MXPA98000322A - Esters of iodine fatty acids, iodine fatty acids and derivatives thereof, produced by iodohidrination using alkilsililated derivatives and alkaline iodues, and their activities farmacologi - Google Patents

Abstract

Iodinated fatty acids, iodinated fatty acids and stable pharmaceutical grade fluid derivatives thereof are obtained by iodohydrinination in an organic medium using alkylsilylated derivatives, for example, trimethylsilyl chloride or trimethylchlorosilane, which react with an alkaline iodide, for example, Sodium iodide, after which an iodhydric acid is formed in situ by exposure to water and the inhydric acid reacts, for example, fatty acid esters and particularly fatty acid methyl esters of rapeseed oil which can be used as a biofuel for gasoline engines to provide a low-cost product, and are used therapeutically, particularly for the treatment of goiter related to a deficiency of io

Description

STERES OF ACIDS IODATED SPASES, IODINE ACIDS DERIVATIVES THEREOF, PRODUCED POP IODOHIDP I ATION EMPLOYING DERIVATIVES ALKILLSILI SIDES AND IODUPOS ALKALINE, AND ITS PHARMACOLOGICAL ACTIVITIES DESCRPTION The p? This invention relates to esters of iodinated acids and iodinated acids and derivatives thereof obtained by means of iodine and diolination which includes the introduction of the lchi derivatives or 11 sides with alkaline iodides employed in the same. amienfco endemic goiter and pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and co or vehicle for the cellulite. Endemic goiter is a disease of irtauficiencia that constitutes one of the most serious public health problems facing the World Health Organization (WHO) In accordance with official records of the World Health Organization, one billion people, that is 20V »of the world population, are affected by a lack of iodine, mainly in developing countries (Hetzel BS, Potter BJ and Dulbeig EM The Iodine deficiency disorderss nature, pathogenesis and epidemics (disorders of iodine insufficiency: nature, pathogenesis and demiology), World Re. Nutr. Diet. > 2: 59-119 (1990)). Almost all these countries are affected cor-vai? O-_. degrees of pt «valencia. In the case of regions plus g? affected, it is possible that the number of subjects that μade > In a single operation of the Litoid reach the BO'A of the population ?! e = > is manifested by the appearance of a hypertrophy of non-active aspect of the glands that can de? roliai e in a secondary ipo i t ism with ptob lernas neut olog? co = > . Adolescents and women of childbearing age are the most exposed and can give birth to a high proportion of up to 10% of babies who suffer from a pa t icient form of an irreversible mental illness known as endemic cretinism and considered as the medical and social complication. It is accepted that there is an insufficiency of diet in the primary and predominant cause of this traditional problem. The geological nature and the geographical environment therefore seem to be the main problems that determine this situation even though some dietary factors are involved as secondary causes aggravating. The appropriate treatment therefore includes the complement; I n of deficient populations with iodine additions to meet physiological requirements. Theoretically, this goal is easy to achieve. However, the experience of the last few decades has shown that traditional vehicles for compilation of water (drinking water, s l mess, bread flour) p? «Sti fi p important diffusion problems related to the ci nspoi te, storage and conditions of corinumo e? Reg? One = > 'ub) tropical. In fact, the iodine is administered in sodium or potassium iodate or sodium iodide that releases halogen in one I went to the acenable in the adipose tissues. Therefore, it is necessary to take the iodine vehicle daily for years. The nutritive benefits are irregular and slow to obtain, and this form of compilation does not allow for rapid overcoming of the urgent problems that are found in high-priority regions. E¡ < It is also an iodized oil that has long-term effects known as Lipiodol (mr) fSoc íété Suerbet) which, when administered in a single oral or parenteral annual dose has shown prophylactic and therapeutic effects against goiter. This iodized oil, designed as a contrast product in radiology, is produced from a relatively expensive and scarce poppy seed oil (Saaim fer papaverurtt). Although the high tolerance and healing properties of Lipiodol (mr) have been known for a long time, this product has not been established as a tool for higher errication due to the relatively high cost in relation to the required ? important issues of the third world.

