DE102008038222A1 - Indazol-5-carboxylic acid derivatives - Google Patents

Abstract

New oxadiazole derivatives of the formula I, $ F1 wherein Ar, G, R, X1, X2, X3, Y and n have the meanings given in claim 1, are kinase inhibitors and can be used for the treatment of diseases and conditions such as diabetes, obesity, metabolic Syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular diseases and kidney disease, commonly used in any type of fibrosis, inflammatory processes, tumors and tumors.

Description

BACKGROUND OF THE INVENTION

Of the Invention was based on the object, new compounds with valuable Find properties, especially those for the production of medicines can be used.

The The present invention relates to compounds in which the inhibition, Regulation and / or modulation of 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 pharmaceutical compositions containing these compounds included, as well as the use of the compounds for treatment 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 preferred selective inhibitors of SGK-1. Furthermore, they can inhibitors the SGK-2 and / or SGK-3.

in the In particular, the present invention relates to compounds containing the Inhibit, regulate and / or modulate signal transduction of the SGK, Compositions containing these compounds, as well as methods for their use in the treatment of SGK-related diseases and conditions such as 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 heart failure, Arteriosclerosis) and renal diseases (eg glomerulosclerosis, nephrosclerosis, Nephritis, nephropathy, electrolyte clearance disorder), common to any type of fibrosis and inflammatory Processes (eg liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, Rheumatism and arthritis, Crohn's disease, chronic bronchitis, Radiation fibrosis, sclerodermatitis, 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, especially in forms, which are triggered by stress.

The Compounds of the invention continue to find Use for the treatment of coagulopathies, such. B. dysfibrinogenemia, Hypoproconvertinemia, hemophilia B, Stuart-Prower defect, Prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, Immunocoagulopathy or complex coagulopathies, as well as in 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 of the invention can also to increase the ability to learn and attention be used therapeutically. In addition, the effect Cell aging compounds of the invention and stress and thus increase life expectancy and the Fitness in old age.

The compounds of the invention are also used in the treatment of tinitus.

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

It has been found that the inventive Compounds and their salts are very well tolerated possess valuable pharmacological properties.

Especially show inhibitory properties of SGK.

The present invention therefore relates to compounds according to the invention as a medicament tel 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 manufacture of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said diseases comprising the administration of one or more Compounds according to the invention to a patient in need of such administration.

Of the The host or patient may be of any mammalian species, z. A primate species, especially humans; Including rodents Mice, rats and hamsters; Rabbits; Horses, cattle, Dogs, cats, etc. Animal models are for experimental Investigations of interest, being a model for treatment to provide a human disease.

To identify a signal transduction pathway and to detect interactions between different signal transduction pathways, suitable models or model systems have been developed by various scientists, e.g. B. cell culture models (e.g. Khwaja et al., EMBO, 1997, 16, 2783-93 ) and models of transgenic animals (eg White et al., Oncogene, 2001, 20, 7064-7072 ). To determine certain stages in the signal transmission cascade, interacting connections can be used to modulate the signal (eg. 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 a technique well known to those skilled in the art. Generic test systems for determining kinase activity with substrates, e.g. B. histone (eg. Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338 ) or myelin basic protein are described in the literature (e.g. Campos-González, 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 with γATP is measured. In the presence of an inhibitory compound, no or a reduced radioactive signal is detectable. Furthermore, homogenous time-resolved fluorescence resonance energy transfer (HTR-FRET) and fluorescence polarization (FP) technologies are useful as assay methods ( Sills 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 with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence ( Ross et al., Biochem. J., 2002, 366, 977-981 ).

It can be shown that the invention Compounds in a xenograft tumor model in vivo have antiproliferative activity. The invention Compounds are given to a patient with a hyperproliferative Administered disease, z. B. for inhibiting tumor growth, for Reduction of those associated with a lymphoproliferative disorder Inflammation, 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" as a reference both on the prevention of diseases as well as the treatment of pre-existing ones Suffering used. Prevention of proliferation is by Administration of the compounds of the invention before developing the obvious disease, z. B. to prevent tumor growth, prevention of metastatic growth, reduction cardiovascular surgery-related restenosis etc. reached. As an alternative, the compounds are for treatment persistent diseases by stabilization or improvement of the used clinical symptoms of the patient.

The Susceptibility of a particular cell the treatment with the compounds according to the invention can be determined by testing in vitro. Typically will a culture of the cell with an inventive Compound at different concentrations for a period of time combined, sufficient to enable the active agents Induce cell death or inhibit migration, usually between about an hour and a week. For testing in vitro can use cultured cells from a biopsy sample become. The remaining viable after treatment Cells are then counted.

The Dose varies depending on the specific used Connection, specific disease, patient status, etc. Typically, one therapeutic dose is sufficient to treat the unwanted cell population in the target tissue significantly increased diminish while maintaining the patient's viability becomes. The treatment is generally continued until a significant Reduction is present, for. B. at least about 50% reduction in cell load and can be continued until essentially no unwanted Cells are detected more in the body.

STATE OF THE ART

Other aminoaryl compounds are known 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 in WO 2006/064189 A1 for the treatment of diabetes mellitus and obesity.

Other heterocyclic derivatives are in WO 2006/024034 A1 described among other things for the treatment of cancer and inflammation.

Indoles and other heterocyclic derivatives are known as kinase inhibitors in US 2005/250829 disclosed.

Other heterocyclic oxadiazole derivatives are known WO 2002/72549 A1 ,

In the WO 00/62781 describes the use of drugs containing inhibitors of the cell volume-regulated human kinase H-SGK. Heterocyclic indazole derivatives for the treatment of diabetes and / or cancer are known WO 2006/044860 and WO 2005056550 ,

In US 2005090529 indazole derivatives are disclosed for the treatment of diabetic retinopathy.

