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Definitions

• the present application relates to new cyclopenta [b] benzofuran derivatives, processes for their preparation and their use for the manufacture of medicaments, in particular for the prophylaxis and / or therapy of acute or chronic diseases which are characterized by increased cellular stress, by local or systemic inflammatory processes or through hyperproliferation.
• the compounds according to the invention are derived from a class of natural substances known as Rocaglaole / Rocaglamide, which can be extracted from different types of the Aglaia plant. Since the first isolation of a dihydrocyclopentabenzofuranol derivative called Rocaglamid (J. Chem. Soc, Chem. Commun. 1982, 1150; US 4,539,414), several new, also synthetically produced derivatives and their biological effects have been described (cf. for example J. Chem. Soc, Chem. Commun.
• NF- ⁇ B Nuclear Factor kappa B
• NF- ⁇ B exists as a cytoplasmic, inactive form by binding to an inhibitory protein (I- ⁇ B).
• I- ⁇ B is rapidly phosphorylated by I- ⁇ B kinases and, as a result, proteolytic degradation of I-KB.
• I- ⁇ B is rapidly phosphorylated by I- ⁇ B kinases and, as a result, proteolytic degradation of I-KB.
• NF- ⁇ B activates or modulates the expression of various genes, especially those whose products are responsible for inflammatory reactions and for cell growth and differentiation [J. Biol. Chem. 274, 27339 (1999)].
• AP-1 is a transcription factor composed of dimers of the Jun, Fos, Maf and ATF family of proteins and is located in the cell nucleus.
• the activity of AP-1 is induced by a variety of stimuli, including cytokines, bacterial and viral infections, and various forms of physical or chemical stress.
• Activating signals lead on the one hand to an increased formation of the individual components of the transcription factor, and on the other hand by stimulation of certain kinases, such as Jun kinases, to phosphorylation of specific amino acids.
• pro-inflammatory cytokines e.g. Interleukin-1 (IL-1) or tumor necrosis factor (TNF), and oxidative stress potent activators of NF- ⁇ B and AP-1 mediated signal transmission.
• IL-1 Interleukin-1
• TNF tumor necrosis factor
• oxidative stress potent activators of NF- ⁇ B and AP-1 mediated signal transmission e.g. Interleukin-1 (IL-1) or tumor necrosis factor (TNF)
• oxidative stress potent activators of NF- ⁇ B and AP-1 mediated signal transmission e.g. Interleukin-1 (IL-1) or tumor necrosis factor (TNF)
• oxidative stress potent activators of NF- ⁇ B and AP-1 mediated signal transmission e.g. Interleukin-1 (IL-1) or tumor necrosis factor (TNF)
• oxidative stress potent activators of NF- ⁇ B and AP-1 mediated signal transmission e.g. Interleukin-1 (IL
• NF- ⁇ B and AP-1 are therefore central factors in the induction and maintenance of inflammatory processes.
• the pathogenesis or pathophysiology of a variety of diseases is characterized by acute, excessive, or chronic inflammatory reactions, which may be local to a tissue or systemic in nature. These diseases are characterized by locally or systemically increased cytokine and / or chemokine levels and by an increased presence of various types of inflammatory cells, such as macrophages, polymorphonuclear leukocytes, T lymphocytes or B cells.
• These diseases include chronic inflammatory and autoimmune diseases (such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, lupus, asthma, diabetes), cardiovascular diseases (such as coronary heart diseases, myocardial infarction, atherosclerosis, restenosis, Thrombosis), fibrotic diseases of the liver and other organs, cerebrovascular diseases (such as stroke, traumatic brain injury, spinal cord injuries) and chronic neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, Amyotrophic lateral sclerosis, peripheral neuropathies and chronic pain).
• chronic inflammatory and autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, lupus, asthma, diabetes
• cardiovascular diseases such as coronary heart diseases, myocardial infarction, atherosclerosis, restenosis, Thrombosis
• cytokine / chemokine formation is also causally linked to the development or consequences of radiation damage, graft rejection, sepsis and septic shock, and bacterial meningitis.
• the inhibition or Modulation of the transcriptional activity of NF- ⁇ B and / or AP-1, as described for the compounds according to the invention, could thus represent a promising new therapeutic principle for the diseases listed above.
• NF- ⁇ B and AP-1 are of major importance in the regulation of cell division, cell growth and cell differentiation.
• cellular signaling pathways are activated, which under normal conditions control cell growth, differentiation and other biological processes.
• a variety of tumor-inducing substances and factors (such as epidermal growth factor (EGF), phorbol esters, UV radiation) lead to the activation of NF- ⁇ B and / or AP-1, and a number of those caused by NF- ⁇ B and / or AP- 1 controlled genes belong to the oncogenes (such as c-myc, c-rel, Melanoma Growth Stimulating Activity (MGSA)).
• EGF epidermal growth factor
• MGSA Melanoma Growth Stimulating Activity
• the use of the compounds according to the invention could thus be a new therapeutic principle for the treatment of hyperproliferative diseases such as solid tumors (such as breast cancer, lung cancer, tumors of the brain and the Nervous system, skin cancer, liver cancer, tumors of the reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system, tumors of various hormone glands, tumors of the eye), lymphomas (such as Hodgkin's disease, lymphomas of the central nervous system), sarcomas (such as osteosarcomas Lymphosarcomas) and leukemia (such as acute myeloid leukemia, lymphoblastic leukemia, myelogenic leukemia).
• solid tumors such as breast cancer, lung cancer, tumors of the brain and the Nervous system, skin cancer, liver cancer, tumors of the reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system, tumors of various hormone glands, tumors of the eye
• lymphomas such as Hod
• NF- ⁇ B and AP-1 also play an important role in the replication of lymphotrophic viruses such as HIV, HTLV and Epstem-Barr virus.
• the activation of viral genes necessary for replication can be effected via the virus-mediated activation of NF- ⁇ B and / or AP-1 in the host cell.
• a positive influence on gene expression in cytomegalovirus (CMV) as well as in adenoviruses by NF- ⁇ B / AP-1 is also suspected.
• Inhibitors modulators of NF- ⁇ B and / or AP-1 activity could thus also have anti-viral effects.
• the present invention relates to compounds of the general formula (I)
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (-CC 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) -alkylamino, (C 3 -C8) -cycloalkylamino, N- (C 3 -C 8 ) -cycloalkyl-N- (-C-C 6 ) -alkylamino or by a 4- to 7-membered bonded via a ⁇ atom Heterocycle can be substituted, wherein mono- and di- (-C 6 ) alkylamino in turn can be substituted by hydroxy, (-C-C 4 ) alkoxy, amino, mono- or di- (-C 4 ) alkylamino .
