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    • 专利摘要:
    The present invention relates to novel lipid derivatives of phosphonocarboxylic acids of formula (I), tautomers and physiologically resistant esters thereof and salts of inorganic or organic bases, as well as methods for their preparation and pharmaceutical preparations containing the compounds. ; [Formula I] [Wherein, the definition of each symbol is the same as the specification]
    公开号:KR20000064374A
    申请号:KR1019980704352
    申请日:1996-12-16
    公开日:2000-11-06
    发明作者:하랄트 칠히；디이터 헤르만；한스-게오르그 오피츠；게르트 찜머만
    申请人:로셰 디아그노스틱스 게엠베하；포케어 헤르베르트；베버 만프레트；
    IPC主号:
    专利说明:

    Phospholipid derivatives of phosphono-carboxylic acids, their preparation and use as antiviral agents
    The present invention is directed to novel lipid derivatives of phosphonocarboxylic acids and esters thereof, tautomers thereof, physiologically resistant salts of inorganic or organic bases thereof, as well as methods for their preparation and pharmaceutical preparations containing the compounds. Is about:
    [Wherein,
    R 1 is a straight or branched, saturated or unsaturated alkyl chain having 9 to 13 carbon atoms,
    R 2 may be a straight or branched, saturated or unsaturated alkyl chain having 8 to 12 carbon atoms,
    R 3 is a straight or branched chain alkyl chain having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, neopentyl, texyl or phenyl; Choline, ethanolamine, carnitine, a C 5 -C 7 -cycloalkyl moiety, benzyl or one of the following groups;
    (n is 0, 1 or 2,
    m represents 0, 1, 2, or 3).
    Since the compounds of formula (I) contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also compounds of the invention.
    The compounds of formula (I) are also believed to include salts, tautomers, esters, optically active forms and racemic mixtures below.
    Caused by a malignant tumor (cancer, sarcoma, hematologic tumor), infectious disease or autoimmune disease, as well as viruses or retroviruses, such as, for example, AIDS, ARC (AIDS-related complex symptoms), cytomegaly infections, herpes infections or hepatitis Treatment of the resulting disease is accompanied by severe side effects and inadequate efficacy of the therapeutic substance used. These results can be explained by inadequate in vivo selectivity and limited therapeutic range of pharmacologically active substances used. Advantageous pharmacological in vitro properties of pharmacologically active substances may often not apply in vivo.
    Thus, there have been attempts for many years to change the chemical structures of pharmacologically active substances and to provide novel substances with improved properties in terms of their therapeutic range. Moreover, new pharmaceutical dosage forms have been developed for the purpose of specifically transferring active substances to the site of action for which they are intended to exhibit a therapeutic action. This is especially to avoid undesirable interactions with healthy cells. One possibility of improving the therapeutic range is to improve the solubility or resistance of the active substance by slightly modifying the pharmacologically active substance, for example by preparing acid or base addition salts or by preparing pharmacologically stable esters. To alter the physical properties of the fatty acid, for example fatty acid esters; J. Pharm. Sci. 79, 531 (1990). These chemically modified compounds are called “prodrugs” because they are converted into therapeutically effective agents in contact with body fluids or in the liver (first pass metabolism) almost immediately. Such prodrugs are also included in the present invention.
    In order to improve the stability of catabolism, nucleosides such as ara-C and ara-A have been chemically bound to phospholipids. These derivatives showed lower toxicity and higher stability in vivo compared to non-modified nucleosides. However, uptake and cell permeation were hardly affected. J. Med. Chem. 32, 367 (1989), Cancer Res. 37, 1640 (1977) and 41, 2707 (1981). In addition, phospholipid derivatives of nucleosides can be known, for example, from the following references:
    The preparation and use of liponucleotides as antiviral pharmaceutical agents is described in J. Biol. Chem. 265, 6112 (1990). In this case, however, only dimyristoylphosphatidyl and difamitylphosphatidyl residues coupled with known nucleotides having fatty acid ester structures such as AZT and ddC have been investigated and synthesized.
    Nucleotide conjugates of cytidine diphosphate and thioether lipids, which have anticancer activity and can be used oncologically, are described in J. Chem. Med. Chem. 33, 1380 (1990).
    Chem. Pharm. Bull. 36, 209 (1988), discloses appropriate nucleosides and phosphes in the presence of 5 '-(3-SN-phosphatidyl) -nucleosides with anti-leukemic activity, as well as phospholipase D with transferase activity. A method of enzymatically synthesizing them from pocholine is described.
