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Definitions

• the present invention relates to inhibitors of sphingosine kinase and their physiologically acceptable salts, derivatives, prodrugs, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios
• the invention was based on the object, new compounds with valuable
• the present invention relates to compounds and the use of
• compositions containing these compounds are provided.
• the present invention relates to compounds of formula (I) which preferentially inhibit the enzyme sphingosine kinase 1, which regulates sphingosine phosphate levels by phosphorylation of sphingosine, compositions containing these compounds, and methods for their use in the treatment of diseases and conditions such as cancer, tumorigenesis, growth and spread, arteriosclerosis, eye diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, heart disease, wound healing or graft rejection.
• diseases and conditions such as cancer, tumorigenesis, growth and spread, arteriosclerosis, eye diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, heart disease, wound healing or graft rejection.
• Sphingosine phosphate belongs to the family of sphingolipids which, in addition to their role as structural building blocks of cell membranes, also perform important functions as extracellular and intracellular signaling molecules.
• Sphingosine phosphate (S1P) is produced in the cell from sphingomyelin, which is first degraded to ceramide and sphingosine and the latter is phosphorylated by sphingosine kinases.
• SphK1 sphingosine kinase 1
• sphingosine phosphate has an adverse effect on the cell and increases the resistance to apoptosis, cell growth and the release of messengers that increase blood flow
• Angiogenesis is an important process in tumor growth, from which new blood vessels are formed from existing blood vessels, thus ensuring the supply of nutrients to the tumor. For this reason, the inhibition of angiogenesis is an important starting point for cancer and tumor therapy. (Folkman, 2007, Nature Reviews Drug Discovery Vol. 6, pages 273-286).
• S1P stimulates chemotactic movement of endothelial cells and induces differentiation into multicellular structures, both early steps in the formation of new blood vessels (Lee et al., 1999 Biochem Biophys Res Commun Vol 264 page 325, Argraves et al., 2004 J Biol Chem Vol 279, page 50580 ).
• S1 P promotes the migration of bone marrow-derived endothelial progenitor cells to neovascular initiation sites (Annabi et al., 2003, 2003, Hematology Vol 31, 640), and transactivates the receptor of VEGF, one of the most important pro-angiogenic factors, in particular in the
• S1P also has intracellular functions, such as the activation of the transcription factor NF- ⁇ , which plays a major role in the apoptosis resistance of cancer cells (Xia et al., 2002 J Biol Chem Vol 277, page 7996). However, the intracellular interaction partners of S1P have not yet been identified.
• SphK1 can thus be classified as an oncogene.
• SphK1 plays an important role in the modulation of chemotherapeutic induced apoptosis of cancer cells. So increases through
• SphK1 Overexpression of SphK1 the resistance of breast cancer, prostate cancer and leukemia cells to chemotherapeutic agents such as anthracyclines, docetaxel, Camptothecin or doxorubicin (Nava et al 2002 Exp Cell Res Vol 281 page 115; Pchejetski 2005 Cancer Res Vol 65 p 11667; Bonhoure 2006 Leukemia Vol 20 p 95). It could be shown that the increased presence of SphK1 leads to a shift of the ceramide / S1 P equilibrium in the direction of the chemotherapeutic agents such as anthracyclines, docetaxel, Camptothecin or doxorubicin (Nava et al 2002 Exp Cell Res Vol 281 page 115; Pchejetski 2005 Cancer Res Vol 65 p 11667; Bonhoure 2006 Leukemia Vol 20 p 95). It could be shown that the increased presence of SphK1 leads to a shift of the ceramide / S1 P equilibrium in the direction of the chemo
• apoptosis resistance-promoting S1 P leads.
• One possible mechanism is the inhibition of mitochondrial cytochrome C ejection by SphK1, which is usually an early event in programmed cell death (Cuvilier et al 2001 Blood Vol 98 page 2828, Bonhoure 2006 Leukemia Vol 20 page 95).
• glioblastoma or prostate cancer trigger apoptosis or increase the efficacy of chemotherapeutic agents (Bonhoure 2006 Leukemia Vol 20 page 95, Taha et al 2004 J Biol Chem Vol 279 page 20546; Taha et al 2006 FASEB J Vol 20 Page 482; Van Brocklyn et al., 2005 J Neuropathol Exp Neural Vol. 64, page 695; Pchejetski, 2005 Cancer Res Vol 65, page 11667).
• S1 P signaling pathway in heart diseases is also supported by the fact that in mice in which the expression of the S1 P3 receptor was deliberately suppressed, the formation of cardiovascular fibroses is strongly inhibited (Takuwa 2008 Biochimica and Biophysica Acta in press). In other organs, such as the lungs, S1P also plays a role in the differentiation of fibroblasts into myofibroblasts and thus in the development and progression of fibrous diseases (Kono et al., 2007, J J Respir Cell Mol Biol, page 395).
• the compounds according to the invention cause specific inhibition of sphingosine kinase 1, but not sphingosine kinase 2.
