WO2000025768A1 - Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof - Google Patents

Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof Download PDF

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Publication number
WO2000025768A1
WO2000025768A1 PCT/US1999/025331 US9925331W WO0025768A1 WO 2000025768 A1 WO2000025768 A1 WO 2000025768A1 US 9925331 W US9925331 W US 9925331W WO 0025768 A1 WO0025768 A1 WO 0025768A1
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Prior art keywords
thiocarbamyl
carbamyl
substituted
chloro
benzene
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PCT/US1999/025331
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English (en)
French (fr)
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WO2000025768A8 (en
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R. Normand Hebert
Amy L. Hannah
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Trega Biosciences, Inc.
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Priority to AU14555/00A priority Critical patent/AU1455500A/en
Priority to EP99971314A priority patent/EP1126833A4/de
Publication of WO2000025768A1 publication Critical patent/WO2000025768A1/en
Publication of WO2000025768A8 publication Critical patent/WO2000025768A8/en

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the present invention relates generally to the synthesis of compounds comprising heterocyclic rings.
  • the invention provides novel oxadiazoles as well as novel combinatorial libraries comprised of such compounds.
  • the process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional "one-at- a-time" synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional "one-at-a-time” synthesis methods, except over a time frame of years or even decades.
  • Patent 5,182,366 describes a method of preparing a mixture of peptides having known composition using three essential steps, dividing an amount of a mixture of amino acid derivatized resins, coupling a subsequent amino acid and combining a known amount of a different resin together to obtain peptide mixtures. Also described are methods to retrieve and analyze the amino acid sequence. Appel et al . in WO PCT 92/09300, describes the synthesis of complex mixtures of solid support-coupled amino acids in which the mixture contains an equimolar representation of each reacted amino acid coupled.
  • Geysen in published European Patent Application 0 138 855 describes a method of synthesizing a peptide library and detecting a peptide comprising a sequence of amino acids which has antigenic activity.
  • Pirrung et al . in U.S. Patent 5,143,854 describe polypeptide arrays synthesized using photoremovable groups. Synthesized combinatorial libraries have provided an extraordinary number of various peptides in such libraries and the availability of rapid screening of the library which can identify lead pharmaceutical peptides.
  • Oxadiazoles for example, have been the subject of investigation in a number of different biological areas.
  • a number of patents cite oxadiazole derivatives as pesticides and acaricides. 1, 2, 4-Oxadiazoles have been proposed as: (a) muscarinic receptor agonists (as described by esser W. S. Jr., et al . , J " . Med. Chem.
  • Oxadiazoles with a 5-chloromethyl substituent have been described as plant growth regulators (Jpn. Kokai Tokkyo Koho, 4 pp. CODEN: JKXXAF, JP 57188503 A2 821119; Showa, Application Ser. No.:
  • Liang and Feng used the symmetrical anhydrides generated from 2-hydroxy carboxylic acids in the presence of a carbodiimide as the acylating species to give 5-hydroxymethyl substituted oxadiazoles (Liang, G. B., et al . Tetrahedron Lett . , 37:
  • the present invention satisfies these needs and provides related advantages as well.
  • the present invention overcomes the known limitations to classical organic synthesis of oxadiazoles, for example, as well as the shortcomings of combinatorial chemistry related to heterocycles .
  • the present invention allows for rapid generation of large diverse libraries of complex heterocycles as discrete molecules or molecules bound to a resin.
  • the present invention can utilize a readily available pool of building blocks that can be incorporated into the various regions of the molecule .
  • the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionality. Therefore, building blocks, such as those described above, can provide libraries that consist of large numbers as well as libraries that are extremely diverse with respect to the functionality contained within those libraries.
  • the present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new oxadiazole, thiadiazole and triazole compounds .
  • the present invention relates to novel oxadiazole, thiadiazole and triazole compounds of the following formula:
  • the invention further relates to combinatorial libraries containing two or more such compounds, and to the generation of such combinatorial libraries composed of such compounds .
  • Figure 2 provides Reaction Scheme 2 showing the attachment of cyanophenols to solid support .
  • Figure 3 provides Reaction Scheme 3 showing linking nitriles to solid support.
  • Figure 4 provides Reaction Scheme 4 showing the conversion of resin-bound nitriles into oxadiazoles.
  • Figure 5 provides Reaction Scheme 5 showing the derivatization of oxadiazoles.
  • the present invention provides novel compounds and libraries of novel compounds of Formula (I) :
  • T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
  • X is H, -NHC(0)NR 1 R 2 , -C0 2 R 1# -OR lf -NR ⁇ , -C(0)NR x R 2 , or wherein R ⁇ is a hydrogen atom or a functionalized resin; and R 2 is a hydrogen atom, ⁇ to C 6 alkyl, C : to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to cy substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, heteroaryl or substituted heteroaryl, heterocycle or substituted heterocycle; or - RiR 2 together is of the formula :
  • Q is a hydrogen atom or functionalized resin
  • X 2 is Ci to C 12 alkylene, Cj to C 12 substituted alkylene, C 2 to C 7 alkenylene, C 2 to C 7 substituted alkenylene, C 2 to C 7 alkynylene, C 3 to C 7 cycloalkylene, C 3 to C substituted cycloalkylene, C 5 to C 7 cycloalkenylene, C 5 to C 7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 7 to C 12 phenylalkylene, or C 7 to C 12 substituted phenylalkylene C 7 to C 12 phenylalkox, or C 7 to C 12 substituted phenylalkoxy; or
  • X 2 is of the formula:
  • n and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is phenylene or substituted phenylene; or
  • X 2 is of the formula:
  • R 3 is a hydrogen atom, C ⁇ to C 6 alkyl, C x to C 6 substituted alkyl, C ⁇ to C 7 acyl, C ⁇ to C 7 substituted acyl, Ci to C 4 alkyl sulfonyl, C 1 to C 4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 6 alkylaminocarbonyl, C ⁇ to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C ⁇ to C 6 alkylaminothiocarbonyl, C ⁇ to C 6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl; substituted phenylaminothiocarbony
  • X 7 is of the formula (II) :
  • n is an integer selected from 0 to 6;
  • R 4 and R 5 are together or independently a hydrogen atom, Cj to C 6 alkyl, C : to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, C ⁇ to C 7 acyl, C x to C 7 substituted acyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 7 to C 12 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy,
  • J is phenylene or substituted phenylene
  • K is phenylene or substituted phenylene
  • m and n are independently selected from O and I;
  • X is of the formula (IV) or (V) :
  • X is absent or of the formula:
  • R 4 and R 5 are together or independently a hydrogen atom, Ci to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C ⁇ to C 6 substituted alkyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, ⁇ to C 7 acyl, C ⁇ C 7 substituted acyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C to C 12 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy, phenyl, substituted phenyl, naphthyl,
  • X 3 is of the formula (Via) or (VIb) :
  • m and n are independently selected from O, 1, 2, 3 and 4 and, preferably, are 1; and wherein in formula (VIb) m is O, 1, 2, 3 or 4 and, preferably, is O; or
  • X 3 is of the formula:
  • R 6 is a hydrogen atom, amino, amino-protecting group, -NRR 8 , carboxy, carboxy-protecting group, C(0)NR 7 R 8 wherein R 7 and R 8 are independently selected from a hydrogen atom, C : to C 6 alkyl, C 2 to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 2 to C 7 acyl, C : to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C ⁇ to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C : to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C : to C 6 alkylaminothiocarbon
  • R 7 and R 8 are independently selected from a hydrogen atom, Ci to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 acyl, Ci to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminothiocarbonyl, C x to C 6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbon
  • R 9 is a hydrogen atom, -OH, hydroxy-protecting group, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C x to C 7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; and
  • R 7 and R 8 are independently selected from a functionalized resin, a hydrogen atom, C x to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminocarbonyl, C phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylamino
  • R 9 and R x0 are independently selected from a hydrogen atom, C x to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C x2 phenylalkyl, C 7 to C X2 substituted phenylalkyl, C 7 to C X2 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminothiocarbonyl, C x
  • T is N, U is O and V is N;
  • X x is -C0 2 R x , -OR x , -NR X R 2 or -C (0) NR x R 2 ; or -NR X R 2 together is of the formula:
  • X 2 is C x to C x2 alkylene, C x to C x2 substituted alkylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 7 to C x2 phenylalkylene, or C 7 to C X2 substituted phenylalkylene; or
  • X 2 is of the formula:
  • n 1 to 4;
  • X 2 is of the formula (II)
  • X 2 is of the formula (III) :
  • n and n are integers independently selected from 0 and 1;
  • X 3 is absent or of the formula:
  • R 4 and R 5 are together or independently a hydrogen atom, C x to C 6 alkyl, C 7 to C x2 substituted phenylalkyl, substituted phenyl, hydroxymethyl, protected hydroxymethyl, C 3 to C 7 cycloalkyl or C 3 to C 7 substituted cycloalkyl; or
  • X 3 is of the formula (VIb) :
  • X 3 is of the formula
  • X 4 is of the formula (VII) , (X) , (XI) , (XII) or (XIII) :
  • R 9 is a hydrogen atom or -OH, and R 7 , R 8 , q, r, s and t are as described above .
