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WO1998015532A1 - Synthese en phase solide de composes heterocycliques - Google Patents

Synthese en phase solide de composes heterocycliques Download PDF

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Publication number
WO1998015532A1
WO1998015532A1 PCT/EP1997/005547 EP9705547W WO9815532A1 WO 1998015532 A1 WO1998015532 A1 WO 1998015532A1 EP 9705547 W EP9705547 W EP 9705547W WO 9815532 A1 WO9815532 A1 WO 9815532A1
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Prior art keywords
solid phase
aryl
phase synthesis
heterocyclic ring
ring according
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PCT/EP1997/005547
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English (en)
Inventor
Andreas Marzinzik
Eduard Felder
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Novartis Ag
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Priority to AU49456/97A priority Critical patent/AU4945697A/en
Publication of WO1998015532A1 publication Critical patent/WO1998015532A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D211/86—Oxygen 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—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
    • C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, 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
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the current invention concerns a process of solid phase synthesis of a heterocyclic ring, characterized in that it comprises the following steps a) a solid carrier having reactive surface groups is loaded directly or via a spacer group with a compound bearing an aldehyde or a methylketone function, b) said function is modified using the Wittig reaction or the aldol condensation, c) the heterocyclic ring is closed using a compound comprising two nucleophiles, wherein at least one of said nucleophiles is NH 2 .
  • step a) the compound bearing an aldehyde or a methylketone function is of formula 1 or 2 HOOC R1 (2) wherein:
  • R 1a or R 1b is arylene, X-aryl, aryl-Y, X-aryl-Y, wherein X and Y are the same or different and are selected from the group consisting of C- ⁇ -C 10 alkylene, OCrC ⁇ 6 alkylene with preference given to OCrC 10 alkylene, C 2 -C 10 alkenylene and OC 2 -C ⁇ 0 alkenylene; wherein the X and Y group may be unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy, and wherein aryl and arylene are as defined below.
  • Suitable X and Y groups independent of one another are, for example, CH 2 , C 2 H 2) OCH 2 , OCH 2 CH 2)
  • R 1a is arylene, X-aryl, aryl-Y, or X-aryl-Y, wherein X and Y are the same or different and are selected from the group consisting of C C 4 alkylene and Od-C 4 alkylene; wherein the X and Y group may be unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy, and wherein aryl and arylene are as defined below.
  • Suitable X and Y groups are, for example, CH 2 , C 2 H 2 , OCH 2 , and OCH 2 CH 2 .
  • R 1a is phenylene,
  • R 1b preferably is arylene or X-aryl, wherein X is CrC ⁇ 0 alkylene, OC C ⁇ 0 alkylene, C 2 -C 10 alkenylene or OC 2 -C 10 alkenylene unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy, and wherein aryl and arylene are as defiend below.
  • R 1b is phenylene, biphenylene, pyrrolylene,
  • step b) the reagent for the Wittig reaction is of formula 3 and the reagent for the aldol condensation is of formula 4 or 5 wherein:
  • R 2 is unsubstituted or substituted aryl, XH, X-aryl, aryl-Y, or X-aryl-Y, wherein X and Y are the same or different and are selected from the group consisting of C C ⁇ 0 alkyiene, C 2 -C ⁇ 0 alkenylene and C 2 -C ⁇ 0 alkinylene, and wherein aryl is as defined below.
  • R 2 is C ⁇ -C 4 alkyl, CrC 4 alkenyl, or C C 4 alkinyl, unsubstituted or substituted with fluoro, chloro, or bromo, or R 2 is aryl wherein aryl is as defined below.
  • R 2 of formula 3 is C 1 -C 4 alkyl, phenyl, naphthyl, 4-NO 2 C 6 H 4) 2,4-(NO 2 ) 2 C 6 H 3 , 2,4-CI 2 C 6 H 3l 2,4-(CH3) 2 C6H 3) 2,4- (CH 3 O) 2 C 6 H 3 , 4-CH 3 OC 6 H 4 , 2-CIC 6 H 4 , thienyl, pyrrolyl or pyrazinyl.
  • R 2 is aryl, wherein aryl is as defined below; more preferred is phenyl, naphthyl, biphenyl, thienyl, furyl, quinolyl, pyridinyl, pyrrolyl or pyrazinyl unsubstituted or substituted with nitro, methoxy, ethoxy, bromo, chloro, fluoro, methyl or ethyl.
