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WO1998015532A1 - Solid phase synthesis of heterocyclic compounds - Google Patents

Solid phase synthesis of heterocyclic compounds 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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solid phase
aryl
phase synthesis
heterocyclic ring
ring according
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PCT/EP1997/005547
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French (fr)
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/en

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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
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    • 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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Abstract

Here we report a study on a reaction sequence on solid phase, suitable for the generation of molecular diversity on small heterocycles. For each reaction, suitable conditions on solid phase were worked out and a variety of reactive agents (building blocks) was utilized in an effort to grasp the system's breadth of applicability. The inventive reaction sequence can be applied, for example, to exploit by the combinatorial approaches of the split and mix concept. The reaction sequence 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 methylketon function, b) said function is modified using the Witting reaction or the aldol condensation, c) the heterocyclic ring is closed using a compound comprising two nucleophiles, wherein at least one of the said nucleophiles is NH2.

Description

SOLID PHASE SYNTHESIS OF HETEROCYCLIC COMPOUNDS
The synthesis of combinatorial compound libraries is rapidly taking on the role of a powerful component within modern lead finding processes that aim at the identification of compounds with novel target activities of interest. In the drug discovery context, the ability to synthesize small organic molecules with high yield on a solid support has a definite strategic relevance. It facilitates the preparation of compound arrays in multiple parallel syntheses and enables the application of combinatorial methods for the synthesis of large libraries suitable for systematic evaluations in biochemical or biological test systems. In view of the expected biostability and bioavailability, small organics (e.g. heterocycles) rather than chain-like biooligomers are more attractive leads for subsequent medicinal chemistry efforts.
Here we report a scope and limitation study on a reaction sequence on solid phase, suitable for the generation of molecular diversity on small heterocycles. For each reaction, suitable conditions on solid phase were worked out and a variety of reactive agents (building blocks) was utilized in an effort to grasp the system's breadth of applicability. The inventive reaction sequence can be applied, for example, to exploit the combinatorial approaches of the split and mix concept. Surprisingly, using the inventive method a new facile way for the synthesis of combinatorial compound libraries consisting of modified heterocyclic rings in high yields and purity is provided. These combinatorial compound libraries serve as valuable reservoirs for the screening for pharmaceutically active compounds.
Detailed description of the invention
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 NH2.
In a preferred embodiment of the invention in step a) the compound bearing an aldehyde or a methylketone function is of formula 1 or 2 HOOC R1 (2)
Figure imgf000004_0001
wherein:
R1a or R1b 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-ι-C10alkylene, OCrCι6alkylene with preference given to OCrC10alkylene, C2-C10alkenylene and OC2-Cι0alkenylene; 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, CH2, C2H2) OCH2, OCH2CH2)
Figure imgf000004_0002
In a preferred embodiment of the invention R1a 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 C4alkylene and Od-C4alkylene; 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, CH2, C2H2, OCH2, and OCH2CH2. In a more preferred embodiment of the invention R1a is phenylene,
furanylene, thienylene, 1 -methyl-pyrrolylene or
Figure imgf000004_0003
R1b preferably is arylene or X-aryl, wherein X is CrCι0alkylene, OC Cι0alkylene, C2-C10alkenylene or OC2-C10alkenylene unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy, and wherein aryl and arylene are as defiend below. Suitable X groups are, for example, (CH2)1-4, (C H2)ι^O, CH=CH(CH2)ι-4, o r CH=CH(CH2)1-4θ. In a more preferred embodiment of the invention, R1b is phenylene, biphenylene, pyrrolylene,
Figure imgf000004_0004
In another preferred embodiment of the invention in 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
Figure imgf000005_0001
wherein:
R2 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 Cι0alkyiene, C2-Cι0alkenylene and C2-Cι0alkinylene, and wherein aryl is as defined below.
In case of formula 3, in a preferred embodiment R2 is Cι-C4alkyl, CrC4alkenyl, or C C4alkinyl, unsubstituted or substituted with fluoro, chloro, or bromo, or R2 is aryl wherein aryl is as defined below. In a more preferred embodiment R2 of formula 3 is C1-C4alkyl, phenyl, naphthyl, 4-NO2C6H4) 2,4-(NO2)2C6H3, 2,4-CI2C6H3l 2,4-(CH3)2C6H3) 2,4- (CH3O)2C6H3, 4-CH3OC6H4, 2-CIC6H4, thienyl, pyrrolyl or pyrazinyl.
