WO2000002864A1 - Precurseur pour monomeres de pna - Google Patents

Precurseur pour monomeres de pna Download PDF

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WO2000002864A1
WO2000002864A1 PCT/EP1998/004281 EP9804281W WO0002864A1 WO 2000002864 A1 WO2000002864 A1 WO 2000002864A1 EP 9804281 W EP9804281 W EP 9804281W WO 0002864 A1 WO0002864 A1 WO 0002864A1
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group
formula
boc
amino
mmol
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Jürgen Martens
Wolfgang Maison
Imre Schlemminger
Ole Westerhoff
Harald GRÖGER
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Priority to AU90645/98A priority Critical patent/AU9064598A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C07K14/003—Peptide-nucleic acids (PNAs)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention is directed to compounds that are precursors for the synthesis of monomeric units usefull in the synthesis of polynucleotide analoues which bind to complementary DNA and RNA strands more strongly then corresponding DNA.
  • the invention concerns compounds for the synthesis of peptide nucleic acids.
  • PNAs peptide nucleic acids
  • the present invention provides precursors of monomers for the synthesis of PNA and PNA analogues with at least one protected carboxyiic group. These compounds have a protected carboxyiic end belonging to an ⁇ -amino acid. Furthermore two different groups are linked to the amino end of mentioned ⁇ -amino acid: an acyl residue and a organyl group which is substituted in the ⁇ -position by a hetero atom.
  • Fig. 1 is an example for the synthesis of a PNA monomer starting with an isocyanide, an oxo compound, an amino compound and a carboxyiic acid substituted by a nucleo base (thymine).
  • Fig. 2 is an example for the synthesis of a PNA monomer starting with an isocyanide, an imine and a carboxyiic acid substituted by a protected nucleo base (2-amino-6-benzyloxy purine).
  • each R and R ⁇ is independently selected from the group consisting of hydrogen, hydroxy, amino, fluorine, chlorine, bromine, iodine, (C]-C4)alkyl which may be amino- or hydroxy- or alkoxy- or alkylthio-substituted and (C6-Cio)aryl.
  • B is selected from the group consisting of hydrogen, (C ⁇ -C4)alkyl, naturally occuring nucleobases, non-naturally occuring nucleobases, aromatic moieties, heterocyclic moieties, DNA intercalators, nucleobase-binding groups, reporter ligands, vinyl, chlorine, bromine, iodine, and hydroxy.
  • D is ortho-phenylene or selected from the group consisting of formula (III)
  • R 4 R 6 (HI) where each R ⁇ , R4, R5 and R6 J S independently selected from the group consisting of hydrogen, (Ci-Cl3)alkyl, aryl which may both be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups and carbohydrate moieties, or R ⁇ and R ⁇ taken together complete an alicyclic system, or R J and R ⁇ taken together complete an alicyclic system;
  • E is CR ⁇ R ⁇ , where R ⁇ and R° is selected independently from the group consisting of hydrogen, (C ⁇ -Ci3)alkyl, aryl which may both be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups and carbohydrate moieties, or R ⁇ and R taken together complete an alicyclic or heterocyclic system which both may be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups.
  • each R9, Rl O and R ⁇ is independently selected from the group consisting of hydrogen, (C i -Cz ⁇ alkyl and aryl, or R9 and R ⁇ taken together with the vinyl group in formula (IV) complete a five or sixmembered alicyclic system which may be substituted by (C ⁇ -C4)alkyl or aryl, or R9 and R ⁇ O taken together with the vinyl group in formula (IV) complete an aromatic or heteroaromatic system which may both be substituted by nitro-, alkoxy-, and halogen groups.
  • Y is NR1 2R 1 3 ) where Rl 2 and R 3 is selected independently from the group consisting of hydrogen and an amino protecting group, or OR ⁇ , or SR ⁇ 4 where Rl 4 J S selected from the group consisting of hydrogen and a hydroxy or mercapto protecting group.
  • a preferred embodiment of the invention comprises compounds of formula (I) which are characterized in that
  • A is selected from the group consisting of a single bond, ortho-phenylene, or a group of formula (II) where n is 1, 2 or 3; each R! and R ⁇ is independently selected from the group consisting of hydrogen, hydroxy, chlorine, bromine, iodine, (Ci-C4)alkyl, and phenyl.
  • B is selected from the group consisting of hydrogen, (Ci-C4)alkyl, naturally occuring nucleobases, non-naturally occuring nucleobases, aromatic moieties, heterocyclic moieties, DNA intercalators, nucleobase-binding groups, reporter ligands, vinyl, chlorine, bromine, iodine, and hydroxy.
  • D is ortho-phenylene or selected from the group consisting of formula (III) where each R3 , R4 ; R5 and R° is independently selected from the group consisting of hydrogen, (C ⁇ - C6)alkyl, and phenyl or R- 5 and R ⁇ taken together complete an alicyclic system, or R ⁇ and Re ⁇ taken together complete an alicyclic system.
  • E is CR7R° , where R ⁇ and R ⁇ is selected independently from the group consisting of hydrogen, (C i-C i 3)alkyl, aryl which may both be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups and carbohydrate moieties, or R ⁇ and R ⁇ taken together complete an alicyclic or heterocyclic system which both may be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups.
  • X is a group of formula (IV) where each R ⁇ , R!
