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WO2008154905A2 - Nouveaux produits pharmaceutiques, leur procédé de fabrication et leur utilisation en thérapie médicale - Google Patents

Nouveaux produits pharmaceutiques, leur procédé de fabrication et leur utilisation en thérapie médicale Download PDF

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Publication number
WO2008154905A2
WO2008154905A2 PCT/DE2008/000993 DE2008000993W WO2008154905A2 WO 2008154905 A2 WO2008154905 A2 WO 2008154905A2 DE 2008000993 W DE2008000993 W DE 2008000993W WO 2008154905 A2 WO2008154905 A2 WO 2008154905A2
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Prior art keywords
compounds
general formula
group
methyl
direct bond
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German (de)
English (en)
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WO2008154905A3 (fr
Inventor
Hans Scheefers
Ursula Scheefers-Borchel
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ScheBo Biotech AG
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ScheBo Biotech AG
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Application filed by ScheBo Biotech AG filed Critical ScheBo Biotech AG
Priority to DE112008002230T priority Critical patent/DE112008002230A5/de
Publication of WO2008154905A2 publication Critical patent/WO2008154905A2/fr
Publication of WO2008154905A3 publication Critical patent/WO2008154905A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • Cancers are still a common cause of death for people in industrialized countries. In Germany alone, about 395,000 new cancers are diagnosed each year. The cure rate is 30-60%. Despite a number of known drugs for the treatment of cancer, there are a number of tumors that do not respond to therapeutics. In addition, the known therapies are characterized by a variety of side effects.
  • Ar is a benzyl, aryl or heteroaryl radical which can carry 1-3 substituents, which are selected independently of one another from the group -F, -Cl, -CrC 4 -AlkVl, -OH, -O-C 1 -C 4 -Alkyl, -CF 3 , -NH 2 ,
  • Z, Z, Z are each independently of one another a direct bond or an oxygen or a sulfur atom, Y 1 , Y 2 independently of one another for a direct bond, for N (-R 2 ), -
  • n is a natural number from 1 to 10,
  • n is an integer from 0 to 4,
  • r is zero or 1
  • s is zero or 1
  • R 1 represents a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or heteroaryl radical, where the benzyl, aryl or
  • Heteroaryl may carry 1-3 substituents which are independently selected from the group -F, -Cl, -CrC 4 - alkyl, -OH, -0-C 1 -C 4 -alkyl, -CF 3 , -NH 2 .
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • This finding is based on all the compounds described in this document. Detailed description of the invention and preferred embodiments
  • the compounds of general formula I according to the invention are novel substituted linear dicarboxylic acids.
  • an oxy-amine grouping designed according to the invention is linked to an aromatic compound. It may be, for example, a phenoxyamine group.
  • the aromatic Ar can also be a heteroaromatic, e.g. a pyridine derivative, but it may also be a condensed aromatic, e.g. an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene, quinoline, isoquinoline or chroman derivative.
  • the aromatic or heteroaromatic compound may furthermore also be substituted, for example with fluoro, methyl, ethyl or trifluoromethyl.
  • the alkylene chain between the two carboxylic acids can contain 1 to 10 CH 2 groups. It preferably contains 5-7 CH 2 groups, more preferably it contains 6 CH 2 groups.
  • R 1 may be hydrogen or a branched or unbranched C r C 4 alkyl radical. Furthermore, R 1 may also be benzyl, aryl or benzyl
  • Heteroaromatics Ar also apply to the aromatics or heteroaromatics optionally contained in R 1 .
  • R 1 is hydrogen, methyl or ethyl, most preferably hydrogen.
  • the group R 2 may be hydrogen or a branched or unbranched
  • C 1 -C 4 alkyl for example methyl, ethyl, propyl, isopropyl, butyl,
  • Y 1 and Y 2 each represent a direct bond, an oxygen atom, a sulfur atom, or a group
  • Y 1 is a direct bond and Y 2 is -ON (-H) -.
  • the groups Z 1 , Z 2 , Z 3 each independently represent a direct bond or an oxygen or a sulfur atom. Preferred are - A -
  • the compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form.
  • stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the invention may be present, which are also subject of the invention. This also applies to the compounds of alternative embodiments II-XVII mentioned below.
  • the compounds of the general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They are used in particular for the treatment of hematological or solid
  • Tumors e.g. non-Hodgkin's tumors, or of T-cell lymphomas.
  • the effect of the compounds according to the invention as cancer therapeutics can be attributed to their suitability for the inhibition of histone deacetylase.
  • the compounds of the invention therefore fall into the class of HDAC inhibitors.
  • the suitability as cancer therapeutics is due to the effect of these compounds on the modulation of the cell cycle, the modulation of cell differentiation, apoptosis and angiogenesis.
  • the compounds of the general formula I lead to a dose-dependent inhibition of colony formation in the colony assay of the company Oncotest (Freiburg).
  • Six concentrations of the substance were measured between 0.3 ⁇ M and 100 ⁇ M compared to 5-FU.
  • IC 50 values in 25 different cell culture lines including MCF-7, HT-29, BxPC-3, MDA-MB-453, NK1, LXFA 629, LXFS615, MAXF583, OVXF1023, RXF-631) were generally between 4 and 40 ⁇ M.
  • the mean ICvo value was determined at just below 100 ⁇ M.
  • Outstanding high selectivity was found in small cell lung carcinoma (LXFS650), followed by renal carcinoma (RXF 1393). Noteworthy were the low selectivity differences between the different tumor cell lines, which speaks for a very good suitability for the therapy of various tumor types. The best results were found with the following substance:
  • the invention therefore teaches the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases selected from the group consisting of cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colorectal cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer , Skin cancer, gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, asthma, allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowel disease, degenerative joint disease, diseases of the Cartilage, sepsis, autoimmune diseases, type I diabetes, Hashimoto's thyroiditis, autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, uveitis, psoriasis,
  • the present invention teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way.
  • Free Carboxylic acid groups may also be present in the form of their salts with physiologically acceptable counterions such as Mg ++ , Ca ++ , Na + , K + , Li + or ammonium derivatives such as cyclohexylammonium.
  • Amino-containing compounds may also be present in the form of an ammonium salt, for example as chloride, bromide, mesylate, tosylate, oxalate, orotate or tartrate.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (IV, Lp, in, sc) or nebulization (aerosols), preparation forms forzelpulverinhalation, transdermal systems and preparations with sustained release drug, in the preparation of conventional auxiliaries such as carriers, disintegrants, binders, coatings, swelling, lubricants or lubricants, flavoring agents, sweeteners and solubilizers are used.
  • adjuvants are, for example, magnesium carbonate, titanium dioxide, lactose, manidine and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile Water and mono- or polyhydric alcohols, for example, called glycerol.
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in defined doses with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate.
  • N, N-dibenzylethylenediamine, diethanolamine ethylenediamine, N-methylglucamine
  • N-benzylphenethylamine diethylamine
  • phosphate sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • dosage units such as tablets, capsules, dragees or suppositories this dose 0.1-1,000 mg, preferably 1-300 mg, and for injection solutions in the form of ampoules 0.01-1,000 mg, preferably 1-100 mg.
  • the preparation of infusion solutions is another preferred embodiment.
  • daily doses for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active substance, preferably 1-500 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
  • the preparations according to the invention can be prepared, for example, as follows:
  • 1 drag core contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
  • a tableting machine compacts are made with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1, 5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is on a Tabletting machine pressed into tablets with the desired shape.
  • Core weight 230 mg
  • the coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax. Dragee weight: 245 mg.
  • Composition 1 tablet contains:
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet mass (2.0 mm mesh size) and drying in a rack oven at 50 0 C is sieved again (1, 5 mm mesh size) and admixed with the lubricant. The ready-to-use mixture is processed into tablets.
