EP1003740A2 - Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagoists - Google Patents

Pyrrolidine-3-carboxylic acid derivatives and their use as endothelin antagoists

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Publication number
EP1003740A2
EP1003740A2 EP98937139A EP98937139A EP1003740A2 EP 1003740 A2 EP1003740 A2 EP 1003740A2 EP 98937139 A EP98937139 A EP 98937139A EP 98937139 A EP98937139 A EP 98937139A EP 1003740 A2 EP1003740 A2 EP 1003740A2
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EP
European Patent Office
Prior art keywords
loweralkyl
hydrogen
aryl
benzodioxol
methoxyphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP98937139A
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German (de)
English (en)
French (fr)
Inventor
Martin Winn
Steven A. Boyd
Charles W. Hutchins
Hwan-Soo Jae
Andrew S. Tasker
Thomas W. Von Geldern
Jeffrey A. Kester
Bryan K. Sorensen
Bruce G. Szczepankiewicz
Kenneth J. Henry
Gang Liu
Steven J. Wittenberger
Steven A. King
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Abbott Laboratories
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Abbott Laboratories
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Filing date
Publication date
Priority claimed from US08/905,913 external-priority patent/US6162927A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1003740A2 publication Critical patent/EP1003740A2/en
Ceased legal-status Critical Current

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D207/00—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
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    • 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
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    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and 20 compositions for antagonizing endothelin.
  • ET Endothelin
  • Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility i_n vit ro, stimulate mitogenesis in vascular smooth muscle cells i n vitro.
  • non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus i n v itro, increase airway resistance i n vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor i n vitro and i n vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release
  • vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 41 1 (1988), FEBS Letters 23J. 440 (1988) and Biochem. Biophys. Res. Commun. 1 54 868 (1988)).
  • An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial 5 effects in a variety of therapeutic areas.
  • an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J.
  • an anti-endothelin antibody attenuated the nephrotoxic i o effects of intravenously administered cyclospori ⁇ (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 1 14 (1990)).
  • a nonpeptide ET-A/B antagonist prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally.
  • SAH subarachnoid hemorrhage
  • Z is -C(Ri 8)(Ri 9)- or -C(O)- wherein R ⁇ ⁇ and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1 ;
  • R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is 20 (a) -C(0)2-G wherein G is hydrogen or a carboxy protecting group,
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R 3 is (a) R 4 -C(0)-R 5 - , R4-R ⁇ a- , R4-C(0)- R 5 -N(R 6 )- , R 6 -S(0) 2 -R7- or R 2 6-S(0)-R 2 7- wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R o)-R8- or -R 8a -N(R 20 )-R 8 - wherein R 8 and R 8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cylcoalkyl or cycloalkylalkyl or (v) -O-R9- or -R 9a -0-R 9 - wherein R9 and R 9a are independently
  • R ⁇ a is (i) alkylene or (ii) alkenylene;
  • R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R2i )-R ⁇ o- or -R 1 0a -N(R2i )-R ⁇ o- wherein R10 and R 1 0a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi;
  • R4 and Re are independently selected from the group consisting of (i) (Rn )(Ri2)N- wherein R- ⁇ and R12 are independently selected from
  • R26 is (i) loweralkyl, (ii) haloalkyi, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyi, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyi, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyi; and
  • R27 is alkylene or alkenylene
  • a preferred embodiment of the invention is a compound of formula ( I I )
  • substituents -R2, -R and -R1 exist in a trans, trans relationship and Z, n, R, R1 , R2, and R3 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is -CH2-.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- , R6-S(0)2-R7- or R26-S(0)-R27- wherein R 4 , R 5 , R 6> R 7 , R 26 and R 27 are as defined above.
  • Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is alkoxyalkyl or aikoxyalkoxyalkyi.
  • a more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-Rs- wherein R4 is (R- ⁇ ⁇ )(Ri2)N- as defined above and R5 is alkylene or R3 is R6-S(0)2-R7- or R26-S(0)-R27- wherein R7 is alkylene, R27 is alkylene and RQ and R26 are defined as above.
  • Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2- and R3 is R -C(0)-N(R2o)-R ⁇ - or R 6 -S(0)2-N(R ⁇ )-R ⁇ o- wherein R 8 and R , o are alkylene and R4, Re, R20 and R21 are defined as above.
  • An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or -C(0)2-G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is
  • R 1 and R are independently selected from (i) loweralkyl, (ii) cycloalkyi, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyi, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N- alkylaminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (R- ⁇ ⁇ )(R-i2)N- wherein R ⁇ and R 12 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl, haloalk
  • a yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
  • R 2 is substituted or unsubstituted
  • R 3 is R 4 -C(0)-N(R 2 o)-R ⁇ - or R6-S(0) -N(R ⁇ )-R ⁇ o- wherein R 8 and R 1 0 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and RQ is loweralkyl, haloalkyi, alkoxyalkyl, aryl or arylalkyi.
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl,
  • R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(0)-R ⁇ - wherein R5 is alkylene and R4 is (Rn )(Ri2)N- wherein R ⁇ and R 1 2 are independently selected from loweralkyl, haloalkyi, alkoxyalkyl
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
  • R 16 wherein R 16 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) aryl, (vii) (N-alkanoyl-N- alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4- benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluor
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl, haloalkyi or aryl, Z is -CH2-, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyi, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl, (vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 3-fluoro-4-e
  • R3 is R6-S(0)2-N(R2i)-R ⁇ o- wherein R-i o is alkylene, RQ is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi and R21 is loweralkyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, aryl or arylalkyi.
  • Another yet more preferred embodiment of the invention is a compound of formula (I) or (ll) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R 1 6 wherein R 1 6 is loweralkyl or haloalkyi, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (allkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyi,, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (Rn)(Ri2)N- wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic
  • a still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 R-
  • R 2 is 1 ,3-benzodioxolyl
  • R3 is R4-C(0)-R ⁇ - wherein R5 is alkylene and R4 is (R ⁇ ⁇ )(Ri 2)N- wherein R- d and R 12 are independently selected from loweralkyl, aryl, arylalkyi, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)- NHS(0) 2 R-
  • a most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, be
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzo
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4- methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyi, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyi, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4
  • R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyi, aryl, (N- alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R5 is alkylene and R4 is (R- ⁇ ⁇ )(R-i2)N- wherein R and R 12 are independently selected from alkyl, aryl, hydroxyalkyi, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R and R 12 is alkyl.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, and R3 is R4-C(0)-R ⁇ - wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is loweralkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkenyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is heterocyclic (alkyl), and R3 is R4-C(0)-Rs- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is aryloxyalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (Rn )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, R1 is arylalkyi, and R3 is R4-C(0)-Rs- wherein R4 is (Rn)(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is aryl, and R3 is R4-C(0)-R ⁇ - wherein R4 is (R- ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is (N- alkanoyl-N-alkyl)aminoalkyl, and R3 is R4-C(0)-Rs- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is -CH2-, Rl is alkylsulfonylamidoalkyl, and R3 is R4-C(0)-R5- wherein R4 is (R ⁇ ⁇ )(Ri2)N- as defined therein and R5 is alkylene.
  • the present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
  • the present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
  • the invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
  • the compounds of the invention comprise two or more asymmetrically substituted carbon atoms.
  • racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention.
  • S and R configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • carboxy protecting group 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.
  • 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.
  • 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.
  • carboxy protecting groups are Ci to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyi; alkenyl; cycloalkyi and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentyimethyl and the like; arylalkyi, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like
  • alkanoylaminoalkyl such as acetylaminomethyl and the like
  • heterocycliccarbonyloxyalkyl such as 4-methylpiperazinylcarbonyloxymethyl and the like
  • dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl
  • 5-(loweralkyl)-2-oxo-1 ,3- dioxolen-4-yl)alkyl such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4- yl)methyl and the like
  • 5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
  • N-protecting group or "N-protected” as used herein
  • N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyi, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like;
  • sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyioxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methyiethoxycarbonyl, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzy
  • N-protecting groups are formyl, acetyl, benzoyi, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • alkanoyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group.
  • alkanoyl include acetyl, propionyl and the like.