• the compounds of the invention preferably exhibit a beneficial biological activity that is detectable in the assays described, for example, herein.
• the compounds of the present invention exhibit and effect an inhibiting effect, usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
• IC 50 values usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
• all solid and non-solid tumors can be treated with the compounds of formula (I), such as monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal, ovarian, and lung carcinoma, among them
• Lung adenocarcinoma and small cell lung carcinoma include prostate, pancreatic and breast carcinoma.
• the compounds of the invention are useful in the prophylaxis and / or treatment of diseases that are affected by inhibition of SphK1.
• the host or patient may belong to any mammalian species, e.g. one
• the sensitivity of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro.
• a culture of the cell is combined with a compound of the invention at various concentrations for a time sufficient to allow the active agents to lower the intracellular S1P concentration and, in addition, to block the secretion of angiogenesis promoting substances or to induce cell death .
• cultured cells from a biopsy specimen or established cancer cell lines expressing SphK1 can be used.
• the dose varies depending on the specific compound used, the specific disease, the patient status, etc. Typically, one
• the treatment is generally continued until there is a significant reduction, eg, at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells can be detected in the body.
• Lymphatic, gastric, laryngeal, ovarian and lung carcinoma including
• Lung adenocarcinoma and small cell lung carcinoma include colon, prostate, pancreas and breast carcinoma.
• angiogenesis In addition to the function of cell growth, S1 P also plays a role in the formation of new blood vessels (angiogenesis). In many disease processes, angiogenesis is either causally at the heart of the disease or worsens the progression of the disease. For example, in
• angiogenesis causes the tumor to enlarge and spread to other organs.
• Other diseases in which angiogenesis plays an important role are psoriasis, arthrosis, arteriosclerosis and eye diseases such as diabetic retinopathy, age-related macular degeneration, rubeosis iridis or neovascular glaucoma.
• the basis of this invention compounds of the formula I which inhibit SphK1 and thus regulate and / or modulate the S1P level, compositions containing them
• Contain compounds, and the methods described can thus be used for the treatment of these diseases.
• SphK1 and S1P influence the proliferation, differentiation, migration and secretion of immune cells (Rosen and Goetzl 2005 Nat Rev Immunol Vol. 5 page 560) and are thus involved in various functions of the immune system
• SphK1 Platelet cells and some mononuclear phagocytes (Stunff et al 2004 J Cell Biochem Vol 92 p 882, Olivera and Rivera 2005 j Immunol Vol 174 p 1153).
• the activity of SphK1 is greatly enhanced, in particular, by factors such as tumor necrosis factor (TNF) and cross-linking of IgG receptors (Stunff et al., 2004 J Cell Biochem Vol. 92, page 882, Delon et al., 2004 J Biol Chem Vol 279 page 44763).
• TNF tumor necrosis factor
• SphK1 and S1P are important for the TNF-dependent production of proinflammatory enzymes such as cyclooxygenase-2 (COX-2) and nitric oxide synthase (NOS) (Pettus et al., 2003 FASEB J Vol 17, 1411; et al., 2001 J Biol Chem Vol. 276, pages 10627-33).
• COX-2 cyclooxygenase-2
• NOS nitric oxide synthase
• compositions containing these compounds as well as the methods described can thus be used for the treatment of inflammatory diseases such as arthrosis, arteriosclerosis, psoriasis, multiple sclerosis, chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis), asthma and other allergic diseases.
• inflammatory diseases such as arthrosis, arteriosclerosis, psoriasis, multiple sclerosis, chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis), asthma and other allergic diseases.
• the compounds of formula (I) can be used to isolate and study the activity or expression of Sph kinase. In addition, they are particularly suitable for use in diagnostics.
• the compounds according to the invention have an in vivo antiproliferative action in a xenograft tumor model.
• the Compounds of the invention are administered to a patient with a
• hyperproliferative disease e.g. for the inhibition of
• Tumor growth to reduce inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection or neurological damage due to tissue repair, etc.
• the present compounds are useful for prophylactic or therapeutic purposes.
• the term "treating" is used to refer to both the prevention of disease and the treatment of pre-existing conditions
• the prevention of proliferation is prevented by the administration of the compounds of the invention against the development of obvious disease, for example to prevent tumor growth, prevent metastasis Growth, the reduction of cardiovascular surgery-related restenosis, etc.
• the compounds are treated
• the host or patient may belong to any mammalian species, e.g. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they are a model for
• the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted.
• the dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, one therapeutic dose will be sufficient to treat the undesired cell population in the human body
• Target tissues decrease significantly while the patient's viability is maintained.
• the treatment is generally continued until there is a significant reduction, eg, at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
• interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105).
• the compounds according to the invention can also be used as reagents for testing kinase-dependent
• interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105).
• the compounds according to the invention can also be used as reagents for testing kinase-dependent
• Another non-radioactive ELISA assay method uses a specific antibody against S1 P to quantify S1 P (Assay System from Echelon).
