NZ514170A - Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists - Google Patents

Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists

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Publication number
NZ514170A
NZ514170A NZ514170A NZ51417097A NZ514170A NZ 514170 A NZ514170 A NZ 514170A NZ 514170 A NZ514170 A NZ 514170A NZ 51417097 A NZ51417097 A NZ 51417097A NZ 514170 A NZ514170 A NZ 514170A
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New Zealand
Prior art keywords
trans
benzodioxol
heterocyclic
pyrrolidine
compound
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NZ514170A
Inventor
Martin Winn
Steven A Boyd
Charles W Hutchins
Hwan Soo Jae
Andrew S Tasker
Geldern Thomas V Von
Jeffrey A Kester
Bryan K Sorensen
Bruce G Szczepankiewicz
Kenneth J Henry
Gang Liu
Steven J Wittenberger
Steven A King
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Abbott Lab
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Application filed by Abbott Lab filed Critical Abbott Lab
Priority to NZ514170A priority Critical patent/NZ514170A/en
Publication of NZ514170A publication Critical patent/NZ514170A/en

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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

A process for preparing a compound of formula (I), wherein: E is a carboxy-protecting group and R1 and R2 are loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,aminocarbonyalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl Wherein cycloalkyl, aryl and heterocyclic may be optionally substituted, provided at least one of the following conditions apply: (a) R1 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl, and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl, (c) at least on of the optionally substituted aryl groups has at least on substituent selected from hydroxyalkyl and cyano or (d) at least one of the optionally substituted heterocyclic groups has at least one substituent selected from alkyloxycarbonyl, nitro and cyano; comprises a) catalytic hydrogenation of a compound of Formula (II) 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. Also described is the compound (2R, 3R, 4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl-aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid. This compound can be used in the manufacture of a medicament for antagonizing endothelin treating hypertension, congestive heart failure, restinosis cerebral or myocardial ischemia or atherosclerosis, treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporine-induced nephrotoxicity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardio toxicity nociception, colitis, vascular permeability disorders, ischemia-reperfusion injury raynaud's disease, migraine and for treating bone pain. (62) Divided out of 503365

Description

New Zealand Paient Spedficaiion for Paient Number 514170 5U170 IUTELLLCTUAL PR0?ifRTV Q--F1CE OF N.Z. 1 3 SEP 2001 R £ C EIV £ D NEW ZEALAND PATENTS ACT, 1953 No: Date: Divided out of No. 503365 Dated 12 February 1997 COMPLETE SPECIFICATION NOVEL BENZO-1,3-DIOXOLYL- AND BENZOFURANYL SUBSTITUTED PYRROLIDINE DERIVATIVES AS ENDOTHELIN ANTAGONISTS We, ABBOTT LABORATORIES, a United States company of CHAD 0377/AP6D-2,100 Abbott Park Road, Abbott Park, Illinois 60064-3500, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) -la- HOVa BENZO-13-DI0X0LYL-. ^ggOF^ANYL SUBSTTHT® PYKROUIXNE ENDOTHEUN AOTAGONISIS Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and compositions for antagonizing endothelin. Methods for antagonizing endothelin are described but not claimed.
Background of the Invention The reader's attention is directed to our related New Zealand Patent Specification No. 330818, which describes and claims compounds, processes and uses described but not claimed herein. The readers attention is further directed to our related New Zealand Patent Specification No. 514171, which describes and claims compounds, pharmaceutical compositions and uses described but not claimed herein.
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 "Intellectual property uh-ii* of n.z. 1 1 8 NOV 20M binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest S3. 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 22. 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 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, £, 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 -3-(followed by 3a) proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners. Disclosure of the Invention In a first aspect, the present invention provides a process for the preparation of a compound of the formula: wherein E is a carboxy-protecting group and Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: wherein E, Rj and R2 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, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, wherein aryl by itself or as part of another group may be optionally substituted by one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, c02e oon co2e intellectual property office of n.z 284593 l.DOC 1 8 NOV 200*1 - 3a -(followed by 3b) hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aiyloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy,alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aryl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic by itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, provided that at least one of the following conditions apply: (a) Rt is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano, In a further aspect, the present invention provides a process for the preparation of a compound of the formula: c02e intellectual property office of nx 1 8 NOV m -3b-(followed by 3c) wherein E is a carboxy-protecting group, Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocaibonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (Ri l)(Rl2)N- wherein Ri 1 and R12 are independently selected from (1) loweralkyl, (2) haloalkyl, (3) alkoxyalkyl, (4) haloalkoxyalkyl, (5) alkenyl, (6) alkynyl, (7) cycloalkyl, (8) cycloalkylalkyl, (9) aryl, (10) heterocyclic, (11) arylalkyl and (12) (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: wherein E, Rj and R2 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) alkylation of the product of step c) with a compound of the formula r3-X wherein X is a leaving group and r3 is defined as above, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, OoN co2e intellectual property office of m.z. 1 8 NOV 2004 -3c-(followed by 3d) thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, wherein aryl by itself or as part of another group may be optionally substituted by 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, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aryl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic by itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, provided that at least one of the following conditions apply: (a) Rj is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano.
In a yet further aspect, the present invention provides a process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula: nh CO2E intellectual property office of n.z. 1 8 NOV 2004 RECEIVED I -3d-(followed by 3e) wherein E is loweralkyl, Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl, or a salt thereof, comprising reacting a mixture of the (+) and (-) enantiomers of the compound of the formula: with S-(+)- mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, wherein aryl by itself or as part of another group may be optionally substituted by 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, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aryl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic by itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, COjjE - 3e -(followed by 3f) provided that at least one of the following conditions apply: (a) Rj is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, aiylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano. intellectual property office OF n.z. 2 0 DEC 2084 R 6 C 6 i v F ^ - 3f-(followed by 3g) In another aspect, the present invention provides a compound selected from the group consisting of: trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -{2-(N-propyl-N- [2-(N,N-dimethylamino)]ethanesulfonylamino)ethyl}pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-(N-propyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-(N-isobutyl-N- (3-chloropropanesulfonyl)amino) ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N- (2,2,3,3,3-pentafluoropropoxyethanesulfonyl)amino) ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-(N-(2- methoxyethyl)-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N-propyl-N- ((2,2,2-trifluoroethoxyethane)sulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(1 -methoxy-1,3-benzodioxol-5-yl)-1 - (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-propyl-N- propoxyamino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-butyl-N- ethylamino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(3- aminopropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(3- dimethylaminopropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(3- trimethylammoniopropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; and trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4- aminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for antagonizing endothelin in a mammal in need thereof. 284593 l.DOC (followed by 3h) In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating hypertension, congestive heart failure, restinosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis in a mammal in need thereof.
In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament 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 cardio toxicity, nociception, colitis, vascular permeability disorders, ischemia-reperfusion injury, raynaud's disease and migraine in a mammal in need thereof.
In another aspect, the present invention provides a use of a compound of the! invention in the manufacture of a medicament for treating bone pain associated with bone cancer in a mammal in need thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
In another aspect, the present invention provides a use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for antagonizing endothelin in a mammal in need thereof. intellect!!Ai PROPERTY OFFICE -,c HZ 2 0 DEC 2004 RECEivr-, 284593_I.DOC - 3h -(followed by 3i) In another aspect, the present invention provides a use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating hypertension, congestive heart failure, restinosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis in a mammal in need thereof.
In another aspect, the present invention provides a use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament 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 cardio toxicity, nociception, colitis, vascular permeability disorders, ischemia-reperfusion injury, raynaud's disease or migraine in a mammal in need thereof.
In another aspect, the present invention provides a use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating bone pain associated with bone cancer in a mammal in need thereof.
In another aspect, the present invention provides (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
INTELLECTUAL PROPERTY office OF N.Z. 2 0 DEC R£C6:r*'r'-- I 304770 l.DOC - 3i -(followed by 4) Described herein are compounds of the formula (I): (CHdn (I) wherein Z is -C(Ri8)(Ri9)- or -C(O)- wherein R-is and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2>m-W wherein m is an integer from 0 to 6 and W is (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group, (b) -PO3H2, ^ (c) -P(0)(0H)E wherein E is hydrogen, loweralkyl or arylalkyl, fo (d) -CN, (e) -C(0)NHRi7 wherein R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, G) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2Ri6 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, (m) -S(0)2NHC(0)R-|6 wherein R16 is defined as above, intellectual PROPERTY office OF N.Z. 2 0 DEC 2004 RECEIVE ^ HO .o (n) A (O) HO ° OH *C' (P) O NH (q) ° ,N H (r) ° N-°X s=o (S) H , .JCV* (t) H , or ^ jp— NHSO2CF3 (u) Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyaikyi, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonyiaikyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amlnoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (RaaKRbb)N"Rcc* wherein Raa is aryl or arylalkyl, Rbfa is hydrogen or alkanoyl and Rcc is alkyiene, with the proviso that one or both of R1 a R2 is other than hydrogen; R3 is (a) R4-C(0)-R5- , R4-R5a". R6~S(0)2-R7- or R26-S(0)-R27- wherein R5 is (i) a covalent bond, (ii) alkyiene, (iii) alkenylene, (iv) -N(R2o)-Rs- or -R8a"N(R2o)"R8" wherein Rs and R8a are independently selected from the group consisting of alkyiene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R9a-0-R9- wherein Rg and R9a are independently selected from alkyiene; Rsa is (i) alkyiene or (ii) alkenylene; R7 is (i) a covalent bond, (ii) alkyiene, (iii) alkenylene or (iv) -N(R2i)-Rio- or-R10a-N(R2i)-Rio- wherein R10 and R10a are independently selected from the group consisting of alkyiene 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 0) (Rii)(Ri2)N- wherein Rn and R12 are independently selected from (1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) haloalkoxyalkyl, (6) alkenyl, (7) alkynyl, (8) cycloalkyl, (9) cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl, (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) diaikylaminoalkyl, (xx) alkoxy, and wherein z is 0-5 and R7a is alkyiene; R26 »s (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) (xxi) o (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xil) alkoxy-substituted haloalkyl; and R27 is alkyiene or alkenylene; (b) R22-0-C(0)-R23- wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkyiene, (iii) alkenylene or (iv) -N(R24)-R25-wherein R25 is alkyiene and R24 is hydrogen or loweralkyl, loweralkyl, (d) alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (m) alkoxyalkyl, (n) alkoxyalkoxyalkyl, or (o) Ri3-C(0)-CH(Ri4)- wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or Ris-C(O)- wherein R15 is amino, alkylamino or ™ dialkylamino; or a pharmaceutically acceptable salt thereof. (c) <d) (e) (f) (9) <h) (0 (i) (k) (I) Also described herein is a compound of formula (II) intellectual property office | of N.Z. 18 NOV 2004 RECEIVED wherein the substituents -R2. -R and -Ri exist in a trans,trans relationship and Z, n, R, Ri, R2, and R3 are as defined above.
Also described herein is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
Also described herein is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is —CH2~, and R3 is R4-C(0)-R5~, Rg-S(0)2-R7- or R26-S(0)-R27- wherein R4, R5, R6, R7, R26 and R27 are as defined above.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
Also described herein is a compound of formula (1) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs-wherein R4 is (Rn)(Ri2)N- as defined above and R5 is alkyiene or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein R7 is alkyiene, R27 is alkyiene and R6 and R26 are defined as above.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R4-C(0)-N(R2o)-R8- or R6-S(0)2-N(R2i)-Rio- wherein Rs and R10 are alkyiene and R4, R6. R20 and R21 are defined as above.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(0)-NHS(0)2Ri6 where'" R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, intellectual property office of n.z. 1 8 NOV 2004 (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, (v) alkenyl, (vi) heterocyclic (alky!), (vii) arylalkyl, (viii) 5 aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rii)(Ri2)N- wherein R^ and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkyiaminoalkyi, 10 and R5 is alkyiene; or R3 is R4-C(0)-N(R2o)-Rs- or R6-S(0)2-N(R2i)-Rio- wherein R4 is loweralkyl, aryl, alkoxy, | alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R$ and R10 are alkyiene and R20 and R21 are loweralkyl; or R3 is R6-S(0)2-R7- or R26-S(0)-R27-15 wherein R6 is loweralkyl or haloalkyl, R7 is alkyiene, R26 is loweralkyl and R27 is alkyiene.
„ Also described herein is a compound of of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (Hi) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fiuorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyI, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxy phenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, intellectual property office of n.z. 1 8 NOV 2004 RECEIVED 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-N(R2o)-R8- or R6-S(0)2-N(R2i)-Rio- wherein Rs and R10 are alkyiene, R20 and R21 are loweraJkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyi, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alky!)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 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 and R3 is R4-C(0)-Rs- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N-wherein Rni and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N- INTELLECTUAL property ! OF NX 1 8 NOV 2004 alkyl)aminoaikyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyi, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyi, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-Rs- wherein R5 is alkyiene and R4 is (Rii)(Ri2)N- wherein R^ is loweralkyl and R12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyi, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyI, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 2-fiuorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6-S(0)2-N(R2i)-Rio- wherein R10 is alkyiene, R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Also described herein Is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, Ri is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, intellectual property office of n.z. 1 8 NOV 2004 3-fluoro-4-ethoxy phenyl, 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), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-aikyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6-S(0)2-N(R2i)-Rio- wherein R10 is alkyiene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl .alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-aikyl)aminoalkyl,, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N- wherein R^ and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0)2R-i6 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri 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, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, intellectual property office of n.z. 1 8 NOV 2004 (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl ,or (ix) phenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N- wherein R-,-] and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(0)2R16 wherein R16 is loweralkyl or haloalkyl, Z is -CH2-, Ri is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-a!kanoyi-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N-wherein R11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri 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, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N- wherein Rt1 and R12 are independently selected from loweralkyl. intellectual property office of n.z. 1 8 NOV 2004 RECEIVED Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri 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, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-Rs- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N- wherein R^ is loweralkyl and R12 is aryl.
Also described herein Is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri 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, R2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is ' R6-S(0)2-N(R2i)-Rio- wherein R10 is alkyiene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl or alkoxyalkyl.
Also described herein is a compound of formula (I) or (II) wherein n is Xk RJs -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, (Intellectual proper) y umw i of n.z.
I 1 8 NOV 2001* 1 received^ 4-methoxymethoxyphenyI, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N-wherein R1t is alkyl and R12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
Also described herein is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, Ri is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Rn)(Ri2)N- wherein Rn and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or Rt1 and R12 is alkyl.
Also described herein is a compound of formula (I) or (II) wherein njs 0, Z is -CH2-, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is loweralkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is alkenyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene. intellectual property office of n.z. 1 8 NOV 2004 RECEIVED Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is heterocyclic (alkyl), and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N-as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is aiyloxyalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is arylalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and Rs is alkyiene.
Also described herein is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is (N- alkanoyl-N-aIkyl)aminoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Also described herein is a compound of formula (l) or (II) wherein n is 0, Z is -CH2-, R1 is alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rii)(Ri2)N- as defined therein and R5 is alkyiene.
The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
Described, but not claimed herein, is a method of antagonizing endothelin in a mammal (preferably, a human) in need of such intellectual property office of n.z. 1 8 NOV 2004 RECEIVED _ Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is heterocyclic (alkyl), and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N-as defined therein and R5 is alkyiene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is aryloxyalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is arylalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2>N- as defined therein and R5 is alkyiene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, Z is -CH2-, Ri is aryl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is (N-alkanoyl-N-alkyl)aminoa!kyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkyiene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Ri is alkylsulfonylamidoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rii)(Ri2)N- as defined therein and R5 is alkyiene.
The present invention also relates to processes for preparing the compounds of formula (i) and (ll) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (ll).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (ll).
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 "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
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 Ci to Cs alkyl (e.g., methyl, ethyl or tertiary butyl and the iike); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethy! and the like); alkanoyloxyalkyi groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-l-ethyl, 1-(pivaloyloxyl)-1 -ethyl, 1-methyl-1-(propionyloxy)-l-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyciohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyi, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyioxyalkyi, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1 -ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-buty!-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyt, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-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-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -<p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyioxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbony!, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyioxym ethyl 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 "alkanoy!" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkyiene group.
The term "alkanoyioxyalkyl" as used herein refers to R30-O-R31-wherein R30 is an alkanoyl group and R31 is an alkyiene group. Examples of alkanoyioxyalkyl 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-carton double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-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-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, 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 (-O-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
The term "alkoxy" as used herein refers to R41O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term "alkoxyalkoxy" as used herein refers to RsoO-RsiO-wherein Rso is loweralkyl as defined above and Rsi is alkyiene. 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 methoxy ethoxy ethyl, 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 through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to R34-C(0)-R35- wherein R34 is an alkoxy group and R35 is an alkyiene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyI and the like.
The term "alkoxycarbonyiaminoalkyl" as used herein refers to R38-C(0)-NH-R39- wherein R38 is an alkoxy group and R39 is an alkyiene group.
The term "alkoxycarbonyioxyalkyi" as used herein refers to R36-C(0)-0-R37- wherein R36 is an alkoxy group and R37 is an alkyiene group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (aikoxycarbonyl)thioaikoxy 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, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbuty!, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "(N-alkanoyl-N-alkyl)aminoalkyl" as used herein refers to R85C(0)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkyiene.
The term "alkylamino" as used herein refers to R51NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term "alkyiaminoalkyP as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropyiaminocarbonyl 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 R40-C(O)-NH-R4i- wherein R40 is an alkylamino group and R41 is an alkyiene group.
The term "alkyiene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH2C(CH3)2CH2- and the like.
The term "alkylsulfonylamidoalkyl" as used herein refers R88S(0)2NHR89- wherein R88 is loweralkyl and R89 is alkyiene.
The term "aikylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(0)2-NH-) group. Examples of aikylsulfonylamino 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 -CsC-H, H-CsC-CH2-, H-C=C-CH(CH3)- 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-, -CsC-CH2-, -CsC-CH(CH3)- 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 alkyiene.
The term "aminocarbonyl" as used herein refers to H2N-C(0)- .
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH2C(0)-) group.
The term "aminocarbonylalkoxy" as used herein refers to H2N-C(0)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH2C(0)-) group.
The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R93)- wherein Rgo, R91, and R92 are independently selected from loweralkyl and R93 is alkyiene.
The term "aroyloxyalkyl" as used herein refers to R32-C(0)-0-R33- wherein R32 is an aryl group and R33 is an alkyiene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "aryl" as used herein refers to a mono- or bicyciic carbocyciic 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, aikylsulfonylamino, 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 "arylalkoxy" as used herein refers to R42O- wherein R42 is an arylalkyl group, for example, benzyloxy, and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "aryloxy" as used herein refers to R45O- wherein R45 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 (i.e., R62C(0)0- wherein R62 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(0)H.
The term "carboxy" as used herein refers to a carboxylic acid radical, -C(0)0H.
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 (-CN) 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 (i.e., R60'C(O)-O- wherein R60 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" 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 R56R57N-wherein R56 and R57 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 (-C(O)-) linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term "dialkylaminocarbonyialkyl" as used herein refers to Rbo-C(0)-Rbi- wherein R50 »s a dialkylamino group and R51 is an alkyiene 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 heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered 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 quaternized. The term ■heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyi, quinolyi, isoquinoiyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinoiyi, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include; aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyi, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyi, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazoiyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinoiinyl, benzimidazolyi, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazoiyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
Heterocyclics also include compounds of the formula where X* is -CH2- or -O- and Y* is -C(O)- or [-C(R")2-]v where R" is hydrogen or Ci-C4-aikyl 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 (=0), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H, J* alkoxycarbonyl, nitro, cyano and loweralkyl. in addition, nitrogen containing heterocycies can be N-protected.
The term "(heterocyclic)alkoxy' as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
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 R46-C(0)-0-R47- wherein R46 is a heterocyclic group and R47 is an alkyiene group.
The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-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 haiide (for example, CI, Br or 1) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
The term "mercapto" as used herein refers to -SH.
The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl 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 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 R70S- wherein R70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The term "thioalkoxyalkoxy" as used herein refers to RsoS-ReiO-wherein Rso is loweralkyl as defined above and Rsi is alkyiene. Representative examples of alkoxyalkoxy groups include CH3SCH20-, EtSCH20-, t-BuSCH20- 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 CH3SCH2CH2OCH2CH2-f CH3SCH2OCH2-, and the like.
The term 'trans,trans" as used herein refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown Ri The term "trans,cis" as used herein refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown radical -vVN or a tautomer thereof.
R2^^-Z\„/R3 R2/ 2 R3 R2 yy JsJPH* r r or . This definition encompasses both the case where R and R2 are cis and R and Ri are trans and the case where R2 and R are trans and R and R-i are cis.
The term "cis,cis" as used herein refers to the orientation of substituents (Ri and R2) relative to the central substituent R as shown Described herein are compounds selected from the group consisting of: frans-frans-2-(4-Methoxphenyl)-4-(1,3-benzodioxoI-5-yl)-1-[3-(N-propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl>— (2-(N-propyl-N-n-pentanesulfonyIamino)ethyl]pyrrolidine-3-carboxyiic acid; fra/7slfrans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol -5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, frans-2-(3,4-DimethoxyphenyI)-4-(1,3-benzodioxo!-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans,trans-2-{ 4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N-propyl-N-r7-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; frans,frans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(((N,N-dibutylamino)carbonyl)methyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; frans,fra/7s-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-1 -[2-(N-propyl-N-/?- hexanesulfonylamino)ethyi]pyrrolidine-3-carboxylic acid; frans,frans-2-{3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl3pyrrolidine-3-carboxylic acid; frans,fra/7s-2-(4-Methoxy-3-fluorophenyi)-4-(7-methoxy-1,3-benzodioxo!-5-yi)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrroiidine-3-carboxyiic acid; trans, frans-2-(1,4-Benzodioxan-6-yi)-4-(7-methoxy-1,3-benzodioxol 5-yI)-1-[2-(N-propyi-N-(/?- pentanesuifonyl)amino)ethyI]pyrroiidine-3-carboxylic acid; frans,frans-2-(3-Fluoro-4-methoxyphenyI)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyi-N-(pentanesuifonylamino)ethyi)pyrrolidine-3-carboxyiic acid; trans, ?ra/7s-2-(3-Fiuoro-4-methoxyphenyl)-4-(1,3-benzodioxoi-5-yI)-1 -(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyi)pyrrolidine-3-carboxylic acid; frans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) 1-(2-(N-(2-methoxyethyl)-N-(butanesulfonyiamino)ethyi)-pyrrolidine-3-carboxylic acid; intellectual kkuperty OFFICF I OF N.Z. " I 1 8 NOV 2004 ! i RECFlv/Pn J fra/?s,fra/is-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2- methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxyIic acid; fra/7S,fra/7S-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-1-(2-{N-isobutyi-N-(butanesulfonylamino))ethyl)pyrrolidine-3- carboxyiic acid; frans,frans-2-(2-Methyipentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutyiaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; fra/7S,tra/JS-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N- dibutyiaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; fra/?s,frans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrroIidine-3-carboxylic acid; trans, fra/7S-2-(2-(2-Tetrahydro-2H-pyran)ethyi)-4-(1,3-benzodioxoi-5-yl)-1-(N,N-dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; fra/7S,fra/?s-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-1 -(N,N-dibutylaminocarbonyimethyl)-pyrroiidine-3-carboxyiic acid; trans, trans-2-(2,2,-Dimethyi-2-(1,3-dioxoian-2-yi)ethyl)-4-(1,3-benzodioxol-5-yi)-1-(N,N-dibutyiaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyI)-4-(1,3-benzodioxoi-5-yl)-1 -[[A/-4-heptyi-A/(2 methyl-3-fluorophenyl)] amino carbonylmethyl]-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-{1,3-Dioxoi-2-yl)ethyi)-4~(7-methoxy-1,3-benzodioxoi-5-yl)-1-{N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; fra/?s,frans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-{N,N-dibutyiaminocarbony!methyi)-pyrrolidine-3-carboxylic acid; (2S, 3fl,4S>2-(2,2-Dimethyipentyl)-4-(1 f3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fIuoro-3-methylphenyl))aminocarbonyimethyi)-pyrrolidine-3-carboxylic acid; frans,fra/7s-2-(2-(2-Oxopyrroiidin-1-yl)ethy!)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonyimethyi)-pyrrolidine-3-carboxy!ic acid; trans, frans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-rnethylphenyl))aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; trans, fra/7S-2-(2,2-Dimethylpentyi)-4-(7-methoxy-1,3-benzodioxoi-5-yl)-1-(NfN-dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxyHc acid; trans, frans-2-(2,2J-Dimethyl-2-(1,3-dioxoian-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yi)-1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; trans, frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxoI-5-yl)-1-(NfN-dibutylaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; trans, ffans-2-(2,2-Dimethyl-3-(Ej-penteny!)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,ffans-2-(2-(2-pyridyl)ethyI)-4-(1 .S-benzodioxoi-S-yO-l-fN.N-dibutylaminocarbonyimethyO-pyrroHdine-S-carboxyHc acid; (2S, 3R, 4S)-2-(2-(2-oxopyrroiidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yI)-1-(N,N-dibutylaminocarbonyimethyl)-pyrrolidine-3-carboxyiic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yI)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fiuoro-3- methylphenyi))aminocarbonylmethyl)-pyrroIidine-3-carboxyHc acid; frans,frans-2-(2-(1-pyrazoiy!)ethyl)-4-(1,3-benzodioxol-5-yi)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra/?s,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyHc acid; (r2fl,3f?,4S>2-(3-Fiuoro-4-methoxyphenyi)-4-(1,3-benzodioxol-5-yI) 1 -(2-(N-propyl-N-pentanesuifonylamino)ethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethyiamino)butyl)aminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; frans, frans-2-(2,2-Dimethylpentyi)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxoi-5-yi)-1-((N-butyl-N-(4- dimethylamino)butyl)aminocarbonylmethyt)-pyrrolidine-3-carboxyiic acid; frans, frans-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yi)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)« pyrroIidine-3-carboxyIic acid; frans,frans-2-(2,2-Dimethylpent-3-eriyl)-4-(1 ,3-benzodioxol-5-yi)-1-((N-butyl-N-(4 dimethylamino)butyl)aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2,2-Dimethyipent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N,N-dibutyl)aminocarbonyimethyi)-pyrroIidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyipent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyi-N-(4-fluoro-3-methylphenyi))aminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; fra/7s,fra/7S-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,fra/7S-2-(2,2,4-Trimethyipent-3-enyl)-4-(1,3-benzodioxoi-5-yi) 1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; frans,fra/7S-2-(2,2,4-Trimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yi) 1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; fra/?s,frans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-y!)-1-((N,N-dibutyl)aminocarbonylmethyl)-yrrolidine-3-carboxyIic acid; fra/7S,fra/7S-2-(2f2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-ber»zodioxol-5-yi)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyi))aminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; fra/7s,frans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethyiamino)butyl)aminocarbonyimethyl)-pyrrolidine-3-carboxyiic acid; trans, trans-2-(2-( 1,3-Dioxoi-2-yi)ethyl)-4-(1,3-benzodioxol-5-yi)-1 [(N-butyl-N-(4-dimethylaminobutyi)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans,trans'2'( 2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans,trans-2-(2,2,-Dimethyl-2-(1,3-Dioxol-2-yi)ethyi)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyi-N-(4-fiuoro-3-methyiphenyl))aminocarbonyimethyi)-pyrrolidine-3-carboxylic acid; fra/7S,frans-2-(2,2-Dimethyi-2-(1,3-dioxoian-2-yl)ethyl)-4-(1,3-benzodioxoi-5-yi)-1 -[(N-butyi-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroIidine-3-carboscylic acid; fra/7s,fra/7S-2-(2,2,-DimethyI-2-(1,3-Dioxol-2-yi)ethyl)-4-(7- methoxy-1,3-benzodioxoi-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3-methyiphenyl))aminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; tra/7S,fra/7s-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; frans,fra/7S-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-f luoro-3- methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/7S,fra/7S-2-(2-(2-Methoxyphenyi)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyi)amino)carbonyimethyI]-pyrroiidine-3-carboxylic acid; frans,fra/is-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yi)-1-[((N,N-dibutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methyiphenyl))amino)carbonyimethyl]-pyrroiidine-3-carboxylic acid; frans,frans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methcxy-1,3-benzodioxol-5-yl)-1-[(N-buty!-N-(4-dimethyiaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/JS,frans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl) 1-(N-4-heptyi-N-(4-fiuoro-3- methylphenyl))amino)carbonyimethyi]-pyrrolidine-3-carboxylic acid; trans, frans-2-((2-Methoxyphenoxy )-methy l)-4-( 1,3-benzodioxol-5-yl) 1-[(N-butyl-N-(4-dimethyiaminobutyl)amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid; fra/7S,fra/7S-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yI)-1 -[((N,N-dibutyl)amino)carbonyimethyl]-pyrrolidine-3-carboxy!ic acid; frans,frans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-berizodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; trans,trans-2-(2-(2-Oxo 1,2-dihydro pyridin-1-yi)-ethyI)-4-(1,3-benzodioxol-5-yl)-1-[((N,N-dibutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyridiri-1-yl)-ethyl)-4-(1,3-benzodioxoi-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-{1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-{2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[((N,N-dibutyl)amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid; trans, frans-2«(2-(2-Oxopy ridin-1 -yl)-ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyridin-1 -y!)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; trans, trans-2-(2(-2-Oxopiperidin-1-yl)-ethyi)-4-(1,3-benzodioxol-5-yi)-1-[((NtN-dibutyl)amino)carbonylmethyl3-pyrrolidine-3-carboxyiic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-( 1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methy!phenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,fran5-2-(2-(2-Oxopiperidin-1-yl)-ethy!)-4-(7-methoxy-1,3-benzodioxoI-5-yl)-1-[((N,N-dibutyl)amino)carbonylmethyi}-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopiperidin- 1-y l)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[((N,N-dibutyl)amino)carbonylmethyi]-pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-f luoro-3- methylphenyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; frans,fra/7s-2-(2-(2-Oxopiperidin-1-yi)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyi-N-(4-dimethyiaminobutyl)amino)carbonyimethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(2-Oxopyrrolidin-1-yl)ethyi)-4-(1,3-benzodioxoi-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyi]-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyrroiidin-1 -yi)ethyi)-4-(1,3-benzodioxol-5-yl)-1-[(N-buty!-N-(propoxy)amino)carbonylmethyij-pyrrolidine-3-carboxyiic acid; frans,frans-2-(2-(2-Oxopyrrolidin-1-yi)ethyl)-4-(1,3-benzodioxoi-5-yl)-1 -[(N-butyl-N-(4 dimethyiaminobutyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(2-Oxopyrroiidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yi)-1-[(N-butyi-N-(4- trimethylammoniobutyl)amino)carbonylmethyi]-pyrrolidine-3-carboxylic acid; fra/7S,fra/7S-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yi)-1-(N,N-dibutyiaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; ffa/7S,fra/7s-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yi)-1-[(N-butyl-N-(3- hydroxypropyl)amino)carbonylmethyl]-pyrroiidine-3-carboxy!ic acid; trans, fraf?s-2-(2-(2-Oxopyrroiidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fiuoro-3-methyIphenyi)amino)carbonylmethyl]-pyrroiidine-3-carboxyiic acid; frans,frans-2-(2-(2-Oxopyrroiid"m-1-yl)ethyl)-4-(7-methoxy-1>3-benzodioxol-5-yi)-1-[(N-butyl-N- (propoxy)amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid; fra/7S,frans-2-(2-(2-Oxopyrrolidin-1-yi)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(4-dimethyiaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; frans, frans-2-(2-(2-Oxopy rrolidin-1-yl)ethyi)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonyImethyl]-pyrrolidine-3-carboxyiic acid; frans,frans-2-(2-(2-Oxopyrrolidin-1-yl)ethyI)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopy rrolidin-1 -yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methyiphenyl)amino)carbonyimethyl]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopy rrolidin-1-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yi)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid; frans,frans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3 benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyI)-yrrolidine-3-carboxyiic acid; frans,frans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1 -yl)ethyl)-4-(1,3 benzodioxol-5-yI)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fransffrans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3 benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyi)amino)carbonylrnethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yi)ethyl)-4-(1,3 benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3 benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyi)amino)carbonyimethyi]-pyrroiidine-3-carboxylic acid; frans,frans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3 benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, fra/7S-2-(2-(1-propanesultamyl)ethyi)-4-(-1,3-benzodioxol-5-yl) 1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyHc acid; fra/?s,frans-2-(2-(1-propanesiJitamyl)ethyl)-4-(1,3-benzodioxol-5-yl) 1-[(N-4-heptyl-N-(4-fluoro-3- methylphenyi)amino)carbonylmethyl]-pyrroiidine-3-carboxylic acid; fra/7s,frans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-berizodioxol-5-yl) 1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyi]-pyrroiidine-3-carboxyiic acid; frans,frans-2-(2-(1-propanesultamyl)ethyi)-4-(1,3-benzodioxol-5-yl) 1-[(N-butyl-N-(propoxy)amino)carbonylmethyi]-pyrrolidine-3-carboxyiic acid; fra/7s,tra/JS-2-(2-(1-propanesuitamyl)ethyl)-4-(1,3-benzodioxol-5-yl) 1 -[(N-butyl-N-(4 dimethyiaminobutyl)amino)carbonyimethyi]-pyrrolidine-3-carboxylic acid; fra/7s,frans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxo!-5-yl)-1-(N,N-dibutyiaminocarbonyimethyl)-pyrroiidine-3-carboxyiic acid; trans, frans-2-(2-(1-propanesultamyl)ethy!)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyi-N-(4-fluoro-3-methyiphenyl)amino)carbonyimethyi]-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-(1-propanesuitamyl)ethyl)-4-(7-methoxy-1,3-benzodioxoi-5-yI)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyI]-pyrrolidine-3-carboxyiic acid; frans,trans-2-(2-(1-propanesultamyi)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonyimethyi)-pyrrolidine-3-carboxylic acid; fra/is,fra/7S-2-(2-(1-propanesultamyl)ethyi)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fiuoro-3-methylphenyl)amino)carbonylmethyl]*pyrroiidine-3-carboxylic acid; frans,frans-2-(2-(1-propanesuitamyl)ethyi)-4-(2,3-dihydro-benzof uran-5-yi)-1-[(N-butyi-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans,trans- 2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[CN- 4-heptyl-N-(4-fiuoro-3-methylphenyl)amino)carbonylmethyl3-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(1-pyrazolyl)ethyi)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl3-pyrrolidine-3-carboxyiic acid; trans, frans-2-(2-(1-pyrazo!yl)ethyi)-4-(1,3-benzodioxol-5-yl)-1-(N-butyl-N-(propoxy)amino)carbonylmethyl3-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dirnethylaminobutyi)amino)carbonylmethyl3-pyrroiidine-3-carboxyiic acid; frans,frans-2-(2-(1-pyrazoiyi)ethyl)-4-(7-methoxy-1,3-benzodioxol- -yl)-1-(N,N-dibutylaminocarbonyimethyl)-pyrroIidine-3-carboxylic acid; frans,frans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methylphenyi)amino)carbonylmethyl3-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4- dimethylaminobutyl)arnino)carbonylmethyl3-pyrrolidine-3-carboxyiic acid; trans, frans-2-(2-(1 -pyrazolyi)ethyl)-4-(2,3-dihydro-benzof uran-5- yl)-1-(N,N-dibutylaminocarbonyimethyl)-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-{1 -pyrazoiyl)ethyl)-4-(2,3-dihydro-benzof uran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methyiphenyl)amino)carbony!methyl3-pyrroiidine-3-carboxylic acid; trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzof uran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyi)amino)carbonylmethyJ3-pyrrolidine-3-carboxylic acid; fra/7s,frans-2-(2-(2-oxazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N- dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N- 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonyimethyl]-pyrrolidine-3-carboxylic acid; fra/7s,tra/7S-2-(2-(Oxazoi-2-yi)ethyi)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrroiidine-3-carboxyiic acid; trans, *rans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-{propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; trans, #rans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxo!-5-yl)-1-[(N-butyl-N-(4-dimethy!aminobutyl)amino)carbonylmethyi]-pyrrolidine-3-carboxyiic acid; frans,fra/7S-2-(2-(Oxazoi-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol- -yl)-1-(N,N-dibutylaminocarbor»ylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(Oxazol-2-yl)ethyi)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methylphenyl)amino)carbonyimethyI]-pyrrolidine-3-carboxylic acid; frans,fra/7S-2-(2-(Oxazol-2-yi)ethy!)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-buty!-N-(4- dimethylaminobutyl)amino)carbonylmethy!3-pyrrolidine-3-carboxyiic acid; frans, fra/7S-2-(2-(5-Methyloxazol-2-yI)ethy!)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyfic acid; trans, frans-2-(2-(5-Methyloxazol-2-yl)ethy l)-4-( 1,3-benzodioxo!-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3- methyiphenyl)amino)carbonyimethyl]-pyrro!idine-3-carboxylic acid; trans, frans-2-(2-(5-Methyloxazol-2-yl)ethyI )-4-(1,3-benzodioxol-5-yi)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl3-pyrroiidine-3-carboxyiic acid; frans,fra/7s-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,fra/?s-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methy!phenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/JS,frans-2-(2-(2,5-Dioxopyrrolidin-1-yi)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyIic acid; trans, frans-2-(2-(2,5-Dioxopy rrolidin-1 -yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine 3-carboxylic acid; fra/7S,fra/7s-2-(2-(2,5-Dioxopyrroiidin-1~yl)ethyl)-4-(1,3-benzodioxol -yl)-1-[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; trans, fraAJs-2-(2«(2,5-Dioxopy rrolidin-1 -yl)ethyi)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyi-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N 4-heptyl-N-(4-fluoro-3-methylphenyi)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; fra/7s,fra/7s-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N butyl-N-(3-hydroxypropyI)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, fra/?s-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxoI-5-yl)-1-[(N butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N1N-dibutylaminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yi)-1 -[(N-4-heptyl-N-(4-fluoro-3-methylphenyi)amino)carbonyimethyI3-pyrrolidine-3-carboxylic acid; trans, frans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxyiic acid; frans,frans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N.N-dibutyiaminocarbonylmethyO-pyrrolidine-S-carboxyiic acid; trans, frans-2-(2-(Py rimidin-2-yl)ethyl)-4-( 1,3-benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fiuoro-3- methylphenyl)amino)carbonylmethy!]-pyrroiidine-3-carboxylic acid; frans, fra/7s-2-(2-(Pyrimidin-2-yl)ethyi)-4-(1,3-benzodioxol-5-yl)-1-{(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; frans,frans-2-(2-(1,3-benzodioxol-4-yl)ethyi)-4-<1,3-benzodioxoi-5-yl)-1-(N,N-dibutyiaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; trans, frans-2-(2-(1,3-benzodioxol-4-yi)ethyl)-4-(1,3-benzodioxoi- 5-yI)-1-[(N-4-heptyl-N-(4-fluoro-3- methylphenyi)amino)carbonylmethy!]-pyrroiidine-3-carboxyIic acid; and trans, frans-2-(2-(1,3-benzodioxol-4-yi)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyi-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt.
Also described herein are compounds selected from the group consisting of: consisting of: trans, frans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; intellectual property officf of n.z. 1 8 NOV 2004 frans,fra/7S-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-t>er\zod\oxo\'5-y\)-*\-(N,N~clibutylammocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, fra/JS-2-<2-(1,3-Dioxol-2-yl)ethyl)-4-( 1,3-benzodioxol-5-y!)— [[N-4-heptyl-N-(2-methyi-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans,trans-2-(2-(1,3-Dioxo!-2-yI)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonyimethyl)-pyrrolidine-3-carboxyiic acid; trans, fra/7S-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; trans, frans-2-(2-(2-Oxopyrrolidin-1 -yl)ethy!)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans,trans- 2-(2-(1,3-Dioxol-2-yl)ethyi)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; frans,fra/7S-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; trans, frans-2-(2,2,-Dimethyl-2-(1,3-dioxoian-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxoI-5-yl)-1 -(N,N-dibutyiaminocarbonyimethyl)-pyrrolidine-3-carboxyIic acid; trans, frans-2-(2-(2-Methoxyphenyl)-ethyI)-4-(1,3-benzodioxol-5-yl)-l-(N,N-dibutyiaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(2,2-Dimethyi-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutyiaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; trans, frans-2-(2-(2-pyridyl)ethyi)-4-(1,3-benzodioxol-5-yi)-1-(N,N- dibutylaminocarbonyimethyi)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyi)-pyrrolidine-3-carboxyiicacid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fluoro-3- methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N- dibutylaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; and (2S, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3-carboxyiic acid; or a pharmaceuticaily acceptable salt thereof.
Methods for preparing the compounds described herein are shown in Schemes l-XV.
Scheme I illustrates the general procedure for preparina the compounds when n and m are 0, Z is -CH2- and W is ; -CO2H. A p-ketoester 1_, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound Z, 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 2. 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 (1) acylated or sulfonylated with R3-X (R3 is R4-C(0)- or R6-S(0)2- and x is a leaving group such as a halide (CI is preferred) or X taken together with R4-C(0)- or R6-S(0)2- forms an activated ester including esters or intellectual property office of n.z. anhydrides derived from formic acid, acetic acid arid the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, CI, 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 ethyiamine or triethyiamine and the like to give the N-derivatized pyrrolidine §. which is still a mixture of trans, trans and cis,trans isomers. Hydrolysis of the ester §L (for example, using a base such a sodium hydroxide in EtOH/HaO) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and &, which are readily separated.
Scheme 11 illustrates a general procedure for preparing the 1 compounds when n is 1, m is 0, Z is -CH2- and W is -CO2H. A substituted benzyl chloride £ is reacted with a lithio dithiane 10 in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound JUL is formed using a base such as n-butyllithium and then reacted with Ri-CH2-X' 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 12.. Reaction of ketone 12. with benzyl amine and formaldehyde gives the keto piperidine compound 14. Treatment , of compound 14. with an activated nitrile such as trimethyisilyi cyanide followed by a dehydrating agent such as phosphorous oxychioride provides the isomeric ene nitriles 15.
Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile UL. 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 Ifi. Compound 18 is further elaborated by the procedures described in Scheme I for compound 5. to give the final product compound 12..
Scheme 111 illustrates a general procedure for preparing the compounds when m and n are 0, Z is -C(O)- and W is -CO2H. p-^eto ester 2H (Wherein E is loweralkyl or a carboxy intellectual property office of nz 1 8 NOV 2004 protecting group) is reacted with an a-haloester Z1 (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 tert-butoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with R3-NH2 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 25.
Scheme IV illustrates a general procedure for preparing the compounds when n is 0, m is 1, Z is -CH2- and W is -CO2H. The trans,trans compound 7, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyi chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is CI). 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 repetition of the above described process.
A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate 26. is reacted with a nitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyciization 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 (3D- Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (31) of trans,trans and cis,trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in acetonitriie in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 22,, 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 22. from the cis,trans ester 34.
Scheme VII illustrates the preparation of a specific piperidinyi compound. Benzodioxolyl methyl chloride 25. is reacted with lithio dithiane 22. to give the alkylated compound 2Z- Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 22- Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 2£ with benzylamine and formaldehyde gives the keto piperidine 4£t. 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 piperidinyi nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 42- 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 21 resulting in the formation of the N-derivatized carboxylic acid 45..
A preferred embodiment of the process shown in Scheme 11 Ms shown in Scheme VIII. 4-Methoxybenzoylacetate 4f5 (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 42 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 4JL The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 5Q.. Epimerizatipn 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 SI- Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid. Compound 55. which \ can 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 ££.. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile §Z-Nitrile 5Z under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 53_. Alternatively nitrile £7 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 5E- The amidoxime £2 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 cyciization to compound ££.. 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 acyimethylene group. A carboxylic acid £2 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N-dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone 63. Pyrrolidine ester 5. where E is lower alkyl or a carboxy protecting group, prepared in Scheme 1, is alkylated with the a-chloroketone 63 to provide alkylated pyrrolidine M- Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 65.
Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5., prepared in Scheme I, is reacted with a difunctionalized compound X-Rs-X where Rs is alkyiene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound QS_. Treatment of ££ with an amine (R20NH2) affords secondary amine fiZ. This amine (£Z) can be reacted with an activated acyl compound (for example, R4-C(0)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide M- Alternatively amine £7 can be reacted with an activated sulfonyl compound (for example, R6-S(0)2-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69.
Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 7Q. are known to add to unsaturated esters such as Z1 to provide pyrrolidines such as compound 72 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S.
Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. §2 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. Q2 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 72 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 Z4 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine ££.. 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 Boc-nitrogen protected (for example, by treatment with B0C2O) 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 ZiL The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid Z£. 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 fiH. 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 acetonitriie in the presence of diisopropylethylamine) to give optically active compound £1. 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. F., et.a!., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, the azomethine ylide precursor (where R55 is hydrogen or methyl) is condensed with a substituted acrylate £2. (wherein R2 is as described herein and R56 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 §§_. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid £7.
A preferred process is shown in Scheme XV. Nitro vinyl compound (88^ is reacted with beta-keto ester ££ in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitriie, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 90. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound ££L in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitriie and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium 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 £2 as the cis, cis-isomer. Epimerization at C-3 is effected by treatment of compound £2 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -20° C to about 120° C to give the trans,trans compound £2- Compound £2 itself can optionally be resolved into enantiomers prior to reacting with X-R3. The substantially pure (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound £2. is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 32. with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitriie, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+)-isomer of £2. selectively crystallizes as the salt, leaving the (-)-isomer of £2. in solution. Alternatively, the substantially pure (i.e., at least 95% of the desired isomer) optically active (-)-isomer of compound £2. can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of £2. with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)-isomer of compound £2 in solution.
Compound £2. (racemic or optically active) is reacted with X-R3 (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 acetonitriie, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester £4. The ester can be isolated or converted in situ to the carboxylic acid (95^ using hydrolysis conditions such as base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THF-ethanol and the like.
Scheme I Ri CO2E R2 ^^no2 - co2e H /—N § R2 V >-R! CO;>E Mixture of Cis-Cis Trans-Trans Cis-Trans [h] r2 co2e 4 x-rg ,R3 /~~N R2-0-RI § co2e Mixture of Trans-Trans Cis-Trans [H20] r3 N R2—\ J—R, 7 co2h Trans-Trans + ,R3 /~-N R2»«<1_RI co2e s Cis-Trans Scheme il ^ci 9 + JO —- 1"^ i d R2^A^Rl "" / a C02E R2n^4^ D ^ 12 I J5 + ISOMER hn-^y"2 R3-N^YR2 Y^COzE Y^"-co2H Rt Rt JS 19 Scheme III Halo R,-<^ *ar°j r X^0O2E ^—COzE + O ^ R1 J 2L J02C R2 Halo = CI, Br, or I °V -R3 r-H co2e 24 Vn'"3 R2"^y^-R1 Z co2h Trans-Trans Q- ..RS -v., - ^ co2e 22.
R3 Scheme IV rj-0-f>i —►. r2-0-ri CO2H J O^L CH2N2 R3 /-N r-N R2 — | I O^CHN2 ^co2H Scheme V ch3o Et02C 26 27 /-OCH3 COOEt OCH3 Mixture of 3Sl Cis-Cis NaCNBH3 COOEt Trans-Trans y Chromatographic separation Cis-Trans Cis-Cis + Mixture of Trans-Trans and Cis-Trans 31 Scheme VI BrCHgCONHC^y nhc3h7 COOEt Trans-Trans ^ ^-OCH3 COOEt Trans-Trans and Cis-Trans 2£ NaOH , H2O, EtOH NHQ3H7 OCH3 COOH Trans-Trans O a { NHC3H7 och3 COOEt Cis-Trans & & c.=) Scheme VII 0X« * n 36 CCUO 3Z o OMe < 39 MeO ^ 38 cro: cn > + ISOMER OMe OMe 40 41 Scheme VII cont.
Scheme Vlll ch3o- s\ C02E £l CH3O /^CH och /^•CH OCH3 /—ch3 OCH3 Scheme IX R3 .R3 N r—u & 1 n nh n=n m (CH2)m (CH2)m I I co2h conh2 I R3 ,*3 n' r~ n R2-< J-R, R2 (CHaJm (CH2)m cn S I A ,R3 "2-o-R, R2-o-R, r2-0-R, (CH2)m (CH*2)m ^ <CH2)m HN^n HjN-^.NOH hn^N >-° >-° 0 59 o fiQ 61 Scheme X VH * "V - "-r* o o + co2h r4 r2 o m. 64 Scheme XI h /—N co2e 5 ^R8—X r2 /"—N -yU co2e 2 r8-n /-n' h -yU co2h >-r< 68 /—N xr8-nhr20 co2e E 0,,Re /—N M -y-R, a co2h sb Scheme XII ?1 ^3 v.
N+ CH2* 22 ♦ ( C02Et R2 71 r3^c°2b r2 22 Me3Si * o och3 o 73 OCH3 HN^V-C°2Et $ 74 COaEt OCH3 Bu2N Scheme XIII cozet 1. Boc20 2. NaOH, EtOH H2Q -CO2H HCI och3 C02Et 1. (+)-cinchonirte 2. recrystallize frorrj EtOAc/hexane 3. Na2C03 HCI EtOH COah (+) 22 Bu2NC(0)CH2Br EtNiPr2, CH3CN pCH3 CO2H v.
(+) SI OJ Scheme XIV rss R2^oo2Rm r r55 1 f~ fg Ph Bi^Si^-OMe ~ LV-COjRw Me^ ™-°«* * SL H 2 N-"\ v' r2 M RsBr t>rtfr\u\ tn HN*"\. BmNlorNal Pd(OH)2/C j y- C02RS6 Sl CH3CN r, NaOH or UOH r, XYo^ EtOKHsO^ >Q.COlH R2 R2 Scheme XV r2 ^^N02 sa o o + eo' v ~r, sa /—N j—N Ra»y>-Ri r2»<>~Ri CO2E 91a coge 91b O2N. r2 CO2E 22 /~nh Ra^-C^Ri CO2E 92 /—nh co2e 22 / R3 n r2 / R3 n r2i co2h 95 c02e M Compounds which are useful as intermediates for the preparation of compounds described herein are: wherein n is 0 or 1; m is 0 to 6; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamide), (l) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6, (III) (n) o I /~A (0) intellb (P) (q) (r) (s) NH o N-°v S—O / N H Kr^N SJC ^~CF3 (t) H , or -\-C V— NHSO2CF3 (u) ; and Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloaikylalkyi, aminocarbonylalkyl, alkyiaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkyiaminocarbonylalkenyl, hydroxy alkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxy alkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(^bb)N"Rcc" wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkyiene, with the proviso that one or both of R1 an R2 is other than hydrogen; or a salt thereof; or a compound of the formula: (CH2)n NH (CH2)m R2//( (CHaJn NH W Rl (IV) or (V) w R1 wherein n is 0 or 1; m is 0 to 6; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, 0) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6, HO 0 O (o) HO 0 OH o (q) NH b-"4> (r) (s) tk o fr \ s=o / H N £>-^3 (t) H , or y~~ NHS02CF3 (u) ; and Ri 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, arylalkoxy alky I, (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 Rcc is alkyiene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (111), (IV) and (V) wherein m is zero or 1; W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (III), (IV) and (V) wherein n and m are both 0; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; 5 and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted dimethoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-10 methylphenyl, | 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy- 1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofumayi, 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 described herein are: wherein n is 0 or 1; m is 0 to 6; Rsb is alkyiene; Q is a leaving group; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (|) alkoxy, (k) sulfonamide), (1) -C{0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6, (n) o (0) n° 0 01 o o (s) (r) (t) H , or nhso2cf3 ki^.n i y-o=3 -s M (U) and Ri and R2 are Independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkyiaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N"Rcc" wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkyiene, with the proviso that one or both of R-j « R2 is other than hydrogen; or a salt thereof; or a compound of the formula: (VII) (Vlll) wherein n is 0 or 1; m is 0 to 6; Rsb is alkyiene; Q is a leaving group; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHR-|7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)R16, vJ" .0 -K # r (o) *° ° oh O (q) o (r) o (S) s=o / N H n-n jV-3 5c* N (t) s H , or "v\ rl— nhso2cf3 (u) — ; and Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haioalkyi, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkyiene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII) and (Vlll). wherein m is zero or 1; Rsb is alkyiene; Q is a leaving group; W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (VI), (VII) and (Vlll) wherein n and m are both 0; R5b is alkyiene; Q is a leaving group; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyi, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxy phenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy- 1.3-benzodioxolyl, 1.4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyi, 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 described herein are: (IX) wherein n is 0 or 1; m is 0 to 6; R5b is alkyiene; R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, ioweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) sulfonamido, (I) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6, <n) o (o) n° 0 OH O (q) o (0 o (t) (U) * Kr-N JO- CFa N H or ■K> NHS02CF3 and Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkyiaminocarbonyialkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxy alkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyciic)alkyl and (Raa)(Rbb)N"Rcc" wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkyiene, with the proviso that one or both of R-, and R2 is other than hydrogen; or a salt thereof; or a compound of the formula: ^R5b-NHR20a <CH2>n (X) or (XI) ✓^sb* NHRaoa N I (CH2)„ wherein n is 0 or 1; m is 0 to 6; Rsb is alkyiene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(0H)E where E is hydrogen, loweralkyl or arylalkyl, (d) -CN, (e) -C(0)NHRi7 where R17 is loweralkyl, (f) alkylaminocarbonyl, (g) dialkylaminocarbonyl, (h) tetrazolyl, (i) hydroxy, (j) alkoxy, (k) suifonamido, (I) -C(0)NHS(0)2Ri6 where R16 is loweralkyl, phenyl or dialkylamino, (m) -S(0)2NHC(0)Ri6, (n) o oh O (q) o (r) o / "NHS02CF3 (u) ; and Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkyiaminocarbonylalkyl, aminocarbonylalkenyi, alkyiaminocarbonyialkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxy alkyl, (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 Rcc is alkyiene, with the proviso that one or both of R1 and R2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1; Rsb is alkyiene; R2oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0; R5b is alkyiene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafiuoroethyiphenyl, 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, haioalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyi)aminoaikyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure (+)- or (-)-isomer thereof.
The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept. The following abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1,8-diazabicycio[5.4.0]undec-7-ene, EDCI for 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et3N for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran. trans, trans- 2-(4-MethoxvphenvlV4-f 1.3-benzodioxol-5-vn-1 -foroDviaminocarbonvlmethvlVovrrolidine-3-carboxvlic acid Example 1A Ethvl 2-(4-methoxvbenzovfl-4-n itrom ethvl-3-( 1.3-benzodioxole-5-vnbutvrate To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2-nltrovinyl)-1,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 °C was added 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved. The solution was stirred without heating for 30 minutes (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography (5% ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and 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 Ethvl 2-(4-methoxvphenvlV4-(1.3-benzodioxol-5-vlV4.5-dihvdro-3H-pvrroie-3- carboxvlate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 g). (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
Example 1C Ethvl 2-(4-methoxvDhenvl-4-( 1.3-benzodioxol-5-vn-Pvrrolidine-3-carboxvlatel - 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,frans-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.
Example 1D trans.trans-2-f4-Methoxvphenvn-4-f 1.3-benzodioxol-5-vn-1 -foroovlaminocarbonvlmethvfl-pvrrolldine-3-carboxvlic acid The mixture of 64% trans,trans- and 34% c/s,frans-pyrrolidlnes (the mixture resulting from Example 1C) (5.72 g, 15.50 mmol), ethyidiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by the method of Weaver, W.E. and Whaley, W.M., J. Amer. Chem. Soc., §£: 515 (1947), in 30 mL of acetonitriie was heated at 50 °C for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis,trans- ethyl esters.
This mixture was dissolved in a solution of 50 mL of ethanol and 15 mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and 60 mL of water added. The mixture was extracted with ether to remove the unreacted cis,trans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound, m.p. 151-153 °C. 1H NMR (CD3OD, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.49 (sextet, J s 7 Hz, 2H), 2.84 ( d, J = 16 Hz, 1H), 2.95-3.20 (m, 4H), 3.20 (d, J = 16 Hz, 1H), 3.34-3.42 (m, 1H), 3.58-3.66 (m, 1H), 3.78 (s, 3H), 3.88 (d, J = 10 Hz, 1H), 5.92 (s, 2H), 6.75 (d, J = 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J = 1 Hz, 1H), 6.90 (d, J = 9 Hz, 2H), 7.02 (d, J = 1 Hz, 1H), 7.40 (d, J = 9 Hz, 2H).
Example 2 trans. frans-2-(4-MethoxvPhenvlV4-( 1.3-benzodioxol-5-vn-1 -faminocarbonvlmethvn-Pvrrolidine-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 resulting from Example 1C), 220 mg of diisopropylethylamine and 184 trig iodoacetamide were reacted at 45 °C in 1 mL acetonitriie to give 291 mg of a mixture of tran$,trans- and cis,trans- N-alkylated esters. A portion (270 mg.) was hydroiyzed 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 1D were used to give 134 mg of the title compound, m.p. 246-248 °C. 1H NMR (DMSO-d6, 300 MHz) 8 2.61 (d, J = 16 Hz, 1H), 2.71 (t, J - 9 Hz, 1H), 2.90 (t, J = 9 Hz, 1H), 2.98 (d, J s 16 Hz, 1H),3.25-3.35 (m, 1H), 3.45-3.55 (m, 1H), 3.71 (s, 3H), 3.75 (d, J = 10 Hz, 1H), 6.00 (s, 2H), 6.81 (s, 2H), 6.90 (d, J « 8 Hz, 2H), 7.10 (s, 1H), 7.17 (s, 1H), 7.34 (s, 1H), 7.38 (d, J = 8 Hz, 2H).
Example 3 frans. frans-2-f4-MethoxvphenvB-4-h.3-benzodioxol-5-vr>-1-(4-fltiorobenzvlV. pvrrolidine-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 resulting from Example 1C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitriie to give 387 mg of a mixture of trans,trans- and c/s,frans-N-alkylated esters. A portion (360 mg) was hydroiyzed 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. 1H NMR (CDCl3. 300 MHz) 8 2.74 (t, J = 9 Hz, 1H), 2.95 (t, J = 7 Hz, 1H), 2.98 (d, J « 14, 1H), 3.07 (dd, J = 9 Hz, 1 Hz, 1H), 3.42-3.53 (m, 1H), 3.70 (d, J = 9 Hz, 1H), 3.78 (d, J = 14, 1H), 3.81 (s, 3H), 5.92 (s, 2H), 6.70 (d, J = 8 Hz, 1H), 6.77 (dd, J = 8 Hz, 1 Hz, 1H), 6.91 (d, J = 9 Hz, 2H), 6.94 -7.00 (m, 3H), 7.20 - 7.25 (M, 1H), 7.44 (d, J = 9 Hz, 2H).
Example 4 trans. frans-2-(4-MethoxvphenvlM-n. 3-benzodioxol-5-vlV1-(2-ethoxvethvl>- pvrrolidine-3-carboxvlic acid Using the method described in Example 1D, 300 mg. of the mixture of 64% trans,trans- and 34% c/s,frans-pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitriie for 3 hours (bath temperature at 95 °C) to give 346 mg of a mixture of trans,trans- and cis,trans-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 140 mg of the title compound, m.p. 88 - 90 °C. 1H NMR (CDCI3, 300 MHz) 8 1.25 (t, J » 7 Hz, 3H), 2.21-5 2.32 (m, 1H), 2.70-2.80 (m, 1H), 2.85-2,94 (m, 2H), 3.38-3.55 (m, 6H), 3.67 (d, J = 10 Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J = 8 Hz, 1H), 6.84 (m, 1H), 6.84 (d, J = 9 Hz, 2H), 7.08 (d, J — 1 Hz, 1H), 7.33 (d, J = 9 Hz, 2H).
Example 5 frans.frans-2-(4-MethoxvohenvlM-f 1.3-benzodioxol-5-vn-1 -fg-proooxvethviV pvrrolidine-3-carboxvlic acid Using the method described in Example 1D, 520 mg of the mixture resulting from Example 1C, 364 mg of diisopropylethylamine, 50 mg 15 potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitriie for 4 hours to give 517 mg of a mixture of trans, trans- and cis, trans-esters. A portion (500 mg) was hydroiyzed 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. 1H NMR 20 (CDCI3, 300 MHz) 8 0.87 (t, J = 7 Hz, 3H), 1.53 (sextet, J = 7 Hz, 2H), 2.28-2.41 (m, 1H), 2.71-2.83 (m, 1H), 2.92-3.08 (m, 2H), 3.30 (t, J = 7 Hz, 2H), 3.40-3.60 (m, 4H), 3.72-3.83 (m, 1H), 3.76 (s, 3H), 5.92 (s, 2H), 6.71 (d, J = 8 Hz, 2H), 6.74 (dd, J = 8 Hz, 1 Hz), 6.71 (d, J = 9 Hz, 2H), % 7.07 (d, J F 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H). trans. frans-2-(4-MethoxvphenvlV4-f 1.3-benzodioxol-5-vl>-1 -!2-f2-methoxvethoxvtethvn-pvrrolidine-3-carboxvlic acid Example 6A Ethvl trans.frans-2-(4-methoxvphenvlY-4-( 1.3-benzodioxol-5-vn pvrrolidine-3- carboxvlate To the pure cis,cis-compound resulting from Example 1C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% 35 sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutralized with HCI in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).
Example $B trans. frans-2-f4-Methoxvphenvtt-4-f 1.3-benzodioxol-5-vl)-1 -\2-(2-methoxvethoxv)ethvn-Pvrrolidine-3-ca rboxvlic acid Using the method described in Example 1D, 250 mg of the compound resulting from Example 6A, 150 mg of 2-(2-methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitriie were heated at 100 °C for 3 hours to give 229 mg of the trans,trans-ester. A portion (200 mg) was hydroiyzed 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. 1H NMR (CD3OD, 300 MHz) 8 2.9-3.9 (m, 13H), 3.81 (s, 3H), 4.49 (d, J = 10 Hz, 1H), 5.94 (s, 2H), 6.79 (d, J = 8 Hz, 1H), 6.89 (dd, J = 8 Hz, 1 Hz, 1H), 7.00 (d, J = 9 Hz, 2H), 7.05 (d, J = 1 Hz, 1H), 7.49 (d, J « 9 Hz, 2H).
Example 7 frans.frans-2-(4-Methoxvphenvfl-4-/1.3-benzodioxol-5-vlV1 -f2-(2-ovridvnethvn- pvrrolidine-3-carboxvlic acid The. compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydroiyzed by the method described in Example 1D to give 202 mg of the title compound as the dihydrate. m.p. 77-80 °C. 1H NMR (CD3OD, 300 MHz) 8 2.8 - 3.3 (m, 6H), 3.55-3.70 (m, 2H), 3.76 (s, 3H), 3.99 (d, J = 10 Hz, 1H), 5.92 (d, J « 1 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.80 (dd, J = 8 Hz, 1 Hz), 6.85 (d, J = 9 Hz, 2H), 6.92 (d, J = 1 Hz, 1H), 7.20 (d, J = 9 Hz, 2H), 7.20-7.32 (m, 2H), 7.70-7.80 (m, 2H), 8.40 (d, J = 4 Hz, 1H).
Example 8 trans, frans-2-f 4-Methoxvphen vO-4- (1.3-benzodioxol-5-vn-1 -(moroholin-4-vlcarbonvllpvrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydroiyzed by the method described in Example 1D to give 288 mg of the title compound, m.p. 244-246 °C. 1H NMR (DMSO-ds, 300 MHz) 8 2.96 (dd, J = 12,Hz, 13 Hz, 1H), 3.03-3.13 (m, 2H), 3.20-3.30 (m, 2H), 3.40-3.60 (m, 5H), 3.74 (s, 3H), 3.70-3.85 (m, 3H), 5.10 (d, J = 10 Hz, 1H), 5.99 (d, J = 1 Hz, 2H), 6.80-6.90 (m, 2H), 6.87 (d, J = 9 Hz, 2H), 7.07 (s, 1H), 7.25 (d, J = 9 Hz, 2H).