  • alkanoylamino refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
  • alkanoylaminoalkyl refers to R43-NH-R44- wherein R43 is an alkanoyl group and R44 is an alkylene group.
  • alkanoyloxyalkyl refers to R30-O-R31- wherein R30 is an alkanoyl group and R31 is an alkylene group.
  • alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 - methyl-2-buten-1 -yl and the like.
  • alkenyloxy refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-0-) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like. i o
  • alkoxy refers to R41O- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
  • alkoxyalkoxy refers to R 8u 0-R 8 -
  • aikoxyalkoxyalkyi refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
  • Representative examples of aikoxyalkoxyalkyi groups include 20 methoxyethoxyethyl, methoxymethoxymethyl, and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. 25
  • alkoxycarbonyl 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.
  • alkoxycarbonylalkenyl refers to an 30 alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
  • alkoxycarbonylalkyl refers to R34-C(0)-R35- wherein R34 is an alkoxy group and R35 is an alkylene 35 group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
  • alkoxycarbonylaminoalkyl refers to R3 8 -C(0)-NH-R39- wherein R3 8 is an alkoxy group and R39 is an alkylene group.
  • alkoxycarbonyloxyalkyl refers to R 3 6-C(0)-0-R37- wherein R36 is an alkoxy group and R37 is an alkylene group.
  • (alkoxycarbonyl)thioalkoxy refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
  • Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
  • alkoxyhaloalkyl refers to a haloalkyi radical to which is appended an alkoxy group.
  • alkyl and “loweralkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • (N-alkanoyl-N-alkyl)aminoalkyP refers to R ⁇ 5C(0)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
  • alkylamino refers to R51 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • alkylaminoalkyl refers to a loweralkyl radical to which is appended an alkylamino group.
  • alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
  • alkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylalkyl refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
  • alkylaminocarbonylaminoalkyl refers to R40-C(O)-NH-R4i- wherein R40 is an alkylamino group and R41 is an alkylene group.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -,
  • alkylsulfonylamidoalkyl refers R88S(0)2NHR89- wherein R88 is loweralkyl and R ⁇ 9 is alkylene.
  • alkylsulfonylamino refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(0)2-NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond.
  • alkynylene include -C ⁇ C-, -C ⁇ C-CH 2 -, -C ⁇ C-CH(CH 3 )- and the like.
  • aminoalkyl refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
  • aminocarbonyl refers to H2N-C(0)- .
  • aminocarbonylalkenyl refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkoxy refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkoxy examples include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkyl refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 C(0)-) group.
  • aminocarbonylalkyl refers to (R90)(R91 )(R92)N(Rg3)- wherein R90, R91 , and R92 are independently selected from loweralkyl and R93 is alkylene.
  • aroyloxyalkyl refers to R32-C(0)-0-R33- wherein R 3 2 is an aryl group and R33 is an alkylene group.
  • Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • aryl 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, haloalkyi, haloalkoxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyciic)alkoxy, hydroxy, hydroxalkoxy, phenyl
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
  • arylalkoxy refers to R42O- wherein R42 is an arylalkyi group, for example, benzyloxy, and the like.
  • arylalkoxyalkyl refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
  • arylalkyi refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
  • aryloxy refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the like.
  • arylalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R 62 C(0)0- wherein R 62 is an arylalkyi group).
  • aryloxyalkyl refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
  • carboxydehyde refers to a formaldehyde 5 radical, -C(0)H.
  • carboxy refers to a carboxylic acid radical, -C(0)OH.
  • carboxyalkenyl refers to a carboxy group as previously defined appended to an alkenyl radical as previously i o defined.
  • Examples of carboxyalkenyl include 2-carboxyethenyl, 3- carboxy-1 -ethenyl and the like.
  • carboxyalkoxy refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, 15 carboxyethoxy and the like.
  • cyanoalkoxy refers to an alkoxy radical as previously defined to which is appended a cyano (-CN) group.
  • cyanoalkoxy examples include 3-cyanopropoxy, 4-cyanobutoxy and the like.
  • cycloalkanoyloxyalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R 60 -C(O)-O- wherein R 60 is a cycloalkyi group).
  • cycloalkyi refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not 25 limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyi groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and 3o carboxamide.
  • cycloalkylalkyl refers to a cycloalkyi group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl .
  • dialkylamino refers to R56R57N- 35 wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
  • dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent 5 molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
  • dialkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group. i o
  • dialkylaminocarbonylalkyl refers to
  • R50-C(O)-R5i- wherein R50 is a dialkylamino group and R51 is an alkylene group.
  • halo or halogen as used herein refers to I, Br, Cl or F.
  • haloalkenyl refers to an alkenyl radical 15 to which is appended at least one halogen substituent.
  • haloalkoxy refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
  • haloalkoxyalkyi refers to a loweralkyl radical to which is appended a haloalkoxy group.
  • haloalkyi refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or 25 pentafluoroethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7- membered ring containing one, two or three nitrogen atoms; one oxygen 30 atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds.
  • the 35 nitrogen heteroatoms can be optionally quatemized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
  • Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl
  • Heterocyclics also include compounds of the formula where X * is -CH 2 - or -O- and Y * is -C(O)- or [-C(R") -] V where R" is hydrogen or C ⁇ -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.
  • nitrogen containing heterocycles can be N-protected.
  • (heterocyclic)alkoxy 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.
  • (heterocyclic)alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocycliccarbonyloxyalkyl refers to R46-C(0)-0-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
  • hydroxy refers to -OH.
  • hydroxyalkenyl refers to an alkenyl radical to which is appended a hydroxy group.
  • hydroxyalkoxy refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group.
  • hydroxyalkoxy include 3-hydroxypropoxy, 4- hydroxybutoxy and the like.
  • hydroxyalkyi refers to a loweralkyl radical to which is appended a hydroxy group.
  • leaving group refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
  • mercapto refers to -SH.
  • 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
  • tetrazolyl refers to a radical of the formula
  • tetrazolylalkoxy 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.
  • thioalkoxy refers to R70S- wherein R70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • thioalkoxyalkoxy refers to R 8u S-R 8 -
  • alkoxyalkoxy groups include CH 3 SCH 2 0-, EtSCH 2 0-, t-BuSCH 2 0- and the like.
  • thioalkoxyalkoxyalkyi refers to a thioalkoxyalkoxy group appended to an alkyl radical.
  • aikoxyalkoxyalkyi groups include CH 3 SCH 2 CH 2 OCH 2 CH 2 -, CH 3 SCH 2 OCH 2 -, and the like.
  • trans, cis refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
  • Preferred compounds of the invention are selected from the group consisting of: 5 fra ⁇ s-?ra/7s-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[3-(N- propyl-N-A7-pentanesulfonylamino)propyl]-pyrrolidine-3- carboxylic acid; trans, trans-2-(4-Me ⁇ hoxy methoxyphenyl) -4- ( 1 ,3-benzodioxol-5-yl)---
  • trans trans-2- ( (2- Methoxyph en oxy)-methy I) -4- (1 ,3-benzodioxol-5-yl)- ⁇ o 1 -[(N-b utyl-N-(4-di methy la mi no butyl) ami no)carbonylmethyl]- pyrrolidine-3-carboxylic acid; trans, trans-2-((2-W ⁇ ei oxyp he noxy)- methy I) -4- (7-methoxy-1 ,3- benzodioxol-5-yl)-1 - (N,N-di(n-buty I) am inocarbony I methy I)- pyrrolidine-3-carboxylic acid; 15 trans, fra
  • Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH2- and W is -CO2H.
  • a ⁇ -ketoester J_, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • 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
  • a protic solvent such as ethanol or methanol and the like
  • Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans, trans and cis, trans isomers which is further elaborated.
  • the cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans, trans isomer and then carried on as described below.
  • the pyrrolidine nitrogen is (1) acylated or sulfonylated with R3-X (R3 is R4-C(0)- or R ⁇ -S(0)2- and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4-C(0)- 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, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3-X where X is a leaving group (for example, X is a halide (for example, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the
  • Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1 , m is 0, Z is -CH2- and W is -CO2H.