Indazole derivatives for the treatment of tumors are in WO 2005000813 discloses such for the treatment of cardiovascular diseases in WO 2004060318 ,

Other heterocyclic compounds for treating tumors are known WO 2004052280 ,

In addition, other heterocycles for the treatment of psychotic disorders in EP 328200 disclosed.

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

In Bioorganic & Medicinal Chemistry Letters 13 (2003) 3059-3062 J. Witherington et al. the production of indazole derivatives. Indazole derivatives are known as kinase inhibitors in WO 2003097610 described. Indazole derivatives are known as GSK-3 inhibitors in WO 2003051847 disclosed. 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 of C. Doerig in Cell. Biol. Lett. Vol. 8, no. 2A, 2003, 524-525 described. The use of kinase inhibitors in obesity is of N. Perrotti in J. Biol. Chem. 2001, March 23; 276 (12): 9406-9412 described.

• 1: Chung EJ, Sung YK, Farooq M, Kim Y, Im S, Tak WY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression Profile analysis in human hepatocellular carcinoma by cDNA 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 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 signalling 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 .

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 YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA 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 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 si gnals 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 ,
• 8th: C. 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

worin
G H oder NH₂,
R H oder A,
X¹, X², X³ jeweils unabhängig voneinander H, Hal, A, Ar, Het, OH, OA, OAr, OHet, SH, SA, SAr, NH₂, NHA, NAA', NHAr, NHHet, N(Ar)₂, NAAr, SOA, SOAr, SO₂A, SO₂Ar, NO₂, CN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NACOA, NHCONH₂, NHCONHA, NHCONA₂, NHSO₂A, NASO₂A, CHO, COA, COAr, SO₃H, SO₂NH₂, SO₂NHAr, SO₂N(Ar)₂, CH(OH)A oder CH(OH)Ar,
Y CR⁷R⁸, OCR⁷R⁸, CR⁷R⁸O, NR⁹CR⁷R⁸, CR⁷R⁸NR⁹, CR⁷R⁸SO₂ oder SO₂R⁷R⁸,
R⁷, R⁸, R⁹ jeweils unabhängig voneinander H oder A,
R¹¹ Alkyl mit 1-6 C-Atomen, worin 1-5 H-Atome durch F ersetzt sein können,
A, A' jeweils unabhängig voneinander unsubstituiertes oder ein-, zwei- oder dreifach durch =S, =NR⁷ und/oder =O (Carbonylsauerstoff) substituiertes Alkyl mit 1-10 C-Atomen, worin eine, zwei oder drei CH₂-Gruppen durch O, S, SO, SO₂, NH, NR¹¹ und/oder durch -CH=CH-Gruppen und/oder auch 1-7 H-Atome durch F und/oder Cl ersetzt sein können,
oder cyclisches Alkyl mit 3-7 C-Atomen,
Ar unsubstituiertes oder ein-, zwei-, drei- oder vierfach durch A, Hal, OH, OA, Ar', OAr', Het, OHet, SH, SA, SAr', SHet, NH₂, NHA, NAA', NHAr', N(Ar')₂, NHHet, N(Het)₂, NAAr', NAHet, SOA, SOAr', SOHet, SO₂A, SO₂Ar', SO₂Het, NO₂, CN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NACOA, NHCONH₂, NHCONHA, NHCONA₂, NHSO₂A, NASO₂A, CHO, COA, COAr', COHet, SO₃H, SO₂NH₂, SO₂NHAr', SO₂N(Ar')₂, SO₂NHHet und/oder SO₂N(Het)₂ substituiertes Phenyl, Naphthyl oder Biphenyl,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der ein-, zwei- oder dreifach durch A, Hal, OH, CA, Ar, OAr, Het', OHet', SH, SA, SAr', SHet', NH₂, NHA, NAA', NHAr', N(Ar')₂, NHHet', N(Het')₂, NAAr', NAHet', SOA, SOAr', SOHet', SO₂A, SO₂Ar', SO₂Het', NO₂, CN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NACOA, NHCONH₂, NHCONHA, NHCONA₂, NHSO₂A, NASO₂A, CHO, COA, COAr', COHet', SO₃H, SO₂NH₂, SO₂NHAr', SO₂N(Ar')₂, SO₂NHHet' oder SO₂N(Het')₂, =S, =NR⁷ und/oder =O (Carbonylsauerstoff) substituiert sein kann,
Ar' unsubstituiertes oder ein-, zwei-, drei- oder vierfach durch A, Hal, OH, OA, OPhenyl, SH, SA, NH₂, NHA, NAA', NHPhenyl, SOA, SOPhenyl, SO₂A, SO₂Phenyl, NO₂, CN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NACOA, NHCONH₂, NHCONHA, NHCONA₂, NHSO₂A, NASO₂A, CHO, COA, COPhenyl, SO₃H, SO₂NH₂, SO₂NHPhenyl und/oder SO₂N(Phenyl)₂ substituiertes Phenyl,
Het' einen einkernigen gesättigten Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der ein-, zwei- oder dreifach durch A, Hal, OH, OA, NH₂, NHA, NAA', NO₂, CN, COOH, COOA, CONH₂, CONHA, CONA₂, =S, =NR⁷ und/oder =O (Carbonylsauerstoff) substituiert sein kann,
Hal F, Cl, Br oder I,
n 0, 1 oder 2
sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.The invention relates to compounds of the formula I.

