Process for the production of polyol-based esters of acylprotected 3-hydroxycarboxylic acids

Abstract

The invention relates to a process for preparing polyol esters, in particular polyglycerol esters, of 3-hydroxybutyric acid blocked or with terminal acyl groups, to the products that can be obtained in this way and to their functionalized (e.g., esterified) derivatives, as well as to various uses and applications of these products.

Description

[0001] The present invention relates to the field of ketone bodies and the associated metabolism, as well as the therapy of related diseases.

[0002] In particular, the present invention relates to a process for the production of polyol esters or polyglycerol esters of acyl-capped (acyl-blocked) or acetoacetyl-capped 3-hydroxybutyric acid, as well as the reaction products obtainable or produced in this way (i.e., polyol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid, namely polyglycerol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid) and their functionalized (e.g., esterified) derivatives, as well as their use, in particular in pharmaceutical compositions such as pharmaceuticals or medicines, or in food and / or food products, as well as their further applications or uses.

[0003] Furthermore, the present invention relates to pharmaceutical compositions, in particular pharmaceuticals or medicines, which comprise the reaction products obtainable or produced according to the manufacturing process according to the invention (i.e. polyol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid, namely polyglycerol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid) or their functionalized (e.g. esterified) derivatives, as well as their applications or uses.

[0004] Finally, the present invention relates to food and / or food products, in particular food supplements, functional foods ( Functional Food ), Novel FoodFood additives, nutritional supplements, dietary foods, power snacks, appetite suppressants and strength and / or endurance sports supplements, which comprise the reaction products obtainable or produced according to the manufacturing process according to the invention (i.e. polyol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid, namely polyglycerol esters of acyl-capped or acyl-blocked 3-hydroxybutyric acid) or their functionalized (e.g. esterified) derivatives, as well as their applications or uses.

[0005] In human energy metabolism, glucose is the readily available energy carrier, which is metabolized into energy in the mitochondria, releasing water and carbon dioxide. However, the liver's glycogen stores are depleted during sleep. Yet, the human central nervous system (CNS) and the heart, in particular, require a constant energy supply.

[0006] The physiological alternative to glucose, which is primarily available to the central nervous system, are the so-called ketone bodies (also known as ketone bodies or, in English, as ketones). "Keton Bodies" designated).

[0007] The term "ketone bodies" is a collective term for three compounds that are primarily formed in catabolic metabolic states (such as during starvation, weight-loss diets, or low-carbohydrate diets) and can potentially lead to ketosis. The term "ketone bodies" specifically encompasses the three compounds acetoacetate (also known as acetoacetate or 3-oxobutyrate), acetone, and 3-hydroxybutyric acid (hereinafter also referred to as beta-hydroxybutyric acid or BHB or 3-BHB) or its salt (i.e., 3-hydroxybutyrate or beta-hydroxybutyrate), with the latter being the most significant of the three. 3-Hydroxybutyric acid or its salt occurs physiologically as the (R)-enantiomer, i.e. as (R)-3-hydroxybutyric acid (also called (3R)-3-hydroxybutyric acid, to emphasize the chiral center in the 3-position) or its salt.

[0008] These ketone bodies are also physiologically produced in large numbers during fasting or starvation from lipids stored in the body through lipolysis and almost completely replace the energy carrier glucose.

[0009] Ketone bodies are produced in the liver from acetyl-coenzyme A (acetyl-CoA), which originates from beta-oxidation; they represent a transportable form of acetyl-coenzyme A in the human body. To utilize ketone bodies, however, the brain and muscles must first adapt by expressing enzymes required to convert ketone bodies back into acetyl-coenzyme A. Particularly during periods of fasting, ketone bodies contribute significantly to energy production. For example, after some time, the brain can function with only one-third of its daily glucose requirement.

[0010] Physiologically, ketone bodies are synthesized from two molecules of activated acetic acid in the form of acetyl-coenzyme A, the normal intermediate of fatty acid degradation. First, acetoacetyl-coenzyme A is formed with the help of acetyl-coenzyme A acetyltransferase. This is then elongated to the intermediate 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) using another acetyl-coenzyme A unit and the enzyme HMG-CoA synthase. Finally, HMG-CoA lyase cleaves off the acetoacetate. These three steps take place exclusively in the mitochondria of the liver (Lynen cycle), with 3-hydroxybutyrate ultimately being produced in the cytosol by D-beta-hydroxybutyrate dehydrogenase. HMG-CoA is also an end product of the breakdown of the amino acid leucine, while acetoacetate is produced during the breakdown of the amino acids phenylalanine and tyrosine.

[0011] Acetoacetate spontaneously decarboxylates to form acetone; it is occasionally detectable in the breath of diabetics and those on a diet. The body cannot utilize it further. However, the proportion of acetone among ketone bodies is small.

[0012] Acetoacetate is thus reductively converted into the physiologically relevant form of 3-hydroxybutyric acid or 3-hydroxybutyrate, but can also decompose into the physiologically unusable acetone with the release of carbon dioxide, which is detectable and perceptible by smell in the urine and exhaled air in cases of severe ketosis, ketoacidosis (e.g. in type 1 diabetes patients without insulin substitution).

[0013] 3-Hydroxybutyric acid is currently used and marketed in the field of strength sports as a sodium, magnesium or calcium salt.

[0014] However, 3-hydroxybutyric acid is either not known to humans from an evolutionary perspective or only exists in very small amounts, as plants do not produce it and it is only found in dead, emaciated animals in ketosis. Therefore, oral administration of 3-hydroxybutyric acid induces nausea. Furthermore, 3-hydroxybutyric acid, in its free form and its salts, has a very bitter taste and can cause severe vomiting and nausea.

[0015] Furthermore, patients, especially newborns but also adults, cannot permanently tolerate larger amounts of 3-hydroxybutyric acid salts, as these compounds can damage the kidneys.

[0016] Furthermore, the plasma half-life of 3-hydroxybutyric acid and its salts is so short that even with an intake of several grams, ketosis only lasts for approximately three to four hours. This means that patients, especially during the night, cannot continuously benefit from therapy with 3-hydroxybutyric acid or its salts. In patients with metabolic disorders, this can lead to life-threatening situations.

[0017] Therefore, in the case of the therapy of such metabolic diseases, so-called medium-chain triglycerides, so-called MCTs, are used today for ketogenic therapy, i.e. the metabolic conversion of caproic, caprylic and capric acid (i.e. of saturated linear C 6, C 8 and C 10 fatty acids) from the corresponding triglycerides is intended.

[0018] In principle, from a pharmaceutical and clinical point of view, 3-hydroxybutyric acid and acetoacetate, as the physiological precursor of 3-hydroxybutyric acid, represent a more effective pharmaceutical-pharmacological target molecule, which, according to the state of the art, could in principle be used for the therapy of a large number of diseases, but cannot be used there due to its lack of physiological compatibility (e.g., in diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, or neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, etc., lipid metabolism disorders, etc.).

[0019] The following table illustrates, purely by way of example but by no means as a limitation, potential therapeutic options or possible indications for the active ingredient 3-hydroxybutyric acid as well as for acetoacetate (and thus for the 3-hydroxybutyric acid obtained physiologically by reduction of acetoacetate or its salt). indication Therapeutic effect Traumatic brain injury BHB reduces the rate of apoptosis and necrosis of nerve cells. stroke BHB reduces the rate of apoptosis and necrosis of nerve cells. Refeeding syndrome In cases of anorexia, discontinuation of enteral or parenteral nutrition, and after prolonged periods of starvation, the consumption of starch or glucose can lead to death (see also the WHO Peanut Butter Scheme). BHB can be used therapeutically in these situations to accelerate the return to normal food intake. Appetite suppressant BHB suppresses the feeling of hunger in the central nervous system (CNS). epilepsy Conventional ketogenic diets for significantly reducing seizure frequency are extremely poorly tolerated by patients. BHB offers an immediately effective alternative. Alzheimer's disease, dementia Patients taking BHB show improved cognitive performance. BHB is also effective in the prevention of neurodegenerative diseases. Disorders of fatty acid oxidation (e.g., electron transfer protein defect) Compensation for a nutrient deficiency in case of a defect in energy metabolism.

[0020] Therefore, from a pharmaceutical and clinical point of view, it is desirable to be able to find effective precursors or metabolites which physiologically allow direct or indirect access to 3-hydroxybutyric acid or its salts as well as to acetoacetate (and thus physiologically to 3-hydroxybutyric acid or its salts), especially in the physiological metabolism of the human or animal body.

[0021] Consequently, there has been no shortage of attempts in the prior art to find physiologically suitable precursors or metabolites for 3-hydroxybutyric acid or its salts. However, no efficient compounds of this kind have yet been found in the prior art. Furthermore, access to such compounds is not currently possible or readily available according to the prior art.

[0022] WO 2013 / 150153 A1 concerns ketone bodies and ketone body esters for oral administration for the purpose of improving or maintaining muscle strength, wherein certain esters of hydroxybutyrate monomers are organoleptically acceptable and lead to high absorption from the intestine into the blood, thereby enabling a rapid increase in the hydroxybutyrate concentration in the blood and a physiological response including improved power output during exercise, as well as compositions containing the ketone bodies or ketone body esters.

[0023] Furthermore, WO 2004 / 108740 A2 concerns compounds and compositions containing (R)-3-hydroxybutyrate derivatives, where the compounds and compositions are used as food supplements to enhance physical performance and as therapeutics to alleviate the symptoms of diseases, in particular neurological diseases such as Alzheimer's or similar diseases, as well as their manufacturing processes, wherein, for example, a supercritical solvent such as supercritical carbon dioxide is used and a lipase-catalyzed esterification or transesterification reaction is carried out to produce the (R)-3-hydroxybutyrate derivatives.

[0024] WO 95 / 09145 concerns compositions intended to be useful as nutrients, wherein the compositions are preferably water-soluble parenteral nutrients and represent glycerol esters of β-acyloxybutyrates, and wherein the compositions are intended to be useful as a substitute for glucose in intravenous nutrition.

[0025] Furthermore, WO 95 / 09144 A1 concerns compositions which are intended to be useful as parenteral nutrients, wherein these compositions are water-soluble glycerol esters of 3-hydroxybutyric acid, and wherein the compositions are intended to be useful as a substitute for glucose in intravenous nutrition.

[0026] Furthermore, WO 2018 / 118369 A1 concerns a procedure for the treatment or reduction of migraine symptoms and / or for treatment and / or prophylaxis using 3-hydroxybutyrate glycerides.

[0027] WO 2006 / 012490 A2 relates to a ketogenic compound with the general formula (R(OCH(CH 3 )CH 2 C(O)) n O) m -A, where n is an integer between 1 and 10, m is an integer between 1 and 200,000, A is a monosaccharide, polysaccharide or olisaccharide residue, and R is selected from the group consisting of H, C 1 -C 6 -alkyl and acetoacetyl.

[0028] WO 2010 / 021766 A1 relates to a compound which is 3-hydroxybutyl-3-hydroxybutyrate of formula (I) enriched with respect to (3R)-hydroxybutyl-(3R)-hydroxybutyrate antiomer, wherein the compounds of formula (I) are an effective and palatable precursor of the ketone body (3R)-hydroxybutyrate and can be used to treat a condition caused, aggravated or associated with elevated plasma levels of free fatty acids in a human or animal (for example, a condition in which weight loss or weight gain is a factor), or to promote alertness or improve cognitive function, or to treat, prevent or reduce the effects of neurodegeneration, free radical toxicity, hypoxic conditions or hyperglycemia.

[0029] WO 2019 / 063984 A1 relates to a method for suppressing hunger by lowering plasma ghrelin levels through the administration of a compound selected from: (i) (R)-3-hydroxybutyrate; (ii) an ester of (R)-3-hydroxybutyrate; and (iii) an oligomer of (R)-3-hydroxybutyrate units; or a pharmaceutically acceptable salt or solvate thereof. WO 2019 / 063984 A1 further relates to a method for administering such a compound at a dosage effective in reducing hunger, thereby achieving cosmetically advantageous weight loss or maintenance of body weight by lowering plasma ghrelin levels.

