DE102004050353A1 - Use of stable ammonium salts of lipoic acid for the treatment of diabetic and other disorders - Google Patents

Abstract

The present invention relates to the use of stable ammonium salts of alpha-lipoic acid for the treatment of a number of disease states, including, in particular, diabetic disorders and disorders of diabetogenic genesis. The salts DOLLAR A (Lp) (A) I DOLLAR A are formed from alpha-lipoic acid (Lp) and amino compounds (A) of the general formula II DOLLAR F1 or the general formula III DOLLAR F2. DOLLAR A Further uses of the salts are in particular the treatment of cardiovascular disorders, neurodegenerative disorders and diseases associated with chronic renal failure and / or dialysis treatment; Retinopathies, nephropathies, proteinuria, hyperlipidemias, hypertriglyceridemias, hypercholesterolemias, proliferating smooth muscle cells of the arteries, collagenoses, arthritis, fibromyalgia, kidney stones, inflammation, cancer, amyloidoses, osteoporosis, overweight and obesity, HIV infections and AIDS; a metabolic syndrome; oxidative stress and the associated diseases; and directed by aging processes.

Description

The The present invention relates to the use of stable ammonium salts the α-lipoic acid to Treatment of a number of disease states, in particular diabetic disorders and disorders diabetogenic genesis.

newer estimates Around 135 million people worldwide suffer from diabetes mellitus Patients out. By the year 2025 will increase to about 300 million. In the US alone, about 15.7 million people suffer that is 5.9% of the population, of diabetes mellitus. Among them are about 5.4 million, whose Illness was not diagnosed yet.

diabetes mellitus, usually Also referred to as diabetes, is a disorder of carbohydrate metabolism. Essentially, two types of this disease are encountered: diabetes Type I due to insulin deficiency and therefore also as insulin-dependent diabetes mellitus (IDDM), and type II diabetes due to decreased Insulin action, therefore also as non-insulin-dependent diabetes mellitus (NIDDM) designated. Type I usually manifests in children and Adolescents and is needed to treat a lifelong insulin delivery. More than 90% of all cases However, the type II, which is usually in adulthood manifests. Treating this essentially for insulin resistance attributable Type usually takes place with a special diabetes diet and antidiabetics with regular control the blood sugar level. Only in the late stage is a treatment Type II with insulin indicated.

When Coenzyme in the oxidative decarboxylation of α-keto acids can be found in almost every lipoic acid Cell of an organism. Antiphlogistic, analgesic and cytoprotective Properties as well as their antioxidant effect make lipoic acid one interesting ingredient for Pharmacy, cosmetics, food industry and adjacent areas (Biothiols in Health and Disease, ed Packer L. and Cadenas E., Marcel Dekker Inc., New York, Basel, Hong Kong). So will over Various studies have been reported in diabetic patients in whom the administration of lipoic acid Effect showed. For example, Jacob et al., Arzneim.-Forsch./Drug Res. 45 (II) No. 8 (1995) 872-874 a significant improvement in the glucose utilization of patients with diabetes type II after a single parenteral dose of 1000 mg lipoic acid. Similar Results were for chronic parenteral administration (Jacob et al., Exp. Clin. Endocrinol. Diabetes 104 (1996) 284-288). In a study on Treatment of diabetic neuropathy with lipoic acid (ALADIN) took symptomatic Complaints at 3 weeks intravenous Daily administration 600 mg lipoic acid (Ziegler et al., Diabetologia (1995) 38: 1425-1433). Recently, in a sequel of this study on the symptomatic treatment of diabetic polyneuropathy with lipoic acid (ALADIN III), however, no distinguishable from placebo effect on neuropathic symptoms, although the 3-week intravenous and subsequent 6-month oral treatment with lipoic acid neuropathic deficiencies in cheaper Seemed to influence (Ziegler et al., Diabetes Gare 22: 1296-1301, 1999). There was no significant change in the DEKAN study cardiovascular autonomic symptoms are observed in NIDDM patients 4 months Every day 800 mg lipoic acid (Ziegler et al., Diabetes Care 20 (1997) 369-373). In a recent multi-center study in patients with type II diabetes was found to be a 1 to 3-mound daily oral administration of 600 mg of lipoic acid could affect insulin sensitivity (Jacob et al., Free Radical Biology & Medicine, Vol. 27, Nos. 3/4, 309-314, 1999 and BioFactors 10 (1999) 169-174). Stoll also reported et al. in Pharmacology Biochemistry and Behavior, Vol. 46, pp. 799-805 (1993) and in Ann. NY Acad. Sci., Vol. 717, pp. 122-128 (1994) that lipoic acid has the Long-term memory old mice or cognitive abilities of rodents can improve. T.M. Hagen et al. describe in FASEB journal, Vol. 13, pp. 411-418 (1999) found a revitalizing effect of orally administered lipoic acid old rats.

α-lipoic acid is therapeutically for the treatment of liver diseases and diabetic and alcoholic polyneuropathy, one with metabolic diseases accompanying change peripheral nerves, used.

To EP-A 0 947 194, the R-enantiomer is mainly antiphlogistic, the S-enantiomer is mainly antinociceptive.

The cyclic disulfide of α-lipoic acid can be converted to dihydrolipoic acid, the open-chain, reduced form, in redox reactions. In the pyruvate-dehydrogenase complex of the mitochondrial membrane, it acts as an acyl carrier. It acts as an antioxidant and is a hydrogen carrier in the reduction of α-keto acids. In the enzyme dressing, it is bound as amide to the ε-amino group of a lysine residue.