wherein
GH or NH ₂ ,
RH 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 ', 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 can be replaced by O, S, SO, SO ₂ , NH, NR ¹¹ and / or by -CH = CH groups and / or also 1-7 H atoms by F and / or Cl,
or cyclic alkyl having 3-7 C atoms,
Ar is unsubstituted or substituted once, twice, three or four times by A, Hal, OH, OA, Ar ', OAr', Het, OHet, SH, SA, SAr ', SHet, NH ₂ , NHA, NAA', NHAr ', N (Ar') _2, NHHet, N (Het) _2, naar ', draws near, 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 ', COHet, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ', SO ₂ N (Ar') 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, one, two or three times by A, Hal, OH, CA, Ar, OAr, Het ', OHet', SH, SA, SAr 'SHet', NH _2, NHA, NAA ', NHAr', N (Ar ') _2, NHHet', N (Het ') _2, naar', draws near ', 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 ', COHet', SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ', SO ₂ N (Ar') ₂ , SO ₂ NHHet 'or SO ₂ N ( Het ') ₂ , = S, = NR ⁷ and / or = O (carbonyl oxygen) may be substituted,
Ar 'is unsubstituted or mono-, di-, tri- or quadruple by A, Hal, OH, OA, OPhenyl, SH, SA, NH ₂ , NHA, NAA', 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,
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) may be substituted,
Hal F, Cl, Br or I,
n 0, 1 or 2
and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including mixtures thereof in all ratios.

• a) eine Verbindung der Formel II
  
  worin Ar, R, Y und n die in Anspruch 1 angegebenen Bedeutungen haben, und L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewandelte OH-Gruppe bedeutet, mit einer Verbindung der Formel III
  
  worin G, X¹, X² und X³ die in Anspruch 1 angegebenen Bedeutungen haben, umsetzt, oder
• b) eine Verbindung der Formel IV
  
  worin G, X¹, X², X³ die in Anspruch 1 angegebenen Bedeutungen haben, und L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewandelte OH-Gruppe bedeutet, mit einer Verbindung der Formel V
  
  worin Ar, R, Y und n die in Anspruch 1 angegebenen Bedeutungen haben, umsetzt,

und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.The invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I 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 reactively functionally modified OH group, with a compound of formula III
  
  wherein G, X ¹ , X ² and X ^{3 have} the meanings given in claim 1, 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 reactively functionally modified OH group, with a compound of formula V
  
  in which Ar, R, Y and n have the meanings given in claim 1,

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

The compounds of the formula I are also understood as meaning the hydrates and solvates of this compound gene, further pharmaceutically usable derivatives. The invention also relates to the stereoisomers (E, Z isomers) and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are z. As mono- or dihydrate or alcoholates.

Under pharmaceutically usable derivatives are understood z. As the salts the compounds of the invention as well as so-called Prodrug compounds.

Under Prodrug derivatives are understood with z. B. alkyl or acyl groups, Sugars or oligopeptides modified compounds of the formula I, which in the organism rapidly to the effective compounds of the invention be split.

These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995) is described.

Of the Expression "effective amount" means the amount of one Medicinal product or a pharmaceutical active substance containing a biological or medical response in a tissue, system, animal or causes people who z. B. by a researcher or physician sought or desired.

Moreover, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in:
improved curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a condition, a disorder or side effects or even a reduction in the progression of a disease, a condition or a disorder. The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

object The invention also mixtures of the invention Compounds of the formula I, for. B. Mixtures of two diastereomers or enantiomer z. In the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000.

Especially these are preferably mixtures of stereoisomeric compounds, in particular, the compounds of the invention are as a racemate.

For all radicals that occur several times, that 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 'is, in each case independently, alkyl unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 8, 9 or 10 carbon atoms. A, A 'are preferably methyl, furthermore Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, 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, further preferably z. B. trifluoromethyl.

A, A 'is 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 is particularly preferably alkyl having 1-6 C atoms, wherein 1-5 H atoms may 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 means z. 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-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-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-, 2,5-, 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-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-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 unsubstituted or mono-, di- or trisubstituted substituted by Hal, OH and / or OA phenyl, such as. B. 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 ' is preferably 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-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-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-, 2,5-, 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-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-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferred 1,2,3-triazole-1, -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-thiadiazol-2 or -5-yl, 1,2,4-thiadiazole-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-, 4-, 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 be hydrogenated.

Het So z. B. also mean 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, tetrahydro-2-or 3-thienyl, 2,3-dihydro-1, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or 5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- 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-, -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-dioxane-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-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-oxomethylenedioxy) -phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, further preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a mononuclear aromatic heterocycle with 1 to 4 N, O and / or S atoms.

Het particularly preferably denotes 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, 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-yl or -5-yl, 1,2,4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazole-4 or -5-yl, 3- or 4-pyridazinyl or pyrazinyl.

Het very particularly preferably pyrrolyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl.

Het ' preferably means a mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms, which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and / or OA can be substituted.

In In another embodiment, Het 'means extra preferably unsubstituted or mono-, di- or trihydric A, Hal, OH and / or OA substituted furyl, thienyl, pyrrolyl, Imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, Pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

The Compounds of formula I may be one or more chiral Possess centers and therefore in different stereoisomeric forms occurrence. 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, wherein however
in Ia RH means;
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, in which 1-5 H atoms may be replaced by F and / or Cl,
means;
unsubstituted or mono-, di- or trisubstituted by Hal, OH and / or OA in Ie Ar,
means;
in If GH or NH ₂ ,
R H,
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 unsubstituted or mono-, di- or trisubstituted by Hal, OH and / or OA-substituted phenyl,
Hal F, Cl, Br or I,
n 0, 1 or 2
mean;
and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions.

The compounds according to the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart ), under reaction conditions which are known and suitable for the said reactions. One can also make use of known per se, not mentioned here variants.

The If desired, starting materials can also be used in be formed so that they can be removed from the reaction mixture not isolated, but immediately further to the invention Connections implemented.

The Starting compounds are generally known. Are they new, like that but they can be prepared by methods known per se become.

links of the formula I can preferably be obtained by a hydrazide of the formula III with a compound of the formula II implements.

