CA2362085A1 - Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries - Google Patents
Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries Download PDFInfo
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- CA2362085A1 CA2362085A1 CA002362085A CA2362085A CA2362085A1 CA 2362085 A1 CA2362085 A1 CA 2362085A1 CA 002362085 A CA002362085 A CA 002362085A CA 2362085 A CA2362085 A CA 2362085A CA 2362085 A1 CA2362085 A1 CA 2362085A1
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- 0 *CC*C(C(*)(*)N(C(C(*)(*)C(N1*)=O)=O)C1=O)=O Chemical compound *CC*C(C(*)(*)N(C(C(*)(*)C(N1*)=O)=O)C1=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
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- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
A support template of Formula (1).
Description
WO 00/46211 PCT/US00/02998 - __.
Description USE FOR THE SYNTHESIS OF CHEMICAL LIBRARIES
Field of the Invention The present invention relates to method of synthesis of compounds of Formula 1 (referred to herein as support templates) as follows:
O O~\\~~~~0 IO
Formula 1 where x, R2, R3, R", X3, and X4 are as defined below, the use of Formula 1 for the synthesis of chemical libraries, and cleavage of the heterocycle compounds of the libraries to provide compounds of therapeutic use.
Table of Abbreviations Alloc allyloxycarbonyl BOC tert-butyloxycarbonyl CBZ benzyloxycarbonyl Fmoc 9-fluorenylmethyloxycarbonyl g gram h hour LC liquid chromatography MS mass spectroscopy ml milliliter mmole millimole min minute M molar Ph phenyl rt room temperature Background of the Invention As is known, solid support synthesis is carried out on a substrate made of a polymer, cross-linked polymer, functionalized polymeric pin, or other insoluble material. These polymers or insoluble materials have been described in the literature and are known to those who are skilled in the art of solid phase synthesis (see, Stewart JM, Young J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Some of the supports are based on polymeric organic substrates such as polyethylene, polystyrene, polypropylene, polyethylene glycol, polyacrylamide, and cellulose. Additional types of supports include composite structures such as grafted copolymers and polymeric substrates such as polyacrylamide supported within an inorganic matrix such as kieselghuhr particles, silica gel, and controlled pore glass.
Such polymers are substituted with linkers that modulate the stability of the linkage to the support resin. The linkers incorporate reactive functionalities (e.g. amino, hydroxy, oximo, phenolic, silyl, etc.) for loading of monomers suitable for carrying out a plurality of further reactions to synthesize the desired products (see, Hemkens, P. H. H., Ottenheijm, H. C.
J., and Rees, D., Tetrahedron Lett., 1996, Vol. 52, pp. 4527-4554).
Examples of well known support resins and linkers are given in various reviews (see, Barany, G. and Merrifield, R.B., "Solid Phase Peptide Synthesis", The Peptides - Analysis, Synthesis, Biology, Vol. 2, [Gross, E.
and Meienhofer, J., Eds.], Academic Press, Inc., New York, 1979, pp. 1-284, and Backes, B. J. and Ellman, J. A., Curr. Opin. Chem. Biol. 1997, Vol. 1, p.
86) and in commercial catalogs (see, Advanced ChemTech, Louisville, Kentucky, United States of America and Novabiochem, San Diego, California, United States of America). Some examples of particularly well known functionalized resin/linker combinations that are meant to be illustrative and not limiting in scope include hydroxymethyl polystyrene resin, Wang resin, hydroxymethylbenzoic acid resin (HMBA resin), hydroxymethylphenoxy functionalized TentagelT"~ resin, ArgogelT"" resin, oxime resin, 4-hydroxymethyl-3-methoxyphenoxybutyric acid-BHA resin (HPPB-BHA resin), and polyethylene glycol type A resin (PEGA resin).
Also, well known is a type of solid phase synthesis method referred to as the "pin method", which was developed by Geysen et al. and is useful for combinatorial solid-phase peptide synthesis (see, Geysen et al., J. Immunol.
Meth., 1987, Vol. 102, pp. 259-274). According to this method, a series of 96 polymeric pins are mounted on a block, in an arrangement and a spacing which correspond to a 96-well microtiter reaction plate, and the surface of each polymeric pin is functionalized (also referred to as derivatized) to contain a terminal functional group linker. The polymeric pin block is then WO 00/46211 PCT/LTS00/02998 - __.
Description USE FOR THE SYNTHESIS OF CHEMICAL LIBRARIES
Field of the Invention The present invention relates to method of synthesis of compounds of Formula 1 (referred to herein as support templates) as follows:
O O~\\~~~~0 IO
Formula 1 where x, R2, R3, R", X3, and X4 are as defined below, the use of Formula 1 for the synthesis of chemical libraries, and cleavage of the heterocycle compounds of the libraries to provide compounds of therapeutic use.
Table of Abbreviations Alloc allyloxycarbonyl BOC tert-butyloxycarbonyl CBZ benzyloxycarbonyl Fmoc 9-fluorenylmethyloxycarbonyl g gram h hour LC liquid chromatography MS mass spectroscopy ml milliliter mmole millimole min minute M molar Ph phenyl rt room temperature Background of the Invention As is known, solid support synthesis is carried out on a substrate made of a polymer, cross-linked polymer, functionalized polymeric pin, or other insoluble material. These polymers or insoluble materials have been described in the literature and are known to those who are skilled in the art of solid phase synthesis (see, Stewart JM, Young J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Some of the supports are based on polymeric organic substrates such as polyethylene, polystyrene, polypropylene, polyethylene glycol, polyacrylamide, and cellulose. Additional types of supports include composite structures such as grafted copolymers and polymeric substrates such as polyacrylamide supported within an inorganic matrix such as kieselghuhr particles, silica gel, and controlled pore glass.
Such polymers are substituted with linkers that modulate the stability of the linkage to the support resin. The linkers incorporate reactive functionalities (e.g. amino, hydroxy, oximo, phenolic, silyl, etc.) for loading of monomers suitable for carrying out a plurality of further reactions to synthesize the desired products (see, Hemkens, P. H. H., Ottenheijm, H. C.
J., and Rees, D., Tetrahedron Lett., 1996, Vol. 52, pp. 4527-4554).
Examples of well known support resins and linkers are given in various reviews (see, Barany, G. and Merrifield, R.B., "Solid Phase Peptide Synthesis", The Peptides - Analysis, Synthesis, Biology, Vol. 2, [Gross, E.
and Meienhofer, J., Eds.], Academic Press, Inc., New York, 1979, pp. 1-284, and Backes, B. J. and Ellman, J. A., Curr. Opin. Chem. Biol. 1997, Vol. 1, p.
86) and in commercial catalogs (see, Advanced ChemTech, Louisville, Kentucky, United States of America and Novabiochem, San Diego, California, United States of America). Some examples of particularly well known functionalized resin/linker combinations that are meant to be illustrative and not limiting in scope include hydroxymethyl polystyrene resin, Wang resin, hydroxymethylbenzoic acid resin (HMBA resin), hydroxymethylphenoxy functionalized TentagelT"~ resin, ArgogelT"" resin, oxime resin, 4-hydroxymethyl-3-methoxyphenoxybutyric acid-BHA resin (HPPB-BHA resin), and polyethylene glycol type A resin (PEGA resin).
Also, well known is a type of solid phase synthesis method referred to as the "pin method", which was developed by Geysen et al. and is useful for combinatorial solid-phase peptide synthesis (see, Geysen et al., J. Immunol.
Meth., 1987, Vol. 102, pp. 259-274). According to this method, a series of 96 polymeric pins are mounted on a block, in an arrangement and a spacing which correspond to a 96-well microtiter reaction plate, and the surface of each polymeric pin is functionalized (also referred to as derivatized) to contain a terminal functional group linker. The polymeric pin block is then WO 00/46211 PCT/LTS00/02998 - __.
lowered into the 96-well microtiter reaction plate to immerse the pins in the wells of the plate where coupling (i.e., linking) with a compound occurs at the terminal functional group linkers. Next, a plurality of further reactions are carried out in a similar fashion on each compound by having reagents varying in their substituent groups occupy the wells of the plate in a predetermined array, in order to achieve as ultimate products, a unique product on each pin. Each product is then cleaved from each polymeric pin.
