WO2017207340A1 - Nouveaux benzimidazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments - Google Patents
Nouveaux benzimidazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments Download PDFInfo
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- WO2017207340A1 WO2017207340A1 PCT/EP2017/062367 EP2017062367W WO2017207340A1 WO 2017207340 A1 WO2017207340 A1 WO 2017207340A1 EP 2017062367 W EP2017062367 W EP 2017062367W WO 2017207340 A1 WO2017207340 A1 WO 2017207340A1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- Novel substituted benzimidazoles processes for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
- the present application relates to novel substituted benzimidazoles, the use of the novel substituted benzimidazoles for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular proliferative diseases, autoimmune diseases, metabolic and inflammatory diseases such as Rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis and ankylosing spondylitis), chronic obstructive pulmonary disease (abbreviation: COPD), multiple sclerosis, systemic lupus erythematosus, gout, metabolic syndrome, fatty liver hepatitis, insulin resistance, renal disease, endometriosis, and inflammation-degenerated or chronic pain as well as lymphoma.
- proliferative diseases such as Rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis
- the present invention relates to novel substituted benzimidazoles of general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4).
- IRAK4 interleukin-1 receptor-associated kinase 4
- IRAK4 interleukin-1 receptor-associated kinase 4
- TLR Toll-like receptors
- IL interleukin
- IRAK4 knockout mice nor human cells from patients lacking IRAK4 respond to the stimulation of TLRs (except TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002, Davidson, Currie, et al , The Journal of Immunology, 2006; Ku, Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
- MyD88 interacts with IRAK4 to form an active complex which interacts with and activates the IRAK1 or IRAK2 kinases (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004, Precious et al. Biol. Chem., 2009).
- NF nuclear factor
- MAPK mitogen-activated protein kinase
- inflammatory signaling molecules and enzymes such as cytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammation-associated genes such as COX-2, IL-6 (interleukin-6), IL-8 (Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001, Datta, Novotny, et al., The Journal of Immunology, 2004).
- these processes may be associated with the proliferation and differentiation of certain cell types such as monocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi, et al., Nat Immunol, 2006, McGettrick and J. OTS Supplementl, British Journal of Haematology, 2007).
- IRAK4 KDKI The central role of IRAK4 in the pathology of various inflammatory diseases has already been demonstrated by the direct comparison of wild-type (WT) mice with genetically modified animals with a kinase-inactive form of IRAK4 (IRAK4 KDKI).
- IRAK4 KDKI animals have an improved disease pattern in the animal model of multiple sclerosis, atherosclerosis, myocardial infarction and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008, Maekawa, Mizue, et al., Circulation, 2009; Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012).
- IRAK4 has been shown that deletion of IRAK4 in the animal model protects against viral-induced myocarditis as a result of an improved anti-viral response with concomitantly reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013).
- expression of IRAK4 has been shown to correlate with the extent of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
- IRAK4 immune-complex-mediated IFNa (interferonpha) production by plasmacytoid dendritic cells, a key process in the pathogenesis of systemic lupus erythematosus (SLE), has been demonstrated (Chiang et al., The Journal of Immunology, 2010).
- the signaling pathway is associated with obesity (Ahmad, R., P. Shihab, et al., Diabetology & Metabolism Syndrome, 2015).
- IRAK4 affects the differentiation of the so-called Th17 T cells, components of adaptive immunity.
- Th17 T cells fewer IL-17 producing T cells (Th17 T cells) are generated compared to WT mice.
- IRAK4 By the inhibition of IRAK4 is the prophylaxis and / or treatment of atherosclerosis, diabetes mellitus type 1, rheumatoid arthritis, spondyloarthritis (especially psoriatic psoriasis and ankylosing spondylitis), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, inflammatory bowel disease and viral diseases such HIV (human immunodeficiency virus), hepatitis virus possible (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal of Inflammation, Vol.
- IRAK4 Due to the central role of IRAK4 in the MyD88-mediated signaling cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be used for the prophylaxis and / or treatment of disorders mediated by said receptors.
- TLRs as well as components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis such as Behcet's disease, granulomatosis with polyangiitis and giant cell arteritis, pancreatitis, systemic lupus erythematosus, dermatomitis and polymyositis Including metabolic syndrome including, for example, insulin resistance, hypertension, dyslipoproteinemia and obesity, diabetes mellitus (type 1 and type 2), diabetic nephropathy, osteoarthritis, Sjogren's syndrome, and sepsis (Yang, Tuzun, et al., J Immunol Candia, Marquez et al., The Journal of Rheumatology, 2007; Scanzello, Plaas, et al Curr Opin Rheumatol, 2008; Deng, Ma-Krupa, et al.
- Diabetes Complications 2014; Kaplan, Yazgan, et al., Scand J Gastroenterol, 2014; Talabot-Aye, et al., Cytokines, 2014; Zong, Dorph, et al., Ann Rheum Di, 2014; Ballak, Stienstra, et al., Cytokines, 2015; Timper, Seelig, et al., J. Diabetes Complications, 2015).
- Skin diseases such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway and the IL-1R family, respectively (Schmidt, Mittnacht, et al.
- pulmonary diseases such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension show an association with various TLR-mediated signaling pathways.
