TW514633B - Fatty acid derivatives - Google Patents

Abstract

An N-alkylpolyhydroxyamine salt of an n-6 or n-3 essential fatty acid (EFA) that is beyond the 6-desaturation step, or of any polyunsaturated fatty acid, other than those belonging to the n-6 and n-3 series, having 16 to 26 carbon atoms and up to six double bonds, the double bonds being in the cis or trans configuration, the salt being formed with the fatty acid either as such or in the form of a covalent derivative, through the carboxyl group, of a bifunctional compound itself having a free acid function.

Description

514633 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (1) Scope of the invention The present invention relates to fatty acid derivatives. BACKGROUND OF THE INVENTION The inventors have discussed the important therapeutic functions of η · 6 and η-3 essential fatty acids in many previous patent applications. These essential fatty acids (EFAs) and their specific conversion pathways are described in Table 1 below. Table 1 n-6 EFA, s n-3 EFA, s 18: 2n-6 18: 3n-3 (post-octadecanoic acid, LA) (α octadecadiate, ALA) 1 (ί-6 -Desaturation 18: 3η-6 18: 4η-3 (r-octadecanoic acid, GLA) (octadecanoic acid, SA) (Please read the precautions on the back before filling this page)

1 20: 3n-6 (dinan carbon-7 *-octadecyl diamine) DGLA) i 20: 4n-6 (eicosatetetracarboxylic acid, AA) 1 22: 4n-6 (adrenal acid) I Extended action β -5 -Desaturation Extended action I 20 · 4n-3I 20: 5n-6 (Eicosapentapentanoic acid, EPA) 1 22: 5η · 3 Ti-4-desaturation-4- This paper The standard is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 514633 22: 5n-6 Patent Application No. 85108424 Amendment Chinese Manual (August 87) 5. Description of the invention (2 22: 6n-3 ( Eicosahexaenoic acid (DHA) are essentially cis-structured acids, systematically named after the corresponding octadecanoic acid, twentieth edition, or eleven, such as z, z-eighteen -9,1 2 _ dicarboxylic acid or 2,2,12,2,2-docosalyl-4,7,10,13,16,19_hexaenoic acid, but the numbers are named according to carbon The number of atoms is oligo, the number of centers of unsaturated action and the number of carbon atoms at the end of the chain starting from unsaturated action, such as 1 8: 2n-6 or 22: 6n-3 are named accordingly. In some examples, Will use uppercase names, such as EPA, and abbreviations such as two Decapentaenoic acid is a common name. The preferred fatty acids in wheat invention are 10 n_ and η-3 essential fatty acids after the 6-desaturation step, and preferably both have cis structure, but the invention is not limited thereto For them, they are not limited to those containing repeated _CH = CH-CH2-units in the chain. For example, columbinic acid and α-octadecanoate are equivalent to e, z, and z, respectively. -Octadecyl-5,9,12-trienoic acid and z, e, e, z-octadecyl_9,11,13,15-tetraenoic acid. Expected effects for the treatment of many different diseases, including Cardiovascular diseases' Diabetes' skin diseases, inflammatory diseases and immune diseases, cancer, mental disorders' kidney diseases, prostate disorders, and gastrointestinal and other diseases. By their nature, EFAs are highly hydrophobic compounds, which are only slightly soluble. However, there are many reasons why these compounds need to be water-soluble. For example, these water-soluble derivatives can be more easily absorbed from the intestine by the hepatic hilar system; they can be easily injected intravenously. The method of applying this paper is applicable to Chinese National Standards (CNS) A4 specification (210X297 mm (please read the precautions on the back before filling this page)

Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 514633 No. 85108424 Chinese Patent Specification Correction Sheet (August 87) A7 B7 Amendment V. Invention Description (3) Medicines; and can be used in many other areas, such as Topical prescriptions, topical prescriptions, novel oral formulations, including beverages, enteral foods, and skin care products including lotions, shampoos, creams, and more. Meglumine (N-methyl glucosamine, an N-amylamine) is a widely used pharmaceutical formulation with extremely safe properties. Its formula is: CH ^ NHMe.

