MXPA98004755A - Novedous derivatives of fosfolipidos of phosphonocarboxilic acids, the production of them, as well as their use as pharmaceutical agents antivira - Google Patents
Novedous derivatives of fosfolipidos of phosphonocarboxilic acids, the production of them, as well as their use as pharmaceutical agents antiviraInfo
- Publication number
- MXPA98004755A MXPA98004755A MXPA/A/1998/004755A MX9804755A MXPA98004755A MX PA98004755 A MXPA98004755 A MX PA98004755A MX 9804755 A MX9804755 A MX 9804755A MX PA98004755 A MXPA98004755 A MX PA98004755A
- Authority
- MX
- Mexico
- Prior art keywords
- phosphinyl
- hydroxy
- propoxy
- acid
- formula
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 239000008177 pharmaceutical agent Substances 0.000 title abstract description 11
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- 150000007513 acids Chemical class 0.000 title description 4
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- 150000003839 salts Chemical class 0.000 claims abstract description 14
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- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 3
- -1 phospholipid derivatives of phosphonocarboxylic acids Chemical class 0.000 claims description 113
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 11
- 239000000969 carrier Substances 0.000 claims description 9
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
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Abstract
The present invention relates to novel derivatives of phosphonocarboxylic acid lipids of the general formula I (See Formula) in which the meaning of the symbols is elucidated in the description, tautomers thereof, and their esters and salts of inorganic or organic bases , physiologically tolerated, as well as the procedures for the production thereof and the pharmaceutical agents containing these compounds
Description
NOVEDOUS DERIVATIVES OF PHOSPHOLIPIDS OF CIDOS PHOSPHONOCARBOXILICOS, THE PRODUCTION OF THEM, AS WELL AS THEIR USE AS ANTIVIRAL PHARMACEUTICAL AGENTS
DESCRIPTION OF THE INVENTION
The present invention relates to lipid derivatives of novel phosphonocarboxylic acids and their esters of general formula I,
wherein R1 is a linear or branched alkyl chain, saturated or unsaturated with 9-13 carbon atoms, R2 can be a straight or branched alkyl chain, saturated or unsaturated with 8-12 carbon atoms, R3 represents hydrogen, a linear or branched alkyl chain, with 1-6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, REF: 27662 pentyl, hexyl, neopentyl, texil or phenyl, choline , ethanolamine, carnitine, a C5-C7 cycloalkyl residue, benzyl or one of the following groups
n denotes 0, 1 or 2 and m represents 0, 1, 2 or 3, tautomers thereof, their salts of physiologically tolerated organic or inorganic bases, as well as the processes for the production thereof and the pharmaceutical agents containing these compounds . Since the compounds of general formula I contain asymmetric carbon atoms, all optically active racemic forms and mixtures of these compounds are also subject matter of the present invention. It is also understood that the compounds of formula
I, include optically active salts, tautomers, esters, forms and racemic mixtures, in the following. The therapy of malignant neoplasms (carcinomas, sarcomas, hematological neoplasms), inflammatory diseases or autoimmune diseases, as well as diseases caused by viruses and retroviruses, such as for example AIDS, CRS (AIDS-related complexes), cytomegalic infections, Herpes infections or hepatitis are often also accompanied by extreme side effects, in addition to the inadequate efficacy of the therapeutic substances used. This effect can be explained by inadequate in vivo selectivity and the limited therapeutic range of the pharmacologically active substances used. The advantageous pharmacological properties in vitro of the pharmacologically active substances often can not be extrapolated to the in vivo conditions. Therefore, it has been tried for years to provide novel substances with improved properties, with respect to their therapeutic range, by modifying the chemical structure of pharmacologically active substances. Moreover, new pharmaceutical forms of administration are frequently developed, in order to transport the active substances specifically to their site of action, in which they are supposed to show their therapeutic action. In this case, it is intended, in particular, to avoid unwanted interaction with healthy cells. One possibility to improve the therapeutic range is to change the physical properties of the underlying active substance, in such a way that the solubility or tolerance of the active substance is improved by a slight modification of the pharmacologically active substance, for example, by producing acid or base addition salts, or preparing pharmacologically safe esters [e.g., esters of fatty acids; J. Pharm. Sci. 79, 531 (1990)]. These slightly modified compounds from the chemical point of view are often denoted as "prodrugs", since they are almost immediately converted into the therapeutically active agent, contact with body fluids or in the liver (first step of metabolism). Said "prodrugs" are included in the invention. In order to improve the catabolic stability, nucleosides such as for example ara-C and ara-A have been chemically bonded to phospholipids. The corresponding derivatives exhibit lower toxicity and higher stability in. live, compared to unmodified nucleosides. Absorption and cell penetration were, however, hardly influenced. [J. Med. Chem. 32, 367 (1989), Cancer Res. 37, 1640 (1977) and 41, 2707 (1981)]. From the following references in the literature, for example, phospholipid derivatives of nucleosides are known: The production and use of liponucleotides as antiviral pharmaceutical agents is described in J. Biol Chem. 265, 6112 (1990). However, in this case, only the residues of dimyristoylphosphatidyl and dipamityl-phophatidyl,