- COPD obstructive pulmonary disease
- ARDS acute respiratory distress syndrome
- ALI acute lung injury
- ILD interstitial lung disease
- sarcoidosis pulmonary hypertension
- the pathogenesis of pulmonary diseases can be both infectiously mediated and non-infectious mediated processes (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004, Jeyaseelan, Chu, et al., Infection and Immunity , Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al ., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research
- TLRs as well as IL-1R family members are also involved in the pathogenesis of other inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
- inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
- TLR- and IL-1R family-mediated gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, especially endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia
- IRAK4 inhibitors Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima, et al., Journal of Obstetrics and Gynecology Research, 2013; Santulli, Borghes
- IRAK4 inhibitors may also positively affect atherosclerosis (Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sei, 2013).
- IRAK4-mediated TLR processes in the pathogenesis of eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis are described (Kaamiranta and Salminen, J Mol Med (Berl), 2009, Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012; Guo Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012, Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).
- Inhibition of IRAK4 is also a suitable therapeutic approach for fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Biochim Biophys Acta., 2015).
- fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Bio
- IRAK4 has in TLR and IL-1R family-mediated diseases can be chronic liver diseases such as fatty liver hepatitis and especially non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic fatty liver disease (NASH) steatohepatitis), alcoholic hepatitis (ASH - alcoholic steatohepatitis) can be preventively and / or therapeutically treated with IRAK4 inhibitors (Nozaki, Saibara, et al., Alcohol Clin Exp Res, 2004, Csak, T., A. Velayudham, et al.
- NASH non-alcoholic fatty liver disease
- IRAK4 inhibitors are also useful in the treatment of renal dysfunction and kidney disease, such as chronic kidney disease (CKD), chronic renal failure, glomerular disease, diabetic nephropathy, lupus nephritis, IgA nephritis (Berger's disease), nephrosclerosis.
- CKD chronic kidney disease
- chronic renal failure glomerular disease
- diabetic nephropathy lupus nephritis
- IgA nephritis (Berger's disease)
- nephrosclerosis nephrosclerosis
- the inhibition of IRAK4 also includes the treatment / and / or prevention of cardiovascular and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension, hypertension (Oyama, Blais, et al., Circulation Timmers, Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med Sei Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sei (Lond), Christina and Frangogiannis, European Journal of Clinical Investigation, 2013, Thompson and Webb, Clin Sei (London), 2013; Hernanz, Martinez-Revelles, et al., British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015 Bomfim, Echem, et al., Life Sciences, 2015) as well as Alzheimer's, stroke, stroke, craniocerebral
- TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 Due to the involvement of TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 in itching and pain, including acute, chronic, inflammatory and neuropathic pain, a therapeutic effect in the indicated indications due to the inhibition of IRAK4 can be assumed.
- pain examples include hyperalgesia, allodynia, premenstrual pain, endometriosis-associated pain, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain
- CRPS complex regional pain syndrome
- trigeminal neuralgia prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain
- Wilf Livshits, et al., Brain, Behavior, and Immunity, 2008
- Kim Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al., Annais of the New York Academy of Sciences, 2012; Guerrero, Cunha
- lymphomas such as ABC-DLBCL (activated B cell diffuse large B-cell lymphoma), mantle cell lymphoma and Waldenström's disease as well as chronic lymphocytic leukemia, melanoma, pancreatic tumors and hepatocellular carcinoma are characterized by mutations in MyD88 or changes in MyD88 activity , which can be treated by an IRAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Ochi, Nguyen, et al., J Exp Med, 2012; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; (Liang, Chen, et al., Clinical Cancer Research, 2013).
- ABC-DLBCL activated B cell diffuse large B-cell lymphoma
- MyD88 plays an important role in Ras-dependent tumors, so that IRAK4 inhibitors are also suitable for their treatment (Kfoury, A., KL Corf, et al., Journal of the National Cancer Institute, 2013 It is also of therapeutic benefit in breast cancer, ovaria carcinoma, colorectal carcinoma, head and neck carcinoma, lung cancer, prostate cancer due to the inhibition of IRAK4, as the indicated indications are associated with the signaling pathway (Szczepanski, Czystowska, et al., Cancer Res, 2009; Zhang, He, et al., Mol Biol Rep, 2009; Wang, Qian, et al., Br J Cancer Kim, 2010; Jo, et al., World J Surg Oncol, 2012; Zhao, Zhang, et al .; Front Immunol, 2014; Chen, Zhao, et al., Int J Clin Exp Pathol, 2015).
- Inflammatory diseases such as CAPS (cryopyrin-associated periodic syndromes), including FCAS (familial cold urticaria), MWS (Mückle-Wells syndrome), NOMID (neonatal-onset multisystem mflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular) syndrome; FMF (Familial Mediterranean Fever), HIDS (Hyper-IgD Syndrome), TRAPS (Tumor Necrosis Factor Receptor 1 -associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Hepet's Disease, Rheumatoid Arthritis, Osteoarthritis, Keratoconjunctivitis sicca, PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne), Schnitzler syndrome and Sjögren syndrome are treated by blocking the IL-1 signaling pathway, so here too an IRAK4 inhibitor is suitable for the treatment of these diseases (
- the ligand of IL-33R, IL-33 is particularly involved in the pathogenesis of acute renal failure, so inhibition of IRAK4 for prophylaxis and / or treatment is a suitable therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011).
- Components of the IL-1 receptor family are associated with myocardial infarction, various pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), thus providing a prophylactic and / or therapeutic action in said indications by the inhibition of IRAK4 is expected
- pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS)
- ARDS acute respiratory distress syndrome
- IRAK4 inhibitors are known from the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 177-133).
