WO2010020307A2 - Indazole-5-carboxylic acid hydrazide derivatives - Google Patents

Abstract

The invention relates to novel indazole derivatives of formula (I) wherein Ar, G, R, X¹, X², X³, Y and n have the designations cited in claim 1. Said derivatives are kinase inhibitors and can be used to treat illnesses and complaints such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonal hypertonia, cardiovascular diseases and liver diseases, any type of fibrosis, inflammatory processes, tumours, and tumour diseases.

Description

 indazol-5-carboxylic acid derivatives

BACKGROUND OF THE INVENTION

The invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.

The present invention relates to compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK) plays a role, and also pharmaceutical compositions containing these compounds and the use of the compounds for the treatment of SGK-related diseases.

The SGK with the isoforms SGK-1, SGK-2 and SGK-3 are a serine / threonine protein kinase family (WO 02/17893).

The compounds of the invention are preferably selective inhibitors of SGK-1. Further, they may be inhibitors of SGK-2 and / or SGK-3.

In particular, the present invention relates to compounds containing the

Inhibit, regulate and / or modulate signal transduction of SGK, compositions containing these compounds, as well as methods for their use in the treatment of SGK-related diseases and

Conditions such as diabetes (e.g., diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular disorders (e.g., cardiac fibrosis following myocardial infarction, cardiac hypertrophy and heart failure,

Arteriosclerosis) and kidney diseases (eg glomerulosclerosis, Nephrosclerosis, nephritis, nephropathy, disturbed electrolyte excretion), in general for all types of fibrosis and inflammatory processes (eg cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease ).

The compounds according to the invention can also inhibit the growth of tumor cells and tumor metastases and are therefore suitable for tumor therapy.

The compounds according to the invention are also used in the treatment of peptic ulcers, in particular in forms which are triggered by stress. The compounds of the invention are also used for the treatment of coagulopathies, such as dysfibrinogenemia, hypoproconvertinemia, hemophilia B ₁ Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis,

Immunocoagulopathy or complex coagulopathies, as well as neuronal excitability, e.g. Epilepsy. The invention

Compounds can also be used in the treatment of glaucoma or

Cataract can be used therapeutically.

The compounds of 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 for

Increase the learning ability and attention to be used therapeutically. Moreover, the compounds of the invention counter cell aging and stress and thus increase life expectancy and fitness in old age.

The compounds of the invention are also used in the

Treatment of Tinitus. The identification of small compounds that specifically inhibit, regulate and / or modulate the signal transduction of the SGK is therefore desirable and an object of the present invention.

It has been found that the compounds according to the invention and their salts possess very valuable pharmacological properties with good compatibility. In particular, they show inhibitory properties of SGK.

The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.

The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats etc.

Animal models are of interest for experimental studies, providing a model for the treatment of human disease.

To identify a signal transmission path and to detect

Interactions between different signal transduction pathways have been suitable models by different scientists or

Model systems developed, e.g. Cell culture models (e.g., Khwaja et al., EMBO,

1997, 16, 2783-93) and models of transgenic animals (eg White et al., - A -

Oncogene, 2001, 20, 7064-7072). To determine particular levels in the signal transduction cascade, interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.

The measurement of kinase activity is well known to those skilled in the art

Technology. Generic Assay Systems for Determining Kinase Activity with Substrates, e.g. Histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the myelin basic protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).

Various assay systems are available for the identification of kinase inhibitors. In the Scintillation Proximity Assay (Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19) and the FlashPlate assay, the radioactive phosphorylation of a protein or peptide as a substrate is measured with γATP. In the presence of an inhibitory compound, no or a reduced radioactive signal is detectable. Furthermore, the

Homogeneous Time-resolved Fluorescence Resonance Energy Transfer

(HTR-FRET) and fluorescence polarization (FP) technologies are useful as assay methods (SiIIs et al., J. of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK). The phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., Biochem. J., 2002, 366, 977-981). It can be shown that the compounds according to the invention have an in vivo antiproliferative action in a xenograft tumor model. The compounds of the invention are administered to a patient with a hyperproliferative disorder, e.g. B. to inhibit the

Tumor growth, for the reduction of lymphoproliferative

Disease, to inhibit graft rejection or neurological damage due to tissue repair, etc. The present compounds are useful for prophylactic or therapeutic purposes. As used herein, the term "treating" is used to refer to both the prevention of disease and the treatment of pre-existing conditions The prevention of proliferation is accomplished by administering the compounds of the present invention prior to developing the evident disease, e.g., to prevent tumor growth , Prevention of metastatic growth, reduction of cardiovascular surgery-associated restenosis, etc. Alternatively, the compounds are used to treat persistent diseases by stabilizing or ameliorating the clinical symptoms of the disease

Patients used.

The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted. The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, one therapeutic dose will be sufficient to treat the undesired cell population in the human body

To significantly reduce target tissue, while the viability of the Patient is maintained. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.

STATE OF THE ART

Other aminoaryl compounds are as tyrosine kinase inhibitors in WO

2006/064375 A2 for the treatment of cancer, allergic and inflammatory diseases, rheumatoid arthritis and autoimmune diseases.

Other oxadiazole derivatives are described in WO 2006/064189 A1 for the treatment of

Diabetes mellitus and obesity revealed. Other heterocyclic derivatives are disclosed in WO 2006/024034 A1, et al. to

Treatment of cancer and inflammation described.

Indoles and other heterocyclic derivatives are known as kinase inhibitors in US

2005/250829.

Other heterocyclic oxadiazole derivatives are known from WO 2002/72549

A1.

WO 00/62781 contains the use of medicaments

Inhibitors of cell volume-regulated human kinase H-SGK. Heterocyclic indazole derivatives for the treatment of diabetes and / or

Cancers are known from WO 2006/044860 and WO 2005056550.

