EP1517898A1 - Arylcarbonylpiperazines and heteroarylcarbonylpiperazines and the use thereof for treating benign and malignant tumour diseases - Google Patents

Arylcarbonylpiperazines and heteroarylcarbonylpiperazines and the use thereof for treating benign and malignant tumour diseases

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Publication number
EP1517898A1
EP1517898A1 EP03761482A EP03761482A EP1517898A1 EP 1517898 A1 EP1517898 A1 EP 1517898A1 EP 03761482 A EP03761482 A EP 03761482A EP 03761482 A EP03761482 A EP 03761482A EP 1517898 A1 EP1517898 A1 EP 1517898A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
heteroaryl
heterocyclyl
cycloalkyl
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Withdrawn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
EP03761482A
Other languages
German (de)
French (fr)
Inventor
Peter Emig
Matthias Gerlach
Emmanuel Polymeropoulos
Gilbert MÜLLER
Peter Schmidt
Silke Baasner
Eckhard Günther
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.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
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Filing date
Publication date
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1517898A1 publication Critical patent/EP1517898A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Aryl- and heteroarylcarbonylpiperazines and their use for the treatment of benign and malignant tumor diseases are provided.
  • tumors are a fundamental disease of higher organisms in the plant, animal and human kingdoms.
  • the generally recognized multi-step model of cancer development assumes that the accumulation of several mutations in a single cell changes their proliferation and differentiation behavior in such a way that a malignant state with metastasis is ultimately achieved via benign intermediate stages.
  • the term cancer or tumor hides a clinical picture with more than 200 different individual diseases. Tumor diseases can be benign or malignant.
  • the main tumors are those of the lungs, breast, stomach, cervix, prostate, head and neck, colon and rectum, liver and blood system.
  • the present invention relates to new aryl- and heteroaryl-substituted piperazinylcarbonyls and their homologues, their production and use as medicaments, in particular for the treatment of benign and malignant tumors in humans and mammals.
  • the patents WO2002008194, WO2002008192 and WO2002008190 from the company Zentaris AG describe substituted and unsubstituted acridine, quinoline or pyridinecarbonylpiperazides with anticancerogenic properties.
  • Xanthene derivatives are described in the literature as antispasmodics (US 2742472) and anti-ulcers (US3284449). A tumor effect is neither described nor suggested. Cinnoline derivatives of the above In the literature, substance types have different biological properties, for example as
  • Isoquinoline derivatives and their use as local anesthetics are described by F. Duro et al. in Farmaco, 1981, 36 (6), 400-411.
  • isoquinolines of the above Structure types Use as antipyretics, antiarrhythmics and sedatives (DE2811312, DE2818423). Tumor activity is neither described nor suggested.
  • Isoxazoles and isothiazoles are described in US4001237 and by A. Carenzi et al. Arneistoff Forsch. 1989, 39, 642 as potential antihypertensives. Furthermore, isoxazoles are described as fungicides (J. Heindl et al. Eur. J. of Med. Chem. 1975,10, 591). Isoxazoles are also used as analgesics (DE2065430), muscarinic receptor antagonists (H. g. Striegel et al. European J. of Med. Chem. 1995, 30, 839), with antibacterial properties (A. Pae et al. Biorg. Med Chem. Lett. 1999, 18, 2679) in the literature.
  • R1 fluoren-9-one, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1 H-pyrazole, where the binding can take place via any and possible ring member of the heteroaryl or aryl radical and the aromatics and heteroaromatics can be substituted one or more times or can be unsubstituted,
  • R2 O, S;
  • R3 represents one or up to 16 substituents selected from the group: H, unsubstituted or substituted alkyl, halogen, COOH, CONH2, where the substituents can be arranged vicinally or geminally on the heterocycle;
  • R4 unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylhetaryl;
  • halogen includes the halogen atoms fluorine, chlorine, bromine and iodine.
  • metal in this sense of this invention includes metal ions such as sodium, potassium, lithium, magnesium, calcium, zinc and manganese ions.
  • alkyl includes acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or mono- or polysubstituted may be substituted, having 1 to 20 carbon atoms, ie, Cr 2 o-alkanyls, C 2-20 alkenyls, and C 2 -..
  • 2 o-alkynyl case have alkenyls at least one C-C double bond and alkynyls one C-C triple bond
  • cycloalkyl for the purposes of this invention means cyclic hydrocarbons having 3-12 carbon atoms, which can be saturated or unsaturated, unsubstituted or substituted.
  • the cycloalkyl radical can also be part of a bi- or polycyclic system.
  • heterocyclyl stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical which contains at least 1, possibly 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or are different and the cyclic radical is saturated or unsaturated but not aromatic and can be unsubstituted or mono- or polysubstituted.
  • the heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • heterocyclyl radical is selected from the group containing tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, it being possible for the bond to the compound of the general formula 1 to be effected via any ring member of the heterocyclyl radical.
  • aryl means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls.
  • the radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be unsubstituted or mono- or polysubstituted , wherein the aryl substituents may be the same or different and in any and possible position of the aryl.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different and the heterocycle being unsubstituted or can be substituted one or more times; in the case of substitution on the heterocycle, the heteroaryl substituents can be identical or different and in any and possible position of the heteroaryl his.
  • the heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • the heteroaryl radical is selected from the group consisting of pyrrolyl, furyl, thienyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoliazylyl Contains, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, carbazolyl, phenazinyl, phenothiazinyl, purinyl, acridinyl, phenanthrinyl, the binding to the compounds of general formula 1 taking place via any and possible ring member of the heteroaryl radical can.
  • alkyl-cycloalkyl means for the purposes of the present invention that alkyl and cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and that Cycloalkyl, heterocyclyl, aryl or heteroaryl radical is bonded via a C1-8 alkyl group to the compound of general formula 1.
  • alkyl In connection with “alkyl”, “alkenyl” and “alkynyl”, the term substituted in the sense of this invention means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 !
  • one or more substituted means one or more, for example two, three or four times, substitution of one or more Hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH , N (alkyl) 2 , NC (0) alkyl, N (alkyl aryl) 2 , N (alkyl heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl OH) 2 , NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-aryl, S-al
  • the compounds of general formula 1 according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds of the invention may be in the form of the tautomers.
  • the compounds of general formula 1 according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
  • the compounds of general formula 1 according to the invention if they have a sufficiently basic group, such as a secondary or tertiary amine, can be converted into salts with inorganic and organic acids.
  • the pharmaceutically acceptable salts of the compounds according to the invention are preferably of the general structure 1 with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, tartaric acid , Malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, Citric acid, taurocholic acid, glutamic acid or aspartic acid are formed.
  • the salts formed include hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates , Lactates, citrates and glutaminates.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • the compounds of general formula 1 according to the invention if they contain a sufficiently acidic group, such as the carboxy group, sulfonic acid, phosphoric acid or a phenolic group, can be converted into their physiologically tolerable salts with inorganic and organic bases.
  • suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution.
  • One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the compounds of general formula 1 according to the invention can exist in various polymorphic forms, and certain modifications can be metastable.
  • the compounds according to the invention are provided according to the general formula 1, characterized in that R 1, R 2 , R 3 , n and m have the meanings given above and R represents phenyl which is unsubstituted or with one to five equal to or various (CrC 6 ) alkoxy groups is substituted, and adjacent oxygen atoms can also be linked by (CC 2 ) alkylene groups.
  • compounds according to general formula 1 are provided, characterized in that R, R 1, R 2 , R 3 , n and m have the meanings given above and R is 3,5-dimethoxyphenyl.
  • compounds according to general formula 1 are provided, characterized in that R 1, R 2 , R 3 , n and m have the meanings given above and R 4 is 3-methoxyphenyl.
  • a process for the preparation of the compounds according to the invention is claimed, which is characterized in that a carboxylic acid derivative of the general formula 2, in which R 1 and R 2 have the meanings given above and Y for a leaving group such as halogen, hydroxy , (CrCe) -alkoxy preferably methoxy and ethoxy, -O-tosyl, -O-mesyl, tetrazolyl or imidazolyl,
  • R1 aryl, heteroaryl
  • the starting compounds 2 and 3 are either commercially available or can be prepared by processes known per se.
  • the starting materials 2 and 3 represent valuable intermediates for the preparation of the compounds of formula 1 according to the invention.
  • reaction parameters to be used such as reaction temperature and duration, are known to the person skilled in the art on the basis of his expert knowledge.
  • the compounds of general formula 1 according to the invention are suitable as active ingredients in medicaments, in particular as anti-tumor agents, for the treatment of humans and mammals.
  • Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep and the like.
  • the medicinal effect of the compounds according to the invention can be based, for example, on an interaction with the tubulin system by inhibiting tubulin polymerization.
  • other known and unknown mechanisms of action to combat tumor cells are also conceivable.
  • a method for combating tumors in humans and in mammals which is characterized in that at least one compound according to the invention according to general formula 1 is administered to humans or a mammal in an amount effective for tumor treatment ,
  • the therapeutically effective dose of the respective compound according to the invention to be administered for the treatment is directed inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment.
  • the pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms.
  • the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, anti-foaming agents, gel formers, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell corrections.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, anti-foaming agents, gel formers, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell corrections.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers
  • the medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; over the oral and tongue mucosa, buccal, lingual or sublingually as tablets, lozenges, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organs, intra
  • the compounds of general structure 1 according to the invention can be extended with regard to practical therapeutic requirements by means of suitable measures in their drug action. This goal can be achieved chemically and / or galenically. Examples of achieving an extension of activity are the use of implants, liposomes, slow-release forms, nanoparticle suspensions and so-called prodrugs of the compounds according to the invention, the formation of sparingly soluble salts and complexes or the use of crystal suspensions.
  • the compounds of general structure 1 according to the invention can be used as a single substance or in combination with other cytotoxic substances, e.g. Cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate or in combination with immunomodulators or antibodies and in particular in combination with signal transduction inhibitors, such as e.g. Herceptin, Glivec or Iressa can be used.
  • cytotoxic substances e.g. Cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate or in combination with immunomodulators or antibodies and in particular in combination with signal transduction inhibitors, such as e.g. Herceptin, Glivec or Iressa can be used.
  • Drugs which contain at least one compound from the following group of the compounds according to the invention are particularly preferred: 4- [4- (3,5-Dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1) 4- [4- (6-methyl-pyridin-2-yl) piperazin-1 -carbonyl] -fluoren-9-one (2) 4- [4- (3-hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3) [4- (3,5-dimethoxy- phenyl) piperazin-1-yl] - (5-methyl-3-phenyl-isoxazol-4-yl) - methanone (4)
  • Example 3 (implementation according to scheme 1, variant 2):
  • the most preferred compounds of the present invention are substances of general formula 1 in the form of their bases or their pharmaceutically acceptable salts, which are selected from the following group:
  • the substances according to the invention were tested for their anti-proliferative activity in a proliferation test on established tumor cell lines.
  • the test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
  • the cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line. H460 (NCI 503473).
  • an RKOp27 cell system was used to investigate the cell cycle-specific effect of the substance (M. Schmidt et al.
  • RKO is a humane one Colon carcinoma line in which the cell cycle inhibitor p27 k ⁇ p1 can be induced by means of the Ecdyson expression system and brought to a cell cycle arrest specifically in G2.
  • a non-specific substance inhibits proliferation regardless of whether the RKO cell is locked in G1 or G2 or not.
  • cell cycle-specific substances such as tubulin inhibitors are only cytotoxic if cells are not locked and the cell cycle is followed.
  • Table 1 shows the cytotoxic or growth-inhibiting activities of the described compound with / without expression of p27 k ⁇ p1 .
  • the tested compounds showed no cytotoxic activities in the induced state of p27 k ⁇ p1 .
  • the results show a very potent inhibition of the proliferation of selected tumor cell lines by the compounds according to the invention.
  • the adherent growing tumor cell lines KB / HeLa, SKOV-3, SF-268 and NCI-H460 were cultivated under standard conditions in a gas incubator at 37 ° C, 5% C0 2 and 95% humidity.
  • the cells are detached with trypsin / EDTA and pelleted by centrifugation.
  • the cell pellet is then resuspended in the respective culture medium in the appropriate cell number and converted into a 96-well microtiter plate.
  • the plates are then cultivated overnight in the fumigation incubator.
  • the test substances are prepared as 1 mg / ml stock solutions in DMSO and diluted with culture medium in the appropriate concentrations on test day 2.
  • the assay is carried out in 96-well plates. By inducible expression of p27 k ⁇ p1 , the cells are completely arrested for growth, but do not die. By comparing the effectiveness on induced and non-induced cells, conclusions can be drawn about the mechanism of action (cell cycle specificity) of the therapeutic agents. Uninduced cells are sown in approximately three times the number of cells, since there is no division during the assay compared to uninduced cells (20,000 cells / well induced, 6,250 cells / well not induced). The controls are untreated cells (+/- induction). Induction is carried out with 3 ⁇ M M steron A. On the 1st day, the cells are exposed (+/- Muristeron A) and incubated for 24 hours at 37 ° C. On day 2, the test substance is added (control DMSO) and incubated for a further 45 h at 37 ° C. before a standard XTT assay is carried out.
  • Lyophylized bovine tubulin (cytoskeleton, ML 113 tubulin 30% MAPs, TL238 tubulin MAP free) is used in a concentration of 2mg / ml (ML113 in 80mM PIPES, 0.5mM EGTA, 2mM MgCl 2 , pH6.9, 1mM GTP). or 5mg / ml (TL238 in 80mM PIPES, 1mM EGTA, 0.5mM MgCl 2 , 20% (v: v) glycerol pH6.9, 1mM GTP).
  • test substances are diluted in 10% DMSO (v: v) and 5 ⁇ l of the dilutions are transferred to a 96-well microtiter plate (Nunc, half area plate).
  • a 96-well microtiter plate (Nunc, half area plate).
  • the polymerization at 340 nm is determined in a Spectramax 190 microtiter plate reader (molecular devices) using a kinetics program at 30 second intervals over a period of 20 minutes.
  • the resulting area under curve values are used to calculate the inhibition in relation to the untreated control and in the form of a concentration-effect curve applied semi-logarithmically.
  • the EC 50 is calculated using a regression analysis from the concentration-effect curve using the Graphpad Prism program.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

Abstract

The invention relates to novel arylcarboxamides and heteroarylcarboxamides of general formula (I), to the production thereof, and to the use of the same as pharmaceuticals, especially for treating tumours.

Description

Aryl- und Heteroarylcarbonylpiperazine und deren Verwendung zur Behandlung gutartiger und bösartiger TumorerkrankungenAryl- and heteroarylcarbonylpiperazines and their use for the treatment of benign and malignant tumor diseases
Für die nächsten Jahre wird ein dramatischer Anstieg der Tumorerkrankungen und der Tumor bedingten Todesfälle weltweit erwartet. In 2001 waren weltweit etwa 10 Mio Menschen an Krebs erkrankt und über 6 Mio Menschen sind an dieser Erkrankung gestorben. Die Entwicklung von Tumoren ist eine fundamentale Erkrankung höherer Organismen im Pflanzen-, im Tierreich und beim Menschen. Das allgemein anerkannte Mehrschrittmodell der Krebsentstehung geht davon aus, daß durch Anhäufung von mehreren Mutationen in einer einzelnen Zelle diese so in ihrem Proliferations- und Differenzierungs-verhalten geändert wird, daß letztendlich über benigne Zwischenstufen ein maligner Zustand mit Metastasierung erreicht wird. Hinter dem Begriff Krebs oder Tumor verbirgt sich ein Krankheitsbild mit mehr als 200 verschiedenen Einzelerkrankungen. Tumorerkrankungen können gutartig oder bösartig verlaufen. Die wichtigsten Tumoren sind die der Lunge, der Brust, des Magens, des Gebärmutterhalses, der Prostata, des Kopfes und Halses, des Dick- und Enddarmes, der Leber und des Blutsystems. Hinsichtlich Verlauf, Prognose und Therapieverhalten gibt es große Unterschiede. Mehr als 90% der erkannten Fälle betreffen solide Tumoren, die insbesondere in fortgeschrittenem Stadium bzw. bei Metastasierung schwer oder nicht therapierbar sind. Die drei Säulen der Krebsbekämpfung sind nach wie vor operative Entfernung, Bestrahlung und Chemotherapie. Trotz großer Fortschritte ist es bisher nicht gelungen, Medikamente zu entwickeln, die bei den weitverbreiteten soliden Tumoren eine deutliche Verlängerung der Überlebenszeit oder gar komplette Heilung bewirken. Es ist deshalb sinnvoll, neue Arzneimittel zur Bekämpfung der Krebserkrankung zu erfinden.A dramatic increase in tumor diseases and tumor-related deaths worldwide is expected over the next few years. In 2001, around 10 million people worldwide had cancer and over 6 million people died from the disease. The development of tumors is a fundamental disease of higher organisms in the plant, animal and human kingdoms. The generally recognized multi-step model of cancer development assumes that the accumulation of several mutations in a single cell changes their proliferation and differentiation behavior in such a way that a malignant state with metastasis is ultimately achieved via benign intermediate stages. The term cancer or tumor hides a clinical picture with more than 200 different individual diseases. Tumor diseases can be benign or malignant. The main tumors are those of the lungs, breast, stomach, cervix, prostate, head and neck, colon and rectum, liver and blood system. There are big differences in the course, prognosis and therapy behavior. More than 90% of the identified cases relate to solid tumors that are difficult or not treatable, particularly in an advanced stage or with metastasis. The three pillars of cancer control are still surgical removal, radiation, and chemotherapy. Despite great advances, it has so far not been possible to develop drugs which, in the case of the widespread solid tumors, bring about a significant increase in survival time or even complete healing. Therefore, it makes sense to invent new drugs to fight cancer.
Die vorliegende Erfindung betrifft neue Aryl- und Heteroaryl-substituierte Piperazinylcarbonyle und deren Homologe, deren Herstellung und Verwendung als Arzneimittel, insbesondere zur Behandlung von gutartigen und bösartigen Tumoren am Menschen und Säugetier. Beispielsweise werden in den Patentschriften WO2002008194, WO2002008192 und WO2002008190 von der Firma Zentaris AG substituierte und unsubstituierte Acridin- , Chinolin- oder Pyridincarbonylpiperazide mit anticancerogenen Eigenschaften beschrieben.The present invention relates to new aryl- and heteroaryl-substituted piperazinylcarbonyls and their homologues, their production and use as medicaments, in particular for the treatment of benign and malignant tumors in humans and mammals. For example, the patents WO2002008194, WO2002008192 and WO2002008190 from the company Zentaris AG describe substituted and unsubstituted acridine, quinoline or pyridinecarbonylpiperazides with anticancerogenic properties.
In den Patentschriften DE1102747 und US3843657 werden Fluoren-derivate mit antispasmolytischer bzw. mit antibakteriellen und Fungiziden-Eigenschaften beschrieben. Eine Tumorwirkung wird weder beschrieben noch nahegelegt.In the patents DE1102747 and US3843657 fluorene derivatives with anti-spasmolytic or antibacterial and fungicidal properties are described. A tumor effect is neither described nor suggested.
Xanthenderivate sind in der Literatur als Antispasmolytika (US 2742472) und Anti- Ulcera (US3284449) beschrieben. Eine Tumorwirkung wird weder beschrieben noch nahegelegt. Cinnolinderivate des o.g. Substanztypes sind in der Literatur mit unterschiedlichen biologischen Eigenschaften, beispielsweise alsXanthene derivatives are described in the literature as antispasmodics (US 2742472) and anti-ulcers (US3284449). A tumor effect is neither described nor suggested. Cinnoline derivatives of the above In the literature, substance types have different biological properties, for example as
Entzündungshemmer (J. Med. Chem. 1966, 9, 664) oder mit ZNS-Aktivitäten erwähnt (A. Stanczak et al. Pharmazie 1997, 521 , 91-97; US3299070). Eine Tumorwirkung wird weder beschrieben noch nahegelegt.Anti-inflammatory (J. Med. Chem. 1966, 9, 664) or mentioned with CNS activities (A. Stanczak et al. Pharmazie 1997, 521, 91-97; US3299070). A tumor effect is neither described nor suggested.
Isochinolinderivate und ihre Verwendung als Lokalanasthetika werden von F. Duro et al. in Farmaco, 1981 , 36(6), 400-411 beschrieben. Darüber hinaus finden Isochinoline des o.g. Strukturtyps Verwendung als Antipyretika, Antiarrhythmika und Sedativa (DE2811312, DE2818423). Eine Tumoraktivität ist weder beschrieben noch nahegelegt.Isoquinoline derivatives and their use as local anesthetics are described by F. Duro et al. in Farmaco, 1981, 36 (6), 400-411. In addition, isoquinolines of the above Structure types Use as antipyretics, antiarrhythmics and sedatives (DE2811312, DE2818423). Tumor activity is neither described nor suggested.
