WO2011057892A1 - Dérivés de 2,3-dihydrobenzoxazine et de 2,3-dihydrobenzothiazine utilisés en tant qu'inhibiteurs des hif pour le traitement du cancer et des maladies inflammatoires - Google Patents

Dérivés de 2,3-dihydrobenzoxazine et de 2,3-dihydrobenzothiazine utilisés en tant qu'inhibiteurs des hif pour le traitement du cancer et des maladies inflammatoires Download PDF

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WO2011057892A1
WO2011057892A1 PCT/EP2010/066175 EP2010066175W WO2011057892A1 WO 2011057892 A1 WO2011057892 A1 WO 2011057892A1 EP 2010066175 W EP2010066175 W EP 2010066175W WO 2011057892 A1 WO2011057892 A1 WO 2011057892A1
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benzo
dihydro
oxazin
alkyl
carbonitrile
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Jorge Alonso
Arantxa Encinas Lopez
Marcel MÜLBAIER
Christoph Schultes
Bernd Wendt
Bernd Janssen
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Elara Pharmaceuticals Gmbh
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides novel 2,3-dihydrobenzazine compounds that are useful in therapy of diseases and disorders.
  • novel compounds inhibit cell prolifera- tion and cell division and they also inhibit the activation of Hypoxia Inducible Factor (HIF)-mediated transcription and signaling under hypoxic conditions.
  • the compounds of the present invention are useful for the preparation of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia-related pathology and a disease characterized by excessive vascularisation.
  • a pharmaceutical composition comprising a compound of the invention and a second therapeutic agent or radiation, useful for the treatment or prevention of the mentioned diseases or disorders.
  • hypoxia signaling pathway The normal response of cells to inadequate oxygen supply is mediated by the hypoxia signaling pathway. This response is important for a number of physiolocial functions such as tumor development and metastasis, resistance to apoptosis, induc- tion of new blood vessel formation, and metabolism among others.
  • hypoxia signaling see e.g. Qingdong Ke and Max Costa, Molecular Pharmacology (2006), vol. 70, no. 5.
  • HIF-1 a As a result of hypoxia, augmented levels of a heterodimeric complex of transcription factors (Hypoxia Inducible Factor, HIF), most notably HIF-1 a and HIF-1 ⁇ , are observed in e.g. tumors to compensate in cooperation with additional co-factors for the reduced availability of oxygen and nutrients in this fast growing tissue type.
  • HIF-1 a Under anaerobic conditions, homeostasis of HIF-1 a is imbalanced by its reduced degradation, thus enabeling enhanced signaling through the Hypoxia Responsive Element (HRE) and resulting in increased expression of a large number of survival and growth factors.
  • HRE Hypoxia Responsive Element
  • retinopathy is a general term that refers to non-inflammatory damage to the retina of the eye. This condition is most commonly caused by an insufficient blood supply leading to hypoxia. Particularly people with diabetes mellitus are at risk of retinopathy.
  • the lack of oxygen in the retina of diabetics causes fragile, new, blood vessels to grow along the retina and in the clear, gel-like vitreous humour that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause fractional retinal detachment. The new blood vessels can also grow into the anterior chamber of the eye and cause neovascular glaucoma.
  • HIF-1 inhibition could also act to prevent inflammation, by virtue of its role in the activation and infiltration of macrophages and neutrophils into affected tissues (see e.g. Giaccia et al., Drug Discovery, vol. 2, October 2003).
  • compounds that inhibit HIF function are valuable medicaments for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia-related pathology and a disease characterized by excessive vascu- larisation.
  • HIF-1 inhibitors for cancer therapy.
  • a number of small molecules and RNA constructs, like siRNA, have been reported to exhibit inhibition of the HIF-1 pathway, e.g. Kung AL et al, Cancer Cell (2004), vol. 6, p. 33 ff; Rapisarda A, et al. Cancer Res. (2002), vol. 62, p. 4316 ff.; Tan C.et al, Cancer Res. (2005), vol. 65, p. 605 ff; Mabjeesh NJ, et al, Cancer Cell, (2003), vol. 3, p. 363ff;.
  • WO 2005/007828 discloses S-2-amino-3-[4'-amino-N,N-bis-(2-chloroethyl)- amino]phenyl propionic acid N-oxide dihydrochloride, which is also known as PX-478, to be useful for regulating HIF-1 a levels under normoxid or hypoxic conditions.
  • WO 2006/050734 discloses LNA oligonucleotides which are suitable for down- regulating HIF-1 a expression.
  • WO 2006/066846 discloses thiazolidinone compounds which inhibit HIF-1 acti- vation by inhibiting the interaction of HIF-1 with the coactivator p300 of HIF-1 expression.
  • WO 2007/025169 discloses certain chromene compounds which in the 6- position carry a N-(arylsulfonyl) aminomethyl radical.
  • the compounds are mentioned to be HIF-1 inhibitors.
  • WO 2007/130037 suggests that bidentate zinc chelates of aromatic 1 ,3- diketones which inhibit HIF-1 are useful for treating cancer or tumor.
  • WO 2008/004798 discloses phenoxyacetic acid anilides or N-pyridylamides and 2-(phenoxymethyl) benzazoles as inhibitors of HIF-1 .
  • the scientific literature cited above emphasizes the high medical need for new therapeutic agents to provide more efficient treatment of different proliferative and inflammatory diseases or disorders, hypoxia-related pathologies and diseases characterized by excessive vascularisation.
  • WO 2004/056820 discloses 2,3-dihydobenzazine compounds which in the 6- position carry an (azoline-2-one-3-yl)methylene radical.
  • the compounds are mentioned to be suitable for the treatment of disorders which respond to the inhibition of phosphi- nositide-3-kinases including certain inflammatory diseases and certain cancer diseases.
  • A is e.g. CO, CONH or S0 2
  • Z is O, S, SO or SO2
  • Ri is alkyl, cycloalkyl, optionally substituted aryl or optionally substituted het- erocyclyl
  • R 2 , R 3 are hydrogen or alkyl
  • R 4 is selected from COOR5, CONR5R6, aryl which is optionally substituted by 1 , 2 or 3 radicals selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, CF3 or OCF3, and heterocyclyl, which is optionally substituted by 1 , 2 or 3 radicals selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, Cs-Cs-cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, CF3 or OCF3.
  • the compounds bind to cannabinoid receptors CB1 or CB2 on the surface of mammalian cells thereby modulating the intracellular cAMP concentration. Therefore compounds are suggested to be useful in the treatment of cannabinoid receptor associated disorders including treatment of pain, pruritis, skin disorders, inflammatory diseases, neurodegenerative, neuroinflammatory or psychiatric disorders, lung disorders, ophthalmic disorders, car- diosvascular disorders, gastrointestinal disorders and certain cancer diseases.
  • the present invention provides novel compounds capable of prevention or treatment of a disease or disorder.
  • Data presented herein establish that compounds accord- ing to the present invention are surprisingly very potent inhibitors of (i) the activation of HIF mediated transcription under hypoxic conditions and of (ii) cell proliferation.
  • the present invention relates to 2,3-dihydrobenzazine compounds having a structure according to formula (I):
  • R 1 is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1 , 2 or 3 radicals R 1 a which are identical or different;
  • R 1 a is selected from the group consisting of halogen, cyano, NO2, N H2, OH , SH , Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-C6-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluorinated Ci-C2-alkyl, SF 5 , fluorinated Ci-C 2 -alkoxy, C(0)R 3 , N R 4 R 5 , N(OR 6 )R 7 and C(0)OR 8 , or two radicals R 1 a , which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk-0, wherein Alk is selected from CH2, CH2CH2, CH F
  • R 2 is phenyl or C- or N-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1 , 2 or 3 radicals R 2a which are identical or different;
  • R 2a is selected from the group consisting of halogen, cyano, NO2, N H2, OH , SH , Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-C6-alkoxy, Ci-C6-alkylthio, hydroxy-Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluorinated Ci-C2-alkyl, SF 5 , fluorinated Ci-C 2 -alkoxy, C(0)R 3 , N R 4 R 5 , N(OR 6 )R 7 and C(0)OR 8 , or two radicals R 2a , which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk'-O, wherein Alk' is selected from CH 2 , CH2CH2, CH F
  • R 3 is Ci-C 4 -alkyl
  • R 4 is hydrogen or d-C 6 -alkyl
  • R 5 is d-Ce-alkyl, hydroxy-C 2 -C 6 -alkyl, Ci-C 4 -alkoxy-C2-C 4 -alkyl or a radical C(0)R x , wherein R x is Ci-C4-alkyl; or
  • R 4 , R 5 together with the nitrogen atom, to which they are bound, form an N-bound, 5- or 6-membered saturated nitrogen heterocycle
  • R 6 is hydrogen or Ci-C6-alkyl
  • R 7 is hydrogen or Ci-C6-alkyl
  • R 8 is hydrogen, Ci-C6-alkyl, hydroxy-C2-C6-alkyl or Ci-C4-alkoxy-C2-C4-alkyl;
  • R 1 and R 2 are a nitrogen containing 5- or 6-membered heteroaryl, the N-oxides thereof and the pharmaceutically acceptable salts of said N-oxides.
