WO2006010568A2 - Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, and use thereof as inhibitors of tnf-alpha release - Google Patents

Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, and use thereof as inhibitors of tnf-alpha release Download PDF

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WO2006010568A2
WO2006010568A2 PCT/EP2005/008031 EP2005008031W WO2006010568A2 WO 2006010568 A2 WO2006010568 A2 WO 2006010568A2 EP 2005008031 W EP2005008031 W EP 2005008031W WO 2006010568 A2 WO2006010568 A2 WO 2006010568A2
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alkyl
phenyl
substituted
optionally substituted
optionally
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PCT/EP2005/008031
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German (de)
French (fr)
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WO2006010568A3 (en
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Claudia Reichelt
Alexander Ludwig
Alexander Schulze
Mohammed Daghish
Siegfried Leistner
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Curacyte Discovery Gmbh
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Priority claimed from EP04017543A external-priority patent/EP1619197A1/en
Priority claimed from DE102005013622A external-priority patent/DE102005013622A1/en
Application filed by Curacyte Discovery Gmbh filed Critical Curacyte Discovery Gmbh
Publication of WO2006010568A2 publication Critical patent/WO2006010568A2/en
Publication of WO2006010568A3 publication Critical patent/WO2006010568A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to heterocycles which are as bislactams of the general formula 1a or monolactams of the general formula 1b of the hitherto little known tricyclic pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidine system and of thieno [2,3-d: 4,5-d '] dipyrimidine system are to be regarded.
  • the invention further relates to the suitability of corresponding compounds as TNF ⁇ release inhibitors.
  • the invention accordingly provides the compounds themselves, processes for their preparation, pharmaceutical preparations containing these compounds and / or their tautomers, pharmacologically conventional prodrug formulations and physiologically tolerable salts obtainable therefrom and / or their solvates, and the pharmaceutical use of these compounds their tautomers, salts or solvates, including prodrug formulations as inhibitors of TNF ⁇ release.
  • Prodrug formulations herein include all those substances which are formed by simple transformation including hydrolysis, oxidation, or reduction, either enzymatically, metabolically, or otherwise. In particular, if such a prodrug of this compounds of the invention has been applied to a patient, and this prodrug is transformed into a substance of the general formulas Ia and Ib, whereby the desired pharmacological effect is achieved.
  • the cytokine tumor necrosis factor is one of 17 known members of a structurally very similar protein family. It owes its name to the ability to trigger necrosis of transplanted tumor cells in the mouse model. In addition to its apoptosis-inducing effect was very quickly recognized that TNF ⁇ is also very significantly involved in the regulation of the inflammatory response and the immune response. Overproduction of TNF ⁇ or activation of the TNF ⁇ -mediated signaling cascades play a role in the pathogenesis of a variety of diseases, e.g. Sepsis, cerebral form of malaria, neurodegenerative diseases such as Mb. Alzheimer's disease, Mb.
  • Parkinson's disease in diabetes mellitus, COPD / asthma, tumors and in particular tumors of the hemopoietic system such.
  • Leukemias and lymphomas such as e.g. Acquired Immune Deficiency Syndrome (AIDS), Guillain-Barre Syndrome, Allergic Rhinitis, Allergic Conjunctivitis, Systemic Scleroderma, Graft versus Host Disease (GvHD), Systemic Lupus Erythematosus (SLE), Osteoporosis, Toxic Shock Syndrome, Acute Glomerulonephritis, Acute and Chronic Pain, Atherosclerosis, myocardial infarction, stroke, sarcoidosis, multiple sclerosis, rheumatoid arthritis (RA), osteoarthritis, ulcerative colitis, vasculitis, uveitis, Mb.
  • AIDS Acquired Immune Deficiency Syndrome
  • GvHD Graft versus Host Disease
  • SLE Systemic Lupus
  • TNF ⁇ is one of the most important proinflammatory cytokines, which is essential in the pathogenesis of almost all chronic inflammatory diseases is involved.
  • TNF ⁇ which has also been described as chachectin, macrophage cytotoxin (MCT), tumor necrosis factor- ⁇ and macrophage cytotoxic factor (MCF), is stimulated by various cells after stimulation with lipopolysaccharide (LPS), interferons (IFNs), IL- 2, bradykinin, GM-CSF, antigen-antibody complexes, substance P, and numerous other biologically active compounds.
  • TNF ⁇ is formed under physiological conditions mainly by activated macrophages, T lymphocytes, microglial cells and NL cells. Stimulated and thus activated fibroblasts, smooth muscle cells, astrocytes, keratinocytes, endothelial cells and lung epithelial cells also secrete TNF ⁇ .
  • Human TNF ⁇ is a 17 kDa protein that consists of 157 amino acids and associates with dimers and trimers. There is another molecular variant of this molecule with a molecular mass of 26 kDa, which is anchored as a transmembrane protein in the cell membrane. It is now known that the higher-molecular-weight transmembrane form is first synthesized into the cell membrane and, if necessary, its extracellular domain is cleaved off by the TNF ⁇ -converting enzyme (TACE). The soluble TNF ⁇ circulates as a homotrimer and binds to its specific receptors on cell surfaces.
  • TACE TNF ⁇ -converting enzyme
  • TNF ⁇ TNF ⁇ to its receptors (TNFR1, TNFR2) causes in these a conformational change and dimerization or clustering, which mediate the biological effect of TNF ⁇ via a signal cascade.
  • TNFR1 TNFR1 receptors
  • Numerous studies have shown that the binding of TNF ⁇ to TNFR1 produces the most biological effects. This involves the induction of apoptosis via activation of caspase 8 and subsequent activation of caspases 3, 6 and 7, which then lead to apoptosis of the cell.
  • TNF TNF- K B
  • c-Jun TNF- K B
  • NF- K B nuclear factor-kappaB
  • NF- K B regulates, inter alia, the genes for IL-1 ⁇ , IL-1 ⁇ , IL-2, IL-3, IL-6, IL-8, IL-12, TNF ⁇ , LT- ⁇ , IFN- ⁇ / ⁇ , G-CSF, M-CSF, GM-CSF 1 for the cytokine receptor IL-2R ⁇ , for the adhesion molecules ICAM-1, VCAM-1, MAdCAM, E-selectin, for the immunoregulatory molecules light chain of Ig ⁇ , MHC Class I and II , TCR ⁇ and ß, ß 2 microglobulin, TAP1, iNOS and for the acute phase proteins SAA, ⁇ r acid glycoprotein and TSG-14 / PTX3.
  • Activation of p38 is essential for the production of the pro-inflammatory cytokines IL-1 ⁇ , TNF ⁇ and IL-6, and is also responsible for the induction and expression of the chronic inflammation-associated enzymes COX-2 and iNOS (Ono K, Han J (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12 1-13). Further activation pathways also induce the important transcription factors activating transcription factor 2 (ATF2) and activator protein-1 (AP-1), which have a directly stimulating influence on the expression of pro-inflammatory molecules such as E-selectin, RANTES, IL-1. 12, IL-6 and IL-8 (Guicciardi ME, Gores GJ (2003) J Clin Invest, 1813-1815).
  • ATF2 activating transcription factor 2
  • AP-1 activator protein-1
  • TNF ⁇ The biological activity of TNF ⁇ is mediated primarily by two specific receptor types (TNFR1, TNFR2), which are transmembrane and with an extracellular and intracellular portion on a variety of cells of the human body.
  • TNF ⁇ has a very broad spectrum of biological activities and regulates almost all cells. He is from today's point of view an essential mediator in inflammatory and immune reactions, but also in apoptosis, cell differentiation, in the induction of fever and numerous other pathophysiological regulatory processes.
  • TNF ⁇ occupies a central position in endothelial cell activation during the inflammatory process. Activation of the vascular endothelial cells represents a significant step in the initiation phase of inflammatory reactions in the tissue.
  • Pro-inflammatory cytokines with TNF ⁇ at the tip, lead to the expression of endothelial adhesion molecules and chemotactically active chemokines, which in turn cause macrophages and T lymphocytes Possibility to dock at the endothelium and to come via an active migration into the inflammatory tissue (extravasion).
  • extravasion an active migration into the inflammatory tissue
  • TN Fa thus causes a local activation of the vascular endothelium, a release of nitric oxide (NO) with subsequent increase of the vascular permeability, an increased expression of adhesion molecules and an increased expression of "class I!
  • MHC II major histocompatibility molecules
  • TNF ⁇ itself induces the synthesis of other pro-inflammatory cytokines such as 1L-1, IL-6, IL-8 and GM-CSF, leading to a vicious circle of the inflammatory process.
  • TNF ⁇ is still important in other pathophysiological processes such as articular cartilage destruction in rheumatic diseases, bone resorption processes, inhibition of bone formation, inhibition of proteoglycan synthesis, and induction of matrix metalloproteinases (MMPs) and prostaglandin E 2 (Mease P (2002) Psoriatic arthritis: The role of TNF inhibition and the effect of its inhibition with etanercept., Clin Exp Rheumatol 20 (Suppl. 28) S116-S121).
  • MMPs matrix metalloproteinases
  • anti-inflammatory cytokines e.g. IL-10, pentoxifylline, thalidomide or analogues, corticosteroids, cyclosporin A, PDE-4 inhibitors and antisense oligonucleotides.
  • Antisense therapy is still in a very early stage of development and has been able to demonstrate the hoped-for efficacy, at least in the first animal examinations, but here, too, extensive basic research is necessary.
  • TACE metalloproteinase TNF converting enzyme
  • TAGE inhibitors are still in the phase of applied basic research.
  • TSUKIDA et al. 2004 hydroxamic acid derivatives that inhibit TAGE in vitro (Tsukida T, Moriyama H, Inoue Y, Kondo H, Yoshino K, Nishimura S (2004) Synthesis and biological activity of selective azasugar-based TACE inhibitors, Bioorg Med Chem Lett., 22 1569-1572 ).
  • Some matrix metalloproteinase inhibitors also non-specifically inhibit TACE but are not suitable for pharmaceutical development because of their MMP inhibitory activity. WILLIAMS et al.
  • TNF ⁇ inhibitors are intracellular protein kinases that activate transcription factors via phosphorylation and thereby directly interfere with gene expression.
  • IKB intracellular protein kinases that activate transcription factors via phosphorylation and thereby directly interfere with gene expression.
  • IKB protein kinases
  • IKK-1 and IKK-2 protein kinases
  • a partial degradation of IKB occurs which causes the release of NFKB from the complex.
  • the transcription factor NFKB can migrate from the cytosol into the nucleus and directly increase the expression of TNF ⁇ , for example.
  • Remicade ® and Humira TM have approved two monoclonal anti-TNF antibodies by the FDA and also by the EMEA as anti-inflammatory therapeutics.
  • Remicade (Essex / Centrocor) was approved by the FDA in 1998 for the indication Mb. Crohn and in 2000 for the indication Rheumatoid Arthritis. Clinical trials are currently underway for psoriasis vulgaris and psoriatic arthropatica.
  • Remicade is a chimeric monoclonal antibody to human TNF ⁇ . In the clinical studies, the preparation showed good to very good activity in Mb. Crohn.
  • side effects such as increased Infection risk, gastrointestinal discomfort, headache and allergic reactions have been reported. Part of the side effects are attributed to the mouse portion of the monoclonal antibody, which is recognized as "foreign" by the human organism, producing antibodies to it Remicade is administered intravenously and the annual drug cost is over $ 12,000 per patient.
  • Humira (Abbott) has been approved in the US for rheumatoid arthritis since 2002 and in Europe since 2003. Clinical studies on the treatment of psoriasis vulgaris have shown very good therapeutic results. Headache, increased susceptibility to infections, gastrointestinal complaints and allergic reactions have been reported as common side effects. Humira is a fully humanized monoclonal antibody to human TNF ⁇ . The preparation is administered subcutaneously (s.c.). The annual cost of treatment for this product is over $ 12,000 per patient.
  • Enbrel (Immunex / Wyeth) was first approved by the FDA in 1998 for the indication Rheumatoid Arthritis and since 2000, the product is also on the European market. The approval for the indication psoriasis vulgaris and psoriasis arthropatica is expected in 2004 by the FDA.
  • Enbrel is a recombinant (CHO cell) dimeric fusion protein in which two extracellular binding domains of the p75 portion of the TNF receptor are coupled to the Fc portion of the human IgGI molecule, thereby ligating soluble TNF ⁇ in the blood / tissue and thus can neutralize.
  • this fusion protein has a low immunogenic potential, but cases have also been described in which antibody formation against the fusion protein was observed.
  • Common side effects include allergic reactions, susceptibility to infections and the formation of autoantibodies (ANA).
  • ANA autoantibodies
  • the drug is administered subcutaneously and the annual cost of treatment is also over $ 10,000 per patient.
  • the therapeutic concept of inhibiting TNF ⁇ has proven to be a biological endpoint, a viable clinical entity.
  • proteinogenic drugs monoclonal antibodies, fusion proteins
  • their intravenous or subcutaneous administration form is very stressful for patients and is associated with correspondingly poor compliance. The very high production and thus also treatment costs also limit their use.
  • MAAEI-Neairy (Phosphorys, Sulfur and Silicon 1999, 189) has prepared 8-acetyl-7-methyl- ⁇ -p-nitrophenyl-pyridoCS ' ''', ⁇ -thienofS'-dlpyrimidine ⁇ CI H.SHJ-dione and its 9 p-dimethylamino analog and VAArtemov et al.
  • X is CR 2 or nitrogen
  • Ci-i 2 alkyl (optionally substituted with R ⁇ ),
  • benzyl phenyl (C 2 - ⁇ ) alkyl, phenyl (optionally mono- (optionally mono- to pentasubstituted independently of one another by R ⁇ substituted) to five times independently of one another by R ⁇ substituted),
  • Heterocyclylacyl [eg nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyi] (optionally substituted with R ⁇ )
  • CONH 2 , CONHAIk and CONAIk 2 (with "Alk” in each case Ci- 6 ),
  • Ci -6 alkylamino di (Ci -5) alkylamino (in each case optionally substituted with R ⁇ on the alkyl residue),
  • Benzyl, phenyl (C 2 - 6 ) alkyl (each optionally with R ⁇ one or more times, the same or not equal to the aromatic and / or aliphatic moiety substituted); - Phenacyl (optionally with R ⁇ one or more times, the same or different substituted on the aromatic moiety);
  • -CH 3, -CHF 2, -CH 2 F 1 is -CF 3, -C 2 H O, -C (CHa) 2, - (CH 2) 2 CH 3, - (CH 2) 3 CH 3, -CH 2 CH 2 OH, -CH 2 CH 2 SH, -CH 2 CH 2 SCHa, -CH 2 CF 3 , -CH 2 CCIs, -CH 2 CBr 3 -CH 2 CHF 2 , -CH 2 CHCl 2 , -CH 2 CHBr 21 -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, -Cyclopentylmethyl, -Cyclohexyl, -Cyclohexylmethyl, -F , -Cl, -Br, -I,
  • alkyl, alkenyl, alkynyl, alkoxy, etc. also in word compositions such as alkylsulfonyl, alkylamino or alkoxycarbonyl, etc., mean both the unbranched and the branched possible compounds.
  • alkenyl and alkynyl means the correspondingly possible monounsaturated or polyunsaturated compounds, as well as the corresponding cyclic compounds.
  • the invention also relates to physiologically acceptable salts of the compounds of the general formulas 1a and 1b.
  • physiologically acceptable salts are prepared in a conventional manner by reacting basic compounds of the general formulas 1a and 1b with inorganic or organic acids, if appropriate also in the presence of compounds having acidic properties, for example when one of the substituents R 1 , R 2 , R 3 or R 4 in these compounds -COOH or -SO 3 H means, by neutralization with inorganic or organic bases, obtained.
  • inorganic acids are preferably hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, as organic acids for example formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, mandelic acid, tartaric acid, malic acid, citric acid, malonic acid, maleic acid, fumaric acid, succinic acid, alginic acid, benzoic acid, , 3- and 4-alkyloxy and acyloxybenzoic acids, ascorbic acid, Ci-C 3 , alkylsulfonic acids, benzenesulfonic acid, nicotinic acid, isonicotinic acid and amino acids for use.
  • organic acids for example formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, mandelic acid, tartaric acid, malic acid, citric acid, malonic acid, maleic acid, fumaric acid, succinic acid, alginic acid, benzoic acid, , 3- and 4-alky
  • the inorganic bases used are, for example, ammonia, sodium hydroxide and potassium hydroxide solution and, as organic bases, alkylamines, CrC 3 , pyridine, quinoline, isoquinoline, piperazine and derivatives, picolines, quinaldine or pyrimidine.
  • physiologically acceptable salts of the compounds according to the general formulas 1a and 1b can be obtained by reacting those substances which as substituents have a tertiary amino group in a manner known in principle with alkylating agents, such as, for example, alkyl or aralkyl halides the corresponding quaternary ammonium salts can be converted.
  • alkylating agents such as, for example, alkyl or aralkyl halides the corresponding quaternary ammonium salts can be converted.
  • the invention also relates to solvates of the compounds, including the pharmaceutically acceptable salts, acids, bases and esters and their active metabolites and optionally their tautomers according to the general formulas 1a and 1b, including prodrug formulations.
  • Prodrug formulations herein include all those substances which are formed by simple transformation including hydrolysis, oxidation, or reduction, either enzymatically, metabolically, or otherwise.
  • a suitable prodrug contains, for example, a substance of the general formulas 1a and 1b which, via an enzymatically cleavable linker (eg carbamate, phosphate, N-glycoside or a disulphide group) to a solution-improving substance (eg tetraethylene glycol, saccharides, amino acids or glucuronic acid, etc .) is bound.
  • a prodrug of a compound of the present invention may be administered to a patient, and this prodrug may be transformed into a substance of the general formulas 1a and 1b, thereby achieving the desired pharmacological effect.
  • the diseases treatable by the compounds of the invention include any of those in which TNF-alpha is involved and which are positively affected by inhibition or inhibition thereof, e.g. chronic inflammatory diseases, autoimmune diseases, cardiovascular disease
  • AIDS acquired immunodeficiency syndrome
  • cancer especially degeneration of the hematopoietic system.
  • AIDS acquired immunodeficiency syndrome
  • COPD chronic obstructive pulmonary disease
  • Mb cerebral form of the Malaria
  • neurodegenerative diseases such as Mb. Alzheimer's, Mb.
  • Parkinson's Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft-versus-host disease (GvHD), systemic lupus erythematosus (SLE), vasculitis, uveitis, insulin-dependent diabetes mellitus, adult respiratory distress syndrome (ARDS), multiple organ failure after trauma, acute glomerulonephritis, acute and chronic pain, arteriosclerosis, myocardial infarction, stroke, inflammatory dermatoses, atopic dermatitis, psoriasis vulgaris, alopecia, rhinitis allergica, allergic Conjunctivitis, acute meningitis, myasthenia gravis, scleroderma and sarcoidosis.
  • GvHD systemic lupus erythematosus
  • ARDS adult respiratory distress syndrome
  • arteriosclerosis myocardial infarction
  • stroke inflammatory dermatoses
  • the compounds of the invention can be administered in a variety of ways, e.g. oral, parenteral, cutaneous, subcutaneous, intravenous, intramuscular, rectal or inhalation. Preference is given to intravenous or inhalational administration.
  • the compound is administered to a patient in need of therapy of a disease falling within the range of indications of the compounds of the invention for a period to be determined by the physician.
  • the compound can be administered to both humans and other mammals.
  • the dosage of the compounds according to the invention is determined by the physician on the basis of the patient-specific parameters, e.g. Age, weight, sex, severity of the disease, etc. are determined.
  • the dosage is between 0.001 mg / kg to 1000 mg / kg body weight, preferably 0.01 to 500 mg / kg body weight and most preferably 0.1 to 100 mg / kg body weight.
  • the medicament is suitably formulated, e.g. in the form of solutions or suspensions, simple or sugar-coated tablets, hard or soft gelatin capsules, reconstitution pre-use powders, aerosols, inhalation sprays, active substance patches, granules, suppositories, ovules, injectables, creams, ointments, gels, microspheres, implants, according to customary galenic processes.
  • the compounds according to the invention can be formulated together with further active compounds and with excipients customary in pharmaceutical compositions, for example depending on the preparation to be prepared talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols (especially polyethyleneglycol), various plasticizers, dispersants or emulsifiers, pharmaceutically acceptable gases (eg air, oxygen, carbon dioxide, etc.). , Preservatives.
  • excipients customary in pharmaceutical compositions, for example depending on the preparation to be prepared talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols (especially polyethyleneglycol), various plasticizers, dispersants or emulsifiers, pharmaceutically acceptable gases (eg air, oxygen, carbon dioxide, etc.). ,
  • additives such as sodium chloride solution, ethanol, sorbitol, glycerin, olive oil, almond oil, propylene glycol or ethylene glycol can be used.
  • these are preferably aqueous solutions or suspensions, it being possible to prepare them before use, for example from lyophilized preparations containing the active ingredient alone or together with a carrier such as mannitol, lactose, glucose, albumin and the like.
  • a carrier such as mannitol, lactose, glucose, albumin and the like.
  • the ready-to-use solutions are sterilized and optionally mixed with adjuvants such as preservatives, stabilizers, emulsifiers, solubilizers, buffers and / or osmotic pressure control salts. Sterilization can be achieved by sterile filtration through filters of small pore size, after which the composition is optionally can be lyophilized. Small amounts of antibiotics may also be added to ensure sterility maintenance.
  • inhalation compositions e.g. in the form of aerosols, sprays, or micronized powder.
  • the compounds of the invention are either dissolved or suspended as in pharmaceutically customary solvents and finely distributed by means of overpressure in a certain volume and inhaled.
  • overpressure working applicators are included here.
  • the invention also relates to pharmaceutical preparations containing a therapeutically effective amount of the active ingredient (Compound of the invention Formula (1 a) or (1b)) together with organic or inorganic solid or liquid pharmaceutically acceptable carriers which are suitable for the intended administration and which do not adversely interact with the active ingredients.
  • a therapeutically effective amount of the active ingredient Compound of the invention Formula (1 a) or (1b)
  • organic or inorganic solid or liquid pharmaceutically acceptable carriers which are suitable for the intended administration and which do not adversely interact with the active ingredients.
  • the invention also relates to processes for the preparation of pharmaceutical preparations which are characterized in that the compound according to the invention is mixed with a pharmaceutically acceptable carrier.
  • the compounds according to the invention are also suitable in the context of combination therapies with already known active compounds for the treatment of the abovementioned diseases.
  • surprising synergy effects are to be used to increase the therapeutic effectiveness of the substances according to the invention.
  • the combination may be to offer a single pharmaceutical composition comprising at least one of the compounds of the present invention in combination with one or more of the following, or simultaneously or temporally displaced to the patient, several agents containing one or more of the following active ingredients administered.
  • TNF-alpha production or TNF-alpha activity e.g., recombinant TNF ⁇ receptor constructs
  • Cytokine antagonists e.g., IL-1 ⁇ , IL-6, IL-12
  • Cytokine agonists include immunomodulatory agents, e.g. Cyclosporin A, Methodrexate,
  • Cytostatics ß 2 -adrenoceptor agonists eg terbutaline, salbutanol, salmetanol,
  • Leukotriene antagonists either enzyme inhibitors [such as 5-
  • Receptor antagonists e.g. Pranlukast, Montelukast, Zafirlukast, Zileuton
  • Antihistamines preferably those with mast cell stabilizing
  • Muscarinic receptor antagonists e.g. Spiriva
  • the combination with the medicines or active principles listed above is particularly useful for influencing the state of the disease to be treated acutely in its manifestation at the earliest possible stage and not for making it chronic, since the compounds according to the invention in combination with the other active substances allow complementary / additive aspects ,
  • the combination results in a positive effect u.a. from the fact that a smaller amount of substance per principle can be used and thus on the one hand an improvement of the therapeutic effect, lower ADRs and on the other hand a saving effect can be achieved.
  • the compounds according to the invention may be added to the other active substances in the combination in the ratio of 1: 10,000 to 10,000: 1, preferably 1: 1000 to 1000: 1, very preferably 1:10 to 10: 1, available.
  • the invention further relates to processes for the preparation of the compounds of the invention.
  • alkoxide preferably potassium te / t-butoxide
  • suitable solvent preferably toluene
  • a thiocyanate preferably ammonium thiocyanate
  • a suitable solvent preferably dioxane
  • the compounds of general formula 7 (with identical meaning of X, Y, R 1 , and R 3 as above) are represented by the compounds of general formula 5, also characterized in that these compounds with choracetamide initially in preferably ethanolic solution in the presence of preferably triethylamine or in anhydrous acetonic solution in the presence of sodium or potassium bicarbonate to the compounds of general formula 6,
  • C 2 -i 4 alkyl Ca-uCycloalkyl, C i 2 4 alkenyl, C 3 -i 4 cycloalkenyl, C 2 4 alkynyl -i (in each case optionally at the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals with R ⁇ substituted) ;
  • R 4 is the same as in the compounds of general formula 8, in each case in excess and in the boiling heat, optionally together with pyridine or an aprotic, high-boiling
  • Solvents such as toluene or xylene
  • X, Y 1 R 1 and R 3 are the same as above and Alk * (Ci -8 ) alkyl, (C 2 - 8 ,) alkenyl, (C 3 - 6 ) alkynyl, in each case unbranched or optionally branched and optionally with one Substituted such as -CN, -SCN, -NO 2 , phenyl and (C 3-7 ) cycloalkyl, mean
  • Phenyl and (Cs- 7 ) cycloalkyl is substituted means
  • embodiments of the invention may be that the preparation of the tricyclic pyrimidine-2,4-diones of the general formula 1a or of the tricyclic pyrimidin-4-ones of the general formula 1b is realized by using a microwave device,
  • LPS Lipopolysaccharides
  • TNF ⁇ a stimulus for studying the release of TNF ⁇ .
  • LPS is a component of bacterial cell walls and is released when the bacteria are killed (by antibiotics or the natural immune system).
  • LPS stimulates the activity of phagocytic leukocytes (tissue macrophages, granulocytes, monocytes) and causes the infiltration of peripheral blood leukocytes into the affected tissue.
  • phagocytic leukocytes tissue macrophages, granulocytes, monocytes
  • a cytokine of particular importance for these mechanisms is TNF ⁇ , which is secreted in large quantities by the affected cells.
  • Main source are monocytes and macrophages. TNF ⁇ initiates and prolongs the inflammatory process in interaction with other mediators.
  • the leukocytes are stimulated by addition of lipopolysaccharides (LPS) from Salmonella abortus equi to a final concentration of 1 ⁇ g / ml.
  • LPS lipopolysaccharides
  • the blood is centrifuged and the concentration of TNF ⁇ in the cell-free supernatant accurately measured using a commercial ELISA (BD Biosciences) according to the manufacturer's instructions.
  • IC ⁇ o values in the range of 10 "6" to 10 10 M were determined for the substances described in the invention.
  • the compounds of the general formulas 1 a and 1 b are weak inhibitors of phosphodiesterase 4 and extremely strong inhibitors of the release of TNF ⁇ .
  • Examples 2-8, 11-14, 16-38, 42 and 45-52 are obtained by reacting the corresponding compounds of general formula 7 with chloroformic acid trichloromethyl ester (diphosgene) analogously to Example 1:
  • Example 39

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Abstract

The invention relates to novel pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=C-H, Y=S), thieno[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=N, Y=S), in addition to pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=C-H, Y=0) and furo[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=N, Y=O) of general formulae 1a and 1b. The invention also relates to a method for the production thereof, pharmaceutical preparations containing said compounds and/or tautomers thereof and physiologically compatible salts which can be produced therefrom and/or solvates thereof, in addition to the pharmaceutical use of said compounds, tautomers thereof, salts or solvates, as inhibitors of TNFα-release.

Description

Substituierte Pyrido[3',2':4J5]thieno[3!2-d]pyrimidin-2,4(1 HJ3H)dione und - 4(3H)one, substituierte Thieno[2J3-d:4,5-d']dipyrimidin-254(1 H,3H)-dione und - 4(3H)-one, substituierte Pyrido[3',2':4,5]f uro[3,2-d]-pyrimidin-2,4(1 H,3H)-dione und -4(3H)one sowie substituierte Furo[2,3-d:4,5-d']dipyrimidin-2,4(1 H,3H)- dione und -4(3H)-one, diese enthaltende pharmazeutische Zusammensetzungen und die Verwendung ais Inhibitoren der TN Fa- Freisetzung sowie Verfahren zu deren HerstellungSubstituted pyrido [3 ' , 2 ' : 4 J 5] thieno [3 ! 2-d] pyrimidine-2,4 (1 H J 3H) dione and - 4 (3H) one, substituted thieno [2 J 3-d: 4,5-d '] dipyrimidine-2 5 4 (1 H, 3 H ) -diones and - 4 (3H) -ones, substituted pyrido [3 ' , 2 ' : 4,5] uro [3,2-d] pyrimidine-2,4 (1H, 3H) -diones and 4 (3H) one and substituted furo [2,3-d: 4,5-d '] dipyrimidine-2,4 (1H, 3H) -dione and -4 (3H) -one, pharmaceutical compositions containing them and the Use as inhibitors of TN-Fas release and method for their production
Beschreibungdescription
Die Erfindung betrifft Heterocyclen, die als Bislactame der allgemeinen Formel 1a bzw. Monolactame der allgemeinen Formel 1b des bisher wenig bekannten tricyclischen Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-Systems sowie des Thieno[2,3- d:4,5-d']dipyrimidin-Systems anzusehen sind. Die Erfindung betrifft weiterhin die Eignung entsprechender Verbindungen als TNFα-Freisetzungshemmer.The invention relates to heterocycles which are as bislactams of the general formula 1a or monolactams of the general formula 1b of the hitherto little known tricyclic pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidine system and of thieno [2,3-d: 4,5-d '] dipyrimidine system are to be regarded. The invention further relates to the suitability of corresponding compounds as TNFα release inhibitors.
Figure imgf000003_0001
Figure imgf000003_0001
Gegenstand der Erfindung sind demzufolge die Verbindungen selbst, Verfahren zu deren Herstellung, pharmazeutische Zubereitungen, die diese Verbindungen und/oder deren Tautomere, pharmakologisch übliche Prodrug-Formulierungen und daraus herstellbare physiologisch verträgliche Salze und/oder deren Solvate enthalten, sowie die pharmazeutische Verwendung dieser Verbindungen, deren Tautomere, Salze oder Solvate, einschließlich Prodrug-Formulierungen als Inhibitoren der TNFα-Freisetzung. Prodrug-Formulierungen umfassen hierbei alle jene Substanzen, die durch einfache Transformation einschließlich Hydrolyse, Oxidation, oder Reduktion entweder enzymatisch, metabolisch oder auf andere Art und Weise entstehen. Insbesondere, wenn ein solches Prodrug dieser erfindungsgemäßen Verbindungen einem Patienten appliziert wurde, und dieses Prodrug in eine Substanz der allgemeinen Formeln Ia und Ib transformiert wird, wodurch der gewünschte pharmakologische Effekt erzielt wird.The invention accordingly provides the compounds themselves, processes for their preparation, pharmaceutical preparations containing these compounds and / or their tautomers, pharmacologically conventional prodrug formulations and physiologically tolerable salts obtainable therefrom and / or their solvates, and the pharmaceutical use of these compounds their tautomers, salts or solvates, including prodrug formulations as inhibitors of TNFα release. Prodrug formulations herein include all those substances which are formed by simple transformation including hydrolysis, oxidation, or reduction, either enzymatically, metabolically, or otherwise. In particular, if such a prodrug of this compounds of the invention has been applied to a patient, and this prodrug is transformed into a substance of the general formulas Ia and Ib, whereby the desired pharmacological effect is achieved.
Stand der TechnikState of the art
Das Zytokin Tumour necrosis factor (TNFα) ist eines von heute 17 bekannten Mitgliedern einer strukturell sehr ähnlichen Proteinfamilie. Seinen Namen verdankt es der Fähigkeit, eine Nekrose von transplantierten Tumorzellen im Mausmodell zu triggem. Neben seiner Apoptose-induzierenden Wirkung wurde sehr schnell erkannt, dass TNFα auch ganz maßgeblich in die Regulation der Entzündungsantwort und der Immunantwort eingebunden ist. Eine Überproduktion von TNFα oder die Aktivierung der TNFα-vermittelten Signalkaskaden spielen in der Pathogenese einer Vielzahl von Erkrankungen, wie z.B. Sepsis, cerebrale Form der Malaria, neurodegenerativen Erkrankungen wie z.B. Mb. Alzheimer, Mb. Parkinson, bei Diabetes mellitus, COPD/Asthma, Tumorerkrankungen und hier insbesondere Tumoren des Blutbildenden Systems wie z.B. Leukämien und Lymphome, virale Erkrankungen und hier insbesondere retrovirale Erkrankungen wie z.B. das erworbene Immundefizienz Syndrom (AIDS), Guillain-Barre Syndrom, Rhinitis allergica, allergische Konjunktivitis, systemische Sklerodermie, Graft versus host disease (GvHD), Systemischer Lupus Erythematodes (SLE), Osteoporosis, Toxisches Schocksyndrom, Akute Glomerulonephritis, akute und chronische Schmerzen, Arteriosklerose, Herzinfarkt, Schlaganfall, bei Sarkoidose, Multiple Sklerose, Rheumatoid Arthritis (RA), Osteoarthritis, Colitis ulcerosa, Vasculitis, Uveitis, Mb. Crohn, Mb. Behcet, Myastenia Gravis und chronisch entzündlichen Hauterkrankungen wie Psoriasis, atopische Dermatitis, Ekzeme und Alopecie, eine zentrale Rolle (Chen G, Goeddel DV (2002 TNF-R1 signaling: a beautiful pathway. Science 296 1634-1635; Ware CF (2003) The TNF superfamily. Cytokine & Growth Factor reviews 1_4 181-184; Dempsey PW (2003) The signaling adaptors and pathways activated by TNF superfamily. Cytokine & Growth Factor reviews 14 193-209).The cytokine tumor necrosis factor (TNFα) is one of 17 known members of a structurally very similar protein family. It owes its name to the ability to trigger necrosis of transplanted tumor cells in the mouse model. In addition to its apoptosis-inducing effect was very quickly recognized that TNFα is also very significantly involved in the regulation of the inflammatory response and the immune response. Overproduction of TNFα or activation of the TNFα-mediated signaling cascades play a role in the pathogenesis of a variety of diseases, e.g. Sepsis, cerebral form of malaria, neurodegenerative diseases such as Mb. Alzheimer's disease, Mb. Parkinson's disease, in diabetes mellitus, COPD / asthma, tumors and in particular tumors of the hemopoietic system such. Leukemias and lymphomas, viral diseases, and especially retroviral diseases such as e.g. Acquired Immune Deficiency Syndrome (AIDS), Guillain-Barre Syndrome, Allergic Rhinitis, Allergic Conjunctivitis, Systemic Scleroderma, Graft versus Host Disease (GvHD), Systemic Lupus Erythematosus (SLE), Osteoporosis, Toxic Shock Syndrome, Acute Glomerulonephritis, Acute and Chronic Pain, Atherosclerosis, myocardial infarction, stroke, sarcoidosis, multiple sclerosis, rheumatoid arthritis (RA), osteoarthritis, ulcerative colitis, vasculitis, uveitis, Mb. Crohn, Mb. Behcet, Myastenia Gravis and chronic inflammatory skin conditions such as psoriasis, atopic dermatitis, eczema and alopecia , Central role (Chen G, Goeddel DV (2002 TNF-R1 signaling: a beautiful pathway, Science 296 1634-1635, Ware CF (2003) The TNF superfamily Cytokine & Growth Factor reviews 1_4 181-184; Dempsey PW (2003 The signaling adaptors and pathways activated by TNF superfamily Cytokines & Growth Factor reviews 14 193-209).
Bei TNFα handelt es sich um eines der wichtigsten pro-inflammatorischen Zytokine, der in die Pathogenese fast aller chronisch entzündlichen Erkrankungen maßgeblich eingebunden ist. TNFα, welches auch als Chachektin, Makrophagen-Cytotoxin (MCT), E tumor necrosis factor-a und als macrophage cytotoxic factor (MCF) beschrieben wurde, wird von verschiedensten Zellen nach Stimulation mit Lipopolysaccharid (LPS), Interferronen (IFN's), IL-2, Bradykinin, GM-CSF, Antigen- Antikörper-Komplexen, Substanz P und zahlreichen weiteren biologisch aktiven Verbindungen synthetisiert und sezemiert. TNFα wird unter physiologischen Bedingungen hauptsächlich von aktivierten Makrophagen, T-Lymphozyten, Mikrogliazellen und NL-Zellen gebildet. Stimulierte und somit aktivierte Fibroblasten, glatte Muskelzellen, Astrozyten, Keratinozyten, Endothelzellen und Lungen- Epithelzellen sezernieren gleichfalls TNFα.TNFα is one of the most important proinflammatory cytokines, which is essential in the pathogenesis of almost all chronic inflammatory diseases is involved. TNFα, which has also been described as chachectin, macrophage cytotoxin (MCT), tumor necrosis factor-α and macrophage cytotoxic factor (MCF), is stimulated by various cells after stimulation with lipopolysaccharide (LPS), interferons (IFNs), IL- 2, bradykinin, GM-CSF, antigen-antibody complexes, substance P, and numerous other biologically active compounds. TNFα is formed under physiological conditions mainly by activated macrophages, T lymphocytes, microglial cells and NL cells. Stimulated and thus activated fibroblasts, smooth muscle cells, astrocytes, keratinocytes, endothelial cells and lung epithelial cells also secrete TNFα.
