WO2007014608A1 - Quadratsäurederivate ii - Google Patents
Quadratsäurederivate ii Download PDFInfo
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- WO2007014608A1 WO2007014608A1 PCT/EP2006/006379 EP2006006379W WO2007014608A1 WO 2007014608 A1 WO2007014608 A1 WO 2007014608A1 EP 2006006379 W EP2006006379 W EP 2006006379W WO 2007014608 A1 WO2007014608 A1 WO 2007014608A1
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- Prior art keywords
- cyclobut
- ylamino
- dione
- benzimidazol
- ene
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- 0 CC(*)(C=CC=C1N2)C=C1NC2=O Chemical compound CC(*)(C=CC=C1N2)C=C1NC2=O 0.000 description 8
- YEHIFBPZRHVLQG-UHFFFAOYSA-N CC(C)(C=C1)C=C2NN=NC2=CC1(C)[IH]C Chemical compound CC(C)(C=C1)C=C2NN=NC2=CC1(C)[IH]C YEHIFBPZRHVLQG-UHFFFAOYSA-N 0.000 description 1
- WRCRCUCZGWATOF-UHFFFAOYSA-N CC(C)(C=C1)C=CC(S2)=C1N1C2=NCC1 Chemical compound CC(C)(C=C1)C=CC(S2)=C1N1C2=NCC1 WRCRCUCZGWATOF-UHFFFAOYSA-N 0.000 description 1
- HIMZEJFZDZZMML-UHFFFAOYSA-N CN(C)CCNC(CC(c1cc(O)ccc1)NC(C(C1=O)=O)=C1Nc1ccc2[nH]cnc2c1)O Chemical compound CN(C)CCNC(CC(c1cc(O)ccc1)NC(C(C1=O)=O)=C1Nc1ccc2[nH]cnc2c1)O HIMZEJFZDZZMML-UHFFFAOYSA-N 0.000 description 1
- FVGSYQJYISCKLY-UHFFFAOYSA-N CN(C)CCOc1cc(CNC(C(C2=O)=O)=C2Nc2ccc3[nH]cnc3c2)ccc1 Chemical compound CN(C)CCOc1cc(CNC(C(C2=O)=O)=C2Nc2ccc3[nH]cnc3c2)ccc1 FVGSYQJYISCKLY-UHFFFAOYSA-N 0.000 description 1
- XBLNSZFLKNUTLJ-UHFFFAOYSA-N Oc1cccc(CNC(C(C2=O)=O)=C2Nc(cc2)nc3c2nc[nH]3)c1 Chemical compound Oc1cccc(CNC(C(C2=O)=O)=C2Nc(cc2)nc3c2nc[nH]3)c1 XBLNSZFLKNUTLJ-UHFFFAOYSA-N 0.000 description 1
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Definitions
- the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular of the tyrosine kinases and / or serine / threonine kinases, also pharmaceutical compositions containing these compounds, and the use of the compounds to treat kinase-related diseases.
- the present invention relates to compounds in which the inhibition
- CHK1 and CHK2 - kinase as well as the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK) plays a role, also pharmaceutical compositions containing these compounds, as well as the use of the compounds for the treatment of CHK1-, CHK2- and SGK-related diseases.
- Cell cycle control points are regulatory pathways that control the order and timing of cell cycle transitions. They ensure that important events, such as DNA replication and chromosomal segregation, are completed with high reliability. The control of this
- Control of the critical activation of a control point pathway which arrests the cell cycle to provide time for repair and induces transcription of genes to facilitate repair and prevent immediate cell death.
- CHK1 Ser / Thr kinase checkpoint kinase 1
- ⁇ c phosphorylates the cdc25 phosphatase at serine 216, possibly contributing to the inhibition of cdc2 / cyclin B activation and mitosis. (Sanchez et al., Science, 277: 1497 (1997)). Therefore, inhibition of CHK1 should enhance the effect of DNA-damaging substances by initiating mitosis before the DNA
- CHK2 Another essential checkpoint kinase that plays a critical role in p53-dependent apoptosis is CHK2. Inhibition of CHK2 can protect normal sensitive tissue against chemotherapeutic agents (B.B.S. Zhou et al., Progress in Cell Cycle Research, Vol. 5, 413-421, 2003). Compounds of formula I can be shown to inhibit checkpoint kinase activity. For inhibitors of the checkpoint
- the compounds of formula I can be used for the treatment of neoplastic disease.
- the compounds of formula I and their salts can be used against neoplastic diseases such as carcinoma of the brain, breast, ovary, lung, colon, prostate, skin or other tissues as well as leukemias and lymphomas, tumors of the central and peripheral nervous system and other tumor types, such as melanoma, sarcoma,
- Fibrosarcoma and osteosarcoma are used.