    In addition, enzymatic synthesis of liponucleotides is particularly described in Tetrahedron Lett. 28, 199 (1987) and Chem. Pharm. Bull. 36, 5020 (1988).
    WO94 / 13324 describes orally active substances having 1-O-alkyl, 1-O-acyl, 1-S-acyl and 1-S-alkyl-sn-glycero-3-phosphate as lipid carriers. .
    Application EP 418814 and J. Pat. Med. Chem. 34, 1912 (1991), describes isoprenoid hydroxyfinylformates as squalene synthetase inhibitors.
    Biochem. Biophys. Res. Commun. 171, 458 (1990), describes lipid conjugates of antiretroviral Foscarnet with palmitylphosphonoformate, and the anti- of (hexyloxy) -hydroxyphosphinylacetic acid. HIV action is described in J. Med. Chem. 20, 660 (1977).
    In general, finding an effective method of transferring the concentration of a therapeutic pharmaceutical agent to each target organ or target cell, for example, an effective method of transferring the cells of the immune system and lymphatic system, which in the case of AIDS are considered the primary reservoirs of viral replication. It is very advantageous.
    PFA (phosphono formic acid) and PAA (phosphonoacetic acid) have excellent antiviral activity against HSV 1 and 2, influenza, HBV, VZV, EVB as well as retroviral infections.
    Under certain conditions, PFA / PAA and derivatives thereof may be an effective alternative / adjuvant for nucleosides because they broadly inhibit DNA and RNA polymerases as well as reverse transcriptases of retroviruses with appropriate selectivity. PFA and PAA itself are toxic because they resemble pyrophosphate by accumulating in bone.
    The compounds of the present invention also have important pharmacological properties. They are especially RNA viruses such as herpes simplex virus, human herpes virus 6, cytomegali virus, papova virus, varicella zoster virus, hepatitis virus or DNA virus such as Epstein-bara virus, influenza virus, or toga virus. Or, in particular, for the treatment and prevention of infections caused by retroviruses such as the oncovirus HTLV-I and II as well as the lentiviral visna and human immunodeficiency viruses HIV-1 and 2.
    Compounds of formula (I) may be used in humans, such as persistent generalized lymphadenopathy (PGL), progression of AIDS-related complex symptoms (ARC), and complete clinical symptoms of CMV and HSV-related infections as well as AIDS. It appears to be particularly suitable for treating the clinical symptoms of retroviral HIV infection.
    In HIV patients with CMV retinitis, the antiviral / antiretroviral action of foscarnet (phosphonoformate trisodium salt / PFA) is described in J. Chem. Infect. Dis. 172, 225 (1995).
    Antiviral action against rat CMV is described in Antiviral Res. 26, 1 (1995).
    In addition, JAMA 273, 1457 (1995) describes PFAs used for the treatment of CMV retinitis.
    PFA- and PAA-2 ', 3'-dideoxy-3'-thiacytidine conjugates that inhibit HIV-1 replication are described in J. Med. Chem. 37, 2216 (1994), acyloxyalkyl esters of poscarnets are described in J. Chem. Pharm. Sci. 83, 1269 (1994).
    However, US Application No. 5,194,654 and PCT-application WO 94/13682 are of particular interest. Lipid derivatives of phosphonocarboxylic acids and their use in liposomes which form particularly stable lipozomal complexes are described in this document. Apart from a very broad and very uncertain claim, it is described at the heart of this application that 1-O-alkyl-sn-glycero-3-phosphonocarboxylic acid is particularly well incorporated into the lipid bilayer of liposomes. Claimed alkyl moieties may comprise 2 to 24 carbon atoms.
    Only compound 1-O-octadecyl-sn-glycero-3-phosphono-formate (batylphosphonoformate) is described in the examples and is supported by data on antiviral action. The compound was found to be unstable during study and during manufacture. Unlike the patent application, the compound is used as a pure substance in solution / suspension, but not in liposomes.
    The compounds of formula (I) according to the invention are stable under the same conditions and have obvious advantages not only in vitro but also in vivo (MCMV-model in mice). In particular, the carboxylic esters are stable upon oral administration and have better in vivo activity than the corresponding free carboxylic acids.
    A very close relationship of structure-action was surprisingly found in terms of the chain length of the saturated alkyl residues used. Only when using two alkyl moieties having a chain length of 10 to 13 carbon atoms shows the optimum effect.