Humanes TNFα ist ein 17 kDa großes Protein, welches aus 157 Aminosäuren besteht und zu Dimeren und Trimeren assoziiert. Es existiert eine weitere höhermolekulare Variante dieses Moleküls mit einer Molmasse von 26 kDa, das als Transmembranprotein in der Zellmembran verankert ist. Man weiß heute, dass zunächst die höhermolekulare Transmembranform synthetisiert in die Zellmembran eingelagert wird und bei Bedarf deren extrazelluläre Domäne durch das TNFα Converting enzyme (TACE) abgespalten wird. Das lösliche TNFα zirkuliert als ein Homotrimer und bindet sich an seine spezifischen Rezeptoren an Zelloberflächen. Die Bindung von TNFα an seine Rezeptoren (TNFR1 , TNFR2) bewirkt bei diesen eine konformative Änderung und Dimerisierung bzw. Clusterung, welche über eine Signalkaskade den biologischen Effekt von TNFα vermitteln. In zahlreichen Untersuchungen konnte gezeigt werden, dass über die Bindung von TNFα an den TNFR1 die meisten biologischen Effekte realisiert werden. Dies beinhaltet die Induktion der Apoptose über eine Aktivierung der Caspase 8 und nachfolgender Aktivierung der Caspasen 3, 6 und 7, die dann zur Apoptose der Zelle führen.Human TNFα is a 17 kDa protein that consists of 157 amino acids and associates with dimers and trimers. There is another molecular variant of this molecule with a molecular mass of 26 kDa, which is anchored as a transmembrane protein in the cell membrane. It is now known that the higher-molecular-weight transmembrane form is first synthesized into the cell membrane and, if necessary, its extracellular domain is cleaved off by the TNFα-converting enzyme (TACE). The soluble TNFα circulates as a homotrimer and binds to its specific receptors on cell surfaces. The binding of TNFα to its receptors (TNFR1, TNFR2) causes in these a conformational change and dimerization or clustering, which mediate the biological effect of TNFα via a signal cascade. Numerous studies have shown that the binding of TNFα to TNFR1 produces the most biological effects. This involves the induction of apoptosis via activation of caspase 8 and subsequent activation of caspases 3, 6 and 7, which then lead to apoptosis of the cell.
Ein weiterer wichtiger Signalweg durch TNFα ist die Aktivierung von zwei wichtigen Transkriptionsfaktoren, dem nuclear factor-kappaB (NF-KB) und c-Jun. Diese beiden Transkriptionsfaktoren spielen eine außerordentlich wichtige Rolle in der Regulation der Genexpression bei der Zelldifferenzierung, dem Zellwachstum, bei der Immun- und Entzündungsantwort, bei Zellstressregulationsvorgängen und bei der Tumorgenese. NF-KB reguliert unter anderem die Gene für IL-1α, IL-1ß, IL-2, IL-3, IL-6, IL-8, IL-12, TNFα, LT-α, IFN-α/ß, G-CSF, M-CSF, GM-CSF1 für den Zytokinrezeptor IL-2Rα, für die Adhäsionsmoleküle ICAM-1 , VCAM-1 , MAdCAM, E-Selektin, für die immunregulatorischen Moleküle leichte Kette des lgγ, MHC Class I und II, TCRα und ß, ß2 Mikroglobulin, TAP1 , iNOS und für die Akute Phase Proteine SAA, αrsaures Glycoprotein und TSG-14/PTX3.Another important pathway by TNF is the activation of two major transcription factors, the nuclear factor-kappaB (NF- K B) and c-Jun. These two transcription factors play an extremely important role in the regulation of gene expression in cell differentiation, cell growth, in the immune and inflammatory response, in cell stress regulatory processes and in tumorigenesis. NF- K B regulates, inter alia, the genes for IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-8, IL-12, TNFα, LT-α, IFN-α / β, G-CSF, M-CSF, GM-CSF 1 for the cytokine receptor IL-2Rα, for the adhesion molecules ICAM-1, VCAM-1, MAdCAM, E-selectin, for the immunoregulatory molecules light chain of Igγ, MHC Class I and II , TCRα and ß, ß 2 microglobulin, TAP1, iNOS and for the acute phase proteins SAA, α r acid glycoprotein and TSG-14 / PTX3.
Über die tatsächliche physiologische Bedeutung der Bindung von TNFα an den TNFR2 existieren heute noch erhebliche Widersprüche. Deshalb ist die Aufdeckung der genauen molekularen Signaltransduktionsabläufe noch Gegenstand der Grundlagenforschung. Mehrheitlich geht man heute davon aus, dass die Bindung von TNFα an den TNFR2 auch die Mitogen-aktivierten Proteinkinase Kinasen (MAPKK) aktiviert, im speziellen die MEKK1 und die ASK1 , die über eine Aktivierungskaskade zur Aktivierung der c-Jun Kinase (JNK) und damit zu einer Aktivierung des Transkriptionsfaktors c-Jun führt. In diesen Regulationsweg ist auch die Aktivierung der p38 Kinase eingebunden, die zur Aktivierung von p38 führt. Die Aktivierung von p38 ist essentiell für die Produktion der pro-inflammatorischen Zytokine IL-lß, TNFα und IL-6 und ist darüber hinaus auch verantwortlich für die Induktion und Expression der mit chronischen Entzündung vergesellschafteten Enzyme COX-2 und iNOS (Ono K, Han J (2000) The p38 Signal transduction pathway: activation and function. Cell Signal 12 1-13). Über weitere Aktivierungswege werden auch die wichtigen Transkriptionsfaktoren activating- transcrip-tion factor 2 (ATF2) und das Aktivatorprotein-1 (AP-1) induziert, welche unmittelbar stimulierenden Einfluss auf die Expression pro-inflammatorischer Moleküle wie E-Selectin, RANTES, IL-12, IL-6 und IL-8 ausüben (Guicciardi ME, Gores GJ (2003)J Clin Invest rπ 1813-1815).There are still considerable contradictions regarding the actual physiological significance of the binding of TNFα to TNFR2. Therefore, the discovery of the precise molecular signal transduction processes is still the subject of basic research. Today, it is generally assumed that the binding of TNFα to TNFR2 also activates the mitogen-activated protein kinase kinases (MAPKK), in particular the MEKK1 and the ASK1, which via an activation cascade for the activation of c-Jun kinase (JNK) and thus leading to an activation of the transcription factor c-Jun. In this regulatory pathway, the activation of the p38 kinase is also involved, which leads to the activation of p38. Activation of p38 is essential for the production of the pro-inflammatory cytokines IL-1β, TNFα and IL-6, and is also responsible for the induction and expression of the chronic inflammation-associated enzymes COX-2 and iNOS (Ono K, Han J (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12 1-13). Further activation pathways also induce the important transcription factors activating transcription factor 2 (ATF2) and activator protein-1 (AP-1), which have a directly stimulating influence on the expression of pro-inflammatory molecules such as E-selectin, RANTES, IL-1. 12, IL-6 and IL-8 (Guicciardi ME, Gores GJ (2003) J Clin Invest, 1813-1815).
Die biologische Bedeutung von TNF erkannten zuerst 1969 GRANGER et al. (Granger GA, Shacks SJ, Williams TW, KoIb WP (1969) Lymphocyte in vitro cytotoxicity: specific release of lymphotoxin-like materials from tuberculin-εensitive lymphoid cells. Nature 221 1155-1157) die zeigen konnten, dass ein von Lymphozyten und Makrophagen sezemiertes Protein (Lymphotoxin) zur Lyse von Zellen, insbesondere von Tumorzellen, führt. 1984 konnten GRAY et al. (Gray PW, Aggarwal BB, Benton CV, Briingman TS, Henzel WJ, Jarrett JA, Leung DW, Maffatt B, Ng P, Svedersky LP et al. (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 312 721-724) und PENNICA et al. {Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Deyrynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV (1984) Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Natur 312 724- 729) die cDNA für TNFα klonieren und das Protein exprimieren.The biological importance of TNF was first recognized in 1969 by GRANGER et al. (Granger GA, Shacks SJ, Williams TW, KoIb WP (1969) Lymphocyte in vitro cytotoxicity: specific release of lymphotoxin-like materials from tuberculin-sensitive lymphoid cells, Nature 221 1155-1157) which could demonstrate that one of lymphocytes and macrophages secreted protein (lymphotoxin) for lysing cells, especially tumor cells. In 1984, GRAY et al. (Gray PW, Aggarwal BB, Benton CV, Briingman TS, Henzel WJ, Jarrett JA, Leung DW, Maffatt B, Ng P, Svedersky LP et al. (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 312 721-724) and PENNICA et al. {Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Deyrynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV (1984) Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Natur 312 724-729) clone the cDNA for TNFα and express the protein.
Die biologische Aktivität von TNFα wird hauptsächlich über zwei spezifische Rezeptortypen (TNFR1 , TNFR2) vermittelt, die sich transmembran und mit einem extra- und intrazellulären Anteil auf einer Vielzahl Zellen des menschlichen Körpers befinden.The biological activity of TNFα is mediated primarily by two specific receptor types (TNFR1, TNFR2), which are transmembrane and with an extracellular and intracellular portion on a variety of cells of the human body.
TNFα besitzt ein sehr breites Spektrum an biologischen Aktivitäten und reguliert fast alle Zellen. Er ist aus heutiger Sicht ein wesentlicher Mediator bei Entzündungs- und Immunreaktionen, aber auch bei der Apoptose, der Zelldifferenzierung, bei der Induktion von Fieber und zahlreichen weiteren pathophysiologischen Regulationsprozessen.TNFα has a very broad spectrum of biological activities and regulates almost all cells. He is from today's point of view an essential mediator in inflammatory and immune reactions, but also in apoptosis, cell differentiation, in the induction of fever and numerous other pathophysiological regulatory processes.
Eine zentrale Stellung nimmt TNFα bei der Endothelzellaktivierung während des Entzündungsprozesses ein. Hierbei stellt die Aktivierung der vaskulären Endothelzellen einen wesentlichen Schritt in der Initiationsphase der entzündlichen Reaktionen im Gewebe dar. So führen pro-inflammatorische Zytokine, mit TNFα an der Spitze, zur Expression endothelialer Adhäsionsmoleküle und chemotaktisch wirksamer Chemokine, die ihrerseits Makrophagen und T-Lymphozyten die Möglichkeit geben, am Endothel anzudocken und über eine aktive Wanderung ins entzündliche Gewebe (Extravasion) zu kommen. Man unterscheidet heute in diesem Zusammenhang eine lokale Wirkung von TNFα von einer systemischen. Die lokalen Effekte sind wie oben angeführt eine verstärkte Diapetese von Immun- und Entzündungszellen ins entzündliche Gewebe und eine starke Adhäsion von Thrombozyten an den Blutgefäßwänden. Der systemische Effekt von TNFα führt zu Ödemen, einer Verringerung des Blutvolumens, Hypoproteinämie, verbreitete intravaskuläre Blutgerinnung und in ihrer Maximalvariante zu multiplem Organversagen (septischer Schock). TN Fa bewirkt also eine lokale Aktivierung des vaskulären Endothels, eine Freisetzung von Stickoxid (NO) mit nachfolgender Steigerung der vaskulären Permeabilität, eine erhöhte Expression von Adhäsionsmolekülen und eine erhöhte Expression von „class I! major histocompatibility molecules" (MHC II). Das Ergebnis ist ein Einwandern von Entzündungs- und Immunzellen, Antikörpern und Komplementfaktoren in das entzündliche Gewebe. TNFα verursacht gleichfalls in den lokalen Lymphknoten eine antigenspezifische Aktivierung der B- und T-Lymphozyten. Des Weiteren aktiviert TNFα Thrombozyten und verstärkt deren Adhäsion an den Gefäßwänden.TNFα occupies a central position in endothelial cell activation during the inflammatory process. Activation of the vascular endothelial cells represents a significant step in the initiation phase of inflammatory reactions in the tissue. Pro-inflammatory cytokines, with TNFα at the tip, lead to the expression of endothelial adhesion molecules and chemotactically active chemokines, which in turn cause macrophages and T lymphocytes Possibility to dock at the endothelium and to come via an active migration into the inflammatory tissue (extravasion). In this context, a local effect of TNFα is differentiated from a systemic one. The local effects are as mentioned above an increased diapetesis of immune and inflammatory cells into the inflammatory tissue and a strong adhesion of platelets to the blood vessel walls. The systemic effect of TNFα leads to edema, a decrease in blood volume, hypoproteinemia, widespread intravascular coagulation and in its maximum variant to multiple organ failure (septic shock). TN Fa thus causes a local activation of the vascular endothelium, a release of nitric oxide (NO) with subsequent increase of the vascular permeability, an increased expression of adhesion molecules and an increased expression of "class I! major histocompatibility molecules (MHC II), which results in the influx of inflammatory and immune cells, antibodies and complement factors into the inflammatory tissue TNFα also causes antigen-specific activation of B and T lymphocytes in the local lymph nodes Platelets and increases their adhesion to the vessel walls.
TNFα selbst induziert die Synthese anderer pro-inflammatorischer Zytokine wie 1L-1 , IL-6, IL-8 und GM-CSF und führt dadurch zu einem Circulus vitiosus des entzündlichen Prozesses. Zusätzlich ist TNFα noch maßgeblich in weitere pathophysiologische Prozesse, wie die Gelenkknorpelzerstörung bei rheumatischen Erkrankungen, Knochenresorptionsprozesse, Hemmung der Knochenbildung, Hemmung der Proteoglycansynthese und Induktion von Matrix Metalloproteinasen (MMP's) und Prostaglandin E2 (Mease P (2002) Psoriatic arthritis: The role of TNF Inhibition and the effect of its inhibition with etanercept. Clin Exp Rheumatol 20 (Suppl. 28) S116-S121) involviert.TNFα itself induces the synthesis of other pro-inflammatory cytokines such as 1L-1, IL-6, IL-8 and GM-CSF, leading to a vicious circle of the inflammatory process. In addition, TNFα is still important in other pathophysiological processes such as articular cartilage destruction in rheumatic diseases, bone resorption processes, inhibition of bone formation, inhibition of proteoglycan synthesis, and induction of matrix metalloproteinases (MMPs) and prostaglandin E 2 (Mease P (2002) Psoriatic arthritis: The role of TNF inhibition and the effect of its inhibition with etanercept., Clin Exp Rheumatol 20 (Suppl. 28) S116-S121).
Übersicht der abgesicherten biologischen Wirkung von TNFα auf humane Zellen/OrganeOverview of the confirmed biological effect of TNFα on human cells / organs
Tabelle 1Table 1
Figure imgf000008_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000009_0001
Entwicklung von TNFα InhibitorenDevelopment of TNFα inhibitors
In der Vergangenheit gab es zahlreiche therapeutische Strategien, um die biologische Aktivität von TNFα zu hemmen und damit den chronischen Entzündungsprozess zu unterbrechen.In the past, there have been numerous therapeutic strategies to inhibit the biological activity of TNFα and thereby disrupt the chronic inflammatory process.
• An erster Stelle standen Bemühungen, die Synthese von TNFα zu hemmen. Hierzu kamen anti-inflammatorische Zytokine, wie z.B. das IL-10, Pentoxifylline, Thalidomid bzw.-Analoga, Kortikosteroide, Ciclosporin A, PDE- 4 Inhibitoren und Antisense Oligonukleotide zum Einsatz.• Efforts to inhibit the synthesis of TNFα were at the forefront. To this end, anti-inflammatory cytokines, e.g. IL-10, pentoxifylline, thalidomide or analogues, corticosteroids, cyclosporin A, PDE-4 inhibitors and antisense oligonucleotides.
Am erfolgreichsten werden seit Jahren Kortikosteroide in der akuten Phase eines schweren entzündlichen Prozesses eingesetzt. Ihre breitere und besonders längere Anwendung ist auf Grund der schweren unerwünschten Arzneimittelwirkungen stark limitiert. Diese Gründe treffen auch für das gleichfalls seit Jahren zugelassene Immunsuppresivum Cyclosporin A zu. Pentoxifylline und Thalidomidanaloga zeigten in den klinischen Studien nur eine unzureichende therapeutische Wirksamkeit.For years, corticosteroids have been used most successfully in the acute phase of a severe inflammatory process. Their wider and longer duration of use is severely limited due to their severe adverse drug reactions. These reasons also apply to the also for years approved immunosuppresivum Cyclosporin A. Pentoxifylline and thalidomide analogues have shown insufficient therapeutic efficacy in clinical trials.
• Der Einsatz von PDE-4 Inhibitoren zeigt über die intrazelluläre Steigerung der cAMP Konzentration einen inhibierenden Einfluss auf die TNFα Freisetzung. Momentan sind mit Cilomilast, AWD 12-81 (GSK) und Roflumilast (Altana) drei Entwicklungskandidaten in der fortgeschrittenen klinischen Prüfung bzw. stehen kurz vor der Zulassung. Die klinische Anwendung dieser Substanzen geht jedoch auch mit unerwünschten Arzneimittelwirkungen, hauptsächlich emetischer Natur, einher.• The use of PDE-4 inhibitors has an inhibitory effect on TNFα release via the intracellular increase in cAMP concentration. At present, three development candidates are in late-stage clinical trials or nearing approval with cilomilast, AWD 12-81 (GSK) and roflumilast (Altana). The clinical application of these substances However, it is also associated with adverse drug reactions, mainly of an emetic nature.
• Die Antisense-Therapie befindet sich noch in einer sehr frühen Entwicklungsphase und hat zumindest in den ersten Tieruntersuchungen die erhoffte Wirksamkeit nachweisen können, aber auch hier sind noch umfängliche grundlagenorientierte Arbeiten notwendig.• Antisense therapy is still in a very early stage of development and has been able to demonstrate the hoped-for efficacy, at least in the first animal examinations, but here, too, extensive basic research is necessary.
• Ein weiterer Ansatz bestand in der Inhibierung des TNFα Prozessings durch Inhibitoren der Metalloproteinase TNF Converting enzyme (TACE).• Another approach was the inhibition of TNFα processing by inhibitors of metalloproteinase TNF converting enzyme (TACE).
Die Entwicklung von niedermolekularen TAGE Inhibitoren befindet sich noch in der Phase der angewandten Grundlagenforschung. So beschrieben TSUKIDA et al. 2004 Hydroxamsäurederivate, die TAGE in vitro hemmen (Tsukida T, Moriyama H, Inoue Y, Kondo H, Yoshino K, Nishimura S (2004) Synthesis and biological activity of selective azasugar-based TACE Inhibitors. Bioorg Med Chem Lett. 22 1569-1572). Einige Matrix Metalloproteinase Inhibitoren hemmen auch unspezifisch TACE, sind aber auf Grund ihrer MMP- inhibitorischen Aktivität für eine pharmazeutische Entwicklung nicht geeignet. WILLIAMS et al. konnten überraschend zeigen, dass der MMP Inhibitor BB- 2275 paradoxerweise sowohl TAGE, als auch das Shedding der TNFα Rezeptoren (TNFR1, TNFR2) hemmt und dadurch keinen TNFα inhibierenden Effekt hatte {Williams LM, Gibbons DL, Gearing A, et al. (1996) Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. J Clin Invest 97 2833-2841). Alle heute bekannten TACE Inhibitoren sind in ihrer hemmenden Wirkung unspezifisch, d.h. auch andere wichtige Metalloenzyme werden durch sie gehemmt, mit der Wahrscheinlichkeit unerwünschter (Neben)Wirkungen.The development of low molecular weight TAGE inhibitors is still in the phase of applied basic research. Thus TSUKIDA et al. 2004 hydroxamic acid derivatives that inhibit TAGE in vitro (Tsukida T, Moriyama H, Inoue Y, Kondo H, Yoshino K, Nishimura S (2004) Synthesis and biological activity of selective azasugar-based TACE inhibitors, Bioorg Med Chem Lett., 22 1569-1572 ). Some matrix metalloproteinase inhibitors also non-specifically inhibit TACE but are not suitable for pharmaceutical development because of their MMP inhibitory activity. WILLIAMS et al. could surprisingly show that the MMP inhibitor BB-2275 paradoxically inhibited both TAGE and shedding of the TNFα receptors (TNFR1, TNFR2) and thus did not have a TNFα-inhibiting effect {Williams LM, Gibbons DL, Gearing A, et al. (1996) Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. J Clin Invest 97 2833-2841). All TACE inhibitors known today are unspecific in their inhibitory effect, i. it also inhibits other important metalloenzymes, with the likelihood of undesirable side effects.
• Momentan sind zahlreiche nichtproteinogene (small molecules) TNFα Inhibitoren in der präklinischen und klinischen Entwicklung. Haupttarget dieser Wirkstoffe sind intrazelluläre Proteinkinasen, die über eine Phosphorylierung Transkriptionsfaktoren aktivieren und dadurch unmittelbar in die Genexpression eingreifen. Am besten untersucht ist in diesem Zusammenhang die Regulation des Transkriptionsfaktors NFKB. NFKB befindet sich komplexiert mit IKB, der als Inhibitor für NFKB wirkt. Wird dieser Inhibitor durch die Proteinkinasen IKK-1 und IKK-2 phosphoryliert, kommt es zu einer partiellen Degradation von IKB, die die Freisetzung des NFKB aus dem Komplex verursacht. Jetzt kann der Transkriptionsfaktor NFKB vom Zytosol in den Zellkern wandern und dort direkt die Expression von z.B. TNFα erhöhen. Es ist hierbei offensichtlich, dass es bei einer Hemmung der Proteinkinase IKK zu keiner Phosphorylierung der IKB und damit zu keiner Aktivierung des NFKB kommt, mit dem Resultat, dass die Expression von z.B. TNFα, aber auch anderer NFκB-abhängiger Mediatoren, nicht stimuliert wird. Die Firma Boehringer Ingelheim beschrieb in zwei Patenten (US 2004/0180922 A1 und US 2005/0038104 A1) Aminoamide und Benzothiophene, die sehr effektiv die Aktivität der beiden Proteinkinasen IKK- 1 und IKK-2 hemmten und dadurch u.a. einen anti-entzündlichen Effekt erzielten. Ausgewählte Vertreter der in diesem Patent beschriebenen Verbindungen, hemmten jedoch nicht die IKK-1 bzw. IKK-2. Es kann deshalb zu Grunde gelegt werden, dass die in diesem Patent beschriebenen Substanzen über einen gänzlich anderen Regulationsweg die Freisetzung von TNFα hemmen.• Currently there are many nonproteinogenic (small molecules) TNFα inhibitors in preclinical and clinical development. The main target of these drugs are intracellular protein kinases that activate transcription factors via phosphorylation and thereby directly interfere with gene expression. The best investigation is in this Related regulation of the transcription factor NFKB. NFKB is complexed with IKB, which acts as an inhibitor of NFKB. When this inhibitor is phosphorylated by the protein kinases IKK-1 and IKK-2, a partial degradation of IKB occurs which causes the release of NFKB from the complex. Now, the transcription factor NFKB can migrate from the cytosol into the nucleus and directly increase the expression of TNFα, for example. It is obvious here that inhibition of the protein kinase IKK does not lead to phosphorylation of the IKB and thus to no activation of the NFκB, with the result that the expression of eg TNFα, but also of other NFκB-dependent mediators, is not stimulated. The company Boehringer Ingelheim described in two patents (US 2004/0180922 A1 and US 2005/0038104 A1) aminoamides and benzothiophenes, which very effectively inhibited the activity of the two protein kinases IKK-1 and IKK-2 and thereby achieved inter alia an anti-inflammatory effect , However, selected members of the compounds described in this patent did not inhibit IKK-1 or IKK-2. It can therefore be assumed that the substances described in this patent inhibit the release of TNFα via an entirely different regulatory pathway.
In neuerer Zeit haben sich Strategien zur Blockierung des TNFα durch Antikörper gegen TNFα und lösliche TNF-Rezeptoren durchgesetzt.More recently, strategies to block TNFα have been established by antibodies to TNFα and soluble TNF receptors.
Zum jetzigen Zeitpunkt sind mit Remicade® und Humira™ zwei monoklonale anti-TNF Antikörper von der FDA und auch von der EMEA als anti-inflammato¬ rische Therapeutika zugelassen worden.At present, Remicade ® and Humira ™ have approved two monoclonal anti-TNF antibodies by the FDA and also by the EMEA as anti-inflammatory therapeutics.
Remicade (Essex/Centrocor) wurde durch die FDA 1998 für die Indikation Mb. Crohn und in 2000 für die Indikation Rheumatoide Arthritis zugelassen. Momentan laufen klinische Studien für die Anwendung bei Psoriasis vulgaris und Psoriasis arthropatica. Bei Remicade handelt es sich um einen chimaeren monoklonalen Antikörper gegen das humane TNFα. In den klinischen Studien zeigte das Präparat gute bis sehr gute Wirkeigenschaften beim Mb. Crohn. Jedoch wurde über teilweise erhebliche Nebenwirkungen, wie erhöhte Infektionsgefahr, Magen-Darm Beschwerden, Kopfschmerz und allergische Reaktionen berichtet. Ein Teil der Nebenwirkungen wird auf den Maus-Anteil des monoklonalen Antikörpers zurückgeführt, der vom menschlichen Organismus als „fremd" erkannt wird, wodurch Antikörper dagegen gebildet werden. Remicade wird intravenös verabreicht und die jährlichen Medikamentenkosten belaufen sich auf über $ 12.000 pro Patient.Remicade (Essex / Centrocor) was approved by the FDA in 1998 for the indication Mb. Crohn and in 2000 for the indication Rheumatoid Arthritis. Clinical trials are currently underway for psoriasis vulgaris and psoriatic arthropatica. Remicade is a chimeric monoclonal antibody to human TNFα. In the clinical studies, the preparation showed good to very good activity in Mb. Crohn. However, there have been some significant side effects, such as increased Infection risk, gastrointestinal discomfort, headache and allergic reactions have been reported. Part of the side effects are attributed to the mouse portion of the monoclonal antibody, which is recognized as "foreign" by the human organism, producing antibodies to it Remicade is administered intravenously and the annual drug cost is over $ 12,000 per patient.
Humira (Abbott) ist für die Behandlung der Rheumatoiden Arthritis seit 2002 in USA und seit 2003 in Europa zugelassen. Klinische Studien zur Behandlung der Psoriasis vulgaris zeigten sehr gute Therapieerfolge. Als häufige Nebenwirkungen wurden Kopfschmerz, erhöhte Infektanfälligkeit, Magen- Darm Beschwerden und allergische Reaktionen beobachtet. Bei Humira handelt es sich um einen vollhumanisierten monoklonalen Antikörper gegen humanes TNFα. Das Präparat wird subcutan (s.c.) verabreicht. Die jährlichen Behandlungskosten belaufen sich auch bei diesem Präparat auf über $ 12.000 pro Patient.Humira (Abbott) has been approved in the US for rheumatoid arthritis since 2002 and in Europe since 2003. Clinical studies on the treatment of psoriasis vulgaris have shown very good therapeutic results. Headache, increased susceptibility to infections, gastrointestinal complaints and allergic reactions have been reported as common side effects. Humira is a fully humanized monoclonal antibody to human TNFα. The preparation is administered subcutaneously (s.c.). The annual cost of treatment for this product is over $ 12,000 per patient.
Enbrel (Immunex/Wyeth) wurde erstmals durch die FDA 1998 für die Indikation Rheumatoide Arthritis zugelassen und seit 2000 ist das Präparat auch auf dem europäischen Markt. Die Zulassung für die Indikation Psoriasis vulgaris und Psoriasis arthropatica wird noch 2004 von der FDA erwartet. Bei Enbrel handelt es sich um ein rekombinantes (CHO-Zellen) dimeres Fusionsprotein, bei dem zwei extrazelluläre Bindungsdomänen des p75- Anteils des TNF Rezeptors an den Fc-Anteil des humanen IgGI -Moleküls angekoppelt sind und dadurch lösliches TNFα im Blut/Gewebe abbinden und somit neutralisieren kann. Laut Herstellerangaben besitzt dieses Fusionsprotein ein geringes immunogenes Potential, wohingegen aber auch Fälle beschrieben wurden, in denen eine Antikörperbildung gegen das Fusionsprotein beobachtet wurde. Als häufige Nebenwirkungen wurden allergische Reaktionen, Infektanfälligkeit und die Bildung von Auto-Antikörpern (ANA) beschrieben. Das Präparat wird subcutan verabreicht und die jährlichen Behandlungskosten belaufen sich gleichfalls auf über $ 10.000 pro Patient. Zusammenfassend kann festgestellt werden, dass sich das therapeutische Konzept der Hemmung von TNFα als biologischer Endpunkt, als tragfähig in der Klinik erwiesen hat. Momentan stehen nur proteinogene Präparate (monoklonale Antikörper, Fusionsproteine) zur Verfügung, die eine Reihe von unerwünschten Arzneimittelnebenwirkungen aufweisen. Darüber hinaus ist deren intravenöse bzw. subkutane Applikationsform für Patienten sehr belastend und geht mit einer entsprechend schlechten Compliance einher. Die sehr hohen Herstellungs- und somit auch Behandlungskosten limitieren ebenfalls deren Einsatz.Enbrel (Immunex / Wyeth) was first approved by the FDA in 1998 for the indication Rheumatoid Arthritis and since 2000, the product is also on the European market. The approval for the indication psoriasis vulgaris and psoriasis arthropatica is expected in 2004 by the FDA. Enbrel is a recombinant (CHO cell) dimeric fusion protein in which two extracellular binding domains of the p75 portion of the TNF receptor are coupled to the Fc portion of the human IgGI molecule, thereby ligating soluble TNFα in the blood / tissue and thus can neutralize. According to the manufacturer, this fusion protein has a low immunogenic potential, but cases have also been described in which antibody formation against the fusion protein was observed. Common side effects include allergic reactions, susceptibility to infections and the formation of autoantibodies (ANA). The drug is administered subcutaneously and the annual cost of treatment is also over $ 10,000 per patient. In summary, it can be stated that the therapeutic concept of inhibiting TNFα has proven to be a biological endpoint, a viable clinical entity. Currently, only proteinogenic drugs (monoclonal antibodies, fusion proteins) are available that have a number of adverse drug side effects. In addition, their intravenous or subcutaneous administration form is very stressful for patients and is associated with correspondingly poor compliance. The very high production and thus also treatment costs also limit their use.
Es besteht deshalb nach wie vor Bedarf an niedermolekularen, nichtproteinogenen Wirkstoffen, die oral verabreicht werden können und eine bessere Verträglichkeit aufweisen. Zurzeit existieren noch keine bekannten niedermolekularen Verbindungen, die selektiv die Synthese von TNFα hemmen, ohne mit anderen Stoffwechselwegen zu interagieren und die oben beschriebenen unerwünschten Arzneimittelwirkungen nicht aufweisen.There is therefore still a need for low molecular weight, nonproteinogenic agents that can be administered orally and have better tolerability. There are currently no known low molecular weight compounds that selectively inhibit the synthesis of TNFα without interacting with other metabolic pathways and lacking the undesirable drug effects described above.
Es besteht deshalb die Aufgabe, neuartige und oral applizierbare niedermolekulare Wirkstoffe zu entwickeln, die zu einer signifikanten Inhibition der TNFα-Freisetzung aus relevanten humanen Zellpopulationen führen.It is therefore the object to develop novel and orally administrable low molecular weight drugs that lead to a significant inhibition of TNFα release from relevant human cell populations.
Diese Aufgabe wird von VerbindungenThis task is by connections
Figure imgf000013_0001
Figure imgf000013_0001
der allgemeinen Formeln 1a und 1b gelöst.of the general formulas 1a and 1b solved.
In bisher nur wenigen Fällen ist über biologisch aktive Pyrido[3',2':4,5]thieno- [3,2-d]pyrimidin-Derivate, jedoch noch nicht über entsprechende -2,4(1 H,3H)-dione berichtet worden: So wurden von J. M. Quintθla etai: Bioorg. Med. 6 (1998) 1911-1925, die Synthese von mehreren 2-Dimethylamino-(oder 2-H)-4-sek.amino-7-ethoxy-8-cyano-(oder 8- H)-9-phenyl- und auch das strukturanaloge 4-Ethoxy-pyrido[3',2':4,5]thieno[3,2- d]pyrimidin-Derivat beschrieben. Einige dieser Verbindungen zeigten eine die Histamin-Freisetzung aus Mastzellen von Ratten inhibierende Wirkung. Abdel- Rahmann et al.: Pharmazie 58 (2003) 372-377 berichteten über die Synthese von 8- Acetyl-3-amino-7-methyl-4-imino-9-substituierten Phenyl-pyrido[3',2':4,5]thieno[3,2- d]pyrimidinen mit antimikrobieller Wirksamkeit. Weiterhin wurden Derivate dieses Heterosystems mit unter anderem signifikanter cholesterolsenkender {C.J.Shishoo, M.B.Devani und V.S.Bhadti: Indian Patent 151.456 (1983); Chem. Abstr.: 100, 209858 (1984); und V.P.Arya, Drugs Future, 10, 123 (1985)), mit analgetischer (C.G.Dave et al.: J. Indian Chem.Soc. 66, 48 (1989)), mit antipyretischer (E.Bousquet et al.: Farmaco Ed.Sci. 40, 869 (1985); und E.Bousquet et al.: Farmaco Ed.Sci. 39, 110 (1984)), mit antianaphylaktischer (H.Vieweg, S.Leistner, G.Wagner et al.: East German Patent DD 257830 (1988); Chem. Abstr.: 110, 95262p (1989); und H. Vieweg, S.Leistner, G. Wagner et al.: East German Patent DD 258234 (1988)); mit antiinflammatorischer (E.F.EIslager, P.W.Jacob und M.Leslic: J.Heterocyclic Chem. 9, 775 (1972); und M.Chaykovskyet al.: J.Med.Chem. W, 188 (1973); und LA.Radinovskaya und A.Sharanin: Khim.Geterotsikl.Soedin. 805 (1988); und S.Leistner et al.: Pharmazie 41_, 54 (1986)); mit klinisch effektiver antiallergischer (G.D.Madding und M.D.Thompson: J.Heterocyclic Chem. 24, 581 (1987)); und mit potentiell antineoplastischer Wirksamkeit (C.C.Cheng:in Progress in Medicinal Chemistry25, 35 (1989) beschrieben.In so far only a few cases, biologically active pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidine derivatives, but not yet corresponding to -2,4 (1 H, 3H) - dione has been reported: Thus, JM Quintθla et al .: Bioorg. Med. 6 (1998) 1911-1925, the synthesis of several 2-dimethylamino (or 2-H) -4-sec-amino-7-ethoxy-8-cyano- (or 8-H) -9-phenyl- and also the structurally analogous 4-ethoxy-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidine derivative. Some of these compounds showed inhibition of histamine release from rat mast cells. Abdel-Rahmann et al .: Pharmacie 58 (2003) 372-377 reported the synthesis of 8-acetyl-3-amino-7-methyl-4-imino-9-substituted phenyl-pyrido [3 ' , 2 ' : 4 , 5] thieno [3,2-d] pyrimidines with antimicrobial activity. Furthermore, derivatives of this heterosystem with, inter alia, significant cholesterol-lowering {CJShishoo, MBDevani and VSBhadti: Indian Patent 151,456 (1983); Chem. Abstr .: 100, 209858 (1984); and VP Arya, Drugs Future, 10, 123 (1985)), with analgesic (CGDave et al .: J. Indian Chem. Soc 66, 48 (1989)), with antipyretic (E.Bousquet et al .: Farmaco Ed. Sci. 40, 869 (1985); and E. Bousquet et al .: Farmaco Ed. Sci., 39, 110 (1984)), with antianaphylactic (H.Vieweg, S. Listner, G. Wagner et al .: East German Patent DD 257830 (1988); Chem Abstr .: 110, 95262p (1989); and H. Vieweg, S. Leistner, G. Wagner et al .: East German Patent DD 258234 (1988)); with anti-inflammatory (EFEIslager, PWJacob and M.Leslic: J. Heterocyclic Chem. 9, 775 (1972); and M. Haykovsky et al .: J.Med.Chem.W, 188 (1973); and LA.Radinovskaya and A. Sharanin: Khim.Geterotsikl. Soedin 805 (1988); and S. Léstner et al .: Pharmacie 41, 54 (1986)); with clinically effective anti-allergic (GDMadding and MDThompson: J. Heterocyclic Chem. 24, 581 (1987)); and with potential antineoplastic activity (CCCheng: in Progress in Medicinal Chemistry 25, 35 (1989)).