- the compounds of the formula I are also suitable for the treatment of other proliferative disorders.
- the compounds of formula I may also be used in combination with a wide range of DNA damaging agents, but may also be used as a single substance.
- the present invention therefore relates to the use of the compounds of the formula I for the treatment of diseases or conditions in which an inhibition of the CHK1 and / or CHK2 activity is advantageous.
- SGK belongs to the serine / threonine kinases.
- the present invention further relates to the use of
- the SGK plays a role in the treatment of SGK-related diseases.
- the SGK with the isoforms SGK-1, SGK-2 and SGK-3 are one
- the compounds according to the invention are inhibitors of SGK-1. Further, they may be inhibitors of SGK-2 and / or SGK-3. 5
- the present invention thus relates to the use of the compounds of the formula I which inhibit, regulate and / or modulate the signal transduction of SGK, compositions containing these compounds
- diabetes e.g., diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy
- obesity e.g., obesity, metabolic syndrome
- ⁇ c ⁇ c (dyslipidemia), systemic and pulmonary hypertension, cardiovascular diseases (eg cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriosclerosis) and kidney diseases (eg glomerulosclerosis, nephrosclerosis, nephritis, nephropathy,
- Fibrosis and inflammatory processes e.g., cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermitis, cystic fibrosis, scarring, Alzheimer's disease).
- the compounds according to the invention can also inhibit the growth of tumor cells and tumor metastases and are therefore suitable for tumor therapy.
- the compounds according to the invention continue to be used
- coagulopathies such as dysfibrinogenemia, hypoproducinemia, hemophilia B, Stuart-Prower deficiency, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathy or complex coagulopathies, as well as neural
- the compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.
- the compounds of the invention are also used in the treatment of bacterial infections and in an anti-infective therapy.
- the compounds of the invention may also be used therapeutically to increase learning and attention.
- the compounds of the invention counter cell aging and stress and thus increase life expectancy and fitness in old age.
- the compounds of the invention are also used in the
- the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the
- 3Q Diseases comprising the administration of one or more compounds of the invention to a patient in need of such administration.
- the host or patient may be of any mammalian species, e.g. B. one
- EMBO, 1997, 16, 2783-93 models of transgenic animals (e.g., White et al., Oncogene, 2001, 20, 7064-7072).
- interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105).
- the compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.
- kinase activity is a technique well known to those skilled in the art.
- Generic Assay Systems for Determining Kinase Activity with Substrates e.g. Histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the myelin basic protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).
- Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
- Phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., Biochem. J., 2002, 366, 977-981).
- Heterocyclic squaric acid amides are described in US 5,605,909, US 5,532,245 and US 5,466,712 as muscle relaxants.
- Substituted thiophene derivatives are as CHK1 inhibitors in WO
- CHK1 anticancer inhibitors are disclosed in WO 2005/028474 A2.
- Aminopyrazole compounds are described as CHK1 inhibitors in WO 2005/009435 A1.
- WO 00/62781 the use of medicaments containing inhibitors of the cell volume-regulated human kinase H-SGK is described.
- the use of kinase inhibitors in anti-infective therapy is described by C.Doerig in Cell. Biol. Lett. Vol.8, No. 2A 1 2003, 524-525.
- the invention relates to compounds of the formula I.
- R 1 , R 1 ' are each independently H, A, Hal, -CO-A, CN, COOH, COOA, CONH 2 , NH 2 , NHA or NAA 1 ,
- R 2 '" , R 2"" are each independently H, OH, OA, NH 2 , NHA, NAA 1 ,
- NHSO 2 Ar 1 NHSO 2 Het, NHCOA, NHCOAr, NHCOHet, -O (CH 2 ) P-
- R 3 is H, SH, A 1 COOH, COOA, CONH 2 , CONHA or CONAA 1 ,
- R 4 is H, A, COOA, CONH 2 , CH 2 NH 2 , CH 2 NHA or CH 2 NAA 1 ,
- R 5 is H, A or COA
- R is H or alkyl having 1, 2, 3 or 4 C atoms
- Ar ' is unsubstituted or mono-, di- or trisubstituted by A, OA,
- Piperazinyl, A 1 A 1 each independently of one another alkyl having 1 to 10 C atoms, wherein also 1-7 H atoms may be replaced by F and / or chlorine,
- Hal is F, Cl, Br or I is 1m 2, 3, 4 or 5, n is 0, 1 or 2, p is 1, 2, 3 or 4, as well as their pharmaceutically acceptable derivatives, solvates, salts, tautomers and stereoisomers, including their mixtures in all proportions.