coupled to the known nucleosides such as AZT and ddC, with their fatty acid ester structure, were investigated and synthesized. The nucleoside conjugates of thioester lipids with cytidine diphosphate, which have an antitumor action and could be used in oncology, are described in J. Med. Chem. 33, 1380 (1990). In Chem. Pharm. Bull. 36, 209 (1988), nucleosides of 5 '- (3-SN-phosphatidyl), having antileukemic action; as well as the enzymatic synthesis of the appropriate nucleosides and phosphocholines, in the presence of phospholipase D, with transferase activity. Enzymatic synthesis of liponucleotides is also described inter alia in Tetrahedron Lett. 2, 199 (1987) and Chem. Pharm. Bull. 36, 5020 (1988). WO 94/13324 describes active substances available orally, with l-S-alkyl-sn-glycero-3-phosphates of 1-O-alkyl, 1-O-acyl, 1-S-acyl and, as lipid carriers. The application EP 418814 and J. Med. Chem. 34, 1912
(1991), describes isoprenoidfoshidroxifinilformiatos as inhibitors of squalene synthetase. In Biochem. Biophys. Res, Commun. 171, 458 (1990), a lipid conjugate of Fiscarnet antiretroviral, with palmitylphosphonoformate and the anti-HIV activity of (hexyloxy) -hydroxyphosphinyl acetic acid, is disclosed in J. Med. Chem. 20, 660 (1997). In general, it is very advantageous to find effective ways to transport concentrations of therapeutic pharmaceutical substances to the respective target organs or target cells, for example, in the case of AIDS, in the cells of the immune system, and the lymphatic system, which is considered which are the main reservoir of viral duplication. PFA (phosphonoformic acid) and PAA (phosphonoacetic acid), have good antiviral activity against
HSV 1 and 2, influenza, HBV, VZV, EBV, as well as retroviral infections. PFA / PAA and derivatives thereof may, under certain circumstances, be an effective alternative / supplement to nucleosides, since they inhibit a broad spectrum of DNA and RNA polymerases, as well as the RT of retroviruses, with selectivity adequate PFA and PAA, by themselves, are toxic, due to their similarity to pyrophosphate by accumulation in the bones. The compounds of the present invention also have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections that are caused by DNA viruses, such as herpes simplex virus, human herpes virus 6, cytomegaly virus, papova virus, varicella zoster virus, hepatitis virus or Epstein-Barr virus, influenza virus or RNA viruses, such as Toga viruses, or especially retroviruses such as the HTLV-I and II oncoviruses, as well as the lentivirus visna and the human immunodeficiency virus HIV-1 and 2. The compounds of formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent generalized lymphadenopathy (PGL), the advanced stage of AIDS-related complex (CRS), and the complete clinical picture of AIDS, as well as infections associated with CMV and HSV. The antiviral / antiretroviral action of Foscarnet (salt of trisodium phosphonoformic acid / PFA), in patients with HIV with CMV retinitis, is described in J. Infect. Dis. 172, 225 (1995). The antiviral action in murine CMV is described in Antiviral Res. 26, 1 (1995). In addition, PFA is used in JAMA 273, 1457 (1995), for the treatment of CMV retinitis. The conjugates of PFA and PAA-2 ', 3'-dideoxy-3'-thiacytidine, which inhibit the duplication of HIV-1, are shown in J. Med. Chem. 37, 2216 (1994) and esters of
Forscarnet acyloxyalkyl, are described in j. Pharm. Sci. 83, 1269 (1994). However, U.S. Application 5,194,654 and PCT Application WO 94/13682 are of particular interest. Lipid derivatives of phosphonocarboxylic acids and their use in liposomes, with formation of a particularly stable liposomal complex, is described therein. Apart from an extremely broad and very speculative claim, 1-0-alkyl-sn-glycero-β-phosphonocarboxylic acids are described as the core of the application, which are particularly well incorporated in the lipid bilayer of the liposomes. The claimed alkyl residues can comprise 2-24 carbon atoms. Only the compound 1-O-octadecyl-sn-glycero-3-phosphonoformate (batyl-phosphonoforimiate) is described as an example, and is supported by data for an antiviral action. This compound proved not to be stable in investigations and during production. In contrast to such patent applications, the compound is used as a pure substance, in a solution / suspension, and not in liposomes. The compounds of general formula I, according to the invention, are stable under the same conditions and have clear in vi tro as well as in vivo advantages (model of MCMV in the mouse). Especially, the carboxylic acid esters are stable when administered orally, and have a better bioavailability than the corresponding free carboxylic acids. Surprisingly, a very close structure-action relationship was found, with respect to the chain length of the alkyl residues used. only the use of two alkyl residues in the chain length range of 10-13 carbon atoms shows optimum effects. The compounds claimed in this application, therefore, represent an improvement, compared to WO 94/13682 and US Patent 5,194,654, which was not expected, although they are covered by these applications, do not represent the core of the application and they are not explicitly mentioned or mentioned by name, nor would their use be obvious to them. The compounds of formula I are novel. In addition to the improved stability (in substance and in solution), the claimed compounds also have a better action, compared with the known lipid derivatives. Surprisingly, the pharmaceutical substances of formula I have a wider therapeutic range, compared to free and unmodified pharmacologically active substances. In addition, they improve their retention time in the body, the bioavailability or permeability of the membrane