In US 2005090529 are indazole derivatives for the treatment of diabetic

Retinopathy revealed. Indazole derivatives for the treatment of tumors are disclosed in WO 2005000813, those for the treatment of cardiovascular diseases in WO

2004060318th

Other heterocyclic compounds for the treatment of tumors are known from WO2004052280. Further, other heterocycles for treating psychotic disorders are disclosed in EP 328200.

Indazole derivatives are described as protein kinase inhibitors in WO 03/064397.

In Bioorganic & Medicinal Chemistry Letters 13 (2003) 3059-3062, J. Witherington et al. the production of indazole derivatives. Indazole derivatives are described as kinase inhibitors in WO 2003097610. Indazole derivatives are disclosed as GSK-3 inhibitors in WO2003051847. Triazolo-pyridazine derivatives are described as met-kinase inhibitors in WO 2007/064797, WO 2007/075567, WO 2007/138472, WO 2008/008539, WO 2008/051805.

The use of kinase inhibitors in anti-infective therapy is described by C.Doerig in Cell. Biol. Lett. Vol.8, No. 2A, 2003, 524-525. The use of kinase inhibitors in obesity is described by N.Perrotti in J. Biol. Chem. 2001, March 23; 276 (12): 9406-9412.

References in the following references suggest and / or describe the use of SGK inhibitors in the treatment of diseases:

1: Chung EJ, Sung YK, Farooq M, Kim Y, S, Tak WY, Hwang YJ, Kim Yl ₁ Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol CeIIs. 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 S, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf R, Lang

F. Expression of the serine / threonine kinase hSGK1 in chronic viral hepatitis.

Cell Physiol Biochem. 2002; 12: 47-54. 4: Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). 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 Chem. 2001: 276: 16649-54.

6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Honkanen RE. Ser / Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry. 1999: 38: 8849-57.

7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear cytoplasmic localization of the serum and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J Biol Chem. 1999; 274: 7253-63.

8: M. Hertweck, C. Göbel, R. Baumeister: C. elegans SGK-1 is the critical component in the Akt / PKB kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577-588, April, 2004.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula

woπn

embedded image in which

GH or NH ₂ ,

R H or A,

X ¹ , X ² , X ^{3 are} each independently H, Hal, A, Ar, Het, OH, OA, OAr, OHet, SH, SA, SAr, NH ₂ , NHA, NAA ¹ , NHAr, NHHet, N (Ar ) ₂ , NAAr, SOA, SOAr, SO ₂ A, SO ₂ Ar, NO ₂ , CN ₁ COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COAr, SO ₃ H, SO ₂ NH ₂ ,

SO ₂ NHAr, SO ₂ N (Ar) ₂ , CH (OH) A or CH (OH) Ar,

Y CR ⁷ R ⁸ , OCR ⁷ R ⁸ , CR ⁷ R ⁸ O, NR ⁹ CR ⁷ R ⁸ , CR ⁷ R ⁸ NR ⁹ , CR ⁷ R ⁸ SO ₂ or

SO ₂ R ⁷ R ⁸ , R ⁷ _> R ⁸ _> R ^{9 are} each independently H or A,

R ^{11 is} alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F,

A, A 'are each independently of the other unsubstituted or mono-, di- or trisubstituted by = S, = NR ⁷ and / or = 0 (carbonyl oxygen) substituted alkyl having 1-10 C atoms, wherein one, two or three CH ₂ - Groups by O, S, SO, SO ₂ , NH, NR ¹¹ and / or by -CH = CH groups and / or 1-7 H atoms may be replaced by F and / or Cl, or cyclic alkyl with 3 -7 carbon atoms,

Ar unsubstituted or one, two, three or four times by A, HaI,

OH, OA, Ar ¹ , OAr ¹ , Het, OHet, SH, SA, SAr ¹ , SHet, NH ₂ , NHA, NAA ¹ , NHAr ¹ , N (Ar ¹ J ₂ , NHHet, N (Het) _2> NAAr ', NAHet, SOA, SOAr ¹ , SOHet, SO ₂ A, SO ₂ Ar ¹ , SO ₂ Het, NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA,

CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A ₁ NASO ₂ A, CHO, COA, COAr ', COHet, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ¹ , SO ₂ N (AO ₂ , SO ₂ NHHet and / or SO ₂ N (Het) ₂ substituted phenyl, naphthyl or biphenyl,

Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the one, two or three times by A, Hal, OH, OA ₁ Ar, OAr, Het 'OHef, SH, SA, SAr', Shef, NH _2, NHA, NAA ^1, NHAr ', N (Ar ¹ J _2, NHHet', N (HEV) _2, naar ^1, NAHef, SOA, Soar ' SOHet ', SO ₂ A, SO ₂ Ar', SO ₂ Het ', NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA,

CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COAr ', COHef, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr', SO ₂ N ( Ar ') ₂ , SO ₂ NHHef or SO ₂ N (HeV) ₂ , = S, = NR ⁷ and / or = O (carbonyl oxygen) may be substituted,

Ar 'unsubstituted or one, two, three or four times by A, HaI,

OH, OA, OPhenyl, SH, SA, NH _2, NHA, NAA ', NHPhenyl, SOA, SOPhenyl, SO ₂ A, SO ₂ phenyl, NO _2, CN, COOH, COOA, CONH _2, CONHA, CONA _2, NHCOA , NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COPhenyl, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHPhenyl and / or SO ₂ N (phenyl) ₂ substituted phenyl,

Het 'is a monocyclic saturated heterocycle having 1 to 4 N, O and / or S atoms, which is mono-, di- or trisubstituted by A, Hal, OH,