  • R 2 is phenyl, naphthyl, 4-NO 2 C 6 H 4 , 2,4-(NO 2 ) 2 C 6 H 3 , 2,4- CI 2 C 6 H 3 , 2,4-(CH 3 ) 2 C 6 H 3 , 2,4-(CH 3 O) 2 C 6 H 3 , 4-CH 3 OC 6 H 4) 2-CIC 6 H 4 , thienyl, pyrrolyl, pyrazinyl or ethylpyrazinyl.
  • R 2 is aryl, or unsubstituted or substituted aryl-Y, wherein aryl is as defined below, and wherein Y is selected from the group consisting of C ⁇ -C ⁇ 0 alkylene, C 2 -C 10 alkenylene and C 2 -C 10 alkinylene.
  • R 2 is aryl, wherein aryl is as defined below; more preferred is phenyl, naphthyl, thienyl, pyridinyl, pyrrolyl or pyrazinyl unsubstituted or substituted with nitro, chloro, fluoro, methyl or ethyl.
  • R 2 is phenyl, naphthyl, 4-NO 2 C 6 H , 2,4- (NO 2 ) 2 C 6 H 3 , 2,4-CI 2 C 6 H 3 , 2,4-(CH 3 ) 2 C 6 H 3 , 2,4-(CH 3 O) 2 C 6 H 3 , 4-CH 3 OC 6 H 4 , 2-CIC 6 H 4 , thienyl, pyrrolyl, pyrazinyl or ethylpyrazinyl, propyl or isopropyl.
  • a preferred R 3 is hydrogen, d-Cioalkyl, C C ⁇ 0 alkenyl and C C ⁇ 0 alkinyl; preferred is hydrogen, methyl or ethyl.
  • the nucleophile is of formula 6, 7, 8, 9, 10 or 10a
  • R 4 is a residue that does not interfere with the ring-closure; preferred is aryl, -X, -OX, - COX, CONHX, CONH 2 , CONHaryl, or -NO 2 wherein X is C C 10 alkyl or C 2 -C 10 alkenyl which is unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or i-propyl; more preferred is COC C 4 alkyI, CONHd- C 4 alkyl, CN and CONHaryl; even more preferred is CONH 2) CN;
  • R 5 is a residue that does not interfere with the ring-closure; preferred is aryl, adamantyl, morpholino, -X, -COX, -NH 2 , -NHY, -NX 2 , C 3 -C 7 cycloalkyl, aryl or -XOaryl unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, carbamoyl, methoxy, ethoxy, methyl, ethyl, propyl, i-propyl or CF 3l wherein X is C ⁇ -C ⁇ oalkyl or C 2 -C ⁇ 0 alkenyl, and wherein Y is C doalkyl, C 2 -C 10 alkenyl, aryl-NH-C(NH)-NH-, ZOOC-CH(NH 2 )-d-C 4 alkyl-NH-, ZOOC- CH(NH(CO-pheny
  • R 6 is a residue that does not interfere with the ring-closure; preferred is COCH 3 , COCH 2 CH 3 , COOCH 3 , COCH 2 CH 3 , C N , S O 2 C C 4 alkyl, SO 2 aryl, and NO 2 ; more preferred is CN, COCH 2 CH 3 , or COCH 3 ;
  • R 7 is a residue that does not inter ere with the ring-closure; preferred is hydrogen, d- C 10 alkyl, CF 3 , and aryl; more preferred is d-C 4 alkyl, CF 3 , and aryl; even more preferred is methyl;
  • R 8 is a residue that does not interfere with the ring-closure; preferred is C ⁇ -C 4 alkyl, unsubstituted or substituted with halogen NO 2 , CN, OH or NH 2 , and aryl; more preferred is phenyl; R 9 is a residue that does not interfere with the ring-closure; preferred is aryl, pyridyl,
  • step c) a nucleophile of formula 10 is used
  • R 9 is as defined above, inclusive the respective preferences.
  • suitable aryl groups are, for example, thienyl, pyrrolyl, indolyl, thiantrenyl, furyl, phenoxanthiinyl, benzofuranyl, isobenzofuranyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, stilbenyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, phenyl, naphthyl, anthranyl and phenanthranyl; wherein these groups are unsubstituted or substituted by groups like fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, e
  • R 1 * is C 2 -C 6 alkyl S " ;
  • R is aryl; preferred is phenyl; R 14 is aryl; preferred is phenyl;
  • R 15 is aryl; preferred is phenyl;
  • R 16 is COOC ⁇ -C 4 alkyl, d-doalkyl, unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, or aryl; preferred is d-C 4 alkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl, isopropyl, COOCH 3 , COOCH 2 CH 3 or CH 3 ; more preferred is COOCH 3 , COOCH 2 CH 3 and CH 3 ; and wherein aryl is as defined above.