  • the invention relates to use of the compounds of the formula I, or their pharmaceutically acceptable salts, or, if one or both of R 1 and R 2 are a nitrogen containing 5- or 6-membered heteroaryl, the N-oxides thereof or the pharmaceutically acceptable salts of said N-oxides in therapy, in particular in the therapy of a a disease or disorder selected from the group consisting of inflammatory diseases, a hyperprolif- erative disease or disorders, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the formula I, or a pharmaceutically acceptable salt thereof, or, if one or both of R 1 and R 2 are a nitrogen containing 5- or 6-membered heteroaryl, an N-oxides thereof or a pharmaceutically acceptable salt of said N-oxide, optionally in combination with at least one second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper-vascularisation, and, optionally, a pharmaceutically acceptable carrier or auxiliary substance (excipi- ent).
  • the present invention relates to a method for treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hypervascularisation, said method comprising administering an effective amount of at least one compound of the formula I, or a pharmaceutically acceptable salt thereof, or, if one or both of R 1 and R 2 are a nitrogen containing 5- or 6-membered heteroaryl, a N-oxides thereof or a pharmaceutically acceptable salt of said N-oxide, optionally in combination with a second therapeutic agent useful for the treatment or prevention of such a disease or disorder to a subject in need thereof.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (lUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • the invention also relates to enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers (ennatiomerically pure), diastereomers and tautomers of the compounds of formula (I) and/or of their salts and/or their N-oxides. Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se.
  • Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent.
  • optically active resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfo- nic acids, such as -camphorsulfonic acid.
  • optically active resolving agent for example dini- trobenzoylphenylglycine
  • an example of a suitable eluent is a hexane/isopropa- nol/acetonitrile mixture.
  • the diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystal- lization. It is also possible to obtain optically active compounds of formula (I) by the methods described below by using starting materials which are already optically active.
  • the invention also relates to "pharmaceutically acceptable salts" of the compounds of the formula (I), especially acid addition salts with physiologically tolerated, i.e. pharmaceutically acceptable acids.
  • suitable physiologically tolerated organic and inorganic acids include, but are not limited to, hydrochloric acid, hydro- bromic acid, phosphoric acid, sulfuric acid, Ci-C4-alkylsulfonic acids, such as methane- sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfo- nic acid, carboxylic acids such as oxalic acid, malic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid, mandelic acid, salicylic acid, phenylpropionic acid, nicotinic acid, benzoic acid acetate, alginic acid, ascorbic acid, aspartic acid, tannic acid, butyric acid, camphoric
  • compositions include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, bu- tyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dode- cylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsani- late, hemisulfate, heptanoate, hexanoate, hexyl
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the invention also relates to N-oxides of the compounds of the formula (I), pro- vided that those compounds contain a basic nitrogen atom, such as the nitrogen atom of a N-heteroaromatic radical which may be present in R 1 and/or R 2 .
  • N- heteroaromatic radicals where the nitrogen may be present in the form of an N-oxide, include pyridinyl, pyrimdinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl and the like.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of general formula (I).
  • a prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
  • prodrugs involving esters
  • examples of a masked acidic anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 1 1 , 1981 ) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitro- gen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes such as deuterium, i.e., 3 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. All isotopic variations of the compounds and compositions of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • alkyl alkyl, aryl, heteroaryl, alkenyl, alkynyl, hydroxyalkyl and alkoxyalkyl are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings. Nevertheless in some instances of their use throughout the specification preferred meanings of these terms are indicated.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.
  • Ci-Cio-alkyl denotes a straight-chain or branched alkyl group having from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.
  • alkyl group examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, pentyl, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1 ,1 - dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 1,
  • fluorinated C1-C2 alkyl denotes an alkyl group having 1 or 2 carbon atoms as defined above, wherein at least one hydrogen atom, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine.
  • Examples of such a group include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1 ,1 ,2,2-tetrafluoroethyl and 1 ,1 ,2,2,2-pentafluoroethyl.
  • pentafluorosulfanyl relates to the radical SF 5 .
  • C1 refers to the carbon atom by which hydroxy-C2-C6-alkyl is bound to the remainder of the molecule.
  • Ci-C6-alkoxy denotes a straight-chain or branched alkyl group having 1 , 2, 3, 4, 5 or 6 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom.
  • alkoxy group examples include methoxy, ethoxy, n-propoxy, iso- propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy, pentyloxy, 1 - methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 2,2-dimethylpropyloxy, 1 - ethylpropyloxy, hexyloxy, 1 ,1 -dimethylpropyloxy, 1 ,2-dimethylpropyloxy, 1 - methylpentyloyx, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy,
  • fluorinated Ci-C2-alkoxy denotes an alkoxy group having 1 or 2 carbon atoms, wherein at least one hydrogen atom, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine.
  • Examples of such a group include fluoromethoxy, difluoro- methoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy and 1 ,1 ,2,2,2-pentafluoroethoxy.
  • Ci-C4-alkoxy-Ci-C4-alkyl denotes a straight-chain or branched alkyl group having from 1 to 4 carbon atoms, wherein one of the hydrogen atoms is replaced by a C1-C4 alkoxy group, such as in methoxymethyl, ethoxymethyl, propoxymethyl,
  • C1-C4-alkoxy-C2-C4-alkyl denotes a straight-chain or branched alkyl group having from 2 to 4 carbon atoms, wherein one of the hydrogen atoms, which is preferably not located at C1 , is replaced by a C1-C4 alkoxy group, such as in 2- methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 3-methoxypropyl or 3- ethoxypropyl.
  • C1 refers to the carbon atom by which Ci-C4-alkoxy-C2-C4- alkyl is bound to the remainder of the molecule.
  • Ci-C6-alkylthio denotes a straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as mentioned above) which are attached to the skeleton via a sulfur atom (-S-).
  • C2-Cio-alkenyl denotes a straight-chain or branched hydrocarbon groups having 2 to 4, 6, 8 or 10 carbon atoms and one or more, e.g. 2 or 3, carbon- carbon double bonds in any position, preferably one carbon-carbon double bond, e.g.
  • C2-C10 alkynyl denotes a straight-chain or branched hydrocarbon groups having 2 to 4, 6, 8 or 10 carbon atoms and one or more, e.g. 2 or 3, carbon- carbon triple bonds in any position, preferably one carbon-carbon triple bond, for example ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 -methyl-2- propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-2-butynyl, 1 -methyl-
  • heteroaryl (also referred to as hetaryl) denotes a monocyclic 5- or 6- membered heteroaromatic radicals comprising as ring members in addition to carbon atom(s) 1 , 2, 3 or 4 heteroatoms selected from N, O and S.
  • C-bound heteroaryl denotes a heteroaromatic radical which is bound via a carbon ring atom while N-bound heteroaryl denotes a heteroaromatic radical which is bound via a nitrogen ring atom.
  • 5- or 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or
  • N-bound, 5- or 6- membered saturated nitrogen heterocycle denotes a saturated heteromonocyclic radical containing one nitrogen atom as a ring member, which is attached to the remainder of the molecule, and optionally one or more, e.g. 1 or 2 further heteroatoms such as O, S or N as ring member, having a total of 5 or 6 ring member atoms.
  • N-bound, 5- or 6-membered saturated nitrogen hetero- cycles are pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl, 4-methylpiperazin-1 -yl, mor- pholin-4-yl, thiomorpholin-4-yl, imidazolidin-1 -yl, oxazolidin-3-yl or thiazolidin-3-yl, es- pecially pyrrolidin-1 -yl, piperazin-1 -yl, 4-methylpiperazin-1 -yl, piperidin-1 -yl and mor- pholin-4-yl.
  • the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is O.
  • These compounds are hereinafter also denominated as dihydrobenzoxazines or compounds of the formula 1.1 .
  • the present invention relates to the compounds of the formula I, to their salts, to their N-oxides and to the salts of the N-oxides, wherein X is S.
  • These compounds are hereinafter also denominated as dihydroben- zothiazines or compounds of the formula 1.2.
  • These compounds are hereinafter also denominated as dihydrobenzothiaz- ine oxides or compounds of the formula 1.3.
  • These compounds are hereinafter also denominated as dihydrobenzothi- azine dioxides or compounds of the formula 1.4.
  • Particular preference is given to the first embodiment, i.e. to compounds of the formula 1.1 .
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 1 is phenyl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different.
  • R 1 is phenyl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different.
  • R 1a radicalst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R 1a .
  • one of the radicals R 1a if present, is located in the para-position with respect to the sulfonyl group.
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 1 is 6-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different.
  • R 1 is 6-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different.
  • those are preferred, wherein the one or more nitrogen ring atom(s) are not located in the ortho position with respect to the sulfonyl moiety.
  • the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R 1a .
  • one of the radicals R 1a if present, is located in the para-position with respect to the sulfonyl group.