HCOH I ~ HOCH

I

HCOH .1

HCOH .1 'CH2〇H [C7H17N〇5; Mw 195.2]' At present, it has been discovered that the McGermin derivative of EFAs is quickly soluble in water and can therefore be used in many different ways for pharmaceutical prescriptions, food, nutritional supplements Products, skin care products and many different kinds of beverages. In addition to these η-6 or η-3 series, which have 16 to 26 carbon atoms, up to 6 double bonds, and cis or trans structures bonded by double bonds, the present invention can also be applied to Xu Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) and many other unsaturated fatty acids. DETAILED DESCRIPTION OF THE INVENTION The present invention provides the aforementioned water-soluble eta-polyunsaturated fatty acid alkylpolyamine salts, especially those eta-6 or eta-3 essential fatty acids after the 6-desaturation step. These salts are stoichiometric and have the structure of formula (1), especially where A + is not only protonated N-fluorenyl glucosamine (Megrumin), but also 6- This paper size applies Chinese national standards (CNS) A4 specification (210X297 mm) 514633 A7 B7 Five invention description (4 is protonated glucosamine or any other alkyl polyhydroxyamine, and FA_ is an anion of essential fatty acid or other fatty acid: A + FA · (1) The present invention also relates to a type in which fatty acids are covalently bonded via a carboxyl group to form an essential fatty acid or other fatty acid derivative, a common ester or amidine, and a bifunctional compound that also contains a free acid function. Salts. Examples include: ascorbic acid and salicylic acid in which fatty acids are like 6-esters. For example, the salts can exist as an aqueous solution or a freeze-dried powder. The solution can also be formed in 0.9% sterile saline. Slowly add the necessary amount of fatty acid or derivative to the aqueous solution or glycosamine salt solution under nitrogen, and stir until a clear solution is generated (acid-base range: 5 to 9) to prepare The solubility of the initial EF As of different solutions and some freeze-dried salts are listed in Table 2 below to illustrate their physical and chemical properties: (Please read the precautions on the back before filling this page) Order the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Employee Consumer Cooperative Society at 2-25 ° C after sonic measurement (w / Solvent EF As McGlumin Salt EFA Water> 20% but <40% &lt; 1% ethanol) 2 0 % But &lt; 50% easy to mix with chloroform in all proportions &gt; 20% but &lt; 50% easy to mix with all proportions The salt can be prepared for oral, parenteral, enteral or other route delivery .The dosage of any one or more fatty acids can be 1 亳 -7-one foot per day-a paper copy applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 514633 A7 B7 _ V. Description of the invention (5) grams to 200 g, preferably 10 mg to 20 mg per day, and 50 mg to 2 g per day is best. When used topically, the concentration of the fatty acid can be prepared from 0.0001 to 50% by weight, 0.01 to 30% Good, and 0.1 to 10% is the best. Example 1 (Meglumin salt of DHA) N-methyl glucosamine B · P · (595.5 mg, 3.05 mmol) was dissolved in pure water (8.0 ml), stirred thoroughly under nitrogen, and Ζ, ζ, ζ, ζ, ζ, ζ · octadecyl-4,7,10,13,16,19-hexadecanoic acid (〇11 八) (1.0 g) was added dropwise for 5 minutes or more. The mixture was stirred until Forms a clear 20% w / v N-methylglucosamine / 2,2,2,2,2,2-octadecyl-457,10,13,16,19-hexaenoate (〇11 人Of Mcgrumin's salt) solution. After filtering the solution with 0.2 filter paper and freeze-drying it, a white wax-like powder that easily forms a solution of more than 30% w / v in water is formed. Example 2 (Meglumin salt of GLA) Operated in a similar manner as in Example 1, but replacing DH A with an equivalent amount of z, z, z-octadecyl · 6,9,12-tricarboxylic acid (GLA) In a 20% w / v aqueous solution, N-methylglucosamine z, z, z-octadecyl-6,9,12 · trienoate (Mgrumin salt of GLA) is formed. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Example 3 (MGLAMIN salt of DGLA) Operate in a similar way to Example 1, but use the same amount of Z Z, Z-eicosyl-8,11,14-trisuccinic acid (DGLA) replaces DHA to form N-methylglucosamine z, z, z-icosyl-8,11,14-trienoic acid salt. Example 4 (Meglumin salt of AA) -8 This paper size applies the Chinese National Standard (CNS) A4 specification (2! 