EP1150565A1 - Derives de thiazole et leurs banques combinatoires - Google Patents

Derives de thiazole et leurs banques combinatoires

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Publication number
EP1150565A1
EP1150565A1 EP00913425A EP00913425A EP1150565A1 EP 1150565 A1 EP1150565 A1 EP 1150565A1 EP 00913425 A EP00913425 A EP 00913425A EP 00913425 A EP00913425 A EP 00913425A EP 1150565 A1 EP1150565 A1 EP 1150565A1
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EP
European Patent Office
Prior art keywords
carbamyl
substituted
ethyl
chloro
benzene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00913425A
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German (de)
English (en)
Inventor
Behrouz Forood
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Sygnis Pharma AG
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Lion Bioscience AG
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Publication date
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Publication of EP1150565A1 publication Critical patent/EP1150565A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates generally to the synthesis of compounds comprising heterocyclic rings.
  • the invention provides novel thiazoles 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.
  • the present invention overcomes the known limitations to classical organic synthesis of thiazoles, 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 as molecules bound to a resin.
  • the present invention can utilize a readily available pool of building blocks, either from commerical sources or available through chemistries known in the art, 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 functionalities. Therefore, building blocks, such as those described herein, 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 thiazole libraries and thiazole compounds.
  • the present invention relates to novel thiazole compounds of formula (I) :
  • 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 1 provides Reaction Scheme 1 showing the steps of attachment of the amino acid, thio-urea formation, thiazole ring formation and cleavage used in the formation of the 2-aminothiazole library.
  • Figure 2 provides Reaction Scheme 2 showing the synthetic steps for the formation of the branched 2- aminothiazole library.
  • the present invention provides novel compounds, and libraries of novel compounds of Formula (I) :
  • q is an integer selected from 0, 1 or 2 ;
  • R ⁇ is a hydrogen or a functionalized resin
  • R 2 is a hydrogen atom, C ⁇ to C 6 alkyl, Ci to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, phenyl, substituted phenyl, naphthyl , substituted naphthyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R l7 N and R 2 together is of the formula:
  • R 9 is a hydrogen or a functionalized resin
  • R 3 is Ci to C 8 alkylene, Ci to C 8 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 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, C 5 to C 7 cycloalkenylene, C 5 to C 7 substituted cycloalkenylene, C 4 to C 10 cycloalkylalkylene, C 4 to C 10 substituted cycloalkylalkylene, C to C 12 phenylalkylene or C 7 to C 12 substituted phenylalkylene; or
  • R 3 is of the formula:
  • R 10 and R are, independently, a hydrogen atom, C ⁇ to C 6 alkyl, Ci 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 x to C 7 acyl , C ⁇ 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, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C 2 to C 7 alkylene, substituted cyclic C 2 to C 7 alkylene
  • R 3 is of the formula (II) or (III) :
  • R 15 is a hydrogen atom, Cj to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C 7 acyl, Cj to C 7 substituted acyl, Ci to C 7 alkoxycarbonyl, C to C 7 substituted alkoxycarbonyl, C x to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R 16 is a hydrogen atom, C a to C 6 alkyl, C to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl,
  • R 3 is of the formula (IV) or (V)
  • n is an integer selected from 1 to 8; R 13 and R 1 ⁇ is the same as described herein above;
  • R 4 is a hydrogen atom, C x to C 6 alkyl, C ⁇ to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, Ci to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl, C : to C 7 acyl, C ⁇ to C 7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl, C ⁇ to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
  • R 3 , N and R 4 together form a heterocycle or substituted heterocycle
  • R 5 is a hydrogen atom, C x to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C 7 acyl, Ci to C 7 substituted acyl, Cj to C 7 alkoxycarbonyl, Ci to C, substituted alkoxycarbonyl, C ⁇ to C 7 alkylaminocarbonyl, C, to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl;
  • R 6 is a hydrogen atom, Ci to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, C x to C 7 acyl, Ci to C 7 substituted acyl, Ci to C 7 alkoxycarbonyl, Ci to C 7 substituted alkoxycarbonyl, C : to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl; or
  • R 5 and R 6 together are fused with the thiazole ring to form a second ring which is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or
  • R 5 and R 6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring, and the third ring which is directly fused to the second ring is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
  • R 7 is C x to C 8 alkylene, C : to C 8 substituted alkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, heteroarylene or substituted heteroarylene ;
  • R 8 is a hydrogen atom, C, to C 6 alkyl, C x to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl, C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
  • the thiazole compounds and libraries are of the Formula (I) :
  • q is 0 or 1 ;
  • R 3 is of the formula:
  • Rio and R X1 are together or independently a hydrogen atom, Cj to C 6 alkyl, Cj to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 3 to C, cycloalkyl, substituted C 3 to C 7 cycloalkyl, hydroxymethyl or protected hydroxymethyl; or
  • R 3 is of the formula (II) or (III) :
  • n is an integer selected from 1 or 2;
  • R 12 is hydrogen, halogen, hydroxy, protected hydroxy, Ci to C 7 alkyl, Ci to C 7 substituted alkyl, C x to C 7 alkoxy, C to C 7 substituted alkoxy; and
  • R 13 is a hydrogen atom, Ci to C 5 alkyl, Ci to C 6 substituted alkyl; and
  • R :4 is a hydrogen, ⁇ to C 6 alkyl, C : to C 6 substituted alkyl, Ci to C 7 acyl, Ci to C 7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl , Q x to C 7 alkylaminocarbonyl, Q ⁇ to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl; or
  • R 3 is of the formula (IV) or (V)
  • R 4 is a hydrogen atom, C : to C 6 alkyl or C to C 6 substituted alkyl;
  • R 7 is phenylene or substituted phenylene
  • R 8 is a hydrogen atom, C : to C 6 alkyl or C : to C 6 substituted alkyl; or
  • q is 1 or 2.