In case of formula 4, R2 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. In an even more preferred embodiment R2 is phenyl, naphthyl, 4-NO2C6H4, 2,4-(NO2)2C6H3, 2,4- CI2C6H3, 2,4-(CH3)2C6H3, 2,4-(CH3O)2C6H3, 4-CH3OC6H4) 2-CIC6H4, thienyl, pyrrolyl, pyrazinyl or ethylpyrazinyl.
In case of formula 5, R2 is aryl, or unsubstituted or substituted aryl-Y, wherein aryl is as defined below, and wherein Y is selected from the group consisting of Cι-Cι0alkylene, C2-C10alkenylene and C2-C10alkinylene. In a preferred embodiment thereof, R2 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. In an even more preferred embodiment thereof, R2 is phenyl, naphthyl, 4-NO2C6H , 2,4- (NO2)2C6H3, 2,4-CI2C6H3, 2,4-(CH3)2C6H3, 2,4-(CH3O)2C6H3, 4-CH3OC6H4, 2-CIC6H4, thienyl, pyrrolyl, pyrazinyl or ethylpyrazinyl, propyl or isopropyl.
A preferred R3 is hydrogen, d-Cioalkyl, C Cι0alkenyl and C Cι0alkinyl; preferred is hydrogen, methyl or ethyl. ln another preferred embodiment of the invention in step c) the nucleophile is of formula 6, 7, 8, 9, 10 or 10a
4 j? (6), R5 (7), R7 (8), Rβ (9) , <1°)
I π2 M HNNI K NIMH„ V 'MNUL U HMN —- KNIMH, M H2MN K NllH,
(10a)
H2N NH2 wherein
R4 is a residue that does not interfere with the ring-closure; preferred is aryl, -X, -OX, - COX, CONHX, CONH2, CONHaryl, or -NO2 wherein X is C C10alkyl or C2-C10alkenyl which is unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or i-propyl; more preferred is COC C4alkyI, CONHd- C4alkyl, CN and CONHaryl; even more preferred is CONH2) CN;
R5 is a residue that does not interfere with the ring-closure; preferred is aryl, adamantyl, morpholino, -X, -COX, -NH2, -NHY, -NX2, C3-C7cycloalkyl, aryl or -XOaryl unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, carbamoyl, methoxy, ethoxy, methyl, ethyl, propyl, i-propyl or CF3l wherein X is Cι-Cιoalkyl or C2-Cι0alkenyl, and wherein Y is C doalkyl, C2-C10alkenyl, aryl-NH-C(NH)-NH-, ZOOC-CH(NH2)-d-C4alkyl-NH-, ZOOC- CH(NH(CO-phenyl))-d-C4alkyl-NH- or ZOOC-CH(OH)-d-C4alkyl-NH-, wherein Z is H, aryl or C C alkyl; more preferred is 2,4-(CH3O)2C6H3, 2,4-CI2C6H3, phenyl, pyrrolyl, pyrazinyl, thienyl, 4-CH3OC6H4, cyclopropyl, pyridyl, isothiazolyl, methyl-isothiazolyl, t- butyl, methyl, trifluoromethyl, amino, -CH2CH2CONH2, -CH2OC6H5, phenyl-NH-C(NH)- N H - , H O O C -CH(NH2)-(CH2)3- N H - , H O O C -CH(NH(CO-phenyl))-(CH2)3- N H - , o r HOOC-CH(OH)-(CH2)3-NH-;
R6 is a residue that does not interfere with the ring-closure; preferred is COCH3, COCH2CH3, COOCH3, COCH2CH3, C N , S O2C C4alkyl, SO2aryl, and NO2; more preferred is CN, COCH2CH3, or COCH3;
R7 is a residue that does not inter ere with the ring-closure; preferred is hydrogen, d- C10alkyl, CF3, and aryl; more preferred is d-C4alkyl, CF3, and aryl; even more preferred is methyl;
R8 is a residue that does not interfere with the ring-closure; preferred is Cι-C4alkyl, unsubstituted or substituted with halogen NO2, CN, OH or NH2, and aryl; more preferred is phenyl; R9 is a residue that does not interfere with the ring-closure; preferred is aryl, pyridyl,
thienyl, purinyl, and
Figure imgf000007_0001
unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, C C4alkyl, CF3| COOCH3, OCH3 or OCH2CH3; more preferred is diaminopyridyl, thienyl, purinyl, and phenyl: and wherein aryl is as defined below.
Further preference is given to a solid phase synthesis according to the present invention, wherein in step c) a nucleophile of formula 10 is used
(10)
&
H2N NH2
wherein R9 is as defined above, inclusive the respective preferences.
