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WO1995008550A1 - Antagonistes d'endotheline - Google Patents

Antagonistes d'endotheline Download PDF

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Publication number
WO1995008550A1
WO1995008550A1 PCT/US1994/010049 US9410049W WO9508550A1 WO 1995008550 A1 WO1995008550 A1 WO 1995008550A1 US 9410049 W US9410049 W US 9410049W WO 9508550 A1 WO9508550 A1 WO 9508550A1
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WIPO (PCT)
Prior art keywords
methyl
amino
ethyl
leucyl
indol
Prior art date
Application number
PCT/US1994/010049
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English (en)
Inventor
Thomas W. Vongeldern
Jeffrey A. Kester
Saul H. Rosenberg
Martin Winn
Charles W. Hutchins
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Abbott Laboratories
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Publication date
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Publication of WO1995008550A1 publication Critical patent/WO1995008550A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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
  • compositions for antagonizing endothelin are compositions for antagonizing endothelin. Background of the Invention
  • ET Endothelin
  • Big ET precursor peptide big endothelin
  • ECE endothelin converting enzyme
  • Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of
  • vasopressin aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of ⁇ onadotropins in vitro. It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res.
  • 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 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. Clin. Invest. 83 1762 (1989)).
  • an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
  • n 0, 1 or 2;
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or (heterocyclic)alkyl;
  • A is -C(O)- or -S(O) 2 -;
  • R 1 is loweralkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, alkoxy, arylalkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, alkylamino, cycloalkylamino, arylamino, cycloalkylalkylamino, arylalkylamino, dialkylamino, diarylamino, (alkyl)cycloalkylamino,
  • B is hydrogen or loweralkyl
  • E is loweralkyl optionally substituted with one, two or three substituents independently selected from cyano, halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy and azido;
  • G is hydrogen or loweralkyl
  • Ar is bicyclic aryl or bicyclic heteroaryl
  • Y and Z are independently selected from the group consisting of
  • R 11 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino or a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group; (9) a radical of the formula -(CH 2 ) n -V wherein V is
  • Y or Z is a radical of the formula -(CH 2 ) n -C(O)-W, -(CH 2 ) n -V or -(CH 2 ) n -NHS(O) 2 R 6 wherein n, W and R 6 are defined as above; or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of the present invention is a compound of formula (II):
  • a preferred embodiment of the invention is a compound of formula (I) or (II) wherein
  • Q is R 1 -C(O)-N(B)-;
  • loweralkyl substituted with one, two or three substituents independently selected from the group consisting of cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy, and halo;
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino and a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group;
  • R 6 is loweralkyl or haloalkyl and at each occurrence n as used above is independently selected from 0, 1 or 2; and R 1 , E, Ar, B, G, m and X are as defined above;
  • Another preferred embodiment of the present invention is a compound of formula (I) or (II) wherein
  • Q is R 1 -C(O)-N(B)-;
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino and a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group;
  • loweralkyl substituted with one, two or three substituents independently selected from the group consisting of cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy, and halo; (4) cycloalkyl;
  • R 10 is hydrogen or a carboxy protecting group
  • n as used above is independently selected from 0, 1 or 2 and R 1 , E, Ar, B, G, m and X are as defined above; or a pharmaceutically acceptable salt thereof.
  • a more preferred embodiment of the present invention is a compound of formula (I) or (II)
  • Q is R 1 -C(O)-N(B)- wherein R 1 is loweralkyl, (alkyl)cycloalkylamino, cycloalkoxy, arylamino, (alkyl)arylamino, diarylamino, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl alkoxy, cycloalkylalkylamino, cycloalkylamino, alkoxy, arylalkylamino, dialkylamino,
  • G is hydrogen
  • Ar is wherein R is hydrogen or loweralkyl
  • Y is hydrogen, arylalkyl, haloalkyl, loweralkyl, aryl or cycloalkyl;
  • Z is a radical of the formula -(CH 2 ) n -CO-W, wherein W is -OR 10 , wherein R 10 is hydrogen or a carboxy protecting group, alkylamino, hydroxyamino or a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group or
  • n as used above is 0 or 1 ;
  • n 0 or 1 ;
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen or loweralkyl; or a pharmaceutically acceptable salt thereof.
  • a yet more preferred embodiment is a compound of formula (I) or
  • Q is R 1 -C(O)-N(B)- wherein R 1 is cycloalkylammo, arylamino, arylalkyl, spiroheterocyclic, heterocyclic, (alkyl)arylamino, cycloalkoxy, or (alkyl)cycloalkylamino and B is hydrogen or methyl;
  • Ar is wherein R is hydrogen or methyl
  • X is -NH- or -O- ;
  • n 0;
  • Y is loweralkyl
  • Z is -CO 2 H
  • 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 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
  • naturally occuring amino acid refers to an ⁇ -amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine,
  • proline serine, threonine, tryptophan, tyrosine and valine.
  • stereochemistry at the asymmetric center can be of the D- or L- configuration.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl,
  • t-butylacetyl 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
  • cyclopentyloxycarbonyl adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl,
  • 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
  • a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference.
  • Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of
  • carboxy-protecting groups are C 1 to C 8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); benzyl and substituted derivatives thereof such as
  • alkoxybenzyl or nitrobenzyl groups and the like dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as pivaloyloxymethyl or propionyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl and the like; alkoxycarbonyloxyalkyl, such as t-buyloxycarbonyloxymethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as
  • methylaminocarbonylaminomethyl and the like alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like;
  • dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl and the like
  • (5-(loweralkyl)-2-oxo-1 ,3-dioxolen-4-yl)alkyl such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like
  • (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.
  • loweralkyl or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • alkylamino refers to R 51 NH- wherein R 51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • 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.
  • alkylaminocarbonylaminoalkyl refers to R 90 -C(O)-NH-R 91 - wherein R 90 is an alkylamino group and R 91 is an alkylene group.
  • alkylaminocarbonylammoalkyl include methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl and the like.
  • dialkylamino refers to R 56 R 57 N- wherein R 56 and R 57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
  • dialkylaminoalkyl refers to dialkylaminoalkyl
  • dialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl, N-ethyl-N-methylaminomethyl, and the like.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylaminocarbonyl,
  • dialkylaminocarbonylalkyl refers to R 100 -C(O)-R 101 - wherein R 100 is a dialkylamino group and R 101 is an alkylene group, for example, dimethylaminocarbonylmethyl and the like.
  • (alkyl)arylamino refers to R 60 R 61 N- wherein R 60 is an aryl group and R 61 is a loweralkyl group.
  • (alkyl)arylalkylamino refers to (alkyl)arylalkylamino
  • (alkyl)cycloalkylamino refers to (alkyl)cycloalkylamino
  • R 58 R 59 N- wherein R 58 is a cycloalkyl group and R 59 is a loweralkyl group.
  • (alkyl)cycloalkylalkylamino refers to R 62 R 63 N- wherein R 62 is an cycloalkylalkyl group and R 63 is a loweralkyl group.
  • alkanoylaminoalkyl refers to alkanoylaminoalkyl
  • R 93 -NH-R 94 - wherein R 93 is an alkanoyl group and R 94 is an alkylene group.
  • alkanoylaminoalkyl include acetylaminomethyl, acetylaminoethyl and the like.
  • alkanoyloxyalkyl refers to R 74 -O-R 75 - wherein R 74 is an alkanoyl group and R 75 is an alkylene group.
  • alkanoyloxyalkyl examples include acetoxy methyl, acetoxyethyl and the like.
  • alkoxy refers to R 41 O- wherein R 41 is a loweralkyl group, as defined above.
  • alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
  • alkoxyalkoxy refers to R 80 O-R 81 O- wherein R 80 is loweralkyl as defined above and R 81 is alkylene wherein alkylene is -(CH 2 ) n - wherein n' is an integer from 1 to 6.
  • alkoxyalkoxy groups include
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • alkoxycarbonylaminoalkyl refers to R 88 -C(O)-NH-R 89 - wherein R 88 is an alkoxy group and R 89 is an alkylene group.
  • alkoxycarbonylalkyl refers to alkoxycarbonylalkyl
  • alkoxycarbonylalkyl examples include
  • alkoxycarbonyloxyalkyl refers to R 86 -C(O)-O-R 87 - wherein R 86 is an alkoxy group and R 87 is an alkylene group.
  • alkoxycarbonyloxyalkyl include tert-butyloxycarbonylmethyl, tert-butyloxycarbonylethyl, and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1 ,2-ethylene, 1 ,1-ethylene, 1 ,3-propylene, 2,2-dimethylpropylene, and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • bicyclic aryl as used herein includes naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and
  • substituted aryl groups include
  • arylalkoxy refers to R 42 O- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.
  • arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
  • arylalkylamino refers to R 55 NH- wherein R 55 is an arylalkyl group, for example benzylamino and the like.
  • arylamino refers to R 53 NH- wherein R 53 is an aryl group, for example, anilino, and the like.
  • aryloxy refers to R 45 O- wherein R 45 is an aryl group, for example, phenoxy, and the like.
  • aroyloxyalkyl refers to R 82 -C(O)-O-R 83 - wherein R 82 is an aryl group and R ⁇ 3 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • cycloalkoxy refers to R 43 O- wherein
  • R 43 is a cycloalkyl group, for example, cyclohexyloxy, and the like.
  • cycloalkylalkoxy refers to R 44 O- wherein R 44 is a cycloalkylalkyl group, for example, cyclohexylmethoxy, and the like.
  • cycloalkylammo refers to R 52 NH- wherein R 52 is a cycloalkyl group, for example, cyclohexylamino, and the like.
  • cycloalkylalkylamino refers to R 54 NH- wherein R 54 is a cycloalkylalkyl group, for example,
  • diarylamino refers to R 30 R 31 N- wherein R 30 and R 31 are independently selected from aryl as defined above.
  • halogen or “halo” as used herein refers to I, Br, Cl or F.
  • haloalkyl refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a
  • 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, quinolyl, isoquinolyl, tetrahydroquinolyl,
  • heterocyclic also includes tricyclic groups in which any of the above heterocyclic rings is fused to two benzene rings or two cyclohexane rings or two other heterocyclic rings (for example, carbazolyl, iminodibenzyl and the like).
  • Heterocyclics include: azetidinyl, benzimidazolyl, 1 ,4-benzodioxanyl, 1 ,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, carbazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazopyridyl, iminodibenzyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl,
  • nitrogen containing heterocycles can be N-protected.
  • the term "(heterocyclic)alkyl” as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • (heterocyclic)amino refers to R 35 NH- wherein R 35 is a heterocyclic group.
