DE102005019094A1 - New aza-heterocycle compounds are tyrosine kinase inhibitors useful to treat and/or prevent e.g. cancer, tumor growth, tumor angiogenesis, arteriosclerosis, diabetic retinopathy and inflammation diseases - Google Patents

Abstract

Aza-heterocycle compounds (I) and their salts, derivatives and/or stereoisomers, are new. Aza-heterocycle compounds of formula (I) and their salts, derivatives and/or stereoisomers, are new. R 1> : H, A, Ar, Ar-A or A-Ar; A : cyclic 1-14C alkyl (where one or two CH 2-group is replaced by O- or S- atom and/or NH, NA, CONH, NHCO or -CH=CH-, 1-7 H-atom is replaced by hal, and/or one or two CH 3 group is replaced by NH 2, NAH, NA 2, NHCOOA, NHCONHA, NHCONHAr or CN); Ar : one or two aromatic homo- or heterocyclic group with 1-4 N-, O- and/or S atoms and 5-10 scaffolding atoms, optionally substituted by carbonyloxide, hal, A, OH, OA, NH 2, NHA, NA 2, NO 2, CN, OCN, SCN, COOH, COOA, CONH 2, CONHA, CONA 2, NHCOA, NHCONH 2, NHSO 2A, CHO, COA, SO 2NH 2 and/or S(O) gA; Ar-A : aryl-alkyl; A-Ar : alkyl-aryl; hal : F, Cl, Br or I; X, Z : CH or N; Y 1> : CH 2 or saturated bond; R-2a, R-2b, R-2c, R-2d : H, hal, OH, CN, NH 2, 1-6C alkyl, where CH 2 is replaced by O or S and/or NH, NA, CONH, NHCO or -CH=CH and/or 1-4 H atoms is replaced by hal, and CH 3 is replaced by NH 2, NAH, NA 2, CN or Ar; R 3> : H, A or Ar-A; dotted line with solid line : single or a double bond; and g : 0-2. Where: one group of X is N then the other two groups of X is CH; and up to two group (preferably 0 or 1) of Z is NH. Independent claims are included for: (1) the preparation of (I); (2) a medicament comprising (I) and at least a further medically active agent; and (3) a kit comprising (I) and the medicament. [Image] ACTIVITY : Cytostatic; Antiangiogenic; Antiarteriosclerotic; Antidiabetic; Ophthalmological; Antiinflammatory. MECHANISM OF ACTION : Tyrosine kinase inhibitor; Insulin like growth factor-1 receptor inhibitor. The ability of (I) to inhibit insulin like growth factor-1 receptor was tested using biological assays. The results showed that N-pyridin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amine (Ia) exhibited an IC 50 value of 0.76 mu M.

Description

worin
R¹ H, A, Ar, Ar-A oder A-Ar,
A unverzweigtes, verzweigtes oder cyclisches Alkyl mit 1-14 C-Atomen, worin eine oder zwei CH₂-Gruppen durch ein O- oder S-Atom und/oder durch eine NH, NA, CONH, NHCO oder -CH=CH-Gruppe und/oder auch 1-7 H-Atome durch Hal ersetzt sein können, und worin eine oder zwei CH₃-Gruppen durch NH₂, NAH, NA₂ oder CN ersetzt sein können,
Ar einen ein- oder zweikernigen aromatischen Homo- oder Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen und 5 bis 10 Gerüstatomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Carbonylsauerstoff, Hal, A, OH, OA, NH₂, NHA, NA₂, NO₂, CN, OCN, SCN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ und/oder S(O)_gA substituiert sein kann,
Hal F, Cl, Br oder I,
X CH oder N, wobei in jeder Verbindung der Formel I eine Gruppierung X N und zwei Gruppierungen X CH sind,
Y CH₂ oder eine gesättigte Bindung,
Z CH oder N, wobei in jeder Verbindung der Formel I höchstens zwei Gruppierungen Z N und vorzugsweise eine oder keine Gruppierung Z N sind,
R^2', R^2'', R^2''' jeweils unabhängig voneinander H, Hal, OH, CN, NH₂, unverzweigtes oder verzweigtes Alkyl mit 1-4 C-Atomen, worin eine CH₂-Gruppe durch ein O oder S-Atom und/oder durch eine NH, NA, CONH, NHCO oder -CH=CH-Gruppe und/oder auch 1-4 H-Atome durch Hal ersetzt sein können, und worin eine CH₃-Gruppe durch NH₂, NAH, NA₂ oder CN ersetzt sein kann,
R³ H oder A,
g 0, 1 oder 2 und

eine Einfach- oder Doppelbindung
bedeuten,
sowie ihre pharmazeutisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.The invention relates to compounds of the formula I,

wherein
R ^{1 is} H, A, Ar, Ar-A or A-Ar,
A straight, branched or cyclic alkyl having 1-14 C atoms, wherein one or two CH ₂ groups by an O or S atom and / or by an NH, NA, CONH, NHCO or -CH = CH group and / or 1-7 H atoms may also be replaced by Hal, and may be replaced wherein one or two CH ₃ groups by NH _2, NAH, NA ₂ or CN,
Ar is a mono- or binuclear aromatic homo- or heterocycle having 1 to 4 N, O and / or S atoms and 5 to 10 skeleton atoms which is unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, OH , OA, NH ₂ , NHA, NA ₂ , NO ₂ , CN, OCN, SCN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ and / or S (O) _g A may be substituted,
Hal F, Cl, Br or I,
X is CH or N, in each compound of the formula I being a group XN and two groups X CH,
Y is CH ₂ or a saturated bond,
Z is CH or N, in each compound of the formula I being at most two groups ZN and preferably one or no group ZN,
R ^{2 '} , R ^{2 "} , R ^{2''' are} each independently H, Hal, OH, CN, NH ₂ , unbranched or branched alkyl having 1-4 C atoms, wherein one CH ₂ group is represented by an O or S atom and / or by an NH, NA, CONH, NHCO or -CH = CH group and / or also 1-4 H atoms may be replaced by Hal, and wherein a CH ₃ group by NH ₂ , NAH , NA ₂ or CN can be replaced,
R ^{3 is} H or A,
g is 0, 1 or 2 and

a single or double bond
mean,
and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

It It has been found that the compounds of the formula I signal transduction, which is mediated by kinases, in particular by tyrosine kinases, inhibit, regulate and / or modulate. In particular, are suitable the compounds of the invention as inhibitors of tyrosine kinases. Thus, medicaments according to the invention and pharmaceutical compositions effective for the treatment of diseases be used by kinases and / or by kinase-mediated Signal transduction causes, mediates and / or propagates. Thus, the compounds of the invention are suitable for treatment and prophylaxis of cancer, tumor growth, arteriosclerosis, diabetic Retinopathy, inflammatory diseases, Psoriasis and the like in mammals.

background the invention

cancer is a disease whose causes include abnormal signal transduction you can see. In particular, deregulated signal transduction via tyrosine kinases plays a central role in the growth and spread of Krebs (Blume-Jensen, P. and T. Hunter, Nature 411: 355-365, 2001; Hanahan D. and R.A. Weinberg, Cell 100: 57-70, 2000). tyrosine kinases and in particular receptor tyrosine kinases and the binding to them Growth factors can so at deregulated apoptosis, tissue invasion, metastasis and generally involved in signal transduction mechanisms that lead to cancer be.

As already mentioned, one of the main mechanisms by which cell regulation is effected is Transduction of extracellular signals across the membrane, which in turn modulate biochemical pathways in the cell. Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, ultimately resulting in a cellular response. These signal transduction cascades are highly regulated and often overlap, as evidenced by the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly at serine, threonine or tyrosine residues, and protein kinases were therefore classified according to their specificity of the phosphorylation site, ie serine / threonine kinases and tyrosine kinases. Since phosphorylation is a very widespread process in cells, and since cell phenotypes are largely influenced by the activity of these pathways, it is presently believed that a large number of disease states and / or diseases are due to either aberrant activation or functional mutations in the molecular components of Kinase cascades are attributed. Consequently, considerable attention has been paid to the characterization of these proteins and compounds capable of modulating their activity (see review article: Weinstein-Oppenheimer et al., Pharm. & Therap. 88: 229-279, 2000).

Various possibilities for the inhibition, regulation and modulation of kinases include, for example, the provision of antibodies, antisense ribozymes and inhibitors. In oncology research in particular tyrosine kinases are promising targets. Thus, numerous synthetic small-molecule tyrosine kinase inhibitors for the treatment of cancer in clinical development such as Iressa ^® or Glivec ^®. However, there are still numerous problems to be solved, such as side effects, dosage, tumor resistance, tumor specificity and patient selection.

at The tyrosine kinases are a class of enzymes that the transfer of the terminal Phosphates of adenosine triphosphate on tyrosine residues in protein substrates catalyze. It is believed that the tyrosine kinases at different Cell functions via Substrate phosphorylation plays an essential role in signal transduction due. Although the exact mechanisms of signal transduction still are unclear, it has been shown that the tyrosine kinases are important factors in cell proliferation, carcinogenesis and cell differentiation represent.

