WO2018041771A1 - (1-methylcyclopropyl)methyl-substituted thienouraciles and use thereof - Google Patents

Abstract

The invention relates to novel, in position N³, thieno[2,3-d]pyrimidine-2,4-dione ("thienouracil")-derivatives supporting (1-Methylcyclopropyl)methyl-substituents, to methods for the production thereof, to the use thereof alone or in combinations for treating and/or preventing diseases, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of pulmonary and cardiovascular disorders and cancers.

Description

 Q-Methyl-cyclopropyl-methyl-substituted thienouracils and their use

The present application relates to novel thieno [2,3-d] pyrimidine-2,4-dione ("thienouracil") derivatives bearing an (1-methylcyclopropyl) methyl substituent in the N ³ position, process for their preparation their use alone or in combinations for the treatment and / or prevention of diseases and their use for the manufacture of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of diseases of the lung and the cardiovascular system and of cancers.

The endogenous purine nucleoside adenosine is ubiquitously formed and modulates a variety of physiological and pathophysiological processes as an important signaling molecule. It is mainly caused by the intracellular and extracellular degradation of adenine nucleotides and, to a lesser extent, by the intracellular hydrolysis of S-adenosyl homocysteine. Under physiological conditions, extracellular adenosine can be re-phosphorylated by adenosine kinase to adenosine monophosphate (AMP) or converted into inosine by adenosine deaminase. The extracellular concentration is between 30 and 300 nM. In case of tissue damage, conditionally e.g. Hypoxia, inflammatory reactions and oxidative stress lead to an increased formation and accumulation of adenosine, so that the extracellular concentration can rise to 15 μΜ.

The biological effects of adenosine are mediated via G-protein coupled plasma membrane-bound receptors. Currently, four adenosine receptor subtypes are detected: Al adenosine receptor (AIR), A2a adenosine receptor (A2aR), A2b adenosine receptor (A2bR) and A3 adenosine receptor (A3R). The A2b receptor has the weakest affinity for adenosine among the four adenosine receptors mentioned above. For this reason, unlike the other adenosine receptors, it is not activated under normal physiological conditions. AI and A3 receptors are coupled to Gi proteins that inhibit adenylate cyclase, whereas A2a and A2b receptors via Gs proteins stimulate adenylate cyclase and thus an intracellular increase in cAMP. Through Gq proteins, both the AI, A3 and A2b receptors activate phospholipase C, which breaks down membrane-bound phosphatidyl inositol 4,5-bisphosphate into inositol-1, 4,5-triphosphate and diacylglycerol. This in turn leads to an increase in the intracellular calcium concentration and activation of further target proteins, such as protein kinase C and MAP kinases.

A2b receptors are expressed on pulmonary epithelial and smooth muscle cells, vascular endothelial and smooth muscle cells, fibroblasts and inflammatory cells. The expression of the A2b receptor on the cell surface is a dynamic process and is greatly increased, for example, by hypoxia, inflammatory factors and free radicals. The adenosine-activated A2b- Receptors lead to the formation and release of proinflammatory and pro-fibrotic cytokines such as IL-6, IL-4 and IL-8. Studies have shown that the A2b receptor plays an important role in the chronic stage of lung diseases in tissue remodeling and, inter alia, promotes the differentiation of fibroblasts into myofibroblasts, which leads to an increased synthesis and deposition of collagen.

In lung tissue samples from patients with idiopathic pulmonary fibrosis, COPD and pulmonary hypertension associated with COPD [Zhou et al, PLoS One 5, e9224 (2010); Selmann et al., PLoS One 2, e482 (2007)] as well as in various animal models of fibro-proliferative lung diseases [Karmouty-Quintana et al, Am. J. Respir. Cell Mol. Biol. 49 (6), 1038-1047 (2013); Karmouty-Quintana et al, FASEB J. 26, 2546-2557 (2012); Sun et al, J. Clin. Invest. 116, 2173-2182 (2006)], an increased expression of the A2b receptor was found. In the animal model of bleomycin-induced pulmonary fibrosis and pulmonary hypertension in the mouse, a genetic knock-out of the A2b receptor inhibited the progression of pulmonary fibrosis as well as pulmonary vascular remodeling and the resulting pulmonary hypertension [Karmouty-Quintana et al. FASEB J. 26, 2546-2557 (2012)]. In the development of pulmonary hypertension associated with pulmonary fibrosis, the release of, inter alia, endothelin-1 (ET-1) and interleukin-6 (IL-6) from the vascular cells modulated by the A2b receptor is thought to play a role. Stimulation of human pulmonary arterial endothelial and smooth muscle cells with 5 '- (N-ethylcarboxamido) adenosine (NECA), an adenosine analog, results in the release of ET-1 and IL-6, which are prevented by A2b receptor inhibition [Karmouty-Quintana et al., FASEB J. 26, 2546-2557 (2012)]. Increased levels of endothelin-1 and IL-6 have been found in the lung tissue and serum of patients with pulmonary hypertension [Giaid et al, N. Engl. J. Med. 329, 1967-1968 (1993); Steiner et al, Circ. Res. 104. 236-244 (2009)]. Furthermore, A2b receptor mediated release of inter alia IL-6 and other profibrotic mediators, as well as stimulation of fibroblast differentiation into myofibroblasts in the lung, is believed to induce fibrosis. Stimulation of human fibroblasts with NECA results in the release of IL-6, which is hypoxia-enhanced and can be prevented by A2b receptor inhibition. In patients with idiopathic pulmonary fibrosis and in animal models of pulmonary fibrosis, increased IL-6 expression has been demonstrated [Zhong et al, Am. J. Respir. Cell Mol. Biol. 32: 2-8 (2005); Cavarra et al, Am. J. Physiol. Lung Cell. Mol. Physiol. 287, LI 186-L1192 (2004)].

The A2b receptor also plays an important role in tissue remodeling after myocardial infarction. In the animal model of permanent ligation of the coronary artery in the mouse, inhibition of the A2b receptor led to a reduction of caspase-1 activity and of the immigrated inflammatory cells in the heart tissue as well as the cytokines and adhesion molecules in the plasma and to an improvement in systolic and diastolic cardiac function [Toldo et al., J. Pharmacol. Exp. Ther. 343, 587-595 (2012)].

In tumors and tumor-surrounding tissues, local adenosine concentration is due to hypoxia, necrotic processes, or genetic and epigenetic alterations of tumor cells leading to increased extracellular production of adenosine, with concomitant reduced degradation and decreased adenosine cell uptake. often greatly increased [J. Blay et al, Cancer Res. 57 (13), 2602-2605 (1997); G. Schulte, B.B. Fredholm, Cell Signal. 15 (9), 813-827 (2003)]. This leads to activation of the previously described adenosine receptors on tumor cells, tumor-associated cells and cells of the tumor-surrounding tissue. The signal chains initiated thereby trigger various processes, the majority of which favor tumor growth and its spread to other locations in the organism. Thus, inhibition of adenosine signaling pathways is a valuable strategy for treating cancers. For example, inhibition of the A2b receptor-mediated adenosine signaling pathway with the A2b receptor antagonist MRS1754 results in decreased growth of colon cancer cell lines [D .-F. Ma et al, Hum. Pathol. 4J_ (11), 1550-1557 (2010)]. The A2b receptor antagonist PSB603 reduces the growth of several prostate cancer cell lines [Q. Wei et al, purinergic signal. 9 (2), 271-280 (2013)].

The influence of adenosine on tumor metastasis seems to be greater than the direct influence on the proliferation of tumor cells. In particular, A2b receptor-mediated adenosine signaling chains are involved, and blockade of the A2b receptor - both genetically and pharmacologically with A2b receptor antagonists - results in reduced migration of tumor cells in vitro and reduced metastasis formation in animal models [J. Stagg et al, Proc. Natl. Acad. Be. USA 107 (4), 1547-1552 (2010); C.J. Desmet et al, Proc. Natl. Acad. Be. USA HO (13), 5139-5144 (2013); E. Nantie et al., Sei. Signal. 6 (277), ra39 (2013)]. Adenosine also has an influence on the tumor-associated vascular endothelium: A2b-receptor-mediated adenosine signaling chains lead to the release of pro-angiogenic factors from various human tumor cell lines, but also from tumor-associated immune cells, thus stimulating tumor growth promoting neovascularization [S. Ryzhov et al, Neoplasia 10 (9), 987-995 (2008); S. Merighi et al, Mol. Pharmacol. 72 (2), 395-406 (2007); S. Merighi et al, Neoplasia U (10), 1064-1073 (2009)].

Increasingly better understood is the importance of the immune system in the suppression of tumorigenesis, tumor growth and metastasis. It shows that adenosine is able to reduce the immune response [S. Gessi et al., Biochim. Biophys. Acta Biomembranes 1808 (5), 1400-1412 (2011); J. Stagg et al, Proc. Natl. Acad. Be. USA 107 (4), 1547-1552 (2010); D. Jin et al, Cancer Res. 70 (6), 2245-2255 (2010); SFM Häusler et al, Cancer Immunol. Immunother. 60 (10), 1405-1418 (2011); J. Spychala, Pharmacol. Ther. 87 (2-3), 161-173 (2000)]. In contrast, the inhibition of the A2b receptor-mediated adenosine signaling pathway with the A2b receptor antagonist PSB603 leads to a reduction in tumor growth and metastasis in animal melanoma models, which is attributed to an inhibition of the tumor-induced suppression of the immune system [W. Kaji et al, J. Toxicol. Be. 39 (2), 191-198 (2014)]. This improvement is due to the fact that the proportion of regulatory T cells that reduce the immune response is reduced in total immune cell infiltrate in the presence of the A2b receptor antagonist. At the same time, the populations of cytotoxic CD8 + T cells and CD4 + T helper cells are increased. In addition, immunosuppressive effects of adenosine on other cells of the immune system are described (Ml and M2 macrophages, dendritic cells, myeloid suppressor cells), some of which are mediated via the A2b receptor [B. Csoka et al, FASEB J. 26 (1), 376-386 (2012); SV Novitskiy et al, Blood 112 (5), 1822-1831 (2008); M. Yang et al, Immunol. Cell Biol. 88 (2), 165-171 (2010); S. Ryzhov et al., J. Immunol. 187 (11), 6120-6129 (2011)]. In animal models of bladder and breast tumors, the A2b receptor antagonist ATL801 causes a slowing of tumor growth and a marked reduction in metastasis [C. Cekic et al, J. Immunol. 188 (1), 198-205 (2012)]. These effects are associated with an ATL801-induced increase in the number of tumor antigen-presenting dendritic cells as well as a strong increase in interferon-y levels and, consequently, increased concentrations of the chemokine CXCLIO, which in turn activates CXCR3 + T cells and ultimately leads to an improved immune defense of tumor growth and metastasis.

Thus, it is believed that the A2b receptor plays an important role in many diseases, injuries and pathological changes whose genesis and / or progression is associated with inflammatory events and / or proliferative and fibro-proliferative tissue and vascular remodeling , These may be, in particular, diseases and / or damage to the lung, the cardiovascular system or the kidney, or it may be a blood disorder, a cancerous disease or other inflammatory diseases.

In particular, idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis are diseases and disorders of the lung to be named in this connection. Diseases and damages of the cardiovascular system in which the A2b receptor is involved are, for example, tissue changes after a myocardial infarction and in heart failure. Renal diseases include renal insufficiency and kidney failure. A disease of the blood is, for example, sickle cell anemia. Examples of one Tissue degradation and remodeling in cancerous processes involve the invasion of cancer cells into the healthy tissue (metastasis) and the rebuilding of supplying blood vessels (neo-angiogenesis). Another inflammatory disease in which the A2b receptor plays a role is, for example, multiple sclerosis. For the suitability of an A2b receptor antagonist for the treatment of these diseases, the antagonistic selectivity of such a substance over other adenosine receptors of great importance, especially with respect to the A2a receptor, especially since the (agonistic) adenosine signaling via the A2a receptor has an anti-inflammatory effect. Activation of the A2a receptor influences the activity of various immune cells, including neutrophils, macrophages and T lymphocytes [Lappas et al, Expert Opin. Investig. Drugs 14, 797-806 (2005)]. Mediated by activation of the A2a receptor, the release of pro-inflammatory cytokines from macrophages, such as IL-12 and TNF-α [Hasko et al, FASEB J. 14, 2065-2078 (2000)], and T- Cells, such as IFN-γ [Lappas et al, J. Immunol. 174, 1073-1080 (2005)], downregulated. On the other hand, A2a receptor knockout mice show increased inflammation and greatly increased mortality after bleomycin instillation into the lungs [Scheibner et al, Am. J. Respir. Cell Mol Biol 40, 251-259 (2009)]. Furthermore, it has been shown in an animal model of bronchiolitis obliterans that A2a receptor knock-out leads to increased inflammation in the allograft and a poorer course of bronchiolitis [Lau et al, Ann. Thorac. Surg. 88, 1071-1078 (2009)]. A strong, nonselective A2a-antagonistic active component of an A2b receptor antagonist would thus be of significant disadvantage in the treatment of the abovementioned disorders.

Idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that, if left untreated, leads to an average death within 2.5 to 3.5 years after diagnosis. Patients are usually older than 60 years of age at the time of diagnosis, and men are more likely to be affected than women. The onset of the disease is gradual and characterized by an increased shortness of breath and dry, irritating cough. IPF belongs to the group of idiopathic interstitial pneumonias (IIP), a heterogeneous group of lung diseases characterized by varying degrees of fibrosis and inflammation, which are distinguished by clinical, imaging and histologic criteria. Within this group, idiopathic pulmonary fibrosis is of particular importance due to its frequency and its aggressive nature [Ley et al, Am. J. Respir. Crit. Care Med. 183. 431-440 (2011)]. IPF can be either sporadic or familial. The causes are currently not clear. In recent years, however, many indications have been found that chronic damage to the alveolar epithelium results in the release of profibrotic cytokines / mediators followed by increased fibroblast proliferation. proliferation and increased collagen fiber formation, resulting in patchy fibrosis and the typical honeycomb structure of the lung [Strieter et al, Chest 136. 1364-1370 (2009)]. The clinical consequences of fibrosis are a decrease in the elasticity of the lung tissue, a reduction in the diffusion capacity and the development of severe hypoxia. Pulmonary functionally a deterioration of the forced vital capacity (FVC) and the diffusion capacity (DLCO) can be detected. Significant and prognostically significant comorbidities of IPF are acute exacerbation and pulmonary hypertension [Beck et al, Pneumologe 10, 105-111 (2013)]. The prevalence of pulmonary hypertension in interstitial lung disease is 10-40% [Lettieri et al, Chest 129, 746-752 (2006); Behr et al, Eur. Respir. J. 31, 1357-1367 (2008)]. There is currently no curative treatment for IPF, except for lung transplantation.

Pulmonary hypertension (PH) is a progressive lung disease that, if left untreated, leads to death on average within 2.8 years of diagnosis. By definition, chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value <20 mmHg). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PH, there is a neomuscularization of primarily non-muscularized pulmonary vessels, and the vascular musculature of the already muscularized vessels increases in size. As a result of this increasing obstruction of the pulmonary circulation, there is a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in right heart failure [M. Humbert et al., J. Am. Coli. Cardiol. 2004, 43, 13S-24S]. Although idiopathic (or primary) pulmonary arterial hypertension (IPAH) is a very rare disease, secondary pulmonary hypertension (non-PAH PH, NPAHPH) is widespread and it is currently believed that PH is the third most common cardiovascular disease Disease group after coronary heart disease and systemic hypertension is [Naeije, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, p 3]. The classification of pulmonary hypertension into different groups according to the respective etiology has been carried out since 2008 according to the Dana Point classification [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ., 2011, pp 197-206].

Despite advances in PH treatment, there is no prospect of healing for this serious condition. Therapies on the market (eg, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, exercise capacity and prognosis of patients. Here, These are systemically applied, primarily hemodynamically acting therapeutic principles that influence vascular tone. The applicability of these drugs is determined by the z. T. serious side effects and / or complicated application forms limited. The period of time during which the clinical situation of patients can be stabilized or improved under a specific monotherapy is limited (eg due to tolerance development). Finally, there is a therapy escalation and thus a combination therapy in which several drugs have to be given at the same time. At present, these standard therapies are only approved for the treatment of pulmonary arterial hypertension (PAH). In secondary forms of PH, such as PH-COPD, these therapeutic principles (eg sildenafil, bosentan) failed in clinical studies, as they led to a decrease (desaturation) of the arterial oxygen content in patients as a result of unselective vasodilation. The reason for this is probably an unfavorable influence on the ventilation-perfusion adaptation within the lungs in heterogeneous lung diseases due to the systemic administration of unselective vasodilators [I. Blanco et al, Am. J. Respir. Crit. Care Med. 2010, 181, D. Stolz et al., Eur. Respir. J. 2008, 32, 619-628].