Farther α-lipoic acid or α-dihydrolipoic acid bioavailability of mineral salts increase (EP-A 1 172 110).

proteins with high durability are exposed to chemical damage (aging), in the form of so-called AGEs (Advanced Glycation Endprodukte) and ALEs (Advanced Lipoxidation end products) is detectable.

The Accumulation of AGEs and also ALEs are associated with many age-related Diseases associated, e.g. with diabetic Complications (Khalifah et al., Biochemical and Biophysical Research Communication 257, pp. 251-258 (1999); Onorato et al., The Journal of Biological Chemistry 275, Pp. 21177-21184 (2000); Metz et al., Archives of Biochemistry and Biophysics 419, Pp. 41-49 (2003); Takatori et al., Diabetes / Metabolism Reseach and Reviews 20, pp. 211-218 (2004)), in particular pathophysiological changes in retinal function (Hammes et al., Diabetologia vol. 42, pp. 728-736 (1999)), diabetic retinopathy (Stitt et al., Diabetes, vol. 51, pp. 2826-2831 (2002)), and diabetic Nephropathy (Alderson et al., Diabetologia 47, pp. 1385-1395 (2004), Atherosclerosis (Baynes et al., Free Radical Biology & Medicine 28, p. 1708-1716 (200)), and dementias such as Alzheimer's disease (Dukic-Stefanovic et al. Biogerontology 2, pp. 19-34 (2001)).

pyridoxamine (4-aminomethyl-5-hydroxymethyl-2-methylpyridin-3-ol) forms with pyridoxol, pyridoxal, pyridoxal phosphate and pyridoxamine phosphate the group of course occurring forms of vitamin B6. Vitamin B6 is the most important Coenzyme of the amino acid metabolism.

About pyridoxamine is reported to inhibit the formation of AGEs and ALEs vermat (Onorato et al., supra; Stitt et al., supra). Because of this assets and the relationship between accumulation described above of AGEs and / or ALEs and the pathogenesis of certain diseases you already varied therapeutic applications for pyridoxamine derived and for this Partially collected experimental evidence in appropriate animal models (for diabetic complications, see for example Stitt et al., supra; Alderson et al., Supra; Takatori et al., Supra; Metz et al., supra; Degenhardt et al., Kidney International 61 pp. 939-950 (2002); for non-diabetic nephropathy, see for example Alderson et al., Kidney International 63, pp. 2123-2133 (2003); to atherosclerosis see, for example, Baynes et al., supra).

Next Pyridoxamine other compounds with similar effect are known. aminoguanidine for example, should also be used as an AGE inhibitor in the treatment diabetic complications useful (Onorato et al., supra) while According to other reports, this compound compared to pyridoxamine in a diabetes animal model was of little use (Takatori et al., supra). Furthermore in W0-A2004 / 019889 a series of synthetic pyridines are described, for the treatment of diabetic nephropathy, proteinuria, decreased glomerular Excretion, retinopathy, neuropathy, atherosclerosis, with diabetes related hyperlipidemia, oxidative modifications of proteins, arthritis, connective tissue diseases, amyloidosis, kidney stone diseases, with obesity related complications, a proliferation smoother Muscle cells in the aorta, coronary arterial occlusions, hypertension and a number of diseases related to dialysis stand, should be usable.

EP-B 702 953 (US-A 5,990,152) and EP-A 947 194 describe dosage forms from solid salts of α-lipoic acid, the used as a drug or food additive.

Loud EP-B 702 953 show dosage forms of solid salts over dosage forms from the free acid increased bioavailability and easier manufacturability. This is the easier manufacturability insist that some salts, unlike the free acid, are local occurring temperature increases tolerate for example, the tableting. Because such temperature effects not excluded in the preparation of numerous dosage forms can be offers a thermostable salt form considerable advantages.

Indeed Most α-lipoic acid salts show extremely low levels Thermal stability.

When Salt formers of stable salts are explicitly trometamol (EP-A 947 194), sodium hydroxide (EP-A 947 194) and zinc nitrate (EP-A 1172110; US-A 2002/0027896) called.

Out EP-A 0 572 922 discloses that combinations of the R-enantiomer of α-lipoic acid and vitamins compared with the effect of the racemic form of the α-lipoic acid alone and the effect of the vitamins alone show increased efficacy, i. act synergistically. EP-A-0 572 922 describes the use of α-lipoic acid and Derivatives thereof in combination with a vitamin for production of medicines containing analgesic, anti-inflammatory, antidiabetic, cytoprotective, antiulcerative, antinecrotic, neuroprotective, detoxifying, anti-ischemic, Liver function-regulating, antiallergic, immunostimulating like antioncogenic effect. In this case, α-lipoic acid is combined with vitamins in that Mixtures of the individual components are produced. The α-lipoic acid is in the form of the free acid or in the form of their usual Salts used. In WO 02/022111 are combination of lipoic acid with conjuenic for the treatment of diabetic disorders proposed. WO 01/85165 describes combinations of lipoic acid with C1 donors such as S-adenosylmethionine and / or 5-methyltetrahydrofolate for treatment of disorders of the central nervous system. According to WO 03/035056 are intended combination of lipoic acid with glutamine the glutathione metabolism can stabilize.

in the Case of combinations of vitamins and α-lipoic acid must be the appropriate form of α-lipoic acid and the vitamin first be mixed before preparing a dosage form can. For preparing a dosage form that is a combination from α-lipoic acid and Vitamin is therefore a first step of the process Mixture preparation necessary.

