309, 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 demonstrated that a similar agent prevents ischemia-repurfusion 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).
Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate 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 -3proteins, 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.
Disclosure of the Invention In accordance with the present invention there are compounds of the formula R2 Z N0 R 3
(CH
2 n
R
R (I) wherein Z is -C(R8i)(R 19 or wherein R 18 and R 1 9 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 -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3
H
2 -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(0)NHR17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0)2R 1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, -S(0) 2 NHC(0)Ri6 wherein R 16 is defined as above, -4- HO 0 0 o)HO 0
OH
(q)0 0 AI-
N
H jC~>-CF3 (M2 H ,or -k-a NHS 2 CF 3
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-alkanoyi-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and
R
2 is other than hydrogen;
R
3 is R 4
-C(O)-R
5 R-Rsa- R 6
-S(O)
2
-R
7 or
R
26
-S(O)-R
27 wherein R5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 2 o)-R 8 or RaN20R8 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 -O-R 9 or -Rga-O-R9- wherein R9 and Rga are independently selected from alkylene; R~a is alkylene or (ii) alkenylene;
R
7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-Rio- or -RlOa-N(R2+)R1o- wherein R 10 and O1a are independently selected from the group
V
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 (Rll)(Rl2)N- wherein R 11 and R 12 are independently selected from hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic, -6- (12) aryl (13) (het (14) hydr alko (16) amin (17) trial~ alkyl, erocyclic)alkyl, oxyalkyl, xy, oalkyl, and kylaminoalkyl, (i i) loweralkyl, (iii) alkenyl, (i v) alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xv i) haloalkoxy, (xv ii) alkoxyhaloalkyl, (Xviii) alkylamninoalkyl, (xix) dialkylamninoalkyl, (xx) alkoxy, and
H
(Xxi) 0 wherein z is 0-5 and R7a is alkylene;
R
2 6 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, alkynyl, -7- (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxysubstituted haloalkyl; and
R
2 7 is alkylene or alkenylene;
R
2 2
-O-C(O)-R
2 3 wherein R 22 is a carboxy protecting group or heterocyclic and R 2 3 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 4
)-R
2 5 wherein R 2 5 is alkylene and R 24 is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, o r Ri 3 -C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R15-C(O)- wherein R 15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formuil
R
2 z. R 3
N
(CH
2 )n 1i (11) -8wherein the substituents -R 2 -R and -R1 exist in a trans,trans relationship and Z, n, R, R1, R 2 and R 3 are as defined above.
Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0 and Z is -CH 2 Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 1 and Z is -CH2-.
0o Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-R 5 Re-S(0) 2
-R
7 or R 2 6-S(O)-R 2 7 wherein R 4
R
5
R
6
R
7
R
2 6 and R 2 7 are as defined above.
I
Another preferred embodiment of the invention is a compound of formula or (II) 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 i** formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R 4 -C(O)-Rswherein R 4 is (R11)(R 1 2 as defined above and Rs is alkylene or R 3 is 2
-R
7 or R 2 6-S(O)-R 2 7 wherein R7 is alkylene, R 2 7 is alkylene and R 6 and R 26 are defined as above. Another more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-N(R 2 0 or R6-S(0) 2
-N(R
2 1)-Rio- wherein R8 and Rio are alkylene and R 4
R
6
R
2 0 and R 2 1 are defined as above.
so An even more preferred embodiment of the invention is a compound of formula or (II) 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(0) 2
R
1 6 wherein R 1 6 is loweralkyl, haloalkyl or aryl, Z is
-CH
2 Ri and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (iii) substituted 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, alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R 3 is R 4 wherein R 4 is (Rll)(Rl 2 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 R 4
-C(O)-N(R
20
)-R
8 or
R
6
-S(O)
2
-N(R
2 1)-Rl 0 wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalk oxyalkyl, aryl or arylalkyl, R 8 and Rjo are alkylene and R 20 and R 2 1 are loweralkyl; or R 3 is R6-S(O) 2
-R
7 or R2 6
-S(O)-R
2 7 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 2 6 is-loweralkyl and R 2 7 is alkylene.
A yet more preferred embodiment of the invention is a compound 99 of formula 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(O) 2 Rl 6 wherein
R
16 is loweralkyl, haloalkyl or aryl, Z is -OH 2
R
1 is loweralkyl, (ii) alkenyl, 9.
(iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluoropoenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-Nalkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl,
R
2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxoiyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R 4
-C(O)-N(R
2 o)-R 8 or R6-S(O) 2
-N(R
2 1 )-Rto- wherein R8 and Rio are alkylene, R 20 and R21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2
R
1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, 06 (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethyiphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-f luoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-Nalkyl)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, dihyd robenzofuranyt, benzofurnayl, W 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difiuo rophenyl and
R
3 is R 4 -C(0)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2
)N-
wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2
R
1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) aryl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, o r (viii) alkylsulfonylamidoalkyl,
R
2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3-benzodi oxolyl, 1,4benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or 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 j)(Rl 2 wherein R 1 1 is loweralkyl and R 12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylam inoalkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0 2
R
1 6 wherein R 1 is loweralkyl, haloalkyl or aryl, Z is -OH 2 R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3flIuorophenyl,* 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 1,3benzodioxolyl,* 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 )-RiO- wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2
R
16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2
R
1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, -12- 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl or 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofu ranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R 6
-S(O)
2
-N(R
2 1 )-Rlo- wherein R1o is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 2 1 is p loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or
NHS(O)
2
R
1 wherein R 1 is loweralkyl or haloalkyl, Z is -OH 2
R
1 is loweralkyl,alkenyl, heterocyclic (ailkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl,, or alkylsulfonylamidoalkyl, and R 3 is-
R
4 wherein IRS is alkylene and R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylami noalkyl, and heterocyclic.
A still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(G)-NHS(O) 2
R
16 whereini
R
1 6 is loweralkyl or haloalkyl, Z is -OH 2
R
1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hyd roxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 1 ,4-benzodi oxanyl or di hyd robenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (Hi) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), aryloxyalkyl, -13- (vi) arylalkyl, (vii) (N-alkanoyi-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, di hyd robe nzof uranyl, benzofuranyl, 4methoxyph enyl, dimnethoxyphenyl, fluorophenyl or difluo rophenyl and R 3 is R 4 wherein IRS is alkylene and R1 4 is (Rii)(Ri 2 wherein
R
11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2
R
16 wherein R 16 is loweralkyl or haloalkyl, Z is -CH 2
R
1 is loweralkyl, alkenyl, heterocyclic (alkyt), aryloxyalkyl, arylalkyl, (Np alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R 4 wherein R 5 is alkylene and Rl 4 is (Rii)(Ri2)Nwherein Rl 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylaminoal kyl, or heterocyclic. A most highly preferred embodiment of the invention is a* compound of formula 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, is substituted or unsubstituted P 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 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, 4methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(0)-R 5 wherein R 5 is alkylene and R4 is (Rii)(Ri 2 wherein
RA
11 and R, 2 are independently selected f rom loweralkyl.
-14- Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2
R
1 is substituted or unsubstituted 4-methoxyphenyl, 4-f luorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4 -pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3benzodioxolyl, 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, 4methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluo rophenyl and R 3 is R4-C(O)-R 5 wherein R5 is alkylene and Rl 4 is (Rll)(Rl 2 wherein
R
11 is loweralkyl and R 12 is aryl. Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2
R
1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3fluorophenyl, 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 substituted or unsubstituted 1,3- benzodioxolyi, 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 l)-Rlo- wherein R1o is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and Rl 21 is loweralkyl, haloalkyl or alkoxyalkyl.
Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is CH 2
R
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 dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy,
R
2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3s 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 R4-C(O)-R 5 wherein R5 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, and heterocyclic.
Another most highly preferred embodiment of the invention is a compound of formula 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, (Nalkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R1)(R 12 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. Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R 2 as defined therein and Rs is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is loweralkyl, and R 3 is R 4
-C(O)-R
5 wherein R 4 is (R11)(R 2 as defined therein and R 5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkenyl, and R 3 is R 4 wherein R 4 is (Rl1)(R 1 2 as defined therein and
R
5 is alkylene.
16- Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is heterocyclic (alkyl), and R 3 is R 4 wherein R 4 is (R 1 1
)(R
12
)N-
as defined therein and R 5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryloxyalkyl, and R 3 is R 4 wherein R 4 is (R11)(R 1 2 as defined therein and R 5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is S arylalkyl, and R 3 is R 4 wherein R 4 is (R1)(R 1 2 as defined therein and Rs is alkylene. Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryl, and R 3 is R 4 wherein R 4 is (R11)(R 1 2 as defined therein and Rs is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkanoyl-N-alkyl)aminoalkyl, and R 3 is R 4
-C(O)-R
5 wherein R4 is (Rll)(R12)N- as defined therein and Rs is alkylene. 925 2 Another most highly preferred embodiment of the invention is a compound of formula 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 (R11)(R 1 2 as defined therein and R 5 is alkylene.
The present invention also relates to processes for preparing the compounds of formula and (II) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such -17treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula or (II).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula or (II).
The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.:.:*.
The terms and configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 is The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C1 to C 8 alkyl methyl, ethyl or tertiary butyl and the -18like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylm ethyl 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, indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryl oxymnethyl, vale ryloxymethyl, isobuty ryloxym ethyl, isovaleryloxymethyl, 1- (propionyloxy)-1 -ethyl, 1 -(pivaloyloxyl)-1 -ethyl, 1-methyl-i- (propionyloxy)-1 -ethyl, pival oyloxy methyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylIcarbo nyl oxym ethyl, cycl oh exyl ca rbonyl oxym ethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyi, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as m ethoxycarbo nyl methyl, cyclohexyloxycarbonylmethyl, 1methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as V. 1.
methoxycarbonyloxymethyl, t-b utylIo xycarbo nyloxymnethyl, 1- eth oxyca rbo nyloxy- 1 -ethyl, 1-cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoal kyl, such as t-butyl oxycarbonylami nomethyl and the like; alkylaminocarbonylaminoalkyl, such as ~methylam inocarbonylami nom ethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyal kyl, such as 4-methylpiperazinylcarbonyloxymethyI and the like; dialkylami nocarbonylalkyl, such as di methylaminocarbonyl methyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo- 1,3-dioxolen-4yl)m ethyl and the like; and (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as (5-ph enyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
The term uN-.protecting group" or nN-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting -19groups are disclosed in Greene, "Protective Groups In Organic Synthesis,m (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chioroacetyl, 2-bromoacetyl, trifluoroacetyl, trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, cz-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-n it robe nzyl oxyca rbo nyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-rnethoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methylethoxycarbonyl, c,a-dimethyl-3 ,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, d ii sop ropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adam antyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, 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 "alkanoylu as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include acetyl, propionyl and the like.
The term 'alkanoylaminow as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to
R
4 3
-NH-R
4 4 wherein R 4 3 is an alkanoyl group and R 4 4 is an alkylene group.
The term "alkanoyloxyalkyl" as used herein refers to R 3 0
-O-R
3 1 wherein R 3 0 is an alkanoyl group and R31 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 include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1methyl-2-buten-l-yl and the like. 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
2
CH=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 linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. The term "alkoxy" as used herein refers to R410- wherein R 4 1 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 RsoO-R810- 025 wherein R 80 is loweralkyl as defined above and R 81 is alkylene.
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 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.
The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety -21through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylalkenyr" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl s radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term ualkoxycarbonylalkylo as used herein refers to R34-C(O)-R 35 wherein R 34 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
The term "alkoxycarbonylaminoalkyl" as used herein refers to R3 8
-C(O)-NH-R
39 wherein R 3 8 is an alkoxy group and R 39 is an alkylene group.
The term ualkoxycarbonyloxyalkyl" as used herein refers to R3 6
-C(O)-O-R
3 7 wherein R 36 is an alkoxy group and R 3 7 is an alkylene group.
The term "(alkoxycarbonyl)thioalkoxyu as used herein refers to alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include 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 including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term u(N-alkanoyl-N-alkyl)aminoalkyl" as used herein refers to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
The term malkylamino" as used herein refers to R51NH- wherein
R
5 1 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
-22- The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, 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 loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylaminoalkyl" as used herein refers to
R
4 0-C(0)-NH-R 4 1 wherein R 4 0 is an alkylamino group and R 4 1 is an alkylene group.. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to carbon atoms by the removal of two hydrogen atoms, for example -CH2-,
-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(0)2NHR89- wherein R88 is loweralkyl and R89 is alkylene. The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino 2 group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like. 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 H-C-C-CH 2
H-C=C-CH(CH
3 and the like.
The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C-C-CH 2
-C-C-CH(CH
3 and the like.
The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
The term "aminocarbonyl" as used herein refers to H 2 N-C(0)- -23- The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl
(NH
2 group.
The term 'aminocarbonylalkoxy" as used herein refers to
H
2 appended to an alkoxy group as previously defined. Examples s of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term maminocarbonylalkylu as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl
(NH
2 group.
The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.
The term "aroyloxyalkyl" as used herein refers to R32-C(0)-O-R 3 3 wherein R 32 is an aryl group and R 3 3 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 -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, 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 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 Oarylalkoxy" as used herein refers to R 4 2 0- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.
-24- 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 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 4 5 is an aryl group, for example, phenoxy, and the like.
The term "arylalkylcarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group
R
6 2 C(0)O- wherein R 6 2 is an arylalkyl group).
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 radical, -C(O)H.
The term "carboxy" as used herein refers to a carboxylic acid radical, The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3- carboxy-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, carboxyethoxy and the like.
The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano group.
Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group
R
6 0 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 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 carboxamide.
The term "cycloalkylalkyl m 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 Rs 6
R
5 7
N-
wherein R 5 6 and R 57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
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 molecular moiety through a carbonyl 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.
The term "dialkylaminocarbonylalkyl" as used herein refers to 5 i- wherein Rso is a dialkylamino group and R51 is an alkylene group. The term "halo" or "halogen" as used herein refers to I, Br, CI or F.
The term "haloalkenyl" as used herein refers to an alkenyl radical 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.
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 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 -26heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7membered ring containing one, two or three nitrogen atoms; one oxygen 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 nitrogen heteroatoms can be optionally quatemrnized. 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 another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
/Y
Heterocyclics also include compounds of the formula where X* is -CH 2 or and Y* is or where Ru is hydrogen or C1-C 4 -alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, -27alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen 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 4pyridylmethoxy, 2-pyridylmethoxy and the like.
The term '(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term "heterocycliccarbonyloxyalkyl" as used herein refers to
R
4 6-C(O)-O-R 4 7 wherein R 4 6 is a heterocyclic group and R 4 7 is an alkylene group.
The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkenyl" as used herein refers to an alkenyl is 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 group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4- hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group. The term "leaving group" as used herein refers to a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like). The term "mercapto" as used herein refers to -SH.
L The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the IUIIILIIIVI~ ~r~V~uu~I auca. tnleedox lonnation ofU a enzodioxoiyi radical.
thylrenedioxy -28substituted on a phenyl ring results in the formation of a benzodioxanyl radical 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 or a tautomer thereof. 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. The term "thioalkoxy" as used herein refers to R 7 0 S- wherein R 7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. i"" The term "thioalkoxyalkoxy" as used herein refers to Ro8S-R 8 1 0wherein R 8 0 is loweralkyl as defined above and R 8 1 is alkylene. Representative examples of alkoxyalkoxy groups include CH 3 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
OCH
2
CH
2
CH
3 SCH20CH 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 Z.N R 3
N
C H 2 n
R
1 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 -29- R3~ R, or hl .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.
The term "cis,cis M as used herein refers to the orientation of substituents (Rj and R 2 relative to the central substituent R as shown
R
21 N% R 1 :0 Preferred compounds of the invention are selected from the group consisting of: trans -tra ns- 2 e th o xp he nyl1) -4 3 -b enzo d io xo I- 5 -y1) -1 3-(N p ropy I- N- n -p en ta ne s ulIfon y Ia m ino) p ro p yJp yrroIi din e -3 carboxylic acid; trans, trans-2-(4-Methoxymeth oxyph enyl)-4- (1 ,3-benzodi oxol-5-yl)--: (2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine.3- 1 5 carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol -5-yl)-1 (N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-( 1,3-benzodioxol-5-yl)- 1 (N-pro pyl -N-n-h exa n es u fo nylImin o )ethyl] py rro lid ine- 3carboxylic acid; trans,trans-2-( 4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 propyl-N-n-pentanesufonylamino)ethyl]pyrrolidine.3-carboxylic acid; trans, trans-2-(3,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 dibutylamino)carbonyl)methyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Dif luorophenyl)-4- (1 ,3-benzodioxol.5-yl)- 1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine.3carboxylic acid; trans, trans-2-(3-Fluo ro-4-meth oxyphenyl)-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 l-(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluo ro-4-methoxyphenyl)-4-(1 1 N-isobutyl-N-(3chloropropanesufony)amino)ethy)pyrroidine-3.carboxylic acid; trans, trans-2-(3-Fluo ro-4-methoxyphenyl)-4-( 1 I -[2-(N-propyl-N-(4- m ethyl butanesulf ony) am ino) ethy] py rro i dine- 3carboxyli c acid; *trans, trans-2-(4-Methoxy-3-fluoropheny)-4-(7-methoxy- 1,3 be nz o d io x o1-5-y1) 1 [2 ro pylI- N pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4- (1 1 2 -(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfony).
amino)ethyl~pyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,4-Benzodi oxan-6-yI)-4-(7-m ethoxy-1, ,3-be nzo di oxol- 5-yI)-1-[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;: trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 l-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino).
ethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-((2,2,2-trifluoroethoxyeth-ane)suifonyl)amino).
ethyl] pyrrolidi ne-3-carboxyl ic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl).4-(1 1 -(2-(N-(2-methoxyethyl)-N-(butanesulf onylami no) ethyl)pyrrolidine-3-carboxylic acid; -31trans, trans-2-(3-Fluoro-4-m ethoxyp hen yl)-4( 1,3-benzodioxol-5yI)-1 -[2-(N-propyl-N-(2methylpropanesufonyl)amino)ethyl]pyrrolidine.3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.( 1 1 2 -(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine- 3 carboxylic acid; trans, trans-2-(2- Methyl pentyl)-4- benzod ioxo 1-5-yi)- 1 dibutylaminocarbonylmeth-yi)-pyrrolidine.3carboxyi~c acid; trans, trans-2-(2,2-DimethylpentyI)-4-(1 ,3-benzodioxol-5-yi)-1 dibutylaminocarbonylmethyI)-pyrrolidine-3carboxylic acid; trans, trans-2-(2.(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxoI-5-yI)- 1 (NN-dibutylaminocarbonylmethy)-pyrrolidine..3-carboxylic acid; trans, trans-2-(2-(2-Tetrahyd ro-2 H-pyran)ethyl)-4-(1 ,3-benzodioxol- 1 N-d ib utyl am inocarbonyl methyl)-pyrro lid ine-3.
carboxylic acid;: trans, trans-2-(2,2,4-Trimethyl-3-pentenyI).4-(1 1 N-dibutylaminocarbonylmethyI)-pyrrolidine.3-carboxylic acid; beriz o d ioxo1- 5- y1) 1 ,N -d ibutyIa m ino c arb ony Im et h y pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (1 ,3-Di oxo-2-y I)ethyl) (1 7 3-benzodioxol- 5-yI)- 1 [[N-4-heptyl-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl]pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-DioxoI-2-yI)ethyI)-4-(7-methoxy.1 ,3- 01benzodioxol-5-yI)- 1-(N,N-dibutylaminocarbonylmethyl).
pyrrolidine-3-carboxylic acid; trans, trans-2-((2- Methoxyphe no xy)- methyl)-4(1 ,3-benzodioxol1-5-yI)- 1 N-dibutylaminocarbonylmeth-yl)-pyrrolidine.3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 h eptyl- N-(4-flIuo ro-3-m ethyl phe nyl) )am i nocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1I -yI)ethyi)-4-( 1,3-benzodioxol-5yI)- 1 N-dibutylaminocarbonylmethyl)-pyrrolidine.3.carboxylic acid; -32trans, trans-2-(2-( 1 3-Dioxo-2-y)ethyI)-4-(7-methoxy-l ,3benzodioxo I-5-yI)- 1 -(N-4-heptyl-N-(4-f Iuoro-3methylphenyl))aminocarbonylmethyl) -py rrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7- met hoxy-1, ,3-benzodioxol1-5yI)-l1 N-dibutyl am inocarbonylmethyl) -pyrrolIidine-3-carboxylic acid; trans, trans-2-(2,2-dimethy IpentyI)-4-(2,3-dihydro-benzof 1 N-dibutylam inocarbonyl meth yI)-pyrro lid ine-3-carboxyli c acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; .0 *0 trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 d ibuty I amin o c arb onyImeth y1) -p y rro I id n e -3 -ca r boxy I ic acid; trans, trans-2 -D imethyl-3- pent enyl)-4-(7- meth oxy 1, ,3- 1 N-d ibutylam inocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-( 1,3-benzodioxol-5-yI)- 1 N- dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;: (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol-5- y1) -1 N -d ib ut yam in o ca rb on yIm e thy1) -p y rroIi d in e -3 -ca r boxy Ii c acid; (2S, SR, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-( 1,3-benzodioxol-5yl)-1 -(N-4-heptyl-N-(4-fluoro-3m ethylp he nyl)) )ami nocarbo nylm ethyl) -py rrol idi ne-3- carboxylic acid; trans, trans-2- 1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 Ndibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 butyl-N-(4-dimethylaminobutyt)amino)carbonylmethyl)pyrrolidine-3-carboxylic acid; (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI) 1- (2-(N-propyl- N-pentan esulf onyla m ino) ethyl) -pyrro lidine-3carboxylic acid; -33trans, trans-2-(2,2-Dimethylpentyl)4-(1 3-benzodioxoI-5-yl)- 1 butyl-N-(4-d imethylami no)butyl) ami nocarbonylmethyl).
pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyi)-4- (7.methoxy. 1 ,3-benzodi yI)-l1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)..pyrrolidine.3-carboxylic acid; trans, trans-2- D imethyl penty)-4- (7-met hoxy 1, ,3-benz od ioxot yI)-l -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine- 3 carboxylic acid; trans, trans-2 -Di methyl pe nt- 3-enyl)-.4 1 3-benz odi oxol
(N-
4 -heptyI.N-(4-fluoro-3-methylphenyI))aminocarbonylmethyI)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethypent3-eny).4.( 1 ,3-benzodioxoI-5-yi)- 1 ((N-butyl-N-(4 dimethylam ino) butyl)amin ocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Di methyl pent- 3-eny).4 (7-met hoxy. 1, 3be nz o d ioxoI- 5 -yI1) -1 N- d ib u ty 1) am ino c arb on ylIm e thy1) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2- Di methypent- 3eny)4-(7-methoxy. 1, 3be nz od io xolI- 5 -y1) 1 (N -4 -h ep t yI- N -flIuo ro -3 m eth y Iphe ny am ino c arbo ny m et hy )p y rroIi d in e-3-c a rb oxy Ii c acid; trans, trans-2 Di methyl pent-3-e nyI)..4(7-methoxy 1, 13b en zod io xolI- 5 -yI1)- 1 bu ty I- N d ime t hyIa m in o) bu ty1) am i n o ca rbon y Im e thy1) -py r r olIi d in e -3 carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-.3enyl)..4-(1 1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl).pyrrolidine-3.carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; -34trans, trans-2-(2,2,4-Trimethypent-3-eny)-4-(7-methoxy- 1 ,3benzodioxol-5-yl)-1 ,N-dibutyI)aminocarbonylmethyl).
yrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4 -Trim ethy pent- 3eny)4 (7-met hoxy.1, 3benzodioxol-5-yI)- 1-(N-4-heptyl-N-(4-fluoro-3methylphenyI))aminocarbonylmethy)-pyrrolidine.3.carboxylic acid; trns tas2(,,-rmtypn--nl4-7mto- ,3benzodioxol-5-yI)-l1-((N-butyl-N-(4dim ethylam ino) buty)am inocarbonyl methy)-pyrroi di ne.3 carboxylic acid; trans, trans-2 DioxoI-2-yI) ethyl) (1 9 3-benzodi oxol -5-yI) -1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonygmethyi]- o pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yi)-l1-[( N-butyl-N-(4- dimethylam inobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans,'trans-2- -D im ethy1-2 D ioxol -2-y1) ethyl) ,3benzodioxol-5-yI)-1-(N-4-heptyl-N-(4-fluoro-3-:~ m et hy Ip he ny am in oc a rbo ny Im et hy 1) -py rro Ii d ine -3 c arb oxy Ii c: acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxoian-2-yI)ethyl)-4-(1 ,3benzodioxol-5-yI)-l1-[( N-butyl-N-(4dimethylaminobutyI)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2- (1 ,3-Dioxol-2-yI)ethyl) 4-(7methoxy-1 ,3-benzodioxol-5-yi)-1 -(N-4-heptyl-N-(4-fluoro-3m ethyliphenyl) )am i nocarbonyl methy)-py rroli di ne-3-carboxy ic acid; trans, trans-2-(2,2-Dimethyl-2-( 1,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxo-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(2-Meth oxyphenyl)-ethyl)-4-( 1 1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine.3.carboxylic acid; trans, trans-2-(2-(2-Methoxypheny)-ethyl>4.( 1 1 -[(N-butyl-N-( 4 -dimethylaminobutyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid; trans, trans-2 Methoxyphe nyl)-ethy1)-4(7-met h oxy. 1, 3benzodioxol-5-yI)-l1-[((N, N-dibutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)ethyl) 4(7methoxy-1,3b e nz od i ox oI- 5 -y1) 1 N -4 he pt ylI-N -f I uco ro -3 m methyl ph enyl)) amino) carbonyl methyl..pyrro lid in e.3carboxy i c acid; trans, trans-2 (2-M ethoxyp henyl) -ethyl) 4(7-m ethcxy 1, ,3benzodioxol-5-yi)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonyl methyl]-pyrrolidine-3-* carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl).4.( 1 1-(N-4-heptyl-N-(4-fluoro-3.
methylphenyl)) amino) carbonyl methyl]-pyrrol idi n4..3.carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl).4-(1 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)4(7.methoxy- 1 ,3- 1 N-dibutyl)amino)carbonylmethyl..
pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methy).4(7.methoxy- 1 ,3benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino) carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenoxy)-methy)4(7methoxy- 1,3benzodioxol-5-yI)-l1-[(N-b utyl-N-(4dimethylaminobutyl)amino)carbonyl methyl]-pyrrolidine-3carboxylic acid; -36trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-1 -yI)-ethyl)-4-(1 ,3benzodioxol-5-yi)-l1-[(( N, N-dibutyl)amino)carbonymethyl].
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrid in-i -yI)-ethyl)-4-( 1,3-benzodioxol-5yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrroidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrid in-i -yI)-ethyl)-4-( 1,3-benzodioxol-5yI)-l -[(N-butyl-N-( 4 -dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin- 1 -yI)-ethyl)-4-(7-methoxy- 1,3benzodioxoi-5-yI)-1 -[((N,N-dibutyl)amino)carbonylmethyl].
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3b e nz od io xo I- 5 1 -4 -h e p t yI-N -fIu o ro -3 methylphenyl) amino) carbonyl methyl]-py rroli dine..a.carboxyli c acid; trans, trans-2 -(2-(2-Oxopyri din- 1 -yI)-ethyl)-4-(7-meth oxy- 1,3benzodioxol-5-yi)-1 -[(N-butyl-N-(4dim ethylaminob utyl)am in o) carbonyl methyll-pyrrol idi ne-3- carboxylic acid; trans, trans-2-(2(-2-Oxopiperidin- 1 -yI) -ethyl) (1 benzod ioxo N-dibutyI)amino)carbonylmethy]-pyrrolidine.3carboxylic acid; trans, trans-2-(2- (2Oxopipe ri din- 1 -yI)-ethyl) (1 ,3-benzodi y I) -1 (N -4 -h ep ty I- N -fIu o ro -3 m eth yI ph e nyI1) am ino)c ar bo n y Imet hy I p y rro I idmin e c arb xy Ii c acid; trans, trans-2 Oxop ipe ridi n- 1 -y I)-ethyl) -4-(7-methoxy-1, ,3be n zod io xol1- 5-yI1) -1 N -d ib u ty1) am in o) c arbon y Im et h y I pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3- 1 N-dibutyI)amino)carbonylmethy]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3- -37m ethylphenyl) amino)ca rbonyl methy]-py rroli di ne-.3- carboxylic acid; trans, trans-2-(2- (2-Oxopi pe ridin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3be nzodioxol-5-yl)- 1 -[(N-butyl-N-(4dim ethyl am ino butyI) am ino) carbon yl methyl] -p yrro lidin pe-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrro i din- 1 -yl) ethyl) ,3-be nzod yl)-l1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethy].
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-xopy rroli in- 1 -yl)ethyl)-4-(1 yl)-1 -butyI- N ropoxy)am ino) carbo nym ethyl-pyrrol idi ne-3carboxylic acid; ptrans, trans-2-(2-(2-Oxopyrrol i din -1 -yl)ethyl)-4-(1 yl)-1 -[(N-butyl-N-(4 dim ethylaminobutyl)amino)carbonylmethyl> pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2 -Oxo py rrol idin- 1 -yl) ethyl) (1 ,3-be nzod ioxol- yl)-1-[(N-butyl-N-(4trimethylammoniobutyl)amino)carbonylmethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyI)-4-(7-methoxy-1 1 ,N-dib ufylami nocarbonyl methyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolilin-1 -yl)ethyl)-4-(7-methoxy-1 ,3b en zo d io xoI- 5 -y1) 1 b u tyI- N h yd roxy pro p y1)a m ino) c arbo ny I m et h yI-p yr roIi di n e -3 carb oxyIi c acid; trans, trans-2- (2-(2-Oxopyrrolidin- 1 -yl)ethyl) -4-(7-methoxy-1, ,3b e nzo dio xolI- 5- y1) 1 -4 he pt yI- N- fIu o ro -3 m et h yIp he ny1) a m ino)c a rb o ny Imet hylI p y rroIi d i ne 3- ca rb oxylIi c acid; trans, trans-2- (2-Oxopyrrolidi n -1 -yI)ethyl) -4-(7-methoxy-1, ,3b en z od io xolI- 5 1 -b u tylI-N (propoxy)amino)carbonylmethy]-pyrroliciine-3-carboxylic acid; trans, trans-2- (2-Oxopy rrol idi n- 1 -y1) ethyl) methoxy 1, ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; -38trans, trans-2-(2-(2-OxopyrrolIidin-1 -y I) ethyI) -4-(7-methoxy- 1,3benzodioxol-5-yI)-1 N-butyl-N-(.4trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-l1-(N, N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl) amino)carbonylmethyll-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yi)-l1-[(N-butyl-N-(4dim ethyl am inobutyl)am ino) carbonyl methyl]-pyrrol idi ne-3is carboxylic acid;: trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrro i din- 1 -y!)ethyl)-4-( 1,3benzodioxol-5-yI)-l1-(N ,N-dibutylaminocarbonylmethyl)yrrolidine-3-carboxylic acid; trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3-* m et hyIph e n y1) am ino) ca rbo n yImet hyI-pyrroIi d in e- 3- c arb oxy Ii c acid; trans, trans-2- Di methyl-2-oxopyrroidin- 1 -yI) ethyl)-4-(1 ,3benzodioxol-5-yI)-1 N-butyl-N-(4d im et hyIa m in ob uty1) am ino)c arb on y Im e t hy Ipy rroIi d in e-3 carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1 -yI)ethyl)-4-( 1,3benzodioxol-5-yI)-l1-(N, N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1 -yI)ethyl)-4-( 1 3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1 -yI)ethyl)-4-( 1,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonyl methyl]-pyrrolidine-3carboxylic acid; -39trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 N-dibutylaminocarbonylmethy)pyrroidine3carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-( 1 1 -[(N-4-heptyl-N-(4-f luoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine.3carboxyijc acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-( 1 1 N-butyl-N-(3-hydroxypropyl)am ino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 ,3-benzodioxoI-5-yi)- 1 -[(N-butyl -N ropoxy) amin o)carbonyl methyl] py rrol idine-3 carboxylic acid; trans, trans-2-(2-(1 propanes ultamyl) ethyl) (1 1 3-benz od ioxoI- 5-yi) 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonymethyl].
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesulItamyl) ethyl) (7-meth oxy-1, ,3benzodi oxol-5-yI)- 1 N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2 (1 -p ropanes ultamyl) ethyl) -4-(7-meth oxyl b enz od io xo I- 5 -y1) 1 4 -h ep tylI- N -flIuo ro -3 methylphenyI)amino)carbonyimethy]pyrroidine3carboxylic acid; transtrans-2-(2-(1 -propanesultamyl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yi)-1-[(N-butyl-N-(4dim ethylam inobutyl)am ino) carbonylmethy!I..pyrroli dine-3 carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2 ,3-dihydrobenzofuran-5-yI)-l1-(N, N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3-dihydro.
benzofuran-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmehyl].pyrrolidine-.3..carboxylic acid; trans, trans-2-(2-( 1 -propanesultamy)ethy)-4-,(2,3-dihydro.
'benzofuran-5-yI)-1-[(N-butyl-N-(4dimethylaminobutyl)am ino)carbonylmethy]-pyrroidine-3carboxylic acid; trans, trans-2-(2-(1 -py razo lyl) ethyl)-4-( 1 3-benzodioxol-5-yI)- 1 4 -he ptyI-N-( 4 -f Iuoro- 3- methyl phenyl) am ino) carbonymethyl].
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(l -pyrazo lyl)ethyl)-4-(1I,3-benzodioxol-5-yI)- 1 butyl-N-(3-hydroxypropyl) ami no)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 3 3-benzodioxol-5-yi)-1 butyI-N-(propoxy)amino)carbonylmethy]-pyrroidine-3.
carboxylic acid; trans, trans-2-(2-(1 -pyrazo lyl)ethyl)-4-(1 ,3-benzodioxol-5-yi)- 1 is b utyl-N- (4-di met hylamn i nobutyl) ami no)carbonylm ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazo lyl) ethyl) -4-(7-methoxy- 1,3-benzodioxol- 5-yi)-l1-(N, N-dibutylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 -py razo lyl) ethyl) -4-(7-methoxy- 1, 3-benzod ioxol -yI)1 1 -h ep tylI N -f I u o ro -3 m ethylphenyI) amino) carbonyl methyI]-pyrrolidi ne-3carboxylic 0 acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(7-methoxy- 1,3-benzodioxol- 5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethy].pyrrolidine.3carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-(2 ,3-dihyd yI)-l1-(N ,N-dibutylam inocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-(2,3-dihydro-benzof yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methyiphenyl) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(2,3-dihydro-benzof yi)-l -[(N-butyl-N-(4-di methylaminobutyI)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; -41trans, trans-2-(2-(2-oxazolyl)ethyl)-4-(1 be nzodioxolI-5-yl)- 1 Ndibutylaminocarbonylmethyl)-pyrrolidne3carboxylic acid; trans, trans-2- (2 -(Oxazo1-2 -y1) ethyl) (1 ,3-be nzod ioxoI1-5-yi)-1 4-etlN(-loo3mtyphnlaiocroymty] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxoI-5-yi)-1 butyl-N-( 3 -hydroxypropyl)amino)carbonylmethyl]-.pyrrolidine.3 carboxylic acid; trans, trans-2- (2 -(Oxazo1-2 -y1) ethyl) (1 ,3-be nzod ioxo I-5-yI)- 1 butyl-N-(propoxy)amino) carbonyimethy]-pyrroidi ne-3carboxylic acid; trans, trans-2- (2 -(Oxazo-2 -y1) ethyl) (1 ,3-benzod ioxol1-5-yI) -1 b utylI- N -d im eth y Iam in o bu ty 1) a m n ocarbonyl methyl]-.
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yI)ethyl)-4-(7-methoxyl 1,3-benzodioxol- 1 N-dibutyl ami nocarbo nyl met hyl)-py rrolid ine.3carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy- 1 ,3-benzodjoxoly 1 N-4 -h ept yI- N flIu oro -3 m eth yIp heny1) am in o)ca rb onyl met hy -pyrroi d in e3-carb oxyl c acid; trans, trans-2-(2-(Oxazol-2-y)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol- 1 N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1 yI)-l1-(NN-dibutylaminocarbonylmethy)-pyrroidmne-3-carboxylic acid; trans, trans-2- Methyl oxazol-2-y)ethyl)-4.( 1 yI)-1-[(N-4-heptyl-N-(4-fluoro-3methyiphenyl) amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid: trans, trans-2 Methyl oxazo1-2-y) ethyl)-4-(1 benzod yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl..
pyrrolidine-3-carboxylic acid; -42trans, trans-2-(2-(2,5-Di oxopyrroli din- -yI)ethyl)-4-(1 ,3-benzodioxog- 1 N-dibutylami nocarbonylmethyl)-pyrrolidine-3.
carboxylic acid; trans, trans-2- Di oxo py rro li din 1 -yI) ethyl) (1 ,3-be nzodi oxol- 5-yI)-1-[(N-4-heptyl-N-(4-fluoro-3m ethylphenyl) amino) carbonyl met hyl]. pyrrol idi ne-3- ca rboxyl ic acid; trans, trans-2-(2-(2,5-Di oxopyrroli din- 1 -yI) ethyl)-4-(1 ,3-benzodi oxoil-[(N-butyl-N-( 3 -hydroxypropyl)amino)carbconylmethy,]pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (2,5-Dioxo pyrroli din-. 1 -yI) ethyl)-4- (1 ,3-benzodi oxol- 5-yl)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl].pyrrolidine- 3-carboxylic acid; trans, trans-2-(2- D ioxo pyrro li din 1 -yI) ethyl) (1 ,3-be nzodi oxol- 5-yI)- 1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidine.3carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1 -y.)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 N-dib utylamin ocarbonylm ethyl)-.
pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidinl -yI) ethyl) meth oxy-1, ,3- 1-[(N-4-heptyl-N-(4-fluoro-3-: methylp henyl) amino) ca rbonyl methyl]-pyrrol idin e-3carboxyli c acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4(1 ,3-benzodioxoI-5-yi)- 1 4 -heptyI-N-( 4 -fluoro-3-methylphenyl)amino)carbonylmethy]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4(1 ,3-benzodioxol-5-yI)-1 butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-.pyrrolidine-3 carboxylic acid; trans, trans-2- (Py rid in -2-yi)ethyl)-4- (1 ,3-benzod ioxolI-5-yI) -1 butyl-N-(propoxy)amino)carbonylmethyl..pyrrolidine-3.
carboxylic acid; transtrans-2-(2- (Py ri din ethyl) 4-(1 ,3-be nzodi oxol-5-yi)-
(N-
butyl-N-(4-dimethylami nobutyl)amino)carbonylmethyl].
pyrrolidine-3-carboxylic acid; -43trans, trans-2- (2-(Pyridin-2-yI) ethyI) -4-(7-methoxy- 1,3-benzodioxolI- 1 N-dibutyl am inocarbonyl methyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-m ethoxy- 1 ,3-benzodioxol- 5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl-pyrrolidine.3.carboxylic acid; trans, trans-2-(2- (Pyridin-2-yl)ethyl)-4-(7-methoxy-1, ,3-benzodi oxol- 1-[(N-butyl-N-(4dim ethyl ami nob utyl)ami no)carbonyl methyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(Pyri midi n-2-yl) ethyl)-4-(1 ,3-benzodi oxol-5-yl) -1 (N ,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 1,3-benzodioxol-5-yl)- 1 [(N-4-heptyl-N-(4-fluoro-3mnethyl ph eny1) amino) carbonyl methyl]- py rrol idi ne-3.carboxyli c acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-( 1,3-benzodioxol-5-yl)- 1:- [(N-butyl-N-(4-di methylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1,3-benzodioxol-4-yl)ethyl)-4-(-1,3-benzodioxol-5- yl)-1 -(NN-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol- yl)-1-[(N-4-heptyl-N-(4-fluoro-3methylp heny1) ami no)carbo nylm ethyl]- pyrroli d ine-3- carboxylic acid; and trans, trans-2-(2-( 1,3-benzodioxol-4-yl)ethyl)-4-(1 yl)- 1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt.
Most preferred compounds: of the invention are selected from -the group consisting of: trans, trans-2 (1 ,3-Dioxol-2-yl) ethyl) (1 .3-benzodi oxol 1 (N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -44trans, trans-2-(2,2, -Dim ethyl (1 ,3-d ioxol an-2-yI)ethyl)-4-(1 13benzodioxol-5-yI)-1 N-dibutylaminocarbonymethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (2 (1,3-DioxolI-2-yI) ethyl) benzod [[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(l ,3-Dioxol-2-yl)ethyl)-4-(7-methoxy- 1,3benzodioxol-5-yi)-1 1 N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-( 1,3-benzodi 1 N-d ib utylami nocarbonyl methyI)-pyrro lid ine-3-carboxylic acid; *trans, trans-2-(2-(2-Oxopyrrolidin- 1 -yi.)ethyl)-4-(1,3bnoixl5 yI)-1 -(NN-dibutyaminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; trans, trans-2- (1 ,3 -DioxoI -2-y1) ethyl)-4- meth oxy-1, ,3be nz od io xo I 5- y1)-1 (N h ep t yI- N -flIu oro 3 me t hy Ip he nyl1)) am in o carb o nyIm et hy 1) -p yrro Ii d ine- 3 -c ar b oxy Ii c acid; trans, trans-2- D imet hylIpentyl) ethoxy-1, benzodi oxol yI)-1 -(NN-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;* trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 dibutylaminocarbonylmethyt)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 N-dibutylaminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2 -D imet hy penteny1) ethoxy- 1 ,3benzodioxol-5-yi)-1 -(N,N-dibutylaminocarbonylmethyl)pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-yI) -1 Ndibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-l -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3carboxylicacid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5yl)-1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; s trans,trans-2-(2-(1 -pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yl)- 1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; and (2S, 3R, 4 S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- 1-[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3carboxylic acid; or a pharmaceutically acceptable salt thereof. Methods for preparing the compounds of the invention are shown in Schemes I-XV. 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
-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 toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic 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 sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R 3 -X (R 3 is R 4 or R6-S(0) 2 and X is a leaving group such as a halide (Cl is preferred) or X taken together with
R
4 or R 6 -S(0) 2 forms an activated ester including esters or -46anhydrides 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 alkylated with R 3 -X where X is a leaving group (for example, X is a halide (for example, Cl, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the Nderivatized pyrrolidine 6 which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and 8, which are readily:: p separated.
Scheme II illustrates a general procedure for preparing the is compounds of the invention when n is 1, m is 0, Z is -CH 2 and W is -C0 2 H. A substituted benzyl chloride 9 is reacted with a lithio dithiane in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with Ri-CH 2 wherein X' is a 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 14.
Treatment of compound 14 with an activated nitrile such as 2s trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound 18 is further elaborated by the procedures described in Scheme I for 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 and W is
-CO
2 H. 13-Keto ester 20 (wherein E is loweralkyl or a carboxy -47protecting group) is reacted with an a-haloester 21 (where J is lower 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 tertbutoxide or lithium diisopropylamide in an inert solvent such as THF or s 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 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 carboxylic acid 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 -C02H. The trans,trans compound 7, prepared in Scheme I, is homologated by the Amdt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of i-: an acid chloride, L is Cl). Compound 52 is treated with diazomethane to give the diazo ketone 53. Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be hydrolyzed. Compounds where m is from 2 to 6 can be obtained by i*" repetition of the above described process.
SA 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 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 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 (31) of trans, trans and cis, trans pyrrolidines -48described in Scheme IV is reacted with N-propyl bromoacetamide in 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 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 3Z with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 4A. Treatment of compound 4Q with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid 45. A preferred embodiment of the process shown in Scheme III 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.
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 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 -49can be prepared by the procedures described in Scheme IV, is converted (for example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56. The carboxamide is dehydrated (for s example, using phosphorus oxychloride in pyridine) to give nitrile Nitrile 57 under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile j7 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, to potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime S is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in cyclization to compound 6Q. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61.
Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 62 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,Ndimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone 3i. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the ca-chloroketone 63 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5, prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 66. Treatment of 6 with an amine (R 2 oNH 2 affords secondary amine 67. This amine can be reacted with an activated acyl compound (for example, R4-C(O)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 6Z can be reacted with an activated sulfonyl compound (for example, R 6 -S(0) 2 -CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters is such as 71 to provide pyrrolidines such as compound 72 Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S.
Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 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 appropriate bromoacetamide (for example, dibutyl bromoacetamide) in i": the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 8Q, which can be further elaborated on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Bocnitrogen protected (for example, by treatment with Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
This diastereomerically pure salt can be neutralized (for example, with -51sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 8Q. Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81. The use of (-)-cinchonine will give the opposite enantiomer.
Scheme XIV describes another procedure for preparation of pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R 55 is hydrogen or methyl) is condensed with a substituted acrylate .8 (wherein R 2 is as described herein and R 6 s is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 4. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to 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 is reacted with beta-keto ester I8 in the presence of a base such Ias 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 temperature of from about 0° C to about 1000 C for a period of time from about 15 minutes to overnight to give compound 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 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 -52platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b. 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, 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 1 o t-butoxide, lithium t-butoxide or potassium t-amyloxide 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 ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -200 C to about 1200 C to give the trans,trans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X-R 3 The substantially pure 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, Dtartaric acid or 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 9a selectively crystallizes as the salt, leaving the (-)-isomer of 93 in solution. Alternatively, the substantially pure 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 (+)-isomer of compound 93 in solution.
Compound 93 (racemic or optically active) is reacted with X-R 3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like 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 -53situ to the carboxylic base such as sodium hydroxide and the like ethanol and the like.
acid (95) using hydrolysis conditions such as a hydroxide or lithium hydroxide or potassium in a solvent such as ethanol-water or THF- Scheme I 0
RC
2
E
CO2E 2 N02
[H]
H
R2- R,
CO
2
E
Mixture of Cis-Cis Trans-Trans Cis-Trans f-N R2-R1
COE
0@
S
0 0
B
*S000 *0
X-R
3
/R
3
N
R2
R
6 CO 2
E
Mixture of Trans-Trans Cis-Trans
R
3 R2 R 1 C02H
[H
2 0] Trans-Trans
R
3
**C
2 E R,
COE
Cis-Trans -54- Scheme II
R
2 ,CI
J,
9 0 1
R
2
R
1 /3
R
2 QJ
S
I
R2
JJ
R1 12 Nr N R 2 14 N;r N R2 C(:)2EE R2
CN
R
1 *r
ISOMER
R2 C N R1 C0 2
E
R
1 R3 CLN R2
R,
19 Scheme III Halo
J
0 C0 2 E R, x C0 2
E
J0 2 C R 2 Halo C1, Br, or I 0
IR
3
N
R
2 -R C0 2
E
24 0 3 C0 2
E
:0 :06.* 0 N 3 2
H
Trans-Trans -56- Scheme IV
R
3 pN R2 2
R
2 R ~C0 2
H
"R
3 52
SCH
2
N
2 N R 3 o CHN 2 -57- Scheme V C H3 EtO 2
C
0_ N 02
DBU
CH
3 0O H2I -OCIA3 COQEt COQEt Mixture of z! NaCNBH 3 Cis-Cis Trans-Trans Crmatographic separation Cis-Trans
U
U.
b U U Cis-Cis Mixture of Trans-Trans and Cis-Trans -58- Scheme VI COQEt as-Trans and BrCH 2
CONHCP
7
OH
3 0 H ir 6OQEt Trans-Trans 2 NEt Trans-Trans and Cis-Trans NaGH H 2 0, EtCH 0 H C3H7 0
OH
3 600H Trans-Trans 0 r~N H C 3
H
7 .Kp&OCH3 COQEt Cis-Trans 0 0 Scheme VII 003(D Cl
LIA
00: us**) o ~~OMe 0 OMe
ISOMER
a S. OMe Scheme VII cont.
0 ~-0 N 0> N 10 CN C N OMe Me* 41 C02Et0 C02Et 44I Me OMe
R->
OMe -61- Scheme VIII .4 C02E Br 4 OE 01 y 0 47
CH
3 Trars-Trarm -62- Scheme IX
R
3
R
2
(CH
2 )m
R
2
I
N i /R3
R
2
(CH
2 m
CNN
b
S
.55.5.
R
2
(CH
2 )m HN
QLN
I vR
R
2 R
(CH
2 )l
H
2 N INOH 59
(CH
2 )m
HN'
0 -63- Scheme X
R
4 )rOH 0 0 0 C0 2
E
R4 )y N C 0 2
H
0 C0 2
E
C.
CCC.
CCC...
-64- Scheme AI
H
C0 2
E
0 -R4 R2
NH
C0 2
H
C0 2
E
/Re-NHR 2 0
N
C0 2
E
0 R 6 C0 2
H
Scheme XI1
R
3 .o.J
N+
CH
2
CO
2 Et R2 C R3 'N -CO 2 Et M e 3 Si O
H
73 Ca O~.C 2 Et 74 a a a. a.
a a a.
.CO
2 Et -66- Scheme X111 00H 3
OCH
3 1. BOC 2 0
CO
2 Et 2. NaOH, EtQH 6c -C0 2
H
H
2 0 C02EtBoc C 0 1. (+)-cinchonine: 2. recrystallize fror EtOAc/hexane 3. Na 2
CO
3 j
OCH
3 QCH 3 HCI INt -COEt-c* EtOH -0 -0( 80 79)
IBU
2
NC(O)CH
2 Br EtNiPr 2
CH
3
CN
OCH
3 -C0 2
H
ii. &j -67- Scheme XIV
R
5 h' -N 'OM e Me 3 Si
H
2 Pd(OH) 2
/C
83 TFA, CH 2
CI
2 FhXNQ _C0 2
R
6
R
3 Br
BU
4 NI or Nal
CH
3
CN
H NQ _C0 2
R
56 9 .9 .9 9 9 9* 9 9.
9 9 .9 ~9 9 9*99*9
R
3 C0 2
R
56 NaOH or UGH EtCH, H 2 0
R
3
N
Q-C0 2
H
-68- Scheme XV Rg NO 2 0 0 EO KAkR 1 0 C02E
C
2
E
CO
2
E
2112 0 2 N 1R2)" rCOR C02E 9 9b 9 9* 9 9 9. 9 99 9
CO
2
E
92 R3 C0 2
H
NH
R2'k
R,
C0 2
E
R3
R
2
R
C0 2
E
94 -69- Compounds which are useful as intermediates for the preparafion of compounds of the invention are:
NH
I.I
I* wherein n is 0 or 1; m mis 0to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR17 where R 17 is loweralkyl, alkylaminocarbonyt,V.
dial kyl aminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,
*S
-C(O)NHS(O)
2 Rl 6 where R 16 is loweralkyl, haloalkyl, P phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 H 0,
OH
(p) 0 0
N-
H
00 N .1 C F 3 4 0 e Mt H or
S
:**see
NHSO
2
CF
3 of and0.
Ri and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, 00 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbo nylal kenyl, alkylaminocarbonylalkenyl, dialkytaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, is al kylsuif onylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylaIkyI, Rbb is hydrogen or alkanoyl and RC 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: -71-
H
2
NHR
21
N
(CH
2 )m CCH 2 )m I I -6 W or W (IV)
(V
wherein n is 0 or 1; m is 0to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR1 7 where R17 is loweralkyl, alkylamninocarbonyl, dial kylami nocarbonyl, tetrazolyl, hydroxy, (1)alkoxy, sulfonamido,
-C(O)NHS(O)
2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamnino, (in) -S(O) 2 NHC(O)Rl 6
HO
0 HO 0
OH
-72- 0 0
H
H o
NHSFCF
and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, al kynyl, alkoxyalkyl, alkoxycarbonylalkyl, hyd roxyal kyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dial kylami nocarbonylal kyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylami nocarbonylal ke nyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic) al kyl and (Raa)(Rbb)N-Rc- wherein Ra is ary o rylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and
R
2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (1ll), (IV) and wherein m is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and RI and R 2 are as defined above; or the substantially pure or (+)isomer thereof.
-73- Particularly preferred intermediates are compounds of formula (1ll), (IV) and 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 loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, 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: (CHH2)m
W
(VI)
-74wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; 0 is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR
17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hdoy ()alkoxy, sulfonamido, -C(O)NHS(0) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6
HO
0
H
OH
(p) 0 (r)N% 0
H
0 an
R
1 nd R 2 are Ndeednl eetdfo yrgn oeakl d ialanoc2arboinyeaekeny hylcdroxyamkhydrog, aryl ralkyl, arlxalkyl, a ylalkoxyalkyl, (alkyanylNalkyl aminoxalkyl, cyalkylfo ylioalkyl, hteoclc,am(heteocycalicalylan (Raa)(Rbb)N-R wherein Ra is aryl or arylalkyl, Rb is hydrogen or is alkanoyl and RC 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:
R
2 N*Rsb N" RSb- 1 1
(CH
2 )m (CH2) W Ror W R (V II) (Vill) wherein n is 0 or 1; m is 0 to 6; -76- Rsb is alkylene; Q is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR
17 where R 17 is loweralkyl, alkylamninocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, (k sulfonamido,
-C(O)NHS(O)
2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 ()HO 0
OH
NH
C
0 -77- 0 A-JL.
N
H
CF
3 (tN H ,or
NHSO
2
CF
3 an
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, mncroyakl alkylaminocarbonylalkyl, dialkyiaminocarbonylalkyl, amino carbonylalke nyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-R cc wherein Raa is aryl or a rylalkyl, Rbb is hydrogen or alkanoyl and RC is alkylene, with the proviso that one or both of R, and
R
2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (VII) and (Vill). wherein m is zero or 1; o RIS is alkylene; o is a leaving group; W is -C02-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 (VII) and (ViII) wherein n and m are both 0; Rsb is alkylene; 0 is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; -78and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-f luorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4 -methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1,4benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxyis 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: N R5b -NHR2oa (CHH2)m
(IX)
wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; -79- W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR
17 where R 17 is loweralkyl, alkylamninocarbonyl, dial kylamninocarbo nyl, tetrazolyl, hydroxy, alkoxy, (k suifonamido,
-C(O)NHS(O)
2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6
HO
0 ()HO 0
OH
0 0 (r) 0
H
YIk- CF 3 (t 'H ,or NH0C3 and
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyal kyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, ayakl 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 alkanoyl and RC 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: N* N (0H 2 )m I
(CH
2 W Ror (X (XI) wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3
H
2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -C N, -81-
-C(O)NHR
17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbony:, tetrazolyl, hydroxy, alkoxy, sulfonamido,
-C(O)NHS(O)
2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)Rl 6 HO 0 0 HO 0
OH
0 0.
0
AN
0, 4 -H ,or -82-
NHSO
2
CF
3 an R, 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)alkyi and (Raa)(Rbb)NRc wherein Raa is arylor aryalkl, Rbb is hydrogen or alkanoyl and RC 0 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 (X) and (Xl) wherein 0 m is zero or 1; is alkylene;
R
2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, *0 haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, 0 and R1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof. :4: Particularly preferred intermediates are compounds of formula and (Xl) wherein n and m are both 0; is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protepfling group; and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- -83ethoxyphenyl, 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, 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 ,3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1 4-benzodioxanyi, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyt 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.O]undec-7-ene, EDCI for 1-(3dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtCH for ethanol, HOBt for 1-hydroxybenzotriazole, Et 3
N
.for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran. Examlle 1 trans. trans- 2- (4-MethoXyghenfl)-4- (1 .3-benzodioxol-5-yl)- 1- (D2rooylaminocarbonlmethyl).Dyrrolidine-3-carboxlic acid Examlle 1A Ethyl 2-(4-m ethoxybenzoyl)-4-n itrom ethyl-3-( 1. To ethyl (4-m ethoxybenzoyl) acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 4,7_ 20 (1967), and 5-(2nitrovinyl)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 OC was added 1 ,8-diazabicyclo[5,4,O] undec-7ene (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 -84chromatography ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI solution. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g.
of recovered ethyl (4-methoxybenzoyl)acetate.
Example 1B Ethyl 2-(4-methoxyDhenvl)-4-(1.3-benzodioxol-5-vl)-4.5-dihydro-3H-ovrrole-3carboxylate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (The Raney nickel was washed with ethanol three 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 i the desired product.
e e Example 1C O.
Ethyl 2-(4-methoxyphenyl-4-(1.3-benzodioxol-5-yl)-Dvrrolidine-3-carboxylate) 0*.
as a mixture of cis-cis: trans.trans: and cis.trans-isomers The compound resulting from Example 1B (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1:2 concentrated HCI in ethanol at such a rate that the color was kept at light yellow-green. After the yellow color persisted without additional HCI, the solution was stirred an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% trans, trans-compound and 34% cis,trans-compound. Further elution with pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.
Examole 1D trans, trans-2-(4-Methoxvyhenvi.4-(1 .3-benzodioxol-5-yl)-1- (Dropylaminocarbonvlmethyl)-Dvrrolidine-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, J. Amer. Chem. Soc., 9: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was O 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 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 'H NMR (CD30D, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.49 (sextet, J 7 Hz, 2H), 2.84 d, J 16 Hz, 1H), 2.95-3.20 4H), 3.20 J 16 Hz, 1H), 3.34-3.42 1H), 3.58-3.66 1H), 3.78 3H), 3.88 J 10 Hz, 1H), 5.92 2H), 6.75 J 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J 1 Hz, 1H), 6.90 J 9 Hz, 2H), 7.02 J 1 Hz, 1H), 7.40 J 9 Hz, 2H).
Example 2 trans. trans-2-(4-MethoxvDhenvl)-4.(1.3-benzodioxol-5-yl)-1- (aminocarbonvlmethvly-ovrrolidine-3-carboxvlic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture -86resulting from Example 10), 220 mg of diisopropylethylamine and 184 mg odoacetamide 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 1ID were used to give 134 mg of the title compound. m.p. 246-248 OC. 1 H NMR (DMSO-d 6 300 MHz) 8 2.61 (d, J 16 Hz, 1 2.71 J 9 Hz, 1 2.90 J 9 Hz, 1 2.98 J 16 Hz, 1H),3.25-3.35 (in, 1H), 3.45-3.55 (in, 1H), 3.71 3H), 3.75 J 10 Hz, 1H), 6.00 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7.10 (s, 1 7.17 1 7.34 1 7.38 J 8 Hz, 21-).
Example 3 trans. trans-2- (4-Methoxynhenyl)-4-( 1.3-benzodioxol-5-yV 1 -(4-fluorobenzyll- 12yrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mng of the mixture of 64% trans, trans- and 34% cis, trans- pyrrolidines (the mixture resulting from Example 1C), 220 mng of diisopropylethylamine and 185 mng 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 mng) 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 (C DC 3 300 MHz) 5 2.74 J 9 Hz, 1 2.95 J 7 Hz, 1 2.98 J 14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 (in, I1H), 3.70 J 9 Hz, 1 3.78 J 14, 1 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1H), 6.77 (dd, J 8 Hz, 1 Hz, 1H), 6.91 J 9 Hz, 2H), 6.94 -7.00 (n 3H), 7.20 7.25 1H), 7.44 J 9 Hz, 2H).
Example 4 trn.tans-2 Methoxylhenyl)-4-( 1. 3-benzod ioxol-5-yl)-l1-(2-etho ythyl gyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrroidines (the mixture resulting from Example 10), 220 mng of diisopropylethylamine and 152 mg of 2-broinoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for -87- 3 hours (bath temperature at 95 00) 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 00. 1 H NMR (CDC1 3 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21 2.32 (in, 1H), 2.70-2.80 (in, 1H), 2.85-2,94 (in, 2H), 3.38-3.55 (in, 6H), 3.67 J 10 Hz, 1 3.79 3H), 5.94 2H), 6.72 J 8 Hz, 1 H), 6.84 (mn, 1 6.84 J 9 Hz, 2H), 7.08 J 1 Hz, 1 7.33 J 9 Hz, 2H).
Examlle trans. trans-2-(4-Methoxyohenvl)-4-( 1.3-benzodioxol-5-vF)-l1-(2-Dro~oxvethyn- Dyrrolidine-3-carboxylic acid *Using the method described in Example ID, 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 *C 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 (CDC1 3 300 MHz) 8 0.87 J 7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 (in, 1 2.71-2.83 (in, 1 2.92-3.08 (mn, 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 (in, 4H), 3.72-3.83 (in, 1 3.76 3H), 5.92 2H), 6.71 J 8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J 9 Hz, 2H), 7.07 J 9 Hz, 2H), 7.73 J 9 Hz, 2H).
Examlle 6 trans. trans-2-(4-Methoxyrghenyfl-4-( 1. 3-benzodioxol-5-yl)-1 142- (2methoxyethoxy)ethy!1-2yrrolidine-3-ca rboxylic acid Example 6A Ethyl trans. trans Meth oxyghenyl)-4- (1 .3-benzodioxol-5-yi) Dy2rrolidine-3ca rboxylate To the pure cis, cis-coinpound resulting from Example 10 (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 NaQEt was neutralized -88with 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-Methoxyvhenyl)-4-(1.3-benzodioxol-5-vl)-1 -r2-(2methoxyethoxy)ethyll-Dyrrolidine-3-carboxylic acid Using the method described in Example 1D, 250 mg of the compound resulting from Example 6A, 150 mg of 2-(2methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 OC 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. 'H NMR (CD 3 OD, 300 MHz) 8 2.9-3.9 13H), 3.81 3H), 4.49 J 10 Hz, 1H), 5.94 2H), 6.79 J 8 Hz, 1H), 6.89 (dd, J 8 Hz, 1 Hz, 1H), 7.00 J 9 Hz, 2H), 7.05 J 1 Hz, 1H), 7.49 J 9 Hz, 2H).
Example 7 trans. trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-vl)- 1 -2-(2-ovridvl)ethvl]- 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 2methoxyethanol, 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 reconcentrated. 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 1 H NMR (CD 3 OD, 300 MHz) 8 2.8 3.3 6H), 3.55-3.70 2H), 3.76 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1H), 6.80 (dd, J 8 Hz, 1 Hz), 6.85 J 9 Hz, -89- 2H), 6.92 J 1 Hz, 1KH), 7.20 J 9 Hz, 2H), 7.20-7.32 (in, 2H), 7.70-7.80 (in, 2H), 8.40 J 4 Hz, 1 H).
Example 8 trans. trans- 2-(4-Methoxyohenfl)-4-(1. 3-benzodioxol--y-i)-1 -(morpholin-4.
ylcarbonyb)-oyrrolidine-3-carboxylic acid To the compound resulting from Example GA (300 mg) and 164 mg triethylamnine dissolved in 2 mL of methylene chlooide 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 00. 1 H NMR (DMSOd 6 300 MHz) 5 2.96 (dd, J 12,Hz, 13 Hz, 1H), 3.03-3.13 (in, 2H), 3.20- 3.30 (in, 2H), 3.40-3.60 (mn, 5H),'3.74 3H), 3.70-3.85 (in, 3H), 5.10 J =10 Hz, 1KH), 5.99 J 1 Hz, 2H), 6.80-6.90 (in, 2H), 6.87 J 9 Hz, 2H), 7.07 1H), 7.25 J 9 Hz, 2H).
Examn~le 9 trans. trans-2-(4-Methoxy~henyl)-4-(1 .3-benzodioxole-5-y1)-1 -(butlaminocarbonyl)- Dyrrolidine-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 vacua to give the intermediate ester. The ester was hydrolyzed by the method described in Example ID to give 232 mng of the title compound. in.p. 220-221 OC.
'H NMR (DMSO-d 6 300 MHz) 8 0.78 J 7 Hz, 3K), 1.10 (sextet, J 7 Hz, 1.22 (quintet, J 7 Hz, 2H), 2.78-3.05 (in, 3H), 3.40-3.56 (mn, 2H), 3.74 3H), 3.95-4.05 (in, 1KH), 4.93 J 9 Hz, 1KH), 5.80 broad, J 7 Hz, 1KH), 5.99 2K), 6.78-6.86 (in, 2H), 6.88 J 9 Hz, 2K), 7.00 J 1 Hz, 1H), 7.12 J 9 Hz, 2H).
Example trans, trans-2-(4-Meth oxvh enyl)-4-(1.3-benzodioxol-5-yl)-1 meth xoyhenvlaminocarbonyl)-3-pyrrolidine-3-carboxlic acid The compound resulting from Example 6A (300 mg) was treated 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 oC. 1 H NMR (CDCl 3 300 MHz) 8 3.23 (dd, J 12 Hz, 13 Hz, 1H), 3.55-3.68 2H), 3.72 3H), 3.83 3H), 4.50-4.65 1H), 5.06 J 10 Hz, 1H), 5.90 1H), 5.95 1H), 6.72 J 9 Hz, 2H), 6.7-6.8 3H), 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H). Example 11 trans. trans-2-(4-Methoxvyhenyl-4-(1.3-benzodioxol-5-yl)-1 -acetylDvrrolidine-3carboxylic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid:: neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1D to give 211 mg of the title compound. m.p. 248-250 Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d 6 300 MHz) 5 1.55 and 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28 (dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 10Hz, 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 (d, J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).
Example 12 trans. trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-yl)- 1 -(2-furoyl)-pyrrolidine-3carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was -91hydrolyzed by the procedure described in Example- 1 D to give 269 mg of the title compound as an amorphous powder. 1 H NMR (DMSO-d 6 300 MHz) 5 3.06 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 (in, 2H), 4.25 (mn, 1H), 5.19 d, J 10 Hz, 1 6.67.4 (in, 8H), 7.8-7.9 (in, 1 H).
Examole 13 trans. trans-2-(4-Methoxyghenyl)-44(1 .3-benzodioxol-5-yi)- 1- (D2henylaminocarbonyl'-D2yrrolidine-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. in.p. 209-211 0 C. 'H NMR (DMSO-d 6 300 MHz) 8 3.03 (dd, 1 3.55 (in, 1 3.70 (in, 1 3.72 3H), 4.15 (in, 1 5.13 1H), 6.00 2H), 6.88 (mn, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1 H).
Examgle 14 trans, trans-2-(4-Methoxyohenyfl-4-( 1.3-benzodioxol-5-l)-1 1- (allylam inocarbonylmethyl'.D2yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 OC. 1 H NMR (CDCI 3 300 MHz) 8 2.84 1H), 2.90-3.10 (dt, 2H), 3.28 1H), 3.35 (dd, 1H), 3.62 (in, 1H), 3.72- 3.97 (in, 3H), 3.80 3H), 5.13 (bd, 2H), 5.80 (in, 1 5.97 2H), 6.74- 6.97 (in, 5H), 7.38 2H).
Examile trans. trans-2-(4-MethoxyhenyP-4-( 1. 3-benzodioxol-5-yfl- 1 butylaminocarbonylmethyl)-Dyrrolidine-3-carboXylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 105-107 'H NMR (ODC1 3 300 MHz) 8 0.90 (t, 3H), 1.30 (in, 2H), 1.45 (in, 2H), 2.80 I1H), 2.87-3.35 (in, 6H), 3.62 (in, 1H), 3.80 3H), 5.97 2H), 6.75-6.92 (mn, 5H), 7.28 2H).
Exaingle 16 trans, trans-2-(4-Methoxyrhenfl)-4-(1 .3-benzodioxol-5-yl)- 1 -(N-(n-DropYl)-Ninethylaminocarbonylmethyl-Dyrrolidine-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 -92- NMR. 'H NMR (CDCI.
3 300 MHz) 8 0.73, 0.84 (2t, 1.49 (in, 2H), 2.80 (dd, 1 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1 3.40 (d, 1 3.60 (in, 1 3.79 3H), 5.93 2H), 6.73 1 6.86 (in, 2H), 7.03 (in, 1 7.32 2H).
Example 17 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-y)- 1 -(Dvrrolidin- 1ylcarbonylmethyl)-oyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (ODC1 3 300 MHz) 8 1.40- 1.70 (in, 6H), 2.80 I 3.00 (in, 2H), 3.24-3.43 (in, 5H), 3.60 (in, 2H), 3.73 1H), 3.80 3H), 5.95 2H), 6.74 1H), 6.80-6.90 (in, 3H), 7.04 1 7.30 2H).
Exaile 18 trans, trans-2-(4- Methoxyhenyl)-4-( 1. 3-benzodioxol-5-yl)- 1- (isobutylam inocarbonylmethyl)-Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 175-177 OC. IH NMR (CD 3 OD, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, 1H), 2.85 1H), 2.90-3.10 (in, 4H), 3.23 1H), 3.40 (in, 1 3.58-3.67 (in, 1 3.78 3H), 3.89 1 5.92 2H), 6.76 1 6.86 (dd, 1 6.91 2H), 7.02 1 7.40 2H).
Exainole 19 4 trans, trans-2-(4- MethoXyohenyfl-4- (1 .3-benzodioxol-5-yl)- 1- (cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 137-139 OC. 1 H NMR (CDC1 3 300 MHz) 8 1.34 (in, 2H), 1.62 (mn, 4H), 1.90 (in, 2H), 2.76 1IH), 2.90 1H), 3.04 (dd, 1H), 3.22 1 3.28 (dd, 1 3.40 (in, 1 3.80 3H), 4.15 (in, 1 5.97 2H), 6.75-6.95 (in, 5H), 7.27 (in, 2H).
Example 0 trans, trans-2-(4-Methoxvyphenyl)-4-(1 .3-benzodioxol-5-yl)- 1 -(morpholin-4ylam inocarbonylinethyl)-p2yrrolidine-3-carboxcylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 NMVR (CDC1 3 300 MHz) 8 2.82 (d, -93- 1KH), 3.00 (in, 3.24 (mn, 1lH), 3.30-3.52 (in, 3.52-3.75 (in, 8H), 3.80 3H), 5.95 2H), 6.75 1 6.84 3H), 7.00 1 7.28 (d, 2H).
