GB2216522A - Aminoacid salts of long chain unsaturated carboxylic acids - Google Patents

Aminoacid salts of long chain unsaturated carboxylic acids Download PDF

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GB2216522A
GB2216522A GB8905384A GB8905384A GB2216522A GB 2216522 A GB2216522 A GB 2216522A GB 8905384 A GB8905384 A GB 8905384A GB 8905384 A GB8905384 A GB 8905384A GB 2216522 A GB2216522 A GB 2216522A
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acid
general formula
salt
lysine
salts
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Nagy Peter Literati
Maria Boros
Jeno Szilbereky
Istvan Racz
Gyoengyver Soos
Miklos Koller
Alan Pinter
Gabor Nemeth
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BIOREX KFT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Description

t" r r 1. 22- 16 22 NOVEL SALT-TYPE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM AND PROCESS FOR PREPARING SAME This invention relates to novel antiviral and immune system-stimulating salts and pharmaceutical compositions containing these salts.
According to an other aspect of the invention, there is provided a process for the preparation of the new salts.
1D The advantageous antiviral action of W-3 polyun- saturated fatty acids /-5,8,11,14,17-eicosapentaenoic acid (hereinafter: EPA) and 4,7,10,13,16,19-docosahexaenoic acid (hereinafter: DHA)7 called a considerable attention. Szads /-Antimicrobial Agents and Chemoterapy 12, 523 (197727 showed hy in vitro experiments that polyunsaturated fatty acids, e.g. both EPA and DHA, are capable to inhibit virus replication. The same fact was supported by Reinhardt et al. /-J. of Virology 25, 479 (1978)7 investigating the inhibition of the replication on PR 4 bacteriophage.
The antiviral effect of polyunsaturated fatty acids, among these that of EPA and DHA, is described in detail in the United States patent specification No. 4,513,006.
The effect of EPA and DHA was compared in animal experiments on mice and guinea pigs to Acyclovir /-9-(2-hydroxyethoxy- methyl)guanine7 being the most frequently used antiviral agent at present. It has beEn stated that compositions 2 ferable action containing particularly DHA showed a more pre, Y against herpes virus than acyclovir. A number of articles have been"devoted in the literature to the antiviral effect of DHA and EPA, such as: 5 Whitaker et al. /-Proc. Natl. Acad. Sci. USA 76, 5919 (1979)7 as well as Goodnight et al. /-Arterioschlerosis, 2., 87 (1982)7 and Yoshiaki /-Biochimica et Biophysica Acta 793, 80 (198427. Prickett et al. /-Immunology 46, 819 (1982)7 showed that the humoral immune response was stimulated by eicosapentaenoic acid as an arachidonic acid analogue. Under an EPA-rich diet, the specific IgG and IgE production as a response given to egg albumin was increased in inbred Sprague-Dawley rats to a 4 to B-fold value in comparison to the control. According to this paper, an enhanced antibody response was induced by the EPA-rich diet. Further on, there was shown by the investigations that EPA acts through an inhibition of the suppressive prostaglandin system whereby it is capable to inhibit or correct, respectively, the immune deficiency accompanying the ageing and other pathological processes (autoimmune processes, tumouro genesis).
These statements were supported by the articles of Kelley et al. /-J. of Immunol. 134, 1914 (1985)7 as well as Homey et al. /-Clin. Exp. Immunol. 65, 473 (1986)7.
It is long known on the basis Of the in vivo investigations of Pearson et al. /-Proc. Soc. Exp. Biol.
Med. 792 409 (1952)7 that L-lysine has an effect inhibiting the encephalomyelitis virus. Later on, Tankersley J. Bact.
3 87, 609 (1964)7 called the attention to the fact Laht the replication of the herpes simplex virus (hereinafter: HSV) is inhibited by lysine in human cells under in vitro conditions. Based on human examinations, Kagan published /-The Lancet 1, 137 (1974)7 that both the oral and genital HSV-induced laesions very rapidly disappeared on effect of a treatment with L-lysine.
