HK1129364A - Mandelic hydrazides - Google Patents
Mandelic hydrazides Download PDFInfo
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- HK1129364A HK1129364A HK09107012.0A HK09107012A HK1129364A HK 1129364 A HK1129364 A HK 1129364A HK 09107012 A HK09107012 A HK 09107012A HK 1129364 A HK1129364 A HK 1129364A
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Description
Background
The present invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to compounds which inhibit, regulate and/or modulate kinase signal transduction, in particular compounds which act via the cell volume-regulated human kinase h-SGK (human serum and glucocorticoid dependent kinase or SGK), as well as to pharmaceutical compositions containing these compounds and to the use of said compounds for the treatment of SGK-induced diseases.
SGK, having the subtypes SGK-1, SGK-2 and SGK-3, belongs to the serine/threonine protein kinase family (WO 02/17893).
The compounds of the present invention are preferably selective inhibitors of SGK-1. And they may be SGK-2 and/or SGK-3 inhibitors.
In detail, the present invention relates to compounds which inhibit, modulate and/or modulate SGK signal transduction, compositions comprising these compounds and methods for their use in the treatment of SGK-induced diseases and conditions such as diabetes (e.g. diabetes, diabetic nephropathy, diabetic neuropathy, diabetic vasculopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic hypertension and pulmonary hypertension, cardiovascular diseases (e.g. cardiac fibrosis after myocardial infarction, cardiac hypertrophy and insufficiency, angiosclerosis) and kidney diseases (e.g. glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorders), in general any type of fibrotic and inflammatory processes (e.g. cirrhosis, pulmonary fibrosis, fibrotic pancreatitis, rheumatism and arthropathy, crohn's disease, inflammatory processes, Chronic bronchitis, radiation fibrosis, sclerormatitis, fibrocystic disease, scarring, alzheimer's disease).
The compounds of the invention also inhibit the growth of tumor cells and tumor metastasis and are therefore suitable for tumor therapy.
The compounds of the invention can also be used for the treatment of peptic ulcers, especially in stress-induced situations. Furthermore, the compounds of the invention are useful for the treatment of coagulation disorders, such as dysfibrinogenemia, hypoproteinemia, hemophilia B, Stuart-Prower deficiency, prothrombin complex deficiency, wasting coagulopathy, hyperfibrinolysis, immune coagulation disorders or complex coagulation disorders, and neuronal excitation such as epilepsy. The compounds of the invention are also therapeutically useful in the treatment of glaucoma or cataract. In addition, the compounds of the present invention are useful in the treatment of bacterial infections and anti-infective therapy. The compounds of the invention are also useful therapeutically to enhance learning and attention. In addition, the compounds of the present invention count cell senescence and stress, thereby increasing life expectancy and fitness in the elderly.
Furthermore, the compounds of the invention are useful for the treatment of tinnitus.
Therefore, it is desirable and an object of the present invention to identify small compounds that specifically inhibit, modulate and/or modulate SGK signaling.
The compounds of the invention and their salts have been found to possess very valuable pharmacological properties while being well tolerated.
In particular, they exert SGK-inhibiting properties.
The present invention therefore relates to the compounds according to the invention as medicaments and/or pharmaceutically active ingredients for the treatment and/or prophylaxis of the mentioned diseases, to the use of the compounds according to the invention for producing medicaments for the treatment and/or prophylaxis of the mentioned diseases, and to methods for treating the mentioned diseases, which comprise administering one or more compounds according to the invention to a patient in need of such a treatment.
The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents include mice, rats and hamsters; a rabbit; a horse; cow, dog, cat, etc. Animal models are of interest for experimental studies, and they provide a model for the treatment of human diseases.
To determine signal transduction pathways and to detect interactions between various signal transduction pathways, many scientists have developed suitable models or model systems, such as cell culture models (e.g., Khwaja et al, EMBO, 1997, 16, 2783-93) and transgenic animal models (e.g., White et al, Oncogene, 2001, 20, 7064-. To determine certain stages of the signal transduction cascade, compounds that interact can be used in order to modulate the signal (e.g., Stephens et al, biochemical.j., 2000, 351, 95-105). The compounds of the invention are also useful as reagents for the detection of kinase-dependent signal transduction pathways in animal and/or cellular models or in the clinical diseases mentioned herein.
The determination of kinase activity is a technique well known to those skilled in the art. General assay systems for determining kinase activity using substrates such as histones (e.g.Alessi et al, FEBS Lett.1996, 399, 3, 333-338 pages) or basic myelin protein are described in the literature (e.g.Campos-Gonz a lez, R. and Glenney, Jr., J.R.1992, J.biol.chem.267, 14535).
Various assay systems can be used to identify kinase inhibitors. The radioactive phosphorylation of proteins or peptides as substrates was measured using gamma ATP in scintillation proximity assays (Sorg et al, J.of.biomolecular Screening, 2002, 7, 11-19) and flash plating (flashplate) assays. In the presence of the inhibitory compound, a reduced radioactive signal is detected or not detected at all. Furthermore, homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques can be used as assay methods (Sills et al, J.of Biomolecular Screening, 2002, 191-214).
Other non-radioactive ELISA assays use specific phosphor antibodies (phosphor ABs). Phosphor AB binds only to phosphorylated substrates. This binding can be detected by chemiluminescence using another peroxidase-conjugated anti-sheep antibody (Ross et al, biochem. J., 2002, 366, 977-981).
Prior Art
WO 00/62781 describes the use of a medicament comprising a cell volume-modulated human kinase H-SGK inhibitor.
Acylhydrazones as SKG inhibitors are described in WO 2005037773.
Other acylmandelic hydrazides as fungicides are described in WO 96/17840 and P Legral in Tetrahedron 1988, 44, 4805-4814.
Benzylidene benzohydrazides having antibacterial action are described in WO 02/070464a 2. The use of acylhydrazides for the treatment of bacterial infections is disclosed in WO 01/70213.
Other acylhydrazone derivatives, especially acylhydrazone derivatives for the treatment of diabetic complications, are disclosed in JP 11-106371.
Methoxy-substituted aromatic acylhydrazone derivatives for the treatment of cancer are described by T.Kametani et al in Yakugaku Zasshi (1963))83, 851-.
Other aromatic acylhydrazone derivatives as sedative enhancers and hypotensive agents are described in JP 41-20699.
The use of kinase inhibitors in anti-infective therapy is described by c.doerig in cell.mol.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-.