Within the context of the present invention, and if not specified otherwise, 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, ethyl, propyl, isopropyl, hydroxy, phenyl, phenoxy, SCH3, CF3 or CN, of which fluoro, chloro, bromo, nitro, methoxy or ethoxy are preferred. Suitable arylene groups are derived from the respective aryl groups as specified above.
Preferred examples for the claimed reactions are given in the reaction schemes below
Figure imgf000007_0002
,N resin'
Figure imgf000008_0001
Figure imgf000008_0002
wherein the variables R ,1ιaa, r R-)11bD, and R2 to R9 are as defined herein, inclusive the respective preferences;
and in the case of the synthesis of benzodiazepines, which constitutes a preferred embodiment of the present invention, further modifications are possible and useful. These additional modification steps are also part of the invention, and are exemplified as follows:
Figure imgf000009_0001
Figure imgf000010_0001
wherein
R10 is d-C10alkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, or aryl; preferred is d-C4alkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl; more preferred is t-butyl and CF3; R11 is d-dalkyl, C C4alkylCOCH2) CH2=CH-CH2, aryl COCH2l or CNCH2; preferred is methyl and ethyl;
»12
R1* is C2-C6alkyl S";
R is aryl; preferred is phenyl; R14 is aryl; preferred is phenyl;
R15 is aryl; preferred is phenyl;
R16 is COOCι-C4alkyl, d-doalkyl, unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, or aryl; preferred is d-C4alkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl, isopropyl, COOCH3, COOCH2CH3 or CH3; more preferred is COOCH3, COOCH2CH3 and CH3; and wherein aryl is as defined above.
Such reaction steps leading to compounds nos. 11 to 19, respectively, are a preferred embodiment of the present invention.
The resulting compounds can be released from the solid carrier for example by using the following reaction step:
H I .NL 20% TFA CHpC H.NL ^' resin^ »
O O
Usually 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. In a preferred embodiment of the invention 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. Preferred is 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.
Also embraced by the scope of the invention is the combinatorial compound library obtainable by said method.
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.
General method for the synthesis:
Step a)
For example, in a first reaction step, 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. Than the 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.
Step b)
In a second reaction step an α, β-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. Step c)
In a third reaction step a ring is closed by reacting the α, β-unsaturated carbonyl group with a compound comprising two nucleophiles, wherein at least one of said nucleophiles is NH2.
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/CH2CI2 (Rink, Tetrahedron Lett. (1987), 28, 3787).
Also embraced by the scope of the invention is 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.
In order to synthesize a combinatorial compound library, e.g. according to Houghten et al. Nature (1991) 354, 84-86; 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. These separated pools are mixed and, if appropriate, divided again into several separate portions in which the heterocyclic ring is closed using a compound comprising two nucleophiles, as defined above and, afterwards, the separated pools are mixed again. If desired, the mixture may be divided into several separate portions again for carrying out one or more further modifications in common or to generate a further diversity of the library. After mixing, a combinatorial compound library has been created that is suitable, e.g., for screening.
Especially in the case of benzodiazepines further modifications are suitable to increase the variability of the substitution schemes of the individual compounds of the library.
In order to avoid side effects the 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.
Accordingly, 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.
The following examples are given for illustrative purposes without limitation and refer to preferred embodiments of the present invention.
Experimental Part
Abbreviations:
HOBt = 1 -hydroxybenzotriazole
DICD = diisopropylcarbodiimide
DMA = dimethylacetamide
DMF = dimethylformamide
Fmoc = fluorenylmethyloxycarbonyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran General Methods
HPLC(I) analytical separation is achieved using a reverse phase purospher rp-18 5μ 125 mm x 4 mm column, 215 nm, 5-100% CH3CN/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 μ 250 mm x 4.6 mm column, 215 nm, 10-90% CH3CN/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 1 : Preparation of a compound of formula e1
Figure imgf000015_0001
5g (2.25 mmol) 4-(2',4'-Dimethoxyphenyl-fmoc-aminomethyl)phenoxy resin (Rink amide resin) is subjected to repeated washes with 20% piperidine/DMA until no UV absorption from Fmoc is detected in the eluate, followed by 5 washes with DMA. The NH2-linker group is acylated with 22.5 ml of a 0.3M-solution of 4-carboxybenzaldehyde (6.75 mmol) at r.t. (preactivation 40 min with 3.3 eq DICD (7.23 mmol) and 3.3 eq HOBt (7.23 mol)) until the Kaiser test is negative.