By using different combinations of substituents, one achieves a large number of different products with an array of central core structures.
A related known method of synthesis uses porous polyethylene bags (colloquially referred to as the tea bag method) containing the functionalized solid phase resins referred to above (see, Houghton, R.A., et al., Nature, Vol. 354, pp. 84-86, 1991 ). These tea bags of resin can be moved from one reaction vessel to another in order to undergo a series of reaction steps for the synthesis of libraries of products.
Also known is the use of solubilizable resins that can be rendered insoluble during the synthesis process as solid phase supports. This may be achieved by attachment of linkers to resins that can be solubilized under certain solvent and reaction conditions and rendered insoluble for isolation of reaction products from reagents, for instance, by use of high molecular weight polyethyleneglycol as a solubilizable polymeric support (see, Vandersteen, A. M., Han, H., and Janda, K. D., Molecular Diversity, 1996, Vol. 2, pp. 89-96).
Additionally, solid support synthesis is known to provide several advantages over solution chemistry, as shown by the ease of purification and automation of solid support synthesis of peptides (see, Atherton, E. and Sheppard, RC, Solid Phase Peptide Synthesis: A Practical Approach, IRL
Press at Oxford University Press, Oxford, 1989) as well as by the ease of purification and automation of non-peptide-based molecules (see, Lenzoff, C.C., Acc. Chem. Res., 1978, Vol. 11, pp. 327-333). Moreover, solid support synthesis of combinatorial libraries has yielded many biologically active compounds (see, Moos, W. H. et al., Annu. Rep. Med. Chem., 1993, Vol. 28, pp. 315-324, and Terrett, N.K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J., Tetrahedron, 1995, Vol. 51, pp. 8135-8173).
Summary and Objects of the Invention The present invention provides a support template comprising a compound of Formula 1 as follows:
where:
~ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R" are the same or different and are selected from:
WO 00/46211 PCT/US00/02998 - __.
By using different combinations of substituents, one achieves a large number of different products with an array of central core structures.
A related known method of synthesis uses porous polyethylene bags (colloquially referred to as the tea bag method) containing the functionalized solid phase resins referred to above (see, Houghton, R.A., et al., Nature, Vol. 354, pp. 84-86, 1991 ). These tea bags of resin can be moved from one reaction vessel to another in order to undergo a series of reaction steps for the synthesis of libraries of products.
Also known is the use of solubilizable resins that can be rendered insoluble during the synthesis process as solid phase supports. This may be achieved by attachment of linkers to resins that can be solubilized under certain solvent and reaction conditions and rendered insoluble for isolation of reaction products from reagents, for instance, by use of high molecular weight polyethyleneglycol as a solubilizable polymeric support (see, Vandersteen, A. M., Han, H., and Janda, K. D., Molecular Diversity, 1996, Vol. 2, pp. 89-96).
Additionally, solid support synthesis is known to provide several advantages over solution chemistry, as shown by the ease of purification and automation of solid support synthesis of peptides (see, Atherton, E. and Sheppard, RC, Solid Phase Peptide Synthesis: A Practical Approach, IRL
Press at Oxford University Press, Oxford, 1989) as well as by the ease of purification and automation of non-peptide-based molecules (see, Lenzoff, C.C., Acc. Chem. Res., 1978, Vol. 11, pp. 327-333). Moreover, solid support synthesis of combinatorial libraries has yielded many biologically active compounds (see, Moos, W. H. et al., Annu. Rep. Med. Chem., 1993, Vol. 28, pp. 315-324, and Terrett, N.K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J., Tetrahedron, 1995, Vol. 51, pp. 8135-8173).
Summary and Objects of the Invention The present invention provides a support template comprising a compound of Formula 1 as follows:
where:
~ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R" are the same or different and are selected from:
WO 00/46211 PCT/US00/02998 - __.
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C~-Coo alkyl, C~-Coo substituted alkyl, C~-Coo substituted alkyl-aryl, C~-Coo substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C~-Coo alkyloxy, C~-C~0 alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Coo thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~-C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-Coo carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~rC~p alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C~-Coo alkyloxy, C~-C~0 alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Coo thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~-C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-Coo carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~rC~p alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine.
Also, the present invention provides a method of making a support template comprising a compound of Formula 1 as follows:
where:
~ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C1o alkyl, C1-C1o substituted alkyl, C1-C1o substituted alkyl-aryl, C1-C1o substituted alkenyl, and C1-C1o substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C1o alkyloxy, C1-C1o alkyloxy aryl, C1-C1o aminoalkyl, C1-C1o alkylamino, C1-C1o aminoalkyl aryl, C1-C1o aminocarbonyl, C1-C1o aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C1o thioalkyl-aryl, C1-C1o alkylsulfoxide, C1-C1o alkylsulfone, C1-C1o _g_ alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Cio alkyl, C~-Coo alkyl aminocarbonylamino C~-Cep alkyl aryl, C~-Cep alkyloxycarbonyl C~-C10 alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C~0 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C~0 alkyloxycarbonylamino alkyl, C~-C~p alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Cep aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises:
(1 ) coupling a functionalized polymer support ~-x-H with a N-protected alpha-amino acid of Formula A as follows:
Rs N ~O~ H
where R4 and RS are the same or different and are selected from:
_g_ H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R5 with H, and reacting the deprotected resultant with an amine R~~NH2 or an isocyanate R~~NCO under urea-forming reaction conditions to provide a urea-bound solid support resin of Formula 4 as follows:
R3 R ~ ,R11 " H H
O
(3) treating the urea-bound solid support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1.
Hence, it is an object of the invention to provide certain novel solid support templates, chemical libraries produced therewith, and cleaved heterocycle compounds of the libraries.
Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as best described below.
Detailed Description of the Invention WO 00/46211 PCT/US00/02998 - __.
The present invention relates to carbonyl-esters or carbonyl-amides linked to insoluble materials as depicted in Formula 1, and methods for producing chemical libraries generated through a plurality of chemical reactions utilizing support templates of Formula 1.
O~\\~~~~0 O
N~N~R11 Formula 1 where x, R2, R3, R11, X3, and X4 are as defined below.
Optionally, R2 and R3 in Formula 1 may be joined together to form cyclic compounds of Formula 1 a with ring size of 3-8 as follows:
Formula 1 a For instance, the ring system may be selected from:
(a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, WO 00/46211 PCT/US00/02998 - _,_ (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, S02, NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from:
(d) H, (e) mono di- and tri-substituted aryl, and (f) C~-Coo substituted alkyl, C~-Coo -substituted alkyl-aryl C~-Coo substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, vitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Coo thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-Coo alkylsulfonamide, C~-Cep alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~°C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-Coo alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, and C~-Coo alkenyl CONH2, and the like, and where the aryl groups of (e) and (f) are selected from:
WO 00/46211 PCT/US00/02998 - __.
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl, and the like.
Support templates of Formula 1 were synthesized according to Scheme 1 below, x. H
Formula 2 amide-bond R~R ,R5 N
O H formation O H
H. ~N. 5 Formula 3 1 ) Deprotection Formula A
2) (Urea Formation) R~~NH2 or R~~NCO
acid condensation, s R2 O
Formula 1 ~ R~N~N~R11 cyclization O H H
Formula 4 Scheme 1 where x, R2, R3, R5, R", X3, and X4 are as defined below.