  • R 5 and R 6 are fused with the thiazole ring of Formula (I) to form either the two or three ring systems as disclosed above .
  • R 3 is as described above, provided that the carbon to the carbonyl of Formula (I) is chiral . In another preferred embodiment of this invention, R 3 is as described above, except that it does not include methylene. In another preferred embodiment of this invention, R 3 is as described above, except that it does not include C : to C 8 alkylene. In another preferred embodiment of this invention, R 3 is as described above, except that it does not include C x to C 8 alkylene or C x to C 8 substituted alkylene.
  • the compounds are as described above, provided that provided that they are not where q is 0, R l t R 2 , R 4 and R 6 are each a hydrogen atom, R 3 is methylene and R 5 is 4-fluoromethyl .
  • the thiazole compounds and libraries are of the Formula (I) :
  • Ri is a hydrogen atom or polystyryl 4-methylbenzhydryl
  • R is a hydrogen atom, 2- (1-pyrrolidino) ethyl,
  • R 3 is methylene, 1 , 2 -ethylene, 1 , 3-propylene, 1,4- butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1, 7-heptanylene, 1, 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-1, 1- ethylene, D-1 , 1-butylene, D-1 , 1-ethylene, D-1,1- pentylene, D-1 , 1-propylene, D-5-amino-l , 1-pentylene, D-l- amino-1, 5-pentylene, D-2- (2-napthyl) -1, 1-ethylene, D-2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1 , 1-ethylene, D-2- (4- hydroxyphenyl ) -1, 1-ethylene, D-2- (N-formyl-indo
  • R 3 is of the formula (II), (III) , (IV) or (V) :
  • R 12 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentane, methoxy, ethoxy, propoxy or iso-proproxy;
  • R 13 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl , 3-methylbenzyl , 4-methylbenzyl, 2-fluorobenzyl , 3-fluorobenzyl , 4 -fluorobenzyl, 3 - (1-imidazole) propyl ,
  • R i4 is a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl , 4-methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl , 4 -fluorobenzyl , 3 - (1-imidazole ) propyl , 4-aminomethylbenzyl , -methoxybenzyl , 3-chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl , piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl,
  • R 14 is acetyl, alpha-methylcinnamyl, benzoyl , crotonyl, cyclobutanecarbonyl , 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 , triphenylacetyl,
  • R i4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl ,
  • R ⁇ 4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2 - (carbamyl) glutarate diethyl ester, (s)
  • R 15 is hydrogen, methyl, t-butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4-methylphenyl , 4- fluorophenyl, 3-fluorophenyl , 4-cyanophenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- chlorophenyl , 3 , 4-difluorophenyl, 4-nitrophenyl, 3,4- dihydroxyphenyl, 3-nitrophenyl, 3 -methyl -4 -chlorophenyl, adamantyl , 2 , 5-dimethoxyphenyl, 3 -chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4-phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4-t
  • R 4 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl , benzyl, 2-methylbenzyl , 3-methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl , 3 -fluorobenzyl, 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl ,
  • R 4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
  • 3-thiopheneacetyl 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl , 3 , 5-dichloro-4-hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl, 2, 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl, succinamyl,
  • R 4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
  • R 4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( -) -1- (carbamyl) - (1-naphthyl) ethane, (s) - ( +) -1- (carbamyl) - (1 -naphthyl) ethane, (s) -(+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (
  • R 3 , R 4 and the attached nitrogen atom of Formula (I) together form pyrrolidine, 4- (R) -hydroxy-2- (S) - pyrrolidine, 4- (R) -hydroxy-2- (R) -pyrrolidine, 4-(S)- hydroxy-2- (S) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (R) -benzyloxy-2- (S) -pyrrolidine, 4-(R)- benzyloxy-2- (R) -pyrrolidine, 4- (S) -benzyloxy-2- (S) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4- piperidino, 3- (R) -piperidino, 3 - (S) -piperidino, 2- (R) - piperidino, 2- (S) -piperidino, octahydroisoquinoline or dihydroindoy
  • R 5 is methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4-methylphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-cyanophenyl , 2-methoxyphenyl , 3-methoxyphenyl, 4- methoxyphenyl , 4 -chlorophenyl , 3 , 4 -difluorophenyl , 4- nitrophenyl, 3 , 4-dihydroxyphenyl , 3-nitrophenyl , 3- methyl -4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4 -dichlorophenyl , 6- (2-oxo
  • bromophenyl 2- (5 -chloro-3 -methyl ) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5- [3 -(3 ',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole, 5- (3 -phenyl) isoxazole; and
