AU2034499A - Endothelin antagonists - Google Patents

Endothelin antagonists Download PDF

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

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

Description

S F Ref: 362557D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 UNITED STATES OF AMERICA Martin Winn, Steven A. Boyd, Charles W. Hutchins, Hwan-Soo Jae, Andrew S. Tasker, Thomas N. VonGeldern, Jeffrey A. Kester and Bryan K. Sorensen Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Nales, 2000, Australia Endothelin Antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 Technical Fiel The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
Backoround of the Invention Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in lyit, stimulate mitogenesis in vascular smooth muscle cells in Jyit., contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitY, increase airway resistance in iyo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in j ytr and in yiyo, increase plasma levels of wherein Z is -C(Rl 8
)(R
19 or wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n is 0ori1; R is H2)M-W wherein m is an integer from 0 to 6 and W is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, -P0 3
H
2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR
17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,
-C(O)NHS(O)
2 Rl 6 wherein R 16 is loweralkyl, haloalkyt, phenyl or dialkylamino, (in) -S(O) 2
NHC(O)RI
6 HO 0 0 HO 0
OH
0,
NH
0
H
H ,o
NHSO
2
CF
3
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, aminocarbonylalkyt, alkylaminocarbonylalkyl, dialkylaminocarbonyalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyt, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkoxyalkyl, heterocyclic and (Raa)(Rbb)NRc wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RCC is alkylene, with the proviso that one of R, and R 2 is other than hydrogen;
R
3 is R 4 R6-S(O) 2 -R7- or RP.
6 -S(O)-R27wherein R5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20
)-R
8 or -R 8 aCN(R 20
)-R
8 wherein R 8 and R8a are independently selected from alkylene and R 20 is hydrogen, loweralkyt, alkenyl, cylcoalkyl or cycloalkylalkyl or -0-R 9 or (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxysubstituted haloalkyl; and
R
27 is alkylene or alkenylene;
R
22
-O-C(O)-R
2 3- wherein R 2 2 is a carboxy protecting group or heterocyclic and R 2 3 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 2 4)-R2 5 wherein R25 is alkylene and R 2 4 is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, or
R
13 -C(O)-CH(Rl4)wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R 15 wherein R15 is amino, alkylamino or dialkylami no; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula (11)
R
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,
R
2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R 11
)(R
12 wherein R 1 1 and R 12 are independently selected from loweralkyl.
Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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,
R
2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 3 is R6-S(0)2-N(R 21 )-Rlo- wherein Ro 10 is alkylene,
R
6 is loweralkyl and R 2 1 is loweralkyl.
The present invention.also relates to processes for preparing the compounds of formula and (II) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula or (II).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula or (II).
-11- The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used 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 C 1 to C 8 loweralkyl methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl.and substituted derivatives thereof, for -12example, 5-indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-lethyl, 1-(pivaloyloxyl)-1 -ethyl, 1-methyl-i -(propionyloxy)-1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoytoxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbo nylmethyl, cyclohexyloxycarbonylmethyl, 1 -methoxycarbonyl- ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylami noalkyi, such as t-butyloxycarbonylaminomethyl and the like; alkylami nocarbonylami noalkyl, such as methylaminocarbo nylami nomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpipe razinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaninocarbonylmethyl, diethylaminocarbo nylmethyl and the like; (5-(loweralkyl)-2-oxo- 1 ,3-dioxolen-4yl)alkyl, such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like; and phenyl-2-oxo-1 ,3-dioxole n-4-yl)alkyl, such as (5-phenyl-2-oxo-1 ,3-dioxolen-4yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, -13- 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbony, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2,4-di met hoxybe nzyloxycarbo nyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-di methyl-3,5-di metho xybe nzyloxycarbo nyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenyithiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The terms "loweralkyl" or "alkyl" as used herein refer to straight or branched. chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2dimethylpropyl, n-hexyl and the like.
The term "alkylamino" as used herein refers to R51NH- wherein R 51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylami nocarbonyl, isopropylaminocarbonyl and the like.
The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 group.
-14- The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl'(NH 2 group.
The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylaminocarbonylaminoalkyl" as used herein refers to
R
40
-C(O)-NH-R
4 1 wherein R 40 is an alkylamino group and R 4 1 is an alkylene group.
The term "dialkylamino" as used herein refers to R 5 6
R
57 N- wherein R 56 and R 5 7 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkyl" as used herein refers to
R
50
-C(O)-R
5 1 wherein R 50 is a dialkylamino group and R 5 1 is an alkylene group.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino 2 group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkanoylaminoalkyl" as used herein refers to R43-NH-R44wherein R 43 is an alkanoyl group and R44 is an alkylene group.
The term "alkanoyloxyalkyl" as used herein refers to R 30
-O-R
3 1 wherein
R
3 0 is an alkanoyl group and R 3 1 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example -CH 2
-CH
2
CH
2
-CH(CH
3
-CH
2
CH
2
CH
2
-CH
2
C(CH
3 2
CH
2 and the like.
The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH 2 CH=CH-, -C(CH 3
-CH
2
CH=CHCH
2 and the like.
The term "alkoxy" as used herein refers to R 4 1 0- wherein R 4 1 is a loweralkyl group, as defined above. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, 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 "alkoxyalkoxy" as used herein refers to R 8 oO-R 8 1 0- wherein
R
8 0 is loweralkyl as defined above and R 8 1 is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, tbutoxymethoxy and the like.
The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative -16examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylaminoalkyl" as used herein refers to R38-C(O)-NH-R 39 wherein R 3 8 is an alkoxy group and R 3 9 is an alkylene group.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical.
Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to R34-C(O)-R 35 wherein R 34 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
The term "alkoxycarbonyloxyalkyl" as used herein refers to R36-C(O)-O-R 37 wherein R 3 6 is an alkoxy group and R 3 7 is an alkylene group.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -C=C-H, H-CsC-CH 2
H-C=C-CH(CH
3 and the like.
The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 10 carbon atoms and also containing a carboncarbon triple bond. Examples of alkynylene include -CaC-, -C=C-CH 2
-C=C-
CH(CH
3 and the like.
The term "aminocarbonyl" as used herein refers to H2N-C(O)-.
-17- The term "aminocarbonylalkoxy" as used herein refers to H 2
N-C(O)-
appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkoxy" as used herein refers to R 42 0- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "aryloxy" as used herein refers to R450- wherein R 45 is an aryl group, for example, phenoxy, and the like.
The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "aroyloxyalkyl" as used herein refers to R32-C(0)-O-R 3 3 wherein R 32 is an aryl group and R 3 3 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde radical, -C(O)H.
-18- The term "carboxy" as used herein refers to a carboxylic acid radical,
-C(O)OH.
The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined.
Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined.
Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-l-ethenyl and the like.
The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano group. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.
The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
The term "haloalkoxy" as used herein refers to a lower alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2fluoroethoxy, 2,2,2-trifluoroethoxy and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one -19nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in nonadjacent positions; or two sulfur atoms in non-adjacent positions. The membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized.
The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloherane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothidzolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Heterocyclics also include x.
compounds of the formula where X* is -CH 2 or and Y* is or where R" is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SOsH and loweralkyl. In addition, nitrogen containing heterocycles can be Nprotected.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term "(heterocyclic)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term "heterocycliccarbonyloxyalkyl" as used herein refers to R4 6
-C(O)-O-R
47 wherein R 46 is a heterocyclic group and R 4 7 is an alkylene group.
The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term "mercapto" as used herein refers to -SH.
The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl 0 radical. Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl radical The term "tetrazolyl" as used herein refers to a radical of the formula
H,
N- N or a tautomer thereof.
-21- 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 R7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The term "trans,trans"as used herein refers to the orientation of substituents (R1 and R 2 relative to the central substituent R as shown
R
2
ZN'II-R
3
(CH
2 )n
RI
The term "trans,cis" as used herein refers to the orientation of substituents (R 1 and R 2 relative to the central substituent R as shown
R
21
ZN
3 R2 Z, R 3 SI IR (CH2)n (CH)n R
R
R1 or This definition encompasses both the case where R and R 2 are cis and R and R 1 are trans and the case where
R
2 and R are trans and R and R 1 are cis.
The term "cis,cis"as used herein refers to the orientation of substituents
(R
1 and R 2 relative to the central substituent R as shown R3 R" (CH 2 )n R1 Representative compounds of the invention include: trans, trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1- (propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; -22trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 fluorobenzyl)-pyrrolidine-3-carboxylic acid; trans, trans-2 -(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 ethoxyethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yI -1 pro poxyethyl) -py rro lidi ne-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- methoxyethoxy)ethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 pyridyl)ethyl]-pyrro lid i ne-3-carboxylic acid; trans, trans-2- (4-Meth oxyp hen yl)-4-(1 be nzodi oxol-5-yl)- 1 (4morpholinylcarbonyl)-pyrrolidine-3..carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4- (1 ,3-benzodioxole-5-yl)- 1 (butylaminocarbonyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 methoxyp hen ylami nocarbo nyl)-3-pyrro lidi ne.3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 acetylpyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yI)- 1 -(2-fu royl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (phenylami nocarbonyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 (allylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 butylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-n-butyl- N-methylami nocarbonyl methyl)-pyrrolidine-3-carboxylic acid; transtrans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxol-5-yl)- 1 -(pyrro lidi n- 1 -ylcarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (isobutylaminocarbonylmthyl)-pyrroidi ne-3-carboxylic acid; -23trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 (cyclopentylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2 -(4-Methoxyphenyl)-4-( 1,3-benzodioxo-5-yI)- 1- (morpholin-4-ylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 phenoxyethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yI)- 1 methoxyethylam inocarbonyl methyl)-pyrro lid i ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 butoxyethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxol-5-yI)-4-(4-methoxyphe nyl)- 1 (propylami nocarbonylmethyt)-pyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxol-5-yI)-4-(4-methoxyphenyl)- 1 pro poxyethyl)-py rro lidi ne-3-carboxylic acid; trans, trans-2-(1 ,3-Benzodioxo I-5-yI)-4-(4-methoxyphenyl)-1 m eth oxyeth oxy)eth yl)]-pyrro lid in e-3-carboxylIi c acid; trans, trans-2-(1 ,3-Benzodioxol-5-yI)-4-(4- met hoxyphenyl)- 1 butoxyethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,4-benzodioxan-6-y)-1 (propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,4-benzodioxan-6-yI)-1 -(N-methyl- N- pro py lami nocarbo nyl methyI)-pyrroli di ne-3 -carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(N-methyl- N-butylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4- Meth oxy-2- met hoxymet hoxyph e nyl)-4- (1 ,3* benzodioxol-5-y)-1 -(N-methyl-N-butylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 et hoxyp ropyl)-pyrro lid in -5-o ne-3-carboxy li c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 methoxybenzyl)-pyrrolidi n-5-one-3-carboxylic acid; -24trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxol-5-y)- 1 diisoamylaminocarbonylmethyl)-pyrrolidine-3carboxyic acid; trans, trans-2-(4-Methoxypheny)-4-(1 ,3-benzodioxo-5-yl)-1 dipentylaminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yl)-1 -(N,N-di(2met hoxyeth yl)am in ocarbo nyl methyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 hexynyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 cyclopropylmethyl-N-propylami nocarbo nylmethyl)-pyrrolidi ne-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-y)-l -(N-methyl- N-pentylami nocarbonyl met hyl)-pyrrolidi n e3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 1 3-be nzodioxol-5-yl)-1
,N-
diisobutylami nocarbo nylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- Met hoxyph enyl)-4-(1 ,3-be nzodi oxo I-5-y 1 (N-methyl- N-(2-propynyl)ami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)-l 1-(N-methyl- N-(n-hexyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-di(nbutyl)ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- Met hoxyphe nyl) 3-be nzodi oxo1-5-y)- 1 ,NdiethylaminocarbonylmethyI)-pyrroidine3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 -(N-methyl- N-phenylaminocarbonylmethyl)..pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1 -(N-methyl- N-cyclohexylaminocarbonylmethyl)-pyrrolidine.3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,N-di(npro pyI) ami nocarbo n ylmethyI)-pyrroi di ne3carboxy lic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-y)-1 -(N-methyl- N-isobutylaminocarbonylmethy)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)- 1 butyloxycarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphe nyl)-4- (1 -naphthyl)- 1 -(N-methyl-Npropyl)aminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(2,3-dihydrobenzofuran-5-y)- methyl-N-propyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2 ,4-Bis(4-methoxyphenyl)- 1 -(N-methyl-Npro pyl)am in ocarbo nyl methyl)-pyrroIi di ne-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(3 ,4-di methoxyphenyl)- 1 -(N-methyl- N-propyl)ami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4- meth oxyphenyl)- 1 -(N-methyl-Npro pyl)ami n ocarbonyl methyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(2-naphthyl)-1 -(N-methyl-Npro pyl)ami nocarbonyl methyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (ethylsulfinyl)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (i sopro pylsulIfo nylami no) eth yl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (isobutoxy)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)-1 (butylsulfonyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 methyl-N-isobutyrylami no)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo l-5-yI)-1 methyl-N-propionylamino)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 -(N-methyl- N-benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo l-5-yl)-1 -(N-ethyl-Nbutylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(N-methyl- N-(2 ,2-dimethylpropyl)ami nocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 methyl-N-butylsulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 methyl-N-propylsulfonylami no)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (pro pylsu Ifo nyl)ethyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 methylhex-2-enyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- (4-M et hoxyp hen yl)-4- (1 ,3-be nzodi oxo1-5- yl)- 1 N -(transmethyl hex-2-en yl)-pyrro lid ine-3-carboxylic acid; trans, trans-2- (4-m eth oxyphenyl)-4-(1 ben zodioxo1-5-yl)-1 heptylcarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-yI)-1 (vale rylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 di methoxybenzyl)-N-methylaminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 di methoxybenzyl)ami nocarbonylmethyl)pyrrolidi ne-3-carboxylic acid; (2R ,3R,4S)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 R)-1 (N,N-dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid; (2S,3S,4R)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 R)-1 (N ,N-dipropylami nocarbonyl)-1 -butyl)pyrrolidi ne-3-carboxylic acid; (2S,3S,4R)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 S)-1 (N ,N-dipropylami nocarbonyl)-1 -butyl)pyrrolidi ne-3-carboxylic acid; (2R ,3 R,4S)-2- (4-Methoxyphe nyl)-4-( 1,3-benzodioxo-5-y)-1 S)-1 (N ,N-dipropylaminocarbo nyl)- 1 -butyl)pyrrolidi ne-3-carboxylic acid; trans, trans-1 -(2-(N,N-Dibutylaminocarbonylmethyl)-2-(4hydroxyphenyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid hydrochloride salt; trans, trans-i1 Isobutyl-N-propylsulfonylami no)ethyl)-2-(4methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans,trans-1 -(2-(N-Benzenesulfonyl-N-propylamino)eth~yI)-2-(4.
methoxyphenyl)-4-(i ,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i N- (4-M ethoxybe nze nesufo nyl)-N-pro pylami no) ethyl)- 2-(4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans,trans-1 ,N-Di(n-butyl)aminocarbonylmethyl)-2-(2methoxyethoxy-4-methoxyphenyl)-4-(1 yl)pyrrolidine-3-carboxylic acid; trans. trans-i Propyl-N-(2 ,4-di methylbenze nesulfonyl)amino)ethyl)-2-(4-methoxyphenyl)-4-(1 3- carboxylic acid; trans,trans-1 -(2-(N-Propyl-N-(3-chloropropylsulfonyl)amino)ethyl)-2.(4.
methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid;I trans, trans-i ropyl-N-(2-methoxyethylsulfonyl)amino)ethyl)-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i ropyl-N-(2-ethoxyethylsu lfonyl)amino)ethyl)-2-(4methoxyphe nyl)-4-(l1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(5-dimethylami no-i naphthylsu Ifony)amino)ethyl)-2-(4-methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(ethylsulfonyl)ami no)ethyl)-2-(4methoxyphe nyl)-4-(i ,3-benzodioxol-5-y)pyrrolidi ne-3-carboxylic acid; -32trans,trans-i -(N-Methyl-N-propylaminocarbonylmethyl).2-(4methoxyphenyl)-4-(6-indolyl)pyrrolidine3carboxylic acid; trans, trans-i1 -(N-Methyl-N-propylaminocarbonylmethyl)-2(4methoxyphenyl)-4-(3 ,4-difluorophenyI)pyrrolidine-3-carboxylic acid; trans, trans-i1 -(N-Methyl-N-propylaminocarbonylmethyl)-2(4.
met ho xyph enyl)-4- (ph e nyl) pyrro lidi ne3carboxyli c acid; trans, trans-i1 -(N-Methyl-N-propylami nocarbonylmethyl)-2-(4methoxyphenyl)-4-(4-hydroxyphenyI)pyrrolidine.3.carboxylic acid; trans, trans-i -(N-Methyl-N-propylami nocarbonylmethyl)-2-(4methoxyphenyl)-4-(2 ,4-di methoxyphenyI)pyrrolidine-3-carboxylic acid; trans, trans-i N- Dibutylami nocarbonylmethyl)-2- (4-methoxyphenyl)- 4-(5-benzo-2,3-dihydrofuranyl) pyrrolidi ne-3-carboxylic acid; trans, trans-i N- Dibutylaminocarbonylmethyl)2(4-methoxyphenyl).
4-(4-methoxyphenyl)pyrro Iidine-3-carboxylic acid; trans, trans-i N- Dibutylami nocarbonyl methyl)-2. (4-m eth oxyp hen yl)- 4 -(3,4-difluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 N- Di butylami nocarbonyl met hyl)-2-(4-.methoxyphenyl)- 4-(2,4-dimethoxyphenyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i1 ,N-Dibutylami nocarbonylmethyl)-2-phenyl-4-(i ,3benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans,trans-1 N-Dibutylaminocarbonylmethyl)-2-pheny..4-(5-be nzo- 2,3-di h yd rofu ran yl)pyrro lidi ne-3-carboxyl ic acid; trans, trans-i .N-Dibutylaminocarbonylmethyl)-2-(4-t-butyphenyI)-4 (5-benzo-2,3-dihydrofuranyl)pyrroidine3carboxylic acid; trans, trans-2-(N, N- Dibutylaminocarbonylmethy)-2-(4..methoxyphenyl).
4 4 -fluorophenyl)pyrrolidmne-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethyl)-2-(3..furyl)-4{(1,3benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i -(NN-Dibutylaminocarbonylmethyl)-2-(isopropyl)-4(1 ,3ne-3-carboxylic acid; -33trans, trans-i N-Dibutylaminocarbonylinethyl)-2-(4-t-butylphe nyl)-4- (1 ,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i N-DibutylaminocarbonylmethyI)-2-(4-t.butylphe nyl)-4- (5-benzo-2,3-di hydrofu ranyl)pyrro lid ine.3-carboxylic acid; trans, trans-i1 ,N-Dibutylaminocarbonylmethyl)-2-(anti-4methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans, trans-i ,N-Dibutylami nocarbonylmethyl)-2-(syn-47 methoxycyclohexyl)-4-(l ,3-benzodioxol-5-y)pyrrolidine.3carboxylic acid; trans, trans-i 1 N-Dibutylaminocarbonylmethyl)-2 ,4-di (5-benzo-2,3di hydrofu ran yl)pyrro lidi ne-3-carboxylic acid; trans, trans-i1 Dibutylami nocarbo nylmethyl)-2-(3-f uryl)-4-(5-be nzo- 2,3-di hydrofu ranyl)pyrrolidine-3-carboxylic acid; trans, trans- 1 N- Dibutyaminocarbonylmethyl)-2.(4-methoxypheny).
4 -(3-fluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-i N- Dibutylami nocarbonylmethyl)-2-(4-methoxyphenyl)- 4 -(3-pyridyl)pyrrolidine-3-carboxylic acid; trans, trans- 1 N-Dibutylami nocarbonylmethyl)-2-(2-fluorophenyl)-4.
(1 3 -benzodioxoI-5-yl)pyrrolidine-3-carboxylic acid; trans,trans- 1 ,N-Dibutyaminocarbonymethy)-2(3-fluoropheny,)-4 (1 3 -benzodioxoI-5-yi)pyrrolidine-3-carboxylic acid; trans, trans-i N-Dibutylaminophenyl)-2-(4-methoxyphenyl).4-(1 ,3benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans,trans-1 N-Dibutylaminopyrimidin-4-yl)-2-(4-methoxyphenyl).
1,3-benzodioxol-5-y)pyrrolidi ne-3-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (p ropyl am inocarbo nyl met hyl) -pipe ridi ne.4carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (aminocarbonylmhethyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 fluo robenzyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 ethoxyethyl)-piperidine-4-carboxylic acid; -34trans, trans-3-(4-Methoxyphenyl)-5-( f ,3-benzodioxol-5-y)-l propoxyethyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphe nyl)-5-(1 ,3-benzodioxol-5-yI)- 1 methoxyethoxy)ethyl]-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphe nyl)-5-(1 ,3-benzodioxo I- 5 1 pyridyl)ethyl]-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-be nzodioxol-5-yl)-1 (mo rpholin-4-ylcarbonyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphe nyl)-5- (1 ,3-benzodioxo ie-5-yI)- 1- (butylami nocarbonyl)-pipe ridine-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyt)-5-( 1,3-benzodioxol-5-yl)-1 methoxyphenylami nocarbonyl)-3-piperidine-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-( 1,3-be nzodioxol-5-yi)-1 acetylpiperidine-3-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-( 1,3-benzodioxol-5-yI)- 1 -(2-fu royl)piperidine-3-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 (phenylaminocarbonyl)-piperidine-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxo-5-y)-.1 (allylaminocarbonylmethyl)-pipe ridi ne-4-carboxylic acid; trans, trans Meth oxyp hen yl)-5- (1 be nzodi oxo-5-y)- 1 butylami nocarbonylmethyl)-piperidine-4-carboxylic acid; tran;, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 -(N-n-butyl- N- met hyl ami nocarbo nylImethyl)-piperi di ne-4-carboxyli c acid; trans, trans-3-(4-Methoxyphe nyl)-5- (1 ,3-benzodioxol-5-yl)- 1 -(pyrrolidi n- 1 -ylcarbonylmethyl)-piperidine-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (i so buty lami nocarbo nyl met hyI)-pi pe ridin e-4-carboxy li c acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 (cyclopentylaminocarbonylmethyl)-piperidine-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (mo rpho li n -4-ylam inocarbon yl meth yl) -pipe ridi ne-4-carboxylic acid; trans, trans (4-Meth oxyp henyl)-5- (1 be nzo di oxo 1-5-yI1)- 1 phe noxyethyl)-piperidi ne-4-carboxylic acid; trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)- 1 met hoxyethylami no carbo nylm eth yl)-piperidi ne-4-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1- (iso pro pylami n ocarbo nyl methyl)-pyrro lidi n e-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (ethylaminocarbonymethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 met hylpro pytami no carbo nylrmet h yI)pyrro lid in e-3carboxy i c acid; trans, trans-2-(4-Methoxypheny)-4-(1 ,3-benzodioxol-5-y)-1 (phe nylami nocarbo nylm ethyl) -pyrrolidi ne-3carboxyli c acid; trans, trans-2-(4-Methoxyphenyt)-4-( 1,3-benzodioxol-5-yl)-1 (pi peridi nylcarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (propylami nocarbonyl)ethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2- (4-Meth oxypheny)-4-(1 ,3-be nzodioxo 1 (propylaminocarbonyl)be nzyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (4-M ethoxyphe nyl)-4-(1 ,3-be nzodi oxo1-5-yI)- 1 -(bis- (propylami nocarbonyl) methyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphqnyl)-4-(1 ,3-benzodioxol-5-yI)-.1 (propylaminocarbonyl)ethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yi)-1 (propylami nosulfonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 phenethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 (pe ntanoyl met hyl)-pyrro lidi ne- 3-carboxyl ic acid; trans, trans-2- Math oxyp hen yl)-4- (1 ,3-be nzodi oxo 1 (be nzoylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(hexyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphe nyl)-4-(1 ,3-be nzodi oxol-5-y)- 1 -(2-hexynyl)- *pyrrolidine-3-carboxylic acid; -36trans, trans-2-(4-Methoxyphenyl)-4-( 1 3-benzodioxol-5-yI)- 1 (pro poxym et hylcarbo nyl-pyrro lid ine-.3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxo1-5-yi)- 1 -(phenacyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (anilinylcarbonyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 acetylami noethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-yl)- 1 phenoxyethy)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl).4.( 1 ,3-benzodioxol-5-y)-1 benzodioxanylmethyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 tetrahydrofuranylmethyl)-pyrrolidine.3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (propylaminocarbonylamino)ethenyl).pyrrolidine.3-carboxylic acid; trans, trans-2 -(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (propylaminocarbonylamino)ethyl)-pyrrolidine.3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4. (1 ,3-benzodioxol-5-y)- 1 -(3-oxohex- 1 -enyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,4- Di methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (propylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-Carboxy-4-methoxyphenyl)-4(1 ,3-benzodioxol-5-yI)- 1 (propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-Carboxamido-4-methoxyphenyl)-4(1 yi)-l1-(propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-Methanesulfonamido-4-methoxyphenyl)-4(1 ,3benzodioxol-5-yI)-l1-(propylami nocarbonylmethyl)-pyrro lidi ne-3carboxylic acid; trans, trans-2- (2-C arbamoy Im eth oxy4-met hoxyp hen yI)-4(1 ,3benzodioxol-5-yI)-l1-(propylami nocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; -37trans, trans-2-(2-Methoxyethoxy-4-methoxyphenyl)-4(1 ,3-benzodioxo I- 5-yl)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-Carboxymethoxy-4-methoxyphenyl)-4(1 ,3* benzodioxol-5-yI)- 1 -(propylaminocarbonylmethyl)-pyrro lidi ne-3carboxylic acid; trans, trans-2-(4-Methoxy-2-tetrazo lylmethoxyphe n yI)-4(1 3benzodioxol-5-y)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-AIlyloxy4- methoxyphe ny)4(1 1 3-be nzodioxol1-5-yI)- 1 (p ropy lami nocarbo nyl methyl)-pyrroIi din e-3- ca rboxylic acid; trans, trans 2,4-Bis(4-methoxyphenyl)-l1-(propylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans 2,4-Bis(1 ,3-benzodioxol-5-y)-1 (propylaminocarbonylmethyt)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl).4-(1 ,3-benzodioxol-5-y)-1 -(N-methyl- N-propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxole-5-yi)-1 -(N-methyl- N-butylaminocarbonyl)-pyrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4-(1 .3-benzodioxol-5-yl)-1 -(N-methyl- N-(4-methoxyphenyl)ami nocarbonyl)-3-pyrrolidine-3-carboxylic acid; trans, trans-2- Met hoxyphe ny1)-4- (1 ,3-be nzo di oxo-5-y1)- 1 -(N-methyl- N-phenylaminocarbonyl)-pyrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-allylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-methyl- N-isobutylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N- cyclo pe nty lam ino carbo ny Imet hyl)-pyrro lid ine.3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-methyl- N-methoxyethylaminocarbonyl)-pyrrolidine3carboxylic acid; -38trans, trans-2-(4-Methoxyphenyl)-4.( 1 3-benzodioxo-5-y)-1 -(N-methyl- N-butoxyethylaminocarbonyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(1 1 3 -Benzodioxol-5-yl)-4-(4-methoxyphenyl)- 1 -(N-methyl- N- pro pylami nocarbo ny Imeth yI)-pyrroi di ne -3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 1 4-benzodioxan-6-y)-1 -(N-methyl- N-propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4-(1 9 3-benzodioxol-5-yl1-1 -(N-methyl- N-isopropylami nocarbonylmethyl)-pyrrolidine.3-carboxylic acid; trans, trans-2-(4- Met ho xyp he nyl) (1 9 3-be nzo d ioxo 1-5-yl1)- 1 -(N-methyl- N-ethylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4(1 ,3-be nzodioxol-5-yl)- 1 -(N-methyl- N-(1 -methylpropyl)aminocarbonylmethyl)..pyrrolidine-3 carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benfzodioxol-5-yl)- 1 -(N-methyl- N-phenylaminocarbonylmethyl)-pyrroidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxypheny)-4-(1 9 3-benzodioxol-5-y)-1 methyl- N-propy lam i nocarbo n yl)ethyl)-pyrro lidi ne3carboxy li c acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxol-5-yl)- 1 methyl-N-propylami nocarbonyl)benzyl)-pyrrolidine.3.carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y).1 -(N-ethyl-Npropylaminocarbonylmethyl)..pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 .3-benzodioxole-5-yl)- 1 -(N-ethyl- N-butylaminocarbonyl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-N- (4-methoxyphenyl)ami nocarbonyl)-3-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -(N-ethyl-Nphenylaminocarbonyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-ethyl-Nal lylam in ocarbo nylIm ethyl) -pyrro lid ine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-y)-1 -(N-ethyl-N- (n-butyl)ami nocarbo n ylmethyl)pyrroli dine-3-carboxylic acid; -39trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5y). 1 -(N-ethyl-Nisobutylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4(1 1 3-benzodioxol-5-yl). 1 -(N-ethyl-Ncyclopentylaminocarbonylmethyl)-pyrrolidi ne-3-carboxyhic acid; trans, trans-2-(4.Methoxyphenyl)4(1 ,3-benzodioxo l-5-yl)- 1 -(N-ethyl-Nmethoxyethylaminocarbonyl).pyrrolidine3carbxli acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxo-5-yl).1 -(N-ethyl-Nbutoxyethylaminocarbonyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(1 3 -Benzodioxol-5-yi)4(4..methoxyphenyl)- 1 -(N-ethyl-NproPYlaminocarbonylmethyl)pyrrolidine-3carboxylicacd trans, trans-2-(4-Methoxyphenyl)-4.(1 ,4-benzodioxan-6-yi)- 1 -(N-ethyl-Npropylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4-(1 3-benzodioxol-5-yl). 1 -(N-ethyl-NisoPropylaminocarbonylmethyl).pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yi)-l 1-(N ,Ndiethylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4-(l 3-benzodioxo--yl). 1 -(N-ethyl-N- (1 -methylpropyl)aminocarbonylmethyl) pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxo l-S-yl)-1 -(N-ethyl-Nphenylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4-(1,3-be nzodioxol-5-yl)- 1 -(N-ethyl- N-propylaminocarbonyl)ethyl)pyrrolidne3carb,.li acid; trans, trans-2-(4-Methoxyphenyl)-4.(1 ,3-benzodioxol-5-y).1 -(c-(N-ethyl- N-propylaminocarbonyl)be nzyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yl)- 1 -(N-methyl- N-isobutylaminocarbonymethyl)pyrrolidine3carbyic acid; trans, trans-2.(4-Methoxyphenyl)-4(1 9 3-benzodioxol-5-yI).1 -(N-methyl- N-cyclohexylaminocarbonylmethy)pyrrolidine 3 carbyic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-..yl).
,N-
dipropylaminocarbonylmethyl)pyrrolidine3carbcoxyic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5yl)-1 1- (isobutyloxyethyl)pyrrolidine-3carboxylic acid; -41 trans, trans-2-(4-Methoxyphe nyl)-4-(5-indanyl)- 1 -(N-methyl-Npropylaminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans- 2 4 -Methoxypheny 1)-4-(2,3.di hydrobe nzof uran.S..y).1 methyl-Npropyaminocarbonymethyl).pyrroidine3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4-( -methylindo-5-y)-1 -(N-methyl-Npropylami nocarbonylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(2-naphthyl)- 1 -(N-methyl-Npro pylami no carbo nyl met hyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4- Methoxyphe nyl)-4- (1 ,3-be nzodioxol-5-yi)-1 -(N-butyl-Nphenylaminocarbonylmethyl)-pyrrolidine.3carboxylic acid; trans, trans-2-(4-Methoxypheny)4(1 ,2-dimethoxy-4-phenyl)-1 methyI-N-propyaminocarbonylmethyl)..pyrroidine3carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-( -methoxy-3-phenyl)-1 (N-methyl- N-propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxol-5-yl)- 1- [decahydroisoquinolin-.2- carbonylmethyl]-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yI)-l1-(3,3dimethylpiperidinyl- carbonylmethyl]-pyrrolidine-3carboxylic acid; trans-trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yl)-l -[2-(N-propyl-N-isobutoxycarbonylamino)ethyl]-pyrro Iidine-3-carboxylic acid trans-trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)- 1 ,2,3 ,4tetrahydroisoquinoli n-2- carbo nylmethyl]-pyrrolidi ne-3-carboxylic acid; trans-trans-2-(4-Methoxypheny)-4(1 ,3-benzodioxol-5-y)- -2-(Npropyl-Ndimethylami nocarbonylamino)ethyI]-pyrrolidine3carboxylic acid; trans, trans-2- Met hoxyph e nyl1)-4- (1 .3-be nzod ioxo 5-yl)- 1 -(2-(N-propyl-N-(4nitrobenzenesulfonyl)ami no)ethyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4- Met hoxyph enyl)4(1 1 3-benzodi oxol-5-yl)- 1 -(2-(N-propyl-N-npentanesulfonylamino)ethyl)pyrrolidine-3carboxylic acid; trans,tfrans-2-(4- Methoxyphe nyl1)-4- (1 ,37bernzodioxoI-5-yI) -1 -(2-(N-propyl- N-(4trifluoromethoxybenzenesulfonyl)amino)ethyl)-pyrrolidine.3carboxylic acid; -44trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 dilsopropylami nocarbonylmethyl]-pyrrolidi ne-3-carboxylic acid; and trans, trans-2- Fluoro-4-m ethoxyphe nyl)-4- (1 ,3-be nzodioxol-5-yI)- 1 N-propyl-N-butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are selected from the group consisting of: trans, trans- 2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (pro pylami n ocarbo nyl met hylI)-pyrro Ii di ne-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 pro poxyethylI)-pyrro lidi ne-3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1, 3-benzodioxo l-5-yl)-1 (npro pyl)- N-methylami nocarbonyl methyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-y)-1 (isobutylami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (cyclope ntylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxy-2-methoxymethoxyphenyl)-4-( 1,3be nzodioxol-5-yl)- 1 -(N-methyl-N-butylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxo-5-yl)-1 INdi iso amytam in ocarbonylm ethyl) -pyrro lidi ne-3carboxyl ic acid;, trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,Ndipentylaminocarbonylmethyl)-pyrro Iidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)- 1 ,N-di(2methoxyeth yl)ami nocarbo nyl met hyl)-pyrrol idi ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 cyclopropylmethyl-N-propylami nocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2- Met hoxyp he ny1) (1 ,3-be nzo di oxol-5-yl)- 1 Ndi iso butylami nocarbo nyl met hyI)-pyrro li di ne-3-carboxyli c acid; -46trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)- 1 dimethoxybenzyl)ami nocarbonylmethyl)pyrrolidi ne-3-carboxylic acid; (2R,3R,4S)-2-(4-Methoxyphenyl)4.(1 ,3-benzodioxol-5-yi)-1 R)-1 (N,N-dipropylaminocarbonyl)-l -butyl)pyrrolidine-3-carboxylic acid; (2S,3S,4R)-2-(4-Methoxyphenyl)4.(1 ,3-benzodioxol-5y)-1 R)-1 (NN-dipropylaminocarbonyl)-l -butyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (4-Methoxyphenyl)4(1 ,3-benzodioxol-5-yl)- 1 ,N-di(ntrans, trans-2-(4-Fluorophenyl)-4-( 1,3-benzodioxol-5-y)-1 ,N-di( nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-,Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 -(N-n-butyl)- N- (n-propyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2- Met hoxyp hen yl)4.(1 ,3-be nzo di oxo1-5-y) -1 N di pro pyl)amnin ocarbon yl)eth yl] pyrro Ii di ne-3 carboxyli c acid; trans, trans-2- (4-Methoxyphenyl)-4(1 .3-benzodioxol-5-yI)-1 ,N-di(nbutyl)aminocarbonyl)methyl)pyrrolidi ne-3-(Nmethanesulfonyl)carboxamide; trans, trans-2-(4-Methoxypheny)-4-(1 ,3-benzodioxol-5-yI)-1 ,N-di(nbutyl)aminocarbonyl)methyl)pyrrolidine-3(Nbenzenesulfonyl)carboxamide; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1
N-
dibutylamino)carbonyl-1 -(RS)-ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(Pentyl)-4-( 1,3-benzodioxo I-5-yI)-1 Ndibutylamino)carbonylmethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 propyl- N-butyry lam ino)eth yl] pyrro lidi ne3carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 propyI-N-(ethylaminocarbony)amino)ethy]pyrroidine-3 carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)- 1 -[2-(N-butyl- N-butyrylamino)ethyI]pyrrolidine-3-carboxylic acid; -47trans, trans-2- Met hoxyp he nyI)4(1 ,3-be nzo dioxo 1- 5-y 1 -f2-(Npropyl-N-ethoxycarbonylami no)ethyllpyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(i ,3-benzodioxo I-5-yI)- 1 methyI-N-(2-propylvaleryl)ami no)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyly..4-(i 3-benzodioxol-5-y)- 1 propyI-N-( 4 methoxyphenoxycarbonyl)amino)ethyl~pyrrdlidine- 3 carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(i 1 3-benzodioxol-5-yI)- 1 propyl-N-(4-methoxybenzoy)ami no)ethyl]pyrrolidine-3.
carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yI)- 1 propyl-N-benzoylami no)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yI)- 1 propyl-N-benzyloxycarbonylami no)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-y)-1 -[2-(N-butyl- N-ethoxycarbonylami no)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y)-1 -[2-(N-butyl- N-p ropoxycarbo nylam ino)et hy I]pyrro lid in e- 3carboxy i c acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo I-5-yI)- 1 propyl-N-propoxycarbonylamino)ethy~pyrroidi ne-3-carboxylic acid; trans, trans-i ,N-Di(n-buty)aminocarbonyl)methyI2 ,4-di (1,3benzodioxol-5-yl)pyrrolidine.3-carboxylic acid; trans, trans-i 2 (n-B utyl)- N-pro pylsulIfo nyla mi no)ethyl) (4methoxyphenyl)-4-( 1,3-benzodioxol-5-y)pyrrolidi ne-3-carboxylic acid; trans, trans-i ,N-Di(n-butyl)ami nocarbonylmethyl)-2-(4methoxyphenyl).4-(1 ,3-benzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; -48trans,trans-1 2 -(N-Propyl-N-propylsulfonylamino)ethyl).2-(4.
methoxyphenyl)-4-( 1 3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; trans,trans-1 2 -(N-Butyl-N-butylsulfonylamino)ethyl).2(4.
methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; trans, trans-i 1 N-Dibutylaminocarbonylmethyl).2-(4.
methoxymethoxyphenyl)-4(1 ,3-benzodioxol-5-yl)pyrrolidine-3 carboxylic acid; trans, trans-i ,N-Dibutylaminocarbonylmethy).2(4.
hydroxyphe nyl)-4-(1 1 3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid hydrochloride salt; trans, trans-i 2 -(N-Isobutyl-N-propylsulfonylamino)ethyl)-2(4methoxyphenyl)-4-(1 3 -benzodioxol-5-yl)pyrrolidine3carboxylic acid; trans, trans-i 2 -Ben ze nesu lonyl.N-propyami no)ethy)2( 4 methoxyphe nyl)-4-( li 3 -benzodioxol-5-yl)pyrrolidine3carboxylic acid; trans, trans-i 2 4 -Methoxybenzenesulfony)Npropylaino)ethyl)- 2-(4-methoxyphenyl).4(1 ,3-benzodioxol-5.yl)pyrrolidine-3 carboxylic acid; trans, trans-i ,N-Di(n-butyl)aminocarbonylmethyl)-2(2methoxyethoxy-4-methoxyphenyl)4(1 yI)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(2 ,4-di methylbenzenesulfonyl)amino)et hyl)-2-(4- met hoxyph e nyl)-4- (1 3 -benzo di oxo1-5-yl) pyrro lidi n e 3-carboxylic acid; trans,trans-1 PropyI-N-(3-chloropropylsulfonyl)amino)ethyl)-2( 4 methoxyphenyl)-4-(1 3 -benzodioxol-5-yI)pyrrolidine-3.carboxylic acid; trans, trans-i (2-(N-Propyl-N- 2 -methoxyethylsulfonyl)amino)ethyl)2(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)pyrrolidi ne-3-carboxylic acid; -49trans, trans-i 2 -(N-Propyl-N-(2-ethoxyethylsulfonyl)amino)ethyl)-2(4.
methoxyphe nyl)-4-(l1,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(5-dimethylamino- 1naphthylsulfonyl)amj no)ethyl)-2-(4-methoxyphenyl)-4.( 1 ,3benzodioxol-5.yl)pyrrolidine3carboxylic acid; trans, trans-i ropyl-N-(ethylsulfonyl)ami no)ethyl)-2-(4methoxyphe nyl)-4-(1 3 -benzodioxoI-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i 2 -(N-Propyl-N-(4-methylbenzenesulfonyl)ami no)ethyl)-2met hoxyp heny (1,3 -be nzodi oxol1-5-yl) pyrroli d ine-3 carboxylic acid; trans, trans- I ,N-Di(n-buty)aminocarbonymethy)2(3pyridy)4-(1,3benzodioxo I-5-yI)pyrrolidi ne-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(n-butylsu Ifonyl)amino)ethyl)-2-(4methoxyphenyl)-4-(1 3 -benzodioxoI-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(4-ch Iorobenzenesulfonyl)amino)ethyl)-2 (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3 carboxylic acid;' trans, trans-i1 2 Propyl-N -(be nzylsu Ifo nyl)ami no)et hyl)2-(4methoxyphenyl)-4-( 1 3 -benzodioxoI-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i 2 -(N-Propyl-N-(4-fluorobenzenesulfonyl)ami no)ethyl)-2- (4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3 carboxylic acid; trans, trans-i (N-M eth yl-N -pro pylam ino carbo nyl meth yl)2(4methoxyphenyl)-4-(6-benzofuranyl)pyrroidine3-carboxylic acid; trans, trans-i1 N-Di butyamnocarbony methyl)-2(4-methoxyphel)- 4 4 -benzofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 N- Dibutylami nocarbonylmethyl)-2-(4-methoxyphenyl)- 4 4 -benzofurany)pyrroidine-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethyl)2(4-methoxyphenyl)- .4-(6-benzofuranyl)pyrrolidi ne-3-carboxylic acid; trans,trans-l -(NN-Di buty lam inocarbonyl methy)-2-(4.m eth oxypheny).