In general, Scheme 1 is performed as follows. As represented by ~, a material suitable for a support (which may be any of the polymers suitable for a support, which may be a solid support, as mentioned in the referenced WO 00/46211 PCT/US00/02998 - __.
literature that is described above), functionalized with xH (such as amino, hydroxy, oximo, phenolic, or silyl) where x is a linker (such as NH, O, CHNO, PhO, or SiH2, respectively), provided a functionalized polymer support as shown in Formula 2 (i.e., the functionalized ~ also may be any of the funtionalized polymer supports, which may be solid supports, as mentioned in the referenced literature that is described above), which was then reacted with a N-protected alpha-amino acid of Formula A (defined below and in Provisional U.S. Patent Application Serial No. 60/116,915, which was filed on January 22, 1999 and which is the priority application of International PCT Application No. , which was filed on January 21, 2000) using standard amide bond forming reactions (described below) to create a polymer-bound amide as shown in Formula 3. Deprotection of the amine moiety of Formula 3 using standard conditions, followed by reaction with an amine (R'~NH2) or an isocyanate (R"NCO), under urea-forming standard reaction conditions, provided a urea-bound support resin as shown in Formula 4 (see, Buckman, B. O. et al, Tet. Lett., 1996, Vol. 37, p. 4439).
Reaction of a compound of Formula 4 with an acid, followed by cyclization to achieve ring closure, provided a polymer-bound support template of Formula 1, which may be a polymer-bound solid support template.
More particularly, N-protected alpha-amino acids of Formula A have one or two substituents (R2 and/or R3) at the alpha position and are defined as follows:
RsN~O~H
Formula A
where:
R2 and R3 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C~-Coo alkyl, C~-Coo substituted alkyl, C~-Coo substituted alkyl-aryl, C~-Coo substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, vitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Cep thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Cep alkyl, C~-C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C~p alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and the like, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like, and where:
R4 and R5 are the same or different and are selected from:
H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and the like.
Optionally, R2 and R3 in Formula A are joined together to form cyclic compounds of Formula Aa with a ring size of 3-8 as follows:
z Rs N~O~ H
Formula Aa For instance, the ring system may be selected from substituted-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds of Formulae Ab and Ac as follows:
R9 Rs R~~ Rs Rip R~ R6 R~
R
R ~N O~H
R5.N O~H i Formula Ab Formula Ac WO 00!46211 PCT/LTS00/02998 selected from substituted- cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula Ad as follows:
Rs R1o R~ Rs RvN O.H
Formula Ad where Rs and R', Rs and R1°, or R9 and R1° may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its substituents are as defined below vis-a-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is O, S, SO, S02, NH, S02NHR8, NCONHR8, NCOOR8, or NR$ inserted in the ring systems as in compounds of Formulae Ae and Af as follows:
Rs Rs R A Rs Rs A R1o R~ R~
R5-N O~ H R5. N O~ H
Formula Ae Formula Af where the substituents R4 and R5 in Formulae Aa-Af are as defined above and where the substituents (Rs, R', R8, R9, and R1°) in Formulae Aa-Af are the same or different and are selected from:
(d) H, (e) mono-, di-, and tri-substituted aryl, and (f) C~-Coo substituted alkyl, C~-Coo substituted alkyl-aryl, C~-C~0 substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Cep aminoalkyl, C~-Coo alkylamino, C~-Cep aminoalkyl aryl, C~-Coo aminocarbonyl, C~-C~0 aminocarbonylalkyl-aryl, C~-Cep thioalkyl, C~-Cep thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~°C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-Coo alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~-C~0 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C10 alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-Coo alkenyl CONH2, and the like, and where the aryl group of (e) and (f) is selected from:
phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like.
Compounds of Formula A are synthesized according to the following reaction mechanism:
R4NC + NH2-CHR-COOH + R3-CO-R2 convertible isocyanide chiral auxiliary ketone or aldehyde Rs R2 R
R~~ R4~N~N~OR~
where R~ is defined the same o H o as R2 and/or R3 Formula B
1 ) aryl amine cleavage/hydrolysis, R3 R2 including catalytic hydrogenation R ~N~o~H
H O
2) amide cleavage or hydrolysis*, and Formula A
3) amine protection with R5 *It is noted that when proceeding from Formula B to Formula A, 1 ) may be performed prior to 2), 2) may be performed prior to 1 ), or 1 ) and 2) may be performed concurrently.
Reaction of an appropriate aldehyde or ketone (such as but not limited to phenylacetaldehyde or cyclohexanone) with an amino acid/removable chiral auxiliary or salt thereof (such as but not limited to phenyl glycine, i.e., R is phenyl) and an appropriate convertible isocyanide (such as but not limited to R4 is phenyl-, cyclohexenyl-, cyclohexyl-, or t-butyl-) utilizing an appropriate solvent and reaction conditions (such as but not limited to R'OH is methanol, ethanol, or isopropanol, at about -80°C to 220°C) provided compounds of Formula B.
The desired alpha-amino acid of Formula B has a removable amino acid/chiral auxiliary and preferably is selected from compounds where R is WO 00/46211 PCT/US00/02998 - __.
mono, di-, tri-, tetra- or penta-substituted aryl, where the aryl is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, and the substituents are selected from: H, cyano, amino, C~-Coo alkyl, C~-C10 alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-C10 aminoalkyl aryl, and the like.
Then, after cleavage of both the chiral auxiliary amine and the amide portions, compounds of Formula B provided the corresponding alpha-amino acids and their derivatives of Formula A.
For the attachment of the acid group of Formula A, many reagents are known to be suitable (see, Stewart, J.M. and Young, J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Among the many reagents available are:
dialkylcarbodiimide with an additive such as 1-hydroxybenzotriazole;
especially diispropylcarbodiimide/1-hydroxy-7-azabenzotriazole (DIC/HABT);
benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (HBTU); bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP); and Fmoc amino acid fluorides (see for instance, Carpino, L.A., et al., "9-Fluorenylmethyloxycarbonyl Amino Acid Fluorides, Convenient New Peptide Coupling Reagents Applicable to the Fmoc/Tert-Butyl Strategy for Solution and Solid-Phase Synthesis", J. Am. Chem.Soc., 1990, Vol. 112, pp.
9651-9652). The degree of steric hindrance, reactivity of the amine, and other factors may determine which reagent will be most suitable for a particular substrate, but many of the reagents will give a suitable result for most reactions.
As is conventional, the amine group (NHRS of Formula 3) should stay protected (i.e., R5 should not be H in the group) until it is to be utilized in a reaction sequence. Those skilled in the art will appreciate that any of the wide variety of available amino protecting groups for R5 may be used such as tert-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (CBZ), and the like. The choice of a particular protecting group will depend on the specific nature of the substituents and reactions contemplated. Also, more than one type of protecting group may be necessary at any given point in the synthesis (see, e.g., Green, T. and Wuts, P. G. M., Protective Groups In Organic Synthesis 2"d Ed, Wiley, 1991, and references cited therein).
Last, deprotecting of the amine group (NHRS of Formula 3) was conducted with standard conditions, and then, the resultant was reacted with an amine (R~~NH2) or an isocyanate (R"NCO), where R" is defined the same as R2 and/or R3, to provide the urea-bound support resin (which may be a solid support) of Formula 4, which was then treated with an acid (such as 1,3-dichloropropionic acid, malonic acid, their derivatives, and the like) followed by cyclization in the presence of a condensation reagent (such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, 1,1'-carbonyldiimidazole, and the like) to result in Formula 1.
Support templates of Formula 1 (which may be solid support templates) may be reacted with plurality of chemical transformations followed by cleavage from the support ~ of the desired heterocycle compounds under appropriate conditions (such as by trichloroacetic acid/dichloromethane). Some examples of these transformations provided WO 00/46211 PCT/US00/02998 - -~.
desired heterocycle compounds of Formulae B-J, which are referred to as "libraries" prior to cleavage from the support ~, as shown below in Scheme 2.