  • R 6 is hydrogen, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl, 4-methylphenyl; or
  • R 7 is 1 , 3 -phenylene, 3 -methoxy- 1 , 4-phenylene, 2 -methoxy- 1, 4-phenylene, 2-chloro-l , 4-phenylene, 1 , 4-phenylene, 2- methoxy-4-chloro-l , 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l , 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6-chloro-l, 3- phenylene, 5-carboxy- 1 , 3 -phenylene, 5-methoxycarbonyl- 1 , 3 -phenylene, 2 , 6-dimethoxy-l , 3 -phenylene, 2 , 5-dichloro- 1 , 3 -phenylene, 2-bromo-1 , 3 -phenylene, 6-bromo-l,3- phenylene, 2 , 6-d
  • R 8 is a hydrogen atom, 2-pyridinemethyl , allyl,
  • R 8 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , 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, triphenylacetyl, nicotin
  • R 8 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
  • R 8 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( - ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - ( + ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4 -methylvalerate methyl ester, (s) -
  • the present invention also provides a method of preparing libraries containing discrete compounds of Formula (I), in particular, thiazoles, by reacting a resin-bound amine with an amino containing carboxylic acid, where the amino group can be a free amino group, a protected amino group or a masked amino group, such as, for example, a nitro group; and deprotecting or unmasking the amino group, if need be, to give a new amino bound resin.
  • the amino group is preferably a protected amino group.
  • the starting resin-bound amine is preferably a commercially available resin, such as, for example, MBHA (i.e., 4-methylbenzhydrylamine) , or prepared by synthetic methods known to those skilled in the art, such as, for example, the reductive alkylation of MBHA resin with an aldehyde or ketone to give a nitrogen-substituted resin or through the use of an aldehyde-bound resin prepared from Wang resin and reductively alkylating with an amine or diamine to give a nitrogen-substituted resin or yet another method, such as, displacing an alkyl halide-bound resin with an amine or diamine.
  • MBHA i.e., 4-methylbenzhydrylamine
  • the new amino-bound resin is converted to a thiourea with thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, and the resulting intermediate is subsequently allowed to react with ammonia or an ammonia equivalent, to give a thiourea-bound resin.
  • thiourea-bound resin is allowed to react with an ⁇ - haloketone and after cyclization affords a thiazole library containing discrete compounds of Formula (I).
  • Another aspect of this invention is the use of an orthogonally protected amino group that can be introduced in the above mentioned amino containing carboxylic acid and can be further modified, in an dependent or independent manner, either before or after the formation of the thiazole.
  • the amino group, introduced in the amino containing carboxylic acid is masked as a nitro group and converted into the amino group through the use of any one of the different reductive methods know to one skilled in the art, such as, for example, SnCl 2 .
  • the amino group is protected by any one of the variety protecting groups known in the art, such as, for example, a benzyloxycarbonyl (i.e, Cbz), tert-butyloxycarbonyl (i.e., t-Boc) and the like.
  • the amino group either after deprotection or after reduction of a nitro group, can optionally be reacted with an aldehyde or ketone to give a substituted nitrogen.
  • the resulting substituted nitrogen can be optionally alkylated to give a disubstituted nitrogen or reacted with an electrophile such as, for example, an acyl chloride, isocyanates or sulfonyl chlorides to give an amide, carbamoyl or sulfonamide respectively.
  • an electrophile such as, for example, an acyl chloride, isocyanates or sulfonyl chlorides to give an amide, carbamoyl or sulfonamide respectively.
  • the nitrogen, either substituted or unsubstituted can be reacted, as mention above herein, with thiophosgene or a thiophosgene equivalent followed by ammonia to give a thiourea that can be converted into a thiazole library through the use of an ⁇ -haloketone .
  • the library prepared from the above mentioned method can be useful for screening the library on the resin or alternatively can be cleaved from the resin as discrete compounds and screened in absence of resin.
  • the methods described above further comprise the step of cleaving the library from the resin to give discrete compounds.
  • R 10 R 11 can independently be in the R or S configuration, or a mixture of the two.
  • 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 1 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 “Cj 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- pentyny1 , 2 - hexynyl , 3 -hexyny1 , 4 -hexyny1 , 2 -heptyny1 , 3-heptynyl, 4- heptynyl , 5-heptynyl as well as di- and tri-ynes of straight and branched chains.
