WO2006128268A1 - Composes ureidiques, compositions pharmaceutiques les contenant et leur utilisation dans le traitement des maladies inflammatoires - Google Patents

Composes ureidiques, compositions pharmaceutiques les contenant et leur utilisation dans le traitement des maladies inflammatoires Download PDF

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WO2006128268A1
WO2006128268A1 PCT/BR2006/000107 BR2006000107W WO2006128268A1 WO 2006128268 A1 WO2006128268 A1 WO 2006128268A1 BR 2006000107 W BR2006000107 W BR 2006000107W WO 2006128268 A1 WO2006128268 A1 WO 2006128268A1
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quinolin
dioxolo
carboxylate
ethyl
phenylurea
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WO2006128268A8 (fr
Inventor
Eliezer Jesus De Lacerda Barreiro
Carlos Alberto Manssour Fraga
Gilberto Marcelo SPERÃNDIO DA SILVA
Lidia Moreira Lima
Fátima MEDEIROS DE CARVALHO
Luis Eduardo Menezes Quintas
Alexandre LÉGORA MACHADO
Vera Lúcia GONCALVES KOATZ
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Universidade Federal do Rio de Janeiro UFRJ
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Universidade Federal do Rio de Janeiro UFRJ
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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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention is related to ethyl functionalized derivatives of 6-N- alkyl and/or 6-N-aryl urea [1,3]dioxolo[5,4-g]quinolin-7-carboxylate (3a-Z, 4a-Z); and congeners (5a-Z).
  • the present invention is related to derivates of ethyl 6-phenylurea-[1 ,3]-dioxolo-[5,4-g]-quinolin-7-carboxylate (LASSBio-948), ethyl 6-(4-bromophenylurea)-6-phenylurea-[1 ,3]-dioxolo-[5,4- g]-quinolin-7-carboxylate (LASSBio-947), ethyl 6-(4-chlorophenylurea)-[1 ,3]- dioxolo-[5,4-g]-quinolin-7-carboxylate (LASSBio-949) and ethyl 6- cyclohexylurea-[1 ,3]-dioxolo-[5,4-g]-quinolin-7-carboxylate (LASSBio-998) and their isosters and regioisomers, the process for
  • kinases there are those activated by mitogen (mitogen-activated protein kinase, MAPK), belonging to the family of Serine-Threonine kinases that include the kinase regulated by extracellulars signals (extra-cellular signal regulated kinase-2, ERKs), the amino-terminal kinase of junction c (c-jun amino terminal kinase, JNKs) and the protein p38 activated by mitogen (mitogen- activated protein kinase p38, MAPK p38).
  • mitogen mitogen-activated protein kinase
  • MAPK mitogen-activated protein kinase
  • kinases have 60-70% of homology among each other and are characterized by the presence of the sequence Thr-Xaa-Tyr in the active site, so it could be doubly phosphorylated in the threonine and tyrosine aminoacid residues for MAPK kinases (MKK) in response to extracellulars stimulus [Muzio, M. et. AL, Science, 1997, 278, 1612].
  • MKK MAPK kinases
  • MAPK-p38 activation occurs in response to osmotic shock, heat, ultraviolet light, pathogenic agents such as lipopolysaccharides of gram- negative bacteria (LPS) and different interleukins (IL) like IL-1 , IL-2, IL-7, IL-17, IL-18, the cytokines such as the transforming growth factor ⁇ (TGF- ⁇ ) and the tumor necrosis factor ⁇ (TNF- ⁇ ).
  • LPS lipopolysaccharides of gram- negative bacteria
  • IL-7 interleukins
  • TGF- ⁇ transforming growth factor ⁇
  • TNF- ⁇ tumor necrosis factor ⁇
  • the homology degree of p38 ⁇ in view of p38 ⁇ , p38 ⁇ e p38 ⁇ is 75, 62, and 64%, respectively.
  • this enzyme is predominantly expressed in cells involved with the inflammatory and immunomodulatory response of the organism [Lee, J. C. et AL, Nature, 1994, 372, 739], justifying its central role in the development of pathologies of inflammatory origin.