Example 9 frans.frans-2-f 4-MethoxvphenvlV4-( 1.3-benzodioxole-5-vn-1 -(butvlaminocarbonvn- pvrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl isocyanate. After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydroiyzed by the method described in Example 1D to give 232 mg of the title compound, m.p. 220-221 °C. 1H NMR (DMSO-de, 300 MHz) 5 0.78 (t, J = 7 Hz, 3H), 1.10 (sextet, J *= 7 Hz, 2H), 1.22 (quintet, J = 7 Hz, 2H), 2.78-3.05 (m, 3H), 3.40-3.56 (m, 2H), 3.74 (s, 3H), 3.95-4.05 (m, 1H), 4.93 (d, J = 9 Hz, 1H), 5.80 (t, broad, J = 7 Hz, 1H). 5.99 (s, 2H), 6.78-6.86 (m, 2H), 6.88 (d, J = 9 Hz, 2H), 7.00 (d, J = 1 Hz, 1H), 7.12 (d, J = 9 Hz, 2H).
Example 10 trans. trans-2-l 4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -J4-methoxvphenvlaminocarbonvfl-3-pyrrolidine-3-carboxvlic 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 hydroiyzed with NaOH using the method described in Example 1D to give 279 mg of the title compound. m.p. 185-187 °C. 1H NMR (CDCI3, 300 MHz) 5 3.23 (dd, J = 12 Hz, 13 Hz, 1H), 3.55-3.68 (m, 2H), 3.72 (s, 3H), 3.83 (s, 3H), 4.50-4.65 (m, 1H), 5.06 (d, J = 10 Hz, 1H), 5.90 (s, 1H), 5.95 (s, 1H), 6.72 (d, J = 9 Hz, 2H), 6.7-6.8 (m, 3H), 6.92 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H).
Example 11 trans. frans-2-f4-Methoxvphen vtt-4-f 1.3-benzodioxol-5-vtV1 -acetvlpvrrolidina-3- carboxviic 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 hydroiyzed using the method of Example 1D to give 211 mg of the title compound, m.p. 248-250 °C. Rotational isomers are seen in the NMR. 1H NMR (DMSO-de, 300 MHz) 5 1.55 and 2.00 (s, 3H), 2.94 and 3.03 (dd, J a 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 3.72 and 3.76 (s, 3H), 4.12 and 4.28 (dd, J = 12 Hz, 7 Hz, 1H), 4.95 and 5.04 (d, J « 10Hz, 1H), 6.00 (s, 2H), 6.75-6.87 (m, 3H), 6.95 and 7.04 (d, J = 9 Hz, 2H), 7.18 and 7.32 (d, J * 9 Hz, 2H).
Example 12 trans. trans-2-i 4- Met hoxvph en vl M- f 1.3-benzodioxol-5-vn-1 -f2-furovlVpvrrolidine~3- carboxvlic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example 1D to give 269 mg of the title compound as an amorphous powder. 1H NMR (DMSO-d6, 300 MHz) 8 3.06 (dd, J = 12 Hz, 13 Hz, 1H), 3.3-3.6 (m, 2H), 4.25 (m, 1H), 5.19 ( d, J = 10 Hz, 1H), 6.67.4 (m, 8H), 7.8-7.9 (m, 1H).
Example 13 trans. frang-2-/4-MethoxyphenvlV4-f 1.3-ben zodioxol-5-vfl-1 -fphenvlaminocarbonvn-pyrroiidine-3-carboxvlic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared, m.p. 209-211 °C. 1H NMR (DMSO-d6, 300 MHz) 8 3.03 (dd, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 3.72 (s, 3H), 4.15 (m, 1H), 5.13 (d, 1H), 6.00 (s, 2H), 6.88 (m, 5H), 7.07-7.20 (m, 3H), 7.30 (d, 2H), 7.38 (d, 2H), 8.20 (bs, 1H). trans.trans-g-fo-MethoxvphenvlM-f 1.3-benzodioxol-5-vn-1 -fallvlaminocarbonvlmethvO-PVTTolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 138-140 °C. 1H NMR (CDCI3, 300 MHz) 8 2.84 (d, 1H), 2.90-3.10 (dt, 2H), 3.28 (d, 1H), 3.35 (dd, 1H), 3.62 (m, 1H), 3.72-3.97 (m, 3H), 3.80 (s, 3H), 5.13 (bd, 2H), 5.80 (m, 1H), 5.97 (s, 2H), 6.74-6.97 (m, 5H), 7.38 (d, 2H).
Example 1$ trans. trans-2-( 4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -(n-htitviaminocarbonvlmethvn-pyrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 105-107 °C. 1H NMR (CDCI3, 300 MHz) 8 0.90 (t, 3H), 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1H), 2.87-3.35 (m, 6H), 3.62 (m, 1H), 3.80 (s, 3H), 5.97 (s, 2H), 6.75-6.92 (m, 5H), 7.28 (d, 2H). trans, trans-2-f4-Methoxvohenvn-4-f 1.3-benzodioxol-5-viV1 -(N-(n-propvn-N-methvlaminocarbonvlmethvlVpvrrolidine-3-carhoxvlic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) 5 0.73, 0.84 (2t, 3H), 1.49 (m, 2H), 2.80 (dd, 1H), 2.85 (2s, 3H), 2.95-3.20 (m, 3H), 3.20-3.40 (m, 1H), 3.40 (d, 1H), 3.60 (m, 1H), 3.79 (s, 3H), 5.93 (s, 2H), 6.73 (d, 1H), 6.86 (m, 2H), 7.03 (m, 1H), 7.32 (d, 2H).
Example 17 trans, trans-2-(4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vlV1 -/pvrrolidin-1 - vlcarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 1.40-1.70 (m, 6H), 2.80 (d, 1H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1H), 6.80-6.90 (m, 3H), 7.04 (d, 1H), 7.30 (d, 2H).
Example 18 frans.frans-2-f4-Methoxvphenvn-4-f 1.3-benzodioxol-5-vn-1-risobutvlaminocarbonvlmethvfl-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 175-177 °C. 1H NMR (CD3OD, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, 1H), 2.85 (d, 1H), 2.90-3.10 (m, 4H), 3.23 (d, 1H), 3.40 (m, 1H), 3.58-3.67 (m, 1H), 3.78 (s, 3H), 3.89 (d, 1H), 5.92 (s, 2H), 6.76 (d, 1H), 6.86 (dd, 1H), 6.91 (d, 2H), 7.02 (d, 111), 7.40 (d, 21 \f.
Example 19 frans.frans-2-(4-Methoxvphenvfl-4-( 1.3-benzodioxol-5-v0-1 -(cvclopentvlaminocarbonvlmethvlVpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 °C. 1H NMR (CDCI3, 300 MHz) 8 1.34 (m, 2H), 1.62 (m, 4H), 1.90 (m, 2H), 2.76 (d, 1H), 2.90 (t, 1H), 3.04 (dd, 1H), 3.22 (d, 1H), 3.28 (dd, 1H), 3.40 (m, 1H), 3.80 (s, 3H), 4.15 (m, 1H), 5.97 (d, 2H), 6.75-6.95 (m, 5H), 7.27 (m, 2H).
Example 20 frans.frans-2-(4-Methoxvphenvfl-4-( 1.3-ben zodioxol- 5-vlV 1 -(morpholin-4-vlaminocarbonvlmethvlVpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 2.82 (d, 1H), 3.00 (m, 2H), 3.24 (m, 1H), 3.30-3.52 (m, 4H), 3.52-3.75 (m, 8H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, 1H), 6.84 (d, 3H), 7.00 (s, 1H), 7.28 (d, 2H).
Example 21 trans.trans-2-(4-Methoxvphenvl)-4~( 1.3-benzodioxol-5-vn-1 -(2-phenoxvethvn- pvrrolidine-3-carboxvlic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1H NMR (CD3OD, 300 MHz) 8 2.82 10 (m, 1H), 2.96 (dd, 1H), 3.13 (m, 1H), 3.32 (m, 1H), 3.51-3.70 (m, 2H), 3.77 (s, 3H), 4.00 (d, 1H), 4.07 (m, 2H), 5.91 (s, 2H), 6.72 (d, 1H), 6.80-6.95 (m, 6H), 7.03 (d, 1H), 7.22 (dd, 2H), 7.39 (d, 2H). trans. trans-2-( 4-Meth oxvohen vfl-4-( 1.3-benzodioxol-5-vl>-1 -(2- methQxvethvlaminocarbonvlmethvlVpvrrolidin6-3-carboxvlic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 107-109 °C. 1H NMR (CD3OD, 300 MHz) 8 2.82 (d, 1H), 2.97 (q, 2H), 3.21 (d, 1H), 3.38 (m, 1H), 3.32 (s, 3H), 3.44 (m, 4H), 20 3.62 (m, 1H), 3.79 (s, 3H), 3.86 (d, 1H), 5.93 (s, 2H), 6.76 (d, 1H), 6.85 (dd, 1H), 6.91 (d, 2H), 7.01 (d, 1H), 7.38 (d, 2H).
Example 23 £ trans. frans-2-M-MethoxvphenvlM-f 1.3-benzodioxol-5-vlV-1 -(2-butoxvethvlV pvrrolidine-3-carboxvlic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 °C. 1H NMR (CDCI3, 300 MHz) 8 0.88 (t, Js=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (tt, J«6Hz, 6Hz, 1H), 2.92 (q, J=10Hz, 2H), 3.35 (t, J=7Hz, 2H), 3.42-3.56 (m, 30 4H), 3.68 (d, J=10Hz, 1H), 3.78 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.83 (d, J=9Hz, 2H), 6.82-6.87 (m, 1H), 7.06 (d, J=2Hz, 1H), 7.32 (d, Jas9Hz, 2H). MS m/e 442 (M+H)+.
Example 24 trans, trans-2-l 1.3-Benzodioxol-5-vn-4-M-m6thoxvphenyn-1 -(propviamSnocarbonvlmethvn-pvrrolidine-3-carboxvtic acid Using the procedures described in Example 1 and substituting ethyl (1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl)acetate and 4-{2-nitrovinyl)anisole for 5-(2-nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound, m.p. 97-99 °C. 1H NMR (CDCI3, 300 MHz) 6 0.78 (t, J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 (d, J=16Hz, 1H), 2.74 (t, J=10Hz, 1H), 2.80-3.10 (m, 4H), 3.26-3.38 (m, 1H), 3.53 (m, 1H), 3.73 (s, 3H), 3.80 (d, J=10Hz, 2H), 7.80 (t, J=6Hz, 1H). MS (DCI/NH3) m/e 441 (M+H)+.
Example 25 trans.trans-2-( 1 .3-Benzodioxol-5-vn-4-{4-methoxvphenvn-1 -(2-propoxvethvn- pvrrolidine-3-carboxvlic acid Using the procedures described in Example 5 and substituting ethyl (1,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4-methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2-nitrovinyl)-1,3-benzodioxol-5yl afforded the title compound, m.p. 67-69 °C. 1H NMR (CDCI3, 300 MHz) 8 0.89 (t, J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (m, 1H), 2.78-3.00 (m, 3H), 3.32 (t, J=7Hz, 2H), 3.45-3.57 (m, 4H)r-3.73 (m, 1H), 3.79 (s, 3H), 5.93 {s, 2H), 6.22 (d, J=8Hz, 1H) 6.85 (d, J=8Hz, 3H), 6.98 (s, 1H), 7.37 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 428 (M+H)+. trans.trans-2-( 1.3-Benzodioxol-5-vl)-4-(4-methoxvDhenvn-1 -f2-(2-methoxvethoxv)ethvni-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2-methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 85-86 °C. 1H NMR (CD3OD, 300 MHz) 8 3.18-3.90 (m, 15H), 3.79 (s, 3H), 4.57 (d, J=10Hz, 1H), 6.02 (s, 2H), 6.91 (d, Js=8Hz, 1H), 6.95 (d, J=9Hz, 2H), 7.06 (dd, J=8Hz, 1H), 7.12 (dd, J=1Hz, 1H), 7.37 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 444 (M+H)+.
Examole 27 trans, trans-241.3-Benzodioxol-5-vn-4-f 4-methoxvphenvlV 1 -f butoxveth v> V pvrrolidine-3-carboxvlic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 54-56 °C. 1H NMR (CDCI3, 300 MHz) 8 0.89 (t, J-7Hz, 3H), 1.44 (sextet, J^7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (m, 1H), 2.74-2.98 (m, 3H), 3.46 (t, J=7Hz, 2H), 3.42-3.56 (m, 4H)f 3.68 (d, J=10Hz, 1H), 3.80 (s, 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 (s, 1H), 7.36 (d, J=9Hz, 2H).
Example 28 trans. trans-2-( 4-Methoxvphen vH-4-f 1.4-benzodioxan-6-vn-1 -(propviaminocarbonvlmethvfVpvrrolidine-3-carboxviic acid Using the procedures described in Example 1 and substituting 6-(2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxole afforded the title compound, m.p. 80-81 °C. 1H NMR (CDCI3, 300 MHz) 8 0.89 (t, J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 (d, J=16Hz, 1H), 2.92 (t, J=10Hz, 1H), 3.05-3.43 (m, 5H), 3.24 (d, J=16Hz, 1H), 3.52-3.62 (m, 1H), 3.80 (s, 3H), 3.80 (t, J=10Hz, 1H), 4.27 (s, 4H), 6.74-6.93 (m, 5H), Example 29 fran5.frans-2-M-Methoxvphenvn-4-f1.4-benzodioxan-6-vn-1-(N-methvi-N-propvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, substituting 6-(2-nitrovinyl)-1,4-benzodioxane for 5-(2-nitrovinyl)-1,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, m.p. 74-76 °C.
Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) 8 0.73, 0.83 (2t, Jss7Hz, 3H), 1.48 (m, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (m, 3H), 3.27-3.42 (m, 3H), 3.52-3.60 (m, 1H), 3.75 (d, 1H), 3.78 (s, 3H), 4.22 (s, 4H), 6.80-6.98 (m, 5H), 7.32 (d, 2H). MS (DCI/NH3) m/e 469 (M+H)+.
Examole 30 trans.trans-2-U-Methoyymhenv\)-4-( 1.3-ben2odioxol-5-vn-1 -(N-methvl-N- butvlaminocarbonvlmethvn-pvrroHriine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 1H NMR (CD3OD, 300 MHz) S 0.86 (2t, 3H), 1.04-1.50 (m, 4H), 2.85 (2s, 3H), 2.93-3.20 (m, 4H), 3.40 (m, 2H), 3.52 (dd, 1H), 3.60 (m, 1H), 3.80 (s, 3H), 3.85 (m, 1H), 5.91 (s, 2H), 6.74 (d, 1H), 6.83-6.95 (m, 3H), 7.03 (dd, 1H), 7.35 (dd, 2H).
Example 31 frans.frans-2-(4-Methoxv-2-methoxvmethoxvphenvlV4-( 1.3-benzodioxol-5-vn-1 -fN-methvl-N-butvtaminocarbonvimethvO-pvrrolidine-3-carboxvlic acid Example 31A Ethvl 2-(4-methoxv-2-methoxvmethoxvphenvU4-( 1.3-benzodioxol-5-vn-Pvrrolidine- 3-carboxviate^ Using the procedures described in Examples 1A and 1B and substituting ethyl (4-methoxy-2-methoxymethoxybenzoyl)acetate for ethyl (4-methoxybenzoyl)acetate afforded ethyl 2-(4-methoxy-2-methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) was dissolved in 20 mL of methanol, treated with 500 mg of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
Example 31B trans. frans-2-(4-Methoxv-2-methoxvmethoxvphenyfl-4-f 1.3-benzodioxol-5-vn-1 -(N-methvl-N-butvlaminocarbonvlmethvB-pvrrolidine-3-carboxvlic acid The compound resulting from Example 31A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example 1D substituting N-methyl-N-birtyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, 62%). m.p. 65-67 °C. Rotational isomers are seen in the NMR. 1H NMR (CDCI3, 300 MHz) 8 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40-1.48 (m, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 (s, 3H), 3.43-3.65 (m, 2H), 3.78 (s, 3H), 4.30 (t, J=7Hz, 1H), 5.09 (q, J=7Hz, 2H), 5.92 (s, 2H), 6.55 (dd, J=3Hz, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 6.85 (2t, J=1Hz, 1H), 7.04 (t, J=1Hz, 1H), 7.42 (dd, J=3Hz, 1H).
Example 32 trans. fraA7s-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -(3-ethoxvpronvn. pvrrolidin-5-one-3-carboxvlic acid Example 32A Ethvl 2- (4-m eth oxvbenzovO-3-ca rbom ethoxv-1.3-benzod ioxole-5-pronion 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 Ethvl 1 -(3-ethoxvpropvfl-2-M-methoxvphenv0-4-( 1.3-benzodioxol-5-vlV4.5-dihvdro- -OXO-1 H-pvrrole-3-carboxvlate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 °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 mg (42%) of the title compound.
Example 32C Ethvl 1 -(3-ethoxvproovn-2-(4-methoxvphenvn-4-f 1 -3-ben2odioxol-5-vn-Pvrrolidin-5- one-3-carboxvlate The compound resulting from Example 32B (300 mg, 0.64 mmol) in 5 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 f/ans.frans-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -f3-ethoxvpropyn- pvrrolidin-5-one-3-carboxvlic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21% 15 sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue 20 which was washed with ether. The aqueous layer was neutralized with 3 M HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, 64%). m.p. 134-140 °C. 1H NMR (DMSO-d6, 300 MHz) 8 1.04 (t, J=7Hz, 3H), 1.55 (sextet, J=s7Hz, 2H), 2,48-2.56 (m, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 (t, "25 J=7Hz, 2H), 3.28-3.40 (m, 2H), 3.48-3.57 (m, 1H), 3.78 (s, 3H), 3.88 (d, J=10Hz, 1H), 4.72 (d, J=10Hz, 1H), 6.02 (s, 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 (d, J=8Hz, 2H), 6.98 (d, J=8Hz, 2H), 7.38 (d, J=8Hz, 2H). MS " (DCI/NH3) m/e 442 (M+H)+.
Example 33 ft3/?s.f/3ns-2-/4-MethoxvphenvlV4-f 1.3-benzodioxol-5-ylV 1 -f3-methoxvbenzvD- pvrrolidin-5-one-3-carboxvlic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded 35 the title compound (123 mg, 65%). m.p. 150-152 °C. 1H NMR (CD3OD, 300 MHz) 8 2.96 (dd, J=8Hz, 10Hz, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 4.06 (d, J=10Hz, 1H), 4.58 (d, J=8Hz, 1H), 4.92 (q, J=16Hz, 2H), 5.92 (s, 2H), 99 6.55-6.63 (m, 2H), 6.82 (d, J=8Hz, 4H), 6.94 (d, J=8Hz, 2H), 7.15-7.22 (m, 3H). MS (DCI/NH3) m/e 475 (M+H)+. frans. frans-2-r4-Methoxvphenvn-4-n.3-benzodioxol-5-vlVWNNl-diisoamvlaminocarbonvimethvlVpvrrolidin6-3carboxviir. arid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) 8 0.70 -0.90 (m, 12H), 1.10-1.60 (m, 10H), 2.75 (d, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.15 - 3.30 (m, 2H), 3.40 (d, J=10Hz, 1H), 3.40 - 3.52 (m, 2H), 3.55 - 3.62 (m, 1H), 3.75 (d, J=12 Hz, 1H), 3.79 (s, 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 35 frans.f/ans-2-f4-MethoxvphenvlV4-n.3-benzodioxol-5-vlV1-fN.N-dipentvlaminocarbonvlmethvlVpvrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J = 7Hz, 6H), 0.95-1.03 (m, 2H), 1.10-1.30 (m, 8H), 1.40-1.51 (m, 2H), 2.72 (d, J=13Hz, 1H), 2.90-3.08 (m, 4H), 3.25-3.50 (m, 3H), 3.37 (d, J«13Hz, 1H), 3.52-3,60 (m, 1H), 3.70 ( J=10Hz, 1H), 3.75 (s, 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, Jss2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 36 frans. frans-2-(4-MethoxvphenvlV4-n .3-benzodioxol-5-vlV1-fN-N-dK2- methoxvethvnaminocarbonvlmethvlVpvrrolidine-3-carboxvlic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 °C. 1H NMR (CDCI3, 300 MHz) 8 2.82 (d, J=13, 1H), 2.94-3.08 (m, 2H), 3.12 (s, 3H), 3.23 (s, 3H), 3.20-3.70 (m, 11H), 3.73 (d, J=10Hz, 1H), 3.79 (s, 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 (d, Jss8Hz, 1H), 6.80-6.90 (m, 3H), 7.04 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 37 trans. ftans-2-f 4-Methoxvphen vlV4-( 1.3-benzodioxol-5-vn-1 -te-hexvnvlVpyrrolidine- 3-carboxvlic acid Using the procedures described in Example 4, 200 mg. of the pure trans,trans isomer, the compound resulting from Example 6A was reacted with 109 mg of 1-bromo-2-hexyne, prepared by the method described in Perkin I, , 2004 (1987), for 1 hour at 55 °C, to give 226 mg of the intermediate ester. The ester was hydroiyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. 1H NMR (CDCI3, 300 MHz) 5 1.00 (t, J=7Hz, 3H), 1.54 (m, 2H), 2.14-2.22 (m, 2H), 2.96 (dd, J=7Hz, 13Hz, 1H), 3.07 (dd, J=18Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 (t, J=9Hz, 1H), 3.36 (dd, J = 18 Hz, 2Hz, 1H), 3.47-3.55 (m, 1H), 3.79 (s, 3H), 3.88 (d, J=9Hz, 1H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.88 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.22 (d, J=9Hz, 2H).
Example 38 frans.ffans-2-f4-Methoxvphenvn-4-(1.3-benzodioxot-5-vn-1-fN-cvctopropvlmethvi-N-propvlaminocarbonvlmethvlVpvrrolidtne-3-carboxvlic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the NMR. 1H NMR (CDCI3, 300 MHz) 5 -0.1 (m), 0.05 (m), 0.12-0.25 (m), 0.32-0.51 (m), 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 (m), 1.20-1.55 (m), 2.72 (d, vM3Hz, 1H), 2.85-3.29 (m, 4H), 3.30-3.50 (m, 3H), 3.52-3.62 (m, 1H), 3.65-3.73 (2 doublets, J=10Hz, 2Hz, 1H), 3.78 (s, 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (m, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).
Example 39 f/3ns.frans-2-f4-Methoxvphenvfl«4-(1.3-benzodioxol-5-vO-1-(N-methvl-N' pQntvlaminocarbonvlmethvO-pvrrolidine-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. 1H NMR (CDCI3, 300 MHz) 5 0.85 (t, J=7Hz, 3H), 1.00-1.08 (m), 1.13-1.32 (m), 1.35-1,50 (m), 2.72-2.82 (2 doublets, J=13Hz, 1H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets, 3H), 5.92 —: V_01 — (2 singlets, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 40 frans. fra/7s-2-(4-MethoxvphenvlV4-f1.3-benzodioxo!-5-vn-1-fN.N- diisobutvlaminocarbonvlmethvn-pvrrolidine.3-carboxv»ic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 °C. 1H NMR (CDCI3, 300 MHz) 8 0.54 (d, J=7Hzf 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (m, 1H), 1.90-10 2.02 (m, 1H), 2.67 (d, J=13Hz, 1H), 2.70 (d, J=13Hz, 1H), 2.84 (dd, Jss6Hz, 15Hz, 1H), 2.96-3.06 (m, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 m (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (m, 4H), 3.70 (d, J=9Hz, 1H), 3.79 (s, w 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 (d, J=9Hz, 1H), 6.82-6.90 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.31 (d, J=9Hz, 2H).
Example 41 trans. ffans-2-(4-Mathoxvphenvn-4-( 1.3-benzodioxol-5-vl>-1 -(N-methvl-N-f2-propvnvflaminocarbonvtmethv0-pvrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the 20 procedures described in Example 1. Rotational isomers were seen in the NMR. 1H NMR (CDCI3, 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1H), 2.80-3.10 (m, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, 1H), 3.78 (s, 3H), 4.03 (d, J=13Hz, 1H), 4.00-4.30 (m, 3H), 5.93 (s, 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 and £5 7.11 (2 doublets, J = 2Hz, 1H), 7.30 (2 doublets, J=9Hz, 2H). trans.trans-2-f4-Methoxvphenvn-4-( 1.3-benzodioxQl-5-vl V1 - (N-meth vl-N-( n-hexvnaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid 30 The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (m, 8H), 2.72-2.82 (2 doublets, J=13Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (m, 3H), 3.22-3.45 (m, 3H), 3.52-3.62 (m, 1H), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 35 3H), 5.94 (2 singlets, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.87 (m, 3H), 7.03 (2 doublets, J=2Hz, 1H), 7.30 (d, J=9Hz, 1H). | trans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 - (N. N~ d/bufWaro/nocarfcony/mefhW)-Pvrrolidine-3-carboxyKc acid The title compound was prepared using the procedures described 5 in Example 1. m.p. 123-125 °C. 1H NMR (CDCI3, 300 MHz) 8 0.79 (t, J»7Hz, 3H), 0.85 (t, Js=7Hz, 3H), 1.00-1.50 (m, 8H), 2.74 (d, J=13Hz, 1H), 2.90-3.09 (m, 4H), 3.23-3.50 (m, 3H), 3.38 (d, J=13Hz, 1H), 3.52-3.62 (m, 1H), 3.75 (d, J«10 Hz, 1H), 3.78 (s, 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 (d, J=8Hz, 1H), 6.81-6.89 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.30 (d, J=9 Hz, 10 2H). MS (DCI/NH3) m/e 511 (M+H)+. Anal caicd for C29H38N2O6: C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Example 44 trans.trans-2-M-Methoxvphenvn-4-n.3-benzodioxol-5-vn-1-fN.N-15 diethvlaminocarbonvlmethvD-pvrrolidine-3-carboxvlic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 °C. 1H NMR (CDCI3, 300 MHz) 8 0.98 (t, J=7Hz, 3H), 1.06 (t, J=7Hz, 3H), 2.78 (d, J=13 Hz, 1H), 2.95-3.20 (m, 4H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.76 (d, J=12 Hz, 1H), 3.79 20 (s, 3H), 5.93 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.32 (d, J=9Hz, 2H). trans. fran5-2-(4-Methoxvphen vlV4-f 1.3-benzodioxol-5-vlV1 -(N-methvt-N- phenvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CD3OD, 300 MHz) 8 2.75-2.85 (m,2H), 3.05-3.13 (m, 1H), 3.18 (s, 3H), 3.40-3.58 (m, 2H), 3.78* (s, 3H), 3.88 (d, J=12Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.75-30 6.85 (m, 3H), 7.00-7.12 (m, 5H), 7.82-7.92 (m, 3H).
Example 46 frans.frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vlV 1 -(N-meth vl-N-cvclohexvlaminocarbonvlmethvn-pyrrolidine-3-carboxvlic acid 35 The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1H NMR (CD3OD, 300 MHz) 8 1.00-1.85 (m, 10H), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, J=12Hz, 1H), 2.96-3.22 (m, 3H), 3.40-3.65 (m, 3H), 3.68 and 3.82 (2 doublets, J=10Hz, 1H), 3.77 and 3.78 (2 singlets, 3H), 5.92 (s, 2H), 6.72 (2 doublets, J=8Hz, 1H), 6.82-6.88 (m, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.30-7.40 (2 doublets, J=9Hz, 2H).
Example 47 frans.frans-2-(4-Methoxvphenvn-4-M.3-benzodioxol-5-vn-1-(N.N-difn- propvHaminocarbonvlmethvO-Pvrrolidine-3-carboxvHc acid The title compound was prepared using the procedures described in Example 1. m.p. 170-172 °C. 1H NMR (CDCI3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 (t, J=7Hz, 3H), 1.20-1.55 (m, 4H), 2.72 (d, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.25-3.47 (m, 4H), 3.35-3.62 (m, 1H), 3.72 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H).
Example 48 fr3ns.frans-2-f4-MethoxvphenvlV4-M.3-benzodioxol-5-vlM-fN-methvl-N- isQbutvlaminocarbonvlmethvlVpvrrolidine-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. 1H NMR (CD3OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (m, 1H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (m, 4H), 3.10-3.65 (m, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=10Hz, 1H), 5.93 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.80-7.90 (2 doublets, J=9Hz, 2H).
Example 49 Alternate Prepration of Ethvl 2-f4-methoxvbenzoviV4-nitromethvl-3-M.3-benzodtoxole-5-vnbutvrate Example 49A g-2-(3.4-MethvlenedioxvphenvA-1-nitroethene To a stirred solution of piperonal (75g, 500 mmol) in methanol (120 mL) at 10 °C was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while — \o&r— maintaining the temperature between 10-15 °C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below 5 5 °C, until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was 10 neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1H NMR (300MHz, CDCI3) 5 7.94 (1H, d, J=13.5Hz), • ® 7.47 (1H, d, J=13.5Hz), 7.09 (1H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, s). MS (DCI/NH3) m/e 194 (M+H)+, 211 15 (M+H+NH3)+.
Example 49B Ethvl 2-(4-methoxvphenvfloxo-4-nitro-3-(3.4-methvlenedioxvphenv0butvrate 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[5,4,03undec-7-ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with 20% ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eiuted. The solvents were removed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR. 1H NMR (300 MHz, CDCI3,) 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, s), 5.89 (1H, d, J=4Hz), 5.88 (1H, d, J=4Hz), 4.90-4.60 (3H, m), 4.39 (1H, m), 4.18 (2H, q, J=7Hz), 3.94 (2H, m), 3.80 (3H, s), 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) m/e 416 (M+H)+, 433 (M+H+NH3)+.
Example 50 trans.trans-2-f 4-MethoxvphenvlM-( 1.3-benzodioxol-5-vn-1 -ft-butvlQxvcarbonvlmethvn-pyrrolidin6-3-carboxvlic acid To a stirred solution of the compound resulting from Example 1C (100 mg, 0.27 mmol) in acetonitriie (2 mL) was added successively diisopropylethylamine (70 jiL, 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 p.L, 0.29 mmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester. To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mg, 3.75mmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 jiL), and then extracted with ethyl acetate (2x). The combined organic extracts were dried (Na2S04). filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid. 1H NMR (300 MHz, CDCI3) 5 7.36 (2H, d, J=8Hz), 7.13 (1H, d, J=3Hz), 6.90 (1H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1H, d, J=8Hz), 5.96 (2H, s), 3.96 (1H, d, J=9Hz), 3.81 (3H, s), 3.58 (1H, ddd, J=12, 10Hz,3Hz), 3.52 (1H, dd, J=9Hz,3Hz), 3.32 (1H, d, J=17Hz), 3.08 (1H, t, J=10Hz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J=17Hz). MS (DCI/NH3) m/e 456 (M+H)+.
Anal calc for C29H29NO7 • 0.3 H2O: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
Example 51 frans.frans-SM4-MethoxvphenvlV4-( 1 -naphthvfl-1 -(N-methvl-N-propvnaminocarbonvimethvn-pvrrolidine-3-cairboxvlic 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, GDCI3) 8 8.29 (1H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1H. d, J=8Hz), 7.49 (3H, m), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (1H, m), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, s), 3.65 (1H, m), 3.49 (1H, d, J=14Hz), 3.40-2.93 (5H, m), 2.91, 2.83 (3H, s), 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH3) m/e 461 (M+H)+. Anal calcd for C29H29NO7 • 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: C, 70.95; H, 7.00; N, 5.46.
Example 52 trans. trans-2-( 4-Methoxvphenvn-4-f2.3-dihvdrobenzofuran-5-vtV 1 -f N-meth vl-N-propvOaminocarbonvlmethvl>-pvrrolidine-3-carboxvlic acid Example 52A 2.3-Pihvdrobenzofuran-5-carboxaldehvde To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2CI2 (5 mL) maintaining the temperature at or below -35 °C. The mixture was warmed to 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 vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid, b.p. 119-121 °C at 0.3 mm Hg.
Example 52B trans, trans-24 4-MethoxvPhenvfl-4-( 2.3-dihvdrobenzofuran-5-vlV 1 -(N-meth vl-N-. PropvnaminocarbonvlmethvD-pvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the ~ NMR. 1H NMR (300 MHz, CDCI3) 8 7.33 (1H, d, J=8Hz), 7.28 (1H, m), 7.19 (1H, m), 6.87 (1H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 4.56 (1H, t, J=8Hz), 3.83 (1H, d, Js=10Hz), 3.80 (3H, s), 3.63 (1H, m), 3.4-3.0 (9H, m), 2.87, 2.84 (3H, s), 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS (DCI/NH3) m/e 453 (M+H)+. Anal calc for C26H32N2O5 • 0.25 H20: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6,88; N, 5.80.
Example §3 ffans.frans-2.4-Bisf4-methoxvphenvlM-(N-methvl-N-propvflaminocarbonvirnethyO- pvrrolidine-3-carboxvlic 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. 1H NMR (300 MHz, CDCI3) 8 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, m), 3.83 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.
Example 54 frans-frans-2'f4-MethoxvphenvlM-(3.4-dimethoxvphenvl>-1-fN-methvl-N. propvnaminocarbonvlmethvfl-pvrrolidine-3-carboxvfic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1H, m), 6.85 (1H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, s), 3.86 (3H, s), 3.83 (1H, m), 3.79 (3H, s), 3.64 (1H, m), 3.50-2.95 (6H, m), 2.87 (1H, m), 2.85, 2.83 (3H, s), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 471 (M+H)+. Anal calc for C26H34N2O6 • 0.5 H20: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.
Example 55 frans.frans-2-f4-Methoxvphenvfl-4-(3-methoxvphenvfl-1-fN-methvl-N- prppvnaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.05 (2H, m), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1H, m), 3.83 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.64 (1H, m), 3.48-2.97 (6H, m), 2.87, 2.83 (3H, s), 2.85 (1H, m), 1.45 (2H, m), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H)+. Anal calc for C25H32N2O5 • 0.5 H2O: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
Example 56 frans.frans-2-(4-Methoxvphenvn-4-(2-naphthvfl-1-{N-methvl-N-propvflaminocarbonvlmethvl)-pvrrolidine-3-carboxvlte acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthyiene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 6 7.82 (4H, m), 7.69 (1H, m), 7.47 (2H, m), 7.37 (2H, dd, J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78 (3H, s), 3.57 (1H, m), 3.52-2.97 (6H, m), 2.93, 2.85 (3H, s), 2.90 (1H, m), 1.52 (2H, m), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH3) m/e 461 (M+H)+. Anal calc for C28H32N2O4 • 0.5 H20: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.
Example 57 trans. frans-2-f4-MethoxvphenvlV4-f 1.3-benzodioxol-5-vn-1 -(2-( ethvlsulfinvl^ethvIV nvrrolidtne-3-carboxvlic acid To the compound resulting from Example 1C (100 mg, 0.27 mmol) and 2-chioroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitriie was added 10 mg of Kl and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93. mg (75%) of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH2CI2 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 CH2CI2 to afford the sulfoxide (62 mg, 65%).
The ethyl ester was hydroiyzed by the procedure described in Example 1D to afford the title compound as a diastereomeric mixture. m.p. 61-63 °C. MS (DCI/NH3) m/e 446 (M+H)+. 1H NMR (CDCI3. 300 MHz) 6 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 (m, 4H), 2.84-2.96 (m, 3H), 3.02- 3.08 (m, 1H), 3.32, 3.36 (d, J=3Hz, 1H), 3.47-3.58 (m, 2H), 3.65, 3.68 (d, J=7.5Hz, 1H), 3.76, 3.80 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 3.84-3.89 (m, 3H), 7.02 (d, J=6Hz, 1H), 7.30, 7.34 (d, J=7.5Hz, 2H).
Example 58 f/3ns.frans-2-(4-Methoxvphenv0-4-f1.3-benzodioxol-5-vfl-1-(2-rtsopropvisulfonvlaminotethvn-pvrrolidine-s-carboxvlic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous CH3CN was added 1 equivalent of Et3N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl suifonyl chloride and 1 equivalent of Et3N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 mmol) in 3 mL of CH3CN. The mixture was warmed at 50-60 °C for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg (75%) of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydroiyzed by the procedure described in Example 1D to afford the title compound (133 mg, 88%). m.p. 94-96 °C. 1H NMR (CD3OD, 300 MHz) 5 1.26 (d, J=6Hz, 6H), 1.97 (s, 1H), 2.38 (m, 1H), 2.77 (m, 1H), 2.88 (t, J=9Hz, 1H), 3.04 (m, 1H), 3.14 (t, J=7.5Hz, 2H), 3.35 (m, 2H), 3.46 (m, 1H), 3.58. (m, 1H), 3.78 (s, 3H), 5.92 (s, 2H), 6.74 (d, J=9Hz, 1H), 6.86 (dd, J=9Hz,3Hz, 1H), 6.92 (d, J=9Hz, 2H), 7.00 (d, J=3Hz, 1H), 7.36 (d, J=9Hz, 2H). MS (DCI/NH3) m/e (M+H)+.
Example 59 frans. frans-2-f4-MethoxvphenvO-4-(1 ■3-benzodioxol-5-vn-1-f2-0sobutoxv)ethvn- pvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 1C and 2-(isobutoxy)ethyl bromide, m.p. 68-70 °C. 1H NMR (CDCI3, 300 MHz) 5 0.88 (d, J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1H), 2.22 (m, 2H), 2.72-2.79 (m, 1H), 2.86-2.95 (m, 2H), 3.13 (d, J=6Hz, 2H), 3.45-3.56 (m, 4H), 3.68 (d, J=9Hz, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 6.85 (dd, Js=9Hz, 7.5 Hz, 3H), 7.08 (s, 1H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 60 frans.frans-2-te-MethoxvphenvlV4-f1.3-benzodioxol-5-vlV1-(butvlsulfonvn- pvrrolidine-3-carboxvlic add To 100 mg (0.271 mmol) of the compound resulting from Example 1C dissolved in 10 mL of THF was added 1-butanesulfonyl chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mg (90%) of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH~6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid, m.p. 67-69 °C. 1H NMR (CDCl3, 300 MHz) 8 0.82 (t„ J=7.5Hz, 3H), 1.20-1.33 (m, 2H), 1.58-1.68 (m, 2H), 2.48-2.69 (m, 2H), 3.28 (dd, J=9Hz, 1H), 3.49 (t, J=12Hz, 1H), 3.65 (dd, J=12Hz, 1H), 3.82 (s, 3H), 4.32 (dd, J=12Hz, 1H), 5.17 (d, J=9Hz, 2H), 5.95 (s, 2H), 6.70-6.78 (m, 3H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 462 (M+H)+.
Example 61 frans.frans-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -f2-(N-methvl-N-isapronvicarbonvlamino)ethvtVpvrrolidine-3-carboxvlic acid -m- Examole 61A trans.traris-2-f4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vlV1 -f2-bromoethyn-pvrrolidine-3-carboxvlic acid ethvl 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 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated 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 ft3ns.f/3/7s-2>f4-Methoxvphenvn-4-M.3-benzodioxol-5-vlV-1-(2-fmethvlaminotethvn- pvrrolidine-3-carboxvlic acid ethvl ester To the compound resulting from Example 61A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.
Example 61C frans.frans-2-f4-MethoxvphenviV4-( 1.3-benzodioxol-5-vlV1 -(2-f N-methvl-N-isob utvrvl am i n oteth vfl-p vrrol id in e-3-ca rboxvl ic 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 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours. The solvent was removed in vacuo', the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAc-hexanes going to EtOAc and finally using 10% MeOH-EtOAc. - 7 1 <L- The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 M H3PO4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2S04- The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. 1H NMR (CDCI3, 300 MHz) of the major rotamer 6 1.06 (d, 3H, J=10Hz), 1.12 (d, 3H, J=10Hz), 2.15 (m, 1H), 2.5-3.0 (m, 3H), 2.91 (s, 3H), 3.32 (m, 2H), 3.50 (m, 2H), 3.65 (m, 2H), 3.77 (s, 3H), 5.92 (s, 2H), 6.73 (d, 1H, J=8Hz), 6.75-6.9 (m, 4H), 6.96 (d, 1H, J=2Hz), 7.29 <m, 1H). MS (DCI/NH3) miz 469 (M+H)+. Analysis calcd for C26H32N2O6 ■ 0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71;'N, 5.24.
Example 62 trans. trans-2-( 4-Methoxvphenvfl-4-f 1.3-benzodioxol-5-vn-1 -fc-fN-methvl-N-propionvlaminotethvlVpviTolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1H NMR (CDCI3, 300 MHz) of the major rotamer 5 1.13 (t, 3H, Js=8Hz), 2.19 (m, 1H), 2.30 {m, 2H), 2.65-3.0 (m, 3H), 2.85 (s, 3H), 3.25-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.79 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8Hz), 6.75-6.9 (m, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DCi/NH3) m/z 455 (M+H)+. Analysis calcd for C25H30N2O6 • 1.0 H2O: C, 63.55; H, 6.83; N, 5.93 . Found: C, 63.55; H, 6.52; N, 5.73. frans.fraf7s-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vl)-1 -fN-methvl-N-benzvlam inocarbon vlmethvl Vpvrroltdine-3-carboxvtic acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer 8 2.79 (s, 3H), 2.8-3.2 (m, 2H), 3.48 (m, 2H), 3.61 (m, 2H), 3.77 (s, 3H), 3.78 (m, 1H), 4.3-4.5 (m, 2H), 5.95 (d, 2H, J=2Hz), 6.7-6.9 (m, 4H), 7.00 (m, 1H), 7.15-7.35 (m, 7H). MS (FAB/NBA) m/z 503 (M+H)+ Anal calcd for C29H3oN206-0.5 H20: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74; N, 5.36 . -us- Example 64 frans.frans-2-(4-MethoxvphenvlV4-(1.3-benzodioxol-5-vn-1-fN-ethvl-N- butvlaminocarbonvlmethvlVpvrrolidine-3-carboxviic acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer 8 0.88 (t, 3H, J=7Hz), 1.06 (t, 3H, J=7Hz), 1.27 (m, 2H), 1.45 (m, 2H), 2.8-3.6 (m, 11H), 3.79 (s,3H), 3.80 (m, 1H), 5.92 (bd s, 2H), 6.75 (d, 1H, J=8Hz), 6.85 (d, 1H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (s, 1H), 7.33 (d, 1H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+. Anal calcd for C27H34N2O6 • 0.5 HOAc: C, 65.61; H.7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66. frans.fra/?s-2-(4-Methoxvphenvfl-4-f 1.3-benzodioxol-5-vn-1 -(N-methvf-N-feg-dimethvlpropvflaminocarbonvlmethvfl-pvrrolidine-3-carboxviic acid Using the procedures described in Example 1 the title compound was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer 5 0.90 (s, 9H), 2.8-3.1 (m, 4H), 2.94 (s, 3H), 3.3-3.5 (m, 3H), 3.61 (m, 1H), 3.80 (s, 3H), 3.82 (m, 1H), 5.94 (bd s, 2H), 6.74 (d, 1H, J=8Hz), 6.86 (d, 2H, J=8Hz), 6.87 (m, 1H), 7.03 (d, 1H, J=2Hz), 7.33 (d, 2H, J=8Hz). MS (DCI/NH3) m/z 483 (M+H)+.
Example 66 frans.frans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vlV1-(2-fN-methvl-N-butvlsulfonvlamino)ethvfl-pvrroHdine-3-carboxvlic acid To the compound resulting from Example 61B (60 mg, 0.13 mmol) dissolved in 5 mL of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1.1 equivalents) of 1-butanesuifonyl chloride. The mixture was" stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example 1D afforded the title compound, m.p. 64-66 °C. 1H NMR (CDCI3, 300 MHz) 8 0.92 (t, J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (m, 2H), 2.16-2.25 (m, 1H), 2.72 (s, 3H), 2.75-2.92 (m, 5H), 3.12-3.20 (m, 1H), 3.25-3.34 (m, 1H), 3.46-3.55 (m, 2H), 3.65 (d, J=9Hz, 1H), 3.78 (s, 3H), 5.53 (s, 2H), 6.72 (d, J«7.5Hz, 1H), 6.82 (dd, J=7.5Hz,3Hz, 1H), 6.86 (d, J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 519 (M+H)+.
Example 67 tra ns. trar>s-2-( 4-Methoxvphen vft-4-( 1.3-benzodioxol-5-vlV1 -(2-(N-methvl-N-propvisulfonvtaminotethvn-pvrrolidine-3-carboxvnc acid The title compound was prepared by the procedures described in Example 66 substituting 1-propanesulfonyl chloride for 1-butanesulfonyl chloride. m.p. 69-70 °C. 1H NMR (CDCI3, 300 MHz) 8 1.02 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 (m, 1H), 2.72 (s, 3H), 2.75-2.95 (m, 6H), 3.13-3.22 (m, 1H), 3.25-3.35 (m, 1H), 3.47-3.58 (m, 2H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.74 (d, J=7.5Hz, 1H), 6.84 (d,d, J=7.5Hz, 3Hz, 1H), 6.87 (d, J=9Hz, 2H), 7.04 (d, J=3Hz, 1H), 7.43 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 505 (M+H)+.
Example 68 frans.fr3ns-2-(4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-(2-foropvlsulfonvnethvlVpvrrolidine-3-carboxvlic acid To 1-propanediol (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 °C for 1 hours. To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 mmol) in 2 mL THF. Heating was continued at 60-70 °C for an additional 2 hours, and then the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to give 170 mg (95%).
To a solution of 170 mg (0.36 mmol) of the sulfide and 93 mg (0.8 mmol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H20 was added a solution of osmium tetroxide (10 mg) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. Flash chromatography afforded 177 mg (98%) of the ethyl ester which was hydroiyzed by the procedures described in Example 1D to afford the title compound, m.p. 73-75 °C. 1H NMR (CDCI3, 300 MHz) 8 1.04 (t, J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 (m, 1H), 2.84-3.08 (m, 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 (m, 1H), 3.68 (d, J=9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.75 (d, J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 (d, J=9Hz, 2H), 6.99 (d, J=3Hz, 1H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 476 (M+H)+.
Example 69 trans. trans-2-( 4-MethoxvphenvlM-f 1.3-benzodioxol-5-vn-1 -N-f frans-5-methvlh<*y- 2-envn-pyrrolidine-3-carbQxviic acid Example 69A trans-5-Methvlhex-2-enoic acid ethvl 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 °C. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C. Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na2SC>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 g).
Example 69B frans-5-Methvlhex-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 K 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 eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C trans-1 -Bromo-5-methvlhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C 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 frans.frans-2-{4-Methoxvphenvn-4-H-3-benzodioxol-5-vn-1-N-(frans-5-methvlhex- 2-envD-pyrrolidine-3-carboxvlic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. 1H NMR (CDCI3, 300 MHz) 5 0.84 (d, 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 (t, 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,14Hz), 2.86 (t, 1H, J=10Hz), 2.96 (dd, 1H, J=8Hz,10Hz), 3.20 (dd, 1H, J= 5Hz,14Hz), 3.29 (dd, 1H, J=3Hz,10Hz), 3.50 (m, 1H), 3.70 (d, 1H, J=s10Hz), 3.78 (s, 3H), 5.47 (m, 2H), 5.93 (s, 2H), 6.71 (d, 1H, J=8Hz), 6.83 (d, 3H, J=9Hz), 7.05 (s, 1H), 7.32 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for C26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
Example 70 trans. trans-2-( 4-Methoxvphenv0-4-( 1.3-benzodioxol-5-vn-1 -N-f trans- 3.5- riimethvlhex-2-envlVpvrrolidine-3-carboxvlic 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 jiC18) 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: (CDCI3, 300 MHz) 5 0.83 (d, 6H, J=8Hz), 1.56 (s,3H), 1.74 (m, 1H), 1.92 (d, 2H, Js=6Hz), 3.3-3.5 (m, 3H), 3.6-3.8 (rn,4H), 3.78 (s, 3H), 3.9-4.0 (m, 1H), 5.22 (m, 1H), 5.90 (d, 2H, J=12Hz), 6.63 (m, 1H), 6.78 (m, 3H), 6.95 (s, 1H), 7.45 (d, 3H, J=8Hz). MS (DCI/NH3) m/e 438 (M+H)+. Anal calcd for 5 C27H33NO5 • 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-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vl V1 -U-heptvlcarbonvlmethvlVpvrrolidine-3-carboxvlic acid Example 71A 1 -Chloro-3-propvl-2-hexanone To 2-propylpentanoic acid (156.6 pJ, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 |iL, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 ^iL, 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 jiL, 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- Ethvl 2-f4-methoxvphenvn-4-( 1.3-benzodioxol-5-yn-1 -(4-heptvtcarbonvlmethvn-pvrrolidine-3-carboxvlate 35 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 % solution in toluene), diisopropylethylamine (700 jxL, 4.00 mmol) and acetonitriie (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 acetonitriie (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg (46%) of the title compound as a yellow oil.
Example 71C frans.frans-2-(4-Methoxvphenvh-4-(1.3-benzodioxol-5-vn-1-(4-heptvlcarbonvlmethvn-pvrroiidine-3-carboxvlic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the pH to -5. This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1:1 ethyl acetate-hexane to give 86 mg (39%) of the title compound as an off white powder. 1H NMR (CDCI3, 300 MHz) S 0.73-0.97 (m, 6H), 1.03-1.33 (m, 6H), 1.36-1.58 (m, 2H), 2.46 (m, 1H), 2.80-2.98 (m, 3H), 3.38-3.64 (m, 3H), 3.75-3.90 (m, 1H), 3.79 (s, 3H), 5.94 (s, 2H), 6.75 (d, 1H), 6.86 (d, 2H), 6.92 (d, 1H), 7.12 (s, 1H), 7.32 (d, 2H). MS (FAB) m/e 482 (M+H)+. Anal calcd for C28H35NO6: C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.
Example 72 trans. ft3ns-2-f4-Methoxvphen vlV4-f 1.3-benzodioxol-5-vl>-1 -fvatervlmethvlV Pvrrolidine-3-carboxvlic acid Example 72A 1 -Chloro-2-hexanone Using the procedure described in Example 71A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
Example 72B trans.trans-Ethvl 2-(4-methoxvphenvn-4-M .3-benzodioxole-5-vn-1-fvalervlmethvn-pvrrolidine-3-carboxvlate Substituting the compound resulting from Example 72A for 1-chloro-3-propyl-2-hexanone and using the procedure described in Example 71B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil.
Example 72C trans. frans-2-f4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1 -fvalerylmethvh-pvrrolidine-3-carboxylic acid By substituting the compound resulting from Example 72B for trans,trans-Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1- " (4-heptylcarbonylmethyl)-pyrrolidine-3-carboxylate and using the procedure described in Example 71C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg (46%) was obtained as an off white powder. 1H NMR (CDCI3, 300 MHz) 8 0.87 (t, 3H), 1.26 (m, 2H), 1.49 (m, 2H), 2.37 (m, 2H), 2.79-2.98 (m, 3H), 3.31-3.49 (m, 2H), 3.56 (m, 1H), 3.77, 3.79 (d,s, 4H), 5.94 (s, 2H), 6.75 (d, 1H), 6.81-6.93 (m, 3H), 7.09 (d, 1H), 7.33 (d, 2H). MS (FAB) m/e 440 (M+H)+. Anal, calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.
Example 73 frans.fran5-2-f4-Methoxvphenvn-4-n.3-benzodioxol-5-vn-1-fN-f3.4. dimethoxvbenzvn-N-methvlaminocarbonv<methvnpvrrolidine-3-carboxvIic acid Example 73A trans.trans- and c/s.frans-2-f4-MethoxvphenviV4-n .3-benzodioxol-5-yi>-1-rf3.4-dimethoxvben2vhaminocarbonvimethvnpvrroHdine-3- carboxvlic acid ethvl ester Using the procedure of Example 1D, paragraph 1, substituting 3,4-dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
Example 73B trans.trans- and cis.trans-2-(4-MethoxvPhenvn-4-(1.3-benzodioxol-5- vn-1-(N-f3.4-dimethoxvbenzvn-N-methvlaminocarbonvlmethvnpvrrolidine-3-carboxvHc acid ethvl ester The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 (J.L, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et20) indicated incomplete reaction. An additional portion of methyl iodide (28 y.L, 64 mg, 0.45 mmol) and dry 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (50 [lL, 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 (Na2S04)» filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et20 gave the title compounds as an inseparable mixture in 43% yield. 1H NMR (CDCl3, 300 MHz) 82.79 (s) and 2.81 (s), for the N-CH3 signals. MS m/z 591 (M+H)+. -\2s\ — Example 73C trans.frans-2-(4-Methoxvphenvh-4-M .3-benzodtoxol-5-vn-1-(N-f3.4-dimethoxvben2vh-N-methvlaminocarbonvlmethvhpvrrolidine-3- c?rfrpxylic gcicl To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 °C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H2O. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was 10 partitioned between 15 mL H2O and 15 mL Et20. The aqueous phase was extracted with 5 mL Et20, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with w NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2S04), then filtered and concentrated in vacuo to 15 give 40 mg (42%) of the title compound as a white foam. 1H NMR (CD3OD, 300 MHz, two rotameric forms) 8 2.85 (s, 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 (s, 4 H total), 3.70-3.97 (br m), 3.74 (s), 3.76 (s), 3.78 (s), 3.79 (s), 3.81 (s), and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 (s) and 5.93 (s, 2H total), 6.50-6.60 (m, 1H), 6.67-20 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31H35N2O8 (M+H)+: 563.2393. Found: 563.2385.
Example 74 trans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxot-5-vn-1 -fN-(3.4-0| dimethoxvbenzvnaminocarbonvlmethvl)pvrrolidine-3-carboxvlic acid The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound. 1H NMR (CD3OD, 300" MHz) 8 2.85 (d, J=16Hz, 1H), 2.92 (br t, J=9Hz, 1H), 2.98 (br t, J=10Hz, 30 1H), 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1H), 3.67 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (d, J=10 Hz, 1H), 4.21 (d, J=*15Hz, 1H), 4.41 (d, J = 15Hz, 1H), 5.91 (s, 2H), 6.67 (d, J=8Hz, 1H), 6.75-6.95 (m, 7H), 7.33-7.40 (m, 2H). HRMS calcd for C3oH32N208 (M+H)+: 549.2237. Found: 549.2224.
Examole 75 rPR3R4Rl2-M-MethoxvphenvlM-M-3.henzodioxol-5-vn-Wf1Rl1.rNN. dipropvlaminocarfaonvlVI-butvnpvrroHdine-3-carboxvlic acid Example 75A trans. ftans-2-f4-MethoxyphenvlM-f 1.3-benzodioxol-5-vlV1 -(MR 11 -fbenzvlQxvcarbonvnbutvl^Pvrrolidine-3-carboxvlic acid ethvl ester The procedure of Fung, et al., J. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H2O, 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 Na2CC>3 and 25 mL of CH2CI2. The aqueous phase was extracted with 2 x 10 mL CH2CI2, and the combined organic phases were washed with 15 mL brine, dried (Na2S04), then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica get chromatography eluting with 3:1 CH2Cl2-hexane to produce 106 mg (68%) of the title compound as a waxy solid. 1H NMR indicated the presence of two diastereomeric products.
Example 75B trans. frans-2-f4-Methoxvphen vl V4-( 1.3-benzodioxol-5-vn-1 -((1 RV-1-fN.N-dipropvlaminocarbonvn-1-butvnpvrrolidine-3-carboxvlic acid ethvl 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 H2 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 (96%) of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 °C, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 °C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2C03. The organic phase was washed with 10 mL of brine, dried (Na2S04), then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et20-hexane.
Further purification of overlap fractions by preparative TLC eluting with 1:2 Et20-hexane yielded 32 mg (34%) of a less polar product, and 44 mg (46%) of a more polar product.
Example 75C (2R.3R.4m-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-(fim-1-fN.N-dipropvlaminocarbonvn-1-butvnpvrrolidine-3-carboxvHc acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield. [cc]d = -52° (c=0.235, CH3OH). "»H NMR (CD3OD, 300 MHz) 8 0.55 (t, J=7Hz, 3H), 0.87 (t, J=7Hz) and 0.87-0.94 (m, 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (m, overlapping with CD2HOD signal), 3.40-3.60 (br m, 2H), 3.79 (s, 3H), 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1H), 6.92-6.98 (br m, 3H), 7.29-7.39 (m, 2H). MS m/z 525 (M+H)+.
Example 76 (2S.3S.4SV2-(4-Methoxvphenvn-4-n.3-benzodioxol-5-vn-1-(f1R>-1-fN.N-dipropvlaminocarbonvn-1-butvnpvrroridine-3-carboxvlic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [<x]d = +58° (c=0.37, CH3OH). 1H NMR (CD3OD, 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 (m, 6H), 1.08-1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 (br m, 1H), 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 H), 3.69 (s, 3H), 4.03-4.16 (br m, 2H), 5.91 (s, 2H), 6.71-6.83 (m, 2H), 6.86-6.97 (m, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 (M+H)+.
Example 77 r2S.3S.4SV2-U-MethaxvphenvlV4-(1.3-benzodioxol-S-yn-1-((1Sl1-fN-N-dioropvlaminocarbonvlVl -butvnpvrrolidine-3-carboxvlic acid Example 77A trans.trans-2-(4-MethoxvphenvlM-( 1.3-benzodioxol-5-vn-1-rn Sl-1 -fN.N-dipropvlaminocarbonvn-1-butvnpvrrQlidine-3-carboxvlic acid ethyl ester (2R)-N,N-dipropyl 2-hydroxypentanamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 mL THF under an argon atmosphere, diisopropylethylamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 °C. Trifluoromethanesulfonic anhydride (95 mL, 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 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 nL, 75 mg, 0.58 mmol) in 3 mL of CH2CI2 was added. The reaction was stirred at 0 °C 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 Ma2C03. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2S04), filtered and concentrated in vacuo to a yellowish oil. Purification by flash chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg (7%) of a less polar product and 20.1 mg (7%) of a more polar product." 1H NMR spectra and MS were the same as those of Example 76B.
Example 77B (2S.3S.4S>-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-(MSV1-fN.N-dipropvlaminocarbonvn-1 -butvnpvrrolidine-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. 1H NMR (CD3OD, 300 MHz) and MS identical to those of Example 75C. f2R.3R.4RV2-f4-MethoxvphenvlV4-f1.3-benzodioxol-5-vlVWf1SVWN.N-diDropvlaminocarbonvlVI-butvnpvrrolidine-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. 1H NMR (CD3OD, 300 MHz) and MS identical to those of Example 76.
Example 79 trans.trans- 2-f4-MethoxvohenvlV4-f 1.3-ben2odioxol-5-vlVl - (N. N-dibutvlaminocarbonvlmethvl)-3-(5-tetTS-zoM)nvTToM\r)& 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 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound, m.p. 194-196 °C.
Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature. Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3-carbonitrile compound.
To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL ) was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in sodium hydroxide solution, filtered from insoluble material and - 42^ acidified with acetic acid to get 532 mg (62%) of the title compound, m.p. 165-167 °C. 1H NMR (CDCl3) 300 MHz) 8 0.85 (t, J=*7Hz, 3H), 0.87 (t, J=7Hz, 3H), 1.10-1.50 (m, 8H), 3.0-3.6 (m, 8H), 3.70 (s, 3H), 3.7-3.8 (m, 1H), 3.90 (t, J=9Hz, 1H), 4.37 (d, J«9Hz, 1H), 5.86 (s, 2H), 6.62 (d, J=8Hz, 1H), 6.65-6.73 (m, 3H), 6.95 (d, J=2Hz, 1H), 7.11 (d, J=9Hz, 2H). trans. frans-2-/4-FluorophenvO-4-/1.3-benzodioxol-5-vfl-1 -SN.N-dibutvIaminocarbonvlmethvl)ovrro\idme-3-carboxviic acid The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole using the procedures described in Examples 1 and 43. 1H NMR (CDCI3, 300 MHz) 8 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.0-1.55 (m, 8H), 2.81 (d, J=13 Hz, 1H), 2.90-3.10 (m, 4H), 3.15-3.30 (m, 1H), 3.32-3.45 (m, 3H), 3.55-3.65 (m, 1H), 3.86 (d, J=10Hz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J=8 Hz, 1H), 6.86 (d, J= 8 Hz, 1H), 6.95-7.07 (m, 3H), 7.32-7.45 (m, 2H).
Example 81 fra/7S-frafis-2-f4-MethoxvphenviV4-M.3-benzodioxol-5-vn-1-fN.N-dKn- butvflaminomethvlcarbonvODvrrolidine-3-carboxviic acid N.N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C. After cooling to room temperature, 250 mg (0.678 mmol) of ethyl frans,frans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 °C for 30 minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.
The ester was hydroiyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. 1H NMR (CDCI3, 300 MHz) 8 rotational isomers - 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.65-3.20 (m, 6H) 3.43-3.70 (m, 3H), 3.72 (s, 3H), 3.87 (d, Jas15Hz, 1H), 4.49 (dd, J=12Hz, 6Hz) and 5.23 (dd, J=12Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 (m, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 (d, J=9Hz, 2H).
Example 82 trans. fr3ns-2-(4-MethoxvphenvlM-( 1.3-benzodioxol-5-vlV1 -fN-n-butvlVN-fn. propvnaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C. 1H NMR (CDCI3, 300 MHz) rotational isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (m, 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1H), 2.90-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 and 3.75 (two doublets, J=10Hz, 1H), 3.78 (s, 3H), 5.92-5.96 (m, 2H), 6.72 (d, J=8Hz, 1H), 6.83-6.89 (m, 3H), 7.03 (d, J=2Hz, 1H), 7.81 (d, J=*9Hz, 2H).
Example 83 frans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vlV1 -F2-fN.N-di(n- propvnaminocarbonvhethvnpvrrolidine-3-carboxvlic acid The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydroiyzed to the title compound by the method of Example 1D in 83% yield. 1H NMR (CDCI3, 300 MHz) 8 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (m, 4H), 2.35-2.60 (m, 3H), 2.80-3.07 (m, 5H), 3.14-3.21 (m, 2H), 3.31-3.38 (m, 1H), 3.51-3.61 (m, 1H), 3.73 (d, J=12H, 1H), 3.75 (s, 3H), 5.94 (s, 2H), 6,71 (d, J=9Hz, 1H), 6.79-6.85 (m, 3H), 7.04 (d, J=2Hz, 1H)< 7.32 (d, J=9Hz, 2H).
Examole 84 frans. frans-2-(4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vn-1 -(N.N-difn- butvnaminocarbonvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Example 8 using dibutyi carbamoyl chloride, prepared by the method of Hoshino et a/., Syn. Comm., 17: 1887-1892 (1987), as a starting material. ">H NMR (CDCI3, 300 MHz) 8 0.86 (t, J=7Hz, 6H), 1.14-1.28 (m, 4H), 1.35-1.48 (m, 4H), 2.81-2.94 (m, 2H), 3.11 (t, J=12Hz, 1H), 3.30-3.41 (m, 2H), 3.59-3.68 (m, 2H), 3.76 (s, 3H), 3.78-3.85 (m, 1H), 5.81 (d, J=9Hz, 1H), 5.94 (s, 2H), 6.73-6.86 (m, 5H), 7.24 (d, J=9Hz, 2H).
Example 85 trans. trans-2-( 4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vn-1 -(N. N-dibutvlaminocarbonvlmethvl)ovrroMme-3-carboxv\\c acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 °C to yield 627.5 mg of the title compound. fr3/7s.frans-2-(4-Methoxvphenvfl-4-(1.3-benzodioxol-5-vn-1-f2-(N.N-di(n- bgtyl)amino)ethyl]pyrro|idine-3-Carl?oxylic 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 Na2S04 and concentrated. More toluene was added, and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg (87%) of the intermediate ethyl ester.
The ester was hydroiyzed by the method of Example 1D to give the title compound as a white powder. 1H NMR (CD3OD, 300 MHz) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 (m, 4H), 1.44-1.56 (m, 4H), 2.48-2.57 (m, 1H), 2.80-3.08 (m, 8H), 3.14-3.25 (m, 1H), 3.31-3.38 (m, 1H), 3.59-3.60 (m, 1H), 3.74 (s, 3H), 3.75 (d, J=10Hz, 1H), 5.89 (s, 2H), 6.71 (d, J*9Hz, 1H), 6.81 (dd, Jss9Hz, 2Hz, 1H), 6.90 (d, J=10Hz, 2H), 6.96 (d, J=2Hz, 1H), 7.37 (d, J=10Hz, 2H).
Example 87 fmns.frans>2.(4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-(2-rN-fN.N-di(n-hntvnamtnocarbonvlVN-methvtamino1ethvl)pvrrolidine-3-carboxvlic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2S04 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.
