EP1888593A2 - Thienopyridines - Google Patents

Abstract

The invention relates to novel thienopyridine derivatives of formula (I), wherein R1, R2, R3, R4 and Y have the meaning cited in claim 1, are HSP90-inhibitors and can be used for producing a medicament for treating illnesses, wherein the inhibition, regulation and/or modulation of HSP90 plays a roll.

Description

 thienopyridines

BACKGROUND OF THE INVENTION

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

The present invention relates to compounds involving the inhibition, regulation and / or modulation of HSP90, pharmaceutical compositions containing these compounds and the use of the compounds for the treatment of

Diseases in which HSP90 plays a role.

The correct folding and conformation of proteins in cells is ensured by molecular chaperones and is critical for the regulation of the balance between protein synthesis and degradation. Chaperones are important for the regulation of many central functions of cells, e.g. Cell proliferation and apoptosis (Joill and Morimoto, 2000; Smith et al., 1998; Smith, 2001).

Heat shock proteins (HSPs)

The cells of a tissue are responsive to external stress, e.g. Heat, hypoxia, oxidative stress, or toxins such as heavy metals or alcohols with the activation of a number of chaperones known as "heat shock proteins" (HSPs) .The activation of HSPs protects the cell against injuries caused by such stressors triggers the restoration of the physiological state and leads to a stress-tolerant state of the cell.

In addition to this originally discovered by HSPs mediated

Protective mechanism of external stress have been over time other important chaperone functions for individual HSPs are also described under normal stress-free conditions. For example, various HSPs regulate the correct folding, intracellular localization and function, or the regulated degradation of a number of biologically important proteins of cells.

HSPs constitute a gene family of individual gene products whose cellular expression, function and localization differ in different cells. The designation and classification within the family is due to their molecular weight e.g. HSP27, HSP70, and HSP90.

Some human diseases are based on incorrect protein folding (see review, e.g., Tytell et al., 2001; Smith et al., 1998). The

Development of therapies that interfere with the mechanism of chaperone-dependent protein folding might therefore be useful in such cases. For example, in Alzheimer's disease, prion diseases or Huntington's syndrome, misfolded proteins aggregate protein with a neurodegenerative course. Incorrect protein folding may also result in a loss of wild-type function, which may result in a misregulated molecular and physiological function.

HSPs are also considered of great importance in tumor diseases. There are e.g. Evidence that the expression of certain

HSPs are related to the stage of tumor progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;

Jameel et al., 1992; Hoang et al., 2000; Lebeau et al., 1991).

The fact that HSP90 is involved in several central oncogenic

Signaling pathways in the cell and targeting certain natural products with anticancer activity to HSP90 led to the concept that inhibition of HSP90 function would be useful in the treatment of tumor disease. An HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, is currently undergoing clinical trials.

HSP90

HSP90 represents about 1-2% of the total cellular protein mass. It is usually present in the cell as a dimer and is associated with a variety of proteins, so-called co-chaperones (see, e.g., Pratt, 1997). HSP90 is essential for the vitality of cells (Young et al., 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose native folding by external stress, e.g. Heat shock, was changed to restore the original folding or the aggregation of

Prevent proteins (Smith et al., 1998).

There is also evidence that HSP90 is important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding induced by the mutation (Rutherford and Lindquist, 1998).

In addition, HSP90 also has a regulatory significance. Under physiological conditions, HSP90, along with its endoplasmic reticulum homolog, GRP94, plays a role in the cell balance to ensure the stability of the conformation and maturation of various "serving" key proteins, which can be divided into three groups: steroid hormone receptors, sera / Thr or tyrosine kinases (eg ERBB2, RAF-1, CDK4 and LCK) and a

Collection of different proteins such as mutant p53 or the catalytic subunit of telomerase hTERT. Each of these proteins plays a key role in the regulation of physiological and biochemical processes of cells. The conserved human HSP90 family consists of four genes, the cytosolic HSP90α, the inducible HSP90β isoform (Hickey et - A -

al., 1989), GRP94 in the endoplasmic reticulum (Argon et al., 1999) and HSP75 / TRAP1 in the mitochondrial matrix (Felts et al., 2000). It is believed that all members of the family have a similar mode of action but, depending on their location in the cell, bind to different "serving" proteins For example, ERBB2 is a specific "serving" protein of GRP94 (Argon et al., 1999 ), while the type 1 receptor of tumor necrosis factor (TNFR1) or the retinoblastoma protein (Rb) were detected as "clients" of TRAP1 (Song

10 et al., 1995; Chen et al., 1996).

HSP90 is involved in a number of complex interactions with a large number of "serving" proteins and regulatory proteins (Smith, 2001), although precise molecular details have yet to be clarified

^ _C biochemical experiments and investigations with the aid of X-ray crystallography in recent years have increasingly details of the chaperone function of HSP90 can decrypt (Prodromou et al., 1997; Stebbins et al., 1997). Thereafter, HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with dimerization

20 is important for ATP hydrolysis. The binding of ATP results in the

Formation of a toroidal dimer structure, in which the two N-terminal domains are in close contact with each other and cause a "switch" in the conformation (Prodromou and Pearl, 2000)

Known HSP90 inhibitors

The first class of HSP90 inhibitors discovered were benzoquinone ansamycins with the compounds herbimycin A and geldanamycin. Originally, they were used to detect the reversion of the malignant phenotype in fibroblasts induced by transformation with the v-Src oncogene (Uehara et al., 1985).

Later, strong antitumoral activity was demonstrated in vitro (Schulte et al., 1998) 5 and in vivo in animal models (Supko et al., 1995). Immunoprecipitation and affinity matrices studies then showed that the main mechanism of action of geldanamycin involves binding to HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998).

In addition, it has been demonstrated by X-ray crystallographic studies that geldanamycin competes for the ATP binding site and inhibits the intrinsic ATPase activity of HSP90 (Prodromou et al., 1997, Panaretou et al., 1998). This prevents the formation of the multimeric HSP90 complex, which acts as a chaperone for "serving" proteins, and as a consequence "serves" proteins via the ubiquitin-proteasome pathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed an unchanged property in the inhibition of HSP90, the degradation of "serving" proteins and antitumoral activity in

Cell cultures and in xenograft tumor models (Schulte et al, 1998, Kelland et al, 1999) had significantly lower liver cytotoxicity than geldanamycin (Page et all 1997). 17AAG is currently being tested in Phasel / Il clinical trials.

Radicicol, a macrocyclic antibiotic, also demonstrated a revision of the v-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon et al 1992, Zhao et al, 1995). Radicicol downgrades one

Variety of signaling proteins as a consequence of HSP90 inhibition

(Schulte et al., 1998). X-ray crystallographic studies showed that radicicol also binds to the N-terminal domain of HSP90 and inhibits intrinsic ATPase activity (Roe et al., 1998).

Coumarin-type antibiotics are known to bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria. The coumarin, novobiocin, binds to the carboxy-terminal end of HSP90, which is another site in HSP90 than the benzoquinone Ansamycins and Radicicol, which bind to the N-terminal end of HSP90. (Marcu et al., 2000b).

The inhibition of HSP90 by novobiocin results in the degradation of a large number of HSP90-dependent signaling proteins (Marcu et al.

2000a).

With PU3, a purine-derived HSP90 inhibitor, the degradation of signaling proteins, e.g. ERBB2, are shown. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al., 2001).

HSP90 as a therapeutic target

By including HSP90 in the regulation of a large number of signaling pathways that are critically important to the phenotype of a tumor, and the discovery that certain natural products exert their biological effect by inhibiting the activity of HSP90, HSP90 is currently a new target for development of a tumor therapeutic (Neckers et al., 1999).

The main mechanism of action of geldanamycin, 17AAG, and radicicol involves the inhibition of binding of ATP to the ATP binding site at the N-terminal end of the protein and the consequent inhibition of the intrinsic ATPase activity of HSP90 (see, eg, Prodromou et al. 1997; Stebbins et al., 1997; Panaretou et al., 1998). The inhibition of ATPase activity of HSP90 prevents the

Recruitment of co-chaperones and favors the formation of a HSP90

Heterocomplexes that "serve" proteins via the ubiquitin-proteasome pathway of degradation (see, eg, Neckers et al., 1999; Kelland et al., 1999) .Treating tumor cells with HSP90 inhibitors leads to the selective degradation of important proteins of fundamental importance for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often deregulated in tumors (see, eg, Hostein et al., 2001).

An attractive rational for the development of an inhibitor of HSP90 is that a potent tumor therapeutic effect can be achieved by concomitant degradation of several proteins related to the transformed phenotype.

In particular, the present invention relates to compounds which inhibit, regulate and / or modulate HSP90, compositions containing these compounds, and methods for their use in the treatment of HSP90-related diseases such as tumor diseases, viral diseases such as hepatitis B (Waxman , 2002); ^ _c Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; cystic

Fibrosis (filler, 2000); Diseases related to angiogenesis

20

(Hur, 2002 and Kurebayashi, 2001), e.g. diabetic retinopathy,

Hemangiomas, endometriosis and tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration (Rosen et al., WO 02/09696; Degranco et al., WO

25 99/51223; Gold, US 6,210,974 B1); fibrogenetic diseases, e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds _{according to} the invention for the protection of normal cells against toxicity caused by chemotherapy, as well as for use in diseases where protein misfolding or aggregation is a major causative factor, such as scrapie, Creutzfeldt-Jakob disease, Huntington's or Alzheimer's disease

TS

(Sittler, Hum Mol. Genet., 10, 1307, 2001; Tratzelt et al., Proc. Nat. Acad., Sci., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276; 45160, 2001). A. Kamal et al. describe in Trends in Molecular Mediane, Vol. 6 June 2004, Therapeutic and diagnostic applications of HSP90 activation, including for the treatment of central nervous system diseases and cardiovascular diseases. 5

The identification of small compounds that specifically inhibit, regulate and / or modulate HSP90 is therefore desirable and an object of the present invention.

10

It has been found that the compounds of formula I and their salts possess very valuable pharmacological properties with good compatibility.

- _j 5 In particular, they show HSP90-inhibiting properties.

The present invention therefore relates to compounds of the formula I as medicaments and / or active pharmaceutical ingredients in the

Treatment and / or prophylaxis of said diseases and the 0

Use of compounds of the formula I for the preparation of a

A pharmaceutical for the treatment and / or prophylaxis of said diseases, as well as a method for the treatment of said diseases comprising the administration of one or more compounds of formula I to a patient in need of such administration.

The host or patient may be of any mammalian species, e.g. A Q primate species, especially humans; Including rodents

Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, being a model for the treatment of a disease of the

To provide people. 5 STATE OF THE ART

Other pyridothiophene derivatives are as HSP90 inhibitors in WO

2005/034950 and described in WO 2005/021552.

In WO 2005/00300 A1 triazole derivatives are described as HSP90 inhibitors.

In WO 00/53169, the HSP90 inhibition with coumarin or a

Coumarin derivative described. WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.