Griffith et al. /-Dermatologica 156, 257 (1978)7 studied the therapeutic action of L-lysine on 45 patients infected by HSV I and HSV II in various doses, with varied treatment periods. The age of the patients (predominantly women) varied between 8 and 60 years. It was stated that L-lysine exerted only a suppressive but not healing effect on HSV.
The present invention is aimed at novel, therapeuttical- ly effective salts and the use of these salts for preparing pharmaceutical compositions which combine the advantageous therapeutical effects of the CLY-3 unsaturated fatty acids with those of the amino acids such as particularly lysine, ornithine and histidine, and which show a stronger action than any antiviral agent known till now.
The invention is based on the recognition that the salts obtained by the salt-formation of CLI-3 unsaturated fatty acids, particularly EPA and DHA, with amino acids or their derivatives, respectively, particularly with lysine, possess a strong antiviral and immunostimulating effect.
Thus, the present invention relates to the novel antiviral and immunostimulating salts of the general formula (I), R-COO-AH + (I) wherein R means a C 18-24 alkyl group containing at least two double bonds; and A stands for an amino acid occurring in living organisms and/or a derivative thereof containing a carboxyl group substituted by a C 1-4 alkyl group or an amino group or by an alkali metal cation.
According to the invention, these novel salts are prepared by reacting as base component an amino acid "A" as defined for the general formula (I), wherein the substituents are the same as defined above, with an acid of the general formula (II), R-COOH (II) wherein R is the same as defined above, in a polar solvent. The compounds of general formula (I) ar-e preferably salts formed from w-3 unsaturated fatty acids containing at least two double bonds with basic amino acids or their derivatives, respectively.
The eventual toxicity against a cell culture of the salt compounds according to the invention was studied with a salt formed from an CO':-3 polyunsaturated fatty acid mixture (containing 27.6 % of EPA and 44.6 % of DHA) with L-lysine on the basis of its effect exerted on the propaga tion and morphology of Hep 2 cells (human epithelial tumour cell line). These experiments were carried out on a plastic tissue- cultivating sheet containing.6x4 hollow spaces (holes with a bottom surface of 1.9 cm 2 each).
A stock solution containing the test compound in a concentration of 10 mg/ml was prepared in Eagle MEM medium (manufactured by Serva GmbH Co., Heidelberg, German Federal Republic). An aliquot part of the stock solution was diluted 10-fold, the solution obtained was diluted 2-fold and then, by repeating twice the 2-fold dilution of the latter solution, solutions with successively decreasing concentrations of the test compound (solutions Nos. 1 to 5) were prepared. The cells were treated with 1 ml of a solution each containing the active ingredient in the following concentrations:
Solution Concentration of the active ingredient No. /ug/ml 1 10,000 2 1,000 3 500 4 250 125 The treatment was carried out for 1 hour, then the cultures were washed twice with buffered sodium chloride solution (phosphate-buffered saline, hereinafter: PBS), then a nutritive medium was added to the cultures.
After 24 hours and fixation by methanol, the cultures were dyed by ethanolic Giemsa solution (manufactured by Reanal, Budapest, Hungary) and the morphology of the cells was evaluated under light microscope. It could be stated that the test compound proved to be toxic only above a concentration of 1000 /ug/ml.
The virus replication-inhibiting effect was examined on Hep 2 cells as described above. Type I of HSV was used for infection. The concentration of the virus amounted to about 1000 PFU (plaque forming unit). Solutions containing the test compound in a concentration of 1000, 500 and 250 /ug/ml, respectivelly,were used and for the treatment - 0.1 M1 of solution was added to the undiluted virus suspension. The mixture was incubated at 37 0 C for 1 hour. Then, the cells were treated by the virus pre-incubated with the test 20 compound and the development of cytopathologic (herein- after: CP) alterations was observed for 7 days.