New combination therapies are one of the most promising future treatment options for the treatment of pulmonary hypertension. In this context, the exploration of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; E. B. Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. Above all, such new therapeutic approaches, which can be combined with the therapy concepts already on the market, could form the basis of a more efficient treatment and thus bring a great advantage for the patients.

For the purposes of the present invention, the term pulmonary hypertension includes both primary and secondary subforms (NPAHPH), as defined by the Dana Point classification according to their respective etiology [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, ^3rd edition, Hodder Arnold Publ, 2011, pp 197-206. Hoeper et al., J. Am. Coli. Cardiol, 2009, 54 (1), Suppl. S, S85-S96]. In particular, group 1 includes pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively). In addition, PAH also includes persistent pulmonary hypertension in newborns and associated pulmonary arterial hypertension (AP AH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, the use of certain drugs and medications (eg of appetite suppressants), with diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid gland disease. diseases, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy. Group 2 of the Dana Point classification summarizes PH patients with causative left ventricular disease, such as ventricular, atrial or valvular disease. Group 3 includes forms of pulmonary hypertension associated with a lung disease such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and / or hypoxemia (eg sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness , plant-related malformations) are associated. Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, eg in thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or in non-thrombotic embolization (eg as a result of tumor diseases, parasites, foreign bodies). Rarer forms of pulmonary hypertension, such as in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in Group 5.

Bronchiolitis obliterans syndrome (BOS) is a chronic rejection reaction after lung transplantation. Within the first five years after lung transplantation, approximately 50-60% of all patients are affected and over 90% of patients within the first nine years [Estenne et al, Am. J. Respir. Crit. Care Med. 166, 440-444 (2003)]. The cause of the disease is not clear. Despite many advances in the treatment of transplant patients, BOS case numbers have barely changed in recent years. BOS is the most important long-term complication of lung transplantation and is considered the main reason that survival rates are still significantly lower than those of other organ transplants. BOS is an inflammatory event associated with changes in the lung tissue, especially those affecting the small airways. The damage and inflammatory changes of the epithelial cells as well as the subepithelial structures of the smaller airways lead to an excessive fibroproliferation due to an inadequate regeneration of the epithelium and an aberrant tissue repair. There is scarring and eventually destruction of the bronchioles as well as grafting of granulation tissue in the small airways and alveoli, sometimes with vascular involvement. The diagnosis is made on the basis of lung function. BOS worsens FEV1 compared to the average of the two best measured postoperatively. At present, there is no curative treatment for BOS. Some of the patients improve under intensified immunosuppression, in the non-responsive patients there is a persistent deterioration, so that a new transplantation (retransplantation) is indicated.

Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive lung disease characterized by obstruction of respiratory flow, which is characterized by an obstruction of the respiratory flow Pulmonary emphysema and / or chronic bronchitis is caused. The first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea. COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of the over-45s are affected. Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, alleviate the symptoms, prevent acute worsening and slow down the progressive impairment of lung function. Existing pharmacotherapies, which have barely changed over the past two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control the inflammation of the lungs [PJ Barnes, N. Engl. J Med. 343. 269-280 (2000)]. The chronic inflammation of the lungs, caused by cigarette smoke or other irritants, is the driving force of disease development. The underlying mechanism involves immune cells that release proteases and various cytokines as a result of the lung's inflammatory response, leading to pulmonary emphysema and bronchial remodeling. The object of the present invention was therefore to identify and provide new substances which act as potent antagonists of the adenosine A2b receptor with high selectivity to the A2a receptor and with this profile of action in a special way for the treatment and / or prevention of diseases the lungs and the cardiovascular system as well as cancers. WO-2009/037468-A1 discloses 2-aminothieno [3,2-d] pyrimidine-4-carboxamides as adenosine A2b antagonists for the treatment of asthma, COPD, diabetes and cancer. As antagonists of the adenosine A2a receptor, which are particularly suitable for the treatment of CNS and addictive disorders, WO-2007/103776-A2 discloses 6-heteroaryl-substituted and in WO 2008/070529-A2 6-styryl-substituted thieno [ 2,3-d] pyrimidine-2,4-diones described. In WO 98/54190-AI, WO 00/12514-A1, GB 2 363 377-A and US 2004/0122028-A1 various thieno [2,3-d] pyrimidine-2,4-diones are disclosed which are disclosed in US Pat be used for other treatment of inflammatory and proliferative diseases. From US Pat. No. 6,140,325, carboxylate-substituted thieno [2,3-d] pyrimidine-2,4-diones are known as endothelin receptor antagonists. WO 00/61583-A1 claims xanthine analogs which are suitable for the treatment of inflammatory, neurodegenerative and autoimmune diseases. In WO 02 / No. 064598-A1 and WO 2004/014916-A1 describe bicyclic pyrimidinediones as inhibitors of matrix metalloproteinases (MMPs), in particular of MMP-13. WO 2013/071169-A1, WO 2014/182943-A1 and WO 2014/182950-A1 disclose thieno [2,3-d] pyrimidine-2,4-diones as ACC inhibitors for the treatment of infections and metabolic diseases. Cyclic thienouracil-6-carboxamides have recently been described in WO 2015/052065-A1 as adenosine A2b receptor antagonists for the treatment of diseases of the lung and of the cardiovascular system. In WO 2016/023832-A1, 3- (hydroxyalkyl) -substituted thieno [2,3-d] pyrimidine-2,4-diones have recently been disclosed as TRPC5 modulators for the treatment of neurological diseases, and in the meantime, in WO 2016 / 150901 -A1 various 6- (heterocyclylmethyl) -substituted thienouracils have been published as adenosine A2b receptor antagonists.

Surprisingly, it has now been found that certain thieno [2,3-d] pyrimidine-2,4-dione derivatives carrying a specific (1-methylcyclopropyl) methyl substituent in the N ³ position are highly potent and highly selective towards the A2a receptor Represent antagonists of the adenosine A2b receptor and are therefore particularly suitable for the treatment and / or prevention of diseases in which in the course of an inflammatory event and / or a tissue or vascular remodeling of the A2b receptor is involved, should be suitable.

The present invention relates to compounds of the general formula (I)

in welcher der Ring A für einen Aza-Heterocyclus der Formel

in which the ring A is an aza-heterocycle of the formula

worin die Verknüpfung zur angrenzenden CFh-Gruppe markiert und X O oder N(R²) bedeutet, worin stands,

wherein the linkage to the adjacent CFh group is marked and XO or N (R ² ) means in which

R ^{2 represents} cyano, methoxycarbonyl or ethoxycarbonyl, and

R ^{1 is} hydrogen, cyano, cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, tetrahydrofuran-2-yl, or a group of the formula -CH 2 -R ^1A where

R ^{1A is} hydrogen, methyl, fluoromethyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy, and their solvates.

Compounds according to the invention are the compounds of the formula (I) and their solvates, the compounds of the formula (I) of the formulas (1-1), (I-1a), (I-Ib), (I-1c) listed below, (I-ld), (1-2), (1-3), (1-4) and (1-5) and their solvates, as well as those of formula (I), hereinafter described as exemplary compounds and their solvates as far as the compounds listed below are not already solvates.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers; is / Z double bond isomers). The present invention therefore includes the enantiomers, diastereomers and double bond isomers as well as their respective mixtures. From such mixtures, the stereoisomerically uniform constituents can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert und Preferred in the context of the present invention are compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula stands,

where * denotes the link to the adjacent CFh group and

XO or N (R ² ) means in which

R ^{2 is} cyano or methoxycarbonyl, and

R ^{1 is} cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, tetrahydrofuran-2-yl or a group of the formula -CH 2 -R ^1A where

R ^{1A is} trifluoromethyl, ethyl, methoxy or trifluoromethoxy, and their solvates.

A specific embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands,

worin * die Verknüpfung zur angrenzenden CEh-Gruppe markiert, und deren Solvate.

where * marks the link to the adjacent CEh group and their solvates.

A further embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula provides,

worin * die Verknüpfung zur angrenzenden CH₂-Gruppe markiert und

in which * the linkage to the adjacent CH ₂ group is marked and

R ^{2 is} cyano or methoxycarbonyl, and their solvates.

A further embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands,

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert, und deren Solvate.

where * marks the link to the adjacent CFh group and their solvates.

A further embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula

stands,

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert, und deren Solvate.

where * marks the link to the adjacent CFh group and their solvates.

Another embodiment of the present invention relates to compounds of the formula (I) in which R ^{1 is} 2,2-difluorocyclopropyl or cyclobutyl, and their solvates.

Another embodiment of the present invention relates to compounds of the formula (I) in which

R ^{1 is} a group of the formula -CH 2 -R ^1A , wherein

R ^{1A is} trifluoromethyl, methoxy or trifluoromethoxy, and their solvates.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated. Particularly preferred are combinations of two or more of the preferred ranges mentioned above.

Particularly preferred in the context of the present invention are compounds according to formula (I) selected from the group of compounds consisting of

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione,

 [l - ({5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide,

 Methyl [1- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene]

 6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione,

 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3 , 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione,

1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione,

 [1 - ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide,

Methyl [1 - ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene] 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione,

1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione,

 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione,

1-Butyl 5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione,

l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

and

1- (cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione and their solvates.

Very particularly preferred in the context of the present invention are compounds of the formula (I) selected from the group consisting of compounds consisting of

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione,

 [l - ({5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide,

 Methyl [1- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene]

 6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione,

 Methyl [1 - ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene]

 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

and 1- (cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione and their solvates.

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as Ή (deuterium), Ή (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging body half-life or reducing the required dose of the active ingredient; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" denotes compounds which may themselves be biologically active or inactive, but are converted to compounds according to the invention during their residence time in the body by, for example, metabolic or hydrolytic routes.

Depending on the particular type of aza heterocycle A, the compounds of the formula (I) according to the invention can be prepared in different, in some cases also alternative ways. Thus, compounds of the formula (I-1) according to the invention can be

in welcher der Ring A¹ für einen Aza-Heterocyclus der Formel

in which the ring A ¹ for an aza-heterocycle of the formula

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert und X die oben angegebene Bedeutung hat, und stands,

where * denotes the linkage to the adjacent CFh group and X has the meaning given above, and

R ^{1 has} the abovementioned meaning, obtained according to the method shown in Reaction Scheme 1 [in this scheme as well as in the following Reaction Schemes 2-10, the (l-methylcyclopropyl) methyl substituent on N ^{3 is represented} by R ³ for reasons of space ]:

Scheme 1

[Alk = methyl or ethyl].

Thienouracil carbaldehydes of the formula (1) are first reacted here with 1,2-diaminoethane (2) in a reductive amination to form the diamino compounds of the formula (3). In particular, sodium cyanoborohydride in the presence of acetic acid is suitable as the reducing agent. A suitable solvent is methanol, optionally mixed with dichloromethane, and the reaction is preferably carried out in a temperature range between RT and + 70 ° C. The target compounds of the formula (I-la) are obtained by subsequent reaction of the diamino compounds (3) with NN'-carbonyldiimidazole (4). The reactions are preferably carried out at RT and in solvents such as tetrahydrofuran (THF), 1,4-dioxane or dimethyl sulfoxide (DMSO), if appropriate in the presence of a tertiary amine base such as triethylamine. The products of the formula (I-Ib) are obtained by reaction of the diamino compounds (3) with dimethyl N-cyanodithioiminocarbonate (5). The reaction is preferably carried out in N, N-dimethylformamide (DMF) as a solvent in the presence of alkali metal carbonates, for example potassium carbonate, as a base at elevated temperatures of + 80 ° C. The products of the formula (I-Ic) are obtained by reaction of the diamino compounds (3) with methyl or ethyl (dichloromethylene) carbamate (6). The reaction is preferably carried out in dichloromethane as solvent in the presence of a tertiary amine base, such as triethylamine, at RT. Finally, the products of formula (Id) are obtained by reaction of diamino compounds (3) with diethyl oxalate (7). The reaction is preferably carried out in ethanol as a solvent at elevated temperatures by + 80 ° C.

Compounds of the formula (1-2) according to the invention

in welcher der Ring A² für einen Aza-Heterocyclus der Formel

in which the ring A ² for an aza-heterocycle of the formula

stands,

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert und X die oben angegebene Bedeutung hat, und

where * denotes the linkage to the adjacent CFh group and X has the meaning given above, and

R ^{1 has} the meaning given above, Alternatively, they may also be prepared by a general method according to Reaction Scheme 2:

Scheme 2

In the "one pot" variant of this process, an alcohol of formula (8) is first reacted with a chlorinating agent, such as preferably thionyl chloride, in the presence of a tertiary amine base, such as N, N-diisopropylethylamine or triethylamine, into the corresponding chloro compound [corresponding to formula This chlorine compound is not isolated, but in the same reaction vessel with a solution of the deprotonated aza-heterocycle of formula (9) is added, so as to obtain the target compound of formula (1-2) in one step Deprotonation of the heterocycle (9) may be carried out using strong bases, such as alkali metal hydrides or alkali metal amides, preferably sodium hydride or lithium hexamethyldisilazide The chlorination step is usually carried out in a halogenated hydrocarbon as an inert solvent - preferably dichloromethane - in the temperature range around 0 ° C. At the same temperature, the solution d it deprotonated heterocycle (9) added. The substitution reaction to (1-2) then takes place preferably at RT. Suitable solvents for the preparation of the deprotonated heterocycle (9) are in particular N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or mixtures thereof. The deprotonation itself is preferably carried out in a temperature range between 0 ° C and + 60 ° C. Less hydrolysis-sensitive chlorine compounds of formula (10) can be prepared and also isolated by reacting alcohols of formula (8) with a chlorinating agent, preferably thionyl chloride, in an inert solvent such as chloroform or dichloromethane, as before become. The reaction is preferably carried out in a temperature range between RT and + 80 ° C, wherein for the heating above the boiling point of the particular solvent, the use of a microwave oven, using sealed reaction vessels, has proven to be particularly advantageous. In a subsequent, separate reaction step, the isolated chlorine compounds of the formula (10) are then reacted under similar conditions, as explained above, with a solution of the deprotonated heterocycle (9). In the process described above, the subject aza heterocycles of formula (9) may also be used in protected form using a suitable amide protecting group which masks one of the two NH groups, if convenient or necessary to avoid side reactions , Such amide-protecting groups and methods for their introduction and removal are familiar to the person skilled in the art [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

In a further alternative method, compounds of the formula

(1-3)

in welcher der Ring A³ für ein cyclisches Harnstoff-Derivat der Formel

in which the ring A ^{3 is} a cyclic urea derivative of the formula

stands,

worin die Verknüpfung zur angrenzenden CH2-Gruppe markiert, und die oben angegebene Bedeutung hat, gemäß nachfolgendem Reaktionsschema 3 hergestellt werden: Schema 3

wherein the linkage to the adjacent CH2 group is labeled and has the meaning given above, according to the following Reaction Scheme 3: Scheme 3

PMe ₃

aq. NH ₃

Here, aldehydes of the formula (1) are first converted with hydroxylamine into the corresponding oximes of the formula (11). The reaction is preferably carried out at RT using an aqueous hydroxylamine solution in a water-miscible ether, such as tetrahydrofuran (THF), as solvent. The subsequent reduction to the aminomethyl compounds (12) can be achieved by hydrogenation in the presence of a noble metal catalyst. Preferred reaction conditions are 1 bar hydrogen pressure at RT in the presence of a catalytic amount of palladium (5-10% on carbon) in methanol or ethanol as solvent. The hydrogenation is preferably carried out in the presence of aqueous mineral acid, for example concentrated hydrochloric acid. Alternatively, reduction to the aminomethyl compounds (12) may also be with sodium borohydride in the presence of suitable metal salts, such as nickel or cobalt chloride. Preferred reaction conditions here are the use of sodium borohydride in combination with nickel (II) chloride hexahydrate in methanol as solvent at RT. Another route to the aminomethyl compounds of the formula (12) starts from the alcohols of the formula (8) out. These are first converted into the corresponding azides of formula (14) by being reacted with phosphoric acid diphenyl ester azide in the presence of an amine base such as DBU at 0 ° C to RT in tetrahydrofuran (THF). The reduction of the azides (14) to the aminomethyl compounds (12) can then be carried out, for example, by reaction with trimethylphosphine in tetrahydrofuran (THF) and concentrated ammonia water at RT.

