EP2903992A1 - 7-azaindol-2,7-naphthyridine derivative for the treatment of tumors - Google Patents

Abstract

The invention relates to the compound 4-(2-methyl-1H-pyrrolo[2,3-b]pyridino-3-yl)- [2,7]naphthyridino-1-ylamine and its pharmaceutically usable salts and/or tautomers. The invention also relates to the use of said compounds for the treatment of tumors, tumor growth, tumor metastases and/or AIDS.

Description

-AZAINDOL-2,7-NAPHTHYRIDINE DERIVATIVE FOR THE TREATMENT OF TUMORS

The invention relates to the compound 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine

 and its pharmaceutically acceptable salts and / or tautomers.

The invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.

It has been found that the compound according to the invention and its salts and / or tautomers, while being well tolerated, have very valuable pharmacological properties.

In particular, it shows an inhibiting effect of cell proliferation /

 Cell vitality as an antagonist or agonist. The compound according to the invention can therefore be used for the control and / or treatment of tumors, tumor growth and / or tumor metastases.

 The antiproliferative effect can be tested in a proliferation assay / vitality assay.

Accordingly, the compound of the invention or a

pharmaceutically acceptable salt thereof administered for the treatment of cancer, including solid carcinomas, such as carcinomas (eg, the lungs, pancreas, thyroid, urinary bladder, or bladder) Colon), myeloid diseases (eg myeloid leukemia) or

Adenomas (eg villous colon adenoma).

 The tumors also include monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma, pancreatic and / or breast carcinoma.

 The compound is also useful in the treatment of immunodeficiency induced by HIV-1 (Human Immunodeficiency Virus type 1).

Cancerous hyperproliferative disorders include brain, lung, squamous, bladder, stomach, pancreatic, liver, kidney, colorectal, breast, head, neck, esophageal, gynecological, thyroid, lymphoma, chronic leukemia and acute leukemia. In particular, cancerous cell growth is a disease that is an object of the present invention. The present invention is therefore the compound of the invention as a drug and / or drug in the treatment and / or prophylaxis of the diseases mentioned and the use of the compound of the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of the diseases mentioned as well as a method for Treatment of said

 Diseases comprising the administration of the inventive

 Compound to a patient in need of such administration.

It can be shown that the compound of the invention

 has antiproliferative activity. The compound of the invention is administered to a patient with a hyperproliferative disorder, e.g. To inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to

 Tissue repair, etc. The present compound is useful for

prophylactic or therapeutic purposes. As used herein, the Term "treating" as a reference both to the prevention of

Diseases as well as the treatment of pre-existing conditions. Prevention of proliferation / vitality is achieved by administration of the compound of the invention prior to the development of the evident disease, e.g. To prevent tumor growth. Alternatively, the compound is used to treat persistent diseases by stabilizing or ameliorating the clinical symptoms of the patient.

The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.

The susceptibility of a particular cell to treatment with the compound of the invention can be determined by testing in vitro. Typically, a culture of the cell with the invention

Compound is incubated at various concentrations for a time sufficient to allow the active agents to induce cell death or to inhibit cell proliferation, cell vitality or migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The amount of cells remaining after treatment are then determined.

 The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the undesirable cell population in the target tissue while increasing the viability of the patient

Patient is maintained. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body. There are many diseases associated with deregulation of cell proliferation and cell death (apoptosis). The ailments of interest include, but are not limited to, the following conditions. The compound of the invention is useful in the treatment of a series

various conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells in the intimal layer of a vessel is present, resulting in limited blood flow to this vessel, z. In neointimal occlusive lesions. Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, perinastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.

The compound according to the invention also acts as a regulator, modulator or inhibitor of protein kinases, in particular of the serine / threonine kinase type, which include, among others, the phosphoinositide-dependent kinase 1 (PDK 1). A certain effect of the compound of the invention in the inhibition of serine / threonine kinases PDK1, ΙΚΚε and TBK1, as well as in ALK-1.

PDK1 phosphorylates and activates a subset of the AGC protein kinase family, including PKB, SGK, S6K and PKC isoforms. These kinases are involved in the PI3K signaling pathway and control basic cellular functions such as survival, growth, and differentiation. PDK1 is thus an important regulator of diverse metabolic, proliferative and life-sustaining effects.

The compound of the invention also exhibits TGFβ receptor I kinase inhibiting properties. A number of diseases have been linked to the overproduction of TGF-ß1. Inhibitors of the intracellular TGF-β signaling pathway are suitable treatments for fibroproliferative disorders.

Fibroproliferative disorders specifically include renal disorders associated with unregulated TGF-β activity, and severe fibrosis, including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescent GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and nephropathy associated with HIV. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those associated with the incidence of Raynaud's syndrome. Pulmonary fibrosis caused by excessive TGF-β activity includes adult respiratory distress syndrome, idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis, often with

Autoimmune disorders, such as systemic lupus erythematosus and scleroderma, chemical contact or allergies. Another autoimmune disorder associated with fibroproliferative properties is rheumatoid arthritis.

Ocular disorders associated with a fibroproliferative condition include proliferative vitreoretinopathy associated with a

Retinal repair surgery, cataract extraction with intraocular lens implantation, and post-glaucoma drainage surgery, and is associated with TGF-β1 overproduction.

TGF-β1, as a member of the TGF-β family, is a ligand of the TGF-β receptor family consisting of heterodimeric cell membrane-containing proteins having an extracellular receptor portion and an intracellular kinase domain. Members are Type I and Type II Rezptoren; see also Hinck FEBS Lett. 2012 http://dx.doi.Org/10.1016/j.febslet.2012.05.028 Signal transduction of the ligands TGF-β1, -β2 and -β3 via their respective receptors is known to be involved in cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, in wound healing, production

extracellular matrix and immunosuppression play a role, see also review by Massague Annu. Rev. Biochem. 1998. 67: 753-91.

When TGF-B1 binds to a type II receptor, the corresponding type I receptor associates and becomes phosphorylated. This complex phosphorylates a receptor-regulated 4s Smad protein (R-Smad), which subsequently associates with Smad4, migrates to the nucleus and, by activating transcription, leads to a change in cell behavior.

 TGF-β type I receptor, also called ALK5 (activin receptor-like kinase 5) or TβR-1, is well documented in SwissProt under P36897, as well as the type Ii receptor under P37173 and ALK-1 under P37023. For ALK-5, Smad2 and Smad3 are signaling proteins, for ALK-1 are Smad-1, -5 and -8

See also Cunha BLOOD, 30 JUNE 2011 VOLUME 117, NUMBER 26, 6999

The compound according to the invention represents a selection from WO

2012/104007

 The compound according to the invention has a markedly higher activity than the structurally closest compounds from WO 2012/04007.

 WO 2005/095400 A1 describes other azaindole derivatives as protein kinase inhibitors.