• R 1 and R 2 do not simultaneously represent hydrogen
• R 3 is hydroxy or amino
• R means hydrogen or
• R 5 denotes mono- or di- (CC 6 ) -alkylaminocarbonyl
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and halogen, (dC 6 ) alkyl, (C, -C 6 ) alkoxy, (C 6 -C 10 ) aryl , 5- to 10-membered heteroaryl or a group of the formula -NR 9 R 10 , wherein aryl and heteroaryl in turn each one to two times, the same or different, by halogen, cyano, (-C-C 4 ) alkylsulfonyl or one Group of the formula -NR 9 R 10 may be substituted, and wherein
• R 9 and R 10 independently of one another represent hydrogen, (CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclus, and in the ortho position to R ⁇ and is hydrogen, halogen, (-C-C ö ) alkyl, (CC 6 ) alkoxy or is a group of the formula -NR n R 12 , wherein
• R n and R 12 independently of one another for hydrogen, Are phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• the present invention further relates to compounds of the general formula (I) in which
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (-CC 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) -alkylamino, (C 3 -C 8 ) -cycloalkylamino, N- (C 3 -C 8 ) -cycloalkyl-N- (-C-C 6 ) -alkylamino or by a 4- to 7- bonded via a ⁇ atom membered heterocycle may be substituted, wherein mono- and di- (-C 6 ) -alkylamino in turn may be substituted by hydroxy, (-C-C) alkoxy, amino, mono- or di- (CC 4 ) alkylamino,
• R 1 and R 2 do not simultaneously represent hydrogen
• R 3 is hydroxy or amino
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is (C 6 -C ⁇ 0 ) aryl, 5- to 10-membered heteroaryl or a group of the formula -NR 9 R 10 , where aryl and heteroaryl in turn can be substituted one to two times, identically or differently, by halogen, cyano, (C 1 -C 4 ) -alkylsulfonyl or a group of the formula -NR 9 R 10 , and in which
• R 9 and R 10 independently of one another represent hydrogen, (-CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, halogen, (C ⁇ -C 6 ) alkyl, (C ⁇ -C 6 ) - Alkoxy or a group of the formula -NR ⁇ R 12 , wherein
• R ⁇ and R 12 independently of one another represent hydrogen, (-CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• the present invention further relates to compounds of the general formula (I) in which
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (-CC 6 ) alkoxy, amino, mono- or di- (CC 6 ) - alkylamino, (C 3 -C 8 ) -cycloalkylamino, N- (C 3 -C 8 ) -cycloalkyl-N- (C ⁇ ⁇ C 6 ) alkylamino or by a 4- to 7-membered heterocycle bonded via a ⁇ atom may be substituted, whereby mono- and di- (CC 6 ) -alkylamino may in turn be substituted by hydroxy, (-C-C 4 ) alkoxy, amino, mono- or di- (-C-C 4 ) -alkylamino,
• R 1 or R 2 are not both hydrogen at the same time
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (CC 6 ) -alkyl or (-C-C 6 ) -alkoxy,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, halogen, (C ⁇ -C 6 ) alkyl, (C ⁇ -C 6 ) - Alkoxy or a group of the formula -NR ⁇ R 12 , wherein
• R ⁇ and R 12 independently of one another represent hydrogen, (-CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (CC 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) - alk ⁇ lammo, (C 3 -C 8 ) -cycloalkylamino, N- (C 3 -C 8 ) -cycloalkyl-N- (-C-C 6 ) -alkylamino or by a 4- to 7-membered heterocycle bonded via a ⁇ atom may be substituted, wherein mono- and di- (C 1 -C 6 ) -alkylamino in turn may be substituted by hydroxy, (-C-C 4 ) alkoxy, amino, mono- or di- (C ⁇ -C) alkylamino,
• R 1 or R 2 is hydrogen, but not both are hydrogen at the same time
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (CC 6 ) alkyl or (CC 6 ) alkoxy, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, halogen, (C ⁇ -C 6 ) alkyl, (C ⁇ -C 6 ) - Alkoxy or a group of the formula -NR n R 12 , wherein
• R 11 and R 12 independently of one another represent hydrogen, (CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• the present invention further relates to compounds of the general formula (I) in which
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen
• R 2 means ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (Cj-C 6 ) alkoxy, amino, mono- or di- (-C-C 6 ) - alkylamino, (C 3 -C 8 ) - cycloalkylamino, N- (C 3 -C8) cycloalkyl-N- (-C-C 6 ) alkylamino or substituted by a 4- to 7-membered heterocycle bonded via a ⁇ atom are, wherein mono- and di- (-C 6 ) alkylamino in turn can be substituted by hydroxy, (-C-C 4 ) alkoxy, amino, mono- or di- (-C-C 4 ) alkylamino,
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (CC 6 ) -alkyl or (-C-C 6 ) -alkoxy,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclus, and in the ortho position to R 6 and is hydrogen, halogen, (CC 6 ) alkyl, (C ⁇ -C 6 ) alkoxy or is a group of the formula - ⁇ R ⁇ R 12 , wherein
• R 11 and R 12 independently of one another represent hydrogen, (-CC 6 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas encompassed by formula (I) and their salts, solvates and solvates of the salts and those of formula (I) Compounds mentioned below as examples and their salts, solvates and solvates of the salts, insofar as the compounds mentioned below by formula (!) are not already salts, solvates and solvates of the salts.
• the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore encompasses the enantiomers or diastereomers and their respective mixtures.
• the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
• the present invention encompasses all tautomeric forms.
• preferred salts are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not themselves suitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoronic acid, lactic acid, lactic acid, acetic acid, lactic acid, Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• alkali metal salts for example sodium and potassium salts
• alkaline earth metal salts for example calcium and magnesium salts
• ammonium salts derived from ammonia or organic amines having
• solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules.
• Hydrates are a special form of solvate, in which coordination takes place with water. Hydrates are preferred as solvates in the context of the present invention.
• the present invention also includes prodrugs of the compounds according to the invention.
• prodrugs encompasses compounds which can themselves be biologically active or inactive, but are converted to compounds according to the invention during their residence time in the body (for example metabolically or hydrolytically).
• (C Cfi) -alkyl and (GG-alkyl) represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred called: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.
• (C Cs) cycloalkyl and (CC ⁇ ) -Cvcloalkyl stand for a mono- or optionally bicyclic cycloalkyl group with 3 to 8 or 3 to 6 carbon atoms.