  • Examples of (heterocyclic)amino include 4-pyridylamino, 3-pyridylamino, 2-pyridylamino and the like.
  • heterocycliccarbonyloxyalkyl refers to R 96 -C(O)-O-R 97 - wherein R 96 is a heterocyclic group and R 97 is an alkylene group, for example, 4-methylpiperazinylcarbonyloxymethyl and the like.
  • bicyclic heteroaryl refers to a
  • bicyclic heteroaryl examples include indolyl, indolinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • Bicyclic heteroaryl groups can be unsubstituted or
  • nitrogen containing heterocycles can be N-protected.
  • spirocarbocyclic or "spirocarbocycle” as used herein refers to a bicyclic hydrocarbon in which the ring pair has just one carbon-atom in common, which is designated the "spiro atom”.
  • Spirocarbocyclic compounds can be unsubstituted or substituted with one, two or three groups selected from loweralkyl, hydroxy, alkoxy, halo, haloalkyl and carboxy.
  • spirocarbocycles include
  • spiropentane spirohexane, spiro[4.4]nonane and the like.
  • spiroheterocyclic or "spiroheterocycle” as used herein refers to a bicyclic spirocyclic ring system containing carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur. Examples of spiroheterocycles include 1-oxa-4-azaspiro[5.4]decane, 1 ,4-diaza[5.4]decane and the like. Spiroheterocyclics can be substituted in the same way as defined above for heterocyclics.
  • tetrazolyl refers to a radical of the formula or a tautomer thereof.
  • thioalkoxy refers to R 70 S- wherein R 70 is loweralkyl.
  • examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • Representative compounds of the invention include:
  • Preferred compounds are selected from the group consisting of:
  • One process for preparing the compounds of the invention comprises reacting a compound of the formula:
  • Schemes l-V Methods for preparing the compounds of the invention are shown in Schemes l-V.
  • the stereochemistry shown in the schemes is that of the preferred compounds of the invention. Compounds having other stereochemistry than that shown in the schemes can be obtained by starting with amino acids of opposite stereochemistry.
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or (heterocyclic)alkyl; and Y is hydrogen; loweralkyl; loweralkyl substituted with one, two or three groups independently selected from cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, azido, thioalkoxy, and halo; cycloalkyl; (cycloalkyl)alkyl; aryl; or arylalkyl.
  • the acylated glycine is coupled with an appropriately protected activated amino acid residue (P* is an nitrogen protecting group, Ar is bicyclic aryl or bicyclic heteroaryl and A* is an amino acid activating group, for example, chloride, fluoroide or mixed anhydride) to give 3.
  • the heterocyclic ring is prepared using the appropriate reagents (for example, DBU, carbon tetrachloride and triphenylphosphine to prepare an oxazole; ammonium acetate to prepare an imidazole; and Lawesson's reagent to prepare a thiazole) to give compound 4.
  • Method C hydrogenolysis of a benzyl ester
  • R 1 -A- is an nitrogen protecting group
  • P is Boc
  • the heterocyclic intermediate is nitrogen deprotected, coupled with a fully elaborated amino acid (R 1 -C(O)-NH-CH(E)-CO 2 H) residue or an activated ester derivative thereof and then the carboxy protecting group is removed (for example, hydrolysis of an alkyl ester or hydrogenolysis of a benzyl ester) to give the final product 6.
  • Activated ester derivatives of carboxylic acids include acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as
  • N-hydroxysuccinimide derived esters N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbomene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like.
  • heterocyclic intermediate 4 (P* is an nitrogen protecting group, P" is a carboxy protecting group and Ar is bicyclic aryl or bicyclic
  • heteroaryl is carboxy deprotected (for example, hydrolysis of an alkyl ester or hydrogenolysis of a benzyl ester) to give the heterocycle carboxylic acid 11.
  • Activation of compound 11 for example, by formation of the acid chloride
  • treatment with diazomethane, and rearrangement of the resultant diazoketone gives the acetic acid compound 12.
  • Compound 12 can be elaborated to 12a as described in Scheme I. For the case where both m and n are 1 , one would homologate the bicyclic aryl or heteroaryl amino acid as described in the first part of Scheme II and then also homologate the heterocyclic carboxylic acid by the procedure described in the second part of Scheme II. In the case where one desires m and/or n to be 2, one repeats the homologation reaction once again.
  • the heterocyclic ring is prepared using the appropriate reagents (for example, DBU, carbon tetrachloride and triphenylphosphine to prepare an oxazole, ammonium acetate to prepare an imidazole and
  • Boc-Leucyl-OH to give compound 19.
  • the Boc nitrogen protecting group is removed and the residue is coupled with N-methyl-N-phenylcarbamoyl chloride.
  • Hydrogenolysis of the benzyl ester provides the final product 20.
