| Aromatic sulfonamides as peroxynitrite-rearrangement catalysts -> Monitor Keywords |
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Aromatic sulfonamides as peroxynitrite-rearrangement catalystsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Isoquinolines (including Hydrogenated)Aromatic sulfonamides as peroxynitrite-rearrangement catalysts description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050288324, Aromatic sulfonamides as peroxynitrite-rearrangement catalysts. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to sulfonamides as peroxynitrite-rearrangement catalysts, to the preparation thereof and to the use thereof for producing medicaments for treating various disorders. [0002] Peroxynitrite was already described by Beckman et al. (Beckman et al., 1990, Proc. Natl. Acad. Sci. USA. 87, 1620-1624) as a toxic metabolite resulting from the diffusion-controlled reaction between nitric oxide (NO) and superoxide anion (O.sub.2.sup.-). Peroxynitrite is involved in a number of inflammatory processes which play an important part in disorders such as, for example, Alzheimer's dementia, multiple sclerosis, amyotrophic lateral sclerosis, and are thought to be responsible for cell death and the induction of apoptosis. [0003] Peroxynitrite reacts with a large number of proteins by oxidizing or nitrating amino acid residues. Nitrotyrosine residues are found to be increased in the tissue of patients suffering from multiple sclerosis, because peroxynitrite causes nitration of the tyrosine residues of the filaments of the motor neurons. The contraction of the filaments which is impaired in this way results in neuronal dysfunction (Estvez et al., 1999, Science 286, 2498-2500). One reason for the impaired vasoconstriction after a stroke is the peroxynitrite-induced oxidation of the lipid residues in the cell membrane, leading to endothelial injuries and, resulting therefrom, the formation of edema and neutrophils. [0004] A pharmacological intervention in order to prevent the peroxynitrite-mediated effects is possible at either the reactant (NO, and O.sub.2.sup.-) or the product (peroxynitrite). [0005] One approach on the part of the product peroxynitrite was described first by Salvemini et al. (Salvemini et al., 1998, Proc. Natl. Acad. Sci. USA., 95, 2659-2663). [0006] In this approach, peroxynitrite is rearranged by means of a catalyst into harmless end products. It is possible with only low concentrations of catalyst to convert a large quantity of peroxynitrite. One advantage of this approach is that it cannot result in the formation of the disadvantageous decomposition products such as, for example, reactive oxygen species, and that the inhibition of superoxide dismutase (SOD) by peroxynitrite is abolished. Accordingly, the treatment method with novel compounds has a two-fold advantage in the treatment of disorders. Thus, on the one hand, the rate of conversion of peroxynitrite is increased up and, on the other hand, SOD is protected from inactivation by peroxynitrite. [0007] Possible transformation catalysts disclosed to date-are metal-containing complexes .(WO 95/31197, U.S. Pat. No. 6,245,758, WO 98/04132, U.S. Pat. No. 5,872,124, WO 00/75144, WO 01/26655, U.S. Pat. No. 6,372,727). The metalloporphyrins described by Salvemini et al. show a protective effect in models of inflammation (Salvemini et al., 1998, Proc. Natl. Acad. Sci. USA. 95, 2659-2663 and British J. Pharmacol., 1999, 127, 685-692). The same class of compounds were described as effective in a bowel artery occlusion model by Cuzzocrea et al. (Cuzzocrea et al., 2000, FASEB J. 14-(9), 1061-1072 and Cuzzocrea et al., 2001, Pharmacology Rev. 53, 135-159). Cross et al. demonstrated the efficacy of this substance in an MS model ("experimental autoimmune encephalomyelitis"=EAE) in mice (Cross et al., 2000, J. Neuroimmunology 107, 21-28). Mackensen et al. showed for the first time the efficacy of a manganese-containing porphyrin in a focal ischemia model, the focal MCAO (middle cerebral artery occlusion) (Mackensen et al., 2001, J: Neurosci. 21, 4582-4592). [0008] Little is known to date about the side effects such as toxicity, tolerability and in vivo availability, and the blood-brain barrier permeability of these known rearrangement catalysts. [0009] Sulfonamides and analogs are already widely used and well characterized, for example, as dyes (U.S. Pat. No. 5,591,833) for photochemistry (JP 2001092091, JP 2001033922, EP 610653, JP 04346338) and as radio- or chemo-sensitizers (JP 09263581). They are, however, also described as active ingredients such as, for example, factor Xa inhibitors (US 6187797, WO 99/32454, WO 98/57937, WO 98/57951, WO 98/28269, WO 97/38984, WO 97/23212), as modulators for the treatment of obesity and related disorders (WO 01/62737, WO 99/10320). Arylsulfonamides are described as CNS-active substances which achieve their effect through binding to the 5HT.sub.6 receptor (WO 98/27081). Substituted imidazoles show cytokine-inhibitory activity (U.S. Pat. No. 5,859,041) and WO 97/36580 describes substituted sulfonamides as protease inhibitors. Phenyl derivatives of sulfonamides are described in U.S. Pat. No. 6,083,987 as radical scavengers for the treatment and prevention of cerebral infarctions and cerebral edemas. [0010] There is thus a great need for well tolerated, chemically stable and in vivo available substances (catalysts), in order in this way to increase the rearrangement of peroxynitrite into- harmless products, for the treatment and prophylaxis of disorders caused by peroxynitrite-mediated reactions. These substances having in vivo activity can be used to develop medicaments for the treatment of disorders. [0011] It has now been found that compounds of the general formula I 2 [0012] in which [0013] R.sup.1 is a C.sub.5-C.sub.6-cycloalkyl which may optionally be substituted one or more times by C.sub.1-C.sub.6-alkyl and whose ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or may contain one or more possible double bonds in the ring, or is a C.sub.3-C.sub.7-aryl or C.sub.3-C.sub.12-heteroaryl, which may optionally be substituted one or more times, identically or differently, by halogen, hydroxyl, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy, [0014] R.sup.2 and R.sup.3 are each, independently of one another, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy, or [0015] R.sub.2 and R.sup.3 together with the nitrogen atom form a C.sub.5-C.sub.6-cycloalkyl ring which may optionally be interrupted by a further nitrogen atom in the ring, where the C.sub.5-C.sub.6-cycloalkyl ring may optionally be substituted by C.sub.1-C.sub.4-alkyl, and R.sup.4 is hydrogen, hydroxyl, nitro, halogen, C.sub.1-C.sub.6-alkyl or the group COOH, CF.sub.3 or C.sub.1-C.sub.6-alkoxy, [0016] and the isomers, diastereomers, enantiomers and salts thereof, overcome the known disadvantages, i.e. that the compounds of the invention having peroxynitrite-rearranging properties make targeted treatment possible for disorders caused by peroxynitrite. [0017] Alkyl means in each case a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl. [0018] Alkoxy means in each case a straight-chain or branched alkoxy radical such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy or hexyloxy. [0019] Cycloalkyl means in each case cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. [0020] Ring systems in which one or more possible double bonds may optionally be present in the ring mean, for example, cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, where the linkage may take place either at the double bond or at the single bonds. [0021] The aryl radical has in each case 6-12 carbon atoms, such as, for example, naphthyl, biphenylyl and, in particular, phenyl. [0022] The heteroaryl radical comprises in each case 3-16 ring atoms and may contain in place of carbon one or more, identical or different, heteroatoms such as oxygen, nitrogen or sulfur in the ring, and may be mono-, bi- or tricyclic, and may in addition in each case be benzo-fused. [0023] Examples which may be mentioned are: [0024] Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as, for example, quinolyl, isoquinolyl, etc.; or Continue reading about Aromatic sulfonamides as peroxynitrite-rearrangement catalysts... 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