4-(6-benzo-2,3-dihydrofuranyl) pyrrolidi ne-3-carboxylic acid; trans, trans-i1 N- Dibutylami nocarbo nyl methyl)-2- (4-m ethoxyp heny)- 4-(5-benzo-2,3-dihydrofuranyl) pyrrolidi ne-3-carboxylic acid; trans, trans- 1 N-Di butylami nocarbo nyl methyl)-2 (4methoxyp hen yl) 4-(4-methoxyphenyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i N- DibutylaminocarbonylmethyI)-2-(4-methoxyphenyl).
4 3 ,4-difluorophenyI)pyrrolidine-3-carboxylic acid; trans, trans- 1 N- Dibutyami nocarbon ylmet hyl)-2-(4-.methoxyp hen y) 4-(2 ,4-di methoxyphenyl)pyrrolidi ne-3-carboxylic acid; trans, trans-1 N-Dibutylami nocarbo nylmethyl)-2-phenyl-4- (1 ,3be nzodioxol-5-yl)pyrroli di ne-3-carboxylic acid; trans,trans-1 -(NN-Dibutyaminocarbonyimethy)2.pheny4(5-benzo- 2,3-dihydroturanyl)pyrrolidine-3-carboxyhic acid; trans, trans-i1 N-Di butyam in ocarbo nymethy)2(4tbutylphe nyl)-4- (5-benzo-2,3-di hydrofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-2- N- Dibutylami nocarbonyl methyl)-2- (4-m eth oxyp hen yl).
4 4 -fluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 N-Dibutylami nocarbo nylmethyl)-2-(3-furyl)-4-( 1,3benzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid;, trans, trans- N-DibutylarinocarbonylmethyI)-2.(isopropyI)- 4 (l,3be nzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethyl)-2-(4t-butylphe nyl)-4- (1 1 3 -benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethy)-2-(4-t..butylphe nyl)-4- (5-benzo-2,3-di hydrofuranyl)pyrrolidine-3-carboxylic acid; trans, trans-i ,N-Dibutylaminocarbonylmethyl)-2-(anti-4 methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans, trans-i1 N-Dibutylami nocarbonylmethyl)-2-(syn-4methoxycyclohexyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3carboxylic acid; trans, trans-i1 N-Dibutylaminocarbonylmethyl)-2 ,4-di (5-benzo-2,3dihydrofu ranyl)pyrrolidind-3-carboxylic acid; -51trans, trans-i ,N-Dibutylaminocarbonylmethyl)-2- (3-furyl)-4-(5-benzo- 2,3-di hyd rofu ran yl) pyrro lidi ne-3-ca rbo xyli c acid; trans, trans-i1 N- Dibutylaminocarbonylmethyl)-2. (4-methoxyphenyl)- 4 3 -fluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)- 1 -(N-butyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-i ,N-Dibutylami nocarbonylmethyl)-2-(2-flucrophenyl)-4 (1 3 -benzodioxol-5-yl)pyrroldine.3.carboxylic acid; trans, trans-i1 N- Dibutylami nocarbo nylmeth yl)-2-(3-f luoro ph enyl)-4 (1 3 -benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans,trans- 1 ,N-Dibutylaminocarbonylmethyl).2-.(4-ethylphenyl)-4- 3 -benzodioxol-5-yl)pyrrolidine.3-carboxylic acid; trans, trans-i1 N- Dibutylaminocarbonyl methyl)2(3-fuo ro-4 methoxyphenyl)-4- (1 3 -benzodioxol-5-yl)pyrrolidine.3-carboxylic acid; trans, trans-i1 ropyl-N-(n-pentylsu lfonyl)amino)ethyl)-2-(3-f luoro.
4-methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidine.3 carboxylic acid; (2R ,3R ,4S)-(+)-2-(4-methoxyphenyl)-4-(1 .3-benzodioxol-5-yl)-1
N-
di (n-butyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; and trans, trans- 1 N- Dibutylami nocarbo nylmethyl)2(3-fluo roph enyl)- 4 (1 3 -benzodioxol-5-y)pyrrolidine3carboxylic acid; or a pharmaceutically acceptable salt thereof.
Particularly preferred is the compound trans, trans-2-(4-methoxyp henyl)- 4-(1 ,3-benzodioxol--yl).1 -(NN-di(n-butyl)aminocarbonylmethyl)..pyrrolidine-3 carboxylic acid; or a pharmaceutically acceptable salt thereof.
Most particularly preferred is the compound methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 1-(N ,N-di (nbutyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; or a pharmaceutically acceptable salt thereof.
-52- Methods for preparing the compounds of the invention are shown in Schemes I-XIV.
Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH 2 and W is -CO2H. A (-ketoester 1, where E is loweralkyl or a carboxy protecting group and R 1 is aryl or heterocyclic, is reacted with a nitro vinyl compound 2, where R 2 is aryl or heterocyclic, in the presence of a base (for example, 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5 as a mixture of cis-cis, trans,trans and cis,trans products. Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R3-X (R3 is R 4 or Rs-S(0) 2 and X is a leaving group such as a halide (CI is preferred) or X taken together with R 4 or R6-S(0) 2 forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, Nhydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5trichlorophenol and the like) or alkylated with R 3 -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 ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 6 which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester Q (for example, using a base such a sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the trans,trans ester to give a mixture of Z and 8, which are readily separated.
-53- Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH 2 and W is -CO 2 H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 1Q in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with R 1
-CH
2 wherein X' is a leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14. Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles 15. Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile J1.
Hydrolysis of the nitrile using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound .8 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19.
Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is and W is -CO 2 H. O3-Keto ester (wherein E is loweralkyl or a carboxy protecting group) is reacted with an ahaloester 21 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with
R
3
-NH
2 and heating in acetic acid gives the cyclic compound 23. The double bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24.
Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,trans carboxylic acid Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is -CH 2 and W is -CO2H. The trans,trans -54compound Z, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is Cl). Compound 2 is treated with diazomethane to give the diazo ketone U. Rearrangement of compound
Q
(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 21 using 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 2Q 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 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 acetonitrile 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 ethanolwater 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 U from the cis,trans ester 34.
Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride i5 is reacted with lithio dithiane U to give the alkylated compound 32. Treatment of compound 3Z with 4methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 2. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 2. Treatment of 3 with benzylamine and formaldehyde gives the keto piperidine 4Q. Treatment of compound 4Q with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 21 resulting in the formation of the N-derivatized carboxylic acid 4.
A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 4. (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48. Treating compound 48 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 5. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51.
Scheme IX illustrates the preparation of compounds where n is 0, Z is
-CH
2 and W is other than carboxylic acid. Compound 5L, 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 5. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 5Z. Nitrile 5Z under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 5. Alternatively nitrile Z is reacted with hydroxylamine hydrochloride in the presence of a base (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 9. The amidoxime 59 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the -56- O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in cyclization to compound 6Q. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61.
Scheme X illustrates the preparation of compounds in which R 3 is an acylmethylene group. A carboxylic acid 62 (where R 4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N-dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 63 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5f, prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6. Treatment of 66 with an amine (R 2 oNH 2 affords secondary amine 6Z. This amine (6Z) can be reacted with an activated acyl compound (for example, R 4 and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide S. Alternatively amine 6Z can be reacted with an activated sulfonyl compound (for example,
R
6 -S(0) 2 -CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 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 ZQ are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 Tsuge, S. Kanemasa, K.
Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S. Kanemasa, T. Yamada, K.
Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O.
Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also -57shown in Scheme XII. Silylimine 23 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 Z3 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 2&.
Scheme XIII illustrates a method for producing an snantiomerically pure pyrrolidine f, 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 Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt.
This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 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 8.
Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81.
The use of (-)-cinchonine will give the opposite enantiomer.
Scheme XIV describes another procedure for preparation of pyrrolidines.
Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. et.al., J.
Chem. Soc., Perkin Trans. 1, 5:1091-97 (1991). Thus, the azomethine ylide precursor 8Z (where R 55 is hydrogen or methyl) is condensed with a substituted acrylate f8 (wherein R 2 is as described herein and R 56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to -58provide the N-substituted pyrrolidine B. Standard ester hydrolysis of BE produces the desired pyrrolidine carboxylic acid BZ.
-59.
Scheme I 0
R
1 02
H
C0 2
E
C0 2
E
Mixture of Cis-Cis Traris-Tmns Cis-Trans
X-R
3 /R 3
N
2
E
[H
2 0]
R
2
R
60 2
H
Trms-TramE C0 2
E
Cis-Trans Mixture of Trans-Trans Cis-Trans Scheme 11 R2-, Cl Li S 0 /21 Rn
R
2 QQ S-
I
R2 1 Q' N
R
CrN R2 jC
CN
RI
ISOMER
C0 2 E KC( N jz RlRI R3-qR C0 2
H
-61 Scheme '111 Halo 0i 0 Fi C0 2
E
J0 2 C R 2 Halo Cl, Br, or I C0 2
E
R2 R 2
H
Tranis-Trans -62- Scheme IV
R
3 2
R
.R 3 R 2 o L
ICH
2
N
2 0 CHN 2 /R3
N
R2
R
C02H -63- Scheme V C H30 EtO 2 C 0 D 3
_O
C
;OOEt H2I COOEt 0OCH 3 NaCNBH 3 Mixture of Cis-Cis Trans-Trans Cis-Trans Crmatographic separation Cis-Cis Mixture of Trans-Trans and Cis-Trans -64- Scheme VI Cis-Trans and BrCH 2 CONHC3H 7 iPr 2 NEt COOEt Trans-Trans and Cis-Trans NaOH,. H 2 0, EIOH Trans-Trans 0OCH3
COOH
Trans-Trans COOEt Cis-Trans Scheme VII 0 i S 0o~ Iz OMe 0 I I i Cr I
ISOMER
OMe OMe -66- Schemie VII cont.
N 0 N0 C ON -U NC N OMe OMe 41 I 1 H N 'l0
.CQ
2 Et OMe -68- Scheme IX
R
2
(CH
2 )m 00 2
H
RR3
(CH
2 )m NI NH
N=N
HN
0 R3
(CH
2 )m
CONH
2 R2-(LR
(CH
2
)M
C N
R
2 inKZIR 1
(CH
2
)M
H
2 NJ INOH /R 3
R
2 -CL..Rj
(CH
2
)M
I
0 -69- Scheme X
R
4 y OH 0 cI--Y.
1 fC 0 R4 ci 0 -C0 2
E
R4 0 0 2
E
Scheme Xi N' H
R
2 R
CO
2
H
C0 2
E
R
8
-NHR
20 R2
R
C0 2
E
C~s/Rr S. I' C0 2
H
-71 Scheme XII
.R
1
R
3 6H,
CQ
2 Et
R
2 Rl R3, N IC02Et A2 Me 3 Si N 0
OCH
3 -72- Scheme XIII I1. BOC 2 0 2. NaOH, EtOH
H
2 0 W± UZ M± Zfl 1 (+)-cinchanine 2. recrystallize fronj EtOAc/hexane 3. Na 2 00 3
HOI
EtCH
D..Q
W+ 7.2
BU
2
NC(O)CH
2 Br EtNiPr 2
CH
3
CN
11 iV -73- SCHEME XIV
R
55 Ph N OMe Me 3 Si
H
2 Pd(OH) 2
/C
R3,NQ C0 2
R
56 TEA, CH 2
CI
2 H NQ _C0 2
R
56
R
2
J
NaOH or LICH EtCH, H 2 0 flh" NQ _C0 2
R
56
R
2 BUR 3 Br BuNI or Nal
CH
3
CN
R
3 N[ C0 2
H
-74- Compounds which are useful as intermediates for the preparation of compounds of the invention are:
NH
(CH
2 )n
(CH
2 )m w RI wherein n is 0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-ON,
-C(O)NHR1 7 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,
-C(O)NHS(O)
2
RI
6 where R 16 is loweralkyl, hatoalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 ~S 0 ()HO 0,
OH
(p) 0
NH
N 0 s= 0
H
CF
3
NHSO
2
CF
3 an
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonytalkyl, hydroxyalkyl, alkoxyalkoxyalkyl, thi Qalkoxyalkoxyalkyl, cycloalkyl, aminocarbonylalkyl, alkylamninocarbonylalkyl, dialkylami nocarbonylalkyl, ami nocarbonylalkenyl, alkylaminocarbonytalkenyl, d ialkyl ami no carbon ylalke nyl, hydroxyalkenyl, aryl, arylalkoxyalkyl, heterocycli c and -76- (Raa)(Rbb)NRC wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RCC is alkylene, with the proviso that one of R, and R 2 is other than hydrogen; or a salt thereof; and a compound of the formula: NH C 2 1
NH
(CH2)m (CH 2 )m W R1 ~or W R (IV) (V wherein nis 0ori1; m is 0to 6; W is -C(O)2-G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
-CN,
-C(O)NHR
17 where R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyt, hydroxy, 0) alkoxy, sutfonamido,
-C(O)NHS(O)
2 Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6, HO 0 iA 0 -77- HO 0,
OH
(p) 0, 0-- 0,
NN
0)CF (t H ,o
HHO
2
F
an
R
1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, ami nocarbonylalkyl, alkylaminocarbo nylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkoxyalkyl, heterocyclic and -78- (Raa)(Rbb)N-Rc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Roc is alkylene, with the proviso that one of R 1 and R 2 is other than hydrogen; or a salt thereof.
Preferred intermediates include compounds of formula (IV) and (V) wherein m is zero or 1; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above.
Particularly preferred intermediates are compounds of formula (IV) and wherein n and m are both 0; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and Ri is loweralkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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 and R 2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl.
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 tertbutyloxycarbonyl, Cbz for benzyloxycarbonyl, DBU for 1,8diazabicyclo[5.4.0]undec-7-ene, EDCI for 1-(3-dimethylaminopropyl-3ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole, Et3N for triethylamine and THF for tetrahydrofuran.
-79- Example 1 trans.trans- 2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-yl)-l- (Droovlaminocarbonvlmethyl)-ovrrolidine-3-carboxvlic acid Example 1A Ethyl 2-(4-methoxvbenzovl)-4-nitromethyl-3-(1.3-benzodioxole-5-yvlbutvrate To ethyl (4-methoxybenzoyl)acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2-nitrovinyl)-1,3benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to OC was added 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved.
The solution was stirred without heating for 30 minutes and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer chromatography ethyl acetate in methylene chloride) indicated the absence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI solution.
The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to give 21.22 g of the desired product as a mixture of isomers and 9.98 g. of recovered ethyl (4-methoxybenzoyl)acetate.
Example 1B Ethyl 2-(4-methoxvohenvl)-4-(1.3-benzodioxol-5-vl)-4.5-dihvdro-3H-Dvrrole-3carboxvlate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.
-81added. The mixture was extracted with ether to remove the unreacted cis,transethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-153 OC.
H NMR (CD 3 OD, 300 MHz) 5 0.87 J 7 Hz, 3H), 1.49 (sextet, J 7 Hz, 2H), 2.84 J 16 Hz, 1H), 2.95-3.20 4H), 3.20 J 16 Hz, 1 3.34-3.42 (m, 1 3.58-3.66 1 3.78 3H), 3.88 J 10 Hz, 1 5.92 2H), 6.75 J 8 Hz, 1 6.86 (dd, J= 8 Hz, J 1 Hz, 1 6.90 J 9 Hz, 2H), 7.02 J 1 Hz, 1H), 7.40 J 9 Hz, 2H).
Example 2 trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl)-1 (aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 °C in 1 mL acetonitrile to give 291 mg of a mixture of trans,trans- and cis,trans- N-alkylated esters. A portion (270 mg.) was hydrolyzed with 200 mg NaOH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis,trans- ethyl ester.
The isolation and purification procedures described in Example 1D were used to give 134 mg of the title compound. m.p. 246-248 OC. 1H NMR (DMSO-ds, 300 MHz) 8 2.61 J 16 Hz, 1 2.71 J 9 Hz, 1H), 2.90 J 9 Hz, 1 H), 2.98 J 16 Hz, 1 H),3.25-3.35 1 3.45-3.55 1 3.71 3H), 3.75 J 10 Hz, 1 6.00-(s, 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7.10 1 H), 7.17 1 7.34 1 7.38 J 8 Hz, 2H).
Example 3 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-yl)-1 -(4-fluorobenzyl)pvrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from -82- Example 1C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans,trans- and cis,trans-N-alkylated esters. A portion (360 mg) was hydrolyzed with 250 mg NaOH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 1 H NMR (CDCI 3 300 MHz) 6 2.74 J 9 Hz, 1 2.95 J 7 Hz, 1 2.98 J 14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 1 3.70 J 9 Hz, 1H), 3.78 J 14, 1H), 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1 6.77 (dd, J 8 Hz, 1 Hz, 1 6.91 J 9 Hz, 2H), 6.94 -7.00 3H), 7.20 7.25 1 7.44 J 9 Hz, 2H).
Example 4 trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vl)-1-(2-ethoxvethyl)- Dvrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg. of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 152 mg of 2-bromoethyl ethyl ether were refluxed in 1.5 mL acetonitrile for 3 hours (bath temperature at 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 1H NMR (CDCI3, 300 MHz) 6 1.25 J 7 Hz, 3H), 2.21-2.32 1H), 2.70-2.80 1H), 2.85-2,94 2H), 3.38-3.55 6H), 3.67 J 10 Hz, 1 3.79 3H), 5.94 2H), 6.72 J 8 Hz, 1 6.84 1 6.84 J 9 Hz, 2H); 7.08 J 1 Hz, 1 7.33 J =9 Hz, 2H).
Example trans. trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 -(2-Dropoxvethyl)pyrrolidine-3-carboxylic acid Using the method described in Example 1D, 520 mg of the mixture resulting from Example 1C, 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL -83acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,transesters. A portion (500 mg) was hydrolyzed with 315 mg NaOH in 1 mL of water and 4 mL of ethanol to give 225 mg of the title compound as an amorphous powder. 1H NMR (CDCI 3 300 MHz) 5 0.87 J 7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 1 2.71-2.83 1H), 2.92-3.08 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 4H), 3.72-3.83 1H), 3.76 3H), 5.92 2H), 6.71 J 8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J 9 Hz, 2H), 7.07 J 9 Hz, 2H), 7.73 J 9 Hz, 2H).
Example 6 trans. trans-2-(4-Methoxvphenvl-4-(1.3-benzodioxol-5-vl)- 1 methoxvethoxvyethvl]-pvrrolidine-3-carboxvlic acid Example 6A Ethyl trans.trans-2-(4-methoxyphenvl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3carboxylate To the pure cis,cis-compound resulting from Example 1C (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaOEt was neutralized with HCI in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).
Example 6B trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1-{2-(2methoxvethoxy)ethyl]-pyrrolidine-3-carboxylic acid Using the method described in Example 1D, 250 mg of the compound resulting from Example 6A, 150 mg of 2-(2-methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 oC for 3 hours to give 229 mg of the trans,trans-ester. A portion (200 mg) was -84hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 1 H NMR (CD 3 OD, 300 MHz) 5 2.9-3.9 13H), 3.81 3H), 4.49 J 10 Hz, 1 5.94 2H), 6.79 J 8 Hz, 1 6.89 (dd, J 8 Hz, 1 Hz, 1 7.00 J 9 Hz, 2H), 7.05 J =1 Hz, 1H), 7.49 J 9 Hz, 2H).
Example 7 trans.trans-2-(4-Methoxyphenvl)-4-(1.3-benzodioxol-5-yl)-1 -[(2-vridvl)ethyl] vyrrolidine-3-carboxvlic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2-methoxyethanol, and stirred at 100 OC for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 202 mg of the title compound as the dihydrate. m.p. 77- 80 1 H NMR (CD 3 OD, 300 MHz) 8 2.8 3.3 6H), 3.55-3.70 2H), 3.76 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1 H), 6.80 (dd, J 8 Hz, 1 Hz), 6.85 J 9 Hz, 2H), 6.92 J 1 Hz, 1 7.20 J 9 Hz, 2H), 7.20-7.32 2H), 7.70-7.80 2H), 8.40 J 4 Hz, 1H).
Example 8 trans.trans-2-(4-MethoxvDhenvl)-4-(1.3-benzodioxol-5-vyl-1 -(morpholin-4vlcarbonyl)-Dvrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by-the method described in Example 1D to give 288 mg of the title compound.
m.p. 244-246 IDC. 1 H NMR (DMSO-d6, 300 MHz) 562.96 (dd, J 12,Hz, 13 Hz, 1 3.03-3.13 (in, 2H), 3.20-3.30 (in, 2H), 3.40-3.60 (in, 5H), 3.74 3H), 3.70- 3.85 (in, 3H), 5.10 J 10 Hz, 1 5.99 J 1 Hz, 2H), 6.80-6.90 (in, 2H), 6.87 J 9 Hz, 2H), 7.07 1 7.25 J 9 Hz, 2H).
trans. trans-2- Met hoxyphe ny1)-4- (1 .3-be nzod ioxo le -5-ylb- 1 (butylaminocarbonyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mng) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mng of butyl isocyanate.
After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1 D to give 232 mg of the title compound.
in.p. 220-221 OC. 1 H NMR (DMSO-d 6 300 MHz) 6 0.78 J 7 Hz, 3H), 1.10 (sextet, J 7 Hz, 2H), 1.22 (quintet, J 7 Hz, 2H), 2.78-3.05 (in, 3H), 3.40-3.56 (in, 2H), 3.74 3H), 3.95-4.05 (in, 1 4.93 J 9 Hz, 1 5.80 broad, J= 7 Hz, I1H), 5.99 2H), 6.78-6.86 (in, 2H), 6.88 J 9 Hz, 2H), 7.00 J 1 Hz, 1 7.12 J 9 Hz, 2H).
Example trans. trans-2-(4-Mathoxyohenyl)-4-(1 .3-benzodioxol-5-yl'- 1 mnet hoxyph enylami nocarbonyl)-3-p2yrrolidi ne- 3-carboxylic acid The compound resulting from Example 6A (300 mg) was treated with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the method described in Example 1 D to give 279 mg of the title compound. m.p. 185-187 OC. 1 NMR (CDCI 3 300 MHz) 863.23 (dd, J 12 Hz, 13 Hz, 1 3.55-3.68 (in, 2H), 3.72 3H), 3.83 3H), 4.50-4.65 (in, 1 5.06 J 10 Hz, 1 5.90 (s, 1 5.95 1 6.72 J 9 Hz, 2H), 6.7-6.8 (mn, 3H), 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H).
Exmple'l -86trans.trans-2-(4-Methoxvyhenvl)-4-(1.3-benzodioxol-5-vl-1 -acetvlpyrrolidine-3carboxvlic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1D to give 211 mg of the title compound. m.p. 248-250 OC.
Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d 6 300 MHz) 5 1.55 and 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28'(dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).
Example 12 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl- 1 -(2-furoyl)pyrrolidine-3-carboxvlic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred 30 minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was hydrolyzed by the procedure described in Example 1D to give 269 mg of the title compound as an amorphous powder. 1H NMR (DMSO-d 6 300 MHz) 8 3.06 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 4.25 1H), 5.19 J= 10 Hz, 1H), 6.67.4 8H), 7.8-7.9 1 H).
Example 13 trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl- 1 (Dhenylaminocarbonvl)-pyrrolidine-3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 1H NMR (DMSO-d 6 300 MHz) 5 3.03 (dd, 1H), -87- 3.55 (in, 1 3.70 (in, 1 3.72 3H), 4.15 (in, 1 5.13 1 6.00 2H), 6.88 (in, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1 H).
Exmple 14 trans.trans-2-(4-Methoxyphenyl-4-(1 .3-benzodioxol-5-yl)-1 (allylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 0 C. I H NMR (ODC1 3 300 MHz) 5 2.84 1 2.90- 3.10 (dt, 2H), 3.28 1 3.35 (dd, 1 3.62 (in, 1 3.72-3.97 (in, 3H), 3.80 3H), 5.13 (bd, 2H), 5.80 (in, 1 5.97 2H), 6.74-6.97 (in, 5H), 7.38 2H).
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl-1 b-utylaminocarbonylmethyl)-pyrrolidine-3-carboxylic aci-d Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 00. 1 H NMR (ODC1 3 300 MHz) 5 0.90 3H), 1.30 (n 2H), 1.45 (mn, 2H), 2.80 1 2.87-3.35 (in, 6H), 3.62 (in, 1 3.80 3H), 5.97 2H), 6.75-6.92 (in, 5H), 7.28 2H).
trans. trans-2-(4-MethoxyphenyF)-4- (1 .3-benzodioxo -5-yl)-l -(N-(n-Pro~yl)-Nmethylaininocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous'solid. Rotational isomers are seen in the NMR. 1 NMR (CDC1 3 300 MHz) 5 0.73, 0.84 (2t, 3H), 1.49 (in, 2H), 2.80 (dd, 1 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1 3.40 1 3.60 (in, 1 3.79 3H), 5.93 2H), 6.73 1 6.86 (in, 2H), 7.03 (in, 1 7.32 2H).
-88- ExmlJ2ltrans. trans-2-(4-Methioxyphenyl-4-(1 .3-benzodioxol-5-yl)- 1 -(p2yrrolidin-1 ylcarbonylmethy)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 NMR (CDCI 3 300 MHz) 5 1.40-1.70 (in, 6H), 2.80 1 3.00 (in, 2H), 3.24-3.43 (in, 5H), 3.60 (in, 2H), 3.73 1 H), 3.80 3H), 5.95 2H), 6.74 1 6.80-6.90 (in, 3H), 7.04 1 7.30 (d, 2H).
f trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl-1 (isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-1770 -C H NMR (CD 3 OD, 300 MHz) 5 0.87 (dd, 6H), 1.75 (septet, 1 2.85 1 2.90-3.10 (in, 4H), 3.23 1 3.40 (mn, 1 3.58- 3.67 (mn, 1 3.78 3H), 3.89 1 5.92 2H), 6.76 1 6.86 (dd, 1 H), 6.91 2 7.02 1 7.40 2 H).
Exml2l1 trans. trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yl)-1 (cyclopentylaiinocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 137-1390 -C H NMR (ODC1 3 300 MHz) 8 1.34 (in, 2H), 1.62 (in, 4H), 1.90 (in, 2H), 2.76 1 2.90 1 3.04 (dd, 1 3.22 1 3.28 (dd, 1 3.40 (in, 1 3.80 3H), 4.15 (in, 1 5.97 2H), 6.75-6.95 (in, 7.27 (mn, 2H).
trans. trans-2-(4-Methoxyphenyi)-4-( 1.3-benzodioxol-5y)- 1 -(morpholi n-4ylaininocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was pre 'pared as an amorphous solid. 1 H NMR (CDCI 3 300 MHz) 8 2.82 1 H), 3.00 (mn, 2H), 3.24 (in, 1 3.30-3.52 (in, 4H), 3.52-3.75 (mn, 8H), 3.80 3H), 5.95 2H), 6.75 1 6.84 3H), 7.00 1 7.28 2H).
-89- Eamp1l21 trans, trans,--2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5--y)-1 -(2-phenoxyethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMR (CD 3 OD, 300 MHz) 562.82 (in, 1 H), 2.96 (dd, 1 3.13 (in, 1 3.32 (in, 1 3.51-3.70 (in, 2H), 3.77 3H), 4.00 1 4.07 (in, 2H), 5.91 2H), 6.72 1 6.80-6.95 (mn, 6H), 7.03 1 H), 7.22 (dd, 2H), 7.39 2H).
Example22 trans. trans-2-(4- Met hoxyphe nyl)-4-(1 .3-be nzo di oxol-5-yl)-1 methoxyethylaminocarbonylmethyl)-pyrroidine.3.carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-1090-C 1 H NMR (CD 3 OD, 300 MHz) 562.82 1 2.97 2H), 3.21 1 3.38 (mn, 1 3.32 3H), 3.44 (mn, 4H), 3.62 (mn, 1 3.79 3H), 3.86 1 5.93 2H), 6.76 1 6.85 (dd, 1 6.91 2H), 7.01 1 7.38 2H).
Exmle2 trans. trans-2-(4-Methoxynhenyl).4.(1 .3-benzodioxol-5-y)-1 (2-buto xyethyflpyrrolidine-a-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 1 H NMR (CDC1 3 300 MHz) 8 0.88 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (Ut, J=6Hz, 6Hz, 1 H), 2.92 J=1lOHz, 2H), 3.35 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=1lOHz, 1 3.78 3H), 5.94 2H), 6.73 J=8Hz, 1 6.83 J=9Hz, 2H), 6.82- 6.87 (in, 1 7.06 J=2Hz, 1 7.32 J=9Hz, 2H). MS m/e 442 Example24 trans. trans-2-(1 .3-enzodioxol-5-l)-4-(4-nethoxyphenyl)-1 (propylarni no-carbonyl nethyl)-pyrro li din e.3carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1,3be nzodioxol1-5-ytcarbo nyl) acetate for ethyl (4-ineth oxybe nzoyl) acetate and 4- (2-nitrovinyl)anisole for 5-(2-nitrovinyl)-1 ,3-benzodioxol-5yI afforded the title compound. m.p. 97-99 1 H NMR (00013, 300 MHz) 5 0.78 J=7Hz, 3H), 1.39 (sextet, J=7Hz, 2H), 2.72 J=1l6Hz, 1 2.74 J=1lOHz, 1 2.80-3.10 (in, 4H), 3.26-3.38 (in, 1 3.53 (in, 1 3.73 3H), 3.80 J=1lOHz, 2H), 7.80 J=6Hz, 1 MS (DCl/NH3) m/e 441 trans. trans-2-(l .3-Benzodioxol-5-yl)-4-(4-methoxyphenl)-1 -(2-propoxyethyl)pyrrolidine-3-carboxyl c acid Using the procedures described in Example 5 and substituting ethyl (1 ,3be nzod ioxol1-5-ylcarbon yl) acetate for ethyl (4-imeth oxybe nzoyl) acetate and 4- (2-nitrovinyl)anisole for 5-(2-nitrovinyl)- 1,3-be nzodioxol-5y1 afforded the title compound. in.p. 67-69 0C. 1 H NMR (CDCl 3 300 MHz) 5 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (in, 1 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45-3.57 (in, 4H), 3.73 (in, 1 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1 H), 6.85 J=8Hz, 3H), 6.98 1 7.37 J=8Hz, 2H). MS (D01/NH 3 in/e 428 Exmple 2f trans. trans-2- (1 .3-Be nzodi oxol-5-yl)-4-(4-inethOXYphenyl)-14 inethoxyethoxy)ethyl)]-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. in.p. 85-86 TC. 1 H NMR (00300, 300 MHz) 8 3.18-3.90 (in, 3.79 3H), 4.57 J=1lOHz, 1 6.02 2H), 6.91 J=8Hz, 1 6.95 J=9Hz, 2H), 7.06 (dd, J=8Hz, 1 7.12 (dd, J=1 Hz, 1 7.37 J=9Hz, 2H).
MS (OCt/NH 3 m/e 444 Exmple 27 trans. trans-2-(1 .3-Be nzodioxol-5-yl)-4-(4-methoxyphenyl)-1 -(butoxyethyl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2-ethoxyethylbroinide to alkylate -92trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl-1 -(N-methyl-Nbutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic- acid Using the procedures described in Example 1, the title compound was prepared. Rotational isomers are seen in the NMR. 1 H NMR (CD 3 OD, 300 MHz) 5 0.86 (2t, 3H), 1.04-1.50 (in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 4H), 3.40 (in, 2H), 3.52 (dd, 1 3.60 (in, 1 3.80 3H), 3.85 (in, 1 5.91 2H), 6.74 1 6.83-6.95 (mn, 3H), 7.03 (dd, 1 7.35 (dd, 2H).
Exmlle 31 trans. trans-2-(4-Methoxy-2- meth oxymethoxyphenyl)-4-(1 .3-benzodioxo 1 -(N-methyl-N-butylaininocarbonyimethyl)-pyrrolidine.3carboxvlic acid Ethyl 2 -(4-methoxy-2-nethoxynethoxyphenyl.4(1 pyrrolidi ne-3-carboxylate) Using the procedures described in Examples 1 A and 1 B and substituting ethyl (4-meth oxy-2-imet hoxym ethoxybe nzoyl) acetate for ethyl (4mnet hoxybe nzoyl)acetate afforded ethyl 2-(4-methoxy-2methoxymethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-4 ,5-dihydro-3 H-pyrrole-3carboxylate.
The above dihydro pyrrole carboxylate (3.0 g, 7.0 minol) was dissolved in 20 mL of methanol, treated with 500 mng of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chroinatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.
Exmle3 trans. trans-2-(4-Methoxy-2-methoxymethoxyphe nyl)-4-(1 .3-benzodioxo 1 -(N-methyj-N-butylaminocarbonylmethyl-pyrrolidine--3carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mng, 0.23 inmol) was then reacted by the prbcedures described in Example 1 D -93substituting N-methyl-N-butyl bromoacetamide for N-propyl bromoacetamide to give the title compound (75 mg, m.p. 65-67 OC. Rotational isomers are seen in the NMR. 1 H NMR (CDC13, 300 MHz) 50.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40-1.48 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (m, 6H), 3.50 3H), 3.43-3.65 2H), 3.78 3H), 4.30 J=7Hz, 1 5.09 (q, J=7Hz, 2H), 5.92 2H), 6.55 (dd, J=3Hz, 1H), 6.68 1H), 6.72 1 6.85 (2t, J=1 Hz, 1 7.04 J=1Hz, 1 7.42 (dd, J=3Hz, 1 H).
Example 32 trans. trans-2-f4-Methoxvphenvyl-4.1.3-benzodioxol-5-v)-1 -(3-ethoxyoronpN)pyrrolidin-5-one-3-carboxylic acid Example 32A Ethyl 2 4 -methoxybenzoyl)-3-carbomethoxy-1. 3 To ethyl 4 -methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1,3bromoacetate (5.46 g, 0.02 mol) in 5 mL of THF was added.
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 32R Ethyl 1-( 3 -ethoxypropvl)-2-(4-methoxvphenvl)-4-1.3-benzodioxol-5-yl-4.5dihvdro-5-oxo-1 H-pyrrole-3-carboxylate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue -94obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg of the title compound.