  • a substituted benzyl chloride 9_ is reacted with a lithio dithiane 1_ in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct U..
  • the anion of compound J_L is formed using a base such as n-butyllithium and then reacted with R1 -CH2-X' wherein X' is a WO 99/06397 " 4 ? " PCT/US98/15479
  • Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is -C(O)- and W is -CO2H.
  • ⁇ -Keto ester 2_0 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an ⁇ -haloester 2J_ (where J is lower
  • 25 bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 2j4.
  • Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1 , Z is -CH2- and W is -CO2H.
  • the trans,trans compound Z, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is
  • a preferred embodiment is shown in Schemes V and VI.
  • a benzoyi acetate 2_6 is reacted with a nitro vinyl benzodioxolyl compound 2J_ using 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to i o give compound 2J3.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 2_9.
  • the double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 3_0 as a mixture of cis-cis, trans, trans and cis, trans isomers.
  • Scheme VI illustrates the further elaboration of the trans, trans isomer.
  • the mixture (3 1) of trans, trans and cis, trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in
  • Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 3_5 is reacted with lithio dithiane 3_6 to give the alkylated compound 3_Z. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium
  • Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH2-, and W is other than carboxylic acid.
  • Compound 5_5 which can be prepared by the procedures described in Scheme IV, is converted (for
  • carboxamide 5_6 20 example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 5_6.
  • the carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 5_7.
  • Nitrile 5_7 under standard tetrazole forming conditions (sodium azide
  • tetrazole 5_8 25 and triethylamine hydrochloride or trimethylsilylazide and tin oxide is reacted to give tetrazole 5_8.
  • nitrile 5_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,
  • a base for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH
  • amidoxime 5_9 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
  • a conventional organic solvent such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine
  • a base for example, triethylamine, pyridine, potassium carbonate and sodium
  • a carboxylic acid 6_2 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N- dimethylformamide to give the acid chloride.
  • Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the ⁇ -chloroketone 63.
  • Pyrrolidine ester 5. where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the ⁇ -chloroketone 6.3 to provide alkylated pyrrolidine 6_4.
  • Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 6_5.
  • Scheme XI illustrates the preparation of "reverse amides and sulfonamides".
  • the carboxy protected pyrrolidine 5. prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6_6.
  • X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6_6.
  • Treatment of 6_6 with an amine (R20NH2) affords secondary amine 6_7.
  • This amine (67) can be reacted with an activated acyl compound (for example, R4-C(0)-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 6_8-
  • amine 6_7 can be reacted with an activated sulfonyl compound (for example, R 8 -S(0)2-CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 6_9_.
  • Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate.
  • General structures such as compound 70 are known to add to unsaturated esters such as Zl to provide pyrrolidines such as compound 7_2 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 5_2 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn.
  • Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 8J , which can be further elaborated on the pyrrolidine nitrogen.
  • Intermediate racemic pyrrolidine ester J_7 (for example, prepared by the procedure described in Scheme V) is Boc- nitrogen protected (for example, by treatment with B0C2O) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyi pyrrolidine carboxylic acid 7_8.
  • 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 7_9_.
  • 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_0.
  • 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 8_1
  • optically active compound 8_1 The use of (-)-cinchonine will give the opposite enantiomer.
  • Scheme XIV describes another procedure for preparation of pyrrolidines.
  • Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc, Perkin Trans. 1 , 5: 1091-97 (1991 ).
  • the azomethine ylide precursor 8_2 (where R55 is hydrogen or methyl) is condensed with a substituted acrylate 8_3 (wherein R2 is as described herein and R56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 8_4.
  • the N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85. which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 8j6. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 8_Z
  • Nitro vinyl compound 5 (8_8) is reacted with beta-keto ester 8_9 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a i o temperature of from about 0° C to about 100° C for a period of time from about 15 minutes to overnight to give compound 9_Q.
  • Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day
  • reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like,
  • pyrrolidine compound 9_2 as the c/s,c/s-isomer.
  • Epimerization at C-3 is effected by treatment of compound 9_2 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the
  • (+)-isomer of compound 9_3 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 9_3 with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.
  • the (+)-isomer of 9_3 selectively crystallizes as the salt, leaving the (-)-isomer of 9_3 in solution.
  • the substantially pure (i.e., 5 at least 95% of the desired isomer) optically active (-)-isomer of compound 9_3 can be selectively crystallized by reaction of a mixture of the
  • (+)-isomer and the (-)-isomer of 9_3 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired i o (-t-)-isomer of compound 9J3 in solution.
  • Compound 93 (racemic or optically active) is reacted with X-R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like
  • ester 15 in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 100° C to give the intermediate ester 9_4.
  • the ester can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide
  • Grignard reagent for example, propylmagnesium bromide
  • unsaturated ester for example, ethyl 3,3-dimethylacrylate.
  • the resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding ⁇ -ketoester, for example by activation using
  • olefinic ⁇ -ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired ⁇ -ketoester.
  • N-alkyl,0-alkyl bromohydroxamates are prepared according to
  • N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium catalyst.
  • the resultant amine is acylated, for example using bromoacetyl bromide.
  • the ⁇ -ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII.
  • Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH.
  • base for example DBU or potassium t-butoxide
  • the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH.
  • a mixture of isomers are generated, in which the trans- trans is generally preferred.
  • Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above.
  • Treatment with a chiral acid for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can be further enriched through recrystallization.
  • the salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product.
  • the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.
  • Activation of the acid for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically.
  • a similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
  • Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4- heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-( ⁇ - hydroxyalkyl)-N-alkyl haloacetamide.
  • Hydrolysis of the resultant ester for example using sodium hydroxide in aqueous alcohol, provides the product.
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonyl alky I, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R aa is aryl or arylalkyi
  • R b is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R-, and
  • R 2 is other than hydrogen; or a salt thereof; or a compound of the formula:
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • R i and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,
  • Preferred intermediates include compounds of formula (III), (IV) and (V) wherein m is zero or 1 ;
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi,
  • V I (V I ) wherein n is 0 or 1 ; m is 0 to 6; R 5b is alkylene;
  • Q is a leaving group
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl , dialkylaminocarbonylalkyl , aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic,
  • Q is a leaving group
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group, (b) -PO3H2, (c) -P(0)(OH)E where E is hydrogen, loweralkyl or arylalkyi,
  • Ri and R2 are independently selected from hydrd ' gen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl,
  • Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein m is zero or 1 ; R 5b is alkylene;
  • Q is a leaving group
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula
  • Q is a leaving group
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group
  • Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl,
  • Ri and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyi, haloalkyi, haloalkoxyalkyi, aikoxyalkoxyalkyi, thioalkoxyalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyi, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (he
  • R 5b is alkylene
  • R 0a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
  • W is (a) -C(0)2-G where G is hydrogen or a carboxy protecting group
  • R aa is aryl or arylalkyi
  • R bb is hydrogen or alkanoyl
  • R cc is alkylene, with the proviso that one or both of R-, and
  • R 2 is other than hydrogen; or a salt thereof.
  • Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein m is zero or 1 ;
  • R 5b is alkylene
  • R 2 0 a ' s hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi;
  • W is -CO2-G wherein G is hydrogen or a carboxy protecting group, and Ri and R2 are as defined above; or the substantially pure (+)- or (-)-isomer thereof.
  • Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein n and m are both 0;
  • R 5b is alkylene
  • R 20a is hydrogen, loweralkyl, alkenyl, haloalkyi, alkoxyalkyl, haloalkoxyalkyi, cycloalkyi, cycloalkylalkyl, aryl or arylalkyi; W is -CO 2 -G wherein G is hydrogen or a carboxy protecting group; and Ri is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyi, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyI, 3-fluoro-4-methoxyphen
  • Boc for tert-butyloxycarbonyl
  • Cbz for benzyloxycarbonyl
  • DBU for 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • EDCI for 1-(3- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride
  • EtOAc for ethyl acetate
  • EtOH for ethanol
  • HOBt 1-hydroxybenzotriazole
  • Et3N for triethylamine
  • TFA trifluoroacetic acid
  • THF for tetrahydrofuran.
