JPH04316539A - New triglyceride, method of manufacturing same, use thereof for dietic treatment and alimentotherapy and composition containing same - Google Patents

Abstract

PURPOSE: To provide a novel triglyceride having the nature to easily liberate the monoglyceride of a 2-position by the action of the lipase of the pancreas.

CONSTITUTION: The compd. of formula I (R is the oxidized acyl residue of 18 to 22C polyunsaturated fatty acid; (n) is an integer from 2 to 10); for example, 1,3-dioctanoyleisosapentaenoylglycerol. The compd. is obtd. by esterifying a dihydroxyacetone with 2 mol equiv. of a functional deriv. of the acid of formula II, then processing the resulted compd. of formula III with a reducing agent which does not induce the saponification of an ester group and further esterifying the resulted compd. of formula IV with the functional deriv. of the fatty acid of formula R'OH (R' is the acyl residue of 18 to 22C polyunsaturated fatty acid) and oxidizing the resulted compd. of formula V. The compd. has the higher stability than that of the polyunsaturated fatty acid itself and is excellent in the absorption in the alimentary tracts. Then, the compd. is usable for the diet therapy and treatment method and has the anti-coagulation characteristic and immunoregulatory characteristic accompanied by a direct or indirect effect.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention] [Industrial application field]

The present invention relates to novel triglycerides, their preparation, their use in diet and therapy, and pharmaceutical compositions containing them. More specifically, the present invention provides the following general formula (I)

0002

[Chemical formula 9]

(wherein R represents an oxidized acyl residue of a polyunsaturated fatty acid containing 18 to 22 carbon atoms, and n represents an integer from 2 to 16).

0004

BACKGROUND OF THE INVENTION Triglycerides of medium-chain fatty acids containing 2 to 12 carbon atoms are described in French Pharmaceutical Special Patent No. 3598 as substances that improve the absorption of fatty substances. Additionally, triglycerides of polyunsaturated fatty acids have been described in other patents. In particular, the second French patent
, 426, 461, 5, 8, 11, 14, 17-
Triglycerides of eicosapentaenoic acid have been indicated for the treatment of thromboembolism. However, triglycerides of polyunsaturated fatty acids are not a form that ensures good absorption of polyunsaturated fatty acids into living organisms. In particular, if the triglyceride of eicosapentaenoic acid at the 1-position is hardly hydrolyzed by pancreatic lipase, the synthesized triglyceride of eicosapentaenoic acid or docosahexanoic acid does not necessarily end up as a monoglyceride at the 2-position [Nestor R. Bottino;
Lipids 1967, 2(6)]. It is well known that monoglycerides at the 2-position constitute the form that is best absorbed by the human body.

[0005]

SUMMARY OF THE INVENTION It would therefore be very beneficial to be able to obtain effective substances capable of delivering such monoglycerides to living organisms. Here,
It has been found that certain triglycerides of specific structure, especially those that are easily hydrolyzed in the 1 and 3 positions by enzymes of the gastrointestinal tract, meet this purpose. Therefore, the object of the present invention is a triglyceride of formula (I) which has the property of easily releasing monoglyceride at the 2-position by the action of pancreatic lipase. In fact, this enzyme
The medium chain fatty acids are hydrolyzed and the 1 and 3 positions of glycerin are esterified, thus liberating the monoglyceride at the 2 position. Since humans do not have a monoglyceride intestinal lipase active in the 2-position, the polyunsaturated fatty acids bound to the 2-position of glycerin are better protected within the intestinal cavity and are never liberated at this stage. Thus, the triglyceride defined by formula (I) absorbs the monoglyceride at the 2-position very well, and thus enables the living body to utilize the polyunsaturated fatty acids contained in the monoglyceride under the best conditions. let Furthermore, the triglyceride of the present invention has the following properties in order to better absorb the liberated 2-position monoglyceride:
It can be used in lower dosages than regular synthetic triglycerides. Furthermore, the triglyceride of formula (I) is
From the perspective of Galen-style medicine, it gives even more advantages. In fact, polyunsaturated fatty acids decompose easily and, because of this, become malodorous and are therefore difficult to use. However, the triglycerides of the present invention provide a stability that alleviates this disadvantage, so that they constitute a perfectly suitable form for the administration of polyunsaturated fatty acids.