  • Rl 1 is independently selected from the group consisting of hydrogen, (Ci-C4)alkyl and aryl, or R ⁇ and RlO taken together with the vinyl group in formula (IV) complete a five or sixmembered alicyclic system which may be substituted by (C ⁇ -C4)alkyl or aryl, or R ⁇ and R ⁇ ⁇ taken together with the vinyl group in formula (IV) complete an aromatic or heteroaromatic system which may both be substituted by nitro- and alkoxy- groups.
  • Y is NR12R 1 3 ? where Rl 2 and R ⁇ 3 is selected independently from the group consisting of hydrogen and an amino protecting group, or OR ⁇ s where R ⁇ i s selected from the group consisting of hydrogen and a hydroxy protecting group.
  • a further preferred embodiment of the invention comprises compounds of formula (I) which are characterized in that
  • A is selected from the group consisting of ortho-phenylene, or a group of formula (II) where n is 1, 2 or 3; each R and R ⁇ is independently selected from the group consisting of hydrogen, (C ⁇ -C4)alkyl, and phenyl.
  • B is selected from the group consisting of naturally occuring nucleobases, non- naturally occuring nucleobases and nucleobase-binding groups.
  • D is ortho-phenylene or selected from the group consisting of formula (III) where each R , R4, R5 and R° is independently selected from the group consisting of hydrogen, and methyl or R- and R ⁇ taken together complete an alicyclic system.
  • E is CR?R8 , where R ⁇ and R ⁇ is selected independently from the group consisting of hydrogen, (C ⁇ -Cl3)alkyl, aryl which may both be substituted by alkyl-, hydroxy-, alkoxy-, nitro-, aryl-, alkoxycarbonyl-, halogen-groups and carbohydrate moieties, or R? and R ⁇ taken together complete an alicyclic or heterocyclic system.
  • X is a group of formula (IV) where R" and R*0 taken together with the vinyl group in formula (IV) complete a sixmembered alicyclic system which may be substituted by (Cj- C4)alkyl or phenyl, or R9 and RlO taken together with the vinyl group in formula (IV) complete an aromatic system which may be substituted by nitro- and methoxy-groups.
  • Y is NR12R 13 ; where Rl2 and R 3 is selected independently from the group consisting of hydrogen and an amino protecting group.
  • a further preferred embodiment of the invention comprises compounds of formula (I) which are characterized in that X is cyclohexen-1-yl, alkyl cyclohexen-1-yl or ortho-nitro phenyl.
  • a further preferred embodiment of the invention comprises compounds of formula (I) which are characterized in that B is thymine or a suitable protected derivative of adenine, cytosine, or guanine.
  • the invention also provides a method for the production of compounds of the general formula (I) which is characterized in that an oxo compound of the formula (V), where R ⁇ and R ⁇ have the meanings discussed above,
  • the synthesis of compounds of the general formula (I) can be performed in a one pot reaction as outlined in figure 1.
  • the reactants may be added in any sequence.
  • the temperature of the reaction is not critical; depending on the reactivity of the components, a temperature range between - 10°C and the boiling point of the particular solvent or solvent mixture is to be selected.
  • the reactions are carried out with advantage at 10°C to 50°C.
  • the synthesis of compounds of the general formula (I) preferably takes place in organic solvents such as e.g. alcohols, halogenated hydrocarbons, ethers, carboxyiic acid esters, dimethyl sulfoxide, dimethyl formamide, benzene, toluene or mixtures thereof.
  • organic solvents such as e.g. alcohols, halogenated hydrocarbons, ethers, carboxyiic acid esters, dimethyl sulfoxide, dimethyl formamide, benzene, toluene or mixtures thereof.
  • the stoichiometry of the reaction components is not critical; depending on the reactivity of the components per mole of said isocyanide there are employd 1.0 to 2.0 mole of said amino compound, 1.0 to 2.0 mole of said carboxyiic acid, and 1.0 to 10 mole of said oxo compound.
  • the reactions are carried out with advantage employing equimolar stoichiometry and exclusion of moisture.
  • the precipitated product is filtered off.
  • the solvent is distilled off the reaction mixture to give the crude product of the general formula (I) as a solid residue.
  • Such solid residues likewise remain which exhibit sufficient purity directly or after washing, recrystallization or chromatography.
  • the products obtained are then dried at temperatures between 20°C to 70°C.
  • B, D or E contain a DNA binding moiety, e. g. a nucleo base, and
  • B, D or E contain a protected amino group or hydroxy group.
  • Compounds having the formula (VIII) where B, D or E contain no nucleo base but a suitable leaving group, e. g. bromine, hydroxy, that may be replaced by a nucleo base by methods known in the literature (O. Buchardt et al. WO 92/20702 ; S. Thomson et al., WO 93/12129) can thus be transformed to monomers for the synthesis of PNA and PNA analogues.
  • NMR spectra were recorded on a Bruker AM 300 (300 MHz). Chemical shifts are listed in ppm. The following abbrevations are used in the listing of NMR-data: T-Ac-, N-l - thyminacetyl-; C-Z-Ac-, ⁇ -benzyloxycarbonyl-N-1 -cytosinacetyl-; A-Z-Ac, N 6 - benzyloxycarbonyl-N-9-adeninacetyl-; G-Z-Ac-, N -benzyloxycarbonyl-N-9-guaninacetyl-; G-Bz-Ac-, 2-amino-6-benzyloxy-N-9-purinacetyl; Th-Ac-, N-7-carboxymethyltheophylline, U-Ac-, N-1-carboxymethyluracil.