The following references suggest and/or describe the use of SGK inhibitors in the treatment of disease:
1：Chung EJ，Sung YK，Farooq M，Kim Y，Im S，Tak WY，HwangYJ，Kim YI，Han HS，Kim JC，Kim MK.Gene expression profile analysisin human hepatocellular carcinoma by cDNA microarray.Mol Cells.2002；14：382-7。
2：Brickley DR，Mikosz CA，Hagan CR，Conzen SD.Ubiquitinmodification 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，PestelS，Tanneur V，Waldegger S，Zipfel A，Viebahn R，Haussinger D，BroerS，Kandolf R，Lang F.Expression of the serine/threonine kinase hSGK1 inchronic viral hepatitis.Cell Physiol Biochem.2002；12：47-54。
4：Brunet A，Park J，Tran H，Hu LS，Hemmings BA，GreenbergME.Protein kinase SGK mediates survival signals by phosphorylating theforkhead 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 associatedwith induction of the serine/threonine survival kinase gene，sgk-1.J BiolChem.2001；276：16649-54。
6：Zuo Z，Urban G，Scammell JG，Dean NM，McLean TK，AragonI，Honkanen RE.Ser/Thr protein phosphatase type 5(PP5)is a negativeregulator of glucocorticoid receptor-mediated growth arrest.Biochemistry.1999；38：8849-57。
7：Buse P，Tran SH，Luther E，Phu PT，Aponte GW，Firestone GL.Cellcycle and hormonal control of nuclear-cytoplasmic localisation of theserum-and glucocorticoid-inducible protein kinase，Sgk，inmammarytumourcells.A novel convergence point of anti-proliferative andproliferative cell signalling pathways.J Biol Chem.1999；274：7253-63。
8：M.Hertweck，C.Gbel，R.Baumeister：C.elegans SGK-1 is thecritical component in the Akt/PKB Kinase complex to control stressresponse and life span.Developmental Cell，Vol.6，577-588，April，2004。
summary of The Invention
The invention relates to compounds of formula I
Wherein
R1、R2Independently of one another H, CHO or an acetyl group,
R3、R4、R5、R6、R7、R8、R9、R10、R11h, A, OSO are represented independently of each other2A、Hal、NO2、OR12、N(R12)2、CN、O-COA、-[C(R12)2]nCOOR12、O-[C(R12)2]oCOOR12、SO3H、-[C(R12)2]nAr、-CO-Ar、O-[C(R12)2]nAr、-[C(R12)2]nHet、-[C(R12)2]nC≡CH、O-[C(R12)2]nC≡CH、-[C(R12)2]nCON(R12)2、-[C(R12)2]nCONR12N(R12)2、O-[C(R12)2]nCON(R12)2、O-[C(R12)2]oCONR12N(R12)2、NR12COA、NR12CON(R12)2、NR12SO2A、N(SO2A)2、COR12、S(O)mAr、SO2NR12Or S (O)mA，
R3And R4Together also CH-CH,
R3and R4、R7And R8Or R8And R9Together also denotes alkylene having 3, 4 or 5 carbon atoms, wherein one or two CH' s2The group may be replaced by oxygen in the presence of oxygen,
a represents an unbranched or branched alkyl radical having 1 to 6C atoms, in which 1 to 7H atoms may be substituted by F, or a cycloalkyl radical having 3 to 7C atoms,
ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or trisubstituted by: hal, A, OR12、N(R12)2、NO2CN, phenyl, CON (R)12)2、NR12COA、NR12CON(R12)2、NR12SO2A、COR12、SO2N(R12)2、S(O)mA、-[C(R12)2]n-COOR12and/or-O [ C (R)12)2]o-COOR12，
Het represents a mono-or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: hal, A, OR12、N(R12)2、NO2、CN、COOR12、CON(R12)2、NR12COA、NR12SO2A、COR12、SO2NR12、S(O)mA、＝S、＝NR12And/or ═ O (carbonyl oxygen),
R12represents a group of a compound represented by the formula H or A,
hal represents F, Cl, Br or I,
m represents 0, 1 or 2,
n represents 0, 1, 2 or 3,
o represents 1, 2 or 3,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
The present invention relates to compounds of formula I and salts thereof, and to a process for the preparation of compounds of formula I and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof according to claims 1 to 16, characterized in that
a) Reacting a compound of formula II
Wherein
R1、R7、R8、R9、R10And R11Having the meaning indicated in claim 1,
with compounds of the formula III
Wherein
L represents Cl, Br, I or a free or reactive functional group-modified OH group, and
R2、R3、R4、R5and R6Having the meaning indicated in claim 1,
or
b) Reacting a compound of formula IV
Wherein
R2、R3、R4、R5And R6Having the meaning indicated in claim 1,
with compounds of the formula V
Wherein
L represents Cl, Br, I or a free or reactive functional group-modified OH group, and
R1、R7、R8、R9、R10and R11Having the meaning indicated in claim 1,
or
c) Cleavage of the ether by hydrolysis or hydrogenolysis of the radical R in the compounds of the formula I1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11Conversion to another group R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11，
And/or converting a base or acid of formula I into one of its salts.
The invention also relates to stereoisomers (E, Z isomers) and hydrates and solvates of these compounds. Solvates of a compound means the addition of inert solvent molecules to the compound, which are formed due to their mutual attraction. For example, the solvate is a mono-or dihydrate or an alcoholate.
Pharmaceutically acceptable derivatives represent, for example, salts of the compounds of the invention and so-called prodrug compounds.
Prodrug derivatives represent compounds of formula I which are modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which decompose rapidly in the organism to form the active compounds of the invention.
These also include biodegradable polymer derivatives of the compounds of the invention, as described, for example, in int.11561-67 (1995).
The expression "effective amount" means the amount of a drug or pharmaceutically active ingredient that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought or targeted, for example, by a researcher or physician.
In addition, the expression "therapeutically effective amount" means an amount that, compared to a corresponding individual not receiving this amount, produces the following result:
improved treatment, cure, prevention, or elimination of a disease, complication, condition, discomfort, disorder, or side effect, or slowing the progression of a disease, condition, or disorder.
The expression "therapeutically effective amount" also encompasses an amount effective to increase normal physiological function.
The invention also relates to mixtures of compounds of the formula I according to the invention, for example, mixtures of two diastereomers or enantiomers, for example in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1: 1000.
The above mixtures are particularly preferably mixtures of stereoisomeric compounds, in particular the compounds according to the invention in the form of racemates.
For all groups which occur more than once, the meanings are independent of one another.
In this context, the radicals and the parameter R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11Have the meaning indicated for formula I, unless otherwise indicated.
A represents an alkyl group which is unbranched (linear) or branched and has 1, 2, 3, 4, 5 or 6C atoms. A preferably represents methyl, and also 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-methylphenyl, 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, for example, trifluoromethyl.
A very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.
