HK1115126A - Thienopyridine derivatives and use thereof as hsp90 modulators - Google Patents

Description

Thienopyridine derivatives and their use as HSP90 modulators

Background

The present invention is based on the object of finding new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to compounds in which the inhibition, regulation and/or modulation of HSP90 plays a role, to pharmaceutical compositions comprising these compounds and to the use of said compounds in 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 crucial for the regulation of the balance between synthesis and degradation of proteins. These chaperones are important for many important functions of the cell, such as the regulation of cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al, 1998; Smith, 2001).

Heat Shock Proteins (HSP)

Cells of a tissue respond to external stress such as heat, hypoxia, oxidative stress, or toxic substances such as heavy metals or alcohols, with activation of many molecular chaperones known as "heat shock proteins" (HSPs).

Activation of HSPs protects cells from damage caused by such stressors, accelerates recovery from physiological states and leads to stress-tolerant states of cells.

In addition to this initially discovered protective mechanism by HSPs against external stress, other important chaperone functions of individual HSPs under normal, non-stressed conditions were ultimately described. Thus, various HSPs regulate the proper folding, intracellular localization and function or controlled degradation of, for example, many biologically important proteins of a cell.

HSPs form gene families with individual gene products, where the cellular expression, function, and localization of the individual gene products differ among different cells. Within this family, naming and classification is based on their molecular weight, e.g., HSP27, HSP70, and HSP 90.

Some human diseases are based on incorrect protein folding (see reviews such as Tytell et al, 2001; Smith et al, 1998). Thus, it may be useful in such circumstances to develop treatments that are involved in chaperone-dependent protein folding mechanisms. For example, in the case of alzheimer's disease, prion disease, or huntington's syndrome, incorrectly folded proteins lead to aggregation of the protein with progression of neurodegeneration. Incorrect protein folding can also lead to loss of wild type function, which can result in incorrectly regulated molecular and physiological functions.

HSPs are also of great importance in tumor diseases. For example, expression of certain HSPs has been shown to be associated with the stage of tumor progression (Martin et al, 2000; Conroy et al, 1996; Kawanishi et al, 1999; Jameel et al, 1992; Honng et al, 2000; Lebeau et al, 1991).

The fact that HSP90 plays a role in many important oncogenic signaling pathways in cells and that certain natural products with cancer inhibitory activity target HSP90 has led to the concept of: inhibition of HSP90 function would be useful in the treatment of neoplastic diseases. The HSP90 inhibitor17-allylamino-17-demethoxygeldanamycin (17AAG) (geldanamycin derivative) is currently undergoing clinical trials.

HSP90

HSP90 represents approximately 1-2% of the total cellular protein mass. It is usually in dimeric form in cells and is associated with a number of proteins, so-called co-chaperones (see e.g. Pratt, 1997). HSP90 is essential for cell viability (Young et al, 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose natural folding has been altered by external stress, such as heat shock, in order to restore the original folding or to prevent aggregation of the proteins (Smith et al, 1998).

HSP90 has also been shown to be important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding caused by mutations (Rutherford and Lindquist, 1998).

In addition, HSP90 also has important regulatory roles. Under physiological conditions, HSP90 plays a role in ensuring conformational stability and cellular balance for maturation of a variety of key client proteins (client proteins) together with its homolog GRP94 in the endoplasmic reticulum. It can be divided into three groups: a collection of catalytic subunits of steroid hormone receptors, Ser/Thr or tyrosine kinases (e.g., ERBB2, RAF-1, CDK4 and LCK) and various proteins such as mutated p53 or telomerase hTERT. Each of these proteins plays a key role in the regulation of physiological and biochemical processes of the cell.

The conserved HSP90 family in humans includes four genes, namely the cytoplasmic HSP90 α, the inducible HSP90 β isoform (Hickey et al, 1989), GRP94 in the endoplasmic reticulum (Argon et al, 1999), and HSP75/TRAP1 in the mitochondrial matrix (Felts et al, 2000). All members of the family are thought to have similar modes of action, but binding to different client proteins depends on their localization in the cell. For example, ERBB2 is a specific client protein of GRP94(Argon et al, 1999), while type 1 tumor necrosis factor receptor (TNFR1) or retinoblastoma protein (Rb) has been found to be a client protein of TRAP1 (Song et al, 1995; Chen et al, 1996).

HSP90 is involved in many complex interactions with a large number of client and regulatory proteins (Smith, 2001). Although the precise molecular details are not yet known, biochemical experiments and studies carried out in recent years with the aid of X-ray crystallography have increasingly been able to explain the details of the function of the HSP90 chaperone (Prodromou et al, 1997; Stebbins et al, 1997). Thus, HSP90 is an ATP-dependent chaperone (Prodromou et al, 1997), whose dimerization is important for the hydrolysis of ATP. Binding of ATP leads to the formation of a circular dimeric structure in which the two N-terminal domains are in close contact with each other and serve as switches for conformation (Prodromou and Pearl, 2000).

Known HSP90 inhibitors

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

Later, strong antitumor activity was demonstrated in vitro (Schulte et al, 1998) and in vivo in animal models (Supko et al, 1995).

Immunoprecipitation and studies on affinity matrices then showed that the major mechanism of action of geldanamycin involved binding to HSP90 (Whitesell et al, 1994; Schulte and Neckers, 1998). In addition, X-ray crystallography studies have shown 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 multimeric HSP90 complexes that function as chaperones for client proteins. Thus, the client proteins are degraded via the ubiquitin-proteasome pathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed no change in the properties of inhibition of HSP90, degradation of client proteins and antitumor activity in cell culture and xenograft tumor models (Schulte et al, 1998; Kelland et al, 1999), but had significantly less hepatotoxicity than geldanamycin (Page et al, 1997). 17AAG is currently undergoing phase I/II clinical trials.

Radicicol (a macrocyclic antibiotic) also showed a modification of the malignant phenotype of v-Src and v-Ha-Ras-induced fibroblasts (Kwon et al, 1992; Zhao et al, 1995). Radicicol degrades many signaling proteins as a result of HSP90 inhibition (Schulte et al, 1998). X-ray crystallography studies have shown that radicicol also binds to the N-terminal domain of HSP90 and inhibits intrinsic ATPase activity (Roe et al, 1998).

As is known, coumarins bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria. The coumarin antibiotic neomycin binds to the carboxy terminus of HSP90, i.e. to a different HSP90 site than the HSP90 sites of benzoquinone-ansamycin and radicicol, and the benzoquinone-ansamycin and radicicol bind to the N-terminus of HSP90 (Marcu et al, 2000 b).

Inhibition of HSP90 by novobiocin results in massive HSP 90-dependent signal protein degradation (Marcu et al, 2000 a).

Degradation of signaling proteins such as ERBB2 was demonstrated using PU 3(a purine-derived HSP90 inhibitor). PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al, 2001)

HSP90 as therapeutic target

Since HSP90 is involved in the regulation of many signaling pathways important in the phenotype of tumors and since it was discovered that certain natural products exert their biological effects by inhibiting the activity of HSP90, HSP90 is currently being tested as a new target for the development of tumor therapeutics (Neckers et al, 1999).

The main mechanisms of action of geldanamycin, 17AAG and radicicol include inhibition of binding of ATP to the ATP binding site at the N-terminus of the protein and inhibition of the intrinsic ATPase activity of the resulting HSP90 (see, e.g., Prodromou et al, 1997; Stebbins et al, 1997; Panaretou et al, 1998). Inhibition of the ATPase activity of HSP90 prevents recruitment of co-chaperones and contributes to the formation of HSP90 heterocomplexes, which cause degradation of client proteins via the ubiquitin-proteasome pathway (see, e.g., Neckers et al, 1999; Kelland et al, 1999). Treatment of tumor cells with HSP90 inhibitors results in the selective degradation of important proteins that are important for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often uncontrolled in tumors (see e.g. Hostein et al, 2001).

An attractive principle for the development of HSP90 inhibitors is that strong tumor therapeutic effects can be achieved by simultaneously degrading multiple proteins associated with the transformed phenotype.

In particular, the present invention relates to compounds that inhibit, modulate and/or modulate HSP90, compositions comprising these compounds and methods of their use for treating HSP 90-induced diseases such as neoplastic diseases, viral diseases such as hepatitis b (Waxman, 2002); immunosuppression in transplantation (Bijlmakers, 2000 and Yorgin, 2000); inflammation-induced diseases (Bucci, 2000), such as rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseases associated with angiogenesis (Hur, 2002 and Kurebayashi, 2001), such as diabetic retinopathy, hemangiomas, endometriosis and tumor angiogenesis; infectious diseases; (ii) an autoimmune disease; ischemia; promotion of nerve regeneration (Rosen et al, WO 02/09696; Degranco et al, WO 99/51223; Gold, US6,210,974B1); fibrotic diseases, such as scleroderma, polymyositis, systemic lupus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds of the invention for protecting normal cells from chemotherapy-induced toxicity and in diseases in which incorrect protein folding or aggregation is a major causative factor, such as scrapie, creutzfeldt-jakob disease, huntington's disease or alzheimer's disease (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). WO01/72779 describes purine compounds and their use in the treatment of GRP94(HSP90 homolog or paralogue) induced diseases, such as tumour diseases, wherein the cancerous tissue comprises a sarcoma or carcinoma selected from: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, neuroblastoma, mesothelioma, neuroblastoma, neuro, Meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease.