OA, NH ₂ , NHA, NAA ', NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , = S, = NR ⁷ and / or = O (carbonyl oxygen), Hal F, Cl, Br or I, n O, 1 or 2 and their pharmaceutically usable derivatives, salts, solvates and

Stereoisomers, including mixtures thereof in all ratios. The invention relates to the compounds of the formula I and their salts and to a process for preparing compounds of the formula I and their pharmaceutically usable salts and stereoisomers, characterized in that a) a compound of the formula II

wherein

Ar, R, Y and n have the meanings given in claim 1, and

L is Cl, Br, I or a free or reactive functionally modified OH group,

with a compound of the formula

wherein

G, X 1, X 2 and X 3 have the meanings given in claim 1,

implements,

or b) a compound of formula IV

wherein G, X ¹ , X ² , X ³ as defined in claim 1

Have meanings, and

L is Cl, Br, I or a free or reactive functionally modified OH group,

with a compound of formula V

wherein Ar, R, Y and n are as defined in claim 1

Have meanings

implements,

and / or converting a base or acid of the formula I into one of its salts.

Among the compounds of formula I is understood to mean the hydrates and

Solvates of these compounds, and pharmaceutically acceptable derivatives.

The invention also relates to the stereoisomers (E, Z isomers) and the hydrates and solvates of these compounds. Under Solvate the Compounds are understood to be attachments of inert solvent molecules to the compounds that form due to their mutual attraction. Solvates are eg mono- or dihydrate or

Alcoholates. 5

Pharmaceutically usable derivatives are understood, for example, as the salts of the compounds according to the invention as well as so-called prodrugs

Links. 10 Prodrug derivatives are understood with z. B. alkyl or acyl groups,

Sugars or oligopeptides modified compounds of the formula I, which in

Organism can be rapidly cleaved to the active compounds of the invention. A _c This also includes biodegradable polymer derivatives of the invention

Connections, as z. In Int. J. Pharm. 115, 61-67 (1995).

The term "effective amount" means the amount of a drug

Or a pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician. Moreover, the term "therapeutically effective amount" means one

Amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of an _OQ disease, a clinical picture, a disease state, a condition, a disorder or side effects or even the reduction of the

Progression of a disease, a disease or a disorder.

The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function. 5 The invention also provides mixtures of the invention

Compounds of the formula I _1, for example mixtures of two diastereomers or

Enantiomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or

1: 1000.

Particularly preferred are mixtures of stereoisomeric

Compounds, in particular, the compounds of the invention are as

Racemate before.

For all residues which occur several times, their meanings are independent of each other.

Above and below, the radicals or parameters Ar, G, R, X ^1, X ^2, X ^3, Y and n have the meanings indicated for the formula I, unless expressly stated otherwise.

A, A ¹ , each independently, alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 8, 9 or 10 C-atoms. A, A ^{1 are} preferably methyl, furthermore ethyl, propyl, isopropyl, butyl,

Isobutyl, sec. Butyl or tert-butyl, and also pentyl, 1-, 2- or 3-

Methylbutyl, 1, 1, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, 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-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2 or 1, 2,2-trimethylpropyl, more preferably, for example Trifluoromethyl.

A, A ^{1 are} very particularly preferably 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 1,1,1-trifluoroethyl.

A particularly preferably denotes alkyl having 1-6 C atoms, in which 1-5 H atoms can be replaced by F and / or Cl.

R is preferably H, furthermore methyl.

Y is preferably CR ⁷ R ⁸ . L is more preferably CH ₂ . X ¹ , X ² , X ^{3 are} preferably each independently H, Hal, OH or OA.

R ⁷ , R ⁸ , R ^{9 are} preferably each independently H or R ¹¹ .

R ⁷ , R ⁸ , R ^{9 are} more preferably each independently H or CH ₃ .

R ¹¹ is preferably alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, furthermore trifluoromethyl ,

Ar is, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-M _c 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-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p- Ethoxyphenyl, o-, m- or p-ethoxycarbonyl-phenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-di-)

20-methylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, , m- or p-cyanophenyl, o-,

25 m- or p-ureidophenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethyl-phenyl, o-, m- or p-carboxymethoxyphenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-,

_{30 is} 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 Di-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3 chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,

35

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-chloro phenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 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 phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, OH and / or OA, e.g. o-, m- or p-methoxyphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- Difluorophenyl or 3-chloro-4-fluoro-phenyl.

Ar ¹ is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, , m- or p-tert-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-methylaminocarbonyl) -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) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, 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, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-Ca rboxymethyl-phenyl, o-, m- or p-carboxymethoxyphenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2 , 3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro , 2-amino-3-chloro, 2-amino-4-chloro, 2-

Amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 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-bromophenyl, 3 Bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.

Het, irrespective of further substitutions, e.g. 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-thiazolyi, 3-, A- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, more preferably 1, 2,3-TriazoM-, -4- or -5-yl, 1, 2,4-triazole-1, -3- or 5-yl , 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazole 2- or -5-yl, 1, 2,4-thiadiazol-3 or -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-isoindolyl, 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-, A-, 5-, 6-,

7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6 yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl. The heterocyclic radicals may also be partially or completely hydrogenated. Het can so z. B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1, -2, -3, -A- or -5 -pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-

1-, 2- or 4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl,

Tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,

1,2,3,4-tetrahydro-1-, 2-, -3-, -A-, -5- or -6-pyridyl, 1-, 2-, 3- or 4- Piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, 3- or 4-pyranyl, 1, A-dioxanyl, 1,3-dioxane-2-, -4- or -5-yi, 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-, -A-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, -2- , 3, 4, 5, 6, 7 or 8 isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran 5- or 6-yl, 2,3- (2-oxo-10-methylenedioxy) -phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3 Dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het is preferably a mononuclear aromatic heterocycle having M _c 1 to 4 N, O and / or S atoms.

