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WO2006010568A2 - Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3h)-ones substituees, thieno[2,3-d:4,5-d']dipyrimidine-2,4(1 h,3h)-diones et thieno[2,3-d:4,5-d']dipyrimidin-4(3h)-ones substituees, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]furo[3,2- - Google Patents

Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3h)-ones substituees, thieno[2,3-d:4,5-d']dipyrimidine-2,4(1 h,3h)-diones et thieno[2,3-d:4,5-d']dipyrimidin-4(3h)-ones substituees, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]furo[3,2- Download PDF

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Publication number
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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Prior art keywords
alkyl
phenyl
substituted
optionally substituted
optionally
Prior art date
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PCT/EP2005/008031
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German (de)
English (en)
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WO2006010568A3 (fr
Inventor
Claudia Reichelt
Alexander Ludwig
Alexander Schulze
Mohammed Daghish
Siegfried Leistner
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Curacyte Discovery GmbH
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Curacyte Discovery GmbH
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Priority claimed from EP04017543A external-priority patent/EP1619197A1/fr
Priority claimed from DE102005013622A external-priority patent/DE102005013622A1/de
Application filed by Curacyte Discovery GmbH filed Critical Curacyte Discovery GmbH
Publication of WO2006010568A2 publication Critical patent/WO2006010568A2/fr
Publication of WO2006010568A3 publication Critical patent/WO2006010568A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

L'invention concerne de nouvelles pyrido[3',2':4,5]thiéno[3,2-d]pyrimidine-2,4(1 H,3H)-diones et pyrido[3',2':4,5]thiéno[3,2-d]pyrimidin-4(3H)-ones substituées (X=C-H, Y=S), thiéno[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones et thiéno[2,3-d:4,5-d']dipyrimidin-4(3H)-ones substituées (X=N, Y=S), pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 H,3H)-diones et pyrido[3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-ones substituées (X=C-H, Y=0) et furo[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones et furo[2,3-d:4,5-d']dipyrimidin-4(3h)-ones substituées (X=N, Y=O) de formules générales (1a) et (1b). L'invention concerne également des procédés pour leur production, des préparations pharmaceutiques contenant ces composés et/ou leurs tautomères et les sels physiologiquement tolérables pouvant être produits à partir de ces composés et/ou leurs solvates, ainsi que l'utilisation pharmaceutique de ces composés, de leurs tautomères, sels ou solvates comme inhibiteurs de la libération du TNF a.
PCT/EP2005/008031 2004-07-23 2005-07-22 Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3h)-ones substituees, thieno[2,3-d:4,5-d']dipyrimidine-2,4(1 h,3h)-diones et thieno[2,3-d:4,5-d']dipyrimidin-4(3h)-ones substituees, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones et pyrido[3',2':4,5]furo[3,2- Ceased WO2006010568A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP04017543.2 2004-07-23
EP04017543A EP1619197A1 (fr) 2004-07-23 2004-07-23 Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1H,3H)diones et -4(3H)ones et Pyrido[3',2':4,5]furo[3,2-d]-pyrimidin-2,4(1H,3H)diones et -4(3H)ones comme inhibiteurs de libération de TNF-alpha
DE102005013622.2 2005-03-24
DE102005013622A DE102005013622A1 (de) 2005-03-24 2005-03-24 Synthese substituierter Thieno[2,3-d:4,5-d']dipyrimidin-2,4(1H,3H)-dione und -4(3H)-one als TNFα-Freisetzungshemmer

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WO2006010568A3 WO2006010568A3 (fr) 2006-09-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100095A1 (fr) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Amides d'acide carboxylique substitues, procede pour les preparer et leur utilisation en tant qu'inhibiteurs de liberation de tnf-alpha
WO2007084560A3 (fr) * 2006-01-17 2007-09-20 Signal Pharm Llc INHIBITEURS DE TNFα, DE PDE4 ET DE B-RAF, COMPOSITIONS COMPRENANT CES INHIBITEURS ET MÉTHODES D'UTILISATION ASSOCIÉES
WO2008082839A3 (fr) * 2006-12-29 2009-01-29 Abbott Lab Inhibiteurs de la pim kinase comme agents chimiothérapeutiques destinés à lutter contre le cancer
US9604994B2 (en) 2011-11-23 2017-03-28 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

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059912A1 (fr) * 1999-03-30 2000-10-12 Nippon Soda Co., Ltd. Composes de thienopyrimidine et leurs sels, et procede de preparation desdits composes et sels
US6608053B2 (en) * 2000-04-27 2003-08-19 Yamanouchi Pharmaceutical Co., Ltd. Fused heteroaryl derivatives
AU5261001A (en) * 2000-04-27 2001-11-12 Imperial Cancer Research Technology Ltd Condensed heteroaryl derivatives
WO2005076861A2 (fr) * 2004-02-04 2005-08-25 University Of Virginia Patent Foundation Composes inhibant la formation de particule du vih

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100095A1 (fr) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Amides d'acide carboxylique substitues, procede pour les preparer et leur utilisation en tant qu'inhibiteurs de liberation de tnf-alpha
WO2007084560A3 (fr) * 2006-01-17 2007-09-20 Signal Pharm Llc INHIBITEURS DE TNFα, DE PDE4 ET DE B-RAF, COMPOSITIONS COMPRENANT CES INHIBITEURS ET MÉTHODES D'UTILISATION ASSOCIÉES
WO2008082839A3 (fr) * 2006-12-29 2009-01-29 Abbott Lab Inhibiteurs de la pim kinase comme agents chimiothérapeutiques destinés à lutter contre le cancer
US8148384B2 (en) 2006-12-29 2012-04-03 Abbott Laboratories Substituted thieno[3,2-d]pyrimidine PIM kinase inhibitors as cancer chemotherapeutics
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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