HSP90-inhibiting pyrazole derivatives which are in the 3- or 5-position by a

Aromatic substituted are known from WO 2004/050087 A1 and WO 2004/056782 A1.

In WO 03/055860 A1, 3,4-diarylpyrazoles are described as HSP90 inhibitors.

Purine derivatives with HSP90-inhibiting properties are described in WO

02/36075 A2.

In WO 01/72779 purine compounds are described, as well as their use for the treatment of GRP94 (homologue or paralogue to HSP90) -related diseases, such as tumors, wherein the cancerous tissue comprises a sarcoma or carcinoma selected from the group consisting of fibrosarcoma, myxosarcoma , Liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, Sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, Choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma

Medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio- 5 blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma,

Neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and severe chain disease.

10 In WO 01/72779 is further the use of the mentioned therein

Discloses compounds for the treatment of viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella,

^ _c adenovirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus , Coxsackie virus, mumps virus,

Measles virus, Röteinvirus, poliovirus, human immunodeficiency virus

20

Type I (HIV-I) and Human Immunodeficiency Virus Type II (HIV-II).

WO 01/72779 further describes the use of the compounds mentioned there for GRP94 modulation, wherein the modulated biological GRP94 activity is an immune reaction in an individual,

25 protein transport from the endoplasmic reticulum, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery from heat stress, or combinations thereof, and / or where the disorder is a type of cancer, an infectious disease,

_O0 a disorder involving disturbed endoplasmic reticulum protein transport, a disorder associated with ischemia / reperfusion, or combinations thereof, wherein the ischemia / reperfusion-associated disorder is a consequence of cardiac arrest;

Asystole and delayed ventricular arrhythmias, heart surgery,

35 cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease,

Huntington's chorea, amyotrophic lateral sclerosis (ALS), or stress 5 in the newborn.

In WO 01/72779, finally, the use of an effective amount of a GRP94 protein modulator for the preparation of a

To alter a subsequent cellular response to an ischemic condition at a tissue site in an individual by treating the cells at the tissue site with the GRP94 protein modulator to allow the GRP94 to

A _c activity in cells is increased so much that a subsequent cellular response is changed to an ischemic condition, the subsequent ischemic condition preferably being the result of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation,

20

Spinal cord injury, head trauma, stroke, thromboembolic

Stroke, haemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress; Tissue site which is donor tissue for transplantation.

_O Q Further literature:

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Bijlmakers M-JJE, Marsh M 2000 "Hsp90 is essential for the synthesis and subsequent membrane association, but not the maintenance, of the src kinase p56lck", Mol. Biol. Cell, Vol. W (5), pp. From 1585 to 1595. Bucci M; Roviezzo F; Cicala C; Sessa WC, Cirino G. 2000 "geldanamycin at inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and inter acts with glucocorticoid receptor in vivo ^5", Brit. J. Pharmacol., Vol. 131 (1), pp. 13-16.

Carreras CW, Schirmer A, Zhong Z, Santi VS. 2003 "Filter binding assay for the geldanamycin-heat shock protein 90 interaction", Analytical 10 Biochem., Vol 317, pp 40-46.

Chen CF, Chen Y, Dai KD, Chen PL, Riley DJ and Lee WH. 1996 "A new member of the hsp90 family of molecular chaperones inter acts with ^ _c the retinoblastoma protein during mitosis and after heat shock", Mol. Cell. Biol., Vol. 16, pp. 4,691 to 4,699.

Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lozenzino

L and Rosen N. 2001 "A small molecule designed to bind to the adenine

20 nucleotide pocket of HSP90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells ", Chem. Biol., Vol. 8, pp. 289-299.

5

Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N 2002 "Development of a purine-scaffold novel class of HSP90 binders that inhibit the proliferation of cancer cells and induce the degradation of her2 tyrosine kinase".

Bioorganic Med. Chem., Vo1 10, pp 3555-3564. 30

Conroy SE and Latchman DS. 1996 "Do heat shock proteins have a role in breast cancer?", Brit. J. Cancer, Vol. 74, pp. 717-721. Felts SJ, Owen BAL, Nguyen P, Trepel J, Thunder DB and Toft DO. 2000 35 "The HSP90-related protein TRAP1 is a mitochondrial protein with distinct functional properties", J. Biol. Chem., Vol. 5, pp. 3305-331 2. Fuller W, Cuthbert AW. 2000 "Post-translational disruption of the delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) - molecular chaperone complex with geldanamycin stabilizes delta F508 CFTR in the rabbit reticulocyte lysates", J. Biol. Chem., Vol. 275 (48), pp , From 37,462 to 37,468.

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Hoang AT, Huang J, Rudra-Gonguly N, Zheng J, Powell WC, Rabindron

SK, Wu C and Roy-Burman P. 2000 "A novel association between the human heat shock transcription factor 1 (HSF1) and prostate adenocarcinoma, Am. J. Pathol., Vol. 156, pp. 857-864.

Hostein I, Robertson D, Di Stefano F, Workman P and Clarke PA. 2001

"Inhibition of signal transduction by the HSP90 inhibitor 17-allylamino-1-demethoxygeldanamycin results in cytostasis and apoptosis", Cancer Res., Vol. 61, pp. 4003 to 4009.

Hur E, Kim HH, Choi SM, Kim JH, Yim S, Kwon HJ, Choi Y, Kim DK, Lee MO ₁ Park H. 2002 "Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1α / aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol ", Mol. Pharmacol., Vol. 62 (5), pp. 975-982.

Jameel A, Skilton RA, Campbell TA, Chander SK, Coombes RC and Luqmani YA. 1992 "Clinical JoIIy C and Morimoto Rl. 2000 "Role of the Heat Shock Response and Molecular Chaperones in Oncogenesis and Cell Death", J. Natl. Cancer Inst., Vol. 92, pp. From 1564 to 1572.

Kawanishi K ₁ Shiozaki H, Doki Y, Sakita I, lnoue M ₁ Yano M, Tsujinata T, Shamma A and Monden M 1999 "Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus", Cancer , Vol. 85, pp. 1649-1657.

10

Kelland LR, Abel G ₁ McKeage MJ, Jones M, Goddard PM, Valenti M, Murrer BA ₁ and Harrap KR. 1993 "Preclinical antitumour evaluation of bis-aceto-amino-dichloro-cyclohexylamine platinum (IV): on orally active

-. π platinum drug ", Cancer Research, Vol. 53, pp. 2581-2586.

Kelland LR ₁ Sharp SY, Rogers PM, Myers TG and Workman P. 1999 "DT-diaphorase expression and tumor cell sensitivity to 17- P ₀ allylamino, 17-demethoxygeldanamycin at inhibitor of heat shock protein 90", J. Natl. Cancer Inst., Vol. 91, pp. 1940-1949.

Kurebayashi J ₁ Otsuki T, Kurosumi M ₁ Soga S, Akinaga S, Sonoo, H. 2001 _o A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factoMα and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts ", Jap. J. Cancer Res., Vol. 92 (12), 1342-1351.

^ O

Kwon HJ, Yoshida M, Abe K ₁ Horinouchi S and Bepple T. 1992 "Radicicol, to agent inducing the reversal of transformed phentoype of src-transformed fibroblasts, Biosci., Biotechnol., Biochem., Vol. 56, pp. 538- 539th

35 Lebeau J, Le Cholony C, Prosperi MT and Goubin G. 1991 "Constitutive overexpression of 89 kDa heat shock protein gene in the HBL100 mammalian cell line transformed into a tumorigenic phenotype by the EJE24 Harvey-ras oncogene ", Oncogene, Vol. 6, pp. 1125-1132.

Marcu MG, Chadli A, Bouhouche I ₁ Catelli M and Necker L. 2000a "The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone", J. Biol. Chem., Vol 275, pp. 37181-37186.

Marcu MG, Schulte TW and Neckers L 2000b "Novobiocin and related coumarin and depletion of heat shock protein 90-dependent signaling proteins", J. Natl. Cancer Inst., Vol. 92, pp. 242-248.

Martin KJ, Kritzman BM ₁ Price LM, Koh B, Kwan CP, Zhang X, MacKay A, O'Hare MJ, Kaelin CM, Mother GL, Pardee AB and Sager R. 2000 "Linking gene expression patterns to therapeutic groups in breast cancer , Cancer Res., Vol. 60, pp. From 2232 to 2238.

Neckers L, Schulte TW and Momnaaugh E. 1999 "Geldanamycin as a

Potential anti-cancer agent: its molecular target and biochemical activity ", Invest., New Druqs, Vol. 17, pp. 361-373.

1997, "Comparison of geldanamycin (NSC-122750) and 17-allylaminogeldanamycin (NSC-330507D) toxicity in rats," Proc. J, Heath J, Fulton R, Yalkowsky E, Tabibi E, Tomaszewski J, Smith A, and Rodman L. At the. Assoc. Cancer Res., Vol. 38, pp. 308th

Panaretou B, Prodromou C, Roe SM ₁ OBrien R, Ladbury JE, Piper PW and Pearl LH. 1998 "ATP binding and hydrolysis are essential to the function of the HSP90 molecular chaperone in vivo", EMBO J., Vol. 17, pp. 4829 to 4836. Pratt WB. 1997 "The role of the HSP90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase", Annu. Rev. Pharmacol. Toxicol., Vol. 37, pp. 297-326.

Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW and Pearl LH. 1997 "Identification and structural characterization of the ATP / ADP-binding site in the HSP90 molecular chaperone", Cell, Vol. 90, pp. 65-75.

Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM, Piper PW and Pearl LH. 2000 "The ATPase cycle of HSP90 drives a molecular" clamp "via transient dimerization of the N-terminal domains", EMBO J., Vol. 19, pp. From 4383 to 4392.

Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW and Pearl LH. 1999 "Structural base for inhibition of the HSP90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin", J. Med. Chem., Vol. 42, pp. 260-266.

Rutherford SL and Lindquist S. 1998 "HSP90 as a Condenser for Morphological Evolution. Nature, Vol. 396, pp. 336-342.

Schulte TW, Akinaga S, Murakata T, Agatsuma T, Sugimoto S, Nakano H, Lee YS, Simen BB, Argon Y, Felts S, Toft DO, Neckers LM and Sharma SV. 1999 "Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones", Mol. Endocrinoloy, Vol. 13, pp. 1435-1448.

Schulte TW, Akinaga S, Soga S, Sullivan W, Sensgard B, Toft D and Neckers LM. 1998 "Antibiotic radicicol binds to the N-terminal domain of HSP90 and shares important biological activities with geldanamcyin", Cell Stress and Chaperones, Vol. 3, pp. 100-108. Schulte TW and Neckers LM. 1998 "The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamcyin binds to HSP90 and shares important biologic activities with geldanamycin", Cancer Chemother. Pharmacol., Vol. 42, pp. 273-279.

Smith DF. 2001 "Chaperones in signal transduction", in: Molecular chaperones in the cell (P Lund, ed., Oxford University Press, Oxford and NY), pp. 165-178.