  • Example A Ethyl 2-(4-methoxybenzov ⁇ -4-nitromethyl-3-(1.3-benzodioxole-5-v ⁇ butyrate
  • ethyl (4-methoxybenzoyl)acetate 23.0 g, 0.104 mol
  • 5-(2- nitrovinyl)-1 ,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 ml_ of toluene and heated to 80 °C was added 1 ,8-diazabicyclo[5,4,0] undec-7- ene (DBU, 0.65 g) with stirring.
  • DBU 1,8-diazabicyclo[5,4,0] undec-7- ene
  • Example 1 D Using the method described in Example 1 D, 300 mg of the mixture of 64% trans, trans- and 34% c/s, fra ⁇ s-pyrrolidines (the mixture resulting from Example 1 C), 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.
  • Example 3 fra ⁇ s. l *rans-2-(4-Methoxyphenvn-4-f 1.3-benzodioxol-5-vn-1 -(4-fluorobe ⁇ zvn- pyrrolidine-3-carboxylic acid
  • 300 mg of the mixture of 64% trans, trans- and 34% cis, trans- pyrrolidines (the mixture resulting from Example 1 C), 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 c/s, fra ⁇ s-N-alkylated esters.
  • Example 4 fra ⁇ s. fra ⁇ s-2-f4-Metho ⁇ yphenyl -(1 ,3-benzodioxol-5-yl)-1-(2-ethoxyethyO- pyrrolidine-3-carboxylic acid Using the method described in Example 1 D, 300 mg.
  • Example 5 trans.frans-2-(4-Methoxyphenv ⁇ -4-f 1.3-benzodioxol-5-vn-1 -(2-Dropoxyethv ⁇ - pyrrolidine-3-carboxylic acid
  • 520 mg of the mixture resulting from Example 1 C 364 mg of diisopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 °C in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans, trans- and c/s, frans-esters.
  • Example 6B rrat7s.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-yl;-1-[2- ⁇ 2- methoxyethoxy)ethyl)-pyrrolidine-3-carboxylic acid
  • -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 °C for 3 hours to give 229 mg of the frans, fra ⁇ s-ester.
  • Example 7 frans. rat7S-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-y ⁇ -1 - 2-(2-pyridyl)ethyl]- pyrrolidine-3-carboxylic acid
  • 2-vinyl pyridine 355 mg
  • acetic acid was dissolved in 2- methoxyethanol, and stirred at 100 °C for 2.5 hours.
  • Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated.
  • Example 8 5 fra ⁇ s, frans-2-(4-MethoxyphenylM-(1 ,3-benzodioxol-5-vO-1 -(morpholin-4- ylcarbonyl)-pyrrolidine-3-carboxylic acid
  • To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1 -morpholinocarbonyl chloride. The mixture i o 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.
  • Example 10 fra ⁇ s.fra ⁇ s-2- ( 4-Methoxyphenyl - ⁇ .3-benzodioxol-5-v ⁇ -1 -(4- ' methoxyphenylaminocarbonyl)-3-pyrrolidine-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 °C.
  • Example 1 fra ⁇ s.frat7S-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y ⁇ -1-acetylpyrrolidine-3- carboxylic acid
  • the compound resulting from Example 6A 250 mg in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid 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 1 D to give 21 1 mg of the title compound, m.p. 248-250 °C.
  • Example 12 frans.frans-2-(4-Methoxyphenvn-4-(1 .3-benzodioxol-5-vn-1 -(2-furovn-pyrrolidine-3- carboxyiic acid
  • 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 1 D to give 269 mg of the title compound as an amorphous powder.
  • Example 13 frans. frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-yl )-1- (phenylaminocarbonyl)-pyrrolidine-3-carboxylic acid
  • phenyl i o isocyanate Starting with the compound resulting from Example 6A, phenyl i o isocyanate and the procedures described in Example 9, the title compound was prepared, m.p. 209-21 1 °C.
  • Example 14 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yO-1- (allylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound 20 was prepared, m.p. 138-140 °C.
  • Example 15 fra ⁇ s.rrans-2-(4-Methoxypheny ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-fn- butylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 105-107 °C. 1 H NMR (CDCI3, 300 MHz) ⁇ 0.90 (t, 3H), 30 1.30 (m, 2H), 1.45 (m, 2H), 2.80 (d, 1 H), 2.87-3.35 (m, 6H), 3.62 (m, 1 H),
  • Example 17 fra ⁇ s.fra ⁇ s-2-f4-Methoxypheny ⁇ -4-(1.3-benzodioxol-5-yl;-1-(pyrrolidin-1 - ylcarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid.
  • H NMR (CDCI3, 300 MHz) ⁇ 1.40- 1.70 (m, 6H), 2.80 (d, 1 H), 3.00 (m, 2H), 3.24-3.43 (m, 5H), 3.60 (m, 2H), 3.73 (d, 1 H), 3.80 (s, 3H), 5.95 (s, 2H), 6.74 (d, 1 H), 6.80-6.90 (m, 3H),
  • Example 18 frat7S,fra ⁇ 5-2-(4-Methoxyphenv ⁇ -4-f1.3-benzodioxol-5-y ⁇ -1- (isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 175-177 °C. 1 H NMR (CD3OD, 300 MHz) ⁇ 0.87 (dd, 6H), 1.75 (septet, 1 H), 2.85 (d, 1 H), 2.90-3.10 (m, 4H), 3.23 (d, 1 H), 3.40
  • Example 20 fra ⁇ s. fra/7S-2-(4-Methoxyphenyl -(1.3-benzodioxol-5-yu-1 -(morpholin-4- ylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid.
  • Example 21 frans. frans-2-(4-Methoxyphenyl -(1 ,3-benzodioxol-5-yO-1 -(2-phenoxyethyl)- pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid.
  • Example 22 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-y0-1 -(2- methoxyethylaminocarbonylmethvO-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared, m.p. 107-109 °C.
  • Example 25 frans.rrans-2-(1.3-Benzodioxol-5-yn-4-(4-methoxyphenyn-1 -(2-propoxyethyn- pyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbonyl)acetate for ethyl (4- methoxybenzoyl)acetate and 4-(2-nitrovinyl)anisole for 5-(2- nitrovinyl)-1 ,3-benzodioxol-5yl afforded the title compound, m.p. 67- 69 °C.
  • Example 26 frans.frans-2-(1.3-Benzodioxol-5-v ⁇ -4-(4-metho ⁇ yphenv ⁇ -1 -[2-(2- methoxyethoxy ) ethyl)l-pyrrolidine-3-carboxylic acid Using the procedures . described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2- methoxyethoxy)ethytbromide to alkylate the pyrrolidine nitrogen afforded the title compound, m.p. 85-86 °C.
  • Example 29 frans.frans-2-(4-Methoxyphenyl)-4-(1.4-benzodioxan-6-y ⁇ -1-(N-methyl-N- propylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • 6-(2- nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-methyl-N-propyl bromoacetamide afforded the title compound, m.p. 74-76 °C. Rotational isomers are seen in the NMR.
  • Example 30 frans.fra ⁇ s-2-t4-Metho ⁇ yphenyl ⁇ -4-f1.3-benzodioxol-5-vn-1-fN-methyl-N- butylaminocarbonylmethy ⁇ -pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 , the title compound was prepared. Rotational isomers are seen in the NMR.
  • Example 31 A Ethyl 2-(4-methoxy-2-methoxymethoxyphenyl-4-(1.3-benzodioxol-5-y0-pyrrolidine-
  • Example 31 B frans. ra ⁇ s-2-(4-Methoxy-2-methoxymethoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1 -(N- methyl-N-butylaminocarbonylmethyl ⁇ -pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 31 A was epimerized by the procedure described in Example 6A.
  • the resulting trans, trans compound (100 mg, 0.23 mmol) was then reacted by the procedures described in Example 1 D substituting N-methyl-N-butyl bromoacetamide for N- propyl bromoacetamide to give the title compound (75 mg, 62%).
  • Example 32A Ethyl 2-(4-methoxybenzoyl ⁇ -3-carbornethoxy-1 ,3-benzodioxole-5-propionate
  • ethyl (4-methoxybenzoyl)acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1 ,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in 5 L of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.