  • the resulting compounds can be released from the solid carrier for example by using the following reaction step:
  • the solid carrier is a particle that is insoluble in the reaction media and to which the ligand can be bound in sufficient amount by means of reactive groups at the surface of the particle.
  • the solid carrier comprises a resin, e.g. polystyrene.
  • the binding of a target compound to the solid carrier is effected, e.g. by a linker bearing a amino, carboxyl, hydroxyl, halogen or silyl group.
  • These reactive groups are usually already constituents of the solid carrier, but they can also be applied or modified subsequently.
  • the solid carrier customarily employed in solid-phase synthesis can be used, for example those used in errifield peptide synthesis. They consist largely of a polystyrene molecule that is crosslinked by copolymerization with divinyl benzene. The molecules are additionally derivatized to attach the reactants in the solid-phase synthesis.
  • a solid carrier comprising a resin, in particular polystyrene, having attached thereto the Rink amide linker (H. Rink, Tetrahedron Lett. (1987), 28, 3787).
  • the inventive solid phase synthesis can be used for the generation of combinatorial compound libraries, e.g., in a the split and mix concept (Furka et al., Abstr. 14th Int. Congr. Biochem., Prague (1988), 5, 47; Furka et al., Int. J. Peptide Protein Res. (1991), 37, 487).
  • the inventive libraries may also be synthesized using taging methods in order to analyze the structure of a hit after screening suitable tagging methods are generally known and are described, for example in WO-9306121 and WO-9408051.
  • Another embodiment of the invention is the use of the inventive solid phase synthesis for the simultaneous synthesis of several single compounds, for example using an array of pins, microtiter plates and the like.
  • the solid carrier is loaded with a carboxylic acid bearing an aldehyde or a methylketone function.
  • the carbonyl group of the added compound is activated by standard methods and anchored, e.g., to the acid labile Rink amide linker on polystyrene (Rink, Tetrahedron Lett. (1987), 28, 3787).
  • 4-(2',4'-Dimethoxyphenyl-fmoc-aminomethyl)phenoxy resin (Rink amide resin) is subjected to repeated washes with about 20% piperidine/DMA until no UV absorption from Fmoc is detected in the eluate.
  • NH2-Nnker group is acylated with about 3 eq of acetyl carboxylic acid at RT (preactivation with about 3.3 eq DICD and about 3.3 eq HOBt) until the Kaiser test (Kaiser et al., Anal. Biochem. (1970), 34, 595) is negative.
  • an ⁇ , ⁇ -unsaturated carbonyl group is introduced by a) applying an aldol condensation to the aldehyde group, e.g., by treating the methyl ketone group with anhydrous dioxane, adding LiOH and a suitable aldehyde, as defined above; or b) applying the Wittig reaction to the mehtylketone group, e.g., by treating the resin bound aldehyde group with a triphenyl phosphine as defined above in DMA.
  • Other suitable conditions for these chemical reactions are generally known and are performed routinely, e.g. the Wadsworth-Emmons reaction.
  • a ring is closed by reacting the ⁇ , ⁇ -unsaturated carbonyl group with a compound comprising two nucleophiles, wherein at least one of said nucleophiles is NH 2 .
  • the compounds are chemically cleaved from the support according to known methods. For example, if the Rink amide linker is used, cleavage from the support is done by treatment with about 20% v/v TFA/CH 2 CI 2 (Rink, Tetrahedron Lett. (1987), 28, 3787).
  • a method for the preparation of a combinatorial compound library comprising, for example, the reaction steps as described above, inclusive the respective preferences, wherein optionally before a reaction step is carried out, a) the resin pool is divided into different portions, b) said reaction step is carried out in each portion using a different chemical compound or reaction, and c) the portions are mixed together.
  • a solid carrier having reactive surface groups is loaded directly or via a spacer group with a compound bearing an aldehyde or a methylketone function; or the resin is divided first into several portions then each portion is loaded directly or via a spacer group with a different compound bearing an aldehyde or a methylketone function and mixed again. Afterwards, if necessary, the pool containing the modified resin is divided into several separate portions again. The Wittig reaction or the aldol condensation is carried out in each portion using a different reagent to get different compounds.