- WO2015091426 describes indazoles, such as example WO2015091426-64, which are substituted at position 2 with a carboxamide side chain and inhibit IRAK-4. However, benzimidazoles are not described.
- WO13042137 describes benzimidazoles as IRAK4 inhibitors which are substituted at position 2 with morpholine, wherein the morpholine is linked via the ring nitrogen with the benzimidazole. Furthermore, the benzimidazoles are not substituted at position 1. The benzimidazoles may be substituted at position 5 with a hydroxyalkyl, with 2-hydroxypropan-2-yl not being disclosed explicitly in WO 13042137.
- WO 13042137-48 (6'-amino-N- (2-morpholino-1H-benzo [d] imidazol-6-yl) - [2,3'-bipyridines] -6-carboxamides) becomes explicit as the sole benzimidazole derivative disclosed.
- WO2006030031 describes, inter alia, benzimidazoles as positive allosteric modulators of mGluR2, which may be substituted at position 1 by C 1 -C 6 -alkyl. However, substitution with methyl is not explicitly disclosed. Also, no benzimidazoles are explicitly disclosed.
- WO2004072069 describes benzimidazole carboxamides as vanilloid receptor (VRI) antagionists for the treatment of pain, which may be substituted at the carboxamide group with substituted heteroaryl. Possible heteroaryls are pyridyl, preferably 3-pyridyl, isothiazolyl, thiazolyl, oxazolyl or pyrazolyl.
- WO2004072069-1 1 N- (1H-benzimidazol-6-yl) -6- (4-fluorophenyl) -2-methyl-nicotinamide
- WO2004072069-12 6- (4-fluorophenyl) 2-methyl-N- (1-methyl-1H-benzimidazol-6-yl) nicotinamide
- WO9422839 describes benzimidazoles as antagonists of the dopamine D4 receptor, which may be substituted at position 5 with a hydrocarbon.
- Hydrocarbons are linear, branched or cyclic groups which can contain up to 18 carbon atoms, such as, for example, C 1 -C 6 -alkyl. However, no benzimidazoles substituted at position 5 with hydroxyalkyl are disclosed.
- WO200157020 describes benzimidazoles as inhibitors of factor Xa.
- the benzimidazoles may be substituted at position 2 with:
- R 10 may be H or C 1 -Cg -alkyl.
- WO 2010042785 describes the use of benzimidazoles for negative chemotaxis.
- the benzimidazoles described may be substitiert at position 5 with C 1 -C 1 o alkyl, but is C 1 - C 1 o-alkyl by itself unsubstituted before.
- WO 2013186229 describes TNF-alpha modulating benzimidazoles. However, 1-methyl substituted benzimidazoles are not disclosed.
- WO2007076092 describes benzimidazoles as Raf kinase modulator, which are not substituted at position 5 with hydroxyalkyl.
- the object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (IRAK4).
- IRAK4 Interleukin-1 Receptor Associated Kinase-4
- the present invention relates to compounds of the general formula (I)
- 1 represents a 5 or 6-membered heteroaryl which contains one or 2 identical or different heteroatoms selected from the group O, S and N and is linked via a ring carbon atom,
- a 5-membered heteroaryl may be easily substituted with C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl which may be substituted with halogen
- pyrazolyl may be substituted at N simply by C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl which may be substituted by halogen;
- 6-membered heteroaryl may be mono- or di-identical or different
- Halogen C 1 -C 3 alkoxy, NH 2, C 1 -C 3 alkyl, which may be substituted by halogen, may be substituted
- heterocycloalkyl which is a heteroatom or a
- the new IRAK4 inhibitors are particularly useful in the treatment and prevention of proliferative, metabolic and inflammatory diseases characterized by an overreacting immune system. Especially mentioned here are inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, neurological diseases, pain disorders and cancers.
- the new IRAK4 inhibitors are suitable for treatment and prevention
- liver diseases such as fatty liver as well
- kidney diseases especially chronic renal disease, nephropathies as well
- gynecological diseases in particular endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia.
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
- Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But are also included salts for pharmaceutical Applications themselves are not suitable, but can be used for example for the isolation or purification of the compounds of the invention.
- Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
- Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
- Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammoni
- Solvates in the context of the invention 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.
- the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
- the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
- the present invention encompasses all tautomeric forms.
- the present invention also includes all suitable isotopic variants of the compounds of 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.
- isotopes incorporated in a compound of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 1231, 1241, 1291 and 1311.
- isotopic variants of a compound of the invention such as those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the Investigation of the mechanism of action or the distribution of active ingredients in the body; because of the comparatively easy production and detectability, compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose.
- isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
- 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 the methods known to the person skilled in the art, for example by the methods described below and the instructions given for the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
- Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs may be present either as a single polymorph or as a mixture of several polymorphs in all mixing ratios.
- the present invention also includes prodrugs of the compounds of the invention.
- prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
- alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
- Examples which may be mentioned are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3 Methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl.
- Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having in each case the number of carbon atoms specified. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Heterocycloalkyl in the context of the invention is a saturated heterocycle having a total of 4 to 6 ring atoms, in which one or two ring carbon atoms are represented by identical or different heteroatoms or heteroatom groups from the series N, NH, N (C 1 -C 3 -alkyl), O, S, and / or SO 2 are replaced.
- Examples which may be mentioned are: piperidin-1-yl, pyrrolidin-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, 1,1-dioxotetrahydrothiophen-3-yl, 1-methylazetidin-3-yl, 1-dioxotetrahydro-2H-thiopyran-3-yl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl.