The Implementation is carried out by methods known to the person skilled in the art. The reaction is usually 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 II.

When inert solvents are suitable for. B. 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, 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 disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.

Especially preferred is DMF.

The Reaction usually takes place in the presence of an acid-binding Preferably by means of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak salt Acid of the alkali or alkaline earth metals, preferably of the Potassium, sodium, calcium or cesium. Also the addition an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can be cheap.

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

Such residues for activating the carboxy group in typical acylation reactions are described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart ;) described.

activated Esters are conveniently formed in situ, e.g. B. by addition of HOBt or N-hydroxysuccinimide.

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

The Reaction is usually 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.

When inert solvents are those mentioned above.

Also the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak acid salt the alkali or alkaline earth metals, preferably potassium, sodium, Calcium or cesium can be cheap.

The Response time varies depending on the conditions used a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, usually between -10 ° and 90 °, in particular between about 0 ° and about 70 °.

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

Such residues for activating the carboxy group in typical acylation reactions are described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart ;) described.

activated Esters are conveniently formed in situ, e.g. B. by addition of HOBt or N-hydroxysuccinimide.

The Cleavage of an ether takes place under methods such as those skilled in the art are known.

A Standard method for ether cleavage, eg. As a methyl ether, is the use of boron tribromide.

hydrogenolytically removable groups, e.g. As the cleavage of a benzyl ether, can z. B. by treatment with hydrogen in the presence of a catalyst (For example, a noble metal catalyst such as palladium, appropriate on a carrier such as coal) are split off. As a solvent are the above specified, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is usually at temperatures between about 0 and 100 ° and Printing between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar performed.

ester can z. With acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between Saponified at 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 also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art. 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, e.g. For example, 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 the formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, eg. As hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and 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, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate , Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galac terat (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-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

Farther are among the base salts of the invention Compounds aluminum, ammonium, calcium, copper, iron (III) -, Iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, Sodium and zinc salts, but not a limitation should represent. Preferred among the above-mentioned salts Ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts Calcium and magnesium. To salts of the compounds of the formula I, derived from pharmaceutically acceptable non-toxic organic Derive bases, salts include primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic Amines and basic ion exchange resins, eg. 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), which are not limiting should.

Compounds of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (C ₁ -C ₄₎ alkyl halides, for example. Methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C ₁ -C ₄ ) alkyl sulfates, e.g. For example, dimethyl, diethyl and diamylsulfate; (C ₁₀ -C ₁₈ ) alkyl halides, e.g. Decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (C ₁ -C ₄ ) alkyl halides, e.g. As benzyl chloride and phenethyl bromide quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

To the abovementioned 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, sulphate, sulphosalicylate, tartrate, thiomalate, tosylate and Tromethamine, which is not a limitation should.

The Acid addition salts of basic compounds of the formula I. are prepared by using the free base form with a sufficient amount of the desired acid in contact with it, whereby in the usual way the salt represents. The free base can be brought into contact salt form with a base and isolate the free base to usual Regenerate way. The free base forms differ in certain sense of their corresponding salt forms in relation to certain physical properties such as solubility in polar solvents; in the context of the invention correspond to the Salts, however, otherwise their respective free base forms.

As mentioned are the pharmaceutically acceptable base addition salts the compounds of the formula I 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 according to the invention Compounds are made by using the free Acid form with a sufficient amount of the desired Base brings into contact, making the salt on usual Way. Leave the free acid by contacting the salt form with an acid and isolating the free acid in a conventional manner regenerate. The free acid forms differ in a sense, of their corresponding salt forms in relation to certain physical properties such as solubility in polar solvents; correspond within the scope of the invention the salts, however, otherwise their respective free acid forms.

contains a compound of the invention more than one Group which can form such pharmaceutically acceptable salts, thus, the invention also encompasses multiple salts. To typical multiple salt forms include, for example, bitartrate, diacetate, Difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this should not be a limitation.

in the In view of the above, it can be seen that under the Expression "pharmaceutically acceptable salt" in The present context is understood to mean an active substance which has a Contains compound of formula I in the form of one of its salts, especially if this salt form compared to the active ingredient to the free form of the active ingredient or any other salt form the active ingredient used previously improved pharmacokinetic properties. The pharmaceutically acceptable Salt form of the drug can also be a desired confer pharmacokinetic properties on which it used to be did not dispose of, and may even have the pharmacodynamics of this Active substance in terms of its therapeutic efficacy in the body influence positively.

invention Compounds of the formula I can, due to their molecular structure be chiral and can be different accordingly enantiomeric forms occur. They can therefore be in racemic or in optically active form.

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

in the Fall racemic amines are from the mixture by reaction with formed an optically active release agent diastereomers. As a release agent are suitable for. As 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 (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active ones Camphorsulfonic acids. Also advantageous is a chromatographic Enantiomer separation using an optically active release agent (For example, dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives carbohydrates or chirally derivatized on silica gel Methacrylate). As eluents are suitable for this purpose aqueous or alcoholic solvent mixtures such as For example, hexane / isopropanol / acetonitrile z. B. in proportion 82: 15: 3rd

object 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 non-chemical Ways. You can do this together with at least one solid, liquid and / or semi-liquid carrier or adjuvant and optionally in combination with one or several other active ingredients in a suitable dosage form become.

object The invention furthermore relates to medicaments containing at least one Compound of the invention and / or its pharmaceutical usable salts and stereoisomers, including theirs Mixtures in all ratios, and optionally Carrier and / or auxiliaries.

pharmaceutical Formulations may take the form of dosage units containing a contain predetermined amount of active ingredient per unit dose, presented become. Such a unit may for example be 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg contain a compound of 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 take the form of dosage units containing a contain predetermined amount of active ingredient per unit dose, presented become. Preferred unit dosage formulations are those the one daily dose or partial dose as stated above or a corresponding one Fraction of it containing an active ingredient. You can continue Such pharmaceutical formulations with one of the pharmaceutical Fachgebiet generally produce known method.

pharmaceutical Formulations can be administered via a any suitable route, for example, oral (including buccalemic or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such formulations can prepared with all methods known in the pharmaceutical art by, for example, adding the active substance to the carrier (s) or adjuvant (s) is brought together.