  • MAPK-p38 ⁇ is involved in cellular events in response to cellular adhesion induced by LPS and may lead to activation of nuclear transcription factors with subsequent synthesis of TNF- ⁇ and IL-1 ⁇ [Reingeaud, J. et AL, MoI. Cell. Biol. 1995, 16, 1247].
  • the biological action of these cytokines can be attributed to the activation of nuclear transcription factor KB (NFKB), contributing for the inflammatory response orchestration [Baeuerle, P. A. and Baltimore, D, Ce//, 1996, 87, 13].
  • MAPK-p38 activity Due to the central role performed in the differents stages of the inflammatory process, MAPK-p38 activity has been linked to several diseases, being important to stress the rheumatoid arthritis [Kumar, S. et. AL, Nature Drug Discovery 2003, 2, 717].
  • rheumatoid arthritis inflammatory process development the presence of a great number of mononuclear cells in synovia is intimately related to the magnitude of the disease.
  • the macrophages in rheumatoid synovia have a high concentration of activated MAPK-p38 with consequent production of TNF- ⁇ and IL-1 ⁇ , essential cytokines in the pathogeny development.
  • the evidence that MAPK-p38 played a key role in inflammatory processes made the enzyme inhibition an attractive therapeutic strategy for the treatment of different inflammatory pathological conditions.
  • the first synthetic prototype able to inhibit selectively MAPK-p38 was the piridinyl imidazolic derivative SFK-86002 [Lee, J. C. et. AL 1 Int. J. Immunopharmacol. 1988, 10, 835; Lee, J. C. et Al. Ann. NY Acad. Sci. 1993, 696, 149], that afterwards was substituted by the derivative 2,4,5-triaryl imidazolic SB-203580 [Gallagher, T. F. et Al. Bioorg. Med. Chem. Lett.1995, 5, 1171], both used as a pharmacological tool in the research of new molecular targets involving cytokines regulation.
  • MAP Kinase inhibitors of of.
  • WO 95/09851 WO 97/16442
  • WO 98/06715 WO 98/07425, WO 98/56377, WO 99/01136, WO 00/01688, WO 00/07991, WO 00/06563, WO 00/12074, WO 01/29041 , WO 01/62731 , WO 01/05744, WO 04/089929, WO 04/016267.
  • inhibitors of MAPK-p38 are in clinical trial stages [Jessie M. et. Al., TRENDS in Pharm. Sciences, 2002, 23, 40] and some examples are illustrated below.
  • inflammatory diseases especially, different types of arthritis, osteoarthritis and asthma, among others.
  • the main limitations and complications associated with the drug therapy, usually in the treatment of inflammatory diseases would be circumvented or minimized by the use of ureidic derivatives that act as MAPK- p38 inhibitors of and/or NFKB'S activation inhibitors.
  • R 1 is OCH 3 or OCH 2 CH 3 or OPh or OBn or NH 2 or NHCH 3 or NHNH 2 ;
  • W is (2 and/or 3 and/or 4 and/or 5 and/or 6)-F or (2 and/or 3 and/or 4 and/or 5 and/or 6)-CI or (2 and/or 3 and/or 4 and/or 5 and/or 6)-Br or (2 and/or 3 and/or 4 and/or 5 and/or 6)-CH 3 or (2 and/or 3 and/or 4 and/or 5 and/or 6)-
  • R 2 is CH 3 or CH 2 CH 3 or (CH 2 ) 2 CH 3 or (CH 2 ) 3 CH 3 or (CH 2 ) 4 CH 3 or (CH 2 ) 5 CH 3 or CH(CH 3 ) 2 or C(CH 3 ) 3 or cyclopropyl, or cyclopentyl or cyclohexyl or cycloheptyl;
  • Ar is 2-Py or 3-Py or 4-Py or 2-thiophene or 2-furane or 2-pirrole or 1- naphtyl or 2-naphtyl or quinoline, or quinoxaline or oxazole or thiazole or thiadiazole, oxadiazole or pyrimidine or triazole or imidazole; It is an additional object of the present invention the process of preparation of ureidic derivatives.
  • such process comprises synthetics steps such as: regiosselective electrophilic aromatic substitution; aldolic condensation with ethyl cyanoacetate; reduction followed by cyclization through intramolecular addition nucleofilic; condensation (intermediary amine with funcionalized isocyanates); interconversion of functional groups.