• the compounds of the invention are useful in the treatment of a variety of conditions involving smooth muscle cell proliferation and / or migration and / or
• Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation,
• WO 2005/103022 describes substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators.
• WO 2006/73167 describes pyrrolidine derivatives.
• pyridine pyrimidine and pyrazine derivatives are described as CXCR3 receptor modulators.
• the invention relates to compounds of the formula (I)
• R 9 and R 1 , R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , R 10 and R 11 , R 11 and R 12 , R 2 and R 13 , R 14 and R 15 , R 15 and R 16 , R 16 and R 17 together are each also cyclic alkyl with 3,
• C (O) N (R 19 ) (R 19 ' ) or N (R 19 ) (R 19' ) may be replaced, or Het with 3, 4, 5, 6 or 7 ring atoms can form, wherein Het preferably a saturated , unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, F, Cl, Br, CN, A, OR 18 , W, SR 18 , N0 2 ,
• Carbonyl oxygen may be substituted
• A is unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, wherein 1, 2, 3, 4, 5, 6 or 7 H atoms by F, Cl , Br, CN and / or OH, OR 19 , OC (O) R 19 , NR 19 C (O) OZ, C (O) OR 19 ,
• Ar is mono-, di- or trisubstituted by Hal, F, Cl, Br, CN, A, OR 18 , W, SR 18 , NO 2 , N (R 19 ) (R 19 ), NR 18 COOZ, OCONHZ, NR 18 S0 2 Z, S0 2 N (R 18) Z, S (0) m Z, COZ, CHO, COZ substituted phenyl, naphthyl or biphenyl,
• n, o is 0, 1 or 2
• p 0, 1, 2, 3 or 4
• the invention further relates to preferred independent embodiments of compounds according to formula (I), wherein each independently of one another means:
• R 9 and R 1 , R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , R 10 and R 11 , R 11 and R 12 , R 12 and R 13 , R 14 and R 5 , R 15 and R 16 , R 16 and R 17 together are each also cyclic alkyl having 3, 4, 5, 6 or 7 C. Atoms or Het with 3, 4, 5, 6 or 7 ring atoms can form;
• Embodiment (E) Mi O, and M 2 N and M 3 CR 19
• Embodiment (G) Mi S, and M 2 N and M 3 N;
• Embodiment (I) Mi O, and M 2 N and M 3 N;
• Embodiment (J) N, and M 2 N and M 3 O;
• Preferred embodiment (K) N, and M 2 N and M 3 S;
• Embodiment (L) CR 19 , and M 2 N and M 3 O;
• Embodiment (M) CR 19 , and M 2 O and M 3 N;
• N N, and Y 2 CR 19 ;
• Preferred Embodiment (O) YN, and Y 2 N
• Preferred Embodiment (P) CR 19 , and Y 2 N;
• Preferred Embodiment (T): Z is Het or A;
• V Preferred embodiment (V): p 0, 1, 2 or 3;
• R 9 and R 1 , R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , R 0 and R 1 , R 11 and R 12 , R 12 and R 13 , R 14 and R 15 , R 15 and R 16 , R 16 and R 17 together are each also cyclic alkyl having 3, 4, 5, 6 or 7 C. Atoms or Het with 3, 4, 5, 6 or 7 ring atoms can form;
• V, W and Y 2 together are each also cyclic alkyl having 3, 4, 5, 6 or 7 C atoms, wherein preferably 1, 2, 3, 4, 5, 6 or 7 H atoms by F, Cl, Br , CN and / or OH, OR 19 , OC (O) R 19 , NR 19 C (O) OZ, C (O) OR 19 ,
• C (O) N (R 19 ) (R 19 ' ) or N (R 19 ) (R 19' ) may be replaced, or Het with 3, 4, 5, 6 or 7 ring atoms can form, wherein Het preferably a saturated , unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal, F, Cl, Br, CN, A, OR 18 , W, SR 18 , N0 2 ,
• Carbonyl oxygen may be substituted
• p 0, 1, 2 or 3;
• the invention further relates to compounds selected from the group consisting of:
• the invention also provides the precursors of the compounds of the formula (I), medicaments containing these compounds and their use for the treatment of diseases, as described for the compounds of the formula (I).
• the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
• Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
• prodrug compounds are understood, for example, as so-called prodrug compounds. Under prodrug derivatives is understood with z.
• alkyl or acyl groups amino acids, sugars or oligopeptides modified compounds of formula (I), which are rapidly cleaved in the organism to the active compounds of the invention.
• biodegradable polymer derivatives of the compounds of the invention as z. In Int. J. Pharm. 115, 61-67 (1995).
• the term "effective amount” means the amount of a drug or pharmaceutical agent that has a biological or medical response in it a tissue, system, animal or human being, for example, sought or sought by a researcher or physician.