  • 1 tablet contains: • active substance 150.0 mg
  • the active substance mixed with milk sugar, corn starch and silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve of 1.5 mm mesh size.
  • Hard gelatine capsules (with 150 mg active substance)
  • 1 capsule contains:
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
  • 1 suppository contains: • Active ingredient 150.0 mg
  • Dest. Water is heated to 7O 0 C.
  • p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
  • 5 ml of suspension contain 50 mg of active ingredient.
  • the active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 10 ml ampoules.
  • Corresponding formulations can be prepared for the below-mentioned compounds of the alternative embodiments Ii-XVII.
  • compounds of the invention may be combined with other drugs known per se.
  • drugs known per se.
  • the compound according to the invention can be mixed with the active substance in the context of a single galenic preparation.
  • the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound according to the invention and in a second preparation of the active ingredient are included.
  • first preparation it is also possible to set up a substance which is different from the active ingredient of the second preparation.
  • the compounds according to the invention are prepared by reacting linear dicarboxylic acid dichlorides with an arylhydroxylamine (for example phenylhydroxylamine) or its hydrochloride in the presence of tert-butyldimethylsilylhydroxylamine.
  • arylhydroxylamine for example phenylhydroxylamine
  • hydrochloride in the presence of tert-butyldimethylsilylhydroxylamine.
  • the compound of the formula C 6 H 5 ONHCO- (CH 2 ) 6 -CO-NHOH can be prepared as follows: tert-butyl-dimethylsilylhydroxylamine (13.78 mmol) and 13.74 mmol of phenylhydroxylamine are dissolved under a protective gas atmosphere 100 ml of pyridine, cooled to 0 0 C and slowly added dropwise a solution of suberoyl chloride (CI-CO- (CH 2 VCO-Cl) in 10 ml of dichloromethane After stirring at room temperature overnight, the solvent is removed in vacuo and coevaporated with toluene After repeated purification by flash chromatography and drying in
  • Phenylhydroxylamine hydrochloride is commercially available, such as a number of other aromatic hydroxylamines. Derivatives which are not commercially available are prepared from the corresponding chlorides by reaction with tert-butyl-dimethylsilylhydroxylamine.
  • R any organic radical
  • LG Leaving group
  • BOC benzyloxycarbonyl
  • Ar is benzyl, aryl or heteroaryl radical, which may bear 1-3 substituents independently selected from the group -F 1 -Cl, -C 1 -C 4 -alkyl, -OH, -O- C 1 1 -C 4 -AlkVl, -CF 3 , -NH 2 ,
  • Z 7 1, Z 7 2, Z -5-3, 1 Z -? 4, Z -, 5 each independently represent a direct bond or an oxygen or a sulfur atom
  • w is an integer from 0 to four
  • R 1 represents a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or heteroaryl radical, where the benzyl, aryl or heteroaryl radical may carry 1-3 substituents which are independently selected from the group -F, -Cl, -C 1 -C 4 -alkyl, -OH, -O-CrOrAlkyl, -CF 3 , -NH 2 ,
  • Each R 2 independently represents a hydrogen atom or a branched or unbranched C 1 -C 6 -alkyl radical
  • the compounds of the general formula II mentioned are, like the compounds of the general formula I, usable as medicaments. In particular, they are useful in the therapy of Parkinson's disease, Alzheimer's and dementia diseases, as well as in the treatment of anxiety disorders, epilepsy, Lennox-Gastaut syndrome and bipolar affective disorders.
  • the aromatic Ar may be a phenyl or anthracenyl radical, but also a heteroaromatic radical, for example a pyridine derivative, but it may also be a condensed aromatic radical, for example an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene radical. , Quinoline, isoquinoline or chroman derivative. The same applies to the aryl or heteroaryl radical optionally contained in the group R 1 .
  • the aromatic or heteroaromatic compound may also be substituted, e.g. with fluoro, methyl, ethyl or trifluoromethyl.
  • Alkylene chains may each contain 0 to 4 CH 2 groups. Each of them preferably contains 1-2 CH 2 groups, more preferably they contain exactly one CH 2 group.
  • the group R 1 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical.
  • R 1 is hydrogen, methyl or ethyl, most preferably hydrogen.
  • R 1 can also be a benzyl, aryl or heteroaryl radical.
  • a phenyl or Anthracenylrest but also a heteroaromatic, such as a pyridine derivative, in question, but also be condensed aromatics, such as an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene, quinoline, Isoquinoline or chroman derivative.
  • the aromatic or heteroaromatic compound may furthermore also be substituted, for example with fluoro, methyl, ethyl or trifluoromethyl.
  • the group R 2 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl
  • R 2 is hydrogen, methyl or ethyl, very particularly preferably Hydrogen.
  • the groups Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently a direct bond or an oxygen or a sulfur atom. Preference is given to compounds in which at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is an oxygen atom.
  • X is an oxygen atom.
  • the compounds of the general formula II according to the invention are prepared by routine methods of preparative organic chemistry.
  • An example scheme is disclosed in FIGS. 5 and 6.
  • the preparative organic chemist knows the usual methods to modify the scheme and thus to get to the compounds of general formula II.
  • Z 1 , Z 2 , Z 3 are each independently a direct bond or an oxygen or sulfur atom
  • u is an integer from 0 to four
  • R 1 represents a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or heteroaryl radical, where the benzyl, aryl or heteroaryl radical may carry 1-3 substituents which are independently selected from the group -F, -Cl, -CrC 4 -alkyl, -OH, -OC r C 4 -alkyl, -CF 3 , -NH 2 ,
  • R 3 is -SH or - SCOCH 3
  • the compounds of the general formula III mentioned like the compounds of the general formula I, are usable in particular in cancer therapy.
  • the alkylene chain indicated by u may contain 0 to 4 CH 2 groups. It preferably contains 1-2 CH 2 groups, more preferably it contains 1 CH 2 group.
  • the group R 1 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical.
  • R 1 is hydrogen, methyl or ethyl, most preferably hydrogen.
  • R 1 can also be used for a benzyl, aryl or heteroaryl radical.
  • a phenyl or Anthracenylrest but also a heteroaromatic, such as a pyridine derivative, in question, but also be condensed aromatics, such as an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene, quinoline, Isoquinoline or chroman derivative.
  • the aromatic or heteroaromatic compound may furthermore also be substituted, for example with fluoro, methyl, ethyl or trifluoromethyl.
  • the group R 2 can stand 4 alkyl, hydrogen or a branched or unbranched Ci-C, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. "butyl.
  • R 2 is hydrogen, methyl or ethyl, especially preferred for hydrogen.
  • the groups Z 1 , Z 2 , Z 3 each independently represent a direct bond or an oxygen or a sulfur atom. Preference is given to compounds in which at least one of Z 1 , Z 2 , Z 3 is an oxygen atom. Particularly preferred are compounds in which exactly one of the radicals Z 1 , Z 2 , Z 3 is an oxygen atom and the other two radicals are a direct bond. Very particular preference is given to compounds in which Z 3 is an oxygen atom and in which the other two radicals are a direct bond.
  • the compounds of the general formula III according to the invention are prepared by routine methods of preparative organic chemistry.
  • Example scheme is disclosed in FIG. The preparative organic chemist knows the usual methods to modify the scheme and thus to arrive at the compounds of general formula III.
