Chemical compounds containing tocopherol

[0001] The invention relates to chemical compounds that contain tocopherol as well as at least one other pharmaceutical active ingredient, process for the production of these chemical compounds as well as their use as pharmaceutical agents or prodrugs.

[0002] When using these chemical compounds as pharmaceutical agents or prodrugs, tocopherol exerts the action of an antioxidant; conversely, the other pharmaceutical active ingredient is preferably a non-steroidal anti-inflammatory agent (NSAID), which is linked directly to tocopherol or via a spacer. This "chemically-attached combination of two pharmaceutical active ingredients" results in more effective as well as more compatible derivatives. In the organism of the patient, the pharmaceutical active ingredient and tocopherol are released from the compounds claimed here by metabolic processes, such as the enzymatically catalyzed ester hydrolysis, and said active ingredient and tocopherol can then exert their known actions. The increase in effectiveness is produced from the optimization of the physicochemical parameters and the improved resorption produced therefrom and the uptake of the active ingredients by the central nervous system (CNS). The improved compatibility is primarily to be attributed to the reduction of possible, locally toxic effects, such as, for example, the reduction of locally-induced toxic effects of the NSAID components in the gastrointestinal tract by masking the carboxylic acid function, as well as the reduction of the active ingredient concentration in the periphery by increased uptake of compounds in the CNS.

[0003] In addition, the invention relates to a process for the production of the above-mentioned chemical compounds as well as their use as pharmaceutical substances or prodrugs for treatment or prophylaxis of degenerative diseases of the central nervous system, such as Alzheimer's disease, Lewy Body dementia, Parkinson's disease, Huntington's disease (chorea), multisystem atrophy and other similar diseases, such as also in the case of diseases caused by TNF (tumor necrosis factor)-alpha, IL (interleukin)-1 beta, IL (interleukin)-6 and/or IL (interleukin)-8 or other infirmities such as pain, diabetes, etc. Also and in particular, the use of the chemical compounds according to the invention in the production of pharmaceutical agents for the treatment of diseases that are influenced by radical stress, such as in diseases of the respiratory system, such as lung inflammation, of the digestive system, of the vascular system, such as leukemia, hemoglobinopathy, of the connective tissue, such as rheumatism, of the eyes, such as in cataracts, are subjects of the invention. The chemical compounds according to the invention are suitable expressly for the production of pharmaceutical agents for the treatment and prophylaxis of diseases in which inflammations and/or oxidative stress occur. The invention therefore comprises the production and the use of these chemical compounds in the case of all conditions covered here by introductory clauses and mentioned below.

[0004] Below, the medical background of the invention is explained in more detail.

[0005] In several respects, inflammatory processes play an essential role in the above-mentioned neurodegenerative diseases. In earlier works, it was postulated that inflammatory processes only occur in the brain in the case of damage to the blood-brain barriers. Later, however, it was proven that the brain can be put into operation and maintain inherent inflammatory processes.

[0006] It is now known that inflammation processes are involved very decisively at the beginning of the disease and as the disease progresses especially in the case of Alzheimer's disease. This is confirmed by a number of epidemiological studies (McGeer, 1992, Akiyama 2000). The thesis that NSAIDs have a positive effect on the course of Alzheimer's disease is also supported in that in the cortex of Alzheimer patients and older control patients, who had both neurofibrillar tangles (NFTs) and .beta.-amyloid plaque, the estimated number of synapses, determined based on immunohistochemical data or loss of synapses, correlates much more strongly with inflammation markers than with the presence of NFTs and B-amyloid deposits (Rogers et al. 1995).

[0007] Even in the case of Alzheimer's disease, inflammation reactions are sometimes a sequela of the damage that sometimes already exists. Nevertheless, the brain in the case of Alzheimer's disease, as in several inflammatory diseases, such as asthma, arthritis, . . . in other body regions offers a number of possibilities for inflammations to develop whereby said inflammations can then cause greater damage than the original pathological changes. In many cases, it is assumed that .beta.-amyloid plaques, however, are not necessarily sufficient for triggering and for advancing Alzheimer's disease. In this connection, inflammation reactions are a highly probable complementary factor that is also necessary for the clinical picture to develop (Rogers et al. 1995). It is advantageous that the toxicity of .beta.-amyloid after the activation of complement proteins occurring in the brine increases by up to 1000.times. (Shalit et al. 1994). Aggregated .beta.-amyloid is significantly more toxic than--more readily soluble--non-aggregated .beta.-amyloid. It was possible to demonstrate in vitro that the complement protein Clq enhances the aggregation of p-amyloid (Webster et al. 1994). This seems especially important if it is considered that aggregated .beta.-amyloid activates Clq (Jiang et al. 1994). Also, tau pathology, which plays an essential role in neurodegeneration in addition to .beta.-amyloid, is closely associated with inflammatory processes and the activation of the complement system (Shen et al. 2001).

[0008] In the case of inflammatory processes, pro-inflammatory cytokines, such as interleukin 1, tumor-necrosis-factor alpha of various cell types, are released as a response to corresponding stimuli (in which, for example, lipopolysaccharide as well as various forms of cell stress are included). In addition to the above-mentioned neurodegenerative processes, an elevated release of the above-mentioned cytokines is associated with various diseases, such as, for example, rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute or chronic myelogenic leukemia, loss of Beta cells, also as accompanying manifestations of insulin-dependent Type I diabetes, osteoarthritis, rheumatoid spondylitis, uratic arthritis, inflammatory intestinal diseases, respiratory distress syndrome of adults, psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, Type I and Type II diabetes, rejection reactions, reperfusion damage after ischemia, arteriosclerosis, cerebral trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, infection-induced fever and myalgia as well as infections with various viruses (HIV 1, HIV 2, HIV 3, CMV, influenza viruses, adeno viruses and herpes viruses. The invention therefore also relates to the use of chemical compounds according to the invention for the production of pharmaceutical agents for treating the above-mentioned diseases.

[0009] In neurodegenerative diseases, oxidative stress represents an especially important factor both in the initial stage and later (Butterfield et al. 2002). A number of anatomical, physiological and biochemical properties suggest that especially the central nervous system is at risk with respect to the damage caused by radicals: the brain consumes an especially large amount of oxygen in comparison to the other body regions. Expressed in numbers, this means a proportion of 20% of the total O.sub.2 requirement at only 2% as a proportion of body weight. The result is an especially large potential for radicals to develop. In this connection, it was demonstrated that several cellular components are altered by oxidative stress: Proteins (Markesbery and Carney 1999), lipids (Sayre et al. 1997, Montine et al. 1998, McKracken et al. 2001), nuclear as well as mitochondrial DNA (Mecocci et al. 1994, Gabbita et al. 1998) and RNA (Nunomura et al. 1999) are--as repeatedly confirmed by literature--affected. Regarding preventive measures, the reduction of oxidative stress to reduce the risk of stroke is very useful (Chen and Zhou 2001, Mattson et al. 2001). Also, however, radical oxygen compounds (ROS) are produced during and directly after ischemia and have a harmful effect on the survival of nerve cells. The cell-biological changes that result therefrom in most cases last longer that the excitoxicity itself. In the course of lipid peroxidation that occurs in the hypoxia, toxic reaction products are produced, such as aldehyde 4-hydroxynonenal (McKracken et al. 2001), which creates both necrotic and apoptotic cell death. Also, it is highly probable that other factors that occur in the acute phase can be positively influenced to a decisive extent by substances that have an antioxidative action (El Kossi and Zakhary, M. M., 2001). Oxidative stress thus plays a significant role in the case of damage caused by stroke both in the first hours and even days later with long-lived reaction products.

[0010] By measurements of the 8-hydroxyguanosine (8OHG) content, it was possible to confirm that elevated oxidative stress is a very early feature of Alzheimer's disease (Nunomura et al. 2001). The development of the main components of the two most recognized theories for Alzheimer's disease, both the .beta.-amyloid pathology and the tau-pathology, are, as confirmed by several bibliographic references, obviously narrow in connection with oxidative stress (Pappolla, M. A. et al. 2002). Especially in the early phases of Alzheimer's disease--even before the development of extracellular .beta.-amyloid deposits--it results in the intracellular concentration of .beta.-amyloid (Gouras et al. 2000). Since the oxidative stress is also especially pronounced during this early stage of the disease, a connection, for example, via metal ions that are bonded to .beta.-amyloid (Nunomura et al. 2001) or neurofibrillar tangles (Sayre et al. 2000) and that can then form hydrogen peroxide directly, is very probable. The malfunction of mitochondria is another explanation that can be readily documented for the radical stress that occurs so early in an enhanced form (Hirai et al. 2001).

[0011] .alpha.-Synuclein, the protein that is also strongly prone to aggregation, which is the focal point of the pathology of Parkinson's disease, also results in the intensification of oxidative stress. In vivo studies and in vitro studies, even sometimes not directly associated with .alpha.-synuclein, confirm that oxidative stress is an early and very marked, detectable parameter in the development of Parkinson's disease (Migliore et al. 2002, Munch et al., 2000, Roghani and Behzadi 2001).