Isoxazole und Isothiazole werden in der Patentschrift US4001237 und von A. Carenzi et al. Arneimittel Forsch. 1989, 39, 642 als potentielle Antihypertensiva beschrieben. Desweiteren werden Isoxazole als Fungizide beschrieben (J. Heindl et al. Eur. J. of Med. Chem. 1975,10, 591 ). Isoxazole werden ausserdem als Analgetika (DE2065430), Muscarin-Rezeptor Antagonisten (H. g. Striegel et al. European J. of Med. Chem. 1995, 30, 839), mit antibakteriellen Eigenschaften (A. Pae et al. Biorg. Med. Chem. Lett. 1999, 18, 2679) in der Literatur belegt. Eine Tumoraktivität ist weder beschrieben noch nahegelegt. Pyrazole werden in der Literatur als Verbindungen mit antünflammatorischen und hypnotischen Eigenschaften (S. Sugiura et al. J.Med. Chem. 1977, 20, 80), als Anxiolytika (J.K. Chakrabarti et al. J.Med. Chem. 1989, 32, 2573), mit antibakteriellen Eigenschaften (G. Palazzino et al. Farmaco Ed. Sei. 1986, 41 , 566), als Cannabinoid Rezeptor Antagonisten (R. Lau et al. J.Med. Chem. 1999, 42, 769; R. Pertwee et al. Eur. J. Pharmacol. 1996, 296, 169), als alpha Adrenoceptor Antagonisten (G. Ermandi et al. Farmaco Ed. Sei. 1998, 53, 519), als Histamin H3-Antagonisten (WO2003004480), als Faktor Xa Inhibitoren (WO01/19798), als Sedativa und Analgetika (EP1006110), als Cholinesterase Inhibitoren (WO98/39000) und als CRF Rezeptor Antagonisten (US9720835) erwähnt. Eine Tumorwirkung wird weder beschrieben noch nahegelegt.Isoxazoles and isothiazoles are described in US4001237 and by A. Carenzi et al. Arneimittel Forsch. 1989, 39, 642 as potential antihypertensives. Furthermore, isoxazoles are described as fungicides (J. Heindl et al. Eur. J. of Med. Chem. 1975,10, 591). Isoxazoles are also used as analgesics (DE2065430), muscarinic receptor antagonists (H. g. Striegel et al. European J. of Med. Chem. 1995, 30, 839), with antibacterial properties (A. Pae et al. Biorg. Med Chem. Lett. 1999, 18, 2679) in the literature. Tumor activity is neither described nor suggested. Pyrazoles are described in the literature as compounds with anti-inflammatory and hypnotic properties (S. Sugiura et al. J.Med. Chem. 1977, 20, 80), as anxiolytics (JK Chakrabarti et al. J.Med. Chem. 1989, 32, 2573), with antibacterial properties (G. Palazzino et al. Farmaco Ed. Sei. 1986, 41, 566), as cannabinoid receptor antagonists (R. Lau et al. J.Med. Chem. 1999, 42, 769; R. Pertwee et al. Eur. J. Pharmacol. 1996, 296, 169), as alpha adrenoceptor antagonists (G. Ermandi et al. Farmaco Ed. Sei. 1998, 53, 519), as histamine H3 antagonists (WO2003004480), as Factor Xa inhibitors (WO01 / 19798), as sedatives and analgesics (EP1006110), as cholinesterase inhibitors (WO98 / 39000) and as CRF receptor antagonists (US9720835). A tumor effect is neither described nor suggested.
Es wurde jetzt überraschend gefunden, daß neue Verbindungen aus der Reihe der Aryl- und Heteroaryl-substituierten Piperazinylcarbonyl-Aromaten zur Herstellung von Arzneimitteln und diese insbesondere zur Behandlung von gutartigen und bösartigen Tumoren geeignet sind. Gemäß diesem Aspekt werden in der vorliegenden Anmeldung neue Verbindungen aus der Reihe der Aryl- und Heteroaryl-substituierten Piperazinylcarbonyl-Verbindungen gemäß der allgemeinen Formel 1 beansprucht,It has now surprisingly been found that new compounds from the series of the aryl- and heteroaryl-substituted piperazinylcarbonyl aromatics are suitable for the production of medicaments and these are particularly suitable for the treatment of benign and malignant tumors. According to this aspect, new compounds from the series of aryl- and heteroaryl-substituted piperazinylcarbonyl compounds according to general formula 1 are claimed in the present application,
wobei die Substituenten folgende Bedeutung haben:where the substituents have the following meaning:
R1 : Fluoren-9-on, Isoxazol, Cinnolin, Isothiazol, Isochinolin, 9H-Fluoren, 9H- Xanthen und 1 H-Pyrazol, wobei die Bindung über jedes beliebige und mögliche Ringglied des Heteroaryl- oder Arylrestes erfolgen kann und die Aromaten und Heteroaromaten ein- oder mehrfach substituiert oder unsubstituiert sein können,R1: fluoren-9-one, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1 H-pyrazole, where the binding can take place via any and possible ring member of the heteroaryl or aryl radical and the aromatics and heteroaromatics can be substituted one or more times or can be unsubstituted,
R2: O, S;R2: O, S;
R3: repräsentiert einen oder bis zu 16 Substituenten ausgewählt aus der Gruppe: H, unsubstituiertes oder substituiertes Alkyl, Halogen, COOH, CONH2, wobei die Substituenten vicinal oder geminal am Heterocyclus angeordnet sein können;R3: represents one or up to 16 substituents selected from the group: H, unsubstituted or substituted alkyl, halogen, COOH, CONH2, where the substituents can be arranged vicinally or geminally on the heterocycle;
R4: unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Alkylaryl, unsubstituiertes oder substituiertes Alkylhetaryl;R4: unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylhetaryl;
m, n: 0-3m, n: 0-3
Der Ausdruck „Halogen" umfasst im Sinne dieser Erfindung die Halogenatome Fluor, Chlor, Brom und lod.For the purposes of this invention, the term “halogen” includes the halogen atoms fluorine, chlorine, bromine and iodine.
Der Ausdruck „Metall" umfasst in diesem Sinne dieser Erfindung Metallionen wie Natrium-, Kalium-, Lithium-, Magnesium-, Calcium-, Zink- und Mangan-Ionen.The term "metal" in this sense of this invention includes metal ions such as sodium, potassium, lithium, magnesium, calcium, zinc and manganese ions.
Der Ausdruck „Alkyl" umfasst im Sinne dieser Erfindung acyclische gesättigte oder ungesättigte Kohlenwasserstoffreste, die verzweigt oder geradkettig sowie unsubstituiert oder ein- oder mehrfach substituiert sein können, mit 1 bis 20 C- Atomen, d.h. Cr2o-Alkanyle, C2-20-Alkenyle und C2-2o-Alkinyle. Dabei weisen Alkenyle mindestens eine C-C-Doppelbindung und Alkinyle mindestens eine C-C- Dreifachbindung auf. Vorteilhaft ist Alkyl aus der Gruppe ausgewählt, die Methyl, Ethyl, n-Propyl, 2-Propyl, n-Butyl, sec.-Butyl, tert.-Butyl, n-Pentyl, iso-Pentyl, neo- Pentyl, n-Hexyl, 2-Hexyl, n-Octyl, Ethylenyl (Vinyl), Ethinyl, Propenyl (-CH2CH=CH2; - CH=CH-CH3, -C(=CH2)- CH3), Propinyl (-CH2-C≡CH, -C≡C-CH3), Butenyl, Butinyl, Pentenyl, Pentinyl, Hexenyl, Hexinyl, Octenyl und Octinyl umfasst.Within the meaning of the term "alkyl" includes acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or mono- or polysubstituted may be substituted, having 1 to 20 carbon atoms, ie, Cr 2 o-alkanyls, C 2-20 alkenyls, and C 2 -.. 2 o-alkynyl case have alkenyls at least one C-C double bond and alkynyls one C-C triple bond Advantageously, at least selected alkyl from the group comprising methyl, ethyl, n-propyl, 2-propyl, n, -Butyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl, ethyleneyl (vinyl), ethynyl, propenyl (-CH 2 CH = CH 2 ; - CH = CH-CH 3 , -C (= CH 2 ) - CH 3 ), propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, Includes octenyl and octynyl.
Der Ausdruck „Cycloalkyl" bedeutet für die Zwecke dieser Erfindung cyclische Kohlenwasserstoffe mit 3-12 Kohlenstoffatomen, die gesättigt oder ungesättigt, unsubstituiert oder substituiert sein können. Der Cycloalkyl-Rest kann auch Teil eines bi- oder polycyclischen Systems sein.The term "cycloalkyl" for the purposes of this invention means cyclic hydrocarbons having 3-12 carbon atoms, which can be saturated or unsaturated, unsubstituted or substituted. The cycloalkyl radical can also be part of a bi- or polycyclic system.
Der Ausdruck „Heterocyclyl" steht für einen 3-, 4-, 5-, 6-, 7- oder 8-gliedrigen cyclischen organischen Rest, der mindestens 1 , ggf. 2, 3, 4 oder 5 Heteroatome enthält, wobei die Heteroatome gleich oder verschieden sind und der cyclische Rest gesättigt oder ungesättigt, aber nicht aromatisch ist und unsubstituiert oder ein- oder mehrfach substituiert sein kann. Der Heterocyclus kann auch Teil eines bi- oder polycyclischen Systems sein. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Es ist bevorzugt, dass der Heterocyclyl-Rest ausgewählt ist aus der Gruppe, die Tetrahydrofuryl, Tetrahydropyranyl, Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpholinyl enthält, wobei die Bindung an die Verbindung der allgemeinen Formel 1 über jedes beliebige Ringglied des Heterocyclyl-restes erfolgen kann.The term “heterocyclyl” stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical which contains at least 1, possibly 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or are different and the cyclic radical is saturated or unsaturated but not aromatic and can be unsubstituted or mono- or polysubstituted. The heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the heterocyclyl radical is selected from the group containing tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, it being possible for the bond to the compound of the general formula 1 to be effected via any ring member of the heterocyclyl radical.
Der Ausdruck „Aryl" bedeutet im Sinne dieser Erfindung aromatische Kohlenwasserstoffe, u.a. Phenyle, Naphthyle und Anthracenyle. Die Reste können auch mit weiteren gesättigten , (partiell) ungesättigten oder aromatischen Ringsystemen kondensiert sein. Jeder Aryl-Rest kann unsubstituiert oder einfach oder mehrfach substituiert vorliegen, wobei die Aryl-Substituenten gleich oder verschieden und in jeder beliebigen und möglichen Position des Aryls sein können.For the purposes of this invention, the term “aryl” means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls. The radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical can be unsubstituted or mono- or polysubstituted , wherein the aryl substituents may be the same or different and in any and possible position of the aryl.
Der Ausdruck „Heteroaryl" steht für einen 5-, 6- oder 7-gliedrigen cyclischen aromatischen Rest, der mindestens 1 , ggf. auch 2, 3, 4 oder 5 Heteroatome enthält, wobei die Heteroatome gleich oder verschieden sind und der Heterocyclus unsubstituiert oder ein- oder mehrfach substituiert sein kann; im Falle der Substitution am Heterocyclus können die Heteroarylsubstituenten gleich oder verschieden sein und in jeder beliebigen und möglichen Position des Heteroaryls sein. Der Heterocyclus kann auch Teil eines bi- oder polycyclischen Systems sein. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Es ist bevorzugt, dass der Heteroaryl-Rest ausgewählt ist aus der Gruppe, die Pyrrolyl, Furyl, Thienyl, Thiazolyl, Triazolyl, Tetrazolyl, Oxazolyl, Isothiazolyl,, Isoxazolyl, Pyrazolyl, Imidazolyl, Pyridinyl, Pyrimidinyl, Pyrazinyl, Triazinyl, Benzthiazolyl, Indolyl, Indolizinyl, Chinolinyl, Isochinolinyl, Cinnolinyl, Chinazolinyl, Chinoxalinyl, Phthalazinyl, Carbazolyl, Phenazinyl, Phenothiazinyl, Purinyl, Acridinyl, Phenanthrinyl, enthält, wobei die Bindung an die Verbindungen der allgemeinen Formel 1 über jedes beliebige und mögliche Ringglied des Heteroaryl-Restes erfolgen kann.The term "heteroaryl" stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different and the heterocycle being unsubstituted or can be substituted one or more times; in the case of substitution on the heterocycle, the heteroaryl substituents can be identical or different and in any and possible position of the heteroaryl his. The heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the heteroaryl radical is selected from the group consisting of pyrrolyl, furyl, thienyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoliazylyl Contains, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, carbazolyl, phenazinyl, phenothiazinyl, purinyl, acridinyl, phenanthrinyl, the binding to the compounds of general formula 1 taking place via any and possible ring member of the heteroaryl radical can.
Die Ausdrücke „Alkyl-Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" oder „Alkyl- Heteroaryl" bedeuten für die Zwecke der vorliegenden Erfindung, dass Alkyl und Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl die oben definierten Bedeutungen haben und der Cycloalkyl-, Heterocyclyl-, Aryl- bzw. Heteroaryl-Rest über eine C1-8 -Alkyl-Gruppe an die Verbindung der allgemeinen Formel 1 gebunden ist.The terms "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" or "alkyl-heteroaryl" mean for the purposes of the present invention that alkyl and cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and that Cycloalkyl, heterocyclyl, aryl or heteroaryl radical is bonded via a C1-8 alkyl group to the compound of general formula 1.
Im Zusammenhang mit „Alkyl", „Alkenyl" und „Alkinyl" versteht man unter dem Begriff substituiert im Sinne dieser Erfindung die Substitution eines Wasserstoffrestes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl- Aryl, NH-Alkyl-Heteroaryl, NH-Heterocyclyl, NH-Alkyl-OH, N(Alkyl)2, N(Alkyl-Aryl)2, N(Alkyl-Heteroaryl)2, N(Heterocyclyl)2! N(Alkyl-OH)2, NO, N02> SH, S-Alkyl, S- Cycloalkyl, S-Aryl, S-Heteroaryl, S-Alkyl-Aryl, S-Alkyl-Heteroaryl, S-Heterocyclyl, S- Alkyl-OH, S-Alkyl-SH, S-Alkyl, S-S-Cycloalkyl, S-S-Aryl, S-S-Heteroaryl, S-S-Alkyl- Aryl, S-S-Alkyl-Heteroaryl, S-S-Heterocyclyl, SS-Alkyl-OH, S-S-Alkyl-SH, S-S-Alkyl- C(O)-NH-Heterocyclyl, OH, O-Alkyl, O-Cycloalkyl, O-Alkylcycloalkyl, O-Aryl, O- Heteroaryl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Heterocyclyl, O-Alkylheterocyclyl, O- Alkyl-OH, O-Alkyl-O-Alkyl, 0-S02-N(Alkyl)2, 0-S02-OH, 0-SO2-0-Alkyl, 0-SO2-0- Cycloalkyl, 0-S02-0-Heterocycloalkyl, 0-S02-0-Alkylcycloalkyl, 0-S02-0- Alkylheterocycloalkyl, O-S02-0-Aryl, 0-S02-O-Heteroaryl, O-S02-O-AIkylaryl, O- SO2-0-Alkylheteroaryl, O-S02-Alkyl, O-SO2-Cycloalkyl, 0-S02-Heterocycloalkyl, O- SO2-Alkylcycloalkyl, 0-S02-Alkylheterocycloalkyl, 0-S02-Aryl, 0-S02-Heteroaryl, O- S02-Alkylaryl, 0-S02-Alkylheteroaryl, 0-C(0)-Alkyl, 0-C(0)-Cycloalkyl, O-C(O)- Heterocycloalkyl, 0-C(0)-Alkylcycloalkyl, O-C(0)-Alkylheterocycloalkyl, 0-C(0)-Aryl, 0-C(0)-HeteroaryI, 0-C(O)-Alkylaryl, 0-C(0)-Alkylheteroaryl, O-C(O)0-Alkyl, O- C(0)0-Cycloalkyl, O-C(O)0-Heterocycloalkyl, 0-C(0)0-Alkylcycloalkyl, O-C(0)0- Alkylheterocycloalkyl, 0-C(0)O-Aryl, 0-C(0)0-Heteroaryl, O-C(0)0-Alkylaryl, O- C(O)0-Alkylheteroaryl, 0-C(O)NH-Alkyl, 0-C(O)NH-Cycloalkyl, 0-C(0)NH- Heterocycloalkyl, O-C(0)NH-Alkylcycloalkyl, 0-C(0)NH-Alkylheterocycloalkyl, O- C(0)NH-Aryl, 0-C(0)NH-Heteroaryl, O-C(O)NH-Alkylaryl, 0-C(0)NH-Alkylheteroaryl, 0-C(0)N(Alkyl)2, 0-C(0)N(Cycloalkyl)2, 0-C(0)N(Heterocycloalkyl)2, O- C(O)N(Alkylcycloalkyl)2, 0-C(O)N(Alkylheterocycloalkyl)2, 0-C(0)N(Aryl)2, O- C(O)N(Heteroaryl)2, 0-C(0)N(Alkylaryl)2, O-C(0)N(Alkylheteroaryl)2, 0-P(O)(OH)2, 0-P(0)(O-Metall)2, 0-P(O)(0-Alkyl)2, 0-P(0)(0-Cycloalkyl)2, O-P(0)(0-Aryl)2, O- P(0)(0-Heteroaryl)2, 0-P(0)(O-Alkylaryl)2, 0-P(0)(0-Alkylheteroaryl)2lO-P(0)(N- Alkyl)2(N-Alkyl)2,0-P(0)(N-Cycloalkyl)2(N-Cycloalkyl)2,0-P(0)(N- Heterocycloalkyl)2(N-Heterocyclo-alkyl)2, 0-P(0)(N-Aryl)2(N-Aryl)2, O-P(0)(N- Heteroaryl)2(N-Heteroaryl)2, 0-P(0)(N-Alkyl-aryl)2(N-Alkylaryl)2, 0-P(0)(N-In connection with “alkyl”, “alkenyl” and “alkynyl”, the term substituted in the sense of this invention means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 ! N (alkyl-OH) 2 , NO, N0 2> SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl , S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, S-alkyl, SS-cycloalkyl, SS-aryl, SS-heteroaryl, SS-alkyl-aryl, SS-alkyl-heteroaryl, SS-heterocyclyl, SS -Alkyl-OH, SS-alkyl-SH, SS-alkyl- C (O) -NH-heterocyclyl, OH, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O- heteroaryl, O-alkyl- Aryl, O-alkyl heteroaryl, O-heterocyclyl, O-alkyl heterocyclyl, O-alkyl-OH, O-alkyl-O-alkyl, 0-S0 2 -N (alkyl) 2 , 0-S0 2 -OH, 0- SO 2 -0-alkyl, 0-SO 2 -0- cycloalkyl, 0-S0 2 -0-heterocycloalkyl, 0-S0 2 -0-alkylcycloalkyl, 0-S0 2 -0- alkyl heterocycloalkyl, O-S0 2 -0-aryl, 0-S0 2 -O-heteroaryl, O-S0 2 -O-alkylaryl, O- SO 2 -0-alkyl heteroaryl, O-S0 2 - Alkyl, O-SO 2 cycloalkyl, 0-S0 2 heterocycloalkyl, O- SO 2 alkylcycloalkyl, 0-S0 2 alkyl heterocycloalkyl, 0-S0 2 aryl, 0-S0 2 heteroaryl, O- S0 2 alkylaryl , 0-S0 2 -alkyl heteroaryl, 0-C (0) -alkyl, 0-C (0) -cycloalkyl, OC (O) - Heterocycloalkyl, 0-C (0) -alkylcycloalkyl, OC (0) -alkyl heterocycloalkyl, 0-C (0) -aryl, 0-C (0) -heteroaryI, 0-C (O) -alkylaryl, 0-C (0 ) -Alkyl heteroaryl, OC (O) 0-alkyl, O- C (0) 0-cycloalkyl, OC (O) 0-heterocycloalkyl, 0-C (0) 0-alkylcycloalkyl, OC (0) 0- alkyl heterocycloalkyl, 0- C (0) O-aryl, 0-C (0) 0-heteroaryl, OC (0) 0-alkylaryl, O- C (O) 0-alkylheteroaryl, 0-C (O) NH-alkyl, 0-C ( O) NH-cycloalkyl, 0-C (0) NH-heterocycloalkyl, OC (0) NH-alkylcycloalkyl, 0-C (0) NH-alkyl heterocycloalkyl, O- C (0) NH-aryl, 0-C (0) NH-heteroaryl, OC (O) NH-alkylaryl, 0-C (0) NH-alkyl heteroaryl, 0-C (0) N (alkyl) 2 , 0-C (0) N (cycloalkyl) 2 , 0-C ( 0) N (heterocycloalkyl) 2 , O- C (O) N (alkylcycloalkyl) 2 , 0-C (O) N (alkylheterocycloalkyl) 2 , 0-C (0) N (aryl) 2 , O- C (O) N (heteroaryl) 2 , 0-C (0) N (alkylaryl) 2 , OC (0) N (alkylheteroaryl) 2 , 0-P (O) (OH) 2 , 0-P (0) (O-metal) 2 , 0-P (O) (0-alkyl) 2 , 0-P (0) (0-cycloalkyl) 2 , OP (0) (0-aryl) 2 , O- P (0) (0-heteroaryl) 2 , 0-P (0) (O-alkylaryl) 2 , 0-P (0) (0-alkylheteroaryl) 2l OP (0) (N-alkyl) 2 (N-alkyl) 2 , 0-P (0) (N-cycloalkylene kyl) 2 (N-cycloalkyl) 2 , 0-P (0) (N-heterocycloalkyl) 2 (N-heterocycloalkyl) 2 , 0-P (0) (N-aryl) 2 (N-aryl) 2 , OP (0) (N- heteroaryl) 2 (N-heteroaryl) 2, 0-P (0) (N-alkyl-aryl) 2 (N-alkylaryl) 2, 0-P (0) (N-
Alkylheteroaryl)2(N-Alkylheteroaryl)2, CHO, C(0)-Alkyl, C(S)-Alkyl, C(O)-Aryl, C(S)- Aryl, C(0)-Alkyl-Aryl, C(S)-Alkyl-Aryl, C(0)-Heterocyclyl, C(0)-Heteroaryl, C(O)-Alkyl- Heteroaryl, C(S)-HeterocycIyl, CO2H, C02-Alkyl, C02-Cyclyl, C02-Heterocyclyl, C02- Aryl, COs-Heteroaryl, C02-Alkyl-Aryl, C(0)-NH2, C(0)NH-Alkyl, C(0)NH-Aryl, C(O)NH-Heterocyclyl, C(O)NH-Alkyl-Heterocyclyl, C(0)N(Alkyl)2, C(0)N(Alkyl-Aryl)2, C(0)N(Alkyl-Heteroaryl)2, C(0)N(Heterocyclyl)2, SO-Alkyl, S02-Alkyl, SO2-Aryl, S02- Alkylaryl, SO2-Heteroaryl, S02-Alkylheteroaryl, S02NH2, S03H, CF3, CHO, CHS, Alkyl, Cycloalkyl, Aryl, Alkylaryl, Heteroaryl, Alkylheterocyclyl und/oder Heterocyclyl, wobei unter mehrfach substituierten Resten solche zu verstehen sind, die entweder an verschiedenen oder an gleichen Atomen mehrfach, z.B. zwei- oder dreifach substituiert sind, beispielsweise dreifach am gleichen C-Atom wie im Falle von CF3, - CH2CF3 oder an verschiedenen Stellen wie im Falle von -CH(OH)-CH=CH-CHCI2. Die Mehrfachsubstitution kann mit dem gleichen oder verschiedenen Substituenten erfolgen.Alkylheteroaryl) 2 (N-alkylheteroaryl) 2 , CHO, C (0) alkyl, C (S) alkyl, C (O) aryl, C (S) aryl, C (0) alkyl aryl, C (S) alkyl aryl, C (0) heterocyclyl, C (0) heteroaryl, C (O) alkyl heteroaryl, C (S) heterocycyl, CO 2 H, C0 2 alkyl, C0 2 - Cyclyl, C0 2 heterocyclyl, C0 2 aryl, COs heteroaryl, C0 2 alkyl aryl, C (0) -NH 2 , C (0) NH alkyl, C (0) NH aryl, C (O ) NH heterocyclyl, C (O) NH alkyl heterocyclyl, C (0) N (alkyl) 2 , C (0) N (alkyl aryl) 2 , C (0) N (alkyl heteroaryl) 2 , C (0) N (heterocyclyl) 2 , SO-alkyl, S0 2 alkyl, SO 2 aryl, S0 2 alkylaryl, SO 2 heteroaryl, S0 2 alkyl heteroaryl, S0 2 NH 2 , S0 3 H, CF 3 , CHO, CHS, alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkylheterocyclyl and / or heterocyclyl, where multiply substituted radicals are to be understood as those which are multiply, for example triply or, for example, triply substituted on different or on the same atoms at the same C atom as in the case of CF 3 , - CH 2 CF 3 or at different points as in the F all of -CH (OH) -CH = CH-CHCI 2 . The multiple substitution can be carried out with the same or different substituents.