It could be stated that the virus replication was directly inhibited by a 500 /ug/ml or 250 /ug/ml dose of the test compound, and the infective titre value of the cytopathologic dose (neg. log. CPD 50) was 1.75 calculated for 0.1 ml in comparison to the neg. log. CP0 50 value of 4.5 of the untreated control virus culture. The value of the virus inhibition exceedsby two orders of magnitude that of the control. Under the same conditions, EPA and DHA did not show any valuable virus inhibition; and lysine in itself inhibited the virus replication to an extent of only about one order of magnitude.
Vaccine virus was also treated in an in vitro experiment carried out in the above manner. The infective titre value (neg. log. CPD 50) of the test compound measured on vaccine virus proved to be 1.75 in comparison to the 5.5 value of the untreated control virus, i.e. the test compound showed virus-inhibiting effect which was by three orders of magnitude stronger than that of the control.
The in vitro action on the immune System Of the compounds according to the invention was studied on the activation of lymphocytes by polyclonal mitogens. The blaStiC transformation of the lymphocytes was investigated in such a way that a lymphocyte cell population obtained on a Fico Uromiro gradient /-Scand. J. Clin. Lab. Invest. 21, 97 (1968)7 was pipetted into the holes of fl2t- ground sheets, 25 /ug/ml of Concanavaline A (hereinafter: Con A) (manu- factured by Ph2rmacia, Uppsala, Sweden) and then a solution containing the novel compound according to the invention in a concentration of 0.1, 1.0 or 10 /ug/ml, respectively, were added to each of the parallel cultures.
A culture containing 25 /ug/ml of Con A without test compuund was used as ccntrol. The sheets were maintained under an air atmosphere containing 5% of carbon dioxide at 37 D C for 72 hours, and 0.4 /uCi of 3 H-thymidine was added to each 8 sample after 64 hours, before ending the cultivation. After 72 hours, the cultures were filtered through a glass filter, the filters were put into a scintillation cuvet and the radioactivity was measured in 5 ml of toluene solution each by using a beta-counter device. The results are summarized in the following Table.
No. Compound Concentration of Counts/minute Evaluation name the active cpm of the inoredient /ug/g effect 1. Control 25 8969-;-2984 (Con A) 2. L-tyrosine 0.1 12915 2045 weakly slgnifiC2.-1-'L grow,th 1.0 12313 + 2003 3. L-lysine 0.1 11063 + 1528 not significant 1.0 11833 + 1823 weakly significant grot,,,th 4. Na salt of an 0.1 12332 + 2235 not significant ce,'-3 fatty acid mixture (see the 1.0 12039 + 1640 not significant composition in Example 1)
5. Control 25 8396 + 2233 (Con A) 6. Product of 0.1 14965 + 2143 strongly significant Example 16
1.0 12517 + 2195 not sionificant 9 Table - continued No. Compound Concentration Counts/minute Evaluation name of the active cpm of the ingredient effect /ug/g 7. Product of 0.1 15985 + 2102 strongly significant Example 1 growth 1.0 14068 + 1665 significant growth It is obvious from these examinations that the compounds according to the invention and particularly the salt of lysine or tyrosine formed with a mixture of Polyunsaturated fatty acids show significant tests results, i. e. a strong immunostimulating effect, whilst the separate salt-forming components in themselves proved to have no or only a weak biological action.
As starting material of C 18-24 CA--3 unsaturated fatty acids being one component of the salts, it is suitable to use first of all oils which can be obtained from fishes of the northern seas such as salmon, codfish, sardine or from their livers but oils arising from fresh-water fishes can also be utilized. The LC--3 polyunsaturated fatty - io - acids are obtained from the above oils by using a known method /-J. Am. Chem. Soc. 59, 117 (198227.
The active compounds of the general formula (I) can be transformed to capsules, tablets, drag6es or other pharmaceutical compositions formulated in a manner known per e by using the carriers and/or additives such as lactose, starch, magnesium stearate and the like commonly used in the pharmaceutical industry.
