US20100022478A1 - Chiral compounds substituted with phosphonate acid ester functions or phosphonic acid functions - Google Patents
Chiral compounds substituted with phosphonate acid ester functions or phosphonic acid functions Download PDFInfo
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- US20100022478A1 US20100022478A1 US12/374,440 US37444007A US2010022478A1 US 20100022478 A1 US20100022478 A1 US 20100022478A1 US 37444007 A US37444007 A US 37444007A US 2010022478 A1 US2010022478 A1 US 2010022478A1
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- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- 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)
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to novel compounds which contain PNA units substituted with phosphonic acid ester functions or phosphonic acid functions, and which exhibit at least one chiral center.
- the known antiviral compounds exhibit an action only upon the immediate first viral daughter generation by interrupting the replication cycle. This circumstance results in a measurable reduction of the number of the viruses compared to untreated host cells. This reduction of the number of the viruses, however, does not happen to 100%. If surviving viruses are isolated, they are further on capable of infecting host cells which have been not infected before, and passing through a complete replication cycle.
- PNAs peptide nucleic acids
- PNAs are produced by connecting peptide bonds between N-acetyl N-(2-aminoethyl)glycine building blocks (PNA monomers). Each of these individual N-acetyl N-(2-amino-ethyl) glycine building blocks represents a PNA unit.
- PNAs are resistant to a hydrolytic (enzymatic) cleavage under physiological conditions. It is known that PNAs may recognize complementary nucleic acid sequences (DNA or RNA) in a sequence specific manner and can bind to those with a higher affinity than their natural prototypes (M. Egholm, O. Buchardt, L. Christensen, C. Behrens, S. M. Freier, D. A. Driver, R. H. Berg, S. K. Kim, B. Norden, P. E. Nielsen, Nature, 1993, 365, 566-568. B. Hyrup, P. E. Nielsen, Bioorg. Med. Chem., 1996, 4, 5-23).
- DNA or RNA complementary nucleic acid sequences
- PNAs are applied for example as antisense oligomers.
- the expression of the proteins is inhibited by hybridization of an antisense oligomer to the protein specific mRNA on the level of translation.
- PNAs are suitable compounds, for example, for the use as diagnostics.
- PNA molecules show the disadvantage that they are hardly water soluble, compared with DNA. Furthermore, the permeation of the cell membrane is a general problem for PNAs so that the reception into the cells occurs extremely slowly only.
- PNAs are known whose water solubility could be enhanced by amine functions at the rest R 1 .
- PNAs modified in such a way exhibit still a poor cell permeability.
- the use of PNAs as antisense active agents in living organisms is very limited.
- oligomers which exhibit one or more phosphonic acid ester functions or phosphonic acid functions. Oligomers modified in such a manner have a better cell permeability compared with PNAs which do not contain these substituents.
- n represents an integer from 7 to 35, preferably from 9 to 28, most preferably from 13 to 20.
- E independently of each other represents a hydrogen atom, a substituted or unsubstituted phenyl rest, a substituted or unsubstituted heterocyclic rest, a nucleobase, optionally substituted by protecting groups, for example a naturally occurring or non-naturally occurring nucleobase, or a DNA intercalator.
- each E independently of each other represents an adeninyl, cytosinyl, pseudoisocytosinyl, guaninyl, thyminyl, uracilyl or phenyl rest.
- Each rest R 1 independently of each other represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkylaryl, aryl, or alicyclic rest having up to 20 carbon atoms, wherein at least one rest R 1 does not represent a hydrogen atom and is substituted with one or more phosphonic acid ester functions or phosphonic acid functions.
- the rest R 1 is not substituted with one or more phosphonic acid ester functions or phosphonic acid functions, it may independently of each other also have for example one or more side chains of a naturally occurring or non-naturally occurring amino acid, and preferably, an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic rest having up to 20 carbon atoms.
- each rest R 1 independently of each other comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- Each rest R 1 independently of each other may be branched or not branched.
- the expression “optionally substituted” relates to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms, or by —COOH, —COOR 8 , —CSOH, —CSOR 8 , —COSH, —COSR 8 , —CONH 2 , —CONHR 9 , —COR 10 R 11 , —OH, —OR 8 , ⁇ O, —SH, —SR 8 , ⁇ S, —NH 2 , ⁇ NH, —NHR 9 , —NR 10 R 11 , —NR 12 NOH, —NOR 13 or —NO 2 groups, phosphonic acid ester functions or phosphonic acid functions.
- this expression relates to groups which are substituted with unsubstituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkinyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 8 heteroaryl, C 7 -C 12 aralkyl or C 2 -C 11 heteroaralkyl groups, wherein the rests R 8 , R 9 , R 10 , R 11 , R 12 and R 13 independently of each other represent C 1 -C 6 alkyl rests.
- Phosphonic acid ester functions may exhibit for example the formula —P( ⁇ O)(OV) 2 or —P( ⁇ O)(OV)(OH).
- each V independently of each other may represent an unsubstituted alkyl, alkenyl, alkylaryl, aryl, or alicyclic rest having up to 20 carbon atoms, more preferably, having up to 7 carbon atoms, and most preferably, a methyl, ethyl, cyclohexyl, or benzyl rest.
