EP1910312A1 - Quadratic acid ii derivatives - Google Patents

Quadratic acid ii derivatives

Info

Publication number
EP1910312A1
EP1910312A1 EP06762312A EP06762312A EP1910312A1 EP 1910312 A1 EP1910312 A1 EP 1910312A1 EP 06762312 A EP06762312 A EP 06762312A EP 06762312 A EP06762312 A EP 06762312A EP 1910312 A1 EP1910312 A1 EP 1910312A1
Authority
EP
European Patent Office
Prior art keywords
cyclobut
ylamino
dione
benzimidazol
ene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06762312A
Other languages
German (de)
French (fr)
Inventor
Werner Mederski
Ulrich Emde
Gerhard Barnickel
Frank Zenke
Hartmut Greiner
Frank Stieber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1910312A1 publication Critical patent/EP1910312A1/en
Withdrawn legal-status Critical Current

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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.

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Abstract

The invention relates to compounds of formula (I), wherein R, X, X' and R<SUP>2</SUP>, R<SUP>2'</SUP>, R<SUP>2"</SUP>, R<SUP>3 "</SUP>, R<SUP>2""</SUP> and R<SUP>7</SUP> have the significances specified in claim 1, wherein said compounds are embodied in the form of CHK1- CHK2- and SGK kinase inhibitors and can be used, inter alia, for treating cancer.

Description

- - - -
Quadratsäurederivate IlSquaric acid derivatives II
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
Die vorliegende Erfindung betrifft Verbindungen und die Verwendung von Verbindungen, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen, insbesondere der Tyrosinkinasen und/oder Serin/Threonin-Kinasen eine Rolle spielt, femer pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten, sowie die Verwendung der Verbindungen zur Behandlung kinasebedingter Krankheiten.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.
Die vorliegende Erfindung betrifft Verbindungen, bei denen die Hemmung,The present invention relates to compounds in which the inhibition,
Regulierung und/oder Modulation insbesondere der CHK1- und CHK2 - Kinase, sowie der zellvolumenregulierten humanen Kinase h-sgk (human serum and glucocorticoid dependent kinase oder SGK) eine Rolle spielt, ferner pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten, sowie die Verwendung der Verbindungen zur Behandlung CHK1-, CHK2- und SGK-bedingter Krankheiten.Regulation and / or modulation in particular of 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.
Zellzyklus-Kontrollpunkte sind Regulationswege, die die Reihenfolge und den Zeitpunkt von Zellzyklusübergängen steuern. Sie gewährleisten, daß wichtige Ereignisse, wie DNA-Replikation und Chromosomensegregation, mit hoher Zuverlässigkeit abgeschlossen werden. Die Steuerung dieserCell 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
Zellzyklus-Kontrollpunkte ist eine wichtige Determinante der Art undCell cycle checkpoints is an important determinant of the species and
Weise, wie Tumorzellen auf viele Chemotherapien und Bestrahlung antworten. Viele effiziente Krebstherapien wirken, indem sie eine DNA- Schädigung hervorrufen; Resistenz gegen diese Mittel bleibt jedoch eine erhebliche Einschränkung bei der Behandlung von Krebs. Es gibt ver- schiedene Mechanismen der Arzneistoffresistenz; einen wichtigen führt man auf die Verhinderung der Zellzyklus-Progression aufgrund der - -How tumor cells respond to many chemotherapy regimens and radiation. Many efficient cancer therapies work by causing DNA damage; However, resistance to these agents remains a significant limitation in the treatment of cancer. There are several mechanisms of drug resistance; One important one leads to the prevention of cell cycle progression due to the - -
Steuerung der kritischen Aktivierung eines Kontrollpunkt-Weges zurück, der den Zellzyklus arretiert, um Zeit für die Reparatur bereitzustellen, und die Transkription von Genen induziert, so daß die Reparatur erleichtert und sofortiger Zelltod verhindert wird.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.
Im Zellzyklus gibt es zwei dieser Kontrollpunkte - den G1/S-Kontrollpunkt, der durch p53 gesteuert wird, und den G2/M-Kontrollpunkt, der durch dieIn the cell cycle there are two of these control points - the G1 / S control point, which is controlled by p53, and the G2 / M checkpoint, which is controlled by the
Ser/Thr-Kinase Checkpoint-Kinase 1 (CHK1 ) überwacht wird.Ser / Thr kinase checkpoint kinase 1 (CHK1) is monitored.
Gelänge es, Kontrollpunkt-Arretierungen, beispielsweise am G2-Kontroll-Can it succeed, checkpoint locks, for example on the G2 control
10 punkt, aufzuheben, ließe sich möglicherweise synergistisch der durch10 point, picking up, could possibly be synergistic through
DNA-Schädigung induzierte Tumorzelltod verbessern und die Resistenz umgehen. (Shyjan et al., U.S.-Patent 6,723,498 (2004)). Humane CHK1 spielt eine Rolle bei der Steuerung der Zellzyklus-Arretierung, indem sieImprove DNA damage-induced tumor cell death and bypass resistance. (Shyjan et al., U.S. Patent 6,723,498 (2004)). Human CHK1 plays a role in controlling cell cycle arrest by acting
^ c die Phosphatase cdc25 an Serin 216 phosphoryliert, was möglicherweise dazu beiträgt, die Aktivierung von cdc2/Cyclin B zu verhindern und die Mitose einzuleiten. (Sanchez et al., Science, 277:1497 (1997)). Daher sollte die Hemmung von CHK1 die Wirkung DNA-schädigender Substanzen verstärken, indem die Mitose eingeleitet wird, bevor die DNA-^ 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
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Reparatur abgeschlossen ist, und dadurch den Tumorzelltod hervorrufen.Repair is complete, thereby causing tumor cell death.
Ein Ansatz für das Design von Chemosensibilisatoren, die den G2/M- Kontrollpunkt aufheben, besteht darin, Inhibitoren der regulatorischen Schlüssel-G2/M-Kinase CHK1 zu entwickeln. In einer Reihe von Konzept- 25 Überprüfungsstudien wurde gezeigt, daß dieser Ansatz funktioniertOne approach to the design of chemosensitizers that override the G2 / M checkpoint is to develop inhibitors of the key regulatory G2 / M kinase CHK1. A number of conceptual review studies have shown that this approach works
(Koniaras et al., Oncogene, 2001 , 20:7453; Luo et al., Neoplasia, 2001 , 3:411 ; Busby et al., Cancer Res., 2000, 60:2108; Jackson et al., Cancer Res., 2000, 60:566).(Koniaras et al., Oncogene, 2001, 20: 7453; Luo et al., Neoplasia, 2001, 3: 411; Busby et al., Cancer Res., 2000, 60: 2108; Jackson et al., Cancer Res. , 2000, 60: 566).
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Eine weitere essentielle Checkpoint Kinase, die eine kritische Rolle bei der p53-abhängigen Apoptosis spielt, ist CHK2 zu nennen. Die Inhibierung von CHK2 kann normales empfindliches Gewebe gegen chemotherapeutische Agenzien schützen (B.-B S. Zhou et al., Progress in Cell Cycle Research, Vol. 5, 413-421 , 2003). Für Verbindungen der Formel I kann gezeigt werden, daß sie die Checkpoint-Kinase-Aktivität hemmen. Für Inhibitoren der Checkpoint-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
Kinase kann gezeigt werden, daß sie es den Zellen ermöglichen, unangebracht zur Metaphase der Mitose voranzuschreiten, was zurKinase can be shown to enable cells to move inappropriately to the metaphase of mitosis, leading to
Apoptose betroffener Zellen führt, und deshalb antiproliferative Wirkungen besitzen. Die Verbindungen der Formel I können zur Behandlung von neoplastischer Erkrankung verwendet werden können. Die Verbindungen der Formel I und ihre Salze können gegen neoplastische Erkrankungen, wie Karzinom des Hirns, der Brust, der Eierstöcke, der Lunge, des Dickdarms, der Prostata, der Haut oder anderer Gewebe sowie gegen Leukämien und Lymphome, Tumoren des zentralen und peripheren Nervensystems und andere Tumortypen, wie Melanom, Sarkom,Apoptosis of affected cells leads, and therefore have antiproliferative effects. 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,
Fibrosarkom und Osteosarkom verwendet werden. Die Verbindungen der Formel I sind auch zur Behandlung anderer proliferativer Erkrankungen geeignet. Die Verbindungen der Formel I können auch in Kombination mit einem breiten Spektrum von DNA-schädigenden Mitteln verwendet werden, können aber auch als einzelne Substanz verwendet werden.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.
Die vorliegende Erfindung betrifft daher die Verwendung der Verbindungen der Formel I zur Behandlung von Krankheiten oder Zuständen, bei denen eine Hemmung der CHK1- und/oder CHK2 - Aktivität vorteilhaft ist.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.
Wie CHK1 und CHK2 gehört SGK zu den Serin/Threonin-Kinasen.Like CHK1 and CHK2, SGK belongs to the serine / threonine kinases.
Die vorliegende Erfindung betrifft weiterhin die Verwendung derThe present invention further relates to the use of
Verbindungen der Formel I, wobei die Hemmung, Regulierung und/oder Modulation der Signaltransduktion der zellvolumenregulierten humanen Kinase h-sgk (human serum and glucocorticoid dependent kinase oderCompounds of the formula I, wherein the inhibition, regulation and / or modulation of the signal transduction of the cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or
SGK) eine Rolle spielt, zur Behandlung SGK-bedingter Krankheiten. Die SGK mit den Isoformen SGK-1 , SGK-2 und SGK-3 sind eineSGK) plays a role in the treatment of SGK-related diseases. The SGK with the isoforms SGK-1, SGK-2 and SGK-3 are one
Serin/Threonin-Proteinkinase Familie (WO 02/17893).Serine / threonine protein kinase family (WO 02/17893).
Die erfindungsgemäßen Verbindungen sind Inhibitoren der SGK-1. Ferner können sie Inhibitoren der SGK-2 und/oder SGK-3 sein. 5The compounds according to the invention are inhibitors of SGK-1. Further, they may be inhibitors of SGK-2 and / or SGK-3. 5
Die vorliegende Erfindung betrifft somit die Verwendung der Verbindungen der Formel I, die die Signaltransduktion der SGK hemmen, regulieren und/oder modulieren, Zusammensetzungen, die diese VerbindungenThe 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
10 enthalten, sowie Verfahren zu ihrer Verwendung zur Behandlung von SGK-bedingten Krankheiten und Leiden wie Diabetes (z.B. Diabetes mellitus, diabetische Nephropathie, diabetische Neuropathie, diabetische Angiopathie und Mikroangiopathie), Fettsucht, metabolisches Syndrom10, as well as methods for their use for the treatment of SGK-related diseases and conditions such as diabetes (e.g., diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome
^ c (Dyslipidämie), systemische und pulmonale Hypertonie, Herzkreislauferkrankungen (z.B. kardiale Fibrosen nach Myokardinfarkt, Herzhypertrophie und Herzinsuffizienz, Arteriosklerose) und Nierenerkrankungen (z.B. Glomerulosklerose, Nephrosklerose, Nephritis, Nephropathie,^ 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,
Störung der Elektrolytausscheidung), allgemein bei jeglicher Art vonDisturbance of the elimination of electrolyte), in general with any kind of
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Fibrosen und entzündlichen Prozessen (z.B. Leberzirrhose, Lungenfibrose, fibrosierende Pankreatitis, Rheumatismus und Arthrosen, Morbus Crohn, chronische Bronchitis, Strahlenfibrose, Sklerodermitis, zystische Fibrose, Narbenbildung, Morbus Alzheimer).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).
25 Die erfindungsgemäßen Verbindungen können auch das Wachstum von Tumorzellen und Tumormetastasen hemmen und sind deshalb für die Tumortherapie geeignet. Die erfindungsgemäßen Verbindungen finden weiterhin Verwendung zurThe 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
3Q Behandlung von Koagulopathien, wie z.B. Dysfibrinogenämie, Hypopro- konvertinämie, Hämophilie B, Stuart-Prower-Defekt, Prothrombin- Komplex-Mangel, Verbrauchskoagulopathie, Hyperfibrinolyse, Immuno- koagulopathie oder komplexer Koagulopathien, wie auch bei neuronaler 3 Q Treatment of 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
Erregbarkeit, z.B. Epilepsie. Die erfindungsgemäßen VerbindungenExcitability, e.g. Epilepsy. The compounds of the invention
35 können auch bei der Behandlung eines Glaukoms oder Katarakt therapeutisch eingesetzt werden. Die erfindungsgemäßen Verbindungen finden ferner Verwendung bei der Behandlung bakterieller Infektionen sowie in einer antiinfektiösen Therapie. Die erfindungsgemäßen Verbindungen können auch zur Steigerung der Lernfähigkeit und Aufmerksamkeit therapeutisch eingesetzt werden.They 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.
55
Darüberhinaus wirken die erfindungsgemäßen Verbindungen der Zellalterung und Stress entgegen und steigern somit die Lebenserwartung und die Fitness im Alter. Die erfindungsgemäßen Verbindungen finden ferner Verwendung bei derMoreover, 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
10 Behandlung von Tinitus.10 Treatment of Tinitus.
Die Identifikation von kleinen Verbindungen, die die Signaltransduktion der SGK hemmen, regulieren und/oder modulieren, ist daher wünschenswert A c und ein Ziel der vorliegenden Erfindung.The identification of small compounds which inhibit, regulate and / or modulate the signal transduction of the SGK is therefore desirable A c and an object of the present invention.
Es wurde gefunden, daß die erfindungsgemäßen Verbindungen und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologischeIt has been found that the compounds of the invention and their salts with good compatibility very valuable pharmacological
Eigenschaften besitzen.Own properties.
2020
So zeigen sie auch inhibierende Eigenschaften der SGK.Thus, they also show inhibiting properties of SGK.
Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäße Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei derThe present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the
25 Behandlung und/oder Prophylaxe der genannten Erkrankungen und die25 Treatment and / or prophylaxis of the diseases mentioned and the
Verwendung von erfindungsgemäßen Verbindungen zur Herstellung eines Pharmazeutikums für die Behandlung und/oder Prophylaxe der genannten Erkrankungen wie auch ein Verfahren zur Behandlung der genanntenUse of compounds of the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said
3Q Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einen Patienten mit Bedarf an einer derartigen Verabreichung.3Q Diseases comprising the administration of one or more compounds of the invention to a patient in need of such administration.
Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einerThe host or patient may be of any mammalian species, e.g. B. one
3535
Primatenspezies, besonders Menschen; Nagetieren, einschließlich Mäusen, Ratten und Hamstern; Kaninchen; Pferden, Rindern, Hunden, Katzen usw. Tiermodelle sind für experimentelle Untersuchungen von Interesse, wobei sie ein Modell zur Behandlung einer Krankheit desPrimate species, especially humans; Including rodents Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, being a model for the treatment of a disease of the
Menschen zur Verfügung stellen.To provide people.
Zur Identifizierung eines Signalübertragungswegs und zum Nachweis von Wechselwirkungen zwischen verschiedenen Signalübertragungswegen wurden von verschiedenen Wissenschaftlern geeignete Modelle oder Modellsysteme entwickelt, z.B. Zellkulturmodelle (z.B. Khwaja et al.,To identify a signal transduction pathway and to detect interactions between different signal transduction pathways, appropriate models or model systems have been developed by various scientists, e.g. Cell culture models (e.g., Khwaja et al.
EMBO, 1997, 16, 2783-93) und Modelle transgener Tiere (z.B. White et al., Oncogene, 2001 , 20, 7064-7072). Zur Bestimmung bestimmter Stufen in der Signalübertragungskaskade können wechselwirkende Verbindungen genutzt werden, um das Signal zu modulieren (z.B. Stephens et al., Biochemical J., 2000, 351 , 95-105). Die erfindungsgemäßen Verbindungen können auch als Reagenzien zur Testung kinaseabhängiger Signalübertragungswege in Tieren und/oder Zellkulturmodellen oder in den in dieser Anmeldung genannten klinischen Erkrankungen verwendet werden.EMBO, 1997, 16, 2783-93) and models of transgenic animals (e.g., White et al., Oncogene, 2001, 20, 7064-7072). To determine particular levels in the signal transduction cascade, interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.
Die Messung der Kinaseaktivität ist eine dem Fachmann wohlbekannte Technik. Generische Testsysteme zur Bestimmung der Kinaseaktivität mit Substraten, z.B. Histon (z.B. Alessi et al., FEBS Lett. 1996, 399, 3, Seiten 333-338) oder dem basischen Myelinprotein sind in der Literatur beschrieben (z.B. Campos-Gonzälez, R. und Glenney, Jr., J. R. 1992, J. Biol. Chem. 267, Seite 14535).The measurement of 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).
Zur Identifikation von Kinase-Inhibitoren stehen verschiedene Assay- Systeme zur Verfügung. Beim Scintillation-Proximity-Assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) und dem FlashPlate-Assay wird die radioaktive Phosphorylierung eines Proteins oder Peptids als Substrat mit γATP gemessen. Bei Vorliegen einer inhibitorischen Verbin- dung ist kein oder ein vermindertes radioaktives Signal nachweisbar. Ferner sind die Homogeneous Time-resolved Fluorescence Resonance Energy Transfer- (HTR-FRET-) und Fluoreszenzpolarisations- (FP-) Technologien als Assay- Verfahren nützlich (SiIIs et al., J. of Biomolecular Screening, 2002, 191-214).Various assay systems are available for the identification of kinase inhibitors. In the Scintillation Proximity Assay (Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19) and the FlashPlate assay, the radioactive phosphorylation of a protein or peptide as a substrate is measured with γATP. In the presence of an inhibitory compound No or a reduced radioactive signal is detectable. Further, Homogeneous Time-resolved Fluorescence Resonance Energy Transfer (HTR-FRET) and Fluorescence Polarization (FP) technologies are useful as assay methods (SiIIs et al., J. of Biomolecular Screening, 2002, 191-214).
Andere nicht radioaktive ELISA-Assay-Verfahren verwenden spezifische Phospho-Antikörper (Phospho-AK). Der Phospho-AK bindet nur das phosphorylierte Substrat. Diese Bindung ist mit einem zweiten Peroxidase- konjugierten Anti-Schaf-Antikörper durch Chemolumineszenz nachweisbar (Ross et al., Biochem. J., 2002, 366, 977-981 ).Other non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK). The phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., Biochem. J., 2002, 366, 977-981).
STAND DER TECHNIKSTATE OF THE ART
Andere Quadratsäurederivate sind in WO 03/080053 A1 und WOOther squaric acid derivatives are described in WO 03/080053 A1 and WO
02/083624 A1 als CXC- Chemokin-Rezeptorantagonisten beschrieben.02/083624 A1 as CXC chemokine receptor antagonists.
In der WO 01/64208 sind andere Quadratsäure-amide zur Behandlung verschiedener Krankheiten offenbart.In WO 01/64208 other squaric acid amides are disclosed for the treatment of various diseases.
Heterocyclische Quadratsäureamide sind in US 5,605,909, US 5,532,245 und US 5,466,712 als Muskelrelaxantien beschrieben.Heterocyclic squaric acid amides are described in US 5,605,909, US 5,532,245 and US 5,466,712 as muscle relaxants.
Substituierte Thiophenderivate sind als CHK1 Inhibitoren in WOSubstituted thiophene derivatives are as CHK1 inhibitors in WO
2005/016909 A1 beschrieben. Andere heterocyclische CHK1 Inhibitoren zur Krebsbekämpfung sind in WO 2005/028474 A2 offenbart. Aminopyrazolverbindungen sind als CHK1 Inhibitoren in WO 2005/009435 A1 beschrieben.2005/016909 A1. Other heterocyclic CHK1 anticancer inhibitors are disclosed in WO 2005/028474 A2. Aminopyrazole compounds are described as CHK1 inhibitors in WO 2005/009435 A1.
In der WO 00/62781 ist die Verwendung von Arzneimitteln enthaltend Hemmstoffe der zellvolumenregulierten humanen Kinase H-SGK beschrieben. Die Verwendung von Kinase-Inhibitoren in der antiinfektiösen Therapie ist von C.Doerig in Cell. Mol. Biol. Lett. Vol.8, No. 2A1 2003, 524-525 beschrieben.In 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.
Die Verwendung von Kinase-Inhibitoren bei Fettsucht ist von N.Perrotti in J. Biol. Chem. 2001 , März 23; 276(12):9406-9412 beschrieben.The use of kinase inhibitors in obesity is described by N.Perrotti in J. Biol. Chem. 2001, March 23; 276 (12): 9406-9412.
In nachstehenden Literaturstellen wird die Verwendung von SGK- Hemmern bei der Behandlung von Krankheiten nahegelegt und/oder beschrieben:The following references suggest and / or describe the use of SGK inhibitors in the treatment of diseases:
1 : Chung EJ, Sung YK1 Farooq M, Kim Y, Im S, Tak WY1 Hwang YJ, Kim Yl, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular Carcinoma by cDNA microarray. Mol CeIIs. 2002; 14:382-7.1: Chung EJ, Sung YK 1 Farooq M, Kim Y, Im S, Tak WY 1 Hwang YJ, Kim Yl, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol CeIIs. 2002; 14: 382-7.
2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1(SGK-1 ). J Biol2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J Biol
Chem. 2002;277:43064-70.Chem. 2002; 277: 43064-70.
3: Fillon S, Klingel K, Wamtges S, Sauter M, Gabrysch S, Pestel S, Tanneur V1 Waldegger S, Zipfel A, Viebahn R1 Haussinger D, Broer S, Kandolf R, Lang F. Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem. 2002;12:47-54.3: Fillon S, Klingel K, Wamtges S, Sauter M, Gabrysch S, Pestel S, Tanneur V 1 Waldegger S, Zipfel A, Viebahn R 1 Haussinger D, Broer S, Kandolf R, Lang F. Expression of the serine / threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem. 2002; 12: 47-54.
4: Brunet A1 Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival Signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001 ;21 :952-654: Brunet A 1 Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001; 21: 952-65
5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem. 2001 ;276:16649-54. 6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Honkanen RE. Ser/Thr protein Phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry.5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine / threonine survival kinase gene, sgk-1. J Biol Chem. 2001; 276: 16649-54. 6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Honkanen RE. Ser / Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry.
1999;38:8849-57. 51999; 38: 8849-57. 5
7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary 10 tumor cells. A novel convergence point of anti-proliferative and proliferative cell signalling pathways. J Biol Chem. 1999;274:7253-63.7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear cytoplasmic localization of the serum and glucocorticoid-inducible protein kinase, Sgk, in mammary 10 tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J Biol Chem. 1999; 274: 7253-63.
8: M. Hertweck, C. Göbel, R. Baumeister: C.elegans SGK-1 is the critical A c component in the Akt/PKB Kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577-588, April, 2004.8: M. Hertweck, C. Göbel, R. Baumeister: C. elegans SGK-1 is the critical A c component in the Akt / PKB kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577- 588, April, 2004.
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ZUSAMMENFASSUNG DER ERFINDUNGSUMMARY OF THE INVENTION
Die Erfindung betrifft Verbindungen der Formel IThe invention relates to compounds of the formula I.
worin R wherein R
(CH2)m X (CH2)n, CHA1 NH, NA , _\ /_ , (CH 2 ) m X (CH 2 ) n , CHA 1 NH, NA, _ \ / _,
CH-(CH2)n-COOH, CH-(CH2)n-COOA,CH- (CH 2 ) n -COOH, CH- (CH 2 ) n -COOA,
CH-(CH2)n-CO-Het2 ) CH-(CH2)n-Het2,CH- (CH 2 ) n -CO-Het 2 ) CH- (CH 2 ) n -Het 2 ,
CH-CH2-CONH-(CH2)1-4-NH2,CH-CH 2 -CONH- (CH 2 ) 1-4 -NH 2 ,
CH-CH2-CONH-(CH2)1-4-NHA, CH-CH2-CONH-(CH2)I-4-NA2,CH-CH 2 -CONH- (CH 2 ) 1-4 -NHA, CH-CH 2 -CONH- (CH 2 ) I -4 -NA 2 ,
CH-CH2-CONH-(CH2)1-4-OH oderCH-CH 2 -CONH- (CH 2 ) 1-4 -OH or
CH-CH2-CONH-(CH2)L4-OA,CH-CH 2 -CONH- (CH 2) L4 -OA,
X1 (CHz)n,X 1 (CHz) n ,
R1, R1' jeweils unabhängig voneinander H, A, HaI, -CO-A, CN, COOH, COOA, CONH2, NH2, NHA oder NAA1,R 1 , R 1 'are each independently H, A, Hal, -CO-A, CN, COOH, COOA, CONH 2 , NH 2 , NHA or NAA 1 ,
R2, R2', R2 R 2 , R 2 ' , R 2
R2'" , R2"" jeweils unabhängig voneinander H, OH, OA, NH2, NHA, NAA1,R 2 '" , R 2""are each independently H, OH, OA, NH 2 , NHA, NAA 1 ,
HaI, A, CONH2, CONHA, CONAA1, CONHAr, CONHHet, SO2NH2, SO2NHA, SO2NAA1, SO2NHAr1 SO2NHHet, NHSO2A,HaI, A, CONH 2 , CONHA, CONAA 1 , CONHAr, CONHHet, SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , SO 2 NHAr 1 SO 2 NHHet, NHSO 2 A,
NHSO2Ar1 NHSO2Het, NHCOA, NHCOAr, NHCOHet, -O(CH2)P- NHSO 2 Ar 1 NHSO 2 Het, NHCOA, NHCOAr, NHCOHet, -O (CH 2 ) P-
OH, -O(CH2)POA,OH, -O (CH 2) P OA,
-O(CH2)PNH2, -O(CH2)PNHA, -O(CH2)PNAA', -O(CH2)PNH-COA, -O(CH2)PNHSO2A, -B(OH)2, NHCOOA,-O (CH 2 ) P NH 2 , -O (CH 2 ) P NHA, -O (CH 2 ) P NAA ', -O (CH 2 ) P NH-COA, -O (CH 2 ) P NHSO 2 A , -B (OH) 2 , NHCOOA,
COOH, COOH, SO2A, NHCHO, NHCONH2,COOH, COOH, SO 2 A, NHCHO, NHCONH 2 ,
-CH(OH)-CH2Ar, Het,-CH (OH) -CH 2 Ar, Het,
zwei benachbarte Reste ausgewählt aus R2, R2 , R2 , R2 , R2 zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -N=CR7-NH, -NH-CO-O-, - 1 - two adjacent radicals selected from R 2 , R 2 , R 2 , R 2 , R 2 together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH-, -N = CR 7 -NH, -NH-CO-O-, - 1 -
-OCH2O-, -NH-CH=C(CH2NAA1)- oder -NH-CH=C--OCH 2 O-, -NH-CH = C (CH 2 NAA 1 ) - or -NH-CH = C-
R3 H, SH, A1 COOH, COOA, CONH2, CONHA oder CONAA1,R 3 is H, SH, A 1 COOH, COOA, CONH 2 , CONHA or CONAA 1 ,
R4 H, A, COOA, CONH2, CH2NH2, CH2NHA oder CH2NAA1,R 4 is H, A, COOA, CONH 2 , CH 2 NH 2 , CH 2 NHA or CH 2 NAA 1 ,
R5 H, A oder COA,R 5 is H, A or COA,
R6 H1 A, OH, NH2, NHA oder NAA1, 7 R 6 H 1 A, OH, NH 2 , NHA or NAA 1 , 7
R H oder Alkyl mit 1 , 2, 3 oder 4 C-Atomen,R is H or alkyl having 1, 2, 3 or 4 C atoms,
R7 und ein Rest ausgewählt aus der Gruppe R2, R2 , R2 , R2 , R2 zusammen auch -CH2CH2-, R8 H, A oder HaI, Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durchR 7 and a radical selected from the group R 2 , R 2 , R 2 , R 2 , R 2 together also -CH 2 CH 2 -, R 8 H, A or Hal, Ar unsubstituted or one, two, three -, four or five times through
A, OA, OH, SH, SA, HaI, NO2, CN, (CH2JnAr1, (CH2)nCOOH, (CH2)nCOOA, CHO, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA1, SO2NHA, SO2NAA1, NH2, NHA, NAA1, OCONH2, OCONHA, OCONAA1, NHCOA, NHCOOA, NACOOA,A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 J n Ar 1 , (CH 2 ) n COOH, (CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA 1 , SO 2 NHA, SO 2 NAA 1 , NH 2 , NHA, NAA 1 , OCONH 2 , OCONHA, OCONAA 1 , NHCOA, NHCOOA, NACOOA,
NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA'.NACONAA1 und/oder NHCO(CH2)nNH2 substituiertes Phenyl, Naphthyl oder Biphenyl,NHSO 2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA'.NACONAA 1 and / or NHCO (CH 2 ) n NH 2 substituted phenyl, naphthyl or biphenyl,
Ar' unsubstituiertes oder ein-, zwei- oder dreifach durch A, OA,Ar 'is unsubstituted or mono-, di- or trisubstituted by A, OA,
OH, SH, SA, HaI, NO2, CN, (CH2)nPhenyl, (CH2)nCOOH, (CH2)nCOOA, CHO, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA1, SO2NHA, SO2NAA1, NH2, NHA, NAA1, OCONH2, OCONHA, OCONAA1, NHCOA, NHCOOA, NACOOA1 NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA,OH, SH, SA, Hal, NO 2 , CN, (CH 2 ) n phenyl, (CH 2 ) n COOH, (CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA 1 , SO 2 NHA, SO 2 NAA 1 , NH 2 , NHA, NAA 1 , OCONH 2 , OCONHA, OCONAA 1 , NHCOA, NHCOOA, NACOOA 1 NHSO 2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA,
NACONHA, NHCONAA1 und/oder NACONAA1 substituiertes Phenyl, Naphthyl oder Biphenyl, Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-NACONHA, NHCONAA 1 and / or NACONAA 1 substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S
Atomen, der ein-, zwei- oder dreifach durch A, OA, OH, SH, SA, HaI1 NO2, CN, (CH2)HAr1, (CH2)nCOOH, (CH2)nCOOA, CHO, COA, SO2A, CONH2, SO2NH2, CONHA1 CONAA1, SO2NHA, SO2NAA1, NH2, NHA, NAA1, OCONH2, OCONHA1 OCONAA1, NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA1 NACONHA1 NHCONAA1,Atoms which are mono-, di- or trisubstituted by A, OA, OH, SH, SA, Hal 1 NO 2 , CN, (CH 2 ) H Ar 1 , (CH 2 ) n COOH, (CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA 1 CONAA 1 , SO 2 NHA, SO 2 NAA 1 , NH 2 , NHA, NAA 1 , OCONH 2 , OCONHA 1 OCONAA 1 , NHCOA, NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA 1 NACONHA 1 NHCONAA 1 .