A new invention has the purpose of overcoming the disadvantage: a new iodinated drug is provided from iodinated fatty acid esters or iodinated fatty acids and derivatives thereof having pharmaceutical purity, stability, absence of tertiary, toxic, totally iodinated contaminants, which do not have double bonds, which are obtained by the addition of a similar alkyl reagent and an alkaline agent on fatty acid esters or fatty acids and have therapeutic properties. For example, it is possible to produce iodinated fatty acid esters at low cost from methyl esters of iodinated fatty acids obtained by original synthesis from d & rapeseed oil (Brassica ampest r is) used as a biofuel and automotive engines that have a very low cost, and this allows the planning of mass campaigns. The new product allows a better bioavailability and an extended therapeutic effect because the iodine is fixed on the three fatty acids (aleic acid n-9, gone 1 i nolico n-6 and acid to 1 faloinic n-3), of which the last two are essential and which are precursors of the three main metabolic pathways of fatty acids. In order to avoid the risks of viral contamination through the bloodstream of hepatitis B and C, HIV, oral administration is exclusively proposed for our iodinated product. Several methods have already been described for the oxidation of fatty acids at the level of the saturated fatty acids in saturated iodine derivatives. "Oleic can = er com pire a hydr ooro ac i on followed by nucleophilic substitution through ± odui e potasio after the action of bromliiidic acid" JF Lañe and HW Herte: Ort cyc li Int rmed l tes Substi u ion Peac ions I The Alkaline Hydrolysis of Some Aliphatic Eromoacids (On cyclic intet ds in substitution reactions I. Alkaline hydrolysis of some aiifatty broinoacids), J. Am. Chem. Soc. 1951, 73, 1 48-1350). The cooled olive oil in the region of the set point is saturated with hydriodic acid. The use of other fatty acids has been proposed. íft. Guerbet, A. Bibaud, G. Tilly, R. Joussot, V. Loth and M. Guerbet; Monoiodosté r a te d'éthyle. (Handheld ethyl ester). Preparation and analytical characters). Ann. phar fr., 1965, 23, No. 11, 663-671). Direct iodination with iodide acid is also carried out using dehydrating substances such as phosphoric acids, phosphorus pentoxide (W. K'uhn, H. Hartner, F. Schlindler, I. Sandner and Hepng, German patent). P 35 13 322. / C 07 C 69/62, 1985). It is also possible to carry out the in vitro treatment with iodine in the presence of alumina-generating hydroiodic acid (LJ Stewart, D. B ay, RM Pagni and GM K'abalfca; A Convenient Method for the addition or Hl to uiib-Luivd hydi uca rbons u ing 17 on A1 03, (A convenient method for the addition of Hl to lu droca i btn u = > measured using 12 in A1203), Tetrahedron Lett, 1987, Vol. 28, No. 39, 4497-4498). The hxd ooditiate ion has also been used for the boron-, N-i t i -lamin complex that includes the ivoduru of boron (C. r-is an Reddy and M.

Per? ta? tty; A new, simple proceed for the generation a.tci addition of Hl to alienes and alkynes using B13; , N-diet i laru] ina complex a d acetic acid. (A novel and simple procedure for the generation and addition of Hl to alkenes and alkynes using the complex B13: N, 1M- d? Et? Lao.1 uta and -_ »? Acetic). T t ahedr Lett., 1990, Vol. 31, No. 13, 1919-1920). The h idr oyod inac t ion with yó * du? or of potassium in acid or tufosfico can also be raised (Orgamc Synthesis, Vol. 9.66). It is also known JP-A-53119817 which presents the synthesis of tp - (2-iodohexadecanoate) from gl icen lo in two stages. In a first stage, 2-bromopalm? oi reacts with glycep in a benzene / water-free solvent to obtain 3% glyceryl tp- (2-bramohexadecaonate) after purification. This is then reacted with Nal in acetone to give 74% of the glyceryl (2-iodohexadecanoate) after treatment with Na2S203, ion purification, drying, etc. In accordance with the specifications, among other parts, in the German patent No. C 07 C 69 / oP / r 37.13 323.8 dated on the 13th of the year 1985 and belonging to W. lulm et ßl, the methods for the ptepar-ación de lo = >; iodine compounds »leads to piod? coughs that contain impurities n prudui-tos that are unstable in the light i uve the piepai ación and storage of them. Our method of ionization leads, par icularly, to a product that has constituent forms and no double bonds that is a source of instability, particularly in the presence of free radical oxidation derivatives. The esters of ocid gra = > or iodinated pi epat two by yoduh and di-mac ion include derivative to l i i i i sides and an alkaline iodide which forms the tea of the invention which has the form of an oily liquid, fluid, light color , stable, purely pharmaceutical that has a relatively low price. The fatty acid esters used for the preparation of iodinated derivatives including an alkali metal compound and an alkali metal iodide can be, for example, triglycerides of fatty acids originating from vegetable oils of rapeseed oil, of poppy, soybean oil, safflower oil, peanut oil, grapeseed oil, sunflower oil, flax oil, wheat oil, olive oil, sesame oil, wheat germ oil, oil coconut and palm oil from oils of animal origin.