- the phosphonic acid functions may exhibit, for example, the formula —P( ⁇ O)(OH) 2 .
- each rest R 1 independently of each other is selected from a group of the formula —(C 1 -C 10 )alkyl-[P( ⁇ O)(O—V) 2 ], wherein each V independently of each other represents a hydrogen atom, a methyl, ethyl, cyclohexyl or a benzyl rest.
- K represents a group of the formula —NR 2 R 3 , —N ⁇ R 2 R 3 R 4 , —NR 2 (CO)R 3 or —NR 2 (CS)R 3 , wherein R 2 , R 3 and R 4 independently of each other represent a hydrogen atom, an alkyl rest, an amino protecting group, reporter ligand, fluorescence marker, intercalator, chelator, amino acid, peptide, protein, carbohydrate, lipid, steroid, fatty acid, oligonucleotide, quantum dot, FRET quencher (fluorescence resonance energy transfer quencher) or a polymer soluble or insoluble in water, wherein each of the above mentioned rests optionally may be substituted.
- R 2 , R 3 and R 4 independently of each other represent a hydrogen atom, an alkyl rest, an amino protecting group, reporter ligand, fluorescence marker, intercalator, chelator, amino acid, peptide, protein, carbohydrate, lipid, steroid,
- K represents a —NH 2 function, a —NH(CO)CH 3 rest, a group of the formula —NR 2 R 3 or —N ⁇ R 2 R 3 R 4 or —NR 2 (CO)R 3 , wherein R 2 , R 3 and R 4 independently of each other represent a hydrogen atom, each an unsubstituted amino acid, peptide or alkyl rest, or an amino acid, peptide or alkyl rest, which are each substituted with phosphonic acid ester functions or phosphonic acid functions, wherein each of the above mentioned rests may be substituted optionally.
- L represents a group of the formula —NR 5 R 6 , —NR 5 (CO)R 6 , —NR 5 (CS)R 6 , —OR 7 or —SR 7 wherein R 5 and R 6 independently of each other represent a hydrogen atom, an alkyl rest, reporter ligand, fluorescence marker, intercalator, chelator, amino acid, amino acid amide, peptide, peptide amide, protein, carbohydrate, lipid, steroid, fatty acid, oligonucleotide, quantum dot, FRET quencher (fluorescence resonance energy transfer quencher) or a polymer soluble or insoluble in water, wherein each of the above mentioned rests optionally may be substituted, and R 7 represents a hydrogen atom, an alkyl rest, reporter ligand, fluorescence marker, intercalator, chelator, amino acid, amino acid amide, peptide, peptide amide, protein, carbohydrate, lipid, steroid, fatty acid, oligon
- L represents a —OH function, a —NH 2 function, a —NH—(C 1 -C 5 )alkyl function, an amino acid, amino acid amide, peptide or peptide amid unit, all of which may be substituted or not with phosphonic acid ester functions or phosphonic acid functions, wherein each of the above mentioned rests optionally may be substituted.
- alkyl rests preferably may have 1-6 carbon atoms, for example, they may represent methyl, ethyl, propyl or butyl groups.
- R 1 does not represent a hydrogen atom
- an asymmetric center (*) is generated due to the bond of the rest R 1 to the backbone of the general compound I at the bonding position. Therefore, at each asymmetric center, there exists an R configuration or an S configuration.
- the configuration at the asymmetric center preferably is defined according to the Cahn-Ingold-Prelog rules, additionally provided that the priority of the ligands is always defined as follows:
- the nitrogen atom at the asymmetric center always receives priority 1.
- the carbon atom of the carboxyl group at the asymmetric center always receives priority 2.
- the carbon atom of the rest R 1 at the asymmetric center always receives priority 3.
- the hydrogen atom at the asymmetric center always receives priority 4.
- oligomers are described which are exclusively prepared from racemic monomers, substituted with phosphonic acid ester functions or phosphonic acid functions. For example, for an oligomer composed of 15 racemic monomers, there are 2 15 different combinations of stereogenic centers (*) or 32.768 different stereoisomers. In this case a mixture of compounds with different chemical and physical properties is obtained.
- the presently described compounds according to the invention preferably are prepared starting from enantiomerically pure monomers, preferably substituted with one or more phosphonic acid ester functions or phosphonic acid functions.
- the compounds of the general formula I exhibit at least two asymmetric centers, wherein at least one rest R 1 is substituted with one or more phosphonic acid ester functions or phosphonic acid functions.
- each second rest R 1 independently of each other corresponds to a side chain of a naturally occurring or non-naturally occurring amino acid, preferably to an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic rest having up to 20 carbon atoms, and at least one rest R 1 represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl or alicyclic rest having up to 20 carbon atoms substituted with one or more phosphonic acid ester functions or phosphonic acid functions, wherein the remaining rests R 1 represent hydrogen atoms.