  • N- 1 -carboxymethylthymine N ⁇ -benzyloxycarbonylcytosin, N ⁇ -benzyloxy- carbonyl-N- 1 -carboxymethylcytosine, ⁇ -benzyloxycarbonyl-N-9-carboxymethyladenine, 2- amino-6-benzyloxy-N-9-carboxymethylpurine (K.L. Dueholm, M. Egholm, C. Behrens, L. Christensen, H.F. Hansen, T. Vulpius, K.H. Petersen, R. H. Berg, P. E. Nielsen, O. Buchardt J. Org. Chem.
  • Example 1 r ⁇ c-2-(7V-l-Thyminyl)-isopropionic acid 10 g (80 mmol) Thymine, 24.5 g (160 mmol) r c-2-bromopropionic acid and 30 g KOH are dissolved in 200 ml water and heated for twelve hours to 80 °C. After cooling to room temperature the solution is acidified to pH 5 with konc. HCl and the resulting precipitate (unreacted thymine) is filtered off. The filtrate is adjusted to pH 1 with konc. HCl and the resulting precipitate is filtered off and dried in vacuo.to give the title compound as a white solid in 3.7 g (23 %) yield.
  • Example 5 r ⁇ c-2-(7V-l-Thyminyl)-phenylacetic acid 5 g (40 mmol) Thymine, 8.30 g methyl r ⁇ c-2-chloro-phenylacetate and 6 g potassium carbonate are suspended in 150 ml dimethylformamide (abs.) and heated to reflux for two hours. The yellowish solution is stirred overnight at room temperature. The solution is evaporated to dryness in vacuo and the residue is dissolved in 200 ml dichloromethane and 200 ml water. After seperation of the two phases the water phase is extracted with 50 ml dichloromethane three times. The combined organic extracts are dried with MgS0 , filtered off and evaporated to dryness in vacuo.
  • the resulting yellowish oil is dissolved in 100 ml 2 N NaO ⁇ and heated to reflux for two hours. After cooling to room temperature the solution is adjusted to p ⁇ 1 with 4 N ⁇ C1. The water phase is extracted three times with 100 ml ethyl acetate and the combined organic extracts are dried with MgS0 , filtered off and evaporated to dryness in vacuo. The resulting precipitate is washed with ether. The product is obtained as a colourless solid in 5.79 g (56 %) yield.
  • the combined organic extracts are dried with MgS0 , filtered off and evaporated to dryness in vacuo.
  • the resulting yellowish oil is identified as the /won ⁇ -protected diamine, which contained less than 10 % by-products (detected by H-NMR-spektroskopy).
  • the pH is raised to twelve with aqueous 20 % NaOH and the solution extracted three times with ether.
  • the organics are combined and dried over MgS0 . Evaporation of the solvent in vacuo gives the amine as a white solid.
  • the precipitated hydrochlorid salt is dissolved in aqueous 2N NaOH and extracted with ether three times. After drying of the organics and evaporation of the solvent the two product portions are combined to give the amine in 323 g (90 %) yield.
  • the amine is dissolved in 311 ml formic acid and cooled to 0°C. To this stirred solution a mixture of 311 ml formic acid and 184 ml acetic anhydride is added via addition funnel.
  • the title compound is prepared as described in example 12 with 22.8 g (0.1 mol) 1-cyano-l- formamido-4-phenyl-cyclohexane being substituted 4-tert.-butyl-l-cyano-l -formamido- cyclohexane.
  • the resulting crude product is stirred with hot ⁇ -hexane and filtered off after cooling to give a white solid in 16.1 g (80 %) yield.
  • Example 15 rac-4-Phenyl-cycIohexen-l-yI-isocyanide
  • the title compound is prepared as described in example 14 with 20.1 g (0.1 mol) rac-N-(4- Phenyl-cyclohexen-l-yl)-formamide being substituted for N-(4-tert.-butyl-cyclohexen-l-yl)- formamide.
  • the resulting crude is applied to flash filtration on silica gel with dichloromethane/methanol, 99:1 to give the title compound as a yellowish solid in 13.1 g (71 %) yield.
  • Example 16 N-(2- ⁇ itro-4-methylphenyl)-formamide
  • 300 ml formic acid 152.2 g (1 mol) 2-nitro-4-methylaniline is dissolved and cooled to 0°C.
  • a mixture of 300 ml formic acid and 112 g acetic anhydride is added via addition funnel.
  • the reaction is quenched with 40 ml water and most of the solvent is evaporated in vacuo.
  • 250 ml of 2 N aqueous NaOH solution is added to the remaining residue and the resulting precipitate is collected, washed with 250 ml water three times and dried with ether.
  • Example 18 2-[(2'-Boc-aminoethyl)-thyminacetyl-amino]-acetic acid-cyclohexen-l"-yl-amide 0.32 g (2 mmol) m ⁇ n ⁇ -Boc-ethylendiamine, 0.37 g (2 mmol) N-1 -carboxymethylthymine and 0.06 g (2 mmol) paraformaldehyde are suspended in 7 ml abs. methanol and stirred for 10 min at room temperature. 0.21 g (2 mmol) cyclohexen-1-yl-isocyanide are added in one portion and the resulting suspension is stirred 48 hours at room temperature.