- the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers 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 due to their mutual
- Solvates are e.g. Mono- or dihydrate or
- Alcoholates By pharmaceutically acceptable derivatives are meant, for example, the salts of the compounds of the invention as well as so-called prodrug compounds.
- the term "effective amount” means the amount of a drug ⁇ 5 or a pharmaceutical active ingredient which causes a biological or medical response in a tissue, system, animal or human, for example, is sought or desired by a researcher or physician.
- Quantity has not resulted in: improved treatment, cure, prevention or elimination of a
- Reduction of the progression of a disease, a disease or a disorder Reduction of the progression of a disease, a disease or a disorder.
- terapéuticaally effective amount also encompasses the O0 amounts that are effective to increase the normal physiological function.
- the invention also provides the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
- Formula I also includes the tautomeric compounds, e.g. the compounds of the formula Ia and Ib
- the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a compound of the formula II
- R and X ' have the meanings given in claim 1, and A is alkyl having 1-4 C atoms,
- A, A 1 are alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
- A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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, i-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl, more preferably, for example, trifluoromethyl.
- A, A 1 are very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Hexyl, trifluoromethyl, pentafluoroethyl or 35 1, 1, 1-trifluoroethyl.
- X is preferably (CH 2 ) m
- R is very particularly preferably benzimidazolyl.
- R 1 is preferably H, A 1 Hal, -CO-A, CN, COOH 1 COOA 1 CONH 2 ,
- R 1 is preferably H, A or Hal.
- R 2 is preferably OH, OA, NH 2 , NHA 1 NAA 1 , Hal, A, CONH 2 ,
- R 2 , R 2 , R 2 , R 2 are preferably each independently H, Hal or OH.
- R very particularly preferably denotes OH, OA, NH 2 or SO 2 NH 2 .
- R 2 , R 2 , R 2 , R 2 , R 2 very particularly preferably mean H.
- R 3 is preferably H, SH or A.
- m is more preferably 2.
- Ar means e.g. 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-
- Ar is preferably unsubstituted or mono-, di-, tri-, tetra- or fivefold by A, Hal 1 OA, (CH 2 ) n COOH, (CH 2 ) n COOA, NHCO (CH 2 ) n NH 2 and / or -O- (CH 2 ) O -Het 1 substituted phenyl.
- Ar is particularly preferably unsubstituted or mono- or disubstituted by A, Hal, (CH 2 ) n COOH, (CH 2 ) n COOA, NHCO (CH 2 ) n NH 2 and / or -O- (CH 2 ) O -Het 1 substituted phenyl.
- Ar is very particularly preferably phenyl which is unsubstituted or mono- or disubstituted by A, OA 1 OH and / or Hal.
- Ar 1 is preferably, for example, phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal phenyl.
- Pyrimidinyl furthermore preferably 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-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-, A- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-
- heterocyclic radicals may also be partially or completely hydrogenated.
- B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -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-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4 Dihydro
- Het is preferably a mono- or binuclear saturated or aromatic heterocycle having 1 to 4 N atoms, which may be monosubstituted or disubstituted by A.
- Het is particularly preferably where A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.
- Het particularly preferably denotes unsubstituted or mono- or disubstituted by A piperidine,
- Piperazine pyrrolidine, pyridine, pyrimidine, pyrrole, indole, indazole, morpholine, Isoxazole, tetrazole, furan or thiophene, wherein A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.
- Het 1 preferably denotes a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A and / or 0O (carbonyl oxygen), particular preference is given to 4-methylpiperazinyl.
- the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
- Formula I encompasses all these forms.
- the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned
- CH-CH 2 -CONH- (CH 2 ) 1-2 -OA means; means;
- R r is H, A or Hal
- R 2 '" , R 2"" denote H
- R 2 '" , R 2 are each independently H, Hal or OH,
- a 1 are each independently alkyl with 1 to 6 C
- Chlorine can be replaced
- R 3 is H, SH or A
- Ig R 4 is H, A, COOA or CONH 2 ;
- Ii Het a mono- or binuclear saturated or aromatic heterocycle having 1 to 4 N atoms, which may be mono- or disubstituted by A, means;
- R 1 is H, A, Hal, -CO-A 1 CN, COOH, COOA, CONH 2 , NH 2 ,
- R 1 ' is H, A or Hal R 2 , R 2' , R 2 ' ,
- R 2 , R 2 are each independently H, Hal or OH,
- R 4 is H, A, COOA or CONH 2 1
- R 5 is H, A or COA 1
- R 6 is H, A, OH, NH 2 , NHA or NAA 1 , 7
- R 7 is H or alkyl having 1, 2, 3 or 4 C atoms
- Piperazinyl, A, A 1 are each independently alkyl of 1 to 6 carbon atoms.