Therapeutic and diagnostic applications of HSP90 activation, particularly for the treatment of central nervous system and cardiovascular diseases, are described by kamal et al in Trends in Molecular Medicine, volume 10, stage 6, month 6 2004.

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

It has been found that the compounds of formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular they exhibit HSP90 inhibiting properties.

The present invention therefore relates to compounds of formula I as medicaments and/or pharmaceutical active ingredients for the treatment and/or prophylaxis of said diseases and to the use of compounds of formula I for the preparation of medicaments for the treatment and/or prophylaxis of said diseases, and also to methods for the treatment of said diseases, which methods comprise the administration of one or more compounds of formula I to a patient in need of such administration.

The host or patient may belong to any mammalian species, e.g. a primate species, particularly humans; rodents, including mice, rats and hamsters; a rabbit; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, where they provide a model for the treatment of human disease.

Prior Art

WO2005/00300A1 describes triazole derivatives as HSP90 inhibitors.

WO00/53169 describes that coumarin or coumarin derivatives inhibit HSP 90.

WO03/041643A2 discloses zearalanol (zearalanol) derivatives which inhibit HSP 90.

Pyrazole derivatives inhibiting HSP90 substituted with an aromatic group in the 3-or 5-position are disclosed in WO2004/050087a1 and WO2004/056782a 1.

WO03/055860A1 describes 3, 4-diaryl pyrazoles as HSP90 inhibitors.

Purine derivatives having HSP90 inhibiting properties are disclosed in WO02/36075a 2.

WO01/72779 describes purine compounds and their use in the treatment of diseases induced by GRP94(a homolog or paralog of HSP90), such as neoplastic diseases, wherein the cancerous tissue comprises a sarcoma or carcinoma selected from: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, neuroblastoma, mesothelioma, neuroblastoma, neuro, Meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease.

WO01/72779 also discloses the use of the compounds mentioned therein for the treatment of viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis a virus, hepatitis b virus, hepatitis c virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus (equinovirus), arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II).

WO01/72779 also describes the use of the compounds mentioned therein in the modulation of GRP94, wherein the modulated biological GRP94 activity causes an immune response, protein transport from the endoplasmic reticulum, recovery from hypoxia/hypoxic stress, recovery from malnutrition, recovery from heat stress or a combination thereof in an individual and/or wherein the disorder is cancer, an infectious disease, a disorder associated with disrupted protein transport from the endoplasmic reticulum, a disorder associated with ischemia/reperfusion or a combination thereof, wherein the disorder associated with ischemia/reperfusion is cardiac arrest, cardiac arrest and delayed ventricular arrhythmia, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus (statistilepticus), Epileptic seizures, anxiety, schizophrenia, neurodegenerative disorders, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), or a consequence of neonatal stress.

Finally, WO01/72779 describes the use of an effective amount of a GRP94 protein modulator in the manufacture of a medicament for altering the response of subsequent cells to an ischemic state at a tissue site in an individual by treating cells at the tissue site with a GRP94 protein modulator to increase GRP94 activity in the cells to an extent that alters the response of subsequent cells to the ischemic state, wherein the subsequent ischemic state is preferably cardiac arrest, asystole and delayed ventricular arrhythmia, cardiac surgery, arterial bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorders, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS) or the consequences of neonatal stress, or wherein the tissue site is transplanted donor tissue.

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Summary of The Invention

The invention relates to compounds of formula (I) and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios

Wherein

Y represents OH, OA, SH, SA, NH₂NHA or NAA',

R¹represents Hal, OH, OA, SH, SA, H or A,

R²is represented by H, Hal or-O- (X)_s-Q，

R³H, Hal, CN, NO₂、A、OH、OA、SH、SA、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA’、NH₂、NHA、NAA’、NHCOOA、NHCONH₂、NHCONHA、SOA、SO₂A、SO₂NH₂、SO₂NHA or SO₂NAA’，

Selected from the group R¹、R²、R³Together two adjacent radicals also denote methylenedioxy or ethylenedioxy,

A. a' independently of one another denote straight-chain or branched alkyl having 1 to 10C atoms, where 1 to 5H atoms may be replaced by F and/or Cl; alk; or cycloalkyl having 3 to 7C atoms,

a and A' together also denote an alkylene chain having 2, 3, 4, 5 or 6C atoms, one CH of which₂The radicals being selected from the group consisting of O, S, SO₂NH, NA or N-COOA,

alk represents an alkenyl group having 2 to 6C atoms,

x represents a straight or branched C₁-C₁₀Alkylene or C₂-C₁₀Alkenylene, each of which is unsubstituted or mono-, di-, tri-or tetra-substituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、Ar、OAr、COOH、COOA、CHO、C(＝O)A、C(＝O)Ar、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA ', naconoaa' and/or ═ O and where 1, 2 or 3C groups can be replaced by O, S, SO₂And/or a substitution of an NH group,

q represents H, Carb, Ar or Het,

carb represents cycloalkyl having 3 to 7C atoms or cycloalkenyl having 3 to 7C atoms, each of which is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

ar' represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or trisubstituted with: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nPhenyl, (CH)₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

het represents a mono-or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂、NHCONHA、NACONHA、NHCONAA’、NACONAA’、SO₂A. (ii) S, ═ NH, ═ NA and/or ═ O (carbonyl oxygen),

hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1.

The present invention relates to processes for the preparation of compounds of formula I and salts thereof, and compounds of formula I and pharmaceutically acceptable derivatives, solvates, salts, tautomers and stereoisomers thereof according to claims 1 to 14, characterized in that

a) Reacting a compound of formula II with a compound of formula III

In the compounds of the formula II, R¹、R²And R³Having the meaning as specified in claim 1,

Y-CO-CH₂-Z III

in the compounds of the formula III, Y has the meaning specified in claim 1 and Z represents Cl, Br, I or a free or reactively functionally modified OH group,

or

(b) By reacting one or more radicals R, for example¹、R²、R³And/or Y into one or more radicals R¹、R²、R³And/or the presence of Y and/or Y,

i) the nitro group is reduced into amino group,

ii) hydrolysis of the ester group to a carboxyl group,

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

iv) alkylating the hydroxyl groups, and (iii) optionally,

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

The invention also relates to hydrates and solvates of these compounds. Solvates of a compound refer to adducts of inert solvent molecules on the compound formed due to their mutual attractive forces. Solvates are, for example, mono-or dihydrate or alcoholates.

The compounds of formula I according to the invention may also exist in tautomeric forms. Formula I includes all such tautomeric forms.

Pharmaceutically acceptable derivatives refer, for example, to salts of the compounds of the invention and to so-called prodrug compounds.

Prodrug derivatives refer to compounds of formula I which have been modified, for example, by alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in vivo to yield the active compounds of the invention.

These also include biodegradable polymer derivatives of the compounds of the invention, for example as in int.j.pharm.11561-67 (1995).

The expression "effective amount" refers to an amount of a drug or pharmaceutical active ingredient that produces a sought or desired biological or medical response in a tissue, system, animal or human, e.g., a sought or desired biological or medical response by a researcher or physician.

In addition, the expression "therapeutically effective amount" refers to an amount that has the following result compared to a corresponding individual not receiving the amount: improved healing treatment, healing, prevention or elimination of a disease, disease manifestation, disease state, discomfort, disorder or side effect, or reduction in progression of a disease, discomfort or disorder.

The term "therapeutically effective amount" also includes an amount effective to enhance normal physiological function.

The invention furthermore relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. Mixtures of stereoisomeric compounds are particularly preferred.

For all groups which occur more than once, their meanings are independent of one another.

In this context, the radicals and the parameter R¹、R²、R³And Y has the meaning specified in formula I, unless otherwise specified.

A or A' preferably represents alkyl, is straight-chain (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. A or A' particularly preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 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-or 1, 2, 2-trimethylpropyl.

A or A' very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or1, 1, 1-trifluoroethyl, and furthermore fluoromethyl, difluoromethyl or bromomethyl.

A or A' also represents cycloalkyl. Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or A' also represents Alk. Alk represents an alkenyl group having 2 to 6C atoms, such as vinyl or propenyl.

Cycloalkylalkylene represents, for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl or cyclopentylethyl.