[0006]

One of the subjects of the invention is therefore triglycerides of the formula (I) as defined above.

Among the triglycerides that are the subject of the present invention, in particular the oxidized acyl residues are hydroxylated, epoxidized, hydroperoxidized and hydroxyepoxidized acyl residues. The above-mentioned compound of formula (I) is exemplified.

Oxidized acyl residues are, for example, hydroxylated fatty acids such as 15-OH-5,8,11,
13-eicosatetraenoic acid, 12-OH-5,8,1
0,14-eicosatetraenoic acid, 11-OH-5,8
, 11,14-eicosatetraenoic acid, 8-OH-5,
9.11,14-eicosatetraenoic acid, 9-OH-5
, 7,11,14-eicosatetraenoic acid, 5-OH-
6,8,11,14-eicosatetraenoic acid, 12-O
It may be a residue of H-5,8,10,14,17-eicosapentaenoic acid, 15-OH-5,8,11,13,17-eicosapentaenoic acid.

[0009] Further, triglycerides in which n represents an integer of 2 to 10 in formula (I), particularly triglycerides where n is 2, 4, 6 or 1
Mention may be made of triglycerides with a value of 0. The above values of n correspond to butyryl, hexanoyl, octanoyl and dodecanoyl groups, respectively. Moreover, in particular, the formula (I
), R is substantially the following polyunsaturated fatty acid, α-
Linolenic acid C18:3, ω3γ-
Linolenic acid C18:3, ω6 Stearidonic acid C18:4, ω3 dihomo-γ-Linolenic acid C20:3, ω6 dihomo-α-
Linolenic acid C20:3, ω3 eicosatetraenoic acid C20:4, ω3 arachidonic acid
C20:4, ω6 eicosapentaenoic acid
C20:5, ω3 docosatetraenoic acid
C22:4, ω6 docosapentaenoic acid C2
2:5,ω6 docosahexaenoic acid C22:
6, ω3 docosapentaenoic acid C22:5,
Mention may be made of the triglycerides corresponding to one acyl residue of ω3, and in particular the following triglycerides, i.e.

[
0010

[Chemical formula 10]

Those corresponding to 1,3-dioctanoyleicosapentaenoylglycerin can be mentioned.

[0012] The subject of the present invention is also a compound of the following formula (II) containing 2 molar equivalents of dihydroxyacetone:

[0013]

[Chemical formula 11]

(where n is as defined above)
Esterification with a functional derivative of the acid of formula (III)

[
0015

[Chemical formula 12]

A compound of the following formula (IV) is obtained and treated with a reducing agent that does not cause saponification of the ester group.

0017
]

[Chemical formula 13]

A compound of the following formula R'-0 was obtained.
H (where R' represents the unoxidized acyl group of the polyunsaturated fatty acid) with a functional derivative of the polyunsaturated fatty acid to obtain the corresponding triglyceride, which is subjected to the action of lipoxygenase or A method for producing a triglyceride of formula (I), which is characterized in that a desired compound of formula (I) having an oxidized acyl residue is obtained by simple oxidation.