NACONAA1, SO2A1 =S, =NH, =NA und/oder =0 (Carbonylsauerstoff) substituiert sein kann, Het1 einen einkernigen gesättigten Heterocyclus mit 1 bis 2 N und/oder O-Atomen, der ein- oder zweifach durch A, OA, OH,NACONAA 1 , SO 2 A 1 = S, = NH, = NA and / or = 0 (carbonyl oxygen) may be substituted, Het 1 is a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, the one or two times by A, OA, OH,
HaI und/oder =0 (Carbonylsauerstoff) substituiert sein kann, Het2 Morpholin-4-yl, Dioxanyl, Piperidinyl, Pyrrolidinyl oderHaI and / or = O (carbonyl oxygen) may be substituted, Het 2 morpholin-4-yl, dioxanyl, piperidinyl, pyrrolidinyl or
Piperazinyl, A1 A1 jeweils unabhängig voneinander Alkyl mit 1 bis 10 C-Atomen, wobei auch 1-7 H-Atome durch F und/oder Chlor ersetzt sein können,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,
HaI F, Cl, Br oder I1 m 2, 3, 4 oder 5, n O, 1 oder 2, p 1 , 2, 3 oder 4 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.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.
Gegenstand der Erfindung sind auch die optisch aktiven Formen (Stereoisomeren), die Enantiomeren, die Racemate, die Diastereomeren sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvate der Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen verstanden, die sich aufgrund ihrer gegenseitigenThe 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
Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oderTrain attraction. Solvates are e.g. Mono- or dihydrate or
Alkoholate. Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. die Salze der erfindungsgemäßen Verbindungen als auch sogenannte Prodrug-Verbindungen.Alcoholates. By pharmaceutically acceptable derivatives are meant, for example, the salts of the compounds of the invention as well as so-called prodrug compounds.
Unter Prodrug-Derivaten versteht man mit z. B. Alkyl- oder Acylgruppen, 5Under prodrug derivatives is understood with z. B. alkyl or acyl groups, 5
Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten werden.Sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved in the organism to the active compounds of the invention.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungs- 10 gemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.These include biodegradable polymer derivatives of the inventive compounds, as described, for. In Int. J. Pharm. 115, 61-67 (1995).
Der Ausdruck "wirksame Menge" bedeutet die Menge eines Arzneimittels ^5 oder eines pharmazeutischen Wirkstoffes, die eine biologische oder medizinische Antwort in einem Gewebe, System, Tier oder Menschen hervorruft, die z.B. von einem Forscher oder Mediziner gesucht oder erstrebt wird.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.
Darüberhinaus bedeutet der Ausdruck "therapeutisch wirksame Menge"Moreover, the term "therapeutically effective amount" means
20 eine Menge, die, verglichen zu einem entsprechenden Subjekt, das diese20 a set that, compared to a corresponding subject, this
Menge nicht erhalten hat, folgendes zur Folge hat: verbesserte Heilbehandlung, Heilung, Prävention oder Beseitigung einerQuantity has not resulted in: improved treatment, cure, prevention or elimination of a
Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines 25 Leidens, einer Störung oder von Nebenwirkungen oder auch dieIllness, a medical condition, a medical condition, a disease, a disorder or side effects, or even those
Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung.Reduction of the progression of a disease, a disease or a disorder.
Die Bezeichnung "therapeutisch wirksame Menge" umfaßt auch die O0 Mengen, die wirkungsvoll sind, die normale physiologische Funktion zu erhöhen.The term "therapeutically effective amount" also encompasses the O0 amounts that are effective to increase the normal physiological function.
Gegenstand der Erfindung ist auch die Verwendung von Mischungen der Verbindungen der Formel I, z.B. Gemische zweier Diastereomerer z.B. im Verhältnis 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 oder 1 :1000. Besonders bevorzugt handelt es sich dabei um Mischungen stereoisomerer Verbindungen.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.
Die Formel I umfasst auch die tautomeren Verbindungen, wie z.B. die Verbindungen der Formel Ia und IbFormula I also includes the tautomeric compounds, e.g. the compounds of the formula Ia and Ib
Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel I sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel IlThe 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
worin R und X' die in Anspruch 1 angegebenen Bedeutungen haben, und A Alkyl mit 1-4 C-Atomen bedeutet,wherein R and X 'have the meanings given in claim 1, and A is alkyl having 1-4 C atoms,
mit einer Verbindung der Formel III with a compound of formula III
worin X und R2, R2 , R2 , R2 , R2 und R7 die in Anspruch 1 angegebenen 10 Bedeutungen haben,in which X and R 2 , R 2 , R 2 , R 2 , R 2 and R 7 have the meanings given in claim 1,
umsetzt,implements,
und/oder 15 eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converting a base or acid of formula I into one of its salts.
Vor- und nachstehend haben die Reste R, X, X', R2, R2 ", R2", R2 ' " und R7 die bei der Formel I angegebenen Bedeutungen, sofern nicht ausdrücklich 20 etwas anderes angegeben ist.Above and below, the radicals R, X, X ', R 2 , R 2 " , R 2" , R 2'" and R 7 have the meanings given for the formula I, unless expressly stated otherwise.
A, A1 bedeuten Alkyl, ist unverzweigt (linear) oder verzweigt, und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. A bedeutet vorzugsweise Methyl, 25 weiterhin Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.- Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1- , 1 ,2- oder 2,2- Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1- , 2- , 3- oder 4-Methylpentyl, 1 ,1- , 1,2- , 1 ,3- , 2,2- , 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl- 1-methylpropyl, i-Ethyl-2-methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl, weiter bevorzugt z.B. Trifluormethyl.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, A1 bedeuten ganz besonders bevorzugt Alkyl mit 1 , 2, 3, 4, 5 oder 6 C- Atomen, vorzugsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl, tert.-Butyl, Pentyl, Hexyl, Trifluormethyl, Pentafluorethyl oder 35 1 ,1 ,1-Trifluorethyl. X bedeutet vorzugsweise (CH2)m 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
(CHz)n, CHA, \ / , C CH-CH2-COOH, CH-CH2-COOA,(CHz) n , CHA, \ /, C CH-CH 2 -COOH, CH-CH 2 -COOA,
CH-CH2-CO-Het2, CH-CH2-Het2,CH-CH 2 -CO-Het 2 , CH-CH 2 -Het 2 ,
CH-CH2-CONH-(CH2)L2-NH2,CH-CH 2 -CONH- (CH 2 ) L 2 -NH 2 ,
CH-CH2-CONH-(CH2)1-2-OH oder CH-CH2-CONH-(CH2)L2-OA.CH-CH 2 -CONH- (CH 2 ) 1-2 -OH or CH-CH 2 -CONH- (CH 2 ) L2 -OA.
R bedeutet ganz besonders bevorzugt Benzimidazolyl.R is very particularly preferably benzimidazolyl.
R1 bedeutet vorzugsweise H, A1 HaI, -CO-A, CN, COOH1 COOA1 CONH2,R 1 is preferably H, A 1 Hal, -CO-A, CN, COOH 1 COOA 1 CONH 2 ,
NH2, NHA oder NAA1. R1 bedeutet vorzugsweise H, A oder HaI.NH 2 , NHA or NAA 1 . R 1 is preferably H, A or Hal.
R2 bedeutet vorzugsweise OH, OA, NH2, NHA1 NAA1, HaI, A, CONH2,R 2 is preferably OH, OA, NH 2 , NHA 1 NAA 1 , Hal, A, CONH 2 ,
CONHA, CONAA1, CONHAr, CONHHet, SO2NH2, SO2NHA, SO2NAA1, SO2NHAr, SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA, NHCOAr, NHCOHet, -O(CH2)POH, -O(CH2)POA, -O(CH2)PNH2, -O(CH2)PNHA, -O(CH2)PNAA\ -O(CH2)PNH-COA, -O(CH2)PNHSO2A, -B(OH)2, NHCOOA, COOH, COOH, SO2A, NHCHO, NHCONH2, -CH(OH)- CH2Ar, Het,CONHA, CONAA 1 , CONHAr, CONHHet, SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , SO 2 NHAr, SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr, NHCOHet, O (CH 2 ) P OH, -O (CH 2 ) P OA, -O (CH 2 ) P NH 2 , -O (CH 2 ) P NHA, -O (CH 2 ) P NAA -O (CH 2 ) P NH-COA, -O (CH 2 ) P NHSO 2 A, -B (OH) 2 , NHCOOA, COOH, COOH, SO 2 A, NHCHO, NHCONH 2 , -CH (OH) -CH 2 Ar, Het .
R2 , R2 , R2 , R2 bedeuten vorzugsweise jeweils unabhängig voneinander H, HaI oder OH.R 2 , R 2 , R 2 , R 2 are preferably each independently H, Hal or OH.
R: bedeutet ganz besonders bevorzugt OH, OA, NH2 oder SO2NH2.R : very particularly preferably denotes OH, OA, NH 2 or SO 2 NH 2 .
R2 , R2 , R2 , R2 bedeuten ganz besonders bevorzugt H. R3 bedeutet vorzugsweise H, SH oder A. R R44 bbeeddeeuutteett vvoorrzzuuggsswweeiissee HH,, AA,, CCOOOA oder CONH2. m bedeutet besonders bevorzugt 2.R 2 , R 2 , R 2 , R 2 very particularly preferably mean H. R 3 is preferably H, SH or A. RR 44 bbeeddeeuutteett vvoorrzzuuggsswweeiissee HH ,, AA ,, CCOOOA or CONH 2 . m is more preferably 2.
Ar bedeutet z.B. Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert- Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitrophenyl, o-, m-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-
10 oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p- (N-Methylaminocarbonyl)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxy- carbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p-10 or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o- , m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, , m- or p-
^ c (N,N-Dimethylaminocarbonyl)-phenyl, o-, m- oder p-(N-Ethylamino)-phenyl, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Methyl- sulfonamido)-phenyl, o-, m- oder p-(Methylsulfonyl)-phenyl, o-, m- oder p-^ c (N, N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m - or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (Methylsulfonyl) -phenyl, o-, m- or p-
Cyanphenyl, o-, m- oder p-Ureidophenyl, o-, m- oder p-Formylphenyl, o-,Cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl, o-,
20 m- oder p-Acetylphenyl, o-, m- oder p-Aminosulfonylphenyl, o-, m- oder p-20 m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-
Carboxyphenyl, o-, m- oder p-Carboxymethyl-phenyl, o-, m- oder p- Carboxymethoxy-phenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-,Carboxyphenyl, o-, m- or p-carboxymethyl-phenyl, o-, m- or p-carboxymethoxyphenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3, 4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-,
25 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibromphenyl, 2,4- oder 2,5-Dinitrophenyl,25 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl,
2,5- oder 3,4-Dimethoxyphenyl, 3-Nitro-4-chlorphenyl, 3-Amino-4-chlor-, 2- Amino-3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oder 2-Amino-6-chlor- phenyl, 2-Nitro-4-N,N-dimethylamino- oder 3-Nitro-4-N,N-dimethylamino-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-dimethylamino
30 phenyl, 2,3-Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Tri- chlorphenyl, 2,4,6-Trimethoxyphenyl, 2-Hydroxy-3,5-dichlorphenyl, p- lodphenyl, 3,6-Dichlor-4-aminophenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4- bromphenyl, 2,5-Difluor-4-bromphenyl, 3-Brom-6-methoxyphenyl, 3-Chlor- 30 phenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-tri chlorophenyl, 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-Chlor-4-acetamidophenyl, 3-Fluor-4-methoxyphenyl,6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl,
3535
3-Amino-6-methylphenyl, 3-Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4- chlorphenyl. Ar bedeutet vorzugsweise unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI1 OA, (CH2)nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2 und/oder -O-(CH2)O-Het1 substituiertes Phenyl.3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl. 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 bedeutet besonders bevorzugt unsubstituiertes oder ein- oder zweifach durch A, HaI, (CH2)nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2 und/oder -O-(CH2)O-Het1 substituiertes 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 bedeutet ganz besonders bevorzugt unsubstituiertes oder ein- oder zweifach durch A, OA1 OH und/oder HaI substituiertes Phenyl.Ar is very particularly preferably phenyl which is unsubstituted or mono- or disubstituted by A, OA 1 OH and / or Hal.
Ar1 bedeutet vorzugsweise z.B. unsubstituiertes oder ein-, zwei- oder dreifach durch HaI substituiertes Phenyl.Ar 1 is preferably, for example, phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal phenyl.
Het bedeutet, ungeachtetet weiterer Substitutionen, z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, A- oder 5-lmidazolyl, 1-, 3-, A- oder 5-Pyrazolyl, 2-, A- oder 5-Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, 4- oderHet, irrespective of further substitutions, e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, A- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2 -, A- or 5-oxazolyl, 3-, 4- or 5-lsoxazolyl, 2-, 4- or
5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-
Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-Triazol-1-, -4- oder -5-yl, 1 ,2,4-Tri- azol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3-Oxadiazol-4- oder -5-yl, 1 ,2,4-Oxadiazol-3- oder -5-yl, 1 ,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4-Thia- diazol-3- oder -5-yl, 1 ,2,3-Thiadiazol-4- oder -5-yl, 3- oder 4-Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 4- oder 5-lsoindolyl, 1-, 2-, A- oder 5-Benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Benzopyrazolyl, 2-, A-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-, 6- oder 7- Benzisoxazolyl, 2-, A-, 5-, 6- oder 7-Benzothiazolyl, 2-, A-, 5-, 6- oder 7- Benzisothiazolyl, A-, 5-, 6- oder 7-Benz-2,1 ,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, A-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, A-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, A-, 5-, 6-, 7- oder 8-Chinazolinyl, 5- oder 6-Chin- oxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo[1 ,4]oxazinyl, weiter bevorzugtPyrimidinyl, 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- , 6- or 7- benzisoxazolyl, 2-, A-, 5-, 6- or 7-benzothiazolyl, 2-, A-, 5-, 6- or 7- benzisothiazolyl, A-, 5-, 6- or 7 Benz-2,1,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinolinyl, oxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferred
1 ,3-Benzodioxol-5-yl, 1 ,4-Benzodioxan-6-yl, 2,1 ,3-Benzothiadiazol-4- oder1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4 or
-5-yl oder 2,1 ,3-Benzoxadiazol-5-yl. Die heterocyclischen Reste können auch teilweise oder vollständig hydriert sein.-5-yl or 2,1,3-benzoxadiazol-5-yl. The heterocyclic radicals may also be partially or completely hydrogenated.
Het kann also z. B. auch bedeuten 2,3-Dihydro-2-, -3-, -A- oder -5-furyl, 2,5-Dihydro-2-, -3-, -A- oder 5-furyl, Tetrahydro-2- oder -3-furyl, 1 ,3-Dioxo- lan-4-yl, Tetrahydro-2- oder -3-thienyl, 2,3-Dihydro-1-, -2-, -3-, -4- oder -5- pyrrolyl, 2,5-Dihydro-1-, -2-, -3-, -4- oder -5-pyrrolyl, 1-, 2- oder 3-Pyrroli- dinyl, Tetrahydro-1-, -2- oder -4-imidazolyl, 2,3-Dihydro-1-, -2-, -3-, -A- oder -5-pyrazolyl, Tetrahydro-1-, -3- oder -4-pyrazolyl, 1 ,4-Dihydro-i-, -2-, -3- oder -4-pyridyl, 1 ,2,3,4-Tetrahydro-1 -, -2-, -3-, -4-, -5- oder -6-pyridyl, 1 -,Het can so z. B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -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-i-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1 -, -2-, -3-, -4-, -5- or -6 -pyridyl, 1 -,
2-, 3- oder 4-Piperidinyl, 2-, 3- oder 4-Morpholinyl, Tetrahydro-2-, -3- oder - 4-pyranyl, 1 ,4-Dioxanyl, 1 ,3-Dioxan-2-, -4- oder -5-yl, Hexahydro-1-, -3- oder -4-pyridazinyl, Hexahydro-1-, -2-, -4- oder -5-pyrimidinyl, 1-, 2- oder 3- Piperazinyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- oder -8-chinolyl, 1 ,2,3,4-Tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- oder -8-isochinolyl, 2-, 3-, 5-, 6-, 7- oder 8- 3,4-Dihydro-2H-benzo[1 ,4]oxazinyl, weiter bevorzugt 2,3- Methylendioxyphenyl, 3,4-Methylendioxyphenyl, 2,3-Ethylendioxyphenyl,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, 3- or - 4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, - 4- or 5-yl, hexahydro-1, -3- or 4-pyridazinyl, hexahydro-1, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4- Tetrahydro-1, -2, 3, 4, 5, 6, 7 or 8 isoquinolyl, 2, 3, 5, 6, 7 or 8 3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,
3,4-Ethylendioxyphenyl, 3,4-(Difluormethylendioxy)phenyl, 2,3-Dihydro- benzofuran-5- oder 6-yl, 2,3-(2-Oxo-methylendioxy)-phenyl oder auch 3,4-3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylendioxy) -phenyl or else 3,4-
Dihydro-2H-1 ,5-benzodioxepin-6- oder -7-yl, ferner bevorzugt 2,3-Dihydro- benzofuranyl oder 2,3-Dihydro-2-oxo-furanyl.Dihydro-2H-1, 5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het bedeutet vorzugsweise einen ein- oder zweikernigen gesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-Atomen, der ein- oder zweifach durch A substituiert sein kann.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 bedeutet besonders bevorzugt, wobei A vorzugsweise Methyl, Ethyl, Propyl, Butyl, Pentyl, Hexyl, Isopropyl oder Trifluormethyl bedeutet.Het is particularly preferably where A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.
In einer weiteren Ausführungsform bedeutet Het besonders bevorzugt unsubstituiertes oder ein- oder zweifach durch A substituiertes Piperidin,In a further embodiment, Het particularly preferably denotes unsubstituted or mono- or disubstituted by A piperidine,
Piperazin, Pyrrolidin, Pyridin, Pyrimidin, Pyrrol, Indol, Indazol, Morpholin, Isoxazol, Tetrazol, Furan oder Thiophen, wobei A vorzugsweise Methyl, Ethyl, Propyl, Butyl, Pentyl, Hexyl, Isopropyl oder Trifluormethyl bedeutet.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.
Het1 bedeutet vorzugsweise einen einkernigen gesättigten Heterocyclus mit 1 bis 2 N- und/oder O-Atomen, der ein- oder zweifach durch A und/oder =0 (Carbonylsauerstoff) substituiert sein kann, besonders bevorzugt ist 4-Methyl-piperazinyl.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.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.For the entire invention, all residues that occur multiple times may be the same or different, i. are independent of each other.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.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.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejeni- gen Verbindungen der Formel I, in denen mindestens einer der genanntenAccordingly, the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned
Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln Ia bis If ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochRests has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to If which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I but in which
(CH2)m in Ia X (CHa)n. CHA, V(CH 2 ) m in Ia X (CHa) n . CHA, V
CH-CH2-COOH, CH-CH2-COOA, CH-CH2-CO-Het2, CH-CH2-Het2, CH-CH2-CONH-(CH2)1-2-NH2, CH-CH2-CONH-(CH2)i-2-OH oderCH-CH 2 -COOH, CH-CH 2 -COOA, CH-CH 2 -CO-Het 2 , CH-CH 2 -Het 2 , CH-CH 2 -CONH- (CH 2 ) 1-2 -NH 2 , CH-CH 2 -CONH- (CH 2 ) i- 2 -OH or
CH-CH2-CONH-(CH2)1-2-OA, bedeutet; bedeutet;CH-CH 2 -CONH- (CH 2 ) 1-2 -OA, means; means;
in Ib R1 H, A, HaI1 -CO-A1 CN, COOH1 COOA1 CONH2, NH2,in Ib R 1 H, A, Hal 1 -CO-A 1 CN, COOH 1 COOA 1 CONH 2 , NH 2 ,
NHA oder NAA1,NHA or NAA 1 ,
Rr H, A oder HaI bedeutenR r is H, A or Hal
in Ic R2 OH, OA, NH2 oder SO2NH2,in Ic R 2 OH, OA, NH 2 or SO 2 NH 2 ,
R2', R2",R 2 ' , R 2 " ,
R2'", R2"" H bedeuten;R 2 '" , R 2"" denote H;
in Id R2 OH, OA, NH2, NHA, NAA1, HaI1 A1 CONH2, CONHA1 in Id R 2 OH, OA, NH 2 , NHA, NAA 1 , Hal 1 A 1 CONH 2 , CONHA 1
CONAA1, CONHAr1 CONHHet. SO2NH2, SO2NHA, SO2NAA1, SO2NHAr1 SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA, NHCOAr1 NHCOHet, -O(CH2)POH,CONAA 1 , CONHAr 1 CONHHet. SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , SO 2 NHAr 1 SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr 1 NHCOHet, -O (CH 2 ) P OH,
-O(CH2)POA, -O(CH2)pNH2l -O(CH2)PNHA,-O (CH 2 ) P OA, -O (CH 2 ) p NH 2l -O (CH 2 ) p NHA,
-0(CH2)PNAA1, -O(CH2)PNH-COA, -O(CH2)PNHSO2A,-0 (CH 2 ) P NAA 1 , -O (CH 2 ) P NH-COA, -O (CH 2 ) P NHSO 2 A,
-B(OH)2, NHCOOA1 COOH1 COOH1 SO2A, NHCHO, NHCONH2, -CH(OH)-CH2Ar, Het,-B (OH) 2 , NHCOOA 1 COOH 1 COOH 1 SO 2 A, NHCHO, NHCONH 2 , -CH (OH) -CH 2 Ar, Het,
R2 , R2 ,R 2 , R 2 ,
R2'", R2 jeweils unabhängig voneinander H, HaI oder OH,R 2 '" , R 2 are each independently H, Hal or OH,
9 91 9" 9"' 9" zwei benachbarte Reste ausgewählt aus R 1 R 1 R 1 R , R zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -N=CR7-NH, -NH-CO-O-, -OCH2O-, -NH-CH=C(CH2NAA1)- oder -NH-CH=C-9 9 1 9 "9"'9"two adjacent radicals selected from R 1 R 1 R 1 R, R together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH -, N = CR 7 -NH, -NH-CO-O-, -OCH 2 O-, -NH-CH = C (CH 2 NAA 1 ) - or -NH-CH = C-
bedeuten; mean;
in Ie A, A1 jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-in Ie A, A 1 are each independently alkyl with 1 to 6 C
Atomen, wobei auch 1-5 H-Atome durch F und/oderAtoms, where also 1-5 H atoms by F and / or
Chlor ersetzt sein können bedeuten;Chlorine can be replaced;
in If R3 H, SH oder A bedeutet;in If R 3 is H, SH or A;
in Ig R4 H, A, COOA oder CONH2 bedeutet;in Ig R 4 is H, A, COOA or CONH 2 ;
in Ih Ar unsubstituiertes oder ein- oder zweifach durch A, OA1 OH und/oder HaI substituiertes Phenyl bedeutet;in Ih Ar unsubstituted or mono- or disubstituted by A, OA 1 OH and / or Hal substituted phenyl;
in Ii Het einen ein- oder zweikernigen gesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-Atomen, der ein- oder zweifach durch A substituiert sein kann, bedeutet;in 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;
in Ij Het unsubstituiertes oder ein- oder zweifach durch A substituiertes Piperidin, Piperazin, Pyrrolidin, Pyridin, Pyrimidin, Pyrrol, Indol, Indazol, Morpholin, Isoxazol,in Ij Het unsubstituted or mono- or di-substituted by A piperidine, piperazine, pyrrolidine, pyridine, pyrimidine, pyrrole, indole, indazole, morpholine, isoxazole,
Tetrazol, Furan oder Thiophen bedeutet;Tetrazole, furan or thiophene;
in Ik (CH2)m in Ik (CH 2 ) m
X (CHa)n, CHA, \ /_ ,X (CHa) n , CHA, \ / _,
CC
CH-CH2-COOH, CH-CH2-COOA,CH-CH 2 -COOH, CH-CH 2 -COOA,
5 CH-CH2-CO-Het2, CH-CH2-Het2,5 CH-CH 2 -CO-Het 2 , CH-CH 2 -Het 2 ,
CH-CH2-CONH-(CH2)1-2-NH2, CH-CH2-CONH-(CH2)1-2-OH oder CH-CH2-CONH-(CH2)1-2-OA,CH-CH 2 -CONH- (CH 2 ) 1-2 -NH 2 , CH-CH 2 -CONH- (CH 2 ) 1-2 -OH or CH-CH 2 -CONH- (CH 2 ) 1-2 - OA,
-JO X1 (CH2)n,-JO X 1 (CH 2 ) n ,
R1 H, A, HaI, -CO-A1 CN, COOH, COOA, CONH2, NH2,R 1 is H, A, Hal, -CO-A 1 CN, COOH, COOA, CONH 2 , NH 2 ,
NHA oder NAA1,NHA or NAA 1 ,
R1' H, A oder HaI R2, R2', R2 ',R 1 'is H, A or Hal R 2 , R 2' , R 2 ' ,
R2 OH, OA, NH2, NHA, NAA1, HaI, A, CONH2, CONHA,R 2 OH, OA, NH 2 , NHA, NAA 1 , Hal, A, CONH 2 , CONHA,
15 CONAA1, CONHAr, CONHHet, SO2NH2, SO2NHA, 15 CONAA 1 , CONHAr, CONHHet, SO 2 NH 2 , SO 2 NHA,
SO2NAA1, SO2NHAr, SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA, NHCOAr, NHCOHet, -O(CH2)POH, -O(CH2)POA, -O(CH2)PNH2, -O(CH2)PNHA,SO 2 NAA 1 , SO 2 NHAr, SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr, NHCOHet, -O (CH 2 ) P OH, -O (CH 2 ) P OA, - O (CH 2 ) P NH 2 , -O (CH 2 ) P NHA,
20 -O(CH2)pNAA\ -O(CH2)PNH-COA, -O(CH2)PNHSO2A,20 -O (CH 2 ) pNAA-O (CH 2 ) p NH-COA, -O (CH 2 ) p NHSO 2 A,
-B(OH)2, NHCOOA, COOH, COOH, SO2A1 NHCHO1 NHCONH2, -CH(OH)-CH2Ar, Het,-B (OH) 2 , NHCOOA, COOH, COOH, SO 2 A 1 NHCHO 1 NHCONH 2 , -CH (OH) -CH 2 Ar, Het,
oder , or,
R2 , R2 ,R 2 , R 2 ,
R2 , R2 jeweils unabhängig voneinander H, HaI oder OH,R 2 , R 2 are each independently H, Hal or OH,
30 zwei benachbarte Reste ausgewählt aus R2, R2 , R2", R2'", R2 zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -N=CR7-NH, -NH-CO-O-, -OCH2O-, -NH-CH=C(CH2NAA1)- oder30 two adjacent radicals selected from R 2 , R 2 , R 2 " , R 2 '" , R 2 together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH- , -N = CR 7 -NH, -NH-CO-O-, -OCH 2 O-, -NH-CH = C (CH 2 NAA 1 ) - or
35 - -35 - -
-NH-CH=C--NH-CH = C-
N R3 H, SH, A, COOH, COOA, CONH2, N R 3 H, SH, A, COOH, COOA, CONH 2 ,
CONHA oder CONAA', R3 H1 SH oder A,CONHA or CONAA ', R 3 H 1 SH or A,
R4 H, A, COOA oder CONH2 1 R 4 is H, A, COOA or CONH 2 1
R5 H, A oder COA1 R 5 is H, A or COA 1
R6 H, A, OH, NH2, NHA oder NAA1, 7 R 6 is H, A, OH, NH 2 , NHA or NAA 1 , 7
R7 H oder Alkyl mit 1 , 2, 3 oder 4 C-Atomen,R 7 is H or alkyl having 1, 2, 3 or 4 C atoms,
R7 und ein Rest ausgewählt aus der Gruppe R2, R2 , R2 , R2 , R2 zusammen auch -CH2CH2-, R8 H, A oder HaI, Ar unsubstituiertes oder ein- oder zweifach durch A, OA,R 7 and a radical selected from the group R 2 , R 2 , R 2 , R 2 , R 2 together also -CH 2 CH 2 -, R 8 H, A or Hal, Ar is unsubstituted or mono- or disubstituted by A, OA,
OH und/oder HaI substituiertes Phenyl, Het einen ein- oder zweikernigen gesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-Atomen, der ein- oder zweifach durch A substituiert sein kann,OH and / or Hal substituted phenyl, Het a mono- or binuclear saturated or aromatic heterocycle having 1 to 4 N atoms, which may be monosubstituted or disubstituted by A,
Het2 Morpholin-4-yl, Dioxanyl, Piperidinyl, Pyrrolidinyl oderHet 2 morpholin-4-yl, dioxanyl, piperidinyl, pyrrolidinyl or
Piperazinyl, A, A1 jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-Piperazinyl, A, A 1 are each independently alkyl of 1 to 6 carbon atoms.
Atomen, wobei auch 1-5 H-Atome durch F und/oderAtoms, where also 1-5 H atoms by F and / or
Chlor ersetzt sein können,Chlorine can be replaced,
HaI F, Cl, Br oder I, m 2, 3, 4 oder 5, n O, 1 oder 2, p 1 , 2, 3 oder 4 bedeuten,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,
sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch 10 machen.and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios. The compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are described, under reaction conditions which are known and suitable for the said reactions. It is also possible to make use of known per se variants not mentioned here.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort * c weiter zu den Verbindungen der Formel I umsetzt.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.
Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel Il mit Verbindungen der Formel IM umsetzt.Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
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Die Verbindungen der Formel Il sind neu, die der Formel III sind in derThe compounds of the formula II are novel, those of the formula III are in the
Regel bekannt.Usually known.
Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel. Die 25 Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwa 0° und 150°, normalerweise zwischen 15° und 100°, besonders bevorzugt zwischen 50 und 85°C.The reaction is usually carried out in an inert solvent. Depending on the conditions used, 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.
3030
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan,Suitable inert solvents are e.g. Hydrocarbons such as hexane,
Petrolether, Benzol, Toluol oder XyIoI; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oderPetroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or
Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol,dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol,
35 n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether,35 n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether,
Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykol- monomethyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylenglykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF);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);
Nitrite wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefel- kohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.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.
Verbindungen der Formel I können weiterhin erhalten werden, indem man sie aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden und/oder hydrogenolysierenden Mittel in Freiheit setzt, indem man eine konventionelle Aminoschutzgruppe durch Behandeln mit einem solvolysierenden oder hydrogenolysierenden Mittel durch Wasserstoff ersetzt oder eine durch eine konventionelle Schutzgruppe geschützte Aminogruppe in Freiheit setzt.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.
Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die sonst der Formel I entsprechen, aber anstelle einer oder mehrerer freier Amino- und/oder Hydroxygruppen entsprechende geschützte Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die anstelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Aminoschutzgruppe tragen, insbesondere solche, die anstelle einer HN-Gruppe eine R'-N-Gruppe tragen, worin R1 eine Aminoschutzgruppe bedeutet, und/oder solche, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z.B. solche, die der Formel I entsprechen, jedoch anstelle einer Gruppe -COOH eine Gruppe -COOR" tragen, worin R" eine Hydroxyschutzgruppe bedeutet.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.