C₁-C₁₀Alkylene preferably denotes methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene, isopropylene, isobutylene, sec-butylene, 1-, 2-or 3-methylbutylene, 1-, 1, 2-or 2, 2-dimethylpropylene, 1-ethylpropylene, 1-, 2-, 3-or 4-methylpentylene, 1-, 1, 2-, 1, 3-, 2-, 2, 3-or 3, 3-dimethylbutylene, 1-or 2-ethyl-butylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 2-or 1, 2, 2-trimethylpropylene, particularly preferably methylene, ethylene, propylene, butylene, pentylene or hexylene.

Alkenylene denotes a hydrocarbon chain having 2 to 10C atoms, having 2 free valences and comprising at least one double bond.

Ac represents acetyl, Bzl represents benzyl, Ms represents-SO₂CH₃。

Y represents OH; OA, preferably methoxy; SH; SA, preferably methylsulfanyl; an amino group; NHA, preferably methylamino; NAA', preferably dimethylamino or diethylamino.

R¹Preferably represents OH or OA, such as methoxy; further H or Hal.

R³Preferably represents H, Hal, OH or OA, for example methoxy.

X preferably represents a linear or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or NH groups.

Ar denotes, for example, 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-acetylaminophenyl, 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- (methylsulphonamido) phenyl, o-, m-or p- (methylsulphonyl) phenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or, 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-carboxymethylphenyl, o-, m-or p-carboxymethoxyphenyl, further 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, o-, m-or p-formylphenyl, 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-phenyl, 2-amino-3-chloro-phenyl, 2-amino-4-chloro-phenyl, 2-amino-5-chloro-phenyl or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-phenyl 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-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 2, 3, 4, 5-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar preferably represents, for example, phenyl, which is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA and/or Hal.

Ar' preferably represents, for example, phenyl, which is unsubstituted or mono-, di-or trisubstituted by Hal.

Het, irrespective of whether it is further substituted or not, denotes, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, further preferably 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1-or 5-tetrazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, optionally substituted, optionally, 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 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, oxanililyl, thianililyl, oxanililyl, thiabendazole, 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-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, further preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl or 2, 1, 3-benzoxadiazol-5-yl.

The heterocyclic group may also be partially or fully hydrogenated. Het may therefore also represent, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or-5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4-or-5-yl, hexahydro-1-, -3-or-4-pyridazinyl, hexahydro-1-, -2-, -4-or-5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-oxazinyl, further preferably 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or-6-yl, 2, 3- (2-oxomethylenedioxy) phenyl or 3, 4-dihydro-2H-1, 5-benzodioxa * -6-or-7-yl, further preferably 2, 3-dihydrobenzofuranyl or 2, 3-dihydro-2-oxofuranyl.

Het preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: hal, OH, OA, A, (CH)₂)_nAr’、(CH₂)_nCOOA and/or ═ O (carbonyl oxygen).

Het particularly preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA。

In a further embodiment, Het preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 2N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA, wherein a preferably represents methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

In a further embodiment, Het particularly preferably represents piperidine, piperazine, pyrrolidine, pyridine, pyrrole or isoxazole, each of which is unsubstituted or mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA, wherein a preferably represents methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

The compounds of formula I may have one or more chiral centers and thus exist in a variety of stereoisomeric forms. Formula I includes all of these forms.

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings specified above. Some preferred groups of compounds may be represented by the following subformulae Ia to II, which correspond to formula I and in which the radicals not specified in more detail have the meanings specified in formula I, but wherein

In the context of the process of the formula Ia,y represents OA or NH₂；

In Ib, R¹Represents OH or OA;

in Ic, R³Represents H, Hal, OH or OA;

in Id, X represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or NH group substitution;

in Ie, Q represents H, Ar or Het;

in If, Ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA and/or Hal;

in Ig, Ar' represents phenyl, wherein phenyl is unsubstituted or mono-, di-or trisubstituted with: A. OA and/or Hal;

in Ih, Het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA；

In Ii, A represents a linear or branched alkyl group having 1 to 6C atoms, wherein 1 to 5H atoms may be replaced by F and/or Cl;

in Ij, Y represents OH, OA, SH, SA, NH₂NHA or NAA',

R¹represents Hal, OH, OA, SH, SA, H or A,

R²is H, Hal, -O- (X)_s-Q，

R³Represents H, Hal, OH or OA,

a represents a linear or branched alkyl group having 1 to 6C atoms, in which 1 to 5H atoms may be replaced by F and/or Cl,

x represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or a substitution of an NH group,

q represents H, Ar or Het in the presence of a metal,

ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted with: A. the OA and/or the Hal are,

ar' represents phenyl, wherein the phenyl is unsubstituted or mono-, di-or trisubstituted with: A. the OA and/or the Hal are,

het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA，

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1;

in Ik, Y represents OA or NH₂，

R¹Represents Hal, OH or OA,

R²is H, Hal, -O- (X)_s-Q，

R³Represents H, Hal, OH or OA,

a represents a linear or branched alkyl group having 1 to 6C atoms, in which 1 to 5H atoms may be replaced by F and/or Cl,

x represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or a substitution of an NH group,

q represents H, Ar or Het in the presence of a metal,

ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted with: A. the OA and/or the Hal are,

ar' represents phenyl, wherein the phenyl is unsubstituted or mono-, di-or trisubstituted with: A. the OA and/or the Hal are,

het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA，

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1;

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

Preferably a compound of formula I selected from:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A1"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A3"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4, 5-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A5"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3, 4-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A6"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4, 5-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 c"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 h"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 i"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 j"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 k"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 l"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2-bromo-5-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 m"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-difluoromethoxy-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 n"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-methyl-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 o"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (5-ethoxycarbonylpentyloxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A4"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-ethoxycarbonylbutoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-carboxybutoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (5-carboxypentyloxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-ethoxycarbonylpropoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 c"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-carboxypropoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 d"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 bis"),

2-ethoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A9"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 d"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 e"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 f"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 g"),

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

Particularly preferred compounds are compounds selected from the group consisting of "a 1", "a 4", "A7", "A7 a", "A7 b", "A7 c", "a 21", "a 693" and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

In addition, the compounds of the invention and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditions which are known and suitable for the reaction in question. Variants of the methods known per se, which are not mentioned here in greater detail, can also be applied.

If desired, the starting materials may also be formed in situ by not isolating them from the reaction mixture, but immediately converting them further into the compounds of the invention.

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

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III.

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

In the compounds of the formula III, Z preferably represents Cl, Br, I or a reaction-modified OH group, for example an alkylsulfonyloxy group having 1 to 6C atoms, preferably a methylsulfonyloxy group, or an arylsulfonyloxy group having 6 to 10C atoms, preferably a phenyl-or p-toluenesulfonyloxy group. Z particularly preferably represents 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. Suitable 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 alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine or diethanolamine.

The reaction is carried out in a suitable inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

The solvent is particularly preferably water and/or tetrahydrofuran, for example.

Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ℃ to 140 ℃, usually from-10 ℃ to 130 ℃, in particular from about 30 ℃ to about 125 ℃.

The compounds of formula I may also be obtained by liberation from functional derivatives by solvolysis, in particular hydrolysis, or hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which contain correspondingly protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which have amino protecting groups instead of H atoms bonded to the N atom, for example those corresponding to formula I but which contain a substitution for NH₂The NHR 'group of the group (wherein R' represents an amino protecting group, such as BOC or CBZ).

Preferred starting materials also include those containing hydroxyl protecting groups in place of hydrogen atoms in hydroxyl groups, such as those corresponding to formula I but containing R 'O-phenyl in place of hydroxyphenyl (where R' represents a hydroxyl protecting group).

There may also be a plurality of identical or different protected amino and/or hydroxyl groups present in the molecule of the starting material. If the protecting groups are different from each other, they may be selectively cleaved in many cases.

The term "amino-protecting group" is a known generic term and relates to groups which are suitable for protecting (blocking) amino groups from chemical reactions, but which are relatively easy to remove after the desired reaction at other sites of the molecule has ended. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl radicals. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical; however, preference is given to those amino-protecting groups having from 1 to 20, in particular from 1 to 8, carbon atoms. The term "acyl" is to be understood in the broadest sense as being relevant to the present process. It includes acyl groups derived from: aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and in particular aralkoxycarbonyl. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and tolyl; aryloxy alkanoyl such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("benzyloxycarbonyl"), 4-methoxy-benzyloxycarbonyl, and FMOC; and arylsulfonyl groups such as Mtr, Pbf, or Pmc. Preferred amino protecting groups are BOC and Mtr, and also CBZ, FMOC, benzyl and acetyl.

The term "hydroxyl-protecting group" is likewise a known generic term and relates to groups which are suitable for protecting hydroxyl groups from chemical reactions, but which are relatively easy to remove after the desired reaction at other sites of the molecule has ended. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. Since the hydroxyl protecting groups are removed after the desired chemical reaction or reaction sequence, their nature and size are not critical. Preference is given to radicals having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of such hydroxy-protecting groups are, in particular, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups are preferably protected in the form of their tert-butyl esters.