The aminomethyl compounds of the formula (12) obtained in one of the ways mentioned are then reacted in a one-pot process with chloroethyl isocyanate (13), initially forming an open-chain urea derivative. The reaction is preferably carried out at RT in a solvent mixture of N, N-dimethylformamide (DMF) and tetrahydrofuran (THF) or in toluene in the temperature range between + 60 ° C. and the boiling point of the solvent. By subsequent addition of a strong base, such as potassium tert-butoxide, to the reaction mixture is then carried out at RT, the ring closure to the target compounds of formula (1-3).

Compounds of the formula (1-4) according to the invention

in welcher der Ring A⁴ für ein l,3-Dihydroimidazol-2-on der Formel

in which the ring A ⁴ for a l, 3-dihydroimidazol-2-one of the formula

stands,

worin die Verknüpfung zur angrenzenden CH2-Gruppe markiert, und R¹ die oben angegebene Bedeutung hat, lassen gemäß nachfolgendem Reaktionsschema 4 erhalten: Schema 4

wherein the linkage to the adjacent CH 2 group is marked, and R ^{1 is} as defined above, can be obtained according to the following Reaction Scheme 4: Scheme 4

Aldehydes of the formula (1) are first heated to reflux with the aminoacetal (15) in the sense of a reductive amination in a suitable solvent, such as methanol or dichloromethane, and then reduced at RT with sodium triacetoxyborohydride to give the compounds of the formula (16). These are then converted with potassium cyanate and aqueous perchloric acid in methanol at RT into the urea derivatives of the formula (17). In the last reaction step acid-catalyzed simultaneous acetal cleavage and ring closure to the target compounds of formula (1-4). The reaction is carried out in methanol at RT with hydrochloric acid of different concen- tration (from 0.5 mol / l to concentrated hydrochloric acid).

In formula (15) and the following intermediates (16) and (17) the dimethylacetal is shown; However, it is also possible to use other customary acetals in this process, in particular cyclic ones such as, for example, 1,3-dioxolane or 1,3-dioxane derivatives.

in welcher der Ring A⁵ für ein 2,4-Dihydro-l,2,4-triazol-3-on der Formel Compounds of the formula (1-5) according to the invention

in which the ring A ^{5 is} a 2,4-dihydro-l, 2,4-triazol-3-one of the formula

stands,

worin * die Verknüpfung zur angrenzenden CFh-Gruppe markiert, und

where * denotes the link to the adjacent CFh group, and

R ^{1 is} as defined above, can be prepared in various ways as depicted in Reaction Schemes 5a, 5b and 5c:

Scheme 5 a

Aldehydes of formula (1) are here by reaction with Boc-protected hydrazine in ethanol and in the presence of a catalytic amount of concentrated hydrochloric acid at RT in the hydrazones of formula (18), which then with sodium cyanoborohydride in methanol at + 65 ° C to the Hydrazine derivatives of the formula (19) can be reduced. In the latter reaction, precise control of the pH value plays a major role: in the presence of bromocresol green as an indicator, a pH of about 3-4 is maintained throughout the reaction time by addition of acetic acid in portions. The compounds of formula (19) are then reacted with trimethylsilyl isocyanate to form urea derivatives of formula (20). The reaction is carried out in an alcohol as a solvent, preferably in isopropanol, at elevated temperature, preferably at about + 50 ° C. At the same time, cleavage of the trimethylsilyl group takes place under these conditions. Ring closure to the target compounds of formula (1-5) is achieved by acid-mediated reaction with trimethyl orthoformate. For this purpose, the compounds of formula (20) are treated in the presence of hydrogen chloride with an excess of trimethyl orthoformate in methanol. This reaction is preferably carried out at room temperature. Scheme 5b

In this process, the protected hydrazine derivative of the formula (19) [see Scheme 5a] is first converted with trifluoroacetic acid in dichloromethane into the free hydrazine of the formula (21). The Boc cleavage takes place in a temperature range between 0 ° C and RT, preferably at 0 ° C. In order to avoid a decomposition of the product, no longer reaction time should be selected here than necessary, in addition, subsequent work-up and cleaning operations should be carried out at maximum at RT. In analogy to a previously described, two-stage process [see US Pat. No. 6,077,814, Referential Production Examples 1 -4], the hydrazine of the formula (21) is first treated with glyoxalic acid (22) under acid catalysis to give the hydrazone of the formula (23) condensed. The reaction is carried out in water in the presence of hydrochloric acid in a temperature range between 0 ° C and RT, preferably at + 10 ° C to + 20 ° C. Subsequently, the hydrazonocarboxylic acid (23) is converted with diphenylphosphoryl azide (DPPA) into the corresponding carboxylic acid azide, which then yields the corresponding isocyanate in situ in the sense of a Curtius rearrangement, which spontaneously cyclizes to the triazolone derivative of the formula (1-5). The reaction is carried out in an inert solvent such as toluene and in the presence of a tertiary amine base such as triethylamine. The reaction is initially carried out in a temperature range between about + 40 ° C and + 80 ° C; in the further course, the reaction temperature is then raised to + 100 ° C to + 110 ° C. Scheme 5c

Alcohols of the formula (8) are here reacted in the sense of a Mitsunobu reaction directly with 2,4-dihydro-l, 2,4-triazol-3-one (24) to the target compounds of formula (1-5). Suitable reagents for this transformation are, for example, triphenylphosphine, polymer-bound triphenylphosphine, tributylphosphine or trimethylphosphine, in each case in combination with diethyl azodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or azodicarboxylic acid dipiperidide (ADDP) [cf. e.g. D.L. Hughes, Org. Reactions 42, 335 (1992); D.L. Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)]. The reaction is preferably carried out in tetrahydrofuran (THF) or dichloromethane as solvent in a temperature range between 0 ° C and RT.

In this process, the 2,4-dihydro-l, 2,4-triazol-3-one (24) can also be used in protected form using a suitable amide protecting group that masks the N ⁴ atom, if to avoid side reactions is appropriate or necessary. Such amide protecting groups and methods for their introduction and removal are well known to those skilled in the art [see, eg, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

The synthesis of the thienouracil intermediates of the formulas (1) and (8) [see Schemes 1, 2, 3, 4, 5a and 5c] used for the preparation of the compounds according to the invention is shown in the following Reaction Schemes 6-10:

Scheme 6

 NaOEt

 20 ° -50 ° C

 [Y = C1, Br, I or OTs].

Here, ethyl 2-amino-4-methylthiophene-3-carboxylate (25) is treated either with 1- (isocyanato-methyl) -l-methylcyclopropane (26) [R ³ = (1-methylcyclopropyl) methyl] or, after activation with NN '. Carbonyldiimidazole (CDI), by reaction with 1- (1-methylcyclopropyl) methanamine (27) [R ³ = (1-methylcyclopropyl) methyl] into the urea derivative of formula (28). The reaction with the isocyanate (26) is preferably carried out in an ethereal solvent, for example in tetrahydrofuran (THF), and in the presence of a tertiary amine base, such as triethylamine, under reflux conditions, or in pure pyridine as solvent and base at a temperature of approx. + 50 ° C. Activation of the 2-amino-4-methylthiophene-3-carboxylic acid ester (25) with CDI is also carried out in the presence of a tertiary amine base such as triethylamine in an inert solvent, preferably in tetrahydrofuran (THF) or dichloromethane RT and sometimes requires longer reaction times of several days. After addition of the amine (27) to the CDI-activated 2-aminothiophene-3-carboxylic acid ester is carried out at RT usually rapid further reaction to the urea of the formula (28). By following treatment with alkali metal alcoholates in the corresponding alcohol as solvent (for example and preferably sodium ethoxide in ethanol), the ring closure to the thienouracil of the formula (29) is achieved in a clean reaction. The reaction takes place in the temperature range between room temperature and approx. + 50 ° C. The subsequent alkylation with the compounds of formula (30) is carried out in the presence of an inorganic base such as potassium or cesium carbonate in an inert solvent such as, for example and preferably N, N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile or mixtures thereof, carried out. The reaction temperature is usually between RT and about + 100 ° C. In the case of volatile alkylating agents (30), the use of sealed reaction vessels and heating by means of a microwave oven proves to be helpful. Depending on the nature of the leaving group Y, it may be advantageous to carry out the alkylation in the presence of a catalytic amount of potassium iodide. The compounds of the formula (31) thus obtained are then converted into the aldehydes of the formula (1) in a Vilsmeier-Haack reaction with a mixture of phosphorus oxychloride and N, N-dimethylformamide (DMF) in an exothermic reaction. Usually, the heat released during the reaction is sufficient to achieve complete conversion. Sometimes, however, it may be necessary to heat the mixture to about + 90 ° C for some time after the reaction heat has subsided.

The above reaction sequence of alkylation and formylation can also be carried out in a reversed order by the Thienouracil of formula (29) is first converted under the conditions of the Vilsmeier-Haack reaction already described in the formyl derivative of formula (32) and then among the also already described conditions with the compounds of formula (30) to the target aldehydes of the formula (1) is alkylated.

Alternatively, the aldehydes of formula (1) can also be prepared by the following general procedure:

Scheme 7

 (29)

R-CH ₂ -Y (30)

K ₂ C0 ₃ or Cs ₂ C0 ₃

 20 ° -100 ° C

tBuLi, -78°C

tBuLi, -78 ° C

 DMF, -78 ° C

 [Y = C1, Br, I or OTs].

The thienouracils (29) or (31) [see Scheme 6] are in this case firstly converted with a brominating agent into the brominated derivatives of the formula (33) or (34). By alkylation with a compound of formula (30), the brominated thienouracil (33) can be converted into the derivatives of formula (34). At the end of the synthesis sequence, a halogen-metal exchange takes place. Reaction of the thus generated in situ metallated species with a formamide yields the aldehydes of formula (1). Suitable brominating agents are, for example, N-bromosuccinimide (NBS) or elemental bromine; preferred is NBS. The reaction takes place in an inert solvent, for example and preferably in dichloromethane or chloroform, in the temperature range between about 0 ° C. and room temperature. The alkylation of the compound (33) to the compounds of the formula (34) is carried out under the same conditions as described above [see Scheme 6: Reaction of (32) to (1) or from (29) to (31)]. The metallation of 6-bromothienouracils (34) is preferably carried out with tert. Butyllithium in an ethereal solvent, such as preferably tetrahydrofuran, at a low temperature of about -78 ° C. At the same temperature, by adding a formamide, preferably N, N-dimethylformamide (DMF), the aldehydes of the formula (1) are obtained.

Instead of the bromine derivatives in the above reaction sequence and the corresponding chlorine or iodine derivatives can be run, which consists of the compounds of formula (29) or (31), for example by use of N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS) or the elemental halogens (instead of NBS or bromine) are accessible.

Scheme 8

 NaOEt

 20 ° -50 ° C

 TFA

 or

 HCI (g) / dioxane

[Y = C1, Br, I or OTs].

From the 5-amino-3-methylthiophene-2,4-dicarboxylic acid ester (35), the thienouracil- tert. butyl ester of the formula (38) in a completely analogous manner to the reactions described for the preparation of the intermediates (31) [see Scheme 6]. Subsequent treatment of the tert. Butyl ester (38) at RT with either trifluoroacetic acid in dichloromethane or a solution of hydrogen chloride in 1,4-dioxane provides the carboxylic acids of formula (39). These can then either directly by reduction with lithium aluminum hydride at about 0 ° C in an inert solvent, such as and preferably tetrahydrofuran (THF) are converted to the alcohols of formula (8), or after prior conversion to the corresponding methyl esters of formula (40) , The latter can be obtained in a one-pot process by first converting the carboxylic acids (39) at room temperature with oxalyl chloride in dichloromethane in the presence of a catalytic amount of N, N-dimethylformamide (DMF) into the corresponding acid chlorides, which are then quenched with methanol Methyl esters of formula (40).

Scheme 9

 NaOEt

 20 ° -50 ° C

LiAlH ₄ , THF

 -40 ° C to 0 ° C

[Y = C1, Br, I or OTs].

From the diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (41), the thieno-uracilethyl esters of the formula (44) can likewise be prepared in a completely analogous manner to the reactions described for the preparation of the intermediates (31) [see Scheme 6 ] receive. The subsequent reduction with a complex metal hydride, such as, for example, and preferably lithium aluminum hydride, then provides the alcohols of the formula in a similar manner as described above in Scheme 8. mel (8). The reaction is typically carried out in a temperature range between -40 ° C and 0 ° C in an inert solvent, such as by way of example and preferably tetrahydrofuran (THF).

Scheme 10

 ° C

CH ₂ Cl ₂ , RT The aldehydes of the formula (1) obtained according to one of the methods described above and alcohols of the formula (8) can, if it appears desirable for synthetic purposes, be interconverted by a number of methods familiar to the person skilled in the art. Thus, for example, the alcohols of the formula (8) can be oxidized with manganese dioxide in dichloromethane or with sulfur trioxide-pyridine complex in dimethylsulfoxide (DMSO) in each case at RT to give the aldehydes of the formula (1). Conversely, the aldehydes of formula (1) can be reduced to the alcohols of formula (8) with complex hydrides, such as lithium aluminum hydride or sodium borohydride. The reduction with lithium aluminum hydride is preferably carried out in tetrahydrofuran (THF) at -78 ° C, while the reduction can be carried out with sodium borohydride, for example in ethanol at RT. 2-Amino-4-methylthiophene-3-carboxylic acid esters such as compound (25) [Scheme 6] and 5-amino-3-methylthiophene-2,4-dicarboxylic acid esters such as compounds (35) and (41) [Schemes 8 and 9 ] can be obtained by a known method via the 3-component reaction of acetone or an acetoacetic acid ester with an α-cyanoacetic acid ester and elemental sulfur ["Gewald reaction"; see, for example, BP McKibben et al, Tetrahedron Lett. 40, 5471-5474 (1999) and further references cited therein].

The compounds of the above-mentioned formulas (2), (4), (5), (6), (7), (9), (13), (15), (22), (24), (25), (26), (27), (30), (35) and (41) are either commercially available or described as such in the literature, or they can be prepared from other commercially available compounds by methods known to those skilled in the art become. Numerous detailed rules and further references are also contained in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates. The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

The compounds according to the invention are very potent antagonists of the adenosine A2b receptor which are highly selective towards the A2a receptor and are therefore particularly suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which a Inflammatory activity and / or a tissue or vascular remodeling of A2b receptor is involved.

For the purposes of the present invention, these include, in particular, diseases such as the group of interstitial idiopathic pneumonia, including idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia Pneumonia, desquamative interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other interstitial pulmonary diseases of unknown cause, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), pulmonary emphysema (eg, cigarette smoke-induced emphysema), cystic fibrosis (CF), inflammatory renal and fibrotic diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid diseases, multiple sclerosis, inflammatory and fibrotic skin diseases, sickle cell anemia and inflammatory and fibrotic eye diseases.

The compounds according to the invention can furthermore be used for the treatment and / or prevention of asthmatic diseases of varying degrees of severity with an intermittent or persistent course (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medications or dust-induced asthma), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and seasonal, allergic rhinitis, eg hay fever) and of polyps.

The compounds according to the invention can moreover be used for the treatment and / or prevention of cardiovascular diseases, such as, for example, hypertension, cardiac insufficiency, coronary heart disease, stable and unstable angina pectoris, renal hypertension, peripheral and cardiac vascular diseases, arrhythmias, atrial and ventricular arrhythmias, and conduction disorders such as grade I-III atrio-ventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis , Valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, as well as for the treatment and / or prevention of thromboembolic disorders and ischaemias, such as myocardial ischemia, myocardial infarction and stroke, cardiac hypertrophy, inflammatory kardiovaskul ren disease, heart failure, endothelial dysfunction, micro- and macrovascular injuries (vasculitis), and after heart transplants and bypass operations.

