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WO1996033972A1 - Procedes de synthese de divers ensembles de pyridines, pyrimidines, derives 1,4-dihydro de ces composes et derives de piperidine - Google Patents

Procedes de synthese de divers ensembles de pyridines, pyrimidines, derives 1,4-dihydro de ces composes et derives de piperidine Download PDF

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Publication number
WO1996033972A1
WO1996033972A1 PCT/US1996/005956 US9605956W WO9633972A1 WO 1996033972 A1 WO1996033972 A1 WO 1996033972A1 US 9605956 W US9605956 W US 9605956W WO 9633972 A1 WO9633972 A1 WO 9633972A1
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group
carbon atoms
compound
dihydropyridine
dihydropyrimidine
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PCT/US1996/005956
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English (en)
Inventor
Mikhail F. Gordeev
Dinesh V. Patel
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Glaxo Group Limited
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Priority to AU59180/96A priority Critical patent/AU5918096A/en
Publication of WO1996033972A1 publication Critical patent/WO1996033972A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/82—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • 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
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • This invention is directed to methods for synthesizing very large
  • This invention is further directed to methods for identifying and isolating 1,4-dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine and piperidine
  • This invention is still further directed to the incorporation of identification tags in such collections to facilitate identification of compounds with desired properties.
  • Compounds having biological activity can be identified by screening diverse collections of compounds (i.e. , libraries of compounds) produced through either molecular biological or synthetic chemical techniques. Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity 1,2 or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels. Correlation of the labelled receptor bound to the substrate with its location on the substrate identifies the binding compound. 3
  • the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm.
  • libraries of diverse compounds are prepared and can be screened either on the solid support or as cleaved products to identify "lead compounds" having good biological activity.
  • 1,4-dihydropyridine 1,4-dihydropyrimidine
  • pyridine 1,4-dihydropyrimidine
  • piperidine compounds 1,4- dihydropyridines are the largest class of organic calcium channel modulators having therapeutic utility in the treatment of cardiac
  • Such compounds typically contain an aryl or substituted aryl functionality at the 4 position of the 1 ,4-dihydropyridine, however, 4- heterocyclic and 4-alkyl substituents also have been reported as possessing calcium channel modulating activity.
  • 1,4-dihydropyridines are employed extensively as biological tools for studies of voltage-activated calcium channel structure and function 8 , and 4-heterocyclic substituents of 1,4-dihydropyridine compounds have been disclosed for use as liver protecting agents.
  • 9.10 4- Alkyl and 4-aryl-1,4-dihydropyridines have also been disclosed as inhibiting platelet aggregation including, for example, platelet aggregation induced by PAF-acether (1-0-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3- phosphorylcholine)" and platelet aggregation induced by B16 amelanotic melanoma.
  • 1,4-dihydropyridines such as pyrido[2,3-d]pyrimidines have also been shown to possess antihypertensive activity.
  • Other disclosed and/or potential biological activities for 1,4-dihydropyridines include antioxidant, antitumor, antimutagenic, geroprotective, anti- atherosclerotic, antifungal, antiviral, antibacterial, bronchodilating, and antidiabetic activity.
  • 1,4-Dihydropyrimidine compounds have been shown to mimic the biological effect of 1,4-dihydropyridines including calcium channel blocking activity and possess vasorelaxant and antihypertensive
  • Pyridine compounds have been disclosed as inhibiting release of myeloperoxidase from polymorphonuclear leukocytes (PMN) which, in turn, is theorized to modulate the tissue destructive nature of adult respiratory distress syndrome. 25 Such compounds as well as pyrimidine structures have also been disclosed as possessing anticonvulsant activity in mice 24 . Additionally, pyridine compounds have been disclosed as possessing zinc chelating properties which can inhibit the binding of HIV-
  • Pyrimidine derivatives have also been disclosed as inhibiting human leukocyte elastase thereby providing useful therapy in disease conditions where elastase activity is ineffectively controlled by endogenous
  • This invention is directed to synthetic methods for incorporating a 1,4-dihydropyridine, a 1,4-dihydropyrimidine, a pyridine, a pyrimidine or a piperidine group onto a solid support which methods can be employed in conjunction with known stochastic methods for preparing libraries of compounds comprising one or more such groups.
  • Solid supports containing such 1,4-dihydropyridine, 1,4-dihydro- pyrimidine, pyridine, pyrimidine or piperidine groups preferably comprise a linking arm which links the solid support to the group.
  • the linking arm can be either cleavable or non-cleavable and when cleavable, can be used to prepare a library of soluble 1,4-dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine or piperidine compounds.
  • the library of such compounds whether soluble or insoluble, can be screened to isolate individual compounds that possess some desired biological activity. In a preferred embodiment, each compound in the library is unique.
  • 1,4- dihydropyridine groups, 1,4-dihydropyrimidine, pyridine, pyrimidine or piperidine groups covalently attached to a solid support are prepared by providing for a Knoevenagel condensation product of an aldehyde and a compound selected from a - ⁇ -keto ester, a ⁇ -keto amide and a ⁇ -diketone and contacting this Knoevenagel condensation product with either an enamino compound under conditions effective to provide for the 1,4- dihydropyridine group or with an amidine compound under conditions effective to provide for the 1,4-dihydropyrimidine group wherein the Knoevenagel condensation product or the enamino/amidine compound is covalently attached to a solid support and further wherein the 1,4- dihydropyridine or 1,4-dihydropyrimidine group is optionally oxidized to a pyridine or a pyrimidine group respectively or the 1,4-dihydro
  • Preferred enamino compounds are represented by the formula:
  • R is selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms
  • R 1 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and 1 to 5 halo atoms, thioalkyl of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms; and
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro, and -PO(NR 3 R 4 ) 2 , -PO(OR 12 ) 2
  • R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N- dialkylalkamino of from 3 to 12 carbon atoms, R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, and R 12 is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalky
  • alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N.N-dialkylalkamino of from 3 to 12 carbon atoms,
  • the enamino compound is covalently attached to a compatible solid support via the R, R 1 or X substituent.
  • the Knoevenagel condensation product is formed by contacting an alkyl or aromatic aldehyde with a compound selected from a ⁇ -keto ester, a ⁇ -keto amide and a ⁇ -diketone where optionally the keto group is masked under conditions which effect condensation.
  • Preferred Knoevenagel condensation products are represented by the formula:
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms or an aryl group of from 6 to 10 carbon atoms,
  • R 6 is alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, carboxyl and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and
  • Y is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and optionally Y and R 5 are joined to form a cyclic or heterocylic structure fused to the 1,4-dihydropyridine ring which structure contains from 2 to 6 carbon atoms and optionally from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur
  • the condensation product is covalently attached to a compatible solid suppo ⁇ via the Y or R 6 substituent.
  • the Knoevenagel condensation product is formed in the presence of the enamino compound so that upon condensation, it in situ reacts with the enamino compound to provide for a 1,4-dihydropyridine group.
  • Preferred amidine compounds include 2-aminoimidazoles, (2- amino)arylimidazoles and compounds represented by the formula:
  • R 9 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms optionally substituted with from 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, carboxyl, and -C(O)NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents selected from halogen, hydroxy, nitro, cyano, alkyl of from 1 to 6 carbon atoms and alkoxy of from 1 to 6 carbon atoms, alkaryl of from 7 to 12 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl ring which substituents
  • Z is selected from the group consisting of O, NH and S.
  • the amidine compound is covalently linked to a compatible solid support via the imidazole ring or the Z substituent.
  • the amidine compounds described above can be reacted directly with a ⁇ -diketone to provide for pyrimidine libraries without the need for oxidation.
  • either the ⁇ -diketone or the amidine compound is attached to a solid support.
  • the solid supports prepared in the methods described above can be used, for example, in creating libraries of compounds in the manner described in International Patent Application Publication No. WO
  • this invention is directed to a library of diverse 1,4-dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine or piperidine structures comprising a plurality of solid supports having a plurality of covalently bound 1,4-dihydropyridine, 1,4- dihydropyrimidine, pyridine, pyrimidine or piperidine groups wherein the 1,4-dihydropyridine, the 1,4-dihydropyrimidine, the pyridine, the pyrimidine, or the piperidine group bound to each of the supports is substantially homogeneous and further wherein each compound bound on one support is different from the compounds bound on the other supports.
  • the library described herein contains on the solid supports a surface bound tag which identifies the molecule attached thereto.