Of the The invention was based on the object of another, easily accessible, Produce thermostable salt of α-lipoic acid and uses for specify this.

steht, worin
R¹, R² unabhängig voneinander für Wasserstoff oder C₁-C₆-Alkyl stehen,
R³, R⁴ unabhängig voneinander für Wasserstoff, C₁-C₈-Alkyl, C₁-C₈-Acyl, Phosphat, Diphosphat oder Triphosphat stehen, und
m,n,o unabhängig voneinander für 0, 1, 2 oder 3 stehen;
oder
A für ein Amin der allgemeinen Formel III

steht, worin
R⁵ für Wasserstoff, C₁-C₈-Alkyl, Phenyl oder Benzyl steht,
zur Behandlung einer Reihe von Erkrankungszuständen, zu denen diabetische Störungen, kardiovaskuläre Störungen, neurodegenerative Störungen und Erkrankungen, die mit chronischem Nierenversagen und/oder Dialysebehandlung einhergehen; Retinopathien, Nephropathien, Proteinurien, Hyperlipidämien, Hypertriglyceridämien, Hypercholesterinämien, Proliferationen von glatten Muskelzellen der Arterien, Kollagenosen, Arthritis, Fibromyalgien, Nierensteinen, Entzündungen, Krebs, Amyloidosen, Osteoporose, Übergewicht, insbesondere Obesität, HIV-Infektionen und AIDS; ein metabolisches Syndrom; oxidativer Stress und die damit einhergehenden Erkrankungen; und Alterungsprozesse gehören, ohne hierauf beschränkt zu sein.An object of the present invention is an ammonium salt of the α-lipoic acid of the general formula I. (Lp) (A) I in which
Lp is α-lipoic acid; and
A is an amine of general formula II

stands in which
R ¹ , R ² independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
R ³ , R ⁴ independently of one another represent hydrogen, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -acyl, phosphate, diphosphate or triphosphate, and
m, n, o are independently 0, 1, 2 or 3;
or
A is an amine of general formula III

stands in which
R ^{5 is} hydrogen, C ₁ -C ₈ -alkyl, phenyl or benzyl,
for the treatment of a variety of disease states, including diabetic disorders, cardiovascular disorders, neurodegenerative disorders and diseases associated with chronic renal failure and / or dialysis treatment; Retinopathies, nephropathies, proteinuria, hyperlipidemias, hypertriglyceridemias, hypercholesterolemias, arterial smooth muscle cell proliferations, collagenoses, arthri tis, fibromyalgia, kidney stones, inflammation, cancer, amyloidosis, osteoporosis, obesity, especially obesity, HIV infection and AIDS; a metabolic syndrome; oxidative stress and the associated diseases; and aging processes include, but are not limited to.

Under the term "α-lipoic acid" are the racemic α-lipoic acid or racemic dihydro-α-lipoic acid, the Enantiomeric (R) - or (S) -α-lipoic acid, (R) - or (S) -dihydro-α-lipoic acid as well any mixtures of the respective enantiomeric forms (R) and (S) understood.

The Compounds of the invention I allow the simultaneous administration of α-lipoic acid and a second, with the α-lipoic acid Salt-forming component A, which is therapeutically or cosmetically effective or as an addition to Food, or nutritional supplements is usable, in the form of a stable salt.

Preferred salt-forming component A are compounds of the general formula II in which R ¹ and R ^2, independently of one another, are hydrogen or C ₁ - to C ₆ -alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2- Methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 Ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl, especially C ₁ to C ₄ alkyl, preferably hydrogen or methyl.

R ³ and R ⁴ independently of one another are hydrogen or C ₁ - to C ₈ -alkyl, such as one of the above-mentioned C ₁ - to C ₆ -alkyl radicals, and also heptyl and octyl, the corresponding acyl radicals, or mono-, di-, or triphosphate. Preferably, R ^{3 is} hydrogen or methyl, more preferably hydrogen. Preferably, R ^{4 is} hydrogen or methyl, more preferably hydrogen.

The Indices m, n or o in formula II are integers with a value from 0 to 3, one of the indices n or o preferably not zero means. More preferably, n is equal to one and o is the same zero. m is preferably for one.

For example, the amines of formula II listed in Table 1 may be mentioned: Table 1:

Especially preferably according to the formula II is pyridoxamine.

According to the invention comes as salt former A also an optionally substituted, aminoguanidine of Formula III in question.

R ⁵ in formula III is hydrogen or C ₁ - to C ₆ -alkyl, such as one of the above-mentioned in detail C ₁ - to C ₆ -alkyl radicals, phenyl or benzyl. Preferably, R ^{5 is} hydrogen, more preferably according to formula III is aminoguanidine.

Surprised it was found that the salts according to the invention have sufficient stability and through a cost-effective Have process made. Preference is given as form of α-lipoic acid, the R-α-lipoic acid and Mixtures of R- and S-α-lipoic acid, e.g. the racemate or mixtures in which the ratio R-form to S-shape greater than 1, e.g. R / S is equal to 70/30.

The Salts of the general formula I can be prepared from α-lipoic acid and amines of the general Formula II or III in a solvent at a temperature of 40 to 80 ° C and isolation of the solid produce in a conventional manner. Appropriately, the value product isolated by passing the reaction mixture until the onset of crystallization cools and subsequently the salt is filtered off.

preferred solvent are protic solvents, in particular alcohols, more preferably methanol, ethanol, propanol, Isopropanol, most preferably ethanol.

to better separation, a filter aid can be used, such as. Silica gel. After isolation, the salt becomes common dried.

The Compounds of the invention of the formula I. inhibit the formation of AGEs and / or ALEs. They are therefore as AGE and / or ALE inhibitors are useful. An object of the present Invention are therefore the compounds of the formula of the invention I for use as AGE and / or ALE inhibitors. Your use as AGE and / or ALE inhibitors may be used in particular for therapeutic purposes, but also the nutritional supplement or a dietary one food strategy serve.