The ester was hydroiyzed by the method of Example 1D to afford 141 mg of the title compound. 1H NMR (CD3OD, 300 MHz) 8 0.92 (t, J=7Hz, 6H), 1.21-1.32 (m, 4H), 1.42-1.53 (m, 4H), 2.62 (s, 3H), 2.65-2.76 (m, 1H), 3.00-3.20 (m, 8H), 3.44-3.55 (m, 1H), 3.62-3.78 (m, 2H), 3.80 (s, 3H), 4.07 (d, J=12 Hz, 1H), 5.93 (s, 2H), 6.75 (d, J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 (d, J=10 Hz, 2H), 7.04 (d, J=2Hz, 1H), 7.40 (d, J=10Hz, 2H).
Example 88 frans. trans- 24 4-MethoxvphenvlV4-f 1.3-benzodioxol-5-vlV1 -(N. N-dUn-butvnaminocarbonvnmethvnpvrrolidine-3-(N-methanesulfonvflcarboxamide Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours.
After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%) of the title compound. m.p. 170-173 °C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.51 (m, 8H), 2.75-2.86 (m, 2H), 2.83-3.25 (m, 4H), 3.17 (s, 3H), 3.32-3.50 (m, 3H), 3.70-3.78 (m, 1H), 3.80 (s, 3H), 3.87 (d, J=10Hz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, J=9Hz, 1H), 6.84 (dd, J=9Hz, 2Hz, 1H), 6.90 (d, J=10 Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.34 (d, J=10Hz, 2H).
Example 89 frans. frans-2-{4-MethoxvphenvlV4-f 1-3-benzodioxot-5-vlVMN. N-difn-butv0aminocarbonvDmethvl)pvrrolidine-3-(N-benzenesulfonvh carboxamide The compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 °C for a sample recrystallized from acetonitriie. 1H NMR (CDCI3, 300 MHz) 8 0.81 (t, J«7 Hz, 3H), 0.89 (t, J«7Hz, 3H), 1.02-1.50 (m, 8H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 4H), 3.80-3.95 (m, 3H), 3.50-3.60 (m, 1H), 3.65 (d, J=10Hz, 1H), 3.81 (s, 3H), 5.94 (s, 2H), 6.70 (s, 2H), 6.81-6.90 (m, 3H), 7.17 (d, JsslOHz, 2H), 7.55 (t, J=7 Hz, 2H), 7.66 (t, J=7Hz, 1H), 8.95 (d, Js=7Hz, 2H).
Exempt? 9Q trans. frans-2-(4-MethoxvphenvlV4-(1.3-benzodioxol-5-vl)-1 -fN. N-difn-butyh aminosulfonvlmethvll-Pvrrolidine-3-carboxvlic acid Chloromethyl sulfenyi chloride, prepared by the method of Brintzinger et. al., Chem. Ber. £5.: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyi chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfeny! chloride which is chlorinated with N-chiorosuccinimide to give chloromethyl sulfenyi chloride by the method of E. Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyi chloride is reacted with the compound resulting from Example 6A to give ethyl trans.trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[N,N-di(n-butyl)aminosulfenylmethyl]-pyrrolidine-3-carb0xylate. This is oxidized with osmium tetroxide and N-methyl morphoiine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 22: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
Exampie 91 f;ans.frans-2-(4-Methoxvphenvfl-4-( 1.3-benzodioxol-5-vlV1 -KN.N-dibutvlaminotearbonvl-1 -(flSVethvnpvrrolidine-3-carboxvlic acid Example 91A feVDibutvl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorphoiine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH2CI2, the solution was cooled to 0 °C under a N2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL, 3.5 mmol). After 10 minutes at 0 °C, 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 aqueous Na2C03 solution, then the organic phase was washed sequentially with 25 mL of 1 M aqueous NaHS04 and 25 mL brine, dried (Na2SC>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 (CDCI3, 300 MHz) 8 0.93 (t, J=7Hz) and 0.97 (t, Js=7.5Hz, 6H total), 1.26-1.60 (m, 7H), 1.60-1.78 (m, 1H), 1.82 (d, J=6Hz, 3H), 3.04-3.27 (m, 2H), 3.42-3.64 (m, 2H), 4.54 (q, J=7H, 1H). MS (DCI/NH3) m/e 264 and 266 (M+H)+ Example 91B trans.trans- and c/s.frans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vl>-1-ffN.N-dibutvlamino^carbonvl-1-(flS^-ethvnpvrrolidine-3-carboxvlic acid ethvl ester A solution of the resultant mixture of trans.trans and cis,trans compounds from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example 91A (183 mg, 0.693 mmol) in 2 mL of CH3CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 °C under a N2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et20 and 10 mL of 1 M aqueous Na2CC>3 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude). The product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 4 diastereomers. 1H NMR (CDCI3, 300 MHz) 8 0.66-1.55 (several m, 19H), 2.63-3.00 (m, 3H), 3.05-3.39 (m, 2H), 3.40-3.76 (m, 4H), 3.78-3.80 (4 s, 3H), 3.84-4.25 •432-- (m, 2.6H), 4.38 (d, J=10.5Hz, 0.2H) and 4.58 (d, J=10.5Hz, 0.2H), 5.90-5.97 (m, 2H), 6.68-6.96 (m, 5H), 7.38-7.43 (m, 2H). MS (DCI/NH3) m/e 553 (M+H)+.
Example 91C trans. frans-2-(4-Methoxvohenvn-4-( 1.3-benzodioxol-5-vn-1 -ttN.N-dibutylamino)carbonyl-1 -(f?S)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant compound from Example 91B for the resultant compound from Example 73B to give the title compound in 61% yield. 1H NMR (CD3OD, 300 MHz) 8 0.70-1.05 (several m, 8H), 1.14 (d, J=6Hz, 2H), 1.17-1.55 (m, 6H), 2.79-3.03 (m, 3.5H), 3.20-3.65 (br m, 4.6H plus CD2HOD), 3.70-3.78 (m, 0.4H), 3.79 (s, 3H), 3.98 (d, J=8Hz, 0.6H), 4.06 (t, J=7.5Hz, 0.4H), 4.25 (d, J=8Hz, 0.4H), 5.92 (s) and 5.94 (s, 2H total 6H), 6.73 (d, J=2.5Hz) and 6.75 (d, J=3Hz, 1H total), 6.78-6.85 (m, 1H), 6.91-7.00 (m, 3H), 7.30-7.38 (m, 2H). MS (DCI/NH3) m/e 525 (M+H)+ Anal calcd for C30H40N2O6-O.5H2O: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
Example 92 f/ans.frans-2-(Pentyn-4-f1.3-benzodioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvnpyrrolidlne-3-carboxvlic acid 20 Example 92A Methvl 2-f4-hexenovn-4-nitro-3-f1.3-benzodioxole-5-vnbutvrate A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanoi was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole (712 mg, £ 3:69 mmol) in 10 mL THF, then DBU (22 p.L, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title 30 compound as a mixture of diastereomers in a 1:1 ratio. 1H NMR (CDCI3, 300 MHz) 8 1.55-1.66 (m, 3H), 2.02-2.17 (br m, 1H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J =8Hz, 0.5H), 4.10-4.20 (m, 1H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 (m, 1H), 6.68 (br s, 1H), 6.75 (d, 7.5Hz, 1H). MS (DCI/NH3) m/e 381 (M+NH4)+. Anal calcd 35 for C18H21NO7: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72. -(33- Example 92B Methvl trans.trans-2-(pentvlV4-f 1.3-benzodioxol-5-vnpvrrolidine-3-carbQxvlate 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 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 NaHC03 diluted with 10 mL water and 30 mL of CH2CI2. The aqueous phase was extracted (2 x 30 mL CH2CI2), then the combined organic phases were washed with 20 mL brine, dried over Na2SC>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 CH2CI2 gave 336 mg (57%) the title compound as a yellow oil. 1H NMR (CDCI3,300 MHz) 8 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1H), 3.34-3.45 (m, 2H), 3.53 (q, J=9Hz, 1H), 3.66 (s, 3H), 5.94 (s, 2H), 6.65-6.75 (m, 3H). MS (DCI/NH3) m/e 320 (M+H)+. Anal calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.
Example 92C trans, trans- 2-f Pentvn-4-f 1.3-benzodioxol-5-vn-1 -(N.N-dibutylaminocarbonvimethvnpvrrolidine-3-carboxvlic acid The procedures of Example 1B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example -1B, to provide the title compound as a white foam. 1H NMR (CDCI3, 300 MHz) 8 0.87 (br t) and 0.89 (br t, 6H total), 0.97 (t, J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 (t, J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 (m, 3H), 3.73 (d, J=14Hz, 1H), 5.98 (AB, 2H), 6.70 (d, J=7Hz, 1H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCI/NH3) m/e 475 (M+H)+. Anal calcd for C27H42N2O5 O.5H2O: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
Exgtmple 93 frans.frans-2-(Pentvn-4-M.3-benzodioxol-5-vn-1-f2-(N-propyl-N-propvlsulfonvlamino^ethvllpvrrolidine-3-carboxvlic acid Methvl trans. trans-2-(pentvD-4-f 1.3-benzodioxot-5-vn-1 -fe-bromoethvnpvrrolidine- 3-ggri?Qxylate 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. 1H NMR (CDCi3, 300 MHz) 5 0.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 (m, 2H), 2.76-2.91 (m, 2H), 3.10-3.22 (m, 2H), 3.36-3.47 (m, 2H), 3.68 (s, 3H), 5.92 (s, 2H), 6.69-6.77 (m, 2H), 6.90-6.94 (m, 1H). MS (DCI/NH3) m/e 426, 428 (M+H)+.
Example 93B Methvl trans.f/ans»2-fPentvH-4-f 1.3-benzodioxol-5-vn-1 -te-fN-propvl-N-propvlsulfonviaminotethvHDvrrolidine-3-carboxvlate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 jimol) in 1 mL EtOH was treated with propylamine (60 pi, 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 Na2C03. The organic phase was washed with 15 mL brine, then dried over Na2S04, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 fiL, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 |iL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH 4), and the mixture was extracted with 2 x 3 mL CH2C12- The combined organic extracts were washed with 2 mL brine, then dried over Na2S04, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg (53%) of the title compound as a waxy solid. Rf = 0.17 (2Q%EtOAc-hexane). MS (DCI/NH3) m/e 511 (M+H)+.
Example 93C trans.trans-2-(Pen\y\)-4-( 1.3-benzodioxol-5-vn-1 -f2-fN-propvl-N-propvlsulfonvlaminotethvllpvrrolidine-3-carboxvlic acid The procedure of Example 71C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 71B, to provide the title compound as a white foam (47 mg, 80%), Rf = 0.14 (5%MeOH-CH2Cl2). 1H NMR (CDCI3, 300 MHz) 8 0.88 (br t) and 0.92 (t, J=7Hz, 6H total), 122-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (m, 2H), 3.05 (br t, J=9Hz, 1H), 3.10-3.30 (m, 3H), 3.30-3.80 (br m, 7H), 5.94 (s, 2H), 6.71 (t, J«8Hz, 1H), 6.77 (dd, J=1.5,8Hz, 1H), 6.89 (d, J=1.5Hz, 1H). MS (DCI/NH3) m/e 497 (M+H)+.
Example 94 trans, frans-2-f Proovl>-4-f 1.3-benzodioxol-5-vn-1 - f N. N-dibirtvlaminocarbonvlmethvOpvrroltdine-3-carboxvlic acid Example 94A Ethvl 2-f4-butanovn-4-nitro-3-(1.3-benzodioxole-5-vnbutvrate The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, 80%), Rf = 0.28 (25%EtOAc-hexane). 1H NMR (CDCI3, 300 MHz) 8 0.74 (t, J=7.5Hz) and 0.91 (t, J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 (t, J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1.5H), 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 (t, J=7Hz) and 2.24 (t, J=7Hz, 0.5H total)2.40-2.54 (m, 1H), 2.60 (t, J=7.5Hz) and 2.67 (t, J=7.5Hz, 0.5H total), 3.93-4.09 (m, 2H), 4.10-4.20 (br m, 1H), 4.23 (q, J=7Hz, 1H), 4.67-4.85 9m, 2H), 5.94 (s, 2H), 6.62-6.75 (m, 3H). MS (DCI/NH3) m/e 369 (M+NH4)+. Anal calcd for C17H21NO7: C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.
Example 94B Ethvl trans.trans-2-(nroo\/\)-4-( 1.3-benzodioxol-5-vnpvrrolidine-3-carboxylate The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MS (DCI/NH3) m/e 306 (M+H)+.
Exgimplfg 94Q trans. frans-2-fPropvlM-f 1.3-benzodioxol-5-vn-1 -rtN.N-dibutvlamino)carbonvnmethvlpvrrolidine-3-carboxvlic acid The procedure of Example 92C was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound. 1H NMR (CDCI3, 300 MHz) 6 0.89 (t, J=7.5Hz), 0.92 (t, J=7.5Hz), and 0.97 (t, J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 (t, J=7.5Hz, 1H), 3.40-3.55 (br m, 2H), 3.55-3.68 (m, 1H), 3.78 (d, J«15Hz, 1H), 5.92 (q, J«1 Hz, 2H), 6.70 (d, J=8Hz, 1H), 6.79 (dd, J=1Hz,8Hz, 1H), 6.90 (d, J=1Hz, H). MS (DCI/NH3) m/e447(M+H)+ Anal calcd for C25H38N2O5 O.5 H2O: C, 65.91; H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94.
Example 95 (2R.3R.4SW+)-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-v0-1-(N.N-di(n-butvh-aminocarbonvlmethvO-pvrrolidine-3-carboxvlic acid Example 95A trans.trans-2-(4-MethoxvphenvlV4-(1.3-benzodioxot-5-vn-1-fflert-butvloxycarbonvlaminocarbonvlmethvllPvrrolidine-3-carboxvlic acid The resulting mixture of 64% trans.trans- and cis,trans-pyrrolidines resulting from Example 1C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetaterhexane, 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. 1H NMR (CDCL3, 300 MHz) 6 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m, 1H), 3.44-3.95 (m, 3H), 3.81 (s, 3H), 4.04 (q, J«7 Hz, 1H), 4.14-4.28 (br m, 1H), 4.89-5.24 (br m, 1H), 5.94 (d, J=3 Hz, 2H), 6.69-6.90 (m, 5H), 7.06-7.20 (m, 2H). MS (DCI/NH3) m/e 470 (M+H)+.
To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water. The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove 'Intellectual property"omn™" •IF "I 1 8 nov 2004 ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH -7) with 1 Ji 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 (Na2SC>4), filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 %). 1H NMR (CDCI3, 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50-3.64 (m, 2H), 3.81 (s, 3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 (s, 2H), 6.71-6.79 (m, 3H), 6.84-6.91 (m, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+.
Example 95B f2R.3R-4SW+V2-(4-MethoxvDhenvO-4-n.3-benzodioxol-5-vn-1-ftert- butvloxvcarbonvlaminocarbonvlmethvlVpvrrolidine-3-carboxvHc acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam. This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate. The pure (2R,3R,4S)-(+)- enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether. The aqueous layer was further extracted twice with 100 mL of ether. The combined ether layers were washed with brine, dried (Na2SC>4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 % of theoretical 50 % maximum, >99.5 ee). 1H NMR (CDC13, 300 MHz) 8 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 (m, 2H), 3.81 (s, 3H), 4.24 (m, 1H), 4.96 (br m, 1H), 5.95 (s, 2H), 6.70-6.79 (m, 3H), 6.86 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 442 (M+H)+. (2R.3R.4SW+VEthvl 2-f4-methoxvPhenvlM-(1.3-benzodioxol-5-vn-Dvrrotidine-3- carboxvlate The compound resulting from Example 95B (251 mg, 0.568 mmol) 5 was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 °C. 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 10 methylene chloride (50 mL). The aqueous layer was further extracted ^ with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 69%). 1H NMR (CDCI3, 300MHz) 8 1.11 (t, J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 (t, 15 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 (m, 2H), 3.80 (s, 3H), 4.07 (q, J=7 Hz, 2H), 4.49 (d, J=9 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J=2 Hz, 2H), 6.81-6.92 (m, 3H), 7.34-7.41 (m, 2H). MS (DCI/NH3) m/e 370 (M+H)+. (2R.3R.4SH+)-2-(4-Methoxvphenviy-4-(1.3-benzodioxot-5-vh-1- (N.N-di(n-butvn-arhinocarbonvlmethvlVpvrrolidine-3-carboxvlic acid To the resulting compound from Example 95C (131 mg, 0.355 9 mmol) was added, diisopropylethylamine (137 mg, 185 jiL, 1.06 mmol), 25 acetonitriie (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 °C. 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 (CDCI3, 30 300MHz) 8 0.81 (t, J=7 Hz, 3H), 0.88 (t, J«7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m, 8H), 2.78 (d, J=14 Hz, 1H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 (d, J=9 Hz, 1H), 3.80 (s, 3H), 4.04 (q, J«7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 (d, J=9 Hz, 1H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H). MS (DCI/NH3) m/e 539 (M+H)+. 35 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 Intellectual property offjcs OF HI 1 8 nov 2004 i warmed slowly to 40 °C. over 2.5 hours at which point ail 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 (Na2S04), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 83%). 1H NMR (CDCI3, 300MHz) 6 0.80 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz, 1H), 6.87 (br d, J=8 Hz, 3H), 7.05 ( br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH3) m/e 511 (M+H)+. [a]22 « +74.42°. Anal calcd for C29H38N2O6 -0.5 H20: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.
Alternate Preparation of f2R.3R.4SM+V2-(4-Methoxvphenvn-4-n.3-benzodioxol-5-yn-1-ftert-butvloxvcarbonvlaminocarbonvlmethvn-pvrroiidine-3-carboxviic acid The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R (+) alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163-167°. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-168°. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-110°. (HPLC of this showed 20%of the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
Example 9$ frans. fra/7S-2-f4-MethoxvDhenvfl-4-f 1.3-benzodioxol-5-vn-1-r2-flM-proovl-N-butvrvlaminotethvflpvrrolidine-3-carboxvlic 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 isobutyry! chloride in Example 61C. The product was purified by preparative HPLC (Vydac nC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 5 0.80 (m, 3H), 0.90 (t, 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 (t, 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 (s, 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1H, J=1Hz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 -1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.
Example 97 frans-frans-2-(4-MethoxvDhenvn-4-( 1.3-benzodioxol-5-vll1 -r2-(N-proovl-N-fethvtaminocarbonvnaminotethvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCb, 300 MHz) mixture of rotamers 8 0.80 (t, J=8Hz) and 1.05 (t, J=8Hz) and 1.20 (m) and 1.42 (m) total of 8H for the four peaks, 2.35 (br s, 1H), 2.70 (m, 1H), 3.0 (m, 3H), 3.2 (m, 3H), 3.25 (dq, 1H, J^I.SHz), 3.42 (m, 1H), 3.6 (m, 1H), 3.75 (m, 1H), 3.78 (s, 3H), 4.8 (br s, 1H), 5.95 (s, 2H), 6.74 (d, 1H, J=8Hz), 6.85 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 498 (M+H)+.
Anal calcd for C27H35N3O6 • 0.75 H20: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.
Example 98 trans. trans- 2-f 4-MethoxvphenvlV4-f 1.3-benzodioxol-5-vlV1 -fg-fN-biitvl-N. butvrvlamino)ethvllpyrrolidine-3-carbQxvlic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The 10 crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (m, % 3H), 0.90 (t, 3H, J=8Hz), 1.45 (m, 4H), 1.6 (m, 2H), 2.20 (t, 3H, J^Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, is 3H), 4.30 (br s, 1H), 5.95 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.04 (d, 1H, J=1Hz), 7.40 (d, 2H, J«8Hz). MS (DCI/NH3) m/e 511 (M+H)+. HRMS calcd for C29H38N2O6: 511.2808. Found: 511.2809 Example 99 trans, frans-2-f 4-Methoxvohen vH-4-f 1.3-benzodioxol-5-vn-1 -te-fN-propvl-N-ethoxvcarbonviamino)ethvflPvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl 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 CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, 3H, J=8Hz), 1.05 (m, 2H), 1.22 (m, 3H), 1.45 (m, 3H), 2.08 (br s, 1H), 2.75 (m, 1H), 2.88 (br q, 2H, J=8Hz), 3.08 (br m, 2H), 3.27 (br m, 2H), 3.44 (m, 1H), 3.54 (dt, 1H, J=1,8Hz), 3.63 (d, 1H, J=8Hz), 3.78 (s, 3H), 4.02 (br d, 2H), 5.93 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.81 (dd, 1H, J=1,8Hz), 6.85 (d, 2H, J=8Hz), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C27H34N2O7 • 0.5 H20: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.
Example 100 frans.frans-2-f4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-r2-fN-methvl.N-f2-6thv>butvrvnamino)ethvllpvrroiidine-3-carboxvlic acid To the compound resulting from Example 61B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N-methylmorpholine (50 jiL), and DMF (2 mL). 2-Ethylbutyric acid was added and the solution stirred overnight at ambient temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 M H3PO4, and brine, dried with Na2S04, and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61C. The crude product was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=:8Hz), 1.05 (m, 2H), 1.25-1.75 (m, 5H), 2.16 (m, 1H), 2.32 (m, 1H), 2.45 (m, 1H), 2.70 (m, 1H), 2.86, 2.94 (s, total 3H), 2.95 <m, 1H), 3.35 (m, 1H), 3.52 (m, 2H), 3.65 (m, 1H), 3.80 (s, 3H), 5.94, 5.96 (s, total 2H), 6.73 (m, 1H), 6.84 (m, 3H), 6.97 (m, 1H), 7.30 (m, 2H). MS (DCI/NH3) m/e 497 (M+H)+. Anal calcd for C28H36N2O6 ■ 0.25 H20: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 frans.frans-2-f4-M6thoxvphenvlV4-(1.3-benzodioxol-5-vn-1-r2-(N-methvl-N-(2-propvlvalervnaminotethvllPvrrolidine-3-carboxvlic acid The title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2-ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac fiC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 5 0.79 (t, 3H, J=8Hz), 0.82 (t, 3H, J=8Hz), 1.10 (m, 4H), 1.2-1.5 (m, 4H), 2.55 (m, 1H), 2.96 (s, 3H), 3.15 (br m, 1H), 3.32 (br m, 1H), 3.56 (m, 2H), 3.68 (m, 1H) 3.68 (s, 3H), 3.70 (m, 1H), 3.80 (m, 2H), 4.65 (br d, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 525 (M+H)+. Anal calcd for C30H40N2O6 • 1.25 TFA: C, 58.51; H, 6.23; N, 4.20. Found: C, 58.52; H, 6.28; N, 4.33.
Example 102 trans. frans-2-f4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vlV1 -f2-(N-propvl-N-ftert. butvloxvcarbonvlmethvOaminotethvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and t-butyl bromoacetate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC13, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.18 (m, 2H), 1.19 (s, 9H), 2.12 (m, 1H), 2.46 (m, 2H), 2.70 (m, 3H), 2.85 (m, 2H), 3.20 (s, 2H), 3.40 (dd, 1H, J=2,8Hz), 3.50 (dt, 1H, J=2,8Hz), 3.62 (d, 1H, J=8Hz), 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.84 (m, 1H), 6.85 (d, 2H, J=8Hz), 7.05 (s, 1H), 7.16 (d,_ 2H, J=8Hz). MS (DCI/NH3) m/e 541 (M+H)+. Anal calcd for C30H40N2O7 * 1.0 H20: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.
Example 103 frans.fr3ns-2-(4-Methoxvphenvfl-4-(1.3-benzodioxol-5-vfl-1-f2-(N-propvl-N-fa-Dropviamtnocarbonvlmethvflaminotethvnpvrrolidine-3-carboxvUc acid The. title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and N-propyl bromoacetamide for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac jiC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.78 (t, 3H, J^Hz), 0.88 (t, 3H, J=8Hz), 1.45 (m, 2H), 1.48 (m, 3H, J=8Hz), 2.55-2.7 (m, 2H), 2.90 (m, 1H), 3.04 (m, 1H), 3.15 (m, 3H), 3.28 (t, 1H, J=8Hz), 3.45 (t, 1H, J=8Hz), 3.60 (m, 2H), 3.70 (d, 2H, J=8Hz), 3.75 (m, 1H), 3.80 (s, 3H), 4.25 (d, 1H, J=8Hz), 5.95 (s, 2H), 6.75(d, 1H, J=8Hz), 6.86 (dt, 1H, J=1,8Hz), 6.88 (d, 2H, J=8Hz), 7.04 (d, 1H, J=1Hz), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 526 (M+H)+. Anal calcd for C29H39N3O6 * 1.85 TFA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
Examote 104 trans.trans-2-(4-Methoxvphen vH-4-( 1.3-benzodioxol-5-vn-1 -f2-f N-propvl-N-f4-m6thoxvphenoxvcarbonvhamino)ethvl1pvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CD3OD, 300 MHz) mixture of rotamers 5 0.88 (m,3H), 1.57 (m, 2H), 2.45 (br s) and 2.60 (br s, total of 1H), 2.90-3.15 (m, 4H), 3.42-3.7 (m, 5H), 3.78 (s, 3H), 3.80 (s, 3H), 3.85 (m) and 4.0 (m, total of 1H), 5.95 (s) and 5.98 (s, total of 2H), 6.63(m, 1H), 6.72 (d, 1H, J=8Hz), 6.81 (m, 2H), 6.93 (m, 5H), 7.40 (m, 2H). MS (DCI/NH3) m/e 577 (M+H)+. Anal calcd for C32H36N2O8 * 1.0 H20: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.
Example 105 frans.frans-2-(4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vn-1 -T2-(N-propvl-N-(4-methoxvbenzovnaminotethvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and .anisoyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) mixture of rotamers 5 0.78 (m) and 0.98 (t, J=8Hz) total of 3H, 1.47 (m) and 1.52 (q, J=8Hz) total of 2H, 2.25 (br s, 1H), 2.78 (br s, 1H), 2.90 (br t, 2H), 3.12-3.68 (m, 7H), 3.80 (s, 3H), 3.82 (s, 3H), 5.94 (s, 2H), 6.75(d, 1H, J=8Hz), 6.83 (m, 5H), 6.94 (m, 1H), 7.22 (m, 4H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 • 0.75 H2O: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.
Example 106 frans. frans-2-(4-Methoxvphenvfl-4-( 1.3-benzodioxo(-5-vn-1 -f2-fN-Dronvl-N-benzovlaminotethvnpvrrolidine-3-carboxvlic 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 CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) mixture of rotamers 8 0.65 and 0.9 (m, total of 3H) , 1.4 and 1.55 (m, total of 2H), 2.05 and 2.15 (m, total of 1H), 2.6 - 3.6 (m, 8H), 5.92 (s, 2H), 6.70(d, 1H, Js=8Hz), 6.82 (m, 4H), 7.2 - 7.4 (m, 6H). MS (DCI/NH3) m/e 531 (M+H)+. Anal calcd for C31H34N2O6 • 0.3 H2O: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.
Example 107 trans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -f2-(N-propvl-N-benzvloxvcarbonvlaminotethvnpvrrolidine-3-carboxvlic 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 nC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.8 (m, 3H) 1.45 (m, 2H), 2.20 (br m, 1H), 2.75 (m, 1H), 2.93 (m, 1H), 3.15 (m, 2H), 3.32 (m, 3H), 3.52 (m, 2H), 3.66 (m, 1H), 3.78 (s, 3H), 5.00 (m, 2H), 5.94 (s, 2H), 6.72(d, 1H, J=8Hz), 6.82 (m, 3H); 7.0 (br d, 1H, J= 15Hz), 12 (s, 4H), 7.30 (m, 3H). MS (FAB) m/e 561 (M+H)+. Anal calcd for C32H36N2O7 * 1.0 TFA: C, 60.53; H, 5.53; N, 4.15. Found: C, 60.66; H, 5.34; N, 4.28.
Example 108 frans.frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1-r2-fN-propvl-N-M-methoxybenzyloxvcarbonvnamino)ethvllpyrrolidine-3-carboxvlic acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61B and 4-methoxybenzyi chloroformate for isobutyryl chloride in Example 61C.
Example 109 frans.frans-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vlV1-r2-(N-butvl-N-ethoxvcart3onviamino)ethvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting butyiamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac p.C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR {CDCI3, 300 MHz) 8 0.82 (t, 3H, J=8Hz), 1.20 (m, 5H), 1.34 (m, 2H), 3.08 (m, 2H), 3.17 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 3.78 (s, 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, 1H), 5.94 (s, 2H), 6.76 (d, 1H, J=8Hz), 6.92 (d, 2H, J=8Hz), 7.03 (br s, 1H), 7.17 (br s, 1H), 7.7 (br s, 2H). MS (FAB) m/e 513 (M+H)+. Anal calcd for C28H36N2O7 • 0.5 TFA: C, 61.15; H, 6.46; N, 4.92. Found: C, 60.99; H, 6.80; N, 4.93.
Example 110 trans.trans-2- (4-Methoxvphen vfl-4- (1.3-benzodioxoi-5-vn-1-r2-(N-butvl-N-propoxvcarbonvlamino)ethvl1pvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example .61, but substituting butyiamine for methylamine in Example 61B and propyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (br s, 1H), 0.85 (t, 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (m, 3H), 1.40 (m, 3H), 1.62 (br m, 1H), 2.15 (br s, 1H), 2.72 (m, 1H), 2.87 (m, 1H), 3.1-3.45 (m, 5H), 3.55 (m, 1H), 3.64 (d, 1H, J=8Hz), 3.79 (s, 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 (s, 2H), 6.73(d, 1H, J=8Hz), 6.85 (m, 3H, 7.0 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (FAB) m/e 527 (M+H)+. Anal calcd for C29H38N2O7 • 0.15 H20: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21.
Example 111 frans-frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -fe-fN-propvl-N-proooxvcarbonvlaminotethvllpvrrolidine-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and propyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, 3H, J=8Hz), 093 (m, 3H), 1.43 (m, 3H), 1.62 (m, 1H), 2.15 (br s, 1H), 2.68-3.45 (m, 8H), 3.54 (m, 1H), 3.66 (m, 1H), 3.78 (s, 3H), 3.94 (m, 2H), 5.94 (s, 2H), 6.72 (d, 1H, J=8Hz), 6.82 (m, 1H), 6.84 (d, 2H, J=8Hz), 7.00 (br s, 1H), 7.33 (m, 2H). MS (DCI/NH3) m/e 513 (M+H)+.
Anal calcd for C28H36N2O7 * 0.15 H2O: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.
Example 112 frans.frans-1-fN.N-Difn-butvnaminocarbonvnmethvl-2.4-dif1.3-benzodioxol-5- ynDvrrolidine-3-carboxvlic acid Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. 47 , 20 (1967) starting with 3,4-methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 °C. 1H NMR (CDCI3, 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (m, 6H), 2.80 (d, J=13Hz, 1H), 2.94-3.12 (m, 4H), 3.28-3,50 (m, 4H), 3.58-3.62 (m, 1H), 3.78 (d, J=9Hz, 1H), 5.95 (s, 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (m, 2H), 6.92 (d, J=1Hz, 1H), 7.01 (d, H=1Hz, 1H). MS (DCI/NH3) m/e 525 (M+H)+.
Example 113 frans.ftans-1-(2-(N-(n-Butvn-N-proovlsulfonvlaminotethvn-2-(4-methoxvphenvlM-(1.3-benzodioxol-5-vnpvrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 64-65 °C. 1H NMR (CDCI3, 300 MHz) 8 0.83 (t, J=7Hz, 3H), 0.98 (t, J=7Hz, 3H), 1.12-1.25 (m, 2H), 1.32-1.41 (m, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (m, 2H), 2.72-3.32 (m, 8H), 3.43 (dd, J=9Hzt 3Hz, 1H), 3.53-3.59 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.83 (dd, J=8Hz, 1Hz, 1H), 6.88 (d, J=9Hz, 2H), 7.02 (d, J=1Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 114 frans.frans-1-fN.N-Dl(n-butvnaminocarbonvlmethvlV2-(4-methoxvphenvn-4-M.3-benzodioxol-5-vnpvrrolidine-3-carboxv»c acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74-76 °C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, J=6Hz, 3H), 0.88 (t, J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (m, 6H), 2.75 (d, J=12Hz, 1H), 2.95-3.09 (m, 4H), 3.26-3.59 (m, 5H), 3.75 (d, J=9Hz, 1H), 3.79 (s, 3H), 4.28 (s, 4H), 6.78 (d, J=9Hz, 1H), 6.85 (d, J=9Hz, 2H), 6.91 (d,d, J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 525 (M+H)+.
Example 115 frans.frans-1-f2-fN-Propyl-N-propvlsulfonvlaminotethvn-2-f4-methoxvDhenvn-4-f1 -3-benzodioxol-5-vnDvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73 °C. 1H NMR (CDCI3, 300 MHz) 8 0.79 (t, J=8Hz, 3H), 0.98 (t, J=8Hz, 3H), 1.43 (sextet, J«8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (m, 1H), 2.69-3.32 (m, 9H), 3.42 (dd, J=3Hz, 12Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=12Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=11Hz, 1H), 6.83 (dd, J=1Hz, 11 Hz, 1H), 6.87 (d, J=r11Hz, 2H), 7.0 (d, J=2Hz, 1H), 7.32 (d, J=11Hz, 2H). MS (DCI/NH3) m/e 533 (M+H)+.
Example 116 frans.frans-1-f2-fN-Butvl-N-butvlsulfonvlamino1ethvlV2-f4-methoxvphenvn-4-f1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 62-63 °C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J=6Hz, 3H), 0.91 )t, J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-1.42 (m, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (m, 1H), 2.70-3.28 (m, 9H)f 3.41 (d, J=8Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J*=8Hz, 1H), 3.79 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.82 (d, J«8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.01 (s, 1H), 7.32 (d, J=8Hz, 2H). MS (DCl/NH3) m/e 561 (M+H)+.
Example 117 frans.frans-1-/2-(N.N-DibutvlaminocarbonvlmethvlV2-f4-methoxvmethoxvphfinylV 4-f1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid 4-Hydroxyacetophenone was treated with chloromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4-methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid, m.p. 48-49 °C. 1H NMR (CDCI3, 300 MHz) 8 0.81 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d, J=12Hz, 1H), 2.94-3.10 (m, 4H), 3.25-3.35 (m, 1H), 3.40 (d, J=12Hz, 1H), 3.43-3.52 (m, 2H), 3.47 (s, 3H), 3.55-3.62 (m, 1H), 3.77 (d, J=9Hz, 1H), 5.15 (s, 2H), 5.94 (m, 2H), 6.73 (d, J=8Hz, 1H), 6.86 (dd, J=1Hz, 8Hz, 1H), 7.0 (d, J^Hz, 2H), 7.04 (d, J=1Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 541 (M+H)+.
Example 118 trans.trans-1 42-fN.N-Dibutvlaminocarbonvlrnethvh-2-(4-hvdroxvphenv0-4-( 1.3-benzQdioxol-5-vnpvrrolidine-3-carboxvlic acid hydrochloride salt The compound resulting from Example 116 was treated with concentrated HCI in 1:1 THF-isopropanol to give the title compound as a white solid, m.p. 211-212 °C. 1H NMR (CD3OD, 300 MHz) 8 0.90 (t, J«8Hz, 6H), 1.12-1.27 (m, 6H), 1.36-1.45 (m, 2H), 3.04 (bs, 1H), 3.14-3.35 (t, J=9Hz, 1H), 3.90 (bs, 3H), 4.17 (d, J=15Hz, 1H), 5.96 (s, 2H), 6.82-6.93 (m, 4H), 7.03 (d, J=1Hz, 1H), 7.42 (bs, 2H). MS (DCI/NH3) m/e 497 (M+H)+.
Example 119 frans.frans-1-f2-fN-lsobutvl-N-propvlsulfonvlamino^ethvn-2-(4-methoxvphenvn-4-M .3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 73-74 °C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (d, J=6Hz, 6H), 0.98 (t, J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, Js=8Hz, 2H), 2.23-2.34 (m, 1H), 2.68-2.98 (m, 7H), 3.08-3.18 (m, 1H), 3.26-3.42 (m, 2H), 3.52-3.58 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.90 (s, 2H), 6.74 (d, J^Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.86 (d, J=8Hz, 2H), 6.98 (d, J=1Hz, 1H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 120 frans.f/ans-1-f2-(N-Benzenesulfonvl-N-propviaminotethvn-2-(4-methoxvDhgnvn-4-M .3-benzodioxol-5-vnpvrrolld}ne-3-carboxvnc acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 89-91 °C. 1H NMR (CDCI3, 300 MHz) 8 0.74 (t, J=6Hz, 3H), 1.33 (sextet, Js6Hz, 2H), 2.20-2.30 (m, 1H), 2.62- 2.72 (m, 1H), 2.85-3.05 (m, 4H), 3.12-3.22 (m, 1H), 3.38 (dd, J=*3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.84 (dd, J=1Hz, 8Hz, 1H), 6.85 (d, J=9Hz, 2H), 7.02 (d, J«1Hz, 1H), 7.28 (d, J=9Hz, 2H), 7.39-7.54 (m, 3H), 7.70 (d, J=7Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+.
Example 121 trans.trans- l-(2-fN-(4-Methoxvbenzenesulfonvn-N-propvlaminotethvn-2-f4-methoxvphenvn-4-n .3-benzodioxol-5-vnDvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 °C. 1H NMR (CDCI3, 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1H), 2.62-2.71 (m, 1H), 2.82-3.03 (m, 4H), 3.08-3.18 (m, 2H), 3.38 (dd, J=3Hz, 9Hz, 1H), 3.48-3.56 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.81 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.81-6.89 (m, 5H), 7.01 (d, J=1Hz, 1H), 7.28 (d, J=s8Hz, 2H), 7.62 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 597 (M+H)+._ Example 122 trans.trans-1 -(N.N-Dif n-butyHaminocarbon vlmethvn-2-(2-methoxvethoxv-4-methoxvphenvn-4-M .3-benzodioxol-5-vnpvrrolidine»3-carboxvlic acid 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2-methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid, m.p. 63-65 °C. 1H NMR (CDCI3, 300 MHz) 8 0.84 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (m, 4H), 2.87-2.94 (m, 2H), 3.00-3.16 (m, 3H), 3.26-3.36 (m, 2H), 3.43 (s, 3H), 3.47-3.54 (m, 3H), 3.66-3.72 (m, 2H), 3.78 (s, 3H), 3.76-3.84 (m, 1H), 4.02-4.10 (m, 2H), 4.25 (d, J=9Hz, 1H), 5.92 (s, 2H), 6.40 (d, J=2Hz, 1H), 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 (d, J=8Hz, 1H), 6.83 (dd, J=1Hz, 8Hz, 1H), 5.98 (d, J=2Hz, 1H), 7.53 (d, J=9Hz, 1H). MS (DCI/NH3) m/e 585 (M+H)+.
Example 123 frans.frans-1-(2-(N-Propvl-N-f2.4-dimethvlbenzenesulfonvnaminotethvfl-2-(4-methoxvphenvn-4-f1.3-benzodioxol-5-vnpvrrQlidlne-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-90 °C. 1H NMR (CDCI3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1H), 2.32 (s, 3H), 2.47 (s, 3H), 2.62-2.69 (m, 1H), 2.78 (t, J=9Hz, 1H), 2.89 (dd, Js=8Hz, 1H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (m, 3H), 3.46-3.55 (m, 1H), 3.60 (d, J=9Hz, 1H), 3.82 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1H), 6.80 (dd, Js=1Hz, 9Hz, 1H), 6.86 (d, J=9Hz, 2H), 6.97 (d, J=1Hz, 1H), 7.03 (bs, 2H), 7.29 (d, J=9Hz, 1H). MS (DCI/NH3) m/e 595 (M+H)+.
Example 124 frans.frans«1-(2-(N-Propvl-N-(3-chloropropvlsulfonvnaminotethvfl-2»(4-methoxvphenvlV4-f 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 75-76 °C. 1H NMR (CDC13, 300 MHz) 8 0.80 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (m, 3H), 2.70-2.80 (m, 1H), 2.85-3.10 (m, 6H), 3.23-3.31 (m, 2H), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (m, 4H), 3.81 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (d, J:=8Hz, 1H), 6.86 (d, J=8Hz, 2H), 7.00 (s, 1H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 567 (M+H)+.
Example 125 f/ans.frans-1-(2-fN-Propvl-N-(2-methoxvethvlsulfonvnamino>ethvn-2-(4-methoxvphenvn-4-f 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, frans, frans-1-(2-(N-Propyl-N-(vinylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid, m.p. 62-64 °C. 1H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (m, 1H), 2.72-2.79 (m, 1H), 2.86-3.05 (m, 4H), 3.10-3.27 (m, 4H), 3.32 (s, 3H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.58 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.69 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.94 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=1Hz, 8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.02 (d, J=1Hz, 1H), 7.33 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 549 (M+H)+.
Example 126 frans.fra/7s-1-f2-fN-Propvl-N-f2-ethoxvethvlsulfonvnamlno)ethvn-2-M-methoxvphenvn-4-f1.3-benzodioxol-5-vnDvrrolidine-3-carbQxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 58-60 °C. 1H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.18 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24-2.33 (m, 1H), 2.70-2.80 (m, 1H), 2.87-3.05 (m, 4H), 3.13-3.20 (m, 2H), 3.22-3.32 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.46 (q, J=7Hz, 2H), 3.52-3.58 (m, 1H), 3.65 (d J=9Hz, 1H), 3.72 (t, J=6Hz, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.83 (dd, J=1Hz, 7Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.00 (d, J=1 Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 563 (M+H)+.
Example 127 frans.frans-1-(2-fN-Propvl-N-f5-dimethvlamino-1-naphthvlsulfonvnamino,>ethvh-2-(4-methoxvphenvH-4-f 1.3-benzodioxol-5-vnpvrrotidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid, m.p. 102-104 °C. 1H NMR (CDCfe, 300 MHz) 8 0.62 (t, J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (m, 1H), 2.78 (t, Js=9Hz, 1H), 2.88 (s, 6H), 2.72-2.89 (m, 1H), 3.05-3.12 (m, 2H), 3.26-3.45 (m, 3H), 3.45-3.52 (m, 1H), 3.58 (d, J=9Hz, 1H), 6.97 (d, J=1 Hz, 1H), 7.13 (d, J=7Hz, 1H), 7.26 (d, J=8Hz, 1H), 7.42-7.50 (m, 2H), 8.08 (dd, J=1 Hz, 7Hz, 1H), 8.20 (d, J=8Hz, 1H), 8.48 (d, J=8Hz, 1H). MS (DCI/NH3) m/e 660 (M+H)+.
Example 128 fra/7S.frang-1-f2-(N-Propvl-N-fethvlsulfonvnamino1ethvn-2-r4-methoxvphenvlV4-h .3-benzodioxol-5-vnpvrrolidine-3-carboxvHc acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 70-72 °C. 1H NMR (CDCI3, 300 MHz) 8 0.79 (t, J=8Hz, 3H), 1.28 (t, J=7Hz, 3H), 1.43 (q, J=8Hz, 2H), 2.22-2.30 (m, 1H), 2.71-2.80 (m, 1H), 2.82-3.10 (m, 6H), 3.18-3.32 (m, 2H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.60 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.82 (dd, J^IHz, 7Hz, 1H), 6.88 (d, J=8Hz, 2H), 7.00 (d, J=1Hz, 1H),. 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 519 (M+H)+.
Example 129 frans.ftans-1-f2-fN-Propvl-N-(4-methvlbenzenesulfonvnaminotethvft-2-{4-methoxvphenv0-4-( 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 78-79 °C. 1H NMR (CDCI3, 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.61-2.72 (m, 1H), 2.83-3.05 (m, 4H), 3.08-3.19 (m, 2H), 3.48 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.81 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.87 (d, J=8Hz, 2H), 7.00 (s, 1H), 7.21 (d, Js=8Hz, 2H), 7.29 (d, J=8Hz, 2H), 7.57 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 581 (M+H)+.
Example 130 trans. fran5-1-(N.N-Di(n-butvnaminocarbonvlmethvn-2-f3-pvridvn-4-(1.3- benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 167-168 °C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J-7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (m, 6H), 2.86-3.20 (m, 6H), 3.34-3.43 (m, 2H), 3.57 (dd, J=3Hz, 9Hz, 1H), 3.75-3.83 (m, 1H), 4.08 (d, J=9Hz, 1H), 5.93 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.90 (dd, J=2Hz, 8Hz, 1H), 7.03 (d, J=2Hz, 1H), 7.38 (dd, J=4Hz, 8Hz, 1H), 8.04 (d, J=8Hz, 1H), 8.48 (dd, J=2Hz, 4Hz, 2H). MS (DCI/NH3) m/e 482 (M+H)+.
Example 131 frans.frflns-1-(2-(N-Proovl-N-fn-butvlsutfonvnaminotethvn-2-M--methoxvphenvl1)-4-n.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 65-66 °C. 1H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.31-1.46 (m, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.12-3.23 (m, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (m, 1H), 3.64 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.96 (s, 2H), 6.72 (d, J=7Hz, 1H), 6.83 (dd, J=1Hz, 7Hz, 1H), 6.86 (d, J=8Hz, 2H), 7.00 (d, J=1Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 547 (M+H)+.
Example 132 trans, trans-1 -f2-f N-Propvl-N-(4-chlorobenzenesulfon vham inotethvh-2-M-methoxvphenvn-4-(1.3-benzodioxol-5-vnpvrroiidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 105-106 °C. 1H NMR (CDCI3, 300 MHz) 8 0.72 (t, Js=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (m, 1H), 2.78-2.86 (m, 1H), 2.96-3.03 (m, 3H), 3.13-3.26 (m, 3H), 3.51 (dd, J=5Hz, 9Hz, 1H), 3.62-3.68 (m, 1H), 3.80 (s, 3H), 3.94 (d, J=9Hz, 1H), 5.92 (s, 2H), 6.75 (d, J=8Hz, 1H), 6.84 (dd, J=2Hz, 8Hz, 1H), 6.94 (d, J=8Hz, 2H), 6.98 (d, J=2Hz, 1H), 7.36 (d, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.68 (d, J=8Hz, 1H). MS (DCI/NH3) m/e 601 (M+H)+.
Example 133 fr3ns.frans-1-(2-(N-ProDvl-N-fbenzyteulfonvnaminotethvn-2-(4-methoxvohenv0-4-M .3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-89 °C. 1H NMR (CDCI3, 300 MHz) 8 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (m, 1H), 2.56-2.67 (m, 1H), 2.75-3.10 (m, 6H), 3.30 (dd, J=2Hz, 9Hz, 1H), 5.95 (s, 2H), 6.73 (d, J=7Hz, 1H), 6.80 (dd, J=1Hz, 7Hz, 1H), 6.86 (d, J=8Hz, 2H), 6.97 (d, J=1 Hz, 1H), 7.27-7.35 (m, 7H). MS (DCI/NH3) m/e 581 (M+H)+.
Example 134 frans.frans-1-(2-fN-Propvl-N-f4-fluorobenzenesulfonvnamino)ethvlV2-(4-methoxvphenvn-4-( 1.3-benzodioxol-5-vPiDvrrolidine-3-carboxvric acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 91-93 °C. 1H NMR (CDCI3, 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1H), 2.56-2.67 (m, 1H), 2.78-2.87 (m, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (m, 2H), 3.33 (dd, J=2Hz, 9Hz, 1H), 3.43-3.50 (m, 1H), 3.57 (d, J=9Hz, 1H), 3.78 (s, 3H), 7.08 (t, J=8Hz, 2H), 7.24 (d, J=8Hz, 2H), 7.69 (dd, J=5Hz, 8Hz, 2H). MS (DC!/NH3) m/e 585 (M+H)+.
Example 135 frans.frans-1-(N-Methvl-N-oropvlaminocarbonvlmethvlV2-(4-methoxvnhenvlV4-(4- benzofuranvflpvrrolidine-3-carboxvlic acid Example 135A Benzofuran-4-carboxaldehvde 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 3-bromophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 °C for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSC>4, filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, 74%). 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, 70%). 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 (80 mL) at -78 °C was added 1.7 M. t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 °C. After stirring for 15 minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated. The organic solution was dried over MgSC>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 g), both as colorless oils.
Example 135B fr3ns.frans-1-(N-Methvl-N-propvlaminocarbonvimethvn-2-f4-methoxvDhenvlM-f4- benzofuranvnpvrrolidine-3-carboxvlic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49A for piperonal. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, m), 6.8 (2H, d, J=8Hz), 4.03 (1H, m), 3.94 (1H, dd, J=8Hz, 3Hz), 3.77 (3H, s), 3.61 (1H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=11Hz, 5Hz), 3.40-2.90 (5H, m), 2.82 (2.81) (3H, s), 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 (M+H)+. Anal.calc. for C26H30N2O5 • AcOH: C, 65.87; H, 6.71; N ,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s Example 136 frans.fr3/7s-1-(N-Methvl-N-oropvtaminocarbonvtmethvn-2-f4-methoxvDhenvlV4-(6- benzofuranvnpvrrolidine-3-carboxvlic 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. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.65 (1H, bd), 7.60 (1H, d, Jss2Hz), 7.55 (1H, d, J=8Hz), 7.35 (3H, m), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1H, dd, J=3Hz, 2Hz), 3.83 (2H, m), 3.79 (3H, s), 3.60-3.0 (7H, m), 2.91 (2.83) (s, 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 (M+H)+. Anal.calc. for C26H30N2O5 * 0.5 H20: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
Example 137 frans./rans-1-fN-Meth vl-N-propylaminocarbon vlmeth vn-2-M-methoxvphen vlV4-(6-benzo-2.3-dihvdrofuranvltovrrolidine-3-carboxvlic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H2 in AcOH, followed by preparative hplc) of the compound resulting from Example 136 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, m), 7.82 (3H, m), 5.40 (1H, dd, J=11Hz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1H, m), 4.10 (1H, m), 3.88 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.35 (1H, m), 3.19 (2H, t, J=8Hz), 3.00 (4H, m), 2.91 (2.78) (s, 3H), 1.53 (1.40) (2H, septet, Js=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) m/e 453 (M+H)+. Anal.calc. for C26H32N2O5 • 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.
Example 138 frans.f/ans-1-(N.N-DibutvlaminocarbonvtmethvlV2-(4-methoxvphenviWU4-benzofuranvnpvrrolidine-3-carboxviic 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-dibuty! bromoacetamide for N-methyl-N-propyl bromoacetamide. 1H NMR (300 MHz, CDCI3) 5 7.62 (1H, d, J=3Hz), 7.39 (1H, dt, J=8Hz, 2Hz), 7.34 (3H, m), 7.26 (1H, d, J=2Hz), 7.23 (1H, d, J=8Hz), 6.84 (2H, d, J=*8Hz), 4.02 (1H, ddd, J=8, 6Hz,4Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.67 (1H, dd, J=10Hz, 3Hz), 3.44 (2H, m), 3.35-3.15 (3H, m), 3.00 (2H, m), 2.84 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
Example 139 frans.frans-1-fN.N-Dibutvlaminocarbonvlmethvfl-2-f4-methoxvphenvn-4-(4-benzofuranvflpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 135A substituted 4-bromophenol for 3-bromophenol, in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1H NMR (300 MHz, CDCI3) 5 7.64 (1H, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, m), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=8Hz), 6.73 <1H," dd, J=3Hz, 1Hz), 3.82 (1H, d, J=11Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=10Hz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.82 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
Example 140 frans.frans-1-fN.N-DibutvlaminocarbonvimethvlV2-(4-methoxvphenvlV4.(6-benzofuranvnpvrrolidine-3-carboxv!ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-N-propyl bromoacetamide. 1H NMR (300 MHz, CDCI3) 8 7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Hz), 7.36 (3H, m), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=11Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=10Hz, 3Hz), 3.44 (2H, m), 3.30 (1H, m), 3.20-2.95 (5H, m), 2.80 (1H, d, J=14Hz), 1.43 (3H, m), 1.23 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 507 (M+H)+. Anal.calc. for C30H38N2O5 • 0.75 H20: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32. frans-frans-1-(N.N-Dibutvtaminocarbonvlmethvn-2-(4-methoxvohenvn-4-(6-benzo-2-3-dihvdrofuranvflpvrroKdine-3-carboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H2 in AcOH, followed by preparative hpic). 1H NMR (300 MHz, CDCI3) 8 7.40 (2H, d, J=8Hz), 7.16 (1H, d, J=8Hz), 6.97 (1H, dd, J=8Hz, 2Hz), 6.89 (3H, m), 5.90 (1H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, m), 3.80 (3H, s), 3.70-3.58 (2H, m), 3.40 (1H, m), 3.30-2.90 (8H, m), 1.40 (2H, m), 1.29 (3H, m), 1.08 (2H, m), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 509 (M+H)+. Anal.calc. for C3oH4oN205 • 0.85 TFA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
Example 142 frans.frans-1-(N-Methvl-N-propvlaminocarbonv)methvn-2-(4-methoxvphenvn-4-(5- indanvr>pvrroHdine-3-carboxviic acid Example 142 A lndane-5-carboxaldehyde lndane-5-carboxaldehyde was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5-carboxaldehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystaiiized from hot acetonitriie to yield the 5-aldimine as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N. hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether. The organic solution was dried over MgSC>4, filtered, and concentated in vacuo. Vacuum distillation of the residue afforded indane-5-carboxaldehyde (1.54 g, 88%) as a colorless liquid, b.p. 88-90 °C at 0.9 mm Hg.
Example 142B frans-frans-1-fN-Methvl-N-Dropvlam'mocarbonvlmethvlV2-f4-methoxvphenvn-4-f5- indanvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.25-7.1 (5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, s), 3.50-2.90 (6H, m), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, s), 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 (M+H)+, 473 (M+Na)+. Anal.calc. for C27H34N2O4 • 2.5 H20 : C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; H, 7.45; N, 5.53.
Example 143 frans.fran^1-fN-Methvl-N-proDvlaminocarbonvlmethvn-2-f4-methoxvphenvn-4-{6- indolvnpvrrolidine-3-carboxviic 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. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 8.43 (IH, brs), 7.57 (1H, d, J=8Hz), 7.43 (1H, s), 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (1H, d, J=8Hz), 7.1 (1H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1H, m), 3.93 (1H, dd, J=6Hz, 3Hz), 3.80 (1H, m), 3.73 (3H, s), 3.60-2.90 (6H, m), 2.86 (2.82) (3H, s), 1.47 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 450 (M+H)+. Anal.calc. for C26H31N3O4 • 0.75 H20: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
Example 144 f/ans.frang-1-(N-Methvl-N-propvlaminocarbonvlmethviV2-(4-methoxvphenv»>-4-(3.4-difluoroDhenvflDvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.60-7.3 (4H, m), 7.13 (1H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1H, m), 3.79 (3H, s), 3.60-2.95 (6H, m), 2.92 (2.78) (3H, s), 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) m/e 447 (M+H)+. Anal.calc. for C24H28F2^204 • 1.80 H20: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
Example 145 frans.frans-1-(N-Methvl-N-propviaminocarbonvlmethv[>-2-(4-methoxvphenvlV4- (phenvflpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.53 (4H, d, J=6Hz), 7.40-7.20 (3H, m), 6.88 (2H, d, J=8Hz), 3.90 (1H, m), 3.79 (3H, s), 3.70-2.95 (8H, m), 2.90 (2.79) (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (DCI/NH3) m/e 411 (M+H)+. Anal.calc. for C24H3oN204 • 2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.
Example 146 fra/?s.frans-1-fN-Methvl-N-propvlaminocarbonvtmethvn-2-f4-methQxvphenvlV4-f4-hvdroxvphenvnpvrrolidine-3-carboxvlic 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, CDCI3-CD3OD) (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, Jss8Hz), 3.81 (3H, s), 3.65 (1H, d, J=8Hz), 3.70-3.00 (8H, m), 2.92 (2.83) (3H, s), 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/NH3) m/e 427 (M+H)+. Anal.calc. for C24H3oN205 • 1.00 H20: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.
Examole 147 f/ans.franfr1-fN-Methvl-N-propvlaminocarbonvlmethvn-2-(4-methoxvphenylV4-f2.4-dimethoxvphenvnpvrroIidine-3-carboxviic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) 8 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J«8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1H, d, J=8Hz), 6.45 (1H, d, J=3Hz), 3.90 (1H, m), 3.81 (3H, s), 3.79 (3H, s), 3.77 (3H, s), 3.70-2.90 (8H, m), 2.85 (3H, s), 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DC!/NH3) m/e 471 (M+H)+. Anal.calc. for C26H34N2O6 -0.75 H2O: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
Example 148 trans. trans-1-(N. N-Dibutvlaminocait)onvlmethvl>-244-methoxvphenvn-4-f5-benzo-2-3-dihvdrofuranvflpvrrolidine-3-carboxvUc 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. 1H NMR (300 MHz, CDCI3) 8 7.31 (2H, d, J*:8Hz), 727 (1H, d, J=2Hz), 7.18 (1H, dd, J=7Hz, 3Hz), 6.86 (2H, d, J=8Hz), 6.72 (1H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, s), 3.62 (1H, m), 3.50-3.25 (4H, m), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, m), 2.79 (1H, d, J=14Hz), 1.43 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 509 (M+H)+. Anal.calc. for C30H40N2O5 • 0.25 H2O: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.
Example 149 fr3ns-fr3ns-1-(N.N-Dibutvlaminocarbonvlmethvn-2-(4-methoxvphenvn-4-M-methoxvphenvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. ""H NMR (300 MHz, CDCI3) 8 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, s), 3.76 (3H, s), 3.63 (1H, m), 3.50-3.20 (4H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=14Hz), 1.43 (3H, m), 1.27 (3H, m), 1.09 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 (M+H)+. Anal.calc. for C29H40N2O5: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.
Example 150 frans. frans-1-(N.N-Dibutvlaminocarbonvlmethvn-2-f4-methoxvphenvlV-4-f3 4-difluorophenvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 8 7.35 (1H, m), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, m), 6.87 (2H, d, J=8Hz), 3.78 (3H, s), 3.79 (1H, m), 3.62 (1H, m), 3.50-3.30 (3H, m), 3.23 (1H, m), 3.15-2.90 (4H, m), 2.78 (1H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 503 (M+H)+. Anal.calc. for C28H36F2N2O4* • 1 H2O: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
Example 151 f/ans.frans-1-fN.N-Dibutvlaminocarbonvlmethvfl-2-(4-methoxvphenvfl-4-(2.4-dimethoxvphenvnpvrrolidine-3-carboxvtic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 8 7.37 (2H, d, J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), 6.49 (1H, dd, J=6Hz, 2Hz), 5.35 (1H, d, J=8Hz), 4.20 (3H, m), 4.10 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.75 (3H, m), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, m), 1.07 (4H, m), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 527 (M+H)+. Anal.calc. for C30H42N2O6 • 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.
Example 152 trans, trans-1 -fN.N-Dibutvlaminocarbonvlmethvn-2-phenvl-4-( 1.3-benzodioxol-5- yOpvrrolidine-3-carboxvlic 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, CDCI3) 8 7.50-7.25 (5H, m), 7.04 (1H, d, J=3Hz), 6.87 (1H, dd, J=7Hz, 3Hz), 6.74 (1H, d, J=8Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.85 (1H, d, J=8Hz), 3.64 (1H, m), 3.42 (3H, m), 3.27 (2H, m), 3.20-2.90 (5H, m), 2.81 (1H, d, J=14Hz), 1.43 (2H, m), 1.27 (4H, m), 1.05 (2H, m), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 481 (M+H)+. Anal.calc. for C28H36N2O5: C, 69.98; H, 7.55; N, 5.83. Found: C, 69.69; H, 7.63; N, 5.71.
Example 153 trans, trans-1 -fN. N-Dibutvlam inocarbonvlm eth v0-2-phenvl-4-(5-benzo-2 3-dihvdrofuranvnpvrrolidine-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-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCi3) 8 7.53 (2H, m), 7.40 (4H, m), 7.13 (1H, dd, J«7Hz, 3Hz), 6.72 (IH, d, J=8Hz), 5.40 (1H, d, J=10Hz), 4.56 (2H, t, J=8Hz), 4.18 (1H, d, J=14Hz), 4.07 (2H, m), 3.79 (2H, m), 3.48 (1H, d, J=14Hz), 3.35 (1H, m), 3.28 (3H, m), 2.95 (2H, m), 1.47 (2H, m), 1.28 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS (DCI/NH3) m/e 479 (M+H)+. Anal.calc. for C29H38N204-1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.
Example 154 frans.frans-1-fN.N-Dibutvlaminocarbonvlmethvn-2-f4-t-butvlPhenvlV4-f5-benzo-2 a-riihvdrofuranvnpvrroltdlne-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967) starting from 4-t-butylacetophenone, in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 8 7.60-7.30 (6H, m), 6.90 (1H, m), 4.50 (2H, m), 3.95 (1H, m), 3.85-2.95 (11H, m), 2.90 (1H, d, J=14Hz), 1..58 (2H, m), 1.50 (7H, m), 1.41 (6H, s), 1.10 (2H, m), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) m/e 535 (M+H)+. Anal.calc. for C33H46N2O4 • 0.25 H20: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
Examole 155 frans.f/ans-2-fN.N-Dibutvtaminocarbonvtmethvn-2-M-methoxvphenvlV-4-f4-fluorophenvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. ">H NMR (300 MHz, CDCI3) 8 7.50 (1H, m), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=8Hz), 3.83 (1H, m), 3.8 (3H, s), 3.67 (1H, m), 3.47 (3H, m), 3.30-2.90 (5H, m), 2.82 (1H, d, J=14Hz), 1.43 (2H, m), 1.28 (4H, m), 1.08 (2H, m), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DC!/NH3) m/e 485 (M+H)+. Anal.calc. for C28H37FN2O4: C, 69.40; H, 7.70; N, 5.78. Found; C, 69.03; H, 8.00; N, 5.74.
Example 156 frans-frans-1-fN.N-Dibutvlaminocarbonvlmethvfl-2-(3-furvn-4-f1.3-benzodioxol-5- ynpvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting p-oxo-3-furanpropionate in Example 49B. 1H NMR (300 MHz, CDCI3) 8 7.41 (2H, m), 6.97 (1H, d, J=3Hz), 6.85 (1H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 6.42 (1H, s), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.90 (1H, m), 3.70-3.25 (5H, m), 3.20-2.90 (4H, m), 2.85 (1H, d, J«14Hz), 1.43 (2H, m), 1.40-1.05 (6H, m), 0.90 (6H, m). MS (DCI/NH3) m/e 471 (M+H)+. Anal.calc. for C26H34N206: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.
Example 157 frans. frans-1-(N ■N-Dibutvlaminoca rbonvlmeth vn-2-fisopropvn-4-M .3-benzodioxor- -vnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B. 1H NMR (300 MHz, CDCI3) 8 6.85 (1H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=8Hz), 5.92 (2H, s), 3.75 (1H, d, J=14Hz), 3.66 (1H, q, Js=7Hz), 3.42 (3H, m), 3.25 (3H, m), 3.11 (2H,m), 2.83 (1H, t, J=7Hz), I.88 (1H, m), 1.55 (4H, m), 1.32 (4H, m), 0.92 (12H, m). MS (DCI/NH3) m/e 447 (M+H)+. Anal.calc. for C25H38N2O5 • 0.50 H20: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.
Example 158 frans.frans-1 -fN.N-DibutvlamlnocarbonvlmethvlV2-(4-t-butvlPhenvn-4-/1.3-benzodioxol-5-vnpvrrolidine-3-carboxviic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoyiacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4-t-butylacetophenone), in Example 49B. 1H NMR (300 MHz, CDCI3) 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=14Hz), 3.65-3.25 (5H, m), 3.15-2.85 (4H, m), 2.73 (1H, d, J=14Hz), 1.45 (2H, m), 1.29 (13H, s), 1.00 (2H, m), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS (DCI/NH3) m/e 537 (M+H)+. Anal.calc. for C32H44N2O5: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
Example 159 frans.frans-1-fN.N-Dibutvlaminocarbonvlmethvn-2-(4-t-butvlphenvlV4-(5-ben2o-2.3-dihvdrofuranvflpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 8 7.30 (1H, s), 7.13 (1H, dd, J=7Hz, 2Hz), 6.82 (1H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1H, s), 3.19 (3H, m), 3.80 (3H, m), 3.48 (2H, m), 3.3 (5H, m), 2.41 (1H, m), 1.65 (4H, m), 1.44 (4H, m), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, m). MS (DCI/NH3) m/e 445 (M+H)+. Anal.calc. for C26H40N2O4 • 1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Example 160 frans. frans-1-(N-N-Dibutvlaminocarbonvlmethvh-2-(anti-4-methoxvcvclohexvlV4-f1 ■3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Example 160A svn and anti Ethvl 4-methoxvcvclohexanovlacetate Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature. At the same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonate potassium salt (7.52 g, 44.2 mmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 °C. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature. The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with 5% potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with 20% ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl p-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl p-keto ester (914 mg) as a colorless oil and the cis 4-methoxycyclohexyl p keto ester (1.07 g) as a colorless oil.