Het more preferably represents 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, A- or 5 Pyrazolyl, 2-, A- or 5-oxazolyl, 3-, A- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, A- or 5-

20

Isothiazolyl, 2-, 3- or 4-pyridyl, 2-, A-, 5- or 6-pyrimidinyl, 1, 2,3-triazole-1,

-A- or -5-yl, 1, 2,4-triazole-1, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or 5-yl , 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1 , 2,3-thiadiazol-4 or -5-yl, 3- or A-25-pyridazinyl or pyrazinyl.

Het most preferably means pyrrolyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl.

30

Het ¹ preferably denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and / or OA.

35

In a further embodiment, Het ¹ particularly preferably denotes unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and / or OA substituted furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms. Formula I encompasses all these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to II, which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I, in which however

in Ia R is H;

in Ib X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA;

in Ic Y is CH ₂ ;

in Id A alkyl having 1-6 C atoms, wherein 1-5 H atoms may be replaced by F and / or Cl, means;

in Ie Ar unsubstituted or one, two or three times by HaI,

OH and / or OA substituted phenyl;

in If GH or NH ₂ , RH,

YN, CH or CR ¹¹ ,

X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA,

Y CH ₂ ,

A is alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F and / or Cl, Ar is unsubstituted or mono-, di- or trisubstituted by

Hal, OH and / or OA substituted phenyl, 0 Hal F, Cl, Br or I ₁ n is 0, 1 or 2;

_c and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios.

The compounds of the invention and also the starting materials for their

Incidentally, preparation is carried out by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, US Pat.

Methods of organic chemistry, Georg Thieme Verlag, Stuttgart) are described, under reaction conditions, which are known and suitable for the said reactions. You can also make use of an5 known, not mentioned variants here.

The starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacts Q to the compounds of the invention.

The starting compounds are generally known. If they are new, they can be produced by methods known per se.

Compounds of the formula I can preferably be obtained by reacting a hydrazide of the formula III with a compound of the formula II. The reaction is carried out by methods known to the person skilled in the art. The reaction is generally carried out in an inert solvent, if appropriate in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine

5 or quinoline or an excess of the carboxy component of

Formula II.

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 tert-butanol; Ethers, such as diethyl ether, diisopropyl ether,. _e 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 like

acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide;

20

Carboxylic acids such as formic acid or acetic acid; Nitro compounds like

Nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents. Particularly preferred is DMF. 25

The reaction is generally carried out in the presence of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline may be beneficial.

In the compounds of the formula II, L is preferably Cl, Br, I or ° a free or a reactively modified OH group such as an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).

Such residues for activation of the carboxy group in typical

Acylation reactions are described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart;

Activated esters are conveniently formed in situ, e.g. B. by the addition of HOBt or N-hydroxysuccinimide.

Compounds of the formula I can furthermore preferably be obtained by reacting a hydrazide of the formula V with a compound of the formula IV.

The reaction is generally carried out in an inert solvent, 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 IV.

Suitable inert solvents are the abovementioned.

Also, the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium may be beneficial. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °.

In the compounds of the formula IV, L preferably denotes Cl, Br, I or a free or a reactively modified OH group, such as, for example activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).

Such residues for activating the carboxy group in typical acylation reactions are described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart; Activated esters are conveniently formed in situ, e.g. B. by the addition of HOBt or N-hydroxysuccinimide.

The cleavage of an ether is carried out by methods known to those skilled in the art.

A standard method for ether cleavage, e.g. a methyl ether, is the

Use of boron tribromide.

Hydrogenolytically removable groups, e.g. the cleavage of a benzyl ether, z. By cleavage with hydrogen in the presence of a catalyst (eg a noble metal catalyst such as palladium, conveniently on a support such as carbon). Suitable solvents are those given above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.

Esters can e.g. be saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Pharmaceutical salts and other forms

The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention

Invention, the use of these compounds in the form of their pharmaceutical ceutically acceptable salts which may be derived from various organic and inorganic acids and bases by art-known procedures. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, eg potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are also included. For certain

Compounds of formula I, acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as

Hydrogen chloride, hydrogen bromide or hydrogen iodide, others

Mineral acids and their corresponding salts such as sulfate, nitrate or

And the like, as well as alkyl and monoaryl sulfonates such as ethane sulfonate, 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 the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfate, caprylate, chloride

Chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulphate, ethanesulphonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,

Glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate,

Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,

Isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, Metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium , Sodium and zinc salts, but this should not be limiting. Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline,

N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine,

Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,

Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, Triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) -methylamine (tromethamine), but this is not intended to be limiting.

Compounds of the present invention containing basic nitrogen-containing

Groups can be, with agents such as (CrC ₄ ) alkyl halides, for example, methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C ₁ -C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (d _o -C ₈₎ alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,

bromide and iodide; and aryl (C _r C ₄ ) alkyl halides, eg benzyl chloride and Phenethylbromide, quaternization. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

Among the above-mentioned pharmaceutical salts which are preferred include

Acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate,

Hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.

The acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid, thereby reducing to common

Way the salt represents. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ, in a sense, from their corresponding salt forms with respect to certain physical ones

Properties such as solubility in polar solvents; As part of the

However, the salts otherwise correspond to their respective free base forms.

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of acidic compounds of this invention are prepared by contacting the free acid form with a sufficient amount of the desired base to yield the

Represents salt in the usual way. The free acid can be determined by contacting Bring the salt form with an acid and isolate the free acid in the usual way regenerate. The free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.

In view of the above, one sees that under the expression

"pharmaceutically acceptable salt" as used herein means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other

Salt form of the active ingredient, which has been used earlier, imparts improved pharmacokinetic properties. The pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.