  • Example 20 r ⁇ c-2-[(2'-Boc-aminoethyl)- ⁇ -Z-cytosinacetyl-amino]-/; ⁇ r ⁇ -nitrophenylacetic acid- cyclohexen-l"-yl-amide 0.32 g (2 mmol) mo ⁇ o-Boc-ethylendiamine and 0.30 g (2 mmol) 4-nitro benzaldehyde are evaporated with toluene three times. The residue is dissolved in 7 ml abs. methanol and 0.61 g (2 mmol) ⁇ -Z-N-1-carboxymethyl cytosine are added.
  • Example 22 2-[(tr ⁇ M -2'-Boc-aminocyclohexyl)- ⁇ -Z-cytosinacetyl-amino]-3-methyl-propionic acid- cyclohexen-1 ⁇ -yl-amide
  • the product containing fractions are collected and the solvent is removed in vacuo to give the title compound as a white solid in 1.29 g (97 %) yield.
  • the product exists as a mixture of rotamers in a 73 : 17 ratio in CDCI 3 at room temperature.
  • the suspension is filtered and the filtrate is concentrated in vacuo.
  • the concentrate was purified by column chromatography on silica gel (dichloromethane/methanol, 9: 1). The product containig fractions were collected and the solvent removed in vacuo to give the title compound as a yellowish solid in 0.98 g (81 %) yield.
  • Example 35 r ⁇ c-2-[(2 , -Ib-amino-phenyl)-thyminacetyl-amino]-biphen-4 M '-yI-acetic acid
  • the title compound was prepared as described in example 29 with 0.35 g (0.55 mmol) rac-2- [(2'-Ib-amino-phenyl)-thyminacetyl-amino]-biphenyl-4-yl-acetic acid-cyclohexen- 1 "-yl-amide being substituted for 2-[(2'-Boc-aminoethyl)-thyminacetyl-amino]-acetic acid-cyclohexen- 1"- yl-amide in 0.20 g (66 %) yield as a yellowish solid.
  • Example 36 r c-2-[(2'-Ib-amino-phenyl)-thyminacetyl-amino]-ort ⁇ o-bromophenylacetic acid- cyclohexen-1 "-yl-amide
  • the title compound was prepared as described in example 19 with 0.37 g (2 mmol) 2-bromo benzaldehyde being substituted for 4-phenylbenzaldehyde as a yellowish solid in 0.56 g (44 %) yield.
  • Example 38 l-[(2'-Boc-aminoethyl)-thyminacetyI-amino]-cyclohexancarboxyIic acid-cyclohexen- l"-yl-amide
  • the title compound is prepared as described in example 18 with 0.20 g (2 mmol) cyclohexanone being substituted for paraformaldehyde as a white solid in 0.50 g (47 %) yield.
  • the title compound was prepared as described in example 29 with 0.60 g (1.2 mmol) 2-[(2'- Boc-aminoethyl)-thyminacety l-amino]-2-methyl-propionic acid-cyclohexen- 1 "-yl-amide being substituted for 2-[(2'-Boc-aminoethyl)-thyminacetyl-amino]-acetic acid-cyclohexen- 1 "-yl- amide as a white solid in 0.40 g (80 %) yield.
  • Example 41 l-[(2'-Boc-aminoethyI)-thyminacetyl-amino]-cyclohexancarboxylic acid
  • the title compound is prepared as described in example 29 with 0.50 g (0.94 mmol) l-[(2'- Boc-anrinoemyl)-thyrnmacetyl-amino]-cyclohexancarboxylic acid-cyclohexen- 1 "-yl-amide being substituted for 2-[(2'-Boc-aminoethyl)-thyminacetyl-amino]-acetic acid-cyclohexen- 1"- yl-amide as a white solid in 0.35 g (82 %) yield.
  • the tilte compound is prepared as described in example 29 with 0.30 g (0.42 mmol) rac-2- [(2'-Boc-aminoethyl)- ⁇ -Z-adeninacetyl-amino]-ort/zo-chlorophenylacetic acid-cyclohexen- 1"- yl-amide being substituted for 2-[(2'-Boc-aminoethyl)-thyminacetyl-amino]-acetic acid- cyclohexen- 1 "-yl-amide as a white solid in 0.21 g (78 %) yield.
  • the tilte compound is prepared as described in example 20 with 0.28 g (2 mmol) 2- chlorobenzaldehyde being substituted for 4-nitrobenzaldehyde as a white solid in 0.70 g (50 %) yield.
  • the tilte compound is prepared analoge to example 21 with 0.34 g (2 mmol) N- l - carboxymethyl uracil being substituted for ⁇ -Z-N-9-carboxymethyl adenine as a white solid in 0.70 g (63 %) yield.
  • the tilte compound is prepared as described in example 21 with 0.60 g (2 mmol) 2-amino-6- benzyloxy-yV-9-carboxymethyl purin being substituted for vv -Z-N-9-carboxymethyl adenine as a white solid in 0.29 g (21 %) yield.