[0030] Finally, WO 2018 / 115158 A1 concerns a compound for use in a method for the treatment or prevention of migraine and / or symptoms thereof, wherein the compound is selected from beta-hydroxybutyric acid (βHB) or a pharmaceutically acceptable salt thereof, acetoacetate (AcAc) or a pharmaceutically acceptable salt thereof, a metabolic precursor of βHB or AcAc, 1,3-butanediol and a compound comprising an acetoacetyl or 3-hydroxybutyrate unit.

[0031] The problem underlying the present invention is therefore the provision of an efficient manufacturing process for physiologically suitable or physiologically compatible precursors and / or metabolites of 3-hydroxybutyric acid or its salts.

[0032] Such a method is intended to make the relevant BHB precursors and / or BHB metabolites accessible in an efficient manner, especially in larger quantities and without significant amounts of toxic by-products.

[0033] In a completely unexpected manner, the applicant has now discovered that polyol esters, namely polyglycerol esters, of acyl-capped (= acyl-blocked) or acetoavetyl-capped 3-hydroxybutyric acid and their functionalized derivatives represent an efficient and physiologically active or physiologically compatible precursor and / or metabolite for the ketone bodies 3-hydroxybutyric acid and acetoacetate, or for 3-hydroxybutyric acid or their salts reductively produced from them under physiological conditions, and has been able to find or develop an efficient manufacturing process for these compounds, which enables direct and effective, in particular economical as well as industrially feasible access to these compounds.

[0034] To solve the problem described above, the present invention therefore proposes – according to a first Aspect of the present invention - a process for the preparation of polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) according to claim 1; further, in particular special and / or advantageous embodiments of this process according to the invention are the subject of the corresponding dependent process claims.

[0035] Furthermore, the present invention relates – according to a second Aspect of the present invention - a polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) according to the relevant independent claim (claim 8) or mixtures thereof according to the relevant claim (claim 10); further, in particular special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claims.

[0036] Likewise, the present invention relates – according to a third Aspect of the present invention - a pharmaceutical composition, in particular a drug or medicine, according to the relevant independent claim (claim 11); further, in particular special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claim.

[0037] Furthermore, the present invention relates – according to a fourth Aspect of the present invention - the use of an optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) or a mixture thereof according to the invention for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of diseases of the human or animal body according to the related independent claim (claim 13).

[0038] Furthermore, the present invention relates – according to a fifth Aspect of the present invention - a food and / or food product according to the related independent claim (claim 14).

[0039] Finally, the present invention relates – according to a sixth Aspect of the present invention - the use of an optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) or a mixture thereof according to the invention in a food and / or food product according to the independent claim relating thereto (claim 15).

[0040] It goes without saying that the following explanations state that embodiments, designs, advantages and the like, which are described below for the purpose of avoiding repetition only with regard to one aspect of the invention, naturally also apply to the other aspects of the invention without the need for separate mention.

[0041] Furthermore, it goes without saying that individual aspects and embodiments of the present invention shall also be deemed disclosed in any combination with other aspects and embodiments of the present invention, and in particular any combination of features and embodiments as they result from the cross-references of all claims shall be deemed to be extensively disclosed, with regard to all possible combinations.

[0042] With regard to all the relative or percentage weight-related specifications mentioned below, in particular relative quantity or weight specifications, it should also be noted that, within the scope of the present invention, these must be selected by the person skilled in the art in such a way that, in sum, including all components or ingredients, in particular as defined below, they always add up to 100% or 100% by weight; however, this is self-evident to the person skilled in the art.

[0043] Furthermore, it should be noted that the person skilled in the art may, if necessary, deviate from the scope specifications listed below, either in relation to the application or due to the specific circumstances of the case, without leaving the scope of the present invention.

[0044] Furthermore, it should be noted that all values ​​or parameters mentioned below, or the like, can generally be determined using standardized or explicitly specified determination procedures, or alternatively, using determination or measurement methods that are generally familiar to those skilled in the field.

[0045] Having said that, the present invention will now be explained in detail below.

[0046] Subject matter of the present invention - according to a first An aspect of the present invention is thus a process for the production of polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid, wherein at least one compound of the general formula (I) CH 3 - CH(OR 2< ) - CH 2 - C(O)OR 1< (I) wherein in the general formula (I) the residue R 1< represents hydrogen or a C 1 - C 4 alkyl, in particular a C 1 - C 4 alkyl, preferably methyl or ethyl, preferably ethyl, and the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, with at least one polyglycerol of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in the general formula (IIb) the variable p represents an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, is reacted, wherein the reaction is carried out in the absence of solvents and wherein the reaction is carried out in the presence of an enzyme as a catalyst, wherein the catalyst is removed after the reaction is recycled so that at least one acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester is obtained as a reaction product,wherein, during the reaction, the compound according to general formula (VI) R 1< - OH (VI) is formed simultaneously, wherein in general formula (VI) the R 1< group represents hydrogen or a C 1-C 4 alkyl, in particular a C 1-C 4 alkyl, preferably methyl or ethyl, preferably ethyl; wherein the compound according to general formula (VI) is continuously withdrawn from the reaction.

[0047] According to the inventive process, a polyol ester results, namely a polyglycerol ester, which has 3-hydroxybutyric acid capped or blocked in the 3-position (= hydroxyl group position) with an acyl group or acetoacetyl group.

[0048] An acyl group is a functional group in organic chemistry with the general structure A⁻(C=O)⁻, where the A⁻ group is an organyl residue (e.g., an alkyl, aryl, or heteroaromatic group, etc.) or a hydrogen atom. Acyl groups are formally derived from carboxylic acids, aldehydes, and carboxylic acid chlorides, in which an OH group, a hydrogen atom, or a chloride is substituted by an A⁻ group. Acylation refers to the introduction of such an acyl group.

[0049] In the event that (as in the case of the invention) the acylation takes place at a hydroxyl group (OH group) (namely at the OH group located in the 3-position of 3-hydroxybutyric acid), an overall acyloxy group is formed which has the general structure A - (C = O) - O - ("A" as defined above).

[0050] According to the invention, an acyl-capped (= acyl-blocked) 3-hydroxybutyric acid is therefore butyric acid acylated at the 3-position (i.e., at the hydroxyl group position) or butanoic acid acyloxylated at the 3-position. Within the scope of the present invention, acetoacetyl capping is specifically provided as the acyl capping.

[0051] As previously stated, the applicant has discovered, quite unexpectedly, that the polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid produced in this way (which may also be functionalized, as described in detail below) represent efficient, physiologically compatible precursors and / or metabolites of free 3-hydroxybutyric acid or its salts or esters, which can be used pharmaceutically or clinically in larger quantities because they are physiologically compatible.

[0052] The aforementioned, optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid, which are made accessible for the first time in an efficient manner by the manufacturing process according to the invention, thus represent a physiologically and pharmacologically relevant alternative to free 3-hydroxybutyric acid or its salts or esters (and also to the further ketone body "acetoacetate").

[0053] The preparation of such compounds via conventional organic synthesis is complex and costly, as 3-hydroxybutyric acid is highly prone to polymerization and other undesirable side reactions (e.g., dehydration, decomposition, etc.). Within the scope of the present invention, an efficient manufacturing process has been provided for the first time, enabling the production of optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid without undesirable side reactions, particularly in a single step.

[0054] The process according to the invention thus enables, for the first time, the production of non-toxic, optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid from known, commercially available, and, above all, physiologically harmless components or starting materials. The resulting optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid can be physiologically cleaved, particularly in the stomach and / or intestine, and release or generate the target molecule "3-hydroxybutyric acid" or its salts (and also the ketone body acetoacetate from the acyl capping, which can physiologically be further converted or reduced to 3-hydroxybutyric acid) as an active ingredient or active component.

[0055] Furthermore, the aforementioned, optionally functionalized, polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid also have an acceptable taste to ensure compatibility even when larger quantities are administered orally over a longer period (e.g., administration of 50 g daily dose or more).

[0056] Likewise, the manufacturing process according to the invention makes it possible to provide the polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid free from toxic impurities.

[0057] During physiological breakdown in the stomach and / or intestine, the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid is cleaved into the keto compounds 3-hydroxybutyric acid and 3-oxobutyrate (acetoacetate and acetoacetate, respectively), which can be further reduced by the body to 3-hydroxybutyrate. Due to the presence of both 3-oxobutyrate and 3-hydroxybutyrate residues or 3-hydroxybutyric acid, the availability and release of the active ingredient 3-hydroxybutyric acid vary. The reaction product according to the invention therefore exhibits a sustained-release effect. Overall, the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid according to the invention thus contains two ketone bodies with different rates of degradation. An additional orFurther retardation is achieved by the fact that the ketone bodies are present in the form of a polyol ester, and thus, in order to release the active ingredients 3-hydroxybutyric acid in free form and acetoacetate, an additional cleavage from the polyol is required. Overall, the active ingredients 3-hydroxybutyric acid and acetoacetate are released from the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid according to the invention through a multi-stage degradation with a retardation effect.

[0058] Furthermore, with appropriate selection of the starting materials, the production can also be carried out enantioselectively. For example, the production process according to the invention makes it possible to enrich or obtain the biologically relevant form, i.e., the (R)-enantiomer, in order to avoid burdening the renal system of patients when administered orally (i.e., elimination via the kidneys). In principle, however, it is also possible and, under certain conditions, may be advantageous to enrich or obtain the (S)-enantiomer.

[0059] The manufacturing process according to the invention typically leads to a mixture of different polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid, i.e., to a mixture of at least two, and in particular at least three, different polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid. The resulting crude reaction product or crude mixture can be purified by methods known per se, in particular freed from any remaining starting materials and / or by-products, and furthermore—if desired—cleaved by methods also known per se, in particular by distillation and / or chromatography (e.g., fractionation into the individual polyol esters, i.e., mono-, di-, tri-, etc. polyol esters of acetoacetyl-capped 3-hydroxybutyric acid, or fractionation into fractions with enriched and depleted proportions of individual esters, etc.).

[0060] Furthermore, the manufacturing process according to the invention, including optional further processing or purification process steps, is economically viable and can also be implemented on an industrial scale.

[0061] In particular, the manufacturing process according to the invention uses readily available starting materials and, moreover, enables relatively simple process control even in large-scale industrial implementation. Nevertheless, excellent yields are achieved within the framework of the manufacturing process according to the invention, while the formation of by-products is minimized (no significant amounts of by-products) or avoided altogether. Furthermore, the starting materials used are themselves physiologically compatible and even pharmaceutically active, so that any remaining starting materials can remain in the reaction product and no or hardly any purification steps are necessary. However, it is generally possible and, under certain conditions, particularly with regard to organoleptic properties, can be advantageous to remove the starting materials from the reaction product.

[0062] In contrast to conventional manufacturing processes of the prior art, the manufacturing process according to the invention requires no complex starting materials and is a single-stage process. Nevertheless, excellent yields are achieved using the manufacturing process according to the invention, while the formation of by-products is minimized or avoided.

[0063] Furthermore, the process according to the invention is simple and economical. The process according to the invention is carried out in the absence of solvents and / or without any solvent at all (i.e., as a mass reaction or as a substance reaction or as a so-called Bulk Reaction Consequently, the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive process after the reaction. Furthermore, no toxic byproducts are formed.

[0064] Within the scope of the present invention, it is preferred if the compound of general formula (I) is used in racemic form or in the form of the (R)-enantiomer. The (R) configuration refers to the chiral carbon atom in the 3-position of the compound of general formula (I).

[0065] According to the invention, it is preferred if in the general formula (I) the residue R 1< represents ethyl.

[0066] In other words, according to the invention, it is preferred that the compound of general formula (I) be ethyl 3-acetylacetobutyrate (ethyl 3-acetylacetobutyrate) of the formula CH3-CH(OR2<)-CH2-C(O)OC2H5, wherein the R2< group has the meaning given above, is used. This enables particularly efficient process control and high yields with minimized or suppressed by-product formation.

[0067] In the process according to the invention, the reaction is carried out in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk Reaction This has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0068] According to the present invention, the reaction is carried out in the presence of an enzyme as a catalyst. The catalyst is recycled after the reaction.

[0069] As previously explained, in the manufacturing process according to the invention, the reaction is carried out in the presence of an enzyme as a catalyst.