• a monocyclic cycloalkyl radical having 3 to 6 carbon atoms is preferred. The following may be mentioned as examples and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• (-C ⁇ n) aryl stands for an aromatic radical with preferably 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• (CC ⁇ ) alkoxy and ( "Cv- VAlkoxy are in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preferred is a straight- chain or branched alkoxy radical with 1 to 4 carbon atoms. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
• Mono-f C j ⁇ -C ⁇ alkylamino and mono ⁇ GC ⁇ alkylamino in the context of the invention represent an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
• D -CfiValkylamino and Di- (C C4. -Alkylamino) in the context of the invention represent an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms.
• Straight-chain are preferred or branched dialkylamino radicals each having 1 to 4 carbon atoms, examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methyl-arnino, N-methyl-Nn-propylamino, N- Isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
• mono- or di- (C 1 -Cfi) -alkylaminocarbonyl or mono- or DKC ⁇ C ⁇ -alkylaminocarbonyl represent an amino group which is linked via a carbonyl group and which is a straight-chain or branched or two has the same or different straight-chain or branched alkyl substituents each having 1 to 6 or 1 to 4 carbon atoms.
• a monocyclic cycloalkyl substituent having 3 to 6 ring carbon atoms is preferred.
• Examples and preferably mentioned are: cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino and cyclooctylamino.
• (C Cd) alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms.
• a straight-chain or branched alkylsulfonyl radical having 1 to 3 carbon atoms is preferred.
• the following may be mentioned by way of example and preferably: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
• a 4- to 7-membered heterocycle represents a saturated or partially unsaturated heterocycle having 4 to 7 ring atoms, which contains a ring nitrogen atom, is linked via this and a further hetero atom from the series N, O, S, SO or S0 2 may contain.
• a 4- to 7-membered saturated, N-linked heterocycle is preferred, which may contain a further heteroatom from the series N, O or S. Examples and preferably mentioned are: azetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thimorpholinyl, azepinyl and 1,4-diazepinyl.
• 5- to 10-membered heteroaryl in the context of the invention represents a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) with up to four identical or different heteroatoms from the series N, O and / or S, which is via a ring carbon atom or optionally a ring nitrogen atom of the heteroaromatic is linked.
• heteroaryl in the context of the invention represents a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) with up to four identical or different heteroatoms from the series N, O and / or S, which is via a ring carbon atom or optionally a ring nitrogen atom of the heteroaromatic is linked.
• Examples include: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benziazylyl, benziazyl, benziazyl Benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl.
• Monocyclic 5- or 6-membered heteroaryl radicals having up to three heteroatoms from the series N, O and / or S such as, for example, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, are preferred , Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.
• radicals in the compounds according to the invention are substituted, the radicals can, unless otherwise specified, be substituted one or more times.
• the meaning of all radicals which occur more than once is independent of one another.
• a substitution with one, two or three identical or different substituents is preferred.
• Substitution with a substituent is very particularly preferred.
• R 8 represents 5- or 6-membered heteroaryl which can be substituted by (CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (-CC 4 ) alkoxy, amino, mono- or di- (-C-C) -alkylamino, (C 3 -C 6 ) -cycloalkylamino, N- (C 3 -C 6 ) -cycloalkyl-N- (-C-C 4 ) -alkylamino or by a 4- to 6-membered bonded via a ⁇ atom Heterocycle can be substituted, wherein mono- and di- (-C 4 ) alkylamino in turn can be substituted by hydroxy, (-C-C) alkoxy, amino, mono- or di- (-C-C 4 ) alkylamino, where R 1 and R 2 do not simultaneously represent hydrogen,
• R 3 is hydroxy or amino
• R 4 represents hydrogen or
• R 5 denotes mono- or di- (-C 4 ) alkylaminocarbonyl
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and halogen, (CC 4 ) alkyl, (C ⁇ -C 4 ) alkoxy, (C 6 -C ⁇ 0 ) aryl, 5- to 6-membered heteroaryl or a group of the formula -NR 9 R 10 means, aryl and heteroaryl in turn in each case one to two times, the same or different, by halogen, cyano, (-C-C) alkylsulfonyl or a group of Formula -NR 9 R 10 can be substituted, and in what
• R 9 and R 10 independently of one another represent hydrogen, (-CC) alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) - Alkoxy or a group of the formula -NR n R 12 , wherein
• R 11 and R 12 independently of one another are hydrogen, (-CC 4 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (CC 4 ) alkoxy, amino, mono- or di- (C 1 -C 4 ) -alkylamino, (C 3 -C 6 ) -cycloalkylamino, N- (C 3 -C 6 ) -cycloalkyl-N- (-C-C 4 ) alkylamino or by a 4- to 7-membered bonded via a ⁇ atom Heterocycle can be substituted, whereby mono- and di- (-C-C 4 ) alkylamino in turn can be substituted by hydroxy, (CC 4 ) - alkoxy, amino, mono- or di- (C 1 -C 4 ) alkylamino, where R 1 and R 2 do not simultaneously represent hydrogen,
• R 3 is hydroxy or amino
• R 4 represents hydrogen or
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is (C 6 -C ⁇ 0 ) aryl, 5- to 6-membered heteroaryl or a group of the formula -NR 9 R 10 , where aryl and heteroaryl in turn can be substituted one to two times, identically or differently, by halogen, cyano, (C 1 -C 4 ) -alkylsulfonyl or a group of the formula -NR 9 R 10 , and in what
• R 9 and R 10 independently of one another represent hydrogen, (CC) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclus, and in the ortho position to R 6 and is hydrogen, halogen, (CC) alkyl, (C ⁇ -C) alkoxy or a group of the formula -NR n R 12 , wherein
• R n and R 12 independently of one another are hydrogen, (CC) alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or
• R 8 represents 5- or 6-membered heteroaryl which can be substituted by (CC 4 ) -alkyl or halogen,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (CC) -alkoxy, amino, mono- or di- (-C-C 4 ) alkylamino , (C 3 -C 6 ) -cycloalkylamino, N- (C 3 -C 6 ) -cycloalkyl-N- (-C-C 4 ) alkylammo or substituted by a 4- to 7-membered heterocycle bonded via a ⁇ atom can be, where mono- and di- (CC 4 ) -alkylamino in turn can be substituted by hydroxy, (CC) -alkoxy, amino, mono- or di- (-C-C 4 ) -alkylamino, where R 1 or R 2 but not both stand for hydrogen at the same time,
• R 4 represents hydrogen or
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (CC 4 ) -alkyl or (C ⁇ -C 4 ) -alkoxy
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclus, and in the ortho position to R 6 and is hydrogen, halogen, (CC 4 ) -alkyl, (-C-C 4 ) -alkoxy or is a group of the formula -NR U R 12 , wherein
• R 11 and R 12 independently of one another are hydrogen, (CC 4 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or
• R 8 represents 5- or 6-membered heteroaryl which can be substituted by (C) -C 4 ) -alkyl or halogen