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SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I. wherein

Y is OH, OA, SH, SA, NH ₂ , NHA, NAA ¹ or NHR ⁵ ,

R ¹ Hal, OH, OA, SH, SA, H or A,

R ² , R ^{3 are} each independently -NHCO- (X) ₃ -Q,

-CONH- (X) ₃ -Q, -CONA- (X) ₃ -Q,

-NH (CO) NH- (X) ₃ -Q, -NH (CO) O- (X) ₃ -Q, -NHSO ₂ - (X) ₃ -Q, -SO ₂ NH- (X) ₃ -Q , -SO ₂ NA- (X) ₃ -Q, - (X) ₃ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H, then R ² = H or Cl,

R ⁴ H, Hal ₁ CN, NO ₂ , A, OH, OA, SH, SA, (CH ₂ ) _n COOH,

(CH ₂ ) _n COOA, CONH ₂ , CONHA, CONAA ', NH ₂ , NHA, NAA ¹ , NHCOOA, NHCONH ₂ , NHCONHA, SOA, SO ₂ A, SO ₂ NH ₂ , SO ₂ NHA and / or SO ₂ NAA ¹ , two adjacent radicals selected from the group R ¹ , R ² , R ³ , R ⁴ together also methylenedioxy or ethylenedioxy,

R ^{5 is} - (CH ₂ ) ₀ -Het ¹ , - (CH ₂ ) _O -NH ₂ , - (CH ₂ ) ₀ -NHA or

- (CH ₂ ) _O -NA ₂ ,

A, A 'each independently of one another are unbranched or branched alkyl having 1-10 C atoms, in which 1-5 H atoms may be replaced by F, Cl and / or Br, Alk or cyclic alkyl having 3-7 C atoms,

A and A 'together also form an alkylene chain having 2, 3, 4, 5 or 6 C atoms, in which one or two CH ₂ groups are represented by O, S, SO, SO ₂ , NH, NA and / or N-COOA can be replaced,

Alk alkenyl with 2-6 C atoms,

X unsubstituted or one, two, three or four times

⁵ by A, OA, OH, SH, SA, Hal, NO ₂ , CN, Ar, OAr,

COOH, COOA, CHO, C (= O) A, C (= O) Ar, SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA , NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA,

10 NHCOOA, NACOOA, NHSO ₂ OA, NASO ₂ OA,

NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA, NHCONAA ¹ , NACONAA ¹ and / or = 0 substituted unbranched or branched C ₁ -C ₁₀ alkylene or

Λ c C ₂ -Ci _O alkenylene, in which also one, two or three C

Groups may be replaced by O, S, SO, SO ₂ , NHCO, NACO, CONH, CONA, SO ₂ NH, SO ₂ NA, NHSO ₂ , NASO ₂ and / or by NH groups,

Q is H, carb, Ar or Het,

20

Carb unsubstituted or mono-, di-, tri-, tetra- or quintuple of A, OA, OH, SH ₁ SA, Hal, NO ₂ , CN, (CH ₂ ) _n Ar (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, CHO, COA, SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ', SO ₂ NHA, 5 SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA,

OCONAA ¹ , NHCOA, NHCOOA, NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA, NHCONAA ¹ and / or NACONAA ¹ Q substituted

Cycloalkyl having 3-7 C atoms or cycloalkenyl having 3-7 C atoms,

Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, OA, OH, SH, SA, Hal, NO ₂ , CN, (CH ₂ J _n Ar ¹ , (CH ₂ ) _n COOH, ( CH ₂ ) _n COOA, CHO ₁ COA ₁ SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA, NHCOOA, NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA,

NACONHA, NHCONAA ', NACONAA ¹ , NHCO (CH ₂ ) _n NH ₂ , and / or -O- (CH ₂ ) _O -Het substituted phenyl, naphthyl or biphenyl,

Ar ^{1 is} unsubstituted or mono-, di- or trisubstituted by A,

OA, OH ₁ SH, SA, Hal, NO ₂ , CN, (CH ₂ ) _n phenyl, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, CHO, COA, SO ₂ A, CONH ₂ ,

SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA, NHCOOA, NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA,

NHCONAA ¹ and / or NACONAA ¹ substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the one-, two- or three-fold by

A, OA, OH, SH, SA, Hal, NO ₂ , CN, (CHz) _n Ar ¹ , (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, CHO, COA, SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ', NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA,

NHCOOA ₁ NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA, NHCONAA ¹ , NACONAA ¹ , SO ₂ A, = S, = NH, = NA and / or = 0 (carbonyl oxygen) can

Het ^{1 is} a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A, OA, OH, Hal and / or 0O (carbonyl oxygen),

Hal is F, Cl, Br or I, n is O, 1, 2, 3 or 4, o is 1, 2, 3 or 4, s is 0 or 1, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

The invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1-14 and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, characterized in that

a) a compound of formula II

wherein

R ¹ , R ² and R ^{3 have} the meanings given in claim 1,

with a compound of the formula

Y-CO-CH ₂ -Z wherein Y has the meaning given in claim 1, and Z denotes Cl, Br, I or a free or reactively functionally modified OH group,

implements,

or

b) that in a compound of formula I one or more radical (s) R ¹ , R ² , R ³ , R ⁴ and / or Y in one or more radical (s) R ¹ , R ² , R ³ , R ⁴ and / or Y converts,

for example

i) reducing a nitro group to an amino group,

ii) hydrolyzing an ester group to a carboxy group,

iii) converting an amino group to an alkylated amine by reductive amination;

iv) alkylating and / or acylating a hydroxy and / or amino group,

and / or converting a base or acid of the formula I into one of its salts.

The invention also relates to the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g.

Mono or dihydrate or alcoholates. The compounds of the formula I according to the invention can also be present in tautomeric forms. Formula I includes all of these tautomeric forms.

5

Pharmaceutically usable derivatives are understood, for example, as the

Salts of the compounds of the invention as well as so-called

Prodrug compounds.

Under prodrug derivatives is understood with z. As alkyl or acyl groups, 10 sugars or oligopeptides modified compounds of formula I _{1 in} the body rapidly to the effective invention

Connections are split.

These include biodegradable polymer derivatives of the inventive ₁₅ compounds, as z. In Int. J. Pharm. H5, 61-67 (1995).

The term "effective amount" means the amount of a drug or pharmaceutical agent that is a biological or therapeutic agent

20 causes medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.

In addition, the term "therapeutically effective amount" 25 means an amount that, compared to a corresponding subject, has this

Quantity has not resulted in: improved treatment, cure, prevention or elimination of a

Illness, a medical condition, a medical condition, an _O0 condition, a disorder or side effects, or even those

Reduction of the progression of a disease, a disease or a disorder.

The term "therapeutically effective amount" also includes the

Quantities that are effective, the normal physiological function too

35. ... increase. The invention also provides mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000th These are particularly preferably mixtures of stereoisomeric compounds.

For all residues which occur several times, their meanings are independent of each other.

Above and below, the radicals or parameters R ¹ , R ² , R ³ , R ⁴ and Y have the meanings given for the formula I, unless expressly stated otherwise.

^ ₅ A or A 'is preferably alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms. A or A 'means particularly preferably methyl, 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-, 0

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, 1,2,2- or 1,2,2-trimethylpropyl.

A or A 'very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl, and also fluoromethyl, difluoromethyl or bromomethyl. A or A ^{1 also} means cycloalkyl. Cycloalkyl is preferably Q cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or A 'also denotes Alk. Alk represents alkenyl having 2-6 C atoms, such as e.g. Vinyl or propenyl.

Cycloalkylalkylene means e.g. Cyclohexylmethyl, cyclohexylethyl,

Cyclopentylmethyl or cyclopentylethyl. 5 C 1 -C ₁₀ -alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene, isopropylene, isobutylene, sec-butylene, 1-, 2- or 3-methylbutylene, 1,1-,

1, 2- or 2,2-dimethylpropylene, 1-ethylpropylene, 1-, 2-, 3- or 4-

Methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1 Ethyl 2-methylpropylene, 1,1,2,2 or 1,2,2-trimethylpropylene, more preferably methylene, ethylene, propylene, butylene, pentylene or hexylene.

Alkenylene means a hydrocarbon chain with 2-10 C atoms, with 2 free valencies and containing at least one double bond.

Ac is acetyl, BzI is benzyl, Ms is -SO ₂ CH ₃ .

Y is preferably amino; NHA, preferably methylamino; NAA ', preferably dimethylamino or diethylamino; NHR ⁵ , preferably -NH- (CH ₂ ) o -NA ₂ , such as 2-dimethylaminoethyl-amino or -NH- (CH ₂ ) _O -HeI ¹ , such as 2- (morpholin-4-yl) ethylamino ,

Y is more preferably NH ₂ .

R ¹ is preferably H, OH or OA, such as methoxy. R ² , R ^{3 are} preferably each independently

-NHCO- (X) ₅ -Q, -CONH- (X) _S -Q, -NH (CO) NH- (X) ₈ -Q ₁ -NH (CO) O- (X) ₅ -Q,

- (X) ₅ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H, then R ² = H or Cl.

R ⁴ preferably denotes H or Hal _{1 is} particularly preferably H.

X is preferably unsubstituted or mono-, di-, tri or tetra-substituted by OA, OH, Hal, COOH, CONH ₂ , NH ₂ and / or NHCOOA straight or branched C ₁ -C 10 alkylene, wherein also one, two or three C groups may be replaced by O, NHCO, CONH, SO ₂ NH, NHSO ₂ and / or by NH groups.

Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert

Butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o- , m- or p- (N-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-ethylamino) -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, o-, m- or p-cyanophenyl, o-, m or p-ureidophenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-

Carboxyphenyl, o-, m- or p-carboxymethyl-phenyl, o-, m- or p-

Carboxymethoxy-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 is preferably unsubstituted or mono-, di-, tri-, tetra- or fivefold by A, Hal, OA, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, NHCO (CH ₂ ) _n NH ₂ and / or -O- (CH ₂ ) ₀ -Het ¹ substituted phenyl.

Ar is particularly preferably unsubstituted or mono- or disubstituted by A ⁵ ₁ Hal, (CH _{2) n} COOH, (CH _{2) n} COOA, NHCO (CH _{2) n} NH ₂ and / or

-O- (CH ₂ ) o -Het ¹ substituted phenyl.

Ar 'preferably means e.g. unsubstituted or mono-, di- or trisubstituted by Hal substituted phenyl.