Examlle 21 trans. trans-2-(4-Methoxylhenyl)-4-( 1.3-benzodioxo-5-vP)- 1 -(2-Dhenoxyethyl Dyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMR (CD 3 OD, 300 MHz) 8 2.82 1H), 2.96 (dd, IH), 3.13 (in, 1H), 3.32 (in, 11H), 3.51-3.70 (in, 2H), 3.77 3H), 4.00 1KH), 4.07 (in, 5.91 2H), 6.72 1KH), 6.80- 6.95 (in, 6H), 7.03 1KH), 7.22 (dd, 2H), 7.39 2H). Exam Die 22 trans, trans-2-(4-Methoxvphenvl)-4-( 1. 3-benzod loxo I-5-yl)- 1 methoxyethvlaminocarbonlmethyl)-yrroidine.3.carbolic -acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-109 OC. 1 H NMR (CD 3 OD, 300 MHz) 8 2.82 (d, 1 2.97 2K), 3.21 1KH), 3.38 (mn, 1KH), 3.32 3K), 3.44 (mn, 4H), 3.62 (in, 1KH), 3.79 3.86 1KH), 5.93 2H), 6.76 1 6.85 (dd, 1 6.91 2K), 7.01 1 7.38 211).: Exaile 23 trans, trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yl)- 1 -(2-butomythyl)ft Dyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 0 C. 1H NMR (CDCI 3 300 MHz) 8 0.88 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (ft, J=6Hz, 6Hz, 1K), 2.92 J=lO~z, 3.35 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=lOHz, 3.78 3K), 5.94 2H), 6.73 J=8Hz, 1H), 6.83 J=9Hz, 2K), 6.82-6.87 (in, 1H), 7.06 J=2Kz, 1H), 7.32 (d, J=9Hz, 2H). MS in/e 442 -94- ExamlDie 24 trans. trans-2-( 1.3-Benzod ioxol-5-yfl-4-(4-methoxyohenyl)- 1- (prolylam inocarbonyim ethyl)-p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl 3 -b enzodioxol-5-ylcarbo nyl) acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxoI-5yl afforded the title compound. m.p. 97- 99 OC. 1' NMR (CDC1 3 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 J=l6Hz, 1H), 2.74 J=lOHz, 1H), 2.80-3.10 (in, 4H), 3.26-3.38 (in, 1H), 3.53 (in, 1H), 3.73 3H), 3.80 J=lOHz, 2H), 7.80 J=6Hz, 1H). MS (DCI/NH 3 m/e 441 Exam le trans. trans-2- (1 .3-Ben zodi oxoI-5-yl)-4-(4-methoxoh enylP-1- (2-propoxyethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-yl carbonyl) acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound.. m.p. 67- 69 OC. 1 NMR (ODC1 3 300 MHz) 8 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (mn, 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45- 3.57 (in, 4H), 3.73 (in, 1 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1 H), 6.85 J=8Hz, 3H), 6.98 1H), 7.37 J=8Hz, 2H). MS (DCI/NH 3 m/e 428 Example 26 trans, trans-2-( 1. 3 -Benzodioxol-5-yl-4-(4-nethovghenyl)-.1 methoxyeth Ky~ethyll U-yrrolidine3carbo,~lic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 OC. 1 H NMR (CD 3 OD, 300 MHz) 8 3.18-3.90 (in, 15H), 3.79 3H), 4.57 J=lOHz, 1H), 6.02 2H), 6.91 J=8Hz, 1H), 6.95 J=9Hz, 2H), 7.06 (dd, J=8Hz, 1H), 7.12 (dd, J=lHz, 1H), 7.37 J=9Hz, 2H), MS (DCI/NH 3 m/e 444 Examlle 27 trans, trans-2 Ben zod ioxo 1-5-yF)-4-(4-m eth oxyphe nyl)- 1 -(butoxyethyb)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example .25 and using 2ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 54-56 00. 1 H NMR (CDC1 3 300 MHz) 8 0.89 J- 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (in, 1H), 2.74-2.98 (mn, 3H), 3.46 J=7Hz, 2H), 3.42-3.56 (mn, 4H), 3.68 (d, J=lOHz, IH), 3.80 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 1H), 7.36 J=9Hz, 2H).
Example 28 tnstans-2-(4 MthxrAeyI--(1.-benzodioxan-6-yl- 1- (propylaminocarbonylmethyl)-pyrrolidine3carboxylic 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 00. IH NMR (CDC1 3 300 MHz) 0.89 J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H),'2.78 J=l6Hz, 1H), 2.92 J=lOHz, 1H), 3.05-3.43 (mn, 5H), 3.24 J=l6Hz, 1H), 3.52-3.62 (mn, 1H), 3.80 3H), 3.80 J=lOHz, 11H), 4.27 4H), 6.74-6.93 (in, 5H), 7.29 J=9Hz, 2H). MS (DCI/NH 3 m/e 455 Example 29 trans. trans-2-(4-Methoxyphenyfl-44 i .4-benzodioxan-6-yl)-l1-(N-methyl-Npropylam inocarbonylmethyl)-pyrrolidin e-3-carboxylic acid Using the procedures described in Example 1, substituting 6-(2nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl broinoacetainide afforded the title compound. in.p. 74-76 00.
Rotational isomers are seen in the NMR. 1 H NMR (CDC1 3 300 MHz) 8 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (in, 3H), 3.27-3.42 (mn, 3H), 3.52-3.60 (in, 1H), 3.75 IIH), 3.78 3H), 4.22 4H), 6.80-6.98 (in, 5H), 7.32 2H). MS (DCI/NH:3) in/e 469 -96- Exam Die trans. trans-2- (4-Methoxyphenyl)-4-( 1. 3-benzod ioxol-5-yl)- 1 -(N-methyl-Nbutylam inoca rbonylm ethyl) -pyrro Iid ine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. IH NMR (CD 3
OD,
300 MHz) 8 0.86 (2t, 3H), 1.04-1.50'(in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 4H), 3.40 (in, 2H), 3.52 (dd, 1 3.60 (in, 1 3.80 3H), 3.85 (in, I1H), 5.91 2H), 6.74 I1H), 6.83-6.95 (in, 3H), 7.03 (dd, 1 7.35 (dd, 2H).
Example 31 trans. trans-2-(4-Methoxy-2-methoxym ethoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 methyl-N-butylam inocarbonylmethyl)-pyrrolidine-3-carboxylic acid: Example 31 A Ethyl 2-(4-methoxv-2-methoxymethoxyphenyl-4- 1 3-ca rboxyla te) Using the procedures described in Examples 1IA and 1 B and substituting ethyl (4-m eth oxy-2 -meth oxy meth oxybe nzoyl) acetate for ethyl (4-methoxybenzoyl) acetate afforded ethyl 2-(4-methoxy-2methoxymethoxyphenyl)-4-( 1 3-benzodioxol-5-yI)-4,5-dihydro-3Hpyrrol e- 3-carboxyl ate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 minol) 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 chroinatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.- Exain~le 31 B trans, trans-2-(4-Methoxy-2-methoxn ethoxyhenyfl-4-( 1.3-benzodioxol-5-yl)- 1 methyl-N-butylamninocarbonylmethyl)-p2yrrolid ine-3-carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 inmol) was then reacted by the procedures described in Example 1 D substituting N-methyl-N-butyl bromoacetainide for Npropyl broinoacetamide to give the title compound (75 mng, m.p.
65-67 00. Rotational isomers are seen in the NMR. IH NMR (CDC1 3 300 -97..
MHz) 8 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40- 1.48 (in, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (in, 6H), 3.50 3H), 3.43- 3.65 (in, 2H), 3.78 3H), 4.30 J=7Hz, 1 5.09 J=7Hz, 2H), 5.92 2H), 6.55 (dd, J=3Hz, 1H), 6.68 1H), 6.72 1H), 6.85 (2t, J=1 Hz, 1H), 7.04 J=lHz, 7.42 (dd, J=3Hz, 11H).
Examlle 32 trans. trans-2-(4-Methoxy~henyl)-4-( 1.3-benzodioxol-5-yfl. 1 -(3-ethoxyDrorny1pyrrolidin-5-one-3-ca bxlic acid Example 32A Ethyl 2-(4-m ethoxybenzoyfl-3-ca rbomethoxv- 1. 3 -benzodioxole--rolipn ate 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 ethoxyoropvl)-2-(4-inethoxyghenyl)-4.( 1. 3-benzodioxol-5-yl)-4.5-dihydro.
5-oxo- 1 H-pyrrole-3-carboxylate A mixture of the compound resulting from Example 32A (700 mg, 1.69 minol), 3-ethoxypropylamine (348 mg, 3.38 minol) and 1 mL of acetic acid in a sealed tube was heated for'18 hours at 125 0 C. 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 mng of the title compound.
-98- Example 320 Ethyl 1 -(3-ethoxyp ropyl)-2-(4-methoxyhenyl)-4-(1 .3-benzodioxol-5-yl-pyrrolidin-5one-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-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yI)- 1 -(3-ethoxygropyl)pyrrolidin-5-one-3-carboxylic acid To the compound resulting from Example 320 (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 sodium ethoxide in ethanol. The mixture was heated to 70-80 *C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was 0 removed under reduced pressure, and water was added to the residue :.0 which was washed with ether. The aqueous layer was neutralized with 3 HCl and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, m.p.
134-140 00. 1 H NMVR (DMSO-d 6 300 MHz) 8 1.04 J=7Hz, 3H), 1.o55 (sextet, J=7Hz, 2H), 2.48-2.56 (in, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 0: J=7Hz, 2H), 3.28-3.40 (in, 2H), 3.48-3.57 (in, 1H), 3.78 3H), 3.88 (d, J=lOHz, 1IH), 4.72 J=lQHz, 1H), 6.02 21H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 J=8Hz, 2H), 6.98 J=8Hz, 2H), 7.38 J=8Hz, 2H). MS-
(DCI/NH
3 m/e 442 Example 33 trans. traris-2 Meth oxyp hen yl)-4- (1 ben zod ioxol-5-yi)- 1 -(3-methoxybenzyl)pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-inethoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mng, m.p. 150-152 00. 'H NMR (CD3OD, 300 MHz) 8 2.96 (dd, J=8Hz, 10OHz, 1 3.72 3H), 3.80 3H), 4.06 (d, J=lOHz, 1H), 4.58 J=8Hz, 1H), 4.92 J=l6Hz, 2H), 5.92 2H), -99- 6.55-6.63 (in, 2H), 6.82 J=8Hz, 4H), 6.94 J=8Hz, 2H), 7.15-7.22 (in, 3H). MS (D01/NH 3 m/e 475 Examlole 34 trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 diisoamyla minoca rbonylmethyl'-D2yrrolidine-3cp rboXylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (00013, 300 MHz) 8 0.70 -0.90 (mn, 12H), 1.10-1.60 (in, 10H), 2.75 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.15 3.30 (in, 2H), 3.40 J=lOHz, 1H), 3.40 3.52 (in, 2H), 3.55 3.62 (in, 1H), 3.75 J=12 Hz, 1H), 3.79 3H), 5.93 (dd, J =1 Hz, 3V.b Hz, 2H), 6.72 J=8Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9Hz, 2H).
Ea e3 trans, trans-2 -(4-Methoxvo~henyl)-4-( 1. 3-benzodioxol-5-yl)- 1 N- dilentylam inocarbonymehyl)-o2yrroidine-3-carboxylic acid bo The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMVR (00013, 300 MHz) 8 0.82 J 7Hz, 6H), 0.95-1.03 (in, 2H), 1.10-1.30 (in, 8H), 1.40-1.51 (in, 2H), 2.72 J=l3Hz, 1H), 2.90-3.08 (mn, 4H), 3.25-3.50 (in, 3H), 3.37 J=l3Hz, 1H), 3.52-3,60 (in, 1H), 3.70 J=lOHz, 1H), 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (mn, 3H), 7.03 2 J=2Hz, 1H), 7.30 J=9Hz, 2H).
Example 36 trans. trans-2-(4-Methoxyp~henylk4- (1 .3-benzod ioxol-5alyfl-(N. N-di(2methoxyethvl'am inocarbonylmethyl)-Dyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 00. 1 H NMR (CDC1 3 300 MHz) 8 2.82 (d, J=13, 1H), 2.94-3.08 (in, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11 3.73 J=1lOHz, 1 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Hz, 1 6.80-6.90 (mn, 3H), 7.04 J=2Hz, 1 7.30 J=9Hz, 2H).
-100- Example 37 trans. trans-2 -M eth oxyphenyl)- 4- (1.3-ben zod ioxol .1 2 -h eXynyl)-_pyrro lid ine.
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 1, 2004 (1987), for 1 hour at 55 OC, to give 226 mg of the intermediate ester. The ester was hydrolyzed using NaOHI in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. 1 H NMR (CDCI 3 300 MHz) 8 1.00 J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 3.07 (dd, J=1l8Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 J=9Hz, 1H), 3.36 (dd, J 18 Hz, 2Hz, 1H), 3.47-3.55 (in, 1H), 3.79 3H), 3.88 J=9Hz, 1H1), 5.95 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (in, 3H), 7.03 J=2Hz, IH), 7.22 is J=9Hz, 2H).
Example 38 *t trans, trans-2-(4- Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(N-CYClOpropylinethy- N-propylamninocarbonylinethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described to in Example 1. in.p. 167-169 00. Rotational isomers were seen in the to NMR. 1 H NMR (ODC1 3 300 MHz) 5 -0.1 0.05 0.12-0.25 0.32- 0.51 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (n,1.20-1.55(i) 2.72 J=l3Hz, 1H), 2.85--3.29 (in, 4H), 3.30-3.50 (mn, 3H), 3.52-3.62 2 (in, 1H), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, 1H), 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (in, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).
Example 39 trans. trans-2- (4-Methoxyohenyl)-4-(1 .3-benzodioxol-5-yl). 1 -(N-methyl-Npentylamninocarbonylmethyl)-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 (ODC1 3 300 MHz) 8 0.85 J=7Hz, 3H), 1.00-1.08 (in), 1.13-1.32 1.35-1,50 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (mn, 3H), 3.52- 3.62 (mn, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets, 3H), 5.92 -101- (2 singlets, 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 2H).
Examlle trans. trans-2-(4-Methoxy=henyl)-4- (1 .3-benzodioxol-5-y)-
N-
diisobutylam inocarbonylmethyl)- Dyrrolid ine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 00. 1 H NMVR (CDC1 3 300 MHz) 8 0.54 (d, J=7Hz, 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (in, 1H), 1.90- 2.02 (in, 1H), 2.67 J=l3Hz, 1H), 2.70 J=l3Hz, 11H), 2.84 (dd, J=6Hz, 15Hz, 1H), 2.96-3.06 (in, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (in, 4H), 3.70 J=9Hz, 1H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 J=9Hz, 1H), 6.82-6.90 (in, 3H), @0 7.03 J=2Hz, 1H), 7.31 J=9Hz, 2H). g.
Examrle 41 trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-y)-1 -(N-methyl-N-(2pro rynyl)am in ocarbonyim ethyl)-Dyrro lid ine-3-ca rboyl ic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the O*0 NMR. 1 H NMR (ODC1 3 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1 H), 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (in, 2H), 3.52-3.62 (in, 1H), 3.78 3H), 4.03 J=l3H1z, 1H), 4.00-4.30 (in, 3H), 5.93 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 and 7.11 (2 doublets, J 2Hz, 1 7.30 (2 doublets, J=9Hz, 2H).
S.
Exam Dle 42 trans. trans-2-(4-Methoxyghenyfl-4-( 1.3-benzodioxol-5-yl)-l1-(N-methyl-N-(nhexyflam inocarbonyim ethyl)-p2yrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example I1. 1 H NMR (ODC1 3 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (mn, 8H), 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (mn, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 1 H).
-102- ExampDle 43 trans. trans-2-(4- Methoxychenyl)-4-(I 1.3-benzodioxo-5-y)-1 dibtya incrbn eth l)-yrrolid ine-3-carboxylic acid The title compound was prepared using the procedures described in Example m.p. 123-125 1 H NMR (CDC1 3 300 MHz) 8 0.79 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.74 J=l3Hz, 1H), 2.90-3.09 (in, 4H), 3.23-3.50 (in, 3H), 3.38 J=l3Hz, 1H), 3.52-3.62 (in, 1H), 3.75 J=10 Hz, 1H), 3.78 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 J=8Hz, 1H), 6.81-6.89 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 mWe 511 Anal calcd for 02 9
H
38
N
2 0 6
C,
68.21; H, 7.50; N, 5.49. Found: 0, 68.07; H, 7.47; N, 5.40.
Exampie 44 trans. trans-2-(4-Methoxyhenyl)-4-( 1. 3-benzodioxol-5-yl)-l1-(N. Ndiethylam inocarbonylmethyl)-pyrrolidine-3-ca rboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 00. 1 H NMR (ODC1 3 300 MHz) -8 0.98 (t,0.0 J=7Hz, 1.06 J=7Hz, 3H), 2.78 J=13 Hz, 1H), 2.95-3.20 (in, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1H), 3.76 J=12 Hz, 1H), 3.79 .000 3H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (d, J=2Hz, 1H), 7.32 J=9Hz, 2H), :0 0.
Example 45 0 trans. trans-2-(4-Methoxyphenyl)-4-( 1. 3-benzod ioxol-5-yl)- 1 -(N-methyl-N- 0.0 phenylam inocarbonylmethyl)-pyrrolidine-3-carboxylic acid :00 The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD 3 OD, 300 MHz) 8 2.75- 2.85 (in, 2H), 3.05-3.13 (in, 1 3.18 3H), 3.40-3.58 (mn, 2H), 3.78~ 3H), 3.88 J=l2Hz, 1H), 5.92 2H), 6.72 J=8Hz, 1H), 6.75- 6.85 (in, 3H), 7.00-7.12 (in, 5H), 7.82-7.92 (mn, 3H).
Example 46 trans. trans-2- Meth oxyp hen yfl-4- 3-b enzod ioxo 1-5-yi)- 1 -m ethyl-N cyclohexylaminocarbonylmethyl)-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. 'H NMR (CD 3 OD, 300 MHz) 8 1.00-1.85 (mn, 10H), 2.72 and 2.78 (2 -103singlets, 3H), 2.75-2.82 (2 doublets, J=l2Hiz, 1H), 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=lOHz, 1H), 3.77 and 3.78 (2 singlets, 3H), 5.92 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.82-6.88 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.30-7.40 (2 doublets, J=9Hz, 2H).
Exam Die 47 trans. trans-2-(4-Methoxvlhenyfl-4- (1 .3-benzodioxol-5:yO- 1 N-di(n- D2rolyI)am inocarbonylmethyl)-Dvrrolidine-3-carboxdic acid The title compound was prepared using the procedures described in Example 1. m.p. 170-172 0 C. 1 H NMIR (ODC1 3 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.20-1.55 (in, 4H), 2.72 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.25-3.47 (in, 4H), 3.35-3.62 (in, 1 3.72 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 11H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1H), 7.30 J=9Hz, 2H-).
Examlle 48 trans, trans-2-(4-Methoxyghenyl)-4-( 1.3-benzodioxol-5.fl)- 1 -(N-methyl-Nisobutylam inocarbonylmethyl)-ovrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (CD 3 OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 1.75-1.95 (in, 1H1), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (mn, 4H), 3.10-3.65 (mn, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=lOHz, 1H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.80-7.90 (2 doublets, J=9HZ, 2H).
Examile 49 Alternate Prelration of Ethyl 2- (4-rnethoxybenzoyl)-4-nitrom ethyl-3- (1.3-benzodioxole-5-vl) butyrate Example 49A 4-Methylenedioxyohenyl)-l1-nitroethene To a stirred solution of piperonal (75g, 500 inmol) in methanol (120 ml-) at 10 00 was added nitromethane (27.1 inL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 minol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while -104maintaining the temperature between 10-15 OC. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below s 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, 1 H NMR (300MHz, CDC13) 8 7.94 (1H, d, J=13.5Hz), 7.47 (1H, d, J=13.5Hz), 7.09 (1H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, MS (DCI/NH 3 m/e 194 (M+H) 211
(M+H+NH
3 Example 49B Ethyl 2 4 -methoxvhenvloxo-4-nitro-3-(3.4-methvlenedioxvDhenyvlbutvrate 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[5,4,0]undec-7- ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was i"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, CDC 3 8 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, 5.89 (1H, d, J=4Hz), 5.88 (1H, d, J=4Hz), 4.90-4.60 (3H, 4.39 (1H, 4.18 (2H, q, J=7Hz), 3.94 (2H, -105in), 3.80 (3H, 3.78 (3H, 1. 19 (3H, t, J=7Hz), 0.99 (3H, t, J=7H-z), MS
(DCI/NH
3 mle 416 433 (M+H+NH 3 Examlle trans. trans-2-(4-M-ethoxylhenvl)-4- (1 .3-benzodioxol5-yl)-1 b utylo xvca rbonylm ethyl)- 1yrrol idi n e- 3ca rboxy ic acid To a stirred solution of the compound resulting from Example (100 mng, 0.27 minol) in acetonitrile (2 ml-) was added successively diisopropylethylamine (70 0.40 inmol, 1.5 eq) and t-butyl bromoacetate (48 0.29 inmol, 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 vacua. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 and then extracted with ethyl acetate The combined organic extracts were dried (Na 2
SO
4 filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid.% 1 H NMR (300 MHz, CDC1 3 5 7.36 (2H, d, J=8Hz), 7.13 (1 H, 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, 3.96 (1H, d, J=9Hz), 3.81 (3H, 3.58 (1H, ddd, J=12, 1OHz,3Hz), 3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=1l7Hz), 3.08 (1 H, t, J=lOHZ), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (DCI/NH 3 0 W/e 456 Anal calc for C 29
H
29
NO
7 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
Example 51 trans, trans-2-(4-MethoXyphenyl)-4-( -naghthyfl- 1 -(N-methyl-N- Drogyl'iamin ocarbonylm ethyl)-p2yrrolidine-3-carboxvlic 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, CDC13) 8 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1H, d, J=8Hz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2H-z), 4.50 (1H, in), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 -106- (1H, in), 3.49 (1H, d, J=l4Hz), 3.40-2.93 (5H, mn), 2.91, 2.83 (3H, 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH 3 W/e 461 Anal calcd for C 29
H
29 N0 7 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71.
Found: C, 70.95; H, 7.00; N, 5.46.
ExampDie 52 trans. trans-2- (4-Meth oxyph enyl)-4- (2.3-dihyd roben zof uran- 5syl).. 1 (N-m ethYl- N 12rooyflam inocarbonylmethyl)-yrrolidine-3-carboxylic acid Example 52A 2. To a stirred solution of c,c-dichloromethyl methyl ether (2.15 g, 19 minol, 1.35 eq) in methylene chloride (30 mL) at -40 0 C was added successively stannic chloride (1.65 g, 17 iniol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH 2
CI
2 mL) maintaining the temperature at or below -35 OC. The mixture was warmed to 0 0 C, 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 vacua, 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. -Examlle 52Bo trans, trans-2- Meth oxoh enyfl-4- (2.3-dihyd robe nzof uran-5-yl.. 1 -(N-methyl-N-o: prop~yflam inocarbonylmethyfl)-Dyrrolidine-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, CDC1 3 8 7.33 (1H, d, J=8Hz), 7.28 (1H, in), 7.19 (1IH, in), 6.87 (1 H, d, J=8Hz), 6.73 (1 H, d, J=8Hz), 4.56 (1 H, t, J=8Hz), 3.83 (1H, d, J=lOHz), 3.80 (3H, 3.63 (1H, in), 3.4-3.0 (9H, in), 2.87, 2.84 (3H, 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS
(DCI/NH
3 in/e 453 Anal calc for C 26
H
32
N
2 0 5 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
-107- Example 53 tans. trans-2.4-Bis(4-methoxyrghenyl)-1 -(N-methyl-N-propyl)a incrbonmehy.
p2yrrolidine-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, ODC1 3 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, in), 3.83 (1 H, mn), 3.81 (3H, 3.79 (3H, 3.64 (1 H, mn), 3.48-2.97 (6H, mn), 2.87, 2.83 (3H, 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz).
MS (DCI/NH 3 m/e 441 Anal calc for C2sH 32
N
2 0 5 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. t-rans- 2 4 -Methox ohenyl)-4-(3.4-dimethoxr.,heny) 1 N-inethyl.N D2ropyl)am inocarbonylmethyl)-12yrrolidine3carbo2Wlic-acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-diinethoxybenzaidehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, ODC1 3 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1 H, in), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, 3.86 (3H, 3.83 (1 H, in), 3.79 (3H, 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS
(DCI/NH
3 m/e 471 Anal caic for 026H3 4
N
2 0 6 0.5 H 2 0: C,* 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
a0 Examlle tra ns. tran -(4-Methoylhenyl)-4-(3-m ethoxyhenyl)- 1 (-ehloropyl)amninocarbonyimethyl)-r2vrrolidine-3-carbo&,lic acid- The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-inethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, ODCd 3 5 7.33 (2H, d, J=7.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.05 (2H, in), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1 H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1H, in), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCIINH 3 m/e 441 Anal caic for C 2 5H 32
N
2
O
5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
-108- Example 56 trans. trans-2-(4-Methoxyvhenyl)-4-(2-n aphthyl)-1 -(N-methyl-N- DroDvl)aminocarbonylmethyl)-vyrrolidine-3-carboxylic acid s 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, CDCI 3 8 7.82 (4H, 7.69 (1H, 7.47 (2H, 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, 3.57 (1H, 3.52-2.97 (6H, 2.93, 2.85 (3H, 2.90 (1H, 1.52 (2H, 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 461 (M+H) Anal calc for C28H 3 2
N
2 0 4 0.5 H 2 0: C, 71.62; H, 7.08; N, S 5.97. Found: C, 71.58; H, 7.11; N, 6.01.
Example 57 trans. trans-2-(4-Methoxy henvl)-4-(1.3-benzodioxol-5-l)-1 -(2-(ethylsulfinvl)ethyl)- Dyrrolidine-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 of the ethylthioethyl compound. To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2 C12 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, The ethyl ester was hydrolyzed by the procedure described in Example 1D to afford the title compound as a diastereomeric mixture.
m.p. 61-63 MS (DCI/NHa) m/e 446 (M+H) 'H NMR (CDC13, 300 MHz) 8 1.25, 1.32 J=9Hz, 3H), 2.45-2.75 4H), 2.84-2.96 3H), 3.02- -109- 3.08 (in 1H), 3.32, 3.36 J=3Hz, 1 3.47-3.5 8 (in, 3.65, 3.68 (d, 1H), 3.76, 3.80 5.94 6.72 J=7.5Hz, 1H), 3.84- 3.89 (in, 7.02 J=6Hz, 1H), 7.30, 7.34 J=7.5Hz, 2H).
Exam Die 58 trans. trans-2-(4-Methoxyghenyfl-4- 1 .3-benzodioxol-5-vpl-1 (isolrooylsulfonylam ino)ethvl)-D2yrrolidine-3-ca rboxylic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous CH3CN 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
C
solution of the compound resulting from Example 10 (185 mg, 0.5 mmol) in 3 mL of CH3CN. The mixture was warmed at 50-60 00 for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mng of the ethyl ester. The ethyl ester (160 ing, 0.31 inmol) was hydrolyzed by the procedure described in Example 1 D to afford the title compound (133 mg, in.p. 94-96 OC. 1 K NMR (CD 3 OD, 300 MHz) 8 1.26 J=6Hz, 1.97 1KH), 2.38 (mn, 1KH), 2.77 (in, 1KH), 2.88 J=9Hz, 11K), 3.04 (in, 3.14 J=7.5Hz, 2H), 3.35 (in, 2H), 3.46 (in, 1KH), 3.58. (in, 1KH), 3.78 5.92 2H), 6.74 J=9Hz, 1KH), 6.86 (dd, J=9Hz,3Hz, 1KH), 6.92 J=9Kz, 2H), 7.00 J=3Hz, 1KH), 7.36 J=9Hz, 2H). MS (DCI/NH3) W/e Examn le 59 trans. trans-2-(4-Meth oxy~henyfl-4- (1 .3-ben zodioxol-5-yl)-l1-(2-(isobutoxy)ethyl)pvrrolidine-3-carboxlic acid The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 10 and 2- (isobutoxy)ethyl bromide. m.p. 68-70 00. 1 H NMR (CDC1 3 300 M~z) 8 0.88 J=6Kz, 6K), 1.82 (quintet, J=6Kz, 11H), 2.22 (in, 2K), 2.72-2.79 (in, 2.86-2.95 (in, 2H), 3.13 J=6Kz, 2H), 3.45-3.56 (in, 3.68 J=9Kz, 1H), 3.79 3K), 5.94 6.72 J=7.5Hz, 1K), 6.85 (dd, -110- J=9Hz, 7.5 Hz, 3H), 7.08 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 m/e 442 Examlle trans-2-(4-Methoxvphenyl)-4-(1 .3-benzodioxol- 1- butylsulfonyll..
Dyrrolid in e-3-carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1 C dissolved in 10 mL of THE was added 1 -butanesulfonyl chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents).
The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by* flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mg of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtCH, and a solution of 100 mg of NaCH in 1lmL 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 mg, 53%) as a white solid. m.p. 67-69 00. 1 H NMVR (ODC1 3 300 MHz) 0.82 J=7.5Hz, 3H), 1.20-1.33 (in, 21H), 1.58-1.68 (in, 2H), 2.48-2.69 (mn, 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=l2Hz, 1H), 3.65 (dd, J=l2Hz, 11H), 3.82 3H), 4.32 (dd, J=l2Hz, 11H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 (mn, 3H), 6.92 J=9Hz, 2H), 7.35 J=9Hz, 2H). MS
(DCI/NH
3 m/e 462 Examole 61 trans. trans-2-(4-M-ethoxvohenvr)-4-(l .3-benzodioxo-5-jL-14-2-(N-m ethyl-Nis rDylcarbonylamino~ethyl)-pyrrolidine-3-carbopxlic acid -111- Example 61A trans.trans-2-(4-Methoxwhenvl)-4-(1.3-benzodioxol-5-vl)- 1 -2-brnmoethvy- Dvrrolidine-3-carboxvlic acid ethyl ester To the mixture of cis,trans and trans,trans pyrrolidines resulting from Example 1C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide. The resultant mixture was heated at 100 OC for 1 hour, and then the solvents were removed in vacuo. 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-Methoxvyhenvl)-4-(1.3-benzodioxol-5-vl)-1-(2-(methlam ino)ethyl)ovrrolidine-3-carboxvlic 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 mg of sodium iodide. The mixture was heated at 80 OC 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-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1 -(2-(N-methyl-Nisobutvrvlamino)ethyl)-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 diisopropylethylamine. The solution was cooled to -40 OC, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.
The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAchexanes going to EtOAc and finally using 10% MeOH-EtOAc.
-112- The ester was dissolved in 1.5 rnL of EIOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 N_1 H 3 P0 4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na 2
SO
4 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 (ODC1 3 300 MHz) of the major rotamer 8 1.06 3H1, J=lOHz), 1.12 3H, J=lOHz), 2.15 (in, 11H), 2.5-3.0 (in, 2.91 3H), 3.32 (mn, 3.50 (in, 2H), 3.65 (in, 2H), 3.77 5.92 (s, 6.73 1H-, J=8Hz), 6.75-6.9 (mn, 4H), 6.96 11H, J=2H-z), 7.29 (in, 1H). MS (DCI/NH 3 inlz 469 Analysis calcd for C26H3 2
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.
Examgle 62 trans. trans- 2-(4-Methoxvythenyfl-4-( 1.3-benzodioxol-5-:yl)-1 ethyl-Npropionylam no)ethyl)-D2yrrolidine3carboxlic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61 C. 1 H NMR (CDC1 3 300 MHz) of the major rotamer 8 1. 13 3H, J=8Hz), 2.19 (mn, 1 2.30 (in, 2H), 2.65-3.0 (in, 3H), 2.85 31-), 3.25-3.4 (mn, 3.5-3.7 (in, 3.79 3H), 5.92 6.74 1H, J=8Hz), 6.75-6.9 (in, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DCI/NH 3 n/z 455 Analysis calcd for C25H 3
ON
2
O
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.
0 Examp~le 63 trans, trans-2 -(4-Methoxyhenvl)-4-( 1. 3-benzod ioxol-5-y)- 1 -(N-methyl-Nbenzvlam inoca rbonylmethyfl-Dyrrolidin e-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI: 3 300 MHz) of the major rotamer 8 2.79 (s, 2.8-3.2 (in, 3.48 (in, 2H), 3.61 (in, 21H), 3.77 3.78 (in, 1H), 4.3-4.5 (in, 5.95 2H, J=2Hz), 6.7-6.9 (in, 4H), 7.00 (in, 1H), 7.15-7.35 (in, 7H). MS (FAB/NBA) m/z. 503 Anal calcd for
C
2 9H- 3 0
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.
-113- Exam Dle 64 trans. trans-2-(4-Methoxyrhenyl)-4-( 1 benzodioxol-5zy-v 1-(N-ethyl-Nbutylam inoca rbonylm ethyll-D2yrrolidine-p-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDC1 3 300 MHz) of the major rotamer 5 0.88 (t, 3H, J=7Hz), 1.06 3H, J=7Hz), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6- (in, 11K), 3.79 3.80 (in, 1H), 5.92 (bd s, 2H), 6.75 1H, J=8H-z), 6.85 1H, J=8Hz), 6.92 2H, J=8Hz), 7.03 IH), 7.33 1H, J=8HZ). MS
(DCI/NH
3 m/z 483 Anal calcd for C27H- 34
N
2 0 6 0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.
Examlle 65 9 t-rans. trans-2-(4-Methoxy~henyl-4-(1 .3-benzodioxol-5-yl)-l1-(N-methyl-N-(2.2- -dimethylpror~vl)am inocarbonylmethyl)-ryrrolidine3carboUlic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (ODC1 3 300 MHz) of the major rotamer 5 0.90 (s, 9H), 2.8-3.1 (in, 4H), 2.94 3K), 3.3-3.5 (in, 3H), 3.61 (in, 1H), 3.80 (s, 3H), 3.82 (in, 1 5.94 (bd s, 2H), 6.74 1 H, J=8Hz), 6.86 2H, J=8Hz), 6.87 (in, 1H), 7.03 1H, J=2Hz), 7.33 2K, J=8Hz). MS
(DCI/NH
3 in/z 483 Examn~le 66 99 trans. trans-2-(4-Methoxcyrhenyl).4-( 1.3-benzodioxol-5-yl)- 1 ethyl-Nbutyl su Ifonvlam in o)ethyl) -12rro Iid in e-S-ca rboXyl ic acid To the compound resulting from Example 61B (60 mg, 0.13 minol) 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 wasstirred for 1 hour at room temperature and then concentrated in vacuo.
The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc-hexane to yield 64 mg of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. m.p. 64-66 00. 1 H NMR (CDC1 3 300 MHz) 8 0.92 3H), 1.39 (hexad, J=7.5Kz, 2K), 1.68-1.76 (in, 2H), 2.16-2.25 (in, 1H), 2.72 3H), 2.75-2.92 (in, 5H), 3.12-3.20 (in, 1K), 3.25-3.34 (in, 1K), 3.46-3.55 (in, 2H), 3.65 J=9Hz, 1K), 3.78 3H), 5.53 2K), 6.72 (d, -114- J=7.SHz, 1 6.82 (dd, J=7.5Hz,3Hz, 1 6.86 J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 J=9Hz, MS (DCI/NH 3 m/e 519 Exam Die 67 trans. trans-2-(4-Methoxvrhenyl)-4-( 1 3-benzodioxo-5-vfl-1 ethyl-N- D2roylsufonylamino)ethl-prrlidine3 carboxlic acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1butanesulfonyl chloride. m.p. 69-70 1 H NMR (CDCI 3 300 MHz) 8 1.02 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 (in, 1H), 2.72 (s, 3H), 2.75-2.95 (in, 6H), 3.13-3.22 (in, 1H), 3.25-3.35 (mn, 1H), 3.47-3.58 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 J=7.5Hz, I1H), 6.84 J=7.5Hz, 3Hz, 1 6.87 J=9Hz, 2H), 7.04 J--3Hz, 1H), 7.43 J=9Hz, 2H). MS (DCI/NH 3 mWe 505 Examlle 68.
trans, trans-2-(4-Meth oxvoh enyl)-4-( 1. 3-benzodioxol-5-yl)-1 (12royisufo-nl~ethl-yrroidine3cprbolic 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 OC for 1 hours. To this mixture was added the compound resulting from Example 61A (180 mng, 0.38 mmol) in 2 mL THF. Heating was continued at 60-70 OC 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- P EtOAc to give 170 mg To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mng (0.8 minol) of N-methylmorpholine N-oxide (NMAO) in a mixture of 20 mL of acetone and 5 mL of H 2 0 was added a solution of osmium tetroxide mng) 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 Na 2
SO
4 and concentrated in vacua. Flash chromatography afforded 177 mg of the ethyl ester which was hydrolyzed by the procedures described in Example 1 D to afford the title compound. in.p. 73-75 1 H NMVR (CDCI 3 300 MHz) 8 1.04 (t, 115- 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1H), 3.68 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.75 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 J=9Hz, 2H), 6.99 J=3Hz, 1H), 7.32 J=9Hz, 2H). MS
(DCI/NH
3 m/e 476 (M+H) Example 69 trans, trans-2-(4-Methoxvohenvl)-4-(1.3-benzodioxol-5-yi)- 1 2-envl)-pyrrolidine-3-carboxylic acid Example 69A trans-5-Methylhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 OC.
Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na 2
SO
4 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 colorless oil (2.1 Example 69B trans-5-Methylhex-2-en-1 -ol The compound resulting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride (1.5 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C 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 removed by filtration and washed with additional ether (2 x 25 mL).
The filtrate was extracted with ether (2 x 25 mL). The ether extractions and washings were combined, dried, and evaported to give a colorless oil which was purified by flash chromatography on silica gel -116eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Examlle 690 trans-i -Bromo-5-methylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 OC in an ice bath. Phosphorus tribromide g, 0.87 mL) was added dropwise and the solution stirred at 0 00 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 is trans. trans-2-(4-MethoXyohenyl)-4-( 1.3-benzodioxo-5-y)- 1 2-enyl-yrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1 D but substituting the compound resulting from Example 690C for N-propyl bromoacetamide. 'H NMR (ODC1 3 300 MHz) 8 0.84 6H, J=-8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,l4Hz), 2.86 1H, J=lOHz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, 1H, J= 5Hz,l4Hz), 3.29 (dd, 1H, J=3Hz,lOHz), 1~50 (in, 1H), 3.70 1H, J=lOHz), 3.78 3H), 5.47 (in, 2H), 5.93 2H), 6.71 1H, J=8HIz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 2H, J=9Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C26H 3 1 NOS: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
Exam ile trans. trans-2-(4-MethoXyrhenvl)-4-( 1.3-benzodioxol-5-yl)-1 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 olefins. The crude product was purified by preparative HPLC (Vydac g018) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product (and its diastereomer) as a white solid. 1H NMR of the major (trans) isomer: -117- (CDC13, 300 MHz) 5 0.83 6H, J=8Hz), 1.56 1.74 1H), 1.92 (d, 2H, J=6Hz), 3.3-3.5 3H), 3.6-3.8 3.78 3H), 3.9-4.0 1H), 5.22 1H), 5.90 2H, J=12Hz), 6.63 1H), 6.78 3H), 6.95 (s, 1H), 7.45 3H, J=8Hz). MS (DCI/NH 3 m/e 438 Anal calcd for
C
27 H33NO5 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-MethoxyDhenvl)-4-(1.3-benzodioxol-5-vl)-1 1 o heptylcarbonvlmethyl)-pyrrolidine-3-carboxylic acid Example 71A )1 -Chloro-3-propyl-2-hexanone To 2-propylpentanoic acid (156.6 I1, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 giL, 4 mole and..
the solution was cooled to 0 °C 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 °C and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 gL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient 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-yl)-1- (4-heptylcarbonvlmethyl)-pyrrolidine-3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 -118solution in toluene), diisopropylethylamine (700 g.L, 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 of the title compound as a 1o yellow oil.
9 9 Example 71C trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl-1 heDtylcarbonylmethyl)-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 mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the i"" pH to This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1:1 ethyl acetate-hexane to give 86 mg of the title compound as an off white powder. 1H NMR (CDCI 3 300 MHz) 8 0.73-0.97 6H), 1.03-1.33 6H), 1.36-1.58 2H), 2.46 1H), 2.80-2.98 3H), 3.38-3.64 3H), 3.75-3.90 1H), 3.79 3H), 5.94 2H), 6.75 1H), 6.86 2H), 6.92 1H), 7.12 1H), 7.32 2H). MS (FAB) m/e 482 Anal calcd for C28H 3 5 N0 6 C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.
-119- Example 72 trans. trans-2- Meth o2W henyl)-4- (1 ben zod ioxol- 5-yl)- 1 -(vale rylmethyl)- D2yrrolidine-3-carboxylic acid Example 72A 1 -Chloro-2-hexanpne 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.
72B o ,.0 trans, trans-Ethyl 2-(4-methoxyphenyr)-4-( 1.3-benzodioxole-5-yn)-i (valerylmethyl)Dyrrolidin. -3-carboxylate *see Substituting the compound resulting from Example 72A for 1chloro-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 to chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg was obtained as a yellow oil.
to Example 72 BsusiuigtecmonreunfrmExample 72 :f:r trans. trans-hl2-(4-methoxyphenyl)-4-(13-benzodioxol-5-yl)- 4 -heptyl carbonyl methyl)- pyrrol id in e-3-carboxylate and using the procedure described in Example 710, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg was obtained as an off white powder. 1 H NMVR (CDC1 3 300 MHz) 5 0.87 (t, 3H), 1.26 (in, 2H), 1.49 (in, 2H), 2.37 (in, 2H), 2.79-2.98 (in, 3H), 3.31- 3.49 (in, 2H), 3.56 (in, 1 3.77, 3.79 4H), 5.94 2H), 6.75 1 H), 6.81-6.93 (in, 3H), 7.09 1H), 7.33 2H). MS (FAB) in/e 440 Anal. calcd for C 25
H
29 N0 6 C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.
-120- Examlle 73 trans. trans-2-(4-Methoxyohenfl)-4-( 1. 3-benzodioxol-5yFI- 4dim ethoxybenzyl)-N-methylam inocarbonylm ethyfl yrrolidine3cp~~cai Examole 73A trans~trans- and cis, trans-2-(4-Methoxyhenyl)-4.(1 yl)-l 3 4 -dimethoxybenzyflaminocarbonylmethyl)Dyvrrolidine- 3 carboxylic acid ethyl ester Using the procedure of Example 1 D, paragraph 1, substituting 3,4dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield. trans~rpns- andExample 73B yl)-1 .4-dimethoxybenzyln-Nmethylaminocarbonylmethyl)pyrrolidine.3carboylic acdehletr The resultant product from Example 73A (220 mg, 0.404 mmol)
S
was dissolved in 2 mL dry THE and added dropwise to a stirred, cooled (0 OC) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THE, under an argon *0 atmosphere. The resulting mixture was stirred at 0 0 C for 1 hour, then methyl iodide (28 p.L, 64 mg, 0.45 mmol) was added. The reaction 00 mixture was stirred at 0 OC for 45 minutes. TLC (Et 2 O) indicated 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(1 H)pyrimidinone (50 gL, 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 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na 2
SO
4 filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et 2
O
gave the title compounds as an inseparable mixture in 43% yield. 1H NMR (CDC1 3 300 MHz) 5 2.79 and 2.81 for the N-CH 3 signals. MS m/z 591 -121- Examile 730 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yb)-1 dimethoxybenzyr)-N-methylam inocarbonylmethyflpyrrolidine.3 carboxylic acid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 OC was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H 2 0. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL H20 and 15 mL Et 2 O. The aqueous phase was extracted with 5 mL Et 2 O, then the aqueous phase was acidified with aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were hcombined, dried (Na 2
SO
4 then filtered and concentrated in vacuo to give 40 mg of the title compound as a white foam. 1 H NMR (CD3OD, 300 MHz, two rotameric forms) 8 2.85 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br in), 3.74 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 and 5.93 2H total), 6.50-6.60 (in, 1H), 6.67- 7.02 (br mn, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for
C
31 H3 5
N
2
O
8 563.2393. Found: 563.2385. Examp~le 74 trans, trans-2-(4-Methoxyhenyll-4-(1 .3-benzodioxol-5ylI- 1 dimethoxvbenzylam inocarbonylmethyl~pyrrolidine-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 73B3, to provide the title compound. 1H NMR (CD 3 OD, 300- M Hz) 8 2.85 J=l16Hz, 1 2.92 (b r t, J=9Hz, 1 2.98 (b r t, J=l1OHz, 1 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 3.67 3H), 3.78 (s, 3H), 3.80 3H), 3.85 J=10 Hz, 1H), 4.21 J=l5Hz, 1H), 4.41 J 1H), 5.91 2H), 6.67 J=8Hz, 1H), 6.75-6.95 (mn, 7H), 7.33-7.40 (in, 2H). HRMS calcd for C 3 oH 32
N
2 0 8 549.2237. Found: 549.2224.
-122- Example (2R.3R.4R)-2-(4-Methoxypheny)-4-(1.3-benzodioxol-5-vyl-1-((1R-.l.-N.NdiDropylaminocarbonyl)-l-butyl)pyrrolidine-3-carboxylic aci s Example trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- 1 R-1 (benzyloxvcarbonvl)butvl)vrrolidine-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, 1o 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
CO
3 and 25 mL of CH 2 Cl 2 The aqueous phase was extracted with 2 x 10 mL CH 2 Cl 2 and the combined organic phases were washed with 15 mL brine, dried (Na2SO 4 then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3:1 CH2CI2-hexane to produce 106 mg of the title compound as a waxy solid. 1 H NMR indicated the presence of two diastereomeric products. 0 Example trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y)-1 R)-1 diprovylaminocarbonyl)-l-butyl)vyrrolidine-3-carboxylic acid ethyl ester 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 give 81.4 mg of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 OC, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature ovemight. The solvent -123was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na 2 C 03.
The organic phase was washed with 10 mL of brine, dried (Na 2
SO
4 then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et2O-hexane.
Further purification of overlap fractions by preparative TLC eluting with 1:2 Et2O-hexane yielded 32 mg of a less polar product, and 44 mg of a more polar product.
Example (2 R, 3R. 4R)- 2 et h oxyh e n y 1) 4 3 -b en zo d io x o I- -ylv R) -1 (N.N-dipropylaminocarbonyl)-1 -butyl)rpyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 758 for the resultant product from Example 73B3, to provide the title compound in 94% yield. [MD -52O (c=0.235, CH 3 OH). 1 H NMR (CD3OD, 300 MHz) 0.55 J=7Hz, 3H), 0.87 J=7Hz) and 0.87-0.94 (in, 6H total), 1.03- 1.25 (br m, 2H), 1.25-1.68 (br mn, 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 (in, overlapping with CD 2
HOD
signal), 3.40-3.60 (br m, 2H), 3.79 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1H), 6.92- 6.98 (br mn, 3H), 7.29-7.39 (mn, 2H). MVS in/z 525 Example 76 (2S.3S.4S)-2-(4-Methoxyphenyl)4.(1 .3-benzodioxol-5-y)-1 R)-1 N-dipropylaininocarbonyl)-1 -butyflo1yrrolidine-3.c-arboxylic 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 73B3, to provide the title compound in 88% yield. [aID =+580 (c=0.37, CH30H). 1 H NMR (CD 3 OD, 300 MHz) 50.57 (br t, J=7Hz, 3H), 0.88-0.98 (in, 6H), 1.08-1.35 (br mi, 2H), 1.35-1.68 (br mn, 4H), 1.75-1.90 (br m, 1H), 2.75-2.86 (br in, 2H), 3.10-3.30 (br in, 2H), 3.51-3.65 (br m, 2 3.69 3H), 4.03-4.16 (br in, 2H), 5.91 2H), 6.71-6.83 (in, 2H), 6.86-6.97 (in, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 -124- Example 77 (2S.3S.4S)-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-((1S)-1-(N.
N-
dipropvlaminocarbonvI)-1-butyl)vyrrolidine-3-carboxylic acid Example 77A trans trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5-y (N.N-diDroDvlaminocarbonvl)-1-butvl)Dyrrolidine-3-carboxylic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, o1 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 OC. Trifluoromethanesulfonic anhydride S (95 p.L, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 OC, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 gIL, 75 mg, 0.58 mmol) in 3 mL of CH 2
CI
2 was added. The reaction was stirred at 0 OC for 3 hours and for an additional 2 days at room temperature.
TLC
(Et20-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 Na2CO 3 The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na 2
SO
4 filtered and concentrated in vacuo to a yellowish oil. Purification by flash S chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg of a less polar product and 20.1 mg of a more polar product.
1 H NMR spectra and MS were the same as those of Example 76B.
Example 77B (2S.3S.4S)-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-y)-1 dipropylaminocarbonyl)-l-butyl)pyrrolidine-3-carboxvlic 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 (CDsOD, 300 MHz) and MS identical to those of Example -125- Example 78 (2R.3R.4R)-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yl-1
N-
diDrovylaminocarbonvl)-1-butvl)pyrrolidine-3-carboxvlic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. 1 H NMR (CD 3 OD, 300 MHz) and MS identical to those of Example 76.
Example 79 trans. trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-yl)- N Carbonyldiimidazole (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 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 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 S with 2:1 hexane-ethyl acetate to give 790 mg of the 3carbonitrile 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 OC (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 -126acidified with acetic acid to get 532 mg of the title compound.
m.p. 165-167 0 C. 1 H NMR (CDCI 3 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 J=7Hz, 3H), 1.10-1.50 (in, 8H), 3.0-3.6 (in, 8H), 3.70 3H), 3.7-3.8 (in, 1H), 3.90 J=9Hz, 1H), 4.37 J=9Hz, 1H), 5.86 2H), 6.62 (d, J=8Hz, 1H1), 6.65-6.73 (in, 3H), 6.95 J=2Hz, 1H), 7.11 J=9Hz, 2H).
Examlle trans. trans-2- (4-Fluoroohenyl)-4-(1 .3-benzodigxol-5-y L-1 1- WN Ndibutydaminocarbony~methvfl yrrolidine3carboxlic acid The title compound was prepared as an amorphous solid from methyl (4-f lourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3benzodioxole using the procedures described in Examples 1 and 43. 1 H NMR (CDCI: 3 300 MHz) 8 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.0-1.55 (in, 8H), 2.81 J=13 Hz, 1H), 2.90-3.10 (in, 4H), 3.15-3.30 (in, 1H), 153.32-3.45 (in, 3H), 3.55-3.65 (in, 1H), 3.86 J=lOHz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 Hz, I1H), 6.95-7.07 (in, 3H), 7.32-7.45 (in, 2H).
Examn~le 81 trans. trans-2-(4-Methoxy=henyfl-4(1 .3-benzodioxol-5-y)- 1 N-di(nbutyl)am inomethylcarbonvfl~pyrrolidine-3-carboxlic acid N,N-Dibutyl glycine (150 mng, 0.813 inmol), prepared by the method of Bowman, J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mng (0.852 mmol) carbonyldiiinidazole and heated for 30 minutes at 50 0 C. After cooling to room temperature, 250 mng (0.678 iniol) of ethyl trans, trans-2-(4-inethoxyphenyl)-4-( 1,3benzodi oxo, -5-yl)-py rrolid in e- 3-carbo xyl ate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 OC for minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mng of the intermediate ethyl ester.
The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mng of the title compound as a white powder. 1H NMR (ODC1 3 300 MI-z) 8 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (in, 8H), 2.65-3.20 (in, 6H) 3.43-3.70 (in, 3H), 3.72 3H), 3.87 J=l5Hz, 1H), 4.49 (dd, J=l2Hz, 6Hz) and 5.23 (dd, J=l2Hz, 8Hz) -127- 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 (in, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 J=9Hz, 2H).
Exam le 82 trans. trans-2-(4-Methoxyghenyl-4.( 1 .3-'benzodioxl-5-ll-l1-(N-n-butyl)..N.(n.
Drol~vF)am inocarbonylmethyl)oyrrplidine.3..cprbowLic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 1 H NMVR (ODC1 3 300 MHz) rotational isomers 5 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (in, 6H), 2.63 and 2.66 (two doublets, J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.23- 3.61 (in, 5H), 3.71 and 3.75 (two doublets, J=lQHz, 1H), 3.78 3H), 5.92-5.96 (mn, 2H), 6.72 J=8Hz, 1H), 6.83-6.89 (in, 3H), 7.03 (d, J=2Hz, 1H), 7.81 J=9Hz, 2H).
Example 83 t-rans. trans-2-(4-Methoxyohenyl)-4.( 1.3-benzod ioxol-5-yl)-l1-r2-(N. N-di (npropyl am inocarb -fehlpyrldn3- bp~ic acid The compound resulting from Example 6A (250 mg, 0.677 minol), 205 mng (1.36 inmol) diallyl acrylamide (Polysciences, Inc.), and 10 mng acetic acid were heated at 85 00 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 mng of the diallyl compound, The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mng) 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 I D in 83% yield. 1 H NMVR (CDC1 3 300 MHz) 8 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (in, 4H), 2.35-2.60 (mn, 3H), 2.80-3.07 (in, 3.14-3.21 (in, 2H), 3.31-3.38 (mn, 1H), 3.51-3.61 (in, 1H), 3.73 (d, J=12H, 1H), 3.75 3H), 5.94 2H), 6,71 J=9Hz, 1H), 6.79-6.85 (in, 3H), 7.04 J=2H-z, 1H)< 7.32 J=9Hz, 2H).
-128- Example 84 trans. trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-vl)- 1-(N.N-di(nbutyl)aminocarbonyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in s 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 (CDCI3, 300 MHz) 0.86 J=7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 4H), 2.81-2.94 2H), 3.11 J=12Hz, 1H), 3.30- 3.41 2H), 3.59-3.68 2H), 3.76 3H), 3.78-3.85 1H), 5.81 (d, J=9Hz, 1H), 5.94 2H), 6.73-6.86 5H), 7.24 J=9Hz, 2H).
Example 85 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 N. Ndibutvlaminocarbonvlmethvl)pyrrolidine-3-carboxylic acid sodium salt is 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 butyl)amino)ethyl]Dyrrolidine-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 °C 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, so and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1D to give the as title compound as a white powder. 1 H NMR (CD 3 OD, 300 MHz) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 4H), 1.44-1.56 4H), 2.48-2.57 1H), 2.80-3.08 8H), 3.14-3.25 1H), 3.31-3.38 1H), 3.59-3.60 (m, -129- 1 3.74 3H), 3.75 J=1lOHz, 1 5.89 2H), 6.71 J=9Hz, 1 H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 J=lOHz, 2H), 6.96 J=2Hz, 1H), 7.37 J=lOHz, 2H).
Examlole 87 trans. trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-yf-1-2F-N -in butyl~am inocarbonyl)-N-methylaminolethyl1Dvroidine3carboxyic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 61 B (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
SO
4 and concentrated. The residue was: chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.
1015The ester was hydrolyzed by the method of Example 1ID to afford 141 mg of the title compound. 1 H NMR (CD3OD, 300 MHz) 8 0.92 (t, J=7Hz, 1.21-1.32 (in, 4H), 1.42-1.53 (in, 4H), 2.62 3H), 2.65-2.76 (mn, 1H), 3.00-3.20 (in, 8H), 3.44-3.55 (mn, 1H), 3.62-3.78 (mn, 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 6.75 J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 J=10 Hz, 2H), 7.04 J=2Hz, 1H), 7.40 (d, J=lOHz, 2H). Example 88 trans. trans-2-(4-MethoXyoheny)-4-( 1.3-benzodioxol-5-y)-1 N-di(nbutylhaminocarbonyflmethyl)o2yrrolidine3(N-methanesulfonyl)carboxam ide Carbonyldiimidazole (75 mg, 0.463 minol) was added to 150 mng 9 (0.294 minol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 OC for 2 hours.
After cooling, 50 mg (0.526 minol) of methanesulfonainide and 68 mg (0.447 iniol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 OC 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 mng of the title compound. in.p. 170-173 1 H NMR (CDC1 3 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.51 (in, 2.75-2.86 (mn, 2H), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-3.50 (in, 3.70-3.78 (in, 1H), 3.80 3H), 3.87 J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, -130- J=9KIz, 1H), 6.84 (dd, J=9Hz, 2Hz, 1H), 6.90 J=10 Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.34 J~10Hz, 2H).
ExamD~le 89 trns. trans-2-(4-Methoxy~henfl)-4-(1 .3-benzodioxol-5-yfl- 1 N-di(nbutvflam inoca rbo nyI~meth yl) gyrrolIidin e- 3-(N -benzenes uIfpnYI) ca rboxpa mide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenes ulf onamide for methanesulfonamide. m-p. 169-171 0 C for a sample recrystallized from acetonitrile. 1 H NMR (CDCI 3 300 MHz) 8 0.81(t, J=7 Hz, 3H), 0.89 J=7Hz, 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, F, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (mn, 1H), 3.65 (d, J=lOHz, 1H), 3.81 3H), 5.94 2H), 6.70 2H), 6.81-6.90 (in, 3H), 7.17 J=lQHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 1H), 8.95 J=7Hz, 2K).
Examlle trans. trans-2- (4-Methoxyohenyl)-4- (1 .3-benzodioxol-5-yl)-1 4-N. N-di (n-butyll aminosulfonylmethvll-1Dyrrolidine-3-carboxylic acid Chloroinethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. R5: 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 chloroinethyl 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 chioroinethyl sulfenyl chloride by the method of E. Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[N,N-di(nbutyl)aminosulfenylmethyl]-pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
-131- Example 91 trans.trans-2-(4-Methoxvyhenyl)-4- (1.3-benzodioxol-5-yl)-1-[(N.Ndibutylamino)carbonvl-1 -(RS)-ethylpyvrrolidine-3-carboxylic aid Example 91A (+)-Dibutyl 2-bromoDroDanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4 -methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH20C 2 the solution was cooled to 0 °C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL, 3.5 mmol). After 10 minutes at 0 OC, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M S aqueous Na 2
CO
3 solution, then the organic phase was washed sequentially with mL of 1 M aqueous NaHSO 4 and 25 mL brine, dried (Na 2
SO
4 filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 1H NMR (CDCl3, 300 MHz) 8 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 7H), 1.60-1.78 1H), 1.82 J=6Hz, 3H), 3.04-3.27 2H), 3.42-3.64 2H), 4.54 J=7H, 1H). MS (DCI/NH 3 m/ei'" 264 and 266 Example 91B trans.trans- and cis trans-2-(4-Methoxvyhenyl)-4-(1 .3-benzodioxol- 5 -vl dibutvlamino)carbonvl-l-(RS)-ethyl)Dvrrolidine-3-carboxvlic acid ethyl ester A solution of the resultant mixture of trans,trans and cis,trans compounds from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example H 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 mL of 1 M aqueous Na 2
CO
3 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 EtOAc-hexane to provide 224 mg of the title compounds as a mixture of 4 diastereomers. 1H NMR (CDC13, 300 MHz) 8 0.66-1.55 (several m, 19H), 2.63- 3.00 3H), 3.05-3.39 2H), 3.40-3.76 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 -132- (in, 4.38 J=10.5Hz, 0.21-) and 4.58 J=10.5Hz, 5.90-5.97 (in, 2H-), 6.68-6.96 (in, 7.38-7.43 (in, MS (DCI/NH 3 mle 553 Examp e 910C trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-vl)- 1 Ndibutylamino)carbonyl-l1-(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 730 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 OD, 300 MHz) 8 0.70-1.05 (9everaI mn, 8H), 1. 14 J=6Hz, 2H), 1. 17-1.55 (in, 6H), 2.79-3.03 (in, 3.5K), 3.20-3.65 (br m, 4.6H- plus CD 2 HQ10D), 3.70-3.78 (in, 0.411), 3.79 3H), 3.98 J=8Hz, 4.06 J=7.5Hz, 0.4K), 4.25 J=8Hz, 0.4K), 5.92 and 5.94 2H total 6.73 and 6.75 J=3Hz, 1 H total), 6.78-6.85 (in, 1 6.91-7.00 (in, 3H1), 7.30- 7.38 (in,2K). MS (DCI/NH 3 m/e 525 Anal calcd for C3 0
H
40
N
2 0 6 *0.5H- 2 0: 0! ,67.52; H, 7.74; N, 5.25. Found: 0,67.63; H, 7.65; N, 5.21. Exmle9 trans. trans-2-( Pentyl)-4-( 1. 3-benzod ioxol-5-yl)- 1 Ndibutylam inocarbonyl methyl)pyrrolidine-3-carboxylic acid Example 92A Methyl 2-(4-hexen oyfl-4-n itro-3-( 1. 3-benzodioxole-5-yl)butyrate *9 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 mng, 3.69 inmol) in 10 mL THE, then DBU (22 0.15 minol) was added. The resulting reddish solution was stirred a t 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 ing (2.42 minol, 82%) of the title compound as a mixture of diastereoiners; in a 1:1 ratio. 1 H NMR (ODCd 3 300 MHz) 8 1.55-1.66 (in, 2.02-2.17 (br in, 1KH), 2.20-2.37 (in, 1.5H), 2.49-2.76 (in, 1.51-), 3.57 1.5H), 3.74 1.5H), 3.97 J=7.5H, 0.51-) and 4.05 J =8H1z, 4.10-4.20 (in, 1KH), 4.68-4.82 (in, 2K), 5.06-5.52 (in, 2H), 5.95 (2s, 2K), 6.65 (in, 1KH), 6.68 (br s, 1KH), 6.75 7.51-z, 1KH). MS (DCI/NH 3 Wne 381 (M+NH 4 Anal calcd for C 18 1- 21 N0 7 C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; K, 5.71; N, 3.72.
-133- Example 92B Methyl trans.trans-2-(pentvl)-4-( 1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylat 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 1A, and the substitution of the this resultant compound for the resultant compound from Example 1B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of 1o sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO s 0. diluted with 10 mL water and 30 mL of CH 2 01 2 The aqueous phase was extracted (2 x 30 mL CH 2 C1 2 then the combined organic phases were washed with 20 mL 915 brine, dried over Na 2
SO
4 filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH 2
CI
2 gave 336 mg the title compound as a yellow oil. 1 H NMR (CDC 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 i 2H), 3.53 J=9Hz, 1H), 3.66 3H), 5.94 2H), 6.65-6.75 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.
:S.
Example 92C trans.trans-2-(Pentyl)-4-(1.3-benzodioxol-5-yl)-1 i:, dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid The procedures of Example 1B-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. 1 H NMR (CDC 3 300 MHz) 8 0.87 (br t) and 0.89 (br t, 6H total), 0.97 J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43- 1.78 (br m, 6H), 2.76 J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 3H), 3.73 (d, J=14Hz, 1H), 5.98 (AB, 2H), 6.70 J=7Hz, 1H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, 1H). MS (DCI/NH 3 m/e 475 Anal calcd for C27H 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.
-134- Example 93 trans, trans-2-(Pentyl)-4-(1.3-benzodioxol-5-yl)- 1 -2-(N-Dropyl-Npropvlsulfonvlamino)ethylvDyrrolidine-3-carboxvlic acid Example 93A Methyl trans.trans-2-(pentyl)-4- 1.3-benzodioxol-5-vy)-1 2 -bromoethvl)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 (CDC 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 2H), 2.76-2.91 2H), 3.10-3.22 2H), 3.36-3.47 2H), 3.68 3H), 5.92 2H), i) 6.69-6.77 2H), 6.90-6.94 1H). MS (DCI/NH 3 m/e 426, 428 Example 93B Methyl trans, trans-2-(Pentyl)-4-(1.3-benzodioxol-5-yl)-1 -[2-(N-proDyl-N- propylsulfonylam ino)ethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 p.mol) in 1 mL EtOH was treated with:.: propylamine (60 0.73 mmol). The solution was warmed to 80 °C for 4 hours.
The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL 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 mL of CH 2
CI
2 diiosopropylethylamine (65 iL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH and the mixture was extracted with 2 x 3 mL CH 2 C1 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 of the title compound as a waxy solid. Rf 0.17 (20%EtOAc-hexane). MS (DCI/NH 3 m/e 511 -135- Example 93C trans. trans-2-(Pentvl)-4-( 1.3-benzodioxol-5-yl)-l1-[2-(N-gropyl-Np~ropylsulfonylam ino)ethyoyrrolidine.3-carboxylic acid The procedure of Example 710C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71 B, to provide the title compound as a white foam (47 mg, Rf 0. 14 2
CI
2 1 HNMR (ODC1 3 300 MHz) 8 0.88 (br t) and 0.92 J=7Hz, 6H total), 1.22-1.52 (br m, 6H1), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H1), 2.89-2.98 (in, 2H), 3.05 (br t, J=9Hz, 1 3.10-3.30 (in, 3H), 3.30-3.80 (br m, 7H), 5.94 2H), 6.71 J=8Hz, 1 6.77 (dd, J=1 .5,8Hz, 1 6.89 J=1 .5Hz, 1 MS (DCI/NH- 3 m/e 497 Example 94 tra ns. tran--Pr 1.3-benzodioxol-5-yv-1-
N
dibutylaminocarbonylmethvl~pyrroliin-3carbo~lic acid Example 94A Ethyl 2-(4-uta noyl)-4-n itro-3-( (1 .3-ben zodio The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, Rf 0.28 (25%EtOAc-hexane). 1 H NMR (CDCI 3 300 MHz) 860.74 J=7.5Hz) and 0.91 J=7.5Kz, 3H1 total), 1.08 (t, J=7Hz) and 1.28 J=7Hz, 3H1 total), 1.45 (sextet, J=7Kz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H1), 2.17 J=7Hz) and 2'.24 J=7Hz, 0.5H total)2.40-2.54 (in, I1H), 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5K total), 3.93-4.09 (in, 2H), 4.10-4.20 (br m, 1H), 4.23 J=711z, 11H), 4.67-4.85 9m, 2H1), 5.94 2K), 6.62-6.75 (in, 3H1). MS
(DCI/NK
3 Wne 369 (M+NH 4 Anal calod for C1 7H 21 N0 7 0, 58.11; H, 6.02; N, 3.99. Found: 0, 58.21; K, 5.98; N, 3.81.
Example 94B Ethyl trans. trans-2-(propyl)-4- (1 3 -benzodiaxol-5-yl)p2yrrli-i-ne-3.ca rboxylate 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 -136- Example, 94C trans. trans-2-(Prooyl)-4-(1 .3-benzodioxol-5-yl)- 1 dibutylam in o)ca rbonyl) methylpyrrolidine.3ca,.boxlic acid The procedure of Example 920 was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 9213, to give the title compound. 1 H NMR (CDd1 3 300 MHz) 8 0.89 J=7.5Hz), 0.92 and 0.97 J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 J=7.5Hz, 1 H), 3.40-3.55 (br m, 2H), 3.55-3.68 (in, 1 3.78 J=lI5Hz, 1 5.92 J=1 Hz, 2H), 6.70 J=8H-z, 1 6.79 (dd, J=1lHz,8Hz, 1 6.90 J=1lHz, MS (DCI/NH 3 m/e 447 Anal calcd for C 25 H38N 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.
Is, Example (2R 3
R.
4 S)-(+)-2-(4-Methoxyphenyl)-4-( 1 .3-benzod ioxol-5-yl)-l1-(tertbutyloxycarbonyl-am inocarbonylmethyfl-yrroidine3-Carbox(Ylic acid ExaMDle trans, trans-2-(4-Metboxyphenyl)-4- (1 .3-benzodioxol-5-f 1 (Rtertbutyloxyarbonylam inocarbonylmethyllgyrrolidine-3.carboxcylic acid The resulting mixture of 64% trans,trans- and cis, transpyrrolidines resulting from Example 10 (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, 1 3.44-3.95 (in, 3H), 3.81 3H), 4.04 J=7 Hz, 1 4.14-4.28 (br m, 1 4.89-5.24 (br m, 1 5.94 J=3 Hz, 2H), 6.69-6.90 (in, 5H), 7.06-7.20 (in, 2H). MS (DCI/NH 3 mn/e 470 To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water.
The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove -137ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH with 1 M hydrochloric acid, then to pH 4 with 10 citric acid and extracted with 5 ethanol in methylene chloride (3 x 100 mL). The combined organic layers dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 1 H NMR (CDCI 3 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50-3.64 2H), 3.81 3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS
(DCI/NH
3 m/e 442 Example 95B: 2 R.3R.4S)-(+)-2-(4-MethoxyDhenylv-4-(1.3-benzodioxol-5-yvi-1-(tert- butvloxvcarbonvlaminocarbonvlmethvl)-ovrrolidine-3-carboxvlic acid is 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 1 H NMR and chiral HPLC. The amount of enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the enantiomer could no longer be detected in the filtrate. The pure enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether.
The aqueous layer was further extracted twice with 100 mL of ether.