• terapéuticaally effective amount means an amount that, as compared to a corresponding subject who has not received that amount, results in:
• terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
• the invention also provides the use of mixtures of
• the invention further relates to a process for the preparation of compounds according to the formula (I) and the preferred embodiments and disclosed compounds shown here, as well as their physiologically acceptable salts,
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 7 , R 8 , R 9 and m are those given herein
• L 2 is the meaning given below has "VH” possibly provided with a protective group ("V-protection group”), and if necessary still below specified connection steps are carried out,
• V-protective group if necessary freed from the protective group ("V-protective group") and with a
• W has the meaning given herein and L is Cl, Br, I or a free or reactively functionally modified OH group,
• A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
• A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4- Methylpentyl, 1-, 1-, 1-, 2-, 1-, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1- Ethyl 2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl, more preferably, for example, trifluoromethyl.
• Cyclic alkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl , o-, m- or p- (N-methylamino) -phenyl
• heterocyclic radicals may also be partially or completely hydrogenated. Regardless of other substitutions Het can thus z. B. also mean 2,3-dihydro
• 3,4-dihydro-2H-benzo [1,4] oxazinyl more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2 , 3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2- oxo-1 / - / - quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,3-d
• the compounds of formula (I) may possess one or more chiral centers and therefore exist in different stereoisomeric forms.
• Formula (I) encompasses all these forms.
• the starting compounds of the formulas (II), (III), (IV) and (V) are generally known. If they are new, they can be produced by methods known per se. The conversion to the compounds of the formula (I) is generally carried out in
• an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.
• an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or Alkaline earth metals preferably potassium, sodium, calcium or cesium may be beneficial.
• the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane,
• Trichlorethylene 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane
• Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol
• Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane
• THF tetrahydrofuran
• Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or
• esters such as ethyl acetate or mixtures of said solvents.
• acetonitrile particularly preferred is acetonitrile, dichloromethane and / or DMF.
• Alkylate alkyl halide suitably in an inert solvent such as
• Preferred starting materials for the solvolysis or hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxyl groups, corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom, are bonded to an N atom is to carry an amino protecting group, for.
• starting materials are preferred, which instead of the H atom of a
• Hydroxy group carry a hydroxy protecting group, for.
• amino protecting group is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups after the
• acyl group is to be understood in the broadest sense in the context of the present process. It encloses of aliphatic,
• alkanoyl such as acetyl, propionyl, butyryl
• Aralkanoyl such as phenylacetyl
• Aroyl such as benzoyl or toluyl
• Aryloxyalkanoyl such as POA
• Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl
• Aralkyloxycarbonyl such as CBZ
• Carbobenzoxy 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr, Pbf or Pmc.
• Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
• hydroxy protecting group is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out at other sites on the molecule. Typical for such Groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups.
• the nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms. Examples of hydroxy protecting groups include tert.
• Aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg Asp (OBut)).
• inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or
• organic for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and
• carboxylic acids such as acetic acid
• ethers such as tetrahydrofuran or dioxane
• amides such as DMF
• halogenated hydrocarbons such as dichloromethane
• alcohols such as methanol, ethanol or isopropanol
• reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
• the groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
• Hydrogenolytically removable protecting groups e.g CBZ or benzyl
• a catalyst e.g.
• Noble metal catalyst such as palladium, conveniently on a support such as carbon
• Suitable solvents are those given above, in particular z.
• alcohols such as methanol or ethanol or ethers such as THF.
• the hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds z.
• the abovementioned compounds according to the invention can be used in their final non-salt form.
• the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
• Pharmaceutically acceptable salt forms of the compounds of formula (I) are for the most part prepared conventionally. If the compound of the formula (I) contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
• bases include, for example, alkali metal hydroxides, including potassium hydroxide,
• Sodium hydroxide and lithium hydroxide Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and
• Forming acid addition salts by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and
• pharmaceutically acceptable organic and inorganic acids e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and
• Benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, too pharmaceutical
• acceptable acid addition salts of the compounds of the formula (I) the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, Bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, Hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
• the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -, sodium and zinc salts, but no
• Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g.
• Arginine betaine, caffeine, chloroprocaine, choline, ⁇ , ⁇ '-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, Histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) - methylamine (tromethamine), which is not intended to be limiting.
• Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4) alkyl halides, e.g. Methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di-1-alkylsulfates, e.g.
• compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate,
• Hydrochloride hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, phosphate, stearate, sulphate, sulphosalicylate, tartrate, thiomalate, tosylate and
• Tromethamine which is not intended to be limiting. Particularly preferred are hydrochloride, dihydrochloride, hydrobromide, maleate,
• the acid addition salts of basic compounds of formula (I) are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
• the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
• the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
• the pharmaceutically acceptable base addition salts of the compounds of formula (I) with metals or amines such as alkali metals and
• Preferred metals are sodium, potassium, magnesium and calcium.