Het, irrespective of further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- ^ _c 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, furthermore preferably 1, 2,3-TriazoM-, -4- or -5-yl, 1, 2,4-tri- azole-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-thia

20-diazol-3 or -5-yl, 1,2,3-thiadiazol-4 or -5-yl, 3- or 4-pyridazinyl,

Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl , 3-, 4-, 5-, 6- or 5-7-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, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4 -, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8 Quinazolinyl, 5- or 6-quin-Q oxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxole-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 may also be partially or completely hydrogenated. 5

Het can so z. B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl,

2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxo lan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-i-, -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-, 5 or -4-pyridyl, 1, 2,3,4- Tetrahydro-1-, 2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetra hydro-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-

10 piperazinyl, 1,2,3,4-tetrahydro-1-, 2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3 , 4-Tetrahydro-1 -, - 2 -, - 3, -A-, -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,

Λ C 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, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

20

Het is preferably a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is mono-, di- or trisubstituted by A, OA, Hal and / or OO ( Carbonyl oxygen) may be substituted. 5

Het more preferably represents a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A and / or OOQ (carbonyl oxygen), where A is preferably Methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

In a further embodiment, Het particularly preferably denotes unsubstituted or mono- or disubstituted by A and / or O5-substituted piperidine, piperazine, pyrrolidine, pyridine, pyrrole, indole, indazole, Morpholine or isoxazole, wherein A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

Het ¹ preferably denotes a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A and / or 0O (carbonyl oxygen), particular preference is given to 4-methylpiperazinyl.

The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms. Formula I encompasses all these forms.

Accordingly, the invention are in particular those compounds of formula I ₁ where at least one of said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be through the following

Partial formulas Ia to Im are expressed which correspond to the formula I and in which the unspecified radicals have the meaning indicated for the formula I but in which

in Ia Y is NH ₂ or NHR ⁵ ;

in Ib R ^{1 is} H, OH or OA;

in Ic R ² , R ^{3 are} each independently -NHCO- (X) _S -Q, -CONH- (X) ₅ -Q, -NH (CO) NH- (X) sQ, -NH (CO) O- ( X) sQ,

- (X) ₃ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H, then R ² = H or Cl;

in Id R ^{4 is} H or Hal; in Ie R ^{5 is} - (CH ₂ ) ₀ -Het ¹ or - (CH ₂ ) _O -NA ₂ ;

in If X unsubstituted or one, two, three or four times by OA, OH, HaI ₁ COOH, CONH ₂ , NH ₂ and / or

NHCOOA substituted straight or branched C1-C1 ₀ alkylene, wherein one, two or three groups by C-O, NHCO, CONH, SO ₂ NH, NHSO ₂ and / or replaced by NH groups may be means;

in Ig Q is H, Ar or Het;

unsubstituted in Ih Ar or A, Hal, OA, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, one, two, three, four or five times,

NHCO (CH ₂ ) _n NH ₂ and / or -O- (CH ₂ ) _O -Het ¹ substituted phenyl;

in Ii Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is mono-, di- or trisubstituted by A ₁ OA ₁ Hal and / or = 0 ( Carbonyl oxygen) may be substituted;

in Ij Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N- and / or

O atoms, one or two times by A and / or = 0

(Carbonyl oxygen) may be substituted means; in Ik Het ¹ a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be mono- or disubstituted by A and / or = 0 (carbonyl oxygen), 5 means;

in Il A is unbranched or branched alkyl having 1-6 C atoms, wherein 1-5 H atoms may be replaced by F and / or Cl 10;

in Im Y NH ₂ or NHR ⁵ ,

15 R ¹ H, OH or OA, R ² , R ^{3 are} each independently -NHCO- (X) ₅ -Q,

-CONH- (X) ₅ -Q, -NH (CO) NH- (X) ₅ -Q, -NH (CO) O- (X) ₅ -Q,

- (X) ₅ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or 20. if R ³ ≠ H, then R ² = H or Cl,

R ^{4 is} H or Hal,

R ^{5 is} - (CH ₂ ) ₀ -Het ¹ or - (CH ₂ ) _O -NA ₂ ,

X unsubstituted or one, two, three or four times

25 by OA, OH, Hal, COOH, CONH ₂ , NH ₂ and / or

NHCOOA substituted straight or branched C ₁ -C _O alkylene, wherein one, two or three groups by C-O, NHCO, CONH, SO ₂ NH,

3Q NHSO ₂ and / or may be replaced by NH groups,

Q H, Ar or Het,

Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, NHCO (CH ₂ ) _n NH ₂ and / or -O - (CH ₂ ) ₀ -Het ¹ substituted phenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, the one, two or three times by

A, OA, Hal and / or = O (carbonyl oxygen) may be substituted,

Het ^{1 is} a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A and / or = O (carbonyl oxygen), A is unbranched or branched alkyl having 1-6 C atoms in which 1-5 H atoms can be replaced by F and / or Cl,

Hal is F, Cl, Br or I, n is 0, 1, 2, 3 or 4, o is 1, 2, 3 or 4, s ordeM;

and their pharmaceutically usable derivatives, solvates, salts,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

The compounds of the formula I are preferably selected from the group

"A35", "A36 ¹¹ ," A37 "and" A38 ".

The compounds according to the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example 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 reactions mentioned. You can do that also make use of known per se, not mentioned here variants.

The starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.

The starting compounds are generally known. If they are new, they can be produced by methods known per se.

Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.

The compounds of formula II and III are known in the rule. If they are not known, they can be prepared by methods known per se.

In the compounds of the formula III, Z is preferably Cl, Br, I or a reactively modified OH group, such as alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl or p-butyl). tolylsulphonyloxy). Z is more preferably Cl.

The reaction is carried out by methods known to the person skilled in the art.

The reaction is preferably carried out under basic conditions. When

Bases are preferably alkali metal hydroxides, including

Potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine or diethanolamine.

The reaction is carried out in a suitable inert solvent. Suitable inert solvents are, for example, 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, 5 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;

10 amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or

A c mixtures of the solvents mentioned.

As the solvent, particularly preferred is e.g. Water and / or tetrahydrofuran.

The reaction time varies depending on the conditions used

20 minutes and 14 days, the reaction temperature between about

-30 ° and 140 °, normally between -10 ° and 130 °, in particular between about 30 ° and about 125 °.

It is furthermore possible to convert a compound of the formula I into another compound of the formula I by reacting one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or Y into one or more radicals ( e) R ¹ , R ² , R ³ , R ⁴ and / or Y converts, for example by nitro groups,

_OQ, for example, by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol, reduced to amino groups and / or converts an ester group into a carboxy group and / or converts an amino group by reductive amination into an alkylated amine 5 and / or

Esterified carboxy groups by reaction with alcohols and / or Acid chlorides are converted by reaction with an amine in an acid amide and / or alkylated a hydroxy group, for example with an alkyl halide.

5

Further, one can acylate free amino groups in the usual manner with an acid chloride or anhydride or alkylate with an unsubstituted or substituted alkyl halide, suitably in an inert solvent such as dichloromethane or THF and / or in the presence of a

10 base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

The compounds of formulas I can furthermore be obtained by liberating them from ^ _c their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which, instead of one or more free amino and / or hydroxyl

20 groups corresponding protected amino and / or hydroxy groups, preferably those which instead of an H atom, which is connected to an N-atom, carry an amino protecting group, for. For example those which conform to the formula I but instead of an _NH2 group contain an NHR ^1-5 group (which means an amino wherein R ^1, for example BOC or CBZ.) Included.

Furthermore, starting materials are preferred which carry a hydroxy protecting group instead of the H atom of an _OQ hydroxy group, for. B. those that the

Formula I, but instead of a hydroxyphenyl group, contain an R "O-phenyl group (wherein R" represents a hydroxy-protecting group).

There may also be several - same or different - protected amino 5 and / or hydroxy groups present in the molecule of the starting material be. If the protecting groups present are different from each other, they can be selectively cleaved in many cases.

The term "amino protecting group" is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. In particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are typical of such groups. Moreover, because the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is not critical; However, preference is given to those having 1-20, in particular 1-8 C atoms. The term "acyl group" is to be understood in the broadest sense in the context of the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids 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 toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr, Pbf or Pmc. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy protecting group" is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction at other sites of the invention

Molecule has been performed. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or Acyl groups, and also alkyl groups. The nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms. Examples of hydroxy-protecting groups include benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. COOH groups are preferably protected in the form of their tert-butyl esters.

10 The in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the protecting group used - z. B. with strong acids, useful with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid

^ _c acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as

20

Tetrahydrofuran or dioxane, amides such as DMF ₁ halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in

25 shot without the 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 cleavage are suitably between about 0 and about 50 °, preferably working

_O0 one between 15 and 30 ° (room temperature).

The groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 °, the FMOC group with an about 5- to 50%

35

Solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °. Pharmaceutical salts and other forms

The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention

The invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by methods known in the art. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding

Reacts base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and

N-methyl-glutamine. The aluminum salts of the compounds of formula I are also included. In certain compounds of formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids

Acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate , Succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate,

Benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, Camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulphate, ethanesulphonate, fumarate, galacterate (from mucic acid),

Galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, 5

Hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,

Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 10 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate Persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

, _{| c} Furthermore, among the base salts of the invention

Compounds aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this should not be a limitation.

Preferred among the above salts are ammonium; the

20

Alkali metal salts sodium and potassium, as well as the alkaline earth metal salts

Calcium and magnesium. Salts of the compounds of formula I ₁ derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted 5 amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine , Caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethyl-Q aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, Histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines,

Theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine 5 and tris (hydroxymethyl) methylamine (tromethamine), which, however, no

To represent restriction. Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C ₄ ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;

Di (C 1 -C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C ₁₀ - C ₈₎ 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.

The above-mentioned pharmaceutical salts which are preferred 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 this is not intended to be limiting.

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

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

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

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the

Invention also 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, it can be seen that the term "pharmaceutically acceptable salt" in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used. The pharmaceutically acceptable salt form of the active ingredient may also be this

It is possible to first give the active substance a desired pharmacokinetic property that it did not previously possess, and even pharmacodynamics this drug in terms of its therapeutic efficacy in the body positively influence.

Compounds of the formula I according to the invention can, on the basis of their

Molecular structure can be chiral and therefore can occur in different enantiomeric forms. They may therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds of formula I may differ, it may be desirable to use the enantiomers. In these cases, the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.

In the case of racemic amines diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, 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 chromatographic enantiomer separation using an optically active resolving agent (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.

The invention furthermore relates to the use of the compounds and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular to non-pharmaceutical chemical way. In this case, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, 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, from 0.1 mg to 3 g, preferably from 1 mg to 700 mg, more preferably from 5 mg to 100 mg of a compound of the invention, depending on the condition 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 of an active ingredient. Furthermore, such pharmaceutical

Make formulations by any of the methods well known in the pharmaceutical 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) routes. Such formulations can be used with all in the pharmaceutical field known methods, for example, by the active ingredient with the carrier (s) or excipient (s) is brought together.

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, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and using a similarly comminuted pharmaceutical grade

Carrier, such as e.g. an edible carbohydrate such as

Starch or mannitol is mixed. A flavor, preservative, dispersant and dye may also be present.

Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. One

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 bonding,

Lubricants and disintegrants as well as dyes also in the mixture be incorporated. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,

Tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,

Waxes, u.a. 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, such as e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. bentonite,

Kaolin or dicalcium phosphate. The powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve. As an alternative to

Granulation can run the powder mixture through a tableting machine, resulting in irregularly shaped lumps, which are broken up into granules. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds of the invention can also be used with a free-flowing inert

Carrier combined and then pressed directly into tablets without performing the granulation or Trockenverpressungsschhtte.

A transparent or opaque protective layer, consisting of a shellac seal, 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. 5

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. Leave syrups

10 can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle. Suspensions may be prepared by dispersing the compound in a non-aqueous solution.

- be _formulated toxic _drug . Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added. 20

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.

The compounds of the formula I and salts, solvates and physiologically _Q functional derivatives thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be made of different phospholipids, such as

Cholesterol, stearylamine or phosphatidylcholines. 5 The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals. Further, the compounds may be coupled to a class of biodegradable polymers suitable for controlled release of a drug, eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical adapted to transdermal administration

Formulations can be used as separate patches for longer, narrow

Be presented with 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 become a Cream can be formulated 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 rapid inhalation 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 carrier include drug solutions in water or oil.

For administration by inhalation adapted pharmaceutical

Formulations include fine particulate dusts or mists, which may be supplied by various types of pressurized dosing dispensers

Aerosols, nebulizers or insufflators can be generated.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject

Recipient is included; 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 vials 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. Injection solutions and suspensions prepared by formulation can be prepared 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 a compound of formula I will depend on a number of factors, including, for example, the age and weight of the human or animal, the exact disease condition requiring treatment, as well as its severity, the nature of the formulation, and the route of administration; is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention for treatment is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would be for usually between 70 and 700 mg, which may be given 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 so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of Formula I per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable _C 1 -C derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.

As further active pharmaceutical ingredients chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby the

20

Inhibit growth and proliferation of tumor cells; preferred are VEGF receptor inhibitors, including robozymes and antisense, which are directed to VEGF receptors, as well as angiostatin and endostatin. 5

Examples of antineoplastic agents that can be used in combination with the compounds of the invention generally include alkylating agents, antimetabolites; Epidophyllotoxin;

_OQ an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; Mitoxantrone or platinum coordination complexes.

Antineoplastic agents are preferably selected from the following classes: 5 Anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynes and podophyllotoxins.

Particularly preferred in the mentioned classes are e.g. Carminomycin, daunorubicin, aminopterin, methotrexate, methopterine, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 5-fluorodeoxyuridine monophosphate, cytarabine, 5-azacytidine, thioguanine, azathioprine, adenosine, pentostatin, erythrohydroxynonyladenine, cladribine, 6-mercaptopurine, gemcitabine, Cytosine arabinoside, podophyllotoxin or Podophyllotoxinderivate, such as Etoposide, Etoposide Phosphate or Teniposide, Melphalan, Vinblastine, Vinorelbine, Vincristine, Leurosidine, Vindesine, Leurosine, Docetaxel and Paclitaxel. Other preferred antineoplastic agents are selected from the group

Discodermolides, epothilones D, estramustins, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, bleomycin, gemcitabine, ifosamide, melphalan, hexamethylmelamine, thiotepa, idatrexate, trimetrexates,

Dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan,

Arabinosyl-cytosine, bicalutamide, flutamide, leuprolide,

Pyridobenzoindole derivatives, interferons and interleukins.

As further active pharmaceutical ingredients antibiotics are preferred. Preferred antibiotics are selected from the group

Dactinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.

As further active pharmaceutical ingredients enzyme inhibitors are preferred. Preferred enzyme inhibitors are selected from the group of histone deacetylation inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA]) and tyrosine kinase inhibitors (e.g., ZD 1839 [Iressa]).

As further active pharmaceutical ingredients, nuclear export inhibitors are preferred. Nuclear export inhibitors prevent the discharge of Biopolymers (eg RNA) from the cell nucleus. Preferred nuclear export inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.

As further active pharmaceutical ingredients, nuclear export inhibitors are preferred. Nuclear export inhibitors prevent the removal of biopolymers (eg RNA) from the nucleus. Preferred nuclear export inhibitors are selected from the group Callystatin, Leptomycin B ₁ Ratjadone.

As further active pharmaceutical ingredients immunosuppressants are preferred. Preferred immunosuppressants are selected from the group rapamycin, CCI-779 (Wyeth), RAD001 (Novartis), AP23573 (Ariad Pharmaceuticals).

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

Packs of

(a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and (b) an effective amount of another active pharmaceutical ingredient.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The kit may contain, for example, separate ampoules in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance are dissolved or lyophilized Form is present. USE

The present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of diseases in which HSP90 plays a role.

The invention thus relates to the use of compounds of the formula I, and their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all

Conditions for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of HSP90 plays a role.

The present invention includes the use of the compounds of

Formula I and / or its physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of tumor diseases, such. Fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma , Sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,

Choriocarcinoma, seminoma, embryonic carcinoma, Wilms tumor,

Cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio- blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma Waldenstrom's macroglobulinemia and severe chain disease; viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes

Simplex type II (HSV-II) ₁ rinderpest, rhinovirus, echovirus, rotavirus, 5 respiratory syncytial virus (RSV), papillomavirus, papovavirus,

Cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumps virus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human

10 immunodeficiency virus type II (HIV-II); for immunosuppression in transplantations; inflammatory diseases such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel

_* c Disease; Cystic fibrosis; Diseases associated with angiogenesis such as diabetic retinopathy, hemangiomas, endometriosis, tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration; fibrogenetic disorders such as scleroderma, polymyositis, systemic lupus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis;

In particular, the compounds of the formula I can inhibit the growth of cancer, tumor cells and tumor metastases and are therefore suitable for tumor therapy.

The present invention further comprises the use of the Q compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the protection of normal cells against toxicity caused by chemotherapy, as well as for the treatment of diseases, wherein protein misfolding or

Aggregation is a major causative factor, such as Scrapie, Creutzfeldt-Jakob- 5

Disease, Huntington's or Alzheimer's. The invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of diseases of the

Central nervous system, cardiovascular disease and cachexia. 5

In a further embodiment, the invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for

10 HSP90 modulation wherein the modulated HSP90 biological activity elicits an immune response in an individual, endoplasmic reticulum protein transport, hypoxic / anoxic stress recovery, malnutrition recovery, recovery from heat stress, or sc combinations thereof; and / or wherein Disorder a kind

Cancer is an infectious disease, disorder associated with impaired protein transport from the endoplasmic reticulum, a disorder associated with ischemia / reperfusion, or combinations thereof, with ischemia / reperfusion-associated disorder resulting from

20

Cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative Disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.

30

The invention also relates in a further embodiment

Use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for

Treatment of ischemia as a result of cardiac arrest, asystole and 5 delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary

Bypass surgery, organ transplantation, spinal cord injury, Head trauma, stroke, thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress ,

Test method for the measurement of HSP90 inhibitors

The binding of geldanamycin or 17-allylamino-17-demethoxy-geldanamycin (17AAG) and their competitive inhibition to HSP90 can be used to determine the inhibitory activity of the compounds of this invention (Carreras et al., 2003, Chiosis et al., 2002). In the special case, a radioligand filter binding test is used. The radioligand used is tritium-labeled 17-allylamino-geldanamycin, [3H] 17AAG. This filter binding assay allows a targeted search for inhibitors that interfere with the ATP binding site.

material

Recombinant human HSP90α (expressing E. coli, 95% purity); [3H] 17AAG (17-allylamino-geldanamycin, [allylamino-2,3- ³ H. Specific activity: 1, 11x10 ¹² Bq / mmol (Moravek, MT-1717);

HEPES filter buffer (50 mM HEPES, pH 7.0, 5 mM MgCl 2, BSA 0.01%) Multiscreen FB (1 μm) filter plate (Millipore, MAFBNOB 50).

method

The 96 well microtiter filter plates are first watered and coated with 0.1% polyethyleneimine.

The test is carried out under the following conditions:

Reaction temperature 22 ^° C. Reaction time: 30 min., Shaking at 800 rpm

Test volume: 50 μl

final concentrations:

50 mM HEPES-HCl, pH 7.0, 5 mM MgCl 2, 0.01% (w / v) BSA

HSP90: 1, 5 μg / assay

[3H] 17AAG: 0.08 μM.

At the end of the reaction, the supernatant in the filter plate is aspirated using a vacuum manifold (Millipore Multiscreen Separation System) and the filter washed twice. The filter plates are then measured in a beta counter (Microbeta, Wallac) with scintillator (Microscint 20, Packard).

From the "counts per minutes" values "% of control" is determined and from this the IC-50 value of a connection is calculated.

Above and below all temperatures are given in ⁰ 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. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1.

LC-MS conditions

Hewlett Packard HP 1100 series system with the following features: Ion source: electrospray (positive mode); Scan: 100-1000 m / z;

Fragmentation voltage: 60 V; Gas temperature: 300 ⁰ C, DAD: 220 nm. Flow rate: 2.4 ml / min. The splitter used reduced the flow rate for the MS to O, 75 ml / min after the DAD. Column: Chromolith SpeedROD RP-18e 50-4.6 Solvent: LiChrosolv grade from Merck KGaA Solvent A: H2O (0.01% TFA)

Solvent B: ACN (0.008% TFA)

Gradient: 20% B → 100% B: 0 min to 2.8 min 100% B: 2.8 min to 3.3 min 100% B → 20% B: 3.3 min to 4 min

The retention times R _f [min] and M + H ⁺ data MW given in the examples below are the measurement results of the LC-MS measurements.

example 1

General Reaction Scheme for the Preparation of Compounds of Formula I wherein R ^{2 represents} an acylated amino group:

Preparation of 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-trifluoromethylbenzoylamino) -phenyl] -thieno [2,3-b] pyridine ("A1")

1.1 A solution of 10 g of 4-methoxy-3-nitrobenzaldehyde in 100 ml of ethanol is mixed with 10.9 g of cyanoacetamide and 9 ml of 4-methylmorpholine and stirred for 48 hours at room temperature. It is mixed with 10% HCl to a pH of 5 and stirred for 16 hours. The precipitated material is separated, washed with ethanol and n-heptane and dried. 9.6 g of 6-amino-3,5-dicyano-4- (4-methoxy-3-nitrophenyl) -2-thioxo-1,2-dihydro-pyridine ("1") are obtained.

1.2 A solution of 30.7 g of "1" in 100 ml of DMF is mixed with one equivalent of KOH in water. Then add 8.8 g of 2-chloroacetamide and stirred for one hour. It is mixed with another equivalent of KOH in water and stirred for 16 hours at room temperature, then for another hour at 100 °. Dilute with the same amount of water, separate the precipitated material, wash with water and dry. This gives 17 g of 2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3-nitrophenyl) thieno [2,3-b] pyridine ("2").