Example 32C Ethyl 1-(3-ethoxvpropyvl-2-(4-methoxvphenyl)-4-(1.3-benzodioxol-5-yl)pyrrolidin-5-one-3-carboxylate The compound resulting from Example 328 (300 mg, 0.64 mmol) in mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
Example 32D trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-yl)-1-(3-ethoxypropyl)pyrrolidin-5-one-3-carboxvlic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21% sodium ethoxide in ethanol. The mixture was heated to 70-80 °C for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue which was washed with ether. The aqueous layer was neutralized with 3 M HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, m.p. 134-140 1 H NMR (DMSO-d 6 300 MHz) 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 1 2.93 (dd, J=9Hz, 1 3.25 (t, J=7Hz, 2H), 3.28-3.40 2H), 3.48-3.57 1H), 3.78 3H), 3.88 1 4.72 J=1 Hz, 1 6.02 2H), 6.74 (dd, J=8Hz, 1 Hz, 1 6.87 (d, J=8Hz, 2H), 6.98 J=8Hz, 2H), 7.38 J=8Hz, 2H). MS (DCI/NH 3 m/e 442
(M+H)
trans.trans.2-(4-Methnxyphenyl.441 .3-benzodioxol-5-yl- -(-methoxybenzyflp2yrrolidi n-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, m.p. 150-1 52 00. IH NMR (00300, 300 MHz) 5 2.96 (dd, J=8Hz, 1 3.72 3H), 3.80 3H), 4.06 J=1lOHz, 1 4.58 J=8Hz, 1 H), 4.92 J=l6Hz, 2H), 5.92 2H), 6.55-6.63 (in, 2H), 6.82 J=8Hz, 4H), 6.94 J=8Hz, 2H), 7.15-7.22 (in, 3H). MS (001/NH 3 m/e 475 Example 4 trans, trans-2- Methoxyph eny 1)4- (1 .3-be nzodi oxo -5-yl)-1l diisoamylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (00013, 300 MHz) 5 0.70 -0.90 (mn, 12H), 1.10-1.60 (in, 10H), 2.75 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.15 3.30 (in, 2H), 3.40 J=1lOHz, 1 3.40 3.52 (in, 2H), 3.55 3.62 (in, 1 H), 3.75 J=12 Hz, 1 3.79 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 (d, J=8 Hz, 1 6.82-6.90 (mn, 3H), 7.03 J=2Hz, 1 7.30 J=9Hz, 2H).
xmle3 trans. trans-2-(4-Methoxyph enyl)-4(1 .3-be nzodoxol-5-y)- 1 dip~entylaininocarbonylinethyl)-pyrrolidi ne-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 NMR (ODC1 3 300 MHz) 8 0.82 J 7Hz, 6H), 0.95-1.03 (in, 2H), 1. 10-1.30 (in, 8H), 1.40-1.51 (in, 2H), 2.72 (d, J=1 3Hz, 1 2.90-3.08 (mn, 4H), 3.25-3.50 (in, 3H), 3.37 J=1 3Hz, 1 3.52- 3,60 (in, 1 3.70 (J=1 0Hz, 1 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=8Hz, 1 6.80-6.88 (in, 3H), 7.03 J=2Hz, 1 7.30 J=9Hz, 2H).
-96- Exam~l 3 trans. trans-2- Met hoxyp he nyl)k4- (1 .3-be nzo dioxol-5-yfl-i1 .N-di(2methoxyethyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-12200C 1 H NMR (ODC1 3 300 MHz) 582.82 J=1 3, 1 H), 2.94-3.08 (in, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11 3.73 (d, J=1 0Hz, 1 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Hz, 1 H), 6.80-6.90 (in, 3H), 7.04 J=2Hz, 1 7.30 J=9Hz, 2H).
Exmple 37 trans. trans-2-(4- Methoxyphe nyl)-4-(1 .3-benzodioxol-5-yl)-1 -(2-hexynyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 4, 200 mg. of the pure trans,trans isomer, the compound resulting from Example 6A was reacted with 109 mg of 1-bromo-2-hexyne, preparedby the method described in Perkin 1,, 2004 (1987), for 1 hour at 55 O, to give 226 mg of the intermediate ester. The ester was hydrolyzed using NaOH in ethanol-water for 3 hours at room temperature to give 175 mng of the title compound. 1 H NMVR (ODC1 3 300 MHz) 8 1.00 J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1 3.07 (dd, J=1 8Hz, 2Hz, 1 3.15 (dd, J=9Hz, 2Hz, 1 3.26 J=9Hz, 1 3.36 (dd, J 18 Hz, 2Hz, 1 3.47-3.55 (in, 1 3.79 3H), 3.88 (d, J=9Hz, 1 5.95 2H), 6.72 J=8Hz, 1 6.80-6.88 (mn,3H), 7.03 (d, J=2Hz, 1 7.22 J=9Hz, 2H).
trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-ben zodioxol-5-yl)- 1 cyclopropylmethyl-N-propylaininocarbonylinethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 167-1 69 00. Rotational isomers were seen in the NMVR. 1
H
NMR (ODC1 3 300 MHz) 58-0.1 0.05 0.12-0.25 0.32-0.51 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 1.20-1.55 2.72 J=1l3Hz, 1 H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3. -52-3.62 (in, 1 3.65-3.73 (2 doublets, J=1 0Hz, 2Hz, 1 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (in, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).
-97- ExmpJl 3 trans. trans-2-(4-MePthoxypheny)-4(1 .3-be nzodioxol-5-yl)- 1 met hyl-N 12entylaminocarbo nylmeth yl)n yrro lid in e-3-crboxli c acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (ODC1 3 300 MHz) 860.85 J=7Hz, 3H), 1.00-1.08 1.13-1.32 (in), 1.35-1,50 2.72-2.82 (2 doublets, J=1l3Hz, 1 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (in, 1 3.72 (2 doublets, 1 3.75 and 3.76 (2 singlets, 3H), 5.92 (2 singlets, 2H), 6.72 J=8Hz, 1 H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 2H).
trans.trans-2-(4-Methoxyp -henyly4-(1 .3-benzodioxol-5-yl)-i diisobutyaminocarbonylrniethyl)pyrrolidine-3carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 OC. 1 H NMR (ODC1 3 300 MHz) 860.54 J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (in, 1 1.90-2.02 (in, 1 H), 2.67 J=1l3Hz, 1 2.70 J=1l3Hz, 1 2.84 (dd, J=6Hz, 15Hz, 1 2.96- 3.06 (in, 2 3.20 (dd, J=9 Hz, 15 Hz, 1 3.35 (dd, J=2 Hz, 10 Hz, 1 3.44- 3.60 (in, 4H), 3.70 J=9Hz, 1 3.79 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 J=9Hz, 1 6.82-6.90 (mn, 3H), 7.03 J=2Hz, 1 7.31 J=9Hz, 2H).
Exmple 41 trans. trans-2-(4- Met hoxyp he ny)-4.(1 .3-benzodioxo 1 (N -methyI- N- (2prooynyl)ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NM R (ODC1 3 .300 MHz) 562.09 and 2.32 (2 friplets, J=2Hz, 1 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (mn, 2H), 3.52-3.62 (in, 1 H), 3.78 3 4.03 J=13 Hz, 1 4.00-4.30 (in, 3 5.93 2 6.72 (2 doublets, J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 and 7.11 (2 doublets, J 2Hz, 1 7.30 (2 doublets, J=9Hz, 2H).
-98- Example 42 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodoxo1-5-y)- 1 -(N-methyl-N-(nhexyl) ami nocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (ODC1 3 300 MHz) 5 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.72-2.82 (2 doublets, J=1l3Hz, 1 H), 2.81 and 2.56 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-.3.45 (mn, 3H), 3.52-3.62 (mn, 1 3.72 (2 doublets, 1 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 J=8Hz, 1 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 1 H).
Example43 trans. trans-2-(4- Methoxyphe nyl)-4-(1 .3-be nzodioxol-5-yl)-1 .N-di(nbutyflaiinocarbonylminthyl)-pyrrolidi ne-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 123-1 25 1 H NMR (ODC1 3 300 MHz) 5 0.79 J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.74 J=1l3Hz, 1 2.90-3.09 (in, 4H), 3.23-3.50 (in, 3H), 3.38 J=1l3Hz, 1 3.52-3.62 (in;1 3.75 J=1 0 Hz, 1 3.78 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 J=8Hz, 1 6.81-6.89 (mn, 3H), 7.03 J=2Hz, 1 7.30 J=9 Hz, 2H). MS (DCIINH 3 m/e 511 -Anal calod for C 29
H
38
N
2 0 6 C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.
Exmple 4 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodoxol-5-yfl- .diethylaiinocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-1 34 OC. 1 H NMR (CDCI 3 300 MHz) 8 0.98 J=7Hz, 3H), 1.06 J=7Hz, 3H), 2.78 J=1 3 Hz, 1 2.95-3.20 (in, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1 3.76 J=12 Hz, 1 3.79 3H), 5.93 2H), 6.72 J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 7.32 J=9Hz, 2H).
-99trans. trana-2--(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-ybl-1 -(N-methyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD 3 00, 300 MHz) 562.75-2.85 (in, 2H), 3.05-3.13 (mn, 1 3.18 3H), 3.40-3.58 (in, 2H), 3.78 3H), 3.88 J=1 2Hz, 1 5.92 2H), 6.72 J=8Hz, 1 6.75-6.85 (mn, 3H), 7.00- 7.12 (in, 5H), 7.82-7.92 (in, 3H).
Example 4.
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-be nzodioxol-5-yl)-1 -(N-methyl-Ncvclohexylaininocarbonylmethyl-pyrrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (CD 3 OD, 300 MHz) 6 1.00-1.85 (in, 10H), 2.72 and 2.78 (2 singlets, 3H), 2.75-2.82 (2 doublets, J=1 2Hz, 1 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=1lOHz, 1 3.77 and 3.78 (2 singlets, 3H), 5.92 2H), 6.72 (2 doublets, J=8Hz, 1 6.82-6.88 (in, 3H), 7.02 (2 doublets, J=2Hz, 1 7.30-7.40 (2 doublets, J=9Hz, 2H).
Example 47 trans. trans-2-(4-Methoxyphe nyl)-4-(1 .3-be nzodioxol-5-yl)-1 .N-diwnpropyl)aminocarbonylmethyl)-pyrrolidine-3-carboxlic acid The title compound was prepared using the procedures described in Example 1. m.p. 170-1720 OC IH NMR (ODC1 3 300 MHz) 6 0.69 J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.20-1.55 (in, 4H), 2.72 J=1l3Hz, 1 2.90-3.10 (in, 4H), 3.25-3.47 (in, 4H), 3.35-3.62 (in, 1 3.72 J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 H), 7.30 J=9Hz, 2H).
-100trans.trans-2-(4-Methoxyvhenvl)-4-1.3-be nzodioxol-5-vl)-1-(N-methyl-Nisobutylaminocarbonvlmethyl)-yDrrolidine-3-carboxvlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
1 H NMR (CD 3 OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (m, 1 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 4H), 3.10-3.65 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=10Hz, 1H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 3H), 7.02 (2 doublets, J=2Hz, 1 7.80-7.90 (2 doublets, J=9Hz, 2H).
Example 49 Alternate Prepration of Ethyl 2 4 -methoxybenzovl)-4-nitromethvl-3-(1.
3 Example 49A E-2-(3.4-Methylenedioxyphenvl-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 maintaining the temperature between 10-15 oC. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (-350 mL) maintaining the temperature below 5 until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4methylenedioxy)-nitrostyrene as yellow needles (53 g, 1H NMR (300MHz, CDCI 3 8 7.94 (1 H, d, J=13.5Hz), 7.47 (1 H, d, J=13.5Hz), 7.09 (1 H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, MS
(DCI/NH
3 m/e 194 (M+H) 211 (M+H+NH 3 -101- Ethyl 2 4 m ethoxyh enyl)oxo-4nitro-33.4methyle nedioxvghe nyl)buty rate 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 methoxybe nzoyl) acetate (11.5 g, 51.7 mmol) in THF (50 ml-) followed by 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 3.0 mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with ethyl acetate-hexaneS changing to 25% ethyl acetate-hexanes as the product elutedi. The solvents were remov ed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR. 1 H NMR (300 MHz, CDCI 3 8 8.06 (2H, d, J=9HZ), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1 H, dd, J=9Hz,3Hz), 6.73 (1 H, d, J=9Hz), 6.65 (1 H, d, J=3Hz), 5.95 (2H, 5.89 (1 H, d, J=4Hz), 5.88 (1 H, d, J=4Hz), 4.90-4.60 (3H, in), 4.39 (1 H, in), 4.18 (2H, q, J=7Hz), 3.94 (2H, in), 3.80 (3H, 3.78 (3H, s), 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) mn/e 416 433 (M+H+NH3) 4 f~ans.trprjs.2(4-MethoXyphenyl)- 4 .3-benzodioxol- -yl)-1 butyloxycarbonylinethvl)-pyrro lidine-3-carboxylic acid To a stirred solution of the compound resulting from Example 10C (100 mng, 0.27 minol) in acetonitrile (2 ml-) was added successively diisopropylethylainine (70 0.40 minol, 1.5 eq) and t-butyl bromoacetate (48 gL-, 0.29 minol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuc 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, 3.7Smmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), -102and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 pL), and then extracted with ethyl acetate The combined organic extracts were dried (Na2SO4), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid. 1 H NMR (300 MHz, ODC1 3 8 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90 (1 H, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz), 6.76 (1 H, d, J=8Hz), 5.96 (2H, 3.96 (1 H, d, J=9Hz), 3.81 (3H, 3.58 (1 H, ddd, J=12, lOHz,3Hz), 3.52 (1 H, dd, J=9Hz,3Hz), 3.32 (1 H, d, J=7Hz), 3.08 (1H, t, J=OHz), 2.92 (1H, dd, J=9Hz,7Hz), 2.83 (1H, d, J2=17Hz). MS (DCI/NH 3 m/e 456 Anal calc for C 2 9H 29 N0 7 0.3 H 2 0: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.
trans. trans-2 -(4-Met hoxyphenyl)-4-(1 -naphthyl)-1 -(N-methyl-Npropyl)aminocarbonylmethvl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene-1 -carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC1 3 5 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1 H, d, J=8Hz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=9Hz,2Hz), 4.50 (1 H, in), 3.94 (1 H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 (1 H, in), 3.49 (1 H, d, J=1 4Hz), 3.40-2.93 in), 2.91, 2.83 (3H, 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz).
MS (DCI/NH 3 in/e 461 Anal calcd for C29H 29 N0 7 0.5 HOAc: C, 71.00; H, 6.99; N, 5.71. Found: 0, 70.95; H, 7.00; N, 5.46.
trans. trans-2-(4-Met hoxyp he nyl)-4-(2 .3-di hyd robe nzofu ran-5-y)- 1 (N -met hyl-N propyliami nocarbonylinethyl)-pyrrolidine-3-carboxylic acid Examl 2A 2 Di hyd robe nzofu ran-5-carboxalde hyde -103- To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 °C was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2 ,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH 2
CI
2 (5 mL) maintaining the temperature at or below -35 The mixture was warmed to 0 OC, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 °C at 0.3 mm Hg.
Example 52B trans.trans-2-(4-MethoxyDhenyl)-4- 2.3-dihydrobenzofuran-5-vyl) -N-methyl-NproDl)aminocarbonvlmethyl)-pyrrolidine-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, CDC3) 8 7.33 (1H, d, J=8Hz), 7.28 (1H, 7.19 (1H, 6.87 (1H, d, J=8Hz), 6.73 (1 H, d, J=8Hz), 4.56 (1 H, t, J=8Hz), 3.83 (1 H, d, J=1 Hz), 3.80 (3H, 3.63 (1 H, 3.4-3.0 (9H, 2.87, 2.84 (3H, 1.51 (2H, septet, J=7Hz), 0.88, 0.78 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 453 (M+H) Anal calc for
C
2 6H 32
N
2 0 5 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.
Example 53 trans.trans-2.4-Bis(4-methoxvDhenyl-1 -(N-methyl-N- ProPDl)aminocarbonylmethyl)-Dvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC3) 6 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, 3.83 (1 H, 3.81 (3H, 3.79 (3H, 3.64 (1H, 3.48-2.97 (6H, 2.87, 2.83 (3H, s), 2.85 (1H, 1.45 (2H, 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 441 -104- Anal calclfor C 25
H
32
N
2 0 5 -0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23.
Found: C, 67.15; H, 7.31; N, 6.00.
trans. trans-2-(4-Methoxyphenyl).4.(34dimethoxyphenyl)-1 -(N-methyl-Npropflaminocarbonylm-ethyl)-pyrrolidine.3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDC1 3 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1 H, d, J=2.0 Hz), 6.98 (1 H, in), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, 3.56 (3H, 3.83 (1 H, mn), 3.79 (3H, 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, mn), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 471 Anal calc for C2 6
H
34
N
2 0 6 -0.5 H 2 0: 0, 65.12; H, 7.36; N, 5.84. Found: 0, 65.22;.H, 7.27; N, 5.59.
trans. trans-2-(4-Methoxyphenyfl-4(3-m thoxyphenyl)-1 -(N-meth yl-Nproyl)ami nocarbonylinethyl)-p2yrrolidine-3c rboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde, for piperonal in Example-49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, ODC1 3 8 7.33 (2H, d, J=7.5 Hz), 7.24 (1 H, t, J=7.5 Hz), 7.05 (2H, in), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1 H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1 H, in), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 in/e 441 Anal calc for 0 25
H
32
N
2 0 5
H
2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.
trans. trans-2-(4-Methoxyphenyl)-4..(2-naphthyl).1 -(N-methyl-Npropyl)ami nocarbonylinethyl)-pyrrolidine-3carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. I H NMR (300 MHz, -105- CDCI3) 8 7.82 (4H, 7.69 (1 H, 7.47 (2H, 7.37 (2H, dd, J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1 H, d, J=8 Hz), 3.78 (3H, 3.57 (1 H, 3.52- 2.97 (6H, 2.93, 2.85 (3H, 2.90 (1 H, 1.52 (2H, 0.86, 0.76 (3H, t, Hz). MS (DCI/NH 3 m/e 461 (M+H) Anal calc for C 28
H
32
N
2 0 4
H
2 0: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.
Example 57 trans.trans-2-(4-Methoxyhenvyl)-4-(1 .3-benzodioxol-5-l)-1 (ethylsulfinvl)ethyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 1C (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound.
To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2
CI
2 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room temperature. A solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and MeOH in CH 2
CI
2 to afford the sulfoxide (62 mg, The ethyl ester was hydrolyzed by the procedure described in Example 1 D to afford the title compound as a diastereomeric mixture. m.p. 61-63 oC.
MS (DCI/NH 3 m/e 446 (M+H) 1 H NMR (CDCI3, 300 MHz) 5 1.25, 1.32 (t, J=9Hz, 3H), 2.45-2.75 4H), 2.84-2.96 3H), 3.02-3.08 1H), 3.32, 3.36 J=3Hz, 1H), 3.47-3.58 2H), 3.65, 3.68 J=7.5Hz, 1 3.76, 3.80 (s, 3H), 5.94 2H), 6.72 J=7.5Hz, 1 3.84-3.89 3H), 7.02 J=6Hz, 1 H), 7.30, 7.34 J=7.5Hz, 2H).
Example 58 -106trans.trans-2-(4-Methoxyvhenvyl-4-(1.3-benzodioxol-5-yv-1 (isopropylsulfonvlamino)ethyl)-ovrrolidine-3-carboxvlic acid To 2-bromoethylamine hydrobromide (1 mmol) suspended in anhydrous
CH
3 CN was added 1 equivalent of Et 3 N. The mixture was stirred for minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et 3 N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 mmol) in 3 mL of CH 3 CN. The mixture was warmed at 50-60 OC for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1 D to afford the title compound (133 mg, m.p. 94-96 oC. 1 H NMR (CD 3 0D, 300 MHz) 5 1.26 J=6Hz, 6H), 1.97 1H), 2.38 1H), 2.77 1H), 2.88 J=9Hz, 1H), 3.04 1H), 3.14 J=7.5Hz, 2H), 3.35 2H), 3.46 1H), 3.58 1H), 3.78 3H), 5.92 (s, 2H), 6.74 J=9Hz, 1 6.86 (dd, J=9Hz,3Hz, 1 6.92 J=9Hz, 2H), 7.00 J=3Hz, 1 7.36 J=9Hz, 2H). MS (DCI/NH 3 m/e (M+H) Example 59 trans. trans-2-(4-Methoxvphenvl)-4-(1.3-be nzodioxol-5-yl- 1 (isobutoxv)ethyl)-ovrrolidine-3-carboxylic 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 OC. 1 H NMR (CDC13, 300 MHz) 8 0.88 J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1 2.22 2H), 2.72-2.79 1 2.86- 2.95 2H), 3.13 J=6Hz, 2H), 3.45-3.56 4H), 3.68 J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1H), 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 m/e 442 (M+H) Examjle -107trans.trans-2-(4-Methoxvphenvil-4-(1.3-benzodioxol-5-vl)-1 -(butvlsulfonyl)pyrrolidine-3-carboxvlic acid To 100 mg (0.271 mmol) of the compound resulting from Example 1C dissolved in 10 mL of THF was added 1-butanesulfonyl chloride (46.7 mg, 1.1 equivalents) and diisopropylethylamine (53 mg, 1.5 equivalents). The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mg of the ethyl ester.
The ester (120 mg, 0.244 mmol) was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL).
The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid. m.p. 67-69 1H NMR (CDCI 3 300 MHz) 5 0.82 J=7.5Hz, 3H), 1.20-1.33 2H), 1.58-1.68 2H), 2.48- 2.69 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=12Hz, 1 3.65 (dd, J=12Hz, 1H), 3.82 3H), 4.32 (dd, J=12Hz, 1H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 3H), 6.92 J=9Hz, 2H), 7.35 J=9Hz, 2H). MS (DCI/NH 3 m/e 462
(M+H)
Example 61 trans.trans-2-(4-Methoxyphenvli-4-(1.3-benzodioxol-5-vl- 1 -(2-(N-methvl-Nisooropvlcarbonvlamino)ethyl)-pyrrolidine-3-carboxvlic acid Example 61 A trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)- 1-(2-bromoethyl)pyrrolidine-3-carboxvlic acid ethyl ester To the mixture of cis,trans and trans,trans pyrrolidines resulting from Example 1C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide.. The resultant mixture was heated at 100 OC for 1 hour, and then the solvents were removed in vacuo.
-108- The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.
Example 61B trans. trans-2-(4- Methoxvphe nyl)-4-(1.3-be nzodi oxol-5-vl- 1 (methylamino)ethyl)-pvrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 61A (450 mg) dissolved in mL of EtOH was added 0.5 mL of 40% aqueous methylamine and 50 mg of sodium iodide. The mixture was heated at 80 OC for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo.
The resultant product was carried on without further purification.
Example 61 C trans.trans-2-(4-Methoxvphenvl.-4-(1.3-benzodioxol-5-vl)- 1-(2-(N-methyl-Nisobutvrylamino)ethvl)-pvrrolidine-3-carboxvlic acid To the compound resulting from Example 61 B (-150 mg) dissolved in mL of 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 OC, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours. The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAc-hexanes going to EtOAc and finally using 10% MeOH- EtOAc.
The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 h H 3 P04 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na 2
SO
4 The solvents were -109removed in vacua to provide 82 mg of the title compound as a white foam.
Rotamers were seen in the NMR. 1 H NMR (CDCI 3 300 MHz) of the major rotamer 5 1.06 3H, J=lOHz), 1.12 3H, J=lOHz), 2.15 (in, 1 2.5-3.0 (in, 3H), 2.91 3H), 3.32 (in, 2H), 3.50 (in, 2H), 3.65 (in, 2H), 3.77 3H), 5.92 (s, 2H), 6.73 1 H, J=5Hz), 6.75-6.9 (in, 4H), 6.96 1 H, J=2Hz), 7.29 (mn, 1 H).
MS (OCI/NH 3 m/z 469 Analysis calcd for C 26
H
32
N
2 0 6 -0.3 TEA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.
Irans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxo1-5-yi)- 1 -(2-(N-methyl-Np~rop1i onylami no~ethyl)-pyrro li din e-3-carboxylic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 610. 1 H NMR (ODC1 3 300 MHz) of the major rotamer 5 1.13 3H, J=8Hz), 2.19 (in, 1 2.30 (in, 2H), 2.65-3.0 (in, 3H), 2.85 3H), 3.25-3.4 (in, 2H), 3.7 (in, 3H), 3.79 3H), 5.92 2H), 6.74 1 H, J=8Hz), 6.75-6.9 (mn, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DC I/N H 3 )mi/z 455 Analysis calcd for C25H 30
N
2
O
6 1.0 H 2 0: C, 63.55; H, 6.83; N, 5.93. Found: C, 63.55; H, 6.52; N, 5.73.
Examl 6 trans, trans-2-(4-Methoxyphenyl)-4-(1 .3-be nzodioxol-5-yl)-1 (N-methyl-Nbenzylaiinocarbonylinethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. I H NMR (00013, 300 MHz) of the major rotainer 8 2.79 3H), 2.8- 3.2 (in, 2H), 3.48 (nm, 2H), 3.61 (in, 2H), 3.77 3H), 3.78 (in, 1 4.3-4.5 (in, 2H), 5.95 2H, J=2Hz), 6.7-6.9 (in, 4H), 7.00 (mn, 1 7.15-7.35 (in, 7H). IMS (FAB/NBA) m/z 503 Anal calcd for C 29
H
30
N
2 0 6 -0.5 H 2 0: C, 68.36; H,5.74; N, 5.50. Found: 0,68.41; H, 5.74; N, 5.36.
F~xmlpie4 -110trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yl-1 -(N-ethyl-Nbutylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI 3 300 MHz) of the major rotamer 8 0.58 3H, J=7Hz), 1.06 3H, J=7Hz), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6 (in, 11 3.79 3.80 (in, 1 5.92 (bd s, 2H), 6.75 1 H, J=8Hz), 6.85 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 1 7.33 I1H, J=BHz). MS (DCI/NH 3 in/z.483 Anal calod for C 27
H
3 4N 2 0 6 0.5 HOAc: C, 65.61; H,7.08; N, 5.46.
Found: C,65.51; H, 6.70; N, 5.66.
trans. trans-2-(4-Methoxyphenyl)-4-(1 .3-be nzodioxol-5-yrk-l -(N-methyl-N-(2.2dimethylnropyl~aininocarbonylmethyl)-p2yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (ODC1 3 300 MHz) of the major rotamer 860.90 9H), 2.8- 3.1 (in, 4H), 2.94 3H), 3.3-3.5 (mn, 3H), 3.61 (in, 1 3.80 3H), 3.82 (mn, 1 5.94 (bd s, 2H), 6.74 1 H, J=8Hz), 6.86 2H, J=5Hz), 6.87 (in, 1 H), 7.03 1 H, J=2Hz), 7.33 2H, J=8Hz). MS (DCI/NH 3 m/z 483 trans. trans-2 -(4-Met hoxyphenyl)-4-(1 .3-benzodoxol-5-yl)- 1 -(2-(N-methyl- Nbutylsulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61 B (60 mg, 0. 13 mmol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mg (0.143 minol, 1.1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then cWncentrated in vacua. The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAchexane to yield 64 mg of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. m.p. 64-66 OC. 1 NMR
(C~DC
3 300 MHz) 5 0.92 J=7.5Hz, 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 -111- 2H), 2.16-2.25 1H), 2.72 3H), 2.75-2.92 5H), 3.12-3.20 1H), 3.25-3.34 1H), 3.46-3.55 2H), 3.65 J=9Hz, 1H), 3.78 3H), 5.53 (s, 2H), 6.72 J=7.5Hz, 1 6.82 (dd, J=7.5Hz,3Hz, 1 6.86 J=9Hz, 2H), 7.02 J=3Hz, 1H), 7.34 J=9Hz, 2H). MS (DCI/NH3) m/e 519 (M+H) Example 67 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-l)- 1 -(2-(N-methyl-N- Dropvlsulfonvlamino)ethvl)-pyrrolidine-3-carboxvlic 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 1 H NMR (CDC13, 300 MHz) 1.02 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2.26 1H), 2.72 3H), 2.75-2.95 6H), 3.13-3.22 1H), 3.25-3.35 1H), 3.47-3.58 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 J=7.5Hz, 1H), 6.84 J=7.5Hz, 3Hz, 1 H), 6.87 J=9Hz, 2H), 7.04 J=3Hz, 1 7.43 J=9Hz, 2H). MS (DCI/NH 3 m/e 505 (M+H) Example 68 trans. trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-v)-1 (proDvysulfonyl)ethvl)-pyrrolidine-3-carboxylic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 oC for 1 hours. To this mixture was added the compound resulting from Example 61A (180 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 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 mL of H 2 0 was added a solution of osmium tetroxide (10 mg) in 0.3 mL of tbutanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H 2 0. The organic phase was washed with brine, dried -112over Na 2
SO
4 and concentrated in vacuo. Flash chromatography afforded 177 mg of the ethyl ester which was hydrolyzed by the procedures described in Example 1D to afford the title compound. m.p. 73-75 OC. 1H NMR (CDCI 3 300 MHz) 8 1.04 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1 H), 2.84-3.08 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1 3.68 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.75 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1 6.88 J=9Hz, 2H), 6.99. J=3Hz, 1 7.32 J=9Hz, 2H). MS
(DCI/NH
3 m/e 476 (M+H) Example 69 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-v)- 1 methvlhex-2-envl)-vyrrolidine-3-carboxvlic acid Example 69A trans-5-Methvlhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 OC.
Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 OC. Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL). The ether extracts were combined, dried with Na 2
SO
4 and evaporated to give a colorless oil which was purified by flash chromatography on silica gel eluting with hexanes. The title compound was isolated as a colorless oil (2.1 g).
Example 69B trans-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 N in toluene, 20 mL) was added dropwise and the solution stirred at 0 °C for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature.
II
-113- Diethyl ether (50 mL) was added, the solids removed by filtration and washed with additional ether (2 x 25 mL). The filtrate was extracted with ether (2 x mL). The ether extractions and washings were combined, dried, and evaported to give a colorless oil which was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).
Example 69C trans-1 -Bromo-5-methvlhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 OC in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °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 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 methvihex-2-enyl)-pyrrolidine-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 69C for Npropyl bromoacetamide. 1 H NMR (CDCI 3 300 MHz) 5 0.84 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,14Hz), 2.86 1H, J=10Hz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, 1H, J= 5Hz,14Hz), 3.29 (dd, 1H, J=3Hz,lOHz), 3.50 1H), 3.70 1H, J=10Hz), 3.78 3H), 5.47 (m, 2H), 5.93 2H), 6.71 1 H, J=8Hz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 (d, 2H, J=9Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C 26
H
31 N0 5
C,
71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.
Example -114trans.trans-2-(4-Methoxyphenvl)-4.(1.3-benzodioxol-5-yl)- 1 dimethylhex-2-envl)-pyrrolidine-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 pC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product (and its diastereomer) as a white solid. 1H NMR of the major (trans) isomer: (CDC13, 300 MHz) 5 0.83 6H, J=8Hz), 1.56 1.74 1H), 1.92 2H, J=6Hz), 3.3-3.5 3H), 3.6-3.8 3.78 3H), 3.9-4.0 1 H), 5.22 1H), 5.90 2H, J=12Hz), 6.63 1H), 6.78 3H), 6.95 1H), 7.45 3H, J=8Hz). MS (DCI/NH 3 m/e 438 Anal calcd for C27H 33 N05 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10; N, 2.34.
Example 71 trans.trans-2-(4-Metho xvphenvl)-4-(1.3-be nzodioxol-5-vyl-1-(4heptvlcarbonvlmethyl)-pyrrolidine-3-carboxylic acid Example 71A 1 -Chloro-3-Drovyl-2-hexanone To 2-propylpentanoic acid (156.6 l1, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 pL, 4 mole and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 gL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 °C and excess -0.3 M ethereal diazomethane solution was added.
The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 glL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient -115temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
Example 71 B trans.trans-Ethyl 2-(4-methoxvphenyl)-4-(1.3-benzodioxol-5-vl)-1-(4heptvlcarbonvlmethyl)-pyrrolidine-3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 glL, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole and the reaction mixture was stirred 18 hours under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 oC with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg of the title compound as a yellow oil.
Example 71C trans.trans-2-(4-MethoxvDhenvl-4-(1.3-benzodioxol-5-vl)-1 heDtvlcarbonvlmethyl)-pvrrolidine-3-carboxylic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the pH to This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL).
The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1:1 ethyl acetate-hexane to give 86 -116mg of the title compound as an off white powder. 1 NMR (ODCd 3 300 MHz) 5 0.73-0.97 (in, 6H), 1.03-1.33 (in, 6H1), 1.36-1.55 (in, 2H), 2.46 (in, 1 H), 2.80-2.98 (in, 3H), 3.38-3.64 (in, 3H), 3.75-3.90 (in, 1 3.79 3H), 5.94 (s, 2H1), 6.75 1 6.86 2H1), 6.92 1 7.12 1 7.32 2H). MS (FAB) m/e 482 Anal calcd for C2 8
H
35 N0 6 C, 69.83; H, 7.32; N, 2.91.
Found: C, 69.57; H, 7.41; N, 2.73.
trans. trans-L2-(4-Methgxyphenyl..4.( 1. 3-benzodigxol-5i-yl)-1 -(valervmethy.)pyrrolidine-3-carboxylic acid ExampleZ7A 1 -Chloro-2-hexpnone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
Example 7a trans. trans-Ethyl 2- (4-inethoxyphenyl)-4-( 1.3-benodioxole--y)-1 (valerylinethyl)-pyrrolidine-3-carboxylpte Substituting the compound resulting from Example 72A for 1 -chloro-3propyl-2-hexanone and using the procedure described in Example 71 B, 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 was obtained as a yellow oil.
trans. trans- -4-Methoxyphenyl)- 1.3-benzodioxol-5-yl)-1 -(valerylinethyl)pyrrolidine-3-carboxylic acid *By substituting the compound resulting from Example 728 for trans,trans- Ethyl 2-(4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-l1-(4he ptylcarbonyl met hyl)-pyrro lidi ne3carboxylate and using the procedure -117described in Example 710C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg was obtained as an off white powder. 1H NMR (CDC1 3 300 MHz) 5 0.87 3H), 1.26 (in, 2H), 1.49 (in, 2H), 2.37 (in, 2H), 2.79-2.98 (in, 3H), 3.31-3.49 (in, 2H), 3.56 (in, 1 3.77, 3.79 4H), 5.94 (s, 2H), 6.75 1 6.81-6.93 (in, 3H), 7.09 1 7.33 2H). MS (FAB) m/e 440 Anal. calcd for C25H 29 N0 6 C, 68.32; H, 6.65; N, 3.19. Found: C, 67.95; H, 6.64; N, 3.05.
Fa~e7 trans.trans-2..4e yeyl- 4 -(l.-enodixol.501ly 4trans. trans- andcs trn-(4-Methoxyp~he nyl)A4-( 1.3-enoioxl.s..-yjy. dimethgxybenzy laminopprbonyletyl2yrroid 3 ab ai ty se Using the procedure of Example 1 D, paragraph 1, substituting 3,4dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
Eam~e 73F3 trans-trpns- aidcis.trans-2-(4-Methoxyhnl( 3-ezdoI.yy1
-(N
(3 4 -dimethoxvbenZ yL)..NmiethIW inocarbony3ineth I) 1d The resultant product from Example 73A (220 mg9, 0.404 minol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 00) suspension of sodium hydride (23 mng of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 inmol) in 0.2 mL THE, under an argon atmosphere.
The resulting mixture was stirred at 0 00 for 1 hour, then methyl iodide (28 gl, 64 ing, 0.45 minol) was added. The reaction mixture was stirred at 0 00 for minutes. TLC (Et 2 O) indicated incomplete reaction. An additional portion of methyl iodide (28 64 mng, 0.45 iniol) and dry 1 ,3-diinethyl-3,456tetrahydro-2(1 HMpyriinidinone (50 4.L, 0.'41 mrnol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was -118poured into 25 mL of 0.5 M aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 mL water and 30 mL brine, then dried (Na 2
SO
4 filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et 2 0 gave the title compounds as an inseparaphy mixture in 43% yield. 1 H NMR (CDCl 3 300 MHz) 2.79 and 2.81 for the
N-CH
3 signals. MS m/z 591 lO N e xamn p le 7c To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 0 OC was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H20. The resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL
H
2 0 and 15 mL Et 2 0. The aqueous phase was extracted with 5 mL Et 2 then the aqueous phase was ac e w aextracted w it h 5 m L E t20, then the aqueous phase was acidified with 10% aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc.
The EtOAc extracts were combined, dried (Na 2
SO
4 then filtered and concentrated in vacuo to give 40 mg of the title compound as a white foam. 1 H NMR
(CD
3 0D, 300 MHz, two rotameric forms) 6 2.85 3H), 2.94- 3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br 3.74 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1 5.91 and 5.93 2H total), 6.50-6.60 1H), 6.67-7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31H3 5
N
2 0 8 563.2393. Found: 563.2385.
E
The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 73B, to provide the title compound. 1 H NMR
(CD
3 OD, 300 MHz) 6 -119- 2.85 J=1l6Hz, 1 2.92 (br t, J=9Hz, 1 2.98 (br t, J=1l0Hz, 1 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 3.67 3H), 3.78 3H), 3.80 3H), 3.85 (d, J=1 0 Hz, 1 4.21 J=1 5Hz, 1 4.41 J 15Hz, 1 5.91 2H), 6.67 (d, J=8Hz, 1 6.75-6.95 (in, 7H), 7.33-7.40 (in, 2H). HRMS calcd for 0 3 oH3 2
N
2 0 8 549.2237. Found: 549.2224.
(2 .3R.4R)-2-(4-Methoxypheny).4(1 .3-benzodaoxol-5-yl)-1-((1 R'-1 .Ndipropylaminocarbonyl)-l -butyl)pyrrolidine-3-carboxylicacid Eamle trans. trans- Meth oxyph enyl)-4(1 .3-be nzodioxo -5-y 1 R)-1 (be nzyloxycarbonyl butyljpyrrolidi ne-3-carboxylic acid ethyl ester The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of H 2 0, and ammonium carbonate (34 mg, 0.35 minol) and (2S)-benzyl 2-bromopentanoate (78 mng, 0.30 minol) were added. The reaction was ref luxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na 2 00 3 and 25 mL of CH 2
CI
2 The aqueous phase was extracted with 2 x 10 mL CH 2
CI
2 and the combined organic phases were washed with 15 mL brine, dried (Na 2
SO
4 then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3:1 CH 2
CI
2 hexane to produce 106 mg of the title compound as a waxy solid. 1H NMVR indicated the presence of two diastereomeric products.
t~rans.tranris--2-(4-Methoxyphenyl).4-(1 .3-benzodixol--yl)-1 R)-1 di ropylami nocarbo-nyl)- 1 -butyl pvrrolidine-3-carboxylic- acid ethyl ester The resultant compound from Example 75A (101 mng, 0. 180 inmol) and mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H 2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst. The combined filtrate and -120wash were concentrated in vacuo to give 81.4 mg of the crude acid as a white solid.