 In WO 2008/079988 A2 quinazoline derivatives are described as PDK1 inhibitors for the fight against cancer.

 In WO 2008/112217 A1 benzonaphthyridine derivatives are described as PDK1 inhibitors for combating cancer.

 Pyridinonyl derivatives are known as PDK1 inhibitors for combating cancer from WO 2008/005457.

 Pyrrolo-pyridine kinase anticancer modulators are available in WO

2008/124849 described. In WO 2006/106326 A1 and WO 2008/156726 A1 others are

heterocyclic compounds described as PDK1 inhibitors for the fight against cancer.

 In WO 2009/054941 A1 pyrrolopyridine derivatives are described as PDK1 inhibitors for combating cancer.

ΙΚΚε and TBK1 are serine / threonine kinases that have high homologies with each other and with other IkB kinases. Both kinases play an integral role in the innate immune system.

Double-stranded RNA viruses are recognized by the Toll-like receptors 3 and 4, as well as the RNA helicases RIG-I and MDA-5, and lead to activation of the TR1F-TBK1 / IKKE-IRF3 signaling cascade, resulting in a type I interferon Answer leads.

Boehm and colleagues described in 2007 ΙΚΚε as a novel breast cancer oncogene [J.S. Boehm et al., Cell 129, 1065-1079, 2007]. 354 kinases were screened for their ability to collaborate with an activated form of the MAPK kinase mek to recapture the Ras transforming phenotype. ΙΚΚε was considered as a cooperative

Oncogene identified. In addition, the authors were able to show that IKBKE is amplified and overexpressed in numerous breast cancer cell lines and tumor samples. The reduction of gene expression by RNA interference in breast cancer cells induces apoptosis and impairs its proliferation. Eddy and colleagues came in 2005 to similar

 Findings that emphasize the importance of ΙΚΚε in breast cancers [S.F. Eddy et al., Cancer Res. 2005; 65 (24), 11375-11383].

A protonorigenic effect of TBK1 was first reported in 2006

reported. Korherr and colleagues identified in a screening of a 251,000 cDNA gene library with TRIF, TBK1 and IRF3 three genes, which is typically involved in the innate immune response are, as pro-angiogenic factors [C. Korherr et al., PNAS, 103, 4240-4245, 2006].

 Chien and colleagues published in 2006 [Y. Chien et al., Cell 127, 157-170, 2006] that TBK1 - / - cells are only conditionally transformable with oncogenic Ras, suggesting an involvement of TBK1 in Ras-mediated transformation. Furthermore, they showed that an RNAi-mediated knock-down of TBK1 induces apoptosis in MCF-7 and Panc-1 cells. Recently, Barbie and colleagues published that TBK1 is essential in numerous cancer cell lines with mutant K-Ras, suggesting that TBK1 intervention in corresponding tumors may be more therapeutic

[DABarbie et al., Nature Letters 1-5, 2009].

S.I. Cunha and K. Pietras describe in Blood, 117 (26), 6999-7006 (2011), the delay of tumor growth by inhibiting the receptor ALK1, particularly in breast carcinoma and melanoma.

Protein kinase-mediated diseases are characterized by abnormal activity or hyperactivity of such protein kinases. Abnormal activity involves either: (1) expression in cells that usually do not express these protein kinases; (2) increased kinase expression leading to unwanted cell proliferation such as cancer; (3) increased kinase activity resulting in undesired cell proliferation, such as cancer, and / or hyperactivity of the corresponding protein kinases. Hyperactivity refers to either amplification of the gene encoding a particular protein kinase or the generation of an activity level that can be correlated with a cell proliferative disorder (ie, as the kinase level increases, the severity of one or more symptoms of the cell proliferative disorder increases). The bioavailability of a protein kinase may also be due to the

Presence or absence of a set of binding proteins of this kinase. The major cancers that can be treated using the compound of the invention include colorectal cancer,

small cell lung cancer, non-small cell lung cancer, multiple myeloma as well as renal cell carcinoma and endometrial carcinoma, especially cancers in which PTEN is mutated, and the like. a. Breast cancer, prostate cancer and glioblastoma.

In addition, the compound of the present invention can be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiation and / or to restore the efficacy of certain existing cancer chemotherapies and radiation.

The compound according to the invention is also understood as meaning the hydrates and solvates of this compound, furthermore pharmaceutically usable derivatives. The invention also relates to the salts, and the hydrates and solvates of this compound. Solvates of the compound are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.

 Of course, the invention also encompasses the solvates of the salts of the compound according to the invention.

 Pharmaceutically usable derivatives are understood, for example, as the salts of the compound of the invention as well as so-called prodrug compounds.

 Prodrug derivative is understood to mean the z. B. alkyl or acyl groups, sugars or oligopeptides modified inventive compound which is rapidly cleaved in the organism to the active compound of the invention.

These include biodegradable polymer derivatives of the compound of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995). The term "effective amount" means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, or human, such as is sought or sought by a researcher or physician.

 Moreover, 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 clinical picture, a disease state, a condition, a disorder or side effects or even a reduction in the progression of a disease, a condition or a disorder.

The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

The invention provides the compound 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and its salts and a process for the preparation of this compound and their pharmaceutically acceptable salts and tautomers, characterized in that

in a Masuda reaction, a compound of formula II

wherein R is Br or I and R ^{2 is} an aza-indole protecting group, reacted with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the intermediately formed boronic pinacol ester in a Suzuki reaction with a compound of formula III

wherein X is Cl, Br or I,

wherein R ^{2 is} an aza-indole protecting group, and then the protecting group R ^{2 is} split off from the compound of formula IV, and / or 4- (2-methyl-1H-pyrrolo [2,3-b] pyridine-3 -yl) - [2,7] naphthyridin-1-ylamine converts to one of its salts.

Above and below, the radicals R ¹ and R ^{2 have} the meanings given for the formulas II, II and IV, unless expressly stated otherwise.

R ¹ is Br or I, preferably I.

R ^{2 represents} an azaindole protective group, preferably tert-butyloxycarbonyl or benzenesulphonyl, more preferably benzenesulphonyl.

The benzenesulfonyl protecting group may also be replaced by other sulfonyl or oxycarbonyl protecting groups known to those skilled in the art. The cleavage of alkyl or Arylsulfonylgruppen carried out with alkali metal hydroxide and primary alcohols under standard conditions.

The compound 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and also the starting materials for their preparation are otherwise per se Known methods prepared as described in the literature (eg in the standard works such as Houben-Weyl, methods of organic chemistry, Georg Thieme Verlag, Stuttgart), under

Reaction conditions which are known and suitable for the said reactions. One can also make use of known per se, not mentioned here variants.

The compound 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine can preferably be obtained by dissolving in a

reaction of a compound of the formula II with a compound of the formula III in a sequential Masuda / Suzuki reaction.