• Preferred organic amines are ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
• the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
• the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
• the free acid forms differ in some sense from their corresponding salt forms in relation to certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms. If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
• pharmaceutically acceptable salt as used herein means an active ingredient containing a compound of formula (I) in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the drug that has been used previously confers improved pharmacokinetic properties.
• the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
• a corresponding use for the manufacture of a medicament for the treatment and / or prophylaxis of the aforementioned conditions is intended to be included.
• compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• a unit may, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a novel
• compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof, of an active ingredient. Furthermore, such pharmaceutical
• compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
• Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
• Pharmaceutical formulations adapted for oral administration may be presented as separate entities, such as capsules or tablets; Powder or granules;
• Solutions or suspensions in aqueous or non-aqueous liquids comprising edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• the active ingredient component in the form of a tablet or capsule, can be mixed with an oral, non-toxic and
• powders are prepared by comminuting the compound to a suitable fine size and comminuting it in a similar manner
• compositions e.g. an edible carbohydrate such as starch or annit.
• a flavor, preservative, dispersant and dye may also be present.
• Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
• Lubricants such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
• a disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
• suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
• suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethylcellulose,
• the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.
• a powder mixture is produced, by suitably comminuting the compound with a diluent or a base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer such as paraffin, a resorption accelerator such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate.
• the powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulosic or polymeric materials and pressing through a sieve.
• a binder such as syrup, starch paste, Acadia slime or solutions of cellulosic or polymeric materials
• Run tableting machine resulting in irregularly shaped lumps, which are broken up into granules.
• the granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
• the greased mixture is then compressed into tablets.
• the compounds according to the invention can also be combined with a free-flowing inert carrier and then without carrying out the
• a transparent or opaque protective layer consisting of a
• Shellac sealant a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
• Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
• Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
• Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
• Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.
• the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
• the formulation can be also prepare so that the release is prolonged or retarded, such as
• the compounds of formula (I) as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, e.g. small unilamellar vesicles, large unilamellar vesicles and
• Liposomes can be different
• Phospholipids e.g. Cholesterol, stearylamine or phosphatidylcholines.
• the compounds of formula (I) as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds can also be coupled with soluble polymers as targeted drug carriers.
• Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
• the compounds can be attached to a class of biodegradable
• Polymers suitable for the controlled release of a drug e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
• Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
• the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
• the formulations are preferably applied as a topical ointment or cream.
• the active ingredient can be used with either a paraffinic or water miscible cream base.
• the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
• the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
• compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
• compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
• compositions adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by
• Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
• Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
• compositions adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes, foams or
• Spray formulations are presented.
• Formulations include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
• the formulations may be administered in single or multi-dose containers, e.g. sealed ampoules and vials, presented and freeze-dried
• Carrier liquid e.g. Water for injections, needed immediately before use.
• Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
• formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
• a therapeutically effective amount of a compound of formula (I) will depend on a number of factors, including e.g. the age and weight, the exact state of the disease requiring treatment, and the severity of the disease
• an effective amount of a compound of the invention is for the treatment of neoplastic
• Growth eg, colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg body weight per day.
• the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
• An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se.
• the invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to the formula (I) and the preferred embodiments and disclosed compounds illustrated herein.
• composition as claimed herein containing at least one additional compound selected from the group consisting of physiologically acceptable extenders, excipients, additives, diluents, carriers and / or additional pharmaceutically active substance other than the compounds according to formula (I) and the preferred embodiments shown herein and disclosed compounds.
• the invention also provides a kit comprising a therapeutically effective amount of at least one compound according to formula (I) and the preferred embodiments and disclosed compounds and / or at least one pharmaceutical composition as shown herein and a therapeutically effective amount of at least one other pharmacologically active Substance other than the compounds of formula (I) and the preferred embodiments and disclosed compounds illustrated herein.
• the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
• the set may e.g. containing separate ampoules, in each of which an effective amount of a compound of formula (I) and / or its pharmaceutically acceptable derivatives, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance are dissolved or lyophilized Form is present.
• the instant compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of sphingosine kinase-related diseases. These diseases include the proliferation of tumor cells, the pathological neovascularization (or angiogenesis) that causes the proliferation of tumor cells, the pathological neovascularization (or angiogenesis) that causes the proliferation of tumor cells, the pathological neovascularization (or angiogenesis) that causes the proliferation of tumor cells, the pathological neovascularization (or angiogenesis) that causes the
• the present invention comprises the use of the compounds of formula (I) and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer.
• Preferred carcinomas for the treatment are from the group of brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma.
• Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, prostate cancer, colon cancer, pancreatic cancer, ovarian cancer, kidney cancer, liver carcinoma,
• angiogenesis is an eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration, and the like.
• inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction, and the like.
• a medicament for treating or preventing a disease or a disease in a mammal which method comprises treating a diseased mammal in need of such treatment with a therapeutically effective amount of a mammal
• the administered compound of the invention depends on the particular disease and can be determined by the skilled person without too much effort.