R~~HN
NHR~6 R~2 O O O
O O O O O NH O ~ NH
O
N N~ ~~ N N~ » N N~ ~~
HzN~ z R H2N~ z R H2N~~ z R
R R~ R R~ R R
B I J
R~s R~z 'O
O O
~N N
HzN~~~Nz N~R~~ HzN HzN R3 Rz~ ~Rm O
C D E
R~~NN
O
13 O N-Rya O O
~ ~ N N
HzN/\ HzN%~ z ~R~~
R R / \R~
O O
F G H
Scheme 2 WO 00/46211 PCT/US00/02998 - __.
where each of R", R'2, R'3, R14~ R15~ R~s, R~~~ and R'8 is C~-Coo alkyl, C~-Coo aryl, or C~-Coo alkyl-aryl.
For example, reaction of Formula 1 with an acid chloride (R'2COCI, or equivalent) or an alkyl halide (R'2Br, R'2CI, R'2F, or equivalent) using standard conditions followed by cleaving the product from the support (under standard conditions described above) provided compounds of Formula A
and Formula C, respectively, after cleavage from the support.
Moreover, cyclization of Formula B (prior to cleavage from the support) with an amine (where R'2 = R'4-CH-NH-R'$) followed by cleavage provided compounds of Formula H, after cleavage from the support.
On the other hand, reaction of compounds of Formula B (prior to cleavage from the support) with a hydrazine (R'3NHNH2) provided compounds of Formula G, after cleavage from the support.
Also, reaction of Formula 1 with an alpha-halomethyl ketone (R'SCOCH2Br, R'SCOCH2CI, or R'SCOCH2F, or equivalent) provided compounds of Formula E, after cleavage from the support.
Additionally, reaction of Formula E (prior to cleavage from the support) with a hydrazine (R'3NHNH2) provided compounds of Formula D, after cleavage from the support.
When R' in Formula B was -CH(CH2NHR")NHR's, compounds of Formula F were obtained, after cleavage from the support.
Furthermore, selective amine deprotection (R's, R") of Formula F
and cyclization provided compounds of Formula I and Formula J, after cleavage from the support.
WO 00/46211 PCT/US00/02998 - _~.
It is noted that in Formulae B through J, linker x was amine resulting in the pendent moiety NH2; however, if linker x was O, for instance, the result would be the pendent moiety OH.
Laboratory Examples General Methods of Synthesis:
Compounds of Formula 1 were prepared according to the general process outlined below in Scheme 1.
~H +
x O
H
Formula 2 x%'~N~RS
O ~ R3 R2 H
N
HO ~R5 Formula 3 Formula A
Formula 1 O ~ O
/~~H II
x N O ~~~N O
/\x R3 R2 HN ~ g R2~
R
N
~R~ ~ ~R11 Formula 4 X1--~~O
O
Formula 5 Scheme 1 More specifically, a N-protected alpha-amino acid of Formula A
(defined as above) was attached to the solid support of Formula 2 (described above) in the presence of a coupling reagent such as N,N'-WO 00/46211 PCT/US00/02998 - __.
diisopropylcarbodiimide to produce compounds of Formula 3. Deprotection of the amino moiety in standard conditions, followed by reaction with either an isocyanate (R~~NCO) or 4-nitrophenyl chloroformate and a primary amine (R~~NH2), provided a urea-bound solid support resin of Formula 4.
Compounds of Formula 1 were obtained by condensation of Formula 4 with a malonic acid derivative of Formula 6.
O O
I
X~ X2 Formula 6 where X~ = halogen, hydroxy, alkoxy, acyloxy;
X2 = halogen, alkoxy, or acyloxy; and preferably, X~ + X2 = OC(CH3)2O
to provide an intermediate compound of Formula 5. In carrying out the condensation, either reactivity of the amide nitrogen in Formula 4 is enhanced by treatment with N,O-bis(trimethylsilyl)acetamide or instead the carbonyl moiety in Formula 6 is activated by formation of chloroanhydrides, mixed anhydrides, or active esters. Ring closure occurs via an intermediate compound of Formula 5, which may be isolated, if desired. Compounds of Formula 5 were cyclized in the presence of a condensation reagent, such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1,1'-carbonyldiimidazole, to provide compounds of Formula 1.
Compounds of Formula 1 underwent a variety of chemical transformations and cleavage of the library from ~, to yield diverse derivatives, i.e., the desired heterocycle compounds, of Formula 7 O O
O
x N~N~R~~
H Rs R2 lfO
Formula 7 where x = O; R2, R3, and R'~ are as defined above;
X3 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine;
X4 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine;
and when both X3 and X4 are not H, preferably X3 + X4 = carbocycle or heterocycle.
More specifically, provided were the following acids of Formula 7 as per EXAMPLES 1-12 below.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid O H \~~O
N\ /N
O ~' O
N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, Wang resin supplied by NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was then added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 251 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)phenylalanine on Wang resin.
The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
WO 00/46211 PCT/US00/02998 - __.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 337 (M+H)+.
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 319 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-(4-methylbenzyl)barbituric acid O HO~~~O
N\ /N
O ~' \ O
/ \
N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h.
The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The WO 00/46211 PCT/US00/02998 - __.
resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min.
The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). 4-methylbenzylamine (0.656 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 313 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-((4-methylbenzyl)carbamoyl)phenylalanine on Wang resin. The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 399 (M+H)+.
N-(carboxymethylcarbonyl)-N-((4-methylbenzyl)carbamoyl)phenylala-nine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2 dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The resulting product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 381 (M+H)+.
1-(1-carboxy)ethyl-3-propylbarbituric acid OHO~~~~O
N\ /N
O' O
N-Fmoc-alanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol), and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol).
WO 00/46211 PCT/US00l02998 - __.
Propylamine (0.411 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 175 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)alanine on Wang resin. The resulting slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2 dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 261 (M+H)+.
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)alanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 1-(1-Carboxy)ethyl-3-propylbarbituric acid was cleaved from the WO 00/46211 PCT/US00/02998 - __.
dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for h. LC/MS analysis: m/z 243 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid OH ~~~~0 N\ /N
O ~' O
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was swelled in 1 ml of 1 M solution of 1,1'-carbonyldiimidazole in 1,2-dichloroethane. The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 319 (M+H)+.
5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid \i OHO~~~'~~O
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml tetrahydrofuran. The resulting suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M benzyl bromide in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 499 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-propionyl-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __.
O
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M propionyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of propionyl chloride were combined.
The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 375 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-(2-butenoyl)-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __.
O
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M crotonyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of crotonyl chloride were combined. The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 387 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-(3-phenyl-2-((9-fluorenylmethoxycarbonyl) amino)pro-pionyl)-3-propylbarbituric acid O
O
~N
H
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N-(9-fluorenylmethoxycarbo-nyl)phenylalanine and 1,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 688 (M+H)+.
5-(2-amino-3-((9-fluorenylmethoxycarbonyl)amino)propionyl)-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __ H
O N\ /O
O O ~O
OH
N\ /N
O' ~ -O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N"-(tent-butyloxycarbonyl)-N~'-(9-fluorenylmethoxycarbonyl)propionic acid and 1,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 627 (M+H)+.
5-acetyl-3-benzyl-1-(1-(2-Phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid WO 00/46211 PCT/US00/02998 - __-O
/ O O O
N N
N
H
\ O
/ \
2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene (100 mg, loading 0.5 mmol/g, Novabiochem) was mixed with triethyl orthoformate (1 ml) and 1 M
2-phenylethylamine in 1,2-dichloroethane (1 ml). Nitrogen was bubbled into the resulting slurry for 2 h. The resulting solution was removed by suction, and the resulting resin was treated with 1 M sodium cyanoborohydride in tetrahydrofuran (1 ml) and 1 % acetic acid in N,N-dimethylformamide (1 ml) overnight under nitrogen. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The resulting resin was treated with 0.25 M symmetric anhydride prepared in situ from N-(9-fluorenylmethoxycarbonyl)phenylalanine and 1,3-diisopropylcarbodiimide in 3 ml 1-methyl-2-pyrrolidinone overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 491 (M+H)+.