  • the compounds and libraries are of Formula (I) wherein:
  • X x is -C0 2 R x , -OR x , -NR X R 2 or -C(0)NR x R 2 ; or -NR X R 2 together is of the formula:
  • X x is OH or C0NH 2 ;
  • X 2 is methylene, 1, 1-cyclopropyl, 1, 3 -phenylene, 1, 4 -phenylene, 1-methyl-l- (4-oxyphenylene) ethane; 3 -methoxy-1, 4 -phenylene, 2-fluoro-1, 4 -phenylene, 4 , 4 ' -biphenylene, 1, 2 -phenylene,
  • X 3 is 1-aminomethylene, 1- (1-aminoethyl) , 1- (2-aminoethyl) , 1- (l-amino-2- (3-pyridyl) ethyl) , 1- (l-amino-2- (2-thienyl) ethyl) , 1- (1-aminopropyl) , 1- (3-aminopropyl) , 1- (5-aminopentyl) ,
  • X 4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, eyelobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4- ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4 -fluorophenylacetyl , tetrahydro-3 -furoyl , trans-3 - (3 -pyridyl ) acrylyl , trimethylacetyl , triphenylace
  • the present invention also provides a method of preparing libraries wherein compounds of Formula (I) , in particular, oxadiazoles, are made by reacting a resin- bound amine with a nitrile-containing carboxylic acid, nitrile-containing isocyanate or nitrile-containing radical with a leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an oxadiazole amine; and reacting the oxadiazole amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library.
  • compounds of Formula (I) in particular, oxadiazoles
  • Another method of preparing oxadiazole libraries comprises reacting a resin-bound amine with a nitrile-containing carboxylic acid, isocyanate or leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary amine or secondary amine to obtain a oxadiazole secondary amine or oxadiazole tertiary amine; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library.
  • the resin-bound amine can be prepared by displacing a resin-b ⁇ und leaving group with a primary amine.
  • the resin-bound amine can be prepared by reducing a resin-bound imine formed from either a resin-bound aldehyde with a primary amine or a resin-bound primary amine with an aldehyde.
  • Yet another method comprises reacting a resin- bound leaving group with a nitrile-containing phenoxide ion or amine to obtain a resin-bound nitrile; cyclizing the nitrile to obtain to an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an amine; and reacting the amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library.
  • Still another method comprises reacting a resin-bound leaving group with a nitrile-containing phenoxide ion to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary or secondary amine to obtain a secondary or a tertiary amine of the oxadiazole library; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library.
  • the present invention also provides a method of preparing oxadiazole libraries wherein oxadiazole compounds of Formula (I) are made by reducing an imine formed between a resin-bound aldehyde and an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin; deprotecting the protected carboxylic acid to give a resin bound carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library.
  • Another method of preparing oxadiazole libraries comprises reacting a resin-bound alcohol with an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin through a carbamate linkage; deprotecting the protected carboxylic acid to give a carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library.
  • the methods described above further comprise the step of cleaving the library from the resin.
  • the chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
  • C x to C 6 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl and the like.
  • the preferred "C x to C 6 alkyl” groups are methyl, iso-butyl, sec-butyl and iso- propyl.
  • C 2 to C 7 alkenyl denotes such radicals as vinyl, allyl, 2-butenyl, 3-butenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains .
  • C 2 to C 7 alkynyl denotes such radicals as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3- pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2 -heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tri-ynes of straight and branched chains.
  • C x to C 6 substituted alkyl denotes that the above C x to C 6 alkyl groups and C 2 to C 7 alkenyl and C 2 to C 7 alkynyl groups and C x to C X2 alkylene are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C 3 to C 7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C x to C 7 alkoxy
  • Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl , chloromethyl , hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl, propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexy1 , 2,4- dichloro (n-butyl) , 2-aminopropyl 1-chloroethyl, 2- chloroethyl, 1- bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl,
  • Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propen-l-yl, 3-chloro- buten-1-yl, 3-methoxy-propen-2-yl, 3 -phenyl-buten-2-yl, l-cyano-buten-3-yl and the like.
  • the geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.
  • Examples of the above substituted alkynyl groups include phenylacetylen-1-yl, 1-phenyl-2-propyn-1- yl and the like.
  • C 2 to C 7 alkenylene denotes an alkene group that is linked by two different substitutents .
  • C 2 to C 7 alkynylene denotes an alkyne group that is linked by two different substitutents.
  • C 2 to C 7 substituted alkenylene denotes an alkene group that is linked by two different substitutents and is further substituted by one or two halogen, hydroxy, protected hydroxy, oxo, protected oxo, C 3 to C 7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide
  • protected oxo denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
  • C x to C 7 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy.
  • C x to C 7 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to C x to C 6 substituted alkyl.
  • C x to C 7 phenylalkoxy as used herein means "C x to C 7 alkoxy" bonded to a phenyl raidcal .
  • C x to C 7 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • C x to C 7 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like.
  • Preferred acyl groups are acetyl and benzoyl.
  • C x to C 7 substituted acyl denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, C x to C 6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected N-
  • C x to C 7 substituted acyl groups examples include 4-phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3 -dimethylaminobenzoyl .
  • C 3 to C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • the substituent term “C 3 to C, substituted cycloalkyl” indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted)
  • C 3 to C 7 cycloalkylene means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups.
  • C 3 to C 7 substituted cycloalkylene means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.