For inhibiting the oxidation of the composition, the use of d-tocopherol. (vitamin E), glutathione or the traditional antioxidants such as buty1hydroxytoluene is suitable.
The main advantages of the compounds according to the invention and of the pharmaceutical compositions prepared therefrom can be summarized as follows.
1. They can be used against acute virus infections; they are particularly preferable in the herpes virus infection for suppressing the infection in a beginning state.
2. Owing to their immunostimulating effect, they -an preferably be used against retroviruses, especially against the immunodeficiency syndromes (e.g. AIDS) induced by HT'LV III and HTLV IV type viruses.
3. They contain exclusively native active agents which are essential from biological viewpoint. Thus, they are useful for a prophylactic, long-lasting, CUre-like treatment in case of a danger of virus infection as well as in diseases of the immune system.
- -9:- - 4. They act also internally. Thus, the inconvenient external treatment commonly used in the antiviral therapy can be avoided.
The compounds and compositions according to the invention and their process of preparation are illustrated in detail by the following non limiing Examples. Example 1 To 164 g (1 mole) of L-lysine monohydrate dissolved 10 in 500 ml of water at room temperature, 320 g (about 1 mole) of an OX-3 polyunsaturated fatty acid mixture (containing 27.6 % of EPA, 44.6 % of DHA and 0.1 % of vitamin E) are dropped. The mixture is stirred under mild heating (at 40'C) and under nitrogen for 3 hours and then evaporated under 15 reduced pressure (4 to 5.3 kPa) to obtain 465 g of a crystalline salt, m. p. 188-195 0 C (with decomposition), the unsaturated fatty acid composition of which is identical to that of the starting mixture. 20 Example 2 155 9 (1 mole) of L-histidine are dissolved in 450 mI of water at room temperature and 320 g (about 1 mole) of an Ur-3 polyunsaturated fatty acid mixture (containing 27.6 % of EPA and 44.6 % of DHA) are dropwise added to the solution during 5 minutes. Further on the process of Example 1 is followed to give 471 g of a crystalline substance, m. p.: 192-200 0 C (with decomposition).
Examole 3 The process described in Example 2 is followed, except that 133 9 of L(+)-ornithine are used instead of L-histidine to obtain 449 g of a crystalline product, m. p.: 189-195 OC (with decomposition).
Example 4 After dissolving 1.64 9 (0.01 mole) of L-lysine monohydrate in 5 ml of water at room temperature, 3.02 g 10 (0.01 mole) of eicosapentaenoic acid /-manufactured by Sigma Co. St. Louis, USA under catalogue number E-7006 (1987)7 are added to the solution in little portions. The mixture is maintained at 40 OC under nitrogen for 3 hours, then evaporated under a pressure of 4-5.3 kPa to give 4.9 g 15 of a yellowish-brown crystalline salt, m. p.: 104-196 OC (with decomposition). Example 5 The process described in Example 4 is followed, 20 except that 3.28 g (0.01 mole) of docosahexaenoic acid /- manufactured by Sigma Co., St. Louis, USA under the catalogue number D- 6508 (198727 are used instead of eicosapentaenoic acid to give 4.85 g of a crystalline salt, m.p.: 195-198 0 C (with decomposition). 25 Example 6 The process described in Example 4 is followed, except that 1.55 g (0.01 mole) of L-histidine are used instead of L- lysine monohydrate to obtain 4.8 g of a crystalline salt, m. p.: 196-200 0 C (with decomposition).
Example 7
The process described in Example 4 is followed, except that 1.55 g (0.01 mole) of L-histidine instead of L-lysine monohydrate and 3.28 g (0.01 mole) of DHA instead of EPA are employed to give 3.78 g of a crystalline salt, m. p.: 196-199 0 C (with decomposition).