(for example, the blood-brain barrier, cell membrane, etc.) of pharmacologically active substances, which is often known to be a critical factor. The compounds of formula I thus serve as a carrier system (carrier) for pharmacologically active substances. With respect to their function, the conjugates of formula I can be referred to as an intracellular drug storage system, to target and release the drug. They allow the pharmacologically active substance to be released intracellularly after oral administration, and advantageously, this release does not take place non-specifically in all the cells, organs or tissues of the body, but specifically in those cells that contain a particular enzyme . However, it is particularly surprising that rupture does not occur even during transport of the substrate by body fluids, such as blood, serum or lymphatic fluid, or by the liver, but only in or within the respective target cells. In this way the undesired excretion of phosphonocarboxylic acid by the kidney or the breakdown of the conjugate in the liver is prevented, so that most of the active substance is transported to or within the respective target cells. As already mentioned above, such cells are in particular physiologically or pathologically activated cells, which come into consideration as a target or target for the administration of pharmacologically active substances, such as for example, blood leukocytes, lymphocytes, macrophages and other cell populations of the immunological lymphatic system. These are in particular, activated cells (for example, macrophages, granulocytes, lymphocytes, leukocytes, thrombocytes, monocytes, etc.), which play a pathophysiological or symptomatic role in the process of the respective disease. In addition, these are cells, which are infected by viruses, bacteria, fungi or other microorganisms. Surprisingly, it was also found that the pharmacological range of a pharmacologically active phosphonocarboxylic acid, and the esters thereof, is significantly improved when the substance is coupled to a carrier molecule-similar to a very special lipid. The conjugate prepared in this manner serves as a novel activated substance for the production of pharmaceutical dosage forms. In its entirety, the coupling results in a better in vivo effect of the pharmaceutically active phosphonocarboxylic acid, since the pharmacologically active substance is located in the target cells by the delivery system or delivery of the resulting drug, and therefore , the efficiency and tolerance of the pharmacologically active substance are improved. This means that, on the one hand, the amount of pharmacologically active phosphonocarboxylic acid to be administered can be reduced, or on the other hand, it is possible to achieve a better pharmacological effect, while maintaining the same effective amount. The pharmacologically active phosphonocarboxylic acid is released from the conjugate by the enzymatic hydrolysis of the conjugate. The conjugates of formula I exhibit significant advantages compared to phosphonocarboxylic acid or its unconjugated pharmacologically active ester. The specific carrier covalently linked to the pharmacologically active substance improves the bioavailability of poorly resorbed pharmacologically active substances, the tolerance to potentially toxic active molecules, the retention time of the rapidly eliminated or metabolized pharmaceutical agents and the penetration into the membrane of compounds with poor membrane permeability (eg, blood-brain, cells, etc.). The enzymatic cleavage of the lipid portion in vivo usually does not occur in the serum, but only intracellularly. In addition, the carrier portion with its structure similar to lecithin, which is essential for the claimed effect, improves penetration or permeability of the membrane of the pharmacologically active substance, and exhibits a cumulative effect. In addition, the gastrointestinal tolerance of the lipid conjugates is considerably better than that of pure pharmacologically active phosphonocarboxylic acid. The lipid conjugate also exhibits better penetration through the structures of the membranes during resorption, and therefore, is better able to overcome the resorption barriers. The same applies to penetration, for example, the blood-brain barrier. In addition, the in vivo distribution is improved by a better binding of the conjugate to plasma and tissue proteins. The conjugate is oxidized first by the normal biotransformation of a thioether (n = 0), to a sulfoxide
(n = l), which, however, due to the equipotent action of the sulfoxide in comparison with the thioether, does not represent a disadvantage. The slow release of the pharmacologically active phosphonocarboxylic acid from the conjugate ensures a low level of active substance, which is, however, constant over a prolonged period of time, and thus improves efficiency and / or avoids toxic side effects. The pharmacologically active substance released in the form of a monophosphate, does not penetrate more into the cell, due to its high hydrophilicity. The half-lives in the cells, as well as in the organs throughout the body of the pharmacologically active substance, are considerably prolonged by conjugation, due to the longer retention time of the conjugate in the organism. Due to the lack of breakthrough activity in the serum and in various organs, slight or almost no toxicity can be observed in the bone marrow and organs. It is particularly advantageous if the conjugates of formula I accumulate