Ac represents acetyl, Bn represents benzyl, Ms represents-SO2CH3。
R1Preferably H, CHO or acetyl, particularly preferably H.
R2Preferably represents H.
R3、R4、R5、R6、R7、R8、R9、R10、R11Independently of one another preferably represents H, A, Hal, OR12Or O- [ C (R)12)2]nAr。
R3Particularly preferably H, A or Hal.
R6Particularly preferably represents OH.
R8Particularly preferably OH, A, phenoxy orHal。
R4、R5、R7、R9、R10、R11Particularly preferably represents H or A.
R7、R10、R11Also, independently of one another, particularly preferably represents H or Hal.
R12Particularly preferably represents H.
Ar denotes, 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-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-acetylaminophenyl, 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- (methylsulfinamido) 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-carboxymethylphenyl, o-, m-or p-carboxymethoxyphenyl, further 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.
Ar preferably represents, for example, phenyl which is unsubstituted or mono-, di-or trisubstituted by: hal, A, OR10、SO2A、COOR10Or CN, very particularly preferably phenyl which is unsubstituted or mono-, di-or trisubstituted by Hal and/or A. In particular Ar represents phenyl.
Het, irrespective of the further substituents, denotes, for example, 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 more preferably 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-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 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-benzene-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, further 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 group may also be partially or fully hydrogenated. Het therefore also denotes, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, 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-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4-or 5-yl, hexahydro-1-, -3-or 4-pyridazinyl, hexahydro-1-, -2-, -4-or 5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or 8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-oxazinyl, further preferably 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or-6-yl, 2, 3- (2-oxomethylenedioxy) phenyl or 3, 4-dihydro-2H-1, 5-benzodioxepan-6-or-7-yl, and preferably 2, 3-dihydrobenzofuranyl or 2, 3-dihydro-2-oxofuranyl.
Het preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle containing 1 to 2N and/or O atoms, which may be unsubstituted or mono-, di-or trisubstituted by A, Hal, OH and/or OA.
Het particularly preferably represents a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be unsubstituted or mono-or disubstituted by A.
In another embodiment, Het very particularly preferably represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.
In a further embodiment, Het particularly preferably represents furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono-, di-or trisubstituted by A, Hal, OH and/or OA.
The compounds of formula I may have one or more chiral centers and may therefore exist in different stereoisomeric forms. Formula I encompasses all of these forms.
Accordingly, the present invention relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the following sub-formulae Ia to Io, which correspond to formula I, and wherein the groups not specified in more detail have the meaning specified for formula I, but wherein
In Ia, R1Represents a compound of formula (I) or a compound of formula (CHO),
R2represents H;
in the Ib, the first step is to add,
R3、R4、R5、R6、R7、R8、R9、R10、R11independently of one another, H, A, Hal, OR12Or O- [ C (R)12)2]nAr；
In Ic, R6Represents OH;
in Id, R3Representation H, A or Hal;
in Ie, R8Represents OH, A, phenoxy or Hal;
in If, R4、R5、R7、R9、R10、R11Represents H or A;
in Ig, R7、R10、R11Independently of one another, H or Hal;
in Ih, Ar represents phenyl which is unsubstituted or mono-, di-or trisubstituted by Hal and/or a;
in Ii, Ar represents phenyl;
in Ii Het represents a monocyclic saturated, unsaturated or aromatic heterocycle containing 1 to 2N and/or O atoms which may be unsubstituted or mono-, di-or trisubstituted by a, Hal, OH and/or OA;
in Ik, Het represents a monocyclic saturated heterocycle containing 1 to 2N and/or O atoms, which may be unsubstituted or mono-or disubstituted by a;
in Il, Het represents furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono-, di-or trisubstituted by a, Hal, OH and/or OA;
in Im, R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
R3、R4、R5、R6、R7、R8、R9、R10、R11independently of one another, H, A, Hal, OR12Or O- [ C (R)12)2]nAr；
In, R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
R3the representation H, A or Hal is,
R4、R5、R7、R9、R10、R11represents a group of a compound represented by the formula H or A,
R6represents an OH group, and is represented by,
R8represents OH, A, phenoxy or Hal;
in Io, R1Represents a group represented by H, CHO or an acetyl group,
R2the expression "H" is used to indicate the formula,
R3the representation H, A or Hal is,
R4、R5、R7、R10、R11h, A or Hal are represented independently of each other,
R6represents an OH group, and is represented by,
R8represents OH, A, phenoxy or Hal,
R9the representation of either H, Hal or OA is,
R8and R9Together also represents methylenedioxy;
and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios.
The compounds of the formula I are particularly preferably selected from:
in addition, the compounds of the invention and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example standard works such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), which are clear under reaction conditions known and suitable for the reaction in question. Variants known per se which have not been mentioned here in more detail can also be used.
If desired, the starting materials can optionally also be formed by not isolating them from the reaction mixture, but immediately converting them further into the compounds of the invention.
The starting compounds are generally known. However, if they are novel, they can be prepared by methods known per se.
The compounds of the formula I can preferably be obtained by reacting hydrazides of the formula II with compounds of the formula III. 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, 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 carboxyl component of formula III.
Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 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, ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents.
Particularly preferred solvents are water or DMF.
It may also be advantageous to add a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal or another weak acid salt of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium.
Depending on the conditions used, the reaction time is from a few minutes to 14 days, the reaction temperature is from about-30 ° to 140 °, normally from-10 ° to 90 °, in particular from about 0 ° to about 70 °.
In the compounds of the formula III, L preferably represents Cl, Br, I or a free or reactively modified OH group, for example an activated ester, an onium imidazole (imidazolide) or an alkylsulphonyloxy group having 1 to 6C atoms, preferably a methylsulphonyloxy or trifluoromethylsulphonyloxy group, or an arylsulphonyloxy group having 6 to 10C atoms, preferably a phenyl-or p-toluenesulphonyloxy group.
Groups of this type which activate the carboxyl group in a typical acylation reaction are described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart;).
The activated ester is conveniently formed in situ, for example by the addition of HOBt or N-hydroxysuccinimide.
Furthermore, the compounds of the formula I can preferably be obtained by reacting hydrazides of the formula IV with compounds of the formula V.
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 carboxyl component of formula V.
Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 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, ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents.
It may also be advantageous to add a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal or another weak acid salt of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium.
Depending on the conditions used, the reaction time is from a few minutes to 14 days, the reaction temperature is from about-30 ° to 140 °, normally from-10 ° to 90 °, in particular from about 0 ° to about 70 °.