Example 16QB trans. frans-1-(N.N-DibutvlaminocarbonvlmethvD-2-(anti-4-methoxvcvclohexvfl-4-(1.3-benzodioxol-5-vftpvrrolidine-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. "»H NMR (300 MHz, CDCI3) 8 6.84 (1H, d, J=s2Hz), 6.76 (1H, dd, J=7Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, s), 3.69 (2H, m), 3.50-3.27 (5H, m), 3.26 (3H, s), 3.25-3.00 (3H, m), 2.88 (1H, m), 1.95 (2H, m), 1.62 (7H, m), 1.33 (9H, m), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal.calc. for C29H44N2O6 •0.50 H20: C, 66.26; H, 8.63; N, 5.33. Found; C, 66.27; H, 8.50; N, 5.13." Example 161 frans-fra/?s-1-fN.N-Dibutvlaminocarbonvlmethvfl-2-fsvn-4-methoxvcvclohexvi>-4-(1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic 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. 1H NMR (300 MHz, CDCI3) 8 6.84 (1H, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 2Hz), 6.61 (1H, d, J=8Hz), 5.92 (2H, s), 3.65 (2H, m), 3.42 (2H, m), 3.32 (3H, s), 3.30-3.00 (6H, m), 2.82 (1H, m), 2.10 (2H, m), 1.83 (2H, m), 1.52 (6H, m), 1.33 (4H, m), 1.20-1.00 (4H, m), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH3) m/e 517 (M+H)+. Anal.calc. for C29H44N2O6 • 0.30 H2O: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.
Example 162 frans.frans-1-fN.N-Dibutviaminocarbonvlmethvn-2.4-dif5-benzo-2.3-dihvdrofuranvnpvrrolidine-3-carboxvlic acid Example 162A 5-Acetvl-2.3-dihvdroben zof u ra n To a 0 °C solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 °C. The solution was stirred 15 minutes at 0 °C, and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 °C. The dark red solution was stirred 1 hour at 2 °C and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Example 162B frans.frang-1-fN.N-DibutvlaminocarbonvlmethvlV2-4-dif5-benzo-2.3- dihvdrofuranvnpvrrolidine-3-carboxvlic 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. 1H NMR (300 MHz, CDCI3) 8 7.43 (1H, s), 7.38 (1H, s), 7.06 (2H, m), 6.75 (1H, d, J=6Hz), 6.70 (1H, d, J=6Hz), 5.40 (1H, d, Js=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, m), 3.82 (2H, m), 3.57 (1H, d, J=14Hz), 3.38 (1H, m), 3.30-3.05 (6H, m), 2.95 (2H, q, J=6Hz), 1.50 (2H, m), 1.30 (4H, m), 1.15 (2H, m), 0.94 (3H, t, J*7Hz), 0.83 (3H, t, J*=7Hz). MS (DCI/NH3) m/e 521 (M+H)+. Anal.calc. for C31H40N2O5 • 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13. ft3ns.frans-1-fN.N-DibutvtaminocarbonvlmethvtV2-r3-furvn-4-f5-benzo-2.3. dihvdrofuranvflpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described In Examples 1 and 49 substituting ethyl p-oxo-3-furanpropionate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. "«H NMR (300 MHz, CDCI3) 8 7.42 (1H, m), 7.38 (1H, m), 7.13 (1H, s), 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, m), 4.57 (2H, t, J=7Hz), 3.95 (1H, d, J=8Hz), 3.63 (1H, m), 3.55 (1H, d, J=14), 3.50-3.25 (4H, m), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, m), 2.87 (1H, d, J=14Hz), 1.45 (4H, m), 1.35-1.10 (4H, m), 0.85 (6H, m). MS (DCI/NH3) m/e 469 (M+H)+. Anal.calc. for C27H36N2O5 • 0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
Example 164 frans.f/3ns-1-(N.N-Dibutvlaminocarbonvlmethvn-2-(4-methoxvphenvfl-4-f3-fluorophenvnpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 8 7.30 (2H, d, J=s8Hz), 7,22 (2H, m), 6.91 (1H, m), 6.86 (2H, d, J=8Hz), 3.79 (1H, m), 3.78 (3H, s), 3.68 (1H, m), 3.55-3.37 (3H, m), 3.29 (1H, m), 3.15-2.90 (5H, m), 2.78 (1H, d, J=14Hz), 1.43 (2H, m), 1.25 (4H, m), 1.07 (2H, m),_ 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal.calc. for C28H37FN2O4 • 0.25 H2O: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.
Example 165 frans.frans-WN.N-Dibutvlaminocarbonvlmethvn-2-(4-methoxvphenv0-4-f3- pvridvflpvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal H69- in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al., Can. J. Chem. 63: 2354 (1985). 1H NMR (300 MHz, CDCI3)5 8.82 (1H, bs), 8.73 (1H, bd, J=9Hz), 8.62 (1H, bd, J=7Hz), 7.78 (1H, bdd, J=9Hz, 3Hz), 7.38 (2H, d, J=10Hz), 6.90 (2H, d, J=10Hz), 4.39 (1H, d, J=12Hz), 3.95 (1H, m), 3.80 (3H, s), 3.79 (1H, m), 3.68 (1H, d, J=18Hz), 3.50-3.30 (3H, m), 3.25-2.90 (6H, m), 1.47 (2H, m), 1.31 (4H, m), 1.20 (2H, m), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) m/e 468 (M+H)+. Anal.calc. for C27H37N3O4 • 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
Example 166 trans, trans-1 -fN. N-Pibutv[aminocarbonvlmethvlV2-(2-fluorophenvl)-4-n .3-benzodioxol-5-vQpvrrolidine-3-carboxvHc acid The title compound was prepared by the procedures described in 15 Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B. 1H NMR (300 MHz, CDCI3) 8 7.52 (1H, dt, J=7Hz, 3Hz), 7.25 (1H, m), 7.13 (1H, dt, J=7Hz, 3Hz), 7.02 (2H, m), 6.88 (1H, dd, J=7Hz, 3Hz), 6.73 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 4.25 (IH, d, J=9Hz), 3.68 (1H, m), 3.42 (3H, m), 3.39 (1H, m), 3.20-2.95 (4H, 20 m), 2.91 (1H, d, J=14Hz), 1.45 (3H, m), 1.26 (3H, m), 1.08 (2H, m), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal.calc. for C28H35FN2O5 • 0.25 H20: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.
Example 167 trans.trans-1 -fN.N-Dibutvlaminocarbonvlmethvn-2-f3-fluorophenvn-4-( 1.3-benzodioxol-5-vl')Pvrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-fluorobenzoylacetate in 30 Example 49B. ">H NMR (300 MHz, CDCI3) 8 7.38 (1H, m), 7.18 (1H, d, J=7Hz), 7.15 (1H, m), 7.00 (1H, d, J=2Hz), 6.95 (1H, m), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.94 (1H, d, J=14Hz), 3.63 (1H, m), 3.42 (3H, m), 3.35-2.95 (5H, m), 2.87 (1H, d, J=14Hz), 1.44 (3H, m), 1.27 (3H, m), 1.10 (2H, m), 0.88 (3H, t, 35 J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal.calc. for C28H35FN2O5: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
Example 168 trans, trans-1 -f4-N. N-Dibutviam inoohen vn-2-(4-m ethoxvphen v0-4-( 1.3- benzodioxol-5-vnDvrrolidine-3-carboxvlic acid 4-Nitro-1-fluorobenzene, ethyl trans.trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl trans,trans-2-{4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(4-nitrophenyl)-pyrrolidine-3-carboxylate. The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chem. Soc. 93: 2897 (1971) to give the corresponding N,N-dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1D affords the title compound.
Example 169 trans.trans-1 -f2-N.N-Dibutviaminopvrimtdin-4-vlV2-(4-methoxvphenvn-4-f 1.3-benzodiPxol-5-vftpvrrolidine-3-carboxvlic acid 2-(Dibutylamino)-4-chloropyrimidine is prepared from 2,4-dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem. 24: 205 (1987) and reacted with ethyl trans,trans-2-{4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (the compound resulting from Example 6A) and diisoproplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydroiyzed with sodium hydroxide using the method of Example 1D to the title compound.
Examples 170-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.
Ex. No. Name 170 fra/is,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1- (isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -1^1 171 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 172 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(1 - methylpropylaminocarbonylmethyl)-pyrroIidine-3-carboxylic acid; 173 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-1-(phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 174 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(piperidinylcarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 175 frans,frans-2-(4-Methoxypheny!)-4-(1,3-benzodioxol-5-yI)-1 -(1 -(propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid; 176 trans, frans-2-(4-Methoxyphenyl)-4-{1,3-benzodioxol-5-yl)-1-(a-(propylaminocarbonyi)benzyl)-pyrrolidine-3-carboxylic acid; 177 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(bis-(propylaminocarbonyl)methyl)-pyrroiidine-3-carboxyiic acid; 178 trans,trans-2-(4-MethoxyphenyI)-4-(1,3-benzodioxol-5-yl)-1-(2-(propyiaminocarbonyl)ethyl)-pyrro!idine-3-carboxylic acid; 179 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxoI-5-yI)-1-(propylaminosu!fonylmethyl)-pyrroHdine-3-carboxylic acid; 180 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenethyl)-pyrrolidine-3-carboxylic acid; 181 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(pentanoylmethyi)-pyrrolidine-3-carboxyiic acid; 182 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-1-(benzoylmethyl)-pyrrolidine-3-carboxylic acid; 183 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(hexyl)-pyrrolidine-3-carboxylic acid; 184 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-1-(2-hexyny!)-pyrrolidine-3-carboxylic acid; 185 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propoxymethylcarbonyl-pyrrolidine-3-carboxylic acid; 186 frans,frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxoi-5-yi)-1-(phenyiacetyl)-pyrrolidine-3-carboxylic acid; 187 frans,frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yl)-1-(anilinyicarbonyl)-pyrrolidine-3-carboxyIic acid; 188 trans.trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-y1)-1 -(2-acetylaminoethyl)-pyrroiidine-3-carboxylic acid; 189 frans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-phenoxyethyI)-pyrro!idine-3-carboxyIic acid; 190 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-benzodioxanylmethyl)-pyrrolidine-3-carboxylic acid; 191 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxoi-5-y!)-1-(2-tetrahydrofuranylmethyl)-pyrrolidine-3-carboxylic acid; 192 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-y!)-1-(2- (propylaminocarbonylamino)ethenyl)-pyrrolidine-3-carboxylic acid; 193 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2- (propyiaminocarbonylamino)ethyl)-pyrrolidine-3-carboxylic acid; 194 fra/7S,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(3-oxohex-1 -enyl)-pyrrolidine-3-carboxylic acid; 195 trans, frans-2-(2,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-y!)-1-(propy1aminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; 196 trans, fra/7S-2-(2-Carboxy-4-methoxy phenyl)-4-(1,3-benzodioxol-5-yl)-1 -(propylaminocarbonylmethy!)-pyrrolidine-3-carboxylic acid; 197 trans,trans-2-(2-Aminocarbonyl-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yI)-1 -(propyiaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; 198 trans, frans-2-(2-Methanesulfonamido-4-methoxypheny!)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; 199 trans, frans-2-(2-Aminocarbonyimethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonyimethyl)-pyrroIidine-3-carboxylic acid; 200 trans, fra/7S-2-(2-Methoxyethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propyiaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; 201 trans, frans-2-(2-Carboxyrnethoxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(propylaminocarbonylmethyl)-pyrro!idine-3-carboxylic acid; 202 trans.trans-2-(4-Methoxy-2-tetrazolyimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propyiaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 203 trans, fra/JS-2-(2-Allyioxy-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 204 trans.trans 2,4-Bis(4-methoxyphenyl)-1-(propylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 205 trans.trans 2,4-Bis(1,3-benzodioxol-5-yl)-1-(propylaminocarbonyimethyl)-pyrroiidine-3-carboxylic acid; 206 ffa/?s,fra/?s-2-(4-MethoxyphenyI)-4-(1,3-benzodioxo!-5-yl)-1-(N-methy!-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 207 trans.trans- 2-(4-Methoxyphenyl)-4-(1,3-benzodioxole-5-yl)-1-(N-methyl-N-butylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 208 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(4-methoxyphenyl)aminocarbonyl)-3-pyrrolidine-3-carboxylic acid; 209 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonyl)-pyrroIidine-3-carboxylic acid; 210 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-1-(N-methyl-N-allyiaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; 211 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 212 trans, frans-2-(4-MethoxyphenyI)-4-(1,3-benzodioxol-5-yi)-1 -(N-methyl-N-isobutyiaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 213 trans, frans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -(N-methyl-N-cyclopentyIaminocarbonyimethyi)-pyrrolidine-3-carboxyiic acid; 214 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(2-methoxyethyl)aminocarbonyl)-pyrrolidine-3-carboxylic acid; 215 trans,trans- 2-(4-Methoxyphenyi)-4-( 1,3-benzodioxol-5-y!)-1-(N-methyl-N-butoxyethyIaminocarbonyl)-pyrroiidine-3-carboxylic acid; 216 trans,trans-2-(1,3-Benzodioxol-5-yl)-4-(4-methoxyphenyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 217 frans, fra/is-2-(4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 218 frans,frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-isopropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 219 trans, frans-2-(4-Methoxypheny l)-4-( 1,3-benzodioxol-5-yi)-1-(N-methyl-N-ethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 220 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(1-methylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 221 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-phenylaminocarbonylmethyI)-pyrroiidine-3- carboxylic acid; 222 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-y!)-1-(1-(N-methyl-N-propylaminocarbonyl)ethyl)-pyrrolidine-3- carboxylic acid; 223 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(a-(N-methyl-N-propylaminocarbonyl)benzyl)-pyrrolidine-3-carboxyiic acid; 224 frans,frans-2-(4-Methoxypheny!)-4-{1,3-benzodioxol-5-yl)-1 -(N-ethyl-N-propylaminocarbonylmethyi)-pyrrolidine-3-carboxylic acid; 225 frans,frans-2-(4-Methoxyphenyl)-4-{1,3-benzodioxole-5-yl)-1-(N-ethyi-N-butylaminocarbonyI)-pyrroiidine-3-carboxylic acid; 226 trans,frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yI)-1-(N-ethyl-N-(4-methoxyphenyi)aminocarbonyl)-3-pyrrolidine-3-carboxylic acid; 227 . trans,frans-2-(4-Methoxyphenyi)-4-( 1,3- benzodioxol-5-yl)-1 -(N-ethyl-N- phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; 228 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(N-ethyl-N-aHylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 229 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yi)-1-(N-ethyl-N-isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 230 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(N-ethy!-N-cyclopentylaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 231 frans,frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yI)-1-(N-ethyl-N-methoxyethylaminocarbonyl)-pyrrolidine-3-carboxyiic acid; 232 frans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyl-N-butoxyethyiaminocarbonyl)-pyrrolidine-3-carboxylic acid; 233 trans.trans-2-(1,3-Benzodioxol-5-y!)-4-(4-methoxyphenyl)-1 -(N-ethyi-N-propylaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; 234 trans,trans-2-( 4-Methoxyphenyl)-4-(1,4-benzodioxan-6-yl)-1 -(N-ethyl-N-propylaminocarbonylmethyi)-pyrroiidine-3-carboxylic acid; 235 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(N-ethyl-N-isopropylaminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; 236 frans,frans-2-(4-Methoxypheny!)-4-(1,3-benzodioxol-5-yl)-1 -(N,N-diethylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 237 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-ethyi-N-(1-methylpropyl)aminocarbonylmethyl)-pyrroiidine-3-carboxylic acid; 238 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1-(N-ethyl-N-phenylaminocarbonyImethyl)-pyrrolidine-3-carboxylic acid; 239 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(1-(N-ethyl-N-propylaminocarbonyl)ethyl)-pyrroiidine-3-carboxylic acid; 240 trans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(a-(N-ethyl-N-propylaminocarbonyl)benzyI)-pyrroiidine-3-carboxylic acid; 241 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methy!-N-isobutylaminocarboriylmethyl)-pyrrolidine-3-carboxyiic acid; 242 frans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-cyclohexyiaminocarbonylmethyl)-pyrrofidine-3-carboxyiic acid; 243 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(N,N-dipropylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 244 trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(isobutyloxyethyl)-pyrrolidine-3-carboxylic acid; 245 . frans,frans-2-(4-Methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1-(buty!sulfonyl)-pyrroiidine-3-carboxylic acid; 246 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1- (isopropylsulfonylaminoethyl)-pyrrolidine-3-carboxyiic acid; 247 trans,frans-2-(4-Methoxyphenyl)-4-( 1,3- . benzodioxol-5-yl)-1- (ethoxymethylcarbonylmethyl)-pyrroiidine-3-carboxylic acid; 248 trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxoi-5-yl)-1-(2-ethylbutyrylmethyi)-pyrrolidine-3-carboxylic acid; 249 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-(3,4-dimethoxybenzyl)aminocarbonylmethy!)-pyrrolidine-3-carboxylic acid; 250 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(1 R)-1-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrolidine-3-carboxylic acid; 251 frans, frans-2-(4-MethoxyphenyI)-4-(1,3-benzodioxol-5-yl)-1-[(1S)-1-(N-methyl-N-propylaminocarbonyl)butyl]-pyrrolidine-3-carboxylic acid; 252 trans,trans-2-( 4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3-isopropoxypropyl)-pyrrolidine-3-carboxylic acid; 253 frans, frans-2-(4-Methoxyphenyi)-4-(1,3-benzodioxol-5-yi)-1-(5-methyihexyl)-pyrroIidine-3-carboxyiic acid; 254 frans, frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(5-methyl-2-hexenyi)-pyrroIidine-3-carboxylic acid; 255 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-y!)-1-(5-methyl-4-hexenyl)-pyrrolidine-3-carboxylic acid; 256 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(3,5-dimethyl-2-hexenyl)-pyrrolidine-3-carboxyiic acid; 257 trans, frans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -(2-(N-methyl-N-isobutyrylamino)ethyl)-pyrrolidine-3-carboxylic acid; 258 frans,frans-2-(4-Methoxyphenyl)-4-(1,3-ber»zodioxol-5-yl)-1-(N-methyI-N-(2,2-dimethylpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodidxol-5-yl)-1 -(N-ethyl-N-butylaminocarbonyimethyl)-pyrrolidine-3-carboxyiic acid; frans,frans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-methyl-N-benzyiaminocarbonyimethyl)-pyrrolidine-3- carboxylic acid; trans, frans-2-(4-Methoxyphenyl)-4-(5-indanyl)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; trans,trans- 2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N-methyl-N-propylaminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; trans, frans-2-(4-Methoxyphenyl)-4-( 1 -methylindol-5-yI)-1-(N-methyl-N-propylaminocarbonyimethy!)-pyrrolidine-3-carboxylic acid; trans, frans-2-(4-Methoxyphenyl)-4-(2-naphthyl)-l-(N-methyl-N-propyiaminocarbonylmethyl)-pyrroiidine-3-carboxyiic acid; 265 trans, frans-2-(4-Methoxypheny!)-4-( 1,2-dimethoxy-4-phenyi)-1 -(N-methyl-N-propyiaminocarbonylmethyl)-pyrrolidine-3-carboxyiic acid; 266 trans, fra/7S-2-(4-Methoxyphenyl)-4-(1 -methoxy-3-phenyI)-1-(N-methyl-N-propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; Examples 267-288 Following the procedures described in Example 1 and Scheme ll, the following compounds can be prepared. 259 260 262 262 263 264 r-VfcV~ 267 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(propyiaminocarbonylmethyl)-piperidine-4-carboxylic acid; 268 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxoi-5-yl)-1-(aminocarbonylmethyl)-piperidine-4-carboxylic acid; 269 trans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(4-fluorobenzyl)-piperidine-4-carboxylic acid; 270 frans, frans-3-(4-Methoxypheny!)-5-(1,3-benzodioxol-5-yl)-1-(2-ethoxyethyI)-piperidine-4-carboxyiic acid; 271 frans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yI)-1-(2-propoxyethy!)-piperidine-4-carboxylic acid; 272 trans, frans-3-(4-Methoxypheny i)-5-( 1,3-benzodioxol-5-yl)-1-[2-(2-methoxyethoxy)ethyl]-piperidine-4-carboxylic acid; 273 trans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yI)-1 -[2-(2-pyridyl)ethyl]-piperidine-4-carboxylic acid; 274 trans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(morphofin-4-ylcarbonyl)-piperidine-4-carboxyIic acid; 275 . trans,trans-3-(4-MethoxyphenyI)-5-( 1,3- benzodioxole-5-yi)-1 -(butylaminocarbonyl)-piperidine-4-carboxylic acid; 276 trans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1 -(4-methoxyphenylaminocarbonyl)-3-piperidine-4-carboxylic acid; 277 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-acetyipiperidine-3-carboxylic acid; 278 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(2-furoyl)-piperidine-3-carboxyiic acid; - \<b 279 frans, frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(phenylaminocarbonyl)-piperidine-4-carboxylic acid; 280 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yI)-1-(allylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 281 trans, frans-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1 -(n-butylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 282 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(N-n-butyl-N-methylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 283 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1-(pyrroiidin-1-ylcarbonylmethyi)-piperidine-4-carboxylic acid; 284 trans, frans-3-(4-MethoxyphenyI)-5-( 1,3-benzodioxoJ-5-yl)-1- (isobutytaminocarbonyImethyl)-piperidine-4-carboxylic acid; 285 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxol-5-yl)-1 - (cyclopentylaminocarbonylmethyl)-piperidine-4-carboxylic acid; 286 trans, frans-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yl)-1-{morphoHn-4-ylaminocarbonylmethyi)-piperidine-4-carboxyIic acid; 287 frans,frans-3-(4-Methoxyphenyl)-5-(1,3-benzodioxo!-5-yl)-1-(2-phenoxyethyi)-piperidine-4-carboxy!ic acid; 288 trans, frans-3-(4-Methoxyphenyi)-5-( 1,3-benzodioxol-5-yl)-1-(methoxyethylaminocarbonyl)-piperidine-4-carboxyHc acid.
Example 289 trans.trans- 2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vh-1- 14-dibutylaminophenvn-Pvrrolidine-3-carboxvlic acid 4-Nitro-fluorobenzene, ethyl trans.trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A) and di-isopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(4-nitrophenyl)-pyrrolidine-3-carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch (J. Am Chem. Soc., 93, 2897, 1971) to give the corresponding N,N-dibutylaminophenyl compound, which is hydroiyzed with sodium hydroxide using the method of example 1D to give the title compound.
Example 290 frans.frans-2-M-Methoxvphenvn-4-{ 1.3-benzodioxol-5-vn-1 -12-dibutviamino-pvrimidine-4-vl)-Dvrrolidine-3-carboxvlic acid 2-(Dibutylamino) 4-chloropyrimidine is prepared from 2-4-dichloropyrimidine according to the method of Gershon (J. Heterocyclic Chem. 24, 205, 1987). This compound, ethyl trans ,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydroiyzed with sodium hydroxide using the method of example 1D to give the title compound.
Example 291 trans.trans-2-(4-MethoxvphenvlV4-( 1.3-benzodioxol-5-vn-1-(N-butvl-N- phenviaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid The title compound was prepared according to the general procedure of Example 1. 1H NMR (CD3OD) : S 0.87 (t,3H,J=8); 1.2-1.35 (m,2H); 1.35-1.5 (m,2H); 2.78 (m, 2H); 3.10 (t,1H, J=9); 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10); 3.5-3.7 (m,3H); 3.77 (m,1H); 3.78 (s,3H); 5.93 (s^H); 6.7-6.9 (m,4H); 7.0-7.2 (m,5H); 7.4 (m,3H). MS (DCl/NH3): m/e 531 (M+H)+. Anal calcd for C31H34N206: C, 70.17; H, 6.46; N, 5.28. Found: C,70.36; H, 6.52; N, 4.99. hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1° 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 21° C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Example 292C Ethvl 2-<4-methoxvbenzovn-3-(1.3-benzodioxol-5-vn-4-nitro- frUtanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicycio[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Example 292D Ethvl 2-(4-methoxvDhenvn-4-M.3-benzodioxol-5-vn-4.5-dihvdm-3H- pvrro(-3-carboxvlate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi # 28 (300 g). The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (0° C). The solids were dried in vacuo at 50° C to a constant weight of 193.4 g (21% yield, melting point 80-81° C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Example 292 E Ethvl 2-M-methoxvphenvn-4-( 1.3-benzodioxol-5-vn-Pvrrolidine 3- carboxvlate 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-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 (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCI was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHC03 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. NaHC03 and once with 2.5 L of 23% aq. NaCI, the dried over 190g MgS04) filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
Example 292 F Ethvl 2-f4-methoxvphenvV4-M.3-ben2odioxol-5-vn-1-fN.N- dibutvlaminocarbonvl methvH pyrrolidine 3-carboxvlate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyi)-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 mo!) were added. The mixture was refluxed at 78° 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 (0° C). Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgS04 and filtered. Concentration as above provided 3.112 kg (96 % yield) of the title compound as a dark oil.
Example 292G frans.frans-2-(4-Methoxvphenvn-4-(1.3-ben2odioxol-5-vn-pvrrolidine 3-carboxvlate and preparation of trans.trans 2-(4-methoxvphenvlV4-(3.4-dioxvphenvlVDvrrolidine-3-carboxvtic acid ethvl 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-methylenedioxypheny!)-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 79° C for 1 hr. The mixture was cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 15° C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deion'ced water and extracted with 28 L of ether. The ether solution was washed with 9.5 L deioni2ed 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 MgS04 , filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The . undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 65° C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 10° C and filtered. The crystals were washed with 2 L ether (0° 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 fra/?s.frans-2-f4-methoxvphenvn-4-M.3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvl methvtt pyrrolidine 3-carboxvlate 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 in vacuo at 50° C to a constant weight of 0.937 kg (97% yield) of the title compound.
Example 293 frans-frans-2-f4-Methoxvphenvn-4-f 1.3-benzodioxol-5-vh-1 -rdecahvdroisoauinolin-2- carbonvlmethvll-pvrrolidine-3-carboxvlic acid- The title compound was prepared using the procedures described in example 1. NMR (CDsOD, 300 MHz) shows a mixture of isomers. MS (DCI/NH3) m/z 521. Anal calcd for C30H36N2O6 . 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 . Found: C, 58.34; H, 5.58; N, 4.00 .
Example 294 frans-frans-2-f4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-r3.3-dimethvlDiperidinvl- carbonvlmethvll-pvrrolidine-3-carboxvlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. 8 0.84 (s, 3H), 0.86 (s, 3H), 1.35-1.6 (m, 4H), 3.83 (s, 3H), 5.96 (s, 2H), 6.81 (d, 1H, J=8), 6.90 (dd, 1H, J=1,8), 7.01 (d, 2H, J=9), 7.03 (s, 1H), 7.47 (d, 2H, J=9). MS (DCI/NH3) m/z 495. Anal calcd for C28H34N2O6 . 1.4 TFA: C, 56.55; H, 5.45; N, 4.28 . Found: C, 56.52; H, 5.83; N, 4.26 .
Example 295 frans-frans-2-r4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-r2-rN-propvl-N-iso-butoxvcarbonvlaminotethvn-pvrrolidine-3-carhoxvlic acid The title compound was prepared by the methods detailed in 15 Example 61, but substituting propylamine for methylamine in Example 61B and isobutyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 20 MHz) 8 0.80 (t, 3H, J=7), 0.92 (m, 3H), 1.43 (h, 2H, J=7Hz), 1.7-1.9 (m, 1H), 2.72 (m, 1H), 2.90 (m, 2H), 3.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1H), 3.55 (m, 1H), 3.62 (m, 1H), 3.7-3.9 (m, 2H) 3.78 (s, 3H), 5.95 (s, 2H), 6.72 (d, 1H, J= 8Hz), 6.82 (m, 3H), 7.00 (s, 1H), 7.30 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 527 (M+H)+. Anal calcd for C29H38N2O6 • 0.5 H20: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
Example 296 frans-frans-2-r4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-f 1.2.3.4-tetrahvdroisoauinolin-2- carbonvlmethvH-pvrrolidine-3-30 carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. 8 2.97 (m, 2H), 4.68 (s, 3H), 5.97 (s, 2H), 6.83 (d, 1H, J=8), 6.9-7.0 (m, 3H), 7.03 (d, 1H, J=2), 7.1-7.3 (m, 4H), 7.4-7.5 (m, 2H). MS (DCI/NH3) m/z 35 515.
Examole 297 frans-frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-r?-fN-propvl-N-dimethvlaminocarbonviamino^ethvt1-Pvrrolidine-3-carhf>YvtiR acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and dimethylcarbamyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac fiC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.1H NMR (CDCI3, 300 MHz) 8 0.70 (t, 3H, J=7), 1.28 (m, 2H), 2.75 (s, 3H), 2.82 (m, 2H), 3.1-3.45 (m, 4H), 3.70 (m, 1H), 3.80 (s, 3H), 3.90 (m, 3H), 4.72 (m, 1H), 5.95 (s, 2H), 6.75 (d, 1H, 8Hz), 6.87 (m, 3H), 7.05 (s, 1H), 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 498 (M+H)+. Anal calcd for C27H35N3O6 • 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.
Example 298 frans.frans-2-(4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-r2-fN-propvl-N-f4-nttrobenzenesulfonvhamincAethvn-pvrroUdinft-3- carboxvlic acid Using the procedures described in Eample 66, the title compound was prepared as a yellow solid, m.p. 85-87°C. 1H NMR (CDC13, 300 MHz) 8 0.77 (t, J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (m, 1H), 2.57-2.66 (m, 1H), 2.82-3.15 (m, 4H), 3.22 (t, J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, 1H), 3.49-3.57 (m, 1H), 3.59 (d, J=9Hz, 1H), 3.83 (s, 3H), 5.96 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=1Hz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 (d, J=1Hz, 1H), 7.27 (d, J=9Hz, 2H), 7.82 (d, J=9Hz, 2H)," 8.23 (d, J=s9Hz,2H). MS (DCI/NH3) m/e 612 (M+H)+- Example 299 trans.trans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-(2-(N-proPvl-N-n-pentanesulfonvlamino)ethvn-pyrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 59-61 °C 1h NMR (CDCI3, 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 0.90 (t, J=6Hz, 3H), 1.26-1.32 (m, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (m, 2H), 2.23-2.32 (m, 1H), 2.70-3.08 (m, 7H), 3.15-3.32 (m,2H), 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (m, 1H), 3.63 (d, Js=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=7.5Hz, 1H), 6.83 (dd, J=1Hz,J=7.5Hz, 1H), 6.87(d, J^Hz, 2H), 7.00 (d, J=1Hz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 561 (M+H)+- Example 300 fra/7S.frar7S-2-f4-MethPxvphenvn-4-M.3-benzodioxpl-5-vn-1.f2-rN-propvl-N-f4-trifluoromethoxvbenzenesulfpnvnamino\ethvh-Dvrrolidine-3-carboxvtic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.122-124°C. 1H NMR (CD30D, 300MHz) 8 0.75 (t, J=7.5Hz, 3H), 1.26-1.45 (m, 2H), 2.96-3.08 (m, 2H), 3.23 (bs, 2H), 3.35-3.45 (m, 2H), 3.52 (t, J=10Hz, 1H), 3.81 (d, J=9Hz, 2H), 3.86 (s, 3H), 3.92 (t, J=9Hz, 1H), 4.63 (d, J=10Hz, 1H), 5.97 (s, 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=r9Hz, 1H), 7.06-7.08 (m, 3H), 7.46 (d, J=9Hz, 2H), 7.56 (d, J=9Hz, 2H), 7.89 (d, J=9Hz, 2H). MS (DCI/NH3), m/e 651 (M+H)+.
Example 301 frans.frans-2-f4-Methoxvphenvn-4-f1.3-benzpdioxol-5-vn-1-f2-fN-propvl-N-(2-methvl-2-propenesulfonvnamino^ethvn-pvrrolidine-3- carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 69-71 °C.. NMR (CDCI3, 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 (s, 3H), 2.25-2.35 (m, 1H), 2,68-2.77 (m, 1H), 2.85-3.28 (m, 7H), 3.40 (d, J=9Hz, 1H), 3.52-3.68 (m, 2H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 4.92 (s, 1H), 5.07 (s, 1H), 5.97 (s, 2H), 6.74 (d, J=7Hz, 1H), 6.82-6.89 (m,3H), 7.01 (s,1H), 7.33 (d, Js=9Hz, 2H). MS (DCI/NH3), m/e 545 (M+H)+.
Example 302 frans-frans-2-(4-Methoxvphenvn-4-(1 .S-benzodioxol-S-vn-l-re-ethvlpiDeridinvl-carbonvlmethvri-pvrrolidine-S-carboxvlic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD30D, 300 MHz) shows a mixture of isomers. 8 0.75 (t, 3H, J=7), 1.4-1.7 (m, 8H), 3.84 (s, 3H), 5.96 (s, 2H), 6.83 (d, 1H, J=8), 6.91 (d, 1H, Js=8), 7.0-7.1 (m, 3H), 7.52 (d, 2H, J=9). MS (DCI/NH3) m/z 495. Anal calcd for C28H34N2O6 . 1.6 TFA: C, 55.35; H, 5.30; N, 4.14 . Found: C, 55.26; H, 5.37; N, 4.01 .
Example 303 frans.frans-2-f4-Methoxvphenvn-4-(1.3-benzodioxol-5-vl>-1-(2-fN-propvl-N-(2-methvlpropanesulfonvhamino^ethvlVpvrroHdine-3- carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73°C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, Js=7.5Hz, 3H),1.04 (d, J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 (m,2H), 2.57-2.75 (m, 2H), 2.84-3.08 (m, 3H), 3.12-3.21 (m, 1H), 3.23-3.45 (m, 1H), 3.43 (d, J=11Hz, 1H), 3.55-3.62 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d, J=9Hz, 1H), 6.83 (dd, J=1Hz,J=9Hz, 1H), 6.87(d, J=9Hz, 2H), 7.02 (d, J=1Hz, 1H), 7.33 (d, Jss9Hz, 2H). MS (DC1/NH3) m/e 547 M+H)+.
Example 304 frans. frans-2-(4-MethoxvDhenvh-4-n.3-benzodioxol-5-vh-1-f2-(N-propvl-N-heptanesulfonvlamino^ethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59°C. 1H NMR (CDCI3, 300MHz) S 0.80(t, J=7.5Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.23-1.36 (m, 8H), 1.94 (q, J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (m, 1H), 2.70-3.09(m, 7H), 3.13-3.32 (m,2H), 3.43(dd, J=3Hz,J=9Hz, 1H), 3.52-3.58(m,1H), 3.65(d, J=9Hz, 1H), 3.80 (s, 3H), 5.96(s, 2H), 6.73 (d, J=7Hz, 1H), 6.83 (dd, J=1Hz, J=7Hz, 1H), 6.87(d, J=9Hz, 2H), 7.01 (d, J=1Hz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) m/e 589 M+H)+.
Examole 305 frans-frans-2-f4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1 -r2«fN-ethvl-N-ethoxvcarbonvlamino^ethvll-Pvrrolidine-3-carboxvHc acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by preparative HPLC (Vydac nC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 5 0.90 (t, 3H, J=7), 1.22 (m, 3H), 3.0-3.2 (m, 4H), 3.42 (m, 2H), 3.78 (s, 3H), 3.82 (m, 4H), 4.10 (q, 2H, J=7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 (d, 1H, 8Hz), 6.84 (m, 3H), 7.00 (s, 1H), 7.42 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 485 (M+H)+. Anal calcd for C26H32N2O7 • 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
Example 306 fra/7S.frans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-f2-fN-Dropvl-N-hexanesulfonvlaminotethvn-Dvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60°C. ^H NMR (CDCI3, 300MHz) 8 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, J=7.5Hz, 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1H), 2.72-3.08(m, 7H), 3.15-3.32(m, 2H), 3.43(d, J=9Hz, 1H), 3.55-3.62(m, 1H), 3.65 (d, J=10Hz, 1H), 3.80(s, 3H), 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 (M+H)+.
Example 307 frans-frans-2-(4-EthvlPhenvh-4-(1.3-benzodioxol-5-vn-1-rN.N-dHn-butvnammocarbonvlmethvn-Pvrrolidine-3-carboxvlic acid. The title compound was prepared using the procedures described in examples 1 and 49, substituting ethyl 4-ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (CDCI3, 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, m), 3.53-3.23 (5H, m), 3.13-2.90 (4H, m), 2.73 (1H, d, J=14Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, m), 1.40-1.10 (6H, m), 1.02 (2H, m), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCI, NH3) 509 (MH+) Anal.calc. for C30H40N2O5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25 .
Example 308 frans-irans-2-(4-MethoxvDhenvl>-4-M.3-benzodioxol-5-vn-1-r2-fN-propvl-N-(2-chloroethoxv^carbonvlamino^ethvl1-pyrrolidine-3- carboxvlic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and 2-chloroethyl chloroformate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, 3H, J=7), 1.22 (m, 3H), 2.15 (m, 1H), 2.75 (m, 1H), 2.85 (m, 1H), 3.1 (m, 2H), 3.25 (m, 2H), 3.5 (m, 3H), 3.65 (m, 2H), 3.80 (s, 3H), 4.18 (m, 1H), 4.30 (m, 1H), 5.98 (s, 2H), 6.72 (m, 1H), 6.82 (m, 3H), 7.00 (m, 1H), 7.30(m, 2H). MS (DC!/NH3) m/e 533 (M+H)+. Anal calcd for C27H33N2O7CI: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
Example 309 frans-frans-2-(2-Methoxvethvn-4-M .3-benzodioxol-5-vn-1-rN.N-di(n-butvnamino carbonvlmethvn-Pvrrplidine-3-carboxvlic acid. The title compound was prepared using the procedures described in example 1, substituting ethyl 5-methoxy-3-oxopentanoate for ethyl 4-methoxybenzoylacetate in Example 1 A. The title compound is a yellow foam. 1H NMR (CDCI3, 300 MHz) 8 0.91 (t, J=7Hz) and 0.95 (t, J=7Hz, 6H total), 1.28-1.41 (br m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t, J=9Hz, 1H), 3.30 (s) and 3.20-3.68 (br m, 11H total), 3.72-4.10 (br m, 4H), 5.92 (s, 2H), 6.72 (d, J=8.5Hz, 1H), 6.82 (dd, J=1.5, 8.5Hz, 1H), 6.91 (d, J=1.5Hz, 1H); MS (FAB) m/e 463 (M+H)+. Anal calcd for C25H38N20sH2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
Example 310 trans.frans-2-f4-MethoxvDhenvn-4-M.3-benzodioxol-5-vn-1-(2-fN-ethvl-N-n-pentanesulfonvlaminotethvn-pvrrolidine-3-carboxvlic 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, J=7.5Hz, 2H), 2.22-2.32(m,1H), 2.71-2.96(m,5H), 3.08-3.30(m,4H), 3.95(d, J=9Hz, 1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz,1H), 3.80(s, 1H), 5.97(s, 2H), 6.73(d, J=9Hz, 1H), 6.82(d, J=9Hz,1H), 6.88(d, J=9Hz, 2H),7.02(s,1H), 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 (M+H)+.
Example 311 trans-trans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vh-1 -fN.N-dicvclohexvlamino carbonvlmethvll-Pvrrolidine-3-carboxvHc acid.
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) 8 1.0-2.0 (m, 20H), 3.0-3.1 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.75 (d. 1H, J=8), 6.86 (dd, 1H, J=2,8), 6.95 (d, 2H, Js=9), 7.04 (d, 1H, J=2), 7.38 (d, 2H, J=9). MS (DCI/NH3) m/z 563.
Anal calcd for C33H42N2O6 . 0.5 H2O: C, 69.33; H, 7.58; N, 4.90 . Found: C, 69.42; H, 7.29; N, 4.78.
Example 312 frans-franfi-2-f4-Methoxvphenvn-4-(1.3-benzpdioxol-5-vn-1-r2-(N-propvl-N-tert-butoxvcarbonvlamino^ethvll-pvrrolidine-3-carboxylic acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61C. NMR (CDsOD, 300 MHz) suggests presence of rotamers 8 0.81 (t, 3H, J=7), 1.2-1.5 (m, 11H), 3.78 (s, 3H), 5.92 (dd, 2H, J=1,2), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2,8), 6.92 (d, 2H, J=9), 6.99 (bd s, 1H), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 527. Anal calcd for C29H38N2O7 : C 66.14; H, 7.27; N, 5.32 . Found: C, 66.,05; H, 7.36; N, 5.15.
Example 313 frans-frans-2-f4-M6thoxv-3-fluoroDhenvn-4-(1.3-benzodioxol-5-vn-1-rN.N-difn-butvnamino carbonvlmethvll-PvrroHdine-3-carboxvlic acid.
The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. m.p. 142-143 °C. NMR (CDCI3, 300 MHz) 5 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.03-1.50 (m, 8H), 2.82 (d, J=13Hz, 1H), 2.90-3.13 (m, 4H), 3.20-3.50 (m, 3H), 3.39 (d, J=13H, 1H), 3.55-3.65 (m, 1H), 3.82 (d, J=10Hz, 1H), 3.87 (s, 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 (d, J«8Hz, 1H), 6.83-6.91 (m, 2H), 6.99 (d, J=2Hz, 1H), 7.06 (m, 2H). Anal calcd for C29H37N2O6F : C, 65.89; H, 7.06; N, 5.30 . Found: C, 65.82; H, 7.13; N, 5.29.
Example 314 frans. fraf7S-2-(Propvfl-4-(1.3-benzodioxol-5-vfl-1-f2-f N-oropvl-pentanesutfonvlamino^ethvl^pvrrolidine-3-carboxvlic acid Example 314A Propyl pentanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL CH2CI2 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 CH2Cl2 under a nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then at 25 °C for 4 h. The solution was partitioned between 20 mL oll.O M aqeous NaHS04 and 25 mL CH2CI2. The organic phase was washed sequentially with 25 mL H2O and 25 mL brine, then dried (Na2S04), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1H NMR (CDCI3, 300 MHz) 6 0.92 (t, J=7Hz, 3H), 0.97 (t, J=7Hz, 3H), 1.28-1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCI/NH3) m/e 211 (M+NH4)+.
Example 3149B Ethvl trans, trans-4~( 1 .3-benzodioxol-5-vfl-1 -(2-bromoethvjV2-DropvlDvrroiidine-3- carboxvlate The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 94B for the pyrrolidine mixture.
Example 314C Ethvl frans. trans- 2-fPropvn-4-f 1.3-benzodioxol-5-vlV1 -(2-fN-propvl-pentanesulfonvlamino^ethvnpvrrolidine-3-carboxvlate A solution of the compound of Example 314A (6.6 mg, 34 jimol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, 50 nmol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mg, 22 jimol) 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 °C overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCOa, 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 mL brine, dried by passing through a plug of Na2S04, and the filtrate concentrated in vacuo to an oil. The crude product was purified by preparative TLC (silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg (73%) of the title compound as a wax.
Example 314D trans, trans- 4-f 1.3-benzodioxol-5-vlV2-f Propyl)-1 -(2-(N-prooyl-pentanesutfonvlaminotethvnpvrrolidine-3-carboxvlic acid The title compound was prepared according to the procedure of Example 71C. 1H NMR (CDCI3, 300 MHz) 8 0.88-1.00 (m, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (m, 3H), 1.70-1.85 (br m, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br m, 6H), 3.26-3.90 (br m, 6H), 5.95 (s, 2H), 6.76 (d, J=8Hz, IH), 6.79 (m, 1H), 6.93 (br s, 1H); HRMS (FAB) calcd for C25H41N2O6S (M+H)+ 497.2685, found 497.2679.
Example 315 frans.fra/7S-2-(4-MethoxvphenvO-4-n .3-benzodioxol-5-vl>-1-(2-(N-proPvl-N-dimethvisulfamovlamino>ethvn-Pvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. m.p.59-61°C. ^H NMR (CDCI3, 300MHz) 8 0.79 (t, J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1H), 2.65(s, 6H), 2.70-2.79(m, 1H), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 (t, J=9Hz,1H), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1H), 6.83(d, J*=9Hz, 1H), 6.88(d, J=9Hz, 2H), 7.02(s, 1H), 7.34(d, J=9Hz, 2H). MS (DC1/NH3) m/e534 (M+H)+.
Examole 316 ffaf7S-frans-2-f4-Methoxphenvn-4-M.3-benzodSoxol-5-vh-1-r2-rN-propvl-N-f4-methQXVPhenvnsulfonvlamino>propv11-Dvrrolidme-3- carboxvlic acid Example 316A Ethvl trans-trans and cis-trans 2-(4-Methoxvphenvh-4-M.3-benzodtox-5-vh -1-f3-bromopropvn pvrrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodiox-5-yl) -pyrrolidine-3-carboxy!ate (4.00 g; prepared according to example 1C), 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 100° for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2SC>4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 (98%) of the title compound.
Example 316B Ethvl trans-trans and cis-trans 2-f4-MethoxvphenvlV4-M .3-benzodiox-5-vh -1-(3-propvlaminopropvn pvrrolidine-3-carboYvlate The compound described in Example 316A (5.22 g) was heated at 80° 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 (Na2S04). 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 fra/7S-frans-2-f4-Methoxphenvn-4-M.3-benzodioxol-5-vl)-1-r2-(N-propyl-N-f4-methoxvphenvnsulfonvlamino)propvn-pvrrolidine-3- carboxvlic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulfonyl chloride in acetonitriie containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydroiyzed to the title compound by the method of example 1D. NMR (CDCI3, 300 MHz) 8 0.83 (t, J=7Hz, 3H), 1.40-1.52 (m, 2H), 1.56-1.70 (m, 2H), 2.00-2.11 (m, 1H), 2.40-2.51 (m, 1H), 2.69-2.78 (m, 1H), 2.84-3.03 (m, 4H), 3.19-3.34 (m, 2H), 3.48-3.59 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.85 (d, J=8Hz, 3H), 6.93 (d, J=8Hz, 2H), 7.02 (d, J=2Hz, 1H), 7.29 (d, J=8Hz, 2H), 7.69 (d, J=8Hz, 2H). Anal calcd for C32H38N2O8S : C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.
Example 317 frans-frans-2-(4-Methoxphenvn-4-M.3-benzodioxol-5-vn-1-rg-fN- Dropvl-N-proDvlsulfonvlamino^propvri-pvrrolidine-3-carboxvlic arid Using the method described in example 66, the propylamino compound prepared in Example 316B was reacted with propanesulfonyi chloride in acetonitriie containing diisopropylethylamine. The resuling product was chromatographed on silica gel (30% EtOAc in hexane) and hydroiyzed to the title compound by the method of example 1D. NMR (CDCI3, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 1.02 (t, J=7Hz, 3H), 1.47-1.60 (m, 2H), 1.65-1.85 (m, 4H), 2.04-2.16 (m, 1H), 2.42-2.57 (m, 1H), 2.72-3.11 (m, 5H), 3.25-3.41 (m, 2H), 3.50-3.62 (m, 2H), 3.80 (s, 3H), 5.85 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.80-6.90 (m, 3H), 7.02 (d, J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C28H38N2O7S: C, 61.52; H, 7.01; N, 5.12 . Found: C, 61.32; H, 7.01; N, 5.01.
Example 318 tra/7s.fraf?s~2-(3-Fluoro-4-methoxvphenvn-4-n.3-benzodioxol-5-vni-f2-fN-propvl-N-pentanesulfonvlamino^ethvn-pvrrolidine-3- carbpxylic grid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68°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(m, 2H), 2.25-2.33(m, 1H), 2.72-2.92(m, 5H), 2.97-3.12(m, 2H), 3.16-3.33{m,2H), 3.43(dd, J=3Hz,J=9Hz,1 H), 3.53-3.60(m, 1H), 3.66(d, J=10Hz, 1H), 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(dd, J=1Hz,J=8Hz,1 H), 6.92(t, J=8Hz,1H), 6.97(d, J=1Hz, 1H), 7.12(d, J=8Hz, 1H), 7.18(dd, J=1Hz,J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+.
Examole 319 frans-frans-2-f4-Pvridinvn-4-M .3-benzodioxol-5-vl>-1-rN.N-difn-butyhamino carbonvlmethvll-Dvrrolfdine-3-carboxvlic acid. The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propanoate (J. Am. Chem. Soc. 1993, 115, 11705) in place of ethyl (4-methoxybenzoyl)acetate. m.p. 131-132 °C. NMR (CDCI3, 300 MHz) 8 0.82 (t, J+7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.97 (d, J«13Hz, 1H), 3.00-3.25 (m, 4H), 3.32 (m, 1H), 3.39 (d, J«13Hz, 1H), 3.45-3.52 (m, 1H), 3.67-3.78 (m, 1H), 4.10 (d, J=9Hz, 1H), 5.92 (dd, Js=2Hz, 4 Hz, 2H), 6.75 (d, J=9Hz, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H), 7.02 (d, J=2Hz, 1H), 7.45 (d, J=8Hz, 2H), 8.50 (d, J=8Hz, 2H). Anal calcd for C27H35N3O5: C, 67.34; H, 7.33; N, 8.73 . Found: C, 67.39; H, 7.45; N, 8.61.
Example 320 frans-frans-2-(4-Methoxvphenvn-4-f1.3-benzodioxol-5-vl>-1-r2-{N-propvl-N-diethvlaminocarbonviamino^ethvn-pvrrolidine-3-carboxvlic acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61B and diethylcarbamyl chloride for isobutyryl chloride in Example 61C. NMR (CD3OD, 300 MHz) 8 0.74 (t, 3H, J=7), 1.09 (t, 6H, J=7), 1.33 (m, 2H), 3.17 (q, 4H, J=7), 3.78 (s, 3H), 4.04 (m, 1H), 5.93 (s, 2H), 6.86 (d, 1H, J=8), 7.06 (dd, 1H, J=2,8), 6.94 (d, 2H, J«9), 7.04 (d, 1H, J=2), 7.40 (d, 2H, J=9). MS (DCI/NH3) m/z 526. Anal calcd for C29H39N3O6 . 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 . Found: C, 65.33; H, 7.43; N, 8.14.
Example 321 frar7S-frans-2-f4-Methoxvphenvn-4-n.3-benzodioxol-5-viM-r3.5-dimethylpiperidinvl- carbonvlmethvn-pvrrolidine-3-carboxvlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows mixture of isomers. 8 0.88 (d, 3H, J=7), 0.93 (d, 3H, J=7), 3.82 (s, 3H), 5.95 (s, 2H), 6.82 (d, 1H, J=8), 6.89 (dd, 1H, J=1,8), 7.00 d, 2H, J=9), 7.03 (m, 1H), 7.47 (d, 2H, J=9). MS (DCI/NH3) m/z 495.
Example 322 frans-frans-2-(4-Methoxvphenvn-4-M.3-benzpdioxol-5-vn-1-rN.N-difs-butvnamino carbonvlmethvn-pvrrolidine-3-carboxvlic acid. The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) suggests a mixture of isomers. 8 0.83 (t, 6H, J=8), 1.27 (d, 6H, J=7), 1.6 (m, 2H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, 1H, Jj=8), 6.86 (d, 1H, J=8), 6.94 (d, 2H, J=9), 7.03 (d, 1H, J=2), 7.35 (d, 2H, J=9). MS (DCI/NH3) m/z 511.
Example 323 frans-frans-2-M-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-rN-f2-Methvlphenvn-N-butvlamino carbonvlmethvll-pvrrolidine-3-carboxvHc acid.
The title compound was prepared using the procedures described in example 1. MS (DCI/NH3) m/z 545. Anal calcd for C32H36N2O6 . 0.9 H20: C, 68.53; H, 6.79; N, 4.99 . Found: C, 68.56; H, 6.62; N, 4.71.
Example 324 frans-frans-2-(4-Methoxvphenvn-4-n.3-benzodioxol-5-vn-1-rN-(3-Methvlphenvn-N-butvlamino carbonvlmethyll-pvrrolidine-3-carboxvlic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) d 0.88 (t, 3H, J=7), 1.2-1.5 (m, 4H), 2.31 (s, 3H), 2.8 (m, 2H), 3.14 (t, 1H, J=10), 3.3 (m, 1H), 3.44 (dd, 1H, J=5,10), 3.53 (m, 1H), 3.60 (t, 2H, J=7), 3.79 (s, 3H), 3.82 (m, 1H), 5.93 (s, 2H), 6.74 (d, 1H, J=8), 6.8-6.9 (m, 5H), 7.06 (d, 1H, J=2), 7.09 (d, 2H, J=9), 7.18 (d, 1H, J=7), 7.27 (t, 1H, J=7). MS (DCI/NH3) m/z 545. Anal calcd for C32H36N2O6 . 0.8 H2O: C, 68.75; H, 6.78; N, 5.01 . Found: C, 68.70; H, 6.67; N, 4.85.
Examole 325 frans.frans-4-M.3-Benzodioxol-5-vlV2-(benzvloxvm6thvl)-1-rfN.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Example 325A Ethvl trans.trans-A-( 1.3-BenzQdioxol-5-vn-2-(ben2vloxvmethvlV1-^N N- dibutvlaminocarbonvtmethvnpvrrolidine-3-carboxvlate The procedures of Example 1A-1D were followed, substituting ethyl 4-benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetatein Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; 1H NMR (CDCl3, 300 MHz) 5 0.88 (t, J=7Hz, 6H), 1.17 (t, J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (brm, 3H), 2.85 (t, J=8Hz, 1H), 2.98-3.30 (m, 5H), 3.39-3.60 (m, 3H), 3.64-3.75 (m, 2H), 3.92 (d, J-14Hz, 1H), 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 2H), 5.91 (m, 2H), 6.69 (d, J=9Hz, 1H), 6.77 (dd, J=1.5, 9Hz, 1H), 6.91 (d, J=1.5Hz, 1H); MS (DCl/NH3) m/e 553 (M+H)+.
Example 325B trans.trans-A-l 1.3-Benzodioxol-5-vO-2-fbenzvloxvmethvfl-1 -((N.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid The title compound was prepared according to the procedure of Example 71C, as a colorless glass. TLC (5% MeOH-CH2CI2) Rf 0.13; 1H NMR (CDCI3, 300 MHz) S 0.86 (t, J=7Hz), and 0.90 (t, J=7Hz, 6H total), 1.15-1.52 (br m, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3,13Hz, 1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.84 (dd, J=1,8Hz, 1H), 6.93 (d, J=1Hz, 1H), 7.28-7.39 (m, 5H); MS (DCI/NH3) m/e 524 (M+H)+.
Example 326 frans.f/ans-4-(1.3-Benzodioxol-5-vl>-2-fhvdroxvmethvlV1-(fN.N-dibutylaminocarbonvlmethvl>pvrrolidine-3-carboxvlic acid Example 326A Ethyl trans. trans-A-( 1.3-Benzodioxol-5-vl V2-fl-ivdroxvmethvr>-1 -f CN.N- dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlate The resultant product from Example 325A (128 mg, 0.232 mmol) and 25 mg of 20% Pd(OH)2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Example 326B trans.trans-4-(1.3-Benzodioxol-5-vlV2-(hvdroxvmethvn-1 -f(N.N-dibutvlaminotoarbonvnmethvlPvrrolidine-3-carboxvlic acid The title compound was prepared according to the procedure of Example 71C.
Example 327 /rans-ft*ans-4-/1.3-Benzodioxol-5-vO-2-fN-methvlpropenamid-3-vfl-WnM.N-dibutylaminocarbonvlmethvflpvrrolidine-3-carboxvlic acid Example 327A Ethvl trans.trans-A-tt .3-Benzodioxol-5-vlV2-fformvn-1-((N.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlate The title compound is made by selective oxidation (e.g. using the Swern oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess-Martin periodinane) of the compound of Example 326A.
Example 327B Ethvl trans.trans-4-f 1.3-Benzodioxol-5-vn-2-fO-tert-butylpropenoat-3-vn-1 -f(N.N-dibutvlaminocarbonvlmethvQpvrrolidine-3-carboxvlate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH2CI2 solution.
Example 327C Ethvl trans.trans-4-f 1.3-Benzodioxol-5-vn-2-(propenoic acid-3-vlVI-f(N.N- ' dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH2CI2 (1:1).
Example 327D Ethyl frans.f/ans~4-f1.3-Benzodioxol-5-vlV2-fN-methvlpropenamid-3-vn-WfN.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carfaoxylatQ The title compound is produced by condensing the compound of Example 327C with methylamine hydrochloride in the presence of a carbodiimide (e.g. N-ethyl-N-(3-dimethylamino)propylcarbodiimide, DCC).
Example 327E trans, trans- 4-f 1.3-Benzodioxol-5-vn-2-( N-methvlpropenam id-3-vn-1 -ffNN-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic arid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71C.
Example 328 trans. trans-A-l 1.3-Benzodioxol-5-vn-2-C 1 -hvdroxv-2-propen-3-vlV 1 -ffN.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Example 328A Ethvl trans.trans-4-f 1.3-Benzodioxol-5-vn-2-f 1 -hvdroxv-2-propen-3-vn-1 -ffN.N-dibutviaminocarbonvlmethvnpvrrolidine-3-carboxvlate The title compound is produced by reacting the compound of Example 327C with borane methyl sulfide complex.
Example 328B trans.trans-A-( 1.3-Benzodioxol-5-vh-2-f 1 -hvdrox-2-oropen-3-vn-1 -ffN.N- dtbutvlaminocarbonvlmethv0pyrrolidine-3-carboxvlic 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-f 1.3-Benzodioxol-5-vn-2-fN-benzvlaminomethvn-1 -ffN.N-riihtitvlaminocarbonvlmethynpvrrolidine-3-carboxvlic acid Examcle 329A Ethvl frans. frans--4-f1.3-Benzodioxol-5-vfl-2-fN-benzvlaminomethvfl-1-ffN.N-dibutvlaminocarbonvlmethvflpvrrolidine-3-carboxvlate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
Example 329B frans-frans-4-f1.3-Benzodioxol-5-vfl-2-fN-benzvlaminomethvn-1-ffN.N- dibtJtvlaminocarbonvlmethvQpvrrolidine-3-carboxvlic acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C.
Example 33Q frans.ffans-4-f1.3-Benzodioxol-5-vfl-2-fN-acetvl-N-benzvlaminomethvfl-1-ffN.N-dibutvlaminocarbonvlmethvflpvrrolidine-3-carboxvlic acid Example 330A Ethvl trans.trans-4-f 1.3-Benzpdioxol-5-vn-2-fN-acetvl-N-benzvlaminomethvfl-1 -ffN.N-dibutvlaminocarbonvtmethvflovrrolidine-3-carboxvlate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.
Example 330B trans.trans- 4-f 1.3-Benzodioxol-5-vfl-2-fN-acetvl-N-benzvlaminomethvn-1 -f fN.N-dibutvlaminocarbonvlmethvflpvrrolidine-3-carboxvlic acid The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71C.
Example 331 trans.trans- 4-f 1.3-Benzodioxol-5-vfl-2-f ethvnyfl-1 -f fN.N-dihutvlaminocarbonvlmethvflpvrrolidine-3-carboxylic acid -nMo Example 331A Ethvl trans.trans~4-C\ .3-Benzodioxol-5-vn-2-tethvnvn-1 .«NN-dibutylaminocarbonvlmethvnpvrroiidine-3-carbQxvlate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.
Example 331B frans.frans—4-f 1.3-Benzodioxol-5-vO-2-(ethvnvfl-1 -ffN.N-dibutvlaminocarbonvlmethvQpvrrolidine-3-carboxvlin acid The title compound is produced by reacting the compound of Example 331A with lithium hydroxide according to the procedure of Example 71C.
Example 332 trans. trans-4-( 1.3-Benzodioxol-5-vn-2-( 1 -pentvnvH-l-ffN.N-dibutylaminocarbonvlmethvflpvrrolidine-3-carboxvlic acid Example 332A Ethvl trans.trans—441.3-Benzodioxol-5-vlV2-fpentvnvfl-1 -ffN.N-dibutviaminocarbonvlmethvOpvrrolidine-3-carboxvlate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. (J. Org. Chem. 1989, 54(15), 3618-24).
Example 332B trans. trans-4-( 1.3-Benzodioxol-5-vfl-2-f 1 -pentvnvD-1 -ff N. N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of Example 71C.
Example 333 frans-frans-2-f4-Methoxphenvn-4-n.3-benzodioxol-5-vn-1-f2-(2.6-dioxopiperidinvh ethvB-pvrrolidine-3-carboxvlic acid The compound of example 61A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydroiyzed to the title compound by the method of example 1D.
Example 334 fra/TS-frans-2-f4-Methoxvphenvn-4-M.3-benzodioxol-5-vt)-1-rN.N-diphenvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid. The title compound was prepared according to the procedures described in Example 1. 1H NMR (300 MHz, CD3OD) 8 2.83 (dd, 1, J = 8.1, 9.7), 2.99 (d, 1, J = 15.4), 3.19 (t, 1, J = 9.5), 3.49 (d, 1, J = 15.3), 3.51 (dd, 1, J = 4.6, 9.5), 3.57 (m, 1), 3.79 (s, 3), 3.85 (d, 1,J 8 9.5), 5.90 (s, 2), 6.71 (d, 1, J = 8.0), 6.84 (m, 3), 7.04 (d, 1, J = 1.6), 7.14-7.16 (m, 6), 7.19-7.34 (m, 6); MS (DCI/NH3) m/z 551; Anal Calcd for C33H30N2O6-0.65H2O.0.35C2H5OCOCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
Example 335 fra/7S-frans-2-(4-MethPXVPhenvn-4-(1.3-benzodioxol-5-vn-1-fN.N-diisopropvlaminocarbonvlmethvn-pvrrolidine-3-carboxvHc acid. The title compound was prepared according to the procedures described in Example 1. 1H NMR (300 MHz, CD3OD) 8 0.95 (d, 3, J = 6.5), 1.24 (d, 3, J « 6.4), 1.30 (d, 6, J = 6.8), 2.85 (d, 1, J = 12.5), 3.04 (dd, 1, J = 8.1, 9.8), 3.14 (t, 1, J = 9.7), 3.32-3.55 (m, 3), 3.63 (m, 1), 5.92 (s, 2), 6.75 (d, 1, J = 8.1), 6.85 (dd, 1, J = 1.7, 8.1), 6.93 (m, 2), 7.02 (d, 1, J = 1.7), 7.35 (m, 2). MS (DCI/NH3) m/z 483. Anal Calcd for C27H34N2O6 • 0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.
Example 336 trans.trar>s-2-( 3-Fluoro-4-methoxvphenvlV4-( 1.3-benzodioxol-5-vn-1-f2-N-propvl-N-butanesulfonvlamino)ethvh-pvrrolidine-3-carboxvlic 2£id Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66°C. 1H NMR (CDCI3, 300MHz) 8 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34-1.52(m, 4H), 1.72(quintet, J=7.5Hz,2H), 2.25-2.35(m,1H), 2.72-2.94(m, 5H), 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, -20$- 1H), 6.82(d, J=8Hz, 1H), 6.92(t, J=9Hz, 1H), 6.97(s, 1H), 7.12(d, J=9Hz, 1H), 7.18(d, J=12Hz, 1H). MS (DCI/NH3) m/e 565 (M+H)+.
Example 337 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared. > Table 1 R R R -20&- Table 1 cont.
R -rxx ,XJa 6. 7. 8. 9. o o d'^o . 11- 12. o,.P jO*C* 14. 15. ir; n r\ ri rr o-<^ 16. 17. 18. ox,. ox; °"0,C> <Tb do ^ o*o 19. 20. 21. -1\o 28. 34.
Table 1 cont.
O*o ^ o*o r o o 22. 23. 24.
HsCOv^v ys,^ XXjC^ Fj^c^ oo . 26. 27. p3C—FH2Cv^s:>k^. FHaC^^N^vJ.