The Tyrosine kinases can be expressed in receptor tyrosine kinases and cytosolic Divide tyrosine kinases. The receptor tyrosine kinases have one extracellular Part, a transmembrane part and an intracellular part on, while the cytosolic tyrosine kinases are exclusively intracellular.

The Receptor tyrosine kinases consist of a variety of transmembrane receptors with different biological effectiveness. So were about 20 different Subfamilies of receptor tyrosine kinases identified. A tyrosine kinase subfamily, which bears the name EGFR or HER subfamily exists from EGFR, HER2, HER3 and HER4. To the ligands of this receptor subfamily counting the epithelial growth factor (EGF), the tissue growth factor (TGF-α), amphi regulin, HB-EGF, betacellulin and Heregulin. The insulin subfamily to which INS-R, IGF-IR and IR-R counting, represents another subfamily of these receptor tyrosine kinases The PDGF subfamily includes the PDGF α and β receptor, CSFIR, c-kit and FLK-II. Furthermore There is the FLK family, which consists of the kinase domain domain receptor (KDR) or VEGFR-2, the fetal Liver kinase 1 (FLK-1), the fetal Liver kinase-4 (FLK-4) and fms-tyrosine kinase-1 (flt-1) or VEGFR-1 consists. The PDGF and FLK family are usually due to the between similarities between the two groups in the group of splitkinase domains receptor tyrosine kinases summarized (Laird, A.D. and J.M. Cherrington, Expert. Opin. Investig 12 (1): 51-64, 2003). For one For a detailed discussion of the receptor tyrosine kinases, see the work of Plowman et al., DN & P 7 (6): 334-339 (1994).

The cytosolic tyrosine kinases also consist of a variety subfamilies including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further in divided into different subgroups. For example, the Src subfamily one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src enzyme subfamily has been implicated in oncogenesis. For one more detailed discussion of cytosolic tyrosine kinases, see Work by Bolen, Oncogene, 8: 2025-2031 (1993).

Either the receptor tyrosine kinases as well as the cytosolic tyrosine kinases are on signal transmission paths the cell that leads to suffering such as cancer, psoriasis and hyperimmune reactions, involved.

The present invention now relates to compounds of the formula I, preferably as regulators, modulators or inhibitors of receptor tyrosine kinases of the insulin subfamily, to which the insulin receptor IR, the "insulin-like growth factor-1 receptor" IGF-1R and the "insulin related receptor" IRR count. The compounds according to the invention show particular activity in the inhibition of the receptor tyrosine kinase IGF-1R.

As previously mentioned, belongs insulin-like Growth factor-1 receptor (IGF-1R) to the family of transmembrane tyrosine kinase receptors, such as from platelets derived growth factor receptor (platelet derived growth factor receptor), the epidermal growth factor receptor and the insulin receptor. There are two known ligands for the IGF-1R receptor. These are IGF-1 and IGF-2. As used herein, refers the term "IGF" refers to both IGF-1 as well as on IGF-2. An overview of the insulin-like Growth factor family ligands, receptors and binding proteins can be found in Krywicki and Yee, Breast Cancer Research and Treatment, 22: 7-19, 1992.

By IGF / IGF-1R-mediated diseases are due to an abnormal activity or hyperactivity of IGF / IGF-1R characterized. Abnormal IGF activity affects either: (1) IGF or IGF-1R expression in cells, usually not IGF or IGF-1R expressing; (2) increased IGF or IGF-1R expression leading to unwanted cell proliferation, like cancer, leads; (3) increased IGF or IGF-1R activity, that cause unwanted cell proliferation, such as cancer, and / or leads to hyperactivity of IGF or IGF-1R. Hyperactivity of IGF or IGF 1R refers to either amplification of the gene, encoding IGF-1, IGF-2, IGF-1R, or generation of a mirror the IGF activity, which can be correlated with a cell proliferative disorder (i.e. As the level of IGF increases, the severity of one or more increases Symptoms of cell proliferation disease) bioavailability of IGF-1 and IGF-2 may also be due to the presence or absence of a Set of IGF-binding proteins (IGF-BP's) of which six are known. Hyperactivity of IGF / IGF-1R can also be caused by a down-regulation of IGF-2, the one IGF-2 binding domain, but no intracellular kinase domain contains. examples for Diseases caused by IGF / IGF-1R include the various with IGF / IGF-1R related malignancies People, over Cullen et al., Cancer Investigation, 9 (4): 443-454, 1991, for a review give. On the clinical significance and role of IGF / IGF-IR For the regulation of osteoblast function see Schmid, Journal of Internal Medicine, 234: 535-542, 1993.

The activities of IGF-1R thus include: (1) phosphorylation of IGF-1R protein; (2) phosphorylation an IGF-1R protein substrate; (3) interaction with an IGF adapter protein; (4) surface expression of the IGF-1R protein. Further activities of the IGF-1R protein can be found under Use of standard techniques can be identified. The IGF-1R activity can by Measuring one or more of the following activities: (1) Phosphorylation of IGF-1R; (2) phosphorylation of an IGF-1R substrate; (3) activation of an IGF-1R adapter molecule; and (4) activation of downstream signaling molecules and / or (5) increased cell division. These activities may be described using the following and techniques known in the art.

IGF-1R was considered essential for the generation and maintenance of the transformed phenotype in several cell types in vitro and in vivo (R. Baserga, Cancer Research 55: 249-252, 1995). Herbimycin A was said to be it is the IGF-1R protein tyrosine kinase and cell proliferation in human breast cancer cells (Sepp-Lorenzino et al., J. Cell Biochem. Suppl. 18b: 246, 1994). Experiments to study the Role of IGF-1R in the transformation, where antisense strategies, dominant negative mutations and antibodies against IGF-1R to the hypothesis that IGR-1R is a preferred therapeutic target Interventions can be.

Over his Role in the supply of nutrients and in type II diabetes, IGF-1R was also associated with several Cancer has been linked. For example, one has IGF-1 as an autocrine growth stimulator in several tumor types, e.g. human breast carcinoma cells (Arteago et al., J. Clin. Invest., 84: 1418-1423, 1989) and small lung tumor cells (Macauley et al., Cancer Res., 50: 2511-2517, 1989). Besides, it seems IGF-1, which is inseparable from normal growth and normal Differentiation of the nervous system is linked, even an autocrine Stimulator of human glioma. Sandberg-Nordqvist et al., Cancer Res., 53: 2475-2478 (1993).

An example of the potential involvement of IGF-2 in colorectal cancer could be the upregulation of IGF-2 mRNA in colon tumors compared to normal colon tissue. (Zhang et al., Science: 276: 1268-1272, 1997) IGF-2 may also play a role in hypoxia-causing nevascularization of tumors. (Mines et al., Int. J. Mol. Med. 5: 253-259, 2000) IGF-2 may also play a role in tumorigenesis via activation of an insulin receptor isoform-A. IGF-2 activation of insulin receptor isoform A activates signaling pathways for cell survival, but the extent of its contribution to tumor cell growth and survival is currently unknown. The Insulin Receptor Isoform A Kinase Domain is identical to that of the standard insulin receptor (Scalia et al., J. Cell Biochem 82: 610-618, 2001).

The Importance of IGF-1R and its ligands in cell types in culture (Fibroblasts, epithelial cells, smooth muscle cells, T lymphocytes, Myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) is through the ability of IGF-1, to stimulate cell growth and proliferation (Gold Ring and Gold Ring, Eukaryotic Gene Expression, 1: 301-326, 1991). In a series of recent publications Baserga et al. suggest that IGF-1R plays a key role in the mechanism of Transformation plays and as such a preferred therapeutic target Interventions in a wide range of human malignant diseases could be (Baserga, Cancer Res., 55: 249-252, 1995; Baserga, Cell, 79: 927-930, 1994; Coppola et al., Mol. Cell. Biol., 14: 4588-4595, 1994; Baserga, Trends in Biotechnology, 14: 150-152, 1996; HM. Khandwala et al. Endocrine Reviews, 21: 215-244, 2000).

The major cancers produced using a compound of the invention can be treated include breast cancer, prostate cancer, colorectal cancer, small cell Lung cancer, non-small cell lung cancer, multiple myeloma as well as renal cell carcinoma and endometrial carcinoma.

IGF-1 has also been associated with neovascularization of the retina. In some patients with high IGF-1 levels, a proliferative Diabetes retinopathy was observed. (L. E. Smith et al., Nature Medicine, 5: 1390-1395, 1999)

The Compounds of the invention can but also suitable as a means of aging delay. It was observed that there is a connection between IGF signals and aging. Experiments have shown that calorie-restricted mammals Diet low Insulin and IGF-1 levels exhibit and a longer one Have life. Similar Observations have also been made in insects (see C. Kenyon, Cell, 105: 165-168, 2001; E. Strauss, Science, 292: 41-43, 2001; K. D. Kimura et al., Science, 277: 942-946, 1997; M. Tatar et al. Science, 292: 107-110, 2001).

object The present invention thus also relates to the use of the compounds of the formula I for the prevention and / or treatment of diseases associated with unregulated or impaired receptor activity. Especially can be the Verbindun conditions of the invention Therefore, in the treatment of certain forms of cancer use, such as. Breast cancer, prostate cancer, colon cancer, small cell and non-small cell lung cancer, multiple myeloma, renal cell carcinoma or corpus carcinoma.