[0070] The enzyme can be selected, in particular, from synthetases (ligases), catalases, esterases, lipases, and combinations thereof. According to the invention, synthetases (synonymous with ligases) are specifically enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by a covalent bond. Catalases, as used in the present invention, are in particular enzymes capable of converting hydrogen peroxide to oxygen and water. The term esterases refers in particular to enzymes capable of hydrolytically cleaving esters into alcohols and acids (saponification); these are therefore, in particular, hydrolases, with fat-splitting esterases also being referred to as lipases. Lipases, as used in the present invention, are in particular enzymes capable of cleaving free fatty acids from lipids, such as glycerides (lipolysis).

[0071] Within the scope of the present invention, the enzyme used as a catalyst can in particular be derived from Candida antarctica, Mucor miehei ( Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar and Pseudomonas sp. and their combinations, preferably of Candida antarctica, Mucor miehei ( Rhizomucor miehei ) and Thermomyces lanuginosus.

[0072] According to a particular embodiment, the enzyme can be used in immobilized form, immobilized on a support, preferably on a polymeric support, preferably on a polymeric organic support, particularly preferably with hydrophobic properties, most preferably on a poly(meth)acrylic resin-based support.

[0073] As previously stated, the enzyme is intended to be recycled after conversion.

[0074] According to the invention, the reaction is carried out in the presence of an enzyme as a catalyst within the framework of the manufacturing process according to the invention; it is preferred if the reaction is carried out at temperatures in the range of 10 °C to 80 °C, in particular in the range of 20 °C to 80 °C, preferably in the range of 25 °C to 75 °C, particularly preferably in the range of 45 °C to 75 °C, and most preferably in the range of 50 °C to 70 °C.

[0075] The amount of enzyme used can vary widely. In particular, the enzyme can be used in amounts, relative to the total amount of starting compounds (I) and (IIb), in the range of 0.001 wt% to 20 wt%, more specifically in the range of 0.01 wt% to 15 wt%, preferably in the range of 0.1 wt% to 15 wt%, and more preferably in the range of 0.5 wt% to 10 wt%. However, depending on the specific case or application, it may be necessary to deviate from the aforementioned amounts without departing from the scope of the present invention.

[0076] The applied pressure range can also vary widely. In particular, when the reaction is carried out in the presence of an enzyme as a catalyst, it can be performed at a pressure in the range of 0.0001 bar to 10 bar, especially in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most especially at about 1 bar.

[0077] As for the quantity of reactants or starting compounds, this can also be varied widely.

[0078] Taking into account process economy and optimization of the process flow, especially with regard to minimizing by-products, it is advantageous if the compound of general formula (I), based on the hydroxyl groups of the polyglycerol (IIb), is used in molar amounts in a range from equimolar amount to a molar excess of 200 mol%, in particular in a range from equimolar amount to a molar excess of 150 mol%, preferably in a range from equimolar amount to a molar excess of 100 mol%.

[0079] Equally taking into account process economy and optimization of the process flow, especially with regard to minimizing by-products, it is advantageous if the compound of general formula (I) and the polyglycerol (IIb) are used in a molar ratio of compound of general formula (I) / polyglycerol (IIb) in a range of 1 :1 to 10 : 1, in particular in a range of 2 : 1 to 8 : 1, preferably in a range of 3 : 1 to 6 : 1.

[0080] As regards the compound of general formula (I) that can be used in the process according to the invention, it is particularly preferred if the compound of general formula (I) used as a starting compound is an acetoacetyl-capped 3-hydroxybutyric acid or its salt or ester.

[0081] According to a particular embodiment of the present invention, it may be provided in particular that the starting compound of general formula (I), in particular the acetoacetyl-capped 3-hydroxybutyric acid, is obtained or is available by reacting a compound of general formula (IV) CH 3 - CH(OH) - CH 2 - C(O)OR 1< (IV) wherein in the general formula (IV) the residue R 1< represents hydrogen or a C 1 -C 4 alkyl, in particular a C 1 -C 4 alkyl, preferably methyl or ethyl, preferably ethyl, with at least one compound of the general formula (V) CH 3 - C(O) - CH 2 - C(O)OR 3< (V) wherein in the general formula (V) the residue R 3< represents a C 1 -C 4 alkyl, in particular methyl or ethyl, preferably ethyl.

[0082] In particular, the reaction of the compound of general formula (IV), as defined above, with the compound of general formula (V), as defined above, can be carried out in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk Reaction This has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0083] According to a particular embodiment of the present invention, the reaction of the compound of general formula (IV), as defined above, with the compound of general formula (V), as defined above, can be carried out in the presence of a catalyst, in particular an enzyme and / or a metal-containing and / or metal-based, acidic or basic catalyst, preferably in the presence of an enzyme. This has the advantage that, in particular, the formation of byproducts is suppressed or reduced and the reaction rate is further increased. In this embodiment, it is preferred if the catalyst is recycled after the reaction.

[0084] Taking into account process economy and optimization of the process flow, particularly with regard to minimizing by-products, it is advantageous if the compound of general formula (V) and the compound of general formula (IV) are used in a molar ratio of compound of general formula (V) / compound of general formula (IV) in a range of 1.1 : 1 to 10 : 1, preferably in a range of 1.5 : 1 to 9 : 1, particularly in a range of 2 : 1 to 8 : 1, and preferably in a range of 3 : 1 to 6 : 1. In this way, by-product formation, in particular the formation of dimeric 3-hydroxybutyric acid and its acyl-capped derivatives, is efficiently counteracted.

[0085] According to the inventive process, a polyglycerol of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) is used, wherein in the general formula (IIb) the variable p represents an integer from 1 to 4, preferably 1 or 2, particularly preferably 1.

[0086] According to a further particular embodiment of the process according to the invention, the polyglycerol (IIb) can be a diglycerol of formula (IIc) HO - CH 2 - CH(OH) - CH 2 - O - CH 2 - CH(OH) - CH 2 - OH (IIc).

[0087] According to the invention, the polyglycerol (IIb) is not a propane-1,2,3-triol, i.e., the polyglycerol (IIb) is not a glycerol.

[0088] According to a preferred embodiment of the present invention, the present invention relates, according to this aspect of the invention, to a process for the preparation of polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid), in particular as defined above, wherein at least one compound of the general formula (I) CH 3 - CH(OR 2< ) - CH 2 - C(O)OR 1< (I) wherein in the general formula (I) the residue R 1< represents ethyl and the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, with at least one polyglycerol of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in the general formula (IIb) the variable p represents an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, such that one or more acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters are obtained as reaction product.

[0089] A particularly preferred method according to the invention is illustrated by the following reaction or synthesis scheme (with "EtOH" = ethanol and "Cat" = catalyst) (where, depending on the reaction procedure, either one of the esters or a mixture of two or more thereof is obtained):

[0090] In the process according to the invention, the compound according to the general formula (VI) R 1< - OH (VI) is formed simultaneously during the reaction, wherein in the general formula (VI) the residue R 1< represents hydrogen or a C 1 -C 4 alkyl, in particular a C 1 -C 4 alkyl, preferably methyl or ethyl, preferably ethyl.

[0091] In this context, it is particularly intended that the compound according to general formula (VI) is continuously removed from the reaction, preferably by continuous distillation. In this way, the reaction equilibrium is efficiently shifted towards the reaction products. The formation of byproducts is also minimized or prevented in this way.

[0092] Within the framework of the manufacturing process according to the invention, the reaction product, in particular the composition of the reaction product, especially the presence of several and / or different acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters and their proportion in the case of a mixture, can be controlled and / or controlled by means of the reaction conditions, in particular by selecting the reaction temperature and / or selecting the reaction pressure and / or providing a catalyst and its selection with regard to type and / or quantity and / or selecting the quantities of the starting compounds and / or providing the removal of the compound according to the general formula (VI), as defined above.

[0093] Following the reaction, the resulting product can be subjected to further usual or known purification or work-up steps.

[0094] In this context, the reaction product obtained after the reaction has taken place can be fractionated, in particular fractionated by distillation.

[0095] Unreacted starting compounds (I) and / or (II) can also be separated from the reaction product and subsequently recycled. This enables a particularly economical process.

[0096] According to a particularly preferred embodiment of the present invention, the present invention relates, according to this aspect of the invention, to a process for the preparation of polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid, in particular a process as defined above, (a) wherein in a first process step (a) at least one compound of the general formula (IV) CH 3 - CH(OH) - CH 2 - C(O)OR 1< (IV) where in the general formula (IV) the residue R 1< represents hydrogen or a C 1 - C 4 alkyl, in particular a C 1 - C 4 alkyl, preferably methyl or ethyl, preferably ethyl, is reacted with at least one compound of the general formula (V) CH 3 - C(O) - CH 2 - C(O)OR 3< (V) where in the general formula (V) the residue R 3< represents a C 1 - C 4 alkyl, in particular methyl or ethyl, preferably ethyl, is reacted, such that a compound of the general formula (I) CH 3 - CH(OR 2< ) - CH 2 - C(O)OR 1< (I) where in the general formula (I) the residue R 1< has the meaning given above and the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) - represents, is formed;and subsequently (b) in a second process step (b) the compound of general formula (I) obtained in this way, as defined above, is reacted with at least one polyglycerol (IIb), as defined above, such that at least one acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester is obtained as the reaction product.

[0097] A particularly preferred method according to the invention, consisting of the synthesis of the acetoacetyl-capped 3-hydroxybutyric acid ethyl ester and the subsequent reaction with diglycerol, is illustrated by the following reaction or synthesis scheme (where, depending on the reaction procedure, either one of the esters or a mixture of two or more thereof is obtained):

[0098] According to a particular embodiment of the manufacturing process according to the invention, it is particularly possible to proceed in such a way that hydroxyl groups still present in the reaction product after the reaction has taken place are at least partially, preferably completely, functionalized, in particular by esterification.

[0099] In other words, according to a particular embodiment of the invention, the conversion can be followed by a partial, in particular complete, functionalization, in particular esterification, of any remaining hydroxyl groups.

[0100] In this particular embodiment of the process according to the invention, the functionalization, in particular esterification, of the hydroxyl groups in the reaction product can be carried out with at least one carboxylic acid anhydride of the general formula (VII) R 4< -OR 4< (VII) wherein in the general formula (VII) the residue R 4< is, independently of each other, the same or different, a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl)- C(O)-, in particular (C 4 -C 33 -alkyl)- C(O)-, preferably (C 7 -C 33 -alkyl)- C(O)-.

[0101] In this particular embodiment of the method according to the invention, it is preferred if in the general formula (VII) the residue R 4< is, independently of each other, the same or different, a fatty acid residue, in particular a C 5 -C 34 fatty acid residue, preferably a C 8 -C 34 fatty acid residue.

[0102] Furthermore, in this particular embodiment of the process according to the invention, it is preferred if the carboxylic acid anhydride of general formula (VII) is a fatty acid anhydride, in particular a C 5 -C 34 fatty acid anhydride, preferably a C 8 -C 34 fatty acid anhydride.

[0103] In particular, it is preferred if the carboxylic anhydride of general formula (VII) is a compound in which the R< 4 substituents are identical. In other words, a symmetrical carboxylic anhydride of general formula (VII) is used.

[0104] According to an alternative embodiment, it is preferred if the carboxylic anhydride of general formula (VII) is a compound in which the R 4< substituents are different from each other. In other words, an unsymmetrical carboxylic anhydride of general formula (VII) is used.

[0105] According to the invention, the functionalization of the hydroxyl groups still present in the reaction product after the reaction has taken place with the at least one carboxylic acid anhydride of general formula (VII) can be carried out at temperatures in the range of 60 to 150 °C, in particular in the range of 70 to 120 °C, preferably in the range of 80 to 100 °C.

[0106] The functionalization according to the invention of the hydroxyl groups still present in the reaction product after the reaction with the at least one carboxylic acid anhydride of general formula (VII) can be carried out in particular at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0107] In particular, it is preferred if the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with the at least one carboxylic anhydride of general formula (VII) in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk Reaction This has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0108] Within the framework of the functionalization according to the invention of the hydroxyl groups still present in the reaction product according to the invention with the at least one carboxylic acid anhydride of the general formula (VII) a compound according to the general formula (VIII) R 4< - OH (VIII) is formed simultaneously, wherein the residue R 4< has the meaning given above.