  • compositions comprising the ureidic derivatives and their use in the treatment of inflammatory diseases and conditions. More specifically, such pharmaceutical compositions are able of inhibit to p38 MAP-Kinase and/or to inhibit NFKB activation.
  • Figure 2 Values of plC50 proposed for some of the ureidic derivatives planned as MAPK-p38 inhibitors, comparative to the values of prototypes GK 00687 and SB 203580 plC50, from model of CoMFA.
  • FIG. 3 Effect of LASSBio-947 (3d) and of SB202190 on MAPK-p38 activation of peritoneal murine macrophage stimulated with LPS, showing the autoradiography (A) with the respective columns representing the relative optical densities of each band (B).
  • Preparations: RPMI naive macrophages;
  • LPS macrophages stimulated with LPS 10 g/ml
  • LASSBio-947 macrophages stimulated with LPS in the presence of different concentrations of LASSBio-947 (3d) (1 , 10, 100 and 1000 ⁇ M)
  • SB macrophages stimulated with LPS in the presence of different concentrations of SB202190 (1 and 10 ⁇ M).
  • IC 50 (LASSBio-947 (3d)) 8,7 ⁇ M.
  • FIG. 4 Effect of LASSBio-948 (3a) in MAPK-p38 activation of peritoneal murine macrophages stimulated with LPS, showing the autoradiography (A) with the respective columns representing the relative optical densities of each band (B).
  • LASSBio-948 macrophages stimulated with LPS in the presence of different concentrations of LASSBio-948 (3a) (1 , 10, 100 and 1000 ⁇ M).
  • IC 50 (LASSBio-948 (3a)) 13,6 ⁇ M.
  • Figure 5 Effect of LASSBio-949 (3c) on MAPK-p38 activation of peritoneal murine macrophages stimulated with LPS, showing the autoradiography (A) with the respective columns that represent the relative optical densities of each band (B).
  • RPMI naive macrophages
  • RPMI+DMSO naive macrophages in the presence of DMSO 0,5%
  • LPS macrophages stimulated with LPS 10 ⁇ g/ml
  • LASSBio-949 macrophages stimulated with LPS in the presence of different concentrations of LASSBio-949 (3c) (1 , 10, 100 and 1000 ⁇ M)
  • SB macrophages stimulated with LPS in the presence of different concentrations of SB202190 (1, 10 and 100 ⁇ M).
  • IC 50 (LASSBio-949 (3c)) 30 ⁇ M.
  • FIG. 6 Effect of LASSBio-998 (4m) on MAPK-p38 activation of peritoneal murine macrophages stimulated with LPS, showing the autoradiography (A) with the respective columns that represent the relative optical densities of each band (B).
  • IC 50 (LASSBio-998 (4m)) 5,5 ⁇ M.
  • Figure 7 Decrease of weight gain on left popliteus lymphonode in mice that received zymosan and were treated with LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c).
  • Groups of 8 animals received s.c. injection of sterile saline or injection of 150 ⁇ g of zymosan (prepared in saline) on the left paw. Seventy two hours after the injection, the animals were treated i.p. with 10 mg/kg of L-947, L-948 and L-949 for 4 days. After that period, the left popliteus lymphonode was dissected and weighed. The values are presented as the average + WITHOUT, in which **p ⁇ 0,01 and ***p ⁇ 0,001.
  • Figure 8 Lymphocytes number reduction in the left popliteus lymphonode in mice that received zymosan and were treated with LASSBio- 947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c).
  • Groups of 8 animals received injection s.c. of sterile saline or of 150 ⁇ g of zymosan (prepared in saline) on the left paw. Seventy two hours after the injection, the animals were treated with i.p 10 mg/kg of the substances L-947, L-948 and L-949 for 4 days. After that period, the lymphonodes cells were isolated and counted in Neubauer chamber.
  • Figure 9 Inhibition of NFKB translocation of mice C57BI6 lymphonodes lymphocytes treated with the compounds LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c). Auto-radigraph image obtained from the nuclear extract of the lymphocytes after eletroforetic run in polyacrilamide gel.