The combined ether layers were washed with brine, dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum, >99.5 ee). 1 H NMR (CDCI 3 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 2H), 3.81 (s, 3H), 4.24 1H), 4.96 (br m, 1H), 5.95 2H), 6.70-6.79 3H), 6.86 J=9 Hz, 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 -138- Example (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyhenvl)-4-(1.3-benzodioxol-5-yl)-pyrrolidine.3 carboxylate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 with stirring for 18 hours at which point all of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2
SO
4 filtered, concentrated and dried under high vacuum to S give the title compound as an almost colorless oil (158 mg, 1 H NMR (CDCl 3 300MHz) 8 1.11 J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 J= 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 2H), 3.80 3H), 4.07 J=7 Hz, 2H), 4.49 J=9 Hz, 1H), 5.94 2H), 6.73 J=2 Hz, 2H), 6.81-6.92 3H), 7.34-7.41 2H). MS (DCI/NH 3 m/e 370 Example (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl-l-(tert- i butyloxvcarbonyl-aminocarbonvlmethyl)-Dvrrolidine-3-carboxylic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 LL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum; and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oil. 1H NMR (CDCI 3 300MHz) 8 0.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.10 J=7 Hz, 3H), 1.00-1.52 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 4H), 3.23-3.61 5H), 3.71 J=9 Hz, 1H), 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, Hz, 2H), 6.74 J=9 Hz, 1H), 6.83-6.90 3H), 7.03 J=2 Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 m/e 539 To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then -139warmed slowly to 40 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, 1H NMR (CDC13, 300MHz) 8 0.80 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.08 2H), 1.28 3H), 1.44 3H), 2.70-3.77 (svr br m, 12H), 3.79 3H), 5.95 2H), 6.75 J=8 Hz, 1H), 6.87 (br d, J=8 Hz, 3H), S 7.05 br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH 3 m/e 511 [a]22..
+74.420. Anal calcd for C29H38N 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 Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methoxvhenyl)-4-(1.3-benzodioxol-5- vl)-l-(tert-butvloxvcarbonvlaminocarbonvlmethvl)-Dvrrolidine-3-carboxvlic 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 S cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 1670. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-1680. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-1100. (HPLC of this showed the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was -140added. After stirring for a few minutes the crystals were filtered.
Yield: 1.401 g, m.p. 164-1720.
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-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 12-(N-Drogyl-Nbutyrylamin-o'ethylllyrrolidine-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 p.C1B) eluting with a 10-70% gradient of CH3CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMVR (CDCI 3 300 MHz) 5 0.80 (in, 3H), 0.90 3H, J=8H-z), 1.42 (in, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1H), 5.95 2H), 6.75 (d, 1 H, J=BF-z), 6.84 (mn, 1 6.85 2H, J=8Hz), 7.04 1 H, J=1lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 497 Anal calcd for C28H 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.
Exaingle 97 trans. trans-2-(4-Methoxyghenyl)k4-( 1.3-benzodioxol-5-yfl- 1 -l2-(N-groDyl-N- (ethylamninocarbonyfl am ino~ethyll1Drrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for methylainine 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. 1H NMVR (CDC1 3 300 MHz) mixture of rotamers 8 0.80 J=8Hz) and 1.05 J=8Hz) and 1.20 (in) and 1.42 (in) total of 8H for the four peaks, 2.35 (br s, 1 2.70 (in, 1 3.0 (in, 3H1), 3.2 (in, 3H), 3.25 (dq, 1H, J=1,8Hz), 3.42 (mn, 1H), 3.6 (in, 1H), 3.75 (mn, 1H), 3.78 3H), 4.8 (br s, 1H), 5.95 2H), 6.74 1H, J=8Hz), 6.85 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (DCI/NH 3 nWe 498 -141- 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.
ExampDle 98 trans. trans-2- Methoxvlhenyl)-4- (1 ben zod ioxol-5-yl). 1 -12- (N-butyl-Nbutyrylamino)ethyll Dvrrolidine-3-carboxylic -acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61iC. The crude product was purified by trituration with 1:1 diethyl ether-hexane.
The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white 'solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.45 (in, 4H), 1.6 (mn, 2H), 2.20 3H, 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br mn, 4H), 3.80 (br mn, 2H), 3.82 (s, 3H), 4.30 (br s, 1 5.95 2H), 6.75 1 H, J=8Hz), 6.84 (mn, 1 6.85 2H, J=8Hz), 7.04 1H, J=1 Hz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 511 HRMS calcd for C 2 9H3 8
N
2 0 6 511.2808. Found: 511.2809 Examp~le 99 trans. trans-2-(4-Methoxylhenyfl-4-( 1.3-benzodioxol-5-yfl- 1 -2-(N-DrooYl-Nethoxycarbonylamino)ethlloyrrolidine-3-carbo~,lic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61B and ethyl chloroforinate for isobutyryl chloride in Example 61C.
The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC1 3 300 MHz) 8 0.80 3H, J=BHz), 1.05 (in, 2H), 1.22 (in, 3H), 1.45 (in, 3H), 2.08 (br s, 1H), 2.75 (in, 1H), 2.88 (br q, 2H, J=8Hz), 3.08 (br in, 2H), 3.27 (br in, 2H), 3.44 (mn, 1H), 3.54 (dt, 1H, J=1,8HZ), 3.63 1H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 2H), 6.72 1H, J=8Hz), 6.81 (dd, 1H, J=1,8Hz), 6.85 2H, J=8Hz), 7.00 1H), 7.30 2H, J=8Hz). IMS
(DCIINH
3 in/e 499 Anal calcd for C27H3 4
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.
-142- Example 100 trans, trans-2-(4-Methoxylhenyl)-4- (1 .3-benzodioxol-5-ylF-l1 [2-(N-mehy;- N-(2ethylbutyryl)am ino)ethyl]Dyrrolid ine-3-carboxylic acid To the compound resulting from Example 61 B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), Nmethylmorpholine (50 gL), and DMF (2 ML). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water mL) was added, and the mixture was extracted with EtOAc (2 x mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 N H3P 04, and brine, dried with Na 2 S 04, and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The 01 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 (CDC1 3 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (in, 2H), 1.25-1.75 (in, 2.16 (mn, 1 2.32 (mn, 1 H), 2.45 (mn, 1 2.70 (in, 1 2.86, 2.94 total 3H), 2.95 (in, 1 3.35 (in, 1 3.52 (in, 2H), 3.65 (in, 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 (in, 1H), 6.84 (in, 3H), 6.97 (in, 11H), 7.30 (in, 2H). MS (DCI/NH 3 m/e 497 Anal calcd for C 28
H
36
N
2 0 6 -0.25 H 2 0: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56. Exain~le 101 trans. trans-2-(4-Methoxyhenyfl-4-( 1.3-benzodioxol-5-yl)- 1 [2-(N-methyl- N-(2propylvalerylbam ino~ethylllpyrrolidine-3-carboxyl ic acid The title compound was prepared by the procedure described in- Example 100, but substituting -2-propylpentanoic acid for 2ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac p.C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.
1 H NMR (CDCI 3 300 MHz) 8 0.79 3H-, J=8Hz), 0.82 3H, J=8Hz), 1.10 (mn, 4H), 1.2-1.5 (in, 4H), 2.55 (in, 1 2.96 3H), 3.15 (br mn, 1 3.32 (br mn, 1 3.56 (in, 2H), 3.68 (in, 1 H) 3.68 3H), 3.70 (in, 1 3.80 (in, 2H), 4.65 (br d, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (mn, 1 6.85 2H, J=8Hz), 7.05 1 7.42 2H, J=8Hz). MS (DCIINH 3 m/e 525 -143- Anal calcd for C 3 0
H
4 oN 2
O
6 1.25 TEA: C, 58.51; H, 6.23; N, 4.20.
Found: C, 58.52; H, 6.28; N, 4.33.
Examlle 102 trans. trans-2-(4-MethoXvlhenvfl-4-(1 .3-benzodioxol-5-y)-1 4-2-(N-jDropyl-N-tert..
butyloXyca rbony m ethyl) am in o)ethyll gyrrol idine- 3-cp rboxvl ic 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 etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMVR (CDC1 3 300: p MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 1.19 9H), 2.12 (in, 1H), 2.46 (in, 2H), 2.70 (in, 3H), 2.85 (mn, 3.20 3.40 (dd, 11-, J=2,8Hz), 3.50 (dt, 1H, J=2,8Hz), 3.62 1H, J=8Hz), 3.78 3H), 5.95 2H),: 6.72 1 H, J=8Hz), 6.84 (mn, 1 6.85 2H, J=8Hz), 7.05 1 7.16 2H, J=8Hz). .MS (DCI/NH 3 m/e 541 Anal calcd for 4
ON
2 0 7 -1.0 H 2 0: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.
Exaingle 103 trans. trans-2-(4-Methoxyhenyr)-4-(1 .3-benzodioxol-5-vl)- 1 -2-(N-12roc~yl-N-(n- Dropvlaininocarbonylm ethyl)am ino)ethyl]loyrrolidine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for inethylamine in Example 61B and N-propyl broinoacetamide for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac jiCi8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR
(CDCI
3 300 MHz) 8 0.78 3H, J=8Hz), 0.88 3H, J=8Hz), 1.45 (in, 2H), 1.48 (in, 3H, J=8Hz), 2.55-2.7 (mn, 2H), 2.90 (in, 1H), 3.04 (mn, 1H1-), 3.15 (mn, 3H), 3.28 1H, J=8Hz), 3.45 11H, J=8Hz), 3.60 (in, 3.70 (d, 2H, J=8Hz), 3.75 (in, I1H), 3.80 3H), 4.25 1KH, J=8Kz), 5.95 2H), 6.75(d, 1H, J=8Hz), 6.86 (dt, 1H, J=1,8Hz), 6.88 2H-, J=BHz), 7.04 (d, 1IH, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 526 Anal calcd for C 2 9
H
3 9 N30 6 -1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
-144- Examlle 104 trans, trans-2-(4-Methoxyhenyl).4-(1 .3-benzodioxol-5-vl'- 1 -r2-(N-jDropyl-N-(4mehahnxcroy~mn~tyi~roiie3croyi acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (00300, 300 MHz) mixture of rotamers 8 0.88 1.57 (in, 2H), 2.45 (br s) and 2.60 (br s, total of I1H), 2.90-3.15 (in, 4H), 3.42-3.7 (in, 3.78 3H), 3.80 3H), 3.85 (in) and 4.0 (in, total of 1 5.95 and 5.98 total of 2H), 6.63(m, 1H), 6.72 1H, J=8Hz), 6.81 (mn, 2H), 6.93 (in 5H), 7.40 (in, 2H). MS (DCI/NH 3 m/e 577 Anal calcd for 032H 3 6
N
2 08 1.0 H 2 0: 0, 64.63; H, 6.44; N, 4.71. Found: 0, 64.70; H, 6.38;0 N, 4.63.
Example 105 trans. trans-2-(4-Methoxyhenyl-4-(1 .3-benzodioxol-5-y)- 1 N-groo~yl-N-(4- methoxybenzoyl)am ino'~ethyllpyrrolid ine-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylainine in Example a 61B and anisoyl chloride for isobutyryl chloride in Example 610. 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 (00013, 300 MHz) mixture of rotamers 6 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1.52 (q, J=BHz) total of 2H, 2.25 (br s, 1 2.78 (br s, 1 2.90 (br t, 2H), 3.12- 3.68 (in, 7H), 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 1H, J=8Hz), 6.83 (in, 5H), 6.94 (in, 1H), 7.22 (mn, 4H). MVS (FAB) m/e 561 Anal calcd for C 32
H
36
N
2 07 -0.75 H20: 0, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.
-145- Examlle 106 trans, trans-2-(4-Methoxcyphenyl)-4-( 1. 3-benzodioxol-5-y)- 1 ropyl-N..
benzoyl am in o)eth yll pyrro li din e-3-ca rboxyl ic 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. 1H NMR .(CDC1 3 300 MHz) mixture of rotamers 8 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (in, total of 1 2.6 3.6 (in, 8H), 5.92 2H), 6.70(d, 1 H, J=8Hz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH 3 m/e 531 Anal calcd for C 3 1
H
3 4
N
2 0 6 0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23. Found: C, 0 69.48; H, 6.19; N, 4.84.
Example 107 trans. trans-2-(4-MethoXyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 (2-(N-propyl-Nbenzyloxycarbonylam ino)ethyllpyrrolidine-3-carbox(ylic 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 .C 18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (ODC1 3 300 MHz) 8 0.8 (in, 3H) 1.45 (in, 2H), 2.20 (br m, I1H), 2.75 (mn, 1H), 2.93 (in, 1H), 3.15 (in, 2H), 3.32 (in, 3H), 3.52 (in, 2H), 3.66 (in, 11H), 3.78 3H), 5.00 (in, 2H), 5.94 2H), 6-72(d, 1H, J=8Hz), 6.82 (in, 3H)-, (br d, 1 H, J= 15Hz), 7.2 4H), 7.30 (in, 3H1). MS (FAB) in/e 561 Anal calod for C32H3 6
N
2 0 7 -1.0 TFA: C, 60.53; H, 5.53; N, 4.15.
Found: C, 60.66; H, 5.34; N, 4.28.
Examlle 108 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxo-5-yl). 1 -[-(N-propyl-N-(4m ethoxybenzyloxyca rbonyl~am in o)ethyllp~yrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylainine for methylainine in Example 61 B -146and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61 C.
Examlole 109 trans. trans-2-(4-Methoxyohenvl)-4-( 1.3-benzodioxol-5-yl)-i -r2-(N-butyl-Neth oxca rbonviamr ino) ethvtlovyrro li din e-3-ca rboyl ic- 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 .C 18) 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 NMR p (CDC1 3 300 MHz) 8 0.82 3H, J=8Hz), 1.20 (in, 5H), 1.34 (in, 2H), 3.08 (in, 2H), 3.17 (mn, 2H), 3.52 (in, 2H), 3.75 (in, 3.78 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, 1 5.94 2H), 6.76 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 (br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). MS (FAB) m/e 513 Anal calcd for C 28
H
36
N
2 0 7 -0.5 TEA: C, 61.15; H, 6.46; N, 4.92.
Found: C, 60.99; H, 6.80; N, 4.93.
Examogle 110:.* trans. trans-2-(4-Methoxyphenyfl)4-( 1.3-benzodioxol-5-yl)-1 -r2-(N-butyl-N- Droloxcarbonylamino)ethvlloyrrolidine-3-carbowlic acid The title compound was prepared by the methods described in Example ,61, but substituting butylamine for methylainine in Example 618 and propyl chloroformate for isobutyryl chloride in Example 61C.
The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC1 3 300 MHz) 8 0.80 (br s, 1H), 0.85 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (in, 3H), 1.40 (in, 3H), 1.62 (br in, I1H), 2.15 (br s, 1 2.72 (in, 1 2.87 (mn, 1 H), 3.1-3.45 (in, 5H), 3.55 (in, 1 3.64 1 H, J=8Hz), 3.79 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 2H), 6.73(d, 1H, J=8Hz), 6.85 (in, 3H, 1H), 7.30 2H, J=8Hz). MS (FAB) in/e 527 Anal calcd for C29H 38
N
2 0 7 -0.15 H 2 0: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21.
-147- Example 111 trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -[2-(N-propy[-Npropoxycarbonylam ino'ethyllpyrrolidine-3-carbox)Lip acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and propyl chioroformate for isobutyryl chloride in Example 61C.
The crude product was purified by trituration with 1:1 diethyl etherhexane. 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 8 0.80 3H, J=8Hz), 093 (in, 3H), 1.43 (in, 3H), 1.62 (in, 1H), 2.15 (br s, 1 2.68-3.45 (in, 8H), 3.54 (in, 1 3.66 (in, 1 3.78 3H), 3.94 (in, 5.94 6.72 1 H, J=8Hz), 6.82 (in, 1 6.84 2H, J=8Hz), 7.00 (br s, 1H), 7.33 (in, 2H). MS (DCI/NH 3 m/e 513 Anal calcd for C 28
H
3 6
N
2
O
7 0.15 H 2 0: 0, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.
Examlle 112 tra ns. t trn.tans-i N- Di(n-butyflaminocarbonyl)methyl-2. 4-di(l1.3-benzodioxolyl~pyrrolidine-3-carboxylic acid Ethyl (3,4-methyl enedi oxybe nzoyl) acetate, prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 3,4- methylenedioxyacetophenone instead of 4-methoxyacetophen one, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 00. 1 H NMVR (CDC1 3 300 MHz) 8 2 0.87. (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (mn, 6H), 2.80 J=l3Hz, 1H), 2.94-3.12 (in, 4H), 3.28-3.50 (in, 4H), 3.58-3.62 (in, 1H), 3.78 J=9Hz, 1H), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (mn, 2H), 6.92 J=lHz, 1H), 7.01 H=lHz, MS
(DCI/NH
3 in/e 525 Examp~le 113 trans, trans-i1 -(2-(N-(n-Buty)-N-propylsulfonylainino)ethyl)2-(4-methoyhenyl)-4.
(1 .3-benzodioxol-5-yl)o2yrrolidine-3-carboXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 OC. 1 H NMR (CDC13, 300 MHz) 8 0.83 J=7H-z, 3H), 0.98 J=7Hz, 3H), 1.12-1.25 (mn, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2.72-3.32 (mn, 8H), -148- 3.43 (dd, J=9Hz, 3Hz, 1 3.53-3.59 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.95 2H), 6.73 J=8Hz, 1 6.83 (dd, J=8Hz, 1 Hz, I 6.88 J=9Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH 3 mWe 547 Example 114 trans. trans-. 1 N-Di(n-butflam inocarbonylmethyl)-2-(4.metho-%henyl)-4-(1.3ben zodioxol- 5-yI)12yrrolidine-3-ca rboxvlic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74-76 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=l2Hz, 1H), 2.95-3.09 (in, 4H), 3.26-3.59 (in, 5H), 3.75 J=9Hz, 1H), 3.79 3H), 4.28 4H), 6.78 (d, J=9Hz, 1H), 6.85 J=9Hz, 2H), 6.91 J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 J=9Hz, 2H). MS (DCI/NH 3 m/e 525 Example 115 trans. trans-i -(2-(N-Prol~vl-N-2rolylsu lfonvlamino)ethyfl-2-(4-methoxymhenyl)-4 (1 .3-benzodioxol-5-yl'yrrolidine--carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 OC. 1 H NMR (CDCI 3 300 MHz) 8 0.79 J=8Hz, 3H), 0.98 J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (mn, 1 2.69-3.32 (mn, 9H), 3.42 (dd, J=3Hz, 12Hz, 1H), 3.52-3.58 (in, 1H), 3.64 J=l2Hz, 1H), 3.80 3H), 5.95 2H), 6.73 J=llHz, 1H), 6.83 (dd, J=lHz, 11Hz, 1H), 6.87 (d, J=llHz, 2H), 7.0 J=2Hz, 1H), 7.32 J=llHz, 2H). MS (DCI/NH 3 mn/e 533 ExaMDle 116 trans. trans-i -(2-(N-Butvl-N-butylsulfonylam ino~ethyl)-2-(4-methoxyrhenyl).4-( 1.3ben zod ioxoI- 5-yfln yrro lid in e-3-ca rboxyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 OC. 1 H NMR (CDC13, 300 MHz) 8 0.82 J=6Hz, 3H), 0.91 J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33- 1.42 (mn, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (in, 1H), 2.70-3.28 (mn, 9H), 3.41 J=8Hz, 1H), 3.52-3.58 (mn, 1H), 3.65 J=BHz, 1H), 3.79 (s, -149- 3H), 5.95 2H), 6.72 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.87 J=8Hz, 2H), 7.01 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Examlle 117 trans. trans- -Dibutylam inocarbonlmethy)..2-(4-methoxymethopwyheny)- 4- (1 .3-be nzod ioxo 1-5 -yflyrro lid in e-3-ca rboxylic acid 4-Hydroxyacetophenone was treated with chioromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title cornpound as a white solid.
m.p. 48-49 00. 1 HNMR (ODC1 3 300 MHz) 8 0.81 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 1.44 (quintet,: p J=7Hz, 2H), 2.75 J=l2Hz, 1H), 2.94-3.10 (in, 4H), 3.25-3.35 (in, 1H), 3.40 J=l2Hz, 1H), 3.43-3.52 (in, 2H), 3.47 3H), 3.55-3.62 (in, 1H), 3.77 J=9Hz, 1 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1 6.86 (dd, J=lHz, 8Hz, 1H), 7.0 J=8Hz, 2H), 7.04 J=lHz, 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 541 Examlle 118 trans, trans-i1 N-Dibutylam inocarbonvlmethyfl-2-(4-hydroxyrhenyl).4-(1 3ben zodioxol-5-yflpyrroli di ne-3-carboxylic acid hydrochloride salt The compound resulting from Example 116 was treated with a.
concentrated HCl in 1:1 THF-isopropanol to give the title compound as a white solid. in.p. 211-21200C 1 H NMR (CD 3 OD, 300 MHz) 8 0.90 (t, J=8Hz, 6H), 1.12-1.27 (mn, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 1H), 3.14- 3.35 J=9Hz, 1H), 3.90 (bs, 3H), 4.17 J=l5Hz, 1H), 5.96 2H), 6.82-6.93 (in, 4H), 7.03 J=lHz, 1H), 7.42 (bs, 2H). MS (DCI/NH 3 m/e 497 Examp~le 119 trans. trans-i (N-I sobutyl-N-grolylsulfonylamino~ethy;).2(4..methoylDhenyl)-4 (1 .3-benzodioxol-5-yvrpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 73-.74 OC 1 H NMR (CDC1 3 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, J=8Hz, 2H), 2.23-2.34 (mn, 1H), 2.68-2.98 (mn, 7H), 3.08-3.18 (in, 1H), 3.26-3.42 (mn, 2H), 3.52-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.80 (s, -150- 3H), 5.90 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.86 J=8Hz, 2H), 6.98 (d J=1lHz, 1 7.33 J=8H-z, 2H). MVS (DCI/NH 3 m/e 547 Example 120 trans. trans-i -(2-(N-Ben zenesulfonyl-N.D2rol~vlam ino'~ethyI)-2-(-methowxvhenyl..4 3 -benzodioxol-5-yfloyrrolidine-3-cprboxlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 1 H NMR (CDCI 3 300 MHz) 8 0.74 J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.72 (in, 1H), 2.85-3.05 (in, 4H), 3.12-3.22 (in, 3.38 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 1H), 3.62 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.73 Kd J=8Hz, 1H), 6.84 (dd, J=lHz, 8Hz, 1H), 6.85 J=9Hz, 2H), 7.02 J=lHz, 1H), 7.28 J=9Hz, 2H), 7.39-7.54 (mn, 3H), 7.70 J=7Hz, 2H). MS (DCI/NH 3 m/e 567 Examgle 121 trans. trans-.1 -(2-(N-(4-Methoxybenzenesulfonl)-N-.Drolplm ino~ethyfl-2-(4-:...
methoxyohenyl)-4-(1 3 -benzodioxol-5-vflp1yrrolidine-3-cprboxlic acid Using the procedures. described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 0* 2.71 (in, 1H), 2.82-3.03 (mn, 4H), 3.08-3.18 (in, 3.38 (dd, J=3Hz, 9Hz, 1H), 3.48-3.56 (in, 1H), 3.62 J=9Hz, 1H), 3.81 3H), 3.86 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.81-6.89 (in, 5H), 7.01 J=lHz, 1H), 1 7.28 J=8Hz, 2H), 7.62 J=8Hz, 2H). MS (DCI/NH 3 m/e 597 Examgle 122 trans, trans- 1 N-Di(n-butyl)am inoca rbonylmethyl)-2-(2-m ethoxyethon-4m ethoxvohenyl)-4- (1 ben zodioxoI- 5-ylD yrro Iidine-3..ca rboxl ic acid 2- Hyd roxy- 5-m eth oxyacetophe none was treated with sodium hydride and bromoethyl methyl ether in THF at 70 00 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 CC. I H NMR (CDC1 3 300 MHz) 8 0.84 J=7Hz, 3H1), 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (mn, 3H), 3.26-3.36 -151- (in, 2H), 3.43 3H), 3.47-3.54 (in, 3H), 3.66-3.72 (in, 2H), 3.78 3H), 3.76-3.84 (in, 1H), 4.02-4.10 (in, 2H), 4.25 J=9Hz, 1H), 5.92 2H), 6.40 J=2Hz, 1H), 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 J=8Hz, 1H), 6.83 (dd, J=lHz, 8Hz, 1H), 5.98 J=2Hz, 1H), 7.53 (d J=9Hz, 1H). MS
(DCI/NH
3 m/e 585 Example 123 trans, trans- 1 -(2-(N-ProlyI-N-(2 .4-dimethylbenzenesulfonyl)pm ino ehvfI.-( methoxyohenyl)-4-( 1. 3 -benzodioxol5-ylpv2rrolidine.3.cprbpwlic -acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 00. 1 H NMVR (ODC1 3 300 MHz) 8 0.69 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 2.32 3H), 2.47 3H), 2.62-2.69 (in, 1H), 2.78 J=9Hz, 1H), 2.89 (dd, J=8Hz, 1H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (in, 015 1 3.60 J=9Hz, 1 3.82 3H), 5.96 2H), 6.72 J=7Hz, 1 6.80 (dd, J=lHz, 9Hz, 1H), 6.86 J=9Hz, 2H), 6.97 J=lHz, 1H), 7.03 (bs, 2H), 7.29 J=9Hz, 1 MVS (DCI/NH 3 m/e 595 (M+H)I.
Examlle 124 trans. trans-i1 -(2-(N-ProIyl-N-(3-ch lorogrogylsulfonyl~pm ino~ethyl)-2-(4methoXyvohenyl)-4-(1 3 -benzodioxol-5-yfLo)yrrolidine3carbo~lic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 00. 1 H NMVR (CDC1 3 300 MHz) 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (in, 3H), 2.70- 2.80 (in, 2.85-3.10 (in, 6H), 3.23-3.31 (in, 2H), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (in, 4H), 3.81 3H), 5.94 6.73 J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.86 J=8Hz, 2H), 7.00 7.33 J=8Hz, 2H). MS
(DCI/NH
3 m/e 567 Examile 125 trans. trans-i1 ropyl-N-(2-m ethoxyethylsulfonyl) am ino~ethyl)-2- (4methoxyphenyl)-4- (1 3 -benzodioxol-5-ylpvrrolidine-3-carbo)lic acid Using the procedures described in Example 66, trans, trans-i1 Propyl- N-(vi nyl suIf onyI)ani no) ethyl) -2-(4-ineth oxyphenyl).4-( 1,3benzodioxol-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 OC. 1 H NMR (CDC1 3 300 -152- MHz) 8 0.78 J=7Kz, 3H), 1.42 (sextet, J=7Hz, 2.23-2.32 (in, 1 H), 2.72-2.79 (in, 1KH), 2.86-3.05 (in, 4H), 3.10-3.27 (in, 4H), 3.32 3H), 3.43 (dd, J=3Hz, 9Hz, 1KH), 3.53-3.58 (in, 1 3.65 J=9Hz, 1KH), 3.69 (t, J=6Hz, 2H), 3.80 3H), 5.94 6.73 J=8Kz, 1 6.82 (dd, J=1lHz, 8Hz, 1 6.87 J=8Hz, 7.02 J=1lHz, I1H), 7.33 J=8Hz, 2H). MS (DCI/NH 3 m/e 549 Examrle 126 trans, trans- 1 42-(N-Propvl-N- (2-ethoxyethylsulfonyl)am ino~ethl methoXyvohenyl)-4-( 1. 3- ben zod ioxo- 5-vl) pyrrol idine-3-ca rboxyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 58-60 0 C. 1H NMVR (ODC1 3 300 MHz) 8 0.78 J=7Kz, 3K), 1.18 J=7Kz, 1.43 (sextet, J=7Kz, 2K), 2.24- 2.33 (in, 1K), 2.70-2.80 (in, 1K), 2.87-3.05 (in, 4K), 3.13-3.20 (mn, 2K), 3.22-3.32 (in, 2H), 3.42 (dd, J=2Kz, 9Hz, 1H), 3.46 J=7Kz, 3.52- 3.58 (in, 1KH), 3.65 (d J=9Kz, 1KH), 3.72 J=6Hz, 2K), 3.80 3K), 5.95 2H), 6.73 J=7Hz, 1H), 6.83 (dd, J=lHz, 7hz, 1H), 6.87 J=8Hz, 2H), 7.00 J=l~z, 1K), 7.32 J=8Kz, 2K). MVS (DCI/NK 3 m/e 563 Example 127 trans. trans-i1 -(2-(N-ProlyI-N-(5-dimethylamino-l1-nap~hthylsulfonyl)am ino)ethyl)-2 (4-rnethoxyphenyl)-4-(1 .3-benzod ioxol-5-yl) pyrrolidine-3-garboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 0C. IH NMR (CDC1 3 300 MHz) 8 0.62 J=7Hz, 3K), 1.28 (sextet, J=7Kz, 2K), 2.12-2.20 (in, 1H), 2.78 J=9hz, 1H), 2.88 6H), 2.72-2.89 (in, 11K), 3.05-3.12 (in, 2H), 3.26-3.45 (in, 3K), 3.45-3.52 (in, 11K), 3.58 J=9Kz, 1K), 6.97 (d, J=lHz, 1H), 7.13 J=7Kz, 1K), 7.26 J=8Kz, 7.42-7.50 (in, 2H), 8.08 (dd, J=l~z, 7Hz, 8.20 J=8Kz, 1H), 8.48 J=8Hz, MS
(DCIINH
3 m/e 660 Example 128 trans. trans- 1 -(2-(N-Prolyl-N-(ethylsulfonyflam in -)thvl)-2-(4-methoXyphenyl)-4- (1 .3-benzodioxol-5-yl~pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 00. 'H NMR (CDC13, 300 MHz) -153- 8 0.79 J=8Hz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 (in, 1H), 2.71-2.80 (in, 1H), 2.82-3.10 (in, 6H), 3.18-3.32 (in, 2H), 3.43 (dci, J=3Hz, 9Hz, 1H), 3.53-3.60 (mn, 1H), 3.65 (ci, J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.73 (ci, J=7Hz, 1H), 6.82 (dci, J=lHz, 7Hz, 1H), 6.88 (d, J=8Hz, 2H), 7.00 J=lHz, 7.32 (ci, J=8Hz, 2H). MS (DCI/NH 3 m/e 519 Examile 129 trans, trans-i1 2 -(N-Prorvl-N-(4-methylbenzenesulfonyl)am ino)ethvl)-2-(4methoxyphenyl)-4- (1 3 -benzodioxol-5-yl~prroliciine-3-carbolic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 00. 1H NMR (CDC1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.40 3H), 2.61-2.72 (in, 1H), 2.83-3.05 (in, 4H), 3.08-3.19 (in, 2H), 3.48:: (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 3.62 J=9Hz, 1H), 3.81 3H), 5.95 2H), 6.73 (di, J=8Hz, 1H), 6.82 (ci, J=8Hz, 1H), 6.87 (ci, J=8Hz, 2H), 7.00 1 7.21 (ci, J=8Hz, 2H), 7.29 (ci, J=8Hz, 2H), 7.57 (ci, J=8Hz, 2H).
MS (DCI/NH 3 m/e 581 Example 130 trans, trans-i1 N-Diin-butyflam inoca rbonymethyl)-2(3-pyriiyp,-4-(1 .3benzodioxol-5-yl)Dyrrolidine-3-carboxylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et at., 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 00. 1 H NMR (CDC1 3 300 MHz) 5 0.82 J-7Hz, 3H), 0.89 J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (in, 6H), 2.86-3.20 (in, 6H), 3.34-3.43 (in, 2H1), 3.57 (dci, J=3Hz, 9Hz, 1H), 3.75-3.83 (in, 1H), 4.08 (ci, J=9Hz, 1H), 5.93 2H), 6.73 (ci, J=8Hz, 1H), 6.90 (dci, J=2Hz, 8Hz, 1H), 7.03 (ci, J=2Hz, 1H), 7.38 (dci, J=4Hz, 8Hz, 1H), 8.04 (ci, J=8Hz, 1 8.48 (dci, J=2Hz, 4Hz, 2H). MS (DC I/NH 3 in/e 482 (M+H)I.
Examgle 131 trans. trans-i -(2-(N-Propyl-N-(n-butylsulfonyl)am ino)-ethyt)-2-(4-methoXyDhenyl)-4 (1 .3-benzodioxol-5-y)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 CC. 1 H NMR (CDC1 3 300 MHz) -154- 8 0.78 J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.31-1.46 (in, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (in, 1H), 2.70-3.08 (in, 7H), 3.12-3.23 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (in, 1H), 3.64 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.72 J=7Hz, 1H), 6.83 (dd, J=lHz, 7Hz, 1H), 6.86 J=8Hz, 2H), 7.00 J=lHz, IH), 7.32 J=8Hz, 2H). MS (DCt/NH 3 mle 547 Example 132 trans. trans-i1 -(2-(N-Prolyl-N-(4-ch lorobenzenesulfonvflam ino-)ethyl)-2-(4.
methoxyghenyl)-4-(1 3 -benzodiox 1-5-yflyrrolidine3carbowlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 OC 1 H NMR (ODC1 3 300 MHz) 8 0.72 J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (in, 1H), 2.78-2.86 (in, 1H), 2.96-3.03 (in, 3H), 3.13-3.26 (in, 3H), 3.51 (dd, J=5Hz, 9Hz, 1H), 3.62-3.68 (in, 1H), 3.80 3H), 3.94 J=9Hz, 1H), 5.92 2H), 6.75 J=8Hz, 1 6.84 (dd, J=2Hz, 8Hz, 1 6.94 (d, J=8Hz, 2H), 6.98 J=2Hz, 1H), 7.36 J=8Hz, 1H), 7.49 J=8Hz, 1H), 7.68 J=8Hz, 1 MS (DCI/NH 3 in/e 601 Example 133 trans. trans- 1 (N-Propyl-NJ-benzylsulfnyl~am ino)ethyl)-2-(4-methoxyrhenyl)-4 (1 3 -benzodiox 1-5-yl)p2yrrolidine:3carbpylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 00. 1 H NMR (ODC13, 300 MHz) 8 0.72 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2.06-2.16 (mn, 1H), 2.56- 2.67 (mn, 1H), 2.75-3.10 (in, 6H), 3.30 (dd, J=2Hz, 9Hz, 1H), 5.95 2H), 6.73 J=7Hz, 1H), 6.80 (dd, J=lHz, 7Hz, 1H), 6.86 J=8Hz, 2H), 6.97 J=lHz, 1H), 7.27-7.35 (mn, 7H). MS (DCI/NH 3 m/e 581 Examlle 134 trans. trans-i1 -(2-(N-Propyl- lorobenzen Iuf nlIam ino~ethyl)--( methoXyphenyl-4-(1 -benzodioxol-5-yl)pyrrLQidine3car-boclic -acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 00. I H NMR (ODd1 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2.18-2.27 (mn, 1H), 2.56- 2.67 (mn, 1H), 2.78-2.87 (in, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (in, 2H), 3.33 (dd, J=2Hz,- 9Hz, 1 3.43-3.50 (mn, 1 3.57 J=9Hz, I1H), -155- 3.78 3H), 7.08 J=8Hz, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, 8Hz, 2H). MS (DCl/NH 3 m/e 585 (M+H) Example 135 trans.trans-1 -(N-Methyl-N-DroDylaminocarbonvlmethyl)-2-( 4 -methoxvyhenvl-4-(4benzofuranyl)pyrrolidine-3-carboxylic acid Example 135A Benzofuran-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 °C was added a solution of 3bromophenol (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 OC for 2.5 hours.
The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO 4 filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, b.p. 160-163 °C at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the.
above compound (17.1 g. 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yield a colorless liquid (8.13 g, b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether mL) at -78 OC was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 After stirring for minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated.
The organic solution was dried over MgSO 4 and concentated in vacuo.
The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 both as colorless oils.
-156- Example 135B trans. trans-i -(N-Methyl-N-o2roDvlam inocarbonylmehyl)-2-(4-meth xv~hAnyl) 4 4 benzof ura nyl) pyrro lid in e- -ca rbiolic 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) 8 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, in), 6.8 (2H, d, J=8Hz), 4.03 (1 H, mn), 3.94 (1 H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1 H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=llHz, 5Hz), 3.40-2.90 (5H, in), 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 Anal.calc. for C26H 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-propylam inocarbonylinethyl)-2(4methoYphenyl)-4(6.
benzofuran-Yl)pyrrolidine-3-ca rboxylic 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, in), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1H, dd, J=3Hz, 2Hz), 3.83 (2H, in), 3.79 (3H, 3.60-3.0 (7H, in), 2.91
X
(2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 451 Anal.calc. for C26H 3
ON
2 05 0.5 H 2 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
Example 137 trans. trans-i (N -Methyl- N-Dr)ropyla min ocarbonyl methyl').2-(4-m eth o= henvl)-4-(6.
ben zo-2. 3-di hyd rof uran yl) pyrrol idin e.S.carboxlic 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, CDC1 3 (minor rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, in), 7.82 (3H, mn), 5.40 (1H, dd, J=llHz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1H, in), 4.10 (1 H, in), 3.88 (1 H, in), 3.79 (3H, 3.60 (1 H, in), 3.35 (1 H, in), 3.19 (2H, t, J=8Hz), 3.00 (4H, in), 2.91 (2.78) 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH 3 in/e 453 -157- Anal.calc. for C 26
H
32
N
2 0 5 1.25 TFA: C, 57.53; H, 5.63; N, 4.71.
Found: C, 57.68; H, 5.68; N, 4.70.
Example 138 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(4-meth oxypheny)-4- 4benzofuranyflp1yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1 HNMR (300 MHz, CDCI 3 8 7.62 (1H, d, J=3Hz), 7.39 (1H, dt, J=8Hz, 2Hz), 7.34 (3H, in), 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 3.67 (1H, dd, J=lQHz, 3Hz), p 3.44 (2H, in), 3.35-3.15 (3H, in), 3.00 (2H, in), 2.84 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.23 (3H, mn), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 507 Anal.calc. for C 3 oH3 8
N
2 0 5 C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
Example 139 trans, trans-i N-Dibutylaminocarbonylmethyl)-2- (4-methoxyphenyl)-4-(4ben zof uranyl) pyrro lid ine-3-carboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 1 35A substituted 4broinophenol for 3-broinophenol, in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamnide for N-methyl-N-propyl bromoacetamnide. 1 H NMVR (300 MHz, CDCI3) 8 7.64 (1H, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, d, 1 J=8H1z), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.30 (1H, in), 3.20-2.95 in), 2.82 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MVS (DCt/NH 3 m/e 507 Anal.calc. for C 30
H
38
N
2 0 5 C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
-158- Example 140 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(4-m ehoxy herNyl)4A.In benzofuranyl)pyrroli-dine-3-carboxylc aid 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, CDC1 3 7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, in), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3l-z, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, mn), 3.30 (1H, in), 3.20-2.95 (5H, in), 2.80 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 507 Anal.calc. for 030H3 8
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-i1 N-Dibutylam inoabnlehl- (-eto~pey)4(-ez_ 2 .3-dihydrofu ranyl'pyrrolidine-3-carboxylicai The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, followed by preparative hplc). 1 H NMR (300 MHz, CDCI 3 8 7.40 (2H, d, J=8Hz), 7.16 (1H, d, J=8Hz), 6.97 (1H, dd, J=8Hz, 2Hz), 6.89 (3H, in), 5.90 (1 H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, in), 3.80 (3H, 3.70- 3.58 (2H, in), 3.40 (1H, in), 3.30-2.90 (8H, in), 1.40 (2H, in), 1.29 (3H, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS
(DCI/NH
3 mle 509 AnaI.calc. for C3 0
H
4
ON
2 0 5 0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
Examlle 142 trans, trans-i1 -(N-Methvl-N-nrogylam inocarbonylmethl-2(4methmhenyl)-4(5 indanyl)Dvyrrolidine-3-carboxylic acid Example 142A lndane-5-carboxaldehyde was prepared by forinylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5-carboxaldehydes was purified -159as follows: to a 6:1 mixture of indane-4-carboxaldehyde and 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 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 MgSO 4 filtered, and concentated in vacua. Vacuum distillation of the residue afforded carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 0 C at 0.9 mm Hg. tas rExample 142B h. .*2enl-4 trn.tans-i -(N-Methyl-N-D2ropylam inocarbonylmethvfl-2-(4-m indanyl)D2yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehycie for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 (minor rotamer) 8 7.25-7.1 in), 6.78 (2H, d, J=8Hz), 3.89 (1 H, d, J=8Hz), 3.75 (3H, 3.50- 2.90 (6H, in), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCIINH 3 m/e 451 473 Anal.calc. for C27H- 34
N
2 0 4 -2.5 H 2 0 C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.
Examn~le 143 trans, trans-i1 -(N-Methyl-N-Drogylam inocarbonylmethyD)-2-(4-m-ethoxyohenyl)..4-(6 indolyflo]yrrolidine-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, ODC1 3 (minor rotamer) 8 8.43 (1H, brs), 7.57 (1 H, d, J=8Hz), 7.43 (1 H, 7.31 dd, J=6Hz, 3Hz), 7.22 (1 H, d, J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 01H, in), 3.93 (1 H, dd, J=6Hz, 3Hz), 3.80 (1 H, in), 3.73 3.60-2.90 (6H, in), 2.86 (2.82) (3H, 1.47 septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 450 Anal.calc. for C261- 31
N
3 0 4 .0.75 H 2 0: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
-160- Example 144 trans, trans-i 1 -N-Methyl-N-propylam inoca rbonylmethyl)-2-(4-metho-xyohenyl).4- (3.4-difluoro12henyl)1ovrrolidine-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, CDCI 3 (minor rotamer) 8 7.60-7.3 (4H, in), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1 H, in), 3.79 (3H, 3.60-2.95 (6H, in), 2.92 (2.78) (3H, 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 mle 447 Anal.calc. for
C
24
H
28
F
2
N
2 0 4 -1.80 H 2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
h Example 145 trans. trans-i1 -M ethyl- N -Dropvla m inoca rbon yl methyl)-2 -meth oxvhenyn)-4 (phenyfl)yrrolidin-e-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 NMVR (300 MHz, CDCI 3 (minor rotainer) 8 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, mn), 6.88 (2H, d, J=8Hz), 3.90 (1H, mn), 3.79 (3H, 3.70- 2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 411 Anal.calc. for C 24
H
30
N
2 0 4 2.00 H 2 0: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
Example 146 trans. trans-i1 -(N-Methyl-N-12rogylam inocarbonylinethyl)-2-(4-methoy.henyl.4-(4.
hydroXyoheny112yrrolidine-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 OD) (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, 3.65 (1H, d, J=8Hz), 3.70-3.00 (8H, in), 2.92 (2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MIS
(DCI/NH
3 m/e 427 Anal.calc. for C2 4
H
3
ON
2 0 5 -1.00 H 2 0: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
-161- Examlle 147 trans.trans-l -(N-Methyl-N-propylam inocarbonylmethyfl-2-(4-methoxyhenyl4 (2 .4-d imethoxyp hen yfl 1yrrol idin e-3-ca rboxyl ic 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, CDCI 3
-CD
3 OD) (minor rotamer) 8 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 (1KH, in), 3.81 (3H, 3.79 (3H, 3.77 (3H, 3.70-2.90 (8H, in), 2.85 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7HZ). MS (DCI/NH 3 m/e 471 Anal.calc. for 0 2 6H3 4
N
2 0 6 -0.75 H 2 0: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
Example 148 trans, trans-i1 N-Dibutylam in ocarbonylmethyl)-2-(4-methoxyphenyl),.4..(5-benzo.
2.3-dihydrofuranyl~yrrolidine-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, CDCI 3 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 (1KH, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, 3.62 (1 H, in), 3.50-3.25 (4H, in), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H1, 2.79 (1K, d, J=l4Hz), 1.43 (3H, mn), 1.26 (3H, mn), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3K, t, J=7Hz). MS (DCI/NH 3 m/e 509 Anal.calc. for C 30
H
4
ON
2 0 5 -0.25 H 2 0: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.
Examlle 149 trans, trans-i1 N-Dibutylam inocarbonylmethyfl-2-(4-methoxyphenyl)-4-(4methoxph enyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-inethoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 3.76 (3H, 3.63 (1KH, in), 3.50-3.20 (4H, in), 3.15-2.90 (5H, mn), 2.78 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.27 (3H, mn), 1.09 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, -162- J=7Hz). MS (DCI/NH 3 mle 497 Anal.calc. for C29H 4
ON
2 0 5
C,
70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
Example 150 trans. trans-i N-Dibutylam inocarbonylmethyfl-2-(4-methoxvphenyl)-4.(3.
4 difluoroph en yflpyrro lid in e-3-ca rboxy ic 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, CDCl 3 8 7.35 in), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, in), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1H, in), 3.62 (1H, in), 3.50-3.30 (3H, rn), 3.23 (1H, in), 3.15-2.90 (4H, in), 2.78 (OH, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, mn), 1.08 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 503 Anal.calc.
for C28H 3 6F 2
N
2
O
4 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: 0, 64.59; H, 7.20; N, 5.35.
Examp~le 151 Mrans. trans-i1 N-Dibulylam inocarbonylmethyl')-2-(4-methoxyphenyl)4(2.4dim eth oxyphe nyl) pyrrol id ine-3-ca rboyl ic 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, 00013) 5 7.37 (2H, J=BHz), 7.20 (1H, d, J=8Hz), 6.92 d, J=8Hz), 6.60 (1H, d, J=3Hz), 6.49 (1H, dd, J=6Hz, 2Hz), 5.35 (1H, d, J=8Hz), 4.20 (3H, in), 4.10 s), 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, 0 t, J=7Hz), 1.30 (4H, 1.07 (4H, 0.87 (3H, t, J=7Hz), 0.80 (3H1, t, J=7Hz). MS (DCI/NH 3 m/e 527 Anal.calc. for C30H 42
N
2 OG 1 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
Examn~le 152 trans, trans-i1 N-Dibutlaminocarbonylmethyl-2-2heny-4-(1 yl)Dyrrolidine-3-carboLxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.
1H NMR (300 MHz, CDCl 3 8 7.50-7.25 (5H, in), 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 (11H, -163d, J=4Hz), 3.85 (1 H, d, J=8Hz), 3.64 (1 H, in), 3.42 (3H, in), 3.27 (2H, i) 3.20-2.90 (5H, in), 2.81 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 481 Anal-calc. for C 2 8
H
36
N
2 0 5 C, 69.98; H, 7.55; N, 5.83.
Found: C, 69.69; H, 7.63; N, 5.71.
Examlle 153 trans, trans-i1 N-Dibutylam incroymty)2Deni4-( e~l23 dihydrofuranyl)Dyrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3- dihyd robe nzof uran-5-carboxald ehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 5 7.53 (2H, in), 7.40 (4H, in), 7.13 (1H, dd, J=7Hz, 3Hz), 6.72 (OH, d, J=8Hz), 5.40 (OH, d, J=lOHz), 4.56 (2H, t9 J=8Hz), 4.18 (1H, d, J=l4Hz), 4.07 (2H, in), 3.79 (2H, in), 3.48 (1H, d, J=l4Hz), 3.35 (1H, in), 3.28 (3H, in), 2.95 (2H, in), 1.47 (2H, in), 1.28 (4H, mn), 1.10 (2H, in), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 479 Anal.calc. for C 29
H
3 8
N
2 0 4 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.
Example 154 trans. trans-i1 N- Dib utyl am inoca rbonylm ethyfl-2- butylph enyl)4 5ben zo 2.3-dihydrofuranyl~oyrrolidine-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-tbutylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, ODC13) 8 7.60-7.30 (6H, in), 6.90 (1H, in), 4.50 (2H, in), 3.95 (1H, in), 3.85-2.95 (11H, in), 2.90 (1H, d, J=14Hz), 1-.58 (2H, in), 1.50 (7H, in), 1.41 (6H, 1.10 (2H, in), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 535 Anal.calc. for C 33
H-
46
N
2 0 4 0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
-164- Example 155 trans. trans-2-(N N-Dibutylam inocarbonylmethyl)-2-(4-m ethonyrhen-Yl)-4-(4fluorophenyflyrrolidine-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. 1 H NMR (300 MHz, ODC1 3 8 7.50 (1H, in), 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 (1 H, in), 3.8 (3H, 3.67 (1 H, mn), 3.47 (3H, in), 3.30-2.90 (5K, in), 2.82 (1H, d, J=l4Kz), 1.43 (2H, mn), 1.28 (4H, in), 1.08 (2H, mn), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 485 Anal.calc.
for C 28
H
37
FN
2 0 4 C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74. trans. trans-i1 N-Dibutylam inocabonylethy)-2- (3-4 urylW4-( 1.3-benzodioxol-5yl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting P-oxo-3-furanpropionate in Example 6 49B. 1 H NMR (300 MHz, ODC1 3 8 7.41 (2K, in), 6.97 (1H, d, J=3Hz), 6.85 (1H, dd, J=7Kz, 3Hz), 6.72 (1KH, d, J=8Hz), 6.42 (1KH, 5.94 (1KH, d, J=4Kz), 5.92 (1K, d, J=4Kz), 3.90 (1H, in), 3.70-3.25 (5K, in), 3.20-2.90 (4K, mn), 2.85 (1K, d, J=l4Kz), 1.43 in), 1.40-1.05 (6K, mn), 0.90 (6K, in). MS (DCI/NH 3 m/e 471 Anal.calc. for C26H 34
N
2 0 6 C, 66.36;
S.
K, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Examlle 157 trans, trans-i1 N-Dibutylaminocarbonymethyl)2-(isorolyl).4.( 1 .3-benzodioxoFidine-3-carboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B.
1 K NMR (300 MHz, CDCI 3 5 6.85 (1H, d, J=2Kz), 6.76 (1KH, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=8Hz), 5.92 (2K, 3.75 (1K, d, J=l4Kz), 3.66 (1K, q, J=7Hz), 3.42 (3K, in), 3.25 (3H, in), 3.11 (2K,in), 2.83 (1K, t, J=7Kz), 1.88 (1K, in), 1.55 (4H, in), 1.32 (4K, in), 0.92 (12K, in). MS (DCI/NK 3 W/e 447 Anal-calc. for C25K 38
N
2 05 0.50 K 2 0: C, 65.91; K, 8.63; N, 6.15. Found: C, 66.07; K, 8.10; N, 6.03.
-165- Examlole 158 trans. trans-i1 N-Dibutylam inocarbonylmethyl)W2-(4-t-butylphenylb4-(1.3benzodioxo 1-5-yl~yrroli din e-3-ca rboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbe nzoyl acetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4t-butylacetophenone), in Example 49B. 1 H NMR (300 MHz, CDC1 3 8 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=l4Hz), 103.65-3.25 (5H, in), 3.15-2.85 (4H, mn), 2.73 (1H, d, J=l4Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, in), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz).
MS (DCI/NH3) m/e 537 Anal.calc. for C 32
H
44
N
2 0 5 C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11. Examole 159 trans. trans-i1 N-Dibutylam inocarbonylmethyl-2-(4-t-butyllhenyfl)4-(5-benzo- 2.3-dihyd rofuranyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyryl acetate in Example 49B and 2, 3-di hyd robe nzof uran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 6 7.30 (1H, 7.13 (1H, dd, J=7Hz, 2Hz), 6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, 3.19 (3H, mn), 3.80 (3H, in), 3.48 (2H, in), 3.3 (5H, in), 2.41 (1 H, in), 1.65 (4H, in), 1.44 (4H, mn), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, in). MS (DCI/NH: 3 m/e 445 Anal.calc. for C 2 6H 4
ON
2 0 4 1.2 TEA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Examole 160 trans, trans-i1 N-Dibutylam inocarbonymethyl-2-(anti-4-methoxycyclohexyl)-4- (1 .3-benzodioxol-5-yl) Dyrrolidine-3-carboxvlip acid ExamD~le 160A syn and anti Ethyl 4-methoxycyclohexanoylacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 inmol) and carbonyldiiinidazole (6.15 g, 37.9 iniol, 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 iniol) and ethyl -166malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 oC. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature.
s The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl p-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4- methoxycyclohexyl p-keto ester (914 mg) as a colorless oil and the cis 4 -methoxycyclohexyl 1 keto ester (1.07 g) as a colorless oil. Example 160B trans trans-1 -(N.N-Dibutylaminocarbonylmethvl)-2-(anti-4-methoxvcvcloheyxvil-4-.
(1.3-benzodioxol-5-vl) Drrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the anti-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 6.84 (1H, d, J=2Hz), 6.76 (1H, dd, J=7Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, 3.69 (2H, 3.50-3.27 (5H, 3.26 (3H, 3.25-3.00 (3H, 2.88 (1H, i 1.95 (2H, 1.62 (7H, 1.33 (9H, 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 517 (M+H) Anal.calc. for C29H 4 4
N
2 0 6 S0.50 H 2 0: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.
Example 161 trans. trans--(N. N-Dibutylaminocarbonvlmethvl)-2-(svn- 4 -methoxvcvclohexvl-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 the syn-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 6.84 (1H, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, 3.65 (2H, 3.42 (2H, 3.32 (3H, 3.30-3.00 (6H, 2.82 (1H, 2.10 (2H, 1.83 (2H, 1.52 (6H, 1.33 (4H, 1.20-1.00 (4H, 0.96 -167- (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
44
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-Dibutylam inocarbonylmethyl2.4-di5beno dihydrofuranyl)ovrrolidine-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 The solution was stirred 15 minutes at 0 and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 OC. The dark red solution was stirred 1 hour at 2 °C and then poured into 50 mL of ice water. The reaction was stirred an additional minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Example 162B trans.trans-i N-Dibutylam inocarbonylm ethyl)-2.4-di(5-benzo-2.3dihydrofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in Example 49B and 2 3 -dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.43 (1H, 7.38 (1H, 7.06 (2H, 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, 3.82 (2H, 3.57 (1H, d, J=14Hz), 3.38 (1H, 3.30-3.05 (6H, 2.95 (2H, q, J=6Hz), 1.50 (2H, 1.30 (4H, 1.15 (2H, 0.94 (3H, t, J=7Hz), -168- 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 521 Anal.calc. for
C
3
H
40
N
2 0 5 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.
Examlle 163 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(3-fu ryI-4-(5-benzo-..23 dihydrofu ranyfloyrrolildine-3-ca rboxlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl f0-oxo-3-furanpropionate in Example 49B and 2 3 -dihydrobenzofuran-5.carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 5 7.42 (1 H, in), 7.38 (1 H, in), 7.13 (1 H, 7.16 (1 H, dd, J=7Hz, 3Hz), 6.70 (1 H, d, J=8Hz), 6.41 (1 H, in), 4.57 (2H, t, J=7H~z), 3.95 d, J=8Hz), 3.63 (1H, in), 3.55 (1H, d, J=14), 3.50-3.25 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 in), 2.87 d, J=l4Hz), 1.45 (4H, in), 1.35-1.10 in), 0.85 (6H, in). MS (DCI/NH 3 m/e 469 AnaI-calc. for C 27
H-
36
N
2 0 5 0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
Example 164 trans. trans-i1 N-Dibutylam inocarbonylmethyl)-2-(4-m ethoxyrhernyl)-4-(3flIu o rophen yl) Dyrro lid ine-3-carboxyl ic 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, CDC1 3 8 7.30 (2H, d, J=8Hz), 7.22 (2H, in), 6.91 (1H, in), 6.86 (2H, d, J=8Hz), 3.79 in), 3.78 (3H, 3.68 (1H, in), 3.55-3.37 (3H, in), 3.29 (1H, in), 3.15-2.90 in), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.25 in), 1.07 mn),_ 0.87 (3H, t, J=7Hz), 0.80 (311, t, J=7Hz). MS (DCI/N H 3 ine 485 Anal.calc. for C 28
H:
37
FN
2 0 4 0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.
Examlle 165 trans. trans-i1 N-Dibulylam inocarbonylmethyl)-2- (4-in ethoxcyphenyP)-4-(3- Dvridyl) Dyrrolidin e-3-carboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal -169in 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, ODC1 3 8 8.82 (1 H, bs), 8.73 (1 H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (1H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=lOHz), 6.90 (2H, d, J=lOHz), 4.39 (1H, d, J=l2Hz), 3.95 (1H, in), 3.80 (3H, 3.79 (1H, in), 3.68 (1H, d, J=l8Hz), -3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, in), 1.31 (4H, in), 1.20 (2H, in), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS
(DCI/NH
3 m/e 468 Arial.calc. for 027H 3 7N 3 0 4 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
Examgle 166 trans, trans-i1 N-Dibutylam inocarbonylmethyfl-2-(2-fluoropheny;l..4-(1.3benzodioxol-5-yl)D2yrrolidine-3-carboXylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2'-fluorobenzoylacetate in Example 49B. 1 H NMR (300 MHz, ODC1 3 8 7.52 (1H, dt, J=7Hz, 3Hz), 7.25 (1 H, in), 7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H, in), 6.88 (1 H, dd, J=7Hz, 3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 4.25 (1 H, d, J=9Hz), 3.68 (1 H, mn), 3.42 (3H, in), 3.39 (1 H, in), 3.20-2.95 (4H, in), 2.91 (1H, d, J=l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 499 Anal.calc. for C 28
H
35
FN
2 0 5 0.25 H 2 0: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.* Examole 167 trans. trans-i1 N-Dibutylam inocarbonylmethyfl-2-(3-fluoroohenyn.-4-(1.3benzodioxol-5-yflo1yrrolidine-3-ca rboxvlic 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, CDC1 3 8 7.38 (1H, in), 7.18 (1H, d, J=7Hz), 7.15 (1H, in), 7.00 (1H, d, J=2Hz), 6.95 (1H, in), 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=l4Hz), 3.63 (1H, in), 3.42 (3H, in), 3.35-2.95 (5H, in), 2.87 (1H, d, J=l4Hz), 1.44 (3H, in), 1.27 (3H, in), 1.10 (2H, in), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 499 AnaI.calc.
for C 28
H
35
FN
2 0 5 C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
-170- Examle 168 trans, trans-i1 N-DibutylaminophenylV.2. -4-methoXVPhenyl).4-( 1.3ben zodioxol-5-ylyrrolid ine3ca rbo~lic acid 4-Nitro-l1-fluorobenzene, ethyl trans, trans-2 methoxyphe nyl)-4-(1 3 -benzodioxol-5y)pyrrolidine3carboxyI ate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl transtrans-2-(4-methoxyphenyI)- 4 (1 ,3-benzodioxol-5-yl)-1 4 -nitrophenyl) -pyrrolidi ne3ca rboxyl ate.
The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohyd ride 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 1ID affords the title compound.
Examole 169 trans. trans-i1 N. N -Dib utyla minolyrim id in- 4 -fl-2- (4-m ethoxypbhenyl).4.1.3benzodioxol-5-yl)ovyrrlidine3carbo~ic -acid 2 -(Dibutylamino)-4-chloropyrimidine is prepared from 2,4- 0.0 dichloropynimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans, trans-2-(4methoxypheny) 3 -be nz odi oxol-5y) py rrol idin e3carboxy Iate (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example 1 D to the title compound.
Examlles 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 benzodioxol-5-yl)-1 (isopropylaminocarbonylmethyl )-pyrrolidine-3..
carboxylic acid; -1 '71- 1 71 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(ethylamin ocarbonylmethyl)pyrrolidine-3-carboxylic acid; 1 72 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-1 methylpropylaminocarbonylmethy)-pyrroidine.3 carboxylic acid; 1 73 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodi oxoi-5-yI 1 -(phenyl am inocarbonyl met hyl)pyrrolidine-3-carboxylic acid; 174 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1 -(pipe ridinylcarbonylmethyl)pyrrolidine-3-carboxylic acid; 1 75 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yi)-1 (propylaminocarbonyl)ethyl)-pyrrolidine-3-: carboxylic acid; 176 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-l1-(cx- (p ropyl am in oca rb onyl1) b enzyl) -py rrolIi din e- 3 carboxylic acid; 177 trans, trans-2- Methoxyph enyl1)-4- b en zo d iox o I- 5-y1) 1 (b is (p ropyIa m in oca rb o ny1) methyl1) -py rro Ii d ine -3 carboxylic acid; 1 78 trans, trans-2-(4-M ethoxyphenyl)-4-(1 ,3- 1 (propylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 179 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3be nzod ioxol 1 ropyl ami nosulf onyl methyl)pyrrolidine-3-carboxylic acid; 180 trans, trans-2-(4-M ethoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 -(2-phenethyl)-pyrrolidine-3carboxylic acid; 172- 181 trans, trans-2-(4-M ethoxyphenyl)-4-(1 ,3- 1 -(pentanoylmethyl)pyrrolidine-3-carboxylic acid; 1 82 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-l1-(benzoyl methyI)-pyrroidine- 3-carboxylic acid; 1 83 trans, trans-2-(4-Methoxypheny)-4-(1 13benzodioxol-5-yI)-l1-(hexyl)-pyrrolidine-3carboxylic acid; 1 84 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-l1-(2-hexynyl)-pyrrolid ine-3- carboxylic acid; 185 trans, trans-2- Methoxyph enyl)-4.(1 ,3benzodi oxol-5-yI)- 1 -(pro poxymethylcarbonyl- pyrrolidine-3-carboxylic acid; 1 86 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 -(phenylacetyl)-pyrrolidine-3-
U
carboxylic acid; 1 87 trans, trans-2-(4-Methoxyphenyi)-4-( 1,3- 1-(anilinylcarbonyl)- pyrrolidine-3-carboxylic acid; 188 trans, trans-2-(4-Methoxypheny)-4-(1 ,3benzodioxol-5-yI)-l1-(2-acetylarninoethyl)pyrrolidine-3-carboxylic acid; 1 89 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- )-l1-(2-phenoxyethyl)-pyrrolidi ne- 3-carboxylic acid; 190 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-l1-(2-benzodioxanylmethyl)pyrrolidine-3-carboxylic acid; 1 91 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzod ioxol 1 -(2-tet rahyd rof uranyl met hyl)pyrrolidine-3-carboxylic acid; 1 92 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 (propylaminocarbonylamino)ethenyl)-pyrrolidine.
3-carboxylic acid; -173- 193 trans, trans-2-(4-M ethoxypheny1) 1,3benzodioxol-5-yi)-1 (p ropylaminocarbonylamino)ethyl)-pyrrolidine-3carboxylic acid; 194 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodi oxol 1 oxo hex-i1 -enyl)pyrrolidine-3-carboxylic acid; 195 trans, trans-2-(2,4-Di methoxyphenyl)-4-(1 ,3- 1 -(propyl ami nocarbonyl methyl)pyrrolidine-3-carboxylic acid; 1 96 trans, trans-2-(2-Carboxy-4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yI)-1 (p ropylIa m in oc arb on yIm e thyl1) -p yrrolIi d ine -3 carboxylic acid; 1 97 trans, trans-2-(2-Aminocarbonyl-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1- (p ropylami nocarbo nyl m ethyl)- py rrol id ine-3carboxylic acid; 1 98 trans, trans-2-(2 -Methanes uIf on amido-4m e th oxy p he ny1)-4 ,3-b en zo d io xoI- 5-y 1) -1 (p ro pyIa m in o ca rb on yIm et hyl1) -py r r oIi d ine -3 carboxylic acid; 199 trans, trans-2-(2-Aminocarbonylmethoxy-4methoxyphenyl)-4-(1,3-benzodioxol-5-yI)-1- (propylaminocarbonylmethyl)-py rrolidine-3carboxylic acid; 200 trans, trans-2- Met hoxyethoxy-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1- (propylaminocarbonylmethyl)-py rrolidi ne-3carboxylic acid; 201 trans, trans-2-(2-Carboxymethoxy-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (propylaminocarbonytmethyl)-pyrrolidine-3carboxylic acid; -174- 202 trans, trans-2-(4-Methoxy-2tet raz olyl methoxyp henyl1)-4-( 1,3 -benzo d ioxoI yI)-l1 -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 203 trans, trans-2-(2-Allyloxy-4-methoxyphenyl)-4 (1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonylmethyl)-pyrrolidine-3.
carboxylic acid; 204 trans, trans 2 ,4-Bis(4-methoxyphenyI)- 1 (p ropy lami nocarbonyl methyl)-py rrolidne-3.
carboxylic acid; 205 trans, trans 2,4- B is(1 ,3 -benzo d ioxo1-5 -yl) -1 (p ropylIa m ino c arb on y Im e thy -p yrro I d n e 3 carboxylic acid; 206 trans, trans-2-(4-Methoxyphenyl)-4..(1,3 benzodioxol-5-yl)-l1-(N-rnethyl-Npropylaminocarbonylmethyl)-pyrrolidine-3.
carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxole-5-yl)-l1-(N-methyl-N- butylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 208 trans, trans-2 -Met hoxyp heny 1,3benzodioxol-5-yi)-1 -(N-methyl-N-(4methoxyphenyl)aminocarbonyl)-3-pyrrolidine.3carboxylic acid; 209 trans, trans Met hoxyphe ny1) 1,3- 1 ethyl- Nphenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 210 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(N-methyl-Nallylaminocarbonylmethyl)-pyrrolijine-3.
carboxylic acid; 211 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-1 -(N-methyl-N-(nbutyl)aminocarbonylmethyl)-pyrroicjine-3.
carboxylic acid; -175- 212 trans, trans Methoxyp he nyl)-4-(1 ,3- 1 -(N-rnethyl-Nisobutyl aminoca rbonylmethyl )-pyrrol idi ne-3carboxylic acid; 213 trans, trans-2-(4 -Met hoxyphenyl)-4-(l ,3- 1 -(N-methyl-Ncyclopentylaminoca rbonylmethyl)-pyrrolidine-3carboxylic acid; 214 trans, trans-2-(4 -Met hoxyp henyl)-4-(1 ,3benzodioxol-5-yI)-1 -(N-methyl-N-(2methoxyethyl)aminocarbonyl)-pyrrolidine-3- carboxylic acid; 215 trans,trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1 ethyl- Nbutoxyethylaminocarbonyl)-pyrrol idine-3carboxylic acid; 216 trans, trans-2-(1 ,3-Benzod ioxo 1-5-yI)-4-(4methoxyphenyl)-1 -(N-methyl-N- 00 p ro pyIa m in o carb o nyIm et hy1) -p y rroIi d in e -3 carboxylic acid; :o.
217 trans, trans-2-(4- Met hoxyphenyl)-4-( 1,4- o: benzodioxan-6-yl)- 1 -(N-methyl-N.- o o propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 218 trans, trans -2 Meth oxyphe nyl1)-4-( 1,3benzodioxol-5-yl)-1 -(N-rnethyl-Nisopropylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; 219 trans, trans-2-(4- Met hoxyphe nyl1)-4-(1 ,3benzodioxol-5-yl)-1 -(N-rnethyl-Nethyl arinocarbo nyl methyl)- pyrrol idine-3carboxylic acid; 220 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(N-rnethyl-N-( 1methylpropyl)am inocarbonylmethyl)-pyrrolidine-3carboxylic acid; -176- 221 trans, trans-2-(4- Met hoxyphenyl)-4-( 1,3- 1 -(N-methyl-Nphenylaminocarbonyl methyl)-pyrrol idi ne-3carboxylic acid; 222 trans, trans-2-(4-Methoxyphenyl)4(1 ,3- -(N-methyl-Npropylaminocarbonyl)ethyl)-pyrrolidine.3carboxylic acid; 223 trans, trans-2-(4-Methoxyphenyl)4-(1,3benzodioxol-5-yI)-1 -(a-(N-methyl-Npropylaminocarbonyl)benzyl)-pyrrolidi ne-3- carboxylic acid; 224 trans, trans-2-(4- Met hoxyp h enyl) 1,3b en z od io xolI- 5 1 (N -e th ylI-N p ro pyIa m in o carb on yIm e th y1) -p yr rolI i d ine -3 carboxylic acid; 225 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxoie-5-yl)-l1-(N-ethyl-Nbutylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 226 trans, trans-2-(4-Methoxyphenyl)-4-(1,3- 1 -(N-ethyl-N-(4-: met ho xyph enfl )aminoca rb onyI)- 3- pyrro lid in e-3carboxylic acid; 227 trans, trans-2-(4- Methoxyphenyl)4(1 ,3benzodioxol-5-yl)-l1-(N-ethyl-Nphenylaminocarbonyl)-pyrrolidine-3..carboxylic acid; 228 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(N-ethyl-Nallylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 229 trans, trans-2,-(4-Methoxyphenyl)-4(1 13benzodioxol-5-yl)-1 -(N-ethyl-Nisobutylaminocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; -177- 230 trans, trans -2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-Ncycl opentylami nocarbonylm ethyl) -pyrrolIid i ne- 3carboxylic acid; 231 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-Nmethoxyethylaminocarbonyl)-pyrrolidi ne-3carboxylic acid; 232 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 -(N-ethyl-Nbutoxyethylaminocarbonyl)-pyrrolidine-3-
V.
carboxylic acid;C.