Farther the use of the compounds according to the invention for treatment is conceivable of diabetic retinopathy or to delay the aging process. In particular, they are suitable for use in diagnostic procedures to diseases associated with unregulated or impaired IGF-1R activity.

moreover can the compounds of the invention used to treat certain existing cancer chemotherapies and irradiations to achieve additive or synergistic effects and / or the effectiveness of certain existing cancer chemotherapies and irradiations.

A A series of aza-indole compounds have previously been described as kinase inhibitors. for example in WO 02/092603, WO 04/043388 or WO 04/016609.

Of the Invention was now the object of new compounds with to find advantageous therapeutic properties, the Production of drugs can be used.

So is the identification and provision of chemical compounds, specifically inhibiting the signal transduction of tyrosine kinases, regulate and / or modulate, desirable and therefore an objective of present invention.

description the invention

It has been found that the compounds of formula I and their salts possess very valuable pharmacological properties with good compatibility. In particular, it has been found that the erfindungsge Genetic compounds of formula I are surprisingly effective kinase inhibitors, in particular, they show a tyrosine kinase-inhibiting effect, and in particular a IGF-R1 inhibitory activity.

As a general rule applies that all Radicals that are multiple, may be the same or different, i. independently of each other are. Above and below, the radicals or parameters have the formula I mean, unless expressly stated otherwise is.

Accordingly are the subject of the invention, in particular those compounds of the formula I in which at least one of the radicals mentioned is a has the preferred meanings given below.

Hal is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

A is alkyl, is unbranched (linear), branched or cyclic, and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.

So A is, for example, methyl, furthermore ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl or tert-butyl, and 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, linear or branched heptyl, octyl, Nonyl or decyl.

A is preferably alkyl having 1, 2, 3, 4, 5 or 6 C atoms, wherein one or two CH ₂ groups by O or S atoms and / or by NH, NA, CONH, NHCO or -CH = CH groups and / or 1-7 H atoms may be replaced by F and / or Cl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl , Trifluoromethyl, pentafluoroethyl, 1,1-difluoromethyl, 1,1,1-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, and wherein one or two CH ₃ groups by NH _2, NAH, NA ₂ or CN may be replaced, such as, N, N'-dimethylaminoalkyl or cyanoalkyl.

cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Ar means e.g. unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, Ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, Acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, Dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, Ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, Phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl mono-, di- or trisubstituted phenyl, naphthyl or biphenyl.

Ar is furthermore 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-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethyl-amino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar further preferably is unsubstituted or mono-, di- or tri-for example by carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl, phenyl, benzyl, -CH ₂ -cyclohexyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino , Nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbo nyl, dimethylaminocarbonyl, acetamino, ureido, methylsulfonylamino, formyl, acetyl, aminosulfonyl and / or methylsulfonyl substituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1, 2, 4 - or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3 -, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 5-, or 6-pyrazine-1 or 4 -yl, furthermore preferably 1,2,3-triazole-1, -4- or -5-yl, 1,2,4-triazole-1, -3- or 5-yl, 1- or 5-tetrazolyl , 1,2,3-oxadiazol-4 or -5-yl, 1,2,4-oxadiazol-3 or -5-yl, 1,3,4-thiadiazol-2 or -5-yl, 1 , 2,4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazol-4 or -5-yl, 3- or 4-pyridazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4- or 5-isoindolyl, 2-, 6- or 8-purinyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2- , 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8- Quinazolinyl, 5- or 6-quinoxalinyl, 4-, 5-, or 6-phthalazinyl, 2-, 3-, 5-, 6-, 7-, or 8-2H-benzo [1,4] oxazinyl, more preferably 1 , 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also partially or completely be hydrogenated and mean e.g. also 2,3-dihydro-2-, -3-, -4- or 5-furyl, 2,5-dihydro-2, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1, -2, -3, -4 or 5-pyrazolyl, Tetrahydro-1-, 3- or 4-pyrazolyl, 1,4-dihydro-1, -2, -3 or 4-pyridyl, 1,2,3,4-tetrahydro-1, -2-, -3-, -4-, -5- or -6-pyridyl, 2-, 3-, 5- or 6-piperidine-1 or 4-yl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, Hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4- tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-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-oxomethylendioxy) -phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, further preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

The The term "substituted" preferably refers to the substitution with the abovementioned substituents, wherein several different degrees of substitution are possible, if not otherwise specified.

Also according to the invention all physiologically acceptable salts, derivatives, solvates and stereoisomers including these compounds their mixtures in all proportions.

The Compounds of the formula I can have one or more chiral centers. You can accordingly occur in different enantiomeric forms and in racemic or in optically active form. Subject of the invention are therefore also the optically active forms (stereoisomers), the Enantiomers, the racemates, the diastereomers and hydrates and Solvates of these compounds.

There the pharmaceutical activity of racemates or stereoisomers the compounds of the invention may differ, it may be desirable be to use the enantiomers. In these cases, the end product or but already the intermediates in enantiomeric compounds, by chemical or physical measures known to the person skilled in the art, separated or already used as such in the synthesis become.

in the Fall racemic amines are from the mixture by reaction with formed an optically active release agent diastereomers. As a release agent are suitable e.g. optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric dibenzoyltartaric, Mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Also advantageous is a chromatographic enantiomer separation with Aid of an optically active release agent (e.g., dinitrobenzoylphenylglycine, Cellulose triacetate or other derivatives of carbohydrates or on silica gel fixed chirally derivatized methacrylate polymers). As eluents are suitable for this purpose aqueous or alcoholic solvent mixtures such as. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.

A elegant method of cleaving racemates with ester groups (e.g. Acetyl ester) represents the use of enzymes, in particular esterases, represents.

worin R¹, R², R³, Y und Z die für die Formel I angegebene Bedeutung haben sowie ihre pharmazeutisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.A preferred group of compounds of the formula I corresponds to the formula AII

wherein R ¹ , R ² , R ³ , Y and Z have the meaning given for the formula I and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

worin Y eine Bindung, Z CH, R³ N bedeutet und R¹ bzw. R² die für die Formel I bzw. AII angegebene Bedeutung haben sowie ihre pharmazeutisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Another preferred group of compounds of the formula AII corresponds to the formula AIII

wherein Y is a bond, Z is CH, R ³ N and R ¹ and R ^{2 have} the meaning given for the formula I or AII as well as their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

wobei die Verknüpfung mit dem Grundkörper der Formeln I, AII bzw. AIII jeweils über die nach links stehende Bindung, die keine Methylgruppe ist, erfolgt,
bedeutet
und R² die für die Formel I angegebene Bedeutung hat,
bei der Teilformel Ab
R^2', R^2'', R^2''' jeweils unabhängig voneinander H, Methoxy, Ethoxy, n-Propoxy oder i-Propoxy bedeuten
und R¹ die für die Formel I angegebene Bedeutung hat,
bei der Teilformel Ac
R^2', R^2'', R^2''' jeweils unabhängig voneinander H oder Methoxy bedeuten
und R¹ die für die Formel I angegebene Bedeutung hat,
bei der Teilformel Ad
R^2', R^2'', R^2''' jeweils Methoxy bedeuten
und R¹ die für die Formel I angegebene Bedeutung hat,
bei der Teilformel Ae
R^2', R^2'', R^2''' jeweils unabhängig voneinander H, Methoxy, Ethoxy, n-Propoxy oder i-Propoxy bedeuten
und R¹ die für die Teilformel Aa angegebene Bedeutung hat,
bei der Teilformel Af
R^2', R^2'', R^2''' jeweils unabhängig voneinander H oder Methoxy bedeuten
und R¹ die für die Teilformel Aa angegebene Bedeutung hat,
bei der Teilformel Ag
R^2', R^2'', R^2''' jeweils Methoxy bedeuten
und R¹ die für die Teilformel Aa angegebene Bedeutung hat
sowie ihre pharmazeutisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Further preferred subgroups of compounds of the formula I, AII and AIII can be expressed by the following sub-formulas Aa to Ag, which correspond to the formulas I, AII and AIII, respectively, wherein, however
in the sub-formula Aa
R ^{1 is} unsubstituted or mono- or polysubstituted by Hal, cyano, methyl or methoxy-substituted phenyl, phenylmethyl, pyridyl, pyridylmethyl, pyridylethyl, pyrimidyl, piperazyl, quinolinyl, imidazoyl, imidazolylpropyl, pyrrolyl, pyrrolylethyl, furthermore H, N, N'-dimethylaminopropyl or cyanobutyl or one of the following radicals

wherein the linkage with the main body of the formulas I, AII or AIII is in each case via the bond to the left, which is not a methyl group,
means
and R ^{2 has} the meaning given for the formula I,
at the subform Ab
R ^{2 '} , R ^{2 "} , R ^{2''' are} each independently H, methoxy, ethoxy, n-propoxy or i-propoxy
and R ^{1 has} the meaning given for the formula I,
in the sub-formula Ac
R ^{2 '} , R ^2'' , R ^2''' each independently represent H or methoxy
and R ^{1 has} the meaning given for the formula I,
at the subform Ad
R ^{2 '} , R ^{2 "} , R ^{2'" are} each methoxy
and R ¹ has the meaning indicated for the formula I,
in the partial formula Ae
R ^{2 '} , R ^{2 "} , R ^{2''' are} each independently H, methoxy, ethoxy, n-propoxy or i-propoxy
and R ^{1 has} the meaning given for the partial formula Aa,
in the sub-formula Af
R ^{2 '} , R ^2'' , R ^2''' each independently represent H or methoxy
and R ^{1 has} the meaning given for the partial formula Aa,
in the partial formula Ag
R ^{2 '} , R ^{2 "} , R ^{2'" are} each methoxy
and R ^{1 has} the meaning given for the partial formula Aa
and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

Particular preference is given to compounds selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. Table 1

Under understands pharmaceutically or physiologically harmless derivatives one e.g. Salts of the compounds according to the invention, as well as so-called prodrug compounds. Such derivatives are in known to the skilled person. An overview to physiologically compatible Derivatives deliver burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and practice. By prodrug compounds is meant by e.g. alkyl or acyl groups, sugars or oligopeptides modified compounds of the formula I, which rapidly in the organism to the active compounds of the invention split or released. These include biodegradable polymer derivatives the compounds according to the invention, as e.g. in Int. J. Pharm. 115: 61-67 (1995).