  • One innovative characteristic of the present invention is the synthesis of ethyl functionalized derivatives of 6-N-alkyl and/or 6-N-aryl urea [1 ,3]dioxolo[5,4-g]quinolin-7-carboxylate (3a-Z, 4a-Z); and congeners (5a-Z).
  • LASSBio-948 ethyl 6-phenylurea-[1 ,3]-dioxolo-[5,4-g]-quinolin-7- carboxylate derivatives
  • LASSBio-947 ethyl 6-(4- bromophenylurea)-[1 ,3]dioxolo[5,4-g]quinolin-7-carboxylate
  • LASSBio-949 ethyl 6-(4-chlorophenylurea)-[1 ,3]dioxolo[5,4-g]quinolin-7- carboxylate
  • LASSBio-998 ethyl 6-cyclohexylurea- [1 ,3]dioxolo[5,4-g]quinolin-7-carboxylate
  • LASSBio-998 ethyl 6-cyclohexylurea- [1 ,3]dioxolo[5,4-g]quinolin-7-carbox
  • the new compounds were obtained in good to excellent chemical yields, employing the synthetic methodology herein described, according to scheme below, that is characterized by presenting few steps, starting from commercially available compounds, qualifying this synthetic methodology for industrial application.
  • the compounds of the present invention were planned through convergent synthesis, using classical chemical reactions such as: ⁇ Regiosselective Aromatic Electrophilic Substitution
  • the compounds (3a-Z; 4a-Z; 5a-Z) of the present invention can be prepared from a process that comprises the steps of:
  • the heating is turned off, and after cooling of the reactional medium the cyano-derivative 9 (0,58Og, 2mmol) solubilized in 5 mL of THF is dripped into the solution. It is observed a change in the coloration, in the reactional medium to a black-reddish color.
  • the reactional mixture is submitted to the magnetic agitation in r.t. for 1 hour and 30min.
  • the isolation is done pouring the flask content to a beaker containing 40 mL of aqueous solution of K2CO3 10%. Then it is added about 100 mL of dichloromethane letting the resultant suspension under vigorous magnetic agitation until there is extraction to the organic phase. The suspension is vacuum filtered, washing exhaustively with dichloromethane. The filtrate is transferred to a separation funnel and is washed with water. The organic phase is dried with anhydrous Na 2 SO 4 and concentrated to an amorphous solid of brown coloration in yield of 84%. Afterwards it is accomplished the purification through recrystallization in hydroalcoholic mixture.
  • This derivative was obtained in 96% yield, through the nucleofilic addition of the 2-amino-quinolin derivative (10) to phenylisocyanate, as a clear brown amorphous solid with mp.: 202-203 0 C.
  • This derivative was obtained in 95% yield, through the nucleofilic addition of the 2-amino-quinolin derivative (10) to the 4-bromo-phenylisocyanate, as a clear brown amorphous solid with mp.: 213-215 0 C.
  • This derivative was obtained in 80% yield, through the nucleofilic addition of the derivative 2-amino-quinolin (10) to cyclohexylisocyanate, as an amorphous brown solid with mp.: 179-182 0 C.
  • NMR 13 C (50 MHz, DMSO-d 6 ) ⁇ : 14, 1 (RCOOCH 2 CH 3 ); 24, 2 e 24, 6 (C3 1 e C5'); 25, 3 (C4 1 ); 32, 5 e 33, 4 (C2 1 e C6 1 ); 47, 9 (C1'); 54, 9 (RCOOCH 2 CH 3 ); 102, 6 (OCH 2 O); 102, 7 (C8); 105, 0 (C5); 107, 8 (C3); 119, 0 (C4a); 141 , 4 (C4); 145, 0 (C8a); 146, 7 (NCON); 150, 0 (C7); 153, 0 (C6); 154, 2 (C1); 166, 1 (RCOOR') ppm.
  • LASSB ⁇ o-947 3d
  • LASSBio-948 3a
  • LASSBio-949 3c
  • LASSBio-998 4m
  • Western blot is one immunochemical technique usually employed to proteins detection in complex mixtures.