  • This invention is also directed to methods for preparing a synthetic 1,4-dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine or piperidine compound library produced by synthesizing on each of a plurality of solid supports a single compound wherein each compound comprises either a 1,4-dihydropyridine group, a 1,4-dihydropyrimidine group, a pyridine group, a pyrimidine or a piperidine group, which library is synthesized in a process comprising:
  • a) apportioning the supports comprising a covalently bound Knoevenagel condensation product or a covalently bound compound selected from the group consisting of an enamino group or an amidine group among a plurality of reaction vessels, and
  • 1,4-dihydropyridine or the 1,4-dihydropyrimidine groups are optionally oxidized to pyridine and pyrimidine groups respectively or the 1,4-dihydropyridine group is optionally reduced to a piperidine group.
  • 1,4-dihydropyridine compounds bound to a solid support are prepared by contacting the Knoevenagel condensation product with an enamino compound wherein either the condensation product or the enamino compound is covalently attached to a solid support.
  • 1,4-dihydropyrimidine compounds bound to a solid support are prepared by contacting the Knoevenagel condensation product with an amidine compound wherein either the condensation product or the amidine compound is covalently attached to a solid support.
  • This invention is still further directed to a method for preparing a synthetic 1,4-dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine or piperidine compound library which library is synthesized in a process comprising:
  • apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels
  • the adduct prepared in procedure f) is separated from the support and then cyclized to either the 1,4-dihydropyridine compound or the 1,4-dihydropyrimidine compound.
  • the 1,4-dihydropyridine group or the 1,4- dihydropyrimidine group is first cyclized on the solid support and then optionally separated from the support to provide for soluble 1,4- dihydropyridine and 1,4-dihydropyrimidine compounds.
  • this invention is directed to a method for preparing a synthetic 1,4-dihydropyridine, pyridine or piperidine compound library which library is synthesized in a process comprising: a) apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels,
  • condensation product and the enamino group form an adduct
  • this invention is directed to a method for preparing a synthetic 1,4-dihydropyrimidine or pyrimidine compound library which library is synthesized in a process comprising: a) apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels, b) combining into each reaction vessel a different amidine group or an amidine precursor group such that the amidine group or the amidine precursor group becomes covalently attached to the linking arm through the amino or hydroxyl functionality wherein, in the case of the amidine precursor groups, the attachment converts the amidine precursor group to an amidine group,
  • condensation product and the amidine group form an adduct
  • FIG. 1 illustrates one means for the covalent attachment of keto esters on solid supports.
  • FIG. 1 also illustrates conversion of the resin bound keto ester to 3-methyl-3-pyrazoline-5-one as a basis to determine the loading efficiency of the keto ester to the resin.
  • FIG. 2 illustrates the solid phase synthesis of 1,4-dihydropyridine compounds attached to a Wang solid support via the 3-carboxyl group of the 1,4-dihydropyridine and subsequent oxidation of the 1,4-dihydro- pyridine compound to the pyridine compound.
  • FIG. 3 illustrates the preparation of 1,4-dihydropyridine compounds via a solid support prepared using an N-immobilized enamino ester.
  • FIG. 4 illustrates the solid phase synthesis of 1,4-dihydropyrimidine compounds on a solid support via the 3-carboxyl group of the 1,4-dihydro- pyrimidine and subsequent separation of these compounds from the solid support to provide for a solution phase library of these compounds.
  • FIG. 5 illustrates the preparation of a library of 1,4-dihydropyridine compounds via the use of solid phase tethered enamino compounds.
  • FIG. 6 illustrates the synthesis of a library of pyrimidine compounds from amidine compounds tethered to a solid support and ⁇ -diketones.
  • FIG. 7 illustrates the use of an amino acid bound to a solid support to effect solid phase synthesis of dihydropyridines.
  • FIG. 8 illustrates that the use of 2-aminouracil in place of an enamino compound leads to the solid phase synthesis of pyrido[2,3- d]pyrimidine compounds.
  • FIG. 9 is a synthetic scheme for preparing immobilized keto esters.
  • FIG. 10 illustrates the guanylation reactions on solid phase amino acids.
  • FIG. 11 illustrates the solid phase synthesis of nicotinic acids and pyrido[2,3-d]pyrimidines.
  • This invention is directed to synthetic methods for preparing 1,4- dihydropyridine, 1,4-dihydropyrimidine, pyridine, pyrimidine and piperidine compounds on solid supports and the use of these methods to incorporate such compounds into large synthetic compound libraries.
  • calcium antagonist or “calcium channel blocker” refers to a compound that alters the cellular function of calcium by inhibiting calcium entry into a cell and/or calcium release from a cell and/or interfering with one or more intracellular actions of calcium.
  • calcium agonist refers to a compound that increases the amount of calcium entering or releasing from a cell.
  • calcium modulators refers to those compounds which are either calcium agonists or antagonists.
  • substrate or “solid support” refers to a material having a rigid or semi-rigid surface which contains or can be derivatized to contain reactive functionality which covalently links a compound to the surface thereof.
  • materials are well known in the art and include, by way of example, silicon dioxide supports containing reactive Si-OH groups, polyacrylamide supports, polystyrene supports, polyethyleneglycol supports, and the like.
  • Such supports will preferably take the form of small beads, pellets, disks, or other conventional forms, although other forms may be used.
  • at least one surface of the substrate will be substantially flat.
  • the ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone compound employed is not critical but preferably has no more than about 20 carbon atoms.
  • ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone compounds are represented by the formula:
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms or an aryl group of from 6 to 10 carbon atoms
  • Y is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, -NR 3 R 4 where R 3 and R4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and optionally Y and R 5 are joined to form a cyclic or heterocylic structure fused to the 1,4-dihydropyridine ring which structure contains from 2 to 6 carbon atoms and optionally from 1 to 3 hetereo atoms selected from oxygen, nitrogen and sulfur
  • condensation product is covalently attached to a compatible solid support via the Y substituent.
  • Knoevenagel condensation product refers to the condensation product formed between an aldehyde and a ⁇ -keto ester, a ⁇ -keto amide, or a ⁇ -diketone. Condensation of the aldehyde with such ⁇ -keto compounds results in the formation of unsaturation at the carbon atom intermediate between the ⁇ -keto functionality and the ester, amide or ketone functionalities.
  • Knoevenagel condensation products are known per se in the art and the particular product employed is not critical.
  • the aldehyde employed to prepare the Knoevenagel condensation product is not critical and can be an aromatic, heterocyclic or alkyl aldehyde preferably having no more than 20 carbon atoms.
  • Knoevenagel condensation products are represented by the formula:
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms or an aryl group of from 6 to 10 carbon atoms,
  • R 6 is an alkyl group of from 1 to 6 carbon atoms, an aryl group of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, and carboxyl, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and
  • Y is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and optionally Y and R 5 are joined to form a cyclic or heterocylic structure fused to the 1,4-dihydropyridine ring which structure contains from 2 to 6 carbon atoms and optionally from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur still further wherein, optionally, the condensation product is covalently attached to a compatible solid support via the Y or R 6 substituent.
  • amino compound group or functionality
  • R 1 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and 1 to 5 halo atoms, thioalkyl of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms; and
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro, and -PO(NR 3 R 4 )2 -PO(OR 12 ) 2
  • R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N- dialkylalkamino of from 3 to 12 carbon atoms, R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, and R 12 is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of
  • the enamino compound is covalently attached to a compatible solid support via the R, R 1 or X substituent.
  • amidine compound refers to those compounds, groups and functionalities having an amidine moiety which is reactive with Knoevenagel condensation products to form 1,4- dihydropyrimidine compounds.
  • Compounds comprising an amidine moiety are known per se in the art and the particular compound employed is not critical.
  • Preferred amidine compounds include 2-aminoimidazoles, (2- amino)arylimidazoles of 6 to 10 carbon atoms in the aryl group, 2- aminoarylimidazoles of 6 to 10 carbon atoms in the aryl group (e.g., benzimidazoles) and compounds represented by the formula:
  • R 9 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms optionally substituted with from 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, carboxyl, and -C(O)NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents selected from halogen, hydroxy, nitro, cyano, alkyl of from 1 to 6 carbon atoms and alkoxy of from 1 to 6 carbon atoms, alkaryl of from 7 to 12 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl ring which substituents
  • Z is selected from the group consisting of O, NH and S.