In Bezug auf Aryl, Heterocyclyl, Heteroaryl, Alkyl-Aryl sowie Cycloalkyl versteht man im Sinne dieser Erfindung unter ein- oder mehrfach substituiert die ein- oder mehrfache z.B. zwei-, drei- oder vierfache Substitution eines oder mehrerer Wasserstoffatome des Ringsystemes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, NH-Heterocyclyl, NH-Alkyl-OH, N(Alkyl)2, NC(0)Alkyl, N(Alkyl-Aryl)2, N(Alkyl-Heteroaryl)2, N(Heterocyclyl)2, N(Alkyl- OH)2, NO, NO2, SH, S-Alkyl, S-Aryl, S-Heteroaryl, S-Alkyl-Aryl, S-Alkyl-Heteroaryl, S- Heterocyclyl, S-Alkyl-OH, S-Alkyl-SH, OH, O-Alkyl, O-Cycloalkyl, O-Alkylcycloalkyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Heterocyclyl, O- Alkylheterocyclyl, O-Alkyl-OH, O-Alkyl-O-Alkyl, 0-SO2-N(Alkyl)2, 0-SO2-OH, 0-S02- O-Alkyl, 0-S02-0-Cycloalkyl, 0-SO2-0-Heterocycloalkyl, O-SO2-0-Alkylcycloalkyl, 0-S02-0-Alkylheterocycloalkyl, 0-S02-0-Aryl, 0-S02-0-Heteroaryl, 0-S02-0- Alkylaryl, O-S02-0-Alkylheteroaryl, 0-S02-Alkyl, 0-S02-Cycloalkyl, 0-S02- Heterocycloalkyl, O-S02-Alkylcycloalkyl, 0-S02-Alkylheterocycloalkyl, O-S02-Aryl, O- S02-Heteroaryl, O-S02-Alkylaryl, O-S02-Alkylheteroaryl, 0-C(0)-Alkyl, O-C(O)- Cycloalkyl, 0-C(0)-Heterocycloalkyl, 0-C(0)-Alkylcycloalkyl, O-C(O)-With regard to aryl, heterocyclyl, heteroaryl, alkyl-aryl and cycloalkyl, for the purposes of this invention, one or more substituted means one or more, for example two, three or four times, substitution of one or more Hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH , N (alkyl) 2 , NC (0) alkyl, N (alkyl aryl) 2 , N (alkyl heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl OH) 2 , NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkylheterocyclyl, O-alkyl-OH, O-alkyl-O-alkyl, 0-SO 2 -N (alkyl) 2 , 0-SO 2 -OH, 0-S0 2 - O-alkyl, 0-S0 2 -0-cycloalkyl, 0-SO 2 -0-heterocycloalkyl, O-SO 2 -0-alkylcycloalkyl, 0-S0 2 -0-alkylheterocycloalkyl, 0-S0 2 -0-aryl, 0-S0 2 -0-heteroaryl, 0-S0 2 -0- alkylaryl, O-S0 2 -0-alkylheteroaryl, 0-S0 2 - alkyl, 0-S0 2 -cycloalkyl, 0-S0 2 - heterocycloalkyl, O-S0 2 -alkyl cycloalkyl, 0-S0 2 -alkyl heterocycloalkyl, O-S0 2 -aryl, O-S0 2 -heteroaryl, O-S0 2 -alkylaryl , O-S0 2 alkyl heteroar yl, 0-C (0) -alkyl, OC (O) - cycloalkyl, 0-C (0) -heterocycloalkyl, 0-C (0) -alkylcycloalkyl, OC (O) -
Alkylheterocycloalkyl, 0-C(0)-Aryl, O-C(0)-Heteroaryl, O-C(0)-Alkylaryl, O-C(O)- Alkylheteroaryl, 0-C(0)O-Alkyl, 0-C(O)0-Cycloalkyl, 0-C(0)0-Heterocycloalkyl, O- C(O)O-Alkylcycloalkyl, O-C(0)0-Alkylheterocycloalkyl, O-C(0)0-Aryl, 0-C(0)0- Heteroaryl, 0-C(O)0-Alkylaryl, O-C(0)0-Alkylheteroaryl, 0-C(0)NH-Alkyl, O- C(O)NH-Cycloalkyl, 0-C(0)NH-Heterocycloalkyl, 0-C(O)NH-Alkylcycloalkyl, O- C(O)NH-Alkylheterocycloalkyl, 0-C(O)NH-Aryl, 0-C(0)NH-Heteroaryl, 0-C(O)NH- Alkylaryl, 0-C(0)NH-Alkylheteroaryl, 0-C(0)N(Alkyl)2, O-C(0)N(Cycloalkyl)2, O- C(O)N(Heterocycloalkyl)2, 0-C(O)N(Alkylcycloalkyl)2, O-Alkyl heterocycloalkyl, 0-C (0) aryl, OC (0) heteroaryl, OC (0) alkylaryl, OC (O) - alkyl heteroaryl, 0-C (0) O-alkyl, 0-C (O) 0- Cycloalkyl, 0-C (0) 0-heterocycloalkyl, O- C (O) O-alkylcycloalkyl, OC (0) 0-alkylheterocycloalkyl, OC (0) 0-aryl, 0-C (0) 0- heteroaryl, 0- C (O) 0-alkylaryl, OC (0) 0-alkylheteroaryl, 0-C (0) NH-alkyl, O- C (O) NH-cycloalkyl, 0-C (0) NH-heterocycloalkyl, 0-C ( O) NH-alkylcycloalkyl, O- C (O) NH-alkyl heterocycloalkyl, 0-C (O) NH-aryl, 0-C (0) NH-heteroaryl, 0-C (O) NH-alkylaryl, 0-C ( 0) NH-alkylheteroaryl, 0-C (0) N (alkyl) 2 , OC (0) N (cycloalkyl) 2 , O- C (O) N (heterocycloalkyl) 2 , 0-C (O) N (alkylcycloalkyl) 2 , O-
C(O)N(Alkylheterocycloalkyl)2, O-C(0)N(Aryl)2, 0-C(0)N(Heteroaryl)2, O- C(O)N(Alkylaryl)2, O-C(O)N(Alkylheteroaryl)2, 0-P(O)(OH)2, O-P(O)(0-Metall)2, O- P(O)(O-Alkyl)2, 0-P(0)(O-Cycloalkyl)2, 0-P(0)(0-Aryl)2, O-P(0)(0-Heteroaryl)2, O- P(O)(0-Alkylaryl)2, 0-P(O)(0-Alkylheteroaryl)2,0-P(0)(N-Alkyl)2(N-Alkyl)2,0-P(0)(N- Cycloalkyl)2(N-Cycloalkyl)2,0-P(0)(N-Heterocycloalkyl)2(N-Hetero-cycloalkyl)2> O- P(O)(N-Aryl)2(N-Aryl)2, O-P(0)(N-Heteroaryl)2(N-Heteroaryl)2, 0-P(0)(N-C (O) N (alkylheterocycloalkyl) 2 , OC (0) N (aryl) 2 , 0-C (0) N (heteroaryl) 2 , O- C (O) N (alkylaryl) 2 , OC (O) N ( Alkylheteroaryl) 2 , 0-P (O) (OH) 2 , OP (O) (0-metal) 2 , O- P (O) (O-alkyl) 2 , 0-P (0) (O-cycloalkyl) 2 , 0-P (0) (0-aryl) 2 , OP (0) (0-heteroaryl) 2 , O- P (O) (0-alkylaryl) 2 , 0-P (O) (0-alkylheteroaryl) 2 , 0-P (0) (N-alkyl) 2 (N-alkyl) 2 , 0-P (0) (N-cycloalkyl) 2 (N-cycloalkyl) 2 , 0-P (0) (N-heterocycloalkyl ) 2 (N-heterocycloalkyl) 2> O- P (O) (N-aryl) 2 (N-aryl) 2 , OP (0) (N-heteroaryl) 2 (N-heteroaryl) 2 , 0-P (0) (N-
Alkylaryl)2(N-Alkylaryl)2, O-P(O)(N-Alkylheteroaryl)2(N-Alkylheteroaryl)2, CHO, C(O)- Alkyl, C(S)-Alkyl, C(0)-Aryl, C(S)-Aryl, C(0)-Alkyl-Aryl, C(S)-Alkyl-Aryl, C(O)- Heterocyclyl, C(S)-Heterocyclyl, CO2H, CO2-Alkyl, CO2-Alkyl-aryl, C(0)-NH2, C(O)NH-Alkyl, C(0)NH-Aryl, C(O)NH-Heterocyclyl, C(0)N(Alkyl)2, C(O)N(Alkyl-Aryl)2, C(O)N(Alkyl-Heteroaryl)2, C(0)N(Heterocyclyl)2, SO-Alkyl, S02-Alkyl, SO2-Aryl, S02- Alkylaryl, SO2-Heteroaryl, S02-Alkylheteroaryl, SO2NH2, S03H, CF3, CHO, CHS, Alkyl, Cycloalkyl, Aryl, Alkylaryl, Heteroaryl, Alkylheterocyclyl und/oder Heterocyclyl, an einem oder ggf. verschiedenen Atomen (wobei ein Substituent ggf. seinerseits substituiert sein kann). Die Mehrfachsubstitution erfolgt dabei mit dem gleichen oder mit unterschiedlichen Substituenten.Alkylaryl) 2 (N-alkylaryl) 2 , OP (O) (N-alkylheteroaryl) 2 (N-alkylheteroaryl) 2 , CHO, C (O) - alkyl, C (S) -alkyl, C (0) -aryl, C (S) aryl, C (0) alkyl aryl, C (S) alkyl aryl, C (O) heterocyclyl, C (S) heterocyclyl, CO 2 H, CO 2 alkyl, CO 2 -Alkyl-aryl, C (0) -NH 2 , C (O) NH-alkyl, C (0) NH-aryl, C (O) NH-heterocyclyl, C (0) N (alkyl) 2 , C (O ) N (alkyl-aryl) 2 , C (O) N (alkyl-heteroaryl) 2 , C (0) N (heterocyclyl) 2 , SO-alkyl, S0 2 -alkyl, SO 2 -aryl, S0 2 - alkylaryl, SO 2 heteroaryl, S0 2 alkyl heteroaryl, SO 2 NH 2 , S0 3 H, CF 3 , CHO, CHS, Alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkylheterocyclyl and / or heterocyclyl, on one or possibly different atoms (where a substituent may in turn be substituted). The multiple substitution takes place with the same or with different substituents.
Sofern die erfindungsgemäßen Verbindungen der allgemeinen Formel 1 mindestens ein Asymmetriezentrum aufweisen, können sie in Form ihrer Racemate, in Form der reinen Enantiomeren und/oder Diastereomeren oder in Form von Mischungen dieser Enantiomeren und/oder Diastereomeren vorliegen. Die Mischungen können in jedem beliebigen Mischungsverhältnis der Stereoisomeren vorliegen.If the compounds of general formula 1 according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The mixtures can be present in any mixing ratio of the stereoisomers.
Sofern möglich, können die erfindungsgemäßen Verbindungen in Form der Tautomeren vorliegen.If possible, the compounds of the invention may be in the form of the tautomers.
So lassen sich beispielsweise die erfindungsgemäßen Verbindungen gemäß der allgemeinen Formel 1 , welche ein oder mehrere Chiralitätszentren aufweisen und die als Racemate auftreten, nach an sich bekannten Methoden in ihre optischen Isomeren, also Enantiomere oder Diastereomere auftrennen. Die Trennung kann durch Säulentrennung an chiralen Phasen oder durch Umkristallisation aus einem optisch aktiven Lösungsmittel oder unter Verwendung einer optisch aktiven Säure oder Base oder durch Derivatisierung mit einem optisch aktiven Reagenz, wie beispielsweise einem optisch aktiven Alkohol, und anschließender Abspaltung des Restes erfolgen.For example, the compounds of general formula 1 according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel 1 können, falls sie eine ausreichend basische Gruppe, wie zum Beispiel ein sekundäres oder tertiäres Amin besitzen, mit anorganischen und organischen Säuren in Salze überführt werden. Vorzugsweise werden die pharmazeutisch annehmbaren Salze der erfindungsgemäßen Verbindungen gemäß der allgemeinen Struktur 1 mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, p- Toluolsulfonsäure, Kohlensäure, Ameisensäure, Essigsäure, Sulfoessigsäure, Trifluoressigsäure, Oxalsäure, Malonsäure, Maleinsäure, Bernsteinsäure, Weinsäure, Traubensäure, Äpfelsäure, Embonsäure, Mandelsäure, Fumarsäure, Milchsäure, Citronensäure, Taurocholinsäure, Glutaminsäure oder Asparaginsäure gebildet. Bei den gebildeten Salzen handelt es sich u.a. um Hydrochloride, Hydrobromide, Sulfate, Phosphate, Methansulfonate, Tosylate, Carbonate, Hydrogencarbonate, Formiate, Acetate, Sulfoacetate, Triflate, Oxalate, Malonate, Maleate, Succinate, Tartrate, Malate, Embonate, Mandelate, Fumarate, Lactate, Citrate und Glutaminate. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.The compounds of general formula 1 according to the invention, if they have a sufficiently basic group, such as a secondary or tertiary amine, can be converted into salts with inorganic and organic acids. The pharmaceutically acceptable salts of the compounds according to the invention are preferably of the general structure 1 with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, tartaric acid , Malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, Citric acid, taurocholic acid, glutamic acid or aspartic acid are formed. The salts formed include hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates , Lactates, citrates and glutaminates. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel 1 können, falls sie eine ausreichend saure Gruppe, wie zum Beispiel die Carboxygruppe, Sulfonsäure, Phosphorsäure oder eine phenolische Gruppe enthalten, mit anorganischen und organischen Basen in ihre physiologisch verträglichen Salze überführt werden. Als anorganische Basen kommen beispielsweise Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, als organische Basen Ethanolamin, Diethanolamin, Triethanolamin, Cyclohexylamin, Dibenzylethylendiamin und Lysin in Betracht. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.The compounds of general formula 1 according to the invention, if they contain a sufficiently acidic group, such as the carboxy group, sulfonic acid, phosphoric acid or a phenolic group, can be converted into their physiologically tolerable salts with inorganic and organic bases. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
Ebenfalls bevorzugt sind Solvate und insbesondere Hydrate der erfindungsgemäßen Verbindungen, die z. B. durch Kristallisation aus einem Lösungsmittel oder aus wässriger Lösung erhalten werden können. Es können sich dabei ein, zwei, drei oder beliebig viele Solvat-oder Wasser-Moleküle mit den erfindungsgemäßen Verbindungen zu Solvaten und Hydraten verbinden.Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution. One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
Es ist bekannt, dass chemische Substanzen Festkörper ausbilden, die in verschiedenen Ordnungszuständen vorliegen, die man als polymorphe Formen oder Modifikationen bezeichnet. Die verschiedenen Modifikationen einer polymorphen Substanz können sich in ihren physikalischen Eigenschaften stark unterscheiden. Die erfindungsgemäßen Verbindungen der allgemeinen Formel 1 können in verschiedenen polymorphen Formen vorliegen, dabei können bestimmte Modifikationen metastabil sein. Gemäß einer weiteren Ausführungsform werden die erfindungsgemässen Verbindungen gemäß der allgemeinen Formel 1 bereitgestellt, dadurch gekennzeichnet, daß R-i, R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R für Phenyl steht, welches unsubstituiert oder mit ein bis fünf gleich oder verschiedenen (CrC6)-Alkoxygruppen substituiert ist, wobei benachbarte Sauerstoffatome auch durch (C C2)-Alkylen-Gruppen verknüpft sein können.It is known that chemical substances form solids which are in various states of order, which are referred to as polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds of general formula 1 according to the invention can exist in various polymorphic forms, and certain modifications can be metastable. According to a further embodiment, the compounds according to the invention are provided according to the general formula 1, characterized in that R 1, R 2 , R 3 , n and m have the meanings given above and R represents phenyl which is unsubstituted or with one to five equal to or various (CrC 6 ) alkoxy groups is substituted, and adjacent oxygen atoms can also be linked by (CC 2 ) alkylene groups.