  • Ar is a benzyl, aryl or heteroaryl radical, 1-3
  • Substituents independently of one another selected from the group -F, -Cl, -Ci -C 4 -alkyl, -OH, -O-Ci-C 4 alkyl, -CF 3 , -NH 2 ,
  • Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom
  • R 2 is a hydrogen atom or a branched or unbranched dC 4 alkyl
  • R 4 is -Cl, -F, -Br, -CF 3 or -OCF 3 , -NO 2 or -OCH 3
  • the compounds of the general formula II mentioned are, like the compounds of the general formula I, usable as medicaments. In particular, they are useful in the therapy of Parkinson's disease, Alzheimer's and dementia diseases, as well as in the treatment of anxiety disorders, epilepsy, Lennox-Gastaut syndrome and bipolar affective disorders.
  • the aromatic Ar may be a phenyl or anthracenyl radical, but also a heteroaromatic radical, for example a pyridine derivative, but it may also be a condensed aromatic radical, for example an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene radical. , Quinoline, isoquinoline or chroman derivative. The same applies to the aryl or heteroaryl radical optionally contained in the group R 1 .
  • the aromatic or heteroaromatic compound may furthermore also be substituted, for example with fluoro, methyl, ethyl or trifluoromethyl.
  • Ar is preferably an optionally substituted phenyl radical.
  • Ar is more preferably a disubstituted phenyl radical.
  • Especially preferred substituents of Ar are fluorine or chlorine atoms or trifluoromethyl groups, in particular fluorine atoms.
  • Ar is a 2,6-disubstituted phenyl radical.
  • the group R 2 may be hydrogen or a branched or unbranched C 1 -C 4 -alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl.
  • R 2 is hydrogen, methyl or ethyl, most preferably hydrogen.
  • the groups Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of the radicals Z 1 , Z 2 , Z 3 , Z 4 is a
  • Oxygen atom is. Particular preference is given to compounds in which exactly one of the radicals Z 1 , Z 2 and one of the radicals Z 3 , Z 4 is an oxygen atom and the other radicals are a direct bond. Very particular preference is given to compounds in which exactly one of the radicals Z 1 , Z 2 is an oxygen atom and the other radicals Z 2 , Z 3 , Z 4 are a direct bond.
  • the compounds of the general formula IV according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula IV.
  • Ar is a benzyl, aryl or heteroaryl radical, 1-3
  • Substituents independently of one another selected from the group -F, -Cl, -CrC 4 alkyl, -OH, -O-C 1 -C 4 -AlkVl, -CF 3 , -NH 2 ,
  • Z 1 , Z 2 , Z 3 , Z 4 ', Z 5 , Z 6 each, independently of one another, represents a direct bond or represents an oxygen or a sulfur atom
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • n the natural numbers 1, 2, 3 or 4
  • the compounds of the general formula II mentioned are, like the compounds of the general formula I, usable as medicaments. In particular, they are useful in the therapy of Parkinson's disease, Alzheimer's and dementia diseases, as well as in the treatment of anxiety disorders, epilepsy, Lennox-Gastaut syndrome and bipolar affective disorders.
  • the aromatic Ar may be a phenyl or anthracenyl radical, but also a heteroaromatic, e.g. a pyridine derivative, but it may also be a condensed aromatic, e.g. an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene, quinoline, isoquinoline or chroman derivative.
  • aromatic or heteroaromatic compound may also be substituted, e.g. With
  • Ar is preferably an optionally substituted phenyl radical.
  • the group R 2 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl
  • R 2 is hydrogen, methyl or ethyl, very particularly preferably Hydrogen.
  • the groups Z 1 , Z 3 , Z 3 , Z 4 , Z 5 , Z 6 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of Z 1 , Z 3 , Z 3 , Z 4 , Z 5 , Z 6 is an oxygen atom. Particular preference is given to compounds in which exactly one of the radicals Z 1 , Z 2 Z 3 and exactly one of the radicals Z 4 , Z 5 , Z 6 is an oxygen atom and the other radicals are a direct bond.
  • the compounds of the general formula V according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula V.
  • Ar is a benzyl, aryl or heteroaryl radical which can carry 1-3 substituents which are selected independently of one another from the group -F, -Cl, -CrC 4 -alkyl, -OH, -O-C 1 -C 4 -AlkVl, -CF 3 , -NH 2 ,
  • Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • R 5 is a hydrogen atom, a branched or unbranched
  • n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4,
  • the compounds of the general formula VI mentioned are, like the compounds of the general formula I-V, usable as medicaments. In particular, they are useful in the therapy of Parkinson's disease, Alzheimer's and dementia diseases, as well as in the treatment of anxiety disorders, epilepsy, Lennox-Gastaut syndrome and bipolar affective disorders.
  • the aromatic Ar can be a phenyl or anthracenyl radical, but also a heteroaromatic, for example a pyridine derivative, but it can also be a condensed one Aromatic, such as an anthracene, indolizine, indole, isoindole, coumarone, thionaphthene, quinoline, isoquinoline or chroman derivative.
  • the aromatic or heteroaromatic compound may also be substituted, e.g. with fluoro, methyl, ethyl or trifluoromethyl.
  • Ar is preferably an optionally substituted indole residue.
  • the group R 2 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl, Preferably R 2 is hydrogen, methyl or ethyl, completely especially preferred for hydrogen.
  • the groups Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of Z 1 , Z 2 , Z 3 , Z 4 is an oxygen atom. Particularly preferred are compounds in which exactly one of the radicals Z 1 , Z 2 , Z 3 is an oxygen atom and the other radicals Z 1 , Z 2 , Z 3 are a direct bond. Regardless, Z 4 is preferably an oxygen atom.
  • the index n can be 1-4. Preferably, n is two.
  • the index m can be 1-4.
  • m is one.
  • the compounds of general formula VI according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula VI.
  • Z 1 , Z 3 , Z 4 , Z 5 , Z 6 each, independently of one another, represents a direct bond or represents an oxygen or a sulfur atom
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • Y is a direct bond, an oxygen atom, a sulfur atom, or a group
  • the compounds of the general formula II mentioned are, like the compounds of the general formula I, usable as medicaments. In particular, they are useful in the therapy of Parkinson's disease, Alzheimer's and dementia diseases, as well as in the treatment of anxiety disorders, epilepsy, Lennox-Gastaut syndrome and bipolar affective disorders.
  • the group R 2 can be hydrogen or a branched or unbranched C 1 -C 4 -alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl, R 2 being particularly preferably hydrogen, methyl or ethyl preferred for hydrogen.
  • the groups Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of the radicals Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 is a Oxygen atom is. Particular preference is given to compounds in which exactly one of the radicals Z 1 , Z 2 , Z 3 or in which exactly one of the radicals Z 4 , Z 5 , Z 6 is an oxygen atom and the other radicals Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 stand for a direct bond.
  • Y represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • Y stands for a direct bond or for -O-N (-H) -.
  • the compounds of the general formula VII according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula VII.
  • a synthesis scheme is attached as FIG.
  • Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom
  • R 4 is -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R, 4B is -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group, n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4,
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • the compounds of the general formula VIII mentioned are, like the compounds of the general formula I, usable as medicaments. In particular, they are in the therapy of depression, schizophrenia and anxiety disorders, further in the therapy of sexual dysfunction, especially in reduced sexual desire in women (sexual desire disorder, libido loss).
  • the substances are particularly effective as 5HTi a and 5HT2a serotonin receptor antagonists, they are also effective in the therapy of other disease states mediated through these receptors.
  • the groups Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of the radicals Z 1 , Z 2 , Z 4 , Z 5 , represents an oxygen atom. Particularly preferred are compounds in which exactly one of the radicals Z 1 , Z 2 or in which exactly one of the radicals Z 4 , Z 5 is an oxygen atom and the other radicals Z 1 , Z 2 , Z 4 , Z 5 for a direct bond stand.
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • Y 1 is preferably a direct bond or -ON (-H) -.
  • the group R 4 may be -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 . It is preferably -CF 3 , -C 2 Fs or -OCF 3 , very particularly preferably -CF 3 .