In the compounds of the formula III, X is preferably Cl, Br or I. After the reaction of the compounds of the formula II with the compounds of the formula III, the removal of the aza-indole-protecting group R ^{2 also takes place} .

The reaction occurs under conditions of Suzuki coupling.

The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about -30 ° and 140 °, normally between 0 ° and 110 °, in particular between about 70 ° and about 100 °.

 Suitable inert solvents are 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; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; 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, dimethylacetamide or dimethylformamide (DMF); Nitrites such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.

 Particularly preferred is dimethoxyethane, diglyme, methanol and / or dioxane. Pharmaceutical salts and other forms

 The said compound of the invention can be used in its final non-salt form. On the other hand, the present invention also encompasses the use of this compound in the form of its pharmaceutically acceptable salts derived from various organic and

inorganic acids and bases can be derived by art-known procedures. Pharmaceutically acceptable salt forms of the compound according to the invention are mostly prepared conventionally. The acid addition salts can be formed by adding the

Compound of the invention with pharmaceutically acceptable

organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, others

Mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such

 Ethansulfonat, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compound of the invention include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,

Chloride, chlorobenzoate, citrate, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate , Mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate,

Persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

The compound of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C C) alkyl halides, e.g.

Methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Ci ₀ -C ₁₈ ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl- (C 1 -C ₄ ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but no

 To represent restriction.

The acid addition salts of the compound of the invention are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ, in a sense, from their corresponding salt forms with respect to certain physical ones Properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.

In view of the above, one sees that under the expression

"pharmaceutically acceptable salt" as used herein means an active ingredient containing the compound of the invention in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient previously used, imparts improved pharmacokinetic properties. The pharmaceutical

In addition, acceptable salt form of the active ingredient may provide this drug with a desired pharmacokinetic property that it has not previously possessed, and may even positively affect the pharmacodynamics of that drug in terms of its therapeutic efficacy in the body.

The invention furthermore relates to medicaments containing 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its

pharmaceutically usable salts and tautomers, and optionally excipients and / or adjuvants.

Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of the compound of the invention, depending on the condition of the disease being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. 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 pharmaceutical formulations with one of the im

pharmaceutical process well known in the art.

Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways, adapt. Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).

Pharmaceutical formulations adapted for oral administration may be administered 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.

Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerine, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.

Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Sliding and

Lubricants, such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. A disintegrants or solubilizers, e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch,

Gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethylcellulose, 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. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.

A powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, 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 wetting it with a binder such as syrup, starch paste, Acadia slime, or solutions of cellulosic or polymeric materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are in granules

be broken up. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compound of the invention may also be combined with a free-flowing inert carrier and then compressed directly into tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque

Protective layer consisting of a shellac sealant, a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.

Oral fluids, e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax, etc. The compound of the invention and salts and tautomers thereof can also be in the form of Liposomenzuführsystemen, such as small

unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be different

Phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines.

The compound of the invention as well as the salts and tautomers thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g.

 Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid,

 Polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels, be coupled.

Pharmaceutical adapted to transdermal administration

Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986). Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient may be either paraffinic or water-miscible

Cream base can be used. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

To the topical application in the mouth adapted pharmaceutical

 Formulations include lozenges, lozenges and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by Schneilinhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for

Administration as a nasal spray or nasal drops with a liquid as a carrier substance comprise solutions of active substance in water or oil. For administration by inhalation adapted pharmaceutical

Formulations include fine particulate dusts or nebulas containing various types of pressurized dosing dispenser

Aerosols, nebulizers or insufflators can be generated.

Pharmaceutical formulations adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes, foams or

Spray formulations are presented.

Pharmaceutical formulations adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed

Ampoules and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use. Formulated injection solutions and

Suspensions can be made from sterile powders, granules and tablets.

It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.

A therapeutically effective amount of the compound of the invention will depend on a number of factors including, for example, age and age Weight of the animal, the exact disease state that requires treatment, and its severity, the nature of the formulation and the route of administration, and is ultimately determined by the doctor or veterinarian. However, an effective amount of a compound of the invention for the treatment of neoplastic growth, eg, colon or breast carcinoma, is generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or tautomer thereof may be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other disease states mentioned above.

The invention furthermore relates to medicaments comprising 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its

 pharmaceutically acceptable salts and tautomers, and at least one further active pharmaceutical ingredient.

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

 (A) an effective amount of 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or their pharmaceutically acceptable salts and

 (b) an effective amount of another drug.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can eg separate ampoules in which in each case an effective amount of 4- (2-methylm H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or their

pharmaceutically acceptable salts and tautomers and an effective amount of another active pharmaceutical ingredient dissolved or in lyophilized form.

USE

The present compound is useful as a pharmaceutical agent for mammals, especially for humans, in the treatment and

Fighting cancer.

The invention further provides 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and its pharmaceutically acceptable salts and tautomers for use in treatment tumors, tumor growth, tumor metastases and / or AIDS.

The invention further provides 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and its pharmaceutically acceptable salts and tautomers, for use with Treatment of fibrosis, restenosis, HIV infection, Alzheimer's disease, atherosclerosis and / or to promote wound healing.

The present invention encompasses the use of 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its

physiologically acceptable salts and tautomers for the manufacture of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment are from the brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma colorectal cancer. Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.

Also included is the use of 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomers A pharmaceutical composition for the treatment and / or control of a tumorigenic disease in a mammal, which process comprises administering to a diseased mammal in need of such treatment a therapeutically effective amount of a compound of the invention. The therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.

Especially preferred is the use for treating a disease wherein the disease is a solid tumor.

The solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, Urogenital tract, lymphatic system, stomach, larynx and / or lungs.

The solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.

Further preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, the

chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia. The invention furthermore relates to the use of the compound according to the invention for the treatment of bone pathologies, the bone pathology originating from the group osteosarcoma, osteoarthritis and rickets.

4- (2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine may also be used in conjunction with other well-known therapeutics, due to their respective suitability for the treated condition are selected.

 The present compound is 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 agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly useful for co-administration with radiotherapy. "Estrogen Receptor Modulators" refers to compounds that inhibit the binding of estrogen to the

Disrupt or block the receptor, regardless of how this happens. For example, estrogen receptor modulators include

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-dinitrophenylhydrazone and SH646, but this is not intended to be limiting.

 "Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done. "Androgen receptor modulators include, for example, finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide , Liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor. depending on how this happens. Such retinoid receptor modulators include, 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 agents" refers to compounds that cause cell death or interfere with cell myosis, primarily through direct action on cell function, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

 The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine. pidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane -1, 6-diamine) -mu- [diamine-platinum (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-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide,

MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting.

 The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 \ 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, 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, rubitecan, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-Methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5-kl] acridine-2- (6H) propanarnine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9 -hydroxy-4-methyl-1H, 12H-benzo [en] - , 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-methylam

phenyl] -5 _I 5a _l 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 aminopropyl amino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] - ^{acridine-6-ο} η, 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.