Example 8
The process described in Example 4 is followed, except that 1.32 g (0.01 mole) of L(+)-ornithine are used instead of L-lysine monohydrate to give 4.6 g of a crystalline salt, m. p.: 190-193 0 C (with decomposition). Example 9 The process described in Example 4 is followed, 20 except that 1.32 g (0.01 mole) of L(+)-ornithine instead of L-lysine monohydrate and 3.28 g (0.01 mole) of DHA ins-mad of EPA are used to give 4.55 g of a crystalline salt, m. p.: 191-195 D C (with decomposition). 25 Example 10 2 9 (22 m.T.. oles) of L-alanine are dissolved in the solution of 0.88 9 (22 mmoles) of sodium hydroxide in 20 mI 4 of water under stirring at room temperature, then 7.5 g (22 mmoles) of an W-3 polyunsaturated fatty acid mixture (containing 27.6 % of EPA, 44.6 % of DHA and 0.1 % of vitamin E) are dropwise added at 40 0 C to the above solution. The mixture is stirred under nitrogen at 40 0 C for 2 hours, then the solvent is distilled off under a reduced pressure of 4 to 5.3 kPa to give 10.4 g of a pale brown paste-like solid product, m. p.: 210-220 0 C.
In the following Examples 11 to 14, the process described in Example 10 is followed, except that the corresponding amino acid is used instead of L-alanine.
Example 11
L-Proline 1.5 g (13.0 mmoles) Water 40.0 ml Sodium hydroxide 0.52 g (13.0 mmoles) Cli-3 fatty acid mixture(according 4.35 g (13.0 mmoles) to Example 10) A brown oily product is obtained in a yield of 6.3 g.
Example 12
L-Leucine 1.0 g (7.6 mmoles) Water 5.0 ml Sodium hydroxide 0.3 g (7.6 mmoles) W -3 fatty acid 2.54 g (7.6 mmoles) A brown crystalline product is obtained in a yield of 3.70 g which liquifies in the air.
- i5 Example 13
LThreonine 0.5 g (4.2 mmoles) Water 10.0 M1 Sodium hydroxide 0.16 g (4.2 mmoles) 1-kY-3 fatty acid 1.4 9 (4.2 mmoles) A yellow crystalline product is obtained in a yield of 1.95 9, m. p.: 204- 213 0 C (with decomposition).
Example 14
L-Aspartic acid 1.0g (7.5 mmoles) Water 40.0 ml Sodium hydroxide 0.6 g (15.0 mmoles) W -3 fatty acid 2.5 g (7.5 mmoles) A yellow crystalline salt is obtained in a yield of 3.97 g, m. p.: 200 DC (with decomposition).
Example 15
7.1 mmoles of sodium metal are dissolved in 20 ml of anhydrous ethanol, then the solution is cooled between 0 oC and 10 OC and 1.5 9 (7.1 mmoles) of L-arginine hydro chloride are added. After stirring at room temperature for 20 minutes, the mixture is filtered and the filtrate is evaporated under reduced pressure. The evaporation residue is dissolved in the solution of 0.28 g (7.1 mmoles) of hydroxide in 15 ml of water, then 2.37 g (7.1 mmoles) of an W -3 polyunsaturated fatty acid mixture (containing 27.6 of EPA, 44.6 % of DHA and 0.1 % of vitanin E) are added.
The mixture is then stirred at 40 OC under nitrogen for 2 hours, thereafter the solvent is distilled off under a reduced pressure of 4-5.3 kPa to give 4.05 g of a yellow crystalline salt, m.p.: 207-211 0 C (with decomposition). 5 Example 16
2.0 g (11.0 mmoles) of L-tyrosine are dissolved in a solution containing 0.44 g (11.0 mmoles) of sodium hydroRide in 20 ml of water and 20 ml of methanol at room temperature, then 3.68 g (11.0 mmoles) of an CC'-3 polyunsaturated fatty acid mixture (with the same composition as described in Example 1) are dropped to the above solution at 40 0 C. After stirring the reaction mixture under nitrogen at 40 0 C for 2 hours, the solvents are evaporated under a reduced pressure of 4 to 5.3 kPa to give a yellowish, solid powder-like crystalline salt residue in a yield of 6.18 g, m. p.: 150 0 C (with partial decomposition).