When Acid addition salts come inorganic or organic salts of all physiological or pharmacologically acceptable acids in question, for example halides, especially hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, Fumarates, oxalates, acetates, phosphates, methyl sulfonates or p-toluenesulfonates.

Under Solvates of the compounds of formula I are additions of inert Solvent molecules to the Compounds of formula I understood that due to their mutual Train attraction. Solvates are for example hydrates, such as monohydrates or dihydrates or alkoxides, i. addition compounds with alcohols such as methanol or ethanol.

Of the Expression "effective Quantity "means the amount of a drug or pharmaceutical agent, the one biological or medical answer in a tissue, System, animal or human, e.g. from a researcher or medics is sought or desired.

In addition, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in:
improved curative treatment, cure, prevention or elimination of a disease, a condition, a disease state, a disease, a disorder or prevention of side effects or even the reduction of the progression of a disease, a disease or a disorder. The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

object The invention also relates to mixtures of the compounds according to the invention of the formula I, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000.

Especially These are preferably mixtures of stereoisomeric compounds.

worin X die oben angegebenen Bedeutung hat mit einer Verbindung der Formel VIII,

worin Z, Y und R² die oben angegebenen Bedeutungen haben, zu einer Verbindung der Formel VII umsetzt,

die ggf. zu einer entsprechenden 2,3-Dihydro-Indolverbindung reduziert wird und aus der dann im nächsten Schritt eine Verbindung der Formel VI hergestellt wird,

worin L eine Abgangsgruppe wie bspw. Cl, Br, I, Mesylat, Tosylat, Phenylsulfonat oder Trifluoracetat ist,
und die Verbindung der Formel VI dann in einem weiteren Schritt mit einer Verbindung der Formel V R¹-NH₂ zur Reaktion gebracht wird, um eine Verbindung der Formel IV

zu erhalten, die schließlich mit einem Rest R³ zu einer Verbindung der Formel I verknüpft wird,
und ggf. eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.Furthermore, the present invention relates to a process for the preparation of compounds of formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, characterized in that in a first step, a compound of formula IX,

in which X has the abovementioned meaning with a compound of the formula VIII,

wherein Z, Y and R ^{2 have} the meanings given above, to give a compound of formula VII,

which is optionally reduced to a corresponding 2,3-dihydro-indole compound and from which in the next step a compound of formula VI is prepared,

where L is a leaving group such as, for example, Cl, Br, I, mesylate, tosylate, phenylsulfonate or trifluoroacetate,
and the compound of the formula VI is then reacted in a further step with a compound of the formula V R ¹ -NH ₂ is reacted to form a compound of formula IV

which is finally linked to a radical R ³ to form a compound of the formula I,
and optionally converting a base or acid of the formula I into one of its salts.

The Compounds of formula IX and VIII are known in the rule. are they are new, so can they are prepared by methods known per se, as they are in the literature (e.g., in standard works such as Houben-Weyl, Methoden of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York).

The Compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the Literature (e.g., in standard works such as Houben-Weyl, Methoden der Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), under reaction conditions, as for the said reactions are known and suitable. It can we also make use of known per se, not mentioned here variants.

• a) Eine Verbindung der Formel IX wird analog Davis et al. (Tetrahedron 1992, 48 (5), 939-952) bei tiefer Temperatur in einem inerten Lösungs mittel vorgelegt. Anschließend wird eine Verbindung der Formel VIII zugeben und das Reaktionsgemisch gerührt. Nach Beendigung der Reaktion wird das Reaktionsgemisch aufgereinigt und das Produkt als Feststoff, vorzugsweise kristallin, isoliert. An diesen Schritt kann sich wahlweise in die Reduzierung des gebildeten Aza-Indolderivats nach an sich bekannten Methoden (z.B. durch selektive Hydrierung) zu einem 2,3-Dihydroindolderivat anschließen.
• b) Das Reaktionsprodukt aus Schritt (a) wird analog Chou et al. (J. Phys. Chem. A 2003, 107, 1459-1471) an der 4-Position des Indolkörpers mit einer Abgangsgruppe (z.B. Cl) versehen.
• c) Das Reaktionsprodukt aus Schritt (b) wird bei erhöhter Temperatur mit einem Amin der Formel V zur Reaktion gebracht. Das Produkt dieser Reaktion, der gewünschte Aza-Heterozyklus der Formel I, wird aufgereinigt und aus dem Reaktionsgemisch abgetrennt.

The aza-heterocycles of the formula I can preferably be obtained by proceeding as follows:

• a) A compound of the formula IX is analogously Davis et al. (Tetrahedron 1992, 48 (5), 939-952) presented at low temperature in an inert solvent medium. Subsequently, a compound of formula VIII is added and the reaction mixture is stirred. After completion of the reaction, the reaction mixture is purified and the product as a solid, preferably crystalline, isolated. Optionally, this step can be followed by reduction of the aza-indole derivative formed by methods known per se (eg, by selective hydrogenation) to give a 2,3-dihydroindole derivative.
• b) The reaction product from step (a) is analogously Chou et al. (J. Phys. Chem. A 2003, 107, 1459-1471) at the 4-position of the indole body with a leaving group (eg Cl).
• c) The reaction product from step (b) is reacted at elevated temperature with an amine of formula V. The product of this reaction, the desired aza heterocycle of formula I, is purified and separated from the reaction mixture.

The reactions described above are usually carried out in an inert Solvent. As an inert solvent for the reactions described above are suitable e.g. hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; 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, N-methylpyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitriles like acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; carboxylic acids like formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned. Prefers are sulfoxides such as dimethyl sulfoxide (DMSO).

The Amount of solvent is not critical, preferably 5 g to 500 g of solvent be added per g of the product to be formed.

In The rule is carried out at a pressure of 1 to 200 bar, preferably but at normal pressure.

The Reaction temperature for the reactions described above will vary depending on the conditions used between about -10 and 200 ° C, usually between -5 and 100 ° C, preferably between 0 and 80 ° C.

The Response time varies depending on the conditions used a few minutes and several days, preferably in the range of several hours.

The Reaction can also be carried out in a heterogeneous phase, preferably an aqueous phase and a benzene or toluene phase. Here comes a phase transfer catalyst is used, such as tetrabutylammonium iodide and optionally an acylation catalyst, such as Dimethylaminopyridine.

A The obtained base of the formula I can be converted with an acid into the associated acid addition salt. For this Reaction suitable acids, provide the physiologically acceptable salts. So can inorganic acids can be used, e.g. Sulfuric acid, Hydrogen halides like hydrochloric acid or hydrobromic acid, phosphoric like orthophosphoric acid, Nitric acid, sulfamic, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, like formic acid, Acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, benzoic, salicylic, 2-phenylpropionic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methane or ethanesulfonic acid, ethanedisulfonic, 2-hydroxyethanesulfonic acid; benzenesulfonic, p-toluenesulfonic acid, Naphthalene mono- and di-sulphonic acids, Lauryl sulfuric acid.

The free bases of the formula I can, if desired, from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate set free if there are no further acidic groups in the molecule.

links of the formula I can Furthermore, they can be obtained by removing them from one of their functional Derivatives by treatment with a solvolysierenden or hydrogenolyzing Sets funds in freedom.

preferred Starting materials for the solvolysis or hydrogenolysis are those which are otherwise of the formula I, but instead of one or more free amino and / or Hydroxy groups corresponding protected amino and / or hydroxy groups contain, preferably those which instead of an H atom, with an N-atom, carry an amino protecting group, in particular those which, instead of an HN group, carry an R'-N group, where R 'is an amino-protecting group means, and / or those which instead of the H atom of a hydroxy group carry a hydroxy protecting group, e.g. those which correspond to the formula I, However, instead of a group -COOH carry a group -COOR '', wherein R '' is a Hydroxy protecting group.

preferred Starting materials are also the Oxadiazolderivate, which in the corresponding Amidino compounds are transferred can.