  • inventive library can be cleaved from the resin before or after screening.
  • Methods for the identification of the inventive compounds are generally known. For example, such methods are based on tagging or sequential unrandomization, or on microanalytical technologies, like cleavage of single beads and mass spectrometry identification.
  • a further embodiment of the invention comprises a compound library produced with or obtainable by the inventive method, inclusive the respective preferences thereof, and the use of this compound library, especially for screening purpose.
  • HOBt 1 -hydroxybenzotriazole
  • DICD diisopropylcarbodiimide
  • HPLC(I) analytical separation is achieved using a reverse phase purospher rp-18 5 ⁇ 125 mm x 4 mm column, 215 nm, 5-100% CH 3 CN/0.1% TFA over 20 min, 1 ml/min.
  • a part of the eluate (split 1 :25) is introduced into a Quattro-BQ mass spectrometer (VG Biotech, Altrincham, England), operated at a source temperature of 60°C and a cone voltage of 50 V, via an electrospray interface (El).
  • the mass range from 100 to 800 Dalton is scanned in 4 seconds.
  • HPLC(II) analytical separation is achieved using a reverse phase nucleosil C18 5 ⁇ 250 mm x 4.6 mm column, 215 nm, 10-90% CH 3 CN/0.1% TFA over 30 min, 1 ml/min.
  • HPLC(III) analytical separation is achieved using the same conditions as described for HPLC(II), however, the gradient is run for 10 min.
  • Kaiser test is performed as described in Kaiser et al., Anal. Biochem. (1970), 34, 595.
  • Example 6 Claisen-Schmidt reaction of immobilized methylketone To a 4 ml glass vial containing 50.0 mg of compound of formula e3 on Rink amide resin (20.2 ⁇ mol) in 1.6 ml anhydrous dioxane is added 17.0 mg of LiOH-H 2 O (404 ⁇ mol) and 404 ⁇ mol of the appropriate aldehyde (R 2 COH; see table 2). The vial is capped and shaken for 16 hours at room temperature. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH 2 CI 2 consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 ⁇ l 20 % v/v TFA/ CH 2 CI 2 for 15 min affords chalcone derivatives of formulae e4a- e4g (see table 2).
  • Example 15 Synthesis of pyridines of formulas e11 a to e11 c (a) Synthesis of a pyridine of formula e11 a
  • a dry flask is charged with 2.76 mmol LDA and 10 ml THF at -78°C under N 2 atmosphere, and a solution of diethyl methyl phosphonate (365 ml, 2.5 mmol) in 12.5 ml THF is added. After stirring for 1 h at -78°C, a solution of m-tolunitril in 5 ml THF is added. 1 ml of this reaction mixture is then added to a vial containing 10 mg (4.5 mmol) of the compound of formula e2a on Rink amide resin. The mixture is shaken for 14 h at rt under air atmosphere.
  • the resin is washed with glacial acetic acid, DMA, i-PrOH and CH 2 CI 2 consecutively and air dried.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une étude portant sur une séquence réactionnelle sur phase solide, conçue pour la production d'une diversité moléculaire sur de petits hétérocycles. Pour chaque réaction, on a mis au point des conditions appropriées sur phase solide, et on a utilisé divers agents réactifs (éléments structuraux) dans une tentative de saisir l'ampleur des possibilités d'application du système. On peut appliquer la séquence réactionnelle de l'invention, par exemple pour exploiter des approches combinatoires du concept 'cliver et mélanger'. La séquence réactionnelle comprend les étapes suivantes consistant: a) à charger, directement ou via un groupe espaceur, un support solide possédant des groupes de surface réactifs, à l'aide d'un composé portant un aldéhyde ou une fonction méthylcétone, b) à modifier cette fonction en utilisant une réaction de Wittig ou la condensation d'aldol, et c) à fermer le noyau hétérocyclique à l'aide d'un composé comprenant deux nucléophiles, dont l'un au moins est NH2.