  • the heterocyclic intermediate is de-protected, coupled with N-(N-methyl-N-phenylaminocarbonyl)-Leucyl-OH and the benzyl group
  • P 1 is hydrogen or an N-protecting group
  • n 0, 1 or 2;
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or (heterocyclic)alkyl;
  • G is hydrogen or loweralkyl
  • Ar is bicyclic aryl or bicyclic heteroaryl
  • Y and Z are independently selected from the group consisting of
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino or a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group; (9) a radical of the formula -(CH 2 ) n -V wherein V is
  • P 1 is hydrogen or an N-protecting group
  • n 0, 1 or 2;
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or (heterocyclic)alkyl;
  • G is hydrogen or loweralkyl
  • Ar is bicyclic aryl or bicyclic heteroaryl
  • Y and Z are independently selected from the group consisting of
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino or a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group;
  • Preferred intermediates include compounds of formula (III) or (IV) wherein
  • loweralkyl substituted with one, two or three substituents independently selected from the group consisting of cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy, and halo;
  • R 10 is hydrogen or a carboxy protecting group
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino and a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group;
  • R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino, N-hydroxyl-N-alkylamino and a naturally occurring ⁇ -amino acid wherein the amino acid is bonded through the ⁇ -amino group;
  • loweralkyl substituted with one, two or three substituents independently selected from the group consisting of cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy, and halo;
  • R 10 is hydrogen or a carboxy protecting group and at each occurrence n as used above is independently selected from 0, 1 or 2.
  • Particularly preferred intermediates are compounds of formula (III) or (IV) wherein
  • G is hydrogen
  • a Ar is wherein R is hydrogen or loweralkyl
  • Y is loweralkyl
  • Z is a radical of the formula -CO-W, wherein W is -OR 10 , wherein R 10 is hydrogen or a carboxy protecting group;
  • n 0 or 1 ;
  • X is -NH- or -O- .
  • Example 1A The compound resulting from Example 1A (5.0 g) was dissolved in acetic acid (15 mL). Ammonium acetate (4.0 g) was added and the mixture heated at reflux for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue taken up in saturated NaHCO 3 solution and extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and evaporated in vacuo. The resulting orange oil was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexane to afford 3.60 g (73%) of the title compound.
  • Example 1 B The compound resulting from Example 1 B (1.7 g) was dissolved in EtOH (10 mL). The solution was purged of oxygen, 10% Pd/C (0.5 g) was added, and the mixture was stirred at room temperature under an atmosphere of hydrogen. After two hours the catalyst was removed by filtration and the solvent evaporated in vacuo to give a white solid (1.2 g).
  • Example 1 C The compound resulting from Example 1 C (68 mg) was dissolved in THF (2 mL). HOBt (30 mg), the acid prepared in Example 1 D (55 mg) and EDCI (42 mg) were added. N-Methylmorpholine (10 ⁇ L) and DMF (1 mL) were added and the mixture stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc. The solution was washed with saturated NaHC03 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 , and evaporated in vacuo to give an orange oil which was purified by flash chromatography on silica gel eluting with 50% EtOAc-hexane.
  • Example 1 B The title compound was prepared by the procedures described in Example 1 but substituting benzylamine for ammonium acetate in Example 1 B.
  • Homopiperidine (6 mL) was dissolved in diethyl ether (250 mL) and cooled to 0 °C in an ice bath. HCI gas was bubbled through the solution and the resulting white solid collected by filtration and dried in vacuo. The solid was taken up in sulfuryl chloride (20 mL) and the mixture heated at reflux. The reaction became very thick and additional sulfuryl chloride (10 mL) was added and reflux continued for 16 hours. The remaining sulfuryl chloride was evaporated and the residue distilled (90-100 °C, 0.1 mm) to give homopiperidinesulfonyl chloride as a colorless oil (9.06 g, 86%).
  • the benzyl ester (0.85 g) was dissolved in MeOH (20 mL) and 10% Pd/C (0.75 g) was added. The mixture was stirred at room temperature under an H 2 atmosphere for 2.5 hours. The catalyst was filtered off and the solvent evaporated to give the product as a colorless oil (0.66 g, 100%).
  • Example 16A The compound resulting from the procedure in Example 16A (100 mg) was dissolved in THF (2 mL) and a solution of LiOH (50 mg) in H 2 O (1 mL) was added. The mixture was heated in a Carius tube at 110 °C for 15 hours. The solvents were evaporated under reduced pressure and the residue taken up in 1 N H 3 PO 4 (5 mL). The suspension was dissolved in water and acetonitrile, and the product purified by
  • Example 16A The compound resulting from Example 16A (0.11 g) was taken up in 4 N HCI/dioxane (2 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc (10 mL). The solution was washed with saturated NaHCO 3 solution and brine, dried with MgSO 4 and evaporated in vacuo to give a white solid which was dissolved in THF (5 mL). Et 3 N (50 ⁇ L) was added followed by benzyl isocyanate (38 mg, 35 ⁇ L). The solution was stirred at room temperature for 5 hours. The solvent was
  • Example 17A To the compound resulting from Example 17A (100 mg) dissolved in THF (3 mL) was added a solution of LiOH (0.1 g) in H 2 O (3 mL). The mixture was heated in a Can us tube at 110 °C for 15 hours. The solvents were evaporated under reduced pressure and the residue taken up in 1 N H 3 PO 4 (5 mL). The suspension was dissolved in water and acetonitrile and the product purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid.
  • Example 17A The title compound is prepared according to the procedures described in Example 17 but substituting 1-naphthoyl chloride for benzyl isocyanate in Example 17A.
  • Example 20A The compound resulting from Example 20A (100 mg) was dissolved in THF (3 mL) and a solution of LiOH (0.1 g) in H 2 O (3 mL) was added. The mixture was heated in a Carius tube at 110 °C for 15 hours. The solvents were evaporated under reduced pressure and the residue taken up in 1 N H 3 PO 4 (5 mL). The suspension was dissolved in water and acetonitrile, and the product purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1 % TFA. The desired fractions were lyophilized to give the product as a white solid.