  • the tilte compound is prepared as described in example 24 with 0.76 g (2.5 mmol) vv -Z-N-l- carboxymethyl cytosine being substituted for N-1-carboxymethyl thymine
  • the crude product is applied to column chromatography on silica gel (dichloromethane/methanol, 95:5) and is obtained as a white solid in 1.38 g (99 %) yield.
  • the tilte compound is prepared as described in example 24 with 0.81 g (2.5 mmol) N ⁇ -Z-N-9- carboxymethyl adenine being substituted for N-l -carboxymethyl thymine.
  • the crude product is applied to column chromatography on silica gel (dichloromethane/methanol, 95:5) and is obtained as a white solid in 0.91 g (63 %) yield.
  • the title compound is prepared as described in example 24 with 0.20 g (2 mmol) cyclohexanone being substituted for pivalaldehyde and 0.37 g (2 mmol) rac- l-isocyano-4- phenyl-cyclohexene being substituted for rac- l-isocyano-4-tert.-butyl-cyclohexene as a white solid in 1.10 g (90 %) yield.
  • Example 50 l[(2'-Boc-aminoethyl)-thyminaceryl-amino]-cyclohexancarboxylic acid-4"-methoxy-2"- nitrophenylamide 0.32 g (2.00 mmol) wo «o-Boc-ethylendiamine and 0.19 g (2.00 mmol) cyclohexanone are solved in 20 ml toluene three times and evaporated. The residue is solved in 7 ml abs. methanol and 0.36 g (2.00 mmol) 4-methoxy-2-nitrophenylisocyanide and 0.37 g (2.00 mmol) N-1-carboxymethylthymine are added.
  • the reaction mixture is heated for five minutes and stirred for three days at room temperature with exclusion of moisture.
  • the reaction mixture is evaporated to dryness, diluted with 25 ml diethylether and stirred for 30 minutes.
  • the precipitate is filtered off, washed with diethylether three times and dried in vacuo.
  • the crude product is purified by flash filtration (neutral alumina, dichloromethane / methanol 95 : 5) to give the title compound as a yellow-brown powder in 0.64 g (53 %) yield.
  • Example 52 8[(2 , -Boc-aminoethyl)-thyminacetyl-amino]-l,4-dioxaspiro[4.5]decan-8- carboxylic acid-4"-methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 51 with 4-phenylcyclohexanone substituted by 0.31 g (2.00 mmol) 1 ,4-cyclohexandione m ⁇ Hoethylene ketal to give the title compound as a yellow powder in 1.09 g (83 %) yield.
  • 0.32 g (2.00 mmol) wo «o-Boc-ethylendiamine and 0.40 g (2.00 mmol) dihexylketone are solved in 20 ml toluene three times and evaporated. The residue is solved in 7 ml abs. methanol and 0.36 g (2.00 mmol) 4-methoxy-2-nitrophenylisocyanide and 0.37 g (2.00 mmol) N-1-carboxymethylthymine are added. The reaction mixture is heated for five minutes and stirred for three days at room temperature with exclusion of moisture. The reaction mixture is evaporated to dryness, diluted with 25 ml diethylether and stirred for 30 minutes. The precipitate is filtered off.
  • Example 54 4[(2'-Boc-aminoethyl)-thyminacetyl-amino]-l-benzyl-piperidin-4-carboxylic acid-4"- methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 50 with cyclohexanone substituted by 0.38 g (2.00 mmol) 1 -benzy 1-4-piperidone to give the title compound as a red-brown powder in 0.80 g (58 %) yield.—
  • Example 55 c-l[(tr ⁇ n5-2'-Boc-aminocyclohexyl)-thymmacetyl-amino]-cyclohexancarboxylic acid- 4"-methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 50 with moflo-Boc-ethylendiamine substituted by 0.43 g (2.00 mmol) tr ⁇ « ⁇ -l,2-wo «o-Boc-cyclohexylendiamine to give the title compound as a yellow-brown powder in 0.64 g (49 %) yield.
  • the title compound is prepared as described in example 55 with cyclohexanone substituted by 0.31 g (2.00 mmol) 1 ,4-cyclohexandione wo ⁇ oethylene ketal to give the title compound without flash filtration as a yellow-brown powder in 1.10 g (77 %) yield.
  • the title compound is prepared as described in example 55 with trans-l ,2-mono-Boc- cyclohexylendiamine substituted by 0.35 g (2.00 mmol) r ⁇ e-l-Boc-amino-2-aminopropane to give the title compound without flash filtration as a yellow-brown powder in 0.81 g (65 %) yield.
  • the title compound is prepared as described in example 57 with cyclohexanone substituted by 0.31 g (2.00 mmol) 1 ,4-cyclohexandione morcoethylene ketal to give the title compound without flash filtration as a yellow-brown powder in 1.09 g (81 %) yield.
  • Example 59 r ⁇ c-l[(tr ⁇ ns-2'-Boc-aminocyclohexyl)-(/v -Z-cytosinacetyl)-amino]-cyclohexan- carboxylic acid-4"-methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 55 with N- 1 -carboxy methylthymine substituted by 0.61 g (2.00 mmol) ⁇ -Z-N-l -carboxymethyl cytosine to give the title compound without flash filtration as a yellow-brown powder in 1.13 g (73 %) yield.
  • the title compound is prepared as described in example 55 with cyclohexanone substituted by 0.06 g (2.00 mmol) paraformaldehyde to give the title compound without flash filtration as a orange-brown powder in 0.75 g (64 %) yield.