Es können auch mehrere - gleiche oder verschiedene - geschützte Amino- und/oder Hydroxygruppen im Molekül des Ausgangsstoffes vorhanden sein. Falls die vorhandenen Schutzgruppen voneinander verschieden sind, können sie in vielen Fällen selektiv abgespalten werden. Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Umsetzungen zu schützen (zu blockieren), die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen desThere may also be several - same or different - protected amino and / or hydroxy groups present in the molecule of the starting material. If the protecting groups present are different from each other, they can be selectively cleaved in many cases. The term "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
Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind insbesondere unsubstituierte oder substituierte Acyl-, Aryl-, Aralkoxymethyl- oder Aralkylgruppen. Da die Aminoschutzgruppen nach der gewünschten Reaktion (oder Reaktionsfolge) entfernt werden, ist ihre Art und Größe im übrigen nicht kritisch; bevorzugt werden jedoch solche mit 1-20, insbesondere 1-8 C-Atomen. Der Ausdruck "Acylgruppe" ist im Zusammenhang mit dem vorliegenden Verfahren in weitestem Sinne aufzufassen. Er um- schließt von aliphatischen, araliphatischen, aromatischen oder hetero- cyclischen Carbonsäuren oder Sulfonsäuren abgeleitete Acylgruppen sowie insbesondere Alkoxycarbonyl-, Aryloxycarbonyl- und vor allem Aralkoxycarbonylgruppen. Beispiele für derartige Acylgruppen sindMolecule has been performed. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Moreover, because the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is not critical; however, preference is given to those having 1-20, in particular 1-8 C atoms. The term "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 wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Benzoyl oder Toluyl; Aryloxyalkanoyl wie POA; Alkoxycarbonyl wieAlkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl as
Methoxycarbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, BOC (tert.-Butyloxycarbonyl), 2-lodethoxycarbonyl; Aralkyloxycarbonyl wie CBZ ("Carbobenzoxy"), 4-Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl wie Mtr. Bevorzugte Aminoschutzgruppen sind BOC und Mtr, ferner CBZ, Fmoc, Benzyl und Acetyl.Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
Der Ausdruck "Hydroxyschutzgruppe" ist ebenfalls allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Hydroxygruppe vor chemischen Umsetzungen zu schützen, die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind die oben genannten unsubstituierten oder substituierten Aryl-, Aralkyl- oderThe term "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
Acylgruppen, ferner auch Alkylgruppen. Die Natur und Größe der Hydroxy- schutzgruppen ist nicht kritisch, da sie nach der gewünschten chemischen Reaktion oder Reaktionsfolge wieder entfernt werden; bevorzugt sind Gruppen mit 1-20, insbesondere 1-10 C-Atomen. Beispiele für Hydroxy- schutzgruppen sind u.a. Benzyl, 4-Methoxybenzyl, p-Nitrobenzoyl, p- Toluolsulfonyl, tert.-Butyl und Acetyl, wobei Benzyl und tert.-Butyl besonders bevorzugt sind.Acyl groups, and also alkyl groups. The nature and size of the hydroxy-protecting groups is 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.
Das In-Freiheit-Setzen der Verbindungen der Formel I aus ihren funktionellen Derivaten gelingt - je nach der benutzten Schutzgruppe - z. B. mitThe in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the protecting group used - z. B. with
10 starken Säuren, zweckmäßig mit TFA oder Perchlorsäure, aber auch mit anderen starken anorganischen Säuren wie Salzsäure oder Schwefelsäure, starken organischen Carbonsäuren wie Trichloressigsäure oder Sulfonsäuren wie Benzol- oder p-Toluolsulfonsäure. Die Anwesenheit10 strong acids, useful with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence
-. j- eines zusätzlichen inerten Lösungsmittels ist möglich, aber nicht immer erforderlich. Als inerte Lösungsmittel eignen sich vorzugsweise organische, beispielsweise Carbonsäuren wie Essigsäure, Ether wie Tetrahydrofuran oder Dioxan, Amide wie DMF, halogenierte Kohlenwasserstoffe wie Dichlormethan, femer auch Alkohole wie Methanol,-. An additional inert solvent is possible, but not always required. 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,
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Ethanol oder Isopropanol, sowie Wasser. Ferner kommen Gemische der vorgenannten Lösungsmittel in Frage. TFA wird vorzugsweise im Überschuß ohne Zusatz eines weiteren Lösungsmittels verwendet, Perchlorsäure in Form eines Gemisches aus Essigsäure und 70 %iger Perchlor- 25 säure im Verhältnis 9:1. Die Reaktionstemperaturen für die Spaltung liegen zweckmäßig zwischen etwa 0 und etwa 50°, vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).Ethanol or isopropanol, as well as water. Also suitable are mixtures of the abovementioned solvents. 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).
OQ Die Gruppen BOC, OBut und Mtr können z. B. bevorzugt mit TFA in Dichlormethan oder mit etwa 3 bis 5n HCl in Dioxan bei 15-30° abgespalten werden, die FMOC-Gruppe mit einer etwa 5- bis 50 %igen Lösung von Dimethylamin, Diethylamin oder Piperidin in DMF bei 15-30°. OQ 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 °.
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Hydrogenolytisch entfernbare Schutzgruppen (z. B. CBZ, Benzyl) können z. B. durch Behandeln mit Wasserstoff in Gegenwart eines Katalysators (z. - -Hydrogenolytically removable protecting groups (eg CBZ, benzyl) may e.g. B. by treatment with hydrogen in the presence of a catalyst (eg. - -
B. eines Edelmetallkatalysators wie Palladium, zweckmäßig auf einem Träger wie Kohle) abgespalten werden. Als Lösungsmittel eignen sich dabei die oben angegebenen, insbesondere z. B. Alkohole wie Methanol oder Ethanol oder Amide wie DMF. Die Hydrogenolyse wird in der Regel 5 bei Temperaturen zwischen etwa 0 und 100° und Drucken zwischen etwaAs a noble metal catalyst such as palladium, expediently on a carrier such as coal) are split off. Suitable solvents are those given above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is usually 5 at temperatures between about 0 and 100 ° and pressures between about
1 und 200 bar, bevorzugt bei 20-30° und 1-10 bar durchgeführt. Eine Hydrogenolyse der CBZ-Gruppe gelingt z. B. gut an 5 bis 10 %igem Pd/C in Methanol oder mit Ammomiumformiat (anstelle von Wasserstoff) an 10 Pd/C in Methanol/DMF bei 20-30°.1 and 200 bar, preferably carried out at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds z. B. good at 5 to 10% Pd / C in methanol or with Ammomiumformiat (instead of hydrogen) at 10 Pd / C in methanol / DMF at 20-30 °.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder XyIoI; chlorierte Kohlenwasserstoffe wie ^ c Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff,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,
Trifluormethylbenzol, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oderTrifluoromethylbenzene, 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
Dioxan; Glykolether wie Ethylenglykolmonomethyl- oder -monoethyletherdioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether
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(Methylglykol oder Ethylglykol), Ethylenglykoldimethylether (Diglyme);(Methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme);
Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methylpyrrolidon (NMP) oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); 25 Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure;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;
Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.
2Q Ester können z.B. mit Essigsäure oder mit NaOH oder KOH in Wasser,For example, 2 Q esters can be treated with acetic acid or with NaOH or KOH in water,
Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift werden.Water THF or water dioxane be saponified at temperatures between 0 and 100 °.
Ferner kann man freie Aminogruppen in üblicher Weise mit einem Säure-Furthermore, free amino groups can be prepared in the customary manner with an acid
35 chlorid oder -anhydrid acylieren oder mit einem unsubstituierten oder substituierten Alkylhalogenid alkylieren, oder mit CH3-C(=NH)-OEt umsetzen, zweckmäßig in einem inerten Lösungsmittel wie Dichlormethan oder THF und /oder in Gegenwart einer Base wie Triethylamin oder Pyridin bei Temperaturen zwischen -60 und +30°.Acylate or alkylate with an unsubstituted or substituted alkyl halide, or with CH 3 -C (= NH) -OEt implement, suitably in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.
Pharmazeutische Salze und andere FormenPharmaceutical salts and other forms
Die genannten erfindungsgemäßen Verbindungen lassen sich in ihrer endgültigen Nichtsalzform verwenden. Andererseits umfaßt die vorliegende Erfindung auch die Verwendung dieser Verbindungen in Form ihrer pharmazeutisch unbedenklichen Salze, die von verschiedenen organischen und anorganischen Säuren und Basen nach fachbekannten Vorgehensweisen abgeleitet werden können. Pharmazeutisch unbedenkliche Salzformen der Verbindungen der Formel I werden größtenteils konventionell hergestellt. Sofern die Verbindung der Formel I eine Carbonsäuregruppe enthält, läßt sich eines ihrer geeigneten Salze dadurch bilden, daß man die Verbindung mit einer geeigneten Base zum entsprechenden Basenadditionssalz umsetzt. Solche Basen sind zumThe abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases are for
Beispiel Alkalimetallhydroxide, darunter Kaliumhydroxid, Natriumhydroxid und Lithiumhydroxid; Erdalkalimetallhydroxide wie Bariumhydroxid undExample alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and
Calciumhydroxid; Alkalimetallalkoholate, z.B. Kaliumethanolat und Natriumpropanolat; sowie verschiedene organische Basen wie Piperidin, Diethanolamin und N-Methylglutamin. Die Aluminiumsalze der Verbindun- gen der Formel I zählen ebenfalls dazu. Bei bestimmten Verbindungen der Formel I lassen sich Säureadditionssalze dadurch bilden, daß man diese Verbindungen mit pharmazeutisch unbedenklichen organischen und anorganischen Säuren, z.B. Halogenwasserstoffen wie Chlorwasserstoff, Bromwasserstoff oder Jodwasserstoff, anderen Mineralsäuren und ihren entsprechenden Salzen wie Sulfat, Nitrat oder Phosphat und dergleichen sowie Alkyl- und Monoarylsulfonaten wie Ethansulfonat, Toluolsulfonat und Benzolsulfonat, sowie anderen organischen Säuren und ihren entsprechenden Salzen wie Acetat, Trifluoracetat, Tartrat, Maleat, Succinat,calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are also included. For certain compounds of formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. 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,
Citrat, Benzoat, Salicylat, Ascorbat und dergleichen behandelt. Dementsprechend zählen zu pharmazeutisch unbedenklichen Säureadditions- salzen der Verbindungen der Formel I die folgenden: Acetat, Adipat, Alginat, Arginat, Aspartat, Benzoat, Benzolsulfonat (Besylat), Bisulfat, Bisulfit, Bromid, Butyrat, Kampferat, Kampfersulfonat, Caprylat, Chlorid, Chlorbenzoat, Citrat, Cyclopentanpropionat, Digluconat, Dihydrogen- phosphat, Dinitrobenzoat, Dodecylsulfat, Ethansulfonat, Fumarat, Galacterat (aus Schleimsäure), Galacturonat, Glucoheptanoat, Gluconat, Glutamat, Glycerophosphat, Hemisuccinat, Hemisulfat, Heptanoat, Hexanoat, Hippurat, Hydrochlorid, Hydrobromid, Hydroiodid, 2-Hydroxy-Citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, Dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-
10 ethansulfonat, lodid, Isethionat, Isobutyrat, Lactat, Lactobionat, Malat, Maleat, Malonat, Mandelat, Metaphosphat, Methansulfonat, Methylbenzoat, Monohydrogenphosphat, 2-Naphthalinsulfonat, Nicotinat, Nitrat, Oxalat, Oleat, Pamoat, Pectinat, Persulfat, Phenylacetat, 3-10 ethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3 -
^ 5 Phenylpropionat, Phosphat, Phosphonat, Phthalat, was jedoch keine Einschränkung darstellt.^ 5 phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
Weiterhin zählen zu den Basensalzen der erfindungsgemäßenFurthermore, the base salts of the invention include
Verbindungen Aluminium-, Ammonium-, Calcium-, Kupfer-, Eisen(lll)-,Compounds aluminum, ammonium, calcium, copper, iron (III) -,
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Eisen(ll)-, Lithium-, Magnesium-, Mangan(lll)-, Mangan(ll), Kalium-,Iron (II), lithium, magnesium, manganese (III), manganese (II), potassium,
Natrium- und Zinksalze, was jedoch keine Einschränkung darstellen soll. Bevorzugt unter den oben genannten Salzen sind Ammonium; die Alkalimetallsalze Natrium und Kalium, sowie die ErdalkalimetalsalzeSodium 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
25 Calcium und Magnesium. Zu Salzen der Verbindungen der Formel I, die sich von pharmazeutisch unbedenklichen organischen nicht-toxischen Basen ableiten, zählen Salze primärer, sekundärer und tertiärer Amine, substituierter Amine, darunter auch natürlich vorkommender substituierter25 calcium and magnesium. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones
O0 Amine, cyclischer Amine sowie basischer lonenaustauscherharze, z.B. O0 amines, cyclic amines and basic ion exchange resins, eg
Arginin, Betain, Koffein, Chlorprocain, Cholin, N,N'-Dibenzylethylendiamin (Benzathin), Dicyclohexylamin, Diethanolamin, Diethylamin, 2-Diethyl- aminoethanol, 2-Dimethylaminoethanol, Ethanolamin, Ethylendiamin, N-Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
Ethylmorpholin, N-Ethylpiperidin, Glucamin, Glucosamin, Histidin,Ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
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Hydrabamin, Iso-propylamin, Lidocain, Lysin, Meglumin, N-Methyl-D- glucamin, Morpholin, Piperazin, Piperidin, Polyaminharze, Procain, Purine, Theobromin, Triethanolamin, Triethylamin, Trimethylamin, Tripropylamin sowie Tris-(hydroxymethyl)-methylamin (Tromethamin), was jedoch keine Einschränkung darstellen soll.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.
Verbindungen der vorliegenden Erfindung, die basische stickstoffhaltigeCompounds of the present invention containing basic nitrogen-containing
Gruppen enthalten, lassen sich mit Mitteln wie (C1-C4) Alkylhalogeniden, z.B. Methyl-, Ethyl-, Isopropyl- und tert.-Butylchlorid, -bromid und -iodid; Di(CrC4)Alkylsulfaten, z.B. Dimethyl-, Diethyl- und Diamylsulfat; (C10- Ci8)Alkylhalogeniden, z.B. Decyl-, Dodecyl-, Lauryl-, Myristyl- undGroups 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
Stearylchlorid, -bromid und -iodid; sowie Aryl-(Ci-C4)Alkylhalogeniden, z.B. Benzylchlorid und Phenethylbromid, quarternisieren. Mit solchen Salzen können sowohl wasser- als auch öllösliche erfindungsgemäße Verbindungen hergestellt werden.Stearyl chloride, bromide and iodide; and aryl- (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.
Zu den oben genannten pharmazeutischen Salzen, die bevorzugt sind, zählen Acetat, Trifluoracetat, Besylat, Citrat, Fumarat, Gluconat,The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
Hemisuccinat, Hippurat, Hydrochlorid, Hydrobromid, Isethionat, Mandelat,Hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
Meglumin, Nitrat, Oleat, Phosphonat, Pivalat, Natriumphosphat, Stearat,Meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate,
Sulfat, Sulfosalicylat, Tartrat, Thiomalat, Tosylat und Tromethamin, was jedoch keine Einschränkung darstellen soll.Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
Die Säureadditionssalze basischer Verbindungen der Formel I werden dadurch hergestellt, daß man die freie Basenform mit einer ausreichenden Menge der gewünschten Säure in Kontakt bringt, wodurch man auf übliche Weise das Salz darstellt. Die freie Base läßt sich durch In-Kontakt-Bringen der Salzform mit einer Base und Isolieren der freien Base auf üblicheThe 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
Weise regenerieren. Die freien Basenformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; imRegenerate way. The free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the
Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Basenformen. Wie erwähnt werden die pharmazeutisch unbedenklichen Basenadditionssalze der Verbindungen der Formel I mit Metallen oder Aminen wie Alkalimetallen und Erdalkalimetallen oder organischen Aminen gebildet. Bevorzugte Metalle sind Natrium, Kalium, Magnesium und Calcium. Bevor- zugte organische Amine sind N.N'-Dibenzylethylendiamin, Chlorprocain, Cholin, Diethanolamin, Ethylendiamin, N-Methyl-D-glucamin und Procain.However, the salts of the invention otherwise correspond to their respective free base forms. As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
Die Basenadditionssalze von erfindungsgemäßen sauren Verbindungen werden dadurch hergestellt, daß man die freie Säureform mit einer ausreichenden Menge der gewünschten Base in Kontakt bringt, wodurch man das Salz auf übliche Weise darstellt. Die freie Säure läßt sich durch In-Kontakt-Bringen der Salzform mit einer Säure und Isolieren der freien Säure auf übliche Weise regenerieren. Die freien Säureformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Säureformen.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.
Enthält eine erfindungsgemäße Verbindung mehr als eine Gruppe, die solche pharmazeutisch unbedenklichen Salze bilden kann, so umfaßt die Erfindung auch mehrfache Salze. Zu typischen mehrfachen Salzformen zählen zum Beispiel Bitartrat, Diacetat, Difumarat, Dimeglumin,If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine,
Diphosphat, Dinatrium und Trihydrochlorid, was jedoch keine Einschränkung darstellen soll.Diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
Im Hinblick auf das oben Gesagte sieht man, daß unter dem Ausdruck "pharmazeutisch unbedenkliches Salz" im vorliegenden Zusammenhang ein Wirkstoff zu verstehen ist, der eine Verbindung der Formel I in der Form eines ihrer Salze enthält, insbesondere dann, wenn diese Salzform dem Wirkstoff im Vergleich zu der freien Form des Wirkstoffs oder irgendeiner anderen Salzform des Wirkstoffs, die früher verwendet wurde, verbesserte pharmakokinetische Eigenschaften verleiht. Die pharma- - -In view of the above, it can be seen that 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 pharmaceutical - -
zeutisch unbedenkliche Salzform des Wirkstoffs kann auch diesem Wirkstoff erst eine gewünschte pharmakokinetische Eigenschaft verleihen, über die er früher nicht verfügt hat, und kann sogar die Pharmakodynamik dieses Wirkstoffs in bezug auf seine therapeutische Wirksamkeit imIt is also possible to give this active substance its desired pharmacokinetic property, which it has not previously possessed, and may even determine the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the
Körper positiv beeinflussen.Positively influence the body.
Gegenstand der Erfindung sind ferner Arzneimittel, enthaltend mindestens eine Verbindung der Formel I und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.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.
Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Eine solche Einheit kann beispielsweise 0,5 mg bis 1 g, vorzugsweise 1 mg bis 700 mg, besonders bevorzugt 5 mg bis 100 mg einer erfindungsgemäßen Verbindung enthalten, je nach dem behandeltenPharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such 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
Krankheitszustand, dem Verabreichungsweg und dem Alter, Gewicht undDisease state, the route of administration and the age, weight and
Zustand des Patienten, oder pharmazeutische Formulierungen können inCondition of the patient, or pharmaceutical formulations may be in
Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Bevorzugte Dosierungs- einheitsformulierungen sind solche, die eine Tagesdosis oder Teildosis, wie oben angegeben, oder einen entsprechenden Bruchteil davon eines Wirkstoffs enthalten. Weiterhin lassen sich solche pharmazeutischen Formulierungen mit einem der im pharmazeutischen Fachgebiet allgemein bekannten Verfahren herstellen.Form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
Pharmazeutische Formulierungen lassen sich zur Verabreichung über einen beliebigen geeigneten Weg, beispielsweise auf oralem (einschließlich buccalem bzw. sublingualem), rektalem, nasalem, topischem (einschließlich buccalem, sublingualem oder transdermalem), vaginalem oder parenteralem (einschließlich subkutanem, intramuskulärem, intravenösem oder intradermalem) Wege, anpassen. Solche Formulierungen können mit allen im pharmazeutischen Fachgebiet bekannten Verfahren hergestellt werden, indem beispielsweise der Wirkstoff mit dem bzw. den Trägerstoff(en) oder Hilfsstoff(en) zusammengebracht wird.Pharmaceutical formulations 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).
An die orale Verabreichung angepaßte pharmazeutische Formulierungen können als separate Einheiten, wie z.B. Kapseln oder Tabletten; Pulver oder Granulate; Lösungen oder Suspensionen in wäßrigen oder nichtwäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder ÖI-in-Wasser-Flüssigemulsionen oder Wasser-in-ÖI-Flüssigemulsionen dargereicht werden.Pharmaceutical formulations 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.
So läßt sich beispielsweise bei der oralen Verabreichung in Form einer Tablette oder Kapsel die Wirkstoffkomponente mit einem oralen, nichttoxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glyzerin, Wasser u.a. kombinieren. Pulver werden hergestellt, indem die Verbindung auf eine geeignete feine Größe zerkleinert und mit einem in ähnlicher Weise zerkleinerten pharmazeutischenThus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component 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
Trägerstoff, wie z.B. einem eßbaren Kohlenhydrat wie beispielsweise Stärke oder Mannit vermischt wird. Ein Geschmacksstoff, Konservierungsmittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein.Carrier, such as e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
Kapseln werden hergestellt, indem ein Pulvergemisch wie oben beschrieben hergestellt und geformte Gelatinehüllen damit gefüllt werden. Gleit- und Schmiermittel wie z.B. hochdisperse Kieselsäure, Talkum, Magnesiumstearat, Kalziumstearat oder Polyethylenglykol in Festform können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. Ein Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfügbarkeit des Medikaments nach Einnahme der Kapsel zu verbessern. Außerdem können, falls gewünscht oder notwendig, geeignete Bindungs-, Schmier- und Sprengmittel sowie Farbstoffe ebenfalls in das Gemisch eingearbeitet werden. Zu den geeigneten Bindemitteln gehören Stärke,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. In addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch,
Gelatine, natürliche Zucker, wie z.B. Glukose oder Beta-Lactose, Süß- 5Gelatin, natural sugars, e.g. Glucose or beta-lactose, sweet 5
Stoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia,Corn, natural and synthetic gums, e.g. acacia,
Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmiermitteln gehören Natriumoleat, Natriumstearat, Magnesiumstearat, Natrium-Tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium
10 benzoat, Natriumacetat, Natriumchlorid u.a. Zu den Sprengmitteln gehören, ohne darauf beschränkt zu sein, Stärke, Methylzellulose, Agar, Bentonit, Xanthangummi u.a. Die Tabletten werden formuliert, indem beispielsweise ein Pulvergemisch hergestellt, granuliert oder trocken-10 benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or drying
^ g verpreßt wird, ein Schmiermittel und ein Sprengmittel zugegeben werden und das Ganze zu Tabletten verpreßt wird. Ein Pulvergemisch wird hergestellt, indem die in geeigneter Weise zerkleinerte Verbindung mit einem Verdünnungsmittel oder einer Base, wie oben beschrieben, und gegebenenfalls mit einem Bindemittel, wie z.B. Carboxymethylzellulose,^ g is pressed, a lubricant and a disintegrating agent are added and the whole is pressed into tablets. 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,
20 einem Alginat, Gelatine oder Polyvinylpyrrolidon, einem Lösungsverlang- samer, wie z.B. Paraffin, einem Resorptionsbeschleuniger, wie z.B. einem quatemären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit, Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßtAn alginate, gelatin or polyvinylpyrrolidone, 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 is mixed. The powder mixture leaves
25 sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärkepaste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymer- materialen benetzt und durch ein Sieb gepreßt wird. Als Alternative zur Granulierung kann man das Pulvergemisch durch eine Tablettiermaschine25 can be granulated by mixing with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve. As an alternative to granulation, the powder mixture can be passed through a tableting machine
OQ laufen lassen, wobei' ungleichmäßig geformte Klumpen entstehen, die in Granulate aufgebrochen werden. Die Granulate können mittels Zugabe von Stearinsäure, einem Stearatsalz, Talkum oder Mineralöl gefettet werden, um ein Kleben an den Tablettengußformen zu verhindern. Das gefettete Gemisch wird dann zu Tabletten verpreßt. Die erfindungs-O Q run, with ' unevenly shaped lumps are formed, which are broken up into granules. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The invention
35 gemäßen Verbindungen können auch mit einem freifließenden inerten35 compounds can also be used with a free-flowing inert
Trägerstoff kombiniert und dann ohne Durchführung der Granulierungs- oder Trockenverpressungsschritte direkt zu Tabletten verpreßt werden. Eine durchsichtige oder undurchsichtige Schutzschicht, bestehend aus einer Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymermaterial und einer Glanzschicht aus Wachs, kann vorhanden sein. DiesenCarrier combined and then without performing the granulation or dry pressing steps are compressed directly into tablets. 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. this
Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unterschiedlichen Dosierungseinheiten unterscheiden zu können.Coatings can be added to dyes to distinguish between different dosage units.
Orale Flüssigkeiten, wie z.B. Lösung, Sirupe und Elixiere, können in Form von Dosierungseinheiten hergestellt werden, so daß eine gegebeneOral fluids, e.g. Solution, syrups and elixirs, can be prepared in the form of dosage units, so that a given
Quantität eine vorgegebene Menge der Verbindung enthält. Sirupe lassen sich herstellen, indem die Verbindung in einer wäßrigen Lösung mit geeignetem Geschmack gelöst wird, während Elixiere unter Verwendung eines nichttoxischen alkoholischen Vehikels hergestellt werden.Quantity contains a given amount of the compound. Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
Suspensionen können durch Dispersion der Verbindung in einem nichttoxischen Vehikel formuliert werden. Lösungsvermittler und Emulgiermittel, wie z.B. ethoxylierte Isostearylalkohole und Polyoxyethylensorbitolether,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,
Konservierungsmittel, Geschmackszusätze, wie z.B. Pfefferminzöl oder natürliche Süßstoffe oder Saccharin oder andere künstliche Süßstoffe, u.a. können ebenfalls zugegeben werden.Preservatives, flavoring additives, e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
Die Dosierungseinheitsformulierungen für die orale Verabreichung können gegebenenfalls in Mikrokapseln eingeschlossen werden. Die Formulierung läßt sich auch so herstellen, daß die Freisetzung verlängert oder retardiert wird, wie beispielsweise durch Beschichtung oder Einbettung von partikulärem Material in Polymere, Wachs u.a.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.
Die Verbindungen der Formel I sowie Salze, Solvate und physiologisch funktionelle Derivate davon lassen sich auch in Form von Liposomen- zuführsystemen, wie z.B. kleinen unilamellaren Vesikeln, großen unilamellaren Vesikeln und multilamellaren Vesikeln, verabreichen.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.
Liposomen können aus verschiedenen Phospholipiden, wie z.B.Liposomes can be prepared from various phospholipids, such as e.g.
Cholesterin, Stearylamin oder Phosphatidylcholinen, gebildet werden. Die Verbindungen der Formel I sowie die Salze, Solvate und physiologisch funktionellen Derivate davon können auch unter Verwendung monoklonaler Antikörper als individuelle Träger, an die die Verbindungsmoleküle gekoppelt werden, zugeführt werden. Die Verbindungen können auch mit löslichen Polymeren als zielgerichtete Arzneistoffträger gekoppelt werden. Solche Polymere können Polyvinylpyrrolidon, Pyran-Copolymer, PoIy- hydroxypropylmethacrylamidphenol, Polyhydroxyethylaspartamidphenol oder Polyethylenoxidpolylysin, substituiert mit Palmitoylresten, umfassen. Weiterhin können die Verbindungen an eine Klasse von biologisch abbaubaren Polymeren, die zur Erzielung einer kontrollierten Freisetzung eines Arzneistoffs geeignet sind, z.B. Polymilchsäure, Polyepsilon-Caprolacton, Polyhydroxybuttersäure, Polyorthoester, Polyacetale, Polydihydroxy- pyrane, Polycyanoacrylate und quervernetzte oder amphipatische Block- copolymere von Hydrogelen, gekoppelt sein.Cholesterol, stearylamine or phosphatidylcholines. The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof 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. Further, 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.
An die transdermale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to transdermal administration
Formulierungen können als eigenständige Pflaster für längeren, engenFormulations can be used as separate patches for longer, narrow
Kontakt mit der Epidermis des Empfängers dargereicht werden. So kann beispielsweise der Wirkstoff aus dem Pflaster mittels lontophorese zugeführt werden, wie in Pharmaceutical Research, 3(6), 318 (1986) allgemein beschrieben.Be presented with contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen, Pulver, Lösungen, Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Für Behandlungen des Auges oder anderer äußerer Gewebe, z.B. Mund und Haut, werden die Formulierungen vorzugsweise als topische Salbe oder Creme appliziert. Bei Formulierung zu einer Salbe kann der Wirkstoff entweder mit einer paraffinischen oder einer mit Wasser mischbarenFor treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient may be either paraffinic or water-miscible
Cremebasis eingesetzt werden. Alternativ kann der Wirkstoff zu einer Creme mit einer Öl-in-Wasser-Cremebasis oder einer Wasser-in-ÖI-Basis formuliert werden.Cream base can be used. Alternatively, the active ingredient can become a Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
Zu den an die topische Applikation am Auge angepaßten pharma- zeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel, gelöst oder suspendiert ist.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.
An die topische Applikation im Mund angepaßte pharmazeutischeTo the topical application in the mouth adapted pharmaceutical
Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel.Formulations include lozenges, lozenges and mouthwashes.
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden.Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.
An die nasale Verabreichung angepaßte pharmazeutische Formulierungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobesPharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse
Pulver mit einer Teilchengröße beispielsweise im Bereich von 20-500Powder with a particle size, for example, in the range of 20-500
Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommen wird, verabreicht wird, d.h. durch Schnellinhalation über die Nasenwege aus einem dicht an die Nase gehaltenen Behälter mit dem Pulver. Geeignete Formulierungen zur Verabreichung als Nasenspray oder Nasentropfen mit einer Flüssigkeit als Trägersubstanz umfassen Wirkstofflösungen in Wasser oder Öl.Microns administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
An die Verabreichung durch Inhalation angepaßte pharmazeutische Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mit Aerosolen, Verneblern oder Insufflatoren erzeugt werden können.Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
An die vaginale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to vaginal administration
Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten,Formulations can be used as pessaries, tampons, creams, gels, pastes,
Schäume oder Sprayformulierungen dargereicht werden. Zu den an die parenterale Verabreichung angepaßten pharmazeutischen Formulierungen gehören wäßrige und nichtwäßrige sterile Injektionslösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch die die Formulierung isotonisch mit dem Blut des zu behandelndenFoams or spray formulations are presented. Pharmaceutical formulations 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
Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfach- dosisbehältern, z.B. versiegelten Ampullen und Fläschchen, dargereicht und in gefriergetrocknetem (lyophilisiertem) Zustand gelagert werden, so daß nur die Zugabe der sterilen Trägerflüssigkeit, z.B. Wasser für Injektionszwecke, unmittelbar vor Gebrauch erforderlich ist. Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden.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. Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
Es versteht sich, daß die Formulierungen neben den obigen besonders erwähnten Bestandteilen andere im Fachgebiet übliche Mittel mit Bezug auf die jeweilige Art der Formulierung enthalten können; so können beispielsweise für die orale Verabreichung geeignete Formulierungen Geschmacksstoffe enthalten.It will be understood that in addition to the above particularly mentioned ingredients, the 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.