[0109] In this context, it is particularly preferred if the compound according to the general formula (VIII) is removed during or after the reaction, especially after the reaction has taken place, preferably by distillation.

[0110] Following the functionalization according to the invention of the hydroxyl groups still present in the reaction product after the reaction with the at least one carboxylic acid anhydride of general formula (VII), the product obtained can be subjected to further conventional or known purification or work-up steps.

[0111] In this context, functionalization is followed by distillation and / or chromatography, preferably distillation. In particular, any remaining reactants and reaction byproducts, especially compounds according to the general formula (VIII), are distilled off.

[0112] Within the framework of the functionalization according to the invention, it is provided that in the case that the R 4< groups in the general formula (VII) are different from one another, and / or in the case that in the general formula (VII) the R 4< groups each represent an alkyl group with more than two carbon atoms, the carboxylic anhydride of the general formula (VII) is obtainable and / or is obtained by reacting acetic anhydride with at least one carboxylic acid, in particular fatty acid, of the general formula (VIII) R 4< - OH (VIII) wherein the R 4< group has the meaning given above.

[0113] In this context, the reaction of acetic anhydride with at least one carboxylic acid, in particular fatty acid, of the general formula (VIII) takes place according to the reaction equation where the residue R 4< has the meaning given above, but with the proviso that the residues R 4< are different from each other, and / or that the residues R 4< each independently represent an alkyl residue with more than two carbon atoms.

[0114] According to a particular embodiment of this process according to the invention, a symmetrical carboxylic anhydride of general formula (VII) is prepared. In other words, in general formula (VII), the R4< groups are identical and represent an alkyl group with more than two carbon atoms. According to an alternative particular embodiment of this process according to the invention, an asymmetrical carboxylic anhydride of general formula (VII) is prepared. Thus, in general formula (VII), the R4< groups are different from one another; preferably, in general formula (VII), each R4< group represents an alkyl group with more than two carbon atoms.

[0115] A particularly preferred method according to the invention, which provides for the functionalization, in particular esterification, of any remaining hydroxyl groups (completely or partially) following the reaction, is illustrated by the following reaction or synthesis scheme (where, depending on the reaction procedure, either single esters or a mixture of two or more thereof are obtained during the reaction, and where in the following reaction or synthesis scheme the residue R denotes hydrogen or a residue of the formula CH 3 - (CH 2 ) x = 0-28 - C(O) -):

[0116] According to an alternative embodiment of the functionalization, in particular esterification, of the hydroxyl groups remaining in the reaction product after the reaction has taken place, this can be achieved in particular by reaction with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (IX) R 4< - O - R 8< (IX) wherein in the general formula (IX) the residue R 4< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -, and the residue R 8< is hydrogen or a C 1 -C 4 -alkyl, in particular methyl or ethyl, preferably hydrogen, be performed.

[0117] In this context, it is particularly preferred if the carboxylic acid and / or the carboxylic acid ester of general formula (IX) is a fatty acid and / or a fatty acid ester, in particular a C 5 -C 34 fatty acid and / or a C 5 -C 34 fatty acid ester, preferably a C 8 -C 34 fatty acid and / or a C 8 -C 34 fatty acid ester.

[0118] In particular, this embodiment of the invention functionalizes the hydroxyl groups remaining in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX) in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk ReactionThis has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0119] According to a preferred embodiment, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX) in the presence of a catalyst, in particular an enzyme and / or a metal-containing and / or metal-based, acidic or basic catalyst.

[0120] In this context, it is particularly preferable if the catalyst is recycled after the conversion process.

[0121] As previously stated, according to a preferred embodiment, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction has taken place can be carried out with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (IX) in the presence of an enzyme as a catalyst.

[0122] The enzyme can be selected, in particular, from synthetases (ligases), catalases, esterases, lipases, and combinations thereof. According to the invention, synthetases (synonymous with ligases) are specifically enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by a covalent bond. Catalases, as used in the present invention, are in particular enzymes capable of converting hydrogen peroxide to oxygen and water. The term esterases refers in particular to enzymes capable of hydrolytically cleaving esters into alcohols and acids (saponification); these are therefore, in particular, hydrolases, with fat-splitting esterases also being referred to as lipases. Lipases, as used in the present invention, are in particular enzymes capable of cleaving free fatty acids from lipids, such as glycerides (lipolysis).

[0123] In this particular embodiment, the enzyme used as a catalyst can be derived from Candida antarctica, Mucor miehei ( Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar and Pseudomonas sp. and their combinations, preferably of Candida antarctica, Mucor miehei ( Rhizomucor miehei ) and Thermomyces lanuginosus.

[0124] It is particularly preferred if the enzyme is used in immobilized form, in particular immobilized on a support, preferably on a polymeric support, preferably on a polymeric organic support, particularly preferably with hydrophobic properties, most preferably on a poly(meth)acrylic resin-based support.

[0125] As already explained in connection with the catalyst in general, it is preferable if the enzyme is recycled after the reaction.

[0126] If the functionalization according to the invention of the hydroxyl groups still present in the reaction product after the reaction has taken place with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (IX) is carried out in the presence of an enzyme as a catalyst, it is preferred if the reaction is carried out at temperatures in the range of 10 °C to 80 °C, in particular in the range of 20 °C to 80 °C, preferably in the range of 25 °C to 75 °C, particularly preferably in the range of 45 °C to 75 °C, and most preferably in the range of 50 °C to 70 °C.

[0127] When using an enzyme as a catalyst, the amount of enzyme employed can vary widely. In particular, the enzyme can be used in amounts, relative to the total amount of the starting materials, ranging from 0.001 wt% to 20 wt%, more specifically from 0.01 wt% to 15 wt%, preferably from 0.1 wt% to 15 wt%, and more preferably from 0.5 wt% to 10 wt%. However, depending on the specific case or application, it may be necessary to deviate from the aforementioned amounts without departing from the scope of the present invention. In this context, the starting materials are the acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester and the carboxylic acid and / or the carboxylic acid ester of general formula (IX).

[0128] If, according to a particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX) in the presence of an enzyme as a catalyst, the applied pressure range can also vary widely. In particular, when carried out in the presence of an enzyme as a catalyst, the reaction can be carried out at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0129] According to an alternative embodiment of the functionalization according to the invention of the hydroxyl groups still present in the reaction product after reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX), the functionalization can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst.

[0130] According to this alternative embodiment of the functionalization according to the invention, wherein the functionalization is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the catalyst may in particular be selected from (i) basic catalysts, in particular alkali or alkaline earth hydroxides and alkali or alkaline earth alcoholates, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe and Na(OBu-tert.), (ii) acidic catalysts, in particular mineral acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminium compounds, such as titanium tetrabutylate, stannic acids, zinc acetate, aluminium trichloride and aluminium triisopropyl and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminium oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas, and combinations thereof.

[0131] In this embodiment, an alkali or alkaline earth alcoholate can be used as a catalyst.

[0132] In particular, in this embodiment of functionalization, it is also preferred if the catalyst based on the metal-containing and / or metal-based acidic or basic catalyst is recycled after the reaction.

[0133] If, according to this particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX) is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the temperatures can be varied over a wide range. In particular, the reaction in the presence of a metal-containing and / or metal-based acidic or basic catalyst can be carried out at temperatures in the range of 20 °C to 150 °C, particularly in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0134] Furthermore, in this embodiment, the catalyst (i.e., the metal-containing and / or metal-based, acidic or basic catalyst) can also be varied over a wide range of quantities: The catalyst, based on a metal-containing and / or metal-based, acidic or basic catalyst, can be used in amounts, relative to the total amount of the starting compounds, in the range of 0.01 wt.% to 30 wt.%, particularly in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, and more preferably in the range of 0.2 wt.% to 10 wt.%. However, depending on the application or specific circumstances, it is possible to deviate from the aforementioned amounts without departing from the scope of the present invention. In this context, the starting compounds are the acetoacetyl-capped 3-hydroxybutyric acid polyol ester and the carboxylic acid and / or the carboxylic acid ester of general formula (IX).

[0135] If, according to this particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (IX) is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the pressure range can likewise vary over a wide range: In particular, the reaction in the presence of a metal-containing and / or metal-based, acidic or basic catalyst can be carried out at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0136] Within the framework of this particular embodiment of the functionalization of the hydroxyl groups still present in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (IX), a compound of the general formula (XI) R 8< - OH (XI) is formed simultaneously, wherein the residue R 8< has the meaning given above.

[0137] In this context, it is particularly preferred if the compound of general formula (XI) is removed during or after the reaction, especially during the reaction, preferably by distillation. This efficiently shifts the reaction equilibrium towards the products. It also minimizes or prevents the formation of byproducts.

[0138] According to a particular embodiment of the process according to the invention, the ester groups introduced into the reaction product by the previously described process can be subjected to partial transesterification using a compound of the general formula (IX), as defined above. In other words, the ester groups introduced into the reaction product by the previously described process can be partially exchanged by a residue R 4< with the meaning given above by means of transesterification.

[0139] In this context, the transesterification according to this particular embodiment of the present invention can be carried out under reaction conditions as previously described for the inventive functionalization of the hydroxyl groups still present in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester.

[0140] Within the scope of the present invention, a functionalization, in particular fatty acid functionalization, of the polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid is also provided. For this purpose, a process for the production of functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) can be employed within the scope of the invention. (A) wherein according to a (first) synthesis route (A) in a first process step at least one compound of the general formula (I) CH 3 - CH(OR 2< ) - CH 2 - C(O)OR 1< (I) wherein in the general formula (I) the residue R 1< represents hydrogen or a C 1 - C 4 alkyl, in particular a C 1 - C 4 alkyl, preferably methyl or ethyl, preferably ethyl and the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) - is reacted with at least one polyglycerol, in particular as defined above, followed by a second process step, wherein the second process step (i) involves at least partial functionalization, in particular at least partial esterification, of any remaining hydroxyl groups by means of at least one fatty acid and / or its ester or anhydride, in particular by means of at least one C 5 - C 34 fatty acid and / or its ester or anhydride,preferably by means of at least one C8-C34 fatty acid and / or its ester or anhydride, and / or (ii) a partial transesterification of ester groups introduced in the first process step by means of at least one fatty acid and / or its ester, in particular by means of at least one C5-C34 fatty acid and / or its ester, preferably by means of at least one C8-C34 fatty acid and / or its ester; , or(B) wherein, according to a (second, alternative to (A)) synthesis route (B), in a first process step at least one polyglycerol, in particular as defined above, is reacted with at least one fatty acid and / or its ester or anhydride, in particular with at least one C5-C34 fatty acid and / or its ester or anhydride, preferably with at least one C8-C34 fatty acid and / or its ester or anhydride, followed by a second process step, wherein the second process step comprises (i) at least partial esterification of remaining hydroxyl groups by means of a compound of general formula (I), as defined above, and / or (ii) partial transesterification of ester groups introduced in the first process step by means of a compound of general formula (I), as defined above; so that the reaction product is one or more fatty acid-functionalized, preferably C 5 -C 34 -fatty acid functionalized, preferably C 8 -C 34 -fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters are obtained.

[0141] In particular, the manufacturing process described above can be carried out according to synthesis route (A) in accordance with the previously described process according to the invention.

[0142] As regards the fatty acid and / or fatty acid ester that can be used in the process described above according to synthesis route (B), it is particularly preferred if the fatty acid and / or fatty acid ester is a carboxylic acid and / or a carboxylic acid ester of the general formula (IX), as defined above.

[0143] As regards the fatty acid anhydride that can be used in the previously described process according to synthesis route (B), it is particularly preferred if the fatty acid anhydride is a carboxylic acid anhydride of the general formula (VII), as defined above.

[0144] In particular, in the previously described process according to synthesis route (B), the first process step involves the reaction being carried out in the absence of solvents and / or without any solvent at all. As explained previously, this means that the reaction is carried out as a mass reaction, a substance reaction, or as a so-called Bulk ReactionThis has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0145] According to a particular embodiment of the previously described process according to synthesis route (B), in the first process step, if fatty acid and / or its esters are used as starting material, the reaction can be carried out in the presence of a catalyst, in particular a metal-containing and / or metal-based, acidic or basic catalyst.