  • Example 20A The title compound was prepared according to the procedures described in Example 20 but substituting cycloheptanecarboxylic acid for cyclohexaneacetic acid in Example 20A.
  • Example 20 The title compound was prepared according to the procedures described in Example 20 but substituting 2-norbornylacetic acid for cyclohexylacetic acid in Example 20A. 1 H NMR of the major
  • Example 20 The title compound was prepared according to the procedures described in Example 20 but substituting 3,3-dimethylbutyric acid for cyclohexylacetic acid in Example 20A. 1 H NMR of the major
  • Example 20 The title compound was prepared according to the procedures described in Example 20 but substituting 2-propylpentanoic acid for cyclohexylacetic acid in Example 20A. 1 H NMR of the major
  • hexamethyldisilazide (12.5 mL, 1 N solution in THF) was added slowly over 10 minutes, and the resulting yellow slurry was stirred at -78 °C for 30 minutes. The slurry was then transferred via cannula to a solution of acetyl chloride (0.93 mL) in THF (25 mL) at -78 °C . After the addition was complete, the reaction was allowed to warm to room temperature and stirring was continued for four hours. The reaction was then quenched with 2 N HCI (15 mL). The THF was evaporated and the resulting aqueous solution was washed with EtOAc (2 ⁇ 50 mL). The organic phases were discarded and the aqueous phase was
  • Fmoc-D-(1-methyl)-Tryptophan (5.75 g), prepared by the method of Cook, et al., Chem. Pharm. Bull. IS 88 (1965), was dissolved in THF (20 mL) and the solution cooled to -20 °C. N-Methylmorpholine (1.45 mL) was added followed by the dropwise addition of
  • Example 27C The compound resulting from Example 27A (5.0 g) was dissolved in acetic acid (25 mL). Ammonium acetate (4.0 g) was added and the mixture heated at reflux for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue taken up in saturated NaHCO 3 solution and extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and evaporated in vacuo. The resulting orange oil was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexane to afford 1.10 g (23%) of the title compound. Exampie 27C
  • Example 27B The imidazole resulting from Example 27B (80 mg) was suspended in 3 mL of THF. Piperidine (0.3 mL) was added, and the resulting solution was stirred at ambient temperature for 45 minutes. The solvents were removed in vacuo, and the residue was triturated with hexanes, filtered, and dried under vacuum for 15 minutes to afford the title compound (50 mg, 100% yield).
  • Leucine benzyl ester ⁇ p-TsOH (100 mg) was dissolved in CHCI 3 (2 mL). Et 3 N (51 mg, 75 ⁇ L) was added and the solution cooled to 0 °C in an ice bath. Carbonyldiimidazole (41 mg) was added and the solution stirred at 0 °C for one hour. The bath was removed, and the solution was stirred an additional one hour at room temperature.
  • the hydrogen was evacuated and the flask filled with nitrogen.
  • the catalyst was removed by filtration through a pad of Celite ® and the solvent removed in vacuo.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The appropriate fraction was lyophilized to give the product as a white solid (34.7 mg, 62 %).
  • Example 27 The title compound was prepared according to the procedures described in Example 27 but substituting endo-2-norbomylamine for cyclohexylamine in Example 27D.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid (29 mg).
  • Example 27 The title compound was prepared according to the procedures described in Example 27 but substituting exo-2-norbornylamine for cyclohexylamine in Example 27D.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid (45 mg).
  • Example 27 The title compound was prepared according to the procedures described in Example 27 but substituting 2-methylcyclohexylamine (mixture of cis and trans) for cyclohexylamine in Example 27D.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid.
  • Example 27 The title compound was prepared according to the procedures described in Example 27 but substituting 3-methylcyclohexylamine (mixture of cis and trans) for cyclohexylamine in Example 27D.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid.
  • Example 27 The title compound was prepared according to the procedures described in Example 27 but substituting 4-methylcyclohexylamine (mixture of cis and trans) for cyclohexylamine in Example 27D.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid (28 mg).
  • Example 1 The title compound was prepared by the procedures described in Example 1 but substituting trifluoroacetyl chloride for acetyl chloride in Example 1 A. Saponification of the ethyl ester gives the dicarboxylic acid through concomitant hydrolysis of the trifluoromethyl group.
  • the crude product was purified by flash chromatography on silica gel eluting with a gradient of 3:1 going to 1 : 1 hexanes-ethyl acetate to elute the product (2.63 g, 89% yield) as a colorless oil.
  • the organics were extracted with 0.25 N NaOH (100 mL).
  • the aqueous extract was acidified with 1 N H 3 PO 4 and extracted twice with EtOAc.
  • the organic extracts were washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 , and concentrated in vacuo to afford the crude product, which was used without further purification.
  • Example 1 but substituting the compound resulting from Example 40A for Cbz-D-tryptophan in Example 1 A.
  • the crude material was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 0-80% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the title compound as a white solid (17 mg).
  • Boc-D-Trp(Me)-OH (0.955 g, 3.0 mmol) was dissolved in THF (25 mL) and cooled to -20 °C.