Example 2: Preparation of a compound of formula e3
(e3)
Figure imgf000015_0002
5g (2.25 mmol) 4-(2',4'-Dimethoxyphenyl-fmoc-aminomethyl)phenoxy resin (Rink amide resin) is subjected to repeated washes with 20% piperidine/DMA until no UV absorption from Fmoc is detected in the eluate, followed by 5 washes with DMA. The NH2-linker group is acylated with 22.5 ml of a 0.3 M-solution of acetophenone-4-carboxylic acid (6.75 mmol) at r.t. (preactivation 40 min with 3.3 eq DICD (7.23 mmol) and 3.3 eq HOBt (7.23 mol)) until the Kaiser test is negative.
Example 3: Preparation of compounds of formulae e2a -e2i
Figure imgf000016_0001
To a 4 ml glass vial containing 50.0 mg the compound of formula e1 on Rink amide resin (19.7 μmol) in 1.6 ml anhydrous DME is added 16.5 mg of LiOH-H2O (394 μmol) and 394 μ mol of the appropriate methylketone (R2COCH3; see table 1). The vial is capped and shaken for 16 hours at room temperature. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min affords chalcone derivatives of formulae e2a-e2i.
Table 1
X R2 purity Rf ) M X R2 purity Rf(l) M
2a CβHs 93 % 11.5 251 2f 2-NO2C6H4 80 % 10.7 296
2b 2,4-(CH3O)2C6H3 94 % 1 1.6 311 2g 2-CIC6H4 83 % 11.8 285
2c 4-CH3OC6H4 44 % 11.6 281 2h CH3CH2CH2 18 % 10.2 217
2d «- 83 % 10.5 281 " 78 % 10.8 257 2i cχ
2e 100% 9.3 240
NH Example 4: Preparation of compounds of formula e2a by Wittig reaction
23.6 ml of a 0.5 M solution of
Figure imgf000017_0001
(5.91 mmol) in DMA is added to 2.00 g
(788 μmol) of the resin bound compound of formula e1 and the resulting mixture is shaken at 60°C for 14 hours. The resulting mixture is filtered, washed with DMA and i-PrOH and air dried in the filter. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min affords α, β-unsaturated ketone of formula e2a (see table 1 ; purity >95%, Rf(l)=11.5, M=251).
Example 5: Preparation of compounds of formula e2j by Wittig reaction
Figure imgf000017_0002
LI . ppn 23.6 ml of a 0.5 M solution of ^^ 3 (5.91 mmol) in DMA is added to 2.00 g (788 μmol) of the resin bound compound of formula e1 and the resulting mixture is shaken at
60°C for 14 hours. The resulting mixture is filtered, washed with DMA and i-PrOH and air dried in the filter. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA CH2CI2 for 15 min affords α, β-unsaturated ketone of formula e2j (see table 1 ; purity >95%, R<(l)=7.3,
M=189).
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 μmol) in 1.6 ml anhydrous dioxane is added 17.0 mg of LiOH-H2O (404 μmol) and 404 μmol of the appropriate aldehyde (R2COH; 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 CH2CI2 consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/ CH2CI2 for 15 min affords chalcone derivatives of formulae e4a- e4g (see table 2).
Figure imgf000017_0003
Table 2:
X R2 purity Rf(l) M X R2 purity Rf(l) M a CβHβ 94 % 11.6 251 4e 2,4-CI2C6H3 77 % 14.5 320 b naphthyl 79 % 13.7 301 4f 2,4-(CH3O)2C6H3 92 % 13.5 279 c 4-NO2C6H3 89 % 11.9 296 4g i-propyl 49 % 10.7 217 d 2,4-(NO2)2C6H3 36 % 10.7 341
Example 7: Cyclization to pyrimidines of formulae e5a-e5m
To a solution of the
Figure imgf000018_0001
amidine hydrochloride (96 μmol, see table 3) in 96 μl DMA is added 96 μl of a 1 M suspension of NaOEt in DMA. Free amidines are used without treatment of NaOEt. The suspension is mixed by ultrasound for 5 min and centrifuged. The resultant solution is added to a the resin bound chalcone derivative e2a (9.6 μmol) in a reacti vial and the suspension is stirred under air atmosphere at 100°C over night. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min affords pyrimidines of formulae e5a- e5m (see table 3).