Compounds of the formula I according to the invention can, on the basis of their

Molecular structure can be chiral and therefore can occur in different enantiomeric forms. They may therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or the stereoisomers of the compounds of the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.

In the case of racemic amines diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer separation using an optically active resolving agent (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.

The invention further relates to the use of the compounds and / or their physiologically acceptable salts for the preparation of a medicament (pharmaceutical preparation), in particular by non-chemical means. In this case, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.

The invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants. Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a unit may for example be 0.5 mg to 1 g, preferably

5

1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be in the form of dosage units,

10 containing a predetermined amount of active ingredient per unit dose are presented. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Continue to leave

A [- prepare such pharmaceutical formulations by any of the methods well known in the pharmaceutical art.

Pharmaceutical formulations may be administered for administration by any suitable route, for example, oral (including

20 buccalem or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).

_O0 Pharmaceutical formulations adapted for oral administration may be administered as separate entities such as capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water

Liquid emulsions or water-in-oil liquid emulsions are presented. 35 Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.

Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants and lubricants (eg lubricants such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form may be added to the powder mixture before the filling process.) A disintegrating agent or solubilizer such as agar-agar, calcium carbonate or sodium carbonate may also be added be added to the availability of the

20

Drug after taking the capsule to improve.

In addition, if desired or necessary, suitable bonding, lubricating and disintegrating agents and dyes may also be included in the mixture

25 are incorporated. Suitable binders include starch,

Gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. To

_{O0 include} the lubricants used in these dosage forms

Sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, a powder mixture

35, granulated or dry pressed, a lubricant and a

Blasting agents are added and the whole is pressed into tablets. A powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a 5

Solution slower, such as paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime, or solutions of cellulosic or polymeric materials and pressing through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape, which are burst into granules aufgeb _e. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then without any penetration.

20 guide the granulation or dry compression steps directly to

Tablets are pressed. A transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units. Q Oral fluids, e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a nontoxic vehicle. Suspensions can through

Dispersion of the compound can be formulated in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.

The compounds according to the invention and their salts can also be prepared in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.

The compounds of the invention and the salts can also be mentioned

Use of monoclonal antibodies as individual carriers to which the compound molecules are coupled are supplied. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinyl pyrrolidone, pyran

Copolymer, Polyhydroxypropylmethacrylamidphenol, Polyhydroxyethylaspart- amidphenol or Polyethylenoxidpolylysin substituted with Palmitoylresten include. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipathic

Block copolymers of hydrogels to be coupled. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, troches and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid contain a coarse powder a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is taken, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for the 5

Administration as a nasal spray or nasal drops with a liquid as

Vehicle include drug solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.

,,, Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Among the adapted for parenteral administration pharmaceutical

20

Formulations include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions containing

25 suspending agent and thickener may contain. The formulations may be administered in single or multiple dose containers, e.g. sealed ampoules and vials, and stored in freeze-dried (lyophilised) condition, so that only the addition of the sterile

O _Q liquid, eg water for injections, is required immediately before use. Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.

35

It is understood that the formulations in addition to the above-mentioned particularly mentioned constituents other conventional means with respect to may contain the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.

5 A therapeutically effective amount of a compound of the present invention

The invention depends on a number of factors, including e.g. the age and weight of the individual or animal, the exact condition of the disease requiring treatment, and the severity of the condition

^ Q of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention for treatment is generally in the range of 0.1 to 100 mg / kg body weight of the recipient

(Mammal) per day and more typically in the range of 1 to 10 mg / kg

15

Body weight per day. Thus, would be for a 70 kg adult

Mammals the actual amount per day is usually between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per day

20 can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be

P ₅ assume that similar dosages are suitable for the treatment of the other, above-mentioned disease states.

The invention furthermore relates to medicaments containing at least one compound according to the invention and / or their pharmaceuticals

30 usable salts and stereoisomers, including mixtures thereof in all proportions, and at least one further active pharmaceutical ingredient.

The invention is also a set (kit), consisting of separate 35 packages of (A) an effective amount of a compound of the invention and / or its pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions, and 5

(b) an effective amount of another drug.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. separate ampoules

Each containing an effective amount of a compound of the invention and / or its pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance or dissolved

, ₅ is present in lyophilized form.

USE

The present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of SGK-related diseases.

The invention thus relates to the use of compounds

25 according to claim 1, as well as its pharmaceutically usable derivatives,

Solvates and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of kinase signal transduction is involved. Preferred here is SGK.

Preference is given to the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of diseases which are affected by inhibition of SGK by the compounds of claim 1.

The present invention comprises the use of the compounds of the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular diseases (eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, atherosclerosis) and renal diseases (eg glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, disturbance of excretion of electrolytes), in general for all types of fibrosis and inflammatory processes (eg liver cirrhosis,

Pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis,

Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring, Alzheimer's disease).

The compounds of the invention can also increase the growth of

Cancer, tumor cells and tumor metastases inhibit and are therefore suitable for tumor therapy.

The compounds of the invention are also used for the treatment of coagulopathies, e.g. Dysfibrinogenemia, hypoproducinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immunocagulopathy or complex coagulopathies, as well as neuronal excitability, e.g. Epilepsy. The compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.

The compounds of the invention are also used in the

Treatment of bacterial infections as well as in an anti-infective Therapy. The compounds of the invention may also be used therapeutically to increase learning and attention.

Preferred is the use of compounds according to claim 1, as well as their pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the manufacture of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertension , Cardiovascular diseases and kidney diseases, in general for all types of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastases, coagulopathies, neuronal excitability, glaucoma, cataracts, bacterial infections and in an anti-infective therapy to increase learning and attention, as well as for treatment and prophylaxis of cell aging and stress.

Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.

Cardiovascular diseases are preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.

