Title of Invention

A PHARMACEUTICAL PREPARATION AND A METHOD FOR PREPARING THE SAME

Abstract

ABSTRACT 751/CHENP/2004 A PHARMACEUTICAL PREPARATION AND A METHOD FOR PREPARING THE SAME The present invention relates to a pharmaceutical preparation for the treatment of tumor diseases, autoimmune diseases, cardiovascular diseases, infections or viral diseases, comprising one or more salts of guanidine derivatives corresponding to the formula wherein the substituents are as described in the description. This invention also relates to a method for preparing the same.

Full Text

The invention relates to new salts of guanidine derivatives and pharmaceutical preparations containing these as the active ingredient, as well as their preparation. WO 97/45401 discloses guanidine derivatives of the general formula (1) in which X represents the group, -R1, -NHR1, -NH-NH-CHR1R2 or -NH-N^R^2, whereby R1 and R2 independent of each other represent hydrogen, a linear or branched C3-C20 alkyt or C3-C20 cycloalkyi, adamantyl, norbornyl, tricyclodecyl or benzyl, pyridyl, indolyl, quinolyl, anthracyl, phenantryl, perinaphtyl or quinuclidinyl radical. The use of the compounds as active ingredient in pharmaceutical Due to their detergent structure, the bases described and their salts obtained by neutralization with inorganic acids or by dissolution in buffered saline (physiological sodium chloride solution) possess strong hemolytic and tissue-damaging properties. Moreover, in the presence of inorganic phosphate ions, inorganic salts form phosphates of the guanidines which are insoluble in aqueous solutions, this causes them to be precipitated, and thereby rendered pharmaceutically inactive, in the blood at relatively low concentrations. For these reasons, the pharmaceutical utility of guanidine derivatives is strongly limited, Thus, it was the object of the present invention to provide a physiologically tolerable and, at the same time, efficacious form of administration for the guanidine derivatives. wherein X represents a valence bond, -CH2-NH-, -CH2-NH-NH- or -CH-N-NH-, and R represents a linear or branched G1-C30 alkyl, C3-C20 cycloalkyl, adamantyl, norbornyl, tricyclodecyi, benzyl, furyl, pyridyt, anthracyi, naphtyl, phenanthryt, perinaphtyl or quinuclidinyl residue, which can be substituted by one or more hydroxyl groups, C1-C4 alkoxy groups, C1-C4 alkyl groups and/or one or more halogen atoms or one or more amino groups, and Y represents a linear or branched C1-C12 alkyl, C3-Ca cycloalkyl, benzyl, furyl or pyridyl residue, which can be substituted by one or more hydroxyl groups, carboxylic acid groups, C1-C4 alkoxy groups, C1-C4 alkyl groups and/or one or more halogen atoms or one or more amino groups. It is preferred for R to represent pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, cyclododecyl, tricyclo[5,2,1 .O^-decyl, bicyclo[2,2,1]-cyclohexyl or toluyl. A decyl residue is particularly advantageous. It is preferred for X to represent -CH2-NH-NH- or -CH=N-NH- with -CH=N-NH-being particularly preferred. It is particularly advantageous for Y to represent methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl as well as hydroxyethy! and 2-hydroxy-2,3-dicarbaxylic acid propyl. Particularly preferred are methyl, ethyl, octyl, nonyl, decyl, undecyl, and dodecyl as well as hydroxyethyl and 2-hydroxy-2,3-dicarboxyIic acid propyl. Particularly preferred compounds according to the present invention are undecylaminoguanidine acetate, undecylaminoguanidine lactate, undecylaminoguanidine oenanthate, undecylaminoguanidine pelargonate, and, in particular, undecylideneaminoguanidine acetate, undecylideneaminoguanidine lactate, undecylideneaminoguanidine oenanthate, undecylideneaminoguanidine pelargonate. In place of the carboxylic acids, the correspondingly substituted sulfonic acids or phosphonic acids can be inserted. It is self-evident that the present invention relates, as far as applicable, to the pure optical isomers and their mixtures as well as racemates, tautomers or stereoisomers. aqueous solution by phosphate ions. The efficacy, in contrast, in particular as it concerns the inhibition of sphingomyelinase, is not or not significantly affected. The preparation of the guanidines is known, for instance from WO 97/45401. The guanidine salts according to the invention are simple to prepare by contacting the free bases with the corresponding free acids. This can be done in suitable solvents, mainly water, as well as without solvents, especially if the acid and/or the base is a liquid. It can be advantageous to add an excess of the acid. The present invention also relates to pharmaceutical preparations containing the salts of the guanidine derivatives according to the invention as active ingredient. The pharmaceutical preparations can be used for the treatment of tumor diseases, autoimmune diseases, cardiovascular diseases, infections, and, in particular, viral diseases. The active ingredients