    The compounds claimed in the present application therefore exhibited unexpected improvements in comparison with WO 94/13682 and US 5,194,654 and do not represent the core of the application, even if they fall within the scope of the applications, and are clearly mentioned. It has not been named or named and its use is not clear.
    The compounds of formula (I) are novel. In addition to improved stability (in materials and solutions), the claimed compounds also have a better action compared to known lipid derivatives.
    Surprisingly, the pharmaceutical substances of formula (I) have a wider therapeutic range compared to free and non-aqueous substances with pharmacological activity. Moreover, they improve the retention time, in vivo activity or membrane permeability (eg, blood brain barrier, cell membrane, etc.) of the pharmacologically active substance known as in vivo activity or important factor. Thus, the compounds of formula (I) provide a carrier system (carrier) for pharmacologically active substances. In view of their action, the conjugates of formula I may be referred to as intracellular drug reservoirs, drug targeting and drug delivery systems. They allow the pharmacologically active substance to be released intracellularly after oral administration, and advantageously such release occurs specifically in cells containing specific enzymes, but not specific to all cells, organs or tissues of the body. However, it is particularly surprising that cleavage does not occur either by body fluids such as blood, serum and lymph, or during transport of the substrate by the liver, but only on or within each target cell. In this way, a major portion of the active substance is delivered to or within each target cell, avoiding undesirable secretion of phosphonocarboxylic acid by the kidneys or cleavage of the conjugate in the liver. As already mentioned, these cells are, in particular, physiologically or pathologically active cells which are considered targets for the administration of pharmacologically active substances such as, for example, blood leukocytes, lymphocytes, macrophages and other cell populations of the immune lymphatic system. These are, in particular, active cells (eg, macrophages, granulocytes, lymphocytes, leukocytes, platelets, monocytes, etc.) that play a pathological or symptomatic role in each disease progression. In addition, the cells are cells that are infected by viruses, bacteria, fungi or other microorganisms.
    Surprisingly, it has also been found that when the pharmacologically active phosphonocarboxylic acid and its esters are coupled with very specific lipid-like carrier molecules, the therapeutic range of the substance is significantly improved. Conjugates prepared by this method are provided as novel active substances for the preparation of pharmaceutical dosage forms. In general, coupling results in in vivo activity of the pharmacologically active phosphonocarboxylic acid because the resulting drug delivery transport system results in ubiquitous pharmacologically active substances within the target cells, thereby improving the efficiency and resistance of the pharmacologically active substance. Increase. This means, on the one hand, that the amount of pharmacologically active phosphonocarboxylic acid to be administered can be reduced, and on the other hand, improved pharmacological effects can be obtained while maintaining the same effective amount.
    Pharmacologically active phosphonocarboxylic acid is released from the conjugate by enzymatic hydrolysis of the conjugate.
    Conjugates of formula (I) show significant advantages over nonconjugate pharmacologically active phosphonocarboxylic acids or esters thereof. Specific carriers covalently bound to a pharmacologically active substance are those that are poorly absorbable in vivo, resistant to potentially toxic active molecules, have poor duration and membrane permeability of pharmaceutical agents that are rapidly eliminated or metabolized. Enhance the transmembrane of the compound (eg, blood-brain, cells, etc.).
    Enzymatic cleavage of the lipid moiety in vivo usually does not occur in serum but only in cells. In addition, the carrier portion having a lecithin-like structure, essential for the claimed effect, enhances the passage or transmembrane of the pharmacologically active substance and exhibits a storage effect. Moreover, the gastrointestinal resistance of lipid conjugates is significantly better than pure pharmacologically active phosphonocarboxylic acids. Lipid conjugates also exhibit better passage through the membrane structure during reabsorption, thus better overcoming reabsorption barriers. The same applies to the passage of the blood brain barrier, for example.
    In addition, distribution in vivo is enhanced by better binding of the conjugates to plasma and tissue proteins. The conjugate is first oxidized from thioether (n = 0) to sulfoxide (n = 1) by normal in vivo transformation, which, due to the equivalent action of sulfoxide compared to thioether, does not show a disadvantage. The sustained release of the pharmacologically active phosphonocarboxylic acid from the conjugate maintains a low concentration of active substance, which is constant for a long time thus improving efficacy and / or avoiding toxic side effects. Released pharmacologically active substances in the form of monophosphates no longer pass through the cells due to their high hydrophilicity.