1.3 1, 8 "2" in 100 ml of DMF are prepared according to standard procedures with Pd-C-5%

(56% water) hydrogenated as a catalyst. After separation of the catalyst and removal of the solvent g is obtained in quantitative yield

2-aminocarbonyl-3,6-diamino-5-cyano-4- (3-amino-4-methoxyphenyl) thieno [2,3-b] pyridine ("3"),

¹ H NMR 250 MHz, DMSO-d ₆ ) δ 15.00 (b), 7.62 (d, 1H), 7.51 (d, 1 H), 7.48

(d, 1H), 4.06 (S, 3H).

1.4 A solution of 45 μl of 3- (trifluoromethyl) benzoyl chloride and 48 mg of 1-hydroxybenzotriazole hydrate in 1 ml of DMF is combined with 47 μl of 4-methylmorpholine and stirred at room temperature for 1 hour. Add 100 mg of "3" and stir for 16 hours. The mixture is stirred into 10 ml of water, the precipitated material is separated off, washed with water and purified by chromatography (RP-flash chromatography; Isco Companion ^®). This gives 24 mg of "A1", M + H ⁺ 527.50

Analog is obtained by reacting "3" with

acetyl chloride,

trifluoroacetyl,

Glutarsäuremethylesterchlorid,

1H-pyridin-2-on-4-carboxylic acid chloride,

4-methoxycarbonyl-benzoyl chloride,

Chlorcarbonylmethoxy-methyl acetate,

3-trifluoromethyl-phenyl sulfonyl,

the connections

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3-acetamidophenyl) thieno [2,3-b] pyridine ("A2"), M + H ⁺ 397.43;

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3-trifluoroacetamido-phenyl) -thieno [2,3-b] pyridine ("A3"), M + H ⁺ 451.40;

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-methoxycarbonyl-butyrylamino) -phenyl] thieno [2,3-b] pyridine ("A4a"),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (1H-pyridin-2-one-4-carbonylamino) -phenyl] -thieno [2,3-b] pyridine ( "A5"), M + H ⁺ 476.49;

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-methoxycarbonyl-benzoylamino) -phenyl] thieno [2,3-b] pyridine ("A6a") . 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-methoxycarbonylmethoxy-acetamido) -phenyl] -thieno [2,3-b] pyridine ("A7a"),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-trifluoromethyl-phenyl-sulfonamido) -phenyl] -thieno [2,3-b] pyridine ("A9") , M + H ⁺ 563.55;

Example 2

By ester hydrolysis is obtained under standard conditions

from "A4a" the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-carboxy-butrylamino) -phenyl] -thieno [2,3-b] pyridine ( "A4"), M + H ⁺ 469.49;

from "A6a" the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-carboxy-benzoylamino) -phenyl] -thieno [2,3-b] pyridine ( "A6")

M + H ⁺ 503.51;

from "A7a" the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-carboxymethoxy-acetamido) -phenyl] -thieno [2,3-b] pyridine ( "A7"), M + H ⁺ 471.46.

Example 3

A solution of 55 mg BOC-glycine (BOC-Gly-OH) and 48 mg 1-hydroxybenzotriazole hydrate in 1 ml DMF is treated with 82 mg N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (DAPECI) and 47 μl 4- Methylmorpholine and stirred for 1 hour at room temperature. Add 100 mg of "3" and stir for 16 hours. It is stirred in 10 ml of water, the precipitated material is separated off and washed with water. You get 2-Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2 - [(tert-butyloxycarbonyl) -amino] -acetamido} -phenyl) -thieno [2,3-b ] pyridine ("A10"),

Analog is obtained by reacting "3" with

BOC-β-Ala-OH (BOC-β-alanine),

BOC-GABA-OH (BOC-γ-aminobutyric acid),

1 H-indole-7-carboxylic acid,

BOC-His-OH (BOC-histidine),

BOC-Asn-OH (BOC-asparagine),

Λ / - (2-carbamoyl-acetyl) -glycine,

1H-indazole-7-carboxylic acid,

BOC-Ser (O-tert-butyl) -OH (BOC- (S) -serine-tert-butyl ether),

the connections

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {3 - [(tert-butyloxycarbonyl) -amino] -propionylamino} -phenyl) -thieno [2,3-b ] pyridine ("A11"), M + H ⁺ 526.59;

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {4 - [(tert-butyloxycarbonyl) -amino] -butyrylamino} -phenyl) -thieno [2,3-b ] pyridine ("A12"), M + H ⁺ 540.61;

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (indol-7-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A13"), M + H ⁺ 498.54; (S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2 - [(tert-butyloxycarbonyl) -amino] -3- (1 / - / - imidazole 4-yl) -propionylamino} -phenyl) -thieno [2,3-b] pyridine ("A14a"),

(S) -2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2 - [(tert-butyloxycarbonyl) -amino] -3-aminocarbonyl-propionylamino} -phenyl) thieno [2,3-b] pyridine ( ¹¹ AISa "),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- [2- (2-carbamoyl-acetylamino) -acetylamino] -phenyl] thieno [2,3-b] pyridine (" A16 "), M + H ⁺ 497.51;

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (indazol-7-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A17"), M + H ⁺ 499.52;

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2 - [(tert-butyloxycarbonyl) -amino] -3- (tert -butyloxy) - propionylamino} -phenyl) thieno [2,3-b] pyridine ("A18a").

Example 4

By cleavage of the BOC protective groups and cleavage of the tert.-

Butyl ether in HCI / dioxane is obtained from

"A11 ¹¹ ," A12 ",

"A14a", "Aiδa ¹¹ , ¹¹ A 18a",

the connections

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-amino-propionylamino) -phenyl] thieno [2,3-b] pyhdine ("A21"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-amino-butyrylamino) -phenyl] -thieno [2,3-b] pyridine ("A22"), M + H ⁺ 440.50;

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [2-amino-3- (1 / - / - imidazol-4-yl) -propionylamino] - phenyl} thieno [2,3-b] pyridine ("A14")

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2-amino-3-aminocarbonyl-propionylamino} -phenyl) -thieno [2,3-b] pyridine ("A15"),

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-amino-3-hydroxypropionylamino) -phenyl] -thieno [2,3-b] pyridine ("A18").

Example 5

By reacting 2-aminocarbonyl-3,6-diamino-5-cyano-4- (2-amino-4-methoxyphenyl) thieno [2,3-b] pyridine ("3a") with 3-thfluoromethyl- phenyl isocyanate is obtained under standard conditions the compound

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- (3-trifluoromethyl-phenylureido) -phenyl] thieno [2,3-b] pyridine ("A22").

Example 6

Analogously to Example 1, reaction of 2-aminocarbonyl-3,6-diamino-5-cyano-4- (2-amino-4-methoxyphenyl) thieno [2,3-b] pyridine ("3a") is obtained. With Benzoyl chloride, 3-carbamoyl-propionic acid,

Λ / - (phenylsulfonyl) glycine,

the connections

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-2-benzoylaminophenyl) thieno [2,3-b] pyridine ("A8"), M + H ⁺ 459.50;

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- (3-carbamoyl-propionylamino) -phenyl] -thieno [2,3-b] pyridine ("A19"), M + H ⁺ 454.48;

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- [2- (phenylsulfonyl) -acetylamino] phenyl] thieno [2,3-b] pyridine ("A20 "), M + H ⁺ 552.60.

Example 7

Preparation of 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- [2-

(3-ethyl-ureido) -ethylcarbamoyl] -phenyl] -thieno [2,3-b] pyridine ("A23")

7.1 Reaction scheme for the preparation of the precursor "A23a"

7.2 A mixture of "A23a", "A23b"

Palladium (II) acetate (47% Pd), 1,8-diazabicyclo [5.4.0] undec-7-ene, THF and molybdenum hexacarbonyl are microwaved for 1 hour at 120 ° in the microwave. After usual work-up one receives

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- [2- (3-ethyl-ureido) -ethylcarbamoyl] -phenyl] thieno [2,3-b] pyridine ( "A23"), M + H ⁺ 497.55

Analogously to Example 7.2 is obtained by reaction of

with 7-amino-indazole in the presence of Mo (CO) ₆ and Pd (OAc) ₂ the compound

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [3- (indazol-7-ylcarbamoyl) -phenyl] thieno [2,3-b] pyridine ("A24"), M + H ⁺ 469.50

Analogously to Example 7.2 is obtained by reaction of

with 4-amino-butyramide in the presence of Mo (CO) ₆ and Pd (OAc) ₂ the compound

2-aminocarbonyl-3,6-diamino-5-cyano-4- [5-chloro-3- (3-carbamoyl-propylcarbamoyl) -phenyl] -thieno [2,3-b] pyridine ("A25"), M + H ⁺ 472.93

Example 8

To 3-fluorobenzylzinc bromide (0.5 M in THF) is added PdCl ₂ (dppf) and stirred for 5 minutes at room temperature under argon atmosphere. Subsequently, a solution of "A26a"

added dropwise in THF and stirred at 45 ° for 30 minutes, then at 65 ° for 1 hour. It is cooled, poured onto saturated NH ₄ Cl solution and worked up as usual. There are obtained 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-fluorobenzyl) phenyl] thieno [2,3-b] pyridine ("A26"). , M + H ⁺ 448.49

Example 9

9.1 A mixture of "A27a"

2-Vinyl-pyridine, triethylamine, palladium (II) acetate (47% Pd), tri-o-tolyl-phosphine and acetonitrile is in the microwave for 30 minutes at 160 ° irradiated. The reaction mixture is treated with toluene and extracted several times with water. The organic phase is dried and concentrated. The product is purified by chromatography (ISCO / 40 g column; petroleum ether / ethyl acetate: 4/1 to 1/1). One receives "A27b ^M

9.2 A mixture of "A27b", Pd-C-5% (56% water) and THF is hydrogenated for 16 hours at 1, 4 bar and room temperature in a BuCHI apparatus. After removal of the catalyst and removal of the solvent, 2-aminocarbonyl-3,6-diamino-5-cyano-4- {3-chloro-4-methoxy-2- [2- (pyridin-2-yl) ethyl] - phenyl} thieno [2,3-b] pyridine ("A27"), M + H ⁺ 497.96

Analogously to Example 9.1, the compound "A28a" is obtained by reacting "A26a" with methyl acrylate.

and from this by hydrogenation analogously to Example 9.2 and ester cleavage the compound

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-carboxyethyl) -phenyl] thieno [2 _r 3-b] pyridine ("A28"), M + H ⁺ 412.44

Example 10

A mixture of "A26a", "A29a ^M

Propanol, palladium (II) acetate, triphenylphosphine, sodium carbonate solution and water are heated in a Suzuki reaction for 16 hours under N ₂ - atmosphere and under reflux. Cool off, work up as usual and get the connection

2-aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thieno [2,3-b ] pyridine ("A29"), M + H ⁺ 558.68

Example 11

Analogously to Example 10, by reacting "A30a"

with ^M A30b "

the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [3-

(2-aminoacetylamino) phenyl] phenyl} thieno [2,3-b] pyridine ("A30"), M + H ⁺ 559.66

Example 12

Analogously to Example 1 is obtained by reacting "A31a"

with glutaric acid methyl ester chloride the compound "A31b"

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3-chloro-2- (4-methoxycarbonyl-butyrylamino) -phenyl] -thieno [2,3-b] pyridine ("A31b "). Ester cleavage gives 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3-chloro-2- (4-carboxy-butyrylamino) -phenyl] thieno [2,3-b ] pyridine ( ¹¹ ASI "), M + H ⁺ 503.94

Example 13

Analogously to Example 1 is obtained by reacting "A32a"

with "A32b"

the connection "A32" 2-Aminocarbonyl-3,6-diamino-5-cyano-4- {2-chloro-4-difluoromethoxy-3- [3- (4-methylpiperazin-1-yl) -propionylamino] -phenyl} thieno [ 2,3-b] pyridine ("A32"), M + H ⁺ 580.03

Example 14

Analogously to Example 1, by reacting "A33a"

with glutaric acid methyl ester chloride the compound "A33b"

Ester cleavage gives 2- (2-morpholin-4-yl-ethyl-carbamoyl) -3,6-diamino-5-cyano-4- [2- (4-carboxy-butyrylamino) -phenyl] -thieno [2 , 3-b] pyridine ("A33"), M + H ⁺ 552.63.