Eine therapeutisch wirksame Menge einer Verbindung der Formel I hängt von einer Reihe von Faktoren ab, einschließlich z.B. dem Alter und Gewicht des Tiers, dem exakten Krankheitszustand, der der Behandlung bedarf, sowie seines Schweregrads, der Beschaffenheit der Formulierung sowie dem Verabreichungsweg, und wird letztendlich von dem behandelnden Arzt bzw. Tierarzt festgelegt. Jedoch liegt eine wirksame Menge einer erfindungsgemäßen Verbindung für die Behandlung von neoplastischem Wachstum, z.B. Dickdarm- oder Brustkarzinom, im allgemeinen im Bereich von 0,1 bis 100 mg/kg Körpergewicht des Empfängers (Säugers) pro Tag und besonders typisch im Bereich von 1 bis 10 mg/kg Körpergewicht proA 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. However, 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
Tag. Somit läge für einen 70 kg schweren erwachsenen Säuger die tatsächliche Menge pro Tag für gewöhnlich zwischen 70 und 700 mg, wobei diese Menge als Einzeldosis pro Tag oder üblicher in einer Reihe von Teildosen (wie z.B. zwei, drei, vier, fünf oder sechs) pro Tag gegeben werden kann, so daß die Gesamttagesdosis die gleiche ist. Eine wirksame Menge eines Salzes oder Solvats oder eines physiologisch funktionellen Derivats davon kann als Anteil der wirksamen Menge der erfindungsgemäßen Verbindung per se bestimmt werden. Es läßt sich annehmen, daß ähnliche Dosierungen für die Behandlung der anderen, obener- wähnten Krankheitszustände geeignet sind.Day. Thus for a 70 kg adult mammal would be 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.
Gegenstand der Erfindung sind ferner Arzneimittel enthaltend mindestens eine Verbindung der Formel I und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.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.
Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrenntenThe invention is also a set (kit), consisting of separate
Packungen vonPacks of
(a) einer wirksamen Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und (b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.(a) 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 (b) an effective amount of another active pharmaceutical ingredient.
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, individuelle Flaschen, Beutel oder Ampullen. Das Set kann z.B. separate Ampullen enthalten, in denen jeweils eine wirksame Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs gelöst oder in lyophilisierter Form vorliegt. VERWENDUNGThe 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. USE
1. Die offenbarten Verbindungen der Formel I sind besonders bei therapeutischen Anwendungen in Verbindung mit einer durch CHK1 vermittelten Störung geeignet. Wie hier verwendet, umfasst der Begriff "durch CHK1 vermittelte Störung" jede Störung, jede Erkrankung oder jeden Zustand, die/der durch einen Anstieg der CHK1 -Expression oder - Aktivität verursacht wird oder gekennzeichnet ist oder der CHK1 -Aktivität erfordert. Der Begriff "durch CHK1 vermittelte Störung" umfasst ferner jede Störung, jede Erkrankung oder jeden Zustand, bei der/dem eine Hemmung der CHK1 -Aktivität vorteilhaft ist.1. The disclosed compounds of formula I are particularly useful in therapeutic applications in conjunction with a CHK1-mediated disorder. As used herein, the term "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. The term "CHK1-mediated disorder" further includes any disorder, disease or condition in which inhibition of CHK1 activity is beneficial.
CHK1 -Hemmung kann dazu verwendet werden, eine günstige therapeutische oder prophylaktische Wirkung, beispielsweise bei Patienten mit einer proliferativen Störung, zu erzielen. Nichtbeschränkende Beispiele für proliferative Störungen sind u.a. chronische entzündliche proliferative Störungen, z.B. Psoriasis und rheumatoide Arthritis, proliferative Augenstörungen, z.B. diabetische Retinopathie, gutartige proliferative Störungen, z.B. Hämangiome, sowie Krebs. Wie hier verwendet, betrifft der Begriff "Krebs" eine zelluläre Störung, die durch eine unkontrollierte oder falsch regulierte Zellproliferation, verringerte Zelldifferenzierung, die unange- messene Fähigkeit, in umgebendes Gewebe einzudringen, und/oder die Fähigkeit, neues Wachstum an ektopischen Stellen zu etablieren, gekennzeichnet ist. Der Begriff "Krebs" umfasst, ist aber nicht beschränkt auf, solide Tumoren und im Blut entstehende Tumoren. Der Begriff "Krebs" umfasst Erkrankungen von Haut, Geweben, Organen, Knochen, Knorpel,CHK1 inhibition can be used to achieve a beneficial therapeutic or prophylactic effect, for example in patients with a proliferative disorder. Non-limiting examples of 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. As used herein, the term "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. The term "cancer" includes diseases of the skin, tissues, organs, bones, cartilage,
Blut und Gefäßen. Der Begriff "Krebs" umfasst ferner primäre und metastasierende Krebserkrankungen.Blood and vessels. The term "cancer" further includes primary and metastatic cancers.
Nichtbeschränkende Beispiele für solide Tumoren, die mit den offenbarten CHK1-Inhibitoren behandelt werden können, sind u.a. Pankreaskrebs, Blasenkrebs, Kolorektalkrebs, Brustkrebs, einschließlich metastasieren- dem Brustkrebs, Prostatakrebs, einschließlich androgenabhängigem und androgenunabhängigem Prostatakrebs, Nierenkrebs, einschließlich z.B. metastasierendem Nierenzellkarzinom, Leberzellkrebs, Lungenkrebs, einschließlich z.B. nicht-kleinzelligem Lungenkrebs (NSCLC)1 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
Bronchioloalveolarkarzinom (BAC) und Adenokarzinom der Lunge, Ovarkrebs, einschließlich z.B. progressivem epithelialem oder primären Peritonealkrebs, Gebärmutterhalskrebs, Magenkrebs, Speiseröhrenkrebs, Kopf- und Halskrebs, einschließlich z.B. Schuppenzellkarzinom desBronchioloalveolar carcinoma (BAC) 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
Kopfes und des Halses, Melanom, neuroendokriner Krebs, einschließlich metastasierender neuroendokriner Tumoren, Hirntumoren, einschließlich z.B. Gliom, anaplastischem Oligodendrogliom, Glioblastoma multiforme bei Erwachsenen und anaplastischem Astrozytom bei Erwachsenen, Knochenkrebs und Weichgewebesarkom.Head and neck, melanoma, 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.
Nichtbeschränkende Beispiele für hämatologische Malignitäten, die mit den offenbarten CHK1 -Inhibitoren behandelt werden können, sind u.a. akute myeloische Leukämie (AML), chronische myeologene LeukämieNon-limiting examples of hematological malignancies that may be treated with the disclosed CHK1 inhibitors include: acute myeloid leukemia (AML), chronic myeologenic leukemia
(CML), einschließlich beschleunigter CML und CML-Blastenphase (CML- BP), akute lymphoblastische Leukämie (ALL), chronische lymphozytische Leukämie (CLL), Hodgkin-Erkrankung (HD), Non-Hodgkin-Lymphom (NHL), einschließlich follikulärem Lymphom und Mantelzelllymphom, B- Zell-Lymphom, T-Zell-Lymphom, multiples Myelom (MM), Waldenström- Makroglobulinämie, myelodysplastische Syndrome (MDS), einschließlich refraktärer Anämie (RA), refraktärer Anämie mit Ringsideroblasten (RARS), refraktärer Anämie mit Blastenüberschuss (RAEB) und RAEB in Transformation (RAEB-T), sowie myeloproliferative Syndrome.(CML), including accelerated CML and CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom's macroglobulinemia, myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with RRS, refractory anemia with blast excess (RAEB) and RAEB in transformation (RAEB-T), as well as myeloproliferative syndromes.
Die offenbarten Verbindungen der Formel I eignen sich besonders zurThe disclosed compounds of the formula I are particularly suitable for
Behandlung von Krebsarten oder Zelltypen, bei denen CHK1 -Protein oderTreatment of cancers or cell types in which CHK1 protein or
-Aktivität hochreguliert ist, einschließlich, ohne Beschränkung, schnell proliferierender Zellen und arzneistoffresistenter Zellen (Shyjan et al., U.S.- Patent Nr. 6,723,498 (2004)) sowie Retinoblastomen, wie Rb-negative oder inaktivierte Zellen (Gottifredi et al., Mol. Cell Biol., 21 :1066 (2001)), oder bei denen der ARFp14/p19-Locus inaktiviert oder falsch reguliert ist. Die offenbarten CHK1 -Inhibitoren eignen sich auch besonders zur Behandlung von Krebsarten oder Zelltypen, bei denen ein anderer Kontrollpunkt-Weg mutiert oder aufgehoben ist, einschließlich, ohne Beschränkung, Krebsarten oder Zelltypen, bei denen p53 oder der p53-Weg inaktiviert oder aufgehoben ist.Activity, including, without limitation, rapidly proliferating cells and drug-resistant cells (Shyjan et al., US Pat. Patent No. 6,723,498 (2004)) as well as retinoblastomas such as Rb-negative or inactivated cells (Gottifredi et al., Mol. Cell Biol., 21: 1066 (2001)) or in which the ARF inactivates p14 / p19 locus or is wrongly regulated. The disclosed 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.
Die offenbarten Verbindungen der Formel I können in Verbindung mit anderen Therapeutika, einschließlich Antikrebsmitteln, verabreicht werden. Wie hier verwendet, betrifft der Begriff "Antikrebsmittel" jedes Mittel, das einem Patienten mit Krebs zum Zweck der Behandlung des Krebses verabreicht wird.The disclosed compounds of Formula I can be administered in conjunction with other therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
Die hier definierte Antikrebsbehandlung kann als alleinige Therapie angewendet werden oder zusätzlich zu der erfindungsgemäßen Verbindung herkömmliche Operation oder Strahlungstherapie oder Chemotherapie umfassen. Eine derartige Chemotherapie kann eine oder mehrere der folgenden Kategorien von Antitumormitteln umfassen: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:
(i) antiproliferative/antineoplastische/DNA schädigende Mittel und Kombinationen davon, wie in der medizinischen Onkologie verwendet, wie Alkylierungsmittel (zum Beispiel Cisplatin, Carboplatin, Cyclophosphamid, Nitrogen Mustard, Melphalan, Chlorambucil, Busulphan und Nitroso- harnstoffe); Antimetaboliten (z.B. Antifolate, wie Fluorpyrimidine, wie 5- Fluoruracil und Tegafur, Raltitrexed, Methotrexat, Cytosinarabinosid, Hydroxyharnstoff und Gemcitabin); Antitumor-Antibiotika (z.B. Anthra- cycline, wie Adriamycin, Bleomycin, Doxorubicin, Daunomycin, Epirubicin, Idarubicin, Mitomycin-C, Dactinomycin und Mithramycin); antimitotische(i) 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
Mittel (zum Beispiel Vinca-Alkaloide, wie Vincristin, Vinblastin, Vindesin und Vinorelbin, und Taxoide, wie Taxol und Taxoter); Topoisomerase-Agents (for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere); topoisomerase
Inhibitoren (zum Beispiel Epipodophyllotoxine, wie Etoposid und Teniposid, Amsacrin, Topotecan, Irinotecan und Camptothecin) und zeildifferenzierende Mittel (zum Beispiel all-trans-Retinsäure, 13-cis- Retinsäure und Fenretinid);Inhibitors (for example epipodophyllotoxins, such as etoposide and Teniposide, amsacrine, topotecan, irinotecan and camptothecin) and diverting agents (for example, all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide);
(ii) zytostatische Mittel, wie Anti-Östrogene (z.B. Tamoxifen, Toremifen, Raloxifen, Droloxifen und lodoxyfen), den Östrogenrezeptor nach unten regulierende Mittel (zum Beispiel Fulvestrant), Anti-Androgene (z.B. Bicalutamid, Flutamid, Nilutamid und Cyproteronacetat), LHRH- Antagonisten oder LHRH-Agonisten (zum Beispiel Goserelin, Leuprorelin und Buserelin), Progesterone (zum Beispiel Megestrolacetat), Aromatase- Inhibitoren (zum Beispiel Anastrozol, Letrozol, Vorazol und Exemestan) und Inhibitoren der 5α-Reduktase, wie Finasterid; (iii) Mittel, die die Invasion von Krebszellen hemmen (zum Beispiel Metalloproteinase-Inhibitoren, wie Marimastat und Inhibitoren der Urokinase-Plasminogenaktivator-Rezeptor-Funktion); (iv) Inhibitoren der Wachstumsfaktor-Funktion, zum Beispiel umfassen solche Inhibitoren Wachstumsfaktor-Antikörper, Wachstumsfaktor- Rezeptor-Antikörper (zum Beispiel den Anti-erbb2-Antikörper Trastuzumab(ii) 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 5α-reductase, such as finasteride; (iii) agents that inhibit the invasion of cancer cells (for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example, such inhibitors include growth factor antibody, growth factor receptor antibody (for example, the anti-erbb2 antibody trastuzumab
[Herceptin™] und den Anti-erbb1 -Antikörper Cetuximab [C225]), Farnesyl- transferase-lnhibitoren, Tyrosinkinase-Inhibitoren und Serin / Threonin- Kinase-Inhibitoren, zum Beispiel Inhibitoren der epidermalen Wachstumsfaktor-Familie (zum Beispiel Inhibitoren der Tyrosinkinasen der EGFR- Familie, wie N-(3-Chlor-4-fluorphenyl)-7-methoxy-6-(3-morpholinopropoxy)- chinazolin-4-amin (Gefitinib, AZD1839), N-(3-Ethinylphenyl)-6,7-bis(2- methoxyethoxy)chinazolin-4-amin (Erlotinib, OSI-774) und 6-Acrylamido-N- (3-chlor-4-fluorphenyl)-7-(3-morpholinopropoxy)chinazolin-4-amin (Cl 1033)), zum Beispiel Inhibitoren der von Plättchen abstammenden Wachstumsfaktor-Familie und zum Beispiel Inhibitoren der Hepatozytenwachs- tumsfaktor-Familie; (v) antiangiogene Mittel, wie solche, die die Wirkungen des vaskulären endothelialen Wachstumsfaktors hemmen (zum Beispiel der[Herceptin ™] and the anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase 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 platelet-derived growth factor family inhibitors and, for example, inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents, such as those which inhibit the effects of the vascular endothelial growth factor (e.g.
Antikörper gegen den vaskulären Endothelzell-Wachstumsfaktor Bevacizumab [Avastin™], Verbindungen, wie die in den veröffentlichten internationalen Patentanmeldungen WO 97/22596, WO 97/30035, WO 97/32856 und WO 98/13354 offenbarten) und Verbindungen, die durch andere Mechanismen wirken (zum Beispiel Linomid, Inhibitoren der lntegrin-αvß3-Funktion und Angiostatin);Antibody to the vascular endothelial cell growth factor Bevacizumab [Avastin ™], compounds such as those disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354), and compounds that act by other mechanisms (for example, linomide, inhibitors the integrin αvβ3 function and angiostatin);
(vi) gefäßschädigende Mittel, wie Combretastatin A4 und in den internationalen Patentanmeldungen WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 und WO 02/08213 offenbarte Verbindungen;(vi) 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;
(vii) Antisense-Therapien, zum Beispiel diejenigen, die gegen die vorstehend aufgelisteten Ziele gerichtet sind, wie ISIS 2503, ein anti-Ras- Antisense; (viii) Genetherapieansätze, einschließlich beispielsweise Ansätze zum Ersetzen von veränderten Genen, wie verändertem p53 oder verändertem BRCA1 oder BRCA2, GDEPT- (gene-directed enzyme pro-drug-Therapie-) Ansätze, die diejenigen, die Cytosindesaminase, Thymidinkinase oder ein bakterielles Nitroreduktase-Enzym verwenden, sowie Ansätze zur(vii) antisense therapies, for example, those directed against the targets listed above, such as ISIS 2503, an anti-Ras antisense; (viii) 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
Erhöhung der Patiententoleranz gegenüber Chemotherapie oderIncrease patient tolerance to chemotherapy or
Strahlungstherapie, wie Multi-Drug-Resistence-Gen-Therapie; undRadiation therapy, such as multi-drug resistance gene therapy; and
(ix) Immuntherapieansätze, einschließlich beispielsweise Ex-vivo- und(ix) immunotherapy approaches, including, for example, ex vivo and
In-vivo-Ansätzen zur Erhöhung der Immunogenität von Patiententumor- zellen, wie Transfektion mit Cytokinen, wie Interleukin 2, Interleukin 4 oder Granulozyten-Makrophagen-Kolonie-stimulierendem Faktor, Ansätze zur Verringerung der T-Zell-Anergie, Ansätze unter Verwendung transfizierter Immunzellen, wie mit Cytokin transfizierter dendritischer Zellen, Ansätze unter Verwendung mit Cytokin transfizierter Tumorzelllinien und Ansätze unter Verwendung anti-idiotypischer Antikörper.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.
Bevorzugt aber nicht ausschliesslich werden die Arzneimittel der nachstehenden Tabelle 1 mit den Verbindungen der Formel I kombiniert. Tabelle 1.Preferably, but not exclusively, the medicaments of Table 1 below are combined with the compounds of the formula I. Table 1.
Alkylierungsmittel Cyclophosphamid LomustinAlkylating agent Cyclophosphamide Lomustine
Busulfan ProcarbazinBusulfan procarbazine
Ifosfamid AltretaminIfosfamide altretamine
Melphalan EstramustinphosphatMelphalan estramustin phosphate
Hexamethylmelamin MechlorethaminHexamethylmelamine mechlorethamine
Thiotepa StreptozocinThiotepa streptozocin
Chlorambucil TemozolomidChlorambucil Temozolomide
Dacarbazin SemustinDacarbazine Semustin
Carmustincarmustine
Platinmittel Cisplatin CarboplatinPlatinum agent cisplatin carboplatin
Oxaliplatin ZD-0473 (AnorMED)Oxaliplatin ZD-0473 (AnorMED)
Spiroplatin Lobaplatin (Aetema)Spiroplatin Lobaplatin (Aetema)
Carboxyphthalatoplatinum Satraplatin (JohnsonCarboxyphthalatoplatinum Satraplatin (Johnson
Tetraplatin Matthey)Tetraplatinum Matthey)
Ormiplatin BBR-3464 (Hoffmann-LaOrmiplatin BBR-3464 (Hoffmann-La
Iproplatin Roche)Iproplatin Roche)
SM-11355 (Sumitomo)SM-11355 (Sumitomo)
AP-5280 (Access)AP-5280 (Access)
Antimetabolite Azacytidin TomudexAntimetabolite azacytidine Tomudex
Gemcitabin TrimetrexateGemcitabine trimetrexate
Capecitabin DeoxycoformycinCapecitabine deoxycoformycin
5-Fluoruracil Fludarabin5-fluorouracil fludarabine
Floxuridin PentostatinFloxuridine pentostatin
2-Chlordesoxyadenosin Raltitrexed2-chlorodeoxyadenosine Raltitrexed
6-Mercaptopurin Hydroxyhamstoff6-mercaptopurine hydroxyurea
6-Thioguanin Decitabin (SuperGen)6-thioguanine decitabine (SuperGen)
Cytarabin Clofarabin (Bioenvision)Cytarabine Clofarabine (Bioenvision)
2-Fluordesoxycytidin Irofulven (MGI Pharma)2-Fluorodeoxycytidine Irofulvene (MGI Pharma)
Methotrexat DMDC (Hoffmann-LaMethotrexate DMDC (Hoffmann-La
Idatrexate Roche)Idatrexate Roche)
Ethinylcytidin (Taiho )Ethinylcytidine (Taiho)
Topoisomerase- Amsacrin Rubitecan (SuperGen)Topoisomerase Amsacrine Rubitecane (SuperGen)
Inhibitoren Epirubicin Exatecanmesylat (Daiichi)Inhibitors Epirubicin Exatecan Mesylate (Daiichi)
Etoposid Quinamed (ChemGenex)Etoposide Quinamed (ChemGenex)
Teniposid oder Gimatecan (Sigma- Tau)Teniposide or Gimatecan (Sigma-Tau)
Mitoxantron Diflomotecan (Beaufour-Mitoxantrone diflomotecan (Beaufour
Irinotecan (CPT-11 ) Ipsen)Irinotecan (CPT-11) Ipsen)
7-Ethyl-10- TAS-103 (Taiho) hydroxycamptothecin Elsamitrucin (Spectrum)7-Ethyl-10-TAS-103 (Taiho) hydroxycamptothecin Elsamitrucine (Spectrum)
Topotecan J-107088 (Merck & Co)Topotecan J-107088 (Merck & Co)
Dexrazoxanet BNP-1350 (BioNumerik)Dexrazoxanet BNP-1350 (BioNumerik)
(TopoTarget) CKD-602 (Chong Kun(TopoTarget) CKD-602 (Chong Kun
Pixantron (Novuspharrna) Dang) Rebeccamycin-Analogon KW-2170 (Kyowa Hakko)Pixantron (Novuspharrna) Dang) Rebeccamycin analog KW-2170 (Kyowa Hakko)
(Exelixis)(Exelixis)
BBR-3576 (Novuspharrna)BBR-3576 (Novuspharrna)
Antitumor- Dactinomycin (Actinomycin AmonafidAntitumor Dactinomycin (Actinomycin Amonafide
Antibiotika D) AzonafidAntibiotics D) Azonafide
Doxorubicin (Adriamycin) AnthrapyrazolDoxorubicin (adriamycin) anthrapyrazole
Deoxyrubicin OxantrazolDeoxyrubicin Oxantrazole
Valrubicin LosoxantronValrubicin losoxantrone
Daunorubicin BleomycinsulfatDaunorubicin bleomycin sulfate
(Daunomycin) (Blenoxan)(Daunomycin) (Blenoxan)
Epirubicin BleomycinsäureEpirubicin bleomycinic acid
Therarubicin Bleomycin ATherarubicin Bleomycin A
Idarubicin Bleomycin BIdarubicin bleomycin B
Rubidazon Mitomycin CRubidazone mitomycin C
Plicamycinp MEN-10755 (Menarini)Plicamycin p MEN-10755 (Menarini)
Porfiromycin GPX-100 (GernPorfiromycin GPX-100 (glad
Cyanomorpholino- Pharmaceuticals) doxorubicinCyanomorpholino-pharmaceuticals) doxorubicin
Mitoxantron (Novantron)Mitoxantrone (Novantrone)
Antimitotische Paclitaxel SB 408075Antimitotic Paclitaxel SB 408075
Mittel Docetaxel (GlaxoSmithKline)Agent Docetaxel (GlaxoSmithKline)
Colchicin E7010 (Abbott)Colchicine E7010 (Abbott)
Vinblastin PG-TXL (CellVinblastine PG-TXL (Cell
Vincristin Therapeutics)Vincristin Therapeutics)
Vinorelbin IDN 5109 (Bayer)Vinorelbine IDN 5109 (Bayer)
Vindesin A 105972 (Abbott)Vindesin A 105972 (Abbott)
Dolastatin 10 (NCI) A 204197 (Abbott)Dolastatin 10 (NCI) A 204197 (Abbott)
Rhizoxin (Fujisawa) LU 223651 (BASF)Rhizoxin (Fujisawa) LU 223651 (BASF)
Mivobulin (Warner- D 24851 (ASTA Medica)Mivobulin (Warner-D 24851 (ASTA Medica)
Lambert) ER-86526 (Eisai)Lambert) ER-86526 (Eisai)
Cemadotin (BASF) Combretastatin A4 (BMS)Cemadotin (BASF) Combretastatin A4 (BMS)
RPR 109881A (Aventis) Isohomohalichondrin-BRPR 109881A (Aventis) isohomohalichondrin-B
TXD 258 (Aventis) (PharmaMar)TXD 258 (Aventis) (PharmaMar)
Epothilon B (Novartis) ZD 6126 (AstraZeneca)Epothilone B (Novartis) ZD 6126 (AstraZeneca)
T 900607 (Tularik) PEG-Paclitaxel (Enzon)T 900607 (Tularik) PEG paclitaxel (Enzon)
T 138067 (Tularik) AZ10992 (Asahi)T 138067 (Tularik) AZ10992 (Asahi)
Cryptophycin 52 (EIi Lilly) !DN-5109 (lndena)Cryptophycin 52 (Eli Lilly)! DN-5109 (lndena)
Vinflunin (Fabre) AVLB (PrescientVinflunin (Fabre) AVLB (Prescient
Auristatin PE (Teikoku NeuroPharma)Auristatin PE (Teikoku NeuroPharma)
Hormone) Azaepothilon B (BMS)Hormones) azaepothilone B (BMS)
BMS 247550 (BMS) BNP- 7787 (BioNumerik)BMS 247550 (BMS) BNP-7787 (BioNumerik)
BMS 184476 (BMS) CA-4-Prodrug (OXiGENE)BMS 184476 (BMS) CA-4 prodrug (OXiGENE)
BMS 188797 (BMS) Dolastatin-10 (NrH)BMS 188797 (BMS) Dolastatin-10 (NrH)
Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase- Aminoglutethimid ExemestanTaxoprexin (Protarga) CA-4 (OXiGENE) Aromatase-aminoglutethimide exemestane
Inhibitoren Letrozol Atamestan (BioMedicines)Inhibitors Letrozole Atamestane (BioMedicines)
Anastrazol YM-511 (Yamanouchi)Anastrazole YM-511 (Yamanouchi)
Formestanformestane
Thymidylat- Pemetrexed (EIi Lilly) Nolatrexed (Eximias) synthase- ZD-9331 (BTG) CoFactor™ (BioKeys)Thymidylate pemetrexed (EIi Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor ™ (BioKeys)
Inhibitoreninhibitors
DNA- Trabectedin (PharmaMar) Mafosfamid (BaxterDNA Trabectedin (PharmaMar) Mafosfamide (Baxter
Antagonisten Glufosfamid (Baxter International)Antagonists glufosfamide (Baxter International)
International) Apaziquon (SpectrumInternational) Apaziquon (Spectrum
Albumin + 32P (Isotope Pharmaceuticals)Albumin + 32P (Isotope Pharmaceuticals)
Solutions) O6-BenzylguaninSolutions) O6-Benzylguanine
Thymectacin (NewBiotics) (Paligent)Thymectacin (NewBiotics) (Paligent)
Edotreotid (Novartis)Edotreotide (Novartis)
Famesyltrans- Arglabin (NuOncology Tipifarnib (Johnson & ferase-lnhibitoren Labs) Johnson) lonafarnib (Schering- Perillylalkohol (DORFamesyltrans-Arglabin (NuOncology Tipifarnib (Johnson & Ferase Inhibitors Labs) Johnson) lonafarnib (Schering-Perillyl Alcohol (DOR
Plough) BioPharma)Plow) BioPharma)
BAY-43-9006 (Bayer)BAY-43-9006 (Bayer)
Pumpen- CBT-1 (CBA Pharma) Zosuquidar-TrihydrochloridPump CBT-1 (CBA Pharma) Zosuquidar trihydrochloride
Inhibitoren Tariquidar (Xenova) (EIi Lilly)Inhibitors Tariquidar (Xenova) (EIi Lilly)
MS-209 (Schering AG) Biricodar-Dicitrat (Vertex)MS-209 (Schering AG) Biricodar dicitrate (vertex)
Histonacetyltrans- Tacedinalin (Pfizer) Pivaloyloxymethylbutyrat ferase-lnhibitoren SAHA (Aton Pharma) (Titan)Histone acetyl trans-Tacedinalin (Pfizer) pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (titanium)
MS-275 (Schering AG) Depsipeptid (Fujisawa)MS-275 (Schering AG) Depsipeptide (Fujisawa)
Metalloproteinase- Neovastat (Aeterna CMT -3 (CollaGenex)Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)
Inhibitoren Laboratories) BMS-275291 (Celltech)Inhibitors Laboratories) BMS-275291 (Celltech)
Ribonucleosidred Marimastat (British Tezacitabin (Aventis) uktase- Biotech) Didox (Molecules forRibonucleosidred Marimastat (British Tezacitabine (Aventis) uktase-Biotech) Didox (Molecules for
Inhibitoren Galliummaltolat (Titan) Health)Inhibitors gallium maltolate (titanium) Health)
Triapin (Vion)Triapin (Vion)
TNF-alpha- Virulizin (Lorus Revimid (Celgene)TNF-alpha-virulizine (Lorus Revimid (Celgene)
Agonisten / AntaTherapeutics) gonisten CDC-394 (Celgene)Agonists / AntaTherapeutics) gonisten CDC-394 (Celgene)
Endothelin-A- Atrasentan (Abbot) YM-598 (Yamanouchi)Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)
Rezeptor- ZD-4054 (AstraZeneca)Receptor ZD-4054 (AstraZeneca)
Antagonisten Retinsäure- Fenretinid (Johnson & Alitretinoin (Ligand) rezeptor- Johnson)antagonists Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand) Receptor - Johnson)
Agonisten LGD-1550 (Ligand)Agonists LGD-1550 (Ligand)
ImmunInterferon Dexosom-Therapie modulatoren Oncophage (Antigenics) (Anosys)Immune Interferon Dexosome Therapy Modulators Oncophage (Antigenics) (Anosys)
GMK (Progenics) Pentrix (Australian CancerGMK (Progenics) Pentrix (Australian Cancer