Renal diseases are preferably glomeruli.

Sclerosis, nephrosclerosis, nephritis, nephropathy and disorder of the

Electrolyte excretion.

Fibrosis and inflammatory processes are preferably liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis,

Rheumatism and arthritis, Crohn's disease, chronic bronchitis, Radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring, Alzheimer's disease.

ASSAYS

5

The compounds of the invention described in the Examples were tested in the assays described below and found to have kinase inhibitory activity. Other assays are known in the literature and could be readily performed by those skilled in the art (see, eg, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et Biol. 38: 237-248; Gimbrone et al., J. J. Med.

Natl. Cancer Inst. 52: 413-427; Nicosia et al., In Vitro 18: 538-549).

15

The inhibition of SGK1 protein kinase can be determined in the filter binding procedure.

Above and below all temperatures are given in ⁰ C. In the 20 examples below, "usual workup" means adding water if necessary, if necessary depending on the constitution of the

Final product to pH values between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium _? -Sulfate, evaporated and purified by chromatography on silica gel and / or by crystallisation. Rf values on silica gel; Eluent: ethyl acetate / methanol

9: 1st

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺

30

ESI (Electrospray Ionization) (M + H) ⁺ (unless otherwise indicated)

HPLC method

35 A (polar): Hewlett Pachard system of the HP 1100 series with the following

Characteristics: ion source: ES (positive mode), scan 100-1000 m / z,

Fragmentation voltage: 60 V, gas temperature: 300 ⁰ C, DAD 220 nm

Column: Chromolith SpeedROD RP-18e, 50-4.6

Flow rate 2.4 ml / min

The splitter used reduced the flow rate for the MS after the DAD

0.75 ml / min

Solvent A: water + 0.1% TFA

Solvent B: acetonitrile + 0.08% TFA

Gradient:

0.0 min 5% B

2.8 min 100% B

3.3 min 100% B

B:

Column: Chromolith SpeedROD RP-18e, 50-4.6

Flow rate 2.4 ml / min

Solvent A: water + 0.1% TFA

Solvent B: acetonitrile + 0.1% TFA

Gradient:

0.0 min 4% B

2.6 min 100% B

3.3 min 100% B

HPLC-MS-Esi1.Rod.rn / Polar.m / Unpolar.m Method Column Chromolith Speed Rod RP 18e 50-4.6 mm Flow 2.4 ml / min Buffer A 0.01% TFA / water Buffer B 0.008% TFA / acetonitrile Wavelength 220 nm Gradient 0.0-2.8 min 20% -100% Buffer B; 2.8-3.3min 100% Buffer B; Esi1.rod.rn 3.3-3.4 min 100% -20% Buffer B; 3.4-3.8min 20% buffer B

Gradient 0.0-3.0min 5% -100% Buffer B; 3.0-3.5min 100% Buffer B;

Polar.m 3.5-3.6 min. 100% -5% Buffer B; 3.6-3.8min 20% buffer B

Gradient 0.0-2.5 min 40% -90% Buffer B; 2.5-3.8min 90% buffer B;

Unpolar.m 3.8-3.9 min 90% Buffer B: 3.9-4, 1 min 90% -40% Buffer B

Abbreviations:

DCM = dichloromethane

EE = ethyl acetate

PE = petroleum ether

RT = room temperature

DAPECI = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride

DMF = dimethylformamide

HOBT = 1-hydroxybenzotriazole

NCS = N-chlorosuccinimide

TFA = trifluoroacetic acid

synthesis Examples

Method 1: (Compounds A1-A2)

Example 1 :

Preparation of 4-methoxy-1H-indazole-5-carboxylic acid N '- [2-hydroxy-2- (3-methoxyphenyl) acetyl] hydrazide ("A1")

Step 1: Clutch 49 mg of 4-methoxy-1H-indazole-5-carboxylic acid, 57.5 mg of DAPECI ₁ 45.9 mg of HOBT hydrate and 50 mg of hydroxy- (3-methoxyphenyl) -acetic acid hydrazide in 1 ml of DMF are placed in a screw-cap vial dissolved and stirred for 1 hour at RT. The reaction mixture is drawn onto silica gel and purified by chromatography on silica gel (heptane / EA). After combining the appropriate fractions and removing the solvent, 48 mg of a solid are obtained. This is again stirred with 1 N HCl (removal of HOBT residues), filtered off with suction and dried. This gives 32 mg of colorless crystals; 33% yield; MS-FAB (M + H ⁺ ) = 371, 1; R _f (polar method): 1, 33 min; 1 H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 13.33 (1H, s, br), 10.22 (1H, s, br), 9.88 (1H, s, br ), 8.47 (1H, s, br), 7.74 (1H, d, J = 8.6Hz), 7.26 (1H, t, J = 8.0Hz), 7.21 ( 1 H, d, J = 8.8 Hz), 7.14 (1 H, s, br), 7.10 (1H, d, J = 8.0 Hz), 6.86 (1H, dd, J = 8.0 Hz, J = 2.6 Hz), 6.16 (1H, d, J = 5.5 Hz), 5.10 (1H, d, J = 5.5 Hz), 4.31 (3H, s), 3.78 (3H, s).

By this method, the compound A2 is also obtained:

Grundsätzlich ist die oben beschriebene Methode auch auf andere substituierte lndazol-5-carbonsäuren und andere Mandelsäurehydrazide übertragbar.

In principle, the method described above is also applicable to other substituted indazole-5-carboxylic acids and other mandelic acid hydrazides.