Gemäß einer weiteren Ausführungsform werden Verbindungen gemäß der allgemeinen Formel 1 bereitgestellt, dadurch gekennzeichnet, daß R, R-i, R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R für 3,5- Dimethoxyphenyl steht.According to a further embodiment, compounds according to general formula 1 are provided, characterized in that R, R 1, R 2 , R 3 , n and m have the meanings given above and R is 3,5-dimethoxyphenyl.
Gemäß einer weiteren Ausführungsform werden Verbindungen gemäß der allgemeinen Formel 1 bereitgestellt, dadurch gekennzeichnet, daß R-i, R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R4 für 3-Methoxyphenyl steht.According to a further embodiment, compounds according to general formula 1 are provided, characterized in that R 1, R 2 , R 3 , n and m have the meanings given above and R 4 is 3-methoxyphenyl.
Am meisten bevorzugt sind Verbindungen gemäß der allgemeinen Formel 1 , die in der folgenden Auswahl getroffen sind:Most preferred are compounds according to general formula 1, which are made in the following selection:
4-[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (1 ) 4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-carbonyl]-fluoren-9-on (2) 4-[4-(3-Hydroxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (3) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)- methanon (4)4- [4- (3,5-Dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1) 4- [4- (6-methyl-pyridin-2-yl) piperazin-1 -carbonyl] -fluoren-9-one (2) 4- [4- (3-hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3) [4- (3,5-dimethoxy- phenyl) piperazin-1-yl] - (5-methyl-3-phenyl-isoxazol-4-yl) - methanone (4)
Cinnolin-4-yl-[4-(3,5-dimethyl-phenyl)-piperazin-1-yl]-methanon (5) Cinnolin-4-yl-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-methanon (6) (3,5-Bis-methylsulfanyl-isothiazol-4-yl)-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]- methanon (7) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-isochinolin-1 -yl-methanon (8) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-fluoren-1 -yl)-methanon (9) (9H-Fluoren-9-yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (10) (9H-Fluoren-1-yl)-[4-(3-methoxyphenyl)-piperazin-1-yl]-methanon (11) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (12) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (13) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (14) [4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (15) [4-(3-Hydroxy-phenyl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (16) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-[1 -(4-nitrophenyl)-5-trifluormethyl-1 H- pyrazol-4-yl]-methanon (17)Cinnolin-4-yl- [4- (3,5-dimethylphenyl) piperazin-1-yl] methanone (5) Cinnolin-4-yl- [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone (6) (3,5-bis-methylsulfanyl-isothiazol-4-yl) - [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] - methanone (7) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] isoquinoline-1-yl methanone (8) [4- (3,5-dimethoxyphenyl) piperazin-1 -yl] - (9H-fluoren-1 -yl) -methanone (9) (9H-fluoren-9-yl) - [4- (3-methoxyphenyl) piperazin-1 -yl] -methanone (10) (9H -Fluoren-1-yl) - [4- (3-methoxyphenyl) piperazin-1-yl] methanone (11) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] - (9H-xanthene-9-yl) methanone (12) [4- (3-methoxy-phenyl) piperazin-1-yl ] - (9H-xanthene-9-yl) methanone (13) [4- (3-methoxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) methanone (14) [4- (6-Methyl-pyridin-2-yl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) methanone (15) [4- (3- Hydroxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (16) [4- (3,5-dimethoxy-phenyl) piperazin-1-yl] - [1 - (4-nitrophenyl) -5-trifluoromethyl-1H-pyrazol-4-yl] methanone (17)
Gemäß einem weiteren Aspekt der Erfindung wird ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen beansprucht, welches dadurch gekennzeichnet ist, daß ein Carbonsäure-Derivat der allgemeinen Formel 2, worin Ri und R2 die vorstehend genannten Bedeutungen besitzen und Y für eine Abgangsgruppe wie Halogen, Hydroxy, (CrCe)-Alkoxy vorzugsweise Methoxy und Ethoxy, -O-Tosyl, -O- Mesyl, Tetrazolyl oder Imidazolyl steht,According to a further aspect of the invention, a process for the preparation of the compounds according to the invention is claimed, which is characterized in that a carboxylic acid derivative of the general formula 2, in which R 1 and R 2 have the meanings given above and Y for a leaving group such as halogen, hydroxy , (CrCe) -alkoxy preferably methoxy and ethoxy, -O-tosyl, -O-mesyl, tetrazolyl or imidazolyl,
R1 : Aryl, Heteroaryl R1: aryl, heteroaryl
Formel 2 Formel 3Formula 2 Formula 3
mit einem Amin der allgemeinen Formel 3, worin R4, m und n die vorstehend genannten Bedeutungen besitzen, gegebenenfalls unter Verwendung eines Kondensationsmittels und/oder Katalysators sowie von Verdünnungs- und Hilfsmitteln unter Bildung der gewünschten Produktes gemäss der allgemeinen Formel 1 umgesetzt wird. Synthese der erfindungsgemäßen Verbindungenwith an amine of the general formula 3, in which R 4 , m and n have the meanings given above, optionally using a condensing agent and / or catalyst and diluents and auxiliaries to form the desired product according to general formula 1. Synthesis of the compounds according to the invention
Die Verbindungen der allgemeinen Formel 1 sind beispielsweise gemäß dem folgenden Schema 1 erhältlich:The compounds of the general formula 1 can be obtained, for example, according to the following scheme 1:
Schema 1Scheme 1
Variante 1 :Version 1 :
O π / — v Py-BOP / VO π / - v Py-BOP / V
R1 Λx Λ + »T \ / « — N N--MMnetthhuyll-- - ° 1 -\_ΛR4 morpholin R1R1 Λ x Λ + "T \ /" - N N - MMnetthhuyll-- - ° 1 - \ _ Λ R4 morpholine R1
X= OH, Cl Variante 2:X = OH, Cl variant 2:
1 1
Die Ausgangsverbindungen 2 und 3 sind entweder im Handel erhältlich oder können nach an sich bekannten Verfahrensweisen hergestellt werden. Die Edukte 2 und 3 stellen wertvolle Zwischenverbindungen für die Herstellung der erfindungsgemäßen Verbindungen der Formel 1 dar.The starting compounds 2 and 3 are either commercially available or can be prepared by processes known per se. The starting materials 2 and 3 represent valuable intermediates for the preparation of the compounds of formula 1 according to the invention.
Die gegebenenfalls zu verwendenden Lösungs- und Hilfsmittel und anzuwendenden Reaktionsparameter wie Reaktionstemperatur und -dauer sind dem Fachmann aufgrund seines Fachwissens bekannt.The solvents and auxiliaries to be used and the reaction parameters to be used, such as reaction temperature and duration, are known to the person skilled in the art on the basis of his expert knowledge.
Die erfindungsgemäßen Verbindungen gemäß der allgemeinen Formel 1 sind als Wirkstoffe in Arzneimitteln, insbesondere als Antitumormittel, zur Behandlung von Menschen und Säugetieren geeignet. Säugetiere können Haustiere wie Pferde, Kühe, Hunde, Katzen, Hasen, Schafe und dergleichen sein. Die medizinische Wirkung der erfindungsgemäßen Verbindungen kann zum Beispiel auf einer Wechselwirkung mit dem Tubulin-System durch Hemmung der Tubulin- Polymerisation beruhen. Daneben sind noch weitere bekannte und unbekannte Wirkmechanismen zur Bekämpfung der Tumorzellen denkbar.The compounds of general formula 1 according to the invention are suitable as active ingredients in medicaments, in particular as anti-tumor agents, for the treatment of humans and mammals. Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep and the like. The medicinal effect of the compounds according to the invention can be based, for example, on an interaction with the tubulin system by inhibiting tubulin polymerization. In addition, other known and unknown mechanisms of action to combat tumor cells are also conceivable.
Gemäß einem weiteren Aspekt der Erfindung wird ein Verfahren zur Bekämpfung von Tumoren beim Menschen und in Säugetieren bereit gestellt, welches dadurch gekennzeichnet ist, daß mindestens eine erfindungsgemässe Verbindung gemäß der allgemeinen Formel 1 dem Menschen oder einem Säugetier in einer für die Tumorbehandlung wirksamen Menge verabreicht wird. Die für die Behandlung zu verabreichende therapeutisch effektive Dosis der jeweiligen erfindungsgemäßen Verbindung richtet sich u.a. nach der Art und dem Stadium der Tumorerkrankung, dem Alter und Geschlecht des Patienten, der Art der Verabreichung und der Dauer der Behandlung. Die erfindungsgemäßen Arzneimittel können als flüssige, halbfeste und feste Arzneiformen verabreicht werden. Dies erfolgt in der jeweils geeigneten Weise in Form von Aerosolen, Pulver, Puder und Streupuder, Tabletten, Dragees, Emulsionen, Schäume, Lösungen, Suspensionen, Gele, Salben, Pasten, Pillen, Pastillen, Kapseln oder Suppositorien.According to a further aspect of the invention, there is provided a method for combating tumors in humans and in mammals, which is characterized in that at least one compound according to the invention according to general formula 1 is administered to humans or a mammal in an amount effective for tumor treatment , The therapeutically effective dose of the respective compound according to the invention to be administered for the treatment is directed inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment. The pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms. This takes place in the most suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.
Die Arzneiformen enthalten neben mindestens einem erfindungsgemäßen Bestandteil je nach eingesetzter galenischer Form gegebenenfalls Hilfsstoffe, wie unter anderem Lösungsmittel, Lösungsbeschleuniger, Lösungsvermittler, Emulgatoren, Netzmittel, Antischaummittel, Gelbildner, Verdickungsmittel, Filmbildner, Bindemittel, Puffer, Salzbildner, Trocknungsmittel, Fließregulierungsmittel, Füllstoffe, Konservierungsstoffe, Antioxidatien, Farbstoffe, Formentrennmittel, Gleitmittel, Sprengmittel, Geschmacks- und Geruchskorrigentien. Die Auswahl der Hilfsstoffe sowie die einzusetzenden Mengen derselben hängt von der gewählten galenischen Form ab und orientiert sich an die dem Fachmann bekannten Rezepturen.In addition to at least one constituent according to the invention, depending on the galenic form used, the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, anti-foaming agents, gel formers, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell corrections. The selection of the auxiliaries and the amounts to be used depends on the galenic form chosen and is based on the recipes known to the person skilled in the art.
Die erfindungsgemäßen Arzneimittel können in einer geeigneten Darreichungsform auf die Haut, epicutan als Lösung, Suspension, Emulsion, Schaum, Salbe, Paste oder Pflaster; über die Mund- und Zungenschleimhaut, buccal, lingual oder sublingual als Tablette, Pastille, Dragees, Linctus oder Gurgelwasser; über die Magen- und Darmschleimhaut, enteral als Tablette, Dragees, Kapsel, Lösung, Suspension oder Emulsion; über die Rectumschleimhaut, rectal als Suppositorium, Rectalkapsel oder Salbe; über die Nasenschleimhaut, nasal als Tropfen, Salben oder Spray; über das Bronchial- und Alveolarepithel, pulmonal oder per inhalationem als Aerosol oder Inhalat; über die Conjunctiva, conjunctival als Augentropfen, Augensalbe, Augentabletten, Lamellae oder Augenwasser; über die Schleimhäute der Genitalorgane, intravaginal als Vaginalkugeln, Salben und Spülung, intrauterin als Uterus-Pessare; über die ableitenden Harnwege, intraurethral als Spülung, Salbe oder Arzneistäbchen; in eine Arterie, intraarteriell als Injektion; in eine Vene, intravenös als Injektion oder Infusion, paravenös als Injektion oder Infusion; in die Haut, intracutan als Injektion oder Implantat; unter die Haut, subcutan als Injektion oder Implantat; in den Muskel, intramusculär als Injektion oder Implantat; in die Bauchhöhle, intraperitoneal als Injektion oder Infusion verabreicht werden.The medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; over the oral and tongue mucosa, buccal, lingual or sublingually as tablets, lozenges, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organs, intravaginally as vaginal balls, ointments and lavage, intrauterinely as uterine pessaries; via the urinary tract, intraurethrally as a rinse, ointment or medicine stick; into an artery, intraarterially as an injection; into a vein, intravenously as an injection or infusion, paravenously as an injection or infusion; into the skin, intracutaneously as an injection or implant; under the skin, subcutaneously as an injection or implant; in the muscle, intramuscularly as an injection or implant; into the abdominal cavity, intraperitoneally as an injection or infusion.
Die erfindungsgemässen Verbindungen der allgemeinen Struktur 1 können in Hinblick auf praktische therapeutische Erfordernisse mittels geeigneter Maßnahmen in ihrer Arzneistoffwirkung verlängert werden. Dieses Ziel kann auf chemischem und/oder galenischem Wege erreicht werden. Beispiele für die Erzielung einer Wirkungsverlängerung sind der Einsatz von Implantaten, Liposomen, Retardformen, Nanopartikelsuspensionen und so genannter Prodrugs der erfindungsgemäßen Verbindungen, die Bildung von schwerlöslichen Salzen und Komplexen oder der Einsatz von Kristall-Suspensionen.The compounds of general structure 1 according to the invention can be extended with regard to practical therapeutic requirements by means of suitable measures in their drug action. This goal can be achieved chemically and / or galenically. Examples of achieving an extension of activity are the use of implants, liposomes, slow-release forms, nanoparticle suspensions and so-called prodrugs of the compounds according to the invention, the formation of sparingly soluble salts and complexes or the use of crystal suspensions.
Die erfindungsgemäßen Verbindungen der allgemeinen Struktur 1 können als Einzelsubstanz oder in Kombination mit weiteren cytotoxischen Substanzen, wie z.B. Cisplatin, Carboplatin, Doxorubicin, Ifosfamid, Cyclophosphamid, 5-FU, Methotrexat bzw. in Kombination mit Immunomodulatoren oder Antikörpern und insbesondere in Kombination mit Hemmstoffen der Signaltransduktion, wie z.B. Herceptin, Glivec oder Iressa eingesetzt werden.The compounds of general structure 1 according to the invention can be used as a single substance or in combination with other cytotoxic substances, e.g. Cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate or in combination with immunomodulators or antibodies and in particular in combination with signal transduction inhibitors, such as e.g. Herceptin, Glivec or Iressa can be used.
Besonders bevorzugt sind dabei Arzneimittel, die mindestens eine Verbindung aus der nachfolgenden Gruppe der erfindungsgemässen Verbindungen enthalten: 4-[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (1 ) 4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-carbonyl]-fluoren-9-on (2) 4-[4-(3-Hydroxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (3) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)- methanon (4)Drugs which contain at least one compound from the following group of the compounds according to the invention are particularly preferred: 4- [4- (3,5-Dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1) 4- [4- (6-methyl-pyridin-2-yl) piperazin-1 -carbonyl] -fluoren-9-one (2) 4- [4- (3-hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3) [4- (3,5-dimethoxy- phenyl) piperazin-1-yl] - (5-methyl-3-phenyl-isoxazol-4-yl) - methanone (4)
Cinnolin-4-yl-[4-(3,5-dimethyl-phenyl)-piperazin-1-yl]-methanon (5) Cinnolin-4-yl-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-methanon (6) (3,5-Bis-methylsulfanyl-isothiazol-4-yl)-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]- methanon (7)Cinnolin-4-yl- [4- (3,5-dimethylphenyl) piperazin-1-yl] methanone (5) Cinnolin-4-yl- [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone (6) (3,5-bis-methylsulfanyl-isothiazol-4-yl) - [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] - methanone (7)
[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-isochinoIin-1 -yl-methanon (8) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-fluoren-1 -yl)-methanon (9) (9H-Fluoren-9-yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (10) (9H-Fluoren-1 -yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (11) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(9H-xanthen-9-yl)-methanon (12) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (13) [4-(3-Methoxy-phenyl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (14) [4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (15) [4-(3-Hydroxy-phenyl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (16) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-[1 -(4-nitrophenyl)-5-trifluormethyl-1 H- pyrazol-4-yl]-methanon (17)[4- (3,5-dimethoxy-phenyl) piperazin-1-yl] -isoquinoline-1-yl-methanone (8) [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (9H-fluoren-1 -yl) -methanone (9) (9H-fluoren-9-yl) - [4- (3-methoxyphenyl) -piperazin-1 -yl] -methanone (10) (9H-fluoren-1 -yl) - [4- (3-methoxyphenyl) piperazin-1-yl] methanone (11) [4- (3,5-dimethoxy-phenyl) piperazin-1-yl] - (9H-xanthene-9 -yl) -methanone (12) [4- (3-methoxy-phenyl) -piperazin-1 -yl] - (9H-xanthene-9-yl) -methanone (13) [4- (3-methoxy-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (14) [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] - ( 2-phenyl-2H-pyrazol-3-yl)) - methanone (15) [4- (3-hydroxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) -methanone (16) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] - [1 - (4-nitrophenyl) -5-trifluoromethyl-1 H-pyrazol-4-yl] methanone ( 17)
und sowohl als freie Base als auch als Salze physiologisch verträglicher Säuren vorliegen können.and can be present both as a free base and as salts of physiologically acceptable acids.
Gemäß dieser allgemeinen Vorschrift, denen das Syntheseschema 1 zugrunde liegt, wurden folgende Verbindungen synthetisiert, die unter der Angabe der jeweiligen chemischen Bezeichnung aus der nachfolgenden Übersicht hervorgehen. Die analytische Charakterisierung der erfindungsgemäßen Verbindungen erfolgte durch ihre Schmelzpunkte bzw. 1H-NMR-spektroskopisch und/oder massenspektrometrisch. Die eingesetzten Chemikalien und Lösungsmittel wurden kommerziell bei den herkömmlichen Anbietern erworben (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) oder synthetisiert.In accordance with this general rule, which is based on synthesis scheme 1, the following compounds were synthesized, which can be seen from the following overview by stating the respective chemical name. The compounds according to the invention were characterized analytically by their melting points or 1 H-NMR spectroscopy and / or mass spectrometry. The chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) or synthesized.
Die Erfindung soll anhand der nachfolgenden Beispiele näher erläutert werden, ohne darauf beschränkt zu sein.The invention is to be explained in more detail with reference to the following examples, without being restricted thereto.
Beispiel 1 (Umsetzung gemäß Schema 1 , VarianteD:Example 1 (implementation according to scheme 1, variant D:
4-[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -carbonyl]-f luoren-9-on (1 )4- [4- (3,5-dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1)
Eine Lösung von 1g (4.12 mMol) 9-Fluorenon-4-carbonylchlorid in 30 ml Dimethylformamid wurde nacheinander mit 0.67g (6.59 mMol) N-Methylmorpholin, 0.92g (4.12 mMol) 1-(3,5-Dimethoxyphenyl)piperazin und 2.36 g (4.53 mMol) Py- BOP (1-Benzotriazolyl-tripyrrolidinophosphoniumhexafluorphosphat) versetzt. Man rührte 12 Stunden bei Raumtemperatur, ließ über Nacht bei Raumtemperatur stehen, destillierte Dimethylformamid i. Vak. ab und reinigte den Rückstand über eine Kieselgelsäule (Kieselgel 60, Fa. Merck AG, Darmstadt) unter Anwendung des Elutionsmittels Dichlormethan/Methanol (95:5 V/V).A solution of 1 g (4.12 mmol) of 9-fluorenone-4-carbonyl chloride in 30 ml of dimethylformamide was sequentially treated with 0.67 g (6.59 mmol) of N-methylmorpholine, 0.92 g (4.12 mmol) of 1- (3,5-dimethoxyphenyl) piperazine and 2.36 g (4.53 mmol) of PyBOP (1-benzotriazolyl tripyrrolidinophosphonium hexafluorophosphate) were added. The mixture was stirred at room temperature for 12 hours, left to stand at room temperature overnight, dimethylformamide was distilled i. Vak. and cleaned the residue on a silica gel column (Kieselgel 60, Merck AG, Darmstadt) using the eluent dichloromethane / methanol (95: 5 V / V).
Ausbeute: 1.4 g (79.3% d. Th.)Yield: 1.4 g (79.3% of theory)
Fp.: 161 °CMp: 161 ° C
1H-NMR (DMSO-d6) δ= 7.71-7.4 (m, 7H), 6.08 (s, 2H), 6.0 (s, 1 H), 3.98-3.85 (m, 2H), 3.68 (s, 6H), 3.45-2.9 (m, 6H) ppm. 1 H NMR (DMSO-d6) δ = 7.71-7.4 (m, 7H), 6.08 (s, 2H), 6.0 (s, 1H), 3.98-3.85 (m, 2H), 3.68 (s, 6H) , 3.45-2.9 (m, 6H) ppm.