The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4 -methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 oC, then 1-ethyl-3- 3 -dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 oC and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na 2
CO
3 The organic phase was washed with 10 mL of brine, dried (Na 2
SO
4 then filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et 2 0hexane. Further purification of overlap fractions by preparative TLC eluting with 1:2 Et20-hexane yielded 32 mg of a less polar product, and 44 mg (46%) of a more polar product.
Example (2R.3R.
4
R)-
2 -(4-Methoxyohenyl)-4(1.3-ben zodioxol-5i-y)-1-((1 diProDvlaminocarbonvl)-1 -butvl)vrrolidine-3-crboxylic 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. [c]D -520 (c=0.235, 1 H NMR (CD 3 OD, 300 MHz) 8 0.55 J=7Hz, 3H), 0.87 J=7Hz) and 0.87-0.94 6H total), 1.03-1.25 (br m, 2H), 1.25-1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 overlapping with
CD
2 HOD signal), 3.40-3.60 (br m, 2H), 3.79 3H), 4.04 (br d, J=9 Hz, 1H), 5.92 (dd, J=3,5 Hz, 2H), 6.72 J=8 Hz, 1H), 6.79 (dd, J=1.5,8 Hz, 1 6.92- 6.98 (br m, 3H), 7.29-7.39 2H). MS m/z 525 Example 76 -121- (2S.3S.4S)-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-l)-1
.N-
dipropvlaminocarbonyv-1 -butyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 88% yield. [a]D +580 (c=0.37, 1H NMR (CD 3 0D, 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 6H), 1.08- 1.35 (br m, 2H), 1.35-1.68 (br m, 4H), 1.75-1.90 (br m, 1 2.75-2.86 (br m, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br m, 2 3.69 3H), 4.03-4.16 (br m, 2H), 5.91 2H), 6.71-6.83 2H), 6.86-6.97 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 Example 77 2
S.
3 S.4S)-2-(4-MethoxvDhenyl)-4-(1 .3-benzodioxol-5-vy)-1-((1 diDroDvlaminocarbonvl-1 -butylvnprrolidine-3-carboxvlic acid Example 77A trans.trans-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-vl)-1 diDrovylaminocarbonv- 1 -butvl)pyrrolidine-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 oC. Trifluoromethanesulfonic anhydride (95 pL, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 OC, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 gL, 75 mg, 0.58 mmol) in 3 mL of CH 2
CI
2 was added. The reaction was stirred at 0 OC for 3 hours and for an additional 2 days at room temperature. TLC (Et20-hexane 1:2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na 2
CO
3 The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2SO4), filtered and concentrated in vacuo to a yellowish oil. Purification by flash -122chromatography on silica gel eluting with 1:2 Et20-hexane gave 19.9 mg of a less polar product and 20.1 mg of a more polar product. 1 H NMR spectra and MS were the same as those of Example 768.
Example 77B 2 S.3S.4S)-2-(4- Methoxyvhenvyl.4(1 .3-benzodioxol-5-vl)--(( 1 diropylaminoarhonyl)-1 pvrrine-3-arylic acid The procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 100% yield. 1 H NMR (CD3OD, 300 MHz) and MS identical to those of Example Example 78 2 R15 3 R -4R-4MthOXhn -4 benzodioxol-... diproDvylaminocarbonvyl)-l-butvyl)pyrrolidine-3-carboxpc acid The procedure of Example 73C was followed, with the substitution of the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. 1 H NMR (CD3OD, 300 MHz) and MS identical to those of Example 76.
Example 79 trans.trans-2-(4-Methoxvphenvyl)-4-(1.3-benzodioxo5yil1-(N.N-di(n- Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 OC. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg of the 3-carboxamide compound. m.p.
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 -123was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg of the 3-carbonitrile compound.
To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid to get 532 mg of the title compound. m.p. 165- 167 oC. 1 H NMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 J=7Hz, 3H), 1.10-1.50 8H), 3.0-3.6 8H), 3.70 3H), 3.7-3.8 1H), 3.90 J=9Hz, 1H), 4.37 J=9Hz, 1H), 5.86 2H), 6.62 J=8Hz, 1H), 6.65-6.73 3H), 6.95 J=2Hz, 1 7.11 J=9Hz, 2H).
Example trans.trans-2- 4- Fluorophenv-4-(1.3-benzodioxol-5-l-1 (N .N-di(nbutvl)aminocarbonvlmethvlvpyrrolidine-3-carboxlic aci The title compound was prepared as an amorphous solid from methyl (4flourobenzoyl) acetate and 5-(2-nitrovinyl)-1,3-benzodioxole using the procedures described in Examples 1 and 43. 1 H NMR (CDCI 3 300 MHz) 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.0-1.55 8H), 2.81 J=13 Hz, 1H), 2.90-3.10 4H), 3.15-3.30 1H), 3.32-3.45 3H), 3.55-3.65 1H), 3.86 J=1 Hz, 1 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 Hz, 1 6.95-7.07 3H), 7.32-7.45 2H).
Example 81 trans.trans-2-(4-Methoxvyhenl)-4-(1.3-benzodioxol-5-vyl- -(N.N-di(nbutvl)aminomethvlcarbonvl)vrrolidine-3arboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C.
-124- After cooling to room temperature, 250 mg (0.678 mmol) of ethyl trans,trans-2- (4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 °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 hydrolyzed with sodium hydroxide in water and ethanol to give 265 mg of the title compound as a white powder. 1 H NMR (CDCl 3 300 MHz) 5 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 8H), 2.65-3.20 6H) 3.43-3.70 3H), 3.72 3H), 3.87 J=15Hz, 1 4.49 (dd, J=12Hz, 6Hz) and 5.23 (dd, J=12Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 2H), 6.63-6.78 3H), 6.86 and 7.04 J=9Hz, 2H), 7.22 J=9Hz, 2H).
Example 82 trans.trans-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vl)-1 -(N-n-butvl)-N-(n- DroDpylaminocarbonvlmethyl)vyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Example 1. m.p. 160-162 oC. 1 H NMR (CDCl 3 300 MHz) rotational isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 6H), 2.63 and 2.66 (two doublets, J=13Hz, 1H), 2.90-3.10 4H), 3.23-3.61 5H), 3.71 and 3.75 (two doublets, J=10Hz, 1H),.3.78 3H), 5.92-5.96 2H), 6.72 J=8Hz, 1H), 6.83-6.89 3H), 7.03 J=2Hz, 1H), 7.81 J=9Hz, 2H).
Example 83 trans.trans-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl)-1 provyl)aminocarbonvylethvlloprrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg, 0.677 mmol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 OC 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 of the diallyl compound.
The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was -125removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
The ester was hydrolyzed to the title compound by the method of Example 1D in 83% yield. 1H NMR (CDCI 3 300 MHz) 5 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 4H), 2.35-2.60 3H), 2.80-3.07 3.14-3.21 2H), 3.31-3.38 1H), 3.51-3.61 1H), 3.73 J=12H, 1H), 3.75 3H), 5.94 2H), 6,71 J=9Hz, 1H), 6.79-6.85 3H), 7.04 (d, J=2Hz, 1H)< 7.32 J=9Hz, 2H).
Example 84 trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vl)-1 -N .N-di(nbutvl)aminocarbonyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino etal., Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1
H
NMR (CDCI3, 300 MHz) 6 0.86 J=7Hz, 6H), 1.14-1.28 4H), 1.35-1.48 (m, 4H), 2.81-2.94 2H), 3.11 J=12Hz, 1 3.30-3.41 2H), 3.59-3.68 (m, 2H), 3.76 3H), 3.78-3.85 1 5.81 J=9Hz, 1 5.94 2H), 6.73-6.86 5H), 7.24 J=9Hz, 2H).
Example trans.trans-2-(4-Methoxvyhenyl)-4-1 .3-benzodioxol-5-vyl-1 -(N.N-di(nbutvl)aminocarbonvlmethyl)pyrrolidine-3-carboxvlic 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 °C to yield 627.5 mg of the title compound.
Example 86 -126trans.trans-2-(4-Methoxvyhenvyl).4(1.3-benzodioxol-5-l) N-di(nbutvl)aminocarbonvlethyllvyrrolidine-3-carboxylic acid A solution of the bromoethyl compound resulting from Example 61A (150 mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 °C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2
SO
4 and concentrated. More toluene was added, and the solution was again concentrated to get rid of excess dibutylamine. The residue was dissolved in warm heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mg of the intermediate ethyl ester.
The ester was hydrolyzed by the method of Example 1D to give the title compound as a white powder. 1 H NMR (CD 3 0D, 300 MHz) 8 0.89 J=7Hz, 6H), 1.16-1.30 4H), 1.44-1.56 4H), 2.48-2.57 1H), 2.80-3.08 8H), 3.14-3.25 1H), 3.31-3.38 1H), 3.59-3.60 1H), 3.74 3H), 3.75 (d, 1H), 5.89 2H), 6.71 J=9Hz, 1H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 J=10Hz, 2H), 6.96 J=2Hz, 1H), 7.37 J=10Hz, 2H).
Example 87 trans.trans-2-(4-Methoxyphenyvl-4(1.3-benzodioxol-5-yl)-1 N-di(nbutl)aminocarbonvl-N-methvlaminoethvlyrrolidine-3-carboxylic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound resulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na 2
SO
4 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.
The ester was hydrolyzed by the method of Example 1 D to afford 141 mg of the title compound. 1H NMR (CD 3 OD, 300 MHz) 5 0.92 J=7Hz, 6H), 1.21- 1.32 4H), 1.42-1.53 4H), 2.62 3H), 2.65-2.76 1H), 3.00-3.20 (m, 8H), 3.44-3.55 1H), 3.62-3.78 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 2H), 6.75 J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 J=10 Hz, 2H), 7.04 J=2Hz, 1H), 7.40 J=1 Hz, 2H).
-127trans.tra s2(~ehoxypihenyl)..
4 -(l.3-benzodioxo-5-y')-1 .N-di (nbutylaminoarbonLmehyhjpyrrolidin n- 3 -(N-methanesufonicrxmd 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 OC 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 OC for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg of the title compound. m.p. 170-173 00. 1 H NMR (ODC1 3 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.51 (in, 8H), 2.75-2.86 (in, 2H), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-3.50 (in, 3H), 3.70-3.78 (in, 1H), 3.80 3H), 3.87 (d, J=1lOHz, 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 J=9Hz, 1 6.84 (dd, J=9Hz, 2Hz, 1 6.90 J=1 0 Hz, 2H), 7.01 J=2Hz, 1 7.34 J=1 0Hz, 2H).
Exam~le 8 trans,.trans-2-4-Methoxyphenvyp)4-(l 3-enoioxol-5yly.1 N-di(nbutyl) mncrbonyl)neth~lyrlopyrrolidiN-e 3(Nbenzenmir 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 00 for a sample recrystallized from acetonitrile. 1 H NMR (ODC1 3 300 MHz) 8 0.81 J=7 Hz, 3H), 0.89 J=7Hz, 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (in, 1 3.65 J=l10Hz, 1 3.81 3 5 .94 2H), 6.70 2H), 6.81-6.90 (mn, 3H), 7.17 J=lOHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 1 8.95 J=7Hz, 2H).
mJI2 -128trans. trans-2-(4-Methoxphenylv)-4-(1.3-benzodioxol-5-vl)-1-[N.N-di(n-buty) aminosulfonylmethyll-pyrrolidine-3-rhoxylic acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et.
al., Chem. Ber. Ila: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann. Chem. 1055-1063 (1980) to give N,Ndibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraflouroborate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with Nchlorosuccinimide to give chloromethyl sulfenyl chloride by the method of E.
Vilsmaier, described in the above reference.
The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans,trans-2-(4- Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[N,N-di(nbutyl)aminosulfenylmethyl]-pyrrolidine-3-carboxylate. This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 2: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.
Example 91 trans.trans-2-(4-Methoxyphenvl-4(1.3-benzodioxol-5-vl)-1 dibutylaminocarbonvl-1-(RS)-ethvyllDvrrolidine-3-carboxylic acid Example 91A (+)-Dibutyl 2 -bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 mL, 6.73 mmol) were dissolved in 10 mL of CH 2
CI
2 the solution was cooled to 0 OC under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL 3.5 mmol). After 10 minutes at 0 OC, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 OC for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na 2
CO
3 solution, then the organic phase was washed sequentially with 25 mL of 1 M aqueous NaHSO 4 and 25 mL brine, dried (Na 2
SO
4 filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 1 H NMR -129- (CDC1 3 300 MHz) 8 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 (in, 7H), 1.60-1.78 (in, 1 1.82 J=6Hz, 3H), 3.04-3.27 (in, 2H), 3.42-3.64 (in, 2H), 4.54 J=7H, 1 MS (DCI/NH 3 m/e 264 and 266 Example 91 B trans~tan and c/s.trans-2-(4-Methoxyphenyr-4-(1 .3-benzodioxol-5-vl)-1 .N-dibutylamino)cprbonvl-1 -(RS)J-ethyl~pyrrolidine-3-carboxylic acid ethyl a2teL A solution of the resultant mixture of trans,trans and cis,trans compounds from Example 10C (232 mg, 0.628 inmol) and the resultant compound from Example 91 A (183 mng, 0.693 minol) in 2 mL of CH 3 CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol). The solution was stirred at 60-80 00 under a N 2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et 2 O and 10 mL of 1 _M aqueous Na 2 00 3 so lution. The organic phase was washed with mL water and 20 mL brine, dried over Na 2
SO
4 filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude). The product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mng of the title compounds as a mixture of 4 diastereoiners. 1 H NMR (ODC1 3 300 MHz) 8 0.66-1.55 (several m, 19H),.2.63-3.00 (in, 3H), 3.05-3.39 (in, 2H), 3.40-3.76 (in, 4H), 3.78-3.80 (4 s, 3.84-4.25 (in, 2.6H), 4.38 J=10O.5Hz, 0.2H) and 4.58 J=10.5Hz, 0.2H), 5.90-5.97 (mn, 2H), 6.68-6.96 (in, 5H), 7.38-7.43 (in, 2H).
MS (DCI/NH 3 m/e 553 trans, trans-2- Met hoxyphe nyl)-4- (1 .3-bezodioxo 1 N dibutylam ino)carbonyl-l1-( RS)-ethyl)pyrrolidi ne-3-carboxylic acid The procedure of Example 730 was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield. 1 H NMR (CD3OD, 300 MHz) 80.70-1.05 (several m, 8H), 1.14 J=6Hz, 2H), 1.17-1.55 (mn, 6H), 2.79-3.03 (in, 3.20-3.65 (br mn, 4.6H plus CD 2 HOD), 3.70-3.78 (mn, 0.4H), 3.79 3H), 3.98 (d, J=8 Hz, 0.6H), 4.06 J=7.5Hz, 0.4H), 4.25 J=8Hz, 0.4H), 5.92 and 5.94 -130- 2H total 6H), 6.73 J=2.5Hz) and 6.75 J=3Hz, 1H total), 6.78-6.85 (m, 1H), 6.91-7.00 3H), 7.30-7.38 2H). MS (DCI/NH 3 m/e 525 Anal calcd for C30H4oN 2 0 6 .0.5H 2 0: C, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.
Example 92 trans.trans-2-(Pentl)-4-(1.3-benzodioxol-5-yi)-1 dibutvlamino)carbonvlmethvylvrrolidine-3-carboxylic acid Examle 92A Methyl 2 4-hexenol-4-nitro-3-(1 3 A solution of methyl 3 -oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 UL, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes.
TLC
(ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture of diastereomers in a 1:1 ratio. 1H NMR (CDC13, 300 MHz) 5 1.55-1.66 3H), 2.02-2.17 (br m, 1H), 2.20-2.37 (m, 2.49-2.76 1.5H), 3.57 1.5H), 3.74 1.5H), 3.97 J=7.5H, and 4.05 J =8Hz, 0.5H), 4.10-4.20 1 4.68-4.82 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 1 6.68 (br s, 1 6.75 7.5Hz, 1 MS
(DCI/NH
3 m/e 381 (M+NH 4 Anal calcd for C18H21N0 7 C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.
Example 92R Methyl trans.trans-2-(Dentyl)-4-(1.
3 -benzodioxol-5-vlrrolidine-3-carboxylate 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,
L
-131- 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO 3 diluted with 10 mL water and mL of CH 2
CI
2 The aqueous phase was extracted (2 x 30 mL CH 2
CI
2 then the combined organic phases were washed with 20 mL brine, dried over Na 2
SO
4 filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with methanol in CH 2
CI
2 gave 336 mg the title compound as a yellow oil. 1
H
NMR (CDCI 3 300 MHz) 8 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1 3.34-3.45 2H), 3.53 J=9Hz, 1 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS (DCI/NH3) m/e 320 Anal calcd for C 1 8
H
25 N0 4 C, 67.69; H, 7.89; N, 4.39. Found: C, 67.39; H, 7.84; N, 4.37.
Example 92C trans.trans-2-(Pentvl)-4-(1.3-benzodioxol-5-yl)-1 -f(N.Ndibutylamino)carbonvlmethyllDvrrolidine-3-carboxylic acid The procedures of Example 1B-1 D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam. 1H NMR (CDCI 3 300 MHz) 5 0.87 (br t) and 0.89 (br t, 6H total), 0.97 J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43-1.78 (br m, 6H), 2.76 J=7Hz, 1 3.02-3.30 (br m, 6H), 3.40- 3.60 3H), 3.73 J=14Hz, 1 5.98 (AB, 2H), 6.70 J=7Hz, 1 6.77 (dd, J=1.5,7Hz, 1H), 6.89 J=1.5Hz, 1H). MS (DCI/NH 3 m/e 475 Anal calcd for C27H42N 2 0 5 -0.5H 2 0: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.
-132trans.trans-2-(Pentvl)-4-(1.3-benzodioxol-5-yvl- -[2-(N-propyl-NproDvlsulfonvlamino)ethyllpvrrolidine-3-carboxylic acid Example 93A Methyl trans, trans-2-(pentyl)-4-(1.3-benzodioxol-5-yl)-1 -(2 bromoethvl)pyrrolidine-3-carboxylate The procedure of Example 61A was used, with the substitution of the resultant compound from Example 92B for the resultant compound from Example 1C, to provide the title compound as a yellow oil. 1 H NMR (CDC 3 300 MHz) 5 0.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 2H), 2.76-2.91 2H), 3.10-3.22 2H), 3.36-3.47 2H), 3.68 3H), 5.92 2H), 6.69-6.77 2H), 6.90-6.94 1 MS (DCI/NH 3 m/e 426, 428 Example 93B Methyl trans, trans-2-(Pentyl)-4-(1.3-benzodioxol-5-yi)- 1-2-(N-propyl-Npropylsulfonylamino)ethyllpyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 pmol) in 1 mL EtOH was treated with propylamine (60 pL, 0.73 mmol). The solution was warmed to °C for 4 hours. The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous Na 2
CO
3 The organic phase was washed with 15 mL brine, then dried over Na 2
SO
4 filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg). The crude amine was dissolved in 1 mL of CH 2
CI
2 diiosopropylethylamine (65 L, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 gL, 0.26 mmol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH and the mixture was extracted with 2 x 3 mL CH2CI2. The combined organic extracts were washed with 2 mL brine, then dried over Na 2
SO
4 filtered, concentrated in vacuo.
Purification by flash chromatography eluting with 20% ethyl acetate in hexane -133provided 65.0 mg of the title compound as a waxy solid. Rf 0. 17 MS (DCI/NH 3 m/e 511 trans. trns-2-(Pentyl)-4-(1 .3-benzodioxol-5-ylyi -f2-(N-prooyl-N- APYlsuIfonylamino)ethyllpvrrolidine-3croxylic cid The procedure of Example 710C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example 718B, to provide the title compound as a white foam (47 mg, Rf= 0.14 (5%MeQH-CH 2
CI
2 1 HNMR (ODC1 3 300 MHz) 8 0.88 (br t) and 0.92 (t, J=7Hz, 6H total), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 (in, 2H), 3.05 (br t, J=9Hz, 1 3.10-3.30 (in, 3H), 3.30-3.80 (br mn, 7H), 5.94 2H), 6.71 J=8Hz, 1 6.77 (dd, J=1 .5,8Hz, 1 6.89 (d, J=1 .5Hz, 1 MS (DC I/N H 3 in/e 497 Exampla4 trans, trans-2-:( Propyl)b4-( 1.3 -benodioxol-5-ya)-
N-
dlibutylamino)car onylm-ethyqpyrrolidine3carboylic acidcf Eape-4 Ethyl 2 -(4-utanoyl)-4-nitro-3-(1 -benzodixoe..y utre The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mg, Rf 0.28 hexane). 1 H NMR (CDCI 3 300 MHz) 6 0.74 J=7.5Hz) and 0.91 3H total), 1.08 J=7Hz) and 1.28 J=7HZ, 3H total), 1.45 (sextet, J=7Hz, 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2.24 J=7Hz, total)2.40-2.54 (in, 1 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5H total), 3.93-4.09 (in, 2H), 4.10-4.20 (br m, 1 4.23 J=7Hz, 1 4.67-4.85 9mn, 2H), 5.94 2H), 6.62-6.75 (in, 3H). MS (DCI/NH 3 m/e 369 (M+NH 4 Anal calcd for C17H2 1 N0 7 0, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.
Exmple 4B E-thyl trans trans-2-(popyl)-4(1 -ben zodioxol5yl)pyrrolidine.3carboxylate -134- The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound-from Example 92A, to afford the title compound. MS (DC I/NH 3 m/e 306 Exampe 4C trans. trans-2-(Propyl)-4-(1 .3-ben zodioxo-5)yl)-1
N-
dibuityamirio)carbonyl)methylpyrrolidine-3.crboQxylic acid The procedure of Example 92C was followed, with the substitution of the resultant product from Example 948 for the resultant product from Example 92B, to give the title compound. 1 H NMR (ODC1 3 300 MHz) 8 0.89 0.92 J=7.5Hz), and 0.97 J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 (t, 1 3.40-3.55 (br m, 2H), 3.55-3.68 (in, 1 3.78 J=1 5Hz, 1 H), 5.92 J=1 Hz, 2H), 6.70 J=8Hz, 1 6.79 (dd, J=1 Hz,8Hz, 1 6.90 (d, J=1 Hz, MS (DCI/NH 3 m/e 447 Anal calcd for C25H 38
N
2 0 5
H
2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 65.91; H, 8.68; N, 5.94.
ExampJle 9 (2R.3R 4 S)-(+)-2-(4-Methoxyphenyl)-4.(l.3-benzodixL--l')- -(tertbutyloxyvcarbonyl-aminocarbonylmethyl)..pyrrolidine3carboxylic acid ExampleI9A tranis. trans-2-(4-Methoxyphenyl)-4(1 .3-be nzodioxol-s-YQlyl -(ftertbutvloxycarbon yla-minocarbontymethyllnyrrolidine.3-carboxylic acid The resulting mixture of 64% trans,trans- and cis,trans- pyrrolidines resulting from Example 10C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1) indicated that all of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. 1 HNMR
(CDCL
3 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1.11-1.62 (several br m, 9H), 3.05 (br m, 1 3.44-3.95 (in, 3H), 3.81 3H), 4.04 J=7 Hz, 1 4.14- -135- 4.28 (br m, 1 4.89-5.24 (br m, 1 5.94 J=3 Hz, 2H), 6.69-6.90 7.06-7.20 2H). MS (DCI/NH 3 m/e 470 To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water. The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with 250 mL of ether. The organic phase acidified to slight cloudiness (pH with 1 N hydrochloric acid, then to pH 4 with 10 citric acid and extracted with 5 ethanol in methylene chloride (3 x 100 mL).
The combined organic layers dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to give the title compound as a white foam (2.19 g, 60 1 H NMR (CDC13, 300 MHz) 8 1.16 (v br s, 9H), 3.11 (br m, 1 3.50-3.64 2H), 3.81 3H), 4.24 (br m, 1 4.96 (br m, 1 5.94 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 Example 2 R.3R.4S)-(+)-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vl-1 -(tertbutYloxvcarbonvlaminocarbonvlmethyl)-Dvrrolidine.3-carboxvlic 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 1 H NMR and chiral HPLC. The amount of enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the enantiomer could no longer be detected in the filtrate.
The pure enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether. The aqueous layer was further extracted twice with 100 mL of ether. The combined ether layers were washed with brine, dried (Na 2
SO
4 filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum, >99.5 ee). 1H -136- NMR (CDCI 3 300 MHz) 5 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 (m, 2H), 3.81 3H), 4.24 1 4.96 (br m, 1 5.95 2H), 6.70-6.79 3H), 6.86 J=9 Hz, 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 Example (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyDhenyl)-4-(1.3-benzodioxol-5-vy)-Dyrrolidine- 3-carboxylate The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol. The resulting solution was heated at 50 with stirring for 18 hours at which point all of the precipitated solid had dissolved. The reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer was further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2
SO
4 filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 1H NMR (CDCI3, 300MHz) 8 1.11 J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 J= 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 2H), 3.80 3H), 4.07 J=7 Hz, 2H), 4.49 J=9 Hz, 1H), 5.94 2H), 6.73 J=2 Hz, 2H), 6.81- 6.92 3H), 7.34-7.41 2H). MS (DCI/NH 3 m/e 370 Example (2R.3R.4S)-(+)-2-(4-Methoxvphenyl)-4-(1.3-benzodioxol-5-vyl-1-(tertbutvloxvcarbonvl-aminocarbonvlmethv)-pyrrolidine-3-carboxvlic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 gL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oil. 1H NMR (CDCs, 300MHz) 8 0.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H),.1.10 J=7 Hz,.3H), 1.00-1.52 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 4H), 3.23-3.61 5H), 3.71 J=9 Hz, 1 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, -137- Hz, 2H), 6.74 J=9 Hz, 1 6.83-6.90 3H), 7.03 J=2 Hz, 1 7.30 (d, J=9 Hz, 2H). MS (DCI/NH 3 m/e 539 To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40 over hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous hydrochloric acid until cloudy, and the pH was then adjusted to -4-5 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol-methylene chloride (3 x 50 mL). The combined extracts were dried (Na 2
SO
4 filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 1 H NMR (CDCl 3 300MHz) 6 0.80 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.08 2H), 1.28 3H), 1.44 3H), 2.70-3.77 (svr br m, 12H), 3.79 3H), 5.95 2H), 6.75 J=8 Hz, 1 6.87 (br d, J=8 Hz, 3H), 7.05 (br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH 3 m/e 511 [a] 22 +74.420. Anal calcd for C 29
H
38
N
2 0 6 -0.5 H 2 0: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.
Example Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-( .3benzodioxol-5-vl)-1-(tert-butyloxvcarbonylaminocarbonylmethyl)-pyrrolidine-3carboxvlic acid The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 1670. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-1680. The filtrate was concentrated again and put in the refrigerator and let stand -138overnight giving 1.6906 g, m.p. 102-1100. (HPLC of this showed the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-172°.
Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
Example 96 trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-l)-1 2 -(N-ropvl-Nbutvrylamino)ethyllpvrrolidine-3-carboxyi acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The product was purified by preparative HPLC (Vydac gC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. IH NMR (CDC13, 300 MHz) 5 0.80 3H), 0.90 3H, J=8Hz), 1.42 (m, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1 5.95 2H), 6.75 1 H, J=8Hz), 6.84 1 6.85 2H, J=8Hz), 7.04 1 H, J=1 Hz), 7.40 2H, J=8Hz). MS (DCI/NH 3 m/e 497 Anal calcd for C2 8
H
3 6
N
2 06 1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.
Example 97 trans. trans-2-(4-Methoxvyhenvl)-4-1.3-benzodioxol-5-yvi-1 -12-(N-oroDy-N- (ethylaminocarbonyl)amino)ethvilyrrolidine-3-carboxylic aci 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.- H NMR (CDC13, 300 MHz) mixture of rotamers 8 0.80 J=8Hz) and 1.05 -139- J=8Hz) and 1.20 (in) and 1.42 (mn) total of 8H for the four peaks, 2.35 (br s, 1 2.70 (in, 1 3.0 (in, 3H), 3.2 (in, 3H), 3.25 (dq, 1 H, J=1 ,8Hz), 3.42 (in, 1 H), 3.6 (mn, 1 3.75 (in, 1 3.78 3H), 4.8 (br s, 1 5.95 2H), 6.74 1 H, J=8Hz), 6.85 (mn, 3H), 7.00 1 7.30 2H, J=8Hz). MS (DCI/NH 3 m/e 498 Anal calcd for C27H 35
N
3 0 6 -0.75 H 2 0: 0, 63.45; H, 7.20; N, 8.22.
Found: C, 63.38; H, 7.29; N, 8.44.
trstrans (4Methoxynheno- 4 -(l.3-benzodio ol-5-yl)-[-2-(N-buty-N butyrvlamin' hlprrolidine.3.carboxylicQ acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for inethylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. 1 H NMR
(CDC
3 300 MHz) 5 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.45 (mn, 4H), 1.6 (mi, 2H), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br in, 2H), 3.5 (br m, 4H), 3.80 (br in, 2H), 3.82 3H), 4.30 (br s, 1 5.95 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 H), 6.85 2H, J=8Hz), 7.04 1 H, J=1 Hz), 7.40 2H, J=8Hz). MS (D01/NH 3 nile 511 HRMS calcd for C29H 38
N
2 0 6 511.2808. Found: 511.2809 trans. trans-2-(4-Methioxyphenyj):4.(.3-be zdoo-y) -[2(-rplN ethoxyca-rbonylamino)ethyl11pyrroldine3-carhxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for inethylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (00013, 300 MHz) 5 0.80 3H,J=8Hz), 1.05 (mn, 2H), 1.22 (in, 3H), 1.45 (mn, 3H), 2.08 (br s, 1 2.75 (in, 1 2.88 (br q, 2H, J=8Hz), 3.08 (br mn, 2H), 3.27 (br mn, 2H), 3.44 (in, 1 3:~54 (dt, 1 H, J=1 ,8Hz), 3.63 1 H, J=8Hz), 3.78 3H), 4.02 (br d, 2H), 5.93 2H), 6.72 1 H, J=8Hz), 6.81 (dd, 1 H, -j~1,8Hz), 6.85 2H, J=8Hz), 7.00 1 7.30 2H, J=8Hz).
MS
-140-
(DCI/NH
3 m/e 499 Anal calcd for C 27
H
34
N
2 0 7 0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.
Example 100 transtrans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-vyl-1 -[2-(N-methyl-N-(2ethvlbutvryl)amino)ethyllovrrolidine-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 UIL), 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 N H 3 P0 4 and brine, dried with Na 2
SO
4 and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61C. The crude product was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 2H), 1.25-1.75 (m, 2.16 1 2.32 1 2.45 1H), 2.70 1 2.86, 2.94 total 3H), 2.95 1 3.35 1 3.52 2H), 3.65 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 1 6.84 3H), 6.97 1H), 7.30 2H). MS
(DCI/NH
3 m/e 497 Anal calcd for C2 8
H
36
N
2 0 6 0.25 H 2 0: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.
Example 101 trans.trans-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yl)-1-[2-(N-methyl-N-(2provylvalervylaminoethvlvpyrrolidine-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 iC1l8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.
1 H NMR (CDC3, 300 MHz) 5 0.79 3H, J=8Hz), 0.82 3H, J=8Hz), 1.10 (m, 4H); 1.2-1.5 4H), 2.55 1H), 2.96 3H), 3.15 (br m, 1H), 3.32 (br m, 1H), -141- 3.56 (in, 2H), 3.68 (in, 1 H) 3.68 3H), 3.70 (in, 1 3.80 (in, 2H), 4.65 (br d, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.05 (s, 1 7.42 2H, J=8Hz). MS (DOI/NH 3 mle 525 Anal calcd for 030H 40
N
2 0 6 -1.25 TFA: C, 58.51; H, 6.23; N, 4.20. Found: C, 58.52; H, 6.28; N, 4.33.
trans.trans-2-(4.Methoxyphenyl-4-(l.3-benodrioxol-5-y)-1 -42-(N-propyl-N- (tert-butyloxycarbonylmethyl~ami no)ethyllDyrrolidinQ-3-rcarhoxylic aid The title compound was prepared by the methods described in Example 6 1, but substituting propylamine for methylamine in Example 61iB and t-butyl bromoacetate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (00013, 300 MHz) 8 0.82 3H, J=8Hz), 1. 18 (in, 2H), 1. 19 (s, 9H), 2.12 (in, 1 2.46 (in, 2H), 2.70 (in, 3H), 2.85 (in, 2H), 3.20 2H), 3.40 (dd, 1 H, J=2,8Hz), 3.50 (dt, 1 H, J=2,8Hz), 3.62 1 H, J=8Hz), 3.78 3H), 5.95 2H), 6.72 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.05 1 7.16 2H, J=8Hz). MS (DCIINH 3 m/e 541 Anal calcd for C30H 4 oN 2 0 7 1.-0 H 2 0: C, 64.50; H, 7.58; N, 5.0 1. Found: 0, 64.75; H, 7.35; N, 4.86.
traps. trans- 2-(4-Methoyyphenyl).4.(.3-be nzodioxol--yl)X-1 -12-(N-p2ropyl-N-(n- Propvlaminocar onylmethyl~amingjethylllpyrrolidi-n-e.3..arboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 610C. The crude product was purified by preparative HPLC (Vydac p.018) eluting with a 10-70% gradient of CH 3 ON in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (00013, 300 MHz) 860.78 3H, J=8Hz), 0.88 3H, J=8Hz), 1.45 (in, 2H), 1.48 (in, 3H, J=8Hz), 2.55-2.7 (in, 2H), 2.90 (in, 1 3.04 (in, 1 3.15 (in, 3H), 3.28 1 H, J=8Hz), 3.45 1 H, J=8Hz), 3.60 (in, 2H), 3.70 2H, J=8Hz), 3.75 (mn, 1 3.80 3H), 4.25 1 H, J=8Hz), -142- 5.95 2H), 6.75(d, 1 H, J=8Hz), 6.86 (dt, 1 H, J=1 ,8Hz), 6.88 2H, J=8Hz), 7.04 1 H, J=1 Hz), 7.40 2H, J=8Hz). MS (DCl/NH 3 m/e 526 Anal calcd for 029H 39
N
3 0 6 1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.
trans. transq-2-(4-Methoxyphenyl)-4(1 .3-bn 'doxol-5-lj..1-[2-tN-prpv--(.
methoxvphenoxcaroylaino~ethylyrroli-zdexblacid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 618 and 4methoxyphenylchloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (CD 3 OD, 300 MHz) mixture of rotamers 8 0.88 1.57 (in, 2H), 2.45 (br s) and 2.60 (br s, total of 1 2.90-3.15 (in, 4H), 3.4-2-3.7 (in, 5H), 3.78 3H), 3.80 3H), 3.85 (in) and 4.0 (in, total of 1 5.95 and 5.98 total of 2H), 6.63(mn, 1 6.72 1 H, J=8Hz), 6.81 (in, 2H), 6.93 (in, 5H), 7.40 (in, 2H). MS (DCI/NH 3 m/e 577 Anal calcd for C32H 36
N
2 0 8 1.0 H-20: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N,.
4.63.
Exampnle trans, trans-2-(4-Methoxyghenyll.4.( ezdol5yg.% 4[2(Np^nylN-..
methoxyben zoyl)am in2)ethylln-yrrolidi ne-3-carboxylc aid The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in
CH
3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (00013, 300 MHz) mixture of rotamers 8 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1.52 J=8Hz) total of 2H, 2.25 (br s, 1 2.78 (br s, 1 2.90 (br t, 2H), 3.12-3.68 (mn, 7H), 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 1 H, J=8Hz), 6.83 (mn, 5H), 6.94 (in, 1 7.22 (in, 4H). MS (FAB) m/e 561 -143- Anal calcd for C3 2
H
36
N
2 0 7 -0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6:38; N, 4.59.
-E a ll 0 trans, trans-2-(4-Methoxyphenyli.4-(1 .3-benzodioxol-5-yvi- -[2-(N-p-ropvl-Nbenzoylam.ino)ethylprrolidine.3.carboxylic aid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and benzoyl chloride for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and lyophilizeci to give the product as a white solid. 1 H NMR (ODC1 3 300 MHz) mixture of rotamers 8 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (in, total of 1 2.6 -3.6 (in, 8H), 5.92 (s, 2H), 6.70(d, 1 H, J=8Hz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH 3 m/e 531 Anal calcd for C31H 34
N
2
O
6 0.3 H 2 0: 0, 69.46; H, 6.51; N, 5.23.
Found: C, 69.48; H, 6.19; N, 4.84.
Examle 107 trans, trans-2-(4-Methoxyphenyl)-4(1 .3-bnodixl--l).1 -[2-(N-p2ropyl-Nben zyloxycarbo nyljaini no)ethyl~yrro lidi-ne-3-carboxvlic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for inethylainine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 610C. The crude product was purified by preparative HPLC (Vydac AC18) eluting with a 10-70% gradient of
CH
3 CN in 0.1 TFA. The desired fractions were lyophilized to give the product as a white solid. 1 NMR (ODC1 3 300 MHz) 5 0.8 (in, 3H) 1.45 (mn, 2H), 2.20 (br m, 1 2.75 (in, 1 2.93 (in, 1 3.15 (in, 2H), 3.32 (in, 3H), 3.52 (in, 2H), 3.66 (in, 1 3.78 3H), 5.00 (in, 2H), 5.94 2H), 6.72(d, 1 H, J=8Hz), 6.82 (in, 3H), 7.0 (br d, 1 H, J= 15Hz), 7.2 4H), 7.30 (in, 3H). MS (FAB) m/e 561 Anal calcd for C3 2 H3 6
N
2
O
7 1.0 TFA: C, 60.53; H, 5.53; N, 4.15.
Found: C, 60.66; H, 5.34; N, 4.28.
-144trans. trans-2-(4-Methoxyp~henv)1:4.( 1 .3-benzodioxol-5-y).1j-2-(-N-prop2yl-N-(4.
methoxyb2enzyloxycarhonyl~aminoQ)ethyllpvrrolidn aboy.ai The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61 B and 4methoxybenzyl chioroformate for isobutyryl chloride in Example 610.