  • Example 32B Ethyl 1 -(3-ethoxypropylV2-(4-methoxyphenvn-4-H .3-benzodioxol-5-v0-4.5-dihvdro- 5-QXO-1 H-pyrrole-3-carboxylate
  • Example 32C Ethvl 1-f3-ethoxypropvlV2-(4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pvrrolidin-5- one-3-carboxylate
  • the compound resulting from Example 32B (300 mg, 0.64 mmol) in 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature.
  • the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.
  • Example 32D frans.frans-2-f4-Methoxypheny ⁇ -4-f1.3-benzodioxol-5-y ⁇ -1-(3-ethoxypropy ⁇ - pyrrolidin-5-one-3-carboxylic acid
  • To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 % sodium ethoxide in ethanol. The mixture was heated to 70-80 °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.
  • Example 33 frans.fra ⁇ s-2-(4-Metho ⁇ yphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-(3-methoxybenzy ⁇ - pyrrolidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamine for 3-ethoxypropylamine afforded the title compound (123 mg, 65%). m.p. 150-152 °C. 1 H NMR (CD3OD ,
  • Example 34 frans.frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-yn-1-(N.N- diisoamylaminocarbonylmethyl»-pyrrolidine-3carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 35 frat7g,frans-2-(4-Meth ⁇ >xyphenyl)-4-(1 ,3-benz ⁇ >diQXQl-5-yl)-1-(N,N- dipentylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 36 frans.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1-(N.N-di(2- methoxyethv ⁇ aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 120-122 °C. 1 H NMR (CDCI3, 300 MHz) ⁇ 2.82 (d,
  • Example 39 frans.frans-2-(4-MethoxyPhenvn-4-(1.3-benzodioxol-5-vn-1-(N-cvclopropylmethyl- N-propylaminocarbonylmethyl)-pyrrplidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 167-169 °C. Rotational isomers were seen in the NMR.
  • Example 39 frans.rrans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-y ⁇ -1 -(N-methyl-N- pentylaminocarbonylmethvn-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.
  • Example 40 fra ⁇ s.frans-2-(4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1 -(N.N- diisobutylaminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 141-143 °C.
  • Example 41 frans.frans-2- 4-Methoxyphenvn-4-f1.3-benzodioxol-5-yl ⁇ -1-fN-methyl-N- ⁇ 2- propynyl)aminocarbonylmethy ⁇ -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.
  • Example 42 frans.f-ans-2-f4-Metho ⁇ yphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1-(N-methyl-N-(n- hexyl)aminocarbony!methy0-pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1.
  • Example 43 frans.fra ⁇ s-2-r4-Methoxyphenyl.-4-f1.3-benzodioxol-5-yl ⁇ -1-t ⁇ . ⁇ /-cy/Yn- butvnaminocarbonylmethyl -o ⁇ /rro ⁇ d ⁇ r ⁇ e-3-ca ⁇ box ⁇ c acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 123-125 °C. 1 H NMR (CDCI 3 , 300 MHz) ⁇ 0.79 (t,
  • Example 46 rrans.frans-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1 -(N-methyl-N- cyclohexylaminocarbonylmethvn- p yrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the
  • Example 47 frans.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-y ⁇ -1-(N.N-dim- propyl)aminocarbonylmethylVpyrroHdine-3-carboxylic acid i o
  • the title compound was prepared using the -procedures described in Example 1. m.p. 170-172 °C.
  • Example 48 fra ⁇ s.fra ⁇ s-2-f4-MethoxyphenylV4-(1.3-benzodioxol-5-v ⁇ -1 -(N-methyl-N- isobutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid 20
  • the title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR.
  • Example 49A E-2-(3.4-Methylenedioxyphenyl)-1-nitroethene
  • piperonal 75g, 500 mmol
  • methanol 35 120 mL
  • sodium hydroxide 21 g, 525 mmol, 1.05 eq
  • Example 49B Ethyl 2-(4-methoxyphenvhoxo-4-nitro-3-(3.4-methylenedioxyphenyl ⁇ butyrate To a stirred solution of the nitrostyrene resulting from Example
  • Example 50 ffans.frans-2-r4-Methoxyphenyn-4-(1.3-benzodioxol-5-yl,-1-ft- butyloxycarbonylmethyl.-pyrrolidine-3-carboxylic acid
  • acetonitrile 2 mL
  • diisopropylethylamine 70 ⁇ L, 0.40 mmol, 1.5 eq
  • t-butyl bromoacetate 48 ⁇ L, 0.29 mmol, 1.1 eq
  • Example 52B fra ⁇ s.frans-2-f4-Methoxypheny ⁇ -4-f2.3-dihvdrobenzofuran-5-y ⁇ -1-(N-methyl-N- propyl,aminocarbonylmethyn-pyrrolidine-3-carboxylic acid
  • Example 53 frans.rran5-2.4-Bisf4-methoxyphenyh-1-(N-methyl-N-propy ⁇ aminocarbonylmethv ⁇ - pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • Example 54 trans. frans-2-»4-Methoxyphenv ⁇ -4-(3.4-dimethoxyphenv ⁇ -1-fN-methyl-N- propyl ⁇ aminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid
  • Example 55 rans.fran5-2-f4-Methoxyphenyn-4-f3-methoxyphenyn-1-(N-methyl-N- propy ⁇ aminocarbonylmethylVpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR.
  • Example 56 fra ⁇ s.frans-2-(4-Metho ⁇ yphenyl ' )-4-f2-naphthyl>-1-(N-methyl-N-
  • Dr ⁇ Dylteminocarbonylmethv ⁇ -pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) ⁇ 7.82 (4H, m), 7.69 (1 H, m>, 7.47 (2H, m), 7.37
  • Example 57 frans. frans-2-(4-Methoxyphenyl ⁇ -4-M .3-benzodioxol-5-yl I -f2-(ethylsulfinv ⁇ ethyl ' >- pyrrolidine-3-carboxylic acid
  • 2-chloroethyl ethyl sulfide 67.5 mg, 0.5 mmol, 2 equivalents
  • Kl 0.5 mmol, 2 equivalents
  • Example 59 frans.frans-2-(4-Methoxypheny ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-(2-(isobutoxy ⁇ ethy ⁇ - pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 1 D from the compound resulting from Example 1 C and 2- (isobutoxy) ethyl bromide, m.p. 68-70 °C.
  • Example 60 fra ⁇ s.frans-2-f4-Methoxyphenv ⁇ -4-f1.3-benzodioxol-5-v ⁇ -1 -fbutylsulfonyl)-
  • the ester 120 mg, 0.244 mmol was dissolved in 1 mL of EtOH, and a solution of 100 mg of NaOH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid, m.p. 67-69 °C.
  • Example 61 frar7S.?rans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -,2-(N-methyl-N- isopropylcarbonylamino')ethv ⁇ -pyrrolidine-3-carboxylic acid
  • Example 61 A frans.frans-2-f4-Methoxy p henyn-4-M .3-benzodioxol-5-vn-1-(2-bromoethyl,- pyrrolidine-3-carboxylic acid ethyl ester
  • trans pyrrolidines resulting from Example 1 C 400 mg
  • dissolved in 9 mL of 1 ,2-dibromoethane was added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide.
  • Example 61 B frans.fra ⁇ s-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -(2-fmethylamino l ethyl,- pyrrolidine-3-carboxylic acid ethyl ester
  • EtOH aqueous methylamine
  • sodium iodide 50 mg
  • Example 61 C fra ⁇ s.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-yn-1-r2-rN-methyl-N- isobutyrylamino ⁇ ethy ⁇ -pyrrolidine-3-carboxylic acid
  • the solution was cooled to -40 °C, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.
  • Example 62 rra ⁇ s.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-v ⁇ -1- ⁇ 2-(N-methyl-N- propionylamino)ethyl)-pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61 C.
  • Example 64 rans.frans-2- ⁇ 4-MethoxyDhenyl)-4-f1.3-benzodioxol-5-v ⁇ -1-fN-ethyl-N- butylaminocarbonylmethyn-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared.