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 1 is 5-membered C-bound heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different.
  • the radicals R 1a if present, have the aforementioned meanings and are preferably selected from halogen, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF 5 , fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoro- methoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-
  • R 1 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R 1a which are identical or different, preference is given to those compounds, wherein R 1 in the formulae I, 1.1 , I.2, 1.3 or I.4 is a radical of the formula AM :
  • # indicates the point of attachment to the SO2 group
  • K is N or C-R 11 .
  • L is N or C-R 12 .
  • M is N or C-R 13 .
  • R 11 , R 12 and R 13 independently of each other, are hydrogen or have one of the meanings given for R 1a , in particular one of the preferred meanings.
  • R 1 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different
  • R 11 , R 13 are independently of each other selected from the group consisting of hydrogen, halogen, OH, CN, SH, C1-C4 alkyl, especially methyl, ethyl or iso- propyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, NR 4 R 5 such as NHCH3 or N(CH3)2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci- C4-alkoxy
  • R 12 if present, is selected from the group consisting of hydrogen, halogen, OH,
  • Alk is selected from CH 2 , CH2CH2, CHF and CF 2 .
  • R 1 is a radical of the formulae Ar1 , Ar1 .1 , Ar1 .2, Ar1 .3, Ar1 .4 or Ar1 .5
  • R 11 , R 12 and R 13 if present, indi- vidually or in particular in combination have the following meanings:
  • R 11 is selected from the group consisting of hydrogen, halogen, OH, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy;
  • R 12 is selected from the group consisting of halogen, OH , SH, CN , NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 al- kynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, SF 5 , fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl
  • R 11 and R 12 together may also form a moiety O-Alk-0, wherein Alk is selected from CH 2 , CH2CH2, CHF and CF 2 ;
  • R 13 if present, is hydrogen.
  • G is O, S or N-R 8 ,
  • G' is O, S or N-R 19 ,
  • R 14 , R 15 , R 16 and R 17 independently of each other, are hydrogen or have one of the meanings given for R 1a
  • R 18 and R 19 are hydrogen, cyano, NH2, OH, Ci-Cio-alkyl, in particular Ci-C4-alkyl, especially methyl, ethyl or isopropyl, C2-C10- alkenyl, in particular C2-C4-alkenyl, especially ethenyl or 3-propenyl, C2-Cio-alkynyl, in particular C2-C4-alkynyl, especially ethynyl or 3-propynyl, Ci-C6-alkoxy, in particular Ci- C4-alkoxy, especially methoxy or ethoxy, hydroxy-C2-C6-alkyl, in particular hydroxy-C2- C4-alkyl, especially 2-ethoxyethyl, Ci-C4-alkoxy-C2-C4-alkyl
  • R 1 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which is unsubstituted or which carries 1 , 2 or 3 radicals R 1a which are identical or different
  • # indicates the point of attachment of R 1 to the SO2 group, wherein R 14 , R 15 , R 16 , R 17 , R 18 and R 19 have the meanings given above.
  • R 1 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, particular embodiments of the invention relate to compounds, wherein, the variables R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , if present, individually or in particular in combination have the following meanings:
  • R 14 if present, is hydrogen
  • R 15 if present, is hydrogen
  • R 16 if present, is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF 5 , fluorinated Ci- C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci-C4-alkoxy-Ci-C4-al
  • R 17 if present, is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, C1-C4- alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF 5 , fluorinated Ci- C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, Ci-C4-alkoxy-Ci-C4-al
  • R 18 if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, fluorinated Ci-alkyl, especially difluoromethyl or trifluoro- methyl, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl and Ci-C4-alkoxy-C2-C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl; in particular, R 18 is hydrogen or methyl.
  • R 19 if present, is selected from the group consisting of hydrogen, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, fluorinated Ci-alkyl, especially difluoromethyl or trifluoro- methyl, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl and Ci-C4-alkoxy-C2-C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl.
  • R 19 is hydrogen or methyl.
  • radicals R 1 are given in the following tables A, which are particular embodiments according to the present invention.
  • R 2 is phenyl or a 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl carry a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R 2a which are identical or different.
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 2 is phenyl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R 2a which are identical or different.
  • R 2 is phenyl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R 2a which are identical or different.
  • those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the point of attachment to the benzazine core of (I) do not carry a radical R 2a .
  • the CN group is located in the para-position with respect to the point of attachment to the benzazine core of (I).
  • phenyl carries a CN radical and may additionally carry 1 or 2 radicals R 2a , which are identical or different.
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 2 is 6-membered heteroaryl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R 2a which are identical or different.
  • 6-membered heteroaryl carries a CN radical and may additionally carry 1 radical R 2a .
  • those are preferred, wherein the one or more nitrogen ring atom(s) are not located in the ortho position with respect to the point of attachment to the benzazine core of (I).
  • the carbon ring atom(s) which are located in the ortho position with respect to the point of attachment to the benzazine core of (I) do not carry a radical R 2a .
  • the CN group is located in the para-position with respect to the point of attachment to the benzazine core of (I).
  • the present invention relates to the compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 2 is 5-membered C-bound heteroaryl, which carries a CN radical and may additionally carry 1 , 2 or 3, in particular 1 or 2 radicals R 2a which are identical or different. Amongst these compounds, those are preferred, wherein the carbon ring atom(s) which are located in the ortho position with respect to the sulfonyl moiety do not carry a radical R 2a .
  • 5-membered heteroaryl carries a CN radical and may additionally carry 1 radical R 2a .
  • the radicals R 2a if present, have the aforementioned meanings and are preferably selected from halogen, OH, SH, CN, NO2, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoromethyl or trifluoromethyl, SF 5 , fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, NH2, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, Ci-C4-alkoxy-Ci
  • 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R 2a which are identical or different, preference is given to those compounds, wherein R 2 in the formulae I, 1.1 , I.2, 1.3 or I.4 is a radical of the formula Ar3: wherein # indicates the point of attachment to the benzazine core of (I),
  • K' is N or C-R 21 .
  • L' is N or C-R 22 .
  • M' is N or C-R 23 ,
  • P is N or CH
  • R 21 , R 22 and R 23 independently of each other, are hydrogen or have one of the meanings given for R 2a , provided that 1 or 2 of the variables K', L' or M', are C- CN.
  • R 2 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is phenyl or 6-membered heteroaryl, which are unsubstituted or which carry 1 , 2 or 3 radicals R 2a which are identical or different
  • R 21 , R 22 and R 23 independently of each other, are hydrogen or have one of the meanings given for R 2a provided that one of the radicals R 21 , R 22 or R 23 is CN.
  • R 22 is preferably CN while R 21 , and, if present, R 23 are different from CN.
  • R 2 is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, preferred embodiments of the invention relate to compounds, wherein, the variables R 21 , R 22 and R 23 , if present, individually or in particular in combination have the following meanings, provided that one of the radicals R 21 , R 22 or R 23 is CN.
  • R 21 is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxym ethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.
  • R 22 is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.
  • R 23 is selected from hydrogen, halogen, OH, CN, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, C1-C4- alkylthio, especially methylthio or ethylthio, fluorinated Ci-C2-alkyl, especially difluoro- methyl or trifluoromethyl, fluorinated Ci-C2-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2- hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl,
  • R 2 is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, more preferred embodiments of the invention relate to compounds, wherein, the variables R 21 , R 22 and R 23 , if present, individually or in particular in combination have the following meanings, provided that one or two of R 21 , R 22 or R 23 is (are) CN:
  • R 21 is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy;
  • R 22 if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy; and
  • R 23 if present, is selected from the group consisting of hydrogen, halogen, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoro- methoxy
  • R 21 is selected from hydrogen, halogen, OH, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4- alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, and Ci-C4-alkoxy-Ci- C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or 2-methoxyethyl.
  • R 22 is CN.
  • R 23 is selected from hydrogen, halogen, OH, C1-C4 alkyl, especially methyl, ethyl or isopropyl, Ci-C4-alkoxy, especially methoxy or ethoxy, Ci-C4-alkylthio, especially methylthio or ethylthio, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-Ci-C4-alkyl, especially hydroxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, and Ci-C4-alkoxy-Ci-C4-alkyl, especially methoxymethyl, ethoxymethyl, 1 -methoxyethyl or
  • R 21 is selected from the group consisting of hydrogen, halogen, OH, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.
  • R 22 is CN.
  • R 23 if present, is selected from the group consisting of hydrogen, halogen, OH, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.
  • R 2 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which carries a CN radical and which may additionally carry 1 , 2 or 3 radicals R 2a which are identical or different, preference is given to those compounds, wherein R 1 in the formulae I, 1.1 , I.2, 1.3 or 1.4 is a radical of the formulae Ar4, Ar5 or Ar6:
  • Ar4 Ar5 Ar6 wherein # indicates the point of attachment of R 2 to the benzazine core of (I), A is N or C-R 24 ,
  • A' is N or C-R 25 ,
  • D is N or C-R 26 .