Adenokarzinom-Impfstoff Technology)Adenocarcinoma Vaccine Technology)
(Biomira) JSF-154 (Tragen)(Biomira) JSF-154 (Carrying)
CTP-37 (AVI BioPharma) Krebsimpfstoff (Intercell)CTP-37 (AVI BioPharma) cancer vaccine (Intercell)
JRX-2 (Immuno-Rx) Norelin (Biostar)JRX-2 (Immuno-Rx) Norelin (Biostar)
PEP-005 (Peplin Biotech) BLP-25 (Biomira)PEP-005 (Peplin Biotech) BLP-25 (Biomira)
Synchrovax-Impfstoffe MGV (Progenics)Synchrovax vaccines MGV (Progenics)
(CTL Immuno) !3-Alethin (Dovetail)(CTL Immuno)! 3-Alethine (Dovetail)
Melanom-Impfstoff (CTL CLL-Thera (Vasogen)Melanoma vaccine (CTL CLL-Thera (Vasogen)
Immuno) p21-RAS-lmpfstoffImmuno) p21 RAS vaccine
(GemVax)(GemVax)
Hormonelle und Östrogene Prednison antihormonelle konjugierte Östrogene MethylprednisolonHormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone
Mittel Ethinylöstradiol PrednisolonAgent ethinyl estradiol prednisolone
Chlortrianisen AminoglutethimidChlorotrienes Aminoglutethimide
Idenestrol LeuprolidIdenestrol Leuprolide
Hydroxyprogesteron- Goserelin caproat LeuporelinHydroxyprogesterone-Goserelin caproat Leuporelin
Medroxyprogesteron BicalutamidMedroxyprogesterone Bicalutamide
Testosteron FlutamidTestosterone Flutamide
Testosteronpropionat OctreotidTestosterone Propionate Octreotide
Fluoxymesteron NilutamidFluoxymesterone nilutamide
Methyltestosteron MitotanMethyltestosterone mitotane
Diethylstilbestrol P-04 (Novogen)Diethylstilbestrol P-04 (Novogen)
Megestrol 2-MethoxyöstradiolMegestrol 2-Methoxyestradiol
Tamoxifen (EntreMed)Tamoxifen (EntreMed)
Toremofin Arzoxifen (EIi Lilly)Toremofin Arzoxifen (EIi Lilly)
Dexamethasondexamethasone
Photodynamische Talaporfin (Light Sciences) Pd-BacteriopheophorbidPhotodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide
Mittel Theralux (Yeda)Central Theralux (Yeda)
(Theratechnologies) Lutetium-Texaphyrin(Theratechnologies) Lutetium Texaphyrin
Motexafin-Gadolinium (Pharmacyclics)Motexafin Gadolinium (Pharmacyclics)
(Pharmacyclics) Hypericin(Pharmacyclics) Hypericin
Tyrosinkinase- Imatinib (Novartis) Kahalid F (PharmaMar)Tyrosine kinase imatinib (Novartis) Kahalid F (PharmaMar)
Inhibitoren Leflunomid CEP- 701 (Cephalon)Inhibitors Leflunomide CEP-701 (Cephalon)
(Sugen/Pharmacia) CEP-751 (Cephalon)(Sugen / Pharmacia) CEP-751 (Cephalon)
ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis)ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis)
Science) Phenoxodiol OScience) phenoxodiol O
Canertjnib (Pfizer) Trastuzumab (Genentech)Canertjnib (Pfizer) Trastuzumab (Genentech)
Squalamin (Genaera) C225 (ImCIone)Squalamine (Genaera) C225 (ImCIone)
SU5416 (Pharmacia) rhu-Mab (Genentech)SU5416 (Pharmacia) rhu-Mab (Genentech)
SU6668 (Pharmacia) MDX-H210 (Medarex)SU6668 (Pharmacia) MDX-H210 (Medarex)
ZD4190 (AstraZeneca) 2C4 (Genentech)ZD4190 (AstraZeneca) 2C4 (Genentech)
ZD6474 (AstraZeneca) MDX-447 (Medarex)ZD6474 (AstraZeneca) MDX-447 (Medarex)
Vatalanib (Novartis) ABX-EGF (Abgenix)Vatalanib (Novartis) ABX-EGF (Abgenix)
PKI166 (Novartis) IMC-1C11 (ImCIone)PKI166 (Novartis) IMC-1C11 (ImCIone)
GW2016GW2016
(GlaxoSmithKline)(GlaxoSmithKline)
EKB-509 (Wyeth)EKB-509 (Wyeth)
EKB-569 (Wyeth)EKB-569 (Wyeth)
Verschiedene SR-27897 (CCK-A- BCX-1777 (PNP-lnhibitor,Various SR-27897 (CCK-A-BCX-1777 (PNP inhibitor,
Mittel Inhibitor, Sanofi- BioCryst)Medium Inhibitor, Sanofi-BioCryst)
Synthelabo) RanpirnaseSynthelabo) Ranpirnase
Tocladesin (cyclisches- (Ribonuclease-Stimulans,Tocladesin (cyclic (ribonuclease stimulant,
AMP-Agonist, Ribapharm) Alfacell)AMP agonist, Ribapharm) Alfacell)
Alvocidib (CDK-Inhibitor, Galarubicin (RNA-Alvocidib (CDK inhibitor, galarubicin (RNA
Aventis) Synthese-Inhibitor, Dong-Aventis) Synthesis Inhibitor, Dong-
CV-247 (COX-2-lnhibitor, A)CV-247 (COX-2 inhibitor, A)
Ivy Medical) TirapazaminIvy Medical) Tirapazamine
P54 (COX-2-lnhibitor, (Reduktionsmittel, SRIP54 (COX-2 inhibitor, (reducing agent, SRI
Phytopharm) International)Phytopharm) International)
CapCell™ (CYP450- N-AcetylcysteinCapCell ™ (CYP450-N-acetylcysteine
Stimulans, Bavarian (Reduktionsmittel,Stimulant, Bavarian (reducing agent,
Nordic) Zambon)Nordic) Zambon)
GCS-IOO (gal3- R-Flurbiprofen (NF-GCS-IOO (gal3-R-flurbiprofen (NF-
Antagonist, kappaB-lnhibitor, Encore)Antagonist, kappaB inhibitor, Encore)
GlycoGenesys) 3CPA (NF-kappaB-GlycoGenesys) 3CPA (NF-kappaB-
G17DT-lmmunogen Inhibitor, Active Biotech)G17DT immunogenic inhibitor, Active Biotech)
(Gastrin-Inhibitor, Aphton) Seocalcitol (Vitamin-D-(Gastrin inhibitor, Aphton) seocalcitol (vitamin D
Efaproxiral (Oxygenator, Rezeptor-Agonist, Leo)Efaproxiral (oxygenator, receptor agonist, Leo)
Allos Therapeutics) 131-I-TM-601 (DNA-Allos Therapeutics) 131-I-TM-601 (DNA
PI-88 (Heparanase- Antagonist,PI-88 (heparanase antagonist,
Inhibitor, Progen) TransMolecular)Inhibitor, progene) TransMolecular)
Tesmilifen (Histamin- Eflornithin (ODC-Inhibitor,Tesmilifen (histamine eflornithine (ODC inhibitor,
Antagonist, YM ILEX Oncology)Antagonist, YM ILEX Oncology)
BioSciences) MinodronsäureBioSciences) Minodronic acid
Histamin (Histamin-H2- (Osteoclasten-Inhibitor,Histamine (histamine H2 (osteoclast inhibitor,
Rezeptor- Agonist, Maxim) Yamanouchi)Receptor agonist, Maxim) Yamanouchi)
Tiazofurin (I MPDH- Indisulam (p53-Stimulans,Tiazofurin (I MPDH-indisulam (p53 stimulant,
Inhibitor, Ribapharm) Eisai)Inhibitor, Ribapharm) Eisai)
Cilengitid (Integrin- Aplidin (PPT-Inhibitor,Cilengitide (Integrin Aplidine (PPT inhibitor,
Antagonist, Merck KGaA) PharmaMar)Antagonist, Merck KGaA) PharmaMar)
SR-31747 (IL-1- Rituximab (CD20- Antagonist, Sanofi- Antikörper, Genentech)SR-31747 (IL-1 rituximab (CD20- Antagonist, Sanofi antibody, Genentech)
Synthelabo) Gemtuzumab (CD33-Synthelabo) gemtuzumab (CD33-
CCI-779 (mTOR-Kinase- Antikörper, Wyeth Ayerst)CCI-779 (mTOR kinase antibody, Wyeth Ayerst)
Inhibitor, Wyeth) PG2 (Hämatopoese-Inhibitor, Wyeth) PG2 (hematopoietic
Exisulind (PDE-V-Inhibitor, Verstärker,Exisulind (PDE-V inhibitor, enhancer,
Cell Pathways) Pharmagenesis)Cell Pathways) Pharmagenesis)
CP-461 (PDE-V-Inhibitor, Immunol™ (Triclosan-CP-461 (PDE-V inhibitor, Immunol ™ (triclosan)
Cell Pathways) Oralspülung, Endo)Cell Pathways) Oral Irrigation, Endo)
AG-2037 (GART-Inhibitor, Triacetyluridin (Uridin-AG-2037 (GART inhibitor, triacetyluridine (uridine)
Pfizer) Prodrug, Wellstat)Pfizer) prodrug, Wellstat)
WX-UK1 SN-4071 (Sarkom-Mittel,WX-UK1 SN-4071 (sarcoma agent,
(Plasminogenaktivator- Signature BioScience)(Plasminogen activator Signature BioScience)
Inhibitor, Wilex) TransMID-107™Inhibitor, Wilex) TransMID-107 ™
PBI-1402 (PMN-Stimulans, (Immunotoxin, KSPBI-1402 (PMN stimulant, (immunotoxin, KS
ProMetic LifeSciences) Biomedix)ProMetic LifeSciences) Biomedix)
Bortezomib (Proteasom- PCK-3145 (Apoptose-Bortezomib (proteasome PCK-3145 (apoptosis)
Inhibitor, Millennium) Förderer, Procyon)Inhibitor, Millennium) promoter, Procyon)
SRL-172 (T-ZeII- Doranidazol (Apoptose-SRL-172 (T-cell doranidazole (apoptosis
Stimulans, SR Pharma) Förderer, PoIa)Stimulant, SR Pharma) promoter, PoIa)
TLK-286 (Glutathion-S- CHS-828 (cytotoxischesTLK-286 (glutathione-S-CHS-828 (cytotoxic
Transferase-Inhibitor, Mittel, Leo)Transferase inhibitor, agent, Leo)
Telik) trans-RetinsäureTelik) trans-retinoic acid
PT-100 (Wachstumsfaktor- (Differentiator, NIH)PT-100 (growth factor (differentiator, NIH)
Agonist, Point MX6 (Apoptose-Förderer,Agonist, Point MX6 (apoptosis promoter,
Therapeutics) MAXIA)Therapeutics) MAXIA)
Midostaurin (PKC-Inhibitor, Apomin (Apoptose-Midostaurin (PKC inhibitor, apomin (apoptosis
Novartis) Förderer, ILEX Oncology)Novartis) Sponsors, ILEX Oncology)
Bryostatin-1 (PKC- Urocidin (Apoptose-Bryostatin-1 (PKC-urocidin (apoptosis)
Stimulans, GPC Biotech) Förderer, Bioniche)Stimulant, GPC Biotech) promoter, Bioniche)
CDA-II (Apoptose- Ro-31-7453 (Apoptose-CDA-II (apoptosis-Ro-31-7453 (apoptosis
Förderer, Everlife) Förderer, La Roche)Conveyor, Everlife) conveyor, La Roche)
SDX-101 (Apoptose- Brostallicin (Apoptose-SDX-101 (apoptosis-brostallicin (apoptosis)
Förderer, Salmedix) Förderer, Pharmacia)Promoter, Salmedix) promoter, Pharmacia)
Ceflatonin (Apoptose-Ceflatonin (apoptosis
Förderer, ChemGenex)Conveyor, ChemGenex)
Alkylierungsmittel Cyclophosphamid LomustinAlkylating agent Cyclophosphamide Lomustine
Busulfan ProcarbazinBusulfan procarbazine
Ifosfamid AltretaminIfosfamide altretamine
Melphalan EstramustinphosphatMelphalan estramustin phosphate
Hexamethylmelamin MechlorethaminHexamethylmelamine mechlorethamine
Thiotepa StreptozocinThiotepa streptozocin
Chlorambucil TemozolomidChlorambucil Temozolomide
Dacarbazin SemustinDacarbazine Semustin
Carmustin Platinmittel Cisplatin Carboplatincarmustine Platinum agent cisplatin carboplatin
Oxaliplatin ZD-0473 (AnorMED)Oxaliplatin ZD-0473 (AnorMED)
Spiroplatin Lobaplatin (Aetema)Spiroplatin Lobaplatin (Aetema)
Carboxyphthalatoplatinum Satraplatin (JohnsonCarboxyphthalatoplatinum Satraplatin (Johnson
Tetraplatin Matthey)Tetraplatinum Matthey)
Ormiplatin BBR-3464 (Hoffmann-LaOrmiplatin BBR-3464 (Hoffmann-La
Iproplatin Roche)Iproplatin Roche)
SM-11355 (Sumitomo)SM-11355 (Sumitomo)
AP-5280 (Access)AP-5280 (Access)
Antimetabolite Azacytidin TomudexAntimetabolite azacytidine Tomudex
Gemcitabin TrimetrexateGemcitabine trimetrexate
Capecitabin DeoxycoformycinCapecitabine deoxycoformycin
5-Fluoruracil Fludarabin5-fluorouracil fludarabine
Floxuridin PentostatinFloxuridine pentostatin
2-Chlordesoxyadenosin Raltitrexed2-chlorodeoxyadenosine Raltitrexed
6-Mercaptopurin Hydroxyharnstoff6-mercaptopurine hydroxyurea
6-Thioguanin Decitabin (SuperGen)6-thioguanine decitabine (SuperGen)
Cytarabin Clofarabin (Bioenvision)Cytarabine Clofarabine (Bioenvision)
2-Fluordesoxycytidin Irofulven (MGI Pharma)2-Fluorodeoxycytidine Irofulvene (MGI Pharma)
Methotrexat DMDC (Hoffmann-LaMethotrexate DMDC (Hoffmann-La
Idatrexate Roche)Idatrexate Roche)
Ethinylcytidin (Taiho )Ethinylcytidine (Taiho)
Topoisomerase- Amsacrin Rubitecan (SuperGen)Topoisomerase Amsacrine Rubitecane (SuperGen)
Inhibitoren Epirubicin Exatecanmesylat (Daiichi)Inhibitors Epirubicin Exatecan Mesylate (Daiichi)
Etoposid Quinamed (ChemGenex)Etoposide Quinamed (ChemGenex)
Teniposid oder Gimatecan (Sigma- Tau)Teniposide or Gimatecan (Sigma-Tau)
Mitoxantron Diflomotecan (Beaufour- lrinotecan (CPT-11) Ipsen)Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
7-Ethyl-10- TAS-103 (Taiho) hydroxycamptothecin Elsamitrucin (Spectrum)7-Ethyl-10-TAS-103 (Taiho) hydroxycamptothecin Elsamitrucine (Spectrum)
Topotecan J-107088 (Merck & Co)Topotecan J-107088 (Merck & Co)
Dexrazoxanet BNP-1350 (BioNumerik)Dexrazoxanet BNP-1350 (BioNumerik)
(TopoTarget) CKD-602 (Chong Kun(TopoTarget) CKD-602 (Chong Kun
Pixantron (Novuspharrna) Dang)Pixantron (Novuspharrna) Dang)
Rebeccamycin-Analogon KW-2170 (Kyowa Hakko)Rebeccamycin analog KW-2170 (Kyowa Hakko)
(Exelixis)(Exelixis)
BBR-3576 (Novuspharrna) Antitumor- Dactinomycin (Actinomycin AmonafidBBR-3576 (Novuspharrna) Antitumor Dactinomycin (Actinomycin Amonafide
Antibiotika D) AzonafidAntibiotics D) Azonafide
Doxorubicin (Adriamycin) AnthrapyrazolDoxorubicin (adriamycin) anthrapyrazole
Deoxyrubicin OxantrazolDeoxyrubicin Oxantrazole
Valrubicin LosoxantronValrubicin losoxantrone
Daunorubicin BleomycinsulfatDaunorubicin bleomycin sulfate
(Daunomycin) (Blenoxan)(Daunomycin) (Blenoxan)
Epirubicin BleomycinsäureEpirubicin bleomycinic acid
Therarubicin Bleomycin ATherarubicin Bleomycin A
Idarubicin Bleomycin BIdarubicin bleomycin B
Rubidazon Mitomycin CRubidazone mitomycin C
Plicamycinp MEN-10755 (Menarini)Plicamycin p MEN-10755 (Menarini)
Porfiromycin GPX-100 (GemPorfiromycin GPX-100 (gem
Cyanomorpholinodoxorubi Pharmaceuticals) einCyanomorpholinodoxorubi Pharmaceuticals)
Mitoxantron (Novantron)Mitoxantrone (Novantrone)
Antimitotische Paclitaxel SB 408075Antimitotic Paclitaxel SB 408075
Mittel Docetaxel (GlaxoSmithKline)Agent Docetaxel (GlaxoSmithKline)
Colchicin E7010 (Abbott)Colchicine E7010 (Abbott)
Vinblastin PG-TXL (CellVinblastine PG-TXL (Cell
Vincristin Therapeutics)Vincristin Therapeutics)
Vinorelbin IDN 5109 (Bayer)Vinorelbine IDN 5109 (Bayer)
Vindesin A 105972 (Abbott)Vindesin A 105972 (Abbott)
Dolastatin 10 (NCI) A 204197 (Abbott)Dolastatin 10 (NCI) A 204197 (Abbott)
Rhizoxin (Fujisawa) LU 223651 (BASF)Rhizoxin (Fujisawa) LU 223651 (BASF)
Mivobulin (Warner- D 24851 (ASTA Medica)Mivobulin (Warner-D 24851 (ASTA Medica)
Lambert) ER-86526 (Eisai)Lambert) ER-86526 (Eisai)
Cemadotin (BASF) Combretastatin A4 (BMS)Cemadotin (BASF) Combretastatin A4 (BMS)
RPR 109881A (Aventis) Isohomohalichondrin-BRPR 109881A (Aventis) isohomohalichondrin-B
TXD 258 (Aventis) (PharmaMar)TXD 258 (Aventis) (PharmaMar)
Epothilon B (Novartis) ZD 6126 (AstraZeneca)Epothilone B (Novartis) ZD 6126 (AstraZeneca)
T 900607 (Tularik) PEG-Paclitaxel (Enzon)T 900607 (Tularik) PEG paclitaxel (Enzon)
T 138067 (Tularik) AZ10992 (Asahi)T 138067 (Tularik) AZ10992 (Asahi)
Cryptophycin 52 (EIi Lilly) !DN-5109 (lndena)Cryptophycin 52 (Eli Lilly)! DN-5109 (lndena)
Vinflunin (Fabre) AVLB (PrescientVinflunin (Fabre) AVLB (Prescient
Auristatin PE (Teikoku NeuroPharma)Auristatin PE (Teikoku NeuroPharma)
Hormone) Azaepothilon B (BMS)Hormones) azaepothilone B (BMS)
BMS 247550 (BMS) BNP- 7787 (BioNumerik)BMS 247550 (BMS) BNP-7787 (BioNumerik)
BMS 184476 (BMS) CA-4-Prodrug (OXiGENE)BMS 184476 (BMS) CA-4 prodrug (OXiGENE)
BMS 188797 (BMS) Dolastatin-10 (NrH)BMS 188797 (BMS) Dolastatin-10 (NrH)
Taxoprexin (Protarga) CA-4 (OXiGENE)Taxoprexin (Protarga) CA-4 (OXiGENE)
Aromatase- Aminoglutethimid ExemestanAromatase-aminoglutethimide exemestane
Inhibitoren Letrozol Atamestan (BioMedicines)Inhibitors Letrozole Atamestane (BioMedicines)
Anastrazol YM-511 (Yamanouchi)Anastrazole YM-511 (Yamanouchi)
Formestan Thymidylatsyntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se-lnhibitoren ZD-9331 (BTG) CoFactor™ (BioKeys)formestane Thymidylate Syntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se Inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)
DNA- Trabectedin (PharmaMar) Mafosfamid (BaxterDNA Trabectedin (PharmaMar) Mafosfamide (Baxter
Antagonisten Glufosfamid (Baxter International)Antagonists glufosfamide (Baxter International)
International) Apaziquon (SpectrumInternational) Apaziquon (Spectrum
Albumin + 32P (Isotope Pharmaceuticals)Albumin + 32P (Isotope Pharmaceuticals)
Solutions) O6-BenzylguaninSolutions) O6-Benzylguanine
Thymectacin (NewBiotics) (Paligent)Thymectacin (NewBiotics) (Paligent)
Edotreotid (Novartis)Edotreotide (Novartis)
Farnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-lnhibitoren Labs) Johnson) lonafarnib (Schering- Perillylalkohol (DORFarnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se Inhibitors Labs) Johnson) lonafarnib (Schering-Perillyl Alcohol (DOR
Plough) BioPharma)Plow) BioPharma)
BAY-43-9006 (Bayer)BAY-43-9006 (Bayer)
Pumpen- CBT-1 (CBA Pharma) Zosuquidar-TrihydrochloridPump CBT-1 (CBA Pharma) Zosuquidar trihydrochloride
Inhibitoren Tariquidar (Xenova) (EIi Lilly)Inhibitors Tariquidar (Xenova) (EIi Lilly)
MS-209 (Schering AG) Biricodar-Dicitrat (Vertex)MS-209 (Schering AG) Biricodar dicitrate (vertex)
Histonacetyltransf Tacedinalin (Pfizer) Pivaloyloxymethylbutyrat erase- SAHA (Aton Pharma) (Titan)Histone acetyl trans Tacedinalin (Pfizer) pivaloyloxymethyl butyrate erase SAHA (Aton Pharma) (titanium)
Inhibitoren MS-275 (Schering AG) Depsipeptid (Fujisawa)Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)
Metalloproteinase- Neovastat (Aeterna CMT -3 (CollaGenex)Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)
Inhibitoren Laboratories) BMS-275291 (Celltech)Inhibitors Laboratories) BMS-275291 (Celltech)
Ribonucleosidred Marimastat (British Tezacitabin (Aventis) uktase- Biotech) Didox (Molecules forRibonucleosidred Marimastat (British Tezacitabine (Aventis) uktase-Biotech) Didox (Molecules for
Inhibitoren Galliummaltolat (Titan) Health)Inhibitors gallium maltolate (titanium) Health)
Triapin (Vion)Triapin (Vion)
TNF-alpha- Virulizin (Lorus Revimid (Celgene)TNF-alpha-virulizine (Lorus Revimid (Celgene)
Agonisten/Antago Therapeutics) nisten CDC-394 (Celgene)Agonists / Antago Therapeutics) nest CDC-394 (Celgene)
Endothelin-A- Atrasentan (Abbot) YM-598 (Yamanouchi)Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)
Rezeptor- ZD-4054 (AstraZeneca)Receptor ZD-4054 (AstraZeneca)
Antagonistenantagonists
Retinsäurerezepto Fenretinid (Johnson & Alitretinoin (Ligand) r-Agonisten Johnson)Retinoic Acid Fenretinide (Johnson & Alitretinoin (Ligand) R-agonist Johnson)
LGD-1550 (Ligand) ImmunInterferon Dexosom-Therapie modulatoren Oncophage (Antigenics) (Anosys)LGD-1550 (ligand) Immune Interferon Dexosome Therapy Modulators Oncophage (Antigenics) (Anosys)
GMK (Progenics) Pentrix (Australian CancerGMK (Progenics) Pentrix (Australian Cancer
Adenokarzinom-Impfstoff Technology)Adenocarcinoma Vaccine Technology)
(Biomira) JSF-154 (Tragen)(Biomira) JSF-154 (Carrying)
CTP-37 (AVI BioPharma) Krebsimpfstoff (Intercell)CTP-37 (AVI BioPharma) cancer vaccine (Intercell)
JRX-2 (Immuno-Rx) Norelin (Biostar)JRX-2 (Immuno-Rx) Norelin (Biostar)
PEP-005 (Peplin Biotech) BLP-25 (Biomira)PEP-005 (Peplin Biotech) BLP-25 (Biomira)
Synchro vax- 1 m pf stoff e MGV (Progenics)Synchro vax- 1 m substance e MGV (Progenics)
(CTL Immuno) !3-Alethin (Dovetail)(CTL Immuno)! 3-Alethine (Dovetail)
Melanom-Impfstoff (CTL CLL-Thera (Vasogen)Melanoma vaccine (CTL CLL-Thera (Vasogen)
Immuno) p21-RAS-lmpfstoffImmuno) p21 RAS vaccine
(GemVax)(GemVax)
Hormonelle und Östrogene Prednison antihormonelle konjugierte Östrogene MethylprednisolonHormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone
Mittel Ethinylöstradiol PrednisolonAgent ethinyl estradiol prednisolone
Chlortrianisen AminoglutethimidChlorotrienes Aminoglutethimide
Idenestrol LeuprolidIdenestrol Leuprolide
Hydroxyprogesteroncaproa Goserelin t LeuporelinHydroxyprogesterone caproa Goserelin t Leuporelin
Medroxyprogesteron BicalutamidMedroxyprogesterone Bicalutamide
Testosteron FlutamidTestosterone Flutamide
Testosteronpropionat OctreotidTestosterone Propionate Octreotide
Fluoxymesteron NilutamidFluoxymesterone nilutamide
Methyltestosteron MitotanMethyltestosterone mitotane
Diethylstilbestrol P-04 (Novogen)Diethylstilbestrol P-04 (Novogen)
Megestrol 2-MethoxyöstradiolMegestrol 2-Methoxyestradiol
Tamoxifen (EntreMed)Tamoxifen (EntreMed)
Toremofin Arzoxifen (EIi Lilly)Toremofin Arzoxifen (EIi Lilly)
Dexamethasondexamethasone
Photodynamische Talaporfin (Light Sciences) Pd-BacteriopheophorbidPhotodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide
Mittel Theralux (Yeda)Central Theralux (Yeda)
(Theratechnologies) Lutetium-Texaphyrin(Theratechnologies) Lutetium Texaphyrin
Motexafin-Gadolinium (Pharmacyclics)Motexafin Gadolinium (Pharmacyclics)
(Pharmacyclics) Hypericin (Pharmacyclics) Hypericin
Maxim) PharmaMar) Maxim) PharmaMar)
Tiazofurin (IMPDH- Rituximab (CD20-Tiazofurin (IMPDH-rituximab (CD20-
Inhibitor, Ribapharm) Antikörper, Genentech)Inhibitor, ribapharm) antibody, Genentech)
Cilengitid (Integrin- Gemtuzumab (CD33-Cilengitide (integrin-gemtuzumab (CD33-
Antagonist, Merck KGaA) Antikörper, Wyeth Ayerst)Antagonist, Merck KGaA) antibodies, Wyeth Ayerst)
SR-31747 (IL-1- PG2 (Hämatopoese-SR-31747 (IL-1 PG2 (hematopoietic)
Antagonist, Sanofi- Verstärker,Antagonist, Sanofi amplifier,
Synthelabo) Pharmagenesis)Synthelabo) Pharmagenesis)
CCI-779 (mTOR-Kinase- Immunol™ (Triclosan-CCI-779 (mTOR kinase Immunol ™ (triclosan)
Inhibitor, Wyeth) Oralspülung, Endo)Inhibitor, Wyeth) Oral Irrigation, Endo)
Exisulind (PDE-V- Triacetyluridin (Uridin-Exisulind (PDE-V-triacetyluridine (uridine)
Inhibitor, Cell Pathways) Prodrug, Wellstat)Inhibitor, cell pathways) prodrug, Wellstat)
10 CP-461 (PDE-V-Inhibitor, SN-4071 (Sarkom-Mittel,10 CP-461 (PDE-V inhibitor, SN-4071 (sarcoma agent,
Cell Pathways) Signature BioScience)Cell Pathways) Signature BioScience)
AG-2037 (GART-Inhibitor, TransMID-107™AG-2037 (GART inhibitor, TransMID-107 ™
Pfizer) (Immunotoxin, KSPfizer) (immunotoxin, KS
WX-UK1 Biomedix)WX-UK1 Biomedix)
(Plasminogenaktivator- PCK-3145 (Apoptose-(Plasminogen activator PCK-3145 (apoptosis
15 Inhibitor, Wilex) Förderer, Procyon)15 inhibitor, Wilex) promoter, Procyon)
PBI-1402 (PMN- Doranidazol (Apoptose-PBI-1402 (PMN-doranidazole (apoptosis)
Stimulans, ProMetic Förderer, PoIa)Stimulant, ProMetic promoter, PoIa)
LifeSciences) CHS-828 (cytotoxischesLifeSciences) CHS-828 (cytotoxic
Bortezomib (Proteasom- Mittel, Leo)Bortezomib (proteasome agent, Leo)
Inhibitor, Millennium) trans-RetinsäureInhibitor, millennium) trans -retinoic acid
SRL-172 (T-ZeII- (Differentiator, NIH)SRL-172 (T-cell (differentiator, NIH)
20 Stimulans, SR Pharma) MX6 (Apoptose-Förderer,20 stimulants, SR Pharma) MX6 (apoptosis promoter,
TLK-286 (Glutathion-S- MAXIA)TLK-286 (glutathione-S-MAXIA)
Transferase-Inhibitor, Apomin (Apoptose-Transferase inhibitor, apomin (apoptosis
Telik) Förderer, ILEX Oncology)Telik) Sponsors, ILEX Oncology)
PT-100 Urocidin (Apoptose-PT-100 urocidin (apoptosis
(Wachstumsfaktor- Förderer, Bioniche)(Growth factor promoter, Bioniche)
Agonist, Point Ro-31-7453 (Apoptose-Agonist, Point Ro-31-7453 (apoptosis
2525
Therapeutics) Förderer, La Roche)Therapeutics) Sponsors, La Roche)
Midostaurin (PKC- Brostallicin (Apoptose-Midostaurin (PKC-brostallicin (apoptosis
Inhibitor, Novartis) Förderer, Pharmacia)Inhibitor, Novartis) promoter, Pharmacia)
Bryostatin-1 (PKC-Bryostatin-1 (PKC
Stimulans, GPC Biotech)Stimulant, GPC Biotech)
CDA-II (Apoptose-CDA-II (apoptosis
30 Förderer, Everlife)30 conveyors, Everlife)
SDX-101 (Apoptose-SDX-101 (apoptosis
Förderer, Salmedix)Conveyor, Salmedix)
Ceflatonin (Apoptose-Ceflatonin (apoptosis
Förderer, ChemGenex)Conveyor, ChemGenex)
35 Eine derartige gemeinsame Behandlung kann mithilfe gleichzeitiger, aufeinander folgender oder getrennter Dosierung der einzelnen Komponenten der Behandlung erzielt werden. Solche Kombinationsprodukte setzen die erfindungsgemäßen Verbindungen ein. 535 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
2. Die vorliegenden Verbindungen der Formel I eignen sich weiterhin als pharmazeutische Wirkstoffe für Säugetiere, insbesondere für den Menschen, bei der Behandlung von SGK-bedingten Krankheiten.2. 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.
1010
Gegenstand der Erfindung ist somit die Verwendung von Verbindungen nach Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allenThe 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
A c Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen eine Rolle spielt. Bevorzugt ist die Verwendung von Verbindungen gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereo-A c conditions for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the signal transduction of kinases plays a role. Preferred is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereo
20 isomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung der SGK durch die Verbindungen nach Anspruch 1 beeinflußt werden.20 isomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of diseases which are affected by inhibition of SGK by the compounds of claim 1.
2525
Die vorliegende Erfindung umfasst die Verwendung der erfindungsgemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zurThe 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
OQ Behandlung oder Vorbeugung von Diabetes (z.B. Diabetes mellitus, diabetische Nephropathie, diabetische Neuropathie, diabetische Angiopathie und Mikroangiopathie), Fettsucht, metabolisches Syndrom (Dyslipidämie), systemische und pulmonale Hypertonie, Herzkreislauferkrankungen (z.B. kardiale Fibrosen nach Myokardinfarkt, Herz- OQ treatment or prevention of diabetes (eg diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiovascular diseases (eg cardiac fibrosis after myocardial infarction, cardiac fibrosis)
35 hypertrophie und Herzinsuffizienz, Arteriosklerose) und Nierenerkrankungen (z.B. Glomerulosklerose, Nephrosklerose, Nephritis, Nephropathie, Störung der Elektrolytausscheidung), allgemein bei jeglicher Art von Fibrosen und entzündlichen Prozessen (z.B. Leberzirrhose, Lungenfibrose, fibrosierende Pankreatitis, Rheumatismus und Arthrosen,35 hypertrophy and heart failure, arteriosclerosis) and kidney diseases (eg glomerulosclerosis, nephrosclerosis, nephritis, Nephropathy, disturbance of elimination of electrolytes), in general for any type of fibrosis and inflammatory processes (eg liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis,
Morbus Crohn, chronische Bronchitis, Strahlenfibrose, Sklerodermitis, 5 zystische Fibrose, Narbenbildung, Morbus Alzheimer). Die erfindungsgemäßen Verbindungen können auch das Wachstum von Krebs, Tumorzellen und Tumormetastasen hemmen und sind deshalb für die Tumortherapie geeignet.Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, 5 cystic fibrosis, scarring, Alzheimer's disease). The compounds according to the invention can also inhibit the growth of cancer, tumor cells and tumor metastases and are therefore suitable for tumor therapy.