  • N-Methylmorpholine (0.33 mL, 1.0 eq)
  • isobutyl chloroformate (0.39 mL, 1.0 eq) were added and the slurry stirred for 30 minutes at which time a solution of concentrated ammonia (0.2 mL) in THF (3 mL) was added. The mixture was warmed slowly to 0 °C over 1 hour.
  • Boc-D-(1-methyl)-Tryptophanyl amide (0.50 g, 1.57 mmol) was dissolved in THF (10 mL) and Lawesson's reagent (770 mg, 1.90 mmol, 1.2 eq) was added. The solution was stirred at ambient temperature for 65 hours. The solvents were removed in vacuo, and the residue was taken up in EtOAc and washed with 1 :1 saturated sodium bicarbonate solution/water and brine. The organic phase was dried over Na2S ⁇ 4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 2:1 hexanes-ethyl acetate to give the product (442 mg, 86% yield) as a light yellow foam.
  • Example 41 B The amidine resulting from Example 41 B (130 mg, 0.41 mmol) was combined in THF (2 mL) with ethyl bromopyruvate (88 mg, 0.45 mmol, 1.1 eq) and propylene oxide (29 mg, 0.5 mmol). The solution was stirred overnight at ambient temperature and the solvents removed in vacuo. The crude product was taken up in pyridine (2 mL) and methanesulfonyl chloride (7 drops) and triethylamine (5 drops) were added. The mixture was heated at 80 °C for 5 hours.
  • Leu-OBn ⁇ p-TsOH (2.0 g) was suspended in THF (5 mL). N- Methyl morpholine (0.56 mL, 0.51 g) and phenyl isocyanate (0.55 mL, 0.6 g) were added and the solution stirred at ambient temperature for four hours. The solvent was evaporated and the residue dissolved in EtOAc (20 mL). The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 , and evaporated under reduced pressure to give a colorless oil which was dissolved in EtOH (25 mL). 10% Palladium on carbon (200 mg) was added.
  • the flask was fitted with a three-way stopcock connected to a hydrogen-filled balloon and a nitrogen/vacuum manifold.
  • the flask was evacuated, filled with nitrogen, evacuated again, and then put under a hydrogen atmosphere.
  • the mixture was stirred at ambient temperature for 14 hours.
  • the hydrogen was evacuated and the flask filled with nitrogen.
  • the catalyst was removed by filtration through a pad of Celite ® and the solvent removed in vacuo to give a colorless oil which solidified on standing (1.08 g, 85% yield).
  • Example 43B Example 43B
  • N-Boc-N-methyl-Leu-OH (85mg), prepared by the method of Cheung and Benoiton, Can. J. Chem. 55906 (1977), was dissolved in THF (4 mL) and DMF (2 mL).
  • 2-[(1 R)-1-Amino-2-(1-methyl-indol-3-yl)ethyl]-5-methyl-imidazole-4-carboxylic acid benzyl ester (63 mg), prepared according to the procedures described in Example 27C, HOBt (42 mg), N-methylmorpholine (8 drops), and EDCI (57 mg) were added and the mixture stirred at ambient temperature for 18 hours.
  • Example 45A The compound resulting from Example 45A (0.335 g) was dissolved in THF (5 mL). Lawesson's reagent (0.45 g) was added and the mixture stirred at reflux for five hours. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc (20 mL). The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 and evaporated under reduced pressure to give a yellow oil which was purified by flash chromatography eluting with 15% EtOAc-hexane to give the product as a white solid (155 mg, 46%).
  • Example 45D The compound resulting from Example 45B (72 mg, 0.15 mmol) was dissolved in 2 mL of 30% HBr in HOAc and stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na 2 SO 4 . The solvents were removed in vacuo, and the crude product was used directly for subsequent coupling reactions.
  • Example 45D The compound resulting from Example 45B (72 mg, 0.15 mmol) was dissolved in 2 mL of 30% HBr in HOAc and stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na 2 SO 4 . The solvents were removed in vacuo, and the crude product was used directly for subsequent coupling reactions.
  • Example 45D The compound resulting from
  • Example 45 The title compound was prepared according to the procedures described in Example 45, substituting propionyl chloride for acetyl chloride in Example 45A.
  • the crude product was dissolved in 100 mL of methanol, and a solution of 1.0 g of silver benzoate in 10 mL of triethylamine (filtered through a short pad of Celite) was added over a 5 minute period. After stirring for 60 minutes the solution had turned dark brown. The solvents were removed in vacuo; the residue was stirred with 120 mL of a 1 :1 water-ethyl acetate mixture for 10 minutes, then filtered through a pad of Celite. The organic layer was washed with brine, dried over Na 2 SO 4 and stripped in vacuo.
  • the crude product was purified by flash chromatography on silica gel eluting with a gradient of 3:1 going to 1 :1 hexanes-ethyl acetate to elute the product (2.63 g, 89% yield) as a colorless oil.
  • Example 45 substituting the compound resulting from Example 53A for Cbz-D-tryptophan in Example 45A.
  • Boc-D-(N i -methyl)-Tryptophanyl-CSNH 2 A solution of 0.955 g (3.0 mmol) of Boc-D-Trp(Me)-OH, prepared according to the method of Cook etal., Chem. Pharm. Bull.13(1) 88 (1965), in 25 mL of THF was cooled to -20 °C. N-Methylmorpholine (0.33 mL, 1.0 eq) was added, followed by 0.39 mL (1.0 eq) of isobutyl chloroformate. The resultant slurry was stirred for 30 minutes, and then a solution of 0.2 mL of concentrated ammonia in 3 mL of THF was added.