WO 00/46211 PCT/US00/02998 - __ The resin was treated with piperidine/dimethylformamide (1:1 ) for 3 h, then washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. 1 M benzyl isocyanate in 1,2-dichloroethane (3 ml) was added to the resulting resin. The resulting mixture was agitated for 4h. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 402 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (1 ml) and tetrahydrofuran (1 ml) were added to the obtained resin. The resulting slurry was heated at 50°C
for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane.
1 M solution of Meldrum's acid in 1,2-dichloroethane (3 ml) was added to the resulting resin. The reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 488 (M+H)+.
The resin was swelled in 1 M acetic anhydride/1,2-dichloroethane (3 ml). The resulting mixture was agitated by bubbling of nitrogen overnight.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
WO 00/46211 PCT/US00/02998 - __.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 512 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-propyl-5-(N,N'-diisopropylamidino)barbituric acid HN i N
OH ~ OH
N\ /N
O ~' O
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was treated with 1 M N,N'-diisopropylcarbodiimide in 1-methyl-2-pyrrolidinone under nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 445 (M+H)+.
WO 00/46211 PCT/US00/02998 - _~.
5-acetyl-3-benzyl-1-(1-(2-phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid hydrazone / O O
N N
N
H
O
/ \
5-acetyl-3-benzyl-1-( 1-(2-phenylethylaminocarbonyl)-2-phenyl) ethylbarbituric acid on resin (50 mg) (see Example 11 ) was treated with 0.7 M hydrazine hydrate in 1-methyl-2-pyrrolidinone under nitrogen overnight.
The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 526 (M+H)+.
3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethyl-5,5-bis(phenacyl)bar-N~NH2 O
bituric acid WO 00/46211 PCT/US00/02998 - __ N
3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethylbarbituric acid on the resin (50 mg) was swelled in 1 ml tetrahydrofuran. The suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M 2-bromoacetophenone in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 630 (M+H)+.
It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation-the invention being defined by the claims.
Also, the present invention provides a method of making a support template comprising a compound of Formula 1 as follows:
where:
~ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C1o alkyl, C1-C1o substituted alkyl, C1-C1o substituted alkyl-aryl, C1-C1o substituted alkenyl, and C1-C1o substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C1o alkyloxy, C1-C1o alkyloxy aryl, C1-C1o aminoalkyl, C1-C1o alkylamino, C1-C1o aminoalkyl aryl, C1-C1o aminocarbonyl, C1-C1o aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C1o thioalkyl-aryl, C1-C1o alkylsulfoxide, C1-C1o alkylsulfone, C1-C1o _g_ alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Cio alkyl, C~-Coo alkyl aminocarbonylamino C~-Cep alkyl aryl, C~-Cep alkyloxycarbonyl C~-C10 alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C~0 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C~0 alkyloxycarbonylamino alkyl, C~-C~p alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Cep aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises:
(1 ) coupling a functionalized polymer support ~-x-H with a N-protected alpha-amino acid of Formula A as follows:
Rs N ~O~ H
where R4 and RS are the same or different and are selected from:
_g_ H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R5 with H, and reacting the deprotected resultant with an amine R~~NH2 or an isocyanate R~~NCO under urea-forming reaction conditions to provide a urea-bound solid support resin of Formula 4 as follows:
R3 R ~ ,R11 " H H
O
(3) treating the urea-bound solid support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1.
Hence, it is an object of the invention to provide certain novel solid support templates, chemical libraries produced therewith, and cleaved heterocycle compounds of the libraries.
Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as best described below.
Detailed Description of the Invention WO 00/46211 PCT/US00/02998 - __.
The present invention relates to carbonyl-esters or carbonyl-amides linked to insoluble materials as depicted in Formula 1, and methods for producing chemical libraries generated through a plurality of chemical reactions utilizing support templates of Formula 1.
O~\\~~~~0 O
N~N~R11 Formula 1 where x, R2, R3, R11, X3, and X4 are as defined below.
Optionally, R2 and R3 in Formula 1 may be joined together to form cyclic compounds of Formula 1 a with ring size of 3-8 as follows:
Formula 1 a For instance, the ring system may be selected from:
(a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, WO 00/46211 PCT/US00/02998 - _,_ (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, S02, NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from:
(d) H, (e) mono di- and tri-substituted aryl, and (f) C~-Coo substituted alkyl, C~-Coo -substituted alkyl-aryl C~-Coo substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, vitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Coo thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-Coo alkylsulfonamide, C~-Cep alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~°C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-Coo alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, and C~-Coo alkenyl CONH2, and the like, and where the aryl groups of (e) and (f) are selected from:
WO 00/46211 PCT/US00/02998 - __.
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl, and the like.
Support templates of Formula 1 were synthesized according to Scheme 1 below, x. H
Formula 2 amide-bond R~R ,R5 N
O H formation O H
H. ~N. 5 Formula 3 1 ) Deprotection Formula A
2) (Urea Formation) R~~NH2 or R~~NCO
acid condensation, s R2 O
Formula 1 ~ R~N~N~R11 cyclization O H H
Formula 4 Scheme 1 where x, R2, R3, R5, R", X3, and X4 are as defined below.
In general, Scheme 1 is performed as follows. As represented by ~, a material suitable for a support (which may be any of the polymers suitable for a support, which may be a solid support, as mentioned in the referenced WO 00/46211 PCT/US00/02998 - __.
literature that is described above), functionalized with xH (such as amino, hydroxy, oximo, phenolic, or silyl) where x is a linker (such as NH, O, CHNO, PhO, or SiH2, respectively), provided a functionalized polymer support as shown in Formula 2 (i.e., the functionalized ~ also may be any of the funtionalized polymer supports, which may be solid supports, as mentioned in the referenced literature that is described above), which was then reacted with a N-protected alpha-amino acid of Formula A (defined below and in Provisional U.S. Patent Application Serial No. 60/116,915, which was filed on January 22, 1999 and which is the priority application of International PCT Application No. , which was filed on January 21, 2000) using standard amide bond forming reactions (described below) to create a polymer-bound amide as shown in Formula 3. Deprotection of the amine moiety of Formula 3 using standard conditions, followed by reaction with an amine (R'~NH2) or an isocyanate (R"NCO), under urea-forming standard reaction conditions, provided a urea-bound support resin as shown in Formula 4 (see, Buckman, B. O. et al, Tet. Lett., 1996, Vol. 37, p. 4439).
Reaction of a compound of Formula 4 with an acid, followed by cyclization to achieve ring closure, provided a polymer-bound support template of Formula 1, which may be a polymer-bound solid support template.
More particularly, N-protected alpha-amino acids of Formula A have one or two substituents (R2 and/or R3) at the alpha position and are defined as follows:
RsN~O~H
Formula A
where:
R2 and R3 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C~-Coo alkyl, C~-Coo substituted alkyl, C~-Coo substituted alkyl-aryl, C~-Coo substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, vitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-Coo aminoalkyl aryl, C~-Coo aminocarbonyl, C~-Coo aminocarbonylalkyl-aryl, C~-Cep thioalkyl, C~-Coo thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~-C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-C~o alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Cep alkyl, C~-C10 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C~p alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-C~o alkenyl CONH2, and the like, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like, and where:
R4 and R5 are the same or different and are selected from:
H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and the like.