  • amidine compound is covalently linked to a compatible solid support via the imidazole ring or the Z substituent.
  • Linking arms are well known in the art and include, by way of example only, conventional linking arms such as those comprising ester, amide, carbamate, ether, thioether, urea, amine and the like linking groups.
  • the linking group is formed by coupling complementary reactive groups found on the linking arm and the compound to be attached.
  • an amide linking group can be formed by reacting an amine functionality on the linking arm with an carboxylic acid or ester functionality on the compound to be linked.
  • an ester linking arm can be formed by reacting a hydroxyl functionality on the linking arm with an carboxylic acid or ester functionality on the compound to be linked.
  • the linking arm can be cleavable or non-cleavable.
  • “Cleavable linking arms” refer to linking arms wherein at least one of the covalent bonds of the linking arm which attaches the compound comprising the 1,4- dihydropyridine, the 1,4-dihydropyrimidine group, the pyridine group or the pyrimidine group to the solid support can be readily broken by specific chemical reactions thereby providing for such compounds free of the solid support ("soluble compounds").
  • the chemical reactions employed to break the covalent bond of the linking arm are selected so as to be specific for bond breakage thereby preventing unintended reactions occurring elsewhere on the compound.
  • the cleavable linking arm is selected relative to the synthesis of the compounds to be formed on the solid support so as to prevent premature cleavage of this compound from the solid support as well as not to interfere with any of the procedures employed during compound synthesis on the support.
  • Suitable cleavable linking arms are well known in the art and include photolabile linking arms such as those disclosed in U.S. Patent No. 5,143,854 and the commercially available Rink resin with 4-[(2',4'- dimethoxyphenyl)-aminomethyl]phenoxy linking arms which is a super acid-labile linking arm.
  • Non-cleavable linking arms refer to linking arms wherein the covalent bond(s) linking the 1,4-dihydropyridine, the 1,4-dihydropyrimi- dine, the pyridine and the pyrimidine group to the solid support can only be cleaved under conditions which chemically alters unintended parts of the structure of the compound attached thereto.
  • the .term " 1.4-dihydropyridine” refers to compounds having the base or core structure of
  • Substituents to the 1,4-dihydropyridine group can occur at any of the 1, 2, 3, 4, 5 and 6 positions thereof including the nitrogen atom in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of 1,4- dihydropyridine compounds.
  • 1,4-dihydropyridine compounds (or groups) have the formula
  • R is selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms
  • R 1 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and 1 to 5 halo atoms, thioalkyl of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms;
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms or an aryl group of from 6 to 10 carbon atoms,
  • R 6 is alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atom, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and carboxyl, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen,
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro, -PO(NR 3 R 4 ) 2 and -PO(OR 12 ) 2
  • R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N- dialkylalkamino of from 3 to 12 carbon atoms, R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, R 12 is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of from
  • 1,4-dihydropyridine is optionally attached to a solid support through the R, R 6 , Y or X substituent.
  • pyridine refers to compounds having the base or core structure of
  • Substituents to the pyridine group can occur at any of the 2, 3, 4, 5 and 6 positions thereof in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of pyridine compounds.
  • the pyridine compounds (or groups) have the formula
  • R 1 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and 1 to 5 halo atoms, thioalkyl of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms,
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms or an aryl group of from 6 to 10 carbon atoms,
  • R 6 is alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and carboxyl, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen,
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro, -PO(NR 3 R 4 ) and -PO(OR 12 ) 2
  • R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N- dialkylalkamino of from 3 to 12 carbon atoms, R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, R 12 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and
  • Y is selected from the group consisting of alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and optionally Y and R 5 are joined to form a cyclic or heterocylic structure fused to the 1,4-dihydropyridine ring which structure contains from 3 to 6 carbon atoms and optionally from 1 to 3 hetereo atoms selected from oxygen, nitrogen and sulfur,
  • pyridine is optionally attached to a solid support through the R 6 , Y or X substituent.
  • a heterocylic structure fused to the 1,4-dihydropyridine ring refers to structures as set forth above wherein Y and R 5 or X and R 1 are joined to form a heterocyclic ring structure which, with the carbon atoms of the 1,4-dihydropyridine structure, contains from 3 to 6 carbon atoms and 1 to 3 hetero atoms.
  • lower alkyl refers to straight and branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, 2-methylpentyl, and the like.
  • lower alkoxy refers to straight and branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,
  • alkalkoxy refers to substituents of the general formula
  • alkalkoxy groups have from 2 to 8 carbon atoms and from 1 to 3 ether oxygens.
  • alkamino refers to substituents of the general formula
  • R 10 is an alkylene group of from 1 to 6 carbon atoms.
  • N-alkylalkamino refers to substituents of the general formula -R 10 NHR 11 where R 10 is an alkylene group of from 1 to 6 carbon atoms and R" is an alkyl group of from 1 to 6 carbon atoms.
  • N,N-dialkylalkamino refers to substituents of the general formula -R 10 N(R"), where R 10 is an alkylene group of from 1 to 6 carbon atoms and each R 11 is independently an alkyl group of from 1 to 6 carbon atoms.
  • heterocyclic group refers to well known cyclic groups containing from 2 to 6 carbon atoms and 1 to 3 hetereoatoms selected from nitrogen, oxygen and sulfur.
  • groups include, by way of example, furazanyl, furyl, imidazolidinyl, imidazolyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g. morpholino), oxazolyl, piperazinyl (e.g. 1- piperazinyl), piperidyl (e.g.
  • These heterocyclic groups can be substituted or unsubstituted. Where a group is substituted, the substituent can be lower alkyl, lower alkoxy, halogen, substituted or unsubstituted aryl of from 6 to 10 carbon atoms and such substitution is typically from 1 to 2 independent substituents.
  • aryl refers to aromatic substituents comprising carbon and hydrogen such as phenyl, naphthyl and the like.
  • alkaryl refers to alkyl substituents having from 1 to 3 aryl substituents including, by way of example, benzyl, -(CH 2 ) 2 ⁇ , and the like.
  • 1,4-dihydropyrimidine refers to compounds having the base or core structure of
  • Substituents to the 1,4-dihydropyrimidine group can occur at any of the 1, 2, 4, 5 and 6 positions thereof in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of 1,4-dihydropyrimidine compounds.
  • the 1,4-dihydropyrimidine compounds can occur at any of the 1, 2, 4, 5 and 6 positions thereof in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of 1,4-dihydropyrimidine compounds.
  • the 1,4-dihydropyrimidine compounds can occur at any of the 1, 2, 4, 5 and 6 positions thereof in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of 1,4-dihydropyrimidine compounds.
  • the 1,4-dihydropyrimidine compounds can occur at any of the 1,
  • R is selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms
  • R 1 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and 1 to 5 halo atoms, thioalkyl of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms,
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms, an aryl group of from 6 to 10 carbon atoms or -ZR 9 where Z and R 9 are as defined above,
  • R 6 is alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and carboxyl, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro, -PO(NR 3 R 4 ) 2 and -PO(OR 12 ) 2
  • R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N- dialkylalkamino of from 3 to 12 carbon atoms, R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, R 12 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms
  • 1,4-dihydropyrimidine is optionally attached to a solid support through the R, R 6 or X substituent.
  • pyrimidine refers to compounds having the base or core structure of
  • Substituents to the pyrimidine group can occur at any of the 2, 4, 5 and 6 positions thereof in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of pyrimidine compounds.
  • the pyrimidine compounds (or groups) have the formula
  • R 1 is selected from the group consisting of hydrogen, alkyl of from
  • R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, and -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms,
  • R 5 is hydrogen, a linear alkyl group of from 1 to 6 carbon atoms, an aryl group of from 6 to 10 carbon atoms, or -ZR 9 where Z and R 9 are as defined above,
  • R 6 is alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms optionally substituted with from 1 to 2 substituents selected from the group consisting of nitro, cyano, halo, alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms and carboxyl, or a heterocyclic group of from 2 to 9 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and
  • X is selected from the group consisting of -C(O)R 2 , -S(O) 2 R 2 , cyano, nitro and -PO(OR 2 ) 2 where R 2 is alkyl of from 1 to 6 carbon atoms, haloalkyi of from 1 to 2 carbon atoms and from 1 to 5 halo atoms, alkoxy of from 1 to 6 carbon atoms, alkalkoxy of from 2 to 8 carbon atoms and from 1 to 3 ether oxygens, -NR 3 R 4 where R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms, alkamino of from 2 to 6 carbon atoms, N-alkylalkamino of from 2 to 10 carbon atoms and N,N-dialkylalkamino of from 3 to 12 carbon atoms and optionally X and R 1 are joined to form a cyclic or heterocyclic structure fused to the pyrimidine ring which structure contains from 3 to
  • substantially homogeneous refers to collections of molecules wherein at least 50%, preferably at least about 70% , more preferably at least about 90% and more preferably at least about 95 % of the molecules are a single compound or stereoisomer thereof.