The fatty acid esters employed can also be mixtures of methyl esters of fatty acids > _ > Ethyl esters of fatty acids that originate from olive oil are rapeseed oil, poppyseed oil, soybean oil, safflower oil, peanut oil, grapeseed oil, olive oil. sunflower oil, flax oil, olive oil, olive oil, sesame oil, wheat germ oil, coconut oil, and palm oil and animal oils. For the large-scale production of the drug, it is particularly interesting to use a raw material for the synthesis of methyl esters of fatty acid that originate from rapeseed oil used as a biofuel for vehicle engines that has a low cost. . Fatty acids of the oleic acid, linaleic acid, alpha-linolenic acid, erucic acid, arachidonic acid and ricinoleic acid type can also be used as raw materials. The process for obtaining esters of iodinated fatty acids or iodinated fatty acids includes the reaction of an alkali iodide with an alkali metal halide in an organic medium which, in the presence of water, causes the in situ reaction of hydroiodic acid. either with the ester or esters of fatty acid or with fatty acids. To obtain iodinated acid esters or iodinated fatty acids, for example, S IJ iodide reacts. The ortho-chloride of sodium pyridinium is followed by the action of water and an addition of either niaatut fatty acid esters or d * - > the fatty acids = insulated. - The iodinated iodine of fatty acids can be carried out according to the following reaction: CH3CN H20 (1) Nal + S? Me3Cl - NaCl + S? Me3I - S? Me30H + Hl-iodohydrin I) fatty acid esters or fatty acids The mode of operation, for example, for esters of unsaturated fatty acids is as follows: 89.25 ml of methylpyridine are added to the either 11% chloride and 11% Si) to a solution of 3C7.1 g of sodium iodide in 550 ml of acetomitrile in a nitrogen atmosphere at a temperature of 0 ° C. 6.65 ml of water are added dropwise after the total addition of the trichloride. 70 g is added after a solution of methyl or ethyl esters of unsaturated fatty acids of rapeseed oil. Despres 24-hour reaction under stirring, the reaction is suspended with 700 ml of water. The mixture is extracted using ether. The organic phase is washed several times with a 10% solution of sodium thiosulfate and then several times with water. It is dried in anhydrous sodium sulfate and the ether is evaporated at 90 ° C under a pressure of 16 mm Hg < 2133 Pa) in order to eliminate the remains of l e? of silica. The residue is coffee. The iodine fatty acid esters dissolved in ether are then bleached with carbon and f i H = t in alumina to remove the peroxides. The ether is evaporated and the solvent traces are removed using a fin pump. The mixture of iodinated fatty acid esters obtained has a golden yellow color and has good fluidity. This mixture can be identified by means of espetrometry with 1H NMP and 13C NMP. This method of synthesis of iodinated fatty acid ester s was carried out in large quantities. Other non-miscible solvents eit water were used. The insolubility of sodium chloride in acetone itplo allows the total displacement of the reaction towards the formation of iodide of tpme lsi 11 o. This reaction is exothermic and allows the generation of hydroxylated acid and trimethylsulfide. The secondary product S? Me30H is removed after the reaction of iodohydrin ion by simple evaporation under reduced pressure and washing in water. The reaction of iodohidpnac ion is to follow visually by whitening (bleaching) the solution. ET1 sodium thiosulfate allows the elimination of iodine present in oxidized form. In the final product, no signal of NMP d 3 proton is observed and the NMP signal of carbon 13 corresponds to an ethylene system. On the other hand, no degradation of product in NMP of the proton is observed.