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (C r C 4 ) alkoxy, amino, mono- or di- (-C-C 4 ) -alkylamino, (C 3 -C 6 ) -cycloalkylamino, N- (C 3 -C 6 ) -cycloalkyl-N- (-C-C 4 ) -alkylamino or by a 4- to 7- bonded via an N atom membered heterocycle can be substituted, with mono- and di- (-C 4 ) alkylamino in turn substituted by hydroxy, (-C-C 4 ) alkoxy, amino, mono- or di- (-C 4 ) alkylamino where either R 1 or R 2 is
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (CC 4 ) -alkyl or (C ⁇ -C 4 ) -alkoxy, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) - Alkoxy or a group of the formula -NR n R 12 , wherein
• R 11 and R 12 independently of one another are hydrogen, (-CC 4 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or R 6 and R 7 together with the phenyl ring to which they are attached form a group of the formula
• R 8 represents 5- or 6-membered heteroaryl, which can be substituted by (-CC) alkyl or halogen,
• R 2 means ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 2- or 3-position by (-C-C 4 ) alkoxy, amino, mono- or di- (C 1 -C 4 ) -alkylamino, (C 3 -C 6 ) - cycloalkylamino, N- (C 3 -C 6 ) -cycloalkyl-N- (-C-C 4 ) alkylamino or by a 4- to 7-membered bonded via a ⁇ atom Heterocycle are substituted, whereby mono- and di- (-C-C 4 ) -alkylamino may in turn be substituted by hydroxy, (-C 4 ) -alkoxy, amino, mono- or di- (-C-C 4 ) -alkylamino,
• R 4 represents hydrogen or
• R 5 represents hydrogen
• n the number 0, 1, 2 or 3
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) alkoxy, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclus, and in the ortho position to R 6 and is hydrogen, halogen, (C 1 -C 4 ) -alkyl, (C 1 -C) alkoxy or a group of the formula -NR n R 12 , wherein
• R 11 and R 12 independently of one another are hydrogen, (-CC 4 ) -alkyl, phenyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or
• R 1 and R 2 independently of one another are hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 3-position by methoxy, ethoxy, amino, methyl ino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidino or pyrrolidino are substituted,
• R 1 and R 2 do not simultaneously represent hydrogen
• R 3 denotes hydroxy or amino
• R 4 represents hydrogen
• R 5 denotes methylaminocarbonyl or dimethylaminocarbonyl
• n the number 0 or 1
• R 6 is in the para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,
• R 7 represents hydrogen
• R 8 represents pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which can each be substituted by methyl, ethyl, fluorine or chlorine,
• R 2 signifies hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 3-position by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, Dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, azetidino or pyrrolidino can be substituted,
• R 1 and R 2 do not simultaneously represent hydrogen
• R 3 denotes hydroxy or amino
• R 4 represents hydrogen
• R 5 represents hydrogen
• n the number 0 or 1
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is phenyl, thienyl, indolyl, quinoxalinyl or a group of the formula - ⁇ R 9 R 10 , phenyl, thienyl and indolyl in each case being one - Can be substituted twice, identically or differently, by fluorine, chlorine, bromine, cyano or amino, and in which
• R 9 and R 10 independently of one another represent hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a pyrrolidino ring,
• R 7 represents hydrogen
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 3-position by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N- methylamino, azetidino or pyrrolidino can be substituted,
• R 1 and R 2 do not simultaneously represent hydrogen
• R 3 denotes amino
• R 4 is hydrogen
• R 5 represents hydrogen
• n the number 0 or 1
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula - ⁇ R ⁇ R 12 means in which
• R n and R 12 independently of one another represent hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring,
• R 8 represents pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which can each be substituted by methyl, ethyl, fluorine or chlorine,
• R 2 is hydrogen, ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 3-position by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N- methylamino, azetidino or pyrrolidino can be substituted,
• R 1 or R 2 is hydrogen, but not both are hydrogen at the same time
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0 or 1
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, and
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula -NR ⁇ R 12 means in which
• R 11 and R 12 independently of one another represent hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring,
• R 8 represents pyridyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl or thiadiazolyl, which can each be substituted by methyl, ethyl, fluorine or chlorine,
• R 2 denotes ethoxy or n-propoxy, where ethoxy in the 2-position and n-propoxy in the 3-position by methoxy, ethoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, Azetidino or Pyrrolidino are substituted,
• R 4 means hydrogen
• R 5 represents hydrogen
• n the number 0 or 1
• R 6 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and is fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy,
• R 7 is in the meta or para position, relative to the point of attachment of the phenyl ring to the tricyclic ring, and in the ortho position to R 6 and is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy or a group of the formula -NR n R 12 means in which
• R 11 and R 12 independently of one another represent hydrogen, methyl, ethyl, benzyl or pyridylmethyl or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring,
• radical definitions given in the respective combinations or preferred combinations of radicals are replaced independently of the radical combinations of the radicals given by radical definitions of other combinations.
• the compounds of the formula (I) according to the invention in which R 5 represents hydrogen can in principle be prepared by the processes described in WO 00/08007.
• the content of WO 00/08007, in particular pages 14-26, is hereby expressly included as part of the disclosure.
• individual process steps described in WO 00/08007 are in some cases only connected with very low yields.
• the present invention therefore furthermore relates to a new process for preparing the compounds of the formula (I) according to the invention in which R 5 represents hydrogen, characterized in that either
• X 1 for a suitable escape group such as halogen, mesylate, tosylate or triflate and stands for (-O-alkyl,
• T 2 , T 3 and T 4 are the same or different and each represents (C 1 -C 4 ) -alkyl or phenyl,
• Z represents hydrogen or methyl or both Z groups together form a CH 2 CH 2 or C (CH 3 ) 2 -C (CH 3 ) 2 bridge,
• Process step (VH) ⁇ (IX) can also be carried out using a three-stage one-pot process using the silyl enol ether of the formula (XVI) obtainable from (VII) by customary methods
• Inert solvents for process step (II) + (HI) - (TV) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned. 2-Butanone, diethyl ether, diox
• the usual inorganic or organic bases are suitable as bases for process step (11) + (DT) - »(IV).
• These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates or hydrogen carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or sodium or potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride, amides such as Sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• Sodium or potassium hydroxide, sodium or potassium carbonate or sodium hydride are particularly preferred.