  • stereoisomer refers to a chemical compound having the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light.
  • stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation.
  • the compounds described herein may have one or more asymmetrical carbon atoms and therefore include various stereoisomers. All stereoisomers are included within the scope of the invention.
  • removable protecting group or “protecting group” refers to any group which when bound to a functionality such as hydroxyl, amino, or carboxyl groups prevents reactions from occurring at these functional groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group.
  • the particular removable protecting group employed is not critical.
  • halogen refers to fluorine, chlorine, bromine and iodine and preferably fluorine and chlorine.
  • salts refers to alkali metal, alkaline earth metal, and ammonium salts commonly employed including, by way of example, sodium, potassium, lithium, calcium, magnesium, barium, ammonium, and protamine zinc salts, which are prepared by methods well known in the art.
  • the term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid.
  • Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate. and napsylate salts, and the like.
  • the particular salt employed is not critical.
  • the salt is non-toxic and
  • the synthesis of a 1,4-dihydropyridine group on the solid support is effected by reaction of a Knoevenagel condensation product and an enamino compound.
  • the Knoevenagel condensation product is generated by condensation of an aldehyde with a ⁇ -keto ester, a ⁇ -keto amide or a ⁇ - diketone by methods well known in the art for solution chemistry.
  • FIGs. 1 and 2 An example of the entire reaction process employing a ⁇ -keto ester covalently attached to a solid support is depicted in FIGs. 1 and 2 which figures illustrate formation of a solid phase ⁇ -keto ester 3 (derived from resin 1 and a soluble ⁇ -keto ester 2); subsequent reaction of the solid phase ⁇ -keto ester 3 with aldehyde 4 forms Knoevenagel condensation product 5 which, in turn, is reacted with enamino compound 6 in the presence of a dehydrating agent (e.g., molecular sieves) to provide for 1,4-dihydro- pyridine compound 7 bound to a solid support.
  • a dehydrating agent e.g., molecular sieves
  • FIG. 1 One such procedure for attaching the ⁇ -keto ester to the solid support is specifically illustrated in FIG. 1 with further examples set forth in Table 1 below.
  • resin 1 having a hydroxyl functionality (amine functionalities can also be used but are not illustrated), is reacted with an excess of ⁇ -keto ester, a ⁇ -keto carboxylate lithium salt in the presence of HATU and dimethylaminopyridine [DMAP], or a masked ⁇ -keto ester (i.e. , diketene acetonate) in the presence of DMAP.
  • DMAP dimethylaminopyridine
  • X is an amine functionality
  • Removable masking groups are well known in the art and include, by way of example, ketal groups.
  • the reaction is typically conducted in a suitable inert diluent under conditions suitable to effect covalent attachment of the ⁇ -keto functionality to the solid support.
  • keto ester on the resins can be evaluated via cleavage/heterocyclization of the keto ester by ethanolic hydrazine with subsequent photometry of the resulting 3-methyl-3-pyrazoline-5-one 2
  • the latter product is identified by, for example, nuclear magnetic resonance spectroscopy and thin layer chromatography and compared against authentic compound.
  • The.cesins employed are selected to be compatible with the keto esters and include, by way of example, commercially available TentaGel S
  • PHB resin (contains hydroxyl functionality), Wang resin (contains hydroxyl functionality), Kaiser resin (contains hydroxyl functionality) and PAL resin (contains amine functionality).
  • This table establishes procedures available to prepared covalently attached keto esters to solid supports.
  • acetoacetylation using t-butyl acetoacetate achieves about 87% loading efficiency but the procedure employing diketene in the presence of catalytic DMAP is technically more convenient (e.g. , about -50°C to RT overnight versus slow removal of t-butanol by distillation).
  • FIG. 2 The procedure for converting the solid phase ⁇ -keto ester to a solid phase 1,4-dihydropyridine is specifically illustrated in FIG. 2.
  • ⁇ -keto ester 2 acetoacetate covalently bound to Wang resin for illustrative purposes
  • a suitable base to form the Knoevenagel condensation product 5 .
  • the particular base employed is not critical and is selected relative to its ability to effect condensation.
  • Preferred bases include by way of example only, pyridine, piperidine, etc.
  • the reaction is typically conducted in a suitable inert diluent such as acetonitrile, benzene, toluene, xylene, isopropanol, etc. under conditions sufficient to effect condensation.
  • the reaction is conducted at a temperature of from about 20°C to about 100°C for a period of from about 4 to about 48 hours and preferably for from about 12 to about 24 hours.
  • the resulting condensation product can then be recovered by conventional means such as centrifugation, filtration, etc. or alternatively is contacted with the enamino compound without recovery and/or purification.
  • Reaction of the Knoevenagel condensation product 5 with enamino compound 6 is typically conducted by contacting at least a stoichiomet ⁇ c amount of enamino compound 6 in an inert diluent optionally in the presence of a dehydrating agent (e.g.. molecular sieves) to form the 1,4-dihydropyridine product 7.
  • a dehydrating agent e.g.. molecular sieves
  • This reaction is conducted under conditions sufficient to effect formation of dihydropyridine product 2 and is preferably conducted at a temperature of from about 20°C to about 100°C for a period of from about 4 to about 48 hours and preferably for from about 12 to about 24 hours.
  • Preferred solvents include, by way of example, ethanol, methanol, pyridine, dimethylformamide, N,N-dimethylacetamide (DMA).
  • Knoevenagel condensation product formation is preferably conducted in the presence of an enamino compound which, upon in situ formation of the condensation product, reacts with the enamino compound to form the 1,4-dihydropyridine compound.
  • the Knoevenagel condensation product is recovered from the first reaction medium and then added to a reaction solution comprising the enamino compound.
  • the resulting 1,4-dihydropyridine compound 2 can be recovered by conventional methods, i.e., filtration, centrifugation, etc. Confirmation that the resin (i.e., solid support) contains the desired dihydropyridine compound can be accomplished by cleaving the dihydropyridine compound from a small portion of the treated resins (if a cleavable linking arm is employed) and subjecting this product to conventional analysis, e.g., nuclear magnetic resonance spectroscopy ( ⁇ , 13 C, etc.), high performance liquid chromatography, and the like. Alternatively, the reaction can be monitored by use of appropriate resins using gel-phase C 13 -nuclear magnetic resonance spectroscopy.
  • FIG. 2 illustrates formation of dihydropyridine 7 from a ⁇ - keto ester covalently attached to a solid support
  • aldehyde 4 could likewise be covalently attached to the solid support to form a covalently attached Knoevenagel condensation product.
  • enamino compound 6 can be replaced by, for example, 6-aminouracil leads to the solid phase synthesis of pyrido[2,3- d]pyrimidine compounds.
  • FIG. 3 illustrates still another method for forming 1,4-dihydropyridine compounds wherein enamino compound 12 is covalently attached to the solid support and then subsequently reacted with either a Knoevenagel condensation product 12 or with ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone 14 and aldehyde 15 which, in situ forms a
  • adduct 17 is believed to be formed. It being contemplated that any adduct 16 formed during reaction may be isomerized in the presence pyridine to adduct 17. Adduct 17, in the presence of a cleaving agent such as TFA undergoes cyclization and cleavage to provide for soluble 1,4-dihydropyridine compound 18.
  • a cleaving agent such as TFA
  • ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone 11 (Y and R 5 are as defined above) is contacted with a suitable resin 10 having a reactive amine functional group such as PAL resins or resins having an amino acid or peptide bound thereto (through the carboxyl group) under conditions suitable to covalently attach - ⁇ -keto ester, ⁇ -keto amide or ⁇ - diketone 11 to resin 10 to provide for enamino compound 12.
  • ⁇ -keto ester, ⁇ -keto amide or ( ⁇ -diketone 11 serve as an enamino precursor compound insofar as upon contact with resin 10, these compounds are converted to enamino compounds.