CHARACTERISTICS OF YELLOW FATTY CIDOS ESTERS COLZA OIL: Nuclear magnetic resonance of the proton (NMP1H) \ carbon 13 ÍNMR13C). A spectrum of NMP1H from iodinated fatty acid esters of rapeseed oil allows review of the disappearance of ethylene protons compared to the non-iodinated fatty acid ester spectrum of rapeseed oil. In addition, this allows to review the absence of traces of solvent diethyl ether and silica ether. In addition, a spectrum of NMP13C allows the review of the disappearance of the carbons that carry the insatura ione. The NMP1H spectra obtained for various productions of ethyl esters of iodinated fatty acids of rapeseed oil are identical. No spectrum reveals the presence of diethyl ether or silica ether. * The NMR1H spectrum of ethyl esters of iodinated fatty acids (NMR1H (CDC13) at 200 MHz): 0.89 ppm (3H, m, CH3), 1.20-2.00 ppm í < n, CH2 of the chains and CH3CH2Q), 2.3 ppm < 2H, t, CH2-CQ0Et), 4.2 ppm (m, CHI, CH2-00C). * The NMR13C spectrum of ethyl esters of iodinated fatty acids (NMR13C (CDC13) at 200 MHz): 14 ppm < CH3 in e3 chain end of CH3CH20), 28-29 ppm < CHS) 22-24, 30-31, 34 ppm INCH2 in the chains), 39-41 ppm 'CH2-CHI), 60 ppm (CH2-0), 173 ppm (C00).

The infrared absorption specimen (NaCi) has the following characteristic bands: gamma t'C-0 ester) at 1740 cm-1: gamma (CH -atured) at 2850 cm-1, gamma (unsaturated CH) at 2950 cm-1 * Specimen of NMP1H of iodinated fatty acid iodine (NMP1H (CDC13) at 200 MHz): 0.89 pm (3H,, CH3>, 1.25-1.30 ppm (m, CH2 of the chains, 1.60- 1.80 ppm (, CH2), 2.3 ppm (2H, t, CH2-C00), 3.66 ppm (3H, », CH3-00C), 4.12 ppm ((, CHI) .The spectrum of NMP13C of methyl esters of acids iodinated fatty acids (NMP13C) (CDC13) at O0 MHz): 14 pμ <CH3 at the chain end), 28-29 ppm (CHI), 22-24, 31-34 ppm (CH2 of the chains), 38- 41 ppm '(CHZ-CHI), 51 ppm (CH3-Q), 173 ppm (C00) Stability: since iodinated products are generally unstable substances, it is necessary to ensure the stability of iodinated fatty acid esters and / or of iodinated fatty acids, stability is investigated by means of NMP1H, by thin-film chromatography, and by the quantitative analysis of iodine bound to fatty acid esters or fatty acids, NMR1H spectra were produced after 2 months, 3 months and 8 months of storage at a temperature of 20 ° C a 22 ° C, protected from light. All three were identical to the spectrum obtained during production. Thin-film chromatography (plate of the silica GF 254 - mobile rocket: di et i léter '' hei ano 1:20 - in in ultraviolet light at 254 nm and after atomization of a. m / V of idiodic phosphomol acid R in alcohol and heating of the silver at 120 ° C for 5 minutes) pioporciona the observed bands where the intensity of position are identical in the fresh product and the product stored for 8 months. Stability of ionized fatty acid esters of rapeseed oil that was used in therapy in the field: the mixture of iodized fatty esters of rapeseed oil was used in research in patients in Africa in a region of endemic goiter. During these investigations, the iodinated steres were subjected to extreme conditions (transport, exposure to the lur and at temperatures of approx. 45ßC). After 2 weeks of investigations, the iodinated fatty acid esters were analyzed: the NMP1H spectrum was found to be identical to the spectrum of a freshly synthesized oil and the thin-layer chromatography gave bands identical to the iodinated fatty acid ester bands newly synthesized and does not indicate any degradation product. Tolerance test in rats: before administering the mixture of iodinated fatty acid esters of rapeseed oil to patients affected by goiter, the tolerance of the mixture of iodinated esters was tested in adult male rats weighing approximately 3 g. Each test group consists of 5 rats each cryo receives an oral administration of 0.5 ml of the mixture of iodated fatty acid esters of rapeseed agent. They kept the rats low observation. After one week, the general condition of the rats and the behavior in each test group are normal and identical to the behavior and general state of the rats in the colzo group. Iodinated products prepared from the above-described method are generally used as co-drugs, for example as anti-i-goiter drugs in the pure state or in combination with appropriate excipients in the form of a drinkable or ingestible liquid, capsules and ampoules. for example. These iodinated products can also be used as general or topically administered drugs, for example co or contrast products or as anti-inflammatory agents in retinoid therapy. These products can be used as drugs that are administered in a vascular, local or general way in the treatment of some cancer by chemoembolization that involves the administration of an anticancer drug emulsified in esters of iodinated fatty acids that act as vehicles for liptophilic tumor cells. s.