At the oral administration adapted pharmaceutical formulations can be used as separate units, such as B. capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or nonaqueous liquids; Eatable Foams or foam foods; or oil-in-water liquid emulsions or Water-in-oil liquid emulsions are presented.

So can be, for example, in oral administration in the form of a tablet or capsule, the active component with a oral, non-toxic and pharmaceutically acceptable inert Carrier, such. As ethanol, glycerol, water u. ä. combine. Powders are made by adding the compound to a suitable fine size crushed and with a similarly, pharmaceutical excipient, such as As an edible carbohydrate such as Starch or mannitol is mixed. A flavor, Preservative, dispersant and dye also be present.

capsules are prepared by mixing a powder mixture as described above made and shaped gelatin shells filled with it become. Lubricants and lubricants such. B. fumed silica, Talc, magnesium stearate, calcium stearate or polyethylene glycol In solid form, the powder mixture before the filling process be added. An explosive or solubilizer, such as As agar-agar, calcium carbonate or sodium carbonate, can also be added to the availability of the drug to improve after ingestion of the capsule.

Furthermore may, if desired or necessary, appropriate Binders, lubricants and disintegrants, as well as dyes be incorporated into the mixture. To the suitable binders include starch, gelatin, natural Sugar, such as As glucose or beta-lactose, sweeteners from corn, natural and synthetic gums, such as B. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, Waxes, u. Ä. To those used in these dosage forms Lubricants include sodium oleate, sodium stearate, magnesium stearate, Sodium benzoate, sodium acetate, sodium chloride and the like. Ä. To The explosives include, but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum u. Ä. The tablets are formulated by, for example a powder mixture is prepared, granulated or dry-pressed, a lubricant and a disintegrant are added and the Whole is pressed into tablets.

One Powder mixture is prepared by comminuting in a suitable manner Compound with a diluent or a base, as described above, and optionally with a binder, such as Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution slower, such. Paraffin, a resorption accelerator, such as A quaternary salt and / or an absorbent, such as As bentonite, kaolin or dicalcium phosphate is mixed. The powder mixture can be granulated by it with a binder, such as. B. syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve. As alternative for granulation, the powder mixture by a tableting machine run, with unevenly shaped lumps arise, which are broken up into granules. The granules can by adding stearic acid, a stearate salt, talc or mineral oil to be greased to stick to the tablet molds to prevent. The greased mixture is then compressed into tablets. The compounds of the invention can also with a free-flowing inert carrier combined and then without carrying out the granulation or dry pressing steps directly into tablets become. A transparent or opaque protective layer, consisting from a shellac sealant, a layer of sugar or Polymer material and a gloss layer of wax, may be present be. Dyes can be added to these coatings be differentiate between different dosage units to be able to.

oral Liquids, such. Solution, syrups and elixirs, can be prepared in the form of dosage units, so that a given quantity is a given Amount of the compound contains. Syrups can be prepared, by placing the compound in an aqueous solution with appropriate taste is dissolved while Elixir using a non-toxic alcoholic vehicle getting produced. Suspensions can be by dispersion of the compound in a non-toxic vehicle.

solubilizers and emulsifiers, such as. B. ethoxylated isostearyl alcohols and Polyoxyethylene sorbitol ethers, preservatives, flavorings, such as As peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, u. Ä. can also be added.

The Dosage unit formulations for oral administration may optionally be encapsulated in microcapsules. The formulation can also be prepared in this way that the release is prolonged or retarded is, as for example by coating or embedding of particulate material in polymers, wax u. ä.

The compounds of the invention and their salts can also be in the form of Liposomenzuführsystemen, such as. Small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be made of various phospholipids, such as. Cholesterol, stearyl amine or phosphatidylcholines.

The Compounds according to the invention and the salts can also be made using monoclonal antibodies as individual carriers to which the compound molecules be coupled, are supplied. The connections can also with soluble polymers as targeted excipients be coupled. Such polymers may include polyvinylpyrrolidone, Pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine substituted with palmitoyl radicals, include. Furthermore, the connections to a class of biodegradable polymers used to obtain a controlled Release of a drug are suitable, for. B. polylactic acid, Polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoester, Polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

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 can be delivered from the patch by iontophoresis, as in Pharmaceutical Research, 3 (6), 318 (1986) generally described.

At the topical administration adapted pharmaceutical compounds can be used as ointments, creams, suspensions, lotions, powders, Solutions, pastes, gels, sprays, aerosols or oils be formulated.

For Treatments of the eye or other external tissues, z. As mouth and skin, the formulations are preferably as applied topical ointment or cream. When formulated into a Ointment may be the active ingredient with either a paraffinic or an ointment a water-miscible cream base can be used. alternative The active ingredient can be a cream with an oil-in-water cream base or a water-in-oil basis.

To the adapted to the topical application to the eye pharmaceutical Formulations include eye drops, where the active ingredient in a suitable carrier, in particular an aqueous Solvent, dissolved or suspended.

At the topical application in the mouth adapted pharmaceutical Formulations include lozenges, lozenges and mouthwashes.

At rectal administration adapted pharmaceutical formulations can be in the form of suppositories or enemas be presented.