[0146] In this context, it is particularly preferable if the catalyst is recycled after conversion.

[0147] As an alternative to this particular embodiment, according to synthesis route (B), the reaction is carried out in the absence of a catalyst and / or without a catalyst in the case of the use of fatty acid anhydride as a starting material.

[0148] As previously stated, according to a particular embodiment of the previously described manufacturing process according to synthesis route (B), in the first process step, the reaction can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst if fatty acid and / or its esters are used as starting material.

[0149] The catalyst may be selected from (i) basic catalysts, in particular alkali or alkaline earth hydroxides and alkali or alkaline earth alkoxides, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe and Na(OBu-tert.), (ii) acidic catalysts, in particular mineral acids and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminum compounds, such as titanium tetrabutylate, stannic acids, zinc acetate, aluminum trichloride and aluminum triisopropyl, and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminum oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas, as well as combinations thereof.

[0150] In this embodiment, an alkali or alkaline earth alcoholate can be used as a catalyst.

[0151] In this context, as mentioned previously, it is particularly preferable if the catalyst is recycled after the conversion process.

[0152] If, according to the particular embodiment, the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, it is preferred if the reaction is carried out at temperatures in the range of 20 °C to 150 °C, in particular in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0153] In particular, according to this embodiment, it is also preferred if the catalyst is used in amounts, based on the total amount of the starting compounds, in the range of 0.01 wt.% to 30 wt.%, in particular in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, preferably in the range of 0.2 wt.% to 10 wt.%.

[0154] Furthermore, according to this embodiment, it is preferred if the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most especially at about 1 bar.

[0155] In the context of the previously described manufacturing process according to synthesis route (B), if fatty acid and / or its esters are used as starting material, the compound of general formula (XI), as defined above, is formed simultaneously during the reaction.

[0156] In this context, it is particularly preferred if the compound of general formula (XI) is removed during or after the reaction, especially during the reaction, preferably by distillation.

[0157] In the context of the previously described manufacturing process according to synthesis route (B), if fatty acid anhydride is used as a starting material, the compound of the general formula (VIII), as defined previously, is formed simultaneously during the reaction.

[0158] It is particularly preferred if the compound of general formula (VIII) is removed during or after the reaction, preferably by distillation.

[0159] In particular, in the previously described process according to synthesis route (B), the second process step is also carried out in the absence of solvents and / or without any solvent.

[0160] Furthermore, in the previously described process according to synthesis route (B), the second process step is also carried out in the presence of a catalyst, in particular a metal-containing and / or metal-based, acidic or basic catalyst, in particular as defined above.

[0161] In this context, it is also preferable if the catalyst is recycled after the conversion process.

[0162] In this particular embodiment of the previously described process, the compound of general formula (X) R 1< - O - R 5< (X) is formed simultaneously in the second process step according to synthesis route (B), wherein in general formula (X) the residue R 1< represents hydrogen or a C 1 -C 4 alkyl, in particular a C 1 -C 4 alkyl, preferably methyl or ethyl, preferably ethyl, and the residue R 5< each independently, of the same or different, represents hydrogen or a residue R 4< as defined above.

[0163] In this context, it is particularly intended that the compound of general formula (X) is removed during or after the reaction, especially during the reaction, preferably by distillation.

[0164] According to the invention, it is particularly provided that the fatty acid, preferably the C5-C34 fatty acid, preferably the C8-C34 fatty acid, particularly in free form or in the form of its ester or anhydride, is selected from the group consisting of caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, lacceric acid, geddic acid, undecylenic acid, myristoleic acid, palmitoleic acid, margaroleic acid, petroselinic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, cetoleic acid, erucic acid, nervonic acid, linoleic acid, linolenic acids, calendic acid, punicic acid, and eleostearic acids. Stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and tetracosahexaenoic acid, as well as mixtures thereof.

[0165] According to a particular embodiment of the present invention, it is preferred that the fatty acid, preferably the C5-C34 fatty acid, preferably the C8-C34 fatty acid, particularly in free form or in the form of its ester or anhydride, is selected from the group consisting of myristic acid, pentadecanoic acid, palmitoleic acid, cetoleic acid, oleic acid, gadoleic acid, cetoleic acid, erucic acid, arachidonic acid, eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosahexaenoic acid and mixtures thereof, preferably eicosapentaenoic acid and docosahexaenoic acid and mixtures thereof.

[0166] According to a further particular embodiment, the fatty acid, preferably the C 5 -C 34 fatty acid, preferably the C 8 -C 34 fatty acid, particularly in free form or in the form of its ester or anhydride, is selected from the group of fish oil-based and / or fish oil-containing fatty acids, in particular eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid and tetracosahexaenoic acid and mixtures thereof, preferably eicosapentaenoic acid, docosahexaenoic acid and mixtures thereof.

[0167] Within the framework of the process according to the invention, one or more optionally functionalized, preferably optionally fatty acid functionalized, preferably optionally C 5 -C 34 -fatty acid functionalized, in particular optionally C 8 -C 34 -fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III') can be obtained as a reaction product.

[0168] Furthermore, one or more acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters can be obtained as a reaction product within the framework of the process according to the invention.

[0169] Furthermore, within the framework of the process according to the invention, one or more functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, preferably C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III') can be obtained as a reaction product.

[0170] Furthermore, the present invention relates – according to a second Aspect of the present invention - a reaction product obtainable according to the inventive process or a polyglycerol ester of the acetoacetyl-capped 3-hydroxybutyric acid (beta-hydroxybutyric acid, 3-hydroxybutanoic acid) as described above or mixtures thereof.

[0171] According to this aspect of the invention, the present invention thus relates to an optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester of the general formula (IIIb) R 6< O - CH 2 - CH(OR 6< ) - CH 2 - [O - CH 2 - CH(OR 6< ) - CH 2 ] p - OR 6< (IIIb) wherein in the general formula (IIIb) The variable p represents an integer 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< represents, independently of one another, the same or different: hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, or a residue R 4< , wherein the residue R 4< represents a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 - C 33 -alkyl) - C(O) -, in particular (C 4 - C 33 -alkyl) - C(O) -, preferably (C 7 - C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above.

[0172] According to a particular embodiment of the present invention, the reaction product can comprise one or more optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34 fatty acid-functionalized, and in particular optionally C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIb) R6< O-CH2-CH(OR6< )-CH2-[O-CH2-CH(OR6< )-CH2]p-OR6< (IIIb)), wherein in the general formula (IIIb) where the variable p is an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< is, independently of one another, the same or different, hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< is a residue CH 3 - C(O) - CH 2 - C(O) -, or a residue R 4< , wherein the residue R 4< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 - C 33 -alkyl) - C(O) -, in particular (C 4 - C 33 -alkyl) - C(O) -, preferably (C 7 - C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above.

[0173] According to a further particular embodiment of the present invention, the reaction product can comprise one or more optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34 fatty acid-functionalized, and in particular optionally C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIc) R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc"), wherein in the general formula (IIIc") the residue R6< represents, independently of one another, the same or different: hydrogen or a residue CH3-CH(OR2< )-CH2-C(O)-, wherein the residue R2< represents a residue CH3-C(O)-CH2-C(O)-, or a residue R4<, wherein the residue R4< is a residue of the linear type (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33 alkyl) - C(O) -,in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above.

[0174] According to a particular embodiment of the present invention, the reaction product may in particular comprise a mixture of at least two different, optionally functionalized, preferably optionally fatty acid functionalized, preferably optionally C 5 -C 34 fatty acid functionalized, in particular optionally C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III"), in particular as defined above.

[0175] According to a further particular embodiment of the present invention, the reaction product may in particular comprise a mixture of at least three different, optionally functionalized, preferably optionally fatty acid functionalized, preferably optionally C 5 -C 34 fatty acid functionalized, in particular optionally C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III"), in particular as defined above.

[0176] In particular, the reaction product may comprise one or more acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIb) R 7< O - CH 2 - CH(OR 7< ) - CH 2 - [O - CH 2 - CH(OR 7< ) - CH 2 ] p - OR 7< (IIIb), wherein in the general formula (IIIb) where the variable p is an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 1< is each independently of one another, the same or different, representing: hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, but with the proviso that at least one residue R 7< , in particular at least two residues R 7< , does not represent hydrogen.

[0177] According to a particular embodiment of the present invention, the reaction product can comprise one or more acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIc) R 7< O - CH 2 - CH(OR 7< ) - CH 2 - O - CH 2 - CH(OR 7< ) - CH 2 - OR 7< (IIIc), wherein in the general formula (IIIc) the residue R 7< represents, independently of one another, the same or different: hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, but with the proviso that at least one residue R 7< , in particular at least two residues R 7< , does not represent hydrogen.

[0178] According to a particular embodiment, the reaction product may in particular comprise a mixture of at least two different acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters, in particular as defined above.

[0179] According to a further particular embodiment, the reaction product may in particular comprise a mixture of at least three different acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters, in particular as defined above.

[0180] In particular, the reaction product can comprise one or more functionalized, especially fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIb') R6< O-CH2-CH(OR6< )-CH2-[O-CH2-CH(OR6< )-CH2]p-OR6< (IIIb'), wherein in the general formula (IIIb') where the variable p is an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and where the residue R< 6< is independently, identically, or differently, represented by: hydrogen or a residue CH3-CH(OR2)-CH2-C(O)-, wherein the residue R2 represents a residue CH3-C(O)--CH2-C(O)-, or a residue R< 4< , wherein the residue R4 is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl)-C(O)-, in particular (C4-C33-alkyl)-C(O)-, preferably (C7-C33-alkyl)-C(O)-, but with the proviso that at least two residues R< 6< do not represent hydrogen, and with the proviso that at least one residue R< 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 -C(O) -, as defined previously, andwith the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 4< , as previously defined.

[0181] In particular, in the general formula (IIIb'), the residue R 6< can each independently, the same or different, represent: a residue CH 3 -CH(OR 2< ) - CH 2 - C(O) -, as defined above, or a residue R 4< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above. and provided that at least one remainder R 6< represents a remainder R 4< as defined above.

[0182] It is particularly preferred if, in the general formula (IIIb'), the residue R 6< does not represent hydrogen, whether independently of each other, the same or different.

[0183] According to a particular embodiment of the present invention, the reaction product can comprise one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters of the general formula (IIIc') R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc'), wherein in the general formula (IIIc') the residue R6< is, independently of one another, the same or different, hydrogen or a residue CH3-CH(OR2< )-CH2-C(O)-, wherein the residue R2< represents a residue CH3-C(O)-CH2-C(O)-, or a residue R4<, wherein the residue R4< is a residue of the linear type (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33 alkyl) - C(O)-, in particular (C4-C33 alkyl) - C(O)-, preferably (C7-C33 alkyl) - C(O)-, represents,however, with the proviso that at least two residues R 6< do not represent hydrogen, , and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 4< , as previously defined.

[0184] In particular, in the general formula (IIIc') the residue R 6< can each independently, the same or different represent: a residue CH 3 -CH(OR 2< ) - CH 2 - C(O) -, as defined above, or a residue R 4< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above, and provided that at least one remainder R 6< represents a remainder R 4< as defined above.

[0185] It is particularly preferred if, in the general formula (IIIc'), the residue R 6< does not represent hydrogen, whether it is the same or different from each other.

[0186] According to a particular embodiment, the reaction product may in particular comprise a mixture of at least two different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, preferably C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III'), in particular as defined above.

[0187] According to a further particular embodiment, the reaction product may in particular comprise a mixture of at least three different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, preferably C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III'), in particular as defined above.

[0188] A further object of the present invention according to this aspect of the invention is - as already explained above - also an optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyol ester (III"), in particular as described above, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C 5 -C 34 fatty acid-functionalized, in particular optionally C 8 -C 34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester of the general formula (IIIb) corresponds to R 6< O - CH 2 - CH(OR 6< ) - CH 2 - [O - CH 2 - CH(OR 6< ) - CH 2 ] p - OR 6< (IIIb)), wherein in the general formula (IIIb) the variable p represents an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< represents, independently of one another, the same or different, hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, or a residue R 4< , wherein the residue R 4< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -,in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, , and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as previously defined.