In the compounds of the formula V, L preferably represents Cl, Br, I or a free or reactively modified OH group, for example an activated ester, an onium imidazole or an alkylsulfonyloxy group containing 1 to 6C atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy, or an arylsulfonyloxy group containing 6 to 10C atoms, preferably phenyl-or p-tolylsulfonyloxy.
Groups of this type which activate the carboxyl group in a typical acylation reaction are described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart;).
The activated ester is conveniently formed in situ, for example by the addition of HOBt or N-hydroxysuccinimide.
Furthermore, the compounds of the formula I can be prepared by reacting the radicals R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11Conversion to another group R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11Obtained, for example, by hydrolysis or hydrocracking of the ether.
The cleavage of the ether is carried out by methods known to the person skilled in the art.
The standard method of ether cleavage, e.g. methyl ether, is to use boron tribromide.
The cleavage of the hydrogenolytically removable group, e.g. ditolyl ether, can be effected, for example, by treating the cleavage with hydrogen in the presence of a catalyst, e.g. a noble metal catalyst, e.g. palladium, conveniently on a support, e.g. carbon. Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ℃ and a pressure of about 1 to 200bar, preferably 20 to 30 ℃ and 1 to 10 bar.
Esters can be saponified, for example with acetic acid or with NaOH or KOH, water/THF or water/dioxane in water, at temperatures of 0 to 100 °.
Pharmaceutical salts and other forms
The compounds of the invention may be used in their final non-salt form. In another aspect, the invention also encompasses the use of these compounds in forming pharmaceutically acceptable salts thereof, which can be derived from a variety of organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are most often prepared by conventional methods. If a compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting said compound with a suitable base to give the corresponding base addition salt. Such bases are, 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 alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula I. For certain compounds of formula I, acid addition salts may be formed by treating such compounds with pharmaceutically acceptable organic and inorganic acids, for example, hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other inorganic acids and their corresponding salts such as sulfates, nitrates or phosphates and the like, and alkyl-and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following salts: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (benzenesulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galac (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, dihydrogensulfonate, camphorsulfonate, camphorate, naproxen, isobutyrate, galacturonate, malate, levulin, Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not intended to be limiting.
Further, base salts of the compounds of the present invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this is not meant to be limiting. Among the salts mentioned above, ammonium is preferred; sodium and potassium alkali metal salts, and alkaline earth metal calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines, and also naturally occurring substituted amines, cyclic amines and base ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine), this is not meant to be limiting.
The compounds of the invention containing basic nitrogen-containing groups may be quaternized using the agents described below: (C)1-C4) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; two (C)1-C4) Alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates; (C)10-C18) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)1-C4) Alkyl halides, such as benzyl chloride and phenethyl bromide. The water and oil soluble compounds of the present invention can be prepared using these salts.
Preferred pharmaceutically acceptable salts mentioned above include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, although this is not intended to be limiting.
Acid addition salts of the basic compounds of formula I are prepared by contacting the free base with a sufficient amount of the desired acid to allow the salt to form in a conventional manner. The free base can be regenerated by contacting the salt form with the base and isolating the free base by conventional methods. The free base form differs from its corresponding salt form in some way, with respect to certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, salts otherwise correspond to their respective free base forms.
As mentioned above, pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, such as alkali 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-glucosamine and procaine.
The base addition salts of the acidic compounds of the present invention are prepared by contacting the free acid with a sufficient amount of the desired base to allow the salt to form in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid by conventional methods. The free acid form differs from its corresponding salt form in some way, with respect to certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, salts otherwise correspond to their respective free acid forms.
If the compounds of the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, hydrogen fumarate, meglumine, diphosphate, disodium, and trihydrochloride, but this is not intended to be limiting.
From the foregoing, it can be seen that the expression "pharmaceutically acceptable salt" in this context denotes an active ingredient comprising a compound of formula I in one of its salt forms, especially when this salt form has improved pharmacokinetic properties of the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient also provides for the first time this active ingredient with the desired pharmacokinetic properties, which it has earlier not possessed in terms of its therapeutic effectiveness in the body, and which may even have a positive impact on the pharmacodynamics of the active ingredient.
Due to their molecular structure, the compounds of formula I according to the invention can be chiral and accordingly can be produced in various enantiomeric forms. Thus, they may exist in racemic or optically active form.
Since racemates or stereoisomers of the compounds of the present invention have different pharmaceutical activities, it is desirable to use enantiomers. In these cases, the end products or even intermediates can be isolated from the enantiomeric compounds by chemical or physical methods known to the person skilled in the art or even used in the synthesis.
For racemic amines, diastereomers are formed from a mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid in the R and S form, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g.N-benzoylproline or N-phenylsulphonylproline), or various optically active camphorsulphonic acids. Enantiomeric resolution by chromatographic methods is also advantageous with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derived polymers of methacrylic acid immobilized on silica gel. Eluents suitable for this purpose are water-soluble or alcohol-soluble solvent mixtures, for example hexane/isopropanol/acetonitrile, for example in the ratio 82:15: 3.
Furthermore, the present invention relates to the use of a compound and/or a physiologically acceptable salt thereof for the preparation of a medicament (pharmaceutical composition), in particular by non-chemical methods. They can be converted into suitable dosage forms together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if desired, in combination with one or more further active ingredients.
Furthermore, the present invention relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.
The pharmaceutical preparations are administered in dosage units, each dosage unit containing a predetermined amount of the active ingredient. Such a unit may contain, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparation may be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing the daily dose or partial dose indicated above or the active ingredient corresponding thereto. In addition, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.
The pharmaceutical formulations are adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared using all methods known in the art of pharmacy, for example by combining the active ingredient with excipients or auxiliaries.
Pharmaceutical formulations adapted for oral administration may be administered in discrete units, such as capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Thus, for example, for oral administration in the form of a tablet or capsule, the active ingredient component may be combined with oral, non-toxic and pharmaceutically acceptable inert excipients, such as ethanol, glycerol and water. Powders are prepared by grinding the compound to the appropriate size and mixing it with a similarly ground pharmaceutical excipient such as starch or mannitol. Perfumes, preservatives, dispersants and dyes may additionally be present.
Capsules were produced by preparing a powder mixture as described above and filling gelatin shells with it. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating agents and cosolvents, such as agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the drug availability after capsule administration.