Beispiel 2 (Umsetzung gemäß Schema 1 , VarianteD:Example 2 (implementation according to scheme 1, variant D:
[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (12) Eine Lösung von 3g (13.26 mMol) Xanthen-9-carbonsäure in 90 ml Dimethylformamid wurde nacheinander mit 2.15g (21.2 mMol) N-Methylmorpholin, 2.95g (13.26 mMol) 1-(3,5-Dimethoxyphenyl)piperazin und 7.59 g (14.59 mMol) Py- BOP ( 1-Benzotriazolyl-tripyrrolidinophosphoniumhexafluorphosphat) versetzt. Man rührte 12 Stunden bei Raumtemperatur, ließ über Nacht bei Raumtemperatur stehen, destillierte Dimethylformamid i. Vak. ab und reinigte den Rückstand über eine Kieselgelsäule (Kieselgel 60, Fa. Merck AG, Darmstadt) unter Anwendung des Elutionsmittels Dichlormethan/Methanol (95:5 V/V).[4- (3,5-dimethoxyphenyl) piperazin-1-yl] - (9H-xanthene-9-yl) methanone (12) A solution of 3 g (13.26 mmol) of xanthene-9-carboxylic acid in 90 ml of dimethylformamide was sequentially treated with 2.15 g (21.2 mmol) of N-methylmorpholine, 2.95 g (13.26 mmol) of 1- (3,5-dimethoxyphenyl) piperazine and 7.59 g ( 14.59 mmol) Py-BOP (1-benzotriazolyl tripyrrolidinophosphonium hexafluorophosphate) was added. The mixture was stirred at room temperature for 12 hours, left to stand at room temperature overnight, dimethylformamide was distilled i. Vak. and cleaned the residue on a silica gel column (Kieselgel 60, Merck AG, Darmstadt) using the eluent dichloromethane / methanol (95: 5 V / V).
Ausbeute: 2.88 g (50.4% d. Th.)Yield: 2.88 g (50.4% of theory)
Fp.: 155°CMp: 155 ° C
1H-NMR (DMSO-d6) δ= 7.28 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H), 7.07 (t, 2H), 6.12 (s, 2H), 6.03 (s, 1 H), 5.72 (s, 1 H), 4.03 (m, 2H), 3.71 (s, 6H), 3.58 (m, 2H), 3.23-3.06 (m, 4H) ppm. 1 H-NMR (DMSO-d6) δ = 7.28 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H), 7.07 (t, 2H), 6.12 (s, 2H), 6.03 (s, 1H), 5.72 (s, 1H), 4.03 (m, 2H), 3.71 (s, 6H), 3.58 (m, 2H), 3.23-3.06 (m, 4H) ppm.
Beispiel 3 (Umsetzung gemäß Schema 1 , Variante2):Example 3 (implementation according to scheme 1, variant 2):
[4-(3-Methoxy-phenyl)-piperazin-1yl]-(2-phenyl-2H-pyrazol-3-yl)methanon (14)[4- (3-methoxyphenyl) piperazin-1yl] - (2-phenyl-2H-pyrazol-3-yl) methanone (14)
Eine Lösung von 3.03g (16.1 mMol) 1-Phenyl-1 H-pyrazol-5-carbonsäure in 40 ml Dimethylformamid wurde mit 13.56g (25.76 mMol) polymergebundenem N-Benzyl-N- cyclohexylcarbodiimid (1.66 mMol/g) versetzt, auf 60°C erwärmt und 30 Minuten miteinander zur Reaktion gebracht. Hierzu gab man 2.48g (12.88 mMol) von 1-(3- Methoxyphenyl)piperazin und ließ für weitere 4 Stunden reagieren. Danach ließ man Abkühlen, trennte vom Harz ab, destillierte das Dimethylformamid i. Vak. ab und reinigte den Rückstand über eine Kieselgelsäule (Kieselgel 60, Fa. Merck AG, Darmstadt) unter Anwendung des Elutionsmittels Dichlormethan/Methanol (95:5 VA/).A solution of 3.03 g (16.1 mmol) of 1-phenyl-1 H-pyrazole-5-carboxylic acid in 40 ml of dimethylformamide was mixed with 13.56 g (25.76 mmol) of polymer-bound N-benzyl-N-cyclohexylcarbodiimide (1.66 mmol / g) Heated 60 ° C and reacted with each other for 30 minutes. 2.48 g (12.88 mmol) of 1- (3-methoxyphenyl) piperazine were added and the mixture was left to react for a further 4 hours. Then allowed to cool, separated from the resin, distilled the dimethylformamide i. Vak. and cleaned the residue on a silica gel column (Kieselgel 60, Merck AG, Darmstadt) using the eluent dichloromethane / methanol (95: 5 VA /).
Ausbeute: 0.75 g (12.6% d. Th.) 1H-NMR (DMSO-d6) δ= 7.82 (s, 1 H), 7.54-7.46 (m, 4H), 7.4 (t, 1 H), 7.11 (t, 1 H), 6.73 (d, 1H), 6.46 (m, 1 H), 6.41-6.38 (m, 2H), 3.72 (m, 5H), 3.33 (m, 2H), 3.10 (m, 2H), 2.82 (m, 2H) ppm.Yield: 0.75 g (12.6% of theory) 1 H NMR (DMSO-d6) δ = 7.82 (s, 1 H), 7.54-7.46 (m, 4H), 7.4 (t, 1 H), 7.11 (t, 1 H), 6.73 (d, 1H) , 6.46 (m, 1H), 6.41-6.38 (m, 2H), 3.72 (m, 5H), 3.33 (m, 2H), 3.10 (m, 2H), 2.82 (m, 2H) ppm.
Folgende Verbindungen der allgemeinen Formel 1 wurden analog zum Syntheseweg (Variante 1 oder 2) in Schema 1 synthetisiert:The following compounds of general formula 1 were synthesized analogously to the synthetic route (variant 1 or 2) in scheme 1:
Formel 1formula 1
Beispiel 4: 4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1 -carbonyl]-fluoren-9-on (2)Example 4: 4- [4- (6-methyl-pyridin-2-yl) piperazin-1-carbonyl] -fluoren-9-one (2)
1H-NMR (DMSO-d6) δ= 7.72 (d, 1 H), 7.68 (d, 1 H), 7.62 (t, 1 H), 7.54 (d, 1 H), 7.51- 7.40 (m, 4-H), 6.6 (d, 1 H), 6.55 (d, 1 H), 3.95 (m, 1 H), 3.87 (m, 1 H), 3.7 (m, 2H), 3.52- 3.25 (m, 4H), 2.28 (s, 3H) ppm. 1 H NMR (DMSO-d6) δ = 7.72 (d, 1 H), 7.68 (d, 1 H), 7.62 (t, 1 H), 7.54 (d, 1 H), 7.51-7.40 (m, 4 -H), 6.6 (d, 1H), 6.55 (d, 1H), 3.95 (m, 1H), 3.87 (m, 1H), 3.7 (m, 2H), 3.52-3.25 (m, 4H) ), 2.28 (s, 3H) ppm.
Beispiel 5: 4-[4-(3-Hydroxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (3)Example 5: 4- [4- (3-Hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3)
ESI-MS: 385.1 [M+H]ESI-MS: 385.1 [M + H]
Beispiel 6: [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(5-methyl-3-phenyl-isoxazol-4- yl)-methanon (4)Example 6: [4- (3,5-Dimethoxyphenyl) piperazin-1-yl] - (5-methyl-3-phenylisoxazol-4-yl) methanone (4)
1H-NMR (DMSO-d6) δ= 7.58 (m, 2H), 7.47 (m, 3H), 5.96 (m, 3H), 3.75-3.63 (m, 8H), 3.26 (m, 4H), 3.15 (m, 2H), 2.48 (s, 3H) ppm. Beispiel 7: Cinnolin-4-yl-[4-(3,5-dimethyl-phenyl)-piperazin-1 -yl]-methanon (5) 1 H NMR (DMSO-d6) δ = 7.58 (m, 2H), 7.47 (m, 3H), 5.96 (m, 3H), 3.75-3.63 (m, 8H), 3.26 (m, 4H), 3.15 ( m, 2H), 2.48 (s, 3H) ppm. Example 7: Cinnolin-4-yl- [4- (3,5-dimethylphenyl) piperazin-1-yl] methanone (5)
Fp.: 114°CMp .: 114 ° C
1H-NMR (DMSO-d6) δ= 9.45 (s, 1 H), 8.58 (d, 1 H), 8.04 (m, 1 H), 7.96 (m, 2H), 6.58 (s, 2H), 6.48 (s, 1 H), 3.95 (m, 2H), 3.34 (m, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 2.21 (s, 6H) ppm. 1 H NMR (DMSO-d6) δ = 9.45 (s, 1 H), 8.58 (d, 1 H), 8.04 (m, 1 H), 7.96 (m, 2H), 6.58 (s, 2H), 6.48 (s, 1H), 3.95 (m, 2H), 3.34 (m, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 2.21 (s, 6H) ppm.
Beispiel 8: Cinnolin-4-yl-[4-(6-methyl-pyridin-2-yl)-piperazin-1 -yl]-methanon (6)Example 8: Cinnolin-4-yl- [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone (6)
1H-NMR (DMSO-d6) δ= 9.43 (s, 1 H), 8.58 (d, 1 H), 8.05 (m, 1 H), 7.95 (m, 2H), 7.45 (t, 1 H), 6.63 (d, 1H), 6.54 (d, 1 H), 3.90 (m, 2H), 3.72 (m, 2H), 3.48-3.2 (m, 4H), 2.3 (s, 3H) ppm. 1 H-NMR (DMSO-d6) δ = 9.43 (s, 1 H), 8.58 (d, 1 H), 8.05 (m, 1 H), 7.95 (m, 2H), 7.45 (t, 1 H), 6.63 (d, 1H), 6.54 (d, 1H), 3.90 (m, 2H), 3.72 (m, 2H), 3.48-3.2 (m, 4H), 2.3 (s, 3H) ppm.
Beispiel 9: (3,5-Bis-methylsulfanyl-isothiazol-4-yl)-[4-(6-methyl-pyridin-2-yl)- piperazin-1-yl]-methanon (7)Example 9: (3,5-bis-methylsulfanyl-isothiazol-4-yl) - [4- (6-methyl-pyridin-2-yl) - piperazin-1-yl] methanone (7)
1H-NMR (DMSO-d6) δ= 7.45 (t, 1 H); 6.65 (d, 1 H), 6.57 (d, 1 H), 3.8-3.3 (m, 8H), 2.66 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H) ppm. 1 H NMR (DMSO-d6) δ = 7.45 (t, 1 H); 6.65 (d, 1H), 6.57 (d, 1H), 3.8-3.3 (m, 8H), 2.66 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H) ppm.
Beispiel 10: [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-isochinolin-1-yl-methanon (8)Example 10: [4- (3,5-Dimethoxyphenyl) piperazin-1-yl] isoquinolin-1-yl methanone (8)
1H-NMR (DMSO-d6) δ= 8.54 (d, 1 H), 8.06 (d, 1 H), 7.98 (d, 1 H), 7.92 (d, 1 H), 7.83 (t, 1 H), 7.72 (t, 1 H), 6.08 (s, 2H), 5.99 (s, 1 H), 3.95 (m, 2H), 3.68 (s, 6H), 3.35 (m, 2H), 3.24 (m, 2H), 3.05 (m, 2H) ppm. Beispiel 11: [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-fluoren-1 -yl)-methanon 0) 1 H NMR (DMSO-d6) δ = 8.54 (d, 1 H), 8.06 (d, 1 H), 7.98 (d, 1 H), 7.92 (d, 1 H), 7.83 (t, 1 H) , 7.72 (t, 1H), 6.08 (s, 2H), 5.99 (s, 1H), 3.95 (m, 2H), 3.68 (s, 6H), 3.35 (m, 2H), 3.24 (m, 2H) ), 3.05 (m, 2H) ppm. Example 11: [4- (3,5-Dimethoxyphenyl) piperazin-1-yl] - (9H-fluoren-1-yl) -methanone 0)
Fp.: 148°CMp: 148 ° C
1H-NMR (DMSO-d6) δ= 7.98 (d, 2H), 7.94 (d, 2H), 7.58 (d, 1 H), 7.48 (t, 1 H), 7.4 (t, 1 H), 7.35 (t, 1 H), 7.28 (d, 1H), 6.10 (s, 2H), 5.99 (s, 1 H), 3.88 (s, 2H), 3.82 (m, 2H), 1 H NMR (DMSO-d6) δ = 7.98 (d, 2H), 7.94 (d, 2H), 7.58 (d, 1 H), 7.48 (t, 1 H), 7.4 (t, 1 H), 7.35 (t, 1 H), 7.28 (d, 1H), 6.10 (s, 2H), 5.99 (s, 1 H), 3.88 (s, 2H), 3.82 (m, 2H),
3.67 (s, 6H), 3.41 (m, 2H), 3.28 (m, 2H), 3.08 (m, 2H) ppm.3.67 (s, 6H), 3.41 (m, 2H), 3.28 (m, 2H), 3.08 (m, 2H) ppm.
Beispiel 12: (9H-Fluoren-9-yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (10)Example 12: (9H-Fluoren-9-yl) - [4- (3-methoxyphenyl) piperazin-1-yl] methanone (10)
Fp.: 162-163°CMp: 162-163 ° C
1H-NMR (DMS0-d6) δ= 7.86 (d, 2H), 7.37 (d, 2H), 7.32 (t, 2H), 7.22 (t, 2H), 7.03 (t, 1 H), 6.46 (m, 1 H), 6.38 (s, 1 H), 6.30 (d, 1H), 5.32 (s, 1 H), 3.95-3.42 (m, 7H), 3.25-3.0 (m, 4H) ppm. 1 H NMR (DMS0-d6) δ = 7.86 (d, 2H), 7.37 (d, 2H), 7.32 (t, 2H), 7.22 (t, 2H), 7.03 (t, 1 H), 6.46 (m , 1 H), 6.38 (s, 1 H), 6.30 (d, 1H), 5.32 (s, 1 H), 3.95-3.42 (m, 7H), 3.25-3.0 (m, 4H) ppm.
Beispiel 13: (9H-Fluoren-1 -yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (11 )Example 13: (9H-Fluoren-1 -yl) - [4- (3-methoxyphenyl) piperazin-1 -yl] -methanone (11)
Fp.: 124°CMp .: 124 ° C
1H-NMR (DMS0-d6) δ= 7.99 (d, 1 H), 7.96 (d, 1 H), 7.61 (d, 1 H9, 7.48 (t, 1 H), 7.42 (t, 1 H), 7.35 (t, 1 H), 7.29 (d, 1 H), 7.12 (t, 1 H), 6.54 (m, 1 H), 6.48 (s, 1 H), 6.39 (m, 1 H), 3.89 (s, 2H), 3.83 (m, 2H), 3.71 (s, 3H), 3.41 (m, 2H), 3.27 (m, 2H), 3.08 (m, 2H) ppm. 1 H-NMR (DMS0-d6) δ = 7.99 (d, 1 H), 7.96 (d, 1 H), 7.61 (d, 1 H9, 7.48 (t, 1 H), 7.42 (t, 1 H), 7.35 (t, 1 H), 7.29 (d, 1 H), 7.12 (t, 1 H), 6.54 (m, 1 H), 6.48 (s, 1 H), 6.39 (m, 1 H), 3.89 ( s, 2H), 3.83 (m, 2H), 3.71 (s, 3H), 3.41 (m, 2H), 3.27 (m, 2H), 3.08 (m, 2H) ppm.
Beispiel 14: [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (13)Example 14: [4- (3-methoxyphenyl) piperazin-1-yl] - (9H-xanthene-9-yl) methanone (13)
Fp.: 110°CMp .: 110 ° C
1H-NMR (DMSO-d6) δ= 7.30 (t, 2H), 7.22 (t, 2H), 7.15-7.05 (m, 5H), 6.56 (d, 1H), 6.48 (d, 1H), 6.4 (d, 1H), 5.74 (s, 1H), 4.05 (m, 2H), 3.74 (s, 3H), 3.58 (m, 2H), 3.2-3.06 (m, 4H) ppm. Beispiel 15: [4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))- methanon (15) 1 H NMR (DMSO-d6) δ = 7.30 (t, 2H), 7.22 (t, 2H), 7.15-7.05 (m, 5H), 6.56 (d, 1H), 6.48 (d, 1H), 6.4 ( d, 1H), 5.74 (s, 1H), 4.05 (m, 2H), 3.74 (s, 3H), 3.58 (m, 2H), 3.2-3.06 (m, 4H) ppm. Example 15: [4- (6-methyl-pyridin-2-yl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (15)
1H-NMR (DMSO-d6) δ= 7.83 (s, 1 H), 7.55-7.37 (m, 6H), 6.74 (d, 1 H), 6.57 (d, 1 H), 6.53 (d, 1 H), 3.68 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.18 (m, 2H), 2.32 (s, 3H) ppm. 1 H NMR (DMSO-d6) δ = 7.83 (s, 1 H), 7.55-7.37 (m, 6H), 6.74 (d, 1 H), 6.57 (d, 1 H), 6.53 (d, 1 H) ), 3.68 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.18 (m, 2H), 2.32 (s, 3H) ppm.
Beispiel 16: [4-(3-Hydroxy-phenyl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))- methanon (16)Example 16: [4- (3-Hydroxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (16)
1H-NMR (DMSO-d6) δ= 9.2 (s, 1 H), 7.82 (d, 1 H), 7.53-7.46 (m, 4H), 7.4 (t, 1 H), 6.98 (t, 1 H), 6.73 (d, 1 H), 6.33 (m, 1 H), 6.23 (m, 2H), 3.68 (m, 2H), 3.35 (m, 2H), 3.05 (m, 2H), 2.75 (m, 2H) ppm. 1 H NMR (DMSO-d6) δ = 9.2 (s, 1 H), 7.82 (d, 1 H), 7.53-7.46 (m, 4H), 7.4 (t, 1 H), 6.98 (t, 1 H ), 6.73 (d, 1 H), 6.33 (m, 1 H), 6.23 (m, 2H), 3.68 (m, 2H), 3.35 (m, 2H), 3.05 (m, 2H), 2.75 (m, 2H) ppm.
Beispiel 17: [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-[1 -(4-nitrophenyl)-5- trifluormethyl-1 H-pyrazol-4-yl]-methanon (17)Example 17: [4- (3,5-Dimethoxyphenyl) piperazin-1-yl] - [1 - (4-nitrophenyl) -5-trifluoromethyl-1 H-pyrazol-4-yl] methanone (17)
1H-NMR (DMSO-d6) δ= 8.45 (d, 2H), 8.18 (s, 1 H), 7.88 (d, 2H), 6.1 (s, 2H), 6.0 (s, 1 H), 3.77 (m, 2H), 3.69 (s, 6H), 3.53 (m, 2H), 3.2 (m, 2H), 3.12 (m, 2H) ppm. 1 H NMR (DMSO-d6) δ = 8.45 (d, 2H), 8.18 (s, 1 H), 7.88 (d, 2H), 6.1 (s, 2H), 6.0 (s, 1 H), 3.77 ( m, 2H), 3.69 (s, 6H), 3.53 (m, 2H), 3.2 (m, 2H), 3.12 (m, 2H) ppm.