Mandelic acid hydrazides are z.T. commercially available or can be prepared by the following reaction sequence (method 1a):

Example 1a:

Hydroxy- (3-methoxy-phenyl) -acetic acid hydrazide (last step)

In a reaction vessel 3 g of methyl hydroxy- (3-methoxy-phenyl) - acetate are heated with 1, 5 ml of hydrazine hydrate in 40 ml of 2-propanol for 2 hours at 90 ⁰ C bath temperature. The solvent is distilled off, the residue is taken up in THF and the product is precipitated by the addition of heptane. 2.0 g of hydroxy- (3-methoxyphenyl) -acetic acid hydrazide are obtained as colorless crystals (66% yield); MS-FAB (M + H ⁺ ) = 197.1; R _f (polar method): 0.77 min.

Example 1b:

Hydroxy- (3-fluoro-phenyl) -acetic acid hydrazide Hydroxy (3-fluorophenyl) -acetic acid hydrazide is prepared analogously to Example 1a: (68% yield); MS-FAB (M + H ⁺ ) = 185.1; R _f (polar method): 0.73 min.

Substituted indazole-5-carboxylic acids are either commercially available or can be prepared by methods known to those skilled in the art, see e.g. in WO2008065508 and WO2003101968 (synthesis of 4-methoxy-indazole-5-carboxylic acid).

In WO2003101968 also the synthesis of 4-fluoro-indazole-5-nitrile and 4-fluoro-indazole-5-carboxylic acid methyl ester is described. From 4-fluoro-indazole-5-nitrile, the carboxylic acid can be obtained by acid hydrolysis, from the ester e.g. by basic hydrolysis ..

Method 2: (Compounds A3-A6)

Example 2: Preparation of 3-amino-1H-indazole-5-carboxylic acid N '- ((R) -3-hydroxy-3-phenylpropionyl) hydrazide ("A5")

80.0 mg of (R) -3-hydroxy-3-phenylpropionic acid, 115.0 mg of DAPECI and 91.9 mg of 3-amino-1H-indazole-5-carboxylic acid hydrazide are dissolved in 1 ml of DMF in a screw-cap vial and stirred overnight at RT. The reaction mixture is carefully concentrated and the residue is purified by column chromatography on silica gel (eluent EA / MeOH). 100 mg of 3-amino-1H-indazole-5-carboxylic acid N '- ((R) -3-hydroxy-3-phenyl-propionyl) hydrazide are obtained (yield: 61%). MS-FAB (M + H ⁺ ) = 340.4. R _f (polar method): 0.45 min.

Example S. ^¬ Preparation of 7-chloro-1 H-indazol-5-carboxylic acid N '- [2- (3,4-difluoro-phenyl) -2-hydroxy-acetyl] hydrazide ( "A3")

115 mg (3,4-difluoro-phenyl) -hydroxyacetic acid, 151.0 mg of DAPECI, 67 μl of N-methylmorpholine and 150.0 mg of 7-chloro-1H-indazole-5-carboxylic acid hydrazide hydrochloride in 1 ml. Are placed in a screw-cap vial Dissolved DMF and stirred overnight at RT. The reaction mixture is added to water, extracted three times with EA and the organic phase is dried and concentrated. The residue is purified by column chromatography on silica gel (eluent EA / MeOH). This gives 90 mg of 7-chloro-1 H-indazole-5-carboxylic acid N '- [2- (3,4-difluorophenyl) -2-hydroxy-acetyl] hydrazide (yield: 39%); MS-FAB (M + H ⁺ ) = 381.5; R _f (method polar): 1, 47 min.

Analogously, the following compounds are obtained

Pharmacological data

Table 1 SGK inhibition

IC ₅₀ : 1 nM-0.1 μM = A 0.1 μM-10 μM = B> 10 μM = C The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 2 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar 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 ingredient.

Example C: Solution

A solution of 1 g of an active ingredient according to the invention is prepared,

9.38 g of NaH ₂ PO ₄ • 2H ₂ O, 28.48 g of Na ₂ HPO ₄ ^• 12H ₂ O and 0.1 g

Benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

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: Tablets

A mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient. Example F: dragees

Tablets are pressed analogously to Example E, which are then treated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and

Dye are coated.

Example G: Capsules

2 kg of active ingredient are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