- Heteroaryl is in the context of the invention for a monocyclic, aromatic ring system having 5 or 6 ring atoms, which contains one or two ring heteroatoms and which is bonded via a ring carbon atom.
- the heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
- heteroaryl or heteroaryl moieties include all possible isomeric forms thereof, e.g. Tautomers and positional isomers with respect to the point of attachment to the remainder of the molecule.
- pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
- alkoxy represents a linear or branched alkoxy radical with the number of carbon atoms indicated in each case.
- Examples include methoxy, ethoxy, n-propoxy, and isopropoxy, called.
- Halogen is in the context of the invention for fluorine, chlorine and bromine. Preference is given to fluorine.
- Hydroxy is OH in the context of the invention.
- a symbol * on a bond means the point of attachment in the molecule.
- radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly.
- R 1 is a group selected from
- R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl which may be substituted by halogen,
- R is C 1 -C 3 alkoxy, NH 2 or C 1 -C 3 alkyl which may be substituted by halogen, and
- R 5 is hydrogen or halogen
- R 1 is a group selected from
- R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl which may be substituted by halogen, and
- R 4 is C 1 -C 3 alkoxy, NH 2 or C 1 -C 3 alkyl which may be substituted by halogen, and R 5 is hydrogen or halogen and
- R is C 1 -C 3 -alkyl, which may be substituted by halogen
- R 4 is C 1 -C 3 -alkyl, which may be substituted by halogen
- R 5 is hydrogen
- R 1 is a group selected from 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazole-4 -yl, 4- (trifluoromethyl) -1,3-thiazol-2-yl, 6- (1,1-difluoroethyl) pyridin-2-yl.
- R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl, which may be substituted one to five times by fluorine atoms.
- R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 3 -alkyl, which may be mono- to trisubstituted by fluorine atoms.
- R 3 is cyclopropyl or C 1 -C 3 -alkyl, which may be mono- to trisubstituted by fluorine atoms.
- R 4 is C 1 -C 3 -alkoxy, NH 2 or C 1 -C 3 -alkyl, which may be substituted one to five times by fluorine atoms.
- R 4 is C 1 -C 3 -alkoxy, NH 2 or C 1 -C 3 -alkyl, which may be monosubstituted to trisubstituted by fluorine atoms.
- R 4 is methoxy, NH 2 or C 1 -C 3 -alkyl, which may be mono- to trisubstituted by fluorine atoms.
- R 4 is C 1 -C 3 -alkyl, which may be monosubstituted to trisubstituted by fluorine atoms.
- R 5 is hydrogen or halogen.
- R 5 is hydrogen or fluorine.
- R 5 is hydrogen.
- Another embodiment of A is a bond or C 1 -C 3 alkyl.
- R 2 is a group selected from morpholin-4-yl, 1-methylazetidin-3-yl and 4-methylpiperazin-1-yl.
- Another object of the present invention are compounds of the general formula (I), in which
- R 1 for a group is selected
- R 3 is cyclopropyl or C 1 -C 3 -alkyl, where C 1 -C 3 -alkyl may be mono- to trisubstituted by fluorine atoms,
- R 4 is H, methoxy, NH 2 , C 1 -C 3 -alkyl, which may be substituted one to three times by fluorine atoms,
- R 5 is hydrogen or fluorine
- A is a bond or C 1 -C 3 -alkyl
- Another object of the present invention are compounds of the general formula (I), in which
- R 1 for a group is selected
- R 3 is cyclopropyl or C 1 -C 3 -alkyl, where C 1 -C 3 -alkyl may be mono- to trisubstituted by fluorine atoms,
- R 4 is H, C 1 -C 3 -alkyl which may be monosubstituted to trisubstituted by fluorine atoms,
- R 5 is hydrogen
- A is a bond or C 1 -C 3 -alkyl
- R 2 in the case of the AC 1 -C 3 alkyl is hydrogen, or a 6-membered heterocycloalkyl containing one or two identical or different heteroatoms or heteroatom groups selected from O, N, NH-CH 3 and either via a ring carbon atom or ring nitrogen is linked, stands,
- R 1 is 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 4- (trifluoromethyl) - l, 3-thiazol-2-yl, 6- (l, l -difluoroethyl) pyridin-2-yl;
- A is a bond or C 1 -C 3 -alkyl
- R 2 in the case of the AC 1 -C 3 alkyl, morpholin-4-yl or 4-methylpiperazin-l-yyl or
- R 2 when A is a bond, is 3-hydroxy-3-methylbutyl or 1,1-dioxotetrahydro-2H-thiopyran-3-yl
- Another object of the present invention are compounds of the general formula (I), in which
- R 1 is 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 6- (1,1-difluoroethyl) pyridin-2-yl;
- R 2 is 3-hydroxy-3-methylbutyl or 1,1-dioxotetrahydro-2H-thiopyran-3-yl, and their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
- a further subject of the present invention is the list of the following compounds:
- a further subject of the present invention is in particular the list of the following compounds:
- the compounds of the invention act as inhibitors of IRAK4 kinase, and show a surprising, valuable spectrum of pharmacological activity.
- gynecological diseases inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, autoimmune diseases, pain disorders, metabolic diseases, gout, liver diseases, metabolic syndrome, insulin resistance, kidney diseases and cancers with the IRAK4 inhibitors according to the invention particularly preferred.
- the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular of TLR (except TLR3) and / or IL-1 receptor family-mediated diseases or diseases whose pathology is mediated directly by IRAK4 is.