PCT/EP1997/005547 1996-10-09 1997-10-08 Synthese en phase solide de composes heterocycliques WO1998015532A1 (fr)

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Cited By (10)

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WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones
US6376535B2 (en) 1998-09-03 2002-04-23 Kyowa Hakko Kogyo Co., Ltd. Oxygen-containing heterocyclic compounds
US6914069B2 (en) 2000-05-19 2005-07-05 Applied Research Systems Ars Holding N.V. Pharmaceutically active compounds and methods of use
JP2008515992A (ja) * 2004-10-13 2008-05-15 ピーティーシー セラピューティクス，インコーポレーテッド 体細胞変異に起因する疾患の阻止／治療用医薬を製造するための規定化合物の使用
US7737164B2 (en) 2006-05-18 2010-06-15 Wisconsin Alumni Research Foundation Cyanopyridine antibacterial agents
US20110306775A1 (en) * 2010-06-10 2011-12-15 Kaohsiung Medical University Synthesis and biological evaluation of 2',5'-dimethoxychalcone derivatives as microtubule-targeted anticancer agents
US8367680B2 (en) 2008-03-28 2013-02-05 Wisconsin Alumni Research Foundation Antibacterial small molecules and methods for their synthesis
EP2581849A1 (fr) 2002-07-24 2013-04-17 Keddem Bio-Science Ltd. Procédé de découverte de médicaments
US8815943B2 (en) 2007-03-19 2014-08-26 Wisconsin Alumni Research Foundation Modulation of bacterial quorum sensing with synthetic ligands
US10526278B2 (en) 2017-10-19 2020-01-07 Wisconsin Alumni Research Foundation Inhibitors of quorum sensing receptor LasR

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US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support
WO1996030393A1 (fr) * 1995-03-27 1996-10-03 Warner-Lambert Company Procede de synthese de melanges de composes

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WO1996030393A1 (fr) * 1995-03-27 1996-10-03 Warner-Lambert Company Procede de synthese de melanges de composes

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J. S. FRÜCHTEL; G. JUNG: "Organic Chemistry on Solid Supports", ANGEWANDTE CHEMIE, INT. ED. ENGL., vol. 35, no. 1, 19 January 1996 (1996-01-19), pages 17 - 42, XP000548938 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376535B2 (en) 1998-09-03 2002-04-23 Kyowa Hakko Kogyo Co., Ltd. Oxygen-containing heterocyclic compounds
WO2000053545A1 (fr) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Procede de synthetisation de dihydropyridones
US6914069B2 (en) 2000-05-19 2005-07-05 Applied Research Systems Ars Holding N.V. Pharmaceutically active compounds and methods of use
US7456201B2 (en) 2000-05-19 2008-11-25 Laboratoires Serono Sa Pharmaceutically active compounds and methods of use
EP2581849A1 (fr) 2002-07-24 2013-04-17 Keddem Bio-Science Ltd. Procédé de découverte de médicaments
JP2008515992A (ja) * 2004-10-13 2008-05-15 ピーティーシー セラピューティクス，インコーポレーテッド 体細胞変異に起因する疾患の阻止／治療用医薬を製造するための規定化合物の使用
US9315467B2 (en) 2004-10-13 2016-04-19 Ptc Therapeutics, Inc. Compounds for nonsense suppression, and methods for their use
US8227616B2 (en) 2006-05-18 2012-07-24 Wisconsin Alumni Research Foundation Cyanopyridine antibacterial agents and methods of use thereof
US7737164B2 (en) 2006-05-18 2010-06-15 Wisconsin Alumni Research Foundation Cyanopyridine antibacterial agents
US8618327B2 (en) 2006-05-18 2013-12-31 Wisconsin Alumni Research Foundation Antibacterial agents and methods of use thereof
US8815943B2 (en) 2007-03-19 2014-08-26 Wisconsin Alumni Research Foundation Modulation of bacterial quorum sensing with synthetic ligands
US9796694B2 (en) 2007-03-19 2017-10-24 Wisconsin Alumni Research Foundation Modulation of bacterial quorum sensing with synthetic ligands
US8367680B2 (en) 2008-03-28 2013-02-05 Wisconsin Alumni Research Foundation Antibacterial small molecules and methods for their synthesis
US20110306775A1 (en) * 2010-06-10 2011-12-15 Kaohsiung Medical University Synthesis and biological evaluation of 2',5'-dimethoxychalcone derivatives as microtubule-targeted anticancer agents
US10526278B2 (en) 2017-10-19 2020-01-07 Wisconsin Alumni Research Foundation Inhibitors of quorum sensing receptor LasR

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