In addition, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture to give a tablet. The powder mixture is prepared by mixing the compound ground in a suitable manner with a diluent or base, as described above, and optionally with a binder, for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, a dissolution retardant, for example paraffin, an absorption enhancer, for example a quaternary salt, and/or an absorbent, for example bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acadia glue or a solution of cellulose or polymer substance and pressing it through a sieve. According to another method of granulation, the powder mixture may be passed through a tablet press to obtain a non-uniformly shaped mass that can be broken up into granules to form granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet mould. The lubricated compound is then compressed to give tablets. The compounds of the invention may also be combined with free-flowing inert excipients and then compressed directly to give tablets without the need for granulation or a dry-compression step. There may be a clear layer or an opaque protective layer consisting of a shellac coating, a sugar layer or polymeric substance and a waxy luster layer. Dyes may be added to these packets to enable differentiation among different dosage units.
Oral liquids, such as solutions, syrups and elixirs, can be prepared in the form of dosage units so that the resulting amount contains the compound in the predetermined amount. Syrups can be prepared by dissolving the compound and a suitable flavoring in an aqueous solution, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be prepared by dispersing the compound in a non-toxic vehicle. It is also possible to add cosolvents and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, such as peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, etc.
Dosage unit formulations for oral administration may be microencapsulated if desired. The formulations may also be prepared in such a way as to provide prolonged or delayed release, for example by coating or embedding the particular substance in a polymer, wax or the like.
The compounds of the invention and their salts, solvates and physiologically functional derivatives may be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, unilamellar vesicles and multilamellar lipid vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearamide, or lecithin.
The compounds of the invention and their salts, solvates and physiologically functional derivatives can also be delivered to the partner compound molecule using monoclonal antibodies as individual carriers. The compounds may also be coupled to soluble polymers as targeting drug carriers. These polymers may comprise polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyethyleneoxide polylysine, substituted with palmitoyl groups. In addition, the compounds may be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polynitrile acrylates, and crosslinked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be administered as a separate plaster with intimate contact with the epidermis of the recipient, which is delayed. Thus, for example, the active ingredient may be delivered from the plaster by iontophoresis, as described in Pharmaceutical Research, 3(6), 318(1986) in general.
Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, patches, gels, sprays, aerosols or oils.
For treatment of the eye or other external tissues, such as the mouth and skin, the formulation preferably employs a topical ointment or cream. In the case of formulations for use as ointments, the active ingredient may be used in a cream base mixed with paraffin or water. Alternatively, the active ingredient may be formulated with a water-in-oil cream base or an oil-in-water base to provide a cream.
Pharmaceutical formulations adapted for topical use on the eye, including eye drops, in which 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, pastilles and mouthwashes.
Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.
Pharmaceutical formulations in which the carrier material is a solid suitable for intranasal administration comprise a coarse powder having a particle size, for example in the range 20 to 500 microns, which is administered by inhalation, i.e. by rapid inhalation through the nasal passage with the container containing the powder held close to the nose. Suitable dosage forms for administration as liquids of carrier materials in the form of nasal sprays or nasal drops include solutions of the active ingredient in water or oil.
Pharmaceutical formulations adapted for administration by inhalation include fine particle powders or mists, which may be generated by various types of pressurised dispersions with aerosols, sprays or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous or non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes, by means of rendering the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain a suspension medium and a thickening agent. The formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition, so that only the addition of the sterile carrier liquid, for example water for injections, is required prior to use.
Injectable solutions and suspensions formulated according to the prescription can be prepared from sterile powders, granules, and tablets.
It goes without saying that, in addition to the components specifically mentioned above, it is also possible for the particular type of formulation to comprise other agents customary in the art; thus, for example, a formulation suitable for oral administration may comprise a flavouring agent.
The therapeutically effective amount of a compound of the present invention will depend upon a variety of factors including, for example, the age and weight of the human or animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the physician or veterinarian of treatment. However, an effective amount of a compound of the invention for treatment is typically from 0.1 to 100mg/kg body weight of the recipient (mammal) per day, particularly typically from 1 to 10mg/kg body weight per day. Thus, the actual amount per day for an adult mammal weighing 70kg is typically 70 to 700mg, and this amount may be administered as a single dose per day or as a series of partial doses (e.g., two, three, four, five or six) that are typically greater per day, so that the total daily dose is the same. A therapeutically effective amount of a salt or solvate or physiologically functional derivative thereof is determined with the compound of the invention itself being an effective amount of the moiety. It is hypothesized that similar dosages are applicable to treat the other conditions mentioned above.
Furthermore, the present invention relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.
The invention also relates to a combination (kit) containing the individual packages
(a) An effective amount of a compound of the present invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios,
and
(b) an effective amount of another pharmaceutically active ingredient.
The combination comprises a suitable container, such as a box, individual bottle, bag or ampoule. For example, the combination may comprise separate ampoules, each containing, in a dissolved or lyophilized form, a therapeutically effective amount of a compound of the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of another pharmaceutically active ingredient.
Use of
The compounds of the present invention are suitable as pharmaceutically active ingredients in mammals, especially humans, for the treatment of SGK-induced diseases.
The present invention therefore relates to the use of compounds according to claim 1 and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which inhibition, modulation and/or modulation of kinase signal transduction plays a role. SGK is preferred herein.
Preferred are compounds according to claim 1 and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases which are affected by the inhibition of SGK by a compound according to claim 1.
The invention comprises the use of a compound according to claim 1 and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prophylaxis of: diabetes (e.g. diabetes, diabetic nephropathy, diabetic neuropathy, diabetic vasculopathy and microangiopathy), obesity, metabolic syndrome (dyslipidaemia), systemic hypertension and pulmonary hypertension, cardiovascular diseases (e.g. cardiac fibrosis after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, arteriosclerosis) and renal diseases (e.g. glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, disorders of electrolyte excretion), generally any type of fibrotic and inflammatory process (e.g. cirrhosis of the liver, pulmonary fibrosis, fibrotic pancreatitis, rheumatic and joint diseases, crohn's disease, chronic bronchitis, radioactive fibrosis, sclerormatitis, fibrovesicular disease, scarring, alzheimer's disease).
The compounds of the invention also inhibit cancer, tumor cell growth and tumor metastasis and are therefore suitable for tumor therapy.
Furthermore, the compounds of the invention are useful for the treatment of coagulation disorders, such as dysfibrinogenemia, hypoproteinemia, hemophilia B, Stuart-Prower deficiency, prothrombin complex deficiency, wasting coagulopathy, hyperfibrinolysis, immune coagulation disorders or complex coagulation disorders, and neuronal excitation such as epilepsy. The compounds of the invention are also therapeutically useful in the treatment of glaucoma or cataract. In addition, the compounds of the present invention are useful in the treatment of bacterial infections and anti-infective therapy. The compounds of the invention are also useful therapeutically to enhance learning and attention.