O^'O « ° ° ° O O O O 29. 30. ^sOC^* 31. 32. 33' ^1 ^ ^ F2HC,c/^:'W' F3(XC^>;Ms-^ F3CvC^S;Ns>-/^- f2 o *0 fjo o f20 o . 36. o o 10° o o 37. 38. 39. ^2-11 OOyY Table 1 cont.
R R F^ccy. ^ 40. 41. 42.
^V^ll ^ HaC^ (^ kA^»^ k^*^. d*o d o o* o 43. 44. 45. 46. 47. 48. sv 49. 9^ 50. 51. o 52.
XV 53. 9 ov 0* J ~—i OY* 55.
V TV 54.
J*r* 57. c v— 0 58. oo« f o 59.
CX^OY^V 0 60.
Table 1 cont. R Q-Oy'W 61. 62. . rr. 63. cnP* crr^ CVC^ 64. 65. 66. r- rt „ c. cyc; vw^ Yyy^ 67. 68. 69.
OrY^ 70. 71. 72.
OjC, O^C, 73. 74. 75.
XV* A . A 76. o O O 77- 78.
Table 1 cont. R R R H3C0V^ 79. 80' 81 ■ fO (JO v_cyO* — o 82. 85. 88.
X o 91. 7 7 7 cyN^t -~°YN^L ck^°Yn^£ 94 95. 96. 83. 84.
A 86. 87. ?< cr^'0^^^- 89.
V 90.
V r1 r ck^°YNv^' o 92. 93. •^lA- Table 1 cont. 97. r 100. ri r^ O 103. ^ r* vy^ o 106. ch3 r^ av^ 109. o 112.
-V* o 115. 98. r- 101. ri r- YW o 104.
CrV^ 107. ch3 r^ CY^ 110. r^ Y^°YNv-0S' 99.
CX 113. ?h3 <fo * 116. r- 102. ^ r^ 105. h r* or^ 108. 111. <5^v^- £py^* 114. ?»3 r- vw 0 O 117.
Table 1 cont.
R 6V 118. 121.
(XV 124. 2r 127. or "CX&3 130. nr 133.
CV QrV 119.
CrV 122.
CrV F 125. prV CI 128.
QT OCH, V* o 131.
V* o 134. 120. rvV* 123. ,xSV 126. :rjSV 129.
X?T» H3CO' 132.
'V* 135.
Table 1 cont.
R Y* 137. 140. 148. 143. o o 146. ?«»r* <To * 149.
Sv 138. 141. o o 144. cr^ 147. c? o 150.
HjC H^?-o 151.
SN O 152. oV 153.
Table 1 cont. iTYV* O 154. 155. 156. 157. f- i 160. gr 163. w* 158. 161. oV 164. y* 165. o o 166.
F3CV^NvS''^Sw/^ FFCTO ^ 167.
O O 168.
Table 1 cont.
KF O O 169.
V , o o 172.
Y , Fa^s^-x.sr d"o 175.
V , d* o 178. o*' o 181.
H3CCf o o 184. h3co^ S-'W o o 187.
V , o o 170.
F3S^.rN^^ r r n n F.F Y F3C^°vxri^TsX^ o o 179.
FVF o o 182. h3cct^ ^—X"W o o 185.
H3CCT^j F3cs^^;>Ns>^f O O 188.
Y , o o 171. xOCji o o 174. 177. F F cTo ^ 183. o o 186.
HgCO^I F3Cv^grf^W FFO^O r 189. o o 196.
Table 1 cont.
R H3CCf^ HaCO^j F, F H3CC^<| F3C^"0 ^sr T cTo r o% O ' O O 190. 191. 192- o o 197.
A "S 199. 200. 205. 206. 193. 194. 195. o'^b ^ o o 198. "l ~ 1 vy^STMn-^ i F F o' o I cro f FsC^O^^^N^-^ o o 201.
F3e>^0^>srY^ ck ^.Aw V 0 i 202. ^ o U 5 203. "yV^ 204. v V aT7V XrV a^V 207.
Table 1 cont.
R R R V rye £y XrV XrY' 208. 209. 210. w V "Wr* L> uY' 211. 212. 213. uY XXV OH "V XrV rv w 214. 215. 216.
ScrV ^ar OH Y w 217. 218. 219. rv CP x/ rv h>v Nyr Nyr 220. 221. 222.
Table 1 cont.
R R R "XrV 223.
* V XrY* 224. cf3 225. • ,.v "TOY* V xrr 227 ~v rye 228.
UU. -\r w 229.
MH< • V 230.
V XXV 231.
• V XrV 232.
V XTY* 233.
A yrc 234. 234 •XfY* yyr* yyt* 235. 236. 237.
V * 238. 241.
Table 1 cont. 244. 245. 250. 251. o X "VS-V* 239. 240. v v v "XrV -ryY* "rj'r , *5 242. 243.
V ,, "t?v xrv Wr 246. . y i V p V ixyv Xfr' 247. 248. 249. "iOrY* 252.
Table 1 cont.
R R R "V~ w 253 V 254.
V V "ov 256.
,V O 257. 255. 258. 0 ^Cnr* Syr* 259. 260.
"S 261. \>\ Vvv «s^N 0 .
Wv FA^N 0 rv VyV1 pA^N 0 262. 263. 264. iTV Vs-V pA^N 0 , V i V ifirV r ^ 265. 266. 267.
Table 1 cont.
Syr 268. \ yyr 271. \ ■"nrY* 274.
\ VY* N O 277.
W* O 280.
OH \ ^av 269. *xiV 272.
,\ Syr" 275. 278.
VY^ O 281. ?*» \ 270. ioV 273. 276.
V YV* N O 279.
N O 282. •225- V w o 286. w* 4s.n o 289. w n o 292.
V rW* o 295.
Table 1 cont. R w* n o 284.
V w * n o 287.
W \ 293. rVV* O 296.
VY"* n 0 285.
VY* -*n o -W* >n o 291. j&T" -jGV 294.
J-VV^ 297. 304. 310. -22 b- Table 1 cont.
V -\r i, -jyy oCrV oCrV 298. 299. 300. uiV ucrv 301. 302. 303.
V ~V V <-OV i.,CrY* usV 305. 306. uCrV o^r" 307. 308. 309. w \xyy< voV 311. 312. 319. \yy* \w 322.
Table 1 cont.
V* o W rVV* o V "l rw* ^ /YV* > fW 313. 314. 315- ^ \ . ^ uyy vyr- Syr 316. 317. 318.
V , \ rVY* ns^ o o 320. 321.
-Y* ^ 0 u I 323. 324. 325. 326. 327.
Table 1 cont.
\ ^ CcY* OCT 329. 331. 332. 330. v \ £W C^Y* CcV 333.
^ V v Ccjr* (XT' efr 334- 335. 336. o.V 337. 338. 339.
V . \ cc£ Hy-* 340. 341' 3A2' 349. 352.
Table 1 cont. 343. 344. 345. ■ v v , \ Sy^ icr~ 346. 347. 348. iiy* 'ty 350. 351. i v . v v 353. 354. \v^ \\Cm JJ U YY-* 355. i^N 356. 357. 358.
V 370.
Table 1 cont.
R R R vk \V 359. 361. 362. 364. 365. 367. 368. 360. vX' ■ V^ 363. 368.
V o0^ 371. 372.
Table 1 cont.
R R R V 373.
V oCr"* 374. ~v ■JX~* 375.
V ay jy* 376. 377. 378.
Sr uCr"^ V uCr"^ 379. 380. 381. 385. 386. 387. 394. r *<syi 397.
Table 1 cont.
XCrCv \xY^ xx^- 389. 391. 392. 390. \cr~ vcr^ ^ \ k krV*1-^ 395. 396.
V x\ 398. 399.
Ns^ 401. 402. 406. 409. k rY*"*- 412. \ % 415.
Table 1 cont.
R \ NssiA 407.
V rV^* 410. <y^* NsA. 413. °v 416. 405. ry-* Mk 408. \ ry^ 411.
(-V^ fl^sA 414.
Table 1 cont. 418. 419. 420. \ yw COOEt ^N02 421. 422. 423• ^ V V ^NO2 —NO2 424- 425. 426. \ s V r or cc- 427. 428. 429 V ^ ^ CC" 430. 431 • ^ °2 436. o ^ o V V* 445.
Table 1 cont.
V a ^ I J O Dal ' 433. 434 435. o ^ V V cvX-* o o 437. 438.
\ V* YYV * y; o 439. 440. 441.
V* ~^y V* YlV 442. 443. 444.
.XTr* 446. 447.
Table 1 cont.
R R R \ jj'c XrV ~v pcyr 448. 449. i 450. -y~ V xr"r V ~^yrA 451. 452. 453.
V Xfi* 454.
MeO-^A^Ny^ 0 455.
MeO^V O 456. 0 A |l» ■!!■ MeoY^V 0 A 457. 458. 459.
MaoYT\/ Me0v^ V Y* MeO^^V^ O 0 o 460. 461. 462.
MeO' 466.
Table 1 cont. 463. 464. 465. aV . 372. 473. 475. 476. 467. 468. „^o5y* MooXxbX X^LX^ 469. 470. 471. 474. ;aV »~V 477. 481. 23$ Table 1 cont. ,v V* ° o 478. 479. 482. o o 487. 488. o 480.
I^X-* O o 483.
Y* aXXJYyi 484. 485. o 486.
X^y* 'do^y 489.
X>i o ° o 490. 491 • 492- Table 1 cont.
R 493. 496. 499. 502. jo!x 505.
XxV 494.
V JX V* 497. jc6 v* 500. jo6^ 503.
V* o 495.
V* 498. 501. x6 504. 506.
OMe O 507.
Table 1 cont.
R R R .JpLV OMe 0 508.
MeO''^^X^ OMe 0 509.
OMe 0 MeO-Q^W OMe O 511.
OMe 0 512. 510. r\ V MeO'^fs^'NV^»«I OMe O 513.
OMe O MeOy^ yLv1 OMe O "ViN OMe O 514. 515. 516.
MeCSr^i OMe O 517.
"•Vi v Vjos^y-* OMe 0 518.
OMe O 519.
•«Vs k yLy1 OMe O Me°V^ OMe O ■ViV OMe O 520. 521. 522.
Table 1 cont.
R R R kxo «J^y* OMe L o 523.
OMe jf 524. > x/\ w 525.
\/V rxV* 526.
V yyr* 527.
^Y" BW C;OR ~y~ V w o^o« w 529. 530. 531.
\ "CrV 532.
"W 533.
V "tyv 534. /S /N V XXV 535. w 536. ^■r XXV 537.
Table 1 cont.
V V X xxy -oar* xxr 539. 551. 540.
\ V Xxy -COT* 540- 542. 543. v ,X)V XK* XrV 544. 545. 546. v \ ^ XK* XrV .»V 547- 548. 549.
V V ~v &** »r xo" 550* 552.
Table 1 cont.
R R R YYV* F^a° 553.
V xcr 554.
V YYV F^a° 555.
\ YYV* FA^ao w V FA^Xao 556. > 557.
N/S 558. /\ V BryyY* ■W* XrV 559. 560. 561.
V 562.
V yyY* 563. \ yn" 564.
V XrV" 565. 566. 567. 577.
Table 1 cont.
R - :&¥ * 568. 569. 570. 571. 572. 573. ^jV v ~V XrV ^-v 574. 575. 576. v v v* "~V 578. 579° r ^ o 580. cY O 581.
V o 582. rV 0 583. rTy o 584. cX 0 585. 598.
Table 1 cont.
R C ^ C ^ C ^ o Oo 586. 587 • 588. v -7V XrV XTV 589. 59a S91' V V \ ^yv ^yv ~-yx* 592. 593. 594.
A V "7 V -TV 595. 596. 597.
V XTY* xtv XTV 599. 600. v s V ^yY* 601. 602. 603- H V* 604. 607. ^6rV 610. 613. 611.
H o 614. 606.
H V* o 609. r H V* 612. 615.
H V* O 616. 619. 617. 620. 621.
Table 1 cont.
R R € , -O irV 622. 623. 625. 626.
H v* o 629. o 631. 632. o 624. 634. 635. 636.
V v X " XX V XXV 637. 638- 639.
Table 1 cont.
R R R © 640.
V O 641. xxic, o 642.
O 643. o 644.
"OV o 645.
^ V o XXSy-ji xxb o 646. 0 647. 648.
XX& o 649. "xxY* 650. 651. *oV 652.
VI "Xfi* 653. 654.
Table 1 cont. "xrV" "-oV 655. 656. a 657.
ScV* W* 658. 659. 660.
^ ScrS* 661. 662. 663. ^oV1 xrV" 664. 665. 666. \jl Y XjV" "O'r crt 667 668. 669. 670.
X/ Table 1 cont.
V ^ ^ "crV6 671. 672.
"*V"VV 673. 674. 682. 683.
W* 675. ioV" 676. 677 • 678. yV IcrY" 679. ^ 681.
XjV* ,ȴ< xii" 684. o 688. ^ o 694 ;x>V 607.
Table 1 cont. 685. 686. 698. 687. ^r* 689. r " 690.
X& Xrt* xr^ 691. gg2 byki- 693. ^ ;xr^ 695. 696. o 699. r*! H 700. o 703. 706.
% Table 1 cont. R 701.
XX^* 704. o 707. \ o 702.
V* 705.
XX* Yl 'V* 708. o o 709.
H V* 712. 710.
H 713. 711.
F3c^^s;f<Os; o o 714.
A o *o 715.
Example 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.
Table 2A MOMO F. MOMO ..COOH Ft- 13. momo omom Table 2A cont, momo momo 14. 17. . och3 18. 28.
OMOM 31.
Table 2A cont. 29. 32. . 33.
OMOM OMOM 40.
OMOM Table 2A cont. 41. 42. 45.
MOMO Table 2A cont. 58. 61.
Table 2A cont. 60. // ,y. COOH •V-o ft- Table 2A cont. och. och.
OCH3 OCH3 OCH3 89. och. och OCHa —I- Table 2A cont.
Table 2A cont. h3co H3C0 H3C0 h3co H3C0 _^cooh *°fc3 112. cooh 115. cooh r-n 118. 120.
Table 2A cont. ( ts, h3co 3 V X^cooh s° \ JyWJH Fb^y000" > ,% ~a(4- ^sch3 133.
Table 2A cont. 137. •265- Table 2A cont. 145. 148. cooh OCH3 149. r-n cooh 151. OCH3 omom cooh r-n' 152. omom omom cooh h3co och, 156. 154. 155. 3bb Table 2 A cont. 161. 162. momo -Ife?- Table 2A cont. momo 169 momo 175. momo momo momo 178 179. 180. -aft- Table 2A cont. momo 182 183. 184. momo momo 187. r-n momo 190. momo O O O 191. f chg 192. 2fr9 Table 2A cont. momq 194. 195. momo momo XK. 198.
Table 2A cont. 206. 207. 208. 209. 2 210. 211. och3 212.
OCH, 213. och3 och3 EtQ F 223.
-W- Table 2A cont.
EtQ F OCH, 224.
EtQ F 219.
EKJ p 225. 226. 227. 53-2.
Table 2A cont. h3cq och. h3cq ocr 230. 233. h3co och 231. och3 h3cq och. 234. 240. tf~o 241. 244. 247. -2?3- Table 2A cont. 242. 245. °°h3 248. 251. 243. 246. 249. 252. och3 Table 2A cont.
K F F, F K F 254.
K F 257. 260. 255.
F* F 258. 261. 262. 263. 265. 266.
OCH, 264. 267. 268. -2*6- Table 2A cont. 269. 271. 272. 270. 274. 275. 278. 276. 279. >6 3 choo *t63 '883 *583 863 '363 '063 *hoo "Z83 >83 983 •383 i-U hooo* •JUOO V3 ©10*1 T"?? Table 2A cont. 296. 297. 298. 299. 300. 301. och3 302. 303. 304. 305. 0-7^ Table 2A cont. .cooh R"* ^r—o' 3 307.
COOH 309. 310. 311. 312. 316 317. 318. 319. 321.
Table 2A cont. 326. 327. 335. 4 VjDOOH RjCCa> 336. 337. 340. 343. 346.
Table 2A cont. 338. 344. 347. 350. 339. 345. 348. 351. 2$\ Table 2A cont. 352.
Qfjr ..'S-CHg EtQ 353.
^ ° Q &./■ 354. och3 355. och3 358. 359. 360.
-S-CH3 362. 363. 7&Z Table 2A cont.
Qo? s-ch j ^ S-CH >n^ch3 ' h O 367. 368. 369. 370. f .nh An 371. 372. 0 373. 374. 375.
Table 2A cont. af >-N y m O- .S-ch3 \ 376.
FT O °*o N H ch, 378. 379. 380. n*N I NH •^k 381. n*h i nh 382. 383.
NsN 384. nssK WNH 385. 386.
NSN.
L nh >N 387. iJbY Table 2A cont.
Oo." p U ■ch3 -°> ■o 388. 389. 390. 391. 394. 397. f,cf. 399.
ZS5" Table 2A cont. 406. och, 409. 401 404. 407. 410. 405. 408.
V ,»COOH 412. 413. 414. 416. 421. wCOOH Q 419. 422. 420. 423. 424. .cooh 425. 428. 426.
Table 2A cont. 430. 4 \£°OH 433. 436.
O ^cooh K^~o 439. 431. 434. 437. <,cooh rjCLo$ 432. r\. ,cooh 435. 441. 442. 443. 444. 445. 448. 451.
Table 2A cont. 446. 449. 452. 450. 453. 454. 455. 456. 457. 460. 463.
Table 2A cont. 458. 461. 464. 459. 462. 465.
Table 2B o 1. -i -V* o 4.
V* .
°YNLvx^- o 13. ct^0Yhk-^ o 16. 0**0 ■v* o A 'V . 8. o 11. v^°YNy^ 14. hac( r- 17. •v* 3.
A 6. 9.
O'o 12. cK""— .
H3CY^ vyw o 18. 19. . 21.
Table 2B cont.
R R R xCOw aX^d'-o H3CYI r* o-5^ "^Ogc; (fb 22. 23. 24. —jj. o' o H3CQs^S.^N>S(^-^> o' o FaCs.^v.^Nvx^l . 26. 27. o' "o ^1 FH2C^N_^W o'"o d"o 28. 29. . m2acr^.srNv-^ f2 d o F2 d' "o F2 do 31 • 32. 33.
F^Os FzO'O 34. . 36.
O 0 yx^ 37. 38. 39.
O O o o 40. 41. 42.
Table 2B cont.
^ FsCVvii o o 43. 44. 45. i c, ""cxx: ""cuc, o" *'o OO^ 6'"b 46. 47. 4Q ^ /N/N, N^N/Sj TV rrV rvV* 49.
O >v^ O 50- 51. qV* ,P o 52. 53. 54. rVY"* rrV* o o 55. F 56. 57. qV ^ka° ^ - a 58. a 59. 60.
Table 2B cont.
R oct 61. 64. pV och, 65.
V* o 68. rrv* H3ccA^ 0 63. 66. 69. ?h3 o' o 70. 73. ?»3 V,-, o o 71.
X" o o oV 72. 75. 76. 77. 78.
VSj <$ o 82.
Table 2B cont.
R -^1 80.
F F o O 83. <$ o 81.
^ , Fa&s^Ov><<^xg^ O O 84.
F.F F3cr^Ck^s:s:N^o^ •mL 0 O 85.
Y J o'"o 86. or V J 87. >r o o >v^^C^e O 0 88. 89. 90.
PaQs^>«g^NS((^«j^ 0* O T*b* 91. 92. 93.
V , FvF Y F3crX^a-^TH^ o o ^ , FF0wO ^ 94. 95. 96.
F.F "^l F3C^q-^W H3CO^ cPo r 97. 98. 99.
R H3CO^j o o 100. h3co^ o o 103.
Table 2B cont.
R h3cct j o o 101.
HaCOT^t p3o^ ^ o o h3co"N o o 102. 104. h3co<S 3CVX^S'^^ f f (To ^ 105.
H3CCr^ YX^ 106. o **o 109.
A :.<W O O 112.
F F n r O O 115.
H3CCr^| F3CvO>„x,v»g'"s^-vi 0"0 107.
A cr o o 110. o*"o 113.
^ , I o o 116. f. f h3cc^s 108.
A vw oo 111. \ p3c— O O 114.
FsCX^O O 0 117.
Table 2B cont.
R I R R F F O O 118.
"V °X?Y* 119.
~V w 120.
"V "xyy V "xrr* V ""CY* 121. 122.
S^/s. 123.
Scrv rv Sav* Soy* 124. 125. 126.
, V Sov "TTT* i V S^v 127. 128. 129.
S?v OH "xyr* 'Qfa* 130. 131. 132.
?*■ O. 145.
Table 2B cont. ■j* Y 9" T oh w uf "xrr 133. 134. cf, v cf, 135.
Vv cf3 Y ?p3 T v "OV w 136. 137. 138. oV °ioV °xyr* 139. 140. 141. v ^CrV TXV* 17V 144. 142. 143. nr V V sqV XrV V 146. 147.
Table 2B cont.
R R R V XXV 148.
"V 149.
~V ■XfV 150.
• V "XxV* V a;oV 151. 152. 153.
V 154. ~v "XXY* 155.
XrV 156.
• V "xxv* 157.
V yyy* 158.
V 159.
V ^0"V Ixrr* iov 160. 161. 162.
Table 2B cont.
R R R XrV , V [}r FXrY* 163. 164. s 165. l0T "W ~v "XfX' 166. 167. 168. ■or V V -TOV 169. 170. 171.
V "XrV U M r\ 172. 173.
S^N U 174.
L.Y XlY* 1 V XfV 175. 176. 177. 181. 187.
Ni 190.
Table 2B cont.
^.N O 191. 0 o 178. 179. 180.
ScrV ^ Ittrr 182. 183.
, V r\ IxrY* "err 184. 185. 186. ^oV "oV !x>V 188. 189. 'vX'* I \ s^N O 192.
Table 2B cont.
R 193. \yr 196. 205. \yr 194. 197. 200. 203. 206. 195. 198. 204. 207. 211.
^•N O 220.
Table 2B cont.
Tf jxv uyr- 208.
V -vXXY* jVY* /VSr* 209. 210. 212. 217. 218.
*N O 221.
V v s -jCSV jyr jjr 214. 215. 216. uyr^ uCff Jfvy 219.
V v .. T K) x uCfV . * N O Tabie 2B cont. uCfV xftV 223. 224. 225. v v v XXXV1 xxyr* \jCtV 226■ 227. 228.
Sorv Scxy* 235. v vyv xcsv \j&V 229. 230. 231 • xjy** scrv s$V 232. 233. 234. 236. 237. 238. rVV* O 250.
Table 2B cont.
V VV CrV xxV 239. 240. 241. 242. 243.
\ Ct,V 244. 245. 246 V V rVY* AY N^jjjsL O O 247. 248. 249.
S V v ■v'' (YV 252. 252. 265.
Table 2B cont.
R or 253. 254. 255. v A , V Sor c*^" 256. 257. 258.
SOT 259. 260. 261.
Scy~^ 262. 263. 264. iCf^ W-* SrY^ fA^n 266. 267.
Table 2B cont. 268. 271. 274.
S V 269. 270. \y~~ \v^ \Y^* 272. 273. 275. 277. 278.
VV1^ 1 280. 281. 282.
Table 2B cont.
R i^N ■s^N 283. 284. 285. \er-~ \ oCf^ V 286. 287. 288.
V "V 289. -jCT^ 290.
V \A^N 291.
-,Cr'"v oCr~ 292. 293. 294. \ v v ay^ uX"" ay-" 295. 296. 297.
Table 2B cont.
R uCr^ 298.
V uOr^ 299.
V ay*"* OrtA uCs^ oUO.
Xu^ 301. 302. 303.
V XC> 304.
V xcy^ 305.
V "LCt"-* 306. 307.
V 30R %r K XOT^ 310. wV/O* 311. 309. 312.
Table 2B cont. *<syl 313. v 314. 315.
'K—*yL 317. 320. \ fk^sL 323. \ 327.
R Table 2B cont. ^ of- noti k 1 330. 329. \ ^ 334. 335 Ct~* 331. 332. 333. £y^* \yw OOP, COOEt ^ COOEt 336.
\ NOj 337. 338. 339. s V V or or ec 340. 341 342. 352.
Table 2B cont..
R 350. 345.
OCT 346. ^ 34a o V o o 353. 354. yr -prv w 355. 356. 357. 367.
V XrY* Table 2B cont. 358. 359. 364. 365. 360. y ^ \r -V yv ;crY* 362. 363. \ i, ^rV xrV 366. v v XrV xrX* 368. 369. 370. *n- 372 Table 2B cont.
"■Vi V mjo'VsA^ o 378. u^XXlXw _IX MaoAsA^'W 0 o 379. 380. 381. xc 388. 389. 390- V-4 o o ,v o ^ 406 Table 2B cont.
Y* O o 391. 392. a a 394. 395. 398. ° o 400. 401. o o 403. 404. xxit •V* o 393. a a ^ av\V a" — — o o 399. o o 407. 408. :xxx 409.
V* o 412. ,c6c Table 2B cont.
V XOy* 410. xxlx.
M ^ o 413.
O o 415. 416.
Y* 421. 422. ° uJ&r* OMe O 0Me o 424. 425.
XXjy-* JCL^X V* o 417. o o 418. 419. 420. 423. 426.
Table 2B cont.
R R m^X^sIX^ MeO OMe O OMe MeO' 430. 431.
Mecy^ y "Vl^ lyk^Ns^ y^v* y-V* OMe O 437.
OMe O 427. 428. 429.
"W.
OMe O OMe O OMe O 432.
M OMe O OMe O 433. 434. 435.
Xw OMe O 438. jf^l H OMe A MeO^^^Y^ XXV 440. 441. w BrX7V 443. 444.
Table 2B cont.
V v "CrV "OV ^CV 445. 446. 447. *oV *oV 448. 449. 450. xxv xxv xxv 451. 452. 453. v v \ xxv "XXV -a,v 454' 455' 456.
\ V V XXV XXV ■JCV 457. 458. 459. 469.
Table 2B cont.
R ^Xre Xnr 460.
I 461. joV Xnr 463. 464.
V V jyr xor 466. 467. v r<¥ xxy 470. 472. 473.
V ;ov 462. i* 465.
YYV pAAc,0 471. w* »V ;a!r 474.
Table 2B cont.
Xrf* B)oV 478. 479. 484. 485. v yyv VyY* X ® ^ o 476. 477. 480. :cV >rc :iyr- 481. 482. 433 7V~ .oV-* "ytyv Xrv 486.
S V f\ fj °xsv "fey xrv 487. 488. 489. •v* o 493. o 499. o 502.
Table 2B cont. jyi XnT —v 490. 491. 492. o o 494. 495. cY V O 497. 498.
^ -X- 506. 507.
Table 2B cont.
R v v \ 508. 509. 510. ^yx* 511.
^Y* 512.
XXY* 514. 515, V s XX Y* 517.
XJYa 518.
V xjV 520. 521 XTY* 513.
V 516.
V NQ'(y/ 519.
Table 2B cont.
R 523. h V* 526. 527. 529. 530. h Y* O 525. 528. h V* O 531. h Y* O 532.
✓ SJrV 535. 533. h V* O 536. 537.
V* 538. 541. 547. 550.
Table 2B cont.
R ri 539. 542. 548.
Y* 540.
V* 546. 549. 551. 552. 556.
Table 2B cont.
V V X XTt* XrV ' 565. 566. 553. S54- 555.
XTV xiY* 557. 558. vO^Y* 559- 560. 561. 562. 563. 564. v, V, 567.
R Table 2B cont. R R "toV* ceo v a^0rV* v • www* "~v 571. 569. ■^oV* 572. 570. v "TCrV4 573. 574. "~v so-v* 575. w 576.
• Vx* 577. ^oV4 580. 578.
^CrV 581.
SaV^ 579.
XrV* 582. 586.
Table 2B cont. R 583. 584. 589. 590. 585. xyV4 xrV1 xrV4 587. 588. v t/T*' yV W9. xr& icrt* a 591. 592. 593* 594. 595. 596- 597.
R Table 2B cont. R R XrV* "V xrY* 'VT XrV* 598. 599. 600.
V, xV _vi ,l5nr 601. 602. 603.
FX?V 604. xrV* 605.
FXr^ 606.
,XrV 607.
"V" fXOr 608.
Vy Xn* fin Q Xn* 610.
"Vi 611.
Qw.
X^ 612.
R » - o 616.
MeO' 619.
Table 2B cont. 614. 613. 615. 617. 620. 622. 623. o 618.
XXv^ 621.
\ V V Ur YxV* —V 624.
Xf \ ^ O 0 625. 626. 627.
Table 2B cont.
R V* H V* FaC<vOsrNN^3S o o 628. 629. 630.
A F3C^^srri^^ CTX> O O 631. 632.
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.
Table 3A 11. 12. 16. 19.
Table 3A cont. 17. . 18. 21.
Table 3B -v* o 1.
-N1 o JO V"* O 7.
. X^I o 13. —£ o 16. d"o 19.
Y* O 2.
A •Y* . 8. -o^'V^ o 11.
—'Y1^ o 14.
K!CVi ^ Vy»v^ 0 17. . 9. ci^Nv'0YNv/^ o .
H- 18. ✓v-N. o o 21.
Tabie 3B cont.
R 22.
H3CQSw/^xsrN>^^ <r° . 0 28. f2 cT o 31. f2o''o 34.
Cw 37. <fo 23. 26. fh2Cv^>»^Nvx«-^L o' o 29.
H3C1 "^VVW fao o 32.
Fj 0* 0 40. -^1 O 0 41. "o*c; d'^o * 24.
F3C^«A^ c? o 27. f2o"o 33. 36. 39. o' o 42.
Table 3B cont.
R —i Wfi F,cr^W 43. 44. 45. i*c» "cgc; "*o,c» 00 00 o o 46. 47.
Nv^S^N.
YV rvV* rrV ^ o 49.
O 4^ 0 50. 51.
OY* 9rV xrf* 52. 53. 54. oV gV* ,^V f 55. 56. 57. cor* js^ ^ o ci 58. 59. 60- Table 3B cont.
Sir 61. 64. och, 62. 65. cSV 68. h3o i5V 63. 66. irv 69. ?»3 70. 73. ?h3 cTo 71. cTc 74. o' o 77. oV 72. 78.
Table 3B cont. 82.
R Cl 6*0 80. ff&'o r 83.
^L-Ov^t o o 81.
O O 84.
F.F F3{rx^a^^N^0^ owo 85.
V *VX o o 86. a" V 87.
V , 88.
V cT o 91.
V J FaC^ Nss^^ O O 94. o o 89.
F^,<W 92.
FyF Y F3cT^a^xK^-/ o o 95.
O O 90.
Y J YX^< 93.
^ , FsCX^^g FF 6% r 96.
FsCs^O^^ 97.
F.F 98. h3co^i o o 99.
HaCOr"^ o o 100. h3cc<^ o o 103.
Table 3B cont.
R h3co<N o o 101.
HgCCfS F3cC^srN^y. o "o 104.
H3C0r^j F F CTo r 105. h3cc<^ YS«^ 106. a"^ o o 109.
A 112.
F3Spg: FF o O 115. hacct^j o o 107.
A O O 110. o o 113.
A , I o o 116. f.f haco""^, F3C^°^^0* o o 108.
A o o 111. o "o 114.
Fa^^O^^s.
O O 117.
Table 3B cont.
R FVF 0 0 118.
R R 119. ~v ^OV V" "TXY* 121. "xX* 122. 120. w 4 rs*} T5rV M ^ A k> uv 1^3. w 124. 125. 126.
, V ScrV °TX* iSr \rx* 127. 128. 129.
' OL OH SoV 5v 130. 131. 132.
Table 3B cont.
R qh >< 9H "r T-. , f« V oh V Vv XTr4 ^Q-V 133. 134. 135. ,v 136. cf3 Syr 137. rv Syr 138.
AT Syr 139. », v XrV 140. 9f3 XrV* 141.
"S_ yN. ,.v Wr* 142. xfr* 143. 144.
XXV 145.
V 146.
V "CV 147.
Table 3B cont. R R V 157.
V V t?v ypr yyr* 148. 149- 150.
V V yyy* axty* avyy^ 151. 152. 153. 154. 160. 155. 156.
-V V 158. 159. !»v 161. ixyv* 162.
Table 3B cont.
R R R icv , V !xxv i V fbav 163. 164.
N 165. |xyY* 166. 167. 168.
V ■"oV4 V 169. 170. 171.
V Vr* IL ^.N o 172. 173. 174.
, V Syr* i V SliV 175. 176. 177.
Table 3B cont.
R R R syr jy yyv pA#»N O "yvy* pA^N O 178. 179. 180. w O , v pJl^N 0 i v vw J-A^N O 181. 182. 183. , v SfVY* pA^N o 184.
OH \ sav 185. 186. \ "xrv pxxv* !xj"v 187.
•S- 188. 189. "xnr* 190.
WV "k^N 0 191. vvv fA^n O 192. 193. \yr 196.
Table 3B cont.
R V \yr- 194. 199. 200.
V u M ~ -9 \ ^ CTV XrY* 202. 203. I C rVY* \vv< I^N 8 \^N 0 205. 206. 195. 198. 201. 204.
Table 3B cont.
R R \ Scyr rVY* o 208. 209.
V fW ° 211.
('YYv nA^n ° V 212. rVV^ O 91a fW ■v^v^n o 01 c c. if. \ .
V uCfV 217 uCrV 218. •■ll* V U>v uOrV 220. 221.
V jrw^ 210. rW o 213.
|W \A^N o 216.
V ayr 219.
V uCrV Table 3B cont. R R * n o 226. 223. 224. v v xjyv XCEV vffr 227. 228.
XjCtV xCrV XjCtV4 229. 230. 231 • xjx** Syr 232- 233. 234.
SfirV VvC o 235. 236. 237. \irsr* \vv 238.
Table 3B cont. <VY* O 239. 240. 244. 245. o O 247. 248. 241. 242. 243. o^r- 246.
V V ^ rYY* f\v CCV* 249.
V cor* 250. 252. 252.
Table 3B cont.
\ ^ /YY* CcV 256. 265. 253. 254. 255.
V . \ ccr* Sor-* 257. 258.
Sx^ 259. 260. 261 • 't5rCy 'tST* 262. 263. 264.
.Sx" lay^ 266. 267.
Table 3B cont.
JxX* SrV^ 268. 271. 274. 269. 270.
\ \ \ V \vlU, _ N 275. \ ^ •s^N 277. 278. 272. 273. 279. 280. 281. 282.
Table 3B cont.
R -SS.N 285. 286.
V 289. 287.
V \A^n 290. 288. ~v V oty 291. 292. 293. 294.
\ V V 295. 296. 297.
Table 3B cont.
R R R V u¥~ 298. u0r~ 299.
V 300. my* uey* xxy* 301. 302. 303.
V 304.
V xor* 305.
V xjcc^ 306.
A xxy 307. s 310.
V xxy 308.
A 311. xxf" 309. 312. 313.
Table 3B cont.
R u0' ltyc^ 314. 315.
U^fj 317. 318.
Yv^ 319. 320. \ s rV^ 322. 323. 324.
S V \ 'V oc 325* 326. 327^ Table 3B cont. ay of* ^ 329. ^ 334. 335- 330. ty* cy 331. 332. 333.
SrV^w SrV cooEt Nv^COOEt 336. i no2 \vx^ set* cx NnsA COOEt 337. 338. 339' oir a'r cc 340. 341. 342. 352.
Table 3B cont. cn 344- 345. o.
Y 350.
-Cr"^ Oa 347. 348 o 351.
Oyic* o o 353. 354.
TprV W 355. 356. 357. 358. 361. 367.
Table 3B cont.
'Y* v y* o 364. 365.
V 360.
XXV 362. 363. xrv TJ-V 366.
XjV ^yv 368. 369.
V ;av 370. *'1* 372.
Table 3B cont. 0 373.
MeO' O 382. 375. rxi£ ro^, :DOL£, ■ o 376. 377. 378. o ° o MeO' ^ MeO^^^-NY^ O o 379. 380. 381.
" -Y* o 385. 386. 387. o 388. 389.
Table 3B cont. xx!x o o 391. 392. a a ci a 398.
Y* o 393.
Y* _ ,. 394. 395. o 396. * :1 V* O O 399. <x^c« 400. 401. 402. ° o 405. xiX* O O 407. 408.
Table 3B cont. o 415. jxs: y* o 421.
MeO'^0^NY'"^ OMe O 424.
,Y po\* 410. ° v* o 412. 6 413. jxV y* O 419.
XXj£^-* -XXhy* jQLV y* o 417.
O OMe O 422. 423.
Table 3B cont.
R R R ««^x!xw OM. O OM. I OM. o 427. 428. 429. -yX* -y?h^ OMe O OMe O OMe O 430. 431. 432.
Mei Hyjx£ OMe O OMe O 433. 434. 435. y* yyy* yyx* 442. aa"% 443. 444.
Table 3B cont.
R /\ /V R R 445.
^ V ^QfV* 446 V XrV 447 \ XfV 448. > II v« s b^q'v>; 449.
V w 450. v XX** 451 xxv A?V? w 453 *TW 1 • V xxv 454.
HJb. xxv 4cc tyu.
\ XXV \ 'ccr 457. nw3.
V XXV 458. 456.
V X"V 459.
R 0 463. i ' O 466. x Table 3B cont. v r xrr ^ 460. 461. 462. v \ .xrr* .xrr" .jj-v 465.
V V yyV 468. yyV54 F^a° 471.
F^^va° F^a0 469. 470. xiy »V 472. 473. 474 Table 3B cont.
R R R XrV bx?y* 475. 476. 477. yyr* V yxr °xiV 478. 479. 480. yyya V )irr 481. 482. 483. °&r* yxr* xv XrV 484. 485. 486. j'v xrv A XrY" 487. 488. 489. •v* O 493. o 499. o 502.
Table 3B cont. ~v ov: Xnf ~~v 490. 491. 492. .by-* O O 494. 495.
(V V O o 496. 497. 498. "0"V ~y 506. o 507.
Table 3B cont.
R R R V XrY* V XxY* \ 508. 509. 510. 511.
V 512.
V XrV 513.
XXY* XXY* 514. 515, V XrY* XJ-V^ 517. 518. xSv XJV 520. 521.
V XX Y* 516.
V XTY* 519.
V 522.
Table 3B cont. R 526. 529. h y* O 532. 535. 527. h Y* O 530. 533. j S&V 536. 525. 528. h V* O 531. 537.
Table 3B cont.
SiV SfSV 538. 539. o 541. 542.
H o H o 545. o 548. 549.
XrV xrV 551. 552.
Table 3B cont.
R R R v * 0 553. o v ^ory* o 554. v •—vv* o \ 0 555. x)ic* 556. 557. 0 558. xlxr, 559. -oi£ 560. xiv 561. 562. xi 563. ««w xxb v^ty* 564. -iv O 565. 566. ct)v' 567.
Table 3B cont.
R aTxV* 568.
R v 569.
R 'CrV "xX* 0/U. v 571. 572. 573.
SaV* 574. 575. vv* 576. 577. l0£!* 578.
W4* 579.
SoV1 580.
S>"!% 581. x&* 582. 586. 595.
Tabie 3B cont.
.V. v XrV* 583. 584. 589. 590. 585. xxS* xxV6 587. 588. xrf* Vr/' 591. yv* tfp 592. 593' 594. iCrV ^"r" ' ^ 596. 597.
Table 3B cont.
R xX* ^ 598. 599. 600. x&* x&1 Y xxr* 601. 602. 603. 604. 605. 606. pryi* 607. \r Xrr6 608.
Vy xfy* CAft ;£n* 610.
Xn* 611. buy. 612.
Table 3B cont.
O o /J 8 616. 617- 620. 622. 623. v \ ■V -—"t* 11 • • 614. 613. 615.
--QvV* u^OyY4 O 618. 619. xx° 621.
\S v* 624. 625. 626. 627.
Table 3B cont.
A H v* —"v cr o o o 631. 632. o* o 628. 629. S30- Example 340 trans. trans-4-C\ .3-Benzodtoxol-5-vn-2-(4-methoxvphenvn-1-fN-f3-methvlbut-1-vlVN-phenvhammocarbonvlmethvlVDvrrolidine-3- carboxvllc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.85 (d, J=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (m, 1H), 3.43-3.85 (m, 9H), 3.88s (3), 5.95 (s, 2H), 6.80 (d, J=7 Hz, 1H), 6.86 (dd, J=9 Hz, 1H), 6.89-7.00 (m, 2H), 6.97 (d, J=1 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.40-7.47 (m, 3H). MS (C.I.) m/e C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).
Example 341 trans, trans-4-( 1 ■3-Ben2odioxoi-5-vl)-2-f4-methoxvphenvn-1 N-butvl-N-(4-methvlphenvnaminocarbonvlmethvh-Pvrrolidine-3- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-1.47 (m, 4H), 2.37 (s, 3H), 2.83 (q, J=7 Hz, 2H), 3.06-3.25 (m, 2H), 3.40-3.50 (m, 1H), 3.51-3.63 (m, 3H), 3.80 (s, 3H), 3.87 (d, J=9 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=8 Hz, 1H), 6.80-6.86 (m, 3H), 6.89 (d, J=8 Hz, 2H), 1 0 7.04 (d, J=2 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H). MS (DCI) m/e 545 (M+H)+. Analysis calcd for C32H36N2O6: C, 70.57; H, 6.66; N, 0 5.14. Found: C, 70.20; H, 6.81; N, 5.03.
Example 342 1 5 trans. trans-4-( 1.3-Ben20dioxol-5-vn-2-(4-propoxvphenvn-W(YN.N- dibutvlamtno>carbonv0methvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1.H (300MHz, CDCI3 ) 8 7.30 (2H, d, J=9), 7.03 (1H, d, J=2), 6.83 (3H, m), 6.72 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 20 3.88 (2H, t, J=7), 3.73 (1H, d, J=12), 3.58 (1H, m), 3.53-3.20 (4H, m), 3.10-2.90 (4H, m), 2.72 (1H, d, J=15), 1.79 (2H, q, J=8), 1.50-1.05 (8H, m), 1.02 (3H, t, J=7), 0.87 (3H, t, J=7), 0.80 (3H, t, J=7). MS (DCI/NH3) m/e 539 (M+H)+. Anal calcd for C31H42N2O6 • 0.5H20: C, 67.98; H ^ ,7.91; N, 5.11. Found; C,68.24; H, 7.70; N, 5.03.
Example 343 trans.trans-4-H ■S-Benzodioxol-S-vn^-^-propvlphenvn-l-fffN-N-dibutvlammotearbonvhmethvnpvrrolidine-S-carboxviic acid Using the procedures described in Example 1, the title compound 30 was prepared. 1H (300MHz, CDC13 ) 8 7.31 (2H, d, J=9), 7.13 (2H, d, J=9), 7.03 (1H, d, J=2), 6.84 (1H, dd, J=6, 2), 6.73 (1H, d, J=9), 5.95 (1H, d, J=2), 5.93 (1H, d, J=2), 3.76 (1H, d, J=10), 3.60 (1H, m), 3.55-3.20 (4H, m), 3.13-2.88 (4H, m), 2.75 (1H, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q, J=8), 1.50-1.00 (8H, m), 0.92 (3H, t, J=7), 0.85 (3H, t, J=7), 0.78 (3H, t, 35 J=7). MS (DCI/NH3) m/e 523 (MH+). Anal calcd for C31H42N205-0.25 H2O ; C, 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.
Example 344 trans-trans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-r3-(N-propvf-N-n-pentanesulfonvlammo^propvnpvrrolidine-3-carhoxvHc acid Using the procedures described in Example 316, the title compound was prepared. 1H NMR (300MHz, CDCI3) 8 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.3-1.4 (m, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (m, 4H), 2.05-2.15 (m, 1H), 2.43-2.56 (m, 1H), 2.72-3.1 (m, 7H), 3.27-3.4 (m, 2H), 3.5-3.6 (m, 2H), 3.80 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.8-6.9 (m, 1H), 6. 85 (d, J= 9Hz, 2H), 7.02 (d, J=2Hz, 1H), 7.80 (d, J=9Hz, 2H).
Example 345 trans.trans-4-l 1.2-Dihvdrobenzofuran-5-vl>-2-(4-ethvlphenvn-1 -(((N.N-dibutvlaminotearbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) 8 7.40 (3H, m), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 3), 6.72 (1H, d, J=9), 5.28 (1H, d, J=12), 4.55 (2H, t, J=9), 4.15 (1H, d, J=18), 4.03 (2H, m), 3.75 (2H, m), 3.40 (2H, m), 3.20 (2H, t, J=9), 3.15 (1H, m), 3.10-2.90 (2H, m), 2.63 (2H, q, J=9), 1.47 (2H, m), 1.31 (4H, m), 1.12 (3H, t, J=8), 1.10 (2H,m), 0.92 (3H, t, J=9), 0.80 (3H, t, J=9). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N2O4 • 1.0 TFA: C ,63.86 ; H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.
Example 346 frans. frans-4-( 1.3-Benzodioxoi-5-vn-2-(4-methoxvphenvn-1-(((N-(3-pentvlVN-phenvlamino>carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. NMR (300 MHz, CD3OD) 8 0.93 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H), 1.33 (m, 4H), 2.72 (d, J=15.2 Hz, 1H), 2.81 (m, 1H), 3.11-3.23 (m, 2H), 3.45-3.57 (m, 2H), 3.79 (s, 3H), 3.83 (d, J=9.8 Hz, 1H), 4.54 (m, 1H), 5.92 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.83 (m, 3H), 6.98 (bs, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.07 (2), 7.37 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H33N2O6 • 0.35H20: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.
Example 347 frans. frans-4-f1.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-fff N-butvh-N-f3-trifluoromethvlphenvhamino)carbonvhmethvhpvrrolidine- 3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=6.6 Hz, 3H), 1.17-1.45 (m, 4H), 2.65 (d, J=16.5 Hz, 1H), 2.72 (m, 1H), 3.10 (t, J=9.5 Hz, 1H), 3.21-3.27 (m, 1H), 3.40 (dd, J=4.1, 9.9 Hz, 1H), 3.54 (m, 1H), 3.61-3.74 (m, 3H), 3.77 (s, 3H), 5.93 (s, 2H), 6.73-6.85 (m, 4H), 7.02 (m, 3H), 10 7.33 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H). MS (DCI) m/e 599 (M+H+). Anal calcd for C32H33F3N2O6: C, 64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57.
Example 348 trans, trans-4-f 1.3-Benzodioxol-5-vn-2-f4-methoxyphenvn-1 -fN- propvl-N-f4-morpholinvlcarbonvnaminocarbonvtmethvn-pyrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.78 (t, J=7 Hz, 3H), 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (m, 1H), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (m, 5H), 3.05 (3.70, J=m Hz, 11H), 3.76 (s, 3H), 5.88 (s, 2H), 6.67 (d, J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (m, 2H), 6.98 (d, J=2 Hz, 1H), 7.32-7.39 (m,2H). MS m/e calc'd for (M+H) C29H39N3O7: (M+H) 540.2710,. Found (M+H) 540.2713.
Example 349 trans. trans-4-(1.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-fc/s-2.6-dimethvlpiperidin-1-vncarbonvlmethvh-pvrrolidine-3-carboxvlic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.94 (d, J=7 Hz, 3H), 1.15d (7, 3H), 1.10-1.70 (m, 6H), 1.70-1.90 (m, 1H), 2.9. (d, J=13 Hz, 1H), 3.00-3.20 (m, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 (s, 3H), 3.80-4.00 (m, 1H), 4.10-4.65 (m, 2H), 5.95 (s, 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (m, 2H). MS m/e calc'd for (M+H)+ C28H35N2O6: (M+H) 495.2495. Found (M+H) 495.2493.
Example 350 trans, trans-2-f4-Methoxvmethoxvphenvn-4-( 1.3-benzodioxol-5-vh-1-f2-fN-propvl-N-n-pentanesulfonvlamino>ethvl1pvrrolidin6-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 57-59 °C. 1H NMR (CDCI3, 300 MHz) 8 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.28-1.36 (m, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 (t, J=7Hz, 2H), 2.20-2.32 (m, 1H), 2.72-3.10 (m, 7H), 3.18-3.41 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.48 (s, 3H), 3.52-3.59 (m, 1H), 3.68 (d, J=9Hz, 1H), 5.15 (s, 2H), 5.94 (s,2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=1Hz, J=8Hz, 1H), 6.98-7.02 (m, 3H), 7.32 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 591 (M+H)+.
Example 351 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-ff(N-f2-butvl>-N-phenvlamino)carbonvl)methvl)pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.79-0.89 (m, 6H), 1.14-1.21 (m, 1H), 1.25-1.40 (m, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 (t, J=9.0 Hz, 1H), 3.05-3.13 (m, 2H), 3.37-3.49 (m, 2H), 3.70 (s, 3H), 3.80 (d, J=9.8 Hz, 1H), 4.53 (m, 1H), 5.83 (m, 2H), 6.65 (d, J=8.1 Hz, 1H), 6.72 (-6.76, J=m Hz, 3H), 6.87 (m, 2H), 6.95 (d, J=1.7 Hz, 1H), 7.03 (m, 2H), 7.29 (m, 3H). MS (DCI) m/e 531 (M+H+). Anal calcd for C31H34N2O6 • 0.4H20: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.
Example 352 frans.frans-4-f1.3-Benzodioxol-5-vn-2-M-methoxvphenvn-1-(((N-(2-propvn-N-phenvlaminotearbonvnmethvhpvrrolidine-3-carboxvHc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.99 (d, J=6.8 Hz, 6H), 2.71 (d, J=15.6 Hz, 1H), 2.84 (m, 1H), 3.13-3.18 (m, 2H), 3.45-3.58 (m, 2H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, 1H), 4.80 (m, 1H), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (m, 3H), 6.96 (br s, 2H), 7.04 (d, J=1.7 Hz, 1H), 7.13 (m, 2H), 7.38 (m, 3H). MS (DCI) m/e 517 (M+H+). Anal calcd for C30H32N2O6 • 0.4H20 • O.O8CH3CO2C2H5: C, 68.65; H, 6.28; N, 5.28. Found: C, 68.64; H, 6.35; N, 5.14.
Example 353 frans.frans-4-f4-Propoxvphenvn-2-(4-methoxvphenvn-1-mN.N- riibutY»aminotearbonvnmethvnpvrro»dine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) 8 7.42 (2H, d, J=10Hz), 7.38 (2H, d, J=10Hz), 6.92 (2H, d, J=10Hz), 6.88 (2H, d, J=10Hz), 5.13 (1H, bd, ^0 J=12Hz), 4.02 (2H, m), 3.90 (2H, t, J=8Hz), 3.80 (3H, s), 3.71 (3H, m), W 3.40 (2H, m), 3.19 (1H, m), 3.10-2.90 (2H, m), 1.80 (2H, m), 1.48 (2H, m), 1.29 (4H, m), 1.13 (2H, m), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 (3H, t, J=9Hz). MS (DCI/NH3) m/e 525 (MH+). Anal calcd for C31H44N205-1 TFA : C, 62.06 H 7.10; N, 4.39 . Found: C, 62.43; H, 7.28; N, 4.39.
Example 354 trans.trans-4-(1 .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-((1.2.3.4-tetrahvdroouinolin-1 -vncarbonvnmethvnpvrrolidine-3-20 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 1.88 (quintet, J=6.5 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.87 (t, J=8.6 Hz, 1H), 3.14 (m, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1H), 3.53-3.70 (m, 3H), 3.72-3.78 (m, 1H), 3.77 (s, 3H), 25 3.86 (d, J«=9.6 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.83 (m, 3H), 6.98 (d, J»1.1 Hz, 1H), 7.02-7.23 (m, 6H). MS (DCI) m/e 515 (M+H+).
Anal calcd for C30H30N2O6 ■ O.3H2O • 0.15 CH3CO2C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.
Example 355 trans.t rans-3-f 3.4-Dimethoxvphenyn-4-M .3-benzodioxol-5-yn-1-(N.N-di(n-butvnamino>carbonvnmethvn-PvrroUdme-3-carboxvUc acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 64-65 °C. ^ H NMR 35 (CDCI3, 300MHz) 8 0.79 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H),1.07 (sextet, J=7Hz, 2H), 1.20-1.35 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, J=13.5Hz, 1H), 2.94-3.17 (m, 4H), 3.22-3.42 (m, 1H), 3.40-3.48 (m, 3H), 3.58-3.65 (m, 1H), 3.82 (s, 3H), 3.85 (s, 4H),5.92 (s, 2H), 6.73 (d, J=8Hz, 1H), 6.81 (d, J=8Hz, 1H), 6.86-6.96 (m, 3H), 7.07 (d, J=3Hz, 1H). MS (DCI/NH3) m/e 541 (M+H)+ Example 356 frans.frans-2-f3.4-Dimethoxvphenvl>-4-n.3-benzodioxol -5-vh-1-rg-(N-propyl-N-n-pentanesulfonvlamino^ethvllpvrrolidine-3-carbQyylin add Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 75-86 °C. 1H NMR (CD3OD, 300 MHz) 8 0.75 (t, J=7Hz, 3H), 0.82 (t, J=7Hz, 3H), 1.32-1.43 (m, 6H), 1.65-1.77 (m, 2H), 3.0-3.09 (m, 4H), 3.23-3.27 (m, 2H), 3.44 (t, J=6Hz, 1H), 3.47-3.56 (m, 2H), 3.78 (d, J=9Hz, 1H), 3.83-3.93 (m, 2H), 3.87 (s, 3H), 3.92 (s, 3H), 4.63 (d, J=13Hz, 1H), 5.97 (s, 2H), 6.82 (d, J=7Hz, 1H), 6.93 (d, J=7Hz, 1H), 7.06 (d, J=7Hz, 1H), 7.08 (d, J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, 1H), 7.27 (d, J=3Hz, 1H). MS (DCI/NH3) m/e 591 (M+H)+.
Example 357 trans. fran.«;-2-f3.4-Dimethoxvphenvn-4-( 1.3-benzodioxol-5-vl>-1 -f2-fN-oropyl-N-n-hexanesulfonvlamino^ethvllPvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 65-66 °C. 1H NMR (CDCI3, 300 MHz) 8 0.80 (t, J=7Hz, 3H), 0.89 (t, J=7Hz, 3H), 1.23-1.48 . (m, 6H), 1.43 (sextet, J=:7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (m, 1H), 2.73-3.10 (m, 7H), 3.19-3.32 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.59 (m, 1H), 3.68 (d, J=9Hz, 1H),3.87 (s, 6H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.79-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.02 (s, 1H). MS (DCI/NH3) m/e 605 (M+H)+.
Examole 358 trans. fra/?s-2-r4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-rg.-(phthaHmidotethvn-Pvrrolidine-3-carboxvlic acid The compound of Example 1C (250 mg), N-bromoethylphthalimide (206 mg), and diisopropylethylamine (175 mg) were dissolved in 1 mL of acetonitriie and heated for 2.5 hours at 95 °C. Toluene was added, and the mixture was washed with KHCO3 solution. The solution was dried (Na2S04) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 10 mg of an intermediate ethyl ester which was hydroiyzed by the method of Example 1D to give 130 mg of the title compound as a white powder. 1H NMR (300 MHz, CDCI3) 8 3.12-3.26 (m, 2H), 3.60-3.75 (m, 2H), 3.70 (s, 3H), 3.98-4.12 (m, 2H), 4.45-4.55 (m, 1H), 4.69 (d, J=9Hz, 1H), 4.76-4.88 (m, 1H), 5.96 (s, 2H), 6.55 (d, J=8Hz, 1H), 6.60-6.70 (m, 3H), 6.79 15 (d, J=8Hz, 1H), 7.05-7.45 (m, 5H), 7.75 (d, J=7Hz, 1H).
Example 359 trans.trans-4~("\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-(ffN-f2-pentvh-N-phenvlamino)carbonvhmethvnpvrrolidine-3-carboxvlic acid 20 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.86-0.98 (m, 6H), 1.17-1.22 (m, 1H), 1.23-1.41 (m, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1H), 2.83 (m, 1H), 3.10-3.21 (m, 2H), 3.45-3.60 (m, 2H), 3.79 (s, 3H), 3.86 (m, 1H), 4.74 (m, 1H), 5.91 (m, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (m, 2H), 7.04-25 7.14 (m, 3H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N2O6 • 0.25 CH3CO2C2H5: C, 69.95; H, 6.76; N, 4.94. Found: C,. 70.03; H, 6.54; N, 4.78.
Example 360 3 0 trans.trans-4-( 1.3-Benzodioxol-5-vn-2-(4-methoxvphenvlV1-(N- butvl-N-f2-naphthvnaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.83 (t, J=7 Hz, 3H), 1.23-35 1.39 (m, 4H), 1.40-1.55 (m, 3H), 2.60-2.72 (m, 2H), 3.00-3.80 (m, 5H), 3.66 (s, 3H), 5.87 (s, 2H), 6.39 (d, J=9 Hz, 2H), 6.74-6.85 (m, 3H), 7.17 (d, J=2 H2, 1H), 7.40 (dd, J=8 Hz, 1H), 7.52-7.62 (m, 3H), 7.80-7.90 (m, 1H), 7.90-8.00 (m, 2H). MS (DCI) m/e 581 (M+H)+. Analysis calcd for C35H36N2O6 ■ 0.3 H2O: 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-Propoxvphenvn-4-M .3-benzodioxol-5-vtM-r2-rN-propvl-N-n-pentanesulfonvlamino^ethvllpvrrolidine-3-carhoyylic acid Using the procedures described in Example 66, the title compound j 0 was prepared and isolated as a white solid, m.p. 53-54 °C. 1H NMR (CDCI3, 300MHz) 8 0.79 (t, J=7Hz, 3H), 0.89 (t, J^Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (m, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (m, 2H), 1.80 (sextet, 2H), 2.23-2.33 (m, 1H), 2.72-2.93 (m, 5H), 3.05 (septet, Js=7Hz, 2H), 3.15-3.35 (m, 2H), 3.42 (d, J=9Hz, 1H), 3.54-3.62 15 (m, 1H), 3.67 (d, J=9Hz, 1H), 4.90 (t, J=7Hz, 2H), 5.95 (s, 2H), 6.73 (d, Js=8Hz, 1H), 6.85 (d, J=8Hz, 2H), 7.02 (s, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) m/e 589 (M+H)+.
Example 362 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1 -((2-methvlindolin-1-vncarbonvhmethvhpvrroHdine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereomers, 0.95 (m, 1.5 (CH3 )), 1.05 (d, 6.3H, 1.5 (CH3)), 2.62 (m, 25 1H), 3.01 (m, 2H), 3.14-3.25 (m, 1H), 3.37-3.52 (m, 1.5H), 3.56-3.80 (m, 2H), 3.65 (s, 1.5 (CH3O)), 3.76 (s, 1.5 (CH3O)), 3.93 (m, 0.5H), 4.05-4.13 (m, 0.5H,), 4.42 (m, 0.5H), 4.65-4.74 (m, 1H), 5.91 (m, 2H), 6.72 (d, J=8.1 Hz, 0.5H), 6.75 (m, 0.5H), 6.85 (m, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.00-7.06 (m, 2H), 7.14 (t, J=7.7 Hz, 1H), 7.21 (t, J=6.6 Hz, 1H), 7.38 (m, 2H), 7.99 30 (m, 1H). MS (DCI) m/e 515 (M+H+). Anal calcd for C30H30N2O6 • 0.35H20 • 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.
Example 363 trans.trans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-fg-hvdroxv-3-propvlhex-1 -vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 5 was prepared. "*H NMR (300 MHz, CD3OD) 8 1.06 (m, 6H), 1.26-1.60 (m, 9H), 3.16 (dd, J=10.9, 12.6 Hz, 1H), 3.18 (d, J=11 Hz, 1H), 3.44 (d, J=2.0 Hz, 1H), 3.61 (t, J=11 Hz, 1H), 3.73 (t, J=11.0 Hz, 1H), 3.85 (m, 1H), 3.96-4.17 (m, 2H), 4.02 (s, 1.5 (CH3O diastereomer)), 4.03 (s, 1.5 (CH3O diastereomer)), 6.15 (s, 2H), 7.01 (d, J=8.1 Hz, 0.5H), 7.00 (d, J=8.1 Hz, 10 0.5H), 7.10 (m, 1H), 7.23 (m, 3H), 7.77 (m, 2H). MS (DCI.) m/e 484 W (M+H+). Anal calcd for C28H37NO6 • 0.33 H3PO4: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.
Example 364 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1 -(((N-(4-heptvn-N-f3.4-dimethoxvbenzvnamino^carbonvnmethvnpvrroHdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 81:1 mixture of rotamers, 0.61 20 (t, J=7.1 Hz, 1.5H), 0.72 (7.3, 1.5H), 0.76 (t, J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.5H), 1.05-1.60 (m, 8H), 2.84-3.10 (m, J=2.5, 3.18, t, 9.7 Hz, 0.5H), 3.41-3.52 (m, 2H), 3.47-3.69 (m, 2H), 3.66 (s, 1.5H), 3.73 (s, 1.5H), 3.77 ^ (s, 1.5H), 3.78 (s, 1.5H), 3.79 (s, 1.5H), 3.86 (d, J=9.8 Hz, 0.5H), 4.19 (d, ^ J=17.7 Hz, 0.5H), 4.29 (d, J=15.2 Hz, 0.5H), 4.40-4.49 (m, 0.5H), 4.47 (d, 25 J=15.3 Hz, 0.5H), 4.60 (d, J=17.6 Hz, 0.5H), 5.93 (m, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.5H), 6.52 (d, J=2.0 Hz, 0.5H), 6.74 (m, 2.5H), 6.80 (s, 1H), 6.83-6.88 (m, 1H), 6.92 (m, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (m, 1H), 7.36 (m, 1H). MS (DCI) m/e 647 (M+H+). Anal calcd for C37H46N2O8: C, 68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.
Example 365 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-mndolin-1 -vhcarbonvnmethvhpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 35 was prepared. 1H NMR (300 MHz, CD3OD) 82.97 (dd, J=8.1, 9.5 Hz, 1H), 3.10 (t, J=8.1 Hz, 2H), 3.16-3.22 (m, 2H), 3.51-3.68 (m, 3H), 3.73 (m, 3H), 3.83-4.05 (m, 3H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.86 (m, 3H), 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 (d, J=0.7 Hz, 1H), 7.11 (m, 1H), 7.18 (d, J=7.1 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 8.02 (8.1, 1H). MS (C.I.) m/e 501 (M+H+). Anal calcd for C29H28N2O6 • 0.5 H2O *0.15 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.
Exempt? 36$ trans. frans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvh-1-fN-butvl-N-(2-chloroDhenvnaminocarbonvlmethvhpvrrolidlne-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 80.89 (dt, J=7 Hz, 3H), 1.23-1.51 (m, 4H), 2.52-4.00 (m, 8H), 3.78 (d, J=6 Hz, 3H), 5.92 (d, J=6 Hz, 2H), 6.70-6.87 (m, 4H), 7.02-7.21 (m, 4H), 7.27-7.52 (m, 3H). MS (DCI) m/e 565 (M+H)+. Analysis calcd for C31H32N2O6CI • O.6H2O: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.
Example 367 trans.frans-2-{4-Methoxphenvn-4-M.3-benzodioxol-5-vn-1 - (3.4.5-trimethoxvbenzvnpvrrolidine-3-carboxvHc acid The compound resulting from Example 1C (0.25 g) was reacted with 0.169 g of 3,4,5-trimethoxybenzy! chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitriie for 2 hours at room temperature. The resulting ester was isolated and then hydroiyzed by the method of Example 1D to give 0.193 g of the title compound, m.p. 108-110 °C. 1H NMR (300 MHz, CDCI3) 82.75 (t, J=9Hz, 1H), 2.95-3.05 (m, 2H), 3.20 (d, J=11 Hz, 1H), 3.45-3.55 (m, 1H), 3.7-3.8 (m, 2H), 3.84 (s, 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.30-6.35 (m, 1H), 6.90 (d, J=9Hz, 2H), 7.13 (d, J=2Hz, 1H), 7.43 (d, J=9Hz, 2H).