Von M.A.A.EI-Neairy (Phosphorys, Sulfur and Silicon 1999, 189) wurden 8-Acetyl-7- methyl-θ-p-nitrophenyl-pyridoCS'^'^.δlthienofS^-dlpyrimidin^^CI H.SHJ-dion und dessen 9-p-Dimethylamino-Analogon und von V.A.Artemov et al. (Chemistry of Heterocyclic Compounds 30, 110 (1994) das entsprechende 7,9-Dimethyl-2,4-dion- Derivat beschrieben. Angaben über pharmakologische Eigenschaften dieser Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1 H,3H)-dione sind bisher nicht bekannt.MAAEI-Neairy (Phosphorys, Sulfur and Silicon 1999, 189) has prepared 8-acetyl-7-methyl-θ-p-nitrophenyl-pyridoCS ' ''',δ-thienofS'-dlpyrimidine ^^ CI H.SHJ-dione and its 9 p-dimethylamino analog and VAArtemov et al. (Chemistry of Heterocyclic Compounds 30, 110 (1994) describe the corresponding 7,9-dimethyl-2,4-dione derivative.) Information on pharmacological properties of these pyrido [3 ', 2': 4,5] thieno [3,2 -d] pyrimidine-2,4 (1H, 3H) -diones are not yet known.
Als Inhibitoren der TNFα-Freisetzung sind Verbindungen der allgemeinen Formeln 1a und 1b (jeweils für X=C-R2) jedoch bisher völlig unbekannt. Einige Vertreter des tricyclischen Thieno[2,3-d:4,5-d']dipyrimiclin-heterosystems sind als solche bereits bekannt.As inhibitors of TNFα release, however, compounds of the general formulas 1a and 1b (in each case for X =CR 2 ) are hitherto completely unknown. Some members of the tricyclic thieno [2,3-d: 4,5-d '] dipyrimiclin heterosystem are already known as such.
Es handelt sich bei den Verbindungen der allgemeinen Formel 1a (für X=N) um R1- und R3-substituierte Bislactame und bei den Verbindungen der allgemeinen Formel 1 b (für X=N) um R1-, R3- und R4-substituierte Monolactame des Thieno[2,3-d:4,5- d']dipyrimidin-heterosystems.The compounds of the general formula 1a (for X =N) are R 1 - and R 3 -substituted bis-lactams and in the case of the compounds of the general formula 1 b (for X =N) R 1 -, R 3 - and R 4 -substituted monolactams of the thieno [2,3-d: 4,5-d '] dipyrimidine heterosystem.
Von den Verbindungen der allgemeinen Formel 1a (für X=N) ist eine Substanz (mit R1 = H und R3 = NHMe) beschrieben (Clark,J. und Hitiris,G. J.Chem.Soc, Perkin Trans. 1984, 2005). Ein Hinweis auf pharmakologische Eigenschaften findet sich nicht.Of the compounds of general formula 1a (for X = N), a substance (with R 1 = H and R 3 = NHMe) is described (Clark, J. and Hitiris, GJ Chem. Soc, Perkin Trans. 1984, 2005). There is no indication of pharmacological properties.
Von den Verbindungen der allgemeinen Formel 1b (für X=N) sind dagegen derzeit 24 Substanzen literaturbekannt.Of the compounds of general formula 1b (for X = N), on the other hand, 24 substances are currently known from the literature.
Es handelt sich dabei vorwiegend um Verbindungen mit R1 = Ph und R3 = Me und verschiedenen R4-Substituenten wie Me, SH, SAIk, SCH2COR5, NHNH2 und daraus dargestellte Hydrazone sowie substituierte 3,5-Pyrazol-1-yl-Reste. Als R1 tritt auch H, Me, OH und 3,5-Dimethylpyrazol-1 -yl und als R3 auch Ph, NHMe (in diesem Fall R1 = H; R4 = NH2). In der Veröffentlichung von Wagner.G. Vieweg.H. und Leistner.S. Pharmazie 48, 588 (1993) ist ein Hinweis auf nicht sehr ausgeprägte Wirkung am PCA-Test der Ratte gegeben. Ein Hinweis auf andere pharmakologische Eigenschaften findet sich laut Recherche nicht.These are predominantly compounds with R 1 = Ph and R 3 = Me and various R 4 substituents such as Me, SH, SAIk, SCH 2 COR 5 , NHNH 2 and hydrazones thereof and substituted 3,5-pyrazole-1 yl radicals. As R 1 , H, Me, OH and 3,5-dimethylpyrazole-1-yl and, as R 3, also Ph, NHMe (in this case R 1 = H; R 4 = NH 2 ) also occur. In the publication of Wagner.G. Vieweg.H. and Leistner.S. Pharmazie 48, 588 (1993) gives an indication of not very pronounced effect on rat PCA test. An indication of other pharmacological properties is not found, according to research.
Vor der vorliegenden Erfindung bekannte Struktur-Wirkungsbeziehungen erlaubten keine seriöse Voraussage, ob Verbindungen der allgemeinen Formel 1a (für X=N), aber auch 1b (für X=N) nützliche pharmakologische Eigenschaften aufweisen. Es ist daher überraschend, daß erstmals festgestellt werden konnte, daß Derivate der Titelverbindungen 1a und 1b die TNFα-Freisetzung inhibieren. Beschreibung der ErfindungStructure-activity relationships known prior to the present invention did not allow a serious prediction as to whether compounds of general formula 1a (for X = N) but also 1b (for X = N) have useful pharmacological properties. It is therefore surprising that it was found for the first time that derivatives of title compounds 1a and 1b inhibit TNFα release. Description of the invention
Die Erfindung betrifft neue Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1 H,3H)-clione und -4(3H)-one (X=C-H1 Y=S), Thieno[2,3-d:4,5-d']dipyrimidin-2,4(1 H,3H)-dione und -4(3H)-one (X=N, Y=S) sowie Pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2,4(1H,3H)-dione und -4(3H)-one (X=C-H, Y=O) und Furo[2,3-d:4,5-d']dipyrimidin-2l4(1 H,3H)-dione und -4(3H)-one (X=N, Y=O) der allgemeinen Formeln 1a und 1 bThe invention relates to novel pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidine-2,4 (1 H, 3H) -clione and -4 (3H) -one (X = CH 1 Y = S), thieno [2,3-d: 4,5-d '] dipyrimidine-2,4 (1H, 3H) -diones and -4 (3H) -one (X = N, Y = S) and pyrido [3 ' , 2 ' : 4,5] furo [3,2-d] pyrimidine-2,4 (1H, 3H) -diones and -4 (3H) -ones (X = CH, Y = O) and furo [2,3-d: 4,5-d '] dipyrimidine-2 L 4 (1 H, 3H) -diones and -4 (3H) -ones (X = N, Y = O) of general formulas 1a and 1 b
Figure imgf000016_0001
Figure imgf000016_0001
worin bedeuten:in which mean:
X C-R2 oder StickstoffX is CR 2 or nitrogen
Y Schwefel oder Sauerstoff undY sulfur or oxygen and
R1 und R3, gleich oder ungleich unabhängig voneinander,R 1 and R 3 , the same or different independently,
- Wasserstoff,- hydrogen,
- Ci-i2Alkyl (ggf. mit R§ substituiert),- Ci-i 2 alkyl (optionally substituted with R § ),
- C-2-12 Alkenyl und C-2-12 Alkinyl (jeweils ggf. mit R§ substituiert ),- C-2 12 alkenyl and C 2-12 alkinyl (each optionally substituted with R §),
- Benzyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert)), Phenyl-(C2-β)alkyl , Phenyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert),- benzyl), phenyl (C 2 -β) alkyl, phenyl (optionally mono- (optionally mono- to pentasubstituted independently of one another by R § substituted) to five times independently of one another by R § substituted),
- Monofluormethyl, Difluormethyl, Trifluormethyl,Monofluoromethyl, difluoromethyl, trifluoromethyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert),- 1-naphthyl, 2-naphthyl (each optionally substituted with R § ),
- C3-i4Cycloalkyl, C3-i4Cycloalkenyl (jeweils ggf. mit R§-substituiert),- C 3 -i 4 cycloalkyl, C 3 i 4 cycloalkenyl (in each case optionally with R § -substituted)
- mono- oder bicyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen (ggf. ein oder mehrfach mit R§ substituiert) mit 5 - 14 Ringatomen darunter 1 - 4 Heteroatome, die vorzugsweise N, O und S sind und ggf. am Heteroatom ein oder mehrfach oxidiert sind, - Ci-i2Alkylacyl (ggf. mit R§ substituiert),- mono- or bicyclic saturated or mono- or polyunsaturated heterocycles (if necessary, one or more times with R § substituted) with 5 - 14 ring atoms including 14 heteroatoms which are preferably N, O and S and possibly one on the hetero atom or are oxidized several times, - Ci-i2Alkylacyl (optionally substituted with R § ),
- Benzoyl, 1- und 2-Naphthoyl (jeweils ggf. mit R§ substituiert),- benzoyl, 1- and 2-naphthoyl (each optionally substituted with R § ),
- Heterocyclylacyl [z.B. Nicotinoyl, Isonicotinoyl, 2-Picolinoyl, 2-Thienoyl, 2- Furoyi] (ggf. mit R§ substituiert)Heterocyclylacyl [eg nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyi] (optionally substituted with R § )
- Hydroxy,- hydroxy,
- Sulfhydryl,Sulfhydryl,
- C1-10 Alkoxy,C1-10 alkoxy,
- Alkylthio, Alkylsulfinyl und Alkylsulfonyl (jeweils Ci-6 )- alkylthio, alkylsulfinyl and alkylsulfonyl (each Ci -6 )
- Formyl, Carboxyl, Ci-4Alkoxycarbonyl;- formyl, carboxyl, Ci -4 alkoxycarbonyl;
- CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils Ci-6),CONH 2 , CONHAIk and CONAIk 2 (with "Alk" in each case Ci- 6 ),
- Cyano, Rhodano, Nitro, SO3H, SO2OAIk (mit „Alk": Ci-5),Cyano, Rhodano, Nitro, SO 3 H, SO 2 OAlk (with "Alk": Ci -5 ),
- Chlor, Brom, lod, Fluor,Chlorine, bromine, iodine, fluorine,
- Amino, Ci-6Alkylamino, Di(Ci-5)alkylamino (jeweils ggf. mit R§ am Alkylrest substituiert),- amino, Ci -6 alkylamino, di (Ci -5) alkylamino (in each case optionally substituted with R § on the alkyl residue),
- Morpholino, Thiomorpholino, Thiomorpholino-S,S-Dioxid, Pyrrolidino,- morpholino, thiomorpholino, thiomorpholino-S, S-dioxide, pyrrolidino,
- Piperidino, 1-Piperazino, 4-Methyl-1-piperazino, 4-Hydroxyethyl-1-piperazino, 4-Phenyl-1 -piperazino,Piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino,
- Cycloalkylamino, C3-I4 Arylamino und Heteroarylamino [z.B. Phenyl-, 1τ und 2-Naphthyl-, 2-, 3- oder 4-Pyridyl-, Chinolinyl-, Isochinolinyl-, Acridinyl-, Phenothiazinyl-, 2-Thienyl- und 2-Furylamino] (ggf. jeweils an den carbo- bzw. heterocyclischen Ringen mit R§ substituiert);- Cycloalkylamino, C 3 -I4 arylamino and heteroarylamino [eg phenyl, 1τ and 2-naphthyl, 2-, 3- or 4-pyridyl, quinolinyl, isoquinolinyl, acridinyl, phenothiazinyl, 2-thienyl and 2-furylamino] (optionally substituted on the carbo- or heterocyclic rings with R § );
R2 R 2
- Wasserstoff,- hydrogen,
- Ci-i2Alkyl> - Ci-i 2 alkyl >
- C2-i2Alkenyl und C2-12 Alkinyl,- C 2 -i 2 alkenyl, and C 2 - 12 alkynyl,
- Benzyl, Phenyl(C2-6)alkyl (jeweils ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen und/oder aliphatischen Molekülteil substituiert); - Phenacyl (ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen Molekülteil substituiert);- Benzyl, phenyl (C 2 - 6 ) alkyl (each optionally with R § one or more times, the same or not equal to the aromatic and / or aliphatic moiety substituted); - Phenacyl (optionally with R § one or more times, the same or different substituted on the aromatic moiety);
- Carboxyl, C1-4 Alkoxycarbonyl, CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils C1-6),Carboxyl, C 1-4 alkoxycarbonyl, CONH 2 , CONHAIk and CONAIk 2 (with "Alk" in each case C1-6),
- FTCO- (worin R* Wasserstoff, Cπ2Alkyl bedeuten sowie ggf. mit R§ substituiert),- FTCO- (wherein R * is hydrogen, Cπ 2 mean alkyl and optionally with R § substituted),
- Cyano, Nitro, Amino, Ci-6Alkylamino, Di(Ci-6)alkylamino, -N=N-C6H5, -N=N- C6H4-R§,- cyano, nitro, amino, Ci -6 alkylamino, di (Ci -6) alkylamino, -N = NC 6 H 5, -N = NC 6 H 4 -R §,
- 1 ,3-DiphenyI-pyrazol-4-yl, Thiazolin-2-yl, lmidazolin-2-yl und 3,4,5,6- Tetrahydro-pyrimidinyl;- 1, 3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl and 3,4,5,6-tetrahydropyrimidinyl;
RA R A
- C2-i4A!kyl, C3-i4Cycloalkyl, C2-i4Alkenyl, Ce-nCycloalkenyl, C2-i4Alkinyl (jeweils ggf. am C-Skelett der vorgenannten aliphatischen oder cycloaliphatischen Reste mit R§ substituiert);- C i 2 4 A kyl, C 3 -i 4 cycloalkyl, C 2 i 4 alkenyl, Ce-nCycloalkenyl, C 2- 4 alkynyl i (in each case optionally at the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals with R § substituted);
- Phenyl, 2-R§-Phenyl, 3-R§-Phenyl, 4-R§-Phenyl, 2-R§,5-R§-Phenyl,- phenyl, 2-R § -phenyl, 3-R § -phenyl, 4-R § -phenyl, 2-R §, 5-R § -phenyl,
3-R§,5-R§-Phenyl, 3-R§,4-R§-Phenyl, 3-R§,4-R§,5-R§-Phenyl, 2-R§,3-R§,4-R§-Phenyl,3-R § , 5-R § -phenyl, 3-R § , 4-R § -phenyl, 3-R § , 4-R § , 5-R § -phenyl, 2-R § , 3-R § , 4-R § -phenyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert);- 1-naphthyl, 2-naphthyl (each optionally substituted with R § );
- mono-, bi- oder tricyclische gesättigter oder ein- oder mehrfach ungesättigter heterocyclischer Rest mit insgesamt 4-14 Ring-Atomen, davon 1 -5 Heteroatomen, die vorzugsweise N, O, S und Se sind (jeweils ggf. mit R§ substituiert);- mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocyclic radical having a total of 4-14 ring atoms, of which 1-5 heteroatoms, which are preferably N, O, S and Se (each optionally substituted with R § );
- CH2OAIk* (mit Alk*: C1-6Alkyl),- CH 2 OAlk * (with Alk * : C 1-6 alkyl),
- CH2OCOR' (mit R': Ci-6Alkyl, C2-6Alkenyl, Phenyl sowie mit R§ substituiert),- CH 2 OCOR '(R': Ci -6 alkyl, C 2-6 alkenyl, phenyl, and with R § substituted),
- COOH, COOAIk** (mit Alk**: Ci-5Alkyl),COOH, COOAlk ** (with Alk ** : Ci -5 alkyl),
- NH2, NHAIk*, (mit Alk*: C1-6Alkyl )- NH 2 , NHAlk *, (with Alk *: C 1-6 alkyl)
- NHNH2, NHNHCOR' (mit R': Ci-6Alkyl, Ci-6Alkenyl, Phenyl sowie mit R§ substituiert),- NHNH 2, NHNHCOR '(with R': Ci -6 alkyl, Ci -6 alkenyl, phenyl and substituted with R §),
- SO3H, S-Phenacyl, S-Alkyl, SO-Alkyl, SO2-Alkyl (jeweils C1-S )SO 3 H, S-phenacyl, S-alkyl, SO-alkyl, SO 2 -alkyl (each C 1 -S)
- S-Alkenyl, SO-Alkenyl, SO2-Alkenyl (jeweils C2-8), S-Alkinyl, SO-Alkinyl, SO2-Alkinyl (jeweils C2-6) (ggf- jeweils am C-Skelett der oben genannten aliphatischen Reste mit -OH, -CN, -SCN, -NO2, Phenyl oder (C3-7)Cycloalkyl substituiert) Der oben erwähnte Ausdruck „ggf. mit R§ substituiert" bedeutet, daß die genannten Reste einfach oder mehrfach, gleich oder ungleich unabhängig voneinander, substituiert sein können, wobei R§ folgende Bedeutung hat:- S-alkenyl, SO-alkenyl, SO 2 alkenyl (each C 2 - 8 ), S-alkynyl, SO-alkynyl, SO 2 -alkynyl (each C2-6) (optionally on the C skeleton of the above aliphatic residues with -OH, -CN, -SCN, -NO 2, phenyl or (C 3-7) cycloalkyl substituted) The above-mentioned expression "possibly substituted with R § "means that the radicals mentioned may be monosubstituted or polysubstituted, identical or different, independently of one another, where R § has the following meaning:
OH1 -SH, -O-C1-8Alkyl, -0-C6-I4 Aryl, -S-Ci-4 Alkyl, -S-C6-i4Aryl, -SO-C1-4AIkVl, -SO-C6-I4ArVl1 -SO2-C1-4Alkyl, -SO2-C6-I4AIyI1 -SO3H, -OSO2C1-8Alkyl, -OSO2C6-14Ary I, -COOH, -COOCi-8Alkyl, -(CO)Ci-8Alkyl, -COOH, -COOCi-8Alkyl, -CONH2, -CONHCi-6Alkyl, -CON(Ci-6Alkyl)2, -NH2, -NHC1-6Alkyl, -N(C1-6Alkyl)2, -NHC6-i4Aryl, -NH-Hetaryl, -N(C6-I4AIyI)2, -N(CiVMM)(C6-I4ArVl),OH 1 -SH, -OC 1-8 alkyl, -O-C 6 -I 4 aryl, -S-Ci -4 alkyl, -SC 6 -i 4 aryl, -SO-C 1-4 AlkVl, -SO- C6 - I4 -aryl 1 -SO 2 -C 1-4 alkyl, -SO 2 -C 6 - I4 Aiyi 1 -SO 3 H, -OSO 2 C 1-8 alkyl, -OSO 2 C 6-14 ary I, -COOH, -COOCi -8 alkyl, - (CO) Ci -8 alkyl, -COOH, -COOCi -8 alkyl, -CONH 2 , -CONHCi -6 alkyl, -CON (Ci -6 alkyl) 2 , -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , -NHC 6 -i 4 aryl, -NH-hetaryl, -N (C 6 -I 4- AIyI) 2 , -N (CiVMM) ( C 6 -I 4 ArVl),
-CH3, -CHF2, -CH2F1 -CF3, -C2HO, -C(CHa)2, -(CH2)2CH3, -(CH2)3CH3, -CH2CH2OH, -CH2CH2SH, -CH2CH2SCHa, -CH2CF3, -CH2CCIs, -CH2CBr3 -CH2CHF2, -CH2CHCI2, -CH2CHBr21 -CH2CH2F, -CH2CH2CI, -CH2CH2Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, - -Cyclopentylmethyl, -Cylohexyl, -Cyclohexylmethyl, -F, -Cl, -Br, -I, -CN1 -NO2, und -SCN-CH 3, -CHF 2, -CH 2 F 1 is -CF 3, -C 2 H O, -C (CHa) 2, - (CH 2) 2 CH 3, - (CH 2) 3 CH 3, -CH 2 CH 2 OH, -CH 2 CH 2 SH, -CH 2 CH 2 SCHa, -CH 2 CF 3 , -CH 2 CCIs, -CH 2 CBr 3 -CH 2 CHF 2 , -CH 2 CHCl 2 , -CH 2 CHBr 21 -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, -Cyclopentylmethyl, -Cyclohexyl, -Cyclohexylmethyl, -F , -Cl, -Br, -I, -CN 1 -NO 2 , and -SCN
Ausgenommen vom Stoffschutz sind die folgenden Verbindungen der Formel 1a:The following compounds of the formula 1a are excluded from the substance protection:
R1 X R3 R 1 XR 3
1. Me C-H Me1st Me C-H Me
2. Me C-Ac 4-NMe2Ph2. Me C-Ac 4-NMe 2 Ph
3. Me C-Ac 4-NO2Ph3. Me C-Ac 4-NO 2 Ph
Ausgenommen vom Stoffschutz sind auch die folgenden Verbindungen der Formel 1 b mit folgenden Resten:The following compounds of the formula 1 b with the following radicals are also excluded from the substance protection:
jeweils R1 = OEt, X = C-CN, R3 = Ph mit R4= Benzyl, Phenyl, z.T. mehrfach mit Me,each R 1 = OEt, X = C-CN, R 3 = Ph with R 4 = benzyl, phenyl, sometimes several times with Me,
OMe, NO2 und Cl substituiert und 3,4-Methylendioxy-phenyl; jeweils R1 = Ph, X = C-H, R3 = Ph mit R4= Phenyl, p-OCH3-Ph, p-CI-Ph,OMe, NO 2 and Cl substituted and 3,4-methylenedioxy-phenyl; each R 1 = Ph, X = CH, R 3 = Ph with R 4 = phenyl, p-OCH 3 -Ph, p-CI-Ph,
2,3,4-Tn-OCH3-Ph und 2-Thienyl; jeweils R1 = Me, X =C-H, R3 = Me mit R4 = CH2OMe, CH2OEt, CH2OCOMe,2,3,4-Tn-OCH 3 -Ph and 2-thienyl; each R 1 = Me, X = CH, R 3 = Me with R 4 = CH 2 OMe, CH 2 OEt, CH 2 OCOMe,
CH2COOPh, SCH2COPh, NH2, NHNH2, COOH1 Ph; sowie:CH 2 COOPh, SCH 2 COPh, NH 2 , NHNH 2 , COOH 1 Ph; such as:
R1 = Me, R3 = Ph1 R4 = COOEt; X = C-H; R1 = Me, R3 = p-Br-Ph, R4 = COOEt; X = C-H; R1 = p-Br-Ph, R3 = Me, R4 = COOMe; X = C-H; R1 = Me, R3 = Me, R4 = COOMe; X = C-Benzyl R1 = R3 = Me, R4 = COOMe, X = C-Me R1 = Ph, R3 = Me, R4 = SEt, X = N.R 1 = Me, R 3 = Ph 1 R 4 = COOEt; X = CH; R 1 = Me, R 3 = p-Br-Ph, R 4 = COOEt; X = CH; R 1 = p-Br-Ph, R 3 = Me, R 4 = COOMe; X = CH; R 1 = Me, R 3 = Me, R 4 = COOMe; X = C-benzyl R 1 = R 3 = Me, R 4 = COOMe, X = C-Me R 1 = Ph, R 3 = Me, R 4 = SEt, X = N.
In der Erfindungsbeschreibung bedeuten die Begriffe "Alkyl, Alkenyl, Alkinyl, Alkoxy, usw.", auch in Wortzusammensetzungen wie Alkylsulfonyl, Alkylamino oder Alkoxycarbonyl usw. sowohl die unverzweigten wie auch die verzweigten möglichen Verbindungen. Ebenso bedeuten „Alkenyl und Alkinyl" die entsprechend möglichen einfach oder mehrfach ungesättigten Verbindungen. Das gleiche gilt auch für die entsprechenden cyclischen Verbindungen.In the specification of the invention, the terms "alkyl, alkenyl, alkynyl, alkoxy, etc.", also in word compositions such as alkylsulfonyl, alkylamino or alkoxycarbonyl, etc., mean both the unbranched and the branched possible compounds. Likewise, "alkenyl and alkynyl" means the correspondingly possible monounsaturated or polyunsaturated compounds, as well as the corresponding cyclic compounds.
Im Sinne der Erfindung gelten alle Reste als miteinander kombinierbar, soweit bei der Definition der Reste nichts anderes angegeben ist. Es sollen alle denkbaren Untergruppierungen als offenbart gelten.For the purposes of the invention, all radicals are to be combined with one another, unless stated otherwise in the definition of the radicals. All possible subgroups should be considered revealed.
Die Erfindung betrifft auch physiologisch verträgliche Salze der Verbindungen der allgemeinen Formeln 1a und 1b.The invention also relates to physiologically acceptable salts of the compounds of the general formulas 1a and 1b.
Die physiologisch verträglichen Salze werden auf übliche Weise durch Umsetzung basischer Verbindungen der allgemeinen Formeln 1a und 1b mit anorganischen oder organischen Säuren, ggf. auch bei Vorliegen von Verbindungen mit aciden Eigenschaften, wenn z.B. einer der Substituenten R1, R2, R3 oder R4 in diesen Verbindungen -COOH bzw. -SO3H bedeutet, durch Neutralisation mit anorganischen oder organischen Basen, erhalten.The physiologically acceptable salts are prepared in a conventional manner by reacting basic compounds of the general formulas 1a and 1b with inorganic or organic acids, if appropriate also in the presence of compounds having acidic properties, for example when one of the substituents R 1 , R 2 , R 3 or R 4 in these compounds -COOH or -SO 3 H means, by neutralization with inorganic or organic bases, obtained.
Als anorganische Säuren kommen vorzugsweise Salzsäure, Schwefelsäure, Salpetersäure oder Bromwasserstoffsäure, als organische Säuren zum Beispiel Ameisensäure, Essigsäure, Propionsäure, Glykolsäure, Milchsäure, Mandelsäure, Weinsäure, Äpfelsäure, Zitronensäure, Malonsäure, Maleinsäure, Fumarsäure, Succinsäure, Alginsäure, Benzoesäure, 2-, 3- und 4-Alkyloxy- und Acyloxy- benzoesäuren, Ascorbinsäure, Ci-C3,Alkylsulfonsäuren, Benzolsulfonsäure, Nicotinsäure, Isonicotinsäure und Aminosäuren zur Anwendung. Als anorganische Basen kommen zum Beispiel Ammoniak, Natron- und Kalilauge sowie als organische Basen Alkylamine, CrC3, Pyridin, Chinolin, Isochinolin, Piperazin und -Derivate, Picoline, Chinaldin oder Pyrimidin zur Anwendung.As inorganic acids are preferably hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, as organic acids for example formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, mandelic acid, tartaric acid, malic acid, citric acid, malonic acid, maleic acid, fumaric acid, succinic acid, alginic acid, benzoic acid, , 3- and 4-alkyloxy and acyloxybenzoic acids, ascorbic acid, Ci-C 3 , alkylsulfonic acids, benzenesulfonic acid, nicotinic acid, isonicotinic acid and amino acids for use. The inorganic bases used are, for example, ammonia, sodium hydroxide and potassium hydroxide solution and, as organic bases, alkylamines, CrC 3 , pyridine, quinoline, isoquinoline, piperazine and derivatives, picolines, quinaldine or pyrimidine.
Weiterhin können physiologisch verträgliche Salze der Verbindungen gemäß der allgemeinen Formeln 1a und 1 b dadurch gewonnen werden, dass jene Substanzen, die als Substituenten eine tertiäre Amino-Gruppe besitzen, in prinzipiell bekannter Weise mit alkylierenden Agentien - wie zum Beispiel Alkyl- oder Aralkylhalogeniden - in die entsprechenden quatemären Ammoniumsalze übergeführt werden können.Furthermore, physiologically acceptable salts of the compounds according to the general formulas 1a and 1b can be obtained by reacting those substances which as substituents have a tertiary amino group in a manner known in principle with alkylating agents, such as, for example, alkyl or aralkyl halides the corresponding quaternary ammonium salts can be converted.
Die Erfindung betrifft auch Solvate der Verbindungen, einschließlich der pharmazeutisch akzeptablen Salze, Säuren, Basen und Ester sowie deren aktive Metabolite und gegebenenfalls deren Tautomere gemäß der allgemeinen Formeln 1 a und 1 b einschließlich Prodrug-Formulierungen. Prodrug-Formulierungen umfassen hierbei alle jene Substanzen, die durch einfache Transformation einschließlich Hydrolyse, Oxidation, oder Reduktion entweder enzymatisch, metabolisch oder auf andere Art und Weise entstehen. Ein geeignetes Prodrug enthält beispielsweise eine Substanz der allgemeinen Formeln 1 a und 1 b, die über einen enzymatisch spaltbaren Linker (z.B. Carbamat, Phosphat, N-Glycosid oder eine Disulfidgruppe) an eine lösungsverbessemde Substanz (z.B. Tetraethylenglykol, Saccharide, Aminosäuren oder Glucuronsäure, etc.) gebunden ist. Ein solches Prodrug einer erfindungsgemäßen Verbindung kann einem Patienten appliziert werden, und dieses Prodrug kann in eine Substanz der allgemeinen Formeln 1a und 1b transformiert werden, wodurch der gewünschte pharmakologische Effekt erzielt wird.The invention also relates to solvates of the compounds, including the pharmaceutically acceptable salts, acids, bases and esters and their active metabolites and optionally their tautomers according to the general formulas 1a and 1b, including prodrug formulations. Prodrug formulations herein include all those substances which are formed by simple transformation including hydrolysis, oxidation, or reduction, either enzymatically, metabolically, or otherwise. A suitable prodrug contains, for example, a substance of the general formulas 1a and 1b which, via an enzymatically cleavable linker (eg carbamate, phosphate, N-glycoside or a disulphide group) to a solution-improving substance (eg tetraethylene glycol, saccharides, amino acids or glucuronic acid, etc .) is bound. Such a prodrug of a compound of the present invention may be administered to a patient, and this prodrug may be transformed into a substance of the general formulas 1a and 1b, thereby achieving the desired pharmacological effect.
Die durch die erfindungsgemäßen Verbindungen behandelbaren Erkrankungen schließen alle ein, bei denen TNF-alpha eine Rolle spielt und die durch eine Hemmung oder Inhibierung desselben positiv zu beeinflussen sind, z.B. chronische Entzündungserkrankungen, Autoimmun-Erkrankungen, cardiovaskuläreThe diseases treatable by the compounds of the invention include any of those in which TNF-alpha is involved and which are positively affected by inhibition or inhibition thereof, e.g. chronic inflammatory diseases, autoimmune diseases, cardiovascular
Erkrankungen, virale Erkrankungen und hier insbesondere retrovirale Erkrankungen wie z.B. das erworbene Immundefizienz Syndrom (AIDS) sowie Krebs, insbesondere Entartungen des blutbildenden Systems. Insbesondere sind dies Rheumatoide Arthritis, Osteoarthritis, Osteoporosis, Asthma bronchiale, chronische obstruktive pulmonäre Erkrankung (COPD), Multiple Sklerose, Sepsis, cerebrale Form der Malaria, neurodegenerativen Erkrankungen wie z.B. Mb. Alzheimer, Mb. Parkinson, Guillain-Barre-Syndrom, Crohns Disease, Colitis ulcerosa, Psoriasis, Graft-versus- Host-Disease (GvHD), systemischer Lupus erythematodes (SLE), Vasculitis, Uveitis, insulin-abhängiger Diabetes mellitus, Respiratorisches Distress-Syndrom beim Erwachsenen (ARDS), multiples Organversagen nach Trauma, aktute Glomerulonephritis, akute und chronische Schmerzen, Arteriosklerose, Herzinfarkt, Schlaganfall, entzündliche Dermatosen, atopische Dermatitis, Psoriasis vulgaris, Alopecie, Rhinitis allergica, allergische Konjunktivitis, akute Meningitis, Myastenia Gravis, Sklerodermie und Sarkoidose.Diseases, viral diseases and especially retroviral diseases such as the acquired immunodeficiency syndrome (AIDS) and cancer, especially degeneration of the hematopoietic system. In particular, these are rheumatoid arthritis, osteoarthritis, osteoporosis, bronchial asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, sepsis, cerebral form of the Malaria, neurodegenerative diseases such as Mb. Alzheimer's, Mb. Parkinson's, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft-versus-host disease (GvHD), systemic lupus erythematosus (SLE), vasculitis, uveitis, insulin-dependent diabetes mellitus, adult respiratory distress syndrome (ARDS), multiple organ failure after trauma, acute glomerulonephritis, acute and chronic pain, arteriosclerosis, myocardial infarction, stroke, inflammatory dermatoses, atopic dermatitis, psoriasis vulgaris, alopecia, rhinitis allergica, allergic Conjunctivitis, acute meningitis, myasthenia gravis, scleroderma and sarcoidosis.
Die erfindungsgemäßen Verbindungen können auf verschiedenen Wegen verabreicht werden, z.B. oral, parenteral, kutan, subkutan, intravenös, intramuskulär, rektal oder inhalativ. Bevorzugt ist die intravenöse oder inhalative Verabreichung. Die Verbindung wird einem Patienten, der eine Therapie einer unter das Indikationsspektrum der erfindungsgemäßen Verbindungen fallenden Krankheit bedarf, über einen vom Arzt zu bestimmenden Zeitraum verabreicht. Die Verbindung kann sowohl Menschen als auch anderen Säugern verabreicht werden.The compounds of the invention can be administered in a variety of ways, e.g. oral, parenteral, cutaneous, subcutaneous, intravenous, intramuscular, rectal or inhalation. Preference is given to intravenous or inhalational administration. The compound is administered to a patient in need of therapy of a disease falling within the range of indications of the compounds of the invention for a period to be determined by the physician. The compound can be administered to both humans and other mammals.
Die Dosierung der erfindungsgemäßen Verbindungen wird vom Arzt anhand der patientenspezifischen Parameter wie z.B. Alter, Gewicht, Geschlecht, Schwere der Erkrankung, etc. bestimmt. Bevorzugt beträgt die Dosierung zwischen 0,001 mg/kg bis 1000 mg/kg Körpergewicht, bevorzugt 0,01 bis 500 mg/kg Körpergewicht und ganz bevorzugt 0,1 bis 100 mg/kg Körpergewicht.The dosage of the compounds according to the invention is determined by the physician on the basis of the patient-specific parameters, e.g. Age, weight, sex, severity of the disease, etc. are determined. Preferably, the dosage is between 0.001 mg / kg to 1000 mg / kg body weight, preferably 0.01 to 500 mg / kg body weight and most preferably 0.1 to 100 mg / kg body weight.
Entsprechend der Art der Verabreichung wird das Medikament in geeigneter Weise formuliert, z.B. in Form von Lösungen bzw. Suspensionen, einfachen oder dragierten Tabletten, Hart- oder Weichgelatinekapseln, Pulver zur Rekonstitution vor Gebrauch, Aerosolen, Inhalationssprays, Wirkstoffpflastern, Granulaten, Suppositorien, Ovula, Injektionspräparaten, Cremes, Salben, Gels, Mikrospheren, Implantaten, die nach üblichen galenischen Verfahren hergestellt werden.According to the mode of administration, the medicament is suitably formulated, e.g. in the form of solutions or suspensions, simple or sugar-coated tablets, hard or soft gelatin capsules, reconstitution pre-use powders, aerosols, inhalation sprays, active substance patches, granules, suppositories, ovules, injectables, creams, ointments, gels, microspheres, implants, according to customary galenic processes.
Die erfindungsgemäßen Verbindungen können gegebenenfalls zusammen mit weiteren Wirkstoffen und mit in pharmazeutischen Zusammensetzungen üblichen Exzipientien formuliert werden, z.B. je nach herzustellendem Präparat Talk, Gummi arabicum, Lactose, Stärke, Magnesiumstearat, Kakaobutter, wäßrige und nichtwäßrige Träger, Fettkörper mit tierischem oder pflanzlichem Ursprung, Paraffinderivate, Glykole (insbesondere Polytethylenglykol), verschiedene Weichmacher, Dispergiermittel oder Emulgatoren, pharmazeutisch verträgliche Gase (z.B. Luft, Sauerstoff, Kohlendioxid usw.), Konservierungsstoffe.If appropriate, the compounds according to the invention can be formulated together with further active compounds and with excipients customary in pharmaceutical compositions, for example depending on the preparation to be prepared talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols (especially polyethyleneglycol), various plasticizers, dispersants or emulsifiers, pharmaceutically acceptable gases (eg air, oxygen, carbon dioxide, etc.). , Preservatives.