  • the reaction is typically conducted in an inert diluent preferably under dehydrating conditions to effect formation of enamino compound 12.
  • the inert diluent is not critical and preferred diluents include chloroform, dichloromethane, ethyl acetate, etc. and suitable dehydrating conditions include, for example, the use of molecular sieves (MS 4A) or the use of trimethyl orthoformate or tetramethyl orthosilicate.
  • the reaction is typically conducted at a temperature of from about 15° to 60°C and preferably at room temperature for a period of from about 24 to about 72 or more hours.
  • a protonating catalyst such as p-toluenesulfonic acid (TsOH) is employed at about from 0.1 to about 0.5 equivalents.
  • TsOH p-toluenesulfonic acid
  • the resulting enamino compound covalently attached to a solid support 12 can then be converted to soluble 1,4-dihydropyridine compounds 18 by one of two routes.
  • solid phase enamino compound 12 is contacted in an inert diluent with at least a stoichiometric amount of Knoevenagel condensation product 13 (X, R 1 and R 6 are as defined above) in the presence of a base under conditions to effect formation of adduct 17.
  • this embodiment employs only two reagents, this embodiment is sometimes referred to herein as the two component condensation.
  • enamino compound 12 is contacted with ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone 14 (X and R 1 are as defined above) and aldehyde 15 (R 6 is as defined above) which, in situ, forms a Knoevenagel condensation product and then subsequently forms adduct 16.
  • X and R 1 are as defined above
  • aldehyde 15 R 6 is as defined above
  • this embodiment employs three reagents, this embodiment is sometimes referred to herein as the three component condensation. In either case, the presence of a suitable base permits isomerization of the unsaturation in adduct 16 to a position a to the keto group in adduct 17.
  • the particular inert diluent employed in either the two component condensation or the three component condensation reaction is not critical and suitable diluents include ethyl acetate, chloroform, toluene, benzene, dichloromethane, and the like.
  • the inert diluent is a weak base (e.g., pyridine).
  • the reaction is typically conducted at from about 10° to about 80°C for a period of time to effect formation of adduct 17.
  • the reaction is complete within from about 12 to about 24 hours.
  • dehydrating conditions as described above, are employed in this reaction.
  • the two component condensation procedure tolerates both donor, neutral and acceptor aryl substituents.
  • the three component condensation procedure is best conducted with neutral and acceptor aryl substituents.
  • the solution phase components in either the two or three component reactions are used in excess to the solid phase component.
  • the solution phase components are used from about a 5 to 50 fold excess relative to the solid phase component.
  • Adduct 17 is then converted to 1,4-dihydropyridine compound 18 by contact with a strong acid (e.g. , 3% TFA in DCM) under an inert atmosphere such as argon.
  • a strong acid e.g. , 3% TFA in DCM
  • adduct 15 first cleaves from the resin and then cyclizes to form soluble 1.4- dihydropyridine compound 18 as shown in Route II of FIG . 3.
  • the particular order of reaction is believed to be dependent on factors such as the linking arm employed, the particular adduct contained on the resin and the cleavage conditions.
  • a library of soluble 1,4- dihydropyridine compounds 18 is prepared. Final cleavage and isolation of the 1,4-dihydropyridine compounds
  • solid phase bound 1,4- dihydropyridine adduct 2 is oxidized to solid phase bound pyridine adduct 8 by reaction with eerie ammonium nitrate (CAN) in the presence of an inert diluent such as DMA at room temperature.
  • CAN eerie ammonium nitrate
  • the solid phase particle can be cleaved by treatment with a strong acid such as TFA to provide for soluble pyridine compound 8a.
  • Freshly prepared CAN solution in DMA should be delivered immediately before an oxidation step to avoid the degradation of the oxidant in the organic solvent.
  • the choice of suitable reagents among the enamino compounds, the Knoevenagel condensation products and/or the ⁇ - keto esters, ⁇ -keto amide and ⁇ -diketones employed to prepared the 1,4- dihydropyridine compounds disclosed herein provides a facile means for preparing 1 , 4-dihydropyridine compounds having a variety of substituents at the 1 , 2, 3, 4, 5 and 6 positions of the 1,4-dihydropyridine. Chemical derivation on the substituents so formed leads to still other substituents. For example, transesterification of carboxyl esters can provide for modification of the ester functionality. Moreover, oxidation of the 1.4- dihydropyridine compounds provides for pyridine compounds.
  • Preferred substituents at the 1, 2, 3, 4, 5 and 6 positions of the 1,4- dihydropyridine and the pyridine compounds can be prepared via the methods described herein from starting materials which are either known per se in the art or which can be prepared by art recognized methods are described above.
  • Solid phase Knoevenagel condensation products are described above whereas solid phase amidine compounds are prepared by reaction of an amino, hydroxyl or thiol functionalized solid support with, for example, known reagent 1-H-pyrazole-1-carboxamidine. Reaction of the
  • 4-dihydropyrimidine compounds to pyrimidine compounds provides a ready route to such libraries whether the library is a solid phase or solution library.
  • suitable oxidation conditions are well known in the art.
  • One preferred set of oxidation conditions is the reaction of solid phase bound 1,4-dihydropyrimidine adduct with cerie ammonium nitrate (CAN) in the presence of a diluent such as DMA at room temperature to provide for the solid phase bound pyrimidine adduct.
  • CAN cerie ammonium nitrate
  • the solid phase particle can be cleaved by treatment with a strong acid such as TFA to provide for soluble pyrimidine compounds.
  • substituents at the 1, 2, 4, 5 and 6 positions of the 1,4-dihydropyrimidine are substituents at the 1, 2, 4, 5 and 6 positions of the 1,4-dihydropyrimidine. Chemical derivation on the substituents so formed leads to still other substituents. For example, transesterification of carboxyl esters can provide for modification of the ester functionality. Moreover, oxidation of the 1,4-dihydropyrimidine compounds provides for pyrimidine compounds.
  • Preferred substituents at the 1, 2, 4, 5 and 6 positions of the 1,4- dihydropyrimidine and the pyrimidine compounds can be prepared via the methods described herein from starting materials which are either known per se in the art or which can be prepared by art recognized methods are described above.
  • solid phase pyrimidine compounds can be prepared by reaction of an amidine compounds with 1 ,3-dicarbonyl compounds such as ⁇ -keto esters, ⁇ -keto amides, ⁇ -diketones and the like at elevated temperatures (e.g. , -- 80°C) in an inert diluent such as dimethylformamide optionally using dehydrating conditions as described above wherein either the 1,3-dicarbonyl compound or the amidine compound is covalently bound to a solid support.
  • 1 ,3-dicarbonyl compounds such as ⁇ -keto esters, ⁇ -keto amides, ⁇ -diketones and the like
  • elevated temperatures e.g. , -- 80°C
  • an inert diluent such as dimethylformamide
  • another method aspect of the invention is a method for preparing pyrimidine groups covalently attached to a solid support which are prepared by contacting a dicarbonyl compound selected from the group consisting of ⁇ -keto ester, a ⁇ -keto amide or a ⁇ -diketone with an amidine compound under conditions effective to provide for the pyrimidine group wherein the dicarbonyl compound or the amidine compound is covalently attached to a solid support.
  • each solid support will preferably contain a single compound which compound is different to the compounds found on the other solid supports but each compound will also comprise a 1, 4-dihydropyridyl, pyridyl, 1,4- dihydropyrimidyl or pyrimidyl group.
  • single compound as used herein includes different regio and stereoisomers of that compound.
  • unsymmetric substitution at the 2,6 and/or 3,5 positions of the 1, 4- dihydropyridine compounds generates a chiral center at the 4-position.
  • individual isomers possess opposite actions on the calcium channel; one showing blocking activity and the other demonstrating activating activity. 22
  • the term “single compound” does not mean that only one copy of that compound is attached to each support. Rather, multiple copies of that compound can be included on the support.
  • such methods can employ either a covalently bound Knoevenagel condensation product or a covalently bound enamino/amidine compound.