It can also several - same or various protected amino and / or hydroxy groups in the molecule be present of the starting material. If the existing protection groups can be different from each other they in many cases be cleaved selectively.

Of the The term "amino protecting group" is well known and refers to groups that are suitable, an amino group to protect against (but block) chemical reactions are easily removable after the desired chemical reaction other parts of the molecule carried out has been. Typical for such groups are especially unsubstituted or substituted Acyl, aryl, aralkoxymethyl or Aralkyl groups. Since the amino protecting groups are according to the desired Reaction (or reaction sequence) is their nature and Size otherwise not critical; however, preferred are those with 1-20, in particular 1-8 C atoms. The term "acyl group" is related to be understood in the broadest sense with the present process. He surrounds of aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids derived acyl groups and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such Acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or tolyl; aryloxyalkanoyl like POA; Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

Further one can free amino groups in usual With an acid chloride acylate or anhydride or with an unsubstituted or substituted Alkylate alkyl halide, or react with CH3-C (= NH) -OEt, suitably in one inert solvent such as dichloromethane or THF and / or in the presence of a base such as Triethylamine or pyridine at temperatures between -60 and + 30 ° C.

Of the Term "hydroxy protecting group" is also generic and refers to groups that are suitable for a hydroxy group protect against chemical reactions, but are easily removable, after the desired chemical reaction has been performed elsewhere in the molecule. Typical for such Groups are the above unsubstituted or substituted ones Aryl, aralkyl or acyl groups, and also alkyl or silyl groups. The nature and size of the hydroxy protecting groups is not critical as it depends on the desired chemical reaction or reaction sequence are removed again; preferred are groups with 1-20, in particular 1-10 C-atoms. Examples of hydroxy protecting groups are u.a. Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred are.

The In-freedom setting of the compounds of formula I from their functional Derivatives succeed - depending on the used protective group - z. With strong acids, appropriate with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or Sulfuric acid, strong organic carboxylic acids like trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always required. As inert solvents are preferably suitable organic, for example carboxylic acids such as acetic acid, ether such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or Isopropanol, as well as water. Furthermore, mixtures of the aforementioned solvent in question. TFA is preferably in excess without addition of another solvent used, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. The Reaction temperatures for the split is appropriate between about 0 and about 50 ° C, It is preferable to work between 15 and 30 ° C (room temperature, RT).

The Groups BOC, OBut and Mtr can z. B. preferably with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 ° C be split off, the FMOC group with about 5 to 50% Solution of Dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C.

hydrogenolytically removable protecting groups (eg CBZ, benzyl or the release the amidino group from its Oxadiazolderivat) can, for. B. by treatment with hydrogen in the presence of a catalyst (eg a noble metal catalyst like palladium, appropriate a carrier like coal) are split off. Suitable solvents are the above, in particular z. As alcohols such as methanol or Ethanol or amides such as DMF. The hydrogenolysis is usually at temperatures between about 0 and 100 ° C and pressures between about 1 and 200 bar, preferably carried out at 20-30 ° C and 1-10 bar. A Hydrogenolysis of the CBZ group succeeds z. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 ° C.

ester can e.g. with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane be saponified at temperatures between 0 and 100 ° C.

Further Methods for removing protecting groups are, for example, in Theodora W. Green, Peter G. M. Wuts: Protective Groups in Organic Synthesis, 3rd Edition John Wiley & Sons (1999).

Compounds of the invention of the formula I can due to their molecular structure be chiral and, accordingly, in different enantiomeric forms occur. You can therefore in racemic or optically active form.

There the pharmaceutical activity of racemates or stereoisomers the compounds of the invention may differ, it may be desirable be to use the enantiomers. In these cases, the end product or but already the intermediates in enantiomeric compounds, by known chemical, biochemical or physical Activities, separated or already used as such in the synthesis become.

By usual workup steps such as. Water addition to the reaction mixture and extraction can the Compounds of formula I are obtained after removal of the solvent. It may be advantageous to further clean the product To connect distillation or crystallization.

One Another object of the invention are medicaments containing at least one compound of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions.

Farther may be a pharmaceutical according to the invention Preparation, further carrier and / or auxiliaries and optionally one or more others Contain active pharmaceutical ingredients.

object The invention further provides a process for the preparation of a medicament, characterized in that a compound of the invention and / or one of their physiologically acceptable salts, derivatives, Solvates and stereoisomers, including mixtures thereof in all conditions together with a solid, liquid or semi-liquid Carrier- or adjuvant into a suitable dosage form.

• a) einer wirksamen Menge einer erfindungsgemäßen Verbindung und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen und
• b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.

The invention is also a set (kit) consisting of separate packages of

• a) an effective amount of a compound of the invention and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions and
• b) an effective amount of another active pharmaceutical ingredient.

The Set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. contain separate ampoules, in each case an effective amount of a compound of the invention and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another drug solved or in lyophilized form.

Drugs may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a unit may for example be 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treated disease state, the route of administration and the age, sex, weight and condition of the patient. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such drugs can be prepared by any of the methods well known in the pharmaceutical art.

drug can be used for administration any suitable route, for example oral (including buccal sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such medicines can be used with all methods known in the pharmaceutical art by, for example, adding the active substance to the carrier (s) or adjuvant (s) is brought together.

At Oral administration adapted drugs may be considered as separate units, e.g. Capsules or tablets; Powder or granules; solutions or suspensions in aqueous or non-aqueous Liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions be presented.

So let yourself for example, in oral administration in the form of a tablet or capsule the drug component with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as e.g. ethanol, Glycerin, water and the like combine. Powders are made by adding the compound crushed a suitable fine size and with a similar one Way crushed pharmaceutical carrier, such. an edible Carbohydrate such as starch or mannitol is mixed. A flavoring, preservative, dispersant and Dye can also be present.

capsules are prepared by mixing a powder mixture as described above prepared and shaped gelatin shells are filled with it. Lubricants and lubricants such as. fumed silica, Talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form the powder mixture before the filling process be added. A disintegrants or solubilizers, e.g. Agar Agar, Calcium carbonate or sodium carbonate, may also be added for availability improve the drug after taking the capsule.

In addition, if required or necessary, suitable binding, lubricating and disintegrating agents as well Dyes are also incorporated into the mixture. To the suitable binders include starch, gelatin, natural Sugars, e.g. Glucose or beta-lactose, sweeteners from corn, natural and synthetic Gum, e.g. Acacia, tragacanth or sodium alginate, carboxymethylcellulose, Polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, Sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, Sodium chloride and the like Belonging to the explosives without limitation to be, strength, Methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated for example, by preparing a powder mixture, granulated or dry pressed, a lubricant and a disintegrant added and the whole thing is compressed into tablets. A powder mixture is prepared by the suitably comminuted compound with a diluent or a base as described above and optionally with one Binders, such as e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or Dicalcium phosphate is mixed. The powder mixture can be granulated by mixing with a binder, e.g. Syrup, starch paste, Acadia mucus or solutions made of cellulose or polymer materials wetted and through a sieve is pressed. As an alternative to granulation, the powder mixture can be used run through a tabletting machine, wherein unevenly shaped Lumps are formed, which are broken up into granules. The granules can by adding stearic acid, a stearate salt, talc or mineral oil are greased to stick to prevent the tablet molds. The greased mixture is then pressed into tablets. The compounds of the invention can also with a free-flowing inert carrier combined and then without implementation the granulation or dry compression steps directly to tablets be pressed. A transparent or opaque protective layer, consisting of a seal made of shellac, a layer of Sugar or polymer material and a gloss layer of wax, can to be available. Dyes can be added to these coatings. to differentiate between different dosage units to be able to.

Oral fluids such as solution, syrups and elixirs may be in the form of dosage units so that a given quantity contains a given amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution of suitable taste, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, or the like. can also be added.

The Dosage unit formulations for oral administration may optionally enclosed in microcapsules. The formulation can be also produce such that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax and the like

The Compounds of the invention and salts, solvates and physiologically functional derivatives thereof can also be used in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can from various phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines.

The Compounds of the invention and the salts, solvates and physiologically functional derivatives of it can also using monoclonal antibodies as individual carriers the the connecting molecules coupled, fed become. The connections can also with soluble Polymers are coupled as targeted drug carrier. Such Polymers can Polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, Polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine, substituted with palmitoyl radicals. Furthermore, the Compounds to a class of biodegradable polymers, for the controlled release of a drug are suitable, e.g. polylactic acid, Polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, Polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels, coupled.

At Transdermal administration can be adapted as independent Plaster for longer, close contact with the epidermis of the recipient be presented. So For example, the drug from the patch by iontophoresis supplied as described in Pharmaceutical Research, 3 (6): 318 (1986) described.

At Drugs adapted for topical administration may be considered as Ointments, creams, suspensions, lotions, powders, solutions, Be formulated pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissue, e.g. Mouth and skin, the formulations are preferably as topical Ointment or cream applied. When formulated into an ointment can the active ingredient either with a paraffinic or one with water Miscible cream base can be used. Alternatively, the active ingredient to a cream with an oil-in-water cream base or a water-in-oil basis be formulated.