    The systemic, cell, as well as organ half-life of the pharmacologically active substance is significantly prolonged by conjugation due to the prolonged duration of the conjugate in the organism. Due to the lack of cleavage in serum and in various organs, bone marrow and organ toxicity is rarely or only slightly present. It is particularly advantageous that the conjugates of formula I accumulate specifically in various target organs, tissues or cells.
    The compounds of formula (I) can be used as active substances for the preparation of pharmaceutical preparations which can be used in all diseases in which high concentrations of pharmacologically active substances are required or advantageous in cells, organs or tissues. An essential element for the system, referred to as "drug-storage-delivery-targeting," is that the cells that react according to the desired treatment have cleavage enzymes, whereby the active agent binds first and then migrates through the cell membrane into the cell. In this process, the active substance is cleaved necessarily at the same time as the movement through the cell membrane or afterwards in part to form a physiologically active phosphonocarboxylic acid. Intracellular cleavage occurs especially when cleavage enzymes are also located intracellularly.
    Suitable target cells are, for example, cells of the immunological lymphatic system (eg blood leukocytes, monocytes, macrophages, lymphocytes) or infected cells.
    Surprisingly, it has also been found that compounds of formula I inhibit the proliferation of DNA or RNA viruses at the stage of virus-specific DNA or RNA transcription. Such substances can affect the replication of retroviruses by inhibiting reverse transcriptase (Comp. Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773, 1987). The inhibitory action against HI virus, which is responsible for the immunodeficiency disease AIDS, is of particular therapeutic interest. Recently, 3'-azido-3'-deoxythymidine (DE-A-3608606) has been recognized among those for the treatment of AIDS in AIDS patients. However, with the toxic side effects of 3'-azido-3'-deoxythymidine on the bone marrow, blood transfusion is required in about 50% of treated patients. Compounds of formula (I) do not have this disadvantage. They have antiviral efficacy at pharmacologically appropriate doses without cytotoxicity.
    The compounds of the present invention and pharmaceutical preparations thereof can be used in combination with other pharmaceutical preparations for the treatment and prevention of the aforementioned infections. Examples of such agents further containing pharmaceutical agents that can be used for the treatment and prevention of HIV infection or diseases accompanying such diseases are 3'-azido-3'-deoxythymidine, 2 ', 3'. 2 ', 3'-dideoxynucleosides, such as dideoxycytidine, 2'3'-dideoxyadenosine and 2', 3'-dideoxyinosine, acyclic nucleosides (eg, acyclovir) Non-nucleoside reverse transcriptase inhibitors, for example protease inhibitors such as invirases, interferons such as interferons α, β, γ, cytokines and interleukins (eg interleukin 16), chemokines such as MIP1α, MIP1β, CC1, Secretion inhibitors such as probenidide, nucleoside migration inhibitors such as dipyridamole, as well as immunomodulators such as interleukin II or granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF, Neutropoetin), thrombopoietin and Romans bopo erythropoietin-stimulating factors, such as a similar argument. The compounds of the present invention and other pharmaceutical preparations may be taken individually or in single or two separate formulations simultaneously and selectively or with time differences to achieve a synergistic effect.
    Alkali, alkaline earth and ammonium salts of carboxyl and phosphonate groups can be considered as possible salts of the compounds of the formula (I) above all. Lithium, sodium and potassium salts are preferred as alkali salts. Magnesium and calcium salts are particularly considered as alkaline earth metal salts. Ammonium salts according to the invention are understood as salts containing ammonium ions which may be substituted up to four times by alkyl residues having 1 to 4 carbon atoms and / or aralkyl residues, preferably benzyl residues. In such cases, the substituents may be the same or different.
    Carboxylic acid esters of phosphonocarboxylic acid lipid derivatives are understood as pharmacologically acceptable esters, which are preferably benzyl, choline, ethanolamine, carnitine, esters having C 5 -C 7 cycloalkyl residues or 1 carbon Straight or branched chain alkyl moieties having from 6 to 6, especially esters having methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, i-butyl, t-butyl, neopentyl or texyl residues. Methyl, ethyl, propyl, butyl, t-butyl and benzyl are particularly preferred.
    Lipid phosphonocarboxylic acid esters are as effective as each free carboxylic acid in vitro. In vivo, however, they have particular advantages when administered orally.