- IRAK4-associated diseases include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondyloarthritis and arthritis.
- the compounds of the invention may also be used for the prophylaxis and / or treatment of MyD88 and TLR (except TLR3) -mediated diseases.
- This includes multiple sclerosis, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis and ankylosing spondylitis), metabolic syndrome including insulin resistance, diabetes mellitus, osteoarthritis, Sjögren's syndrome, giant cell arteritis, sepsis, poly- and dermatomyositis, skin diseases such as psoriasis, atopic dermatitis, alopecia areata , Acne inversa and Acne vulgaris, pulmonary diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension.
- COPD chronic obstructive
- the compounds of the invention are useful in the prophylaxis and / or treatment of TLR-mediated diseases of Behcet's disease, gout, endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschez. Furthermore, the compounds of the invention are useful for the prophylaxis and / or treatment of graft rejection, lupus erythematosus, Adult Still's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
- the use of the compounds according to the invention is also suitable for the treatment and / or prevention of the following diseases: eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis; Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
- eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis
- Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
- the mechanism of action of the compounds of the invention also enables the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated liver diseases, in particular NAFLD, NASH, ASH, liver fibrosis and cirrhosis.
- the compounds according to the invention are suitable for the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated kidney diseases, in particular chronic kidney disease and nephropathies. Furthermore, the prophylaxis and / or treatment of itching and pain, in particular of acute, chronic, inflammatory and neuropathic pain by the compounds of the invention is given.
- the compounds of the invention are suitable for the prophylaxis and / or treatment of oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors.
- oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors.
- the compounds of the invention are useful for the treatment and / or prevention of diseases mediated via the IL-1 receptor family.
- diseases include CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold urticaria), MWS (Mückle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular ) Syndrome, FMF (Familial Mediterranean Fever), HIDS (Hyper-IgD Syndrome), TRAPS (Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Behcet's Disease, Rheumatoid Arthritis, Psoriatic Arthritis , Ankylosing spondylitis, Osteoarthritis, keratoconjunctivitis sicca and sjögren syndrome, multiple sclerosis, lupus ery
- Pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia and ARDS, gynecological diseases such as endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia, chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are associated with a Dysregulation of the IL-1 receptor family associated and suitable for the therapeutic and / or prophylactic use of the compounds of the invention.
- the compounds according to the invention can furthermore be used for the treatment and / or prevention of IL 1 receptor family-mediated neurological disorders such as stroke, Alzheimer's, stroke, traumatic brain injury and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis ,
- the compounds according to the invention are suitable for the treatment and / or prophylaxis of pain disorders, in particular of acute, chronic, inflammatory and neuropathic pain.
- pain disorders in particular of acute, chronic, inflammatory and neuropathic pain.
- hyperalgesia allodynia
- pain in arthritis such as osteoarthritis, rheumatoid arthritis and spondylarthritis
- premenstrual pain endometriosis-associated pain
- postoperative pain pain in interstitial cystitis
- CRPS complex regional pain syndrome
- trigeminal neuralgia pain in prostatitis, pain caused by spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain.
- the present invention also provides 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 according to the invention.
- treatment includes a
- prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder To develop, to experience, to suffer or to have symptoms of such conditions and / or 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.
- the compounds of the invention may be used alone or as needed in combination with other agents.
- Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
- suitable combination active ingredients may be mentioned by way of example and preferably:
- active substances such as antibacterial (eg penicillins, vancomycin, ciprofloxacin), antiviral (eg acyclovir, oseltamivir) and antifungal (eg naftifine, nystatin) substances and gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporin, methotrexate®, TNF antagonists (eg Humira® Etanercept, infliximab), IL-1 inhibitors (eg anakinra, canakinumab, rilonacept), phosphodiesterase inhibitors (eg apremilast), Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin , Mycophenolate mofetil, interferon
- immunotherapy eg aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab, Lenalidomide, lenograstim, mifamurtide, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermine, teceleukin, tocilizumab), antiproliferative substances such as but not limited to amsacrine, arglabine, arsenic trioxide,
- the following active ingredients rituximab, cyclophosphamide, doxorubicin, doxorubicin in combination with estrone, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 1311-chTNT, abiraterone, aclarubicin, alitretinoin, bisantrene, Calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, crisantaspase, darbepoetinefa, decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitoxanol, epoetine alfa, filgrastim, fotemustine, gallium nitrate, gemcitabine, glutoxime, histamine dihydroch
- non-drug therapy such as chemotherapy (eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin), radiotherapy (eg I-125 seeds, palladium-103 seed, radium-223 chloride) or phototherapy (eg temoporfin, talaporfin), which are accompanied by a drug treatment with the IRAK4 inhibitors according to the invention or which are supplemented after completion of the non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy by a drug treatment with the IRAK4 inhibitors according to the invention.
- chemotherapy eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin
- radiotherapy eg I-125 seeds, palladium-103 seed, radium-223 chloride
- phototherapy eg temoporfin, talaporfin
- IRAK4 inhibitors according to the invention can, in addition to those already mentioned, also be combined with the following active substances:
- Active ingredients for Alzheimer's therapy such as acetylcholinesterase inhibitors (eg donepezil, rivastigmine, galantamine, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists (eg memantine); L-DOPA / carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors (eg entacapone), dopamine agonists (eg, ropinrol, pramipexole, bromocriptine), MAO-B (monoamine oxidase B) inhibitors (eg selegiline), anticholinergics (eg trihexyphenidyl) and NMDA antagonists (eg amantadine) for the treatment of Parkinson's; Beta interferon (IFN-beta) (eg IFN beta-lb, IFN beta-la Avonex® and Betaferon®), glatiramer
- rheumatoid diseases such as rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis methotrexate leflunomide, Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), TNF antagonists (eg Humira®, etanercept, infliximab), IL -1 inhibitors (eg anakinra, canakinumab, rilonacept), and biologists for B-cell and T-cell therapy (eg rituximab, abatacept).