AGEs (the abbreviation for the English term "Advanced Glycation end products) are carbohydrate-derived chemical Modifications of proteins. ALEs (the abbreviation for the English term "Advanced Lipoxidation Endproducts ") are lipid-derived chemical modifications of proteins. Both can to a usually irreversible cross-linking of proteins to lead. Especially when long-lived proteins are affected, The accumulation of AGEs and / or ALEs can lead to complications to lead, the need of treatment are. In particular, the inventive AGE and / or ALE inhibition damage to help mitochondria and / or reduce cell nuclei.

The Forming AGEs and / or ALEs is an ongoing process. It is of it assume that with age of an organism AGEs and / or ALEs accumulate and thus increasingly age-related complications can cause. On the other hand certain disorders an organism, e.g. a hyperglycemia or hyperlipidemia, the Reinforce the formation of AGEs and / or ALEs and with the reinforced Cause AGE and / or ALE-related complications.

One AGE and / or ALE inhibitors can cause the formation of AGEs and / or ALEs to inhibit. By the term "inhibition" is meant that the formation of AGEs and / or ALEs is comparatively lower. The term "inhibition" therefore suffices a reduction to a complete suppression of the AGE and / or ALE formation. If an organism is given an AGE and / or ALE inhibitors, this organism becomes comparatively less AGEs and / or ALEs form as without the administration of AGE and / or ALE inhibitor.

In particular, AGEs and ALEs include protein adducts such as those formed in Maillard reactions. These may be reversible Schiff base adducts and Amadori adducts of sugars such as glucose with proteins, as well as post-Amadori products of rather irreversible nature. AGE and / or ALE inhibitors can intervene at any point in such reaction sequences (eg the so-called Hodge path, Wolff path or Namiki path) and thus inhibit the formation of AGEs and / or ALEs. In particular, AGEs and ALEs include N ^ε - (carboxymethyl) -lysine (CML) and N ^ε -carboxyethyl) -lysine (CEL), pentosidine, malondialdehyde-lysine (MDA-LYS) and hydroxynonenal-lysine (HNE-LYS).

The This invention is within the scope of therapeutic applications, a Dietary supplements, a dietary one food strategy or in the area of fortified foods (functional foods) a treatment of individuals.

in the Framework of nutritional supplement will be with the normal diet guaranteed Feed supplements. In this sense, the active ingredient according to the invention is a combination two, maybe even with the ordinary To look at food intake of active ingredients as a nutrient combination. Purpose of this nutritional supplement It may be necessary to compensate for corresponding nutritional deficiencies or one over the usual nutrition guaranteed Ensuring a sufficient supply of these active substances. So serves the use according to the invention for nutritional supplements also nutritional Purposes, in particular the treatment of corresponding deficiency symptoms or the change certain states an individual balanced with a nutritionally supplemental supply of the active ingredient combination according to the invention or can be effected. The failure phenomena and changeable states include the listed below, Treatable according to the invention disorders or achievable effects.

One Aspect of the use according to the invention is the treatment of AGE and / or ALE-related complications.

According to one preferred embodiment is the use according to the invention directed to the treatment of diabetic disorders.

According to one another embodiment is the use according to the invention on the treatment of cardiovascular disorders, neurodegenerative disorders and diseases associated with chronic renal failure and / or dialysis treatment go along, directed.

According to one another particular embodiment is the use according to the invention on the treatment of retinopathies, nephropathies, proteinuria, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, Proliferations of smooth muscle cells of the arteries, collagenoses, Arthritis, fibromyalgia, kidney stones, inflammation, cancer, amyloidosis, Osteoporosis, HIV infections or AIDS.

According to one another preferred embodiment is the use according to the invention directed to the treatment of an individual with obesity, especially obesity.

According to one another preferred embodiment is the use according to the invention directed to the treatment of a metabolic syndrome.

According to one another particular embodiment is the use according to the invention on the treatment of oxidative stress and the associated Disorders directed.

According to one another particular embodiment is the use according to the invention directed to the treatment of aging processes.

Of the Term "treatment" includes both one acute as well as a preventive Treatment and refers to the individual to be treated, which suffers from any of the indicated complication, disorder or disease.

Under diabetic disorders understand disturbances of carbohydrate metabolism. It is characterized by hyperglycemia Syndrome with decreased insulin secretion and / or insulin action accompanied. Which includes especially diabetes type I and the invention particularly treatable Type II diabetes and other disorders diabetogenic genesis. Sometimes belong to the invention treatable diabetic disorders also such disturbances, that can lead to diabetes without that at the time of treatment be given a hyperglycemic state got to. These include, for example insulin resistance and reduced glucose tolerance. Especially can conditions a reduced glucose-stimulated insulin secretion treated become.

To disorders diabetogenic cause especially diseases attributable to hyperglycemic and / or hyperinsulinemic conditions. These are, in particular, micro- and macrovascular complications leading to nervous and blood vessel diseases to lead, such as neuropathies, nephropathies and retinopathies or atherosclerosis, and the attributable thereto Secondary diseases such as cataracts, blindness, kidney failure and / or Amputations. To the treatable neuropathies according to the invention belong in particular polyneuropathies.

A further preferred embodiments The present invention is directed to the treatment of hyperglycemic, in particular Insufin resistance-related hyperglycaemia.

To be treated according to the invention diabetic disorders are common characterized by a progressive development, i. the above described states change Over time, as a rule, the severity increases and if necessary conditions merge or other states to already existing conditions draw near. In particular, disorders of diabetogenic cause take with duration hyperglycemic and / or hyperinsulinemic conditions to. This is how the preventive treatment of disorders diabetogenic cause, in particular of secondary diseases, such as cataract, Blindness, kidney failure and amputation, a particularly valuable Aspect of the treatment according to the invention represents.