[0012] In addition to the above-mentioned diseases in the area of neurodegeneration, oxidative stress can result in arrythmias, myocardial infarction, arteriosclerosis, inflammation of the lungs, cerebral edemas, hemorrhagic and non-hemorrhagic infarctions, such as stroke, diseases of the gastric mucous membrane, the pancreas, cirrhoses, leukemia, hemoglobinopathy, sepsis, various forms of diabetes, stress reactions, diseases of the excretion system, such as inflammation of the kidneys, renal insufficiency, diseases of the supporting apparatus, such as rheumatism, the sense organs, such as cataracts, or make a significant contribution to the development of disease or else influence the course of the convalescence.

[0013] The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a quite pronounced gastrotoxicity. In the case of longer-lasting treatments, it results relatively often in irritations of the gastric mucous membrane, in gastric bleeding as well in the formation of ulcers. NSAIDs are the second most common cause of gastric and duodenal ulcers. The bleeding that occurs can be life-threatening. This fact represents a significant problem, since in the case of neurodegenerative diseases, almost only longer-term treatments appear useful.

[0014] NSAIDs, such as ibuprofen, occupy prominent positions in statistics in pharmaceutical agent side effects. In a report in the New England Journal of Medicine on the side effects of NSAIDs, 16000 people die from necrosis every year in the U.S.A. (Wolfe et al. 1999).

[0015] As can be confirmed by literature, the toxicity of several ibuprofen derivatives is significantly less compared to ibuprofen (Lolli et al. 2001).

[0016] As mentioned above, the use of NSAIDs is an eminently advantageous and realistic possibility for treating degenerative diseases of the central nervous system. Substances that have an antioxidative effect, such as Vitamin E and others, also represent a promising approach, as already mentioned. Nevertheless, the effectiveness of the two treatment strategies is thus limited in that these active substances, in particular the NSAID, can overcome the blood-brain barriers and can get into the CNS only to a very limited extent.

[0017] A strategy for improving the passage of the blood-brain barrier is the formation of prodrugs, i.e., compounds that themselves have only a little or no biological activity. Only by metabolic processes are the actual active ingredients released, and they can then exert their action (Albert, 1958). The claimed compounds represent so-called "Carrier-Mutual Prodrugs," i.e., NSAID and tocopherol can be regarded in each case as carriers of the other components according to the invention. To be able to vary the properties of the compounds to a greater extent, derivatives also according to the invention were represented supplementing the two-component prodrugs with a spacer between the active ingredient groups and thus a three-component prodrug. Not only resorption and CNS accessibility, but also the extent and speed of hydrolysis can be modified by the spacer.

[0018] Chemical compounds of general structure I as racemates, enantiomers as well as diastereomers as well as in the form of their physiologically harmless salts and solvates, especially hydrates as well as addition compounds with alcohols, are subjects of the invention. These compounds are distinguished in that a pharmaceutical active ingredient "R-A" as well as tocopherol "Toc" therein optionally are linked to one another via one one or more spacers B according to formula via an oxygen atom.

[0019] Radical R refers to the unchanged portion of the variable pharmaceutical active ingredient molecule. The structure R-A-OH (if the partial structure `A` can be shown as C.dbd.X or SO.sub.m) or R-AH (for A=X) can thus be attributed to the pharmaceutical active ingredient that is used.

[0020] R symbolizes in particular the acyl radicals of NSAID, such as acetylsalicylic acid, diclofenic acid, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen as well as derivatives thereof, especially reduction products of indomethacin, whereby the CON partial structure is replaced formally by --CH.sub.2N, as well as ketoprofen, whereby the keto-carbonyl group is replaced formally by --CH(OH)-- or by --CH.sub.2--.

[0021] The abbreviation Toc refers to a tocopheryl radical, in which R', R'' and R''' mean H or methyl. As can be seen from the following formula, three asymmetrical C atoms are present here, consequently there are eight diastereomeric forms. All diastereomers as well as mixtures thereof according to the invention are to be claimed.

[0022] The invention comprises the chemical compounds of general formula I with respect to all possible racemates, enantiomers as well as diastereomers. If an acidic or basic partial structure is present in the compounds of formula I (e.g., derivatives of mefenamic acid or diclofenic acid), their physiologically harmless salts are also subjects of this invention. In addition, the invention also comprises solvates, especially hydrates and alcohol addition compounds, compounds I as well as their physiologically harmless salts.

[0023] For all radicals that can occur in several places, such as substituent `X,` it holds true that their meanings are independent of one another:

[0024] A stands for C.dbd.X, SO.sub.m, X or CH.sub.2, whereby