Optionally, R2 and R3 in Formula A are joined together to form cyclic compounds of Formula Aa with a ring size of 3-8 as follows:
z Rs N~O~ H
Formula Aa For instance, the ring system may be selected from substituted-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds of Formulae Ab and Ac as follows:
R9 Rs R~~ Rs Rip R~ R6 R~
R
R ~N O~H
R5.N O~H i Formula Ab Formula Ac WO 00!46211 PCT/LTS00/02998 selected from substituted- cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula Ad as follows:
Rs R1o R~ Rs RvN O.H
Formula Ad where Rs and R', Rs and R1°, or R9 and R1° may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its substituents are as defined below vis-a-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is O, S, SO, S02, NH, S02NHR8, NCONHR8, NCOOR8, or NR$ inserted in the ring systems as in compounds of Formulae Ae and Af as follows:
Rs Rs R A Rs Rs A R1o R~ R~
R5-N O~ H R5. N O~ H
Formula Ae Formula Af where the substituents R4 and R5 in Formulae Aa-Af are as defined above and where the substituents (Rs, R', R8, R9, and R1°) in Formulae Aa-Af are the same or different and are selected from:
(d) H, (e) mono-, di-, and tri-substituted aryl, and (f) C~-Coo substituted alkyl, C~-Coo substituted alkyl-aryl, C~-C~0 substituted alkenyl, and C~-Coo substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C~-Coo alkyloxy, C~-Coo alkyloxy aryl, C~-Cep aminoalkyl, C~-Coo alkylamino, C~-Cep aminoalkyl aryl, C~-Coo aminocarbonyl, C~-C~0 aminocarbonylalkyl-aryl, C~-Cep thioalkyl, C~-Cep thioalkyl-aryl, C~-Coo alkylsulfoxide, C~-Coo alkylsulfone, C~°C10 alkylsulfonamide, C~-Coo alkylsulfonamide aryl, C~-Coo alkylsulfoxide aryl, C~-Coo alkylsulfone aryl, C~-Coo alkyl, aminocarbonylamino C~-Coo alkyl, C~-C~0 alkyl aminocarbonylamino C~-Coo alkyl aryl, C~-Coo alkyloxycarbonyl C~-Coo alkyl, C~-Coo alkyloxycarbonyl C~-Coo alkyl aryl, C~-Coo carboxyalkyl, C~-C10 carboxyalkyl aryl, C~-Coo carbonylalkyl, C~-Coo carbonylalkyl aryl, C~-C10 alkyloxycarbonylamino alkyl, C~-Coo alkyloxycarbonylamino alkyl aryl, guanidino, C~-Coo aIkyICOOH, C~-Coo aIkyICONH2, C~-Coo alkenyICOOH, C~-Coo alkenyl CONH2, and the like, and where the aryl group of (e) and (f) is selected from:
phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like.
Compounds of Formula A are synthesized according to the following reaction mechanism:
R4NC + NH2-CHR-COOH + R3-CO-R2 convertible isocyanide chiral auxiliary ketone or aldehyde Rs R2 R
R~~ R4~N~N~OR~
where R~ is defined the same o H o as R2 and/or R3 Formula B
1 ) aryl amine cleavage/hydrolysis, R3 R2 including catalytic hydrogenation R ~N~o~H
H O
2) amide cleavage or hydrolysis*, and Formula A
3) amine protection with R5 *It is noted that when proceeding from Formula B to Formula A, 1 ) may be performed prior to 2), 2) may be performed prior to 1 ), or 1 ) and 2) may be performed concurrently.
Reaction of an appropriate aldehyde or ketone (such as but not limited to phenylacetaldehyde or cyclohexanone) with an amino acid/removable chiral auxiliary or salt thereof (such as but not limited to phenyl glycine, i.e., R is phenyl) and an appropriate convertible isocyanide (such as but not limited to R4 is phenyl-, cyclohexenyl-, cyclohexyl-, or t-butyl-) utilizing an appropriate solvent and reaction conditions (such as but not limited to R'OH is methanol, ethanol, or isopropanol, at about -80°C to 220°C) provided compounds of Formula B.
The desired alpha-amino acid of Formula B has a removable amino acid/chiral auxiliary and preferably is selected from compounds where R is WO 00/46211 PCT/US00/02998 - __.
mono, di-, tri-, tetra- or penta-substituted aryl, where the aryl is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, and the substituents are selected from: H, cyano, amino, C~-Coo alkyl, C~-C10 alkyloxy, C~-Coo alkyloxy aryl, C~-Coo aminoalkyl, C~-Coo alkylamino, C~-C10 aminoalkyl aryl, and the like.
Then, after cleavage of both the chiral auxiliary amine and the amide portions, compounds of Formula B provided the corresponding alpha-amino acids and their derivatives of Formula A.
For the attachment of the acid group of Formula A, many reagents are known to be suitable (see, Stewart, J.M. and Young, J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Among the many reagents available are:
dialkylcarbodiimide with an additive such as 1-hydroxybenzotriazole;
especially diispropylcarbodiimide/1-hydroxy-7-azabenzotriazole (DIC/HABT);
benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (HBTU); bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP); and Fmoc amino acid fluorides (see for instance, Carpino, L.A., et al., "9-Fluorenylmethyloxycarbonyl Amino Acid Fluorides, Convenient New Peptide Coupling Reagents Applicable to the Fmoc/Tert-Butyl Strategy for Solution and Solid-Phase Synthesis", J. Am. Chem.Soc., 1990, Vol. 112, pp.
9651-9652). The degree of steric hindrance, reactivity of the amine, and other factors may determine which reagent will be most suitable for a particular substrate, but many of the reagents will give a suitable result for most reactions.
As is conventional, the amine group (NHRS of Formula 3) should stay protected (i.e., R5 should not be H in the group) until it is to be utilized in a reaction sequence. Those skilled in the art will appreciate that any of the wide variety of available amino protecting groups for R5 may be used such as tert-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (CBZ), and the like. The choice of a particular protecting group will depend on the specific nature of the substituents and reactions contemplated. Also, more than one type of protecting group may be necessary at any given point in the synthesis (see, e.g., Green, T. and Wuts, P. G. M., Protective Groups In Organic Synthesis 2"d Ed, Wiley, 1991, and references cited therein).
Last, deprotecting of the amine group (NHRS of Formula 3) was conducted with standard conditions, and then, the resultant was reacted with an amine (R~~NH2) or an isocyanate (R"NCO), where R" is defined the same as R2 and/or R3, to provide the urea-bound support resin (which may be a solid support) of Formula 4, which was then treated with an acid (such as 1,3-dichloropropionic acid, malonic acid, their derivatives, and the like) followed by cyclization in the presence of a condensation reagent (such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, 1,1'-carbonyldiimidazole, and the like) to result in Formula 1.
Support templates of Formula 1 (which may be solid support templates) may be reacted with plurality of chemical transformations followed by cleavage from the support ~ of the desired heterocycle compounds under appropriate conditions (such as by trichloroacetic acid/dichloromethane). Some examples of these transformations provided WO 00/46211 PCT/US00/02998 - -~.
desired heterocycle compounds of Formulae B-J, which are referred to as "libraries" prior to cleavage from the support ~, as shown below in Scheme 2.
R~~HN
NHR~6 R~2 O O O
O O O O O NH O ~ NH
O
N N~ ~~ N N~ » N N~ ~~
HzN~ z R H2N~ z R H2N~~ z R
R R~ R R~ R R
B I J
R~s R~z 'O
O O
~N N
HzN~~~Nz N~R~~ HzN HzN R3 Rz~ ~Rm O
C D E
R~~NN
O
13 O N-Rya O O
~ ~ N N
HzN/\ HzN%~ z ~R~~
R R / \R~
O O
F G H
Scheme 2 WO 00/46211 PCT/US00/02998 - __.
where each of R", R'2, R'3, R14~ R15~ R~s, R~~~ and R'8 is C~-Coo alkyl, C~-Coo aryl, or C~-Coo alkyl-aryl.
For example, reaction of Formula 1 with an acid chloride (R'2COCI, or equivalent) or an alkyl halide (R'2Br, R'2CI, R'2F, or equivalent) using standard conditions followed by cleaving the product from the support (under standard conditions described above) provided compounds of Formula A
and Formula C, respectively, after cleavage from the support.
Moreover, cyclization of Formula B (prior to cleavage from the support) with an amine (where R'2 = R'4-CH-NH-R'$) followed by cleavage provided compounds of Formula H, after cleavage from the support.
On the other hand, reaction of compounds of Formula B (prior to cleavage from the support) with a hydrazine (R'3NHNH2) provided compounds of Formula G, after cleavage from the support.