233 trans, trans-2-(1 Be nzod ioxol1-5-yl) (4 m et h oxyp h enyl) 1 (N -e th ylI-N p rop yIa m in o ca rb on yImet hy 1) -py rroi d in e 3 carboxylic acid; 234 trans, trans-2-(4-Methoxyphenyl)-4-( 1,4benzodioxan-6-yl)- 1 -(N-ethyl-Npropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 235 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-N- isopropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 236 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 diethylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 237 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-l1-(N-ethyl-N-( 1methylpropyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 238 trans, transo2 Met hoxyp heny1) 1,3benzodioxol-5-yl)-l1-(N.-ethyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; -178- 239 trans, trans-2-(4- Methoxyphenyl)-4-( 1,3benzodioxolI-5-yI1) -1 -(N-ethyl-Npropylami nocarbonyl)ethyl)-pyrroliciine-3carboxylic acid; 240 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-((x-(N-ethyl-Npropytaminocarbonyl)benzyl)-pyrrolidine.3 carboxylic acid; 241 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzod ioxol 1 -m ethyl- Nisobutylaminocarbonylmethyl)-pyrrolidine.3-: carboxylic acid; 242 trans, trans-2-(4- Methoxyp he nyl)-4-(1 ,3b en z od iox olI- 5 1 (N -m eth ylI-N cycloh exy Ia m in oca rb o ny Imet hy 1) -p yrroIi d in e 3 carboxylic acid; 243 trans, trans-2-(4-Methoxyphenyl)-4.(1 13benzodioxol-5-yl)-1 dipropylaminocarbonymethyl)-pyrrolidine-3carboxylic acid; 244 trans, trans-2-(4-Methoxyphenyl)-4-(1 13-: benzodioxol-5-yl)-l1-(isobutyloxyethyl)-* pyrrolidine-3-carboxylic acid; 245 trans, trans-2-(4-Methoxyphenyl)-4-(1 13benzodioxol-5-yl)-l1-(butylsulfonyl)-pyrroliciine.
3-carboxylic acid; 246 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1- (isopropylsulfonylaminoethyl)-pyrrolidine-3-.
carboxylic acid; 247 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 (ethoxymethylcarbonylmethyl)-pyrrolidine-3carboxylic acid; 248 trans, trans Methoxyp he nyl) (1 ,3benzod ioxol 1 -(2-ethylb utyryl methyl)-.
pyrrolidine-3-carboxylic acid; -179- 249 trans, trans-2-(4- Met hoxypheny1) 1,3- 1 -(N-methyl-N-(3,4di methoxybenzyl)aminoc arbonyl methyl)pyrrolidine-3-carboxylic acid; 250 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 R)-1 -(N-methyl-Npropylaminocarbonyl)butyl]-pyrrolidine-3carboxylic acid; 251 trans, trans-2-(4 -Met hoxyphe nyl)-4- (1,3benzodioxol-5-yl)-l1-[(1 S)-1 -(N-methyl-Npropylaminocarbonyl)butyl]-pyrrolidine-3- carboxylic acid; 252 trans, trans-2-(4- Met hoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(3-isopropoxypropyl)pyrrolidine-3-carboxylic acid; 253 trans, trans-2- Met hoxyp henyl1)-4- (1,3- 1 -(5-methyl hexyl)-pyrrol i dine- 3-carboxylic acid; 254 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(5-methyl-2-hexenyt)- pyrrolidine-3-carboxylic acid; 255 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-* 1 -(5-methyl-4-hexenyl)pyrrolidine-3-carboxylic acid; 256 trans, trans Methoxyp heny1) -4 (1,3benzodioxol-5-yl)-l1-(3,5-dimethyl-2-hexenyl pyrrolidine-3-carboxylic acid; 257 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-l1-(2-(N-methyl-Nisobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid; 258 trans, trans -2 Methoxyp henyl1)-4-( 1,3benzodioxol-5-yl)-1 -(N-methyl-N-(2,2dimethylpropyl)aminocarbonylmethyl)-pyrroliciine- 3-carboxylic acid; -1 259 trans, trans-2 Methoxyphe ny1)-4-(1 ,3be nzodioxol-5-yl)- 1 -(N-ethyl-Nbutyl aminocarbo nyl methyl)-pyrrolidi ne-3carboxylic acid; 260 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-methyl-Nbenzylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; 262 trans, trans-2-(4-Methoxyphenyl)-4(5indanyl)- 1 (N-methyl-N-propyl aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; 262 trans, trans-2 Met hoxypheny (2,3d ih yd ro b en zof ura n -5 -yl1)- 1 (N -rn eth ylI-N p ro py Ia m in oc arb on y Imet hy1) -p y rroIi d in e 3 carboxylic acid; 263 trans, trans-2-(4-M eth oxyphenyl) 1mne th yIi n d oI- 5 -y 1 -me t h yI-N p rop y Iami n oc a rb on y Imet hy1) -p y rro Ii d ine -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 ,2dimethoxy-4-phenyl)-1 -(N-methyl-Npropylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; 266 trans, trans-2-(4-Methoxyphenyl)-4-(1 -methoxy-3phenyl)-l1-(N-methyl-Npropylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; Examgies 267-288 Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.
-181- 267 trans, trans-3-(4-Methoxyphenyl)-5-(1 13- 1 -(propylaminocarbonylmethyl)pipe rid in e-4-carboxylic acid; 268 trans, trans-3-(4- Methoxy phen y) (1 3- 1 -(am inocarbonyl methyl)piperidine-4-carboxylic acid; 269 trans, trans-3-(4-Methoxyphenyl)-s.( 1,3benzodioxol-5-yI)-1 4 -fluorobenzyl)-piperidine.
4-carboxylic acid; 270 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-1 2 -ethoxyethyI)-piperidine-4.
carboxylic acid; 271 trans, trans-3-(4 -M et hoxyp heny1) 1,3b en z o d io xo1-5 -yI1)- 1 2 -p ro p oxy et hy1) -p ipe r id ine 4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-l1-[2-(2-methoxyethoxy)ethyl]piperidine-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphenyl)-5.(1,3..
benzodioxol-5-yi)-1 (2 -pyri dy1) ethyl]piperidine-4-carboxylic acid; 274 trans, trans-3-(4- Met hoxyp h enyl)- 5- benzodioxol-5-yi)-l1-(morphoiin-4-ylcarbonyl)piperidine-4-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3- 1 -(butylaminocarbonyl)piperidine-4-carboxylic acid; 276 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-l1-(4methoxyphenyl am i nocarbo nyl)-3- pipe rid ine-4carboxylic acid; 277 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-l1-acetyl piperidin e-3-carboxylic acid; 278 trans, trans-3-(4-Methoxyphenyl)-5-(1,3benzodioxol-5-yI)-l1-(2-furoyl)-piperidine-3.
carboxylic acid; -1I82~- 279 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3- 1 -(phenylaminocarbonyl)piperidine-4-carboxylic acid; 280 trans, trans-3-(4-Methoxypheny)-5.( 1,3benzodioxol-5-yI)-l1-(allylaminocarbonylmethyl).
piperidine-4-carboxylic acid; 281 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yI)-l1-(nbutylaminocarbonylmethyl)-piperidine.4 carboxylic acid; 282 trans, trans-3-(4-Methoxyphenyl).5.(1,3- 1 -(N-n-butyl-N- m et h y Iam ino c arb on y Imet hy 1) -p ip eri d ine 4 carboxylic acid; 283 trans, trans-3-(4-Methoxyphenyl)-5.( 1,3benzodioxol-5-yi)-1 -(pyrrolidin- 1ylcarbonyimethyI)-piperidine-4-carboxylic acid; 284 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3-* benzodioxol-5-yI)-1 (isobutylaminocarbonylmethyl)-piperidine.4carboxylic acid; 285 trans, trans-3-(4- Methoxyp heny)-5-(1,3- 1- (cyclopentylami nocarbonylmethyl)-piperidine-4carboxylic acid; 286 trans, trans-3-(4-Methoxyphenyl)-5..(1,3 benzodioxol-5-yI)-l1-(morpholin-4ylaminocarbonylmethy)-piperidine-4..carboxylic acid; 287 trans, trans-3-(4-Methoxyphenyl).5.( 1,3benzodioxol-5-yI)-l1-(2-phenoxyethy)-pipericjine.
4-carboxylic acid; 288 trans, trans-3-(4-Methoxyphenyl)-5.(1,3..
1 -(methoxyethylaminocarbonyl).
piperidine-4-carboxylic acid.
-183- Example 289 trans. trans- -2-(4-Methoxyohenyl)-4-(1 .3-benzodioxol-5-yl)-1 (4dibutylaminolhenyfl)-Dyrrolidine-3-cprboxylic acid 4-Nitro-fluorobenzene, ethyl trans, trans-2-(4-methoxyphe nyl (1,3-benzodioxol-5-yI)-pyrrolidine-3-carboxylate (example 6A) and diisopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-(4-nitrophenyl).
pyrrol idine-3-carboxyl ate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohyd ride according to the method of Borch Am Chem. Soc., 93, 2897, 1971) to give the corresponding N,N- dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
Example 290 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1 -(2-i dibutylamino-Dyrimidine-4-yfl-D2yrrolidine-3-carboxylic acid 2-(Dibutylamino) 4-chloropynimidine is prepared from 2-4dichloropyrimidine according to the method of Gershon Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4- methoxyphenyl)-4-(1 3 -benzodioxol.5-yl)-pyrrolidi ne-3-carboxyl ate (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 ethoxyphenyl)-4-( 1. 3-benzodioxol-5-yl)- 1 -(N-butyl-Np2henylaminocarbonylmethyl)-ovrrolidine-3-carboxylic acid The title compound was prepared according to the general procedure of Example 1. 1 H NMVR (CD 3 OD) 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 2H); 3.10 (t,1H, 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10); 3.5-3.7 3.77 3.78 5.93 6.7-6.9 7.0-7.2 7.4 MS (DCI/NH 3 mWe 531 Anal calcd for C 3 1
H
3 4
N
2 0 6 C, 70.17; H, 6.46; N, 5.28.
Found: C,70.36; H, 6.52; N, 4.99.
-184- Example 292 Sodium trans trans-2-(4-MethoxvDhenyl)-4-(1.3-benzodioxol-5-vyl)- (N Ndibu/ylaminoca rbon ylmethyv)-pyrro lid i ne-3-ca rboxylate s Example 292A Ethyl 3-(4-methoxyphenyl)-3-oxopropionate Simultaneous reactions were run in both a 65-L reactor and a 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 i 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% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% 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 150-200 C. The jacket temperature was set to -50 C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium -185hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 100-150 C. When addition was complete, the jacket temperature was reset to 10 C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 210 C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 260 C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper).
The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L: S 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 of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg of a second crop. The yellow product darkened on standing in light and air. 0* 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-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1',8-di&za-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.
-186- Example 292D Ethyl 2-(4-methoxyphenyl)-4-(1 3-benzodioxol-5-yl)-4.5-dihydro-3Hpyrrol-3-carboxylate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi 28 (300 The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 The solids were dried in vacuo at 500 C to a constant weight of 193.4 g (21% yield, melting point 80-810 C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors. Example 292 E Ethyl 2-(4-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- 9 3H -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 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. NaCI, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
-187- Example 292 F Ethyl 2-(4-methoxyDheny)-4-(1.3-benzodioxol-5-yl-1 dibutylaminocarbonyl methyl) 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 Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgSO4 and filtered.
Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil. Example 292G trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-pyrrolidine 3-carboxvlate and preparation of transtrans 2-(4-methoxyphenyl)-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. NaCI, dried with 0.298 kg MgSO4 filtered, and concentrated to -188give 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 C) and dried to constant weight in vacuo at 50° 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-(1.3-benzodioxol-5-vyl-1- (N.N-dibutvlaminocarbonvl methyl) 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 acid (0.927 kg, 1.819 mol). A solution of 0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried **s in vacuo at 500 C to a constant weight of 0.937 kg (97% yield) of the title compound. Example 293 trans-trans-2-(4-Methoxyphenvl)-4-1. 3-benzodioxol-5-yl)-1- Idecahydroisoquinolin-2- carbonylmethyll-pyrrolidine-3-carboxvlic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS
(DCI/NH
3 m/z 521. Anal calcd for C 3 oH 3 6
N
2 06 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 Found: C, 58.34; H, 5.58; N, 4.00 -189- Example 294 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1 -r3.3dimethyljiperidinyl- carbonylmethyll-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 0.84 3H), 0.86 3H), 1.35-1.6 (in, 4H), 3.83 3H), 5.96 2H), 6.81 1H, 6.90 (dd, 1H, 7.01 2H, 7.03 1H), 7.47 2H, MS (DCI/NH 3 m/z 495. Anal calod for C28H34N 2 0 6 1.4 TEA: 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-Methoxvyphenyl)-4-(1 .3-benzodioxol-5-yl)-l prop~yl-N-iso-butoxycarbonylamino)ethyll-p2yrrolidine-3-carboxylic acid a The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamnine 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 (CDC1 3 300 MHz) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in,V.
1H), 2.72 (in, 1H), 2.90 (mn, 2H), 3.10 (in, 2H), 3.25 (in, 2H), 3.40 (in, 1H), 3.55 (in, 1 3.62 (mn, 1 3.7-3.9 (in, 2H) 3.78 3H), 5.95 2H), 6.72 1 H, J= 8Hz), 6.82 (in, 3H), 7.00 1 7.30 2H, J=8Hz). MS
(DCI/NH
3 m/e 527 Anal calcd for C 2 91H 38
N
2
O
6 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
Example 296 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yI)-1 IA .2.3,4-tetrahydroisoguinolin-2- carbonylmethyll-pyrrolidine-3carboxylic a cid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 2.97 (in, 2H), 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1H, 7.1-7.3 (in, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH 3 m/Z 515.
-190- Example 297 trans-trans-2-(4-Methoxyphenyl)-4-( 1 3-benzodioxol-5-yl- 1 propyl-N-dimethylam inocarbonylamino)ethyl1-pyr-rolidine..3-carboxylic aidL The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61iB and dimethylcarbamyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac 4aC 18) eluting with a 10-70% gradient of CH3CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 NMR (CDC1 3 300 MHz) 8 0.70 3H, 1.28 (in, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (mn, 4H), 3.70 (in, I1H), 3.80 31H), 3.90 (in, 3H), 4.72 (mn, 1 1H), 5.95 2H), 6.75 1 H, J= 8Hz), 6.87 (in, 3H), 7.05 1 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 m/e 498 Anal calcd for C27H 3 sN 3 0 6 1.25 TEA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.
Example 298 trans, tr-ans-2-(4-Methoxyphenyl)-4(1 .3-benzodioxol-5-yl)- 1 p ro py I- N- 4 -n it roben zene su If ony 1)a mi no) et hy I-1y rroIi d in e-3 carboxylic- acid Using the procedures described in Eample 66, the title compound was prepared as a yellow solid. m.p. 85-87 0 C. 1 H NMR (CDC13, 300 MHz) 6 0.77 J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (in, 1 H), 2.57-2.66 (mn, 1 2.82-3.15 (in, 4H), 3.22 J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, I1H), 3.49-3.57 (in, I1H), 3.59 J=9Hz, 1 3.83 3H), 5.96 2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 J=lHz, 1H), 7.27 J=9Hz, 2H), 7.82 J=9Hz, 2H), 8.23 J=9Hz,2H). MS (DCI/NH3) Wne 612 Examp~le 299 trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl)-1 prolyl-N-n-pentanesulfon.Ylamino)ethyl)py2rrolidine-3--carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 59-61 OC 1 NMR (CDC1 3 300MHz) 6 0.79 J=7.5H-z, 3H), 0.90 J=6Hz, 31H), 1.26-1.32 (mn, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (in, 21H), 2.23-2.32 (mn, 1H), 2.70-3.08 (in, 71H), 3.15-3.32 (in,2H), 3.42 (dd, J=3HZ,J=9Hz, 1H), 3.52-3.57 (in, -191- 1H), 3.63 J=9Hz, 1H), 3.80 3H), 5.95 2H1), 6.73 J=.7.5Hz, 1H1), 6.83 (dd, J=1lHz,J=7.5Hz, 1 6.87(d, J=8Hz, 2H1), 7.00 J=1lHz, 1 H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 Example 300 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxoLa5-I)1 (2(N propyl-N-( 4 -trifluoromethoxybenzenesufonvILaMino,ethyl) pyrrolidine-3-carboxyuic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 122-124 0 C. 1 NMR (CD3OD, 300MHz) 8 0.75 J=7.5Hz, 3H1), 1.26-1.45 (in, 2H), 2.96-3.08 (in, 2H), 3.23 (bs, 211), 3.35-3.45 (in, 2H1), 3.52 J=lOHz, 1H1), 3.81 J=9Hz, 2H), 3.86 (s, 3H), 3.92 J=9Hz, 1H), 4.63 J=lOHz, 1H1), 5.97 2H), 6.82 J=9Hz, 111), 6.93 (dd, J=3Hz,J=9Hz, 1H1), 7.06-7.08 (in, 3H1), 7.46 J=9Hz, 2H), 7.56 J=9Hz, 211), 7.89 J=9Hz, 2H1). MS (DCI/NH3), m/e 651 Example 301 trans. trans-2-(4-Methoxyphenyr..4-(1 .3-benzodioxol-5-y)- 1 12rop~yl-N-( 2 -methyl-2-propenesulfonyl)amino)ethyl)..pyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71 OC.. 11H NMR (CDCI3, 300MHz) 8 0.79 J=7.5Hz, 311), 1.93 (sextet, J+7.5Hz, 211), 1.92 311), 2.25-2.35 (in, 1H1), 2..68-2.77 (in, 111), 2.85-3.28 (in, 711), 3.40 J=9Hz, 111), 3.52- 3.68 (in, 211), 3.66 J=9Hz, 111), 3.80 311), 4.92 111), 5.07 111), 5.97 211), 6.74 J=7Hz, 111), 6.82-6.89 7.01 (s,111), 7.33 (d, J=9Hz, 211). MS (DCI/NH3), m/e 545 -1 92- Example 302 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxoL-5-yl)-1 -r2ethyl pi1e ri dinyl-ca rbonyl meth yil-Dyrrol idine.3-carbgxyli c acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. 8 0.75 3H, 1.4-1.7 (in, 8H), 3.84 3H), 5.96 2H), 6.83 I1H, 6.91 11H, 7.0-7.1 (in, 3H), 7.52 2H-, MS (DCI/NH 3 m/z 495. Anal calcd for C2 8
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 ~C propyl-N-( 2 -methvyl~ropanesulfonyflaiino')ethyt')..pyrrolidine-3 carboxylic acid Usingthe procedures decie nExample 66 h il compound was prepared as a white solid. m.p. 72-73 0 C. 1 H NMR (CDC13, 300 MHz) 8 0.82 J=7.5Hz, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 2.57-2.75 (in, 2H), 2.84-3.08 (in, 3H), 3.12-3.21 (in, 1 3.23- 3.45 (in, 1 3.43 J=1llHz, 1 3.55-3.62 (in, I1H), 3.66 J=9Hz, 1 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1 6.83 (dd, J=1lHz,J=9Hz, 1 6.87(d, J=9Hz, 2H), 7.02 J=1lHz, 1 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 547 Example 304 trans, trans-2-(4-Methoxyhenyl)-4-(1 .3-benzodioxol-5-yb)-1 propyl-N-hegtanesulfonylamino)ethylp-ryrrolidine-3carboxylic 'acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p.58-59 0 C. 1H NMR (CDC13, 300MHz) a 0.80(t, J=7.5Hz, 3H), 0.88 J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 (q, J=7.5Hz, 2H), 1.71(quintet, J=7Hz, 2H), 2.23-2.32 (mn, 2.70-3.09(m, 7H), 3.13-3.32 3.43(dd, J=3Hz,J=9Hz, 1 3.52-3.58(in,1H), 3.65(d, J=9Hz, 1H), 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1H), 6.83 (dd, J=lHz, J=7Hz, 6.87(d, J=9Hz, 2H), 7.01(d, J=lHz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) m/e 589 trans-trans-2-(4-Methoxyphenyl)-4-( 1 benzodioxo-5--i r2-(Nethyl-N-eth oxycarbonyl am ino) ethyll-pyrrolid-ine-3-ca rboxyl ic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 610. The crude product was purified by preparative HPLC (Vydac 4~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) 5 0.90 3H, J=7), 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (in, 2H), 3.78 3H), 3.82 (in, 4H), 4.10 2H, J=7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 1H, J= 8Hz), 6.84 (in, 3H), 7.00 1 7.42 2H, J=8Hz). MS' (DCI/NH 3 m/e Ip 485 Anal calcd for C 26
H
32
N
2 0 7 -1.2 TEA: 0, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yI)- 1 p royi- N-hexa nesulf onyl aino) ethyfl)-pyrrol id ine-3-carboxy i c acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60 0 C. 1 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, 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=lOHz, 1H), 3.80(s, 5.96(s, 2H), 6.74(d, J=7.5Hz,1H), 6.82(d, 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 Examp~le 307 trans-trans-2- Ethylph eny (1 .3-benzod ioxol-5y)1 -rN.N-di(nbutyl)aininocarbonylmethyll-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. 4-7, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCd 3 300 MHz) 8 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, mn), 3.53-3.23 (5H, in), 3.13-2.90 -194- (4H, in), 2.73 (1H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, in), 1.40- 1.10 (6H, in), 1.02 (2H, in), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH 3 509 Anal.calc. for C 3 oH 4
ON
2 OS 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-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl- 1-r2-(Npropyl-N-(2-chloroethoxy~carbonylamino)ethyl1..pyrrolidine-3 carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and 2-chloroethyl chloroforinate for isobutyryl chloride in Example 61C. The crude product pwas 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 NMVR (CDCI 3 300 MHz) 8 0.80 (t, 3H, 1.22 (in, 3H), 2.15 (in, 1 2.75 (mn, 1 2.85 (in, 1 3.1 (in, 2H), 3.25 (in, 2H), 3.5 (in, 3H), 3.65 (in, 2H), 3.80 3H), 4.18 (in, 11H), 4.30 (in, 1 5.98 2H), 6.72 (in, I1H), 6.82 (in, 3H), 7.00 (in, 1 7.30(m, 2H). MS (DCI/NH 3 m/e 533 Anal calod for C27H 33
N
2
O
7 CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
Example 309 trans-trans-2-(2-Methoxyethyl)-4(1 .3-benzodioxol-5-yfl-1 butyl)amino carbonylmethyll-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in I example 1, substituting ethyl 5-rnethoxy-3-oxopentanoate for ethyl 4inethoxybenzoylacetate in Example 1 A. The title compound is a yellow foam. 1H NMR (CDC1 3 300 MHz) 8 0.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28-1.41 (br m, 1.45-1.63 (br m, 4H), 2.00-2.20 (br mn, 3.06 (br t, J=9Hz, 1 3.30 (s) and 3.20-3.68 (br m, 11 H total), 3.72-4. 10 (br in, 4H), 5.92 6.72 1 6.82 (dd, J=1.5, 8.5H-z, 1 6.91 J= 1.5Hz, 1 MS (FAB) m/e 463 Anal calcd for C 25 H38N 2 0 5
-H
2 O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
-195- Example 310 transtrans-2-(4- Meth oxyI2h enyl .3-benzodioxol-5-vb- 1 ethyl- N-n-pentanesu If onyla mino ethyl)pyrrof id ine3cQArbxyl ic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58*C. 1H NMR (CDCI3, 300MHz) 8 0.89(t, J=7Hz, 3H), 1 .06(t, J=7.5Hz, 3H), 1.26-1 .37(M, 4H), 1 .72(quintet, 2H), 2.22-2.32(m,l1H), 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) mle 547 (M+H)I.
Example 311 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxo-1-5-yl)-1 -rN.N- -dicyclohexylamino carbonylmethyll-p2yrrolidine- -carboxylic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) 8 1.0-2.0 (in, 20H), 3.0-3.1 (in, 2H), 3.80 3H), 5.95 2H), 6.75 1 H, 6.86 (dd, 1 H, 6.95 (d, 2H,- 7.04 1 H, 7.38 2H, MS (DCI/NH 3 m/z 563.
Anal calcd for C33H 4 2
N
2 0 6 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 Found: C, 69.42; H, 7.29; N, 4.78.
Example 312 trans-trans-2-(4-Methoxypohenyl)-4-(1 .3-benzodioxol-5-yl)-1 12ropyl-N-tert-butoxycarbonylamino~ethyl-pyrrolidine3carboxylic..
The title compound was prepared using the procedures described lb in example 61, substituting propylamine, for aqueous methylamine in Example 61 B and di -tert-b utyldi carbonate for isobutyryl chloride in Example 610. NMR (CD3OD, 300 MHz) suggests presence of rotamers 8 0.81 3H, 1.2-1.5 (in, 11 3.78 3H), 5.92 (dd, 2H, J=1,2), 6.74 1 H, 6.84 (dd, 1 H, 6.92 2H, 6.99 (bd s, 1 H), 7.35 2H, MS (DCI/NH 3 mlz 527. Anal calcd for C29H 3 8
N
2 0 7
C,
66.14; H, 7.27; N, 5.32 Found: C, 66.,05; H, 7.36; N, 5.15.
-196- Examiole 313 trans-trans-2-(4-Methoxy--3-fluorophenyl)-4-(1 1 4[N N-di~n-butyl) amino carbonylmethyll-pyrrolidine-3-carbpxylic 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 00. NMR (CDC1 3 300 MHz) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), .1.03-1.50 (in, 8H), 2.82 (d, J=l3Hz, 1H), 2.90-3.13 (in, 4H), 3.20-3.50 (in, 3H), 3.39 J=13H, 1H), 3.55-3.65 (in, 1H), 3.82 J=lOHz, 1H), 3.87 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8Hz, 1H), 6.83-6.91 (in, 2H), 6.99 J=2Hz, 1H), 7.06 (in, 2H). Anal calcd for C2 9 H37N 2 0 6 F: C, 65.89; H, 7.06; N, 5.30 Found: 0, 65.82; H, 7.13; N, 5.29. Example 314 trans, trans-2-(Prooyl)-4-(1 .3-benzodioxol-5-yl)- 1 -(2-(N-IorolYpentanesulfonylamino)ehyloyrrolidine-3-carboxylic acid Examole 314A Progyl ontanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL
CH
2
CI
2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH 2 01 2 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 30 min, then at 25 OC for 4 h. The solution was partitioned between 20 mL of11.0 M aqeous NaHSO 4 and mL CH 2
CI
2 The organic phase was washed sequentially with 25 mL H 2 0 and mL brine, then dried (Na 2
SO
4 filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAchexane) Rf 0.23; 1 HNMR (ODC1 3 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28-1.5.0 (br mn, 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br mn, 2H), 2.98-3.06 (in, 2H), 3.08 J=-6Hz, 2H), 4.10-4.23 (br m, 1 MS (DCI/NH 3 m/e 211 (M+NH 4 Example 3149B Ethyl trans. trans--4 (1 ben zod ioxol-5 -vB- 1 (2 -brom oeth yfl-2-p roo~yl 12rro lidi ne-3ca rboyl ate The title compound was prepared according the procedure of Example 61A, substituting the compound of Example 94B for the pyrrolidine mixture.
-1 97- Example 314C Ethyl trans. trans-2-(Propyfl-4-( 1.3-benzod ioxol-5-yl)- 1 (N-Dropyl pentanesulfonylam ino~ethyfl Dyrrolid ine-3-carboxylate A solution of the compound of Example 314A (6.6 mg, 34 prinol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, pRmol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 gjmol) 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 00 overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO 3 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
SO
4 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 (73/6) of the title compound as a wax.
Examlle 314D trans. trans-4-( 1. 3-benzod ioxol-5-yl)-2- (Propyfl- 1 -(2-(N-Dropyl- 12entanesulfonylamino~ethyl)pyrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71 C. 1 H NMR (ODC1 3 300 MHz) 8 0.88-1.00 (in, 1.20-1.55 (br m, 1.55-1.68 (mn, 3H), 1.70-1.85 (br m, 1.90-2.16 (br mn, 2.84-3.26 (br m, 3.26-3.90 (br m, 6H), 5.95 6.76 (d, J=81-iz, 6.79 (mn, 11H), 6.93 (br s, 1H); HRMS (FAB) calcd for
C
2 61H 41
N
2
O
6 S 497.2685, found 497.2679. :0: Example 315 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl- 1 propyl-N-d im ethyl s uIfam oyl am ino)et hyfl-p2yrrolidi ne-3-ca rboxylic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. in.p.59-61 0 C. 1 H NMR (CDCI3, 300MHz) 8 0.79 J=7.5Hz, 1.45(sextet, J=7.5Hz, 2.22-2.31(m,1H), 2.65(s, 2.70-2.79(m, 1H), 2.85-3.04(m, 3,09-3.32(m, 21-), 3.40(d, J=9Hz, 1H),3.55 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, 11H), 6.88(d, J=9Hz, 2H-), 7.02(s, 7.34(d, J=9Hz, MS (DCI/NH3) m/e534 -198- Example 316 trans-trans-2-(4-Methoxphenyfl)-4-(1 .3-benzodioxol-5-yfl-1 -r2-(Np2ropyl-N-[4-methoxyphenyllsulfonylamino~proyll-pyrrolidine.3.
carboxylic acid Example 316A Ethyl trans-trans and cis-trans 2-(4-Methoxyphenyl)i-4-( 1.3- -1-(3-bromopropyfl 4yrrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4methoxyphenyl)-4-( 1,3-benzodiox-5-yl) -pyrrolidine-3-carboxylate (4.00 g; prepared according to example 1 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 1000 for 1.25 hrs. The excess p dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na 2
SO
4 and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 of the title compound.
Example 316B Ethyl trans-trans and cis-trans 2-(4-Methoxylhenyfl-4-(1,3- 1 -(3-12ropyl amino prolyfl pyrrolidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at*.
800 for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried I (Na2SO 4 The soilution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without purification.
Example 316C trans-trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yfl-1 -r2-(Np~rogyl-N-[4-m ethoxyphenyllsulf onyl amino) g LQyfl-pyrrolid ine-3carboxylic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitrile. containing dii sop ropylethylamine. The resulting product was chromatographed on sil ,Ica gel (30% EtOAc in hexane), and -1 99hydrolyzed to the title compound by the method of example 1 D. NMR
(CDCI
3 300 MHz) 8 0.83 J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (n 2H), 2.00-2.11 (in, 1H), 2.40-2.51 (in, 1H), 2.69-2.78 (in, 1H), 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.85 J=8Hz, 3H), 6.93 J=8Hz, 2H), 7.02 J=2Hz, 1H), 7.29 J=8Hz, 2H), 7.69 J=8Hz, 2H). Anal calcd for C3 2 H38N 2 0 8 S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.
Examn~le 317 trans-trans-2-(4-Methoxohenyfl-4-( 1.3-benzodioxol--i).1 -r2-(Nprol~vl-N-propylsulfonylamino~propyll-pyrrolidine-3.carboxylic acid Using the method described in example 66, the propylamino compound prepared in Example 31 6B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylainine. 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 (ODC1 3 300 MHz) 8 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 (mn, 2H), 1.65-1.85 (mn, 4H), 2.04-2.16 (mn, 1H), 2.42-2.57 (mn, 1H), 2.72- 3.11 (in, 5H), 3.25-3.41 (in, 2H), 3.50-3.62 (in, 3.80 3H), 5.85 (s, 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C 28
H
38
N
2 0 7 S: C, 61.52; H, 7.01; N, 5.12. Found: C, 61.32; H, 7.01; N, 5.01.
Example 318 trans, trans--2-(3-Fluoro-4-methoxyphenyl)-4-( 1.3-benzodioxol-5yl)1 -(2-(N-propyl-N-2entanesulfonylainino)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.66-68 0 C. 1H 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(mn, 2H), 2.25-2.33(m, 1H), 2.72-2.92(mn, 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=lOHz, 1H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(dd, J=lHz,J=BHz,1 6.92(t, J=8Hz,1H), 6.97(d, J=lHz, 1H), 7.12(d, J=8Hz, 1H), 7.18(dd, J=lHz,J=l2Hz, 1H). MS (DCI/NH3) m/e 579 -200- Example 319 trans-trans-2-(4-Pyridinyfl-4-(1 .3-benzodtioxol-5--YI1 -[N.N-di(nbutyl)amino carbonymethyll1Dyrrolidi ne-3-carboxylic -acid.
The title compound was prepared using the methods described in examples 1 and 43, using methyl 3 -oxo- 3 4 -pyridyt)propanoate Am.
Chem. Soc. 1993, 115, 11705) in place of ethyl (4methoxybenzoyl)acetate. m.p. 131-132 OC. NMR (ODC1 3 300 MHz) 8 0.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.97 J=l3Hz, 1H), 3.00-3.25 (in, 4H), 3.32 (in, 1H), 3.39 (d, J=l3Hz, 1H), 3.45-3.52 (in, 1H), 3.67-3.78 (in, 1H), 4.10 J=9Hz, 1H), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 J=9Hz, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H), 7.02 J=2Hz, 1H), 7.45 J=8Hz, 2H), 8.50 J=8Hz, 2H). Anal calod for C27H 35
N
3 0 5 C, 67.34; H, 7.33; N, 8.73 Found: C, 67.39; H, 7.45; N, 00 8.61. 0..
Example 320 tras-ras--(-Mthxyhenyl)4-(1 .3-benzodioxol-5-yn)-1 %00 gropyl-N-diethylaminocarbonylamino)ethvyl-pyrrolidine-3-carboxylic The title compound was prepared using the procedures described in example 61, substituting propylainine for aqueou's methylamine in .00 Example 61 B and diethylcarbainyl chloride for isobutyryl chloride in :o Example 61C. NMR (CD 3 OD, 300 MHz) 8 0.74 3H, 1.09 6H, 1.33 (in, 2H), 3.17 4H, 3.78 3H), 4.04 (in, 1 5.93 (s, 211), 6.86 1 H, 7.06 (dd, 1 H, 6.94 2H, 7.04 1 H, 7.40 2H, MS (DCI/NH 3 in/z 526. Anal calcd for C29H 39
N
3 0 6 0.1 TEA: C, 65.31; H, 7.34; N, 7.82 Found: C, 65.33; H, 7.43; N, 8.14.
Example 321 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 diinethylpip~eridinyl- carbonymethyl-pyrolidine-37-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows mixture of isomers. 8 0.88 3H, 0.93 3H, 3.82 3H), 5.95 2H), 6.82 1H, -201- 6.89 (dd, 1H, 7.00 d, 2H, 7.03 (in, 1H), 7.47 2H, MS (DCI/NH 3 m/z 495.
Example 322 trans-trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yfl-1 -rN.Ndi(s-butyl) amino carbonylmethyll-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) suggests a mixture of isomers. 8 0.83 6H, 1.27 6H, 1.6 (in, 2H), 3.79 3H), 5.93 2H), 6.75 1l-H, 6.86 1 H, 6.94 2H-, 7.03 1 H, J=2), 7.35 2H, MS (DCI/NH 3 m/z 511.
0 Example 323 trans-trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl- 1 M ethyl phenyl)- N-butyl amino carbonylmethyll-p2yrrolidine-3-carboxylic:7 The title compound was prepared using the procedures described in example 1. MS (DCI/NH 3 m/z 545. Anal calcd for C3 2
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.
Examlle 324 tra ns -tra ns- 2 -Me t ho xyp h eny 1) -4 3 -b e nz od io xo I- 5 y 1)-I [rN-(3Q Methylphenyl)-N-butylamino carbonylmethyl]-pyrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described 0 in example 1. NMR (CD 3 OD, 300 MHz) d 0.88 3H, 1.2-1.5 (mn, 4H), 2.31 3H), 2.8 (in, 2H), 3.14 1 H, J=1 3.3 (in, 1 3.44 (dd, 1 H, J=5,10), 3.53 (in, 1 3.60 2H, 3.79 3H 3.82 (mn, I1H), 5.93 2H), 6.74 1 H, 6.8-6.9 (mn, 5H), 7.06 1 H, 7.09 2H, 7.18 1H, 7.27 1H, MVS (DCI/NH 3 m/z 545. Anal calcd for C 32
H
36
N
2 0 6 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 Found: C, 68.70; H, 6.67; N, 4.85.
-202- Example 325 trans, trans-4-( 1.3-Benzodioxol-5-yl-2-(benzyloXymethyiL1
N-
dib utylam inoca rbonylmethyl)D2yrrpi idin e-3-carboxydLcaci Example-325A Ethyl trans, trans-4-( l.
3 -Benzodioxol-5-yl)-2:L(benzyloxym ethyl)- Ndibutylami in o hl~yrldie3crtxlt The procedures of Example lA-iD were followed, substituting ethyl 4benzyloxy-3-oxobutyrate for 4 -methoxybenzoylacetate* in Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; 1 H NMR
(CDCI
3 300 MHz) 5 0.88 J=7Hz, 6H), 1.17 J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 J=8Hz, 1KH), 2.98-3.30. (in, 511), 3.39-3.60 (in, 3H), 3.64- 3.75 (in, 2H1), 3.92 J-l4Hz, 1H), 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (in, 2H), 6.69 J=9Hz, 1H), 6.77 (dd, J=1.5, 9Hz, 1H), 6.91 1 MS (DCI/NH 3 Wne 553 Example 325B trans. trans-4-( 1.
3 -Benzodioxol-5-yfl-2-(benzyloxym ethyl)-l Ndibutylam inocarbgnylmethyl)pyrrolidine-3.carboxlic acid The title compound was prepared according to the procedure of Example:** 710, as a colorless glass. TLC MeOH-CK 2
CI
2 Rf 0.13; IK NMR (CDCI 3 300 MHz) 8 0.86 J=7Kz), and 0.90 J=7Kz, 6K total), 1. 15-1.52 (br in, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2K), 3.80 (dd, J=3, 13Hz, 1KH), 3.88-4.40 (br m, 6H), 4.45 (AB, 2K), 5.90 2K), 6.70 J=8Hz, 1 6.84 (dd, J=i ,8Kz, 1 6.93 J=1 Hz, 1KH), 7.28-7.39 (in, 5H); MIS (DCI/NH 3 m/e 524 Example 326 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2- (hyd roxyethyh-
N-
dibutylam inocarbonylmethyl~pyrrolidine-3..cprbo~lic acid Example 326A Ethyl trans, trans-4-(1 3 -Benzodioxol-5-yl)-2-(hydroxynethyl). 1 Ndibutylam inocarbonylmethyflp1yrrolidine.3carboxylate The resultant product from Example 325A (128 mg,+ 0.232 mmol) and 25 mng of 20% Pd(OK) 2 on charcoal in 7 mL EtOK 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 -203under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Examp ie 326B tra ns. trans-4-( 3-Benzodioxol-5-yl)-2-(hydroxymethv;)-
N-
dibutylam ino)carbonyl)rnethyllyrrolidine-3.carbolicai The title compound was prepared according to the procedure of Example 71GC.
Example 327 trans. trans--4-(1 Ben zod ioxol-5-yi)-2- (N -m ethyl prop~enam id-3-yl)- 1 N d ib utyla m i noca rbo nylm ethyl) pyrrol idin en3-ca rboxylic acid h Example 327A Ethyl trans, trans--4- (1 .3-Be nzod ioxol-5-yi) (form yl)- 1 Ndibutylam inocarbonylmethy~pyrrolidine-3-ca rbox~ylate The title compound is made by selective oxidation using the Swern oxidation with DMS0, oxalyl chloride, ethyiisopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.
Exampl~e 327B Ethyl trans. trans--4- (1 Ben zodioxol-5-yl)-2- (O-ert- butylp ropenoat-3.y.1 N- d ib utylarnin oca rbonyl methyl) yrrolidi ne-3-ca rboxgylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenyiphospho rany lid ine acetate in CH 2
CI
2 solution.
Example 327C Ethyl trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(propenoic acid-3-yl)- Nd ib utylarn in oca rbonylmrnethyf1l~yrrolid in e-3-ca dbogyl ate The title compound is produced by reacting the compound of Example 327B with trif luoacetic acid in CH 2
CI
2 1).
-204- Example 327D Ethyl trans, trans--4-( 1.
3 -Benzodioxol-5-yl)-2-(N-methylpronenam id-3-yi)- 1 Ndibutylaminoca rbonylmethyl)pyrrolidine-3-carbpxylate The title compound is produced by condensing the compound of Example 3270 with methylamine hydrochloride in the presence of a carbodjimide
N-
ethyl-N-(3-dimethylam ino)propylcarbodiim ide, DCC).
Example 327E trans. trans--4-( 1.
3 -Benzodioxol-5-y)-2-(N-methyrpen m id-3-Yl)-1 Ndibutylaminocarbonylmethyl)pyrrolidine-3-c rbo~lic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 710. Examlle 328 trans. trans--4-(1 .3-Benzodioxol-5-yl)-2- (1 -hydroxy-2-propen-3-yl)- 1 N- dibutylaminocarbonylmelhyl)pyrrolidin e-3-carboxylic acid Example 328A Ethyl trans, trans--4-(1 .3-Benzodigxol-5-y)-2-(1 -hydroxy-2-propen-3-l)- 1 .Ndi butylam in oca rbonylmnethyl)pyrrol idi n e3ca rboyl ate The title compound is produced by reacting the compound of Example 327C with borane, methyl sulfide complex.
Examle 328B trans, trans--4-( 1.3-Benzodioxol-5-yl)-2-( 1 -hydrox-2,12ropen-3-yl)- 1 dib utyla m i noca rbonylm ethyl) pyrrol idi ne-3-ca rboxylic acid The title compound is produced by condensing the compound of Example- 328A with lithium hydroxide according to the procedure of Example 71C.
Example 329 trans. trans--4- (1 .3-Benzodioxol-5-yi)-2- (N-b-enzylam inom ethyl)- 1 Ndib utylam inoca rbonylm ethyl) pyrrol idi n e -3carbonyl ic acid -2 Examlle 329A Ethyl trans, trans--4- 3-Ben zodioxol-5-yfl (N-ben zylpam inm eth yl)- 1 Ndibutylam indca rbonvlmethyI)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 327A with benzylamine, in the presence of sodium cyanoborohydride in ethanol.
Examole 329B trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-4N-benzylam inmehl-1(N.dib utyl am inoca rbonylm ethyl pyr rolidi n e-3ca rbogyljc acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71 C.
Example 330 ktrans. trans-4- Ben zod ioxoI- 5-yfl-2- (N-acetyl- N-benzyl am in om ethyl)- 1 N dibutylaminocarbonylmethyl)pyrrolidine3carbo~clic acid Example 330A Ethyl trans. trans--4-( 1.
3 -Benzodioxol-5-yfl-2-(N-acetylNbenzylam inomethyl)- 1- N-dibutylam in ocarbonylm ethyl) pyrrol id ine-3-crb xylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine. Examl* trans, trans--4- (1 Benzodioxol-5-yl-2-(LN- acetyl- N benzyl am inom ethyl)- 1 N- dibutylaminocarbonylmethy)yrrolidin3carboxlic acid The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71 C.
Exaple33 trans. trans--4-( 1. 3-Benzodioxol-5-yfl-2-(ethynyl)-1
N-
dibutylaminoca rbonylmethyl)pyrrolidine-3-carboxylic acid -206- Example 331A Ethyl trans. trans--4- (1 Ben zod ioxo l_5-fl-2-(ethynYFI)- 1 N dibutylaminoca rbonylmethyl)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.
Examlle 331 B trans. trans--4- 3-Ben zodioxoI- 5-yl-2- (ethynyl)- 1 Nd ib utyla m inoca rbonyl methyl) pyrrol id in e-3-cprboaylicacild The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 710C.
Example 332 tans. trans--4-(1 .3-Benzodioxol-5-yl)-2-(l 1pentynyl)- 1- Ndibutylam inocarbonylmethyl)D2yrrolidine-3-carboxylic acid Example 332A Ethyl trans. trans--4-(1 .3-Benzodioxol-5yl)"-2-Dentyoyl)-
N-
dibutylaminogarbonylmethyl)pyrrolidinep-3-carboxcylate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. Org. Chem. 1989, 54(15), 3618-24). Example 3328B.
trans. trans--4-( .a-Benzodioxol-5-yl)-2-(1 -Dentynyl)- 1 Ndibutyl am inoca rbonylm ethyl) pyrrol id ine-3-carboxylic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of- Example 710C.
Example- 333 trans-trans-2- Metho xphenyl)-4-( 1.3-benzodioxo-1-5-yl)- 1 -f 2-(2.6dioxopiperidinyl) ethyll-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 -207glutarimide is hydrolyzed to the title compound by the method of example 1iD.
Examlle 334 trans-trans-2-(4-Methoxynhenyfl-4-(1 dighenylaminocarbonymethyl]-pyrroidine-3..carboxylic acid.
The title compound was prepared according to the procedures described in Example 1. 1 H NMVR (300 MHz, CD 3 OD) 8 2.83 (dd, 1, J 8.1, 2.99 1, J 15.4), 3.19 1, J 3.49 1, J 15.3), 3.51 (dd, 1, J 4.6, 3.57 (in, 3.79 3.85 1, J 5.90 (S, 6.71 1, J 6.84 (in, 7.04 1, J 7.14-7.16 (in, 6), 7.19-7.34 (in, MVS (DCI/NH 3 inlz 551; Anal Calod for C33H30N2O6.0.651200.350 2
H
5 0C0CH 3 C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
EXamnDle 335: tran s -tra ns- 2 et h oxy12h e ny 1) -4 .3 -b enz o d ioxo I- 5 I -r N.N diisopropylaminocarbonylmethyll-pyrrolicdine3-crboxylic acid.
The title compound was prepared according to the procedures described in Example 1. 1 H NMVR (300 MHz, CD 3 OD) 5 0.95 3, J 1.24 3, J 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, J 8.1, 3.14 1, J 3.32-3.55 (in, 3.63 (in, 5.92 6.75 1, J 6.85 (dd, 1, J 1.7, 6.93 (in, 7.02 (d, 1, J 7.35 (in, MVS (DCt/NH 3 m/z 483. Anal Calcd for
C
2 7H 34
N
2 0 6 .0.65 EtOAc: 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336 trans, trans-2-(3-Fluoro-4-methoxylhenyl..4-(1 1 2 -N-p2ropyl-N-butanesulfonylamino)ethvl)-pyrrolidine.3carboxylic 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 NMVR (CDCI3, 300MHz) 8 0.82(t, J=7.5Hz, 0.92(t, J=7.5Hz, 3H), 1.34- 1.52(m, 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1H), 2.72-2.94(m, 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1H), 3.53- 3.60(m, 11-H), 3.67(d, J=9Hz, 11H), 3-89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, -2 08- 1 6.82(d, J=8Hz, 1 6.92(t, J=9Hz, 1 H), 1H), 7.18(d, J=l2Hz, 1H). MS (DCI/NH3) m/e Example 337 Using methods described in the above disclosed in Table 1 can be prepared.
6-97(s, 1H), 7.12(d, J=9Hz, 565 examples, the compounds Table 1
R
02N
R
"INov 2.
S
S*
S S U S
S
-209- Table 1 cont.
R
N3QV ?h~ 00 7.
&'o 1,' H3CO.F2
OS
8.
11.
o4~.9
H
3 00~ 6.
oTh 9.
12.
oC 15.
18.
21.
a a a a a a 13. 14.
16.
19.
17.
0.
20.
0 0 22.
0 0 F3C oo O 28.
FH2C-qe-,~/~ ,xO
F
2 0 0 31.
F
2 0 0 34.
0 0 -210- Table 1 cont.
R
0 0 23.
H,0~ 0 0 26.
0 0 29.
FH
2
C,.
F
2 0 0 32.
F,Chl
F
2 00 35.
NrAKO 0 0 24.
0 0 27.
FH2 0 0 F2HC,
K/~
F
2 0 33.
F
3
C..
F
2 0 0 36.
11"') F ,X 38. 39.
-211- Table 1 cont.
R
43.
43.
0 41.
0 44.
42.
C 45 r 46.
49.
52.
0 58.
47.
50.
48.
'NV
53.
56.
r 0 59.
0,N 54.
57.
0 -212- 0 61.
01""o 64.
oc 0 67.
Table 1 cont.
R
Croy" 62.
-0- 65.
68.
71.
rll* 63.
0o 0 66.
69.
72.
11
A
78.
S.
S
S
S
S
S
73.
76.
C-I
0 74.
A
77.
-213- Table 1 cont.
R
-ThB"
H
3 00 c 81.
0 ~Oy 82.
rk 88.
(K
86.
89.
(K
87.
90.
S
S
S
S
S
*5*55e S. S
S
S.
SS
S
S. S
S
-92. 93.
96.
-214- LOyN 0 97.
0 100.
0 103.
0 106.
CH
3 109.
112.
Table 1 cont.
R
OyN-_ 0 98.
101.
0 104.
H r N~rN,,,o 107.
CH
3 ro 110.
113.
YH3 r( 0 116.
99.
0 102.
0 105.
1 0 1 08.
111.
0 114.
YH3 ro(
S.
S
0 5 00 9 0*@O
S
5@505 OS S S A
SO
5* 0 0 115.
117.
-215- 0C 118.
121.
124.
Nci 0 127.
OC7 130.
133.
Table 1 cont.
R
119.
122.
120.
123.
126.
129.
H
3 CO C 0 132.
125.
0 cl 128.
OCH
3 131.
0* 134. 135.
-216-
IN
136.
139 139.
o~ 142.
oTo 145.
0 148.
H3C
H
3 Crk ,h Table 1 cont.
R
137.
00 140.
oTh 143.
F3 .0 146.
CH3r 149.
0~~ 138.
141.
144.
0 00 147.
150.
0fNf 151.
152. 153.
-217- Table 1 cont.
R
0 9 154.
155.
157.0 157.
0 0 158.
161.
cK
T
0 156.
o 159.
162.
160.
163.
166.0 166.
164.
16FF 7.o 167.
165.
C168.
168.
-218- Table 1 cont.
R
F, F 0 0 169.
Y
00 172.
0 175.
y 00 178.
0 0 181.
00 184.
00 187.
0 170.
doo 173.
F F 176.
F3C- 0 0 179.
0 0 182.
H
3 =C0' 00 185.
188.
Y
00 171.
00 174.
177.
F3C$ FF 0 0 180.
H3co *0 183.
H3cn~ 00 186.
H
3 C0>
F
3
%O
F F 0 189.
-21 Y- Table 1 cont.
R R H3ca,,,> 190.
193.
0 0 196.
F3 C~ F F 6-0 199.
202.
202.
H,CO
F
3 0 0o 191.
0 .0 194.
A4" 00 197.
200.
F F H 3 caCO
F
3 C'-A7 192.
195.
F
3 C L/ 198.
0 0 201.
4 4 4 9 9.
9 9 *99.
203.
204.
C
205.
y 206.
207.
-220- Table 1 cont.
R
208.
y 211.
209.
214.
v C QNr 212.
215.
OH Y 218.
CF
3 ov~y-Nc 210.
213.
H
cOY0 216.
HYI-
219.
CF3 222.
a a. OH-" 0.2/0 217.
OH V 220.
221.
-221-
R
223.
226.
229.
vYr 232.
235.
Table 1 cont.
R
F
3 Yr 224.
227.
y 230.
233.
y 236.
R
CF3 225.
228.
231.
cif y 234.
2 237.
a. c- -222- Table 1 cont.
R R I-Ir 238.
y 241.
244.
239.
242.
240.
K
I-rl- 243.
FO
F'Cr 0 246.
K
249.
252.
245.
a a a 247.
250.
248.
)y NCN51 251.
-223-
R
NCa r 253.
NC.r) 256.
CN 0kA 259.
262.
Table 1 cont.
R
y 254.
257.
R
y 255.
-CN 0 258.
y-r 261.
264.
y 267.
260.
S.
S
S
263.
4 0 266.
265.
268.
NV
271.
274 274.
-224- Table 1 cont.
R
0H> 269.
A)
272.
275.
N ~A y 278.
N 0 CF3 )I> 270.
273.
276.
y -N 0 279.
N 0 282.
S*
277.
0 280.
281.
-225- Table 1 cont.
R
283.
284.
286.
N O 289.
,'CN 0 292.
y 295.
287.
290.
293.
N 0 296.
N 0 285.
.N 0 288.
N 0 291.
K
294.
jN U1, 0 a a a a. a a a a. a 297.
-226v 298.
301.
)y 304.
307.
Table 1 cont.
R
299.
302.
N Or 305.
308.
y 300.
y 303.
v 306.
309.
N 0 a.
a.
a. a a K-r 310.
311. 312.
-227- Table 1 cont.
.R
vKY N 0* 313. 314.
316.
319.
317.
315.
318.
)I)
321.
324.
S
S
S.
S. 320.
323.
322.
)y )-U~r~e 325.
326. 327.
-228- Table 1 cont.
R
328.
0 329.
330.
333.
331.
k 0r 334.
332.
4. a a a. a a a a a a a. a a 335.
336.
337.
338.
0 339.
0r o 340.
341. 32 342.
-229- Table 1 cont.
r,
~I~L~X
343. 344.
R
y
-CN
345.
J
F'X8 348.
346.
349.
y 352.
3 347.
I
I.
IO
I. *I 351. i 350.
K
353.
353.
354.
y 357.
I
I
II I I. II 355.
356.
-230- Table 1 cont.
R
358.
361.
359.
362.
y 365.
360.
.363.
00 0 0 S 0*
S
S S S. *S *5*5
S
S
0S S. 00 364.
367.
370.
366. 005 368.
N
372.
368.
371.
-231- Table 1 cont.
R
y 373.
374.
376.
377.
375.
378.
y 381.
379.
Kx 380.
oS 382.
383.
384.
3J 387. 385.
386.
388.
391.
394.
397.
400.
-232- Table 1 cont.
R
y 389.
392.
395.
390.
393.
396.
399.
402.
398.
401.
-233- Table 1 cont.
R
404.
403.
N
406.
409.
412.
415.
407.
410.
413.
416.
R
405.
408.
r 411.
414.
417.
C.
C
4)*
C
C C -234- Table 1 cont.
R
Ii~ COQEt 419.
420.
418.
421.
NO
2 424.
c:: 427.
CN
430.
COOEt 422.
6NO 2 425.
OCN
428.
NO
2 423.
NO
2 426.
k'aCN 429.
02J,
C
C.
*CC.
431. 432.
-235- Table 1 cont.
R
R
433.
0 436.
A-r- 439.
442.
R
435.
0 438.
434.
0 437.
440.
440.
U
U. U. 443.
441.
444.
447.
445.
445.
446.
448.
451.
454.
457.
-236- Table 1 cont.
R
F)Or 449.
y 452.
450.
453.
455.
M-Ir MeO 0 456.
Me0."k 0 459. 458.
460. 461. 462.
-237- Table 1 cont.
R
463.
464. 465.
466.
467. 468.
MOQ>Y
0 470. 469.
471.
09 *b a. a a. a a a..
372.
473.
474.
477.
475. 46 476.
-238- Table 1 cont.
0 478.
Itlo 0 481.
484.
F
487.
0 490.
479.
cI 0 482.
cl I-rc 0 485.
F)
0 488.
0 0 480.
483.
Cl): 486.
S.
S.
S.
S
*55555 489.
0 491. 492.
-239- Table 1 cont.
R
F" jN"rX 0 494.
497.0 497.
493.
0 496.
o 495.
o 498.
V
4fo 4 501.
0 504.
MeO OMe O 507.
499.
500.
S. S 0 502.
505.
505.
503.
506. 0 -240-
IN-
MOOJ Kyr OMe 0 508.
Table 1 cont.
R
OMe 0 509.
OMe 0 OMe 0 510.
ome 513.
OMe 0 516.
511. 512.
OMe 0 514.
mo~ OMe 0 *9 515.
OMe 0 517. 518.
519.
OMe 0 520. 521.
522.
-241m o r 523.
OMe 0 526.
529.
532.
Table 1 cont.
R
H
524.
527.
y 530.
533.
Me it0 525.
528.
531.
Br ayI-A 534.
C.
C.
C. C. C 535.
536. 57 r NC fL-Irx F 0 537.
-242y 538.
F0 540.
544.
'Ir" 547.
V
550.
Table 1 cont.
R
K
539.
v 542.
545.
548.
551.
540.
543.
y 546.
549.
552.
Sr
S.
S. S -243- 553.
NC
556.
Br~ 559.
y 562.
Bra Table 1 cont.
R
y 554.
557.
560.
y 563.
ByyN{* cl 555.
v 558.
561.
564.
Fr CI A NC S. S 565. 566.
567.
-244- Table 1 cont.
R R 568.
FY'-r 571.
F
574.
0 577.
0 580.
0 583.
569.
F)-
572.
0 575.
y 0 578.
%rx 0 581.
0 584.
0 570.
K
0 573.
576.
0 579.
582.
0 585.
S
S
S
S
-245- 0 586.
NOrX 589.
y 592.
595.
598.
601.
Table 1 cont.
R
ca, 0 587.
590.
593.
596.
>2xV 599.
602.
0 588.
591.
594.
597.
y 600.
603.
0 0*
R
604.
604.
-246- Table 1 cont.
R
605.
R
H
606.
609.
607.
608.
H
ol 610.
611. 612.
4 4 4 4. 4 4. 4 4**4 44*44 4 613. 614.
615.
H
616.
619.
617.
620.
620.
618.
621.
-247-
R
0 6 622.
625.
Table 1 cont.
R
0 623.
H
626.
629.
632.
635.
y-r gj
R
624.
624.
627.
628.
631.
630.
N'
633.
636.
639.
9 a a a.
e a a. a a a. 634.
y 0 637.
638.
-248- 640.
0 643.
0 646.
Table 1 cont.
R
641.
0 644.
0 642.
645.
0 648.
647.
a a.
a a a.
a. a a a~ a. a C 649.
650.
651.
652.
0 653.
654.
-249- Table 1 cont.
655.
656.
657.
658.
659.
660.
4
S
S.
S
S S 5* OS
*OSS
S
*5*5
SO
Son
S
S. S 5 0
S.
0 0 55.5 0S S S S S. S
S
S
*55005 661. 662.
663.
0~Y 666.
664.
%%OA 0 665.
667. 67.668. 669.
-250- Table 1 cont.
R
670.
672.
671.
673.
674.
675.
S. 0 S S 0S
S
OS
OS SO .55.
S
0000
S
0* *5 SS 5.5.
S
OS..
0
S.O.S.
S
5 0 0
S.
5S 0 0S 05 55 0 0050
OS..
0
S
5*5000
S
677.
676. 678.
680.
679.
681.
682.
683. 64 684.
-251- Table 1 cont.
R
y 685.
688.
691.
694.
607.
686.
687.
689.
690.
692.
693.
695.
MeO 6 0698 698.
696.
MeO H 699.
699.
-252- Table 1 cont.
R
701.
0 703.
0 709.
0 702.
704.
705.
707.
0 708.
00 711.
A.
A
A
A
A A 710.
0 F3h 712.
713.
714.
715.
-253- 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 s be prepared.
Table 2A
.COOH
,COOH
R- ,,COOH
R-
4.
MOMO
,COOH
7.
F
.COOH
R-Q
11 0 6.
MOMO
,COOH
11 0 9.
c r r r -2 54- Table 2A cont,
MOMO
COOH
1
NF
F
.COOH
OCH3
*.-COOH
12.
OCH
3
.COOH
-OCH,
MOMO
A- *COOH 16. K 2
OMOM
0) 19. OCH 3
OCH,
A-N
,COOH
0N 0)
OCH
3 17.
F
Af-N
VOCOOH
0)
OCH
3 18.
'COOH
-255-
OMOM
#ICOOH
R-O
22.
Table 2A cont.
00H 3
,.COOH
23. 0
F
R-
-OCOOH
24. 0
.COOH
OCH,
R- ,.COON 26.
OCH
3 R- *,COOH
R-
N
29.
.COOH
OMOM
R- *.COOH5 0 28.
OMOM
R- 4COOH
ICN
31.
F
R- ~CO
N
OCH
3 32.
-256- Table 2A cont.
O.COOH
34.% .COOH3
R-
RN .COOR 4. OCH3
C
3
.*.COOH
R-
35.\I
OCR
3 R-N *.COOH 0 38. OCH 3 O0H 3 R-N COOH P N 0
OCR
3
F
COOH
36.
F
~.oO 39. OCR 3
F
R- ,COOH
N'-
OCH
3 42.
F
R-
*.COOOH
4
OCR
3
,,.COOH
R-
OCR
3
MOMO
R-
OCOOH
46. F
MOMO
R- eCOOH 52.
-257- Table 2A cont.
OCH
3
O.COOH
R-
47.
Fi
OCOOH
0 R-
O)COOH
53.'
F
R-
".COOH
48.
a S C C
'COOH
R- 10000H 56.
F
-OCH
3
-OCH
3 -258- Table 2A cont.
,COOH
PCGOH
*.COOH
62.
COOH
R-N
j .OCH,
OCH
3 R-N
*.COOH
6 8. /0
,COOH
*O.COOH
67. 0 -259- Table 2A cont.
*.OOOH
OCH
3 0
~COOH
pr
COOH
73.
.COOH
COOH
,COOH
OC 0H 3 72.
OCH
3
CH
3 COO H
,COOH
At- 75. 0
OCH
3
.COOH
78.%)
OCH
3 0
'COOH
R-
OCOOH
77.
**eb
OCH
3 0 I-~CO0H R-
*COOH
1
F:
79. F
COOH
-2 Table 2A cont.
OCH3 dCOH 83. 0
OCH
3
OH
pr
COOH
86.
CH
3
OH
R-
OCOOH
8 7. 0CMH3 pr
COOH
0'% -261- Table 2A cont.
CR
3
OCR
3
F
C H, COH3 RI- CAH R-NR- eCH IOCR 3 0~% 9495. -OCH 3 96. 0 F F F
OCCH
3 3 cO' .COOH .,COOH .*CO R- F+ 98. 99. "o F F F
OCR
3 OCR 3 OCR 3 0 od co,\ o~ ,O :f #COOHPICH F
H
3 CO RaCO COO COOH
%~COOH
N ,OO 103.
0.104. %d105.
-262- H,
F
pr
OCOOH
106. 0 Table 2A cont.
H
3 00 R-
ICOOH
107.
108.
H
3 CO
F
OCH
3
OCH-
3 109.
R- IeCOOH 112.
R-
ICOOH
115.
R-
-COOH
113.
R-N
116. 0 R-
,.COOH
ICOOH
S S S S. 55
S
5555
COOH
117. 0
.COOH
,COOH
118. 18.119. 120.
-263-
,.COOH
U
0 121. 0
CH
3 124. 0 R-
.COOH
U
0 127. 0 R- ,O0 130.
Table 2A cont.
R-N
122.
00H 3 R- .C0 125.
OOCH
3 C00 128. 0
H
3
CO
0 R-
-*COOH
131. 0
OCH
3 'N0 126.
OOCH
3 R-
#.COOH
129. 0 0*
,COOH
132.
-2 64-
(SH,
,COOH
133.
OCH
3 N
OOCOOH
136.
OCH
3 4.COOH Ai- 139.
00H 3 A-
-*COOH
142.
Table 2A cont.
H, C. PH 3
N
*COOH
134. 0)
OCH
3 R-
ICOOH
H3CO
OCH
3 137.
OCH3,
R--N
140. 0
OCH
3
.COOH
R-
143.N
OCH
3 141.
OCH
3
R-
H 3 1 4 4 a a a a.
a a a.
a.
a. a a -265-
CH
3 R-
,COOH
H
3
CO\
145.
F
IOCOOH
RI-
148.
Table 2A cont.
OCH3
*.COOH
146. n.CH 3
CH
3
F
COOH
,N.
H
3 CO
-OCH
3 149.
F
R-N ,OCO0H 152.
F
R-
,COOH
11
A
147.
F
*.COOH
N
150.
OMOM
pr- 4 o0OOH 153.
C. C I C
S.
C
C C C. CS e.g.
C
a C C
C.
CCC.
C
S.C.
C
CSaCSC IS C
C
C.
CS
S S
S.C.
C
C C
CC..
C
S
151.
OMOM
IOCOOH
Rr'-O
OMOM
OCOOH
H
3 CO
OCH
,156.
154. 155.
m m.COOH 157. OCH, -266- Table 2A cont.
PNMOM
158. F
OCH
3
,~/OCH
3 Rj-N
I&COOH
H
3 C
OCH
161.
H
3
C
R-N
,COOH
165. OCH 3 0e *e a S. SO 164.
163.
F
H
R-N 4 N 166.67 C018 166. -OCH3 168.
-267- Table 2A cont.
F MOMO
F
HH
TL .N N \N o-N
IN
169. 170. 0 171.
MOMO F
MOMO
H H
H
,N 172. 0173. /174. F MOMO F H
H
1 N ,N 175 17. 17. V: H7 A
H
3
ACH
.I R- I I I 1w.
180.
-268-
F
H
R-
181. 0 Table 2A cont.
MOMO
R-NN
182.
00 I
H
w' SH 3
H
0 0 :000% 188.
F MOMo 0 0 p 191.N 192.
190.
-2 69- Table 2A cont.
00 N 'CH 3
H
193.
194.
195.
H
OCH
3 196.
-OCH
3 197.
MOMO
P- H 200.
ft
S
H
3
CO
F+ N~iCH 2
CH
3 202. I0 203. 24 204.
I U- Table 2A cont.
206. 207.
205.
IH3 208.
209.
210.
H
3
,COOH
'o0 211.
OCH
3
H
3 C
OCH
3 0 '00 214. 0CH 3
F
q*.COOH ~0) 212.
OCH
3
H
3
C
R- 0 ~0 213. OCH 3
S
S
S a 55*555 215. OCH 3 216. OCH 3 -271- 217. OCH3 Table 2A cont.
DOC F C0H 218.
EtC F
.COOH
'0 219.
EtC F ,.CO0H 222.
EtC F
.COOH
~0 220.
EDO F
.COCH
223.
0
,.COOH
'~0 226.
DtO F 221.
EtC F
COOH
OCH
3 224.
C
225.
227. -228.
-2 /2- Table 2A cont.
0 0
IPCOOH
R'
229.
H
3
OCH
3 R- 0 232.
H
3
OCH
3 235.
H
3
OCH
3 238.
OCH
3 0 0
,.COOH
231. OCH, 230.
H
3 CkOCH 3
OOH
'0 233.
H
3 C )O CH 3
~.COOH
R- 236.
0,0 CC00 ~0 239.
H
3 OCH 3 '0 234.
H
3
COCH
3
,COOH
R 0 237.
a 0,0 240.
-2 73- Table 2A cont.
241.
242.
244.
245.
OCH
3 0,0
OOOH
243.
HC F F k
H
3
C>
249.
H
3 C F
.,COOH
~0 252. OCH 3
H
3
F
,COOR
R''
H
3 C F .C00
R-N
0* 247.
248.
H
3
F
.#COOH
-N
250. 251.
-274- F F '00 Table 2A cont.
F F
COOH
'0 F F
,COOH
_0 255.
253.
254.
F F 256.
F F
RN
259.
OCH,
F F 257. 258.
COOH
R-N
Z 0 261.
260.
*.COOH
263.
262.
264.
265. 265. 266. 27 267.
-275-
F
,.COOH
RN
'0 Table 2A cont.
~COOH
C)OH0 268. 269.
270.
OICOOH
v .5l510 COQH 44.COOH 273.
OCH
3 272.
271.
274.
275.
276.
277.
278.
277278.279.
-2 76- Table 2A cont.
280. 0CM 3 281.
283.
284.
4
COOH
287. 0CH 3 0 00 282.
R-
285.
4 C00H 0 ',0 288.
CH
291.
0C 286.
.COOH
'0 289.
,COOH
290.
292.
22.293. 294.
-277- Table 2A cont.
JVCOOH
R-
297.
295.
296.
298.
,.COOH
0 01~ '0 304.
COOH
R- .0 299.
*,COOH
302.
?COOH
-N'
300.
,,COOH
C)
'~0 303.
a. a. a
~COOH
a. a 306.
305.
-278- Table 2A cont.
.COOH
R-0 '0 308. 0CH 3 307.
309.
h
R-'
312. 310. 311.
'1 00 0 314- 313.
~0
R-
316.
315.
C C
C
CC.
C C
C.
CC
CC C
CCCCC
317. 318.
321.
319. 30 320.
-279- Table 2A cont.
~0 7b.,,OOOH Ft- '0 322.
OCH,
323.
325. 326.
328.
COH
329.
OH
OPCOOH
'0 332.
,COH
335.
0 ,eCOOH 324.
0a-0 Ft- 327.
0,0O 330.
OCH
3 eOH 336.
331.
334.
.COOH
337.
-280- Table 2A cont.
COOH
K
0 338.
.COOH
341.
339.
H
0 4
,COOH
342. OCH 3 340.
C 00 343.
345.
344.
347.
346.
348.
H
3 C F
H
350.
EtO h 0 ACH3
>-H
351.
349.
-281o 0 '&S-CH3 4
H
'0 352.
-0 h 0 0 q-9CH 3 0 )i 0 355. OCH 3 0 ',0 358.
o 0
NH
361.
OCH
3 Table 2A cont.
HC F 0 t H 0 O0H 3 353.
H
3 C F _tWNH 0 356.
H
3
F
h NH ',0
OCH
3 359.
EtO F tNH h IL
.N
R'~
OCR
0 357.~ 363.
0 0* 0 *0 0*0* 0 0 362.
-282-
H
3 C 0 h/ H
H
~0 364.
Table 2A cont.
H
3
C
-N
3
H
'0 365.
366.
367.
368.
H
3
C
370.
H
3 W N.
C1, NH R_
F
H
3
C
h/ Nw
~NH
0 371.
N
CH
H
R' 0
H
3
C
L/ NH 369.
H3C h 372.
0 k\ NS CH 3
H
00'A
S
S
S
S S
*SS.
S
S
*S S S S 0* S S 55 5* 55
S
5.55..
373.
373. 374. 375.
-283- Table 2A cont.
OS
h/ 0 ,-CH 3 0 00 377.
0-0 N ogCH 3
H
376.
378.
ho0s-
H
H 0 379.
NH
N
382.
_tNH iN 0 385.
380.
383.
*NH
A
-N
381.
k/ h~
~NH
384.
387.
9 9 9
S.
S
9O S. 00 0*SS
S
S S 0000
S
0
S.O.S.
9 S S *5
S.
9. 0 9 0* 0 0S*S 0 0 9 386.
Table 2A cont.
Ho N,0 388.
~NH
391.
389.
390.
392.
F
3
,COOH
R'0 393.