  • Example 65 rrans.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-yl;-1- ⁇ N-methyl-N-(2.2- dimethylpropynaminocarbonylmethyn-pyrrolidine-3-carboxylic acid
  • Example 66 trans. frans-2-(4-Methoxyphenyn-4-f1.3-benzodioxol-5-ylV1-(2-(N-methyl-N- butylsulfonylamino ⁇ ethy ⁇ -pyrrolidine-3-carboxylic acid
  • Example 61 B To the compound resulting from Example 61 B (60 mg, 0.13 mmol) dissolved in 5 mL of CH3CN was added 0.2 mL of Et3N and 22 mg (0.143 mmol, 1 .1 equivalents) of 1 -butanesulfonyl chloride. The mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 :1 EtOAc-hexane to yield 64 mg (90%) of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound, m.p. 64-66 °C.
  • Example 67 s frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-yl)-1-.2-(N-methyl-N- propylsulfonylaminotethyn-pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 66 substituting 1-propanesuIfonyl chloride for 1- butanesulfonyl chloride, m.p. 69-70 °C. 1 H NMR (CDCI 3 .
  • Example 69 fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenvn-4-(1.3-benzodioxol-5-vn-1-f2- (propylsulfonv ⁇ ethyl -pyrrolidine-3-carboxylic acid
  • 1-propanethiol 3.5 g, 46.05 mmol
  • 632 mg 26.32 mmol
  • NaH sodium hydride
  • the mixture was heated at 60-70 °C for 1 hours.
  • To this mixture was added the compound resulting from Example 61 A (180 mg, 0.38 mmol) in 2 mL THF.
  • Example 69B rrans-5-Methylhex-2-en-1 -ol
  • the compound resulting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath.
  • Example 69C frans-1 -Bromo-5-rnethylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 °C for two hours. The solution was poured onto ice, the-layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).
  • Example 70 frans.frans-2-f4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-vn-1-N-(frans-3.5- dimethylhex-2-env ⁇ -Pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pentanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olefins.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 71 A 1 -Chioro-3-propyl-2-hexanone To 2-propylpentanoic acid (156.6 ⁇ l, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 ⁇ L, 4 mole %), and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 ⁇ L, 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.
  • 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 ⁇ L, 1.10 mmol) was added dropwise over a few minutes.
  • the reaction was stirred 18 hours while warming to ambient temperature.
  • the reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
  • Example 71 B fra ⁇ s. fra ⁇ s-Ethyl 2-(4-methoxyphenyl )-4-M .3-benzodioxol-5-yh- 1 -> 4- heptylcarbonylmethyl ⁇ -pyrrolidine-3-carboxylate
  • Example 71 A To the compound resulting from Example 71 A (1.00 mmol, maximum theoretical yield) was added a solution of the trans, trans ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 % solution in toluene), diisopropylethylamine (700 ⁇ L, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole %), and the reaction mixture was stirred 18 hours 5 under a nitrogen atmosphere at ambient temperature. Additional sodium iodide (24 mg, 20 mole %) and acetonitrile (4 mL) were added, and the reaction mixture was heated at 45-50 °C with stirring for 18 hours.
  • Example 71 C trans. trans-2-( 4- Methoxyp hen yh-4-M .3-benzodioxol-5-v0-1 -(4- 5 heptylcarbonylmethvn-pyrrolidine-3-carboxylic a£id
  • Example 71 B To the compound resulting from Example 71 B (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 0 hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether (50 mL).
  • Example 72A 1-Chloro-2-hexanone Using the procedure described in Example 71 A and substituting pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.
  • Example 72B fra ⁇ s. fra ⁇ s-Ethyl 2-(4-methoxyphenyl ,-4-M .3-benzodioxole-5-vn-1 (valerylmethvn-pyrrolidine-3-carboxylate Substituting the compound resulting from Example 72A for 1- chloro-3-propyl-2-hexanone and using the procedure described in Example 71 B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg (65%) was obtained as a yellow oil.
  • Example 72C frans. frar7s-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1 - (valerylmethvh-pyrrolidine-3-carboxylic acid
  • Example 73A trans.trans- and c/s.fra ⁇ s-2-(4-Methoxyphenyn-4-f 1 ,3-benzodioxol-5- yl )-1 -f(3.4-dimethoxybenzyl )aminocarbonylmethyl )pyrrolidine-3- carboxylic acid ethyl ester
  • Example 1 D, paragraph 1 substituting 3,4- dimethoxybenzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.
  • Example 73B trans.trans- and c;s.fra ⁇ s-2-(4-Methoxyphenyl ⁇ -4-M .3-benzodioxol-5- y ⁇ -1 -(N- ⁇ 3.4-dimethoxybenzyn-N- methylaminocarbonylmethyl )pyrrolidine-3-carboxylic acid ethyl ester
  • Example 73A The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 °C) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 °C for 1 hour, then methyl iodide (28 ⁇ L, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 °C for 45 minutes. TLC (Et2 ⁇ ) indicated incomplete reaction.
  • Example 73C 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.
  • Example 75B fra ⁇ s.frans-2-(4-Methoxyphenv ⁇ -4-(1.3-benzodioxol-5-yn-1 -((1 RV1 -(N.N- dipropylaminocarbonyl ⁇ -1 -butv ⁇ pyrrolidine-3-carboxylic acid ethyl ester
  • the resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours.
  • the reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to give 81.4 mg (96%) of the crude acid as a white solid.
  • Example 75C o 2R.3R.4R ,-2-(4-Methoxyphenyn-4-(1 .3-benzodioxol-5-yn-1 -(( 1 R ,-1 -
  • Example 73C (N.N-dipropylaminocarbony ⁇ -1 -buty ⁇ pyrrolidine-3-carboxylic acid
  • Example 75B substitution of the less polar isomer from Example 75B for the resultant product from Example 73B, to provide the title compound in 94% yield.
  • Example 73C 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.
  • Trifluoromethanesulfonic anhydride (95 ⁇ L, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 °C for 1 hour, and 5 at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 °C, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamine (101 ⁇ L, 75 mg, 0.58 mmol) in 3 mL of CH2CI2 was added. The reaction was stirred at 0 °C for 3 hours and for an additional 2 days at room temperature.
  • Example 77B ⁇ 2S.3S.4S)-2-(4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1 -fn S 1-fN.N- dipropylaminocarbonyl)-1 -butyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73C was followed, with the substitution of the less polar isomer from Example 77A for the resultant product 5 from Example 73B, to provide the title compound in 100% yield.
  • Example 79 frans.frans-2-(4-MethoxyphenylV4-(1.3-benzodioxol-5-vn-1-/ r /V./V-rJ/Yn- butyl)aminocarbonylmethyl)-3-(5-tet ⁇ azoM)ov ⁇ o ⁇ d r ⁇ e
  • Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 °C. The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg (83%) of the 3-carboxamide compound, m.p. 194-196 °C.
  • Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature.
  • Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg (96%) of the 3- carbonitrile compound.
  • Example 90 frans.fra ⁇ s-2-(4-Fluorophenvn-4-n .3-benzodioxol-5-vn-1- ⁇ ./V-fi/rn- ⁇ ;fv/)a / ⁇ ocarb ⁇ n t77ef/7v/)pyrrolidine-3-carboxylic acid
  • the title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3-benzodioxoIe using the procedures described in Examples 1 and .43.
  • Example 81 fra ⁇ s.frans-2-(4-Methoxyphenv ⁇ -4- ⁇ .3-benzodioxol-5-vn-1-fN.N-di(n- butvflaminocarbonylmethvOpyrrolidine-3-carboxylic acid N,N-Dibutyl glycine (150 mg, 0.813 mmol), prepared by the method of Bowman, R.E., J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mg (0.852 mmol) carbonyldiimidazole and heated for 30 minutes at 50 °C.
  • Example 82 rrans.rrans-2-(4-Methoxyphenyn-4-n .3-benzodioxol-5-vn-1 -fN-n-butvn-N-m- propvnaminocarbonvlmethvnpvrrolidine-3-carboxylic acid
  • the title compound was prepared using the procedures described in Example 1. m.p. 160-162 °C.
  • Example 83 fra ⁇ s.frans-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1 -f2-fN.N-di(n- propy ⁇ aminocarbonv ⁇ ethyl]pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 6A 250 mg, 0.677 mmol
  • diallyl acrylamide Polysciences, Inc.