- Jak / STAT inhibitors eg tofacitinib, baricitinib, GLPG0634
- TNF antagonists eg Humira®, etanercept, infliximab
- IL -1 inhibitors eg anakinra, canakinumab, rilonacept
- Neurotrophic substances such as acetylcholinesterase inhibitors (eg donepezil), MAO (Monoamine oxidase) inhibitors (eg selegiline), interferons and anticonvulsants (eg gabapentin); Active substances for the treatment of cardiovascular diseases such as beta-blockers (eg metoprolol), ACE inhibitors (eg benazepril), angiotensin receptor blockers (eg losartan, valsartan), diuretics (eg hydrochlorothiazide), calcium channel blockers (eg nifedipine), statins (eg simvastatin , Fluvastatin); Anti-diabetics such as metformin, glinides (eg nateglinide), DPP-4 (dipeptidyl-peptidase-4) inhibitors (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT
- Lipid lowering agents such as fibrates (eg bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (eg nicotinic acid / laropiprant), ezetimibe, statins (eg simvastatin, fluvastatin), anion exchangers (eg colestyramine, colestipol, colesevelam).
- Agents such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL # 3®, Lactobacillus GG, Lactobacillus plantarem, L.
- Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus.
- NSAIDs non-steroidal anti-inflammatory drugs
- calcineurin inhibitors eg, tacrolimus and ciclosporin
- cell division inhibitors eg, azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus
- rapamycin basiliximab, daclizumab
- anti-CD3 antibodies anti-T lymphocyte globulin / anti-lymphocyte globulin on organ transplantation
- Vitamin D3 analogs such as calcipotriol, tacalcitol or calcitriol
- Salicylic acid urea
- ciclosporin methotrexate
- efalizumab in dermatological diseases.
- Glucocorticoids eg, prednisone
- immunosuppressants such as azathioprines, cyclophosphamide, mycophenolate mofetil; Hydroxychloroquine, ACE inhibitors (eg, captopril, benazepril, enalapril, fosinopril), angiotensin receptor blockers (eg, losartan, valsartan), beta-blockers (eg, metoprolol), calcium channel blockers (eg, nifedipine), and immunosuppressants such as ciclosporin for the treatment of kidney disease , Nephropathies and glomerular diseases.
- ACE inhibitors eg, captopril, benazepril, enalapril, fosinopril
- angiotensin receptor blockers eg, losartan, valsartan
- beta-blockers eg, metoprolol
- calcium channel blockers eg,
- drugs which contain at least one of the compounds according to the invention and one or more further active compounds, in particular EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKRlC 3 inhibitors (aldo-keto reductase family 1 member C 3 inhibitors), for the treatment and / or prevention of the aforementioned diseases.
- EP4 inhibitors prostaglandin E2 receptor 4 inhibitors
- P2X3 inhibitors P2X purinoceptor 3
- PTGES inhibitors prostaglandin E synthase inhibitors
- AKRlC 3 inhibitors aldo-keto reductase family 1 member C 3 inhibitors
- the compounds according to the invention can act systemically and / or locally.
- they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, via the ear or as an implant or stent.
- the compounds according to the invention can be administered in suitable administration forms.
- oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphous 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
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
- a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
- absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
- parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- Inhalation medicines including powder inhalers, nebulizers
- nasal drops solutions or sprays
- lingual, sublingual or buccal tablets films / wafers or capsules
- suppositories ear or ophthalmic preparations
- vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
- Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
- compositions 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.
- excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene).
- glycols glycols
- emulsifiers and dispersing or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
- binders for example polyvinylpyrrolidone
- synthetic and natural polymers for example albumin
- stabilizers for example antioxidants such as ascorbic acid
- dyes for example inorganic pigments such as iron oxides
- Flavor and / or odor remedies for example sodium dodecylsulfate, polyoxysorbitanoleate
- binders for example polyvinylpyrrolidone
- synthetic and natural polymers for example albumin
- stabilizers for example antioxidants such as ascorbic acid
- dyes for example inorganic pigments such as iron oxides
- Flavor and / or odor remedies for example sodium dodecylsulfate, polyoxysorbitanoleate
- binders for example polyvinylpyrrolidone
- synthetic and natural polymers for example albumin
- compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
- parenteral application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results.
- 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.
- R 2 -A-CO 2 H are used in which R 2 has the meaning given under formula (I), which are commercially available or in ways known from the literature or analogous to literature (see, for example, European Journal of Organic Chemistry 2003, 8, 1559-1568, Chemical and Pharmaceutical Bulletin, 1990, 38, 9, 2446-2458, Synthetic Communications 2012, 42, 658-666, Tetrahedron, 2004, 60, 51, 11869-11874) can be.
- Some carboxylic acids R 2 -A- CO2H in which R 2 has the meaning given under the formula (I), can be obtained from saponification or, in the case where it is a tert-butyl ester, by reaction with a carboxylic acid ester Acid such as hydrogen chloride or trifluoroacetic acid (see for example Dalton Transactions, 2014, 43, 19, 7176-7190) are produced.