For the purposes of the present invention, the term cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as specific or related forms thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects Heart valve failure, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy cardiac storage disorders as well as diastolic and systolic heart failure. The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure. For the purposes of the present invention, the terms renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection and immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which may be diagnosed by, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels of urea, nitrogen, potassium and / or creatinine, altered renal enzyme activity such as glutamyl synthase, altered urinary or urinary output, increased microalbuminuria , Macroanaluria, lesions on glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or the need for dialysis may be characterized. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

In addition, the compounds of the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis , Oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases and inflammatory ocular diseases.

The compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrous diseases of the internal organs, such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibroid diseases of the eye , For the purposes of the present invention, the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, morphea, Keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis). The compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, eg, after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin. Also, the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias. The compounds according to the invention are furthermore suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, head and neck tumors, esophageal cancer, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, Ureter, prostate and genital tract, bladder cancer and malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.

In addition, the compounds according to the invention can be used for the treatment and / or prevention of metabolic diseases (hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic late effects such as retinopathy, nephropathy and neuropathy ), diseases of the gastrointestinal tract and abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis), diseases of the central nervous system and of neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, inflammatory ocular diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, chori oiditis, ophthalmitis), viral diseases (by influenza, adeno and coronaviruses, such as HPV, HCMV, HIV, SARS), diseases of the skeletal bone and joints and skeletal muscle (various forms of arthritis such as arthritis alcaptonurica, arthritis ankylosans , Arthritis dysenterica, Arthritis exsudativa, Arthritis fungosa, Arthritis gonorrhoica, Arthritis mutilans, Arthritis psoriatica, Arthritis purulenta, Arthritis rheumatica, Arthritis serosa, Arthritis syphilitica, Arthritis tuberculosa, Arthritis urica, Arthritis villonodularis pigmentosa, Atypical arthritis, Hemophilic arthritis, Juvenile chronic arthritis , rheumatoid arthritis and metastatic arthritis, Still syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome, multiple forms of arthropathies such as arthropathy deformans, arthropathy neurophathica, ovaripriva arthropathy, psoriatic arthropathy and arthropathy t abica, systemic sclerosis, various forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurotica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as the Günther syndrome and Münchmeyer syndrome), inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, arteritis deformans, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, and Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), Mückle-Well syndrome, Kikuchi's disease, polychondritis, sclerodermia and other diseases. Other diseases with an inflammatory or immunological component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, rejection reactions after organ transplantation and wound healing and angiogenesis especially in chronic wounds. Because of their property profile, the compounds of the invention are particularly suitable for the treatment and / or prevention of interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis (CF), myocardial infarction, heart failure, hemoglobinopathies, especially sickle cell anemia, and cancers.

The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Another object of the present invention is thus the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention. The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. The present invention therefore further relates to medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned diseases. Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of

Phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil;

• NO- and heme-independent activators of soluble guanylate cyclase (sGC), in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 ;

NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), in particular riociguat, nelociguat and vericiguat, as well as those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011 / 147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549 described compounds; Prostacyclin analogs and IP receptor agonists such as, by way of example and preferably, iloprost, beraprost, treprostinil, epoprostenol or selexipag; Endothelin receptor antagonists such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan;

Compounds that inhibit human neutrophilic ecstasy (HNE), such as by way of example, and preferably Sivelestat or DX-890 (Reltran); The signal transduction cascade inhibiting compounds, by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib , Cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;

Compounds which inhibit the degradation and remodeling of the extracellular matrix, by way of example and preferably inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (in this case in particular MMP-1, MMP-3, MMP) 8, MMP-9, MMP-10, MMP-11 and MMP-13) and metallo-elastase (MMP-12);

Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT2B receptor such as PRX-08066;

Antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; The Rho kinase inhibiting compounds, such as exemplified and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

Compounds which inhibit the soluble epoxide hydrolase (sEH), such as NN'-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3- {5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea; · The energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

• anti-obstructive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically applied beta-adrenergic receptor agonists (beta-mimetics) and the inhaled anti-muscarinergen substances; anti-inflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, tipelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN-γ, pirfenidone or etanercept; antifibrotic agents such as, by way of example and by way of illustration, pirfenidone, lysophosphatidic acid receptor 1 (LPA-1) antagonists, sphingosine 1-phosphate receptor 3 (SlP3) antagonists, autotaxine inhibitors, FP receptor antagonists, Lysyl oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, vasoactive intestinal peptide (VIP), VIP analogs, α _v β6 integrin antagonists, interferons, KCa3.1 blockers, CTGF inhibitors, ILs 4-antagonists, IL-13 antagonists, TGF-β antagonists, inhibitors of the WNT signaling pathway or CCR2 antagonists; therapeutic antibodies as well as antibody-drug conjugates, such as by way of example and preferably bevacizumab, cetuximab, trastuzumab, trastuzumab emtansine, brentuximab ve- dotin or anetumab ravtansine; immunotherapeutic antibodies such as, by way of example and by way of limitation, ipilimumab, nivolumab, pembrolizumab (lambrolizumab), PF-06801591, pidilizumab, BMS-936559 (MDX-1105), atezolizumab, durvalumab, avelumab, MEDI-0680 or AMP-224; antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances; hypotensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics; lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; and / or chemotherapeutic agents, such as those used for the treatment of neoplasms (neoplasms) of the lungs or other organs. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor such as, by way of example and preferably, rivaxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150 , KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

Among the fat metabolism changing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the AC AT inhibitors, MTP inhibitors, PPAR-alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214). In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an AC AT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

Particularly preferred are combinations of the compounds according to the invention with one or more further active compounds selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists. agonists, antifibrotic agents, anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, and signal transduction cascade inhibiting compounds.

Another object of the present invention are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning, the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Suitable for other routes of administration are, for example, inhalant medicaments (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules , aqueous suspensions (lotions, shake mixtures), lipo- phile suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral and parenteral administration, in particular oral, intravenous and intrapulmonary (inhalative) administration. The compounds of the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight. For intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples. A. Examples

Abbreviations and acronyms: abs. absolutely

 Ac acetyl

aq. aqueous, aqueous solution

 Boc tert. butoxycarbonyl

br. wide (at NMR signal)

 Example. Example

 Bu Butyl

c concentration

about circa, about

cat. catalytic

 CDI NN'-carbonyldiimidazole

 CI chemical ionization (in MS)

d doublet (by NMR)

d day (s)

 DAD diode array detector (by HPLC)

 DBU diazabicyclo [5.4.0] undec-7-ene

 TLC thin layer chromatography

 DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DEAD Diethyl azodicarboxylate

 DIAD diisopropyl azodicarboxylate

 DIPEA N, N-diisopropylethylamine

 DME 1, 2-dimethoxyethane

 DMF N, N-dimethylformamide

 DMSO dimethyl sulfoxide

dq doublet by quartet (by NMR)

dt doublet of triplet (by NMR)

 ΔΤ temperature increase, heating (of a reaction mixture) d. TL of theory (in chemical yield)

ee enantiomeric excess

 EI electron impact ionization (in MS)

eq. Equivalent (s)

ESI electrospray ionization (in MS) Et ethyl

h hour (s)

 HPLC high pressure, high performance liquid chromatography

iPr isopropyl

conc. concentrated (at solution)

 LC liquid chromatography

 LC / MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

 Literature (position)

m multiplet (by NMR)

 Me methyl

min minute (s)

 MPLC medium pressure liquid chromatography (over silica gel; also "flash"

Called chromatography ")

 MS mass spectrometry

 NBS N-bromosuccinimide

 NMM N-methylmorpholine

 NMP N-methyl-2-pyrrolidinone

 NMR nuclear magnetic resonance spectrometry

 Pd / C palladium on charcoal

 PEG polyethylene glycol

 Ph phenyl

 Pr Propyl

q quartet (by NMR)

quant. quantitative (at chemical yield)

quin quintet (by NMR)

 Rf Retention Index (at DC)

 RP reverse phase (reversed phase, for HPLC)

 RT room temperature

R _t retention time (for HPLC, LC / MS)

s singlet (by NMR)

sept septet (by NMR)

sext sextet (by NMR)

 SFC supercritical liquid chromatography

t triplet (by NMR)

TB ME tert. Butyl methyl ether tBu tert. butyl

 TFA trifluoroacetic acid

 THF tetrahydrofuran

 TMS tetramethylsilane

 Ts tosyl (p-toluenesulfonyl)

 UV ultraviolet spectrometry

v / v volume to volume ratio (of a solution)

together

HPLC and LC / MS methods:

Method 1 CLC / MS):

 Instrument MS: Thermo Scientific FT-MS; UHPLC device: Thermo Scientific UltiMate 3000; Column: Waters HSST3 Cl 8 1.8 μιη, 75 mm x 2.1 mm; Eluent A: 1: 1 water + 0.01% formic acid, eluent B: 1: 1 acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B -> 2.5 min 95% B-> 3.5 min 95% B; Temperature: 50 ° C; Flow: 0.90 ml / min; UV detection: 210-300 nm.

Method 2 CLC / MS):

 Instrument: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μιη, 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Temperature: 50 ° C; Flow: 0.40 ml / min; UV detection: 210-400 nm.

Method 3 Preparative HPLC):

 Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: acetonitrile / water with 0.1% formic acid; Gradient: 20: 80-> 95: 5 within 20 min.

More information:

 The following descriptions of the coupling patterns of 'H-NMR signals are based on the visual appearance of the signals concerned and do not necessarily correspond to a rigorous, physically correct interpretation. In general, the indication of the chemical shift refers to the center of the relevant signal; In the case of broad multiplets, an interval is usually specified.

Melting points and melting ranges, where indicated, are not corrected. In cases in which reaction products were obtained by stirring, stirring or recrystallization, it was often possible to isolate further product quantities from the respective mother liquor by chromatography. The description of this chromatography is omitted below, however, because a large part of the total yield could only be isolated in this step.

For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below, and which were not commercially available or obtained from sources which are not generally available, a reference to the published literature is described in which their preparation is described ,

Starting compounds and intermediates:

Example 1A Ethyl 4-methyl-2- ({[(1-methylcyclopropyl) methyl] carbamoyl} amino) thiophene-3-carboxylate

A solution of 3.81 g (20.6 mmol) of ethyl 2-amino-4-methylthiophene-3-carboxylate and 11.5 ml (82.2 mmol) of triethylamine in 120 ml of dichloromethane was treated with 5.0 g (30.8 mmol) of N, N'-carbonyldiimidazole (CDI ) and stirred for 3 days at RT. Then, 5.0 g (41.1 mmol) of [(1-methylcyclopropyl) methyl] amine hydrochloride was added. After 1 h stirring at RT, the reaction mixture was transferred to a separating funnel and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The remaining crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 340 g silica gel, cyclohexane / ethyl acetate 2: 1). Concentration of the product fractions and drying of the residue under high vacuum gave 5.86 g (96% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 10.34 (s, 1H), 7.93 (br.t, 1H), 6.41 (s, 1H), 4.28 3.00 (d, 2H), 2.27 ( s, 3H), 1.32 (t, 3H), 1.04 (s, 3H), 0.43-0.34 (m, 2H), 0.30-0.21 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.12 min, m / z = 297 [M + H] ⁺ . Example 2A

-dione [(l-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) - 5-methyl-3

5.85 g (19.7 mmol) of the compound from Ex. 1A were dissolved in 55 ml of ethanol and treated with 14.7 ml (39.5 mmol) of a 21% solution of sodium ethoxide in ethanol. The reaction mixture was stirred initially at RT for 15 h and then at 50 ° C. for 3 h. Thereafter, it was made acidic by adding about 45 ml of 1 M hydrochloric acid. The product failed. It was filtered off with suction, washed neutral with water and dried under high vacuum. 4.84 g (97% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de, δ / ppm): 12.08 (s, 1H), 6.69 (d, 1H), 3.31 (s, 1H), 2.54 (s, 1H), 2.35 (d, 3H) , 0.98 (s, 3H), 0.65-0.54 (m, 2H), 0.28-0.18 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 251 [M + H]

Example 3A

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine

6-carbaldehyde

A solution of 4.83 g (19.3 mmol) of the compound from Ex. 2A in 14.9 ml (193 mmol) of DMF was added carefully with 21.6 ml (232 mmol) of phosphorus oxychloride. After the strongly exothermic reaction had subsided, the mixture was stirred for a further 15 min. Then it was stirred gently into 1 liter of water. After 1 h of stirring at RT, the precipitated product filtered off with suction, washed neutral with water and dried under high vacuum. There were obtained 5.21 g (95% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 12.57 (br.s, 1H), 10.07 (s, 1H), 3.81 (s, 2H), 2.76 (s, 3H), 0.99 (s , 3H), 0.67-0.54 (m, 2H), 0.31-0.19 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 279 [M + H] ⁺ .

Example 4A

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

2.60 g (9.34 mmol) der Verbindung aus Bsp. 3A und 3.23 g (23.4 mmol) Kaliumcarbonat wurden 15 min bei RT in 50 ml wasserfreiem DMF gerührt, bevor 3.3 ml (28.0 mmol) l,l,l-Trifluor-3- iodpropan hinzugefügt wurden. Danach wurde das Reaktionsgemisch ca. 15 h bei 50°C gerührt. Nach dem Abkühlen auf RT wurde das Reaktionsgemisch mit Wasser versetzt und 30 min bei RT gerührt. Das ausgefallene Produkt wurde abgesaugt, mit Wasser gewaschen und anschließend im Hochvakuum getrocknet. Es wurden 3.41 g (95% d. Th., 95% Reinheit) der Titelverbindung erhalten.

2.60 g (9.34 mmol) of the compound from Ex. 3A and 3.23 g (23.4 mmol) of potassium carbonate were stirred for 15 min at RT in 50 ml of anhydrous DMF before 3.3 ml (28.0 mmol) of 1,1-trifluoro-3-iodopropane were added. Thereafter, the reaction mixture was stirred at 50 ° C for about 15 h. After cooling to RT, the reaction mixture was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. There were obtained 3.41 g (95% of theory, 95% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.11 (s, 1H), 4.19 (br.t, 2H), 3.87 (s, 2H), 2.86-2.72 (m, 2H), 2.80 (s, 3H), 0.99 (s, 3H), 0.63-0.59 (m, 2H), 0.27-0.24 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.15 min, m / z = 375 [M + H] ⁺ . Example 5A 1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde

2.60 g (9.34 mmol) of the compound of Ex. 3A and 3.23 g (23.4 mmol) of potassium carbonate were stirred for 15 min at RT in 50 ml of anhydrous DMF before 1.8 ml (18.7 mmol) of (2-bromoethyl) methyl ether were added. Thereafter, the reaction mixture was stirred at 50 ° C for about 15 h. After cooling to RT, the reaction mixture was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. This gave 2.96 g (88% of theory, 94% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.11 (t, 2H), 3.87 (s, 2H), 3.65 (t, 2H), 3.24 (s, 3H ), 2.78 (s, 3H), 0.99 (s, 3H), 0.65-0.56 (m, 2H), 0.29-0.22 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 337 [M + H] ⁺ .

Example 6A

6 - {[(2-aminoethyl) amino] methyl} -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

1.20 g (3.20 mmol) of the compound from Ex. 4A were dissolved in a mixture of 22 ml of methanol and 10 ml of dichloromethane. Subsequently, 1.3 ml (19.2 mmol) of 1,2-diaminoethane and 734 μΐ (12.8 mmol) of acetic acid were added at RT. After 30 minutes, 806 mg (12.8 mmol) of sodium cyanoborohydride were added. Subsequently, the mixture was stirred at 60 ° C for about 15 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over water. dried magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 1.40 g (88% of theory, 84% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.13 (t, 2H), 3.81 (s, 2H), 3.64 (br, s, 2H), 3.31 (br, s, 3H), 2.85 -2.66 (m, 4H), 2.64-2.58 (m, 2H), 2.35 (s, 3H), 0.97 (s, 3H), 0.65-0.54 (m, 2H), 0.28-0.18 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.54 min, m / z = 419 [M + H] ⁺ . Example 7A

6- {[(2-Aminoethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

1.20 g (3.57 mmol) of the compound from Ex. 5A were dissolved in a mixture of 22 ml of methanol and 11 ml of dichloromethane. Subsequently, 1.4 ml (21.4 mmol) of 1,2-diaminoethane and 817 μΐ (14.3 mmol) of acetic acid were added at RT. After 30 minutes, 897 mg (14.3 mmol) of sodium cyanoborohydride were added. Subsequently, the mixture was stirred at 60 ° C for about 15 h. After cooling to RT, 2M sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product thus obtained gave, after drying under high vacuum, 1.36 g (80% of theory, 80% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.04 (t, 2H), 3.86 (s, 2H), 3.79 (s, 2H), 3.64 (t, 2H), 3.24 (s, 3H ), 2.74-2.64 (m, 2H), 2.63-2.55 (m, 2H), 2.33 (s, 3H), 0.97 (s, 3H), 0.63-0.54 (m, 2H), 0.27-0.18 (m, 2H ).