Example 368 frans.frans-4-M.3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-fN-butvl-N-(3-chlorophenvnaminocarbonv[methvn-pvrroHdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) S0.89 (t, J=7 Hz, 3H), 1.20-1.42 (m, 4H), 3.42-3.87 (m, 9H), 3.9 (s, 3H), 5.96 (s, 2H), 6.75 (7.10, J=m Hz, 7H), 7.33-7.50 (m, 4H). MS (C.I.) m/e 565(M+H). Analysis calcd for C31H33N2O6CM.OCF3COOH: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41; H, 4.99; N, 4.08.
Example 369 frans.frans-2-(4-Methoxphenvn-4-n.3-benzodioxol-5-vn-1-r2-fdi-n-butvlamino^Pvrimidin-4-vl1pvrrolidine-3-carboxvlic acid The compound resulting from Example 1C (0.25 g) was reacted with 0.11 g of 2,4-dichloropyrimidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitriie for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-methoxpheny!)-4-(1,3-benzodioxol-5-yl)-1 -(2-chloro-4-pyrimidyl)-pyrrolidine-3-carboxylate. This compound was reacted with 1 mL of dibutylamine in 2 mL of toluene at 125 °C for 17 hours. The resulting ethyl ester was hydroiyzed by the method of Example 1D to give 0.142 g of the title comopund as a white powder. 1H NMR (300 MHz, CDCI3) 80.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (m, 1H), 3.3-3.5 (br, 2H), 3.55-3.67 (m, 2H), 3.75 (s, 3H), 4.6 (br, 1H), 5.2 (br, 1H), 5.45 (br, 1H), 5.87 (s, 2H), 6.3 (br, 1H), 6.67 (d, J=8Hz, 1H), 6.7-6.85 (m, 4H), 7.10 (d, J=9Hz, 2H).
Example 370 frans.frans-4-n.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-ff(N-(2-methvlbut-2-vn-N-phenvlamino>carbonvhmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.90 (t, J=7.5 Hz, 3H), 1.12 (S, 3H), 1.14 (s, 3H), 2.06 (q, J=7.5 Hz, 2H), 2.73 (d, J=15.3 Hz, 1H), 2.91 (t, J=9.5 Hz, 1H), 3.11 (d, J=15.6 Hz, 1H), 3.21 (t, J=8.8 Hz, 1H), 3.50- 3.61 (m, 2H), 3.80 (s, 3H), 4.00 (d, J=10.2 Hz, 1H), 5.91 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (m, 3H), 6.93 (m, 1H), 6.98 (m, 1H), 7.03 (d, J=1.7 Hz, 1H), 7.17 (m, 2H), 7.36 (m, 3H). MS (DCI) m/e 545 (M+H+). Anal calcd for C32H36N2O6: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; 5 N, 4.97.
Example 371 trans.trans-2-(4-EthvlPhenvn-4-(5-indanvn-1-(N.N-dibutvlaminotearbonvlmethvnpvrroHdine-3-carboxvlic acid 10 Using the procedures described in Example 1, the title compound ) was prepared. 1H (300MHz, CDCI3) 8 7.25 (3H, m), 7.21 (1H, d, 3Hz), 7.17 (3H, m), 3.80 (1H, d, 10Hz), 3.65 (1H, ddd, 6, 5, 3Hz), 3.4 (4H, m), 3.10 (2H, m), 2.98 (2H, m), 2.88 (5H, m), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H,m), 1.42 (2H, m), 1.32 (1H, m), 1.21 (3H, t, 7Hz), 15 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) m/e 505 (M+H+). Anal calcd for C32H44N2O3: 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-Difluorophenvn-4-f1.3-benzodioxol-5-vl>-1-(ffN.N-dihiJtvlaminotearbonvnmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 62-63 °C. 1H NMR (CDCI3, 300 MHz), 8 0.83 (t, J=7Hz, 3H), 0.88 (t, J«7Hz, 3H), 1.13 25 (sextet, J=7Hz, 2H),1.20-1.32 (m,3H), 1.36-1.49 (m,3H), 2.85-2.93 (m,2H), 2.98-3.23 (m, 4H), 3.36-3.45 (m, 3H), 3.58-3.66 (m 1H), 3.94 (d, J=8Hz, 1H), 5.93 (s, 2H), 6.72 (d, J=7.5Hz, 1H), 6.84 (dd, J=1Hz, J=7.5Hz, 1H), 6.98 (d, J=7.5Hz, 1H), 7.08-7.15 (m, 2H), 7.22-7.28 (m, 1H). MS (CDI/NH3) m/e517 (M+H)+ Example 373 trans.trans-2-(3.4-Dii\uoroohenv\)-4-(1.3-benzodioxol-5-vl)-1-r2-(N-propvl-N-n-pentanesulfonvlamino^ethvllpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 35 was prepared and isolated as a white solid, m.p. 71-72 °C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.25-1.38 (m, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H), 2.26-2.36 (m, 1H), 2.72-2.95 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.34 (m, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (m, 1H), 3.71 (d, J=9Hz, 1H), 5.96 (s, 2H), 6.75 (d, J=9Hz, 1H), 3.82 (dd„ J=2Hz, J=r9Hz, 1H), 5.96 (d, J=2Hz, 5 1H), 7.09-7.18 (m, 2H), 7.23-7.34 (m, 1H). MS (CDI/NH3) m/e567 (M+H)+ Example 374 trans.frans-4-M .3-Benzodioxol-5-vn-2-(ethoxvmethvn-1-mN.N-10 dibutylaminQ>carfaonvl)methvnpvrrolldine-3-carboxvHc acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.53. 1H NMR (CDCI3, 300 MHz, rotameric forms) 5 0.70 (t, J=7Hz), 0.80 (t, J=7Hz) and 0.96-1.04 (m, 6H total), 1.04-1.75 (m, 11H), 1.34-1.53 (br m, 4H), 2.65 (AB) and 15 2.80-3.08 (m, 2H total), 3.10-3.82 (br m, 12H), 4.03 (m) and 4.22-4.45 (br m, 2H total), 5.90 (s) and 5.91 (s, 2H total), 6.65-6.84 (m) and 6.93 (m) and 6.99 (m, 3H total). MS (FAB) m/e 463 (M+H)+. Anal calcd for C25H38N2O6 • 1.5 H2O: C, 61.33; H, 8.44; N, 5.72. Found; C, 61.28; H, 7.78; N, 5.62.
Example 375 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-(n-butvl\-1-f((N.N-dibutvlamino^carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 25 was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2Cl2) Rf = 0.37. 1H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.71 (t, J=7Hz) and 0.77-1.05 (m, 9H total), 1.05-1.20 (m, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (m, 1H), 2.87-3.00 (m, 1H), 3.05-3.60 (m, 5H), 3.60-3.80 (br m, 2H), 3.88-4.05 (br m, 1H), 4.28 (br d, J=15Hz, 1H total), 5.90 (s) and 30 5.92 (s, 2H total), 6.67-6.82 (m, 3H total). MS (FAB) m/e 461 (M+H)+. Anal calcd for C26H40N2O5 • 1.75 H2O: C, 63.45; H, 8.90; N, 5.69. Found: C, 63.18; H, 8.22; N, 5.60.
Examole 376 trans. trans-4-(1.3-Benzodioxol-5-vn-2-(2-methvlbutvn-1 -fffN.N-dibutvlamino)carbonvnmethvnpvrrolidine-3-carboxvlic 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. NMR (CDCI3, 300 MHz, rotameric forms and mixture of diastereomers) 5 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, 1H), 2.87-3.01 (br m, 1H), 3.06-3.82 (br m, 7H), 3.90-4.40 (br m, 2H), 5.90 (s) and 5.92 (s, 2H J 0 total), 6.67-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+.
Example 377. trans.trans~4-l"\ .3-Benzodioxol-5-vn-2-(3-methvlbutvh-1-(7fN.N-dibutvlamino^carbonvhmethvhpyrrolidine-3-carboxvlic acid 15 Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2Cl2) Rf = 0.41. ">H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.73 (t, J=7Hz) and 0.77-1.05 (m, 12H total), 1.07-1.75 (m, approx. 14H plus H2O), 2.48-2.63 (m, 1H), 2.87-3.05 (m, 1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, Js=15Hz, 1H), 5.89 (s) and 5.93 (s, 2H total), 6.65-6.90 (m, 3H total). MS (FAB) m/e 475 (M+H)+.
Example 378 frans.frans-2-(4-Methoxvphenvn-4-n .3-benzodioxol-5-vn-1 -\2-( N-25 propvl-N-^N-methvl-N-propvlamino^sulfonvhamino^ethvllpvrrolidine- 3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 58-59 °C. 1H NMR (CDCI3, 300MHz) 8 0.78 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.27 (sextet, 30 J=7Hz, 2H), 1.48 (m, 4H), 2.22-2.30 (m, 1H), 2.62 (s, 3H), 2.68-2.78 (m, 1H), 2.84-3.03 (m, 5H), 3.08-3.31 (m, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (m, 1H), 3.63 (d, J=9Hz, 1H),3.79 (s, 3H), 5.95 (s, 2H), 3.73 (d, J=8Hz, 1H), 6.83 (dd, J=2Hz, J=8Hz, 1H), 3.87 (d, J=9Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.33 (d, J=9Hz, 2H). MS (DCI/NH3) m/e 576 (M+H)+.
Example 379 frans.frans-2.4-Di(3.4-difluorophenvn-1-mN.N-dibutviaminotoarbonvhmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3 ) 8 7.35 (2H, m), 7.18 (4H, m), 4.87 (1H, d, J=12), 4.00-3.60 (5H, m), 3.60-3.10 (3H, m), 3.10-2.90 (2H, m), 1.45 (2H, m), 1.29 (4H, m), 1.15 (2H, m), 0.91 (3H, t, J«9), 0.83 (3H, t, J=9). MS (DCI/NH3) m/e 509 (M+H+). Anal calcd for C27H32F4N203* 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.66.
Example 380 trans.trans-4-(3A-Dimethvlphenvn-2-(4-methoxvphenvn-1-fffN.N-dibutvlamino^carbonvnmethvhpvrrolidine-3-carboxvtic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 8 7.43 (2H, d, J=9), 7.25 (1H, bs), 7.18 (1H, dd, Js=8, 3), 7.11 (1H, d, J=9), 6.90 (2H, d, J=10), 5.48 (1H, d, J=12), 4.26 (IH, d, J==18), 4.16 (2H, m), 3.83 (2H, m), 3.81 (3H, s), 3.56 (1H, bd, J=18), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 2.24 (3H, s), 2.22 (3H, s), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 495 (M+H+). Anal calcd for C30H42N2O4- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.
Example 381 frans. frans-2.4-Di(3-fluoro-4-methoxvphenvn-1-fffN.N-dibutvlamino^carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3 ) 8 7.20 (2H, m), 7.17 (2H, m), 6.93 (2H, m), 5.48 (1H, m), 4.26 (1H, m), 4.16 (2H, m), 3.83 (2H, m), 3.87 (6H, s), 3.56 (1H, m), 3.37 (1H, m), 3.20 (1H, m), 2.96 (2H, m), 1.47 (2H, m), 1.27 (4H, m), 1.10 (2H, m), 0.93 (3H, t, J=9), 0.81 (3H, t, J=9). MS (DCI/NH3) m/e 533 (M+H+). Anal calcd for C29H38F2N205* 0.75 H2O: C, 63.78; H, 7.29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99. frans.frans-4-M.3-Benzodioxol-5-vn-2-(4-methoxvDhenvlM-mN-f2-pentv».N-f3-methvlphenvnamino^carbonvhmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.90 (m, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.13-1.37 (m, 4H), 2.30 (s, 3H), 2.34 (s (CH3 rotamer)), 2.73-2.91 (m, 2H), 3.17-3.26 (m, 2H), 3.32-3.62 (m, 2H), 3.77-4.08 (m, 1H), 3.80 (s, 3H), 4.71 (m, 1H), 5.92 (m, 2H), 6.61-6.84 (m, 6H), 7.04-7.16 10 (m, 3H), 7.23-7.29 (m, 2H). MS (DCI) m/e 559 (M+H+). Anal calcd for A C33H38N2O6 ■ 0.35 H2O • 0.05 CH3CO2C2H5: 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-vn-2-f4-methoxvphenvn-1-(N-butvl-N-M-naphthvnaminocarbonvtmethvnpvrrolidine-3-carboxvlic add Using the procedures described in Example 1, the title compound was prepared. ">H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-20 1.40 (m, 2H), 1.40-1.60 (m, 2H), 2.42-2.80 (m, 2H), 2.85-4.00 (m, 6H), 3.77 (d, J=1.5 Hz, 3H), 4.05-4.20 (m, 1H), 5.94 (d, J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 (m, 4H), 6.95-7.02 (m, 2H), 7.17 (dd, 8H, ^ 1/2), 7.25 (dd, 8H, 1/2), 7.38-7.60 (m, 4H), 7.87-8.00 (m, 2H). MS W (E.S.I.) m/e (M+H) 581. Analysis calcd for C35H36N2O6 • 1.4 H2O: C, 25 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.
Example 384 frans.frans-2-(4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-f2-(N-phenvl-N-n-hexanesuifonvlaminotethvnpvrrolidine-3-carboxvlic acid 30 Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid, m.p. 67-68 °C. 1H NMR (CD3OD, 300 MHz) 8 0.88 (t, J=7Hz, 3H), 1.25-1.40 (m, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (m, 1H), 2.64-2.88 (m, 3H), 3.02 (sextet, J^Hz, 2H), 3.44-3.53 (m, 2H), 3.58 (d, J=9Hz, 1H), 3.56-3.75 (m, 1H), 35 3.78 (s, 3H), 3.88-3.98 (m, 1H), 5.93 (s, 2H), 6.72 (d, J=9Hz, 1H), 5.78- .84 (m, 3H), 6.96 (d, J=2Hz, 1H), 7.20 (d, J=9Hz, 2H), 7.27-7.36 (m, 5H). MS (DCI/NH3) m/e 609 (M+H)+.
Example 385 traris.trans-A-fl .3-Benzodioxol-5-vh-2-(4-methoxvphenvn-1-(2-methvM.2.3.4-tetrahvdroauinolm-1-vncarbonvlmethvnpvrrolidine-3- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 1.03 (m, 3H), 1.10-1.45 (m, JO 1H), 2.10-2.85 (m, 4H), 2.90-4.00 (m, 7H), 3.76 (s, 1.5H), 3.77 (s, 1.5H, ~ isomer), 5.90 (m, 2H), 6.70-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31H32N2O6 * 0.3 H2O: C, 69.73; H, 6.15; N, 5.25. Found: C, 69.74; H, 6.10; N, 5.01.
Example 386 trans.trans-4-("\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-(3-butvl-hepf-2-en-1 -vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. "*H NMR (300 MHz, CD3OD) 8 0.86 (t, J=7.0 Hz, 3H), 0.90 20 (t, J=7.0 Hz, 3H), 1.20-1.41 (m, 8H), 1.95-2.06 (m, 4H), 3.24 (d, J=11.0 Hz, 1H), 3.51-3.59 (m, 3H), 3.60-3.71 (m, 1H), 3.77-3.84 (m, 1H), 3.81 (s, 3H), 4.45 (d, J=11.0 Hz, 1H), 5.52 (t, J=7.4 Hz, 1H), 5.93 (s, 2H), 6.77 (d, J=8.1 Hz, 1H), 6.87 (dd, J=1.8, 8.1 Hz, 1H), 6.99 (m, 3H), 7.46 (m, 2H). MS (DCI) m/e 494 (M+H+). Anal calcd for C30H39NO5: C, 72.99; H, 25 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.
Example 387 trans, trans-2-(3-Fluoro-4-methoxvphenvn-4-f 1.3-benzodioxol-5-vn-1.fg.rN-nropvl-N-n-hexanesulfonvlamino^ethvl1pvrrQlidine-3-30 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 63-65 °C. 1H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=6Hz, 3H), 1.23-1.47 (m, 6H), 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 35 (m, 1H), 2.70-2.93 (m, 5H), 2.96-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.42 (t, Jss8Hz, 1H), 6.96 (s, 1H), 7.12 (d, J=9Hz, 1H), 7.17 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+.
Example 388 trans.trans~4-C\ .3-Benzodioxol-5-vn-2-M-methoxvphenvn-1-(f3-pvridvnmethvnpvrrolidine-3-carbQxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 2.87 (m, 2H), 3.04 (dd, J=3.2, 10 9.7 Hz, 1H), 3.21 (d, J=13.7 Hz, 1H), 3.51 (m, 1H), 3.76-3.85 (m, 2H), # 3.79 (s, 3H), 5.90 (m, 2H), 6.71 (m, 1H), 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (m, 3H), 7.36-7.45 (m, 3H), 7.81 (m, 1H), 8.39 (m, 1H), 8.46 (dd, J=1.4 Hz, 1H). Anal calcd tor C25H24N2O5 • 0.70 H2O • 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-Hexv\)-4-C\ .3-benzodioxol-5-vh-1 -fN.N-dibutvlaminocarbonvlmethvhpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 20 was prepared. ^H NMR (CDCI3, 300 MHz) 8 0.82-1.00 (m, 9H), 1.20-1.40 (m, 12H), 1.45-1.60 (m, 4H), 1,70-1.90 (br m, 2H), 3.10-3.46 (m, 6H), 3.65 (t, J=10.8 Hz, 1H), 3.76 (t, J=11.0 Hz, 1H), 3.92-4.06 (m, 2H), ^ 4.14-4.34 (m, 2H), 5.94 (s, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.79 (dd, J=8.1, • 1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS(DCl/NH3) m/e 489 (M+H)+. Anal 25 calcd for C28H44N2O5 • 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-(i .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-(f(N-(2-30 pentvn-N-(4-fluoro-3- methvlphenvnamino)carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. *>H NMR (300 MHz, CD3OD) 8 0.92 (m, 3H), 0.97 (t, J=7.1 Hz, 3H), 1.13-1.40 (m, 4H), 2.22 (m, 3H), 2.58-2.74 (m, 1H), 2.78-2.87 35 (m, 1H), 3.09-3.25 (m, 2H), 3.39-3.60 (m, 2H), 3.70-3.90 (m, 1H), 3.80 (s, 3H), 4.70 (m, 1H), 5.93 (m, 2H), 6.70-6.76 (m, 1H), 6.75 (dd, J=1.4, 8.1 Hz, 1H), 6.80-6.94 (m, 4H), 6.96-7.13 (m, 4H). MS (DCI.) m/e 577 (M+H+). Anal calcd for C33H37FN2O6 • 0.25 H2O: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.
Example 391 trans.trans-4-("\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1 -((2-pvridvhmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 2.97 (dd, J=7.9, 9.7 Hz, 1H), 3.04 (t, J=9.6 Hz, 1H), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 (d, J=14.0 Hz, 1H), 3.59 (m, 1H), 3.78 (s, 3H), 3.96 (d, J=9.9 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 5.90 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.83 (dd, J=1.7, 7.9 Hz, 1H), 6.92 (m, 2H), 6.96 (d, J=1.8 Hz, 1H), 7.28 (m, 1H), 7.44 (m, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.80 (dt, J=1.8, 7.7 Hz, 1H), 8.42 (m, 1H). MS (DCI) m/e 433 (M+H+). Anal calcd for C25H24N2O5 • 0.35 H2O: C, 68.43; H, 5.67; N, 6.38.
Found: C, 68.44; H, 5.61; N, 6.24.
Example 392 trans. frans-2-(3-Phenvlpropvn-4-M .3-benzodioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3, 300 MHz) 8 0.89-0.97 (m, 6H), 1.22-1.36 (m, 4H), 1.41-1.55 (m, 4H), 1.63-1.95 (m, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (m, 7H), 3.53-3.60 (m, 2H), 3.65-3.76 (m, 1H), 3.82-3.90 (m, 1H), 3.96-4.10 (m, 1H), 5.92 (s, 2H), 6.71 (d, J=8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.5 Hz, 1H), 6.86(d, J=1.2 Hz, 1H), 7.10-7.28 (m, 5H).
MS(DC!/NH3) m/e 523 (M+H)+. Anal calcd for C31H42N2O5 • 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.
Example 393 frans-frans-2-(4-Methoxv-3-fluorophenvn-4-(7-methoxv-1.3-benzodioxol-5-vn-1-r(N.N-difn-butvhamino^carbonvlmethvllpyrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 115-117 °C. "*H NMR (300 MHz, CDCI3) 8 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.5 (m, 8H), 2.85 (d, J=13Hz, 1H), 2.90-3.17 (m, 5H), 3.20-3.35 (m, 1H), 3.35-3.50 (m, 3H), 3.55-3.65 (m, 1H), 3.84 (d, J=10Hz, 1H), 3.87 (s, 3H), 3.92 (s, 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.90 (t, J=8Hz, 1H), 7.05-7.20 (m, 2H).
Example 394 trans-trans-2-( 1.4-Benzodioxan-6-vh-4-f7-methoxv-1.3- benzodioxot-5-vlV1-rfN.N-dirn-butvl^amino^carbonvlmethvllDvrrolidine-3-carboxviic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 107-110 °C. 1H NMR (300 MHz, CDCI3) 5 0.82 (t, J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.05-1.50 (m, 8H), 2.75 (d, J=13Hz, 1H), 2.90-3.12 (m, 4H), 3.32-3.60 (m, 5H), 3.69 (d, 8Hz, 1H), 3.90 (s, 3H), 4.23 (s, 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.78-6.93 (m ,3H).
Example 395 trans.trans-4-( 1.3-Benzodioxol-5-vn-2-f4-methoxvphenvl>-1 -(3-butvl-2-f luoro-hept-2-en-1 -vhpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.84 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H), 1.16-1.37 (m, 8H), 1.83 (t, J=8.5 Hz, 2H), 2.03-2.08 (m, 2H), 2.76-2.92 (m, 2H), 3.02 (t, J=9.3 Hz, 1H), 3.32-3.42 (m, 2H), 3.50 (m, 1H), 3.71 (d, J=9.2 Hz, 1H), 3.78 (s, 3H), 5.91 (m, 2H), 6.72 (d, J=7.8 Hz, 1H), 6.83 (dd, J=1.7, 8.1 Hz, 1H), 6.90 (m, 2H), 7.02 (d, J=1.7 Hz, 1H), 7.34 (m, 2H). MS (DCI) m/e 512 (M+H+). Anal calcd for C30H38FNO5: C, 70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.
Example 396 frans.frans-2-(3-Fluoro-4-ethoxvphenvn-4-(1.3-benzodioxol-5-vn-1-r2-fN-propvl-N-n-pentanesulfonvlamino^ethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 65-66 °C. 1H NMR (CDCI3, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.26-1.36 (m, 4H), 1.41-1.52 (m, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (m, 1H), 2.69-2.96 (m, 5H), 2.97-3.12 (m, 2H), 3.16-3.37 (m, 2H), 3.43 (d, J=9Hz, 1H), 3.52-3.59 (m, 1H), 3.66 (d, J=9Hz, 1H), 4.08 (q, J=7Hz, 2H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.92 (t, J^Hz, 1H), 6.97 5 (s, 1H), 7.07 (d, J=8Hz, 1H), 7.15 (d, J=12Hz, 1H). MS (DCI/NH3) m/e 593 (M+H)+.
Example 397 trans. frans-2-(4-Methoxv-3-fluorophenvl)-4-f7-methoxv-1.3-10 benzodioxol-5-vn-1-l7N-butvl-N- £ propvlamino^carbonvlmethvllPvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid, m.p. 118-120 °C. ^H NMR (300 MHz, CDCI3) 8 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (m, 8H), 15 2.80-3.50 (m, 9H), 3.55-3.65 (m, 1H), 3.82 (d, J= 10Hz, 1H), 3.85 (s, 3H), 3.92 (s, 3H), 5.96 (s, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 6.90 (t, J=8Hz, 1H), 7.08-7.22 (m, 2H).
Example 398 trans.frans-4-M .3-benzodioxol-5-vn-2-f4-methoxyphenvn- 1-fN-butyl-N-(4-chlorophenvnaminocarbonvlmethvnpvrroHdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ">H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-1.50 (m, 4H), 2.66-4.00 (m, 9H), 3.81 (s, 3H), 5.95 (s, 2H), 6.77 (d, J=7 Hz, 1H), 6.85 (d, J=8 Hz, 3H), 7.05 (m, 5H), 7.33-7.42 (m, 2H). MS (C.I,), m/e 565 (M+H). Analysis calcd for C31H33N2O6CI • 0.25 H3PO4: C, 63.16; H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53.
Example 399 trans.frans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-f4-methvl-1 ■2.3.4-tetrahvdroauinolin-1-vhcarbonvlmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound 35 was prepared. 1H NMR (300 MHz, CD3OD) 8 1.27 (d, J=7 Hz, 1.5H), 1.28 (d, 7H, 1.5-diastereomer), 1.39-1.55 (m, 1H), 2.02-2.15 (m, 1H), 2.60- 3.25 (m, 5H), 3.33-4.00 (m, 5H), 3.78 (s, 3H), 5.92 (d, J=3 Hz, 2H), 6.73 (dd, J=8 Hz, 1H), 6.75-6.90 (m, 3H), 6.91-7.35 (m, 7H). MS (DC!) m/e 529 (M+H)+. Analysis calcd for C31H32N2O6: 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-methoxvphenvl>>-4-n .3-benzodioxol-5-vh- 1 -f2-(N-propvl-N-(2-fpiperidin-1 -vnethanesulfonvlamino^ethvllpvrrolidine-3-carboyvlic acid Using the procedures described in Example 66, the title compound 11 was prepared and isolated as a white solid, m.p. 95-96 °C. 1H NMR (CDCI3, 300MHz) 5 0.82 (t, J=7Hz, 3H), 1.43-1.55 (m, 4H), 1.63-1.72 (m, 4H), 2.29-2.38 (m, 1H), 2.64-2.78 (m, 5H), 2.87 (t, J=8Hz, 1H), 2.95-3.04 (m, 5H), 3.20-3.30 (m, 1H), 3.32-3.43 (m, 4H), 3.54-3.63 (m, 1H), 3.78 (d, J=8Hz, 1H), 3.87 (s, 3H), 5.92 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.88 (t, J=8Hz, 1H), 6.94 (d, J=2Hz, 1H), 7.08-7.20 (m, 2H). MS (DCI/NH3) m/e 620 (M+H)+ Example 401 trans.frans-2-(n-Heptvh-4-n .3-benzodioxol-5-vn-1 -(N.N- dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (CDCI3, 300 MHz) 5 0.83-0.98 (s, 9H), 1.18-1.40 * (m, 14H); 1.44-1.60 (m, 4H), 1.72-1.96 (br m, 2H), 3.12-3.45 (m, 6H), 25 3.65 (t, J = 10.5 Hz, 1H), 3.76 (t, J * 11.2 1H), 3.90-4.06 (m, 2H), 4.13-4.33 (m, 2H), 5.93 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 7.8, 1.7. Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H). MS(DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N2O5 • 0.75 TFA: C, 62.28; H, 8.01; N, 4.76. Found: C, 62.20; H, 7.99; N, 4.50.
Example 402 trans.trans-4-Ci .3-Benzodioxol-5-vn-2-(4-methoxvphenvlV1 -(3-methvl-1.2.3.4-tetrahvdroauinolin-1-vncarbonvtmethvnpvrroMdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.99 (d, 1.5H), 1.03 (d, J=6 Hz, 1.5H, second diastereomer), 2.60-4.00m (12), 3.78 (s, 1.5H), 3.79 (s, 1.5H, second diastereomer), 5.92 (s, 1H), 5.93 (s, 1H, diastereomer), 6.65-7.40 (m, 11H). MS (DCI) m/e 529 (M+H)+. Analysis calcd for C31H32N2O6 • 0.8 H2O: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 5 6.10; N, 5.30.
Example 403 trans.trans-4-( 1.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-fN-butvl-N-(4-fluorophenvhaminocarbonvlmethvhpvrrolidine-3-1 0 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.2-1.47 (m, 4H), 2.7 (d, J=12 Hz, 1H), 2.80 (t, J=9 Hz, 1H), 3.09 (t, J=9 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.47 (m, 1H), 3.49-3.65 (m, 3H), 3.75 (d, 15 J=12 Hz, 1H), 3.80 (s, 3H), 5.94 (s, 2H), 6.72-6.86 (m, 4H), 7.00-7.15 (m, 7H). MS (DCI) m/e 549 (M+H)+. Analysis calcd for C31H33N2O6F • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.
Example 404 fra/7S.frans-1-fN-Butvl-N-(3-methvlphenvnaminocarbonvlmethvn-2-{4-methoxvphenyh-4-f5-benzofuranvnpvrroHdine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3) 8 7.66 (1H, bs), 7.60 (1H, d, # J=3Hz), 7.45 (2H, s), 7.15 (4H, m), 6.75 (5H, m), 3.96 (1H, d, J=10Hz), 25 3.78 (3H, s), 3.74 (1H, m), 3.59 (3H, m), 3.21 (1H, t, J=9Hz), 3.19 (1H, d, J=16Hz), 2.92 (1H, t, J=9Hz), 2.70 (1H, d, J=16Hz), 2.29 (3H, s), . 1.41 (2H,m), 1.24 (2H,m), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) m/e 541 (M+H+). Anal, calcd for C33H34N2O • 1 H2O: 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-Butvl-N-f 3-methvlphenvhaminocarbonvlmethvn-2-(4-fluorophenvh-4-f5-benzofuranvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 3 5 was prepared. 1H NMR (300 MHz, CDCI3) 8 7.67 (1H, bs), 7.60 (1H, d, Js=3Hz), 7.45 (2H, m), 7.18 (3H, m), 7.12 (1H, d, J=7Hz), 6.93 (2H, m), 6.76 (1H, d, J=3Hz), 6.70 (2H, bd), 4.02 (1H, m), 3.77 (1H, m), 3.59 (3H, m), 3.29 (1H, m), 3.19 (1H, m), 2.94 (1H, m), 2.71 (1H, m), 2.30 (3H, s), 1.45 (2H, m), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) m/e 529 (M+H+). Anal, calcd for C33H34N2O5 • 0.2 HOAc: C, 5 71.98; H, 6.30; N 5.18. Found : C, 71.68; H, 5.89; N, 5.25.
Example 406 frangfrans-4-n.3-Benzodloxol-5-vn-2-r4-methoxyphenvn-1-(fN.N-fdi-f3-methvlphenvnamino^carbonvnmethvnpvrrolidine-3-carboxvlic 10 acid Using the procedures described In Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) S 2.27 (s, 6H), 2.81 (dd, J=8.1, 9.5 Hz, 1H), 2.98 (d, J=15.3 Hz, 1H), 3.20 (t, J=16.6 Hz, 1H), 3.47-3.60 (m, 3H), 3.80 (s, 3H), 3.85 (d, J=9.5 Hz, 1H), 5.91 (s, 2H), 6.73 (d, J=7.8 15 Hz, 1H), 6.85 (m, 3H), 6.95 (m, 4H), 7.05 (d, J=1.7 Hz, 1H), 7.06-7.24 (m, 6H). MS (DCI) m/e 579 (M+H+). Anal calcd for C35H34N2O6 • 0.15 H2O • 0.20 CH3CO2C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.51.
Example 407 trans.trans-4-C\ .2-Dihvdrobenzofuran-5-vn-2-f4-methoxvphenvn-1-fffN-biityl-N-(3-methvlphenvhamlno^carbonvnmethvl^pyrrolldine-3- carboxvlic acid Using the procedures described in Example 1, the title compound 25 was prepared. 1H (300MHz, CDCI3 ) 8 7.73 (2H, m), 7.40-7.10 (4H, m), 6.92 (2H, m), 6.72 (2H, d, J=9), 6.63 (1H, m), 5.40 (1H, m), 4.55 (2H, t, J=9), 4.30-4.10 (3H, m), 3.84 (3H, s), 3.82 (1H, m), 3.65 (1H, m), 3.39 (1H, m), 3.21 (2H, t, J=9), 3.10-2.90 (2H, m), 2.26 (3H, s), 1.55 (2H, m), 1.45 (2H, m), 0.92 (3H, t, J=9). MS {DCI/NH3) m/e 543 (M+H+). Anal 30 calcd for C33H38N2O5 • 0.65 H2O: C, 71.50; H, 7.15; N, 5.05 . Found: C, 71.47; H, 6.96; N, 4.83.
Example 408 trans. fra/7s-2-(3-Fluoro-4-methoxvphenvn-4-/1.3-benzodioxol-5-vn- 1-f2-fN-proDvl-N-r2-fNN. dimethvlamino^1ethanesulfonvlamino)ethvl}pvrrolidine-3-carboxvHc 5 acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 81-82 °C. 1H NMR (CDCI3, 300 MHz) 5 0.80 (t, J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.15-2.24 (m, 1H), 2.36 (s, 6H), 2.66-2.76 (m, 1H), 2.83-3.04 (m, 6H), 3.18-10 3.41 (m, 5H), 3.55-3.63 (m, 1H), 3.72 (d, J=8Hz, 1H), 3.85 (s, 3H), 5.90 % (d, J=6Hz, 2H), 6.67 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.84 (t, J=s8Hz, 1H), 7.94 (d, J=2Hz, 1H), 7.09 (d, J=8Hz, 1H), 7.20 (dd, J=2Hz, J«12Hz, 1H). MS (DCI/NH3) m/e 580 (M+H)+.
Example 409 ffans.frans-1-fN.N-Dibutvlaminocarbonvlmethvn-2-(4-fluorophenvl\-4-(5>benzofuranvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3) 5 7.88 (1H, bs), 7.80 (2H, m), 20 7.61 (1H, d, J=3Hz), 7.55 (1H, bd, 8Hz), 7.46 (1H, d, J=8Hz), 7.07 (2H, t, J=8Hz), 6.76 (1H, d, J=3Hz), 5.53 (1H, bd, J=11Hz), 4.18 (2H, m), 3.91 (3H, m), 3.55 (1H, d, J=16Hz), 3.30 (3H, m), 3.12 (1H, dd, J=10&9Hz), 2.95 (1H, m), 1.51 (2H, m), 1.31 (4H, m), 1.12 (2H, m), 0.92 (3H, m), 0.83 (3H, t, J=7Hz). MS m/e (DCI, NH3) 595 (M+H+).
Example 410 trans.trans-4-("\ ■2-Dihvdrobenzofuran-5-vn-2-f4-ethvlphenvl)-1-(f(N-butvl-N-(3-methvlphenvnamino>carbonvnmethvhpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 5 7.35 (2H, m), 7.20-7.00 (7H, m), 6.70 (2H, d, J=9), 5.38 (1H, m), 4.55 (2H, t, J=9), 4.05 (1H, m), 3.64 (2H, m), 3.45 (1H, m), 3.21 (2H, t, J=9), 2.95 (1H, m), 2.75 (1H, m), 2.63 (2H, q, J=8), 2.38 (2H, m), 2.27 (3H, s), 1.43 (2H, m), 1.30 (2H, m), 1.22 35 (3H, t, Js=9), 0.89 (3H, t, J=9). MS (DCI/NH3) m/e 541 (M+H+). Anal calcd for C34H40N2O4 • 1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80.
Example 411 trans.trans-4-( 1.2-Dihvdrobenzofuran-5-vn-2-(4-fluorophenvn-1 -«(N.N-dibutvtaminotearbonvnmethvnpvrroHdine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 6 7.40 (2H, m), 7.28 (1H, bs), 7.18 (1H, dd, J=8, 3), 7.00 (2H, t, J=9), 6.72 (1H, d, J=9), 4.53 (2H, t, J=9), 3.92 (1H, m), 3.65 (1H, m), 3.42 (3H, m), 3.19 (2H, t, J=9), 3.15-2.90 (6H, m), 1.43 (3H, m), 1.25 (3H, m), 1.10 (2H, m), 0.90 (3H, t, J=8), 0.83 (3H, t, J=8). MS (DCI/NH3) m/e 497 (M+H+). Anal calcd for C29H37FN2O4 • 0.25 H2O: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.
Example 412 trans.trans-A-C\ .2-Dihvdrobenzofuran-5-vn-2-(4-fluorophenvn»1-«fN-butvl-N-(3-methvlphenvnamino)carbonvnmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 5 7.28 (1H, bs), 7.25-7.00 (5H, m), 6.91 (2H, m), 6.72 (3H, d, J=9), 4.54 (2H, t, J=9), 4.00 (1H, m), 3.60 (3H, m), 3.45 (1H, m), 3.19 (2H, t, J=9), 3.11 (2H, m), 2.84 (1H, m), 2.67 (1H, bd, j=18), 2.26 (3H,s), 1.42 (2H, m), 1.25 (2H, m), 0.88 (3H, t, J=8). MS (DCI/NH3) m/e 531 (M+H+). Anal calcd for C32H35FN2O4 • 0.25 H2O: C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N, 5.03.
Example 413 frans. frans-4-nndan-5-vn-2-(4-methoxvphenvn-1-({(N. N-dibutylaminotearbonvnmethvnpvrrolidine-3-carboxyiic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 5 7.32 (3H, m), 7.18 (2H, m), 6.85 (2H, d, J=9), 3.83 (1H, m), 3.79 (3H, s), 3.67 (1H, m), 3.50-3.20 (4H, m), 3.20-2.92 (4H, m), 2.87 (5H, m), 2.79 (1H, bd, J=15), 2.06 (2H, m), 1.43 (2H, m), 1.27 (4H, m), 1.08 (2H, m), 0.88 (3H, t, J=8), 0.82 (3H, t, J«8). MS (DCI/NH3) m/e 507 (M+H+). Anal calcd for C31H42N2O4: C, 73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.
Example 414 frans. frans-2-(4-Methoxvphenvn-4-(3.4-difluorophenvh-1-l7N-butYl-N-(3-methvlPhenvnamino)carbonvlmethvllPvrrolidine-3-carhoxyltc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300MHz, CDCI3) 8 0.86 (t, J=7Hz, 3H), 1.10-1.35 10 (m, 2H), 1.35-1.52 (m, 2H), 2.29 (s, 3H), 2.63 (d, J=13Hz, 1H), 2.76 (t, # J=7Hz, 1H), 3.06-3.20 (m, 2H), 3.42-3.53 (m, 1H), 3.50-3.64 (m, 3H), 3.80 (s, 3H), 3.86 (d, J=9Hz, 1H), 6.66-6.82 (m, 4H), 7.02-7.22 (m, 6H), 7.30-7.40 (m, 1H).
Example 415 frans.frans-1-(N-Butvl-N-(3-chlorophenvnaminocarbonvlmethvn-2-(4-fluorophenvh-4-(5-benzofuranvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3) 8 7.64 (1H, d, J=2Hz), 7.61 (1H, 20 d, J=3Hz), 7.47 (1H, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1H, dt, J~8&2Hz)f 7.21 (1H, d, J«8Hz), 7.19 (2H, m), 7.00 (1H, bs), 6.94 (2H, t, J=8Hz), 6.83 (1H, bd, J=8Hz), 6.74 (1H, dd, J=2&1Hz), 3.96 (1H, d, ^ J=10Hz), 3.75 (1H, ddd, 6, 5&3Hz), 3.59 (3H, m), 3.23 (1H, t, J=10Hz), ™ 3.18 (1H, d, J=16Hz), 2.92 (1H, dd, J=10&9Hz), 2.69 (1H, d, J=16Hz), 25 1.41 (2H, m), 1.23 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) 549, 551 (M+H+). Anal, calcd for C31H30CIFN2O: 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-Benzodioxol-5-vn-2-(4-methoxvphenyh-1-(f(N-propvl-N-f4-phenoxvbenzvhamino^carbonvhmethynpvrroHdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 8 (rotamer) 7.40-7.20 (5H, 35 m), 7.13 (2H, m), 6.98 (2H, m), 6.93-6.60 (7H, m), 5.93 (1H, d, J=2), 5.88 (5.85) (1H, d, J=2), 4.90 (4.50) (1H, d, J=15), 4.10 (4.25) (1H, d, J=15), 3.77 (3.73) (3H, s), 3.72 (1H, m), 3.60 (1H, m), 3.53-3.20 (3H, m), 3.15-2.75 (4H, m), 1.60-1.20 (2H, m), 0.83 (0.64) (3H, t, J=8). MS (DCI/NH3) m/e 623 (M+H+). Anal calcd for C37H38N2O7 -0.25 H2O: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.
Example 417 fra/7s.frans-4-M.2-Dihvdrobenzofuran-5-vn-2-(4-ethvlphenvn-1-mNl- f2-pentvn-NM4-fluoro-3-methvlphenvOamlnotearbonvnmethvhpvrrolidine-3-carboxvlic acid 10 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) S 7.30 (1H, bs), 7.20-7.00 (5H, m)f 6.87 (1H, m), 6.73 (2H, d, J=9), 6.57 (1H, m), 4.81 (1H, m), 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (1H, m), 3.43 (1H, m), 3.18 (2H, t, J=9), 3.17 (1H, m), 3.06 (1H, dd, J=15, 6), 2.88 (1H, dd, J=11, 9), 2.61 (2H, q, 15 J=8), 2.59 (1H, m), 2.18 (3H, m), 1.40-1.10 (4H ,m), 1.22 (3H, t, J=9), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 573 (M+H+). Anal calcd for C35H41FN2O4 • 0.75 H2O: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56; H, 7.33; N, 4.56.
Example 418 frans.frans-2-f4-Methoxphenvn-4-f1.3-benzodioxol-5-vn-1-r2-fN-Dropvl-N-r2-pvrimidinvnaminotethvPpvrrolidine-3-carboxvlic acid Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[2-(N-propylammo)propyl]pyrroUdine-3-carboxylate, prepared by the 25 procedures of Example 61B (300 mg), 138 mg of 2-bromopyrimidine, and 150 mg of diisopropylethylamine were heated at 95 °C for 15 hours in 2 mL of acetonitriie. The resulting intermediate trans-trans ethyl ester was isolated by chromatography on silica gel eluting with 5-10% ETOAc in CH2CI2 and hydroiyzed with NaOH in ethanol/water to give 95 30 mg of the title compound. ^H NMR (300 MHz, CDCI3) 5 0.82 (t, J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (m, 1H), 2.75-2.97 (m, 3H), 3.40-3.55 (m ,4H), 3.60-3.70 (m, 3H), 3.75 (s, 3H), 5.95 (s, 2H), 6.34 (t, J=s4Hz, 1H), 6.65 (d, J=8Hz, 1H), 6.75-6.82 (m, 1H), 6.78 (d, J=9Hz, 2H), 6.96 (d, J=:2Hz, 1H), 7.27 (d, J=9Hz, 2H), 8.20 (d, J=4Hz, 2H).
Example 419 trans.trans-4-("\ .3-Benzodioxol-5-vn-2-f4-methoxvphenvh-1-f3-butyl-2-chloro-hept-2-en-1 -vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CD3OD) 5 0.84 (t, J=6.8 Hz, 3H), 0.88 (t, Jss6.7 Hz, 3H), 1.19-1.39 (m, 8H), 2.05-2.09 (m, 2H), 2.17-2.23 (m, 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1H), 2.95 (t, J=9.2 Hz, 1H), 3.32-3.37 (m, 2H), 3.49 (m, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.77 (s, 3H), 5.91 (m, 2H), 6.72 (d, J«8.1 Hz, 1H), 6.85 (dd, J=1.9, 8.1 Hz, 1H), 6.89 (m, 2H), 7.08 (d, 10 Jsl.5 Hz, 1H), 7.36 (m, 2H). MS (DCI) m/e 528 (M+H+). Anal calcd for | C30H38CINO5 • 0.25 H2O: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.
Example 420 trans.trans-4-f 1.2-Dihvdrobenzofuran-5-vh-2-(4-methoxvphenvn-1 - f(fN-(2-pentvn-N-(4-fluoro-3-methviphenvhaminotearbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3 ) 8 7.28 (1H, bs), 7.15 (3H, m), 20 6.90 (1H, m), 6.77 (2H, dd, J=9, 3), 6.71 (2H, d, J=9), 6.56 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J=9), 3.92 (1H, m), 3.79 (3H, s), 3.60 (1H, m), 3.45 (1H, m), 3.19 (2H, t, J=9), 3.18 (1H, m), 3.03 (1H, dd, J=15, 6), 2.85 (1H, m), 2.55 (1H, m), 2.18 (3H, m), 1.40-1.05 (4H, m), 1.00-0.80 (6H, m). MS • (DCI/NH3) m/e 575 (M+H+). Anal calcd for C34H39FN2O5 • 0.35 H2O: C, 25 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.
Example 421 trans.trans-4-(1.2-Dihvdrobenzofuran-5-vn-2-(4-methoxvphenvn-1-(ffN-butvl-N-(3-chlorophenvnamino^carbonvnmethvnpvrrolidine-3-30 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. "*H NMR (300 MHz, CDCI3 ) 8 7.29 (1H, d, J=3), 7.25-7.05 (5H, m), 6.98 (1H, bs), 6.80 (2H, m), 6.72 (2H, d, J=9), 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 (3H, s), 3.58 (3H, m), 3.42 (1H, dd, J=10, 6), 35 3.18 (4H, m), 2.87 (1H, m), 2.66 (1H, m), 1.40 (2H, m), 1.25 (2H, m), 0.86 (3H, t, J=9). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C32H35CIN2O5 ' 0.25 H2O: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55.
Example 422 trans.trans-4~("\ .3-Benzodioxol-5-vn-2-(5-ethvlfuran-2-vn-1-f((N.N-dibutvlamino)carbonvhmethvl>pvrro|jdlne-3-carboxvHc acid Using the procedures described in Example 1, the title compound was prepared. NMR (300 MHz, CDCI3 ) 8 7.77 (1H, bs), 7.11 (1H, d, J=3), 7.02 (1H, dd, J=9, 3), 6.82 (1H, d, J=9), 6.52 (1H, d, J=4), 6.08 (1H, d, J=4), 5.98 (2H, s), 5.80 (1H, d, J=6), 4.70 (1H, bd, J=15), 4.37 (2H, m), 3.70 (2H, m), 3.39 (2H, m), 3.20 (1H, m), 3.10-2.82 (2H, m), 2.76 (2H, q, Jss8), 1.45 (2H, m), 1.32 (3H, t, J=9), 1.30-1.10 (6H, m), 0.87 (3H, t, J=9), 0.85 (3H, t, J=9). MS (DCI/NH3) m/e 499 (M+H+). Anal calcd for C28H38N2O6 ■ 1.75 HCI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, 6.96; N, 4.88.
Example 423 frans. frans-4-M .2-Dihvd robenzof uran-5-vH-2-(4-f iuorophenvn-1- (((N-(2-pentvn-N-(4-fluoro-3-methvlnhenvnamino^carbonvnmethvhpvrrolidine-3-carboxyHc acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3 ) 8 7.30-7.10 (4H, m), 6.92 (3H, m), 6.73 (2H, d, J=9), 6.59 (1H, m), 4.80 (1H, m), 4.53 (2H, t, J=9), 4.00 (1H, bd, J=10), 3.62 (1H, m), 3.45 (1H, m), 3.22 (1H, m), 3.21 (2H, t, J=9), 3.02 (1H, dd, J=15, 6), 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 (3H, bs), 1.40-1.30 (3H, m), 1.15 (1H, m), 1.00-0.80 (6H, m). MS (DCI/NH3) m/e 563 (M+H+). Anal calcd for C33H36F2N2O4: 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-Dihvdrobenzofuran-5-vn-2-f4-fluorophenvl>-1 -fffN-butyl-N-f3-chlorophenynamino^carbonvl^methvhpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 7.30 (2H, m), 7.25-7.10 (4H, m), 6.95 (3H, m), 6.82 (1H, bd, J=9), 6.73 (1H, d, J=9), 4.55 (2H, t, J=9), 3.92 (1H, bd, J=11), 3.60 (3H, m), 3.43 (1H, dd, J=9, 6), 3.21 (2H, t, J=9), 3.16 (2H, m), 2.87 (1H, m), 2.69 (1H, m), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=9). MS (DCI/NH3) m/e 551 (M+H+). Anal calcd for C31H32CIFN2O4 • 0.25 H2O: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.
Example 425 trans.trans-4-(1 .2-Dihvdrobenzofuran-5-vn-2-<,4-ethvlphenvn-1-(ffN-butvl-N-(3-chlorophenvhamino>carbonvnmethvnpvrrolldine-3- carboxvllc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 8 7.30 (1H, m), 7.21 (1H, d, J=9), 7.15 (2H, m), 7.09 (4H, bs), 6.96 (1H, bs), 6.80 (1H, bd, J=9), 6.73 (1H, d, J=9), 4.54 (2H, t, J=9), 3.89 (1H, bd, J=11), 3.60 (3H, m), 3.43 (1H, m), 3.22 (2H, t, J=9), 3.18 (2H, m), 2.92 (1H, m), 2.72 (1H, m), 2.62 (2H, q, J«8), 1.41 (2H, m), 1.26 (2H, m), 1.23 (3H, t, J=9), 0.87 (3H, t, J«9). MS (DCI/NH3) m/e 561 (M+H+). Anal calcd for C33H37CIN2O4 • 0.25 H2O: 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-Butvl-N-(3-chlorophenvncarboxamidomethvn-2-f 4-methoxvphenvh-4-(5-benzofuranvhpyrroHdine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 7.67 (1H, bs), 7.60 (1H, d, Js=3Hz), 7.48 (1H, d, J=8Hz), 7.42 (1H, dd, J=8&3Hz), 7.29 (1H, dt, J=8&3Hz), 7.21 (1H, d, J=8Hz), 7.14 (2H, m), 6.99 (1H, bs), 6.76 (4H„ m), 3.88 (1H, d, J=10Hz), 3.75 (1H, ddd, J=6, 5&3Hz), 3.59 (2H, m), 3.53 (1H, dd, J=10&3Hz), 3.22 (1H, t, J=9Hz), 3.19 (1H, m), 2.96( 1H, m), 2.70 (1H, d, J=16Hz), 1.42 (2H, m), 1.26 (2H, m), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) m/e 563, 561 (M+H+). Anal, calcd for C32H33CIN2O5 • 0.5 H2O: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45; H, 5.82; N, 4.68.
Examole 427 trans.trans-4-(1.3-Benzodioxol-5-vn-2-M-methoxvphenvn-l-ff(N-cvclohexvl-N-butvlamino)carbonv0methvnpvrrolidine-3-carboxvlic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) (rotamer) 8 0.78 (0.86) (t, 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) (d, 1H, J=12Hz), 2.9-3.8 (envelope, 10H), 3.78 (3.80) (s, 3H), 5.92 (s, 2H), 6.72 (d, 1H, J=9Hz) 6.86 (m, 3H) 7.03 (d, 1H, J=6Hz), 7.34 (m, 2H). MS (DCI/NH3) m/e 537 1 0 (M+H)+. Anal, calc'd for C31H40N2O6 • 1 H2O: C, 67.13; H, 7.63; N, 5.05. £ Found: C, 67.09; H, 7.34; N, 4.92.
Example 428 trans.frans-4-M .3-Benzodioxol-5-vn-2-(4-ethvlPhenvn-1-mN-(3-15 methvlphenvn-N-butvlamino^carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.86 (t, 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.43 (m, 2H), 2.26 (s, 3H), 2.6 (q, 2H, J=7Hz), 20 2.68 (d, 1H, J=12Hz), 2.86 (t, 1H, J=8Hz), 3.19 (q, 2H, J=7Hz), 3.44 (dd, 1H, J= 3Hz,10Hz), 3.59 (m, 3H), 3.94 (d, 1H, 9Hz), 5.92 (s, 2H), 6.75 (m, 3H), 6.86 (dd, 1H, J= 2Hz, 8Hz), 7.08 (m, 6H), 7.17 (t, 1H, J= 8Hz). MS (DCI/NH3) m/e 543 (M+H)+ Anal, calc'd for C33H38N2O5 • 0.60 H2O: C, # 71.61; H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.
Example 429 trans.frans-4-f Benzofuran-5-vn-2-f4-ethvlphenvn-1 -(((N-(3-methvlphenvn-N-butvlamino'>carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.90 (t, 3H, J=7Hz), 1.30 (t, 3H, J=7Hz), 1.31 (m, 2H), 1.43 (m, 2H), 2.27 (s, 3H), 2.73 (q, 2H, J=7Hz), 3.15 (d, 2H, J=17Hz), 3.61 (t, 2H, J= 8Hz), 3.82 (m, 2H), 4.00 (t, 1 H, 12Hz), 4.26 (m, 2H), 5.53 (br d, 1H), 6.54 (br s, 2H), 6.76 (d, 1H, J= 2Hz), 35 7.14 (m, 3H), 7.28 (s, 1H), 7.40 (m, 3H), 7.48 (d, 1H, J= 8Hz), 7.63 (d, 1H, J=2Hz), 7.73 (s, 1H). HRMS. calc'd for C34H39N2O4 (M+H)+: 539.2910. Found: 539.2891 Example 430 trans.trans-A-( 1.4-Benzodioxan-6-vn-2-(4-ethvl phenyl)-1-((C N-f 3-methvlphenvn-N-butvlamino^carbonvnmethvnpvrrolidine-3-carboxvUc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.87 (t, 3H, J=7Hz), 1.22 (t, 10 3H, J=7Hz), 1.24 (m, 2H), 1.42 (m, 2H), 2.30 (s, 3H), 2.61 (q, 2H, J=7Hz), # 2.67 (d, 1H, J=14Hz), 2.86 (t, 1H, J= 8Hz), 3.18 (q, 2H, J=7Hz), 3.41 (dd, 1 H, J=4,10Hz), 3.59 (m, 3H), 3.93 (d, 1H, J=10Hz), 4.25 (m, 4H), 6.74 (br s, 2H), 6.80 (d, 1H, J=8Hz), 6.93 (dd, 1H, J=2Hz,8Hz), 6.99 (d, 1H, J=2Hz), 7.07 (m, 5H), 7.17 (t, 1H, J=8Hz). MS (DCI/NH3) m/e 557 (M+H)+. Anal. 15 calc'd for C34H40N2O5 • 0.40 H2O: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62.
Example 431 trans. frans-2-r3-Fluoro-4-methoxvphenvh-4-(1.3-benzodioxol-5-yh-1-r2-fN-propvl-N-2-mesitvlenesulfonvlamino>ethvMpvrrolidine-3- carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 80-82 °C. 1H NMR (CDCI3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09-2.17 (m, 1H), 2.24 (s, 3H), 2.53 (s, 6H), 2.54-2.64 (m, 1H), 2.73-2.86 (m, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (m, 3H)), 3.44-3.53 (m, 1H), 3.57 (d, J=9Hz, 1H), 3.89 (s, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.85 (s, 2H), 6.92 (d, J=8Hz, 1H), 9.94 (d, J=2Hz, 1H), 7.06 (d, J=8Hz, 1H), 7.13 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 627 (M+H)+ Example 432 trans. frans-2-(4-Methoxvphenvn-4-f 3.4-difluorophenvl V1-ff N-butyl-N-(3-chlorophenvhamino^carbonvlmethvllpyrrolidine-3-carboxvlic acid 35 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.86 (t, J=7Hz, 3H), 1.18-1.32 (m, 2H), 1.35-1.48 (m, 2H), 2.64 (d, J=13Hz, 1H), 2.71 (t, J= 7Hz, 1H), 3.08-3.18 (m, 2H), 3.42-3.48 (m, 1H), 3.53-3.64 (m, 3H), 3.77 (s, 3H), 3.80 (d, J=9Hz, 1H), 6.73-6.85 (m, 3H), 6.94 (s, 1H), 7.04-7.40 (m, 7H).
Example 433 frans. frans-2-(3-Fluoro-4-methoxvDhenvn-4-n.3-benzodioxol-5-vn-1-(2-(N-Dropvl-N-(3-chioroDropanesulfonvnamino)ethvnpvrroliriinft-3- carboxylic acid Using the procedures described in Example 1, the title compound 1 o was prepared. 1H NMR (CD30D, 300 MHz) 8 0.80 (t, 3H, J=7), 1.47 (bd £ hex, 2H, J=8), 2.15 (pen, 2H, J=7), 2.32 (m, 1H), 2.7-3.2 (m, 9H), 3.46 (dd, 1H, ^4, 10), 3.57 (m, 1H), 3.64 (t, 2H, J=6), 3.67 (d, 1H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.96 (d, 1H, Js=2), 7.06 (t, 1H, J=9), 7.18 (m, 2H). MS (DCI/NH3) m/e 585 (M+H; 15 35ci)+; 587 (M+H; 37q|)+. Anal calcd for C27H34N2O7CIFS: C, 55.43; H, 5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.
Example 434 frans.frans-2-f3-Fluoro-4-methoxvphenvn-4-(1.3-benzodioxol-5-yn- 2 0 1-f2-(N-isobutvl-N-(3-chloropropanesulfonvnamino^ethvnpvrrolidine- 3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.79 (d, 3H, J=7), 0.84 (d, 3H, J=7),1.68 (hept, 1H, J=7), 2.18 (pen, 2H, J=7), 2.8-3.4 (m, 10H), 3.5-3.8 25 (m, 3H), 3.65 (t, 2H, J=6), 3.90 (s, 3H), 5.94 (s, 2H), 6.77 (d, 1H, J=8), 6.87 (dd, 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.13 (t, 1H, J=9), 7.27 (m, 2H). MS (DCI/NH3) m/e 599 (M+H)+. Anal calcd for C28H36N2O7CIFS • 0.3 TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.
Example 435 frans. frans-2-Propoxvmethvl-4-(1.3-benzodioxol-5-vn-1-(N.N-dibtitvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3, 300 MHz) 8 0.87-0.98 (m, 9H), 1.21-1.39 35 (m, 4H), 1.43-1.57 (m, 4H), 1.58-1.70 (m, 2H), 3.13-3.29 (m, 4H), 3.34-3.43 (m, 3H), 3.45-3.55 (m, 3H), 3.69 (dd, J = 10.2, 4.5 Hz, 1H), 3.80- 4.20 (m, 4H), 5.93 (s, 2H), 6.73 (d, J « 7.8 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.93 (d, J - 1.7 Hz, 1H). MS(DCI/NH3) m/e 477 (M+H)+. Anal, calcd for C26H40N206-0.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 60.73; H, 7.74; N, 5.22.
Example 436 frans.fra/7S-2-(3-Fluoro-4-methoxvphenvn-4-M.3-benzodioxol-5-vn-1-r2-fN-propvl-N-M-methvlbutanesulfonvnamino>ethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 65-67 °C. 1H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 (d, J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (m, 3H), 2.24-2.33 (m, 1H), 2.68-2.93 (m, 5H), 2.98-3.12 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (, 1H), 3.65 (d, J=12Hz, 1H), 3.87 (s, 3H), 5.95 (s, 2H), 6.73 (d, J=s8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 (d, J=9Hz, 1Hz) , 7.16 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 579 (M+H)+.
Example 437 trans. frans-2-f4-Methoxv-3-fluorophenvn-4-Y7-methoxv-1.3-benzodioxol-5-vn-1 -f2-f N-proovl-N-f n-pentanesulfonvnaminotethvHpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (300MHz, CDCI3) 8 0.81 (t, J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (m, 4H), 1.44 (sextet, J=7Hz, 2H), 1.67-1.78 (m, 2H), 2.22-2.34 (m, 1H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.33 (m, 2H), 3.45 (dd, J=3Hz, 9Hz, 1H), 3.47-3.56 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 5.95 (s, 2H), 6.55 (s, 1H), 6.65 (s, 1H), 6.92 (t, J=7H, 1H), 7.11 (d, J=9Hz,1H), 7.17 (d, J=12Hz, 1H).
Example 438 frans. frans-2-f 3-Fluoro-4-methoxvphenvn-4-n .3-benzodioxol-5-vn- 1-r2-(N-pr<?pyl-N-(2,2,3.3,3-DentafluoroDroDOXvethanesulfonvnaminotethvnpvrroHdine-3-5 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 63-64 °C. 1H NMR (CDCI3, 300MHz) 8 0.82 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24-2.33 (m, 1H), 2.70-2.82 (m, 1H), 2.85-3.09 (m, 5H), 3.14-3.28 (m, 4H), 10 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (m, 1H), 3.65 (d, J=9Hz, 1H), 3.87 % (s, 3H), 3.92-3.98 (m, 3H), 5.94 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 685 (M+H)+.
Example 439 trans.trans-2-C\ .4-Benzodioxan-6-vl)-4-(7-methoxv-1.3-benzodioxol-5-vn-1-r2-(N-proPvl-N-(n-pentanesulfonvnamino)ethvl1pvrrolidine-3- carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CDCI3) 8 0.81 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.23-1.36 (m, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (m, 2H), 2.20-2.30 (m, 1H), 2.30-2.95 (m, 5H), 2.95-3.10 (m, 2H), 3.15-3.35 (m, 2H), ® 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 (m, 1H), 3.59 (d, J=9Hz, 1H), 3.91 25 <s, 3H), 4.24 (s, 4H), 5.95 (s, 2H), 6.57 (s, 1H), 6.68 (s, 1H), 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 (d, J=2Hz, 1H).
Example 440 trans.trans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvlM-fffN-30 butvl-N-f4-methoxvbenzvnamino)carbonvnmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 8 (rotamer) 7.32 (1H, d, J—10), 7.22 (1H, m), 7.10 (1H, d, J=9), 7.03 (6.98) (1H, d, J=3), 6.90-6.80 35 (4H, m), 6.79 (2H, d, J=9), 6.77 (1H, t, J=8), 5.85 (2H, s), 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (1H, d, J=15), 3.81 (IH, m), 3.79 (3.78) (3H, s), 3.76 (3H, s), 3.62 (1H, m). 3.43 (2H, m), 3.30-2.70 (5H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0.75) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7 • 0.5 H2O: C, 67.91; H, 6.73; N, 4.80. Found: C, 67.78; H, 6.44; N, 4.55.
Example 441 frans.fra/7S-2-(3-Fluoro-4-methoxvphenvn-4-n.3-benzodioxol.S-vn. 1-/2-fN-isobutvl-N-(pentanesulfonvlamino^ethvhpvrrolidine-3- carboxvlic acid Using the procedures described in Example 66, the title compound Q was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.76 (d, 3H, J=7), 0.84 (d, 3H, J«7), 0.92 (t, 3H, Js=7), 1.36 (m, 4H),1.70 (m, 3H), 2.90 (m, 2H), 3.02 (m, 2H), 3.1-3.8 (m, 7H), 3.84 (d, 2H, J=8), 3.91 (s, 3H), 5.96 (s, 2H), 6.80 (d, 1H, J=8), 6.88 (dd, 1H, J=2, 8), 7.00 (d, 1H, J=2), 7.19 (t, 1H, J=9), 7.35 15 (m, 2H). MS (DCI/NH3) m/e 593 (M+H)+. Anal calcd for C30H41N2O7F • 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95.
Example 442 trans.trans- 4-( 1.3-Benzodioxol-5-vn-2-(4-methoxyphenvn-1-(N-butvl-N-(3-fluorophenvlamino^carbonvlmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.10-1.30 (m, 4H), 2.70-2.90 (m, 2H), 3.13 (t, J=8 Hz, 1H), 3.40-3.90 (m, 6H), 3.79 (s, 3H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.80-7.20 (m, 9H), 7.40 (m, 1H). MS (DCI) m/e 549 (M+H)+. Anal calcd for C31H33N2O6F • 0.8 -H2O: C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84.
Example 443 trans. trans-4-C\.3-Benzodioxol-5-vn-2-(4-fluorophenvn-1 -(N-butvl-N-f3-chloronhenvlaminolcarbonvlmethvhpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-1.50 (m, 4H), 2.65-2.85 (m, 2H), 3.05-3.85 (m, 7H), 5.93 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.85 (dd, J=8 Hz, 1H), 6.90-7.10 (m, 4H), 7.10-7.25 (m, 3H), 7.33-7.45 (m, 2H). MS (DCI) m/e 553 (M+H)+. Anal calcd for C30H30N2O5FCI: 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-vn-2-(4-methoxvnhenvh-1 -(f(N-butvl-N-(3.4-dimethoxvbenzvnam»no^carbonvnmethvnpvrrolldlne-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. NMR (300 MHz, CDCI3 ) 8 (rotamer) 7.33 (1H, d, 10 J=10), 7.23 (1H, m), 7.03 (6.97) (1H, d, J=3), 6.90-6.60 (6H, m), 6.47 # (1H, m), 5.93 (2H, m), 4.83 (4.09) (1H, d, J=15), 4.45 (4.22) (1H, d, J=15), 3.83 (3.86) (3H, s), 3.79 (1H, m), 3.77 (3.76) (3H, s), 3.75 (3.65) (3H, s), 3.60 (1H, m), 3.43 (2H, m), 3.28 (1H, m), 3.20-2.70 (4H, m), 1.43 (IH, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) (3H, t, J=8). MS 1 s (DCI/NH3) m/e 605 (M+H+). Anal calcd for C34H40N2O8: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.