By the treatment according to the invention can be a variety of signs, symptoms and / or malfunction treat associated with the aforementioned disorders and conditions. For this belong for example, blurred vision, tiredness, nausea, symptoms of coronary heart disease, Limping, gangrene, Retinal detachment or hemorrhage, Cataract, blindness, nephrotic syndrome, kidney failure, sensory deficits, deafness, painful stinging or burning, abnormal feeling sensations in the extremities, Amputation, fatigue, deep-seated pain, hypersensitivity.

One aspect of a treatment according to the invention relates to the treatment of acute or chronic disorders, conditions, signs, symptoms and / or dysfunctions, especially hyperglycemic and / or hyperinsulinemic conditions; a purpose of this treatment is a correction of the disorders, regulation of the conditions, or alleviation of signs, symptoms and / or dysfunctions, in particular a regulation and especially lowering of the blood glucose and / or blood insulin level or a stimulation of glucose-induced insulin secretion and / or an increase in insulin-mediated glucose uptake. In a particular aspect, the purpose of the treatment may be to reduce the activity of the proinflammatory redox factor NFKB and / or peroxisome proliferator-activated Re to activate detectors (PPAR). Another aspect relates to a preventive treatment (prophylaxis), in particular with regard to the aforementioned disorders of diabetogenic cause; One purpose of this treatment is to prevent the onset of the disorders, conditions, signs, symptoms and / or dysfunctions, including a time delay of onset. The treatment may be symptomatic, for example as symptom suppression. It may be short-term, medium-term, or long-term, for example in the context of maintenance therapy.

Under cardiovascular disorders understand disturbances of the cardiovascular system. These include in particular high-pressure diseases, e.g. Hypertension, i. an elevated one systolic and / or diastolic blood pressure, arteriosclerosis and especially atherosclerosis, coronary heart disease (the various Forms of angina and heart attack included), heart failure and arrhythmias.

Under neurodegenerative disorders one understands in particular those disturbances associated with aging processes, demyelinating processes, ischemic events and / or further morphological changes, those with neuronal changes and in particular deficits, e.g. Infections, traumas, Tumors, deposits and / or diffuse brain atrophic changes, being related. According to the invention treatable neurodegenerative disorders belong Impairments of the mental Features, especially dementia, especially cerebrovascular dementia and dementia of the Alzheimer's type, e.g. senile dementia and Alzheimer's disease, in particular intellectual deficits, such as attention disorders (attention deficit disorders), amnesic and cognitive disorders, e.g. Learning and memory weakness (impaired cognitive function); Multiple sclerosis; Parkinson's and epilepsy.

preferred embodiments The present invention is directed to the treatment of impairments cognitive functions, especially of learning and memory weaknesses, in particular of dementia.

Especially age-related neurodegenerative disorders are treated.

To Diseases associated with chronic renal failure and / or dialysis treatment go hand in hand especially vascular complications, like malfunctions cerebral, cardiac, mesenteric and peripheral vasculature and the related ones disease states or their symptoms. Which includes For example, the formation of thrombi in the vascular system of the treated Individual, ie in particular thromboses of venous and arterial type, in particular deep vein thrombosis, peripheral occlusive disease, shunt thrombosis, Catheter thrombosis, thromboembolism, unstable angina, myocardial infarction and stroke. On factors that increase the risk of such vascular complications increase, belong both disorders of the coagulation system, in particular AT III deficits and increased fibrin genspiegel, thrombocytosis, HIT, as well as hypertension and pre-existing conditions such as coronary heart disease, Diabetes or other vascular diseases. To be treated according to the invention Diseases associated with chronic renal failure and / or dialysis treatment go hand in hand also AB amyloidosis, dementia and carpal tunnel syndrome.

Under oxidative stress is a situation where the formation reactive oxygen and nitrogen species endogenous or exogenous Origin whose neutralization predominates. Oxidative stress may in particular be the disorders described above, so mainly diabetic, cardiovascular and neurodegenerative disorders, entail. The treatment according to the invention of oxidative Stress is therefore particularly in the sense of preventive treatment, i. of the Reduce the incidence of secondary diseases, such as those described above disorders, significant.

A metabolic syndrome is a disease in which several metabolic functions are disturbed. A metabolic syndrome is present in particular when at least two metabolic dysfunctions are present which are selected from a lipid metabolism disorder, in particular a comparatively high triglyceride level (hypertriglyceridemia, eg a triglyceride level of over 200 mg / 100 ml of blood) and / or one comparatively low HDL cholesterol levels, eg HDL cholesterol levels below 35 mg / 100 ml blood; a comparatively high blood pressure, for example a blood pressure of more than 140/90 mm Hg, in particular an arterial hypertension; an obesity, in particular a trunk-stressed body fat distribution, eg at a BMI (abbreviation for body mass index, according to the formula: body weight in kg / height in meters square (m) ² ) of 25 or higher, or an obesity, eg at a BMI of 30 or higher; a carbohydrate metabolism disorder, in particular an insulin resistance (hyperinsulinemia) and / or a disturbed glucose tolerance (eg in the case of blood sugar values of more than 140 mg / dl of blood two hours after ingestion of 100 g of glucose dissolved in 400 ml of water; according to the oral glucose tolerance test); and specifically in female individuals - hyperandrogenemia, especially an android muscle fiber composition. Such a metabolic syndrome may result in particular in the above-described disorders, in particular diabetic, cardiovascular and neurodegenerative disorders. The treatment according to the invention of the metabolic syndrome is therefore of particular importance in the context of preventive treatment, ie the reduction of the incidence of secondary diseases, such as the disorders described above.