  • C 5 to C 7 cycloalkenyl indicates a 1,2, or 3- cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring
  • substituted C 5 to C 7 cycloalkenyl denotes the above C 5 to C 7 cycloalkenyl rings substituted by a C x to C 6 alkyl radical, halogen, hydroxy, protected hydroxy, C x to C 7 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, phenyl, substituted phenyl, amino, or protected amino.
  • C 5 to C 7 cycloalkenylene is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted C 5 to C 7 cycloalkenylene means a cycloalkeneylene further substituted by halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstitute
  • heterocycle or “heterocyclic ring” denotes optionally substituted five-membered or six- membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings may be saturated, fully saturated or partially unsaturated, with fully saturated rings being preferred.
  • An "amino- substituted heterocyclic ring” means any one of the above-described heterocyclic rings is substituted with at least one amino group.
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
  • substituted heterocyce or "substituted heterocyclic ring” means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl , hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • heteroaryl means a heterocyclic aromatic derivative which is a five-membered or six- membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
  • substituted heteroaryl means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 substituted acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • C 7 to C x2 phenylalkyl denotes a C x to C 6 alkyl group substituted at any position by a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl. Examples of such a group include benzyl, 2-phenylethyl,
  • C 7 to C X2 phenylalkyl groups are the benzyl and the phenylethyl groups .
  • C 7 to C X2 substituted phenylalkyl denotes a C 7 to C x2 phenylalkyl group substituted on the C x to C 6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 substituted acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected
  • C 7 to C 12 substituted phenylalkyl examples include groups such as 2-phenyl-l- chloroethyl, 2- (4-methoxyphenyl) ethyl, 4- (2 , 6-dihydroxy phenyl)n-hexyl, 2- (5-cyano-3-methoxyphenyl) n-pentyl, 3- (2, 6-dimethylphenyl) n-propyl, 4-chloro-3-aminobenzyl, 6- (4-methoxyphenyl) -3-carboxy (n-hexyl) , 5- (4- aminomethylphenyl) - 3- (aminomethyl) n-pentyl , 5-phenyl-3- oxo-n-pent-1-yl and the like.
  • C 7 to C x2 phenylalkylene specifies a C 7 to C X2 phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -phenyl-alkyl- and - alkyl-phenyl-alkyl- where "-" represents a bond. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4.
  • C 7 to C X2 substituted phenylalkylene means a C 7 to C X2 phenylalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio,
  • substituted phenyl specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 substituted acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alky
  • substituted phenyl includes a mono- or di (halo) phenyl group such as 2, 3 or 4-chlorophenyl, 2, 6-dichlorophenyl, 2 , 5-dichlorophenyl, 3, 4-dichlorophenyl, 2, 3 or 4-bromophenyl, 3, 4-dibromophenyl, 3 -chloro-4-fluorophenyl, 2, 3 or
  • 2,4-dihydroxyphenyl the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2, 3 or 4-nitrophenyl; a cyanophenyl group, for example, 2, 3 or 4 -cyanophenyl; a mono- or di (alkyl) phenyl group such as 2, 3 or 4 -methylphenyl, 2 , 4-dimethylphenyl, 2, 3 or 4- (iso-propyl) phenyl, 2, 3 or 4.-ethylphenyl, 2, 3 or 4- (n-propyl) phenyl and the like; a mono or di (alkoxyl) phenyl group, for example,
  • substituted phenyl represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4- hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3 -hydroxy-4-nitrophenyl, 2-hydroxy 4-chlorophenyl and the like.
  • phenoxy denotes a phenyl bonded to an oxygen atom.
  • substituted phenoxy specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, N, N-di (C x to C 6 alkyl) carboxamide, trifluoromethyl, N- ( (C x to C 6 al
  • substituted phenoxy examples include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy, 2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy, -cyclopentylphenoxy, 2-fluorophenoxy, - (trifluoromethyl) phenoxy, 2-chlorophenoxy, -bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, -isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, -isopropylphenoxy, 3-tert-butylphenoxy, -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, -fluorophenoxy, 3-chlorophenoxy, 3-bromophenoxy, -iodophenoxy, 3-methoxyphenoxy, - (trifluoromethoxy) phenoxy, 4-methylphenoxy, -e
  • 2,4-dibromophenoxy 2-methoxy-4-methylphenoxy, 4-allyl-2- methylphenoxy, trans-2-ethoxy-5- (1-propenyl) phenoxy, 2-methoxy-4-propenylphenoxy, 3 , 4-dimethoxyphenoxy, 3-ethoxy-4-methoxyphenoxy, 4-allyl-2, 6-dimethoxyphenoxy, 3, 4-methylenedioxyphenoxy, 2,3, 6-trimethylphenoxy, 2, 4-dichloro-3-methylphenoxy, 2,3, 4-trifluorophenoxy, 2,3, 6-trifluorophenoxy, 2,3, 5-trifluorophenoxy, 2,3, 4-trichlorophenoxy, 2,3, 6-trichlorophenoxy, 2, 3 , 5-trimethylphenoxy, 3 , 4 , 5-trimethylphenoxy, 4-chloro- 3 , 5-dimethylphenoxy, 4-bromo-3 , 5-dimethylphenoxy, 2,4, 6-trimethylphenoxy, 2, 6-bis (hydroxymethyl) -4- methylphenoxy, 2, 6-d
  • C 7 to C x2 substituted phenylalkoxy denotes a C 7 to C X2 phenylalkoxy group wherein the C x to C 6 alkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected
  • substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
  • C 7 to C X2 substituted phenylalkoxy examples include groups such as 2- (4- hydroxyphenyl ) ethoxy, 4- (4 -methoxyphenyl) butoxy, (2R) -3- phenyl-2-amino-propoxy, (2S) -3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-1-hexanoxy, cinnamyloxy, (+/-) -2-phenyl-1-propoxy, 2 , 2-dimethyl-3 -phenyl-1-propoxy and the like.
  • phthalimide means a cyclic imide which is made from phthalic acid, also called 1, 2-benzenedicarboxylic acid.
  • substituted phthalimide specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, CI to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected
  • substituted phthalimides examples include
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • substituted naphthyl includes a mono or di (halo) naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2, 6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-bromonaphthyl, 3, 4-dibromonaphthyl, 3-chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-fluoronaphthyl and the like; a mono or di (hydroxy) naphthyl group such as l, 2, 3, 4, 5, 6, 7 or 8-hydroxynaphthyl, 2, 4-dihydroxynaphthyl, the protected- hydroxy derivatives thereof and the like; a nitronaphthyl group such as 3- or 4-nitronaphthyl; a nitronaphthyl
  • substituted naphthyl represents disubstituted naphthyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxynaphth-l-yl, 3-chloro-4- hydroxynaphth-2-yl, 2-methoxy-4 -bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-l-yl, 3-hydroxy-4-nitronaphth-2- yl, 2-hydroxy-4-chloronaphth-l-yl, 2-methoxy-7- bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl , 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-l- yl and the like.
  • naphthylene means a naphthyl radical bonded at two positions connecting together two separate additional groups.
  • substituted napthylene means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkyl,- C x to C 7 alkoxy, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phen
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluoro.
  • (monosubstituted) amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 acyl, C x to C 7 substituted acyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl and heterocyclic ring.
  • the (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted) amino.
  • (disubstituted) amino refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 acyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C 7 to C 12 phenylalkyl, and C 7 to C 12 substituted phenylalkyl.
  • the two substituents can be the same or different.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule.