• the present invention also encompasses the use of compounds of the formula (I) and / or their physiologically acceptable salts and solvates
• Diabetic retinopathy and age-related macular degeneration are also part of the invention.
• the compounds of formula (I) may be administered to patients for the treatment of cancer, especially fast growing tumors.
• the invention thus relates to the use of compounds of the formula I, and their pharmaceutically usable derivatives, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or Modulation of signal transduction of kinases plays a role. Preference is given here to the Sph kinase.
• Inhibition of SphK 1 can be influenced by the compounds according to formula (I) and the preferred embodiments and disclosed compounds illustrated herein.
• the diseases to be treated are preferably selected from the group hyperproliferative disease, inflammatory disease, angiogenic
• the hyperproliferative disease is preferably selected from the group Cancer (tumor disease), atherosclerosis, restenosis, proliferative disease of the mesangial cells, psoriasis.
• the tumor disease is preferably selected from the group
• the proliferative disease of the mesangial cells is preferably selected from the group
• Glomerulonephritis diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, glomerulopathy.
• the inflammatory disease is preferably selected from the group of inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergies, inflammatory kidney disease, multiple sclerosis, chronic obstructive
• Pulmonary disease inflammatory skin diseases, Pardontal diseases, psoriasis, T cell-mediated immune disease.
• Inflammatory bowel disease is preferably selected from the group ulcerative colitis, Crohn's disease, undetermined colitis.
• the T-cell mediated immune disease is preferably selected from the group
• allergic encephalomyelitis allergic neuritis, transplant rejection, graft-versus-host reaction, myocarditis, thyroiditis, nephritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus.
• the arthritis disorder is preferably selected from the group Rheumatoid arthritis, osteoarthritis, Caplan syndrome, Felty syndrome, Sjögren syndrome, ankylosing spondylitis, Still's disease, chondrocalcinosis, metabolic arthritis, rheumatic fever, Reiter's disease, Wissler syndrome.
• the inflammatory kidney disease is preferably selected from the group
• Glomerulonephritis glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture syndrome, Wegener's granulomatosis,
• the inflammatory skin disease is preferably selected from the group
• Psoriasis atopic dermatitis, contact sensitivity, acne.
• the angiogenic disorder is preferably selected from the group of diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi's sarcoma, hemangioma, myocardial angiogenesis, atherosclerotic plaque neovascularization, angiogenic eye diseases, choroidal neovascularization, retrolental fibroplasia, macular degeneration, corneal graft rejection, rubeosis iridis, neurosculares Glaucoma, Oster Webber syndrome.
• the invention furthermore relates to medicaments comprising one or more
• the invention furthermore relates to medicaments comprising one or more compounds of the formula (I) and preferred embodiments and disclosed compounds as well as their physiologically acceptable salts, derivatives, prodrugs, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for use in the treatment of diseases which are affected by inhibition of Sph kinase 1 by the compounds according to formula (I) and and the embodiments and disclosed compounds presented herein, which are to be treated
• Diseases selected from the group consisting of: "hyperproliferative disease, inflammatory disease, angiogenic disease, fibrotic Lung, kidney, liver and heart disease, cancer (tumor disease), atherosclerosis, restenosis, mesangial cell proliferative disease,
• Psoriasis tumor of the squamous epithelium, bladder, stomach, kidneys, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach , larynx, lungs, skin, monocytic leukemia,
• Lung adenocarcinoma small cell lung carcinoma, pancreatic cancer, glioblastoma, breast carcinoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glomerulonephritis, diabetic
• Pardontal diseases T cell-mediated immune disease, ulcerative colitis, Crohn's disease, indeterminate colitis, allergic encephalomyelitis, allergic neuritis, graft rejection, graft-versus-host disease,
• insulin dependent diabetes mellitus rheumatoid arthritis, osteoarthritis, Caplan syndrome, Felty syndrome, Sjögren syndrome, ankylosing spondylitis, Still's disease, chondrocalcinosis, metabolic arthritis, rheumatic fever, Reiter's disease, Wissler syndrome, glomerulonephritis, glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture syndrome, Wegener's granulomatosis, renal vasculitis, IgA nephropathy, idiopathic glomerular disease, atopic dermatitis, contact sensitivity, acne, diabetic
• Retinopathy Kaposi's sarcoma, hemangioma, myocardial angiogenesis,
• medicaments comprising one or more compounds of the formula (I) and the preferred embodiments and disclosed compounds illustrated herein and their physiologically acceptable salts, derivatives, prodrugs, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for use in the treatment of diseases which are affected by inhibition of Sph kinase 1 by the compounds according to formula (I) and the embodiments and compounds disclosed herein, wherein the diseases to be treated are selected from the group consisting of:
• fibrotic disease of the lung kidney, liver and heart, cancer (tumor disease), atherosclerosis, restenosis, proliferative disease of the mesangial cells, psoriasis, squamous cell tumor, bladder, stomach, kidney, head and neck, esophagus , the cervix, the
• Leukemia chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,
• Glomerulopathy inflammatory bowel disease, arthritis, asthma, allergies, inflammatory kidney disease, multiple sclerosis, chronic obstructive
• Lung disease inflammatory skin diseases, Pardontal diseases, T-cell mediated immune disease, ulcerative colitis, Crohn's disease, indefinite colitis, allergic encephalomyelitis, allergic neuritis,
• Glomerulonephritis glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture syndrome, Wegener's granulomatosis, renal vascular tis, IgA nephropathy, idiopathic glomerular disease, atopic Dermatitis, contact sensitivity, acne, diabetic retinopathy, Kaposi's sarcoma, hemangioma, myocardial angiogenesis, atherosclerotic plaque neovascularization, angiogenic eye disease, choroidal neovascularization, retrolental fibroplasia, macular degeneration, corneal graft rejection, rubeosis iridis, neuroscular glaucoma, Oster Webber syndrome
• Treatment of said disorders comprising administering one or more of the compounds of the invention to a patient in need of such administration. should be included here.