In the following Examples 17 and 18 the process described in Example 16 is followed, except that the salt is formed by using the corresponding amino acid instead of L-tyrosine.
Example 17
L-Serine 1.0 g (9.5 mmoles) Methanol 10.00 M1 Water 15.0 ml Sodium hydroxide 0.38 g (9.5 mmoles) CC, -3 fatty acid mixture (ac- 3.17 g (9.5 r,,rno.,es) cording to Example 1) After evaporation, a pale brown crystalline product is obtained in a yield of 4.5 g, which decomposes over 175 0 C.
Example 18
Glutamine 2.0 g (13.77 mmoles) Methanol 20.0 ml Water 105.0 M1 Sodium hydroxide 0.55 g (13.77 mmoles) Ck-r-3 fatty acid mixture 4.60 g (13.77 mmoles) A brownish powder-like crystalline salt is obtained in a yield of 7.11 g, m.p.: 181-190 0 C.
Example 19
Preparation of a pharmaceutical composition in capsule form A salt mixture prepared as described in Example 1 is filled by using a known encapsulation process into hard gelatine capsules capable to receive 500 mg of active ingredient. Example 20 Preparation of tablets 25 From the salt mixture obtained as described in Example 1, tablets are prepared each of which contains the following components:
- i8 - Salt mixture according Example 1 500 mg Lactose 120 mg Starch 63 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 3.5 mg If desired, the tablets may be covered with a sugar coat by using a panning machine.

Claims (16)

- i9 C 1 a i m s
1. Novel antiviral and immunostimulating salts of the general formula (I), R-COO-AH + wherein R means a C 1,-24 alkyl group containing at least two double bonds; and "A" stands for an amino acid occurring in living organisms and/or a derivative thereof containing a carboxyl group substituted by a C 1-4 alkyl group or an amino group or by an alkali metal cation.
2. A salt as claimed in claim 1, which c o m p r i s e s eicosapentaenoic acid (EPA) as acid component and L- lysine as base component.
3. A salt as claimed in claim 1, which c o m p r i s e s docosahexaenoic acid (DHA) as acid component and L-lysine as base component.
4. A salt as claimed in claim 1, which c o m p r i s e s a mixture of docosahexaenoic acid and eicosapentaenoic acid as acid component and L-lysine as base component.
5. An antiviral and immunostimulant pharmaceutical composition, which c o m p r i s e s a salt of the general formula (I), wherein the substituents are as defined in claim 1, in admixture with carriers and/or additives and - 20 in the optionally with antioxidants commonly used cal industry.
6. A process for the preparation of the novel salts of general formula (I), 5 R-COO-AH + wherein R and A are as defined in claim 1, which c o m p r i s e s reacting as base component an amino acid, wherein the substituents are as defined in claim 1, with an acid of the general formula (II), R-COOH wherein R is the same as defined in claim 1, in a polar solvent.
7. A process as claimed in claim 6, which c o m p r i s e s reacting eicosapentaenoic acid with L-lysine.
8. A process as claimed in claim 6, which c o m p r i s e s reacting docosahexaenoic acid with L-lysine.
9. A process as claimed in claim 6, which c o m p r i s e s reacting a mixture of docosahexaenoic acid and eicosapentaenoic acid with L-lysine.
10. A process for preparing pharmaceutical compos-itions of antiviral and immunostimulant effect, which c o m p r i s e s amixing a salt of the general formula (I) 21.
that has optionally been prepared by the process as claimed in claim 6 with carriers and/or auxiliary agents and optionally with antioxidants commonly used in the pharmaceutical industry and transforming the thusobtained mixture in the form of tablets, 5 dragees, capsules, suppositories etc. to pharmaceutical preparations.