Under preferred conditions for carrying out the invention, the above manufacturing process is carried out as follows. The functional derivative of the acid of formula (II) is preferably an acid chloride. Anhydrides, mixed anhydrides or active esters can also be used. Esterification is conveniently carried out in the presence of a tertiary base such as pyridine or triethylamine. The reaction is
It is carried out in a chlorinated solvent such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Solvents such as dimethylformamide or dimethylacetamide can also be used. The reduction of the ketone function at the 2-position of the compound of formula (III) is carried out when the reducing agent that does not cause saponification of the ester group is an alkali metal borohydride, such as sodium borohydride or potassium borohydride; It is characterized in that it is worked in an alcoholic medium and that this alcohol is methanol, ethanol or propanol. The reduction is carried out at a controlled pH, especially between 6.5 and 7.
．． It is carried out at a pH between 5 and 5. The polyunsaturated fatty acid functional derivative of formula R'-OH is preferably an acid chloride,
Anhydrides, mixed anhydrides or active esters are likewise preferred. The esterification of the compound of formula (IV) is preferably carried out under the same conditions as described above for the esterification of dihydroxyacetone. Chemical oxidation of triglycerides in which R' is an unoxidized acyl residue can be achieved, for example, by autoxidation by simple aging, or by the action of pressurized oxygen, or by oxidizing acids such as m-chlorobenzoic acid. may be oxidized by Biochemical oxidation by enzymes such as lipoxygenases or α, β or ω oxidases of fatty acids can also be carried out. The acids of the formula (II) and the functional derivatives of polyunsaturated fatty acids of the formula R'-OH are prepared by methods known per se. Oxidized polyunsaturated fatty acids can be obtained starting from non-oxidized polyunsaturated fatty acids by chemical or biochemical oxidation as described above and directly act on compounds of formula (IV). It is also possible to carry out esterification.

The compounds of the invention exhibit advantageous pharmacological properties. These particularly exhibit the specific activity of polyunsaturated fatty acids bound in the 2-position. The compounds of the invention thus exhibit the following properties: precursor activity for prostaglandin-type derivatives, precursor activity for hydroxylated fatty acids, precursor activity for leukotriene-type substances. These properties vary in their degree of prominence depending on the polyunsaturated fatty acid considered. Furthermore, triglycerides of formula (I) with hydroxylated, epoxidized, hydroperoxidized or hydroxyepoxidized polyunsaturated fatty acid acyl derivatives have the following properties:
That is, it has anti-aggregation properties (by inhibiting the synthesis of prostaglandin 2) and immunomodulatory properties with direct or indirect effects. The compounds of the invention exhibit the essential advantages of greater stability and better absorption in the gastrointestinal tract compared to polyunsaturated fatty acids themselves.

The compound that is the subject of the present invention is also useful in situations where living tissues are deficient in polyunsaturated fatty acids, such as in cases of lipid digestion disorders, metabolic disorders or aging. It can be used whenever you wish to supply. In situations of this type, it is often found that the organism has an increased demand for specific polyunsaturated fatty acids, and the administration of the compounds of the invention therefore meets this need. The subject of the present invention is therefore the use of the above-mentioned triglycerides as food or supplements depending on specific nutritional deficiencies.

For example, among the polyunsaturated fatty acids that the triglycerides of the present invention can provide to undernourished individuals, in particular the following polyunsaturated fatty acids: γ-linolenic acid C18: 3,ω6
Stearidonic acid C18:4, ω3
Examples include dihomo-γ-linolenic acid C20:3, ω6 arachidonic acid C20:4, ω6 eicosapentaenoic acid C20:5, and ω3 docosahexaenoic acid C22:6, ω3. Generally, in such situations, intravenous administration of fatty acids cannot halt the decline in their levels, especially in poorly nourished alcoholic and cirrhotic patients. Therefore, the present invention:
The subject matter is a therapeutic nutritional product containing one or more of the aforementioned triglycerides and optionally mixed with a neutral supplement suitable for oral, enteral or parenteral administration.

The subject of the present invention is also the use of the above triglyceride as a drug. In particular, the subject of the invention is 1,3-dioctanoyl-2 as a medicament.
- In eicosapentaenoylglycerin. According to the invention, said compounds are suitable for the treatment of humans, in particular for lipid digestion disorders, metabolic disorders, malnutrition in poorly nourished alcoholics and cirrhosis patients, arteriosclerosis, hypertension, hyperplatelet aggregation. It is a very useful drug for the treatment of cerebral senescence, cerebral senescence, and conditions in which immunomodulation is desired. In the latter case, the compounds of the invention are useful, for example, in the treatment of autoimmune disorders such as rheumatoid polyarthritis, lupus erythematosus, pemphigus or hemolytic anemia, in the prevention of rejection of transplanted organs or grafts. , or in the treatment of certain reactions of the highly inflammatory or allergic type, inflammatory bronchial syndromes or stenotic bronchial diseases such as asthma. The usual dosage varies depending on the compound used and the disease, but for example, for adults, 50 mg to 6 g per day by oral administration, preferably 1,3-
For dioctanoyleicosapentaenoylglycerin it may be 140 mg to 300 mg per day.