The release of the compounds of the formula I from their functional derivatives depends on the protective group used, for example the use of strong acids, advantageously TFA or perchloric acid, but it is also possible to use other strong mineral acids, for example hydrochloric acid or sulfuric acid; strong organic carboxylic acids, such as trichloroacetic acid or sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of additional inert solvents is possible but not always necessary. Suitable inert solvents are preferably organic solvents, such as carboxylic acids, for example acetic acid; ethers such as tetrahydrofuran or dioxane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; and also alcohols, such as methanol, ethanol or isopropanol; and water. Mixtures of the above solvents are also suitable. TFA is preferably used in excess without addition of further solvents, while perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid (ratio 9: 1). The cleavage reaction temperature is advantageously from about 0 ℃ to about 50 ℃, preferably from 15 ℃ to 30 ℃ (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can be cleaved, for example, preferably at 15 ℃ to 30 ℃ with TFA in dichloromethane or about 3 to 5N HCl in dioxane, and the FMOC group can be cleaved at 15 ℃ to 30 ℃ with about 5 to 50% dimethylamine, diethylamine or piperidine in DMF.

The cleavage of the ether (e.g. dimethyl ether) is carried out in a suitable solvent as indicated above, preferably by addition of boron tribromide.

The reaction is particularly preferably carried out in methylene chloride at a temperature of from about-30 ℃ to 50 ℃, usually from-20 ℃ to 20 ℃, in particular from about-15 ℃ to about 0 ℃.

The protecting group which can be removed by hydrogenolysis (for example CBZ or benzyl) can be cleaved by treatment with hydrogen, for example in the presence of a catalyst (for example a noble metal catalyst, for example palladium, advantageously on a support, for example carbon). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol; amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 ℃ to 100 ℃ and a pressure of about 1bar to 200bar, preferably at 20 ℃ to 30 ℃ and 1bar to 10 bar. Hydrogenolysis of the CBZ group is very successful, for example, at 20 to 30 ℃ in methanol on 5 to 10% Pd/C or in methanol/DMF on Pd/C using ammonium formate (instead of hydrogen).

It is also possible to use by reacting one or more radicals R¹、R²、R³And/or Y is converted into one or more other radicals R¹、R²、R³And/or Y to convert a compound of formula I to another compound of formula I, e.g. to reduce the nitro group to an amino group, e.g. by hydrogenation over Raney nickel or Pd on charcoal in an inert solvent such as methanol or ethanol; and/or converting ester groups to carboxyl groups and/or amino groups to alkylated amines by reductive amination and/or esterifying carboxyl groups by reaction with alcohols and/or converting acid chlorides to amides by reaction with amines and/or alkylating hydroxyl groups, for example using alkyl halides.

In addition, the free amino group can be acylated in a conventional manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures of-60 ℃ to +30 ℃.

Pharmaceutically acceptable salts and other forms

The compounds of the present invention may be used in their final non-salt form. In another aspect, the invention also includes the use of these compounds in the form of pharmaceutically acceptable salts, which can be derived from a variety of organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are in large part prepared by conventional methods. If a compound of formula I contains a carboxy group, one of its suitable salts may be formed by reacting the compound with a suitable base to form the corresponding base addition salt. Such bases are, 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 alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methyl glutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, such as hydrogen halides, for example, hydrogen chloride, hydrogen bromide or hydrogen iodide, other inorganic acids and their corresponding salts, for example, sulfates, nitrates or phosphates, and the like, as well as alkyl-and monoaryl sulfonates, for example, ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, for example, acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following salts: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, picrate, etc, Mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a limitation.

In addition, base salts of the compounds of the present invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, and zinc salts, but this is not intended to represent a limitation. Among the above salts, ammonium salts are preferred; alkali metal salt sodium and potassium salts, and alkaline earth metal salt calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine (meglumine), N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methylamine (tromethamine), this is not intended to be limiting.

Compounds of the invention containing basic nitrogen-containing groups may be quaternized with substances such as (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromine and iodine; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl, diethyl and diamyl sulfate; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts may be used to prepare water-soluble and oil-soluble compounds of the invention.

Preferred such pharmaceutically acceptable salts include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, although this is not intended to represent a limitation.

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 form differs from its corresponding salt form in certain respects, for example in certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, salts are comparable to their respective free base forms.

As mentioned above, pharmaceutically acceptable base addition salts of compounds of formula I are formed with metals or amines, such as alkali 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 the acidic compounds of the present 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 may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in certain respects, for example in certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are comparable to their respective free acid forms.

If the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, the present invention also includes multiple salts. Typical multiple salt forms include, for example, ditartrate, diacetate, difumarate, meglumine, diphosphate, disodium salt, and trihydrochloride. This is not intended to be limiting.

In view of the above, it can be seen that the expression "pharmaceutically acceptable salt" herein refers to an active ingredient comprising a compound of formula I in the form of one of its salts, in particular if this salt form confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt forms of the active ingredient may also provide the active ingredient for the first time with desirable pharmacokinetic properties not previously possessed by it and may even have a positive effect on the pharmacodynamics of the active ingredient in terms of its in vivo therapeutic effect.

Due to their molecular structure, the compounds of formula I of the present invention may be chiral and may therefore exist in the form of a variety of enantiomers. Thus, they may exist in racemic or optically active form.

Since the pharmaceutical activity of racemates or stereoisomers of the compounds of formula I may differ, it may be desirable to use their enantiomers. In these cases, the end products or even intermediates can be separated into enantiomeric compounds by chemical or physical methods known to the person skilled in the art or even used as such in syntheses.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in the R and S form, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, amino acids protected by a suitable N-protection (e.g.N-benzoylproline or N-phenylsulphonylproline) or a variety of optically active camphorsulphonic acids. It is also advantageous to carry out the chromatographic enantiomeric resolution by means of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile, for example in the ratio 82: 15: 3.

The invention also relates to the use of said compounds and/or their physiologically acceptable salts for producing medicaments (pharmaceutical compositions), in particular by non-chemical methods. They can be converted, together with at least one solid, liquid and/or semisolid excipient or adjuvant, into the dosage forms suitable here and, if desired, in combination with one or more further active ingredients.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

The pharmaceutical preparations may be administered in the form of dosage units, each containing a predetermined amount of the active ingredient. Such units may contain, for example, from 0.1mg to 3g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the disease state to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in the form of dosage units, each containing a predetermined amount of active ingredient. Preferred dosage unit formulations are those containing the above-described daily dose or partial dose or a fraction thereof of the active ingredient. In addition, such pharmaceutical preparations can be prepared by methods generally known in the pharmaceutical field.

The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by all methods known in the art of pharmacy, for example by combining the active ingredient with excipients or auxiliaries.

Pharmaceutical formulations adapted for oral administration may be administered as discrete units such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foamed foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as ethanol, glycerol, water and the like. Powders can be prepared by comminuting the compound to a suitably fine size and mixing it with a similarly comminuted pharmaceutical excipient such as an edible carbohydrate such as starch or mannitol. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling into shaped gelatin capsule shells. Glidants and lubricants, for example highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents, such as agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the drug availability after the capsule is used.

In addition, suitable binders, lubricants and disintegrants and dyes may be incorporated into the mixture if desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or dry-tabletting the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture into tablets. Powder mixtures are prepared by mixing the compounds comminuted in a suitable manner with the above-mentioned diluents or bases and optionally with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as paraffin, absorption promoters such as quaternary salts and/or absorbents such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and sieving. As an alternative to granulation, the powder mixture may be passed through a tablet press to give a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated to prevent sticking to the tablet die by the addition of stearic acid, stearate, talc or mineral oil. The lubricated mixture is then compressed into tablets. It is also possible to combine the compounds of the present invention with free-flowing inert excipients and then directly compress the tablets without a granulation or dry compression step. There may be a transparent or opaque protective layer comprising a shellac barrier layer, a sugar or polymer material layer and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids such as solutions, syrups and elixirs can be prepared in dosage unit form so as to contain a predetermined quantity of the compound in a metered amount. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared with a non-toxic alcohol vehicle. Suspensions may be prepared by dispersing the compound in a non-toxic vehicle. 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, and the like may also be added.

Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a form in which the release is prolonged or retarded, for example by coating the particulate material with or embedding it in a polymer, wax or the like.

The compounds of formula I and salts, solvates and physiologically functional derivatives thereof may also be administered in the form of liposome delivery systems such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula I and salts, solvates and physiologically functional derivatives thereof may also be delivered using a monoclonal antibody as a separate carrier to which the compound molecules are coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol (polyhydroxypropylmethacrylamidophenol), polyhydroxyethylaspartamidophenol (polyhydroxyethylaspartamidophenol), or polyethyleneoxide polylysine (substituted with palmitoyl). The compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of a drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymer hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered in the form of a separate plaster for long-term intimate contact with the epidermis of the subject. Thus, for example, iontophoresis may be used to deliver the active ingredient from a plaster, as described, for example, in the general terms of Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations are preferably applied in the form of a topical ointment or cream. In the case of formulating an ointment, the active ingredient may be applied with a paraffinic or water-miscible cream base. Alternatively, the active ingredient may be formulated as a cream in an oil-in-water cream base or a water-in-oil base.