Also, reaction of Formula 1 with an alpha-halomethyl ketone (R'SCOCH2Br, R'SCOCH2CI, or R'SCOCH2F, or equivalent) provided compounds of Formula E, after cleavage from the support.
Additionally, reaction of Formula E (prior to cleavage from the support) with a hydrazine (R'3NHNH2) provided compounds of Formula D, after cleavage from the support.
When R' in Formula B was -CH(CH2NHR")NHR's, compounds of Formula F were obtained, after cleavage from the support.
Furthermore, selective amine deprotection (R's, R") of Formula F
and cyclization provided compounds of Formula I and Formula J, after cleavage from the support.
WO 00/46211 PCT/US00/02998 - _~.
It is noted that in Formulae B through J, linker x was amine resulting in the pendent moiety NH2; however, if linker x was O, for instance, the result would be the pendent moiety OH.
Laboratory Examples General Methods of Synthesis:
Compounds of Formula 1 were prepared according to the general process outlined below in Scheme 1.
~H +
x O
H
Formula 2 x%'~N~RS
O ~ R3 R2 H
N
HO ~R5 Formula 3 Formula A
Formula 1 O ~ O
/~~H II
x N O ~~~N O
/\x R3 R2 HN ~ g R2~
R
N
~R~ ~ ~R11 Formula 4 X1--~~O
O
Formula 5 Scheme 1 More specifically, a N-protected alpha-amino acid of Formula A
(defined as above) was attached to the solid support of Formula 2 (described above) in the presence of a coupling reagent such as N,N'-WO 00/46211 PCT/US00/02998 - __.
diisopropylcarbodiimide to produce compounds of Formula 3. Deprotection of the amino moiety in standard conditions, followed by reaction with either an isocyanate (R~~NCO) or 4-nitrophenyl chloroformate and a primary amine (R~~NH2), provided a urea-bound solid support resin of Formula 4.
Compounds of Formula 1 were obtained by condensation of Formula 4 with a malonic acid derivative of Formula 6.
O O
I
X~ X2 Formula 6 where X~ = halogen, hydroxy, alkoxy, acyloxy;
X2 = halogen, alkoxy, or acyloxy; and preferably, X~ + X2 = OC(CH3)2O
to provide an intermediate compound of Formula 5. In carrying out the condensation, either reactivity of the amide nitrogen in Formula 4 is enhanced by treatment with N,O-bis(trimethylsilyl)acetamide or instead the carbonyl moiety in Formula 6 is activated by formation of chloroanhydrides, mixed anhydrides, or active esters. Ring closure occurs via an intermediate compound of Formula 5, which may be isolated, if desired. Compounds of Formula 5 were cyclized in the presence of a condensation reagent, such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1,1'-carbonyldiimidazole, to provide compounds of Formula 1.
Compounds of Formula 1 underwent a variety of chemical transformations and cleavage of the library from ~, to yield diverse derivatives, i.e., the desired heterocycle compounds, of Formula 7 O O
O
x N~N~R~~
H Rs R2 lfO
Formula 7 where x = O; R2, R3, and R'~ are as defined above;
X3 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine;
X4 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine;
and when both X3 and X4 are not H, preferably X3 + X4 = carbocycle or heterocycle.
More specifically, provided were the following acids of Formula 7 as per EXAMPLES 1-12 below.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid O H \~~O
N\ /N
O ~' O
N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, Wang resin supplied by NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was then added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 251 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)phenylalanine on Wang resin.
The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
WO 00/46211 PCT/US00/02998 - __.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 337 (M+H)+.
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 319 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-(4-methylbenzyl)barbituric acid O HO~~~O
N\ /N
O ~' \ O
/ \
N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h.
The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The WO 00/46211 PCT/US00/02998 - __.
resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min.
The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). 4-methylbenzylamine (0.656 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 313 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-((4-methylbenzyl)carbamoyl)phenylalanine on Wang resin. The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 399 (M+H)+.
N-(carboxymethylcarbonyl)-N-((4-methylbenzyl)carbamoyl)phenylala-nine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2 dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The resulting product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 381 (M+H)+.
1-(1-carboxy)ethyl-3-propylbarbituric acid OHO~~~~O
N\ /N
O' O
N-Fmoc-alanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1:1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol), and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol).
WO 00/46211 PCT/US00l02998 - __.
Propylamine (0.411 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 175 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)alanine on Wang resin. The resulting slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane. 1 M solution of Meldrum's acid in 1,2 dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1 ) for LC/MS analysis: m/z 261 (M+H)+.
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)alanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 1-(1-Carboxy)ethyl-3-propylbarbituric acid was cleaved from the WO 00/46211 PCT/US00/02998 - __.
dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for h. LC/MS analysis: m/z 243 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid OH ~~~~0 N\ /N
O ~' O
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was swelled in 1 ml of 1 M solution of 1,1'-carbonyldiimidazole in 1,2-dichloroethane. The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 319 (M+H)+.
5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid \i OHO~~~'~~O
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml tetrahydrofuran. The resulting suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M benzyl bromide in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 499 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-propionyl-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __.
O
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M propionyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of propionyl chloride were combined.
The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 375 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-(2-butenoyl)-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __.
O
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M crotonyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of crotonyl chloride were combined. The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 387 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-5-(3-phenyl-2-((9-fluorenylmethoxycarbonyl) amino)pro-pionyl)-3-propylbarbituric acid O
O
~N
H
O O
OH
N\ /N
O ~' O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N-(9-fluorenylmethoxycarbo-nyl)phenylalanine and 1,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 688 (M+H)+.
5-(2-amino-3-((9-fluorenylmethoxycarbonyl)amino)propionyl)-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid WO 00/46211 PCT/US00/02998 - __ H
O N\ /O
O O ~O
OH
N\ /N
O' ~ -O
1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N"-(tent-butyloxycarbonyl)-N~'-(9-fluorenylmethoxycarbonyl)propionic acid and 1,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 627 (M+H)+.
5-acetyl-3-benzyl-1-(1-(2-Phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid WO 00/46211 PCT/US00/02998 - __-O
/ O O O
N N
N
H
\ O
/ \
2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene (100 mg, loading 0.5 mmol/g, Novabiochem) was mixed with triethyl orthoformate (1 ml) and 1 M
2-phenylethylamine in 1,2-dichloroethane (1 ml). Nitrogen was bubbled into the resulting slurry for 2 h. The resulting solution was removed by suction, and the resulting resin was treated with 1 M sodium cyanoborohydride in tetrahydrofuran (1 ml) and 1 % acetic acid in N,N-dimethylformamide (1 ml) overnight under nitrogen. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The resulting resin was treated with 0.25 M symmetric anhydride prepared in situ from N-(9-fluorenylmethoxycarbonyl)phenylalanine and 1,3-diisopropylcarbodiimide in 3 ml 1-methyl-2-pyrrolidinone overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 491 (M+H)+.
WO 00/46211 PCT/US00/02998 - __ The resin was treated with piperidine/dimethylformamide (1:1 ) for 3 h, then washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. 1 M benzyl isocyanate in 1,2-dichloroethane (3 ml) was added to the resulting resin. The resulting mixture was agitated for 4h. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 402 (M+H)+.
N,O-bis(trimethylsilyl)acetamide (1 ml) and tetrahydrofuran (1 ml) were added to the obtained resin. The resulting slurry was heated at 50°C
for 5 h. The resulting resin was filtered and washed with 1,2-dichloroethane.
1 M solution of Meldrum's acid in 1,2-dichloroethane (3 ml) was added to the resulting resin. The reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 488 (M+H)+.
The resin was swelled in 1 M acetic anhydride/1,2-dichloroethane (3 ml). The resulting mixture was agitated by bubbling of nitrogen overnight.
The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
WO 00/46211 PCT/US00/02998 - __.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 512 (M+H)+.