    Carboxylic acid esters of compounds of formula (I) exhibit improved bioavailability because of their lower degradation by decarboxylation in acidic media. Therefore, the dose to be administered may be reduced several times compared to each free carboxylic acid. In addition, membrane permeability is improved, for example, when overcoming the blood-brain barrier and passing the cell membrane towards the target cell. Because carboxylic esters are preferentially in vivo cleaved by esterases, the half-life in serum is increased.
    R 1 in formula (I) represents a straight chain C 10 -C 12 alkyl group. R 1 especially represents a decyl, undecyl, dodecyl or tridecyl group.
    n is preferably either 0 or 1.
    R 2 preferably represents a straight chain C 9 -C 12 alkyl group.
    R 2 especially represents a decyl, undecyl or dodecyl group.
    In the conjugates of the formula (I) claimed, the preferred coupled phosphono acids and their esters are the following acids and their esters:
    Phosphonoformic acid
    Phosphonoacetic acid
    Phosphonopropionic acid
    Particularly preferred lipid moieties include n = 0 and combination R 1 = decyl / R 2 = dodecyl, R 1 = undecyl / R 2 = undecyl or R 1 = dodecyl / R 2 = decyl, and further R 1 = Undecyl / R 2 = decyl, R 1 = tridecyl / R 2 = decyl, R 1 = dodecyl / R 2 = undecyl.
    Compounds of formula I can be prepared as follows.
    1. In the presence of an optionally substituted arylsulfonic acid chloride in an organic base or in the presence of a base in an inert organic solvent, a compound of formula II is reacted with formula III, optionally a carboxylic ester followed by alkali saponification Conversion to derivatives or physiologically compatible salts thereof
    [Wherein R 1 , R 2 and n are the same as defined above]
    [Wherein m is the same as defined above and R 3 represents one of the ester residues defined above];
    or
    2. Mixed anhydrides are prepared from compounds of formula III and alkyl- or arylsulfonic acid chlorides, reacted with alcohols of formula II in the presence of a base in an inert organic solvent or directly in a base, optionally followed by a carboxylic ester followed by an alkali Saponification;
    or
    3. The phosphonocarboxylic acid of formula III, wherein R represents hydrogen, is reacted with an alcohol of formula II in the presence of a base and optionally a substituted arylsulfonic acid chloride and, if necessary, converted to a physiologically acceptable salt;
    or
    4. A mixed anhydride of a compound of formula III and an alkyl- or arylsulfonic acid chloride, wherein R represents hydrogen, is optionally reacted with an alcohol of formula II in the presence of a base in an inert organic solvent and the conjugate is selected as a physiologically suitable salt. Switch to;
    or
    5. Forces of formula IV synthesized according to the method described in Bhongle et al. (Synthetic Commun. 17, 1071 (1987)) following the reaction with oxalylchloride starting from phosphonic acid bis-trimethylsilyl ester Phonic acid dichloride is reacted with an alcohol of formula (II) with a molar ratio of 1: 1 to the base.
    or
    6. Tetrahedron Letters Vol. 33, No. 49, pp. 7473-7474, followed by conversion of oxalyl chloride to a compound of formula III to a phosphonic acid dichloride of formula IV; The reaction is carried out with an alcohol of the formula II in the presence of a base having a molar ratio of 1: 1. The phosphonic acid monochloride formed from the intermediate is saponified to form a semiester, and the carboxylic acid ester is converted into a derivative of formula (I) or a pharmaceutically compatible salt thereof by alkaline saponification.
    The free acid of the lipid derivative of phosphono-carboxylic acid can optionally be converted to the desired ester.
    Compounds of formula (II) and their preparation are described in EP-0545699 and in the examples.
    For example, pharmaceutical preparations containing a compound of formula (I) for the treatment of viral infections can be administered parenterally or parenterally in liquid or solid form. In such cases, conventional dosage forms include, for example, tablets, capsules, dragees, syrups, solutions or suspending agents. As an injectable solution containing additives commonly used in injection solutions such as stabilizers, solubilizers and buffers, water is preferably used. Such additives are, for example, tartrate and citrate buffers, complexes such as ethanol, ethylene-diamine tetraacetic acid and nontoxic salts thereof, polymeric polymers such as liquid polyethylene oxides to control the viscosity. The liquid carrier for injection solution should be sterile and preferably filled in ampoules. Solid carriers include, for example, polymer fatty acids such as starch, lactose, mannitol, methyl cellulose, talcum, highly dispersed silisic acid, stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solids such as polyethylene glycol High polymers and the like. Formulations suitable for oral administration may optionally contain flavoring and sweetening agents.