F
3
COOH
R-N0 396.
F
3 R-N0 h 395.
0O 0 0 *000 0*0 :600.
0 0 a 0 0 0 394.
397. 397. 398. 39 399.
-285- Table 2A cont.
FCF,
COOH
0 /0 400.
F
2
CF
3
.COOH
403.
kF 2
CF
3
.COOH
'0 0C4 406.
401.
IF
2
CF
3
COOH
R'0 0) 405.
F
2
CF
3
.COOH
0 404.
408.
407.
*.COOH
410.
411.
409.
412. 412. 413. 44 414.
-286- 0Q eCOOH
R-
415.
Table 2A cont.
>0
.COOH
~0 416.
417.
COOH
418. 419.
420.
421.
422.
423.
0* h
.COOH
FrN 0 '0 425.
424.
426.
*,COOH0 429.
427. 427. 428.
-287- Table 2A cont.
4PCOOH Rr0 430. 431.
433.
434.
437.
J
.QCO)H
0 432.
O 0H 435.
438.
,..COOH
441.
.,COOH
x 0 0 0 00 0 000000 436.
439. 440.
1 0 HCO O 0 R-0 442. 42.443. 444.
-2 88- Table 2A cont.
445.
446.
~0) 450.
448.
449.
Q
0 451.
.COOH
RtN 0 452.
C0H 453.
454.
455. 455. 456.
-289- Table 2A cont.
.*COOH
457.
,,COOH
'0 459.
458.
460.
,eCOOH 461.
O*COOH
R- 0 '0 464.
462.
a. a *aa a. a 463.
465.
-290- 0~T 0 0 4.
0 0 13.
0 16.
Table 2B
R
0 2.
8.
.OIINh 0 11.y 0 14.
H
3 CcQ 0 17.
3.
6.
9.
C),
12.
-Thy 0 0 18.
-T0 -291c'0 22.
28.
FH
2
F
2 0 0 31.
F
2 0 34.
37.
Table 2B cont.
R
H
3
C
23.
H
3 CQ",,.4N 26.
29.
FH
2
C.S
F
2 0 0 32.
F
3
C
F
2 do ci'0 38.
41.
24s.
27.
30.
F
2 H C..C
F
2 33.
F3C
F
2 0 6' 0 36.
39.
42.
-292o 0 43.
F
3 cQ~ 0 0 46.
Table 2B cont.
R
-1h
F
3
CSZ'-,
0 0 44.
H,.
0 0 47.
F
3
CQ~
0 0 48.
49.
52.
1 6Cl 0 58.
50.
53.
0 51.
54.
F~QO
57.
0 -56.
59. -293- Table 2B cont.
R
61.
OCH
3 62.
64.
63.
66.
69.
72.
9H3 r' 00 73.
0 68.
YH
3 71.
00 74.
oTh
C.
.C C
*CC.
*CCCC
o 00 0 79.
doo 82.
F F 00 y 88.
00 91.- F3C M 94.
-1h 97.
-294- Table 2B cont.
R
0 0 80.
FC./l' FF 6-0 83.
00 86.
0 0 89.
F
3 y s F F g0 92.
F F y~ 95.
F3cx -T 0 0Lr 81.
F3Io/~ 00 84.
y 0 0 87.
y 6 ,0 93.
F
3 C~LK F F 0 .96.
H
3 CO0\ 00 -295-
R
H
3 d o 100.
103.
H
3
CO
106.
00 109.
doo 112.
A
F
3 C F F do *o 115.
Table 2B cont.
R
H
Cn 1 00 101.
H
3 Ca**> F3 S. 11- 00 104.
H
3 C0> 00 107.
00 110.
00 113.
0 116.
R
102.
FH
3
CO"T
F F o-o 105.
F F H 3
C>
108.
0 0 111.
00 114.
F
3 I,0-v 00 117.
R
118.
2J4 C"o".N 121.
124.
y ic7 127.
-296- Table 2B cont.
R
119.
122.
R
120.
y 123.
126. 125.
128.
OH
130. 132.
129.
130.
132.
R
133.
136.
CF
3 139.
142.
145.
-297- Table 2B cont.
R
134.
137.
CF3 LT 140.
143.
y 146.
R
OH
135.
138.
141.
144.
0
V
147.
a a.
a a a. a a.
a a -298-
R
148.
151.
154.
y 157.
160.
Table 2B cont.
R
149.
y 152.
155.
158.
R
150.
153.
156.
162.
S
S*
S
S S 55 5.
S
S
S
S
S. S S S 5 S. S S S 5S 5
S
S
161.
-299- Table 2B cont.
163.
166.
164.
167.
y 170.
R
"k-r 165.
n-r NCyrNr 168.
K
171.
169.
S.
S
S
0
S
S
0
*SSS
S
S. S 172.
o 173.
y .N 0 174.
K-C
175.
176.
177.
-300- Table 2B cont.
R
179.
179. 178.
180.
N 0 183.
F~LN0 181.
182.
F I 184.
187.
OH
NtAo 185.
188.
186.
FS7O 189.
N rA N o 192.
190.
191.
-301- Table 2B cont.
R
193.
y 195. 194.
196.
198.
197.
199.
200.
201.
a.
a a a a a a. a a a.
a 202.
203.
204.
205. 26 206.
207.
-302- .N 0 208.
y 211.
N0 214.
217.
Y220 220.
Table 2B cont.
R
209.
jN 0 212.
215.
ly 218.
KtNO y 210.
~N 0s 213.
216.
y 219.
V
KGN0 r r 221.
222.
223.
yI -rx -303- Table 2B cont.
R
224.
y fN 225.
228.
231.
226.
227.
229.
232.
235.* r 235.
,N 0 230.
233.
N,,f.
234.
236.
237.
-304- Table 2B cont.
R
N
238.
239. 240.
N N)rX 0 241.
242.
243.
244.
247.
250.
N-
245.
246.
249.
248.
252. 252.
-305- Table 2B cont.
253. 254.
255.
256.
K-CN%
259.
y 262.
265.
257.
260.
258.
y 261.
264.
267.
S
S. S
S.
263.
266.
-306- Table 2B cont.
R
yNKI- 269.
268.
271.
272.
270.
y 273.
-N
276.
279.
282.
274.
C
CC
C.
C
C
275.
277. 278.
280. 21 281.
-307- Table 2B cont.
R
283.
286.
y 289.
292.
295 295.
284.
287.
290.
293.
296.
296.
y
NN
288.
291.
294.
y 297.
S*
S
S
S S -308- Table 2B cont.
298.
299.
301.
304.
~N
302.
y 305.
R
300.
A, N 303.
306.
309.
312.
S
S.
S.
S.S
307.
308.
310.
311.
-309- Table 2B cont.
R
313.
316.
315.
314.
317.
318.
319.
322.
320.
323.
321.
324.
325.
327.
326.
-310-
R
328.
331.
334.
Table 2B cont.
R
329.
332.
330.
333.
0 o.
0. 0 335.
'-COOEt 338.
336.
N0 2 339.
N0 2 342.
337.
340.
341.
-311- Table 2B cont.
R
343.
346.
O 2 N 349.
0 352.
344.
347.
350.
0 353.
CN
345.
348.
A"
0 351.
0 354.
S
S
0 355.
7A 355. 357.
357.
-312- 358.
361.
F Cr 364.
F&O
367.
F&O
370.
Table 2B cont.
R
359.
v 00 362.
365.
y 368.
y 0 360.
363.
F 0 366.
369.
9* 4 4 4* 4 4 44 4* 4 4444* "C N Y-1Meo VA 0 2 0 371. 372.
R
0 373.
-3 13'- Table 2B cont.
R
moo 0 374.
376.
0 379.
IIrr 382.
moolc 0 385.
377.
meo '6 0 380.
meo 14 0 383.
ko 0 386.
XXNCA
0 389.
R
Mo0~.o 0 375.
moo, 0 378.
meozic 0 381.
Me0~ S 0 384.
)c 0 387.
0 390.
S
S.
S
S
S
S
*555
S
*5 .555 388.
-314- Table 2B cont.
R
uN54 0 391.
0 394.
0 397.
400.
392.
C,
0 395.
393.
396.
0 399.
0 402.
398.
0 401.
S
0*
S
S
S
S)S
S 0* S S. S 0@
S
.5.5
S
OS..
403.
404.
405.
F0 0I
F
F 0 406.
407. 408.
-315- FmL 0 409.
0 412.
0 415.
Table 2B cont.
R
F
0 410.
Nk~k 0 413.
0 416.
411.
414.
0 417.
418.
419.
420.
0 421.
OMe 0 424.
422. 0 OMe 0 423.
OMe 0 OMe 0 425. 426.
-316- Table 2B cont.
R
OMe 0 OMe 427. 428.
OMe 0 430.
OMe 0 433.
OMe 0 429.
OMe 0 432.
OMe 0 431.
Meo OMe 0 434.
b be. be, o 0 0b 0:.:o 435.
436. 437.
H
439.
M
442.
440.
443.
moo OMe 0 438.
OMe
<NC
441.
444.
-317- 445.
B"N"
448.
Asr F0 451.
y 454.
)I)4s Table 2B cont.
R
y 446.
449.
452.
y 455.
vcr 447.
450.
r 453.
456.
Ba "0 457.
458. 459.
460.
-318- Table 2B cont.
R
461.
464.
467.
y 462.
463.
465.
BVO
466.
468.
469.
470.
471
FU
2 CIO0 474.
472. 43 473.
-319- Table 2B cont.
R
A-r"r Bro 475.
476.
477.
478.
Br.
479.
480.
vr 481. 482.
F
F~%AO
483.
F Y 486.
r
SF
ci 484.
y F 485.
487.
488. 489.
-320-
R
F
490.
0 493.
o 496.
o 499.
o 502.
505.
505.
Table 2B cont.
R
o 491.
o 494.
0 497.
o 500.
500.
R
o 492.
o 495.
V-
0 498.
0 501.
504.
507.
506.
506.
-321-
R
y 508.
511.
514.
517.
520.
Table 2B cont.
R
0 509.
v 512.
N>cx 515, 518.
R
510.
NrA 513.
y KXYml 516.
V
519.
H
r
D
o 521.
-322- Table 2B cont.
R
H
Vy 0 0 523.
524.
525.
526.
'i 527.
530.
H
4NOL 0 528.
0 531.
529.
H
0 532.
535.
533.
H
NC-
536.
534.
537.
-323- Table 2B cont.
R
0-c f-)i 0
H
16v 540.
538.
539.
H
541.
H
544.
0? 542.
545.
58 548.
aNr, 0Ja~
H
Ny- 543.
r r r 546.
547.
03~ 549.
>xY0 A r at' )r, 550. 551. 552.
-324- Table 2B cont.
R
54 554.
y 553.
0, 555.
v auarx 556.
557. 558.
559.
560. 561.
564.
S
S.
S*
562.
0 565.
563.
566. 567.
-325- Table 2B cont.
R R 568.
569. 570.
571. 572. 573.
573.
I- rr 0 r 0 574. 575. 576.
~C 577. 578. 579.
580. 581. 582.
-326- Table 2B cont.
x 583. 584.
585.
586.
589.
587.
588.
FSfNyo 591.
590.
594.
592. 593.
595.
596.
597.
-327- Table 2B cont.
R R R FVO FV
FV
598. 599. 600.
y )r .9 9-
S..
601. 602. 603.
9"y 604. 605.
606.
607. 608. 609.
610.F 611. 612.
611.
612.
R
613.
Mej r -328- Table 2B cont.
R
614.
Moo
R
615.
6 618.
616. 617.
0 619.
620.
621.
9 9.
9 9*9* 9 99 9 99 9 99 9. 9 .99..
622. 623.
624.
NY
0 00 625. 626. 627.
-329- Table 2B cont.
R
0 628.
0 631.
1H 629.
-Th 632.
FC*sN%.'A 0 630.
OS S S
S.
S
S
S* @0
S
0@ OS 0@*O
S
*000 0 0000*5
S
S
*5
S.
S 54 0 05 5O 0 000S 0060
S
S
SS OS S
S
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.
-330- Table 3A
F
*eCOOH 4.
F
R- OCOOH
R-N
I.
6. F
.COOH
CH
3 A- .VCOOH 7.
A-
8. 0 0CH3 A-N
CO
,N0 9. 0) *6 3* 331
N
1k 0 13. 0 Table 3A cont.
H
3
C
,COOH
14. -~0
,COOH
15. 0
OCH,
OCH
3 16.
\j.C0OH 0 19.
S
-332- Table 3B 1.
4.
7.
0 13.
0 0 2.
0 5.
0 8.
0 11.
0 7* 3.
0 6.
9.
0 12.
0 14.
H3CQ 0 0 H3CQ( 18.
00-~ 0-, 0 21.
-333- 6'o 22.
FH
2
Q..
F
2 0 0 31.
F
2 6' 0 34.
0 37.
Table 3B cont.
R
23.
0 26.
29.
FH
2
C.
F
2 e' 32.
H3C !P, 24.
0 o~% 27.
30.
F2HC.-C-
F
2 00 33.
F
3 0,
F
2 6 0 00.
38.
F
3
F
2 0 0 36.
39.
-Th y~N~ 0 0 -T0 41. 42.
0 0 43.
F
3 CQ0 r-- 0 0 46.
-334- Table 3B cont.
R
F3CS ,x 0 0 44.
o0 47.
F
3
CO~
0 0 48.
49.
52.
58.
0"& 50.
53.
00 51.
54.
F~#0 57.
c"6~ a a a a a a a 59. -335- Table 3B cont.
R
61.
OCH
3 62.
63.
64.
9H 3 00 73.
do 76.
68.
YH3 71.
0 0 74.
0 66.
69.
72.
a a a a 0 0 00 77. 78.
-336d0o 79.
82.
0 0 y 88.
F
3 00 91.
F3Ck 11- I 94.
97.
Table 3B cont.
R
0 0 80.
FO
F F f -b 83.
0 0 86.
00 89.
F F -'0 92.
F3CiS~%~/ 00 95.
F. F F3~L 9r
<A
81.
0 0 84.
87. y Md 93.
F
3 LS- FF6'oO 96.
0 0 99.
a a a S S -337- 0 0 100.
H
3 C0~~ 103.
106.
0 0 109.
00 Table 3B cont.
R
H
3 CO-h O"o 101.
F3H 3 Ca0-> 104.
H
3 C0',> c* *0o 107.
A> g 0 0 110.
00 113.
H.c 102.
H3CO'> 105.
F F H 3 C0n 0 0 108.
0 0 114.
0 0 117.
0..
0 o .o 115.
115. 116.
-338- F3XA 118.
121.
A-r 124.
y 127.
Table 3B cont.
R
119.
y 122.
125.
C128 128.
120.
y
C
123.
126.
~y K-cr 0 129.
S
S
S
a. S 130.
131. 132.
H
I-
0 133.
136.
.F
3 ov~rA -339- Table 3B cont.
R
y 134.
137.
CF, y Ov~lrx
OH
IIIr 135.
138.
PF
3 141.
144.
y 139.
140.
9F 3 142.
NQNr 0"s 143.
y %QCt 0'6 145.
146. 147.
-340-
R
v 148.
151.
154.
y 157.
1 160.
Table 3B cont.
R
Iy 149.
y 152.
155.
158.
R
150.
ly F 0 153.
PK0Ncr 156.
159.
162.
161.
-341- Table 3B cont.
R
y 164.
y 165.
163.
166.
NC-
167.
169.
y 170.
0 173.
y I U7rl 168.
S
S S 171.
S
172.
ly Yr',0 175.
176.
177.
178.
181.
-342- Table 3B cont.
R
~I(N
F -N 0 179.
y 182.
OH 185.
188.
191.
180.
183.
0* V.000 V. 0 o O S. S
S
184. 186.
cv 187.
190.
F 0' 189.
192.
-343- Table 3B cont.
R R R K yy
N~N{
193. 194. 195.
0 NV @0 V 00.0 196. 198.
197. 0S..
.000 0 0 *boos: 199. 200. 201.
0 SB SN'" e 202. 0 203. 204.
205.
206. 207.
-344- .CN 0 208.
y 211.
v 214.
217.
220.
Table 3B cont.
R
JN 0 209.
212.
r 215.
y 218.
221 221.
y 210.
N 0 213.
216.
y 219.
222.
*c 00000 -345- 223.
Cr c(Y.- Table 3B cont.
R
224.
y cN 0 226.
227.
225.
228.
231.
234.
229.
232.
230.
233.
V. 235.
236.
237.
-346- Table 3B cont.
R
240.
238.
239.
241.
242.
243.
244.
247.
250.
0 250.
245.
V
248.
246.
r249.
249.
a a a a a.
252. 252.
-347- Table 3B cont.
253.
254.
255.
256.
257.
I-CIN
259. 260.
I-g 258.
y 261.
F
264.
262. 263.
265.
266. 267.
-348- Table 3B cont.
R
y~NU1- 269.
F1X 270.
268.
271.
272.
273.
274.
0 0 275.
276.
277.
278.
-N
279.
N~N
280. 20.281. 282.
-349- Table 3B cont.
R
283.
286.
y 289.
292.
295.
284.
285.
287.
290.
n'-x 293.
296.
y 288.
291.
,N
294.
y
NK"A
297.
S
CS
S
S. .5555 -350- Table 3B cont.
R
298.
301.
Ay 304.
299.
302.
y 305.
KLN
300.
303.
>JN
306.
309.
312.
307. 308.
310.
Sor~ 311.
-351- Table 3B cont.
R
313.
316.
314.
315.
317. 318.
319.
322.
320.
323.
321.
324.
325.
v 326.^ 327.
R
328.
331.
334.
-352- Table 3B cont.
R
329.
332.
R
330.
333.
335.
'COOEt -COOEt 336.
NO
2 339.
342.
337. 338.
340.
341.
-353- Table 3B cont.
R
CCN
343.
346.
o 2 w Y 349.
QITI A 0 352.
344.
02N': 347.
350.
0 353.
1CN 345.
348.
cy,1
%J
351.
0 354.
0 355.
0 355. 357.
357.
R
358.
361.
364.
367.
3 370.
-354- Table 3B cont.
R
359.
362.
365.
y
F&O
368.
R
y 360.
F Ky0- 363.
&O
366.
369.
9 .9 9 9* 9 9.
9* 99 9 *999 9999.
371. 372.
-355- Table 3B cont.
R R MeO, Meo 0 373.
0 376.
Mao '6 0 379.
Nk~ oe meoXsiL 0 382.
0 385.
374. 375.
377.
0 380.
Me a 1 MoO 0 383.
0 386.
0 389.
0 378.
MOO a 0 381.
MOO J4 0 384.
0 387.
0 390.
9 9* 9. 9 9**9 99** 9 999.9 388.
-356- Table 3B cont.
R
0 392.
0 391.
0 394. 395.
0 393.
396.
ci
CI~~A
0 399.
0 402.
397.
cl 0 398.
401.
0 400.
s ee 9* .00.
00 0 9* 9 0.9 .9 @9 9 9 403.
404.
405.
406.
407. 408.
-357- 0 409.
0 412.
0 415.
Table 3B cont.
R
F0 410.
0 413.
411.
414.
0 417.
416.
0 0e
S
0S
S
5055 0 00@**0 a 0 *4 @0 0 0@S@ 05 0 00 *0 S 00000.
418.
419.
0 421.
OMe 0 424.
420.
1 OMe 0 423.
422.
OMe 0 425. 426.
-358- Table 3B cont.
R
MeOYN~ OMe 0 427. 428.
ome 0 430.
OMe 0 433.
OMe 0 431.
OMe 0 434.
M(e' OMe 0 429.
OMe 0 432.
OMe 0 435.
moo, ome 0 438.
436. 437.
MOO
439. 440.
443.
441..
Br~Ny0 444.
442.
"ci! 445.
A)h 448.
NQJX
451.
y 454.
0a -359- Table 3B cont.
R
y 446.
449.
452.
y 455.
v Ny-A' 447.
450.
453.
456.
0 4.
457.
458. 459.
-360- Table 3B cont.
R
461.
y 462.
460.
463.
464.
465.
BVON
466.
467.
0* 468.
K,-
CI0 471.
469.
470.
N
KY
472.C 42.473. 474.
-361ly &r1 N 475.
Table 3B cont.
R
Br y 476.
K
479.
Br~y'y* 477.
478.
480.
B
1 F"a 481. 482.
F
I
484.
K '-r
N,,
F
483.
F Y 486.
F 489.
485.
F
487.
488.
-362-
R
FV
Fb^ 1 0 ?:6~orA 490.
0 493.
L^AI
o 496.
0 499.
0 o 502.
0 505.
Table 3B cont.
R
o 0 491.
o 0 494.
0 0 497500.
500.
R
FV
0 492.
o 495.
0 498.
o 501.
504. 0 0 507.
503.
506.
-363-
R
y 508.
511.
514.
517.
520.
Table 3B cont.
R
509.
512.
515, N258 518.
R
510.
513.
y 516.
519.
521. 522.
-364- Table 3B cont.
H
523.
H
0
H
524.
525.
-J
H
526.
H
527.
H
160C 528.
I- 0 531.
529.
530.
H
0 532.
535.
~ry* 533. 534.
536.
537.
-365-
R
538.
541.
Table 3B cont.
R
539.
542.
545.
R
540.
544.
547.
550.
0) 548.
551.
543.
H
546.
549.
552.
C
C
*CCCC.
-366y 553.
zrV Table 3B cont.
R
554.
555.
v
V
o0 556.
557. 558.
559.
561.
564. 562.
o 565.
563.
566.
567.
-367- Table 3B cont.
R
568.
a yNY0 571.
569.
570.
572.
573.
S.
S
S.
S. S S S S. S 574.
575. 576.
0cNY 579.
577. 578.
580.
580. 581. 52 582.
-368- Table 3B cont.
R R R ~e e V 583. 584. 585.
0* 0 586. 587. 588.
N-CrV F 589. 590. 591.
591.
595.* *97 592. 593. 594.
595. 596. 597.
369 Table 3B cont.
R R R 598. 599. 600.
y r V 601. 602. 603.
-y 0 604. 605. 6.
606.
liAi FVO~ ~K 607. 608. 69* 609. x/ F&0 610.
F
611.
612.
-370- Table 3B cont.
R
0 613.
Me0"3~y 616.
Mej()
H
MO&~XO
0 619.
622.
MeOQy-y 0 614.
M6O 617.
I H 615.
618.
618.
620.
621.
9 9* 9 9 9* 9 .9 9* 9 9 .9 9 9 99 9 9999 999..
623.
624.
V
0 i, o 00 625. 626. 627.
371 Table 3B cont.
R
H
628.
AP
631.
H
0 0 0h 629.
630.
0 0 632.
Examgle 340 trans. -trans-4-(1 .3-Benzodioxol-5-yl)-2-(4- methoxyPheQnyl)-1 (3-methylibut-1 -yl)-N-phenyl)aminocarbonylmethyl-1pyrrolidine3.
carboxcylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.85 J=6 Hz, 6H), 1.25 J=7 Hz, 2H), 1.42-1.56 (in, 1H), 3.43-3.85 (in, 9H), 3.88s 5.95 2H), 6.80 J=7 Hz, 1 6.86 (dd, J=9 Hz, 1 6.89-7.00 (in, 2H), 6.97 J=1 Hz, 1 7.04 J=9 Hz, 2H), 7.37 J=9 Hz, 2H), 7.40- 7.47 (mn, 3H). MS m/e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).
0e 0 @0
S.
0
SO
S. SO a
OSSS
0 S S 55 0S @500 0 5555
S
5*5050 @5 0 5 5*
S.
S S
*SSS
55 Oe 50 0 555.
0 505000
S
-372- Example 341 trans. -trans-4-(l .3-Benzodioxol-5-yl)-2-(4-methoxyphben-yly.1-(Nbutyl-N-(4-methylphenyflaminocarbonyl methyI-D1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.47 (in, 4H), 2.37 3H), 2.83 J=7 Hz, 211), 3.06-3.25 (in, 2H), 3.40- 3.50 (in, 1 3.51-3.63 (in, 3H), 3.80 3H), 3.87 J=9 Hz, 1 5.92 2H), 6.74 J=8 Hz, 1 6.80-6.86 (in, 3H), 6.89 J=8 Hz, 2H), 1 0 7.04 J=2 Hz, 1H), 7.12 J=8 Hz, 2H), 7.19 J=8 Hz, 2H). MS (DCI) m/e 545 Analysis calcd for C32H36N206: 0, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03.
Example 342 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-rpropoxyphenyl)- 1 dibutylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 .H (300MHz, CDC13 8 7.30 (2H, d, 7.03 (1 H, d, 6.83 (3H, in), 6.72 (1 H, d, 5.95 (1 H, d, 5.93 (1 H, d, J=2), 3.88 (2H, t, 3.73 (1H, d, J=12), 3.58 (1H, in), 3.53-3.20 (4H, in), 3.10-2.90 (4H, in), 2.72 (1H, d, J=15), 1.79 (211, q, 1.50-1.05 (8H, mn), 1.02 (3H, t, 0.87 (3H, t, 0.80 (3H, t, MS (DCIINH3) mWe 539 Anal calcd for 031 H42N206 -0.5H20: C, 67.98; H J7.91; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03.
trans, trans-4-(1 .3-Benzodioxol-5yl)-2-(4-propylphenyl)-1
N-
dibutylamino~carbonyflmethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.31(2H, d, 7.13 (2H, d, J=9), 7.03 (1H, d, 6.84 (1 H, dd, J=6, 6.73 (1 H, d, 5.95 (1 H, d, 5.93 (1H, d, 3.76 (1H, d, J=10), 3.60 in), 3.55-3.20 (4H, in), 3.13-2.88 (4H, in), 2.75 (1H, d, J=15), 2.55 t, J=8),1.62 (2H, q, 1.50-1.00 (8H, in), 0.92 (3H, t, 0.85 (3H, t, 0.78 (3H, t, MS (DCI/NH3) mWe 523 Anal calod for 031 H42N205*0.25 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.
-373- Example 344 trans-trans-2-(4-Methoxypheny')-4-( .3bnoix L-yl1 3(N pro pyl- N- n-plentanesu If onylam i no)Dropyflpyrrolidine-3- crbox lic acidj Using the procedures described in Example 316, the title compound was prepared. 1 HNMR (300MHz, CDCI3) 5 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.3-1.4 (in, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (in, 4H), 2.05-2.15 (in, 1H), 2.43-2.56 (mn, 1H), 2.72-3.1 (in, 7H), 3.27- 3.4 (mn, 2H), 3.5-3.6 (mn, 2H), 3.80 3H), 5.95 2H), 6.73 J=8Hz, 1 0 1 6.8-6.9 (in, 1 6. 85 J= 9Hz, 2H), 7.02 J=2Hz, 1 7.80 (d, J=9Hz, 2H).
Example 345 trans, trans-4-(1.2D hy oezfurn -l--4ehl~ey) N-dibutylam ino~carbonyl) methyflp1yrro i dine- 3carboxylic acid 0 Using the procedures described in Example 1, the title compound 1 was prepared. 1 H (300MHz, CDC13 8 7.40 (3H, in), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 6.72 (1H, d, 5.28 (1H, d, J=12), 4.55 (2H, t, 4.15 (1H, d, J=18), 4.03 (2H, mn), 3.75 (21H, mn), 3.40 (2H, mn), 3.20 (2H, t, 3.15 (1H, in), 3.10-2.90 (2H, in), 2.63 (2H, q, 1.47 (2H, in), 1.31 (4H, in), 1.12 (3H, t, 1.10 0.92 (3H, t, 0.80 (3H, t, MS (DCI/NH3) m/e 507 Anal calod for C31H42N204 *:o TFA: C ,63.86 H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43. o Example 346 *trans, trans-4-(1 .3-Benzodioxol-5-yi)-2-(4-methoxyphenyl) -3 12entyfl-N-12henylaiinocarbonylinethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.93 J=7.3 Hz, 3H), 0.94 J=7.3 Hz, 3H), 1.33 (in, 4H), 2.72 J=15.2 Hz, 1H), 2.81 (in, 1H), 3.11-3.23 (mn, 2H), 3.45-3.57 (in, 2H), 3.79 3H), 3.83 J=9.8 Hz, 1 4.54 (in, 1 5.92 2H), 6.73 J=7.8 Hz, 1 6.83 (mn, 3H), 6.98 (bs, 2H), 7.04 J=1.7 Hz, 1H), 7.07 7.37 (mn, 3H). MS (DCI) in/e 545 Anal calod for C32H33N206 -0.35H20: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.
-374- Example 347 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl).. 1 butyl)-N-(3-trifluoromethylohenyl)amino)carbonyl)melhyl)D2yrrolidine.
3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 0.87 J=6.6 Hz, 3H), 1.17- 1.45 (in, 4H), 2.65 J=16.5 Hz, 1H), 2.72 (in, 3.10 J=9.5 Hz, 1H), 3.21-3.27 (in, 1H), 3.40 (dd, J=4.1, 9.9 Hz, 1H), 3.54 (in, 1H), 3.61- 3.74 (in, 3H), 3.77 3H), 5.93 2H), 6.73-6.85 (in, 4H), 7.02 (in, 3H), 7.33 J=7.5 Hz, 1 7.40 1 7.58 J=7.8 Hz, 1 7.69 Hz, 1 MS (DCI) m/e 599 Anal calcd for C32H33F3N20 6
C,
64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57.
Examlle 348 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 p rop~yl-N-(4-mo rphol in ylca rbonyfl)am ino carbonyl methyl) Pyrrol idi ne-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.78 J=7 Hz, 3H), 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (in, 1H), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (mn, 3.05 (3.70, J=m Hz, 11H), 3.76 3H), 5.88 2H), 6.67 J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (in, 6.98 J=2 Hz, 1H), 7.32- 7.39 (in, 2H). MVS We calc'd for C29H39N307: 540.2710,. 0 Found 540.2713.
Example 349 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methox.Yphenyl)- 1 -(cis- 2 .6-dimethylpi peri din- 1 -yflcarbonylmethyfl-pyrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.94 J=7 Hz, 3H), 1.15d 3H), 1.10-1.70 (in, 6H), 1.70-1.90 (mn, 1H), 2.9. J=13 Hz, 1H), 3.00-3.20 (mn, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 3H), 3.80-4.00 (in, 1H), 4.10-4.65 (mn, 2H), 5.95 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (in, 2H). MS in/e calc'd for C28H35N206: 495.2495. Found 495.2493.
-375- Example 350 trans. trans-2-(4-Methoxymethoxyphenyl)-4-(1 1 2 -(N-propyl-N-n-pentanesulfonylamino~ethyllpyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 00. 1 HNMR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.28-1.36 (in, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 J=7Hz, 2H), 2.20-2.32 (in, 1H), 2.72-3.10 (in, 7H), 3.18-3.41 (in, 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.48 3H), 3.52-3.59 (in, 1H), 3.68 J=9H-z, 1H), 5.15 2H), 5.94 (s,2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz, J=8Hz, 1H), 6.98-7.02 (in, 3H), 7.32 J=9Hz, 2H). MS (DCI/NH3) mn/e 591 Examlle 351 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyheny)- 1 butyPl-N-phenylamino)carbonyflmethyflprrolidine..3.carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.79-0.89 (in, 6H), 1. 14-1.21 (in, 1H), 1.25-1.40 (in, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 Hz, 1 3.05-3.13 (in, 2 3.37-3.49 (mn, 2H), 3.70 3H), 3.80 J=9.8 Hz, I1H), 4.53 (in, 1 5.83 (in, 2H), 6.65 J=8.1 Hz, 1 6.72 6.76, J=m Hz, 3H), 6.87 (mn, 6.95 J=1.7 Hz, 1H), 7.03 (mn, 2H), 7.29 (mn, 3H). MS (DCI) in/e 531 Anal calod for 031 H34N206 O.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:-I)-2-(4-methOXYpheny)- 1 propyl)- N-p2henyl amino) ca rbonyfl)methyl) pyrrol id ine- 3..carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3O1D) 8 0.99 J=6.8 Hz, 6H), 2.71 J=15.6 Hz, 1H), 2.84 (in, 1H), 3.13-3.18 (mn, 2H), 3.45-3.58 (mn, 2H), 3.79 3H), 3.88 J=9.8 Hz, 1 4.80 (in, I1H), 5.92 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (mn, 3H), 6.96 (br s, 2H), 7.04 J=1.7 Hz, 1H), 7.13 (mn, 2H), 7.38 (mn, 3H). MS (DCI) in/e 517 Anal calod for -376- C30H32N206 0.4H20 -0.08CH3002C2H5: C, 68.65; H, 6.28; N, 5.28.
Found: C, 68.64; H, 6.35; N, 5.14.
Examp le 353 trans. trans-4-(4-Prooxyphenyl)2-(4-methoxy~henvly.1
N-
dibutylamino~carbonyl)methyl)2yrrolidine-3-c-arboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.42 d, J=1lOHz), 7.38 (2H, d, J=lOHz), 6.92 (2H, d, J=lOHz), 6.88 (2H, d, J=lOHz), 5.13 (1H, bd, 1 0 J=l2Hz), 4.02 (2H, in), 3.90 (2H, t, J=8Hz), 3.80 (3H, 3.71 (3H, in), 3.40 (2H, in), 3.19 (1H, in), 3.10-2.90 (2H, in), 1.80 (2H, in), 1.48 (2H, mn), 1.29 (4H, in), 1.13 (2H, in), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz). MS (DCI/NH3) in/e 525 Anal calcd for C31 H4N2OS. 1 TFA C, 62.06 H 7.10; N, 4.39 Found: C, 62.43; H, 7.28; N, 4.39. Example 354 trans, trpns-4-(1 .3-Benzodioxol-5-yl-2-(4-methoxyphenyly.1 .2.3.4-tetrahydroguinolin-1 -yl)carbonyl)methyl)p2yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.88 (quintet, J=6.5 Hz, 2H), 2.67 J=6.4 Hz, 2H), 2.87 J=8.6 Hz, 1 3.14 (in, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1 3.53-3.70 (in, 3H), 3.72-3.78 (mn, 1 3.77 3H),% s3.86 (d J=9.6 Hz, 1IH), 5.91 2H), 6.73 J=8.1 Hz, 1 6.83 (mn, 3H), W 6.98 J=1.1 Hz, 1H), 7.02-7.23 (mn, 6H). MS (DCI) m/e 515 Anal calcd for C30H30N206 -0.3H20 0.15 CH3002C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.
Example 355 trans.t rans-2-(3.4-Diinethoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 (N.N-di(n-butyl)amino)carbonyl)methyl)-pyrrolidine-3..carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in.p. 64-65 OC. 1 HNMR (CDCI3, 300MHz) 8 0.79 J=7Hz, 3H), 0.88 J=7Hz, 3H),1.07 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, -377- J=13.5Hz, 1H), 2.94-3.17 (in, 4H), 3.22-3.42 (in, 1H), 3.40-3.48 (in, 3H), 3.58-3.65 (in, 1H), 3.82 3H), 3.85 4H),5.92 2H), 6.73 J=8Hz, 1H), 6.81 J=8Hz, 1H), 6.86-6.96 (in, 3H), 7.07 J=3Hz, 1H). MS (DCl/NH3) m/e 541 Example 356 trans. trans-2-(3.4-Dimethoxylhenyl)-4-( 1.3-benzodioxoI -5-yl')-1-r2- (N-propyl-N-n-pentanesulfonylamino'ehyllpyrrolidine-a-carboxylic Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 75-86 OC. 1 HNMR (CD3OD, 300 MHz) 8 0.75 J=7Hz, 3H), 0.82 J=7Hz, 3H), 1.32-1.43 (mn, 6H), 1.65-1.77 (in, 2H), 3.0-3.09 (in, 4H), 3.23-3.27 (in, 2H), 3.44 J=6Hz, 1 3.47-3.56 (mn, 2H), 3.78 J=9Hz, 1 3.83-3.93 (in, 2H), is 3.87 3H), 3.92 3H), 4.63 J=l3Hz, 1H), 5.97 2H), 6.82 (d, J=7Hz, 1H), 6.93 J=7Hz, 1H), 7.06 J=7Hz, 1H), 7.08 J=3Hz, 1 7.16 (dd, J=3Hz, J=7Hz, 1 7.27 J=3Hz, 1 MS (DCI/NH3) in/e 591 Example 357 trans, trans-2-(3.4-Dimethoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1 -re- 12ro pyI- N h exan esu I fo ny I am in o)eth y 112pyrroIi d in e- 3- c arb o x4icq Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 65-66 OC. 1 H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.23-1.48 (in, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7-z, 2H), 2.25-2.35 (mn, 1H), 2.73-3.10 (in, 7H), 3.19-3.32 (mn, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.59 (in, 1H), 3.68 J=9Hz, 1H),3.87 6H), 5.95 2H), 6.74 J=8Hz, 1H), 6.79-6.86 (in, 2H), 6.92-6.97 (in, 2H), 7.02 1H).
MS (DCI/NH3) in/e 605 -37 8- Example 358 trans, tran-s-2-(4-Methoxyphenyl)-4- 1 .3-benzodioxoL-5-yl)-1 -r2- (D2hthalimido)ethyll-pyrrolidine-3-carboxyl'ic acid The compound of Example 10 (.250 mg), N-bromoethylphthajimide (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitnile and heated for 2.5 hours at 95 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 1 0 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) 3.12-3.26 (in, 2H), 3.60-3.75 (in, 2H), 3.70 3H), 3.98-4.12 (in, 2H), 4.45-4.55 (in, 1H), 4.69 J=9Hz, 1H), 4.76- 4.88 (in, 1H), 5.96 2H), 6.55 J=8Hz, 1H), 6.60-6.70 (in, 3H), 6.79 J=8Hz, 1H), 7.05-7.45 (mn, 5H), 7.75 J=7Hz, 1H).
Examlle 359 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyn)- 1 12entyfl-N-phenylainino)carbonyflinethyl)pyrrolidine.3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3QD) 5 0.86-0.98 (mn, 6H), 1.17-1.22 V.: (in, 1KH), 1.23-1.41 (in, 3H), 2.70 (dd, J=1 1.2, 15.3 Hz, 1 2.83 (in, 1 3.10-3.21 (in, 2H), 3.45-3.60 (in, 2H), 3.79 3H), 3.86 (in, 1H), 4.74 (in, 1H),,5.91 (in, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (in, 2H), 7.04- 7.14 (in, 3H), 7.36 (in, 3H). MS (DCI) m/e 545 Anal calcd for C32H36N?06 0.25 CH3C02C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C,.
70.03; H, 6.54; N, 4.78.
Example 360 trans, trans-4-(1 .3-Benzodioxol-5-y)-2-(4-nethoxyphen-yl)- 1 butyl- N-(2-nap~hthyl aininocarbonyl methyl'kpyrrolidfine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.83 J=7 Hz, 3H), 1.23- 1.39 (in, 4H), 1.40-1.55 (in, 3K), 2.60-2.72 (in, 2H), 3.00-3.80 (mn, 3.66 3H), 5.87 2H), 6.39 J=9 Hz, 2H), 6.74-6.85 (in, 3H), 7.17 -379- J=2 Hz, 1 7.40 (dd, J=8 Hz, 1 7.52-7.62 (in, 3H), 7.80-7.90 (in, 1H), 7.90-8.00 (in, 2H). MS (DCI) m/e 581 Analysis calcd for C35H36N206 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-Proooxyphenyl)-4-(1 .3-benzodioxol-s5yli -l2-(N- 12ropyl-N-n-pentanesulfonylamino~iethyll pyrrolidine-3-carb-oxylic a-cid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 53-54 OC. 1 HNMR (CDCI3, 300MHz) 8 0.79 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (in, 2H), 1.80 (sextet, 2H), 2.23-2.33 (in, 1H), 2.72-2.93 (in, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (in, 2H), 3.42 J=9Hz, 1 3.54-3.62 (mn, 1H), 3.67 J=9Hz, 1H), 4.90 J=7Hz, 2H), 5.95 2H), 6.73 (d, J=8Hz, 1H), 6.85 J=8Hz, 2H), 7.02 7.32 J=8Hz, 2H). MS (DCI/NH-3) m/e 589 Example 362 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxy2hey)- 1 inethylindolin-1 -yflcarbonyl~methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereomers, 0.95 (in, 1.5 (CH3 1.05 6.3H, 1.5 2.62 (mn, 1H), 3.01 (mn, 2H), 3.14-3.25 (in, 1H), 3.37-3.52 (in, 1.5H), 3.56-3.80 (in, 2H), 3.65 1.5 (CH3O)), 3.76 1.5 (CH3O)), 3.93 (in, 0.5H), 4.05-4.1-3 (mn, 4.42 (in, 0.5H), 4.65-4.74 (in, 1H), 5.91 (in, 2H), 6.72 J=8.1 Hz, 0.5H), 6.75 (mn, 0.5H), 6.85 (in, 2H), 6.92 J=8.5 Hz, 1H), 7.00-7.06 (mn, 2H), 7.14 J=7.7 Hz, 1 7.21 J=6.6 Hz, 1IH), 7.38 (in, 2H), 7.99 (in, 1H). MS (DCI) nile 515 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.
-380- Example 363 trans, trans-4- Benz odi oxol-5 -yl)-2 etho xyphenyn) 1 hyd roxy-3-prolyl hex- I -yl)pyrrol id ine-3-carboxylic a cid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 6 1.06 (in, 6H), 1.26-1.60 (in, 9H), 3.16 (dd, J=1 0.9, 12.6 Hz, 1 3.18 J=1 1 Hz, 1 3.44 Hz, 1 3.61 J=1 1 Hz, I1H), 3.73 J=1 1.0 Hz, 1 3.85 (in, 1 H), 3.96-4.17 (in, 2H), 4.02 1.5 (CH3O diastereomer)), 4.03 1.5 (CH3O diastereomer)), 6.15 2H), 7.01 J=8.1 Hz, 0.5H), 7.00 J=8.1 Hz, 1 0 0.5H), 7.10 (in, 1H), 7.23 (mn, 3H), 7.77 (in, 2H). MS (DCI.) in/e 484 Anal calcd for C28H37N06 0.33 H3P04: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.: Example 364 trans, trans-4-(1 .3-Benzodioxol-5-.yfl-2-(4-nethoxypheny)- 1 he1tyfl- N- (3.4-di m eth oxybenzyl) am ino)ca rbonyl) met hyl) 1yrroli dine-3.. carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 81:1 mixture of rotainers, 0.61 J=7.1 Hz, 1.5H), 0.72 0.76 J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.05-1.60 (in, 8H), 2.84-3.10 (in, J=2.5, 3.18, t, 9.7 Hz, 0.5H), 3.41-3.52 (in, 2H), 3.47-3.69 (in, 3.66 1.5H), 3.73 1.5H), 3.77 1.5H), 3.78 1.5H), 3.79 1-5H), 3.86 J=9-8 Hz, 0.5H), 4.19 J=17.7 Hz1, 4.29 J=15.2 Hz, 0.5H), 4.40-4.49 (in, 4.47 (d, J=15.3 Hz, 0.5H), 4.60 J=17.6 Hz, 0.5H), 5.93 (in, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.5H), 6.52 J=2.0 Hz, 0.5H), 6.74 (mn, 2.5H), 6.80 1IH), 6.83- 6.88 (in, 1H), 6.92 (in, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (in, 1H), 7.36 (mn, 1H). MS (DCI) m/e 647 Anal calcd for C37H46N208: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.
Example 365 trans, trans-4-(1 .3-Benzo-dioxol-5-yl)-2-(4-meth-oxylheny)- 1 ((indoli n- I -yflcarbonyl) m ethyl) pyrroli di ne-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 82.97 (dd, J=8.1, 9.5 Hz, 1 H), 3.10 J=8.1 Hz, 2H), 3.16-3.22 (in, 2H), 3.51-3.68 (in, 3.73 (in, -381- 3H), 3.83-4.05 (in, 5.90 (in, 6.73 J=8.1 Hz, 1 6.86 (in, 3H), 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 J=0.7 Hz, 11H), 7.11 (in, 1H), 7.18 J=7.1 Hz, 1H), 7.38 J=8.5 Hz, 2H), 8.02 1H). MS m/e 501 Anal calcd for C29H28N206 -0.5 H20 -0.15 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.
Examlle 366 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)1 1 0 butyl- N-(2-chlo ro h enyl) amino ca rbonyl methyfl y rr lidine-3 carboxylic acid wsUsing the procedures described in Example 1, the title compound wsprepared. 1 H NMR (300 MHz,. CD3OD) 80.89 (dt, J=7 Hz, 3H), 1.23- 1.51 (in, 4H), 2.52-4.00 (in, 8H), 3.78 J=6 Hz, 5.92 J=6 Hz, 1 5 2H), 6.70-6.87 (in, 7.02-7.21 (in, 4H), 7.27-7.52 (in, 3H). MS (DCI) m/e 565 Analysis calcd for 031 H32N20601*- 0.6H20: 0, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.
Example 367 trans, trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yfl-1 (3.4.5-trimethoxybenzyl)pyrrolidine-3--carboxylic acid The compound resulting from Example 10 (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 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 OC. 1 KH NMR (300 MHz, CDCI3) 82.75 J=9Kz, 1KH), 2.95-3.05 (mn, 2K), 3.20 J=11 Hz, 1H), 3.45-3.55 (in, 1K), 3.7-3.8 (in, 2H), 3.84 3K), 5.95 (dd, J=2Kz, 6H-z, 2H), 6.55 6.70 J=8Hz, 1H), 6.30-6.35 (in, 1K), 6.90 J=9Hz, 2H), 7.13 J=2Hz, 1K), 7.43 (d, J=9Hz, 2H).
-382- Example 368 trans. trans-4- (1 Benzo d ioxol -5-yi)-2 -(4-meth oxypheDnYl)-1 (Nbutyl-N-(3-chlororphenyI)aminocarbonylmethyl-pyrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMVR (300 MHz, CD3OD) 5 0.89 J=7 Hz, 3H), 1.20- 1.42 (in, 3.42-3.87 (in, 9H),-3.9 5.96 2H), 6.75 (7.10, J=m Hz, 7.33-7.50 (in, 4H). MS m/e 565(M+H). Analysis calcd for C31 H33N2O6C1*1.OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41; H, 4.99; N, 4.08.
Example 369: trans, trans-2-(4-M~ethoxphenyl)-4-( 1 .3-benzodioxol-5-yi)l- -r2-(di-nbutylamino)pyrimidin-4-yllpyrrolidine-3-carboxylic aci-d The compound resulting from Example 1C (0.25 g) was reacted with 0.11 g of 2,4-di chi oropy rimid ine 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-(1,3benzodioxol-5-yI)-l1-(2-chloro-4-pyriinidyl)-pyrrolidine-3carboxylate. This compound was reacted with 1 mL of dibutylainine in 2mL of toluene at 125 OC for 17 hours. The resulting ethyl ester was hydrolyzed by the method of Example ID to give 0.142 g of the title* comnopund as a white powder. 1 HNMVR (300 MHz, CDCI3) 80.75-0.90 (broad, 6H), 1.1-1.3 (br, 1.35-1.55 (br, 3.05 (mn, 1H), 3.3-3.5 (br, 3.55-3.67 (in, 2H), 3.75 4.6 (br, 5.2 (br, 1H), 5.45 (br, 5.87 2H), 6.3 (br, 11H), 6.67 J=8Hz, 1H), 6.7-6.85 (mn, 4R-), 7.10 J=9Hz, 2H-).
Example 370 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-inethoxyphenyn)- 1 methylbut-2-yfl-N-o2henyl aiino~carbonyl)inethyl)p2yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMVR (300 MHz, CID3O1D) 8 0.90 J=7.5 Hz, 3H), 1.12 1.14 2.06 J=7.5 Hz, 2.73 J=15.3 Hz, 1H), 2.91 J=9.5 Hz, 1H), 3.11 J=15.6 Hz, 3.21 J=8.8 Hz, 1H), 3.50- -383- 3.61 (in, 2H), 3.80 3H), 4.00 J=1 0.2 Hz, 1 5.91 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (in, 3H), 6.93 (in, 1H), 6.98 (in, 1H), 7.03 J=1.7 Hz, 1H), 7.17 (in, 2H), 7.36 (in, 3H). MVS (DCI) m/e 545 Anal calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 4.97.
Example 371 trans. trans-2-(4- Ethyl phe nyl) (5-i nd anyl~ 1.U-N .Ndibutylamino~carbonylmethyl)pyrrolidine-3-carboxylic -acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3) 8 7.25 (3H, in), 7.21 (1 H, d, 3Hz), 7.17 (3H, in), 3.80 (1 H, d, 10OHz), 3.65 (1 H, ddd, 6, 5, 3Hz), 3.4 (4H, mn), 3.10 (2H, mn), 2.98 (2H, in), 2.88 (5H, in), 2.79 (1 H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, in), 1.42 (2H, in), 1.32 (1 H, in), 1.21 (3H, t, 7Hz), 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) mWe 505 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 trans. -rans-2-(3.4-Difluorophenyb)-4-(1 .3-benzodioxol-5-yl)l
.N-
dibutylamino~carbonyflmethyl)-pyrroli-dine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 62-63 OC. 1 HN MR (CDCI3, 300 MHz), 8 0.83 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.13 (sextet, J=7Hz, 2H),1.20-1.32 1.36-1.49 2.85-2.93 2.98-3.23 (mn, 4H), 3.36-3.45 (mn, 3H), 3.58-3.66 (in 1H), 3.94 (d, J=8Hz, 1H), 5.93 2H), 6.72 J=7.5Hz, IH), 6.84 (dd, J=lHz, 1H), 6.98 J=7.5Hz, 1H), 7.08-7.15 (mn, 2H), 7.22-7.28 (mn, 1H). MS (CDI/NH3) m/e517 Exampe 373 trans. trans-2-(3.4-Dif luorophenylb-4-(1 .3-benzodioxol-5-yl)- 1 propyvl-N-n-pentanesulfonylaminoethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 71-72 00. 1 HNMR (CDCI3, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.25-1.38 -384- (in, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (in, 1H), 2.72-2.95 (mn, 5H), 2.98-3.12 (mn, 2H), 3.15-3.34 (in, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (in, 1H), 3.71 J=9Hz, 1H), 5.96 (s, 2H), 6.75 J=9Hz, 1H), 3.82 J=2Hz, J=9Hz, 1H), 5.96 J=2Hz, 1H), 7.09-7.18 (in, 2H), 7.23-7.34 (in, 1H). MVS (CDI/NH3) m/e567 Example 374 trans. trans-4-(1 3 -Benzodioxol-5-y)-2-(ethoxymethyl..1-(((N
.N-
dibutylamino)carbonyl)methyflp1yrrolidine.3.carboxylic acid Using the procedures 'described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.53. 1 H NMVR (CDCI3, 300 MHz, rotameric forms) 8 0.70 J=7Hz), 0.80 J=7Hz) and 0.96-1.04 (in, 6H total), 1.04-1.75 (in, 11H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 2.80-3.08 (in, 2H total), 3.10-3.82 (br m, 12H), 4.03 (in) and 4.22-4.45 (br mn, 2H total), 5.90 and 5.91 2H total), 6.65-6.84 (in) and 6.93 (in) and 6.99 (in, 3H total). MS (FAB) m/e 463 Anal calcd for C25H38N206 1.5 H-20: C, 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62.
Examng e 375 trans. trans-4-( 1.3-Benzodioxol-5-yfl-2-(n-butyl)-1 dibutylamino~carbonyl)methyl)pyrrolidine-3-carboxylic- acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2C 12) Rf 0.37. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.71 J=7Hz) and 0.77-1.05 (mn, 9H total), 1.05-1.20 (mn, 1.20-1.72 (br m, 13H), 2.48-2.52 (mn, 1H), 2.87-3.00 (mn, 1H), 3.05-3.60 (mn, 5H), 3.60-3.80 (br mn, 2H), 3.88-4.05 (br mn, 1H), 4.28 (br d, J=l5Hz, 1H total), 5.90 and 5.92 2H total), 6.67-6.82 (mn, 3H total). MS (FAB) m/e 461 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.
-385- Example 376 trans. trans-4-(1 Benzod ioxol -5 -yfl (2-m ethyl butyfl)-1 Ndibutylamino~carbonyl)methyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated. as a colorless glass. TLC (10% MeOH- CH2CI2) Rf 0.49. 1H NMR (CDCI3, 300 MHz, rotamenic 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 mn, 1H), 2.87-3.01 (br m, 1H), 3.06-3.82 (br m, 7H), 3.90-4.40 (br m, 5.90 and 5.92 2H total), 6.67-6.90 (in, 3H total). MS (FAB) m/e 475 Example 377. V trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(3-methylbutyfl-1 d ibutyl amino) carbonyfl)methyl) pyrro lid ine-3-ca rboxylic -acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.41. 1 H NMR (CDCI3, 300 MHz, rotaineric forms) 8 0.73 J=7Hz) and 0.77-1.05 (in, 12H total), 1.07-1.75 (in, approx. 14H plus 1-20), 2.48-2.63 (in, 11H), 2.87-3.05 (in, 1H), 3.05-3.60 (several br in, 5H), 3.62-4.02 (br mn, 4.29 (br d, J=l5Hz, 1H), 5.89 and 5.93 2H total), 6.65-6.90 (mn, 3H total). MS (FAB) m/e 475 Example 378 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl-1 p2rolyl-N-((N-methyl-N-prooylanino~sulfonylbamino~ethyllr~yrrolidine- 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 00. 1 H NMR (CDCI3, 300MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (mn, 4H), 2.22-2.30 (in, 1IH), 2.62 3H), 2.68-2.78 (in, 11H), 2.84-3.03 (in, 3.08-3.31 (in, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (mn, 1H), 3.63 J=9Hz, 1H),3.79 3H), 5.95 2H), 3.73 (d, J=8Hz, 1H), 6.83 (dd, J=2Hz, J=8Hz, 11H), 3.87 J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 576 -386- Example 379 trans, trans-2 .4-Di(3.4-dif luorolhenyr)- 1 Nd ibutyl am ino)carbonyl) methyflpyrroli din e.3-caboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 8 7.35 (2H, in), 7.18 (4H, in), 4.87 (1H, d, J=12), 4.00-3.60 (5H, in), 3.60-3.10 (3H, in), 3.10-2.90 (2H, mn), 1.45 (2H, in), 1.29 (4H, in), 1.15 (2H, in), 0.91 (3H, t, 0.83 (3H, t, MS (DCI/NH3) m/e 509 Anal calcd for C27H32F4N 2 0 3 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.
Example 380 trans, trans- 4 -(3.4-Dimethylghenyl2.(4..m-ethoxyphenyl)-
.N-
I dibutylamino~carbonyl)methyl)pyrrolidine.3-carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 5 7.43 (2H, d, 7.25 (1 H, bs), 7.18 (1H, dd, J=8, 7.11 (1H, d, 6.90 (2H, d, J=10), 5.48 (1H, d, J=12), 4.26 (IH, d, J=18), 4.16 (2H, in), 3.83 (2H, in), 3.81 (3H, s), 3.56 (1H, bd, J=18), 3.37 (1H, in), 3.20 (1H, in), 2.96 (2H, in), 2.24 (3H, 2.22 (3H, 1.47 (2H, in), 1.27 (4H, in), 1.10 (2H, 0.93 (3H, t, 0.81 (3H, t, MS (DCI/NH3) m/e 495 Anal calcd for C30H-42N204- 1.25 TEA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 0.
7.05; N, 4.38. 9 Exampl-e-381 ~trans, trans-2.4-Di(3-f luoro-4-meth -o xyghenyl)1 dibutylamino)carbonylmethyl)p2yrroliline.3.carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13 5 7.20 (2H, mn), 7.17 (2H, mn), 6.93 (2H, in), 5.48 (1 H, mn), 4.26 (1 H, in), 4.16 mn), 3.83 (2H, mn), 3.87 (6H, 3.56 (1 H, mn), 3.37 (1 H, in), 3.20 (1 H, mn), 2.96 (2H, mn), 1.47 (2H, mn), 1.27 (4H, in), 1. 10 (2H, in), 0.93 (3H, t, 0.81 (3H, t, MVS (DCI/NH3) rn/e 533 Anal calcd for C29H38F2N20 5 0.75 H20: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99.
-387- Example 382 trans, trans-4-(l .3-Benzodioxol-5-yfl)2-(4-methoxyph-enyl) 1 p2entyl) N- (3-m ethylphe nyI)am ino) ca rb onyl) methyl) pyrrol idi ne-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 5 0.90 (in, 3H), 0.95 J=7.3 Hz, 3H), 1.13-1.37 (in, 4H), 2.30 3H), 2.34 (s (CH3 rotainer)), 2.73- 2.91 (in, 2H), 3.17-3.26 (mn, 2H), 3.32-3.62 (in, 2H), 3.77-4.08 (mn, 1H), 3.80 3H), 4.71 (in, 1H), 5.92 (in, 2H), 6.61-6.84 (mn, 6H), 7.04-7.16 1 0 (in, 3H), 7.23-7.29 (in, 2H). MS (DCI) m/e 559 Anal calcd for C33H38N206 -0.35 H20 -0.05 CH3002C2H5: C, 70.03; H, 6.92; N, 4.92.
Found: C, 70.08; H, 6.82; N, 4.95. Example 383 trans. trans-4-( 1.3-Benzodioxol-5-yb-2-(4-methoxyphenyl)-1-(Nbutyl-N-(1 -naphthyl)aminocarbonylmethyfl)1yrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.40 (in, 2H), 1.40-1.60 (mn, 2H), 2.42-2.80 (mn, 2H), 2.85-4.00 (in, 6H), 3.77 J=1.5 Hz, 3H), 4.05-4.20 (in, 1 5.94 J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 (in, 4H), 6.95-7.02 (in, 2H), 7.17 (dd, 8H, 112), 7.25 (dd, 8H, 7.38-7.60 (mn, 4H), 7.87-8.00 (in, 2H). MS m/e 581. Analysis calcd for C35H36N206 1.4 H20: C, 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-(Nphenyl-N-n-hexanesulfonylanino~ethylllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. m-p. 67-68 00. 1 HNMR (CD3OD, 300 MHz) 8 0.88 J=7Hz, 3H), 1.25-1.40 (in, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (in, 1H), 2.64-2.88 (in, 3H), 3.02 (sextet, J=8HZ, 2H), 3.44-3.53 (mn, 2H), 3.58 J=9Hz, 1H), 3.56-3.75 (in, 1H), 3.78 3H), 3.88-3.98 (in, 1H), 5.93 2H), 6.72 J=9Hz, 1H), 5.78- -388- 5.84 (in, 3H), 6.96 J=2Hz, 1 7.20 J=9Hz, 7.27-7.36 (in, MS (DCI/NH3) m/e 609 Example 385 trans, trans-4-(1.3Bnoixl5y)2(-eh ylhey)1 m ethyl-i .2.3.4-tetrahyd roguinol in- 1 -yfl ca rbonyl methyflpy2rrolidine-.3.
carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.03 (mn, 3H), 1.10-1.45 (in, 1H), 2.10-2.85 (in, 4H), 2.90-4.00 (in, 7H), 3.76 1.5H), 3.77 isomer), 5.90 (mn, 2H),.6.70-7.40 (mn, 11H). MS (DCI) m/e 529 Analysis calcd for C31H32N206 0.3 H20: C, 69.73; H, 6.15; N, 5.25.: Found: C, 69.74; H, 6.10; N, 5.01.0.: Example 386 eg.
trans.trans-4-(1 .3-Benzodioxol-5-yl-2-4 4-methoxyphenylp 1 butyl-hept-2-en-1 -yflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title cornpound 0 C1 was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.86 J=7.0 Hz, 3H), 0.90 J=7.0 Hz, 3H), 1.20-1.41 (mn, 8H), 1.95-2.06 (in, 4H), 3.24 J=11.0 Hz, I1H), 3.51-3.59 (in, 3H), 3.60-3.71 (in, 1 3.77-3.84 (in, 1 3.81 3H), 4.45 J=11.0 Hz, 1H), 5.52 J=7.4 Hz, 1H), 5.93 2H), 6.77 J=8.1 Hz, 1 6.87 (dd, J=1 8.1 Hz, 1 6.99 (in, 3H), 7.46 (in, 2H). MS (DCI) in/e 494 Anal calcd for C30H39N05: 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-Fluoro-4-methoxyphenyl)-4-(1 1 2 -(N-propyl-N-n-hexanesulfonylamino~ethyIlpyrrolidine-3 carboxlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-65 OC. 1 HNMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=6Hz, 3H), 1.23-1.47 (mn, 6H), 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (mn, 1H), 2.70-2.93 (mn, 2.96-3.12 (mn, 2H), 3.15-3.35 (mn, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.59 (in, 1H), 3.66 J=9Hz, 1H), 3.87 (s, -389- 3H), 5.95 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.42 (t, J=8Hz, 1H), 6.96 1H), 7.12 J=9Hz, 1H), 7.17 J=l2Hz, 1H). MS (DCI/NH3) m/e 593 Example 388 trans, trans-4-( 1.
3 -Benzodioxol-5-ylb-2-(4-mehXy hey.14(.
pidyl) methyfl) yrro Iidi ne-3-carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.87 (in, 2H), 3.04 (dd, J=3.2, 9.7 Hz, 1H), 3.21 J=13.7 Hz, 1H), 3.51 (in, 1H), 3.76-3.85 (in, 2H), 3.79 3H), 5.90 (in, 2H), 6.71 (in, 1 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (mn, 3H1), 7.36-7.45 (in, 3H), 7.81 (in, 1 8.39 (in, 1 8.46 (dd, J= 1.4 Hz, 1 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.
Example 389 trans, trans-2-(n-Hexyl)-4-(1 .3-be nzodioxol-5-yn- 1 Ndibutylaminocarbonylmethyflp1yrrolidine-3-carboxylic acidV.
Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 5 0.82-1.00 (in, 9H), 1.20-1.40 (i,12H), 1.45-1.60 (in, 4H), 1.70-1.90 (br m, 2H), 3.10-3.46 (in, 6H), 3.65 J=10.8 Hz, 1H), 3.76 J=11.0 Hz, IH), 3.92-4.06 (in, 2H), 4.14-4.34 (in, 2H), 5.94 2H), 6.73 J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 J=1.8 Hz, 1H). MS(DCI/NH3) m/e 489 Anal calcd 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-yi)-2-(4-methoxyphenyl). 1 pentyfl-N-4-fluoro-3methylp~henyflamino~icarbonyl)methyflpyrrolidine-3.crboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.92 (mn, 3H), 0.97 J=7.1 Hz, 3H), 1.13-1.40 (mn, 4H), 2.22 (mn, 3H), 2.58-2.74 (mn, 1H), 2.78-2.87 (mn, 1H), 3.09-3.25 (mn, 2H), 3.39-3.60 (in, 2H), 3.70-3.90 (mn, 1H), 3.80 3H1), 4.70 (in, 1H1), 5.93 (in, 2H), 6.70-6.76 (in, 1H), 6.75 (dd, J=1.4, -390- 8.1 Hz, 1H), 6.80-6.94 (in, 4H), 6.96-7.13 (in, 4H). MS (DCI.) m/e 577 Anal calcd for C33H37FN206 0.25 H20: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.
Example 391 trans, trans-4- (1 Be nzod ioxoI-5-yh-2 -(4-meth oxy2hen l) -1 py ridyflmethyflpyrrol idin e-3-c-arboxyl ip acid Using the procedures described in Example 1, the title cornpound was prepared. 1 H NMR (300 MHz, CD3OD) 5 2.97 (dd, J=7.9, 9.7 Hz, 1 H), 3.04 J=9.6 Hz, 1H), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 J=14.0 Hz, 1H), 3.59 (in, 1 3.78 3H), 3.96 J=9.9 Hz, 1 3.97 J=1 3.6 Hz, 1 H), 5.90 (in, 2H), 6.73 J=8.1 Hz, 1 6.83 (dd, J=1.7, 7.9 Hz, 1 6.92 (in, 2H), 6.96 J=1.8 Hz, 1IH), 7.28 (in, 1H), 7.44 (in, 2H), 7.53 J=8.1 Hz, 1H), 7.80 (dt, J=1.8, 7.7 Hz, 1H), 8.42 (mn, 1H). MVS (DCI) m/e 433 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.
o o Example 392 000 trans. trans-2-(3-Ph enyl pro pyl)-4-(1 benzodi oxol -5-yfl)-1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.89-0.97 (in, 6H), 1.22-1.36 (mn, 4H), 1.41-1.55 (mn, 4H), 1.63-1.95 (in, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (mn, 7H), 3.53-3.60 (in, 2H), 3.65-3.76 (in, 1H), 3.82-3.90 (in, 1H), 3,96-4.10 (in, 1H), 5.92 2H), 6.71 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 (mn, MS(DCI/NH3) m/e 523 Anal calcd for C31H42N205 0.6 TEA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.
Exampe 393 trans-trans-2-(4-Methoxy-3-fluorop~henyl)-4-(7-methoxy-.1 .3- 1 -r(N .N-di(nbutyflamino)carbonylmethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 115-117 00. 1 H NMR (300 MHz, CDCI3) 5 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.5 (mn, -391- 8H), 2.85 J=l3Hz, 1H), 2.90-3.17 (in, 5H), 3.20-3.35 (in, 1H), 3.35- 3.50 (mn, 3H), 3.55-3.65 (in, 11H), 3.84 J=lOHz, 1H), 3.87 3H), 3.92 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 1KH), 6.70 1 6.90 (t, J=8Hz, 1H), 7.05-7.20 (in, 2H).
Example 394 trans-trans-2-(l .4-Benzodioxan-6-yb)-4-(7-methoxy-1 .3- -r(N .N-di(nbutyflamino~carbonylmethyllpyrrolidine-3-carboxylic acid 1 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 107-110 OC. 1 H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.75 J=l3Hz, 1H), 2.90-3.12 (in, 4H), 3.32-3.60 (in, 5K), 3.69 J= 8Hz, 1KH), 3.90 3H), 4.23 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 1KH), 6.70 1 6.78-6.93 (m ,3H).
Example 395 trans.trans-4-(1 .3-Benzodioxol-5-yb)-2-(4-methoxyphenyl)-1 butyl-2-fluoro-hept-2-en-1 -yflp1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 M~z, CD3OD) 8 0.84 J=7.0 Hz, 3K), 0.88 J=7.0 Hz, 3K), 1.16-1.37 (mn, 8H), 1.83 J=8.5 Hz, 2H), 2.03-2.08 (mn, 2H), 2.76-2.92 (in, 2H), 3.02 J=9.3 Hz, 1H), 3.32-3.42 (in, 2H), 3.50 (in, 1KH), 3.71 J=9.2 Hz, 1 3.78 3K), 5.91 (in, 2K), 6.72 (d, J=7.8 Hz, 1KH), 6.83 (dd, J=1.7, 8.1 Hz, 1KH), 6.90 (in, 2K), 7.02 J=1.7 Hz, 1H), 7.34 (in, 2K). MS (DCI) mle 512 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 trans. trans-2-(3-Fluoro-4-ethoxyphenyl)-4-(1 .3-benzodioxoI -5-yfl- 1 F2-(N-1Dropyl-N- n-pentanesulf onylami no'~ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-66 OC. 1 H NMR (CDCI3, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.26-1.36 -392- (in, 4H), 1.41-1.52 (in, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (mn, I1H), 2.69-2.96 (in, 5H), 2.97-3.12 (in, 2H), 3.16-3.37 (in, 2H), 3.43 J=9.Hz, 1 3.52-3.59 (in, 1 3.66 J=9Hz, 1 4.08 J=7Hz, 2H1), 5.95 (s, 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.92 J=8Hz, 1 6.97 1H), 7.07 J=8Hz, 1H), 7.15 J=l2Hz, 1H). MS.(DCI/NH3) m/e 593 Example 397 trans. trans-2-(4-Methoxy-3-fluoro1henyl).4.(7methoxy-1.3benzodioxol-5-yl)- 1 -[(N-butyl-Npropylamino)carbonylmethyllpyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 OC. 1 H NMR (300 MHz, 0D013) 8 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (in, 8H), 2.80-3.50 (in, 9H), 3.55-3.65 (in, 1H), 3.82 J= 10Hz, 1H), 3.85 3H), 3.92 3H), 5.96 2H), 6.62 1H), 6.70 1H), 6.90 J=8Hz, 1H), 7.08-7.22 (in, 2H).
Example 398 trans.trans-4-(1 .3-benzodioxol-5-yfl-2-(4-methoxyp~henyl)1 butyl-N-(4-chlorophenyflaminocarbonylmethyl)pyrrolidinep3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.66-4.00 (in, 9H), 3.81 3H), 5.95 2H), 6.77 J=7 Hz, 11H), 6.85 J=8 Hz, 3H), 7.05 (in, 7.33-7.42.(in, 2H). MS mn/e 565 Analysis calcd for C31 H33N206C1 0.25 H3P04: 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 Benz odi oxol- 5-yi) (4-m ethoxyp he nyl) 1 methyl-i .2.3.4-tetrahydroguinolin-1 -ylcarbonylmethyfl)1yrrolidine-3.
carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.27 J=7 Hz, 1.5H), 1.28 711, 1.5-diastereomer), 1.39-1.55 (mn, 1H), 2.02-2.15 (mn, 111), 2.60- -393- 3.25 (in, 5H), 3.33-4.00 (in, 5H), 3.78 3H), 5.92 J=3 Hz, 2H), 6.73 (dd, J=8 Hz, 1H), 6.75-6.90 (in, 3H), 6.91-7.35 (in, 7H). MS (DCI) m/e 529 Analysis calod for C31 H32N206: C, 70.44; H, 6.10; N, 5.30.
Found: C, 70.16; H, 6.04; N, 5.04.