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

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration, in which the carrier substance is a solid, comprise a coarse powder having a particle size of, for example, 20 to 500 microns, which can be administered by nasal inhalation, i.e. by rapid inhalation through the nasal passages from a powder-containing container near the nose. Suitable formulations for administration as nasal sprays or nasal drops comprise solutions of the active ingredient in water or oil, with liquid as carrier material.

Pharmaceutical formulations adapted for administration by inhalation comprise a fine particulate powder or mist which may be generated by various types of aerosol-containing pressurised dispensers, nebulisers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include: aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the subject being treated; and aqueous and non-aqueous sterile suspensions, which may contain suspending media and thickening agents. The formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile carrier liquid, for example water for injections, immediately prior to use.

Injection solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.

It goes without saying that the formulations may comprise, in addition to the components specifically mentioned above, other substances commonly used in the art for this particular type of formulation; thus, for example, formulations suitable for oral administration may contain flavouring agents.

The 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 precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the present invention is generally 0.1 to 100mg/kg body weight of a subject (mammal) per day and particularly typically 1 to 10mg/kg body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, wherein the amount may be administered as one individual dose per day or typically as a series of partial doses per day (e.g. two, three, four, five or six partial doses) such that the total daily dose is the same. The effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound of formula I per se. Similar dosages may be considered as suitable for the treatment of the other conditions mentioned above.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

The further pharmaceutically active ingredient is preferably a chemotherapeutic agent, in particular those which inhibit angiogenesis and thus inhibit the growth and spread of tumor cells; VEGF receptor inhibitors are preferred herein, including ribozymes (robozymes) and antisense sequences directed against VEGF receptors, as well as angiostatin and endostatin.

Examples of antineoplastic agents that may be used in combination with the compounds of the present invention generally include alkylating agents; an antimetabolite; epidophyllotoxin; an anti-tumor enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone or platinum coordination complexes.

The antineoplastic agent is preferably selected from the following classes: anthracyclines, vinca drugs, mitomycins, bleomycin, cytotoxic nucleosides, epothilones (epothilones), discormolides, pteridines, enediynes (diynenes), and podophyllotoxins.

Among the species, particular preference is given to, for example, nordaunorubicin, daunorubicin, aminopterin, methotrexate, methyl folic acid (methopterin), methotrexate dichloride, mitomycin C, posomycin, 5-fluorouracil, 5-fluorodeoxyuridine monophosphate, cytarabine (cytarabine), 5-azacytidine, thioguanine, azathioprine, adenosine, pentostatin, erythrohydroxynonyladenosine, cladribine, 6-mercaptopurine, gemcitabine, cytarabine (cytosidine), podophyllotoxin or podophyllotoxin derivatives (e.g., etoposide phosphate or teniposide), melphalan, vinblastine, vinorelbine, vincristine, isocvinblastine, vindesine, vinblastine, docetaxel and paclitaxel. Other preferred antineoplastic agents are selected from: discormolide, epothilone D, estramustine, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide, melphalan, hexamethylmelamine, thiotepa, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, arabinocytosine, bicalutamide, flutamide, leuprolide, pyridobenzindole derivatives, interferons, and interleukins.

The other pharmaceutically active ingredient is preferably an antibiotic. Preferred antibiotics are selected from the group consisting of: actinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.

The other pharmaceutically active ingredient is preferably an enzyme inhibitor. Preferred enzyme inhibitors are selected from: histone deacetylation inhibitors (e.g. suberoylanilide hydroxamic acid [ SAHA ]) and tyrosine kinase inhibitors (e.g. ZD 1839 (Iressa)).

The other pharmaceutically active ingredient is preferably a nucleation inhibitor. The nuclear export inhibitors prevent the export of biopolymers (e.g., RNA) from the nucleus of the cell. Preferred nucleation inhibitors are selected from: callystatin, leptomycin B, ratjadone.

The other pharmaceutically active ingredient is preferably a nucleation inhibitor. The nuclear export inhibitors prevent the export of biopolymers (e.g., RNA) from the nucleus of the cell. Preferred nucleation inhibitors are selected from: callystatin, leptomycin B, ratjadone.

The other pharmaceutically active ingredient is preferably an immunosuppressant. Preferred immunosuppressive agents are selected from: rapamycin, CCI-779(Wyeth), RAD001(Novartis), AP23573(ariad pharmaceuticals).

The invention also relates to a kit of parts comprising individual packs of

(a) An effective amount of a compound of formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of other pharmaceutically active ingredients.

The kit comprises a suitable container, such as a box, a separate bottle, a bag or an ampoule. The kit of parts may, for example, comprise separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, in dissolved or freeze-dried form, and an effective amount of the other pharmaceutically active ingredient.

Use of

The compounds of the present invention are suitable as pharmaceutically active ingredients for mammals, especially humans, for the treatment of diseases in which HSP90 plays a role.

The invention therefore relates to the use of compounds of formula I and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

Preferably the use of a compound of formula I and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof (including mixtures thereof in all ratios) in the manufacture of a medicament for use in the treatment of: neoplastic diseases, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical carcinoma, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, angiosarcoma, neuroblastoma, chondrosarcoma, and neuroblastoma, Acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease;

viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus (echinovirus), arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II);

for immunosuppression in transplantation; inflammation-induced diseases, such as rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease; cystic fibrosis; diseases associated with angiogenesis, such as diabetic retinopathy, hemangioma, endometriosis, tumor angiogenesis; infectious diseases; (ii) an autoimmune disease; ischemia; promotion of nerve regeneration; fibrogenic diseases such as scleroderma, polymyositis, systemic lupus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis;

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

The invention also encompasses the use of compounds of formula I and/or their physiologically acceptable salts and solvates for the preparation of a medicament for protecting normal cells from toxicity caused by chemotherapy and for the treatment of diseases in which incorrect protein folding or aggregation is a major causative factor, such as scrapie, creutzfeldt-jakob disease, huntington's disease or alzheimer's disease.

The invention also relates to the use of the compounds of the formula I and/or their physiologically acceptable salts and solvates for producing medicaments for treating central nervous system diseases, cardiovascular diseases and cachexia.

In another embodiment, the invention also relates to the use of a compound of formula I and/or physiologically acceptable salts and solvates thereof in the manufacture of a medicament for HSP90 modulation wherein the modulated biological GRP94 activity causes an immune response in an individual, protein transport from the endoplasmic reticulum, recovery from hypoxic/anoxic stress, recovery from malnutrition, recovery from thermal stress or a combination thereof, and/or wherein the disorder is cancer, an infectious disease, a disorder associated with disrupted protein transport from the endoplasmic reticulum, a disorder associated with ischemia/reperfusion or a combination thereof, wherein the disorder associated with ischemia/reperfusion is cardiac arrest, cardiac arrest and delayed ventricular arrhythmia, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, Hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizures, anxiety, schizophrenia, neurodegenerative disorders, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), or a consequence of neonatal stress.

In another embodiment, the invention also relates to the use of compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment of ischemia due to cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizures, anxiety, schizophrenia, neurodegenerative disorders, alzheimer's disease, huntington's disease, Amyotrophic Lateral Sclerosis (ALS), or neonatal stress.

Assay for measuring HSP90 inhibitors

The inhibitory activity of the compounds of the invention can be determined by the binding of geldanamycin or17-allylamino-17-demethoxygeldanamycin (17AAG) to HSP90 and its competitive inhibition (Carreras et al 2003, Chiosis et al 2002).

In particular cases, radioligand filter binding assays were used. As used herein, the radioligand is tritiated 17-allylaminogeldanamycin, [3H ]17 AAG. This filter binding assay allows for targeted searching for inhibitors that interfere with ATP binding sites.

Material

Recombinant human HSP90 α (expressed by e.coli, purity 95%);

[3H]17AAG (17-allylaminogeldanamycin, [ allylamino-2, 3-³H. Specific activity: 1.11X 10¹²Bq/mmol(Moravek，MT-1717)；

HEPES Filter buffer (50mM HEPES, pH7.0, 5mM MgCl)₂，BSA0.01％)

Multiscreen FB (1 μm) filter plates (Millipore, MAFBNOB 50).

Method

First, 96-well microtiter filter plates were rinsed and coated with 0.1% polyethyleneimine.

The test was carried out under the following conditions:

reaction temperature: 22 deg.C

Reaction time: shaking at 800rpm for 30 minutes

Test volume: 50 μ L

Final concentration:

50mM HEPES HCl，pH7.0，5mM MgCl₂，0.01％(w/v)BSA

HSP 90: 1.5. mu.g/assay

[3H]17AAG：0.08μM。

At the end of the reaction, the supernatant in the filter plate was removed by suction with a vacuum manifold (Multiscreen Separation System, Millipore) and the filter plate was washed twice.