 Antiproliferative agents 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, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidene cytidine, 2'-fluoromethylene -2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) -sulfonyl-N-diS-dichlorophenyl urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E. ) -tetradecadienoyl] glycylamino] -L-glycero-BL-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-diazatetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-Amino-pyridine-2-carboxaldehyde-thiosemicarbazone. The "antiproliferative agents" other monoclonal antibodies against growth factors than those already mentioned under the "angiogenesis inhibitors", such as Trastuzu-mab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Pat. No. 6,069,134).

Preferably, but not exclusively, the medicaments of

Table 1 below is combined with 4- (2-ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) [2,7] naphthyridin-1-ylamine.

Table 1.

 Alkylating agent Cyclophosphamide Lomustine

 Busulfan procarbazine

 Ifosfamide altretamine

 Melphalan estramustin phosphate

Hexamethylmelamine mechlorethamine

 Thiotepa streptozocin

 Chlorambucil Temozolomide

 Dacarbazine Semustin

 carmustine

Platinum agent cisplatin carboplatin

 Oxaliplatin ZD-0473 (AnorMED)

 Spiroplatin Lobaplatin (Aetema)

 Carboxyphthalatoplatinum Satraplatin

 Tetraplatinum (Johnson Matthey)

 Ormiplatin BBR-3464 (Hoffrnann-La

Iproplatin Roche)

 SM-11355 (Sumitomo)

AP-5280 (Access)

Antimetabolite azacytidine Tomudex

 Gemcitabine trimetrexate

 Capecitabine deoxycoformycin

 5-fluorouracil fludarabine

 Floxuridine pentostatin

 2-chlorodeoxyadenosine Raltitrexed

 6- ercaptopurine hydroxyurea

 6-thioguanine decitabine (SuperGen)

Cytarabine Clofarabine (Bioenvision)

2-Fluorodeoxycytidine Irofulvene (MGI Pharma)

Methotrexate DMDC (Hoffmann Idatrexate La Roche)

 Ethinylcytidine (Taiho)

Topoisomerase Amsacrine Rubitecane (SuperGen)

Inhibitors Epirubicin Exatecan Mesylate (Daiichi)

 Etoposide Quinamed (ChemGenex)

Teniposide or Mitoxantrone Gimatecan (Sigma-Tau)

Irinotecan (CPT-11) diflomotecan (Beaufour

7-ethyl-10-Ipsen) hydroxycamptothecin TAS-103 (Taiho)

 Topotecan Elsamitrucin (Spectrum)

Dexrazoxanet (TopoTarget) J-107088 (Merck & Co)

Pixantron (Novuspharrna) BNP-1350 (BioNumerik)

Rebeccamycin analog CKD-602 (Chong Kun

(Exelixis) Dang)

 BBR-3576 (Novuspharrna) KW-2170 (Kyowa Hakko)

Antitumor Dactinomycin (Actinomycin I Amonafide

 Antibiotics doxorubicin (adriamycin) azonafide

 Deoxyrubicin anthrapyrazole

 Valrubicin oxantrazole

 Daunorubicin (Daunomycin) Losoxantrone

 Epirubicin bleomycin sulfate (blenoxan)

Therarubicin bleomycinic acid

 Idarubicin bleomycin A

 Rubidazone bleomycin B

 Plicamycin mitomycin C

 Porfiromycin MEN-10755 (Menarini)

Cyanomorpholino-GPX-00 (Gern

 doxorubicin Pharmaceuticals)

 Mitoxantrone (Novantrone)

Antimitotic Paclitaxel SB 408075 (GlaxoSmith

Agent docetaxel Kline)

 Colchicine E7010 (Abbott)

 Vinblastine PG-TXL (Cell Therapeutics)

Vincristine IDN 5109 (Bayer)

 Vinorelbine A 105972 (Abbott)

 Vindesin A 204197 (Abbott)

 Dolastatin 10 (NCI) LU 223651 (BASF)

 Rhizoxin (Fujisawa) D 24851 (ASTA Medica)

Mivobulin (Warner-Lambert) ER-86526 (Eisai)

 Cemadotin (BASF) Combretastatin A4 (BMS)

RPR 109881A (Aventis) isohomohalichondrin-B

TXD 258 (Aventis) (PharmaMar)

 Epothilone B (Novartis) ZD 6126 (AstraZeneca)

T 900607 (Tularik) PEG paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi)

 Cryptophycin 52 (Eli Lilly)! DN-5109 (Indena)

 Vinflunin (Fabre) AVLB (Prescient

 Auristatin PE (Teikoku NeuroPharma)

 Hormones) Azaepothilone B (Bs) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4 prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH)

 Taxoprexin (Protarga) CA-4 (OXiGENE)

Aromatase-aminoglutethimide exemestane

Inhibitors Letrozole Atamestane (BioMedicines)

 Anastrazole YM-511 (Yamanouchi)

formestane

Thymidylate pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor ™ (BioKeys)

inhibitors

DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter

 Glufosfamide (Baxter International)

 International) Apaziquon (Spectrum Albumin + 32P (Isotope Pharmaceuticals)

 Solutions) O6-Benzylguanine (Paligent) Thymectacin (NewBiotics)

 Edotreotide (Novartis)

Farnesyltrans-Arglabin (NuOncology Labs Tipifarnib (Johnson & ferase inhibitors lonafamib (Schering-Plow Johnson)

 BAY-43-9006 (Bayer) Perillyl Alcohol (DOR

 BioPharma)

Pump CBT-1 (CBA Pharma) Zosuquidar Trihydrochloride Inhibitors Tariquidar (Xenova) (Eli Lilly)

 MS-209 (Schering AG) Biricodar dicitrate (vertex)

Histone acetyl trans-Tacedinalin (Pfizer) pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (titanium)

 MS-275 (Schering AG) Depsipeptide (Fujisawa)

Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)

Inhibitors Laboratories) BMS-275291 (Celltech)

Ribonucleoside marimastat (British Biotech) tezacitabine (Aventis) reductase gallium maltolate (titanium) Didox (Molecules for Health

Inhibitors Triapine (Vion)

TNF-alpha-virulizine (Lorus Therapeutic? Revimid (Celgene) Agonists / anti-CDC-394 (Celgene)

qonisten

Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)

Receptor ZD-4054 (AstraZeneca)

 Antaqonisten

Retinoic Acid Fenretinide (Johnson & Alitretinoin (Ligand) Agonist Johnson)

 LGD-1550 (ligand)

Immunomodulators interferon dexosome therapy

 Oncophage (Antigenics) (Anosys)

 GMK (Progenics) Pentrix (Australia Cancer Adenocarcinoma Vaccine Technology)

 (Biomira) JSF-154 (Carrying)

 CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin (Biostar)