- each third rest R 1 independently of each other corresponds to a side chain of a naturally occurring or non-naturally occurring amino acid, preferably to an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic rest having up to 20 carbon atoms, and at least one rest R 1 represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl or alicyclic rest having up to 20 carbon atoms and is substituted with one or more phosphonic acid ester functions or phosphonic acid functions, wherein the remaining rests R 1 represent hydrogen atoms.
- two, three or more adjacent rests R 1 independently of each other correspond to a side chain of a naturally occurring or non-naturally occurring amino acid, preferably to an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic rest having up to 20 carbon atoms, and at least one rest R 1 represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl or alicyclic rest having up to 20 carbon atoms and is substituted with one or more phosphonic acid ester functions or phosphonic acid functions, wherein the remaining rests R 1 represent hydrogen atoms.
- each rest R 1 independently of each other corresponds to the side chain of a naturally occurring or non-naturally occurring amino acid, preferably to an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic rest having up to 20 carbon atoms, and at least one rest R 1 represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl or alicyclic rest having up to 20 carbon atoms and is substituted with one or more phosphonic acid ester functions or phosphonic acid functions.
- one or more of the rests R 1 independently of each other exhibit at least one phosphonic acid ester function or phosphonic acid function.
- R 1 having one or more phosphonic acid ester functions or phosphonic acid functions are present in the compound of the general formula I, at least 66% of the number of the asymmetric centers having rests with one or more phosphonic acid ester functions or phosphonic acid functions exhibit the R configuration, preferably 70%, more preferably 75%, more preferably 80%, more preferably 85%, more preferably 90%, more preferably 95%, and most preferably 100%. 2.
- At least 70% of the number of the asymmetric centers having rests with one or more phosphonic acid ester functions or phosphonic acid functions exhibit the R configuration, more preferably 75%, more preferably 80%, more preferably 85%, more preferably 90%, more preferably 95%, and most preferably 100%.
- At least 70% of the number of the asymmetric centers having rests with one or more phosphonic acid ester functions or phosphonic acid functions exhibit the S configuration, more preferably 75%, more preferably 80%, more preferably 85%, more preferably 90%, more preferably 95%, and most preferably 100%.
- At most 50% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- At most 40% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- At most 30% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- At most 20% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- At most 10% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- At most 4% of the number of the rests R 1 are substituted with phosphonic acid ester functions or phosphonic acid functions, and the remaining rests R 1 represent hydrogen atoms.
- all asymmetric centers (*) of the general compound I exhibit the same configuration.
- all asymmetric centers (*) of the general compound I exhibit the S configuration.
- all asymmetric centers (*) of the general compound I exhibit the R configuration.
- compositions according to the invention which contain one or more compounds according to the invention, optionally in combination with usual adjuvants.
- the synthesis of the compounds according to the general formula I is preferably carried out from enantiomerically pure monomers.
- individual asymmetric centers may change their prior defined configuration in a small percentage due to the chemical synthesis conditions.
- the maximum percentage of the compounds of the general formula I formed during the synthesis is, however, stereoisomerically pure. Also these compositions are able to fulfil the object of the invention.
- a compound of the general formula I may be connected through the rests K and L as linkers with a second compound of the general formula I, wherein the rests are defined as above.
- the configuration at the asymmetric centers of the first compound of the general formula I is independent of the configuration of the asymmetric centers of the second compound of the general formula I that is connected by the linker.
- all asymmetric centers of the first compound of the general formula I may exhibit the R configuration
- all asymmetric centers of the second connected compound of the general formula I may exhibit the S configuration.
- all asymmetric centers of the first compound of the general formula I may exhibit the R configuration
- all asymmetric centers of the second connected compound of the general formula I may exhibit the R configuration.
- the linker especially serves for the purpose to adjust the distance between the two compounds of the general formula I in such a way that between the two compounds of the general formula I having a linker and the single stranded RNA or DNA, or the double stranded DNA, respectively, a reciprocal interaction can take place via the respective nucleobases.
- linkers all known linkers and all linker molecules are suitable that are applied or applicable for this purpose.
- a linker may represent an optionally substituted alkyl chain, a peptide, an oligonucleotide or an oligomer that is composed of at least three units of 8-amino-3,6-dioxaoctanoic acid (eg1 units).
- the substitution by a phosphonic acid ester function or a phosphonic acid function, respectively, at the rest R 1 in principle is responsible for the cell permeability of the compounds according to the invention.
- the cell permeability of the compounds according to the invention is maintained or is reduced only marginally, respectively, if not a substituted rest R 1 is present at each of the possible positions, that is to say, if the number of the phosphonic acid ester functions or phosphonic acid functions, respectively, and therefore, the number of the asymmetric centers in the compounds according to the invention is reduced.
- the good cell permeability of the compounds according to the invention is maintained in living tissue too.
- Medaka fishes Japanese killifish; Oryzias latipes
- the fishes were transferred into fresh water in order to wash out the compounds according to the invention again out of the gastrointestinal tract the compounds of which did not penetrate into the tissue of the gastrointestinal tract.
- the fishes were investigated on different days under a fluorescence microscope. The results show that the compounds according to the invention accumulate both in the gastrointestinal tract and in the air bladder of the Medaka fishes.