]=-ampJe 109 trans, trans-2-(4-Methoxyphenyl-).4(1.-enzodixol-5-ly. 1 -r2-(N-butyl-Nethoxycarbon- lam in o)ethylllpyrr li di ne-3.caprhxylic acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac p.018) eluting with a 10-70% gradient of
CH
3 CN in 0.1 TEA. The desired fractions were lyophilized to give the product as a white solid. 'H NMR (CDC1 3 300 MHz) 5 0.82 3H, J=8Hz), 1.20 (in, 1.34 (in, 2H), 3.08 (in, 2H), 3.17 (in, 2H), 3.52 (in, 2H), 3.75 (in, 2H), 3.78 (s, 3H), 4.06 2H, J=8Hz), 4.35 (br s, 1 5.94 2H), 6.76 1 H, J=8Hz), 6.92 2H, J=8Hz), 7.03 (br s, 1 7.17 (br s, 1 7.7 (br s, 2H). MS (FAB) m/e 513 Anal calcd for C28H3 6
N
2
O
7 0.5 TEA: C, 61.15; H, 6.46; N, 4.92.
Found: C, 60.99; H, 6.80; N, 4.93.
trans, trans-2-(4-MethoDxyphenyl-4- (1 .3-benodiixol5yl.. [2-(N-butyl-Np2ro2 Dxycarbony amino)-ethylpyrrolidine3carboxyjic acid The title compound was prepared by the methods described in Example 61, but substituting butylainine for inethylamine in Example 61 B and propyl chloroformate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 NMR (ODC1 3 300 MHz) 8 0.80 (br s, 1 0.85 3H, J=8Hz), 0.92 (br s, 1 1.22 (in, 3H), 1.40 (mn, 3H), 1.62 (br in, 1 2.15 (br s, 1 2.72 1 H), 2.87 (in, I1H), 3.1-3.45 (mn, 5H), 3.55 (in, 1 3.64 1 H, J=8Hz), 3.79 3H), 3.88 (br s, 1 3.97 (br s, 1 5.95 2H), 6.73(d, 1 H, J=8Hz), 6.85 (mn, 3H, 1 7.30 2H, J=8Hz). MS (FAB) Wne 527 Anal calcd for -145- C29H 38
N
2 0 7 -0.15
H
2 0: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.21.
tr ns~ran..24.. ethxyphenyl) 4 3-benZnodioxol-5y V (N ro yl.N Pro)QoXYca;rbonylamino)ethylIlpYrrl[iine- 3 crbohic aid 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 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (OD1 3 300 MHz) 6 0.80 3H, J=8Hz), 093 (in, 3H), 1.43 (mn, 3H), 1.62 (in, 1 2.15 (br s, 1 2.68-3.45 (in, 8H), 3.54 (mn, 1 3.66 (in, 1 H), 3.78 3H), 3.94 (in, 2H), 5.94 2H), 6.72 I1H, J=8Hz), 6.82 (in, I1H), 6.84 2H, J=8Hz), 7.00 (br s, 1 7.33 (in, 2H). MS (DCI/NH 3 m/e 513 Anal calcd for C2 8 H1 36
N
2 0 7 -0.15
H
2 0: C, 65.26; H, 7.10; N, 5.44. Found:
C,
65.22; H, 6.74; N, 5.06.
trn.tas- (..i-nbutyl i eoaboy~thl 2 4 di vl)12yrrolidi ne-3-carb 22lic cUid Ethyl (3,4 m t l eixb zy)aeae prepared by the method of Krapcho et al, Org. Syn. A.Z, 20 (1967) starting with 3,4mehlndoyaeohnn instead of 4 -inethoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. in.p. 58-60 OC. 1 H NMR (00013, 300 MHz) 5 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (in, 6H), 2.80 J=l3Hz, 1 H), 2.94-3.12 (mn, 4H), 3.28-3.50 (in, 4H), 3.58-3.62 (in, I1H), 3.78 J=9Hz, 1 H), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (mn, 2H), 6.92 J=1 Hz, 1 H), 7.01 H=1 Hz, 1 MS (DC1/NH 3 Wne 525 ExaMAW. 113 1-Q -146trans.trans1 2 -(N-(n-Butyl)-N-ropyslslfovlmino)ethvh-2f 4 methoxyphenyfl-4-(i 3 -benzodi l5 Ylprrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 OC. IH NMR (CDC1 3 300 MHz) 5 0.83 (t, J=7Hz, 3H), 0.98 J=7Hz, 3H), 1.12-1.25 (in, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2H), 2.72-3.32 (in, 8H), 3.43 (dd, J=9Hz, 3Hz, 1 3.53-3.59 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.95 2H), 6.73 (d, J=8Hz, 1 6.83 (dd, J=8Hz, 1 Hz, 1 6.88 J=9Hz, 2H), 7.02 J=1 Hz, 1 7.33 J=9Hz, 2H). MS (DCI/NH 3 m/e 547 trans.trpns-1 -(N.N-Di(nbutylamnocarbonylinetyI-2(4methxwyhl) 4 (1 3 -benzdixo ,,.nyrolidine-.3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. in.p. 74-76 0 C. 'H NMR (ODC1 3 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8 Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=1l2Hz, 1 2.95-3.09 (mn, 4H), 3.26-3.59 (in, 3.75 J=9Hz, 1 3.79 3H), 4.28 4H), 6.78 J=9Hz, 1 6.85 (d, J=9Hz, 2H), 6.91 J=3Hz, 9Hz, 1 6.98 J=3Hz, 1 7.32 J=9Hz, 2H). MS (DCI/NH 3 m/e 525 trans,. trans-i -(-NPoy--2oysfoyaioehU24mtoy~ey) 4-(1 3 -benzodioxol-5-ylpyrrolidinre-3carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 72-73 00. 1 H NMR (ODC1 3 300 MHz) 8 0.79 (t, J=8Hz, 3H), 0.98 J=8Hz, 3H), 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (in, 1 2.69-3.32 (in, 9H), 3.42 (dd, J=3Hz, 12Hz, 1 3.52- 3.58 (in, 1 3.64 J=1 2Hz, 1 3.80 3H), 5.95 2H), 6.73 J=1 1 Hz, 1 6.83 (dd, J=1 Hz, 11 Hz, 1 6.87 J=1 1 Hz, 2H), 7.0 J=2Hz, 1 7.32 J=1 1 Hz, 2H). MS (DCI/NH 3 m/e 533 Examl2le 116 -147trans. trans- 1 -(-NB~lNbuysloyaio~tvL2(-ehxaMyo-4 (1 3 -benz-odioxol-5-yl~yrrolidine-3-carboxlc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 00. 1 H NMR (ODC1 3 300 MHz) 5 0.82 (t, J=6Hz, 3H), 0.91 J=6Hz, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33-1.42 (in, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (in, 1 2.70-3.28 (in, 9H), 3.41 J=8Hz, 1 3.52-3.58 (in, 1 3.65 J=8Hz, 1 3.79 3H), 5.95 2H), 6.72 (d, J=8Hz, 1 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.01 1 7.32 (d, J=8Hz, 2H). MS (DCI/NH 3 m/e 561 trans. trpn- 1 (N N-Dnibutylami no carboyl methyD.2z4methoxym -ox hny)(1 3 -benzodioxol-5-flpyrrolidine..3-arboxylic acid 4 -Hydroxyacetophenone was treated with chioromethyl methyl ether and triethylamine in THF at room temperature to give ethyl 4methoxymethoxybenzoylacetate which was treated by the procedures described in Example 1 to afford the title compound as a white solid. m.p. 48- 49 1 H NMR (CDC 3 300 MHz) 5 0.81 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d, J=1l2Hz, 1 2.94-3.10 (in, 4H), 3.25-3.35 (in, 1 3.40 J=1l2Hz, 1 3.43- 3.52 (in, 2H), 3.47 3H), 3.55-3.62 (in, 1 3.77 J=9Hz, 1 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1 6.86 (dd, J=1 Hz, 8Hz, 1 7.0 J=8Hz, 2H), 7.04 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (DCI/NH 3 in/e 541 -Eaml~le-l 1 trans, trans- 1 -(2-(.NUDibUtyaiinocarbonylmety).(..yrxpenvl) 4 (l .3ne-3-carboxyl-ic aid hydrhrieal The compound resulting from Example 116 was treated with concentrated HCl in 1:1 THE-isopropanol to give the title compound as a white solid. in.p. 211-21200C 1 H NMR (CD 3 OD, 300 MHz) 560.90 J=8Hz, 6H), 1. 12-1.27 (in, 6H), 1.36-1.45 (in, 2 3.04 (bs, 1 3.14-3.35 J=9Hz, 1 H), 3.90 (bs, 3H), 4.17 J=1l5Hz, 1 5.96 2H), 6.82-6.93 (in, 4H), 7.03 (d, J=1 Hz, 1 7.42 (bs, 2H). MS (DCIINH 3 Wne 497 -148- Examplei11 trans.trpns-1 -(-NI~uy--rlyslovaioehl--4mtoy~ey) 4-(1 3 -benzodoxol-5-ybyrrolidine-3carbpXylic a-cid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 0C. 1 H NMR (0013, 300 MHz)8~0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1 1.74 (sextet, J=8Hz, 2H), 2.23-2.34 (in, 1 2.68-2.98 (in, 7H), 3.08-3.18 (in, 1 3.26-3.42 (in, 2H), 3.52-3.58 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.90 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.86 J=8Hz, 2H), 6.98 J=1 Hz, 1 7.33 J=8Hz, 2H). MS (001/NH 3 m/e 547 Fxample trpns.trpns-1 2 -(N-Benz7enesulfo ny [.N.:propylanino)ethyl).2( 4 inethoxyphenyl)-4-(1 3 -benzodioxol-5-yl)yroiine.3--carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 00. 1 H NMR (00013, 300 MHz) 8 0.74 (t, J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (mn, 1 2.62-2.72 (mn, 1 H), 2.85-3.05 (in, 4H), 3.12-3.22 (mn, 1 3.38 (dd, J=3Hz, 9Hz, 1 3.49-3.57 (in, 1 3.62 J=9Hz, 1 3. *82 3H), 5.96 2H), 6.73 J=8Hz, 1 6.84 (dd, J=1 Hz, 8Hz, 1 6.85 J=9Hz, 2H), 7.02 J=1 Hz, 1 7.28 J=9Hz, 2H), 7.39-7.54 (mn, 3H), 7.70 J=7Hz, 2H). MS (001/NH 3 m/e 567 Exmple 121 trarls.trpns-l 2 4 -Methoxybenzenesulfonyl)-N-nrpliin~ty)( methoxyphemnyl)-4-(1 3 -benzodioxol-5-yl)pyrrolidine.3carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 96-97 00. 1 H NMR (ODC1 3 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1 2.62-2.71 (in, 1 H), 2.82-3.03 (in, 4H), 3.08-3.18 (mn, 2H), 3.38 (dd, J=3Hz, 9Hz, 1 3.48-3.56 (in, 1 3.62 J=9Hz, 1 3.81 3H), 3.86 3H), 5.95 2H), 6.73 J=8Hz, 1 6.81-6.89 (in, 5H), 7.01 J=1 Hz, I1H), 7.28 J=8Hz, 2H), 7.62 (d, J=8Hz, 2H). MS (DCI/NH 3 in/e 597 *Fxample 12.
-149trans. trans- 1 N- D in-buty1) ami nocarbo nylImethyl) -2(2-Methoxth x-4.
methoxyphenyl)-4-(1 .3-benzodoxol-5-yI)pyrrolidine-3-carboxylic -acid was treated with sodium hydride and bromoethyl methyl ether in THF at 70 00 to provide ethyl 2m eth oxyet hoxy-4- meth oxybe nzoyl acetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. m.p. 63- 0C. 1 H NMR (00013, 300 MHz) 5 0.84 J=7Hz, 3H). 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (in, 3H), 3.26-3.36 (in, 2H), 3.43 3H), 3.47-3.54 (in, 3H), 3.66-3.72 (in, 2H), 3.78 3H), 3.76-3.84 (in, 1 4.02-4.10 (in, 2H), 4.25 (d, J=9Hz, 1 5.92 2H), 6.40 J=2Hz, 1 6.52 (dd, J=2Hz, 9Hz, 1 6.70 J=8Hz, 1 6.83 (dd, J=1 Hz, 8Hz, 1 5.98 J=2Hz, 1 7.53 J=9Hz, 1 MS (D01/NH 3 m/e 585 Examole 12, trpns~trpns-1 -(2-(N-Propyl-N-(24-diiethylbenzenesulfonyl)amin)ethyl2-(4methoxyphieny)-4-(1 3-benzodioxol-5-vI)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 00. I H NMR (00013, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1 2.32 3H), 2.47 (s, 3H), 2.62-2.69 (in, 1 2.78 J=9 Hz, 1 2.89 (dd, J=8Hz, 1 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (in, 1 3.60 J=9Hz, 1 3.82 (s, 3H), 5.96 2H), 6.72 J=7Hz, 1 6.80 (dd, J=1 Hz, 9Hz, 1 6.86 (d, J=9Hz, 2H), 6.97 J=1 Hz, 1 7.03 (bs, 2H), 7.29 J=9Hz, 1 MS (001/NH 3 m/e 595 Example 24 trans, trans-il ropyl-N- (3-chloroprorpylsulfonyl)amino)ethyl)-2-(4.
methoxyph enyl)-4-(1 3-benzodioxol-5-y)pyrrolidine-3- carboxylic acd Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 I1 NMR (00013, 300' MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (mn, 3H), 2.70-2.80 (in, 1 H), 2.85-3.10 (in, 6H), 3.23-3.31 (in, 2H), 3.43 (bd, J=9Hz, 1 3.55-3.66 (in, 4H), -150- 3.81 3H), 5.94 2H), 6.73 J=8Hz, 1 6.82 (d J=8Hz, 1 6.86 (d, J=8Hz, 2H), 7.00 1 7.33 J=8Hz, 2H). MS (DCI/NH 3 m/e 567 trans.trpns-1 -(2-(N-PoyN-2 ul niol+1 methoxyphnl.( 3 bnoioo5yyrrolidine3.cpbxi aci Using the procedures described in Example 66, trans, trans- 1 P ropy-N (vi nylsuo nyl)am in o)ethyl)2(4ethoxyh y) 4 -(l,3-be nzodi oxolI- 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 1 H NMR (ODC1 3 300 MHz) 850.78 J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (in, 1 2.72-2.79 (in, 1 2.86-3.05 (in, 4H), 3.10-3.27 (in, 4H), 3.32 3H), 3.43 (dd, J=3Hz, 9Hz, 1 3.53-3.58 (in, 1 H), 3.65 J=9Hz, 1 3.69 J=6Hz, 2H), 3.80 3H), 5.94 2H), 6.73 (d, J=8Hz, 1 6.82 (dd, J=1 Hz, 8Hz, 1 6.87 J=8 Hz, 2H), 7.02 J=1 Hz, 1 7.33 J=.8Hz, 2H). MS (DCI/NH 3 m/e 549 trans. rans- (N-Propvl-N-(2ethoxyethylulonIamino)ethyh) 2 4 methoxyphenyl-4.(1 3 -ezdooh5ylyr die.coYlai Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 58-60 00. 1 H NMR (ODC1 3 300 MHz) 8 0.78 (t, J=7Hz, 3H), 1.18 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24-2.33 (in, 1 H), 2.70-2.80 (in, 1 2.87-3.05 (in, 4H), 3.13-3.20 (in, 2H), 3.22-3.32 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 3.46 J=7Hz, 2H), 3.52-3.58 (in, 1 3.65 (d J=9Hz, 1 3.72 J=6Hz, 2H), 3.80 3H), 5.95 2H), 6.73 J=7Hz, 1 6.83 (dd, J=1 Hz, 7Hz, 1 6.87 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H).
MS (DCI/NH 3 m/e 563 -151- Exmple 127 trans-trpns-1 naphthylsulfonl)aminoethyl2(4methoxyphenyl-4-(1 yl~pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. m.p. 102-104 OC. 1 H NMR (CDC1 3 300 MHz) 8 0.62 J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1 2.78 J=9Hz, 1 2.88 6H), 2.72-2.89 (in, 1 3.05-3.12 (in, 2H), 3.26-3.45 (in, 3H), 3.45- 3.52 (mn, 1 3.58 J=9Hz, 1 6.97 J=1 Hz, 1 7.13 J=7Hz, 1 7.26 J=8Hz, 1 7.42-7.50 (mn, 2H), 8.08 (dd, J=1 Hz, 7Hz, 1 8.20 J=8Hz, 1 8.48 J=8Hz, 1 MS (DCI/NH 3 m/e 660 Exmlk2a2 trans. trpns-1 2 Pro yl-N-(ethyLsulfonyIamnino~ethy2(4-meth-oxyphenyI 3 -benzodioxol-5-Yfl.pyrrolidine-3ca boxyIc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 1 H NMVR (ODC1 3 300 MHz) 8 0.79 (t, J=8Hz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 (in, 1 2.71- 2.80 (in, 1 2.82-3.10 (in, 6H), 3.18-3.32 (mn, 2H), 3.43 (dd, J=3Hz, 9Hz, 1 H), 3.53-3.60 (in, 1 3.65 J=9Hz, 1 3.80 3H), 5.96 2H), 6.73 (d, J=7Hz, 1 6.82 (dd, J=1 Hz, 7Hz, 1 6.88 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 519 Example 29 trans.trpns-1 2 Propyl-N-(4- met hylbenze nesu lfonyjainp~ethyl).2-(4methoxyphenyl)-4-(1 3 -benZodioxol-5-yl~pyrrlidine-3cgaboxy&Q acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 1 H NMR (ODC1 3 300 MHz) 8 0.73 (t, J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (mn, 1 2.40 3H), 2.61-2.72 (mn, 1 2.83-3.05 (in, 4H), 3.08-3.19 3.48 (dd, J=3Hz, 9Hz, 1 3.49- 3.57 (in, 1 3.62 J=9Hz, 1 3.81 3H), 5.95 2H), 6.73 J=8Hz, 1 H), -152- 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.00 1 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Hz, 2H). MS (DCI/NH 3 m/e 581 trarls.trans-1 N-Di(nbutyaminocar oymtv)(.l 3 benzodiioxols5yl)pyrrolidine-3-crhxy acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures described in Example i to provide the title compound as a white solid. m.p. 167-1 68 00. 1 H NMR (COCl 3 300 MHz) 5 0.82 J-7Hz, 3H), 0.89 J=7Hz, 3H), 1.14 (sextet, J=7Hz, 2H), 1.23-1.48 (in, 6H), 2.86-3.20 (in, 6H), 3.34-3.43 (in, 2H), 3.57 (dd, J=3Hz, 9Hz, 1 3.75-3.83 (in, 1 4.08 J=9Hz, 1 5.93 2H), 6.73 J=8Hz, 1 6.90 (dd, J=2Hz, 8Hz, 1 7.03 J=2Hz, 1 7.38 (dd, J=4Hz, 8Hz, 1 8.04 J=8Hz, 1 8.48 (dd, J=2Hz, 4Hz, 2H).
MS
(DCI/N
H
3 m/e 482 trans trp 5 s- -K-nh~% methoxyohenyl)-4(1 3 benodioxol.s..ynpyrroidine.3:cprboxlca d Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 1 H NMR (00013, 300 MHz) 5 0.78 (t, J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.31-1.46 (in, 4H), 1.68 (quintet, J=7Hz, 2H), 2.21-2.32 (in, 1 2.70-3.08 (in, 7H), 3.12-3.23 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1 3.52-3.58 (in, 1 3.64 J=9Hz, 1 3.80 3H), 5.96 2H), 6.72 (d, J=7Hz, 1 6.83 (dd, J=1 Hz, 7Hz, 1 6.86 J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (D01/NH 3 m/e 547 FxapjQ_=~ tran s. trans-i 2 N -P lN~4hlorobenze7 s )fnfamin2)ethYD).2.(4 methoxyphenYl)-4..(.3 -benodioxol- 5Yl) p2yrro lid ne3carboxy acidl Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106'OC. 1 H NMR
(C~DC
3 300 MHz) 8 0.72 J=7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (in, I1H), 2.78-2.86 (in, 1 2.96-3.03 (mn, 3H), 3.13-3.26 (in, 3H), 3.51 (dd, J=5Hz, 9Hz, 1 3.62-3.68 -153- (in, 1 3.80 3H), 3.94 J=9Hz, 1 5.92 2H), 6.75 J=8Hz, 1 6.84 (dd, J=2Hz, 8Hz, 1 6.94 J=8Hz, 2H), 6.98 J=2Hz, 1 7.36 J=8Hz, 1 7.49 J=8Hz, 1 7.68 J=8Hz, 1 MVS (DCI/NH 3 m/e 601 Examl~l 3 trpns.trpns-1 2 -(N-Propyl-N-(henzylsulfonyl)amino)ethyl)2(4methoxyphenyl)-4.(1 3 -benzodioxol-5-yl)p2y-rrodine..3:cprboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 00. 1 H NMR (ODC1 3 300 MHz) 5 0.72 (t, J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (in, 1 2.56-2.67 (in, 1 H), 2.75-3.10 (mn, 6H), 3.30 (dd, J=2Hz, 9Hz, 1 5.95 2H), 6.73 J=7Hz, 1 H), 6.80 (dd, J=1 Hz, 7Hz, 1 6.86 J=8Hz, 2H), 6.97 J=1 Hz, 1 7.27-7.35 (in, 7H). MS (DCI/NH 3 in/e 581 Example 14 trans. trans-i 2 Propyl-N-(4-f luo robe nze nesulfo nyl) mino)et hyl)2-( 4 i-ethoxvphenyl)-4-(1 3 -benzodioxol-5-ylnorrolidine-3carboxyli-c acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 00. 1 H NMR (CDd 3 300 MHz)580.73 (t, J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1 2.56-2.67 (in, 1 H), 2.78-2.87 (in, 2H), 2.97 (septet, J=8Hz, 2H), 3.11-3.16 (mn, 2H), 3.33 (dd, J=2Hz, 9Hz, 1 3.43-3.50 (in, 1 3.57 J=9Hz, 1 3.78 3H), 7.08 J=8Hz, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, J=5Hz, 8Hz, 2H). MS (DCI/NH 3 in/e 585 Exmnle 135 trpns.trpns-1 -(N-Methyl-N-1ro~ylaminocarbonymethyl)2q4-methoxypheflyl- 4 (4-benzofuranyl)pyrrolidine-3-carboxylic acid Examje 1 3A Ben zofu ra n-4,-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 inmol, 1.25 eq) in DMF (60 inL) at 0 00 was added a solution of 3-bromophenol (13.8 g, 80 ininol) in DMF (5 inL). After 10 minutes, broinoacetaldehyde diethyl -154acetal (14.9 mL, 96.6 mmol, 1.24 eq) was added, and the resultant mixture then heated at 120 OC for 2.5 hours. The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO 4 filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, b.p. 160-163 °C at 0.4 mm Hg.
To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 mmol) in benzene (50 mL). The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yield a colorless liquid (8.13 g, b.p. 62-72 °C at 0.6 mm Hg.
To a solution of the above compounds (8.11 g, 41.5 mmol) in ether mL) at -78 °C was added 1.7 M t-butyllithium (48.8 mL, 83 mmol, 2 eq) such that the temperature did not exceed -70 OC. After stirring for 15 minutes, a solution of DMF (6.5 mL, 83 mmol, 2 eq) in ether (20 mL) was added, and the mixture allowed to warm to room temperaure over 2 hours. The mixture was poured into water and the phases separated. The organic solution was dried over MgSO 4 and concentated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 g) and benzofuran-4-carboxaldehyde (1.86 both as colorless oils.
Example 135B trans.trans-1 -(N-Methyl-N-proDvlaminocarbonylmethyl)-2-(4-methoxyphenyl)-4 (4-benzofuranyl)pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 135A in Example 49A for piperonal. 1 H NMR (300 MHz, CDC13) (minor rotamer) 6 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, 6.8 (2H, d, J=8Hz), 4.03 (1H, 3.94 (1 H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=11Hz, 3.40-2.90 (5H, 2.82 (2.81) (3H, 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 (M+H) Anal.calc. for -155-
C
26
H
30
N
2 0 5 -AcOH: C, 65.87; H, 6.71; N ,5.49. Found: C, 66.04; H, 6.42; N, 5.60. s Eall 3 trans~trpns-lI Met hyl- N-p ropylam in ocarbonyl met hylU.2.(4-meth2Uyph e n l.
4 (6-benzofuranvl)p2yrrolidine-3-carboxylo- acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal. 1 H NMR (300 MHz, ODC1 3 (minor rotamer) 5 7.65 (1 H, bd), 7.60 (1 H, d, J=2Hz), 7.55 (1 H, d, J=8Hz), 7.35 (3H, in), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1 H, dd, J=3Hz, 2Hz), 3.83 (2H, mn), 3.79 (3H, 3.60-3.0 (7H, mn), 2.91 (2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS (DCIINH 3 in/e 451 Anal.calc. for C2 6
H
3
ON
2 0 5 0.5 H 2 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.
Exml 3 trans. trans-i -(N-Methy-N-o2ropylaminocarbonylnethyl).2(4-miethoxyphenyl).4.
6 -be nzo-2.3-di hyd rof uranyl)pyrro lid in e.3carboxyli c acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H 2 in. AcOH, followed by preparative hplc) of the compound resulting from Example 136 1 H NMR (300 MHz, CDC1 3 (minor rotainer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1 H, d, J=8Hz), 7.00 (1 H, in), 7.82 (3H, in), 5.40 (1 H, dd, J=1 1 Hz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1 H, in), 4.10 (1 H, in), 3.88 (1 H, in), 3.79 (3H, 3.60 (1 H, in), 3.35 (1 H, in), 3.19 (2H, t, J=8Hz), 3.00 (4H, in), 2.91 (2.78) 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DC I/NH 3 m/e 453 Anal.calc. for 026H 32
N
2 0 5 1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: 0, 57.68; H, 5.68; N, 4.70.
-156trans. trans.- -N .N-Dibutylaminocarbonylmethl)-2(4- Ometh eyl- 4 4 ben zof uran yflp yrro lidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-Npropyl bromoacetamide. 1 H NMR (300 MHz, 00013)867.S2 (1 H, d,J=3Hz), 7.39 (1H, dt, J=8Hz, 2Hz), 7.34 (3H,mi), 7.26 (1 H, 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 (1 H, d,J=9Hz) 3.79 (3H, 3.67 (1H, dd, J=lOHz, 3Hz), 3.44 (2H,mi), 3.35-3.15 (3H,mi), 3.00 (2H,mi), 2.84 (1H,d, J=l4Hz), 1.43 (3H,mi), 1.23 (3H,mi), 1.08 (2H,mi), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (001/NH 3 m/e 507(M+H)+.
Anal.calc. for C3 0
H
38
N
2 0 5 0, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.
Example 139 trans. trans-i1 -(N..N-Diutylaiinocarbonyliethyl)2(4methoxyphenyl)- 4 4 ben zofuranyl)p2yrrolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Example 1 35A substituted 4-bromophenol for 3bromophenol, in Example 49A for piperonal and substituting N,N-dibutyl broinoacetainide for N-methyl-N-propyl bromoacetainide. 1 HNMR (300 MHz, ODC1 3 867.64 (1 H, bd), 7.59 (1 H, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=1 1 Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, 3.53 (1 H, dd, J=10OHz, 3Hz), 3.44 (2H, in), 3.30 (1 H, in), 3.20-2.95 (5 H, in), '2.82 (1 H, d, J=1l4Hz), 1.43 (3 H, in), 1.23 (3 H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 507 Anal.calc. for C3 0 H3 8
N
2 0 5 C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 5.29.
Exm~le 140 -157trans. trans-i -(N.N-Dibutylaminocarbonylmethyfl-2-(4..methoxyohen).6ben zofu ran yl)pyrroli'dm ne-3-carbo xylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-methyl-Npropyl bromoacetamide. 1 H NMR (300 MHz, ODC1 3 857.63 (11 H, bd), 7.59 (1 H, d, J=2Hz), 7.53 (1 H, d, J=8Hz), 7.36 (3H, in), 6.85 (2H, d, J=8Hz), 6.73 (1 H, dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=1 1 Hz), 3.89 (1 H, d, J=9Hz) 3.79 (3H, 3.53 (1 H, dd, J=1 0Hz, 3Hz), 3.44 (2H, in), 3.30 (1 H, in), 3.20-2.95 (5H, in), 2.80 (1 H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, MS (DCI/NH 3 m/e 507 AnaI.calc. for C3QH 3 8
N
2 0 5 -0.75 H 2 0: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.
Exa~mpl 4 rpn's. trans- 1 butylaminocarbonvlmethyl).2.(4-methoxyphenyl)-4.(6.
be nzo-? .3-di hydrofuranyl)pyrrolidi ne-3-carboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H 2 in AcOH, followed by preparative hplc). 1 H NMR (300 MHz, ODC1 3 5 7.40 (2H, d, J=8Hz), 7.16 (1 H, d, J=8Hz), 6.97 (1 H, dd, J=8Hz, 2Hz), 6.89 (3H, in), 5.90 (1 H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2H, in), 3.80 (3H, 3.70-3.58 (2H, in), 3.40 (1 H, in), 3.30-2.90 (8H, in), 1.40 (2H, in), 1.29 (3H, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 509 Anal.calc. for C3 0
H
40
N
2 0 5 -0.85 TEA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.
Example 12 trans, trans-il Methy- N-propylamin ocarbo ny methy) 2(4meth oxyp hen yl)-4 (5-indanyl)pyrrolidine-3-carboxylic acid -158- Example 142A I was prepared by formylation of indane under the conditions described for 2,3-dihydrobenzofuran in Example 52A. The resultant mixture of 4- and 5-carboxaldehydes was purified as follows: to a 6:1 mixture of indane-4-carboxaldehyde and indane-5-carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystallized from hot acetonitrile to yield the 5-aldimine as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 h hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether. The organic solution was dried over MgSO 4 filtered, and concentated in vacuo.
Vacuum distillation of the residue afforded indane-5-carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 OC at 0.9 mm Hg.
Example 142B trans.trans-i N -N-orooiaminocarbonvimethyl)-2-(4-methoxvohenvi-4- (5-indanylv)pyrrolidine-3-carboxlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 (minor rotamer) 5 7.25-7.1 (5H, m), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=8Hz), 3.75 (3H, 3.50-2.90 (6H, mn), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 451 473 Anal.calc. for C27H 34
N
2 0 4 2.5 H 2 0: C, 65.44; H, 7.93; N, 5.65. Found:
C,
65.36; H, 7.45; N, 5.53.
Example.143 trans.trans-1 -(N-Methyl-N-Drpylaminoc-rbon -4-methXV2thenvl-4-
I
6 -indolyl)yvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Example 49A. 1H NMR (300 MHz, CDCl 3 (minor rotamer) 8 8.43 (1H, brs), 7.57 (1H, d, -159- J=8Hz), 7.43 (1 H, 7.31 (2H, dd, J=6Hz, 3Hz), 7.22 (1 H, d, J=8Hz), 7.1 (1 H, t, J=3Hz), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1 H, in), 3.93 (1 H, dd, J=6Hz, 3Hz), 3.80 (1 H, in), 3.73 (3H, 3.60-2.90 (6H, in), 2.86 (2.82) (3H, 1.47 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (D01/NH 3 mle 450. Analcalc. for 026H3 1
N
3 0 4 0.75 H 2 0: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.
Example 14 trans. trans--(N-Methy-N-proylaminocarbonlmethyIk2.(4methoxyphenyl-4- (3 .4-difluorophenyl)pvrrolidine-3..carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dif luo robe nzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, 00013) (minor rotainer) 6 7.60-7.3 (4H, in), 7.13 (1 H, q, J=9Hz), 6.90 (2H, d, J=8Hz), 3.90 (1 H, in), 3.79 (3H, 3.60-2.95 (6H, in), 2.92 (2.78) (3H, 1.55 (2H, septet, J=7Hz), 0.88 (0.73) (3H, t, J=7Hz).
MS (D01/NH 3 in/e 447 Anal.calc. for C24H 28
F
2
N
2 0 4 -1.80 H 2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13; H, 6.34; N, 5.84.
Exaple-145 trans. trans-il Met hyl- N-p ropylam inocarbon ymethyI)2.(4m ethoxyp hen yl)- 4 (phenyl)pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A.
1 H NMR (300 MHz, ODC1 3 (minor rotamer) 567.53 (4H, d, J=6Hz), 7.40-7.20 (3H, in), 6.88 (2H, d, J=8Hz), 3.90 (1 H, in), 3.79 (3H, 3.70-2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H, t, J=7Hz). MS (001/NH 3 in/e 411 Anal.calc. for C 24
H
30
N
2 0 4 2.00 H 2 0: C, 64.55; H, 7.67; N, 6.27. Found: 0, 64.37; H, 7.43; N, 6.29.
Exm-J 146 -160trans.trpns-1 -(N-Meth l1N2roylaminocarbonvlmethyl)2( 4 thIQ~bnl 4 -hvdroxyo~henvl)pyrrolidine-3-carboxylic acid.
The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4 -hydroxybenzaldehyde for piperonal in Example 49A. IH NMR (300 MHz, CDCI 3
-CD
3 OD) (minor rotamer) 8 7.35 (2H, d, J=8Hz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89 (2H, d, J=8Hz), 3.81 (3H, 3.65 (1 H, d, J=8Hz), 3.70-3.00 (8H. in), 2.92 (2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz). MS (DCI/NH 3 m/e 427 Anal.calc. for C24H 30
N
2 0 5 -1.00
H
2 0: C, 64.85; H, 7.26; N, 6.30.
Found: C, 64.82; H, 7.39; N, 6.46.
trans. trans- 1 -(NM royaioabnlmty)2 4 h 1 2 4 -diehxpeylprpiie3carboxli acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2 4 -dimethoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3-CD 3 OD) (minor rotamer) 8 7.61 (1 H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=8Hz), 6.55 (1 H, d, J=8Hz), 6.45 (1 H, d, J=3Hz), 3.90 (1 H, in), 3.81 (3H, 3.79 (3H, 3.77.(3H, 3.70-2.90 (8H, in), 2.85 (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.77) (3H, t, J=7Hz).
MS
(DCI/NH
3 m/e 471 Anal.calc. for C26H 34
N
2 0 6 .0.75
H
2 0: C, 64.51; H; 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.
trans- trans-i NDbulainocarbontyl)me(4Tlh.2(4ehhl)- 4 benzo-2.3-dihydrofurny)pyrr di- arb.a d The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2 3 -di hyd robe nzof uran5carboxal de hyde for piperonal in Example 49A. 1 H NMR (300 MHz,
CDCI
3 5 7.31 (2H, d, J=8Hz), 7.27 (1 H, d, J=2Hz), 7.18 (1 H, dd, J=7Hz, 3Hz), 6.86 (2H, d, J=8Hz), 6.72 (1 H, d, J=8Hz), 4.56 (2H, t, J=7Hz), 3.78 (3H, 3.62 (1 H, in), 3.50-3.25 (4H, mn), 3.17 (2H, t, J=7Hz), 3.15-2.90 (5H, in), 2.79 (1 H, d, J=1l41-z), 1.43 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 -161m/e 509 Analcaic. for C30H 4 0'N 2 0 5 -0.25 H 2 0: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.21; H, 7.92; N, 5.36.
EamQle-149 trans. trans-i4 -ibuylminnocaron% ehl2.4.mtoyhnl 4 methoxyohe nyl) pvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4 -methoxybenzaldehyde for piperonal in Example 49A. IH NMR (300 MHz, CDCI 3 8 7.38 (2H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 3.63 (1 H, in), 3.50-3.20 (4H, mn), 3.15-2.90 (5H, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (3H, in), 1.27 (3H, in), 1.09 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 497 AnaI.calc. for C2 9
H
4
ON
2 0 5 C, 70.13; H, 8.12; N, 5.64.
Found: C, 69.78; H, 8.10; N, 5.54.
Exampe trans, trans-ij .N-Dibutylainocarbonylinth)2(4inethoxyphenyl)-44. 4difluorop~henyflprrolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3, 4 -dif luo robe nzalde hyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 87.35 (1H, in), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, in), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1 H, in), 3.62 (1 H, in), 3.50-3.30 (3H, in), 3.23 (1 H, in), 3.15-2.90 (4H, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz).
MS (DCI/NH 3 in/e 503 Anal-calc. for C2 8
H
36
F
2
N
2 0 4 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.
Exm e 151 trans. trans-i1 .N-Dibutylainincarbonylmethyl)2(4-methpxyphenyl)- 4 (24diinetboxyphenylpy-rrolidi ne-3-cabyiccd The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2 ,4-diinethoxybenzaldehyde for piperonal in Example 49A. 1 HNMR (300 MHz, CDCI 3 5 7.37 (2H, d, J=8Hz), 7.20 (1 H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1 H, d, J=3Hz), 6.49 (1 H, dd, J=6Hz, 2Hz), -162- 5.35 (1 H, d, J=8Hz), 4.20 (3H, in), 4.10 (3H, 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, in), 1.07 (4H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 527 Anal.calc. for C30H 42
N
2 0 6 30 TFA: 0, 58.02; H, 6.47; N, 4.15. Found:
C,
57.92; H, 6.43; N, 4.07.
trans. trans- (NNDibu aiocroyethy)2henl 4 -(l.3-be17ndioxol.
The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B. 1 H NMR (300 MHz, COCl 3 5 7.50-7.25 (5H, in), 7.04 (1 H, d, J=3Hz), 6.87 (1 H, dd, J=7Hz, 3Hz), 6.74 (1 H, d, J=8Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.85 (1 H, d, J=8Hz), 3.64 (1 H, in), 3.42 (3H, in), 3.27 (2H, in), 3.20-2.90 (5H, in); 2.81 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (D01/NH 3 in/e 481 Anal.calc. for C28H 36
N
2 0 5 C, 69.98; H, 7.55; N, 5.83. Found: 0, 69.69; H, 7.63; N, 5.71.
trans. trans-1 -t(NNrib) yamnoarbonyiethy)2henl 4 (Sb di hdrofurany yrliie.crboXyUicai The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3for piperonal in Example 49A. 1 NMR (300 MHz, CD013) 57.53 (2H, in), 7.40 (4H, in), 7.13 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=BHz), 5.40 (1 H, d, J=1lOHz), 4.56 (2H, t, J=8Hz), 4.18 (1 H, d, J=1 4Hz), 4.07 (2H, in), 3.79 (2H, in), 3.48 (1H, d, J=l4Hz), 3.35 (1H, in), 3.28 (3H, in), 2.95 (2H, in), 1.47 (2H, in), 1.28 (4H, in), 1.10 (2H, in), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 479 Anal.calc. for C29H 38
N
2 0 4 1.10 TFA: 0, 62.04; H, 6.52; N, 4.64. Found: 0, 61.89; H, 6.44; N, 4.57.