LC / MS (Method 2, ESIpos): R _t = 0.47 min, m / z = 381 [M + H] ⁺ . Example 8A tert-Butyl 2- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,2,3,4 -tetrahydrothieno [2,3-d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Eine Lösung von 400 mg (1.07 mmol) der Verbindung aus Bsp. 4A in 10 ml Ethanol wurde zunächst mit 212 mg (1.60 mmol) tert. -Butyl-hydrazincarboxylat und dann mit 3 Tropfen konzentrierter Salzsäure versetzt. Nachdem das Reaktionsgemisch ca. 18 h bei RT gerührt worden war, wurde der Großteil des Ethanols am Rotationsverdampfer entfernt. Der verbliebene Rückstand wurde mit 150 ml Wasser verdünnt und durch Zusatz von gesättigter wässriger Natriumhydrogen- carbonat-Lösung neutralisiert. Der dabei ausgefallene Feststoff wurde abgesaugt, mit wenig Wasser gewaschen und im Hochvakuum getrocknet. Es wurden 502 mg (91% d. Th., 95% Reinheit) der Titelverbindung erhalten.

A solution of 400 mg (1.07 mmol) of the compound from Example 4A in 10 ml of ethanol was first tert with 212 mg (1.60 mmol). Butylhydrazincarboxylat and then mixed with 3 drops of concentrated hydrochloric acid. After the reaction mixture had been stirred for about 18 h at RT, most of the ethanol was removed on a rotary evaporator. The remaining residue was diluted with 150 ml of water and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered off, washed with a little water and dried under high vacuum. 502 mg (91% of theory, 95% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.88 (br.s, 1H), 8.30 (s, 1H), 4.16 (t, 2H), 3.86 (s, 2H), 2.89-2.71 (m, 2H), 2.46 (s, 3H), 1.46 (s, 9H), 0.98 (s, 3H), 0.64-0.56 (m, 2H), 0.27-0.20 (m, 2H). LC / MS (Method 1, ESIneg): R _t = 2.35 min, m / z = 487 [MH] -.

Example 9A tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methylene) hydrazinecarboxylate

Analog zu dem unter Bsp. 8A beschriebenen Verfahren wurden aus 400 mg (1.19 mmol) der Verbindung aus Bsp. 5A und 236 mg (1.78 mmol) tert. -Butyl-hydrazincarboxylat 524 mg (97% d. Th.) der Titelverbindung hergestellt.

Analogously to the process described under Ex. 8A, from 400 mg (1.19 mmol) of the compound from Ex. 5A and 236 mg (1.78 mmol) of tert. Butylhydrazinecarboxylate 524 mg (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.85 (br.s, 1H), 8.29 (s, 1H), 4.08 (t, 2H), 3.86 (s, 2H), 3.65 (t , 2H), 3.25 (s, 3H), 2.45 (s, 3H), 1.46 (s, 9H), 0.98 (s, 3H), 0.63-0.56 (m, 2H), 0.27-0.21 (m,

2H).

LC / MS (Method 1, ES Ineg): R _t = 2.35 min, m / z = 449 [MH] -. Example 10A tert-Butyl 2- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -1,3,3, 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

A solution of 495 mg (1.01 mmol) of the compound from Ex 8A in 11.5 ml of methanol was treated with 159 mg (2.53 mmol) of sodium cyanoborohydride and a little bromocresol green. Subsequently, enough titrated with acetic acid that the indicator color just turned from blue to yellow. Then the reaction mixture was heated to 65 ° C. After 1 h, a further 159 mg (2.53 mmol) of sodium cyanoborohydride were added. During the entire reaction time, the pH value was adjusted again and again by adding further acetic acid, so that the indicator color remained just yellow. After a total of 3 h, the volatile constituents of the reaction mixture were largely removed on a rotary evaporator. The remaining residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to dryness. The product was isolated by chromatography (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After combining the product fractions, concentrating and drying in a high vacuum, 408 mg (82% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.27 (br, s, 1H), 5.06 (br, s, 1H), 4.14 (t, 2H), 3.98 (br, d, 2H) , 3.87 (s, 2H), 2.86-2.70 (m, 2H), 2.33 (s, 3H), 1.38 (s, 9H), 0.97 (s, 3H), 0.63-0.55 (m, 2H), 0.26-0.20 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.19 min, m / z = 491 [M + H] ⁺ . Example IIA tert. Butyl 2- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analogously to the process described under Example 10A, 207 mg (40% of theory) of the title compound were prepared from 515 mg (1.14 mmol) of the compound from Example 9A.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.26 (br, s, 1H), 4.99 (br, s, 1H), 4.04 (t, 2H), 3.96 (br, d, 2H) , 3.87 (s, 2H), 3.64 (t, 2H), 3.25 (s, 3H), 2.32 (s, 3H), 1.38 (s, 9H), 0.97 (s, 3H), 0.62-0.55 (m, 2H ), 0.27-0.19 (m, 2H).

Beispiel 12A tert. -Butyl-2-carbamoyl-2-( {5-methyl-3 - [( 1 -methylcyclopropyl)methyl] -2,4-dioxo- 1 -(3 ,3 ,3 -trifluor- propyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl}methyl)hydrazincarboxylat LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 321

Example 12A tert. Butyl 2-carbamoyl-2- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1, 2, 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Eine Lösung von 400 mg (815 mmol) der Verbindung aus Bsp. 10A in 15 ml Isopropanol wurde mit 219 μΐ (1.63 mmol) Trimethylsilylisocyanat versetzt und ca. 16 h bei RT gerührt. Danach wurde das Reaktionsgemisch zur Trockene eingeengt. Der verbliebene Rückstand wurde mittels MPLC gereinigt (Biotage Isolera One, Kartusche SNAP KP-Sil, 50 g Kieselgel, Laufmittel Cyclo- hexan/Ethylacetat 1 :2). Die Produktfraktionen wurden vereinigt, eingeengt und im Hochvakuum getrocknet. Es wurden 365 mg (83% d. Th.) der Titelverbindung erhalten.

A solution of 400 mg (815 mmol) of the compound from Ex. 10A in 15 ml of isopropanol was treated with 219 μΐ (1.63 mmol) of trimethylsilyl isocyanate and stirred for about 16 h at RT. Thereafter, the reaction mixture was concentrated to dryness. The remaining residue was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, mobile phase cyclohexane / ethyl acetate 1: 2). The product fractions were combined, concentrated and dried under high vacuum. 365 mg (83% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.93 (br.s, 1H), 6.21 (br.s, 2H), 4.95-4.27 (broad, 2H), 4.14 (t, 2H) , 3.87 (s, 2H), 2.85-2.68 (m, 2H), 2.35 (s, 3H), 1.38 (br, s, 9H), 0.96 (s, 3H), 0.61 -0.56 (m, 2H), 0.26 -0.19 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.95 min, m / z = 532 [MH] -.

Example 13A tert. Butyl 2-carbamoyl-2- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) hydrazinecarboxylate

Analog zu dem unter Bsp. 12A beschriebenen Verfahren wurden aus 200 mg (0.442 mmol) der Verbindung aus Bsp. I IA und 119 μΐ (0.884 mmol) Trimethylsilylisocyanat 182 mg (83% d. Th.) der Titelverbindung hergestellt.

Analogously to the process described under Example 12A, 200 mg (0.442 mmol) of the compound from Ex. I IA and 119 μΐ (0.884 mmol) of trimethylsilyl isocyanate were used to prepare 182 mg (83% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 8.94 (br, s, 1H), 6.18 (br, s, 2H), 4.58 (broad, 2H), 4.04 (t, 2H), 3.88 ( s, 2H), 3.64 (t, 2H), 3.24 (s, 3H), 2.33 (s, 3H), 1.38 (br, s, 9H), 0.97 (s, 3H), 0.59-0.56 (m, 2H) , 0.26-0.19 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.93 min, m / z = 496 [M + H] ⁺ .

Example 14A

6- {[(2,2-dimethoxyethyl) amino] methyl} -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

300 mg (0.801 mmol) of the compound from Ex. 4A were dissolved in 20 ml of dichloromethane and treated with 130 μΐ (1.20 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 509 mg (2.40 mmol) sodium triacetoxyborohydride were added and stirring continued at RT. After 16 h and after 30 h, in each case an additional 43 μΐ (0.401 mmol) of 2,2-dimethoxyethanamine and 169 mg (0.801 mmol) of sodium triacetoxyborohydride were added. After a further 24 h, 43 μΐ (0.401 mmol) of 2,2-dimethoxyethanamine and 169 mg (0.801 mmol) of sodium triacetoxyborohydride were added again and the mixture was subsequently stirred at 35 ° C. Then the following amounts of acetic acid were added at intervals of 24 h: 138 μΐ (2.40 mmol), 46 μΐ (0.801 mmol), 138 μΐ (2.40 mmol) and 138 μΐ (2.40 mmol). After the last acetic acid addition, the reaction mixture was stirred for a further 24 h at 35.degree. It was then cooled to RT and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product thus obtained was purified by MPLC (Instrument Biotage Isolera One, cartridge SNAP KP-Sil, 25 g of silica gel, eluent cyclohexane / ethyl acetate 1: 1). After combining the product fractions, concentrating and drying in a high vacuum, 190 mg (49% of theory, 97% purity) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.42 (t, 1H), 4.12 (t, 2H), 3.86 (br, s, 2H), 3.84 (br, s, 2H), 3.27 (s, 6H), 2.84-2.69 (m, 2H), 2.64 (br d, 2H), 2.34 (s, 3H), 0.97 (s, 3H), 0.62-0.56 (m, 2H), 0.26-0.20 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.71 min, m / z = 464 [M + H] ⁺ . Example 15A

6 - {[(2,2-Dimethoxyethyl) amino] methyl} -1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2 , 4 (lH, 3H) -dione

300 mg (0.892 mmol) of the compound from Ex. 5A were dissolved in 20 ml of dichloromethane and treated with 145 μΐ (1.34 mmol) of 2,2-dimethoxyethanamine. The mixture was heated to 35 ° C for 1 h. After cooling to RT, 567 mg (2.68 mmol) of sodium triacetoxyborohydride were added and stirring continued at RT. After 16 h, an additional 48 μΐ (0.446 mmol) of 2,2-dimethoxyethanamine and 189 mg (0.982 mmol) of sodium triacetoxyborohydride were added. After a further 24 h at RT, the reaction mixture was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated to dryness. The crude product thus obtained was purified by means of MPLC (Instrument Biotage Isolera One, cartridge SNAP Ultra, 25 g of silica gel, eluent cyclohexane / ethyl acetate 1: 1). After combining the product fractions, concentrating and drying under high vacuum, 277 mg (72% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 4.41 (t, 1H), 4.04 (t, 2H), 3.86 (br, s, 2H), 3.82 (br, s, 2H), 3.63 (t, 2H), 3.27 (s, 6H), 3.23 (s, 3H), 2.63 (br, s, 2H), 2.32 (s, 3H), 2.26 (broad, 1H), 0.98 (s, 3H), 0.61-0.55 (m, 2H), 0.26-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 321 [M + HC ₄ HnNO ₂ ] ⁺ .

Example 16A 1- (2,2-Dimethoxyethyl) -1- {5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) urea

Eine Lösung von 185 mg (0.329 mmol, 97% Reinheit) der Verbindung aus Bsp. 14A in 4 ml Methanol wurde bei RT zunächst mit 74 mg (0.918 mmol) Kaliumcyanat und dann mit 59 μΐ (0.678 mmol) Perchlorsäure (70% in Wasser) versetzt. Nach ca. 16 h wurde das Reaktionsgemisch mit halbgesättigter wässriger Natriumhydrogencarbonat-Lösung versetzt und anschließend mit Ethylacetat extrahiert. Der organische Extrakt wurde mit gesättigter Natriumchlorid-Lösung gewaschen, über wasserfreiem Magnesiumsulfat getrocknet, filtriert und eingeengt. Nach Trocknen des erhaltenen Rückstands im Hochvakuum wurden 208 mg (91 > d. Th., 86% Reinheit) der Titelverbindung erhalten, die ohne weitere Aufreinigung für Folgereaktionen verwendet wurden.

A solution of 185 mg (0.329 mmol, 97% purity) of the compound from Ex. 14A in 4 ml of methanol was initially treated with 74 mg (0.918 mmol) of potassium cyanate and then with 59 μΐ (0.678 mmol) of perchloric acid (70% in water ). After about 16 h, the reaction mixture was mixed with half-saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Drying of the residue obtained under high vacuum gave 208 mg (91% of theory, 86% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.05 (s, 2H), 4.56 (s, 2H), 4.45 (t, 1H), 4.10 (t, 2H), 3.86 (s, 2H ), 3.18 (d, 2H), 2.83-2.67 (m, 2H), 2.40 (s, 3H), 0.97 (s, 3H), 0.63-0.56 (m, 2H), 0.27-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.91 min, m / z = 507 [M + H] ⁺ . Example 17A

1- (2,2-dimethoxyethyl) -1- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4 tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) urea

Analogously to the process described in Example 16A, from 275 mg (0.646 mmol) of the compound from Ex. 15A, 121 mg (1.49 mmol) of potassium cyanate and 95 μΐ (1.10 mmol) of perchloric acid (70%) in water) 312 mg (90 %> d. Th., 88% purity) of the title compound, which were used without further purification for subsequent reactions.

Ή NMR (400 MHz, DMSO-de, δ / ppm): 6.03 (s, 2H), 4.54 (s, 2H), 4.45 (t, 1H), 4.05-3.98 (m, 2H), 3.86 (s, 2H), 3.65-3.58 (m, 2H), 3.22 (s, 3H), 3.17 (d, 2H), 2.38 (s, 3H), 0.98 (s, 3H), 0.63-0.54 (m, 2H), 0.27 -0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.66 min, m / z = 469 [M + H] Example 18A

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - [2- (trifluoromethoxy) ethyl] -1,3,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

300 mg (1.08 mmol) der Verbindung aus Bsp. 3A und 372 mg (2.70 mmol) Kaliumcarbonat wurden 15 min bei RT in 6 ml wasserfreiem DMF gerührt, bevor 516 mg (2.16 mmol) 1 -Brom-2-(tri- fluormethoxy)ethan [kommerziell erhältlich; Lit.: P.E. Aldrich, W.A. Sheppard, J. Org. Chem. 1964, 29 (1), 11-15] hinzugefügt wurden. Dann wurde das Reaktionsgemisch ca. 16 h bei 50°C gerührt. Nach dem Abkühlen auf RT wurde mit Wasser versetzt und mit Ethylacetat extrahiert. Der organische Extrakt wurde nacheinander mit Wasser und gesättigter Natriumchlorid-Lösung gewaschen, über wasserfreiem Magnesiumsulfat getrocknet, filtriert und eingeengt. Das verbliebene Rohprodukt wurde mittels präparativer HPLC gereinigt (Methode 3). Nach Einengen der Produktfraktion und Trocknen im Hochvakuum wurden 340 mg (80% d. Th.) der Titelverbindung erhalten.

300 mg (1.08 mmol) of the compound from Ex. 3A and 372 mg (2.70 mmol) of potassium carbonate were stirred for 15 min at RT in 6 ml of anhydrous DMF before 516 mg (2.16 mmol) of 1-bromo-2- (trifluoromethoxy) ethane [commercially available; Ref .: PE Aldrich, WA Sheppard, J. Org. Chem. 1964, 29 (1), 11-15]. Then the reaction mixture was stirred at 50 ° C for about 16 h. After cooling to RT, water was added and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining crude product was purified by preparative HPLC (Method 3). Concentration of the product fraction and drying under high vacuum gave 340 mg (80% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.10 (s, 1H), 4.45-4.38 (m, 2H), 4.33-4.27 (m, 2H), 3.87 (s, 2H), 2.79 (s, 3H), 0.98 (s, 3H), 0.64-0.57 (m, 2H), 0.28-0.22 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.17 min, m / z = 391 [M + H] ⁺ .