- the penetration into the intestinal wall of the fishes could be detected also by tissue sections of the intestine. This circumstance renders the compounds according to the invention especially valuable for the treatment of diseases of the gastrointestinal tract, such as for example cancer of the colon, Morbus Crohn or for the treatment of adiposity.
- each, each second, each third, each fourth, each fifth, each sixth, each seventh, each eighth, each ninth, or each tenth rest R 1 may be substituted with a phosphonic acid ester function or phosphonic acid function, respectively.
- the substitutions with the phosphonic acid ester functions or phosphonic acid functions, respectively, can be regularly or exist at any positions.
- rests R 1 may be substituted with a phosphonic acid ester function or phosphonic acid function, respectively, in a subsequent manner (adjacent alignment).
- adjacent alignment in the compound of the general formula I, also more of these adjacent alignments may be contained.
- the positions with the individual subsequent rests R 1 substituted with a phosphonic acid ester function or phosphonic acid function, respectively, may be arbitrary.
- the inventors have assessed a novel principle of action at a still good cell permeability, as well as a surprisingly strong action.
- the number of HI viruses was investigated via a standard quantitative p24-ELISA assay since the amount of the formed viral protein p24 generally is considered as proportional to the number of the HI viruses formed.
- the infectious cell medium (supernatant) of the first virus daughter generation can be isolated from the host cells by centrifugation. New host cells which have not been infected before, can be infected by this supernatant in subsequent experiments (secondary infection), wherein no further addition of the compounds according to the invention occurs. Afore, this supernatant is diluted (for example 1:5.000) in order to keep the concentration within the measurement range of the p24 assay.
- FIG. 1 schematically demonstrates the novel mechanism of action.
- the HI virus dismisses its viral genomic RNA into the cytosol. Subsequently, the viral DNA is transcribed into DNA by viral reverse transcriptase, and integrated into the genome of the host cell. Upon the activation of the host cell, the viral genomic RNA is formed on one hand, and viral mRNA is formed on the other hand which can be decoded into viral proteins by translation.
- the host cells are treated with the compounds according to the invention, then they are capable of permeating into the cell without further adjuvants (for example transfection reagents).
- the compounds according to the invention can attach to these.
- the translation to distinct viral proteins is blocked.
- This phenomenon is called an antisense effect (1).
- the formation of novel viruses is interrupted (case A).
- the maturation of a virus particle after the burgeoning out of the host cell can be impeded by the absence of distinct viral proteins.
- non-infectious viruses arise (case B).
- An antisense effect that is strong per se is detected in this manner falsely as a weak antisense effect.
- the compounds according to the invention simultaneously also can attach to the genomic RNA having a complementary sequence (antigenomic effect) of the HI virus (RNA + virus) (2). This can happen within the host cell and/or when burgeoning.
- the compounds according to the invention can permeate the membranes of the host cells also after the burgeoning of the viruses and subsequently attach to the complementary sequence of the viral genomic RNA (3).
- viruses (C and D) are still able to infect further host cells.
- the compounds according to the invention simultaneously can attach both to complementary viral genomic RNA and to complementary viral mRNA.
- the compounds according to the invention can leave the first host cell again, and permeate into a second host cell not infected before. This results in a surprising effectiveness that can be observed over two generations of viruses.
- the compounds according to the invention exhibit a superior antisense effect and a stronger effectiveness compared to the stereochemically non-uniform compounds described in EP 1157031.
- the intensity of the antisense effect rises with an increasing number of the monomers that have been used for the preparation of the oligomers, that is to say, with larger values of n.
- the compounds according to the invention are of large interest for the treatment of different diseases due to their ability to bind to complementary nucleic acid sequences.
- diseases can be antagonized which are to be attributed to the presence of DNA or RNA which is alien to the organism.
- diseases are to be mentioned which are caused by viruses, for example HIV, hepatitis B and hepatitis C or HPV.
- diseases which are to be traced back to an overexpression of body's own mRNA can be antagonized by the compounds according to the invention.
- different kinds of cancer can be mentioned, such as skin cancer, lung cancer, liver cancer, prostate cancer, leukemia or brain tumors.
- inflammation diseases for example asthma or psoriasis
- neurological diseases for example Parkinson's disease or metabolic diseases, such as increased cholesterol values
- metabolic diseases such as increased cholesterol values
- mice were administered the compounds according to the invention in a concentration of 25 mg/kg intravenously once daily at three subsequent days, and then, the blood of the mice was analyzed on the fourth day.
- a reduction of ApoB100 and ApoB48 is valuable in respect of the antagonization of diseases related to arteriosclerosis and increased cholesterol values, especially in respect of high risk groups.
- the compounds according to the invention are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent.
- the administration can be applied by one of the following pathways: orally, for example as dragées, coated tablets, pills, semi-solids, soft and hard capsules, solutions, emulsions or suspensions; parenterally, for example as injectable solution; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally.
- the therapeutically useable product may be mixed with pharmacologically inert inorganic or organic drug carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talkum, stearic acid or salts thereof, and fatless powdered milk etc.