Table 3
Figure imgf000018_0002
Figure imgf000019_0001
Example 8: Formation of pyrimidines e6a-e6d
Figure imgf000019_0002
To a solution of benzamidine hydrochloride (79 μmol) in 79 μl DMA is added 79 μl of a 1 M suspension of NaOEt in DMA. The suspension is mixed by ultrasound for 5 min and centrifuged. The resultant solution is added to the corresponding resin bound chalcone derivatives (7.9 mmol, see table 4) in a reacti vial and the
Figure imgf000019_0003
suspension is stirred at 100°C over night under air atmosphere. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/ CH2CI2 for 15 min affords pyrimidines of formulae e6a-e6d (see table 4).
Table 4 X R2 purity Rf(l) M X R2 purity R.(i) M
6a 2,4-(CH3O)2C6H3 >95 % 17.4 411 6c 2,4-CI2C6H3 >95 % 19.0 420
6b r >95 % 17.4 340 6d >95 % 16.0 381
(X
Example 9: Formation of pyrimidines e7a-e7e
Figure imgf000020_0001
cr
To a solution of amidine hydrochloride H2N NH2 (78 μmol, see table 5) in 78 μl DMA is added 78 μl of a 1 M suspension of NaOEt in DMA. The suspension is mixed by ultrasound for 5 min and centrifuged. The resultant solution is added to the resin bound
α, β-unsaturated ketone (7.8 μmol) and the suspension is
Figure imgf000020_0002
stirred at 100°C in a reacti vial over night under air atmosphere. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and dried under high vacuum. Cleavage of 3mg of resin with 800 μl 20 % v/v TFA/ CH2CI2 for 15 min affords pyrimidines of formulae e7a-e7e (see table 5).
Table 5
X R6 purity Rf(l) M X R6 purity Rt(l) M
7a CβHs >95 % 26.4 289 7d NH2 >95 % 9.9 228
7b 4-CH3OC6H4 >95 % 25.4 319
7c >95 % 19.8 269 7e (x 291
Figure imgf000020_0003
Example 10; Synthesis of dihvdropyrimidinone e8a
Figure imgf000021_0001
To a 1.5 ml Eppendorf tube containing 4.7 mg (69 μmol) NaOEt in 276 μl anhydrous DMA is added 16.2 mg (6.9 μmol) resin loaded with compound of formula e2a and 5.1 mg (69 μmol) N-methyl urea. The reaction mixture is allowed to stand under Ar over night. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min yielded pyrimidinone of formula e8a (purity 90 %, R (l)=9.6, M=307).
Example 11 : Synthesis of dihvdropyrimidinone e8b
Figure imgf000021_0002
To a 1.5 ml Eppendorf tube containing 6.5 mg (96 μmol) NaOEt in 384 μl anhydrous DMA is added 20.0 mg (9.6 μmol) resin loaded with compound of formula e2a and 14.7 mg (96 μmol) benzyl urea. The reaction mixture is allowed to stand under Ar over night. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min yielded pyrimidinone of formula e8b (purity 90 %, Rf(ll)=24.9, M=383).
Example 12: Synthesis of pyridone of formula e9a
Figure imgf000021_0003
To a 1.5 ml Eppendorf tube containing 19.9 mg (177 μmol) potassium tert-butoxide in 355 μl anhydrous DMA is added 10.0 mg (4.0 μmol) resin loaded with the compound of formula e2a, 18.1 mg (177 μmol) of malonamide, and 23.7 mg (90 μmol) 18-crown-6. The reaction mixture is allowed to stand under Ar for 4 hours. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min yielded pyridone of formula e9a (purity 60 %, Rf(ll)=16.3, M=335).
Example 13: Synthesis of pyridone of formula e9b
Figure imgf000022_0001
To a 1.5 ml Eppendorf tube containing 9.6 mg (86 μmol) potassium tert-butoxide in 171 μl anhydrous DMA is added 10.0 mg (4.0 μmol) resin loaded with the compound of formula e2a, (86 μmol) of 2-cyanoacetamide, and 14.4 mg (54 μmol) 18-crown-6. The reaction mixture is allowed to stand under Ar for 4 hours. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min yielded pyridones of formula e9b (purity 90 %, R (ll)=19.6, M=306).