  • Example 54A The thioamide resulting from Example 54A (100 mg, 0.3 mmol) was combined with 72 mg (0.33 mmol) of ethyl bromopyruvate and 100 mg of propylene oxide in 1 mL of THF in a Carius tube. The solution was heated at 80 °C for 4 hours and then the solvents were removed in vacuo. The crude product was taken up in 1 mL of pyridine, and 10 drops of trifluoroacetic anhydride were added slowly. The resultant dark solution was stirred overnight at ambient temperature. The solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with 1 :1 saturated sodium bicarbonate/water, 1 N H 3 PO 4 , and brine. The organic phase was dried over Na 2 SO 4 and stripped in vacuo. The crude product was purified by flash
  • Example 54B The compound resulting from Example 54B (50 mg) was dissolved in 3 mL of trifluoroacetic acid and stirred at ambient
  • Example 57A The compound resulting from Example 57A (4.44 g) was dissolved in acetonitrile (15 mL). Pyridine (25 mL), carbon tetrachloride (2 mL), DBU (2.90 g) and triphenylphosphine (2.75 g) were added, and the mixture was stirred for 16 hours at room temperature. The solvents were evaporated under reduced pressure and the residue dissolved in EtOAc. The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 , and brine, dried with MgSO 4 and evaporated to give an off-white semi-solid which was purified by flash chromatography on silica gel eluting with 15% EtOAc-hexane to give the title compound.
  • Example 57B The compound resulting from Example 57B (90 mg) was dissolved in EtOH (5 mL) and 10% Pd/C (50 mg) was added. The mixture was purged of oxygen and stirred under a balloon of hydrogen for 5 hours. The solvent was removed in vacuo and the residue taken up in EtOAc and filtered through Celite ® to remove the catalyst . The solvent was evaporated to give the ethyl ester as a yellow oil.
  • N-(Homopiperidin-1-ylcarbonyl)-Leucyl-OH Leucyl-OBn ⁇ pTsOH 100 mg was dissolved in CHCI 3 (2 mL).
  • Et ⁇ N 51 mg, 75 ⁇ L was added and the solution cooled to 0 °C in an ice bath.
  • Carbonyldiimidazole 41 mg was added and the solution stirred at 0 °C for one hour. The bath was removed and the solution was stirred an additional one hour at room temperature.
  • Homopiperidine 44 mg, 50 ⁇ L was added and the solution stirred overnight at room
  • Homopiperidine (6 mL) was dissolved in diethyl ether (250 mL) and cooled to 0 °C in an ice bath. HCI gas was bubbled through the solution. The resulting white solid was collected by filtration and dried in vacuo. The solid was taken up in sulfuryl chloride (20 mL) and the mixture heated at reflux. The reaction became very thick and additional sulfuryl chloride (10 mL) was added and reflux continued for 16 hours. The remaining sulfuryl chloride was evaporated and the residue distilled (90-100 °C, 0.1 mm) to give homopiperidinesulfonyl chloride as a colorless oil (9.06 g, 86%).
  • the sulfonyl choride (0.97 g) was dissolved in DMF (10 mL). Leu-OBn . pTsOH (2.03 g), H ⁇ nig's base (1.75 mL), and then DMAP (0.2 g) were added and the mixture stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate, washed with water, 2 N HCI, saturated NaHCO 3 solution, and brine, dried, and evaporated. Purification by flash chromatography (10% EtOAc-hexane) gave N-(homopiperidin-1-ylsulfonyl)-leucine benzyl ester as a white solid (0.88 g, 47%).
  • the benzyl ester (0.85 g) was dissolved in MeOH (20 mL) and 10% Pd/C (0.75 g) was added. The mixture was stirred at room temperature under an H 2 atmosphere for 2.5 hours. The catalyst was filtered off and the solvent evaporated to give the title compound as a colorless oil (0.66 g, 100%).
  • Example 69 substituting glycine ethyl ester for hydroxylamine.
  • the resulting product was dissolved in THF (2 mL), a solution of LiOH (50 mg) in H 2 O (1 mL) was added and the mixture was stirred at room temperature for 15 hours.
  • the solvents were evaporated under reduced pressure and the residue purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA.
  • the desired fractions were lyophilized to give the product as a white solid.
  • the crude product was purified by flash chromatography on silica gel eluting with 1 :1 hexanes-ethyl acetate.
  • the crude product was purified by flash chromatography on silica gel eluting with a gradient of 1 :1 going to 2:1 ethyl acetate-hexanes to afford the product (13 mg, 6% yield) as a colorless oil.
  • Example 57C-E The title compound was prepared following the procedures described in Example 57C-E, substituting the compound resulting from Example 72A for 2- ⁇ (1 R)-(Benzyloxycarbonylamino)-2-(indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid ethyl ester in Example 57C.
  • the crude product was dissolved in 100 mL of methanol, and a solution of 1.0 g of silver benzoate in 10 mL of triethylamine (filtered through a short pad of Celite) was added over a 5-minute period. After stirring for 60 minutes the solution had turned dark brown. The solvents were removed in vacuo; the residue was stirred with 120 mL of a 1 :1 water-ethyl acetate mixture for 10 minutes, then filtered through a pad of Celite. The organic layer was washed with brine, dried over Na 2 SO4 and stripped in vacuo.