• Process step (D) + (DT) - (TV) is generally carried out in a temperature range from + 20 ° C to + 160 ° C, preferably from + 60 ° C to + 100 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (IV) -> (V) are, for example, water, alcohols such as methanol, ethanol, n-propanol, iso-propanol or n-butanol, hydrocarbons such as benzene or other solvents such as acetone, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Methanol, ethanol, n-propanol and / or water are preferred.
• the usual inorganic bases are suitable as bases for process step (IV) - »(V).
• bases preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth carbonates such as lithium, sodium, potassium or calcium carbonate, or alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert. butoxide.
• alkali hydroxides such as lithium, sodium or potassium hydroxide
• alkali or alkaline earth carbonates such as lithium, sodium, potassium or calcium carbonate
• alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert. butoxide.
• Sodium or potassium hydroxide or sodium or potassium carbonate are particularly preferred.
• Suitable acids for process step (TV) - (V) are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic acid / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
• Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl ester and hydrochloric acid or sulfuric acid in the case of the methyl ester.
• Process step (IV) ⁇ (V) is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from + 40 ° C. to + 80 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Process step (V) - (VI) is preferably carried out without a further solvent.
• the usual inorganic Lewis acids such as aluminum trichloride, iron trichloride, boron trifluoride, boron trichloride, boron tribromide, titanium tetrachloride, titanium trichloride, tin dichloride, tin tetrachloride or zinc dichloride are suitable as Lewis acids for this process step.
• Zinc dichloride is preferred.
• Process step (V) -> (VI) is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 40 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process steps (V ⁇ ) - (VDT) and (LX) - (X) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetra- hydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as Hexane or cyclohexane, or other solvents such as ethyl acetate, dimethylformamide or dimethyl sulfoxide.
• halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethan
• the usual inorganic or organic reagents are suitable as brominating agents for process steps (VE) ⁇ (VTTT) and (LX) -> (X). These preferably include bromine, N-bromosuccinimide, copper dibromide, pyridine hydrotribromide, dimethylbenzylammonium tribromide or phenyltrimethylammonium tribromide. Bromine and copper dibromide are particularly preferred.
• Process steps (VII) ⁇ (VTTT) and (LX) - »(X) are generally carried out in a temperature range from -20 ° C to + 150 ° C, preferably from 0 ° C to + 80 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (VOT) ⁇ (LX) are, for example, water, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetra - Chloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfitrile, pyridine or acetic acid. It is also possible to use
• the usual inorganic or organic bases are suitable as bases for process step (VIII) - »(IX).
• These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth carbonates or hydrogen carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or sodium or potassium hydrogen carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert-butoxide, alkali acetates such as sodium or potassium acetate, alkali hydrides such as sodium hydride, amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• Sodium or potassium hydroxide or sodium acetate are particularly preferred.
• Process step (VTTT) - »(IX) is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from + 20 ° C. to + 80 ° C. With normal, increased or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (X) - »(XI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ether, methyl ether, or methyl ether such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Toluene, hexane, diethyl ether or tetrahydrofuran are preferred.
• bases are suitable as bases for process step (X) -> (XI).
• bases preferably include alkali hydrides such as sodium hydride, amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Lithium diisopropylamide, triethylamine or ethyldiisopropylamine are particularly preferred.
• Process step (X) - »(XI) is generally carried out in a temperature range from -20 ° C to + 50 ° C, preferably from 0 ° C to + 30 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (XI) + (XE) -> ⁇ (XTTT) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran Glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, water , Dimethylformamide, dimethyl
• the usual inorganic or organic bases are suitable as bases for process step (XI) + (XII) - (XEI).
• bases preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal, alkaline earth metal or heavy metal carbonates such as silver, thallium, lithium, sodium, potassium, cesium or calcium carbonate, alkali metal or alkaline earth metal hydrogen carbonates such as sodium - or potassium hydrogen carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or lithium, sodium or potassium tert-butoxide, alkali hydrides such as sodium hydride, amides such as sodium amide, lithium or sodium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, 1,5-Diazabicyclo [5.4.0] undec-5-ene (DBU), N-methylmorph
• Suitable catalysts for process step (XI) + (XII) - ⁇ - (XDT) are the palladium catalysts customary for Suzuki reaction conditions. Catalysts such as, for example, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium (0), palladium (E) acetate or bis (diphenylphosphane ferrocenyl) palladium (E) chloride are preferred.
• Suitable catalyst ligands are preferably the ligands customary for Suzuki reactions, such as triphenylphosphine, tri (o-tolyl) phosphine, tributylphosphine, 2,2'-bis (diphenylphosphino) -l, -binaphthyl (BI ⁇ AP), l, l ' -Bis (diphenylphosphino) ferrocene (dppf) or 1,3-bis (diphenylphosphino) propane (dppp).
• triphenylphosphine tri (o-tolyl) phosphine, tributylphosphine, 2,2'-bis (diphenylphosphino) -l, -binaphthyl (BI ⁇ AP), l, l ' -Bis (diphenylphosphino) ferrocene (dppf) or 1,3-bis (diphenylphosphino)
• Process step (XI) + (XII) - »(XTTT) is generally carried out in a temperature range from + 20 ° C to + 200 ° C, preferably from + 50 ° C to + 150 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (XIII) - (VI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether such as diethylene glycol methyl ether or diethylene dimethyl ether Methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, or other solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or water. It is also possible to use mixtures of the solvents
• the silyl group in process step (XT) - (VT) can alternatively be carried out using a base or an acid using the customary methods.
• Suitable bases are preferably tetrabutylammonium fluoride, pyridine or triethylamine, and preferred acids are hydrogen fluoride, hydrochloric acid / hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid or toluenesulfonic acid.
• Process step (XTTT) - »(VI) is generally carried out in a temperature range from -80 ° C to + 100 ° C, preferably from 0 ° C to + 80 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• R 13 is hydrogen or (CC 6 ) alkyl
• R M stands for (C ⁇ -C6) -Al yl
• the compounds of the formula (XVE) can be obtained by the processes described above or in WO 00/08007.
• the compounds of the formula (XIX) are commercially available or known from the literature.
• Inert solvents for process step (XVII) - »(XVEI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol ether dimethyl ether or methyl ether dimethyl or methyl ether other solvents such as dimethylformamide, dimethyl sulfoxide or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.