  • protected (monosubstituted) amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
  • protected carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • protected N- (C x to C 6 alkyl) carboxamide means there is an amino- protecting group on the carboxamide nitrogen.
  • amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups, such as t-butoxycarbonyl ("Boc”), 2- (4-biphenylyl) propyl-2-oxycarbonyl ("Bpoc”), 2-phenylpropyl-2-oxycarbonyl (“Poc”) , 2- (4-xenyl) isopropoxycarbonyl, 1, 1-diphenylethyl-l- oxycarbonyl, 1, 1-diphenylpropyl-l-oxycarbonyl, 2- (3,5- dimethoxyphenyl) propyl-2-oxycarbonyl (“Ddz”), 2- (p- toluyl) propyl-2-oxycarbonyl , cyclopentanyloxycarbonyl ,
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the compounds.
  • Preferred amino-protecting groups are Boc, Cbz and Fmoc .
  • Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 7, M.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3 , 4 -dimethoxybenzyl, 2 , 4-dimethoxybenzyl, 2,4, 6-trimethoxybenzyl, 2,4, 6-trimethylbenzyl, pentamethylbenzyl, 3 , 4-methylenedioxybenzyl, benzhydryl, 4,4' -dimethoxytrityl, 4,4' ,4" -trimethoxytrityl, 2-phenylpropyl, trimethylsilyl , t-butyldimethylsilyl, phenacyl, 2 , 2 , 2-trichloroethyl, - (trimethylsilyl) ethyl,
  • carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry,” J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene and P.G.M. Wuts, "Protective Groups in
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl,
  • hydroxy-protecting groups are not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by C.B. Reese and E. Haslam, "Protective Groups in Organic Chemistry," J.G.W.
  • C x to C 4 alkylthio refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
  • C x to C 4 alkylsulfoxide indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.
  • C x to C 4 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like.
  • phenylthio, phenylsulfoxide, “ and “phenylsulfonyl” specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group.
  • substituted phenylthio means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • C x to C 6 alkylaminocarbonyl means a C x to C 6 alkyl attached to a nitrogen of the aminocarbonyl group.
  • Examples of C x to C 6 alkylaminocarbonyl include methylaminocarbonyl (from methylisocyanate) , ethylaminocarbonyl (from ethylisocyanate) , propylaminocarbonyl (from propylisocyanate) , butylaminocarbonyl (from butylisocyatate) .
  • C x to C 6 substituted alkylaminocarbonyl denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to C x to C 6 substituted alkyl.
  • C x to C 6 substituted alkylaminocarbonyl examples include, for example, methoxymethylammocarbonyl (from methoxymethylisocyanate) , 2-chloroethylaminocarbonyl (from 2-chloroethylisocyanate) , 2-oxopropylaminocarbonyl (from 2-oxopropylisocyanate) , and 4-phenylbutylaminocarbonyl (from phenylbutylisocyanate) .
  • C x to C 7 alkoxycarbonyl means a
  • C x to C 7 alkoxy group attached to a carobonyl group.
  • C x to C 7 substituted alkoxycarbonyl denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to C x to C 6 substituted alkyl.
  • phenylaminocarbonyl means a phenyl attached to a nitrogen of the aminocarbonyl group.
  • substituted phenylaminocarbonyl denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminocarbonyl include
  • C x to C 6 alkylaminothiocarbonyl means a C x to C 6 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above.
  • C x to C 6 alkylaminothiocarbonyl examples include methylaminothiocarbonyl (from ethylisothiocyanate) , ethylaminothiocarbonyl (from ethylisothiocyanate) , propylaminothiocarbonyl (from propylisothiocyanate) , butylaminothiocarbonyl (from butylisothiocyatate) .
  • C x to C 6 substituted alkylaminothiocarbonyl denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to C x to C 6 substituted alkyl.
  • C x to C 6 substituted alkylaminothiocarbonyl examples include, for example, methoxymethylaminothiocarbonyl (from methoxymethylisothiocyanate) , 2-chloroethylaminothiocarbonyl (from 2-chloroethylisothiocyanate) , 2-oxopropylaminothiocarbonyl (from 2-oxopropylisothiocyanate) , and 4-phenylbutylaminothiocarbonyl (from phenylbutylisothiocyanate) .
  • phenylaminothiocarbonyl means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
  • substituted phenylaminothiocarbonyl denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl .
  • substituted phenylaminothiocarbonyls include
  • C x to C 12 alkylene means a C x to C X2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups.
  • Examples of “C x to C X2 alkylene” include methylene, 1,2-ethyl, 1,1-ethyl, 1,3 -propyl.
  • phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.
  • phenylene includes 1, 2-phenylene, 1, 3 -phenylene, and 1, 4-phenylene .
  • substituted C x to C x2 alkylene means a C x to C X2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • substituted C x to C 12 alkylene includes aminomethylene, 1- (amino) -1, 2-ethyl, 2- (amino) - 1,2-ethyl, 1- (acetamido) -1, 2-ethyl, 2- (acetamido) -1, 2- ethyl, 2-hydroxy-1, 1-ethyl, 1- (amino) -1, 3 -propyl .
  • substituted phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to “substituted phenyl.”
  • substituted phenylene include thoses derived from the building blocks, namely, 3 -methyoxy-1, 4-phenylene from 4-hydroxy-3-methoxybenzonitrile, 2-fluoro-1, 4-phenylene from 2-fluoro-4-hydroxybenzonitrile, 3 , 5-Dibromo-l, 4- phenylene from 3 , 5-dibromo-4-hydroxybenzonitrile, 3 , 5-diiodo-l, 4-phenylene from 3 , 5-diiodo-4- hydroxybenzonitrile, 3 , 4-Dihydroxy-l, 2-phenylene from 3,4-dihydroxybenzonitrile, 2,3,5, 6-tetrafluoro-1, 4-phen
  • substituted cyclic C 2 to C 7 alkylene defines such a cyclic group bonded (“fused") to the phenyl radical resulting in a bicyclic ring system.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C 2 to C 7 heteroalkylene.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, C x to C 4 acyloxy, formyl, C x to C 7 acyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, hydroxymethyl or a protected hydroxymethyl.
  • the cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members.
  • saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring.
  • unsaturated examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl .
  • fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring.
  • fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring.
  • fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.
  • cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
  • Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.
  • Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.
  • carbamoyl means an -NCO- group where the radical is bonded at two positions connecting two separate additional groups.
  • salt encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, sulf ric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • organic or inorganic cation refers to counter-ions for the carboxylate anion of a carboxylate salt.
  • the counter-ions are chosen from -the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium) ; ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such .as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.
  • the compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
  • the solvates and hydrates of such compounds are included within the scope of this invention.
  • One or more compounds of the invention can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form.
  • ester forms induce increased blood levels and prolong the efficacy of the corresponding non- esterified forms of the compounds.
  • Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the - (C x to C 7 ) alkoxyethyl groups, for example methoxyethyl , ethoxyethyl , propoxyethyl , isopropoxyethyl and the like; the 2-oxo-l, 3-diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l, 3-dioxolen-4- ylmethyl, 5-phenyl-2-oxo-l, 3-dioxolen-4-ylmethyl and the like; the C x to C 4 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl
  • amino acid includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • amino acid also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids.
  • non-naturally-occurring amino acids include, for example, norleucine ("Nle”), norvaline (“Nva”), L- or D- naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the peptide art, such as those described in M.