The use of compounds according to claim 1 and their pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or prophylaxis of: diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular and renal diseases, in general any type of fibrotic and inflammatory processes, cancer, tumor cells, tumor metastases, blood clotting disorders, neuronal excitation, glaucoma, cataracts, bacterial infections and anti-infective treatments, for enhancing learning ability and attention, and for treating and preventing cellular aging and stress.
The diabetes is preferably diabetes, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
The cardiovascular diseases are preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
The kidney disease is preferably glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, and electrolyte excretion disorders.
Preferably, the fibrotic and inflammatory process is cirrhosis of the liver, pulmonary fibrosis, fibrotic pancreatitis, rheumatism and arthropathy, crohn's disease, chronic bronchitis, radiation fibrosis, sclerormatitis, fibrocystic disease, scarring, alzheimer's disease.
Assay method
The compounds of the present invention described in the examples were tested using the assays described below and found to have kinase inhibitory activity. Other assays from the literature are known and readily performed by those skilled In the art (see, e.g., Dhanabaal 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).
Inhibition of SGK1 protein kinase can be determined by a filter binding method.
In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional post-processing" means: if necessary, water is added, the pH is adjusted, if necessary, to 2 to 10, depending on the structure of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or crystallization. Rf value on silica gel; the eluent was ethyl acetate/methanol 9: l.
Mass Spectrum (MS): EI (Electron impact ionization) M+
FAB (fast atom bombardment) (M + H)+
ESI (electrospray ionization) (M + H)+(unless otherwise stated)
Example 1
Preparation of N' - [2- (3, 4-difluorophenyl) -2-hydroxyacetyl ] -2, 4-dihydroxy-6-methylbenzhydrazide ("A1") in a manner analogous to the following scheme:
reacting N with 2, 4-dibenzyloxy-6-methylbenzoic acid2H5OH monoacylation. Obtaining: 2, 4-dibenzyloxy-6-methylbenzhydrazide (63%); m.p.: 136 and 137.
Hydrogenation of 2, 4-dibenzyloxy-6-methylbenzhydrazide. 2, 4-dihydroxy-6-methylbenzhydrazide (89%) was obtained; m.p.226 ° (decomposition).
1.3 282mg of 3, 4-difluoromandelic acid, 410mg of 2, 4-dihydroxy-6-methylbenzohydrazide, 431mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSCD) and 164mg of 1-hydroxybenzotriazole (HOBt) were stirred in 1.5ml of DMF for 3 hours. The mixture is then subjected to conventional work-up and to silica gel chromatography. The same fractions were combined, evaporated and recrystallized from EtOAc/petroleum ether. 250mg of "A1" (46%), m.p.220 ℃ were obtained.
The following compounds were obtained analogously:
example 2
Preparation of N' - [ 2-hydroxy-2- (3-hydroxyphenyl) acetyl ] -2-chloro-4, 6-dihydroxybenzohydrazide ("A15")
720mg of N' - [ 2-hydroxy-2- (3-hydroxyphenyl) acetyl ] are dissolved in 20ml of THF +0.2ml of 32% HCl]-2-chloro-4, 6-dibenzyloxybenzohydrazide using 360mg Pd/C with the calculated amount of H2Hydrogenation is carried out. The hydrogenated solution was evaporated and chromatographed on silica gel. The same fractions were combined, evaporated and recrystallized from EtOAc. 310mg (65%) of "A15", m.p.230-231 ℃ are obtained.
The following compounds were obtained analogously:
example 3
Preparation of N' - (2-hydroxy-2-phenylacetyl) -2-methyl-4, 6-dihydroxybenzohydrazide ("A18")
1.6g of 2, 4-dihydroxy-6-methylbenzoic acid are reacted with 4ml of SOCl2Refluxed together until a clear solution formed. Stripping to remove SOCl2Followed by 2 times CH2Cl2The mixture was evaporated to dryness. The acid chloride was then dissolved in 3ml DMF and 1.14g of mandelic hydrazide was added. After the mixture was stirred at room temperature for 2 hours, it was added to H2In O, extracted with EtOAC, dried and evaporated to a smaller volume. 1.49g (50%) of "A18", m.p.188-189 ℃ are obtained.
Alternative preparation (example 4):
1.82g of 2, 4-dihydroxy-6-methylbenzhydrazide are dissolved in 10ml of DMF. 1.71g of mandelic chloride are added slowly. After the mixture was stirred at room temperature for 2 hours, it was added to H2In O, extracted with EtOAC, dried and evaporated to a smaller volume. 2.16g (68%) of "A18", m.p.188-189 ℃ are obtained.
Synthesis of the parent
Example 5
N' - [ 2-hydroxy-2- (3-hydroxyphenyl) acetyl ] -2, 4-dibenzyloxy-6-methylbenzhydrazide
This material was prepared in analogy to example 1 from 2, 4-dibenzyloxy-6-methylbenzhydrazide and 3-hydroxymandelic acid in 47% yield, m.p.181-182 deg.C (from Me)2COH/Et2O)。
The following compounds were obtained analogously:
n' - [ 2-hydroxy-2- (3-hydroxyphenyl) acetyl group]2-chloro-4, 6-dibenzyloxybenzohydrazide, m.p.160-162 ℃ (from Me)2COH/Et2O), yield 61%, and
n' - [ 2-hydroxy-2- (3-hydroxyphenyl) acetyl group]2, 4-dibenzyloxy-6-ethylbenzohydrazide, m.p.205-206 ℃ (from Me)2COH/Et2O), yield 90%.
Example 6
2, 4-dibenzyloxy-6-ethylbenzaldehyde
1.9g of dihydroxy-6-ethylbenzaldehyde, 3.48ml of benzyl chloride and 4.7g of K2CO3Stirred in 5.2ml of DMF at 90 ℃ for 2 hours. The batch was diluted with EtOAc and washed with water. The organic phase utilizes Na2SO4Dried, evaporated and chromatographed on silica gel. The same fractions were combined and evaporated. The oily residue solidified after standing for several days. Treatment with 1:1 ether/petroleum ether gave 3.5g (88%) of 2, 4-dibenzyloxy-6-ethylbenzaldehyde, which was decolorized in air.
Analogously benzylating 3-chloro-2-ethyl-4-hydroxybenzoic acid, 3-chloro-2-ethyl-4-benzyloxybenzoic acid was obtained in 78% yield, m.p.208-210 ℃.
Example 7
2, 4-dibenzyloxy-6-ethylbenzoic acid
3.3g of 2, 4-dibenzyloxy-6-ethylbenzaldehydeDissolved in 63ml of DMSO. Under ice-cooling, 7.9g of NaClO was slowly added2And 7.9g of NaHCO3In a solution of 32ml of water, during which the temperature does not exceed 40 ℃. The mixture was stirred for 2 hours, then further diluted with water and extracted 2 times with EtOAc. The combined organic phases were washed with water and Na2SO4Drying, evaporation, chromatography on silica gel and removal of Me from the mixture2Recrystallization in COH: 2.21g (64%) of 2, 4-dibenzyloxy-6-ethylbenzoic acid are obtained, m.p.126-127 ℃.