  • Example 61 r ⁇ c-2[(2'-Boc-amino- -methyl-ethyI)-thyminaceryl-amino]-acetic acid-4"-methoxy-2"- nitrophenylamide
  • the title compound is prepared as described in example 60 with trans-l ,2-mono-Boc- cyclohexylendiamine substituted by 0.35 g (2.00 mmol) r ⁇ e-l-Boc-amino-2-aminopropane to give the title compound as a red powder in 0.60 g (55 %) yield.
  • the title compound is prepared as described in example 62 with paraformaldehyde substituted by 0.31 g (2.00 mmol) rac-citronellal to give the title compound without flash filtration as a yellow- brown powder in 0.94 g (72 %) yield.
  • the title compound is prepared as described in example 66 with N-1-carboxymethylthymine substituted by 0.34 g (2.00 mmol) N-1-carboxymethyluracil to give the title compound as a red-brown powder in 0.67 g (64 %) yield.
  • Example 72 8[(2'-Boc-aminoethyl)-thymmacetyl-amino]-l,4-dioxaspiro[4.5]decane-8- carboxylic acid-4"-methyl-2"-nitrophenylamide 0.32 g (2.00 mmol) /worco-Boc-ethylendiamine and 0.31 g (2.00 mmol) 1 ,4- cyclohexandione /nofl ⁇ ethylene ketal are solved in 20 ml toluene three times and evaporated. The residue is solved in 7 ml abs.
  • the title compound is prepared as described in example 72 with 1 ,4- cyclohexandione /no ⁇ oethylene ketal substituted by 0.41 g (2.00 mmol) anthracen-9- carbaldehyde to give the title compound as a yellow-brown powder in 0.37 g (27 %) yield.
  • Example 75 r ⁇ e-2[(tr ⁇ «5-2'-Boc-aminocyclohexyl)-thyminacetyl-amino]-3,3-dimethyl-butyric acid- 4"-methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 74 with benzaldehyde substituted by 0.17 g (2.00 mmol) pivalaldehyde and o «o-Boc-ethylendiamine substituted by 0.43 g (2.00 mmol) trans- l ,2-/n ⁇ «o-Boc-cyclohexylendiamine to give the title compound as a yellow-brown powder in 0.82 g (64 %) yield.
  • Example 76 2[(2'-Boc-aminoethyl)-theophyIlinacetyl-amino]-acetic acid-4"-methoxy-2"- nitrophenylamide
  • the title compound is prepared as described in example 73 with anthracen-9-carbaldehyde substituted by 0.06 g (2.00 mmol) paraformaldehyde, 4-methyl-2-nitrophenylisocyanide substituted by 0.36 g (2.00 mmol) 4-methoxy-2-nitrophenylisocyanide and N- l - ⁇ carboxymethylthymine substituted by 0.48 g (2.00 mmol) N -carboxymethyl theophylline.
  • the title compound is prepared as described in example 73 with anthracen-9-carbaldehyde substituted by 0.52 g (2.00 mmol) l ,2:3,4-Di-O-isopropylidene- ⁇ -D-g ⁇ / ⁇ cto-hexodialdo-l ,5- pyranose and 4-methyl-2-nitrophenylisocyanide substituted by 0.36 g (2.00 mmol) 4- methoxy-2-nitrophenylisocyanide.
  • the title compound is prepared as described in example 73 with 4-methyl-2- nitrophenylisocyanide substituted by 0.36 g (2.00 mmol) 4-methoxy-2- nitrophenylisocyanide.
  • the crude product is purified by flash filtration (neutral alumina, dichloromethane / methanol 95 : 5) to give the title compound as a orange-brown powder in 0.42 g (30 %) yield.—
  • Example 80 2[(2'-Boc-aminoethyl)-(2""-amino-6""-benzyloxy-7v -purin acetyI)-amino]-acetic acid- 4"-methoxy-2"-nitrophenylamide
  • the title compound is prepared as described in example 78 with athracen-9-carbaldehyde substituted by 0.06 g (2.00 mmol) paraformaldehyde and N-1 -carboxymethylthymine substituted by 0.60 g (2.00 mmol) 2-amino-6-benzyloxy-N-9-carboxymethyl purine.
  • the crude product is purified by flash filtration (neutral alumina, dichloromethane / methanol 95 : 5) to give the title compound as a yellow-brown powder in 0.48 g (37 %) yield.
  • 0.32 g (2.00 mmol) m ⁇ no-Boc-ethylendiamine and 0.06 g (2.00 mmol) paraformaldehyde are suspened 7 ml abs.
  • methanol and 0.32 g (2.00 mmol) 4-methyl-2-nitrophenylisocyanide and 0.69 g (2.00 mmol) N -Z-N-9-carboxymethyl guanine are added.
  • the reaction mixture is stirred for three days at room temperature with exclusion of moisture.
  • the reaction mixture is evaporated to dryness, diluted with 25 ml dichloromethane and stirred for half an hour.
  • the precipitate is filtered off and the filtrate is evaporated to dryness.
  • the title compound is prepared as described in example 82 with 4-methyl-2- nitrophenylisocyanide substituted by 0.36 g (2.00 mmol) 4-methoxy-2- nitrophenylisocyanide.