11. Salts of the general formula I as defined in claim 1 which are substantially as hereinbefore described in any one of Examples 1 to 18.
12. Use of the salts of the general formula (I) as claimed in any one of claims 1 to 4 or 11 for preparing pharmaceutical compositions of antiviral and immunostimulant activity.
13. Salts of the general formula (I) as claimed in any one of claims 1 to 4 or 11 for use in therapy.
14. A pharmaceutical composition substantially as hereinbefore described in Example 19 or Example 20.
15. A process of preparing a salt of the general formula (I) as cantially as hereinbefore described in any defined in claim 1 subst one of Examples 1 to 18.
16. A pharmaceutical composition containing a salt as claimed in claim 11.
Published 1989 at The Patent OMoe, State House, 66.71 High Holborn, London WClR 4TP. Further copies may be obtained from The Patent Offtce. Wes Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent, Con. 1/87
GB8905384A 1988-03-09 1989-03-09 Amino acid salts of long chain unsaturated fatty acid Expired - Fee Related GB2216522B (en)

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WO1995009622A1 (en) * 1993-10-06 1995-04-13 Peptide Technology Limited Polyunsaturated fatty acids and uses thereof
WO1996012696A1 (en) * 1994-10-20 1996-05-02 Prospa B.V. Salts of omega-3-polyunsaturated fatty acids and pharmaceutical formulations containing them
WO1996013507A1 (en) * 1994-10-26 1996-05-09 Peptide Technology Limited Synthetic polyunsaturated fatty acid analogues
US5756700A (en) * 1995-03-22 1998-05-26 Tularik Inc. Nucleic acid encoding human signal transducer and activator of transcription 4
EP1978971A2 (en) * 2005-12-30 2008-10-15 Revance Therapeutics, Inc. Arginine heteromers for topical administration
WO2016102323A1 (en) * 2014-12-23 2016-06-30 Evonik Degussa Gmbh Process for increasing the stability of a composition comprising polyunsaturated omega-3 fatty acids
EP3248467A1 (en) * 2016-05-25 2017-11-29 Evonik Technochemie GmbH Method for preparing a composition containing omega-3-fatty acid-l-lysin-salts
WO2019034698A1 (en) * 2017-08-15 2019-02-21 Evonik Technochemie Gmbh Tablets with high active ingredient content of omega-3 fatty acid amino acid salts
CN115397960A (en) * 2020-01-30 2022-11-25 硅循环股份有限公司 Process for preparing solid neutral amino acid salts of polyunsaturated fatty acids

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HU227588B1 (en) * 2004-12-03 2011-09-28 Sinnex Mueszaki Fejlesztoe Es Tanacsado Kft Antiviral and immunostimulant pharmaceutical composition containing polyunsaturated fatty acid esters

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WO1995009622A1 (en) * 1993-10-06 1995-04-13 Peptide Technology Limited Polyunsaturated fatty acids and uses thereof
US5767156A (en) * 1993-10-06 1998-06-16 Peptide Technology Limited Polyunsaturated fatty acids and uses thereof
WO1996012696A1 (en) * 1994-10-20 1996-05-02 Prospa B.V. Salts of omega-3-polyunsaturated fatty acids and pharmaceutical formulations containing them
WO1996013507A1 (en) * 1994-10-26 1996-05-09 Peptide Technology Limited Synthetic polyunsaturated fatty acid analogues
US5998476A (en) * 1994-10-26 1999-12-07 Peptide Technology Limited Synthetic polyunsaturated fatty acid analogues
US5756700A (en) * 1995-03-22 1998-05-26 Tularik Inc. Nucleic acid encoding human signal transducer and activator of transcription 4
EP1978971A2 (en) * 2005-12-30 2008-10-15 Revance Therapeutics, Inc. Arginine heteromers for topical administration