  • the term "functionalized resin” means any resin, crosslinked or otherwise, where functional groups have been introduced into the resin, as is common in the art. Such resins include, for example, those functionalized with amino, alkylhalo, formyl or hydroxy groups. Such resins which can serve as solid supports are well known in the art and include, for example,
  • a "combinatorial library” is an intentionally created collection of differing molecules which can be prepared by the means provided below or otherwise and screened for biological activity in a variety of formats (e.g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips or other solid supports) .
  • a "combinatorial library, " as defined above, involves successive rounds of chemical syntheses based on a common starting structure.
  • the combinatorial libraries can be screened in any variety of assays, such as those detailed below as well as others useful for assessing their biological activity.
  • the combinatorial libraries will generally have at least one active compound and are generally prepared such that the compounds are in equimolar quantities.
  • a combinatorial library of the invention can contain two or more of the above-described compounds.
  • the invention further provides a combinatorial library containing five or more of the above-described compounds.
  • a combinatorial library can contain ten or more of the above-described compounds.
  • a combinatorial library can contain fifty or more of the above-described compounds.
  • a combinatorial library of the invention can contain 100,000 or more, or even 1,000,000 or more, of the above-described compounds.
  • the preparation of the combinatorial libraries can use the "split resin approach.”
  • the split resin approach is described by, for example, U.S. Patent 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop et al . , J. Med. Chem. , 37:1233-1251
  • amino acids are indicated herein by either their full name or by the commonly known three letter code. Further, in the naming of amino acids, "D-" designates an amino acid having the "D" configuration, as opposed to the naturally occurring L-amino acids. Where no specific configuration is indicated, one skilled in the art would understand the amino acid to be an L-amino acid.
  • the amino acids can, however, also be in racemic mixtures of the D- and L-configuration or the D-amino acid can readily be substituted for that in the L-configuration.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid.
  • Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories .
  • a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
  • Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
  • compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
  • Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active Oxadiazole.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day.
  • the specific dosages employed can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • the compounds of Formula (I) and combinatorial libraries containing the same can be prepared as set forth in the Reaction Schemes provided in the Reaction Schemes 2 through 5 and described below.
  • cyano carboxylic acids were coupled to resin-bound primary or secondary amines which become incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • resin-bound primary or secondary amines which become incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • These could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, or to any other resin-bound primary or secondary amine prepared by methods known to those skilled in the art.
  • Cyanophenols were coupled to solid support via an ether linkage as shown in Scheme 2 : Attachment of cyanophenols to solid support which releases the free phenol after cleavage, by. alkylation of a benzyl halide resin such as Merrifield resin or alkoxybenzyl bromide resin (Wang bromide resin) .
  • the cyanophenols were coupled to an alkyl halide moiety which remains covalently attached to the oxadiazole product after cleavage from the resin.
  • a primary or secondary amine bound to the resin through a cleavable linker is acylated with chloroacetic anhydride or 3- or 4 -chloromethyl benzoic acid.
  • a cyanophenol was then introduced by nucleophilic displacement of the alkyl halide. In this way, a wide range of cyanophenyl compounds was made, and converted to oxadiazole compounds by the methods described below.
  • nitrile containing compounds can be similarly linked to common resins as shown in Scheme 3: Linking nitriles to solid support. For example, 3- cyanophenyl isocyanate and 4 -cyanophenyl isocyanate were linked to the resin by forming a urea linkage and the nitrile function elaborated into an oxadiazole. Additionally, cyanohydrins may be formed on the resin by the action of Trimethylsilyl cyanide on resin-bound aldehydes and ketones . Alkyl nitriles may be formed by displacement of leaving groups with cyanide anion.
  • N-Boc 2-cyanoethyl glycine was also found to be a useful precursor to a large number of oxadiazole derivatives.
  • the cyanoethyl group was first converted to the oxadiazole followed by conversion of the Boc-protected amine to a variety of derivatives.
  • amidoximes were treated with chloroacetic anhydride to give the 5- chloromethyl oxadiazoles.
  • This primary chloride could be displaced with diverse primary or secondary amines to give substituted 2% or 3% amines. These could be derivatized further to introduce an additional variable substituent.
  • This strategy was particularly useful for the preparation of compounds attached to the resin by TFA labile bonds which preclude the use of N-Boc-protected amino acids (vide infra) . This was also the method of choice with cyanoethyl glycine derivatives.
  • amidoximes were converted to oxadiazoles by reaction with BOC amino acid anhydrides or FMOC amino acid anhydrides to give the substituted oxadiazole derivatives.
  • Natural L-amino acid derivatives e.g. Gly, Phe, Leu
  • D- or L-amino acids e.g. D- or L-amino acids
  • cyclic amino acids e.g. Pro, Nipecotic acid, Isonipecotic acid, tetrahydroisoquinoline carboxylic acid
  • unnatural amino acids or other aliphatic carboxylic acids and anhydrides. In all cases, the carboxylic acid moiety becomes incorporated into the oxadiazole ring.
  • N-BOC or N-FMOC protecting group could be removed under standard conditions and the resulting amine derivatized with an additional diverse set of reagents (Scheme 5: Derivatization of Oxadiazoles) .
  • Scheme 5 Derivatization of Oxadiazoles
  • amide, sulfonamide, urea and thiourea derivatives were obtained by reaction with acid anhydride, sulfonyl chloride, isocyanates and isothiocyanates respectively.
  • the amidoximes can be reacted with activated carboxylic acid derivatives other than anhydrides.
  • acylating reagent known in the art could be used in the synthesis of oxadiazoles, including but not limited to acid chlorides, and fluorides, mixed anhydrides, active esters such as pentafluorophenyl, 4-nitrophenyl, hydroxybenzotriazole, N-hydroxysuccinimide and the like.
  • the libraries are described as having three variable positions, or three diversity sites.
  • the first diversity site is defined by the nitrile containing moiety, or its precursor, attached to the resin. This includes, but is not limited to, cyanocarboxylic acids, cyanobenzyl halides and cyanophenols, and the coupling of these through appropriate chemistry to diverse compounds on solid support. Additionally, these methods are meant to include as starting materials other products synthesized on solid phase whereby an aliphatic, aromatic or heteroaromatic nitrile compound is obtained.
  • the second diversity site is introduced in the oxadiazole formation and is defined by the appropriately functionalized carboxylic acid anhydride used in the cyclization step.
  • the third diversity site is created by the derivatization of a reactive site introduced by the carboxylic acid moiety in the previous step. More specifically, the use of protected amino acid derivatives is particularly useful in the present invention.
  • the amino acid side chain provides the second diversity site as defined above. Derivatization of the amino group with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates, alkyl halides or aldehydes provides the third diversity site. Other reactive functional groups incorporated in protected or unprotected form can also serve to introduce the third diversity element.
  • bifunctional carboxylic acid derivatives are used to form the oxadiazole ring and an attachment point for a third diversity site.
  • This attachment point can be a nucleophilic site (e.g. alcohol, thiol, carbon nucleophile, etc.) or an electrophilic site (halide, tosylate, triflate, activated carboxylate, etc) .
  • cyclic anhydrides such as succinic anhydride, diglycolic anhydride, 1, 2-cyclopropane dicarboxylic anhydride are preferred embodiments.