- the carboxylic acids R 2 -A-C02H can also be used in the form of their alkali metal salts in reactions.
- the preparation of carboxylic acid esters as starting materials for the preparation of the carboxylic acids R 2 -A-CU 2 H may optionally be defined from halogenated building blocks R 2 -AI, R 2 -A-Br or R 2 -A-Cl with R 2 as in formula (I) carried out by reaction in a carbon monoxide atmosphere, optionally under excess pressure in the presence of a phosphine ligand such as, for example, l, 3-bis (diphenylphosphino) propane, a palladium compound such as palladium (II) acetate and a base such as triethylamine with the addition of ethanol or methanol in a solvent such as dimethylsulfoxide (for preparation methods cf., for example, WO2012112743, WO2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948-1949, WO200661715).
- a phosphine ligand such as, for example, l, 3-bis (
- the starting materials R 2 -AI, R 2 -A-Br or R 2 -A-Cl are either commercially available or can be prepared by literature routes. Exemplary methods of preparation are described in WO2012061926, European Journal of Organ ic Chemistry, 2002, 2, 327-330, Synthesis, 2004, 10, 1619-1624, Journal of the American Chemical Society, 2013, 135, 32, 12122-12134, Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039-4043, US2007185058, WO2001 1742 1.
- the compounds 1.1 can react with suitable carboxylic acids R 2 -A-C02H, wherein R 2 has the meaning given in the claim and R 2 may additionally be substituted with a carboxylic acid ester can be prepared.
- suitable carboxylic acids R 2 -A-C02H wherein R 2 has the meaning given in the claim and R 2 may additionally be substituted with a carboxylic acid ester can be prepared.
- Various coupling reagents known in the literature can be used for this purpose (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol.3-Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12 - Peptide-Coupling Reagents, 407). 442; Chem. Soc. Rev., 2009, 38, 606).
- 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride may be used in combination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475, Bioorg. Med. Chem.
- the coupling reagents are HATU, N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide (EDC, CAS-RN 1892-57-5) in combination with 1H-benzotriazole 1-ol hydrate (1: 1) (HOBt , CAS-RN 123333-53-9) and TBTU.
- Preferred as the base is the use of triethylamine or N-ethyl-N-isopropylpropan-2-amine.
- Preferred solvents are THF or DMF.
- the compounds 1.2 can be prepared from compounds 1.1 by treatment with acids, optionally with heating. This reaction can be carried out by treating compounds 1.1, optionally in an inert solvent, with suitable acids at room temperature or at 40 ° C-200 ° C. Suitable acids are, for example, acetic acid, trifluoroacetic acid or hydrochloric acid. The acid can also be used as a solvent.
- the compounds 1.2 can be prepared directly from methyl 3-amino-4- (methylamino) benzoate by reaction with carboxylic acids under acidic dehydrating conditions (eg with Propanephosphonic anhydride) or by reaction of carboxylic acid chlorides in an inert solvent at room temperature or at 40 ° C-200 ° C.
- carboxylic acids under acidic dehydrating conditions (eg with Propanephosphonic anhydride) or by reaction of carboxylic acid chlorides in an inert solvent at room temperature or at 40 ° C-200 ° C.
- the compounds 1.3 can be obtained by nitration of the compounds 1.2.
- the nitration methods known to those skilled in the art such as the use of nitric acid in combination with concentrated sulfuric acid or the use of concentrated sulfuric acid and potassium nitrate are suitable.
- compounds 1.4 can be prepared.
- the nitro group can be reduced with palladium on carbon under a hydrogen atmosphere (WO2007 / 48070), by the use of iron and ammonium chloride in water and ethanol (US2003 / 236260) or tin (II) chloride (WO2008 / 128009).
- the compounds "intermediate" can be prepared from the compounds 1.4, in analogous manner as described for the preparation of the compounds 1.1, with suitable carboxylic acids of the formula R'-COOH, wherein R 1 has the meaning set forth in claim 1, take place.
- the compounds of the general formula (I) can be prepared by Grignard reaction with, for example, methylmagnesium bromide from the intermediates.
- the reaction may be carried out in a suitable solvent such as. Diethyl ether or tetrahydrofuran in the temperature range from - 30 ° C to 50 ° C, but preferably at room temperature.
- radical R 2 contains a carboxylic acid ester, such as, for example, carboxylic acid methyl ester or carboxylic acid ethyl ester, this is converted into a propan-2-ol group under the conditions of the reaction of the intermediates described above to give the compounds of the general formula (I).
- a carboxylic acid ester such as, for example, carboxylic acid methyl ester or carboxylic acid ethyl ester
- protective groups are required in the synthesis of the compounds according to the invention within the scope of the individual synthesis steps, these can be introduced and removed by the methods known to the person skilled in the art (compare PGM Wuts, TW Greene, Greene's Protective for the introduction and removal of suitable protective groups) Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541). Synthesis of Exemplified Compounds Abbreviations and Explanations
- saturated saline means a saturated aqueous solution of sodium chloride
- the 1H NMR data of selected compounds are noted in terms of 1H NMR peaks.
- the ⁇ value in ppm and then the signal intensity in round brackets are listed for each signal peak.
- the ⁇ value signal intensity number pairs of different signal peaks are listed separated by commas; the peak list for a connection therefore has the form: ⁇ (intensity 1), 82 (intensity 2), ..., ⁇ (intensity i), ..., ⁇ (intensity n).