    In principle, the compounds of formula (I) can be administered orally, intratracheally, nasal, vaginal, tongue, intravenous, arterial, intramuscular, intradermal or subcutaneous. The dosage may vary depending on various factors such as the method of administration, species, age or individual difference. The compounds according to the invention are usually administered in an amount of 0.1 to 1000 mg, preferably 2 to 800 mg, more preferably 30 to 250 mg per kg of body weight per day. It is preferred to divide the daily dose into two to five doses, one to two tablets with an active substance content of 0.5 to 3000 mg administered at each dose. In addition, tablets can be delayed, which means that the number of doses can be reduced to 1 to 3 days per day. The effective ingredient content of the delayed tablet may be 20 to 5000 mg. The active substance can also be administered by continuous infusion and usually amounts of from 5 to 10000 mg per day are suitable.
    Apart from compounds derived from the combination of compounds mentioned in the examples and all substituents mentioned in the claims, compounds of the formula (I) are also contemplated within the scope of the invention.
    1. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid
    2. (3-dodecylsulfinyl-2-decyloxy) propoxy hydroxy-phosphinyl- formic acid
    3. (3-dodecylsulfonyl-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid
    4. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid
    5. (3-decylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid
    6. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid
    7. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid
    8. (3-Undecylsulfinyl-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid
    9. (3-Undecylsulfonyl-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid
    10. (3-dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid
    11. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid
    12. (3-Undecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid
    13. (3-Dodecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid
    14. (3-dodecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-formic acid
    15. (3-Undecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-formic acid
    16. (3-Dodecylmercapto-2-octyloxy) propoxy hydroxy-phosphinyl-formic acid
    17. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    18. (3-Dodecylsulfinyl-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    19. (3-Dodecylsulfonyl-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    20. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    21. (3-decylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    22. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-propionic acid
    23. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    24. (3-Undecylsulfinyl-2-undecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    25. (3-Undecylsulfonyl-2-undecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    26. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    27. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    28. (3-Undecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    29. (3-Dodecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-propionic acid
    30. (3-Dodecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-propionic acid
    31. (3-Undecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-propionic acid
    32. (3-Dodecylmercapto-2-octyloxy) propoxy hydroxy-phosphinyl-propionic acid
    33. (3-dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    34. (3-Dodecylsulfinyl-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    35. (3-dodecylsulfonyl-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    36. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    37. (3-decylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    38. (3-tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid
    39. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    40. (3-Undecylsulfinyl-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    41. (3-Undecylsulfonyl-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    42. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    43. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    44. (3-Undecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    45. (3-Dodecylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid
    46. (3-dodecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-acetic acid
    47. (3-Undecylmercapto-2-nonyloxy) propoxy hydroxy-phosphinyl-acetic acid
    48. (3-Dodecylmercapto-2-octyloxy) propoxy hydroxy-phosphinyl-acetic acid
    49. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    50. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    51. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    52. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    53. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    54. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester
    55. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    56. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    57. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    58. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    59. (3-dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    60. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester
    61. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    62. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    63. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    64. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    65. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    66. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester
    67. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    68. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    69. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    70. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    71. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    72. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester
    73. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    74. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    75. (3-Tridecylmercapto-2-decyloxy) -propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    76. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    77. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    78. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester
    79. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    80. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    81. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    82. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    83. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    84. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester
    85. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    86. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    87. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    88. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    89. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    90. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    91. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid neopentyl ester
    92. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid neopentyl ester
    93. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid neopentyl ester
    94. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid neopentyl ester
    95. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid neopentyl ester
    96. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid neopentyl ester
    97. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    98. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    99. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    100. (3 undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    101. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    102. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester
    103. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    104. (3-Undecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    105. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    106. (3-Undecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    107. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    108. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester
    Example
    Example 1
    R, S- (3-dodecylmercapto-2-decyloxy) -propoxy-hydroxy-phosphinyl-formic acid di-sodium salt (DMDOP-PFA) and methyl ester DMDOP-PFA-OMe
    18.2 ml of phosphonoformic acid trimethyl ester are dissolved in 140 ml of dichloromethane and additionally mixed with 72.5 ml of bromotrimethylsilane with stirring. The mixture is stirred at rt for 2 h, evaporated, the residue is combined twice in methanol and the solution is evaporated again each time. The residue is combined in 30 ml anhydrous pyridine and additionally mixed with a solution of 48.7 g of R, S- (3-dodecyl-mercapto-2-decyloxy) -propan-1-ol. The mixture is evaporated to dryness and the residue is admixed with 47.1 g of 2,4,6-tri-isopropyl-benzene sulfochloride and 150 ml of anhydrous pyridine with stirring. After about 30 minutes the initial viscous suspension is lean and stirred at room temperature for 25 hours.