Example 400 trans. trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -2-(N-propyl-N-(2-(piperidin-1 yllethanesulfonylamino~ethyllpyrrolidine-3-carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 95-96 00. 1 HNMR (CDC13, 300MHz) 8 0.82 J=7Hz, 3H), 1.43-1.55 (in, 4H), 1.63-1.72 (in, 4H), 2.29-2.38 (in, 1H), 2.64-2.78 (in, 5H), 2.87 J=8Hz, 1H), 2.95- 3.04 (in, 5H), 3.20-3.30 (mn, 1H), 3.32-3.43 (in, 4H), 3.54-3.63 (in, 11-), 1 5 3.78 J=8Hz, 1 3.87 3H), 5.92 2H), 6.72 J=8Hz, 1 6.78 K.
(dd, J=2Hz, J=8Hz, 1H), 6.88 J=8Hz, 1H), 6.94 J=2Hz, 1H), 7.08- 7.20 (mn, 2H). MS (DCI/NH3) m/e 620 ExaMple 401 trans, trans-2-(n-Heptyl)-4-(1 .3-benzodioxol-5-yfl- 1 di butyl ami nocarbonylmrnethyfl)pyrro lidi ne-3-ca rb-oxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDC13, 300 MHz) 8 0.83-0.98 9H), 1.18-1.40 (in, 14H), 1.44-1.60 (in, 4H), 1.72-1.96 (br m, 2H), 3.12-3.45 (mn, 6H), 3.65 J 10.5 Hz, 1H), 3.76 J =11.2 1H), 3.90-4.06 (in, 2H), 4.13- 4.33 (mn, 2H), 5.93 2H), 6.73 J =7.8 Hz, 1 6.79 (dd, J 7.8, 1.7- Hz, 1H), 6.87 J 1.7 Hz, 1H). MS(DCI/NH3) m/e 503 Anal calcd for C29H46N205 0.75 TEA: 0, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.
Example 402 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphen-yl)-1 methyl-i .2.3.4-tetrahydroguinolin-1 -yflcarbonylmethyfl~yrrol-dine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.99 1.5H), 1.03 J=6 -394- Hz, 1.5H, second diastereomer), 2.60-4.00m 3.78 1.5H), 3.79 (s, 1 .5H, second diastereomer), 5.92 11-H), 5.93 11-H, diastereomer), 6.65-7.40 (in, 11 MS (DCI) m/e 529 Analysis calcd for C31H32N206 0.8 H20: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 6. 10; N, 5.30.
Examole 403 trans, trans-4-( 1.3-Benzodiox-ol-5-yl)-2-(4-methoxypheny)- 1 -(N butyl-N-(4-fluorophenyl)arfinoca rbonylmethyl)pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound V .0 was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.2-1.47 0 (in, 4H1), 2.7 J=12 Hz, 1H), 2.80 J=9 Hz, 1H), 3.09 J=9 Hz, 1H-), 3.25 J=15 Hz, 1H), 3.40-3.47 (in, 3.49-3.65 (in, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 3H), 5.94 2H), 6.72-6.86 (in, 7.00-7.15 (in, 7H). MS (DCI) m/e 549 Analysis calod for C31 H33N206F o 0.4 C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.
Example 404 trans. trpns-1 -(N-Butyl-N-(3-methylphenyflaminocarbonylinethyl)-2-. 4 -inethoxyphenyfl-4-(5-benzofuranyflpyrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1 1H NMR (300MHz, CDC13) 8 7.66 (1H, bs), 7.60 (11H, d, J=3Hz), -7.45 7.15 (4H1, in), 6.75 (5H, in), 3.96 (1H, d, J=lOHz), 3.78 (3H, 3.74 (1 H, in), 3.59 (3H, in), 3.21 (1 H, t, J=9Hz), 3.19 (1 H, d, J=l6Hz), 2.92 (1H, t, J=9Hz), 2.70 d, J=l6Hz), 2.29 (3H, s), 1.41 (2H1, in), 1.24 (2H, in), 0.85 (3H, t, J=7Hz). MS (DCl, NH-3) in/e 541 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.
Example 405 trans.trans-1 -(N-ButyI-N-(3-methylphenyh~aminocarbonylimethyI)-2 (4-fluorophenyfl-4-(5-benzofuranyl)Dyrrolidine-3-carboxylic acidl Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.67 (1 H, bs), 7.60 (1 H, d, J=3Hz), 7.45 in), 7.18 (3H, in), 7.12 (1H, d, J=71Hz), 6.93 in), -395- 6.76 (1H, d, J=3Hz), 6.70 (2H, bd), 4.02 (1H, in), 3.77 (1H, in), 3.59 (3H, in,3.29 (1 H, in), 3.19 (1 H, in), 2.94 (1 H, in), 2.71 (1 H, in), 2.30 (3H, ),1.45 (2H, in), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) m/e 529 Anal. calod for C33H34N205 -0.2 HOAc: C, 71.98; H, 6.30; N 5.18B. Found 71.68; H, 5.89; N, 5.25.
Example 406 trans, trans-4-(1 .3-Benz-odioxol-5-yi)-2-(4-methoxyp-henyl)- 1 N- (di-(3-methylphenyflami-no~carbonyl)methylp1yrroiiine-3-.carboxylic ai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.27 6H), 2.81 (dd, J=8.1, Hz, 1H), 2.98 J=15.3 Hz, 1H), 3.20 J=16.6 Hz, 1H), 3.47-3.60 (in, 3H), 3.80 3H), 3.85 J=9.5 Hz, 1KH), 5.91 2H), 6.73 J=7.8 Hz, 1H), 6.85 (in, 3H), 6.95 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.06-7.24 (in, 611). MS (DCI) m/e 579 Anal calod for C35H34N206 0.15 0.20 CH3002C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.5 1.
V
Example 407 trans. trans-4-( 1.2- Di hyd robenzof uran -5-yl-2-(4-mneth oxyph enyl)- 1 (((N-butyl-N-(3-methylphenyl)amino)carbonyflmethyflpyrrolidine-3- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.73 in), 7.40-7.10 (4H, mn), 6.92 (2H, mn), 6.72 (2H, d, 6.63 (1 H, in), 5.40 (1KH, in), 4.55 (2H, t, 4.30-4.10 (3H, in), 3.84 (3H, 3.82 (1H, in), 3.65 (1H, mn), 3.39 (111, 3.21 (2H, t, 3.10-2.90 in), 2.26 (3H, 1.55 (2H, mn), 1.45 (2H, in), 0.92 (3H, t, MS (DCl/NH3) m/e 543 Anal calcd for C33H38N205 0.65 H20: C, 71.50; H, 7.15; N, 5.05 Found: C, 71.47; H, 6.96; N, 4.83.
-396- Example 408 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 .3-ben-zo 1 -f2-(N-propyl-N-[2-(N.Ndi methylamnino)lethanesulf onylam i n)ethyl Ipyrrof id ine..3..arboxyli c ai Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 00. 1 H NMR (CDC13, 300 MHz) 8 0.80 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15- 2.24 (in, 1H), 2.36 6H), 2.66-2.76 (mn, 1H), 2.83-3.04 (in, 6H), 3.18- 3.41 (in, 5H), 3.55-3.63 (in, 1H), 3.72 J=8Hz, 11H), 3.85 3H), 5.90 J=6Hz, 2H), 6.67 J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.84 J=8Hz, IH), 7.94 J=2Hz, 1H), 7.09 J=8Hz, 1H), 7.20 (dd, J=2Hz, J=12Hz, 1 MS (DCI/NH3) mn/e 580 Example 409 trans. trans-i N-Dibutyl aminocarbonyl methyfl-2-(4-f luorop~henyl)- 4l-(5-benzofuranyflpyrrolidine-3-carboxylic 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, in), 7.61 (1 H, d, J=3Hz), 7.55 (1 H, bd, J=8Hz), 7.46 (1 H, d, J=8Hz), 7.07 (2H1, t, J=8H-z), 6.76 (1H, d, J=3Hz), 5.53 (1H, bd, J=llHz), 4.18 (2H, in), 3.91 (3H, in), 3.55 (1H, d, J=l6Hz), 3.30 (3H, in), 3.12 (1H, dd, J=10&9Hz), 2.95 (1H, mn), 1.51 (2H, in), 1.31 (4H, mn), 1.12 in), 0.92 (3H, in), 0.83 (3H, t, J=7Hz). MS mn/e (DCl, NH3) 595 Examp~le 410 trans, trans-4-(1 .2 -D ihyd ro benzof uran -5-y1) (4-et hyIph e ny1)- 1 b uty I N- meth yl ph enfy 1) am ino)' carb on y 1) m ethyl) 12pyr ro lid i n e- 3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 8 7.35 (2H, in), 7.20-7.00 (7H, in), 6.70 (2H, d, 5.38 (1H, in), 4.55 (2H, t, 4.05 (1H, mn), 3.64 (2H, in), 3.45 (1H, in), 3.21 (2H, t, 2.95 (1H, in), 2.75 (1 H, in), 2.63 (2H, q, 2.38 (2H, in), 2.27 (3H, 1.43 (2H, in), 1.30 (2H, in), 1.22 (3H, t, 0.89 (3H, t, MS (DCI/NH3) m/e 541 Anal -397calod for C34H40N204 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80.
Examlle 411 trans, trans-4-( 1.2- D ihyd robe nzof uran-5-ylP-2-(4-fluorop2henyl.1- (((N.N-dibutylamino)carbonyl)methyflpyrrolidine-3-c-arboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.40 in), 7.28 (1 H, bs), 7.18 (1 H, dd, J=8, 7.00 (2H, t, 6.72 (1 H, d, 4.53 (2H, t, 1 0 3.92 (1 H, in), 3.65 (1 H, in), 3.42 (3H, in), 3.19 (2H, t, 3.15- 2.90 (6H, in), 1.43 in), 1.25 (3H, in), 1.10 (2H, in), 0.90 (3H, t, 0.83 (3H, t, MS (DCIINH3) mle 497 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.
Example 412 trans, trans-4-(1 .2-Dihyd robenzof uran-5-yl-2-(4-f luorophenyl)- 1 (((N-butyl-N-(3-methylphenyl)amino~carbonyflmethyl)pyrrolidine.3= carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.28 (1 H, bs), 7.25-7.00 mn), 6.91 (2H, in), 6.72 (3H, d, 4.54 (2H, t, 4.00 (1iH, in), 3.60 (3H, in), 3.45 (1iH, in), 3.19 (2H, t, 3.11 in), 2.84 (1iH, in), 2.67 (1H, bd, j=18), 2.26 1.42 (2H, in), 1.25 (2H, in), 0.88 (3H, t, J=8).
MS (DCI/NH3) in/e 531 Anal calcd for C32H35FN204 0.25 C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03.
Example 413 trans. trans-4-( lndan-5-yl)-2-(4-inethoxyphenyl)- 1 Ndibutylaino)carbonyl)imnethyl) pyrro Ii d ine-3-carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.32 (3H, in), 7.18 (2H, mn), 6.85 (2H, d, 3.83 (1H, in), 3.79 (3H, 3.67 (iH, mn), 3.50-3.20 (4H, in), 3.20-2.92 (4H, mn), 2.87 (5H, in), 2.79 (1H, bd, J=15), 2.06 (2H, mn), 1.43 (2H, mn), 1.27 (4H1, in), 1.08 (2H, in), 0.88 (3H, t, 0.82 (3H, t, -398- MIS (DC l/NH3) m/e 507 Anal calod for 031 H42N 2 0 4
C,
73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.
Example 414 trans. trans-2-(4-Methoxyphenyl)-4-(3.4-dif luorophenyy.1l -r(N-butyl- -methylphenyflamino~carbonylmethyllDyrrolidine-.3..carboxylic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDCI3) 8 0.86 J=7Hz, 3H), 1.10-1.35 (in, 2H), 1.35-1.52 (in, 2H), 2.29 3H), 2.63 J=l3Hz, 1H), 2.76 (t, J=7Hz, 1H), 3.06-3.20 (in, 2H), 3.42-3.53 (in, 3.50-3.64 (in, 3H), 3.80 3H), 3.86 J=9Hz, 1H), 6.66-6.82 (mn, 7.02-7.22 (in, 6H), 7.30-7.40 (in, 1H).
~Example 415 trans. rans-i -(N-Butyl-N-(3-chlorophenyl)aminocarbonylmethyl).2- 4 -fluorophenyl)-4-(5-benzofuranylp1yrrolidine-3-carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.64 (1 H, d, J=2Hz), 7.61 (1 H, d, J=3Hz), 7.47 (1H, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1H, dt, J=B&2Hz), 7.21 (1H, d, J=8Hz), 7.19 (2H, in), 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, in), 3.23 (1H, t, J=lOHz), 3.18 (1H,d, J=l6Hz), 2.92 (1H, dd, J=1Q&9Hz), 2.69 d, J=l6Hz), 1.41 (2H, in), 1.23 (2H, 0.87 (3H, t, J=7Hz). MS (DCl, NH3) 549, 551 W Anal. calcd for C31 H30CIFN20: C, 67.82; H, 5.51; N, 5.10.
Found: C, 67.43; H, 5.33; N, 4.78.
Example 416 trans. trans-4-(1 .3-Benzodioxo-5-yl)-2-(.4-methoxyphenyl)- 1 propyl-N-(4-phenoxybenzyl)amino)carbonyl)methyl)p2yrrolidine.3.
carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 8 (rotainer) 7.40-7.20 in), 7.13 (2H, in), 6.98 (2H, in), 6.93-6.60 (7H, in), 5.93 (1 H, d, 5.88 (5.85) (1H, di, 4.90 (4.50) (1H, d, J=15), 4.10 (4.25) (1H, d, -399- 3.77 (3.73) (3H, 3.72 (1 H, in), 3.60 (1 H, in), 3.53-3.20 (3H, in), 3.15- 2.75 (4H, in), 1.60-1.20 (2H, in), 0.83 (0.64) t, MS (DCI/NH3) m/e 623 Anal calcd for C37H38N207 .0.25 H20: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.
Example 417 -trans, trans-4- (1 2 Dihyd robe nzof ura n-5-yl) 2-(4-ethyl phenvl).l (2-pentyfl-N-(4-f luoro-3m ethylh enyflamino~carbonyl methylpy rroi d ine3ca rb oxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 5 7.30 H, bs), 7.20-7.00 (5H, in), 6.87 (1 H, in), 6.73 (2H, d, 6.57 (1 H, in), 4.81 (1IH, in), 4.55 (2H1, t, 3.92 (1H, bd, J=11), 3.60 (1H, in), 3.43 (1H, in), 3.18 (2H, t, J=9), 3.17 (1H, in), 3.06 (1H, dd, J=15, 2.88 (11H, dd, J=11, 2.61 (2H, q, 2.59 (1H, in), 2.18 (3H, in), 1.40-1.10 (4H 1.2.2 t, J=9), 1.00-0.80 (6H, in). MS (DCI/NH3) m/e 573 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.
Example 418 trans, trans-2-(4-Methoxphenyfl-4-( 1.3-benzodioxol-5-yfl)-1 .9 P2rolyl-N-[2-primidinylamino)ethyl]pyrrolidine.3carboxylic acid Ethyl 2-(4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 9* p ropylamino)p ropyl] pyrrolid ine-3-carboxyl ate, prepared by the procedures of Example 61B (300 mg), 138 mg of 2-bromopyrimidine, and 150 mng of diisopropylethylamine were heated at 95 00 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 mg of the title compound. 1 H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (in, 1H), 2.75-2.97 (mn, 3H), 3.40-3.55 (m 4H1), 3.60-3.70 (in, 3H), 3.75 3H), 5.95 2H), 6.34 (t, J=4Hz, 1H), 6.65 J=8Hz, 1H), 6.75-6.82 (mn, 1H), 6.78 J=9Hz, 2H), 6.96 J=2Hz, 1H), 7.27 J=9Hz, 2H), 8.20 J=4Hz, 2H).
-400- Example 419 trans, trpns-4- (1 3 Benz odi oxol-5-yl)-2 et ho yh-enyl)-.1-(3butyl-2-chloro-hept-2-en- 1-yfl1yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.84 J=6.8 Hz, 3H), 0.88 J=6.7 Hz, 3H), 1.19-1.39 (in, 8H), 2.05-2.09 (in, 2H), 2.17-2.23 (in, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1H), 2.95 J=9.2 Hz, 1H), 3.32-3.37 (in, 2H), 3.49 (in, 1 3.70 J=9.2 Hz, 1 3.77 3H), 5.91 (in, 2H), 6.72 J=8.1 Hz, 1H), 6.85 (dd, J=1.9. 8.1 Hz, 1H), 6.89 (in, 2H), 7.08 (d, J=1.5 Hz, 1H), 7.36 (in, 2H). MS (DCI) m/e 528 Anal calcd for C30H38C1N05 0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.
tr ns~t ans- 1Exam ple 420methylphenyh~amino)carbonylnmethyl)pyrrolidine.3-carboxylic acid Using the procedures described in Example 1, the title compound
S..
was prepared. 1 H NMR (300 MHz, CDC13 8 7.28 (1 H, bs), 7.15 (3H, in), 6.90 (1IH, in), 6.77 (2H, dd, J=9, 6.71 (2H, d, 6.56 (1 H, mn), 4.80 (1 H, in), 4.53 (2H, t, 3.92 (1 H, in), 3.79 3.60 (1 H, in), 3.45 (1 H, in), 3.19 (2H, t, 3.18 (1 H, in), 3.03 (1 H, dd, J=1 5, 2.85 (1 H, in), 2.55 (1 H, mn), 2.18 (3H, in), 1.40-1.05 (4H, in), 1.00-0.80 (6H, in). MS (DCIINH3) in/e 575 Anal calcd for C34H39FN20 5 .0.35 H20: C, 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.
Example 421 trans. trpns-4- D ihyd ro benzof uran- methoxyh enyl)-1 (((N-butyl-N-(3-chlorophenyl)amino~carbonyl)methyl)pyrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 KH NMR (300 MHz, CDC13 8 7.29 (1 H, d, 7.25-7.05 in), 6.98 (1KH, bs), 6.80 (2H, in), 6.72 (2H, d, 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 (3H, 3.58 (3K, in), 3.42 (1H, dd, J=10, 6), 3.18 (4H, in), 2.87 (1KH, in), 2.66 (1KH, in), 1.40 (2K, in), 1.25 (2H, in), 0.86 (3H, t, MS (DCI/NH3) W/e 563 Anal calcd for -401- C32H-35ClN205 .0.25 H20: 0, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55.
Examlle 422 trans, trans-4-(l .3-Benzodioxol-5-yfl-2- (5-ethylf uran-2-yi)- 1 Ndibutyl am ino~carbonyl) methyl) pyrro Iid ine-3-carb oxyl ic 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 (1 H, d, 7.02 (1 H, dd, J=9, 6.82 (1 H, d, 6.52 (1 H, dl, 6.08 (1 H, 1 0 d, 5.98 (2H, 5.80 (1H, d, 4.70 (1H, bd, J=15), 4.37 (2H, in), 3.70 (2H, in), 3.39 (2H, in), 3.20 (1H, in), 3.10-2.82 (2H, in), 2.76 (2H, q, 1.45 (2H, in), 1.32 (3H, t, 1.30-1.10 (6H, in), 0.87 (3H, t, 0.85 (3H, t, MS (DCI/NH3) m/e 499 Anal calcd for C28H38N206 -1.75 HOI: 0, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, 6.96; N, 4.88.
EXample 423 a..
trans, trans-4- (1 D ihyd robenzof uran Iu orophe nyfl1-1 (((N-(2-pentyfl-N-(4-fl uoro-3- methylphenyflamino~carbonyflmethyflp1yrrolidine-3-carboxylic acid Using the procedures described inT Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30-7.10 (4H, in), 6.92 (3H, in), 6.73 (2H, d, 6.59 (1 H, in), 4.80 (1 H, in), 4.53 (2H, t, 4.00 (1H1, bd, J=10), 3.62 (1H, mn), 3.45 (1H, in), 3.22 (1H, in), 3.21 (2H, t, 3.02 (OH, dd, J=15, 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 (3H, bs), 1.40-1.30 (3H, in), 1.15 (1H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) m/e 563 Anal calcd for C33H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.
Example 424 trans. trans-4-( 1.2- Di hyd robenzof uran- 5-yi)-2-(4-f Iu orop henyl)- (((N-butyl- N-(3-chlorophenyl)amino) carbonyl)inethyl )pyrrolidi ne-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (2H, mn), 7.25-7.10 (4H, in), 6.95 (3H, in), 6.82 (1 H, bd, 6.73 (1 H, d, 4.55 (2H, t, J=9), -402- 3.92 (1 H, bd, J=11), 3.60 (3H, in), 3.43 (1H, dd, J=9, 3.21 (2H, t, j=9), 3.16 (2H, in), 2.87 (1 H, in), 2.69 (1 H, in), 1.42 (2H, in), 1.26 (2H, in), 0.87 (3H, t, MS (DCI/NH3) m/e 551 Anal calcd for C31 H32CIFN204 -0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.7 1; N, 4.76.
Example 425 trans. trpns-4- (1.-Dl hdrbezfurn--i--4et41 henl butyl-N-(3-chlorophenyl)amino~carbonl~methynpyrroiciine.
3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (1 H, in), 7.21 (1 H, d, 7.15 in), 7.09 (4H, bs), 6.96 (1 H, bs), 6.80 (1 H, bd, 6.73 (1 H, d, 4.54 (2H, t, 3.89 (1 H, bd, J=1 3.60 in), 3.43 (1H, in), 3.22 (2H, t, 3.18 in), 2.92 (11H, in), 2.72 in), 2.62 0. 0: (2H, q, 1.41 (2H, in), 1.26 in), 1.23 t, 0.87 (3H, t, MS (DCI/NH3) mn/e 561 Anal calcd for C33H37CIN204. 0.25 H20: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.
Example 426 trans.trans-1 -(N-Butyl-N-(3-chlorophenyl)carboxamidomethyl-2-(4.
inethoXyphenyfl-4-(5-benzofuranyflyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 7.67 (1H, bs), 7.60 (1H, di, J=3Hz), 7.48 (1 H, d, J=8Hz), 7.42 (1 H, dci, J=8&3Hz), 7.29 (1 H, dt, W J=8&3Hz), 7.21 (1 H, di, J=8Hz), 7.14 (2H, mn), 6.99 (1 H, bs), 6.76 (4H,.
in), 3.88 (1 H, d, J=1lOHz), 3.75 (1 H, ddd, 5&3Hz), 3.59 (2H, in), 3.53 (1 H, dd, J=1 0&3Hz), 3.22 (1 H, t, J=9Hz), 3.19 (1 H, in), 2.96( 1 H, in), 2.70 (1H, d, J=l6Hz), 1.42 in), 1.26 mn), 0.87 (3H, t, J=7Hz). MS (DCl, NH3) in/e 563, 561 Anal. calcd for C32H-33CIN20 5 .0.5 H20: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68.
-403- Example 427 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-M4-methoxyphenylI cyclohexyl-Nbutylamino~carbonyflmethyl)pyrrolidine..3-.crboxvlic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13) (rotamer) 8 0.78 (0.86) 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) 1H, J=l2Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) 5.92 2H), 6.72 1H, J=9Hz) 6.86 (in, 3H) 7.03 I1H, J=6Hz), 7.34 (in, 2H). MS (DCI/NH3) m/e 537 1 0 Anal. calc'd for C31 H40N206 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-yl-2-(4-ethylphenyl)..1 1 5 methylphenyl)- N-butylami no) carbonyl) methy) pyrrol id ine3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.86 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (in, 2H), 1.43 (in, 2H), 2.26 2.6 2H, J=7Hz), 2.68 1H, J=l2Hz), 2.86 1H, J=8Hz), 3.19 2H, J=7Hz), 3.44 (dd, 1H, J= 3Hz,lOHz), 3.59 (in, 3H), 3.94 1H, 9Hz), 5.92 2H), 6.75 (in, 3H), 6.86 (dd, 1H, J= 2Hz, 8Hz), 7.08 (mn, 7.17 1H, J= 8Hz). MS (DCI/NH3) m/e 543 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.
Example 429 frans. trans-4-(Be nzof uran- 5-yl-2-(4-ethylphenyl). 1 methyl phenyl)- N-butyl am i no)carbonyl~m ethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13) 8 0.90 3H, J=7Hz), 1.30 (t, 3H1, J=7Hz), 1.31 (mn, 2H), 1.43 (in, 2H), 2.27 2.73 2H, J=71-Z), 3.15 2H, J=l7Hz), 3.61 2H, J= 8Hz), 3.82 (in, 2H), 4.00 1 H, 12Hz), 4.26 (mn, 2H), 5.53 (br d, 1 6.54 (br s, 2H), 6.76 1 H, J= 2Hz), 7.14 (in, 3H), 7.28 1 7.40 (in, 3H), 7.48 1 H, J= 8Hz), 7.63 1 H, -404- J=2Hz), 7.73 1H). HRMS. calc'd for C34H39N204 539.2910.
Found: 539.2891 Exampl e 430 trans, trans-4-( 1.4- Benz odi oxan-6-yi) -2-(4-ethyl phenyll-1 (3methylphenyI)- N-butylamino) carbonyl)m ethyl)pyrra hidine.3-.carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.87 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.24 (in, 2H), 1.42 (in, 2H), 2.30 3H), 2.61 2H, J=7Hz), 2.67 (d I1H, J=l4Hz), 2.86 1H, J= 8Hz), 3.18 2H, J=7Hz), 3.41 (dd, 1 H, J=4,lOHz), 3.59 (in, 3H), 3.93 1H, J=lOHz), 4.25 (in, 4H), 6.74 (br s, 2H), 6.80 1H, J=8Hz), 6.93 (dd, 1H, J=2Hz,8Hz), 6.99 1H, J=2Hz), 7.07 (mn, 5H), 7.17 1H, J=8Hz). MS (DCI/NH3) in/e 557 Anal.
1 5 calc'd for C34H4ON2O5 0.40 H20: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62.
Example 431 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 14- 2 -(N-1ropyl-N-2-mesitylenesulfonylamino)ethyllpyrrolidine-3- carboxyli acid: Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 80-82 OC. 1 HNMR (CDCI3, 300 MHz) 8 0.69 J=7Hz, 3H), 1.37 (sextet, J=7H-z, 2H), 2.09- 2.17 (in, 1H), 2.24 3H), 2.53 6H), 2.54-2.64 1H), 2.73-2.86 (i, W 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (in, 3.44-3.53 (mn, 1H), 3.57 J=9Hz, 1 3.89 3H), 5.94 2H), 6.74 J=8Hz, 1 6.78 (dd, J=2Hz, J=8Hz, 1 6.85 2H), 6.92 J=8Hz, 1 9.94 J=2Hz, 1H), 7.06 J=8Hz, 1H), 7.13 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) mn/e 627 Example 432 trans. trans-2-(4-Methoxyphenyl)-4-(3 .4-dif luorophenyl)-1 -[(N-butyl-
N-(
3 -ch lorophenyl)am ino) carbonyl met hyllpyrroli din e3carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.86 J=7Hz, 3H), 1.18B-1.32 -405- (in, 2H), 1.35-1.48 (in, 2K), 2.64 J=l3Hz, 11H), 2.71 J= 7Hz, 1H), 3.08-3.18 (in, 2H), 3.42-3.48 (in, 1H), 3.53-3.64 (mn, 3H), 3.77 3H), 3.80 J=9Hz, 1H), 6.73-6.85 (in, 3H), 6.94 1H), 7.04-7.40 (in, 7H).
Example 433 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 .3-benzodioxol.s.yl).
l-( 2 -(N-12rolyl-N-(3-chloropropanesulfonyl)amino~ethyl pyrrolidine 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (CD3OD, 300 MHz) 6 0.80 3H, 1.47 (bd hex, 2K, 2.15 (pen, 2H, 2.32 (in, 1 2.7-3.2 (in, 9H), 3.46 (dd, 1KH, J=4, 10), 3.57 (in, 1 3.64 2H-, 3.67 1KH, 3.86 3H), 5.92 2H), 6.74 1 H, 6.84 (dd, 1KH, J=2, 6.96 1 H, 7.06 11H, 7.18 (in, 2H). MS (DCI/NH3) m/e 585 ,00 1 5 3 5Cl)+; 587 370l)+. Anal calcd for C27H34N207C1FS: C, 55.43; H, 0 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.
Example 434 0000 trans, trans-2-(3-Fluoro-4methoxyhenyl)-4(1 1 2 (N -isobutyl- N-(3-chl orop roganesulf onyl)ami no) ethyl) pyrroli di ne-:.
3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.79 31-, 0.84 3K, o:* J=7),1.68'(hept, 1K, 2.18 (pen, 2H, 2.8-3.4 (mn, 10H), 3.5-3.8 (in, 3H), 3.65 2H, 3.90 3H), 5.94 6.77 1 H, J=8), 6.87 (dd, 1KH, J=2, 6.99 1KH, 7.13 1KH, 7.27 (mn, 2H).
MVS (DCIINH3) m/e 599 Anal calcd for C28H36N207CIFS 0.3 TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.
Example 435 trans, trans-2-Propoxymethyl-4-( 1 3-benzodioxol-5-yfl- 1 Ndi butylami nocarbonyl methyl) 1y rrol idin e-3-carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (CDC13, 300 MHz) 8 0.87-0.98 (in, 9K), 1.21-1.39 (mn, 4K), 1.43-1.57 (mn, 4K), 1.58-1.70 (mn, 2K), 3.13-3.29 (in, 4H), 3.34- 3.43 (in, 3K), 3.45-3.55 (in, 3H), 3.69 (dd, J 10.2, 4.5 Hz, 1 3.80- -406- 4.20 (in, 4H), 5.93 2H), 6.73 J 7.8 Hz, 1 6.84 (dd, J 8.2, 1.7 Hz, 1H), 6.93 J 1.7 Hz, 1H). MS(DCI/NH3) m/e 477 Anal.
calcd for 026H40N206*0.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22.
Exam le 436 trans, trans-2-(3-Fluoro-4-methoxyphenyfl)-4-(1 .3-benzodio-xoi--y)- 1 -r2-(N-p2rolyl-N-(4-methlbutanes-ulfonyflamino)ethyllpyrrolidine.3carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-67 OC. 1 H NMVR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (in, 3H), 2.24-2.33 (in, 1H), 2.68-2.93 (in, 2.98-3.12 (mn, 2H), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52- 3.58 1H), 3.65 J=l2Hz, 1H), 3.87 3H), 5.95 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 J=9Hz, 1Hz) ,7.16 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) m/e 579 Exain~le 437 trans. trans-2-(4-Methoxy-3-fluorop~henyfl-4-(7-methoxy- 1 .benzodioxol-5-yf)l--r2-(N-p2ropyl-N-(n-* pentanesulfonyl)amino)ethyllpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 HNMR (300MHz, CDCI3) 8 0.81 J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (in, 4H), 1.44 (sextet, J=7Hz, 2H), 1.67-1.78 (in, 2H), 2.22-2.34 (in, 1H), 2.30-2.95 (in, 5H), 2.95-3.10 (mn, 2H), 3.15-3.33 (mn, 2H), 3.45 (dd, J=3Hz, 9Hz, 1H), 3.47-3.56 (in, 1H), 3.65 J=9Hz, 1H), 3.88 3H), 3.94 3H), 5.95 2H), 6.55 1H), 6.65 1H), 6.92 J=7H, 1H), 7.11 J=9Hz,1H), 7.17 J=l2Hz, 1H).
-407- Exam le 438 trans, trans-24(3 -Flu oro-4-m ethoxyheny)-4- (1 .3-benz odi oxo 1 -r2-(N-projyl-N-f2.2,3,3,3p2entafluoropropoxyethanesufonyl)amn)ethylyrrolidine.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 00. 1 HNMR (CDCI3, 300M1-z) 8 0.82 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 1H), 2.70-2.82 (in, 1H), 2.85-3.09 (in, 5H), 3.14-3.28 (mn, 4H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.87 3H), 3.92-3.98 (in, 3H), 5.94 2H), 6.74 J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8H-z, 1 6.92 J=8Hz, 1 6.97 J=2Hz, 1 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) m/e 685 Example 439 trans. trpns-2-(1 .4-Benzodioxan-6-yl)-4-'7-methoxy- 1 .3-benzodioxol- 2 -(N-propyl-N-(n-pentanesulfonyl)amino~ethylIpyrrolidine-3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMVR (CDCI3) 8 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.23-1.36 (mn, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (nm, 2H), 2.20- 2.30 (in, 1H), 2.30-2.95 (mn, 5H), 2.95-3.10 (mn, 2H), 3.15-3.35 (mn, 2H-), 3.42 (dd,,J=3Hz, 9Hz, 1H), 3.46-3.56 (in, 1H), 3.59 J=9Hz, 1H), 3.91 3H), 4.24 4H), 5.95 2H), 6.57 1 6.68 1 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 J=2Hz, 1H).
Example 440 trans, trans-4-( 1.3-Benzodioxol-5-yfl-2-(4-methoxylhenyl)-1 butyl- N- meth oxybenzyl)am ino) carbonyl)m ethyl) pyrrol id ine.3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.32 (1 H, d, 7.22 (1H, in), 7.10 (1H, d, 7.03 (6.98) (1H, d, 6.90-6.80 (4H, in), 6.79 (2H, d, 6.77 (1H, t, 5.85 (2H, 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (1H, d, J=15), 3.81 (1H, in), 3.79 (3.78) (31H, 3.76 -408- (3H, 3.62 (1KH, in), 3.43 (2H, mn), 3.30-2.70 (5H, in), 1.42 (1KH, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.75) (3H, t, MS (DCI/NH3) m/e 575 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.
Example 441 trans, trans-2-(3-Fluoro-4-methoxyhenyl)I-4-(1 .3-benzodioxoI1-5-yly- 1 -(2-(N-isobutyl-N-(p enta nesuIf onyl ami no) ethyl) pyrrolidine-3carboxylic acid 1 0 Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 5 0.76 3H, 0.84 3H, 0.92 3H, 1.36 (in, 4H),1.70 (in, 3H), 2.90 (in, 2H), 3.02 (in, 2H), 3.1-3.8 (in, 7H), 3.84 2H, 3.91 3H), 5.96 2H), 6.80 (d, 1 H, 6.88 (dd, 1 H, J=2, 7.00 1KH, 7.19 1 H, 7.35 (in, 2H). MS (DCI/NH3) m/e 593 Anal calcd for C30H41 N207F TEA: 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-methoxyphenyl)- 1 (Nbutyl-N-(3-fluorophenylamino'carbonylmethyflp1yrrolidine-3- carboxylic acid: Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.10- 1.30 (in, 4H), 2.70-2.90 (in, 2H), 3.13 J=8 Hz, 1K), 3.40-3.90 (in, 6H), 3.79 3K), 5.93 2H), 6.75 J=8 Hz, 1KH), 6.80-7.20 (in, 9K), 7.40 (in, 1 MS (DCI) m/e 549 Anal calcd for C31 H33N206F 0.8.
C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; K, 5.83; N, 4.84.
Example 443 trans. trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-f luorophenyfl)- -(N-butyl- N-(3-chlorophenylamino)carbonylmethyl)Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I K NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3K), 1.20- 1.50 (in, 4H), 2.65-2.85 (in, 2H), 3.05-3.85 (in, 7K), 5.93 2K), 6.75 (d, J=8 Hz, 1H), 6.85 (dd, J=8 Hz, 1K), 6.90-7.10 (in, 4K), 7.10-7.25 (in, 3K), 7.33-7.45 (in, 2K). MS (DCI) m/e 553 Anal calcd for -409- C30H30N205FCI: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98.
Example 444 trans, trans-4-( 1 3-Benzodioxol-5-yfl-2-(4-methoXyDhenyl)- 1 butyl-N-(3 .4-dimethoxybenzyflamino~carbonyl)methvl)pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 (rotamer) 7.33 (1 H, d, J=10), 7.23 (1H, in), 7.03 (6.97) (1H, d, 6.90-6.60 (6H, in), 6.47 (1 H, in), 5.93 (2H, in), 4.83 (4.09) (1 H, d, J=1 4.45 (4.22) (1 H, d, 3.83 (3.86) (3H, 3.79 (1H, in), 3.77 (3.76) (3H, 3.75 (3.65) 0 (3H, 3.60 (1 H, in), 3.43 (2H, in), 3.28 (1 H, in), 3.20-2.70 (4H, in), 1.43 (1 H, in), 1.23 (2H, in), 1.02 (1 H, in), 0.84 (0.77) (3H, t, MIS (DCI/NH3) in/e 605 Anal calcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.
Example 44 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methOXYphenyfl- 1 butyl-N-(2-methoxybenzyl)amino~carbonyflinethyl)pyrrolidine-3carboxylic acid: Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1 H, d, 7.11 (2H, in), 7.03 (1H, dd, J=8, 6.90-6.60 (7H, mn), 5.93 (2H, mn), 4.83 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=f5), 3.81 (1H, mn), 3.78 (3.73) (3H, 3.72 (3H, 3.59 (1 H, in), 3.43 (2H, in), 3.30 (1 H, mn), 3.20-2.70 (4H, in), 1.42 (1H, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.77) (3H, t, MIS (DCI/NH3) m/e 575 Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 4.61.
-410- Examole 446 trans, trans-4-(1 3 -Benzodioxol-5-yfl-2-(4-methoxyhenyl).1 butyl-N-(3-methoxybenzyflamino~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 (rotainer) 7.31 (1 H, d, 7.13 (OH, d, 7.16 (1H, dt, J=8, 7.03 (1H, dd, J=10, 2), 6.90-6.60 (6H, in), 6.50 (1H, in), 5.94 (2H, in), 4.82 (4.19) (1H, d, 4.50 (4.23) (1 H, d, J=15), 3.78 (3.76) (3H, 3.77 (1H, in), 3.75 (3.67) (3H, 3.59 (1H, in), 3.57-3.35 in), 3.25 (1H, in), 3.20-2.70 (4H, in), 1.43 (1 H, in), 1.23 (2H, in), 1.02 (1 H, in), 0.84 (0.77) (3H, t, MS (DCI/NH3) m/e 575 Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60.
Example 447 trans. trans-2-(3-Fluoro-4methoxyphenyl-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3chloroprolanesulfonyflamino~ethyflyrrolidine-3.carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, 2.33 (mn, 1H), 2.81 (in, 2H); 2.93 1H, 3.1-3.6 (in, 10H), 3.24 3H); 3.65 2H, 3.70 1 H, 3.87 3H), 5.92 2H), 6.74 1 H, 6.84 (dd, 1 H, J=2, 6.97 1 H, 7.07 1 H, 7.17 (n MS (DCI/NH3) m/e 601 Anal calcd for C27H34N208CIFS: 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-methoxyD enyl)-4(1 .3-benzodioxol--y)- 1 -(2-(N-(2-methoxyethyfl-N- (Pentan es ulf onyfl)aino) ethyfl)pyrrolid ine-3-ca rboxyli c acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.93 (in, 3H), 1.34 (in, 4H), 1.69 (in, 2H), 2.33 (mn, 1H), 2.75-3.1 (mn, 7H), 3.23 3H), 3.3-3.6 (in, 6H), 3.70 1 H, 3.86 3H), 5.92 2H), 6.74 1 H, 6.84 (dd, 1 H, J=2, 6.97 I1H, 7.07 1 H, 7.18 (mn, 2H). MS -411- (DCI/NH3) m/e 595 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 trans. trpns-4-(l 3 Benz od ioxo-5-yi) (4-meth o xyphe nyl) -1 heptyI)-N-(4-fluoro-3.
methYlhenylamino)carbonl)methylyrrolidine3carboxyI c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.89 (in, 6H), 1.18-1.36 (in, 8H), 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=14.9 Hz, IH), 2.82 (in, 1H), 3.07-3.29 (in, 2H), 3.32-3.41 (in, 1H), 3.53-3.60 (in, 1H), 3.70-3.79 (in, 1H), 3.79 3H), 4.68 (in, 1H), 5.92 (mn, 2H), 6.69-6.90 (mn, 6H), 6.93-7.07 (in, 4H). MS (DCI) mle 605 Anal calcd for C35H41 FN20 6 C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31; H, 6.78; N, 4.35. Example 450 trans. trarns-4-(1 3 -Benzodioxol-5-y)-2-(4-methoxyphegnyl). 1 nonyl)-N-(4-fluoro-3m ethy 12 eny)amino)ca rbonylmethylpyrrol id ine3ca rboxvlic acid Using the procedures described in Example 1, the title compound
SS
was prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.81-0.90 (in, 6H), 1.30 (in,
.S
12H), 2.14 1.5 (CH3 rotamer)), 2.30 1.5 (CH3 rotainer)), 2.60 (t, J=14.8 Hz', 1H), 2.80 (in, 1H), 3.09-3.24 (in, 2H), 3.33-3.42 (in, 1H), 3.50-3.55 (in, 1H), 3.65-3.77 (mn, 1H), 3.79 3H), 4.64 (in, 5.93 (in, 6.70-6.84 (in, 5H), 6.91-7.13 (in, 5H). MS (DCI) mWe 633 Anal calcd for C37H45FN20 6 C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.
Example 451 trans, trans-4-(1 3 -13enzod ioxol-5-yl)-2- (4-neth oxyhenyl).1 nonylamino)carbonyl)inethy~iDpyrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3O1D) 8 0.80 J=7.0 Hz, 3H), 0.84 J=7.1 Hz, 3H), 1.15-1.55 (in, 12H), 2.88 J=15.9 Hz, 1H), 3.07 (in, 2H), 3.26 J=16.3 Hz, 1H), 3.36 (dd, J=4-4, 9.8 Hz, 1H), 3.64 (mn, 1H), -412- 3.76 (in, 1 3.79 3H), 3.98 J=9.5 Hz, 1 5.93 (mn, 2H), 6.77 (d, J=7.8 Hz, 1 6.85 (dd, J=1.7, 8.1 Hz, 1 6.93 (in, 2H), 6.99 J=1.7 Hz, 1H), 7.39 (in, 2H). MS (DCI) mle 525 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-yI)-2-(4-methoxy -Dhenyly.1 butyl-N-(2-fluorophenyl)amino~carbonylmethyl)jpyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 (dt, J=7 Hz, 3H), 1.15- 1.32 (in, 4H), 3.77 J=2 Hz, 3H), 2.65-5.92 (in, 9H), 5.93 J=4 Hz, 2H), 6.70-6.90 (in, 4H), 7.00-7.45 (in, 7H). MS (DCI) m/e 549 1 5 Anal calcd for 031 H33N206 -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-Methoxphenyl)-4-(1 .3-benzodioxol-5-yb)-1 -r2-(Npropyl-N-(2-benzothiazolyflamino)ethyllpyrrolidine.3-carboxyiic acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-broinopyriinidine. 1 H NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25- 2.37 2.85-2.97 (in, 3H), 3.28-3.36 (mn, 2H), 3.50-3.58 (mn, 3H), 3.60-3.65 (mn, 1H), 3.67 J=9Hz, 1H),3.71 3H), 5.87 J=2Hz, 1H), W 5.91 (d J=2Hz, 1H), 6.57 J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, 1H), 6.76 J=8 Hz, 2H), 6.91 J=2Hz, 1 7.01 J=8Hz, 1 7.22 J=8Hz, I1H), 7.29 J=8Hz, 2H), 7.40 J=7Hz, 1 7.55 J=7Hz, 1 H).
Examlle 454 trans. trans-2-(2-Ethoxyethyl)-4-( 1.3-be nzodioxol-5-yfl-1 .Ndi butylam inocarbonyl methyfl) yrro li din e-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDC13, 300 MHz) 8 0.91 J 7.4 Hz, 3H), 0.94 J 7.4 Hz, 3H), 1.19 J 7.0 Hz, 3H), 1.24-1.38 (mn, 51H), 1.46-1.60 (mn, 41H), 2.03-2.12 (in, 2H), 3.07 J 8.0 Hz, 1 3.07-3.34 (in, 61H), -413- 3.43-3.52 (in, 3H), 3.59-3.74 (in, 3H), 3.80-4.01 (in, 2H), 5.93 2H), 6.72 J 8.1 Hz, 1 6.79 (dd, J 8.2 Hz, 1.7 Hz, 1 6.87 J 1.7 Hz, I1H). MS(DCI/NH3) m/e 477 Anal calcd for C26H40N206 0.4 TEA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29.
Example 455 trans, trans-2-(4-Methoxy-3-f luorophenyl)-4-(1 1 -r2-(N-propyl-N-(2-(morpholin-4yiethyl~sulfonylamino)ethyllpyrrolidine-3-carboxylic acid 1 0 Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(1 1 -[2-(N-propyl-N-[2-vinylsulfonyl]amino)ethyllpyrrolidjne-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 1 5 intermediate ethyl ester which was hydrolyzed to the title 0 compound with NaOH in ethanol/water. 1 HNMVR (300 MHz, CDC13) 8 0.81 J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (in, 4H), 2.70-2.92 (in, 2.97-3.33 (in, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (in, 1H), 3.62- 3.70 (mn, 5H), 3.88 3H), 5.95 2H), 6.72 J=8Hz, 1 6.70 (dd, J=2Hz, 8Hz, 1H), 6.90 J=9Hz, 1H), 6.96 J=2Hz, 1H), 7.10 J=8Hz, IH), 7.18 (dd, J=2Hz, 12Hz, 1H). Exampl~e 456 trans.trcans-2-(3-Fluoro-4-methoxyphenyl-4-(1 1 -[2-(N-propyl-N-((2 .2.2trifuorethxyehan~sulony~amno~thy~pyroliine3-croY lic, acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 95-96 0 C. 1 HNMR (CD3QD, 300MHz) 8 0.80 J=7Hz, 3H), 1.35-1.48 (in, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (in, 8H), 3.80-3.87 (in, 3.93 3H), 3.94- 4.02 (mn, 4H), 4.66 J=l2Hz, 1H), 5.96 2H), 6.83 J=8Hz, 6.94 J=BHz, 1H),7.06 J=2Hz, 1H), 7.23 J=9Hz, 1H), 7.43 J=9Hz, 1H), 7.49 (dd, J=2Hz,J=12Hz, 1H). MS (DCIINH3) m/e 635 -414- Example 457 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-fluorophenynl1-(N-butyl- N-(3-methylphenyflaminocarbonylmethyl)pyrrolidine-3..carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.31 3H), 2.65-2.80 (in, 2H), 3.19 J=7 Hz, 1 3.25 J=10 Hz, 1H), 3.35-3.65 (in, 4H), 3.79 J=10 Hz, 1H), 5.93 2H), 6.74 J=7 Hz, 1H), 6.80-6.90 (in, 3H), 6.91-7.09 (in, 3H), 7.10-7.35 (in, 4H). MS (DCI) m/e 533 Anal calcd for C31 H33N205F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.
Example 458 trans.trans-2-(3-Fluoro-4-methoxyphenyn)-4-(11.3-bgnzodioxo-5-y)- 1-( 2 ethoxyethyl)-N-(butanesuf ony a min o)ethyl) py rrol id ine- 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.94 (in, 3H), 1.23 (hex, 2H, 1.69 (mn, 2H), 3.08 3.20 3H), 3.3-3.5 (in, 10H), 3.77 (mn, 2H), 3.92 3H), 4.60 (in, 1 5.96 2H), 6.81 1 H, 6.88 (dd, 1 H, J=2, 6.99 1 H, 7.22 1 H, 7.38 (mn, 2H). MS (APCI) V W/e 581 Anal calcd for C28H37N208FS 1.1 TEA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.
Example 459 trans. -trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 S 1 -r 2 -(N-propyl-N-(2-methylpropanesulfonyflamino)ethylllpyrr-olidine 3-carboxcylic acid Using the procedures described in* Example 66, the title compound was prepared and isolated as a white solid. m.p. 77-78 OC. 1 HNMR (CDCI3, 300MHz) 8 0.83 J=7Hz, 3H),1.06 J=6Hz, 6H),1.45 (q, J=7Hz, 2H), 2.20 (septet, J=6Hz, 2.26-2.36 (in, 1H), 2.62-2.78 (in, 3H), 2.85-2.95 (mn, 2H), 2.97-3.10 (mn, 2H), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.62 (in, 3.66 J=9Hz, 1H), 3.88 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d J=2Hz, 1H), 7.12 (d J=9Hz, 1H), 7.18 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) rn/e 565 -415- Example 460 trans, trans-4-( 1.3-Benzodioxol-5-yrl-2-(4-methoXYphenl..1 butyl-N-( 4 -nitrobenzyi)amino) ca rbonyl)methyl~yrrolidine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 8.11 (2H, m),7.32 (311, dd, J=9, 7.16 (7.07) (1H, bd, J=10), 6.98 (6.94) (1H, d, J=2), 6.85 (2H, d, 6.83-6.70 (2H, in), 5.99 (5.97) (2H, d, 5.02 (4.18) (11H, d, J=15), 4.63 (4.38) (11H, d, J=15), 3.79 (3.77) (3H, 3.72 (1 H, d, 3.61 (1H, in), 3.48 bd, J=15), 3.43-3.20 (2H, in), 3.06 (2H, in), 2.90 (1H, in), 3.79 (1H, bd, J=14), 1.43 (1H, in), 1.23 (2 H, in), 1. 02 (1 in), 0.84 (0.78) (3H, t, MS (DCI/NH3) mle 590 Anal calcd for C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 1 5 5.85; N, 6.85.
Example 461 trans, trans-2-(4-Ethylphenyl-4-(3.4-dif Iuo rophenyl)-1 -(NNdi butyl ami nocarbonyl methyfl) yrro Ii din e-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 6 0.78 3H, 0.87 3H, 1.02 (hex, 2H, 1.22 3H, 1.27 (mn, 2H), 1.45 (in, 2H, 2.63 2H, 2.77 1H, J=14), 2.94 (dd, 1H, J=7, 3.05 (in, 311), 3.3-3.5 mn, 3H), 3.44 11H, J=14), 3.66 (in, 1H), 3.75 1H, 7.20 (td, 2H, 7.22 (mn, 2H), 7.32 (td, 2H, 7.43 (ddd, 1H, F J=2,8,12). MS (DCI/NH3) Wne 501 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.
Example 462 trans.trans-4-( 1.3-Benzodioxol-5-ylb-2-(4-methoxyphenyl
(N-
butyl-N-(4-fluoro-3-methyl phenyl)ami nocarbonylinethyl)p2yrrolidine- 3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.21 J=2 Hz, 3H), 2.64 J=14 Hz, 111), 2.75 (dd, -416- Hz, 1H), 3.05 J=7 Hz, 1H), 3.25 J=15 Hz, 1H), 3.35-3.70 (in, 3.77 3H), 5.92 2H), 6.70-6.92 (in, 6H), 6.96-7.10 (in, 4H). MS (DCI) m/e 563 Anal calcd for C32H35N206F 0.5 H20: C, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.
Example 463 trans. trans-4-( 1. 3-Benzodioxol-5-yl'-2-(4-methoxyphenyl). 1 butyl-N-((3-isopropyflphenl)aminoJcarbonylmethyl).pyrrolidine.3.
carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.87 3H), 1.17 J=7 Hz, 1.20-1.50 (in, 4H), 2.63 J=15 Hz, 1H), 2.75 J=7 Hz, 2.85 0 (in, 1H), 3.00 J=7 Hz, 1H), 3.25 J=15 Hz, 1H), 3.40-3.70 (in, 3.75 5.90 2H), 6.65-6.80 (in, 3H), 6.71 (dt, J=7 Hz, 7.07 1 5 (in, 7.20-7.35 (in, 2H). MS (DCI) mn/e 573 Anal calcd for C34H40N206 0.15 H3P04: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43.
Example 464 trans, trans-4-(1 Benz odioxol-5-yfl-2-(4-methoxyphenyl)- 1 butyl-N-(3-ethylphenyl)aininocarbonylmethyflpyrrolicine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (300 MHz, CD3OD) 8 0.87 (in, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 1.20-1.47 (in, 4H), 2.50 J=7 Hz, 2H), 2.70-2.85 (mn, 2H), 3.13 J=7 Hz, 1 3.20-4.5 (in, 6H), 3.78 3H), 3.83 J=8 Hz, 1 H), 5.92 6.72 J=8 Hz, 1H), 6.80-6.90 (in, 5H), 7.02-7.13 (in, 31-), 7.15-7.25 (mn, MS (DCI) m/e 559 Anal caicd for C33H38N206 -0.3 H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H, 6.63; N, 4.60.
-417- Example 465 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-ethylphenyl)i-I chlorophenyfl-N-butylamino)carbonylmethyl~yrrolidmne..3.carboxvlir Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) a 0.87 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (in, 2H), 1.41 (mn, 2H), 2.63 2H, J=7Hz), 2.67 (in, 1H), 2.92 (in, 1H), 3.20 (in, 2H), 3.42 (mn, 1 3.60 2H-, J=7Hz), 3.93 (in, 1 5.92 2H), 6.75 I1H, J=8Hz), 6.84 (in, 3H), 6.95 (br s, 1 7.02 1IH), 7.10 (br s, 3H), 7.25 (in, 2H). MS (APOI) mle 563 Anal.
caic'd for C32H35N205C1*- 0.80 H3P04: C, 59.92; H, 5.88; N, 4.37. Found: C, 59.90; H, 5.83; N, 4.07. Example 466* trans, trans-4-(1 4- Benz odi oxan-6-yi)-2- (4-ethyl ph enyl)- 1 chlorophenyfl-N-butylami no)ca rbonyl)inethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.86 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.25 (in, 1.40 (in, 2H), 2.64 2H, J=7Hz), 2.70 (in, 1 2.95 (in, 1 3.20 (mn, 2H), 3.40 (in, 1 3.57 (in, 3H), 3.90 (in, 1 4.25 4H), 6.80 1 H, J=8Hz), 6.95 1 H, J=2Hz), 6.95 (in, 7.07 (br s, 3H), 7.22 (in, 3H). MS (APCI) m/e 577. Anal. calc'd for C33H37N'205CI 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C,,66.92; H, 6.25; N, 4.36.
Example 467 trans. trans-4-(Benzof uran -5-y1) -2 ethyl phenyl)- 1 chlorophenyl)I-N-butylamino~carbonyl)methyflpyrrolidine-3-carboxylic ai Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.85 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (in, 2H), 1.40 (in, 2H), 2.60 2H, J=7Hz), 2.72 (mn, I1H), 2.93 (in, 1 3.22 (mn, 2H), 3.50 (mn, 1 3.55 (mn, 2H), 3.75 (in, 1 3.90 (br d, I1H), 6.75 1 H, J=1 Hz), 6.80 (br d, 1 6.95 (br s, 1 7.08 (in, 4H), 7.20 1 H, J=8Hz), 7.28 1 H, J=8Hz), 7.42 (mn, 2H), 7.58 1 H, -418- J=1 Hz), 7.63 1 MS (APOI) mle 559 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.
Example 468 trans, trans-2-(4-Methoxy-3-fluorophenyl)-4.(7methoxy-1.3l-r 2 -(N-butyl-N-phenylamino~ethyllpyrroidine.3.
carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy.1 ,3- 1 0 benzodioxol-5-yl)-1 2 -(bromoethylI-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 dilsopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white 1 5 powder. 1 H NMR (300 MHz, CDCI3) 5 0.90 J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (in, 1H), 2.68-2.77 (in, 1H), 2.82-2.95 (in, 2H), 3.12-3.22 (in, 2H), 3.30-3.44 (in, 3H), 3.45-3.55 (in 3.62 J=9Hz, 1 3.83 3H), 3.90 3H), 5.95 2H), 6.51 J=7Hz, 2H), 6.55-6.62 (mn, 2H), 6.69 J=2Hz, 1H), 6.84 J=8Hz, 1KH), 7.02-7.15 (in, 3H), 7.19 (dd, J=2Hz, 12Hz, 1H). Example 469 trans. trans-4-(1 .4-Benzodioxan-6-fl-2-4-ethylphenyl)- 1 S.
dibUtylamino)carbonyl)methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.78 3H, J=7Hz), 0.88 (t, 3H-, J=7Hz), 1.05 2H, J=7Hz), 1.23 31-, J=7Hz), 1.28 (in, 2H), 1.45 (mn, 2H), 2.64 2H, J=7Hz), 2.78 (in, 1H), 2.9-3.2 (envelope, 4H), 3.30 (mn, I1H), 3.40 (in, 3H), 3.60 (mn, 1 3.80 (in, 1 4.25 4H), 6.80 (d, 1IH, J=8H-z), 6.90 (in, 1 6.98 1 H, J=2Hz), 7.17 2H, J=8Hz), 7.30 (mn, 2H). MS (APOI) mle 523 Anal. calc'd for C31 H42N205 1 .1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 7.55; N, 4.48.
-419- Examjle 470 trans, trans-4-(l .4-Benzodioxan-6-yb)-2-(4-methoxylhenyly.1 butyl- N- (3-methyl 1h enylam ino) ca rbonyl) methyl) 1y rrol tdine.3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7.1 Hz, 3H), 1.30 (in, 2H), 1.44 (in, 2H), 2.30 3H), 2.80 J=15.2 Hz, 1H), 2.85 J=9.3 Hz, 1H), 3.19 J=9.3 Hz, 1H), 3.33 J=10.2 Hz, 1H), 3.42-3.61 (in, 3H), 3.79 3H), 3.91 J=9.8 Hz, 1H), 4.22 (mn, 4H), 6.75-6.86 (in, 6H), 1 0 6.95 J=2.0 Hz, 1H), 7.09 J=8.8 Hz, 2H), 7.22 J=10.2 Hz, 1H), 7.26 J=7.6 Hz, 1H). MS (DCI) in/e 559 Anal calcd for C33H-38N206 0.4 CH3002C2H5: C, 69.97; H, 6.99; N, 4.72. Found: C,:0.
.0 0.06; H, 6.66; N, 4.48.
ease Example 471 trans. trans-4-(1 .4-Benzodioxan-6-yl'-2-(4-methoxyphenyl)-1 butyl-N-(3-chlorophenylainino~carbonyl)inethyflpyrrolidine-3carboxylic acid :o* Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7.0 Hz, 3H), 1.25 (in, 211), 1.40 (in, 2H), 2.78 J=14.6 Hz, 1H), 2.86 J=9.0 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.34-3.43 (in, 3.48-3.62 (mn, 3H), 3.79 3H), 3.85 J=9.5 Hz, 1H), 4.22 (in, 6.78 J=8.5 Hz, 1H), 6.81- s000 6.86 (in, 3H), 6.93-7.09 (in, 5H), 7.33-7.38 (mn, 2H). MS (DCI) m/e 579 Anal calcd for C32H35CIN2O6 1 .1 CH3CO2C2H5 0.15 H3P04: 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 Benz odi oxol-5-yi) -2 -met hoxyph eny1)- 1 p2yridylmethyl)Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 2.84 J=9.6 Hz, 1 2.88 (dd, J=9.6, 7.3 Hz, 1H), 3.09 (dd, J=3.3, 9.6 Hz, 1H), 3.21 J=14.3 Hz, 1 3.53 (mn, 1 3.78 3H), 3.81 (in, 2H), 5.92 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 6.93 (in, 2H), 6.95 J=1.5 Hz, 1H), 7.43 (in, 4H), 8.44 J=5.2 Hz, 2H). MS (DCI) m/e 433 Anal -420calcd for C25H24N205 0.3 0H3002C2H 5 C, 68.57; H, 5.80; N, 6.10.
Found: C, 68.68; H, 5.60; N, 5.81.
Example 473 trntas4(.-ezdoo--y)2(-etxlhnl-
(N
butyl-N-(3- tert-butylphenylamino~carbonyl)methylp yrrolidin-e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMVR (300 MHz, CD3OD) 8 0.88 J=7.2 Hz, 3H), 1.23 9H), 1.26-1.45 (in, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (in, 3.13 J=9.0 Hz, 1H), 3.29 J=15.1 Hz, 1H), 3.50-3.66 (in, 4H), 3.77 3H), 3.84 J=9.6 Hz, I1H), 5.92 2H), 6.74 J=7.7 Hz, 1 6.79- 6.85 (in, 4H), 6.86-6.90 (in, 1H), 6.99 J=1.8 Hz, 1H), 7.06 J=1.8 Hz, 11-1), 7.13 (in, 2H), 7.33 J=7.7 Hz, 1 7.42 (in, 1 MS (DCI) ml/e 587 1s 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-Benzodioxo-5-y)-2-(-methoxyphenyl..1 butyl-N-(3-n-butylphenylamino~carbonyl)methyl)pyrrolidine3.
carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMVR (300 MHz, CD3OD) 8 0.88 J=7.3 Hz, 3H), 0.92 J=7.3 Hz, 3H), 1.23-1.59 (in, 8H), 2.58 J=7.6 Hz, 2H), 2.75 J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 1H), 3.12 J=9.3 Hz, 1 3.29 W J=15.6 Hz, 1H), 3.46 (dd, J=4.9, 9.7 Hz, 3.52-3.64 (mn, 3H), 3.78- 3H), 3.83 J=9.8 Hz, 1 5.92 2H), 6.74 J=8.1 Hz, 1 6.79- 6.87 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.10 J=8.8 Hz, 2H), 7.20 (d, 7.13H), 7.29 J=7.6 Hz, 1H). MS (DCI) m/e 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.
-421- Example 475 trans, trans-4(3 .4-Dif luorophenyfl-2-(4-ethyl phenyl)-1 -(N-(n--butyw) N-(3-methyl1phenylaminocarbonylmethyfl)pyrrolidine3-carboxyliic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.87 3H, 1.19 3H, 1.28 (in, 2H), 1.43 (in, 2H), 2.28 3H), 2.60 2H, 2.66 (in, 2H), 3.06 (in, 1 3.21 1 H, J=15), 3.42 (dd, 1 H, 3.58 (in, 3H), 3.71 1H, 6.80 2H), 7.06 4H), 7.18 (in, 4H), 7.45 (in, 1H).
MS (APOI) m/e 535 Anal calcd for C32H36N203F2.- 1.3 HOAc: 1 0 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-Ethylhenyl-4-(3.4--dif uoropheny)..1 -(N-(n-butyb)-
N-(
3 -chlorophenyflaminocarbonylmethylnpyrrolicdine-3carboxyi -c acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 6 0.82 3H, 1.16 3H, 1.23 (in, 2H), 1.35 (in, 2H), 2.55 2H, 2.66 (in, 2H), 3.01 (t, 1 H, 3.16 1 H, J=1 3.32 (dd, 1 H, 3.56 (in, 3H), 3.67 (d, 1 H, 6.94 1 H, 7.02 (in, 5H), 7.14 (in, 2H), 7.32 (mn, 3H). MS (APCI) m/e 555 Anal calcd for C31 H33N203CIF2 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.
Examole 477 trans, trans-4-(1 .4-Benzodioxan-6-yl)--2-(4-f luorophenyl)-l utyl-
N-(
3 -chlorop~henyl)aminocarbonylmethyl)p2yrrolidine.3..cprboxylic acid Using the procedures described in Example 1, the title compoundwas prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.10- 1.30 (mn, 4H), 2.60-2.75 (in, 2H), 3.03 J=7 Hz, 1H), 3.15-3.75 (mn, 6H), 4.02 (mn, 4H), 6.75 J=6 Hz, 1 6.85 (dd, J=7 Hz, 1 6.90 (7.19, J=m Hz, 6H), 7.32-7.43 (in, 3H). MS (DCI) mle 567 Anal calcd for C31 H32N205FCI 1.6 H20: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H, 5.54; N, 4.42.
-422- Example 478 trans, trans-4-(B enzof uran -5-yl -2-(4-ethyl he nyl)-1 N dibutylamino)carbonyl)methylpyrrolidine-3-carboxyic- acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, 0D013) 6 0.78 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 2H, J=7Hz), 1.21 3H, J=7Hz), 1.25 (in, 2H), 1.45 (in, 2H), 2.62 2H, J=7Hz), 2.80 1H, J=l3Hz), 3.0 (in, 2H), 3.15 (in, 2H), 3.35 (in, 1 3.43 (mn, 2H), 3.52 (in, 1 4.40 (in, 2H), 6.73 1 H, J=lHz), 7.14 2H, J=8Hz), 7.26 1 7.31 2H, J=8H-z), 7.44 (s, 2H), 7.60 1H, J=1 Hz), 7.65 1H). MS (APCI) m/e 505 Anal.
calc'd for C31 H40N204: C, 73.78; H, 7.99; N, 5.55. Found: 0, 73.69; H, 7.97; N, 5.2 1.: Example 479 trans. trans-2-(4-Methoxy-3-fluorophenyl-4-(7-methoxy-1 .3benzodioxol-5-yl)-l1-r2-(N-propyl-N-(pyrrolidin-e-1 carbonylinethyflamino~ethyllpyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-l1-[2-(N-propyl-aminoethyl]-pyrrolidine-3carboxylate, prepared according to the procedures of Example 61B (300 mg), N-bromoacetyl pyrrrolidine (132 mng) and diisopropylethyiamine (154 mg) were heated for 1 hour at 50 00 in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example 1 D. 1 H NMR (300 MHz, CDC13) 8 0.88 J=7Hz, 3H), 1.30-1.45 (mn, 2H), 1.75-1.92 (in, 4H), 2.30-2.40 (in, W 1H), 2.47-2.58 (in, 2H), 2.70-3.00 (mn, 5H), 3.24-3.45 (in, 6H), 3.50-3.70 (mn, 3.83 3H), 3.86 J=9Hz, 1 3.88 3H), 5.93 2H), 6.58 J=2Hz, 1H), 6.70 J=2Hz, 1H), 6.87 J=8Hz, 1H), 7.10 J=9Hz, 1H), 7.21 (dd, J=2Hz, 12Hz, 1H).
Example 480 trans, trans-2-(4- Met hoxyphenyl)-4-( 1.3- benzodioxol-5-yfl)-1 (p~erhydroazelinylcarbonyfl-(D)-leucyl)amino)ethyl)pyrrolidine-3carboxylic acid -423- Example 480A D-Leucine O-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 The 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%).
o1 Example 480B N-Perhydroazepinylcarbonyl-D-Leucine O-Benzvl 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 and carbonyldiimidazole was added. After 1.5 1 5 hours, TLC indicated complete consumption of starting material, so *.i 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 H3P04 (2 x 20 mL), and brine (20 mL), dried over Na2SO4, decanted and evaporated. The i:.
residue was purified by flash chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).
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 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).
-424- Example 480D trans, trans-2-(4-MethoxyDhenvy)-4-(1,3-benzodioxol-5-yl)-1 (cyanomethyl)-pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 wt.
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 1 o hexanes to give the title compound as a colorless oil (0.28 g, 99%).
Example 480E trans. trans-2-(4-MethoxyDhenl)-4-( 1.3-benzodioxol-5-yl)-1 aminoethyl)-pyrrolidine-3-carboxylic acid ethyl ester 1 5 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 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) 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 Example 480F trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl-1 (DerhydroazeDinylcarbonyl)leucyl)amino)ethyv)-pyrrolidine-3carboxylic acid, ethyl ester The compound resulting from Example 480E (0.10 g) was 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 OC, 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), dried over MgSO4, filtered and evaporated. The residue was purified by -425flash 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 trans, trans-2-(4- Met hoxyohenyl)-4-(1 .3-benzodio xol 1 (1perhydroazepinylcarbonyl)eucylamino)ethl)pyrrolidine.3.carboxylic 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 1 0 2 hours, additional 5 M NaOH (0.090 ml-) was added. After an additional hours, the reaction was evaporated. The residue was dissolved in water (5 mL) and washed with diethyl ether (2 x 2 mL). The aqueous 9 solution was acidified with 1 N H3P04 to pH The solid which precipitated dissolved when the mixture was extracted with 1 5 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 Purification by HPLC (Vydac mCl8) eluting with a 10 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophilization of the desired fractions. 1 H NMR (CDCI3, 300 MHz) 8 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J 5.7, 5.7 Hz, 6H), 1.04-1.28 (in, 3H), 1.34-1.65 (in, 191H), 2.95 (br m, 21H), 3.15-3.40 (in, 14H), 3.40-3.55 (in, 4H), 3.58-3.68 (in, 2H), 3.70- 3.76 (br m, 2H), 3.80 3H), 3.81 3H), 4.15 (br m, 2H), 5.10 (br m, 2H), 5.93, 3H), 5.95 3H), 6.70-6.97 (in, 13H), 7.43-7.56 (br m, 31H), 8.2 (br s, 1H), 8.5 (br s, 1H). MS(DCI/NH3) m/e 623 Anal calcd for C34H46N407 -2.00 TEA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.
Example 481 trans, trans-4-( 1.3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 di (n-hexyl) ainnocarbonylm ethyfl)pyrrol idine-3-carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.80-0.95 (in, 6H), 1.0 (in, 211), 1.07 (1.55, J=in Hz, 14H), 2.70 J=13 Hz, 1H), 2.85-3.15 (mn, 4H), 3.20-3.60 (mn, 9H), 3.64 J=1 0 Hz, 1 3.79 3H), 5.90 (mn, 2H), 6.70 1, 6.80-6.93 (in, 3H), 7.05 1H), 7.35 J=10 Hz, 21H). Anal -426calcd for C33H46N206 1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4. 52.
Example 482 trans. trans-4-(l .4-Benzodioxan-6-yfl-2-('4-f luorophenyl)-1 -(N-butylmethyllhenyl) am inoca rbonyl methyl) 1yrrol id ine-a-ca rboxylic cid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.35 (in, 2H), 1.35-1.40 (in, 2H), 2.32 3H), 2.55-2.70 (in, 2H), 2.97 (t, J=7 Hz, 1H), 3.22 J=14 Hz, 1H), 3.25-3.70 (mn, 5H), 4.20 (in, 4H), 6.97 J=2 Hz, 1 7.09 (mn, 2H), 7.15-7.35 (in, 2H). MS (DCI) in/e 547 Anal calcd for C32H35N205F 1.2 H20: C, 67.64; H, 6.63; N, 4.93., Found: C, 67.73; H, 6.37; N, 4.70.