  • 10 mg acetic acid were heated at 85 °C in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mg (80%) of the diallyl compound.
  • the diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere.
  • the catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl amide ethyl ester in 100% yield.
  • Example 84 frans.fra ⁇ s-2-(4-Methoxyphenyn-4- ⁇ .3-benzodioxol-5-yl,-1-fN.N-dirn- butvnaminocarbonyl.pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyi chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material.
  • Example 87 frans.frans-2-f4-Methoxyphenvn-4-n .3-benzodioxol-5-vn-1-(2-rN-fN.N-dim- butvnaminocarbonvn-N-methylamino1ethyl)pyrrolidine-3-carboxylic acid
  • Dibutyl carbamoyi chloride (135 mg) was added to the compound resulting from Example 61 B (250 mg) and 150 mg triethylamine in 1 mL dichloromethane. After stirring 1 hour at room temperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2S ⁇ 4 and concentrated.
  • Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 mmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 °C for 2 hours. After cooling, 50 mg (0.526 mmol) of methanesulfonamide and 68 mg (0.447 mmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 °C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mg (70%) of the title compound, m.p.
  • Example 89 frans.frans-2-(4-MethoxvphenvlV4-f1.3-benzodioxol-5-vn-1-fN.N-di.n- butv ⁇ aminocarbo ⁇ ylmethyl ⁇ pyrrolidine-3- N-benzenesulfonv ⁇ carboxamide
  • the compound resulting from Example 43 was converted to the title compound by the method of Example 88 substituting benzenesulfonamide for methanesulfonamide. m.p. 169-171 °C for a sample recrystallized from acetonitrile.
  • Example 90 frans. frans-2-f4-Methoxyphenv ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-rN.N-di(n-butv ⁇ aminosulfonylmethyl]-pyrrolidine-3-carboxylic acid Chloromethyl sulfenyl chloride, prepared by the method of
  • N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans, trans-2- ⁇ 4- Methoxyphenyl)-4-( 1 ,3-benzodioxol-5-yl)- 1 -[N, N-di(n- butyl)aminosulfenylmethyl]-pyrroiidine-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.
  • Example 91 A i ⁇ 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 CH2CI2, the solution was cooled to 0 °C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate (0.45 mL , 3.5 mmol). After 10 minutes at 0 °C, dibutylamine (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 °C for 1 hour and for an additional 16 hours at room temperature.
  • Example 91 B trans.trans- and c/s.frans-2- 4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1- ⁇ (N.N- dim-butv ⁇ amino ⁇ carbonyl-1-ff?SVethyliPyrrolidine-3-carboxylic acid ethyl ester
  • a solution of the resultant mixture of trans.trans and cis.trans compounds from Example 1C 232 mg, 0.628 mmol
  • the resultant compound from Example 91 A 183 mg, 0.693 mmol
  • 2 mL of CH3CN was treated with diisopropylethylamine (0.22 mL, 1.3 mmol).
  • the solution was stirred at 60-80 °C under a N2 atmosphere for 16 hours.
  • the reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et2 ⁇ and 10 mL of 1 M aqueous Na2C03 solution.
  • the organic phase was washed with 20 mL water and 20 mL brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude).
  • the product was obtained by flash chromatography on silica gel eluting with 20% EtOAc-hexane to provide 224 mg (70%) of the title compounds as a mixture of 4 diastereomers.
  • Example 91 C frans. fran5-2-f4-Methoxyphenyn-4-n.3-benzodioxol-5-ylV1-f.N.N- dibutylamino)carbonyl-1-(f?S)-ethyl)pyrrolidine-3-carboxylic acid
  • the procedure of Example 73C was used, substituting the resultant compound from Example 91 B for the resultant compound from Example 73B to give the title compound in 61% yield.
  • Example 92 fra ⁇ s.fra ⁇ s-2-(Pentyl -4-( 1.3-benzodioxol-5-yB-1 -(N.N-dim- butyl,aminocarbonylmethyl)pyrrolidine-3-carboxylic acid
  • Example 92A Methyl 2-(4-hexenoylt-4-nitro-3-(1.3-benzodioxole-5-yl)butyrate
  • a solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1 ,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 ⁇ L, 0.15 mmol) was added.
  • the resulting reddish solution was stirred at room temperature for 20 minutes.
  • TLC ethyl acetate-hexane, 1 :3) indicated complete consumption of ketoester.
  • Example 92B Methyl frans.fra ⁇ s-2-fpentyl.-4-f1.3-benzodioxol-5-ynpyrrolidine-3-carboxylate
  • Example 1B and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1 A, and the substitution of the this resultant compound for the resultant compound from Example 1 B, to provide the title compound in crude form as a yellow oil. This crude compound was epimerized under the following conditions.
  • a solution of the crude compound (660 mg, 2.07 mmol) in 3 mL methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol).
  • the resultant solution was heated at reflux for 18 hours.
  • the reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated N HC ⁇ 3 diluted with 10 mL water and 30 mL of CH2CI2.
  • the aqueous phase was extracted (2 x 30 mL CH2CI2), then the combined organic phases were washed with 20 mL brine, dried over Na2S ⁇ 4, filtered and the filtrate concentrated under reduced pressure to afford the crude product.
  • Example 92C frans.frans-2-fPentvn-4-f1.3-benzodioxol-5-yl,-1-(N.N-difn- butv ⁇ aminocarbonylmethyflpyrrolidine-3-carboxylic acid
  • Example 1 B-1D The procedures of Example 1 B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam.
  • Methyl frans.frans-2-(Pentvn-4-(1.3-benzodioxol-5-yn-1-[2-fN-propyl-N- propylsulfonylamino)ethyl]pyrrolidine-3-carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylammonium iodide (6 mg, 16 ⁇ mol) in 1 mL EtOH was treated with propylamine (60 ⁇ L, 0.73 mmol). The solution was warmed to 80 °C for 4 hours.
  • the reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M. aqueous Na2C ⁇ 3. The organic phase was washed with 15 mL brine, then dried over Na2S04, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 mg).
  • the crude amine was dissolved in 1 mL of CH2CI2, diiosopropylethylamine (65 ⁇ L, 0.373 mmol) was added, followed by propylsulfonyl chloride (29 ⁇ L, 0.26 mmol). The solution was stirred at room temperature for 4 hours.
  • Example 71 C rans-2-fPentyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-propyl-N- pro p ylsurfonylamino thyl]pyrrolidine-3-carboxylic acid
  • Example 94 trans. trans-2-( Propyl -f 1.3-benzodioxol-5-yl;-1 -f N.N-di - butyltaminocarbonylmethv ⁇ py ⁇ Olidine-3-carboxylic acid
  • Example 94A Ethyl 2-(4-butanovn-4-nitro-3-( 1.3-benzodioxole-5-ynbutyrate
  • Example 94C frans.frans-g-fPropvn ⁇ -n .S-benzodioxol-S-vlVI-.fN.N-dim- butyl ⁇ aminocarbonvlmethvn-pvrrolidine-3-carboxvlic acid
  • the procedure of Example 92C was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B, to give the title compound.
  • Example 95A fra ⁇ s.fra ⁇ s-2-(4-Methoxyphenyl - ⁇ .3-benzodioxol-5-ylV1 -( tert- butyloxycarbonylaminocarbonylmethyllpyrrolidine-3-carboxylic acid
  • the resulting mixture of 64% trans, trans- and cis, trans- pyrrolidines resulting from Example 1 C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride.
  • Example 95B f2R.3R.4S,-(+,-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-(tert- butyloxycarbonylaminocarbonylmethvB-pyrrolidine-3-carboxylic acid
  • the compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam.
  • This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1 H NMR and chiral HPLC. The amount of (2S,3S,4R)-(-)- enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the (2S,3S,4R)-(-)- enantiomer could no longer be detected in the filtrate.
  • Example 95C ( 2R.3R.4S)-f-i- l -Ethvl 2-f4-methoxyphenvn-4-f1.3-benzodioxol-5-vn-pyrrolidine-3- carboxvlate
  • the compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in anhydrous ethanol.