Example 445 trans. trans-4-( 1.3-Benzodioxol-5-yn-2-(4-methoxvphenvn-1-(((N-20 butvl-N-(2-methoxvbenzvhamino,>carbonvnmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CDCI3 ) 8 (rotamer) 7.33 (1H, d, ■W J=10), 7.11 (2H, m), 7.03 (1H, dd, J=8, 3), 6.90-6.60 (7H, m), 5.93 (2H, 25 m), 4.83 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=15), 3.81 (1H, m), 3.78 (3.73) (3H, s), 3.72 (3H, s), 3.59 (1H, m), 3.43 (2H, m), 3.30 (1H, m), 3.20-2.70 (4H, m), 1.42 (1H, m), 1.23 (2H, m), 1.01 (1H, m), 0.83 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.70; H, 6.56; N, 30 4.61.
Examole 446 trans.tranS'4-( 1.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1 I (N-butvl-N-O-methoxvbenzvnaminolcarbonvnmethvnpvrrolidine-S- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 8 (rotamer) 7.31 (1H, d, J=10), 7.13 (1H, d, J=9), 7.16 (1H, dt, J=8, 3), 7.03 (1H, dd, J=10, 2), 6.90-6.60 (6H, m), 6.50 (1H, m), 5.94 (2H, m), 4.82 (4.19) (1H, d, J=15), 4.50 (4.23) (1H, d, J=15), 3.78 (3.76) (3H, s), 3.77 (1H, m), 3.75 (3.67) (3H, s), 3.59 (1H, m), 3.57-3.35 (2H, m), 3.25 (1H, m), 3.20-2.70 (4H, m), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.77) (3H, t, J=8). MS (DCI/NH3) m/e 575 (M+H+). Anal calcd for C33H38N2O7: C, 68.97; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.55; N, 4.60.
Example 447 trans.frans-2-(3-Fluoro-4-methoxvphenvn-4-M .3-benzodioxol-5-vn- 1 -(2-(N-f2-methoxvethvh-N-(3-chloropropanesulfonvnaminotethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, J=7), 2.33 (m, 1H), 2.81 (m, 2H); 2.93 (t, 1H, J=9); 3.1-3.6 (m, 10H), 3.24 (s, 3H); 3.65 (t, 2H, J=6), 3.70 (d, 1H, J=9), 3.87 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.97 (d, 1H, J=2), 7.07 (t, 1H, J=9), 7.17 (m, 2H). MS (DCI/NH3) m/e 601 (M+H)+. Anal calcd for C27H34N2O8CIFS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.
Example 448 frans-frans-2-(3-Fluoro-4-methoxvphenvn-4-n .3-benzodioxol-5-vn- 1-(2-(N-(2-methoxvethvh-N-fpentanesulfonvnamino^ethvltpvrroHdine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.93 (m, 3H), 1.34 (m, 4H), 1.69 (m, 2H), 2.33 (m, 1H), 2.75-3.1 (m, 7H), 3.23 (s, 3H), 3.3-3.6 (m, 6H), 3.70 (d, 1H, J=9), 3.86 (s, 3H), 5.92 (s, 2H), 6.74 (d, 1H, J=8), 6.84 (dd, 1H, J=2, 8), 6.97 (d, 1H, J=2), 7.07 (t, 1H, J=9), 7.18 (m, 2H). MS -41 1- (DCI/NH3) m/e 595 (M+H)+. Anal calcd for C29H39N2O8FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.
Example 449 trans.trans-4-("\ .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-(ffN-4- heptvn-N-(4-fluoro-3-methylphenvlamlno)carbonvnmethvnpvrrolidine-3-carboxvllc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.89 (m, 6H), 1.18-1.36 (m, 8H), 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=s14.9 Hz, 1H), 2.82 (m, 1H), 3.07-3.29 (m, 2H), 3.32-3.41 (m, 1H), 3.53-3.60 (m, 1H), 3.70-3.79 (m, 1H), 3.79 (s, 3H), 4.68 (m, 1H), 5.92 (m, 2H), 6.69-6.90 (m, 6H), 6.93-7.07 (m, 4H). MS (DCI) m/e 605 (M+H+). Anal calcd for C35H41FN2O6: C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31; H, 6.78; N, 4.35.
Example 450 trans.trans-4-("\ .3-Benzodioxol-5-vh-2-(4-methoxvphenvn-1-^fN^(5- nonvh-N-f4-fluoro-3-methvlphenvnamlnotearbonvnmethvhpvrrolidine-3-carboxvHc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.81-0.90 (m, 6H), 1.30 (m, 12H), 2.14 (s, 1.5 (CH3 rotamer)), 2.30 (s, 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz, 1H), 2.80 (m, 1H), 3.09-3.24 (m, 2H), 3.33-3.42 (m, 1H), 3.50-3.55 (m, 1H), 3.65-3.77 (m, 1H), 3.79 (s, 3H), 4.64 (m, 1H), 5.93 (m, 2H), 6.70-6.84 (m, 5H), 6.91-7.13 (m, 5H). MS (DCI) m/e 633 (M+H+). Anal calcd for C37H45FN2O6: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.
Example 451 trans.frans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1 -((N-f5-nonvlamino^carbonvnmethvl>pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. ^H NMR (300 MHz, CD3OD) 8 0.80 (t, J=7.0 Hz, 3H), 0.84 (t, J=7.1 Hz, 3H), 1.15-1.55 (m, 12H), 2.88 (d, J=15.9 Hz, 1H), 3.07 (m, 2H), 3.26 (d, J=16.3 Hz, 1H), 3.36 (dd, J=4.4, 9.8 Hz, 1H), 3.64 (m, 1H), 3.76 (m, 1H), 3.79 (s, 3H), 3.98 (d, J=9.5 Hz, 1H), 5.93 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.85 (dd, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 6.99 (d, Js1.7 Hz, 1H), 7.39 (m, 2H). MS (DCI) m/e 525 (M+H+). Anal calcd for C30H46N2O6 ■ 0.35 H2O: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11.
Example 452 trans. frans-4-(1.3-Benzodioxol-5-vn-2-(4-methoxvnhenvn-1-((N-' butvl-N-(2-fluorophenvhamino)carbonvlmethvhpvrrondine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (dt, J=7 Hz, 3H), 1.15-1.32 (m, 4H), 3.77 (d, J=2 Hz, 3H), 2.65-5.92 (m, 9H), 5.93 (d, J=4 Hz, 2H), 6.70-6.90 (m, 4H), 7.00-7.45 (m, 7H). MS (DCI) m/e 549 (M+H)+. Anal calcd for C31H33N2O6 • 0.4 H2O: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68.
Example 453 frans.frans-2-(4-Methoxphenvn-4-(1.3-benzodioxol-5-vn-1-r2-(N-Dropyl-N-^-benzothiazolvnamino^ethvllpyrrolidine-S-carboxvlic acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-bromopyrimidine. "*H NMR (300 MHz, CDCI3) 8 0.88 (t, J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25-2.37 (m, 1H), 2.85-2.97 (m, 3H), 3.28-3.36 (m, 2H), 3.50-3.58 (m, 3H), 3.60-3.65 (m, 1H), 3.67 (d, J=9Hz, 1H),3.71 (s, 3H), 5.87 (d, J=2Hz, 1H), 5.91 (d, J=2Hz, 1H), 6.57 (d, J=8Hz, 1H), 6.73 (dd, J=2Hz, 9Hz, 1H), 6.76 (d, J=8 Hz, 2H), 6.91 (d, J=2Hz, 1H), 7.01 (t, J=8Hz, 1H), 7.22 (t, J=8Hz, 1H), 7.29 (d, J=8Hz, 2H), 7.40 (d, J=7Hz, 1H), 7.55 (d, J=7Hz, 1H).
Example 454 frans.frans-2-f2-Ethoxvethvn-4-M.3-benzodioxol-5-vn-1-(N.N-dihiJtvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3, 300 MHz) 8 0.91 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.24-1.38 (m, 5H), 1.46-1.60 (m, 4H), 2.03-2.12 (m, 2H), 3.07 (t, J = 8.0 Hz, 1H), 3.07-3.34 (m, 6H), 3.43-3.52 (m, 3H), 3.59-3.74 (m, 3H), 3.80-4.01 (m, 2H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.87 (d, J « 1.7 Hz, 1H). MS(DCI/NH3) m/e 477 (M+H)+. Anal calcd for C26H40N2O6 • 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29.
Example 455 frans.frans-2-(4-Methoxv-3-fluorophenvn-4-(r1.3-benzodioxol-5-vn-1-f2-(N-propvl-N-(2-(morpholin-4-vlethvhsulfonvlamino)ethvnpvrrolidine-3-carboxvHc acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-[2-vlnylsulfonyl]amino)ethyl]pyrrolidine-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 intermediate ethyl ester which was hydroiyzed to the title compound with NaOH in ethanol/water. 1H NMR (300 MHz, CDCI3) 6 0.81 (t, J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (m, 4H), 2.70-2.92 (m, 5H), 2.97-3.33 (m, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (m, 1H), 3.62-3.70 (m, 5H), 3.88 (s, 3H), 5.95 (s, 2H), 6.72 (d, J=8Hz, 1H), 6.70 (dd, Js=2Hz, 8Hz, 1H), 6.90 (t, J=9Hz, 1H), 6.96 (d, J=2Hz, 1H), 7.10 (d, J=8Hz, 1H), 7.18 (dd, J=2Hz, 12Hz, 1H).
Example 456 trans. trans-2-( 3-Fluoro-4-methoxvphenvn-4-( 1.3-benzodioxol-5-vlV 1-r2-(N-propvl-N-f(2.2.2-trifluoroethoxvethane^sulfonvnamino^ethvllpvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 95-96 °C. 1H NMR (CD3OD, 300MHz) 8 0.80 (t, J=7Hz, 3H), 1.35-1.48 (m, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (m, 8H), 3.80-3.87 (m, 2H), 3.93 (s, 3H), 3.94-4.02 (m, 4H), 4.66 (d, J=12Hz, 1H), 5.96 (s, 2H), 6.83 (d, J=8Hz, 1H), 6.94 (d, J=8Hz, 1H),7.06 (d, J=2Hz, 1H), 7.23 (t, J=9Hz, 1H), 7.43 (d, J=9Hz, 1H), 7.49 (dd, J=2Hz,Js=12Hz, 1H). MS (DCI/NH3) m/e 635 (M+H)+.
Example 457 trans.trans-A-( 1.3-Benzodioxol-5-vn-2-(4-fluorophenvn-1-(N-butvl-N-f3-methvlDhenvl^aminocarbonvlmethvnDvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-1.50 (m, 4H), 2.31 (s, 3H), 2.65-2.80 (m, 2H), 3.19 (t, J=7 Hz, 1H), 3.25 (d, J=10 Hz, 1H), 3.35-3.65 (m, 4H), 3.79 (d, J=10 Hz, 1H), 5.93 (s, 2H), 6.74 (d, J=7 Hz, 1H), 6.80-6.90 (m, 3H), 6.91-7.09 (m, 3H), 7.10-7.35 (m, 4H). MS (DCI) m/e 533 (M+H)+. Anal calcd for C31H33N2O5F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.
Example 458 frans.frans-2-(3-Fluoro-4-methoxvphenvn-4-M .3-benzodioxol-5-vn-1-(2-fN-(2-methoxvethvn-N-{butanesulfonv»amino^ethvnpvrrolidine- 3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.94 (m, 3H), 1.23 (hex, 2H, J=8), 1.69 (m, 2H), 3.08 (m,2H), 3.20 (s, 3H), 3.3-3.5 (m, 10H), 3.77 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 5.96 (s, 2H), 6.81 (d, 1H, J=8), 6.88 (dd, 1H, J=2, 8), 6.99 (d, 1H, J=2), 7.22 (t, 1H, J=9), 7.38 (m, 2H). MS (APCI) m/e 581 (M+H)+ Anal calcd for C28H37N2O8FS • 1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.
Example 459 trans. frans-2-(3-Fluoro-4-methoxvphenvn-4-( 1.3-benzodioxol-5-vh-1-f2-fN-Dropvl-N-f2-methvlpropanesulfonvnamino^ethvl]pvrrolidin&- 3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid, m.p. 77-78 °C. 1H NMR (CDCI3, 300MHz) 8 0.83 (t, J=7Hz, 3H),1.06 (d, J=6Hz, 6H),1.45 (q, J=7Hz, 2H), 2.20 (septet, J=6Hz, 1H), 2.26-2.36 (m, 1H), 2.62-2.78 (m, 3H), 2.85-2.95 (m, 2H), 2.97-3.10 (m, 2H), 3.15-3.35 (m, 2H), 3.43 (dd, Jss3Hz, J=9Hz, 1H), 3.53-3.62 (m, 1H), 3.66 (d, J=9Hz, 1H), 3.88 (s, 3H), 5.95 (s, 2H), 6.74 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 (t, J=8Hz, 1H), 6.97 (d, J=2Hz, 1H), 7.12 (d, J=9Hz, 1H), 7.18 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) m/e 565 (M+H)+.
Example 460 trans.trans-A-( 1.3-Benzodioxol-5-vn-2-f 4-methoxvphenvh-1 ((N-butvl-N-(4-nitroben2vhamino)carbonvnmethvt^pvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3 ) 5 (rotamer) 8.11 (2H, m),7.32 (3H, dd, J=9, 2), 7.16 (7.07) (1H, bd, J=10), 6.98 (6.94) (1H, d, J«2), 6.85 (2H, d, J=9), 6.83-6.70 (2H, m), 5.99 (5.97) (2H, d, J=2), 5.02 (4.18) (1H, d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) (3H, s), 3.72 (1H, d, J=10), 3.61 (1H, m), 3.48 (1H, bd, J=15), 3.43-3.20 (2H, m), 3.06 (2H, m), 2.90 (1H, m), 3.79 (1H, bd, J=14), 1.43 (1H, m), 1.23 (2H, m), 1.02 (1H, m), 0.84 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.
Example 461 frans. frans-2-f4-EthvlPhenvn-4-(3.4-dif luorophenvh-1 -fN.N-dibutvlaminocarbonvlmethvhPvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.78 (t, 3H, J=7), 0.87 (t, 3H, J=7), 1.02 (hex, 2H, J=7), 1.22 (t, 3H, J=7), 1.27 (m, 2H), 1.45 (m, 2H, J=7), 2.63 (q, 2H, J=7), 2.77 (d, 1H, J=14), 2.94 (dd, 1H, J=7, 9), 3.05 (m, 3H), 3.3-3.5 m, 3H), 3.44 (d, 1H, J=14), 3.66 (m, 1H), 3.75 (d, 1H, J=10), 720 (td, 2H, J«1,8), 7.22 (m, 2H), 7.32 (td, 2H, J=1,8), 7.43 (ddd, 1H, Js=2,8f12). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H38N2O3F2 • 0.6 H2O: C, 68.11; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37.
Example 462 trans. trans-A-( 1.3-Benzodioxol-5-vh-2-f4-methoxvphenvn-1 -fN-butvl-N-(4-fiuoro-3-methvlphenvhaminocarbonvlmethvnpvrrolidine- 3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20- I.50 (m, 4H), 2.21 (d, J=2 Hz, 3H), 2.64 (d, J=14 Hz, 1H), 2.75 (dd, J=10 Hz, 1H), 3.05 (t, J=7 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.35-3.70 (m, 5H), 3.77 (s, 3H), 5.92 (s, 2H), 6.70-6.92 (m, 6H), 6.96-7.10 (m, 4H). MS (DCI) m/e 563 (M+H)+. Anal calcd for C32H35N2O6F • 0.5 H2O: 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-vn-2-(4-methoxvphenvh-1-fN-butyl-N-((3-isopropvl)phenvhamlno)carbonvlmethvn-pvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, 3H), 1.17 (d, J=7 Hz, 6H), 1.20-1.50 (m, 4H), 2.63 (d, J=15 Hz, 1H), 2.75 (t, J=7 Hz, 1H), 2.85 (m, 1H), 3.00 (t, J=7 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 3.40-3.70 (m, 5H), 3.75 (s, 3H), 5.90 (s, 2H), 6.65-6.80 (m, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 (m, 3H), 7.20-7.35 (m, 2H). MS (DCI) m/e 573 (M+H)+. Anal calcd for C34H40N2O6 • 0.15 H3PO4: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43.
Example 464 trans.trans- 4-f 1.3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1 -fN-butvl-N-(3-ethvlphenvnaminocarbonvlmethvnpvrrolidine-3-carboxvHc 9cid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (m, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H), 1.20-1.47 (m, 4H), 2.50 (q, J=7 Hz, 2H), 2.70-2.85 (m, 2H), 3.13 (t, J=7 Hz, 1H), 3.20-4.5 (m, 6H), 3.78 (s, 3H), 3.83 (d, J=8 Hz, 1H), 5.92 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.80-6.90 (m, 5H), 7.02-7.13 (m, 3H), 7.15-7.25 (m, 2H). MS (DCI) m/e 559 (M+H)+. Anal calcd for C33H38N2O6 • 0.3 H2O: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31; H, 6.63; N, 4.60.
Example 465 trans.trans-4-C\ .3-Benzodioxol-5-vn-2-(4-ethvlphenvn-1-fffN-f3-chloroDhenvn-N-butvlamino)carbonvnmethvnDvrrolldine-3-carbQxv>ir; acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.87 (t, 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.41 (m, 2H), 2.63 (q, 2H, J=7Hz), 2.67 (m, 1H), 2.92 (m, 1H), 3.20 (m, 2H), 3.42 (m, 1 H), 3.60 (q, 2H, J=7Hz), 3.93 (m, 1H), 5.92 (s, 2H), 6.75 (d, 1H, J=8Hz), 6.84 (m, 3H), 6.95 (br s, 1H), 7.02 (s, 1H), 7.10 (br s, 3H), 7.25 (m, 2H). MS (APCI) m/e 563 (M+H)+. Anal, calc'd for C32H35N2O5CI • 0.80 H3PO4: C, 59.92; H, 5.88; N, 4.37.
Found: C, 59.90; H, 5.83; N, 4.07.
Example 466 trans.frans-4-f1 .4-Benzodioxan-6-vn-2-f4-ethvlphenvn-1-fffN-f3-chlorophenvn-N-butvlaminotearbonvnmethvnpvrrolidine-3-carboxvHc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.86 (t, 3H, J=7Hz), 1.23 (t, 3H, Js=7Hz), 1.25 (m, 2H), 1.40 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.70 (m, 1H), 2.95 (m, 1H), 320 (m, 2H), 3.40 (m, 1 H), 3.57 (m, 3H), 3.90 (m, 1H), 425 (s, 4H), 6.80 (d, 1H, J=8Hz), 6.95 (d, 1H, J=2Hz), 6.95 (m, 2H), 7.07 (br s, 3H), 7.22 (m, 3H). MS (APCI) m/e 577. (M+H)+. Anal, calc'd for C33H37N2O5CI • 0.85 H2O: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.
Example 467 frans. frans-4-fBenzofuran-5-vn-2-(4-ethvl phenyl)-1 -f(f N-f 3-chlorophenvn-N-butvlaminotearbonvnmethvnpvrrolidine-3-carboxvlic frcid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.85 (t, 3H, J=7Hz), 1.26 (t, 3H, J=7Hz), 1.30 (m, 2H), 1.40 (m, 2H), 2.60 (q, 2H, J=7Hz), 2.72 (m, 1H), 2.93 (m, 1H), 3.22 (m, 2H), 3.50 (m, 1H), 3.55 (m, 2H), 3.75 (m, 1H), 3.90 (br d, 1H), 6.75 (d, 1H, J=1Hz), 6.80 (br d, 1H), 6.95 (br s, 1H), 7.08 (m, 4H), 7.20 (t, 1H, J=8Hz), 728 (t, 1H, J=8Hz), 7.42 (m, 2H), 7.58 (d, 1H, Js=1 Hz), 7.63 (s, 1H). MS (APCI) m/e 559 (M+H)+. Anal, calc'd for C33H35N2O4CI • 0.45 H2O: C, 69.88; H, 6.58; N, 4.94. Found: C, 69.83; H, 6.04; N, 4.87.
Example 468 trans. frans-2-(4-Methoxv-3-fluorophenvn-4-(7-methoxv-1.3-benzodioxol-5-vn-1-r2-(N-butvl-N-phenvlamino)ethvnpvrroHdine-3- carboxvlic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(bromoethyl]-pyrrolidine-3-carboxylate, prepared using the procedures of Example 61A (300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) 8 0.90 (t, J=9Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (m, 1H), 2.68-2.77 (m, 1H), 2.82-2.95 (m, 2H), 3.12-3.22 (m, 2H), 3.30-3.44 (m, 3H), 3.45-3.55 (m, 1H), 3.62 (d, J=9Hz, 1H), 3.83 (s, 3H), 3.90 (s, 3H), 5.95 (s, 2H), 6.51 (d, J=7Hz, 2H), 6.55-6.62 (m, 2H), 6.69 (d, J=2Hz, 1H), 6.84 (t, J=8Hz, 1H), 7.02-7.15 (m, 3H), 7.19 (dd, J=2Hz, 12Hz, 1H).
Example 469 trans.trans-4-C\ .4-Benzodioxan-6-vn-2-(4-ethvlphenvn-1-(f(N.N-dibutvlamino)carbonvnmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.78 (t, 3H, J=7Hz), 0.88 (t, . 3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 123 (t, 3H, J=7Hz), 1.28 (m, 2H), 1.45 (m, 2H), 2.64 (q, 2H, J=7Hz), 2.78 (m, 1H), 2.9-3.2 (envelope, 4H), 3.30 (m, 1H), 3.40 (m, 3H), 3.60 (m, 1H), 3.80 (m, 1H), 4.25 (s, 4H), 6.80 (d, 1H, J=8Hz), 6.90 (m, 1H), 6.98 (d, 1H, J=2Hz), 7.17 (d, 2H, J=8Hz), 7.30 (m, 2H). MS (APCI) m/e 523 (M+H)+. Anal, calc'd for C31H42N2O5 • 1.1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 7.55; N, 4.48.
Example 470 trans.trans-4-(1.4-Benzodioxan-6-vh-2-(4-methoxvnhenvn-1-((N-butvl-N-f3-methvlDhenvlamino)carbonvnmethvnpv!ToHd»ne-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7.1 Hz, 3H), 1.30 (m, 2H), 1.44 (m, 2H), 2.30 (s, 3H), 2.80 (d, J=15.2 Hz, 1H), 2.85 (t, J=9.3 Hz, 1H), 3.19 (t, J=9.3 Hz, 1H), 3.33 (d, J=10.2 Hz, 1H), 3.42-3.61 (m, 3H), 3.79 (s, 3H), 3.91 (d, J=9.8 Hz, 1H), 4.22 (m, 4H), 6.75-6.86 (m, 6H), 6.95 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 7.22 (d, J=10.2 Hz, 1H), 726 (t, J=7.6 Hz, 1H). MS (DCI) m/e 559 (M+H+). Anal calcd for C33H38N2O6 • 0.4 CH3CO2C2H5: C, 69.97; H, 6.99; N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48.
Example 471 trans.trans- 4-f 1.4-Benzodioxan-6-vn-2-f4-methoxvphenvn-1-ffN-butvl-N-f3-chlorophenvlamino)carbonvnmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7.0 Hz, 3H), 1.25 (m, 2H), 1.40 (m, 2H), 2.78 (d, J=14.6 Hz, 1H), 2.86 (t, J=9.0 Hz, 1H), 3.16 (t, J=9.5 Hz, 1H), 3.34-3.43 (m, 2H), 3.48-3.62 (m, 3H), 3.79 (s, 3H), 3.85 (d, J=9.5 Hz, 1H), 4.22 (m, 4H), 6.78 (d, J=8.5 Hz, 1H), 6.81-6.86 (m, 3H), 6.93-7.09 (m, 5H), 7.33-7.38 (m, 2H). MS (DCI) m/e 579 (M+H+). Anal calcd for C32H35CIN2O6 • 1.1 CH3CO2C2H5 • 0.15 H3PO4: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.
Example 472 trans.trans-4-( 1,3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-(4-pvridvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 2.84 (t, J=9.6 Hz, 1H), 2.88 (dd, J=9.6, 7.3 Hz, 1H), 3.09 (dd, J=3.3, 9.6 Hz, 1H), 3.21 (d, J=14.3 Hz, 1H), 3.53 (m, 1H), 3.78 (s, 3H), 3.81 (m, 2H), 5.92 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 1H), 6.93 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 7.43 (m, 4H), 8.44 (d, J=5.2 Hz, 2H). MS (DCI) m/e 433 (M+H+). Anal calcd for C25H24N2O5 • 0.3 CH3CO2C2H5: C, 68.57; H, 5.80; N, 6.10. Found: C, 68.68; H, 5.60; N, 5.81.
Example 473 frans. frans-4-(1.3-Benzodioxol-5-vn-2-M-methoxvphen vh-1-ff N-butvl-N-(3-ferf-butvlPhenvlamino)carbonvnmethvhpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.88 (t, J=7.2 Hz, 3H), 1.23 10 (s, 9H), 126-1.45 (m, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (m, 1H), 3.13 ) (t, J=9.0 Hz, 1H), 3.29 (d, J=15.1 Hz, 1H), 3.50-3.66 (m, 4H), 3.77 (s, 3H), 3.84 (d, J=9.6 Hz, 1H), 5.92 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.79-6.85 (m, 4H), 6.86-6.90 (m, 1H), 6.99 (t, J=1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.13 (m, 2H), 7.33 (t, J=7.7 Hz, 1H), 7.42 (m, 1H). MS (DCI) m/e 587 15 (M+H+). Anal calcd for C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.
Example 474 trans.trans-4-M .3-Benzodioxol-5-v^-2-f4-methoxvPhenvlV^1-f(N-20 butvl-N-(3-n-butvlphenvlamino)carbonvnmethvhpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.88 (t, J=7.3 Hz, 3H), 0.92 (t, Js=7.3 Hz, 3H), 1.23-1.59 (m, 8H), 2.58 (t, J=7.6 Hz, 2H), 2.75 (d, 25 J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 1H), 3.12 (t, J=9.3 Hz, 1H), 3.29 (d, *J—15.6 Hz, 1H), 3.46 (dd, J=4.9, 9.7 Hz, 1H), 3.52-3.64 (m, 3H), 3.78 (s, 3H), 3.83 (d, J=9.8 Hz, IH), 5.92 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 6.79-6.87 (m, 4H), 7.05 (d, J=1.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 (t, J=7.6 Hz, 1H). MS (DCI) m/e 587 (M+H+). Anal calcd for 30 C35H42N2O6: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.
Examole 475 frans. frans-4-f 3.4-Dif luorophenvl)-2-f 4-ethvlphenvh-1-fN-f n-butvh-N-f3-methvtphenvl)aminocarbonvlmethvnpvrroiidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.87 (t, 3H, J=7), 1.19 (t, 3H, Js=7), 1.28 (m, 2H), 1.43 (m, 2H), 228 (s, 3H), 2.60 (q, 2H, J=7), 2.66 (m, 2H), 3.06 (m, 1H), 3.21 (d, 1H, J=15), 3.42 (dd, 1H, J=4,9), 3.58 (m, 3H), 3.71 (d, 1H, J=9), 6.80 (s, 2H), 7.06 (s, 4H), 7.18 (m, 4H), 7.45 (m, 1H). MS (APCI) m/e 535 (M+H)+. Anal calcd for C32H36N2O3F2 • 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.
Example 476 trans. frans-2-f4-Ethvlp henvh-4-f 3.4-dif I uorophenvh-1 -f N-f n-butvh-N-(3-chlorophenvhaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.82 (t, 3H, J-7), 1.16 (t, 3H, J=7), 123 (m, 2H), 1.35 (m, 2H), 2.55 (q, 2H, J=7), 2.66 (m, 2H), 3.01 (t, 1H, J=9), 3.16 (d, 1H, J=15), 3.32 (dd, 1H, J=4,9), 3.56 (m, 3H), 3.67 (d, 1H, J=9), 6.94 (d, 1H, J=7), 7.02 (m, 5H), 7.14 (m, 2H), 7.32 (m, 3H). MS (APCI) m/e 555 (M+H)+. Anal calcd for C31H33N2O3CIF2 ■ 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.
Example 477 trans. frans-4-f1.4-Benzodioxan-6-vn-2-f 4-f luorophenvn-1-(N-butvl-N-f3-chlorophenvhaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound, was prepared. ^H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.10-1.30 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (t, J=7 Hz, 1H), 3.15-3.75 (m, 6H), 4.02 (m, 4H), 6.75 (d, J=6 Hz, 1H), 6.85 (dd, J=7 Hz, IH), 6.90 (7.19, J=m Hz, 6H), 7.32-7.43 (m, 3H). MS (DCI) m/e 567 (M+H)+. Anal calcd for C31H32N2O5FCI • 1.6 H2O: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H, 5.54; N, 4.42.
Example 478 frans.frans-4-fBenzofuran-5-vn-2-(4-ethvlphenvn-1-fffN.N-dibutvlaminotearbonvnmethvnpyrroHdine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 0.78 (t, 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 (q, 2H, J=7Hz), 121 (t, 3H, J=7Hz), 1.25 (m, 2H), 1.45 (m, 2H), 2.62 (q, 2H, J=7Hz), 2.80 (d, 1H, J=13Hz), 3.0 (m, 2H), 3.15 (m, 2H), 3.35 (m, 1H), 3.43 (m, 2H), 3.52 (m, 1H), 4.40 (m, 2H), 6.73 (d, 1H, J=1Hz), 7.14 (d, 2H, J=8Hz), 7.26 (s, 1H), 7.31 (d, 2H, J=8Hz), 7.44 (s, 2H), 7.60 (d, 1H, J=1Hz), 7.65 (s, 1H). MS (APCI) m/e 505 (M+H)+. Anal, calc'd for C31H40N2O4: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.21.
Example 479 trans. frans-2-M-Methoxv-3-fluorophenyn-4-f7-methoxv-1.3-ben2odioxol-5-vn-1-f2-(N-propvl-N-(pvrrolidine-1-carbonvlmethvl)amlno)ethvnpvrrolidine-3-carboxviic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-aminoethyl]-pyrrolidine-3-carboxylate, prepared according to the procedures of Example 61B (300 mg), N-bromoacetyl pyrrrolidine (132 mg) and diisopropylethylamine (154 mg) were heated for 1 hour at 50 °C in 1 mL of acetonitriie to give the intermediate ethyl ester. The ester was hydroiyzed to the title compound by the method of Example 1D. 1h NMR (300 MHz, CDCI3) 8 0.88 (t, J=7Hz, 3H), 1.30-1.45 (m, 2H), 1.75-1.92 (m, 4H), 2.30-2.40 (m, 1H), 2.47-2.58 (m, 2H), 2.70-3.00 (m, 5H), 3.24-3.45 (m, 6H), 3.50-3.70, (m, 2H), 3.83 (s, 3H), 3.86 (d, J=9Hz, 1H), 3.88 (s, 3H), 5.93 (s, 2H), 6.58 (d, J=2Hz, 1H), 6.70 (d, J=2Hz, 1H), 6.87 (t, J=8Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.21 (dd, J=2Hz, 12Hz, 1H).
Example 480 frans.frans-2-<,4-Methoxvphenvn-4-n.3-benzodioxol-5-vn-1-f2-(fN-(perhvdroazepinvlcarbonvn-fDVIeucvl)amino)ethvhpvrrolidine-3- carboxvlic acid Example 48QA D-Leucine O-benzvl ester Tosvlate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 g). The 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%).
Example 480B N-Perhvdroazepinvlcarbonvl-D-Leucine Q-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 °C, and carbonyldiimidazole was added. After 1.5 hours, TLC indicated complete consumption of starting material, so hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 M H3PO4 (2 x 20 mL), and brine (20 mL), dried over Na2S04, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 25 - 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).
Example 480C N-Perhvdroazepinvlcarbonvl-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).
Example 480D trans.frans-2-(4-Methoxvphenvn-4-M .3-benzodioxol-5-vl)-1-(cvanomethvn-pvrrolidine-3-carboxvlic acid ethvl ester To the compound resulting from Example 1C (510 mg of a 50 % wt. solution in toluene) dissolved in acetonitriie (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. frans-2-(4-Methoxvphenvn-4-M.3-benzodioxol-5-vn-1-f2-aminoethvh-pyrrolidine-3-carboxvttc acid ethvl ester To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 g), and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) 2 0 and extracted with 1 M HCI (5x1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5x2 mL). The combined organic extracts were dried with MgS04, filtered and evaporated to give the title compound as an unstable oil (0.14 g).
Example 480F fra/?s.frans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-f2-((N-(perhvdroazepinvlcarbonvnieucvnamino)ethvn-pvrrolidine-3- carboxvlic acid, ethvl 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 °C, and EDCl (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 MgS04, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50 - 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%).
Example 480G frans.frans-2-f4-Methoxvphenvl>-4-f 1.3-benzodioxol-5-vn-1 -(2-ffN-{perhvdroazepinvlcarbonvmeucvnamino)ethvnpvrrolidine-3-carboxvlic 9Pi<J The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 mL) and 5 M. NaOH (0.050 mL) was added. After 10 2 hours, additional 5 M. NaOH (0.090 mL) was added. After an additional £ 3.5 hours, the reaction was evaporated. The residue was dissolved in water (5 mL) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 N. H3PO4 to pH « 3. The solid which precipitated dissolved when the mixture was extracted with 15 chloroform (3x3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgS04, filtered and evaporated to give the title compound as a tan solid (0.053 g). Purification by HPLC (Vydac mC18) eluting with a 10 - 70% gradient of CH3CN in 0.1%TFA provided suitable material (0.049 g) after lyophilization of the desired 2 0 fractions. 1H NMR (CDCI3, 300 MHz) 5 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J = 5.7, 5.7 Hz, 6H), 1.04-1.28 (m, 3H), 1.34-1.65 (m, 19H), 2.95 (br m, 2H), 3.15-3.40 (m, 14H), 3.40-3.55 (m, 4H), 3.58-3.68 (m, 2H), 3.70-3.76 (br m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.15 (br m, 2H), 5.10 (br m, • 2H), 5.93 (s, 3H), 5.95 (s, 3H), 6.70-6.97 (m, 13H), 7.43-7.56 (br m, 3H), 25 82 (br s, 1H), 8.5 (br s, 1H). MS(DCI/NH3) m/e 623 (M+H)+. Anal calcd for C34H46N4O7 • 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.
Example 481 trans.trans-4-M .3-Benzodioxol-5-vn-2-(4-methoxvphenvn-1-fN.N-dif n-hexvnaminocarbonvlmethvhpyrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.80-0.95 (m, 6H), 1.0 (m, 2H), 1.07 (1.55, J=m Hz, 14H), 2.70 (d, J=13 Hz, 1H), 2.85-3.15 (m, 4H), 35 320-3.60 (m, 9H), 3.64 (d, J=10 Hz, 1H), 3.79 (s, 3H), 5.90 (m, 2H), 6.70 (d, 8H), 1, 6.80-6.93 (m, 3H), 7.05 (2, 1H), 7.35 (d, J=10 Hz, 2H). Anal calcd for C33H46N2O6 • 1.7 H2O: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52.
Example 482 trans, trans-4-d. 4-Benzodioxan-6-vh-2-(4-f luorophenvh-1 -(N-htitvl-N-f3-methvlphenvnaminocarbonvlmethvnpvrrolidlne-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7 Hz, 3H), 1.20-1.35 (m, 2H), 1.35-1.40 (m, 2H), 2.32 (s, 3H), 2.55-2.70 (m, 2H), 2.97 (t, 10 J=7 Hz, 1H), 3.22 (d, J=14 Hz, 1H), 3.25-3.70 (m, 5H), 4.20 (m, 4H), 6.97 # (d, J=2 Hz, 1H), 7.09 (m, 2H), 7.15-7.35 (m, 2H). MS (DCI) m/e 547 (M+H)+. Anal calcd for C32H35N2O5F • 1.2 H2O: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70. 1 5 Example 483 frans.frans-4-n.3-Benzodioxol-5-vn-2-f4-methoxvphenvn-1-(f(N-butvl-N-f3-nitrobenzvhamino)carbonvnmethvhpvrroHdine-3- carboxvlic acid Using the procedures described in Example 1, the title compound 20 was prepared. 1H NMR (300 MHz, CDCI3 ) 8 (rotamer) 8.14 (2H, m), 8.05 (7.83) (1H, m), 7.60-7.30 (3H, m), 7.13 (1H, m), 7.10-6.70 (5H, m), 5.94 (2H, m), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, ^ m), 4.10 (2H, m), 3.80 (3.76) (3H, s), 3.75-3.40 (3H, m), 3.20-2.80 (2H, ™ m), 1.50 (IH, m), 1.30 (1H, m), 1.20-1.00 (2H, m), 0.91 (0.78) (3H, t, 25 J=8). MS (DCI/NH3) m/e 590 (M+H+). Anal calcd for C32H35N3O8 • 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.frans-4-M .2-Dihvdrobenzofuran-5-vn-2-(4-ethvlphenvn-1-((fN-30 butvl-N-(3.4-dimethoxvbenzvnamino)carbonvnmethvnpvrrolidine-3- carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H (300MHz, CDCI3 ) 8 (rotamer) 7.40 (2H, m), 7.30-7.10 (4H, m), 6.90-6.70 (3H, m), 6.48 (1H, m), 5.45 (1H, m), 4.65 (1H, d, 35 J=15), 4.57 (2H, dt, J=9, 3), 4.40-4.00 (5H, m), 3.87 (3.85) (3H, s), 3.84 (1H, m), 3.83 (3.79) (3H, s), 3.56 (2H, m), 3.20 (2H, t, J=10), 2.90 (1H, m), 2.64 (2H, q, J=8), 1.52 (1H, m), 1.31 (2H, m), 1.22 (3H, dt, J=9, 2), 1.07 (1H, m), 0.92 (0.78) (3H, t, J=8). MS (DCI/NH3) m/e 601 (M+H+).. Anal calcd for C36H44N2O6 • 1.35 TFA: C, 61.59; H, 6.06; N, 3.71.
Found: C, 61.69; H, 6.04; N, 3.63.
Example 485 trans.trans-4-( 1.3-Benzodioxol-5-vn-2-(4-methoxvphenvB-1-fffN-butvl-N-(4-heptvnamino)carbonvnmethvnpvrrondine-3-carboxvHc acid Using the procedures described in Example 1, the title compound d was prepared. 1H NMR (300 MHz, CD3OD) 8 0.71-1.04 (m, 11H), 1.07-1:35 (m, 6H), 1.73-1.53 (m, 4H), 2.79-3.25 (m, 5H), 3.35-3.44 (m, 1H), 3.51-3.68 (m, 3H), 3.78-3.89 (m, 1H), 3.79 (s, 3H), 5.92 (m, 2H), 6.74 (dd, Js=1.7, 8.1 Hz, 1H), 6.85 (td, J=1.7, 8.1 Hz, 1H), 6.93 (m, 2H), 7.02 1 5 (dd, J=1.7, 9.5 Hz, 1H), 7.36 (m, 2H). MS (C.I.) m/e 553 (M+H+). Anal calcd for C32H44N2O6: C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06.
Example 486 trans.frans-2-(4-Methvlcvclohexvn-4-M .3-benzodioxol-5-vn-1 -fN.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 • MHz) 8 0.88 (3H, d, J = 7Hz), 0.92 (3H, t, J = 7Hz), 0.96 (3H, t, J = 7Hz), 1.05 (1H, m), 1.22-1.40 (7H, m), 1.45-1.65 (6H, m), 1.67-1.84 (4H, m), 3.17-3.45 (6H, m), 3.70 (1H, brm), 3.82 (1H, dd, J = 9Hz, 15Hz), 3.86 (1H, d, J = 15Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 501 (M+H)+. Anal calcd for C29H44N2O5 • 0.25 CF3CO2H : C, 66.96; H, 8.43; N, 5.29. 3 0 Found: C, 66.79; H, 8.60; N, 4.87.
Examole 487 trans.frans-2-f2-Propvlpentvl)-4-H .3-benzodioxol-5-vn-1 -(N.N-dibutvtaminocarborivlmethvnpvrrolidine-3-carboyylin ariri Using the procedures described in Example 1, the title compound 5 was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.12-1.40 (13H, m), 1.42-1.68 (6H, m), 2.90 (1H, m), 3.14-3.30 (2H, m), 3.33 (4H, m), 3.72 (1H, brm), 3.90 (1H, brm), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS 10 (DCI/NH3) m/e 517 (M+H)+. Anal calcd for C30H48N2O5 • 0.35 CF3CO2H : C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98.
Example 488 trans.trans-4-M .4-Benzodioxan-6-vh-2-f4-fluorophenvl)-1-fN.N-15 dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.83 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.9.0-1.17 (m, 4H), 1.20-1.65 (m, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1H), 2.95-3.60 (m, 7H), 3.71 (d, J=9 Hz, 1H), 4.21 (s, 4H), 20 6.72 (d, 1H), 6.91 (dd, J=8 Hz, 1H), 6.97 (d, J=2 Hz, 1H), 7.05 (t, J=7 Hz, 2H), 7.40-7.50 (m, 2H). MS (DCI) m/e 513 (M+H)+. Anal calcd for C29H37N2O5F • 1.2C F3COOH: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.81; N, 4.56.
Example 489 trans. frans-2-f3-Methvlpentvn-4-(1 .S-benzodioxol-S-vn-l-fN.N-dibtJtvlamino-carbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 30 MHz) 8 0.83 (3H, t, J = 7Hz), 0.85 (3H, d, J= 7Hz), 0.91 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.05-1.22 (2H, m), 1.22-1.41 (7H, m), 1.43-1.68 (5H, m), 1.89 (1H, m), 2.94 (1H, t, J = 6Hz), 3.15-3.27 (3H, m), 3.29-3.60 (5H, m), 3.72 (1H, brd, J = 6Hz), 3.92 (1H, brd, J = 13.5Hz), 5.93 (2H, dd, J = 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, 35 d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5 • 0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.
Example 490 trans. frans-2-(2-Ethvlbutvh-4-( 1.3-benzodioxol-5-vn-1-fNN- dibutvlaminocarbonvlmethvnpvrroHdine-3-carboxvlic 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 (6H, m), 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.13-10 1.41 (13H, m), 1.43-1.72 (6H, m), 2.96 (1H, brm), 3.12-3.52 (6H, m), a 3.55-3.70 (1H, m), 3.70-3.86 (2H, m), 3.99 (1H, brm), 5.93 (2H, dd, J = ^ 2Hz, 4Hz), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5 • 0.45 CF3CO2H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 15 5.08.
Example 491 frans.frans-2-f3-Fluoro-4-methoxvphenvn-4-M .3-benzodioxol-5-vn-l-^-fN-isobutvl-N-fbutanesulfonvlamino^ethvnpvrrolidine-S-20 carboxylic acid Using the procedures described in Example 66, the title compound was prepared. "»H NMR (CD30D, 300 MHz) 8 0.74 (d, 3H, J=7), 0.83 (d, 3H, J=7), 0.94 <t, 3H, J=7), 1.44 (hex, 2H), 1.67 (m, 4H), 2.91 (d, 2H, J=8), ^ 3.04 (dd, 2H, J=8,10), 3.1-3.6 (m, 5H), 3.78 (m, 2H), 3.92 (s, 3H), 4.60 25 (m, 1H), 5.97 (s, 2H), 6.82 (d, 1H, J=8), 6.89 (dd, 1H, J=2, 8), 7.01 (d, 1H, J=2), 7.22 (t, 1H, J=9), 7.39 (m, 2H). MS (ESI) m/e 579 (M+H)+.
Example 492 trans. frans-2-(4-Methoxv-3-fluorophenvn-4-f 1.3-benzodioxol-5-vn-3 0 1-r2-fN-propvl-N-f4-ethvlpyrimidin-2-vllamino)ethvnpvrrolidine-3- carboxvlic acid 1-Dimethylamino-1-pentene-3-one, prepared by the method described in Syn. Comm. 12 (1), 35 (1982), was converted to 2-amino-4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 35 (1964). This material was converted to 2-bromo-4-ethyl-pyrimidine with NaN02 and HBr, using the method of Helv. Chim. Acta 75, 1629 (1992). This bromopyrimidine was reacted with ethyl 2-(4-methoxphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propylamino)propyl]-pyrrolidine-3-carboxylate, prepared using the procedures of Example 61B, using the procedure for Example 418, to give the title compound as a white powder. 1H NMR (300 MHz, CDCI3) 8 0.83 (t, J=7Hz, 3H), 1.11 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (m, 1H), 2.45 (q, J=7Hz, 2H), 2.80-2.97 (m, 3H), 3.40-3.75 (m, 7H), 3.83 (s, 3H), 5.95 (s, 2H), 6.25 (d, J=4Hz, 1H), 6.68 (d, J=8Hz, 1H), 6.79 (dd, J=2Hz, 8Hz, 1H), 6.82 (t, J=9Hz, 1H), 6.92 (d, J=2Hz, 1H), 7.05 (d, J=9Hz, 1H), 7.15 (dd, J=2Hz, 12Hz, 1H), 8.10 (d, J=4Hz, 1H).
Example 493 trans.trans-A-(1 .3-Benzodioxol-5-vn-2-(4-methoxvDhenvn-1 -((N-butvl-N-f3.4-dimethvlphenvnaminocarbonvhmethvhpvrrolidine-3-15 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (t, J=7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.38-1.43 (m, 2H), 2.22 (s, 3H), 2.29 (s, 3H), 2.79 (d, J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 (t, J=9.5 Hz, IH), 3.32 2 0 (d, J=15.3 Hz, 1H), 3.43-3.61 (m, 4H), 3.79 (s, 3H), 3.88 (d, J=9.8 Hz, 1H), 5.93 (s, 2H), 6.74 (m, 3H), 6.83 (m, 3H), 7.04 (d, J=1.7 Hz, 1H), 7.11 (m, 3H). MS (C.I.) m/e 559(MH+). Anal calcd for C33H38N206*0.3H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.
Example 494 trans.trans- 2-(3-Methvlpent-3-en-1-vh-4-(1.3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvlmethvnpvrrolidine-3-carboxvlic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 30 MHz) 8 0.92 (3H, t, J = 7Hz), 0.97 (3H, t, J = 7Hz), 1.22-1.40 (5H, m), 1.44-1.61 (8H, m), 1.82 (1H, brm), 2.02 (2H, m), 3.05-3.30 (4H, m), 3.3.8 (1H, m), 3.55 (1H, brm), 3.85 (2H, m), 4.12 (1H, brd, J = 15Hz), 5.11 (1H, dd, J = 6Hz, 12Hz), 5.93 (2H, s), 6.73 (1H, d, J = 8Hz), 6.78 (1H, dd, J = 2Hz, 8Hz), 6.88 (1H, d, J = 2Hz). MS (DCI/NH3) m/e 487 (M+H)+. Anal 35 calcd for C28H42N2O5 • 0.7 CF3CO2H : C, 62.34; H, 7.60; N, 4.95. Found: C, 62.49; H, 7.43; N, 4.73.
Example 495 1-fN-Phenvlaminocarbonvlmethvn-2-(4-methoxvphfinvn-4-M .3-ben2od<oxol-5-vnpvrrol?dine-3-carboxvlic acid Example 495A N-Phenvlbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at -50 °C 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 °C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether is (70 mL) and poured into 1 H sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2S04) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title 20 compound.
Example 495B ^ irans.frans-1-(N-Phenvlaminocarbonvlmethvn-2-f4-methoxvphenvn- 4-n.3-henzodioxo[-5-vnpvrrolidine-3-carboxvlic acid 25 Using the procedures described in Example 1 and the compound resulting from Exampe 495A, the title compound was prepared. NMR (300 MHz, CDCI3) 8 8.8 (bs, 1H) 7.49 (2H, d, J=8Hz), 7.38 (4H, m), 7.11 (1H, tt, J=8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1H, d, J=2Hz), 6.81 (1H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 30 3.94 (1H, d, Jj=10Hz), 3.78 (3H, s), 3.70 (1H, ddd, 6, 5&3Hz), 3.42 (1H, dd, «/=10&3Hz), 3.41 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.01 (1H, t, J=10Hz), 2.93 (1H, d, J=16Hz). MS (DCI, NH3) m/e 475 (M+H+). Anal. Calc for C27H26N2O6 • 1 H2O: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38.
Example 496 trans, trans-1 -(N-f 2.3-Dimethvlphenvnaminocarbonvlmftthvn-2-(4-methoxvphenvlV4-f 1.3-benzodioxol-5-vnDvrrolidine-3-carbQxvlir: aniri Using the procedures described in Example 1, the title compound 5 was prepared. 1H NMR (300 MHz, CDCI3) 5 8.68 (1H, bs), 7.64 (d, J=s8Hz), 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=10Hz), 3.80 (3H, s), 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.44 .0 (1H, d, J=16Hz), 3.18 (1H, dd, J=1.1&9Hz), 3.06 (1H, t, J=10Hz), 2.96 (1H, " d, J=16Hz), 2.31 (3H, s), 2.16 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 ■ 0.5 H2O: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29.
Example 497 trans, trans-1 -(N-f 2.4-Dimethviphenvnaminocarbonvlmethvh-2-(4-methoxvphenvh-4-f 1.3-benzodioxol-5-vhpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the titie compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.60 (1H, bs), 7.78 (d, 2 0 J=8Hz), 7.38, (2H, d, J=8Hz), 6.99 (1H, m), 6.95, (1H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.92 (1H, d, | J=r10Hz), 3.79 (3H,s), 3.68 (1H, ddd, J=6, 5&3Hz), 3.43 (1H, dd, «/=10&3H2), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, 25 JsslOHz), 2.95 (1H, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.75 H2O: C, 67.50., . H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13.
Example 498 trans, trans- 1-f N-f 2 ■5-Dimethvlphenvhaminocarbonvlmethvl)-2-f 4-methoxvphenvh-4-f 1 .a-benzodioxol-S-ynpyrrolidine-S-carboxvlic acid Using the procedures described in Example 1, the titie compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.62 (1H, bs), 7.79 (1H, bs), 7.38, (2H, d, J=8Hz), 7.03 (1H, d, J=8Hz), 6.95, (1H, d, J=8Hz), 6.94 35 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, d, J=8Hz), 5.97 (2H, s), 3.92 (1H, d, J=10Hz), 3.78 (3H, s), 3.70 (1H, ddd, J~6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J=16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=10Hz), 2.95 (1H, d, J=16Hz), 2.29 (3H, s), 2.24 (3H, s). MS (DC!, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 • 0.5 H2O: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5 5.89; N, 5.25.
Example 499 frans. frans-1-(N-f 3.4-Dimethvlphenvnaminocarbonvlmethvn-2-(4-methoxvphenvn-4-( 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvHc acid ^ Using the procedures described in Example 1, the title compound 9 was prepared. NMR (300 MHz, CDCI3) 8 8.73 (1H, bs), 7.38 (2H, bd, J=8Hz), 7.30, (1H, d, J=3Hz), 7.20 (1H, bs), 7.08, (1H, d, J=8Hz), 7.01 (1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1H, bs), 6.80 (1H, d, J=8Hz), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=10Hz), 3.78 (3H, s), 15 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.42 (1H, d, J= 16Hz), 3.18 (1H, dd, J=11&9Hz), 3.04 (1H, t, J=10Hz), 2.95 (1H, d, J=16Hz), 2.25 (3H, s), 2.21 (3H, s). MS (DCI, NH3) m/e 503 (M+H+).
Anal. Calc for C29H30N2O6 • 0.75 H2O: C, 67.50; H, 6.15; N 5.43.
Found: C, 67.24; H, 5.94; N, 5.20.
Example 500 trans, trans- 1-(N-(3.5-Dimethvlphenvnaminocarbonvlmethvn-2-(4-methoxvphenvn-4-f 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvlic acid Using the procedures described in Example 1, the title compound 25 was prepared. 1H NMR (300 MHz, CDCI3) 8 8.75 (1H, bs), 7.35, (2H, d, J=8Hz), 7.10 (2H, s), 7.02 (1H, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1H, . d, J=2Hz), 6.80, (1H, d, J=8Hz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=10Hz), 3.79 (3H, s), 3.68 (1H, ddd, 6, 5&3Hz), 3.40 (2H, m), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J^10Hz), 30 2.88 (1H, d, J=16Hz), 2.3 (6H, s). MS (DCI, NH3) m/e 503 (M+H+). Anal. Calc for C29H30N2O6 * 0.5 H2O: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.
Example 501 Alternate Preparation of (+)-trans. trans- 1-fN.N-Di-n-butvlaminocarbonvlmethvh-9-M-methoxvphenvl>-4-( 1.3-benzodioxol-5-vnpvrrolidine-3-carboxvKc aniri Hydrochloride Salt Example 501A N. N-Dibutvl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in 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 °C. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and 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-Nitrovinvn-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 °C. After about 30 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 to 10 °C and filtered. The precipitate was washed with acetic acid (2x8 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 (80%) of the title compound as a bright yellow solid.
Examole 501C 4-Methoxvbenzovl acetate To potassium t-amyiate (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 °C. 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 adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20 °C. The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
Example 501D Ethvl 2-(4-methoxvbenzov0-4-nit^omethvl-3-(, 1.3-benzodioxol-5-vn butvrate 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 °C, sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about 15 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 (95%).
Example 501E Fthvl cis. c/s-2-Y4-methoxvphenvn-4-M .3-benzodioxol-5-vn pvrrolidine-3-carboxvlate Raney nickel (20.0 g), from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple. 1 5 THF (20 mL), the crude compound resulting from Example 501D (40.82 g, 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at 60 psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area % nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine compound. The filtrate was concentrated and chased with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 H NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g (73%) of the title compound.
Example 501F Ethvl trans. frar?s-2-f4-methoxvphenvn-4-M .3-benzodioxol-5-vn pyrrol idine-3-carboxvl ate The solution of the compound resulting from Example 501E (38.1 20 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 °C. When HPLC shows <3% of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to 25 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) 3 0 and neutralized to pH 7 with solid sodium bicarbonate (21 g). The organic layer was separated and found to contain 32.9 g (87%) of the title compound.
Example 501G Ethvi (2R.3R. 4SW+V2-f4-methoxvphenvl)-4-f1 .3-benzoriioxol-5-vn pvrrolidine-3-carboxvlate. (S)-(+) mandelate salt The solution resulting from Example 501F was chased with acetonitriie (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g (40%) of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexane-ethanol-diethylamine; flow - 1 mL/min.; UV detection at 227 nm. Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.
Example 501H (2R.3R.4SW+)-2-/4-methoxvphenvn-4-(1.3-benzodioxol-5-vlV1-fN.N-dibutvlaminocarbonvlmethvn- pvrrolidine-3-carboxvlic 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 acetonitriie (200 mL) to a final volune of 100 mL and cooled to 10 °C. Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution (40%, 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH with 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.4SM+)-2-f4-methoxvphenvn-4-n.3-benzoriioxol-5-vn-1-fN.N-dibutvlaminocarbonvlmethvn- pvrrolidine-3-carboxvlic arid 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) K The resultant solution was filtered to remove foreign matter, concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a 15 volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g (90%) of the title compound.
Example 502 trans. frans-2-f2-Methvlpentvh-4-(1.3-benzodioxol-5-vn-1-(N.N- dibutvlaminocarbonvlmethvn-pyrrolidine-3-carboxvlic acid Example 502A faVEthvl 3-methvlhexanoate 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, 52mmoI). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at 30 room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in 50mL of ethanol and 10% palladium on carbon (6.0g) was added. The 35 vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0g of the title compound.
Example 5Q2B (i)-Ethvl 5-methvl-3-oxooctanoate To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964).
Example 5Q2C trans, trans-2-f2-Methvlpentvn-4-( 1.3-benzodioxol-5-vt)-1 -(N.N-dibutylaminocarbonvlmethvn-pvrrolidine-3-carboxvnc 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. NMR (CDCI3, 300 MHz) 6 0.8-1.0 (m, 12H), 1.2-1.4 (m, 7H), 1.45-1.6 (m, 6H), 1.6-1.74 (m, 1H), 1.8-2.0 (m, 1H), 3.1-3.4 (m, 5H), 3.67-3.78 (m, 1H), 3.8-3.91 (m, 1H), 4.0-4.2 (m, 2H), 4.3-4.5 (m, 2H), 5.93 (d, J=1.5 Hz, 2H), 6.73 (dd, J=8.1, 1.2 Hz, 1H), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 6.86 (dd, J=3.9, 1.5 Hz, 1H). MS (DCI/NH3) m/e 489 (M+H)+. Anal calcd for C28H44N2O5*1.0 TFA- 0.5 H2O: C, 58.91; H, 7.58; N, 4.58. Found: C, 58,91; H, 7.58; N, 4.45.
Examole 503 trans. frans-2-(2.2-Dimethvlpentvn-4-M ■S-benzodioxol-S-vn-l-fN-N- dibutvlammocarbonvlmethvn-Pvrrolidine-S-carboxvHc aciri Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 21, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3-dimethylhexanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.80-0.99 (m, 15H), 1.10-1.37 (m, 8H), 1.43-1.58 (m, 4H), 1.77-1.97 (m, 2H), 3.48-3.12 (m, 5H), 3.60-3.69 (m, 1H), 3.75-3.86 (m, 1H), 3.95-4.16 (m, 2H), 4.28-4.4 (m, 2H), 5.94 (s, 2H), 6.74 (d, J=7.8 Hz, 1H), 6.8 (dd, J=8.1, 1.5 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 (M+H)+. Anal calcd for C29H46N205'1.05TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.
Example 504 trans.trans-2-(2-M .3-Dioxo-2-vnethvn-4-M .3-benzodioxol-5-vn-1 -fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Example 504A Ethvl 5-C1.3-dioxolvn-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 °C 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 before 13.5 mL (0.130 mol) bromomethyl-1,3-dloxane 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 pressure to give an brown oily residue. The crude product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g (20%) of b-keto ester as a light yellow oil.
Example 504C trans. trans-2~( 2-( 1.3-Dioxo-2-vnethvn-4-( 1.3-benzodioxol-5-vn-1 -(N.N-dihutvlaminocarbonvlmethvn-Pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502 and substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate 20 afforded the title compound. NMR (CDCI3, 300 MHz) 8 0.93 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.38 (m, 4H), 1.52 (sextet, J = 7.9 Hz, 4H), 1.85-1.95 (m, 2H), 2.02-2.17 (m, 2H), 3.18 (dd, J = 6.0 Hz, 9.0 Hz, 2H), 3.30 (dd, J = 9.0 Hz, 18.0 Hz, 2H), 3.35 (m, 1H), 3.79 (dd, J = 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88 (m, 3H), 3.97 (dd, J = 4.8 Hz, 6.0 Hz, 1H), 4.05 25 (q, J = 9.6 Hz, 2H), 4.30-4.40 (m, 1H), 4.37 (s, 2H), 4.87 (t, J « 3.6 Hz, 1H), 5.94 (s, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.79 (dd, J = 1.8 Hz, 8.1 Hz, . 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (APCI) (M+H)+ at m/e 505. Anal calcd for C27H40N2O7-1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.
Example 505 trans.trans-P-(2-(2-T etrahvdro-2H-pvran)ethvn-4-( 1.3-benzodioxol-5-vh-1 -fN.N-dibutvlammocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Examole 505A Ethvl 5-(2-tetrahvdro-2H-PvranV3-oxopentanoate Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow oil.
Example 5Q5B trans. ffa/?s-2-(2-(2-Tetrahvdro-2H-Pvran)ethvn-4-M .3-hen7odioxot-5-vh-1-(N.N-dibutvlaminocarbonvlmethvh-ovrrolidine-3-carboxvlic Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2H-pyran)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) as a mixture of two diastereoisomers: 8 0.89 (t, J = 8.1 Hz, 3H), 0.89 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 0.91 (t, J = 8.1 Hz, 3H), 1.20-1.40 (m, 10H), 1.42-1.66 (m, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H), 3.10-3.29 (m. 8H), 3.29-3.52 (m, 6H), 3.54-3.81 (m, 6H), 4.01 (q, J = 9 Hz, 2H), 4.12-4.25 (m, 4H), 4.43 (d, J 3= 9 HZ, 2H), 4.50 (d, J = 2.7 Hz, 2H), 5.94 (s, 2H), 5.95 (s, 2H), 6.76 (s, 2H), 6.76 (s, 2H), 6.81 (s, 1H), 6.81 (s, 1H). MS (APCI) (M+H)+ at m/e 517. Anal calcd for C29H44N206-1-4 TFA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H, 6.99; N, 3.83.
Example 506 trans. frans-2-f2.2.4-Trimethvl-3-pentenvn-4-f1.3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvimethvh-pvrrolidine-3-carboxvlic acid Example 506A Methvl 3.3.5-trimethvl-4-hexenoate To a slurry of isopropyltripenylphosphonium iodide (20.5g, 47mmol) in 200mL of tetrahydrofuran was added n-butyllithium (27mL of a 1.6M solution in hexane, 43mmol), and the solution was briefly warmed to 0°C. After recooling, a solution of methyl 3,3-dimethyl-4- 4' oxobutenoate (5.7g, 40mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., IS. 169 (1986) in 10mL of tetrahydrofuran was added, and the reaction was warmed to 0°C for 30min. The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1g (30%) of the title compound.
Example 506B trans. trans-2-(2.2A-Trimethvl-3-pentenvn-4-M .3-benzodioxol-5-vlV1-fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-methylhexanoate afforded the titie compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.92 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 1.11 (s, 3H), 1.13 (s, 3H), 1.24-1.37 (m, 20 4H), 1.46-1.59 (m, 4H), 1.61 (d, J=1.2 Hz, 3H), 1.69 (d, J=1.2 Hz, 3H), 2.04-2.11 (m, 2H), 3.10-3.20 (m, 2H), 3.30-3.39 (m, 3H), 3.67-3.82 (m, 2H), 3.95-4.08 (m, 1H), 4.32 (m, 2H), 4.37-4.47 (m, 1H), 4.99 (s, 1H), 5.95 (s, 2H), 6.73 (d, J=7.8 Hz, 1H), 6.78 (dd, J=8.4, 1.2 Hz, 1H), 6.84 (d, J=1.2 Hz, 1H). MS (DCI/NH3) m/e 515 (M+H)+. Anal calcd for 25 C30H46N205-1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.
Example 507 trans. frans-2-f2.2--Dimethvl-2-f 1.3-dioxolan-2-vnethvn-4-f 1.3-ben2odioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvh-pvrrolidine-3- carboxvlic acid Example 5Q7A Methvl 3.3-dimethvl-3-( 1.3-dioxolan-2-vhpronannatft Methyl 3,3-dimethyl-4-oxobutanoate (10g, 70mmol), prepared 5 according to the procedure of Hudlicky et al., Synth. Commun., 16 169 (1986), was dissolved in 40mL of benzene, followed by addition of ethylene glycol (20mL), and p-toluenesulfonic acid monohydrate (1.3g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200mL of ether, washed with saturated io sodium bicarbonate, water and brine, dried with anhydrous magnesium 9 sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g (94%) of the title compound.
Example 507B trans. frans-2-(2.2.-Dimethvl-2-( 1.3-dioxolan-2-vnethvn-4-M .3-benzoriioxol-S-vn-l-CN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-S- carboxvlic acid Using the procedures described in Example 502 and substituting 20 methyl 3,3-dimethyl-3-(1,3-dioxolan-2-yl)propanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. NMR (CDCI3, 300 MHz) 8 0.82-1.00 (m, 12H), 1.24-1.40 (m, 4H), 1.43-1.64 (m, 5H), 1.76-1.84 (m, 1H), 2.93-3.00 (m, 1H), 3.15-3.47 (m, 6H), 3.60-3.70 (m, 3H), 25 3.74-3.95 (m, 5H), 4.48 (s, 1H), 5.94 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H). MS (DCI/NH3) m/e 533 .