- drug carrier substances such as vegetable oils, petroleum, animal or synthetic oils, waxes, fats, polyols, may be used.
- drug carrier substances such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum, animal or synthetic oils
- drug carrier substances such as vegetable oils, petroleum, animal or synthetic oils, waxes, fats and polyols may be used.
- compressed gases suitable for this purpose such as oxygen, nitrogen, and carbon dioxide, may be used.
- the pharmaceutically usable agents may also contain additives for conservation, stabilization, emulsifiers, sweeteners, flavors, salts for changing the osmotic pressure, buffer substances, additives for coating and antioxidants.
- the compounds of the general formula I according to the invention may be produced for example by methods described in the literature by a reaction of compounds of the general formula II in a manner known per se (for example L. Christensen, R. Fitzpatrick, B. Gildea, K. H. Petersen, H. F. Hansen, T. Koch, M. Egholm, O. Buchardt, P. E. Nielsen, J. Coull, R. H. Berg, J. Pept Sci. 3, 1995, 175-183. T. Koch, H. F. Hansen, P. Andersen, T. Larsen, H. G. Batz, K. Otteson, H. ⁇ rum, J. Pept. Res. 49, 1997, 80-88. F. Bergmann, W. Bannwarth, S. Tam, Tetrahedron Lett. 36, 1995, 6823-6826).
- a manner known per se for example L. Christensen, R. Fitzpatrick, B. Gildea, K. H. Petersen,
- the rest R 5 represents for example a hydrogen atom or an allyl, benzyl, ethyl, or methyl rest, or a soluble or insoluble polymer.
- Pr represents a hydrogen atom or a cleavable amine protecting group.
- the amine protecting group has to be selectively cleavable in the presence of the nucleobase protecting groups.
- Pr represents a hydrogen atom, an oxocarbamate or thiocarbamate protecting group, most preferably, Pr represents a hydrogen atom or a Fmoc, Boc, Cbz, Mmt or a Bhoc protecting group.
- the asymmetric center (*) which the rest R 1 binds to, may exhibit the R or S configuration.
- the compounds of the general formula II may be produced according to the following method.
- the mixture of the products from reaction step 2 may be used in the following reaction.
- This reaction a reductive amination, can be carried out as described in the literature (G. Haaima, A. Lohse, O. Buchardt, P. E. Nielsen, Angew. Chem. Int. Ed. Engl, 35, 1996, No 17, 1939-1942).
- sodium cyanoborohydride also other reducing agents, for example hydrogen and a catalyst (for example Pd/C), can be used.
- the to reaction products are separated by chromatography.
- Z benzyloxycarbonyl
- Bzl benzyl
- acetyl (Ac) or anisoyl (An) can be carried out as described in the literature (S. A. Thomson, J. A.
- corresponding compounds of the general formula II without an asymmetric center are abbreviated analogically to the compounds of the general formula II having an asymmetric center, with the difference that instead of the capital letter for the nucleobase and the raised letter for the configuration (for example A R ), the respective small letter a is used.
- a compound of the general formula II without an asymmetric center having a PG protected C as nucleobase is abbreviated as c(PG).
- reaction step 1 For the production of the compounds of the general formula II having an S configuration at the asymmetric center, the pyrazine educt having an R configuration is used in reaction step 1, and the reaction steps 1 to 5 are performed analogically. Then, for example a compound of the general formula II is obtained that is abbreviated as A S (PG).
- the compounds according to the invention can be produced for example via solid phase synthesis by reaction of the compounds of the general formula II in a manner known per se. According to the solid phase synthesis, the protecting groups at the nucleobases are cleaved so that compounds of the general formula I are obtained which are abbreviated as follows:
- a compound according to the invention that is produced exclusively from compounds of the general formula II having an asymmetric center with R configuration, and that is capped with an acetyl group, is abbreviated as Ac-A R G R T R C R G R T R T R T R C R A R A R C R C R —NH 2
- a compound according to the invention that is produced from compounds of the general formula II having an asymmetric center with R configuration and from compounds of the general formula II having no asymmetric center, and that is labeled with fluorescein in the final step, and thereafter is cleaved as a primary amide from the resin, is abbreviated as Flu-A R gT R C R G R tT R T R C R aaC R c-NH 2 .
- a compound according to the invention that is produced exclusively from compounds of the general formula II having an asymmetric center with S configuration and from an L-amino acid, such as Boc- ⁇ (L)-trimethyl lysine iodide (Boc- ⁇ (L)TML iodide), at a Boc-Gly-PAM-MBHA resin, and that is capped with an acetyl group in the final step, and thereafter is cleaved as a primary amide from the resin, is abbreviated as Ac- ⁇ (L)TML-A S G S T S C S G S T S T S T S C S A S A S C S C S -Gly-NH 2 .