    The precipitate is suction filtered and washed with a small amount of pyridine. The filtrate is admixed with 150 ml of water with stirring, the mixture is stirred at room temperature for 30 minutes, evaporated and mixed with ether. The reprecipitated precipitate is filtered off and the ether filtrate is shaken with 0.5 N HCl. The ether phase is washed well with water, dried and evaporated.
    The residue (84.2 g) is purified by chromatography on silica gel with dichloromethane / methanol / glacial acetic acid (9: 0.5: 0.5). Fractions containing product are concentrated by evaporation. 45.4 g of the corresponding R, S- (3-dodecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl formic acid methyl ester (DMDPO-PFA-OMe) are obtained.
    TLC on silica gel: R f = 0.3 (acetic acid / acetone / glacial acetic acid / water 10: 4: 0.5: 0.5)
    R f = 0.69 (dichloromethane / methanol 8: 2)
    In order to saponify the carboxylic acid methyl ester, 5 g of the obtained product are dissolved in 70 ml of tetrahydrofuran and additionally mixed with 6.7 ml of 2N NaOH. Stir for 4 hours and leave overnight. The reaction mixture is buffered to pH 8 with 2-ethylhexanoic acid and then evaporated. The residue is stirred with acetone and the precipitate is suction filtered. Fp. 4.1 g of acid having 242-246 C (decomposition) is obtained.
    TLC on silica gel:
    R f = 0.31 (isopropanol / butyl acetate / water / condensed ammonia 10: 6: 3: 1)
    13 C-NMR in D 2 O: COOH (d, 175 ppm, J PC = 231.4 Hz)
    Example 2
    R, S- (3-dodecylmercapto-2-decyloxy) -propoxy-hydroxy-phosphinyl acetate di-sodium salt (DMDOP-PAA) and methyl ester DMDOP-PAA-OMe
    Starting with wax-like products, phosphonoacetic acid trimethyl ester and (3-dodecylmercapto-2-decyloxy) -propan-1-ol, similar to Example 1 Fp. 358-360 C (decomposition) to afford the title compound.
    DMDOP-PAA:
    TLC on silica gel:
    R f = 0.53 (n-butanol / glacial acetic acid / water 2: 1: 1)
    R f = 0.07 (dichloromethane / glacial acetic acid / water 9: 0.5: 0.5)
    DMDOP-PAA-OMe: TLC on silica gel
    R f = 0.6 (u-butanol / glacial acetic acid / water 2: 1: 1)
    R f = 0.1 (dichloromethane / glacial acetic acid / water 9: 0.5: 0.5)
    Example 3
    Detection of bone marrow toxicity in vitro (CFU-GM assay)
    The CFU-GM assay is performed as described in Seidl, H. and J. Kreja, L., "Blut" 47, 139-145, 1983. Bone marrow cells (1 × 10 5 cell counts / ml) of Balb / c mice were intravenously injected with 0.8% methyl cellulose, 20% equine serum, 10 −4 M α-thioglycerol and 50 μg of maridan endotoxin 4 hours Incubation is carried out in Iscove medium containing the optimal volume (12.5 or 25 μl) of endotoxin-active mouse serum (Salmonella abortus equi; Sigma, Deisenhofen, Germany) obtained from later Balb / c mice. After 6 days incubation, colonies were further stained with 2- (p-iodophenyl) -3- (p-nitrophenyl) -5-phenyl tetrazolium chloride hydrate (INT, Sigma) for 24 hours and automatically Count with an image processor (Artek 982 B, Biosys GmbH, Karben, Germany).