The subject of the invention is also a pharmaceutical composition containing one of the above-mentioned drugs as an active ingredient. These compositions are provided in such a way that they can be administered by the gastrointestinal route or parenterally. They may be solid or liquid and may be presented in pharmaceutical forms commonly used in human medicine, such as tablets or dragees, capsules, granules, suppositories, injectable preparations. They are manufactured by conventional methods. The active ingredients can be combined with the adjuvants commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives. , glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

The following examples illustrate the invention but do not limit it in any way. Example 1: 1,3-dioctanoyl eicosapentaenoylglycerin Step A: 1,3-dioctanoyl dihydroxyacetone 22.125 g of dihydroxyacetone and 187.5 c
Mix dichloroethane (c) with stirring and reflux for 10 minutes. Add 60.5 cc of pyridine, then 1
Add 19.75 g of octanoyl chloride and 187.5 cc of dichloroethane dropwise and allow the temperature to return to ambient temperature with stirring for 2 hours. The resulting pyridine hydrochloride was filtered off and the filtrate was washed with distilled water and then with 5% aqueous sodium bicarbonate solution.
It is then washed again with distilled water until a final pH of 5.2 is obtained and the organic solution is then dried. The solvent was removed under reduced pressure to give a viscous residue, which was recrystallized from ethyl acetate and 6
0.16 g of expected product was obtained. MP=60℃. Analysis: C19H34O5 Calculation: C% 66.63 H% 10.01
Actual measurement: 66.9
10.1 Step B: 1,3-dioctanoylglycerin 3
0 g of the product obtained in the above step is dissolved in 1500 cc of ethyl alcohol at 25° C. with stirring. 0.6c
Add 50% aqueous acetic acid solution to bring the pH of the solution to 5.4. Then 8.55 g of sodium borohydride is added and the pH is kept below 7.5 by adding 50% diluted acetic acid. The solvent is kept under reduced pressure and the residue is dissolved in dichloroethane and distilled water. The organic phase was separated by decantation, washed with distilled water, dried and the solvent was removed under reduced pressure to yield 30.19 g of the expected product. MP=2
6℃. Analysis: C19H36O5 Calculation: C% 66.24 H% 10.53
Actual measurement: 66.2
10.6 Step C: 1,3-dioctanoyleicosapentaenoylglycerin 1.35 g of the product obtained in the above step was dissolved in 1.8 cc of dichloroethane and 0.256 cc of pyridine and then dissolved at ambient temperature. 1 g of eicosapentaenoyl chloride and 1.
Add 8 cc of dichloroethane. Add this mixture dropwise. The mixture is stirred at ambient temperature for 20 minutes and kept at +5° C. overnight, the resulting pyridine hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue was dissolved in 14.9 cc of cyclohexane, washed with 2.98 cc of a mixture of 0.1N sodium hydroxide and ethanol (1/1), the organic phase was separated, and 2.98 cc of 0.1N water was added. Wash with sodium oxide-ethanol-water mixture (1/5/5) until pH=7.3, then with 2.98 cc of water and ethanol mixture (1/1) until pH=4.5. The solvent of the organic phase was evaporated under reduced pressure to give 2.07 g of product, which was chromatographed on silica to give 669 mg of expected product. Analysis: C39H64O6 Calculation: C% 74.48 H% 10.26
Actual measurement: 73.0
10.0 NMR Spectrum NMR spectra were evaluated in deuterochloroform. This confirmed the structure of the product.