  • the crude product was purified by flash chromatography on silica gel eluting with a gradient of 3:1 going to 1 :1 hexanes-ethyl acetate to elute the product (2.63 g, 89% yield) as a colorless oil.
  • Example 57B The compound resulting from Example 57B (1.7 g) was dissolved in EtOH (10 mL). 10% Pd/C (0.5 g) was added and the mixture stirred at room temperature under an atmosphere of hydrogen. After two hours the catalyst was removed by filtration and the solvent evaporated in vacuo to give a white solid (1.2 g). The solid was dissolved in THF (10 mL) and added to a solution of Boc-Leu-OH ⁇ H 2 O (1.0 g) and HOBt (0.5 g) in THF (10 mL). EDCI (0.75 g) was added to the solution, followed by DMF (2 mL). The mixture was stirred for 20 hours at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc.
  • Example 75A To the compound resulting from Example 75A (100 mg) dissolved in THF (2 mL) was added a solution of LiOH (50 mg) in H 2 O (1 mL). The mixture was stirred at room temperature for 15 hours. The solvents were evaporated under reduced pressure and the residue purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid.
  • Example 75A The compound resulting from Example 75A (0.15 g) was taken up in 4 N HCI in dioxane (2 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc (10 mL). The solution was washed with saturated NaHCO 3 solution and brine, dried with MgSO 4 and evaporated in vacuo to give a white solid which was dissolved in THF (5 mL). Et 3 N (42 ⁇ L) was added followed by phenylacetyl chloride (44 mg, 26 ⁇ L). The solution was stirred at room temperature for 5 hours. The solvent was evaporated and the residue taken up in EtOAc. The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 , and evaporated in vacuo to give the ethyl ester as a white solid.
  • Example 76A The ethyl ester resulting from Example 76A was dissolved in THF (3 mL) and a solution of LiOH (0.1 g) in H 2 O (3 mL) was added. The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the title compound as a white solid.
  • Example 76A The title compound was prepared by the procedures described in Example 76 but substituting benzyl isocyanate for phenylacetyl chloride in Example 76A.
  • Example 75A The compound resulting from Example 75A (0.10 g) was taken up in 4 N HCI in dioxane (2 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc (10 mL). The solution was washed with saturated NaHCO 3 solution and brine, dried with MgSO 4 and evaporated in vacuo to give a white solid which was dissolved in THF (5 mL).

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Abstract

Composé représenté par la formule (I), ou un de ses sels pharmaceutiquement acceptable, ainsi que procédés et intermédiaires servant à leur préparation, procédés et compositions antagonistes de l'endothéline.
PCT/US1994/010049 1993-09-24 1994-09-07 Antagonistes d'endotheline WO1995008550A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011927A1 (fr) * 1994-10-12 1996-04-25 Abbott Laboratories Antagonistes de l'endotheline
WO1996033740A1 (fr) * 1995-04-24 1996-10-31 Genentech, Inc. Utilisation d'antagonistes du facteur d'inhibition de la leucemie et de l'endotheline
US5837241A (en) * 1995-04-24 1998-11-17 Genentech, Inc. Method of treating heart failure using leukemia inhibitory factor antagonists optionally with endothelin antagonists
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
JP2003535844A (ja) * 2000-06-06 2003-12-02 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 第ＶＩＩａ因子阻害剤である（チオ）尿素誘導体、その製造方法およびその使用
US7238695B2 (en) * 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
US7566734B2 (en) 2000-08-01 2009-07-28 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Imidazolyl derivatives
US8193372B2 (en) 2009-03-04 2012-06-05 Idenix Pharmaceuticals, Inc. Phosphothiophene and phosphothiazole HCV polymerase inhibitors

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EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline

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EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011927A1 (fr) * 1994-10-12 1996-04-25 Abbott Laboratories Antagonistes de l'endotheline
WO1996033740A1 (fr) * 1995-04-24 1996-10-31 Genentech, Inc. Utilisation d'antagonistes du facteur d'inhibition de la leucemie et de l'endotheline
US5837241A (en) * 1995-04-24 1998-11-17 Genentech, Inc. Method of treating heart failure using leukemia inhibitory factor antagonists optionally with endothelin antagonists
US6156733A (en) * 1995-04-24 2000-12-05 Genentech, Inc. Use of leukemia inhibitory factor and endothelin antagonists
US6653287B1 (en) 1995-04-24 2003-11-25 Genentech, Inc. Use of leukemia inhibitory factor and endothelin antagonists
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
US7238695B2 (en) * 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
JP2003535844A (ja) * 2000-06-06 2003-12-02 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 第ＶＩＩａ因子阻害剤である（チオ）尿素誘導体、その製造方法およびその使用
JP4809570B2 (ja) * 2000-06-06 2011-11-09 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 第ＶＩＩａ因子阻害剤である（チオ）尿素誘導体、その製造方法およびその使用
US7566734B2 (en) 2000-08-01 2009-07-28 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Imidazolyl derivatives
US7638546B1 (en) 2000-08-01 2009-12-29 Ipsen Pharma S.A.S. Imidazolyl derivatives
US8193372B2 (en) 2009-03-04 2012-06-05 Idenix Pharmaceuticals, Inc. Phosphothiophene and phosphothiazole HCV polymerase inhibitors

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