  • the oxadiazole cyclization produces a pendant carboxylic acid which can be further activated with standard coupling reagents and coupled to diverse amines .
  • Another preferred embodiment of the invention is the use of chloroacetic anhydride or other halocarboxylic acid anhydrides in the oxadiazole cyclization creating a chloromethyl group which is readily displaced with diverse nucleophiles such as amines, thiols, alcohols, phenols or carbon nucleophiles.
  • nucleophiles such as amines, thiols, alcohols, phenols or carbon nucleophiles.
  • primary amines or secondary diamines are used which are derivatized further with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates or alkyl halides.
  • a carboxylic acid moiety could be attached to the solid support in a variety of different ways, for example, an amino acid ester is attached to a resin by reductive amination, or by reaction with a chloroformate resin derivative, followed by hydrolysis of the ester.
  • a resin bound amine can be reacted with a cyclic anhydride such as succinic anhydride.
  • a cyclic anhydride such as succinic anhydride.
  • Other methods of providing a free carboxylic acid on solid support are known in the art.
  • the carboxylic acid is then converted to an activated derivative such as the mixed anhydride with isobutyl chloroformate, or an active ester with pentafluorophenol, 4-nitrophenol, N- hydroxysuccinimide, HOBT or other activated derivatives such as those used routinely in the formation of amide or ester bonds.
  • This activated resin bound carboxylate is then treated immediately with a solution of amidoxime, prepared by the reaction of a nitrile compound with hydroxylamine under standard conditions.
  • the nonsupport-bound combinatorial libraries can be screened as mixtures in solution in assays such as radio-receptor inhibition assays, anti-bacterial assays, anti-fungal assays, calmodulin-dependent phosphodiesterase (CaMPDE) assays and phosphodiesterase (PDE) assays, as described in detail below.
  • Deconvolution of highly active mixtures can then be carried out by iterative or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the combinatorial libraries of the present invention using any one of the below- described assays or others well known in the art.
  • the compounds of the present invention can be used for a variety of purposes and indications and as medicaments for any such purposes and indications.
  • compounds of the present invention including oxadiazole derivatives, can be used as pesticides, acaricides, receptor agonisits and antiviral agents.
  • the subject compounds can be useful as analgesics.
  • Assays which can be used to test the biological activity of the instant compounds include antimicrobial assays, a competitive enzyme-linked immunoabsorbent assay and radio-receptor assays, as described below.
  • the ability of the compounds to inhibit bacterial growth, and therefore be useful to that infection, can be determined by methods well known in the art.
  • Compounds of the present invention were shown to have antimicrobial activity by the in vi tro antimicrobial activity assay described in Example 36 below and, therefore, are useful as antimicrobial agents.
  • the concentration of cells is established by plating 100 ⁇ l of the culture solution using serial dilutions (e.g., 10 "2 , 10 "3 and 10 "4 ) onto solid agar plates.
  • serial dilutions e.g., 10 "2 , 10 "3 and 10 "4
  • compounds, individual or in mixtures are added to the bacterial suspension at concentrations derived from serial two-fold dilutions ranging from 1500 to 2.9 ⁇ g/ml .
  • the plates are incubated overnight at 37°C and the growth determined at each concentration by OD 620 nm.
  • the IC 50 (the concentration necessary to inhibit 50% of the growth of the bacteria) can then be calculated.
  • the MAb is added at a fixed dilution in which the bicyclic guanidine in solution effectively competes for MAb binding with the antigenic peptide adsorbed to the plate.
  • the remaining steps are the same as for direct ELISA.
  • the concentration of compound necessary to inhibit 50% of the MAb binding to the control peptide on the plate (IC 50 ) is determined by serial dilutions of the compound.
  • radio- receptor assays can be selective for any one of the ⁇ , K, or ⁇ opiate receptors.
  • Compounds of the present invention can be useful in vitro for the diagnosis of relevant opioid receptor subtypes, such as K, in the brain and other tissue samples. Similarly, the compounds can be used in vivo diagnostically to localize opioid receptor subtypes.
  • radio-receptor assays are also an indication of the compounds' analgesic properties as described, for example, in Dooley et al . , Proc . Natl .
  • these compounds can be used for therapeutic purposes to block the peripheral effects of a centrally acting pain killer.
  • morphine is a centrally acting pain killer.
  • Morphine has a number of deleterious effects in the periphery which are not required for the desired analgesic effects, such as constipation and pruritus (itching) .
  • the subject compounds can have value in blocking the periphery effects of morphine, such as constipation and pruritus.
  • the subject compounds can also be useful as drugs, namely as analgesics, or to treat pathologies associated with other compounds which interact with the opioid receptor system.
  • Ligands for the ⁇ receptor can be useful as antipsychotic agents, as described in Abou- Gharbia et al . , Annual Reports in Medicinal Chemistry,
  • Radio-receptor assays can be performed with particulate membranes prepared using a modification of the method described in Pasternak et al . , Mol . Pharmacol .
  • Rat brains frozen in liquid nitrogen can be obtained from Rockland (Gilbertsville, PA) . The brains are thawed, the cerebella removed and the remaining tissue weighed. Each brain is individually homogenized in 40 ml Tris-HCl buffer (50 mM, pH 7.4, 4°C) and centrifuged (Sorvall ® RC5C SA-600: Du Pont, Wilmington, DE) (16,000 rpm) for 10 minutes. The pellets are resuspended in fresh Tris-HCl buffer and incubated at 37°C for 40 minutes.
  • reaction is terminated by filtration through GF-B filters on a Tomtec harvester (Orange, CT) .
  • the filters are subsequently washed with 6 ml of Tris-HCl buffer, 4°C.
  • Bound radioactivity is counted on a Pharmacia Biotech Betaplate Liquid Scintillation Counter (Piscataway, NJ) and expressed in cpm.
  • standard curves in which 3 H-DAMG0 is incubated in the presence of a range of concentrations of unlabeled DAMGO (0.13-3900 nM) are generally included in each plate of each assay (a 96-well format) .
  • IC 50 values (the concentration necessary to inhibit 50% of 3 H-DAMGO binding) are then calculated. IC 50 values of less than 1000 nM are indicative of highly active opioid compounds which bind to the ⁇ receptor, with particularly active compounds having IC 50 values of 100 nM or less and the most active compounds with values of less than 10 nM.
  • assays selective for K receptors can be carried out using [ 3 H]-U69,593 (3 nM, specific activity 62 Ci/mmol) as radioligand.
  • Assays selective for ⁇ opiate receptors can be carried out using tritiated DSLET ( [D- Ser 2 , D-Leu 5 ] -threonine-enkephalin) as radioligand.
  • Assays selective for the ⁇ opiate receptor can use radiolabeled pentazocine as ligand.
  • Screening of combinatorial libraries and compounds of the invention can be done with an anti-fungal assay.
  • Compounds of the present invention can be useful for treating fungal infections.
  • Screening of combinatorial libraries and compounds of the invention also can be done with a calmodulin-dependent phosphodiesterase (CaMPDE) assay.
  • CaMPDE calmodulin-dependent phosphodiesterase
  • Compounds of the present invention can be useful as calmodulin antagonists.
  • Calmodulin which is the major intracellular calcium receptor, is involved in many processes that are crucial to cellular viability.
  • Calmodulin is implicated in calcium- stimulated cell proliferation.
  • Calmodulin antagonists are, therefore, useful for treating conditions associated with increased cell proliferation, for example, cancer.