To the drug adapted for topical application to the eye belong Eye drops, wherein the active ingredient in a suitable carrier, in particular an aqueous one Solvent, solved or suspended.

At the topical application in the mouth adapted drugs Lozenges, lozenges and mouthwashes.

At The rectal administration adapted drugs can be administered in Form of suppositories or enemas become.

At the nasal administration adapted drugs in which the vehicle is a solid, contains a coarse powder with a particle size, for example in the range of 20-500 microns, that in the way Snuff is administered, i. by rapid inhalation over the Nasal passages from a container held close to the nose the powder. Suitable formulations for administration as a nasal spray or nose drops with a liquid as a carrier include drug solutions in water or oil.

At include administration by inhalation adapted drugs fine particulate dusts or nebulae, which are pressurized by means of various types Dosing dispensers with aerosols, nebulizers or insufflators produced can be.

At Vaginal administration-adapted drugs may be considered as Pessaries, tampons, creams, gels, pastes, foams or spray formulations be presented.

To The drugs adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, the antioxidants, buffers, bacteriostats and solutes, by the the formulation is made isotonic with the blood of the recipient to be treated will contain; as well as watery and non-aqueous sterile suspensions containing suspending agents and thickeners can. The formulations can in single or multiple dose containers, e.g. sealed ampoules and vials, presented and in freeze-dried (lyophilized) state be stored so that only the addition of the sterile carrier liquid, e.g. Water for Injections, needed immediately before use. Prescribed injection solutions and suspensions can from sterile powders, granules and tablets.

It is understood that the medicaments of the invention in addition to above-mentioned components particularly mentioned others common in the art Means related to the particular type of pharmaceutical formulation can contain; so can for example oral administration suitable drug flavorings contain.

A therapeutically effective amount of a compound of the present invention depends on a number of factors, including e.g. the age and weight Recipient, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the Route of administration, and will ultimately be given by the attending physician or veterinarian. However, an effective amount is one Compound of formula I for the treatment of the diseases of the invention generally in the range of 0.1 to 100 mg / kg of body weight Recipient (Mammal) per day and more typically in the range of 1 to 10 mg / kg of body weight per day. Thus would be for one 70 kg adult mammal the actual Amount per day for usually between 70 and 700 mg, taking this amount as a single dose per day or more usual in a series of sub-doses (such as two, three, four, five, or six) per day can be given, so that the total daily dose the same is. An effective amount of a salt or solvate or a physiologically functional derivative thereof may be used as a proportion the effective amount of the compound of the invention determined per se become.

The compounds of the present invention exhibit beneficial biological activity which is readily detectable in enzyme assays. In such enzyme-based assays, the compounds of the invention preferably 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.

object of the present invention are compounds of the invention as effectors, preferably as inhibitors of the signaling pathways described herein. Especially preferred subject of the invention are therefore compounds of the invention as activators and inhibitors of tyrosine kinases, preferably as Inhibitors of receptor tyrosine kinases, in particular the insulin subfamily, to the INS-R, IGF-IR and IR-R. This show the compounds of the invention a special effect in the inhibition of receptor tyrosine kinase IGF-1R.

As discussed above are the compounds of the invention influenced signaling pathways for different diseases relevant. Accordingly, the compounds of the invention useful in the prophylaxis and / or treatment of diseases caused by the said signaling pathways through interaction with one or more dependent of said signal paths are.

One Another object of the present invention is therefore the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, especially those diseases caused by kinases and / or kinase-mediated Signal transduction causes, mediates and / or propagates. Preferred here are tyrosine kinases selected from the group of receptor tyrosine kinases. This is particularly preferably IGF-1R.

Also suitable the present compounds as pharmaceutical active ingredients for mammals, in particular for the People in the treatment of tyrosine-kinase-related diseases. The term "tyrosine kinase-related Diseases "refers on pathological conditions, the of the activity one or more tyrosine kinases are dependent. The tyrosine kinases are either directly or indirectly at the signal transduction pathways different cell activities, including proliferation, adhesion and migration as well as differentiation involved. To the diseases, those with tyrosine kinase activity are associated Cancer, tumor growth, arteriosclerosis, diabetic retinopathy and inflammatory diseases.

Usually will The diseases discussed here are divided into two groups, in hyperproliferative and non-hyperproliferative disorders. In psoriasis, arthritis, inflammation, Endometriosis, scarring, benign prostatic hyperplasia, immunological Diseases, autoimmune diseases and immunodeficiency diseases as non-cancerous Diseases, of which arthritis, inflammation, immunological diseases, Autoimmune diseases and immunodeficiency diseases usually as non-hyperproliferative disorders.

In Brain cancer, lung cancer, squamous cell carcinoma, Bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, Colon cancer, breast cancer, head cancer, cervical cancer, esophageal cancer, gynecological Cancer, thyroid cancer, Lymphomas, chronic leukemia and acute leukemia as cancerous diseases, all of which are commonly used to treat Group of hyperproliferative disorders are counted. In particular, cancerous Cell growth and in particular directly or indirectly mediated by IGF-1R Cancerous cell growth is a disease that is a target of represents present invention.

object The present invention is therefore the use of compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis said diseases as well as a method of treatment the said diseases, comprising the administration of one or several inventive compounds to a patient in need of such administration.

Of the receiver or patient may be of any mammalian species belong, z. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are for experimental studies of interest, where they are a model to treat a human disease.

The responsiveness to a particular cell the treatment with the compounds of the invention can by be determined in vitro tests. Typically, a culture becomes the cell with a compound of the invention at various Concentrations for a period of time sufficient to allow the active ingredients to Induce cell death or inhibit migration, usually between about one Hour and a week. Cultured cells can be selected for in vitro tests a biopsy sample can be used. The remaining after the treatment viable Cells are then counted.

The Dose varies depending of the specific compound used, the specific disease, patient status etc. Typically, this is a therapeutic Dose sufficient to the unwanted To significantly reduce cell proliferation in the target tissue, while the viability of the patient is maintained. The treatment is generally continued until a significant reduction is present, for. At least about 50% reduction in specific cell count and can continue until substantially no more unwanted cells are detected in the body become.

for Identification of kinase inhibitors are available in various assay systems. In scintillation proximity assay (Sorg et al., J. of Biomolecular Screening: 7, 11-19, 2002) and The FlashPlate assay involves the radioactive phosphorylation of a Protein or peptide as a substrate with γATP measured. In presence an inhibitory compound is not or a diminished radioactive signal detectable. Furthermore, the Homogeneous are time-resolved Fluorescence Resonance Energy Transfer (HTR-FRET) and fluorescence polarization (FP) technologies are useful as assay methods (Sills et al., J. of Biomolecular Screening, 191-214, 2002).

Other Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK). The phospho-AK binds only the phosphorylated substrate. This bond is reactive with a second peroxidase-conjugated anti-sheep antibody Chemiluminescence detectable (Ross et al., Biochem J. 366: 977-981, 2002).

It There are many with a deregulation of cell proliferation and the Cell death (apoptosis) associated diseases and disease states. The Diseases and disease states the compounds according to the invention treated, prevented or mitigated include the following listed Diseases and disease states, but are not limited to this. The compounds of the invention are useful in the treatment and / or prophylaxis of a number of different Diseases and disease states, in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells is present in the intimal layer of a vessel, as a result of restricted Circulation of this vessel, z. In neointimal occlusive lesions. To occlusive graft vascular disease of interest Atherosclerosis, coronary vascular disease after transplantation, venous graft stenosis, peri-anastomotic Denture restenosis, restenosis after angioplasty or stent placement and the same.

The The present invention encompasses the use of the compounds of the invention for the treatment or prevention of cancer. Subject of the invention is in particular the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment and / or prophylaxis of solid tumors, the solid tumor being particularly preferred the group consisting of brain tumor, tumor of the urogenital tract, Tumor of the lymphatic system, gastric tumor, laryngeal tumor, lung tumor selected is. Preferred may also selected solid tumors from the group consisting of monocytic leukemia, lung adenocarcinoma, small cell and non-small cell lung carcinoma, renal cell carcinoma, endometrial carcinoma, multiple myeloma, prostate cancer, colorectal cancer, pancreatic cancer, Glioblastomas and breast carcinoma with drugs containing compounds of the invention be treated.

The Compounds of the invention can be administered to patients for the treatment of cancer. The present Compounds inhibit over binding to IGF-1R tumor angiogenesis and thus influence the Growth of tumors (S.E. Dunn et al Mol Carcinog 2000 Jan; 27 (1): 10-7). The properties of the compounds according to the invention leave them also for the treatment of certain forms of blindness associated with retinal neovascularization in context, appear appropriate.

object Therefore, the invention is also the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and Stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment and / or prophylaxis of Diseases caused by angiogenesis, mediates and / or be propagated.

A such disease involving angiogenesis is one Eye disease, such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.

object Therefore, the invention is also the use of the compounds of the invention for Preparation of a medicament for treatment and / or prophylaxis the above diseases.