  • the group may be positioned anywhere within the phenyl ring, for example in the 2, 3, 4 position (ortho, meta or para) to Z 5 . Preferably, it is in the 3-position (metastatic).
  • the group R 4B may be -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 .
  • it is -OH, -F or -CF 3 , most preferably -OH.
  • the group may be positioned anywhere within the phenyl ring, for example in the 2, 3, 4 position (ortho, meta, or para) to Z 1 . It is preferably in the 3- or 4- position (meta- or para-stable to Z 1 ).
  • the group T represents a carbonyl group or a thiocarbonyl group.
  • T may represent a methylene group or an oxygen atom.
  • T is a carbonyl group.
  • indices n and m independently represent the natural numbers 1, 2, 3 or 4.
  • the compounds of the general formula VIII according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula VIII.
  • Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom
  • D 2 each independently represents a carbon atom, a group CH or a nitrogen atom
  • Each D 3 independently represents a CH or a nitrogen atom
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4
  • Alkyl group means
  • R 4 is -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 4B is -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 6 is hydrogen or a branched or unbranched
  • Ci-C4-alkyl group means
  • n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4,
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • the said compounds of general formula IX are useful as the compounds of general formula I as medicaments.
  • they are in the therapy of depression, schizophrenia and anxiety disorders, further in the therapy of sexual dysfunction, especially in reduced sexual desire in women (sexual desire disorder, libido loss).
  • the substances are particularly effective as 5HTi a and 5HT 2a serotonin receptor antagonists, they are also effective in the therapy of other disease states mediated through these receptors.
  • the groups Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of the radicals Z 1 , Z 2 , Z 4 , Z 5 , represents an oxygen atom. Particularly preferred are compounds in which exactly one of the radicals Z 1 , Z 2 or in which exactly one of the radicals Z 4 , Z 5 for a Oxygen atom and the other radicals Z 1 , Z 2 , Z 4 , Z 5 are a direct bond.
  • the groups D 1 stand for a CH group or a nitrogen atom.
  • the groups D 2 stand for a carbon or a nitrogen atom.
  • the carbon atom is hydrogenated (CH in the aromatic ring, or CH 2 in the non-aromatic ring) or formed as a carbonyl function (in the non-aromatic ring).
  • the ring formed by the D 1 and D 2 groups can be saturated, partially unsaturated or aromatic. The chemist is aware that embodiments in which at least one group D 2 is a nitrogen atom can not be aromatic.
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • Y 1 is preferably a direct bond or -ON (-H) -.
  • the group R 6 may be hydrogen or a branched or unbranched C 1 -C 4 alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert- butyl, Preferably R 6 is hydrogen, methyl or ethyl, completely especially preferred for hydrogen.
  • the group R 4 may be -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 . It is preferably -CF 3 , -C 2 F 5 or -OCF 3 , very particularly preferably -CF 3 .
  • the group may be positioned at any position within the phenyl ring, for example in the 2, 3, 4 position (ortho, meta, or para) to Z 5 . Preferably, it is in the 3-position (metastatic).
  • the group R 4B may be -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 .
  • it is -OH, -F or -CF 3 , most preferably -OH.
  • the group may be positioned anywhere within the phenyl ring, for example in the 2, 3, 4 position (ortho, meta, or para). always in the case of an aromatic ring) to Z 1 . It is preferably in the 3- or 4- position (meta- or para-stable to Z 1 in the case of an aromatic ring).
  • the group T represents a carbonyl group or a thiocarbonyl group.
  • T may be a methylene group, a nitrogen atom or an NH group, or an oxygen atom.
  • T is a carbonyl group.
  • indices n and m independently represent the natural numbers 1,2,3 or 4.
  • the compounds of the general formula IX according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get to the compounds of general formula IX.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently a direct bond or an oxygen or sulfur atom
  • Each D 1 independently represents a CH group or a nitrogen atom
  • D 2 is a group CH or a nitrogen atom
  • n is a natural number 1, 2, 3 or 4,
  • the compounds of general formula X are useful as the compounds of general formula I as medicaments.
  • the compounds of general formula X according to the invention and their corresponding pharmaceutically acceptable salts are capable of affecting all those conditions or diseases which may be affected by inhibition of DPP-IV activity . It is therefore to be expected that the invention compounds for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes mellitus, prediabetes, diminution of glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or neuropathy), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance, Metabolic syndrome, dyslipidemias of various genesis, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation, and calcitonin-induced osteoporosis.
  • diseases or conditions such as type 1 and type 2 diabetes mellitus, prediabetes, diminution of glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephro
  • these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells.
  • the substances are further suited to improve or restore the functionality of pancreatic cells, in addition to increase the number and size of pancreatic B cells.
  • glucagon-like peptides such as GLP-1 and GLP-2 and their linkage to DPP-IV inhibition, it is expected that the compounds of this invention will be useful to provide, inter alia, a sedative or anxiolytic effect
  • catabolic states after surgery or hormonal stress responses can be favorably influenced or the mortality and morbidity after myocardial infarction can be reduced.
  • the compounds of the invention are also useful as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
  • the compounds according to the invention can be used for the treatment of inflammatory diseases of the respiratory tract.
  • they are suitable for the prevention and treatment of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as in pancreatitis.
  • IBS irritable bowel syndrome
  • Crohn's disease Crohn's disease or ulcerative colitis
  • pancreatitis pancreatitis
  • DPP-IV inhibitors can be used to treat infertility or to improve fertility in humans or mammalian organisms, especially if infertility is associated with insulin resistance or polycystic Ovarian syndrome is.
  • these substances are suitable for influencing sperm motility and thus can be used as contraceptives for use in men.
  • the substances are suitable for influencing deficiency states of growth hormone associated with shortage growth, as well as being useful for all indications in which growth hormone can be used.
  • the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease etc. Moreover, they can be used in viral diseases as well as in HIV infections, for example.
  • Alzheimer's Disease Compounds described are also to be used for the therapy of tumors, in particular for the modification of tumor invasion as well as metastasis Use in T-cell lymphoma, acute lymphoblastic leukemia, cell-based thyroid carcinoma, basal cell carcinoma or breast carcinoma
  • Other indications include stroke, ischemia of various origins, Parkinson's disease and migraine Follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritides, lipodystrophies, as well as psychosomatic, depressive and neuropsychiatric diseases of various genesis.
  • the compounds of the general formula X according to the invention can also be used in combination with other active ingredients.
  • suitable therapeutics for such a combination include, for example, antidiabetics, such as metformin, sulfonylureas (eg glibenclamide, tolbutamide, glimepiride), nateglinides, repaglinides, thiazolidinediones (eg rosiglitazone, pioglitazone), PPAR-gamma agonists (eg Gl 262570) and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), PPAR-gamma / alpha / delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, 1 1 ⁇ -HSD- inhibitors, FGF19 agonists or mimetics, alpha-glucosidase inhibitors (eg acarbose
  • SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose -1, 6-bis-phosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as H MG-CoA reductase inhibitors (eg simvastatin, atorvastatin), fibrates (eg bezafibrate, fenofibrate ), Nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol absorption inhibitors such as
  • a combination with drugs for influencing hypertension such as All antagonists or ACE inhibitors, diuretics, ⁇ -blockers, Ca antagonists and others or combinations thereof are suitable.
  • the groups Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently a direct bond or an oxygen or sulfur atom. Preference is given to compounds in which at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 is an oxygen atom. Particularly preferred are compounds in which exactly one of the radicals Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 is an oxygen atom and the other radicals Z ⁇ Z 2 , Z 3 , Z 4 , Z 5 , Z 6 stand for a direct bond.
  • the groups D 1 stand for a CH group or a nitrogen atom.
  • the group D 2 represents a CH group or a nitrogen atom.