• Process step (XVE) - (XVEI) is generally carried out in a temperature range from 0 ° C. to + 200 ° C., preferably from + 50 ° C. to + 150 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (XVEI) + (XLX) - »(XX) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert.- butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethylacetamide, dimethylsulfonide or methyne pyridine. It is also possible to use mixtures
• Suitable condensation agents for the amide formation in process step (XVIE) + (XIX) -> (XX) are, for example, carbodiimides such as N, N'-diethyl-, N, N'-dipropyl-, NN'-diisopropyl-, N, N- Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or phosgene derivatives such as N, N'- Carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perch
• BOP, PyBOP or HATU are preferred in each case in combination with triethylamine or NN-diisopropylethylamine.
• Process step (XVIE) + (XLX) - ⁇ (XX) is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• R 1 and R 2 each represent ethoxy or n-propoxy, in the 2- or 3-position by amino, mono- or di- (-C 6 ) alkylamino , (C 3 -C 8 ) -cycloalkylamino, N- (C 3 -C 8 ) -cycloalkyl-N- (-C-C 6 ) -alkylamino or substituted by a 4- to 7-membered heterocycle bonded via a ⁇ atom can also be prepared by using compounds of the formula (XXI)
• X 2 for a suitable escape group such as halogen, mesylate or tosylate
• n the number 2 or 3
• R 15 is hydrogen, (dC 6 ) alkyl or (C 3 -C 8 ) cycloalkyl
• R 16 represents hydrogen or (-CC 6 ) alkyl
• R 15 and R 16 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
• the compounds of the formula (XXI) can be obtained by the processes described above or in WO 00/08007.
• the compounds of the formula (XXE) are commercially available or known from the literature.
• Inert solvents for process step (XXI) + (XXE) - »(XXIE) are, for example, ethers such as tetrahydrofuran, dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert.- Butanol, hydrocarbons such as toluene or xylene, or other solvents such as acetone, dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of the solvents mentioned. Ethanol, dimethylformamide, dimethyl sulfoxide or xylene are preferred.
• the usual inorganic or organic bases are suitable as auxiliary bases for process step (XXI) + (XXII) - »(XXEI).
• These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium or potassium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as triethylamine or ethyl diisopropylamine.
• Process step (XXI) + (XXE) ⁇ (XXEI) is generally carried out in a temperature range from + 20 ° C to + 200 ° C, preferably from + 70 ° C to + 150 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• the compounds according to the invention can also be prepared by synthetic conversions of functional groups of individual substituents into compounds of the formula ( ⁇ ), which are obtained by the processes described above.
• Such conversions Lungs of functional groups are carried out according to methods customary in the literature and include, for example, processes for alkylation, acylation, amination, esterification, ester cleavage, hydrogenation, oxidation and reduction.
• [X halogen; a): potassium carbonate, 2-butanone, 80 ° C; b): potassium carbonate, methanol / water, 65 ° C; c): Phosphoryl chloride, zinc chloride, 0 ° C ⁇ RT].
• the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals. They are also characterized by increased metabolic stability compared to the compounds described in WO 00/08007.
• the compounds according to the invention are potent inhibitors / modulators of NF- ⁇ B and / or AP-1 activity and, as such, are particularly suitable for the treatment of chronic inflammatory and autoimmune diseases (such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, multiple Sclerosis, lupus, asthma, diabetes), cardiovascular diseases (such as coronary heart diseases, myocardial infarction, atherosclerosis, restenosis, thromboses), fibrotic diseases of the liver and other organs, cerebrovascular diseases (such as stroke, traumatic brain injury, spinal cord injuries ) and chronic neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, peripheral neuropathies and chronic pain). They can also be used for the prophylaxis and / or therapy of radiation damage, graft rejection, sepsis and septic shock, and bacterial meningitis.
• chronic inflammatory and autoimmune diseases such
• the compounds according to the invention are suitable for the treatment of hyperproliferative diseases such as solid tumors (such as breast cancer, lung cancer, tumors of the brain and nervous system, skin cancer, Liver cancer, tumors of the reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system, tumors of various hormone glands, tumors of the eye), lymphomas (such as Hodgkin's disease, lymphomas of the central nervous system), sarcomas (such as osteosarcomas, lymphosarcomas) and leukemia (such as acute myeloid leukemia, lymphoblastic leukemia, myelogenic leukemia).
• solid tumors such as breast cancer, lung cancer, tumors of the brain and nervous system, skin cancer, Liver cancer, tumors of the reproductive organs, tumors of the digestive tract, bladder cancer, tumors of the urinary system, tumors of various hormone glands, tumors of the eye
• lymphomas such as Hodgkin's disease, lymphomas of the
• the compounds according to the invention can be used for the prophylaxis and / or therapy of viral diseases, in particular diseases triggered by HIV, HTLV, Epstein-Barr virus, cytomegalovirus (CMV) and / or adenoviruses.
• viral diseases in particular diseases triggered by HIV, HTLV, Epstein-Barr virus, cytomegalovirus (CMV) and / or adenoviruses.
• the present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• the present invention furthermore relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• Another object of the present invention is a method for the treatment and / or prophylaxis of . Diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds according to the invention.
• the compounds according to the invention can be used alone or, if necessary, in combination with other active ingredients.
• the present invention furthermore relates to medicaments containing at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
• suitable combination active ingredients are cytostatic or cytotoxic substances, anti-inflammatory substances (e.g. corticosteroids, NSAXDs) and neuroprotective substances.
• the compounds according to the invention can act systemically and / or locally.
• they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• suitable administration forms which deliver the compounds according to the invention quickly and / or modified and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as e.g. Tablets (non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or Soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Tablets non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention
• rapidly disintegrating tablets or films / wafers, films / lyophilisates capsules (for example hard or Soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions
• Parenteral administration can be done by bypassing a resorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
• a resorption step e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally
• absorption e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
• Application forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhaled pharmaceutical forms including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or eye preparations
• vaginal capsules aqueous suspensions (lotions, shake mixes)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, scattering powder, implants or stents.
• Oral or parenteral administration is preferred, in particular oral administration.
• the compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
• auxiliaries include Carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), Stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) and taste and / or odor correctors.
• Carriers e.g. microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• the present invention furthermore relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and to their use for the purposes mentioned above.
• the dosage is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg and very particularly preferably 0.1 to 10 mg / kg body weight.