specifically in various organs, tissues or target cells. The compounds of formula I can be used as active substances for the production of pharmaceutical agents, which can be used for all diseases in which a high level of pharmacologically active substance in the cells, organs or tissues is required or beneficial. An essential requirement for this system denoted "storage-supply-objective-drug" ', is that the cells, which respond according to the intended therapy, have the enzyme that effect the break, so that the active substance binds in a first stage, and is subsequently transported through the cell membrane to the interior of the cell in the processes in which the active substance is fragmented to form the pharmacologically active phosphonocarboxylic acid, either simultaneously with the transport through the membrane of the cell or even later, partially inside the cell. The intracellular rupture -. takes place especially in those cases in which the enzyme that makes the break is also located inside the cell. Suitable target cells are, for example, cells of the immunological lymphatic system (for example, blood leukocytes, monocytes, macrophages, lymphocytes) or infected cells. Surprisingly, it was also found that the compounds of the general formula I, inhibit the multiplication of the DNA and RNA viruses, at the level of the specific transcription of the DNA and RNA viruses. The substances can influence the reproduction of retroviruses by inhibiting the reverse transcriptase enzyme (see Proc. Nati, Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773, 1987). The inhibitory action of the Hl virus, which causes the immunodeficiency disease, AIDS, is of particular therapeutic interest. Today, the 3 '-Azido-3' -deoxitimidine (DE-A-3608606) is approved, among other things, for the treatment of AIDS in patients with AIDS. However, the toxic effects of 3'-azido-3'-deoxythymidine in the bone marrow, require a blood transfusion in approximately 50% of treated patients. The compounds of general formula I do not have these disadvantages. They have antiviral efficiency without being cytotoxic in pharmacologically relevant doses.
The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other pharmaceutical agents for the treatment and prophylaxis of the infections mentioned above. Examples of these agents containing additional pharmaceutical agents that can be used in the treatment and prophylaxis of HIV infections, or diseases that accompany this disease are 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleosides, such as 2 ', 3' -dideoxycytidine, 2 ', 3' -dideoxyadenosine and 2 ', 3'-dideoxyinosine, acyclic nucleosides (eg Acyclovir), non-nucleoside RT inhibitors, protease inhibitors such as for example Invirase, interferons such as interferon a, β, β, cytokines and interleukins (eg, interleukin 16), chemokines such as MlPla, MlPlβ, CCl , inhibitors of renal excretion such as probenicide, nucleoside transport inhibitors, such as dipyridamole, as well as immunomodulators such as mteryleucine II or stimulating factors, such as the stimulating factors of the granulocyte macrophage colony (GM-CSF) , stimulating factors of the granulocyte colony (G-CSF, neutropoietin), trcmbopoietin factors and thrombopoietin-like. The compounds of the present invention and the other pharmaceutical agent can be administered individually or simultaneously, and optionally in a single formulation or two, separate, at different times, in order to achieve a synergistic effect. The alkali, alkaline earth and ammonium salts of the carboxyl group and the above phosphonate are all considered as possible salts of the compounds of the general formula I. The lithium, sodium and potassium salts are preferred as the alkali metal salts. The magnesium and calcium salts come into particular consideration as the alkaline earth salts. It is understood that the ammonium salts according to the invention are salts containing the ammonium ion which can be substituted up to four times by alkyl residues with 1-4 carbon atoms and / or by aralkyl residues, preferably residues of benzyl. In this case, the substituents may be the same or different. It is understood that the carboxylic acid esters of the lipid derivatives of phosphonocarboxylic acid are pharmacologically acceptable esters, and these are preferably esters of benzyl, choline, ethanolamine, carnitine, a C5-C7 cycloalkyl residue or with a residue straight or branched chain alkyl, with 1-6 carbon atoms, in particular a residue of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, i-butyl, t-butyl, neopentyl or texil. Methyl, ethyl, propyl, butyl, t-butyl and benzyl are particularly preferred. The lipid phosphonocarboxylic acid esters are, in vi tro, as effective as the respective free carboxylic acids. However, in vivo they have significant advantages, especially when administered orally. The carboxylic acid esters of the compounds of formula I, exhibit a minor decomposition by decarboxylation in an acidic medium, and therefore, have a better bioavailability. The dose to be administered can, therefore, be reduced several times compared to the free carboxylic acid, respectively. In addition, it improves the permeability of the membrane, for example, when it overcomes the blood-brain barrier and when it passes through the cell membrane in the target cell. Since the ester of the carboxylic acid must first be fragmented, in vivo, by the esterases, the serum half-life is increased. R1 in the general formula I, preferably represents a straight chain C? -C12 alkyl group. R: in particular represents a decyl, undecyl, dodecyl or tridecyl group. n is preferably one of the number 0 or 1. R 2 preferably denotes an alkyl group of j-Ci., straight chain.