Example 19A

1, 5-Dimethyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

250 mg (0.898 mmol) der Verbindung aus Bsp. 3A und 439 mg (1.35 mmol) Cäsiumcarbonat wurden 10 min bei RT in 4 ml wasserfreiem DMF gerührt, bevor 127 μΐ (1.35 mmol) Dimethylsulfat hinzugefügt wurden. Dann wurde das Reaktionsgemisch in einem Mikrowellenofen (Biotage Initiator mit dynamischer Steuerung der Einstrahlleistung) 1 h lang auf 60°C erhitzt. Nach dem Ab- kühlen auf RT wurde das Reaktionsgemisch mit Wasser versetzt und 30 min bei RT gerührt. Das ausgefallene Produkt wurde abgesaugt, mit Wasser gewaschen und anschließend im Hochvakuum getrocknet. Es wurden 235 mg (84% d. Th., 94% Reinheit) der Titelverbindung erhalten, die ohne weitere Aufreinigung für Folgereaktionen verwendet wurden.

250 mg (0.898 mmol) of the compound of Ex. 3A and 439 mg (1.35 mmol) of cesium carbonate were stirred for 10 min at RT in 4 ml of anhydrous DMF before 127 μΐ (1.35 mmol) of dimethyl sulfate were added. Then the reaction mixture was heated in a microwave oven (Biotage Initiator with dynamic control of the Einstrahlleistung) for 1 h at 60 ° C. After cooling to RT, the reaction mixture was mixed with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. There were obtained 235 mg (84% of theory, 94% purity) of the title compound, which were used without further purification for subsequent reactions.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 3.86 (s, 2H), 3.48 (s, 3H), 2.79 (s, 3H), 0.99 (s, 3H ), 0.64-0.59 (m, 2H), 0.28-0.23 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 293 [M + H] ⁺ .

Example 20A

1-Butyl-5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde

4A, 300 mg (1.08 mmol) of the compound from Example 3A and 397 mg (2.16 mmol) of iodobutane 335 mg (92% of theory) of the title compound were prepared analogously to the process described under Example 4A. The reaction was in this case not at 50 ° C, but at RT.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.10 (s, 1H), 3.94 (t, 2H), 3.86 (s, 2H), 2.79 (s, 3H), 1.67 (quin, 2H ), 1.36 (sext, 2H), 0.98 (s, 3H), 0.92 (t, 3H), 0.64-0.57 (m, 2H), 0.29-0.22 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.36 min, m / z = 335 [M + H] ⁺ .

Example 21A l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidine-6-carbaldehyde (racemate)

500 mg (1.80 mmol) of the compound from Ex. 3A and 497 mg (3.59 mmol) of potassium carbonate were stirred for 15 min at RT in 10 ml of anhydrous DMF before 461 mg (2.70 mmol) of racemic 2- (bromomethyl) -l, l- difluorocyclopropane were added. The reaction mixture was then stirred at RT for 2 days and then at 50 ° C. for a further 24 h. After cooling to RT, the mixture was treated with water and stirred at RT for 30 min. The precipitated product was filtered off, washed with water and then dried under high vacuum. There were obtained 654 mg (90% of theory, 92% purity) of the title compound, which were used without further purification for subsequent reactions. Ή-NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.11 (s, 1H), 4.21 (ddd, 1H), 4.02 (dd, 1H), 3.93-3.81 (m, 2H), 2.80 (s , 3H), 2.30-2.16 (m, 1H), 1.78-1.64 (m, 1H), 1.55-1.43 (m, 1H), 0.99 (s, 3H), 0.66-0.57 (m, 2H), 0.30-0.22 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.14 min, m / z = 369 [M + H] ⁺ . Example 22A 1- (Cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6 carbaldehyde

4A, 250 mg (0.898 mmol) of the compound from Example 3A and 268 mg (1.80 mmol) (bromomethyl) cyclobutane 290 mg (88% of theory, 95% purity) of the title compound were prepared analogously to the process described under Example 4A produced. Ή-ΝΜΡν (400 MHz, DMSO-d ₆ , δ / ρρηι): 10.09 (s, 1H), 4.01 (d, 2H), 3.86 (s, 2H), 2.88-2.70 (m, 1H), 2.78 (s , 3H), 2.03-1.92 (m, 2H), 1.90-1.74 (m, 4H), 0.98 (s, 3H), 0.66-0.53 (m, 2H), 0.30-0.20 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.42 min, m / z = 347 [M + H] ⁺ . Example 23A

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - [(2R) -tetrahydrofuran-2-ylmethyl] -1,2,3,4-tetrahydrothieno [2,3-d ] pyrimidine-6-carbaldehyde

300 mg (1.08 mmol) of the compound from Ex. 3A and 372 mg (2.70 mmol) of potassium carbonate were stirred for 15 min at RT in 6 ml of anhydrous DMF before 356 mg (2.16 mmol) of (2R) -2- (bromine). methyl) tetrahydrofuran were added. Then, the reaction mixture was stirred at 50 ° C. After 3 days, another 149 mg (1.08 mmol) of potassium carbonate and 178 mg (1.08 mmol) of (2R) -2- (bromomethyl) tetrahydrofuran were added and stirring was continued at 60 ° C. Since the conversion was not complete even after a further 3 days, the reaction mixture was finally heated to 100 ° C. for 2 h in a microwave oven (Biotage Initiator with dynamic control of the irradiation power). After cooling to RT, water was added to the reaction mixture and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 3). Concentration of the product fraction and drying under high vacuum gave 200 mg (51% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.09 (s, 1H), 4.30-4.19 (m, 1H), 4.12 (dd, 1H), 3.87 (s, 2H), 3.84-3.70 (m, 2H), 3.67-3.57 (m, 1H), 2.78 (s, 3H), 2.06-1.75 (m, 3H), 1.74-1.61 (m, 1H), 0.99 (s, 3H), 0.65-0.56 (m, 2H), 0.30-0.21 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 2.04 min, m / z = 363 [M + H] ⁺ . Example 24A

6 - {[(2-Aminoethyl) amino] methyl} -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d] pyrimidine -2,4 (lH, 3H) -dione

Analog zu dem unter Bsp. 6A beschriebenen Verfahren wurden aus 200 mg (0.512 mmol) der Verbindung aus Bsp. 18A, 205 μΐ (3.07 mmol) 1 ,2-Diaminoethan und 129 mg (2.05 mmol) Natrium- cyanoborhydrid 255 mg (91% d. Th., 80% Reinheit) der Titelverbindung hergestellt, welche ohne weitere Reinigung für Folgereaktionen verwendet wurden.

Analogously to the process described under Example 6A, 200 mg (0.512 mmol) of the compound from Ex. 18A, 205 μΐ (3.07 mmol) of 1,2-diaminoethane and 129 mg (2.05 mmol) of sodium cyanoborohydride gave 255 mg (91%). Th., 80% purity) of the title compound, which were used without further purification for subsequent reactions.

Example 25A 6- {[(2-Aminoethyl) amino] methyl} -1,5-dimethyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione

H ₂ N- ^ ^H I

2 CH ₃

Analogously to the process described under Example 6A, from 230 mg (0.740 mmol, 94% purity) of the compound from Ex. 19A, 297 μΐ (4.44 mmol) of 1,2-diaminoethane and 186 mg (2.96 mmol) of sodium cyanoborohydride 230 mg ( 85% of theory, 92% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.43 min, m / z = 337 [M + H] ⁺ .

Example 26A

6- {[(2-Aminoethyl) amino] methyl} -1-butyl-5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -dione

Analogously to the process described under Example 6A, 200 mg (0.598 mmol) of the compound from Ex. 20A, 240 μΐ (3.59 mmol) of 1,2-diaminoethane and 150 mg (2.39 mmol) of sodium cyanoborohydride gave 280 mg (98%). Th., 80% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 319 [M + HC ₂ H ₈ N ₂ ] ⁺ .

Example 27A

6- {[(2-Aminoethyl) amino] methyl} -1 - [(2,2-difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d ] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to the process described under Example 6A, from 650 mg (1.62 mmol, 92% purity) of the compound from Ex. 21A, 651 μΐ (9.74 mmol) of 1,2-diaminoethane and 408 mg (6.49 mmol) of sodium cyanoborohydride 810 mg ( 94% of theory, 78% purity) of the title compound, which were used without further purification for subsequent reactions. LC / MS (Method 2, ESIpos): R _t = 0.54 min, m / z = 413 [M + H] ⁺ .

Example 28A

6 - {[(2-Aminoethyl) amino] methyl} -1- (cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione

Analogously to the process described under Example 6A, from 285 mg (0.781 mmol, 95% purity) of the compound from Ex. 22A, 313 μΐ (4.69 mmol) of 1,2-diaminoethane and 196 mg (3.13 mmol) of sodium cyanoborohydride 345 mg ( 96% of theory, 85% purity) of the title compound, which were used without further purification for subsequent reactions.

LC / MS (Method 2, ESIpos): R _t = 0.58 min, m / z = 391 [M + H] ⁺ .

Example 29A

6- {[(2-aminoethyl) amino] methyl} -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1 - [(2R) -tetrahydro-furan-2-ylmethyl] thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 6A, 198 mg (0.546 mmol) of the compound from Ex. 23A, 219 μΐ (3.28 mmol) of 1,2-diaminoethane and 137 mg (2.19 mmol) of sodium cyanoborohydride gave 222 mg (99% of theory). Th.) Of the title compound.

LC / MS (Method 1, ESIpos): R _t = 0.86 min, m / z = 347 [M + HC ₂ H ₈ N ₂ ] Exemplary embodiments: Example 1

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 350 mg (0.703 mmol, 84% purity) of the compound from Example 6A and 147 μΐ (1.05 mmol) of triethylamine in 8 ml of THF was admixed with 137 mg (0.843 mmol) of NN'-carbonyldiimidazole (CDI) and ca. Stirred at RT for 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 3). After concentration of the combined product fractions, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and dilute hydrochloric acid. After renewed drying over anhydrous magnesium sulfate, filtration and concentration, 115 mg (36% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.54 (s, 1H), 4.37 (s, 2H), 4.11 (t, 2H), 3.86 (s, 2H), 3.29- 3.25 (m , 2H), 3.24-3.17 (m, 2H), 2.85-2.68 (m, 2H), 2.40 (s, 3H), 0.98 (s, 3H), 0.63-0.56 (m, 2H), 0.26-0.20 (m , 2H).

LC / MS (Method 1, ESIpos): R _t = 1.83 min, m / z = 445 [M + H] ⁺ . Example 2

[l - ({5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide

350 mg (0.703 mmol, 84% purity) of the compound from Ex. 6A were dissolved in 7 ml of DMF and admixed with 154 mg (1.05 mmol) of dimethyl N-cyanodithioiminocarbonate and 194 mg (1.41 mmol) of potassium carbonate. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was stirred at RT with a little acetonitrile. After aspirating and drying in a high vacuum, 170 mg (51% of theory) of the title compound were obtained.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.09 (s, 1H), 4.50 (s, 2H), 4.12 (t, 2H), 3.86 (s, 2H), 3.54- 3.37 (m , 4H), 2.86-2.69 (m, 2H), 2.42 (s, 3H), 0.97 (s, 3H), 0.63-0.56 (m, 2H), 0.26-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.90 min, m / z = 469 [M + H] ⁺ .

Example 3 Methyl [1- ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4- tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] carbamate

350 mg (0.703 mmol, 84% purity) of the compound from Ex. 6A and 196 μΐ (1.41 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated with a solution of 219 mg (1.41 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane added. After the reaction mixture was stirred at RT for about 16 h, it was concentrated to dryness. The remaining The residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was then purified by preparative HPLC (Method 3). Concentration of the product fraction and drying of the residue under high vacuum gave 155 mg (44% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.03 (s, 1H), 4.58 (s, 2H), 4.10 (t, 2H), 3.86 (s, 2H), 3.53 (s, 3H ), 3.50-3.42 (m, 2H), 3.40-3.33 (m, 2H), 2.83-2.68 (m, 2H), 2.43 (s, 3H), 0.97 (s, 3H), 0.63-0.55 (m, 2H ), 0.26-0.20 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.83 min, m / z = 502 [M + H] ⁺ . Example 4

6 - [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

350 mg (0.703 mmol, 84% purity) of the compound from Ex. 6A were dissolved in 15 ml of ethanol and treated with 179 .mu.l (1.30 mmol) of diethyl oxalate. After the reaction mixture was stirred for about 16 h at 80 ° C, it was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was then purified by preparative HPLC (Method 3). Concentration of the product fraction and drying of the residue under high vacuum gave 123 mg (36% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 4.71 (s, 2H), 4.11 (t, 2H), 3.86 (s, 2H), 3.56-3.45 (m, 2H), 3.36-3.31 (m, 2H, partially covered by the water signal), 2.86-2.69 (m, 2H), 2.44 (s, 3H), 0.97 (s, 3H), 0.64-0.55 (m , 2H), 0.27-0.19 (m, 2H).

LC / MS (Method 1, ESIneg): R _t = 1.65 min, m / z = 517 [M-H + HC0 ₂ H] - Example 5

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) methyl] -1- (3 , 3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione

365 mg (0.684 mmol) of the compound from Ex. 12A were dissolved in a mixture of 20 ml each of methanol and trimethyl orthoformate, and 1.7 ml (6.84 mmol) of a 4 M solution of hydrogen chloride in dioxane were added. After the reaction mixture was stirred at RT for about 16 h, it was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated again. The product was isolated by preparative HPLC (Method 3). Concentration of the product fractions and drying under high vacuum gave 80 mg (26% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 11.61 (br.s, 1H), 7.84 (s, 1H), 4.96 (s, 2H), 4.09 (t, 2H), 3.86 (s , 2H), 2.89-2.68 (m, 2H), 2.46 (s, 3H), 0.97 (s, 3H), 0.65-0.53 (m, 2H), 0.27-0.18 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 444 [M + H] ⁺ .

Example 6 1- (2-Methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

Eine Lösung von 340 mg (0.715 mmol, 80% Reinheit) der Verbindung aus Bsp. 7A und 149 μΐ (1.07 mmol) Triethylamin in 8 ml THF wurde mit 139 mg (0.858 mmol) NN'-Carbonyldiimidazol (CDI) versetzt und ca. 16 h bei RT gerührt. Anschließend wurde zur Trockene eingeengt. Der verbliebene Rückstand wurde in Ethylacetat aufgenommen und nacheinander mit Wasser und gesät- tigter Natriumchlorid-Lösung gewaschen. Nach Trocknen über wasserfreiem Magnesiumsulfat wurde filtriert und eingeengt. Der feste Rückstand wurde durch zweimalige präparative HPLC gereinigt (jeweils Methode 3). Nach Einengen der vereinigten Produktfraktionen und Trocknen im Hochvakuum wurden 82 mg (28% d. Th.) der Titelverbindung erhalten.