  • the crude product is purified by chromatography (silica gel, dichloromethane / methanol 95 : 5) to give the title compound as a yellow-brown powder in 0.27 g (20 %) yield.—
  • the title compound is prepared as described in example 82 with 4-methyl-2- nitrophenylisocyanide substituted by 0.36 g (2.00 mmol) 4-methoxy-2- nitrophenylisocyanide, /nono-Boc-ethylendiamine substituted by 0.12 g (2.00 mmol) ethanolamine, paraformaldehyde substituted by 0.36 g (2.00 mmol) pivalaldehyde and N 2 -Z- iV-9-carboxymethyl guanine substituted by 0.37 g (2.00 mmol) N-1-carboxymethylthymine to give the title compound as a yellow-brown powder in 0.17 g (17 %) yield.
  • reaction mixture is evaporated to dryness and the remaining crude product is purified by chromatography (silica gel, «-hexane / ethyl acetate 7 : 3) to give the title compound as a orange powder in 3.20 g (68 %) yield.
  • the title compound is prepared as described in example 89 with 2[(2'-Boc-aminoethyl)- thyminacetyl-amino]-acetic acid-4"-methoxy-2"-nitrophenylamide substituted by 0.21 g (0.50 mmol) 2[(2'-Boc-aminoethyl)-uracilacetyl-amino]-acetic acid-4"-methoxy-2"-nitro- phenyl-amide to give the title compound as a yellowish solid in 0.08 g (43 %) yield.
  • ⁇ -NMR is consistent to literature (O. Buchardt, P. E. Nielsen, R. H. Berg, WO 92/20702).
  • the title compound is prepared as described in example 89 with 2[(2'-Boc-aminoethyl)- thyminacetyl-amino]-acetic acid-4"-methoxy-2"-nitrophenylamide substituted by 0.25 g (0.40 mmol) r ⁇ c-2[(2'-Boc-aminoethyl)-thyminacetyl-amino]-2-phenylacetic acid-4"- methoxy-2"-nitrophenylamide.
  • Example 102 r ⁇ c-2-[(2'-Boc-aminoethyl)-(thymin-methylen-ortAo-benzoyl)-amino]-acetic acid-4"- tert.-butyl-cyclohexen-l"-yl-amide
  • the title compound is prepared as described in example 93 with cyclohexen-1-yl-isocyanide and 3-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l -yl)-propionic acid substituted by 0.33 g (2 mmol) 4-tert.-butyl-cyclohexen-l-yl-isocyanide and 0.52 g (2 mmol) N- 1 -thyminyl- methylen-ort/20-benzoic acid as a yellowish solid in 0.83 g (71 %) yield.
  • the title compound is prepared as described in example 93 with paraformaldehyde, mono- Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-propionic acid substituted by 0.14 g (2 mmol) isobutyraldehyde, 0.42 g (2 mmol) tr ⁇ s-l-(N-tert.-Boc- amino)-2-amino-cyclohexan and 0.45 g (2 mmol) 4-(N- 1 -thyminyl)-butyric acid as a colourless solid in 0.19 g (14 %) yield.
  • the title compound is prepared as described in example 93 with mo «o-Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-propionic acid substituted by 0.35 g (2 mmol) rac- l-Boc-amino-2-aminopropane and 0.52 g (2 mmol) N-1-thyminyl-methylen- ort/zo-benzoic acid as a yellowish solid in 0.60 g (54 %) yield.
  • the product was obtained by chromatography on silica gel (dichloromethane/methanol 95:5).
  • the title compound is prepared as described in example 93 with paraformaldehyde and 3- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-propionic acid substituted by 0.15 g (2 mmol) pivalaldehyde and 0.52 g (2 mmol) N-1-thyminyl-methylen-ort r ⁇ -benzoic acid as a yellowish solid in 0.35 g (32 %) yield.
  • the title compound is prepared as described in example 93 with paraformaldehyde, cyclohexen-1 -yl-isocyanide, mo «o-Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H- pyrimidin-l-yl)-propionic acid substituted by 0.12 g (2 mmol) acetone, 0.33 g (2 mmol) 4- tert.-butyl-cyclohexen-1-yl-isocyanide, 0.36 g (2 mmol) motto-Ib-ort/z ⁇ -phenylendiamine and 0.40 g (2 mmol) 3-(N-l-thyminyl)-propionic acid as a yellowish solid in 0.29 g (25 %) yield.
  • the title compound is prepared as described in example 93 with paraformaldehyde, cyclohexen-1-yl-isocyanide, mo «o-Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H- pyrimidin-l -yl)-propionic acid substituted by 0.14 g (2 mmol) isobutyraldehyde, 0.33 g (2 mmol) 4-tert.-butyl-cyclohexen- l -yl-isocyanide, 0.36 g (2 mmol) mono-Vo-ortho- phenylendiamine and 0.40 g (2 mmol) 3-(N-l-thyminyl)-propionic acid as a yellowish solid in 0.32 g (27 %) yield.
  • the title compound is prepared as described in example 93 with paraformaldehyde, cyclohexen-1-yl-isocyanide, mono-Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H- pyrimidin-l-yl)-propionic acid substituted by 0.14 g (2 mmol) isobutyraldehyde, 0.33 g (2 mmol) 4-tert.-butyl-cyclohexen-l-yl-isocyanide, 0.35 g (2 mmol) r ⁇ ol-Boc-amino-2- amino propane and 0.52 g (2 mmol) N-l-thyminyl-methylen-ort/20-benzoic acid as a colourless solid in 0.56 g (46 %) yield.