Example 14: Synthesis of pyrazole of formula e10
Figure imgf000022_0002
To a 1.5 ml Eppendorf tube containing 10.0 mg of the compound of formula e2a on Rink amide resin (4.5 μmol) is added 450 μl 0.5M solution of phenylhydrazine in DMA. The reaction mixture is shaken for 16 hours at room temperature. The resin is washed with DMA and i-PrOH consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/ CH2CI2 for 15 min affords pyrazole of formula e10 (purity 85 % one regioisomer,
Figure imgf000022_0003
Example 15: Synthesis of pyridines of formulas e11 a to e11 c (a) Synthesis of a pyridine of formula e11 a
Figure imgf000023_0001
To a 1.5 ml Eppendorf tube containing 20.0 mg of the compound of formula e2a on Rink amide resin (4.8 μmol) is added 350 μl acetonitrile and 10 mg (89 μmol) potassium tert- butoxide. The reaction mixture is sonicated for 50 min at room temperature under Ar and is allowed to stand over night. The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min affords pyrazole of formula e1 1 a (purity >95 % , Rf(ll)=13.2, M=313).
(b) Synthesis of a dihydropyridine of formula e11 b
Figure imgf000023_0002
To a vial containing 15.5 mg (6.5 mmol) of the compound of formula e2a on Rink amide resin, 14.6 mg (132 mmol) 3-amino-2-cyclohexane-1 -one, 0.35 ml DMSO and 14.8 mg (132 mmol) tert. BuOK are added. The reaction mixture is shaken for 5 h at rt under Argon . The resin is washed with glacial acetic acid, DMA, i-PrOH and CH2CI2 consecutively and air dried. The product is cleaved from the resin with 20% (v/v) TFA/CH2CI2 to afford dihydropyridine of formula e11 b (purity 72%, Rf(lll) =6.22, M=342).
(c) Synthesis of a pyridine of formula e11 c
Figure imgf000024_0001
A dry flask is charged with 2.76 mmol LDA and 10 ml THF at -78°C under N2 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 CH2CI2 consecutively and air dried. The product is cleaved from the resin with 20% (v/v) TFA/CH2CI2 to afford pyridine of formula e1 1c (purity 75%, Rf(lll) =8,95, M=364).
Example 16: Synthesis of a benzodiazepine of the formula e12
Figure imgf000024_0002
To a 5 ml glass vial containing 400 mg of the compound of formula e2a on a polyethylene glycol polystyrene based resin functionalized with the Rink linker (80 μmol) in 1 .6 ml anhydrous toluene is added 86.5 mg of ortho-Phenylenediamine (800 μmol) and 123 μl triethylamine (880 μmol). The vial is capped and shaken for 4 hours at 100°C. The resin is washed with H2O, DMA, and i-PrOH consecutively and air dried. The resulting resin is again treated with the same amount of reagents for 16 hours at 100°C. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 5 min affords benzodiazepine of formula e12 (R,(ll)=17.1 , M=341). Example 17: Acylation of the Benzodiazepin of formula e12
To a 1.5 ml Eppendorf tube containing 10.0 mg of the compound of formula e12 on Rink amide resin (4 μmol) is added a mixture of 5.9 μl acetylbromide (80 μmol) and 6.5 μl pyridine (80 μl) in DMA. The reaction mixture is standing for 2 hours at room temperature. The resin is washed with H2O, DMA, i-PrOH and CH2CI2 consecutively and air dried. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 5 min affords acetyl benzodiazepine of formula e13 (Rf(ll)=22.5, M=384).
Figure imgf000025_0001
Example 18: Synthesis of oxadiazolo benzodiazepines of formula e14
Figure imgf000025_0002
To a 5 ml reacti vial containing 20.0 mg of a compound of formula e13 on Rink amide resin (8 μmol) in 363 μl anhydrous toluene is added 8.7 μl of phenyl isocyanate (80 μmol), 2.9 μl nitroethane (40 μmol) and 11.2 μl triethylamine (80 μmol). The mixture is stirred for 5 hours at 100°C. The resin is washed with DMA, H2O and i-PrOH consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 15 min affords oxadiazolo benzodiazepines of formula e14 (regioisomers, R<(l)a=10.8, Rι(l)b=11.3, M=440). Example 19: Synthesis of oxadiazolo benzodiazepines of formula e15
Figure imgf000026_0001
To a 5 ml reacti vial containing 20.0 mg of a compound of formula e13 on Rink amide resin (8 μmol) in 363 μl anhydrous toluene is added 8.7 μl of phenyl isocyanate (80 μmol), 4.4 μl ethyl nitroacetate (40 μmol) and 1 1 .2 μl triethylamine (80 μmol). The mixture is stirred for 5 hours at 1 00°C. The resin is washed with DMA, H2O and i-PrOH consecutively and dried under high vacuum. Cleavage of 3 mg of resin with 800 μl 20 % v/v TFA/CH2CI2 for 1 5 min affords oxadiazolo benzodiazepines of formula e1 5 (regioisomers, R,(l)a=12.3, Rf(l)b=12.6, M=498).