0 &gt; &lt; 297 mm) 514633 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 2. Description of the invention (6) Operate in a similar manner to Example 1, but replace the same with z, z, z, z-eicosyl 5,8511514-tetraenoic acid (eight or eight) at 20 % \ ¥ / ¥ forms N-methylglucosamine ζ, ζ, ζ, ζ · icosyl-5,8,11,14-tetraphosphonate (Meglumin salt of AA) in aqueous solution. Example 5 (Spring Grummin Salt of GLA Ascorbic Acid) Hydrogen chloride gas (2.0 g) was added to N, N-dimethylacetamide (26.5¾ liters) at 0 ° C to foam. Dichloromethane (13.25 ml) raw material in which ascorbic acid (9.69 g) was dissolved was added to the resulting raw material, and the mixture was stirred at 0 ° C until a solution was formed. Add z, z, z-octadecyl-6,9,12-tris (34.8 g) acid gas (14.8 g) to this solution under nitrogen at 0 ° C. It takes more than 4 hours. The resulting mixture can be in the above Let stand at temperature for 18 hours, and room temperature for 1 hour. Upon cooling to 0 ° C, ethyl acetate (200 ml) and water (100 ml) were added and the mixture was stirred for 1 hour. The organic layer was washed with brine (5 X 100 mL), dried over Na2S04, evaporated at 50 ° C / 10 mm Hg 'and then formed at 50 C / 0 · 1 mm / 4 hours Pale yellow worm-shaped ascorbic acid 6-[(z, z, z) -octadecyl-6,9,12-triphosphonate (18.25 g, 88%) (ascorbic acid GLA). After vigorous stirring under nitrogen for 10-15 minutes in pure water (600 parts), a soap-like ascorbic acid GL A emulsion (112 parts) was formed. While stirring, pure water (200 parts) in which N-methylglucosamine B · P · (66 parts) was dissolved was added to the mixture for more than 10 to 15 minutes until a clear solution was formed. The mixture was filtered with 0.2 // m filter paper, and then freeze-dried to produce N-methylglucosamine 6-[(z, z, z)-octadecyl-6 , 9,12-Trisamidine ascorbic acid solid. -9-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the notes on the back before filling this page) Ordered by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative 514633 A7 __B7_ Description of the invention (7) Salicylic acid r-octadecanosuccinic acid Mcgrumin salt) Operated in a similar manner, but with the same amount of salicylic acid GLA derivative, 2- (ζ, ζ, ζ-deca Octyl-6,9,12-trimethoxy) benzoic acid replaces ascorbic acid GLA to form N-methylglucosamine 2- (z, z, z-octadecyl-6,9,12-trienyloxy Base) benzoate. The salicylic acid GLA derivative itself was prepared by the following method. Step 1: 2,2,2-Trichloroethylsalicylate: Stir a mixture of salicylic acid (90 g), 2,2,2-trigas ethanol (270 g) and concentrated sulfuric acid (50 g), And heated at 100 ° C for 4 hours. The mixture was diluted with chloroform (800 ml) and extracted with water (2 X 500 ml). After further extraction with a saturated aqueous sodium bicarbonate solution (1000 ml), the organic layer was washed with water (2 X 500 ml) and dried over MgS04. Remove the chloroform and excess tri-gas ethanol under empty air (65 ° C / 20 mmHg), and then distill the product (110-112. (: /0.5 mmHg) to produce a clear that will solidify when cooled. Liquid 2,2,2-trichloroethylsalicylate (104 g, 59%) 〇 Step 2: 2,2,2 · trichloroethyl 2-[(z, z, z) · octadecyl -6,9,12-trimethoxy] benzoate: (z, z, z) -octadecyl-6,9,12-triene dropwise at 0-5 ° C under nitrogen. (137.5 g) was added to a solution of 2,2,2 · trigasethylsalicylate (104 g) in dry pyridine (500 ml) for more than 1 hour. It can be stirred at room temperature The reaction mixture was removed for 20 hours, and then pyridine was removed under a vacuum (25 ° C / 0.5 mmHg). The residue was dissolved with diethyl ether (2000 ml) and water (1000 ml), and the resulting two phases were shaken. System, and slowly add 2M tritium acid to acidify until the acidity reaches pH 1. The diethyl ether layer is separated to 'wash with water (4 X 1000 ml), and any emulsion formed is blocked by adding sodium chloride. Drying with Na2 S04 After the organic layer, its solvent was removed under a vacuum. Liquid (Please read the precautions on the back before filling this page)