The following compounds were prepared analogously:
2, 4-dibenzyloxy-6-chlorobenzoic acid, m.p.135-136 ℃ (35%) and 3-chloro-2-ethyl-4-hydroxybenzoic acid was obtained from 3-chloro-2-ethyl-4-hydroxybenzaldehyde: the yield is 51 percent, and the m.p.138-139 ℃.
Example 8
2, 4-dibenzyloxy-6-ethylbenzohydrazide
This material was prepared from 2, 4-dibenzyloxy-6-ethylbenzoic acid and hydrazine hydroxide according to the method described in example 1: the yield is 75 percent, and the m.p.140-141 ℃.
Similar preparation also yields 2, 4-dibenzyloxy-6-chloro-benzohydrazide: yield 61%, m.p.166-167 ℃ and 4-benzyloxy-3-chloro-2-ethylbenzohydrazide: the yield is 85 percent, and the m.p.182-184 ℃.
Example 9
2, 4-dibenzyloxy-6-chlorobenzaldehyde
12g of chloro-3, 5-dibenzyloxybenzene were dissolved in 40ml of DMF. Slowly dropping 12ml of POCl at 5-10 deg.C3. The mixture was further allowed to react at room temperature for 90 minutes and then at 80 ℃ overnight. The solution is placed in Rotavapor was evaporated and then 200ml ice water was added. The mixture was extracted 3 times with EtOAc, washed with water, dried and evaporated. Chromatography on silica gel gives 8.2g (63%) of 2, 4-dibenzyloxy-6-chlorobenzaldehyde, prepared from (Me)2C)2O crystal, m.p.85-86 deg.C.
Example 10
Acetoxy (3-chlorophenyl) acetic acid
1g of racemic 3-chloromandelic acid was mixed with 2ml of acetyl chloride. A clear solution was formed, which was evaporated in Rotavapor 2 hours later and (Me) was utilized2C)2And crystallizing the O/petroleum ether. Yield 670mg (55%), m.p.118 ℃.
Example 11
3-chloro-2-ethyl-4-hydroxybenzohydrazide
This compound was prepared by hydrogenation of 300mg of Pd/Cu supported 3-chloro-2-ethyl-4-benzyloxybenzohydrazide in 10ml MeOH and 145. mu.l 32% HCl. Yield 165mg (78%), 233-.
The following compounds were prepared analogously: 5-chloro-2, 4-dihydrobenzohydrazide, yield 84%, m.p.260 ℃.
Example 12
3-chloro-2-ethyl-4-hydroxybenzaldehyde
3.4g were dissolved in 40ml of CHCl over 45 minutes3The N-chlorosuccinimide is dissolved in 80ml of CHCl dropwise3And 1.5ml of concentrated HCl in 4g of 2-ethyl-3-hydroxybenzaldehyde. The mixture was further stirred for 1 hour. Washed with water, dried and evaporated.
Chromatography on silica gel afforded 1g (20%) of 3-chloro-2-ethyl-4-hydroxybenzaldehyde (m.p.85 ℃, polar material, using 1:1 ether/petroleum ether as eluent on silica gel) in addition to 5-chloro-2-ethyl-4-hydroxybenzaldehyde (m.p.83 ℃, medium polarity) and 3, 5-dichloro-2-ethyl-4-hydroxybenzaldehyde (m.p.117-118 ℃, non-polar).
The following examples relate to pharmaceutical compositions:
example A: injection bottle
A solution of 100g of the active ingredient according to the invention and 5g of disodium hydrogen phosphate in 3l of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.
Example B: suppository
A mixture of 20g of the active ingredient of the invention with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into a mould and cooled. Each suppository contains 20mg of active ingredient.
Example C: solutions of
Preparation of 1g of active ingredient according to the invention, 9.38g of NaH2PO4·2H2O、28.48gNa2HPO4·12H2O and 0.1g benzalkonium chloride in 940ml double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1l and sterilized by irradiation. The solution can be used in the form of eye drops.
Example D: ointment
500mg of the active ingredient of the invention are mixed with 99.5g of vaseline under sterile conditions.
Example E: tablet formulation
A mixture of 1kg of active ingredient, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed into tablets in a conventional manner so that each tablet contains 10mg of active ingredient.
Example F: sugar-coated tablet
Similar to example E, tablets were compressed and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and a dye.
Example G: capsule
2kg of active ingredient are placed in hard gelatin capsules in the usual way so that each capsule contains 20mg of active ingredient.
Example H: ampoule (CN)
A solution of 1kg of the active ingredient of the invention in 601 redistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.