R2 in particular represents a decyl, undecyl or dodecyl group. The phosphonic acids of esters of the iti-Tsmos, preferred couplers, in the claimed conjugates of the general formula I are the following acids and their esters: phosphonophoric acid, phosphonoacetic acid, phosphonopropionic acid. The preferred lipid portions are n = 0 and the combination Ri = decyl / R2 = dodecyl, Ri = undecyl / R2 = undecyl or Ri = dodecyl / R2 = decyl, and further Ri = undecyl / R2 = decyl, Ri = tridecyl / R2 = decile, Ri = dodecyl / R2 = undecyl. The compounds of general formula I can be prepared
1. reacting a compound of the general formula II,
wherein R1, R2 and n have the stated meaning with a compound of general formula III,
wherein m has the meaning given above and R3 represents one of the aforementioned ester residues, in the presence of an optionally substituted arylsulfonic acid chloride, in an organic base or in the presence of the base in an inert organic solvent, and optionally the carboxylic acid ester is subsequently converted into a derivative of formula I or a physiologically compatible salt thereof, by means of an alkaline saponification; or 2. preparing a mixed anhydride from the compound of formula III and an alkyl or arylsulfonic acid chloride, and reacting, in the presence of a base in an inert organic solvent, or directly in the base with an alcohol of formula II, and the arylsulfonic acid ester optionally subjected to alkaline saponification;
3. a phosphonocarboxylic acid of formula III, in which R denotes hydrogen, is reacted with an alcohol of formula II, in the presence of a base and an optionally substituted arylsulfonic acid chloride, and if necessary, converted into a physiologically acceptable salt; OR 4. a mixed anhydride of a compound of formula III, in which R denotes hydrogen and an alkyl or arylsulfonic acid chloride, is reacted in the presence of a base, optionally in an inert organic solvent, with an alcohol of the formula II, and the conjugate is optionally converted to a physiologically compatible salt; or 5. the phosphonic acid dichloride of general formula IV _
I // O = P (CH2) m-C. | 0R * Cl
which is synthesized as described in Bhongle et al.
(Synthetic Commun., 17, 1071 (1987)), starting from an ester of bis-trimethylsilylphosphonic acid, and the following reaction with oxalyl chloride, subsequently reacts with an alcohol of general formula II, together with a base in a molar ratio of 1: 1 or 6. converting a compound of formula III with oxalyl chloride as described in Tetrahedron Letters Vol. 33, No. 49, p. 7473-7474, in the respective phosphonic acid dichloride of formula IV, which is subsequently reacted with an alcohol of formula II, in the presence of a base in a molar ratio of 1: 1. The monochloride of the phosphonic acid forming an intermediate is subjected to saponification to form a half ester and the carboxylic acid ester is converted to a derivative of formula I, or a physiologically compatible salt thereof, by alkaline saponification. The free acids of the lipid derivatives of the phosphonocarboxylic acids can optionally be converted into the desired esters. The compounds of formula II and their production are described in EP-0545699, and the examples. Pharmaceutical agents containing compounds of formula I, for the treatment of, for example, viral infections, can be administered enterally or parenterally in a solid or liquid form. In this case, the usual forms of administration come into consideration, such as, for example, tablets, capsules, dragees, syrups, solutions or suspensions. Preferably water is used as the injection medium, which contains the additives usually used in injection solutions, such as stabilizers, solubilizers and buffers. Such additives are for example, tartrate and citrate buffer, ethanol, complexing agents such as ethylenediaminetetraacetic acid, and nontoxic salts thereof, high molecular weight polymers, such as liquid polyethylene oxide, to regulate viscosity. The liquid carriers for the injectable solutions have to be. sterile and preferably filled in ampoules. The solid carriers are for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed salicylic acids, high molecular weight fatty acid fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, fats animals and vegetables, high molecular weight polymers, such as polyethylene glycols, etc. Suitable preparations for oral application may optionally contain flavors and sweeteners. In principle, the compounds of formula I can be administered orally, intrathecally, rectally, nasally, vaginally, lingually, intravenously, intraarterially, intramuscularly, intradermally or subcutaneously. The dose may depend on several factors, such as the manner of application, species, age or individual status. The compounds according to the invention are usually administered in amounts of 0.1-1000 mg, preferably 2-800 mg, and more preferably, 30-250 mg per day and per kg of body weight. It is preferable to divide the daily dose into 2-5 applications, 1-2 tablets with an active substance content of 0.5-3000 mg, administered in each application. The tablets can also be delayed, which means that the number of applications can decrease to 1-3 per day. The active substance content of the delayed effect tablets can be 20-5000 mg. The active substance can also be administered as a continuous infusion, the amounts of 5-10000 mg per day, are normally adequate. In addition to the compounds mentioned in the examples and the compounds derived from the combination of all the meanings of the substituents mentioned in the claims, the following compounds of the formula I also come into consideration, within the meaning of the present invention: 1. Acid ( 3-dodecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-formic. 2. Acid (3-dodecylsulfinyl-2-decyloxy) propoxy-hydroxy-phosphinyl-formic acid. 3. Acid (3-dodecr? Suifonil-2-decyloxy) propoxy-hydroxy-phosphinyl-formic.