  • Ci to C 6 substituted alkyl denotes that the above Cj to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl groups and Ci to C 8 alkylene groups 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 ⁇ to C 7 alkoxy, Cj to C 7
  • Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3 -oxo-but-1-yl , cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl , propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylammomethyl , methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4- dichloro (n-butyl) , 2-aminopropyl , 1-chloroethyl , 2- chloroethyl, 1- bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroe
  • 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 and “C 3 to C 7 substituted alkynylene” as used herein denote, respectively, an alkene group or alkyne 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, alkoxy, C : to C acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano,
  • oxo denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.
  • 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.
  • d to C 7 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to C 6 substituted alkyl.
  • C 7 to C 13 phenylalkoxy as used herein means "Cj . to C 7 alkoxy" bonded to a phenyl radical .
  • C 1 to C 7 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • C ⁇ 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 to C 7 alkoxy, C x to C 7 acyl, C ⁇ to C 7 acyloxy, nitro, Cj to C 6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, methylsulfonylamino, thiol, Ci to C 4 alkylthio or C x to C 7 alkyl,
  • Cj 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.
  • C 5 to C 7 cycloalkyl includes the cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C 3 to C 7 substituted cycloalkyl and “C 5 to C 7 substituted cycloalkyl” indicate the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C 4 alkylthio, Ci to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl, C ⁇ to C 4 substituted alkylthio, Ci to C 4 substituted alkylsulfoxide, C ⁇ to C 7 substituted alkylsulfonyl, C ⁇ to C 6 alkyl, C x to C 7 alkoxy, Cj to C 6 substituted alkyl, C ⁇ to C 7 substituted alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, pheny
  • 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 substitution in the same manner as in relation to C 3 to C 7 substituted cycloalkyl .
  • 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
  • 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 ⁇ to C 4 alkylthio, C a to C 4 alkylsulfoxide, C : to C 7 alkylsulfonyl, x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 substituted alkylsulfonyl , C ⁇ to C 6 alkyl, C : to C 7 alkoxy, C x to C 6 substituted alkyl, C ⁇ 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 pyrrolidino, morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
  • substituted heterocycle 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 can be the same or different.
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, Cj to C 7 alkoxy, ⁇ to C 7 substituted alkoxy, C 1 to C 7 acyl, C ⁇ 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 or trifluoromethyl groups.
  • 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 can be the same or different.
  • the 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 : to C 7 acyl, C ⁇ to C 7 substituted acyl, C ⁇ 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 or trifluoromethyl groups.
  • heteroarylene means the above described definition for “heteroaryl” wherein the heteroaryl is bonded at two positions connecting together two separate additional groups.
  • substituted heteroarylene means the above described heteroarylene is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different .
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C : to C 7 substituted alkoxy, Ci to C 7 acyl, C ⁇ to C 7 substituted acyl, Ci 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 or trifluoromethyl groups.
  • heteroarylalkylene means the above described definition for “heteroaryl” wherein the heteroaryl is substituted with an alkylene and is bonded at two positions connecting together two separate additional groups.
  • the definition includes groups of the formula : -heteroaryl -alkyl- and -alkyl-heteroaryl-alkyl- where "-" represents a bond.
  • substituted heteroarylalkylene means the above described heteroarylalkylene is substituted on the heteroaryl group, alkylene group or both with, for example, one or more, and preferably one or two, substituents which can be the same or different.
  • the 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 2 to C 7 acyl, C x to C 7 substituted acyl, Ci 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 or trifluoromethyl groups .
  • C 7 to C 12 phenylalkyl denotes a C x to
  • C 6 alkyl group substituted at any position by a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl.
  • a phenyl substituted phenyl, heteroaryl or substituted heteroaryl.
  • Examples of such a group include benzyl, 2-phenylethyl, 3 -phenyl (n-propyl) , 4-phenylhexyl, 3 -phenyl (n-amyl) , 3- phenyl (sec-butyl) and the like.
  • Preferred C 7 to C 12 phenylalkyl groups are the benzyl and the phenylethyl groups .
  • C 7 to C 12 substituted phenylalkyl denotes a C 7 to C 12 phenylalkyl group substituted on the Ci 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 1 to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C ⁇ to C 7 substituted alkoxy, C x to C 7 acyl, Ci to C 7 substituted acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl , carboxamide, protected carboxamide, cyano,
  • C 7 to C i2 substituted phenylalkyl examples include groups such as 2 -phenyl- 1- 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 12 phenylalkylene specifies a
  • C 7 to C 12 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.
  • C 7 to C 12 substituted phenylalkylene means a C 7 to C 12 phenylalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, C to C 4 alkylthio, C x to C 4 alkylsulfoxide, C ⁇ to C 7 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted
  • 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, trifluoromethyl and phenyl, wherein the second phenyl is substituted or unsubstituted, such that, for example, a biphenyl, wherein the second
  • 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 4-fluorophenyl and the like; a mono or di (hydroxy) phenyl group such as 2, 3 or 4-hydroxyphenyl,
  • 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, Ci 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 or trifluoromethyl .