- Chlorine can be replaced
- Hal is F, Cl, Br or I, m is 2, 3, 4 or 5, n is O, 1 or 2, p is 1, 2, 3 or 4,
- the starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately * c further reacted to the compounds of formula I.
- the reaction is usually carried out in an inert solvent.
- the reaction time is between a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, normally between 15 ° and 100 °, particularly preferably between 50 and 85 ° C.
- Suitable inert solvents are e.g. Hydrocarbons such as hexane,
- Ethers such as diethyl ether, diisopropyl ether,
- Tetrahydrofuran (THF) or dioxane 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);
- Nitrites such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Sulfur carbon; 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.
- Sulfoxides such as dimethylsulfoxide (DMSO); Sulfur carbon
- 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.
- Compounds of formula I can be further obtained by liberation thereof from one of their functional derivatives by treatment with a solvolyzing and / or hydrogenolysing agent by replacing or passing through a conventional amino-protecting group by treatment with a solvolyzing or hydrogenolysing agent a conventional protecting group releases protected amino group.
- Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom, which is connected to an N atom, carry an amino protecting group, in particular those which carry an R'-N group instead of an HN group, in which R 1 represents an amino protecting group, and / or those which instead of the H atom of a Hydroxy group carry a hydroxy protecting group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "where R" represents a hydroxy protecting group.
- amino protecting group is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction at other sites of the process
- acyl group is to be understood in the broadest sense in the context of the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are
- Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl as
- Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
- hydroxy protecting group is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out at other sites on the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or
- hydroxy-protecting groups are not critical, as they depend on the desired chemical Reaction or reaction sequence are removed again; preferred are groups having 1-20, in particular 1-10 C-atoms.
- examples of hydroxy-protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
- Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol,
- Ethanol or isopropanol as well as water.
- mixtures of the abovementioned solvents are also suitable.
- TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1.
- the reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
- the groups BOC, OBut and Mtr can eg. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 °, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
- Hydrogenolytically removable protecting groups may e.g. B. by treatment with hydrogen in the presence of a catalyst (eg. - -
- a noble metal catalyst such as palladium
- a carrier such as coal
- Suitable solvents are those given above, in particular z.
- alcohols such as methanol or ethanol or amides such as DMF.
- the hydrogenolysis is usually 5 at temperatures between about 0 and 100 ° and pressures between about
- Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as ⁇ c trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride,
- Trifluoromethylbenzene 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
- Glycol ethers such as ethylene glycol monomethyl or monoethyl ether
- Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); 25 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.
- 2 Q esters can be treated with acetic acid or with NaOH or KOH in water,
- Water THF or water dioxane be saponified at temperatures between 0 and 100 °.
- the abovementioned compounds according to the invention can be used in their final non-salt form.
- 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 are for
- Example alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and
- 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,
- base salts of the invention include
- Sodium and zinc salts but this is not intended to be limiting.
- Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts
- Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones
- Arginine betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
- Hydrabamine iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, Theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) -methylamine (tromethamine), but this is not intended to be limiting.
- Groups can be, with 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, eg dimethyl, diethyl and diamylsulfate; (C 10 -C 8 ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and
- compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
- the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
- the free base can be prepared by contacting the salt form with a base and isolating the free base to standard
- the salts of the invention otherwise correspond to their respective free base forms.
- the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
- metals are sodium, potassium, magnesium and calcium.
- Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
- the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
- the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
- the free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
- a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
- Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine,
- the term "pharmaceutically acceptable salt” in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
- the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
- compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
- a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
- Condition of the patient, or pharmaceutical formulations may be in
- dosage units containing a predetermined amount of active ingredient per dosage unit are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
- pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
- compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
- Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
- compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
- the active ingredient component in the case of oral administration in the form of a tablet or capsule, can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and using a similarly comminuted pharmaceutical grade
- Carrier such as e.g. an edible carbohydrate such as starch or mannitol.
- a flavor, preservative, dispersant and dye may also be present.
- Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
- Lubricants and lubricants such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
- a disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
- suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
- Suitable binders include starch,
- Gelatin natural sugars, e.g. Glucose or beta-lactose, sweet 5
- the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium
- the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the tablets are formulated by, for example, preparing a powder mixture, granulating or drying
- a powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. carboxymethylcellulose,
- a dissolution reducer such as, e.g. Paraffin
- a resorption accelerator such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate
- the powder mixture can be passed through a tableting machine
- the invention may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
- 35 compounds can also be used with a free-flowing inert
- a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present.
- Coatings can be added to dyes to distinguish between different dosage units.
- Oral fluids e.g. Solution, syrups and elixirs
- Oral fluids e.g. Solution, syrups and elixirs
- Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
- Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
- Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
- flavoring additives e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
- the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
- the formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.
- the compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be prepared from various phospholipids, such as e.g.