1-(1-carboxy-2-phenyl)ethyl-3-propyl-5-(N,N'-diisopropylamidino)barbituric acid HN i N
OH ~ OH
N\ /N
O ~' O
N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was treated with 1 M N,N'-diisopropylcarbodiimide in 1-methyl-2-pyrrolidinone under nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 445 (M+H)+.
WO 00/46211 PCT/US00/02998 - _~.
5-acetyl-3-benzyl-1-(1-(2-phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid hydrazone / O O
N N
N
H
O
/ \
5-acetyl-3-benzyl-1-( 1-(2-phenylethylaminocarbonyl)-2-phenyl) ethylbarbituric acid on resin (50 mg) (see Example 11 ) was treated with 0.7 M hydrazine hydrate in 1-methyl-2-pyrrolidinone under nitrogen overnight.
The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 526 (M+H)+.
3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethyl-5,5-bis(phenacyl)bar-N~NH2 O
bituric acid WO 00/46211 PCT/US00/02998 - __ N
3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethylbarbituric acid on the resin (50 mg) was swelled in 1 ml tetrahydrofuran. The suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M 2-bromoacetophenone in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum.
The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS
analysis: m/z 630 (M+H)+.
It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation-the invention being defined by the claims.
Claims (16)
1. A support template comprising a compound of Formula 1 as follows:
where:
.cndot. of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, C1-C10 alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine.
where:
.cndot. of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, C1-C10 alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine.
2. The support template of claim 1, where linker x is selected from NH, O, CHNO, PhO, and SiH2.
3. The solid support template of claim 1, where the groups R2 and R3 are joined together to form cyclic compounds with a ring system as represented by Formula 1a where the ring system has a ring size of 3 to 8 members.
4. The support template of claim 3, where the ring system is selected from:
(a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, SO2, NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from:
(d) H, (e) mono di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, and C1-C10 alkenyl CONH2, and where the aryl groups of (e) and (f) are selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.
(a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, SO2, NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from:
(d) H, (e) mono di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, and C1-C10 alkenyl CONH2, and where the aryl groups of (e) and (f) are selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.
5. The chemical library cleaved from the support .cndot. of the template of claim 1, whereby .cndot. is replaced with H.
6. The cleaved chemical library of claim 5, comprising a compound selected from:
and
and
7. The cleaved chemical library of claim 5, comprising a compound selected from:
8. A method of making a support template comprising a compound of Formula 1 as follows:
where:
.cndot. of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, C1-C10 alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises:
(1) coupling a functionalized support .cndot.-x-H with a N-protected alpha-amino acid of Formula A as follows:
where R4 and R5 are the same or different and are selected from:
H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R5 with H, and reacting the deprotected resultant with an amine R11NH2 or an isocyanate R11NCO under urea-forming reaction conditions to provide a urea-bound support resin of Formula 4 as follows:
(3) treating the urea-bound support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1.
where:
.cndot. of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where:
R2, R3, and R11 are the same or different and are selected from:
(a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, C1-C10 alkenyl CONH2, and where the aryl group of (b) and (c) is selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X3 and X4 are the same or different and are selected from:
H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises:
(1) coupling a functionalized support .cndot.-x-H with a N-protected alpha-amino acid of Formula A as follows:
where R4 and R5 are the same or different and are selected from:
H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R5 with H, and reacting the deprotected resultant with an amine R11NH2 or an isocyanate R11NCO under urea-forming reaction conditions to provide a urea-bound support resin of Formula 4 as follows:
(3) treating the urea-bound support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1.
9. The method of claim 8, where linker x is selected from NH, O.
CHNO, PhO, and SiH2.
CHNO, PhO, and SiH2.
10. The method of claim 8, where the groups R2 and R3 are joined together to form cyclic compounds with a ring system as represented by Formula 1a where the ring system has a ring size of 3 to 8 members.
11. The method of claim 10, where the ring system is selected from:
(a) mono-, di- tri- or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di- tri- or tetra-substituted cyclopropyl, cyclobuteynyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di- tri- or tetra-substituted heterocyclic ring system, where O, S, SO, SO2, NH, or substituted N is inserted in the ring system, where the substituents in (a), (b), and (c) are selected from:
(d) H, (e) non di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, wherein the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, and C1-C10 alkenyl CONH2, and where the aryl groups of (e) and (f) are selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.
(a) mono-, di- tri- or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di- tri- or tetra-substituted cyclopropyl, cyclobuteynyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di- tri- or tetra-substituted heterocyclic ring system, where O, S, SO, SO2, NH, or substituted N is inserted in the ring system, where the substituents in (a), (b), and (c) are selected from:
(d) H, (e) non di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl C1-C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, wherein the substituents of (e) and (f) are selected from:
H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, C1-C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH2, C1-C10 alkenylCOOH, and C1-C10 alkenyl CONH2, and where the aryl groups of (e) and (f) are selected from:
phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.
12. The method of claim 8, where in step (3), the acid is selected from 1,3-dichloropropionic acid, malonic acid, and their derivatives.
13. The method of claim 8, where in step (3), cyclization is conducted in the presence of a condensation reagent selected from acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, and 1,1'-carbonyldiimidazole.
14. The method of claim 8, further including:
(a) cleaving the chemical library from the support .cndot. of the template, whereby .cndot. is replaced with H.
(a) cleaving the chemical library from the support .cndot. of the template, whereby .cndot. is replaced with H.
15. The method of claim 14, wherein the cleaved chemical library comprises a compound selected from:
16. The method of claim 14, wherein the cleaved chemical library comprises a compound selected from:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11854799P | 1999-02-04 | 1999-02-04 | |
| US60/118,547 | 1999-02-04 | ||
| PCT/US2000/002998 WO2000046211A1 (en) | 1999-02-04 | 2000-02-04 | Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2362085A1 true CA2362085A1 (en) | 2000-08-10 |
Family
ID=22379282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002362085A Abandoned CA2362085A1 (en) | 1999-02-04 | 2000-02-04 | Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1155002A4 (en) |
| JP (1) | JP2002536368A (en) |
| AU (1) | AU3223200A (en) |
| CA (1) | CA2362085A1 (en) |
| MX (1) | MXPA01007869A (en) |
| WO (1) | WO2000046211A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3247127A (en) * | 1960-04-14 | 1966-04-19 | Eastman Kodak Co | Light-absorbing water-permeable colloid layer containing an oxonol dye |
| US4833148A (en) * | 1987-04-09 | 1989-05-23 | Washington University | Method of using alkenyl- or alkynyl-substituted thiobarbiturates to reduce neurotoxic injury |
| US4971889A (en) * | 1988-09-01 | 1990-11-20 | Fuji Photo Film Co., Ltd. | Silver halide photographic emulsions |
| WO1991010165A1 (en) * | 1989-12-22 | 1991-07-11 | Eastman Kodak Company | Improved performance of photographic emulsions at high silver ion activities |
| JPH05249593A (en) * | 1992-03-04 | 1993-09-28 | Konica Corp | Silver halide photographic sensitive material |
| JPH07276810A (en) * | 1994-04-04 | 1995-10-24 | Fuji Photo Film Co Ltd | Diazo thermal recording material |
-
2000
- 2000-02-04 AU AU32232/00A patent/AU3223200A/en not_active Abandoned
- 2000-02-04 CA CA002362085A patent/CA2362085A1/en not_active Abandoned
- 2000-02-04 JP JP2000597281A patent/JP2002536368A/en active Pending
- 2000-02-04 WO PCT/US2000/002998 patent/WO2000046211A1/en not_active Application Discontinuation
- 2000-02-04 MX MXPA01007869A patent/MXPA01007869A/en not_active Application Discontinuation
- 2000-02-04 EP EP00910081A patent/EP1155002A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
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| EP1155002A4 (en) | 2003-03-19 |
| EP1155002A1 (en) | 2001-11-21 |
| AU3223200A (en) | 2000-08-25 |
| MXPA01007869A (en) | 2003-06-04 |
| JP2002536368A (en) | 2002-10-29 |
| WO2000046211A1 (en) | 2000-08-10 |
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