• UV ultraviolet v / v volume to volume for liquid / liquid mixtures
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790
• Eluent B acetonitrile + 0.05% »formic acid, eluent A: water + 0.05% formic acid
• Flow 0.0 min 0.75 ml / min ⁇ 4.5 min 0.75 ml / min ⁇ 5.5 min 1.25 ml / min
• UV detection 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC TSP P4000, TSP AS300, TSP UV3000
• Column Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3.0 ⁇ m
• Eluent A water + 250 ul 50% formic acid / 1
• eluent B acetonitrile + 250 ul 50% formic acid / 1
• Gradient 0.0 min 0% B - »0.2 min 0% B ⁇ 2.9 min 70%
• Oven 50 ° C
• Flow 0.8 ml / min
• UV detection 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790
• Eluent B acetonitrile + 500 ⁇ l 50% formic acid / 1
• Eluent A water + 500 ⁇ l 50% formic acid / 1
• Oven 50 ° C
• UV detection 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A, flow 1 ml / min -> 2.5 min 30% A, flow 2 ml / min ⁇ 3.0 min 5% A, flow 2 ml / min - »4.5 min 5% A, flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 7 Method 7:
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm; Eluent A: water + 500 ⁇ l 50% formic acid / 1; Eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0 min 10% B ⁇ - 3.0 min 95% B -> 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min ⁇ 3.0 min 3.0 ml / min ⁇ 4.0 min 3.0 ml / min; UV detection: 210 nm.
• Device type MS Micromass TOF (LCT); Device type HPLC: 2-column circuit, Waters 2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A ⁇ 1.8 min 25% A ⁇ 1.9 min 10% A ⁇ 3.2 min 10% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790; Column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B ⁇ 2.0 min 40% B ⁇ 4.5 min 90% B ⁇ 5.5 min 90% B; Oven: 45 ° C; Flow: - 0.0 min 0.75 ml / min ⁇ 4.5 min 0.75 ml / min ⁇ 5.5 min 1.25 ml / min; UV detection: 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC HP 1100 Series
• UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm
• Eluent A 1 1 water + 0.5 ml 50% formic acid
• eluent B 1 1 acetonitrile + 0.5 ml 50% formic acid
• Flow 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min
• Oven 50 ° C
• UV detection 210 nm.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm; Eluent A: water + 500 ul 50% formic acid / 1, eluent B: acetonitrile + 500 ul 50% formic acid / 1; Gradient: 0.0 min 10% B - »2.0 min 95% B ⁇ 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min ⁇ 2.0 min 3.0 ml / min ⁇ 4.0 min 3.0 ml / min; UV detection: 210 nm.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 20 mm; Eluent: i-hexane / ethanol + 0.2% diethylamine 40:60 (v / v); Flow: 20 ml / min; UV detection: 220 nm; Temperature: 30 ° C; Sample application in i-hexane ethanol 1: 1.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: i-hexane / ethanol + 0.2% diethylamine 40:60 (v / v); Flow: 0.7 ml / min; UV detection: 220 nm; Temperature: 30 ° C; Sample application in the eluent.
• Method 16A preparative :
• Pillar Chiral silica gel selector Daicel Chiralpak AD-H; 5 ⁇ m, 250 x 20 mm; Eluent: acetonitrile / methanol + 0.2% diethylamine 90:10 (v / v); Flow: 20 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in acetonitrile / methanol 54:46 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD-H; 5 ⁇ m, 250 x 20 mm; Eluent: acetonitrile / methanol + 0.2% diethylamine 85:15 (v / v); Flow: 20 ml / min; UV detection: 230 nm; Temperature: 25 ° C; Sample application in acetonitrile.
• Pillar Chiral silica gel selector Daicel Chiralpak AD-H; 5 ⁇ m, 250 x 4.6 mm; Eluent: methanol / acetonitrile + 0.5% diethylamine 20:80 (v / v); Flow: 0.5 ml / min; UV detection: 230 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD-H; 5 ⁇ m, 250 x 20 mm; Eluent: acetonitrile / methanol + 0.2% diethylamine 60:40 (v / v); Flow: 20 ml / min; UV detection: 230 nm; Temperature: 25 ° C; Sample application in acetonitrile / methanol 58:42 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD-H; 5 ⁇ m, 250 x 4.6 mm; Eluent: methanol / acetonitrile + 0.5% diethylamine 20:80 (v / v); Flow: 1.0 ml / min; UV detection: 230 nm; Temperature: 30 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 10 mm; Eluent: ethanol + 0.2% diethylamine; Flow: 10 ml / min; UV detection: 220 nm; Temperature: 40 ° C; Sample application in ethanol.
• Method 19B analytical:
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: ethanol + 0.2% diethylamine; Flow: 0.7 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 20 mm; Eluent: i-hexane ethanol + 0.2% diethylamine 90:10 (v / v); Flow: 25 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in i-hexane / ethanol 5: 1 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 20 ⁇ m, 500 x 40 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 85:15 (v / v); Flow: 100 ml / min; UV detection: 220 nm; Temperature: 30 ° C; Sample application in isopropanol.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 85:15 (v / v); Flow: 1.0 ml min; UV detection: 250 nm; Temperature: 25 ° C; Sample application in the eluent.
• Method 26A (preparative):
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 20 ⁇ m, 350 x 30 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 75:25 (v / v); Flow: 50 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in isopropanol / methanol 75:25 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: isopropanol methanol + 0.2% diethylamine 85:15 (v / v); Flow: 1.0 ml / min; UV detection: 250 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 20 ⁇ m, 500 x 40 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 75:25 (v / v); Flow: 50 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in isopropanol / methanol 75:25 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: isopropanol / methanol + 0.2% diethylamine 85:15 (v / v); Flow: 1.0 ml / min; UV detection: 250 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 20 ⁇ m, 500 x 40 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 85:15 (v / v); Flow: 50 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in isopropanol / methanol 85:15 (v / v).
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 5: 1 (v / v); Flow: 1 ml / min; UV detection: 250 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 20 mm; Eluent: i-hexane ethanol + 0.2% diethylamine 85:15 (v / v); Flow: 25 ml / min; UV detection: 220 nm; Temperature: 25 ° C; Sample application in ethanol.
• Method 29B analytical:
• Pillar Chiral silica gel selector Daicel Chiralpak AD; 10 ⁇ m, 250 x 4.6 mm; Eluent: isopropanol / methanol + 0.1% diethylamine 5: 1 (v / v); Flow: 1 ml / min; UV detection: 250 nm; Temperature: 25 ° C; Sample application in the eluent.
• Pillar Chiral silica gel selector ZWE 803 AB; 10 ⁇ m, 250 x 4.6 mm; Eluent: methyl tert-butyl ether; Flow: 1 ml / min; UV detection: 254 nm; Temperature: 25 ° C; Sample application in the eluent.