- Cholesterol, stearylamine or phosphatidylcholines can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds can also be coupled with soluble polymers as targeted drug carriers.
- Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidophenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
- the compounds may be useful in a class of biodegradable polymers suitable for controlled release of a drug, eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxy-pyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels be coupled.
- a drug eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxy-pyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels be coupled.
- Formulations can be used as separate patches for longer, narrow
- the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
- Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
- the formulations are preferably applied as a topical ointment or cream.
- the active ingredient may be either paraffinic or water-miscible
- Cream base can be used.
- the active ingredient can become a Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
- the pharmaceutical formulations adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
- Formulations include lozenges, lozenges and mouthwashes.
- compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
- compositions adapted for nasal administration in which the vehicle is a solid contain a coarse
- Powder with a particle size for example, in the range of 20-500
- Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
- Fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
- Formulations can be used as pessaries, tampons, creams, gels, pastes,
- compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject
- Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
- the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
- sterile carrier liquid e.g. Water for injections
- formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
- a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
- an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, 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 body weight per
- the actual amount per day is usually between 70 and 700 mg, which may be given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per day so that the total daily dose is same is.
- An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
- the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
- the invention is also a set (kit), consisting of separate
- the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
- the kit may contain, for example, separate ampoules in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance are dissolved or lyophilized Form is present.
- CHK1-mediated disorder includes any disorder, disease or condition caused or characterized by an increase in CHK1 expression or activity or which requires CHK1 activity.
- CHK1-mediated disorder further includes any disorder, disease or condition in which inhibition of CHK1 activity is beneficial.
- CHK1 inhibition can be used to achieve a beneficial therapeutic or prophylactic effect, for example in patients with a proliferative disorder.
- proliferative disorders include i.a. chronic inflammatory proliferative disorders, e.g. Psoriasis and rheumatoid arthritis, proliferative eye disorders, e.g. diabetic retinopathy, benign proliferative disorders, e.g. Hemangiomas, as well as cancer.
- cancer refers to a cellular disorder resulting from uncontrolled or misregulated cell proliferation, decreased cell differentiation, the inability to invade surrounding tissue, and / or the ability to establish new growth at ectopic sites , is marked.
- the term “cancer” includes, but is not limited to, solid tumors and blood-borne tumors.
- cancer includes diseases of the skin, tissues, organs, bones, cartilage,
- cancer further includes primary and metastatic cancers.
- Non-limiting examples of solid tumors that can be treated with the disclosed CHK1 inhibitors include pancreatic cancer, Bladder cancer, colorectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and androgen-independent prostate cancer, kidney cancer, including, for example, metastatic renal cell carcinoma, hepatocellular carcinoma, lung cancer, including, for example, non-small cell lung cancer (NSCLC) 1
- NSCLC non-small cell lung cancer
- Bronchioloalveolar carcinoma and lung adenocarcinoma, ovarian cancer, including e.g. progressive epithelial or primary peritoneal cancer, cervix cancer, gastric cancer, esophageal cancer, head and neck cancer, including e.g. Scab cell carcinoma of the
- Neuroendocrine cancer including metastatic neuroendocrine tumors, brain tumors, including e.g. Glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults and anaplastic astrocytoma in adults, bone cancer and soft tissue sarcoma.
- brain tumors including e.g. Glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults and anaplastic astrocytoma in adults, bone cancer and soft tissue sarcoma.
- Non-limiting examples of hematological malignancies that may be treated with the disclosed CHK1 inhibitors include: acute myeloid leukemia (AML), chronic myeologenic leukemia
- CML CML
- CML-BP accelerated CML and CML blast phase
- ALL acute lymphoblastic leukemia
- CLL chronic lymphocytic leukemia
- HD Hodgkin's disease
- NHL non-Hodgkin's lymphoma
- MDS Waldenstrom's macroglobulinemia
- RA refractory anemia
- RRS refractory anemia with blast excess
- RAEB refractory anemia with blast excess
- RAEB-T RAEB in transformation
- CHK1 inhibitors are also particularly useful in the treatment of cancers or cell types in which another checkpoint pathway is mutated or abolished, including, without limitation, cancers or cell types in which p53 or the p53 pathway is inactivated or abolished.
- anticancer agent refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
- the anticancer treatment as defined herein may be used as a sole therapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compound of the present invention.