10 Die erfindungsgemäßen Verbindungen finden weiterhin Verwendung zur Behandlung von Koagulopathien, wie z.B. Dysfibrinogenämie, Hypopro- konvertinämie, Hämophilie B, Stuart-Prower-Defekt, Prothrombin- Komplex-Mangel, Verbrauchskoagulopathie, Hyperfibrinolyse, Immuno-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-
^ c koagulopathie oder komplexer Koagulopathien, wie auch bei neuronaler Erregbarkeit, z.B. Epilepsie. Die erfindungsgemäßen Verbindungen können auch bei der Behandlung eines Glaukoms oder Katarakt therapeutisch eingesetzt werden.^ 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.
Die erfindungsgemäßen Verbindungen finden ferner Verwendung bei derThe compounds of the invention are also used in the
2020
Behandlung bakterieller Infektionen sowie in einer antiinfektiösenTreatment of bacterial infections as well as in an anti-infective
Therapie. Die erfindungsgemäßen Verbindungen können auch zur Steigerung der Lernfähigkeit und Aufmerksamkeit therapeutisch eingesetzt werden.Therapy. The compounds of the invention may also be used therapeutically to increase learning and attention.
2525
Bevorzugt ist die Verwendung von Verbindungen gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zurPreferred is the use of compounds according to claim 1, as well as their pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, to
OQ Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von O Q Preparation of a medicament for the treatment or prevention of
Diabetes, Fettsucht, metabolischem Syndrom (Dyslipidämie), systemischer und pulmonaler Hypertonie, Herzkreislauferkrankungen und Nierenerkrankungen, allgemein bei jeglicher Art von Fibrosen und entzündlichenDiabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertension, cardiovascular diseases and kidney disease, common to all types of fibrosis and inflammatory
Prozessen, Krebs, Tumorzellen, Tumormetastasen, Koagulopathien,Processes, cancer, tumor cells, tumor metastases, coagulopathies,
35 neuronaler Erregbarkeit, Glaukom, Katarakt, bakteriellen Infektionen sowie in einer antiinfektiösen Therapie, zur Steigerung der Lernfähigkeit und Aufmerksamkeit, sowie zur Behandlung und Prophylaxe von Zellalterung und Stress.35 neuronal excitability, glaucoma, cataracts, bacterial infections as well as in an anti-infective therapy, to increase the ability to learn and Attention, as well as for the treatment and prophylaxis of cell aging and stress.
Bei Diabetes handelt es sich vorzugsweise um Diabetes mellitus, diabetische Nephropathie, diabetische Neuropathie, diabetische Angiopathie und Mikroangiopathie.Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
Bei Herzkreislauferkrankungen handelt es sich vorzugsweise um kardiale Fibrosen nach Myokardinfarkt, Herzhypertrophie, Herzinsuffizienz und Arteriosklerose.Cardiovascular diseases are preferably cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
Bei Nierenerkrankungen handelt es sich vorzugsweise um Glomerulosklerose, Nephrosklerose, Nephritis, Nephropathie und Störung derRenal diseases are preferably glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and disorder of the
Elektrolytausscheidung.Electrolyte excretion.
Bei Fibrosen und entzündlichen Prozessen handelt es sich vorzugsweise um Leberzirrhose, Lungenfibrose, fibrosierende Pankreatitis,Fibrosis and inflammatory processes are preferably liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis,
Rheumatismus und Arthrosen, Morbus Crohn, chronische Bronchitis,Rheumatism and arthritis, Crohn's disease, chronic bronchitis,
Strahlenfibrose, Sklerodermitis, zystische Fibrose, Narbenbildung, MorbusRadiation fibrosis, sclerodermatitis, cystic fibrosis, scarring, morbus
Alzheimer.Alzheimer.
ASSAYSASSAYS
Die in den Beispielen beschriebenen Verbindungen der Formel I können in den unten beschriebenen Assays auf eine kinasehemmende Wirkung geprüft werden. Weitere Assays sind aus der Literatur bekannt und können vom Fachmann leicht durchgeführt werden (siehe z.B. Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem. 274:9116-9121 ; Sheu et al., Anticancer Res. 18:4435-4441 ; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al, In Vitro 18:538- 549). Messung der CHK1 KinaseaktivitätThe compounds of the formula I described in the examples can be tested for kinase-inhibiting activity in the assays described below. Other assays are known in the literature and can be readily performed by those skilled in the art (see, eg, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et Biol. 38: 237-248; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427; Nicosia et al., In., Anticancer Res. 18: 4435-4441; Ausprunk et al., Dev Vitro 18: 538-549). Measurement of CHK1 kinase activity
Die CHK1 Kinase wird zum Zweck der Proteinproduktion in Insektenzellen 5 (Sf21 ; S. frugiperda) und der anschließenden affinitätschromato- graphischen Aufreinigung als Fusionsprotein mit Glutathion S-Transferase in einem Baculovirus-Expressionsvektor exprimiert. Die Kultivierung, Infektion und der Aufschluss der Zellen, sowie die säulenchromato- graphische Aufreinigung des Fusionsproteins erfolgen entsprechend Hersteller-orientierter generischer Arbeitsanweisungen.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.
Zur Messung der Kinase-Aktivität wird auf verschiedene zur Verfügung stehender Meßsysteme zurückgegriffen. Beim Scintillation-Proximity- (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19), dem FlashPlate- 15To measure the kinase activity, reference is made to various available measuring systems. In Scintillation Proximity (Sorg et al., J. of Biomolecular Screening, 2002, 7, 11-19), the FlashPlate 15
Verfahren oder dem Filterbindungstest wird die radioaktive Phosphorylierung eines Proteins oder Peptids als Substrat mit radioaktiv markiertem ATP (γ32P-ATP, (γ33P-ATP) gemessen. Bei Vorliegen einer inhibitorischen Verbindung ist kein oder ein vermindertes radioaktives SignalMethod or the filter binding assay is the radioactive phosphorylation of a protein or peptide as a substrate with radioactively labeled ATP (γ 32 P-ATP, (γ 33 P-ATP) measured.) In the presence of an inhibitory compound is no or a reduced radioactive signal
20 nachweisbar. Ferner sind die Homogeneous Time-resolved Fluorescence20 detectable. Furthermore, the Homogeneous Time-resolved fluorescence
Resonance Energy Transfer- (HTR-FRET-) und Fluoreszenzpolarisations- (FP-) Technologien als Assay-Verfahren nützlich (SiIIs et al., J. of Biomolecular Screening, 2002, 191-214).Resonance Energy Transfer (HTR-FRET) and fluorescence polarization (FP) technologies are useful as assay methods (SiIIs et al., J. of Biomolecular Screening, 2002, 191-214).
Andere nicht radioaktive ELISA-Assay-Verfahren verwenden spezifische Phospho-Antikörper (Phospho-AK). Der Phospho-Antikörper bindet nur das phosphorylierte Substrat. Diese Bindung ist mit einem zweiten Peroxidase-konjugierten Antikörper durch Chemilumineszenz nachweis- 30 bar (Ross et al., 2002, Biochem. J.).Other non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK). The 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.).
Flashplate-Verfahren (CHKD:Flashplate procedure (CHKD:
Als Testplatten dienen 384-well Streptavidin-beschichtete FlashplatesThe test plates are 384-well streptavidin-coated flashplates
PlusR der Firma Perkin Eimer (Cat.No. SMP410A001 PK). Die Assay PlattePlus R from Perkin Elmer (Cat.No. SMP410A001 PK). The assay plate
Ob wird 30 min vor Versuchsbeginn mit je 75 μl Assay-Puffer pro well equilibriert. Der Puffer wird vor Versuchsbeginn abgesaugt und die Komponenten der unten beschriebenen Kinasereaktion werden auf die Platte pipettiert. Die CHK1 Kinase, ein biotinyliertes Substratpeptid (z. Bsp. CHKtide: KKKVSRSGLYRSPSMPENLNRPR) wird mit radioaktiv markiertem ATP inWhether it is 30 min before the start of the experiment with 75 ul each assay buffer per well equilibrated. The buffer is aspirated before starting the experiment and the components of the kinase reaction described below are pipetted onto the plate. The CHK1 kinase, a biotinylated substrate peptide (eg CHKtide: KKKVSRSGLYRSPSMPENLNRPR), is labeled with radiolabeled ATP in
An- und Abwesenheit von Testsubstanzen bei 30° Celsius und einem Gesamtvolumen von 50 μl inkubiert. Die Reaktion wird mit 25μl einer 0,2 M EDTA-Lösung abgestoppt. Nach Inkubation für 30 min bei Raum- temperatur werden die Überstände abgesaugt und die wells dreimal mit je 100 μl 0,9% NaCI-Lösung gewaschen. Die Messung der gebundenen Radioaktivität erfolgt mittels eines Szintillationsmessgerätes (Topcount NXT, Fa. Perkin-Elmer). Als Vollwert wird die Inhibitor-freie Kinasereaktion verwendet. Dieser sollte ca. im Bereich von 3000-4000 cpm liegen. Als pharmakologischer Nullwert wird Staurosporin in einer Endkonzentration von 0,1 μM verwendet. Eine Bestimmung der Hemmwerte (IC50) erfolgt unter Verwendung desPresence and absence of test substances incubated at 30 ° C and a total volume of 50 ul. The reaction is stopped with 25 μl 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 μl 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 μM. A determination of the inhibition values (IC50) is carried out using the
Programms RS1_MTS ().Program RS1_MTS ().
Kinase-Reaktionsbedingungen pro well: 5-20 mU CHK1 KinaseKinase reaction conditions per well: 5-20 mU CHK1 kinase
0,15 μg CHKtide (KKKVSRSGLYRSPSMPENLNRPR) 8 μM ATP, kalt 0,2 μCi γ33P-ATP 50 μl Gesamtvolumen (1-fach Assaypuffer-Reaktionsbedingungen)0.15 μg CHKtide (KKKVSRSGLYRSPSMPENLNRPR) 8 μM ATP, cold 0.2 μCi γ 33 P-ATP 50 μl total volume (1-fold assay buffer reaction conditions)
Verwendete Lösungen: - Assay-Puffer: 50 mM Tris 0,1 mM Titriplex VI (EGTASolutions used: Assay buffer: 50 mM Tris 0.1 mM Titriplex VI (EGTA
10 mM Magnesiumacetat10 mM magnesium acetate
0,1 % Mercaptoethanol 0,02% Brij35 pH= 7,5 (einzustellen mit Salzsäure)0.1% mercaptoethanol 0.02% Brij35 pH = 7.5 (to be adjusted with hydrochloric acid)
Die Zugabe von Rinderserumalbumin (Endkonzentration 0,1 %) erfolgt erst kurz vor Verwendung.The addition of bovine serum albumin (final concentration 0.1%) takes place shortly before use.
- Stopp-Lösung:- Stop solution:
0,2 M Titriplexlll (EDTA)0.2 M Titriplex III (EDTA)
. γ33P-ATP (Perkin-Elmer), γ 33 P-ATP (Perkin-Elmer)
- CHK1 Kinasepräparationen: spezifische Aktivität > 50 U/mg- CHK1 kinase preparations: specific activity> 50 U / mg
- CHKtide-Lösung: biotinyliertes Peptidsubstrat (Firma Biotrend) als Stocklösung (Konzentration 0,15 mg/ml) aufbewahrt.- CHKtide solution: biotinylated peptide substrate (Biotrend) stored as stock solution (concentration 0.15 mg / ml).
Filterbindunqs- Verfahren (CHK1):Filter binding method (CHK1):
5-20 mU CHK1 Kinase (verdünnt in 20 mM MOPS pH7.5, 1 mM EDTA,5-20 mU CHK1 kinase (diluted in 20 mM MOPS pH 7.5, 1 mM EDTA,
0,1% ß-Mercaptoethanol, 0,01% Brij-35, 5% Glyzerin, 1 mg/ml BSA) werden in Gegenwart von 30-200 μM CHKtide in 25,5 μl in 1-fach0.1% β-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg / ml BSA) are incubated in the presence of 30-200 μM CHKtide in 25.5 μl in 1-fold
Reaktionspuffer (8 mM MOPS pH7, 0,2 mM EDTA, 10 mM Magnesiumacetat, 0,02 mM γ33P-ATP [500-1000 cpm/pmol]) für 30 min bei Raumtemperatur inkubiert. Die Reaktion wird mit 5 μl 0,5 M ortho- Phosphorsäure gestoppt und durch P81 Filterplatten filtriert. Nach mehrmaligem Waschen der Filterplatten erfolgt die Bestimmung der gebundenen Radioaktivität im Szintillationszähler.Reaction buffer (8 mM MOPS pH7, 0.2 mM EDTA, 10 mM magnesium acetate, 0.02 mM γ 33 P-ATP [500-1000 cpm / pmol]) for 30 min at room temperature. The reaction is stopped with 5 μl 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.
Messung der CHK2 KinaseaktivitätMeasurement of CHK2 kinase activity
Filterbindunqs-Verfahren (CHK2):Filter binding method (CHK2):
5-20 mU CHK2 Kinase (verdünnt in 20 mM MOPS pH7.5, 1 mM EDTA, 0,1% ß-Mercaptoethanol, 0,01 % Brij-35, 5% Glyzerin, 1 mg/ml BSA) werden in Gegenwart von 30-200 μM CHKtide5-20 mU CHK2 kinase (diluted in 20 mM MOPS pH 7.5, 1 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg / ml BSA) are added in the presence of 30-200 μM CHKtide
(KKKVSRSGLYRSPSMPENLNRPR) in 25,5 μl in 1-fach Reaktionspuffer (8 mM MOPS pH7, 0,2 mM EDTA, 10 mM Magnesiumacetat, 0,02 mM Y33P-ATP [500-1000 cpm/pmol]) für 30 min bei Raumtemperatur inkubiert. Die Reaktion wird mit 5 μl 0,5 M ortho-Phosphorsäure gestoppt und durch(KKKVSRSGLYRSPSMPENLNRPR) in 25.5 μl in 1-fold reaction buffer (8 mM MOPS pH 7, 0.2 mM EDTA, 10 mM magnesium acetate, 0.02 mM Y 33 P-ATP [500-1000 cpm / pmol]) for 30 min at room temperature. The reaction is stopped with 5 μl of 0.5 M ortho-phosphoric acid and passed through
P81 Filterplatten filtriert. Nach mehrmaligem Waschen der Filterplatten erfolgt die Bestimmung der gebundenen Radioaktivität im Szintillations- zähler.Filtered P81 filter plates. After repeated washing of the filter plates, the determination of the bound radioactivity is carried out in the scintillation counter.
Die Hemmung der SGK1 Proteinkinase kann im Filterbindungsverfahren (analog zu CHK1 , CHK2) bestimmt werden.The inhibition of SGK1 protein kinase can be determined in the filter binding method (analogous to CHK1, CHK2).
Vor- und nachstehend sind alle Temperaturen in 0C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie anAbove and below all temperatures are given in 0 C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography
Kieselgel und /oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel:Silica gel and / or by crystallization. Rf values on silica gel; Eluent:
Ethylacetat/Methanol 9:1.Ethyl acetate / methanol 9: 1.
Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ ESI (Electrospray lonization) (M+H)+ APCI-MS (atmospheric pressure chemical ionization - mass spectrometry)FAB (Fast Atom Bombardment) (M + H) + ESI (Electrospray Ionization) (M + H) + APCI-MS (atmospheric pressure chemical ionization - mass spectrometry)
(M+H)+.(M + H) + .
Beispiel 1example 1
Die Herstellung von 3-(1/-/-Benzimidazol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion ("A1 ") erfolgt analog nachstehendem Schema The preparation of 3- (1 / - / - benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-en-1, 2-dione ("A1") is carried out analogously to the following scheme
1.1 6,2 g (35,7 mmol) 3,4-Diethoxy-3-cyclobuten-1 ,2-dion 1 werden in 50 ml_ Ethanol gelöst, mit 5,0 g (35,7 mmol) 3H-Benzimidazol-5-ylamin 2 versetzt und 20 h bei 75°C gerührt. Danach arbeitet man wie üblich auf und so erhält man 8,93 g (97%) 3-(1H-Benzimidazol-5-ylamino)-4-ethoxy- cyclobut-3-en-1 ,2-dion 3; MS-FAB (M+H+) = 358, F. 243-244°.1.1 6.2 g (35.7 mmol) of 3,4-diethoxy-3-cyclobutene-1, 2-dione 1 are dissolved in 50 ml of ethanol, with 5.0 g (35.7 mmol) of 3H-benzimidazole-5 -ylamine 2 and stirred at 75 ° C for 20 h. Thereafter, the usual procedure to give 8.93 g (97%) of 3- (1H-benzimidazol-5-ylamino) -4-ethoxy-cyclobut-3-en-1, 2-dione 3; MS-FAB (M + H + ) = 358, m. 243-244 °.
1.2 200 mg (0,78 mmol) 3 werden in 5 ml_ Ethanol gelöst, mit 287,1 mg (2,33 mmol) 3-Aminomethyl-phenol versetzt und 48 h bei 75°C gerührt. Danach arbeitet man wie üblich auf und so erhält man 230 mg (88%) 3- (1/-/-Benzimidazol-5-ylamino)-4-(3-hydroxy-benzylamino)-cyclobut-3-en- 1 ,2-dion ("AT); MS-FAB (M+H+) = 335.1.2 200 mg (0.78 mmol) of 3 are dissolved in 5 ml of ethanol, treated with 287.1 mg (2.33 mmol) of 3-aminomethyl-phenol and stirred at 75 ° C for 48 h. Thereafter, the reaction is carried out as usual and 230 mg (88%) of 3- (1 / - / - benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene 1, 2 are obtained -dione ("AT); MS-FAB (M + H + ) = 335.
Analog Beispiel 1 erhält man die nachstehenden VerbindungenAnalogously to Example 1, the following compounds are obtained
- - - -
- - - -
- - - -
"A42" 3-(2,3-Dihydro-1H-indol-6-ylamino)-4-(3- 336 hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion"A42" 3- (2,3-Dihydro-1H-indol-6-ylamino) -4- (3-336-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A43" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3,4-difluor- 355 benzylamino)-cyclobut-3-en-1 ,2-dion"A43" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3,4-difluoro-355-benzylamino) -cyclobut-3-en-1,2-dione
"A44" 3-(1H-Benzimidazol-5-ylamino)-4-[3- 412 (methylaminosulfonyl)-benzylamino]- cyclobut-3-en-1 ,2-dion"A44" 3- (1H-Benzimidazol-5-ylamino) -4- [3-412 (methylaminosulfonyl) benzylamino] -cyclobut-3-ene-1,2-dione
"A45" 3-(1 H-Benzimidazol-5-ylamino)-4-(3- 376 acetamido-benzylaminoJ-cyclobut-S-en-i ,2- dion"A45" 3- (1H-Benzimidazol-5-ylamino) -4- (3-376 acetamidobenzylamino) -cyclobut-S-en-i, 2-dione
"A46" 3-(3-Oxo-2,3-dihydro-1H-indazol-5-ylamino)-"A46" 3- (3-oxo-2,3-dihydro-1H-indazol-5-ylamino) -
4-(3-hydroxy-benzylamino)-cyclobut-3-en-4- (3-hydroxy-benzylamino) -cyclobut-3-ene
1 ,2-dion1, 2-dione
"A47" 3-(9-Ethyl-9H-carbazol-3-ylamino)-4-(3- 412 hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion"A47" 3- (9-Ethyl-9H-carbazol-3-ylamino) -4- (3-412-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A48" 3-(2,3-Dihydro-benzo[c/]imidazo[2,1-b]thiazol- 6-ylamino)-4-(3-hydroxy-benzylamino)- cyclobut-3-en-1 ,2-dion -7 -"A48" 3- (2,3-dihydrobenzo [c /] imidazo [2,1-b] thiazol-6-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1, 2-dione -7 -
- - - -
- - - -
- 0 - - 0 -
"A95" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3-amino- 362 carbonyl-benzylamino)-cyclobut-3-en-1 ,2- dion"A95" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3-amino-362-carbonyl-benzylamino) -cyclobut-3-ene-1, 2-dione
"A96" 3-(1H-Benzimidazol-5-ylamino)-4-[(3- 415 dimethylaminomethyl-1H-indol-6-ylmethyl)- amino]-cyclobut-3-en-1 ,2-dion"A96" 3- (1H-Benzimidazol-5-ylamino) -4 - [(3-415 dimethylaminomethyl-1H-indol-6-ylmethyl) -amino] -cyclobut-3-ene-1,2-dione
"A97" 3-(1H-Benzimidazol-5-ylamino)-4-(3-hydroxy- 349 2-methyl-benzylamino)-cyclobut-3-en-1 ,2- dion"A97" 3- (1H-Benzimidazol-5-ylamino) -4- (3-hydroxy-349 2-methylbenzylamino) -cyclobut-3-en-1, 2-dione
"A98" 3-(3-Hydroxy-benzylamino)-4-(2-methyl- 366 benzothiazol-5-ylamino)-cyclobut-3-en-1 ,2- dion"A98" 3- (3-Hydroxybenzylamino) -4- (2-methyl-366benzothiazol-5-ylamino) -cyclobut-3-en-1, 2-dione
"A99" 3-[2-(1H-Benzimidazol-5-ylamino)-3,4-dioxo- 393 cyclobut-1-enylamino]-3-(3-hydroxy-phenyl)- propionsäure"A99" 3- [2- (1H-Benzimidazol-5-ylamino) -3,4-dioxo-393-cyclobut-1-enylamino] -3- (3-hydroxy-phenyl) -propionic acid
"A100" 3-[2-(1H-Benzimidazol-5-ylamino)-3,4-dioxo- 421 cyclobut-1-enylamino]-3-(3-hydroxy-phenyl)- propionsäure-ethylester"A100" 3- [2- (1H-Benzimidazol-5-ylamino) -3,4-dioxo-421-cyclobut-1-enylamino] -3- (3-hydroxy-phenyl) - propionate
"A101" 3-[2-(1/-/-Benzimidazol-5-ylamino)-3,4-dioxo- 407 cyclobut-1-enylamino]-3-(3-hydroxy-phenyl)- propionsäure-methylester"A101" 3- [2- (1 / - / - Benzimidazol-5-ylamino) -3,4-dioxo-407-cyclobut-1-enylamino] -3- (3-hydroxyphenyl) propionic acid methyl ester
"A102" 3-(1H-Benzimidazol-5-ylamino)-4-[(3-pyridin- 435"A102" 3- (1H-Benzimidazol-5-ylamino) -4 - [(3-pyridine-435
4-yl-1H-indol-5-ylmethyl)-amino]-cyclobut-3- en-1 ,2-dion4-yl-1H-indol-5-ylmethyl) -amino] -cyclobut-3-ene-1,2-dione
nA103" 3-(1H-Benzimidazol-5-ylamino)-4-(2-fluor-3- 353 hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion n A103 "3- (1H-Benzimidazol-5-ylamino) -4- (2-fluoro-3-353-hydroxy-benzylamino) -cyclobut-3-en-1,2-dione
"A104" 3-(1H-Benzimidazol-5-ylamino)-4-(3-ethoxy- 363 benzylamino)-cyclobut-3-en-1 ,2-dion"A104" 3- (1H-Benzimidazol-5-ylamino) -4- (3-ethoxy-363-benzylamino) -cyclobut-3-ene-1,2-dione
"A105" 3-(1 H-Benzimidazol-5-ylamino)-4-[1 -(3- 462 hydroxy-phenyl)-3-morpholin-4-yl-3-oxo- propylamino]-cyclobut-3-en-1 ,2-dion"A105" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (3-462-hydroxy-phenyl) -3-morpholin-4-yl-3-oxo-propylamino] -cyclobut-3-ene -1, 2-dione
"A106" 3-(1H-Benzimidazol-5-ylamino)-4-[3-(2- 393 methoxy-ethoxy)-benzylamino]-cyclobut-3- en-1 ,2-dion methylsulfonylamino-ethoxy)-benzylamino]- cyclobut-3-en-1 ,2-dion"A106" 3- (1H-Benzimidazol-5-ylamino) -4- [3- (2-393-methoxy-ethoxy) -benzylamino] -cyclobut-3-ene-1,2-dione methylsulfonylamino-ethoxy) -benzylamino] - cyclobut-3-ene-1,2-dione
"A1 1 1 " 3-(4-Butyl-1H-benzimidazol-5-ylamino)-4-(3- 391 hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion"A1 1 1" 3- (4-Butyl-1H-benzimidazol-5-ylamino) -4- (3-391-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A112" 3-(1 H-Benzimidazol-5-ylamino)-4-[1 -(3- 461 hydroxy-phenyl)-3-oxo-3-piperazin-1-yl- propylamino]-cyclobut-3-en-1 ,2-dion"A112" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (3-hydroxyphenyl) -3-oxo-3-piperazin-1-yl-propylamino] -cyclobut-3-ene -1, 2-dione
"A113" 3-[2-(1H-Benzimidazol-5-ylamino)-3,4-dioxo- 463 cyclobut-1-enylamino]-N-(2-dimethylamino- ethyl)-3-(3-hydroxy-phenyl)-propionamid"A113" 3- [2- (1H-Benzimidazol-5-ylamino) -3,4-dioxo-463-cyclobut-1-enylamino] -N- (2-dimethylamino-ethyl) -3- (3-hydroxy-phenyl ) propionamide
"A114" 3-(1H-Benzimidazol-5-ylamino)-4-[(R)-1-(3- 377 methoxy-phenyl)-propylamino]-cyclobut-3-en-"A114" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-37,7-methoxyphenyl) -propylamino] -cyclobut-3-ene
1 ,2-dion 1, 2-dione
- - - -
hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion hydroxy-benzylamino) -cyclobut-3-ene-1,2-dione
"A137" 3-(1 /-/-Benzimidazol-5-ylamino)-4-[(1 H-indol- 358 6-ylmethyl)-amino]-cyclobut-3-en-1 ,2-dion"A137" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(1H-indol-358 6-ylmethyl) -amino] -cyclobut-3-ene-1,2-dione
"A138" 3-(1H-Benzimidazol-5-ylamino)-4-[3- 463 [1 ,3]dioxan-2-yl-1 -(3-methoxy-phenyl)- propylamino]-cyclobut-3-en-1 ,2-dion"A138" 3- (1H-Benzimidazol-5-ylamino) -4- [3-463 [1, 3] dioxan-2-yl-1 - (3-methoxy-phenyl) -propylamino] -cyclobut-3-ene -1, 2-dione
"A139" 3-(1Ay-Benzimidazol-5-ylamino)-4-(4-hydroxy- 335 benzylamino)-cyclobut-3-en-1 ,2-dion"A139" 3- (1-yl-benzimidazol-5-ylamino) -4- (4-hydroxy-335-benzylamino) -cyclobut-3-ene-1,2-dione
"A140" 3-(1/-/-Benzimidazol-5-ylamino)-4-[2-(4- 349 hydroxy-phenyl)-ethylamino]-cyclobut-3-en- 1 ,2-dion"A140" 3- (1 / - / - Benzimidazol-5-ylamino) -4- [2- (4-hydroxypropyl) -ethylamino] -cyclobut-3-ene-1, 2-dione
"A141" 3-(1/V-Benzimidazol-5-ylamino)-4-[4-(4- 417 methyl-piperazin-1-yl)-benzylamino]-cyclobut- 3-en-1 ,2-dion"A141" 3- (1 / V-Benzimidazol-5-ylamino) -4- [4- (4-417methylpiperazin-1-yl) -benzylamino] -cyclobut-3-ene-1,2-dione
"A142" 3-(1H-Benzimidazol-5-ylamino)-4-[2-(3- 349 hydroxy-phenyl)-ethylamino]-cyclobut-3-en- 1 ,2-dion"A142" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (3-349-hydroxyphenyl) ethylamino] -cyclobut-3-ene-1,2-dione
"A143" 3-(1H-Benzimidazol-5-ylamino)-4-[2-(2- 363 methoxy-phenyl)-ethylamino]-cyclobut-3-en- 1 ,2-dion"A143" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (2-363-methoxyphenyl) -ethylamino] -cyclobut-3-ene 1, 2-dione
"A144" 3-(1H-Benzimidazol-5-ylamino)-4-(2- 349 methoxy-benzylamino)-cyclobut-3-en-1 ,2- dion"A144" 3- (1H-Benzimidazol-5-ylamino) -4- (2, 349methoxybenzylamino) -cyclobut-3-en-1, 2-dione
"A145" 3-(1 H-lndazol-5-ylamino)-4-[(R,S)-1 -(3- 391 ureido-phenyl)-ethylamino]-cyclobut-3-en-"A145" 3- (1H-indazol-5-ylamino) -4 - [(R, S) -1 - (3-391ureido-phenyl) -ethylamino] -cyclobut-3-ene
1 ,2-dion1, 2-dione
"A146" 3-(1 H-Benzimidazol-5-ylamino)-4-[2-(1 -tert.- 518 butyloxycarbonyl-piperidin-4-yloxy)-benzyl- amino]-cyclobut-3-en-1 ,2-dion"A146" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (1-tert-518-butyloxycarbonyl-piperidin-4-yloxy) -benzyl-amino] -cyclobut-3-en-1, 2-dione
"A147" 3-(1H-Benzimidazol-5-ylamino)-4-(4- 362 dimethylamino-benzylamino)-cyclobut-3-en- 1 ,2-dion"A147" 3- (1H-Benzimidazol-5-ylamino) -4- (4-362 dimethylaminobenzylamino) -cyclobut-3-ene-1,2-dione
"A148" 3-(1 H-Benzimidazol-5-ylamino)-4-[2- 418 (piperidin-4-yloxy)-benzylamino]-cyclobut-3- en-1 ,2-dion"A148" 3- (1H-Benzimidazol-5-ylamino) -4- [2-4- (piperidin-4-yloxy) -benzylamino] -cyclobut-3-ene-1,2-dione
"A149" 3-(1 H-Benzimidazol-5-ylamino)-4-[2-(2- 349 hydroxy-phenyl)-ethylamino]-cyclobut-3-en- "A149" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (2-349-hydroxyphenyl) -ethylamino] -cyclobut-3-ene
"A159" 3-(1H-Benzimidazol-5-ylamino)-4-(4-amino- 362 carbonyl-benzylaminoJ-cyclobut-S-en-i ^- dion "A159" 3- (1H-Benzimidazol-5-ylamino) -4- (4-amino-362-carbonyl-benzylamino) -cyclobut-S-ene-1-dione
"A160" 3-(1/-/-Benzimidazol-5-ylamino)-4-[(2-oxo- 376 2,3-dihydro-benzoxazol-5-ylmethyl)-amino]- cyclobut-3-en-1 ,2-dion"A160" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(2-oxo-376 2,3-dihydro-benzoxazol-5-ylmethyl) -amino] -cyclobut-3-ene-1 , 2-dione
"A161" 3-(1 H-Benzimidazol-5-ylamino)-4-[3-(1- 453 hydroxy-2-p-tolyl-ethyl)-benzylamino]- cyclobut-3-en-1 ,2-dion"A161" 3- (1H-Benzimidazol-5-ylamino) -4- [3- (1-453-Hydroxy-2-p-tolyl-ethyl) -benzylamino] -cyclobut-3-ene-1,2-dione
"A162" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3,4- 387 dichlor-benzylamino)-cyclobut-3-en-1 ,2-dion"A162" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3,4-387 dichlorobenzylamino) -cyclobut-3-ene-1,2-dione
"A163" 3-(1/-/-Benzimidazol-5-ylamino)-4-[(3-oxo- 387 3,4-dihydro-chinoxalin-6-ylmethyl)-amino]- cyclobut-3-en-1 ,2-dion"A163" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(3-oxo-387 3,4-dihydro-quinoxalin-6-ylmethyl) -amino] -cyclobut-3-ene-1 , 2-dione
"A164" 3-(3H-Benzimidazol-5-ylamino)-4-(3- 385 difluormethoxy-benzylamino)-cyclobut-3-en- 1 ,2-dion"A164" 3- (3H-Benzimidazol-5-ylamino) -4- (3-385 difluoromethoxybenzylamino) -cyclobut-3-ene 1, 2-dione
"A165" 3-(3H-Benzimidazol-5-ylamino)-4-(3,5- 379 dimethoxy-benzylamino)-cyclobut-3-en-1 ,2- dion"A165" 3- (3H-Benzimidazol-5-ylamino) -4- (3,5,379-dimethoxybenzylamino) -cyclobut-3-ene-1, 2-dione
"A166" 3-(3/-/-Benzimidazol-5-ylamino)-4-(3- 403 trifIuormethoxy-benzylamino)-cyclobut-3-en- 1 ,2-dion"A166" 3- (3 / - / - Benzimidazol-5-ylamino) -4- (3-403 trifluoromethoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A167" 3-[3-(2-Diethylamino-ethyl)-3H-benzimidazol- 486 5-ylamino]-4-[4-(1H-tetrazol-5-yl)- benzylamino]-cyclobut-3-en-1 ,2-dion"A167" 3- [3- (2-diethylamino-ethyl) -3H-benzimidazole-486 5-ylamino] -4- [4- (1H-tetrazol-5-yl) -benzylamino] -cyclobut-3-ene 1, 2-dione
"A168" 3-[1 -(2-Diethylamino-ethyl)-1 /-/-benzimidazol- 462 5-ylamino]-4-[(R)-1-(3-methoxy-phenyl)- ethylamino]-cyclobut-3-en-1 ,2-dion"A168" 3- [1- (2-Diethylamino-ethyl) -1 / - / - benzimidazole-462 5-ylamino] -4 - [(R) -1- (3-methoxy-phenyl) -ethylamino] -cyclobut -3-en-1, 2-dione
"A169" 3-(3-Hydroxy-benzylamino)-4-(3H- 336 imidazo[4,5-jt)]pyridin-5-ylamino)-cyclobut-3- en-1 ,2-dion "A169" 3- (3-Hydroxy-benzylamino) -4- (3H-336-imidazo [4,5-yl] -pyridin-5-ylamino) -cyclobut-3-ene-1,2-dione
Pharmakologische DatenPharmacological data
Affinität zu Rezeptoren Tabelle 1Affinity to receptors Table 1
- - - -
+ IC50 >1μM+ IC 50 > 1μM
++ IC50 < 1μM++ IC 50 <1μM
+++ IC50 <100nM Die nachfolgenden Beispiele betreffen Arzneimittel:+++ IC 50 <100nM The following examples relate to drugs:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 N SaIz- säure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: Solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel D: SalbeExample D: Ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen. Beispiel E: Tabletten500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. Example E: Tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I1 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel F: DrageesExample F: dragees
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.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.