  • the indices n and m independently represent the natural numbers 1,2,3 or 4.
  • the compounds of the general formula X according to the invention are prepared by routine methods of preparative organic chemistry, for example the synthesis routes mentioned in DE 10 2005 035891.
  • the preparative organic chemist knows the usual methods in order to arrive at the compounds of general formula X starting therefrom.
  • the synthetic routes mentioned for the above-mentioned formula IX find analogous application.
  • Z 3 , Z 4 , Z 5 , Z 6 each, independently of one another, represents a direct bond or represents an oxygen or a sulfur atom
  • R B is an aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring system which may be fused with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a Cyano group, a nitro group or a C 1 -C 4 -alkyl group, or a C 1 -C 4 -alkoxyl group, a C 2 -C 4 -alkenyl group of a C 2 -C 4 -alkynyl group which may be branched or unbranched and optionally also mono- or polyunsaturated can wherein the C1-C4 Alkyl distr.die Ci-C4 alkoxyl group, the C 2 -C 4 - alkenyl or C 2 -C 4 alkynyl group is in turn substitiert with phenyl groups, or halogenated phenyl groups, L
  • R 6 is hydrogen or a branched or unbranched
  • Ci-C 4 alkyl group means
  • the compounds of general formula XI mentioned are, like the compounds of general formula I, usable as medicaments.
  • the compounds of general formula XI according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which may be influenced by an inhibition of DPP-IV activity .
  • the pharmacological properties, the possible indications and the possible combinations with other active ingredients correspond to those of the general formula X (see above).
  • the group R B preferably represents a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2, 6-difluoro-benzyl, 3, 4-difluoro-benzyl, 2-chlorobenzyl, 3 Chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl or 4-trifluoromethylbenzyl group, a 3-trifluoromethoxybenzyl or 4-trifluoromethoxybenzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl, a 2, 6-dicyanobenzyl, 3, 4-dicyanobenzyl, 3, 5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl, 3 Nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyan
  • the group R B particularly preferably represents a 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2, 6-difluoro-benzyl, 3, 4-difluoro-benzyl, a 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl or 4-trifluoromethylbenzyl group, a 3-trifluoromethoxybenzyl or 4-trifluoromethoxybenzyl group, a 2-cyanobenzyl, 3-cyano-benzyl or 4-cyano-benzyl group, 2,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4 methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-Cyano-4-fluor
  • the linker L represents an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched alkyl chain, for example a methyl, ethyl, “propyl, ' “ propyl, " “ butyl,' “ butyl, or tert- butyl group.
  • R 6 is a hydrogen atom or a methyl group.
  • the compounds of the general formula XI according to the invention are prepared by routine methods of preparative organic chemistry, for example the synthesis routes mentioned in DE 10 2005 035891 or WO 2005/085246.
  • the preparative organic chemist knows the usual methods in order to arrive at the compounds of general formula XI.
  • heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
  • Ci-Cio C1-C5-alkoxy-substituted alkoxy group, which is one or more times by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or
  • 25 aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated, 5 an optionally 1-3-fold hydroxy, halogen or Ci-C 5 alkoxy substituted (Crdo) alkylthio group , one or more times by oxygen, nitrogen or sulfur atoms or by carbonyl or
  • 10 sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may also be mono- or polyunsaturated
  • a (C 1 -C 5 ) -perfluoroalkyl group which may be unbranched or branched and which may optionally also be mono- or polyunsaturated, with the proviso that at least one of the radicals R s does not equal hydrogen,
  • R 6S is hydrogen or a branched or unbranched
  • Ci-C 4 alkyl group means
  • n 1, 2, 3 or 4
  • n 1, 2, 3 or 4
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • the compounds of general formula XII mentioned can be used as medicaments.
  • the compounds of the general formula XII according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which are caused by an inhibition of the M2- PK activity can be influenced.
  • cancers inter alia, lung, prostate, breast, skin, intestine, brain, neck, pancreas, liver, bile, esophagus, ovaries.
  • diabetes type I and II
  • diabetes type I and II
  • Obesity, autoimmune diseases and proliferative disorders including BPH, psoriasis.
  • the invention therefore provides the use of a compound of general formula XII according to the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases from the group consisting of "cancer, such as lung cancer, leukemia, ovarian cancer, sarcoma, Meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer, skin cancer, gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, asthma, allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowel disease, degenerative joint diseases, rheumatic diseases with cartilage degradation, sepsis, autoimmune diseases, type I diabetes, Hashimoto's thyroiditis, autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, uveitis
  • the linker L represents an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched one
  • Alkyl chain for example a methyl, ethyl, "propyl, ' “ propyl, " ' butyl, ' “ butyl, or terf- butyl group.
  • R 6 is a hydrogen atom or a methyl group.
  • the compounds of the general formula XII according to the invention are prepared by routine methods of preparative organic chemistry, for example the synthesis routes mentioned in WO 2008/019139.
  • the preparative organic chemist knows the usual methods to get therefrom to the compounds of general formula XII.
  • Z 1 is a direct bond or an oxygen or sulfur atom
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • the compounds of the general formula XIII can be used as medicaments.
  • the compounds of general formula XIII according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which can be influenced by an inhibition of DPP-IV activity .
  • the pharmacological properties that Possible indication areas and the possible combinations with other active ingredients correspond to those of the general formula X (see above).
  • the group Z 1 stands for a direct bond or for an oxygen or a sulfur atom.
  • the linker L represents an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched one
  • Alkyl chain for example a methyl, ethyl, "" propyl, “” propyl, “" butyl, 'butyl, or tert “butyl group.
  • R 6 is a hydrogen atom or a methyl group.
  • the compounds of the general formula XIII according to the invention are prepared by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods in order to arrive at the compounds of general formula XIII.
  • Z V 2 independently of one another represents a direct bond or represents an oxygen or a sulfur atom
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 7 is hydrogen or a branched or unbranched C 1 -C 6 -alkyl group
  • L 1 , L 2 , L 3 are independently for
  • R b is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group, have the same positive properties as the compounds of general formula I to XIII.
  • the compounds of general formula XIV mentioned are, like the compounds of general formula I, usable as medicaments.
  • the compounds of the general formula XIV according to the invention and their corresponding pharmaceutically acceptable salts are suitable for treating infections, in particular severe infections.
  • the compounds of the general formula XIV according to the invention act on Gram-positive, Gram-negative, atypical and multi-resistant germs. The compounds can therefore be used both as a monotherapeutic, as well as with other therapeutics - especially other antibiotics.
  • the groups Z 1 and Z 2 stand for a direct bond or for an oxygen or a sulfur atom.
  • the linkers L 1 , L 2 and L 3 is an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched one
  • Alkyl chain for example a methyl, ethyl, "" propyl, “” propyl, “" butyl, “” butyl, or tert “butyl group.
  • R 6 represents a hydrogen atom or a methyl group.
  • R 2 represents a hydrogen atom or a straight or branched alkyl chain, for example a methyl, ethyl, " 'propyl,'" propyl, "" butyl, 'butyl, or fert' butyl group.
  • R 2 is a hydrogen atom or a methyl group.
  • R 7 represents a hydrogen atom or a linear or branched C r C 6 alkyl chain, for example a methyl, ethyl, " 'propyl,' propyl, '' butyl, 'butyl, tert” -butyl, " " Pentyl, 'pentyl, ⁇ eo pentyl, " ⁇ exyl or' ⁇ exyl group.
  • R 7 is a sterically demanding group, such as for example a tert- butyl group.
  • the preparation of the compounds of the general formula XIV according to the invention can be carried out by routine methods of preparative organic chemistry, it being expediently based on natural compounds which can be isolated from fungi of the genus Streptomyces.