- the intensity of sharp signals correlates with the height of the signals in cm in a printed example of an NMR spectrum and shows the true ratios of signal intensities compared to other signals. For wide signals, multiple peaks or the center of the signal as well as their relative intensity may be listed compared to the most intense signal in the spectrum.
- the lists of 1H NMR peaks are similar to the classical 1H NMR prints and thus usually contain all the peaks listed in a classical NMR interpretation. In addition, like classical 1H NMR prints, they may have solvent signals, stereoisomer signals of the subject target compound, peaks of impurities, 13C satellite peaks, and / or rotational side bands.
- the peaks of stereoisomers of the target compound and / or peaks of impurities usually have on average a lower intensity than the peaks of the target compound (for example with a purity of> 90%). Such stereoisomers and / or impurities may be typical of the particular preparation process. Their peaks can thus help to detect a reproduction of the manufacturing process from "by-product fingerprints".
- An expert calculating the peaks of a target compound by known methods can isolate the peaks of the target compound as needed, using additional intensity filters if necessary. This isolation would be similar to peak picking in classical 1H NMR interpretation.
- the MinimumHeight parameter can be set between 1% and 4%. Depending on the type of chemical structure and / or depending on the concentration of the compound to be measured, however, it may also be expedient to set the parameter "MinimumHeight" to ⁇ 1%.
- Methyl 2- (3-methoxy-3-oxopropyl) -1-methyl-6 - ( ⁇ [6- (trifluoromethyl) pyridin-2-yl] carbonyl ⁇ amino) -1H-benzimidazole-5-carboxylate 0.5 g (1.7 mmol) of methyl 6-amino-2- (3-methoxy-3-oxopropyl) -1-methyl-1H-benzimidazole-5-carboxylate and 492 mg (2.5 mmol) of 6- (trifluoromethyl) pyridine-2-carboxylic acid (CAS -RN 131747-42-7) were reacted with 979 mg (2.5 mmol) of HATU in the presence of 359 ⁇ L ⁇ (2.5 mmol) of triethylamine in 4.6 mL of DMF at RT for 1.5 h.
- intermediate 1-1 step 4 The following intermediates were prepared from methyl 6-amino-2- (3-methoxy-3-oxopropyl) -1-methyl-1H-benzimidazole-5-carboxylate (intermediate 1-1 step 4) and the corresponding carboxylic acids (column 1). prepared in analogy to the synthesis of intermediate 1-1 stage 5.
- Methyl 6- ( ⁇ [6- (1,1-difluoroethyl) pyridine-1H), 9.06 (s, 1H), 13.45 (s, 1H).
- Methyl 2- (2-methoxyethyl) -1-methyl-1H-benzimidazole-5-carboxylate Prepared in analogy to stage 2 of intermediate 1 -1 from methyl 3 - [(3-methoxypropanoyl) amino] -4- (methylamino ) benzoate.
- Methyl 2- (2-methoxyethyl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylate Prepared in analogy to stage 3 of intermediate 1 -1 from methyl 2- (2-methoxyethyl) -1-methyl -lH-benzimidazole-5-carboxylate.
- Methyl 2- (3-methoxypropyl) -l-methyl-6-nitro-1H-benzimidazole-5-carboxylate Prepared in analogy to Step 3 of intermediate 1-1 from methyl 2- (3-methoxypropyl) -l-methyl - lH-benzimidazole-5-carboxylate.
- Methyl 6-amino-2- (3-methoxypropyl) -l-methyl-1H-benzimidazole-5-carboxylate Prepared in analogy to Step 4 of Intermediate 1-1 from methyl 2- (3-methoxypropyl) -1-methyl 6-nitro-1H-benzimidazole-5-carboxylate.
- Methyl benzimidazole-5-carboxylate (intermediate) was dissolved in THF and cooled to 0-5 ° C. Then 6 equivalents of methylmagnesium bromide solution (commercially available solution in 2-methyltetrahydrofuran, THF or diethyl ether) were added dropwise, the temperature of the
Abstract
La présente invention concerne de nouveaux benzimidazoles substitués, leur procédé de préparation, leur utilisation seuls ou en associations pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie de l'endométriose, ainsi que des douleurs associées à l'endométriose et d'autres symptômes associés à l'endométriose tels que la dysménorrhée, la dyspareunie, la dysurie et la dyschésie, de lymphomes, de la polyarthrite rhumatoïde, des spondylarthrites (en particulier de la spondylarthrite psoriasique et de la spondylarthrite ankylosante), du lupus érythémateux, de la sclérose en plaques, de la dégénérescence maculaire, de la BPCO, de la goutte, des maladies de la stéatose du foie, de l'insulino-résistance, des néphropathies, des maladies tumorales et du psoriasis.
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EP16172162.6 | 2016-05-31 | ||
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PCT/EP2017/062367 WO2017207340A1 (fr) | 2016-05-31 | 2017-05-23 | Nouveaux benzimidazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments |
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AR (1) | AR108642A1 (fr) |
TW (1) | TW201803866A (fr) |
UY (1) | UY37267A (fr) |
WO (1) | WO2017207340A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022156788A1 (fr) * | 2021-01-22 | 2022-07-28 | 武汉人福创新药物研发中心有限公司 | Composé de benzimidazole et son utilisation |
WO2022267673A1 (fr) | 2021-06-21 | 2022-12-29 | 上海勋和医药科技有限公司 | Indazole substitué par sulfoximide inhibiteur de la kinase irak4, son procédé de préparation et son utilisation |
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