  • E is N or C-R 27 ,
  • G is O, S or N-R 28 ,
  • G' is O, S or N-R 29 ,
  • R 24 , R 25 , R 26 and R 27 independently of each other, are hydrogen or have one of the meanings given for R 2a
  • R 28 and R 29 are selected from hydrogen, cyano, NH2, OH, Ci-Cio-alkyl, in particular Ci-C4-alkyl, especially methyl, ethyl or isopropyl, C2-Cio-alkenyl, in particular C2-C4-alkenyl, especially ethenyl or 3-propenyl, C2-Cio-alkynyl, in particular C2-C4-alkynyl, especially ethynyl or 3-propynyl, C1-C6- alkoxy, in particular Ci-C4-alkoxy, especially methoxy or ethoxy, hydroxy-C2-C6-alkyl, in particular hydroxy-C2-C4-alkyl, especially 2-ethoxyethyl, Ci-C4-alkoxy-C2-C
  • R 2 in the formulae I, 1.1 , 1.2, 1.3 or 1.4 is C-bound 5-membered heteroaryl, which carries a CN radical and which may additionally carry 1 , 2 or 3 radicals R 2a which are identical or different
  • # indicates the point of attachment of R 2 to the benzazine core of (I), wherein R 24 , R 25 , R 26 , R 27 , R 28 and R 29 have the meanings given above and wherein either R 24 or R 26 or R 27 in the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.15, Ar6.1 , Ar6.2 and Ar6.3 is CN.
  • R 2 is selected from radicals of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 and Ar6.3, particular embodiments of the invention relate to compounds, wherein, the variables R 24 , R 25 , R 26 , R 27 , R 28 and R 29 , if present, individually or in particular in combination have the following meanings:
  • R 24 is selected from the group consisting of hydrogen and cyano, more preferably hydrogen
  • R 25 is selected from the group consisting of hydrogen and halogen, more preferably hydrogen
  • R 28 is selected from the group consisting of hydrogen, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl, and Ci-C4-alkoxy-C2- C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl.
  • R 29 is selected from the group consisting of hydrogen, C1-C4 alkyl, especially methyl, ethyl or isopropyl, C2-C4 alkenyl, especially ethenyl, C2-C4 alkynyl, especially ethynyl, Ci-C4-alkoxy, especially methoxy or ethoxy, fluorinated Ci-alkyl, especially difluoromethyl or trifluoromethyl, fluorinated Ci-alkoxy, especially difluoromethoxy or trifluoromethoxy, hydroxy-C2-C4-alkyl, especially 2-hydroxyethyl, and Ci-C4-alkoxy-C2- C4-alkyl, especially 1 -methoxyethyl or 2-methoxyethyl.
  • R 2 is selected from radicals of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 and Ar6.3, particular embodiments of the invention relate to compounds, wherein, the variables R 24 , R 25 , R 26 , R 27 , R 28 and R 29 , if present, individually or in particular in combination have the following meanings:
  • R 24 is hydrogen
  • R 25 is hydrogen
  • R 26 is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoro- methoxy and trifluoromethoxy.
  • R 27 is selected from the group consisting of hydrogen, halogen, in particular fluorine or chlorine, OH, CN, methyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.
  • R 28 is hydrogen or C1-C4 alkyl, especially hydrogen or methyl.
  • R 29 is hydrogen or C1-C4 alkyl, especially hydrogen or methyl.
  • a particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N-oxides, wherein R 1 is a radical of the formula Ar1 and wherein R 2 is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6,
  • Another particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formula Ar1 and wherein R 2 is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.
  • a further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formulae Ar2 or Ar2' and wherein R 2 is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formulae Ar2 or Ar2' and wherein R 2 is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formula Ar1 .1 to Ar1.5, in particular a radical Ar1 .1 or Ar1 .3, and wherein R 2 is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.
  • a further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , I.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formula Ar1 .1 to Ar1 .5, in particular a radical Ar1 .1 or Ar1 .3, and wherein R 2 is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar4.6, Ar4.7, Ar4.8, Ar4.9, Ar4.10, Ar4.1 1 , Ar4.12, Ar4.13, Ar4.14, Ar4.15, Ar5.1 , Ar5.2, Ar5.3, Ar5.4, Ar5.5, Ar5.6, Ar5.7, Ar5.8, Ar5.9, Ar6.1 , Ar6.2 or Ar6.3, especially a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, in particular from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R 2 is a radical of the formula Ar3, in particu- lar a radical of the formulae Ar3.1
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2.3, Ar2.4, Ar2.5, Ar2.6, Ar2.7, Ar2.8, Ar2.9, Ar2.10, Ar2.1 1 , Ar2.12, Ar2.13, Ar2.14, Ar2.15, Ar2.16, Ar2.17, Ar2.18, Ar2.19, Ar2'.1 , Ar2'.2, Ar2'.3, Ar2'.4, Ar2'.5, Ar2'.6, Ar2'.7, Ar2'.8, Ar2'.9, Ar2'.10, Ar2'.1 1 and Ar2'.12, in particular from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R 2 is a radical of the formulae Ar4, Ar5 or Ar6, in particular a radical of the formulae
  • a further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formulae Ar1 .1 or Ar1 .3, and wherein R 2 is a radical of the formulae Ar3.1 , Ar3.2, Ar3.3, Ar3.4, Ar3.5, Ar3.6, Ar3.7, Ar3.8, Ar3.9, Ar3.10, Ar3.1 1 or Ar3.12, especially a radical of the formulae Ar3.1 or Ar3.3.
  • a further particular embodiment of the invention relates to compounds of the for- mulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is a radical of the formulae Ar1 .1 or Ar1 .3, and wherein R 2 is a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , I.2, 1.3 and I.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R 2 is a radical of the formula Ar3, in particular a radical of the formulae Ar3.1 and Ar3.3.
  • a further particular embodiment of the invention relates to compounds of the formulae I, 1.1 , 1.2, 1.3 and 1.4, to their salts, to their N-oxides and to the salts of the N- oxides, wherein R 1 is selected from radicals of the formulae Ar2.1 , Ar2.2, Ar2'.1 and Ar2'.2 and wherein R 2 is a radical of the formulae Ar4.1 , Ar4.2, Ar4.3, Ar4.4, Ar4.5, Ar5.1 , Ar5.2, Ar5.3, Ar5.7 or Ar5.8.
  • radical C(0)R 3 the following meanings are particular embodiments of R 3 : methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl. In particu- lar the radical C(0)R 3 is selected from acetyl or propionyl.
  • R 4 hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl.
  • R 5 C1-C4- alkyl, in particular methyl, ethyl, n-propyl, isopropyl or n-butyl.
  • R 4 , R 5 together with the nitrogen atom, to which they are bound, form an N-bound, 5- or 6-membered saturated nitrogen heterocycle, such as pyrrolidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1 -yl or 4-methylpiperazin-1 -yl.
  • radical NR 4 R 5 is selected from methylamino, ethylamino, n-propylamino, isopropylamino, di- methylamino, diethylamino, N-methyl-N-ethylamino, N-methyl-N-isopropylamino, N- methyl-N-propylamino, pyrrolidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1 -yl and 4-methylpiperazin-1 -yl.
  • R 6 hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n- propyl, isopropyl or n-butyl.
  • R 7 hydrogen or Ci-C4-alkyl, in particular hydrogen, methyl, ethyl, n-propyl, isopropyl or n- butyl.
  • R 8 Ci-C4-alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl.
  • the radical C(0)OR 8 is selected from methoxycar- bonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl or tert.-butoxycarbonyl.
  • R x the following meanings are particular embodiments of R x : Ci-C4-alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl.
  • the radical C(0)R x is selected from acetyl or propionyl.
  • Suitable compounds according to the present invention are the compounds of the formula (I) as given in the following tables 1 to 94, 95 to 188, 189 to 282 and 283 to 376, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides.