The Use of compounds of the invention and / or their physiologically acceptable salts and solvates Preparation of a medicament for treatment and / or prophylaxis of inflammatory diseases, falls as well within the scope of the present invention. To such inflammatory diseases counting for example rheumatoid arthritis, psoriasis, contact dermatitis, Late Type the hypersensitivity reaction and the same.

Prefers is the use for the treatment of diseases, preferably from the group of hyperproliferative and non-hyperproliferative diseases.

in this connection are cancer or non-cancerous diseases.

object The invention is also the use of compounds according to the invention and / or their physiological harmless salts, derivatives, solvates and stereoisomers, including theirs Mixtures in all proportions for the manufacture of a medicament for the treatment of diseases, selected consisting of the group of non-cancerous diseases Psoriasis, arthritis, inflammation, Endometriosis, scarring, benign prostatic hyperplasia, immunological Diseases, autoimmune diseases and immunodeficiency diseases.

Another object of the invention is the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions for the manufacture of a medicament for the treatment of diseases selected from the group of cancerous diseases consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, Liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, cervical cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, multiple myeloma, chronic leukemia and acute leukemia.

The Present compounds are also suitable for combination with known Anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, Androgen receptor modulators, retinoid receptor modulators, cytotoxic Substances, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, growth factor inhibitors and angiogenesis inhibitors. The present compounds are suitable especially for common use with radiotherapy.

"Estrogen receptor modulators" refers to Compounds that interfere with the binding of estrogen to the receptor or these inhibit, independently of how this happens. To the estrogen receptor modulators counting for example tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, Toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3 yl] -phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl hydrazone and SH646, this listing no restriction should represent.

"Androgen receptor modulators" refers to Compounds that interfere with the binding of androgens to the receptor or these inhibit, independently of how this happens. The androgen receptor modulators include Example finasteride and other 5α-reductase inhibitors, nilutamide, Flutamide, bicalutamide, liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to Compounds that interfere with the binding of retinoids to the receptor or these inhibit, independently of how this happens. To such retinoid receptor modulators counting for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.

"cytotoxic Substances "refers focus on compounds primarily through direct exposure on cell function lead to cell death or cell mitosis inhibit or disturb including alkylating agents, tumor necrosis factors, intercalators Agents, microtubulin inhibitors and topoisomerase inhibitors.

To include the cytotoxic substances for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, Lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin, Temozolomide, Heptaplatin, Estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulven, Dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, Benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane-1,6-diamine) -mu- [diaminoplatinum (II)] bis [diamine (chloro) platinum (II)] - tetrachloride, Diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, Zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, Pinafid, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-desoxo-10-hydroxycarminomycin, Annamycin, galarubicin, elinafide, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl daunorubicin (see WO 00150032), but this is not intended to be limiting.

To include the microtubulin inhibitors for example, paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, Docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, Anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidenchartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5- kl] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4 ': b, 7] indolizino [1,2b] quinoline-10,13 (9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxan, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazole-1-carboxamide, Asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-3,5-dimethoxyphenyl] - 5,5a, 6,8,8a, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3- (methylenedioxy) 5-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3-aminopropylamino) - 7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9 -oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy 7H-indeno [2,1-c] quinolin-7-one and dimesna.

To the "antiproliferative Means "include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, Fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabic sodium hydrate, Raltitrexed, Paltitrexide, Emitefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, furarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-B-L-mannoheptopyranosyl] adenine, Aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazine-6-yl (S. ) ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1,11-diaza-tetracyclo (7.4.1.0.0) -tetradeca-2,4,6 -trien-9-ylessigsäureester, Swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative Means " also monoclonal antibodies against growth factors such as Erbitux, trastuzumab and tumor suppressor genes, like p53, over recombinant virus-mediated Gene transfer can be delivered (see, e.g., U.S. Patent No. 6,069,134).

Example 1: Preparation of 3,4,5-trimethoxy-4- (1H-pyrrolo [2,3-b] pyridin-2-yl) -phenol

Under Nitrogen becomes 0 ° C 33 mL lithium diisopropylamide solution (1 M in THF) and with stirring at 0-5 ° C, a solution of 3.6 g of 3-methylpyridine 1 in 50 mL THF was added dropwise. At the specified temperature becomes 30 Stirred for a few minutes and subsequently a solution of 5 g of 3,4,5-trimethoxybenzonitrile in 50 mL of THF. you stirs 1.5 h at 0-5 ° C after all and finally gives add another 33 mL lithium diisopropylamide solution. Connecting will be the reaction mixture at 80 ° C for 2 h heated. For working up you leave the Cool the batch to room temperature and pours the mixture on ice. After the phase separation is still three times extracted with 100 mL dichloromethane, the combined organic Phases dried and the solvent removed in a vacuum. The residue is over with ethyl acetate a silica gel column purified by chromatography. 4.3 g of yellow crystals are obtained which show a melting point of 174.0-175.5 ° C.

• – 2,6-Dimethoxy-4-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenol und
• – 2-(1H-Indol-5-yl)-1H-pyrrolo[2,3-b]pyridin

Further compounds of the formula VII which can be prepared in this way are, for example:

• - 2,6-dimethoxy-4- (1H-pyrrolo [2,3-b] pyridin-2-yl) -phenol and
• - 2- (1H-indol-5-yl) -1H-pyrrolo [2,3-b] pyridine

Example 2: Preparation of 4-chloro-2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridine

To a solution from 1 g of 7-azaindole prepared according to Example 1 in 30 mL redistilled 1,2-dimethoxyethane is added to 1.5 g of 3-chloroperbenzoic acid and stirred for 1.5 h at room temperature.

Finally there To 40 mL diethyl ether and left for 1.5 h stir at room temperature. The resulting crystals are filtered off, washed with ether and dried in the air. This gives 0.9 g (56%) of yellow crystals.

A Suspention from 0.9 g of the 3-chloroperbenzoate is dissolved in 10 mL of water solved and with a saturated one Potassium carbonate solution first adjusted to pH = 9 then to pH = 12 and stirred for 12 h at room temperature, where Crystals fail. The crystals are sucked off, with water washed and at 80 ° C Dried in vacuo for 3 h. 0.5 g (85%) of beige crystals are obtained.

500 mg of the N-oxide are heated together with 10 ml of POCl ₃ 2h at 110 ° C. After cooling, the reaction mixture is poured into ice-water and adjusted to pH = 13 with concentrated sodium hydroxide solution. The resulting precipitate is stirred with ethyl acetate, filtered with suction through kieselguhr and the residue is discarded. From the filtrate, the organic phase is separated, dried and the solvent in vac removed. The residue is chromatographed with ethyl acetate and the product fractions are crystallized from ethyl acetate. 0.4 g (75%) of yellow crystals having a melting point of 188.0-190.0 ° C. are obtained.

A other compounds of formula VI prepared in this way can be 4-chloro-2- (3-methoxy-phenyl) -1H-pyrrolo [2,3-b] pyridine

Example 3: Production of quinolin-3-yl- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3b] pyridin-4-yl] -amine

2 g of the compound of the formula VI prepared according to Example 2 are dissolved in 50 ml of dioxane, 1.1 g of potassium tert-butylate are added and the mixture is heated to 80.degree. Then 20 mg of 2- (dimethylamino) ferrocene-1-yl-palladium (II) chloride dinorbornyl-phosphine complex are added and finally 1.15 g of 3-aminoquinoline. After 12 h, the batch is allowed to cool to room temperature and the reaction mixture is partitioned between ethyl acetate and water. The organic phase is dried, freed from the solvent in vacuo and chromatographed on silica gel. This gives 1.1 g of yellow crystals (melting point 279.5-280 ° C). 300 mg of the product thus prepared are dissolved in 20 ml of acetone and 20 ml of methanol, and the pH of the solution is adjusted to 3 with ethanolic hydrochloric acid. The precipitated crystals are filtered off with suction, washed with diethyl ether and dried in air. 300 mg of orange-colored crystals are obtained. Melting point: 227.0-228.5 ° C

• – 3-[2-(3,4,5-Trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-benzonitril
• – (2-Pyridin-2-yl-ethyl)-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – (2-Pyridin-3-yl-ethyl)-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – Pyridin-3-ylmethyl-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – Pyrimidin-2-yl-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – (3-Chloro-4-fluoro-phenyl)-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – (3-Fluoro-phenyl)-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – [4-Methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin
• – Pyridin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-amin

Further compounds of the formula I which can be prepared in this way are, for example:

• - 3- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-ylamino] benzonitrile
• - (2-pyridin-2-yl-ethyl) - [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• - (2-pyridin-3-yl-ethyl) - [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• - Pyridin-3-ylmethyl- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• - Pyrimidin-2-yl- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• - (3-chloro-4-fluoro-phenyl) - [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• - (3-fluoro-phenyl) - [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine
• [4-methoxy-3- (4-methylpiperazin-1-yl) -phenyl] - [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridine 4-yl] -amine
• - Pyridin-3-yl- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -amine

Example 4: Inhibition of IGF-1R (IC ₅₀ )

cultivated human tumor cells expressing the IGF1 receptor (IGF1R) (e.g. MCF-7 or Calu-6), are probed with human IGF1, the natural Ligand of IGF1R stimulated. The stimulation induces autophosphorylation of tyrosine residues in the cytoplasmic IGF1R domain, which triggers signal transduction cascades leading to apoptosis inhibition and proliferation of cells.