EP1978971A4 (en) * 2005-12-30 2012-03-28 Revance Therapeutics Inc Arginine heteromers for topical administration
US8628756B2 (en) 2005-12-30 2014-01-14 Revance Therapeutics, Inc. Arginine heteromers for topical administration
US8815954B2 (en) 2005-12-30 2014-08-26 Revance Therapeutics, Inc. Arginine heteromers for topical administration
WO2016102323A1 (en) * 2014-12-23 2016-06-30 Evonik Degussa Gmbh Process for increasing the stability of a composition comprising polyunsaturated omega-3 fatty acids
US11805798B2 (en) 2014-12-23 2023-11-07 Evonik Operations Gmbh Process for increasing the stability of a composition comprising polyunsaturated omega-3 fatty acids
AU2015371376B2 (en) * 2014-12-23 2020-04-23 Evonik Operations Gmbh Process for increasing the stability of a composition comprising polyunsaturated omega-3 fatty acids
US10798962B2 (en) 2014-12-23 2020-10-13 Evonik Operations Gmbh Process for increasing the stability of a composition comprising polyunsaturated omega-3 fatty acids
WO2017202935A1 (en) * 2016-05-25 2017-11-30 Evonik Technochemie Gmbh Method for preparing a composition comprising omega-3 fatty acid salts and amines
CN109152377A (en) * 2016-05-25 2019-01-04 赢创工业化学有限公司 The method of composition of the preparation comprising omega-fatty acid salt and amine
US11219235B2 (en) 2016-05-25 2022-01-11 Evonik Operations Gmbh Method for preparing a composition comprising omega-3 fatty acid salts and amines
AU2017269495B2 (en) * 2016-05-25 2022-03-10 Evonik Operations Gmbh Method for preparing a composition comprising omega-3 fatty acid salts and amines
EP3248467A1 (en) * 2016-05-25 2017-11-29 Evonik Technochemie GmbH Method for preparing a composition containing omega-3-fatty acid-l-lysin-salts
CN111032032A (en) * 2017-08-15 2020-04-17 赢创运营有限公司 Tablets of omega-3fatty acid amino acid salts with high active ingredient content
WO2019034698A1 (en) * 2017-08-15 2019-02-21 Evonik Technochemie Gmbh Tablets with high active ingredient content of omega-3 fatty acid amino acid salts
US11622952B2 (en) 2017-08-15 2023-04-11 Evonik Operations Gmbh Tablets with high active ingredient content of omega-3 fatty acid amino acid salts
CN111032032B (en) * 2017-08-15 2024-01-02 赢创运营有限公司 Tablet of omega-3fatty acid amino acid salt with high active ingredient content
AU2018317802B2 (en) * 2017-08-15 2024-04-04 Evonik Operations Gmbh Tablets with high active ingredient content of omega-3 fatty acid amino acid salts
CN115397960A (en) * 2020-01-30 2022-11-25 硅循环股份有限公司 Process for preparing solid neutral amino acid salts of polyunsaturated fatty acids
EP4097202A4 (en) * 2020-01-30 2024-01-03 Silicycle Inc. Process for manufacturing solid neutral amino acid salts of polyunsaturated fatty acids

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IT1229563B (en) 1991-09-04
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FR2628419A1 (en) 1989-09-15
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LU87470A1 (en) 1990-10-02
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SE8900827L (en) 1989-09-10
AT398073B (en) 1994-09-26
HU199775B (en) 1990-03-28
ES2010439A6 (en) 1989-11-01
FR2628419B1 (en) 1992-02-14
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SE508603C2 (en) 1998-10-19
ATA50989A (en) 1994-01-15
JP2751068B2 (en) 1998-05-18
DE3907688A1 (en) 1989-09-21
DE3907688C2 (en) 1996-09-05
KR0140993B1 (en) 1998-07-01
GB2216522B (en) 1992-01-02
JPH024746A (en) 1990-01-09
FI93949B (en) 1995-03-15
IT8919705A0 (en) 1989-03-09
HUT49564A (en) 1989-10-30

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