To Aging processes belong in particular the above-described chemical modifications of Proteins. Thus, you can particularly according to the invention age-related disorders and especially age-related forms of those described above disorders and diseases are treated.

Therefore wins the treatment according to the invention in adult individuals with increasing age in importance. In humans, the treatment brings in the group of over 40 years and especially the over 50 years special advantages with it. Overweight Individuals make another group more treatable Individuals. These include also overweight Pets and pets, e.g. overweight Dogs or cats.

The use according to the invention of the compounds of formula I is included in the treatment a procedure. In this case, the individual to be treated, preferably a mammal, especially a human, and also a useful or pet, e.g. of a dog or cat, an effective amount of one or more Compounds of formula I, usually of the pharmaceutical, veterinary or formulated according to food technology practice, administered. Whether such treatment is indicated and in which Shape she has to do depends from individual case and can both a professional medical (in the rule foreign diagnosis) as well as a non-expert Assessment (usually self-diagnosis) are subject to existing Signs, symptoms and / or dysfunctions, risks, specific Develop signs, symptoms and / or dysfunction, and more Can involve factors.

The Treatment is usually done by one or more times daily Administration, if appropriate together or in alternation with others Active substances or active substance-containing preparations, so that one to be treated Individual a daily dose of about 0.1 mg to 5 g, preferably from about 1 mg to 2 g, more preferably 10 mg to 0.5 g of a or more compounds of the formula I in the case of oral administration, as well as of about 0.1 mg to 5 g, preferably from about 50 mg to 1.5 g of a or more compound of formula I administered by parenteral administration becomes.

The The invention also relates to the preparation of treatment agents an individual, preferably a mammal, especially a human, Commercial or pet, e.g. a dog or a cat. such Agents comprise one or more compounds of the formula I and if applicable, a formulation basis.

To belong to the means in particular pharmaceutical agents, dietary supplements and food, especially functional and dietary Foodstuffs The foods according to the invention have in addition to a predominantly nutrition-related Additional function an active substance-related function. They are therefore considered functional or dietary Food or food called. Dietary supplements serve as a supplement the daily nutrition with the active ingredient combination according to the invention, wherein the nutritional Function of the dietary supplement for themselves Taken into the background. To the food and nutritional supplements belong also feed or feed supplements, in particular Feed or feed supplement for pets, like dogs and cats.

The Formulation basis of formulations according to the invention contains physiological acceptable excipients. Physiologically acceptable are those in the field pharmacy, food technology and adjacent areas known usable excipients, especially those in relevant pharmacopoeias (e.g. DAB, Pi. Euer., BP, NF), as well as other auxiliaries, whose properties do not conflict with a physiological application. Excipients in the sense of the invention can also a nutritional value and therefore commonly used as a nutritional component become. Also essential nutrients can this includes.

Suitable auxiliaries may be: wetting agents, emulsifying and suspending agents, preserving agents, antioxidants, anti-irritants, chelating agents, coating auxiliaries, emulsion stabilizers, film formers, Gelling agents, odor masking agents, flavoring agents, resins, hydrocolloids, solvents, solubilizers, neutralizing agents, permeation enhancers, pigments, quaternary ammonium compounds, lipid and superfatting agents, ointment, cream or oil bases, silicone derivatives, spreaders, stabilizers, sterilants, suppository bases, Tablet excipients, such as binders, fillers, lubricants, disintegrants or coatings, propellants, desiccants, opacifiers, thickeners, waxes, plasticizers, white oils. A related embodiment is based on expert knowledge, such as in Fiedler, HP, Lexicon of excipients for pharmacy, cosmetics and related fields, 4th edition, Aulendorf: ECV Editio Kantor Verlag, 1996, is shown.

food components usually contain one or more amino acids, carbohydrates or fats and are for suitable for human and / or animal nutrition. They include Single components, common vegetable and also animal products, in particular sugar, if appropriate in the form of syrups, fruit preparations, such as fruit juices, nectar, Fruit pulps, purees or dried fruits, for example, apple juice, grapefruit juice, orange juice, applesauce, Tomato sauce, tomato juice, tomato puree; Cereal products, like Wheat flour, Rye flour, Oatmeal, Corn flour, Barley flour, Spelled flour, Corn syrup, as well as starches the said cereals; Dairy products, such as milk protein, whey, Yogurt, lecithin and lactose. Typical examples of food components are toddler food, breakfast preparations, especially in the form of cereals or bars, sports drinks, complete meals, especially in the Framework of fully balanced diets, which can be administered orally or enterally, dietetic preparations, such as Diet drinks, diet meals and diet bars.

To the essential nutrients counting especially vitamins, provitamins, minerals, trace elements, amino acids and fatty acids. As essential amino acids may be mentioned isoleucine, leucine, lysine, methionine, phenylalanine, Threonine, tryptophan and valine. These include semi-essential amino acids that be supplied for example in growth phases or deficiencies have to, such as glutamine, arginine, histidine, cysteine and tyrosine. As trace elements may be mentioned: essential trace elements and minerals whose Need for Man is proven and their deficiency manifestation of clinical symptoms leads: Iron, copper, zinc, chromium, selenium, calcium, magnesium, potassium, manganese, Cobalt, molybdenum, iodine, Silicon, fluorine. Likewise, elements whose function for humans not enough is secured: tin, nickel, vanadium, arsenic, lithium, lead, boron. As for humans essential fatty acids may be mentioned: linoleic acid and linolenic acid, ARA (arachidonic acid) and DHA (docosahexaenoic acid) for infants and possibly EPA (eicosapentaenoic acid) and DHA too for Adults. A comprehensive list of vitamins can be found in "reference values for the Nutrient Supply ", 1st Edition, Umschau Braus Verlag, Frankfurt am Main, 2000, edited by the Germans Organisation for; society for; party for Nutrition.