  • Table 1 Compounds of the formula (I), wherein X is O and R 2 is 3-cyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A
  • Table 4 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-3- chlorophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-637 to I-848);
  • Table 5 Compounds of the formula (I), wherein X is O and R 2 is 3,4- dicyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-849 to 1-1060);
  • Table 6 Compounds of the formula (I), wherein X is O and R 2 is 3-methyl-4- cyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1061 to 1-1272);
  • Table 7 Compounds of the formula (I), wherein X is O and R 2 is 3-ethyl-4- cyanophenyl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1273 to 1-1484);
  • Table 8 Compounds of the formula (I), wherein X is O and R 2 is 3-methoxy-4- cyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1485 to 1-1696);
  • Table 9 Compounds of the formula (I), wherein X is O and R 2 is 3-hydroxy-4- cyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1697 to 1-1908);
  • Table 10 Compounds of the formula (I), wherein X is O and R 2 is 3,5-difluoro-4- cyanophenyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1909 to 1-2120);
  • Table 14 Compounds of the formula (I), wherein X is O and R 2 is 6-cyanopyridine- 2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-2757 to I-2968);
  • Table 15 Compounds of the formula (I), wherein X is O and R 2 is 4-cyanopyridine- 2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-2969 to 1-3180);
  • Table 17 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-6- methoxypyridine-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-3393 to I-3604);
  • Table 18 Compounds of the formula (I), wherein X is O and R 2 is 6-cyano-5- methoxy-pyridine-3-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-3605 to 1-3816);
  • Table 19 Compounds of the formula (I), wherein X is O and R 2 is 6-cyano-5-fluoro- pyridine-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-3817 to I-4028);
  • Table 20 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4- fluoropyridine-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-4029 to I-4240);
  • Table 21 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4- methylpyridine-2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-4241 to I-4452);
  • Table 22 Compounds of the formula (I), wherein X is O and R 2 is 2-cyano-6- methylpyridine-4-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-4453 to I-4664);
  • Table 23 Compounds of the formula (I), wherein X is O and R 2 is 6-cyano-5- hydroxypyridine-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-4665 to I-4876);
  • Table 24 Compounds of the formula (I), wherein X is O and R 2 is 5- cyanopyrimidine-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-4877 to I-5088);
  • Table 25 Compounds of the formula (I), wherein X is O and R 2 is 2- cyanopyrimidine-4-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-5089 to I-5300);
  • Table 27 Compounds of the formula (I), wherein X is O and R 2 is 6- cyanopyrimidine-4-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-5513 to I-5724);
  • Table 28 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanopyrazin-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-5725 to I-5936);
  • Table 33 Compounds of the formula (I), wherein X is O and R 2 is 6-cyano-1 ,2,4- triazin-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-6785 to I-6996);
  • Table 34 Compounds of the formula (I), wherein X is O and R 2 is 6-cyano-5- methoxy-1 ,2,4-triazin-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-6997 to I-7208);
  • Table 36 Compounds of the formula (I), wherein X is O and R 2 is 3-cyanofuran-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-7421 to I-7632);
  • Table 37 Compounds of the formula (I), wherein X is O and R 2 is 4-cyanofuran-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-7633 to I-7844);
  • Table 38 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanofuran-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-7845 to I-8056);
  • Table 39 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanofuran-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-8057 to I-8268);
  • Table 40 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanofuran-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-8269 to I-8480);
  • Table 41 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4- fluorofuran-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-8481 to I-8692);
  • Table 42 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4- chlorofuran-2-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-8693 to I-8904);
  • Table 43 Compounds of the formula (I), wherein X is O and R 2 is 3-cyano-2-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-8905 to 1-91 16);
  • Table 44 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-2-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-91 17 to I-9328);
  • Table 45 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-2-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-9329 to I-9540);
  • Table 46 Compounds of the formula (I), wherein X is O and R 2 is 2-cyano-3-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-9541 to I-9752);
  • Table 47 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-3-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-9753 to I-9964);
  • Table 48 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4-fluoro- 2-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds I-9965 to 1-10176);
  • Table 49 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4-chloro- 2-thienyl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10177 to 1-10388);
  • Table 50 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanopyrrol-1 -yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10388 to 1-10600);
  • Table 51 Compounds of the formula (I), wherein X is O and R 2 is 3-cyanopyrrol-1 -yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10601 to 1-10812);
  • Table 52 Compounds of the formula (I), wherein X is O and R 2 is 3-cyano-4- methyl-pyrrol-1 -yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-10813 to 1-1 1024)
  • Table 53 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-pyrrol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1 1025 to 1-1 1236);
  • Table 54 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-pyrrol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-1 1237 to 1-1 1448);
  • Table 59 Compounds of the formula (I), wherein X is O and R 2 is 1 -methyl-2- cyano-pyrrol-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12297 to 1-12508);
  • Table 60 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-pyrrol-3- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12509 to 1-12720);
  • Table 61 Compounds of the formula (I), wherein X is O and R 2 is 1 -methyl-5- cyanopyrrol-3-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-12721 to 1-12932);
  • Table 64 Compounds of the formula (I), wherein X is O and R 2 is 2-cyano-1 - methylimidazol-4-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13357 to 1-13568);
  • Table 65 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-imidazol- 1 -yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13569 to 1-13780);
  • Table 66 Compounds of the formula (I), wherein X is O and R 2 is 2-cyano-1 - methyl-imidazol-5-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13781 to 1-13992)
  • Table 67 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-imidazol- 2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-13993 to 1-14204);
  • Table 68 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-imidazol- 2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14205 to 1-14416);
  • Table 69 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-1 - methylimidazol-2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14417 to 1-14628);
  • Table 70 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-1 - methylimidazol-2-yl, and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14629 to 1-14840);
  • Table 71 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanothiazol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-14841 to 1-15052);
  • Table 72 Compounds of the formula (I), wherein X is O and R 2 is 4-cyanothiazol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15053 to 1-15264);
  • Table 73 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanothiazol-4- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15265 to 1-15476);
  • Table 74 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanothiazol-5- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15477 to 1-15688);
  • Table 75 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanooxazol-4- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15689 to 1-15900);
  • Table 76 Compounds of the formula (I), wherein X is O and R 2 is 2-cyanooxazol-5- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-15901 to 1-1612);
  • Table 77 Compounds of the formula (I), wherein X is O and R 2 is 4-cyanooxazol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-161 13 to 1-16324);
  • Table 78 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanooxazol-2- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16325 to 1-16536);
  • Table 79 Compounds of the formula (I), wherein X is O and R 2 is 3-cyanoisoxazol- 5-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16537 to 1-16748);
  • Table 80 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanoisoxazol- 3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16749 to 1-16960);
  • Table 81 Compounds of the formula (I), wherein X is O and R 2 is 3- cyanoisothiazol-5-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-16961 to 1-17172);
  • Table 82 Compounds of the formula (I), wherein X is O and R 2 is 5- cyanoisothiazol-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17173 to 1-17384);
  • Table 83 Compounds of the formula (I), wherein X is O and R 2 is 3-cyanopyrazol-5- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17385 to 1-17596); Table 84 Compounds of the formula (I), wherein X is O and R 2 is 5-cyanopyrazol-3- yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17597 to 1-17808);
  • Table 85 Compounds of the formula (I), wherein X is O and R 2 is 3-cyano-1 - methylpyrazol-5-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-17809 to 1-18020);
  • Table 86 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-1 - methylpyrazol-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18021 to 1-18232);
  • Table 87 Compounds of the formula (I), wherein X is O and R 2 is 3-cyano-pyrazol- 1 -yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18233 to 1-18444);
  • Table 88 Compounds of the formula (I), wherein X is O and R 2 is 4-cyano-pyrazol- 1 -yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-18445 to 1-18656);
  • Table 94 Compounds of the formula (I), wherein X is O and R 2 is 5-cyano-4- methyl-1 ,2,4-triazol-3-yl and wherein R 1 has one of the meanings given in rows 1 to 212 of table A (Compounds 1-19717 to 1-19928).
  • Examples of particular preferred compounds according to the present invention are the compounds listed below, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides:
  • Examples of particular preferred compounds according to the present invention are the compounds listed below, their pharmaceutically acceptable salts, their N-oxides and the pharmaceutically acceptable salts of said N-oxides:
  • the compounds I according to the invention are prepared in analogy with methods known from the literature.
  • Compounds of the formula I, wherein X is oxygen or sulfur can be prepared e.g. starting from 6-halogen-3,4-dihydro-2H- benzo[b][1 ,4]oxazine II and 6-halogen-3,4-dihydro-2H-benzo[b][1 ,4]thiazine II, respectively, or the salts thereof as depicted in schemes 1 , 2 and 3.
  • R 1 and R 2 have the aforementioned meanings.
  • R a and R b are hydroxyl or Ci-C4-alkoxy such as methoxy or ethoxy or R a and R b together form a moiety 0-R-O, wherein R is ethan-1 ,2-diyl, 1 ,1 ,2,2-tetramethylethan-1 ,2-diyl, propan- 1 ,3-diyl, 2, 2-dimethylpropan-1 ,3-diyl or 1 ,1 ,3-trimethylpropan-1 ,3-diyl.
  • Hal and Hal' are each independently chlorine, bromine or iodine, preferably bromine or chlorine.
  • Pd denominates a Pd(0) catalyst or a Pd(0) precursor compound, optionally in combination with a suitable ligand.
  • Base denominates a suitable basic compound which assists in the formation of the sulfonylamide formation.
  • the halogen compound II or a salt thereof e.g. an acid addition salt such as the salt with a hydrohalic acid
  • a boronic compound III e.g. an acid addition salt such as the salt with a hydrohalic acid
  • the reaction is usually carried out in the presence of a base and a palladium catalyst, such as for example described in the following literature: Synth. Commun. Vol. 1 1 , p. 513 (1981 ); Acc. Chem. Res. Vol. 15, pp. 178-184 (1982); Chem. Rev. Vol. 95, pp. 2457-2483 (1995); Organic Letters Vol. 6 (16), p.