Example 15

By implementing "A34a"

with benzyl alcohol, under standard conditions, the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4- [2- (benzyloxycarbonylamino) phenyl] thieno [2,3-b] pyridine ("A34") , M + H ⁺ 489.53 ("A34")

Example 16

Analogously to the preparation of "A1", the following compounds are obtained

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-trifluoromethylbenzoylamino) -phenyl] -thieno [2,3-b] pyridine ("A35"),

¹ H NMR 250 MHz, DMSO-d ₆₎ δ 9.99 (b), 8.16 (d, 1 H), 7.92 (d, 2H) ₁ 7:37 (d, 2H), 7:02 (s, 1 H), 5.90 (s , 1H), 3.96 (s, 3H);

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-trifluoromethylbenzoylamino) -phenyl] thieno [2,3-b] pyridine ("A36").

Analogously to the preparation of "A17", the compounds are obtained

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (pyridin-4-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A37")

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (prop-2-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A38").

Pharmacological data

Affinity to receptors Table 1

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

5

A solution of 100 g of an active ingredient according to 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 10 injection vial contains 5 mg of active ingredient.

Example B: Suppositories

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

Example C: Solution

A solution of 1 g of an active ingredient according to the invention, 0

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

Benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. These

Solution can be used in the form of eye drops. 5

Example D: Ointment

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

30

Example E: Tablets

A 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 added in the usual manner

Tablets compressed so that each tablet contains 10 mg of active ingredient. 35 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 active ingredient are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of an active ingredient 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

1. Compounds of the formula

wherein Y is OH, OA, SH, SA, NH ₂ , NHA, NAA ¹ or NHR ⁵ ,

R ¹ Hal, OH, OA, SH, SA, H or A,

R ² , R ^{3 are} each independently -NHCO- (X) ₃ -Q,

-CONH- (X) ₅ -Q, -CONA- (X) ₅ -Q,

-NH (CO) NH- (X) ₈ -Q, -NH (CO) O- (X) ₅ -Q, -NHSO ₂ - (X) ₅ -Q, -SO ₂ NH- (X) ₅ -Q , -SO ₂ NA- (X) ₅ -Q, - (X) ₅ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H, then R ² = H or Cl,

R ^{4 is} H, Hal, CN, NO ₂ , A, OH, OA, SH, SA, (CH ₂ ) _n COOH,

(CH ₂ ) _n COOA, CONH ₂ , CONHA, CONAA ¹ , NH ₂ , NHA, NAA ¹ , NHCOOA, NHCONH ₂ , NHCONHA, SOA, SO ₂ A, SO ₂ NH ₂ , SO ₂ NHA and / or SO ₂ NAA ¹ , two adjacent radicals selected from the group R ¹ , R ² , R ³ , R ⁴ together also methylenedioxy or ethylenedioxy,

R ^{5 is} - (CH ₂ ) ₀ -Het ¹ , - (CH ₂ ) _O -NH ₂ , - (CH ₂ ) ₀ -NHA or

- (CH ₂ ) _O -NA ₂ ,

A, A 'are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which 1-5 H atoms may be replaced by F, Cl and / or Br, AIk or cyclic alkyl having 3-7 C atoms, A and A 'together also an alkylene chain having 2, 3, 4, 5 or 6 C atoms, wherein one or two CH ₂ groups by O ₁ S, SO ₁ SO ₂ , NH, NA and / or N-COOA can be replaced,

Alk alkenyl with 2-6 C atoms,

X is unsubstituted or mono-, di-, tri- or tetravalent by A, OA, OH, SH, SA, Hal, NO ₂ , CN, Ar ₁ OAr, COOH ₁ COOA ₁ CHO ₁ C (= O) A, C ( = O) Ar, SO ₂ A, CONH ₂ ,

SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA, NAA ', OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA, NHCOOA ₁ NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA,

NHCONAA ^1, NACONAA ¹ and / or = 0 substituted straight or branched C1-C1 ₀ alkylene or C ₂ -C _O alkenylene in which one, two or three C

Groups represented by O, S, SO, SO ₂ , NHCO, NACO, CONH,

CONA, SO ₂ NH, SO ₂ NA, NHSO ₂ , NASO ₂ and / or may be replaced by NH groups, QH, Carb, Ar or Het,

Carb is unsubstituted or mono-, di-, tri-, tetra- or quintuple by A, OA, OH, SH, SA, Hal, NO ₂ , CN,

(CHz) _n Ar ¹ , (CH ₂ ) n COOH, (CH ₂ ) _n COOA, CHO, COA, SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA, NHCOOA, NACOOA, NHSO ₂ OA,

NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA, NHCONAA ¹ and / or NACONAA ¹ substituted

Cycloalkyl of 3-7 C atoms or cycloalkenyl of 3-7

C-atoms, Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, OA, OH, SH, SA, Hal, NO ₂ , CN, (CH 3) _n Ar ¹ , (CH ₂ ) _π COOH, (CH ₂ ) _π COOA, CHO, COA, SO ₂ A ₁ CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA,

OCONAA ¹ , NHCOA, NHCOOA, NACOOA, NHSO ₂ OA, NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA, NHCONAA'.NACONAA ¹ , NHCO (CH ₂ ) _n NH ₂ and / or -O- (CH ₂ ) _O -Het ¹ substituted phenyl, naphthyl or biphenyl,

Ar ^{1 is} unsubstituted or mono-, di- or trisubstituted by A,

OA, OH, SH, SA, Hal, NO ₂ , CN, (CH ₂ ) _n phenyl, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, CHO, COA, SO ₂ A, CONH ₂ ,

SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA, SO ₂ NAA ¹ , NH ₂ , NHA ₁ NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA, NHCOOA, NACOOA ₁ NHSO ₂ OA ₁ NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA ₁ NACONHA ₁ NHCONAA 'and / or NACONAA ¹ substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which passes through one, two or three times

A ₁ OA, OH, SH ₁ SA, Hal, NO ₂ , CN ₁ (CH ₂ ) _n Ar 1 (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, CHO ₁ COA, SO ₂ A, CONH ₂ , SO ₂ NH ₂ , CONHA, CONAA ¹ , SO ₂ NHA ₁ SO ₂ NAA ¹ , NH ₂ , NHA, NAA ¹ , OCONH ₂ , OCONHA, OCONAA ¹ , NHCOA ₁

NHCOOA, NACOOA, NHSO ₂ OA ₁ NASO ₂ OA, NHCONH ₂ , NACONH ₂ , NHCONHA, NACONHA ₁ NHCONAA ', NACONAA ¹ , SO ₂ A ₁ = S, = NH, = NA and / or = 0 (carbonyl oxygen) Het ^{1 may be} a mononuclear saturated heterocycle having 1 to 2 N and / or O atoms, which may be mono- or disubstituted by A, OA, OH, Hal and / or = O (carbonyl oxygen), HalF, Cl, Br or I, n is 0, 1, 2, 3 or 4, o is 1, 2, 3 or 4, s is O or i , and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

2. Compounds according to claim 1 of the formula I, wherein Y is NH ₂ or NHR ⁵ , and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions.

3. Compounds according to claim 1 or 2, wherein

R ^{1 is} H, OH or OA, and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

4. Compounds according to one or more of claims 1-3, wherein R ² , R ^{3 are} each independently -NHCO- (X) ₅ -Q, -CONH- (X) ₅ -Q, -NH (CO) NH- ( X) ₅ -Q, -NH (CO) O- (X) ₅ -Q,

- (X) ₅ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H, then R ² = H or Cl, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

5. Compounds according to one or more of claims 1-4, wherein R ^{4 is} H or Hal, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions.

6. Compounds according to one or more of claims 1-5, wherein R ^{5 is} - (CH ₂ ) ₀ -Het ¹ or - (CH ₂ ) ₀ -NA ₂ , and their pharmaceutically usable derivatives, salts, solvates,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

7. Compounds according to one or more of claims 1-6, wherein

X unsubstituted or one, two, three or four times by

OA, OH, Hal, COOH, CONH ₂ , NH ₂ and / or NHCOOA substituted unbranched or branched C 1 -C 10 alkylene, wherein also one, two or three C groups by O, NHCO, CONH, SO ₂ NH, NHSO ₂ and or may be replaced by NH groups, as well as their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

8. Compounds according to one or more of claims 1-7, wherein Q is H, Ar or Het, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

5

9. Compounds according to one or more of claims 1-8, wherein

Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, OA, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA, NHCO (CH ₂ ) _n NH ₂ and / or -O - (CH ₂ ) _O -Het ¹ substituted 10 phenyl, as well as their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in ^ _c all ratios.

10. Compounds according to one or more of claims 1-9, wherein Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O- and / or S-

20

Atoms which may be mono-, di- or trisubstituted by A, OA, Hal and / or = O (carbonyl oxygen), as well as their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all conditions.