- an L-amino acid such as Boc- ⁇ (L)-trimethyl lysine iodide (Boc- ⁇ (L)TML iodide)
- Boc-Gly-PAM-MBHA resin Boc-Gly-PAM-MBHA resin
- a compound according to the invention that is produced exclusively from compounds of the general formula II having an asymmetric center with S configuration and from four L-amino acids, such as Boc- ⁇ -(L)-trimethyl lysine iodide (Boc- ⁇ (L)TML iodide), at a Boc-Gly-PAM-MBHA resin, and that is capped with an acetyl group in the final step, and thereafter is cleaved as a primary amide from the resin, is abbreviated as Ac- ⁇ (L)TML- ⁇ (L)TML- ⁇ (L)TML- ⁇ (L)TML-A S G S T S C S G S T S T S T S C S A S A S C S C S -Gly-NH 2 .
- L-amino acids such as Boc- ⁇ -(L)-trimethyl lysine iodide (Boc- ⁇ (L)TML iodide)
- a compound according to the invention that is produced from compounds of the general formula II having an asymmetric center with R configuration and from compounds of the general formula II having no asymmetric center, from glycine, and from two amino acids, such as 4-(diethoxy-phosphoryl)-2-(tert.-butoxycarbonylamino) butyric acid (Boc-DEPABS), at a Boc-Gly-PAM-MBHA resin, and that is capped with an acetyl group in the final step, and thereafter is cleaved as a primary amide from the resin, is abbreviated as Ac-(DEPABS)-2-Gly-gcgtG R tG R ggaagG R cA R g-Gly-NH 2 .
- Boc-DEPABS 4-(diethoxy-phosphoryl)-2-(tert.-butoxycarbonylamino) butyric acid
- a compound according to the invention that is produced from compounds of the general formula II having an asymmetric center with R configuration and from compounds of the general formula II having no asymmetric center, from the amino acids L-lysine (L-Lys), L-arginine (L-Arg), L-valine, (L-Val), at a Boc-Gly-PAM-MBHA resin, and that is capped with an acetyl group in the final step, and thereafter is cleaved as a primary amide from the resin, is abbreviated as Ac-(L-Lys)-(L-Lys)-(L-Lys)-(L-Arg)-(L-Lys)-(L-Val)-agctC R cT R cgcccT R tG R c-Gly-NH 2 .
- a compound according to the invention that is produced from compounds of the general formula II having an asymmetric center with R configuration, from compounds of the general formula II having no asymmetric center, and from the amino acids Boc- ⁇ -(L)-trimethyl lysine iodide (Boc- ⁇ (L)TML iodide) and from the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert.
- (2R,5S)-2-(8-dibenzyloxyphosphoryl)octyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine is produced starting from (S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl pyrazine and dibenzyl-(8-bromooctyl)phosphonate.
- (2S,5R)-2-(4-(dicyclohexyloxyphosphoryl)but-2-enyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine is produced starting from (R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl pyrazine and dicyclohexyl-(4-bromo-but-2-enyl) phosphonate.
- the basic solution is extracted six times with dichloromethane, wherein the pH value is controlled and optionally corrected each time.
- the dichloromethane phases are combined, dried over MgSO 4 , and the solvent is removed in vacuo.
- the resulting yellow oil is immediately used in the following reaction, an reductive amination.
- the yellow oil (a complete reaction is assumed) is solved in 600 ml of methanol and cooled to 0° C. Subsequently, 0.76 mol of N-Boc-amino acetaldehyde are added. After stirring for 30 min at 0° C., at first 0.90 mol of anhydrous acetic acid and then 0.40 mol of sodium cyanoborohydride are added. The reaction mixture is stirred at 0° C., until the generation of gas is completed, and then the solvent is removed by a rotating evaporator.
- the further purification is carried out by SPE over a glass frit filled with silica gel. Impurities and unwanted products are at first eluted with a mixture of hexane and acetic acid ethyl ester (1:1), and then with pure acetic acid ethyl ester. The desired product is finally obtained by extraction with 10% methanol in dichloromethane.
- (2R)-2-[2-(tert.-butoxycarbonylamino) ethyl]-amino-10-(dibenzyloxy-phosphoryl)-decanoic acid methyl ester is produced starting from (2R,5S)-2-(8-(dibenzyloxy-phosphoryl)octyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine.
- (2S)-2-[2-(tert.-butoxycarbonylamino) ethyl]-amino-6-(dicyclohexyloxy-phosphoryl)-hex-4-enoic acid methyl ester is produced starting from (2S,5R)-2-(4-(dicyclohexyloxy-phosphoryl)-but-2-enyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine.
- the solution is separated from insoluble parts by filtration, and the solvent is removed in vacuo.
- the residue is solved in dichloromethane and is stored overnight in a refrigerator. In this process, further dicyclohexyl urea precipitates which is separated by filtration.
- the filtrate is washed two or three times with diluted sodium bicarbonate solution (1 ⁇ 3 saturated sodium bicarbonate solution, 2 ⁇ 3 water), one or two times with diluted potassium hydrogen sulfate solution (1 ⁇ 3 saturated potassium hydrogen sulfate solution, 2 ⁇ 3 water), dried over MgSO 4 and concentrated by means of a rotating evaporator.
- the further purification is carried out by solving in acetic acid ethyl ester and storing overnight in the refrigerator, whereupon further optionally precipitated dicyclohexyl urea is separated by filtration and the solvent is removed again.