  • substituted phenoxy examples include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy,
  • 2-tert-butylphenoxy 2-allylphenoxy, 2-propenylphenoxy, 2 -eyelopentylphenoxy, 2 -fluorophenoxy, 2- (trifluoromethyl) phenoxy, 2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, 2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3 -isopropylphenoxy, 3 -tert-butylphenoxy, 3 -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, 3-fluorophenoxy, 3-chlorophenoxy, 3 -bromophenoxy, 3-iodophenoxy, 3 -methoxyphenoxy, 3- (trifluoromethoxy) phenoxy, 4-methylphenoxy,
  • C 7 to C 13 substituted phenylalkoxy denotes a C 7 to C 13 phenylalkoxy group wherein the C x to C 7 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 (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, 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, cyano, thiol, C x to C 4 alkylthio and C x to C 7 alkylsulfonyl groups; and/or the phenyl group can be substituted
  • C 7 to C 13 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, Ci to C 6 alkyl, C x to C 7 alkoxy, Ci to C 7 substituted alkoxy, Cl to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • substituted phthalimides examples include 4 , 5-dichlorophthalimido, 3 -fluorophthalimido, 4-methoxyphthalimido, 3-methylphthalimido, 4-carboxyphthalimido and the like.
  • 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, Ci to C 6 alkyl, Ci to C 7 alkoxy, C x to C, 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-d
  • 4-di (hydroxymethyl) naphthyl a mono- or di (amino) naphthyl or (protected amino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (amino) naphthyl or 2, 4- (protected amino) -naphthyl , a mono- or di (aminomethyl) naphthyl or (protected aminomethyl) naphthyl such as 2 , 3, or 4- (aminomethyl) naphthyl or 2, 4- (protected aminomethyl)- naphthyl; or a mono- or di- (N-methylsulfonylamino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (N-methylsulfonylamino) naphthyl .
  • 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 -y1 , 4-ethyl-2-hydroxynaphth-l-yl, 3 -hydroxy-4 -nitronaphth-2- yl, 2 -hydroxy-4-chloronaphth- 1-yl, 2 -methoxy- 7- bromonaphth-1-yl , 4-ethyl-5-hydroxynaphth-2-yl ,
  • 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 7 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 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, phenyl sulfonyl, substituted phenyl sulfonyl, C x to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl , 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
  • (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, Ci 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.
  • 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 , cycl
  • 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. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed.
  • protected guanidino refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of “protected guanidino” groups are described by T.W. Greene and P.G.M. Wuts; M. Bodanzsky; and Stewart and Young, supra.
  • 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
  • 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 Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference.
  • a related term is "protected carboxy, " which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • protected carboxymethyl refers to a carboxy portion of the carboxymethyl substituted with one of the above carboxy-protecting groups.
  • 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, 4 , 4 ' -dimethoxytrityl, 4 , 4 ', 4 " -trimethoxytrityl , benzyl, allyl, trimethylsilyl, (t-butyl) dimethylsilyl , 2 , 2 , 2-trichloroethoxycarbonyl groups and the like.
  • 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,
  • 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 7 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 " “substituted phenylsulfoxide, " and “substituted phenylsulfonyl” means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • C to C 7 alkylaminocarbonyl means a
  • Ci to C 7 alkyl attached to a nitrogen of the aminocarbonyl group examples include methylaminocarbonyl , ethylaminocarbonyl , propylaminocarbonyl, butylaminocarbonyl .
  • the term " C x to C 7 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 7 substituted alkyl.
  • C to C 7 substituted alkylaminocarbonyl examples include, for example, methoxymethylaminocarbonyl , 2 -chloroethylaminocarbonyl , 2-oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.
  • C x to C 7 alkoxycarbonyl means a “Ci to C 7 alkoxy” group attached to a carbonyl 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.
  • substituted phenylaminocarbonyl include 2 -chlorophenylaminocarbonyl (from 2-chlorophenylisocyanate) , 3 -chlorophenylaminocarbonyl (from 3-chlorophenylisocyanate) , 2-nitorphenylaminocarbonyl (from
  • C x to C 6 alkylaminothiocarbonyl means a Ci 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 methylisothiocyanate) , 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 5 substituted alkylaminothiocarbonyl examples include, for example, methoxymethylaminothiocarbonyl (from methoxymethylisothiocyanate) , 2 -chloroethylaminothiocarbonyl (from 2-chloroethylisothiocyanate) , 2-oxopropylaminothiocarbonyl (from 2-oxopropylisothiocyanate) , and
  • 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 2-chlorophenylaminothiocarbonyl (from
  • C x to C 8 alkylene or "C 2 to C 8 alkylene” means a C to C 8 or C 2 to C 8 alkyl group where the alkyl radical is bonded at two positions or, regarding a C x alkylene, at one position, connecting together two separate additional groups.
  • Examples of “ C x to C 8 alkylene” include methylene, 1,2-ethyl, 1,1-ethyl, 1, 3 -propyl .
  • C x to C e substituted alkylene means a Ci to C 8 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • n C x to C 8 substituted alkylene include 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 .