Die am meisten bevorzugten Verbindungen der vorliegenden Erfindung sind Substanzen der allgemeinen Formel 1 in Form ihrer Basen oder ihrer pharmazeutisch annehmbaren Salze, die aus der folgenden Gruppe ausgewählt sind:The most preferred compounds of the present invention are substances of general formula 1 in the form of their bases or their pharmaceutically acceptable salts, which are selected from the following group:
4-[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (1 ) 4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1 -carbonyl]-fluoren-9-on (2) 4-[4-(3-Hydroxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (3) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)- methanon (4) Cinnolin-4-yl-[4-(3,5-dimethyl-phenyl)-piperazin-1-yl]-methanon (5) Cinnolin-4-yl-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-methanon (6) (3,5-Bis-methylsulfanyl-isothiazol-4-yl)-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]- methanon (7) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-isochinolin-1 -yl-methanon (8) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-fluoren-1 -yl)-methanon (9) (9H-Fluoren-9-yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (10) (9H-Fluoren-1 -yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (11 ) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(9H-xanthen-9-yl)-methanon (12) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (13)4- [4- (3,5-Dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1) 4- [4- (6-methyl-pyridin-2-yl) piperazin-1 -carbonyl] -fluoren-9-one (2) 4- [4- (3-hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3) [4- (3,5-dimethoxy- phenyl) piperazin-1-yl] - (5-methyl-3-phenyl-isoxazol-4-yl) - methanone (4) Cinnolin-4-yl- [4- (3,5-dimethylphenyl) piperazin-1-yl] methanone (5) Cinnolin-4-yl- [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone (6) (3,5-bis-methylsulfanyl-isothiazol-4-yl) - [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] - methanone (7) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] isoquinoline-1-yl methanone (8) [4- (3,5-dimethoxyphenyl) piperazin-1 -yl] - (9H-fluoren-1 -yl) -methanone (9) (9H-fluoren-9-yl) - [4- (3-methoxyphenyl) piperazin-1 -yl] -methanone (10) (9H -Fluoren-1 -yl) - [4- (3-methoxyphenyl) piperazin-1-yl] -methanone (11) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] - (9H -xanthene-9-yl) methanone (12) [4- (3-methoxyphenyl) piperazin-1-yl] - (9H-xanthene-9-yl) methanone (13)
[4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (14) [4-(6-Methyl-pyridin-2-yl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (15) [4-(3-Hydroxy-phenyl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (16) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-[1 -(4-nitrophenyl)-5-trifluormethyl-1 H- pyrazol-4-yl]-methanon (17)[4- (3-methoxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) methanone (14) [4- (6-methylpyridin-2-yl ) -piperazin-1 -yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (15) [4- (3-hydroxy-phenyl) -piperazin-1 -yl] - (2-phenyl -2H-pyrazol-3-yl)) methanone (16) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] - [1 - (4-nitrophenyl) -5-trifluoromethyl-1 H pyrazol-4-yl] methanone (17)
Biologische Wirkungen der erfindungsgemäßen VerbindungenBiological effects of the compounds according to the invention
Die in-vitro Testung an ausgewählten Tumormodellen ergab die nachfolgenden pharmakologischen Aktivitäten.In vitro testing on selected tumor models revealed the following pharmacological activities.
Beispiel 18: Antiproliferative Wirkung an verschiedenen TumorzellinienExample 18: Antiproliferative effect on various tumor cell lines
Die erfindungsgemäßen Substanzen wurden in einem Proliferationstest an etablierten Tumorzellinien auf ihre anti-proliferative Aktivität hin untersucht. Der verwendete Test bestimmt die zelluläre Dehydrogenase-Aktivität und ermöglicht eine Bestimmung der Zellvitalität und indirekt der Zellzahl. Bei den verwendeten Zellinien handelt es sich um die humane Cervixkarzinom Zellinie KB/HeLa (ATCC CCL17), die ovariale Adeno-karzinomzellinie SKOV-3 (ATCC HTB77), die humane Glioblastom Zellinie SF-268 (NCI 503138) und die Lungenkarzinom Zellinie NCI-H460 (NCI 503473). Des weiteren wurde zur Untersuchung der Zellzyklus-spezifischen Wirkung der Substanz ein RKOp27 Zellsystem verwendet (M. Schmidt et al. Oncogene19(20):2423-9, 2000). Bei RKO handelt es sich um eine humane Kolonkarzinomlinie, in der der Zellzyklusinhibitor p27kιp1 mittels des Ecdyson Expressionssystems induziert zur Expression gebracht und zu einem Zellzyklusarrest spezifisch in G2 geführt werden kann. Eine unspezifisch wirkende Substanz hemmt die Proliferation unabhängig davon, ob die RKO Zelle in G1 oder G2 arretiert ist oder nicht. Zelizyklus-spezifische Substanzen wie beispielsweise Tubulininhibitoren sind hingegen nur dann zytotoxisch, wenn Zellen nicht arretiert sind und der Zellzyklus durchlaufen wird. In Tabelle 1 sind die zytotoxischen bzw. wachstumshemmenden Aktivitäten der beschriebenen Verbindung mit / ohne Expression von p27kιp1gezeigt. Die getesteten Verbindungen zeigten im induzierten Zustand von p27kιp1 keine zytotoxischen Aktivitäten. Die Ergebnisse zeigen eine sehr potente Hemmung der Proliferation ausgewählter Tumorzelllinien durch die erfindungsgemässen Verbindungen.The substances according to the invention were tested for their anti-proliferative activity in a proliferation test on established tumor cell lines. The test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number. The cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line. H460 (NCI 503473). In addition, an RKOp27 cell system was used to investigate the cell cycle-specific effect of the substance (M. Schmidt et al. Oncogene19 (20): 2423-9, 2000). RKO is a humane one Colon carcinoma line in which the cell cycle inhibitor p27 kιp1 can be induced by means of the Ecdyson expression system and brought to a cell cycle arrest specifically in G2. A non-specific substance inhibits proliferation regardless of whether the RKO cell is locked in G1 or G2 or not. In contrast, cell cycle-specific substances such as tubulin inhibitors are only cytotoxic if cells are not locked and the cell cycle is followed. Table 1 shows the cytotoxic or growth-inhibiting activities of the described compound with / without expression of p27 kιp1 . The tested compounds showed no cytotoxic activities in the induced state of p27 kιp1 . The results show a very potent inhibition of the proliferation of selected tumor cell lines by the compounds according to the invention.
Verbindung XTT Proliferationsassay, EC50 in μg/mlCompound XTT proliferation assay, EC50 in μg / ml
KB/He SKOV3 SF-268 NCI- RKOP27 RKOP27 la H460 ind.KB / He SKOV3 SF-268 NCI- RKOP27 RKOP27 la H460 ind.
1 0.555 0.400 0.309 0.312 0.208 >3.161 0.555 0.400 0.309 0.312 0.208> 3.16
2 2.592 0.585 0.939 0.886 0.326 >3.162 2,592 0.585 0.939 0.886 0.326> 3.16
3 4.322 0.397 0.478 0.853 0.726 >3.163 4,322 0.397 0.478 0.853 0.726> 3.16
5 1.212 0.496 0.474 0.348 0.250 >3.165 1,212 0.496 0.474 0.348 0.250> 3.16
7 2.710 1.010 n.d. 1.540 1.200 >3.167 2,710 1,010 n.d. 1,540 1,200> 3.16
8 0.929 0.287 0.775 0.439 0.291 >3.168 0.929 0.287 0.775 0.439 0.291> 3.16
9 0.613 0.341 0.692 0.427 0.217 >3.169 0.613 0.341 0.692 0.427 0.217> 3.16
10 0.166 0.082 0.094 0.085 0.082 >3.1610 0.166 0.082 0.094 0.085 0.082> 3.16
12 0.080 0.029 0.075 0.064 0.058 >3.1612 0.080 0.029 0.075 0.064 0.058> 3.16
13 0.628 0.293 0.408 0.29 0.193 >3.1613 0.628 0.293 0.408 0.29 0.193> 3.16
14 0.012 0.008 0.009 0.005 0.006 >3.1614 0.012 0.008 0.009 0.005 0.006> 3.16
15 0.040 0.018 0.036 0.024 0.022 >3.1615 0.040 0.018 0.036 0.024 0.022> 3.16
16 0.147 0.082 0.100 0.087 0.064 >3.1616 0.147 0.082 0.100 0.087 0.064> 3.16
n.d.: nicht durchgeführtn.d .: not carried out
Tabelle 1 : Proliferationshemmung ausgewählter Verbindungen im XTT Zytotoxizitätstest an humanen Tumorzellinien Beispiel 19: Inhibierung der Polymerisation von TubulinTable 1: Inhibition of proliferation of selected compounds in the XTT cytotoxicity test on human tumor cell lines Example 19: Inhibition of tubulin polymerization
Ausgewählte Substanzen wurden in einem in-vitro Test auf Hemmung der Polymerisation von Rindertubulin getestet. In diesem Test wird durch Zyklen von Polymerisation und Depolymerisation aufgereinigtes Tubulin eingesetzt, welches durch Zugabe von GTP und Erwärmung zur Polymerisation gebracht wird. In Tabelle 2 sind die EC5o Werte der Polymerisationshemmung von Tubulin mit 30% assoziierten Proteinen (MAPs) und von MAP-freiem Tubulin angegeben. Die Ergebnisse zeigen eine gute bis sehr gute Hemmwirkung der erfindungsgemässen Substanzen auf die Polymerisation von Tubulin.Selected substances were tested in an in vitro test for inhibition of the polymerization of bovine tubulin. In this test, tubulin purified by cycles of polymerization and depolymerization is used, which is brought to polymerization by adding GTP and heating. Table 2 shows the EC are given 5 o values of polymerization inhibition of tubulin with 30% associated proteins (MAPs) and MAP-free tubulin. The results show a good to very good inhibitory effect of the substances according to the invention on the polymerization of tubulin.
Verbindung Hemmung der Tubulin- Polymerisation, EC50 in μg/ml mit 30% MAPs ohne MAPsCompound inhibition of tubulin polymerization, EC50 in μg / ml with 30% MAPs without MAPs
1 0.86 1.361 0.86 1.36
3 4.77 n.d.3 4.77 n.d.
8 5.66 n.d.8 5.66 n.d.
10 1.18 n.d.10 1.18 n.d.
12 1.16 1.7112 1.16 1.71
13 0.73 n.d.13 0.73 n.d.
14 0.46 n.d.14 0.46 n.d.
15 0.88 n.d.15 0.88 n.d.
16 4.20 n.d.16 4.20 n.d.
n.d.: nicht durchgeführtn.d .: not carried out
Tabelle 2: Hemmung der Tubulin-Polymerisation. Durchschnittswert aus zwei unabhängigen Versuchen. Beschreibung der verwendeten MethodenTable 2: Inhibition of tubulin polymerization. Average of two independent tests. Description of the methods used
XTT-Test auf zelluläre Dehydrogenase-AktivitätXTT test for cellular dehydrogenase activity
Die adherent wachsenden Tumorzellinien KB/HeLa, SKOV-3, SF-268 und NCI-H460 wurden unter Standardbedingungen im Begasungsbrutschrank bei 37°C, 5% C02 und 95% Luftfeuchtigkeit kultiviert. Am Versuchstag 1 werden die Zellen mit Trypsin / EDTA abgelöst und durch Zentrifugation pelletiert. Nachfolgend wird das Zellpellet in dem jeweiligen Kulturmedium in der entsprechenden Zellzahl resuspendiert und in eine 96-well Mikrotiterplatte umgesetzt. Die Platten werden dann über Nacht im Begasungsbrutschrank kultiviert. Die Testsubstanzen werden als 1 mg/ml Stammlösungen in DMSO angesetzt und am Versuchstag 2 mit Kulturmedium in den entsprechenden Konzentrationen verdünnt. Die Substanzen in Kulturmedium werden dann zu den Zellen gegeben und für 45h im Begasungsbrutschrank inkubiert. Als Kontrolle dienen Zellen, die nicht mit Testsubstanz behandelt werden. Für das XTT- Assay werden 1 mg/ml XTT (Natrium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]- bis(4-methoxy-6-nitro) benzensulfonsäure) in RPMI-1640 Medium ohne Phenolrot gelöst. Zusätzlich wird eine 0,383 mg/ml PMS (N-Methyl Dibenzopyrazine Methylsulfat) Lösung in Phosphat-gepufferter Salzlösung (PBS) hergestellt. Am Versuchstag 4 wird auf die Zellplatten, die inzwischen 45 h mit den Testsubstanzen inkubiert wurden, 75μl/well XTT-PMS-Mischung pipettiert. Dazu wird kurz vor Gebrauch die XTT-Lösung mit der PMS-Lösung im Verhältnis 50:1 (Vol:Vol) gemischt. Anschließend werden die Zellplatten im Begasungsbrutschrank für weitere 3h inkubiert und im Photometer die optische Dichte (OD 9onm) bestimmt. Mittels der bestimmten OD4gonm wird die prozentuale Hemmung relativ zur Kontrolle berechnet und in Form einer Konzentrations-Wirkungskurve halblogarithmisch aufgetragen. Die EC50 wird mittels einer Regressionsanalyse aus der Konzentrations-Wirkungskurve mit dem Programm Graphpad Prism berechnet . Zellzyklusanalyse mittels des RKOp27 ModeliesThe adherent growing tumor cell lines KB / HeLa, SKOV-3, SF-268 and NCI-H460 were cultivated under standard conditions in a gas incubator at 37 ° C, 5% C0 2 and 95% humidity. On test day 1, the cells are detached with trypsin / EDTA and pelleted by centrifugation. The cell pellet is then resuspended in the respective culture medium in the appropriate cell number and converted into a 96-well microtiter plate. The plates are then cultivated overnight in the fumigation incubator. The test substances are prepared as 1 mg / ml stock solutions in DMSO and diluted with culture medium in the appropriate concentrations on test day 2. The substances in culture medium are then added to the cells and incubated for 45 hours in the fumigation incubator. Cells that are not treated with test substance serve as a control. For the XTT assay, 1 mg / ml XTT (sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid) are dissolved in RPMI-1640 medium without phenol red , In addition, a 0.383 mg / ml PMS (N-methyl dibenzopyrazine methyl sulfate) solution in phosphate-buffered saline (PBS) is prepared. On test day 4, 75 μl / well XTT-PMS mixture is pipetted onto the cell plates, which have now been incubated with the test substances for 45 h. For this purpose, the XTT solution is mixed with the PMS solution in a ratio of 50: 1 (vol: vol) shortly before use. The cell plates are incubated in the gassing incubator for a further 3h and the photometer, the optical density (OD 9 o n m) is determined. Using the determined OD 4 go n m, the percentage inhibition is calculated relative to the control and is plotted in the form of a concentration-activity curve using half-log. The EC 50 is calculated using a regression analysis from the concentration-effect curve using the Graphpad Prism program. Cell cycle analysis using the RKOp27 model
Das Assay wird in 96-well Platten durchgeführt. Durch induzierbare Expression von p27kιp1 werden die Zellen vollständig wachstumsarretiert, sterben aber nicht ab. Durch Vergleich der Wirksamkeit auf induzierte und nicht induzierte Zellen lassen sich Rückschlüsse auf den Wirkmechanismus (Zellzyklus-Spezifität) der Therapeutika ziehen. Nicht induzierte Zellen werden in etwa dreifach höherer Zellzahl ausgesät, da keine Teilung mehr während des Assays im Vergleich zu uninduzierten Zellen erfolgt (20000 Zellen/ Well induziert, 6250 Zellen / Well nicht induziert). Die Kontrollen sind unbehandelte Zellen (+/- Induktion). Die Induktion erfolgt mit 3μM Mu steron A. Am 1. Tag werden die Zellen ausgesetzt (+/- Muristeron A) und für 24h bei 37°C inkubiert. Am Tag 2 wird die Testsubstanz zugegeben (Kontrolle DMSO) und für weitere 45h bei 37°C inkubiert, bevor ein Standard XTT Assay durchgeführt wird.The assay is carried out in 96-well plates. By inducible expression of p27 kιp1 , the cells are completely arrested for growth, but do not die. By comparing the effectiveness on induced and non-induced cells, conclusions can be drawn about the mechanism of action (cell cycle specificity) of the therapeutic agents. Uninduced cells are sown in approximately three times the number of cells, since there is no division during the assay compared to uninduced cells (20,000 cells / well induced, 6,250 cells / well not induced). The controls are untreated cells (+/- induction). Induction is carried out with 3μM M steron A. On the 1st day, the cells are exposed (+/- Muristeron A) and incubated for 24 hours at 37 ° C. On day 2, the test substance is added (control DMSO) and incubated for a further 45 h at 37 ° C. before a standard XTT assay is carried out.
Tubulin Polymerisations AssayTubulin polymerization assay
Das Assay wird basierend auf der Methode von Bollag et.al. durchgeführt. Lyophylisiertes Rindertubulin (Cytoskeleton, ML 113 Tubulin 30% MAPs, TL238 Tubulin MAP frei) wird in einer Konzentration von 2mg/ml (ML113 in 80 mM PIPES, 0.5 mM EGTA, 2 mM MgCI2, pH6.9, 1 mM GTP). bzw 5mg/ml (TL238 in 80 mM PIPES, 1 mM EGTA, 0.5mM MgCI2, 20% (v:v) Glycerol pH6.9, 1 mM GTP) gelöst. Die Testsubstanzen werden in 10% DMSO (v:v) verdünnt und 5μl der Verdünnungen auf eine 96-Well Mikrotiterplatte (Nunc, half area plate) transferiert. Nach Zugabe von 45 /I der Tubulinlösung wird die Polymerisation bei 340nm in einem Spectramax 190 Mikrotiterplattenreader (Molecular devices) mittels Kinetik Programm in 30sec Intervallen über einen Zeitraum von 20min bestimmt. Die resultierenden area under curve Werte werden zur Berechnung der Inhibition in Bezug auf die unbehandelte Kontrolle verwendet und in Form einer Konzentrations-Wirkungskurve halblogarithmisch aufgetragen. Die EC50 wird mittels einer Regressionsanalyse aus der Konzentrations-Wirkungskurve mit dem Programm Graphpad Prism berechnet.The assay is based on the method of Bollag et.al. carried out. Lyophylized bovine tubulin (cytoskeleton, ML 113 tubulin 30% MAPs, TL238 tubulin MAP free) is used in a concentration of 2mg / ml (ML113 in 80mM PIPES, 0.5mM EGTA, 2mM MgCl 2 , pH6.9, 1mM GTP). or 5mg / ml (TL238 in 80mM PIPES, 1mM EGTA, 0.5mM MgCl 2 , 20% (v: v) glycerol pH6.9, 1mM GTP). The test substances are diluted in 10% DMSO (v: v) and 5 μl of the dilutions are transferred to a 96-well microtiter plate (Nunc, half area plate). After adding 45 / I of the tubulin solution, the polymerization at 340 nm is determined in a Spectramax 190 microtiter plate reader (molecular devices) using a kinetics program at 30 second intervals over a period of 20 minutes. The resulting area under curve values are used to calculate the inhibition in relation to the untreated control and in the form of a concentration-effect curve applied semi-logarithmically. The EC 50 is calculated using a regression analysis from the concentration-effect curve using the Graphpad Prism program.
Beispiele für pharmazeutische DarreichungsformenExamples of pharmaceutical dosage forms
Beispiel IExample I
Tablette mit 50 mg WirkstoffTablet with 50 mg of active ingredient
Zusammensetzung:Composition:
(1 ) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Milchzucker 98,0 mg(2) milk sugar 98.0 mg
(3) Maisstärke 50,0 mg(3) corn starch 50.0 mg
(4) Polyvinylpyrrolidon 15,0 mg(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesiumstearat 2,0 mg(5) Magnesium stearate 2.0 mg
Summe: 215,0 mgTotal: 215.0 mg
Herstellung:production:
(1 ), (2) und (3) werden gemischt und mit einer wäßrigen Lösung von (4) granuliert. Dem getrockneten Granulat wird (5) zugemischt. Aus dieser Mischung werden Tabletten gepreßt.(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture.