A solution of 340 mg (0.715 mmol, 80% purity) of the compound from Ex. 7A and 149 μΐ (1.07 mmol) of triethylamine in 8 ml of THF was admixed with 139 mg (0.858 mmol) of NN'-carbonyldiimidazole (CDI) and ca. Stirred at RT for 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by twice preparative HPLC (each method 3). Concentration of the combined product fractions and drying under high vacuum gave 82 mg (28% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.35 (s, 2H), 4.03 (t, 2H), 3.86 (s, 2H), 3.63 (t, 2H ), 3.29-3.17 (m, 4H), 3.23 (s, 3H), 2.39 (s, 3H), 0.98 (s, 3H), 0.63-0.55 (m, 2H), 0.27-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 407 [M + H]

Example 7

[1 - ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide

340 mg (0.715 mmol, 80% purity) of the compound from Ex. 7A were dissolved in 7 ml of DMF, and 157 mg (1.07 mmol) of dimethyl N-cyanodithioiminocarbonate and 198 mg (1.43 mmol) of potassium carbonate were added. The mixture was stirred for 4 h at 80 ° C in a microwave oven (Biotage initiator with dynamic control of the irradiation power). Thereafter, the reaction mixture was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was purified by preparative HPLC (Method 3). The product fractions were combined and concentrated, and the residue was then stirred at RT with a little acetonitrile. After aspirating and drying in a high vacuum, 78 mg (25% of theory) of the title compound were obtained. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 8.08 (s, 1H), 4.48 (s, 2H), 4.04 (t, 2H), 3.86 (s, 2H), 3.64 (t, 2H ), 3.53-3.37 (m, 4H), 3.24 (s, 3H), 2.40 (s, 3H), 0.98 (s, 3H), 0.63-0.54 (m, 2H), 0.27-0.18 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.70 min, m / z = 431 [M + H] ⁺ . Example 8

Methyl [1 - ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] carbamate

340 mg (0.751 mmol, 80% purity) of the compound from Ex. 7A and 209 μΐ (1.50 mmol) of triethylamine were dissolved in 10 ml of dichloromethane and treated with a solution of 234 mg (1.50 mmol) of methyl (dichloromethylene) carbamate in 5 ml of dichloromethane added. After the reaction mixture was stirred at RT for about 16 h, it was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was then purified by twice preparative HPLC (each method 3). Concentration of the product fraction and drying of the residue under high vacuum gave 117 mg (33% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.02 (s, 1H), 4.56 (s, 2H), 4.01 (t, 2H), 3.86 (s, 2H), 3.62 (t, 2H ), 3.53 (s, 3H), 3.50-3.42 (m, 2H), 3.39-3.32 (m, 2H), 3.22 (s, 3H), 2.42 (s, 3H), 0.98 (s, 3H), 0.62- 0.54 (m, 2H), 0.26-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 464 [M + H] ⁺ .

Example 9

6 - [(2,3-dioxopiperazin-1-yl) methyl] -1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] thieno [2,3-d] pyrimidine 2,4 (lH, 3H) -dione

340 mg (0.715 mmol, 80% purity) of the compound from Ex. 7A were dissolved in 15 ml of ethanol and admixed with 182 .mu.l (1.32 mmol) of diethyl oxalate. After the reaction mixture was stirred for about 16 h at 80 ° C, it was concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The crude product was first precleaned by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 50 g of silica gel, cyclohexane / ethyl acetate 2: 1 ^→ dichloromethane / methanol 10: 1). This was followed by a second purification by preparative HPLC (Method 3). Concentration of the product fraction and drying of the residue under high vacuum finally gave 95 mg (29% of theory, 97% purity) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 8.62 (br.s, 1H), 4.69 (s, 2H), 4.03 (t, 2H), 3.86 (s, 2H), 3.63 (t , 2H), 3.55-3.45 (m, 2H), 3.34-3.30 (m, 2H, largely masked by the water signal), 3.23 (s, 3H), 2.43 (s, 3H), 0.98 (s, 3H), 0.65-0.52 (m, 2H), 0.28-0.16 (m, 2H). LC / MS (Method 1, ES Ineg): R _t = 1.40 min, m / z = 479 [M-H + HCO 2 H] ^" .

Example 10 1- (2-Methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazole-1 -yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analog zu dem unter Bsp. 5 beschriebenen Verfahren wurden aus 180 mg (0.363 mmol) der Verbindung aus Bsp. 13A und Orthoameisensäuretrimethylester 55 mg (37% d. Th.) der Titelverbindung hergestellt.

Analogously to the process described in Example 5, from 180 mg (0.363 mmol) of the compound from Ex. 13A and trimethyl orthoformate 55 mg (37% of theory) of the title compound were prepared.

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 11.61 (br.s, 1H), 7.84 (s, 1H), 4.93 (s, 2H), 4.01 (t, 2H), 3.86 (s , 2H), 3.62 (t, 2H), 3.22 (s, 3H), 2.45 (s, 3H), 0.97 (s, 3H), 0.63-0.54 (m, 2H), 0.27-0.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 406 [M + H]

Example 11

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] -1- (3,3,3-trifluoropropyl) ) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

206 mg (0.350 mmol, 86% purity) of the compound from Ex. 16A were dissolved in a mixture of 4 ml of methanol and 0.8 ml of water, and 0.8 ml of 1 M hydrochloric acid were added. After the reaction mixture was stirred for 5 days at RT, it was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining residue was purified by preparative HPLC (Method 3). Concentration of the product fraction and drying under high vacuum gave 126 mg (81% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 10.00 (br.s, 1H), 6.46 (t, 1H), 6.35 (t, 1H), 4.81 (s, 2H), 4.09 (t , 2H), 3.86 (s, 2H), 2.84-2.68 (m, 2H), 2.47 (s, 3H), 0.97 (s, 3H), 0.63-0.54 (m, 2H), 0.28-0.18 (m, 2H ).

LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 443 [M + H] ⁺ .

Example 12 1- (2-Methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl ] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 11, from 310 mg (0.582 mmol, 88% purity) of the compound from Ex. 17A, 145 mg (61% of theory) of the title compound were prepared. The reaction time was 3 days. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 10.00, 6.45 (t, 1H), 6:35 (t, 1H), 4.79 (s, 2H), 4.01, ((br s, 1H). t, 2H), 3.86 (s, 2H), 3.61 (t, 2H), 3.22 (s, 3H), 2.45 (s, 3H), 0.97 (s, 3H), 0.62-0.55 (m, 2H), 0.26 -0.19 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.81 min, m / z = 405 [M + H] ⁺ .

Example 13 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione

A solution of 255 mg (0.470 mmol, 80% purity) of the compound of Ex. 24A and 98 μM (0.704 mmol) of triethylamine in 5 ml of THF was admixed with 91 mg (0.563 mmol) of NN'-carbonyldiimidazole (CDI) and ca. Stirred at RT for 16 h. It was then concentrated to dryness. The remaining residue was taken up in ethyl acetate and washed successively with 1 M hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and concentrated. The solid residue was purified by preparative HPLC (Method 3). Concentration of the product fraction and drying under high vacuum gave 124 mg (57% of theory) of the title compound. 'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.39 (t, 2H), 4.36 (s, 2H), 4.20 (t, 2H), 3.87 (s, 2H ), 3.28-3.16 (m, 4H), 2.40 (s, 3H), 0.97 (s, 3H), 0.63-0.56 (m, 2H), 0.26-0.20 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.97 min, m / z = 461 [M + H] ⁺ . Example 14

1, 5-Dimethyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] thi

pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described in Example 13, 230 mg (0.629 mmol, 92% purity) of the compound of Ex. 25A and 122 mg (0.755 mmol) of CDI 73 mg (32% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.52 (s, 1H), 4.36 (s, 2H), 3.86 (s, 2H), 3.42 (s, 3H), 3.29- 3.17 (m , 4H), 2.40 (s, 3H), 0.98 (s, 3H), 0.64-0.53 (m, 2H), 0.29-0.16 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 363 [M + H] ⁺ .

Example 15 1-Butyl-5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 ( lH, 3H) -dione

Analogously to the process described under Example 13, 280 mg (0.592 mmol, 80% purity) of the compound from Example 26A and 115 mg (0.710 mmol) of CDI 120 mg (50% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-de, δ / ρρηι): 6.53 (s, 1H), 4.35 (s, 2H), 3.95-3.76 (m, 2H), 3.86 (s, 2H), 3.29-3.17 (m, 4H), 2.39 (s, 3H), 1.65 (quin, 2H), 1.34 (sec, 2H), 0.97 (s, 3H), 0.91 (t, 3H), 0.65-0.50 (m, 2H), 0.29-0.17 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.95 min, m / z = 405 [M + H] ⁺ . Example 16 l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2, 3-d] pyrimidine-2,4 (1H, 3H) -dione (racemate)

Analogously to the process described in Example 13, 810 mg (1.53 mmol, 78% purity) of the compound from Example 27A and 298 mg (1.84 mmol) of CDI 354 mg (52% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.37 (s, 2H), 4.19-4.07 (m, 1H), 3.97 (dd, 1H), 3.92-3.82 (m, 2H), 3.29-3.16 (m, 4H), 2.40 (s, 3H), 2.28-2.11 (m, 1H), 1.80-1.61 (m, 1H), 1.54-1.37 (m, 1H), 0.98 (s, 3H), 0.69-0.51 (m, 2H), 0.34-0.17 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.84 min, m / z = 439 [M + H] ⁺ .

Example 17 1- (Cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2, 4 (lH, 3H) -dione

Analog zu dem unter Bsp. 13 beschriebenen Verfahren wurden aus 345 mg (0.751 mmol, 85% Reinheit) der Verbindung aus Bsp. 28A und 146 mg (0.901 mmol) CDI 158 mg (50% d. Th.) der Titelverbindung hergestellt.

Analogously to the process described under Example 13, 345 mg (0.751 mmol, 85% purity) of the compound of Ex. 28A and 146 mg (0.901 mmol) of CDI 158 mg (50% of theory) of the title compound were prepared.

'H-NMR (400 MHz, DMSO-de, δ / ppm): 6.53 (s, 1H), 4.35 (s, 2H), 3.94 (d, 2H), 3.86 (s, 2H), 3.29- 3.17 (m , 4H), 2.84-2.70 (m, 1H), 2.39 (s, 3H), 2.04-1.91 (m, 2H), 1.90-1.75 (m, 4H), 0.97 (s, 3H), 0.65-0.52 (m , 2H), 0.28-0.17 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.97 min, m / z = 417 [M + H] ⁺ . Example 18

5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] -1 - [(2R) -tetrahydrofuran-2-ylmethyl] thieno [2,3 -d] pyrimidine-2,4 (lH, 3H) -dione

Analogously to the process described under Example 13, from 220 mg (0.541 mmol) of the compound from Ex. 29A and 105 mg (0.649 mmol) of CDI 131 mg (55% of theory) of the title compound were prepared. 'H-NMR (400 MHz, DMSO-d _6, δ / ppm): 6:52 (s, 1H), 4:35 (s, 2H), 4:28 to 4:17 (m, 1H), 4:02 (dd, 1H), 3.87 ( s, 2H), 3.79-3.67 (m, 2H), 3.66-3.55 (m, 1H), 3.29-3.16 (m, 4H), 2.39 (s, 3H), 2.06-1.74 (m, 3H), 1.72- 1.59 (m, 1H), 0.98 (s, 3H), 0.68-0.50 (m, 2H), 0.30-0.12 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.70 min, m / z = 433 [M + H] ⁺ .

Example 19 1 - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2, 3-d] pyrimidine-2,4 (1H, 3H) -dione (enantiomer 1)

164 mg of the racemic compound from Ex. 16 were dissolved in 40 ml of acetonitrile / methanol mixture and separated in 130 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: carbon dioxide / methanol 87:13; Flow: 70 ml / min; Temperature: 40 ° C; Detection: 210 nm]. Evaporation of the appropriate product fractions and drying of the solid in a high vacuum gave 135 mg (78% of theory) of enantiomer 1 (> 99% ee, chiral analytical SFC-HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.53 (s, 1H), 4.37 (s, 2H), 4.20-4.06 (m, 1H), 3.97 (dd, 1H), 3.92-3.81 (m, 2H), 3.29-3.16 (m, 4H), 2.40 (s, 3H), 2.29-2.11 (m, 1H), 1.80-1.62 (m, 1H), 1.54-1.37 (m, 1H), 0.98 (s, 3H), 0.66-0.53 (m, 2H), 0.30-0.18 (m, 2H).

Chiral analytical SFC-HPLC [column: Daicel Chiralcel OJ-H, 3 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 80:20; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]:

Example 20 1 - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-imidazolidin-1-yl) methyl] thieno [2,3- d] pyrimidine-2,4 (1H, 3H) -dione {enantiomer 2)

164 mg of the racemic compound from Ex. 16 were dissolved in 40 ml of acetonitrile / methanol mixture and separated in 130 portions by preparative SFC-HPLC on a chiral phase into the enantiomers [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Eluent: carbon dioxide / methanol 87:13; Flow: 70 ml / min; Temperature: 40 ° C; Detection: 210 nm]. After evaporation of the corresponding product fractions and drying of the solid in a high vacuum, 113 mg (65% of theory) of enantiomer 2 were obtained (98.5% ee, chiral analytical SFC-HPLC).

Ή-ΝΜΡ (400 MHz, DMSO-d ₆ , δ / ppm): 6.53 (s, 1H), 4.37 (s, 2H), 4.19-4.06 (m, 1H), 3.97 (dd, 1H), 3.92-3.81 (m, 2H), 3.29-3.16 (m, 4H), 2.40 (s, 3H), 2.29-2.12 (m, 1H), 1.77-1.62 (m, 1H), 1.53-1.38 (m, 1H), 0.98 (s, 3H), 0.67-0.52 (m, 2H), 0.31-0.16 (m, 2H).

Chiral analytical SFC-HPLC [column: Daicel Chiralcel OJ-H, 3 μm, 50 mm × 4.6 mm; Eluent: carbon dioxide / methanol 80:20; Flow: 3 ml / min; Temperature: 40 ° C; Detection: 210 nm]: R _t = 0.91 min.

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vz ^'vo studies, as they are known in the art. The following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.

B-l. Cellular in vitro tests for the determination of A2b receptor activity and adenosine receptor selectivity

The identification of selective antagonists of the human adenosine A2b receptor and the quantification of the activity and selectivity of the compounds according to the invention was carried out with the aid of recombinant cell lines for the human adenosine receptors AI, A2a, A2b and A3. These cell lines are originally derived from a hamster ovary epithelial cell (Chinese Hamster Ovary, CHO-Kl, American Type Culture Collection, Manassas, VA 20108, USA). The cell lines for testing the activity at the AI, A2a and A2b receptors contain, in addition to the respectively recombinantly expressed adenosine receptor, a reporter gene construct in which the expression of the firefly (Photinus pyralis) luciferase is under the control of a promoter, which can be activated via intracellular signaling cascades by stimulation of the receptors with the (not subtype-selective) adenosine receptor agonist NECA (5'-N-ethylcarboxamidoadenosine) [SJ Hill, J.G. Baker, S. Rhees, Curr. Opin. Pharmacol. \, 526-532 (2001)].

In the case of the A2a and A2b cell lines, it is a minimal promoter with several cAMP-responsive elements (CRE). Stimulation of the G _s -coupled A2b or A2a receptors by NECA ultimately leads, via the formation of cAMP, to CRE-dependent induction of luciferase expression, which is detected 3 hours after starting incubation with NECA with a detection solution in a suitable Luminometer is detected. To test the antagonists, the first step in a preliminary experiment is to determine the concentration of NECA which leads to the half-maximal stimulation of luciferase expression on the respective test day (ECso concentration). By co-incubation of this ECso concentration of NECA with the substances to be tested then their antagonistic effect can be determined.

The cell line for testing the Gi-linked AI receptor contains another reporter gene construct in which the expression of the firefly luciferase is under the control of a NF (nuclear factor of activated T cells) promoter. In addition to the AI receptor and the NFAT reporter gene, this cell line was also labeled with another gene coding for the promiscuous Goti6 protein [TT Amatruda, DA Steele, VZ Slepak, MI Simon, Proc. Natl. Acad. Be. USA 88, 5587-5591 (1991)], either independently or stably transfected as a fusion gene. The resulting test cells respond to stimulation of the normally Gi-linked Al receptor with an increase in intracellular calcium concentration, which then results in NFAT-dependent luciferase expression. The experimental procedure for testing the antagonists on the AI receptor corresponds to the procedure for testing with the A2a and A2b cell lines.

In the generation of the A3 receptor cell line, a co-transfection of A3 receptor and the promiscuous Gai6 protein was also performed, so that here too the stimulation of the receptor leads to an increase in the intracellular calcium concentration. This calcium increase is in the A3 receptor test but directly through the calcium-sensitive photoprotein Photina ^® [S. Bovolenta, M. Foti, S. Lohmer, S. Corazza, J. Biomol. Screen. 12, 694-704 (2007)]. After determining the ECso concentration of NECA, the substance effects are measured after 5-10 minutes of pre-incubation with substance by adding this ECso concentration in the measuring position in a suitable dispensable luminometer.

In the following Table 1A, the IC50 values from the A2a and the A2b receptor assay are listed for the exemplary embodiments (in some cases as averages of several independent individual determinations and rounded to two significant digits):

Table 1A

A2a receptor A2b receptor

 Example no.