  • 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 phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, and 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-1, 2 -phenylene from 3 , 4-dihydroxybenzonitrile, 2 ,
  • 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, Ci to C 4 acyloxy, formyl, C x to C 7 acyl, C x to C 6 alkyl, C x to C 7 alkoxy, Ci to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl , halo, amino, protected amino,
  • the cyclic alkylene or heteroalkylene group fused on to the benzene radical can contain two to ten ring members, but preferably contains three to six members. Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring. When the cyclic groups are 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.
  • C 4 to C 10 cycloalkylalkylene means a cycloalkyl substituted with an alkyl group.
  • the cycloalkylalkylene radical is bonded at two positions connecting together two separate additional groups where one bond is directly to the cycloalkyl and the second bond is to the alkyl.
  • Examples of “cycloalkylalkylene” include cyclohexyl -2 -methylene, cyclohexyl -3 -methylene, and cyclohexyl -4 -methylene.
  • C 4 to C 10 substituted cycloalkylalkylene means a cycloalkylalkylene group that is substituted at the cycloalkyl group or the alkyl group or both with one or more groups but preferrably, one or two groups, such as halogen, hydroxy, protected hydroxy, Ci to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl, C to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C ⁇ to C 7 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino,
  • 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, sulfuric, 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, cyclohexylamme; 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, even when in a library, can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester- form. Such 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 , pi
  • 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 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, 4 -methylbenzhydrylamine-copoly (styrene-1% divinylbenzene) (MBHA) , 4 -hydroxymethylphenoxymethyl-copoly (styrene-1% divinylbenzene) , 4 -oxymethyl-phenyl-acetamido- copoly (stryene-1% divinylbenzene) (Wang), 4- (oxymethyl) - phenylacetamido methyl (Pam) , and TentagelTM, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly (styrene-1% divinylbenzene) (
  • 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 thiazole.
  • 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 Reaction Schemes 1 and 2 as well as the description provided below.
  • the amino containing carboxylic acids could be coupled to resin- bound primary or secondary amines which can be incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • resin-bound primary or secondary amines which can be incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • These amines could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, by displacement of a resin-bound halide, such as chloro or bromo, by a primary amine or by any other methods known to those skilled in the art.
  • the amino containing carboxylic acid coupled to the resin-bound amine from Step 1 was converted to a thiourea through the use of thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 2: Thio-urea formation).
  • the resin-bound thiourea from Step 2 was converted to a thiazole through the use of a variety a- haloketones (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 3: Thiazole ring formation).
  • Discrete compounds from the libraries can be obtained by cleavage from the resin by treatment with hydrofluoric acid (i.e., HF) or other methods known by those skilled in the art (Scheme 1: Library Synthesis Scheme, 2-Amino-Thiazoles; Step 4: Cleavage) .
  • hydrofluoric acid i.e., HF
  • Scheme 1 Library Synthesis Scheme, 2-Amino-Thiazoles; Step 4: Cleavage
  • the amino-containing carboxylic acid can have a second amino group attached that is either orthogonally protected or masked, such a with a nitro group (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 1: Amino acid attachment).
  • the carboxylic acid was coupled directly to a resin-bound primary amine such as methyl benzhydrylamine (MBHA) , or other resins known in the art that afford a primary amide upon cleavage.
  • MBHA methyl benzhydrylamine
  • the amino-containing carboxylic acid from Step 1 was coupled to a variety of second carboxylic acids via amide bond (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 2: Acylation of the amino group).
  • the second masked amino group then was reduced using SnCl 2 to prodice the free amine (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 3: Reduction of the nitro group) .
  • the free amine was then converted to a thiourea by using thiophosgene or a thiophosgene equivalent such as 1, 1 ' -thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 4: Thiourea formation).
  • the resulting thiourea was then converted to a thiazole by using a variety of ⁇ -haloketones (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 5: Thiazole ring formation) .
  • Discrete compounds from the libraries can then be obtained by cleavage from the resin by treatment with hydrofluoric acid (HF) or other methods known in the art (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 6: Cleavage).
  • HF hydrofluoric acid
  • amino acids can be used for the first building block of the library of the present invention.
  • Amino acids that can be used for this building block include, natural and unnatural amino acids (i.e., both D and L forms, as well as racemic mixtures) and compounds that are contain simply contain a carboxylic acid for which to couple to the resin and an amino group that can be further modified as described above herein to a substituted thiazole. This represents a very large class of compounds the basis of the first diverse building block.
  • the free amino group can be reductively alkylated with a wide range of commerically available or synthetically prepared aldehydes.
  • the primary amine or secondary amine can be reacted with thiophosgene or an equivalent to give a thiourea that is converted to a substituted thiazole to provide still another site of diversity.
  • This third diverse building block originates from a-haloketones .
  • amino containing carboxylic acid i.e., amino acid
  • a second amino group that is either orthogonally protected or masked, such as a nitro group, that can be treated in a similar manner as described above or in an independent manner to give di-substituted amines, aminothiazoles or N-substituted-aminothiazoles, providing optionally three additional building blocks respectively.