Claims (29)
1. A compound of formula I
Wherein
R1、R2Independently of one another H, CHO or an acetyl group,
R3、R4、R5、R6、R7、R8、R9、R10、R11independently of one another, H,A、OSO2A、Hal、NO2、OR12、N(R12)2、CN、O-COA、-[C(R12)2]nCOOR12、O-[C(R12)2]oCOOR12、SO3H、-[C(R12)2]nAr、-CO-Ar、O-[C(R12)2]nAr、-[C(R12)2]nHet、-[C(R12)2]nC≡CH、O-[C(R12)2]nC≡CH、-[C(R12)2]nCON(R12)2、-[C(R12)2]nCONR12N(R12)2、O-[C(R12)2]nCON(R12)2、O-[C(R12)2]oCONR12N(R12)2、NR12COA、NR12CON(R12)2、NR12SO2A、N(SO2A)2、COR12、S(O)mAr、SO2NR12Or S (O)mA，
R3And R4Together also CH-CH,
R3and R4、R7And R8Or R8And R9 together also denote an alkylene group having 3, 4 or 5 carbon atoms, in which one or two CH groups2The group may be replaced by oxygen in the presence of oxygen,
a represents an unbranched or branched alkyl radical having 1 to 6C atoms, in which 1 to 7H atoms may be substituted by F, or a cycloalkyl radical having 3 to 7C atoms,
ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or trisubstituted by: hal, A, OR12、N(R12)2、NO2CN, phenyl, CON (R)12)2、NR12COA、NR12CON(R12)2、NR12SO2A、COR12、SO2N(R12)2、S(O)mA、-[C(R12)2]n-COOR12and/or-O [ C (R)12)2]o-COOR12，
Het represents a mono-or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: hal, A, OR12、N(R12)2、NO2、CN、COOR12、CON(R12)2、NR12COA、NR12SO2A、COR12、SO2NR12、S(O)mA、＝S、＝NR12And/or ═ O (carbonyl oxygen),
R12represents a group of a compound represented by the formula H or A,
hal represents F, Cl, Br or I,
m represents 0, 1 or 2,
n represents 0, 1, 2 or 3,
o represents 1, 2 or 3,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
2. A compound according to claim 1, wherein
R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
3. A compound according to claim 1 or 2, wherein
R3、R4、R5、R6、R7、R8、R9、R10、R11Independently of one another, H, A, Hal, OR12Or O- [ C (R)12)2]nAr，
And pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
4. A compound according to one or more of claims 1 to 3, wherein
R6Represents an OH group, and is represented by,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
5. A compound according to one or more of claims 1 to 4, wherein
R3The representation H, A or Hal is,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
6. A compound according to one or more of claims 1 to 5, wherein
R8Represents OH, A, phenoxy or Hal,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
7. The compound according to one or more of claims 1 to 6, wherein
R4、R5、R7、R9、R10、R11Represents a group of a compound represented by the formula H or A,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
8. The compound according to one or more of claims 1 to 7, wherein
R7、R10、R11Independently of one another, represents H or Hal,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
9. The compound according to one or more of claims 1 to 8, wherein
Ar represents phenyl which is unsubstituted or mono-, di-or trisubstituted by Hal and/or A,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
10. A compound according to one or more of claims 1 to 9, wherein
Ar represents a phenyl group, and Ar represents a phenyl group,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
11. The compound according to one or more of claims 1 to 10, wherein
Het represents a monocyclic saturated, unsaturated or aromatic heterocycle containing 1 to 2N and/or O atoms which may be unsubstituted or mono-, di-or trisubstituted by A, Hal, OH and/or OA,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
12. The compound according to one or more of claims 1 to 11, wherein
Het represents a monocyclic saturated heterocycle containing 1 to 2N and/or O atoms, which may be unsubstituted or mono-or disubstituted by A,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
13. The compound according to one or more of claims 1 to 12, wherein
Het represents furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may be unsubstituted or mono-, di-or trisubstituted by A, Hal, OH and/or OA,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
14. The compound according to one or more of claims 1 to 13, wherein
R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
R3、R4、R5、R6、R7、R8、R9、R10、R11independently of one another, H, A, Hal, OR12Or O- [ C (R)12)2]nAr，
And pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
15. The compound according to one or more of claims 1 to 14, wherein
R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
R3the representation H, A or Hal is,
R4、R5、R7、R9、R10、R11represents a group of a compound represented by the formula H or A,
R6represents an OH group, and is represented by,
R8represents OH, A, phenoxy or Hal,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
16. The compound according to one or more of claims 1 to 15, wherein
R1Represents a compound of formula (I) or a compound of formula (CHO),
R2the expression "H" is used to indicate the formula,
R3the representation H, A or Hal is,
R4、R5、R7、R9、R10、R11the representation H, A or Hal is,
R8and R9Together also represent a methylenedioxy group,
R6represents an OH group, and is represented by,
R8represents OH, A, phenoxy or Hal,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
17. The compound according to one or more of claims 1 to 16, wherein
R1Represents a group represented by H, CHO or an acetyl group,
R2the expression "H" is used to indicate the formula,
R3the representation H, A or Hal is,
R4、R5、R7、R10、R11h, A or Hal are represented independently of each other,
R6represents an OH group, and is represented by,
R8represents OH, A, phenoxy or Hal,
R9the representation of either H, Hal or OA is,
R8and R9Together also represent a methylenedioxy group,
and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
18. A compound according to claim 1 selected from
And pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
19. Process for the preparation of compounds of formula I according to claims 1 to 18, as well as pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, characterized in that
a) Reacting a compound of formula II
Wherein
R1、R7、R8、R9、R10And R11Has the following advantagesThe meaning indicated in claim 1 is as follows,
with compounds of the formula III
Wherein
L represents Cl, Br, I or a free or reactive functional group-modified OH group, and
R2、R3、R4、R5and R6Having the meaning indicated in claim 1,
or
b) Reacting a compound of formula IV
Wherein
R2、R3、R4、R5And R6Having the meaning indicated in claim 1,
with compounds of the formula V
Wherein
L represents Cl, Br, I or a free or reactive functional group-modified OH group, and
R1、R7、R8、R9、R10and R11Having the meaning indicated in claim 1,
or
c) Cleavage of the ether by hydrolysis or hydrogenolysis of the radical R in the compounds of the formula I1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11Conversion to another group R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And/or R11，
And/or converting a base or acid of formula I into one of its salts.
20. Pharmaceutical comprising at least one compound according to claims 1 to 18 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.
21. The use of compounds of the formula I according to claims 1 to 18 and their pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment and/or prophylaxis of diseases in which inhibition, modulation and/or modulation of kinase signal transduction plays a role.
22. Use according to claim 21, wherein the kinase is SGK.
23. The use of compounds according to claims 1 to 18, and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, according to claim 22, for the preparation of medicaments for the treatment of diseases which are affected by the inhibition of SGK by the compounds according to claims 1 to 18.
24. Compounds according to claims 1 to 18, as well as pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, according to claim 23, for the preparation of medicaments for the treatment or prophylaxis of the following diseases: diabetes, obesity, metabolic syndrome (dyslipidemia), systemic hypertension and pulmonary hypertension, cardiovascular and renal diseases, generally any type of fibrous and inflammatory processes, cancer, tumor cells, tumor metastases, blood coagulation disorders, neuronal excitation, glaucoma, cataracts, bacterial infections and anti-infective treatments, for enhancing learning ability and attention, for treating and preventing cell aging and stress, and for the treatment of tinnitus.
25. The use according to claim 24, wherein the diabetes is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic vasculopathy and microangiopathy.
26. Use according to claim 25, wherein the cardiovascular disease is cardiac fibrosis, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis after myocardial infarction.
27. Use according to claim 24, wherein the fibrotic and inflammatory process is cirrhosis of the liver, pulmonary fibrosis, fibrotic pancreatitis, rheumatic and arthritic diseases, crohn's disease, chronic bronchitis, radioactive fibrosis, sclerormatitis, fibrocystic disease, scarring and alzheimer's disease.
29. A medicament comprising at least one compound according to claims 1 to 18 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.
30. A kit of parts consisting of the following individually packaged (a) and (b):
(a) an effective amount of a compound according to claims 1 to 18 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios;
and
(b) an effective amount of another pharmaceutically active ingredient.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006006648.0 | 2006-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1129364A true HK1129364A (en) | 2009-11-27 |
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