-163trans. trans-i -(N.N-Dibujtylaminocarbonylmethyl).2(4tutylphenyl)(5 benzo-2 3 -dihydrofu-ranyl)Dyrrolidine.3..crboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47:20 (1967) starting from 4 -t-butylacetophenone, in Example 49B and 2,3-di hyd robe nzof uran-5-carboxaldehyde for piperonal in Example 49A. IH NMR (300 MHz, ODC1 3 8 7.60-7.30 (6H, in), 6.90 (1 H, mn), 4.50 (2H, in), 3.95 (1 H, in), 3.85-2.95 (11 H, in), 2.90 (1 H, d, J=1l4Hz), 1-.58 (2H, in), 1.50 (7H, in), 1.41 (6H, 1. 10 (2H, mn), 1.00 (3H, t, J=7Hz), 0.90 (3 H, t, J=7Hz). MS (DCI/NH 3 m/e 535 Anal.calc. for C33H 46
N
2
O
4 -0.25
H
2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.
trans trans 2 (N.N-Dibutyl in abnocarboyl--n-ethn~xyphe nyl)(L4 fluoophnylpyrolidine.3-carboxylic acid The title compound was prepared by the procedures desciibed in Examples 1 and 49 substituting 4-f luo robe nzalde hyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 5 7.50 (1 H, in), 7.42 (1 H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1 H, d, J=8Hz), 3.83 (1 H, in), 3.8 (3H, 3.67 (1 H, in), 3.47 (3H, in), 3.30-2.90 (5H, in), 2.82 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.28 (4H, in), 1.08 (2H, in), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 485 Anal.calc. for C28H3 7
FN
2 0 4
C,
69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.
trans~trans-1-(N .N-Dibutylaiinocarbonyliethyl2(3.fucl) 4 .3-benzodioxol- .ne-3-carbo-xyjic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting f0-oxo-3-furanpropionate in Example 49B. 1H NMR (300 MHz, CDC1 3 5 7.41 (2H, in), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8Hz), 6.42 (1 H, 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, in), 3.70-3.25 (5H, in), 3.20-2.90 (4H, in), 2.85 (1 H, d, J=l 4Hz), 1.43 (2H, in), 1.40-1.05 (6H, in), 0.90 (6H, in). MS (DCI/NH 3 in/e 471 -164- Anal.calc. for 0 2 6H 34
N
2 0 6 C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.57.
benzodioxol-5-yl)p2yrrolidine.3cprboxylic -acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 498. 1H NMR (300 MHz, ODC1 3 5 6.85 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=6Hz, 2Hz), 6.71 (1 H, d, J=8Hz), 5.92 (2H, 3.75 (1 H, d, J=1l4Hz), 3.66 (1 H, q, J=7Hz), 3.42 (3H, in), 3.25 (3H, in), 3.11 2.83 (1 H, t, J=7Hz), 1.88 (1 H, in), 1.55 (4H, in), 1.32 (4H, in), 0.92 (12H, in). MS (001/NH 3 m/e 447 Anal.calc. for 38
N
2 0 5 .50 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: 0, 66.07; H, 8.10; N, 6.03.
rantpns-1 -(N.,tN-Dib2Utyaioaroyethyl) -,(4+butylp~henvl)- 4 be nzodioxol-5-yl) pyrrolidine-3-carboxylip add The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4-tbutylacetophenone), in Example 49B. I 1 H NMR (300 MHz, 00013) 8 7.32 (4H, d, J=3Hz), 7.04 (1 H, d, J=2Hz), 6.87 (1 H, dd, J=8Hz, 3Hz), 6.74 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 J=4Hz), 3.77 (1 H, d, J=1l4Hz), 3.65-3.25 in), 3.15-2.85 (4H, in), 2.73 (1 H, d, J=1l4Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, in), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS (001/NH 3 m/e 537 Anal.calc. for C 32 H44N 2
O
5 C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.
Example159 -165trans trans-1 -(N.N-Dibutvlaminocarbonvlmethvl-2-f4-t-butvlphenvly-4-(5benzo-2.3-dihvdrofuranvl)pyrrolidine-3-carboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2 ,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC13) 8 7.30 (1H, 7.13 (1H, dd, J=7Hz, 2Hz), 6.82 (1H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, 3.19 (3H, 3.80 (3H, 3.48 (2H, 3.3 (5H, 2.41 (1H, 1.65 (4H, 1.44 (4H, 1.21 (3H, d, 1.17 (3H, d, J=5Hz), 1.05 (6H, MS (DCI/NH 3 m/e 445 (M+H) Anal.calc.
for C26H 40
N
2 0 4 1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.
Example 160 trans.trans-1 -(N.N-Dibutylaminocarbonvlmethyl)-2-(anti-4-methoxvcyclohexyvl- 4-(1.3-benzodioxol-5-vl)pyrrolidine-3-carboxylic acid Example 160A syn and anti Ethyl 4-methoxvcyclohexanovlacetate 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 mL) for 6 hours at 50 oC. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature. The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with 20% ethyl acetate in hexanes.
Pure fractions of the syn and anti methoxycyclohexyl P-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycyclohexyl p-keto ester (914 mg) as a colorless oil and the cis 4 -methoxycyclohexyl p keto ester (1.07 g) as a colorless oil.
-166trans, trans- 1 N p bUtylai nocarbo nyl met hyl2.(nti4met hxycyc h y) 4-(1 3 -benzodioxol-5-y)pyrrolidne.3--carboxylic-acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the anti-compound resulting from Example 1 60A in Example 49B. 1 HNMR (300 MHz, CDC1 3 8 6.84 (1 H, d, J=2Hz), 6.76 (1 H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, 3.69 (2H, in), 3.50-3.27 mn), 3.26 (3H, 3.25-3.00 (3H, in), 2.88 (1 H, in), 1.95 (2H, in), 1.62 (7H, in), 1.33 (9H, in), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MS (DC I/NH 3 m/e 517 AnaI.calc. for C29H44N 2
O
6 0.50 H 2 0: C, 66.26; H, 8.63; N, 5.33.
Found: C, 66.27; H, 8.50; N, 5.13.
Pxample 16 1 trpns.trpns-1j .N-Dibt ylaminocar ony-lmethy)2(syn4methP~xycyclhea- 4-(1 3 -benzdioxp-5-yXiyrrolidine.3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 1 60A i n Example 49B. 1 H NMR (300 MHz, ODC1 3 8 6.84 (1 H, d, J=2Hz), 6.77 (1 H, dd, J=6Hz, 2Hz), 6.61 (1 H, d, J=8Hz), 5.92 (2H, 3.65 (2H, in), 3.42 (2H, in), 3.32 (3H, 3.30-3.00 (6H, mn), 2.82 (1 H, in), 2.10 (2H, in), 1.83 (2H, in), 1.52 (6H, in), 1.33 (4H, in), 1.20-1.00 (4H, in), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCI/NH 3 in/e 517 Anal-calc. for C29H44N 2 0 6 -0.30
H
2 0: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.
-Exam~le-12 trans. trans-i -(N.N-Dibutylaminocarbonyiethyl)24d5benzo 2 3 di hydrofuranyI)p2yrrolidine-3..carboxylic idl 5-Acetyl-2 3-ihyd robenzofurp-n -167- To a 0 °C solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5 The solution was stirred 15 minutes at 0 and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8 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 trans. trans- -(N.N-Dibutvlaminocarbonvlmethyl)-2.4-di(5-benzo-2.3dihydrofuranyl)ovrrolidine-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, CDCI 3 5 7.43 (1H, 7.38 (1H, 7.06 (2H, 6.75 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1 H, d, J=9Hz), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=14Hz), 4.09 (2H, 3.82 (2H, 3.57 (1H, d, J=14Hz), 3.38 (1 H, 3.30-3.05 (6H, 2.95 (2H, q, J=6Hz), 1.50 (2H, 1.30 (4H, m), 1.15 (2H, 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 521 Anal.calc. for C31H 40
N
2 0 5 -1.25 TFA: C, 60.67; H, 6.27; N, 4.22.
Found: C, 60.49; H, 6.18; N, 4.13.
-168trans. trans-i1 .N-Dibutylamiriocarbonylmethy)-2-(3.furYl).4.(5--benz- 2 3 di hvdrof uranyl)pyrro lid ine- 3-ca rbpxy lic ac-id The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl fP-oxo-3-furanpropionate in Example 49B and 2 3 -di hyd robe nzofu ran-5-ca rboxal de hyde for piperonal in Example 49A.
1 H NMR (300 MHz, CDCI 3 867.42 (1 H, in), 7.38 (1 H, in), 7.13 (1 H, 7.16 (1 H, dd, J=7Hz, 3Hz), 6.70 (1 H, d, J=5Hz), 6.41 (1 H, mn), 4.57 (2H, t, J=7Hz), 3.95 (1 H, d, J=8Hz), 3.63 (1 H, mn), 3.55 (1 H, d, J=1 3.50-3.2 '5 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, mn), 2.87 (1 H, d, J=1l4Hz), 1.45 (4H, in), 1.35-1.10 (4H, mn), 0.85 (6H, in). MS (DCI/NH 3 in/e 469 Anal.calc. for C27H3 6
N
2 0 5 0.25 H 2 0: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.
trans. trans-il -(N.N-ibutylaminocarbonylmethyl)y2.(4..inethoxyphenvl).
4 3 fluorop~henyflpyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and.49 substituting 3-fluorobenzenecarboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 6 7.30 (2H, d, J=8Hz), 7.22 (2H, in), 6.91 (1 H, in), 6.86 (2H, d, J=8Hz), 3.79 (1 H, in), 3.78 (3H, 3.68 (1 H, in), 3.55-3.37 (3H, in), 3.29 (1 H, in), 3.15-2.90 (5H, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (2H, in), 1.25 (4H, in), 1.07 (2H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz).
MS (DCI/NH 3 m/e 485 Anal.calc. for C2 8
H
37
FN
2 0 4 0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.
trans. trans-i1 .N-Dibutylaiinocarbonylinethyl)-2.(4-miethoxyphenyl)-4( 3 pyrdyl)pyr-rolidi ne-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperonal in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al., Can. J. Chein. 63: 2354 (1985). 1 HNMR (300 MHz, CDC1 3 5 8.82 (1 H, 8.73 (1 H, bd, J=9 Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (1 H, bdd, J=9 Hz, 3 Hz), -169- 7.38 (2H, d, J=1lOHz), 6.90 (2H, d, J=1lOHz), 4.39 (1 H, d, J=1l2Hz), 3.95 (1 H, i) 3.80 (3H, 3.79 (1 H, in), 3.68 (1 H, d, J=1l8Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, in), 1.31 (4H, in), 1.20 (2H, in), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (001/NH 3 m/e 468 Anal.calc. for C27H 37
N
3 0 4 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.
trans. trans- 1 N-D-iiutylam in ocarbonylmethyl-2-(2-.loohnl.( benzodioxoL.5..yflpyrolidine..3.carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-fluorobenzoylacetate in Example 49B.
1 H NMR (300 MHz, 00013) 6 7.52 (1 H, dt, J=7Hz, 3Hz), 7.25 (1 H, in), 7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H, in), 6.88 (1 H, dd, J=7Hz, 3Hz), 6.73 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 4.25 (1 H, d, J=9Hz), 3.68 (1 H, in), 3.42 (3H, mn), 3,39 (1 H, in), 3.20-2.95 (4H, in), 2.91 (1 H, d, J=1l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz).
MS
(001/NH 3 m/e 499 Anal.calc. for C28H 35
FN
2 0 5 0.25 H 2 0: 0, 66.85; H, 7.11; N, 5.57. Found: 0, 66.51; H, 6.67; N, 5.18.
transg.trpns-1 .N-Dibutylaminocarbonylm-ethyl)-2-(3furpey)(.3 be nzodioxol-5-y 1lpyrrolidi ne-3-croxlcai The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3 -fluorobenzoylacetate in Example 49B.
1 H NMR (300 MHz, 00013) 6 7.38 (1 H, in), 7.18 (1 H, d, J=7Hz), 7.15 (1 H, in), 7.00 (1 H, d, J=2Hz), 6.95 (1 H, in), 6.86 (1 H, dd, J=7Hz, 2Hz), 6.75 (1 H, d, J=8Hz), 5.93 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.94 (1 H, d, J=1 4Hz), 3.63 (1 H, in), 3.42 (3H, in), 3.35-2.95 (5H, in), 2.87 (1 H, d, J=1l4Hz), 1.44 (3H, in), 1.27 (3H, in), 1.10 (2H, in), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz).
MS
(DCI/NH
3 Wne 499 Anal.calc. for C28H3SFN 2 OS: 0, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.
-170trans. trans-1 .N-Dibutylaminophenyfl.2(4..methoxy henyl) 4 benzodoo-5.yflpyrrolidine.3--carboxylic acid 4-Nitro-1 -fluorobenzene, ethyl trans, trans-2- moth oxyphe nyl)4-(1,3 benzodioxol-5-yl).pyrrolidi ne,,3-carboxylate (the compound resulting from Example 6A), and diisopropylethylamine are heated in dioxane to give ethyl trans, trans-2-(4..methoxyphenyl)-4(1 ,3-be nzodioxol-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 NN-dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1 D affords the title compound.
E xmpnteJ1trans. trans-i .N-Dibutylaminyrmidin4yn..2(4-methoxyphtenvl)- 4 be nzodioxo-5-yfl p1yrrolidi ne-3-carboxylic ci 2 -(Dibutylamino)-4-chloropyri midi ne is prepared from 2,4dichloropyrimidine according to the method of Gershon, J. Heterocyclic Chem.
24: 205 (1987) and reacted with ethyl trans, trans-2-(4-methoxyphenyl)-4..(i,3benzodioxol.s-y).pyrrolidine..3.carboxylate (the compound resulting from Example 6A) and diisop roplyethylamine in dioxane with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of Example 1 D to the title compound.
Examples 170-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.
Ex. No. Name 170 trans, trans-2-(4-Methoxyphenyl)-4.(1 ,3-benzodioxol-5-y)-1 (isopropylami nocarbonyl methyl)-pyrrolidi ne-3-carboxylic acid; -171- 171 trans, trans-2-(4-Methoxyphenyl)-4-(1 1 3-benzodioxol-5-yi)- 1- (ethylaminocarbonylmethyl)-pyrrolidine.3carboxylic acid; 172 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo1-5-yl)-l methylpropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 173 trans, trans-2-(4-Methoxyphenyl)4-(1 3-benzodioxoI-5-yI)-1 (phe nylaminocarbonylmethyl)-pyrro Iidine-3-carboxylic acid; 174 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxoI-5-yI)- 1 (pipe ridi nylcarbo nylmethyl)-pyrrolidi ne-3-carboxylic acid; 175 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo 1-5-yI)- 1 (pro pylami no carbo nyl)ethyl) pyrroIi d i ne- 3-carboxy li c acid; 176 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo 1- 5 (propylaminocarbonyl)benzyl)-pyrroidi ne-3-carboxylic acid; 177 trans, trans-2-(4-Methoxyphenyl)-4(1 .3-benzodioxol-5-yI)- 1 (bis- (pro pylami nocarbo nyl) methyl)-pyrrolidine-3-carboxylic acid; 178 trans, trans-2-(4-Methoxyphenyl)-4-(1 7 3-benzodioxol-5-yI)- 1 (pro pylami nocarbo nyI)ethyI)-pyrro lidi ne-3-carboxylic acid; 179 trans, trahs-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxoI-5-yI)- 1 (propylaminosulfonylmethyl)pyrrolidine-3carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo I-5-yI)- 1 phenethyI)-pyrrolidine-3-carboxylic acid; 181 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yl)- 1- (pentanoylmethyI)-pyrroidine3-caroxylic acid; 182 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y)-1 (benzoylmethyl)-pyrrolidi ne-3-carboxylic acid; 183 trans, trans-2-(4-Methoxyphenyl)-4.(1 ,3-benzodioxol-5-yI)- 1 hexyl)pyrrolidine-3-carboxylic acid; 184 trans, trans-2-(4-Methoxyphenyl)-4- (1 ,3-benzodioxoI-5-yl)-1 hexynyl)-pyrrolidine-3-carboxylic acid; 185 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxoI-5-yi)-1 (pro poxym et hylcarbo nyI-pyrroi di ne3crboxyli c acid; 186 trans, trans-2-(4-Methoxyphenyl)4(1 1 3-benzodioxol-5-yl)-1 (phenylacetyl)-pyrrolidi ne-3-carboxylic acid; -172- 157 trans, trans-2-(4-Methoxyphenyl)-4(1 1 (anilinylcarbo nyl)-pyrrolidi ne-3-carboxylic acid; 188 trans, trans-2-(4-Methoxyphenyl)-4.(1 1 3-benzodioxol.5-yl)-.1 acetylaminoethyl)-pyrroidi ne-3-carboxylic acid; 189 trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxo-5-yi).1 phenoxyethyI)-pyrrolidine.3crboxylic acid; 190 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y). 1 benzodioxanylmethyl)-pyrrolidi ne-3-carboxylic acid; 191 trans, trans-2-(4-Methoxyphenyl)-4.(1 .3-benzodioxol-5-yi)-l1-(2tetrah yd rofu ran yl met hyl)-pyrro li din e-3carboxyl ic acid; 192 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo I-5-yI)-1 (propylaminocarbo nylamino)ethenyl)..pyrrolidine3carboxylic acid; 193 trans, trans-2-(4-Methoxyphenyl)-4 (1 .3-benzodioxo 1 (propylaminocarbonylamino)ethyl)-pyrroidine3carboxylic acid; 194 trans, trans-2-(4-Methoxypheny)-4(1 1 3-benzodioxol-5-y).1 oxohex-1 -enyl)-pyrrolidine-3-carboxylic acid; 195 trans, trans-2-(2,4-Dimethoxyphenyl)-4.( 1 3-benzodioxol-5-yl). 1 (pro pylami nocarbo ny m ethyl) -pyrro lidi ne- 3-carboxyli c acid; 1-96 trans, trans-2-(2-Carboxy-4meth-oxypheny) 4 -(l,3-benzodioxo yl)-1 -(propylam n ocarbo nyl methy,)-pyrro id i ne-3-carboxy li c acid; 1 97 trans, trans-2-(2-Ami nocarbo nyl4methoxypheny) 4 benzodioxol-5-y)-1 -(propylami nocarbonylmethy)-pyrrolidine.3carboxylic acid; 1 9 8 trans, trans2(2 Methanesu Ifonamido4methoxh y) 4 benzodioxol-5-yl)-1 -(propylaminocarbonylmethyl).pyrrolidi ne-3carboxylic acid; 199 trans, trans-2-(2-Ami nocarbonylmethoxy4methoxyphe ny) 4 1 -(propylam i no carbon ylm ethyl)-pyrro lid i ne -3carboxylic acid; 2 00 trans trans-2-(2Meth oxyethoxy4.methoxypheny) 4 3benzodioxol-5-y)-1 -(propylami nocarbonylmethyl)-pyrrolidine-3 carboxylic acid; -173- 201 trans, trans-2-(2-Carboxymethoxy4methoxyph eny) 4 benzodioxol-5-y)-1 -(propylaminocarbonylmethyl)..pyrrolidine- 3 carboxylic acid; 202 trans, trans-2-(4-Methoxy-2.-tetrzolymethoxyphenyl)4-(1,3benzodioxol-5-y).1 -(propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 203 trans, trans-2-(2-AIlyoxy4methoxyphenyl)-4 (1 yI)-1 .(propylaminocarbonylmethyl)-pyrrolidine.3carboxylic acid; 204 trans, trans 2,4-Bis(4-methoxyphenyl)- (pro pylami noca rbo nyl methy I)-pyrro Iidi n e- 3carboxyli c acid; 205 trans,trans 2,4-Bis(1 1 3-benzodioxol-5-yi)-1 (pro pylami nocarbonyl methyl)-pyrro lidi ne-3-carboxylic acid; 206 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-berlzodioxo 1 methyl-N-propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 207 trans, trans-2-(4-Methoxyphenyl)4(1 1 3-benzodioxole-5-yl)- 1 methyI-N-butylaminocarbony)pyrrolidine3carboxylic acid; 208 trans, tra ns-2-(4-Methoxyphenyl)4-(1 ,3-benzodioxol-5-yl)- 1 methyl-N-(4-methoxyphenyl)ami nocarbonyl)-3-pyrrolidi ne-3carboxylic acid; 209 trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxoI-5-yI)- 1 methyI-Nphenyaminocarbony)pyrrolidine-3carboxylic acid-, 210 trans, trans-2-(4-Methoxyphenyl).4-(1 1 3-benzodioxol-5-yI)- 1 methyl-N-allylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 211 trans, trans-2-(4-Methoxyphenyl)-4 (1 ,3-benzodioxol-5-yl)- 1 met hyI-N(nbuty) am inocarbo nymeth y).pyrro idi ne3carboxyli c acid; 212 trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxol-5-yI)- 1 methyl-NisobutyaminocarbonylmethyI)-.pyrroidine3carboxyic acid; 213 trans,' trans-2- Met hoxyph enyl)4-(1 ,3-be nzodi oxo1-5-y1) 1 methyl-Ncycopentyaminocarbonymethy)pyrroidine3carboxyic acid; -174- 214 trans, trans-2-(4-Methoxyphenyl)>4-(1 ,3-benzodioxol-5-y,) -1 methyl-N(2methoxyethy)aminocarbony)pyrroidine 3 aboy acid; 215 trans, trans-2-(4-Methoxypheny>.
4 (l ,3-benzodioxo 1 methyl-N-butoxyethylami nocarbonyl)-pyrrolidi ne-3-carboxylic acid; 216 trans, trans-2-(l 3 -Be nzodioxoI-5-yi)-4- (4..methoxyph enyl)- 1 (NmethyI-Npropyaminocarbonymethy)pyrroidine 3 cabyic acid; 217 trans, trans-2-(4-Mthoxyphe nyI)..
4 (l 4-be nzodioxan-6-yl)y1 methyl-N-propylami nocarbonylmetfiy)-pyrrolidi ne-3-carboxylic acid; 218 trans, trans-2-(4-Methoxyphenyl)4(1 1 3-benzodioxol-5-yl). 1 methyI-Nisopropyaminocarbonymethy)pyrroidine 3 aboy acid; 219 trans, trans-2-(4Methoxypheny) 4 3-benzodioxo 1-5-yly.1 m ehyl Nethlam ncaro ylethy/-pyrroidi ne-3-carboxyli c acid; 220 trans, trans-2-(4-Methoxyphenyl)4-(l,3-benzodioxo I-5-yI)- 1 methyl-N-(l -methylpropyl)aminocarbonylmethy)pyrrolidine- 3 carboxylic acid; 221 trans, trans-2-(4-Methoxyphany) 4 -(l 1 3-benzodioxo1-5-y).1 m ethyl-Nphe nyam inocarbo ny mthy)pyrroidi e--cabyic acid; 222 trans, trans-2-(4Methoxyphe ny) 4 3-be nzodioxol-5-y). 1 .methyl-N-propylami nocarbonyl)ethyl)-pyrrolidine3-carboxylic acid; 223 trans, trans-2-(4-Methoxyphenyl)4-(1 3-benzodioxol-5-yi)-1 methyI-Npropyainocarbony)benzypyrriine-3-eabxl acid; 224 trans, trans-2-(4-Methoxyphenyl)-4 (1 1 3-benzodioxol-5-yI)- 1 ethyI-Npropyaminocarbonymethy).pyrroidine3carbyic acid; 225 trans, trans-2-(4-Methoxypheny)4-(l 1 3-benzodioxole-5-yi)-1 eth ylIN buty am ino carbo ny) pyrro lidi e-3 carboxyli c acid; 226 trans, trans-2-(4-Methoxyphenyl)4(1 .3-benzodioxol-5-y)-1 ethyl- N- meth oxyph e nyl)ami no carbo nyl1)-3- pyrro lidi ne-3 carboxylic acid; -175- 227 trans, trans-2-(4-Methoxyphenyl)-4-(1 1 3-benzodioxol-5-yl)- 1 ethyl-N-phenylami nocarbonyl)-pyrrolidi ne-3-carboxylic acid; 228 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yi)-1 ethyl- N-allylami no carbo nyl methyl)-pyrro lidi ne-3-carboxylic acid; 229 trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol1-5-y)- 1 ethyl-N-isobutylami nocarbonylmethyl)-pyrrolidine.3carboxylic acid; 230 trans, trans-2-(4- Met ho xyph e n yl)-4- (1 ,3-be nzodioxo I- 5-y 1) -1 ethyI-Ncycopentyaminocarbonymeth)pyrroidine3carbyic acid; 231 trans, trans-2-(4-Methoxyphenyl)4-(1,3-benzodioxo 1-5-yI)- 1 ethy-Nmethoxyethyaminocarbony)pyrroidine3carboxyic acid; 232 trans, trans-2-(4-Methoxypheny)4(1 ,3-benzodioxol-5-yl)-1 ethyl-N-butoxyethylaminocarbonyl)-pyrroidi ne-3-carboxylic acid; 233 trans, trans-2-(1 3 -Benzodioxol-5-yi)4(4methoxyphenyl) 1 ethyl-N-propylaminocarbonylmethyl)-pyrroidi ne-3-carboxylic acid; 234 trans, trans-2-(4-Methoxyphe nyl)-4- (1 1 4-benzodioxan-6-yI)- 1 ethyl-N-propylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 235 trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yI)- 1 ethyl-N-isopropylami nocarbonylmethy)-pyrrolidine.3.carboxylic acid; 236 trans, trans-2-(4-Methoxypheny)-4(1 .3-benzodioxo1-5-yly..1
N-
diethylaminocarbonylmethyl)-pyrroidi ne-3-carboxylic acid; 237 trans, trans-2-(4-Methoxyphenyl)4(1 1 3-benzodioxol-5-yI)- 1 ethyl-N-(1 -methylpropyl)ami nocarbonyl methyl)-pyrro lid ine- 3 carboxylic acid; 238 trans, trans-2-(4-Methoxyphenyl)-4(1t3-benzodioxol-5-yI)- 1 ethyl-N-phe nylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 239 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yi)- 1 ethyl-N-propylaminocarbonyl)ethyl)-pyrroidi ne-3-carboxylic acid; 240 trans, trans-2-(4- Met ho xyphe nyl1) 3-be nzodi oxol1-5-yI) 1 ethyl-N-propylami nocarbonyl)benzyl)-pyrrolidine3carboxylic acid; -176- 241 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo I-5-yl)- 1 methyI-N-isobutylaminocarbonylmethy).pyrroidi ne-3-carboxylic acid; 242 trans, trans-2-(4-Methoxypheny,)-4 (1 ,3-benzodjoxo I-5-yI)- 1 methyl-Ncycohexyaminocarbonymethy)pyrriidin-cabyic acid; 243 trans, trans-2-(4Methoxypheny)4-(l 3-benzodioxo 1-5-yI)- 1 Ndipropylaminocarbonylmethyl)pyrrolidine-3carboxylic acid; 244 trans, trans-2-(4-Methoxypheny)4-(1 ,3-benzodioxol-5-yI)- 1 (isobutyloxyethyl)pyrrolidine3carboxylic acid; 245 trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-y). 1 (butylsulfonyI)-pyrrolidine.3-.carboxylic acid; 246 trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yI)- 1 (isop ropyl s ulfony lam i noet hylI)-pyrrol idi ne- 3-carboxylic acid; 247 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yi)- 1 (ethoxymethylcarbonylmethyl)-pyrrolidine-3carboxylic acid; 248 trans, trans-2-(4-Methoxypheny)4(1 ,3-benzodioxo 1-5-yt)-1 ethytbutyryl met hyl)pyrro lidi ne-3carboxyli c acid; 249 trans, trans-2-(4-Methoxyphenyl)-4(1 9 3-benzodioxol-5-y). 1 methyl-N-(3 1 4 -dimethoxybenzyl)aminocarbonylmethy).pyrrolidi ne- 3-carboxylic acid; 250 trans, trans-2-(4-Methoxyphe nyl).4-(1,3-be nzodioxo 1-5-yI)- 1 1- (N-methyl-N-propylami nocarbony)buty]-pyrrolidine..3.carboxylic acid; 251 trans, trans-2-(4-Methoxyphenyl)4(1 ,3-be nzodioxo 1-5-yI)-1 1- (N-methyl-N-propylami nocarbonyI)butyl]-pyrrolidine.3-carboxylic acid; 252 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxo i-5-yI)- 1 isoPropoxypropyI)-pyrrolidine-3carboxylic acid; 253 trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-be nzodioxo 1-5-yI)- 1 m ethyl hexyl)-pyrro lidi n e-3-carboxyli c acid; 254 trans, trans-2-(4-Methoxyphenyl)-4 (1 1 3-benzodioxol-5-yI)-1 methyl- 2 -hexenyI)-pyroidine3carboxylic acid; -177- 255 trans, trans-2-(4-Methoxypheny,)-4 (1 ,3-benzodioxol-5-yl). 1 methyl- 4 -hexenyl).pyrrolidine3carboxylic acid; 256 trans, trans-2-(4- Met hoxyp hen yl)-4 (1 ,3-benlzodioxo 1-5-yl) 1 dimethyl-2-hexe nyl)-pyrro fidine-3-carboxylic acid; 257 trans, trans-2-(4-Methoxyphe nyl)-4(1 ,3-benzodioxo-5yl)..1 m eth yl-Ni sob utyrylam ino)eth y) pyrroi dine 3-carboxyli c acid; 258 trans, trans-2-(4-Methoxypheny)-4(1 1 3-benzodioxol-5-yi).1 methyl-N-(2,2dimethypropy)aminocarbonymethy)pyrroide 3 carboxylic acid; 2 59 trans, trans-2-(4- Met hoxyph enyl)-4-(1 ,3-be nzodioxo I- 1 (Nethyl-N-butylaminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 260 trans, trans-2-(4-MethoxyphenyI)- 4 (1 ,3-benzodioxol-5-yi)- 1 methyl-Nbenzyaminocarbonymethy)pyrroidin 3 cbxli acid; 262 trans, trans-2- (4-M eth oxyphe nyl)-4. (5-i ndanyl)- 1 -(N-methyl-Npropylaminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; 2 62 trans, trans-2-(4 Methoxyphe ny)4(23dihydrobe nzof ran 1 (N-mty--roaioabonylmeNpoplmioaroylmety,)rroidin dincbyic acid; 263 trans, trans-2- (4-Methoxyphenyl)-4-(1 -methyli ndol-5-yl)- 1 -(N-methyl- N-propylaminocarbonymethyl)pyrroidine3carboxylic acid; 2 64 trans, trans-2-(4-Methoxyphenyl)- 4 (2-naphthyl)- 1 -methyl-
N-
propylami nocarbonylmethyl)-pyrrolidine.3-carboxylic acid; 265 trans, trans-2-(4-Methoxyphe nyl)4-(l,2-di methoxy-4-pheny1)- 1 methyl-N-propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; 266 trans, trans-2- Met hoxyp hen -methoxy-3-pheny,)-1 methyl-N-propylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.
-178- 267 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 (propylami nocarbonylmethyl)-piperidi ne-4-carboxylic acid; 268 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 (aminocarbonylmethyl)-piperidine-4-carboxylic acid; 269 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodiaxol-5-yi)-1 f luo robe nzyl)-piperidi ne-4-carboxylic acid; 270 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 ethoxyet hyl)- piped di ne-4-carboxyl ic acid; 271 trans, trans-3-(4-Methoxyphenyl)-5- (1 ,3-benzodioxo I-5-yI)- 1 propoxyethyl)-piperidi ne-4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)- 1 methoxyethoxy)ethyl]-piperidi ne-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzociioxol-5-yI)- 1 pyridyl)ethylJ-piperidine-4-carboxylic acid; 274 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 (morpholi n-4-ylcarbonyl)-piperidi ne-4-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxo Ie-5-yI)-1 (butylaminocarbonyl)-piperidine-4-carboxylic acid; 276 trans, trans-3- Met hoxyph enyl)-5- (1 ,3-be nzod ioxol1-5-yI) -1 methoxyphenylami nocarbonyl)-3-piperidine-4-carboxylic acid; 277 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yi)-1 acetylpiperidi ne-3-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5- (1 ,3-benzodioxo I- 5 1 furoyl)-piperidine-3-carboxylic acid; 279 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)-1 (phenylami nocarbonyl)-piperidine-4-carboxylic acid; 280 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yI)-1 .(allylaminocarbo nylmethyl)-piperidine-4-carboxylic acid; 281 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-y)-1 butylaminocarbonylmethyl)-piperidine-4-carboxyllc acid; 2 82 trans, trans- 3- (4-Methoxyphenyl)-5-(1 ,3-benzodioxol-5-yl)- 1 butyl-N-methylaminocarbonylmethyl)-piperidine-4-carboxylic acid; -179- 283 trans, trans-3-(4-Methoxyphenyl).5(1 ,3-benzodioxol--yl)-1 (pyrrolidin- 1-ylcarbonylmethyl)-pipe ridine-4-carboxylic acid; 284 trans, trans-3-(4-Methoxyphenyl)-5(1 ,3-benzodioxol-5-yl)- 1 (isobutylami nocarbo nylmethyl)-pipe ridi ne-4-carboxylic acid; 285 trans, trans-3-(4-Methoxyphenyl)5(1 ,3-benzodioxol-5-y)- 1 (cyclopentylami nocarbo nyl meth yl)-pipe rid in e.4carboxyli c acid; 256 trans, trans-3-(4-Methoxypheny)5(1 ,3-benzodioxol-5-yl)- 1- (morpholin-4ylaminocarbonylmethyl)piperidine4carboxyic acid; 287 trans, trans-3-(4-Methoxypheny,)-5.(1 ,3-benzodioxo I-5-yl) -1 phenoxyethyl)-piperidi ne-4-carboxylic acid; 288 trans, trans-3-(4-Methoxyphenyl)5-(1 3-benzodioxol-5-yl)- 1 (methoxyethylaminocarbo nyl)-pipe ridi ne-4-carboxylic acid.
trans. trans- 2-(4-Methovghenvl)-4(1 .3-benzodixo-5-vl)- 1- (4dibutvlaminojhenvl)pyvrrlidine- r ovic cid 4 -Nitro-fluorobebzene, ethyl trans, trans-2-(4methoxyphenyl)4-(l,3ne-3-carboxylate (example 6A) and di-isopropyl ethylamine are heated in dioxane to give ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxolks-y)-1 -(4-nitrophe nyl)-pyrrolidi ne-3carboxylate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoboro hyd ride according to the method of Borch Am Chem. Soc., 93, 2897, 1971) to give the corresponding N,N-dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
trans. trans-2-(4-Meh xpe nvfl-4-(1 'Ibnodoo-5l 1 ibtlmo D2yri midine-.4-vl)-pyrrolidine3cp-lc acid 2-(Dibutylamino) 4-chloropyrimidine 'is prepared from 2-4dichloropyrimidine according to the method of Gershon Heterocyclic Chem.
24, 205, 1957). This compound, ethyl trans, trans-2-(4-methoxyphenyl).4-(1 ,3- -180be nzodi oxol-5-yl)-pyrro lid in e -3.ca rboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.
trans.trans-2..(4.Methxhnvl)4-(1.3-henzdioxol5.yl)-.1 -(N-b-utyl-Nphenylamninoaboymthyl)pyrro -Idi .crbxicad The title compound was prepared according to the general procedure of Example 1.
MS (DCI/NH 3 531 Anal calcd for 031 H 34
N
2 0 6 C, 70.17; H, 6.46; N, 5.28. Found: C, 70.36;
H,
6.52; N, 4.99.
NMR (CD 3 OD) 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 2H); 3.10 (t,1 H, 3.26 (d,1 H,J1l5); 3.44 (dd,1 H,J=5,1 3.5-3.7 3.77 (m,1 3.78 5.93 6.7-6.9 7.0-7.2 7.4 Fxamll222 Sodium tastrns2-(Mtoypey)( .3-enoixl5l.l (.Nd n butyflaminocronlethy)..yrrolidi e3cbUl Eth yl 3 4 -ethoxyphnl)-3oxorpint Simultaneous reactions were run in both a 65-L reactor and a reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oil and 32 L toluene were charged into the ambient temperature reactors.
The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 0 minutes, allowed to settle and 28 L of the toluene solution was aspirated.
68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4 -methoxyacetophenone in -181- 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperaturewas reduced to 100 C and stirring continued for 16 hours. A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% aqueous sodium chloride The organinc solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Example 292B 3 4 -Methylenedioxy-1-( 2 -nitroethenyl)-benzene In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15 0 -200 C. The jacket temperature was set to -50 C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 100-150 C. When addition was complete, the jacket temperature was reset to 10 C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve 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 260 C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were -182dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 40 C.
Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg of a second crop. The yellow product darkened on standing in light and air.
Example 292C Ethyl 2 -(4-methoxvbenzovl)-3.(3. 4 -methvienedioxphenv).4-nitrobutanoat Into a 45-L stirred reactor at ambient .temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-l-(2-nitroethenyl)-benzene and 24 L ethyl acetate A solution of 5.355 kg (24.1 moles) ethyl 3-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1, 8 -diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Example 292D Ethyl 2 4 methoxvphenvl-4-(3.4-methylenedioxvphenyl.4.dihd 3
H-
pyrrol-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 The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore.
The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until -183crystals formed. The solution was cooled to 0° C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 The solids were dried in vacuo at 50° C to a constant weight of 193.4 g (21% yield, melting point 80-810 C) of the title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.
Example 292 E Ethyl 2 -(4-methoxyDhenyl)-4-3 4-methylenedionxyphenv)rrin carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H -pyrrole-3carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen.
Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCI was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, L of 7% aq. NaHCO 3 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. NaHCO 3 and once with 2.5 L of 23% aq. NaCI, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
Example 292 F Ethvl 2 -4-mthxYphenv-4(3.4-methyenedioxvheny)-1-(N.
N-
dibutylaminocarbonvl methvl opyrrolidine 3-carboxvlate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2 4 -methoxyphenyl)-4-(3,4methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol). The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg -184dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 780 C for 17 hrs. After the disappearance of starting material the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (00 Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgSO4 and filtered. Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil.