  • the nonsupport-bound combinatorial libraries can be screened as mixtures or discrete arrays of single compounds 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 thiazole derivatives, can be used as pesticides, acaricides, receptor agonisits and antimicrobial agents, including antibacterial 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 7 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 competitive ELISA method which can be used here is a modification of the direct ELISA technique described previously in Appel et al . , J. Immunol.
  • multi-well microplates are coated with the antigenic peptide (Ac-GASPYPNLSNQQT-NH 2 ) at a concentration of 100 pmol/50 ⁇ l .
  • MAb 125-10F3 Appel et al . , supra
  • 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 , 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 . Na tl .
  • 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 . , Moi . 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.
  • the 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
  • 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 (CaM) 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 assay that identifies CaM antagonists is a CaMPDE assay.
  • 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
  • 10 ⁇ l of CaCl 2 4.5 mM
  • 25 ⁇ l of calmodulin stock solution (Boehringer Mannheim; 0.01 ⁇ g/ ⁇ l) is then added and the samples then sit at room temperature for 10 minutes.
  • adenosine 3', 5 '-cyclic monophosphate (c7AMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1 hour at 30°C and then vortexed.
  • 200 ⁇ l of trichloroacetic acid (TCA) (55% in water) is added to a 200 ⁇ l sample aliquot, which is then vortexed and centrifuged for 10 minutes.
  • 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.
  • 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-(lH- 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-(lH- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2, 3 , 6-trimethyl-4-methoxybenzenesulfonyl
  • Step 1 Coupling of N-Protected amino acid to MBHA resin.
  • Step 2 Thiourea formation using Thiophosgene and Ammonia .
  • the packet was shaken in a solution of Thiophosgene (1.84g, 16 mmol) and DIEA (2.02g, 16 mmol) in DCM (40 mL) at room temperature for 1 hours.
  • the packet was washed several times with anhydrous DCM (3x80 mL) and then was reacted with ammonia (80mL, 0.5M solution in dioxane) for 1 hour at RT .
  • Packet was washed with dioxane (3x80mL) and alternatively with DMF (80 mL) and MeOH (80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) .
  • the packet was air-dried overnight.
  • Step 3 Reaction with halo-ketones to form thiazoles.
  • the packet was cut open and the resin was suspended DMF (50 mL) .
  • the suspension was distributed equally into 48 wells of a microtiter plate (lmLx48) .
  • N N-DIMETHYL-2-CHLOROACETOACETAMIDE 12 ETHYL 4-CHLOROACETOACETATE
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 199.27 Found (M+l) : 200.4
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 275.37 Found (M+l) : 276.2
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 185.24 Found (M+l) : 186.3
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 241.35 Found (M+l) : 242.3
  • Halo-Ketone N, -DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 256.32 Found (M+l) : 257
  • Halo-Ketone 1-ADAMANTYL BROMOMETHYL KETONE Calcd. MW: 305.44 Found (M+l) : 306.2
  • Step 1 Coupling of 4-amino-benzoic acid to MBHA resin.
  • Step 2 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 3 Reaction with halo-ketones to form thiazoles.
  • Halo-Ketone 2 -BROMOACETOPHENONE Calcd. MW: 295.35 Found (M+l) : 296.5
  • Step 1 Coupling of 3-Nitro-benzoic acid to MBHA resin
  • Step 2 Reduction of the nitro group to amine.
  • the packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature.
  • the packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
  • Step 3 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • Compounds 25 represent variations at the 2, 4 and 5 position of the amino-thiazole template derived from 3- Nitrobenzoic acids, and various halo-ketones.
  • Step 1 Coupling of Boc-Lysine (Fmoc) to MBHA resin.
  • the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) .
  • the packets were air-dried for 2 h.
  • the packet was shaken with 55% TFA/DCM (8L) at room temperature for 40 minutes and washed with DCM (3 X 8L) , 5% DIEA/DCM (2x8L) and MeOH (2x8L) .
  • the packets were air-dried overnight.
  • Step 2 Acylation of alpha-amino group using Carboxylic acids.
  • the packet was washed alternatively with DMF (3x80 mL) and MeOH (2x80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) .
  • the packet was air-dried for 2 h.
  • the packet was then shaken with 25% PIP/DMF (80 mL) at room temperature for 40 minutes and washed with DMF (3x80 mL) , 5% DIEA/DCM (2x80 mL) and MeOH (2x80 mL) . Resin was air dried for 2 hours.
  • Step 3 Thiourea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • the packet was cut open and the resin was suspended DMF (25 mL) .
  • the suspension was distributed equally into 24 wells of a microtiter plate (lmlx24) . Excess DMF was removed and the resin was washed several times using MeoH (3x1.5ml per well) .
  • the resin was air-dried overnight.
  • a solution of corresponding halo-ketone (see Table x) in ethoxyethanol (200 ⁇ L X 0.4 M) was added to each well.
  • the plate was tightly capped, shaken and incubated at 65° C for 15 hours. Each plate was washed alternatively with DMF (10 X 1 mL/well) and MeOH (14 xl mL/well) .