Examples suitable pharmaceutical formulations are solid dosage forms, such as powders, powders, granules, tablets, in particular film-coated tablets, Pastilles, sachets, cachets, dragees, capsules such as hard and soft gelatine capsules, Suppositories or vaginal drug forms, semi-solid dosage forms, such as ointments, creams, hydrogels, pastes or patches, as well as liquid dosage forms, like solutions, Emulsions, in particular oil-in-water emulsions, Suspensions, for example lotions, injection and infusion preparations, Eye and ear drops. Implanted delivery devices can also be used for Administration of active compounds according to the invention be used. Furthermore, can also liposomes or microspheres come into use. In any case, the active ingredients can each optionally combined with appropriate excipients and carriers.

Suitable excipients and carriers are, for example, substances such as fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents or antioxidants. Examples of the excipients and auxiliaries are gelatin, natural sugars such as cane sugar or lactose, lecithin, pectin, starch (for example maize starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talc, lycopodium , Silica, cellulose, cellulose derivatives (for example, cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols, for example, methyloxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate); Fatty acids and magnesium, calcium or aluminum salts of fatty acids having 12 to 22 carbon atoms, in particular the saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, Wheat germ oil, sunflower seed oil, cod liver oil, each also hydrogenated); Glycerol esters and polyglycerol esters of saturated fatty acids C ₁₂ H ₂₄ O ₂ to C ₁₈ H ₃₆ O ₂ and mixtures thereof, wherein the glycerol hydroxy groups are completely or even partially esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or polyhydric alcohols and Polyglycols such as polyethylene glycols (molecular weights eg between 300 and 1500) and derivatives thereof, polyethylene oxide, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, in particular 10 to 18 C atoms) with monohydric aliphatic alcohols (1 to 20 C atoms) Atoms) or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glycerol formal, tetrahydrofurfuryl alcohol, polyglycol ethers with C ₁ -C ₁₂ -alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonates, silicones (especially medium-viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other auxiliary so-called disintegrants come (substances which cause the disintegration of the tablet) in question, such as crosslinked polyvinylpyrrolidone (Kollidon CL ^®), sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used, such as polymers and copolymers of (meth) acrylic acid and / or esters thereof, copolymers of acrylic and methacrylic acid esters with a low content of ammonium groups (for example, Eudragit ^® RS), copolymers of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate ( for example, Eudragit ^® RL), polyvinyl acetate; Fats, oils, waxes, fatty alcohols, hydroxypropylmethylcellulose phthalate or acetate succinate; Cellulose acetate phthalate, starch acetate phthalate, and polyvinylacetate phthalate, carboxymethylcellulose, methylcellulose phthalate, methylcellulose succinate, phthalate succinate and methylcellulose phthalic acid half ester, zein, ethylcellulose and ethylcellulose succinate, shellac, gluten, ethylcarboxyethylcellulose, ethacrylate-maleic anhydride copolymer, maleic anhydride-vinylmethylether copolymer, styrene-maleic acid copolymers, 2-ethyl -hexyl acrylate maleic anhydride, crotonic acid vinyl acetate copolymer, glutamic acid / glutamic acid ester copolymer, carboxymethyl ethyl cellulose glycerol monoocianoate, cellulose acetate succinate, polyarginine. Further possible ingredients are plasticizers for coatings such as citric and tartaric acid esters (acetyltriethyl citrate, acetyltributyl, tributyl, triethyl citrate), glycerol and glycerol esters (glycerol diacetate, triacetate, acetylated monoglycerides, castor oil), phthalic acid esters (dibutyl, diamyl, diethyl, dimethyl, Dipropyl phthalate), di (2-methoxy or 2-ethoxyethyl) phthalate, ethyl phthalyl glycolate, butyl phthalyl ethyl glycolate and butyl glycolate, alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di- (2-methoxy or 2-ethoxyethyl) - adipate), benzophenone, diethyl and dibutyl sebacate, dibutyl succinate, dibutyl tartrate, diethylene glycol dipropionate, ethylene glycol diacetate, dibutyrate, dipropionate, tributyl phosphate, tributyrin, polyethylene glycol sorbitan monooleate (polysorbates such as polysorbate 80), sorbitan monooleate.

to Production of solutions or suspensions come, for example, water or physiologically compatible organic solvents in question, such as, for example, alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, Partial esters of glycerin) and oils (for Example peanut oil, Olive oil).

The Formulations are preferably administered by the oral route. she can but also especially in the field of drugs rectal, intraperitoneal, transdermal, intracutaneous, subcutaneous, intravenous, intraarterial, intracardiac, intramuscularly, be administered pulmonary, inhalational, lingual or intranasal.

Example 1: Reaction R-α lipoic acid with pyridoxamine

1 mol of R-α-lipoic acid dissolved in portions at room temperature in ethanol. 1 mol (dissolved in ethanol) pyridoxamine is stirring added. The batch is heated to 50 ° C heated and stirred for 30 minutes at this temperature. Then the solid becomes filtered under water jet vacuum and the filter cake with ethanol washed.