Example 292G ethyl trans, trans 2 4 -methoxyphenvl)-4-(3.4-dioxyphenv pyrrolidine 3carboxylate and preparation of trans, trans 2 -(4-methoxyDhenvl-4-(3.4dioxvphenvl-)pyrrolidine-3-carboxylic acid Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2 -(4-methoxyphenyl)-4-(3,4methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol). 16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 790 C for 1 hr. The mixture was cooled to 150 C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 150 C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether.
The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M HCI was added to the aqueous layer. The aqueous layer was extracted with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCI, dried with 0.298 kg MgSO4 filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 650 C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 100 C and -185filtered. The crystals were washed with 2 L ether (00 C) and dried to constant weight in vacuo at 500 C to give 0.846 kg (43% yield, melting point 119-120) of crude product, which was further purified by normal phase silica gel chromatography.
Sodium rn trans- 2 methoxyhenyl)4(3A-methyIendixpbany)- (N .N-dibutylaminocprbo nyl methyl) pyrro lid-ine 3-carbo -xylaten Into a 20-L flask was charged trans,trans 2 -(4-methoxyphenyl)-4-(3,4methyledioxyphenyl)1l(NN-dbutylamrno 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 500 C to a constant wyeight of 0.937 kg (97% vield) of the title compound.
trans-rans-2-(4-Mtoyhnl)4( env3--benzo4iox-5-y.- [decahydroisopuinolin- crIonlmetyl-yrrolidi ne-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers.
MS
(DCI/NH
3 m/z 521. Anal calcd for C3 0
H-
36
N
2 0 6 .1.3 TFA: C, 58.54; H, 6.62; N, 4.19. Found: C, 58.34; H, 5.58; N, 4.00.
frans-frans.24(4-M thoxyphen)4-(1 .3-bnoixlSl.1-33 imtypp ii ny-croymtYlpyrrOLd n-3-carboxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 0.84 (s, 3H), 0.86 3H), 1.35-1.6 (in, 4H), 3.83 3H), 5.96 2H), 6.81 1 H, J=8), 6.90 (dd, 1 H, J=1 7.01 2H, 7.03 1 7.47 2H,
MS
-186-
(DCI/NH
3 m/z 495. Anal calcd for 028H 34
N
2 0 6 .1.4 TFA: C, 56.55; H, 5.45; N, 4.28. Found: C, 56.52; H, 5.83; N, 4.26.
trans-trans-2,j4-Met-hoxY henyl)..4(l.3-benzodixol-5.yl}.1 -[2-(N-proyl .iso.
butoXvca-rbonylam-inog)ethyq.. yrrolidine-qcarboxylic acidl The title compound was prepared by the methods dietailed in Example 61, but substituting propylamine for methylamine in Example 61 B and isobutyl chloroformate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether! hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (ODC1 3 300 MHz) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1 2.72 (in, 1 2.90 (mn, 2H), 3.10 (in, 2H), 3.25 (in, 2H), 3.40 (in, 1 3.55 (mn, 1 3.62 (in, 1 3.7-3.9 (in, 2H) 3.78 3H), 5.95 (s, 2H), 6.72 1 H, J= 8Hz), 6.82 (in, 3H), 7.00 1 7.30 2H, J=8Hz).
MS
(DCI/NH
3 in/e 527 (M+Hye-. Anal calcd for C29H 38
N
2 0 6 0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.
trans-traqns-2-(4-Methoxyphenvl)4(1 3-benzodioxnl-5-y~. -[.234tetrahydroisogui nolin-2- caronylethyl-pyr ide-carboxylac acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotainers. 8 2.97 (in, 2H), 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1 H, 7.1-7.3 (in, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH 3 in/z 515.
trans-trans-2-(4-Methox jphenly.4-(1 .3-enzDioxol-5-l). -12-(N-nppldimethyjamonoca-rbonylainino~et yl1..prrolidine3-carboxylic acid The title compound was prepared by the methods detailed in Example 6 1, but substituting propylamine for inethylamine in Example 61 B and diinethylcarbainyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac gC1 8) eluting with a 10-70% gradient of CH3CN in 0. 1% TFA. The desired fractions were lyophilized to give -187the product as a white solid. 1 H NMR
(CDCI
3 300 MHz) 5 0.70 3H, 1.28 (in, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (in, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 4.72 (in, 1 5.95 6.75 1 H, J= 8Hz), 6.87 (mn, 3H), 7.05 1 7.40 2H, J=8Hz). MS (DCI/NH 3 mle 498 Anal calcd for C27H 35
N
3 0 6 1.25 TFA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71;
N,
6.41.
trransas- 4 Mt 9vhnyl)4(l.-ezdoo..y) ropyl- (4 nitrobeznsufnl -iOethrl)-py rlidine-3 coxlcci Using the procedures described in Eample 66, the title compound was prepared as a yellow solid. m.p. 85-87 0 C. 1 HNMR (CDCI3, 300 MHz) 8 0.77 (t, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (in, I1H), 2.57-2.66 (in, 1 H), 2.82-3.15 (mn, 4H), 3.22 J=7.5Hz, 2H) 3.38 (dd, J=3Hz,J=9Hz, IH), 3.49-8.57 (in, 1 3.59 J=9Hz, 1 3.83 3H), 5.96 2H), 6.73 J=8Hz, 1 6.82 (dd, J=I Hz,J=8Hz, 1 6.87 J=9Hz, 2H), 6.98 J=1 Hz, 1 7.27 Id, J=9Hz, 2H), 7.82 J9Hz, 2H), 8.23 J=9Hz,2H). MS (DCI/NH3) nv/e 612 aplM pentnes lfnylamino)ethy)-p trrolidi ne-3-carb2xlicaid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 59-61 OC 1 HNMR
(CDCI
3 300MHz) 6 0.79 (t, J=7.5Hz, 3H), 0.90 J=6Hz, 3H), 1.26-1.32 (mn, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (in, 2H), 2.23-2.32 (mn, 1 2.70-3.08 (in, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1 3.52-3.57 (in, 1 3.63 J=9Hz, 1 3.80 3H), 5.95 6.73 J=7.5Hz, 1 6.83 (dd, J1IHz,J=7.5Hz, 1 6.87(d, J=8Hz, 2H), 7.00 J=1 Hz, 1 7.32 J=8Hz, 2H). MS (DCI/NH 3 in/e 561 -188trns tas-2z(4-Methoxvnhe -l4.(1 .3-benzodioxpl-5-vn-1 A N(-rov-(4trifluoromethoxbenzenesufonvl~mino)ethlprridineaLbgxyi acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.1 22-124-C. 1 H NMR (CD3OD, 300MHz) 6 0.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (in, 2H), 3.23 (bs, 2H), 3.35-3.45 (in, 2H), 3.52 J=1lOHz, 1 3.81 J=9Hz, 2H), 3.86 3H), 3.92 J=9Hz, 1 4.63 J=l10Hz, 1 5.97 2 6.82 J=9 Hz, 1 6.93 (dd, J=3Hz,J=9Hz 1 7.06-7.08 (in, 3H), 7.46 J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MS (DCI/NH3), mWe 651 trans. trans-2-(4-M thoxph Al)( /-benz ioxol-5-yl). -(QNpyol--2 -methvl -ropnsufnyl)ainnothyl)yrlidie 3 -c uacidAQ1! Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 69471OC.. 1 NMR (00013, 300MHz) 6 0.79 (t, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 3H), 2.25-2.35 (in, 1 2.68- 2.77 (in, 1 2.55-3.28 (in, 7H), 3.40 J=9Hz, 1 3.52-3.68 (mn, 2H), 3.66 (d, J=9Hz, 1 3.80 3H), 4.92 1 5.07 1 5.97 2H), 6.74 J=7Hz, 1 6.82-6.89 7.01 (s,1 7.33 J=9Hz, 2H). MS (DCI/NH3), m/e 545 trans-trans-2-(4-Methoxyphenvl)4-(.3-benzodioxol-.yl).1 -rp-ethylwi pe ridi nylcarbonylinehyg-pyrrplidi ne-3-carboxylcacid.
The title compound was prepared using the procedures described in example 1. NMR (00300, 300 MHz) shows a mixture of isomers. 6 0.75 (t, 3H, (mn, 8H), 3.84 3H), 5.96 2H), 6.83 1 H, 6.91 (d, 1 H, 7.0-7.1 (mn, 3H), 7.52 2H, MS (DCI/NH 3 rn/z 495. Anal calcd for C28H 34
N
2 0 6 .1.6 TFA: C, 55.35; H, 5.30; N, 4.14.- Found: 0, 55.26; H, 5.37; N, 4.01 -189tans, trans-2-(4-Methoxyp hen yl).4- (1 .3-benzodioxol-5-yl)- 1-(2-(N-propyl-N-2methylnropanesulfonyl)amino)ethyl)p1yrrolidine.3carboxylic aci Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-730C. 1 NMR (CDC13, 300 MHz) 5 0.82 (t, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.1 5-2.33 2.57- 2.75 (in, 2H), 2.84-3.08 (in, 3H), 3.12-3.21 (in, 1 3.23-3.45 (in, 1 3.43 (d, J=1 1 Hz, 1 3.55-3.62 (in, 1 3.66 J=9Hz, 1 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1 6.83 (dd, J=1 Hz,J=9Hz, 1 6.87(d, J=9Hz, 2H), 7.02 (d; J=1 Hz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 547 trans, trans-2-(4-Methoxyhenvlo-4-(1 .3-be nzodioxo l-5-yl)-1 -(2-(Nj-Qropyl-Nheptanesuffonylamino)ethyl)p1yrrolidine-3carboxylic -acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.58-59 0 C. 1 H NMR (CDC13, 300MHz) 5 0.80(t, 3H), 0.88 0t, J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 J=7.5Hz, 2H), 1.71 (quintet, J=7Hz, 2H), 2.23-2.32 (in, 1 2.70-3.09(mn, 7H), 3.13-3.32 3.43(dd, J=3Hz,J=9Hz, 1 3.52-3.58(in,1 3.65(d, J=9Hz, 1 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1 6.83 (dd, J=1 Hz, J=7Hz, 1 6.87(d, J=9Hz, 2H), 7.01 J=1 Hz, 1 7.32(d, J=9Hz, 2H). MS (DCI/NH3) m/e 589 trans-trans-2-(4-Methoxyphenyfl4-(1.3-be nzodioxol-5:-l1-f2-(-N-propyl-N- -ethoxycarbo nylainino)ethyl]-pyrrolidine:3-car oxvlic acid Prepared by the methods detailed in Example 61, but substituting ethylainine for inethylainine in Example 61 B and ethyl chloroformat6 for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac giC1 8) eluting with a 10-70% gradient of CH 3 CN in 0.1 TFA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 5 0.90 3H, 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (in, 2H), 3.78 3H), 3.82 (in, 4H), 4.10 2H, J=7Hz), 3.5 (br s, 1 H), 5.97 (dd, 2H, J=1,7Hz), 6.72 1 H, J= 8Hz), 6.84 (in, 3H), 7.00 1 7.42 (d, -190- 2H, J=8Hz). MS (DCI/NH 3 mle 485 Anal calcd for C26H 32
N
2 c, 7 1.2 TEA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.
trans, trans-2- Met hoxyphe nyl). 3-bezdoo-5y). (-(-rplN hexanesulfonylamino)ethl)..prrolidine3carbol. aacd Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60 0 C. 1 NMR (CDCI3, 300MHz) 5 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.
2 5-1.36(m, 6H), l.53(sextet, J=7.5Hz, 2H), 1.72(quintet, J=7Hz, 2H), 2 .23-2.32(m, 1 2 7 2-3.08(m, 7H), 3 .15-3.32(m, 2H), 3.43(d, J=9Hz, 1 3 .55-3.62(m, 1 3.65 J=1 0Hz, 1 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1 6.82(d, J=7.5Hz,l 6.87(d, J=9Hz, 2H), 7.01 (s,1 H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 xmeq7 trans-trans-2-(4-Ethylphenyl)- 4 3-benzodioxol-5.yl).1 N-di(nbutyl)am in ors rhonyl methyll-pyrrolidi ne-3-carbonxylic acid The title compound was prepared using the procedu res described in examples 1 and 49, substituting ethyl 4 -ethylbenzoylacetate (prepared by the method of Krapcho et al., Org. Syn. 4Z, 20 (1967) starting with 4'ethylacetophenone) in proqedure 49B. NMR (ODC1 3 300 MHz) 5 7.31 (2H, d, J=8Hz), 7.16 (2H, d, 1=8Hz), 7.03 (1 H, d, J=3Hz), 6.56 (1HM, dd, J=8&3Hz), 6.73 (1 H, d, J=9Hz), 5.94 (1 H, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1 H, in), 3.53-3.23 (5H, mn), 3.13-2.90 (4H, in), 2.73 (1 H, d, J=1l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, in), 1.40-1.10 (6H, in), 1.02 (2H, in), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCl, NH 3 509 Anal.calc. for 4
ON
2 0 5 C 70.84, H 7.93, N 5.51. Found C 70.80, H 7.85, N 5.25.
ExampijaQ= -191trn-rn--4Mtoyh ylA(.3-benzodioxol-5-vl)- -[2-N-propy 4.2.
chloroethoxy)carbo nylamino)ethyll-pyrrolidi ne-3-carboxvlic acid Prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and 2-chioroethyl chioroformate for isobutyryl chloride in Example 610C. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1 H NMR (ODC1 3 300 MHz) 8 0.80 3H, 1.22 (in, 3H), 2.15 (in, 1 2.75 (in, 1 H), 2.85 (in, 1 3.1 (mn, 2H), 3.25 (in, 2H), 3.5 (mn, 3H), 3.65 (in, 2H), 3.80 3H), 4.18 (in, 1 4.30 (in, 1 5.98 2H), 6.72 (in, 1 6.82 (in, 3H), 7.00 (mn, 1 7.30(m, 2H). MS (DCI/NH 3 Wne 533 Anal calcd for C27H3 3
N
2
O
7 CI: 0, 60.54; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.
trans-trpns-2-(2- Methoxyethyl)-4-('1.3-benodioxol--yl)--1 N-di(nbutylhamino cabnlneh v.prrolidine3-ca xyjic acid.
The title compound was prepared using the procedures described in example 1, substituting ethyl 5-inethoxy-3-oxopentanoate for ethyl 4methoxybenzoylacetate in Example 1 A. The title compound is a yellow foam.
1 H NMR (ODC1 3 300 MHz) 8 0.91 J=7Hz) and 0.95 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, 1 3.30 and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br in, 4H), 5.92 2H), 6.72 J=8.5Hz, 1 6.82 (dd, J=1 8.5Hz, 1 6.91 J=1 .5Hz, 1 MS (FAB) m/e 463 Anal calcd for 025H38N20 5
-H
2 0: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.
trans. trans-2-( -Met-hoxy henyl).4-(1 .3-benzodioxol-5:-yl-(2- (N-ethyl-N-npentnes Ifnylmin~etyl)pyroliine..3ca.boxylic acd Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 0. 1 H NMR (CDCI3, 300MHz) 5 0.89(t, J=7Hz, 3H), 1 .06(t, J=7.5Hz, 3H), 1.26-1 .37(mn, 4H), 1 .72(quintet, J=7.5Hz, 2H), 2 22 -2.32(m,1 2.71 -2.96(in,5H), 3.08-3.30(m,4H), 3.95(d, J=9Hz, 1 3.53- 3.60(mn, 1 3.67(d, J=9Hz,1 3.80(s, 1 5.97(s, 2H), 6.73(d, J=9Hz, 1 H), -192- 6.82(d, J=9Hz,l 6.88(d, J=9Hz, 2H),7.02(s,1 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 trarns-trans2..(4..Methxyphenyl- 4 .3-benzodioxl.5vi)-l
[N.N-
dicyclohexylgm-in cronlethylJ-pyrrolidine..3..rroxXLa c aidL The title compound was prepared using the procedures described in example 1. NMR
(CD
3 OD, 300 MHz) 5 1.0-2.0 (in, 20H), 3.0-3.1 (in, 2H), 3.80 3H), 5.95 2H), 6.75 1 H, 6.86 (dd, 1 H, 6.95 2H, J=9), 7.04 1 H, 7.38 2H, MS (DCI/NH 3 m/z 563. Anal calod for C33H- 42
N
2 0 6 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90. Found: C, 69.42; H, 7.29;
N,
4.78.
FxamnQ 312 trans-tran-2-(4-Methioxyphe nyl)-4-(1 3b ldoo--l.. [-Npov-.tr buitoxycarbonvlgmi no)ethyll-pyrro lidi ne-3crovcaid The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in Example 61 C. NMR
(CD
3 0D, 300 MHz) suggests presence of rotamers 5 0.81 3H, 1.2-1.5 (in, 11 3.78 3H1), 5.92 (dd, 2H, J=1 6.74 1 H, 6.84 (dd, 1 H, 6.92 2H, 6.99 (bd s, 1 7.35 2H, MS (DCI/N
H
3 m/z 527. Anal calcd for C29H 38
N
2 cj 7 C, 66.14; H, 7.27; N, 5.32. Found: C, 66.,05; H, 7.36; N, 5.15.
trans-trans32..(4-Methoy ~ophenyl) 4 3bnoixl-5ylbl .N-di(nbutyl)amin bnlethyll-1yrrolodine-3-arboxli acid.
The title compound was prepared using the methods described in examples 1 and 43, using 4 -methoxy-3-fluoro acetophenone in place of 4inethoxy acetophenone. in.p. 142-143 OC. NMR (CDC1 3 300 MHz) ,8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.03-1.50 (in, 8H), 2.82 J=1l3Hz, 1 2.90- 3.13 (in, 4H), 3.20-3.50 (in, 3H), 3.39 J=1 3H, 1 3.55-3.65 (mn, 1 3.82 (d, J=1lOHz, 1 3.87 3H), 5.91 (dd, J=2Hz, 4Hz, 211), 6.72 J=8Hz, 1 6.83- -193- 6.91 (in, 2H), 6.99 J=2Hz, 1 7.06 (in, 2H). Anal calcd for C29H37N 2 0 6
F:
C, 65.89; H, 7.06; N, 5.30. Found: C, 65.82; H, 7.13; N, 5.29.
trans. trans-2-(P ropyl.)-4-(l.3-ben fl~inxQl-5-yfl.. 1 -2-M(-propyl- Pe;ntanesqulfonyLaino)ethyl)nyrrolidine-,crrhxylic acid Propyl enntgneslffopmide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL
CH
2
CI
2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH 2
CI
2 under a nitrogen atmosphere. The reaction was stirred at 0 OC for 30 min, then at 00 for 4 h. The solution was partitioned between 20 mL of 1.0 M aqeous NaHS0 4 and 25 mL 01-2CI2. The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na 2
SO
4 fitered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1 HNMR (ODC1 3 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28-1.50 (br m, 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br mn, 2H), 2.98-3.06 (mn, 2H), 3.08 J=6Hz, 2H), 4.10-4.23 (br m, 1 MS (DCI/NH 3 mWe 211 (M+NH 4 Ethyl trans. trans-41 .3-henzodioxlS) 1(2-hrnmoethyl).2propylpyrrolidin-3crbo ate The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 94B for the pyrrolidine mixture.
Ethyltrans._ trans--2-(Propyl)4-(1.3-enzodixl 5-y) 1 2 -_(N-propy.pentanesu Ijfo nXlainno)ethyl)pyrrnlidine3carbp-xvlate A solution of the compound of Example 314A (6.6 ing, 34 pgmol) in 0.1 mL DMF was treated with sodium hydride (2 ing, 60% oil dispersion, 1.2 mng NaH, 50 jxmol). The resulting mixture was stirred at room temperature for -194min, then a solution of the compound of Example 1898 (9.0 mg, 22 4.moI) 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 OC overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO 3 1 mL water and 5 mL EtOAc.
The organic phase was washed with 1 mL brine, dried by passing through a plug of Na 2
SO
4 and the filtrate concentrated in vacuo to an oil. The crude product was purified by preparative TLC (silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mg of the title compound as awax Exam~le S14 tran.trans-4-( 1.3-ben nodioxo1-5-yl-2-(Proyl).1-(2-(N-pro pylpentanesu fnlmNo-eh&-pyroI%-. e....caboxylic acid The title compound was prepared according to the procedure of Example 71 C. 1 H NMR (ODC1 3 300 MHz) 5 0.88-1.00 (in, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (in, 3H), 1.70-1.85 (br in, 2H), 1.90-2.16 (br m, 2H), 2.84-3.26 (br in, 6H), 3.26-3.90 (br m, 6H), 5.95 2H), 6.76 J=8Hz, 1 6.79 (in, 1 H), 6.93 (bjr s, 1 HRMS (FAB) calcd for C25H41N 2 06S 497.2685, found 497.2679.
Exml 1 trans~trans-2-(4-Methoxyphenvyl)4(1 .3-benzodioxo-5-l.1-2(-rplN di methylsulf amoylarnino)ethyl)-pyrroidi ne-3I-carboxylmic acid Using the procedures described in Example 66, the title compound was preapred as a white solid. in.p.59-61 OC. 1 H NMR (CDCI3, 300MHz) 8 0.79 (t, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31 (m,1 2.65(s, 6H), 2.70- 2.79(m, 1 2 .85-3.04(mn, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1 H),3.55 (t, J=9Hz,1 3.65(d, J=9Hz,1 3.81 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1 H), 6.83(d, J=9Hz, 1 6.88(d, J=9Hz, 2H), 7.02(s, 1 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 -195trans-trans-2-(4..Methpxphe nyl)-4.( 1.3-be nzodioXo l-5-yfl-l1-r2-(N-prpl-( methoxyphnlsloypioppvlyrldn~l acid, Ethyl trans-tranis nd. cis-trans Exa4meoyhnl.4( .3be16Ao-5y) 1 (3-bromorr prro lidi ne-1-carboxyl-ate, A 2:1 mixture of trans-trans and cis-trans ethyl 2 (4--methoxyphenyl)-4 (1 ,3-benzodiox-5-yl) -pyrrolidine-3-carboxylate (4.00 g; prepared according to example 1 32 ml dibromopropane, and 200 mg sodium iodide, were heated at 1000 for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na 2
SO
4 and the solution concentrated.
The residue was ch~romatographed on silica gel eluting with 5:1 hexane:EtOAc.
yielding 5.22 of the title co mpound.
Ethyl tran-tran~s and cs-trans 2 -4-eho henyl).4-.(1 3 -popylainoppropyi) pyrrolidine-3-arboxylate The compound described in Example 316A (5.22 g) was heated at 800 for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents-were removed in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution and dried (Na 2
SO
4 The soilution was concentated in vacuum to give 4.96 g of the title compound as an orange oil. This was used in the next step without purification.
trans-trans2..4Mthppenl-- 3-ezim xlSl. -2(NppyN methoxy-phenyljsulff n~aionvopi1-pyrrli *e..pbxYlic add Using the method described in example*66, the compound prepared in Example 316B was reacted with 4 -methoxybenzenesulfonyl chloride in acetonitrile containing diisopropylethylatnine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1 D. NMR (CDC1 3 300 MHz) 5 0.83 -196- J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (in, 2H), 2.00-2.11 (mn, 1 2.40- 2.51 (in, 1 2.69-2.78 (in, 1 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1 6.85 (d, J=8Hz,*3H), 6.93 J=8Hz, 2H), 7.02 J=2Hz, 1 7.29 J=8Hz, 2H), 7.69 J=8Hz, 2H). Anal calcd for C32H3 8
N
2 0 8 S: 0, 62.93; H, 6.27; N, 4.59.
Found: C, 62.97; H, 6.39; N, 4.45.
transq-trans2- Me- xhenyl)4-(l.3-enodiool5-0-).1 pyl-Nproo~vlsulfonylamino~prnpvll-12yrroii croxyaacacd Using the method described in example 66, the propylainino compound prepared in Example 316B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropylethylamine. The resuling product was chroinatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 10D. NMR (00013, 300 MHz) 5 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 (mn, 2H), 1.65-1.85 (in, 4H), 2.04- 2.16 (in, 1 2.42-2.57 (in, 1 2.72-3.11 (mn, 5H), 3.25-3.41 (mn, 2H), 3.50-3.62 (in, 2H), 3.80 3H), 5.85 2H), 6.72 J=8Hz, 1 6.80-6.90 (in, 3H), 7.02 J=2Hz, 1 7.30 J=9Hz, 2H). Anal calcd for 028H 38
N
2 0 7 61.52;
H,
7.01; N, 5.12. Found: C, 61.32; H, 7.01; N, 5.01.
trans. trns-- 2 3 Flu or -4-_ethoxypheny) 4 -(.3-benzdioxol-5-y~ propyl-N-pentan-esulfnylpino)ethyl)-Dyrrolidi ne-3-carboxylic ai Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68 0 C. 1 NMR (00013, 300MHz) 8 0.81 (t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1 .35(m, 4H), 1 .45(sextet, J=7.5Hz, 2H), 1.68-1 .76(m, 2H), 2 2 5 -2.33(m, 1 2 7 2-2.92(mn, 2 9 7 -3.12(mn, 2H), 3 .16-3.33(in,2H), 3.43(dd, J=3Hz,J=9Hz,1 3.53- 3.60(m, 1 3.66(d, J=lOHz, 1 3.88(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1 H), 6.82(dd, J=1lHz,J=8Hz,1 6.92(t, J=8Hz,1 6.97(d, J=1 Hz, 1 7.12(d, J=8Hz, 1 7.18(dd, J=1 Hz,J=l 2Hz, 1 MS (DCI/NH3) W/e 579 -197trans-trans-2-(4-Pyridinyl>4-(1 .3-benzodioxol-5-y)-l- 4 N.N-dii(n-butyl)amn carbonylmethyll-pyrrolidi ne-3-carboxylic -acid- The title compound was prepared using the methods described in examples 1 and 43, using methyl 3 -oxo- 3 4 -pyridyl)propanoate Am. Chem.
Soc. 1993, 115, 11705) in place of ethyl 4 -methoxybenzoyl)acetate. m.p.
131-1 32 0 C. NMR (CDC1 3 300 MHz) 5 0.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1 2.97 J=1 3Hz, 1 3.00-3.25 (in, 4H), 3.32 (in, 1 3.39 J=1 3Hz, 1 3.45-3.52 (mn, 1 3.67-3.78 (in, 1 4.10 J=9Hz, 1 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 J=9Hz, 1 6.90 (dd, J=9Hz, 2Hz, 1 7.02 J=2Hz, 1 7.45 J=8Hz, 2H), 8.50 J=8Hz, 2H). Anal calcd for 027H 35
N
3 0 5 C, 67.34; H, 7.33; N, 8.73. Found: C, 67.39; H, 7.4 5; N, 8.61.
Fxmple 32 trans-trans-2-(4..Methoxphenl)4-(.3-enoixol-5..yvD.1 -[2-(N-propyl-Ndiethylaiinocarbonylamino)ethyll-ipyrlidi ne-3-carboxyvlic acid.
The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and diethylcarbainyl chloride for isobutyryl chloride in Example 61C. NMR
(CD
3 OD, 300 MHz) 560.74 3H, 1.09 6H, 1.33 (mn, 2H), 3.17 (q, 4H, 3.78 3H), 4.04 (mn, 1 5.93 2H), 6.86 1 H, 7.06 (dd, 1 H, 6.94 2H, 7.04 (d,l1H, 7.40 2H, MS (DCI/NH 3 m/z 526. Anal calcd for C29H 39
N
3 0 6 0.1 TFA: C, 65.31; H, 7.34; N, 7.82.
Found: C, 65.33; H, 7.43; N, 8.14.
Exmple 321 trans-trans-2-(4-Methoxyohenayl)-4 (1.3-be nzodioxol1-5-yl)-l1-[3.5diinethyiipe rid! nyl- onylmetylpyrrolidine..3-croxylic acid.
The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows mixture of isomers. 6 0.88 3H, 0.93 3H, 3.82 3H), 5.95 2H), 6.82 1 H, 6.59 (dd, 1 H, J=1 7.00 d, 2H, 7.03 (mn, 1 7.47 2H, MVS (DCI/NH 3 m/z 495.
-198- Examole32 trans-trans-2-(4-Methoxyphenyl).4-(1 .3-benzodioxol--y-vi--N .N-di(sbutyl~amino-carbonlmethyl1pyrrolidine-3-carboxylip acid, The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) suggests a mixture of isomers. 6 0.83 (t, 6H, 1.27 6H, 1.6 (in, 2H), 3.79 3H), 5.93 2H), 6.75 1 H, 6.86 1 H, 6.94 2H, 7.03 1 H, 7.35 2H, J=9).
MS (DCI/NH 3 m/z 511.
Exam~l 32 trans-trans-2-(4..Met oxyhenyl)4(13-benzodioxol-5-vfl- Met hyl~h e-nyl)-N-butylam ino ca ronyl methynpyrro lidn e.3carboxylic acid.
The title compound was prepared using the procedures described in example 1. MS (DI/N H 3 in/z 545. Anal calcd for C32H 36
N
2 0 6 0.9 H 2 0: C, 68.53; H, 6.79; N, 4.99. Found: C, 68.56; H, 6.62; N, 4.71.
Ira ns-trans-2- Meth oxyp he ny)-4-(1.3-be nzodioxo -5-y 1 Methylp~henyj)-N-butylm 'no carbo n ymet hyll-nyrro lid in e-1-carboxylic aid The title compound was prepared using the procedures described in example NMR (CD3OD, 300 MHz) d 0.88 3H, 1.2-1.5 (in, 4H), 2.31 3 2.8 (in, 2H), 3.14 1 H, J=1 3.3 (in, 1 3.44 (dd, 1 H, J=5,10), 3.53 (in, 1 3.60 2H, 3.79 3H), 3.82 (in, 1 5.93 2H), 6.74 1 H, 6.8-6.9 (in, 5H), 7.06 1 H, 7.09 2H, 7.18 1 H, 7.27 1 H, MS (DCI/N H 3 m/z 545. Anal calcd for C32H 36
N
2 0 6 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 Found: C, 68.70; H, 6.67; N, 4.85.
trans. trans-:4-(1 .3-Benfzodioxol-5-yl)-2-(benzyoxymethy).1
N-
dibuty Iam in o)carbo nyl)i methyl)p1yrroIi di ne-3-ca rboxyli c acid -199- Ethyl trans. trans- 4- Benzodi onol-5-yl)-2-(be n zyloym ethyl)-
N-
dibutyla-m-ino)carbony)Me~thyl)p2yrrlidine-3-carboxylate The procedures of Example 1 A-i 0 were followed, substituting ethyl 4benzyloxy-3-oxobutyrate for 4 -methoxybenzoylacetate in Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0. 18; 1H NMR (CDCl 3 300 MHz) 8 0.58 J=7Hz, 6H), 1.17 J=7Hz, 3H), 1.20-1.34 (br m, 4H), 1.40-1.56 (br m, 3H), 2.85 J=8Hz, 1 2.98-3.30 (in, 5H), 3.39-3.60 (in, 3H), 3.64-3.75 (in, 2H), 3.92 J-1l4Hz, 1 4.10 (two overlapping q, 2H), 4.53 2H), 5.91 (in, 2H), 6.69 J=9Hz, 1 6.77 (dd, 9Hz, 1 6.91 J=1.5Hz, 1 MS (D01/NH 3 m/e 553 tranls. trans-4-(1 3 -Benzodioxol-5-yl)-2-(hnZyjoxymethyl)1
-N-
dibutylam Vcr hnlmetfhyl)DrrpIdi -carboxlic acid The title compound was prepared according to the procedure of Example 710, as a colorless glass. TLC MeOH-CH 2
CI
2 Rf 0.13; 1 H NMR (C D13, 300 MHz) 860.86 J=7Hz), and 0.90 J=7Hz, 6H total), 1. 15-1.52 (br mn, 8H), 2.96-3.35 (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 1 H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 2H), 6.70 J=8Hz, 1 6.84 (dd, J=1 ,8Hz, 1 6.93 J=1 Hz, 1 7.28-7.39 (in, 5H); MS (001/NH 3 mle 524 F-ame--2 trans. trans-4-(1 3 -B nodioxol5-l,(yrxmty) dibutylamino)carbonyl) met-hyl),pyrrolidine-3-carboxylic aid Ethyl transtrans-4-( 3 -Benzodioxol-5-yl)-2(hydroxyinethyl)-1
N-
dibutylaminocarbo -n mthyl)p2yrolidine-3cp-rboxylate The resultant product from Example 325A (128 ing, 0.232 iniol) and mng 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 -200washes were concentrated under reduced pressure to afford the crude product.
Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.
Exmp1le 26B trans. trans-4-(1 3- Benzodioxol-5-yl-2-hyroxymethyj)y.1 dibutylamino)carbonyl)methylpyrrolidine-3carboxylic acidu The title compound was prepared according to the procedure of Example 71 C.
Example 327 trans. trans--4-(l 3 -Be nzodioxol-5yl)-2-(N-methylprop2enamid.3-yl).
1
N-
dibutylaminocarbonyflmethyl)pyrrouidine-3.crboxylic aci Exmpl 27A Ethyl transitrns--4-(1 .3-Be nzodioxol-5yl)-2-(formyl)1-((U(N
.N-
dibutylamino)carbonyr) methyl)pyrrolidi ne-3-carboxylate The title compound is made by selective oxidation using the Swern oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.
Example 3278J Ethyl trans, trans--4-(1 3 -Benzodioxol-5-yl)-2-(O-tert-hI t lpropenoat3-Yl)-.1- N-dibutylamino)carbo nyl)methyl) pyrro lidine-3-carboxvlat e The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2
CI
2 solution.
Ethyl trans.trans--4-(1 .3-Benzodoxol-5-yl)-2-(propenoicacid-3-yl)-
N-
dibutylamino)carbonl)methyl)pyrlidine.3.carboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2
CI
2 1- Example :27D Ethyl trans trans--4-(1 3 -Benzodioxol-5-!41)-2z(N-m thylp-ropnmd. l1- N-dibutyla-mino )carbo nyl)methyl)pyrrlidi ne- -carboxylate The title compound is produced by condensing the compound of Example 3270 with methylamine hydrochloride in the presence of a carbodjimide N-ty--3dmtyain~rplabdiie
DCC).
trans. trans--4-(l 3 -Be nzodioxol-5..yl)2(N-mehyl ropenarnid-3-y) 1 dibuitylam-ino)cparbo nyl) methyflpy2rrold ne3coxvlic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 710C.
trans- trns--4 (1 .3-Ben7odi oxo 15y0-2-(1 -hy -roxy-2-roen3yl)-1 fibuittylamino) arbonyl)mehyl)p2yrrolidine-3-carboxylic cd Ethyl tras trans--(1 .3-e~nodioxol-5-yl)-2( -hydroxy-2-p rope l)-1- .N-cibtylamino)carbony)mety)yrrolidine3car olat The title compound is produced by reacting the compound of Example 3270 with borane methyl sulfide complex.
trans. trans--4-(1 .3-Be nzodioxol1-5-yl)-2-(l -hydrox-2-propen--Yl).1
N-
dibutyamino)carbonyl)methlyrroplidine-3carboxyjic aid The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 710C.
trans. trans--4-(1 3 -enzodioxol-5-yl)-2(Nbnzylamin methylUl dibutylamino)carbonyl)methyl)nyrrolidine-.cprboxylic acid -202- Ethyl trans. trans--4- (1.3B n zodox 1-:,-Nbnzl in- ty L4N dibutylamino)carbonyj) methyl)p2yrolidine-3-carhoxylate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohydride in ethanol.
trans. trans--4-(l 3 -Benzodioxol.:5yW)2-(N- enzylamin-omethyl) 1 dibutylamino~carbony;)mthyl)Dyvrrolidine3carboxylic aci The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71 C.
trans.trans--4-(1.-enlxl5-u2(-ctl -bnz-l O~e U1 iutylaminojcajbonylhmethyl)p2yrrolidine.cprrboXy. add Ethyl trans. trans--4-(1 3 -Benzodioxol-5-yl)-2-(Nacetyl-ben-lpinomethyl)- 1 Ndibutylamino'carbony)methyI PYrrolidine3 ela The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.
trans.trans-4-(1-e dox--:U 1y--ezl ioehl (((NN-dibutylamin2)Jcarbonl) methyl)pvrrolidine,-3-arhoxylic acid The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 71 C.
Exaw~l 3t trans, trans--4-(1 .3-enzodioxol--yl)-2-(ethynyl)1
.N-
dibutylamino~carbo nyl) Methyl)6yrrolidi ne-3-carboxylic acid -203- Ethyl trans, tns--4-(1 3 -Benzodioxol-5-vfl..2(ethynyy
N
dibutylamiocaon) methyl)o2yrrolidine3carboxylate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Left. 1972, 3769-72), using the compound of Example 327A.
Urns.trans-4(11 -Bezdxl-5yl)2(ethynyl) 1 dibutylamino)carbo nylDMethvl)pyrrolidi ne-3-cabxlcai The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 710C.
trans. trans--4-(1 3-enzodo y1)2(1 -pntynyl)-
N-
dibuylainocaron)methylyrrlidine 3 coaid Ethyl nstas--4-(1 Bzdoxl5yll.2Dentnl. dilnutylamino)c -oy~ehl~yr~d 3 -clI The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. Org. Chem. 1989, 54(15), 36185-24).
Exmpe 3321 trans. trans--4-(1 -3-1Benz o- SYl)-241 -pntyyi
N
dibu yaino)caronyl)methl)pyrolidine 3 cp.ai The title compound is produced by reacting the compound of Example 332A with lithium hydroxide according to the procedure of Example 710C.
-204trans-trans-2-(4-Me -ny)(1 .3-benzodioxo1-5-yl1 .6dioxopiperidinyn) ethll-pyrrolidine-3-carboxyl ic acid ~The compound of example 61 A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of example 1 D.
Eapl-3 trans-trans-2-(4-MethOxYphenYl)- 4 (1.3-be nzodi-oxoll-5-yl)- 1-f N. Ndighe-nylam.InoabnymtYll..p2vrrolidinpe3crbpylr aid The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 OD) 5 2.83 (dd, 1, J 8.1, 2.99 (d, 1, J= 15.4), 3.19 1, J 3.49 1, J= 15.3), 3.51 (dd, 1, J 3.57 (in, 3.79 3.85 1, J 5.90 6.71 1, J 6.84 (in, 7.04 1, J 7.14-7.16 (in, 7.19-7.34 (mn, MS (DCI/NH 3 m/z 551; Anal Calcd for C33H30N20 6 -0.65H 2 0.3502H50C0CH 3 C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.
trans-trans-2-(4..Methoxyphenyl4( 1 .3-be nzo-dioxol-5-yl)-1 diisorp~ylaminocarbonvlmethylpyrrp*iine-3carbpXyli acid, The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD 3 OD) 5 0.95 3, J 1.24 3, J= 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, J 8.1, 3.14 (t, 1, J 3.32-3.55 (in, 3.63 (in, 5.92 6.75 1, J 6.85 (dd, 1, J 1.7, 6.93 (in, 7.02 1, J 7.35 (in, MS (DCI/NH 3 m/z 483. Anal Calcd for C27H 34
N
2 0 6 .0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19.