• such a drug contains at least one additional pharmacologically active substance (therapeutic agent, medicament, ingredient).
• the drug is applied before and / or during and / or after treatment with at least one additional pharmacologically active substance.
• anticancer agent refers to any agent that is administered to a patient with cancer for the purpose of treating the cancer.
• anticancer treatment as defined herein may be used as a sole therapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compound of the present invention.
• Such chemotherapy may include one or more of the following categories of anti-tumor agents:
• antiproliferative / antineoplastic / DNA damaging agents and combinations thereof as used in medical oncology such as alkylating agents (for example cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
• alkylating agents for example cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas
• Antimetabolites e.g., antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate,
• Anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, Idarubicin, mitomycin C, dactinomycin and ithramycin
• antimitotic agents for example vinca alkaloids, such as vincristine, vinblastine, vindesine and vinorelbine, and
• Taxoids such as Taxol and Taxoter
• Topoisomerase inhibitors for example
• Epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell differentiating agents (for example, alkrans-retinoic acid, 13-cis-retinoic acid and fenretinide);
• cytostatic agents such as anti-estrogens (eg tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfen), the estrogen receptor downregulating agents (eg fulvestrant), anti-androgens (eg bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH Antagonists or LHRH agonists (for example
• Goserelin, leuprorelin and buserelin Goserelin, leuprorelin and buserelin), progesterone (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase, such as finasteride;
• progesterone for example megestrol acetate
• aromatase inhibitors for example anastrozole, letrozole, vorazole and exemestane
• inhibitors of 5a-reductase such as finasteride
• agents that inhibit the invasion of cancer cells for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function;
• inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example, the anti-erbb2 antibody trastuzumab [Herceptin TM] and the anti-erbb1 antibody cetuximab [C225]), Farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example inhibitors of the tyrosine kinases of the EGFR family, such as N- (3-chloro-4-fluorophenyl) -7- methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774 ) and 6-acryl
• antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, the vascular endothelial cell growth factor bevacizumab antibody [Avastin TM], compounds such as those disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds which act by other mechanisms (for example, linomide, inhibitors of integrin-av ⁇ 3 function and angiostatin); (vi) vascular damaging agents such as combretastatin A4 and in the
• antisense therapies for example, those directed against the targets listed above, such as ISIS 2503, an anti-Ras antisense;
• GDEPT gene-directed enzyme pro-drug therapy
• Chemotherapy or radiation therapy such as multi-drug resistance gene therapy
• immunotherapy approaches including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to reducing T Cell anergy, batches using transfected immune cells such as cytokine-transfected dendritic cells, batches using cytokine-transfected tumor cell lines, and anti-idiotypic antibody approaches.
• cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
• approaches to reducing T Cell anergy batches using transfected immune cells such as cytokine-transfected dendritic cells, batches using cytokine-transfected tumor cell lines, and anti-idiotypic antibody approaches.