- Such chemotherapy may include one or more of the following categories of anti-tumor agents:
- antiproliferative / antineoplastic / DNA damaging agents and combinations thereof, as used in medical oncology such as alkylating agents (for example, cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
- Antimetabolites e.g., antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine
- Anti-tumor antibiotics e.g., anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
- antimitotic for example, cisplatin, carboplatin, cyclo
- agents for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere); topoisomerase
- Inhibitors for example epipodophyllotoxins, such as etoposide and Teniposide, amsacrine, topotecan, irinotecan and camptothecin
- diverting agents for example, all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide
- cytostatic agents such as anti-estrogens (eg, tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfen), estrogen receptor downregulating agents (eg, fulvestrant), anti-androgens (eg, bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH Antagonists or LHRH agonists (for example, goserelin, leuprorelin and buserelin), progesterone (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase, such as finasteride; (iii) agents that inhibit the invasion of cancer cells (for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasm
- farnesyltransferase inhibitors for example inhibitors of the epidermal growth factor family (for example inhibitors of the tyrosine kinases of the EGFR family such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine ( Cl 1033)), for example inhibitors of the epidermal growth factor family (for example inhibitors of the tyrosine kinases of the EGFR family such as N- (3-chloro-4-fluorophenyl) -7-meth
- vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
- antisense therapies for example, those directed against the targets listed above, such as ISIS 2503, an anti-Ras antisense
- gene therapy approaches including, for example, approaches to replace altered genes, such as altered p53 or altered BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, those that include cytosine deaminase, thymidine kinase or a bacterial nitroreductase Use enzyme, as well as approaches to
- Radiation therapy such as multi-drug resistance gene therapy
- In vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines, such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to reducing T-cell anergy, approaches using transfected immune cells , as with cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
- cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
- the medicaments of Table 1 below are combined with the compounds of the formula I. Table 1.
- Rhizoxin (Fujisawa) LU 223651 (BASF)
- Epothilone B Novartis
- ZD 6126 AstraZeneca
- Auristatin PE (Teikoku NeuroPharma)
- Taxoprexin Protarga
- CA-4 Aromatase-aminoglutethimide exemestane
- Thymidylate pemetrexed (EIi Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor TM (BioKeys)
- Histone acetyl trans-Tacedinalin Pfizer pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (titanium)
- TNF-alpha-virulizine (Lorus Revimid (Celgene)
- Retinoic acid Fenretinide Johnson & Alitretinoin (Ligand) Receptor - Johnson
- CapCell TM CYP450-N-acetylcysteine
- Antagonist kappaB inhibitor, Encore
- Efaproxiral oxygenator, receptor agonist, Leo
- PI-88 heparanase antagonist
- SR-31747 (IL-1 rituximab (CD20- Antagonist, Sanofi antibody, Genentech)
- SRL-172 T-cell doranidazole (apoptosis
- TLK-286 glutthione-S-CHS-828 (cytotoxic)
- PT-100 growth factor (differentiator, NIH)
- Point MX6 apoptosis promoter
- CDA-II apoptosis-Ro-31-7453 (apoptosis
- SDX-101 apoptosis-brostallicin (apoptosis)
- Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
- Rhizoxin (Fujisawa) LU 223651 (BASF)
- Epothilone B Novartis
- ZD 6126 AstraZeneca
- Auristatin PE (Teikoku NeuroPharma)
- Taxoprexin (Protarga) CA-4 (OXiGENE)
- TNF-alpha-virulizine (Lorus Revimid (Celgene)
- LGD-1550 ligand
- Immune Interferon Dexosome Therapy Modulators Oncophage (Antigenics) (Anosys)
- SR-31747 (IL-1 PG2 (hematopoietic)
- SRL-172 T-cell (differentiator, NIH)
- TLK-286 (glutathione-S-MAXIA)
- PLC-brostallicin apoptosis
- Such joint treatment can be achieved by simultaneously, sequentially or separately dosing the individual components of the treatment.
- Such combination products employ the compounds of the invention. 5
- the present compounds of the formula I are furthermore suitable as pharmaceutical active ingredients for mammals, in particular for humans, in the treatment of SGK-related diseases.
- 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
- the present invention encompasses the use of the compounds according to the invention as claimed in claim 1 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for
- diabetes eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy
- metabolic syndrome e.g., diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy
- cardiovascular diseases eg cardiac fibrosis after myocardial infarction, cardiac fibrosis
- kidney diseases eg glomerulosclerosis, nephrosclerosis, nephritis, Nephropathy, disturbance of elimination of electrolytes
- fibrosis and inflammatory processes eg liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis
- 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 according to the invention are furthermore used for the treatment of coagulopathies, e.g. Dysfibrinogenemia, hypopro- convertinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathies, e.g. Dysfibrinogenemia, hypopro- convertinemia, hemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-
- ⁇ C coagulopathy or complex coagulopathies and also in neuronal excitability, for example epilepsy.
- the compounds of the invention may also be used therapeutically in the treatment of glaucoma or cataract.
- the compounds of the invention are also used in the
- the compounds of the invention may also be used therapeutically to increase learning and attention.
- Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
- Cardiovascular diseases are preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
- Renal diseases are preferably glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and disorder of the
- Fibrosis and inflammatory processes are preferably liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis,
- CHK1 kinase is expressed in a baculovirus expression vector for the purpose of protein production in insect cells 5 (Sf21, S. frugiperda) and subsequent affinity chromatography purification as a fusion protein with glutathione S-transferase.
- the culture, infection and disruption of the cells, as well as the column chromatographic purification of the fusion protein are carried out according to manufacturer-oriented generic work instructions.
- Method or the filter binding assay is the radioactive phosphorylation of a protein or peptide as a substrate with radioactively labeled ATP ( ⁇ 32 P-ATP, ( ⁇ 33 P-ATP) measured.) In the presence of an inhibitory compound is no or a reduced radioactive signal
- HTR-FRET Resonance Energy Transfer
- FP fluorescence polarization
- Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
- Phospho-AK phospho-antibody binds only the phosphorylated substrate. This binding is detectable with a second peroxidase-conjugated antibody by chemiluminescence (Ross et al., 2002, Biochem. J.).
- test plates are 384-well streptavidin-coated flashplates
- CHK1 kinase a biotinylated substrate peptide (eg CHKtide: KKKVSRSGLYRSPSMPENLNRPR), is labeled with radiolabeled ATP in
- Presence and absence of test substances incubated at 30 ° C and a total volume of 50 ul.
- the reaction is stopped with 25 ⁇ l of a 0.2 M EDTA solution. After incubation for 30 min at room temperature, the supernatants are filtered off with suction and the wells are washed three times with 100 ⁇ l each of 0.9% NaCl solution.
- the measurement of the bound radioactivity is carried out by means of a scintillation meter (Topcount NXT, Perkin-Elmer). As a whole, the inhibitor-free kinase reaction is used. This should be approximately in the range of 3000-4000 cpm.
- the pharmacological zero value used is staurosporine in a final concentration of 0.1 ⁇ M.
- a determination of the inhibition values (IC50) is carried out using the
- bovine serum albumin (final concentration 0.1%) takes place shortly before use.
- Reaction buffer (8 mM MOPS pH7, 0.2 mM EDTA, 10 mM magnesium acetate, 0.02 mM ⁇ 33 P-ATP [500-1000 cpm / pmol]) for 30 min at room temperature.
- the reaction is stopped with 5 ⁇ l of 0.5 M ortho-phosphoric acid and filtered through P81 filter plates. After repeated washing of the filter plates, the determination of the bound radioactivity takes place in the scintillation counter.
- the inhibition of SGK1 protein kinase can be determined in the filter binding method (analogous to CHK1, CHK2).
- “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
- Example A Injection glasses
- a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.
- a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
- a solution of 1 g of an active compound of the formula I, 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 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
- a mixture of 1 kg of active ingredient of the formula I 1 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.
- Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
- a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.
Abstract
Description
Claims
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US11/997,073 US20080234266A1 (en) | 2005-07-29 | 2006-06-30 | Squaric Acid Derivatives II |
CA002616669A CA2616669A1 (en) | 2005-07-29 | 2006-06-30 | Squaric acid derivatives_ii |
AU2006275161A AU2006275161A1 (en) | 2005-07-29 | 2006-06-30 | Quadratic acid II derivatives |
JP2008523157A JP2009505958A (ja) | 2005-07-29 | 2006-06-30 | スクアリン酸誘導体ii |
EP06762312A EP1910312A1 (de) | 2005-07-29 | 2006-06-30 | Quadratsäurederivate ii |
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DE102005035742A DE102005035742A1 (de) | 2005-07-29 | 2005-07-29 | Quadratsäurederivate II |
DE102005035742.3 | 2005-07-29 |
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US (1) | US20080234266A1 (de) |
EP (1) | EP1910312A1 (de) |