    Table 1 shows phosphono-formic acid, DMDOP-PFA, phosphonoacetic acid, DMDOP-PAA, (3-octadecyloxy-2-hydroxy)-in comparison to the cell proliferation inhibitor cisplatin (Cis-DDP) and doxorubicin. Several concentrations for propoxy-hydroxy-phosphinylform ethyl ester (OOHP-PFAE) and (3-octadecyloxy-2-hydroxy) -propoxy-hydroxy-phosphinyl formic acid (OOHP-PFA) IC 50 concentrations obtained from dependent experiments are shown. As can be seen from the table, the highest test concentrations of up to 100 μg / ml DMDOP-PFA and DMDOP-PAA show no toxicity to the bone marrow stem cells of the granule / monocyte cell line. When applied also to phosphono-formic acid, the conjugates OOHP-PFAE and OOHP-PFA as well as phosphonoacetic acid are more toxic compared to DMDOP-PFA and DMDOP-PAA.
    IC 50 values (μg / ml) for cis-DDP, doxorubicin, phosphonoformic acid (phospharnet), DMDOP-PFA, phosphonoacetic acid, DMDOP-PAA, OOHP-PFAE and OOHP-PFA in the CFU-GM assay matterIC 50 inch (μg / ml) aCis-DDP (cisplatin)0.45 ± 0.11 (5) Doxorubicin0.046 ± 0.007 (4) Phosphonoformic Acid (Foscarnet)> 100 (6) DMDOP-PFA> 100 (6) Phosphonoacetic acid62.88 (2) DMDOP-PAA> 100 (2) OOHP-PFAE59.35 (3) OOHP-PFA94.49 (3) a mean ± SEM; Number of experiments carried out in a concentration-dependent method for n, 2 or 3 measurements
    Example 4
    Oral In vivo Activity in a Murine Giant Virus (MCMV) Model
    Female Balb / c mice are treated with 8 × 10 5 PFU (flag forming unit) doses. Survival rates of animals increase in the following order: untreated <Foscarnet treated <DMDOP-PFA treated <DMDOP-PFA-OMe.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] Novel phospholipid derivatives of phosphono-carboxylic acids of formula I, tautomers thereof, optical isomers and racemates, physiologically resistant esters and physiologically resistant salts of inorganic or organic bases:
    [Formula I]
    [Wherein,
    R 1 is a straight or branched, saturated or unsaturated alkyl chain having 9 to 13 carbon atoms,
    R 2 may be a straight or branched, saturated or unsaturated alkyl chain having 8 to 12 carbon atoms,
    R 3 is a straight or branched chain alkyl chain having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, neopentyl, texyl or phenyl; Choline, ethanolamine, carnitine, a C 5 -C 7 -cycloalkyl moiety, benzyl or one of the following groups;

    (n is 0, 1 or 2,
    m represents 0, 1, 2, or 3).
    [2" claim-type="Currently amended] A compound of formula I according to claim 1, wherein R 1 represents a decyl, undecyl, dodecyl or tridecyl group.
    [3" claim-type="Currently amended] A compound of formula I according to claim 1 or 2, wherein R 2 represents a decyl, undecyl or dodecyl group.
    [4" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 3, wherein n represents a number of zero or one.
    [5" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 4, wherein m represents a number of zero, one or two.
    [6" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 5, wherein R 3 represents a methyl, ethyl, propyl, butyl, t-butyl or benzyl group.
    [7" claim-type="Currently amended] A pharmaceutical composition, characterized in that it further contains a conventional pharmaceutical adjuvant and a carrier in at least one compound of formula (I) as claimed in claim 1.
    [8" claim-type="Currently amended] Use of at least one compound of formula (I) as claimed in claim 1 for the manufacture of a medicament for the treatment of autoimmune disease, tumor, inflammation, viral or retroviral disease.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-12-15|Priority to DE19547023.0
    1995-12-15|Priority to DE1995147023
    1996-10-22|Priority to DE19643416.5
    1996-10-22|Priority to DE1996143416
    1996-12-16|Application filed by 로셰 디아그노스틱스 게엠베하, 포케어 헤르베르트, 베버 만프레트
    1996-12-16|Priority to PCT/EP1996/005647
    2000-11-06|Publication of KR20000064374A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19547023.0|1995-12-15|
    DE1995147023|DE19547023A1|1995-12-15|1995-12-15|New phosphatidyl alkanoic acid derivatives|
    DE19643416.5|1996-10-22|
    DE1996143416|DE19643416A1|1996-10-22|1996-10-22|New phospho:lipid derived from phosphono-carboxylate and thio-glycerol|
    PCT/EP1996/005647|WO1997022613A1|1995-12-15|1996-12-16|Phospholipid derivatives of phosphono-carboxylic acids, the production of said derivatives and the use of said derivatives as antiviral medicaments|
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