  • calmodulin antagonists such as compounds of the subject invention are useful both in vitro and in vivo for identifying the role of calmodulin in other biological processes.
  • the disadvantages of known antagonists such as trifluoperazine and N- (4-aminobutyl) - 5-chloro-2-naphthalenesulfonamide (W13) include their non-specificity and toxicity.
  • advantages of the combinatorial libraries and compounds of the subject invention as calmodulin antagonists include their reduced flexibility and ability to generate broader conformational space of interactive residues as compared to their linear counterparts.
  • An example of an assay that identifies CaM antagonists is a CaMPDE assay. In brief, samples are mixed with 50 ⁇ l of assay buffer (360 mM Tris, 360 mM Imidazole, 45 mM Mg(CH 3 COO) 2 , pH 7.5) and 10 ⁇ l of CaCl 2 (4.5 mM) to a final volume of 251 ⁇ l .
  • calmodulin stock solution (Boehringer Mannheim; 0.01 ⁇ g/ ⁇ l) is then added and the samples then sit at room temperature for 10 minutes. 14 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of P
  • 5 ' -nucleotidase (Sigma; 100 Units dissolved in 10 ml of 10 mM Tris-HCl containing 0.5 mM Mg(CH 3 COO) 2 , pH 7.0; stock concentration: 10 Units/ml) .
  • the samples are then incubated for 10 minutes at 30°C.
  • 50 ⁇ l of adenosine 3 ',5 '-cyclic monophosphate (cAMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1 hour at 30°C and then vortexed.
  • cAMP adenosine 3 ',5 '-cyclic monophosphate
  • trichloroacetic acid 55% in water
  • 80 ⁇ l of the resulting supernatants of each sample is transferred to a 96 -well plate, with 2 wells each containing 80 ⁇ l of each sample.
  • 80 ⁇ l of ammonium molybdate (1.1% in 1. IN H 2 S0 4 ) is then added to all the wells, and the OD of each were determined at 730nm, with the values later subtracted to the final OD reading.
  • 16 ⁇ l of reducing agent (6g sodium bisulfite, 0.6g sodium sulfite and 125mg of l-amino-2-naphtol-4-sulfonic acid in 50ml of water) is then added to one of each sample duplicate and 16 ⁇ l of water is added to the other duplicate. After sitting for 1 hour at room temperature, the OD of each well is determined at 730nm. The percent inhibition of calmodulin activity is then calculated for each sample, using as 0% inhibition a control sample containing all reagents without any test samples and as 100% inhibition a control sample containing test samples and all reagents except calmodulin.
  • the percent inhibition of phosphodiesterase activity was determined by following a similar protocol as the CaMPDE assay described above, except not adding calmodulin to the sample mixture and calculating the percent inhibition by using as 0% inhibition a control reagent without any test samples and as 100% inhibition a control sample containing test samples and all reagents except cAMP.
  • TBU 2- (1H- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2,3, 6-trimethyl-4-methoxybenzenesulfonyl
  • MBH 4,4 ' -dimethoxybenzyhydryl
  • ADA adamanyl
  • PMEOBZL p-methoxybenzyl
  • 2-CL-Z 2 -chlorobenzyl-oxycarbonyl
  • 2-BR-Z 2 -bromobenzyloxycarbonyl
  • TMOB 2- (1H- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2,3, 6-trimethyl-4-methoxybenzenesulfonyl
  • MBH 4,4 '
  • a teabag containing 100 g of resin bound piperazine from Examples 5 (120 mmol) was swollen in DCM and a solution of chloroacetic anhydride (41 g, 240 mmol) in 500 ml DCM was added, followed by DIEA (42 ml, 240 mmol) .
  • the solution was shaken at RT overnight, and washed with DCM, DMF, IPA and MeOH and dried to yield 4- chloroacetyl piperazine bound resin.
  • Other primary and secondary amines of Example 4 and 5 are also used.
  • halo carboxylic acids shown below can be substituted for chloroacetic anhydride and used in a similar manner, such as, preparing the anhydride of the carboxylic acid with dusopropyl carbodiimide in DCM for 30 minutes before addition of the amine resin.
  • a teabag containing 300 g of resin bound amine from Examples 4 and 5 (360 mmol) was swollen in DMF (1.51) and 4-cyanobenzyl bromide (200g, 1.02 mmol) was added, followed by DIEA (177 ml, 1.02 mol).
  • the solution was shaken at RT overnight and then washed with DCM, IPA and MeOH.
  • the resin was dried under high vacuum to provide N- (4-cyano) benzyiamine bound resin.
  • MBHA-HC1 resin (5.0g, 4.05 mmol) was neutralized with 10% DIEA in DMF, then washed with DCM.
  • Resin bound nitrile compounds prepared in examples 6,7,8,9,10, and 11 above were placed in teabags. Hydroxylamine-HCl (4-10 eq. based on loading of resin) and DIEA (4-10 eq) were placed in sufficient 2- methoxyethanol to give a 0.2 M solution. The resin was added and the solution heated to 80-85-C overnight. The solution was cooled to RT and the resin washed 4X with MeOH and dried to yield in each case the desired amidoxime bound to resin.
  • Each of the nitrile resins from Example 3 was distributed to 36 bags with 400 mg of resin each according to Table 1: Distribution of Nitrile Resins and a number of control bags were made. To each of 36 tubes was added 55 ml of anhydrous 2 -methoxyethanol, 0.83 g (12mmol) of Hydroxylamine Hydrochloride and 2.08 ml (12 mmol) DIEA. Once all the solids were dissolved the bags containing nitrile resins A-E were added (see table below) and the reaction tubes were heated to 85-C overnight . The tubes were cooled and the bags washed with MeOH (4X) and dried to yield the corresponding amidoxime .
  • Resin B 1-Cyano-1-cyclopropane carboxylic acid: 18.1 g, 162.5 mmol
  • a resin bound amidoxime of Example 12 was swollen in 2-methoxyethyl ether.
  • a solution of the appropriate carboxylic acid anhydride (7 eq) in 2- methoxyethyl ether (0.2M) was added to the amidoxime.
  • the anhydride was not commercially available it was prepared from a solution of carboxylic acid (14 eq, 0.4M) in 2-methoxyethyl ether to which was added DIC (7 eq, 0.2M) and shaken for 30 minutes before addition of the resin bags.
  • the solution of anhydride and the resin bound amidoxime were heated to 60-C for 16 hours. The solution was cooled and the resin washed twice with fresh 2-methoxyethyl ether.
  • Boc-protected amino acid derivatives according to Table 2: Distribution of Amino Acids. Each amino acid (28 mmol) was dissolved in 55 ml of 2-methoxyethyl ether. To each tube was then added DIC (14 mmol) and the solution stirred at RT for 1 hr at which time a white precipitate had formed. The appropriate bags containing amidoxime from the previous step were then added and the reaction tubes were placed in a heating block at 60-C for 16 hr. The supernatant was removed and the resins washed twice with fresh 2- methoxyethyl ether. The bags were placed in 50 ml 2- methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- (N-Boc-amino) substituted oxadiazoles bound to resin.
  • the bags were placed in 10 ml 2-methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- ( (N-FMOC- amino) substituted oxadiazoles bound to resin.