  • Suitable catalysts are in tetrakis(triphenylphosphine)palladium(0);
  • Suitable bases are, in general, inorganic compounds, such as alkali metal and al- kaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, caesium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, po- tassium ethoxide and potassium tert.-butoxide, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines, preferably potassium carbonate.
  • organic bases for example tert
  • Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, ethers, such as diisopropyl ether, tert. -butyl methyl ether, 1 ,4-dioxane, anisole and tetrahydrofuran and dimethoxyethane, alkanol, e.g. Ci-C6-alkanols such as methanol, ethanol or n- propanol, or mixtures of these solvents, particularly preferably ethers, such as dioxane or a mixture of toluene/methanol.
  • aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether
  • aromatic hydrocarbons such as toluene, o-, m-
  • the compound IV intermediate is reacted with a sulfonylchloride V in accordance with standard methods of organic chem- istry and as described in the experimental part of this application.
  • This reaction is usually carried out in an inert organic solvent.
  • Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloro- methane, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert. -butyl methyl ether, dioxane, anisole and tetrahydrofuran.
  • Suitable bases are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogen carbonate or potassium hydrogen carbonate, and organic bases, for example trialkylamines, such as triethylamine, or pyridine compounds, such as pyridine, lutidine, 4-dimethylamino- pyridine and the like.
  • the auxiliary base is customarily employed in at least equimolar quantities, based on the amine compound IV.
  • the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed.
  • the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the Suzuki coupling (with regard to reactions using microwaves, see Tetrahedron 2001 , 57, p. 9199 ff. and p. 9225 ff. and also, in a general manner, "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002.
  • first step of scheme 2 can be performed under conditions as described for the second step of scheme 1 .
  • second step of scheme 2 can be performed under conditions as described for the first step of scheme 1.
  • schemes 1 and 2 include an additional step as shown in scheme 3.
  • compound II is first converted into the arylboronic compound I la under conditions of a Suzuki coupling. The conversion can be performed e.g. as described above for the first step of scheme 1 .
  • the diboron ester Ilia is bis(pinacolato)diboron, bis(neopentyl glycolato)diboron or bis(hexylene glycolato)diboron, especially bis(pinacolato)diboron.
  • compound I la can be converted into compound I either by reacting I la with an appropriate heteroaro- matic or aromatic halogenide VII to give compound IV intermediate and reacting the obtained compound IV intermediate with a sulfonylchloride V as described in scheme 1 or by reacting I la with an appropriate sulfonylchloride V to give compound Via interme- diate and then reacting the obtained compound Via intermediate with a (het)arylhalide R 2 Hal' (compound VII) under conditions of a Suzuki coupling as described in scheme 2.
  • Boronic compounds III and Ilia are commercially available or can be prepared according to "Science of Synthesis” Vol. 6, Thieme, 2005.
  • sulfonylchlorides V are not commercially available, they can be obtained ac- cording to procedures known in the art without undue burden following routine laboratory practice.
  • an oxidizing agent in particular an inorganic or organic peroxide or hydroperoxide, e.g. a percarboxylic acid such as 3-chloroperbenzoic acid or monoperphthalic acid or with an appropriate amount of alkali metal periodate or hydroperoxide.
  • Compounds of the formula I, wherein X is SO2 can be prepared by, for example, treating the compound of formula I, wherein X is S or SO, with an appropriate amount of an oxidizing agent, in particular an inorganic or organic peroxide or hydroperoxide, e.g. a percarboxylic acid such as 3-chloroperbenzoic acid or monoperphthalic acid or with an appropriate amount of alkali metal periodate or hydroperoxide.
  • an oxidizing agent in particular an inorganic or organic peroxide or hydroperoxide, e.g. a percarboxylic acid such as 3-chloroperbenzoic acid or monoperphthalic acid or with an appropriate amount of alkali metal periodate or hydroperoxide.
  • N-oxides of compounds of formula I can be prepared by, for example, treating a compound of the formula I with an oxidizing agent, in particular an inorganic or organic peroxide or hydroperoxide, such as hydrogen peroxide, or percarboxylic acids, such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid.
  • an oxidizing agent in particular an inorganic or organic peroxide or hydroperoxide, such as hydrogen peroxide, or percarboxylic acids, such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid.
  • the advantageous properties of the compounds of the invention include their ability of effectively inhibiting cell proliferation and their activity as HIF inhibitors.
  • the compounds of the present invention were shown to inhibit the activation of HIF-mediated transcription under hypoxic conditions.
  • the compounds of the invention can be used for the preparation of a medicament for the treatment of a disorder characterized by pathophysiological HIF signaling.
  • a person skilled in the art of medical, biological and/or pharmacological science can de- termine with routine methodology if a disorder is characterized by undesirable HIF signaling. Tissues affected by such diseases will overexpress genes that are induced by activation of the HIF responsive element (HRE).
  • HIF-1 acts by binding to HIF- responsive elements (HREs) in promoters that generally contain the sequence
  • NCGTG NCGTG.
  • the genes affected by HIF activity which are regulated by said promoters are well known in the art and were also described in multiple reviews (see e.g. figure 3 of Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3).
  • HIF-1 overexpression is associated with increased tumor growth, increased vascularisation, metastasis and fibrosis, e.g. renal fibrosis (see: Semenza, G, Drug Discovery Today, vol. 12, no. 19/20, October 2007; Kimura, Kuniko, et al., American Journal of Physiology (2008), 295(4, Pt. 2), F1023-F1029 and for a review see N.J. Mabjeesh et al., Histol. Histopathol (2007) 22:559-572).
  • Fibrosis is the formation or development of excess fibrous connective tissue in an organ or tissue.
  • HIF-1 activity also acts to prevent inflammation, by virtue of its essential role in the activation and infiltration of macro- phages and neutrophils into affected tissues (see e.g. Giaccia et al., Drug Discovery, vol. 2, October 2003).
  • a compound of the present invention can be used to treat an inflammatory disease, a hyperproliferative disease or disorder, a hy- poxia related pathology and also diseases characterized by pathophysiological hyper- vascularisation. Therefore, as a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of the present invention, optionally together with at least one physiologically acceptable carrier or auxiliary substance.
  • the invention provides a therapeutical composition which, in addition to the compound of the invention comprises at least one further pharmaceutically active compound that is useful to treat one of the aforementioned diseases or disorders.
  • Such therapeutical compositions are useful because the therapeutic efficiency of the compounds of the invention can be amplified by the presence of said at least one further pharmaceutically active compound and vice versa.
  • inhibiting HI F1 a activity via antisense gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma (see Liu, Feng- jun et. al., Cancer Science (2008), 99(10), 2055-2061 ).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention and a second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper- vascularisation, and, optionally, a pharmaceutically acceptable carrier or excipient.
  • a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hyper- vascularisation, and, optionally, a pharmaceutically acceptable carrier or excipient.
  • Such compositions are also useful to obtain synergistic therapeutic effects and also to prevent drug resistance of tumor cells, for example. It is also for these reasons, that current chemotherapy generally involves administering a cocktail of different cytotoxic and/or cytostatic compounds to improve the effectiveness of the treatment and reduce the possibility of tumor cell adaptation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention in combination with radiation therapies.
  • composition of the present invention may be admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.
  • a pharmaceutical carrier excipient or diluent
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients" , 2nd Edition, (1994), Edited by A Wade and PJ Weller. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985).
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dis- persible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of the active compound or active compounds.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • HIF inhibitors such as the compounds of the invention, can prevent the development of tumor resistance towards chemotherapeutic drugs and can make cancer cells more sensitive towards radiotherapy (see e.g. Palayoor ST, et al., Int J Cancer. 2008 Nov 15;123(10):2430-7 and Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3).
  • useful second therapeutic agents that can be combined with a compound of the invention to produce the pharmaceutical composition of the invention include, without limitation, a (further) HIF-1 inhibitor, a cytotoxic compound and cy- tostatic compounds.
  • a HIF-1 inhibitor can be, e.g. selected from the group consisting of PX-478 (S-2- amino-3-[4'-/S/,A/,-bis(2-chloroethyl)amino]phenyl propionic acid A/-oxide dihydrochlo- ride); a topoisomerase-1 inhibitor such as 8,9-Dimethoxy-5-(2-/S/,/V- dimethylaminoethyl)-2,3-methylenedioxy-5/-/-dibenzo[c, ?][1 ,6] naphthyridin-6-one (also known as ARC-1 1 1 or topovale) or (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9- dihydroxy-1 H-pyrano[3' ,4' :6,7] indolizino [1 ,2-b]quinoline-3,14-(4H ,12H)-dione monohydrochloride (also
  • NSC289491 cyclosporine A; 3-[2-[4-[bis(4-fluorophenyl)methylene]-1 -piperidinyl]-2,3- dihydro-2thioxo-4(1 H)-quinazolinone (R59949); an inhibitor of the PIK3K/Akt/mTor sig- nailing cascade, e.g., LY294002, wortmannin or rapamycin; an inhibitor of the MAPK signalling cascade, e.g.