are also suitable for prophylaxis. Preferred active ingredients are: undecylideneaminoguanidine acetate, undecylideneaminoguanidine lactate, and, in particular, undecylideneaminoguanidine oenanthate and undecylideneaminoguanidine pelargonate. Aside from the active ingredient according to the invention, the preparations according to the invention commonly contain excipients and additives facilitating the formulation into forms of administration. Moreover, for instance for combination preparations, other active ingredients can be added provided they are chemically compatible with the active ingredients according to the invention. The following forms of administration are considered: liquid preparations for injection; tablets, capsules, powders, solutions, suspensions or elixirs for oral application; ointments, creams, emulsions or lotions for topical application; powders and solutions for inhalation; and suppositories. The methods for the preparation of forms of administration are known to a person skilled in the art. Aside from processing the salts according to the invention to the forms of administration, these active ingredients can also be processed to forms of administration by providing the free base and acid, preferably in equimolar amounts, and processing this mixture, if applicable, in the presence of additional excipients and additives. Thereby, the salt is formed either in situ or upon release from the form of administration in the body. Usable concentrations are in the range from 0.5 to 30% active ingredient in injection solutions and at least 1 % active ingredient in preparations for the remaining forms of administration. The daily adult dose is between 5 and 1,000 mg. The following examples are presented to further illustrate the present invention without limiting it to the examples presented. Example 1: Preparation of undecylideneaminoquanidine acetate Atotal of 23.4 g (0.1 mol)undecyiideneaminoguanidine (i.e. Ci0H2i-CH=N-NH-C(NH)-NH2, hereinafter abbreviated as C11AG) are slurried in 234 ml distilled water, heated to 60DC, and then 6.005 g glacial acetic acid are added slowly under stirring. After stirring for 30 minutes, the sample is filtered, and chilled to 0°C. The crystallized salt is removed by filtration and washed with ice-cold water. A total of 27.8 g of the acetate are obtained (yield 94.5 %). Example 2: Preparation of undecylidene_am[noguanidine oenanthate Atotal of 23.4 g (0.1 mol) undecyiideneaminoguanidine (C11AG) are slurried in 234 ml distilled water, heated to 6Q°C, and then 13.02 g oenanthic acid are added slowly under stirring. After stirring for 30 minutes, the sample is filtered, and chilled to 0°C. The crystallized salt is removed by filtration and washed with ice-cold water. A total of 22 g of the oenanthate are obtained (yield 60.4 %). Example 3; Preparation of undecvlideneaminoguanidine pelargonate A total of 23.4 g (0.1 mol) undecylideneaminoguanidine (C11 AG) are slurried in 234 ml distilled water, heated to 60°C, and then 15.82 g of pelargonic acid are added slowly under stirring. After stirring for 30 minutes, the sample is filtered, and chilled to 0°C, The crystallized salt is removed by filtration and washed with ice-cold water. A total of 36.1 g of the pelargonate are obtained (yield 92 %). Example 4: Preparation of additional undecvlideneaminoguanidine salts A total of 1.1 mmol acid and 1mmolC11AG (234 mg) were dissolved in 3 ml ethylacetate. The excess of acid was removed by extracting thrice with distilled water. After drying in a vacuum, the salt was obtained with the yield being in excess of 90 %. Table 1 shows an overview of the solubilities of the salts thus obtained as well as their melting points and the corresponding data of the salts from examples 1-3. i The salts of lactic acid, acetic acid, hydrochloric acid, oenanthic acid, and pelargonic acid were prepared as described above. Mouse blood (obtained from the tail vein) was diluted 1:100 in isotonic glucose solution. The various C11AG salts were added to 0.1 ml aliquots of diluted mouse blood each at final concentrations of 4-4,000 jig/ml. After mixing and incubating at room temperature for 20 minutes, the samples were briefly centrifuged and the optical density at 405 nm was measured. The optical density is a measure of the quantity of hemoglobin released from the erythrocytes. Fig. 1 shows the optical density readings as a function of the logarithm of the concentration of the guanidine derivative. The final Example 6: Solubility of C11AG salts in phosphate buffer A 1 M potassium phosphate buffer solution, pH 7.4, was prepared. The salts of lactic acid, acetic acid, hydrochloric acid, oenanthic acid, and pelargonic acid, were added to a dilution series containing between 1,000 mM and 1 mM phosphate to establish a final concentration of the C11AG salt of 4 mM. The formation of crystals was monitored by microscope at 40-fold magnification. The results are shown in