  • the preparative organic chemist knows the usual methods to get therefrom to the compounds of general formula XIV.
  • R 4C independently of one another are -H, -OH, -Cl, -F, -Br 1 -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , -OCH 3 or a mono- or polyhalogenated phenyl ring,
  • R c is an aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring system which may be fused with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a
  • Cyano group a nitro group or a C 1 -C 4 -alkyl group, or a C 1 -C 4 -alkoxyl group, a
  • C 2 -C 4 alkenyl group of a C 2 -C 4 alkynyl group may be substituted, which may be branched or unbranched and optionally also mono- or polyunsaturated with the C- ⁇ -C 4 alkyl group, the C
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 4F is -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , - NO 2 , or -OCH 3 is,
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • L A is a direct bond or a CiC-io-alkylene bridge, which one or more times with a halogen atom, a hydroxy group, a cyano group, a nitro group or a Ci-C 4 alkoxyl group, a C 2 -C 4 alkenyl group of a C C 2 -C 4 -alkynyl group may be substituted, which may be branched or unbranched and optionally also mono- or polyunsaturated while also cyclic units and heteroatoms may be included
  • the said compounds of general formula XV are useful as the compounds of general formula I as medicaments. They are particularly suitable for the treatment of cancer. They are used in particular for the treatment of hematological or solid
  • Tumors e.g. non-Hodgkin's tumors, or of T-cell lymphomas.
  • the effect of the compounds of general formula XV according to the invention as cancer therapeutics is possibly due to their suitability for inhibiting histone deacetylase.
  • the compounds of general formula XV according to the invention therefore fall into the class of HDAC inhibitors.
  • the suitability as cancer therapeutics is on the effect of these compounds on the Cell cycle modulation, modulation of cell differentiation, apoptosis and angiogenesis.
  • IC 5 o values in 25 different cell culture lines are generally between 4 and 40 ⁇ M.
  • High selectivity is found in small cell lung carcinoma (LXFS650), followed by renal carcinoma model (RXF 1393).
  • the linker L 1 is an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched alkyl chain, for example a methyl, ethyl, "propyl, "" propyl,” ' butyl,' ' butyl, or ferf' butyl group
  • R 6 is a hydrogen atom or a methyl group.
  • the linker L A is in the simplest case for an alkylene bridge. This may be branched or unbranched, saturated or unsaturated. They are not further mono- or polysubstituted, in particular with hydroxyl or alkoxy groups or with halogen atoms.
  • the linker L A may also contain cyclic (C 5 -C 7 ) elements, such as cyclohexyl or piperidyl rings. Further, it may also contain heteroatoms (preferably N or O).
  • R 2 represents a hydrogen atom or a straight or branched alkyl chain, for example a methyl, ethyl, "propyl,” propyl, "" butyl, 'butyl, or te * butyl group.
  • R 2 for a hydrogen atom or a methyl group.
  • the group T represents a carbonyl group or a thiocarbonyl group.
  • T may represent a methylene group or an oxygen atom.
  • T is a carbonyl group.
  • the preparation of the compounds of general formula XV according to the invention can be carried out by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods in order to arrive at the compounds of general formula XV. In support of this, he can refer to the methods described in WO 2007/085205.
  • R 41 independently of one another are -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , or -OCH 3 ,
  • R 1 independently of one another for an aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring system, which may be condensed with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a cyano group, a nitro group, or a C r C 4 alkyl group, or a Ci-C 4 alkoxyl group, a C 2 -C 4 alkynyl group may be substituted 2 -C 4 alkenyl group of a C which is branched or unbranched and optionally also may be mono- or polyunsaturated, wherein the -C 4 alkyl group, the d- C 4 alkoxyl group, the C 2 -C 4 alkenyl or C 2 -C 4 - alkynyl group is substitiert turn with phenyl groups, or halogenated phenyl groups,
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 21 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • L A is independently a direct bond or a CIC-10-alkylene bridge, which one or more times with a
  • Halogen, a hydroxy group, a cyano group, a nitro group or a Ci-C 4 alkoxyl group, a C 2 -C 4 - alkenyl group of a C 2 -C 4 alkynyl may be substituted, the branched or unbranched and optionally also one or more times which may be unsaturated as well as cyclic units as well
  • Heteroatoms may be included
  • the compounds of the general formula XVI mentioned are, like the compounds of the general formula I, usable as medicaments. They are particularly suitable for the treatment of cancer. They are particularly useful for the treatment of hematological or solid tumors, e.g. non-Hodgkin's tumors, or of T-cell lymphomas.
  • the effect of the compounds of the general formula XVI according to the invention as cancer therapeutics is possibly due to their suitability for inhibiting various kinases, such as, for example, AbI, Bcr-Abl, cSrc, TPR-Met, Tie2,
  • the compounds of general formula XVI according to the invention therefore fall into the class of kinase inhibitors, in particular the above-mentioned kinases.
  • the suitability as cancer therapeutics is due to the effect of these compounds on the modulation of the cell cycle, the modulation of cell differentiation, apoptosis and angiogenesis.
  • IC 50 values in 25 different cell culture lines are generally between 4 and 40 ⁇ M. High selectivity exists in the small cell
  • LXFS650 Lung carcinoma (LXFS650), followed by renal carcinoma model (RXF 1393).
  • linkers L 1 and L 2 independently of one another represent an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • R 6 represents a hydrogen atom or a straight-chain or branched one
  • Alkyl chain for example a methyl, ethyl, "propyl,” “propyl,” “butyl,” “butyl, or tert” butyl group.
  • R 6 represents a hydrogen atom or a methyl group.
  • the linkers L A are independent of each other in the simplest case for an alkylene bridge. This may be branched or unbranched, saturated or unsaturated. They are not further mono- or polysubstituted, in particular with hydroxyl or alkoxy groups or with halogen atoms.
  • the linker L A may also contain cyclic (C 5 -C 7 ) elements, such as cyclohexyl, pyridinyl or piperidyl rings. Furthermore, it can also contain heteroatoms (preferably N or O).
  • R 2 and R 2 independently represent a hydrogen atom or a straight or branched alkyl chain, for example a methyl, ethyl, "" propyl, “propyl,” “butyl,” “butyl, or tert” butyl -Group.
  • R 2 is a hydrogen atom or a methyl group.
  • the group T represents a carbonyl group or a thiocarbonyl group.
  • T may represent a methylene group or an oxygen atom.
  • T is a carbonyl group.
  • the preparation of the compounds of general formula XVI according to the invention can be carried out by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get therefrom to the compounds of general formula XVI. In support of this he can refer to the methods described in WO 2006/052936.
  • Z independently of one another represents a direct bond or represents an oxygen or a sulfur atom
  • R 4 is independently -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , or -OCH 3 ,
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • the compounds of general formula XVII mentioned can be used as medicaments. They are particularly suitable for the treatment of cancer. They are used in particular for the treatment of hematological or solid
  • Tumors e.g. non-Hodgkin's tumors, or of T-cell lymphomas.
  • R 2 represents a hydrogen atom or a straight or branched alkyl chain, for example a methyl, ethyl, " 'propyl, propyl,” “butyl,” “butyl or fert' butyl group.
  • R 2 is a hydrogen atom or a methyl group.
  • the group T represents a carbonyl group or a thiocarbonyl group.
  • T may represent a methylene group or an oxygen atom.
  • T is a carbonyl group.
  • the groups Z stand for a direct bond or for an oxygen or a sulfur atom. Preference is given to those compounds in which at least one Z is an oxygen atom. Very particular preference is given to those compounds in which exactly one Z represents an oxygen atom.
  • the preparation of the compounds of general formula XVII according to the invention can be carried out by routine methods of preparative organic chemistry.
  • the preparative organic chemist knows the usual methods to get therefrom to the compounds of general formula XVII.