11. Compounds according to one or more of claims 1-10, wherein _Q Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms, the one or two times by A and / or = O (carbonyl oxygen) may be substituted, 5 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

12. Compounds according to one or more of claims 1-11, wherein

Het ^{1 is} a mononuclear saturated heterocycle having 1 to 2 N and / or O atoms, which may be mono- or disubstituted by A and / or = 0 (carbonyl oxygen), and their pharmaceutically usable derivatives, salts, solvates,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

13. Compounds according to one or more of claims 1-12, wherein

A is unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F and / or Cl, and their pharmaceutically usable derivatives, salts, solvates,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

14. Compounds according to one or more of claims 1-13, wherein Y is NH ₂ or NHR ⁵ ,

R ^{1 is} H, OH or OA,

R ² , R ^{3 are} each independently -NHCO- (X) ₅ -Q, -CONH- (X) ₅ -Q, -NH (CO) NH- (X) ₅ -Q, -NH (CO) O- ( X) ₅ -Q,

- (X) ₅ -Q or H, where, if R ² ≠ H, then R ³ = H or Cl, or if R ³ ≠ H ₁ then R ² = H or Cl, R ⁴ H or Hal, R ⁵ - (CH ₂ ) ₀ -Het ¹ or - (CH ₂ ) ₀ -NA ₂ , X unsubstituted or one, two, three or four times by

OA, OH, Hal, COOH ₁ CONH _2, NH ₂ and / or NHCOOA substituted straight or branched _C1-C10 alkylene, in which one, two or three groups by C-O, NHCO, 5

CONH, SO ₂ NH, NHSO ₂ and / or may be replaced by NH groups, QH, Ar or Het,

Ar is unsubstituted or mono-, di-, tri-, tetra- or quintupleto A, Hal, OA, (CH ₂ ) _n COOH, (CH ₂ ) _n COOA,

NHCO (CH ₂ ) _n NH ₂ and / or -O- (CH ₂ ) ₀ -Het ¹ substituted

phenyl,

Het a mono- or binuclear saturated, unsaturated or ^ _C aromatic heterocycle having 1 to 4 N, O and / or S

Atoms which may be monosubstituted, disubstituted or trisubstituted by A, OA, Hal and / or = O (carbonyl oxygen), Het ^{1 is} a mononuclear saturated heterocycle having 1 to 2 N and / or O atoms, the one or twice by A and / or 0

= 0 (carbonyl oxygen) may be substituted,

A is unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F and / or Cl,

Hal denotes F, Cl, Br or I, 5 n is O, 1, 2, 3 or 4, o is 1, 2, 3 or 4, s is O or 1, mean ₃₀ and pharmaceutically usable derivatives, salts, solvates,

Tautomers and stereoisomers, including mixtures thereof in all ratios.

15. Compounds according to claim 1 selected from group 5

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-trifluoromethylbenzoylamino) -phenyl] thieno [2,3-b] pyridine ("A1"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3-acetamido-phenyl) -thieno [2,3-b] pyridine ("A2"),

2-Aminocarbonyl-3, 6-d iam ino-5-cya n-4- (4-methoxy-3-trifluoroacetamido-phenyl) -thieno [2,3-b] pyridine ("A3"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-methoxycarbonyl-butyrylamino) -phenyl] thieno [2,3-b] pyridine ("A4a"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (1H-pyridin-2-one-4-carbonylamino) -phenyl] thieno [2,3-b] pyridine ( "A5"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-methoxycarbonyl-benzoylamino) -phenyl] -thieno [2,3-b] pyridine (" a6a ")

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-methoxycarbonylmethoxy-acetamido) -phenyl] -thieno [2,3-b] pyridine ("A7a"),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-trifluoromethyl-phenyl-sulfonamido) -phenyl] -thieno [2,3-b] pyridine ("A9") .

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-carboxy-butrylamino) -phenyl] -thieno [2,3-b] pyridine ("A4"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-carboxy-benzoylamino) -phenyl] thieno [2,3-b] pyridine ("A6"), 2 -Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-carboxymethoxy-acetamido) -phenyl] thieno [2,3-b] pyridine ("A7"), 2- Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2 - [(tert -butyloxycarbonyO-amino-acetamido-phenyl-thieno) -1-blipyridine

( "A10")

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {3 - [(tert-butyloxycarbonyl) -amino] -propionylamino} -phenyl) thieno [2,3-b ] pyridine ("A11"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {4 - [(tert-butyloxycarbonyl) -amino] -butyrylamino} -phenyl) -thieno [2,3-b ] pyridine

( "A12")

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (indol-7-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A13"), (S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2- [(tert-butyloxycarbonyl) -amino] -3- (1H-imidazole-4-) yl) -propionylamino} - phenyl) thieno [2,3-b] pyridine ("A14a"),

(S) -2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2-5

[(tert -butyloxycarbonyl) -amino] -3-aminocarbonyl-propionylamino} -phenyl) -thieno [2,3-b] pyridine ("A15a"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- [2- (2-carbamoyl-acetylamino) -acetylamino] -phenyl-1-thieno ^, S-b-pyridine 10 ( ⁿ A16 "),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (indazol-7-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A17"),

(S) -2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2- ^ _c [(tert-butyloxycarbonyl) -amino] -3- (tert -butyloxy ) -propionylamino} -phenyO-thieno ^ .S-bJpyridine fAiδa "),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-amino-propionylamino) -phenyl] thieno [2,3-b] pyridine ("A21"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-amino-0-butyrylamino) -phenyl] -thieno [2,3-b] pyridine ("A22")

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [2-amino-3- (1H-imidazol-4-yl) -propionylamino] -phenyl} - thieno [2,3-b] pyridine ("A14"), 5 (S) -2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-3- {2-amino-3-) aminocarbonyl-propionylamino} -phenyl) -thieno [2,3-b] pyridine ("A15 ¹¹ ),

(S) -2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- ( _2-3- amino-3-hydroxypropionylamino) -phenyl] -thieno [2,3-b ] pyridine

("A 18"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- (3-trifluoromethyl-phenylureido) -phenyl] thieno [2,3-b] pyridine ("A22")

2-aminocarbonyl-3,6-diamino-5-cyano-4- (4-methoxy-2-5-benzoylamino-phenyl) -thieno [2,3-b] pyridine ("A8"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- (3-carbamoyl-propionylamino) -phenyl] -thieno [2,3-b] pyridine ("A19"), 2 aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- [2-

(phenylsulfonyl) acetylamino] phenyl] thieno [2,3-b] pyridine ("A20"), 5

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-2- [2- (3-ethyl-ureido) -ethylcarbamoyl] -phenyl] thieno [2,3-b] pyridine ( "A23"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- [3- (indazol-7-ylcarbamoyl) -phenyl] -thieno [2,3-b] pyridine ("A24"), 10 2-aminocarbonyl-3,6-diamino-5-cyano-4- [5-chloro-3- (3-carbamoyl-propylcarbamoyl) -phenyl] -thieno [2,3-b] pyridine ("A25"),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (3-fluoro-benzyl) -phenyl] -thieno [2,3-b] pyridine ("A26"), ^ c 2-aminocarbonyl-3,6-diamino-5-cyano-4- {3-chloro-4-methoxy-2- [2-

(pyridin-2-yl) ethyl] phenyl} thieno [2,3-b] pyridine ("A27"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-carboxyethyl) phenyl] thieno [2,3-b] pyridine ("A28"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thieno [2,3- b] pyridine ("A29"),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- {4-methoxy-3- [3- (2-aminoacetylamino) phenyl] phenyl} thieno [2,3-b] pyridine (" A30 ")

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3-chloro-2- (4-5-methoxycarbonyl-butyrylamino) -phenyl] thieno [2,3-b] pyridine (" A31b "),

2-Aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3-chloro-2- (4-carboxy-butyrylamino) -phenyl] -thieno [2,3-b] pyridine ("A31 ")

2-Aminocarbonyl-3,6-diamino-5-cyano-4- {2-chloro-4-Q-difluoromethoxy-3- [3- (4-methylpiperazin-1-yl) -propionylamino] -phenyl} -thieno [2,3-b] pyridine ("A32 ¹¹ ),

2- (2-morpholin-4-yl-ethylcarbamoyl) -3,6-diamino-5-cyano-4- [2- (4-carboxybutyrylamino) -phenyl] thieno [2,3-b] pyridine ( "A33")

2-aminocarbonyl-3,6-diamino-5-cyano-4- [2- (benzyloxy-5-carbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A34"), 2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (4-trifluoromethylbenzoylamino) -phenyl] -thieno [2,3-b] pyridine ("A35"),

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (2-trifluoromethylbenzoylamino) -phenyl] thieno [2,3-b] pyridine ("A36").

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (pyridin-4-ylcarbonylamino) -phenyl] -thieno [2,3-b] pyridine ("A37")

2-aminocarbonyl-3,6-diamino-5-cyano-4- [4-methoxy-3- (prop-2-ylcarbonylamino) -phenyl] thieno [2,3-b] pyridine ("A38")

and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.

16. A process for the preparation of compounds of the formula I according to claims 1-15 and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, characterized in that

a) a compound of formula II

wherein

R ¹ , R ² and R ^{3 have} the meanings given in claim 1, with a compound of formula III

Y-CO-CH ₂ -Z IM

in which Y has the meaning given in claim 1, and Z denotes Cl ₁ Br ₁ I or a freely or reactively functionally modified OH group, converts 0,

or 5 b) that in a compound of the formula I one or more radical (s) R ¹ , R ² , R ³ , R ⁴ and / or Y in one or more radical (s) R ¹ , R ² , R ³ , R ⁴ and / or Y converts,

0 by example

i) reducing a nitro group to an amino group,

₅ ii) hydrolyzing an ester group to a carboxy group,

iii) converting an amino group to an alkylated amine by reductive amination;

Q iv) a hydroxy and / or amino group alkylated and / or acylated,

and / or converting a base or acid of the formula I into one of its salts. 5

17. Medicaments containing at least one compound of the formula I. and / or their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants. 5

18. Use of compounds of formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all 10 ratios, for the manufacture of a medicament for the treatment and / or prophylaxis of diseases in which the inhibition, regulation and / or modulation of HSP90 plays a role.

_c

19. Use according to claim 18 of compounds of the formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for

Treatment or prevention of tumor diseases, viral

20

Diseases, immunosuppression in transplantation, inflammatory diseases, cystic fibrosis, diseases related to angiogenesis, infectious diseases, autoimmune diseases, ischemia, fibrogenetic diseases, for the promotion of nerve regeneration, for inhibiting the growth of cancer, tumor cells and

Tumor metastases, ₀ normal to protect cells against toxicity caused by chemotherapy, for the treatment of diseases in which incorrect protein folding or aggregation is a principal causal factor.

5

20. Use according to claim 19, wherein the tumors are fibrosarcoma, myxosarcoma, liposarcoma, Chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma , Papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,

Seminoma, embryonic carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,

Hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and

Heavy chain disease is.

21. Use according to claim 19, wherein the viral pathogen of the viral diseases is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, adenovirus, herpes simplex type I (HSV-I) ₁ herpes simplex type II

(HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumps virus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I ) and human immunodeficiency virus type II (HIV-II).

22. Use according to claim 19, wherein the inflammatory diseases are rheumatoid arthritis, asthma, multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease.

23. Use according to claim 19, wherein the diseases 5 associated with angiogenesis are diabetic retinopathy,

Hemangiomas, endometriosis and tumor angiogenesis.

24. Use according to claim 19, wherein it is in the

10 fibrogenetic disorders are scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.

- _j e

Use according to claim 19, wherein the diseases in which protein misfolding or aggregation is a major causative factor are scrapie, Creutzfeldt-Jakob disease, Huntington's or Alzheimer's disease.

² ^

26. Medicaments containing at least one compound of the formula I and / or pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and at least one other

25 active pharmaceutical ingredient.

27. Set (kit) consisting of separate packs of

(A) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions, and

(b) an effective amount of a further medicament active ingredient ^35.