  • the resulting solution was heated at 50 °C. with stirring for 18 hours at which point all of the precipitated solid had dissolved.
  • the reaction mixture was concentrated to a solid which was partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL).
  • Example 95B Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.
  • Example 61 The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C.
  • the product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid.
  • Example 61 (ethylaminocarbonynamino)ethvnpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl isocyanate 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 Iyophilized to give the product as a white solid.
  • the title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B and butyryl chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :4 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 99 frans.frans-2-(4-Methoxyphenv ⁇ -4-M .3-benzodioxol-5-v ⁇ -1-[2-(N-propyl-N- ethoxycarbonylamin ⁇ )ethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 100 frans.fra/7S-2-f4-Methoxyphenyl,-4-f1.3-benzodioxol-5-vn-1-r2-fN-methyl-N-f2- ethylbutyryl ⁇ amin ⁇ )ethyl]pyrrolidine-3-carboxylic acid
  • HOBt 60 mg
  • EDCI 85 mg
  • N- methylmorpholine 50 ⁇ L
  • DMF 2 mL
  • Example 101 frans.frans-2-(4-Methoxyphenvn-4-f1.3-benzodioxol-5-ylV1-r2-(N-methyl-N-(2- propytvaleryl)aminotethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2- ethylbutyric acid.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA. The desired fractions were Iyophilized to give the product as a white solid.
  • Example 102 rrans.frat7S-2-f4-Methoxvphenyn-4-n .3-benzodioxol-5-vn-1-r2-fN-propyl-N-.tert- butyloxycarbonylmethyl.amino.ethyllpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and t-butyl bromoacetate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether- hexane.
  • Example 103 frans.fra ⁇ s-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-[2-(N-propyl-N-(n- propylaminocarbonylmethyl)amin ⁇ ethyl1pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 61 C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 61 but substituting propylamine for methylamine in Example 61 B and 4-methoxyphenylchloroformate for isobutyryl chloride in Example 61C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a whjje solid.
  • Example 105 rans.fra ⁇ s-2-(4-Methoxyphenvn-4-M .3-benzodioxol-5-vn-1-r2-fN-propyl-N-(4- methoxybenzovnamino ethyHpyrrolidine-3-carboxylic acid
  • Example 61 The title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane. The resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 106 frar7S.frans-2-(4-Methoxyphenyn-4-M .3-benzodioxol-5-yl,-1-f2-(N-propyl-N- benzoylamino.ethyl]pyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzoyi chloride for isobutyryl chloride in Example 61 C.
  • the crude product was purified by trituration with 1 :1 diethyl ether-hexane.
  • the resulting solid was dissolved in CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 1Q7 fra ⁇ s.frans-2-,4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1 -r2-(N-propyl-N- benzyloxycarbonylamino ⁇ ethyllpyrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and benzyl chloroformate for isobutyryl chloride in Example 61 C.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C 18) eluting with a 10-70% gradient of CH3CN in 0.1 % TFA.
  • Example 61 substituting propylamine for methylamine in Example 61 B and 4-methoxybenzyl chloroformate for isobutyryl chloride in Example 61C.
  • 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 ⁇ C18) eluting with a 10-70% gradient of CH3CN in 0.1% TFA.
  • the desired fractions were Iyophilized to give the product as a white solid.
  • Example 110 fra ⁇ s.fra ⁇ s-2-f4-Methoxyphenvn-4-f1.3-benzodioxol-5-vn-1-r2-(N-butyl-N- propoxycarbonylamino ethyl]pyrrolidine-3-carboxylic aci '
  • the title compound was prepared by the methods described in Example 61 , but substituting butylamine for methylamine in Example 61 B 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 CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 111 frans.frar>s-2- 4-Methoxyphenyn-4-(1.3-benzodioxol-5-yn-1-f2-.N-propyl-N- propoxvcarbonylamino)ethv ⁇ pvrrolidine-3-carboxylic acid
  • the title compound was prepared by the methods described in Example 61 , but substituting propylamine for methylamine in Example 61 B and 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 CH3CN and water and Iyophilized to give the product as a white solid.
  • Example 112 fra ⁇ s.frans-1-fN.N-Di(n-butyl ⁇ aminocarbonylmethylV2.4-dif1.3-benzodioxol-5- yl)Pyrrolidine-3-carboxylic acid
  • Ethyl (3,4-methylenedioxybenzoyl)acetate prepared by the method of Krapcho et al., Org. Syn. 42, 20 (1967) starting with 3,4- methylenedioxyacetophenone instead of 4-methoxyacetophenone, was reacted by the procedures described in Example 1 to give the title compound as a white solid, m.p. 58-60 °C. 1 H NMR (CDCI3.
  • Example 113 fra ⁇ s.frans-1-(2-fN-m-Butvn-N-propylsulfonylamino)ethvn-2-f4-methoxyphenyn-4- (1 r 3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 64-65 °C.
  • Example 114 fra ⁇ s.fra ⁇ s-1-fN.N-Di(n-butynaminocarbonylmethyl>-2-(4-metho ⁇ yphenvn-4-M .3- benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid, m.p. 74 76 °C. 1 H NMR
  • Example 115 frans.frans-1-f2-fN-Propyl-N-propylsulfonylamino ⁇ ethyn-2-f4-methoxyphenvn-4- (1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 72-73 °C. 1 H NMR (CDCI3.
  • Example 116 trans, frans-1 -(2-fN-Butyl-N-butylsulfonylamino ethvn-2-(4-metho ⁇ yphenvn-4- ⁇ .3- benzodioxol-5-ynpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 62-63 °C.
  • Example 118 fra ⁇ s.frans-1-f2-fN.N-Dim-butyl aminocarbonylmethvn-2-(4-hydroxyphenvn-4-(1.3- benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid hydrochloride salt
  • the compound resulting from Example 1 16 was treated with concentrated HCI in 1 :1 THF-isopropanol to give the title compound as a white solid, m.p. 211-212 °C. 1 H NMR (CD3OD.
  • Example 121 trans.trans-1 -(2-(N-(4-Methoxybenzenesulfonvn-N-propylamino ethyl ⁇ -2-(4- methoxyphenyl ;-4-(1.3-benzodioxol-5-ynpyrrolidine-3-carboxylic acid
  • Example 122 ra ⁇ s.frans-1 -fN.N-Dim-butynaminocarbonylmethyn-2-(2-methoxyethoxy-4- methoxyphenvn-4-(1.3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid
  • 2-Hydroxy-5-methoxyacetophenone was treated with sodium hydride and bromoethyl methyl ether in THF at 70 °C to provide ethyl 2- methoxyethoxy-4-methoxybenzoylacetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid, m.p. 63-65 °C.
  • Example 123 frans.frans-1-f2-fN-Propyl-N- l 2.4-dimethylbenzenesurfonynamino.ethvn-2-(4- methoxyphenyn-4-f1.3-benzodioxol-5-vnpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 88-90 °C.
  • Example 124 frans.frans-1- l 2-fN-Propyl-N-(3-chlcropropylsulfonvnaminoiethvn-2-(4- methoxyphenyn-4-M .3-benzodioxol-5-yl)Pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid, m.p. 75-76 °C.

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BG104216A (bg) 2000-12-29
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NO20000542D0 (no) 2000-02-02
AU748469B2 (en) 2002-06-06
TW552260B (en) 2003-09-11
PL342500A1 (en) 2001-06-04
CA2297894A1 (en) 1999-02-11
IL134175A0 (en) 2001-04-30
NO20000542L (no) 2000-04-04
WO1999006397A3 (en) 1999-12-09
WO1999006397A2 (en) 1999-02-11
TR200101234T2 (tr) 2002-06-21
HUP0003484A2 (hu) 2002-01-28
BR9815296A (pt) 2001-11-20
HUP0003484A3 (en) 2002-02-28
JP2001512119A (ja) 2001-08-21
TR200000993T2 (tr) 2000-12-21
AU8592198A (en) 1999-02-22
SK1452000A3 (en) 2001-05-10
CN1301264A (zh) 2001-06-27
NZ502395A (en) 2002-08-28

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