• the drugs of the following include, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin
• Paclitaxel SB 408075 (GlaxoSmithKline)
• Rhizoxin (Fujisawa) ER-86526 (Eisai)
• Cryptophycin 52 (Eli Lilly) AVLB (Prescient NeuroPharm; Vinflunin (Fabre) Azaepothilone B (BMS) Auristatin PE (Teikoku Hormor BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4 prodrug (OXiGENE) BMS 184476 (BMS) Dolastatin -10 (NrH)
• Taxoprexin (Protarga)
• Aromatase Inhibitors Aminoglutethimide Exemestane
• Histone acetyl trans-Tacedinalin Pfizer
• pivaloyloxymethyl butyrate Teitai ferase inhibitors SAHA (Aton Pharma) depsipeptide (Fujisawa)
• Marimastat British Biotech
• BMS-275291 Celltech
• Tamoxifen 2-Methoxyestradiol EntreMed Toremofin Arzoxifen (Eli Lilly)
• Theralux (Theratechnologies) Lutetium Texaphyrin
• Bryostatin-1 (PKC stimulant, ILEX Oncology)
• Urocidin apoptosis promoter
• CDA-II Apoptosis promoter, Bioniche
• SDX-101 (apoptosis promoter, La Roche)
• Cyanomorpholinodoxorubicin GPX-100 (Gern Pharmaceutic Mitoxantrone (Novantron)
• Paclitaxel SB 408075 (GlaxoSmithKline)
• TXD 258 (Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG Paclitaxel (Enzone) T 900607 (Tularik) AZ10992 (Asahi)
• Cryptophycin 52 (Eli Lilly) AVLB (Prescient NeuroPharm Vinflunin (Fabre) Azaepothilone B (BMS) Auristatin PE (Teikoku Hormor BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4 prodrug (OXiGENE) BMS 184476 (BMS) Dolastatin 10 (NrH)
• Taxoprexin (Protarga)
• Aromatase Inhibitors Aminoglutethimide Exemestane
• Marimastat British Biotech
• BMS-275291 Celltech
• Tamoxifen 2-Methoxyestradiol EntreMed Toremofin Arzoxifen (Eli Lilly)
• Theralux (Theratechnologies) Lutetium Texaphyrin
• Tocladesin cyclic AMP ranibirnase (ribonuclease)
• CDA-II apoptosis promoter, brostallicin (apoptosis promoter) Everlife
• Such joint treatment can be achieved by simultaneously, sequentially or separately dosing the individual components of the treatment.
• Such combination products employ the compounds of the invention.
• the invention relates to compounds selected from the group consisting of:
• “usual work up” means: if necessary, remove the solvent, add water if necessary, adjust to pH values between 2 and 10, if necessary, to the final product, extracted with ethyl acetate or dichloromethane, separated, the organic phase is washed with saturated NaHC0 3 solution, optionally with water and saturated NaCl solution, the organic phase is dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel, by preparative HPLC and / or by crystallization The purified compounds are optionally freeze-dried.
• MS Mass spectrometry
• reaction mixture was diluted with water and extracted three times with ethyl acetate.
• the combined organic phases were washed with saturated NaHC0 3 solution and saturated NaCl solution, dried over Na 2 S0 4 and evaporated.
• the residue was chromatographed on silica gel by column chromatography.
• the preparation is carried out as described above starting from 3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the reaction mixture was irradiated for 3 hours at 60 ° C in the microwave. After cooling, the reaction mixture was concentrated, treated with water, the residue was filtered off with suction and washed with a little water.
• the reaction with the bromocarbonyl compound is carried out as described above.
• the preparation is carried out as described above starting from piperidine-4-ylmethyl-carbamic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out as described above starting from pyrrolidin-3-yl-carbamic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out as described above starting from (2-piperidin-4-yl-ethyl) -carbamic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out as described above starting from 4-piperidin-4-yl-morpholines.
• the preparation is carried out as described above starting from 3,9-diazaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out as described above starting from 3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• Product is available as hydrochloride.
• the preparation is carried out as described above starting from 3-piperidin-4-yl-propan-1-ol.
• the preparation is carried out as described above starting from 2-piperidine-3-yl-ethanol.
• the preparation is carried out as described above starting from 3-piperidin-3-yl-propan-1-ol.
• the preparation is carried out as described above starting from 3-piperazin-1-yl-propane-1, 2-diol.
• the preparation is carried out as described above starting from dimethylpiperidin-4-yl-amines.
• the preparation is carried out as described above starting from (4-carbamoylcyclohexyl) -carbamic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out as described above starting from 2-piperazine-1-yl-cyclohexanol.
• the preparation is carried out as described above starting from piperazine 1-carboxylic acid tert-butyl ester.
• the cleavage of the Boc protective group is carried out as described with 4 N HCl in dioxane.
• the preparation is carried out starting from 3- [4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -thiazol-2-yl] -piperidine hydrobromide and Chloropropan-1-ol.
• the product is present as hydrochloride.
• the product is available as TFA salt.
• the reaction mixture was stirred at room temperature and then concentrated.
• the product was purified by preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
• the preparation is carried out starting from 4- (5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl) -2-pyrrolidin-3-yl-thiazole hydrobromide and 4-bromo-butyl acetate.
• the deprotection is carried out by means of a 1 N NaOH solution in Methanol.
• the product was purified by preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
• the preparation is carried out starting from 3- [4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -thiazol-2-yl] -piperidine hydrobromide and Chloropentyl acetate.
• the deprotection is carried out by means of a 1 N NaOH solution in methanol.
• the product was purified by preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
• the preparation is carried out starting from 3- [4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -thiazol-2-yl] -piperidine hydrobromide and Bromobutyl acetate.
• the deprotection is carried out as described by means of a 1 N NaOH solution in methanol.
• the product was purified by preparative HPLC and by treatment with methanolic HCl in the

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