Beispiel IIExample II
Kapsel mit 50 mg Wirkstoff Zusammensetzung:Capsule with 50 mg active ingredient composition:
(1 ) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Maisstärke getrocknet 58,0 mg(2) Dried corn starch 58.0 mg
(3) Milchzucker pulverisiert 50,0 mg(3) Milk sugar powdered 50.0 mg
(4) Magnesiumstearat 2,0 mg Summe: 160,0 mg Herstellung:(4) Magnesium stearate 2.0 mg total: 160.0 mg production:
(1 ) wird mit (3) verrieben. Diese Verreibung wird der Mischung aus (2) und (4) unter intensiver Mischung zugegeben. Diese Pulvermischung wird auf einer Kapselabfüllmaschine in Hartgelatine-Steckkapseln Größe 3 abgefüllt. (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

Claims

Patentansprüche claims
1. Neue Aryl- und Heteroaryl-substituierte Piperazinylcarbonyl-Verbindungen gemäß der allgemeinen Formel (1 ),1. New aryl- and heteroaryl-substituted piperazinylcarbonyl compounds according to the general formula (1),
wobei die Substituenten folgende Bedeutung haben:where the substituents have the following meaning:
R1 : Fluoren-9-on, Isoxazol, Cinnolin, Isothiazol, Isochinolin, 9H-Fluoren, 9H- Xanthen und 1 H-Pyrazol, wobei die Bindung über jedes beliebige und mögliche Ringglied des Heteroaryl- oder Arylrestes erfolgen kann und die Aromaten und Heteroaromaten ein- oder mehrfach substituiert oder unsubstituiert sein können,R1: fluoren-9-one, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1 H-pyrazole, whereby the binding can take place via any and possible ring member of the heteroaryl or aryl radical and the aromatics and heteroaromatics can be mono- or polysubstituted or unsubstituted,
R2: O, S;R2: O, S;
R3: repräsentiert einen oder bis zu 16 Substituenten ausgewählt aus der Gruppe: H, unsubstituiertes oder substituiertes Alkyl, Halogen, COOH, CONH2, wobei die Substituenten vicinal oder geminal am Heterocyclus angeordnet sein können;R3: represents one or up to 16 substituents selected from the group: H, unsubstituted or substituted alkyl, halogen, COOH, CONH2, where the substituents can be arranged vicinally or geminally on the heterocycle;
R4: unsubstituiertes oder substituiertes Aryl, unsubstituiertes oder substituiertes Heteroaryl, unsubstituiertes oder substituiertes Alkylaryl, unsubstituiertes oder substituiertes Alkylhetaryl; m, n: 0-3R4: unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylhetaryl; m, n: 0-3
2. Aryl- und Heteroarylcarbonylpiperazin-Verbindungen der allgemeinen Formel (1 ) nach Anspruch 1 , worin2. aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to claim 1, wherein
„Halogen" die Halogenatome Fluor, Chlor, Brom und lod umfasst,"Halogen" includes the halogen atoms fluorine, chlorine, bromine and iodine,
„Metall" Metallionen wie Natrium-, Kalium-, Lithium-, Magnesium-, Calcium-, Zink- und Mangan-Ionen, umfasst"Metal" includes metal ions such as sodium, potassium, lithium, magnesium, calcium, zinc and manganese ions
„Alkyl" acyclische gesättigte oder ungesättigte Kohlenwasserstoffreste, mit 1 bis 20 C-Atomen, verzweigt oder geradkettig sowie unsubstituiert oder ein- oder mehrfach substituiert umfasst, wobei Alkenyle mindestens eine C-C-Doppelbindung und Alkinyle mindestens eine C-C-Dreifachbindung aufweisen,“Alkyl” comprises acyclic saturated or unsaturated hydrocarbon radicals, having 1 to 20 carbon atoms, branched or straight-chain and unsubstituted or mono- or polysubstituted, alkenyls having at least one C-C double bond and alkynyls having at least one C-C triple bond,
„Cycloalkyl" cyclische Kohlenwasserstoffe mit 3-12 Kohlenwasserstoffen, gesättigt oder ungesättigt, unsubstituiert oder substituiert umfaßt, deren Bindung an die Verbindungen der allgemeinen Formel (1 ) über jedes beliebige und mögliche Ringglied des Cycloalkyl-Restes erfolgen kann und der Cycloalkyl-Rest auch Teil eines bi- oder polycyclischen Systems sein kann,“Cycloalkyl” comprises cyclic hydrocarbons with 3-12 hydrocarbons, saturated or unsaturated, unsubstituted or substituted, whose binding to the compounds of the general formula (1) can take place via any and possible ring member of the cycloalkyl radical and the cycloalkyl radical also part a bi- or polycyclic system,
„Heterocyclyl" für einen 3-, 4-, 5-, 6-, 7- oder 8-gliedrigen cyclischen organischen Rest, unsubstituiert oder ein- oder mehrfach substituiert, gesättigt oder ungesättigt, jedoch nicht aromatisch steht, der mindestens 1 , ggf. 2, 3, 4 oder 5 Heteroatome, bevorzugt Stickstoff, Sauerstoff und Schwefel enthält, wobei die Heteroatome gleich oder verschieden sind und dessen Bindung an die Verbindungen der allgemeinen Formel (1) über jedes beliebige und mögliche Ringglied des Heterocyclyl-Restes erfolgen kann, wobei der Heterocyclus auch Teil eines bi- oder polycyclischen Systems sein kann,"Heterocyclyl" for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical, unsubstituted or mono- or polysubstituted, saturated or unsaturated, but not aromatic, which is at least 1, optionally Contains 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and sulfur, where the heteroatoms are the same or different and can be bound to the compounds of general formula (1) via any and possible ring member of the heterocyclyl radical, where the heterocycle can also be part of a bi- or polycyclic system,
„Aryl" aromatische Kohlenwasserstoffe, unsubstituiert oder einfach oder mehrfach substituiert, u.a. Phenyle, Naphthyle und Anthracenyle bezeichnet, deren Reste auch mit weiteren gesättigten, (partiell) ungesättigten oder aromatischen Ringsystemen kondensiert sein können und deren Bindung an die Verbindungen der allgemeinen Formel (1 ) über jedes beliebige und mögliche Ringglied des ArylRestes erfolgen kann,"Aryl" aromatic hydrocarbons, unsubstituted or mono- or polysubstituted, including phenyls, naphthyls and anthracenyls, and their residues can be condensed with further saturated, (partially) unsaturated or aromatic ring systems and their binding to the compounds of the general formula (1) can take place via any and possible ring member of the aryl radical,
„Heteroaryl" für einen 5-, 6- oder 7-gliedrigen cyclischen aromatischen Rest, unsubstituiert oder ein- oder mehrfach, gleich oder verschieden substituiert steht, der mindestens 1 , ggf. auch 2, 3, 4 oder 5 Heteroatome, bevorzugt Stickstoff, Sauerstoff und Schwefel enthält, wobei die Heteroatome gleich oder verschieden sind und dessen Bindung an die Verbindungen der allgemeinen Formel (1 ) über jedes beliebige und mögliche Ringglied des Heteroaryl-Restes erfolgen kann, wobei der Heterocyclus auch Teil eines bi- oder polycyclischen Systems sein. kann,"Heteroaryl" represents a 5-, 6- or 7-membered cyclic aromatic radical, unsubstituted or mono- or polysubstituted, identically or differently, which has at least 1, optionally also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, Contains oxygen and sulfur, where the heteroatoms are the same or different and can be bound to the compounds of general formula (1) via any and possible ring member of the heteroaryl radical, the heterocycle also being part of a bi- or polycyclic system. can
„Alkyl-Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" oder „Alkyl-Heteroaryl" die für Alkyl, Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl definierten Bedeutungen haben und der Cycloalkyl-, Heterocyclyl-, Aryl- bzw. Heteroaryl-Rest über eine C1-8— Alkyl- Gruppe an die Verbindungen der allgemeinen Formel (1 ) gebunden ist,“Alkyl-cycloalkyl”, “alkyl-heterocyclyl”, “alkyl-aryl” or “alkyl-heteroaryl” have the meanings defined for alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl and cycloalkyl-, heterocyclyl-, aryl- or heteroaryl Radical is bonded to the compounds of the general formula (1) via a C1-8 alkyl group,
„substituiert" im Zusammenhang mit „Alkyl", „Alkenyl" und „Alkinyl" die Substitution eines Wasserstoffrestes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH- Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, NH-Heterocyclyl, NH-Alkyl- OH, N(Alkyl)2, N(Alkyl-Aryl)2, N(Alkyl-Heteroaryl)2, N(Heterocyclyl)2, N(Alkyl-OH)2, NO, N02, SH, S-Alkyl, S-Cycloalkyl, S-Aryl, S-Heteroaryl, S-Alkyl-Aryl, S-Alkyl- Heteroaryl, S-Heterocyclyl, S-Alkyl-OH, S-Alkyl-SH, S-Alkyl, S-S-Cycloalkyl, S-S-Aryl, S-S-Heteroaryl, S-S-Alkyl-Aryl, S-S-Alkyl-Heteroaryl, S-S-Heterocyclyl, SS-Alkyl-OH, S-S-Alkyl-SH, S-S-Alkyl-C(0)-NH-Heterocyclyl, OH, O-Alkyl, O-Cycloalkyl, O- Alkylcycloalkyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O- Heterocyclyl, O-Alkylheterocyclyl, O-Alkyl-OH, O-Alkyl-O-Alkyl, 0-S02-N(Alkyl)2, O- S02-OH, 0-S02-0-Alkyl, 0-SO2-0-Cycloalkyl, 0-S02-0-Heterocycloalkyl, 0-S02-0- Alkylcycloalkyl, 0-S02-0-Alkylheterocycloalkyl, 0-S02-0-Aryl, 0-S02-0-Heteroaryl, 0-S02-0-Alkylaryl, 0-S02-O-Alkylheteroaryl, 0-S02-Alkyl, 0-S02-Cycloalkyl, 0-S02- Heterocycloalkyl, 0-S02-Alkylcycloalkyl, 0-S02-Alkylheterocycloalkyl, 0-S02-Aryl, O- S02-Heteroaryl, 0-S02-Alkylaryl, 0-S02-Alkylheteroaryl, 0-C(0)-Alkyl, O-C(O)- Cycloalkyl, 0-C(0)-Heterocycloalkyl, 0-C(0)-Alkylcycloalkyl, O-C(O)-"Substituted" in connection with "alkyl", "alkenyl" and "alkynyl" the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl , NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, N0 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl heteroaryl, S-heterocyclyl, S- Alkyl-OH, S-alkyl-SH, S-alkyl, SS-cycloalkyl, SS-aryl, SS-heteroaryl, SS-alkyl-aryl, SS-alkyl-heteroaryl, SS-heterocyclyl, SS-alkyl-OH, SS- Alkyl-SH, SS-alkyl-C (0) -NH-heterocyclyl, OH, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl heteroaryl , O-heterocyclyl, O-alkylheterocyclyl, O-alkyl-OH, O-alkyl-O-alkyl, 0-S0 2 -N (alkyl) 2 , O- S0 2 -OH, 0-S0 2 -0-alkyl, 0-SO 2 -0-cycloalkyl, 0-S0 2 -0-heterocycloalkyl, 0-S0 2 -0-alkylcycloalkyl, 0-S0 2 -0-alkyl heterocycloalkyl, 0-S0 2 -0-aryl, 0-S 0 2 -0-heteroaryl, 0-S0 2 -0-alkylaryl, 0-S0 2 -O-alkylheteroaryl, 0-S0 2 -alkyl, 0-S0 2 -cycloalkyl, 0-S0 2 - heterocycloalkyl, 0-S0 2 -Alkylcycloalkyl, 0-S0 2 -alkyl heterocycloalkyl, 0-S0 2 -aryl, O- S0 2 -heteroaryl, 0-S0 2 -alkylaryl, 0-S0 2 -alkylheteroaryl, 0-C (0) -alkyl, OC (O ) - Cycloalkyl, 0-C (0) heterocycloalkyl, 0-C (0) -alkylcycloalkyl, OC (O) -
Alkylheterocycloalkyl, O-C(0)-Aryl, 0-C(0)-Heteroaryl, 0-C(0)-Alkylaryl, O-C(O)- Alkylheteroaryl, 0-C(0)0-Alkyl, 0-C(0)0-Cycloalkyl, 0-C(0)0-Heterocycloalkyl, O- C(0)O-Alkylcycloalkyl, 0-C(0)0-Alkylheterocycloalkyl, 0-C(0)0-Aryl, 0-C(0)0- Heteroaryl, 0-C(0)0-Alkylaryl, 0-C(0)0-Alkylheteroaryl, 0-C(0)NH-Alkyl, O- C(0)NH-Cycloalkyl, 0-C(0)NH-Heterocycloalkyl, 0-C(0)NH-Alkylcycloalkyl, O- C(0)NH-Alkylheterocycloalkyl, 0-C(0)NH-Aryl, 0-C(0)NH-Heteroaryl, 0-C(0)NH- Alkylaryl, O-C(0)NH-Alkylheteroaryl, 0-C(0)N(Alkyl)2, 0-C(0)N( ycloalkyl)2, O- C(0)N(Heterocycloalkyl)2l 0-C(0)N(Alkylcycloalkyl)2l O- C(0)N(Alkylheterocycloalkyl)2l 0-C(0)N(Aryl)2, 0-C(0)N(Heteroaryl)2, O- C(0)N(Alkylaryl)2, 0-C(0)N(Alkylheteroaryl)2, 0-P(0)(OH)2, 0-P(0)(0-Metall)2, O- P(0)(0-Alkyl)2, 0-P(0)(0-Cycloalkyl)2, 0-P(0)(0-Aryl)2, 0-P(0)(0-Heteroaryl)2, O- P(0)(0-Alkylaryl)2, 0-P(0)(0-Alkylheteroaryl)2,0-P(0)(N-Alkyl)2(N-Alkyl)2,0-P(0)(N- Cycloalkyl)2(N-Cycloalkyl)2,0-P(0)(N-HeterocycloaIkyl)2(N-Heterocycloalkyl)2, O- P(0)(N-Aryl)2(N-Aryl)2, 0-P(0)(N-Heteroaryl)2(N-Heteroaryl)2, 0-P(0)(N-Alkyl heterocycloalkyl, OC (0) aryl, 0-C (0) heteroaryl, 0-C (0) alkylaryl, OC (O) - alkyl heteroaryl, 0-C (0) 0-alkyl, 0-C (0) 0-cycloalkyl, 0-C (0) 0-heterocycloalkyl, O- C (0) O-alkylcycloalkyl, 0-C (0) 0-alkyl heterocycloalkyl, 0-C (0) 0-aryl, 0-C (0) 0- heteroaryl, 0-C (0) 0-alkylaryl, 0-C (0) 0-alkyl heteroaryl, 0-C (0) NH-alkyl, O- C (0) NH-cycloalkyl, 0-C (0) NH heterocycloalkyl, 0-C (0) NH alkylcycloalkyl, O- C (0) NH alkyl heterocycloalkyl, 0-C (0) NH aryl, 0-C (0) NH heteroaryl, 0-C (0) NH-alkylaryl, OC (0) NH-alkyl heteroaryl, 0-C (0) N (alkyl) 2 , 0-C (0) N (ycloalkyl) 2 , O-C (0) N (heterocycloalkyl) 2l 0-C (0) N (alkylcycloalkyl) 2l O- C (0) N (alkylheterocycloalkyl) 2l 0-C (0) N (aryl) 2 , 0-C (0) N (heteroaryl) 2 , O- C (0) N (Alkylaryl) 2 , 0-C (0) N (alkylheteroaryl) 2 , 0-P (0) (OH) 2 , 0-P (0) (0-metal) 2 , O- P (0) (0- Alkyl) 2 , 0-P (0) (0-cycloalkyl) 2 , 0-P (0) (0-aryl) 2 , 0-P (0) (0-heteroaryl) 2 , O- P (0) ( 0-alkylaryl) 2 , 0-P (0) (0-alkylheteroaryl) 2 , 0-P (0) (N-alkyl) 2 (N-alkyl) 2 , 0-P (0) (N-cycloalkyl) 2 (N-cycloalkyl) 2, 0-P (0) (N-Heterocy cloaIkyl) 2 (N-heterocycloalkyl) 2 , O- P (0) (N-aryl) 2 (N-aryl) 2 , 0-P (0) (N-heteroaryl) 2 (N-heteroaryl) 2 , 0- P (0) (N-
Alkylaryl)2(N-Alkylaryl)2, 0-P(0)(N-Alkylheteroaryl)2(N-Alkylheteroaryl)2l CHO, C(O)- Alkyl, C(S)-Alkyl, C(O)-Aryl, C(S)-Aryl, C(0)-Alkyl-Aryl, C(S)-Alkyl-Aryl, C(O)- Heterocyclyl, C(0)-Heteroaryl, C(0)-Alkyl-Heteroaryl, C(S)-Heterocyclyl, C02H, C02- Alkyl, C02-Cyclyl, C02-Heterocyclyl, C02-Aryl, C02-Heteroaryl, C02-Alkyl-Aryl, C(O)- NH2, C(0)NH-Alkyl, C(O)NH-Aryl, C(0)NH-Heterocyclyl, C(0)NH-Alkyl-Heterocyclyl, C(0)N(Alkyl)2, C(0)N(Alkyl-Aryl)2, C(0)N(Alkyl-Heteroaryl)2, C(0)N(Heterocyclyl)2, SO-Alkyl, SO2-Alkyl, SO2-Aryl, S02-Alkylaryl, S02-Heteroaryl, S02-AlkylheteroaryI, S02NH2, SO3H, CF3, CHO, CHS, Alkyl, Cycloalkyl, Aryl, Alkylaryl, Heteroaryl, Alkyl heterocyclyl und/oder Heterocyclyl bedeuten kann, wobei bei mehrfach substituierten Resten solche entweder an verschiedenen oder an gleichen Atomen mehrfach substituiert sein können und die Mehrfachsubstitution mit dem gleichen oder verschiedenen Substituenten erfolgen kann,Alkylaryl) 2 (N-alkylaryl) 2 , 0-P (0) (N-alkylheteroaryl) 2 (N-alkylheteroaryl) 2l CHO, C (O) alkyl, C (S) alkyl, C (O) aryl , C (S) aryl, C (0) alkyl aryl, C (S) alkyl aryl, C (O) heterocyclyl, C (0) heteroaryl, C (0) alkyl heteroaryl, C (S) heterocyclyl, C0 2 H, C0 2 alkyl, C0 2 cyclyl, C0 2 heterocyclyl, C0 2 aryl, C0 2 heteroaryl, C0 2 alkyl aryl, C (O) - NH 2 , C (0) NH-alkyl, C (O) NH-aryl, C (0) NH-heterocyclyl, C (0) NH-alkyl-heterocyclyl, C (0) N (alkyl) 2 , C (0) N ( Alkyl-aryl) 2 , C (0) N (alkyl-heteroaryl) 2 , C (0) N (heterocyclyl) 2 , SO-alkyl, SO 2 -alkyl, SO 2 -aryl, S0 2 -alkylaryl, S0 2 - Heteroaryl, S0 2 -AlkylheteroaryI, S0 2 NH 2 , SO 3 H, CF 3 , CHO, CHS, alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkyl heterocyclyl and / or heterocyclyl can mean, in the case of multiply substituted radicals either such different or on the same atoms can be substituted several times and the multiple substitution can take place with the same or different substituent,