Claims

Claims
1 . A 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 NH2.
2 . A solid phase synthesis of a heterocyclic ring according to claim 1 , characterized in that in step a) the compound bearing an aldehyde or a methylketone function is of formula 1 or 2
HOOCV.R1 (2)
Figure imgf000027_0001
wherein:
R1a or R1 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 d-Cι0alkylene, OCι-d6alkylene, C2-Cι0alkenylene or OCι-Cιoalkenylene; wherein the X and Y grou p may be unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy.
3 . A solid phase synthesis of a heterocyclic ring according to claim 1 , characterized in that in 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
Figure imgf000027_0002
wherein:
R2 is unsubstituted or substituted XH, X-aryl, aryl-Y, or X-aryl-Y; R3 is hydrogen, C Cι0alkyl, C C10alkenyl or C Cι0alkinyl;
X and Y are the same or different and are selected from the group consisting of Cι-C10alkyiene, d-C10alkenyiene and C Cι0alkinylene.
4 . A solid phase synthesis of a heterocyclic ring according to claim 1 , characterized in that in step c) the nucleophile is of formula 6, 7, 8, 9, 10 or 10a 4 π (6),
'2 HN
Figure imgf000028_0001
Figure imgf000028_0002
wherein
R4, R5, R7, R8, and R9 are residues that does not interfere with the ring-closure.
5 . Use of a solid phase synthesis according to claim 1 for the synthesis of a combinatorial compound library.
6. Method for the preparation of a combinatorial compound library, which comprises the reaction steps according to claim 1 , 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.
7. Use of a solid phase synthesis according to claim 1 for the synthesis of benzodiazepines.
8 . A solid phase synthesis of a heterocyclic ring according to claim 2, characterized in that the X and Y groups independent of one another are CH2, C2H2, OCH2, OCH2CH2, (CH2)1-4, (CH2)1-4O, CH=CH(CH2)^, or CH=CH(CH2)1-4O.
9. A solid phase synthesis of a heterocyclic ring according to claim 2, characterized in that R1a 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 d-C4alkylene and Od- dalkylene; wherein the X and Y group may be unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy.
10. A solid phase synthesis of a heterocyclic ring according to claim 2, characterized in
that R1a is phenylene, furanylene, thienylene, 1 -methyl-pyrrolyiene or
Figure imgf000029_0001
1 1. A solid phase synthesis of a heterocyclic ring according to claim 2, characterized in that R1b i s a ry l ene, X-aryl , wh erei n X is C Cι0alkylene, OCι-Cιoalkylene, C2-Cι0alkenylene or OC2-C10alkenylene, unsubstituted or substituted by bromo, chloro, fluoro, nitro, methoxy or ethoxy.
12. A solid phase synthesis of a heterocyclic ring according to claim 2, characterized in t h a t R 1b i s p h e n y l ene, biphenylene, py rro ly l ene, or
Figure imgf000029_0002
Figure imgf000029_0003
13. A solid phase synthesis of a heterocyclic ring according to claim 3, characterized in that R of formula 3 is C C4alkyl, d-dalkenyl, or Cι-C4alkinyl, unsubstituted or substituted with fluoro, chloro, or bromo, or R2 is aryl.
14. A solid phase synthesis of a heterocyclic ring according to claim 3, characterized in that R2 of formula 4 is aryl.
15. A solid phase synthesis of a heterocyclic ring according to claim 3, characterized in that R2 of formula 5 is aryl or aryl-Y, wherein Y is selected from the group consisting of d-C10alkylene, C2-C10alkenylene or C2-Cιoalkinylene.
16. A solid phase synthesis of a heterocyclic ring according to claim 3, characterized in that R3 is hydrogen methyl or ethyl.
17. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R7 is is hydrogen, Cι-C10alkyl, CF3, or aryl;
R8 is d-dalkyl, unsubstituted or substituted with halogen NO2, CN, OH or NH2, or R8 is aryl; and R9 is aryl, pyridyl, thienyl, purinyl,
Figure imgf000030_0001
unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, C C4alkyl, CF3, COOCH3, OCH3 or OCH2CH3.
18. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R4 is aryl, -X, -OX, -COX, CONHX, CONH2, CONHaryl, or -NO2, wherein X is d- Cioalkyl or C2-Cι0alkenyl, unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or i-propyl.
19. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R4 is CONH2 or CN.
20. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R5 is aryl, adamantyl, morpholino, -X, -COX, -NH2, -NHY, -NX2, C3-Cτcycloalkyl, aryl or -XOaryl unsubstituted or substituted with fluoro, chloro, bromo, iodo, nitro, carbamoyl, methoxy, ethoxy, methyl, ethyl, propyl, i-propyl or CF3, wherein X is d- C10alkyl or C2-C10alkenyl, and wherein Y is d-Cι0alkyl, C2-Cιoalkenyl, aryl-NH-C(NH)- NH-, ZOOC-CH(NH2)-d-C4alkyl-NH-, ZOOC-CH(NH(CO-phenyl))-C C4alkyl-NH- or ZOOC-CH(OH)-C C4alkyl-NH-, wherein Z is H, aryl or d-C4alkyl.
21 . A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R5 is 2,4-(CH3O)2C6H3, 2,4-CI2C6H3, phenyl, pyrrolyl, pyrazinyl, thienyl, 4- CH3OC6H4, cyclopropyl, pyridyl, isothiazolyl, methyl-isothiazolyl, t-butyl, methyl, trifluorom ethyl , ami no, -CH2CH2CONH2, o r -CH2OC6H5, phenyl-NH-C(NH)-NH-, HOOC-CH(NH2)-(CH2)3- N H - , H O O C -CH(NH(CO-phenyl))-(CH2)3- N H - , o r HOOC-CH(OH)-(CH2)3-NH-.
22. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R6 is OCH3, COCH2CH3, COOCH3, COCH2CH3, CN, SO2d-C4alkyl, SO2aryl or NO2.
23. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R6 is CN, COCH2CH3 or COCH3.
24. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R7 is methyl.
25. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R8 is phenyl.
26. A solid phase synthesis of a heterocyclic ring according to claim 4, characterized in that R9 is diaminopyridyl, thienyl, purinyl, or phenyl.
27. Use of a solid phase synthesis according to claim 1 for the synthesis of benzodiazepines wherein additional modification steps are added.
28. A solid phase synthesis of a heterocyclic ring according to claim 1 , characterized in that in step c) a nucleophile of formula 10 is used
Q (10).
H2N NH2
wherein R9 is as defined in claim 4.
29. A solid phase synthesis of a heterocyclic ring according to claim 28, characterized in that an additional modification step of formula (11) is added
Figure imgf000031_0001
wherein
R1a ,R2 ,R3 and R9 are as definded in claims 2, 3 and 4;
R10 i s C Cι0alkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, or R10 is aryl.
30. A solid phase synthesis of a heterocyclic ring according to claim 29, characterized in that R10 is d-dalkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl.
31. A solid phase synthesis of a heterocyclic ring according to claim 29, characterized in that the compound according to formula (11 ) is modified according to one of the steps leading to compounds nos.12 to 19
Figure imgf000032_0001
(11) <16>
Figure imgf000032_0002
Figure imgf000033_0001
wherein R1a ,R2 ,R3, R9, and R10 are as defined in claim 29;
R11 is d-dalkyl, C C4alkylCOCH2, CH2=CH-CH2) aryl COCH2, or CNCH2;
R12 is C2-C6alkyl S";
R 3, R 4, R15 are, independent of one another, aryl;
R16 is COOCrdalkyl, C C10alkyl, unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl or isopropyl, or R16 is aryl.
32. A solid phase synthesis of a heterocyclic ring according to claim 31 , characterized in that R13, R14, R15 are phenyl.
33. A solid phase synthesis of a heterocyclic ring according to claim 31 , characterized in that R16 is d-dalkyl unsubstituted or substituted with fluoro, chloro, bromo, nitro, methoxy, ethoxy, methyl, ethyl, propyl, isopropyl, COOCH3, COOCH2CH3 or CH3.
34. Use of a solid phase synthesis according to claim 1 for the synthesis of combinatorial compound library of benzodiazepines.
35. Combinatorial compound library obtainable by a method according to claim 6.
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Cited By (15)

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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 (en) * 1999-03-10 2000-09-14 Axys Pharmaceuticals, Inc. Process for the synthesis of dihydropyridones
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US7456201B2 (en) 2000-05-19 2008-11-25 Laboratoires Serono Sa Pharmaceutically active compounds and methods of use
EP2581849A1 (en) 2002-07-24 2013-04-17 Keddem Bio-Science Ltd. Drug discovery method
JP2008515992A (en) * 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 Use of prescribed compounds for the manufacture of medicaments for the prevention / treatment of diseases caused by somatic mutations
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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