  • the MEK1 inhibitor PD98059 a soluble guanyl cyclase stimulator such as 3-(5'hydroxymethyl-2' -furyl)-1 -benzylindazole (YC-1 ); a heat-shock protein 90 inhibitor, in particular radicicol, the radicicol analogue KF58333 or geldanamy- cin; a microtubule disrupting agent, in particular e.g. taxol, vincristine or 2- methoxyestradiol; a histone deacetylase inhibitor, e.g. FK228; a thioredoxin inhibitor, in particular PX-12 or pleurotin; UCNO-1 ; diphenylene iodonium, genestein and car- boxyamido-triazole.
  • a heat-shock protein 90 inhibitor in particular radicicol, the radicicol analogue KF58333 or geldanamy- cin
  • cytotoxic and cytostatic compounds include, but are not limited to, pure or mixed anti-estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling such as herceptin; any compound that interchelates DNA, such as doxorubicin.
  • cytostatic or cytotoxic drugs which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hor- mones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracen- diones, substituted urea, methylhydr
  • sulfaguanole sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sul- fathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tenyposide, testo- lactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, tri- aziquone, treosulfan, trimethoprim, trofosfamide, UCN-01 , vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin,
  • the compounds of the present invention can be co-administered with other active medicinal agents and/or administered in conjunction with other anticancer, antitumor, or antiproliferative disease therapies.
  • the invention provides a method for treating a hyperproliferative disease or disorder comprising administering a compound according to the invention to a patient prior to, during and/or after said patient was subjected to a radiation therapy, a chemotherapy, an immunotherapy, a la- ser/microwave thermotherapy or a gene therapy using antisense DNA and RNA (for examples see Moeller et al., Cancer Cell 2004 5429-441 ).
  • the invention provides, as already outlined above, the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the therapy, including the treatment or prevention, of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology such as e.g. diabetic retinopathy, ischemic reperfusion injury, ischemic myocardial and limb disease, ischemic stroke, sepsis and septic shock (see, e.g. Liu FQ, et al., Exp Cell Res.
  • a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology such as e.g. diabetic retinopathy, ischemic reperfusion injury, ischemic myocardial and limb disease, ischemic stroke, sepsis and septic shock (see, e.g. Liu FQ, et
  • HIF inhibitors such as the compounds of the invention, are useful to treat inflammatory disease or disorder.
  • oxygen-dependent HIF isoforms are strongly upregulated in psoriatic skin (see e.g. Rosenberger C, et al., J Invest Dermatol. 2007 Oct; 127(10):2445-52).
  • a HIF inhibitor, neovastat inhibits the airway inflammation in asthma (see e.g., Lee SY, et al., Vascul Pharmacol. 2007 Nov-Dec; 47(5-6):313-8).
  • HIF participates under hypoxic conditions in joint inflammation and destruction in rheumatoid arthritis (see e.g., Ahn, J. K., et al., Rheumatology (Oxford, United Kingdom) (2008), 47(6), 834-839).
  • the inflammatory disease is selected form the group consisting of atherosclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, psoriasis, in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichthyosis; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus ery- thematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea;
  • scleroderma alopecia areata Ophiasis type; androgenic alopecia; allergic dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foli- aceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photo
  • a further preferred embodiment of the present invention encompasses a combination of one or more compounds of the present invention and medication in current use for treating such inflammatory diseases or conditions, which can be determined by a person skilled in the art of pharmacological sciences.
  • Such therapeutics for combination can be selected e.g. from a group of anti-inflammatory steroids, antioxidants, therapeutic antibodies or fusion proteins that sequester or bind to certain cytokines or cellular epitopes associated with inflammatory processes, or a dihydrofolate reductase inhibitor like methotrexate.
  • HIF inhibitors such as the compounds of the invention are effective medicaments for the treatment of various cancer diseases (see review article by e.g. Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3 and also review article by N.J. Mabjeesh et al., His- tol. Histopathol (2007), 22:559-572).
  • the hyperproliferative disease is selected from the group consisting of a tumour or cancer disease, precancerosis, dysplasia, histiocytosis, a vascular proliferative disease and a virus-induced proliferative disease.
  • the hyperproliferative disease is a tumor or cancer disease selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lympho- cytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, glioma, bone cancer and soft-tissue sarcomas, common solid tumors of adults such
  • DLBCL diffuse large B-cell lymph
  • the precancerosis treatable with the compounds of the present invention are preferably selected from the group consisting of precancerosis, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray kera- tosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gynaecological precancerosis, in particular carcinoma ductale in situ (CDIS), cervical intraepithelial neop
  • Dysplasia is frequently a forerunner of cancer, and is can be found in e.g. the epi- thelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells.
  • Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism.
  • Dyspla- sia characteristically occurs where there exists chronic irritation or inflammation.
  • Dysplastic disorders which can be treated with the compounds of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dys- plasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epi- physialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphy
  • Estrogen receptor refers to a group of receptors which are activated by the hormone 17 ⁇ -estradiol (estrogen).
  • Estrogen Two types of estrogen receptor exist: ER which is a member of the nuclear hormone family of intracellular receptors and the estrogen G protein coupled receptor GPR30 (GPER), which is a G-protein coupled receptor.
  • Es- trogen and the estrogen receptors have been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer and endometrial cancer and other diseases.
  • the compounds of the invention are capable of inhibiting estrogen receptor-mediated transcriptional activity, they can be used to treat said diseases.
  • the hyperproliferative disorders treat- able according to the invention are those which benefit from a reduced estrogen receptor signalling, i.e. disorders associated with an increased estrogen receptor signaling, if compared to healthy tissue.
  • a reduced estrogen receptor signalling i.e. disorders associated with an increased estrogen receptor signaling
  • preferred diseases, conditions and/or disorders which can be treated are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus.
  • Whether a disease is associated an increased estrogen receptor activity can be measured by a variety of art known methods including determination of ER expression level in the diseased tissue by, e.g. immunological methods, which determine the amount of expressed protein, by methods determining the amount of transcribed ER encoding nucleic acids, e.g. RT-PCR, Northern-blots, nuclear run-ons etc., and determining the activity of a nucleic acid construct comprising an ER-receptor recognition element, which drives expression of a detectable reporter, e.g. CAT, luciferase, GFP etc as described in more detail in the Experimental Section below.
  • a detectable reporter e.g. CAT, luciferase, GFP etc
  • the disorders which benefit from a reduced estrogen receptor signaling are those, which show in the diseased tisse an increase in estrogen receptor signaling by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, if compared to healthy tissue.
  • this increase is measured on the basis of a nucleic acid comprising an ER-receptor recognition element and the increase of the expression of a reporter driven by this element.
  • the compounds utilized in the use of the invention are administered at the initial dosage of about 0.02 mg/kg to about 20 mg/kg daily.
  • a daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 1 mg/kg being most preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • a compound according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes.
  • parenteral administration and particular intravenous administration preferably by depot injection, is preferred.
  • different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.
  • a compound of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a supposi- tory, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebe- sole.
  • Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. bio- compatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if com- pared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chlo- ride may be incorporated in infusion or injection solutions.
  • preservatives e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chlo- ride may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization.
  • the above solu- tions are vacuum-dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • the following excipients can be chosen, without limitation, to be used with the various pharmaceutical forms of a compound of the invention:
  • binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hy- droxyethyl cellulose, polyvinyl pyrrolidone and the like;
  • lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates,
  • disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • suitable excipients can be found in the Handbook of Pharmaceutical Ex- cipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.
  • the average daily dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 3 g.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1 .0 to 1000 mg, preferably ranging from 10 to 500 mg preferably ranging from 50 to 200 mg.
  • the duration of therapy and the dosing frequency with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous.
  • a compound of the invention will be administered in ranges of 50 mg to 3 g, preferably 50 mg to 500 mg, if rectal or intragastric administration is used and in ranges of 10 to 500 mg, if parenteral administration is used.
  • a prophylactic administration of the pharmaceutical composition according to the invention may be possible.
  • the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diag- nosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or until they are improving.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • 2,3-Dihydrobenzazine compounds of the formula 1.1 according to the present invention have been prepared for example according to the following approaches:
  • the compounds of the formula 1.3 and 1.4 can be prepared by selective oxidation of the compounds of the formula 1.2 according to standard procedures as outlined in the following schemes:
  • Method A HPLC/MS, using a Waters X-bridge Ci8-column, 5 ⁇ particle size, 4.6 x 150 mm (diameter x length) at a flow rate of 1 .75 ml/min with a linear gradient (water to methanol, 0.2% formic acid as modifier) from initially 99:1 to 1 :99 over 9.10 min, then held for 1 .80 min. Mass signals were determined using a Waters 3100 Mass Detector.
  • Method B HPLC/MS, using a Waters X-bridge Ci8-column, 5 ⁇ particle size, 4.6 x 150 mm (diameter x length) at a flow rate of 1 .75 ml/min with a linear gradient (water to acetonitrile, 0.2% formic acid as modifier) from initially 99:1 to 1 :99 over 9.10 min, then held for 1 .80 min. Mass signals were determined using a Waters 3100 Mass Detector.