The Amount of phosphorylated IGF1R is regulated by a receptor specific Capture ELISA or a LUMINEX analog assay. The IGF1R from cell lysates is detected by means of a specific antibody a 96-well ELISA plate or LUMINEX beads bound ("Capturing"), and the Tyrosinphosphorylierung with a biotin-labeled anti-phosphotyrosine antibody and a streptavidin-peroxidase conjugate by a chemiluminescent method or by means of a fluorescence-labeled antiphosphotyrosine antibody detected.

for Determination of activity Kinase inhibitors are cells with increasing concentrations of these Connections for Pretreated for 45 min and then stimulated with IGF1 for 5 min. As an internal control, the biological activity of the ligand IGF1 checked as well measure a concentration series of an IGF1R reference inhibitor.

For quinolin-3-yl- [2- (3,4,5-trimethoxyphenyl) -1H-pyrrolo [2,3b] pyridin-4-yl] -amine is prepared according to this The result is the following: The substance inhibits the kinase 50% IGF-1R when the compound is present at a concentration of 14 μM.

Further Inhibition constants of compounds of the invention are in the Table 1 listed.

The The following examples relate to pharmaceutical preparations:

Example 5a: Injection glasses

A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate is double distilled in 3 L Water with 2 N hydrochloric acid adjusted to pH 6.5, sterile filtered, filled into injection jars, under sterile conditions and lyophilized sterile. each Injection glass contains 5 mg active ingredient.

Example 5b: Suppositories

you melts a mixture of 20 g of an active ingredient according to the invention with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and lets cool. Each suppository contains 20 mg of active ingredient.

Example 5c: solution

A solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH ₂ PO ₄ · 2 H ₂ O, 28.48 g Na ₂ HPO ₄ · 12 H ₂ O and 0.1 g of benzalkonium chloride in 940 mL of double-distilled water , Adjust to pH 6.8, make up to 1 L and sterilize by irradiation. This solution can be used in the form of eye drops.

Example 5d: ointment

you mixes 500 mg of an active ingredient according to the invention with 99.5 g Vaseline under aseptic conditions.

Example 5e: Tablets

One Mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual way to tablets compressed so that each tablet contains 10 mg of active ingredient.

Example 5f: dragées

Analogous Example 5e tablets are pressed, which are then in the usual Way with a plating Sucrose, potato starch, Talc, tragacanth and dyestuff coated become.

Example 5g: Capsules

2 kg of active ingredient are in common Way filled in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.

Example 5h: Ampoules

A solution of 1 kg of an active ingredient according to the invention in 60 L double distilled water is sterile filtered, in Filled ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims (14)

Compounds of the formula I,

where R ^{1 is} H, A, Ar, Ar-A or A-Ar, A is unbranched, branched or cyclic alkyl having 1-14 C atoms, in which one or two CH ₂ groups are represented by an O or S atom and / or or by an NH, NA, CONH, NHCO or -CH = CH group and / or also 1-7 H atoms may be replaced by Hal, and wherein one or two CH ₃ groups by NH ₂ , NAH, NA ₂ or CN, Ar is a mono- or binuclear aromatic homo or heterocycle having 1 to 4 N, O and / or S atoms and 5 to 10 skeleton atoms, which is unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen , Hal, A, OH, OA, NH _2, NHA, NA _2, NO _2, CN, OCN, SCN, COOH, COOA, CONH _2, CONHA, CONA _2, NHCOA, NHCONH _2, NHSO ₂ A, CHO, COA , SO ₂ NH ₂ and / or S (O) _g A may be substituted, Hal is F, Cl, Br or I, X is CH or N, wherein in each compound of formula I one group XN and two groupings X are CH, Y CH ₂ or a saturated bond, Z is CH or N, wherein in each compound of formula I at most two Groups Z NH and preferably one or no group Z NH, R ^{2 '} , R ^2'' , R ^{2''' are} each independently H, Hal, OH, CN, NH ₂ , unbranched or branched alkyl having 1-4 C Atoms in which a CH ₂ group can be replaced by an O or S atom and / or by an NH, NA, CONH, NHCO or -CH = CH group and / or also 1-4 H atoms by Hal and wherein a CH ₃ group may be replaced by NH _2, NAH, NA ₂ or CN, R ³ is H or a, g is 0, 1 or 2 and

a single or double bond, as well as their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. Compounds according to claim 1 which correspond to the formula AII

wherein R ¹ , R ² , R ³ , Y and Z have the meaning given for the formula I and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. Compounds according to claim 1 or 2 which correspond to the formula AIII

wherein Y is a bond, Z is CH, R ³ H and R ¹ and R ^{2 have} the meaning given for the formula I or AII, as well as their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. Compounds according to one or more of claims 1 to 3, wherein the unspecified radicals have the meaning given in the formula I, but wherein in the partial formula Aa R ¹ unsubstituted or mono- or polysubstituted by Hal, cyano, methyl or methoxy-substituted phenyl , Phenylmethyl, pyridyl, pyridylmethyl, pyridylethyl, pyrimidyl, piperazyl, quinolinyl, imidazoyl, imidazyolpropyl, pyrrolyl, pyrrolylethyl, furthermore H, N, N'-dimethylaminopropyl or cyanobutyl or one of the following radicals

wherein the linkage with the main body of the formula I, AII or AIII is in each case via the bond to the left, which is not a methyl group, means, in the partial formula Ab R ^{2 '} , R ^2'' , R ^2''' respectively independently of one another are H, methoxy, ethoxy, n-propoxy or i-propoxy, in the partial formula AcR ^{2 '} , R ^{2 "} , R ^2''' each independently of one another denote H or methoxy, in the partial formula Ad R ^{2 '} , R ^{2 ''} , R ^{2 '''} each methoxy, in the partial formula Ae R ^2' , R ^{2 ''} , R ^{2 '''are} each independently H, methoxy, ethoxy, n-propoxy or i-propoxy and R ^{1 has} the meaning given for the sub-formula Aa, in the sub-formula Af R ^{2 '} , R ^2'' , R ^{2''' are} each independently H or methoxy and R ^{1 has} the meaning given for the sub-formula Aa, at the partial formula Ag R ^{2 '} , R ^2'' , R ^{2''' are} each methoxy and R ^{1 has} the meaning given for the partial formula Aa, and their pharmaceutically acceptable salts, De derivatives, solvates and stereoisomers, including mixtures thereof in all ratios. Process for the preparation of compounds of the formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, characterized in that a compound of the formula IX,

in which X has the meaning given for the formula I with a compound of the formula VIII

wherein Z, Y and R ^{2 have} the meanings given in formula I, to give a compound of formula VII,

which is optionally reduced to a corresponding 2,3-dihydro-indole compound and from which in the next step a compound of formula VI is prepared,

wherein L is a suitable leaving group, and then the compound of formula VI in a further step with a compound of formula V R ¹ -NH ₂ is reacted to form a compound of formula IV

to obtain, which is finally linked with a radical R ³ to a compound of formula I, and optionally converts a base or acid of formula I into one of its salts. Compounds according to one or more of claims 1 to 4 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions as a medicine. Medicament containing at least one compound according to one or more of claims 1 to 4 and / or their physiological harmless salts, derivatives, solvates and stereoisomers, including mixtures thereof in all circumstances, and, where appropriate, carrier and / or auxiliaries. Medicament containing at least one compound according to one or more of claims 1 to 4 and / or their physiological harmless salts, derivatives, solvates and stereoisomers, including mixtures thereof in all circumstances and at least one further active pharmaceutical ingredient. Set (kit) consisting of separate packs of a) an effective amount of a compound according to one or more the claims 1 to 4 and / or their physiologically acceptable salts, derivatives, Solvates and stereoisomers, including mixtures thereof in all conditions and b) an effective amount of another active pharmaceutical ingredient. Compounds according to one or more of claims 1 to 4 and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions as activators or inhibitors of kinases, especially tyrosine kinases. Compounds according to one or more of claims 1 to 4 and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions as inhibitors of the receptor tyrosine kinase IGF-1R. Use of compounds according to one or more the claims 1 to 4 and / or their physiologically acceptable salts, Deri vate, Solvates and stereoisomers, including mixtures thereof in all conditions for the manufacture of a medicament for prophylaxis or treatment of diseases in which the inhibition of receptor tyrosine kinase IGF-1R leads to the improvement of the clinical picture. Use of compounds according to one or more the claims 1 to 4 and / or their physiologically acceptable salts, derivatives, Solvates and stereoisomers, including mixtures thereof in all conditions for the manufacture of a medicament for prophylaxis or treatment of cancer, tumor growth, tumor angiogenesis, arteriosclerosis, the diabetic retinopathy and inflammatory diseases. Use of compounds according to one or more the claims 1 to 4 and / or their physiologically acceptable salts, derivatives, Solvates and stereoisomers, including mixtures thereof in all conditions for the manufacture of a medicament for prophylaxis or treatment breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma and renal cell carcinoma and endometrial carcinoma.