[0189] A further object of the present invention is also an optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyol ester (III"), in particular as described above, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34 fatty acid-functionalized, in particular optionally C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester of the general formula (IIIc) corresponds to R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc"), wherein in the general formula (IIIc") the residue R6< represents, independently of one another, the same or different: hydrogen or a residue CH3-CH(OR2< )-CH2-C(O)-, wherein the residue R2< represents a residue CH3-C(O)-CH2-C(O)-, or a residue R4< , wherein the residue R4< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl)-C(O)-, in particular (C4-C33-alkyl)-C(O)-, preferably (C7-C33-alkyl)-C(O)-, but with the proviso thatthat at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, , and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 -C(O) -, as previously defined.

[0190] A further object of the present invention according to this aspect of the invention is, according to a particular embodiment, a mixture comprising at least two different, optionally functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III'), as defined above.

[0191] A further object of the present invention according to this aspect of the invention is, according to a particular embodiment, a mixture comprising at least three different, optionally functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III"), in particular as defined above.

[0192] According to this embodiment, a further object of the present invention is an acetoacetyl-capped 3-hydroxybutyric acid polyol ester, in particular as previously described, wherein the acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester corresponds to the general formula (IIIb) R 7< O - CH 2 - CH(OR 7< ) - CH 2 - [O - CH 2 - CH(OR 7< ) - CH 2 ] p - OR 7< (IIIb) where in the general formula (IIIb) where the variable p is an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 7< is each independently of one another, the same or different, representing: hydrogen or a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, but with the proviso that at least one residue R 7< , in particular at least two residues R 7< , does not represent hydrogen.

[0193] According to this embodiment, a further object of the present invention is an acetoacetyl-capped 3-hydroxybutyric acid polyol ester, in particular as described above, wherein the acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester corresponds to the general formula (IIIc) R 7< O - CH 2 - CH(OR 7< ) - CH 2 - O - CH 2 - CH(OR 7< ) - CH 2 - OR 7< (IIIc), wherein in the general formula (IIIc) the residue R 7< represents, independently of each other, the same or different: hydrogen or a residue CH 3 -CH(OR 2< ) - CH 2 - C(O) -, wherein the residue R 2< represents a residue CH 3 - C(O) - CH 2 - C(O) -, however with the proviso that at least one residue R 7< , in particular at least two residues R 7< , does not represent hydrogen.

[0194] Another object of the present invention according to this aspect of the invention, in accordance with a further particular embodiment, is a mixture comprising at least two different acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters, in particular as defined above.

[0195] A further object of the present invention according to this aspect of the invention, in accordance with a further particular embodiment, is a mixture comprising at least three different acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters, in particular as defined above.

[0196] According to this particular embodiment, a further object of the present invention is a functionalized acetoacetyl-capped 3-hydroxybutyric acid polyol ester (III'), in particular as previously described, wherein the functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester of the general formula (IIIb') R6< O-CH2-CH(OR6< )-CH2-[O-CH2-CH(OR6< )-CH2]p-OR6< (IIIb') corresponds, wherein in the general formula (IIIb') the variable p represents an integer from 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R6< represents, independently of one another, the same or different, hydrogen or a residue CH3-CH(OR2< )-CH2-C(O)-, wherein the residue R2< represents a residue CH3-C(O)-CH2-C(O)-, or a residue R 4< , wherein the residue R 4< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -,represents, however, with the proviso that at least two residues R 6< do not represent hydrogen, , and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) -CH 2 -C(O) -, as defined above, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 4< , as previously defined.

[0197] In particular, in the general formula (IIIb'), the residue R 6< can each independently, the same or different, represent: a residue CH 3 -CH(OR 2< ) - CH 2 - C(O) -, as defined above, or a residue R 4< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above. and provided that at least one remainder R 6< represents a remainder R 4< as defined above.

[0198] In this particular embodiment, it is preferred if, in the general formula (IIIb'), the residue R 6< does not represent hydrogen, whether different or identical, regardless of each other.

[0199] According to this particular embodiment, a further object of the present invention is a functionalized acetoacetyl-capped 3-hydroxybutyric acid polyol ester (III'), in particular as described above, wherein the functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester corresponds to the general formula (IIIc') R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc'), wherein in the general formula (IIIc') the residue R6< represents, independently of one another, the same or different: hydrogen or a residue CH3-CH(OR2< )-CH2-C(O)-, wherein the residue R2< represents a residue CH3-C(O)-CH 2 - C(O) - represents, or a residue R 4< , where the residue R 4< is a residue of the linear (straight-chain) or branched type,saturated or mono- or polyunsaturated (C1-C33-alkyl)-C(O)-, in particular (C4-C33-alkyl)-C(O)-, preferably (C7-C33-alkyl)-C(O)-, but with the proviso that at least two R6< substituents do not represent hydrogen, and with the proviso that at least one R6< substituent, in particular at least two R6< substituents, represents a CH3-CH(OR2<)-CH2-C(O)- substituent as defined above, and with the proviso that at least one R6< substituent, in particular at least two R6< substituents, represents a R4< substituent as defined above.

[0200] In particular, in the general formula (IIIc') the remainder R 6< can each independently, equally or differently represent: a remainder CH 3 -CH(OR 2< ) - CH 2 - C(O) -, as defined above, or a remainder R 4< , as defined above, but with the proviso that at least one remainder R 6< , in particular at least two remainders R 6< , represents a remainder CH 3 - CH(OR 2< ) - CH 2 - C(O) -, as defined above, and with the proviso that at least one remainder R 6< represents a remainder R 4< , as defined above.

[0201] In this particular embodiment, it is preferred if, in the general formula (IIIc'), the residue R 6< does not represent hydrogen, whether independently of each other, the same or different.

[0202] A further object of the present invention according to this aspect of the invention is, according to a further particular embodiment, a mixture comprising at least two different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, preferably C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III'), in particular as defined above.

[0203] A further object of the present invention according to this aspect of the invention is, according to a further particular embodiment, a mixture comprising at least three different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, preferably C 8 -C 34 fatty acid functionalized, acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters (III'), in particular as defined above.

[0204] As the applicant has surprisingly discovered, the polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or the mixture, as defined above, and obtained according to the manufacturing process according to the invention, are particularly suitable as a precursor or metabolite of 3-hydroxybutyric acid or its salts, since it is physiologically cleaved, particularly in the gastrointestinal tract, to the ketone bodies 3-hydroxybutyric acid and 3-oxobutyrate (= acetoacetate or acetoacetate), which is ultimately physiologically converted or reduced to 3-hydroxybutyric acid or its salts, and simultaneously exhibits good physiological compatibility or tolerability, particularly with regard to non-toxicity and acceptable organoleptic properties.In particular, the delayed release of the physiologically active substance in the gastrointestinal tract is advantageous in the medical field, as the active ingredient 3-hydroxybutyric acid can thus be made available over a longer period of time, thereby enabling ketosis therapy.

[0205] Therefore, the polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or the mixture, as defined above, and obtained according to the manufacturing process or as defined above, are suitable as effective precursors or metabolites that physiologically enable direct or indirect access to 3-hydroxybutyric acid or its salts as well as to acetoacetate (and thus physiologically again to 3-hydroxybutyric acid or its salts), particularly in the physiological metabolism of the human or animal body.

[0206] During physiological breakdown in the stomach and / or intestine, the polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or the mixture, as defined above, and obtained according to the manufacturing process or as defined above, are broken down into the keto compounds 3-hydroxybutyric acid and 3-oxobutyrate (acetoacetate or acetoacetate), which can be further reduced by the body to 3-hydroxybutyrate.

[0207] The presence of both 3-oxobutyrate and 3-hydroxybutyrate residues, or 3-hydroxybutyric acid, results in different rates of availability and release of the active ingredient 3-hydroxybutyric acid. Consequently, the reaction product according to the invention exhibits an intrinsic, internally differentiated sustained-release effect. This is because the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid according to the invention contains two ketone bodies with different rates of degradation. An additional or further sustained release occurs because the ketone bodies are present in the form of a polyol ester, meaning that the release of the active ingredients 3-hydroxybutyric acid in free form and acetoacetate requires additional cleavage from the polyol.Overall, the active ingredients 3-hydroxybutyric acid and acetoacetate are released from the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid according to the invention by a multi-stage degradation with a retardation effect.

[0208] The process according to the invention thus enables, for the first time, the production of non-toxic, optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid from known, commercially available, and, above all, physiologically harmless components or starting materials. The resulting optionally functionalized polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid can be physiologically cleaved, particularly in the stomach and / or intestine, releasing or generating the target molecule "3-hydroxybutyric acid" or its salts as the active ingredient or active component. Simultaneously, the further ketone body acetoacetate from the acyl capping of the 3-hydroxybutyric acid is also physiologically released (which is then further reduced to 3-hydroxybutyric acid).

[0209] Furthermore, the polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or the mixture, as defined above, which is obtainable or optionally functionalized according to the manufacturing process according to the invention, is readily available synthetically on an industrial scale, and also with the required pharmaceutical or pharmacological quality.

[0210] Furthermore, the optionally functionalized polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or the mixture obtainable according to the manufacturing process according to the invention, as defined above, can be provided in an enantiomerically pure or enantiomerically enriched form.

[0211] The polyglycerol ester of acetoacetylcapped 3-hydroxybutyric acid, as defined above, obtainable according to the manufacturing process according to the invention or optionally functionalized according to the invention, and / or the mixture obtainable according to the manufacturing process according to the invention, as defined above, thus represents an efficient pharmacological drug target in the context of ketone body therapy of the human or animal body.

[0212] The remaining aspects of the invention will be explained in more detail below.

[0213] Further subject matter of the present invention - according to a third An aspect of the present invention is a pharmaceutical composition, in particular a drug or medicament, which comprises a polyglycerol ester of acetoacetylcapped 3-hydroxybutyric acid, as defined above, obtainable by the manufacturing process according to the invention or optionally functionalized according to the invention, and / or a mixture, as defined above, obtainable by the manufacturing process according to the invention or according to the invention.

[0214] In particular, according to this aspect of the invention, the present invention relates to a pharmaceutical composition for the prophylactic and / or therapeutic treatment of diseases of the human or animal body. These may include, in particular, diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV,rheumatic diseases such as rheumatoid arthritis and gout, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy.

[0215] A polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, and / or a mixture, as defined above, and obtained according to the manufacturing process or as defined above, are also suitable for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as, in particular, traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.Lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and gout, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy.

[0216] Likewise, a further subject matter of the present invention - according to a vi e rten An aspect of the present invention is the use of at least one optionally functionalized polyglycerol ester of acetoacetylcapped 3-hydroxybutyric acid, as defined above, and / or the use of a mixture, as defined above, for the prophylactic and / or therapeutic treatment or for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as, in particular, traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect).VL-FAOD and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and gout, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy.

[0217] Furthermore, the use of a polyglycerol ester of acetoacetylcapped 3-hydroxybutyric acid or its salt or ester, as defined above, obtainable or optionally functionalized according to the inventive manufacturing process, and / or the use of a mixture obtainable or according to the inventive manufacturing process, as defined above, for prophylactic and / or therapeutic treatment or for the manufacture of a medicament for prophylactic and / or therapeutic treatment or for use in / during catabolic metabolic states, such as starvation, diets or low-carbohydrate diets, may be provided.

[0218] Likewise, a further subject matter of the present invention - according to a fifth An aspect of the present invention is a food and / or food product comprising a polyglycerol ester of acetoacetyl-capped 3-hydroxybutyric acid, as defined above, obtainable by the manufacturing process according to the invention or optionally functionalized according to the invention, and / or a mixture, as defined above, obtainable by the manufacturing process according to the invention or according to the invention.

[0219] According to a particular embodiment, the food and / or food product may in particular be a food supplement, a functional food ( Functional Food ), a Novel Food It could be a food additive, a nutritional supplement, a dietary food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0220] Finally, another subject matter of the present invention is – according to a sixth Aspect of the present invention - the use of a polyglycerol ester of acetoacetylcapped 3-hydroxybutyric acid, as defined above, obtainable by the manufacturing process or optionally functionalized according to the invention, and / or a mixture obtainable by the manufacturing process or according to the invention, as defined above, in a food and / or food product.