Zur Herstellung flüssiger Präparate können Additive wie Natriumchloridlösung, Ethanol, Sorbit, Glycerin, Olivenöl, Mandelöl, Propylenglycol oder Ethylenglycol verwendet werden.For the preparation of liquid preparations, additives such as sodium chloride solution, ethanol, sorbitol, glycerin, olive oil, almond oil, propylene glycol or ethylene glycol can be used.
Bei der Verwendung von Infusions- oder Injektionslösungen sind diese sind bevorzugt wäßrige Lösungen oder Suspensionen, wobei es möglich ist, diese vor Gebrauch herzustellen, beispielsweise aus lyophilisierten Präparaten, die den Wirkstoff alleine oder zusammen mit einem Träger, wie Mannit, Lactose, Glucose, Albumin und dergleichen, enthalten. Die gebrauchsfertigen Lösungen werden sterilisiert und gegebenenfalls mit Hilfsmitteln vermischt, beispielsweise mit Konservierungsstoffen, Stabilisatoren, Emulgatoren, Lösungsvermittlern, Puffern und/oder Salzen zur Regulierung des osmotischen Drucks. Die Sterilisierung kann durch Sterilfiltration durch Filter mit einer kleinen Porengröße erzielt werden, wonach die Zusammensetzung gegebenenfalls lyophilisiert werden kann. Geringe Mengen an Antibiotika können auch zugesetzt werden, um die Beibehaltung der Sterilität zu gewährleisten.When using infusion or injection solutions, these are preferably aqueous solutions or suspensions, it being possible to prepare them before use, for example from lyophilized preparations containing the active ingredient alone or together with a carrier such as mannitol, lactose, glucose, albumin and the like. The ready-to-use solutions are sterilized and optionally mixed with adjuvants such as preservatives, stabilizers, emulsifiers, solubilizers, buffers and / or osmotic pressure control salts. Sterilization can be achieved by sterile filtration through filters of small pore size, after which the composition is optionally can be lyophilized. Small amounts of antibiotics may also be added to ensure sterility maintenance.
Weiter bevorzugt werden Inhalationszusammensetzungen, z.B. in Form von Aerosolen, Sprays, oder als mikronisiertes Pulver hergestellt. Dazu werden die erfindungsgemäßen Verbindungen entweder als in pharmazeutisch üblichen Lösungsmitteln gelöst bzw. suspendiert und mittels Überdruck in einem bestimmten Volumen fein verteilt und inhaliert. Ein entsprechendes Vorgehen erfolgt bei den zu inhalierenden Festsubstanzen, die gleichfalls mittels Überdruck fein verteilt und inhaliert werden. Ebenfalls andere als mit Überdruck funktionierende Applikatoren sind hierbei eingeschlossen.Further preferred are inhalation compositions, e.g. in the form of aerosols, sprays, or micronized powder. For this purpose, the compounds of the invention are either dissolved or suspended as in pharmaceutically customary solvents and finely distributed by means of overpressure in a certain volume and inhaled. A similar procedure takes place with the solid substances to be inhaled, which are likewise finely distributed and inhaled by means of overpressure. Other than with overpressure working applicators are included here.
Die Erfindung betrifft auch pharmazeutische Zubereitungen, die eine therapeutisch wirksame Menge des aktiven Inhaltsstoffs (erfindungsgemäße Verbindung der Formel (1 a) oder (1 b)) zusammen mit organischen oder anorganischen festen oder flüssigen pharmazeutisch verträglichen Trägern, die für die beabsichtigte Verabreichung geeignet sind, und die mit den aktiven Inhaltsstoffen nicht nachteilig wechselwirken, enthalten.The invention also relates to pharmaceutical preparations containing a therapeutically effective amount of the active ingredient (Compound of the invention Formula (1 a) or (1b)) together with organic or inorganic solid or liquid pharmaceutically acceptable carriers which are suitable for the intended administration and which do not adversely interact with the active ingredients.
Die Erfindung betrifft auch Verfahren zur Herstellung pharmazeutischer Zubereitungen, die dadurch gekennzeichnet sind, dass die erfindungsgemäße Verbindung mit einem pharmazeutisch verträglichen Träger vermischt wird.The invention also relates to processes for the preparation of pharmaceutical preparations which are characterized in that the compound according to the invention is mixed with a pharmaceutically acceptable carrier.
Die erfindungsgemäßen Verbindungen eignen sich auch im Rahmen von Kombinationstherapien mit schon bekannten Wirkstoffen zur Behandlung der oben genannten Erkrankungen. Dabei sollen überraschende Synergieeffekte zur Steigerung der therapeutischen Wirksamkeit der erfindungsgemäßen Substanzen genutzt werden. Die Kombination kann zum einen darin bestehen, eine einzige pharmazeutische Zusammensetzung anzubieten, die mindestens eine der erfindungsgemäßen Verbindungen in Kombination mit einem oder mehrere der nachfolgend genannten Wirkstoffen enthält oder dem Patienten werden gleichzeitig oder zeitlich versetzt mehrere Mittel, die einen oder mehreren der nachfolgenden Wirkstoffe enthalten, verabreicht.The compounds according to the invention are also suitable in the context of combination therapies with already known active compounds for the treatment of the abovementioned diseases. In this case, surprising synergy effects are to be used to increase the therapeutic effectiveness of the substances according to the invention. The combination may be to offer a single pharmaceutical composition comprising at least one of the compounds of the present invention in combination with one or more of the following, or simultaneously or temporally displaced to the patient, several agents containing one or more of the following active ingredients administered.
Es ist bevorzugt eine oder mehrere der erfindungsgemäßen Verbindungen mit einem oder mehreren der folgenden Wirkstoffe zu kombinieren:It is preferred to combine one or more of the compounds according to the invention with one or more of the following active substances:
Corticosteroidecorticosteroids
(monoklonale) Antikörpern gegen TNF-alpha oder andere Wirkstoffe, die die(monoclonal) antibodies to TNF-alpha or other agents containing the
Bildung bzw. Freisetzung von TNF-alpha oder die Aktivität von TNF-alpha hemmen (z.B. rekombinante TNFα-Rezeptorkonstrukte)Inhibit TNF-alpha production or TNF-alpha activity (e.g., recombinant TNFα receptor constructs)
Zytokin-Antagonisten (z.B. IL-1 ß, IL-6, IL-12)Cytokine antagonists (e.g., IL-1β, IL-6, IL-12)
Chemokin-AntagonistenChemokine antagonists
Zytokin-Agonisten (z.B. IL-10) immunmodulatorische Wirkstoffe wie z.B. Cyclosporin A, Methodrexat,Cytokine agonists (e.g., IL-10) include immunomodulatory agents, e.g. Cyclosporin A, Methodrexate,
Leflunomid, D-Penicillamin, AuranofineLeflunomide, D-Penicillamine, Auranofine
Substanz P-AntagonistenSubstance P antagonists
Bradykinin-AntagonistenBradykinin antagonists
PAF-Antagonisten Adenosin-Rezeptor-AntagonistenPAF antagonists Adenosine receptor antagonists
Antibiotika/Virostatika α-MimetikaAntibiotics / antivirals α-mimetics
Zytostatika ß2-Adrenoceptor Agonisten (z.B. Terbutalin, Salbutanol, Salmetanol,Cytostatics ß 2 -adrenoceptor agonists (eg terbutaline, salbutanol, salmetanol,
Fenoterol, Formoterol)Fenoterol, formoterol)
Leukotrien-Antagonisten (entweder Enzym-Inhibitoren [wie 5-Leukotriene antagonists (either enzyme inhibitors [such as 5-
Lipoxygenaseinhibitoren oder Arachidonsäure-Enzyminhibitoren] oderLipoxygenase inhibitors or arachidonic acid enzyme inhibitors] or
Rezeptorantagonisten) , z.B. Pranlukast, Montelukast, Zafirlukast, ZileutonReceptor antagonists), e.g. Pranlukast, Montelukast, Zafirlukast, Zileuton
Antihistaminika (bevorzugt solche mit Mastzellen-stabilisierendenAntihistamines (preferably those with mast cell stabilizing
Eigenschaften oder Leukotrien-antagonisierenden Aspekten, wie z.B.Properties or leukotriene antagonizing aspects, e.g.
Loratadin, Astemizol, Mizolastin, , OlopatadinLoratadine, Astemizole, Mizolastine,, Olopatadine
Theophyllintheophylline
Muscarinrezeptor-Antagonisten, z.B. SpirivaMuscarinic receptor antagonists, e.g. Spiriva
Die Kombination mit oben aufgeführten Arzneimitteln bzw. Wirkprinzipien dient besonders dazu, den akut zu behandelnden Krankheitszustand in einem möglichst frühen Stadium in seiner Manifestation zu beeinflussen und nicht chronisch werden zu lassen, da die erfindungsgemäßen Verbindungen in Kombination mit den anderen Wirkstoffen komplementäre/additive Aspekte ermöglichen. In der Kombination ergibt sich ein positiver Effekt u.a. daraus, dass eine geringere Substanzmenge pro Prinzip angewendet werden kann und damit zum einen eine Verbesserung des therapeutischen Effektes, geringere UAWs und zum anderen ein Spareffekt zu erreichen ist.The combination with the medicines or active principles listed above is particularly useful for influencing the state of the disease to be treated acutely in its manifestation at the earliest possible stage and not for making it chronic, since the compounds according to the invention in combination with the other active substances allow complementary / additive aspects , The combination results in a positive effect u.a. from the fact that a smaller amount of substance per principle can be used and thus on the one hand an improvement of the therapeutic effect, lower ADRs and on the other hand a saving effect can be achieved.
Abhängig von der Krankheitsausprägung und den zugrunde liegenden Symptomen können die erfindungsgemäßen Verbindungen zu den anderen Wirkstoffen in der Kombination im Verhältnis von 1 :10.000 bis 10.000:1 , bevorzugt 1 :1000 bis 1000:1 , ganz bevorzugt 1 :10 bis 10:1 , vorliegen.Depending on the disease severity and the underlying symptoms, the compounds according to the invention may be added to the other active substances in the combination in the ratio of 1: 10,000 to 10,000: 1, preferably 1: 1000 to 1000: 1, very preferably 1:10 to 10: 1, available.
Die Erfindung betrifft weiterhin Verfahren zur Herstellung der erfindungsgemäßen Verbindungen.The invention further relates to processes for the preparation of the compounds of the invention.
Die erfindungsgemäßen Verfahren zur Herstellung der Verbindungen der allgemeinen Formeln 1a und 1 b mit den zuvor aufgeführten Bedeutungen von R1, R3, R4, X und Y sind gekennzeichnet durch folgende Verfahrensweisen:The inventive method for preparing the compounds of general formulas 1a and 1b having the abovementioned meanings of R 1 , R 3 , R 4 , X and Y are characterized by the following procedures:
A)A)
Für X=N: Darstellung der 2-Aminonitrile der allgemeinen Formel 2For X = N: Preparation of the 2-aminonitriles of the general formula 2
Figure imgf000026_0001
Figure imgf000026_0001
durch Umsetzung von Acetonitril mit einem Nitril der allgemeinen Formel 3 (mit identischer Bedeutung von R3)by reaction of acetonitrile with a nitrile of the general formula 3 (with identical meaning of R 3 )
Figure imgf000026_0002
Figure imgf000026_0002
in Gegenwart eines Alkoxides, vorzugsweise Kalium-te/t-butoxid in einem geeigneten Lösungsmittel, vorzugsweise Toluol.in the presence of an alkoxide, preferably potassium te / t-butoxide in a suitable solvent, preferably toluene.
Umsetzung eines Säurehalogenids der allgemeinen Formel 4 (mit identischer Bedeutung von R1)Reaction of an acid halide of the general formula 4 (with identical meaning of R 1 )
R1— COCI 4R 1 - COCI 4
mit einem Thiocyanat, vorzugsweise Ammoniumthiocyanat, in einem geeignetem Lösungsmittel, vorzugsweise Dioxan, zum Carbonsäure-isothiocyanat welches mit einem 2-Aminonitril der allgemeinen Formel 2 zum Pyrimidin-5-carbonitril der allgemeinen Formel 5 (mit X=N) umgesetzt wird.with a thiocyanate, preferably ammonium thiocyanate, in a suitable solvent, preferably dioxane, to give the carboxylic acid isothiocyanate which is reacted with a 2-aminonitrile of the general formula 2 to give the pyrimidine-5-carbonitrile of the general formula 5 (where X = N).
- Umsetzung der dargestellten Pyridin- bzw Pyrimidin-3-carbonitrile der allgemeinen Formel 5,Reaction of the illustrated pyridine or pyrimidine-3-carbonitriles of the general formula 5,
Figure imgf000026_0003
mit identischer Bedeutung von R1, R3, X und Y wie oben, in an sich bekannter Weise mit Chloracetamid, CICH2CONH2, in methanolischer oder ethanolischer Lösung in Gegenwart eines Natriumalkoxides, vorzugsweise Natriummethoxid oder Natriumethoxid, zunächst zu den Verbindungen der allgemeinen Formel 7, mit identischer Bedeutung von X, R1, R3 und Y
Figure imgf000026_0003
with identical meaning of R 1 , R 3 , X and Y as above, in a conventional manner with chloroacetamide, CICH 2 CONH 2 , in methanolic or ethanolic solution in the presence of a sodium alkoxide, preferably sodium methoxide or sodium ethoxide, first to the compounds of the general Formula 7, with identical meaning of X, R 1 , R 3 and Y
Figure imgf000027_0001
Figure imgf000027_0001
- Die Verbindungen der allgemeinen Formel 7 (mit identischer Bedeutung von X, Y, R1, und R3 wie oben) sind aus den Verbindungen der allgemeinen Formel 5, auch dadurch darstellbar, dass diese Verbindungen mit Choracetamid zunächst in vorzugsweise ethanolischer Lösung in Gegenwart von vorzugsweise Triethylamin oder in wasserfreier acetonischer Lösung in Gegenwart von Natrium- oder Kaliumhydrogencarbonat zu den Verbindungen der allgemeinen Formel 6,- The compounds of general formula 7 (with identical meaning of X, Y, R 1 , and R 3 as above) are represented by the compounds of general formula 5, also characterized in that these compounds with choracetamide initially in preferably ethanolic solution in the presence of preferably triethylamine or in anhydrous acetonic solution in the presence of sodium or potassium bicarbonate to the compounds of general formula 6,
Figure imgf000027_0002
Figure imgf000027_0002
worin X, Y, R1 und R3 die oben genannten Bedeutungen aufweisen, umgesetzt werden und diese Verbindungen in einem weiteren Syntheseschritt in vorzugsweise wasserfreier ethanolischer Lösung mit einer katalytischen Menge Natrium¬ methoxid oder Natriumethoxid durch Erhitzen unter Rückfluss gleichfalls in die oben genannten Verbindungen der allgemeinen Formel 7 übergeführt werden;wherein X, Y, R 1 and R 3 have the abovementioned meanings, are reacted and these compounds in a further synthesis step in preferably anhydrous ethanolic solution with a catalytic amount of Natrium¬ methoxide or sodium ethoxide by heating under reflux also in the abovementioned compounds of converted to general formula 7;
- Umsetzung der Verbindungen der allgemeinen Formel 7 mit Phosgen oder Trichlormethylchlorformiat (Diphosgen) in einem vorzugsweise aprotischen, hochsiedenden Lösungsmittel wie Dioxan, Tetrahydrofuran oder Toluol bzw. deren Mischungen unter Erhitzen, ggf. in Anwesenheit katalytischer Mengen eines Matriumalkoxides, wie zum BeispielReaction of the compounds of general formula 7 with phosgene or trichloromethyl chloroformate (diphosgene) in a preferably aprotic, high-boiling solvent such as dioxane, tetrahydrofuran or toluene or mixtures thereof with heating, if appropriate in the presence of catalytic amounts of Matriumalkoxides, such as
Natriumethylat, zu Verbindungen der allgemeinen Formel 1a,Sodium ethylate, to compounds of general formula 1a,
Figure imgf000028_0001
worin X, Y, R1 und R3 dasselbe wie oben bedeuten;
Figure imgf000028_0001
wherein X, Y, R 1 and R 3 are the same as above;
oderor
B)B)
Umsetzung der bekannten bzw. nach prinzipiell bekannten Methoden dargestellten Pyridin- bzw. Pyrimidin-3-carbonitrile der allgemeinen Formel 5,Reaction of the known pyridines or pyrimidine-3-carbonitriles of the general formula 5, which are prepared by methods which are known in principle,
Figure imgf000028_0002
mit identischer Bedeutung von X, Y, R1 und R3 wie oben, mit N-Chloracetylurethan, CICH2CONHCOOC2H5, in methanolischer oder ethanolischer Lösung oder in Butoxyethoxyethanol in Gegenwart einer organischen Base vorzugsweise Triethylamin, unter Erwärmen zu den Verbindungen der allgemeinen Formel 1a,
Figure imgf000028_0002
with identical meaning of X, Y, R 1 and R 3 as above, with N-chloroacetylurethane, CICH 2 CONHCOOC 2 H 5 , in methanolic or ethanolic solution or in butoxyethoxyethanol in the presence of an organic base, preferably triethylamine, with heating to the compounds of general formula 1a,
Figure imgf000028_0003
worin X, Y, R1 und R3 dasselbe wie oben bedeuten; oder C)
Figure imgf000028_0003
wherein X, Y, R 1 and R 3 are the same as above; or C)
- Umsetzung der Verbindungen der allgemeinen Formel 7, worin X, Y, R1 und R3 dasselbe wie oben bedeuten, mit Carbonsäurehalogeniden der allgemeinen Formel 8,Reaction of the compounds of general formula 7 in which X, Y, R 1 and R 3 are the same as above, with carboxylic acid halides of general formula 8,
R4-CO— Z 8 worin R4 R 4 -CO-Z 8 wherein R 4
C2-i4Alkyl, Ca-uCycloalkyl, C2-i4Alkenyl, C3-i4Cycloalkenyl, C2-i4Alkinyl (jeweils ggf. am C-Skelett der vorgenannten aliphatischen oder cycloaliphatischen Reste mit R§ substituiert);C 2 -i 4 alkyl, Ca-uCycloalkyl, C i 2 4 alkenyl, C 3 -i 4 cycloalkenyl, C 2 4 alkynyl -i (in each case optionally at the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals with R § substituted) ;
Figure imgf000029_0001
Figure imgf000029_0001
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert);- 1-naphthyl, 2-naphthyl (each optionally substituted with R § );
- mono-, bi- oder tricyclische gesättigter oder ein- oder mehrfach ungesättigter heterocyclischer Rest mit insgesamt 4-14 Ring-Atomen, davon 1-5 Heteroatomen, die vorzugsweise N, O, S und Se sind (jeweils ggf. mit R§ substituiert);- mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocyclic radical having a total of 4-14 ring atoms, of which 1-5 heteroatoms, which are preferably N, O, S and Se (each optionally substituted with R § );
- CH2OAIk* (mit Alk*: C1-6AIkyl),CH 2 OAlk * (with Alk *: C 1-6 alkyl),
- CH2OCOR' (mit R': Ci-6AIkyl, C2-6Alkenyl, Phenyl sowie mit R§ substituiert),- CH 2 OCOR '(R': Ci -6 -alkyl, C 2-6 alkenyl, phenyl, and with R § substituted),
- COOH, COOAIk** (mit Alk**: C1-5Alkyl),COOH, COOAlk * * (with Alk ** : C 1-5 alkyl),
bedeutet undmeans and
Z = Chlor oder BromZ = chlorine or bromine
oderor
- Umsetzung der Verbindungen der allgemeinen Formel 7 (worin X, Y, R1 und R3 dasselbe wie oben bedeuten), mit Carbonsäureanhydriden der allgemeinen Formel 9, (R4CO)2O 9Reaction of the compounds of general formula 7 (in which X, Y, R 1 and R 3 denote the same as above) with carboxylic acid anhydrides of general formula 9, (R 4 CO) 2 O 9
worin R4 dasselbe wie bei den Verbindungen der allgemeinen Formel 8 bedeutet, jeweils im Überschuss und in der Siedehitze, gegebenenfalls zusammen mit Pyridin oder einem aprotischen, hochsiedendenwherein R 4 is the same as in the compounds of general formula 8, in each case in excess and in the boiling heat, optionally together with pyridine or an aprotic, high-boiling
Lösungsmittel, wie zum Beispiel Toluol oder XyIoI,Solvents, such as toluene or xylene,
Behandlung des gebildeten Niederschlages mit wässerig-ethanolischer Natronlauge oder mittels konz. wässeriger Ammoniak-Lösung, jeweils bis zu einem pH-Wert vonTreatment of the precipitate formed with aqueous-ethanolic sodium hydroxide solution or by means of conc. aqueous ammonia solution, each up to a pH of
8-10, unter Erwärmen, nachfolgendem Ansäuern mit verdünnter Salzsäure unter Bildung der Verbindungen der allgemeinen Formel 1b,8-10, with heating, subsequent acidification with dilute hydrochloric acid to give the compounds of general formula 1b,
Figure imgf000030_0001
Figure imgf000030_0001
worin X, Y, R1 und R3 dasselbe wie oben bedeuten und R4 die bei den Verbindungen der allgemeinen Formel 8 angegebene Bedeutung aufweistwherein X, Y, R 1 and R 3 are the same as above and R 4 has the meaning given in the compounds of general formula 8
oderor
D)D)
- Umsetzung der aus den Verbindungen der allgemeinen Formel 5 und Chloressigsäurealkylestem, C1-Cs, darstellbaren bekannten oder nach prinzipiell bekannten Methoden darstellbaren Verbindungen der allgemeinen Formel 10,Reaction of the compounds of the general formula 10 which can be prepared from the compounds of the general formula (5) and chloroacetic acid alkyl esters, C 1 -Cs, or which can be prepared by methods which are known in principle,
Figure imgf000030_0002
worin X, Y, R1 und R3 dasselbe wie oben und Alk Alkyl, CrC3, bedeuten, mit Benzoylisothiocyanat, PhCONCS, in aprotischen, dipolaren Lösungsmitteln, vorzugsweise Aceton oder Dioxan unter Erwärmen zu den Verbindungen der allgemeinen Formel 11 ,
Figure imgf000030_0002
wherein X, Y, R 1 and R 3 are the same as above and Alk alkyl, CrC 3 , with benzoylisothiocyanate, PhCONCS, in aprotic, dipolar solvents, preferably acetone or dioxane with heating to the compounds of general formula 11,
Figure imgf000031_0001
Figure imgf000031_0001
worin X, Y, R1 und R3 dasselbe wie oben und Alk Alkyl, CrC3, bedeuten,wherein X, Y, R 1 and R 3 are the same as above and Alk alkyl, CrC 3 ,
- Umsetzung der Verbindungen der allgemeinen Formel 11 mit Natrium- oder- Reaction of the compounds of general formula 11 with sodium or
Kaliumhydroxid in protischen oder aprotischen polaren Lösungsmitteln oderPotassium hydroxide in protic or aprotic polar solvents or
Lösungsmittelgemischen unter Erwärmen,Solvent mixtures with heating,
Zugabe von Brom- oder lodalkanen, -alkenen oder alkinen, C3-C7ZU der erkalteten alkalischen Reaktionslösung, mäßiges Erwärmen bis zur Beendigung der Umsetzung,Adding bromine or iodoalkanes, alkenes or alkynes, C 3 -C 7 to the cooled alkaline reaction solution, moderate heating until the reaction is complete,
Ansäuern mit verdünnter Salzsäure unter Entstehung der Verbindungen der allgemeinen Formel 1 b,Acidification with dilute hydrochloric acid to give the compounds of general formula 1 b,
Figure imgf000031_0002
Figure imgf000031_0002
worin X, Y1 R1 und R3 dasselbe wie oben und Alk* (Ci-8 )Alkyl, (C2-8,)Alkenyl, (C3-6) Alkinyl, jeweils unverzweigt oder gegebenenfalls verzweigt und ggf. mit einem Rest wie -CN, -SCN, -NO2, Phenyl und (C3-7)Cycloalkyl substituiert ist, bedeuten,wherein X, Y 1 R 1 and R 3 are the same as above and Alk * (Ci -8 ) alkyl, (C 2 - 8 ,) alkenyl, (C 3 - 6 ) alkynyl, in each case unbranched or optionally branched and optionally with one Substituted such as -CN, -SCN, -NO 2 , phenyl and (C 3-7 ) cycloalkyl, mean
oder E)or e)
- Umsetzung von Verbindungen der allgemeinen Formel 1b bei denen R4 SAIk* und- Reaction of compounds of general formula 1b in which R 4 SAIk * and
Alk* (Ci-8)Alkyl, (C2-8,)Alkenyl, (C3-6) Alkinyl, jeweils unverzweigt oder verzweigt und ggf. mit einem Rest wie -CN, -SCN, -NO2, Phenyl und (C3-7)CycloaIkyl substituiert ist, bedeutet, mit annähernd äquimolarer Menge Dihydrogenperoxid in Essigsäure oderAlk * (Ci -8 ) alkyl, (C 2-8 ,) alkenyl, (C 3 - 6 ) alkynyl, in each case unbranched or branched and optionally with a radical such as -CN, -SCN, -NO 2 , phenyl and ( C3 -7 ) cycloalkyl is substituted, with approximately equimolar amount of dihydrogen peroxide in acetic acid or
Ameisensäure unter dc-Kontrolle bei Raumtemperatur oder mit KIO4 in protischen oder aprotischen, dipolaren Lösungsmitteln unterFormic acid under dc control at room temperature or with KIO 4 in protic or aprotic, dipolar solvents under
Erwärmen zu jenen Verbindungen der allgemeinen Formel 1 b, worin X, Y, R1 und R3 dasselbe wie oben bedeuten und R4 SOAIk* und Alk* (d-8)Alkyl, (C2-8,)Alkenyl, (C3-6) Alkinyl, jeweils unverzweigt oder verzweigt und ggf. mit einem Rest wie -CN, -SCN, -NO2,Heating to those compounds of general formula 1b wherein X, Y, R 1 and R 3 are the same as above and R 4 SOAlk * and Alk * (d -8 ) alkyl, (C 2 -8,) alkenyl, (C 3 - 6 ) alkynyl, in each case unbranched or branched and optionally with a radical such as -CN, -SCN, -NO 2 ,
Phenyl und (Cs-7) Cycloalkyl substituiert ist, bedeutetPhenyl and (Cs- 7 ) cycloalkyl is substituted means
oderor
F)F)
- Umsetzung jener Verbindungen der allgemeinen Formel 1b bei denen R4 SAIk* oder SOAIk* und Alk* (Ci-8 )Alkyl, (C2-8,)Alkenyl, (C3-6) Alkinyl, jeweils unverzweigt oder verzweigt und ggf. mit einem Rest wie -CN, -SCN, NO2, Phenyl und (C3-7) Cycloalkyl substituiert ist, bedeutet, mit überschüssigem Dihydrogenperoxid in Essigsäure oder Ameisensäure unter dc- Kontrolle bei Raumtemperatur, gegebenenfalls auch unter mäßigem Erwärmen oder mit KMnO4 in protischen oder aprotischen, dipolaren Lösungsmitteln unter Erwärmen zu den Verbindungen der allgemeinen Formel 1b, worin X, Y, R1 und R3 dasselbe wie oben bedeuten und R4SO2AIk* und Alk*(C1-8) Alkyl, (C2-8,)Alkenyl, (C3-6) Alkinyl, jeweils unverzweigt oder verzweigt und ggf. mit einem Rest wie -CN, -SCN, NO2, Phenyl und (C3-7)Cycloalkyl substituiert ist, bedeutet.- Reaction of those compounds of the general formula 1b in which R 4 SAlk * or SOAlk * and Alk * (Ci -8 ) alkyl, (C 2-8 ,) alkenyl, (C 3 - 6 ) alkynyl, in each case unbranched or branched and optionally is substituted with a radical such as -CN, -SCN, NO 2 , phenyl and (C 3-7 ) cycloalkyl, means with excess dihydrogen peroxide in acetic acid or formic acid under dc control at room temperature, optionally also with moderate heating or with KMnO 4 in protic or aprotic dipolar solvents with heating to the compounds of general formula 1b, wherein X, Y, R 1 and R 3 are the same as above and R 4 SO 2 Alk * and Alk * (C 1-8 ) alkyl, (C 2 -8,) alkenyl, (C 3 - 6) alkynyl, each linear or branched and optionally substituted with one radical, such as -CN, -SCN, NO 2, phenyl and (C 3-7) cycloalkyl is substituted, means ,
Entsprechend der vorliegenden Erfindung können die unter A) bis F) beschriebenen Verfahren innerhalb weiter Grenzen variiert werden.According to the present invention, the methods described under A) to F) can be varied within wide limits.
Weitere Ausführungsformen der Erfindung können beispielsweise darin bestehen, dass die Darstellung der tricyclischen Pyrimidin-2,4-dione der allgemeinen Formel 1a bzw. die der tricyclischen Pyrimidin-4-one der allgemeinen Formel 1 b unter Verwendung eines Mikrowellengeräts realisiert wird,For example, other embodiments of the invention may be that the preparation of the tricyclic pyrimidine-2,4-diones of the general formula 1a or of the tricyclic pyrimidin-4-ones of the general formula 1b is realized by using a microwave device,
Methodenbeschreibung der Hemmung der TNFα Freisetzung nach LPS Stimulation von humanem VollblutMethod description of inhibition of TNFα release after LPS stimulation of human whole blood
Die Stimulierung isolierter Leukozyten für die Freisetzung von Zytokinen kann auf verschiedenen Wegen erfolgen. Lipopolysaccharide (LPS) stellen einen Stimulus für die Untersuchung der Freisetzung von TNFα dar. LPS ist Bestandteil bakterieller Zellwände und wird beim Abtöten der Bakterien (durch Antibiotika oder das natürliche Immunsystem) freigesetzt. LPS stimuliert insbesondere die Aktivität phagozytierender Leukozyten (Gewebsmakrophagen, Granulozyten, Monozyten) und verursacht die Infiltration von Leukozyten vom peripheren Blut in das betroffene Gewebe. Ein Zytokin von besonderer Bedeutung für diese Mechanismen ist TNFα, das in großen Mengen durch die betroffenen Zellen sezemiert wird. Hauptquelle dabei sind Monozyten und Makrophagen. TNFα initiiert und prolongiert den Entzündungsprozess im Zusammenspiel mit anderen Mediatoren.The stimulation of isolated leukocytes for the release of cytokines can take place in various ways. Lipopolysaccharides (LPS) are a stimulus for studying the release of TNFα. LPS is a component of bacterial cell walls and is released when the bacteria are killed (by antibiotics or the natural immune system). In particular, LPS stimulates the activity of phagocytic leukocytes (tissue macrophages, granulocytes, monocytes) and causes the infiltration of peripheral blood leukocytes into the affected tissue. A cytokine of particular importance for these mechanisms is TNFα, which is secreted in large quantities by the affected cells. Main source are monocytes and macrophages. TNFα initiates and prolongs the inflammatory process in interaction with other mediators.
Für die Untersuchung des Effektes auf die LPS-induzierte TNFα-Freisetzung wurde eine Methode verwendet, die von MARX et al. {Marx D, Tassabehji M, Heer S, Hüttenbrink KB, Szelenyi I (2002) Pulmonary Pharmacology & Therapeutics 15 7-15) beschrieben wurde. Die Methode in Kürze: Humanes Blut wird von verschiedenen Spendern entnommen, durch Zusatz von 10 mM Na-Citrat ungerinnbar gemacht und 1 :5 mit RPMI 1640 Zellkulturmedium verdünnt. Die Testsubstanzen werden den Blutproben in verschiedenen Konzentrationen zugefügt. 15 Minuten später werden die Leukozyten durch Zusatz von Lipopolysacchariden (LPS) aus Salmonella abortus equi in einer Endkonzentration von 1μg/ml stimuliert. Nach Inkubation der Testansätze für 24 Stunden bei 37°C. und unter 5% CO2 in wassergesättigter Luft, wird das Blut zentrifugiert und die Konzentration an TNFα im zellfreien Überstand unter Verwendung eines käuflichen ELISA (BD Biosciences) nach Angaben des Herstellers exakt vermessen. ICδo-Werte im Bereich von 10"6"bis 10'10 M wurden für die in der Erfindung beschriebenen Substanzen bestimmt.For the study of the effect on LPS-induced TNFα release, a method was used which was described by MARX et al. {Marx D, Tassabehji M, Heer S, Hüttenbrink KB, Szelenyi I (2002) Pulmonary Pharmacology & Therapeutics 15 7-15). The method in brief: Human blood is taken from different donors, made incusible by the addition of 10 mM Na citrate, and diluted 1: 5 with RPMI 1640 cell culture medium. The test substances are added to the blood samples in different concentrations. 15 minutes later, the leukocytes are stimulated by addition of lipopolysaccharides (LPS) from Salmonella abortus equi to a final concentration of 1 μg / ml. After incubation of the test mixtures for 24 hours at 37 ° C. and below 5% CO 2 in water-saturated air, the blood is centrifuged and the concentration of TNFα in the cell-free supernatant accurately measured using a commercial ELISA (BD Biosciences) according to the manufacturer's instructions. ICδo values in the range of 10 "6" to 10 10 M were determined for the substances described in the invention.
Die Verbindungen der allgemeinen Formeln 1 a und 1 b sind schwache Inhibitoren der Phosphodiesterase 4 und äußerst starke Inhibitoren der Freisetzung von TNFα.The compounds of the general formulas 1 a and 1 b are weak inhibitors of phosphodiesterase 4 and extremely strong inhibitors of the release of TNFα.
Die nachfolgende Auflistung beinhaltet erfindungsgemäße Substanzen, die im TNFα- Hemmassay bei 1OnM die TNFα-Freisetzung >20% hemmen:The following list contains substances according to the invention which inhibit TNFα release> 20% in the TNFα inhibition assay at 1OnM:
Figure imgf000034_0001
52 9-Methyl-7-naphthalen-2-yl-thieno[2,3-d:4)5-d']dipyrimidin-2)4-(1 H,3H)-dion
Figure imgf000034_0001
52 9-Methyl-7-naphthalen-2-yl-thieno [2,3-d: 4 ) 5-d '] dipyrimidine-2 ) 4- (1H, 3H) -dione
58 9-Methyl-7-biphenyl-2-ethyl-thieno[2,3-d:4,5-d']dipyrimidin-4(3H)-on58 9-Methyl-7-biphenyl-2-ethylthieno [2,3-d: 4,5-d ' ] dipyrimidin-4 (3H) -one
Die nachfolgende Auflistung beinhaltet erfindungsgemäße Substanzen, die im TNFα- Hemmassay einen IC50-Wert von <10 nM aufweisen:The following list includes substances according to the invention which have an IC 50 value of <10 nM in the TNFα inhibition assay:
Figure imgf000035_0001
Figure imgf000035_0001
Besonders bevorzugte Verbindungen der vorliegenden Erfindungen sind nachfolgend aufgelistet:Particularly preferred compounds of the present invention are listed below:
Formel 1 a mit Y = S, wobei die Substituenten Ri , R3, X die folgenden Bedeutungen haben:Formula 1 a with Y = S, where the substituents Ri, R 3 , X have the following meanings:
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000035_0002
Figure imgf000036_0001
Formel 1 a mit Y = O und R1 = Ph, X = C-H und R3 = Me.Formula 1 a with Y = O and R 1 = Ph, X = CH and R 3 = Me.