 PEP-005 (Peplin Biotech) BLP-25 (Biomira)

 Synchrovax Vaccines (CTL MGV (Progenics)

 Immuno)! 3-Alethine (Dovetail) Melanoma Vaccine (CTL CLL-Thera (Vasogen) Immuno)

 p21 RAS vaccine

 (GemVax)

Hormonal and estrogenic prednisone

 antihormonal conjugated estrogens methylprednisolone

 Agent ethinyl estradiol prednisolone

 Chlorotrienes Aminoglutethimide

 Idenestrol Leuprolide

 Hydroxyprogesterone caproate goserelin

 Medroxyprogesterone Leuporelin

 Testosterone Bicalutamide

 Testosterone Propionate Flutamide Fluoxymesterone Octreotide

 Methyltestosterone Nilutamide

 Diethylstilbestrol Mitotane

 Megestrol P-04 (Novogen)

 Tamoxifen 2-Methoxyestradiol Toremofin (EntreMed)

 Dexamethasone Arzoxifen (Eli Lilly)

Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid Agent Theralux (Therapy Technology: (Yeda)

Motexafine Gadolinium Lutetium Texaphyrin (Pharmacyclics) (Pharmacyclics) hypericin

Tyrosine Kinase Imatinib (Novartis) Kahalid F (PharmaMar) Inhibitors Leflunomide CEP-701 (Cephalon)

 (Sugen / Pharmacia) CEP-75 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium)

 Erlotinib (Oncogene Scienc «PKC412 (Novartis)

 Canertjnib (Pfizer) phenoxodiol O

 Squalamine (Genaera) Trastuzumab (Genentech) SU54 6 (Pharmacia) C225 (ImClone)

 SU6668 (Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex) ZD6474 (AstraZeneca) 2C4 (Genentech)

 Vatalanib (Novartis) MDX-447 (Medarex) PKI166 (Novartis) ABX-EGF (Abgenix)

 GW2016 (GlaxoSmithKline) IMC-1C11 (ImClone) EKB-509 (Wyeth)

 EKB-569 (Wyeth)

 Various SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo agent) BioCryst)

 Tociadesin (Cyclic AMP Ranpimase (Ribonuclease Agonist, Ribapharm) Stimulant, Alfacell)

 Alvocidib (CDK inhibitor, galarubicin (RNA synthesis Aventis) inhibitor, Dong-A)

 CV-247 (COX-2 inhibitor, tirapazamine

 Ivy Medical) (Reducing Agent, SRI P54 (COX-2 Inhibitor, International)

 Phytopharm) N-acetylcysteine

 CapCell ™ (CYP450- (Reducing Agent, Zambon) Stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaB-GCS-IOO (gal3 antagonist, inhibitor, Encore)

 GlycoGenesys) 3CPA (NF-kappaB inhibitor, G17DT immunogenic Active Biotech)

 (Gastrin Inhibitor, Aphton) Seocalcitol (Vitamin D Efaproxiral (Oxygenator, Receptor Agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA-PI-88 (Heparanase Antagonist, TransMolecular) Inhibitor, Progene) Eflornithine (ODC inhibitor, tesmilifen (histamine ILEX oncology)

 Antagonist, YM Minodronic Acid

 BioSciences) (Osteoclastic Inhibitor, Histamine (Histamine-H2-Yamanouchi)

 Receptor agonist, Maxim) indisulam (p53 stimulant, tiazofurin (IMPDH inhibitor, Eisai)

 Ribapharm) aplidine (PPT inhibitor, cilengitide (Integrin- PharmaMar)

Antagonist, Merck KGaA) rituximab (CD20- SR-31747 (IL-1 antagonist, antibody, Genentech)

Sanofi-Synthelabo) gemtuzumab (CD33-

CCI-779 (mTOR kinase antibody, Wyeth Ayerst)

Inhibitor, Wyeth) PG2 (hematopoietic

Exisulind (PDE-V inhibitor, enhancer, pharmacogenesis))

Cell Pathways) Immunol ™ (Triclosan

CP-461 (PDE-V inhibitor, oral rinse, endo)

 Cell Pathways) triacetyluridine (uridine

AG-2037 (GART inhibitor, prodrug, Wellstat)

 Pfizer) SN-4071 (sarcoma agent,

WX-UK1 Signature BioScience)

(Plasminogen Activator TransMID-107 ™

 Inhibitor, Wilex) (immunotoxin, KS

 PBI-1402 (PMN stimulant, Biomedix) ProMetic LifeSciences) PCK-3145 (apoptosis-bortezomib (proteasome promoter, Procyon)

 Inhibitor, Millennium) Doranidazole (apoptosis- SRL-172 (T cell stimulant, promoter, Pola)

 SR Pharma) CHS-828 (cytotoxic TLK-286 (glutathione S agent, Leo)

 Transferase inhibitor, Telik) trans -retinoic acid

 PT-100 (growth factor (differentiator, NIH)

 Agonist, Point Therapeutics) MX6 (apoptosis promoter, midostaurin (PKC inhibitor, MAXIA)

 Novartis) apomin (apoptosis

Bryostatin-1 (PKC promoter, ILEX Oncology) stimulant, GPC Biotech) Urocidin (apoptosis-CDA-II (apoptosis promoter, promoter, Bioniche)

 Everlife) Ro-31-7453 (Apoptosis

SDX-101 (Apoptosis promoter, La Roche)

 Förderer, Salmedix) Brostallicin (apoptosis-ceflatonin (apoptosis promoter, Pharmacia)

 Conveyor, ChemGenex)

Particularly preferred is 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and its pharmaceutically acceptable salts and / or tautomers with immunomodulators, preferably combined with anti-PDL-1 or IL-12.

The invention further provides 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomers Use for the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I is administered in combination with a compound of the group of immunomodulators.

The invention further provides 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomers for use for the treatment of tumors, wherein a therapeutically effective amount of a compound of the formula I in combination with radiotherapy and a compound from the group of

Immunomodulators is administered.

Proof of action of pharmacological inhibitors on the

 Proliferation / vitality of tumor cells in vitro

1.0 Background

In the present experimental description, the inhibition of

Tumor cell proliferation / tumor cell vitality described by drugs.

The cells are seeded in suitable cell density in microtiter plates (96-well format) and the test substances are added in the form of a concentration series. After four more days of culture in serum-containing medium, tumor cell proliferation / tumor cell vitality can be determined by means of an Alamarblue test system.

2.0 experimental procedure

2.1 cell culture

 For example, commercially available colon carcinoma cell lines, cell lines of the ovary, cell lines of the prostate, or breast cell lines.

The cells are cultured in medium. At intervals of several days, the cells are detached from the culture dishes with the aid of trypsin solution and seeded in fresh medium at a suitable dilution. The cells are cultured at 37 ° C and 10% C0 ₂ . 2.2. Sowing the cells

 A defined number of cells (for example 2000 cells) are incubated per culture / well in a volume of 180μΙ culture medium in microtiter plates (96 well

Cell culture plates) seeded with a multi-channel pipette. The cells are then cultured in a CO 2 incubator (37 ° C. and 10% CO 2).