Claims (16)

1. CLAIMS 1. A process for obtaining at least one iodinated fatty acid or at least one iodinated fatty acid ester or iodinated derivatives thereof having a pharmaceutical purity, are stable and free from toxic impurities, expensive because it includes the reaction of an alkaline iodide with a reactant to the other side in an organic medium that causes, in the presence of water, the in situ reaction of the acid with the fatty acid (s), the ester (s) Ie) of greasy, or derived from them in such a way that all the double bonds begin 1mante present in the (acidis) fatty) or esterés! of fatty acid or derivatives thereof are saturated in iodine in a ratio of one molecule of iodinated double bond.
2. 2. Process according to claim 1, characterized in that the alkali iodide is sodium iodide.
3. 3. The process of compliance with the rei indicates ion 1, characterized in that the reagent lqui Isi 11 side is a haiuro alqui lsi 11 side.
4. 4. Process according to claim 3, characterized in that the halide alkylsulfide is trimethoxy chloride 11 or else it is a trilectyl chloride.
5. 5. Process according to claim 1, characterized in that the organic medium contains acetoni tp lo.
6. 6. Process according to claim 13, characterized in that the ester (s) of fatty acid consists of p) of fatty acid (s) of fatty acid originating from vegetable oil (e)). i)) within the group consisting of rapeseed oil, poppy oil, soybean oil, safflower oil, peanut oil, grape seed oil, sunflower oil, flax oil, corn oil, oil olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and animal oils.
7. 7. The process according to claim 1, which is termed because the ester (s) "of fatty acid" consists of methyl esters of fatty acid which originates from ace Selected vegetable (s) (i) within a group consisting of rapeseed oil, poppy oil, soybean oil, safflower oil, peanut oil, grapeseed oil, sunflower oil, flax oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil, and oils of animal origin
8. 8. The process according to claim 7, characterized in that the (the) esters of fatty acid methyl ester ester (s) originating from rape, used as an economical biological fuel for automobile engines
9. 9. The process in accordance with the rei indicates ion 1, characterized in that the ester (s) of acid gr-aso consists (n > of ester i) of fatty acid ethyl that originates' n) from vegetable oil (s) (is selected) within a group consisting of rapeseed oil, poppy oil, soybean oil, safflower oil , peanut oil, grape seed oil, sunflower oil, flax oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil, and animal oils .
10. 10. The process according to claim 1, characterized in that the grease (s) is (are) selected from the group consisting of oleic acid, linoleic acid, fa-1 acid Inogenic, erucic acid, araquiodontic acid and pcinoleic acid.
11. 11. Acidic fatty acid (s) iodinated), iodinated fatty acid ester (s) or iodinated derivatives thereof, obtained by the process according to any of claims 1 to 10 and which do not have the double bond, for its use as a drug.
12. 12. The use of iodinated fatty acid iodinated fatty acid ester (s) or iodinated derivatives thereof according to the invention, characterized in that the drug is intended to be used for the prophylactic and / or therapeutic treatment of goiter and is used in the pure state or in combination with apyopylated excipients in drinkable or intangible form, in the form of capsules or ampoules, for example.
13. 13. The use of iodinated iodinated fatty acid ester (s) or iodinated derivatives thereof according to claim 11, characterized in that the drug is provided for antimalarial treatment in rheumatoid therapy, administered by general or topical methods.
14. 14. Acid (s) gaseous (iodinated), ester (s) of iodinated fatty acid) or iodinated derivatives thereof, obtained by the process according to any of claims 1 to 10 for use in the treatment of certain cancers by chemoembolization.
15. 15. Fatty acid iodinated fatty acid (s), iodinated fatty acid ester (s), or iodinated derivatives thereof, obtained by the process according to claim 14 for use as a vehicle (s). ) for anticancer drug emulsified in acidic fatty acid (iodine), iodinated fatty acid ester (s) or derivatives thereof for lipophilic cells or their.
16. 16. Acidáis) fatty (fs) iodinated), ester (s) of iodinated fatty acid) or iodinated derivatives thereof, obtained by the process in accordance with any of the claims 1 to 10 for use as a contrast product .