The filter plates were then measured in a beta counter (Microbeta, Wallac) with a scintillator (Microscint 20, Packard).

"control%" was determined from the "counts per minute" value and the IC-50 value of the compound was calculated therefrom.

TABLE AHSP90 inhibition

In this context, all temperatures are given in degrees Celsius. In the following examples, "conventional processing" refers to: if desired, water is added, the pH is adjusted to 2 to 10, if desired, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallization. Rf value on silica gel; and (3) elution: ethyl acetate/methanol 9: 1.

LC-MS conditions

HP 1100 series Hewlett Packard System with the following characteristics: an ion source: electrospray (positive ion mode); scanning: 100-1000 m/e; crushing voltage: 60V; gas temperature: 300 ℃, DAD: 220 nm.

Flow rate: 2.4 mL/min. After DAD, the flow splitter used reduced the flow rate of MS to 0.75 mL/min.

Column: chromolith SpeedROD RP-18e 50-4.6

Solvent: LiChrosolv mass from Merck KGaA

Solvent A: h₂O (0.01% TFA)

Solvent B: ACN (0.008% TFA)

Gradient:

20% B → 100% B: 0 minute to 2.8 minutes

100% of B: 2.8 to 3.3 minutes

100% B → 20% B: 3.3 to 4 minutes

Retention time R illustrated in the following examples_f[ minute ] of]And M + H⁺Data MW are measurements of LC-MS measurements.

Example 1

Preparation of 2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("a 1"):

1.1 to a solution of 10g of 3, 4-dimethoxybenzaldehyde in 100mL of ethanol, 12.1g of cyanothioacetamide was added. 10mL of 4-methylmorpholine are then added dropwise and the mixture is stirred at room temperature for a further 16 hours. The mixture was then refluxed for 4 hours. The mixture was adjusted to pH5.0 with 10% HCl and stirred at room temperature for a further 16 hours. The precipitated material was separated, washed with ethanol and n-heptane and dried to give 9.2g of 6-amino-3, 5-dicyano-4- (3, 4-dimethoxyphenyl) -2-thio-1, 2-dihydropyridine ("1")

1.2 Add 255 μ L of 47% aqueous KOH to 1g of "1" in 5mL DMF. Then 300mg 2-chloroacetamide was added and the mixture was stirred at room temperature for another 1 hour. An additional 255 μ L of 47% aqueous KOH was added and the mixture was stirred at room temperature for 1 hour and at 100 ℃ for 4 hours. The precipitated material was separated, washed with water and dried to give 1.0g of "A1".

The following compounds were obtained in a similar manner:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4-dimethoxyphenyl) thieno [2, 3-b]Pyridine ("A2"), R_f 1.179，MW 370.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 5-dimethoxyphenyl) thieno [2, 3-b]Pyridine ("A2 a"), R_f 1.149，MW 370.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3-dimethoxyphenyl) thieno [2, 3-b]Pyridine ("A2 b"), R_f 1.134，MW 370.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxy-phenyl) thieno [2, 3-b]Pyridine ("A3"), R_f 0.857，MW 356.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4, 5-trimethoxyphenyl) thieno [2, 3-b]Pyridine ("A5"), R_f 1.011，MW 400.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3, 4-trimethoxyphenyl) thieno [2, 3-b]Pyridine ("A6"), R_f 1.130，MW 400.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4, 5-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 c"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 h"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 i"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 j"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 k"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 l"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2-bromo-5-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 m"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-difluoromethoxy-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 n"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-methyl-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 o").

Example 2

Preparation of 2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (5-ethoxycarbonylpentyloxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("a 4"):

2.1A mixture of 100mg of "A3", 60. mu.L of ethyl bromohexanoate, 100mg of potassium carbonate and 1mL of DMF is stirred at 50 ℃ for 4 hours. The entire mixture was added to 20mL of water, the precipitated material was separated and dried to give 129mg of "A4", R_f 1.569，MW 498.6。

The following compounds were obtained in a similar manner:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-ethoxycarbonylbutoxy) -4-methoxyphenyl]Thieno [2, 3-b ]]Pyridine ("A7"), R_f 1.450，MW 484.5。

Ester hydrolysis of "A7" in NaOH/methanol to give the compound

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-carboxybutoxy) -4-methoxyphenyl]Thieno [2, 3-b ]]Pyridine ("A7 a"), R_f 1.531，MW 456.5。

Ester hydrolysis of "A4" in NaOH/methanol to give the compound

2-aminocarbonyl-3, 6-diammine5-cyano-4- [3- (5-carboxypentyloxy) -4-methoxyphenyl radical]Thieno [2, 3-b ]]Pyridine ("A7 b"), R_f 1.612，MW 470.5。

The following compounds were obtained in a similar manner:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-ethoxycarbonylpropoxy) -4-methoxyphenyl]Thieno [2, 3-b ]]Pyridine ("A7 c"), R_f 1.366，MW 470.5；

And thereby obtain

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-carboxypropoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 d").

Example 3

In analogy to example 1, "1" was reacted with methyl chloroacetate to give the compound 2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 bis").

The following compounds were obtained in a similar manner:

2-ethoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A9"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 d"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 e"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 f"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 g").

Example 4

Analogously to example 2, "A3" was reacted with the corresponding chloride to give the compound of formula Ia shown in Table 1

TABLE 1 Compounds of formula Ia A10-A50, A667-A681 and A682-A695

Compound numbering	R2	Rf	MW
				A10	Benzyloxy radical	1.548	446.5
A11	2-methylbenzyloxy	1.666	460.5
				A12	3-methylbenzyloxy	1.672	460.5
A13	4-Methylbenzyloxy group	1.658	460.5
				A14	2-Fluorobenzyloxy group	1.559	464.5
A15	3-Fluorobenzyloxy group	1.583	464.5
				A16	4-Fluorobenzyloxy group	1.585	464.5

Example 5

Analogously to example 2, "A8 a" was reacted with the corresponding chloride to give the compound of formula Ib, shown in Table 2

TABLE 2 Compounds of formula Ib A51-A91 and A696-A698

Example 6

Analogously to example 2, "A8 b" was reacted with the corresponding chloride to give the compound of formula Ic shown in Table 3

TABLE 3 Compound A92-A of formula Ic

Compound numbering	R2	Rf	MW
				A92	Benzyloxy radical

Example 7

Analogously to example 2, "A8 c" was reacted with the corresponding chloride to give the compound of formula Id shown in Table 4

TABLE 4 Compounds A133-A of formula Id

Compound numbering	R2	Rf	MW
				A133	Benzyloxy radical
A134	2-methylbenzyloxy
				A135	3-methylbenzyloxy
A136	4-Methylbenzyloxy group
				A137	2-Fluorobenzyloxy group
A138	3-Fluorobenzyloxy group
				A139	4-Fluorobenzyloxy group
A140	2-chlorobenzyloxy
				A141	3-chlorobenzyloxy
A142	4-chlorobenzyloxy
				A143	2-trifluoromethyl benzyloxy group
A144	3-trifluoromethyl benzyloxy group
				A145	4-trifluoromethyl benzyloxy group

Example 8

Analogously to example 2, "A8 d" was reacted with the corresponding chloride to give the compound of formula Ie shown in Table 5

TABLE 5 Compounds A174-A of the formula Ie

Compound numbering	R2	Rf	MW
				A174	Benzyloxy radical
A175	2-methylbenzyloxy
				A176	3-methylbenzyloxy
A177	4-Methylbenzyloxy group
				A178	2-Fluorobenzyloxy group
A179	3-Fluorobenzyloxy group
				A180	4-Fluorobenzyloxy group
A181	2-chlorobenzyloxy
				A182	3-chlorobenzyloxy
A183	4-chlorobenzyloxy
				A184	2-trifluoromethyl benzyloxy group
A185	3-trifluoromethyl benzyloxy group
				A186	4-trifluoromethyl benzyloxy group
A187	Phenylethoxy group
				A188	2- (tert-Butoxycarbonylamino) ethoxy
A189	3- (tert-Butoxycarbonylamino) propoxy group
				A190	4- (tert-Butoxycarbonylamino) butoxy
A191	5- (tert-Butoxycarbonylamino) pentyloxy

Example 9

Analogously to example 2, "A8 e" was reacted with the corresponding chloride to give the compound of formula If shown in Table 6

TABLE 6 Compounds of formula If A215-A

Compound numbering	R2	Rf	MW
				A215	Benzyloxy radical
A216	2-methylbenzyloxy

Example 10

Analogously to example 2, "A8 f" was reacted with the corresponding chloride to give the compound of formula Ig, shown in Table 7