At the nasal administration adapted pharmaceutical formulations, in which the carrier is a solid a coarse powder with a particle size, for example in the range of 20-500 microns that in the way as snuff is absorbed, d. H. by Quick inhalation via the nasal passages from a close to the nose held container with the powder. suitable Formulations for administration as a nasal spray or nose drops comprising a liquid as a carrier substance Active substance solutions in water or oil.

At administration by inhalation adapted pharmaceutical Formulations include fine particulate dusts or nebulae, which are pressurized by means of various types Dosing dispensers with aerosols, nebulizers or insufflators produced can be.

At the vaginal administration adapted pharmaceutical formulations Can be used as pessaries, tampons, creams, gels, pastes, foams or spray formulations are presented.

To the pharmaceutical adapted for parenteral administration Formulations include aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, Bacteriostats and solutes through which the formulation is isotonic is done with the blood of the recipient to be treated, contain; as well as aqueous and non-aqueous sterile suspensions containing suspending agents and thickeners can. The formulations can be administered in single dose or multi-dose containers, e.g. B. sealed ampoules and vials, and in freeze-dried (lyophilized) state, so that only the addition the sterile carrier liquid, z. B. water for Injections, needed immediately before use. the recipe prepared injection solutions and suspensions can from sterile powders, granules and tablets.

It It is understood that the formulations in addition to the above particularly mentioned constituents others common in the art Means with respect to the respective type of formulation included can; for example, for the oral administration suitable formulations flavorings contain.

A therapeutically effective amount of a compound of the present invention depends on a number of factors, including z. The age and weight of the human or animal, the exact state of the disease, which requires treatment, as well as its severity, nature the formulation as well as the route of administration, and ultimately will determined by the attending physician or veterinarian. However, it lies an effective amount of a compound of the invention for treatment 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 of body weight per day. Thus, would be for a 70 kg adult mammal the actual amount per day usually between 70 and 700 mg, taking this amount as a single dose per day or more commonly in a number of subdoses (such as two, three, four, five or six) can be given a day, so that the total daily dose is the same. An effective Amount of a salt or solvate or a physiologically functional Derivatives thereof can be used as a proportion of the effective amount of the invention Compound be determined per se. It can be assume that similar dosages for the Treatment of the other, above-mentioned disease states are suitable.

object The invention further comprises medicaments containing at least one Compound of the invention and / or its pharmaceutical usable salts and stereoisomers, including theirs Mixtures in all proportions, and at least one another active pharmaceutical ingredient.

• (a) einer wirksamen Menge an einer erfindungsgemäßen Verbindung und/oder ihrer pharmazeutisch verwendbaren Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und
• (b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.

The invention is also a set (kit), consisting of separate 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
• (b) an effective amount of another drug.

The Set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set can z. B. separate ampoules contain, in each of which an effective Amount of a compound of the invention and / or their pharmaceutically acceptable salts and stereoisomers, including their mixtures in all proportions, and an effective Amount of another active pharmaceutical ingredient dissolved or is present in lyophilized form.

USE

The Present compounds are useful as pharmaceutical agents for mammals, in particular for the People in the treatment of SGK-related diseases.

object The invention thus relates to the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and Stereoisomers, including mixtures thereof in all proportions, for the manufacture of a medicament for the treatment of diseases, which inhibit, regulate and / or modulate signal transduction of kinases plays a role. Preferred here is SGK.

Prefers is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and Stereoisomers, including mixtures thereof in all Conditions for the preparation of a medicament for Treatment of diseases caused by inhibition of SGK the compounds of claim 1 are affected.

The The present invention includes the use of the invention Compounds according to claim 1 and / or their physiologically harmless 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 disease (For example, cardiac fibrosis after myocardial infarction, cardiac hypertrophy and Heart failure, arteriosclerosis) and kidney disease (eg Glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, disorder electrolyte excretion), in general for any type of fibrosis and inflammatory processes (eg liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthritis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, 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 are therefore suitable for tumor therapy.

The Compounds of the invention continue to find Use for the treatment of coagulopathies, such. B. dysfibrinogenemia, Hypoproconvertinemia, hemophilia B, Stuart-Prower defect, Prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, Immunocoagulopathy or complex coagulopathies, as well as in 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 and in an anti-infective therapy. The compounds of the invention can also to increase the ability to learn and attention be used therapeutically.

Prefers is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and Stereoisomers, including mixtures thereof in all Conditions for the preparation of a medicament for Treatment or prevention of diabetes, obesity, metabolic syndrome (Dyslipidemia), systemic and pulmonary hypertension, Cardiovascular diseases and kidney diseases, in general any kind of fibrosis and inflammatory processes, Cancer, tumor cells, tumor metastases, coagulopathies, neuronal Excitability, glaucoma, cataracts, bacterial infections as well as in an anti-infective therapy, to increase the ability to learn and attention, as well as for the treatment and prophylaxis of cell aging and stress.

at Diabetes is preferably diabetes mellitus, diabetic Nephropathy, diabetic neuropathy, diabetic angiopathy and Microangiopathy.

at Cardiovascular diseases are preferably cardiac Fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and atherosclerosis.

at Kidney disease is preferably glomerulosclerosis, Nephrosclerosis, nephritis, nephropathy and disorder of the Electrolyte excretion.

at Fibroids and inflammatory processes are preferred liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, Sclerodermatitis, cystic fibrosis, scarring, Alzheimer's disease.

ASSAYS

The compounds of the invention described in the Examples were tested in the assays described below and found to have kinase inhibitory activity. Further assays are known from the literature and could easily be carried out by a person skilled in the art (see, for example, US Pat. Dhanabal et al., Cancer Res. 59: 189-197 ; Xin et al., J. Biol. Chem. 274: 9116-9121 ; Sheu et al., Anticancer Res. 18: 4435-4441 ; Ausprunk et al., Dev. Biol. 38: 237-248 ; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427 ; Nicosia et al., In Vitro 18: 538-549 ). The inhibition of SGK1 protein kinase can be determined in the filter binding procedure.