(M+H)+. Anal calcd for C29H44N2O7 *1.1 TFA-0.2 H2O: 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-("\ .3-Dioxo-2-vnethvn-4-(1.3-benzodioxol-5-vl>-1-rrA/-4-heptvl-A/-f2-methvl-3-fluorophenvm amino carbonvlmethvll- pvrrolidine-3-carboxvlic acid Examole 508A 4-Heptanol To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in 5 20 mL of diethyl ether was added 370 mg (10.0 mmol) of 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 H2O, 0.4 mL 15% (wlv) NaOH(aq), and 1.2 mL H2O. After stirring another 45 minutes, MgS04 was added until the salts were free flowing, then the ^0 reaction was filtered. The salts were washed with diethyl ether (3x5 ™ mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g (100%).
Example 508B 4-Methanesulfonvloxvheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute.
The mixture was stirred at 0 °C for 30 minutes, then extracted with H2O (1x15 mL), 5% NH4OH (2x15 mL), 1M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgS04, filtered, and concentrated to an oil.
Yield 1.31g (94%). 1H NMR (300 MHz, CDCI3) d 0.96 (t, 6, J = 9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J = 5).
Example 508C 4-Fluoro-3-methvlaniline 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 (94%) of a colorless oil.
Example 5Q8D A/-HePtvl-4-fluoro-3-methvlaniHne To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline 5 in 30 mL of acetonitriie was added 7.64 g (3.93 mmol) of 4- methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHC03(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2 x 30 mL). The combined ether layers were back extracted with brine (1 x 30 mL), dried over MgS04, ^ 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 (35%) of a pale yellow oil.
Example 508E A/.AM4-HeptvlW4-fluoro-3-methvnphenvlbromoacetamide To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4-fluoro-3-methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl 20 bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 °C, 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 H2O (2 x 50 mL), saturated NaHC03(ag) (2 x 50 mL), and brine (1 x 50 mL), dried over 25 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 (99%) of a light yellow oil. ^H NMR (300 MHz, CDCI3) d 0.94 (t, 6, J = 5), 1.33 (m, 4), 1.43 (m, 4), 2.30 (s, 1.5), 2.31 (s, 1.5), 3.54 (s, 2), 4.72 (quintet, 1, J = 5), 6.96-7.04 (m, 2), 7.07(d, 1, J = 30 7).
Example 5Q8F trans.traris-2-(2-( 1.3-Dioxol-2-vnethvh-4-n.3-benzodioxol-5-vh-1 -rr/S/-4-heptvl-A/-(2-methvl-3-fluorophenvni amino carbonvlmethvrf- pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and A/,A/-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for /V,A/-dibutylbromoacetamide afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.93 (brt, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9.0 Hz, 1H), 3.52-3.67 (brm, 2H), 3.73 (t, J = 9.0 Hz, 1H), 3.81-4.02 (m, 6H), 4.13 (brm, 1H), 4.72 (quintet, J = 6.9 Hz, 1H), 4.86 (t, J = 4.0 Hz, 1H), 5.93 (s, 2H), 6.72 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 6.96 (m, 2H), 7.08 (t, J = 9.0 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 599. Anal Calcd for C33H43N2O7F-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.trans-2-(2-(1.3-Dioxol-2-vnethvn-4-M .3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvlmethvn-pvrrolidlne-3'Carboxvlic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxblyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.93 (t, J = 7.8 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H), 1.31 (m, 4H), 1.53 (m, 4H), 1.90 (m, 2H), 2.09 (m, 2H), 3.19 (dd, J = 8.4 Hz, 8.4 Hz, 2H), 3.30 (q, J = 9.6 Hz, 2H), 3.25-3.42 (m, 1H), 3.73 (q, J = 10.5 Hz, 1H), 3.78-3.94 (m, 4H), 3.88 (s, 3H), 3.96 (dd, J = 5.1 Hz, 6.0 Hz, 1H), 4.03 (dd, J = 3.0 Hz, 6.3 Hz, 2H), 4.33 (m, 3H), 4.87 (t, J = 3.6 Hz, 1H), 5.94 (s, 2H), 6.53 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 535. Anal calcd for C28H42N208-1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N, 4.26.
Example 510 frans.frans-2-((2-Methoxvphenoxv)-methvn-4-M .3-benzodioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvh-pvrrolidine-3-carhoxvlic acid Using the procedures described in Example 502, substituting o- methoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 0.90 (t, J=7Hz, 3H), 1.15-1.35 (m, 4H), 1.40-1.55 (m, 4H), 3.05-3.25 (m, 4H), 3.28-3.55 (m, 4H), 3.58-3.68 (m, 1H), 0 3.75-3.80 (m, 1H), 3.82 (s, 3H), 3.91 (d, J=14Hz, 1H), 4.05-4.15 (m, 1H), 1 4.23-4.33 (m, 1H),5.91 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.82-6.95 (m, 5H), 7.03 (s, 1H). MS (DCI/NH3) (M+H)+ at m/e 541. Anal calcd for C30H40N2O7: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.
Example 511 /gS.3ft.4S)-2-f2.2-Dimethvlpentvn-4-f1 .3-benzodioxol-5-vn-1-fN-4-heptvl-N-(4-fluoro-3-methvlphenvh)aminocarbonvlmethvh-pvrrolidine-3-carboxvlic acid Example 511A trans. trans-N-tert-Butoxvcarbonvl-2-(2.2-dimethvlDentv1)-4-( 1.3-benzodioxol-5-vn-Pvrrolidine-3-carboxvlic acid Ethyl trans, trans-2-(2,2-dimethylpentyl)-4-(1,3-benzodioxol-5- yl)-pyrro!idine-3-carboxylate (2.5g, 6.9mmol), prepared according to . Example 503, was dissolved in 50mL of methylene chloride and di-tert-butyldicarbonate (1.5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the 3 0 residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 50mL of ethanol followed by addition of sodium hydroxide (10mL of a 5M aqueous solution). After stirring for 20 hours at room temperature, the 35 solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water, and acidified with concentrated phosphoric acid. The mixture was extracted with chloroform (3X50mL), arid 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 Methvl trans. frans-2-(2.2-dimethvlpentvh-4-( 1.3-benzodioxol-5-vh-1 -fN-4-heptvl-N-f4-fluoro-3-methvlphenvn)aminocarbonvlmethvn-pvrrolidine-3-carboxvlate: As a single enantiomer The product from Example 51 OA (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0°C, followed by addition of DMF (0.017mL, 5%), and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at 0°C under a stream of nitrogen. The residue was dissolved in 5mL of benzene and evaporated. In a separate flask, (S)-4-benzyl-2-oxazoIidinone (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, 43%), then elution with 20% ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%).
The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of 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 acetonitriie 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 acetonitriie. After 21 hours, the reaction was warmed to 50°C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oil.
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 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 15-20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5°C).
Example 511C (2S.3R:4S)-trans. frans-2-f2.2-Dimethvlpentvn-4-( 1.3-benzodioxol-5-vn-1-fN-4-heptvl-N-(4-fluoro-3-methylphenvmaminocarbonvimethvn-pvrrolidine-3-carboxvlate .
The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.0mL of methanol and sodium hydroxide (0.1 mL 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 from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) d 0.78-0.95 (m, 15H), 1.04-1.46 (m, 12H), 1.76-2.95 (m, 2H), 2.31 (s, 3H), 3.23-3.33 (m, 1H), 3.47-3.58 (m, 1H), 3.6-3.75 (m, 2H), 3.80-3.95 (m, 2H), 4.05-4.15 (m, 1H), 4.73 (m, 1H), 5.94 (s, 2H), 6.70-6.80 (m, 2H), 6.82-6.93 (m, 2H), 6.96-7.14 (m, 2H). MS (DCI/NH3) m/e 597 (M+H)+. Anal calcd for C35H49N2FO5 •0.05H2O *0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: C, 63.84; H, 7.18; N, 3.94. [a]p1=+46° (c 2.7g/L, CHCI3) Example 512 frans./rans-2-(2-f2-Qxopyrrolidin-1-vnethvn-4-f1.3-benzodioxol-5-vl)-1-(N.N-dibutviaminocarbonvlmethvn-Pvrrolidine-3-carboxvlic acid Example 512A 2-Oxopvrrolidin-1 -vlpropionic acid To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin-1-ylpropionitrile in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 °C over night. The reaction mixture was then allowed to cool to 20 room temperature, extracted with methylene chloride three times. The extracts were combined and washed with saturated brine solution once, ^ dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g (25%) of acid as a brown oil.
Example 512B Ethvl 5-f2-oxopvrrolidin-1-yn-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Bram and Vilkas, Bui. Chem. Soc. Fr., 945 (1964).
Example 512C frans.frans-2-(2-(2-Oxopvrrolidin-1-vnethvn-4-( 1.3-benzodioxol-5-vn-1-fN.N-dibutvlam»nocarbonvlmethvh-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting 35 ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl 3- methylhexanoate afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.91 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J = 6.9 Hz, 2H), 2.12-2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, 1H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J = 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H), 3.66 (t, J = 6.9 Hz, 1H), 3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.89 (dd, J « 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N306-1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.
Example 513 trans. trans-2-(2-( 1.3-Dioxol-2-vnethvn-4-(7-methoxv-1.3-benzodioxol-5-vn-1-fN-4-heptvl-N-f4-fluoro-3-methvlphenvh)aminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate, N-4-heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.93 (br t, 6H), 1.23-1.47 (m, 8H), 1.67-2.10 (m, 4H), 2.32 (s, 3H), 3.16 (t, J = 9 Hz, 1H), 3.60-4.03 (m, 8H), 3.88 (s, 3H), 4.21 (brs, 1H), 4.72 (quintet, J = 6.6 Hz, 1H), 4.86 (t, J = 3.6 Hz, 1H), 5.93 (s, 2H), 6.49 (s, 1H), 6.61 (s, 1H), 6.96 (m, 2H), 7.08 (t, J = 9 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 629. Anal calcd for C34H45N2O8F.I.O TFA: C, 58.21; H, 6.24; N, 3.77. Found: C, 58.11; H, 6.11; N, 3.58.
Example 514 frans.f/-ans-2-(2.2-Dimethvlpentvn-4-(7-methoxv-1.3-benzodioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. ^H NMR (CDCI3, 300 MHz) 8 0.81 (s, 3H), 0.84 (s, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 6.9 Hz, 3H), 1.09-1.38 (m, 8H), 1.45-1.59 (m, 4H), 1.84-2.00 (m, 2H), 3.15 (dd, J « 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (m, 3H), 3.72 (t, J = 10.5 Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), 3.88 (s, 3H), 4.02 (q, J = 10.0 Hz, 1H), 4.12 (d, J = 16.8 Hz, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.41 (brm, 1H), 5.94 (s, 1H), 6.52 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 533. Anal calcd for C30H48N206-0.9 TFA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33.
Example 515 frans. frans-2-(2.2-dimethvlpentvh-4-f 2.3-dihvdro-henzof uran-5-vh-1-fN.N-dibutvlaminocarbonvlmethvn-pvrroUdine-3-carboxvlic acid Using the procedures described in Example 502, substituting ethyl 3,3-dimethylhexanoate for ethyl 3-methylhexanoate and 2,3-dihydro-benzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H2O. 1H NMR (300 MHz, CDCI3) 6 0.83 (s, 3H), 0.85 (s, 3H), 0.86 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.09-1.39 (m, 8H), 1.44-1.59 (m, 4H), 1.88 (dd, J=15.0, 7.2 Hz, 1H), 2.00 (d, J=15.0 Hz, 1H), 3.09 (m, 2H), 3.18 (t, J=9.0 Hz, 2H), 3.27-3.38 (m, 3H), 3.65-3.95 (m, 2H), 4.05 (q, J=10.0 Hz, 1H), 4.18 (d, J=16.8 Hz, 1H), 4.30-4.45 (m, 2H), 4.55 (t, J=9.0 Hz, 2H), 6.70 (d, J=8.4 Hz, 1H), 7.04 (dd, J=8.4, 2.1 Hz, 1H), 7.23 (brs, 1H). MS (DCI/NH3) at m/e 501 (M+H)+. Anal calc'd for C30H48N204-1.05 TFA: C, 62.14; H, 7.97; N, 4.51.
Found: C, 62.19; H, 8.00; N, 4.43.
Example 516 trans. trans-2-( 2.2.-Dimethvl-2-f 1.3-dioxolan-2-vl)ethvn-4-M -methoxv-1.3-benzodioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvh- pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting methyl 3,3-dimethyl-3-(1,3-dioxolan-2-yl)propanoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H2O. 1h NMR (CDCI3, 300 MHz) 8 0.93 (t, J=72 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 0.95 (s, 3H), 0.96 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (m, 4H), 1.93 (dd, J=15.9, 6.0 Hz, 1H), 2.13 (d, J=15.9 Hz, 1H), 3.20 (dd, J=7.7, 7.7 Hz, 1H), 326-3.40 (m, 3H), 3.60 (m, 1H), 3.75-3.86 (m, 3H), 3.88 (s, 3H), 3.93-4.01 (m, 3H), 4.00-4.11 (m, 1H), 4.23 (d, J=15.9 Hz, 1H), 4.37-4.48 (m, 2H), 4.49 (s, 1H), 5.94 (s, 2H), 6.51 (d, J=2.1 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H). MS (DCI/NH3) at m/e 563 (M+H)+. Anal calcd for C30H46N2O8 O.9 TFA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05.
Example 517 frartS.irans-2-(2-(2-MethoxvDhenvn-ethvn-4-M .3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvlmethvl>-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, substituting o-methoxyphenyipropionic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (t, J=7Hz, 3H), 0.91 (t, J=7Hz, 3H), 1.10-1.27 (m, 4H), 1.42-1.60 (m, 4H), 1.72-1.89 (m, 1H), 1.91-2.02 (m, 1H), 2.55-2.77 (m, 2H), 2.94 (t, J=6Hz, IH), 3.05-330 (m, 6H), 3.59-3.82 (m, 3H), 3.73 (d, J=14Hz, 1H), 3.77 (s, 3H), 5.91 (s, 2H), 6.70 (d, J=8Hz, 1H), 6.78-6.88 (m, 3H),6.92 (d, J=2Hz, 1H), 7.08-7.19 (m, 2H). MS (DCI/NH3) (M+H)+ at m/e 539. Anal calcd for C31H42N2O6: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; R 7.70; N, 4.99.
Example 518 trans. trans-2-(2.2-Dimethyl-3-(F)-peritenvl)-4-(1-methoxv-1.3-benzodioxol-5-vl\-1-fN.N-dibutvlaminocarbonvlmethyn-pvrrolidine-3- carboxvlic acid Example 518A 4-Methvl-3-penten-2-ol To a stirred solution of 3-methyI-2-butenal (8.7g, 103mmol) in 100mL of tetrahydrofuran under N2 at 0 °C was added methylmagnesium bromide (38mL of a 3.0M solution in ethyl ether, 114mmol) dropwise. The resulting mixture was allowed to warm to. room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting 5 biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g (81%) of alcohol as a colorless oil.
M Example 518B ^ frans-Ethvl 3.3-dimethvl-4-pentenoate A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmoI), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) 15 was heated at 150 °C for 7 hours. The product was then distilled under normal pressure (200-220 °C) to give 5.0g of crude ester as a colorless oil.
Example 518C trans. frans-2-(2.2-Dimethvl-3-fg)-pentenvn-4-f 1-methoxv-1.3- benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonv1methvn-pvrrolidine-3- carboxvlic acid Using the procedures described in Example 502, substituting 25 frans-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 TFA/CH3CN. NMR (CDCI3, 300 MHz) 5 0.92 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, 30 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 (d, J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 (m, 3H), 3.75 (m, 2H), 3.87 (s, 3H), 3.99 (q, J=9 Hz, 2H), 4.11-4.30 (m, 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 (s, 2H), 6.50 (d, J=1.8 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H). MS (DCI/NH3) at m/e 531 (M+H)+. 35 Analysis calc'd for C30H46N2O6-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.
Example 519 trans. frans-2-f3-f2-Pvridvnethvn-4-M .3-benzodioxol-5-vn-1-fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Example 519A 3-(2-Pvridvl)-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and w concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 °C. After the addition was completed, the mixture was held at 50 °C until the 15 color of the reaction mixture turned brown, then heated at 80 °C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for 5 20 min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, 78%).
Example 519B trans. frans-2-(3-(2-pvridvnethvn-4-(1.3-benzodioxol-5-vn-1-(N.N-25 dibutvlaminocarbonvlmethvl>-pvrroHdine-3-carboxvlic acid Using the procedure described in Example 502, the titie compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 8.65 (d, J=6.0 Hz, 1H), 8.06 3 0 (t, J=6.91 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.51 (t, J=6.91 Hz, 1H), 6.82-6.66 (m, 3H), 5.91 (s, 2H), 4.45 (s, 2H), 4.29-4.18 (m, 1H), 4.04 (dd, J=20.1, 10.5 Hz, 1 H), 3.84 (t, J=12.6 Hz, 1 H), 3.62 (dd, J=13.8, 9.6 Hz, 1H), 3.46-3.13 (m, 7H), 2.51 (broad s, 2H), 1.60-1.43 (m, 4H), 1.37-1.22 (m, 4H), 0.91 (t, J=8.4 Hz, 6H). MS (DCI/NH3) m/e 510 (M+H)+. Anal 35 calcd for C29H3gN305*1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81.
Examole 520 (2S. 3R. 4S)-2-(2-(2-oxopvrrolidin-1 -vhethvh-4-( 1.3-ben2odioxol-5-vn-1-(N.N-dibutvlaminocarbonvlmethvh-pvrrolidine-3-carboxvlic acid Example 520A 12S. 3R. 4S)-Ethvl-2-(2-(2-oxopvrrolidm-1-vnethvn-4-n.3- benzodioxol-5-vnpvrrolidine-3-carboxvlate-(S)-Mandelate The racemic amino ester from Example 512 (3.45g, 8.98mmol) in 10mL of ethyl acetate was treated with (S)-(+)-mandelic acid (0.75g, 4.93mmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring till the solution became light cloudy. The solution was left stirred at room temperature over night. The crystals was then collected by filtration, recrystalized from ethyl acetate/hexane twice to give a yield of 800 mg (17%) of pure salt.
Example 520B 12S. 3R. 4S)-Ethvl-2-(2-(2-oxopvrrolidm-1-vnethvn-4-(1.3-benzodioxoi-5-vn-1-(N.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3- carboxvlate To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added A/,A/-dibutylbromoacetamide(84 mg, 0.34 mmol) and diisopropylethylamine (98uL, 0.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.
Example 520C /2S. 3R. 4S)-2-(2-f2-oxopvrrolidin-1-vhethvn-4-f 1.3-ben2odioxol-5-vl>-1-fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Using the procedures described in Example 502, the titie compound was prepared as an amorphous solid by lyophylization with CH3CN/TFA/H2O, 1H NMR (CDCI3. 300 MH2) 5 0.91 (t, J = 7.5 H2, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.23-1.38 (m, 4H), 1.44-1.60 (m ,4H), 2.05 (t, J ■ 6.9 Hz, 2H), 2.12-2.25 (m, 1H), 2.38 (td, J = 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (m, 1H), 3.17 (dd, J = 6.0 Hz, 8.7 Hz, 2H), 3.24 (t, J = 9 Hz, 1H), 3.32 (t, J « 7.8 Hz, 2H), 3.38-3.48 (m, 3H), 3.52 (t, J = 9 Hz, 1H), 3.66 (t, J * 6.9 Hz, 1H),.3.96 (m, 2H), 4.14 (m, 1H), 4.38 (brs, 2H), 5.93 (s, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.89 (dd, J = 1.8 Hz, 8.1 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/e 516. Anal calcd for C28H41N306-0.85 TFA: C, 58.23; H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.
Example 521 (2S. 3R. 4S)-2-(2-(2-oxopvrrolidin-1-vnethvn-4-M.3-benzodioxol-5-vn-1-(N-4-heptvl-N-(4-fluoro-3-methvlnhenvl^aminocarbonvlmethvl>-pyrrolidine-3-carboxvHc acid Using the procedures described in Example 520, substituting N,N~ (4-heptyl)-(4-fluoro-3-methyi)phenyl-bromoacetamide for N,N-dibutylbromoacetamide afforded the title compound as an amorphous solid by lyophylization with CH3CN/TFA/H2O. 1H NMR (CDCI3, 300 MHz) 5 0.85-0.98 (m, 6H), 1.22-1.55 (m, 8H), 2.04 (quintet, J=7.9 Hz, 4H), 2.32 (s, 3H), 2.36 (t, J=7.9 Hz, 2H), 2.61 (m, 1H), 3.14 (m, 1H), 3.25-3.61 (m, 5H), 3.66-3.77 (m, 1H), 3.79-3.90 (m, 2H), 3.92-4.03 (m, 1H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 (s, 2H), 6.71 (s, 2H), 6.78 (s, 1H), 6.93-7.13 (m, 3H); MS (DCI/NH3) at m/e 610 (M+H)+. Anal calc'd for C34H44N3O6FM.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.
Example 522 trans. trans-2-(2-( 1 -pyrazolvDethvlW-f 1.3-benzodioxol-5-vn-1 -fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid Example 522A 3-n-Pvrazolvh-propionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.
Example 522B trans. trans-2-(2-( 1 -Pvrazolvnethvn-4W 1.3-benzodioxol-5-vn-1 -fN.N-dibutvlaminocarbonvlmethvn-pvrrolidine-3-carboxvltc acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid 1H NMR (CDCI3, 300 MHz) 5 7.56 (d, J=3.0 Hz, 1H), 7.50 (d, J=3 Hz, 1H), 6.83-6.66 (m, 3H), 6.28 (t, J=3 Hz, 1H), 5.91 (s, 2H), 15 4.55-3.98 (m, 6H), 3.83-3.72 (t, J=10.5 Hz, 1H), 3.61-3.40 (t, J=10.5 Hz, 1 H), 3.36-3.12 (m, 5H), 2.69-2.43 (m, 2H), 1.59-1.42 (m, 4H), 1.38-1.21 (m, 4H), 0.91 (t, J=7.5 Hz, 6H). MS (DCI/NH3) at m/e 499 (M+H)+. Anal calcd for C27H38N405»0.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.
Example 523 trans. frans-2-f4-Methoxvphenvn-4-f1.3-benzodioxol-5-vn-1-l7N-butvl-N-(3-hvdroxvpropvnamino)carbonvlmethvn-pvrrolidine-3- carboxvlic acid Example 523A N-Butvl-N-(3-hvdroxvpropvn-amine To a solution of 15.9g (100 mmol) of methyl 3-A/-(n-30 butyl)aminopropionate in 150 mL of diethyl ether at 0 *C was added 50 mL (0.35 mmol) of 1.0M UAIH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 *C for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 mL 15%w/v NaOH(aq). and 5.7 mL H2O. After stirring for 30 min, the salts 35 were filtered and washed with diethyl ether, then the filtrate was concentrated to 11.3 g (86%) of a light yellow oil.
Examole 523B N-Butv!-N-(3-hvdroxvpropvn-chioroacetamide To an ice cooled solution of 1.31 g (10,0 mmol) of /V-butyl,A/-(3-hydroxypropyl)amine in 20 mL of ethyl acetate was added a solution of 1.71g (10.0 mmol) of chloroacetic anhydride in 10mL of ethyl acetate. The mixture was stirred, and gradually warmed to room termperature over 18 hours. The reaction was extracted with H2O (1 x 50 mL), saturated NaHC03 (aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgS04, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes:ethyi acetate to give 723 mg (35%) of a light yellow oil.
Example 523C trans. frans-2-(4-Methoxvphenvh-4-M .3-benzodioxol-5-vl>-1-r(N-butvi-N-(3-hvdroxvDroDvhamino)carbonvlmethvn-Dvrrolidine-3- carboxvlic acid Using the procedures described in Example 1D, substituting N-butyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMSO as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CD3OD, 300 MHz) 8 0.78-0.95 (m, 3H), 1.00-1.80 (m, 4H), 2.80-3.65 (m, 15H), 3.80 (d, J=1.5 Hz, 2H), 5.93 (s, 2H), 6.72-7.05 (m, 5H), 7.33-7.40 (m, 2H). MS (DCI/NH3) at m/e 513 (M+H)+. Anal calc'd for C28H36N207#1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.21; N, 4.88.
Example 524 trans. frans-2-(4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-f(N-propvl-N-nronoxvamino)carbonvlmethvn-pvrrolidine-3-carboxvlic acid Example 524A N-Boc-Q-allvlhvdroxvlamine 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 the residue taken up in EtOAc (25 mL), and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil (6.5g) which was used without any further purification.
Example 524B N-Boc-N-propvi-O-aHvlhvdroxvlamine 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 titie compound as a colorless oil (6.0g).
Example 524C N-Boc-N-propvl-N-propoxvamine 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 Ceiite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8g).
Example 524D N-Propvl-N-propoxvamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N HCI/dioxane (10mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1g) was collected by filtration and 20 washed with diethyl ether.
Example 524E N-nronvl-N-propoxv-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitriie 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 -20°C for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent 30 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.
Examole 524F trans. frans-2-(4-MethoxvDhenvn-4-M .3-benzodioxol-5-vn-1-r(N-butvl-N-f3-hvdroxvpropvnamino)carbonvtmethvn-pvrrolldin6-3- carboxvlic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was purified by preparative HPLC (Vydac mC18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 5 0.87 (m, 6H, J=8Hz), 1.49 (m, 2H, J=8Hz), 1.61 (m, 2H, J=8Hz), 3.55 (m, 6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.00 (m, 2H), 4.13 (d, 2H, Js=17Hz), 5.96 (s, 2H), 6.77 (d, 1H, J=9Hz), 6.90 (m, 3H), 7.05 (d, 1H, J=1Hz), 7.44 (d, 2H, J=9Hz). MS (DCI/NH3) m/e 499 (M+H)+. Anal calcd for C27H34N2O7 . 1.20 TFA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, 5.58; N, 4.55.
Example 525 trans. frar>s-2-(4-Methoxvphenvn-4-n .3-ben20dioxol-5-vn-1-ffN- butvl-N-ethvlamino)carbonvlmethvn-pyrrolidine-3-carboxvlic acid Example 525A N-butyl-N-f2-hvdroxvethvh-amine In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide . was condensed at -78*C. To this12.5 ml (120 mmol) of butyiamine was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50'C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound. intellectual property office OF n.z. 1 8 nov 2004 Example 525B N-Butvl-NM2-azidoethvn-chloroacetamidft To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of 5 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 o hours, then poured into 50 mL of 0.6M NaHC03(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 MgS04, 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 15 an oil. This was taken up in 10 mL of saturated NaHCC>3(ag.) and extracted with diethyl ether (3x5 mL). The combined ether layers were back extracted with brine (1x5 mL), dried over MgSC>4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 20 mg (17%) of an oil.
Example 525C trans. frans-2-(4-Methoxvphenvn-4-n .3-benzodioxol-5-vn-1-(7N-butvl-N-f2-aminoethvnamino)carbonvlmethvn-pvrrolidine-3-25 carboxylic acid According to the procedure of Example 523C, N-butyl-N-(2-azidoethyl)-chloroacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. 30 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 35 to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2S04. To 100 mg (0.10 mmol) of the azide was added 1mL of 1M HCl(ag.), °-5 mL °* 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% 5 aqueous TFA gradient to give the title compound as its TFA salt. 1H NMR (CD3OD, 300 MHz) 8 0.92 (t, J=7.0 Hz, 3H), 0.96 (t, rotamer), 1.23 (m, 2H), 1.41 (m, 2H), 3.06 (m, 4H), 3.39 (m, 2H), 3.69 (m, 2H), 3.84 (s, 3H), 3.94 (m, 3H), 4.18 (m, 2H), 5.05 (bd, J=10.7 Hz, 1H), 5.98 (s, 2H), 6.84 (d, J=7.7 Hz, 1H), 6.93 (dd, J=1.8, 8.1 Hz, 1H), 7.05 (m, 3H), 7.56 (m, ^ 2H). MS (DCI/NH3) at m/e 498 (M+H)+. Anal calcd for C27H35N306*3.15 ® TFA: C, 46.68. H, 4.49. N, 4.90. Found: C, 46.61; H, 4.73; N, 4.79.
Example 526 trans. frans-2-f4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-ffN-15 butvl-N-f3-aminopropvnamino)carbonvlmethvl1-pvrrolidine-3- carbcxvlic 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 20 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% H3PO4, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x 2.5 mL), dried over MgS04, filtered, and concentrated to an oil. To a 25 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 *C, then poured into 10 mL of water and extracted with diethyl ether (3x5 mL). The combined ether layers were back extracted with brine (1x5 mL), dried over MgS04, filtered, and 30 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 35 added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2S04. To this azide was added 1mL of 1M HCI(aqr.), 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. ^ H NMR (D6-DMSO, 300 MHz) 8 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 (m, 2H), 1.30 (m, 2H), 1.67 (m, 2H), 2.71 (m, 2H), 3.04 (m, 1H), 3.21 (m, 3H), 3.45 (m, 1H), 3.75 (m, 3H), 3.97 (s, 3H), 3.85-4.80 (broad m, 3H), 6.03 (m, 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.01 (m, 2H), 7.16 (m, 1H), 7.55 (m, 2H), 7.72 (m, 2H), 7.85 (m, 1H); MS (DCI/NH3) (M+H)+ at m/e 512. Anal calcd for C28H37N306-3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.
Example 527 trans. frans-?-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-r(N-butvl-N-(3-dimethvlaminopropvnam»no)carbonvlmethvn-pyrrolidine- 3-carboxvlic acid Example 527A N-hntvl-N-f3-bromopropvnbromoacetamide To 1.50g (11.4 mmol) of N-butyl-N-(3-hydroxy)propylamine was added 3 mL of 48% HBr(aq.), and 1.5 mL of conc. H2SO4. The reaction 25 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(ag.). 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 25 30 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(ag.) (2 x 25 mL) saturated NaHC03(aq.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was 35 dried over MgSQ4, filtered, and concentrated to an oil. This was purified via siiica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1.47g of a colorless oil.
Example 527B Ethvl trans. frans-2-(4-Methoxvphenvh-4-f1.3-benzodioxol-5-vn-1-TfN-butvl-N-(3-bromopropvnamino)carbonvlmethvn-pvrroHdine-3- carboxvlate According to the procedure of Example 523C, N-butyl-N-(3-m 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 527C trans. fra/?s-2-(4-Methoxvphenvn-4-(1.3-benzodiQxol-5-vh-1-ffN-butv>-N-f3-dimethvlaminopropvnamino)carbonvlmethvn-pvrrotiriine- 3-carboxvlic 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 THF. The reaction was heated at 50 *C for 3h, then stirred at room temperature ^ for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was 25 purified via silica gel chromatography, eluting with 9:1 CH2CI2: MeOH over about 20 mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted 30 with ethen the aqueous layer was acidified to pH 4 with 1N H3PO4, and the product was purified by preparative HPLC. 1H NMR (CD3OD, 300 MHz) 8 0.92 (t, J=7.0 Hz, 3H), 1.22 (m, 2H), 1.39 (m, 2H), 1.90 (m, 2H), 2.87 (s, 6H), 3.07 (m, 4H), 3.24 (m, 1H), 3.43 (m, 1H), 3.62 (m, 1H), 3.84 (s, 3H), 3.88 (m, 3H), 4.07 (m, 1H), 4.17 (m, 1H), 4.97 (m, 1H), 5.97 (s, 35 2H), 6.83 (d, J=8.1 Hz, 1H), 6.93 (dd, J=1.7, 8.1 Hz, 1H), 7.05 (m, 3H), 7.53 (m, 2H). MS (DCI/NH3) at m/e 540 (M+H)+. Anal calcd for C30H41N3O6-2.95TFA: C, 49.22. H, 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.
Example 528 trans. frans-2-(4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-l7N-butvl-N-(3-trimethvlammoniopropvhamlno)carbonvlmethvl1-pvrrolidine-3-carboxvlic acid Prepared according to the procedures of Example 527C, ^ substituting aqueous Me3N for Me2NH. 1H NMR (CD3OD, 300 MHz) 8 0.91 ® (m, 3H), 1.24 (m, 2H), 1.40 (m, 2H), 1.99 (m, 2H), 3.13 (s, 9H), 3.18 (s, rotamer), 3.20 (m, 3H), 3.39 (m, 4H), 3.72 (m, 1H), 3.84 (s, 3H), 4.03 (m, 3H), 4.35 (m, 1H), 5.19 (m, 1H), 5.97 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.96 (dd, J=1.7, 7.9 Hz, 1H), 7.10 (m, 3H), 7.62 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+. Anal calcd for C31H44N306*0.1 H20*1.65 TFA: C, 47.25. H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.
Example 529 trans. frans-2-(4-Methoxvphenvn-4-n .3-benzodioxol-5-vn-1-ffN-20 butvl-N-f4-aminobutvnamino)carbonvlmethvl1-pvrrolidine-3- carboxvlic acid 0 Example 529A N-butvl-N-(4-hvdroxvbutvn-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 mmol) of the resultant N-butyl -4-30 hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DlBAL(25%W). The solution was heated with stirring at 70 *C for 18 hours. After cooling to 0*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 35 with EtOAc; the organic extracts were washed with brine and dried over Na2S04.
Example 529B N-butvl-N-f4-hvdroxvbutvn-chloroacetamide Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at O'C, and then was allowed to warm to room temperature.
Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.
Example 529C Ethvl trans. fra/7S-2-(4-Methoxvohenvl)-4-M .3-benzodioxol-5-vn-1-r(N-butvl-N-M-hvdroxvbutvnamino)carbonvlmethvn-pvrrolidine-3- carboxvlate According to the procedure of Example 523C, N-butyl-N-(4-hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was chromatographed on silica gel.
Example 529D Ethvl trans, trans-2-(4-Methoxvphenvh-4-M .3-ben2odioxol-5-vh-1-ffN-butvl-N-(4-bromobutvnamino)carbonvlmethvll-pvrrolidine-3- carboxvlate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at O'C for 2 hours and was slowly warmed to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.
Example 529E trans. frans-2-(4-Methoxvphenvn-4-M.3-ben2odtoxol-5-vlV1-ffN-butvl-N-f4-aminobutvhamino)carbonvlmethvH-pvrrolidine-3- carboxvlic 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 flushed with hydrogen by placing a balloon filled with hydrogen. The reaction was allowed to stir for 4 hours under hydrogen 15 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 H3PO4, and 20 the product was purified by preparative HPLC. ^H NMR (CD3OD, 300 MHz) 8 0.90 (t, J=7 Hz, 3H), 1.10-1.65 (m, 6H), 2.85-2.95 (m, 2H), 3.00-4.10 (m, 14H), 5.50 (d, J=3 Hz, 2H), 5.97 (s, 2H), 6.82 (d, J=8 Hz, 1H), 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 (m, 3H), 7.45-7.55 (m, 2H). MS (DCI/NH3) at m/e 526 (M+H)+. Anal calc'd for C29H39N306-2.2 TFA: C, 25 51.75; H, 5.35; N, 5.41. Found: C, 51.75; H, 5.31; N, 5.30.
Example 530 trans. frans-2-f4-MethoxvphenvlV4-(1.3-benzodioxol-5-vn-1-r(N-butvl-N-M-riimethvlaminobutvnaminolcarbonvlmethvn-pyrrolidine-S-30 carboxylic acid The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1H NMR (CD3OD, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (m, 8H), 2.75 (d, J=7 Hz, 6H), 3.0-35 4.25 (m, 16H), 5.97 (s, 2H), 6.83 (d, J=8 Hz, 1H), 6.93 (dd, J=8 Hz, 1H), 7.02-7.08 (m, 3H), 7.49-7.56 (m, 2H). MS (DCI/NH3) at m/e 554 (M+H)+.
Anal calc'd for C31H43N306*2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.
Example 531 trans. fra/7s-2-f4-Methoxvphenvn-4-(1.3-benzodioxol-5-vn-1-rfN-butvl-N-f3-pvridvnammo)carbonvlmethvl1-pvrrolidine-3-carbpyylin acid Example 531A ^ N-butvl-N-(3-pvridvB-amine To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the 15 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(aqr.). and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted 20 with brine (1 x 50 mL), dried over MgS04, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting with 3:1 ethyl acetate: hexanes to give 1.18g (79%) of a colorless solid.
Example 531B trans. frans-2-T4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-f(N-butvl-N-(3-pvridvhamino)carbonvlmethvn-Pvrrolidme-3-carboxvlic . acid The compound of Example 531A was reacted according to the 30 procedures of Example 523, to give the title compound. 1H NMR (D6- DMSO, 300 MHz) 8 0.80 (t, J=6.4 Hz, 3H), 1.15-1.99 (m, 4H), 2.59 (m, 1H), 3.05 (m, 2H), 3.26 (m, 2H), 3.49 (m, 2H), 3.56 (t, J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 (s, 2H), 6.80 (m, 3H), 6.85 (d, J=8.1 Hz, 1H), 6.98 (m, 2H), 7.04 (m, 1H), 7.41 (dd, J=1, 4.7 Hz, 8.1H), 7.58 (m, 1H), 8.36 (bs, 1H), 8.54 35 (bs, 1H), 12.24 (bs, 1H). MS (DCI/NH3) at m/e 532 (M+H)+. Anal calcd for C30H33N306-0.1 H3PO4: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.
Example 532 trans. fra/?s-2-M-Methoxvphenvn-4-n .S-benzodioxol-S-vn-l-rfN-butvl-N-f3-aminomethvlPhenvnamino)carbonvlmethvn-ovrrolidine-3. carboxylic acid Example 532A N-butvl-N-(3-hvdroxvmethvlphenvn-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 NaHC03 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50 *C for 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.
Example 532B N-butvl-N-(3-hvdroxvmethvlphenvlVbromoacetamide 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 H3PO4, water, and brine.
Example 532C Ethvl trans. frans-2-(4-Methoxvphenvn-4-f1.3-ben?ndioxol-5-vh-1- f(N-butvl-N-r3-chioromethvlphenv»amino)carbony[methvn-pvrrol}dine-3-carboxvlat6 According to the procedure of Example 523C, N-butyl-N-(3-hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0°C; 19 mg of LiCI was added, followed by 85 |il 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 Na2S04« Example 532D trans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodtoxol-5-vh-1 -I7N-batvl-N-f3-ammomethvlphenvnamino)carbonvlmethvl]-pvrrolidine-3- carboxvlic acid The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, 6.5 eq) of sodium azide. The resultant solution was heated at 115 °C for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2S04.
Example 532E trans. frans-2-(4-Methoxvphenvn-4-( 1.3-benzodioxol-5-vn-1-r(N-butvl-N-(3-aminomethvlphenvnamino)carbonvlmethvn-pvrrolidine-3- carboxvlic acid In a 50 ml round bottom flask 0.090 gm Tin (ll) chloride was suspended in 1 ml acetonitriie. Triethylamine (0.2 mL) was added, followed by 0.19 ml of thiophenol ; the reaction mixture turned yellow. Reaction flask was cooled to O'C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitriie was added. The mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI . The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was 5 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 ethen the aqueous layer was acidified to pH 4 with 1N H3PO4, and the product was purified by preparative HPLC. 1H NMR (CD3OD, 300 §o MHz) 8 0.88 (t, J=7 Hz, 3H), 1.15-1.45 (m, 4H), 3.40-4.20 (m, 14H), 5.97 1 (s, 2H), 6.82 (d, J=8 Hz, 1H), 6.88 (dd, J=8 Hz, 1H), 6.97-7.20 (m, 5H), 7.40 (d, J=9 Hz, 2H), 7.56 (d, J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 (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. frar7s-2-(4-Methoxvphenvn-4-M .3-benzodioxol-5-vn-1-ffN-butvl-N-f3-trimethvlammoniomethvlphenvnamino)carbonvlmethvn- pvrrolidine-3-carboxvlic 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; 25 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. 1H NMR (300 MHz, D6-DMSO) 8 0.83 (t, J=7 Hz, 3H), 1.15-1.40 (m, 4H), 2.62 (s, 2H), 3.35 (s, 9H), 3.40-3.80 (m, 10H), 4.47 (s, 2H), 6.00 (s, J=3 Hz, 2H), 6.75-6.90 (m, 30 3H), 7.25-7.37 (m, 2H), 7.45-7.60 (m, 3H). MS (DCI/NH3) at m/e 602 (M+H)+.
Example 534 ^R3f?.4S)-2-f3-Fluoro-4-methoxvDhenvl)-4-n.3-ben2odiQxol-5-vf)1-(2-fN-propvl-N-pentanesulfonvlamino)ethvn-Pvrrolidine-3-carboxylic acid Example 534A Ethvl (3-fluoro-4-methoxy)ben2ovlacetate 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 °C, and a solution of 25 g of 3-fluoro-4-methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then the reaction is cooled to room temperature. A solution of 50 ml of concentrated HCI in 75 ml of ice water is added slowly, and the mixture is stirred. The mixture is extracted with toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product is dried over Na2S04 and decolorized with charcoal to give 34.5 g (97%) of the title compound.
Example 534B Ethvl 2-(3-Fluoro-4-methoxvphenvn-4-f 1.3-ben2odioxol-5-vn- pvrrolidine-3-carboxvlate The compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3- . ben2odioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 mi 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 MgS04. The residue was flashed on silica, using CH2CI2 to eiute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2CI2. 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 5 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 MgS04. The crude 10 product is purified by flash chromatography on silica, eluting with 2:1 ^ EtOAc/hexanes. Yield 5.92 g (58%) of a 2:1 mixture of trans-trans and cis-trans isomers.
Example 534C 1 5 Ethvl rgf?.3/9.45)-2-f3-Fluoro-4-methoxvphenvn-4-M .3-benzodioxol- -vn-Pvrrolidine-3-carboxvlatft 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 20 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 25 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 7.5 g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene 30 chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1:1 ethenhexane 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, 80 35 ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-168°C. After one recrystallization, chiral HPLC analysis, using a Regis Whelk-0 column, indicated >99.5 % e.e. The salt was dissolved in 500 mi of 36% HCI in ethanol; a white solid forms. The resultant suspension was heated for 16 hours at 52°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 (Na2S04) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate to get 6.9 g (99%) of the resolved amino ester.
Example 534D Ethvl (2R.3R.4S)-2-(3-Fluoro-4-methoxvphenvn-4-( 1.3-benzodioxol- -vni-f2-fN-propvlamino)ethvn-pvrrolidine-3-carboxvtate The compound of Example 534C was dissolved in 1,2-dibromoethane ( 10 mL per 1 g of starting material ); diisopropylethylamine (1 mL per 1 g of starting material ) and Nal ( 100 mg per 1 g of starting material) were added, and the mixture was stirred at 100°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 (85-92%). This compound was combined with n-propylamine (3.5 eq.) and Nal (10% by weight of bromide) in ethanol ( 5 mL per 1 g of bromide), and was heated at 80°C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2SC>4), 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.
Example 534E 1-Pentanesulfonvl chloride 1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was 5 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 SOCI2- The residue is partitioned between CH2CI2 and ice water; the 10 organic layer is dried over Na2S04 . The crude product is purified by A distillation (bp 54-56 °C @ 0.5 mm Hg) to give a clear oil, 61% yield.
Example 534F /2f?.3R4S)-2-(3-Fluoro-4-methoxvphenvh-4-f1.3-benzodioxol-5-vni-15 (2-(N-propvl-N-pentanesulfonvlamino>ethvn-pvrrolidine-3-carboxvlic acid The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N,N-20 diisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvent was evaporated • under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHC03 solution, 1N H3PO4, and 25 brine, dried over Na2S04 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with 40% EtOAc/hexane to give 220 mg of product (85%). This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H2O. This mixture was stirred for 3 hours at room 30 temperature. The solution was concentrated in vacuo using low (<40°C) 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 (Na2S04) 35 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 white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.
Example 534H /gf?.3f?.4g)-2-(3-Fluoro-4-methoxvphenvn-4-f 1.3-benzodioxol-5-vni -f2-fN-propvl-N-pentanesulfonvlamino)ethvl>-pvrrolidine-3-carboxylin acid, hydrochloride salt The free amine is dissolved in iPrOH; a slight excess of HCI in 1 o iPrOH is added, and the solution is concentrated in vacuo. More IPA is 9 added, and the solution is reconcentrated. The resultant sticky material is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 °C. Yield 95%.
Example 535 The compounds in Table 3C may be prepared using methods 20 presented in the above Examples.
Table 3C.
II I Vi —"V^N' -COOH 12 -••COOH «2 o 14 -if t?r 16 ••"COOH I ^ yv '•COOH 22 +tQT X^' -"COOH CH}0 O •iCOOH xrv 17 18 chfeo o '•«<COOH -o •"•COOH >..>COOH 21 -'•COOH 23 "•COOH -"f 26 n+ ^ o C"// -MCOOH 28 29 CHjO 0- Cl-feC O O j -"COOH -MCOOH 40 xrvnc - h°v^s^Ns^nJ 33 ^ r ■* 36 •"COOH -'COOH 39 •COOH ovt 41 42 S"n +or y^l^-"°ooh ^^qrv^t5^°°h ^o^vt$-"c°°h K. y^ o b- 43 44 45 YYVn"( x o l>-'cooh HOs<-^n^NY^n-N-" 46 "COOH 47 ■"•COOH COOH 48 i ^ 50 51 ^r>...COOH ^1 'COOH y 53 54 ^1 "COOH 0Yt -uCOOH 55 uCOOH •oV 57 •mCOOH 58 59 60 Vs* o ch.
S L -0. p%io VL 21 HOOOl" H00°" "•OAXjUc zi Q p^o mjck 01 HOOOi* 69 89 HOOOIM HOOOl.. 99 HOOOl.- O 1 k/x S9 HOOO"< q ,o«ho e9 29 sru HOOOi.. 4IO HOOOi." ^-N^-^OH k*"\ hoook k^\ 19 HOOOw- n^n^-">C O OeHO *9 hoooi..-< i^lln^mi5h k/\ 19 HOOOi"' qjljx ~ 17817 " ■^ov SOL KH SOI HOOOl'- SOL «vJ^nXXJ<: 00 L HOOOtn.
HOOO"- HOOOf- 16 HOOO*- 'Nv^^>iC kxx 1 86 HOOOUK -!)^Ln/^»zH '•COOH 106 -«COOH 109 CH3U o 112 oVt - 115 CH} "COOH 107 I! 1 V'COOH CH3O 0 j 110 113 •crvt •«COOH 116 COOH 108 "^i HiN^V>- v^ooh v> ••'COOH 111 CH3cr b -'•COOH -COOH 114 *novt^ 117 p\ 118 119 120 488 - n i >-«COOH H2nt^s^'nY^N 121 122 123 r^X" h*'^'vywh cooh 124 125 H2hr^^s^'NNj|^1 N' 127 —•COOH | 128 Yr. :c^n cooh .L^ > » | cooh 126 cooh T L >- •COOH 129 ^rt ;ooh 131 iiCOOH yyr 132 HO^^N. 133 134 137 -iCOOH %S^VS^NX^l "v^— 135 H2N^-Nv^N » [ -UCOOH 138 H2NA/,V%/n( (ij I >-«COOH IICOOH 143 itAVW I J M l •" o 146 iCOOH 144 ^xrv 147 -•iCOOH CH3O % ;xyr^H "^irrc •'iCOOH 149 150 CHacr b o J :Crs 'f >-'<COOH 160 Jr^ -<COOH ""COOH "COOH 157 c^cr b- ""^xftx ;tx^ 161 ,ot Y*Y O .-.COOH 153 CH3or b o j h2N^v^v^'nY^n 156 -'iCOOH 'COOH h "•COOH 159 CHjO b- 162 h0^s^N^n 163 164 165 081 6Z.1- 211 HOOO"-< I ii , III ""tv^Ok-Jc ^ XUOu-* 911 fll £11 N\ANr-^x^,-^C on HOOOi" 691.
HOOOi»-< I ll •m>vAn'^^n^ k^. 1 131 } H000I»-<1 I? H k^v. " 1617 - 991.
«COOH ~*-^i i*irvvy .
"COOH H2ftv/V,N,|^N' 183 186 "x^O'NV^N- il I '-'ICOOH 192 193 194 'TO- iCOOH 195 493 - "COOH 196 199 202 xm 205 H2n^Sv-'nY^' h2N^-^nY^N "COOH 197 -•COOH ovi "COOH ovc • 200 -"COOH 203 208 206 •COOH 209 210 s zz vzz s zz HOOOii. w kx*\ 1 O O HOOO»-< J, it HOOOi." o n k^ 612 HOOOi.-< I it HOOOi- "1 I? f\ | kx"\ o SIZ 91Z HOOOi"- SJ-2 kx\ N^k|-^-^M3H k^\ 132 022 HOOOi.- k^\ 81-2 LVZ HOOOii k/\ nz k^\ HOOOi"- k/*\ 212 HZ HOOD"- " 17617 " - 495 '"COOH 226 ••'iCOOH r~ V" xfvw>-co°h 229 230 COOH 233 228 COOH 231 -COOH 234 COOH 238 239 240 SS2 P9Z ess HOOO,"'< N*H k^s. zsz 'Q p^o 9PZ HOOOtt.
-Q p£HO £PZ HOOOi'- - 96fr - 497 - v*f «COOH T X^'rt-.MCOOH 256 259 'COOH 262 H2N^N^N' 265 268 257 258 260 H°—-V-N- o $ -"COOH 263 266 COOH H2ir^/V^NY^ 269 // 261 "COOH 267 uCOOH 270 'COOH •COOH 271 274 >-"cooh 277 278 H2N--^^NY^N 281 279 I ^ •cooh 282 "icooh ch3o o- c^c "cooh w>° ■J 499 - 283 284 285 286 289 292 h2N^^'n"^*v- ■«cooh 295 293 ^1 ^ | -'cooh 296 294 i 297 ^ Try- "COOH ^ rJ ^ "Y^lS""000" -COOH 298 299 ^1 "COOH ov? 301 300 ^av6-H 302 303 Hz n^tcft*"^00* i t^°°h fju o ^ 'OCH3 304 305 / uon3 yt>»» 306 " M, CHa \ ^ / OCH3 COOH 307 309 310 CH3 311 312 ^1 HjN^-— 313 oyt - och >-COOH | 314 316 317 "COOH 315 H,N^QrY> 318 319 CHjO 322 323 I ^ /Nv/V^ ch3o o Y^fV^ ,,COOH 321 324 ch30 b % bch3 ••■COOH V^' )ch3 CH30 b ch, >-'COOH C>° j 325 326 327 - 503 340 342 Yr ••■ 'och3 iCOOH :ovl 346 347 T -iyrrc™ yrns- -« ^rx - 349 345 h2n'^x^^nx^t^s'',icooh y \\ 348 'CH3 350 351 'OCHg ^nrxc°°» ^rrv q-o cu a I OCH, O 352 r r r-w $ | p>-«COOH or 353 354 OCH3 bJ x^L^','C00 «COOH w <* o J 355 356 'Tt- 358 :orv? 357 C Hj N-<5yNY^N-^ -COOH llJ 5 l^>-"COOH f° 359 r^DCH3 361 362 CH3 xr"rt>- 364 367 360 k> ^x5v* 363 366 r-0 HaN^N ^ OCH* ^^-vv... 369 h2Nx^^^NY^i ch3o o CH3Cf O- ch3o o- 505 - 370 371 372 ft "OCKj A °CH3 «COOH ch3o 373 374 d J xyvx 375 'och3 O - q won3 *oyrf-" •wncryt^-«» ;^no*rr5- 376 377 ? CHjO b-^ O, "1 ft r 0CH3 0 0 Y^VcOOH ^x^"vxf"cooh ^6 OCH3 v 379 380 < ^na v? - 384 ^1 ..ICOOH H2N^-^ n o 385 386 387 394 9l yri-=« crvr 389 390 •s^i i OCH3 H2fT^V<:V^Y^N--\ |1 J « J ^-"'COOH P*» ■•',cooH // 392 393 xrvr 398 396 399 ro- H2N-xX^^NY^N- 507 400 401 403 404 406 409 407 xon CKjCf b 410 H2N^Ss^NY^ 412 405 q.
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Binding Assay ETa Receptor Preparation of membranes from MMQ cells: MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells)] cells from 150 mL culture flasks were collected by centrifugation (1000xg for 10 min) and then homogenized in 25 mL of 10 mM Hepes (pH 7.4) containing 0.25 M. sucrose and protease inhibitors [3 mM EDTA , 0.1 mM PMSF, and 5 ng/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80°C until used. Protein content was determined by the Bio-Rad dye-binding protein assay. [12511ET-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 MgCl2. 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 [125I]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 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times. Nonspecific binding was determined in the presence of 1 jxM. 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.
Example 1D 2 3 4 6B 7 8 9 10 14 16 17 18 19 21 22 23 26 27 28 29 31B % Inhibition of ETa at 1 mM 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 Table 4 Binding Data Example 34 36 37 38 39 40 41 42 43 44 45 46 47 48 52 54 55 56 57 58 59 60 61C 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 Example 64 65 66 67 68 69D 70 71 72C 73C 74 75C 76 79 80 82 83 84 86 87 88 89 91C 92C 93C 95D 96 97 % Inhibition of 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 -611-Example 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 % Inhibition of ETa at 1 mm 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 Example 123 124 129 130 131 132 133 134 135B 136 138 139 140 141 142B 143 144 145 146 147 148 149 150 151 152 153 154 155 % Inhibition of ETa at 1 mM 89.7 91.0 100.1 91.0 89.5 90.0 88.6 92.2 77.7 79.4 83.0 98.6 106.3 92.8 78.7 .6 78.2 32.4 25.0 73.0 94.7 84.6 93.6 80.5 86.9 97.1 80.2 92.7 Example 156 157 158 159 160B 161 162B 163 164 165 166 167 291 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 % Inhibition of ETa at 1 mM 92.6 83.8 91.8 36.2 80.3 93.6 91.5 90.6 98.6 54.1 91.6 94.4 100.0 89.8 77.7 93.0 87.1 84.4 93.3 90.4 96.1 96.7 86.6 87.2 89.7 87.4 93.3 92.2 Example 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 % Inhibition of ETa at 1 mM 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 Example 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 % Inhibition of ETa at 1 mM 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 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 % Inhibition of ETa at 1 mM 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 Example 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 of 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 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 459 460 461 462 463 464 465 466 467 468 469 470 471 475 476 477 479 495 496 497 498 499 500 % Inhibition of ETa at 1 mM 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 Exampie. % 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 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 (PH Hvdrolvsis MMQ cells (0.4 x 10® cells/mL) were labeled with 10 fiCi/mL of [3H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and 10 mM LiCl 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 jiL) 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.
Table 5 Phosphatidylinositol Hydrolysis Example IC50 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 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 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA , 0.1 mM PMSF, 5 ng/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.
Protein content was determined by the Bio-Rad dye-binding protein assay.
Binding assays were performed in 96-welI 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 jig/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 [125I]ET-1 (for ETA assay in MMQ or CHO ceils transfected with human ETa receptor) or [125l]ET-3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETb receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 °C. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence of 1 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 EXAMPLE mET-A mET-A pET-B Selectivity hET-A hET-B Selectivity NO. (%l @ ic50 ic50 (mA/pB ic50 ic50 (hA/hB 1jiM) (nM) (nM) ratio) (nM) (nM) ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.92 52,000 56,000 504 97.1 505 95.8 506 99.7 3.1 >100,000 2.0 60,000 3.2 >100,000 >32,000 4.6 30,000 5.7 >31,000 3.0 >100,000 >21,000 68,000 12,000 61.000 20,000 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 523 524 99.3 3.0 >100,000 >33,000 1.63 >100,000 97.6 1.9. 45,000 23,000 2.1 51,000 100 0.56 30,000 53,000 0.51 23,000 100 0.50 35,000 68,000 1.0 11,000 >.2 0.81 n.d. 0.60 15,000 98.9 0.42 >80,000 >190,000 0.58 60,000 98.0 0.30 8,800 29,000 0.36 14,000 100 1.0 26,000 26,000 0.36 9,800 99.1 1.6 >62,000 >37,000 6.7 >100,000 99.7 0.71 29,000 40,000 1.8 37,000 94.1 1.0 30,000 30,000 0.43 12,000 96.3 1.3 85,000 63,000 0.31 38,000 99.1 0.38 14,000 36,000 0.23 19,000 97.4 0.20 28,000 130,000 100 0.67 37,000 54,000 99.0 0.42 360 880 0.33 290 99.2 0.79 1,700 2,100 0.82 890 100 8.2 560 70 526 100 42 1 7 7,400 440 527 96.6 7.9 528 98.3 1 1 529 98.1 3.6 ,000 1,300 43,000 3,800 6,300 1,700 531 99.8 532 100 533 97.9 534 1.2 .1 3,200 76 7,900 0.12 0.36 0.71 630 100 40 3.0 0.08 870 1,200 22,000 560 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 filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 fiL sample of the ultrafiltratewas transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 jiL 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 = [1-(Cu/Ci)] * 100% where 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 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 Margulies, et al., Circulation £2 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. 51 711 (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. ££ 915 (1987) or Matsumura, et al., Life Sci. 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. M 1762 (1989).
The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44. 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol. 256 G661 (1989).
The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 2Z 1487 (1990).
The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. ZE 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. £7 1213 (1989).
The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 23. 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 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. 32. 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
The ability of the compounds of the invention to treat pialetet 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. fiZ 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. 22. 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, 2QR, 261-269).
The abiiitv of the compounds of the invention to treat ischemia-reperfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, a, 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, Intellectual property os-nut OF N,Z.
V 8 NOV 200^ MeASlt/fin camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthaienesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyi 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 (I), 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 the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception, 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 wilt 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 pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes 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, 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 wetting 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 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, nadolol, 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, lisinopri! 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.

Claims (24)

-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. - 631 - claims What We Claim Is:
1. A process for the preparation of a compound of the formula: /—nh co2e wherein E is a carboxy-protecting group and Ri and R.2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: wherein E, R| and R2 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, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, wherein aryl by itself or as part of another group may be optionally substituted by one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, - 632- 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,aikylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aryl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic fey itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, provided that at least one of the following conditions apply: (a) is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano,
2. The process of claim 1 wherein E is loweralkyl, Ri and R2 are as defined therein.
3. A process for the preparation of a compound of the formula: c02e - 633- wherein E is a carboxy-protecting group, Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl and R3 is R4-C(0)-R5- wherein R5 is alkyiene and R4 is (Ri l)(Rl2)N- wherein Rl l and R12 are independently selected from (1) loweralkyl, (2) haloalkyl, (3) alkoxyalkyl, (4) haloalkoxyalkyl, (5) alkenyl, (6) alkynyl, (7) cycloalkyl, (8) cycloalkylalkyl, (9) aryl, (10) heterocyclic, (11) arylalkyl and (12) (heterocyclic)alkyl; or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: wherein E, Rj and R2 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) alkylation of the product of step c) with a compound of the formula R3-X wherein X is a leaving group and R3 is defined as above, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, C02E INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 8 NOV 2QM nr^EH/cn - 634- thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, wherein aryl by itself or as part of another group may be optionally substituted by 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,aikylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aryl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic by itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, provided that at least one of the following conditions apply: (a) Rj is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano.
4. The process of Claim 3 wherein E is loweralkyl, Rj and R2 are as defined above, and R3 is -CH2C(0)NRj jR^ wherein Rj j and Rj2 are independently selected from the group consisting of loweralkyl, aryl and heterocycle.
5. The process of any one of Claims 1,2 and 3 wherein the hydrogenation catalyst is Raney nickel and the acid is a mixture of acetic acid and trifluoroacetic acid. intellectual property ohhut i of n.z ! 1 8 NOV 20M I i - 635-
6. The process of any one of Claims 1, 2 and 3 wherein E is loweralkyl, Rj is 4- methoxyphenyl, R2 is l,3-benzodioxol-5-yl, r3 is -CH2C(0)N(n-Bu)2 and X is a halogen or sulfonate leaving group.
7. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula: wherein E is loweralkyl, Ri and R2 are independently selected from loweralkyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, heterocyclic and (heterocyclic)alkyl, or a salt thereof, comprising reacting a mixture of the (+) and (-) enantiomers of the compound of the formula: with S-(+)- mandelic acid and separating the mandelate salt of the (+)-trans,trans optical isomer, wherein cycloalkyl by itself or as part of another group may be optionally substituted with one, two or three groups independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, c02e co2e wherein aryl by itself or as part of another group may be optionally substituted by one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, - 636- (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy,aikylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxyalkoxy, phenyl and tetrazolylalkoxy or aiyl may be tetrafluorophenyl or pentafluorophenyl, and wherein heterocyclic by itself or as part of another group may be optionally substituted with one or two groups independently selected from hydroxy, halo, oxo, alkylimino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -S03H, alkoxycarbonyl, nitro, cyano and loweralkyl or heterocyclic may be N-protected, provided that at least one of the following conditions apply: (a) R.J is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (b) R2 is selected from haloalkyl, haloalkoxyalkyl, cycloalkylalkyl, arylalkyl, aryloxyalkyl and (heterocyclic)alkyl, (c) at least one of said optionally substituted aryl groups has at least one substituent selected from hydroxyalkyl and cyano, or (d) at least one of said optionally substituted heterocyclic groups has at least one substituent selected from alkoxycarbonyl, nitro and cyano.
8. A use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for antagonizing endothelin in a mammal in need thereof. intellectual property office OF n.z. 2 0 DEC 2004 PEceivr; 1 -637-
9. A use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating hypertension, congestive heart failure, restinosis following arterial injury, cerebral br myocardial ischemia or atherosclerosis in a mammal in need thereof.
10. A use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament 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 cardio toxicity, nociception, colitis, vascular permeability disorders, ischemia-reperfusion injury, raynaud's disease or migraine in a mammal in need thereof.
11. A use of (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating bone pain associated with bone cancer in a mammal in need thereof.
12. A compound selected from the group consisting of: trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -{2-(N-propyl-N-[2-(N,N-dimethylamino)]ethanesulfonylamino)ethyl}pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(2-(N-propyl-N-(3- chloropropanesulfonyl)amino)ethyl)pyrrolidine-3 -carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l -(2-(N-isobutyl-N- (3-chloropropanesulfonyl)amino) ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l -[2-(N-propyl-N- (2,2,3,3,3-pentafluoropropoxyethanesulfonyl)amino) ethyl]pyrrolidine-3 -carboxylic acid; trans, trans-2-(3 -Fluoro-4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)-1 -(2-(N -(2- methoxyethyl)-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l -[2-(N-propyl-N- 304622_1.DOC -638- ((2,2,2-trifluoroethoxyethane)sulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(l -methoxy-1,3-benzodioxol-5-yl)-1 - (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)-1 -[(N-propyl-N- propoxyamino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N- ethylamino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(3- aminopropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l -[(N-butyl-N-(3- dimethylaminopropyl)amino)carbonylmethyl] -pyrrolidine-3 -carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(3- trimethylammoniopropyl)amino)carbonylmethyl] -pyrrolidine-3 -carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-[(N-butyl-N-(4- aminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; and or a pharmaceutically acceptable salt thereof.
13. A use of a compound according to Claim 12 in the manufacture of a medicament for antagonizing endothelin in a mammal in need thereof.
14. A use of a compound according to Claim 12 in the manufacture of a medicament for treating hypertension, congestive heart failure, restinosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis in a mammal in need thereof.
15. A use of a compound according to Claim 12 in the manufacture of a medicament 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 cardio toxicity, nociception, colitis, vascular permeability disorders, ischemia-reperfusion injury, raynaud's disease and migraine in a mammal in need thereof. 3Q4622_1.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 0 DEC 200<l RECEIVED -639-
16. A use of a compound according to Claim 12 in the manufacture of a medicament for treating bone pain associated with bone cancer in a mammal in need thereof.
17. (2R, 3R, 4S)-(+)-2-(4-Methoxyphenyl)-4-(l,3-benzodioxol-5-yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound as claimed in Claim 12 or Claim 17 and a pharmaceutically acceptable carrier, diluent or excipient.
19. A process as defined in Claim 1 substantially as herein described with reference to any example thereof.
20. A process as defined in Claim 3 substantially as herein described with reference to any example thereof.
21. A process as defined in Claim 7 substantially as herein described with reference to any example thereof.
22. A use as defined in any one of Claims 8-11 and 13-16 substantially as herein described with reference to any example thereof.
23. A compound as claimed in Claim 12 or Claim 17 substantially as herein described with reference to any example thereof.
24. A pharmaceutical composition as claimed in Claim 18 substantially as herein described with reference to any example thereof. 304622 l.DOC
NZ514170A 1997-02-12 1997-02-12 Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists NZ514170A (en)

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