TABLE 7 Compounds of formula Ig A256-A

Compound numbering	R2	Rf	MW
				A256	Benzyloxy radical
A257	2-methylbenzyloxy
				A258	3-methylbenzyloxy
A259	4-Methylbenzyloxy group
				A260	2-Fluorobenzyloxy group
A261	3-Fluorobenzyloxy group
				A262	4-Fluorobenzyloxy group
A263	2-chlorobenzyloxy
				A264	3-chlorobenzyloxy
A265	4-chlorobenzyloxy
				A266	2-trifluoromethyl benzyloxy group
A267	3-trifluoromethyl benzyloxy group

Example 11

Analogously to example 2, "A8 g" was reacted with the corresponding chloride to give the compound of formula Ih, shown in Table 8

TABLE 8 Compounds A297-A of the formula Ih

Compound numbering	R2	Rf	MW
				A297	Benzyloxy radical
A298	2-methylbenzyloxy
				A299	3-methylbenzyloxy
A300	4-Methylbenzyloxy group
				A301	2-Fluorobenzyloxy group
A302	3-fluorobenzyloxy
				A303	4-Fluorobenzyloxy group
A304	2-chlorobenzyloxy
				A305	3-chlorobenzyloxy
A306	4-chlorobenzyloxy
				A307	2-trifluoromethyl benzyloxy group
A308	3-trifluoromethyl benzyloxy group
				A309	4-trifluoromethyl benzyloxy group
A310	Phenylethoxy group
				A311	2- (tert-Butoxycarbonylamino) ethoxy
A312	3- (tert-Butoxycarbonylamino) propoxy group
				A313	4- (tert-Butoxycarbonylamino) butoxy
A314	5- (tert-Butoxycarbonylamino) pentyloxy

Example 12

Analogously to example 2, "A8 h" was reacted with the corresponding chloride to give the compounds of formula Ii shown in Table 9

TABLE 9 Compound A338-A of formula Ii

Compound numbering	R2	Rf	MW
				A338	Benzyloxy radical
A339	2-methylbenzyloxy

Example 13

Analogously to example 2, "A8 i" was reacted with the corresponding chloride to give the compound of formula Ij shown in Table 10

TABLE 10 Compounds A379-A of formula Ij

Compound numbering	R2	Rf	MW
				A379	Benzyloxy radical
A380	2-methylbenzyloxy
				A381	3-methylbenzyloxy
A382	4-Methylbenzyloxy group
				A383	2-Fluorobenzyloxy group
A384	3-Fluorobenzyloxy group
				A385	4-Fluorobenzyloxy group
A386	2-chlorobenzyloxy
				A387	3-chlorobenzyloxy
A388	4-chlorobenzyloxy
				A389	2-trifluoromethyl benzyloxy group
A390	3-trifluoromethyl benzyloxy group
				A391	4-trifluoromethyl benzyloxy group
A392	Phenylethoxy group

Example 14

Analogously to example 2, "A8 j" was reacted with the corresponding chloride to give the compound of formula Ik shown in Table 11

TABLE 11 Compounds of formula Ik A420-A

Example 15

Analogously to example 2, "A8 k" was reacted with the corresponding chloride to give the compound of formula Il shown in Table 12

TABLE 12 Compound of formula Il A461-A

Compound numbering	R2	Rf	MW
				A461	Benzyloxy radical
A462	2-methylbenzyloxy
				A463	3-methylbenzyloxy
A464	4-Methylbenzyloxy group
				A465	2-Fluorobenzyloxy group
A466	3-Fluorobenzyloxy group
				A467	4-Fluorobenzyloxy group
A468	2-chlorobenzyloxy
				A469	3-chlorobenzyloxy
A470	4-chlorobenzyloxy
				A471	2-trifluoromethyl benzyloxy group

Example 16

Analogously to example 2, "A8 l" was reacted with the corresponding chloride to give the compound of formula Im shown in Table 13

TABLE 13 Compounds A502-A of formula Im

Compound numbering	R2	Rf	MW
				A502	Benzyloxy radical
A503	2-methylbenzyloxy
				A504	3-methylbenzyloxy
A505	4-Methylbenzyloxy group
				A506	2-Fluorobenzyloxy group
A507	3-Fluorobenzyloxy group
				A508	4-Fluorobenzyloxy group
A509	2-chlorobenzyloxy
				A510	3-chlorobenzyloxy
A511	4-chlorobenzyloxy
				A512	2-trifluoromethyl benzyloxy group
A513	3-trifluoromethyl benzyloxy group
				A514	4-trifluoromethyl benzyloxy group
A515	Phenylethoxy group
				A516	2- (tert-Butoxycarbonylamino) ethoxy
A517	3- (tert-Butoxycarbonylamino) propoxy group
				A518	4- (tert-Butoxycarbonylamino) butoxy
A519	5- (tert-Butoxycarbonylamino) pentyloxy

Example 17

Analogously to example 2, "A8 m" was reacted with the corresponding chloride to give the compounds of formula In shown In Table 14

TABLE 14 Compounds of formula In A543-A

Compound numbering	R2	Rf	MW
				A543	Benzyloxy radical
A544	2-methylbenzyloxy
				A545	3-methylbenzyloxy

Example 18

Analogously to example 2, "A8 n" was reacted with the corresponding chloride to give the compound of formula Io shown in Table 15

TABLE 15 Compound A584-A of formula Io

Compound numbering	R2	Rf	MW
				A584	Benzyloxy radical
A585	2-methylbenzyloxy
				A586	3-methylbenzyloxy
A587	4-Methylbenzyloxy group
				A588	2-Fluorobenzyloxy group
A589	3-Fluorobenzyloxy group
				A590	4-Fluorobenzyloxy group
A591	2-chlorobenzyloxy
				A592	3-chlorobenzyloxy
A593	4-chlorobenzyloxy
				A594	2-trifluoromethyl benzyloxy group
A595	3-trifluoromethyl benzyloxy group

Example 19

Analogously to example 2, "A8 o" was reacted with the corresponding chloride to give the compound of formula Ip shown in Table 16

TABLE 16 Compound A625-A of formula Ip

Example 20

The following compounds were obtained analogously to example 1 or example 2:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2-methoxyphenyl) thieno [2, 3-b]Pyridine ("A666"), R_f 1.124，MW 340.4；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4-dichlorophenyl) thieno [2, 3-b]Pyridine ("A667"), R_f 1.432，MW 379.2；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-chlorophenyl) thieno [2, 3-b]Pyridine ("A668"), R_f 1.354，MW 344.7；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-chlorophenyl) thieno [2, 3-b]Pyridine ("A669"), R_f 1.311，MW 344.8；

2-AmmoniaAlkylcarbonyl-3, 6-diamino-5-cyano-4- (2-chlorophenyl) thieno [2, 3-b]Pyridine ("A670"), R_f 1.344，MW 344.8；

2-aminocarbonyl-3, 6-diamino-5-cyano-4-phenylthieno [2, 3-b]Pyridine ("A671"), R_f 1.116，MW 310.3；

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A672"),

(″A673″)，

(″A674″)，

(″A675″)，

(S) -4- [5- (3, 6-diamino-2-carbamoyl-5-cyanothieno [2, 3-b ] -pyridin-4-yl) -2-methoxyphenoxy ] -3-hydroxybutyric acid methyl ester

(″A676″)，

(″A682″)。

The following examples relate to pharmaceutical compositions:

example A: injection vial

A solution of 100g of the active ingredient according to the invention and 5g of disodium hydrogen phosphate in 3L of bidistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred into injection vials, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.

Example B: suppository

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

Example C: solution preparation

From 1g of active principle according to the invention, 9.38g NaH₂PO₄·2H₂O、28.48gNa₂HPO₄·12H₂A solution of O and 0.1g benzalkonium chloride in 940mL of double distilled water was prepared. The pH was adjusted to 6.8 and the solution was brought to 1L and radiation sterilized. The solution may be used in the form of eye drops.

Example D: ointment formulation

500mg of the active ingredient according to the invention are mixed with 99.5g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1kg of the active ingredient of the invention, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed into tablets in a conventional manner so that each tablet contains 10mg of the active ingredient.

Example F: pastille

The tablets were compressed in a similar manner to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule preparation

2kg of active ingredient of the invention are introduced into hard gelatin capsules in a conventional manner so that each capsule contains 20mg of active ingredient.