• Hydrogen chloride gas is passed into a solution of 188 g (1.49 mol) of phloroglucinol in 600 ml of ethanol under RF for 5 h. After cooling, the mixture is stirred at RT overnight. Then hydrogen chloride gas is introduced again under RF for 5 h. After cooling, the reaction mixture is concentrated and the residue is taken up in dichloromethane and water. The organic phase is separated off, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is distilled in vacuo (bp: 145-150 ° C / 0.5 mbar).
• the distillate is dissolved in dichloromethane and extracted five times with 5% to remove 5-ethoxyresorcinol. aqueous potassium carbonate solution, the organic phase dries over sodium sulfate, filtered and concentrated. 156 g (57% of theory) of the product are obtained.
• a pH of 2 is set in the aqueous phase by adding 10% hydrochloric acid, the mixture is extracted three times with ethyl acetate, the combined ethyl acetate phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 16.1 g (99% of theory) of the product are obtained.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 7A. The compound is used directly in the next stage without further characterization.
• Example 10A The title compound is prepared analogously to the synthesis
• Example 2A The title compound is prepared in analogy to the synthesis of Example 2A starting from methyl bromo (4-chlorophenyl) acetic acid.
• Example 3A The title compound is prepared analogously to the synthesis of Example 3A starting from Example 10A.
• Example 4A The title compound is prepared analogously to the synthesis of Example 4A starting from Example HA.
• Example 5A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 12A.
• Example 6A The title compound is prepared analogously to the synthesis of Example 6A starting from Example 13A.
• Example 7A The title compound is prepared analogously to the synthesis of Example 7A starting from Example 14A.
• Example 8A The title compound is prepared analogously to the synthesis of Example 8A starting from Example 15A. Yield: 83% of theory Th.
• the mixture is stirred at 50 ° C. for 2 hours.
• the mixture is then concentrated, the residue is taken up in a mixture of diethyl ether and water, the phases are separated and the aqueous phase is extracted twice with diethyl ether.
• the aqueous phase is adjusted to a pH of 5 with concentrated hydrochloric acid and extracted three times with diethyl ether.
• the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After gradient chromatography on silica gel 60 (mobile phase: toluene / ethyl acetate), 9.20 g (10% of theory) of the product are obtained.
• Example 18A The title compound is prepared analogously to the synthesis of Example 2A starting from Example 18A.
• Example 3A The title compound is prepared analogously to the synthesis of Example 3A starting from Example 19A.
• Example 4A The title compound is prepared analogously to the synthesis of Example 4A starting from Example 20A.
• Example 5A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 21A.
• Example 23A The title compound is prepared analogously to the synthesis of Example 2A starting from Example 23A.
• Example 3A The title compound is prepared analogously to the synthesis of Example 3A starting from Example 24A.
• Example 4A The title compound is prepared analogously to the synthesis of Example 4A starting from Example 25A.
• Example 5A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 26A.
• Example 27A The title compound is prepared analogously to the synthesis of Example 6A starting from Example 27A.
• Example 7A The title compound is prepared analogously to the synthesis of Example 7A starting from Example 28A.
• Example 8A The title compound is prepared analogously to the synthesis of Example 8A starting from Example 29A.
• Example 23A The title compound is prepared analogously to the synthesis of Example 2A starting from Example 23A.
• Example 31A The title compound is prepared analogously to the synthesis of Example 3A starting from Example 31A.
• Example 4A The title compound is prepared analogously to the synthesis of Example 4A starting from Example 32A.
• Example 5A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 33A.
• Example 6A The title compound is prepared analogously to the synthesis of Example 6A starting from Example 34A.
• Example 2A The title compound is prepared analogously to the synthesis of Example 2A starting from 3-ethoxyphenol.
• Example 3A The title compound is prepared analogously to the synthesis of Example 3A starting from Example 36A. Yield: 96% of theory Th.
• Example 4A The title compound is prepared analogously to the synthesis of Example 4A starting from Example 37A.
• Example 5A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 38A. Yield: 19% of theory Th. (Pure diastereomer)
• Example 17A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 24. The compound is used directly in the next stage without further characterization.
• the solid is stirred with ethyl acetate, filtered off with suction, washed with ethyl acetate and the solid is dried.
• the solid is taken up in a mixture of 4N hydrochloric acid and ethyl acetate, the phases are separated and the aqueous phase is extracted once more with ethyl acetate.
• the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After column chromatography on silica gel 60 twice (1st solvent: toluene, 2nd solvent: cyclohexane), 232 g (55% of theory) of the product are obtained.
• reaction mixture After cooling, the reaction mixture is poured into a mixture of ice-cold, saturated ammonium chloride solution and diethyl ether, the phases are separated, the aqueous phase is extracted twice with diethyl ether, the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered and constricts. After column chromatography on silica gel 60 (mobile phase: toluene / cyclohexane 1: 1), 1.69 g (78% of theory) of the product are obtained.
• Example 46A The title compound is prepared analogously to the synthesis of Example 5A starting from Example 46A.
• Example 47A The title compound is prepared analogously to the synthesis of Example 6A starting from Example 47A.
• Example 7A The title compound is prepared analogously to the synthesis of Example 7A starting from Example 48A. Yield: 92% of theory Th.
• Example 8A The title compound is prepared analogously to the synthesis of Example 8A starting from Example 50A.
• Example 17A The title compound is prepared analogously to the synthesis of Example 17A starting from Example 50A. The compound is used in the next stage without further purification.
• Example 52A The title compound is prepared in analogy to the synthesis of Example 16 starting from Example 52A.
• Example 53 A The title compound is prepared analogously to the synthesis of Example 17 starting from Example 53 A.
• Example 14 The title compound is prepared in analogy to the synthesis of Example 14 starting from Example 50A.
• Example 15 The title compound is carried out analogously to the synthesis of Example 15 starting from Example 55A.
• Example 43 A The title compound is prepared analogously to the synthesis of Example 43 A starting from Example 58A.
• Example 44A The title compound is prepared analogously to the synthesis of Example 44A starting from Example 59A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of diastereomers) is prepared analogously to the synthesis of Example 5A starting from Example 60A.
• Example 62A The title compound (as a mixture of
• Example 41A The title compound is prepared starting from 2,6-dihydroxyacetophenone in analogy to the synthesis of Example 41A.
• Example 42A The title compound is prepared analogously to the synthesis of Example 42A starting from Example 62A.
• Example 43A The title compound is prepared analogously to the synthesis of Example 43A starting from Example 63A.
• Example 44A The title compound is prepared analogously to the synthesis of Example 44A starting from Example 64A.
• Example 45A The title compound is prepared analogously to the synthesis of Example 45A starting from Example 65A.

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