- the crude product is then solved in dichloromethane (5 ml per 3 g crude product respectively), and again precipitated with diethyl ether (25 ml per 3 g crude product respectively) and hexane (5 ml per 3 g crude product respectively).
- the solvent with the impurities is removed and the product is dried in vacuo.
- reaction solution is diluted with 130 ml water and sodium chloride solution and once extracted with dichloromethane (200 ml).
- the aqueous phase is adjusted with 2 M potassium hydrogen sulfate solution to a pH value of 2-3, and several times extracted with dichloromethane. Thereby, the pH value is controlled and optionally corrected again and again.
- the combined organic phases are dried over MgSO 4 , and the solvent is removed in vacuo. If necessary, the crude product can be reprecipitated from dichloromethane with diethyl ether. Finally, the product is dried by a lyophylisator.
- a compound of the general formula I is obtained that is bound to the resin at the carboxylic acid terminal end.
- the resin with the compound according to the invention is stirred in an aqueous ammonia solution (28-30 weight percent NH 3 in H 2 O) at 60° C. for 20 h.
- the cleaved resin is subsequently filtered, and the filtrate is concentrated in vacuo and dried.
- the crude product is purified by preparative HPLC over a RP-C18 column with methanol and water.
- the compound according to the invention is obtained as a colorless solid in a yield of about 50%.
- the molecular weight of the compound according to the invention is characterized by MALDI-TOF.
- a compound of the general formula I is obtained that is bound to the resin at the carboxylic acid terminal end.
- the resin with the compound according to the invention is stirred in an aqueous ammonia solution (28-30 weight percent NH 3 in H 2 O) at 60° C. for 20 h.
- the cleaved resin then will be separated by filtration, and the filtrate is concentrated in vacuo and dried.
- the crude product is purified by preparative HPLC via a RP-C18 column with methanol and water.
- the compound according to the invention having a linker is obtained as a colorless solid in a yield of 50%.
- the molecular weight of the compound according to the invention having a linker is characterized by MALDI-TOF.
- H9 cells chronically infected with strain HIV-1-NL4-3 are washed twice with a PBS buffer in order to remove viruses already produced.
- the cells are incubated in a 96-well plate with 104 cells/well, 4 wells per sample, in 200 ⁇ l culturing medium with or without a compound according to the invention or Ritonavir, respectively, at a distinct concentration. After 5 days of incubation, 40 ⁇ l of the cell suspension are taken from each of the 4 wells and inactivated with 40 ⁇ l Nonidet P-40.
- the amount of the antigen p24 GAG is determined by a quantitative ELISA assay (Sandwich-ELISA-Biotin-Strepavidin-HRP) according to the standard method of the Institute for Applied Microbiology in Vienna. As a standard, samples with a known amount of p24 are used to investigate the standard calibration curve.
- Human CD4 + T-lymphocytes (M8166) were preincubated with the compounds according to the invention for 24 hours, and subsequently infected with HIV (primary infection).
- the supernatant with the new formed HI viruses is separated from the cells by centrifugation.
- the supernatant is diluted as necessary in order to obtain a HIV proliferation during the subsequent infection (secondary infection) in a range that could be measured according to the standard method (ca. 1:5.000).
- non-infected cells M8166 were infected with HIV from the diluted supernatant, and the amount of p24 is measured by means of a quantitative p24 ELISA test after further 6 days.
- the compounds according to the invention having an effective HIV sequence (match) which can bind to HIV RNA due to their sequence, are used. Furthermore, the compounds according to the invention are used whose sequence does not exhibit a match for a binding to HIV RNA (no-match).
- the obtained measurements from the quantitative p24 ELISA test after the secondary infection were correlated with the obtained measurements from the positive control for which no compounds according to the invention were used, and the results are summarized in the following table.
- the compounds according to the invention accumulate surprisingly strong in cells that have a complementary DNA or RNA sequence, respectively.
- the FACS analysis of the respective cells exhibits a significantly higher accumulation of the compounds according to the invention having a HIV sequence in the HIV-infected cells, where a complementary DNA or RNA sequence, respectively, is present.
- the cell permeability of compounds according to the invention having a substituting rest R 1 at each asymmetric center is compared with the cell permeability of compounds according to the invention at which the rest R 1 is replaced by a hydrogen atom at each second asymmetric center.
- Medaka fishes were kept for two days in a 100 ⁇ M solution of the compound according to the invention TxRed-( ⁇ TML) 4 -A R GC R TC R CT R CG R CC R CT R TGC-Gly-NH 2 , and then, they are transferred into fresh water. Subsequently, the distribution of the compound according to the invention within the fishes at day one, as well as at days 2 and 5 after the transfer into fresh water is investigated under the fluorescence microscope. The pictures show that even after 5 days the compounds according to the invention can be detected in the gastrointestinal tract.
- FIG. 5 shows the corresponding fluorescence microscopic photographs.
- the compound according to the invention Ac-( ⁇ TML)-4-gtatT R cA R gtgtgA R tG R a-Gly-NH 2 , representing a matching sequence to the target sequence of ApoB100, was investigated in respect of its pharmacological effectiveness in mice.