  • the plate was dried in air overnight and under vacuum for 4 hours .
  • the plate was treated with gaseous HF at room temperature for 1.5 hours. After complete removal of HF under a nitrogen stream followed by vacuum, the plate was extracted with AcOH (4 x 0.5 mL/well). The extractions were lyophilized to give the title compounds.
  • Halo-Ketone N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
  • Carboxylic Acid Ethoxyacetic acid
  • Halo-Ketone N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
  • Step 1 Coupling of Boc-Lysine (Fmoc) to MBHA resin.
  • the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) .
  • the packets were air-dried for 2 h.
  • the packet was shaken with 25% PIP/DMF (8L) at room temperature for 40 minutes and washed with DMF (3x8L) , 5% DIEA/DCM (2x8L) and MeOH (3x8L) . Resin was air-dried overnight .
  • Step 2 Acylation of epsilon-amino group using Carboxylic acids .
  • Step 3 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • Step 1 Coupling of Boc-p-nitro-Phe to MBHA resin.
  • Step 3 Reduction of the nitro group to amine.
  • the packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature.
  • the packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
  • Step 4 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 5 Reaction with halo-ketones to form thiazoles.
  • Compounds 29-32 represent the variations at 2,4 and 5 position of the amino-thiazole template derived from Boc- p-nitro-Phe, carboxylic acids and various halo-ketones.
  • Halo-Ketone N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 519 Found (M+l) : 520

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de thiazole de formule (I): dans laquelle q, R1, R2, R3, R4, R5, R6, R7 et R8 ont la signification susmentionnée. Cette invention concerne, en outre, des banques combinatoires présentant au moins deux de ces composés, et les procédés de préparation de banques combinatoires constituées de tels composés.
EP00913425A 1999-02-08 2000-02-08 Derives de thiazole et leurs banques combinatoires Withdrawn EP1150565A1 (fr)

Applications Claiming Priority (5)

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US246523 1981-03-23
US24652399A 1999-02-08 1999-02-08
US49941900A 2000-02-07 2000-02-07
US499419 2000-02-07
PCT/US2000/003475 WO2000045635A1 (fr) 1999-02-08 2000-02-08 Derives de thiazole et leurs banques combinatoires

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GB0112834D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
CA2469228A1 (fr) 2001-12-03 2003-06-12 Japan Tobacco Inc. Compose azole et utilisation medicinale de celui-ci
EA200801716A1 (ru) 2006-01-18 2009-04-28 Амген Инк. Тиазольные соединения и их применение
EP1939181A1 (fr) 2006-12-27 2008-07-02 sanofi-aventis Carboxamides hétérocycliques et leur utilisation pour la stimulation de l'expression de la NO synthase
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB
EP2173728A2 (fr) 2007-07-17 2010-04-14 Amgen Inc. Modulateurs hétérocycliques de pkb
AU2012352349B2 (en) * 2011-12-12 2017-08-17 Receptos Llc Carboxylic acid derivatives comprising four cycles acting as GLP-1 receptor modulators for therapy of diseases such as diabetes
US9290489B2 (en) 2012-07-06 2016-03-22 Duke University Activation of TRPV4 ion channel by physical stimuli and critical role for TRPV4 in organ-specific inflammation and itch
KR102271179B1 (ko) 2013-06-11 2021-07-01 셀진 인터내셔널 Ii 에스에이알엘 신규의 glp-1 수용체 조절제
US10329265B2 (en) 2014-08-22 2019-06-25 Duke University TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch
WO2016094729A1 (fr) * 2014-12-10 2016-06-16 Celgene International Ii Sarl Nouveaux modulateurs du récepteur du glp-1
US11229628B2 (en) 2015-01-09 2022-01-25 Duke University TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch
JP2019513749A (ja) 2016-04-07 2019-05-30 デューク ユニバーシティ 衛生化及び麻酔用のｔｒｐｖ４及びｔｒｐａ１の小分子二重阻害剤

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FI91859C (fi) * 1987-06-17 1994-08-25 Eisai Co Ltd Analogiamenetelmä antiallergisena aineena aktiivisen bentsotiatsolijohdannaisen valmistamiseksi
US5296486A (en) * 1991-09-24 1994-03-22 Boehringer Ingelheim Pharmaceuticals, Inc. Leukotriene biosynthesis inhibitors
US5733882A (en) * 1994-01-17 1998-03-31 Smithkline Beecham Corporation Retroviral protease inhibitors
ES2218554T3 (es) * 1994-10-27 2004-11-16 Fujisawa Pharmaceutical Co., Ltd. Piridopirimidonas, quinolinas y n-heterociclos condensados que son antagonistas de bradiquinina.
HUP0001054A3 (en) * 1997-08-06 2001-01-29 Daiichi Asubio Pharma Co Ltd 1-aryl-1,8-naphthyridin-4-one derivative as type iv phosphodiesterase inhibitor

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