Formel 1 b mit Y = S , wobei die Substituenten R1 , X , R3 ,R4 die folgenden Bedeutungen haben:Formula 1 b with Y = S, where the substituents R 1 , X, R 3 , R 4 have the following meanings:
Figure imgf000036_0002
Figure imgf000036_0002
Ganz speziell seien die nachfolgenden Verbindungen als bevorzugt genannt:In particular, the following compounds may be mentioned as preferred:
7-(4-Methoxy-phenyl)-9-methyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1H,3H)- dion;7- (4-methoxy-phenyl) -9-methyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione;
9-Methyl-7-phenyl-pyrido[3l J2':4J5]thieno[3l2-d]pyrimidin-2,4(1 H]3H)-dion;9-methyl-7-phenyl-pyrido [3 l J 2 ': 4 Y 5] thieno [3 l 2-d] pyrimidine-2,4 (1 H] 3H) -dione;
7-(4-Methoxy-phenyl)-9-methyl-thieno[2,3-d:4J5-d']dipyrimidin-2,4-(1 H,3H)-dion;7- (4-methoxyphenyl) -9-methylthieno [2,3-d: 4 J 5-d '] dipyrimidine-2,4- (1H, 3H) -dione;
9-Methyl-7-(4-methyl-phenyl)-thieno[2J3-d:4,5-d>]dipyrimidin-2,4-(1 H,3H)-dion; 7-(4-Cyano-phenyl)-9-methyI-thieno[2I3-d:4,5-d']dipyrimidin-2)4-(1 Hl3H)-clion;9-methyl-7- (4-methylphenyl) thieno [2 J 3-d: 4,5-d > ] dipyrimidine-2,4- (1H, 3H) -dione; 7- (4-Cyano-phenyl) -9-methyl-thieno [2 3 I-d: 4,5-d '] dipyrimidine-2) 4- (1 H l 3H) -clion;
7-(4-Brom-2-fluor-phenyl)-9-methyl-thieno[2,3-d:4l5-d']dipyrimidin-2,4-(1 H,3H)-dion;7- (4-bromo-2-fluoro-phenyl) -9-methyl-thieno [2,3-d: 4 l 5-d '] dipyrimidine-2,4- (1H, 3H) -dione;
9-Methyl-7-biphenyI-2-ethyl-thieno[2,3-d:4,5-d']dipyrimidin-4(3H)-on9-Methyl-7-biphenyl-2-ethyl-thieno [2,3-d: 4,5-d '] dipyrimidine-4 (3H) -one
2-Ethyl-9-methyl-7-phenyl-pyrido[3',2':4,5]thieno[3,2d]pyrimidin-4(3H)-on2-ethyl-9-methyl-7-phenyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2d] pyrimidin-4 (3H) -one
7-(3)4-Dimethoxy)-9-methyl-pyndo[3',2':4,5]thieno[3,2-d]pyrinnidin-2,4(1 Hl3H)-dion;7- (3) 4-dimethoxy) -9-methyl-pyndo [3 ', 2': 4,5] thieno [3,2-d] pyrinnidin-2,4 (1 H l 3H) -dione;
7-Phenyl-2-n-propyl-9-(pyrid-3-yl)-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-on;7-phenyl-2-n-propyl-9- (pyrid-3-yl) -pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one;
7-(4-Fluor-phenyl)-9-methyl-pyrido[3',2':4,5]thieno[3>2-d]pyrimidin-2,4(1 H)3H)-dion;7- (4-fluoro-phenyl) -9-methyl-pyrido [3 ', 2': 4,5] thieno [3 > 2-d] pyrimidine-2,4 (1H ) 3H) -dione;
7-(4-Methoxy-phenyl)-9-methyi-pyrido[3',2':4l5]thieno[3,2-d]pyrimidin-2,4(1 H,3H)- dion;7- (4-methoxyphenyl) -9-methylpyrido [3 ', 2': 4 l 5] thieno [3,2-d] pyrimidine-2,4 (1 H, 3 H) -dione;
7-Phenyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-on-2-carbonsäure;7-phenyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one-2-carboxylic acid;
9-Methyl-7-phenyl-pyrido[3l >2':4>5]thieno[3I2-d]pyrimidin-2,4(1 H,3H)-dion;9-methyl-7-phenyl-pyrido [3 L > 2 ': 4 > 5] thieno [3 I 2-d] pyrimidine-2,4 (1 H, 3 H) -dione;
7-Phenyl-pyrido[3',2':4,5]thieno[3I2-d]pyrimidin-4(3H)-on-2-carbonsäure;7-phenylpyrido [3 ', 2': 4,5] thieno [3 I 2-d] pyrimidin-4 (3H) -one-2-carboxylic acid;
7,9-Dimethyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1 H,3H)-dion;7,9-dimethyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione;
Die Erfindung wird durch die nachfolgenden Beispiele näher erläutert:The invention is explained in more detail by the following examples:
Beispiel 1example 1
7-(3,4-DimethoxyphenyI)-9-methyI-pyrido[3'52':4,5]thieno[3,2-c(Ipyrimidin-2,4- dion7- (3,4-dimethoxyphenyl) -9-methylpyrido [3 ' 5 2 ' : 4,5] thieno [3,2-c (pyrimidine-2,4-dione
(allgemeine Formel 1a: R1=S^-(MeO)2-Ph, X=C-H, R3=Me, Y=S) 3.0 g (8.7 mmol) 3-Amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-Jb]pyridin-2- carbonsäureamid (Beispiel 62; Experiment 7a; allgemeine Formel 7: Ri=3,4-(CH3O)2- Ph, X=C-H, R3=Me, Y=S) werden in 100 ml abs. Dioxan suspendiert. Anschließend werden 1.1 ml (8.7 mmol) Chlorameisensäuretrichlormethylester (Diphosgen) zugegeben und 3 Stunden unter Rückfluß erhitzt. Nach Abkühlen wird der Niederschlag abgesaugt und anschließend in 50 ml Wasser suspendiert. Die Suspension wird mit konz. Ammoniak-Lösung auf pH 8 eingestellt und der Niederschlag abgesaugt, mit wenig Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 °C getrocknet.(general formula 1a: R 1 = S ^ - (MeO) 2 -Ph, X = CH, R 3 = Me, Y = S) 3.0 g (8.7 mmol) of 3-amino-6- (3,4-dimethoxyphenyl) -4-methylthieno [2,3-Jb] pyridine-2-carboxamide (Example 62, Experiment 7a, general formula 7: R i = 3,4- (CH 3 O) 2 -Ph, X = CH, R 3 = Me, Y = S) are dissolved in 100 ml abs. Dioxane suspended. Subsequently, 1.1 ml (8.7 mmol) of trichloromethyl chloroformate (diphosgene) are added and heated under reflux for 3 hours. After cooling, the precipitate is filtered off with suction and then suspended in 50 ml of water. The suspension is treated with conc. Adjusted ammonia solution to pH 8 and the precipitate was filtered off with suction, washed with a little water, sucked dry and i. Vak. dried at 50 ° C.
Ausbeute: 3.08 g (96 %); HPLC tR: 13.8 min, Reinheit: 99.9 % (s. a in Tab. 1); MS (ESl, m/e): 368 [M-H]" Yield: 3.08 g (96%); HPLC t R : 13.8 min, purity: 99.9% (see a in Table 1); MS (ESL, m / e): 368 [MH] "
Ausgehend von den nachfolgend beschriebenen Vorstufen werden durch Umsetzung der entsprechenden Verbindungen der allgemeinen Formel 7 mit Chlorameisen- säuretrichlormethylester (Diphosgen) analog Beispiel 1 die folgenden Beispiele 2-8, 11-14, 16-38, 42 und 45-52 erhalten:Starting from the precursors described below, the following Examples 2-8, 11-14, 16-38, 42 and 45-52 are obtained by reacting the corresponding compounds of general formula 7 with chloroformic acid trichloromethyl ester (diphosgene) analogously to Example 1:
Beispiel 2Example 2
7-(4-l\/lethoxyphenyl)-9-methyl-pyrido[3',2':4,5]thieno[3,2-c/lpyrJmidin-2,4-dion (allgemeine Formel 1a: R1=4-MeO-Ph, X=C-H, R3=Me, Y=S)7- (4-lethoxyphenyl) -9-methyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-c / 1-pyridine-2,4-dione (general formula 1a: R 1 = 4-MeO-Ph, X = CH, R 3 = Me, Y = S)
Analog Beispiel 1 aus 3-Amino-6-(4-methoxyphenyl)-4-methyl-thieno[2,3-ö]pyridin-2- carbonsäureamid (Beispiel 62; Experiment 7b; allgemeine Formel 7: R-ι=4-MeO-Ph, X=C-H, R3=Me1 Y=S) (s. Tab. 1)Analogously to Example 1, 3-amino-6- (4-methoxyphenyl) -4-methylthieno [2,3-o] pyridine-2-carboxamide (Example 62, Experiment 7b, general formula 7: R-1 = 4) MeO-Ph, X = CH, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 3Example 3
7-(4-Fluorphenyl)-9-methyl-pyrido[3',2':4,5]thieno[3,2-c(lpyrimidin-2,4-dion (allgemeine Formel 1a: R1=4-F-Ph, X=C-H, R3=Me5 Y=S)7- (4-fluorophenyl) -9-methyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-c (1-pyrimidine-2,4-dione (general formula 1a: R 1 = 4-F -Ph, X = CH, R 3 = Me 5 Y = S)
Analog Beispiel 1 aus 3-Amino-6-(4-fluorphenyl)-4-methyl-thieno[2,3-jb]pyridin-2- carbonsäureamid (Beispiel 62; Experiment 7c; allgemeine Formel 7: R-ι=4-F-Ph, X=C-H, R3=Me, Y=S) (s. Tab. 1) Beispiel 4Analogously to Example 1 from 3-amino-6- (4-fluorophenyl) -4-methylthieno [2,3-jb] pyridine-2-carboxamide (Example 62, Experiment 7c, general formula 7: R-1 = 4 F-Ph, X = CH, R 3 = Me, Y = S) (see Table 1) Example 4
9-Methyl-7-phenyl-pyrido[3^2':4,5]thieno[3,2-c(]pyrimidin-2,4-dion (aligemeine Formel 1a: R1=Ph, X=C-H, R3=Me, Y=S)9-Methyl-7-phenyl-pyrido [3 ^ 2 ' : 4,5] thieno [3,2-c (] pyrimidine-2,4-dione (general formula 1a: R 1 = Ph, X = CH, R 3 = Me, Y = S)
Analog Beispiel 1 aus 3-Amino-4-methyl-6-phenyl-thieno[2,3-/?]pyridin-2- carbonsäureamid (Beispiel 62; Experiment 7d; allgemeine Formel 7: Ri=Ph, X=C-H, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1 from 3-amino-4-methyl-6-phenylthieno [2,3- /?] Pyridine-2-carboxamide (Example 62, Experiment 7d, general formula 7: Ri = Ph, X = CH, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 5Example 5
7-Methyl-9-phenyl-pyrido[3',2':4,5]thieno[3,2-c(]pyrimidin-2,4-dion (Beispiel 5; allgemeine Formel 1a: Ri=Me5 X=C-H, R3=Ph, Y=S)7-Methyl-9-phenyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-c (] pyrimidine-2,4-dione (Example 5, general formula 1a: R i = Me 5 X = CH, R 3 = Ph, Y = S)
Analog Beispiel 1 aus 3-Amino-6-methyl-4-phenyl-thieno[2,3-£>]pyridin-2-carbon- säureamid (Beispiel 62; Experiment 7e; allgemeine Formel 7: Ri=Me, X=C-H, R3=Ph, Y=S) (S. Tab. 1)Analogously to Example 1 from 3-amino-6-methyl-4-phenylthieno [2,3-] pyridine-2-carboxylic acid amide (Example 62, Experiment 7e, general formula 7: Ri = Me, X = CH , R 3 = Ph, Y = S) (see Table 1)
Beispiel 6Example 6
7,9-Diphenyl-pyrido[3',2':455]thieno[3,2-d|pyrimidin-2,4-dion (allgemeine Formel 1a: R1=Ph, X=C-H, R3=Ph, Y=S)7,9-Diphenyl-pyrido [3 ' , 2 ' : 4 5 5] thieno [3,2-d] pyrimidine-2,4-dione (general formula 1a: R 1 = Ph, X = CH, R 3 = Ph, Y = S)
Analog Beispiel 1 aus 3-Amino-4,6-diphenyl-thieno[2,3-ό]pyridin-2-carbonsäureamid (Beispiel 62; Experiment 7f; allgemeine Formel 7: Ri=Ph, X=C-H, R3=Ph, Y=S) (s. Tab. 1)Analogously to Example 1 from 3-amino-4,6-diphenyl-thieno [2,3-ό] pyridine-2-carboxamide (Example 62, Experiment 7f, general formula 7: Ri = Ph, X = CH, R 3 = Ph , Y = S) (see Table 1)
Beispiel 7Example 7
7,9-Dimethyl-pyrido[3',2':4,5]thieno[3,2-cdpyrimidin-2,4-dion (allgemeine Formel 1a: R1=Me, X=C-H, R3=Me, Y=S) Analog Beispiel 1 aus 3-Amino-4,6-dinnethyl-thieno[2,3-ib]pyπdin-2-carbonsäureamici (Beispiel 62; Experiment 7g; allgemeine Formel 7: Ri=Me, X=C-H, R3=Me, Y=S) (s. Tab. 1)7,9-dimethylpyrido [3 ' , 2 ' : 4,5] thieno [3,2-cdpyrimidine-2,4-dione (general formula 1a: R 1 = Me, X = CH, R 3 = Me, Y = S) Analogously to Example 1 from 3-amino-4,6-dinethylthieno [2,3-ib] -pymidine-2-carboxylic acid amici (Example 62, Experiment 7g, general formula 7: Ri = Me, X = CH, R 3 = Me , Y = S) (see Table 1)
Beispiel 8Example 8
7,9-Dimethyl-8-(4 -nitrobenzyl)-pyrido[3',2':4,5]thieno[3,2-cGpyrimidin-254-dion (allgemeine Formel 1a: Ri=Me, X=C-CH2-Ph-4'-NO2 , R3=Me5 Y=S)7,9-Dimethyl-8- (4-nitrobenzyl) -pyrido [3 ' , 2 ' : 4,5] thieno [3,2-cGpyrimidine-2 5 4-dione (general formula 1a: R i = Me, X = C-CH 2 -Ph-4'-NO 2 , R 3 = Me 5 Y = S)
Analog Beispiel 1 aus 3-Amino-4,6-dimethyl-5-(4'-nitrobenzyl)-thieno[2,3-jb]pyridin-2- carbonsäureamid (Beispiel 62; Experiment 7h; allgemeine Formel 7: Ri=Me, X=C- CH2-Ph-^-NO2, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 3-amino-4,6-dimethyl-5- (4 'nitrobenzyl) thieno [2,3-jb] pyridine-2- carboxamide (Example 62; Experiment 7h; general formula 7: R = Me , X = C-CH 2 -Ph - ^ - NO 2 , R 3 = Me, Y = S) (see Table 1)
Beispiel 9Example 9
9-Methyl-7-phenyl-pyrido[3',2':4,5]furo[3J2-c0pyrimidin-2,4-dion (allgemeine Formel 1a:
Figure imgf000040_0001
R3=Me, Y=O)9-methyl-7-phenyl-pyrido [3 ', 2': 4,5] furo [3 2 J-c0pyrimidin-2,4-dione (general formula 1a:
Figure imgf000040_0001
R 3 = Me, Y = O)
Zu 1.0 g (3.4 mmol) 3-Amino-4-methyl-6-phenyl-furo[2,3-b]pyridin-2-carbonsäure- ethylester (allgemeine Formel 10: Ri=Ph, X=C-H, R3=Me, Y=O)* in 20 ml abs. Aceton werden 1.0 g (6.8 mmol) Benzoylisocyanat gegeben und 30 Minuten bei Raumtemperatur gerührt. Das Lösungsmittel wird entfernt und der nach Zugabe von Wasser ausgefallene Niederschlag abgesaugt und trocken gesaugt. Der Niederschlag wird in 6.8 ml (6.8 mmol) Natriumhydroxid-Lösung (1 M) und 20 ml Ethanol 15 Minuten unter Rückfluss erhitzt. Das Lösungsmittel wird entfernt und der Rückstand mit 100 ml abs. Dichlormethan aufgenommen. Nach Zugabe von 0.44 ml (5.1 mmol) Oxalylchlorid wird 1 Stunde bei Raumtemperatur gerührt. Das Lösungsmittel wird entfernt und der Rückstand mit Wasser suspendiert. Der entstandene Niederschlag wird abgesaugt, mit wenig Ethanol gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet.To 1.0 g (3.4 mmol) of 3-amino-4-methyl-6-phenyl-furo [2,3-b] pyridine-2-carboxylic acid ethyl ester (general formula 10: Ri = Ph, X = CH, R 3 = Me, Y = O) * in 20 ml abs. Acetone are added 1.0 g (6.8 mmol) of benzoyl isocyanate and stirred for 30 minutes at room temperature. The solvent is removed and the precipitate which precipitated out after addition of water is filtered off with suction and sucked dry. The precipitate is refluxed in 6.8 ml (6.8 mmol) of sodium hydroxide solution (1 M) and 20 ml of ethanol for 15 minutes. The solvent is removed and the residue with 100 ml of abs. Added dichloromethane. After addition of 0.44 ml (5.1 mmol) of oxalyl chloride is stirred for 1 hour at room temperature. The solvent is removed and the residue is suspended with water. The resulting precipitate is filtered off, washed with a little ethanol, sucked dry and i. Vak. dried at 50 0 C.
Ausbeute: 0.85 g (85 %); HPLC tR: 15.0 min, Reinheit: 85.1 % (s. a in Tab. 1); MS (ESI, m/e): 294 [M+H]+ (* Lit.: Wagner G., Prantz J. Pharmazie (1990); 45, 213-214) Beispiel 10Yield: 0.85 g (85%); HPLC t R : 15.0 min, purity: 85.1% (see a in Table 1); MS (ESI, m / e): 294 [M + H] + (* ref .: Wagner G., Prantz J. Pharmacie (1990); 45, 213-214) Example 10
θ-Trifluormethyl-y^-methoxy-phenyO-pyridoja'^'^jδlthienotS^-dlpyrimidin-θ-trifluoromethyl-y ^ methoxy-Phenyo-pyridoja '^' ^ ^ jδlthienotS -dlpyrimidin-
2,4-dion* 2,4-dione *
(allgemeine Formel 1a: R1=^MeO-Ph, X=C-H, R3=CF3, Y=S)(general formula 1a: R 1 = ^ MeO-Ph, X = CH, R 3 = CF 3 , Y = S)
Zu 1 ,55 g (5 mmol) 4-Trifluormethyl-2-mercapto-6-(4-methoxyphenyl)-pyridin-3- carbonitril (Beispiel 61 ; Experiment 5i; allgemeine Formel 5: R1=4-MeO-Ph, X=C-H, R3=CF3, Y=S) in 25 ml Butoxyethoxyethanol werden 1 ,00 g (5.5 mmol) N- chloracetylurethan sowie 0.96 ml (12.5 mmol) Triethylamin gegeben und der Ansatz 30 Minuten bei 80 °C gerührt. Anschließend wird der gerührte Ansatz für 30- 60 Minuten auf 180 °C erwärmt. Nach Abkühlen wird der Niederschlag abgesaugt, erst mit Ethanol, anschließend mit Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet.To 1.55 g (5 mmol) of 4-trifluoromethyl-2-mercapto-6- (4-methoxyphenyl) -pyridine-3-carbonitrile (Example 61, experiment 5i, general formula 5: R 1 = 4-MeO-Ph, X = CH, R 3 = CF 3 , Y = S) in 25 ml of butoxyethoxyethanol are added to 1 00 g (5.5 mmol) of N-chloroacetylurethane and 0.96 ml (12.5 mmol) of triethylamine and the mixture is stirred at 80 ° C for 30 minutes. Subsequently, the stirred batch is heated to 180 ° C for 30-60 minutes. After cooling, the precipitate is filtered off with suction, washed first with ethanol, then with water, sucked dry and i. Vak. dried at 50 0 C.
Ausbeute: 1.62g (82%); HPLC tR: — min, Reinheit: 99.9 % (s. a in Tab. 1); MS (ESI, m/e): 394 [M+H]+ Yield: 1.62g (82%); HPLC t R : - min, purity: 99.9% (see a in Tab. MS (ESI, m / e): 394 [M + H] +
(* in Anlehnung an: Shestopalov, A. M.; Nikishin, K. G.; Gromova, A. V.; Rodinovskaya, L A. Russ.Chem. Bull. (2003), 52(10), 2203-2206)(* following: Shestopalov, A.M., Nikishin, K.G., Gromova, A.V., Rodinovskaya, L A. Russ.Chem. Bull. (2003), 52 (10), 2203-2206)
Ausgehend von den nachfolgend beschriebenen Vorstufen werden durch Umsetzung der entsprechenden Verbindungen der allgemeinen Formel 5 mit N-chloracetyl- urethan analog Beispiel 10 die folgenden Beispiele 39-41 , 43 und 44 und erhalten:Starting from the precursors described below, the following Examples 39-41, 43 and 44 are obtained by reacting the corresponding compounds of the general formula 5 with N-chloroacetylurethane analogously to Example 10:
Beispiel 11Example 11
9-Methyl-7-(thiophen-2-yl)-thieno[2,3-d:455-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=Thiophen-2-yl, X=N, R3=Me, Y=S)9-Methyl-7- (thiophen-2-yl) thieno [2,3-d: 4 5 5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R i = thiophene -2-yl, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-(thiophen-2-yl)-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7j; allgemeine Formel 7: Ri=Thiophen-2-yl, X=N1 R3=Me1 Y=S) (S. Tab. 1) Beispiel 12Analogously to Example 1 from 5-amino-4-methyl-2- (thiophen-2-yl) thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7j; general formula 7: Ri = thiophene) 2-yl, X = N 1 R 3 = Me 1 Y = S) (see Table 1) Example 12
θ-Methyl-T^-nitro-phenylHhieno^^-d^^-d'ldipyrimidin-a^iH^HJ-dion (allgemeine Formel 1a: Ri=4-NO2-Ph, X=N, R3=Me, Y=S)θ-Methyl-T ^ -nitrophenylHhieno ^^ - d ^^ - Idipyrimidin-a ^ iH ^ HJ-dione (general formula 1a: Ri = 4-NO 2 -Ph, X = N, R 3 = Me , Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-(4-nitro-phenyl)-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7k; allgemeine Formel 7: R-ι=4-Nθ2-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1 from 5-amino-4-methyl-2- (4-nitro-phenyl) -thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7k, general formula 7: R-1 = 4-NO 2 Ph, X = N, R 3 = Me 1 Y = S) (p tab. 1)
Beispiel 13Example 13
9-Methyl-7-naphthalen-1-yl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1 H,3H)-dion (allgemeine Formel 1a: Ri=Naphthalen-1-yl, X=N, R3=Me, Y=S)9-Methyl-7-naphthalen-1-yl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = naphthalene) 1-yl, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-4~methyl-2-naphthalen-1-yl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7I; allgemeine Formel 7: Ri=Naphthalen-1-yl, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-4-methyl-2-naphthalen-1-yl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7I; general formula 7: Ri = naphthalene-1; yl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 14Example 14
7-(Chinolin-6-yl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R^Chinolin-6-yl, X=N, R3=Me, Y=S)7- (Quinolin-6-yl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1) quinoline -6-yl, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(chinolin-6-yl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7m; allgemeine Formel 7: R-ι=Chinolin-6-yl, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2- (quinolin-6-yl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7m, general formula 7: R-1 = Quinolin-6-yl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 15Example 15
7-(4-Amino-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=4-NH2-Ph, X=N, R3=Me, Y=S) 5.5 g (15.5 mmol) 9-Methyl-7-(4-nitro-phenyl)-thieno[2,3-d:4,5-d']dipyπmidin-2,4- (1H,3H)-dion (Beispiel 12, allgemeine Formel 1a: R1=4-NO2-Ph, X=N1 R3=Me, Y=S) werrden mit 9.9 g (56.9 mmol) Natriumdithionit und 31.5 ml Glykolmonomethylester in 30 ml Wasser suspendiert und 3 Stunden unter Rückfluß erhitzt. Danach werden 20 ml Wasser und 20 ml konz. HCl zugetropft und es wird weitere 30 Minuten unter Rückfluss erhitzt. Nach Erkalten wird auf 100 ml Eiswasser gegossen und mit Natriumcarbonat alkalisiert. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet.7- (4-Amino-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = 4 -NH 2 -Ph, X = N, R 3 = Me, Y = S) 5.5 g (15.5 mmol) of 9-methyl-7- (4-nitrophenyl) thieno [2,3-d: 4,5-d '] diphenylmidine-2,4- (1H, 3H) -dione (Example 12, general formula 1a: R 1 = 4-NO 2 -Ph, X = N 1 R 3 = Me, Y = S) are suspended with 9.9 g (56.9 mmol) of sodium dithionite and 31.5 ml of glycol monomethyl ester in 30 ml of water and 3 hours heated to reflux. Thereafter, 20 ml of water and 20 ml of conc. HCl is added dropwise and it is refluxed for a further 30 minutes. After cooling, is poured onto 100 ml of ice water and alkalized with sodium carbonate. The precipitate is filtered off with suction, washed with water and dried.
Ausbeute 4.8 g (95%); HPLC tR: 10.6 min, Reinheit: 93.0 % (s. a in Tab. 1); MS (ESI, m/e): 324 [M+H]~ Yield 4.8 g (95%); HPLC t R : 10.6 min, purity: 93.0% (see a in Table 1); MS (ESI, m / e): 324 [M + H] ~
Beispiel 16Example 16
g-Wlethyl-T^-phenyloxy-phenyO-thienota^-d^^-d'ldipyrimidin-a^-OH^H)- dion (allgemeine Formel 1a: Ri-=4-Ph-O-Ph, X=N, R3=Me, Y=S)g-Wlethyl-T ^ -phenyloxy-pheny-o-thienota ^ -d ^^ - dodipyrimidine-a ^ -OH ^ H) -dione (general formula 1a: Ri- = 4-Ph-O-Ph, X = N , R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-(4-phenyloxy-phenyl)-thieno[2,3- d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7o; allgemeine Formel 7: R-i=4- Ph-O-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-4-methyl-2- (4-phenyloxyphenyl) thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7o; general formula 7: Ri = 4- Ph-O-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 17Example 17
9-Methyl-7-(4-n-propyl-phenyl)-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=4-n-Pr-Ph, X=N, R3=Me5 Y=S)9-Methyl-7- (4-n-propylphenyl) thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 4-n-Pr-Ph, X = N, R 3 = Me 5 Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-(4-n-propyl-phenyl)-thieno[2,3-d]pyrimidin- 6-carboxamid (Beispiel 62; Experiment 7p; allgemeine Formel 7: R-ι=4-n-Pr-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, 5-amino-4-methyl-2- (4-n-propyl-phenyl) -thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7p, general formula 7: R- ι = 4-n-Pr-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 18 y^-Trifluormethyl-phenyO-θ-methyl-thienofa^-d^^-d'ldipyrimidin^^-CI H^H)- dion (allgemeine Formel 1a: R1=^CF3-Ph, X=N, R3=Me, Y=S)Example 18 y ^ -trifluoromethyl-phenyl-θ-methyl-thienoyl ^ -d ^^ - Idipyrimidin ^^ - CI H ^ H) - dione (general formula 1a: R 1 = ^ CF 3 -Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-trifluormethyl-phenyl)-4-methyl-thieno[2,3- d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7q; allgemeine Formel 7: Ri=4- CF3-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2- (4-trifluoromethyl-phenyl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7q, general formula 7: Ri = 4- CF 3 -Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 19Example 19
7-(4-Brom-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=4-Br-Ph, X=N, R3=Me, Y=S)7- (4-Bromo-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = 4 -Br-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-brom-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7r; allgemeine Formel 7: R-ι=4-Br-Ph, X=N, R3-=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2- (4-bromo-phenyl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7r, general formula 7: R-1 = 4-Br-Ph, X = N, R 3 - = Me, Y = S) (see Table 1)
Beispiel 20Example 20
4-(9-Methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion-7-yl)- benzoesäureethylesterEthyl 4- (9-methylthieno [2,3-d: 4,5-d '] -dipyrimidine-2,4- (1H, 3H) -dion-7-yl) -benzoate
(allgemeine Formel 1a: R1=EtOCO-Ph, X=N, R3=Me, Y=S)(general formula 1a: R 1 = EtOCO-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 4-(5-Amino-6-carbamoyl-4-methyl-thieno[2,3-d]pyrimidin-2-yl)- benzoesäureethylester (Beispiel 62; Experiment 7s; allgemeine Formel 7: R1=EtOCO-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, ethyl 4- (5-amino-6-carbamoyl-4-methylthieno [2,3-d] pyrimidin-2-yl) benzoate (Example 62, Experiment 7s, general formula 7: R 1 = EtOCO -Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 21Example 21
9-l\Λethyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1 H,3H)- dion (allgemeine Formel 1a: R1=4-iso-PrO-Ph, X=N, R3=Me, Y=S) Analog Beispiel 1 aus 5-Amino-2-(4-iso-propoxy-phenyl)-4-methyl-thieno[2,3- d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7t; allgemeine Formel 7: R-ι=4- iso-PrO-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)9-Ethyl ethyl 7- (4-iso-propoxy-phenyl) thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 4-iso-PrO-Ph, X = N, R 3 = Me, Y = S) Analogously to Example 1, 5-amino-2- (4-isopropoxy-phenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7t; ι = 4-iso-PrO-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 22Example 22
7-(4-Iod-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=4-I-Ph, X=N, R3=Me, Y=S)7- (4-iodo-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 4-I-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-lod-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7u; allgemeine Formel 7: Ri=4-I-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1, 5-amino-2- (4-iodo-phenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, experiment 7u; general formula 7: Ri = 4) I-Ph, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 23Example 23
θ-Methyl^^-methyl-phenyO-thienota^-d^^-d'ldipyrimidin^^-OH^HJ-dion (allgemeine Formel 1a: Ri=4-Me-Ph, X=N, R3=Me, Y=S)θ-methyl ^^ -methyl-phenyl-thienoyl-d ^^ -dipipyrimidine ^^ - OH ^ HJ-dione (general formula 1a: Ri = 4-Me-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-(4-methyl-phenyl)-thieno[2,3-d]pyrimidin- 6-carboxamid (Beispiel 62; Experiment 7v; allgemeine Formel 7: Ri=4-Me-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1, 5-amino-4-methyl-2- (4-methylphenyl) thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7v; general formula 7: Ri = 4-) Me-Ph, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 24Example 24
7-(4-Chlor-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=4-CI-Ph, X=N, R3=Me, Y=S)7- (4-Chloro-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 4-Cl-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-chlor-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7w; allgemeine Formel 7: Ri=4-Cl-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1) Beispiel 25Analogously to Example 1, 5-amino-2- (4-chlorophenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62; Experiment 7w; general formula 7: Ri = 4-) Cl-Ph, X = N, R 3 = Me 1 Y = S) (see Table 1) Example 25
T^-Cyano-phenyO-θ-methyl-thienota^-d^^-d'ldipyrimidin^j^iH^HHion (allgemeine Formel 1a: R1=4-CN-Ph, X=N, R3=Me, Y=S)T ^ -cyano-phenyl-O-methyl-thienoyl-d ^^ -dipipyrimidine-1-yl-1HHione (general formula 1a: R 1 = 4-CN-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-cyano-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7x; allgemeine Formel 7: R1=^CN-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1 from 5-amino-2- (4-cyano-phenyl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7x, general formula 7: R 1 = ^ CN-Ph, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 26Example 26
7-(3-Fluor-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H53H)-dion (allgemeine Formel 1a: R1=S-F-Ph, X=N, R3=Me, Y=S)7- (3-fluoro-phenyl) -9-methyl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4 (1 H 5 3 H) -dione (general formula 1a: R 1 = SF-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(3-fluor-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7y; allgemeine Formel 7: Ri=3-F-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, 5-amino-2- (3-fluorophenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, experiment 7y; general formula 7: Ri = 3) F-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 27Example 27
7-(4-Methoxy-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=4-MeO-Ph, X=N, R3=Me, Y=S)7- (4-methoxyphenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 4-MeO-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-methoxy-phenyl)-4-methyl-thieno[2,3-d]- pyrimidin-6-carboxamid (Beispiel 62; Experiment 7z; allgemeine Formel 7: R-ι=4- MeO-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, 5-amino-2- (4-methoxyphenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7z, general formula 7: R-1 = 4 MeO-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 28Example 28
7-(4-Brom-2-fluor-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)- dion (allgemeine Formel 1a:
Figure imgf000046_0001
X=N, R3=Me, Y=S) Analog Beispiel 1 aus 5-Amino-2-(4-brom-2-fluor-phenyl)-4-methyl-thieno[2,3-d]- pyrimidin-6-carboxamid (Beispiel 62; Experiment 7aa; allgemeine Formel 7: Ri=4- Br,2-F-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)7- (4-Bromo-2-fluoro-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a :
Figure imgf000046_0001
X = N, R 3 = Me, Y = S) Analogously to Example 1, 5-amino-2- (4-bromo-2-fluoro-phenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7aa, general formula 7 : Ri = 4-Br, 2-F-Ph, X = N, R 3 = Me, Y = S) (see Table 1)..