Table 2. While the chloride forms insoluble phosphates at concentrations as low as 1 mM, the acetate and the lactate precipitate only at a phosphate concentration of 10 mM and the oenanthate and the pelargonate are stable even in solutions containing 1,000 mM phosphate ions. Example 7: Inhibition of neutral sphingomyelinase The salts of lactic acid, acetic acid, hydrochloric acid, oenanthic acid, and pelargonic acid, were prepared as described above or in an analogous fashion. Paranitrophenylphosphoryl-choline was dissolved to a final concentration of 1 mg/ml in 0.1 M Tris at pH 7.2 and 10 mM Mg2CI2. After adding 0.1 unit of neutral sphingomyelinase from Bacillus cereus, the various C11 AG salts were added at concentrations between 0.1 and 1,000 u.g/ml. After incubation at 37°C for 24 h, the optical density at 405 nm was measured. The optical density is a measure for the quantity of cleaved substrate. Dose-effect curves were used to determine the concentration at which the enzyme activity is inhibited by 50 % (IC50). The results are listed in Table 3. It is evident that the efficacy is even improved in some cases, but definitely in none of the cases is reduced significantly below the efficacy of the chloride. Example 8: Physiological tolerability of various C11 AG salts The salts of acetic acid, hydrochloric acid, oenanthic acid, and pelargonic acid were used to prepare solutions in isotonic glucose solution at concentrations of 4 mM, 20 mM, 40 mM, and 120 mM. Aliquots of 0.1 ml each were administered to 3 nude mice (strain: Swiss, Nu/Nu) by subcutaneous application. After 24 h, the degree of tissue damage was recorded. The results are shown in Table 4, in which no visible damage = -, reddening = +, edemas = ++, and necroses = +++. It is evident that the chloride leads to reddening and edemas at concentrations as low as 20 mM. The acetate is well-tolerated up to 20 mM and only at 120 mM shows the same degree of damage that was observed with 20 mM of the chloride. The preferred oenanthates and pelargonates show no damage whatsoever even at 120 mM. WE CLAIM: 1. A pharmaceutical preparation for the treatment of tumor diseases, autoimmune diseases, cardiovascular diseases, infections or viral diseases, comprising one or more salts of guanidine derivatives corresponding to the formula R represents a linear or branched Ci-C30 alkyl, C3-C20 cycloalkyl, or tricyclodecyl residue, which can be substituted by one or more hydroxyl groups, C1-C4 alkoxy groups, C1-C4 alkyl groups and/or one or more halogen atoms or one or more amino groups, and Y represents pentyl, hexyl, heptyl or nonyl. 2. The pharmaceutical preparation as claimed in claim 1, wherein it comprises pharmaceutically acceptable additives and/or excipients. 3. The pharmaceutical preparation as claimed in claim 1 or 2, wherein R represents a pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, cyclododecyl, tricyclo[5,2,l,02,6]-decyl, or bicyclo[2,2,l]-hexyl residue. 4. The pharmaceutical preparation as claimed in any one of claims 1 to 3, wherein R represents a decyl residue. 5. The pharmaceutical preparation as claimed in claim 1, said salt being undecylideneaminoguanidineoenanthate. 6. The pharmaceutical preparation as claimed in claim 1, said salt being undecylideneaminoguanidine decanoate. 7. The pharmaceutical preparation as claimed in claim 1, said salt being undecylideneaminoguanidineoctanoate. 8. The pharmaceutical preparation as claimed in claim 1, said salt being undecylideneaminoguanidine hexanoate. 9. A method for the preparation of a pharmaceutical preparation as claimed in claim 1, wherein a salt of a guanidine derivative corresponding to the formula R represents a linear or branched C1-C30 alkyl, C3-C20 cycloalkyl, or tricyclodecyl residue, which can be substituted by one or more hydroxyl groups, CrC4 aikoxy groups, Ci-C4 alkyl groups and/or one or more halogen atoms or one or more amino groups, and Y represents pentyl, hexyl, heptyl or nonyl is combined with pharmaceutically acceptable additives and/or excipients to an administrable form. 10. The method as claimed in claim 9, wherein a salt as claimed in claim 1 is processed to an administrable form by providing approximately equimolar amounts of the corresponding base and acid and combining with pharmaceutically acceptable additives and/or excipients.

Documents:

0751-chenp-2004 abstract.pdf

0751-chenp-2004 claims-duplicate.pdf

0751-chenp-2004 claims.pdf

0751-chenp-2004 correspondences others.pdf

0751-chenp-2004 correspondences po.pdf

0751-chenp-2004 descripition(completed)-duplicate.pdf

0751-chenp-2004 descripition(completed).pdf

0751-chenp-2004 drawings-duplicate.pdf

0751-chenp-2004 drawings.pdf

0751-chenp-2004 form-1.pdf

0751-chenp-2004 form-18.pdf

0751-chenp-2004 form-26.pdf

0751-chenp-2004 form-3.pdf

0751-chenp-2004 form-5.pdf

0751-chenp-2004 pct.pdf

0751-chenp-2004 petition.pdf

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