-10-

514633 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (δ) 'to produce orange / brown oil. This material was placed in MPLC (column size: diameter 5 cm x 40 cm, column combination: silica matrix, pore size 60A, particle size 35-75, solvent: initially hexane, then i 5 was dissolved 〇 / 〇 Diethyl ether: 'amount of the residue: 1000 ml). Evaporation of the desired fraction under aerospace conditions gave 2,252 · trichloroethyl-2-[(z, z, z) -octadecyl-6,9,12_trimethyloxy] benzyl as a pale yellow oil. Acid salt (1.89 g, 93% yield). Step 3: 2-[(z, z, z) -octadecyl-6,9,12-trienyloxy] benzoate: 2,2,2-trichloroethyl_2-[( z, z, z) -octadecyl-6,9,12-trienoxy] benzoate (151 g) was dissolved in tetrahydrofuran (750 mg), acetic acid (675 ml) and water (75)耄) mixture. Add zinc dust (50 g). The mixture was stirred at room temperature under nitrogen for 1.5 hours, and then allowed to stand for 20 hours. After filtering excess zinc and zinc salts through celite, the filter plate was washed with tetrahydrofuran (1000 ml), The filtrate was then evaporated at 25 ° C / 10 mm Hg to remove tetrahydrogalan. Then remove acetic acid and water at 25 ° C / 0 · 5 mm Hg. The product was easily decomposed at higher temperatures, and the resulting oil was dissolved in diethyl ether (1000 liters) 'and the resulting solution was washed with water (4 x 200 ml). After drying with Na2S04, the hair strip ether (2 5 X: / 10 mm Hg) formed a light yellow oil, and then the oil was placed in a dry column (composition: silica matrix (丨 kg), The pore size is 60 A, the particle size is 35-75 // m, and the amount of distillate is 1000 ml). The necessary residue was collected, and the solvent was evaporated as described above. 〇 / 〇 · 丨 The final residue is removed under the condition of rice mercury, and 2 _ [(2,2,2) _octadecyl-6,9,12-trienoxy will be solidified into a wax in the refrigerator. Base] Benzoic acid (77.8 g, 68%) 〇 Example of application (please read the precautions on the back before filling this page) Installation · 1 item and fill in the under-order Φ 11-This paper size applies to China National Standard (CNS) A4 specifications (210 × 297 public celebration) 514633 A7 __B7 V. Description of the invention (9) 1 · A sterile solution containing 0.1-20% by weight of any of the EFA derivatives in Preparation Examples 1 to 4 for topical or topical use. 2. An E F A derivative according to any one of Preparation Examples 1 to 6, which contains 100 mg to 1 g of an oral pharmaceutical product in 5 ml. 3. A sterile pharmaceutical solution containing any two e F A derivatives of Preparation Examples 1 to 6 at a weight percentage of 0.1 to 20% for intravenous injection. 4. A skin or hair care product comprising the efA derivative of any one of Preparation Examples 1 to 4 at a concentration of 0.1 to 40% by weight. 5 · A milk, fruit juice or other food or beverage product comprising the eFA derivative of any one of Preparation Examples 1 to 4 or 5 at a concentration of 0.1 to 40% by weight. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -12- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

Claims (1)

Patent Application No. 085108424: Application for the amendment of the scope of the application (Aug. 91, June, the scope of the patent application • 6 or n_3 essential fatty acids (EFA) or galenbinic acid after the 6-desaturation step (C〇lumbinic acid) or octadecatetraenoic acid via an amine salt. The Λ salt is formed from adipic acid itself or from a bifunctional compound with free acid ear energy by covalent derivation via a carboxyl group. 2. The salt according to item 1 of the scope of the patent application, wherein the alkyl polyhydroxylamine salt is N-methylglucosamine. A 3. The salt according to item 1 or 2 of the scope of patent application, The fatty acid is selected from the group consisting of r-ten human carbon trimer, kappa ten human carbon trimer, eicosate tetracarboxylic acid, and adrenal acid; 22: 5 n-6 acid, stearidonic acid; 20 acid 4. n-3 acid, eicosapentapentaic acid; 22: 5 domains, eicosahexan 4. The salt according to item 1 or 2 of the scope of the patent application, wherein the bifunctional compound with free acid officials is ascorbic acid Or salicylic acid. 5. According to the scope of the patent application, the salt is used for the preparation of oral, topical, enteral Parenteral drugs. 6. The salt according to item 1 or 2 of the scope of the patent application, which is used to prepare tablets: capsules, solutions, suspensions, emulsions or other types of nutritional supplements 7. According to the scope of the patent application No. 2 or 3, which is used to prepare skin and hair care products. 8. The salt according to item 2 of the scope of the patent application, which is used to prepare foods and beverages, including fruits, milk and Fruit juice products. 9 ·-A composition for medical use, which contains salt or 2 suitable diluents or carriers in accordance with the scope of the patent application. National Paper Standard (CNS) A4 Specification (2i〇) X297 public reply) 514633 8 8 8 8 AB c D Patent application scope 10. A composition for nutritional use, which comprises a salt according to item 1 or 2 of the patent application scope and an appropriate diluent or carrier. 11. A A composition for cosmetic use, which includes a salt according to item 1 or 2 of the patent application scope and an appropriate diluent or carrier. -2- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)