Above and below, all temperatures are given in ° C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase 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): EI (electron impact ionization) M ⁺ FAB (Fast Atom Bombardment) (M + H) ⁺ ESI (Electrospray Ionization) (M + H) ⁺ (unless otherwise indicated)

HPLC method

• A (polar): Hewlett Pachard HP 1100 series system with the following
• Features: Ion Source: ES (positive mode), Scan 100-1000 m / z,
• Fragmentation voltage: 60 V, gas temperature: 300 ° C, DAD 220 nm
• Column: Chromolith SpeedROD RP-18e, 50-4.6
• Flow rate 2.4 ml / min

• Solvent A: Wasser + 0.1% TFA
• Solvent B: Acetonitiril + 0.08% TFA
• Gradient: 0.0 min 5% B 2.8 min 100% B 3.3 min 100% B
• B: Säule: Chromolith SpeedROD RP-18e, 50-4.6 Flußrate 2.4 ml/min
• Solvent A: Wasser + 0.1% TFA
• Solvent B: Acetonitril + 0.1% TFA
• Gradient: 0.0 min 4% B 2.6 min 100% B 3.3 min 100% B

HPLC-MS- : Esi1.Rod.m/Polar.m/Unpolar.m Methode Säule : Chromolith Speed Rod RP 18e 50-4,6 mm Fluß : 2,4 ml/min Puffer A : 0,01% TFA/Wasser Puffer B : 0,008% TFA/Acetonitril Wellenlänge : 220 nm Gradient : 0,0–2,8 min 20%–100% Puffer B; 2,8–3,3 min 100% Puffer B; Esi1.rod.m 3,3–3,4 min 100%–20% Puffer B; 3,4–3,8 min 20% Puffer B Gradient : 0,0–3,0 min 5%–100% Puffer B; 3,0–3,5 min 100% Puffer B; Polar.m 3,5–3,6 min 100%–5% Puffer B; 3,6–3,8 min 20% Puffer B Gradient : 0,0–2,5 min 40%–90% Puffer B; 2,5–3,8 min 90% Puffer B; Unpolar.m 3,8–3,9 min 90% Puffer B: 3,9–4,1 min 90%–40% Puffer B The splitter used reduced the flow rate for MS after the DAD to 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.m / Polar.m / Unpolar.m method pillar : Chromolith Speed Rod RP 18e 50-4,6 mm River : 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; 2.8-3.3 min. 100% buffer B; Esi1.rod.m 3.3-3.4 min 100% -20% Buffer B; 3.4-3.8 min 20% buffer B gradient : 0.0-3.0 min 5% -100% Buffer B; 3.0-3.5 min. 100% Buffer B; Polar.m 3.5-3.6 min. 100% -5% Buffer B; 3.6-3.8 min 20% buffer B gradient : 0.0-2.5 min 40% -90% Buffer B; 2.5-3.8 min 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-methoxy-phenyl) -acetyl] -hydrazide ("A1")

Step 1: Clutch

49 mg of 4-methoxy-1H-indazole-5-carboxylic acid, 57.5 mg of DAPECI, 45.9 mg of HOBT hydrate and 50 mg of hydroxy- (3-methoxyphenyl) -acetic acid hydrazide are dissolved in 1 ml of DMF in a screw-cap vial 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 (1H, d , J = 8.8 Hz), 7.14 (1H, 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:

in principle the method described above is also substituted on others Indazole-5-carboxylic acids and other Mandelsäurehydrazide transferable.

Mandelsäurehydrazide are z. T. commercially available or represented 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 (3-methoxy-phenyl) methyl acetate are heated with 1.5 ml of hydrazine hydrate in 40 ml of 2-propanol for 2 hours at 90 ° 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. In WO 2008065508 and WO 2003101968 (Synthesis of 4-methoxy-indazole-5-carboxylic acid).

In WO 2003101968 also describes the synthesis of 4-fluoro-indazole-5-nitrile and 4-fluoro-indazole-5-carboxylic acid methyl ester. From 4-fluoro-indazole-5-nitrile, the carboxylic acid can be obtained by acid hydrolysis, from the ester z. B. 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-phenyl-propionic acid, 115.0 mg 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 3:

Preparation of 7-chloro-1H-indazole-5-carboxylic acid N '- [2- (3,4-difluoro-phenyl) -2-hydroxy-acetyl] -hydrazide ("A3")

In a screw-top vial, 115 mg (3,4-difluorophenyl) hydroxyacetic acid, 151.0 mg DAPECI, 67 μl N-methylmorpholine and 150.0 mg 7-chloro-1H-indazole-5-carboxylic acid hydrazide Hydrochloride dissolved in 1 ml of DMF and overnight stirred at RT. The reaction mixture is added to water, extracted three times with EA and the organic phase dried and concentrated. The residue is purified by column chromatography on silica gel (eluent EE / MeOH).

This gives 90 mg of 7-chloro-1H-indazole-5-carboxylic acid N '- [2- (3,4-difluoro-phenyl) -2-hydroxy-acetyl] hydrazide (yield: 39%); MS-FAB (M + H ⁺ ) = 381.5; R _f (polar method): 1.47 min.

Analogously, the following compounds are obtained

Pharmacological data

• IC₅₀: 1 nM–0,1 μM = A 0,1 μM–10 μM = B > 10 μM = C

Table 1 SGK inhibition Connection no. Inhibition IC ₅₀ (enzyme) "A1" A "A2" A "A3" C "A4" C "A5" B "A6" B

• IC ₅₀ : 1 nM-0.1 μM = A 0.1 μM-10 μM = B> 10 μM = C

The The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A Solution of 100 g of an inventive Active ingredient and 5 g of disodium hydrogenphosphate in 2 times twice distilled water adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection jars, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

you melts a mixture of 20 g of an inventive Active ingredient with 100 g soy lecithin and 1400 g cocoa butter, pours in forms and lets cool. Every suppository contains 20 mg of active ingredient.