Example 483 trans. trans-4-( 1 .3-Benzodioxol-5-yi)-2-(4-methoxyphenyl)- 1 butyl-N-(3-nitrobenzyl)amino)carbonyl)inethvl~pyrrolidine-3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotainer) 8.14 (2H, in), 8.05 (7.83) (1H, in), 7.60-7.30 (3H, in), 7.13 (1H, in), 7.10-6.70 (5H, in), 5.94 (2H, in), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, in), 4.10 (2H, in), 3.80 (3.76) (3H, 3.75-3.40 (3H, mn), 3.20-2.80 (2H, mn), 1.50 (1H, in), 1.30 (1H, in), 1.20-1.00 (2H, in), 0.91 (0.78) (3H, t, MS (DCI/NH3) mle 590 Anal calcd for C32H35N308 2.1 TFA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.
Example 484 trans, trans-4-(1 .2-Dihydrobenzof uran-5-yl)-2-(4-ethylphenyl).1 butyl- N- (3.4-di methoxybenzyl) am ino)carbonyl) methyl) pyrrdl id ine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 (rotainer) 7.40 (2H, in), 7.30-7.10 (4H, in), 6.90-6.70 (3H, in), 6.48 (1 H, in), 5.45 (1 H, in), 4.65 (1 H, d, J=15), 4.57 (2H, dt, J=9, 4.40-4.00 (5H, in), 3.87 (3.85) (3H, 3.84 (1H, in), 3.83 (3.79) (3H, 3.56 (2H, in), 3.20 (2H, t, J=10), 2.90 (1H, -427in), 2.64 (2H, q, 1.52 (1 H, in), 1.31 (2H, in), 1.22 (3H, dt, J=9, 2), 1.07 (1H, in), 0.92 (0.78) (3H, t, MVS (DCI/NH3) m/e 601 Anal calcd for C36H44N2O6 1.35 TFA: 0, 61.59; H, 6.06; N, 3.71'.
Found: 0, 61.69; H, 6.04; N, 3.63.
Examp e 485 trans, trpns-4-(l 3 -Benzodioxol-5-yfl-2-(4-methoxyphenyl)-1 butyl-N-(4-heptyflamino~carbonflmethyr) pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (300 MHz, CD3O1D) 8 0.71-1.04 (in, 11H), 1.07- 1.35 (mn, 6H), 1.73-1.53 (in, 4H), 2.79-3.25 (in, 5H), 3.35-3.44 (m,1H), 9 3.51-3.68 (in, 3H), 3.78-3.89 (in, 1H), 3.79 3H), 5.92 (in, 2H), 6.74 (dd, J=1.7, 8.1 Hz, 1H), 6.85 (td, J=1.7, 8.1 Hz, 1H), 6.93 (mn, 2H), 7.02 (dd, J=1.7, 9.5 Hz, 1H), 7.36 (in, 2H). MIS m/e 553 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 trans, trans-2-(4-Methylcyclohexyfl-4-(1 .3-benzodioxol-5-yfl)-1-(N.Ndibutylaminocarbonyl1methyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDC13, 300 MI-iz) 8 0.88 (3H, d, J 7Hz), 0.92 (3H, t, J 7Hz), 0.96 (3H, t, J 7Hz), 1.05 (1H, in), 1.22-1.40 (7H, mn), 1.45-1.65 (6H, in), 1.67-1.84 (4H, in), 3.17-3.45 (6H, in), 3.70 (1 H, brm), 3.82 (1 H, dd, J 9Hz, 15Hz), 3.86 (1H, d, J 15Hz), 5.93 (2H, 6.73 (1 H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). NIS (DCI/NH3) m/e 501 Anal calcd for 029H44N205 0.25 CF3002H C, 66.96; H, 8.43; N, 5.29.
Found: C, 66.79; H, 8.60; N, 4.87.
-42 8- Example 487 trans. trans-2-(2-Propylp~entyl)-4-(1 .3-benzod-ioxol-5-yi)-l1-(N.Ndibutylaminocarbonylmethyl'iprrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3K, t, J 7Hz), 1.12- 1.40 (13H, in), 1.42-1.68 (6H, in), 2.90 (1H, in), 3.14-3.30 (2H, in), 3.33 (4H, in), 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 (DCI/NH3) m/e 517 Anal calcd for C30H48N20 5 0.35 CF3002H 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-yl-2-(4-f Iuo rohenyl)..1
N-
dibutviaminocarbonylmethy)pyrrolidine3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 K NMR (300 MHz, CD3OD) 5 0.83 J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3K), 0.9.0-1.17 (in, 4K), 1.20-1.65 (in, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1KH), 2.95-3.60 (in, 7H), 3.71 J=9 Hz, 1KH), 4.21 4K), 6.72 1 6.91 (dd, J=8 Hz, 1KH), 6.97 J=2 Hz, 1KH), 7.05 J=7 Hz, 2H), 7.40-7.50 (in, 2H). MS (DCI) m/e 513 Anal calcd for C29H-37N\205F 1.20 F3COOK: C, 58.07; K, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56.
Example 489 -trans, trans-2-(3-Methylpentylp4( 1 .3-benzodioxol-5-yn)-1 I' dibutylamino-carbonylinethylpyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 K NMR (CDC13, 300 MHz) 8 0.83 (3K, t, J 7Hz), 0.85 (3K, d, J= 7Hz), 0.91 (3K, t, J 7Hz), 0.97 (3K, t, J 7Hz), 1.05-1.22 (2K, in), 1.22-1.41 (7K, in), 1.43-1.68 in), 1.89 (1KH, in), 2.94 (1KH, t, J 6Hz), 3.15-3.27 (3K, in), 3.29-3.60 in), 3.72 (1KH, brd, J 6Hz), 3.92 (1KH, brd, J 13.5Hz), 5.93 (2K, dd, J 2Hz, 4Hz), 6.73 (1K, d, J 8H-z), 6.78 (1K, dd, J= 2Hz, 8Hz), 6.88 (1K-, d, J 2Hz). MS (DCI/NK3) m/e 489 Anal calcd for C28K44N205 -429- 0.30 CF3002H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.
Example 490 trans, trans-2-(2-Ethylbutyl)-4-(1 .3-benzodioxol-5-yly..1
N-
dibutylaminocarbonylmethflpyrrolidine.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) 5 0.85 (OH, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.13- 1 0 1.41 (13H, in), 1.43-1.72 (6H, in), 2.96 (1H, brm), 3.12-3.52 (6H, in), 3.55-3.70 (1H, in), 3.70-3.86 (2H, in), 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 Anal calcd for C28H44N205.
0.45 CF3002H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 5.08.
Example 491 trans, trans-2- F1uo ro-4-meth oxyp henyb)-4-(1 .3-b enz 0di oxol- 1 2 iso b uty I- N ut a n es u f ony Ia m in get hy yrro I id in e 3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 5 0.74 3H, 0.83 3H, 0.94 3H, 1.44 (hex, 2H), 1.67 (mn, 4H), 2.91 2H, J=8), 3.04 (dd, -2H, J=8,10), 3.1-3.6 (mn, 5H), 3.78 (in, 2H), 3.92 3H), 4.60 5 1 5.97 2H), 6.82 I1H, 6.89 (dd, 1 H, J=2, 7.01 1 H, FJ=2), 7.22 1 H, 7.39 (mn, 2H). MS (ES I) m/e 579 Examp~le 492 trans, trans-2-(4-Methoxy-3-f luorophenyn)-4-( 1 1 -r 2 -(N-propyl-N-[4-ethvl pyri mid in-2-yllamino)ethvyllprrolidi ne-3 carboxylic acid 1 -Diimethylainino- 1-pentene-3-one, prepared by the method described in Syn. Comm. 12 35 (1982), was converted to 2-amino- 4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2 -bromo-4-ethyl-pyriinidine with NaNO2 and HBr, using the method of Helv. Chim. Acta 75, 1629 -430- (1992). This bromopyrimidine was reacted with ethyl 2-(4methoxphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -12-(N-propylamino)propyl]..
pyrrolidi ne-3-ca rboxyl ate, prepared using the procedures of Example 6113, using the procedure for Example 418, to give the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) 5 0.83 J=7H-z, 3H), 1.11 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1H), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (in, 3H), 3.40-3.75 (in, 7H), 3.83 3H), 5.95 (s, 2H), 6.25 J=4Hz, 1H), 6.68 J=8Hz, 1H), 6.79 (dd, J=2Hz, 8Hz, 1H), 6.82 J=9Hz, 1H), 6.92 J=2Hz, 1H), 7.05 J=9Hz, 1H), 7.15 (dd, J=2Hz, 12Hz, 8.10 J=4Hz, 1H).
Example 493 trans. trans-4-(1 .3-Benzodioxol-5-yI) -2-(4-methoxylheny1) -1 butyl-N-(3 .4-dim ethyl phenyflam inocarb onyt) methyfl) yrro Iid in carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.87 J=7.3 Hz, 3H), 1.23- 0 1.36 (in, 2H), 1.38-1.43 (in, 2H), 2.22 3K), 2.29 3K), 2.79 :0.
J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 J=9.5 Hz, 1K), 3.32 J=15.3 Hz, 11K), 3.43-3.61 (in, 4H), 3.79 3K), 3.88 J=9.8 Hz, :1 1 1H), 5.93 2K), 6.74 (in, 3K), 6.83 (in, 3K), 7.04 J=1.7 Hz, 1K), 7.11 1:o (in, 3K). MS m/e 559(MH+). Anal calcd for C33H38N206-0.3H20: 0.
C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.
Example 494 trans, trans-2-(3- MethylpDent-3-en- 1 .3-benzodi oxol-5-yli- (N.N-dibutylaminocarbonylinethyl)p2yrrolidine-3-carboxylic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.22-1.40 (5H, in), 1.44-1.61 (8K, mn), 1.82 (1K, brm), 2.02 (2K, in), 3.05-3.30 (4K, in), 3.3.8 (1K, in), 3.55 (1KH, bin), 3.85 (2H, in), 4.12 (1KH, brd, J 15Hz), 5.11 (1K dd, J 6Hz, 12Hz), 5.93 (2H, 6.73 (1KH, d, J 8Hz), 6.78 (1KH, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NK3) m/e 487 Anal calcd for C28K42N205 -0.7 CF3002K C, 62.34; H, 7.60; N, 4.95.
Found: C, 62.49; H, 7.43; N, 4.73.
-431- Example 495 1 henylaminocarbonylmethyF)-2-(4-methoxyphenr)-4.(1 .3benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Examlle 495A N-Phenylbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride ml-) at -50 OC was added successively N,N-diisopropylethylamine (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 OC. On: completion of the addition, the cooling bath was removed, and the 0 reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether 1 5 (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 compound.
Example 495B 0.0 trans, trans- 1 -(N-Phenylaminocarbonylmethyvl)-2-(4-methoxyphenyl)- 4 benzodioxol -5-ybo yrroli din e-3-carboxylic acid Using the procedures described in Example l and the compound resulting from Exampe 495A, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 6 8.8 (bs, 1H) 7.49 d, J=BHz), 7.38 (4H, in), 7.11 (1KH, tt, J=8&2Hz), 6.99 (1 H, d, J=2Hz), 6.91 (2H, d, J=8H-z), 6.86 (1 H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 3.94 (1K, d, J=lOHz), 3.78 (3H, 3.70 (1H, ddd, J=6, 5&3Hz), 3.42 (1H, dd, J=10&3Hz), 3.41 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9Hz), 3.01 (1 H, t, J=1lOHz), 2.93 (1KH, d, J=1l6Hz). MS (DCI, NH3) m/e 475 Anal. Caic for C27H26N206 1 H20: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38.
-432- Example 496 trans, trans-i1 .3-Dimethylghenyl~aminocarbonylmethylj-2-(4methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylc-. acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 8.68 (1 H, bs), 7.64 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, 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.44 (1H, d, J=l6Hz), 3.18 (11H, dd, J=1.1&9Hz), 3.06 (1H, t, J=lOHz), 2.96 (1H, d, J=l6Hz), 2.31 (3H, 2.16 (3H, MS (DCl, NH3) m/e 503 Anal. Calc for C29H3ON2O6 0.5 H20: C, 68.09, H, 6.11, N, 5.48. Found: *1 C, 68.13, H, 5.91, N, 5.29.
Example 497 trans. trans-i1 Di methylphenyl) am inocarbo nyl methyl)-2- (4.
fee# methoxyphenyl)-4-(1 .3-benzodioxol-5-yflpyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound 000 was prepared. 1 H NMR (300 MHz, CDC13) 8 8.60 (1 H, bs), 7.78 (d, J=8H-14 7.38, (2H, d, J=8Hz), 6.99 (1 H, in), 6.95, (1 H, d, J=8Hz), 6.94:e* (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 dd, J=8&3Hz), 6.77 (1 H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2H-z), 3.92 (1H, d, J=lOHz), 3.79 (3H, 3.68 (1H, ddd, J=6, 5&3Hz), 3.43 (1H, dd, J=lO&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9-z), 3.04 (1 H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MS (DCI, NH3) m/e 503 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.
Examp~le 498 trans. trans-i1 Dim ethyl 1heny Iaminocarbonylmethyl)-2-(4methoxyphenyfl-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, di, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, di, J=8Hz), 6.82 (1H, dci, J=8&3Hz), 6.77 (1H, d, J=BHz), 5.97 (2H, 3.92 (1H, d, J=lOHz), 3.78 (3H, 3.70 (1H, -433ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MS (DCI, NH3) m/e 503 Anal. Calc for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5.89; N, 5.25.
Example 499 trans. trans-i1 -(N-(3.4-Dimethylphenyl)aminocarbonylmethyl)-2-(4.
methoxyphenyl)-4-(l .3-benzodioxol-5-yfloyrrolidine-3-carboxvlic acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 5 8.73 (1 H, 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 0 (1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1H, bs), 6.80 (1H, d, J=8Hz), 5.99 (1H, d, J=3H-z), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.78 (3H, s), 3.70 (1H, ddd, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=l6Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.25 (3H, 2.21 (3H, MS (DCl, NH3) m/e 503 Anal. Caic for C29H30N206 0.75 H20: C, 67.50; H, 6.15; N 5.43.
Found: C, 67.24; H, 5.94; N, 5.20.
Example 500 trans, trans- 1 Dim ethyl phenybami nocarbonyl methyfl-2 (4methoxyphenyl)-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, CDC13) 8 8.75 (1 H, bs), 7.35, (2H, d, WJ= .8Hz), 7.10 (2H, 7.02 (1 H, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1 H, d, J=2Hz), 6.80, (1H, d, J=8Hz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 (1 H, d, J=3FHz), 3.92 (1 H, d, J=1lOHz), 3.79 (3H, 3.68 (1 H, ddd, J=6, 5&3Hz), 3.40 (2H, in), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J=lOHz), 2.88 d, J=l6Hz), 2.3 (6H, MS (DCI, NH3) mle 503 Anal.
Caic for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.
-434- Example 501 Alternate Preparation of (+)-trans, trans--1 -(N.N-Di-n-butylaminocarbonvlmethyl)-2-(4methoxyvhenyl)-4-(1.
3 -benzodioxol-5-vl)pyrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A N, N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in 1 o toluene (500 mL) cooled to 0 °C was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 Upon completion of S the addition, the reaction mixture was stirred at 0 OC for 15 minutes. A solution of 2.5% aqueous H3P04 (500 mL) was slowly introduced, and 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.
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), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 After about minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled t 10 °C 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 °C for 2 days to afford 15.94 kg of the title compound as a bright yellow solid.
-435- 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 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 The reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 °C and quenched by 1 0 adding to a mixture of acetic acid (8 kg) and water (90 kg) over minutes while maintaining the temperature at <20 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 °C during the distillation. The 1 5 yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg Example 501D Ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1 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 OC, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about minutes, the nitrostyrene was completely dissolved. Soc n 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 -14.9 kg Example 501 E Ethyl cis, cis-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) pyrrolidine-3-carboxylate Raney nickel (20.0 from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple.
-436- 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 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 S nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g of the title compound.
Example 501 F Ethyl trans. trans-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxyl ate 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 When HPLC shows 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 The organic layer was separated and found to contain 32.9 g of the title compound.
-437- Example 501G Ethyl (2R.3R. 4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate. 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 1 0 oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g 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 S hexane-ethanol-diethylamine; flow 1 mL/min.; UV detection at 227..
nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.
Example 501H (2 R.3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1 dibutylaminocarbonylmethyl)- 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 OC.
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 so volume of 100 mL. Sodium hydroxide solution 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 -438with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.
Example 5011 (2R.3R.4S)-(+)-2-(4-methoxyphenl)-4-(1.3-benz odioxol-5-yl)-1-(N
N-
dibutylaminocarbonvlmethyl)- 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 1 o 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 I 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 of the title compound. Example 502 trans, trans-2-(2-Methylpentyl)-4-(1.3-benzodioxol-5-yl- 1 dibutylaminocarbonylmethyl)-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 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 -439solvent was removed under reduced pressure to give 3.0g of the title compound.
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 1 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.
p 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-benzodioxol-5-yl)-1-(N.Ndibutylaminocarbonylmethyl)-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 (CDCI3, 300 MHz) 6 0.8-1.0 12H), 1.2-1.4 7H), 1.45-1.6 6H), 1.6-1.74 1H), 1.8-2.0 1H), 3.1-3.4 5H), 3.67-3.78 1H), 3.8-3.91 1H), 4.0-4.2 2H), 4.3-4.5 2H), 5.93 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- C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.
-440- Example 503 trans, trans-2-(2,2- Dim ethylpentyl)-4-(1 .3-bLenzod io dibutylaminocarbonylmethyl)-pyrrolidine-.3-carb-X-Ylic acid Ethyl 3,3-dimethyihexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., a1, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3dimethylhexanoate for ethyl 3-methyihexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CDCI3, 300 MHz) 8 0.80-0.99 (in, 15H), 1.10-1.37 (in, 8H), 1.43-1.58 (in, 4H), 1.77-1.97 (mn, 3.48-3.12 (in, 5H), 3.60- 3.69 (in, 1 3.75-3.86 (in, 1 3.95-4.16 (in, 2H), 4.28-4.4 (in, 2H), 5.94 2H), 6.74 J=7.8 Hz, 1 6.8 (dd, J=8.1, 1.5 Hz, 1 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 Anal calcd for C29H46N2O01.05 TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.
ExamI2le 504 trans, trans-2-(2-(1 .3-Dioxo-2-yflethyfl-4-(1 .3-benzodioxol-5-yl)- 1 (N.-dbutlainc arbn ehf~yrroliine-3carboxylic acid Example 504A Ethyl 5-(1 .3-dioxolyl)-3-oxopentanoate 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 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 00 for additional 10 min. To above mixture was then added 48.4 mL (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise manner. The resulting orange color solution was stirred for 10 min -441before 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 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 1 o 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 of b-keto ester as a light yellow oil..
Example 504C trans.trans-2-(2-(1 .3-Dioxo-2-yl)ethyl)-4-(1.3-benzodioxol-5-yi)-1- (N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound. 1 H NMR (CDCI3, 300 MHz) 8 0.93 J 7.2 Hz, 3H), 0.95 J 7.2 Hz, 3H), 1.23-1.38 4H), 1.52 (sextet, J 7.9 Hz, 4H), 1.85-1.95 2H), 2.02-2.17 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 1H), 3.79 (dd, J 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88 3H), 3.97 (dd, J 4.8 Hz, 6.0 Hz, 1H), 4.05 J 9.6 Hz, 2H), 4.30-4.40 1H), 4.37 2H), 4.87 J 3.6 Hz, 1H), 5.94 2H), 6.73 J 8.1 Hz, 1H), 6.79 (dd, J 1.8 Hz, 8.1 Hz, 1H), 6.87 J 1.8 Hz, 1H). MS (APCI) 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.
Example 505 trans trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1,3-benzodioxol- 1 N-di butyl aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid -442- Examlle 505A Ethyl 5-(2-tetrahydro-2H-12yran)-3-oxolentanopte 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.
trans. trans-2-(2-(2-Tetrahydro-2 H-pyran~ethyn-4-( 1.3-benzodioxol- 1 0 5-yl)-1 -(N.N-dibutylaminocarbon.ylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2 H-pyran)-2-oxopentanoate for ethyl 3- e*oo methylhexanoate afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) as a mixture of two diastereoisomers: 8 0.89 J =8.1 Hz, 3H), 0.89 J 8.1 Hz, 3H), 0.91 J 8.1 Hz, 3H), 0.91 J =8.1 Hz, 3H), 1.20-1.40 (in, 10H), 1.42-1.66 (in, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (bin, 4H), 3.10-3.29 (mn. 8H), 3.29-3.52 (in, 6H), 3.54-3.81 (mn, 6H), 4.01 J 9 Hz, 2H), 4.12-4.25 (in, 4H), *0 4.43 J 9 Hz, 2H), 4.50 J 2.7 Hz, 2H), 5.94 2H), 5.95 2H), 6.76 2H), 6.76 2H), 6.81 1H), 6.81 1H). MS (APOI) at 0* 0 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.
iExamole 506 trans, trans-2-(2 .2,4-Trimethyl-3-p-entenyb)-4-(1 yl)-1 -(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic- acid Examp~le 506A Methyl 3.3.5-t rim ethyl-4-hexeno ate To a slurry of isopropyltripenylphosphoniumn iodide (20.5g, 47mmol) in 200rnL of tetrahydrofuran was added n-butyllithiumn (27inL of a 1.6M solution in hexane, 43mmol), and the solution was briefly warmed to 0 0 C. After recooling, a solution of methyl 3,3-diinethyl-4- -443oxobutenoate (5.7g, 4Ommol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 1E~ 169 (1986) in lOmL of tetrahydrofuran was added, and the reaction was warmed to 0 0 C for 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 of the title compound.
506 trans, trans-2-(2.2,4-Trimethyl-3-pentenyfl-4-(1 yl)-l -(N.N-dibutylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid 1 5 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 TFN/CH3CN. H NMR (0D013, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 1. 11 3H), 13 3H), 1.24-1.37 (in, 4H), 1.46-1.59 (in, 4H), 1.61 J=1.2 Hz, 3H), 1.69 J=1.2 Hz, 3H), 2.04-2.11 (in, 2H), 3.10-3.20 (in, 2H), 3.30-3.39 (mn, 3H), 3.67-3.82 (in, 2H), 3.95-4.08 (in, 1H), 4.32 (in, 2H), 4.37-4.47 (in, 1H), 4.99 1H), a 5.95 2H), 6.73 J=7.8 Hz, 1 6.78 (dd, J=8.4, 1.2 Hz, 1 6.84 S.
J=1.2 Hz,' 1H). MS (DCI/NH3) Wne 515 Anal calcd for C30H46N\205-1.05 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- -Dim ethyl-2-(1 .3-dioxolan-2-yflethyl)-4-(1 .3benzodioxol-5-yl)-1 .N-dibutylaminocarbonylmethyfl-pyrrolidine-3carboxy ic acid -444- Example 507A Methyl 3.3-dimethyl-3-(1 3 -dioQxolan-2-yflpropanoate Methyl 3,3-dimethyl-4-oxobutanoate (10Og, 7Ommol), prepared according to the procedure of Hudlicky et al., Synth. Commun., j 169 (1986), was dissolved in 4OmL- of benzene, followed by addition of ethylene glycol (2OmL-), and p-toluenesulfonic acid monohydrate (1 .3g).
The reaction was ref luxed with azeotropic removal of water for 1 hour.
The reaction was poured into 200mL- of ether, washed with saturated 1 0 sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g of the title compound. Example 507B is trans, trans-2-(2.2.-Dimethyl-2-(1.3dioxolan2 )ethyl4(1,3 benzodioxol-5-yl)-1 N-dibutylaminocarbonylmethylhp1yrrolidine-3 carboxylic acid.
Using the procedures described in Example 502 and substituting methyl 3 ,3-d im ethyl -3-(1,3-dioxo lan-2-yl) prop anoate for ethyl 3- methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMVR (CDCI3, 300 MHz) 8 0.82-1.00 (in, 12H), 1.24-1.40 (in, 4H), 1.43-1.64 (in, 5H), 1.76- 1.84 (in, 1H), 2.93-3.00 (in, 1H), 3.15-3.47 (in, 3.60-3.70 (in, 3H), 3.74-3.95 (in, 5H), 4.48 1H), 5.94 (in, 6.72 J=8.0 Hz, 1H), 6.83 F(dd, J=8.0, 1.2 Hz, 6.94 J=1.2 Hz, 1H). MS (DCI/NH3) m/e 533 Anal calcd for 029H44N207 -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.
Example 508 trans, trans-2-(2-(1 .3-Dioxo-2-yl)ethyl)-4-(1 .3-benzodioxol-5-y)-1 rrN-4-heptyl-N-(2-methyl-3-fluoroDhenyl)1 amino carbonylmethyllpyrrolidine-3-carboxylic- acid -445- Example 508A 4-Heptanol To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 20 mL of diethyl ether was added 370 mg (10.0 mmol) of LiAIH4, in portions to keep ether reflux at a minimum. After 45 minutes, the reaction was quenched by sequential dropwise addition of 0.4 mL 0.4 mL 15% NaOH(aq), and 1.2 mL H20. After stirring another minutes, MgSO4 was added until the salts were free flowing, then the 1 o reaction was filtered. The salts were washed with diethyl ether (3 x mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g Example 508B 4-Methanesulfonyloxyheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 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.
The mixture was stirred at 0 °C for 30 minutes, then extracted with (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 1 H NMR (300 MHz, CDCI3) d 0.96 6, J 1.43 1.64 3.00 4.73 (quintet, 1 J Example 508C 4-Fluoro-3-methylaniline To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 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 of a colorless oil.
-446- Example 508D N-H eptyl-4-fl uoro-3- methylaniline To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4methanesulfonyloxyheptane, 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 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, 1 o filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5: 2.5 hexanes: ethyl acetate, to give 2.56g of a pale yellow oil.
Example 508E N.N-(4-Heptyl)-(4-fluoro-3-methyl)phenylbromoacetamide To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4fluoro-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 bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 OC, 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 MgS04, 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 of a light yellow oil. 1H NMR (300 MHz, CDCI3) d 0.94 6, J 1.33 1.43 2.30 2.31 (s, 3.54 4.72 (quintet, 1, J 6.96-7.04 7.07(d, 1, J 7).
-447- Example 508F trans, trans-2-(2-(1 .3-Dio xol-2-ylbethyl)-4-(1 .3-benzodioxol-5-y)- 1 [FN-4-heptyl-N-(2-methyl-3-fluorophenym) amino carbonylmethyfipyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and N, N-(4-h eptyl)-(4-flIuo ro-3-m ethyl) ph enyl-b romoacetami de for N,N-dibutylbromoacetamide afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (brt, 6H), 1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3.16 J 9.0 Hz, 1 3.52- 3.67 (brm, 2H), 3.73 J 9.0 Hz, 11H), 3.81-4.02 (in, 6H), 4.13 (brm,: 1H), 4.72 (quintet, J 6.9 Hz, 1H), 4.86 J 4.0 Hz, 1H), 5.93 2H), 6.72 J 8.1 Hz, 1 6.78 (dd, J 1.8 Hz, 8.1 Hz, 1 6.85 J 1.8 Hz, 1H), 6.96 (in, 2H), 7.08 J 9.0 Hz, 1H). MS (DCI/NH3) 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 trans, trpns-2(2- (1 .3-Dioxol-2-ylethyl)-4-(1 .3-benzodioxol-5-yl)- 1 (N.N-dibutylaminocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 J 7.8 Hz, 3H), 0.95 J 7.8 Hz, 3H), 1.31 (mn, 4H), 1.53 (mn, 4H), 1.90 (mn, 2H), 2.09 (in, 2H), 3.19 (dd, J 8.4 Hz, 8.4 Hz, 2H), 3.30 J 9.6 Hz, 2H), 3.25- 3.42 (mn, 1 3.73 J 10.5 Hz, 1 3.78-3.94 (in, 4H), 3.88 3H), 3.96 (dd, J 5.1 Hz, 6.0 Hz, 1 4.03 (dd, J 3.0 Hz, 6.3 Hz, 2H), 4.33 (mn, 3H), 4.87 J 3.6 Hz, 1 5.94 2H), 6.53 J 1.8 Hz, 1 H), 6.63 J 1.8 Hz, 1H). MS (DCI/NH3) 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.
-44 8- Example 510 trans, trans-2-((2-M ethoxyphenoxy)-m ethyfl-4-(1 1 N-dibutyl aminocarbonylmethyl)-pyrroli din e-3-carboxylic acid Using the procedures described in Example 502, substituting omethoxyphenoxyacetic acid for 3-m ethylihexanoic acid, the above compound was prepared as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.15-1.35 (in, 4H), 1.40- 1.55 (in, 4H), 3.05-3.25 (in, 4H), 3.28-3.55 (in, 4H), 3.58-3.68 (in, 1H), 3.75-3.80 (in, 1H), 3.82 3H), 3.91 J=l4Hz, 1H), 4.05-4.15 (in, 1H), 4.23-4.33 (in, 1H),5.91 2H), 6.70 J=8Hz, 1H), 6.82-6.95 (in, 7.03 1H). MS (DCI/NH3) 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.
Example 511 (2S 3P. 4S)-2-(2.2-Di methyl pentyl)-4-( 1 3-benzodi oxol 1 heptyl- N-(4 -f uo ro-3-m ethyl ph enyl)am inoca rbonyl methylpyrrolidine-3-carboxylic acid Example 511 A trans, trans-N-tert-Butoxycarbonyl-2-(2.2-dimethylpentyfl-4-( 1.3rrolidine-3-carboxy lic acid Ethyl trans, trans-2-(2,2-dimethylpentyl)-4-(1 yl)-pyrrolidine-3-carboxyl ate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 5OmL of methylene chloride and di-tertbutyldicarbonate (1 .5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 5OimL of ethanol followed by addition of sodium hydroxide (1 OiL of a SM aqueous solution). After stirring for 20 hours -at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 1 5OmL of water, and acidified with concentrated -449phosphoric acid. The mixture was extracted with chloroform (3X50mL), 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.
Example 511B Methyl trans, trans-2-(2,2-dimethylpentyl)-4-(1 1 -(N-4-heptyl-N-(4-fluoro-3-methylDhenyl)aminocarbonylmethy)pyrrolidine-3-carboxylate: As a single enantiomer The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0°C, followed by addition of DMF (0.017mL, and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at 0°C under a stream of nitrogen. The residue 1 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 (4.0mL 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 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 chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, then elution with 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 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- N-(4-fluoro-3-methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was -450warmed to 50 0 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.
The above amide (200mg, 0.26mmol) was dissolved in 2.0mL 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 1 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 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 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.50C). Example 511C (2S.3R.4S)-trans, trans-2-(2.2-Dimethylpentvl)-4-(1.3-benzodioxol- 5-yl)-1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylate The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.0mL of methanol and sodium hydroxide (0.1mL of a 5M aqueous 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, dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization -451 from dilute aqueous TFNICH3CN. 1 H NMR (CDCI3, 300 MHz) d 0.78-0.95 (in, 15H), 1.04-1.46 (in, 12H), 1.76-2.95 (in, 2H), 2.31 3H), 3.23-3.33 (in, 1H), 3.47-3.58 (mn, 1H), 3.6-3.75 (in, 2H), 3.80-3.95 (in, 2H), 4.05- 4.15 (in, 1H), 4.73 (in, 1H), 5.94 2H), 6.70-6.80 (mn, 2H), 6.82-6.93 (in, 2H), 6.96-7.14 (in, 2H). MS (DCI/NH3) mle 597 Anal calcd for C35H49N2F05 -0.05H20 *0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: 0, 63.84; H, 7.18; N, 3.94. [a]D2 (c 2.7g/L, 0H013) Example 512 trans, trans-2- (2 -(2-Oxopy rro lidi n- 1 -yl) ethyl) .3-benzodi oxol- yb)-i-(NN-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 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 0C 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 of acid as a brown oil.
Example 512B Ethyl 5-(2-oxopyrrolid in-i -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).
Examole 5120 trans, trans-2- (2-Oxopyrrol idi n- 1 -yb) ethyl)-4-( 1.3- benzod ioxol- yI)-1 -(N.N-dibutylaminocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl 3- -452methyihexanoate afforded the title compound as an amorphous solid.
I H NMR (CDCI3, 300 MHz) 5 0.91 J 7.5 Hz, 3H), 0.94 J =7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (m 2.05 J 6.9 Hz, 2H), 2.12- 2.25 (in, 1H), 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (in, 1H), 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J =9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1 3.66 J 6.9 Hz, 1 3.96 (in, 2H), 4.14 (in, 1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, I1H), 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1lH), 6.87 J 1.8 Hz, 1 MS (DCI/NH3) at mle 516. Anal calcd for C28H41 N306-1.4 TFA: C, 1 0 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.
Example 513 trans, trans-2-(2-(1 .3-Dioxol-2-ylethyl-4-(7-methoxy.1 .3b e nz od io x o I-5- y1)- 1 (N-4 he 12ty I- N flIu oro -3 methylphenyfl)aminocarbonylmethyl)-pyrrolidine.3-carboxvlic acid Using the procedures described in 'Example 502, substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethylihexano ate, N-4-heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,Ndibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (br t, 6H), 1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3H), 3.16 J 9 Hz, 1 3.60-4.03 (in, 8H), 3.88 3H), 4.21 (brs, 1 4.72 (quintet, J 6.6 Hz, 1 4.86 J 3.6 Hz, 1 5.93 2H), 6.49 1H), 6.61 1H), 6.96 (in, 2H), 7.08 J 9 Hz, 1H). MS (DCI/NH3) 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.
Example 514 trans. trans-2-(2.2-Dimethylentyl)-4-(7-methoxy.1 yfl)-1-(N.N-dibutylaminocarbonylmethyb)-pyrrolidine.3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3-methylhexanoate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.81 3H), 0.84 3H), -453- 0.86 J 6.9 Hz, 3H), 0.93 J 6.9 Hz, 3H), 0.96 J 6.9 Hz, 3H), 1.09-1.38 (in, 8H), 1.45-1.59 (in, 4H), 1.84-2.00 (mn, 2H), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (in, 3H), 3.72 J 10.5 Hz, 1H), 3.86 (t, J 10.5 Hz, 1H), 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, I1H), 4.29 J 16.8 Hz, 1 4.41 (bin, 1 5.94 1 6.52 J 1.8 Hz, 1H), 6.67 J 1.8 Hz, 1H). MS (DCI/NH3) 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 frans, trans-2-(2.2-di methyl 1entyl)-4- (2,3-d ihyd ro-benzof 1 -(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carbgxylic acid Using the procedures described in Example 502, substituting 1 5 ethyl 3,3-dimethyihexanoate for ethyl 3-m ethyl hexanoate and 2,3for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CNJTFA/H20. 1 HNMR (300 MHz, CDCI3) 8 0.83 3H), 0.85 3H), 0.86 J=7.2 Hz, 3H), 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 1.09-1.39 (in, 8H), 1.44-1.59 (in, 4H), 1.88 (dd, J=15.0, 7.2 Hz, 1H), 2.00 J=15.0 Hz, 1H), 3.09 (in, 2H), 3.18 J=9.0O Hz, 2H), 3.27-3.38 3H), 3.65-3.95 (in, 2H), 4.05 J=10.0 Hz, 1H), 4.18 J=16.8 Hz, 1H), 4.30-4.45 (mn, 2H), 4.55 J=9.0 Hz, 2H), 6.70 J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DCIINH3) at m/e 501 %0 Anal calc'd for C30H48N204-1.05 TEA: C, 62.14; H, 7.97; N, 4.51.
16 Found: C, 62.19; H, 8.00; N, 4.43.
Example 516 trans, trans-2-(2.2.-Dimethyl-2-(1 .3-dioxolan-2-yl)ethyl)-4-(1 methoxy-1 .3-benzodioxol-5-yl)-1-(N.N-dibutylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3-( 1,3-dioxolan-2-yl)propanoate for ethyl 3methyl hexanoate and 6-methoxypiperonal for pipe ronal afforded the title compound as an amorphous solid by lyophylization with -4 54- CH3CN/TFA/H20. 1 H NMR (CDCl3, 300 MHz) 8 0.93 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 0.95 3H), 0.96 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (in, 4H), 1.93 (dd, J=15.9, 6.0 Hz, 1H), 2.13 J=15.9 Hz, 1H), 3.20 (dd, J=7.7, 7.7 Hz, 1H), 3.26-3.40 (in, 3.60 (in, 1H), 3.75-3.86 (in, 3H), 3.88 3H), 3.93-4.01 (in, 3H), 4.00-4.11 (in, 1H), 4.23 J=15.9 Hz, 1 4.37-4.48 (in, 2H), 4.49 1 5.94 2H), 6.51 J=2.1 Hz, 1H), 6.64 J=2.1 Hz, 1H). MS (DCI/NH3) at m/e 563 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.
Example 517 trans, trans-2-(2-(2- Met hoxyphenyl)-ethy)-4-(1 benzod I I-(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyitc acid Using the procedures described in Example 502, susiuigom ethoxyphenyi prop ionic acid for 3-methyihexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.91 J=7Hz, 3H), 1.10-1.27 (in, 4H), 1.42- 1.60 (mn, 4H), 1.72-1.89 (in, 1H), 1.91-2.02 (in, 1H), 2.55-2.77 (in, 2H), 2.94 J=6Hz, 1H), 3.05-330 (in, 6H), 3.59-3.82 (in, 3H), 3.73 J=l4Hz, 1H), 3.77 3H), 5.91 2H), 6.70 J=8Hz, 1H), 6.78-6.88 (mn, 3H),6.92 J=2Hz, 1 7.08-7.19 (mn, 2H). MS (DCI/NH3) 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.
Example 518 trans. trans-2-(2 .2-Diinethyl-3-(E)-pentenyl)-4-( 1 -methoxy-1 .3benzodioxol-5-yi)-1 N-dibutylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid Example 518A 4-M ethyl- 3-p2enten- 2-oI To a stirred solution of 3-methyl-2-butenal (8.7g, lO3mmol) in l00mL- of tetrahydrofuran under N2 at 0 "C was added -455methylmagnesium bromide (38mL of a I.OM solution in ethyl ether, 1 l4mmol) 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 of alcohol as a colorless oil.
Example 518B trans-Ethyl 3.3-di methyl pente noate 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 OC for 7 hours. The product was then distilled under normal pressure (200-220 00) to give 5.Og of crude ester as a colorless oil.
Example 5180 trans, trans-2-(2.2-Dimethyl-3-(E)-o2entenyl)-4-' 1-methoxy- 1.3- benzodioxol-5-yl)-1 .N-dibutylaminocarbonylmethyl)-D2yrrohidine-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 amorphous solid by lyophilization from dilute aqueous TFN/CH3CN. 1H NMR (CDCI3, 300 MHz) 5 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 0.97 3H), 0.99 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 J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 (in, 3H), 3.75 (in, 2H), 3.87 3H), 3.99 J=9 Hz, 2H), 4.11-4.30 (in, 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 2H), 6.50 J=1.8 Hz, 1H), 6.63 J=1.8 Hz, 1H). MVS (DCI/NH3) at m/e 531 Analysis calc'd for C30H46N\206-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.
-456- Example 519 trans. trans-2-(3-(2-p2yridyflethyl)-4-(1 dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic -acid Example 519A 3-(2-Pvridyl)-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was 1 0 placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mnL) 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 00. After the addition was completed, the mixture was held at 50 OC until the 1 5 color of the reaction mixture turned brown, then heated at 80 00 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 min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, Example 51 9B trans. trans-2-(3-(2-pyridyflethyl)-4-(1 .3-benzodioxol-5-ylb-1-(N
.N-
~di butyl am inoca rbonyl methyl)-pyrroli din e-3-carboxyl ic acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1HNMR (CDCI3, 300 MHz) 8 8.65 J=6.0 Hz, 1 8.06 J=6.91 Hz, 1 7.70 J=9.0 Hz, I1H), 7.51 J=6.91 Hz, 1 6.82- 6.66 (in, 3H), 5.91 2H), 4.45 2H), 4.29-4.18 (in, 1 4.04 (dd, J=20.1, 10.5 Hz, 1 3.84 J=12.6 Hz, 1 3.62 (dd, J=13.8, 9.6 Hz, 1H), 3.46-3.13 (in, 7H), 2.51 (broad s, 2H), 1.60-1.43 (in, 4H), 1.37-1.22 (in, 4H), 0.91 J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 Anal calcd for C29H39N305*1.75 TFA: 0, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81.
7- Example 520 (2S. 3Ri. 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 yb)-I N-dibutylaminocarbonylmethyl-pyrrolidine-3-carboxylic- acid Example 520A (2S. 3R. 4S)-Ethyl-2-(2-(2-oxor~yrrolidin-1 -yl)ethyb)-4-(1 .3benzodioxol-5-ylbpyrrolidin-e-3-carboxylate-(S)- Mandel ate 1 0 The racemic amino ester from Example 512 (3.45g, 8.98mmol) in l0mL- of ethyl acetate was treated with (+)-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 1 5 crystals was then collected by filtration, recrystalized from ethyl: acetate/hexane twice to give a yield of 800 mg of pure salt.
Example 520B: (2S. 3R. 4S)- Ethyl-2-(2-(2-oxo pyrroli din- 1 -yhethyl)-4-(1 .3benzodioxol-5-yb)-1-(N.N-dibutylaminocarbonylmethyl)-pyrrolidine-3- 0. carboxylate To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added N,N-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.5Gmmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.
Examole 5200 (2S, 3R, 4S)-2-(2-(2-oxopyrro lid in- 1 -ylbethyb)-4-(1 yb)-l1-(N .N-dibutylaminocarbonylmethyb-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with CH3CNITFA/H20., 1 HNMVR (0D013, 300 MHz) 8 0.91 J 7.5 Hz, 3H), -458- 0.94 J 7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (m 2.05 J 6.9 Hz, 2H), 2.12-2.25 (in, 1 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (in, 1 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J =9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1 3.66 J 6.9 Hz, 1 -3.96 (in, 2H), 4.14 (in, 1 4.38 (brs, 5.93 2H), 6.74 J 8.1 Hz, 1H), 6.89 (dd, J 1.8 Hz, 8.1 Hz, 6.87 J 1.8 Hz, 1H). MS (DCI/NH3) at m/e 516. Anal calcd for C28H-41N306.0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.
Example 521 (2S, 3R, 4 S)-2-(2-(2-oxopyrroIi din- 1-yflethyl)-4-(13benzodioxol-5-yl)-l1-(N-4-heptyl-N-(4-fluoro-3m ethyl ph enym))am inocarb onyl methyl)2y rro idine.3carboxyl ic acid Using the procedures described in Example 520, substituting N,N- 4 -heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N, Ndibutylbromoacetamide afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFAIH2O. 1H NMR (CDC13, 300 MHz) 8 0.85-0.98 (in, 6H), 1.22-1.55 (in, 8H), 2.04 (quintet, J=7.9 Hz, 4H), e' 2.32 3H), 2.36 J=7.9 Hz, 2.61 (in, 3.14 (in, 1H), 3.25-3.61 (in, 5H), 3.66-3.77 (in, 1 3.79-3.90 (in, 2H), 3.92-4.03 (in, 1 4.69*.
(quintet, J=6.8 Hz, 1 5.95 2H), 6.71 211), 6.78 1 6.93-7.13 (mn, 3H); MS (DCI/NH3) at mn/e 610 Anal calc'd for 2 C34H44N306F1.1.45 TEA: 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 -pyrazolybethyl)-4-(1 .3-benzo-dioxol-5-yl)-1- N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 522A 3-(1-Pyrazolyfl)-Dropionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 minol), acrylic acid (0.50 -459mL, 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.
Example 522B trans. trans-2-(2-(1 -pyrazolyl)ethyfl-4-(1 (N.N-dibutylaminocarbonylmethyfl-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 1HNMR (CDCI3, 300 MHz) 8 7.56 J=3.0 Hz, 1 7.50 J=3 Hz, 1 6.83-6.66 (in, 3H), 6.28 J=3 Hz, 1 5.91 2H), 4.55-3.98 (in, 6H), 3.83-3.72 J=10.5 Hz, 1H), 3.61-3.40 J=10.5 Hz, 1 3.36-3.12 (mn, 5H), 2.69-2.43 (in, 2H), 1.59-1.42 (in, 4H), 1.38-1.21 (in, 0.91 J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 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.
Example 523: trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 -r(Nbutyl-N-(3-hydroxypropyflainino~carbonylinethyll-pyrrolidine-3carboxylic acid% Example 523A N-Butyl-N-(3-hydroxyzpropyb)-ainine To a solution of 15.9g (100 minol) of methyl 3-N-(nbutyl)aminopropionate in 150 mL of diethyl ether at 0 *C was added mL (0.35 iniol) of 1 .OM LiAIH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 *0 for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 rnL 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 concentrated to 11.3 g of a light yellow oil.
-460- Example 523B N-Butyl-N-(3-hyd roxypropyfl-chloroacetam ide To an ice cooled solution of 1.31g (10.0 mmol) of N-butyl,N-(3hydroxypropyl)amine in 20 mL of ethyl acetate was added a solution of 1 .71g (10.0 mmol) of chloroacetic anhydride in l0mL- 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), 1 0 saturated NaHCO3 (aq) (2 x 50 mL), and brine (1 x 50 rnL), dried over 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 of a light yellow oil. Example 5230C trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y)-1 b uty I- N- Q -h y droxy pro py 1)a m ino) c arb on y Ime th y11 -p yr r o Iid ine 3 carboxylic acid Using the procedures described in Example I D, substituting N- butyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMS0 as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 H NMR (CD3OD, 300 MHz) 8 0.78-0.95 (in, 3H), 1.00-1.80 4H), 2.80-3.65 (mn, 15H), 3.80 J=1-5 Hz, 2H), 5.93 2H), 6.72- 7.05 (in, 5H), 7.33-7.40 (in, 2H). MS (DCI/NH3) at W/e 513 Anal calc'd for C28H-36N207*1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.2 1; N, 4.88.
Example 524 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-1 -r(N- Dropv-N-Drooxvaiino)carbonylmethyll-pyrrolidine-3-carboxvlic acid -461- Example 524A N-Boc-0-allylhyd roxylamine O-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0°C in an ice bath.
Diisopropylethylamine (8mL) and di-t-butyldicarbonate (10.0g) were added. The mixture was stirred at 0°C for 1 hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo and 1 o the residue taken up in EtOAc (25 mL), and washed with water (1 x 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 0 with sodium sulfate and evaporated to give a light yellow oil which was used without any further purification. Example 524B N-Boc-N-propyl-O-allylhydroxylamine N-Boc-O-allylhydroxylamine (6.5g) from the above procedure 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 5 min. The resulting mixture was stirred for 30 min at 0°C. 1-lodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 0°C 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), 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, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil -462- 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 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 1 o which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the title compound as a colorless oil Example 524D N-Propyl-N-propoxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCl/dioxane (10mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl i:.
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°C. Pyridine (0.2 mL) was added.
Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -200C 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.
-463- Example 524F trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yfl)-1-[(Nbutyl-N-(3-hyd roxylropylhamino)carbonylmethyll-pyrrolidine-3carboxylic acid Prepared according to the procedure of Example 5230, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 1,3- benz od ioxoI- 5-yl)-pyrrol id ine-3-carboxyl ate. The crude product was purified by preparative HPLC (Vydac m018) eluting with a 10-70% 1 0 gradient of CH3CN in 0.1% TEA. The appropriate fraction was lyophilized to give the product as a white solid. 1HNMVR (CDCI3, 300 MHz) 8 0.87 (in, 6H, J=8Hz), 1.49 (in, 2H, J=8Hz), 1.61 (mn, 2H, J=8Hz), 3.55 (in, 6H), 3.80 (in, 2H), 3.81 3H), 4.00 (mn, 2H), 4.13 2H, J=l7Hz), 5.96 2H), 6.77 1H, J=9Hz), 6.90 (in, 3H), 7.05 1H, J=lHz), 7.44 2H, J=9Hz). MS (DCI/NH3) m/e 499 Anal calcd for 027H34N207 1.20 TFA: 0, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55.
ExamDle 525 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yI -1 butyl-N-propoxyamino)carbonylmethyll-pyrrolidine-3--carboxylic acid Example 525A N-butyl-N-(2-hydroxyethyl)-amine In a thick walled glass tube 5 ml (100 inmol) of ethylene oxide was condensed at -78*C. To thisl12.5 ml (120 inmol) of butylamine was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50.0 for 18 hours. Unreacted reagents were removed by evaporation to give the title compound.
-464- Example 525B 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 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 1 0 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 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 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 30% ethyl acetate: hexanes, to give 161 mg of an oil.
Example 5250 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(N- butyl-N-(2-aminoethyl)amino)carbonylmethyll-pyrrolidine-3- carboxylic acid According to the procedure of Example 523C, N-butyl-N-(2azidoethyl)-chloroacetamide 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 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 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 H3P04 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To 100 mg (0.10 -465mmol) of the azide was added 1mL of 1M HCl(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 its TFA salt. 1H NMR (CD30D, 300 MHz) 8 0.92 J=7.0 Hz, 3H), 0.96 rotamer), 1.23 2H), 1.41 2H), 3.06 4H), 3.39 2H), 3.69 2H), 3.84 (s, 3H), 3.94 3H), 4.18 2H), 5.05 (bd, J=10.7 Hz, 1H), 5.98 2H), 6.84 J=7.7 Hz, 1H), 6.93 (dd, J=1.8, 8.1 Hz, 1H), 7.05 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.
S**
Example 526 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-r(N- butyl-N-(3-aminopropyl)amino)carbonylmethyll-pyrrolidine-3- carboxylic acid 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 and extracted once with 5mL of water to which had been added 1 drop of 85% H3P04, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x 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 at 50 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 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 H3P04 and extracted with EtOAc. The latter -466organic extract was washed with brine and dried over Na2SO4. To this azide was added 1mL of 1M HCl(aq.), 0.5 mL of dioxane, and 5 mg of 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 s via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1H NMR (D6-DMSO, 300 MHz) 8 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 2H), 1.30 2H), 1.67 2H), 2.71 2H), 3.04 1H), 3.21 3H), 3.45 1H), 3.75 3H), 3.97 3H), 3.85-4.80 (broad m, 3H), 6.03 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1H), 6.92 J=7.8 Hz, 1H), 7.01 2H), 7.16 1H), 7.55 2H), 7.72 2H), 7.85 1H); MS (DCI/NH3) 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.
Example 527 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(Nbutvl-N-(3-dimethylaminoDropyl)amino)carbonvlmethyl]-pyrrolidine- 3-carboxylic acid Example 527A N-butyl-N-(3-bromopropyl)bromoacetamide.:* 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. H2S04. The reaction s 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 solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x 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 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 -467purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1 .47g of a colorless oil.
Example 527B Ethyl trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yt)-1 f(N-butyl-N-(3-bromopropyflamincricarbonylmethyll-pyrrolidine-3carboxylate According to the procedure of Example 5230, N-butyl-N-(3- 1 0 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 hexanes to elute.
Example 5270C trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1-r(Nb utyI- N im e th yIa m in o pro py1)a m i no) ca rb on yIm eth y11- p yrroIi d in e 3-carboxylic acid 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 THE. The reaction was heated at 50 *C for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was PAO purified via silica gel chromatography, eluting with 9:1 CH2012: 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 vacuc and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) 8 0.92 J=7.0 Hz, 3H), 1.22 (in, 1.39 (in, 1.90 (in, 2H), 2.87 3.07 (in, 4H), 3.24 (in, 1 3.43 (in, I1H), 3.62 (mn, 1 3.84 3.88 (in, 3H), 4.07 (in, 4.17 (in, 4.97 (in, 5.97 (s, 2H), 6.83 J=8.1 Hz, 1H), 6.93 (dd, J=1.7, 8.1 Hz, 7.05 (mn, 3H), 7.53 (in, MIS (DCI/NH3) at in/e 540 Anal calcd for -468- C30H41 N306-2.95 TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.
Example 528 trans. trans-2-(4-Methoxyphenyl)-4-(1 butyl-N Q-tri methyl am Mon iopropyl) am ino)carbonyl methyl]pyrrolidine-3-carboxylic acid.
Prepared according to the procedures of Example 5270, 1 0 substituting aqueous Me3N for Me2NH. 1 NMR (CD3OD, 300 MHz) 5 0.91 (in, 3H), 1.24 (in, 2H), 1.40 (in, 2H), 1.99 (in, 3.13 9H), 3.18 rotamer), 3.20 (mn, 3H), 3.39 (in, 4H), 3.72 (in, 1 3.84 3H), 4.03 (in, 3H), 4.35 (in, 1 5.19 (in, 1 5.97 2H), 6.84 J=8.1 Hz, 1 6.96 (dd, J=1.7, 7.9 Hz, 1 7.10 (in, 3H), 7.62 (in, 2H). MS (DCI/NH3) at m/e 554 Anal calod for C31 H44N30601 H20-1.65 TFA: 0, 47.25.
H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.
Examlle 529 trans. trans-2-(4-Methoxyphenyb-4-(1 .3-benzodioxol-5-yfl)-1-f(Nbutyl-N-( 4 -aminobutyl)amino)carboymethyll.Dyrrolidine.3.
carboxylic acid Example 529A N-butyl-N-14-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 a solution of 3.18 gm (20 inmol) of the resultant N-butyl -4hydroxybutyrainide in 50 ml of toluene were added 120 ml (120 inmol) 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 saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried aver Na2SO4.
-469- Example 529B 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) chioroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at 0*C, and then was allowed to warm to room temperature.
1 0 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 5290 1 5 Ethyl trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl)-1- [(N-butyl-N-(4-hydroxybutyflamino)carbonylmethyll-12yrrolidine-3carboxylate According to the procedure of Example 5230, N-butyl-N-(4hydroxybutyl-chloroacetamide was coupled with ethyl Methoxyphenyl)-4-(1 benzo di oxol -5-yl)-pyrroli d ine- 3-ca rboxyl ate.: The crude product was chromatographed on silica gel.
Examle 5 29D Ethyl trans. trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yl)-1 f(N-butyl-N-(4-bromobutyl)amino~carbonylmethyl]-pyrrolidine-3carboxylate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 5290 in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of Plr3 was added. The reaction mixture was allowed to stir at 0.0 for 2 hours and was slowly warmed 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.
-470- Example 529E trans. trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(Nbutyl-N-(4-aminobutyl)amino)carbonylmethyl1-pyrrolidine-3carboxylic acid To a solution of 0.135 gm (0.21 mmol) of the compound of 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 added, the nitrogen from the reaction flask was evacuated and was S flushed with hydrogen by placing a balloon filled with hydrogen.
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 was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1 H NMR (CD30D, 300 MHz) 8 0.90 J=7 Hz, 3H), 1.10-1.65 6H), 2.85-2.95 2H), 3.00- 4.10 14H), 5.50 J=3 Hz, 2H), 5.97 2H), 6.82 J=8 Hz, 1H), 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 3H), 7.45-7.55 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 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-[(Nbutyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl1-pyrrolidine-3carboxylic acid The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1 H NMR (CD30D, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 8H), 2.75 J=7 Hz, 6H), 4.25 16H), 5.97 2H), 6.83 J=8 Hz, 1H), 6.93 (dd, J=8 Hz, 1H), 7.02-7.08 3H), 7.49-7.56 2H). MS (DCI/NH3) at m/e 554 (M+H) -471- Anal calc'd for C31 H43N306-2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.
Examlle 531 trans, trans-2-(4-Methoxyp~henfl)-4-(1 .3-benzodioxoL-5-yl)-1 -r(Nbutyl-N-(3-pyridybamino)carbonylmethyll-pyrrol idine-3-carboxyl ic acid Example 531 A N -butyl-N -(3-p2yridyl)-a m ine To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL I of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the.
is 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 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 of a colorless solid. Exam~le 531 B trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y)-1 p butyl-N-(3-pyridyflamino~carbonylmethyll-pyrrolidine-3-carboxylic acid The compound of Example 531A was reacted according to the procedures of Example 523, to give the title compound. 1 H NMR (D6- DMS0, 300 MHz) 5 0.80 J=6.4 Hz, 3H), 1.15-1.99 (in, 4H), 2.59 (mn, 1H), 3.05 (in, 211), 3.26 (mn, 2H), 3.49 (in, 2H), 3.56 J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 2H), 6.80 (in, 3H), 6.85 (d J=8.1 Hz, 1 6.98 (mn, 2H), 7.04 (in, 1 7.41 (dd, J=1, 4.7 Hz, 8.1 7.58 (mn, 1 8.36 (bs, 1 8.54 (bs, 1 12.24 (bs, 1 MS (DCI/NH3) at m/e 532 Anal calcd -472for C30H33N306-0.1 H3P04: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.
Example 532 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)- butvl-N-( 3 -aminomethylDhenyl)amino)carbonvlmethvl]-Dyrrolidine-3carboxvlic acid Example 532A N-butyl-N-(3-hydroxymethylphenyl)-amine To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 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 18 hours (ovemight). Reaction was worked up by adding 250 ml water i 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-hydroxymethylphenyl)-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 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 H3P04, water, and brine.
-473- Example 5320 Ethyl trans, trans-2-(4-Methoxyo~henyfl-4-(1 .3-benzodioxol-5-yfl-i r(N-butyI-N-(3-chloromethylphenyl)amino~carbonyl methynl- 12yrrol idi ne-3-carbgxyl ate According to the procedure of Example 5230, N-butyl-N-(3hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4- Methoxyp henyl)-4- (1,~3-benzod ioxol -5-yl)-py rrol id in e-3- carboxyl ate.
The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 000; 19 mg of LiCI was added, followed by 85 p.1 of thionyl chloride.
The mixture was allowed to stir for 30 min;.water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.
Example 532D trans. -trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-y)-1 -r(Nbutyl-N-(3-aminomethylphenyl) aminocarbonyl methy1yrro line.3.
carboxylic acid The compound of Example 5320 (182 mg) was dissolved in 1 mL of DMVF. Two drops of water were added, followed by 126 mg (2.0 mmol, *.0 eq) of sodium azide. The resultant solution was heated at 115 OC for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.
Example 532E trans. trans- Metho xyp he nyfl-4- 1.3-benzodi oxol-5-Yl) -1 (Nbutyl- N-(3-ami nom ethyl phenyfl)ami no)carbonyl methyll-pyrrolid ine.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 00C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The -474mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI The aqueous extract was 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 with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1H NMR (CD30D, 300 MHz) 8 0.88 J=7 Hz, 3H), 1.15-1.45 4H), 3.40-4.20 14H), 5.97 2H), 6.82 J=8 Hz, 1H), 6.88 (dd, J=8 Hz, 1H), 6.97-7.20 5H), 7.40 J=9 Hz, 2H), 7.56 J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 (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.
Example 533 trans, trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl)-1 butvl-N-(3-trimethylammoniomethylphenyl)aminokcarbonylmethyllpyrrolidine-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 temperature under nitrogen atmosphere for 4 hours. 1N 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 J=7 Hz, 3H), 1.15-1.40 4H), 2.62 2H), 3.35 (s, 9H), 3.40-3.80 10H), 4.47 2H), 6.00 J=3 Hz, 2H), 6.75-6.90 (m, 3H), 7.25-7.37 2H), 7.45-7.60 3H). MS (DCI/NH3) at m/e 602
(M+H)
-475- Example 534 (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)1- 2 -(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid Example 534A 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 heated to 90 OC, and a solution of 25 g of 3-fluoro-4- Smethoxyacetophenone 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 is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product is dried over Na2SO4 and decolorized with charcoal to give 34.5 g of the title compound. e* Example 534B Ethyl 2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-** pyrrolidine-3-carboxylate The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 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 HCI. 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 -476concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2C12. 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 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 of a 2:1 mixture of trans-trans and cis-trans isomers. Example 534C Ethyl 2 R.3R.4S)-2-(3-Fluoro-4-methoxyDhenyl)-4-(1.3-benzodioxol- 5-yl)-pyrrolidine-3-carboxylate 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 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 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 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, ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl -477acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-168 0 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 52 0
C.
After concentrating in vacuo, the residue was combined with toluene 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 1 o acetate to get 6.9 g of the resolved amino ester.
Example 534D I Ethyl (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol- 1 (N-propylamino)ethyl)-pyrrolidine-3-carboxylate The compound of Example 534C was dissolved in 1,2dibromoethane 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 100 0 C for 1 hour. Toluene was added, and the mixture was 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- 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 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 desired product (86-93% yield), which was used for the next step without further purification.
-478- Example 534E 1-Pentanesulfonyl chloride 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 °C for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOC12. The residue is partitioned between CH2CI2 and ice water; the 1 o organic layer is dried over Na2SO4 The crude product is purified by distillation (bp 54-56 OC 0.5 mm Hg) to give a clear oil, 61% yield. Example 534F (2R. 3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-( 1.3-benzodioxol-5-yl) 1 (2-(N-propyl-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,Ndiisopropylethylamine 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 H3P04, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexane to give 220 mg of product 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 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 -479white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.
Example 534H 2F?.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4.(1 3-benz7odioxol-5-yfl 1- (2-(N-propyl-N-pentanesulfonylamino~ethvl)-pyrrolidine.3.carboxylic acid, hvdrochloride salt The free amine is 1 0 iPrOH is added, and the added, and the solution material is stirred with is collected by filtration dissolved in iPrOH; a slight excess of HCl in solution is concentrated in vacuo. More IPA is is reconcentrated. The resultant sticky ether overnight to give a white powder, which and dried overnight in vacuo at 60 OC. Yield Example 535 The compounds in Table 30 may be prepared using methods presented in the above Examples.
480 Table 3C.
HON_< N *siCOOH 0 *"ziCOOH 0
C
0 0-i 3 0..:ICOOH 00 0
-J
6
NI..H
00 0 N
."'COCH
0 0 0-J
N
0 0-i 11 12
."ICOOH
00 0
H
2 N .':COOH -0 0 0 iJ 481 16 N N
ICOOH
00 0 19 *l .':COOH 0C 0
CH
3 0- 22 02 N "COOH 0
CM
3 0 ""C0OH 0 c Fb i 18 0 0 0 00 CR0 0 "COCH "iCO10H 0 0
I
0 0
CR
3 b O~ CR 3 n~
N.
","COOH
00 26 27
H
2 W N 'C -NOO N 'tCOOH 00 0 0 C3 0 C6 0 29 482
"-,COOH
00 31
*-.COOH
0 0 34
-,'COOI-
00 37 32
H
2 N{ N 'C0 0C I o.
400 rN 44 483
."COOH
0 0-i 47 .nCOOH -0-i 48
*'IICOOH
0 51 54
*'COOH
0-J 57 a ,ICO 0a C14 3 0
C
C.
52 II IIC00H 0 0 0-I 56
N
0 N-<,N"'COOH a-i 59 0 H00011-
N
r 0 o- H 0 H0001- 0.kNJ~ 0 0.0 1 0 H003ii- 0~k~J H000iw. 0 99 HOOD- 0* H 000w1. 0~1~ 09 HO 0
C..
N
11 1-
HO
0 H003i- 0 vt 485 N ."COOH Ha i .COOH O 1IN*
-COOH
76 77 780 0 -COO .COOH
.,COQH
0 0 0 79 80 81 -'lCO0H lN "COOH N~lC0 0 0 0 CO 82 83 84 0
IN~T
0 *'COH "'.ICOOH *"'iC00H 0 0 86 87 H2 I'r N* N 0 0O .iC00H
.ICOOH
0 0 0 0 88 89 so L t"o L
S
**0e
S.
S S
SS
S S S. S S
S.
S
S
*S S. 95 a S
S
*5 S 5* *5 0 CH 0 HOOi.-
N
66 0 96 0 00 N..JkN-J 0 C0 L 0 00 t 0 HOOO"* N Nl 4 f- 0 H003-. 0~k~N 96 0 0 HOO31- 0 fK_ 0 H0001'- 1.6 0b 99V 0 SL1.
0 OO0
ICHO
N~
N,
9LL sec...
to..: o..
00.
00*0 0 eq fr
CH
0 HOOOis' 0~k J~ ft.
0 H
L
OLL
0 HO 0 0 0 0~N 0c H H000ii- 0 Nuh 0 L3v 488 0 125 126 0 0 V* o.
0 .0:0 0 127 128 N
N
.'ICOOH+
130 i 129 ,0 132 Y N '.iCOOH 0 c 0 0-J
-N+
I 0 .mjCOOH 00 0 -i o OCHO H 0, 0 II
II,..
0 HOOO'** NU 0 0 0 0 N1 0 HOOOil N
Q"
1-0 0 HOOOi"* lb..
f-0~ H00:.
NI-AN9
ZL
0 0 HOOOt- 0 0 HOO'l* *0 N
ZH
r_ 0 HOO"" 0 9E L 0 HOO"", 0 N"'kN0.
68V' 490 151 0 ,CO 00
CR
3 0o 0-' 154 I COCH 0 0 157 H2 N -N N .,COOH 0C 0 C 3 152
""ICOCH
~~0 155 0 t 0 157
H
2
COOH
0 0
OH
3 n 153
*"ICOOH
0 0 CR36 156 N K~ ff~ 0 CR3 n- 159
NN
I I .iiCOOH ~-0 0 CR3 160 161 .1COOH 00 163 F N ICOOH
H,
0 164 -165 491 169 170 COH I o "ICOOH 0 0 173 174
H
2 "I(COOH T 0 0 0O c 176 177 O'N--IrN ICOH N *.ICOOH 0 0 179 180 S S 175
HN~
178 96L t16 L HOOOi- HOOD- 0 0 0 r
H
0 HOOOi. 0 0 68 L 0) 0 0 H00On'-- 0 K'~l-
K_
0 HOOO"'* 0 t "'0 f- 0 0 06 L 0 HOOa. N )1 N N, 0 H0O311- N
ZH
0
C'
0 HOOD- 0 Ko 0 H0O'. 0 Z6tV 0 LZ 60Z 0 9oZ 0 H00s.. 0 00 0 HOO011--
N&,
a.
0 00 0 H0.. 0
NN
~Loz ooz 0 H000'. N 0JI~Q~ 66 L H000t- 0 96 L H00i- N 0 0y 0 H000ij.. 0~k~
N~-
E6t7 HOoOD- 0 0 0 H-400il-..
fill.
a. a a 62L 0 H-4000"- 0 ~0 0 0 /itOa.. N"Jtj1-NH t'L 0 HOQO"" NN L2 0 0 H00is- 0 0, 92L
SL
0 0 t76V 495 226 227 228 229 232
N-
235 cI- 238 230 233 0 H0~Ny
"COOH
0C 0 H13 234
.COOH
0 0 237 H
H
2 N~N
N
00 240 040 236
COOH
0 0 CH3 239 0 0 H000i. 0 0 H 0 o9z a a a a a. a a a a.
a.
6t'Z 8t'z Lt,~ 0- 0 CHO 0 1- Hoools.. 0 O0i.
4N_. HOO3k. N" o N b.
ro Ho 0 HOli NkNI3J 0
HODOI..--
96t7 497 256 yN~ 259 0 262 258 260 261 263 264 265 266 267 I *.:iCOOH 0 0 o-J 268 28269 270
I
OR~
S
*5
S
S
S
*55* 55 S S 55 Se
L
0 HOO~oa.. 0 N 0 N"kNI~KN 0~c 26V~ 499 283 285 0 0 288 Cu 3 b 0-i 286
C.
289 4 293 *9
U
U.
U
a U. U U a
U.
U a 292 4 2 F N
N'
-r L 0 295 25296 297 0L 0 806 0OLE a 0@ *0 SS S a.
a o E* 0 r- 00 HOQOt'.- 0~k~.N~ 906
LOS
SOS
'N Jo,,
ZH
L-
6*00 Gs. OS
HOOO:'*
0 0oS 66Z HOOO,, 00
NZ
86Z: 0 HoooY' 0 oos 501
OCH
H
2 t< N *ecool 0 0 1 313 3
H
3 OCHb I 't*.COOH 00 315
OCH
3
H
2 N N
-ICOCH
318
NN
TtN J~iN *..uCOOH 0 0-J 319
CH:
Y-"YI .'ICOOH 0 0
"COOH
0
OH
3 OH OCH 3 02N N N 'COOH 0 C O 0 0
OH
3 0~ 0K
OH
3 N<N -"CO0H 0 0
OH
3 0- 502 326 327 0H 3
H
2 N~ 0 -NN *'COOH 0
CH
3
O
CH
3 0
OH
3 i
I
N
-"COOH
00 Ctt0 0-i 329 330
CH
00 331 z'
CH
3 H2NCNQN 0
CH
3 0 0-i 333 332 334 335 336
OCH:
H0~~-N <N .tiCOOH 00
OH
3 N -ICOOH 0 338
OH
3
H
2 gN
-COO
0 339 I 503 340 341 C O H~ ,NN *C O O H 0
CH
3 CH 3 r -COOH H 2 N N *",COOH O 0 -rN usICOOH 0 349 -in0 POCH 3 0 0 0
N-OJ
350 qOCH 3 0
H
2 'iN.1COOH 0 0
-J
353 0IIOCH 3 -N~NrN
COOH
0 -i ~bCH: 0
,I"COIOH
0
'CO
351 0 H2N~N~ L *."COOH 0- 354
QCH
0
H
2 W' N
COOH
0 r H IO~~ 0 69C o C HO H0Oio 0 896 L96 0 HOOOi-
N
oi JN' 99C 99c f-0 0 I ~HOO0- 0 JNllN
CHO
096 696 0 Nl CHOO
QI'
0 HOOOi-' 0~J CHO 06 0
HOOD,-
CHO 6 9sf: tos 505 370 372 0 0 ""1COOH CH3O 0 373 0 00 374 -0POCH 3
IYOCH
3 0 "iCOOH
H
0 376OH qOCH 3 Nfl-- "COOH 0 0 379 0 0 382
QOCH
3 0 0
CH
3 1 2 N NrN ,C00H CH-3 0 380
CH
3 0 0 383
.*"COOH
I0 $'CH2
OH'
3 0 378 P-bCH 3 0 H0~N~~...ICOOH 0 381
LPOCH
0
H
2
"COOH
384
OCH
3 0 0
O
0 66C 0
HOODY"
0 0 96C 0 0 N L6C
K-
96C 0
HOO"
0 N 0 HOO 0.
bH00KN 0 HO0- H00,' o r222 0 H-4000'" Oo 062 aool 0 N H0 H003"' N~JJ ROU ':HO 0 0 99C 926 909 507 400 Qo 0 C O
O
0 0-i 403 406
.*"COOH
0
CC
404 7Qo\ Fj2W-,- N N "'COOH 0 0-i 407 0 0 C 410 K2 N' Njf'
-*ICOOH
00 0140
N!