„substituiert" im Zusammenhang mit Aryl, Heterocyclyl, Heteroaryl, Alkyl-Aryl sowie Cycloalkyl die Substitution eines oder mehrerer Wasserstoffreste des Ringsystemes durch F, Cl, Br, I, CN, NH2, NH-Alkyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Heterocyclyl, NH-Alkyl-OH, N(Alkyl)2, NC(0)Alkyl, N(Alkyl- Aryl)2, N(Alkyl-Heteroaryl)2, N(Heterocyclyl)2, N(Alkyl-OH)2, NO, N02, SH, S-Alkyl, S- Aryl, S-Heteroaryl, S-Alkyl-Aryl, S-Alkyl-Heteroaryl, S-Heterocyclyl, S-Alkyl-OH, S- Alkyl-SH, OH, O-Alkyl, O-Cycloalkyl, O-Alkylcycloalkyl, O-Aryl, O-Heteroaryl, O- Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Heterocyclyl, O-Alkylheterocyclyl, O-Alkyl-OH, O- Alkyl-O-Alkyl, 0-SO2-N(Alkyl)2, 0-S02-OH, 0-S02-0-Alkyl, 0-S02-0-Cycloalkyl, O- S02-0-Heterocycloalkyl, 0-S02-0-AIkylcycloalkyl, O-S02-0-Alkylheterocycloalkyl, O- S02-0-Aryl, 0-S02-0-Heteroaryl, 0-S02-0-Alkylaryl, 0-S02-0-Alkylheteroaryl, O- S02-Alkyl, 0-S02-Cycloalkyl, 0-S02-Heterocycloalkyl, 0-S02-Alkylcycloalkyl, 0-S02- Alkylheterocycloalkyl, 0-S02-Aryl, 0-S02-Heteroaryl, 0-S02-Alkylaryl, 0-S02- Alkylheteroaryl, 0-C(0)-Alkyl, 0-C(0)-Cycloalkyl, O-C(0)-Heterocycloalkyl, O-C(O)- Alkylcycloalkyl, 0-C(0)-Alkylheterocycloalkyl, 0-C(0)-Aryl, 0-C(0)-Heteroaryl, O- C(0)-Alkylaryl, 0-C(0)-Alkylheteroaryl, 0-C(0)0-Alkyl, 0-C(0)0-Cycloalkyl, O- C(0)0-Heterocycloalkyl, 0-C(0)0-Alkylcycloalkyl, O-C(0)0-Alkylheterocycloalkyl, O- C(0)0-Aryl, 0-C(O)0-Heteroaryl, 0-C(0)0-Alkylaryl, 0-C(0)0-Alkylheteroaryl, O- C(0)NH-Alkyl, 0-C(0)NH-Cycloalkyl, 0-C(0)NH-Heterocycloalkyl, 0-C(0)NH- Alkylcycloalkyl, 0-C(0)NH-Alkylheteracycloalkyl, 0-C(0)NH-Aryl, 0-C(0)NH- Heteroaryl, 0-C(O)NH-Alkylaryl, 0-C(0)NH-Alkylheteroaryl, 0-C(0)N(Alkyl)2, O- C(0)N(Cycloalkyl)2, 0-C(0)N(Heterocycloalkyl)2, 0-C(0)N(Alkylcycloalkyl)2, O- C(0)N(Alkylheterocycloalkyl)2, 0-C(0)N(Aryl)2, 0-C(0)N(Heteroaryl)2, O- C(0)N(Alkylaryl)2, 0-C(0)N(Alkylheteroaryl)2, 0-P(0)(OH)2, 0-P(0)(0-Metall)2, O- P(0)(0-Alkyl)2, 0-P(0)(0-Cycloalkyl)2> 0-P(0)(0-Aryl)2, 0-P(0)(0-Heteroaryl)2, O- P(0)(0-Alkylaryl)2, 0-P(0)(0-Alkylheteroaryl)2jO-P(0)(N-Alkyl)2(N-Alkyl)2,0-P(0)(N- Cycloalkyl)2(N-Cycloalkyl)2,0-P(0)(N-Heterocycloalkyl)2(N-Hetero-cycloalkyl)2l O- P(0)(N-Aryl)2(N-Aryl)2, 0-P(0)(N-Heteroaryl)2(N-Heteroaryl)2, 0-P(0)(N-"Substituted" in connection with aryl, heterocyclyl, heteroaryl, alkyl-aryl and cycloalkyl, the substitution of one or more hydrogen radicals of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl , NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , NC (0) alkyl, N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, N0 2 , SH, S-alkyl, S- Aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S- alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O- Aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl heterocyclyl, O-alkyl-OH, O-alkyl-O-alkyl, 0-SO 2 -N (alkyl) 2 , 0-S0 2 -OH, 0-S0 2 -0-alkyl, 0-S0 2 -0-cycloalkyl, O-S0 2 -0-heterocycloalkyl, 0-S0 2 -0-alkylcycloalkyl, O-S0 2 -0 -Alkyl heterocycloalkyl, O-S0 2 -0-aryl, 0-S0 2 -0-heteroaryl, 0-S0 2 -0-alkylaryl, 0-S0 2 -0-alkylheteroaryl, O-S0 2 -alkyl, 0-S0 2 -Cycloalkyl, 0-S0 2 -heterocycloalkyl, 0-S0 2 -alkylcycloalkyl, 0-S0 2 - alkylheterocycloalkyl, 0-S0 2 -aryl, 0-S0 2 -heteroaryl, 0-S0 2 -alkylaryl, 0-S0 2 - Alkyl heteroaryl, 0-C (0) alkyl, 0-C (0) cycloalkyl, OC (0) heterocycloalkyl, OC (O) - alkylcycloalkyl, 0-C (0) alkyl heterocycloalkyl, 0-C (0) - Aryl, 0-C (0) heteroaryl, O-C (0) alkylaryl, 0-C (0) alkyl heteroaryl, 0-C (0) 0-alkyl, 0-C (0) 0-cycloalkyl, O - C (0) 0-heterocycloalkyl, 0-C (0) 0-alkylcycloalkyl, OC (0) 0-alkylhete rocycloalkyl, O- C (0) 0-aryl, 0-C (O) 0-heteroaryl, 0-C (0) 0-alkylaryl, 0-C (0) 0-alkylheteroaryl, O- C (0) NH- Alkyl, 0-C (0) NH-cycloalkyl, 0-C (0) NH-heterocycloalkyl, 0-C (0) NH-alkylcycloalkyl, 0-C (0) NH-alkyl heteracycloalkyl, 0-C (0) NH- Aryl, 0-C (0) NH-heteroaryl, 0-C (O) NH-alkylaryl, 0-C (0) NH-alkyl heteroaryl, 0-C (0) N (alkyl) 2 , O- C (0) N (cycloalkyl) 2 , 0-C (0) N (heterocycloalkyl) 2 , 0-C (0) N (alkylcycloalkyl) 2 , O- C (0) N (alkyl heterocycloalkyl) 2 , 0-C (0) N ( aryl) 2, 0-C (0) N (heteroaryl) 2, O- C (0) N (alkylaryl) 2, 0-C (0) N (alkylheteroaryl) 2, 0-P (0) (OH) 2 , 0-P (0) (0-metal) 2 , O- P (0) (0-alkyl) 2 , 0-P (0) (0-cycloalkyl) 2> 0-P (0) (0-aryl ) 2 , 0-P (0) (0-heteroaryl) 2 , O- P (0) (0-alkylaryl) 2 , 0-P (0) (0-alkylheteroaryl) 2j OP (0) (N-alkyl) 2 (N-alkyl) 2 , 0-P (0) (N-cycloalkyl) 2 (N-cycloalkyl) 2 , 0-P (0) (N-heterocycloalkyl) 2 (N-heterocycloalkyl) 2l O- P (0) (N-aryl) 2 (N-aryl) 2 , 0-P (0) (N-heteroaryl) 2 (N-heteroaryl) 2 , 0-P (0) (N-
Alkylaryl)2(N-Alkylaryl)2, 0-P(0)(N-Alkylheteraaryl)2(N-Alkylheteroaryl)2, CHO, C(O)- Alkyl, C(S)-Alkyl, C(0)-Aryl, C(S)-Aryl, C(0)-Alkyl-Aryl, C(S)-Alkyl-Aryl, C(O)- Heterocyclyl, C(S)-Heterocyclyl, C02H, C02-Alkyl, C02-Alkyl-aryl, C(0)-NH2, C(0)NH-Alkyl, C(O)NH-Aryl, C(0)NH-Heterocyclyl, C(0)N(Alkyl)2, C(0)N(Alkyl-Aryl)2, C(0)N(Alkyl-Heteroaryl)2, C(0)N(Heterocyclyl)2, SO-Alkyl, S02-Alkyl, S02-Aryl, S02- Alkylaryl, S02-Heteroaryl, S02-Alkylheteroaryl, SO2NH2, S03H, CF3, CHO, CHS, Alkyl, Cycloalkyl, Aryl, Alkylaryl, Heteroaryl, Alkylheterocyclyl und/oder Heterocyclyl bedeuten kann, wobei die Substituenten gleich oder verschieden sein und in jeder beliebigen und möglichen Position des Aryl, Heterocyclyl, Heteroaryl, Alkyl-Aryl und Cycloalkyl restes vorkommen können und wobei mehrfach substituierte Reste entweder an verschiedenen oder an gleichen Atomen mehrfach, mit dem gleichen oder mit verschiedenen Substituenten erfolgen können.Alkylaryl) 2 (N-alkylaryl) 2 , 0-P (0) (N-alkylheteraaryl) 2 (N-alkylheteroaryl) 2 , CHO, C (O) - alkyl, C (S) -alkyl, C (0) - Aryl, C (S) aryl, C (0) alkyl aryl, C (S) alkyl aryl, C (O) heterocyclyl, C (S) heterocyclyl, C0 2 H, C0 2 alkyl, C0 2 -alkyl-aryl, C (0) -NH 2 , C (0) NH-alkyl, C (O) NH-aryl, C (0) NH-heterocyclyl, C (0) N (alkyl) 2 , C (0) N (alkyl-aryl) 2 , C (0) N (alkyl-heteroaryl) 2 , C (0) N (heterocyclyl) 2 , SO-alkyl, S0 2 -alkyl, S0 2 -aryl, S0 2 - Alkylaryl, S0 2 heteroaryl, S0 2 alkyl heteroaryl, SO 2 NH 2 , S0 3 H, CF 3 , CHO, CHS, alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkyl heterocyclyl and / or heterocyclyl, where the substituents are the same or be different and can occur in any and possible position of the aryl, heterocyclyl, heteroaryl, alkyl-aryl and cycloalkyl radical, and where multiply substituted radicals can be carried out either repeatedly on different or on the same atoms, with the same or with different substituents.
3. Aryl- und Heteroarylcarbonylpiperazin-Verbindungen der allgemeinen Formel (1) nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Alkylrest Methyl, Ethyl, n-Propyl, 2-Propyl, n-Butyl, sec.-Butyl, tert.-Butyl, n-Pentyl, iso-Pentyl, neo- Pentyl, n-Hexyl, 2-Hexyl, n-Octyl, Ethylenyl (Vinyl), Ethinyl, Propenyl (-CH2CH=CH2; - CH=CH-CH3, -C(=CH2)- CH3), Propinyl (-CH2-C--:CH, -C≡C-CH3), Butenyl, Butinyl, Pentenyl, Pentinyl, Hexenyl, Hexinyl, Octenyl und Octinyl sein kann.3. aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to claims 1 and 2, characterized in that the alkyl radical is methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert. -Butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-octyl, ethyleneyl (vinyl), ethynyl, propenyl (-CH 2 CH = CH 2 ; - CH = CH-CH 3 , -C (= CH 2 ) - CH 3 ), propynyl (-CH 2 -C -: CH, -C≡C-CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, octenyl and octynyl can be.
4. Aryl- und Heteroarylcarbonylpiperazin-Verbindungen der allgemeinen Formel (1) nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Heterocyclyl-Rest Tetrahydrofuryl, Tetrahydropyranyl, Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpholinyl sein kann.4. aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to claims 1 and 2, characterized in that the heterocyclyl radical can be tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
5. Aryl- und Heteroarylcarbonylpiperazin-Verbindungen der allgemeinen Formel (1 ) nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Heteroaryl-Rest Pyrrolyl, Furyl, Thienyl, Thiazolyl, Triazolyl, Tetrazolyl, Oxazolyl, Isothiazolyl,, Isoxazolyl, Pyrazolyl, Imidazolyl, Pyridinyl, Pyrimidinyl, Pyrazinyl, Triazinyl, Benzthiazolyl, Indolyl, Indolizinyl, Chinolinyl, Isochinolinyl, Cinnolinyl, Chinazolinyl, Chinoxalinyl, Phthalazinyl, Carbazolyl, Phenazinyl, Phenothiazinyl, Purinyl, Acridinyl, Phenanthrinyl sein kann.5. aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to claims 1 and 2, characterized in that the heteroaryl radical pyrrolyl, furyl, thienyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, Imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzthiazolyl, indolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, carbazolyl, phenazinyl, phenothiazinyl, purinyl, acridinyl, phenanthrinyl.
6. Verbindungen der allgemeinen Formel (1 ) nach den Ansprüchen 1-5, dadurch gekennzeichnet, daß Ri, R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R4 für Phenyl steht, welches unsubstituiert oder mit ein bis fünf gleich oder verschiedenen (CrC-6)-Alkoxygruppen substituiert ist, wobei benachbarte Sauerstoffatome auch durch (C C2)-Alkylen-Gruppen verknüpft sein können.6. Compounds of general formula (1) according to claims 1-5, characterized in that R 1, R 2 , R 3 , n and m have the meanings given above and R 4 is phenyl which is unsubstituted or with one to five the same or different (CrC- 6 ) alkoxy groups is substituted, and adjacent oxygen atoms can also be linked by (CC 2 ) alkylene groups.
7. Verbindungen der allgemeinen Formel (1) nach Ansprüchen 1-5, dadurch gekennzeichnet, daß R, R-ι, R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R für 3,5-Dimethoxyphenyl steht. 7. Compounds of general formula (1) according to claims 1-5, characterized in that R, R-ι, R 2 , R 3 , n and m have the meanings given above and R is 3,5-dimethoxyphenyl.
8. Verbindungen der allgemeinen Formel (1 ) nach Ansprüchen 1-5, dadurch gekennzeichnet, daß R, R1 , R2, R3, n und m die vorstehend genannten Bedeutungen besitzen und R für 3-Methoxyphenyl steht.8. Compounds of the general formula (1) according to Claims 1-5, characterized in that R, R1, R2, R3, n and m have the meanings given above and R is 3-methoxyphenyl.
9. Physiologisch verträgliche Salze der Verbindungen nach Formel (1 ) gemäß Ansprüchen 1-8, gekennzeichnet durch Neutralisation der basischen Verbindungen mit anorganischen und organischen Säuren bzw. Neutralisation der sauren Verbindungen mit anorganischen und organischen Basen, sowie deren Solvate und Hydrate.9. Physiologically acceptable salts of the compounds of formula (1) according to claims 1-8, characterized by neutralization of the basic compounds with inorganic and organic acids or neutralization of the acidic compounds with inorganic and organic bases, and their solvates and hydrates.
10. Aryl- und Heteroarylcarbonylpiperazin-verbindungen der allgemeinen Formel (1 ) nach den Ansprüchen 1-9, mit mindestens einem asymmetrischen Kohlenstoffatom in Form ihrer Racemate, in Form der reinen Enantiomeren und/oder Diastereomeren oder in Form von Mischungen dieser Enantiomeren und/oder Diastereomeren oder in Form der Tautomeren.10. Aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to Claims 1-9, with at least one asymmetric carbon atom in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or Diastereomers or in the form of tautomers.
11. Verbindungen der allgemeinen Formel (1 ), insbesondere eine der folgenden Verbindungen:11. Compounds of the general formula (1), in particular one of the following compounds:
4-[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (1 ) 4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-carbonyl]-fluoren-9-on (2) 4-[4-(3-Hydroxy-phenyl)-piperazin-1 -carbonyl]-fluoren-9-on (3) [4-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)- methanon (4)4- [4- (3,5-Dimethoxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (1) 4- [4- (6-methyl-pyridin-2-yl) piperazin-1 -carbonyl] -fluoren-9-one (2) 4- [4- (3-hydroxyphenyl) piperazin-1-carbonyl] -fluoren-9-one (3) [4- (3,5-dimethoxy- phenyl) piperazin-1-yl] - (5-methyl-3-phenyl-isoxazol-4-yl) - methanone (4)
Cinnolin-4-yl-[4-(3,5-dimethyl-phenyl)-piperazin-1-yl]-methanon (5) Cinnolin-4-yl-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-methanon (6) (3,5-Bis-methylsulfanyl-isothiazol-4-yl)-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]- methanon (7) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-isochinolin-1 -yl-methanon (8)Cinnolin-4-yl- [4- (3,5-dimethylphenyl) piperazin-1-yl] methanone (5) Cinnolin-4-yl- [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone (6) (3,5-bis-methylsulfanyl-isothiazol-4-yl) - [4- (6-methyl-pyridin-2-yl) -piperazin-1-yl] - methanone (7) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] isoquinolin-1-yl methanone (8)
[4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-fluoren-1 -yl)-methanon (9) (9H-Fluoren-9-yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (10) (9H-Fluoren-1 -yl)-[4-(3-methoxyphenyl)-piperazin-1 -yl]-methanon (11 ) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (12) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(9H-xanthen-9-yl)-methanon (13) [4-(3-Methoxy-phenyl)-piperazin-1 -yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (14) [4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (15)[4- (3,5-dimethoxyphenyl) piperazin-1-yl] - (9H-fluoren-1-yl) -methanone (9) (9H-fluoren-9-yl) - [4- (3- methoxyphenyl) piperazin-1 -yl] -methanone (10) (9H-fluoren-1 -yl) - [4- (3-methoxyphenyl) -piperazin-1 -yl] -methanone (11) [4- (3,5-dimethoxyphenyl) piperazin-1-yl] - (9H-xanthene-9-yl) methanone (12) [4- (3-methoxy-phenyl) piperazin-1-yl ] - (9H-xanthene-9-yl) methanone (13) [4- (3-methoxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) methanone (14) [4- (6-Methyl-pyridin-2-yl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) - methanone (15)
[4-(3-Hydroxy-phenyl)-piperazin-1-yl]-(2-phenyl-2H-pyrazol-3-yl))-methanon (16) [4-(3,5-Dimethoxy-phenyl)-piperazin-1 -yl]-[1 -(4-nitrophenyl)-5-trifluormethyl-1 H- pyrazol-4-yl]-methanon (17)[4- (3-Hydroxyphenyl) piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl)) methanone (16) [4- (3,5-dimethoxyphenyl) - piperazin-1 -yl] - [1 - (4-nitrophenyl) -5-trifluoromethyl-1 H-pyrazol-4-yl] methanone (17)
12. Verfahren zur Herstellung von Aryl- und Heteroarylcarbonylpiperazin Verbindungen nach einem der Ansprüche 1 bis 11 , dadurch gekennzeichnet, daß eine Carbonsäure der allgemeinen Formel 2, worin R1 und R2 die vorstehend genannten Bedeutungen besitzen und Y für eine Abgangsgruppe wie Halogen, Hydroxy, (C1-C6)-Alkoxy vorzugsweise Methoxy und Ethoxy, -O-Tosyl, -O-Mesyl, Tetrazolyl oder Imidazolyl steht,12. A process for the preparation of aryl and heteroarylcarbonylpiperazine compounds according to any one of claims 1 to 11, characterized in that a carboxylic acid of the general formula 2, wherein R1 and R2 have the meanings given above and Y for a leaving group such as halogen, hydroxy, ( C1-C6) -alkoxy preferably methoxy and ethoxy, -O-tosyl, -O-mesyl, tetrazolyl or imidazolyl,
R1 : Aryl, Heteroaryl R1: aryl, heteroaryl
Formel 2 Formel 3Formula 2 Formula 3
mit einem Amin der allgemeinen Formel 3, worin R , m und n die vorstehend genannten Bedeutungen besitzen, gegebenenfalls unter Verwendung eines Kondensationsmittels und /oder Katalysators sowie von Verdünnungs- und Hilfsmitteln unter Bildung der gewünschten Produkte umgesetzt wird.with an amine of the general formula 3, in which R, m and n have the meanings given above, optionally using a condensing agent and / or catalyst and diluents and auxiliaries to form the desired products.
13. Verwendung der Aryl- und Heteroarylcarbonylpiperazin- Verbindungen der allgemeinen Formel (1 ) nach einem der Ansprüche 1 bis 11 als therapeutische Wirkstoffe zur Herstellung eines Arzneimittel zur Behandlung von Tumoren im Menschen und in Säugetieren. 13. Use of the aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to one of claims 1 to 11 as therapeutic agents for the manufacture of a medicament for the treatment of tumors in humans and in mammals.
14. Arzneimittel zur Verwendung bei der Behandlung von Tumoren im Menschen und in Säugetieren, enthaltend mindestens eine Verbindung der allgemeinen Formel (1 ) nach einem der Ansprüche 1 bis 11 , vorzugsweise zusammen mit üblichen pharmazeutisch verträglichen Hilfs-, Zusatz- und Trägersstoffen.14. Medicaments for use in the treatment of tumors in humans and in mammals, containing at least one compound of the general formula (1) according to one of claims 1 to 11, preferably together with customary pharmaceutically acceptable auxiliaries, additives and carriers.
15. Arzneimittel, enthaltend eine oder mehrere Verbindungen der allgemeinen Formel (1 ) nach einem der Ansprüche 1-11 neben üblichen physiologisch verträglichen Hilfs- , Zusatz- und Trägerstoffen.15. Medicament containing one or more compounds of the general formula (1) according to any one of claims 1-11 in addition to the usual physiologically compatible auxiliaries, additives and carriers.
16. Verfahren zur Herstellung eins Arzneimittels nach Anspruch 15, dadurch gekennzeichnet, dass ein oder mehrere Aryl- und Heteroarylcarbonylpiperazin- Verbindungen der allgemeinen Formel (1 ) nach einem der Ansprüche 1-11 mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen zu pharmazeutischen Zubereitungen verarbeitet, beziehungsweise in eine therapeutisch anwendbare Form gebracht werden.16. A method for producing a medicament according to claim 15, characterized in that one or more aryl and heteroarylcarbonylpiperazine compounds of the general formula (1) according to one of claims 1-11 with common pharmaceutical carriers and / or diluents or other auxiliaries to pharmaceutical Preparations processed, or brought into a therapeutically applicable form.
17. Verfahren zur Behandlung von gutartigen und bösartigen Tumoren im Menschen und Säugetieren, dad urch gekennzeichnet, daß mindestens eine Verbindung der allgemeinen Formel (1 ) nach einem der Ansprüche 1 bis 11 dem Menschen oder Säugetier in einer für die Tumorbehandlung wirksamen Dosis verabreicht wird. 17. A method for the treatment of benign and malignant tumors in humans and mammals, characterized in that at least one compound of the general formula (1) according to one of Claims 1 to 11 is administered to humans or mammals in a dose effective for tumor treatment.
EP03761482A 2002-06-29 2003-06-20 Arylcarbonylpiperazines and heteroarylcarbonylpiperazines and the use thereof for treating benign and malignant tumour diseases Withdrawn EP1517898A1 (en)

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