Beispiel G: KapselnExample G: Capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active compound of the formula I are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: Ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

Patentansprüche claims
1. Verbindungen der Formel I1. Compounds of the formula I
worin R wherein R
(CH2)m (CH 2 ) m
X (CH2Jn, CHA, NH1 NA , __\ /__ ,X (CH 2 J n , CHA, NH 1 NA, __ \ / __,
C CH-(CH2)n-COOH, CH-(CH2)n-COOA,C is CH- (CH 2 ) n -COOH, CH- (CH 2 ) n -COOA,
CH-(CH2)n-CO-Het2, CH-(CH2)n-Het2,CH- (CH 2 ) n -CO-Het 2 , CH- (CH 2 ) n -Het 2 ,
CH-CH2-CONH-(CH2)1-4-NH2l CH-CH 2 -CONH- (CH 2 ) 1-4 -NH 2l
CH-CH2-CONH-(CH2)i-4-NHA, CH-CH2-CONH-(CH2)1-4-NA2,CH-CH 2 -CONH- (CH 2 ) i- 4 -NHA, CH-CH 2 -CONH- (CH 2 ) 1-4 -NA 2 ,
CH-CH2-CONH-(CH2)L4-OH oderCH-CH 2 -CONH- (CH 2 ) L 4 -OH or
CH-CH2-CONH-(CH2)L4-OA,CH-CH 2 -CONH- (CH 2 ) L 4 -OA,
XI (CHz)n.X I (CHz) n .
R1, R1 jeweils unabhängig voneinander H, A1 HaI1 -CO-A, CN1 COOH, COOA, CONH2, NH2, NHA oder NAA1,R 1 , R 1 are each independently H, A 1 Hal 1 -CO-A, CN 1 COOH, COOA, CONH 2 , NH 2 , NHA or NAA 1 ,
R2, R2', R2",R 2 , R 2 ' , R 2 " ,
R2 , R2 jeweils unabhängig voneinander H1 OH, OA, NH2, NHA, NAA1, HaI, A, CONH2, CONHA1 CONAA1, CONHAr1 CONHHet, SO2NH2, SO2NHA, SO2NAA1, SO2NHAr,R 2 , R 2 are each independently H 1 OH, OA, NH 2 , NHA, NAA 1 , Hal, A, CONH 2 , CONHA 1 CONAA 1 , CONHAr 1 CONHHet, SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , SO 2 NHAr,
SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA, NHCOAr, NHCOHet, -O(CH2)POH, -O(CH2)POA, -O(CH2)pNH2, -O(CH2)PNHA, -0(CH2)PNAA1, -O(CH2)PNH-COA, -O(CH2)PNHSO2A, -B(OH)2,SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA, NHCOAr, NHCOHet, -O (CH 2 ) P OH, -O (CH 2 ) P OA, -O (CH 2 ) pNH 2 , O (CH 2 ) p NHA, -O (CH 2 ) p NAA 1 , -O (CH 2 ) p NH-COA, -O (CH 2 ) p NHSO 2 A, -B (OH) 2 ,
NHCOOA, COOH, COOH1 SO2A, NHCHO, NHCONH2, -CH(OH)-CH2Ar, Het,NHCOOA, COOH, COOH 1 SO 2 A, NHCHO, NHCONH 2 , -CH (OH) -CH 2 Ar, Het,
zwei benachbarte Reste ausgewählt aus R2, R2 , R2 , R2 , R2 zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -N=CR7-NH, -NH-CO-O-, -OCH2O-, -NH-CH=C(CH2NAA')- oder -NH-CH=C- two adjacent radicals selected from R 2 , R 2 , R 2 , R 2 , R 2 together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH-, -N = CR 7 -NH, -NH-CO-O-, -OCH 2 O-, -NH-CH = C (CH 2 NAA ') - or -NH-CH = C-
R3 H, SH1 A1 COOH, COOA, CONH2, CONHA oderR 3 H, SH 1 A 1 COOH, COOA, CONH 2 , CONHA or
CONAA1, R4 H, A, COOA, CONH2, CH2NH2, CH2NHA oder CH2NAA1,CONAA 1 , R 4 H, A, COOA, CONH 2 , CH 2 NH 2 , CH 2 NHA or CH 2 NAA 1 ,
R5 H, A oder COA,R 5 is H, A or COA,
R 36° H1 A, OH, NH2, NHA oder NAA1,R 36 ° H 1 A, OH, NH 2 , NHA or NAA 1 ,
R7 H oder Alkyl mit 1 , 2, 3 oder 4 C-Atomen,R 7 is H or alkyl having 1, 2, 3 or 4 C atoms,
R7 und ein Rest ausgewählt aus der Gruppe R2, R2 , R2 , R2 , R2 zusammen auch -CH2CH2-, R8 H, A oder HaI,R 7 and a radical selected from the group R 2 , R 2 , R 2 , R 2 , R 2 together also -CH 2 CH 2 -, R 8 H, A or Hal,
Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A1 OA, OH, SH, SA, HaI1 NO2, CN, (CH2)HAr1, (CH2)nCOOH, (CH2)nCOOA, CHO, COA1 SO2A1 CONH2, SO2NH2, CONHA, CONAA', SO2NHA1 Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A 1 OA, OH, SH, SA, Hal 1 NO 2 , CN, (CH 2 ) H Ar 1 , (CH 2 ) n COOH, ( CH 2 ) n COOA, CHO, COA 1 SO 2 A 1 CONH 2 , SO 2 NH 2 , CONHA, CONAA ', SO 2 NHA 1
SO2NAA1, NH2, NHA, NAA1, OCONH2, OCONHA, OCONAA1, NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA,SO 2 NAA 1 , NH 2 , NHA, NAA 1 , OCONH 2 , OCONHA, OCONAA 1 , NHCOA, NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA,
NACONHA, NHCONAA'.NACONAA' und/oderNACONHA, NHCONAA'.NACONAA 'and / or
NHCO(CH2)nNH2 substituiertes Phenyl, Naphthyl oderNHCO (CH 2 ) n NH 2 substituted phenyl, naphthyl or
Biphenyl,biphenyl,
Ar1 unsubstituiertes oder ein-, zwei- oder dreifach durch A,Ar 1 is unsubstituted or mono-, di- or trisubstituted by A,
OA, OH, SH, SA, HaI, NO2, CN, (CH2)nPhenyl, (CH2)nCOOH, (CH2)nCOOA, CHO1 COA, SO2A, CONH2,OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 ) n phenyl, (CH 2 ) n COOH, (CH 2 ) n COOA, CHO 1 COA, SO 2 A, CONH 2 ,
SO2NH2, CONHA, CONAA', SO2NHA, SO2NAA1, NH2, NHA, NAA', OCONH2, OCONHA, OCONAA1, NHCOA, NHCOOA, NACOOA, NHSO2OA1 NASO2OA1 NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA1 und/oder NACONAA1 substituiertes Phenyl, Naphthyl oder Biphenyl, Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der ein-, zwei- oder dreifach durch A1 OA, OH, SH, SA, HaI, NO2, CN, (CH2)HAr1, (CH2)nCOOH, (CH2)nCOOA, CHO, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA1, SO2NHA, SO2NAA1, NH2, NHA, NAA1, OCONH2, OCONHA, OCONAA1, NHCOA,SO 2 NH 2 , CONHA, CONAA ', SO 2 NHA, SO 2 NAA 1 , NH 2 , NHA, NAA', OCONH 2 , OCONHA, OCONAA 1 , NHCOA, NHCOOA, NACOOA, NHSO 2 OA 1 NASO 2 OA 1 NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA 1 and / or NACONAA 1 substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the one-, two- or three-fold A 1 OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 ) H Ar 1 , (CH 2 ) n COOH, (CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA 1 , SO 2 NHA, SO 2 NAA 1 , NH 2 , NHA, NAA 1 , OCONH 2 , OCONHA, OCONAA 1 , NHCOA,
NHCOOA, NACOOA, NHSO2OA, NASO2OA1 NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA1, NACONAA1, SO2A, =S, =NH, =NA und/oder =0 (Carbonylsauerstoff) substituiert sein kann,NHCOOA, NACOOA, NHSO 2 OA, NASO 2 OA 1 NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA 1 , NACONAA 1 , SO 2 A, = S, = NH, = NA and / or = 0 (carbonyl oxygen) can
Het1 einen einkernigen gesättigten Heterocyclus mit 1 bis 2 N und/oder O-Atomen, der ein- oder zweifach durch A, - OA, OH, HaI und/oder =0 (Carbonylsauerstoff) substituiert sein kann, ?Het 1 is a mononuclear saturated heterocycle having 1 to 2 N and / or O atoms, which may be mono- or disubstituted by A, - OA, OH, Hal and / or = 0 (carbonyl oxygen),?
Her Morpholin-4-yl, Dioxanyl, Piperidinyl, Pyrrolidinyl oderHer morpholin-4-yl, dioxanyl, piperidinyl, pyrrolidinyl or
Piperazinyl,piperazinyl,
A, A1 jeweils unabhängig voneinander Alkyl mit 1 bis 10 C-A, A 1 each independently of one another alkyl with 1 to 10 C
Atomen, wobei auch 1-7 H-Atome durch F und/oder Chlor ersetzt sein können,Atoms, wherein also 1-7 H atoms can be replaced by F and / or chlorine,
HaI F1 CI, Br oder I, m 2, 3, 4 oder 5, n O1 1 oder 2, P 1 , 2, 3 oder 4 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze,HaI F 1 is Cl, Br or I, m is 2, 3, 4 or 5, n is O 1 1 or 2, P is 1, 2, 3 or 4, and their pharmaceutically usable derivatives, solvates, salts,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
2. Verbindungen nach Anspruch 1 , worin (CH2)m X (CH2)n> CHA, \ /_ ,2. Compounds according to claim 1, wherein (CH 2 ) m X (CH 2 ) n> CHA,
CH-CH2-COOH, CH-CH2-COOA, CH-CH2-CO-Het2, CH-CH2-Het2,CH-CH 2 -COOH, CH-CH 2 -COOA, CH-CH 2 -CO-Het 2 , CH-CH 2 -Het 2 ,
CH-CH2-CONH-(CH2)1-2-NH2> CH-CH2-CONH-(CH2)1-2-OH oder CH-CH2-CONH-(CH2)1-2-OA, bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.CH-CH 2 -CONH- (CH 2 ) 1-2 -NH 2> CH-CH 2 -CONH- (CH 2 ) 1-2 -OH or CH-CH 2 -CONH- (CH 2 ) 1-2 - OA, as well as their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
3. Verbindungen nach Anspruch 1 oder 2, worin3. Compounds according to claim 1 or 2, wherein
R1 H, A, HaI, -CO-A, CN, COOH, COOA, CONH2, NH2, NHA oder NAA', R1' H, A oder HaI bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.R 1 is H, A, Hal, -CO-A, CN, COOH, COOA, CONH 2 , NH 2 , NHA or NAA ', R 1' is H, A or Hal, and their pharmaceutically usable derivatives, solvates, salts, Tautomers and stereoisomers, including mixtures thereof in all ratios.
4. Verbindungen nach einem oder mehreren der Ansprüche 1-3, worin4. Compounds according to one or more of claims 1-3, wherein
R2 OH, OA, NH2 oder SO2NH2,R 2 is OH, OA, NH 2 or SO 2 NH 2 ,
R2 , R2 ,R 2 , R 2 ,
R2 , R2 H bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.R 2 , R 2 signify H, as well as their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
5. Verbindungen nach einem oder mehreren der Ansprüche 1-4, worin R2 OH1 OA1 NH2, NHA, NAA1, HaI, A, CONH2, CONHA1 5. Compounds according to one or more of claims 1-4, wherein R 2 OH 1 OA 1 NH 2 , NHA, NAA 1 , Hal, A, CONH 2 , CONHA 1
CONAA', CONHAr1 CONHHet, SO2NH2, SO2NHA1 SO2NAA', SO2NHAr1 SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA1 NHCOAr1 NHCOHet, -O(CH2)POH, -O(CH2)POA, -O(CH2)pNH2, -O(CH2)PNHA,CONAA ', CONHAr 1 CONHHet, SO 2 NH 2 , SO 2 NHA 1 SO 2 NAA', SO 2 NHAr 1 SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA 1 NHCOAr 1 NHCOHet, -O ( CH 2 ) P OH, -O (CH 2 ) P OA, -O (CH 2 ) p NH 2 , -O (CH 2 ) P NHA,
-O(CH2)PNAA', -O(CH2)PNH-COA, -O(CH2)PNHSO2A, -B(OH)2, NHCOOA, COOH, COOH1 SO2A1 NHCHO, NHCONH2, -CH(OH)-CH2Ar, Het,-O (CH 2 ) P NAA ', -O (CH 2 ) P NH-COA, -O (CH 2 ) P NHSO 2 A, -B (OH) 2 , NHCOOA, COOH, COOH 1 SO 2 A 1 NHCHO , NHCONH 2 , -CH (OH) -CH 2 Ar, Het,
R2', R2",R 2 ' , R 2 " ,
R2'", R2 jeweils unabhängig voneinander H, HaI oder OH1 R 2 '', R 2 are each independently H, Hal or OH 1
zwei benachbarte Reste ausgewählt aus R2, R2 , R2 , R2 , R2 zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -N=CR7-NH, -NH-CO-O-, -OCH2O-, -NH-CH=C(CH2NAA1)- odertwo adjacent radicals selected from R 2 , R 2 , R 2 , R 2 , R 2 together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH-, -N = CR 7 -NH, -NH-CO-O-, -OCH 2 O-, -NH-CH = C (CH 2 NAA 1 ) - or
-NH-CH=C--NH-CH = C-
bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
6. Verbindungen nach einem oder mehreren der Ansprüche 1 -5, worin6. Compounds according to one or more of claims 1-5, wherein
A1 A1 jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-A 1 A 1 each independently of one another alkyl with 1 to 6 C
Atomen, wobei auch 1-5 H-Atome durch F und/oderAtoms, where also 1-5 H atoms by F and / or
Chlor ersetzt sein können, bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Chlorine can be replaced means and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
7. Verbindungen nach einem oder mehreren der Ansprüche 1-6, worin R3 H1 SH oder A bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.7. Compounds according to one or more of claims 1-6, wherein R 3 is H 1 SH or A, and their pharmaceutically acceptable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all proportions.
8. Verbindungen nach einem oder mehreren der Ansprüche 1-7, worin R4 H, A, COOA oder CONH2 bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze,8. Compounds according to one or more of claims 1-7, wherein R 4 is H, A, COOA or CONH 2 , and their pharmaceutically usable derivatives, solvates, salts,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
9. Verbindungen nach einem oder mehreren der Ansprüche 1-8, worin Ar unsubstituiertes oder ein- oder zweifach durch A, OA,9. Compounds according to one or more of claims 1-8, wherein Ar is unsubstituted or mono- or disubstituted by A, OA,
OH und/oder HaI substituiertes Phenyl bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.OH and / or Hal substituted phenyl, as well as their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
10. Verbindungen nach einem oder mehreren der Ansprüche 1-9, worin10. Compounds according to one or more of claims 1-9, wherein
Het einen ein- oder zweikernigen gesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-Atomen, der ein- oder zweifach durch A substituiert sein kann, bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Het a mono- or binuclear saturated or aromatic heterocycle having 1 to 4 N atoms, which may be mono- or disubstituted by A, means and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
11. Verbindungen nach einem oder mehreren der Ansprüche 1-10, worin11. Compounds according to one or more of claims 1-10, wherein
Het unsubstituiertes oder ein- oder zweifach durch A substituiertes Piperidin, Piperazin, Pyrrolidin, Pyridin, Pyrimidin, Pyrrol, Indol, Indazol, Morpholin, Isoxazol, Tetrazol, Furan oder Thiophen bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze,Het is unsubstituted or mono- or di-substituted by A piperidine, piperazine, pyrrolidine, pyridine, pyrimidine, pyrrole, indole, indazole, morpholine, isoxazole, tetrazole, furan or thiophene, and their pharmaceutically usable derivatives, solvates, salts,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
12. Verbindungen nach einem oder mehreren der Ansprüche 1-11 , worin12. Compounds according to one or more of claims 1-11, wherein
(CH \(CH \
X (CH2)n, CHA, \ / ,X (CH 2 ) n , CHA, \ /,
CC
CH-CH2-COOH, CH-CH2-COOA, CH-CH2-CO-Het2, CH-CH2-Het2,CH-CH 2 -COOH, CH-CH 2 -COOA, CH-CH 2 -CO-Het 2 , CH-CH 2 -Het 2 ,
CH-CH2-CONH-(CH2)I-2-NH2, CH-CH2-CONH-(CH2)I-2-OH oder CH-CH2-CONH-(CH2)i-2-OA,CH-CH 2 -CONH- (CH 2 ) 1 -2 -NH 2 , CH-CH 2 -CONH- (CH 2 ) 1 -2 -OH or CH-CH 2 -CONH- (CH 2 ) i -2 - OA,
XI (CH2Jn, R1 H, A, HaI, -CO-A, CN, COOH, COOA, CONH2, NH2,X 1 (CH 2 J n , R 1 H, A, Hal, -CO-A, CN, COOH, COOA, CONH 2 , NH 2 ,
NHA oder NAA1,NHA or NAA 1 ,
R1' H1 A oder HaI R2, R2', R2",R 1 ' H 1 A or Hal R 2 , R 2' , R 2 " ,
R2 OH1 OA, NH2, NHA, NAA', HaI, A, CONH2, CONHA, CONAA', CONHAr, CONHHet, SO2NH2, SO2NHA,R 2 OH 1 OA, NH 2 , NHA, NAA ', Hal, A, CONH 2 , CONHA, CONAA', CONHAr, CONHHet, SO 2 NH 2 , SO 2 NHA,
SO2NAA1, SO2NHAr, SO2NHHet, NHSO2A, NHSO2Ar, NHSO2Het, NHCOA1 NHCOAr, NHCOHet, -O(CH2)pOH, -O(CH2)POA, -O(CH2)pNH2, -O(CH2)PNHA, -0(CH2)PNAA1, -O(CH2)PNH-COA, -O(CH2)PNHSO2A, -B(OH)2, NHCOOA, COOH, COOH, SO2A1 NHCHO, NHCONH2, -CH(OH)-CH2Ar, Het,SO 2 NAA 1 , SO 2 NHAr, SO 2 NHHet, NHSO 2 A, NHSO 2 Ar, NHSO 2 Het, NHCOA 1 NHCOAr, NHCOHet, -O (CH 2 ) p OH, -O (CH 2 ) P OA, -O (CH 2 ) p NH 2 , -O (CH 2 ) P NHA, -O (CH 2) P NAA 1, -O (CH 2) P NH-COA, -O (CH2) P NHSO 2 A, -B (OH) 2, NHCOOA, COOH, COOH, SO 2 A 1 NHCHO, NHCONH 2, - CH (OH) -CH 2 Ar, Het,
R2', R2",R 2 ' , R 2 " ,
R2 , R2 jeweils unabhängig voneinander H, HaI oder OH,R 2 , R 2 are each independently H, Hal or OH,
zwei benachbarte Reste ausgewählt aus R2, R2 , R2", R2'", R2 zusammen auch -NH-CO-CH=N-, -NH-CH=CH-, -NH-CO-NH-, -NH-CO-O-, -OCH2O-, -NH-CH=C(CH2NAA1)- oder -NH-CH=C-two adjacent radicals selected from R 2 , R 2 , R 2 " , R 2 '" , R 2 together also -NH-CO-CH = N-, -NH-CH = CH-, -NH-CO-NH-, -NH-CO-O-, -OCH 2 O-, -NH-CH = C (CH 2 NAA 1 ) - or -NH-CH = C-
R3 H1 SH1 A1 COOH1 COOA1 CONH2, CONHA oder CONAA1, R3 H, SH oder A, R 3 H 1 SH 1 A 1 COOH 1 COOA 1 CONH 2 , CONHA or CONAA 1 , R 3 H, SH or A,
R4 H, A, COOA oder CONH2' R5 H, A oder COA1 R 4 is H, A, COOA or CONH 2 'R 5 is H, A or COA 1
R6 H, A, OH1 NH2, NHA oder NAA1,R 6 is H, A, OH 1 NH 2 , NHA or NAA 1 ,
R7 H oder Alkyl mit 1 , 2, 3 oder 4 C-Atomen,R 7 is H or alkyl having 1, 2, 3 or 4 C atoms,
R7 und ein Rest ausgewählt aus der Gruppe R2, R2 , R2 , R2 , R2 zusammen auch -CH2CH2-,R 7 and a radical selected from the group R 2 , R 2 , R 2 , R 2 , R 2 together also -CH 2 CH 2 -,
R8 H, A oder HaI,R 8 is H, A or Hal,
Ar unsubstituiertes oder ein- oder zweifach durch A, OA,Ar unsubstituted or one or two times by A, OA,
OH und/oder HaI substituiertes Phenyl, Het einen ein- oder zweikernigen gesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-Atomen, der ein- oder zweifach durch A substituiert sein kann,OH and / or Hal substituted phenyl, Het a mono- or binuclear saturated or aromatic heterocycle having 1 to 4 N atoms, which may be mono- or disubstituted by A,
Het2 Morpholin-4-yl, Dioxanyl, Piperidinyl, Pyrrolidinyl oderHet 2 morpholin-4-yl, dioxanyl, piperidinyl, pyrrolidinyl or
Piperazinyl,piperazinyl,
A, A1 jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-A, A 1 each independently of one another alkyl with 1 to 6 C
Atomen, wobei auch 1-5 H-Atome durch F und/oder Chlor ersetzt sein können,Atoms, whereby also 1-5 H-atoms can be replaced by F and / or chlorine,
HaI F1 CI, Br oder I, m 2, 3, 4 oder 5, n 0, 1 oder 2, p 1 , 2, 3 oder 4 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze,HaI F 1 is Cl, Br or I, m is 2, 3, 4 or 5, n is 0, 1 or 2, p is 1, 2, 3 or 4, and their pharmaceutically usable derivatives, solvates, salts,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
13. Verbindungen nach Anspruch 1 , ausgewählt aus der Gruppe13. Compounds according to claim 1, selected from the group
"A1" 3-(1H-Benzimidazol-5-ylamino)-4-(3-hydroxy- benzy!amino)-cyclobut-3-en-1 ,2-dion"A1" 3- (1H-Benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A2" 3-(1 H-Benzimidazol-5-ylamino)-4-[(R)-1 -(3-methoxy- phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A2" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-methoxyphenyl) ethylamino] -cyclobut-3-ene-1,2-dione
"A3" 3-(1H-Benzimidazol-5-ylamino)-4-[(R)-1-(3-hydroxy- phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A3" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-hydroxyphenyl) ethylamino] -cyclobut-3-ene-1,2-dione
"A4" 3-(1 H-Benzimidazol-5-ylamino)-4-[(S)-1 -(3-hydroxy- phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion - -"A4" 3- (1H-Benzimidazol-5-ylamino) -4 - [(S) -1- (3-hydroxyphenyl) ethylamino] -cyclobut-3-ene-1,2-dione - -
"A5" 3-(1H-Benzimidazol-5-ylamino)-4-[(R)-1-(3-amino- phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A5" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-amino-phenyl) -ethyl-amino] -cyclobut-3-en-1,2-dione
"A6" 3-(1H-Benzimidazol-5-ylamino)-4-(3-aminosulfonyl- benzylamino)-cyclobut-3-en-1 ,2-dion"A6" 3- (1H-Benzimidazol-5-ylamino) -4- (3-aminosulfonylbenzylamino) -cyclobut-3-ene-1,2-dione
"A7" 3-(1H-Benzimidazol-5-ylamino)-4-[(R)-1-(3-hydroxy- phenyl)-2-methyl-propylamino]-cyclobut-3-en-1 ,2-dion"A7" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-hydroxyphenyl) -2-methyl-propylamino] -cyclobut-3-en-1, 2-dione
"A8" 3-(1H-Benzimidazol-5-ylamino)-4-[1-(3-hydroxy-phenyl)- cyclopropylamino]-cyclobut-3-en-1 ,2-dion"A8" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (3-hydroxyphenyl) -cyclopropylamino] -cyclobut-3-en-1, 2-dione
"A9" 3-(7-Methyl-1/-/-benzimidazol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A9" 3- (7-Methyl-1 / - / - benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-en-1,2-dione
"A10" 3-(1H-Benzimidazol-2-trifluormethyl-5-ylamino)-4-(3- hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion t "lA A A1 H1U 3-(1/-/-Benzimidazol-2-trifluormethyl-5-yl-methylamino)-4- (3-hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion"A10" 3- (1H-Benzimidazole-2-trifluoromethyl-5-ylamino) -4- (3-hydroxy-benzylamino) -cyclobut-3-en-1,2-dione "A A A1 H1U 3- (1 / - / - Benzimidazole-2-trifluoromethyl-5-yl-methylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A12" 3-(1H-Benzimidazol-6-chlor-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A12" 3- (1H-Benzimidazole-6-chloro-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A13" 3-(1/-/-Benzimidazol-5-yl-methylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A13" 3- (1 / - / - Benzimidazol-5-yl-methylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A14" 3-(Benzothiazol-6-ylamino)-4-(3-hydroxy-benzylamino)- cyclobut-3-en-1 ,2-dion"A14" 3- (Benzothiazol-6-ylamino) -4- (3-hydroxy-benzylamino) -cyclobut-3-ene-1,2-dione
"A15" 3-(1H-Benzotriazol-5-yl-methylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A15" 3- (1H-Benzotriazol-5-yl-methylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A16" 3-(1/-/-Benzimidazol-2-trifluormethyl-5-ylamino)-4-[(R)-1- (3-hydroxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A16" 3- (1 / - / - benzimidazole-2-trifluoromethyl-5-ylamino) -4 - [(R) -1- (3-hydroxy-phenyl) -ethylamino] -cyclobut-3-en-1, 2-dione
"A17" 3-(1/-/-Benzimidazol-2-trifluormethyl-5-ylamino)-4-[(S)-1- (S-hydroxy-phenyO-ethylaminol-cyclobut-S-en-i ,2-dion "A17" 3- (1 / - / - benzimidazole-2-trifluoromethyl-5-ylamino) -4 - [(S) -1- (S -hydroxy-phenyl-ethylaminol-cyclobut-S-en-i, 2- dion
imidazo[1 ,2-a]pyridin-6-ylamino)-cyclobut-3-en-1 ,2-dion imidazo [1,2-a] pyridin-6-ylamino) -cyclobut-3-ene-1,2-dione
"A60" 3-(8-Brom-imidazo[1 ,2-a]pyridin-6-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A60" 3- (8-Bromo-imidazo [1,2-a] pyridin-6-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-en-1,2-dione
"A61" 3-[(R)-1-(3-Methoxy-phenyl)-ethylamino]-4-(3-oxo-2,3- dihydro-1 H-indazol-5-ylamino)-cyclobut-3-en-1 ,2-dion"A61" 3 - [(R) -1- (3-Methoxyphenyl) ethylamino] -4- (3-oxo-2,3-dihydro-1H-indazol-5-ylamino) -cyclobut-3 en-1, 2-dione
"A62" 3-[(R)-1-(3-Hydroxy-phenyl)-ethylamino]-4-(3-oxo-2,3- dihydro-1 /-/-indazol-5-ylamino)-cyclobut-3-en-1 ,2-dion"A62" 3 - [(R) -1- (3-Hydroxy-phenyl) -ethylamino] -4- (3-oxo-2,3-dihydro-1 / - / - indazol-5-ylamino) -cyclobutene 3-en-1, 2-dione
"A63" 3-(8-Brom-imidazo[1 ,2-a]pyridin-6-ylamino)-4-[(R)-1 -(3- methoxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A63" 3- (8-Bromo-imidazo [1,2-a] pyridin-6-ylamino) -4 - [(R) -1- (3-methoxyphenyl) -ethylamino] -cyclobut-3-ene -1, 2-dione
"A64" 3-(2,3-Dihydro-benzofuran-5-ylamino)-4-[(R)-1-(3- hydroxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2-dion"A64" 3- (2,3-Dihydro-benzofuran-5-ylamino) -4 - [(R) -1- (3-hydroxy-phenyl) -ethyl-amino] -cyclobut-3-en-1, 2-dione
"A65" 3-[3-(2-Diethylamino-ethyl)-3H-benzimidazol-5~ylamino]-"A65" 3- [3- (2-diethylamino-ethyl) -3H-benzimidazol-5-ylamino] -
4-[(R)-1-(3-methoxy-phenyl)-ethylamino]-cyclobut-3-en-4 - [(R) -1- (3-methoxy-phenyl) -ethylamino] -cyclobut-3-ene
1 ,2-dion1, 2-dione
"A66" 3-[3-(2-Diethylamino-ethyl)-3H-benzimidazol-5-ylamino]- 4-[(R)-1-(3-hydroxy-phenyl)-ethylamino]-cyclobut-3-en- 1 ,2-dion"A66" 3- [3- (2-Diethylamino-ethyl) -3H-benzimidazol-5-ylamino] - 4 - [(R) -1- (3-hydroxy-phenyl) -ethylamino] -cyclobut-3-ene - 1, 2-dione
"A67" 3-[3-(2-Methoxy-ethyl)-3H-benzimidazol-5-ylamino]-4- [(R)-I -(3-methoxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2- dion"A67" 3- [3- (2-Methoxyethyl) -3H-benzimidazol-5-ylamino] -4- [(R) -1- (3-methoxyphenyl) ethylamino] -cyclobut-3-ene -1, 2-dione
"A68" 3-[3-(2-Methoxy-ethyl)-3/-/-benzimidazol-5-ylamino]-4- [(R)-I -(3-hydroxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2- dion"A68" 3- [3- (2-Methoxyethyl) -3 / - / - benzimidazol-5-ylamino] -4- [(R) -1- (3-hydroxy-phenyl) -ethylamino] -cyclobutene 3-en-1, 2-dione