Beispiel 29Example 29
θ-Methyl-T-phenyl-thienop^-d^^-d'Jdipyrimidin-a^-CIH^HJ-dion (allgemeine Formel 1a: R1=Ph, X=N, R3=Me, Y=S)θ-methyl-T-phenyl-thienop ^ -d ^^ - d'-dipyrimidine-α-Ci-1H-dione (general formula 1a: R 1 = Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-phenyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ab; allgemeine Formel 7: Ri=Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, 5-amino-4-methyl-2-phenylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ab, general formula 7: Ri = Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 30Example 30
7,9-DimethyI-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=Me, X=N, R3=Me, Y=S)7,9-DimethyI-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = Me, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2,4-dimethyl-thieno[2,3-d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7ac; allgemeine Formel 7: Ri=Me, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2,4-dimethylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62; Experiment 7ac; general formula 7: R i = Me, X = N, R 3 = Me , Y = S) (see Table 1)
Beispiel 31Example 31
7-Benzyl-9-methyl-thieno[2,3-d:4,5-d'3dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a:
Figure imgf000047_0001
X=N, R3=Me, Y=S)7-Benzyl-9-methylthieno [2,3-d: 4,5-dodipyrimidine-2,4- (1H, 3H) -dione (general formula 1a:
Figure imgf000047_0001
X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-benzyl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ad; allgemeine Formel 7: R1=Bn, X=N, R3=Me, Y=S) (s. Tab. 1) Beispiel 32Analogously to Example 1 from 5-amino-2-benzyl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ad; general formula 7: R 1 = Bn, X = N, R 3 = Me, Y = S) (see Table 1) Example 32
T-Cyclopropyl-θ-methyl-thieno^jS-di^δ-d'jdipyrimidin-a^-CI H^HJ-dion (allgemeine Formel 1a: Ri=CyPr, X=N, R3=Me, Y=S)T-cyclopropyl-θ-methyl-thieno-jS-di-δ-diperipyrimidine-α-C 1 H 1 -H-dione (general formula 1 a: R i = CyPr, X = N, R 3 = Me, Y = S )
Analog Beispiel 1 aus 5-Amino-2-cyclopropyl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ae; allgemeine Formel 7: Ri=CyPr, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1 from 5-amino-2-cyclopropyl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ae, general formula 7: Ri = CyPr, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 33Example 33
7-CyclohexyI-9-methyl-thieno[2,3-d:4,5-d']dipyπmidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=CyHeX, X=N, R3=Me, Y=S)7-Cyclohexyl-9-methylthieno [2,3-d: 4,5-d '] diphenylmidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = CyHeX, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-cyclphexyl-4-methyI-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7af; allgemeine Formel 7: R1=CyHeX, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2-cyclphexyl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62; Experiment 7af; general formula 7: R 1 = CyHeX, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 34Example 34
T-Benzhydryl-S-methyl-thienoI^S-dϊ^δ-d'Jdipyrimidin-a^-OH^HHion (allgemeine Formel 1a: Ri=Benzhydryl, X=N, R3=Me, Y=S)T-Benzhydryl-S-methyl-thienoI, S-dϊ, δ-d'-dipyrimidine-α, -OH, H, ion (general formula 1a: R i = benzhydryl, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-benzhydryl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ag; allgemeine Formel 7: Ri=Benzhydryl, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2-benzhydryl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ag; general formula 7: Ri = benzhydryl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 35Example 35
9-Methyl-7-pyridin-4-yl-thieno[2,3-d:4,5-d'3dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R^Pyridin-4-yl, X=N, R3=Me, Y=S) Analog Beispiel 1 aus 5-Amino-4-methyl-2-pyridin-4-yl-thieno[2,3-d]pyπmidin-6- carboxamid (Beispiel 62; Experiment 7ah; allgemeine Formel 7: R-ι=Pyridin-4-yl, X=N, R3=Me1 Y=S) (S. Tab. 1)9-Methyl-7-pyridin-4-yl-thieno [2,3-d: 4,5-dodipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R ^ pyridine-4- yl, X = N, R 3 = Me, Y = S) Analogously to Example 1, 5-amino-4-methyl-2-pyridin-4-yl-thieno [2,3-d] pymidine-6-carboxamide (Example 62, Experiment 7ah; general formula 7: R-1 = pyridine) 4-yl, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 36Example 36
θ-Methyl-T-styryl-thieno^^-d^^-d'ldipyrimidin^^-CIHjSHJ-dion (allgemeine Formel 1a: Ri=Styryl, X=N, R3=WIe, Y=S)θ-methyl-T-styryl-thieno ^^ - d ^^ - Idipyrimidin ^^ - CIHjSHJ-dione (general formula 1a: Ri = styryl, X = N, R 3 = WIe, Y = S)
Analog Beispiel 1 aus 5-Amino-4-methyl-2-styryl-thieno[2,3-d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7ai; allgemeine Formel 7: R-ι=Styryl, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-4-methyl-2-styryl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ai; general formula 7: R-1 = styryl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 37Example 37
7-(2-Fluor-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dlon (allgemeine Formel 1a: R1=2-F-Ph, X=N, R3=IVIe, Y=S)7- (2-Fluoro-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -done (general formula 1a: R 1 = 2-F-Ph, X = N, R 3 = IVIe, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(2-fluor-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7aj; allgemeine Formel 7: R1=2-F-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1, 5-amino-2- (2-fluorophenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7aj, general formula 7: R 1 = 2 -F-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 38Example 38
7-(2,6-Difluor-phenyl)-9-methyl-thieno[2,3-d:455-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=2,4-F2-Ph, X=N, R3=Me, Y=S)7- (2,6-Difluoro-phenyl) -9-methylthieno [2,3-d: 4 5 5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = 2,4-F 2 -Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(2,4-difluor-phenyl)-4-methyl-thieno[2,3-d]pyrimidin- 6-carboxamid (Beispiel 62; Experiment 7ak; allgemeine Formel 7: R1=2,4-F2-Ph, X=N, R3=Me, Y=S) (s. Tab. 1) Beispiel 39Analogously to Example 1 from 5-amino-2- (2,4-difluoro-phenyl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ak, general formula 7: R 1 = 2,4-F 2 -Ph, X = N, R 3 = Me, Y = S) (see Table 1) Example 39
y^-Brom-phenyO-θ-methyl-thieno^^-d^^-d'ldipyrimidin^^i H.SHJ-dion (allgemeine Formel 1a: Ri=2-Br-Ph, X=N, R3=Me, Y=S)y ^ -bromo-phenyl-θ-methyl-thieno ^^ - d ^^ - Idipyrimidin ^ ^ i H.SHJ-dione (general formula 1a: Ri = 2-Br-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 10 aus 2-(2-Brom-phenyl)-4-mercapto-6-methyl-pyrimidin-5- carbonitril (Beispiel 61 ; Experiment 5al; allgemeine Formel 5: Ri=2-Br-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 10 from 2- (2-bromo-phenyl) -4-mercapto-6-methylpyrimidine-5-carbonitrile (Example 61, Experiment 5al; general formula 5: Ri = 2-Br-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 40Example 40
7-(3-Methoxy-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=3-MeO-Ph, X=N, R3=Me, Y=S)7- (3-Methoxy-phenyl) -9-methyl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = 3 -MeO-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 10 aus 4-Mercapto-2-(3-methoxy-phenyI)-6-methyl-pyrimidin-5- carbonitril (Beispiel 61 ; Experiment 5am; allgemeine Formel 5: R1=S-MeO-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1 )Analogously to Example 10 from 4-mercapto-2- (3-methoxy-phenyl) -6-methyl-pyrimidine-5-carbonitrile (Example 61, experiment 5am; general formula 5: R 1 = S-MeO-Ph, X = N , R 3 = Me 1 Y = S) (see Table 1)
Beispiel 41Example 41
7-(2-Methoxy-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=2-MeO-Ph, X=N, R3=Me, Y=S)7- (2-Methoxy-phenyl) -9-methyl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 2-MeO-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 10 aus 4-Mercapto-2-(2-methoxy-phenyl)-6-methyl-pyrimidin-5- carbonitril (Beispiel 61 ; Experiment 5an; allgemeine Formel 5: Ri=2-MeO-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)4-Mercapto-2- (2-methoxyphenyl) -6-methylpyrimidine-5-carbonitrile (Example 61, Experiment 5an; general formula 5: Ri = 2-MeO-Ph, X = N, analogous to Example 10). R 3 = Me 1 Y = S) (see Table 1)
Beispiel 42Example 42
9-Methyl-7-(2-methyl-phenyl)-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=2-Me-Ph, X=N, R3=Me, Y=S) Analog Beispiel 1 aus 5-Amino-4-methyl-2-(2-methyl-phenyl)-thieno[2,3-d]pyrimidin- 6-carboxamid (Beispiel 62; Experiment 7ao; allgemeine Formel 7: Ri=2-Me-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)9-Methyl-7- (2-methylphenyl) thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 2-Me-Ph, X = N, R 3 = Me, Y = S) Analogously to Example 1 from 5-amino-4-methyl-2- (2-methylphenyl) thieno [2,3-d] pyrimidine-6-carboxamide (Example 62; Experiment 7ao; general formula 7: Ri = 2) Me-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 43Example 43
θ-Methyl-T-pyridin-S-yl-thienop^-d^^-d'ldipyrimidin-aAOH.SHJ-dion (allgemeine Formel 1a: R^Pyridin-3-yI, X=N, R3=Me, Y=S)θ-methyl-T-pyridine-S-yl-thienop ^ -d ^^ - Idipyrimidin-aAOH.SHJ-dione (general formula 1a: R ^ pyridin-3-yl, X = N, R 3 = Me, Y = S)
Analog Beispiel 10 aus 4-Mercapto-6-methyl-2-pyridin-3-yl-pyrimidin-5-carbonitril (Beispiel 61 ; Experiment 5ap; allgemeine Formel 5: Ri=Pyridin-3-yl, X=N, R3=Me, Y=S) (s. Tab. 1)Analogously to Example 10, 4-mercapto-6-methyl-2-pyridin-3-yl-pyrimidine-5-carbonitrile (Example 61; Experiment 5ap; general formula 5: R 1 = pyridin-3-yl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 44Example 44
7-(254-Dimethoxy-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)- dion7- (2 5 4-dimethoxy-phenyl) -9-methyl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4 (1H, 3H) - dione
(allgemeine Formel 1a:
Figure imgf000051_0001
X=N, R3=Me, Y=S)(general formula 1a:
Figure imgf000051_0001
X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 4-Mercapto-2-(2,4-dimethoxy-phenyl)-6-methyl-pyrimidin~5- carbonitril (Beispiel 61 ; Experiment 5aq; allgemeine Formel 5:
Figure imgf000051_0002
X=N, R3=Me, Y=S) (s. Tab. 1)4-Mercapto-2- (2,4-dimethoxyphenyl) -6-methylpyrimidine-5-carbonitrile analogously to Example 1 (Example 61, experiment 5aq, general formula 5):
Figure imgf000051_0002
X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 45Example 45
7-Furan-2-yl-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a:
Figure imgf000051_0003
7-Furan-2-yl-9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a:
Figure imgf000051_0003
Analog Beispiel 1 aus 5-Amino-2-furan-2-yl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ar; allgemeine Formel 7: Ri=Furan-2-yl, X=N, R3=Me, Y=S) (s. Tab. 1) Beispiel 46Analogously to Example 1 from 5-amino-2-furan-2-yl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ar; general formula 7: Ri = furan-2-one) yl, X = N, R 3 = Me, Y = S) (see Table 1) Example 46
7-(3,4-Dimethoxy-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)- dion7- (3,4-Dimethoxyphenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione
(allgemeine Formel 1a: Ri=3,4-(MeO)2-Ph, X=N, R3=Me, Y=S)(general formula 1a: Ri = 3,4- (MeO) 2 -Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(3,4-dimethoxy-phenyl)-4-methyl-thieno[2,3- d]pyπmidin-6-carboxamid (Beispiel 62; Experiment 7as; allgemeine Formel 7:
Figure imgf000052_0001
Analogously to Example 1, 5-amino-2- (3,4-dimethoxyphenyl) -4-methylthieno [2,3-d] pymidine-6-carboxamide (Example 62, Experiment 7as, general formula 7:
Figure imgf000052_0001
Beispiel 47Example 47
7-Methyl-9-phenyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: Ri=Me, X=N, R3=Ph, Y=S)7-Methyl-9-phenylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: Ri = Me, X = N, R 3 = Ph, Y = S)
Analog Beispiel 1 aus 5-Amino-2-methyl-4-phenyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7at; allgemeine Formel 7: Ri=Me, X=N, R3=Ph, Y=S) (S. Tab. 1)Analogously to Example 1 from 5-amino-2-methyl-4-phenylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62; Experiment 7at; general formula 7: Ri = Me, X = N, R 3 = Ph, Y = S) (see Table 1)
Beispiel 48Example 48
9-Methyl-7-(3-methyl-phenyl)-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion (allgemeine Formel 1a: R1=3-Me-Ph, X=N, R3=Me, Y=S)9-Methyl-7- (3-methylphenyl) thieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione (general formula 1a: R 1 = 3-Me-Ph, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(3-methyl-phenyl)~4-methyl-thieno[2,3-d]pyrimidin~ 6-carboxamid (Beispiel 62; Experiment 7au; allgemeine Formel 7: Ri=3-Me-Ph, X=N, R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1, 5-amino-2- (3-methylphenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, experiment 7au; general formula 7: Ri = 3) Me-Ph, X = N, R 3 = Me 1 Y = S) (see Table 1)
Beispiel 49 9-Methyl-7-(4-(methylsulfonyl)-phenyI)-thieno[2,3-d:4,5-d']dipyrirnidin-2,4-Example 49 9-methyl-7- (4- (methylsulfonyl) -phenyl) -thieno [2,3-d: 4,5-d '] dipyrirnidin-2,4-
(1H,3H)-dion(1H, 3H) -dione
(allgemeine Formel 1a: R1=4-WIe-SO2-Ph, X=N, R3=WIe, Y=S)(general formula 1a: R 1 = 4-WIe-SO 2 -Ph, X = N, R 3 = WIe, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-(methylsulfonyl)-phenyl)-4-methyl-thieno[2,3- d]pyrimidin-6-carboxamid (Beispiel 62; Experiment 7av; allgemeine Formel 7: Ri=4- Me-SO2-Ph, X=N1 R3=Me, Y=S) (s. Tab. 1)Analogously to Example 1 from 5-amino-2- (4- (methylsulfonyl) phenyl) -4-methyl-thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7av, general formula 7: Ri = 4-Me-SO 2 -Ph, X = N 1 R 3 = Me, Y = S) (see Table 1)
Beispiel 50Example 50
7-Biphen-4-yI-9-methyl-thieno[2,3-d:455-d']diρyrimidin-2,4-(1H)3H)-dion (allgemeine Formel 1a: R^Biphen-4-yl, X=N, R3=Me, Y=S)7-biphen-4-yl-9-methylthieno [2,3-d: 4 5 5-d '] di-pyrimidine-2,4- (1H ) 3H) -dione (general formula 1a: R 1 biphene-4 -yl, X = N, R 3 = Me, Y = S)
Analog Beispiel 1 aus 5-Amino-2-biphen-4-yl-4-methyl-thieno[2,3-d]pyrimidin-6~ carboxamid (Beispiel 62; Experiment 7aw; allgemeine Formel 7: Ri=Biphen-4-yl, X=N1 R3=Me1 Y=S) (S. Tab. 1)Analogously to Example 1 from 5-amino-2-biphen-4-yl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7aw; general formula 7: Ri = biphen-4 yl, X = N 1 R 3 = Me 1 Y = S) (see Table 1)
Beispiel 51Example 51
7-(4-t-Butyl-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1HJ3H)-dion (allgemeine Formel 1a: R1=4-t-Bu-Ph, X=N, R3=WIe, Y=S)7- (4-t-butylphenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H J 3H) -dione (general formula 1a: R 1 = 4-t Bu-Ph, X = N, R 3 = WIe, Y = S)
Analog Beispiel 1 aus 5-Amino-2-(4-t-butyl-phenyl)-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ax; allgemeine Formel 7: R1=4-t-Bu-Ph, X=N, R3=Me, Y=S) (s. Tab. 1)5-Amino-2- (4-t-butylphenyl) -4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ax, general formula 7: R 1 = 4-t Bu-Ph, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 52Example 52
θ-Methyl^-naphthalen^-yl-thieno^-d^^-d'ldipyrimidin^AOH^HHion (allgemeine Formel 1a:
Figure imgf000053_0001
Analog Beispiel 1 aus 5-Amino-2-naphthalen-2-yl-4-methyl-thieno[2,3-cl3pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ay; allgemeine Formel 7: Ri=Naphthalen-2-yl, X=N, R3=Me, Y=S) (s. Tab. 1)θ-methyl ^ -naphthalene ^ -yl-thieno ^ -d ^^ - ldipyrimidin ^ AOH ^ HHion (general formula 1a:
Figure imgf000053_0001
Analogously to Example 1 from 5-amino-2-naphthalen-2-yl-4-methylthieno [2,3-cl3pyrimidine-6-carboxamide (Example 62, Experiment 7ay; general formula 7: Ri = naphthalen-2-yl, X = N, R 3 = Me, Y = S) (see Table 1)
Beispiel 53Example 53
2-EthyI-9-methyI-7-phenyl-pyrido[3',2':4,5]thieno[3,2-c/lpyrimiciin-4-on (allgemeine Formel 1b: Ri=Ph, X=C-H5 R3=Me, R4=Et, Y=S)2-Ethyl-9-methyl-7-phenyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-c / 1-pyrimicin-4-one (general formula 1b: Ri = Ph, X = CH 5 R 3 = Me, R 4 = Et, Y = S)
Es werden 0.86 g (3.0 mmol) 3-Amino-6-phenyI-4-methyl-thieno[2,3-6]pyridin-2~ carboxamid (Beispiel 62; Experiment 7d; allgemeine Formel 7: Ri=Ph, X=C-H, R3=Me, Y=S) und 5.0 ml (39.2 mmol) Propionsäureanhydrid in 20 ml Toluol 2 Stunden unter Rückfluß erhitzt. Nach Abkühlen wird der Niederschlag abgesaugt, mit ca. 5 m( Ethanol gewaschen und trocken gesaugt. Der Rückstand wird in 5 ml (15.0 mmol) Natriumhydroxid-Lösung (3N) 15 Minuten unter Rückfluß erhitzt. Nach Abkühlen werden 5 ml Wasser zugegeben und es wird mit Essigsäure (10 %) neutralisiert. Anschließend wird der Niederschlag abgesaugt, mit ca. 10 ml Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 0.29 g (30 %); HPLC tR: 17.6 min, Reinheit: 96.2 % (s. Tab. 2); MS (ESI, m/e): 322 [M+H]+ There are obtained 0.86 g (3.0 mmol) of 3-amino-6-phenyl-4-methylthieno [2,3-6] pyridine-2-carboxamide (Example 62, experiment 7d, general formula 7: Ri = Ph, X = CH, R 3 = Me heated, Y = S) and 5.0 ml (39.2 mmol) of propionic anhydride in 20 ml of toluene for 2 hours under reflux. After cooling, the precipitate is filtered off with suction, washed with about 5 m (ethanol) and sucked dry.The residue is refluxed in 5 ml (15.0 mmol) sodium hydroxide solution (3N) for 15 minutes After cooling, 5 ml of water are added and is neutralized with acetic acid (10%) and then the precipitate is filtered off with suction, washed with about 10 ml of water, sucked dry and dried in vacuo at 50 ° C. Yield: 0.29 g (30%); HPLC t R : 17.6 min, purity: 96.2% (see Table 2), MS (ESI, m / e): 322 [M + H] +
Beispiel 54Example 54
9-Methyl-7-phenyl-2-propyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-on (allgemeine Formel 1b: Ri=Ph, X=C-H, R3=Me, R4=πPr, Y=S)9-methyl-7-phenyl-2-propylpyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidin-4-one (general formula 1b: Ri = Ph, X = CH, R 3 = Me, R 4 = πPr, Y = S)
Analog Beispiel 53 aus 3-Amino-6-phenyl-4-methyl-thieno[2,3-ö]pyridin-2-carboxamidAnalogously to Example 53 from 3-amino-6-phenyl-4-methylthieno [2,3-δ] pyridine-2-carboxamide
(Beispiel 62; Experiment 7d; allgemeine Formel 7: Ri=Ph, X=C-H, R3=Me, Y=S) und(Example 62; Experiment 7d; general formula 7: Ri = Ph, X = CH, R 3 = Me, Y = S) and
Buttersäureanhydrid.Butyric anhydride.
Es wird bei 170 0C gerührt. Nach Abkühlen wird mit Natriumhydroxid alkalisiert und kurz erwärmt. Der Niederschlag wird abgesaugt, mit Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 0.55 g (91 %); HPLC tR: 20.3 min, Reinheit: 46.8 % (s. Tab. 2); MS (ESI, m/e): 336 [MH-H]+ It is stirred at 170 0 C. After cooling, it is alkalized with sodium hydroxide and briefly heated. The precipitate is filtered off, washed with water, sucked dry and i. Vak. dried at 50 0 C. Yield: 0.55 g (91%); HPLC t R : 20.3 min, purity: 46.8% (see Table 2); MS (ESI, m / e): 336 [MH-H] +
Beispiel 55Example 55
7-(3,4-Dimethoxyphenyl)-9-methy[-2-propyl-pyrido[3',2':4,5]thieno[3,2- d3pyrimidin-4-on (allgemeine Formel 1b: Ri=3,4-(MeO)2-Ph, X=C-H, R3=Me, R4=nPr, Y=S)7- (3,4-Dimethoxyphenyl) -9-methyl [-2-propylpyrido [3 ' , 2 ' : 4,5] thieno [3,2-d3pyrimidin-4-one (general formula 1b: Ri = 3 , 4- (MeO) 2 -Ph, X = CH, R 3 = Me, R 4 = nPr, Y = S)
Analog Beispiel 53 aus 3-Amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3~£>]- pyridin-2-carboxamid (Beispiel 62; Experiment 7a; allgemeine Formel 7: Ri=3,4-Analogously to Example 53 from 3-amino-6- (3,4-dimethoxyphenyl) -4-methylthieno [2,3- [b]] pyridine-2-carboxamide (Example 62, experiment 7a, general formula 7: Ri = 3,4-
(MeO)2-Ph, X=C-H, R3=Me, Y=S) und Buttersäureanhydrid.(MeO) 2 -Ph, X = CH, R 3 = Me, Y = S) and butyric anhydride.
Der Rückstand wird in 5 ml (15.0 mmol) Natriumhydroxid-Lösung (3N) und 5 mlThe residue is dissolved in 5 ml (15.0 mmol) sodium hydroxide solution (3N) and 5 ml
Ethanol 6 Stunden unter Rückfluß erhitzt. Nach Ansäuern mit Salzsäure (10 %) wird der Niederschlag mit Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 °C getrocknet.Ethanol heated under reflux for 6 hours. After acidification with hydrochloric acid (10%), the precipitate is washed with water, sucked dry and i. Vak. dried at 50 ° C.
Ausbeute: 0.59 g (47 %); HPLC tR: 17.4 min, Reinheit: 89.8 % (s. Tab. 2);Yield: 0.59 g (47%); HPLC t R : 17.4 min, purity: 89.8% (see Table 2);
MS (ESI, m/e): 396 [M+H]+ MS (ESI, m / e): 396 [M + H] +
Beispiel 56Example 56
2-Ethylthio-9-methyl-7-phenyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-on (allgemeine Formel 1b: Ri=Ph, X=C-H, R3=WIe, R4=SEt, Y=S)2-ethylthio-9-methyl-7-phenyl-pyrido [3 ' , 2 ' : 4,5] thieno [3,2-d] pyrimidin-4-one (general formula 1b: Ri = Ph, X = CH, R 3 = WIe, R 4 = SEt, Y = S)
Zu 2.00 g (4.2 mmol) 3-(3-Benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-/?]pyridin- 2-carbonsäureethylester (Beispiel 64; Experiment 11 ; allgemeine Formel 11 : Ri=Ph, X=C-H, R3=Me, Y=S) in 25 ml Ethanol werden 10.5 ml (10.5 mmol) Natriumhydroxid- Lösung (1N) gegeben und 30 Minuten unter Rückfluß erhitzt. Nach Zugabe von 10 ml Λ/,Λ/-Dimethylformamid, 5 ml (5 mmol) Natriumhydroxid-Lösung (1 N) und 0,50 ml lodethan (6.2 mmol) wird 30 Minuten bei Raumtemperatur gerührt. Der nach Ansäuern mit verd. Salzsäure ausgefallene Niedeschlag wird abgesaugt, mit Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 °C getrocknet. Ausbeute: 1.23 g (83 %), HPLC tR: 18.5 min, Reinheit: 98.5 % (s. Tab. 2); MS (ESI, m/e): 354 [M+H]+ To 2.00 g (4.2 mmol) of ethyl 3- (3-benzoylthioureido) -4-methyl-6-phenylthieno [2,3- /?] Pyridine-2-carboxylate (Example 64, Experiment 11, general formula II: Ri = ph, X = CH, R 3 = Me, Y = S) in 25 ml of ethanol, 10.5 ml (10.5 mmol) sodium hydroxide solution (1N) are added and heated for 30 minutes under reflux. After addition of 10 ml of Λ /, Λ / -dimethylformamide, 5 ml (5 mmol) of sodium hydroxide solution (1 N) and 0.50 ml of iodoethane (6.2 mmol) is stirred for 30 minutes at room temperature. The precipitated after acidification with dilute hydrochloric acid sweep is filtered off with suction, washed with water, sucked dry and i. Vak. dried at 50 ° C. Yield: 1.23 g (83%), HPLC t R : 18.5 min, purity: 98.5% (see Table 2); MS (ESI, m / e): 354 [M + H] +
Beispiel 57Example 57
9-Methyl-7-(4-iso-propoxy-phenyl)-2-propyl-thieno[2,3-d:4,5-d']dipyrimidin-9-methyl-7- (4-iso-propoxy-phenyl) -2-propyl-thieno [2,3-d: 4,5-d '] dipyrimidine
4(3H)-on4 (3H) -one
(allgemeine Formel 1b: Ri=4-isoPropO-Ph, X=N, R3=WIe, R4=Prop, Y=S)(general formula 1b: Ri = 4-isoPropO-Ph, X = N, R 3 = like, R 4 = Prop, Y = S)
100 mg (0.3 mmol) 5-Amino-4-methyl-2-(4-iso-propoxy-phenyl)-thieno[2,3-d]- pyrimidin-6-carboxamid (Beispiel 62; Experiment 7t; allgemeine Formel 7: R-ι=4- isoPropO-Ph, X=N, R3=Me1 Y=S) werden zusammen mit 3 ml (18 mmol) Buttersäureanhydrid 45 Minuten in einer Mikrowelle (300 W) auf 160 0C erhitzt. Der entstandene Niederschlag wird abgesaugt und in Ethanol resuspendiert. Man stellt mit 1 M LiOH-Lösung pH 11 ein und rührt 1 Stunde bei Raumtemperatur. Anschließend wird mit verd. HCl angesäuert, der Niederschlag abgesaugt, mit Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 15 mg (13 %), HPLC tR: 6.7 min, Reinheit: 98.1 % (s. Tab. 2); MS (ESI, m/e): 393 [M-H]" 100 mg (0.3 mmol) of 5-amino-4-methyl-2- (4-iso-propoxy-phenyl) thieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7t, general formula 7 : R-ι = 4- isoPropO-Ph, X = N, R 3 = Me 1 Y = S) are heated together with 3 ml (18 mmol) of butyric anhydride for 45 minutes in a microwave (300 W) at 160 0 C. The resulting precipitate is filtered off with suction and resuspended in ethanol. It is adjusted with 1 M LiOH solution pH 11 and stirred for 1 hour at room temperature. The mixture is then acidified with dil. HCl, the precipitate is filtered off, washed with water, sucked dry and i. Vak. dried at 50 0 C. Yield: 15 mg (13%), HPLC t R : 6.7 min, purity: 98.1% (see Table 2); MS (ESI, m / e): 393 [MH] "
Beispiel 58Example 58
9-Methyl-7-biphenyl-2-ethyl-thieno[2,3-d:4,5-d']dipyrimidin-4(3H)-on (allgemeine Formel 1b: R1=4-Ph-Ph, X=N5 R3=Me, R4=Et, Y=S)9-Methyl-7-biphenyl-2-ethylthieno [2,3-d: 4,5-d '] dipyrimidin-4 (3H) -one (general formula 1b: R 1 = 4-Ph-Ph, X = N 5 R 3 = Me, R 4 = Et, Y = S)
Analog Beispiel 57 aus 5-Amino-2-biphen-4-yl-4-methyl-thieno[2,3-/b]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7aw; allgemeine Formel 7: Ri=Biphen-4-yl, X=N, R3=Me, Y=S) und Propionsäureanhydrid (s. Tab. 2)Analogously to Example 57 from 5-amino-2-biphen-4-yl-4-methylthieno [2,3- / b] pyrimidine-6-carboxamide (Example 62, Experiment 7aw; general formula 7: Ri = biphene-4 -yl, X = N, R 3 = Me, Y = S) and propionic anhydride (see Table 2)
Beispiel 59Example 59
9-I\Λethyl-7-biphenyl-2-propyl-thieno[2,3-d:4,5-d']dipyrimidin-4(3H)-on (allgemeine Formel 1b: Ri=4-Ph-Ph, X=N, R3=Me5 R4=Prop, Y=S)9-I \ Λethyl-7-biphenyl-2-propyl-thieno [2,3-d: 4,5-d '] dipyrimidine-4 (3H) -one (general formula 1b: Ri = 4-Ph-Ph, X = N, R 3 = Me 5 R 4 = Prop, Y = S)
Analog Beispiel 57 aus 5-Amino-2-biphen-4-yl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7aw; allgemeine Formel 7: Ri=Biphen-4-yl, X=N, R3=Me, Y=S) und Buttersäureanhydrid (s. Tab. 2)Analogously to Example 57 from 5-amino-2-biphen-4-yl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7aw, general formula 7: Ri = biphene-4 yl, X = N, R 3 = Me, Y = S) and butyric anhydride (see Table 2)
Beispiel 60Example 60
9-Methyl-7-naphthalen-2-yl-2-propyl-thieno[2,3-d:4,5-d']dipyrimidin-4(3H)-on (allgemeine Formel 1b: Ri=Naphthalen-2-yl, X=N, R3=Me, R4=Prop, Y=S)9-Methyl-7-naphthalen-2-yl-2-propylthieno [2,3-d: 4,5-d '] dipyrimidin-4 (3H) -one (general formula 1b: Ri = naphthalene-2-yl) yl, X = N, R 3 = Me, R 4 = Prop, Y = S)
Analog Beispiel 57 aus 5-Amino-2-naphthaIen-2-yl-4-methyl-thieno[2,3-d]pyrimidin-6- carboxamid (Beispiel 62; Experiment 7ay; allgemeine Formel 7: R^Naphthalen^-yl, X=N, R3=Me, Y=S) und Buttersäureanhydrid (s. Tab. 2)Analogously to Example 57 from 5-amino-2-naphthalen-2-yl-4-methylthieno [2,3-d] pyrimidine-6-carboxamide (Example 62, Experiment 7ay; general formula 7: R 1 naphthalenyl) , X = N, R 3 = Me, Y = S) and butyric anhydride (see Table 2)
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
a Retentionszeit (tR) und Reinheit durch HPLC bestimmt:
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
a retention time (t R ) and purity determined by HPLC:
Säule: RP-18 (Waters Nova-Pak Ci8, 60 Angström, 4μm, 3.9x150mm); Eluent A: 0.1% TFA, B: 0.09% TFA / 80% Acetonitril; Flussrate: 1 ml/min; Temp.: 25°C; Detektion: 254nm; Gradient (linear) B: 0-2min: 0%, 2- 20min: 0-100%, 20-25min: 100%, 25-35min: 100-0% b Lit.: Wagner G., Böhm N. Pharmazie (1993); 48, 95-99 c Beispiel für Verbindungen der allgemeinen Formel 1 a mit Y=O d Darstellung erfolgt in Anlehnung an Shestopalov, A. M.; Nikishin, K. G.; Gromova, A. V.; Rodinovskaya, L A. Russ.Chem. Bull. (2003), 52(10), 2203-2206Column: RP-18 (Waters Nova-Pak Ci 8 , 60 angstroms, 4μm, 3.9x150mm); Eluent A: 0.1% TFA, B: 0.09% TFA / 80% acetonitrile; Flow rate: 1 ml / min; Temperature: 25 ° C; Detection: 254nm; Gradient (linear) B: 0-2min: 0%, 2-20min: 0-100%, 20-25min: 100%, 25-35min: 100-0% b Ref .: Wagner G., Bohm N. Pharmacy ( 1993); 48, 95-99 c Example of compounds of general formula 1 a with Y = O d Representation is based on Shestopalov, AM; Nikishin, KG; Gromova, AV; Rodinovskaya, L A. Russ.Chem. Bull. (2003), 52 (10), 2203-2206
Säule: RP-18 (CROM Resolution Star Ci8, 100 Ä, 5 μm, 4.6x50 mm); Eluent A: 0.1 % TFA / Wasser, B: 0.09% TFA / 80% Acetonitril; Flussrate: 1 ml/min; Temp.: 25°C; Detektion: 254 nm; Gradient (linear) B: 0- 0.5 min: 20 %, 0.5-5 min: 20-100 %, 5-7 min: 100 %, 7-7.3 min: 100-20 %, 7.3-9 min 20 % Säule: RP-18 (CROM Resolution Star Ci8, 100 Ä, 5 μm, 4.6x50 mm); Eluent A: 0.1 % TFA / Wasser, B: 0.09 % TFA Acetonitril; Flussrate: 1 ml/min; Temp.: 25 0C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50 %, 0.5-4 min: 50-100 %, 4-6 min: 100 %, 6-6.3 min: 100-50 %, 6-8 min: 50 % n.b. nicht bestimmt ab. 2 Beispiele der allgemeinen Formel 1b (Y=S)Column: RP-18 (CROM Resolution Star CI 8 , 100 Å, 5 μm, 4.6x50 mm); Eluent A: 0.1% TFA / water, B: 0.09% TFA / 80% acetonitrile; Flow rate: 1 ml / min; Temperature: 25 ° C; Detection: 254 nm; Gradient (linear) B: 0- 0.5 min: 20%, 0.5-5 min: 20-100%, 5-7 min: 100%, 7-7.3 min: 100-20%, 7.3-9 min 20% Column: RP-18 (CROM Resolution Star CI 8 , 100 A, 5 μm, 4.6x50 mm); Eluent A: 0.1% TFA / water, B: 0.09% TFA acetonitrile; Flow rate: 1 ml / min; Temp .: 25 ° C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50%, 0.5-4 min: 50-100%, 4-6 min: 100%, 6-6.3 min: 100-50%, 6-8 min: 50% nb not determined from. 2 Examples of General Formula 1b (Y = S)
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000065_0001
Figure imgf000066_0001
Retentionszeit (tR) und Reinheit durch HPLC bestimmt:Retention time (t R ) and purity determined by HPLC:
Säule: RP-18 (Waters Nova-Pak Ci8, 60 Angström, 4μm, 3.9x150mm); Eluent A: 0.1% TFA / Wasser, B:Column: RP-18 (Waters Nova-Pak Ci 8 , 60 angstroms, 4μm, 3.9x150mm); Eluent A: 0.1% TFA / water, B:
0.09% TFA / 80% Acetonitril; Flussrate: 1 ml/min; Temp.: 25°C; Detektion: 254nm; Gradient (linear) B: 0-0.09% TFA / 80% acetonitrile; Flow rate: 1 ml / min; Temperature: 25 ° C; Detection: 254nm; Gradient (linear) B: 0-
2min: 0%, 2-20min: 0-100%, 20-25min: 100%, 25-35min: 100-0%2min: 0%, 2-20min: 0-100%, 20-25min: 100%, 25-35min: 100-0%
Säule: RP-18 (CROM Resolution Star Ci8, 100 Ä, 5 μm, 4.6x50 mm); Eluent A: 0.1 % TFA / Wasser, B:Column: RP-18 (CROM Resolution Star CI 8 , 100 Å, 5 μm, 4.6x50 mm); Eluent A: 0.1% TFA / water, B:
0.09% TFA / 80% Acetonitril; Flussrate: 1 ml/min; Temp.: 25°C; Detektion: 254 nm; Gradient (linear) B: 0-0.09% TFA / 80% acetonitrile; Flow rate: 1 ml / min; Temperature: 25 ° C; Detection: 254 nm; Gradient (linear) B: 0-
0.5 min: 20 %, 0.5-5 min: 20-100 %, 5-7 min: 100 %, 7-7.3 min: 100-20 %, 7.3-9 min 20 %0.5 min: 20%, 0.5-5 min: 20-100%, 5-7 min: 100%, 7-7.3 min: 100-20%, 7.3-9 min 20%
Säule: RP-18 (CROM Resolution Star Ci8, 100 A, 5 μm, 4.6x50 mm); Eluent A: 0.1 % TFA / Wasser, B:Column: RP-18 (CROM Resolution Star CI 8 , 100 A, 5 μm, 4.6x50 mm); Eluent A: 0.1% TFA / water, B:
0.09 % TFA Acetonitril; Flussrate: 1 ml/min; Temp.: 25 0C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50 %,0.09% TFA acetonitrile; Flow rate: 1 ml / min; Temp .: 25 ° C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50%,
0.5-4 min: 50-100 %, 4-6 min: 100 %, 6-6.3 min: 100-50 %, 6-8 min: 50 % n.b. nicht bestimmt0.5-4 min: 50-100%, 4-6 min: 100%, 6-6.3 min: 100-50%, 6-8 min: 50% n.b. not determined
Beispiel 61Example 61
Beispiele zur Herstellung von Verbindungen der allgemeinen Formel 5Examples for the preparation of compounds of the general formula 5
Methode A: Darstellung von 5-unsubstituierten Verbindungen der allgemeinen Formel 5 (X= C-H)Method A: Preparation of 5-unsubstituted compounds of the general formula 5 (X = C-H)
2-Mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridin-3-carbonitril (Experiment 5a; allgemeine Formel 5: Ri=3,4-(MeO)2-Ph, X=C-H, R3=Me, Y=S)2-mercapto-6- (3,4-dimethoxyphenyl) -4-methyl-pyridine-3-carbonitrile (Experiment 5a; general formula 5: Ri = 3,4- (MeO) 2 -Ph, X = CH, R 3 = Me, Y = S)
5.0 g (22.5 mmol) 1-(3,4-Dimethoxyphenyl)butan-1 ,3-dion*, 2.9 g (29.2 mmol) Cyanthioacetamid und 4.0 g (29.2 mmol) Kaliumcarbonat werden bei Raumtemperatur 21 Stunden in 170 ml Aceton gerührt. Anschließend wird das Lösungsmittel entfernt und der Rückstand in Ethanol/Wasser (1 :1) gerade gelöst. Nach Ansäuern mit Eisessig wird der erhaltene Niederschlag abgesaugt, mit wenig Wasser gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 6.34 g (98 %); HPLC tR: 12.9 min, Reinheit: 87.5 % (s. a in Tab. 3); MS (ESI, m/e): 287 [M+H]+ 5.0 g (22.5 mmol) of 1- (3,4-dimethoxyphenyl) butan-1, 3-dione * , 2.9 g (29.2 mmol) of cyanoacetamide and 4.0 g (29.2 mmol) of potassium carbonate are stirred at room temperature for 21 hours in 170 ml of acetone. The solvent is then removed and the residue is just dissolved in ethanol / water (1: 1). After acidification with glacial acetic acid, the resulting precipitate is filtered off, washed with a little water, sucked dry and i. Vak. dried at 50 0 C. Yield: 6.34 g (98%); HPLC t R : 12.9 min, purity: 87.5% (see a in Table 3); MS (ESI, m / e): 287 [M + H] +
(* Nicht kommerziell verfügbare! ,3-Diketone werden nach bekannten Verfahren erhalten und sind in der Fachliteratur beschrieben.)( * Not commercially available!, 3-diketones are obtained by known methods and are described in the literature.)
Analog Methode A werden die folgenden Experimente durchgeführt: 5a-5g, 5i (s. Tab.3)The following experiments are carried out analogously to method A: 5a-5g, 5i (see Table 3)
Methode B: Darstellung von 5-Benzyl-substituierten Verbindungen der allgemeinen Formel 5 mit X=C-CH2-Ph-4-NO2 Method B: Preparation of 5-benzyl-substituted compounds of general formula 5 with X = C-CH 2 -Ph-4-NO 2
4,6-Dimethyl-2-mercapto-5-(4'-nitrobenzyl)-pyridin-3-carbonitril4,6-dimethyl-2-mercapto-5- (4 'nitrobenzyl) pyridine-3-carbonitrile
(Experiment 5h; allgemeine Formel 5: R1=Me, X=C-CH2-Ph-4-NO2, R3=Me, Y=S)(Experiment 5h, general formula 5: R 1 = Me, X = C-CH 2 -Ph-4-NO 2 , R 3 = Me, Y = S)
Zu einer Lösung von 1.28 g (55.7 mmol) Natrium in 50 ml abs. Ethanol werden 5.70 ml (55.2 mmol) Acetylaceton und 0.75 g (5.0 mmol) Natriumiodid gegeben. Nach Eintragen einer Suspension von 13.20 g (61.1 mmol) 4'-Nitrobenzylbromid in 60 ml abs. Ethanol wird 3 Stunden unter Rückfluß erhitzt. Nach Abkühlen und Filtrieren werden 5.23 g (52.2 mmol) Cyanthioacetamid und 5 ml (36.1 mmol) Triethylamin zum Filtrat hinzugefügt. Anschließend wird 4 Stunden unter Rückfluß erhitzt. Der nach Kühlen erhaltene Niederschlag wird abgesaugt, mit ca. 50 ml Ethanol und ca. 10 ml Ether rasch gewaschen, trocken gesaugt und bei i. Vak. bei 50 0C getrocknet.To a solution of 1.28 g (55.7 mmol) of sodium in 50 ml of abs. Ethanol are added 5.70 ml (55.2 mmol) of acetylacetone and 0.75 g (5.0 mmol) of sodium iodide. After adding a suspension of 13.20 g (61.1 mmol) 4 ' -nitrobenzyl bromide in 60 ml abs. Ethanol is refluxed for 3 hours. After cooling and filtration, 5.23 g (52.2 mmol) of cyanothioacetamide and 5 ml (36.1 mmol) of triethylamine are added to the filtrate. The mixture is then heated under reflux for 4 hours. The precipitate obtained after cooling is filtered off with suction, washed rapidly with about 50 ml of ethanol and about 10 ml of ether, sucked dry and treated at i. Vak. dried at 50 0 C.