4. Acid (3-undecylcapto-2-decyloxy) propoxy-hydroxy-phosphinyl-formic acid. 5. (3-decylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-formic acid. 6. (3-Tridecylmer-2-decyloxy) propoxy-hydroxy-phosphinyl-formic acid. 7. Acid (3-undecylcapto-2-undecyloxy) propoxy-hydroxy-phosphinyl-formic acid. 8. Acid (3-undecylsulfinyl-2-undecyloxy) propoxy-hydroxy-phosphinyl-formic acid. 9. (3-undecylsulphonyl-2-undecyloxy) propoxy-hydroxy-phosphinyl-formic acid. 10. Acid (3-dodecylmercapto-2-undecyloxy) propoxy-hydroxy-phosphinyl-formic acid. 11. Acid (3-decylmercapto-2-dodecyloxy) propoxy-hydroxy-phosphinyl-formic acid. 12. Acid (3-undecylcapto-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-undecylcapto-2-nonyloxy) propoxy-hydroxy-phosphinyl-formic acid.
16. Acid (3-dodecylmercapto-2-octyloxy) propoxy-hydroxy-phosphinyl-formic acid. 17 (3-Dodecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 18. (3-Dodecyl-sulfinyl-2-decyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 19. (3-Dodecylsulphonyl-2-decyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 20. (3-undecylcapto-2-decyloxy) propoxy-hydroxy-phosphinyl-prpionic acid. 21. Acid (3-decylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 22. (3-Tridecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 23. Acid (3-undecylcapto-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. Acid (3-dodecylmercapto-2-undecyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 27. Acid (3-decylmercapto-2-dodecyloxy) propoxy-hydroxy-phosphinyl-propionic acid.
28. Acid (3-undecylcapto-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-undecylcapto-2-nonyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 32. (3-Dodecylmercapto-2-octyloxy) propoxy-hydroxy-phosphinyl-propionic acid. 33. Acid (3-dodecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 34. (3-Dodecyl-sulfinyl-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 35. (3-Dodecylsulfonyl-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 36. (3-undecylcapto-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 37. Acid (3-decylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 38. (3-Tridecylmercapto-2-decyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 39. (3-undecylcapto-2-undecyloxy) propoxy-hydroxy-phosphinyl-acetic acid.
40. Acid (3-undecylsulfinyl-2-undecyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 41. (3-undecylsulphonyl-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-undecylcapto-2-dodecyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 4S *. Acid (3-dodecylmercapto-2-dodecyloxy) propoxy-hydroxy-phosphinyl-acetic acid. 46. (3-Dodecylmercapto-2-nonyloxy) propoxy-hydroxy-phosphinyl acetic acid. 47. (3-undecylcapto-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-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester. 51. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester.
52 Methyl ester of (3-undecylcapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 53. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid methyl ester. 54. Acid methyl ester (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic. 55. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester. 56. (3-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester. 57. (3-Tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid methyl ester. 58 (3-undecylcapto-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. Ethyl (3-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinolamic acid ester. 63. (3-Tridecylcapto-2-decyloxy) propoxy hydroxy-phosphin-1-formic acid ethyl ester.
64. Ethyl ester of (3-undecylcapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 65. (3-Dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid ethyl ester. 66. Ethyl (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid. 67. (3-Dodecylmercapto-2-decyloxy) ropoxy hydroxy-phosphinyl-acetic acid ethyl ester. 68. (3-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester. 69. (3-Tridecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester. 70. (3-undecylcapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid ethyl ester. 71. Ethyl (3-dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid ester. 72. Ethyl (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid ester. 73. (3-Dodecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester. 74. (3-undecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic isopropyl ester. 75. (3-Tridecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester.
76. Isopropyl ester of (3-undecyl-mlercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 77. (3-Dodecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic isopropyl ester. 78. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid isopropyl ester. 79. (3-Dodecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 80. (3-undecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 81. (3-Tridecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 82. (3-undecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 83. (3-Dodecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 84. (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid isopropyl ester. 85. Neopentyl ester of (3-dodecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid. 86. Neopentyl ester of (3-undecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid. 87. Neopentyl ester of (3-tridecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid.
88. Neopentyl ester of (3-undecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 89. Neopentyl ester of (3-dodecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 90. Neopentyl ester of (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid. 91. Neopentyl ester of (3-dodecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid. 92. Neopentyl ester of (3-undecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid. 93. Neopentyl ester of (3-tridecyl-mercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid. 94. Neopentyl ester of (3-undecyl mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid. 95. Neopentyl ester of (3-dodecyl-mercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid 96. Neopentyl ester of (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid. 97. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester. 98. (3-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester. 99. (3-Tridecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-formic acid benzyl ester.