0 0-i 408 .o 402 0 C-i 409 412 42413 414 508 7 \OO 0 417 415 NN 0 00 418
"'ICOOH
0 0 419 420 422
CH
3 423
S
421 I QM\Q 0 0 *'IC O O
H
7 0 424 0 425 N *--iCOOH 0 0 426 509 427 00 0 430 428 Qo
-PCOOH
0 H1 2 432 433 434 7Qo\ >if~f.N "COOH 00 438 436 0
".ICOOH
00 0 439
Q
N
'COOH
0 440 441 510 Qo
,COOH
0"C 0 0
-J
442 Qo 0 445
NICO
00 00 -o- 443
.COOH
0 0-J 446
H
2 N
COOH
0* 444 0 447 0*
S
0
S
S. S 0 **SO*s 449 450 H~r<~y0 452
N.
453 451 Qo 00 0
CH-
3
A
511
"COOH
0
O
CH3 0 457 456 H2 R l ,N Y N
"COOH
00
CH
3 459 ci- 462
CNO
N..COOH
0
C
0
CH
3 6 464 0 00 0 0~ 00 OS 006*
S
0006 0~ 0909 0 0~00 S 0 004605 0 00 5 0 0 0* 00 0 0 00 0 .9 0 6 09 0 0006 0000 9 .00.0* 463 465 466 46467 468 512 469 $riIIICirO 0 470 00 0 473 0 471 N0 474 472 0
)H
475 477
III
479 480 513 481 48448 483
.COOH
0
C
0 0-i 486 485 487 N04OOH 0 -a-i 490 00 0
CN
.'iCOOH 0 494
"C
489 492 493 495 OLS 609 909 0 0 r 0 0 i H001* -HOO"
_N)
LOS 909 909 HO r HO CHO HO 0 CHO.~~j~M N 0 0 HODOI' HOD01-HOOD 0 cl0 0 3 ,N~N O" CHOO" 070 COcgHO CHO0OI'O 0 0 o -0 o0 teH0 LOS 009 N~ JI~ HOO~ip* N HOOD- A 0 0 0 0 COLOS CH 09ro- H 66t, HOOD~ N 0 H0EH0 i- 0 H00311.. 0 N N -_o0 6tN LN 96 86V L6t, 96t7 V s 515 rN a N'r N
-COOH
-0
CH
3 511 N
"'COCH
00
CH
3 513 512Z
COOH
515 514 516 oL 518 519
NN
IN T-N -COOH 0 516 523 524 525 rN- 0 0 N "IOO H 2 iI.OO "'OO
-I*ICOOH
00 526 527 528 00 0
N
N r N C O -,Ntr -COOH H O N N -aOOOH 00 0 529 O 530 O 5310- 0 0 rz H2 *.C0H 0I *sCOQH 00 0 532 01 533 01 534 N4Ny 0 N40 N4 0 .tCO0H .',ICOOH *.-COoH 0 0 0 0 i 0-i 535 536 537 517 539 o 0 4 00 0 0
H
2 N 1 N "CQOH 0
'-J
542 543 544 545 0 4 0
CH
3 0 548 547 0--c00 0 4 0
OH
3 0 550 549 N 0
COOH
551 552 518 553 554 555 0 0_r N "iOO 0 N4 0 a N'rN~.
OH
N0 0,OO N 4
O
0 0 0 0 N0 F* 0 00
N
4 N 4 ozr .1 .aCOOHr H2NN >r-N H2N_ N -N _IOH0 .iCOOH *'COOH 0 562 563 564 565 55566 567 519 568 569 570
N~N
0 0 N C O
H
2 N V f l X
.:COOH
0 0 06 N4 N 0 0 4 N Co 0 0 0 574 575 576 00 0 ""OOH H-l~ *'COOH -K IC00H 578 579 069 699 9* .9 9* *9 9 999* 9 .9 99 9 9 9 9 *9*9 *9 9 9 0* 99 999 L9
I
cgs 099 I. 89 0zs 609 Z09 4 4. .4 009 1.09 869 969 L69 969 t,69 369 Lzs 522 4 605 607 610 611 609 612 9 9 9 614 615 069 LZ9 0 0N 0 100,w 06 N K _9 0 HOO3i'- 0 6L9 0 HROQOi..
LZ9 OZ9 0 0 OOI, 0Nk C E s 524 N 0
-COOH
0
CH
3 0 632 631 N 0 H0-N. COO N 634 113 "ICOOH 0C 0 01143 637 H2N 0 ~r 0 iZCOOH 0
CH
3 0- 640
-"COOH
0
OH
3 N>0 0 C H1 3 633 0 "C00H 0
OH
3 0 636 0 .9COOH 0
CH
3 0 635 N 0
."COOH
638 Nr~ 0 "'1COOH 0
CF*
641 4 C. C.
C
0
C
4C C C
C.
C
H
2 N NNN **ICOIOH 0 0 645 099 699 a. L99 HOOOi..* V29 L 9 0 H00010- 0~N~N~ 0N 0 6179 0 0 0 H000i- 0
N,
0
C
LtV9 0 0 GE9 ZL9 699 999 999 L99 t,99 L.99 f-0 E99 0 H 00to' I N 0 -4 p U99 WS9 527 N'o N, a,
,COOH
00 0-i 673 d.OO 0 0
H
2 N N.
675 676 677 680 679 N 0~ 00 682 678 HNN~~N <N "COOH 00 681
"'COOH
0 684 2 cc~Nt
'COOH
00 683 969 Z69 69
CHO
N
L89 989 989 I HO 8 s 529 0 697 H2
-CO
00 700 00 0 698 701 699 a. a a a a a a. a 703 TUN J~0
"'COOH
0 706 704 707 708
OUL
0
/.LLL
6 LL 9 LL
SUL
S
S
S
S S
SU
V LL
ELL
ZLL
N~N~
LLL OLL K 0 0 OES
OCL
'HON~
a. a.
a. a a a 8ZL 9ZL t~~L L ~L ZZL Es 617L
S
S
S. S Ot"L 6SL
LEL
9SL
OO"HO
0 0 0N HS 533 745 S0
NK~
0
-'COOH
0 746 747
H
2 IN N -oL 750 751 9* 752 753 755 756 534 N
"I
0 a-I 758
*"COOH
0 0-OI I "COOH 0 0 760 S. S
S
9*
S
SS
S. Se
S
S S
S
S
5 C 55 5* S S S S 763
-C
766 0
*"'COOH
C0-i 765 F~T~0 *"CaaH
CH
3 5H5 772 770 00 __0 773 I 6 'iCOOH 00 776 Q, 0 COOH 0
CH
3 0_ 779 a: 1
N
0 0 "iC0H 00 0H 3 0 775 0 cH 3 0 778 Oe
S.
S
S. OS
S
.55.
S
S S S* 55
S
0 *500S.
S S
S.
S S S* S S S *5 5 .555
S
0
SOSS..
780 782 783 536 0 0 784 N2;
COOH
0 H 2, rN f ."CO O 0 786 ~~NgN
COO
789 788' 788 787 Olo
N~
sCOOH 0,O 790 0
S.
S
S
0
S
555000 Sc @0 S S S
SO
S.
S
00 0 O 0 0 793 794 795 537 800 0 .'aCOOH 0 0-i 803 798 N 0 0 "C00H 0 C-i 801 N 0
"COOH
00 0i 804 802 806 807 538 809
H
2 N N 810 808 815 813 0 .ICOIOH 0 816 C
C
814 N 0 -0
OH
3 0- 817 818 819 K~8 10C0 o~KNkf7j9 I. ;8 939 SU9 Wo,
NZH
Ll HOOD,,-- I~ 0
N
oze 6CS 540 832 833 po COOH 0 "COOH 0 0 835 836 837 N N.N COOH K~0 0 838 N0 0 00 839 N 0 N .'iCOOH 0 0 0-i
H
2
K-
0 840 .e 842 843 541 844 N 0 1 1 0 N
*.COOH
0 845
'COOH
0 0-i 848 N 0
H
2 ~N **'COIOH 0 0-i 846N 0 ""1COCH 00 849 847 N6 0 0 850
S
S. *5
S
S
852 o-T
H
2 853 83854 855 L98 L98 ~99899 999 C.
C
C. t"98 C98 00 098 1.98 egg Z99 698 998 LSS 0', ,f::b vs 543 868 869 870 871
HON
874 872 873 H2--Ny"<> oL 876 S.
S
S*
S
875 877 87887 879 069 a L89 0 68 0 HOOOii-..
0 99 000"..
IN
09 999 o 0
N
H003-. 0
U
0,
N
tvs 545 892
H
2 ,COOH 00 0 IC
I
0-i 895 0
",COIOH
893 0 -'C0OH 0 896 894 898 897 "*0
H
2 NN "'C00H a-i 900 CH0 a-i 903 3 903
"..COOH
0
C
904 94905 906 0 H000ia.. 0 0 0
~N
QOW
0 0 )A-0 LL6 6L6 0 HOO0in. 0 00 N0 9NL a a a a. a a.
a a a a a. a a a a. a U 6 246 0
HOOO"*-
0- N 606 QL6 906L6 /06 9ts 'N
ZH
S. S
SS
K 0 0 1. N LS6 966 S
S.
S S
S
S. S S S 8Z6 H0Oi- 0 o0QIN CZ6 HOOOi'** N 0JL 0 S N L17s 548
S
00 0 940
N-
0 943
'NN
00 946 0 '0 0 0 0-i 938 ~0 0 0 11-
J
941
)NN~~IIN
0 'COOH -0 939 0-1 I~ .fl 'N
COOH
00 0-i 942 N 0 H2 N
*.'COOH
0 0-i 945 S S S S *5 *S
S
.5.5
S
S. 944 I 947
COOH
0
CH
3 950 <>0
H
2 0
-'COOH
0
CH
3 I 951 949 t,96
S
S S
S
5.
S
S
S S Z96 0 H00011- 0 01, 696 L96 99?6
N
996 996 0<N C96 0 01 0 6t79 550
-"COQH
00 968 0 *.uCOOH .O0 967 N ,I ICOOH 0 970
NA
0 N nICOOH 00 973 N
',ICOOH
0 0 976 HcK~~~~N COOH 0 0 0- 979 972 0 974 975
"OOOH
0 0 0-i 977 00 0 0 -1 0 978
\N'
0,
F"COOH
00 0 9810- 980 I"66 HCHOl- 0
N
L 66 a. a a. a a.
r R 0 06 R00 N 0
N
066 1 0 H -0011-6 1000i'..
0 Z66 0
R
0 0
N
626 0 986 886 986 Z86 LSS 552 I0 997 iCOOH 0l~ 0o 0 -uCO'OH 0 998CH 6 *.COOH 0
CH
3 e
C
553 1000 N
-*--COOH
1003
N
0
-COOH
CH
3 ."oo 1006
\N-
0 -COOH 0 1009 H2N~<N "COCH 1012 ."'COO H 0 0 1015 1001 NIrQ
~N
1 J' r'w *C0O1H 1004
V-'COOH
0"0 1007 1002 1005 N0 0 1008 **"CO0H 00 1011
N
0 c 1 -iO 1014 0*
S.
S
5O SS 0 0*S S9 1010 1013 ha I ""COCH- 0 II **COOH 0 0 1016 1017 ZCQL LCOLI 0
N
0
S
0 *000
S*
S S 6* S S S. S
S
SO
S.
S
0
OS..
5 0505 OS 55 S 0
S
S
SOSO
00 55 5 0 0 65 0
OO
OS
SUO L.
0 H0001-
KN
060 L 00 0
N-N
t'ZO L H000i- 0
C)O
9zO L r 0 0 HO3a. 0HOOO-
NN
sO L H oi- N 0 H H000t suo L ZzO L 6 LO L H000it.
N
0~t VS9 LtO L 0
NCI
t7OO 9170 L O0" 0 elvo L r-OV CH 0 0 t
HO-
NN
6Evo L 9 9 9 9* 99 0 HOOO"*- 0 CR0l L -H
I
NO~s.
oto L
NN
960 L LSO I 9so L t"~O L 660 L H0Oit.. 0 -HOOOi.* N NJ& N '0 '0 sss L L90L 0 690 L.
0 990 L 0 ,t4ZH H000"..
Nu0 090 L LG0 L 0 HOO0it- 0 N~k~N
-NO
990 L 0 ego L HOOD- 0~k~ No 090L.
0
NN
0 H000is.. 0 LgO L A I CH
CHO
00 H003te.. 0N r- 0 0 H003"* i- c
NN
999 LLQL 9L01.
r 0 0 HOO3QI'"
N
i'LO L.
0 H000t-~N~-N~~ LLO L 091 HOOOisa.
091 0 H003w" 0 N +Nl
N
OLO L.
0 HOO0z". 0 L90 L.
0 1790 L GLO L.
0 HOOO"* 0
N
0L 1 091
NN
690 0
N
Lss L60- 0 690[L f-08
LH
0 H003i- N N 080 L 0 CHOL 0 990 L 0OOCHO 0,4 0 aOO,-) H/l 060 L r 0 CHO1 0 HOO0i,'
N
L90 L HCHO N~A 0L H0ODO,--
N
N~~
g 0
K_,N
ess 559 ;fjJ 00 0 1096 1094 1095 1097 1098 1099 1100
-,COO
0 0 1102 N~~N~g~N .COOH 0 1105 1101
N
0 0 1104 1103
N
",,COOH
N
00 1106 1107 FIZ: I LLZLL 0LL 0 f0 00 H0031- 0~
N-
f0 0
N-N
:)03L N0~u.
NLL
r 0 0 HOO0". 0 0 HOOO3- 0
N
0 h 0 H0"- 0%ka~~ 0 0 H0O01- 0 0
N-
80NJ1 0 H003i.. 0~k~J 099 561
-N
N *'I'COOH 00 1123 -I "COOH 0 1126
-N
T. iC O O
H
0 1129
-N
'ICOOH
0
CH
3 1132
-N
*"IICO0H 00 0 1135 1125 1124 1127 1128
'-N
0
""COOH
0 1130
-N
0 0
CH
3 0- 1133
-N
0 0
OH
3 0-
-N
H
2 .*C00H 0 0 CH3 .C 1131
-N
N -';iC00H 0 0 0836 (0) 1134
-N
0
OHF
3
C
C C
C
1136 1137 562 1138 1141
H
2 Nr Nj7JfN IIcoI 1139
-N
F'X 0r "COOH 1142
-N
""LCOCH
00 1145
-N
*.COOH
1148 1140 HO,9J 1143 N~Th 1144 1146 1147 1149
-N
0
COOH
1150 1501151 1152 563 1153 1154
-N
F~a
*'ICOOH
1157 1155 1156 1158 a.
a a a a a 1159 1162 1160
."COOH
0C 0 1163 1161 0 0- 0
-J
1164 564
NN
1165 1166 1167 1168 0
-COOH
0o O-Hs J 1171 1169 1170
OH
a..
1172
-N
H
2 .aCOOH 0 1173 1174 1741175 1176 565 0
,COOH-
1177 1178 1179 1180 1181 1182 4 1183 1184 1185 0 1186 1861187 1188 L6 LL 661. L 0
N-
96L L 86 L 1 ni..
004* *04.
S..
5 a as 176 L. L C6 1 96 L L -0 0 Z6 L L 0 68LL1 L6L1.
06LL 0 1"k N
ZH
999 567
*..ICOOH
1201
-N
13 "COOH 00 1204
-N
)~Ny~N ~COOH 0 0
O-J
1207
-N
N'00 0 -C
H
0 1210 1202 1203
-N
,42v N
.,"COOIH
1205
-N
*'-IC0OH 0 0 -j 1206
-N
1209 o ~0 0* 0 000000 1208
-N
1211 1212 568 12138 0
-COOH
1216
-N
"ICOOH
1219 1214 1215 1217 1218 0 -stCOOH 1220
IN~~~N
Nq OO 0
,OO
0
CH
3
J
0'
CH
3 1221
-N
0
"ICIOOH
00 C14 -0 b, 3 1222 1221223 1224 569
-N
.iCOOH 0 0 1225
-N
ICOOH
0 c b6 0- 1228
-N
0
"-'COOH
0 1231
-N
Ir 'I "'COOH 0 0 1226
-N
H
2 N"N ~N
O
00 CK3 9 1229
-N
00 1227 1230 1234
-N
0 "1COOH 00 1237 1232
-N
H
2 N-_N {N .4CO 1235
-N
N -COOH 0 1238 0
O
1233
-N
H 2 N N N -C O 1236
-N
H2 N
-COOH
0 0 1239 a a. a a a a 570
NN
1240
-N
".ICOOH
00 1243
-N
rN C 1241 1242 1244 1245 1246
-N
0 0-J 1249 1247 1248 H2 N 00 0 1250
H
2 1251 0
-N
0 -*,COOH N.N COOH 0 0 0-J -i~ 1253 1254 1252 571 f 1255 1256 1257 .1258 0 -"COOH 1261
H
2 1 ~N ,Ico( 1259 0
'ICOOH
1262
H
2 N~
ICOOH
0 0
CH
3 1265
-N
YN
0 "CQ0H 0
CH
3 0 1268 1260
-N
H2NN~r 'COOH 00 1266 0
CH
1269 a a a 1264
N
0 0H 3 0 1267 572 1270
-N
*'n-COOH CH3 1273
COOH
00 1276 1271 N, tCOOH 00 1272
CH
3 1275 1274 F'XI~0 'COOH 1277
-'COOH
00 1280
-N
OO
0 0
S
S. S S S 1278 1279
-N
0 0 1282 1281 1283 1284 573 1285 1286 1287
I
1288
N
*'N..COOH
0 a -i 1291 1289 1292 H
_COOH
1295 0
C
a\ a 1290 0 HO~ 0 -'C00H 0 1293 0=>
H
2 ~Nr0 -COOH 0 1296
H
2 N
*ICOOH
a
'-J
O. o *r
S
C
.0 0 1294 OZ0 Co 0-i 1297 1298 1299 574 0=a 0*-COOH 0- 0C 1300 1303
NN
00 0 1306 0.ICOOH 00 13096H
N
0*.COOH 1312 N 0 -I *"ICO0H 0 COj 1301 0 -Co 1304 0 0 1307 0 0
CH
3 1310 ~NZ~ 0 -KN "COOH 00
CH
3
A
-O-j 1302 1305 0= 0140 1308 S. S
S
S
S
S
1311 0 0
H
2 N,
*.COOH
0
CH-
3 0~ 1313 1314 575 I CO0OH 0 0 CH, 3 1315 00 0 CH3 b 1316 0=
H
2 IN~~ N COOH
CH
3 0 1319 1317 1318
CH
3 C3 0--
*"'COOH
0CO 1321
,"COOH
0 *0 1324 0 0 1327 1320 II *COOH 0 0 1323 b 1322 N0
H
2 N-A"j "C0OH 0 0 1325
I'COOH
1328 1326 1329 576
",COOH
0 1330 576 -o 1331 1332 1333 1334 00 0 1337 1335 a 1336 1338
H
2 t
N
0 1339 1340 -L'n 1341
"N
*sCOOH 0 1342 1 4 21 3 4 3 1 3 4 4 577 1345 0@1348 1346 I *.aiCON 00 1349[ O-
H
00 0 0 1352 c 4- l 3
*"-COOH
1347 0C
CH
3 0- 1350 1--c 0I
C.
C C C. C
C
C.
C. C C C C.
C
1351 N 2 COOH 0C 0 C FH3 0- 1354 1353 1355 1356
N
CF13 0 1357 3571358 1359 578 N *'CO 0 13600 0
COOH
0 C-4
O-
3 1362 1361 1363 1364 L 'iC00H 1366 N~Th 1367 H2NN NN
*COOH
1370 1365 *.a'COOH 00 1368
N'
0 1371 I *--iC00H 0o S S S. S S S 1369 579 1372 1373 1375 1376 1378 1379
N~TN
.aCOOH 0 0 -i 1382 1374 0 1377
*'ICOOH
0 0 0-J 1380 0 1383
NCI
.I:COOH
01 03 1386 N'0O V 0. 0 *000 a* 1380 N~Th 1384 1385
NN
N -I*.C00H
H
2
N.-
0 -0-i 580 1387 1388 N "sCOOH 0
C
1391 1389 1390 N~Th 1393 1394 1392 0 C143 0-' 1395 0 0
CH
3 1398
.*.COOH
00 0140 S S *5
S
5S S.
S
*5 5 S S S 5*SS .5
S
S. 5
S
S
S
1396 1397 0 0 C43 1399
N,
H 2 N .C O O H 0 0
CH
3 j 1400 1401
CN
ZH
e ttL S. 9*
S.
OLt'L 60V 4 sot? L I-LotL f- IO 90t, t H000".I HOOOil-
)OC)
901" L t~Qt' I C017 L 0 H-OO~w* tN
-H
007 0 'HO HOO3Z,'** 189 582 1414 N N OO 0i*
*'COOH
1417
NN
0JCOOH 1420 1415 1416 1418 1419
N
if -COOH'i 1421 1424 1422
"N
COOH
0 1425
S
5O
S
S
0 0
S
55 S 56 *5 05 0 @650
S
S. S 555.
1423 1426 1427 1428 0 583 1429N 0< 1432 1430
(N
1433 1431 0N 1434 1435 0 1438 1436 1437
Y-NCOOH
00 1 440 1439
N
H0~Ny% .COH 1411442 1443 1441 0 H00o'"- 0 H03 N,.)IZ
N
ssi L
S
S.
S
S
5555 S
S
S.
S
S
S. S S zslv L st" 0917 L 1--k 6"L HOO9"t H00KN 9"fL
N
"VI
1'89 585 1456
N
1 Kzw,-
COON
0 1459 1462 1457 0 cooH 1460 0 1463
"N
1466 N4
H
1469 -o- 1472 1461 1464 4* 1458 1467 1465 1468 0 0 1471 1470 0 00 0-i 1473 MIL LSVL fr
OH
0 HOOi. 0 0 0 00 6L87 L 0 H0O0.. 0 0 H00041*--N 00 0 0 H00" NIiJ
HSO,-
H0001'. 0~1~.
0 H000i... 0.k 0 H003%#.. 0 aS 98V' L 0 et8 L 09' 0 H0011-- 0
S
0 H 0Q N N 0 989 587 N r CH,d 1489 0 1490 1493 1492 1495 0 1498
NN
N *"COOH 0 1501 1494 1497 a a a.
a
.ICOOH
1599 1500
-'COON
00 1502 1503 588 _Cooti 0 1504 0~T 1507
~TN
0 1505 1508 N..Oh 1506 1509 1510 H2N,,,t, Nn -ICOOH 1513 N sICOCH 0 1516 1511 N-K-l$N -'tCOOH 0 1514 1512 1515 1517 1518 589 c
COOH
1520
CP
2 N -'COOH 00 1521 1519 1522 1523 1524
C
sCOOH -o- 1525 1528
CM
3
N
**'tC-OOH 00 1531 1526 zCOOH 0 1529 CH3
*..'COOH
00
CH
3 0j 1532 1527
CH
3 N
N'
"-COOH
0 0 1530 1533 evs L L179 L 0
HO
0.
£0D HO 00 H0 H0l- 669 L 0 HOOzHO 0 0 HO NA,,)tI
CHO
K-
CHO
0~ HOO0se" 0
CHOL
00
CHO
Ot'9 L f-
CHO,
0 LES L rHO 0 H00011- 00 HOOD--~ 0 0
CHO
0
N-
r CHO 069 591
CH
3
-COOH
1551 1549 1550s 1552 1553 1554
C
'."COOH
00 1557 0 *o 0 0 1555 C~4 3 -atCOOH 1558 1556
CH
3
COH
-o 1560 c~ 0
-TN
-,COOH
1611562 1563 1561 592 0 P2 N uCOOH 1564 1565 1566 1567 1568 1569 .0* 1570 1571 '11 1572
-COOH
0 0 C,4 1573 1731574 1575 593 1576 0 Ct COO, 00 1580 0
CO
1583 cro 1578 1579 0 0* 0* 00 0**0 0 0 0* 0000 00000* 0 0* a.
00 0 0000 1582 1584 0r
"-COOH
00 1587 1586 1585 594 N~Th 1588 1589 1590 1591 1594 0
COOH
0 0 1597 1592 0 0 1595 0
-ICOOH
1598 1593 1596 S S
S.
S
S.
S
S S
S
S
5 S S
S.
5* 5 5*
S.
*5 .5.5
S
S
~Th 1599 595 cr0 1602 1600 0 1603 1601 1604 0
CO
0 0 1607 CH3O
COOH
0 0 0 1605 -T CK 0H 0 0
-J
1608 Os I C OOH 0 C C)
I
*see -000 00.0 so**
S
*000 5* 0*S e0g.
c
C
S
0555S 0 09 S 55 0
S.
1606 1609 1610 1611 596 1613 1612 1614 0 1615 1616 1617 1618 -r cr"Ir
UCOCH
0 1619
CH
3 0
-COOH
0 CsI 3 -i 0 1620 0 0
CH-
3 o o o 0. 0 .0*0 0 1211622 1623 1621 597
CH
3 O
CH
3 0 C143O *.COOH H COOH
COOH
00 1624 C31625 1626
CM
3 o C4 3 162 1628 C 1629 CuCC c~~-Co
C
3 c O H OO I CI0 COOH 0C
O
00 0 1630 Cts 1631 C3 01632
C)
3 0 C40
N~
0 -cooH 0 aON-CC
C
3 0 0M 1633 1634i u, 1633 1634 1 u1j;j 598 CH3 I11 CKIO cito N--mCOOt4 -COH -COOH 1636 1637 1638 cito Clb 0 0 1639 1640 1641 00 0 0 0 0 0 1642 1643 1644
CR
3 O
CH-
3 Cb -,sCOOH 00 -UC00 -uO N t d OOH 0 1645 1646 1647 599 1648 1649 1650 1653 1651 1652
'COOK
0 0 0~ 1654 CH 0 00 0 1657
CH
3 0 N COOH 0 0 0- 1655
CIH
3 0
H
2
-COOH
0 '0 1658 p p 1656
-"COOH
0 1659 600 1660 1661 1663 1664 1662
H
0 1665 0 4..
0 0 -C0 1668 a. a a a a. a a a a a 1666 lp
*-'COOH
00 1669 1667
CH
3 0 00 1670CH
~N
0 1671 601 1672 C h.
~-Th 1673 9~b 1676 1674 1675 K~q--yN-r -nCOOH 1678 1677 %T C~bo sCOOH 1680
S
S S 1679 1811682 1683 1681 602
-CO
0 1684 1687 CH3O 0 0 1685 1688 cl-bo t-'COON 1691 C830 -'Co 1686 2 Ob 1689 1692 .r 1690 1694 1695 1693 603
-COOH
1697 1698 1696 1700 1701 1699 1702
*..COOH
1705 0 0~ 00 1703 0 \I 0 00 ~0 -0-i 1706 1704 a S S 1707
-ICOOH
0C0 CIb- 03 1709 1710 1708 604 0 1712 1711
ICOON
0C0 Ci-b 1713 N'0 0 C8 3 1716 1714 1715 00 1717 z'
-"COOH
0, 0
CH
3 0 1718 1719 z'
-COOH
CH
3 1722 1721 1720 12 605 1723 1724 1725 KN -COOH O *COOH 1726 1727 1728 -ulOOCH M 1729 1730 1731 O zNz c* IH KZ 0 C O O H -nC O
H
0 1732 1733 1734: 00 0 0 1735 1736 1737 0 0 -COCH.COH 0 .COOH Y \1 0 0 606 1738
H
00 1741o 1741 1739
HNAR
0
-ICO
0 1742 04 1745 H 1748 1740 H 0 0 1743 o 0cocHi 1746 H -o I 0 1749 1744 o. 0 0% V* *0 S 0 0 0 0 00 0 00 0 0 1747
H
0 1750 1751 1752 0 -aCO0H 0 0143 1754 1755 1753 607 1756 1757 HNVu 00 1758 1761 1759 H 1762
HNS'
co
CHO
176S 1760
HN-S-
0 1763 1764
HN.
0 N COOH 1767 CH
-COOH
1766 1769 1770 608
I
H -0 0 1771 HN 0
*-COOH
0 1772 H -0 0
H
1775 0CM 1778 1774 0 7H 1777 1773 0= 1776 1.0 H :0 _Co 1779
HN~
0
'COO,
a a.
a. a a 1780 1781 -609- 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 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 -800C 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 NaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 p.g/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 1 2 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 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 .iM 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.
-610- Table 4 Binding Data Example Inhibition ETA at 1 mM 1D 2 3 4 6B 7 8 9 14 16 17 18 19 21 22 23 26 27 28 29 31 B 96.4 58.4 42.2 78.2 95.1 34.9 63.4 53.7 69.2 66.1 86.6 84.8 96.0 73.9 97.3 90.3 80.9 56.3 86.3 85.9 83.0 61.2 63.8 85.3 80.0 93.6 Example 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 52 54 55 56 57 58 59 60 61 C 62 63 Inhibition of ETA at 1 mM 95.5 91.8 94.5 47.9 100.0 83.6 94.8 89.9 95.2 99.2 91.3 85.4 90.4 95.1 96.3 84.0 64.6 50.5 34.3 93.2 81.9 70.8 42.8 90.6 94.1 92.0 S. 0 S S
SO
0 S S SS SO 0 5* 00 5500
SOS.
S
0 0* 0 5 S
OS
OS
@0 0 OS S
*S
05 0
OSSS
0 000000 -611- Example 64 66 67 68 69D 71 72C 73C 74 76 79 82 83 84 86 87 88 89 91C 92C 93C 96 97 Inhibition f ETA at 1 mM 95.0 82.8 87.7 96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 65.3 52.6 62.4 84.3 84.6 91.6 107.4 59.2 82.1 86.1 89.0 Example Inhibition ETA at 1 mM 98 99 100 101 102 103 104 105 106 107 109 110 111 112 113 114 115 116 117 118 119 120 121 122 125 126 127 128 86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6 95.3 97.2 91.7 91.4 95.4 so 0 0 0 0 :0.0: 0 -612- Example Inhibition Example Inhibition of ETA at 1 of ETA at 1 mM mM 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 -613- Example Inhibition ETA at 1 mM Example Inhibition ETA at 1 mM 308 309 310 311 312 313 314 315 316 317 318 319 320 322 323 324 334 335 340 341 342 343 344 345 346 348 349 350 93.0 80.7 87.1 92.3 88.2 96.3 86.0 82.7 74.0 68.5 79.0 79.0 82.2 95.6 91.3 95.0 88.0 84.1 94.0 87.4 89.9 98.7 95.6 86.6 88.9 91.3 73.0 92.1 351 352 353 354 355 356 357 358 359 360 361 362 363 365 366 367 368 370 371 372 373 374 375 376 377 378 379 380 99.0 96.2 73.7 79.3 100 93.5 96.3 62.7 94.7 93.7 92.8 94.1 82.3 59.2 91.5 71.0 94.6 84.3 97.2 91.6 92.9 91.4 97.8 90.2 85.6 91.1 90.7 99.0 -614- Example Inhibition ETA at 1 mM Example 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 95.7 96.8 91.4 79.4 86.2 47.8 98.7 69.2 100 98.2 45.6 93.7 100 97.8 79.8 98.7 100 90.0 59.9 93.0 96.5 80.5 96.1 95.4 86.4 94.5 100 408 409 410 411 412 413 414 415 416 417 418 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 Inhibition ETA at 1 mM 100 89.4 91.4 93.5 86.4 99.5 91.4 87.3 86.4 98.7 100 100 100 96.6 89.1 85.8 90.8 97.2 100 100 100 94.1 99.1 95.5 99.6 100 97.8 i -615- Example 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 Inhibition of ETA at 1 mM 100 100 94.3 94.3 100 98.3 100 100 100 98.1 97.8 96.9 97.4 100.0 99.7 100 100 94.4 96.8 99.1 95.3 88.9 93.4 Example Inhibition ETA at 1 mM 459 460 461 462 463 464 465 466 467 468 469 470 471 475 476 477 479 495 496 497 498 499 500 97.4 91.6 99.6 98.3 96.1 97.1 95.1 94.2 93.6 88.7 98.7 100 100 91.6 82.3 80.1 96.5 95.9 92.7 83.7 81.6 68.5 55.7 -616- Example. Inhibition of ETA at 1 mM 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 -617- 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 gmCi/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 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. 206 587-595 (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. -618- Table Phosphatidylinositol Hydrolysis Example _ICs5 mM 1D 0.025 14 0.017 0.010 16 0.009 18 0.009 19 0.024 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
S.
S
Table 6 ETA/ETB Selectivity MMQ cells, porcine cerebellar tissues (known to contain ETB receptors) and chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in 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 Cg/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 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 containing protease inhibitors and stored at -80 °C until used.
-619- 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 NaCI, 10 mM MgCl2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 jag/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 After incubation, unbound'" S 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 jIM 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 o EXAMPLE mET-A mET-A pET-B Selectivity hET-A hET-B Selectivity NO. IC50 IC50 (mA/pB IC50 IC50 (hA/hB 1 M) (nM) (n M) 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 -620- 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 523 524 525 99.3 97.6 100 100 99.2 98.9 98.0 100 99.1 99.7 94.1 96.3 99.1 97.4 100 99.0 99.2 3.0 100,000 >33,000 1.63 100,000 >60,000 1 .9.
0.56 0.50 0.81 0.42 0.30 1 .0 1 .6 0.71 1 .'0 1 .3 0.38 0.20 0.67 0.42 0.79 45,000 30,000 35,000
N.D.
>80,000 8,800 26,000 >62,000 29,000 30,000 85,000 14,000 28,000 37,000 360 1,700 23,000 53,000 68,000 190,000 29,000 26,000 >37,00 0 40,000 30,000 63,000 36,000 130,000 54,000 880 2,100 2.1 0.51 1.0 0.60 0.58 0.36 0.36 6.7 1.8 0.43 0.31 0.23 0.33 0.82 51,000 23,000 11 ,000 15,000 60,000 14,000 9,800 100,000 37,000 12,000 38,000 19,000 290 890 24,000 45,000 11,000 25,000 102,000 37,000 29,000 >1 5,000 21,000 29,000 124,000 83,000 :.00: 0 880 1,100 560 SUBSTIUT SHEET (RULE 26) -621- 526 100 42 17 7,400 440 527 96.6 7.9 10,000 1,300 528 98.3 1 1 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 Determination of Plasma Protein Binding A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 10X 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 S filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 pL sample of the ultrafiltratewas transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 gL 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 calculated according to the equation: %PB 100% -622where Cu is the ultrafiltrate concentration and Ci is the initial plasma concentration.
Data: Example #43 99.5 Example #532 96.8% Example #533 82.6% The ability of the compounds of the invention to lower blood s 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. 1Q 131 (1983).
The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in ,o Margulies, et al., Circulation 82 2226 (1990). The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990).
The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).
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. 66 915 (1987) or Matsumura, et al., Life S Sci. 49 841-848 (1991).
The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82, (1991).
The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 83 1762 (1989).
-623- The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989).
The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney int. 37 1487 (1990).
The ability of the compounds of the invention to treat endotoxininduced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. Z. 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. Physiol. and Pharmacol. 67 1213 (1989). The ability of the compounds of the invention to treat transplantinduced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis ZB 229-236 (1989). The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods described in Bobik, et al., Am. J. Physiol. 258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990). The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method :o described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).
The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed.
23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 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 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.
-624- The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994).
Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
The ability of the compounds of the invention to treat plaletet o1 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 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). 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. Pharmacol. 1996, 309, 261-269). The ability of the compounds of the invention to treat ischemiarepurfusion 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 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, benzenesulfonate, bisulfate, butyrate, camphorate, -625camphorsulfonate, 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, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.
Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The compounds of the invention are useful for antagonizing endothelin in a human or other mammal. In addition, the compounds of -626the 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 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, S cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, is 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. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic -627pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenriteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, 125 tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, 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.
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 -628wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from 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 can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
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 o 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 agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, -629nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt 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, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin II antagonists include DUP 753, A-81988 and the like. Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative 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 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 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 times, or the therapeutic agents can be given as a single composition.
-630- 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 claims.
o0 o

Claims (63)

1. A compound of the formula: R2 Z I R 3 (CH 2 )n R wherein Z is -C(Rl8)(Rlg)- or wherein R18 and Rig are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(0H2)m-W wherein m is an integer from 0 to 6 and W is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, -P03H2, -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -ON, -C(O)NHR17 wherein R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (in) -S(O)2NHC(0)R16 wherein R 16 is defined as above, -632- HO 0 0 ()HO 0 OH (p) 0 0 9: 0 (t)O NHS0 2 CF 3 Ri is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyt, arylalkoxyalkyl, (N-alkanoyt-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, and (heterocyclic)alkyl; -633- R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N- alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rc 0 is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; R3 is R4-C(O)-R5-, R4-R5a-, R6-S(O)2-R7- or R26-S(O)-R 2 7 wherein R5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R20)-R8- or -R 8 a-N(R 2 O)-R 8 wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or -0-R9- or -R9a-O-Rg- wherein R97: and R9a are independently selected from alkylene; is alkylene or (ii) alkenylene;*. R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21)-R1O- or -RlOaN(R21>-R10 wherein R10 and Ri~a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R6 are independently selected from the group consisting of (i) (Ri i)(R12)N- wherein Ri11 and R12 are independently selected from hydrogen, loweralkyl, -634- haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkytalkyl, aryl, (11) heterocyclic, (12) arylalkyl, and (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl (i i) loweralkyl, (iii) alkenyl, (i v) alkynyl, cyctoalkyl, **o (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, Wx (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, 100 (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, 105 (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and -635- I(CH2)z N R 7 a 110 (xxi) 0 wherein z is 0-5 and R7a is alkylene; R26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl ,(viii) arylalkyl, (ix) 115 heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and V R27 is alkylene or alkenylene; (b)R22-O-C(O)-R23- wherein R22 is a carboxy protecting 120 group or heterocyclic and R23 is a covalent bond, (ii) alkylene, (iii) aikenylene or (iv) -N(R24)-R25- wherein R25 is alkylene and R24 is hydrogen or o. 125 loweralkyl, loweralkyl, alkenyl, alkynyl, 0 cycloalkyl, 130 cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, 135 (heterocyclic) al kyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, o r R 13-C(O)-CH(R 14)- wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or 140 R15-C(O)- wherein R15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof. -636-
2. The compound according to Claim 1 wherein n is 0 and Z is -CH2-. 145
3. The compound according to Claim 1 wherein n is 1 and Z is -CH2-.
4. The compound according to Claim 1 wherein n is 0, Z is 150 -CH2-, and R3 is R4-C(O)-R5- R6-S02-R7- or R26-S(O)-R27- wherein R 4 R 5 R 6 R 7 R 2 6 and R 2 7 are as defined therein. The compound according to Claim 1 wherein n is 0, Z is -CH2-, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene.
6. The compound according to Claim 1 wherein n is 0, Z is -CH2-, R1 is loweralkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene.
7. The compound according to Claim 1 wherein n is 0, -CH2-, R1 is alkenyl, and R3 is R4-C(O)-R5- wherein R4 is (R1 as defined therein and R5 is alkylene. Z is 1)(R12)N-
8. The compound according to Claim 1 wherein n -CH2-, R1 is heterocyclic (alkyl), and R3 is R4-C(O)-R5- (R11)(R12)N- as defined therein and R5 is alkylene. is 0, Z is wherein R4 is
9. The compound according to Claim 1 wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene. The compound according to Claim 1 wherein n is 0, Z is -CH2-, R1 is arylalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene. -637-
11. The compound according to Claim 1 wherein n is 0, Z is -CH2-, R1 is aryl, and R3 is R4-C(O)-R5- wherein R4 is (R1 1)(R12)N- as defined therein and R5 is alkylene.
12. The compound according to Claim 1 wherein n is 0, Z is -CH2-, R1 is (N-alkanoyl-N-alkyl)aminoalkyl, and R3 is R4-C(O)-R 5 wherein R4 is (Ri 1)(R1 2)N- as defined therein and R5 is alkylene.
13. The compound according to Claim 1 wherein n is 0, Z is -CH2-, Ri is alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R 5 wherein R4 is (Rll)(R12)N- as defined therein and R5 is alkylene.
14. 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 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 and R2 are independently selected from loweralkyl, (ii) alkenyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) heterocyclic (alkyl), arylalkyl, (vi) aryloxyalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, and (viii) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(Ri2)N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyl and' is alkylene; or R3 is R4-C(O)-N(R20)-R8- or R-S(O)2-N(R21)-Rlo- wherein' R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R8 and R10 are alkylene and R20 and R21 are loweralkyl; or R3 is R6-S(O)2-R7- or R26-S(O)-R2 7 wherein R6 is loweralkyl or haloalkyl, R7 is alkylene, R26 is loweralkyl and R27 is alkylene. -638- 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 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is loweralkyl or (ii) alkenyl, R 2 is substituted or unsubstituted '1 3-benzodioxolyl, 7-methoxy-1 1 3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihyd robenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Ri 1)(R1I2)N- wherein R, 1 and R1 2 are independently selected V. I from loweralkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl,* trialkylaminoalkyl, and heterocyclic.
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, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein R 16 is loweralkyl, haloalkyl or aryl, 7 is -CH2-, R1. is hetrerocyclic (alkyl), (ii) aryloxyalkyl, (iii) aryalkyl, or (iv) aryl, 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 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Rj 1)(R1 2)N- wherein R 1 1 and R1 2 are independently selected from loweralkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, 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, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is phenyl, or (ii) substituted or unsubstituted 4- methoxyphenyl, 4-fluorophenyl, 2-f luorophenyl, 4-methylphenyl, 4- trif luo romnethyl phenyl, 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 -639- is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Ri 1)(R12)N- wherein-R 1 1 and R 12 are independently selected from haloalkyl, haloalkoxyalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
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, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 1 6 is loweralkyl or haloalkyl, Z is -CH2-, R1 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 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 R3 is wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R 11 and R 12 are independently selected from haloalkyl, haloalkoxyalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
19. The compound according to Claim 1 wherein n isO0, R is -C(O)2-G 'wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, RI is phenyl, or (ii) 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 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 R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is -640- (Ri 1)(R12)N- wherein R 1 1 and R 12 are independently selected from aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
20. 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 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 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- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, 0 dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R 5 wherein R5 is alkylene and R4 is (R1i1)(R 12)N- wherein R, 1 1 and R 1 2 are independently selected from aminoalkyl, trial kylaminoalkyl, aryl, and heterocyci c.
21. The compound according to Claim 1 of the formula: R %I 0-eR (CH 2 )n 0 Ri wherein Z is -C(R18)(R19)- or wherein R18 and Rig 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 -C(O)2-G wherein G is hydrogen or a carboxy protecting group, -P031-2, -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -O N, -C(O)NHRi 7 wherein Ri17 is loweralkyl, -64 1- ()alkylaminocarbonyl, dial kylaminocarbo nyl, tetrazolyl, hydroxy, alkoxy, (k suffonamido, -C(O)NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (in) -S(O)2NHC(O)R16 wherein R 16 is defined as above, HO 0 OH S 050 0 0 H 0S Np) 0 S**O 0 or -642- NHSO 2 CF 3 (u) R 1 is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalky!, alkylsulfonylamidoalkyl, and (heterocyclic)alkyl; R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rc is alkylene, with the proviso that one or both of R 1 and R 2 is other than hydrogen; R3 is R4-C(O)-R5-, R4-R5a-, R6-S(O)2-R7- or R26-S(O)-R27- wherein R5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R20)-R8- or -R 8 a-N(R 2 0 )-R 8 wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or -O-R9- or -R9a-O-Rg- wherein Rg and R9a are independently selected from alIkyle ne; is alkylene or (ii) alkenylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R21)-R1O- or -RlOa-N(R21)-R1o- wherein R10 and Ri0a are independently selected from the group consisting of alkylene and -643- alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R6 are independently selected from the group consisting of (Ri 1)(R12)N- wherein Ri11 and R12 are independently selected f rom hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl,: cycloalkylalkyl, aryl, (11) heterocyclic, (12) arylalkyl, and (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl, (i i) loweralkyl, (iii) alkenyl, (i v) alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, -644- 100 (Xiv) (xv) (xvi) (xvii) (xviii) (Xix) (xx) haloalkenyl, haloalkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkylaminoalkyl, dial kylaminoalkyl, alkoxy, and 105 ~R7a (Xxi) wherein z is 0-5 and R7a is alkylene; R26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arytalkyl, (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and R27 is alkylene I(b) 120 125 (c) (d) (e) Mf (g) (h) (i) (D (k) or alkenylene; R22-O-C(O)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R24)-R25-wherein R25 is alkylene and R24 Is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, -645- (heterocyclic)alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, or R13-C(O)-CH(R14)- 135 wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or wherein R15 is amino, alkylamino or dialkylamino; or a pharmaceutically acceptable salt thereof.
22. The compound according to Claim 21 wherein n is 0 and Z is -CH2-.
23. The compound according to Claim 21 wherein n is 1 and Z is -CH2-.
24. -CH2-, and R 4 R 5 R 6 -CH2-, and therein and The compound according to Claim 1 wherein n is 0, Z is R3 is R4-C(O)-R5- R6-S02-R7- or R26-S(O)-R27- wherein R 7 R 2 6 and R 2 7 are as defined therein. The compound according to Claim 1 wherein n is 0, Z is R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined R5 is alkylene.
26. The compound according to Claim 21 wherein -CH2-, R1 is loweralkyl, and R3 is R4-C(O)-R5- wherein (R11)(R12)N- as defined therein and R5 is alkylene.
27. The compound according to Claim 21 wherein -CH2-, R1 is alkenyl, and R3 is R4-C(O)-R5- wherein R4 as defined therein and R5 is alkylene. n is 0, Z is R4 is n is 0, Z is is (R11)(R12)N-
28. The compound according to Claim 21 wherein n is 0, Z is -CH2-, R1 is heterocyclic (alkyl), and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene.
29. The compound according to Claim 21 wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- as defined therein and R5 is alkylene. -646- The compound according to Claim 21 wherein n is 0, Z is -CH2-, R1 is arylalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R1 1)(R1 2)N- as defined therein and R5 is'alkylene.
31. The compound according to Claim 21 wherein n is 0, Z is -CH2-, R1 is aryl, and R3 is R4-C(O)-R5- wherein R4 is (R11j)(R1 2)N- as defined therein and R5 is alkylene.
32. The compound according to Claim 21 wherein n isO0, Z is -CH2-, R1 is (N-alkanoyl-N-alkyl)aminoalkyl, and R3 is wherein R4 is (R1 1)(R1 2)N- as defined therein and R5 is alkylene. o
33. The compound according to Claim 21 wherein n isO0, Z is 000 -CH2-, R1 is alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein o.. R4 is (Ri 1)(R12)N- as defined therein and R5 is alkylene. o.
34. The compound according to Claim 21 wherein n is 0, R is tetrazolyl or -C(O)2-G wherein G is hydrogen or a carboxy protecting V 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 -CH2-, R1 and R2 are independently selected from loweralkyl, (ii) alkenyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) heterocyclic (alkyl), arylalkyl, (vi) aryloxyalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, and (viii) alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R5- wherein R4 is (R11)(R12)N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, -and arylalkyl and is alkylene; or R3 is R4-C(O)-N(R20)-R8- or R6-S(O)2-N(R21)-R1O- wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyt, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, RB and Ri 0 are alkylene and R20 and R21 are loweralkyl; or R3 is R6-S(O)2-R7- or R26-S(O)-R27- wherein R6 is -647- loweralkyl or haloalkyl, R7 is alkylene, R26 is loweralkyl and R27 is alkylene. 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 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is loweralkyl or (ii) alkenyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1,4- benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihyd robenzofuranyl, benzofuranyl, 4-methoxyphenyl, dim ethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11j)(R1 2)N- wherein R 1 1 and R1 2 are independently selected from loweralkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and 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, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 1 6 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 is hetrerocyclic (alkyl), (ii) aryloxyalkyl, (iii) aryalkyl, or (iv) aryl, 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 difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R1 1)(R1 2)N- wherein R 1 1 and R12 are independently selected from loweralkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
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, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, R 1 is phenyl, or (ii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4- -648- 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-benzodioxanyl, dihydrobenzofuranyi, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R:3 is R4-C(O)-R5- wherein R5 is alkylene and R4 is (Ri 1)(R12)N- wherein R 1 1 and R 12 are independently selected from haloalkyl, haloalkoxyalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
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, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyiphenyl, 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 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is wherein A5 is alkylene and R4 is (R11j)(R1 2)N- wherein R, 1 and RI 2 are independently selected from haloalkyl, haloalkoxyalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl, and heterocyclic.
39. A compound selected from the group consisting of trans-trans-2-(4-Methoxphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 p ropyl-N-n-pentanesulfonylam ino)propyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-(4-Methoxymethoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 (2-(N-propyl- N-n-pentanesulfonylamino)ethyl]pyrrolidine-3- carboxylic acid; -649- trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol -5-yl)-l (N p ro py I N n-pent an es u If on yl am in o )ethyl] py rro lid i n e-3- carboxylic acid; trans, trans-2-(3,4- Dimnethoxyp he nyl) .3-benzodi oxol 1 (N-propyl-N-n-hexanesulfonylami no)ethyl]pyrrolidine-3- carboxylic acid; trans, trans-2-( 4-Propoxyphenyl)-4-( 1,3-benzodioxol-5-yI)-1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Difluorophenyl)-4-( 1,3-benzodioxol-5-yl)-1 di butylam ino) carbonyl) methyl) -pyrrol idi ne-3-carboxyl ic acid; trans, trans-2-(3,4-Dif luorophenyl)-4-( 1,3-benzodioxol-5-yl)- 1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)- *9 1 -[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3- carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- I -(2-(N-isobutyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(4- m ethyl butanesuIf onyl) am ino)ethyl] py rrolidi ne- 3-carboxylic acid;- trans, trans-2-(4-Methoxy-3-fl uorophenyl)-4-(7-methoxy- 1 ,3- benzodioxol-5-yl)-1-[2-(N-pro-pyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 ropyl-N-(2,2,3,3 ,3-pentafl uoropropoxyethanesulfonyl)- ami no) ethyl] pyrrol idi ne-3-carboxylic acid; trans, trans-2- 1,4- Benz odi oxan-6-yI)-4- meth oxy-1, ,3-be nzodi oxo I- 1-[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; -650- trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyI_-N-(pentanesuf onylami no)ethyl)pyrrolidin e-3- carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropan esulfonyl)amino). ethyl) py rrolidi ne-3-carboxyl ic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.(1 1-(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)- I -[2-(N-propyl-N-((2,2,2-trif luoroethoxyethane)suIf onyl) amino)- ethyi]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (2-methoxyethyl)- N-(b utanesulIf onyl am ino) ethyl) pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(2- m ethyl propanesu If onyl) ami no) ethyl]pyrrolid n e-3-ca rboxyl ic acid; and trans, trans-2- Fu oro-4-meth oxyp henyl) ,3 -benzod ioxol 1 (2 is obu t yI-N -(bu t ane sulIf o nyIa m in e th y1) p yrro Ii din e -3 carboxylic acid; trans, trans-2-(2,-DMethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 A dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2(,2- D iethyle hy)-4-(1,3-benzodi oxo-I) 1 -N [dibutyl aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,-Dioxhyo-2-etyl)4-(1 -(,3-benzodioxol-- y-l[(dibutyl amino)carbonylmethyl]-pyrrolidine-3-carboxylicd acid; trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 yI)-1 -(NN-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -651- trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3- be nzod iokol1-5-yI) 1 N -dib utylamiflocarboflylm ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-( 2 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxot-5-yI)- 1 [[N-4-heptyI-N-(2-methy-3-fIuorophel)] amino carbonylmethyl]-pyrrolidile-3-carboxylic acid; trans, trans-2-(2-(l ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3- benzodioxol-5-y)-1-[(dibutyl amino) carbonylmethylhl-pyrrol idine- 3-carboxylic acid trans, trans-2-((2-Methoxypheloxy)methyl 4 7 -methoxyl 3,3- benzodioxol-5-yi)-1-[(dibutyl amino) carbonylm ethyl] -pyrrol id ife- 3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpeltyl)-4-(l ,3-benzodioxot-5-yt>1 hetlN(-loo3mtyphnl)mncroymty) pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidifl1 yI)ethyl)> 4 yI)-l -[(dibutyl amino)carbonylmethyl]-pyrrolidifle-3carboxylic acid; trans, trans-2-(2-(1 ,3-DioxoI-2-yI)ethy)-4-(7-methoxy-1 33- 1 -(N-4-heptyl-N-(4-fluoro-3- m ethyltphe nyl)) am iocarbonl lm ethyl-py rroidi ne 3 carboxy ic acid; trans, trans-2-(2,2 -Dim ethylpeftyl)-4-( 7 -methoxy- 1,3- benzodi oxol-5 100 yi)-l -I(dibutyl amino)carbonymethyll-PYrrolidile-3-carboxylic acid; trans, trans-2- (2 ,2-d i methyl pentyl) 2 ,3-dihyd ro-benfl u 1 -[(dibutyl amino) carbonyl methyl]- pyrrolid inle-3carb oxylic acid; trans, trans-2-(2,2,-Dimlethyl- 2 3-dioxolanl-2-yl)ethyl)-4-(7- 105 methoxy-1 ,3-benzodioxoi-5-yI)-1 (N,N- d ibutyl ami nocarbonyl methyl) pyrrol idife 3 carboxylic acid; trans, trans-2-(2-(2-Methoxypheyl)ethyI- 4 7 methoxy- 1,3- benzodioxol-5-yi)-1-[(dibutyl amino)carbonylmethyl]-pyrrolidifle- 3-carboxylic acid; -652- 110 trans, trans- 2-(2,2 Dimethyl-3(E)pe ntenyl). 4 7 metho xyl 1,3- be nzodi oxol1-5-yl)- 1 N-dibutyla miflocarbolylm ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(2- pyridyl) ethyl) 4 (l,3-benzodioxol- 5-yl) -1 N dibutylaminocarboflylmethyl)-pyrrolidine- 3 -carboxylic acid; 115 (2S, 3R, (2-oxopyrro lidinl- 1 -yl) ethyl)-4- (1 ,3-be nzod ioxolI- yl)-l ,N-dibutylaminocarboflylmethyl)-pyrrolidifle-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 120 methylphenyl))amiflocarboflylmethyl)pyrrolidine- 3 -carboxylic acid; trans, trans-2-(2-(l -pyrazolyl)ethyl)- 4 ,3-benzodioxol-5-yl)-1 (N,N-dibutylaminocarboflylmethyl)-pyrrolidine- 3 -carboxylic acid; trans, trans-2-(4-MethOXyPheflYl)- 4 ,3-benzodioxol-5-yl)-1 0 125 butyl-N-(4-dimethylamilobutyl)amiflo)carbonylmethyl]- pyrrolidine-3-carboxylic acid; (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)- 4 -(l,3-benzodioxol-5-yl) 1 2 ro p yI-N -p e nt a nes uIf on yIa m in o) e th y1-py r ro i d in e 3 carboxylic acid; 130 or a pharmaceutically acceptable salt thereof. A compound of the formula: R 2 NH (CH 2 )n (CH 2 )m q wherein n is 0 or 1; m is 0 to 6; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P031-2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,. -653- -CN, -C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dial kylami nocarbo nyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)R1G, HO 0 00* 0 HO 0 OH INa 0 ~NH 0, (r) H -654- O\ C F, Mt H or -a NHSO 2 CF 3 an R 1 is selected- from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoyl-N-alkyl)amiloalkyl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting: of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoatkyl, alkylsulfonylamnidoalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kyl amino carboflylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a salt'thereof. 4 1. The compound of Claim 40 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.
42. The compound of Claim 40 wherein n and m are both 0; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- methoxyphenyl, 4-f luorophenyl, 3-f luorophenyl, 4-ethoxyphenyl, 4- ethylphenyl, 4-methyipherlyl, 4-trifluoromethyiphenyl, 4- -655- pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1,3-be nzodioxolyl, 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, 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. 020
43. The compound according to Claim 40 of the formula: NH NH (C (CH 2 )m (CH 2 )m SRo r W R wherein n is 0ori1; m is 0to 6; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, P32 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dial kyl ami nocarbo nyl, tetrazolyl, i) hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2RI6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, -656- (i)-S(O)2NHC(O)R16, HO 0 0 OH (p) 0 (q)0 (0 H J4 CF 3 MH ,or -a NHS0 2 CF 3 an R1 is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoyl-N-alkyl)aminoalkyl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, -657- alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulf onyl amid oalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarboflylalkyl, dialkylamninocarboflylalkyl, aminocarbonylalkeflyl, alkylaminocarbOflylalkeflyl, dialkylaminocarbonylalkelyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a salt thereof.
44. The compound according to Claim 43 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. The compound of Claim 43 wherein n and m are both 0; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and Ri is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)amifloalkyt, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- ethylphenyl, 4-methylphenyl, 4-trifluoromethylpheflyl, 4- pentafluoroethyiphenyl, 3-fluoro-4-methoxypheflyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxypheflyl, 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 substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxypheflyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from -658- loweralkyl, alkoxy and halogen; or the substantially pure or (-)-isomer thereof.
46. The substantially pure compound (+)-trans, trans-2 Methoxyphenyl)-4-(1 ,3-benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof.
47. A compound of the formula R2' R5b Q (CH 2 )m (CH 2 )n RI 1 n is 0 or 1; mn is 0 to 6; is alkylene; o is a leaving group; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P03H2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,* -CN, -C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R'16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)R16, -659- HO 0 -NH 0 0 OH (p) ~N Hq 09 H CF 3 Mt H or H0C3 and R1 is selected from loweralkyt, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylaikyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoy-N-alkyl)amiloalkYl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, -660- alkoxyalkoxyalkyl, thioalkoxyalkoxyalkYl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamlidoalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbOflylalkyl, dialkylamilOCarboflylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkell dialkylaminocarboflylalkeflyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)atkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a salt thereof.
48. The compound according to Claim 47 wherein m is zero or 1; is alkylene; Q is a leaving group; and W is -C02-G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (+)isomer thereof.
49. The compound according to Claim 47 wherein n and m are both 0; is alkylene; o is a leaving group; 5 W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)amlinoalkyl, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethylphelyl, 3-fluoro-4-methoxypherlyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxypheflyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofurarlyl 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, -66 1- 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. The compound according to Claim 47 of the formula Q :H2)n .1W (H 2 )n (CH 2 )mC( (CH m wherein nis 0ori1; mn is 0 to 6; is alkylene; 0* 0* 0* 00 0* 0 00 .000 Q is W is a leaving group; -C(O)2-G where G is hydrogen or a carboxy protecting group, -P03H2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -ON, -C(O)NHR17 where R17 is loweralkyl, (M alkylaminocarbonyl, dial kylaminocarbolyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)R16, HO 0 0 -662- (0) OH (p) 0 NH 0 0 SN CF 3 Mt H or NH02F and R I is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoyl-N-alkyl)aminoalkyl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoatkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dial kylami nocarbonylalkyl, aminocarbonylaikenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, -663- hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-RCC wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a salt thereof.
51. The compound according to Claim 50 wherein mn is zero or 1; is alkylene; Q is a leaving group; and *9 *0 5 W is -C02-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 mn are both 0; is alkylene; Q is a leaving group; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- ethylphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4- pentafluoroethyiphenyl, 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 substituted or unsubstituted I ,3-benzodicixolyl, 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 the substantially pure or (-)isomner thereof. -664-
53. A compound of the formula R2 ~N Rsb (CH 2 )n (C 2 )m I R 1 n is 0 or 1; m is 0 to 6; is alkylene;: R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, :m -P03H2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl,phenyl or dial ky lam ino, (in) -S(O)2NHC(O)R16, HO 0 0 .0 -665- OH 0 (q)0 0* 0@* S=O0 H CF 3 N H ,or NHSO 2 CF 3 and R1 is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyt, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoyl-N-alkyl)amifloalkyl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkYl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkYl, dialkylaminocarbonylalkyl, aminocarbonylalkenyt, alkylaminocarbonylalkel dialkylaminocarboflylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and -666- (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a Salt thereof.
54. The compound according to Claim 53 wherein m is zero or 1; is alkylene; R2Oa 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. The compound according to Claim 53 wherein n and m are both 0; is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and Ri is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) V. aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- o methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- ethyiphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4- 6 pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyt, 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 substituted or unsubstituted I ,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 the substantially pure or (+)isomer thereof. -667-
56. The compound according to Claim 53 of the formula R2-I~ NHR 20 a 2 R~b -NHR~oa (CH2)m (cH 2 W R or W R wherein n is 0ori1; m is 0 to 6; is lye; R2Oa is hydrogen, loweralkyl, aikenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cyctoalkyl, cycloalkytalkyl, aryl or arylalkyl; W is -C(O)2-G where G is hydrogen or a carboxy protecting group,:7 -P03H2, -P(O)(OH)E where E is hydrogen, toweralkyl or arylalkyl, -CN, -C(O)NHR17 where R17 is loweralkyl, alkylaminocarboflyl, dialkylaminocarboflyl, tetrazolyl, hydroxy, (W alkoxy, sulfonamido, -C(O)NHS(O)2R 16 where Ri16 is loweralkyl, haloalkyl, phenyl -or dialkylamino, (in) -S(O)2NHC(O)R1 6, HO 0 .NH 0 0J~ HO 0 -668- OH (p) N H 0 N% -~N H 0 ,o NHSO 2 CF 3 and R1 is selected from loweralkyl, alkenyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, (heterocyclic)alkyl, (N-alkanoyl-N-alkyl)aminoalkyl, and alkylsulfonylamidoalkyl, and R2 is selected from the group consisting. of hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, halo al koxyal kyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, atkylsulfonylamidoalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbolylalkyl, dial kylami nocarbonylalkyl, aminocarboiylalkeflyl, alkylaminocarbonylalkeflyl, dial kylami nocarbonylal keflyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic, (heterocyclic)alkyl and -669- (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, or a salt thereof.
57. The compound according to Claim 56 wherein m is zero or 1; R~b is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyi; and W is -C02-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; R~b is alkylene; R2O.a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C02-G wherein G is hydrogen or a carboxy protecting group; and R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, (vii) alkylsulfonylamidoalkyl or (viii) substituted or unsubstituted 4- methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4- ethylphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4- methoxyphenyl, 3-f luoro-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 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, -670- alkoxy and halogen; or the substantially pure or (-)-isomer thereof.
59. A pharmaceutical composition for antagonizing endothelin comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for antagonizing endothelin comprising a therapeutically effective amount of the compound of Claim 21 and a pharmaceutically acceptable carrier.
61. A method for antagonizing endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
62. A method for antagonizing endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.
63. A method for 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 therapeutically effective amount of a compound of Claim 1.
64. 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, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, raynaud's disease and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. -671- A method for 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 therapeutically effective amount of a compound of Claim 21.
66. 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, IL-2 0 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, raynaud's disease and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21.
67. 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 therapeutically effective amount of a compound of Claim 1 in combination with one or more cardiovascular agents.
68.. 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 therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents. -672-
69. A process for the preparation of a compound of the formula: wherein E is a carboxy-protecting group and R1 and R2 are independently selected from loweralkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 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: *r OsN. CO 2 E wherein E, R 1 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. The process of Claim 67 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid.
71. The process of Claim 67 wherein E is loweralkyl and R1 and R2 are as described above. -673-
72. A process for the preparation of a compound of the formula: R 2 R, CO 2 E wherein E is a carboxy-protecting group and R1 and R2 are independently selected from loweralkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 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 CORE CO.. 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 c) epimerization of the product of step b) with a base.
73. The process of Claim 70 wherein E is loweralkyl, R 1 and R 2 are as defined above. -674-
74. The process of Claim 70 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid. A process for the preparation of a compound of the formula: /R 3 E0 2 E wherein E is a carboxy-protecting group, R1 and R2 are independently selected from loweralkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarboflylalkyl, amino ca rbonylalke nyl1, alkylaminocarboflylalkelyl, dialkylaminocarbonylaikenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyi-N-alkyl)amifloalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyl and R 3 is wherein R5 is alkylene and R4 is (Rll)(R12)N- wherein R 11 and Ri 2 are independently selected f rom oeakl haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (10) heterocyclic, (11) arylalkyl, -675- (13) (14) (16) (17) a) catalytic hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, (heterocyclic)alkyl; hydrogenation of a and or a salt thereof, comprising compound of the formula: R 1 0 2 N, 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, 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 is a leaving group and R 3 is defined as above.
76. The process of Claim 73 wherein E is loweralkyl, R 1 and R 2 are as defined above, and R 3 is -CH 2 C(O)NR 1 1 R 1 2 wherein R 1 1 and R 1 2 are independently selected from the group consisting of loweralkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. a a o a a a. .o o a a. a a *a
77. The is Raney nickel trifluoroacetic process of Claim 73 wherein the hydrogenation catalyst and the acid is a mixture of acetic acid and acid. -676-
78. A process for the preparation of the substantially pure trans,trans optical isomer of the compound of the formula: E0 2 E wherein E is loweralkyl, R1 and R2 are independently selected from loweralkyl, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarboflylalkyl, alkylaminocarbonylalkyl, dialkylaminoCarboflylalkyl, aminocarbonylalkenyl, alkylaminocarbolylalkeyll dialkylaminocarbonylalkel aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amfinoalkyl, alkylsulfonylamidoalkyl, heterocyclic and (heterocyclic)alkyi, or a salt thereof, comprising reacting a mixture of the ()and ()enantiomers of the compound of the formula: NH R2 R1 *02E S-*-3nei cd n eaaigtemadl ato h trans~~trans opia ismr Dated 2 Marc,*200 withS-()Pandei acidney anf spatn the mandelate/saltnofetheerson SPRUSON FERGUSON
AU29841/01A 1996-02-13 2001-03-23 Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists Ceased AU781355B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29841/01A AU781355B2 (en) 1996-02-13 2001-03-23 Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US600625 1996-02-13
US794506 1997-02-04
AU22620/97A AU2262097A (en) 1996-02-13 1997-02-12 Novel benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivat ives as endothelin antagonists
AU29841/01A AU781355B2 (en) 1996-02-13 2001-03-23 Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU22620/97A Division AU2262097A (en) 1996-02-13 1997-02-12 Novel benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivat ives as endothelin antagonists

Publications (2)

Publication Number Publication Date
AU2984101A true AU2984101A (en) 2002-08-08
AU781355B2 AU781355B2 (en) 2005-05-19

Family

ID=34578087

Family Applications (1)

Application Number Title Priority Date Filing Date
AU29841/01A Ceased AU781355B2 (en) 1996-02-13 2001-03-23 Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

Country Status (1)

Country Link
AU (1) AU781355B2 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4132709A (en) * 1976-12-20 1979-01-02 Ayerst, Mckenna & Harrison, Ltd. [2]Benzopyrano[4,3-c]pyridine derivatives and process therefor
ATE219077T1 (en) * 1994-08-19 2002-06-15 Abbott Lab ENDOTHELIN ANTAGONIST

Also Published As

Publication number Publication date
AU781355B2 (en) 2005-05-19

Similar Documents

Publication Publication Date Title
AU711832B2 (en) Endothelin antagonists
KR100508200B1 (en) Novel Benzo-1.3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
US6462194B1 (en) Endothelin antagonists
US6946481B1 (en) Endothelin antagonists
EP1003740A2 (en) Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagoists
WO2002017912A1 (en) Endothelin antagonists
US7365093B2 (en) Endothelin antagonists
AU714597B2 (en) 4-(benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivatives as endothelin antagonists
AU781355B2 (en) Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
WO1998057933A1 (en) Pyrrolidine carboxylic acid derivatives as endothelin antagonists
AU2005201160B2 (en) Endothelin antagonists
AU725122B2 (en) Endothelin antagonists
NZ514170A (en) Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists
AU2008201198A1 (en) Endothelin anatagonists
CZ2000348A3 (en) Pyrrolidine-3-karboxylic acid derivatives and their use as endothelin antagonists
EP0991620A1 (en) Pyrrolidine carboxylic acid derivatives as endothelin antagonists
NZ514171A (en) Benzo-1,3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists