MX2008010243A

MX2008010243A - Mandelic hydrazides

Info

Publication number: MX2008010243A
Application number: MXMX/A/2008/010243A
Authority: MX
Inventors: Gericke Rolf; Mederski Werner; Beier Norbert; Lang Florian; Klein Markus
Original assignee: Merck Patent Gmbh
Priority date: 2006-02-14
Filing date: 2008-08-08
Publication date: 2008-10-03

Abstract

New mandelic hydrazides of the formula (I) in which R1- R11are as defined in claim (1) are SGK inhibitors and can be used to treat SGK-associated illnesses and afflictions such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertension, cardiovascular diseases and renal diseases, generally in connection with any kind of fibroses and inflammatory processes.

Description

HIDRAZIDAS DE ACIDO MANDELICO FIELD OF THE INVENTION It was the object of the invention to find new compounds with valuable properties, especially those that can be used to prepare medicines. The present invention relates to compounds - in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular of the cellular volume regulating h-sgk human kinase (human serum and glucoerto- coid dependent kinase or SGK) play an important role, in addition to pharmaceutical compositions containing these compounds, as well as to the use of the compounds for the treatment of diseases caused by SGK. SGK with the isoforms SGK-1, SGK-2 and SGK-3 are a family of serine / threonine protein kinase (WO 2/17893). The compounds according to the invention are preferably selective inhibitors of SGK-1. In addition, they can be inhibitors of SGK-2 and / or SGK-3. In particular, the present invention relates to compounds that inhibit, regulate and / or modulate signal transduction of SGK, to compositions containing these compounds, as well as to processes for their preparation for the treatment of diseases and disorders originated by the eff .: 194483 SGK, such as diabetes (eg, diabetes mellitus, diabetic nephropath, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, cardiocirculatory diseases (eg, cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriesclerosis) and kidney diseases (eg, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, of electrolytic excretion), in general in all types of fibrosis and inflammatory processes eg, liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and osteoarthritis, Crohn's morbus, chronic bronchitis, irradiation fibrosis, scleroderma, chemical fibrosis, scarring, Alzheimer's disease). The compounds according to the invention can also inhibit the growth of tumor cells and tumor metastases and, therefore, are suitable for tumor therapy. The compounds according to the invention are also used in the treatment of peptic ulcer, especially in the case of triggered forms < by stress. The compounds according to the invention are also used for the treatment of coagulopathies such as, for example, dysfibrinogenemia, hypoproconvertinemia, hemophilia B, Stuart-Prowe defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, incoagulopathy or coagulopathies. complex, as well as in case of neuronal irritability, for example epilepsy. The compounds according to the invention can also be used therapeutically in the treatment of glaucoma or cataract. The compounds according to the invention are also used in the treatment of bacterial infections, as well as in an anti-infective therapy. The compounds according to the invention can also be used therapeutically to increase the capacity for learning and attention. Beyond this, the compounds according to the invention counteract cellular aging and stress, thus raising the life expectancy and good health in old age. The compounds according to the invention are also used in the treatment of tinnitus. Therefore, it is desired to identify small compounds that specifically inhibit, regulate and / or modulate signal transduction of the SGK, which is an object of the present invention. It was found that the compounds according to the invention and their salts possess very valuable pharmacological properties, with good tolerance. In particular, they show inhibitory properties of SGK. Therefore, the compounds according to the invention as medicaments and / or medicated active principles in the treatment and / or prevention are the object of the present invention. from the aforementioned diseases and the use of the compounds according to the invention for the preparation of a pharmaceutical product for the treatment and / or prevention of the above-mentioned diseases, as well as a method for the treatment of the aforementioned diseases, comprising the administration of one or several compounds according to the invention to a patient that requires such an administration. The host or the patient can be of any mammalian species, eg, primates, particularly humans; rodents, including mice, rats and hamsters; rabbits equines, bovines, canines, felines; etc. Animal models are of interest for experimental investigations, which provide a model for the treatment of a human disease. The identification of a signal transduction pathway and the detection of crossings with other suitable signal pathways allowed several scientists to generate suitable models or model systems, for example cell culture models (eg Khwaja et al., EMBO, 1997, 16, 27S3 -93) and models of transgenic animals < for example, White et al., Oncogene, 2001, 20, 7064-7? 72). For the analysis of particular steps in the signal transduction cascade, interfering compounds can be used for the modulation of the signal (for example, Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be useful as reagents for the analysis of kinase-dependent s-ene transduction pathways in animal-s and / or cell culture models or any of the clinical disorders listed in -this application. The measurement of kinase activity is a feasible technique well known to any person skilled in the art. Generic test systems for the detection of kinase activity with substrates, for example histone (eg, Alessi et al., FEBS Lett. 1996, 399, 3, page 333 -338) or myelin basic protein are well described in the literature (for example, Campos-Gonzalez,., and | Glenney, Jr., JR 1992 J. Biol. Chem. 267, page 14535). For the identification of kinase inhibitors, there are several test systems. For example, in scintillation proximity tests. { for example, Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19) or flash plate assays, the radioactive phosphorylation of a protein or a peptide can be measured as a substrate with ????. In the presence of an inhibitor compound no signal is detected or a decreased radioactive signal is detected. In addition, energy transfer technologies - resonance by homogeneous time-resolved fluorescence (HTR-FRET), and polarization by - fluorescence (FP) for test methods - are useful (Sills et al., J. of Biomolecular Screening, 2002, 191-214). Other test methods based on non-radioactive ELISA use specific phospho-antibodies (AB). The phospho-AB only binds to the phosphorylated substrate. This binding is detected by an anti-i-ove antibody to secondary conjugated to peroxidase, as measured for example by chemiluminescence (for example Ross et al., Biochem J, 2002, 366, 977-981). BACKGROUND OF THE INVENTION In WO 00/62781 the use of drugs containing substances inhibiting the human kinase regulating cell volume H-SGK is described. Acylhydrazones are described as SGK inhibitors - in WD 2005037773. Other hydrazides of acylmandelic acid are described as fungicides in WD 96/17840 and by P. Legrel in etraheáron 1988, 44, 4805-4814. Benzylidene benzohydrazides with antibacterial action are described in WD 02/070464 A2. The use of acylhydrazides for the treatment of bacterial infections is disclosed in WD 01/70213. Other derivatives of acylhydrazone, for example, for the treatment of diabetic complications, are disclosed in JP 11-106371. The aromatic derivatives of acylhydrazone -substituted with methoxy for the treatment of cancer are described by T. Kametani et al. in Yakugaku Zasshi (1963), 83, 851-855 and in Yakugaku Zasshi (1963), 83, 844-847. Other aromatic derivatives of acylhydrazone as sedative enhancers and to decrease hypertension are disclosed in the JP document 41-20699. The use of inhibitors ie kinase in anti-infective therapy is described by C. Doerig in Cell. Mol. Biol. Lett. Vol.8, N.s 2A, 2003, 524-525. The use of kinase inhibitors in case of obesity is described by N. Perrotti in J. Biol. Chem., March 23, 2001; 276 (12): 9406-9412. In the following bibliographic data it is assumed and / or "describes the use of SGK inhibitors in the treatment -of diseases: 1: Chung EJ, Sung VK, Farooq M, Kim Y, Im S, Tak WY, Hang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expréssion profile analysis in human hepatocellular carcinoma by cDA microarray. Mol Cells. 2002; 14: 382-7. 2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 < SGK-1). J Biol Chem. 2002; 277: 43064-70. 3: Fillon S, Klingel K, Warntges S, Sauter M, • Gabrysch S, Pestel S, Tanneur V, Waldegger ¾, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf R, Lang F. Expression of the serine / threonine kinase hSGKl in < Hronic viral hepatitis. Cell Physiol Biochem. 2002; 12: 47-54. 4: Brunet A, ark J, Tran H, -Hu hS, Hemmings BA, Greenberg ME. Protein kinase 'SGK mediates survival by phosphorilating the fiorkhead transcription factor FKHRL 1 (F0XO3a). Mol Cell Biol 2001; 21: 952 ^ 65. 5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine / threonine survival kinase gene, sgk-1. J Biol Ghem. 2001; 276: 16649-54. 6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon 1, Honkanen RE. 'Ser / Thr protein phosphatase type 5 < PP5) is a negative regulator of glucocorticoid receptor-mediated growth arr-est. Biochemistry 1999; 38: 8849-57. 7: Suse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell < ycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucc > cortix) id-inducible protein kinase, Sgk, in ma mary umor cells. A novel convergence -point of anti-proliferative and proliferative cell signalling pathvays. J Biol. Chem. 1999; 274: 7253-63. 8: M. Hertweck, C. Gobel, R. Baumeister: C. ^ legans SGK-1 is the critical component of the Akt / PKS Kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577-588, April 2004. DETAILED DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula I wherein R1, R2 are in each case, independently -among H, CHO or acetyl, R3 & 4, j- | S i} 6 7 R8, R9, R10, R11 are in each case, independently between YES, H, A, OS02A, Hal, ?? 2, OR12, N < R12) 2 (CN, 0-GOA, - [: {R12) 2] nCOOR12, 0- [C (R12) 2] or C00R12, SO3H, - [C (R12) 2] nAr, -CO-Ar, 0- [€ (R12) 2] nA, -. { C < R12) 2] nHet, - [C (R12) 2] nC = CH, 0- [C (R12) 2] riC = CH, -tC (R12) 2] nCON (R12) 2, - [C (R12) 2] nG0NR1N (R12) 2, O- [C < R12) 2] nC N (R12) 2, 0- [C < R12) 2] oGONR12N (R12) 2, NR12COA, NR1C0N (R12) 2, NR12S02A, N ^ S02A) 2, COR12, S < 0) mAr, S02NR12 or S (0) mA, R3 and R4 are also together CH = CH-CH = CH, R3 and R4, R7 and R8 or R8 and R9 are also together alkylene - with 3, 4 or 5 carbon atoms -C, -wherein one or two CH2 groups can be replaced by oxygen, A is unbranched or branched alkyl with 1-6 C atoms, wherein 1-7 H atoms can be replaced by F, or cyclic alkyl with 3-7 C atoms, Ar is phenyl, naphthyl or biphenyl unsubstituted or mono-, di- or trisubstituted with Hal, A, OR12, • N- (R12) 2, N02, CN, phenyl, C0N (R12) 2 , NR12COA, NR12CON < R12) 2, NR12S02A, COR12, S02N. { R12) 2, 'S < 0) mA, - [C (R12) 2] n-COOR12 and / or -O [C (R12) 2] or ~ COOR 12 Het is a saturated, unsaturated or aromatic mono- or bicyclic heterocycle with 1 to 4 N, 0 and / or S atoms, which may be mono-, di- or trisubstituted with Hal, A, OR12, N (R12) 2, N02, CN, COOR12, CON (R12) 2, NR12COA, NR12S02A, COR12, S02NR12, S (0) mA, = S, = NR12 and / u =? (carbonyl oxygen), R12 is H or A, Hal is F, Cl, Br or I, m is 0, 1 or 2, n is 0, 1, 2 or 3, or is 1, 2 or 3, as well as its derivatives, salt, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. The subject of the invention are the compounds of the formula I and their salts, as well as a process for preparing compounds of the formula I according to claims 1-16, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, characterized in that a) a compound of the formula II is reacted where R1, R7, R8, R9, R10 and R11 have the meanings according to claim 1, with a compound of the formula III wherein L is Cl, Br, I or a free OH group or functionally reactive and R2, R3, R4, R5 and R6 have the meanings according to claim 1, or b) a compound of the formula is reacted IV wherein R2, R3, R4, R5 and R6 have the meanings according to claim 1, with a compound of the formula V wherein L is Cl, Br, I or a free OH group or functionally reactive and R1, R7, R8, R9, R10 and R11 have the meanings according to claim 1, or c) in a compound of the formula I converts a radical R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11 into another radical R1, R2, R3, R, R5, R6, R7, R8, R9, R10 and / or R11, by separating an ether by hydrolysis or hydrogenolysis, and / or converting a base or acid of the formula I into one of its salts. Also the subject of the invention are stereoisomers (E, Z isomers), as well as the hydrates and solvates of these compounds. Solvates of the compounds are adductions of solvent molecules inert to the compounds that are formed by their force or mutual attraction. Solvates are, for example, monohydrates or dihydrates or alcoholates.

Derivatives of pharmaceutical use are understood, for example, as salts of the compounds according to the invention, as well as the so-called pharmacological compounds. By "pharmacological derivatives" is meant the compounds of the formula I which have been modified, for example, with alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body to form the active compounds according to the invention. Also included here are the biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995). The term "effective amount" means the amount of a pharmaceutical drug or active ingredient that elicits a biological or medical response in a tissue, system, animal or human being sought or intended, for example, by a researcher or a doctor. Beyond this, the term "therapeutically effective amount" is an amount that, in comparison with a subject - who did not receive this amount, has the following consequences: better treatment of healing, cure, prevention or elimination of a disease, a symptomatology, a pathological state, a disease, a disorder or collateral effects or also a decrease in the progress of a disease, a medical condition or a disorder. The name "therapeutically effective amount" also comprises the amounts that are effective in elevating normal physiological function. The invention also relates to mixtures of compounds of formula I according to the invention, for example mixtures of two diastereoisomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1. : 5, 1:10, 1: 100 or 1: 1000. In this case, mixtures of stereoisomeric compounds are particularly preferred, in particular these compounds according to the invention are present as racemates. For all the radicals that appear several times, it is worth that their meanings are independent of each other. Previously and subsequently, the radicals or parameters R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the meanings indicated in formula I, except that nothing else is expressly indicated. A is alkyl, is unbranched (linear) or branched and has 1, 2, 3, 4, 5 or 6 C atoms. A is preferably methyl, also ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or ter. -butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-and -propyl, hexyl, 1-, 2-, 3- or 4- methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3, 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl-propyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-tri- Methylpropyl, is also preferred, eg, trifluoromethyl. A means, with very special preference, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1-trifluoroethyl. Ac is acetyl, Bn is benzyl, Ms is -SO2CH3. R1 is preferably H, CHO or acetyl, especially preferably H. R2 is preferably H. R3, R4, R5, R6, R7, R8, R9, R10, R11 are preferably in each case, independently of each other, H , A, Hal, OR12 or • 0-. { C < R12) 2] nAr. R3 is with special preference H, A or Hal. R6 is with special preference OH. R8 is with special preference OH, A, phenoxy or Hal. R4, R5, R7, R9, R10, R11 are preferably H or A. R7, R10, R11 are also with special preference, in each case - independently of each other, H or Hal. R12 is with special preference H. Ar is, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, or-, m- or pi-sopropilphenyl, o-, m- or p-ter. -butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylamino-carbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p-. { N, N-dimethylamino) -phenyl, o-, m- or p-. { N, N-dimethylaminocarbonyl) -f-enyl, o-, m- or p- < N-ethyl-amino) -phenyl, o-, m- or p- < N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-oloro-phenyl, o-, m- or p- < methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, o-, m- or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl, or -, m- or p-acetylphenyl, o-, m- or? -aminosulfonyl phenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethyl-phenyl, o-, m- or p-carboxymethoxy -phenyl, also-2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2 are preferred; 5-, 2,6-, 3,4- or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2, 5-dinitrophenyl, 2,5- or 3,4-dimethoxy-phenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-oloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chloro-phenyl, 2-nitro-4-N, N-dimethylamino- or 3-nitro-4-N , N-di-methyl-aminophenyl, 2, 3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3, 4, 5-trichlorophenyl , 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-b ornofeni1o, 3-brorno- -methoxyphenyl, 3-c paroro-6-methoxy phenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6- methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl. Ar is preferably, for example, unsubstituted or mono-, di- or trisubstituted phenyl with Hal, A, OR10, S02A, COOR10 or CN, with very special preference unsubstituted or mono-, di- or trisubstituted phenyl with Hal and / or A, especially Ar is phenyl.

Het is, without taking into account other substitutions, eg, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5- imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1, 2, 3-triazole-1, -4- or -5-yl are also preferred , 1, 2, 4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazol-4- or -5-yl, 1, 2, 4- oxadiazol-3-o-y-yl, 1, 3, 4-thiadiazol-2-y-5-yl, 1, 2,4-thiadiazol-3- o -5-yl, 1,2,3-thiadiazol- 4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-i-soindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl , 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2, 1, 3 -oxadiazolyl, 2-, 3-, 4-, 5-, -6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5- , 6-, 7- or 8-cinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6- 1. 8 , 7- or 8-2H-benzo [1,4] oxazinyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,3-benzothia-diazole-4 are also preferred - or -5-yl or 2, 1, 3-benzoxadiazol-5-yl. The heterocyclic radicals can also be partially or totally hydrogenated. Het can also be, for example, 2, 3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5- furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydrc-2- or -3-thienyl, 2,3-dihydro-l-, -2-, -3-, - 4- ? -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrr-oli-dinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, , 4-dihydro-l-, -2-, -3- or -4-pyridyl-o, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 - or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8- quinolyl, 1, 2,3,4-tetrahydro-1 -, -2-, -3-, -4-, -5-, -6-, -7- or -8-iso-guinolyl, 2-, 3 -, 5-, 6-, 7- or 8-3, 4-dihydro-2H-benzo [1,4] oxazinyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3- -oxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihi < i-robenzofuran-5- or -6- ilo, 2, 3 - (2-oxo-methylenedioxy) -phenyl or also 3,4-di-hydro-2H-1, 5-benzodioxepin-6- or -7-yl, in addition 2,3-dihydrobenzofuranyl are preferred or 2, 3-dihydro-2-oxo-furanyl. Het is preferably a saturated, unsaturated or aromatic monocyclic heterocycle with 1 to 2 N and / or O atoms, which may be unsubstituted or which may be mono-, di- or trisubstituted with A, Hal, OH and / or OA. Het is preferably a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be unsubstituted or which may be mono- or di-substituted with A. In another embodiment, Het is preferably very special pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl. In another embodiment, Het is especially preferably furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or unsubstituted or mono-, di- or trisubstituted piperazinyl with A , Hal, OH and / or OA. The compounds of the formula I can have one or more centers of -quirality and, therefore, can occur in several stereoisomeric forms. Formula I comprises all these forms. Accordingly, the invention relates in particular to compounds of the formula I, in which at least one of the radicals mentioned has one of the meanings preferred previously indicated. Some preferred groups of compounds can be expressed by the following sub-formulas la a lo, < Which correspond to the formula I and wherein the radicals not designated in greater detail have the meaning indicated in formula I, but where: in R1 is H or GHO, R2 is H; in Ib R3, R, R5, R6, R7, R8, R9, R10, R11 are in each case, independently of each other, H, A, Hal, -0R12 or 0-. { C (R12) 2] nAr; in him R6 is £ > H; in Id R3 is H, A or Hal; in R8 is -OH, A, phenoxy or Hal; in If R4, R5 R7, R9, R10, R11 is H or A; in ig R7, R10, R11 are in each case, independently of each other, H or Hal; in Ih Ar is unsubstituted or mono-, di- or trisubstituted phenyl with Hal and / or A; in Li Ar is phenyl; in ij Het is a saturated, unsaturated heterocycle or monocyclic aromatic with 1 to 2 N and / or 0 atoms, which may be unsubstituted or which may be mono-, di- or trisubstituted with A, Hal, OH and / or OA; is a saturated monocyclic heterocycle with 1 to 2 N and / or 0 atoms, which may be unsubstituted or may be mono- or disubstituted with A; is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl unsubstituted or mono-, di- or trisubstituted with A, Hal, OH and / or OA; is H or CHO, is H, are in each case, independently of each other, H, A, Hal, OR12 or 0- [C (R12) 2] nAr; is H or CHO, is H, is H, A or Hal, R9, R10, R11 is H or A, R6 is OH, R8 is OH, A, phenoxy or Hal; where R1 is H, CHO or acetyl, R2 is H, R3 is H, A or Hal, R4, R5, R7, R10, R11 is -in each case, independently < each other, H, A or Hal, R6 is OH, R8 is OH, A, phenoxy or Hal, R9 is H, Hal or OA, R8 and R9 are also methylenedioxy together; as well as its derivatives, solvates, salts and ester-eoisomers of pharmaceutical utility, including their mixtures in all proportions. Especially preferred are the compounds of the formula I selected from the group The compounds according to the invention and also the starting substances - for their preparation are additionally obtained by methods known per se, as described in the literature (for example, in standard works such as Houben-Weyl, ethoden der organischen Chemie • [Methods of organic chemistry], -Georg-Thieme-Verlag, Stuttgart), to be precise, under reaction conditions - which are known and appropriate for such reactions. The variants known per se can also be used here, but they are not mentioned here in greater detail.

If desired, the starting substances can also be formed in situ so that they are not isolated from the reaction mixture, but instead are converted immediately into the compounds according to the invention. The starting compounds are generally known. If they are new, they can be prepared according to methods known per se. The compounds of the formula I can be obtained preferably by reacting a hydrazide of the formula II with a compound of the formula III. The reaction is carried out according to methods which are known to the specialist. The reaction is generally carried out in an inert solvent, optionally in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of formula III . Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, iisopropanol, n-propanol, n-butanol or ter. -butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as • ethylene glycol monomethyl- or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide < DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitroderivatives such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the solvent mentioned. As solvents, water or DMF are especially preferred. The addition of a hydroxide, carbonate or bicarbonate of alkali or alkaline earth metals or another salt of a weak acid of alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium may also be advantageous. Depending on the conditions applied, the reaction time ranges from a few minutes to 14 days, the reaction temperature varies between approximately -30 ° and 140 °, normally between -10 ° and 90 °, in particular between approximately 0 ° and approximately 70 °. . In the compounds of formula III, L means < preferably Cl, Br, I or a reactive modified or -OH group such as, for example, an activated ester, an imidazolide or an alkylsulfonyloxy having 1-6 carbon atoms (preferably, methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-f-phenylsulfonyloxy). Radicals of this type for activating the carboxy group in typical acylation reactions are described in the literature. { for example, in standard works such as Houben-Weyl, Methoden der organischen C emie [Methods of organic fume], -Georg-Thieme Verlag, Stuttgart). Activated esters are advantageously formed in situ, for example by adding HOBt or N-hydroxysuccinimide. The compounds of formula I can also be obtained preferably by reacting a hydrazide of formula IV with a compound of formula V. The reaction is generally carried out in an inert solvent, optionally in the presence of an acid-binding agent. preferably an organic base such as -DIP-EA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V. Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or ter. -butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl- or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide < DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide < DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitroderivatives such as -nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the mentioned solvents. The addition of a hydroxide, carbonate or bicarbonate of alkali or alkaline earth metals or another salt of a weak acid of alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, may also be advantageous. Depending on the conditions applied, the reaction time ranges from a few minutes to 14 days, the reaction temperature varies between about -30 ° and 140 °, usually between -10 ° and 9 ° 0, in particular between about 0 ° and about 70 °. . In the compounds of the formula V, L preferably means Cl, Br, I or a group? free or reactively modified - such as, for example, an activated ester, an imidazolide or an alkylsulfonyloxy with 1-6 C atoms. { preferably, methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-1? C atoms (preferably, phenyl- or p-tolylsulfonyloxy). Radicals of this type for activating the carboxyl group -in typical acylation reactions are described in the literature for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], -Georg-Thieme Verlag, Stuttgart). Activated esters are advantageously formed in situ, for example by adding HOBt or N-hydroxysuccinimide. The compounds of the formula I can also be obtained by transforming a radical R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and / or R 11 into another radical R 1, R 2, R 3, R 4, R 5, R 6 , R7, R8, R9, R10 and / or R11, separating for example an ether by hydrolysis or hydrogenolysis. The separation of an ether is done - with methods known to the specialist. A standard method for the separation of ether, for example a methyl ether, is the use of boron tribromide. Groups which can be separated by hydrogenolysis, for example the separation of a benzyl ether, can be separated, for example, by treatment with hydrogen in the presence of a catalyst (for example, a noble metal catalyst such as palladium, conveniently in a support such as coal). As solvents, those indicated above are suitable in this case, especially, for example, alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is carried out In general, at temperatures between about 0 and 100 ° and at pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. The esters can be saponified, for example, with ethyl acetate or with NaOH or KOH in water, a-gua-THF or water-dioxane at temperatures between 0 and 100 °. Pharmaceutical salts and other forms The compounds according to the invention mentioned can be used in their non-saline final form. On the other hand, the present invention also comprises the use of these compounds in the form of their pharmaceutically innocuous salts which can be derived from various organic and inorganic acids and bases according to procedures known to those skilled in the art. The pharmaceutically innocuous salt forms of the compounds of the formula I are prepared in the vast majority in a conventional manner. Always < If the compound of formula I contains a carboxylic acid group, one of its appropriate salts can be formed by reacting the compound with a suitable base in the salt by the addition of corresponding aces. Bases of this type are, for example, alkali metal hydroxides, among them potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali-non-ferrous metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alcoholates, by example, potassium ethanolate and sodium propanolate; as well as various organic bases such as piperidine, di ta olamine and N-methylglutamine. The aluminum salts of the compounds of the formula I are also counted here. In certain compounds of formula I, acid addition salts are formed by treating these compounds with pharmaceutically harmless organic and inorganic acids, for example hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, as well as alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and similar. Accordingly, the pharmaceutically acceptable acid addition salts of the compounds of the formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate, and besylate), bisulfate, bisulfite, bromide, butyrate, canferate, canfersulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanpropionate, digluconate, dihydrogen-phosphate, dinitrobenzoate or, dodecyl sulfate, ethanesulfonate, fumarate, galacraterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hipurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleat-o, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, which do not represent any limitations. Furthermore, among the basic salts of the compounds according to the invention are aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese salts < III), manganese (II), potassium, sodium and zinc, which should not represent any limitation. Among the above-mentioned salts, ammonium is preferred; the alkali metal salts sodium and potassium, as well as the alkaline earth metal salts calcium and magnesium. Among the salts of the compounds of the formula I which are derived from non-toxic, pharmaceutically acceptable organic bases, there are added primary, secondary and tertiary amines, substituted amines, including also natural substituted amines, cyclic amines and resins of ion exchange | basic, for example arginine, betaine, caffeine, chloroprocaine, choline,?,? ' -dibencylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidin, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D- glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, tri-ethylamine, tripropylamine, as well as tris- (hydroxymethyl) -methylamine (tromethamine), which should not represent any limitation. Compounds of the present invention containing basic groups can be quaternized with nitrogen, with such agents such as (C 1 -C 4) alkyl halides, eg, methyl, ethyl, isopropyl chloride, bromide and iodide and ter. -butyl; dialkyl (-C1-C4) -sulfates, for example dimethyl-, diethyl- and diamylsulfate; Halides - alkyl (Ci0-Ci8), p. ex. decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; as well as aryl-alkylsulfide "II-CÍ"), eg benzyl chloride and phenethyl bromide. Salts of this type can be prepared according to the invention, which are soluble in both water and oil. Among the above-mentioned preferred pharmaceutical salts are acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hipurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which should not represent any limitations. The acid addition salts of basic compounds of the formula I are prepared by contacting the free basic form with a sufficient amount of the desired acid, the salt being obtained in the usual manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in the usual manner. The basic free forms are distinguished in a sense from their corresponding salt forms in terms of certain physical properties, such as solubility in polar solvents; however, within the scope of the invention, the salts correspond to their corresponding free basic forms. As mentioned, the pharmaceutically innocuous base addition salts of the compounds of the formula I are formed with metals or amines such as alkaline or alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are?,? ' -dibencylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base, obtaining the salt in the usual way. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in the usual manner. The free acid forms are distinguished - in a sense from their corresponding salt forms with respect to certain physical properties such as solubility in polar solvents; however, within the scope of the invention, the salts correspond, moreover, to their relevant free acid forms. If a compound according to the invention contains more than one group which can form pharmaceutically innocuous salts of this type, the invention also comprises multiple salts. Typical multi salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trichlorhydrate, which should not represent any limitation. As regards the above, it can be seen that, by "pharmaceutically safe salt" in the present context, an active principle is understood to contain a compound of the formula I in the form of one of its salts, especially when this salt form confers it at the beginning active improved pharmacokinetic properties, in comparison with the free form of the active principle or another saline form of the active principle that was previously used. The pharmaceutically safe salt form of the active ingredient can also give to this active principle only one property desired pharmacokinetics that previously did not have, and may even positively affect the pharmacodynamics of this active principle with respect to its therapeutic efficacy in the body. The compounds of formula I according to the invention can be chiral due to their molecular structure and, therefore, can be presented in various enantiomeric forms. Therefore, they can also exist in racemic or optically active form. As the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, the use of the enantiomers may be desired. In these cases, the final product or even the intermediate products can be separated into enantiomeric compounds by chemical or physical actions known to those skilled in the art or even used as such in the synthesis. In the case of racemic amines, the diastereomers are formed from the mixture by reaction with an optically active resolving agent. Suitable resolving agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriately N-protected amino acids (e.g. benzoylproline or N-benzenesulfonylproline) or the different optically active camphorsulfonic acids. The chromatographic resolution of the enantiomers by means of an agent of optically active resolution (for example, dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derived methacrylate polymers immobilized on silica gel) is also advantageous. Suitable eluents for this purpose are mixtures of aqueous or alcoholic solvents, such as, for example, hexane / isopropanol / acetonitrile, for example in the ratio 82: 15: 3. It is also an object of the invention to use compounds and / or their physiologically acceptable salts to obtain a medicament (pharmaceutical preparation), in particular by a non-chemical route. They can in this case be converted into an appropriate dosage form together with at least one solid or liquid and / or semi-liquid excipient or adjuvant and, if desired, in combination with one or more other active ingredients. Also the object of the invention are medicaments comprising at least one compound according to the invention and / or its derivatives, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions, as well as optionally excipients and / or coadjuvants. The pharmaceutical formulations can be administered in the form of dosage units - which contain a predetermined amount of active ingredient per unit dose. A unit of this type may contain, for example, 0.5 mg to 1 g, • preferably 1 mg to 700 mg, with special preference, 5 mg to 100 mg of a compound according to the invention, according to the pathological condition treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units - containing a predetermined amount of active ingredient per unit dose. Preferred dosage unit formulations are those which contain a daily dose or sub-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. On the other hand, pharmaceutical formulations of this type can be prepared with a method of general knowledge in the specialized pharmaceutical field. The pharmaceutical formulations can be adapted to be administered by any appropriate route, for example, orally (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral ( including subcutaneous, intramuscular, intravenous or intradermal). Formulations of this type can be prepared with all known processes in the specialized pharmaceutical field, for example by combining the active principle with the excipient (s) or adjuvants. Pharmaceutical formulations adapted for oral administration can be administered as units separated as, eg, capsules or tablets; powders or granulates; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or liquid emulsions of oil in water or liquid emulsions of water in oil. Thus, for example, in the oral administration in the form of a tablet or capsule, the active component can be combined with a non-toxic and pharmaceutically innocuous oral inert excipient, such as, for example, ethanol, glycerin, water, etc. Powders are prepared by grinding the compound to an appropriate fine size and mixing it with a crushed pharmaceutical excipient in the same way as, for example, an edible carbohydrate - such as, for example, starch or mannitol. There may also be a flavoring, a preservative, a dispersant and a colorant. The capsules are obtained by preparing a powder mixture as described above and filling molded gelatin shells with it. Lubricants such as, for example, high-dispersion silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture prior to the filling process. Also, a disintegrant or a solubilizer such as, for example, agar-agar, calcium carbonate or sodium carbonate can be added in order to improve the availability of the drug after the capsule is ingested.

In addition, - if desired or necessary, suitable binders, lubricants and disintegrants, as well as colorants, may be incorporated into the mixture. Suitable binders are starch, gela natural sugars such as, for example, glucose or beta-lactose, corn sweeteners, natural gum and synthetic gum such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes , etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The tablets are formulated by preparing, for example, a powder mixture, granula or compressing it dry, adding a lubricant and a disintegrant and compressing everything into tablets. A pulverulent mixture is prepared by mixing a comminuted compound in a suitable manner with a diluent or a base, as described above, and optionally with a binder such as, for example, carboxymethylcellulose, an alginate, gelaor polyvinylpyrrolidone, a reagent the solution as, for example, paraffin, a resorption accelerator such as, for example, a quaternary salt and / or an absorption agent such as, for example, bentonite, kaolin or dicalcium phosphate. Mix powder can be granulated by moistening it with a binder such as syrup, starch, paste, acadia or solutions of cellulosic or polymeric materials, and pressing it through a sieve. As an alternative for the granulation, the powder mixture is passed through a table machine, where inhomogeneous molded lumps are formed which are split into granules. The granulates can be lubricated by the addition of stearic acid, a salt of stearate, talc or mineral oil, in order to prevent them from sticking to the molten molds for tablets. The lubricated mixture is then compressed to form tablets. The compounds according to the invention can also be combined with a fluid inert excipient and then compressed directly into tablets without performing granulation or dry compression steps. There may also be a transparent or non-transparent protective layer composed of a shellac coa, a layer of sugar or polymeric material and a shiny layer of wax. To these coas dyes can be added to differentiate the various dose units. Oral liquids such as, for example, solutions, syrups and elixirs, can be prepared in the form of dosage units, so that a given amount contains a predetermined amount of compound. The syrups can be prepared by dissolving the compound in an aqueous solution with appropriate flavor, while the elixirs are prepared using a non-toxic alcoholic vehicle. The suspensions can be formulated by dispersing the compound in a non-toxic vehicle. In addition, solubilizers and emulsifiers such as, for example, ethoxylated isostearic alcohols and polyoxyethyletherensitbitol ethers, preservatives, flavoring additives such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can be added. Formulations of dosage units for oral administration may optionally include microcapsules. The formulation can thus be prepared so that the release is prolonged or delayed as, for example, by coa or inclusion of particulate material in polymers, waxes, etc. The compounds according to the invention as well as their physiologically functional derivatives, solvates and derivatives can be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids such as, eg, cholesterol, stearylamine or phosphatidylcholines. The compounds according to the invention, as well as their salts, solvates and physiologically functional derivatives can be supplied using monoclonal antibodies as individual supports, to which the binding molecules are coupled. The The compounds can also be coupled with soluble polymers as targeted medicament carriers. Polymers of this type may comprise polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine, -substituted with palmitoyl radicals. In addition, the compounds may be coupled to a class of biodegradable polymers which are suitable for achieving a controlled release of a medicament, for example, polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthores, polyacetals, polydihydroxypyrans, polycyanoacrylates and copolymers in cross-linked or unfriendly blocks of hydrogels. Pharmaceutical formulations adapted for transdermal administration can be administered as separate patches for prolonged close contact with the epidermis of the recipient. In this way, the active principle of the patch can be administered, for example, by means of iontophoresis, as generally described in Pharmaceutical Research, 3 < 6), 318 (1986). The pharmaceutical compositions adapted for topical administration can be formulated in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For eye or other tissue treatments External, for example mouth and skin, the formulations are preferably applied as ointment or topical cream. In case of formulating an ointment, the active principle can be applied with either a paraffinic cream base or a miscible one - with water. Alternatively, the active ingredient can be formulated in a cream with a creamy base of oil in water or a base of water in oil. Pharmaceutical formulations adapted to topical application in the eyes include ophthalmic drops, wherein the active principle is dissolved or suspended in an appropriate support, especially an aqueous solvent. Pharmaceutical formulations adapted to topical application in the mouth comprise oral dissolution tablets, lozenges and mouth rinses. Pharmaceutical formulations adapted to rectal application can be administered in the form of ovules or enemas. Pharmaceutical formulations adapted for nasal administration, in which the carrier substance is a solid substance, contain a coarse powder with a granule in the range, for example, 2? -5? 0 micrometers, which is administered from the How snuff is inhaled, that is, inhaled rapidly through the nasal passages from a container with the powder held near the nose. The proper formulations to administer as a nasal spray • or nasal drops with a liquid as a support substance comprise active substance solutions in water or oil. Pharmaceutical formulations adapted for administration by inhalation comprise powders of fine particles or mists which can be generated by means of different types of metering-res under pressure with aerosols, nebulizers or insufflators. Pharmaceutical formulations adapted for vaginal administration can be administered - such as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injectable solutions, which contain antioxidants, buffers, bacteriostats and solutes, through which the formulation becomes isotonic with the blood of the patient to be treated as well as sterile aqueous and non-aqueous suspensions which may contain suspending and thickening agents. The formulations can be administered in single or multiple-dose containers, for example, sealed ampoules and vials and stored in the lyophilized state, so that only the addition of the sterile carrier liquid is required, eg, water for injectable purposes. , immediately before use. Injectable solutions and solutions prepared according to the recipe can be prepared from powders, granules and sterile tablets. It is understood that the formulations, in addition to the components mentioned above in particular, may contain other agents customary in the specialized field with respect to the corresponding type of formulation; in this way, the appropriate formulations for oral administration may contain flavored. An amount of therapeutic efficacy of a compound of the present invention depends on a number of factors, including for example the age and weight of the animal, the exact health status that requires treatment, as well as its severity, the nature of the formulation , as well as the route of administration, and ultimately is determined by the attending physician or veterinarian. However, an effective amount of a compound according to the invention generally varies in the range of 0.1 to 100 mg / kg of body weight of the receptor (mammal) per day and especially, typically, in the range of 1 to 10. mg / kg of body weight per day. Thus, for an adult 70 kg mammal the effective amount per day would usually be from 70 to 700 mg, where this amount may be administered as a single dose per day or usually in a series of sub-doses < omo, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of one of its physiologically functional derivatives can be determined per as part of the effective amount of the compound according to the invention. It can be assumed that similar doses are appropriate for the treatment of the others - pathological states mentioned above. Furthermore, the invention relates to medicaments containing at least one compound according to the invention and / or its derivatives, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions, and at least one other active drug ingredient. Also a subject of the invention is a kit consisting of separate packages of (a) an effective amount of a compound according to the invention and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, Y (b) ) an effective amount of another active drug ingredient. The kit contains appropriate containers such as boxes, bottles, sachets or individual ampoules. The kit may contain, for example, separate ampoules each containing an effective amount of a compound according to the invention and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, and an effective amount of another dissolved drug active ingredient or in lyophilized form. USE The present -compounds are suitable as pharmaceutical active ingredients for mammals, especially for humans, in the treatment of diseases caused by SGK.

In this manner, the object of the invention is the use of compounds according to claim 1, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of signal transduction of kinases plays an important role. The SGK is preferred in this case. The use of compounds according to claim 1, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, is preferred for the preparation of a medicament for the treatment of diseases that are influenced by inhibition of The SGK through the compounds according to claim 1. The present invention comprises the use of the compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the treatment or prevention of -diabetes (for example, diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, cardiocyclergic diseases - (for example, cardiac fibrosis - after myocardial infarction, cardiac hypertrophy and heart failure, arteriesclerosis) and kidney diseases (eg, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorder), in general in all types of fibrosis and inflammatory processes (eg, liver cirrhosis, fibrosis pulmonary, fibrosing pancreatitis, rheumatism and osteoarthritis, Crobus morbus, chronic bronchitis, irradiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease). The compounds according to the invention can also inhibit the growth of cancer, tumor cells and tumor metastases and, therefore, are suitable for tumor therapy.

The compounds according to the invention are also used for the treatment of coagulopathies, such as, for example, dysfibri ogenemia, hypoproconvertinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immunocoagulopathy or complex coagulopathies, as also in case of neuronal irritability, for example, epilepsy. The compounds according to the invention can also be used therapeutically in the treatment of a glaueoma or cataract. The compounds according to the invention are also used in the treatment of bacterial infections, as well as in an anti-infective therapy. The compounds according to the invention can also be used therapeutically - to increase the capacity for learning and attention. It is preferred to use the compounds according to claim 1, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for the preparation of a medicament for the treatment or prevention of diabetes, obesity , metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, cardiocirculatory diseases and kidney diseases, in general in all types of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastasis, coagulopathies, neuronal irritability, glaueoma, .catarata, infections bacterial, as well as in an anti-infective therapy, to increase the capacity of learning and attention, as well as for the treatment and prevention of cell aging and stress. In the case of diabetes, diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy are preferentially treated. In the case of cardiccirculatory diseases, cardiac fibrosis is preferentially treated after myocardial infarction, cardiac hypertrophy, heart failure and arteriesclerosis. In the case of: kidney diseases, it is preferably treated glomerulosclerosis, nephosclerosis, nephritis, nephropathy and electrolyte excretion disorder. In the case of fibrosis and inflammatory processes, liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and osteoarthritis, Crohn's morbus, synchronous bronchitis, irradiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease are treated. Assays The compounds according to the invention described in the examples are tested by means of the assays described below and found to have a kinase inhibitory effect. í > and other literature tests are known and can easily be performed by the skilled artisan. { see, for example, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J ". Biol. Che. 214: 9116-9121; -Sheu et al., Anticancer Res. 18: 4435-4441; Ausprunk et al., Dev. Biol. 38: 237-248; Gimbrone et al. al., J. Nati, Cancer Inst. 52: 413-427; Nicosia-et al., In Vitro 18: 538-549.) Inhibition of the SGKl protein-kinases can be determined in the filter-binding procedure. Previously and subsequently, all temperatures are indicated in ° C.

In the examples below, "usual processing" means that, if necessary, water is added, if necessary, depending on the constitution of the final product, at pH values between 2 and 10, it is extracted with acetate of ethyl or dichloromethane, separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; eluent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): The (ionization by electronic impact) + FAB (fast bombardment of atoms) (M + H) + ESI (ionization by electrospray) (M + H) + (unless otherwise indicated) Example 1 The preparation of N '- [2- (3, 4-difluoro-phenyl) -2-hydroxy-acetyl] -hydrazide of 2,4-dihydroxy-6-methyl-benzoic acid ("Al") is carried out in accordance with the following reaction scheme Is monoacy? 2? 5? with 2,4-dibenzyloxy-6-methyl-benzoic acid. Performance: 2,4-dibenzyloxy-6-hydrazide methyl-benzoic acid (63%); F. 136-137 °. 1.2 2, 4-Dibenzyloxy-6-methyl-benzoic acid hydrazide is hydrogenated. Yield: 2-dihydroxy-6-methyl-benzoic acid hydrazide (89%); F. 226 ° - (decomposition). 1.3 282 mg of 3,4-difluoromandelic acid, 410 mg of 2,4-di-d-oxoxy-6-methyl-benzoic acid hydrazide, 431 mg of l-ethyl-3-y, 3- ^ limethylaminopropy1) -carbodiimide are stirred. (WSCD) and 164 mg of 1-hydroxybenzotriazole IHOBt) for 3 h in 1.5 ml of DMF. Work up as usual and chromatograph on silica gel. The unit fractions are combined, concentrated and recrystallized from EtOAc / petroleum ether. Yield 250 mg 'of "Al" (46%), F. 220 C. • The following compounds are obtained analogously Example 2 Preparation of N '-. { 2-Chloro-4, € -dihydroxy-benzoic acid 2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -hydrazide ("A15") 720 mg of N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -hydrazide of 2-chloro-4,6-dibenzyloxy-benzoic acid in 20 ml of THF + 0.2 ml are hydrogenated of * HC1 at 32% with 36 mg-of Pd / C with the calculated amount of H2. The hydrogenation solution is concentrated and chromatographed on silica gel. The unit fractions are combined, concentrated and recrystallized from EtOAc. Yield 310 mg. { 65%) -of WA15", F. 230-231 ° • Analogously, the following compounds are obtained Example 3 Preparation of N '- (2-hydroxy-2-phenyl-acetyl) -hydrazide of 2-methyl-4,6-dihydroxy-benzoic acid ("A18") 1.6 g of 2,4-dihydroxy-6-methyl-benzoic acid are heated to reflux with 4 ml of SOCl2 until a clear solution is produced. The SOCl2 is removed, then it is evaporated another 2 times with CH2Cl2 to dryness. The acid chloride is now dissolved in 3 ml of DMF and 1.14 g of mandelic acid hydrazide is added. After stirring for 2 hours at room temperature, it is poured into? 2 ?, extracted with StOAc, dried and concentrated to a small volume. Yield 1.49 g (50%) of "A18", F. 188-189 °. Alternative preparation (Example 4): 1.82 g of 2,4-dihydroxy-6-methyl-benzoic acid hydrazide are dissolved in 10 ml of DMF. To this is added 1.71 g of mandelic acid chloride slowly. After 2 hours of stirring at room temperature, it is poured into H20, extracted with EtOAc, dried and concentrated to a small volume. Yield 2.16 g < 68%) of WA18", F. 188-189 ° Synthesis of precursors Example 5 N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -hydrazide of 2,4-dibenzyloxy-6 acid -meti1-benzoic The substance is prepared from 2, 4-dibenzyloxy-6-methyl-1-enzoic acid hydrazide and 3-hydroxymandelic acid or with a 47% yield analogously to Example 1, F. L81-182 ° (from Me 2 COH / Et20). In a similar manner, the compounds N '-> 2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -hydrazide of 2-chloro-4, -dibenzyloxy-benzoic acid, F. 160-162 ° < from Me2COH / Et20), 61% yield and N '- [2-hydroxy-2- (3-hydroxy-phenyl) -acetyl] -2,4-dibenzyloxy-6-eti1-benzoic acid hydrazide, F. 205- 206 °. { from Me2COH / Et20), 90% yield. Example 6 2, 4-Bis-benzyloxy-6-ethyl-benzaldehyde 1.9 g of dihydroxy-6-ethyl-benzaldehyde, 3.48 ml of benzyl chloride and 4.7 g of K2CO3 are stirred in 5.2 ml of DMF for 2 h at 90 °. The preparation is diluted with EtOAc and washed with water. The organic phase is dried with Na2S-04, concentrated and chromatographed on silica gel. The unit fractions are combined and removed. The oily residue solidifies on standing for a few days. Treatment with ether / petroleum ether 1: 1 results in 3.5 g (88%) of 2,4-bis-benzyloxy-6-ethyl-benzaldehyde, which decolours with air. Analogously, 3-chloro-2-ethyl-4-hydroxy-benzoic acid is benzylated: 3-chloro-2-ethyl-4-benzyloxy-benzoic acid is obtained with a yield of 7S%, F. 208-210 ° .