100. Benzyl ester of (3-undecylcapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 101. Benzyl ester of (3-dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-formic acid. 102. Benzyl ester of (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-formic acid. 103. (3-Dodecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester. 104. (3-undecylcapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester. - 105. Benzyl ester of (3-tridecylmercapto-2-decyloxy) propoxy hydroxy-phosphinyl-acetic acid. 106. (3-undecylcapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid benzyl ester. 107. Benzyl ester of (3-dodecylmercapto-2-undecyloxy) propoxy hydroxy-phosphinyl-acetic acid. 108. Benzyl ester of (3-decylmercapto-2-dodecyloxy) propoxy hydroxy-phosphinyl-acetic acid.
Example 1
Disodium salt of the acid R, S- (3-dodecylmercapto-2-decyloxy) -propoxy-hydroxy-phosphinyl-formic (DMDOP-PFA) and the methyl ester DMDOP-PFA-OMe 18.2 ml of the trimethyl ester of phosphonoformic acid were dissolved, in 140 ml of dichloromethane, and mixed with 72.5 ml of bromotrimethylsilane, while stirring. The mixture was stirred for 2 hours at room temperature, evaporated and the residue was taken up twice in methanol, and the solution was evaporated again each time. The residue was taken up in 30 ml of absolute pyridine and mixed with a solution of 48.7 g of R, S- (3-dodecyl-mercapto-2-decyloxy) -propan-1-ol. The mixture was evaporated to dryness, the residue was mixed with 47.1 g of 2,4,6-tri-isopropyl-benzene sulfochloride and 150 ml of absolute pyridine while stirring. The initially viscous suspension became more fluid after ca. for 30 min and stirred for 25 hours at room temperature. The precipitate was filtered with suction and washed with a small amount of pyridine. The filtrate was mixed with 150 ml of water, while stirring, the mixture was stirred for 30 min at room temperature, evaporated and mixed with ether. The precipitate, which again precipitated, was removed by filtration and the ether filtrate was stirred with 0.5 N NCl. The ether phase was washed well with water, dried and evaporated. The residue (84.2 g) was purified by chromatography on silica gel with dichloromethane / methanol / glacial acetic acid (9: 0.5: 0.5). The fractions containing the 3-r product were concentrated by evaporation. 45.4 g of the R, S- (3-dodecylmercapto-2-decyloxy) -propoxy-hydroxy-phosphinyl-formic acid methyl ester (DMDOP-PFA-O e) were obtained. TLC on silica gel: Rf = 0.3 (acetic acid / acetone / glacial acetic acid / water 10: 4: 0.5: 0.5) Rf = 0.69 (dichloromethane / methanol 8: 2). In order to subject the methyl ester of the carboxylic acid to saponification, 5 g of the product obtained above were dissolved in 70 ml of tetrahydrofuran, and mixed with 6.7 ml of 2 N NaOH. It was stirred for 4 hours and allowed to stand all night. The reaction mixture was buffered to a pH of 8 with 2-ethylhexanoic acid and evaporated. The residue was stirred with acetone and the precipitated product was filtered off with suction. 4.1 g of the acid were obtained with a Pf of 242-246 C (decomposition). TLC on silica gel: Rf = 0.31 (isopropanol / butyl / acetone / water / concentrated ammonia 10: 6.3: 1) 13 C-NMR in D20; COOH (d, 175 ppm, JP-C = 231.4 Hz)
Example 2
Disodium salt of R, S- (3-dod-cilptercapto-2-decyloxy) -propoxy-hydroxy-phosphinyl-acetic acid (DMDOP-PAA) and the methyl ester DMDOP-PAA-OMe The title compound of Pf. 358- 360 C
(decomposition) was obtained in a manner analogous to Example 1, starting from the trimethyl ester of phosphonoacetic acid, as a product similar to wax and (3-dodecylmercapto-2-decyloxy) -propan-1-ol. DMDOP-PAA; TLC on silica gel; Rf = 0.53 (n-butanol / glacial acetic acid / water 2: 1: 1) Rf = 0.07 (dichloromethane / glacial acetic acid / water
9: 0.5: 0.5) DMDOP-PAA-Ome; TLC on silica gel Rf = 0.6 (n-butanol / glacial acetic acid / water 2: 1: 1) Rf = 0.1 (dichloromethane / glacial acetic acid / water
9: 0.5: 0.5).