  • the ability of the substances and their corresponding salts to inhibit DPP-IV activity can be demonstrated in an experimental set-up using an extract of the human colon carcinoma cell line Caco-2 as a DPP IV source. Differentiation of the cells to induce DPP-IV expression is described as described by Chandlerr et al. in "Increased expression of intestinal cell line Caco-2", Proc. Natl. Acad. Be. Vol. 90, pages 5757-5761 (1993).
  • the cell extract is purified from cells solubilized in a buffer (10mM Tris HCl, 0.15M NaCl, 0.04% aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000g for 30 minutes at 4 ° C (to remove cell debris). won.
  • the DPP-IV assay is performed as follows: 50 ⁇ l of substrate solution (amido-4-trifluoromethylcoumarin, AFC), final concentration 100 ⁇ M, are transformed into black
  • Blank values (corresponding to 0% activity) are obtained in batches without Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100% activity) are obtained in batches without added substance.
  • the potency of the respective test substances expressed as IC 50 values, are calculated from dose-response curves consisting of 8-12 measurement points each. proliferation assay
  • Human tumor cells for example, hormone-independent human mammary carcinoma cells, MCF7, human non-small cell lung carcinoma cells, e.g. DU 145, hormone independent human prostate carcinoma cells, e.g. ATCC HTB-81 or MaTu-MDR, can in one
  • WO 2007/045844 (AstraZeneca).
  • the methods mentioned in WO 2007/045962 (Orchid Research Laboratories Ltd.) are also suitable for determining the suitability of the compounds according to the invention as HDAC inhibitors.
  • Ar is benzyl, aryl or heteroaryl radical, which may bear 1-3 substituents independently selected from the group -F, -Cl, -C-C 4 alkyl, -OH, -O-Ci-C 4- alkyl. -CF 3 , -NH 2 ,
  • Each of Z 1 , Z 2 , Z 3 independently represents a direct bond or represents an oxygen or a sulfur atom
  • Y 1 , Y 2 independently represent a direct bond, for N (-R 2 ), - N (-R 2 ) -O-, -ON (-R 2 ) or represents an oxygen or a sulfur atom
  • n is a natural number from 1 to 10
  • m is an integer from 0 to 4
  • r is zero or 1 stands
  • s stands for zero or 1
  • R 1 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or heteroaryl radical, where the benzyl, aryl or heteroaryl radical can carry 1-3 substituents which are selected independently of one another are from the group -F, -Cl, -C 1 -C 4 -alkyl, -OH, -OC- ⁇ -C 4 alkyl, -CF 3 , -NH 2 ,
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical.
  • Ar is a benzyl, aryl or heteroaryl radical which may carry 1 to 3 substituents, which are selected independently of one another from the group -F, -Cl, -CrC 4 -alkyl, -OH, -O-C r C 4 - Alkyl, -CF 3 , -NH 2 ,
  • Z 1 , Z 2 , Z 3 are each independently a direct bond or an oxygen or sulfur atom, u is an integer from 0 to 4, v is an integer from 0 to 4, w is a an integer from 0 to 4, R 1 represents a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or heteroaryl radical, where the benzyl, aryl or heteroaryl radical carries 1-3 substituents independently of one another are selected from the group -F, -Cl, -CrC 4 -alkyl, -OH, -O-C 1 -C 4 -alkyl, -CF 3 , -NH 2 ,
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • Oxygen atom is.
  • Z 1 , Z 2 , Z 3 are each independently a direct bond or an oxygen or sulfur atom
  • u is an integer from 0 to four
  • R 1 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical, or a benzyl, aryl or
  • Heteroaryl radical where the benzyl, aryl or heteroaryl radical can carry 1-3 substituents which are selected independently of one another from the group -F, -Cl, -Ci-C 4 -alkyl, -OH 1 -OC r C 4 - Alkyl, -CF 3 , -NH 2 ,
  • R 2 independently represent a hydrogen atom or a branched or unbranched C ⁇ -C 4 -alkyl is kylrest
  • R 3 is -SH or - SCOCH 3 .
  • Ar is a benzyl, aryl or heteroaryl radical, 1-3
  • Substituents independently of one another selected from the group -F, -Cl, -CrC 4 -alkyl, -OH, -O-C 1 -C 4 -alkyl, -CF 3 , -NH 2 , Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom,
  • R 2 is a hydrogen atom or a branched or unbranched Ci-C-4-alkyl radical
  • R 4 is -Cl, -F, -Br, -CF 3 or -OCF 3 , -NO 2 or -OCH 3
  • a compound of general formula IV according to item 28 characterized in that R 2 is hydrogen, methyl or ethyl, most preferably hydrogen.
  • Ar is a benzyl, aryl or heteroaryl radical, 1-3
  • C 1 -C 4 -alkyl, -CF 3 , -NH 2 , Z 1 , Z 2 , Z 3 , Z 4 ', Z 5 , Z 6 each, independently of one another, represents a direct bond or represents an oxygen or a sulfur atom,
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • n represents the natural numbers 1, 2, 3 or 4.
  • a compound of general formula V according to item 34 characterized in that R 2 is hydrogen, methyl or ethyl.
  • Ar is a benzyl, aryl or heteroaryl radical which may carry 1 to 3 substituents which are selected independently of one another from the group -F, -Cl, -C-C 1 -C 4 -alkyl, -OH, -O-CIC 4- alkyl, -CF 3 , -NH 2 , Z 1 , Z 2 , Z 3 , Z 4 are each independently a direct bond or an oxygen or sulfur atom,
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • R 5 is a hydrogen atom, a branched or unbranched
  • n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4.
  • a compound of general formula VI according to item 39 characterized in that n is two and m is one.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently a direct bond or an oxygen or sulfur atom
  • R 2 is a hydrogen atom or a branched or unbranched C 1 -C 4 -alkyl radical
  • Y is a direct bond, an oxygen atom, a sulfur atom, or a group
  • Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom
  • R 4 is -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 4B is -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 6 is hydrogen or a branched or unbranched
  • Ci-C 4 alkyl group means
  • n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4,
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • Z 1 , Z 2 , Z 4 , Z 5 are each independently a direct bond or an oxygen or sulfur atom
  • Each D 2 independently represents a carbon atom, a group CH or a nitrogen atom
  • Each D 3 independently represents a CH or a nitrogen atom
  • R 2 is hydrogen or a branched or unbranched Ci-C 4 -
  • Alkyl group means
  • R 4 is -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 4B is -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 or -OCF 3 , -NO 2 or -OCH 3 ,
  • R 6 is hydrogen or a branched or unbranched
  • Ci-C 4 alkyl group means
  • n is a natural number 1, 2, 3 or 4,
  • n is a natural number 1, 2, 3 or 4,
  • Y 1 represents a direct bond, an oxygen atom, a sulfur atom, or a group
  • Z 7 1, Z -72, Z-73, Z 7 4, Z -? 5, Z-76 are each independently of one another a direct bond or an oxygen or a sulfur atom,
  • Each D 1 independently represents a CH group or a nitrogen atom
  • D 2 is a group CH or a nitrogen atom
  • n is a natural number 1, 2, 3 or 4.