IC ₅₀ [nM] IC ₅₀ [nM]

 1 2200 3.2

 2 9600 8.8

 3 1400 2.2

 4> 10000 8.0

 5> 10000 24

 6> 10000 19

 7> 10000 22

 8> 10000 8.5

 9> 10000 72

 10> 10000 90

 11 8200 11

12> 10000 18 A2a receptor A2b receptor

 Example no.

IC ₅₀ [nM] IC ₅₀ [nM]

 13 1400 2.2

 14> 10000 36

 15> 10000 21

 16> 10000 11

 17> 10000 7.6

 18> 10000 38

 19 3500 6.0

 20 5500 21

The data in Table 1A show that the compounds of the present invention are highly potent adenosine A2b receptor antagonists which have more than one hundred to more than a thousand selectivity over the A2a receptor, in many cases a measurable A2a antagonist Activity (ie with an IC50 value <10000 nM / 10 μΜ) can no longer be determined.

Table 1B below lists the corresponding IC50 values for adenosine A2b receptor antagonists, which may be considered structurally closest prior art: Table 1B

It can be seen from the data in Table 1B that the prior art compounds listed are only about 40-fold, i. have markedly poorer selectivity in favor of the A2b receptor with measurable A2a-antagonistic activity (IC50 <10000 nM / 10 μΜ). B-2. Animal model of monocrotaline-induced pulmonary hypertension

Rat monocrotaline-induced pulmonary hypertension is a widely used animal model of pulmonary hypertension. The pyrrolizidine alkaloid monocrotaline is metabolized to the toxic monocrotaline pyrrole after subcutaneous injection in the liver and leads to endothelial damage in the pulmonary circulation within a few days, followed by remodeling of the small pulmonary arteries (mediastrophy, de novo muscularization). A single subcutaneous injection is sufficient to induce severe pulmonary hypertension in rats within 4 weeks [Cowan et al, Nature Med. 6, 698-702 (2000)].

The model uses male Sprague-Dawley rats. On day 0 the animals receive a subcutaneous injection of 60 mg / kg monocrotaline. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) begins at the earliest 14 days after monocrotaline injection and extends over a period of at least 14 days. At the end of the study hemodynamic examinations of the animals are carried out. For hemodynamic measurement, the rats are first anesthetized with pentobarbital (60 mg / kg). The animals are then tracheotomized and artificially ventilated (frequency: 60 breaths / min, inspiration to expiration ratio: 50:50, positive end-expiratory pressure: 1 cm H2O, tidal volume: 10 ml / kg body weight, FIO2: 0.5). The anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is determined in the left carotid artery using a Millar microtip catheter. A polyethylene catheter is advanced through the right jugular vein into the right ventricle to determine right ventricular pressure. Following hemodynamics, the heart is harvested, the ratio of right to left ventricles, including the septum, is determined, and the tissue deep frozen for expression analysis. The lung is also removed, the left half of the lung is fixed in formalin for histopathological examination and the right half of the lung is deep-frozen for expression analysis. Furthermore, plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained. B-3. Animal model of SU5416 / hypoxia-induced pulmonary hypertension

Rat SU5416 / hypoxia-induced pulmonary hypertension is a widely used animal model of pulmonary hypertension. By injecting the VEGF receptor antagonist SU5416 in combination with hypoxia, the effect of reduced oxygen content may be enhanced and result in endothelial changes in the form of plexiform lesions. A single subcutaneous injection, usually 20 mg / kg, is sufficient to induce severe pulmonary hypertension in combination with hypoxia, that is, increased vascular shear through vasoconstriction [Oka et al, Circ. Res. 100. 923-929 (2007)].

The model uses male Sprague-Dawley rats or Dahl salt rats. On day 0, the animals receive a subcutaneous injection of SU5416 and are maintained in a controlled hypoxic atmosphere (10% oxygen). Appropriate control rats receive an injection of vehicle and are kept under normoxic conditions. Chronic hypoxia of at least 14 days with subsequent normoxia of at least 28 days leads to the development of functionally and morphologically detectable pulmonary hypertension. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) begins at the earliest 14 days after SU5416 injection and commencement of the posture in a controlled hypoxic atmosphere and extends over a period of at least 14-28 days.

At the end of the study hemodynamic examinations of the animals are carried out. For hemodynamic measurement, the rats are first anesthetized with pentobarbital (60 mg / kg). Subsequently, tracheostomized and artificially ventilated (frequency: 60 breaths / min; inspiration to expiration ratio: 50:50; positive end-expiratory pressure: 1 cm H2O; tidal volume: 10 ml / kg body weight; FIO2: 0.5). The anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is determined in the left carotid artery using a Millar microtip catheter. A polyethylene catheter is advanced through the right jugular vein into the right ventricle to determine right ventricular pressure. Following hemodynamics, the heart is harvested, the ratio of right to left ventricles, including the septum, is determined, and the tissue deep frozen for expression analysis. The lung is also removed, the left half of the lung is fixed in formalin for histopathological examination and the right half of the lung is deep-frozen for expression analysis. Furthermore, plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained.

B-4. Animal model of bleomycin-induced pulmonary fibrosis

Bleomycin-induced lung fibrosis in the mouse or rat is a widely used animal model for pulmonary fibrosis. Bleomycin is a glycopeptide antibiotic used in oncology for the treatment of testicular tumors, Hodgkin's and non-Hodgkin's tumors. It is eliminated renally, has a half-life of about 3 hours and, as a cytostatic, influences different phases of the division cycle [Lazo et al, Cancer Chemother. Biol. Response Modif. 15, 44-50 (1994)]. Its anti-neoplastic effect is due to an oxidative damaging effect on DNA [Hay et al, Arch. Toxicol. 65, 81-94 (1991)]. The lung tissue is particularly endangered in comparison with bleomycin, since so-called cysteine hydrolases, which lead to inactivation of bleomycin in other tissues, are only present in small numbers. After administration of bleomycin, the animals develop an acute respiratory distress syndrome (ARDS) with subsequent development of pulmonary fibrosis. Administration of bleomycin may be single or multiple intratracheal, inhalational, intravenous or intraperitoneal. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first application of bleomycin or therapeutically 3-14 days later and extends over a period of 2-6 weeks. At the end of the study, pulmonary function measurements, bronchoalveolar lavage to determine cell content and pro-inflammatory and pro-fibrotic markers, and histological assessment of pulmonary fibrosis are performed. B-fifth Animal model of DQ12-Ouarz-induced pulmonary fibrosis

Mouse and rat DQ12 quartz induced lung fibrosis is a widely used animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. DQ12 quartz is a highly active quartz that breaks or grinds. The intratracheal or inhalational application of DQ12 quartz leads to alveolar proteinosis in mice and rats followed by interstitial pulmonary fibrosis. The animals receive a single or multiple intratracheal or inhaled instillation of DQ12 quartz. The treatment of the animals with the test substance (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation) starts on the day of the first instillation of the silicate or therapeutically 3-14 days later and extends over a period of 3-20 weeks. At the end of the study, pulmonary function measurements, bronchoalveolar lavage to determine cell content and proinflammatory and pro-fibrotic markers, and histological assessment of pulmonary fibrosis are performed.

B-sixth Animal Model of DQ12 Quartz or FITC-Induced Pulmonary Inflammation Intratracheal administration of DQ12-quartz or fluorescein isothiocyanate (FITC) to mouse and rat leads to lung inflammation [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. The animals are treated with the test substance on the day of instillation of DQ12 quartz or FITC or one day later for a period of 24 h to 7 days (by gavage, by addition in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperi - tonal injection or by inhalation). At the end of the experiment a bronchioalveolar lavage is performed to determine the cell content and the pro-inflammatory and pro-fibrotic markers.

B. 7 Animal model of ovalbumin-induced allergic airway inflammation and hyperreactivity The animal model of ovalbumin-induced allergic airway inflammation and hyperreactivity is a widely used animal model for bronchial asthma [Rückert et al, J. Immunol. II, 5507-5515 (2005)]. Mice are sensitized on day 0, 14 and 21 by intraperitoneal injection with the allergen ovalbumin in combination with adjuvant, the negative control receives an intraperitoneal injection of NaCl in combination with adjuvant. On days 28 and 29, the animals receive intratracheal instillation of ovalbumin.

On day 30, a hyperreactivity test in the form of an inhaled provocation with a gradually increasing concentration of a bronchoconstrictor, such as methacholine or adenovirus sinmonophosphate. First, the animals are anesthetized by injection anesthesia, then intubated orotracheal intubated or tracheotomized and connected by means of a tube with a pulmonary function. First, pulmonary function is measured by body plethysmography before provocation (including parameters such as tidal volume, respiratory rate, dynamic compliance and lung resistance). Subsequently, the lung function is measured during inhalative provocation with a gradually increasing concentration of the bronchoconstrictor. Thereafter, a broncho-alveolar lavage is performed to determine the cell content and the pro-inflammatory markers.

B-eighth Animal model of elastase-induced pulmonary emphysema Elastase-induced lung emphysema in mouse, rat or hamster is a widely used animal model for pulmonary emphysema [Sawada et al., Exp. Lung Res. 33, 277-288 (2007)]. The animals receive orotracheal instillation of porcine pancreatic elastase. The treatment of the animals begins on the day of the instillation of the porcine pancreatic elastase and extends over a period of 3 weeks. At the end of the study, alveolar armor morphometry is performed. B. 9 Animal model of permanent coronary ligature on mouse and rat

Mice or rats are anesthetized with 5% isoflurane in the anesthesia cage, intubated, connected to a respiratory pump and ventilated with 2% isoflurane / TShO / C. The body temperature is maintained at 37-38 ° C by a heat mat. As a painkiller Temgesic ^{® is} given. The thorax is opened laterally between the third and fourth ribs and the heart is exposed. The coronary artery of the left ventricle (LAD) is punctured with a occlusal thread just below its origin (below the left atrium) and permanently ligated. The thorax is closed again and the muscle layers and the epidermis sewn up. The animals are treated with the test substance from the day of the operation or up to one week later for a period of 4-8 weeks (by gavage, by addition of the test substance in the feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by Inhalation). As a further control, a "sham" group is included, in which only the surgical procedure, but not the LAD occlusion was performed.

At the end of the experiment, the animals are anaesthetized again [1.5% isoflurane (mouse), 2% isoflurane (rat) / N20 / air], and a pressure catheter is introduced into the left ventricle via the carotid artery. There are heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) with the help of the Powerlab system (AD Instruments, ADI-PWLB-4SP) and the Chart5 software (SN 425-0586) was recorded and evaluated. Subsequently, a blood sample is used to determine the substance-plasma removed mirror and plasma biopark and killed the animals. Heart (ventricles, left ventricle plus septum, right ventricle), liver, lung and kidney are removed and weighed.

B-tenth Animal Model of Tumor Growth Syngenic tumor models in immunocompetent mice or xenogeneic tumor models in immunosuppressed mice are used for substance evaluation. For this purpose, tumor cells are cultured in vitro and implanted subcutaneously or orthotopically. The animals are treated by oral, subcutaneous, intraperitoneal or intravenous therapy after the establishment of the tumor or starting with the day of the tumor inoculation. The efficacy of test substances is analyzed in monotherapy and in combination therapy with other pharmacologically active substances. During the experiment, the state of health of the animals is checked daily and the treatments are carried out according to animal welfare regulations. The tumor area is measured with calipers (length L, width B = smaller extent). The tumor volume is calculated according to the formula (L x B ² ) / 2. The inhibition of tumor growth is determined at the end of the experiment as T / C ratio of tumor areas or tumor weights and as TGI value (tumor growth inhibition, calculated according to the formula [1- (T / C)] × 100) (T = Tumor size of the treated group; C = tumor size of the untreated control group).

B-l l. Animal model of the formation of metastases in the lung

Syngeneic tumor models in immunocompetent mice or xenogeneic tumor models in immunosuppressed mice are used for substance evaluation. For this purpose, tumor cells are cultured in vitro and injected intravenously into the tail vein of the test animals. The animals are treated by oral, subcutaneous, intraperitoneal or intravenous therapy. The efficacy of test substances is analyzed in monotherapy and in combination therapy with other pharmacologically active substances. During the experiment, the state of health of the animals is checked daily and the treatments are carried out according to animal welfare regulations. After completion of the experiment, the lungs of the experimental animals are examined microscopically with regard to the number of tumor colonies formed. C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

 The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

 The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv Solution: The compound of the present invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims 1. Compound of formula (I)

in which the ring A is an aza-heterocycle of the formula stands,

where * denotes the link to the adjacent CEb group and XO or N (R ² ) means in which R ^{2 represents} cyano, methoxycarbonyl or ethoxycarbonyl, and R ^{1 is} hydrogen, cyano, cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, tetrahydrofuran-2-yl or a group of the formula -CH 2 -R ^1A where R ^{1A is} hydrogen, methyl, fluoromethyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy, and their solvates. 2. A compound of the formula (I) according to claim 1, in which the ring A is an aza-heterocycle of the formula stands,

in which * the linkage to the adjacent CH ₂ group is marked and XO or N (R ² ) means in which R ^{2 is} cyano or methoxycarbonyl, and R ^{1 is} cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, tetrahydrofuran-2-yl or a group of the formula -CH 2 -R ^1A where R ^{1A is} trifluoromethyl, ethyl, methoxy or trifluoromethoxy, and their solvates. 3. A compound according to claim 1 or 2 selected from the group consisting of compounds 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione,  [1- ({5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide,  Methyl [1 - ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene] 6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione,  5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -methyl] -1 - ( 3, 3, 3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione, [1 - ({1- (2-Methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl} methyl) cyanamide imidazolidin-2-ylidene]  Methyl [1- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene] 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) -methyl] -1 - (3, 3, 3 - trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione,  1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-2,3-dihydro-1H-imidazol-1-yl) methyl] thieno [2 , 3-d] pyrimidine-2,4 -dione (lH, 3H)  5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione,  1-Butyl-5-methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione,  l - [(2,2-Difluorocyclopropyl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxo-imidazolidin-1-yl) methyl] thieno [2,3- d] pyrimidine-2,4 (lH, 3H) -dione  and  1- (cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dion and their solvates. 4. A compound according to claim 1, 2 or 3 selected from the group consisting of compounds 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d] pyrimidine-2,4 (lH, 3H) -dione,  [1- ({5-Methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1- (3,3,3-trifluoropropyl) -l, 2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-6-yl} methyl) imidazolidine-2-ylidene] cyanamide,  Methyl [1 - ({5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo-1 - (3, 3, 3-trifluoropropyl) -1,3,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene] 6- [(2,3-dioxopiperazin-1-yl) methyl] -5-methyl-3 - [(1-methylcyclopropyl) methyl] -1- (3,3,3-trifluoropropyl) thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione, Methyl [1- ({1- (2-methoxyethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -2,4-dioxo, 2,3,4-tetrahydrothieno [2,3- d] pyrimidin-6-yl} methyl) carbamate imidazolidin-2-ylidene] 5-Methyl-3 - [(1-methylcyclopropyl) methyl] -6- [(2-oxoimidazolidin-1-yl) methyl] -1- [2- (trifluoromethoxy) ethyl] thieno [2,3-d ] pyrimidine-2,4 (lH, 3H) -dione  and  1- (cyclobutylmethyl) -5-methyl-3 - [(1-methylcyclopropyl) methyl] -6 - [(2-oxoimidazolidin-1-yl) methyl] thieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dion and their solvates. 5. A compound as defined in any one of claims 1 to 4 for the treatment and / or prevention of diseases. 6. A compound as defined in any one of claims 1 to 4 for use in a method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary Hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anemia and cancer. 7. Use of a compound as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, Myocardial infarction, congestive heart failure, sickle cell anemia and cancer. 8. A medicament containing a compound as defined in any one of claims 1 to 4, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients. 9. A medicament comprising a compound as defined in any one of claims 1 to 4, in combination with one or more further active compounds selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP Receptor agonists, endothelin antagonists, antifibrotic agents, anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, and signal transduction cascade inhibiting compounds. 10. Medicament according to claim 8 or 9 for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, Heart failure, sickle cell anemia and cancer. 11. A method for the treatment and / or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure, sickle cell anemia and cancers in humans and animals by administering an effective amount of at least one A compound as defined in any of claims 1 to 4 or a pharmaceutical composition as defined in any one of claims 8 to 10.