2.3. Addition of the test substances The test substances are dissolved, for example, in DMSO and then used in the cell culture medium in appropriate concentration (if appropriate a dilution series). The dilution levels may vary depending on

Efficiency of the active ingredients and desired spreading of concentrations can be adjusted. The test substances are in corresponding

Concentrations with cell culture medium. The addition of the

 Test substances to the cells can be made on the same day as the Aussat of the cells. For this purpose, from the predilution plate each 20μΙ

Substance solution in the cultures / wells given. The cells are cultured for a further 4 days at 37 ° C and 10% CO ₂ .

2.4. Measurement of the color reaction

 20μΙ AlamarBlue reagent are added to each well and the

For example, microtiter plates are incubated for a further seven hours in a CO2 incubator (at 37 ° C. and 10% CO 2). The plates are measured on a reader with a fluorescence filter at a wavelength of 540 nm. The plates can be easily shaken just before the measurement.

3. Evaluation

The absorbance value of the medium control (no use of cells and test substances) is subtracted from all other extinction values. The Controls (cells without test substance) are set equal to 100 percent and all other absorbance values related thereto (expressed as% of control, for example):

 Bill:

100 ^* (value with cells and test substance - value of medium control)

 (Value with cells - value of the medium control)

The determination of IC ₅₀ values (50% inhibition) is carried out with the help of statistical programs such as RS1.

4.0 Test for inhibition of PDK1

 The experimental approaches are in a flashplate system with 384

Wells / microtitration performed.

The PDK1 sample His ₆ -PDK1 (DL-50) (3.4 nM), the PDK1 substrate biotin-bA-bA-KTFCGTPEYLAPEVRREP- RILSEEEQEMFRDFDYIADWC (400 nM), 4 μM ATP (with 0.2 pCi ³³ P ATP / well) and the test substance are incubated in 50 μΙ standard test solution for 60 min at 30 ° C. The test substances are in corresponding

Concentrations (optionally in a dilution series) used. The control is carried out without test substance. The reaction is stopped by conventional methods and washed. The activity of the kinase is measured by the built-in radioactivity in the topcount. To determine the unspecific kinase reaction (blank), the experimental approaches are carried out in the presence of 100 nM staurosporine.

5.0 evaluation

The radioactivity (decays per minute) of the blank (no use of test substance in the presence of staurosporine) is different from all others

Radiation subtracted. The controls (kinase activity without test substance) are set equal to 100 percent and all others Radioactivity values (after deduction of the blank) are expressed in relation to them (expressed as% of control, for example).

 Bill:

 100 * (value of kinase activity with test substance - blank value)

 (Value of control - blank)

 =% of control

The determination of IC ₅ o values (50% inhibition) is carried out with the help of statistical programs such as RS1. IC ₅₀ data according to the invention

Compounds are given in Table 1.

Material Order No Manufacturer

 Microtiter plates for cell culture 167008 Nunc

(Nunclon Surface 96well Plate)

DMEM P04-03550 Pan Biotech

PBS (10x) Dulbecco 14200-067 Gibco

 96well plates (polypropylene) 267334 Nunc

AlamarBlue ™ BUF012B Serotec

FCS 1302 Pan Biotech GmbH

 Trypsin / EDTA Solution 10xL 2153 Biochrom AG

75cm ² Culture bottles 353136 BD Falcon

A2780 93112519 ECACC

Colo205 CCL222 ATCC

MCF7 HTB22 ATCC

PC3 CRL-1435 ATCC

384well Flash Disks SMP410A001PK Perkin Elmer APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) ⁺ .

IC ₅₀ data of compounds according to the invention are given in Table 1. ΙΚΚε - Kinase Test (IkKepsilon)

 The kinase assay is performed as a 384-well flashplate assay.

1 nM ΙΚΚε, 800 nM biotinylated lKBa (19-42) peptide (Biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) and 10 μΜ ATP (0.3 pCi

3 ³ p_ATP / well) are added in a total volume of 50 μM (10 mM MOPS, 10 mM magnesium acetate, 0.1 mM EGTA, 1 mM dithiothreitol, 0.02% Brij35, 0.1% BSA, 0.1% BioStab, pH 7.5) without or with test substance for 20 min at 30 ° C incubated. The reaction is stopped with 25 .mu.l 200 mM EDTA solution, filtered off with suction after 30 min at room temperature and the wells washed 3 times with 100 .mu.l 0.9% NaCl solution. The unspecific proportion of

Kinase reaction (blank) is determined with 3 μM EMD 1126352 (BX-795). Radioactivity is measured in the topcount. IC ₅₀ values are calculated using RS1.

TBK1 - kinase test

 The kinase assay is performed as a 384-well flashplate assay.

0.6 nM TANK binding kinase (TBK1), 800 nM biotinylated MELK-derived peptide (biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR) and 10 μΜ ATP (with 0.25 μθί ³³ P-ATP / well) are in a total volume of 50μΙ (10 mM MOPS, 10 mM magnesium acetate, 0.1 mM EGTA, 1 mM DTT, 0.02% Brij35, 0.1% BSA, pH 7.5) with or without test substance incubated for 120 min at 30 ° C. The reaction becomes 25μ! Stopped 200 mM EDTA solution, filtered off with suction at room temperature after 30 min and the wells washed 3 times with 100 .mu.Ι 0.9% NaCl solution. The unspecific proportion of

Kinase reaction (blank) is determined with 100 nM staurosporine. Radioactivity is measured in the topcount. IC ₅₀ values are calculated using RS1.

In vitro (enzyme) assay to determine the efficacy of

Inhibitors of inhibition of TGF-beta mediated effects

As an example, the ability of the inhibitors to abrogate TGF-beta mediated growth inhibition is tested.

 Cells of the lung epithelial cell line MvILu are seeded in defined cell density in a 96-well microtiter plate and cultured overnight under standard conditions. On the following day, the medium with medium containing 0.5% FCS and 1 ng / ml TGF-beta, replaced and the test substances in defined

Concentrations, usually in the form of serial dilutions with 5-fold steps added. The concentration of the solvent DMSO is constant at 0.5%. After two more days, crystal violet staining of the cells occurs. After extracting the crystal violet from the fixed cells, absorbance at 550 nm is measured spectrophotometrically. It can be used as a quantitative measure of the existing adherent cells and thus of cell proliferation during culture.

Test for the inhibition of ALK-5

 The experimental approaches are in a flashplate system with 384

Wells / microtitration performed.