  • the resins from Example 17 were placed in a solution of amine according to Table 3 : Primary and secondary amines (0.2 M, 10 eq) in anhydrous DMF and shaken at RT for 2 hrs . The bags were then washed with DMF 4X, DCM 2X and MeOH to give 5-substituted aminomethyl oxadiazoles bound to resin.
  • the Boc-protected Oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate.
  • the supernatant solvent was removed and the following solutions were added: a carboxylic acid solution, a solution of DMAP, HOBT and DIEA, a solution of DIC in DMF or DCM.
  • Other coupling agents such as BOP, PyBOP, HATU, HBTU and others known in the art were also used in separate experiments.
  • the quantities of each solution were adjusted according to the amount of resin per well in the plate, in order to have a five to tenfold excess of reagents.
  • the 96 well plates were capped and shaken overnight at RT. The resins were then washed with DMF (8X) , MeOH (4X) and the resin allowed to dry resulting in the N-acylated-5- (substituted aminomethyl) oxadiazoles bound to resin.
  • the Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate. The supernatant solvent was removed, and the resin washed with acetonitrile.
  • the Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate.
  • the resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base.
  • DCE 1, 2-dichloroethane
  • the following Isocyanates were dissolved to a concentration of 0.2 M in DCE/THF (2:1) and added to the plates. The solutions were shaken at RT overnight and then the plates were washed with DCE/THF (2:1), DMF, MeOH and dried to give N-substituted ureido oxadiazole resins.
  • Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate. The resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base.
  • DCE 2-dichloroethane
  • Boc 2-cyanoethyl glycine was loaded onto MBHA resin and converted to the Amidoxime as described in the general procedures of Example 13.
  • This amidoxime resin was treated with a BOC amino acid anhydride as described in Example 15.
  • the bis BOC protected oxadiazole derivative was then treated with 50 % TFA in DCM (2 X 15 min) and washed with DCM and MeOH.
  • the diamines were then treated with 0.2 M benzoic acid, DIC, HOBT and DIEA in DCM or with acetic anhydride in DCM at RT overnight.
  • the resin was washed with DMF 4X, DCM 2X and MeOH and dried to give the di-acylated oxadiazole resins.
  • the amidoxime is treated with an FMOC amino acid anhydride as in the procedure of Example 16 to give mono-acylated- (FMOC amino) oxadiazole resins.
  • Boc 2-cyanoethyl glycine is loaded onto MBHA resin and converted to the oxadiazole as described in Example 17. Individual tea bags containing portions of the resulting 5-chloromethyl oxadiazole derivative are then treated with diverse amines in DMF as in Example 18.
  • the 5-aminomethyl oxadiazole derivatives are then acylated to give the N-acylated-5- (substituted aminomethyl) oxadiazole resins, sulfonylated to give N- sulfonyl-5- (substituted aminomethyl) oxadiazole resins, alkylated to give N- alkylated-5- (substituted aminomethyl) oxadiazole resins, treated with isocyanates to give N-substituted ureidooxadiazole resins or isothiocyanates to give N- substituted thioureidooxadiazole resins as described in Example 19, Example 20, Example 21, and Example 22.
  • the products are then treated with 50% TFA in DCM to remove the remaining BOC group.
  • the amino group from the groups defined above are further converted to either an amide, sulfonamide, urea or thiourea derivative following the general procedures of Example 19, Example 20, Example 21, and Example 22 to give a diverse library of oxadiazole resins.
PCT/US1999/025331 1998-10-29 1999-10-28 Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof WO2000025768A1 (en)

Priority Applications (2)

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002375A1 (en) * 1999-07-01 2001-01-11 Chemrx Advanced Technologies, Inc. Process for synthesizing oxadiazoles
WO2001054508A1 (en) * 2000-01-28 2001-08-02 Akkadix Corporation Materials and methods for killing nematodes and nematode eggs
WO2001094318A2 (en) * 2000-06-05 2001-12-13 Ortho-Mcneil Pharmaceutical, Inc. Method for synthesis of substituted azole libraries
WO2001094346A1 (en) * 2000-06-08 2001-12-13 F. Hoffmann-La Roche Ag 1,3,8-TRIAZA-SPIRO'4,5!DECAN-4-ONE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS
WO2001094317A2 (en) * 2000-06-05 2001-12-13 Ortho-Mcneil Pharmaceutical, Inc. Method for synthesis of substituted azole libraries
WO2005044797A1 (en) * 2003-11-06 2005-05-19 Addex Pharmaceuticals Sa Allosteric modulators of metabotropic glutamate receptors
US6992096B2 (en) 2003-04-11 2006-01-31 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US7335658B2 (en) 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2008024390A2 (en) 2006-08-24 2008-02-28 Novartis Ag 2- (pyrazin-2-yl) -thiazole and 2- (1h-pyraz0l-3-yl) -thiazole derivatives as well as related compounds as stearoyl-coa desaturase (scd) inhibitors for the treatment of metabolic, cardiovascular and other disorders
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US7453002B2 (en) 2004-06-15 2008-11-18 Bristol-Myers Squibb Company Five-membered heterocycles useful as serine protease inhibitors
US7605171B2 (en) 2003-12-17 2009-10-20 Merck & Co., Inc. (3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists
JP2010509190A (ja) * 2006-07-27 2010-03-25 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺菌・殺カビ性アゾ環式アミド
US7696379B2 (en) 2005-04-25 2010-04-13 Novartis Ag Acetylene derivatives
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
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US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4929628A (en) * 1988-01-21 1990-05-29 Shell Internationale Research Maatschappij, B. V. Oxadiazole compounds, their preparation and their use as pesticides
US5242890A (en) * 1988-07-07 1993-09-07 Korea Research Institute Of Chemical Technology 1,2,4-oxadiazole derivative, useful as selective herbicide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366987A (en) * 1991-08-22 1994-11-22 Warner-Lambert Company Isoxazolyl-substituted alkyl amide ACAT inhibitors
CA2211381C (en) * 1995-01-27 2009-05-19 Novo Nordisk A/S Compounds with growth hormone releasing properties
AU722883B2 (en) * 1995-10-18 2000-08-10 Merck & Co., Inc. Cyclopentyl tachykinin receptor antagonists
SK56798A3 (en) * 1995-10-30 1998-12-02 Smithkline Beecham Corp Protease inhibitors, pharmaceutical composition containing them and their use
AU6320998A (en) * 1997-02-21 1998-09-09 Bristol-Myers Squibb Company Benzoic acid derivatives and related compounds as antiarrhythmic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4929628A (en) * 1988-01-21 1990-05-29 Shell Internationale Research Maatschappij, B. V. Oxadiazole compounds, their preparation and their use as pesticides
US5242890A (en) * 1988-07-07 1993-09-07 Korea Research Institute Of Chemical Technology 1,2,4-oxadiazole derivative, useful as selective herbicide

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GORDEN E. ET AL.: "Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Syntheses, Library Screening Strategies, and Future Directions", J. MED. CHEM., vol. 37, no. 10, 13 May 1994 (1994-05-13), pages 1385 - 1401, XP002927721 *
LIANG G.-B. ET AL.: "An Improved Oxadiazole Synthesis Using Peptide Coupling Reagent", TETRAHEDRON LETTERS, vol. 37, no. 37, 9 September 1996 (1996-09-09), pages 6627 - 6630, XP002927722 *
See also references of EP1126833A4 *

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EP1126833A2 (de) 2001-08-29
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WO2000025768A8 (en) 2000-08-24

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