  • the method is based on proteins electrophoretic separation in polyacrilamide gel in the presence of the anionic detergent sodium dodecyl sulfate (SDS), which are transferred for a immobilizing membrane and incubated with specific antibodies for the desired protein-antigen (primary antibody), and thereafter with the antibody conjugated with an indicator (secondary antibody).
  • SDS anionic detergent sodium dodecyl sulfate
  • the optical density of the signal produced can be quantified with an image analysis system [Thursdays L. E. M. et Al., Biochem Pharmacol. 2000, 60, 741 ; Thursdays, L. E. M. et Al., Biochem Pharmacol. 2002, 64, 1431].
  • the Western blot detection of the MAPK-p38 enzyme in its active, phosphorilated form is widely used employing specific polyclonal antibodies for the phosphopeptidic sequence that contains the aminoacids threonine and tyrosine in positions 180 and 182, respectively.
  • This technique has been employed for identification and characterization of suitable inhibitors for MAPK- p38 activation, such as pyridinylimidazoles [Chun, K. S. et Al., Carcinogenesis, 2004, 25, 713].
  • macrophages obtained from peritoneal washes of lineage C57BI6 male mice weighing about 25g were used.
  • the macrophages were stimulated with LPS in the presence of synthetic molecules 3a, 3c, 3d, 4m in concentrations of 1, 10, 100 and 1000 ⁇ M or prototype pyridinylimidazole SB202190 in concentrations 1 , 10 and/or 100 ⁇ M, used as standard inhibitor.
  • synthetic molecules 3a, 3c, 3d, 4m in concentrations of 1, 10, 100 and 1000 ⁇ M or prototype pyridinylimidazole SB202190 in concentrations 1 , 10 and/or 100 ⁇ M, used as standard inhibitor.
  • Tris-PBS buffer with 0.1% of Tween 20 containing 5% of skim milk powdered, in order to impregnate all nitrocellulose pores with milk casein.
  • IC50 values obtained, determined by densitometry, for derivatives LASSBio-947 (3d), LASSBio-948 (3a), LASSBio- 949 (3c) and LASSBio-998 (4m) were 8.7 ⁇ M, 13.6 ⁇ M, 30 ⁇ M e 5.5 ⁇ M, respectively ( Figures 3, 4, 5 and 6).
  • the inflammation was induced by zymosan intraplantar injection and evaluated by the correspondent popliteus lymphonode weight increase, compared with non-treated animals [Ibrahim, T. et al International lmmunopharmacology 2002, 2, 875].
  • the popliteus lymphonode weight used as inflammation evaluation parameter is based on similarities found between the synovial membrane and the lymphonode, such as:
  • mice received a subcutaneous injection of 150 ⁇ g zymosan (solution prepared in sterile saline) in the left paw.
  • the control group received sterile saline.
  • 72 hours after the injection the animals were treated daily with intraperitoneal injections containing derivatives LASSBio-947 (3d), LASSBio-948 (3a), LASSBio-949 (3c) in doses of 10 mg/kg, during four (4) days. After this period, the animals have been sacrificed, the lymphonodes extracted and weighed.
  • Figure 7 show that the zymosan intraplantar injection increases about 10 times the left paw drainage lymphonode weight.
  • MAPK kinases induces the phosphorylation of others kinases such as l ⁇ B-kinase, freeing NFKB to translocate to the nucleus and to bind in DNA sequences promoting the transcription of pro-inflammatory cytokines.
  • others kinases such as l ⁇ B-kinase, freeing NFKB to translocate to the nucleus and to bind in DNA sequences promoting the transcription of pro-inflammatory cytokines.
  • Figure 9 shows that the treatment with compounds LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c) inhibited the NFKB translocation to the lymphocytes nucleus, measured through the electrophoretic mobility shift assay.
  • 6-N-alkyl and/or 6-N-aryl ureas-[1,3]dioxolo[5,4-g]quinolin-7-carboxylate to inhibit the MAPK-p38 enzyme and the NFKB activation pathways, with consequent reduction of inflammatory response, evaluated in chronic inflammation in vivo model, suggesting the therapeutical use of these substances in the treatment of inflammatory conditions such as different types of arthritis, asthma, Crohn's disease and diabetes mellitus of type I, among others.