  • this method can comprise apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels, combining into each reaction vessel a different ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone such that the ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone becomes covalently attached to the linking arm of the supports through the amino or hydroxyl functionality, pooling the supports and then apportioning the supports among a plurality of reaction vessels, combining into each reaction vessel a different aldehyde under conditions wherein the ⁇ -keto ester, the ⁇ -keto amide or the ⁇ - diketone forrns a Knoevenagel condensation product with the aldehy
  • this method can comprise apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels, combining into each reaction vessel a different enamino/amidine group (or enamino/amidine precursor group) such that the enamino/amidine group (or enamino/amidine precursor group) becomes covalently attached to the linking arm through the amino or hydroxyl functionality wherein, in the case of the enamino/amidine precursor groups, the attachment converts the enamino/amidine precursor group to an
  • pyrimidine compounds respectively by oxidation and the 1,4-dihydropyridine can be converted to libraries of piperidine compounds by reduction (see, e.g. , example 65 below).
  • solid phase libraries can employ either a covalently bound dicarbonyl compound or a covalently bound amidine compound.
  • this method can comprise apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels, combining into each reaction vessel a different ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone or a different ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone precursor such that the ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone becomes covalently attached to the linking arm of the supports through the amino or hydroxyl functionality wherein, in the case of the ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone precursors, the attachment converts these precursor groups to a ⁇ -keto ester ⁇ -keto amide
  • this method can comprise apportioning supports comprising a linking arm having a reactive amino or hydroxyl functionality into a plurality of reaction vessels, combining into each reaction vessel a different amidine group (or amidine precursor group) such that the amidine group (or amidine precursor group) becomes covalently attached to the linking arm through the amino or hydroxyl functionality wherein, in the case of the amidine precursor groups, the attachment converts the amidine precursor group to an amidine group, pooling the supports and then apportioning the supports among a plurality of reaction vessels, combining into each reaction vessel a different dicarbonyl compound selected from the group consisting of ⁇ -keto esters, ⁇ -keto amides and ⁇ - diketones under conditions wherein the Knoevenagel condensation product and the amidine group cycle to form a pyrimidine compound.
  • the library will contain at least about 10 compounds, more preferably from about 10 2 to about 10 10 compounds and still more preferably from about 10 3 to about 10 6 compounds.
  • each solid support is tagged with an identifier tag that can be easily decoded to report the compounds formed on the solid support.
  • the tag can be directly attached either to the solid support or the tag can be included on the compound itself. In this latter embodiment, cleavage of the compound from the solid support will still permit identification of the compound.
  • Each of these embodiments is disclosed in International Patent Application Publication No. WO 93/06121.
  • a portion of the same compounds attached to a single support is cleaved and subjected to mass spectroscopy, nuclear magnetic resonance spectroscopy and/or other forms of direct structural analysis so as to identify the compound on the support.
  • One preferred method for tagging employs a hard tagging scheme which is illustrated by Gallop, et al. 29
  • the 1,4-dihydropyridine, the pyridine, the 1,4-dihydropyrimidine, or the pyrimidine groups can be incorporated into each compound in a library of different compounds all of which are covalently linked to the same solid support in the manner described in U.S. Patent No. 5, 143,854. Such a library of different compounds can be simultaneously screened for receptor binding or some other activity.
  • U.S. Patent No. 5, 143,854 is incorporated herein by reference in its entirety.
  • the libraries of 1,4-dihydropyridine and 1,4-dihydropyrimidine compounds disclosed herein are useful in screening these compounds for activity as organic calcium channel modulators having therapeutic utility in the treatment of cardiac arrhythmias, hypertension, angina pectoris, vasospastic, supraventricular tachycardia, ventricular tachyarrhythmia, congestive heart failure, asthma, cerebral insufficiency and vasospams, and in the protection against ischemic heart damage. 4,5,8 .
  • These libraries can also be employed to screen compounds for use as biological tools for studies of voltage-activated calcium channel structure and function and for use as liver protecting agents.
  • these libraries can be used to screen compounds for use in inhibiting platelet aggregation including, for example, platelet aggregation induced by PAF-acether (1-0-hexadecyl/octa- decyl-2-0-acetyl-sn -glycero-3-phosphoryl-choline) and platelet aggregation induced by B16 amelanotic melanoma.
  • PAF-acether 1-0-hexadecyl/octa- decyl-2-0-acetyl-sn -glycero-3-phosphoryl-choline
  • B16 amelanotic melanoma B16 amelanotic melanoma.
  • Libraries of 14-dihydropyridines can further be screened for antioxidant, antitumor, antimutagenic, geroprotective, antiatherosclerotic, bronchodilating, antifungal, antiviral, antibacterial and antidiabetic activity.
  • pyridine compounds can be screened for inhibition of myeloperoxidase release from polymorphonuclear leukocytes (PMN) which, in turn, is theorized to modulate the tissue destructive nature of adult respiratory distress syndrome.
  • PMN polymorphonuclear leukocytes
  • 25 Pyridine and pyrimidine libraries can also be screened for anticonvulsant activity in mice 24 .
  • pyridine libraries can be screened for zinc chelating properties which can inhibit the binding of HIV-EP1 to NF- ⁇ B recognition sequence. 23
  • libraries of pyrimidine compounds can be screened for inhibiting human leukocyte elastase.
  • the following examples are set forth to illustrate the claimed invention and are not to be construed as a limitation thereof.
  • Examples 1 and 2 illustrate the preparation of specific solid phase enamino compounds covalently bound to a solid support.
  • Example 3 illustrates the solution phase synthesis of a Knoevenagel condensation product.
  • Examples 4-47 illustrate the synthesis of numerous 1,4-dihydro- pyridine compounds via a solid phase enamino group.
  • Examples 48 and 49 illustrate the preparation of libraries of soluble 1,4-dihydropyridine compounds via the methods illustrated in Examples 1 through 47.
  • Knoevenagel condensation products and subsequent conversion of these products to solid phase 1,4-dihydropyridine compounds and 1,4- dihydropyrimidine compounds Examples 57-58 illustrate solid phase conversion of 1,4-dihydropyridine and 1,4-dihydropyrimidine compounds to pyridine and pyrimidine compounds respectively. Examples 59-65 illustrate particular embodiments of this invention.
  • the product is filtered, washed with CCl 3 (3 x 7 mL), ethyl acetate (3 x 7 mL), diethyl ether (7 mL), and dried in a vacuum dessicator (RT, 0.5 Torr).
  • the resin is filtered, washed with methanol (4 x 7 mL) and then with ethvl acetate (4 x 7 mL), and dried in a vacuum dessicator (RT, 0.5 Torr).
  • the resulting resin is stirred under argon with 3% TFA in DCM (1 mL) for 60 minutes.
  • Degassed acetonitrile (4 mL) is added, and the supernatant separated and quickly evaporated in vacuo with addition of toluene (2 mL) to ensure complete TFA removal.
  • the crude products can be further purified by gradient RP HPLC (from 90% of the 0.1 % TFA in water to 70% of the 0.1 % TFA in acetonitrile over 60 minutes) using degassed solvents.
  • Method B The procedure of Method B is analogous to that of Method A, with the exception that a benzylidene ⁇ -keto ester (1 mmol) is employed instead of a mixture of ⁇ -keto ester and aldehyde.
  • Example 4 PAL Resin Supported Adduct 17 from Reaction of N- Immobilized C 2 -2,4 Methyl Aminocrotonate with Methyl 2-(p-Nitrobenzylidene)acetoacetate
  • N-Immobilized l3 C 2 -2,4 methyl aminocrotonate, prepared as above, was reacted with methyl 2-(p-nitrobenzylidene)acetoacetate (prepared per Example 3 above) in the manner of Method B of General Procedure B above to provide for an adduct having the following analytical data: Fast gel phase 13 C NMR in C 6 D 6 ( ⁇ , ppm): 15.3 ( 13 CH 3 ), 90.3 and 91.3 ( 13 CH ).
  • Example 7 Synthesis of 4-(m -Nitrophenyl)-2,6-dimethyl-3- ethoxycarbonyl-5-methoxycarbonyl-1,4-dihydropyridine Prepared according to the Method A of General Procedure B above from an enamino compound N-tethered to Rink resin wherein the enamino compound was derived from methyl acetoacetate and then reacted with m-nitrobenzaldehyde and ethyl acetoacetate. Yield 6.2 mg (75%). MS (M+Na) + 383.0.
  • Example 11 Synthesis of 4-(p-NitrophenyI)-6-ethyl-2-phenyl-3- ethoxycarbonyl-5-methoxy-carbonyl-1,4-dihydropyridine Prepared according to Method A of General Procedure B above from an enamino compound N-tethered to Rink resin wherein the enamino compound was derived from methyl propionylacetate and then reacted with p-nitrobenzaldehyde and ethyl benzoylacetate. Yield 7.0 mg (70%). MS (M+H) + 437.1.