 In each well 31.2 nM GST-ALK5, 439 nM GST-SMAD2 and 3 mM ATP (with 0.3 pCi of 33P-ATPA wells) in each case

 Total volume of 35 μM buffer (20 mM HEPES, 0 mM MgCl 2, 5 mM

MnCl 2, 1 mM DTT, 0.1% BSA, pH 7.4) without or with test substance at 5 to 10 different concentrations at 30 C for 45 min. The reaction is stopped with 25 μM 200 mM EDTA solution and aspirated after 30 min at room temperature. ,

The wells are washed 3 times with 100 μl of 0.9% aqueous NaCl solution and the remaining radioactivity in a TopCount solution. Device (Perkin-Elmer) measured. The IC50 values are calculated using RS1 software.

evaluation

The radioactivity (decays per minute) of the blank (no use of test substance in the presence of 100 nM staurosporine) is subtracted from all other radioactivity values. The controls (kinase activity without test substance) are set equal to 100 percent and all other radioactivity values (after deduction of the blank value) are related thereto (expressed as% of control, for example).

Bill:

100 ^* (value of kinase activity with test substance - blank value)

 (Value of control - blank)

=% of control

The determination of IC ₅₀ values (concentration of the test substance with 50% inhibition) is carried out with the aid of statistical programs such as RS1. IC ₅ o data of compounds according to the invention are given in Table 2.

Test for the inhibition of ALK-1

 The assay known to the person skilled in the art is carried out as described below

URL

http://www.reactionbiology.com/webapps/main/Kinases/lnvitrogen100 14 / ALK 1.pdf specified.

ALK1 / ACVRL1

 (Serine / threonine-protein kinase receptor R3, activin receptor-like kinase 1, ALK-1, TGF-B superfamily receptor type I, TSR-I, SKR3, ACVRLK1)

CAT #: ALK1

 Enzyme: Human ALK1

Substrate: casein, 20 mg / ml ATP 10 μΜ

 Reaction:

 enzyme

Substrate + [γ- Ρ] -ΑΤΡ _* - ³³ P substrate + ADP

HPLC / MS method:

Column: Chromolith SpeedROD RP-18e, 50 x 4.6 mm ²

Gradient: A: B = 96: 4 to 0: 100

Flow rate: 2.4 ml / min

 Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectroscopy: positive mode

F. = melting point

 MS (ESI): mass spectroscopy (electrospray ionization)

MS (El): mass spectroscopy (electron impact ionization)

Above and below, all temperatures are given in ° C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization.

syntheses

The preparation of the compound according to the invention is carried out by Pd-catalyzed cross-coupling of starting material 1 (4-bromo [2,7] naphthyridin-1-ylamine) with starting material 2 (1-benzenesulfonyl) -methyl-S ^^ SS-tetramethylKI.S ^ ldioxa- borolan-2-yl) -1H-pyrrolo [2,3-b] pyridine) and subsequent cleavage of the benzenesulfonyl group with alcohols under basic conditions.

Starting material 1:

 4-Bromo [2,7] naphthyridin-1-ylamine, CAS 959558-28-2 is commercially available and is prepared by bromination of [2,7] naphthyridin-1-ylamine with bromine in

Acetic acid produced.

Alternatively, the compound is prepared from 2H- [2,7] naphthyridin-1-one CAS 67988-50-5, the hydrobromide CAS 950746-19-7 or the hydrochloride CAS 369648-60- 2.

Bromination gives 4-bromo-2,7-naphthyridin-1 (2H) -one CAS 959558- 27-, which is obtained by chlorinating compounds such as POCl ₃ and / or PCI ₅ in 4-bromo-1-chloro- [2, 7] naphthyridine is transferred. The reaction with ammonia or ammonia equivalent gives [2,7] naphthyridin-1-ylamine.

Alternatively, 4-methyl-nicotinonitrile CAS 5444-01-9 is reacted with DMF-acetal (eg CAS 4637-24-5 [dimethyl]) to give 4 - ((E) -2-dimethylamino-vinyl) nicotinonitrile CAS 36106 -34-0 which is cyclized to [2,7] naphthyridin-1-ylamine.

Starting material 2:

1- (benzenesulfonyl) -2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine CAS 943324- 08-1 is commercially available and is prepared from 3-iodo-2-methyl-1- (benzenesulfonyl) -7-azaindole CAS 943324-07-0 by Pd-catalyzed reaction with bis (pinacolato) diboron CAS 73183-34-3 (Seefeld et al., WO 2007/076423 A2, page 170).

Alternatively, instead of 3-iodo-2-methyl-1- (benzenesulfonyl) -7-azaindole, the

Compound 3-bromo-2-methyl-1- (benzenesulfonyl) -7-azaindole CAS 744209-37-8 used.

Examples:

4-Bromo-f2.7lnaphthyridin-1-ylam ^'in

 To a solution of 200 g of 4-methyl-nicotinonitrile in 940 g of DMF are added 940 ml of DMF dimethylacetal and heated under reflux for 3 days at 120-1 0. Man cools to 35 ° C, poured into 10 liters of ice water and cooled for 16 h at 4 ° C. Of the

The precipitate is filtered off, washed with water and dried. This gives 263 g of 4 - ((E) -2-dimethylamino-vinyl) nicotinonitrile; M ~ 173.22 g / mol; M + H found 174, NMR equals.

To 253 g of 4 - ((E) -2-dimethylamino-vinyl) nicotinonitrile in a 4 liter vessel are added 810 g of ammonium formate. Then 300 ml of AcOH are added and the mixture is heated at 15 ° C for 20 h. It is cooled, 5 liters of water are added and extracted 10 times with 0.5 liters of CH ₂ Cl ₂ . The aqueous phase is brought to ~ pH 10 with 160 g NaOH. The aqueous phase is extracted with MTB ether, the organic phase is separated and over sodium sulfate dried. After removal of the solvent and drying, 59 g of [2,7] naphthyridin-1-ylamine, M-45.16 g / mol, M + H found 146, corresponds to NMR. 32 g of [2,7] naphthyridin-1-ylamine is dissolved at room temperature in 200 ml

 Acetic acid dissolved. Then, 35 g of bromine in 200 ml of acetic acid are slowly added so that the temperature does not exceed 25 °. It is stirred for 60 minutes.

 The suspension obtained is dissolved in 500 ml of water and the pH is adjusted to pH 7-8 with 0 500 ml of 25% aqueous ammonia solution.

 It is stirred for 14 h. The brown precipitate is filtered off, washed with water and dried. This gives 28.3 g of crude product. After purification by flash chromatography in ethyl acetate / methanol, 18.5 g of 4-bromo [2,7] naphthyridin-1-ylamine, M-224.06 g / mol, M + H were found 224.