claims 1. Compounds of the formula I

wherein GH or NH ₂ , R ¹ or A, X ¹ , X ² , X ^{3 are} each, independently of one another, H, Hal, A, Ar, Het, OH, OA, OAr, OHet, SH, SA, SAR, NH _2, NHA, NAA ^1, NHAr, NHHet, N (Ar) _2, Naar, SOA, Soar, SO ₂ A, SO ₂ Ar, NO _2, CN, COOH, COOA , CONH ₂ , CONHA, CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COAr, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr, SO ₂ N (Ar) ₂ , CH (OH) A or CH (OH) Ar, Y CR ⁷ R ⁸ , OCR ⁷ R ⁸ , CR ⁷ R ⁸ O, NR ⁹ CR ⁷ R ⁸ , CR ⁷ R ⁸ NR ⁹ , CR ⁷ R ⁸ SO ₂ or SO ₂ R ⁷ R ⁸ , R ⁷ , R ⁸ , R ^{9 are} each independently H or A, R ^{11 is} alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F, A, A 'are each independently of the other unsubstituted or mono-, di- or trisubstituted by = S, = NR ⁷ and / or = O (carbonyl oxygen) substituted alkyl having 1-10 C atoms, wherein one, two or three CH ₂ - Groups by O, S, SO, SO ₂ , NH, NR ¹¹ and / or by -CH = CH groups and / or 1-7 H atoms may be replaced by F and / or Cl, or cyclic alkyl with 3 -7 carbon atoms, Ar unsubstituted or one, two, three or four times by A, Hal, OH, OA, Ar ¹ , OAr ¹ , Het, OHet, SH, SA, SAr ¹ , SHet, NH ₂ , NHA, NAA ¹ , NHAr ¹ , N (AO ₂ , NHHet, N (Het) ₂ , NAAr ¹ , NAHet, SOA, SOAr ¹ , SOHet, SO ₂ A, SO ₂ Ar ¹ , SO ₂ Het, NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COAr ¹ , COHet, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ¹ , SO ₂ N (AO ₂ , SO ₂ NHHet and / or SO ₂ N (Het) ₂ substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the one, two or three times by A, Hal, OH, OA, Ar, OAr, Het ¹ , OHet ¹ , SH, SA, SAr ¹ , SHet ¹ , NH ₂ , NHA, NAA ¹ , NHAr ¹ , N (Ar ¹ J ₂ , NHHet ¹ , N (Het ') ₂₎ NAAr ¹ , NAHet ¹ , SOA, SOAr ¹ , SOHeV, SO ₂ A, SO ₂ Ar ¹ , SO ₂ Het \ NO ₂ , CN , COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO, COA, COAr ¹ , COHef, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ¹ , SO ₂ N (Ar ¹ J ₂ , SO ₂ NHHeV or SO ₂ N (HeV) ₂ , = S, = NR ⁷ and / or = O (carbonyl oxygen) may be substituted, Ar ¹ unsubstituted or one, two, three or four times by A, Hal, OH , OA, OPhenyl, SH, SA, NH ₂ , NHA, NAA ¹ , NH-phenyl, SOA, SOPhenyl, SO ₂ A, SO ₂ phenyl, NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NACOA, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHSO ₂ A, NASO ₂ A, CHO , COA, COPhenyl, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHPhenyl and / or SO ₂ N (phenyl) ₂ substituted phenyl, HeV is a mononuclear saturated heterocycle having 1 to 4 N, O and / or S atoms, which is mono-, di- or trisubstituted by A, Hal, OH, OA, NH ₂ , NHA, NAA ¹ , NO ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , = S, = NR ⁷ and / or = O (carbonyl oxygen) may be substituted, Hal is F, Cl, Br or I ₁ n is 0, 1 or 2, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios. 2. Compounds according to claim 1, wherein R is H, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions. 3. Compounds according to claim 1 or 2, wherein X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA, as well as their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios. 4. Compounds according to claim 1, 2 or 3, wherein Y is CH ₂ , and their pharmaceutically acceptable salts and. Stereoisomers, including mixtures thereof in all ratios. 5. Compounds according to one or more of claims 1-4, w ^orin Ar is unsubstituted or mono-, di- or trisubstituted by Hal, OH and / or OA substituted phenyl, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions. 6. Compounds according to one or more of claims 1-5, wherein A is alkyl having 1-6 C atoms, wherein 1-5 H atoms by F and / or Cl, as well as their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions. 7. Compounds according to one or more of claims 1-6, wherein GH or NH ₂ , R H, Y 11 N, CH or CR ¹ X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA, Y is CH ₂ , A is alkyl having 1-6 C atoms, wherein 1-5 H atoms are represented by F and / or Cl may be substituted, Ar is unsubstituted or mono-, di- or trisubstituted by Hal, OH and / or OA substituted phenyl, Hal, F, Cl, Br or I, n is 0, 1 or 2, and their pharmaceutically acceptable salts and stereoisomers , including mixtures thereof in all proportions. 8. Compounds according to claim 1 selected from the group

and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions. 9. A process for the preparation of compounds of the formula I according to claims 1-8 and their pharmaceutically acceptable salts and stereoisomers, characterized in that a) a compound of formula II

wherein Ar, R, Y and n have the meanings given in claim 1, and L is Cl, Br, I or a free or reactive functionally modified OH group, with a compound of the formula

wherein G ₁ X ¹ , X ² and X ^{3 have} the meanings given in claim 1, implements, or b) a compound of formula IV

wherein G, X ¹ , X ² , X ^{3 have} the meanings given in claim 1, and L is Cl, Br, I or a free or reactive functionally modified OH group, with a compound of formula V

wherein Ar, R, Y and n have the meanings given in claim 1, implements, and / or converting a base or acid of the formula I into one of its salts. 10. A pharmaceutical composition containing at least one compound according to claim 1-8 and / or their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants. 11. Use of compounds according to claim 1-8, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions, for the manufacture of a medicament for the treatment and / or prophylaxis of diseases in which the inhibition, regulation and / or modulation of Signal transduction of kinases plays a role. 12. Use according to claim 11, wherein the kinase is SGK. 13. Use according to claim 12 of compounds according to claim 1-8, as well as their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions, for the preparation of a medicament for the treatment of diseases resulting from the inhibition of SGK by the compounds according to claim 1- 8 are affected. 14. Use according to claim 13 of compounds according to claim 1-8, and their pharmaceutically usable derivatives, solvates and Stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular and renal diseases, in general for any type of fibrosis and inflammatory processes, cancer, tumor cells , Tumor metastases, coagulopathies, neuronal excitability, Glaucoma, cataracts, bacterial infections as well as in an anti-infectious therapy, to increase the ability to learn and Attention, as well as for the treatment and prophylaxis of cell aging and stress and for the treatment of tinitus. Use according to claim 14, wherein diabetes is diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy. 16. Use according to claim 14, wherein cardiovascular diseases are cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis. 17. Use according to claim 14, wherein it is at Renal diseases are glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, and electrolyte clearance disorder. 18. Use according to claim 14, wherein fibrosis and inflammatory processes are cirrhosis of the liver, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, and morbus Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring and Alzheimer's disease. 19. Medicaments containing at least one compound according to claim 1-8 and / or their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all Conditions, and at least one other drug. 20. Set (kit), consisting of separate packs of (a) an effective amount of a compound according to claims 1-8 and / or its pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions, and (b) an effective amount of another Drug ingredient.