  • Example 14 Synthesis of 4-(Pyridin-4-yl)-2,6-dimethyl-3,5- dimethoxycarbonyl-1,4-dihydropyridine Prepared according to Method A of General Procedure B above from an enamino compound N-tethered to Rink resin wherein the enamino compound was derived from methyl acetoacetate which was then reacted with 4-pyridinecarboxaldehyde and methyl acetoacetate. Yield 5.2 mg (75 %). MS (M+H) + 302.5.
  • FIG. 7 illustrates an alternative synthesis for 1,4-dihydropyridines starting with an amino acid bound to a resin via the carboxyl group.
  • the synthesis otherwise follows that set forth above.
  • the dihydropyridines can be made on a solid support via three types of readily available building blocks: amino acids, aldehydes and enamines.
  • amino acids amino acids
  • aldehydes amino acids
  • enamines enamines.
  • readily assessible acyl Meldrum's acids can be employed as diverse diketene synthones for generation of keto amides at the first step of the synthetic scheme.
  • a nine member library of 1,4-dihydropyridine compounds was prepared as shown in FIG. 5. Specifically, the FMOC protecting group was removed from FMOC-NH-RINK resin by treatment with 10% piperidine in DMF and washed with DMF (4 x 7 mL), methanol (3 x 7 mL), CHCl 3 (3 x 7 mL), diethyl ether (7 mL), and dried under vacuum.
  • the resulting resin was split into three groups.
  • the first group was contacted with an excess of methyl acetoacetate (about 30 equivalents) in DCM (optionally over molecular sieves (MS)) for about 48 hours at RT to provide for a first enamino compound covalently bound to a solid support as described above.
  • the second group was contacted with allyl acetoacetate in the manner described above to provide for a second enamino compound covalently bound to a solid support.
  • the third group was contacted with benzyl acetoacetate in the manner described above to provide for a third enamino compound covalently bound to a solid support.
  • the resins were then pooled and split into three additional groups wherein each group was treated with a different Knoevenagel condensation product in the manner described in FIG. 5 and then the solid support was removed by treatment with 3% TFA/THF in argon to provide for the nine member library of soluble 1,4-dihydropyridine compounds.
  • RAM resins were prepared separately as described above from the corresponding amine resin with each of the following keto esters: methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate, t-butyl acetoacetate, methyl propionylacetate, i-butyl acetoacetate, allyl acetoacetate, benzyl acetoacetate, (2-methoxy)ethyl acetoacetate, and methyl (4-methoxy)aceto- acetate.
  • N-tethered enamino esters thus prepared (0.4 g of each resin) were pooled and then split in 10 portions. Every pool of immobilized enamino esters (0.4 g each) was reacted as described above with methyl acetoacetate and one of the following aldehydes: benzaldehyde, 4- chlorobenzaldehyde, 2-fluorobenzaldehyde, 2-trifluoromethylbenzaldehyde, 4-cyanobenzaldehyde, 4-nitrobenzaldehyde, 2-nitrobenzaldehyde, 4- pyridinecarboxaldehyde, 2-pyridinecarboxaldehyde, or 3-thiophene- carboxaldehyde, at 40°C over 24 hours.
  • aldehydes benzaldehyde, 4- chlorobenzaldehyde, 2-fluorobenzaldehyde, 2-trifluoromethylbenzaldehyde, 4-cyanobenzaldehyde,
  • Each of the above compounds has an IC 50 of less than 100 nM in the described assay.
  • This method employs acyl Meldrum's acids. Specifically, a mixture of alcohol resin (0.1 mmol) and an appropriate acyl Meldrum's acid (2 mmol; freshly prepared reagents give better results) in toluene (1.5 mL; in a closed screw-cap vial) is stirred at 60°C (gives cleaner products than 80°C) for 15-18 hours. The resulting resin is filtered, washed
  • FIG. 9 illustrates a synthetic scheme in which Wang resin is first acetylated via either acetic anhydride or acetyl chloride to provide for resin bound acetate. Reaction with LDA at -78°C in THF followed by reaction with a Weinreb amide. This reaction is generally conducted as follows.
  • Solid phase Knoevenagel condensation product prepared in Example 51 above was combined with methyl aminocrotonate in the manner described above in General Procedure E to provide for the title compound covalently attached to the solid support.
  • the title compound covalently attached to TentaGel S PHB resin decomposes if cleavage of this compound is attempted via conventional cleavage conditions, e.g., 95% TFA. It has been found that decomposition is due to the fact that the 5-carboxyl group resulting from cleavage results in an acid unstable product. Accordingly, for the purposes of this invention, TentaGel S PHB resin provides for a non-cleavable linking arm to the solid support when employed with 1,4-dihydropyridine compounds bound via a 3 or 5 carboxyl ester.
  • the TentaGel S PHB resin can be replace with cleavable resins such as those which possess a photo labile group. See, for example, U.S. Patent No. 5, 143,854 as well as Jacobs, et al., Combinatorial Chemistry - Application of Light-directed Chemical Synthesis, Trends in Biotechnology, 12(1): 19-26 (1994) and Fodor, et al. , Light-Directed Spatially Addressable Parallel Chemical Synthesis, Science, 251 :767-773 (1991) all of which are incorporated herein by reference in their entirety.
  • a photolabile linker is employed in conjunction with the synthesis of dihydropyridines. an oxygen-free atmosphere or the use of radical scavengers might be necessary and, in any event, no ortho-phenyl dihydropyridines can be obtained under these conditions. Examples 53-56 below are illustrated in FIG. 2.
  • Example 54 Wang Resin Immobilized 4-PhenyI-2,6-dimethyl-3- (resin)-oxycarbonyl-5-methoxycarbonyl-1 ,4- dihydropyridine ( 13 C-4)
  • Example 55 The resin of Example 55 above was cleaved by treatment with 90% aqueous trifluoroacetic acid (0.2 mL, 45 minutes). The resulting supernatant was lyophilized with water (2 mL) to afford the title compound. HPLC purity > 85 % . MS (M + H)+ 287.0. 1 H NMR in CDCl3 ( ⁇ , ppm): 2.70 (s, 3H, Me), 2.79 (s, 3H, Me), 3.58 (s, 3H, OMe), 7.23-7.53 (m, 5H, Ph).
  • Knoevenagel Condensation product (0.05 g) prepared as in Example 51 above is combined with commercially available 2-methyl-2-thio- pseudourea sulfate and sodium acetate in DMF in the manner of Atwal et al. 18 , to provide for the title compound covalently attached to a solid support.
  • Resin is washed with DMF (3 x 5 mL), THF (3 x 5 mL), and acetylated with Ac 2 O/lutidine/THF (1 mL) and N-methylimidazole/THF (1 mL) for
  • the amine (or peptide) resin thus obtained (0.3 mmol) is stirred with l H-pvrazole- 1 - carboxamidine (2.76 mmol. 0.405 g) and DIEA (3. 13 mmol, 0.545 mL) in DMF (4 x 5 mL), ethyl acetate (4 x 5 mL) and dried under vacuum (RT, 0.5 Torr, 5 hours).
  • guanidine resin (0.03 mmol) in DMF (1 mL) or pyridine (1 mL) is stirred at 20°C to 80°C with an appropriate ⁇ -diketone (1 mmol, for preparation of pyrimidines) or benzylidene ⁇ -keto ester, ⁇ -keto amide or ⁇ -diketone (1 mmol, for the preparation of 1,4-dihydropyrimidines) and dehydrating agent [e.g., molecular sieves 4A, (0.16 g) or
  • Example 58 The resin of Example 58 was combined with acetylacetone in the manner of General Procedure H using molecular sieves 4A as the dehydrating agent over a reaction time of 15 hours to provide for the title compound. A portion of the resulting resin (0.05 g) was cleaved with 10% TFA/DCM (0.7 mL) for 1 hour. Resin was filtered off, and the filtrate evaporated under vacuum to afford the 2-(amidomethyl)amino-4,6-di- methylpyrimidine.
  • Example 58 The resin of Example 58 was combined with 4,4,4-trifluoro-1- phenyl-1,3-butanedione in the manner of General Procedure H using molecular sieves 4 A as the dehydrating agent over a reaction time of 13 hours to provide the title compound.