Example 2 Capsules with the following formulation were prepared. 1,3-Dioctanoyleicosapentaenoylglycerin 100g Auxiliary agent 300
mg (adjuvant details: kaolin, cornstarch, avicel, magnesium stearate, talc, aerosil)

[0027]

Example 3 Soft capsules with the following formulation were prepared. 1,3-Dioctanoyleicosapentaenoylglycerin 200mg Auxiliary agent Enough amount to make 1 capsule

Example 4 An emulsion for intravenous administration was prepared having the following formulation. 1,3-dioctanoyleicosapentaenoylglycerin‥‥‥‥10g DLα-Tocopherol Acetate‥‥‥‥‥‥‥‥‥
0.3g Soybean lecithin
1.2g N-glycerin
1.8g Distilled water 100
Enough amount to make ml

Clinical Study: 160 mg of 160 mg orally daily was administered to 11 subjects, 6 with high platelet aggregation and 5 with normal platelet aggregation.
, 3-dioctanoyl-3-eicosapentaenoylglycerin for one month. The platelet aggregation coefficient was determined by Ann.
Nutr. Alim. 1980, 34, 27
Ph.7-290. Evaluations were made before and after treatment according to the DARCET technique. At the end of one month of treatment, it was observed that the changes in platelet aggregation in subjects who showed normal platelet aggregation were very weak, but the range of change was very large in subjects who showed high platelet aggregation. Ta. After treatment, 4 of the 6 high platelet aggregation subjects had normal platelet aggregation coefficients, 1 had almost normal platelet aggregation coefficients, and 1 had satisfactory platelet aggregation coefficients. It was found that it showed no agglomeration coefficient.

Claims (8)

[Claims] Claim 1: The following general formula (I): where R represents an oxidized acyl residue of a polyunsaturated fatty acid containing 18 to 22 carbon atoms, and n is (representing an integer from 2 to 16). 2. The formula according to claim 1, wherein the oxidized acyl residue is a hydroxylated, epoxidized, hydroperoxidized or hydroxyepoxidized acyl residue ( I) triglycerides. 3. Triglyceride of formula (I) according to claim 1 or 2, characterized in that n represents an integer of 2 to 10. [Claim 4] R is the following polyunsaturated fatty acid, α-linolenic acid C18:3, ω3 γ-linolenic acid C18:3, ω6 stearidonic acid C18:4, ω3 dihomo-γ-linolenic acid C20:3, ω6 Dihomo-α-linolenic acid C20:3,ω3 eicosatetraenoic acid
C20:4, ω3 arachidonic acid
C20:4, ω6 eicosapentaenoic acid
C20:5, ω3 docosatetraenoic acid C
22:4, ω6 docosapentaenoic acid C22
:5, ω6 docosahexaenoic acid C22:6
,ω3 Docosapentaenoic acid C22:5,ω
A triglyceride of formula (I) according to claim 1 representing one oxidized acyl residue of 3. 5. The following general formula (I): (wherein R represents an oxidized acyl residue of a polyunsaturated fatty acid containing 18 to 22 carbon atoms, and n is (representing an integer from 2 to 16), dihydroxyacetone is mixed with 2 molar equivalents of the following formula (
II) Esterification with a functional derivative of an acid of formula (III) (wherein n is as defined above) to obtain a compound of formula (III), which is subjected to saponification of the ester group. Treatment with a non-containing reducing agent gives a compound of the following formula (IV) [Image Omitted], which is converted into a compound of the following formula R'-0H (where R' is a polyunsaturated compound containing 18 to 22 carbon atoms). (representing the acyl residue of the fatty acid) to obtain the following formula (I'):
(wherein R' and n are as defined above) and oxidize this triglyceride by the action of lipoxygenase or simple oxidation to obtain the desired compound of formula (I). A method for producing a triglyceride of formula (I). 6. The production method according to claim 5, wherein the reducing agent that does not cause saponification of the ester group is an alkali metal borohydride. [Claim 7] The following general formula (I) [Image Omitted] (wherein R represents an oxidized acyl residue of a polyunsaturated fatty acid containing 18 to 22 carbon atoms, and n is A therapeutic nutritional product containing at least one triglyceride (representing an integer from 2 to 16), optionally mixed with neutral adjuvants suitable for oral, enteral or parenteral administration. [Claim 8] The following general formula (I) [Image Omitted] (wherein R represents an oxidized acyl residue of a polyunsaturated fatty acid containing 18 to 22 carbon atoms, and n is A pharmaceutical composition containing as active ingredient at least one triglyceride representing an integer from 2 to 16.