"A69" 3-[3-(2-Methoxy-ethyl)-3H-benzimidazol-5-ylamino]-4-[3- (1 H-tetrazol-5-yl)-benzylamino]-cyclobut-3-en-1 ,2-dion"A69" 3- [3- (2-Methoxy-ethyl) -3H-benzimidazol-5-ylamino] -4- [3- (1H-tetrazol-5-yl) -benzylamino] -cyclobut-3-ene 1, 2-dione
"A70" 3-[3-(2-Methoxy-ethyl)-3H-benzimidazol-5-ylamino]-4-(3- aminosulfonyl-benzylamino)-cyclobut-3-en-1 ,2-dion"A70" 3- [3- (2-Methoxy-ethyl) -3H-benzimidazol-5-ylamino] -4- (3-aminosulfonyl-benzylamino) -cyclobut-3-ene-1,2-dione
"A71 " 3-[3-(2-Diethylamino-ethyl)-3H-benzimidazol-5-ylamino]- 4-(3-aminosulfonyl-benzylamino)-cyclobut-3-en-1 ,2-dion"A71" 3- [3- (2-Diethylamino-ethyl) -3H-benzimidazol-5-ylamino] - 4- (3-aminosulfonyl-benzylamino) -cyclobut-3-en-1,2-dione
"A72" 3-[1 -(2-Methoxy-ethyl)-1 /-/-benzimidazol-5-ylamino]-4- [(R)-I -(3-methoxy-phenyl)-ethylamino]-cyclobut-3-en-1 ,2- dion"A72" 3- [1- (2-Methoxyethyl) -1 / - / - benzimidazol-5-ylamino] -4- [(R) -1- (3-methoxy-phenyl) -ethylamino] -cyclobutene 3-en-1, 2-dione
"A73" 3-[1 -(2-Diethylamino-ethyl)-1 /-/-benzimidazol-5-ylamino]- 4-[(R)-1-(3-hydroxy-phenyl)-ethylamino]-cyclobut-3-en- 1 ,2-dion"A73" 3- [1- (2-Diethylaminoethyl) -1 / - / - benzimidazol-5-ylamino] - 4 - [(R) -1- (3-hydroxy-phenyl) -ethyl-amino] -cyclobut-3-ene-1, 2-dione
"A74" 3-[(R)-1 -(3-Hydroxy-phenyl)-ethylamino]-4-[1 -(2-methoxy- ethyl)-1 H-benzimidazol-δ-ylaminol-cyclobut-S-en-i ,2-dion"A74" 3 - [(R) -1- (3-Hydroxy-phenyl) -ethylamino] -4- [1- (2-methoxy-ethyl) -1H-benzimidazol-6-ylamino-cyclobut-S-ene -i, 2-dion
"A75" 3-(1H-Benzimidazol-5-ylamino)-4-[1-(1H-indol-5-yl)- ethylamino]-cyclobut-3-en-1 ,2-dion"A75" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (1H-indol-5-yl) -ethylamino] -cyclobut-3-ene-1,2-dione
"A76" 3-(1H-Benzimidazol-5-ylamino)-4-(4-fluor-3-methoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A76" 3- (1H-Benzimidazol-5-ylamino) -4- (4-fluoro-3-methoxybenzylamino) -cyclobut-3-en-1, 2-dione
"A77" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3-methylsulfonylamino- benzylamino)-cyclobut-3-en-1 ,2-dion"A77" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3-methylsulfonylaminobenzylamino) -cyclobut-3-en-1, 2-dione
"A78" 3-(1/-/-Benzimidazol-5-ylamino)-4-(2l4,5-trifluor-3- hydroxy-benzylamino)-cyclobut-3-en-1 ,2-dion"A78" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (2 l, 4,5-trifluoro-3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A79" 3-(1 H-Benzimidazol-5-ylamino)-4-[(1 H-indol-5-ylmethyl)- amino]-cyclobut-3-en-1 ,2-dion"A79" 3- (1H-Benzimidazol-5-ylamino) -4 - [(1H-indol-5-ylmethyl) -amino] -cyclobut-3-en-1, 2-dione
"A80" 3-(1H-Benzimidazol-5-ylamino)-4-[(2-oxo-2,3-dihydro-1H- benzimidazol-5-ylmethyl)-amino]-cyclobut-3-en-1 ,2-dion"A80" 3- (1H-Benzimidazol-5-ylamino) -4 - [(2-oxo-2,3-dihydro-1H-benzimidazol-5-ylmethyl) -amino] -cyclobut-3-en-1, 2 -dione
"A811 3-(2-Ethoxycarbonyl-1H-indol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion "A81 1 3- (2-Ethoxycarbonyl-1H-indol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
benzylamino)-cyclobut-3-en-1 ,2-dion benzylamino) -cyclobut-3-ene-1,2-dione
"A93" 3-(1H-Benzimidazol-5-ylamino)-4-(2-ethoxy-5-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A93" 3- (1H-Benzimidazol-5-ylamino) -4- (2-ethoxy-5-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A94" 3-(1H-Benzimidazol-5-ylamino)-4-(3,5-dihydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A94" 3- (1H-Benzimidazol-5-ylamino) -4- (3,5-dihydroxybenzylamino) -cyclobut-3-en-1, 2-dione
"A95" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3-aminocarbonyl- benzylamino)-cyclobut-3-en-1 ,2-dion"A95" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3-aminocarbonyl-benzylamino) -cyclobut-3-ene-1,2-dione
"A96" 3-(1 /-/-Benzimidazol-5-ylamino)-4-[(3- dimethylaminomethyl-1H-indol-6-ylmethyl)-amino]- cyclobut-3-en-1 ,2-dion"A96" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(3-dimethylaminomethyl-1H-indol-6-ylmethyl) -amino] -cyclobut-3-ene-1,2-dione
"A97" 3-(1H-Benzimidazol-5-ylamino)-4-(3-hydroxy-2-methyl- benzylamino)-cyclobut-3-en-1 ,2-dion"A97" 3- (1H-Benzimidazol-5-ylamino) -4- (3-hydroxy-2-methylbenzylamino) -cyclobut-3-ene-1,2-dione
"A98" 3-(3-Hydroxy-benzylamino)-4-(2-methyl-benzothiazol-5- ylamino)-cyclobut-3-en-1 ,2-dion"A98" 3- (3-Hydroxybenzylamino) -4- (2-methyl-benzothiazol-5-ylamino) -cyclobut-3-ene-1,2-dione
"A99" 3-[2-(1/-/-Benzimidazol-5-ylamino)-3,4-dioxo-cyclobut-1- enylamino]-3-(3-hydroxy-phenyl)-propionsäure"A99" 3- [2- (1 / - / - Benzimidazol-5-ylamino) -3,4-dioxo-cyclobut-1-enylamino] -3- (3-hydroxy-phenyl) -propionic acid
"A100" 3-[2-(1 /-/-Benzimidazol-5-ylamino)-3,4-dioxo-cyclobut-1 - enylamino]-3-(3-hydroxy-phenyl)-propionsäure-ethylester"A100" 3- [2- (1 / - / - benzimidazol-5-ylamino) -3,4-dioxo-cyclobut-1 - enylamino] -3- (3-hydroxy-phenyl) -propionic acid ethyl ester
"A101 " 3-[2-(1/-/-Benzimidazol-5-ylamino)-3,4-dioxo-cyclobut-1- enylamino]-3-(3-hydroxy-phenyl)-propionsäure- methylester"A101" 3- [2- (1 / - / - Benzimidazol-5-ylamino) -3,4-dioxo-cyclobut-1-enylamino] -3- (3-hydroxyphenyl) -propionic acid methyl ester
"A102" 3-(1 H-Benzimidazol-5-ylamino)-4-[(3-pyridin-4-yl-1 H- indol-5-ylmethyl)-amino]-cyclobut-3-en-1 ,2-dion"A102" 3- (1H-Benzimidazol-5-ylamino) -4 - [(3-pyridin-4-yl-1H-indol-5-ylmethyl) -amino] -cyclobut-3-en-1, 2 -dione
"A103" 3-(1/-/-Benzimidazol-5-ylamino)-4-(2-fluor-3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A103" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (2-fluoro-3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A 104" 3-(1/-/-Benzimidazol-5-ylamino)-4-(3-ethoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A 104" 3- (1 / - / - Benzimidazol-5-ylamino) -4- (3-ethoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A105" 3-(1H-Benzimidazol-5-ylamino)-4-[1-(3-hydroxy-phenyl)-"A105" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (3-hydroxy-phenyl) -
3-morpholin-4-yl-3-oxo-propylamino]-cyclobut-3-en-1 ,2- dion3-morpholin-4-yl-3-oxo-propylamino] -cyclobut-3-ene-1, 2-dione
"A106" 3-(1H-Benzimidazol-5-ylamino)-4-[3-(2-methoxy-ethoxy)- benzylamino]-cyclobut-3-en-1 ,2-dion"A106" 3- (1H-Benzimidazol-5-ylamino) -4- [3- (2-methoxy-ethoxy) -benzylamino] -cyclobut-3-en-1, 2-dione
"A107" 3-(1H-Benzimidazol-5-ylamino)-4-[3-(2-hydroxy-ethoxy)- benzylamino]-cyclobut-3-en-1 ,2-dion "A107" 3- (1H-Benzimidazol-5-ylamino) -4- [3- (2-hydroxy-ethoxy) -benzylamino] -cyclobut-3-en-1, 2-dione
"A108" 3-(1/-/-Benzimidazol-5-ylamino)-4-[3-(2-dimethylamino- ethoxy)-benzylamino]-cyclobut-3-en-1 ,2-dion"A108" 3- (1 / - / - Benzimidazol-5-ylamino) -4- [3- (2-dimethylamino-ethoxy) -benzylamino] -cyclobut-3-en-1, 2-dione
"A109" 3-(1/-/-Benzimidazol-5-ylamino)-4-[3-(2-acetamido- ethoxy)-benzylamino]-cyclobut-3-en-1 ,2-dion"A109" 3- (1 / - / - Benzimidazol-5-ylamino) -4- [3- (2-acetamidoethoxy) -benzylamino] -cyclobut-3-ene-1,2-dione
"A1 10" 3-(1H-Benzimidazol-5-ylamino)-4-[3-(2-methylsulfonyl- amino-ethoxy)-benzylamino]-cyclobut-3-en-1 ,2-dion"A1 10" 3- (1H-Benzimidazol-5-ylamino) -4- [3- (2-methylsulfonyl-amino-ethoxy) -benzylamino] -cyclobut-3-en-1, 2-dione
"A1 1 1 " 3-(4-Butyl-1H-benzimidazol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion "A112" 3-(1 H-Benzimidazol-5-ylamino)-4-[1 -(3-hydroxy-phenyl)- 3-oxo-3-piperazin-1 -yl-propylaminoJ-cyclobut-S-en-i ,2- dion"A1 1 1" 3- (4-Butyl-1H-benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione "A112" 3- (1H-Benzimidazol-5-ylamino) -4- [1- (3-hydroxy-phenyl) -3-oxo-3-piperazine-1-yl-propylamino] -cyclobut-S-en-i , 2- dion
"A113" 3-[2-(1/-/-Benzimidazol-5-ylamino)-3,4-dioxo-cyclobut-1- enylamino]-N-(2-dimethylamino-ethyl)-3-(3-hydroxy- phenyl)-propionamid"A113" 3- [2- (1 / - / - Benzimidazol-5-ylamino) -3,4-dioxo-cyclobut-1-enylamino] -N- (2-dimethylamino-ethyl) -3- (3-hydroxy - phenyl) -propionamide
"A114" 3-(1 H-Benzimidazol-5-ylamino)-4-[(R)-1 -(3-methoxy- phenyl)-propylamino]-cyclobut-3-en-1 ,2-dion"A114" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-methoxyphenyl) -propylamino] -cyclobut-3-en-1, 2-dione
"A115" 3-(1/-/-Benzimidazol-5-ylamino)-4-[(S)-1-(3-methoxy- phenyl)-propylamino]-cyclobut-3-en-1 ,2-dion"A115" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(S) -1- (3-methoxyphenyl) -propylamino] -cyclobut-3-en-1,2-dione
"A116" 3-(1H-Benzimidazol-5-ylamino)-4-(3-methoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A116" 3- (1H-Benzimidazol-5-ylamino) -4- (3-methoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A117" 3-[2-(1 /-/-Benzimidazol-5-ylamino)-3,4-dioxo-cyclobut-1 ■ enylamino]-3-(3-hydroxy-phenyl)-N-(2-methoxy-ethyl)- propionamid "A117" 3- [2- (1 / - / - Benzimidazol-5-ylamino) -3,4-dioxo-cyclobut-1-enylamino] -3- (3-hydroxy-phenyl) -N- (2-methoxy -ethyl) propionamide
"A118" 3-(7-Chlor-1/-/-benzimidazol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A118" 3- (7-Chloro-1 / - / benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-en-1, 2-dione
"A119" 3-(Benzothiazol-5-ylamino)-4-(3-hydroxy-benzylamino)- cyclobut-3-en-1 ,2-dion"A119" 3- (Benzothiazol-5-ylamino) -4- (3-hydroxy-benzylamino) -cyclobut-3-ene-1,2-dione
"A120" 3-(1H-Benzimidazol-5-ylamino)-4-[(R)-1-(3-hydroxy- phenyl)-propylamino]-cyclobut-3-en-1 ,2-dion"A120" 3- (1H-Benzimidazol-5-ylamino) -4 - [(R) -1- (3-hydroxyphenyl) -propylamino] -cyclobut-3-en-1, 2-dione
"A121" 3-(4-Ethyl-1H-benzimidazol-5-ylamino)-4-(3-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A121" 3- (4-ethyl-1H-benzimidazol-5-ylamino) -4- (3-hydroxybenzylamino) -cyclobut-3-ene-1,2-dione
"A122" 3-(Benzothiazol-6-ylamino)-4-(3-methoxy-benzylamino)- cyclobut-3-en-1 ,2-dion"A122" 3- (Benzothiazol-6-ylamino) -4- (3-methoxy-benzylamino) -cyclobut-3-ene-1,2-dione
"A123" 3-[(Benzo[1 ,3]dioxol-5-ylmethyl)-amino]-4-(1 H- benzimidazol-5-ylamino)-cyclobut-3-en-1 ,2-dion"A123" 3 - [(Benzo [1,3] dioxol-5-ylmethyl) -amino] -4- (1H-benzimidazol-5-ylamino) -cyclobut-3-en-1,2-dione
"A124" 3-(4-Diethylamino-7-trifluormethyl-1AV-benzimidazol-5- ylamino)-4-(3-hydroxy-benzylamino)-cyclobut-3-en-1 ,2- dion"A124" 3- (4-Diethylamino-7-trifluoromethyl-1AV-benzimidazol-5-ylamino) -4- (3-hydroxy-benzylamino) -cyclobut-3-en-1, 2-dione
amino]-cyclobut-3-en-1 ,2-dion amino] -cyclobut-3-ene-1, 2-dione
"A138" 3-(1H-Benzimidazol-5-ylamino)-4-[3-[1 ,3]dioxan-2-yl-1-(3- methoxy-phenyl)-propylamino]-cyclobut-3-en-1 ,2-dion"A138" 3- (1H-Benzimidazol-5-ylamino) -4- [3- [1,3] dioxan-2-yl-1- (3-methoxyphenyl) -propylamino] -cyclobut-3-ene 1, 2-dione
"A139" 3-(1H-Benzimidazol-5-ylamino)-4-(4-hydroxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A139" 3- (1H-Benzimidazol-5-ylamino) -4- (4-hydroxybenzylamino) -cyclobut-3-en-1, 2-dione
"A140" 3-(1H-Benzimidazol-5-ylamino)-4-[2-(4-hydroxy-phenyl)- ethylamino]-cyclobut-3-en-1 ,2-dion"A140" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (4-hydroxy-phenyl) -ethylamino] -cyclobut-3-ene-1,2-dione
"A141" 3-(1/-/-Benzimidazol-5-ylamino)-4-[4-(4-methyl-piperazin- 1-yl)-benzylamino]-cyclobut-3-en-1 ,2-dion"A141" 3- (1 / - / - Benzimidazol-5-ylamino) -4- [4- (4-methylpiperazin-1-yl) -benzylamino] -cyclobut-3-ene-1,2-dione
"A142" 3-(1 /-/-Benzimidazol-5-ylamino)-4-[2-(3-hydroxy-phenyl)- ethylamino]-cyclobut-3-en-1 ,2-dion"A142" 3- (1 / - / - Benzimidazol-5-ylamino) -4- [2- (3-hydroxyphenyl) ethylamino] -cyclobut-3-ene-1,2-dione
"A143" 3-(1 H-Benzimidazol-5-ylamino)-4-[2-(2-methoxy-phenyl)- ethylamino]-cyclobut-3-en-1 ,2-dion"A143" 3- (1H-Benzimidazol-5-ylamino) -4- [2- (2-methoxyphenyl) ethylamino] -cyclobut-3-en-1,2-dione
»A144- 3-(1 H-Benzimidazol-5-ylamino)-4-(2-methoxy- benzylamino)-cyclobut-3-en-1 ,2-dion " A144- 3- (1H-Benzimidazol-5-ylamino) -4- (2-methoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A145" 3-(1 /-/-lndazol-5-ylamino)-4-[(R,S)-1 -(3-ureido-phenyl)- ethylamino]-cyclobut-3-en-1 ,2-dion "A145" 3- (1 / - / - Indazol-5-ylamino) -4 - [(R, S) -1- (3-ureido-phenyl) -ethylamino] -cyclobut-3-en-1, 2- dion
benzylamino)-cyclobut-3-en-1 ,2-dion benzylamino) -cyclobut-3-ene-1,2-dione
"A163" 3-(1/-/-Benzimidazol-5-ylamino)-4-[(3-oxo-3,4-dihydro- chinoxalin-e-ylmethyO-aminoJ-cyclobut-S-en-i ^-dion"A163" 3- (1 / - / - Benzimidazol-5-ylamino) -4 - [(3-oxo-3,4-dihydroquinoxaline-e-ylmethyO-amino] -cyclobut-S-ene-1-dione
"A164" 3-(3/-/-Benzimidazol-5-ylamino)-4-(3-difluormethoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A164" 3- (3 / - / - Benzimidazol-5-ylamino) -4- (3-difluoromethoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A165" 3-(3H-Benzimidazol-5-ylamino)-4-(3,5-dimethoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A165" 3- (3H-Benzimidazol-5-ylamino) -4- (3,5-dimethoxybenzylamino) -cyclobut-3-ene-1,2-dione
"A166" 3-(3/-/-Benzimidazol-5-ylamino)-4-(3-trifluormethoxy- benzylamino)-cyclobut-3-en-1 ,2-dion"A166" 3- (3 / - / - Benzimidazol-5-ylamino) -4- (3-trifluoromethoxybenzylamino) -cyclobut-3-en-1, 2-dione
"A167" 3-[3-(2-Diethylamino-ethyl)-3/-/-benzimidazol-5-ylamino]- 4-[4-(1 H-tetrazol-δ-yO-benzylaminol-cyclobut-S-en-i ,2- dion"A167" 3- [3- (2-Diethylamino-ethyl) -3 / - / - benzimidazol-5-ylamino] - 4- [4- (1H-tetrazol-δ-y-benzylaminol-cyclobut-S-ene -i, 2-dion
MA168" 3-[1 -(2-Diethylamino-ethyl)-1 Ay-benzimidazol-5-ylamino]- M A168 "3- [1- (2-diethylamino-ethyl) -1-yl-benzimidazol-5-ylamino] -
4-[(R)-1-(3-methoxy-phenyl)-ethylamino]-cyclobut-3-en-4 - [(R) -1- (3-methoxy-phenyl) -ethylamino] -cyclobut-3-ene
1 ,2-dion 1, 2-dione
"A169" 3-(3-Hydroxy-benzylamino)-4-(3/-/-imidazo[4,5-jb]pyridin-5- ylamino)-cyclobut-3-en-1 ,2-dion"A169" 3- (3-Hydroxybenzylamino) -4- (3 / - / - imidazo [4,5-jb] pyridin-5-ylamino) -cyclobut-3-ene-1,2-dione
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
14. Verfahren zur Herstellung von Verbindungen der Formel I nach den Ansprüchen 1-13 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel Il14. A process for the preparation of compounds of the formula I according to claims 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a compound of the formula II
worin R und X' die in Anspruch 1 angegebenen Bedeutungen haben, und A Alkyl mit 1-4 C-Atomen bedeutet, mit einer Verbindung der Formelwherein R and X 'have the meanings given in claim 1, and A is alkyl having 1-4 C atoms, with a compound of the formula
worin X und R2, R2>, R2 ", R2 ", R2 '" und R7 die in Anspruch 1 angegebenen Bedeutungen haben,wherein X and R 2 , R 2> , R 2 " , R 2" , R 2 '" and R 7 have the meanings given in claim 1,
umsetzt,implements,
und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converting a base or acid of the formula I into one of its salts.
15. Arzneimittel, enthaltend mindestens eine Verbindung der Formel I nach Anspruch 1 und/oder ihre pharmazeutisch verwendbaren15. A pharmaceutical composition containing at least one compound of the formula I according to claim 1 and / or pharmaceutically acceptable
Derivate, Salze, Solvate, Tautomere und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.Derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
16. Verwendung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen eine Rolle spielt.16. Use of compounds of the formula I according to claim 1 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or Modulation of signal transduction of kinases plays a role.
17. Verwendung nach Anspruch 16, wobei die Kinasen ausgewählt sind aus der Gruppe der Serin- / Threoninkinasen. - -17. Use according to claim 16, wherein the kinases are selected from the group of serine / threonine kinases. - -
18. Verwendung nach Anspruch 17, wobei es sich bei den Serin- / Threoninkinasen um CHK1 und CHK2 handelt.Use according to claim 17, wherein the serine / threonine kinases are CHK1 and CHK2.
19. Verwendung nach Anspruch 18 von Verbindungen der Formel I nach Anspruch 1 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung einer Krankheit, die durch Inhibierung der CHK1- und/oder der CHK2 - Kinase durch die Verbindungen der Formel I nach Anspruch 1 beeinflußt wird.19. Use according to claim 18 of compounds of formula I according to claim 1 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of a disease which is caused by inhibition of CHK1- and / or the CHK2 kinase is influenced by the compounds of the formula I according to claim 1.
20. Verwendung nach Anspruch 19, wobei die zu behandelnde Krankheit eine proliferative Störung ist.Use according to claim 19, wherein the disease to be treated is a proliferative disorder.
21. Verwendung nach Anspruch 20, wobei die proliferative Störung ein Krebs ist.The use of claim 20, wherein the proliferative disorder is a cancer.
22. Verwendung nach Anspruch 21 , wobei es sich um einen Krebs handelt, bei dem ein Kontrollpunkt-Weg mutiert oder hochreguliert ist.The use of claim 21, which is a cancer in which a control point pathway is mutated or upregulated.
23. Verwendung nach Anspruch 22, wobei die Verbindung der Formel I in Kombination mit einem anderen Therapeutikum verabreicht wird.23. Use according to claim 22, wherein the compound of the formula I is administered in combination with another therapeutic agent.
24. Verwendung nach Anspruch 23, wobei die Verbindung der Formel I und das andere Therapeutikum als Teil der gleichen pharmazeutischen Zusammensetzung verabreicht werden.Use according to claim 23, wherein the compound of formula I and the other therapeutic are administered as part of the same pharmaceutical composition.
25. Verwendung nach Anspruch 14, wobei die Verbindung der Formel I und das andere Therapeutikum als getrennte pharmazeutische25. Use according to claim 14, wherein the compound of formula I and the other therapeutic agent as a separate pharmaceutical
Zusammensetzungen verabreicht werden und die Verbindung der Λ n Λ Compositions are administered and the compound of Λ n Λ
- 131 -- 131 -
Formel I vor, gleichzeitig mit oder nach der Verabreichung der anderen Substanz verabreicht wird.Formula I is administered simultaneously with or after the administration of the other substance.
26. Verwendung nach Anspruch 25, wobei das andere Therapeutikum ein Antikrebsmittel ist.Use according to claim 25, wherein the other therapeutic agent is an anticancer agent.
27. Verwendung nach Anspruch 16, wobei es sich bei der Kinase um SGK handelt. 027. Use according to claim 16, wherein the kinase is SGK. 0
28. Verwendung nach Anspruch 27 von Verbindungen der Formel I gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines 5 Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung der SGK durch die Verbindungen nach Anspruch 1 beeinflußt werden.28. Use according to claim 27 of compounds of formula I according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the preparation of a medicament for the treatment of diseases resulting from the inhibition of SGK by the compounds Be affected according to claim 1.
29. Verwendung nach Anspruch 28 von Verbindungen gemäß Anspruch 0 1. sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und29. Use according to claim 28 of compounds according to claim 0 1 and their pharmaceutically usable derivatives, solvates and
Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von Diabetes, Fettsucht, metabolischem SyndromStereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome
(Dyslipidämie), systemischer und pulmonaler Hypertonie, Herzkreis- 5 lauferkrankungen und Nierenerkrankungen, allgemein bei jeglicher Art von Fibrosen und entzündlichen Prozessen, Krebs, Tumorzellen, Tumormetastasen, Koagulopathien, neuronaler Erregbarkeit, Glaukom, Katarakt, bakteriellen Infektionen sowie in einer anti- υ infektiösen Therapie, zur Steigerung der Lernfähigkeit und Aufmerksamkeit, sowie zur Behandlung und Prophylaxe von Zellalterung und Stress und zur Behandlung von Tinitus.Running diseases (dyslipidemia), systemic and pulmonary hypertension, Herzkreis- 5 and generally υ infectious kidney disease in any type of fibrosis and inflammatory processes, cancer, tumor cells, tumor metastases, coagulopathies, neuronal excitability, glaucoma, cataract, bacterial infections and in anti Therapy to increase the ability to learn and attention, as well as the treatment and prophylaxis of cell aging and stress and for the treatment of tinitus.
5 ■ I od* -5 ■ I or * -
30. Verwendung nach Anspruch 29, wobei es sich bei Diabetes um Diabetes mellitus, diabetische Nephropathie, diabetische Neuropathie, diabetische Angiopathie und Mikroangiopathie handelt.30. Use according to claim 29, wherein diabetes is diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
31. Verwendung nach Anspruch 29, wobei es sich bei Herzkreislauferkrankungen um kardiale Fibrosen nach Myokardinfarkt, Herzhypertrophie, Herzinsuffizienz und Arteriosklerose handelt.31. Use according to claim 29, wherein cardiovascular diseases are cardiac fibrosis after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
32. Verwendung nach Anspruch 29, wobei es sich beiUse according to claim 29, wherein
Nierenerkrankungen um Glomerulosklerose, Nephrosklerose, Nephritis, Nephropathie und Störung der Elektrolytausscheidung handelt.Renal diseases are glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, and electrolyte clearance disorder.
33. Verwendung nach Anspruch 29, wobei es sich bei Fibrosen und entzündlichen Prozessen um Leberzirrhose, Lungenfibrose, fibrosierende Pankreatitis, Rheumatismus und Arthrosen, Morbus33. Use according to claim 29, wherein fibroses and inflammatory processes are cirrhosis of the liver, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, and morbus
Crohn, chronische Bronchitis, Strahlenfibrose, Sklerodermitis, zystische Fibrose, Narbenbildung und Morbus Alzheimer handelt.Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring and Alzheimer's disease.
34. Set (Kit), bestehend aus getrennten Packungen von34th set (kit), consisting of separate packs of
(a) einer wirksamen Menge an einer Verbindung gemäß Anspruch 1 und/oder ihrer pharmazeutisch verwendbaren Derivate,(a) an effective amount of a compound according to claim 1 and / or its pharmaceutically usable derivatives,
Solvate und Stereoisomere, einschließlich deren Mischungen in allenSolvates and stereoisomers, including mixtures thereof in all
Verhältnissen, und (b) einer wirksamen Menge eines weiterenRatios, and (b) an effective amount of another
Arzneimittelswirkstoffs. Drug ingredient.
EP06762312A 2005-07-29 2006-06-30 Quadratic acid ii derivatives Withdrawn EP1910312A1 (en)

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