  • Peritoneal macrophages C57BI6 mice weighing approximately 25g were chosed. The cells were collected through washing of peritoneal cavity with 5 ml_ RPMl 1640/sodium bicarbonate media (Sigma Chemical Co., the USA) without serum. After that, the cells were washed 3 times with this same media and counted in Neubauer chamber. To separate the macrophages, 10 6 cells had been resuspended in 300 ⁇ L of RPMI/BIC media and placed to adhere in 24-wells plates at 37 0 C in a moist atmosphere of 5% CO 2 . After 1 hour, the plates were washed with media in order to remove the loose cells. The adhered cells had then been used for the assay.
  • MAPK-p38 inhibition Assay The adhered macrophages had been stimulated with 1 ⁇ g/mL LPS for 1 h, in presence of compounds LASSBio-947, LASSBio-948, LASSBio-949 and LASSBio-998 in increasing logarithmic concentrations ( Figures 3, 4, 5 and 6). The control was treated with 0.5% DMSO.
  • Lymphonode lymphocytes wereincubated with 100 ⁇ L of HEPES buffer 10 mM; KCI 10 mM; MgCI 2 2 mM; EDTA 0.1 mM - pH 8.0; PMSF 0.01 mM, DTT 1.0 mM, aprotinin 10 mg/mL and NaF 10OmM (Buffer A) at 4°C for 10 minutes. After the incubation period 6 ⁇ L of nonidet P 40 were added and centrifuged at 1600Og for 20 s. After the centrifugation, the precipitated was resuspended in 100 ⁇ L Buffer A and re-centrifuged at 1600Og at 4° C for 20 s.
  • Electrophoretic mobility shift assay electrophoreses was made in 6% nondenaturating polyacrylamide gel. HeLa cells were used as positive control. The extracts had been incubated with 32 Pi labeled oligonucleotides (Gibco BRL Tech, USA) for 30 min at 37° C. In each well 4 ⁇ g of protein and approximately 100,000 cpm of labeled probe were addes. After 2h at 150 V, the gel was dehydrated and analyzed for autoradiography in the Storm Molecular Scan Dynamics (USA).
  • the animals were treated with the test-compounds intraperitoneally (i.p.) in doses of 10 mg/kg dissolved in 0.5% of DMSO, during four days. After this, the animals were sacrificed by cervical displacement and the popliteus lymphonodes were extracted and weighed. The cells were counted in Neubauer chamber and used for the nuclear extract preparation.
  • the compounds of the invention can be administered in a multitude of dosage forms, for example, orally, in the form of tablets, capsules, sugar or tablets covered with films, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, i.e. intramuscular, or by infusion or intravenous and/or intrathecal and/or intraspinal injection.
  • the present invention also includes pharmaceutical compositions comprising compounds of formula (3a-z; 4a-z; 5a-z), or their acceptable salts, in associations with one pharmaceutically acceptable vehicle (which can be a carrier or diluent).
  • one pharmaceutically acceptable vehicle which can be a carrier or diluent.
  • the solid oral forms can contain, along with the active compound, diluents, such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, such as silica, talc, stearic acid, calcium or magnesium stearate, and/or polyethylene glycols; linking agents, for example starches, Arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, for example starch, alginic acid, sodium starch alginates or glycolate; effervescent mixtures; colorants; wetting agents such as lecithin, polysorbates, lauryl sulphates; generally, not toxic and pharmacologically inactive substances common in pharmaceutical formulations.
  • diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch
  • lubricants such as silica, talc, stearic acid, calcium or magnesium
  • the pharmaceutical preparations can be manufactured using well-known steps, for example, mixture, granulation, tableting, coating or film covering processes.
  • the liquid dispersions for oral administration can be, for example, syrup, emulsions and suspensions.
  • the syrups can contain as carrier, for example, sucrose or sucrose with glycerin and/or manita and/or sorbitol.
  • the suspensions and the emulsions can contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections can contain, along with the active substance, a pharmaceutically acceptable carrier, that is sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol of, and, if desired, adequate amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier that is sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol of, and, if desired, adequate amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions can contain as carrier, for example, sterile water or preferential they can be in form of sterile water, isotonic or aqueous solutions or they may contain as carrier propylene glycol.