Ausbeute: 5.30 g (32 %); HPLC tR: 13.3 min, Reinheit: 95.9 % (s. Tab. 3); MS (ESI, m/e): 300 [M+H]+ Yield: 5.30 g (32%); HPLC t R : 13.3 min, purity: 95.9% (see Table 3); MS (ESI, m / e): 300 [M + H] +
Methode C: Darstellung von Verbindungen der allgemeinen Formel 5 mit X= NMethod C: Preparation of compounds of general formula 5 with X = N
2-Mercapto-6-(4-/so-propoxy-phenyl)-4-methyl-pyrimidin-3-carbonitril (Experiment 5t; allgemeine Formel 5: Ri=4-(isoPropO)-Ph, X=N, R3=Me, Y=S)2-Mercapto-6- (4- / so-propoxy-phenyl) -4-methyl-pyrimidine-3-carbonitrile (Experiment 5t; general formula 5: Ri = 4- (isoPropO) -Ph, X = N, R 3 = Me, Y = S)
5.5 g (28 mmol) 4-/so-Propoxybenzoylchlorid und 2.5 g (33 mmol) Ammoniumthiocyanat werden in 100 ml Dioxan suspendiert und 15 min unter Rückfluss erhitzt. Anschließend werden 3.0 g (36 mmol) (E/Z)-3-Amino- crotonsäurenitril zugegeben. Das Reaktionsgemisch wird 3 h unter Rückfluss erhitzt. Danach wird das Gemisch mit 500 ml Eiswasser gemischt und über Nacht stehen gelassen, anschließend filtriert und i. Vak. bei 50 0C getrocknet. Ausbeute: 7.3 g (92 %); MS (ESI, m/e): 286 [M+H]+ (s. Tab. 3);5.5 g (28 mmol) of 4- / so-propoxybenzoyl chloride and 2.5 g (33 mmol) of ammonium thiocyanate are suspended in 100 ml of dioxane and 15 min under Reflux heated. Then 3.0 g (36 mmol) of (E / Z) -3-aminocrotonitrile are added. The reaction mixture is heated under reflux for 3 h. Thereafter, the mixture is mixed with 500 ml of ice water and allowed to stand overnight, then filtered and i. Vak. dried at 50 0 C. Yield: 7.3 g (92%); MS (ESI, m / e): 286 [M + H] + (see Table 3);
Analog Methode C werden die folgenden Experimente durchgeführt: 5j-5ay (s. Tab.3)The following experiments are carried out analogously to method C: 5j-5ay (see Table 3)
Beispiel 62Example 62
Beispiele zur Herstellung von Verbindungen der allgemeinen Formel 7Examples for the preparation of compounds of general formula 7
3-Amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]pyridin-2- carbonsäureamid3-Amino-6- (3,4-dimethoxyphenyl) -4-methylthieno [2,3-b] pyridine-2-carboxamide
(Experiment 7a; allgemeine Formel 7: R1=S^-(MeO)2-Ph, X=C-H5 R3=Me, Y=S)(Experiment 7a, general formula 7: R 1 = S ^ - (MeO) 2 -Ph, X = CH 5 R 3 = Me, Y = S)
2.1 g (31.4 mmol) Natriumethylat werden in 40 ml abs. Ethanol gelöst. Es werden 3.0 g (10.5 mmol) 2-Mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridin-3-carbonitril (Beispiel 61 ; Experiment 5a; allgemeine Formel 5: Ri=3,4-(MeO)2~Ph, X=C-H, R3=Me, Y=S) und 1.2 g (12.6 mmol) 2-Chloracetamid zugegeben und 1 Stunde unter Rückfluß erhitzt. Nach dem Abkühlen werden 10 ml Wasser zugegeben und der Niederschlag abgesaugt, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 3.4 g (94 %); HPLC tR: 14.0 min, Reinheit: 99.8 % (s. a in Tab. 4); MS (ESI1 m/e): 344 [M+H]+ 2.1 g (31.4 mmol) of sodium ethylate are dissolved in 40 ml of abs. Ethanol dissolved. 3.0 g (10.5 mmol) of 2-mercapto-6- (3,4-dimethoxyphenyl) -4-methylpyridine-3-carbonitrile (Example 61; Experiment 5a; general formula 5: Ri = 3,4- (MeO ) ~ 2 Ph, X = CH, R 3 = Me, Y = S) and 1.2 g (12.6 mmol) of 2-chloroacetamide was added and heated for 1 hour under reflux. After cooling, 10 ml of water are added and the precipitate is filtered off, sucked dry and i. Vak. dried at 50 0 C. Yield: 3.4 g (94%); HPLC t R : 14.0 min, purity: 99.8% (see a in Table 4); MS (ESI 1 m / e): 344 [M + H] +
Analog dargestellte Beispiele der allgemeinen Formel 7 sind in Tab. 4 aufgeführt.Examples of the general formula 7 represented by analogy are listed in Tab.
Beispiel 63Example 63
Beispiele zur Herstellung von Verbindungen der allgemeinen Formel 10 3-Amino-4-methyl-6-phenyl-thieno[2,3-b]pyridin-2-carbonsäureethylester (Experiment 10a; allgemeine Formel 10: Ri=Ph5 X=C-H, R3=Me, Y=S)Examples for the preparation of compounds of general formula 10 Ethyl 3-amino-4-methyl-6-phenylthieno [2,3-b] pyridine-2-carboxylate (Experiment 10a; general formula 10: Ri = Ph 5 X = CH, R 3 = Me, Y = S)
6.45 g (28.5 mmol) 2-Mercapto-6-phenyl-4-methyl-pyridin-3-carbonitril (Beispiel 61 ; Experiment 5d; allgemeine Formel 5: Ri=Ph, X=C-H, Re=Me, Y=S) werden in 100 ml abs. Ethanol vorgelegt und 5.3 ml (50.0 mmol) 2-Chloressigsäureethylester sowie 10 ml (72.1 mmol) Triethylamin hinzugefügt. Es wird 1 Stunde unter Rückfluß erhitzt und der nach Kühlen ausgefallene Niederschlag abgesaugt, mit wenig Wasser und Ethanol gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Anschließend wird der Niederschlag in einer Lösung aus 0.14 g (1.6 mmol) Natriumethylat in abs. Ethanol 1 Stunde unter Rückfluß erhitzt. Der nach Abkühlen ausgefallene Niederschlag wird abgesaugt, mit 30 ml Wasser und 15 ml Ethanol gewaschen, trocken gesaugt und i. Vak. bei 50 0C getrocknet. Ausbeute: 5.0 g (91 %); HPLC tR: 18.0 min, Reinheit: 98.4 % ; MS (ESI, m/e): 313 [M+H]+ 6.45 g (28.5 mmol) of 2-mercapto-6-phenyl-4-methylpyridine-3-carbonitrile (Example 61, experiment 5d; general formula 5: Ri = Ph, X = CH, Re = Me, Y = S) are in 100 ml abs. Provided ethanol and 5.3 ml (50.0 mmol) of 2-chloroacetic acid ethyl ester and 10 ml (72.1 mmol) of triethylamine added. It is heated under reflux for 1 hour and the precipitated out after cooling filtered off, washed with a little water and ethanol, sucked dry and i. Vak. dried at 50 0 C. Subsequently, the precipitate in a solution of 0.14 g (1.6 mmol) of sodium in abs. Ethanol heated for 1 hour under reflux. The precipitated after cooling precipitate is filtered off with suction, washed with 30 ml of water and 15 ml of ethanol, sucked dry and i. Vak. dried at 50 0 C. Yield: 5.0 g (91%); HPLC t R : 18.0 min, purity: 98.4%; MS (ESI, m / e): 313 [M + H] +
Beispiel 64Example 64
Beispiele zur Herstellung von Verbindungen der allgemeinen Formel 11Examples for the preparation of compounds of general formula 11
3-(3-Benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-b]pyridin-2-carbonsäure- ethylester (Beispiel 11 ; allgemeine Formel 11 : R1=Ph, X=C-H, R3=Me, Y=S)3- (3-Benzoylthioureido) -4-methyl-6-phenylthieno [2,3-b] pyridine-2-carboxylic acid ethyl ester (Example 11, general formula 11: R 1 = Ph, X = CH, R 3 = Me, Y = S)
Zu 2.78 g (8.9 mmol) 3-Amino-4-methyl-6-phenyl-thieno[2,3-ö]pyridin-2-carbonsäure- ethylester (Beispiel 63; Experiment 10a; allgemeine Formel 10: Ri=Ph, X=C-H, R3=Me, Y=S) in 10 ml Aceton werden 5 ml (13.3 mmol) acetonischer Benzoylisothiocyanat-Lösung (2M) gegeben und 2 Stunden unter Rückfluß erhitzt. Der nach Abkühlen ausgefallene Niederschlag wird abgesaugt, mit wenig Wasser und Ethanol gewaschen, trocken gesaugt und i. Vak. Bei 50 0C getrocknet. Ausbeute: 3.93 g (93 %); HPLC tR: 19.3 min, Reinheit: 99.9 % (s. ain Tab. 4); MS (ESI, m/e): 476 [M+H]+ Tab. 3 Beispiele der allgemeinen Formel 5 (Y=S)To 2.78 g (8.9 mmol) of ethyl 3-amino-4-methyl-6-phenylthieno [2,3-o] pyridine-2-carboxylate (Example 63, Experiment 10a; general formula 10: Ri = Ph, X = CH, R 3 = Me, Y = S) in 10 ml of acetone, 5 ml (13.3 mmol) benzoyl isothiocyanate acetonic solution (2M) are added and heated for 2 hours under reflux. The precipitated after cooling precipitate is filtered off with suction, washed with a little water and ethanol, sucked dry and i. Vak. Dried at 50 0 C. Yield: 3.93 g (93%); HPLC t R : 19.3 min, purity: 99.9% (see Table 4); MS (ESI, m / e): 476 [M + H] + Tab. 3 Examples of the general formula 5 (Y = S)
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
a Darstellung erfolgt nach Methode A: Erhitzen unter Rückfluß für 3-4 Stunden; nach Abkühlen wird der Ansatz ggf. filtriert und das Filtrat weiterverarbeitet b LJt.: Vieweg H., Leistner S., Wagner G. Pharmazie (1986); 41_, 827-830 c Lit.: Vieweg H., Krasselt U., Boehm N., Prantz J., Wagner G., Pharmazie (1990); 45, 731-733 d Lit.: Schmidt U., Kubitzek H., Chem Ber (1960); 93, 1559-1565 e Darstellung erfolgt nach Methode A: Erhitzen unter Rückfluß für 3-4 Stunden; nach Abkühlen wird der Niederschlag abgesaugt und analog dem Rückstand weiterverarbeitet. f Lit.: Krauze A., Bomika Z, Shestopalov A.M., Rodinovskaya LA., Pelcers J., Duhurs G., Sharanin Y.A., Promonenkov VK. KNm Geterotsikl Soedin (1981); 377-382 g Lit.: Guerrera F., Siracusa M.A., Tornetta B. Farmaco, Ediz Scientif (1976); 3±, 21-30 h Lit.: Wallenfels K, Schuly H„ Ann (1959); 621, 215-221 i Darstellung erfolgt nach Methode B, in Anlehnung an Wagner G., Vieweg H., Leistner S., Böhm N.,
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
a Representation according to method A: heating under reflux for 3-4 hours; after cooling, the batch is filtered if necessary and the filtrate is further processed. LJt .: Vieweg H., Leistner S., Wagner G. Pharmazie (1986); 41, 827-830 c Lit .: Vieweg H., Krasselt U., Boehm N., Prantz J., Wagner G., Pharmazie (1990); 45, 731-733 d Lit .: Schmidt U., Kubitzek H., Chem Ber (1960); 93, 1559-1565 e is carried out according to method A: heating under reflux for 3-4 hours; After cooling, the precipitate is filtered off and processed analogously to the residue. f Lit .: Krauze A., Bomika Z, Shestopalov AM, Rodinovskaya LA., Pelcers J., Duhurs G., Sharanin YA, Promonenkov VK. KNm Geterotsikl Soedin (1981); 377-382 g Lit .: Guerrera F., Siracusa MA, Tornetta B. Farmaco, Ediz Scientif (1976); 3 ±, 21-30 h Lit .: Wallenfels K, Schuly H "Ann (1959); 621, 215-221 i representation according to method B, based on Wagner G., Vieweg H., Leistner S., Bohm N.,
Krasselt U., Hanfeld V., Prantz J., Grupe R. Pharmazie (1990); 45, 102-109 j Darstellung erfolgt nach Methode CKrasselt U., Hanfeld V., Prantz J., Grupe R. Pharmacie (1990); 45, 102-109 j Representation according to method C
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Retentionszeit (tR) und Reinheit durch HPLC bestimmt: ,Retention time (t R ) and purity determined by HPLC:
Säule: RP-18 (Waters Nova-Pak Ci8, 60 Angström, 4μm, 3.9x150mm); Eluent A: 0.1% TFA, B: 0.09% TFAColumn: RP-18 (Waters Nova-Pak Ci 8 , 60 angstroms, 4μm, 3.9x150mm); Eluent A: 0.1% TFA, B: 0.09% TFA
/ 80% Acetonitril; Flussrate: 1 ml/min; Temp.: 25°C; Detektion: 254nm; Gradient (linear) B: 0-2min: 0%,/ 80% acetonitrile; Flow rate: 1 ml / min; Temperature: 25 ° C; Detection: 254nm; Gradient (linear) B: 0-2min: 0%,
2-20min: 0-100%, 20-25min: 100%, 25-35min: 100-0%2-20min: 0-100%, 20-25min: 100%, 25-35min: 100-0%
Säule: CROM Resolution Star Ci8, 100 A, 5 μm, 4.6x50 mm; Eluent A: 0.1 % TFA / Wasser, B: 0.09 % TFAColumn: CROM Resolution Star Ci 8 , 100 A, 5 μm, 4.6x50 mm; Eluent A: 0.1% TFA / water, B: 0.09% TFA
//
Acetonitril; Flussrate: 1 ml/min; Temp.: 25 0C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 20 %, 0.5-5 min: 20-100 %, 5-7 min: 100 %, 7-7.3 min: 100-20 %, 7.3-9 min 20 % Säule: CROM Resolution Star Ci8, 100 Ä, 5 μm, 4.6x50 mm; Eluent A: 0.1 % TFA / Wasser, B: 0.09 %acetonitrile; Flow rate: 1 ml / min; Temp .: 25 ° C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 20%, 0.5-5 min: 20-100%, 5-7 min: 100%, 7-7.3 min: 100-20%, 7.3-9 min 20% Column: CROM Resolution Star Ci 8 , 100 A, 5 μm, 4.6x50 mm; Eluent A: 0.1% TFA / water, B: 0.09%
TFA/TFA /
Acetonitril; Flussrate: 1 ml/min; Temp.: 25 0C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50 %, 0.5-4 min: 50-100 %, 4-6 min: 100 %, 6-6.3 min: 100-50 %, 6-8 min: 50 %acetonitrile; Flow rate: 1 ml / min; Temp .: 25 ° C; λ: 254 nm; Gradient (linear) B: 0-0.5 min: 50%, 0.5-4 min: 50-100%, 4-6 min: 100%, 6-6.3 min: 100-50%, 6-8 min: 50%
Lit.: Litvinov V.P., Sharanin Y.A., Rodinovskaya LA, ShestopalovA.M., Mortikov V.Yu., Promonenkov V.K. SerKhimich (1984); 12, 2760-2765Lit .: Litvinov V.P., Sharanin Y.A., Rodinovskaya LA, ShestopalovA.M., Mortikov V.Yu., Promonenkov V.K. SerKhimich (1984); 12, 2760-2765
C Lit.: Sharanin Y.A., Shestopalov AM, Promonenkov V.K. Zhurnal Organ Khimii (1984); 20, 2012-2020 d Ut.: Shestopalov AM, Sharanin Y.A. Zhurnal Organ Khimii (1984); 20, 1991-2002 e Lit.: Tornetta B., Siracusa M.A., Ronsisvalle G., Guerrera F. Gazz. Chim. Ital. (1978); 108, 57-62 und Shvedov V.l., Sycheva T.P., Sakovlch T.V. Khimiya Geterot Soedin (1979); 1331-1335 n.b. nicht bestimmt C Lit .: Sharanin Y.A., Shestopalov AM, Promonenkov V.K. Zhurnal Organ Khimii (1984); 20, 2012-2020 d Ut .: Shestopalov AM, Sharanin Y.A. Zhurnal Organ Khimii (1984); 20, 1991-2002 e Lit .: Tornetta B., Siracusa M.A., Ronsisvalle G., Guerrera F. Gazz. Chim. Ital. (1978); 108, 57-62 and Shvedov V.l., Sycheva T.P., Sakovlch T.V. Khimiya Geterot Soedin (1979); 1331-1335 n.b. not determined

Claims

Patentansprüche:1) Pyrido[3',2':4I5]thieno[3,2-d]pyrimidin-2,4(1 H)3H)-dione und -4(3H)-one (X=C-H, Y=S), Thieno[2,3-d:4,5-d']dipyrimidin-2J4(1 Hl3H)-dione und -4(3H)-one (X=N, Y=S) sowie Pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2,4(1H,3H)-dione und -4(3H)-one (X=C-H, Y=O) und Furo[2,3-d:4,5-dl]dipyrimidin-2,4(1 H,3H)-dione und -4(3H)-one (X=N, Y=O) der allgemeinen Formeln 1a oder 1 bworin bedeuten:X C-R2 oder StickstoffY Schwefel oder SauerstoffR1 und R3, gleich oder ungleich unabhängig voneinander,- Wasserstoff,- Ci-i2Alkyl (ggf. mit R§ substituiert),- C-2-I2 Alkenyl und C2-i2 Alkinyl (jeweils ggf. mit R§ substituiert ),- Benzyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert), Phenyl-(C2-6)alkyl , Phenyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert),- Monofluormethyl, Difluormethyl, Trifluormethyl,- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert),- C3-i4Cycloalkyl, C3-i4CycloalkenyI (jeweils ggf. mit R§-substituiert), - mono- oder bicyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen (ggf. ein oder mehrfach mit R§ substituiert) mit 5 - 14 Ringatomen darunter 1 - 4 Heteroatome, die vorzugsweise N, O und S sind und ggf. am Heteroatom ein oder mehrfach oxidiert sind,- C1-I2AIkYIaCyI (ggf. mit R§ substituiert),- Benzoyl, 1- und 2-Naphthoyl (jeweils ggf. mit R§ substituiert),- Heterocyclylacyl [z.B. Nicotinoyl, Isonicotinoyl, 2-Picolinoyl, 2-Thienoyl, 2- Furoyl] (ggf. mit R§ substituiert)- Hydroxy,- Sulfhydryl,- Ci-10 Alkoxy,- Alkylthio, Alkylsulfinyl und Alkylsulfonyl (jeweils Ci-6 )- Formyl, Carboxyl, C1-4AlkoxycarbonyI;- CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils C1-6),- Cyano, Rhodano, Nitro, SO3H, SO2OAIk (mit „Alk": C1-5),- Chlor, Brom, lod, Fluor,- Amino, Ci-βAlkylamino, Di(C1-5)alkylamino (jeweils ggf. mit R§ am Alkylrest substituiert),- Morpholino, Thiomorpholino, Thiomorpholino-S,S-Dioxid, Pyrrolidino,- Piperidino, 1-Piperazino, 4-Methyl-1-piperazino, 4-Hydroxyethyl-1 -piperazino, 4-Phenyl-1 -piperazino,- Cycloalkylamino, C3.14 Arylamino und Heteroarylamino [z.B. Phenyl-, 1- und 2-Naphthyl-, 2-, 3- oder 4-Pyridyl-, Chinolinyl-, Isochinolinyl-, Acridinyl-, Phenothiazinyl-, 2-Thienyl- und 2-Furylamino] (ggf. jeweils an den carbo- bzw. heterocyclischen Ringen mit R§ substituiert);R2- Wasserstoff, - C1-12AIkYl,- C2--I2 Alkenyl und C2-12 Alkinyl, - Benzyl, Phenyl(C2-6)alkyl (jeweils ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen und/oder aliphatischen Molekülteil substituiert);- Phenacyl (ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen Molekülteil substituiert);- Carboxyl, Ci-4 Alkoxycarbonyl, CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils C1-6),- R*CO- (worin R* Wasserstoff, Cπ2Alkyl bedeuten sowie ggf. mit R§ substituiert),- Cyano, Nitro, Amino, Ci-6Alkylamino, Di(Ci-6)alkylamino, -N=N-C6H5, -N=N- C6H4-R§,- 1 ,3-Diphenyl-pyrazol-4-yl, Thiazolin-2-yl, lmidazolin-2-yl und 3,4,5,6- Tetrahydro-pyrimidinyl;RA■ C2-i4Alkyl, C3-i4Cycloalkyl, C2-i4Alkenyl, C3-i4Cycloalkenyl, C2-i4Alkinyl (jeweils ggf. am C-Skelett der vorgenannten aliphatischen oder cycloaliphatischen Reste mit R§ substituiert);• Phenyl, 2-R§-Phenyl, 3-R§-Phenyl, 4-R§-Phenyl, 2-R§,5-R§-Phenyl, 3-R§f5-R§-Phenyl, 3-R§,4-R§-Phenyl, 3-R§,4-R§,5-R§-Phenyl, 2-R§,3-R§,4-R§-Phenyl,- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert);- mono-, bi- oder tricyclische gesättigter oder ein- oder mehrfach ungesättigter heterocyclischer Rest mit insgesamt 4-14 Ring-Atomen, davon 1-5 Heteroatomen, die vorzugsweise N, O, S und Se sind (jeweils ggf. mit R§ substituiert);- CH2OAIk* (mit Alk*: Ci-6Alkyl),- CH2OCOR' (mit R': Ci-6Alkyl, C2-6Alkenyl, Phenyl sowie ggf. mit R§ substituiert),- COOH, COOAIk** (mit Alk**: Ci-5Alkyl),- NH2, NHAIk*, (mit Alk*: Ci-6Alkyl )- NHNH2, NHNHCOR1 (mit R': d-eAlkyl, d-βAlkenyl, Phenyl sowie ggf. mit R§ substituiert),- SO3H, S-Phenacyl, S-Alkyl, SO-AIkyl, SO2-Alkyl (jeweils d-β) - S-Alkenyl, SO-Alkenyl, SO2-Alkenyl (jeweils C2-8), S-Alkinyl, SO-Alkinyl, SO2-Alkinyl (jeweils C2-6) (ggf. jeweils am C-Skelett der oben genannten aliphatischen Reste mit -OH, -CN, -SCN, -NO2, Phenyl oder (C3-7)Cycloalkyl substituiert)R§-OH, -SH, -O-Ci-8Alkyl, -O-C6-i4Aryl, -S-Ci-4 Alkyl, -S-C6-i4Aryl, -SO-Ci-4Alkyl, -SO-C6-14Ary I, -SO2-C1.4Alkyl, -SO2-C6-14Ary I, -SO3H, -OSO2C1-8Alkyl, -OSO2C6-14Aryl, -COOH, -COOC1 -8Alkyl, -(CO)C1-8Alkyl, -COOH, -COOC1-8Alkyl, -CONH2, -CONHC1-6Alkyl, -CON(C1-6Alkyl)2, -NH2, -NHC1-6Alkyl, -N(C1-6Alkyl)2> -NHC6-14Aryl, -NH-Hetaryl, -N(C6-14Aryl)2, -N(Ci-6Alkyl)(C6-14Aryl),-CH3, -CHF2, -CH2F, -CF3, -C2HO, -C(CHs)2, "(CH2)2CH3, -(CH2)3CH3, -CH2CH2OH, -CH2CH2SH, -CH2CH2SCHs, -CH2CF3, -CH2CCl3, -CH2CBr3 -CH2CHF2, -CH2CHCI2, -CH2CHBr21 -CH2CH2F, -CH2CH2CI, -CH2CH2Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, - -Cyclopentylmethyl, -Cylohexyl, -Cyclohexylmethyl, -F, -Cl, -Br, -I, -CN, -NO2, und -SCN sowie deren Solvate, einschließlich der pharmazeutisch akzeptablen Salze und Prodrug-Formulierungen und deren aktive Metabolite und gegebenenfalls deren Tautomerewobei die folgenden Verbindungen der Formel 1a ausgenommen sind:R1 X R3 Claims: 1) Pyrido [3 ', 2': 4I5] thieno [3,2-d] pyrimidine-2,4 (1H) 3H) -diones and -4 (3H) -ones (X = CH, Y = S), thieno [2,3-d: 4,5-d '] dipyrimidine-2J4 (1H13H) -diones and -4 (3H) -one (X = N, Y = S) and pyrido [3', 2 ': 4,5] furo [3,2-d] pyrimidine-2,4 (1H, 3H) -diones and -4 (3H) -ones (X = CH, Y = O) and furo [2,3 -d: 4,5-dl] dipyrimidine-2,4 (1H, 3H) -diones and -4 (3H) -ones (X = N, Y = O) of the general formulas 1a or 1 bworin: X C R 2 or nitrogen Y is sulfur or oxygen R 1 and R 3, identical or different, independently of one another, is hydrogen, C 1 -12 -alkyl (optionally substituted by R 8), C 2 -12-alkenyl and C 2 -12-alkynyl (in each case optionally with R 1 § substituted), - benzyl (optionally substituted one to five times independently of each other with R§), phenyl (C2-6) alkyl, phenyl (optionally substituted one to five times independently of one another with R§), - monofluoromethyl, difluoromethyl , Trifluoromethyl, - 1-naphthyl, 2-naphthyl (each optionally substituted by R§), - C3-i4cycloalkyl, C3-i4-cycloalkenyl (each optionally substituted by Rβ-substituted), or bicyclic saturated or mono- or polyunsaturated heterocycles (possibly substituted one or more times by R§) with 5 to 14 ring atoms, including 1 to 4 heteroatoms, which are preferably N, O and S and are optionally oxidized one or more times on the heteroatom, - C1 -12AlkyloCyI (optionally substituted by R§) , - benzoyl, 1- and 2-naphthoyl (each optionally substituted by Rβ), - heterocyclylacyl [eg nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyl] (optionally substituted by Rβ) - hydroxy , - sulfhydryl, - C 1-10 alkoxy, - alkylthio, alkylsulfinyl and alkylsulfonyl (each Ci-6) - formyl, carboxyl, C 1-4 alkoxycarbonyl; - CONH 2, CONHAIk and CONAIk2 (with "Alk" in each case C 1-6), - cyano , Rhodano, nitro, SO3H, SO2OAlk (with "Alk": C1-5), - chlorine, bromine, iodine, fluorine, - amino, Ci-βAlkylamino, di (C1-5) alkylamino (in each case optionally with R§ am Substituted alkyl), - morpholino, thiomorpholino, thiomorpholino-S, S-dioxide, pyrrolidino, - piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino, - Cycloalkylamino, C3.14 arylamino and heteroarylami no [eg phenyl, 1- and 2-naphthyl, 2-, 3- or 4-pyridyl, quinolinyl, isoquinolinyl, acridinyl, phenothiazinyl, 2-thienyl and 2-furylamino] (possibly each substituted at the carbo- or heterocyclic rings with R§), R2- hydrogen, - C1-12Alkyl, - C2 - l2 alkenyl and C2-12 alkynyl, - benzyl, phenyl (C2-6) alkyl (in each case optionally substituted with R§ one or more times, identically or differently, on the aromatic and / or aliphatic moiety), - phenacyl (optionally substituted once or more than once by R 8, identical or different on the aromatic moiety), - carboxyl, C 1-4 alkoxycarbonyl, CONH 2 , CONHAIk and CONAIk2 (with "Alk" in each case C1-6), - R * CO- (in which R * denotes hydrogen, Cπ2alkyl and optionally substituted by R§), - cyano, nitro, amino, C 1-6 alkylamino, di ( C 1-6) alkylamino, -N = N-C 6 H 5, -N = N-C 6 H 4 -R 8, - 1, 3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl and 3, 4,5,6-tetrahydro-pyrimidinyl; RA ■ C 2-4 -alkyl, C 3-14 -cycloalkyl, C 2-14 -alkenyl, C 3-14 -cycloalkenyl, C 2-14 -alkynyl (each optionally substituted by R 8 on the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals) Phenyl, 2-Rβ-phenyl, 3-Rβ-phenyl, 4-Rβ-phenyl, 2-R§, 5-Rβ-phenyl, 3-Rβf5-Rβ-phenyl, 3-Rβ, 4-Rβ-phenyl, 3-R§, 4-R§, 5-R§- Phenyl, 2-Rβ, 3-Rβ, 4-Rβ-phenyl, - 1-naphthyl, 2-naphthyl (each optionally substituted by Rβ), - mono-, bi- or tricyclic saturated or on or polyunsaturated heterocyclic radical having a total of 4-14 ring atoms, of which 1-5 are heteroatoms, preferably N, O, S and Se (each optionally substituted by R§), - CH 2 OAlk * (with Alk *: C 1-6 alkyl ), - CH 2 OCOR '(with R': C 1-6 alkyl, C 2-6 alkenyl, phenyl and optionally substituted with R 8), - COOH, COOAlk ** (with Alk **: C 1-5 alkyl), - NH 2, NHAlk * , (with Alk *: Ci-6Alkyl) - NHNH2, NHNHCOR1 (with R ': d-eAlkyl, d-βAlkenyl, phenyl and optionally substituted with R§), - SO3H, S-phenacyl, S-alkyl, SO- Alkyl, SO 2 -alkyl (in each case d-β) - S-alkenyl, SO-alkenyl, SO 2 -alkenyl (in each case C 2-8), S-alkynyl, SO-alkynyl, SO 2 -alkynyl (in each case C 2-6) each substituted on the C skeleton of the abovementioned aliphatic radicals with -OH, -CN, -SCN, -NO2, phenyl or (C3-7) cycloalkyl) Rβ-OH, -SH, -O-Ci-8Alkyl, -O -C 6 -14-aryl, -S-C 1-4 -alkyl, -S-C 6-14 -alkyl, -SO-C 1-4 -alkyl, -SO-C 6-14 -aryl, -O-C 2-4 -alkyl, -SO 2-C 6-14 -aryl, -SO3H, -OSO2C1-8alkyl, -OSO2C6-14aryl, -COOH, -COOC1 -8alkyl, - (CO) C1-8alkyl, -COOH, -COOC1-8alkyl, -CONH2, -CONHC1-6alkyl, -CON (C1- 6 alkyl) 2, -NH 2, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2> -NHC 6-14 aryl, -NH-hetaryl, -N (C 6-14 aryl) -2, -N (C 1-6 alkyl) (C 6 -alkyl) 14 aryl), - CH3, -CHF2, -CH2F, -CF3, -C2HO, -C (CHs) 2, "(CH2) 2CH3, - (CH2) 3CH3, -CH2CH2OH, -CH2CH2SH, -CH2CH2SCHs, -CH2CF3, - CH2CCl3, -CH2CBr3 -CH2CHF2, -CH2CHCl2, -CH2CHBr21 -CH2CH2F, -CH2CH2Cl-, -CH2CH2Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, --Cyclopentylmethyl, -Cyclohexyl, -Cyclohexylmethyl, -F, - Cl, -Br, -I, -CN, -NO2, and -SCN and their solvates, including the pharmaceutically acceptable salts and prodrug formulations and their active metabolites, and the like and optionally their tautomers, excluding the following compounds of formula 1a: R1 X R3
1. Me C-H Me1st Me C-H Me
2. Me C-Ac 4-NMe2Ph2. Me C-Ac 4-NMe 2 Ph
3. Me C-Ac 4-NO2Ph3. Me C-Ac 4-NO 2 Ph
wobei die die folgenden Verbindungen der Formel 1b mit folgenden Resten ausgenommen sind: jeweils R1 = OEt, X = C-CN, R3 = Ph mit R4= Benzyl, Phenyl, z.T. mehrfach mit Me,wherein the following compounds of the formula 1b are excluded with the following radicals: in each case R 1 = OEt, X = C-CN, R 3 = Ph with R 4 = benzyl, phenyl, in some cases several times with Me,
OMe, NO2 und Cl substituiert und 3,4-Methylendioxy-phenyl; jeweils R1 = Ph, X = C-H, R3 = Ph mit R4= Phenyl, p-OCH3-Ph, p-CI-Ph,OMe, NO 2 and Cl substituted and 3,4-methylenedioxy-phenyl; each R 1 = Ph, X = CH, R 3 = Ph with R 4 = phenyl, p-OCH 3 -Ph, p-CI-Ph,
2,3,4-Tn-OCH3-Ph und 2-Thienyl; jeweils R1 = Me, X = C-H, R3 = Me mit R4 = CH2OMe, CH2OEt, CH2OCOMe,2,3,4-Tn-OCH 3 -Ph and 2-thienyl; each R 1 = Me, X = CH, R 3 = Me with R 4 = CH 2 OMe, CH 2 OEt, CH 2 OCOMe,
CH2COOPh, SCH2COPh, NH2, NHNH2, COOH, Ph; sowie:CH 2 COOPh, SCH 2 COPh, NH 2 , NHNH 2 , COOH, Ph; such as:
R1 = Me, X = C-H, R3 = Ph, R4= COOEt; R1 = Me, X = C-H, R3 = p-Br-Ph, R4 = COOEt; R1 = p-Br-Ph, X = C-H, R3 = Me, R4 = COOMe; R1 = Me, X = C-Benzyl, R3 = Me, R4 = COOMe; R1 = R3 = Me, X = C-Me, R4 = COOMe; R1 = Ph, X = N, R3= Me, R4 = SEt.R 1 = Me, X = CH, R 3 = Ph, R 4 = COOEt; R 1 = Me, X = CH, R 3 = p-Br-Ph, R 4 = COOEt; R 1 = p-Br-Ph, X = CH, R 3 = Me, R 4 = COOMe; R 1 = Me, X = C-benzyl, R 3 = Me, R 4 = COOMe; R 1 = R 3 = Me, X = C-Me, R 4 = COOMe; R 1 = Ph, X = N, R 3 = Me, R 4 = SEt.
2) Verbindung gemäß Anspruch 1 , wobei diese Formel 1a mit Y = S entspricht und die Substituenten R1 , R3, X die folgenden Bedeutungen haben:2) A compound according to claim 1, wherein said formula 1a corresponds to Y = S and the substituents R 1 , R 3, X have the following meanings:
Figure imgf000086_0001
Figure imgf000086_0001
3) Verbindung gemäß Anspruch 1, wobei diese Formel 1a mit Y = O entspricht und R1 = Ph, X= C-H und R3= Me.3) A compound according to claim 1, wherein said formula 1a corresponds to Y = O and R 1 = Ph, X = CH and R 3 = Me.