 Ί5

 1- (BenzenesulfonvD-2-methyl-3- (4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-v - 1H-pyrrolof2,3-blipyridine

To a solution of 1 g of 1- (benzenesulfonyl) -7-azaindole in 20 ml of THF is added dropwise over 20 minutes. at -70 ° C under N ₂ atmosphere 4.8 ml of a 2M solution of lithium diisopropylamine in THF / heptane. Allow to warm to 20 ° for 50 minutes. The suspension is cooled to -70 ° and a solution of 1, 1, g of iodomethane in 20 ml of THF is added dropwise within 20 minutes. The mixture is stirred for one hour at -70 ° and then 14 h

25 room temperature. Dilute with water and extract with dichloromethane.

 It is dried over sodium sulfate, filtered, the solvent is removed and crystallized from cyclohexane. 0.68 g of 2-methyl-1- (benzenesulfonyl) -7-azaindole, M ~ 272.32 g / mol, M + H found 273, corresponds to NMR.

30 bromination in DMF:

To a solution of 34.8 g of 2-methyl-1- (benzenesulfonyl) -7-azaindole in 75 ml of DMF is added 25 g of NBS in 75 ml of DMF. It is stirred for 1 h at room temperature, Pour on water, separating the precipitated precipitate, washed with water and dried. This gives 42 g of 3-bromo-2-methyl-1- (benzenesulfonyl) -7-azaindole, M-351.22 g / mol, M + H found 351. Bromination in acetonitrile:

To a solution of 100 mg of 2-methyl-1- (benzenesulfonyl) -7-azaindole in 3 ml of ChhCN is added 72 mg of NBS in 2 ml of CH ₃ CN. It is stirred for 20 h

Room temperature, poured into water, separates the precipitate and dried. This gives 93 mg of 3-bromo-2-methyl-1- (benzenesulfonyl) -7-azaindole, M-351.22 g / mol, M + H found 351.

To a solution of 3 g of 3-bromo-2-methyl-1- (benzenesulfonyl) -7-azaindole and 2.9 g Bispinacolatodiboron in 30 ml Diethyleneglycoldimethylether are added 2.6 g of potassium acetate and 300 mg PdCl ₂ (PPh ₃ ) 2- Man heated h at 120 °, the mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered off and the solvent is removed. This gives 3 g of 1- (benzenesulfonyl) -2-methyl-3- (4,4,5,5-tetramethyl, 3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine , M ~ 398.29 g / mol, M + H found 399.

4- ^{(1-benzenesulfonyl-2-methyl-1H-p} yrrolo [2.3-b1pyridin-3-ylH2,71naphthyridin-1- ylamine

 To a solution of 12.5 g of 4-bromo [2,7] naphthyridin-1-ylamine in 400 ml of diglyme and 15 ml of water is added under nitrogen atmosphere 23.7 g

Tripotassium phosphate and 3.2 g of trans-dichloro-bis (tricyclohexylphosphine) -palladium (II). The mixture is heated to 125 ° and for 30 minutes 25 g of 1- (benzoylsulfonyl) -2-methyl-3- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-] are added dropwise. b] pyridine in 100 ml diglyme

added. The mixture is stirred for 3 h at 125 °, 20 h at room temperature and

then the solvent is removed and you work up as usual. It is purified by flash chromatography on 330 g of silica with a

 Methanol gradient in ethyl acetate at 200 ml / min with UV detection at 254 nm. A pure fraction (5.1 g) and a contaminated fraction (6.5 g) of 4- (1-benzenesulfonyl-2-methyl-1 H) are obtained. pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine, M ~ 415.47 g / mol, M + H found 416.

4- (2-methyl-1H-pyrrolof2,3-b1pyridin-3-yl) -r2,71naphthyridin-1-ylamine

A mixture of 23 g of 4- (1-benzenesulfonyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and 26 g of cesium carbonate in 400 ml

THF / trifluoroethanol (1: 1 vol) is heated at reflux for 20 h. The mixture is cooled, the solvent is removed and purified via flash chromatography over 220 g of silica with a methanol gradient in ethyl acetate at 150 ml / min with UV detection at 254 nm. 12.2 g of 4- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamines, M-275.31, M + H found 276.2; 1H NMR (500 MHz, DMSO-d ₆₎ ppm [ppm] 1.75 (s, 1 H), 9.64 - 9:57 (m, 1H), 8.50 (d, J = 5.8, 1H), 8.15 (dd, J = 4.7 , 1.5, 1H), 7.98 (s, 1H), 7.42 (dd, J = 7.8, 1.6, 1H), 7.31 (s, 2H), 7.18 (dd, J = 5.8, 0.9, 1H), 6.97 (dd, J = 7.8, 4.7, 1H), 2.29 (s, 3H).

Table 2

 Inhibition of TGF-beta kinase ALK5 and ALK1

 Comparison of the compound of the invention with compounds of the

State of the art

The following examples relate to drugs:

Example A: Injection glasses

A solution of 100 g of the compound of the invention and 5 g

 Disodium hydrogen phosphate is adjusted to pH 6.5 in 2 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed in a sterile manner. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

 A mixture of 20 g of the compound according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

 A solution of 1 g of the compound according to the invention, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water is prepared. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

 500 mg of the compound according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets

 A mixture of 1 kg of the compound of the invention, 4 kg lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way to tablets, such that each tablet 10 mg

Contains active ingredient. Example F: dragees

 Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

 2 kg of the compound of the invention are in the usual way in

Filled hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient. Example H: Ampoules

 A solution of 1 kg of the compound according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

claims

The compound 4- (2-methyl-1H-pyrrolo [2,3-b] pyrid

 [2,7] nap

 and its pharmaceutically acceptable salts and / or tautomers.

2. A pharmaceutical composition containing 4- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its pharmaceutically acceptable salts and tautomers, and optionally carrier and / or

 Excipients.

3. 4- (2-Methyl-1 H -pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-yl-amine

 and its pharmaceutically acceptable salts and / or tautomers, for use in the treatment of tumors, tumor growth, tumor metastases and / or AIDS.

4. 4- (2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - [2,7] naphthyridin-1-yl-amine

 and / or its physiologically acceptable salts and tautomers for use in the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I in combination with a

Compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor , 9) reverse transcriptase inhibitors and 10) further angiogenesis inhibitors are administered. 4- (2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) [27] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomers for use in the treatment of tumors, wherein therapeutically effective amount of a compound of the formula I in combination with radiotherapy and a compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl-protein transferase inhibitor , 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors, and 10) others

Angiogenesis inhibitor is administered.

4- (2-Methyl-1H-pyrrolo [2 _> 3-b] pyridin-3-yl) - [2 ₎ 7] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomers for use in the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I is administered in combination with a compound of the group of immunomodulators.

4- (2-Methyl-1H-pyrrolo [2 _> 3-b] pyridin-3-yl) - [2,7] naphthyridin-1-ylamine and / or its physiologically acceptable salts and tautomeric use for the treatment of tumors, wherein a therapeutically effective amount of a compound of the formula I in combination with radiotherapy and a compound from the group of

Immunomodulators is administered.