Example H: ampoule agent

A solution of 1kg of the active ingredient of the invention in 60L of bidistilled water is sterile-filtered, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (25)

1. Compounds of formula I and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios

Wherein

Y represents OH, OA, SH, SA, NH₂NHA or NAA',

R¹represents Hal,OH, OA, SH, SA, H or A,

R²is represented by H, Hal or-O- (X)_S-Q，

R³H, Hal, CN, NO₂、A、OH、OA、SH、SA、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA’、NH₂、NHA、NAA’、NHCOOA、NHCONH₂、NHCONHA、SOA、SO₂A、SO₂NH₂、SO₂NHA or SO₂NAA’，

Selected from the group R¹、R²、R³Together two adjacent radicals also denote methylenedioxy or ethylenedioxy,

A. a' independently of one another denote straight-chain or branched alkyl having 1 to 10C atoms, where 1 to 5H atoms may be replaced by F and/or Cl; alk; or cycloalkyl having 3 to 7C atoms,

a and A' together also denote an alkylene chain having 2, 3, 4, 5 or 6C atoms, one CH of which₂The radicals being selected from the group consisting of O, S, SO₂NH, NA or N-COOA,

alk represents an alkenyl group having 2 to 6C atoms,

x represents a straight or branched C₁-C₁₀Alkylene or C₂-C₁₀Alkenylene, each of which is unsubstituted or mono-, di-, tri-or tetra-substituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、Ar、OAr、COOH、COOA、CHO、C(＝O)A、C(＝O)Ar、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA ', naconoaa' and/or ═ O and where 1, 2 or 3C groups can be replaced by O, S, SO₂And/or a substitution of an NH group,

q represents H, Carb, Ar or Het,

carb denotes a compound having 3 to 7C atomsCycloalkyl or cycloalkenyl having 3 to 7C atoms, each of which is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

ar' represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or trisubstituted with: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nPhenyl, (CH)₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂NHCONHA, NACONHA, NHCONAA 'or NACONAA',

het tableRepresents a mono-or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. OA, OH, SH, SA, Hal, NO₂、CN、(CH₂)_nAr’、(CH₂)_nCOOH、(CH₂)_nCOOA、CHO、COA、SO₂A、CONH₂、SO₂NH₂、CONHA、CONAA’、SO₂NHA、SO₂NAA’、NH₂、NHA、NAA’、OCONH₂、OCONHA、OCONAA’、NHCOA、NHCOOA、NACOOA、NHSO₂OA、NASO₂OA、NHCONH₂、NACONH₂、NHCONHA、NACONHA、NHCONAA’、NACONAA’、SO₂A. (ii) S, ═ NH, ═ NA and/or ═ O (carbonyl oxygen),

hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1.

2. A compound of the formula I according to claim 1 and its pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

Y represents OA or NH₂。

3. A compound according to claim 1 or 2, and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R¹Represents OH or OA.

4. A compound according to one or more of claims 1 to 3, and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R³Represents H, Hal, OH or OA.

5. The compounds according to one or more of claims 1 to 4 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

X represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or NH groups.

6. The compounds according to one or more of claims 1 to 5 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

Q represents H, Ar or Het.

7. The compounds according to one or more of claims 1 to 6 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

Ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted with: A. OA and/or Hal.

8. A compound according to one or more of claims 1 to 7, and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, wherein

Ar' represents phenyl, wherein the phenyl is unsubstituted or mono-, di-or trisubstituted with: A. OA and/or Hal.

9. The compounds according to one or more of claims 1 to 8 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

Het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA。

10. A compound according to one or more of claims 1 to 9, and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, wherein

A represents a linear or branched alkyl group having 1 to 6C atoms, wherein 1 to 5H atoms may be replaced by F and/or Cl.

11. Compounds according to one or more of claims 1 to 10 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, wherein

Y represents OH, OA, SH, SA, NH₂NHA or NAA',

R¹represents Hal, OH, OA, SH, SA, H or A,

R²is represented by H, Hal or-O- (X)_s-Q，

R³Represents H, Hal, OH or OA,

a represents a linear or branched alkyl group having 1 to 6C atoms, in which 1 to 5H atoms may be replaced by F and/or Cl,

x represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O andwherein 1, 2 or 3C groups may be O, S, SO₂And/or a substitution of an NH group,

q represents H, Ar or Het in the presence of a metal,

ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted with: A. the OA and/or the Hal are,

ar' represents phenyl, wherein the phenyl is unsubstituted or mono-, di-or trisubstituted with: A. the OA and/or the Hal are,

het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA，

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1.

12. A compound according to one or more of claims 1 to 11, and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, wherein

Y represents OA or NH₂，

R¹Represents Hal, OH or OA,

R²is represented by H, Hal or-O- (X)_s-Q，

R³Represents H, Hal, OH or OA,

a represents a linear or branched alkyl group having 1 to 6C atoms, in which 1 to 5H atoms may be replaced by F and/or Cl,

x represents a straight or branched C₁-C₁₀Alkylene radical, wherein C₁-C₁₀Alkylene is unsubstituted or mono-, di-, tri-or tetra-substituted with: OA, OH, Ar, OAr, COOH, COOA, C (═ O) A, C (═ O) Ar, CONH₂、CONHA、CONAA’、NH₂NHA, NAA', NHCOOA and/or ═ O and where 1, 2 or 3C groups may be O, S, SO₂And/or a substitution of an NH group,

q represents H, Ar or Het in the presence of a metal,

ar represents phenyl, wherein the phenyl is unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted with: A. the OA and/or the Hal are,

ar' represents phenyl, wherein the phenyl is unsubstituted or mono-, di-or trisubstituted with: A. the OA and/or the Hal are,

het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be mono-, di-or trisubstituted by: A. (CH)₂)_nAr' and/or (CH)₂)_nCOOA，

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

s represents 0 or 1.

13. The compound of claim 1 selected from the group consisting of:

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A1"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A2 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A3"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 4, 5-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A5"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2, 3, 4-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A6"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3, 4, 5-trimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 c"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 h"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 i"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 j"),

2- (N-methylaminocarbonyl) -3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 k"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4, 5-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 l"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (2-bromo-5-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 m"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-difluoromethoxy-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 n"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- (4-methyl-3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 o"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (5-ethoxycarbonylpentyloxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A4"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-ethoxycarbonylbutoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (4-carboxybutoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 a"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (5-carboxypentyloxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 b"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-ethoxycarbonylpropoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 c"),

2-aminocarbonyl-3, 6-diamino-5-cyano-4- [3- (3-carboxypropoxy) -4-methoxyphenyl ] thieno [2, 3-b ] pyridine ("A7 d"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 bis"),

2-ethoxycarbonyl-3, 6-diamino-5-cyano-4- (3, 4-dimethoxyphenyl) thieno [2, 3-b ] pyridine ("A9"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methoxyphenyl) thieno [2, 3-b ] pyridine ("A8 d"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxyphenyl) thieno [2, 3-b ] pyridine ("A8 e"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-trifluoromethoxyphenyl) thieno [2, 3-b ] pyridine ("A8 f"),

2-methoxycarbonyl-3, 6-diamino-5-cyano-4- (3-hydroxy-4-methylsulfanylphenyl) thieno [2, 3-b ] pyridine ("A8 g"),

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

14. A process for the preparation of compounds of formula I according to claims 1 to 13, and pharmaceutically acceptable derivatives, solvates, salts, tautomers and stereoisomers thereof, characterized in that

a) Reacting a compound of formula II with a compound of formula III

In the compounds of the formula II, R¹、R²And R³Having the meaning as specified in claim 1,

Y-CO-CH₂-Z III

in the compounds of the formula III, Y has the meaning specified in claim 1 and Z represents Cl, Br, I or a free or reactively functionally modified OH group,

or

(b) By reacting one or more radicals R, for example¹、R²、R³And/or Y into one or more radicals R¹、R²、R³And/or the presence of Y and/or Y,

i) the nitro group is reduced into amino group,

ii) hydrolysis of the ester group to a carboxyl group,

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

iv) alkylating the hydroxyl groups, and (iii) optionally,

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

15. Medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

16. The use of compounds of the formula I and pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the production of medicaments for the treatment and/or prophylaxis of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

17. The use of compounds of the formula I according to claim 16 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or prophylaxis of tumor diseases, viral diseases, immunosuppression in transplantation, inflammation-induced diseases, cystic fibrosis, diseases associated with angiogenesis, infectious diseases, autoimmune diseases, ischemia, fibrogenic diseases,

can be used for promoting the regeneration of nerve,

used for inhibiting cancer, tumor cell growth and tumor metastasis,

is used for protecting normal cells from toxicity caused by chemotherapy,

for the treatment of diseases in which incorrect protein folding or aggregation is a major causative factor.

18. The use of claim 17, wherein the neoplastic disease is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchial cancer, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, or a combination thereof, Hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease.

19. The use of claim 17, wherein the viral pathogen of a viral disease is selected from the group consisting of hepatitis a virus, hepatitis b virus, hepatitis c virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II).

20. The use of claim 17, wherein the inflammation-induced disease is rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease.

21. The use of claim 17, wherein the angiogenesis-related diseases are diabetic retinopathy, hemangiomas, endometriosis and tumor angiogenesis.

22. The use of claim 17, wherein the fibrogenic disorder is scleroderma, polymyositis, systemic lupus, cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis.

23. The use of claim 17, wherein the disease in which incorrect protein folding or aggregation is the main causative agent is pruritis, creutzfeldt-jakob disease, huntington's disease or alzheimer's disease.

24. A medicament comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

25. A kit (kit) comprising the following individual packages

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

and

(b) an effective amount of other pharmaceutically active ingredients.