Found: C, 5.74, H, 7.26, N, 5.52.
-205rans-trans-2-(3..Fluo0-4..mthxypenl)l 3-bezdixl5Y). nsu~vamn~thVII-.wrrplnI; cprbxYic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-661C. 1 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 7 2(quintet, J=7.5Hz,2H), 2 2 5-2.35(m,1 2 7 2 -2.94(m, 5H), 2.97-3.1 2(m, 2H), 3 .19-3.46(m, 2H), 3.44(d, J=9Hz,i 3 5 3-3.60(m, 1 3.67(d, J=9Hz, 1 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1 6.82(d, J=8Hz, 1 6.92(t, J=9Hz, 1 6.97(s, 1 7.1 2(d, J=9Hz, 1 7.185(d, J=1 2Hz, 1 MS (DCI/NH3) m/e 565 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared.
-206- TABLE 1 02 H2Q 4 N 13 16 60 19 o2NN:) gS 22 00e 8 H300..F2'S.N%~ 0 g0 14 H'COI)Cl 17 6Io 20 e 23 00 24 aE 3 12 0 0 18 0 2'.
4 r 00 cI~~ 00 -207a 28 FH2C%.%, 31 F 0
F
2
HC,~
34 37 00 o 26 H3 co"W 29 0"CN~.
32FH:?c% 38 27 0 30 -ThC
F
3
C,
0 00 00 42 00 44 486Sr r 50 51 0 -208- TABLE- I (cont'd) 2 0~ pr a p 0 58 0 61 0 64C)'y 67- 0 700 73 76 A 56 r 0 cxoy 570 y 60 0 63 c 66 o 65 r, 00roy" 0 72 N0 74016 0
A
0 -209- TABL I4cntQd 0 0 0 88 0 91 0 94 0
R
0 0 0 <K-Oy 0 0 0 81 84
R
0 0 87 0 <k 90 0 93 0 96 0 990 pj 100 101 1Al 0 105 0 103 104 -210- TABLE 1 (cont'd) 106 109 0
CH,
NY~
107
R
H
CHI
H
108 110 112 0~ 113 0 14 sto
?H
3
K\
117 0 20 OrN< o qH 3 r' 0 0 115 116 118 0 121 (0 124o 12701 1 19 k, 122 123 0 126FIC, 0 129c0 125 128 -211- TABLE l(cnt'd) 130 ILI 0A a 131 OCH, 1 132 H,aC- 133 7134 0 135 &N
Y-
137 0 138 I 136 139 142 140 00 143 141 144 NdTh 00~ d o 145 146 00 147 0 150 d00 0 0 148 0
H
3 1 f 151H3 H3 149 -212- TABLE 1 (cont'd)
A
152 CN
.&P-I
9 0 15500 0 158 0 161 6 1536 0 156 159 0 16264 a 157 0 160 163 6y 1650 -213- Examle 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.
-2 14- TABLE 2A
F
0 27
OH
3 ,C00 0 momo
MOMO
0 6
OCH
3 0
F
6COH
F
',CM
R- .00
F
F
MOMO
.C OOH F 12
,COOH
-215- TABLE A(ot)
F
R-NOCH
OCI-1 14
~,COOH
16) eq.COOH 0 19 OCH 3
MOMO
R 00 OCH3
F
R 0 00O H 00H 3 0 OCH 3
F
R-
COOH
0
OCR
3
F
R-
COOH
0
H
3 I-7 0 21
OM
.j COOH
.OOH
-2 16- TABLE 2A (cont'd)
OM
R-
IOCOOH
0 26
RMOCO
28 0 29
MOM
R-
%COOH.
-N
31 /32
H
3 R-
COOH
o 27
H
3
-OO
F
COOH
0 .C0OH -2 17- TABLE 2A (cont'd) mom
.OCOOH
-COOOH
OCH
3 3 9
H
3
I.OCOOH
41 0
F
,C.OOH
OCH
3 mom
R-ICOOH
OCH
3
M
L
OOOH.
OCH
3
MOOO
I-
OH
3 4 2
F
,..COOH
OCH
3 -218- TABLE 2A ont'd) mom
I*PCOOH
R-
,COOH
0 oe-- R- 0OH
F
R- .COOH R-N
OCOOH
OC 3
R-
0 -219- TABLE 2A (ca-nt'dl R- UOCOH 62
R
64 67 R- UOOOH
,,,COOH
H
3 b 66 0 R-
OCOOH
69 '-O 7 2 0 0 H 3 -220- TABILE 9A (cnt CR3 o'COOH R-N koCOOH 74 CR3 o*-COOH
"O;COOH
ocf3 OCv 3 Q"-COOH
Q"-COOH
R- COOH R- COOH 77 OCR3 0
-COOH
R- k.OOH
/COOH
OCK3 81
H
3
OH
l-
.COOH
-221- TABLE 2A (cont'd)
H
3
OCH
3 OH 3 0 H O H C 3H O.COO .O H*CO IOH OH ,~~COOH IPCOOH C H R\ R- ,HOOO H3f H O
CH
3 OH 3 O H 3 l' o Fl COOH O.COOH
~CO
91 92 IOOO -222- TABLE 2A--(cont'd) F F
F
CH cf* 3
H
3 R .C O O H C O O H O C 0H 97 0 98 099 F F
F
OCH
3 ,.OCH 3 OH R- 0Q R- R-00 O.COOH /NR)
F
100 101 102
-F
F
CH
3 H C F
H
3
C
IOCOOH
_COOH
1
OCH
3 I0 103
OCH
3 104 0100 106 106 107 108 -223- TABLE 2A (cont'd) 109 110 OCH 3 112 115 R
COOH
R-
,COOH
113 116 R-
.COOH
R-
*COOH
o 117 R- OAC0OH 119 R- IOC0OH 0 R- ~.0H 118 120 -224- TABLE 2A (cont'd) 122
CH
3 R-
COOH
0' R-
*OCOOH
123 00H 3 R-
.COOH
126
OOCH
3 R-
COOH
0 129
.COOH
124 125 128
OH
3
IFCOOH
OCH
3 R-
OCOOH
0 127 130 130 ~13113 132 -225- TABLE 2A (cont'd)
H
3
,H
3
*.COOH
0 135 133 136 134
OH
3 137 H 3 C -OCH 3 138
OH
3 R-
ICOOH
0 141
OH
3 A-L ,,kCOOH 139 140 14214 143 144 -227- TABLE A (cont'd Af-
OCOOH
157 OCH 3
MOMH
159 160 163 158 161 164 162 00H 3
IOCH,
16616 167 168 -228- TABLE A (cont'd) F MOMO
F
,L \N
N-
R-R- R 169 170 0 171 MOMO F
MO
R-NR-R
172 173 174 F MO
F
175 'k176 177 MOMO F
MO
R- R R-N F 0083
N
178 F 1170 o~h I iQn I
O~.J
-229- TABLE- 2A (cont'd)
F
H
3
CQ
H
3
CO
fl-N
I>
184 187 182 185 188 183 186 189
MOMO
R-
190 190 192 -230- TABLE-2A (cont'd) 193 196 199 194 197 200
F
R-N
H
07 201 'S N(CH3) 2
H
202 202 203 204 -231- TABLE 2A (cont'd) R-
.COOH
206 0 R COOH 207 0 205 R-NrOH 208 0> 209 0> 210 -232- TABLE Zq 0 0 21 0 14 0 0 0 13 0 16 0 19 22 00oo So 0 H C O l d r l r 170 1~ 20 d' 21 23 2 4 26 3p27
FH
2 29 e 3 0 2 0 0 0)ay 000 F3 h0 -233-
R
31 F 2 0 0
F
2
HC..
34 32 F 2 00 35 F30.
33 2C
F
3
C,
36 F 2 37 38 00 43 o 41 44 d'" FCo",al rl"- 6 -0" 42 00 45 %01- 48 0 51 croc
-T
C I'Y' r 0 57 0 -234- TABLE 2B__(Cont'd) fl 58 v l 600 63 HC0I 61V
O$
64 0 N~Th 0 73 76 68 0 6 71 7No 72 74 75 77 0 7 0 0 -235- TABLE2B(ot) 79 81
<A
00 -236- Example 339 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.
-237- TABLE 3A
MOMO
R
,COOH
F
COOH
CH
3
.%COOH
OCH,
R-
.COOH
OCH
3 R
OCOOH
F
.COOH
RI-§N
,%COH
0 ,COOH COOH ~COOH CO
,COOH
-238- .TABLE 3A-(oont'd)
-N
R- OOH O> 14
OCH
3 R- VC000H OOH-3 17 0 A- COOH \0 0 OC 15 1430 18
'OOH
-239- TIDLE3B 0 0 0 0 a 0 100 13 0 cr- 0 ,y" 16 0 19 0 22 0 28 0 0 0T 14 0 0 12 0 15 0
H
3
CO
18 0 21
H
3 00 24 00 27 0 20- NCO* cIc HaG~kk, 002-.
-240- TABLE 3B (cont'd)
R
31 F 2 0 0
F
2
HC%
0 34 F l: 37 0.0 43 0 0 32
F
2 35 F 2 3C- 38 0 41 O 44 0
R
33
F
2 36 39 42 6"
F
3 C0,a 45 00 48 0 51 FC0(% 0 0 yNy-y 0 -0-Kr 57 F 0 -241- TABLE 3B (contod) Ny-y a cl 61 0a, 62 OCH 3 63 H 3 0 0 64 0 67 ?H3 73 do 76 68 0 69 9H 3 71 072 74 77 o '7 01 S8 00 -242- TABLE 3B (cont'd) 79 00 a -Th 00 aE -243- As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.
Binding Assay ETA 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 pig/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.
[125slET-1 binding to membranes: Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of 125 1]ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 oC. After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times. Nonspecific binding was determined in the presence of 1 IM ET-1. The data are shown in -244- Table 4. The per cent inhibition at a concentration of 1 gM is shown. The data show that the compounds of the invention bind to the endothelin receptor.
Table 4 Binding Data Inhibition of Inhibition of Example ETA at 1 .M Example ETA at 1 I.M 1 D 96.4 30 80.0 2 58.4 31B 93.6 3 42.2 34 95.5 4 78.2 35 91.8 95.1 36 94.5 6B 34.9 37 47.9 7 63.4 38 100.0 8 53.7 39 83.6 9 69.2 40 94.8 66.1 41 89.9 14 86.6 42 95.2 84.8 43 99.2 16 96.0 44 91.3 17 73.9 45 85.4 18 97.3 46 90.4 19 90.3 47 95.1 80.9 48 96.3 21 56.3 52 84.0 22 86.3 54 64.6 23 85.9 55 50.5 26 83.0 56 34.3 27 61.2 57 93.2 28 63.8 58 81.9 29 85.3 59 70.8 42.8 I 93C 59.2 -245- 61 C 62 63 64 66 67 68 69D 71 720 730 74 750 76 79 82 83 84 86 87 88 89 910c 90.6 94.1 92.0 95.0 82.8 87.7 -96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 65.3 52.6 62.4 84.3 84.6 91.6 95D 96 97 98 99 100 101 102 103 104 105 106 107 109 110 i11 112 113 114 115 116 117 118 119 120 121 82.1 86.1 89.0 86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6
I
92C 107.4 1122 95.3 123 124 125 126 127 128 89.7 91.0 97.2 91.7 91.4 95.4 146 147 148 149 150 151 25.0 73.0 94.7 84.6 93.6 80.5 -246- 129 130 131 132 133 134 1358 136 138 139 140 141 142B 143 144 145 100.1 91.0 89.5 90.0 88.6 92.2 77.7 79.4 83.0 98.6 106.3 92.8 78.7 20.6 78.2 32.4 152 153 154 155 156 157 158 159 160B 161 162B 163 164 165 166 167 291 86.9 97.1 80.2 92.7 92.6 83.8 91.8 36.2 80.3 93.6 91.5 90.6 98.6 54.1 91.6 94.4 100.0 Example 293 295 297 299 301 303 305 307 Inhibition of ETA at 1 iM 89.8 93.0 84.4 90.4 96.7 87.2 87.4 92.2 Inhibition of ETA at 1 gM 80.7 92.3 96.3 Example 294 296 298 300 302 304 306 308 Example 310 312 314 Inhibition of
ET
A at 1 iM 77.7 87.1 93.3 96.1 86.6 89.7 93.3 93.0 Inhibition of ETA at 1 LM 87.1 88.2 86.0 Example 309 311 313 -247- 315 82.7 316 74.0 317 68.5 318 79.0 319 79.0 320 82.2 322 95.6 323 91.3 324 95.0 334 88.0 335 84.1 As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the described compounds to inhibit ET-1-induced phosphatidylinositol hydrolysis was measured.
Determination of Phosohatidylinositol (PI) Hydrolysis MMQ cells (0.4 x 106 cells/mL) were labeled with 10 tICi/mL of 3 H]myoinositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and 10 mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of mL of 1:2 chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 chloroform-methanol-water of as described by Berridge (Biochem.
J.
206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 pL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1-X8 (Bio- Rad). The IC 5 0 is the concentration of test compound required to inhibit the ETinduced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.
-248- Table Phosphatidylinositol Hydrolysis Example ICso 1iM 1 D 0.025 14 0.017 0.010 16 0.009 18 0.009 19 0.024 0.001 318 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 18 103 (1990) and Takata, et al., Clin. Exp. Pharmacol.
Physiol. 1 131 (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 8 2226 (1990).
The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114 (1990).
The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ.
Res. 54 711 (1984).
-249- The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J. Neurosurg. 66 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991).
The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J. Pharmacol. 197: 75-82, (1991).
The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin.
Invest. Q 1762 (1989).
The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).
The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am.
J. Physiol. 256 G661 (1989).
The ability of the compounds of the invention to treat cyclosporininduced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 3Z 1487 (1990).
The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. Za 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. Z 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 Z8 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).
i -250- The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 2a 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichiri, et al., J. Clin. Invest. 8Z 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).
The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin.
Invest. 8Z 1867 (1991).
The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat.
Acad. Sci. 92 2691 (1995).
The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J.
Pharmacol. Exp. Therap. 21 156 (1994).
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, -251benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as 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 -252hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of 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 -253subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting -agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be The title compound was prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, lubricating agents such as 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 know6 in the art, liposomes are generally derived from -254phospholipids 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 capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof.
-255- Representative angiotensin II antagonists include DUP 753, A-81988 and the like.
Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representative 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.
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.

Claims (21)

1. A compound of the formula: R2 z 'NR 3 N (CH 2 )n RD wherein Z is -C(R, 8 )(Rl 9 or wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n isO0 orn; R is -(CH2)M-W wherein m is an integer from 0 to 6 and W is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3 H 2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)N HR 17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)Rl6, -257- HO 0 0 0 0) H 0 0 (s)H CF 3 H 0,o N HO 2 F (u0 Rian R ae ndeednl eetdfo ydoelwrlyaknl alyy, loylkl lkxcronllylhdoyakl akxakHyly tholoxakxylycylakyaiocroylly, lyaincro0lly dialkylami~ noc r o yl l y am0c r o y a k n l l y a i o a b n l l e y -258- dialkylami nocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkoxyalkyl, heterocyclic and (Raa)(Rbb)NR wherein Ra is aryl or arylalkyl, Rb is hydrogen or alkanoyl and R 0 C is alkylene, with the proviso that one of R, and R 2 is other than hydrogen; R 3 is R 4 -C(O)-R 5 R 6 -S(O) 2 -R 7 or R 26 -S(O)-R 27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 or -RaN(R 2 0)-R 8 wherein R 8 and R 8 a are independently selected from alkylene and R 20 is hydrogen, loweralkyl, alkenyl, cylcoalkyl or cycloalkylalkyl or -O-R 9 or -R 9 ,-O-R 9 wherein R 9 and R 9 a are independently selected from alkylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-R 10 wherein R10 is alkylene and R 21 is hydrogen or loweralkyl; R 4 and R 6 are independently selected from the group consisting of (R 1 1 )(R 12 wherein R 1 1 and Ri are independently selected from hydrogen, loweralkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclic, arylalkyl, and (11) (heterocyclic)alkyl, (ii) loweralkyl, (iii) alkenyl, (iv) alkynyl, -259- cycloalkyl, (vi cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl and (xi) alkoxyalkyl; R 26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyt, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and R27 is alkylene or alkenylene; R22-O-C(O)-R 23 wherein R 22 is a carboxy protecting group or heterocyclic and R 23 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24 )-R 25 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, or R13-C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino or dialkylamnino and R 1 4 is aryl or R 15 wherein R 15 is amino, alkylamino or dialkylamino; -260- or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 of the formula: wherein R, R 1 R 2 R 3 n and Z are as defined therein.
3. The compound according to Claim 1 or 2 wherein n is 0 and Z is -CH 2
4. The compound according to Claim 1 or 2 wherein n is 1 and Z is -CH 2 The compound according to Claim 1 or 2 wherein n is 0, Z is -CH 2 and R 3 is R 4 -C(O)-R 5 R 6 -SO 2 -R 7 or R2 6 -S(O)-R 27 wherein R 4 R 5 R 6 R 7 R 26 and R 27 are as defined therein.
6. The compound according to Claim 1 or 2 wherein n is 0, Z is -CH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.
7. The compound according to Claim 1 or 2 wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R12)N- as defined therein and R 5 is alkylene or R 3 is R6-S(0) 2 -R 7 or R26-S(O)-R 27 wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are as defined therein.
8. The compound according to Claim 1 or 2 wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-N(R 20 )-R 8 or R6-S(O) 2 -N(R21)-R 1 0 wherein R 8 and Rio are alkylene and R 4 R 6 R 20 and R 21 are as defined therein. -261-
9. The compound according to Claim 1 or 2 wherein n is 0, R is tetrazolyl or -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group or R is -C(O)-NHS(O) 2 Rl 6 wherein R 6 IS loweralkyl or aryl, Z is -OH 2 Rl and R 2 are independently selected from loweralkyl, (ii) cylcoalkyl, (iii) substituted aryl wherein aryl is phenyl substituted with one or two substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy and (iv) substituted or unsubstituted heterocyclic, and R 3 is R 4 -C(O)-R 5 wherein R 4 is (Rll)(R 12 wherein R 11 and R 12 are independently selected from loweralkyl, aryl and arylalkyl and R5 is alkylene; or R 3 is R4-C(O)-N(R 20 )-R 8 or R6-S(O) 2 -N(R 21 )-R 10 wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl, R 8 and Rio are alkylene and R 20 and R 21 are loweralkyl; or R 3 is R6-S(O) 2 -R 7 or R 26 -S(O)-R 27 wherein R 6 is loweralkyl, R 7 is alkylene, R 26 is loweralkyl and R 2 7 is alkylene. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 is loweralkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofu ranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, di hyd robe nzofu ranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-N(R 20 )-R 8 or R6-S(O) 2 -N(R 2 1)-Rlo- wherein R 8 and R 10 are alkylene, R 20 and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl. -262-
11. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 Ri is loweralkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R: 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, aryl and arylalkyl.
12. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 is substituted or u nsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-f luorophenyl, 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, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4 -methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and A 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein Rjj and R 12 are independently selected from loweralkyl, aryl and arylalkyl.
13. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophe nyl, 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, R 2 is 1 ,3-benzodioxolyl, 1 .4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 -263- wherein R 5 is alkylene and R4 is (Rlli)(R1 2 wherein RI, and R 12 are independently selected from loweralkyl.
14. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R, is phenyl or (ii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R6-S(O) 2 -N(R 21 )-R 10 wherein R 10 is alkylene, R 6 is loweralkyl, aryl or arylalkyl and R 21 is loweralkyl, aryl or arylalkyl. The compound according to Claim 1 or 2 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 3 is R6-S(O) 2 -N(R 2 i)-Rl 10 wherein Aio is alkylene, R 6 is loweralkyl and R 21 is loweralkyl.
16. A compound selected from the group con sisting of trans, trans- 2-(4-Methoxyphenyl)-4-(1 1 3-benzodioxol-5-yl)-1. (propylami nocarbonylmethyl)-pyrrolidine..3.carb 0 xylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y)-1 propoxyethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-be.nzodioxol-5-yl)-1 prpl--ehlmncroymty)proiie3croyi acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-be nzodioxol-5-yi)-1 (isobutylaminocarbonylmethyI)-pyrrolidine-3-carboxyli acid; -264- trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (cyclope ntylami nocarbo nylm ethyl) -pyrro lidi ne..3-carboxylic acid; trans, trans-2-(4-Meth oxy.2met hoxymet hoxyph enyl)4-(l,3- benzodioxol-5-y)-1 -(N-methyl-N-butylami nocarbonylm ethyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4.(1 ,3-be nzodioxol-5-yl)- 1 ,N- di isoamylami nocarbon ylmethyl) pyrro lidi ne.3carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4(1 1 3-benzodioxol-5-yl)-1 dipe ntylaminocarbonylmethyl)-pyrrolidine.3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)4(1 ,3-benzodioxol-5-yI)-1 -(N,N-di(2- methoxyethyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y)-1 cyclopropymethyk-N-propylaminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(4-Methoxyphenyl).4-(1 ,3-benzodioxol-5-yl)-1 ,N- diisobutylaminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yl)-1 -(N-methyl- N-(2- propynyI)aminocarbonylmethyl)-pyrrolidine..3-arboylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-y)-1 -(N-methyl- N-(n- hexyl)aminocarbonylmethyl)-pyrrolidine-3.arboxylic acid; trans, trans-2-(4-Methoxyphenyl).4.(1 1 3-benzodioxol-5-yI)- 1 -(N,N-di(n- butyl )ami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4(1 ,3-benzodioxol-5-yl)-1 diethylaminocarbonylmethyl)-pyrrolidine3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl).4(1 ,3-benzodioxol-5-y)-1 -(N-methyl- N- cyclo hexylami nocarbo nylm ethyl)-pyrro lid ine.3-carboxyl ic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-di(n- propyl)aminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4.(1 ,3-benzodioxol-5-yl)- 1 -(N-methyl- N- isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 (ethylsulfi nyl)ethyI)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl).4-(1 ,3-benzodioxo 1- 5 -yl)-1 methyl-N-i so propy Ica rbo ny la mino) ethyl)-pyrroli din e.3carboxy i c acid; -265- trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 methyl-N-propionylamino)ethyl)-pyrrolidile-3-carboxyic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-be nzodioxol-5-y)-1 (N-methyl- N- benzylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)-1 -(N-ethyl-N- butylami nocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxo-5-y)-1 methyl- N- pro pylsu lfo nylami no)ethyl)-pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,4- dimethoxybenzyl)-N-methylaminocarbonylmethyl)pyrrolidine-3- carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 dimethoxybenzyt)ami nocarbonylmethyl)pyrrolidi ne-3-carboxylic acid; (2R,3R,4R)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 R)-1 (N ,N- dipropylaminocarbonyl)-1 -butyt)pyrrolidi ne-3-carboxylic acid; (2S,3S,4S)-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 R)-1 (N ,N- dipropylaminocarbonyl)-1 -butyl)pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 ,N-di (n- butyl) ami n ocarbonyl methy)-3-(5-tetrazoy pyrrol idi fie; trans, trans-2-(4-Fluoropheny)-4-(1 ,3-be nzodioxol-5-yI)-1 ,N-di (n- butyt)aminocarbo nylmethyl)pyrrolidine-3-carboxylic acid; trans, tranis-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 N-n-butyl)- N- (n pro pyl)am inocarbonyl methy)pyrrolidi ne-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 di (n- pro pyl)ami nocarbonyl)ethyl]pyrrolidine-3-carboxyli c acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-di (n- butyl)aminocarbonyl)methyl)pyrrolidi ne-3-(N- methanesulfonyl)carboxamide; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (n- butyl)ami nocarbo nyl)methyl)pyrrolidi ne-3-(N- benzenesulfonyl)carboxamide; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxo 1-5-yl)- 1 N- dibutylamino)carbonyl-1 RS)-ethyl]pyrrolidine-3-carboxylic acid; -266- trans, trans-2-(Pentyl)-4-(1 ,3-benzodioxo I-5-yI)- 1 N- dibutylami no)carbonylmethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo I-5-yI)- 1 propyl-N- butyrylamino)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo 1-5-yI)- 1 propyl- N- (ethylaminocarbonyl)ami no)ethyl]pyrrolidi ne-3- carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo I-5-yi)-1 -[2-(N-butyl- N- butyrylami no)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo I-5-yI)- 1 propyl-N- ethoxycarbonylamino)ethyl]pyrro Iidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4(1 ,3-benzodioxo 1 methyl-N-(2- pro pylvaleryl)ami no)ethyl] pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo I-5-yI)- 1 propyl- N-(4- methoxyphenoxycarbonyl)amino)ethyl]pyrrolidine- 3 carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4{(1,3-benzodioxo-5-y)-1 propyl-N-(4- met hoxybenzoyl)am ino)ethylpyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-y;)- 1 propyl-N- ben zoylam in o)ethyl]pyrro lidi ne-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4{(1,3-benzodioxol-5-yI)- 1 propyl- N- benzyloxycarbo nylami no) ethyl] pyrrolidi ne3carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxol-5-y)- 1 -[2-(N-butyl- N- ethoxycarbonylami no)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- Met hoxyp he nyl)-4{(1,3-be nzodioxol1-5 1 (N -butylI- N- pro poxycarbo nylam i no)et hyllpyrro lidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzodioxo 1- 5 1 propyi- N- pro poxycarbo nylami no)ethyl]pyrrolidi ne-3-carboxylic acid; trans, trans- 1 N-Di (n-buty)ami nocarbo nyl) methyI2,4-di (1 ,3- be nzodioxo I-5-yI)pyrrolidi ne-3-carboxylic acid; trans, trans-i (n-Butyl)-N -pro pylsuIf on ylam i no) et hyl)-2- (4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid; trans,trans-1 -(N.N-Di(n-butyl)aminocarbonylmethyl)-2(4. methoxyphenyl)-4- (1 1 3-benzodioxol-5-yl)pyrrolidi ne-3-carboxylic acid: trans, trans-i 2 -(N-Propyl-N-propylsulfonylamino)ethyl)-2-(4- methoxyphenyl)-4-(1 i 3 -benzodioxol-5-yl)pyrroidine3crboxylic acid; -267- trans, trans- 1 -(2-(N-Butyl-N-butylsulIfo nylamin o)et hyl)-2- methoxyphe nyl)-4- (1 3 ben zodioxol-5-yl) pyrro lidi ne-3-carboxylic acid; trans, trans-i1 -(2-(N,N-Dibutylami nocarbonylmethyl)-.2-(4. meth oxymethoxyphe nyl) ,3-be nzodioxol-5-yI)pyrro lid ine-3. carboxylic acid; trans, trans- 1 -(2-(N,N-Dibutylami nocarbonylmethyl)-2-(4- hydroxyphenyl)-4- (1 ,3-benzodioxol-5-yl)pyrro lidi ne-3-carboxylic acid hydrochloride salt; trans, trans-i lsobutyl-N-propylsulfonylami no) ethyl)-2-(4- methoxyphenyl)-4-(1 3 -benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Benze nesulfonyl-N-propylami no)ethyl)-2-(4- methoxyphenyl)-4-(1 1 3 -benzodioxol-5-yl)pyrrolidine-3..carboxylic acid; trans, trans- 1 2 4 Meth oxybe nze nesuIfo nyl)-N -pro pylami no) ethyl)- 2-(4- methoxyphe nyl)-4-( 1,3-benzodioxo I-5-yl)pyrro lidi ne-3- carboxylic acid; trans, trans-i1 N- D i(n-butyl) ami nocarbonyl meth yl)-2- methoxyethoxy-4- methoxyphenyl)-4-(1 ,3-benzodioxol-5- yl)pyrrolidine-3-carboxylic acid; trans, trans-i Propyl-N-(2 .4-di methylbenze nesulfonyl)amino)- ethyl)-2-(4-methoxyphenyl)-4.(1 ,3-benzodioxol-5-y)pyrrolidine- 3- carboxylic acid; trans, trans-1 P ropyl-N- (3 -ch lo ropropylsulIfo nyl)am i no) ethyl)-2- (4- methoxyphenyl)-4-(1 3 -benzodioxoI-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i 2 -(N-Propyl-N-(2-methoxyethylsulfonyl)amino)ethyl)-2(4. methoxyphenyl)-4-(1 1 3 -benzodioxol-5-yl)pyrrolidine-3..carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(2-ethoxyethylsuIf onyl) ami no)ethyl)-2-(4- methoxyphenyl)-4-(1 7 3 -benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans,trans-1 -(2-(N-Propyl-N-(5-dimethylamino-1 naphthylsulfonyl)amino)ethyl)-2-(4-methoxyphenyl).4-(1 ,3- be nzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i -(2-(N-Propyl-N-(ethylsulfonyl)amino)ethyl).2-(4- methoxyphenyl)-4-(1 3 -benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans- 1 2 (N-P ropyl-N- (4-m et hylbe nzen esu lfonyl)ami no)ethyl).2- (4- methoxyphenyl)-4- (1 ,3-benzodioxo I-5-yl)pyrrolidi ne-3- carboxylic acid; trans,trans-1 -(NN-Di(n-butyl)aminocarbonylmethyl)2(3pyridy) 4 be nzodioxol-5-yl)pyrrolidine-3-carboxylic acid; -268- trans, trans-i ropyl-N-(n-butylsu Ifonyl)amino)ethyl)-2-(4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans,trans-1 -(2-(N-Propyl-N-(4-chlorobenzenesulfonyl)amino)ethyl).2- (4- methoxyphenyl)-4-(l ,3-benzodioxolk5-y)pyrrolidine-3- carboxylic acid; trans,trans-1 -(2-(N-Propyl-N-(benzylsulfonyl)amino)ethyl).2-(4. methoxyphenyl)-4-(1 1 3-benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans- 1 2 Propyl-N-(4-f luo robe nzenesuIf o nyl)arino)eth yl)-2 (4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)pyrrolidine-3- carboxylic acid; trans,trans-1 -(N-Methyl-N-propylaminocarbonylmethyl).2.(4. methoxyphenyl)-4-(6-benzofu ranyl)pyrrolidine-3-carboxylic acid; trans, trans- 1 N-Di buty lami nocarbo nyl methy)-2..(4-.methoxyp he nyl 4-(4- be nzof uranyl)pyrro lid ine-3..carboxylic acid; trans, trans- 1 N-Dibutylami nocarbonyl met hyI)..2(4-.methoxyp he nyl) 4-(4- be nzof uran yl)py rrolidi ne-3-carboxylic acid; trans, trans-1 -(NN-Dibutylaminocarbonylmethyl)-2(4.methoxyphenyl). 4-(6- benzofuranyl)pyrrolidine-3-carboxylic acid; trans,trans-1 -(NN-Dibutylaminocarbonylmethyl).2-(4..methoxyphenyl). 4-(6- benzo-2 ,3-di hydrofu ranyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i1 N- Di butylami nocarbo n ylmet hyl)-2- (4meth oxyphen yl) 4- benzo-2 ,3-di hydrofu ranyl)pyrrolidi ne-3-carboxylic acid; trans, trans- 1 N- Dibutylami nocarbonyl met hyl)-2-(4-.meth oxyp he nyl) 4-(4- met hoxyphe nyl) pyrrolidi ne-3-carboxylic acid; trans, trans- 1 N- Dibutylami nocarbonylmethy)-2-(4..meth oxyp hen y) 4- 3 ,4-difluo rop hen yl)pyrrolidi ne-3-carboxylic acid; trans, trans- 1 N- Dibutylaminocarbonylmethyl)-2-(4..methoxyphenyl)- 4- (2 ,4-dimethoxyphenyl)pyrrolidine-3-carboxylic acid; trans, trans-1 N- Dibutyami nocarbo nylmethyI)-2-p hen yk-4(1 13- benzodioxo I-5-yI)pyrrolidi ne-3-carboxylic acid; trans,trans-1 -(NN-DibutylaminocarbonylmethyI)-2-phenyI-4.(5..benzo- 2,3- di hydrofu ranyl)pyrro lid ine-3-carboxylic acid; trans, trans-i N-Dibutylam inocarbonylmethyl)-2-(4-t-butylphe nyl)-4- ben±o-2 ,3-di hydrofu ran yl) pyrroli di ne-3-carboxylic acid; trans, trans-2-(N, N-Dibutylaminocarbonylmethyl)-2-.(4-methoxyphenyl)- 4-(4- fluorophenyl)pyrrolidine-3-carboxylic acid; -269- trans, trans-i ,N-Dibutylaminocarbonylmethyl)-2-(3-furyl)-4-(1 ,3- benzodioxo I-5-yI)pyrrolidi ne-3-carboxylic acid; trans, trans-l1 N-Di butylami nocarbonyl methyl)-2-(isopropyl)-4- (1 ,3- benzodioxol-5-yI)pyrrolidine-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbonylmethyl)-2-(4-t-butylphe nyl)-4- (1 ,3- benzodioxol-5-yl)pyrrolidine-3-carboxylic acid; trans, trans-i1 N- Dibutylam inocarbo nylm ethyl)-2-(4-t-butylphe nyl)-4- be nzo-2 ,3-di hydrofu ranyl)pyrrolidi ne-3-carboxylic acid; trans, trans-i1 Di butylami nocarbo nylmethyl)-2- (anti-4- methoxycyclohexyl)-4-(l ,3-benzodioxol-5-yI)pyrrolidine-3- carboxylic acid; trans, trans- 1 N- Dibutylami nocarbonylImethyl)-2- (syn -4- methoxycyclo hexyl) (1 ,3-benzodioxol-5-yI) pyrro li din e-3- carboxylic acid; trans, trans- 1 N -Di butylami nocarbo nylImethyl)-2,4-di (5-be nzo-2,3- di hydrofu ranyl)pyrrolidine-3-carboxylic acid; trans, trans-i1 ,N-Dibutylami nocarbonylmethyl)-2- (3-furyl)-4-(5-be nzo- 2,3- di hydrofu ranyl)pyrrolidine-3-carboxylic acid; trans, trans- 1 -(N,N-Dibutylami nocarbonytmethyl)-2-(4-methcixyphenyl)- 4-(3- fluorophenyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)- 1 -(N-butyl-N- phenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans- 1 ,N-Di butylami nocarbo nylmethyt)-2- (2-f lu oro phenyl)-4- (1,3- be nzodioxol-5-yI)pyrrolidine-3-carboxylic acid; (2 R,3 R,4S)-(+)-2-(4-methoxyphenyt)-4-( 1,3-benzodioxol-5-yI)- 1 ,N-di (n- butyl)aminocarbonylmethyl)-pyrrolidi ne-3-carboxylic acid; trans, trans-1 N- Dibutylami nocarbo nylmethyl)-2-(3-f luoroph enyl1)-4- (1 ,3- be nzodioxol-5-y!)pyrrolidi ne-3-carboxylic acid; trans, trans-i ,N-Di butylami nocarbonylmethy luorophenyI)-4- (1,3- be nzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; trans~trans-1 -(N,N-Dibutylaminocarbonylrnethyl)-2-(4-ethylphenyl)-4- (1,3- be nzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; trans, trans-i N-Dibutylaminocarbo nylmethyl)-2-(3-fluoro-4-methoxyphenyl)- 4- (1 ,3-benzodioxol-5-yI)pyrrolidi ne-3-carboxylic acid; and -270- trans, trans-i1 Propyl-N- (n-pentylsu If onyl)ami no)ethyl)-2- (3-f luoro. 4- methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)pyrrolidine-3. carboxylic acid; or a pharmaceutically acceptable salt thereof.
17. The compound trans, trans-2-(4-Methoxyphenyl)-4(1 ,3- -(N,N-di(n-butyl)aminocarbonylmethyl)..pyrrolidine-3 carboxylic acid; or a pharmaceutically acceptable salt thereof.
18. The compound (2R,3R,4S)-(+)-2-(4-methoxyphenyl)4.(1 3- -(NN-di(n-butyl)aminocarbonylmethyl)..pyrrolidine- 3 carboxylic acid; or a pharmaceutically acceptable salt thereof.
19. A compound of the formula: NH (CH 2 )n (CH 2 M wherein n is 0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, (b) -P0 3 H 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, 0) alkoxy, sulfonamido, -27 1- -C(O)NHS(O) 2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 -VN0 0 0 HO 0 OH 0 0 NHSCF (u A n R 1 adR 2 aeineedetyseetd rmhyrgnlwrakl ak0l alyyakxakl loxcrqy)kl yrxalyakxakxakl -272- thioalkoxyalkoxyalkyl, cycloalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkoxyalkyl, heterocyclic and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RcC is alkylene, with the proviso that one of R 1 and R 2 is other than hydrogen; or a salt thereof. The compound according to Claim 19 of the formula: R2 R2 NH R' NH I I (CH2)n VI (CH2)n (CH 2 )m (CH 2 )m I I- W R1 w R1 or W wherein R 1 R 2 W, m and n are as defined therein.
21. The compound of Claim 19 or 20 wherein m is zero or 1; W is -C02-G wherein G is hydrogen or a carboxy protecting group.
22. The compound of Claim 19 or 20 wherein n and m are both 0; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is loweralkyl, (ii) cycloalkyl, (iii) phenyl, (iv) pyridyl, furanyl or (vi) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 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 and R 2 is -273- 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl.
23. A pharmaceutical composition for antagonizing endothelin comprising a therapeutically effective amount of the compound of Claim 1, 2, '17 or 18 and a pharmaceutically acceptable carrier.
24. A method for antagonizing endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of' Claim 1,2, 17 or 18.- A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1, 2, 17 or 18.
26. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1, 2, 17 or 18 in combination with one or more cardiovascular agents. DATED this TENTH day of MARCH 1999 Abbott Laboratories Patent Attorneys for the Applicant SPRUSON FERGUSON
AU20344/99A 1994-08-19 1999-03-10 Endothelin antagonists Ceased AU725122B2 (en)

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