- As a negative control the injection of pure PBS buffer was used.
- the mice were administered three different concentrations (25 mg/kg, 12.5 mg/kg, 6.25 mg/kg) of an effective compound according to the invention (solved in PBS buffer) or of the control buffer in portions of 0.1 ml intravenously once daily at three subsequent days.
- blood samples were taken from the mice and investigated in respect of their content of cholesterol, ApoB100 and ApoB48.
- the values of the following table show the concentrations of cholesterol and ApoB100 in relation to the mice treated only with PBS.
- the compound according to the invention Ac- ⁇ TML-T R cG R gA R gC R cA R gC R cC R cT R t-Gly-NH 2 , representing a matching sequence to the target sequence of Her2/neu was investigated in respect of its proliferation inhibiting action of the cell line MDA453 overexpressing Her2/neu.
- the compound according to the invention Ac- ⁇ TML-cG R cC R tT R aT R cC R gT R aG R cC R -Gly-NH 2 was used which does not represent a matching sequence to the target sequence of Her2/neu, as well as untreated MDA453 control cells.
- the matching sequence according to the invention, or the control sequence according to the invention, respectively are each added in a concentration of 1 ⁇ M.
- the cell medium is changed and replaced by fresh medium containing the compounds according to the invention in a concentration of 1 ⁇ M, respectively.
- the proliferation inhibiting action is specified by the determination of the DNA content in the individual wells by means of propidium iodide.
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DE102006034319A DE102006034319A1 (de) | 2006-07-21 | 2006-07-21 | Chirale mit Phosponsäurester- oder Phosphonsäure- substituierte Verbindungen |
DE102006034319.0 | 2006-07-21 | ||
PCT/EP2007/006483 WO2008009470A1 (de) | 2006-07-21 | 2007-07-20 | Chirale mit phosphonsäureester- oder phosphonsäure- substituierte verbindungen |
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US20170166900A1 (en) * | 2014-05-16 | 2017-06-15 | Ugisense Ag | Peptide nucleic acid monomers and oligomers |
US10350539B2 (en) | 2016-12-06 | 2019-07-16 | Lg Chem, Ltd. | Method of recovering (meth)acrylic acid |
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DE102006050091A1 (de) | 2006-10-24 | 2008-09-11 | Ugichem Gesellschaft für Organische Chemie mbH | Verfahren zur selektiven Lokalisierung von Wirkstoffen an und in Mitochondrien und entsprechende Wirkstoffe |
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US5719262A (en) * | 1993-11-22 | 1998-02-17 | Buchardt, Deceased; Ole | Peptide nucleic acids having amino acid side chains |
US7105648B1 (en) * | 1999-03-03 | 2006-09-12 | Ugichem Gmbh | Oligomers substituted by phosphite acid ester, phosphonic acid or carbaborane functions and the corresponding PNA monomers |
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GB2289677A (en) * | 1993-12-06 | 1995-11-29 | Pna Diagnostics As | Labelling of nucleic acid analogue-peptide chimerae |
DE4408528A1 (de) * | 1994-03-14 | 1995-09-28 | Hoechst Ag | Peptid-Oligonucleotid-Derivate, deren Herstellung und Verwendung |
DE69734783T2 (de) * | 1996-07-24 | 2006-08-17 | Buchardt, Dorte | Peptidnukleinsäuren mit erhöhter bindungsaffinität, sequenzspezifität und löslichkeit |
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US5719262A (en) * | 1993-11-22 | 1998-02-17 | Buchardt, Deceased; Ole | Peptide nucleic acids having amino acid side chains |
US7105648B1 (en) * | 1999-03-03 | 2006-09-12 | Ugichem Gmbh | Oligomers substituted by phosphite acid ester, phosphonic acid or carbaborane functions and the corresponding PNA monomers |
Non-Patent Citations (2)
Title |
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STN Search Report Accession Number 1995:908968, * |
Will et al (Tetrahedron 51(44):12069-12082, 1995) * |
Cited By (2)
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US20170166900A1 (en) * | 2014-05-16 | 2017-06-15 | Ugisense Ag | Peptide nucleic acid monomers and oligomers |
US10350539B2 (en) | 2016-12-06 | 2019-07-16 | Lg Chem, Ltd. | Method of recovering (meth)acrylic acid |
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JP5270543B2 (ja) | 2013-08-21 |
US9951093B2 (en) | 2018-04-24 |
AU2007276381B2 (en) | 2012-07-12 |
EP2041161B1 (de) | 2011-05-18 |
CN101495505A (zh) | 2009-07-29 |
ATE509945T1 (de) | 2011-06-15 |
CA2658633C (en) | 2015-02-24 |
DE102006034319A1 (de) | 2008-01-31 |
AU2007276381A1 (en) | 2008-01-24 |
EP2041161A1 (de) | 2009-04-01 |
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US20130131019A1 (en) | 2013-05-23 |
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JP2009544776A (ja) | 2009-12-17 |
WO2008009470A1 (de) | 2008-01-24 |
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