  • the product was obtained by chromatography on silica gel (dichloromethane/methanol 95:5).
  • Example 110 r ⁇ c-2-[(2'-Ib-amino-phenyl)-(uracil-methylen-ort ro-benzoyl)-amino]-phenylacetic acid- 4"-tert.-butyl-cyclohexen-l"-yl-amide
  • the title compound is prepared as described in example 93 with paraformaldehyde, cyclohexen-1-yl-isocyanide, mo «o-Boc-ethylendiamine and 3-(2,4-dioxo-3,4-dihydro-2H- pyrimidin-l-yl)-propionic acid substituted by 0.21 g (2 mmol) benzaldehyde, 0.33 g (2 mmol) 4-tert.-butyl-cyclohexen-l-yl-isocyanide, 0.36 g (2 mmol) m ⁇ n ⁇ -Ib- ⁇ rt ⁇ o-phenylendiamine and 0.49 g (2 mmol) (2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-methylen-ortAo-benzoic acid as a yellowish solid in 0.60 g (44 %) yield.
  • Example 112 r ⁇ e-2-[(2'-Boc-aminoethyI)-( ⁇ -thymin-hexanoyl)-amino]-ort ⁇ o-chlorophenyl- acetic acid-cyclohexen-1 "-yl-amide
  • the title compound was prepared as described in example 11 1 with biphenylcarbaldehyde, tr ⁇ « ⁇ -l,2-mono-Boc-cyclohexylendiamine and r ⁇ c-2-(N-l-thyminyl)-phenylacetic acid substituted by 0.28 g (2 mmol) 2-chlorobenzaldehyde, 0.32 g (2 mmol) mono-Boc- ethylendiamine and 0.48 g (2 mmol) r ⁇ c-2-(N-l-thyminyl)-hexanoic acid as a yellowish solid in 0.49 g (39 %) yield.
  • the title compound was prepared as described in example 111 with biphenylcarbaldehyde, tr ⁇ s- l ,2-m ⁇ «o-Boc-cyclohexylendiamine and r ⁇ c-2-(N-l-thyminyl)-phenylacetic acid substituted by 0.31 g (2 mmol) benzaldehyde, 0.36 g (2 mmol) mono-lb-ortho- phenylendiamine and 0.40 g (2 mmol) r ⁇ c-2-(N-l-thyminyl)-propionic acid.

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Abstract

L'invention concerne des composés correspondant à la formule (I) dans laquelle A, B, D, E, X et Y sont définis dans la description. Ces composés sont des précurseurs utiles dans la synthèse de monomères pour acides nucléiques peptidiques (PNA).
PCT/EP1998/004281 1998-07-10 1998-07-10 Precurseur pour monomeres de pna Ceased WO2000002864A1 (fr)

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AU90645/98A AU9064598A (en) 1998-07-10 1998-07-10 Precusors for pna-monomers
PCT/EP1998/004281 WO2000002864A1 (fr) 1998-07-10 1998-07-10 Precurseur pour monomeres de pna

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JP2013032373A (ja) * 2005-04-15 2013-02-14 Univ Of North Carolina At Chapel Hill ニューロトロフィン類似体を用いた細胞生存促進法
JP2015511217A (ja) * 2012-01-19 2015-04-16 アジオス ファーマシューティカルズ， インコーポレイテッド 治療活性化合物およびそれらの使用方法
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
CN112851718A (zh) * 2019-11-28 2021-05-28 成都先导药物开发股份有限公司 一种水相Ugi多组分反应构建On-DNA α-氨基酰胺类化合物的方法
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
WO2026082601A2 (fr) 2024-10-15 2026-04-23 UCB Biopharma SRL Procédé de purification

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JP2013032373A (ja) * 2005-04-15 2013-02-14 Univ Of North Carolina At Chapel Hill ニューロトロフィン類似体を用いた細胞生存促進法
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US10640534B2 (en) 2012-01-19 2020-05-05 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
JP2015511217A (ja) * 2012-01-19 2015-04-16 アジオス ファーマシューティカルズ， インコーポレイテッド 治療活性化合物およびそれらの使用方法
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US10717764B2 (en) 2012-01-19 2020-07-21 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11667673B2 (en) 2012-01-19 2023-06-06 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10172864B2 (en) 2013-07-11 2019-01-08 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US12433895B2 (en) 2013-07-11 2025-10-07 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11021515B2 (en) 2013-07-25 2021-06-01 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10799490B2 (en) 2014-03-14 2020-10-13 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US11504361B2 (en) 2014-03-14 2022-11-22 Servier Pharmaceuticals Llc Pharmaceutical compositions of therapeutically active compounds
US10449184B2 (en) 2014-03-14 2019-10-22 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
CN112851718A (zh) * 2019-11-28 2021-05-28 成都先导药物开发股份有限公司 一种水相Ugi多组分反应构建On-DNA α-氨基酰胺类化合物的方法
WO2026082601A2 (fr) 2024-10-15 2026-04-23 UCB Biopharma SRL Procédé de purification

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