The clear filtrate is cooled under a nitrogen atmosphere until crystallization occurs. The crystals are filtered under aspirator vacuum and washed with ethanol. The crystalline solid is dried under exclusion of light in a stream of nitrogen.
Yield: 68% of theory
Melting point: 121-122 ° C Example 2 Pharmaceutical Agents and Nutritional Supplements a) Soft Gelatin Capsule with the Pyridoxamine Lipoate from Example 1 (100 mg Pyridoxamine Lipoate / Capsule) Pyridoxamine lipoate 100 mg D / L-alpha-Tocopherlacetat 30 mg Example 3: Functional Foods a) Bar With the Pyridoxamine Lipoate from Example 1 (50 mg Pyridoxamine Lipoate / Bar (60 g)) Pyridoxamine lipoate 50 mg D / L-alpha-tocopheryl acetate 30 mg Syrup made from fructose 4.2 g glucose 12 g Tanned sugar 3 g glycerin 3 g lecithin 125 mg Hardened vegetable oil 1.2 g Toasted oatmeal 17.975 g puffed rice 7 g Roasted and chopped almonds 5.6 g coconut flakes 4 g b) Muesli with the Pyridoxamine Lipoate from Example 1 (Pyridoxamine Lipoate 50 mg / 100 g Muesli) oatmeal 40 g wheat flakes 27 g raisins 13 g Dried apple slices 6 g Dried apricots 3 g wheat germ 3 g Roasted and ground hazelnuts 6 g Enriched milk powder containing 7 g Pyridoxamine lipoate 50 mg D / L-alpha-tocopheryl acetate 30 mg lecithin 200 mg c) Sports drink with the pyridoxamine lipoate from Example 1 (200 mg pyridoxamine lipoate / 1000 ml beverage) Pyridoxamine lipoate 200 mg sucrose 61 g Sodium citrate dihydrate 400 mg Citric acid monohydrate 2.5 g sodium chloride 80 mg Potassium phosphate (KH ₂ PO ₄ ) 350 mg Pectin, prehydrated (TIC 1694) 2 g ascorbic acid 200 mg water ad 1000 ml d) multivitamin mineral tablet with the pyridoxamine lipoate from Example 1 (3 mg pyridoxamine lipoate / tablet, 1225 mg) Pyridoxamine lipoate 3 mg LycoVit ^® 10% (contains 10 wt .-% of lycopene) 22 mg β-carotene 20% DC (contains 20% by weight β-carotene) 16.5 mg Riboflavin 100 1.9 mg Thiamine mononitrate 1.7 mg Pyridoxine hydrochloride 2.2 mg Copper (II) oxide 2.5 mg nicotinamide 22 mg Calcium D-pantothenate 12 mg Iron (II) fumarate 54.7 mg Manganese (II) sulphate monohydrate 6.9 mg potassium chloride 76.3 mg Ac-Di- ^Sol® (sodium carboxymethylcellulose) 32 mg Vitamin E 50% DC (contains 50% by weight of vitamin E) 66 mg Vitamin C 90% (contains 90% by weight of vitamin C) 80 mg Magnesium oxide SF 165.8 zinc oxide 18.7 mg Calcium hydrogen phosphate 550 mg Avicel ^® PH 101 (microcrystalline cellulose) 75 mg stearic acid 6 mg Syloid ^® 244 FP (silicon dioxide) 6 mg magnesium stearate 6 mg

Claims (17)

Use of a salt of the α-lipoic acid of the general formula I. (Lp) (A) I where Lp is racemic α-lipoic acid, racemic dihydro-α-lipoic acid, (R) - or (S) -α-lipoic acid, (R) - or (S) -dihydro-α-lipoic acid, or mixtures thereof, A is A Amine of the general formula II

in which R ¹ , R ² independently of one another represent hydrogen or C ₁ -C ₆ -alkyl, R ³ , R ⁴ independently of one another represent hydrogen, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -acyl, phosphate, Diphosphate or triphosphate, and m, n, o independently represent 0, 1, 2 or 3; or A is an amine of general formula III

stands in which R ^{5 is} hydrogen, C ₁ -C ₈ alkyl, phenyl or benzyl is for the treatment of diabetic disorders. Use according to claim 1, wherein the diabetic disorder is a type II diabetes Use according to claim 1, wherein the diabetic disorder is an insulin resistance. Use according to claim 1, wherein the diabetic disorder a hyperglycemia is. Use of a salt as defined in claim 1 for the treatment of micro- and / or macrovascular disorders diabetogenic genesis. Use according to claim 5, wherein the micro- and / or macrovascular disorder diabetogenic genesis is among a diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and atherosclerosis. Use according to claim 5, wherein the treatment micro- and / or macrovascular disorders diabetogenic genesis of the preventive Treatment of cataracts, blindness, kidney failure or amputations serves. Use of a salt as defined in claim 1 for the treatment of a metabolic syndrome. Use of a salt as defined in claim 1 for the treatment of overweight Individuals. Use of a salt as defined in claim 1 for the preparation of an agent for the treatment of cardiovascular disorders, neurodegenerative disorders or disturbances, associated with chronic renal failure and / or dialysis treatment; Retinopathies, nephropathies, proteinuria, hyperlipidemias, hypertriglyceridemias, hypercholesterolemias, proliferations smooth muscle cells of the arteries, collagen, arthritis, Fibromyalgia, kidney stones, inflammation, cancer, amyloidoses, Osteoporosis, HIV infections or AIDS; of oxidative stress or the associated disorders; or from aging processes. Use according to one of the preceding claims, wherein A for one Amine of the formula II is. Use according to claim 11, wherein R ¹ , R ^{2 are} hydrogen or methyl. Use according to claim 11, wherein n is equal to 1. Use according to claim 11, wherein either n or o is greater than 0 Use according to claim 11, wherein R ^{3 is} hydrogen. Use according to claim 11 wherein A is pyridoxamine is. Use according to one of the preceding claims, wherein A is aminoguanidine.