4) Verbindung gemäß Anspruch 1 , wobei diese Formel 1b mit Y = S entspricht und die Substituenten R1 , X1 R3 ,R4 die folgenden Bedeutungen haben:4) A compound according to claim 1, wherein said formula 1b corresponds to Y = S and the substituents R 1 , X 1 R 3 , R 4 have the following meanings:
Figure imgf000086_0002
Figure imgf000086_0002
5) Verbindung gemäß Anspruch 1 , wobei diese ausgewählt ist aus:5) A compound according to claim 1, wherein it is selected from:
7-(4-Methoxy-phenyl)-9-methyl-pyrido[3')2':4,5]thieno[3,2-d]pyrimidin-2)4(1 H,3H)- dion; 9-Methyl-7-phenyl-pyrido[3> I2':4,5]thieno[3>2-d]pyrimidin-2,4(1 H,3H)-dion;7- (4-methoxy-phenyl) -9-methyl-pyrido [3 ') 2': 4,5] thieno [3,2-d] pyrimidine-2) 4 (1 H, 3H) - dione; 9-methyl-7-phenyl-pyrido [3 > I 2 ': 4,5] thieno [3 > 2-d] pyrimidine-2,4 (1H, 3H) -dione;
7-(4-Mθthoxy-phenyl)-9-methyl-thiθno[2,3-d:4,5-d']dipyrimidin-2,4-(1 H,3H)-dion;7- (4-methoxy-phenyl) -9-methylthio [2,3-d: 4,5-d '] dipyrimidine-2,4- (1H, 3H) -dione;
9-Methyl-7-(4-methyl-phenyl)-thieno[2,3-d:4,5-d']dipynmidin-2,4-(1 H,3H)-dion;9-methyl-7- (4-methylphenyl) thieno [2,3-d: 4,5-d '] dipynmidine-2,4- (1H, 3H) -dione;
7-(4-Cyano-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2)4-(1 H,3H)-dion;7- (4-cyano-phenyl) -9-methylthieno [2,3-d: 4,5-d '] dipyrimidine-2 ) 4- (1H, 3H) -dione;
7-(4-Brom-2-fluor-phenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidin-2,4-(1H,3H)-dion;7- (4-bromo-2-fluoro-phenyl) -9-methyl-thieno [2,3-d: 4,5-d '] dipyrimidine-2,4 (1H, 3H) -dione;
9-Methyl-7-biphenyl-2-ethyI-thieno[2,3-d:4]5-d']dipyrimidin-4(3/-/)-on9-methyl-7-biphenyl-2-ethylthieno [2,3-d: 4 ] 5-d '] dipyrimidin-4 (3 / - /) - one
6) Pharmazeutische Zusammensetzung enthaltend mindestens eine der nachfolgenden Verbindungen der Formel 1a oder 1b sowie ggf. pharmazeutisch verträgliche Hilfsstoffe und/oder Träger :6) Pharmaceutical composition comprising at least one of the following compounds of the formula 1a or 1b and optionally pharmaceutically acceptable excipients and / or carriers:
Figure imgf000087_0001
Figure imgf000087_0001
worin bedeuten:in which mean:
X C-R2 oder StickstoffX is CR 2 or nitrogen
Y Schwefel oder Sauerstoff undY sulfur or oxygen and
R1 und R3, gleich oder ungleich unabhängig voneinander,R 1 and R 3 , the same or different independently,
- Wasserstoff,- hydrogen,
- Ci-i2Alkyl (ggf. mit R§ substituiert),- Ci-i 2 alkyl (optionally substituted with R § ),
- C-2-I2 Alkenyl und C2-12 Alkinyl (jeweils ggf. mit R§ substituiert ), .- C- 2 - I2 alkenyl and C 2 - 12 alkynyl (each optionally substituted with R § ), ,
- Benzyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert), Phenyl-(C2-6)alkyl , Phenyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert),- benzyl (optionally mono- to pentasubstituted independently of one another by R § substituted), phenyl (C 2-6) alkyl, phenyl (optionally mono- to pentasubstituted independently of one another by R § substituted),
- Monofluormethyl, Difluormethyl, Trifluormethyl,Monofluoromethyl, difluoromethyl, trifluoromethyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert),- 1-naphthyl, 2-naphthyl (each optionally substituted with R § ),
- C3-i4Cycloalkyl, Cs-^Cycloalkenyl (jeweils ggf. mit R§-substituiert),- C 3 -i 4 cycloalkyl, Cs ^ cycloalkenyl (in each case optionally with R § -substituted)
- mono- oder bicyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen (ggf. ein oder mehrfach mit R§ substituiert) mit 5 - 14 Ringatomen darunter 1 - 4 Heteroatome, die vorzugsweise N, O und S sind und ggf. am Heteroatom ein oder mehrfach oxidiert sind,- mono- or bicyclic saturated or mono- or polyunsaturated heterocycles (if necessary, one or more times with R § substituted) with 5 - 14 ring atoms including 14 heteroatoms which are preferably N, O and S and possibly one on the hetero atom or are oxidized several times,
- Ci-i2Alkylacyl (ggf. mit R§ substituiert),- Ci-i 2 alkylacyl (optionally substituted with R § ),
- Benzoyl, 1- und 2-Naphthoyl (jeweils ggf. mit R§ substituiert),- benzoyl, 1- and 2-naphthoyl (each optionally substituted with R § ),
- Heterocyclylacyl [z.B. Nicotinoyl, Isonicotinoyl, 2-Picolinoyl, 2-Thienoyl, 2- Furoyl] (ggf. mit R§ substituiert)- Heterocyclylacyl [for example, nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyl] (optionally substituted with R §)
- Hydroxy,- hydroxy,
- Sulfhydryl,Sulfhydryl,
- C-1-10 Alkoxy,C 1-10 alkoxy,
- Alkylthio, Alkylsulfinyl und Alkylsulfonyl (jeweils Ci-6 )- alkylthio, alkylsulfinyl and alkylsulfonyl (each Ci -6 )
- Formyl, Carboxyl, Ci-4Alkoxycarbonyl;- formyl, carboxyl, Ci- 4 alkoxycarbonyl;
- CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils Ci-6),CONH 2 , CONHAIk and CONAIk 2 (with "Alk" in each case Ci- 6 ),
- Cyano, Rhodano, Nitro, SO3H, SO2OAIk (mit „Alk": C1-5),Cyano, rhodano, nitro, SO 3 H, SO 2 OAlk (with "alk": C 1-5 ),
- Chlor, Brom, lod, Fluor,Chlorine, bromine, iodine, fluorine,
- Amino, Ci-6Alkylamino, Di(Ci-5)alkylamino (jeweils ggf. mit R§ am Alkylrest substituiert),- amino, Ci -6 alkylamino, di (Ci -5) alkylamino (in each case optionally substituted with R § on the alkyl residue),
- Morpholino, Thiomorpholino, Thiomorpholino-S.S-Dioxid, Pyrrolidino,- morpholino, thiomorpholino, thiomorpholino-S.s dioxide, pyrrolidino,
- Piperidino, 1-Piperazino, 4-Methyl-1-piperazino, 4-Hydroxyethyl-1-piperazino, 4-Phenyl-1 -piperazino,Piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino,
- Cycloalkylamino, C3--K Arylamino und Heteroarylamino [z.B. Phenyl-, 1- und 2-Naphthyl-, 2-, 3- oder 4-Pyridyl-, Chinolinyl-, Isochinolinyl-, Acridinyl-, Phenothiazinyl-, 2-Thienyl- und 2-Furylamino] (ggf. jeweils an den carbo- bzw. heterocyclischen Ringen mit R§ substituiert); R2 - cycloalkylamino, C 3 - K arylamino and heteroarylamino [for example, phenyl, 1- and 2-naphthyl, 2-, 3- or 4-pyridyl, quinolinyl, isoquinolinyl, acridinyl, phenothiazinyl, 2-thienyl - and 2-furylamino] (optionally substituted on the carbo- or heterocyclic rings with R § ); R 2
- Wasserstoff, - Ci-I2AIRyI1 - hydrogen, - Ci- I2 AIRyI 1
- C2-i2Alkenyl und C-2-i2Alkinyl,- C 2 alkenyl and C 2- i 2 -i 2 alkynyl,
- Benzyl, Phenyl(C2-6)alkyl (jeweils ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen und/oder aliphatischen Molekülteil substituiert);- Benzyl, phenyl (C 2 - 6 ) alkyl (each optionally with R § one or more times, the same or not equal to the aromatic and / or aliphatic moiety substituted);
- Phenacyl (ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen Molekülteil substituiert);- Phenacyl (optionally with R § one or more times, the same or different substituted on the aromatic moiety);
- Carboxyl, Ci-4 Alkoxycarbonyl, CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils C1-6),- carboxyl, Ci -4 alkoxycarbonyl, CONH 2, CONHAIk CONAIk and 2 (with "Alk" each C 1 -6),
- R*CO- (worin R* Wasserstoff, Cri2Alkyl bedeuten sowie ggf. mit R§ substituiert),(, Cri 2 denote alkyl wherein R * is hydrogen and optionally substituted with R §) R * CO-, -
- Cyano, Nitro, Amino, d-βAlkylamino, Di(Ci-6)alkylamino, -N=N-C6H5, -N=N- C6H4-R§,Cyano, nitro, amino, d-β-alkylamino, di (ci- 6 ) alkylamino, -N = NC 6 H 5 , -N = N-C 6 H 4 -R § ,
- 1 ,3-Diphenyl-pyrazol-4-yl, Thiazolin-2-yl, lmidazolin-2-yl und 3,4,5,6- Tetrahydro-pyrimidinyl;- 1, 3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl and 3,4,5,6-tetrahydropyrimidinyl;
R4 R 4
- C2-i4Alkyl, Cs-uCycloalkyl, Ca-uAlkenyl, C3-i4Cycloalkenyl, C2-i4Alkinyl (jeweils ggf. am C-Skelett der vorgenannten aliphatischen oder cycloaliphatischen Reste mit R§ substituiert);- 2- C i 4 alkyl, Cs-uCycloalkyl, Ca-uAlkenyl, C 3 -i 4 cycloalkenyl, C 2- 4 alkynyl i (in each case optionally at the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals with R § substituted);
- Phenyl, 2-R§-Phenyl, 3-R§-Phenyl, 4-R§-Phenyl, 2-R§,5-R§-Phenyl,- phenyl, 2-R § -phenyl, 3-R § -phenyl, 4-R § -phenyl, 2-R §, 5-R § -phenyl,
3-R§,5-R§-Phenyl, 3-R§,4-R§-Phenyl, 3-R§,4-R§,5-R§-Phenyl, 2-R§,3-R§,4-R§-Phenyl,3-R § , 5-R § -phenyl, 3-R § , 4-R § -phenyl, 3-R § , 4-R § , 5-R § -phenyl, 2-R § , 3-R § , 4-R § -phenyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert);- 1-naphthyl, 2-naphthyl (each optionally substituted with R § );
- mono-, bi- oder tricyclische gesättigter oder ein- oder mehrfach ungesättigter heterocyclischer Rest mit insgesamt 4-14 Ring-Atomen, davon 1-5 Heteroatomen, die vorzugsweise N, O, S und Se sind (jeweils ggf. mit R§ substituiert);- mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocyclic radical having a total of 4-14 ring atoms, of which 1-5 heteroatoms, which are preferably N, O, S and Se (each optionally substituted with R § );
- CH2OAIk* (mit Alk*: C1-6AlkyI), - CH2OCOR' (mit R': C1-6Alkyl, C2-6AIkenyl, Phenyl sowie ggf. mit R§ substituiert),CH 2 OAlk * (with Alk * : C 1-6 alkyl), - CH 2 OCOR '(with R': C 1-6 alkyl, C 2 - 6 alkenyl, phenyl and optionally substituted with R § ),
- COOH, COOAIk** (mit Alk**: C1-5AIkYl)1 - COOH, COOAlk ** (with Alk ** : C 1-5 AIkYl) 1
- NH2, NHAIk*, (mit Alk*: d-eAlkyl )- NH 2 , NHAlk * , (with Alk * : d-eAlkyl)
- NHNH2, NHNHCOR' (mit R': C1-6AIRyI, C1-6Alkenyl, Phenyl sowie ggf. mit R§ substituiert),- NHNH 2 , NHNHCOR '(substituted by R': C 1-6 AIRyI, C 1-6 alkenyl, phenyl and optionally with R § ),
- SO3H, S-Phenacyl, S-Alkyl, SO-Alkyl, SO2-Alkyl (jeweils Cr8 )SO 3 H, S-phenacyl, S-alkyl, SO-alkyl, SO 2 -alkyl (each Cr 8 )
- S-Alkenyl, SO-Alkenyl, SO2-Alkenyl (jeweils C2-8), S-Alkinyl, SO-Alkinyl, SO2-Alkinyl (jeweils C2-6) (ggf. jeweils am C-Skelett der oben genannten aliphatischen Reste mit -OH, -CN, -SCN, -NO2, Phenyl oder (C3-7)CycIoaIky) substituiert)- S-alkenyl, SO-alkenyl, SO 2 -alkenyl (each C 2 - 8 ), S-alkynyl, SO-alkynyl, SO 2 -alkynyl (each C 2 - 6 ) (optionally at the C-skeleton of the above substituted aliphatic radicals with -OH, -CN, -SCN, -NO 2 , phenyl or (C 3 - 7 ) CycIoaIky) substituted)
R§ R §
-OH, -SH, -O-Ci-8Alkyl, -O-C6-i4Aryl, -S-Ci-4 Alkyl, -S-C6-i4Aryl, -SO-C1-4Alkyl, -SO-C6-14Aryl, -SO2-C1-4Alkyl, -SO2-C6-14Aryl, -SO3H, -OSO2Ci-8Alkyl, -OSO2C6-14Ary I, -COOH, -COOC1-8Alkyl, -(CO)Ci-8Alkyl, -COOH, -COOCi-8Alkyl, -CONH2, -CONHC1-6Alkyl, -CON(Ci-6Alkyl)2, -NH2, -NHCi-6Alkyl, -N(C1-6Alkyl)2, -NHC6-14Aryl, -NH-Hetaryl, -N(C6-i4Aryl)2, -N(C1-6Alkyl)(C6-14Aryl),-OH, -SH, -O-Ci -8 alkyl, -OC 6 -i 4 aryl, -S-Ci -4 alkyl, -SC 6 -i 4 aryl, -SO-C 1-4 alkyl, -SO- C 6-14 aryl, -SO 2 -C 1-4 alkyl, -SO 2 -C 6-14 aryl, -SO 3 H, -OSO 2 Ci -8 alkyl, -OSO 2 C 6 - 14 Ary I, - COOH, -COOC 1-8 alkyl, - (CO) Ci -8 alkyl, -COOH, -COOCi -8 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON (Ci -6 alkyl) 2 , -NH 2, -NHCi -6 alkyl, -N (C 1-6 alkyl) 2, -NHC 6-14 aryl, -NH-hetaryl, -N (C 6- i 4 aryl) 2, -N (C 1-6 Alkyl) (C 6-14 aryl),
-CH3, -CHF2, -CH2F, -CF3, -C2H5, -C(CH3)2, -(CH2)2CH3, -(CHa)3CH3, -CH2CH2OH, -CH2CH2SH, -CH2CH2SCH3, -CH2CF3, -CH2CCI3, -CH2CBr3 -CH2CHF2, -CH2CHCI2, -CH2CHBr2, -CH2CH2F, -CH2CH2CI, -CH2CH2Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, - -Cyclopentylmethyl, -Cylohexyl, -Cyclohexylmethyl, -F, -Cl, -Br, -I, -CN, -NO2, und -SCN-CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -C 2 H 5 , -C (CH 3 ) 2 , - (CH 2 ) 2 CH 3 , - (CHa) 3 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 SH, -CH 2 CH 2 SCH 3 , -CH 2 CF 3 , -CH 2 CCI 3 , -CH 2 CBr 3 -CH 2 CHF 2 , -CH 2 CHCl 2 , - CH 2 CHBr 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, --Cyclopentylmethyl, -Cyclohexyl, -Cyclohexylmethyl , -F, -Cl, -Br, -I, -CN, -NO 2 , and -SCN
sowie deren Solvate, einschließlich der pharmazeutisch akzeptablen Salze und Prodrug-Formulierungen und deren aktive Metabolite und gegebenenfalls deren Tautomere.as well as their solvates, including the pharmaceutically acceptable salts and prodrug formulations and their active metabolites and optionally their tautomers.
7) Pharmazeutische Zusammensetzung enthaltend mindestens eine der Verbindungen gemäß einem der Ansprüche 2-5 sowie ggf. pharmazeutisch verträgliche Hilfsstoffe und/oder Träger.7) A pharmaceutical composition comprising at least one of the compounds according to any one of claims 2-5 and optionally pharmaceutically acceptable excipients and / or carriers.
8) Pharmazeutische Zusammensetzung nach Anspruch 6 oder 7 enthaltend zusätzlich einen oder mehrere der folgenden Wirkstoffe:8) A pharmaceutical composition according to claim 6 or 7 additionally containing one or more of the following active substances:
Zytokin-Antagonisten Chemokin-Antagonisten Zytokin-Agonisten immunmodulatorische WirkstoffeCytokine antagonists chemokine antagonists Cytokine agonists immunomodulatory agents
Substanz P-AntagonistenSubstance P antagonists
Bradykinin-AntagonistenBradykinin antagonists
PAF-AntagonistenPAF antagonists
Adenosin-Rezeptor-AntagonistenAdenosine receptor antagonists
Antibiotika/Virostatika α-MimetikaAntibiotics / antivirals α-mimetics
Zytostatikacytostatics
B2-Ad renoceptor AgonistenB 2 -Ad renoceptor agonists
Leukotrien-Antagonisten (entweder Enzym-Inhibitoren [wie 5-Leukotriene antagonists (either enzyme inhibitors [such as 5-
Lipoxygenaseinhibitoren oder Arachidonsäure-Enzyminhibitoren] oderLipoxygenase inhibitors or arachidonic acid enzyme inhibitors] or
Rezeptorantagonisten) ,Receptor antagonists),
Antihistaminika (bevorzugt solche mit Mastzellen-stabilisierendenAntihistamines (preferably those with mast cell stabilizing
Eigenschaften oder Leukotrien-antagonisierenden Aspekten)Characteristics or leukotriene-antagonizing aspects)
Theophyllintheophylline
Muscarinrezeptor-AntagonistenMuscarinic receptor antagonist
9) Verwendung von mindestens einer der nachfolgenden Verbindungen der Formel 1a oder 1b sowie ggf. pharmazeutisch verträgliche Hilfsstoffe und/oder Träger.9) Use of at least one of the following compounds of the formula 1a or 1b and optionally pharmaceutically acceptable excipients and / or carriers.
Figure imgf000091_0001
Figure imgf000091_0001
worin bedeuten:in which mean:
X C-R2 oder StickstoffX is CR 2 or nitrogen
Y Schwefel oder Sauerstoff undY sulfur or oxygen and
R1 und R3, gleich oder ungleich unabhängig voneinander, - Wasserstoff,R 1 and R 3 , the same or different independently, - hydrogen,
- Ci-i2Alkyl (ggf. mit R§ substituiert),- Ci-i 2 alkyl (optionally substituted with R § ),
- C2-I2 Alkenyl und C2-!2Alkinyl (jeweils ggf. mit R§ substituiert ),- C 2- I 2 alkenyl and C 2 - 2. alkynyl (each optionally substituted with R §),
- Benzyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert), Phenyl-(C2-6)alkyl , Phenyl (ggf. ein- bis fünffach unabhängig voneinander mit R§ substituiert),- benzyl (optionally mono- to pentasubstituted independently of one another by R § substituted), phenyl (C 2-6) alkyl, phenyl (optionally mono- to pentasubstituted independently of one another by R § substituted),
- Monofluormethyl, Difluormethyl, Trifluormethyl,Monofluoromethyl, difluoromethyl, trifluoromethyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert),- 1-naphthyl, 2-naphthyl (each optionally substituted with R § ),
- C-3-uCycloalkyl, C3-i4Cycloalkenyl (jeweils ggf. mit R§-substituiert),- C 3 -uCycloalkyl, C 3 i 4 cycloalkenyl (in each case optionally with R § -substituted)
- mono- oder bicyclische gesättigte oder ein- oder mehrfach ungesättigte Heterocyclen (ggf. ein oder mehrfach mit R§ substituiert) mit 5 - 14 Ringatomen darunter 1 - 4 Heteroatome, die vorzugsweise N, O und S sind und ggf. am Heteroatom ein oder mehrfach oxidiert sind,- mono- or bicyclic saturated or mono- or polyunsaturated heterocycles (if necessary, one or more times with R § substituted) with 5 - 14 ring atoms including 14 heteroatoms which are preferably N, O and S and possibly one on the hetero atom or are oxidized several times,
- Ci-i2Alkylacyl (ggf. mit R§ substituiert),- Ci-i 2 alkylacyl (optionally substituted with R § ),
- Benzoyl, 1- und 2-Naphthoyl (jeweils ggf. mit R§ substituiert),- benzoyl, 1- and 2-naphthoyl (each optionally substituted with R § ),
- Heterocyclylacyl [z.B. Nicotinoyl, Isonicotinoyl, 2-Picolinoyl, 2-Thienoyl, 2- Furoyl] (ggf. mit R§ substituiert)- Heterocyclylacyl [for example, nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl, 2-furoyl] (optionally substituted with R §)
- Hydroxy,- hydroxy,
- Sulfhydryl,Sulfhydryl,
- Ci-10 Alkoxy,- Ci -10 alkoxy,
- Alkylthio, Alkylsulfinyl und Alkylsulfonyl (jeweils Ci-β )- alkylthio, alkylsulfinyl and alkylsulfonyl (each Ci-β)
- Formyl, Carboxyl, Ci-4Alkoxycarbonyl;- formyl, carboxyl, Ci -4 alkoxycarbonyl;
- CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils C1-6),CONH 2 , CONHAIk and CONAIk 2 (with "Alk" in each case C 1-6 ),
- Cyano, Rhodano, Nitro, SO3H, SO2OAIk (mit „Alk": C1-5 ),Cyano, rhodano, nitro, SO 3 H, SO 2 OAlk (with "alk": C 1-5 ),
- Chlor, Brom, lod, Fluor,Chlorine, bromine, iodine, fluorine,
- Amino, Ci-6Alkylamino, Di(C1-5)alkylamino (jeweils ggf. mit R§ am Alkylrest substituiert),- amino, Ci -6 alkylamino, di (C1-5) alkylamino (in each case optionally substituted with R § on the alkyl residue),
- Morpholino, Thiomorpholino, Thiomorpholino-S,S-Dioxid, Pyrrolidino,- morpholino, thiomorpholino, thiomorpholino-S, S-dioxide, pyrrolidino,
- Piperidino, 1-Piperazino, 4-Methyl-1-piperazino, 4-Hydroxyethyl-1-piperazino, 4-Phenyl-1 -piperazino, - Cycloalkylamino, C3-H Arylamino und Heteroarylamino [z.B. Phenyl-, 1- und 2-Naphthyl-, 2-, 3- oder 4-Pyridyl-, Chinolinyl-, Isochinolinyl-, Acridinyl-, Phenothiazinyl-, 2-Thienyl- und 2-Furylamino] (ggf. jeweils an den carbo- bzw. heterocyclischen Ringen mit R§ substituiert);Piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino, Cycloalkylamino, C 3 H arylamino and heteroarylamino [eg phenyl, 1- and 2-naphthyl, 2-, 3- or 4-pyridyl, quinolinyl, isoquinolinyl, acridinyl, phenothiazinyl, 2-thienyl and 2-furylamino] (optionally substituted on the carbo- or heterocyclic rings with R § );
R2 R 2
- Wasserstoff,- hydrogen,
- C1-12 Alkyl,C 1-12 alkyl,
- C2-12 Alkenyl und C2-12 Alkinyl,C 2 - 1 2 alkenyl and C 2-12 alkynyl,
- Benzyl, Phenyl(C2-6)alkyl (jeweils ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen und/oder aliphatischen Molekülteil substituiert);- Benzyl, phenyl (C 2-6 ) alkyl (each optionally with R § one or more times, the same or not equal to the aromatic and / or aliphatic moiety substituted);
- Phenacyl (ggf. mit R§ ein oder mehrmals, gleich oder ungleich am aromatischen Molekülteil substituiert);- Phenacyl (optionally with R § one or more times, the same or different substituted on the aromatic moiety);
- Carboxyl, C1-4 Alkoxycarbonyl, CONH2, CONHAIk und CONAIk2 (mit „Alk" jeweils Ct-6),Carboxyl, C 1-4 alkoxycarbonyl, CONH 2 , CONHAIk and CONAIk 2 (with "Alk" in each case Ct-6),
- R*CO- (worin R* Wasserstoff, Cr12Alkyl bedeuten sowie ggf. mit R§ substituiert),- R * CO- (wherein R * is hydrogen, Cr mean 12 alkyl and optionally substituted with R §),
- Cyano, Nitro, Amino, C-i-βAlkylamino, Di(C1-6)alkylamino, -N=N-CeH5, -N=N- C6H4-R§,Cyano, nitro, amino, Ci-β-alkylamino, di (C 1-6 ) alkylamino, -N = N-CeH 5 , -N = N-C 6 H 4 -R § ,
- 1 ,3-Diphenyl-pyrazol-4-yl, Thiazolin-2-yl, lmidazolin-2-yl und 3,4,5,6- Tetrahydro-pyrimidinyl;- 1, 3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl and 3,4,5,6-tetrahydropyrimidinyl;
R4 • C2-14Alkyl, C3-i4CycloaIkyl, C2-14Alkenyl, C3-i4Cycloalkenyl, C2-14Alkinyl (jeweils ggf. am C-Skelett der vorgenannten aliphatischen oder cycloaliphatischen Reste mit R§ substituiert);R 4 • C 2-14 alkyl, C 3- i 4 CycloaIkyl, C 2 - 14 alkenyl, C 3 i 4 cycloalkenyl, C 2-1 4Alkinyl (in each case optionally at the C-skeleton of the abovementioned aliphatic or cycloaliphatic radicals with R § substituted );
Phenyl, 2-R§-Phenyl, 3-R§-Phenyl, 4-R§-Phenyl, 2-R§,5-R§-Phenyl, 3-R§,5-R§-Phenyl, 3-R§,4-R§-Phenyl, 3-R§,4-R§,5-R§-Phenyl, 2-R§,3-R§,4-R§-Phenyl,Phenyl, 2-R § -phenyl, 3-R § -phenyl, 4-R § -phenyl, 2-R §, 5-R § -phenyl, 3-R §, 5-R § -phenyl, 3-R § , 4-R § -phenyl, 3-R § , 4-R § , 5-R § -phenyl, 2-R § , 3-R § , 4-R § -phenyl,
- 1-Naphthyl, 2-Naphthyl (jeweils ggf. mit R§ substituiert);- 1-naphthyl, 2-naphthyl (each optionally substituted with R § );
- mono-, bi- oder tricyclische gesättigter oder ein- oder mehrfach ungesättigter heterocyclischer Rest mit insgesamt 4-14 Ring-Atomen, davon 1-5 Heteroatomen, die vorzugsweise N, O, S und Se sind (jeweils ggf. mit R§ substituiert);mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocyclic radical having a total of 4-14 ring atoms, of which 1-5 heteroatoms, which are preferably N, O, S and Se (in each case optionally with R § substituted);
- CH2OAIk* (mit Alk*: Ci-6Alkyl),- CH 2 OAlk * (with Alk *: Ci -6 alkyl),
- CH2OCOR' (mit R': Ci-6Alkyl, C2-6Alkenyl, Phenyl sowie ggf. mit R§ substituiert),- CH 2 OCOR '(with R': Ci -6 alkyl, C 2-6 alkenyl, phenyl and optionally substituted with R § substituted),
- COOH, COOAIk** (mit Alk**: C1-5Alkyl),COOH, COOAlk ** (with Alk ** : C 1-5 alkyl),
- NH2, NHAIk*, (mit Alk*: C1-6Alkyl )- NH 2 , NHAlk *, (with Alk *: C 1-6 alkyl)
- NHNH2, NHNHCOR' (mit R': C1-6Alkyl, Ci-6Alkenyl, Phenyl sowie ggf. mit R§ substituiert),- NHNH 2, NHNHCOR '(with R': C 1-6 alkyl, Ci -6 alkenyl, phenyl and optionally substituted with R §),
- SO3H, S-Phenacyl, S-Alkyl, SO-Alkyl, SO2-AIkyl (jeweils Cr8 )SO 3 H, S-phenacyl, S-alkyl, SO-alkyl, SO 2 -alkyl (in each case C r8 )
- S-Alkenyl, SO-Alkenyl, SO2-Alkenyl (jeweils C2-8), S-Alkinyl, SO-Alkinyl, SO2-Alkinyl (jeweils C2-6) (ggf- jeweils am C-Skelett der oben genannten aliphatischen Reste mit -OH, -CN, -SCN, -NO2, Phenyl oder (C3-7)Cycloalkyl substituiert)- S-alkenyl, SO-alkenyl, SO 2 -alkenyl (each C 2 - 8 ), S-alkynyl, SO-alkynyl, SO 2 -alkynyl (each C 2 - 6 ) (optionally at the C-skeleton of the above said aliphatic radicals having from -OH, -CN, -SCN, -NO 2, phenyl or (C 3-7) cycloalkyl substituted)
R§ R §
-OH, -SH, -O-C1-8Alkyl, -O-C6-i4AryI, -S-Ci-4 Alkyl, -S-C6-i4Aryl, -SO-Ci-4Alkyl, -SO-C6-i4Aryl, -SO2-Ci-4Alkyl, -SO2-C6-14Aryl, -SO3H, -OSO2C1-8Alkyl, -OSO2C6-14Aryl, -COOH, -COOC1-8Alkyl, -(CO)Ci-8AIkyl, -COOH, -COOCi-8Alkyl, -CONH2, -CONHC1-6Alkyl, -CON(Ci-6Alkyl)2, -NH2, -NHCi-6Alkyl, -N(Ci-6Alkyl)2, -NHC6-i4Aryl, -NH-Hetaryl, -N(C6-i4Aryl)2> -N(Ci-6Alkyl)(C6-i4Aryl),-OH, -SH, -OC 1-8 alkyl, -OC 6- i 4 AryI, -S-Ci -4 alkyl, -SC 6 i 4 aryl, -SO-Ci -4 alkyl, -SO-C 6 -i 4 aryl, -SO 2 -C 4 alkyl, -SO 2 -C 6-14 aryl, -SO 3 H, -OSO 2 C 1-8 alkyl, -OSO 2 C 6 - 14 aryl, -COOH, -COOC 1-8 alkyl, - (CO) Ci -8 alkyl, -COOH, -COOCi -8 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON (Ci -6 alkyl) 2 , -NH 2 , -NHCi- 6 alkyl, -N (Ci -6 alkyl) 2, -NHC 6 i 4 aryl, -NH-hetaryl, -N (C 6 -i 4 aryl) 2> -N (Ci -6 alkyl) ( C 6- i 4 aryl),
-CH3, -CHF2, -CH2F, -CF3, -C2Hs, -C(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -CH2CH2OH, -CH2CH2SH, -CH2CH2SCH3, -CH2CF3, -CH2CCI3, -CH2CBr3 -CH2CHF2, -CH2CHCI2, -CH2CHBr21 -CH2CH2F, -CH2CH2CI, -CH2CH2Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, - -Cyclopentylmethyl, -Cylohexyl, -Cyclohexylmethyl, -F, -Cl, -Br, -I, -CN, -NO2, und -SCN-CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -C 2 Hs, -C (CH 3 ) 2 , - (CH 2 ) 2 CH 3 , - (CH 2 ) 3 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 SH, -CH 2 CH 2 SCH 3 , -CH 2 CF 3 , -CH 2 CCI 3 , -CH 2 CBr 3 -CH 2 CHF 2 , -CH 2 CHCl 2 , - CH 2 CHBr 21 -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 Br, -Cylopropyl, -Cylopropylmethyl, -Cylobutyl, -Cyclobutylmethyl, -Cyclopentyl, --Cyclopentylmethyl, -Cyclohexyl, -Cyclohexylmethyl, -F, -Cl, -Br, -I, -CN, -NO 2 , and -SCN
sowie deren Solvate, einschließlich der pharmazeutisch akzeptablen Salze und Prodrug-Formulierungen und deren aktive Metabolite und gegebenenfalls deren Tautomereas well as their solvates, including the pharmaceutically acceptable salts and prodrug formulations and their active metabolites and optionally their tautomers
zur Herstellung eines Arzneimittels zur Inhibierung von TNF-alpha.for the manufacture of a medicament for inhibiting TNF-alpha.
10) Verwendung mindestens einer der Verbindungen gemäß einem der Ansprüche 2-5 sowie ggf. pharmazeutisch verträglicher Hilfsstoffe und/oder Träger zur Herstellung eines Arzneimittels zur Inhibierung von TNF-alpha. 11) Verwendung nach Anspruch 9 oder 10 zur Behandlung von Rheumatoider Arthritis, Osteoarthritis, Osteoporosis, Asthma bronchiale, chronischer obstruktiver pulmonäre Erkrankung (COPD), Autoimmun-Erkrankungen wie z.B. Systemischer Lupus Erytematodes (SLE), Sklerodermie, Crohns Disease, Colitis ulcerosa, Multipler Sklerose, Guillain-Barre-Syndrom, Crohn 's Disease, Colitis ulcerosa, Psoriasis, Graft-versus-Host-Disease, systemischem Alzheimer-Erkrankung, insulin-abhängiger Diabetes mellitus, Respiratorischem Distress-Syndrom beim Erwachsenen (ARDS), Sepsis, cerebrale Form der Malaria, Guillain-Barre-Syndrom, Graft-versus-Host- Disease (GvHD), multiples Organversagen nach Trauma, aktuter Glomerulonephritis, akute und chronische Schmerzen, Arteriosklerose, Herzinfarkt, Schlaganfall,, entzündlichen Dermatosen wie Psoriasis, atopische Dermatitis, Alopecie, akuter Meningitis, Vasculitis, Uveitis,, atopischer Dermatitis, cardiovaskuläre Erkrankungen, virale Erkrankungen und hier insbesondere retrovirale Erkrankungen wie z.B. das erworbene Immundefizienz Syndrom (AIDS) sowie Krebs, insbesondere Entartungen des blutbildenden Systems, neurodegenarativen Erkrankungen wie z.B. Mb. Alzheimer, Mb. Parkinson, Rhinitis allergica, allergische Konjunktivitis, Myastenia Gravis, und Sarkoidose. 10) Use of at least one of the compounds according to any one of claims 2-5 and optionally pharmaceutically acceptable excipients and / or carriers for the manufacture of a medicament for inhibiting TNF-alpha. 11) Use according to claim 9 or 10 for the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, bronchial asthma, chronic obstructive pulmonary disease (COPD), autoimmune diseases such as systemic lupus erythematosus (SLE), scleroderma, Crohns disease, ulcerative colitis, multiple Sclerosis, Guillain-Barre syndrome, Crohn 's disease, ulcerative colitis, psoriasis, graft-versus-host disease, systemic Alzheimer's disease, insulin-dependent diabetes mellitus, adult respiratory distress syndrome (ARDS), sepsis, cerebral Form of malaria, Guillain-Barre syndrome, graft-versus-host disease (GvHD), multiple organ failure after trauma, acute glomerulonephritis, acute and chronic pain, arteriosclerosis, heart attack, stroke, inflammatory dermatoses such as psoriasis, atopic dermatitis, alopecia , acute meningitis, vasculitis, uveitis, atopic dermatitis, cardiovascular diseases, viral diseases and here in particular e retroviral diseases such as the acquired immunodeficiency syndrome (AIDS) and cancer, especially degeneration of the hematopoietic system, neurodegenerative diseases such as Mb. Alzheimer's, Mb. Parkinson's, rhinitis allergica, allergic conjunctivitis, myasthenia gravis, and sarcoidosis.
PCT/EP2005/008031 2004-07-23 2005-07-22 Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, and use thereof as inhibitors of tnf-alpha release WO2006010568A2 (en)

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EP04017543A EP1619197A1 (en) 2004-07-23 2004-07-23 Substituted Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1H,3H)diones and -4(3H)ones as well as Pyrido[3',2':4,5]furo[3,2-d]-pyrimidin-2,4(1H,3H)diones und -4(3H)ones as inhibitors of TNF-alpha release
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DE102005013622.2 2005-03-24
DE102005013622A DE102005013622A1 (en) 2005-03-24 2005-03-24 New tricyclic thiophene or furan derivatives useful as tumor necrosis factor alpha inhibitors, e.g. for treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis

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WO2006100095A1 (en) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Substituted carboxamides method for production and use thereof as tnf-alpha release inhibitors
WO2007084560A2 (en) * 2006-01-17 2007-07-26 Signal Pharmaceuticals, Llc INHIBITORS OF TNFα, PDE4 AND B-RAF, COMPOSITIONS THEREOF AND METHODS OF USE THEREWITH
WO2007084560A3 (en) * 2006-01-17 2007-09-20 Signal Pharm Llc INHIBITORS OF TNFα, PDE4 AND B-RAF, COMPOSITIONS THEREOF AND METHODS OF USE THEREWITH
WO2008082839A2 (en) * 2006-12-29 2008-07-10 Abbott Laboratories Pim kinase inhibitors as cancer chemotherapeutics
WO2008082839A3 (en) * 2006-12-29 2009-01-29 Abbott Lab Pim kinase inhibitors as cancer chemotherapeutics
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US9604994B2 (en) 2011-11-23 2017-03-28 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
US10183950B2 (en) 2011-11-23 2019-01-22 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
US10954251B2 (en) 2011-11-23 2021-03-23 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
US10536768B2 (en) 2014-08-06 2020-01-14 Valencell, Inc. Optical physiological sensor modules with reduced signal noise

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