[0221] According to this aspect of the invention, the food and / or food product can in particular be a food supplement, a functional food ( Functional Food ), a Novel Food It could be a food additive, a nutritional supplement, a dietary food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0222] Further embodiments, modifications and variations of the present invention are readily apparent or feasible to the person skilled in the art when reading the description, without leaving the scope of the present invention.

[0223] The present invention is illustrated by the following exemplary embodiments, which are not intended to limit the present invention in any way, but merely to explain the exemplary and non-limiting implementation and design of the present invention. EXAMPLES OF EXECUTION: Abbreviations used

[0224] 3-BHB = 3-Hydroxybutyric acid or 3-Hydroxybutyric acid residue (3-Hydroxybutyrate residue) 3-BHB-FS = 3-Hydroxybutyric acid (free acid) PG(2) = Diglycerol: HO - CH 2 - CH(OH) - CH 2 - O - CH 2 - CH(OH) - CH 2 - OH PG(3) = Polyglycerol: HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] 2 - OH 3-BHB dimer ethyl ester = Dimer of the 3-BHB ethyl ester 3-Acetylaceto-BHB 2 - ethyl ester = Dimer of the 3-BHB ethyl ester disguised with ethyl acetoacetate Production examples

[0225] The manufacturing process according to the invention is illustrated by the following exemplary embodiments. The corresponding general reaction scheme is presented and explained in the general description section. Preparation of 3-acetylacetobutyric acid diglycerol ester mixtures

[0226] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 89 g of 3-acetylacetobutyric acid ethyl ester (3-acetylaceto-BHB ethyl ester), 3.5 g of diglycerol, and 0.9 g of immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica, e.g. Novozym ®< 435) submitted.

[0227] The reaction mixture is carried out at 50 °C to 70 °C under vacuum with stirring for 6 h. The resulting ethanol is continuously distilled off. Subsequently, the enzyme is filtered off and excess ethyl 3-acetylacetobutyric acid is distilled off under vacuum. A mixture of mono-, di-, tri-, and tetra-diglycerol esters of 3-acetylacetobutyric acid is obtained. Characterization is performed by gas chromatography (GC), gel permeation chromatography (GPC), and GC-MS analysis (gas chromatography-mass spectrometry).

[0228] During purification, any remaining reactants and reaction byproducts are removed to obtain a pure mixture. A portion of the mixture is separated by chromatography to obtain the various diglycerol esters as pure substances (i.e., pure mono-3-acetylacetobutyric acid diglycerol ester, pure di-3-acetylacetobutyric acid diglycerol ester, pure tri-3-acetylacetobutyric acid diglycerol ester, and pure tetra-3-acetylacetobutyric acid diglycerol ester). Another portion of the mixture is separated by fractional distillation. Further preparation of 3-acetylacetobutyric acid diglycerol esters (not according to the invention)

[0229] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 178 g of 3-acetylacetobutyric acid ethyl ester (3-acetylaceto-BHB ethyl ester) and 29 g of diglycerin are placed.

[0230] At a temperature of 100 °C, 1.4 g of 30% methanolic NaOMe solution are added while stirring. The resulting ethanol is continuously distilled off. After a reaction time of 5 h, the reaction mixture is cooled and washed with NaCl solution. The crude ester mixture is then dried, and the excess ethyl 3-acetylacetobutyric acid ester is distilled off under vacuum.

[0231] The reaction product is a 3-acetylacetobutyric acid diglycerol ester mixture with the following composition: mono-3-acetylacetobutyric acid diglycerol ester, di-3-acetylacetobutyric acid diglycerol ester, tri-3-acetylacetobutyric acid diglycerol ester, and tetra-3-acetylacetobutyric acid diglycerol ester. Characterization is performed by GC, GPC, and GC-MS.

[0232] During purification, reactants and reaction byproducts are removed, resulting in a pure mixture. A portion of the mixture is separated by chromatography to obtain the various diglycerol esters as pure substances (i.e., pure mono-3-acetylacetobutyric acid diglycerol ester, pure di-3-acetylacetobutyric acid diglycerol ester, pure tri-3-acetylacetobutyric acid diglycerol ester, etc.). Another portion of the mixture is separated by fractional distillation. Further production of acyl-capped 3-BHB polyol esters

[0233] The preceding experiments are repeated (with enzyme and with NaOMe (not according to the invention) as catalyst), but with different polyols (namely with glycerol (not according to the invention), polyglycerol PG(3), and 1,2-pentanediol (not according to the invention)). Comparable results are obtained. Purification and fractionation are carried out in the same manner. Here are some more manufacturing examples.

[0234] Various polyol components based on polyhydric alcohols (polyols) are enzymatically reacted with ethyl 3-acetylacetobutyric acid ester.

[0235] The polyols selected are 1,2-pentanediol (not according to the invention) and diglycerol PG(2). The respective polyols are treated at 70 °C for 24 h with immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica, e.g. Novozym ®< 435 from Sigma-Aldrich or Merck or Lipozym ®< 435 from Strem Chemicals, Inc.) (each with 1 wt% enzyme and 40 mol% excess of ethyl 3-acetylacetobutyric acid ester).

[0236] The aforementioned polyols 1,2-pentanediol and diglycerol PG(2) are efficiently converted to the desired products using the aforementioned enzymes. Results comparable to those obtained in previous experiments are performed in the same manner. Purification and separation or fractionation are carried out in the same way.

[0237] The experiments are repeated using sodium methoxide (NaOMe) (not according to the invention) as a catalyst instead of the enzymes and at temperatures between 100 and 120 °C. Comparable results are obtained. Purification and separation or fractionation are carried out in the same manner.

[0238] Since the 3-acetylacetobutyric acid PG(2) esters in particular have only a slightly bitter taste, these esters are a particularly efficient product group for therapeutic applications. Therefore, the preceding experiment with enzyme and diglycerol PG(2) as a polyol will be carried out on a larger scale (2 to 4 kg).

[0239] First, the stoichiometric reaction conditions of the previous experiments are applied on a 2 kg scale (40 mol% excess of ethyl 3-acetylacetobutyrate, 1 wt% enzyme). After 15 h, a portion of the reaction mixture (approx. 200 g) is removed for further investigation. This is a mono / di-PG(2) ester mixture. Then, approximately 1 kg more ethyl 3-acetylacetobutyrate is added.

[0240] The goal is to produce a complete ester. It can be observed that after approximately 20 to 30 hours, a constant concentration of di-PG(2) ester is established; the mono-PG(2) ester fraction decreases, and the tri-PG(2) ester fraction increases. Further analyses (GPC) show that a tetra-PG(2) ester has also formed.

[0241] After distilling off excess ethyl 3-acetylacetobutyric acid, the initially obtained (low-boiling) mono / di-PG(2) ester mixture has only a slightly bitter taste, while the higher-boiling di- / tri- / tetra-PG(2) ester mixture has a somewhat stronger bitter taste. However, both mixtures are organoleptically acceptable and compatible.

[0242] After further purification, removing residual starting materials and reaction by-products, a pure mixture with significantly improved organoleptic properties is obtained. Attempts at functionalization 1. Production of the anhydride

[0243] In a 2000 mL multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 860 g of heptanoic acid are placed, and 445 g of acetic anhydride are added dropwise while stirring at 90 °C. The reaction mixture is stirred under reflux at 130 °C for 6 h. Subsequently, the acetic acid formed and the excess acetic anhydride are distilled off under vacuum. A heptanoic acid / heptanoic anhydride mixture with the following composition is obtained: 15% heptanoic acid, 85% heptanoic anhydride. Characterization is carried out by GC and GC-MS. 2. Functionalization

[0244] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 25 g of heptanoic anhydride and 5 g of a 3-acetylaceto-BHB mono-, di-, tri-, tetra-diglycerol mixture prepared according to the invention are placed. The reaction mixture is stirred at 70 °C for 24 h. Excess heptanoic anhydride and the heptanoic acid formed are then distilled off by short-path distillation. A 3-acetylaceto-BHB / heptanoic acid diglycerol ester mixture is obtained (i.e., in other words, a 3-acetylaceto-BHB diglycerol ester mixture functionalized or heptanoic acid-esterified at the free OH groups).

[0245] Comparable functionalization experiments are also carried out with fatty acids and alternatively fatty acid anhydrides and again alternatively fatty acid esters (each with eicosapentaenoic acid / docosahexaenoic acid mixture and their anhydrides and esters on the one hand, and with oleic acid and its anhydride and esters on the other) and each leads to analogous results (i.e. esterification of the free OH groups), as confirmed by corresponding analysis.

[0246] The experiments show that the intended functionalization (esterification) by reaction with carboxylic acids and alternatively carboxylic anhydrides and again alternatively carboxylic esters leads to the desired products (i.e. esterification of the free OH groups), as confirmed by appropriate analysis. Further syntheses of functionalized 3-acetylaceto-BHB polyol esters (not according to the invention)

[0247] The polyols used are 1,2-pentanediol and diglycerol PG(2). The respective polyols are first reacted with sodium methoxide (NaOMe) as a catalyst at temperatures between 100 and 120 °C with fatty acids and, alternatively, fatty acid anhydrides and, again alternatively, fatty acid esters (each with eicosapentaenoic acid, docosahexaenoic acid, and oleic acid and their anhydrides and esters). This yields the corresponding fatty acid esterified polyols, which are then further reacted with 3-acetylaceto-BHB ethyl ester in a second, subsequent process step. This results in the corresponding 3-acetylaceto-BHB / fatty acid polyol ester mixtures. Comparable results are obtained using the reverse procedure (i.e., first reacting the polyols with 3-oxobutyric acid ethyl ester, followed by a further reaction with the aforementioned fatty acids or, alternatively, their anhydrides and esters). Production of 3-acetylaceto-BHB ethyl ester (= starting material)

[0248] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 52 g of ethyl 3-oxobutyric acid ester (ethyl acetoacetate or acetoacetic ester) and 26 g of ethyl 3-hydroxybutyric acid ester are placed.

[0249] At a temperature of 50 °C and under vacuum, 0.8 g of immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica, e.g., Novozym® (< 435) is added. The reaction mixture is stirred and allowed to react for 6 h. The ethanol produced during the reaction is continuously distilled off. Subsequently, the enzyme is filtered off, and excess ethyl 3-oxobutyrate and excess ethyl 3-hydroxybutyrate are distilled off under vacuum and recycled.

[0250] The reaction product obtained is 3-acetylacetobutyric acid ethyl ester (3-acetylaceto-BHB ethyl ester) and, according to analytical investigation, consists of the following composition: > 90% 3-acetylaceto-BHB ethyl ester (reaction byproducts: 3-BHB dimer ethyl ester < 5% and acetylaceto-BHB dimer ethyl ester < 5%). Distillational purification leads to pure 3-acetylacetobutyric acid ethyl esters (purity > 99.9%). Characterization is carried out by GC and GC-MS. Further production of 3-Acetylaceto-BHB-Ethylester (= reactant)

[0251] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 30 g of ethyl 3-oxobutyric acid ester (ethyl acetoacetate or acetoacetic ester) and 15.25 g of ethyl 3-hydroxybutyric acid ester (3-BHB ethyl ester) are placed.

[0252] At a temperature of 50 °C and under vacuum, 0.46 g of immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica,e.g., Novozym® (< 435) is added. The reaction mixture is stirred and allowed to react for 6 h. The ethanol produced during the reaction is continuously distilled off. Subsequently, the enzyme is filtered off, and excess ethyl 3-oxobutyrate and excess ethyl 3-hydroxybutyrate are distilled off under vacuum and then recycled.

[0253] Characterization is performed using GC and GC-MS. Here are further examples of manufacturing processes. 3-Acetylaceto-BHB-Ethylester (= reactant)

[0254] In a further series of experiments, the influence of the molar ratio of the starting compounds with regard to the formation of by-products (analytically investigated using the two by-products "3-BHB dimer ethyl ester" and "acetylaceto-BHB 2 ethyl ester") is examined.

[0255] It has been shown that a molar excess of 3-oxobutyric acid ethyl ester (ethyl acetoacetate or acetoacetic ester) in relation to the further reactant 3-hydroxybutyric acid ethyl ester (3-BHB ethyl ester) counteracts the formation of by-products.