  • the suppository can contain along with the active substance a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier for example, cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.

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Abstract

L'invention concerne des dérivés fonctionnalisés d'urées éthyl 6-N-alkyl et/ou 6-N-aryl [1,3]dioxolo[5,4-g]quinolin-7-carboxylate (3a-z, 4a-z) et de types similaires (5a-z), de formule générale (I, II, III et IV), utiles dans le traitement et/ou la prévention de maladies inflammatoires, telles que les états inflammatoires aigus ou chroniques, les différents types d'arthrite, l'asthme, la maladie de Crohn et le diabète de type 1, entre autres. Ces dérivés présentent la capacité de moduler le processus inflammatoire en agissant sur la protéine kinase activée par le mitogène p38 (MAPK-p38). De plus, les dérivés selon l'invention présentent des propriétés anti-inflammatoires expressives évaluées dans des modèles in vivo. L'invention concerne également des procédés de production de ces dérivés, ainsi que des compositions pharmaceutiques les contenant.
PCT/BR2006/000107 2005-06-03 2006-06-01 Composes ureidiques, compositions pharmaceutiques les contenant et leur utilisation dans le traitement des maladies inflammatoires Ceased WO2006128268A1 (fr)

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BRPI0502016A BRPI0502016B8 (pt) 2005-06-03 2005-06-03 composto ureídicos, composições farmacêuticas contendo os mesmos e seu uso no tratamento de doenças inflamatórias
BRPI050.2016-6 2005-06-03

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WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
WO2012054996A1 (fr) * 2010-10-25 2012-05-03 Universidade Federal Do Rio De Janeiro Composés aryl- et/ou hétéroaryl-urées fonctionnalisés, procédé de synthèse de ces composés, composition pharmaceutique contenant lesdits composés et utilisations correspondantes
RU2686692C1 (ru) * 2018-06-29 2019-04-30 Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) Применение N-(6,8,8-триметил-8,9-дигидрофуро[3,2-h]хинолин-5-ил)ацетамида в качестве средства для фототерапии псориаза и псориатического артрита
US11518739B2 (en) 2017-08-15 2022-12-06 Inflazome Limited Sulfonamide carboxamide compounds

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WO1999058502A1 (fr) * 1998-05-11 1999-11-18 Vertex Pharmaceuticals Incorporated Inhibiteurs heterocycliques de la proteine p38
WO2004016267A1 (fr) * 2002-08-14 2004-02-26 Boehringer Ingelheim Pharmaceuticals, Inc. Traitement anticoagulant et fibrinolytique a base d'inhibiteurs de p38 map kinase
WO2004078748A2 (fr) * 2003-02-28 2004-09-16 Bayer Pharmaceuticals Corporation Nouveaux derives bicycliques d'uree utiles dans le traitement du cancer et d'autres troubles

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WO1999058502A1 (fr) * 1998-05-11 1999-11-18 Vertex Pharmaceuticals Incorporated Inhibiteurs heterocycliques de la proteine p38
WO2004016267A1 (fr) * 2002-08-14 2004-02-26 Boehringer Ingelheim Pharmaceuticals, Inc. Traitement anticoagulant et fibrinolytique a base d'inhibiteurs de p38 map kinase
WO2004078748A2 (fr) * 2003-02-28 2004-09-16 Bayer Pharmaceuticals Corporation Nouveaux derives bicycliques d'uree utiles dans le traitement du cancer et d'autres troubles

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
WO2012054996A1 (fr) * 2010-10-25 2012-05-03 Universidade Federal Do Rio De Janeiro Composés aryl- et/ou hétéroaryl-urées fonctionnalisés, procédé de synthèse de ces composés, composition pharmaceutique contenant lesdits composés et utilisations correspondantes
US11518739B2 (en) 2017-08-15 2022-12-06 Inflazome Limited Sulfonamide carboxamide compounds
RU2686692C1 (ru) * 2018-06-29 2019-04-30 Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) Применение N-(6,8,8-триметил-8,9-дигидрофуро[3,2-h]хинолин-5-ил)ацетамида в качестве средства для фототерапии псориаза и псориатического артрита

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BRPI0502016A (pt) 2007-01-23

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