Example C: Solution

A solution of 1 g of an active ingredient according to the invention, 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 of benzalkonium chloride in 940 ml of bidistilled water is prepared. 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

you mixes 500 mg of an active ingredient according to the invention with 99.5 g Vaseline under aseptic conditions.

Example E: Tablets

One 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 in the usual Pressed into tablets, so that each Tablet contains 10 mg of active ingredient.

Example F: dragees

Analogous Example E tablets are pressed, which subsequently in the usual way with a coating of sucrose, Potato starch, talc, tragacanth and dye coated become.

Example G: Capsules

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

Example H: Ampoules

A Solution of 1 kg of an inventive Active ingredient in 60 l of double-distilled water is filtered sterile, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

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Claims (20)

Compounds of the formula

in which GH or NH ₂ , RH 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 ', 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 is 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 of one another, 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 one another, unsubstituted or mono-, two or three times 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 cycl is an alkyl having 3-7 C atoms, Ar unsubstituted or one, two, three or four times represented by A, Hal, OH, OA, Ar ', OAr', Het, OHet, SH, SA, SAr ', SHet , NH ₂ , NHA, NAA ', NHAr', N (Ar ') ₂ , NHHet, N (Het) ₂ , NAAr', NAHet, 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 ', Cohet, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ', SO ₂ N (Ar') 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, which is mono-, di- or trisubstituted by A, Hal, OH, CA, Ar, OAr, Het ', OHet', SH, SA, SAr 'SHet', NH _2, NHA, NAA ', NHAr', N (Ar ') _2, NHHet', N (Het ') _2, naar', draws near ', 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 , CO A, COAr ', COHet', SO ₃ H, SO ₂ NH ₂ , SO ₂ NHAr ', SO ₂ N (Ar') ₂ , SO ₂ NHHet 'or SO ₂ N (Het') ₂ , = S, = NR may be substituted = O (carbonyl oxygen) ⁷ and / or Ar 'is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, Hal, OH, CA, 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 'a monocyclic saturated heterocycle having 1 to 4 N-, O- and / or S atoms which are mono-, di- or trisubstituted by A, Hal, OH, OA, NH ₂ , NHA, NM ', 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, n is 0, 1 or 2, and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios. Compounds according to claim 1, wherein R H means such as their pharmaceutically acceptable salts and stereoisomers, including their mixtures in all proportions. Compounds according to claim 1 or 2, wherein X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios. 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. Compounds according to one or more of the claims 1-4, in which Ar unsubstituted or one, two or trisubstituted by Hal, OH and / or OA substituted phenyl means such as their pharmaceutically acceptable salts and stereoisomers, including their mixtures in all proportions. Compounds according to one or more of the claims 1-5, in which A is alkyl having 1-6 C atoms, wherein 1-5 H atoms may be replaced by F and / or Cl, means such as their pharmaceutically acceptable salts and stereoisomers, including their mixtures in all proportions. Compounds according to one or more of claims 1-6, wherein GH or NH ₂ , R is H, YN, CH or CR ¹¹ , X ¹ , X ² , X ^{3 are} each independently H, Hal, OH or OA, Y is CH ₂ , A 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, Hal F, Cl, Br or I, n is 0, 1 or 2, and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios. Compounds according to claim 1 selected from the group

and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all proportions. Process for the preparation of compounds of the formula I according to Claims 1-8 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 reactively functionally modified OH group, with a compound of formula III

wherein G, X ¹ , X ² and X ^{3 have} the meanings given in claim 1, 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 reactively functionally modified OH group, with a compound of formula V

wherein Ar, R, Y and n have the meanings given in claim 1, and / or converts a base or acid of the formula I into one of its salts. Medicament containing at least one compound according to claims 1-8 and / or their pharmaceutically usable Salts and stereoisomers, including mixtures thereof in all circumstances, as well as, if applicable, carrier and / or auxiliaries. Use of compounds according to claim 1-8, as well as their pharmaceutically acceptable salts and Stereoisomers, including mixtures thereof in all Conditions for the preparation of a medicament for Treatment and / or prophylaxis of diseases in which the inhibition, Regulation and / or modulation of signal transduction of kinases plays a role. Use according to claim 11, wherein the Kinase is about SGK. 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 Conditions for the preparation of a medicament for Treatment of diseases caused by inhibition of SGK the compounds of claims 1-8 influenced become. Use according to claim 13 of compounds according to claims 1-8, 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 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 as well as in an anti-infective therapy to increase the ability to learn and attention, as well as for the treatment and prevention of cell aging and stress and for the treatment of tinitus. Use according to claim 14, wherein it is in diabetes diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy. Use according to claim 14, wherein there are cardiovascular diseases Cardiac fibrosis after myocardial infarction, cardiac hypertrophy, heart failure and arteriosclerosis. Use according to claim 14, wherein there are kidney diseases glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and Disruption of the electrolyte excretion is. Use according to claim 14, wherein it is fibrosis and inflammatory processes involving liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthritis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic Fibrosis, scarring and Alzheimer's disease. Medicaments containing at least one compound according to claim 1-8 and / or their pharmaceutically usable salts and stereoisomers, including theirs Mixtures in all proportions, and at least one another active pharmaceutical ingredient. Set (Kit) consisting of separate packs of (A) an effective amount of a compound according to claim 1-8 and / or their pharmaceutically acceptable salts and Stereoisomers, including mixtures thereof in all conditions and (b) an effective amount another drug active ingredient.