[0256] In an initial series of tests, an acetoacetate / 3-BHB ethyl ester molar ratio in the range of 1.5:1 to 9:1 proved particularly efficient with regard to byproduct formation and was also process-economical. Particularly good results were observed in a second series of tests for an acetoacetate / 3-BHB ethyl ester molar ratio in the range of 2:1 to 8:1. Physiological application trials: in-vitro -Digestion experiments Digestion tests (cleavage tests) of acyl-capped 3-hydroxybutyric acid-PG(2) ester mixtures according to the invention

[0257] Cleavage experiments show that acetoacetyl-capped 3-hydroxybutyric acid PG(2) esters or mixtures thereof produced according to the invention, as well as their functionalized (i.e. esterified at three OH groups) derivatives including the reaction by-products, can be cleaved in the human gastrointestinal tract.

[0258] The starting mixture consists, on the one hand, of a purified mixture of mono-3-acetylaceto-BHB diglycerol ester, di-3-acetylaceto-BHB diglycerol ester, tri-3-acetylaceto-BHB diglycerol ester and tetra-3-acetylaceto-BHB diglycerol ester obtained according to the inventive process, and on the other hand, of a purified mixture of functionalized mono-3-acetylaceto-BHB diglycerol ester, functionalized di-3-acetylaceto-BHB diglycerol ester and functionalized tri-3-acetylaceto-BHB diglycerol ester obtained according to the inventive process (functionalization with heptanoic acid or oleic acid or eicosapentaenoic acid / docosahexaenoic acid mixtures).

[0259] For the splitting experiments under conditions close to the body, two media are examined: FaSSGF, which simulates the stomach; FaSSIF, which simulates the intestinal tract.

[0260] Both media are from Biorelevant®, Ltd., UK. In some experiments, porcine pancreas (Panzytrat® 40,000, Allergan) is added to both media.

[0261] The results of hydrolysis experiments in a FaSSGF or FaSSIF medium with and without Panzytrat® (35 °C, 24 h each) show that the samples hydrolyze under FaSSGF conditions with and without Panzytrat®; this is mainly due to the low pH (pH = 1.6) of the medium. Under FaSSIF conditions, less conversion occurs when using Panzytrat®.

[0262] The experiments demonstrate that 3-acetylaceto-BHB diglycerol ester and its functionalized derivatives each represent a suitable physiological precursor for the ketone bodies 3-hydroxybutyric acid and acetoacetate (and thus ultimately 3-hydroxybutyric acid again) for use in the corresponding ketone body therapies. Further digestion tests (cleavage tests) of acetoacetyl-capped 3-hydroxybutyric acid-PG(2) ester mixtures according to the invention Splitting experiments with pancreatin

[0263] 3.5 g each of a mono-3-acetylaceto-BHB diglycerol ester, di-3-acetylaceto-BHB diglycerol ester, tri-3-acetylaceto-BHB diglycerol ester, and tetra-3-acetylaceto-BHB diglycerol ester prepared as described above, on the one hand, and a purified mixture of functionalized mono-3-acetylaceto-BHB diglycerol ester, functionalized di-3-acetylaceto-BHB diglycerol ester, and functionalized tri-3-acetylaceto-BHB diglycerol ester obtained according to the inventive process, on the other hand, are dissolved in 50 g of water and combined with 0.5 g (1 wt%) of pancreatin. The pancreatin is used in the form of the commercially available product Panzytrat®< 40,000 from Allergan. The mixture is stirred on a hot plate at 50 °C; the reaction progress is determined and monitored by continuously measuring the acid number over time.The acid number increases over the observation period (cleavage of the 3-acetylaceto-BHB diglycerol ester mixture to free 3-hydroxybutyric acid and acetoacetate, which can physiologically be reduced to 3-BHB or 3-hydroxybutyrate, respectively). The conversion / time profile of the aqueous cleavage of the esters according to the invention using pancreatin, including the increase in the acid number over time, demonstrates the desired decomposition of the starting material or starting material mixture to the free acid. This is confirmed by appropriate analysis. The experiment demonstrates that both the 3-acetylaceto-BHB diglycerol ester according to the invention and the functionalized derivatives represent suitable physiological precursors for 3-hydroxybutyric acid for the corresponding ketone body therapies. The experiments are repeated and verified using the individual esters in pure form. Comparable results are obtained, i.e.,Both the 3-acetylaceto-BHB diglycerol esters and the functionalized derivatives are cleaved by pancreatin.

[0264] The previously described cleavage experiments demonstrate that the polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid represent efficient precursors or metabolites of free 3-hydroxybutyric acid or its salts, particularly with regard to their intended effect, which is present in a physiologically acceptable or physiologically compatible form. Further digestion tests (cleavage tests) of further 3-acetylaceto-BHB-polyol ester mixtures according to the invention

[0265] Furthermore, the other polyol ester mixtures of 3-acetylacetobutyric acid produced according to the invention are also subjected to digestion tests in a corresponding manner, as described above, and yield analogous results.

[0266] The cleavage experiments also demonstrate that the remaining polyol esters of 3-acetylacetobutyric acid are efficient precursors or metabolites for the ketone bodies 3-hydroxybutyric acid and acetoacetate for use in the corresponding ketone body therapies, especially with regard to their intended effect, which is also present in a physiologically tolerable or physiologically compatible form.

Claims

1. A method for the preparation of polyglycerol esters of acetoacetyl-capped 3-hydroxybutyric acid, wherein at least one compound of the general formula (I)         CH3 - CH(OR2) - CH2 - C(O)OR1     (I) wherein, in general formula (I), the radical R1 represents hydrogen or a C1-C4-alkyl, in particular a C1-C4-alkyl, preferably methyl or ethyl, more preferably ethyl, and the radical R2 represents a radical CH3 - C(O) - CH2 - C(O) -, is reacted with at least one polyglycerol of the general formula (IIb)         HO - CH2 - CH(OH) - CH2 - [O - CH2 - CH(OH) - CH2]p - OH     (IIb) wherein, in the general formula (IIb), the variable p represents an integer from 1 to 4, preferably 1 or 2, most preferably 1, wherein the reaction is carried out in the absence of solvents, and wherein the reaction is carried out in the presence of an enzyme as a catalyst, wherein the catalyst is recycled after the reaction, so that at least one acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester is obtained as the reaction product, wherein, during the reaction, at the same time the compound according to the general formula (VI)         R1 - OH     (VI) is formed, wherein, in general formula (VI), the radical R1 represents hydrogen or a C1-C4-alkyl, in particular a C1-C4-alkyl, preferably methyl or ethyl, more preferably ethyl; wherein the compound according to general formula (VI) is continuously removed from the reaction.

2. The method according to claim 1, wherein the compound of general formula (I), based on the hydroxyl groups of the polyglycerol (IIb), is used in molar amounts in a range from an equimolar amount up to a molar excess of 200 mol%, in particular in a range from an equimolar amount up to a molar excess of 150 mol%, preferably in a range from an equimolar amount up to a molar excess of 100 mol%; and / or wherein the compound of general formula (I) and the polyglycerol (Ilb) are used in a molar ratio of compound of general formula (I) / polyglycerol (IIb) in a range from 1 : 1 to 10 : 1, in particular in a range from 2 : 1 to 8 : 1, preferably in a range from 3 : 1 to 6 : 1.

3. The method according to claim 1 or claim 2, wherein the polyglycerol is a diglycerol of formula (IIc)         HO - CH2 - CH(OH) - CH2 - O - CH2 - CH(OH) - CH2 - OH     (IIc).

4. The method according to any of the preceding claims, wherein hydroxyl groups still present in the reaction product after the reaction has taken place are at least partially, preferably completely, functionalized, in particular esterified.

5. The method according to claim 4, wherein the functionalization, in particular esterification, of the hydroxyl groups still present in the reaction product after the reaction has taken place is carried out with at least one carboxylic acid anhydride of the general formula (VII)         R4 - O - R4     (VII) wherein, in general formula (VII), the radical R4 in each case independently of one another, being the same or different, represents a radical of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -.

6. The method according to claim 4, wherein the functionalization, in particular esterification, of the hydroxyl groups still present in the reaction product after the reaction has taken place is carried out by reaction with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (IX)         R4 - O - R8     (IX) wherein, in general formula (IX), • the radical R4 represents a radical of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, • the radical R8 represents hydrogen or a C1-C4-alkyl, in particular methyl or ethyl, preferably hydrogen.

7. The method according to claim 6, wherein the carboxylic acid and / or the carboxylic acid ester of general formula (IX) represents a fatty acid and / or a fatty acid ester, in particular a C5-C34 fatty acid and / or a C5-C34 fatty acid ester, preferably a C8-C34 fatty acid and / or a C8-C34 fatty acid ester, wherein the fatty acid, preferably the C5-C34 fatty acid, more preferably the C8-C34 fatty acid, in particular in free form or in the form of its ester or anhydride, is selected from the group consisting of caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, lacceroic acid, geddic acid, undecylic acid, myristoleic acid, palmitoleic acid, margaroleic acid, petroselinic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, cetoleic acid, erucic acid, nervonic acid, linoleic acid, linolenic acids, calendulic acid, punicic acid, eleostearic acids, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and tetracosahexaenoic acid, as well as mixtures thereof.

8. An optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester of the general formula (IIIb")         R6O - CH2 - CH(OR6) - CH2 - [O - CH2 - CH(OR6) - CH2]p - OR6     (IIIb") wherein, in the general formula (IIIb"), • the variable p represents an integer from 1 to 4, preferably 1 or 2, more preferably 1, • the radical R6 in each case independently of one another, being the same or different, represents: hydrogen or a radical CH3 - CH(OR2) - CH2 - C(O) -, wherein the radical R2 represents a radical CH3 - C(O) - CH2 - C(O) -, or a radical R4, wherein the radical R4 represents a radical of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, but with the proviso that at least one radical R6, in particular at least two radicals R6, does not represent hydrogen, and with the proviso that at least one radical R6, in particular at least two radicals R6, represents a radical CH3 - CH(OR2) - CH2 - C(O) -, as defined above.

9. The optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester according to claim 8, wherein the optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol ester corresponds to the general formula (IIIc")         R6O - CH2 - CH(OR6) - CH2 - O - CH2 - CH(OR6) - CH2 - OR6     (IIIc"), wherein, in the general formula (IIIc"), the radical R6 in each instance independently of one another, being the same or different, represents: hydrogen or a radical CH3 - CH(OR2) - CH2 - C(O) -, wherein the radical R2 represents a radical CH3 - C(O) - CH2 - C(O) -, or a radical R4, wherein the radical R4 represents a radical of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, but with the proviso that at least one radical R6, in particular at least two radicals R6, does not represent hydrogen, and with the proviso that at least one radical R6, in particular at least two radicals R6, represents a radical CH3 - CH(OR2) - CH2 - C(O) -, as defined above.

10. A mixture comprising at least two, in particular at least three, mutually different, optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters, as defined above.

11. A pharmaceutical composition, in particular a drug or medicament, comprising one or more optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters according to any of claims 8 to 10.

12. The pharmaceutical composition according to claim 11 for use in the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disorder of energy metabolism, in particular keto body metabolism, such as, in particular, traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism diseases such as glucose transporter deficiency (GLUT1-defect), VL-FAOD, and mitochondriapathies such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and arthritis urica, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, particularly ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipidosis, particularly Niemann-Pick disease, diabetes mellitus, and effects or side effects of chemotherapy.

13. Use of one or more optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters according to any of claims 8 to 10 for the preparation of a pharmaceutical composition for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disorder of energy metabolism, in particular keto body metabolism, such as, in particular, traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism diseases such as glucose transporter deficiency (GLUT1-defect), VL-FAOD, and mitochondriapathies such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and arthritis urica, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, particularly ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipidosis, particularly Niemann-Pick disease, diabetes mellitus, and effects or side effects of chemotherapy.

14. A food and / or nutritional product comprising one or more optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters according to any of claims 8 to 10.

15. Use of one or more optionally functionalized acetoacetyl-capped 3-hydroxybutyric acid polyglycerol esters according to any of claims 8 to 10 in a food and / or nutritional product.