JP (1) | JP2009505958A (de) |
AR (1) | AR054877A1 (de) |
AU (1) | AU2006275161A1 (de) |
CA (1) | CA2616669A1 (de) |
DE (1) | DE102005035742A1 (de) |
WO (1) | WO2007014608A1 (de) |
Cited By (6)
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WO2008132500A2 (en) * | 2007-04-27 | 2008-11-06 | Astrazeneca Ab | Chkl inhibitors with b cell depleting antibodies for the treatment of hematologic malignancies |
WO2017087607A1 (en) | 2015-11-19 | 2017-05-26 | Chemocentryx, Inc. | Modulators of chemokine receptors |
CN112125852A (zh) * | 2020-10-12 | 2020-12-25 | 五邑大学 | 具有pH依赖性阴离子跨膜转运活性的方酰胺-双苯并咪唑共轭物、及其合成方法 |
US11040960B2 (en) | 2015-11-19 | 2021-06-22 | Chemocentryx, Inc. | Inhibitors of CXCR2 |
US11207294B2 (en) | 2018-01-08 | 2021-12-28 | Chemocentryx, Inc. | Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2 |
US11421259B2 (en) | 2016-05-04 | 2022-08-23 | Global Life Sciences Solutions Operations UK Ltd | Cell-free protein expression using rolling circle amplification product |
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UA103198C2 (en) | 2008-08-04 | 2013-09-25 | Новартис Аг | Squaramide derivatives as cxcr2 antagonists |
WO2010063802A1 (en) * | 2008-12-05 | 2010-06-10 | Novartis Ag | 3, 4-di-substituted cyclobutene- 1, 2 -diones as cxcr2 receptor antagonists |
ES2340979B1 (es) * | 2008-12-10 | 2011-06-02 | Universitat De Les Illes Balears | Uso de compuestos cicloescuaramidicos como agentes antitumorales. |
BR112014004963A2 (pt) | 2011-09-02 | 2017-03-21 | Novartis Ag | sal de colina do composto anti-inflamatório ciclobutanodiona substituído |
US9926275B2 (en) | 2013-08-22 | 2018-03-27 | Northeastern University | Allosteric modulators of the cannabinoid 1 receptor |
CN113851720B (zh) * | 2021-10-29 | 2023-02-28 | 天津市捷威动力工业有限公司 | 一种锂离子电池非水电解液及其应用 |
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- 2006-06-30 US US11/997,073 patent/US20080234266A1/en not_active Abandoned
- 2006-06-30 EP EP06762312A patent/EP1910312A1/de not_active Withdrawn
- 2006-06-30 AU AU2006275161A patent/AU2006275161A1/en not_active Abandoned
- 2006-06-30 CA CA002616669A patent/CA2616669A1/en not_active Abandoned
- 2006-06-30 WO PCT/EP2006/006379 patent/WO2007014608A1/de active Application Filing
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Cited By (14)
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WO2008132500A2 (en) * | 2007-04-27 | 2008-11-06 | Astrazeneca Ab | Chkl inhibitors with b cell depleting antibodies for the treatment of hematologic malignancies |
WO2008132500A3 (en) * | 2007-04-27 | 2009-08-06 | Astrazeneca Ab | Chkl inhibitors with b cell depleting antibodies for the treatment of hematologic malignancies |
US10988464B2 (en) | 2015-11-19 | 2021-04-27 | Chemocentryx, Inc. | Modulators of chemokine receptors |
EP3383386A4 (de) * | 2015-11-19 | 2019-07-03 | ChemoCentryx, Inc. | Modulatoren von chemokinrezeptoren |
AU2016357413B2 (en) * | 2015-11-19 | 2021-03-04 | Chemocentryx, Inc. | Modulators of chemokine receptors |
WO2017087607A1 (en) | 2015-11-19 | 2017-05-26 | Chemocentryx, Inc. | Modulators of chemokine receptors |
US11040960B2 (en) | 2015-11-19 | 2021-06-22 | Chemocentryx, Inc. | Inhibitors of CXCR2 |
US11820759B2 (en) | 2015-11-19 | 2023-11-21 | Chemocentryx, Inc. | Modulators of chemokine receptors |
US11945805B2 (en) | 2015-11-19 | 2024-04-02 | Chemocentryx, Inc | Inhibitors of CXCR2 |
US11421259B2 (en) | 2016-05-04 | 2022-08-23 | Global Life Sciences Solutions Operations UK Ltd | Cell-free protein expression using rolling circle amplification product |
US11207294B2 (en) | 2018-01-08 | 2021-12-28 | Chemocentryx, Inc. | Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2 |
US11684606B2 (en) | 2018-01-08 | 2023-06-27 | Chemocentryx, Inc. | Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2 |
CN112125852A (zh) * | 2020-10-12 | 2020-12-25 | 五邑大学 | 具有pH依赖性阴离子跨膜转运活性的方酰胺-双苯并咪唑共轭物、及其合成方法 |
CN112125852B (zh) * | 2020-10-12 | 2022-03-22 | 五邑大学 | 具有pH依赖性阴离子跨膜转运活性的方酰胺-双苯并咪唑共轭物、及其合成方法 |
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DE102005035742A1 (de) | 2007-02-01 |
US20080234266A1 (en) | 2008-09-25 |
AR054877A1 (es) | 2007-07-25 |
EP1910312A1 (de) | 2008-04-16 |
CA2616669A1 (en) | 2007-02-08 |
JP2009505958A (ja) | 2009-02-12 |
AU2006275161A1 (en) | 2007-02-08 |
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