  • a portion of the resulting resin (0.05 g) was cleaved with 10% TFA/DCM (0.9 mL) for 2 hours. Resin was filtered off, and the filtrate evaporated under vacuum to afford the 2- (amidomethyl)amino-4-trifluoromethyl-6-phenylpyrimidine.
  • FIG. 6 illustrates a synthetic scheme to prepare a library of soluble pyrimidine compounds via a solid support.
  • the FMOC protecting group is removed from three different FMOC-NH-RINK resin and then converted to guanadine derivatives 31, 32, and 33 in a manner similar to General Procedure G above.
  • the resulting guanadino compounds are pooled together and then split into two groups.
  • the first group is contacted with an excess of 4,4,4-trifluoro- 1 -phenyl- 1 ,3-butanedione in the manner of General Procedure H using molecular sieves 4A as the dehydrating agent to provide for 3 solid phase pyrimidine compounds (not shown).
  • the second group is contacted with an excess of 4,4,4-trifluoro-1-(2-thienyl)- 1 ,3- butanedione in the manner of General Procedure H using molecular sieves as the dehydrating agent to provide for 3 additional solid phse pyrimidine compounds (not shown).
  • FIG. 8 illustrates that the use of 2-aminouracil in place of an enamino compound leads to the solid phase synthesis of pyrido[2,3- d]pyrimidine compounds.
  • the reaction otherwise proceeds as above and the table below illustrates compounds prepared via this method.
  • FIG. 1 1 illustrates a more detailed synthesis of substituted nicotinic acids and pyrido[2,3-d]pyrimidines.
  • the synthetic scheme illustrates coupling of the ⁇ -ketoester to a polystyrene or Tentagei resin followed by Knoevengal condensation using EDAA or piperidine catalyst in isopropanol/benzene at an elevated temperature.
  • FIG. 10 illustrates the solid phase synthesis of pyrimidines prepared using such guanylation reactions. Examples of pyrimidines made according to FIG. 10 are shown in the table below.
  • FIG. 10 illustrates conventional coupling of an FMOC protected amino acid (including natural and unnatural amino acids) to a solid resin through the carboxyl group followed by deprotection with piperidine/DMF. Next, guanalyation is accomplished either with PCA or ASA and then the reaction proceeds as above to provide for the pyrimidine compounds.
  • series of natural and unnatural amino acids have been successfully converted into corresponding 2- aminopyrimidine derivatives on a solid support. The method tolerates aromatic/heteroaromatic substitutions in both amino acid substrates and diketone reagents, and introduction of certain groups is now achievable
  • Example 64 Construction of Combinatorial Library of 2- Aminopyrimidines Using the procedures set forth above, a pyrimidine library was synthesized using building blocks listed below.
  • This library was been designed to incorporate structurally diverse amino acids: (i) lyophilic acyclic amino acids, (ii) lypophilic
  • Piperidine compounds are well known as possessing
  • solid phase dihydropyridine compounds described above provide solid phase intermediates for the solid phase synthesis of piperidines. Conversion of the solid phase dihydropyridine compounds to solid phase piperidines is illustrated below:
  • the reductive reaction stereoselectively provides for an all-trans product.
  • Such products can provide for a library to library conversion of dihydropyridine compounds to piperidine compounds.
  • Preferred piperidine compounds prepared by these methods include those set forth above for the 1,4-dihydropyridine compounds wherein both sites of carbon-carbon unsaturation have been reduced to provide for the piperidine core structure, i.e.,

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Abstract

La présente invention concerne des procédés de synthèse, sur des supports solides, d'ensembles très importants de divers composés de dihydropyridine, dihydropyrimidine, pyridine ou pyrimidine. L'invention concerne aussi des procédés permettant d'identifier et d'isoler, dans de tels ensembles, les composés de dihydropyridine et de dihydropyrimidine manifestant des activités utiles et diverses, y compris l'incorporation d'identificateurs dans de tels ensembles pour faciliter l'identification des composés possédant des propriétés que l'on désire.
PCT/US1996/005956 1995-04-28 1996-04-29 Procedes de synthese de divers ensembles de pyridines, pyrimidines, derives 1,4-dihydro de ces composes et derives de piperidine WO1996033972A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001427A1 (fr) * 1996-07-05 1998-01-15 Basf Aktiengesellschaft Procede de preparation de derives de pyrazolone
EP1085863A4 (fr) * 1998-06-08 2001-03-28 Advanced Medicine Inc Nouveaux medicaments pour traiter les etats dus aux canaux calcium et leurs utilisations
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
WO2003020684A1 (fr) * 2001-08-30 2003-03-13 Pharmacia Corporation Reactifs alpha-haloenamine
WO2004043926A1 (fr) * 2002-11-11 2004-05-27 Bayer Healthcare Ag Derives de phenyl- ou heteroarylamino-alcanes comme antagonistes du recepteur ip
US6818631B1 (en) 2003-08-15 2004-11-16 Nippon Soda Co. Ltd. Fungicidal pyrimidine derivatives
US6893815B1 (en) * 1997-06-30 2005-05-17 Isis Pharmaceuticals, Inc. Nucleobase heterocyclic combinatorialization
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WO2010023295A1 (fr) * 2008-08-29 2010-03-04 Centre National De La Recherche Scientifique (Cnrs) Lieur pipécolique et son utilisation pour une chimie sur support solide
US8093246B2 (en) 2006-12-14 2012-01-10 Lexicon Pharmaceuticals, Inc. O-linked pyrimidin-4-amine-based compounds, compositions comprising them, and methods of their use to treat cancer
WO2013004332A1 (fr) * 2011-07-07 2013-01-10 Merck Patent Gmbh Azahétérocycles substitués pour le traitement du cancer

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001427A1 (fr) * 1996-07-05 1998-01-15 Basf Aktiengesellschaft Procede de preparation de derives de pyrazolone
US6893815B1 (en) * 1997-06-30 2005-05-17 Isis Pharmaceuticals, Inc. Nucleobase heterocyclic combinatorialization
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
EP1085863A4 (fr) * 1998-06-08 2001-03-28 Advanced Medicine Inc Nouveaux medicaments pour traiter les etats dus aux canaux calcium et leurs utilisations
US6897305B2 (en) 1998-06-08 2005-05-24 Theravance, Inc. Calcium channel drugs and uses
US7101909B2 (en) 1998-10-12 2006-09-05 Theravance, Inc. Calcium channel drugs and uses
US7238697B2 (en) * 2001-02-22 2007-07-03 Bayer Cropscience Ag Pyridylpyrimidines for use as pesticides
WO2003020684A1 (fr) * 2001-08-30 2003-03-13 Pharmacia Corporation Reactifs alpha-haloenamine
US6924396B2 (en) 2001-08-30 2005-08-02 Pharmacia Corporation α-haloenamine reagents
WO2004043926A1 (fr) * 2002-11-11 2004-05-27 Bayer Healthcare Ag Derives de phenyl- ou heteroarylamino-alcanes comme antagonistes du recepteur ip
US6818631B1 (en) 2003-08-15 2004-11-16 Nippon Soda Co. Ltd. Fungicidal pyrimidine derivatives
US8093246B2 (en) 2006-12-14 2012-01-10 Lexicon Pharmaceuticals, Inc. O-linked pyrimidin-4-amine-based compounds, compositions comprising them, and methods of their use to treat cancer
WO2010023295A1 (fr) * 2008-08-29 2010-03-04 Centre National De La Recherche Scientifique (Cnrs) Lieur pipécolique et son utilisation pour une chimie sur support solide
JP2012500830A (ja) * 2008-08-29 2012-01-12 サントル、ナショナール、ド、ラ、ルシェルシュ、シアンティフィク、（セーエヌエルエス） ピペコリン酸リンカーおよび固体支持体についての化学へのその使用
US8546533B2 (en) 2008-08-29 2013-10-01 Centre National De La Recherche Scientifique (Cnrs) Pipecolic linker and its use for chemistry on solid support
WO2013004332A1 (fr) * 2011-07-07 2013-01-10 Merck Patent Gmbh Azahétérocycles substitués pour le traitement du cancer
JP2014520767A (ja) * 2011-07-07 2014-08-25 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング がんの処置のための置換されたアザ複素環
US9199962B2 (en) 2011-07-07 2015-12-01 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer
AU2012280725B2 (en) * 2011-07-07 2017-02-02 Merck Patent Gmbh Substituted azaheterocycles for the treatment of cancer

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