Example 3
Determination of the in vitro toxicity of the bone marrow (CFU-GM test)
CFU-GM assays were carried out as described by Seidel and Kreja (Seidl, H. and J. Kreja, L., "Blut" 47, 139-145, 1983). Bone marrow cells (1 x 10 5 cells / ml) were cultured from Balb / c mice, in Iscove's medium, which contained 0.8% methyl cellulose, 20% horse serum, 10"4 M α-thioglycerol and one volume optimal (12.5 or 25 μl) of endotoxin activated mouse serum, which was obtained from Balb / c mice 4 hours before iv injection of 50 μg of endotoxin per animal (Salmonella abortus equi, Sigma, Deisenhofen, Germany). After incubation of the colonies for 6 days, they were stained for an additional 24 hours with 2- (p-iodophenyl) -3- (p-nitrophenyl) -5-phenyl tetrazolium hydrochloride, (INT, Sigma) and then counted with an automated image processor (Art 982 B, Biosys GmbH, Karben, Germany) Table 1 shows the concentrations of the CI5o of several concentration-dependent experiments for phosphono-formic acid, DMDOP-PFA, phosphonoacetic acid,
DMDOP-PAA, (3-octadecyloxy-2-hydroxy) -propoxy-hydroxy-phosphinyl-formic acid (OOHP-PDAE) ethyl ester and acid
(3-Octadecyloxy-l-hydroxy) -propoxy-hydroxy-phosphinylformamic
(OOHP-PFA), compared with the cytostatic agents Cisplatin (Cis-DDP) and Doxorubicin. As can be seen from the table, DMDOP-PFA and DMDOP-PAA, up to the highest tested concentration of 100 μg / ml, showed no toxicity in the germ cells of the bone marrow of the granulocytic / monocytic series. While this also
applied to phosphonoformic acid, phosphonoacetic acid, as well as to the conjugates OOHP-PFAE and OOHP-PFA, are more toxic than DMDOP-PFA and DMDOP-PAA.
Table 1. IC5o values (μg / ml for Cis-DDP, Doxorubicin, phosphonoformic acid (Foscarnet), DMDOP-PFA, phosphonoacetic acid, DMDOP-PPA, OOHP-PFAE and OOHP-PFA in a CFU-GM assay.
Substance CI5o (μg / ml) a
Cis-DDP (Cisplatin) 0.45 ± 0.11 (5)
Doxorubicin 0.046 ± 0.007 (4)
Phosphonoformic acid (Foscarnet) > 100 (6) DMDOP-PFA > 100 (6) Phosphonoacetic acid 62.88 (2) DMDOP-PAA > 100 (2) OOHP-PFAE 59.35 (3) OOHP-PFA 94.49 (3) a means the value ± DEM; n, the number of experiments that were carried out in a concentration-dependent manner, in determinations in duplicate or triplicate.
Example 4 Oral bioavailability in the Murine Cytomegaly Virus Model (MCMV) < . »,
Female mice Balb / c, i.p. with a dose of 8xl05PFU (plate formation units). The percentage of surviving animals increased in the
order of: not treated < treated with Foscarnet < treated with
DMDIP-PFA < DMDOP-PFA-OMe.
It is noted that in relation to this date, the best method known to the applicant to carry. the practice cited invention, is the conventional for the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:
Claims (5)
1. novel phospholipid derivatives of phosphonocarboxylic acids of general formula I characterized in that: R1 is a linear or branched alkyl chain, saturated or unsaturated with 9-13 carbon atoms, R2 can be a straight or branched alkenyl chain, saturated or unsaturated with 8-12 carbon atoms, R3 represents hydrogen, a linear or branched alkyl chain, with 1-6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, neopentyl, texyl or phenyl, choline, ethanolamine, carnitine, a C5-C7 cycloalkyl residue, benzyl or one of "following groups 25 n denotes 0, 1 or 2 and m represents 0, 1, 2 or 3, tautomers, optical isomers and racemates eof, r physiologically tolerated esters and r physiologically tolerated salts of organic or inorganic bases.
2. compound of formula I, according to claim 1, characterized in that R1 represents a decyl, undecyl, dodecyl or tridecyl group.
3. compound of formula I, according to one of claims 1 or 2, characterized in that R2 represents a decyl, undecyl or dodecyl group.
4. compound of formula X, according to one of claims 1 to 3, characterized in that n represents number 0 or 1. compound of formula 2, according to one of claims 1 to 4, characterized in that m represents number 0, 1 or 2. ß. compound of formula X, according to one of claims 1 to 5, characterized in that RJ represents a methyl, ethyl, propyl, butyl, t-butyl or benzyl group. 7. A pharmaceutical composition, characterized in that it contains at least one compound of general formula I, as claimed in one of claims 1 to 6, in addition to usual pharmaceutical auxiliaries and carriers. 8. use of at least one compound of general formula I, according to any of claims 1 to 6, for production of a medicament for treatment of autoimmune diseases, neoplasms, inflammatory, viral or retroviral diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19547023.0 | 1995-12-15 | ||
| DE19643416.5 | 1996-10-22 | ||
| EPEP96/05647 | 1996-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA98004755A true MXPA98004755A (en) | 1999-07-06 |
Family
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