  • MCF-7 human breast adenocarcinoma cells, Caki-1 and A498 clear cell renal carcinoma cells, and PC-3 prostate adenocarcinoma cells were obtained from ATCC (LGC Promochem).
  • MIA PaCa-2 pancreatic carcinoma cells were purchased from ECACC (HPA Culture Collection).
  • the CellSensor® HRE-bla HCT1 16 cell line (colo- rectal carcinoma) was obtained from Invitrogen.
  • the HeLa cervical adenocarcinoma cell line was obtained from the Chemical Biology Core Facility (EMBL).
  • DMEM Dulbecco' s modified Eagle's medium
  • FBS fetal bovine serum
  • penicillin/streptomycin penicillin/streptomycin
  • L-glutamine 2mM L-glutamine
  • the HCT1 16 cell line was grown under the same atmospheric conditions in McCoy's 5A medium supplemented with 10% FBS and penicillin/streptomycin as above, in addition to blasticidin as a selection marker at a final concentration of 5 ⁇ g/ml.
  • ATPIite solution according to the manufacturer's instructions (PerkinElmer, ATPIite 1 - step Luminescence ATP Detection Assay System) and luciferase readout measured on an Envision HTS multilabel plate reader (PerkinElmer) in luminescence mode accord- ing to established protocols.
  • Raw data were imported into an ActivityBase database (IDBS, ID Business Solutions) and EC50 values calculated using the IDBS program ActivityBase XE.
  • ER Transfection assay To determine the effect of the compounds on estrogen receptor (ER)-mediated transcriptional activity a transfection assay using the MCF-7 cell line was performed. A luciferase-coupled ERE-tk-/uc construct was obtained from Dr. G. Reid (EMBL).
  • MCF-7 cells were maintained as described previously and seeded on the first experimental day at a concentration of 3500 cells/well in 10 ⁇ medium and incubated under standard conditions for 24h. Following this initial incubation period, transfection was carried out using 5ng of the ERE-tk-/uc construct (per well) and Exgene 500 transfection reagent (Fermentas) in a final buffered solution containing 150mM NaCI and 20mM Tris pH 8.4. The plates were then maintained for 3-4 hours until cell culture conditions in the incubator before compounds were added at 1 1 X concentrations to yield the final desired compound concentrations in 0.5% DMSO (in the same manner as for the proliferation assays described previously).
  • the compounds of the invention are capable of inhibiting estrogen receptor element-mediated transcriptional activity in an ERa - positive cell line.
  • ER-modulating agents for the treatment of breast, uterine or prostate cancer, as well as metastatic bone disease, is known in the literature.
  • HIF / HRE reporter assay Inhibition of an activated HIF signaling response under chemically-induced hypoxic conditions due to compound treatment was determined using the CellSensor® HRE-bla HCT-1 16 stably transfected reporter cell line from Invitrogen according to the manufacturer's instructions.
  • DFO deferoxamine
  • the Substrate Loading Solution was prepared as described in the manufacturer's protocol and 10 ⁇ added to each well. Following a further 2h incubation period at room temperature and in the dark, fluorescence was measured at two wavelengths (blue channel: ex. 409nm, em. 460nm; green channel: ex. 409nm, em. 530nm) on a PerkinElmer Envision HTS. For the analysis, the average signal of the cell-free wells at 460nm and 530nm was first subtracted from the blue and green channel data, respectively. The blue/green emission ratios were then calculated for each well, dividing the background-corrected blue emission values by the background- corrected green emission values. IC50 values were determined from these ratios using GraphPad Prism (Prism 5, GraphPad software, Inc.).

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Abstract

La présente invention concerne des composés inédits de 2,3-dihydrobenzazine de formule I, leurs sels pharmaceutiquement acceptables, leurs N-oxydes et les sels pharmaceutiquement acceptables desdits N-oxydes. Formule (I). X représente O ou S(=O)n, n étant égal à 0, 1 ou 2; R1 représente un groupe phényle ou un groupe hétéroaryle monocylique à 5 ou 6 chaînons lié à C, ledit groupe phényle et ledit groupe hétéroaryle monocyclique à 5 ou 6 chaînons étant non substitués ou porteurs d'1, 2 ou 3 radicaux R1a qui sont identiques ou différents; R1a est choisi dans le groupe constitué des halogènes, des groupes cyano, NO2, NH2, OH, SH, alkyle en C1-C10, alcényle en C2-C10, alcynyle en C2-C10, alkoxy en C1-C6, alkylthio en C1-C6, hydroxy-alkyle en C1-C6, alkoxy en C1-C4-alkyle en C1-C4, alkyle fluoré en C1-C2, SF5, alkoxy fluoré en C1-C2, C(O)R3, NR4R5, N(OR6)R7 et C(O)OR8, ou deux radicaux R1a, liés à des atomes de carbone adjacents, peuvent également former un groupe fonctionnel pontant O-Alk-O, dans lequel Alk est choisi parmi CH2, CH2CH2, CHF et CF2 ; R2 représente un groupe phényle ou un groupe hétéroaryle monocylique à 5 ou 6 chaînons lié à C ou N, lesdits groupes phényle et hétéroaryle monocylique à 5 ou 6 chaînons portant un radical CN et, éventuellement et en plus, 1, 2 ou 3 radicaux R2a qui sont identiques ou différents; R2a est choisi dans le groupe constitué des halogènes, des groupes cyano, NO2, NH2, OH, SH, alkyle en C1-C10, alcényle en C2-C10, alcynyle en C2-C10, alkoxy en C1-C6, alkylthio en C1-C6, hydroxy-alkyle en C1-C6, alkoxy en C1-C4-alkyle en C1-C4, alkyle fluoré en C1-C2, SF5, alkoxy fluoré en C1-C2, C(O)R3, NR4R5, N(OR6)R7 et C(O)OR8, ou deux radicaux R2a, liés à des atomes de carbone adjacents, peuvent également former un groupe fonctionnel pontant O-Alk'-O, où Alk' est choisi parmi CH2, CH2CH2, CHF et CF2 ; et R3 à R8 sont tels que définis dans les revendications et la description. L'invention concerne l'utilisation de ces composés dans le cadre thérapeutique, en particulier dans le cadre du traitement d'une maladie ou d'une affection choisie dans le groupe constitué des maladies inflammatoires, des maladies ou des troubles hyperprolifératifs, des pathologies liées à l'hypoxie et des maladies caractérisées par une hypervascularisation pathophysiologique.
PCT/EP2010/066175 2009-10-27 2010-10-26 Dérivés de 2,3-dihydrobenzoxazine et de 2,3-dihydrobenzothiazine utilisés en tant qu'inhibiteurs des hif pour le traitement du cancer et des maladies inflammatoires WO2011057892A1 (fr)

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CN103102329A (zh) * 2013-01-24 2013-05-15 华东师范大学 一种2,3-二氢-[1,4]-苯并噻嗪类化合物的合成方法
WO2013080156A1 (fr) 2011-11-30 2013-06-06 Actelion Pharmaceuticals Ltd Antibiotiques d'octahydro-2h-pyrido[4,3-e][1,3]oxazin-2-one 3,7-disubstituée
WO2020055164A1 (fr) * 2018-09-12 2020-03-19 크리스탈지노믹스(주) Dérivé de 7-hydroxy-4h-thiéno[3,2-b]pyridin-5-one et son utilisation
US11059796B2 (en) 2015-06-11 2021-07-13 The Regents Of The University Of Michigan Aryl dihydro-2H benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
WO2023274396A1 (fr) * 2021-07-02 2023-01-05 广东东阳光药业有限公司 Composé de benzazépine hétérocyclique et son utilisation en médecine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013080156A1 (fr) 2011-11-30 2013-06-06 Actelion Pharmaceuticals Ltd Antibiotiques d'octahydro-2h-pyrido[4,3-e][1,3]oxazin-2-one 3,7-disubstituée
US9029368B2 (en) 2011-11-30 2015-05-12 Actelion Pharmaceuticals Ltd. 3,7-disubstituted octahydro-2H-pyrido[4,3-E][1,3]oxazin-2-one antibiotics
CN103102329A (zh) * 2013-01-24 2013-05-15 华东师范大学 一种2,3-二氢-[1,4]-苯并噻嗪类化合物的合成方法
CN103102329B (zh) * 2013-01-24 2015-04-08 华东师范大学 一种2,3-二氢-[1,4]-苯并噻嗪类化合物的合成方法
US11059796B2 (en) 2015-06-11 2021-07-13 The Regents Of The University Of Michigan Aryl dihydro-2H benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
WO2020055164A1 (fr) * 2018-09-12 2020-03-19 크리스탈지노믹스(주) Dérivé de 7-hydroxy-4h-thiéno[3,2-b]pyridin-5-one et son utilisation
WO2023274396A1 (fr) * 2021-07-02 2023-01-05 广东东阳光药业有限公司 Composé de benzazépine hétérocyclique et son utilisation en médecine

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