Example 7 2,4-bis-benzyloxy-6-ethyl-benzoic acid 3.3 g of 2,4-bis-benzyloxy-6-ethyl-benzaldehyde are dissolved in 63 ml of DMSO. To this is added slowly, garlic cooling with ice, a solution of 7.9 g of aClO2 and 7.9 g of NaHG03 in 32 ml of water, and the temperature does not exceed 40 ° C. Stirring is continued for 2 h more, before diluting with more water and extracting twice with EtOAc. The combined organic phases are washed with water, dried over Na 2 SO 4, concentrated, chromatographed on silica gel and recrystallized from Me 2 COH: Yield 2.21 g (64%) of 2,4-bis-acid. benzyloxy-6-ethyl-benzoic acid, F. 126-127 °. The following are prepared analogously: 2,4-bis-benzyloxy-6-chloro-benzoic acid, F. 135-136 ° < 35%) and 3-chloro-2-ethyl-4-hydroxy-benzoic acid from 3-chloro-2-ethyl-4-hydroxy-benzaldehyde: Yield 51%, F. 138-139 °. EXAMPLE 8 2, -Dibenzyloxy-6-ethyl-benzoic acid hydrazide The substance is prepared according to the method shown in Example 1 from 2,4-bis- Benzyloxy-6-ethyl-benzoic acid and hi-drazinium hydroxide: Yield 75%, F. 140-141 °. Analogously, hydrazide is also prepared from 2,4-dibenzyloxy-6-chloro-benzoic acid: yield -61%, F. 166-167 ° and hydrazide of 4-benzyloxy-3-chloro-2-ethyl -benzoic Yield 85%, F. 182-184 °. Example 9 2, 4-Bis-benzyloxy-6-chloro-benzaldehyde 12 g of chloro-3,5-dibenzyloxy-benzene are dissolved in 40 ml of DMF. At 5-10 ° C, 12 ml of POCl3 are added dropwise. It is reacted for 90 min at room temperature, then overnight at 8-0 ° C. The solution is concentrated on the rotary evaporator, then poured into 200 ml of ice water. Extract 3x with EtOAc, wash with water, dry and concentrate. Chromatography on silica gel-results in 8.2 g (63%) of 2,4-bis-benzyloxy-6-chloro-benzaldehyde, which is crystallized from. { Me2C) 20, F. 85-8 € °. EXAMPLE 10 Acetoxy- (3-chloro-phenyl) -acetic acid 1 g of racemic 3-chloromandélico acid is mixed with 2 ml of acetyl chloride A clear solution is formed which is concentrated after 2 h in the rotary evaporator and crystallized with (Me 2 C) O / petroleum ether. Performance € 70 mg (55%), F. 118 °. EXAMPLE 11 3-Chloro-2-ethyl-4-hydroxy-benzoic acid hydrazide The compound is prepared by hydrogenation of 300 mg of 3-chloro-2-ethyl-4-benzyloxy-benzoic acid hydrazide in 1? my of MeOH and 145 μ? of 32% HCl in Pd / Cu. Yield 165 mg (78%), 233-235 ° < EtOAc / MeC). Analogously, it is prepared: 5-chloro-2,4-dihydroxy-benzoic acid hydrazide, yield 84%, F. 260 °. Example 12 3-Chloro-2-ethyl-4-hydroxy-benzaldehyde To 4 g of 2-ethyl-4-hydroxybenzaldehyde, dissolved in 80 ml of CHCl 3 and 1.5 ml of concentrated HCl, 3.4 g of t-chlorosuccinimide are poured into 40 ml of CHCl 3 over a period of 45 min. Stir for 1 h, wash with water, dry and concentrate. Chromatography on silica gel results in 1 g (20%) of 3-chloro-2-ethyl-4-hydroxy-benzaldehyde (F. 85 °, polar substance on silica gel with ether / petroleum ether 1: 1) in addition to 5-chloro-2-ethyl-4-hydroxy-benzaldehyde (F.83 °, medium polar) and 3,5-dichloro-2-ethyl-4-hydroxy-benzaldehyde (F. 117 -118 °, not polar). The following examples refer to pharmaceutical preparations: EXAMPLE A: BOTTLES-AMPOLLA FOR INJECTABLE A solution of 100 g of an active principle according to the invention and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to a pH value 6, 5 using 2N hydrochloric acid, filtered in sterile form, transferred to ampoule bottles for injection, lyophilized under sterile conditions and sealed in sterile form. Each vial-ampoule for injection contains 5 mg of active ingredient. EXAMPLE B: SUPPOSITORIES A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active principle. EXAMPLE C: SOLUTION A solution of 1 g of an active principle according to the invention, 9.38 g of NaH2P04 · 2 H20, 28.48 g of Na2HP04 · 12 H20 and 0.1 g of benzalkonium chloride in 940 ml are prepared. of double-distilled water. The solution is adjusted to a pH value of 6,8, completed to 1 1 and sterilized by irradiation. This solution can be used in the form of ophthalmic drops. € 6 EXAMPLE D: OINTMENT 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions. EXAMPLE E: COMPRESSED A mixture of 1 kg of an active ingredient, 4 kg of lactose, 1.2 kg of potato starch, is compressed? , 2 kg of talc and 0.1 kg of magnesium stearate in conventional manner to form tablets, so that each tablet contains 10 mg of active ingredient. EXAMPLE F: GRAGEAS Analogously to Example E, the corytiitides are pressed, which are then coated in a conventional manner with a covering of sucrose, potato starch, talc, gum tragacanth and dye. EXAMPLE G: CAPSULES 2 kg of active ingredient are placed conventionally in hard gelatin capsules, so that each capsule contains 20 mg of active ingredient. EXAMPLE H: AMPOLLAS A -olution of 1 kg of an active principle according to the invention in 60 1 of bidistilled water - it is sterile filtered, transferred to ampoules, lyophilized under sterile conditions and sealed under sterility. Each ampoule contains 10 mg of active ingredient. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims

7 CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the formula I they are in each case, independently of each other, H, CHO or acetyl, are in each case, independently of each other, H, A, OS02A, Hal, N02, OR12, N < R12) 2, CN, O-COA, -.C < R12) 2] nCOOR12, O- [C (R12) 2] or C00R12, S03H, -tC < R12) 2] nAr, -CO-Ar, 0- [C (R12) 2] nAr,. { CtR12) 2] nHet, - [C < R12) 2] nC = CH, O-. { C < R12) 2] n: = CH, -. { C < R12) 2] nCON (R12) 2, -IC ^ R12) 2] nCONR12N. { R12) 2, O- (C (R12) 2] rfCON (R12) 2, O- [Ci R12) 2] oCONR12N < R12) 2, NR12-GOA, NR12CON (R1) 2, NR12'S02A, N < S02A) .2, € 8 COR12, S (0) mAr, S02NR12 or S- (0) mA, are also together CH = CH-CH = CH, they are also alkylene together with 3, 4 or 5 carbon atoms, wherein one or two CH2 groups can be replaced by oxygen, is unbranched or branched alkyl with 1-6 carbon atoms, wherein 1-7 carbon atoms can be replaced by F, or cyclic alkyl with 3-7 C atoms, is phenyl, naphthyl or biphenyl unsubstituted or mono-, di- or trisubstituted with "al, A, OR12, N (R12) 2, N02, CN , phenyl, CON (R12) 2, NR12 € OA, NR12CON. { R12) 2, NR12S02A, COR12, S02N < R12) 2, S < O) mA, -i-C < R12) 2] n-C OR12 and / u -0. { -C (R12) 2] 0-COOR12 is a saturated, unsaturated or aromatic mono- or bicyclic heterocycle with 1 to 4 N, 0 and / or S atoms, which may be mono-, di- or trisubstituted with dial, A, OR12, N (R12) 2, N02, CN, C00R12, G0N (R1) 2, NR12COA, NR12S02A, COR12, -S02NR12, W) m, = S, = NR12 and / u =? (carbonyl oxygen), is it? or A, is F, Cl, Br or I, m is 0, 1 or 2, n is 0, 1, 2 or 3, or is 1, 2 or 3, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
2. Compounds according to claim 1, characterized in that R1 is H or CHO, R2 is H, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
3. Compounds according to claim 1 or 2, characterized in that R8, R9, R10, R11 are in each case, independently of each other, H, A, Hal, R12 or 0-i-C < R1) 2] nAr, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
4. Compounds according to one or more of claims 1-3, characterized in that R6 is OH, 7 as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. S.
Compounds according to one or more of claims 1-4, characterized in that R3 is H, A or Hal, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
Compounds according to one or more of claims 1-5, characterized in that R8 is OH, A, phenoxy or Hal, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions.
7. Compounds according to one or more of claims 1-6, characterized in that R4, R5, R7, R9, R10, R11 are H or A, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
8. Compounds in accordance with one or more < of claims 1-7, characterized in that R7, R10, R11 are in each case, independently of each other, H or Hal, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
9. Compounds according to one or more of claims 1-8, characterized in that Ar is unsubstituted or mono-, di- or trisubstituted phenyl with Hal and / or A, as well as its derivatives, salts, solvates and stereoisomers of utility. pharmaceutical, including their mixtures in all proportions.
10. Compounds in accordance with one or more of claims 1-9, characterized in that Ar is phenyl, as well as -its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
11. Compounds according to one or more of claims 1-1, characterized in that Het is a saturated, unsaturated or monocyclic aromatic heterocycle with 1 to 2 atoms-of N and / or 0, which may be unsubstituted or may be substituted. be mono-, di- or trisubstituted with A, Hal, OH and / or OA, as well as their derivatives, salts, solvates and is e-isomers of pharmaceutical utility, including their mixtures in all proportions.
12 Compounds according to one or more of claims 1-11, characterized in that Het is a monocyclic saturated heterocycle with 1 to 2 N and / or 0 atoms, which may be unsubstituted or may be mono- or di-substituted with A, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
13 Compounds according to one or more of claims 1-12, characterized in that Het is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or unsubstituted piperazinyl or mono-, di- - or trisubstituted with A, -Hal, OH and / or OA, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions.
14 Compounds according to one or more of claims 1-13, characterized in that R1 is H or CHO, R2 is H, R8, R9, R10, R11 are in each case, independently of each other, H, A, Hal, OR12 or 0-tC. { R12) 2] nAr, as well as its derivatives, salts, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions.
15. Compounds according to one or more of claims 1-14, characterized in that R1 is H or CHO R2 is H, R3 is H, A or Hal, R4, R5, R7, R9, R10, R11 are H or A, R6 OH, R8 is OH, A, phenoxy or Hal, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions.
16. Compounds according to one or more of claims 1-15, characterized in that R1 is H or CHO, R2 is H, R3 is H, A or Hal, R4, R5, R7, R9, R10, R11 are H, A or Hal, R8 and R9 are also methylenedioxy together, R6 OH, R8 OH, A, phenoxy or Hal, as well as their derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
17. Compounds according to one or more of claims 1-16, characterized in that R1 is H, CHO or aoethyl, R2 is H R3 is H, A or Hal, R10, R11 are in each case, independently of each other, H, A or Hal, R6 is ??, R8 is OH, A, phenoxy or Hal, R9 is H, Hal or OA, R8 and R9 are also methylenedioxy together , as well-as its derivatives, salts, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
18. Compounds -in accordance with claim 1, characterized in that they are selected from the group 7 as well as its derivatives, salts, solvates and stereoisomers, pharmaceutical utility, including their mixtures in all proportions. YES
19. Process for preparing compounds of the formula I according to claims 1-18, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, characterized in that a) a compound of the formula II is reacted wherein R1, R7, R8, R9, R10 and R11 have the meanings of-according to claim 1, with a compound of the formula III wherein L - is Cl, Br, l or a free OH group or functionally reactive and R2, R3, R4, R5 and R6 have the meanings according to claim 1, or b) a compound of the formula IV is reacted wherein R2, R3, R4, R5 and R6 have the meanings -in accordance with claim 1, with a compound of the formula V wherein L is Cl, Br, I or a free OH group or functionally reactive and R1, R7, R8, R9, R10 and R11 have the meanings according to claim 1, or c) in a compound of the formula I converts a radical R1, "R2, R3, R, R5, R6, R7, R8, R9, R10 and R11 into another radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and / or R11, when separating an ether by hydrolysis or hydrogenolysis, and / or a base or acid of the formula I is converted into one of its salts.
20. Medicament characterized in that it contains at least one compound according to claims 1-18 and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, as well as optionally excipients and / or adjuvants.
21. Use of compounds according to claims 1-18, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, to prepare a medicament for the treatment of diseases in which inhibition, the regulation and / or modulation of signal transduction of kinases plays an important role.
22. Use according to claim 21, wherein in the case of the kinase it is the SGK.
23. Use according to claim 22 of compounds according to claims 1-18, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, to prepare a medicament for the treatment of diseases that are influenced by inhibition of SGK to through the compounds according to claim 1-18.
24. Use according to claim 23 of compounds according to claims 1-18, as well as their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for the preparation of a medicament for the treatment or the prevention of diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertonia, cardiocirculatory diseases and nephropathies, in general in case of any type of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastasis, coagulopathies, neuronal irritability, glaucoma, cataract, bacterial infections, as well as in an anti-infective therapy, to increase the capacity of learning and attention, as well as for the treatment and prevention of cell aging and stress and for the treatment of tinnitus.
25. Use according to claim 24, wherein in the case of diabetes it is diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
26. Use according to claim 24, wherein in the case of cardiocirculatory diseases it is cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and arteriosclerosis.
27. Use according to claim 24, wherein in the case of renal diseases it is glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and disorder of electrolytic excretion.
28. Use according to claim 24, wherein in the case of fibrosis and inflammatory processes is liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and osteoarthritis, Crohn's morbus, chronic bronchitis, fibrosis by irradiation, sclerodermitis, cystic fibrosis , scarring and Alzheimer's disease.
29. A medicament characterized in that it contains a minimum of a compound according to claims 1-18 and / or its derivatives, solvates and tereoi shams of pharmaceutical utility, including their mixtures in all proportions, and at least some other active substance of the drug .
30. Kit characterized in that it is composed of separate packages of (a) an effective amount of a compound according to claims 1-18 and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, and (b) an effective amount of another medicament active ingredient.