  • Z 3 Z 4 Z 5 Z 6 each independently represents a direct bond or represents an oxygen or a sulfur atom
  • R E is an aliphatic or aromatic 5-7 ring atoms-containing homo- or heterocyclic ring system which may be condensed with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a cyano group, a nitro group or a -C 4 alkyl group, or a C 1 -C 4 - alkoxy group, a C 2 -C 2 -C 4 alkenyl group, a C 4 - alkynyl group may be substituted, branched or unbranched, and optionally also one may or polyunsaturated and which C 1 -C 4 - Alkyl distr.die -C 4 alkoxyl group, the C 2 -C 4 - alkenyl or C 2 -C 4 alkynyl group is in turn substitiert with phenyl groups, or halogenated phenyl groups, L for
  • R 6 is hydrogen or a branched or unbranched
  • Trifluoromethoxybenzyl group a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group, a 2, 6-dicyanobenzyl, 3, 4-dicyanobenzyl, 3, 5-dicyanobenzyl, 2-trifluoromethyl- 4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl , 2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano
  • 4-fluoro-benzyl 4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chloro-benzyl, 2-chloro-4-cyano-benzyl, a (3-cyanopyridin-2-yl) methyl, (6-cyanopyridin-2-yl) methyl, (5-cyanopyridin-2-yl) methyl, (4-cyanopyridin-2-yl) methyl -, (4-Cyano-pyridin-3-yl) methyl-, (3-cyano-pyridin-4-yl) -methyl-, (2-cyano-pyridin-3-yl) -methyl-, (2-cyano-pyridine -4-yl) methyl, (5-cyano-pyridine -4-yl) methyl, (5-
  • R ⁇ independently, a hydrogen atom, a hydroxy group, a halogen atom, a
  • CiC ⁇ - alkoxy-substituted (C- ⁇ -C- ⁇ o) alkyl group one or more times by oxygen, nitrogen or
  • Sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may also be mono- or polyunsaturated 5,
  • Sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and the
  • 15 may also be monounsaturated or polyunsaturated,
  • CiC ⁇ - alkoxy substituted (C- ⁇ -C- ⁇ o) -alkylthio group which is optionally 1-3-fold hydroxy, halogen or CiC ⁇ - alkoxy substituted (C- ⁇ -C- ⁇ o) -alkylthio group, which is optionally 1-3-fold hydroxy, halogen or CiC ⁇ - alkoxy substituted (C- ⁇ -C- ⁇ o) -alkylthio group, which
  • Sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted,
  • 30 may be branched and which may optionally also be mono- or polyunsaturated,
  • R 6S is hydrogen or a branched or unbranched
  • C 1 -C 4 -alkyl group means
  • n 1, 2, 3 or 4
  • n 1, 2, 3 or 4
  • R 6 is hydrogen or a branched or unbranched
  • Ci-C 4 alkyl group Ci-C 4 alkyl group.
  • Z 1 is a direct bond or an oxygen or sulfur atom
  • R 6 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group.
  • O 1 is 1, 2, 3 or 4
  • R 7 is hydrogen or a branched or unbranched C 1 -C 6 -alkyl group
  • R 6 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group.
  • R 4C independently of one another are -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , -OCH 3 or a mono- or polyhalogenated phenyl ring,
  • R c is an aliphatic or aromatic 5-7 ring atoms-containing homo- or heterocyclic ring system which may be condensed with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which with a halogen atom, a cyano group, a nitro group or a -C 4 alkyl group, or a Ci-C 4 alkoxyl group, a C 2 -C 2 -C 4 alkynyl may be substituted one or more times a C 4 alkenyl group which branched or unbranched, and optionally also one or more times may be unsaturated wherein the C- ⁇ -C4 alkyl, Cr C 4 alkoxyl group, the C 2 -C 4 alkenyl or C 2 -C 4 - alkynyl group, in turn, with Substituted phenyl groups or halogenated phenyl groups,
  • R 2 is hydrogen or a branched or unbranched CrC 4 -
  • Alkyl group means
  • R 4F is -H, -OH 1 -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , - NO 2 , or -OCH 3 is,
  • R 6 denotes hydrogen or a branched or un branched CrC 4 -alkyl group
  • L A is a direct bond or a Ci-Cio-alkylene bridge, containing one or more times with a halogen atom, a hydroxy group, a cyano group, a nitro group or a -C 4 alkoxyl group, a C 2 -C 4 alkenyl group of C 2 - C 4 alkynyl may be substituted, which may be branched or unbranched and optionally also mono- or polyunsaturated wherein also cyclic units and heteroatoms may be included.
  • R 41 independently of one another are -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , or -OCH 3 ,
  • R 1 independently represent an aliphatic or aromatic 5-7
  • Ring atoms containing homo- or heterocyclic ring system which with 1 or 2 further aliphatic or aromatic 5-7
  • Ring atoms containing homo- or heterocyclic ring systems may be condensed, and which one or more times with a halogen atom, a
  • Cyano group a nitro group or a C- ⁇ -C 4 alkyl group, or a C- ⁇ -C 4 alkoxyl group, a
  • C 2 -C 4 alkenyl group of a C 2 -C 4 alkynyl group may be substituted, branched or unbranched, and optionally also one or more times may be unsaturated wherein the Ci-C 4 alkyl group which Cr C 4 alkoxyl group, the C 2 -C 4 alkenyl or C 2 -C 4 - alkynyl group in turn with phenyl or halogenated phenyl groups is substituted,
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 2 ' is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • L A is independently a direct bond or a C 1 -C 1 0-alkylene bridge, containing one or more times with a halogen atom, a hydroxy group, a cyano group, a nitro group or a -C 4 alkoxyl group, a C 2 -C 4 - Alkenyl group of a C 2 -C 4 alkynyl group may be substituted, which may be branched or unbranched and optionally also mono- or polyunsaturated may also contain cyclic units and heteroatoms.
  • Z independently of one another represents a direct bond or represents an oxygen or a sulfur atom
  • R 4 is independently -H, -OH, -Cl, -F, -Br, -CF 3 , -C 2 F 5 , -OCF 3 , -SO 2 CH 3 , -N-SO 2 CH 3 , -NO 2 , or -OCH 3 ,
  • R 2 is hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • Cancers in particular hematological or solid tumors, non-Hodgkin's tumors or T-cell lymphomas,
  • Parkinson's disease Alzheimer's disease, seizure disorders, anxiety disorders, epilepsy, Lennox-Gastaut syndrome or bipolar mood disorders,
  • Diabetes mellitus type 1 and type 2 prediabetes, reduction of glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or neuropathy), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidaemias of various genesis,
  • inflammatory diseases of the respiratory tract are for the prevention and treatment of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as pancreatitis Autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease
  • Stroke ischemia of various origins, Parkinson's disease and migraine.
  • other indications are follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritides, lipodystrophies, as well as psychosomatic, depressive and neuropsychiatric diseases of various genesis
  • Diabetes type I and II
  • obesity obesity
  • autoimmune diseases including BPH, psoriasis
  • proliferative diseases including BPH, psoriasis

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Abstract

L'invention concerne de nouveaux produits pharmaceutiques, leur procédé de fabrication et leur utilisation en thérapie médicale
PCT/DE2008/000993 2007-06-16 2008-06-16 Nouveaux produits pharmaceutiques, leur procédé de fabrication et leur utilisation en thérapie médicale Ceased WO2008154905A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung
CN107522654A (zh) * 2016-06-21 2017-12-29 中国人民解放军军事医学科学院毒物药物研究所 新的α‑氨基酰胺衍生物及其医药用途

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JPS4018294B1 (fr) * 1962-01-30 1965-08-18
US3262978A (en) * 1963-06-19 1966-07-26 Colgate Palmolive Co O-arylamino-and-aralkyl-amino-alkylhydroxyl-amines
US7288567B2 (en) * 2000-03-24 2007-10-30 Methylgene Inc. Inhibitors of histone deacetylase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung
CN107522654A (zh) * 2016-06-21 2017-12-29 中国人民解放军军事医学科学院毒物药物研究所 新的α‑氨基酰胺衍生物及其医药用途
CN107522654B (zh) * 2016-06-21 2020-09-01 中国人民解放军军事医学科学院毒物药物研究所 新的α-氨基酰胺衍生物及其医药用途

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