- IMIDAZOQUINOLINE-TYPE COMPOUNDS AND USES THEREOF
-
Provided in the present disclosure are imidazoquinoline-type compounds, methods for their preparation, pharmaceutical compositions thereof and their use, wherein the imidazoquinoline-type compounds, upon local administration, form depots inducing cell mediated immune response while mitigating a systemic proinflammatory immune response.
- -
-
Paragraph 0012; 0092; 0093; 00101
(2021/10/11)
-
- LOCALLY ACTING TOLL-LIKE RECEPTOR 7 (TLR7) AND/OR TLR8 AGONIST IMMUNOTHERAPY COMPOUNDS AND THEIR USES
-
Provided in the present disclosure are immunotherapy compounds, pharmaceutical compositions thereof and their use, wherein the immunotherapy compounds, upon local administration, form depots inducing cell mediated immune response while mitigating a systemic proinflammatory immune response.
- -
-
Paragraph 0032; 00186-00187; 00189
(2020/10/19)
-
- Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia
-
Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers.
- Yang, Jincheng,Chen, Kun,Wang, Bin,Wang, Liudi,Qi, Shuya,Wang, Weihua
-
-
- SUBSTITUTED IMIDAZOQUINOLINES
-
The invention relates to imidazoquinoline derivatives and to pharmaceutical compositions containing the imidazoquinoline derivatives. The imidazoquinoline derivatives of the invention are useful as toll-like receptor agonists, in particular agonists of TLR7, and promote induction of certain cytokines.
- -
-
Page/Page column 40-41
(2019/04/10)
-
- SUBSTITUTED IMIDAZOQUINOLINES AS AGONISTS OF TLR7
-
The invention relates to imidazoquinoline derivatives and to pharmaceutical compositions containing the imidazoquinoline derivatives. The imidazoquinoline derivatives of the invention are useful as toll-like receptor agonists, in particular agonists of TLR7, and promote induction of certain cytokines.
- -
-
Page/Page column 41; 42
(2019/04/10)
-
- Nitrogenous five-membered heterocycle quinoline compound and salt, preparation method, pharmaceutical composition and application thereof
-
The invention relates to a nitrogenous five-membered heterocycle quinoline compound and a salt, a preparation method, a pharmaceutical composition and application thereof. The structural formula of the nitrogenous five-membered heterocycle quinoline compound is shown by I in the description; the preparation method of the nitrogenous five-membered heterocycle quinoline compound comprises the following steps: with a 4-hydroxyquinoline compound as a starting raw material, sequentially performing nitrification, halogenation, amination, reduction and cyclization reaction to obtain a final product.The nitrogenous five-membered heterocycle quinoline compound and the pharmaceutically acceptable salt thereof have the advantages that a hair follicle proliferation function can be realized and can beused for preparing medicines for treating common alopecia, alopecia caused by chemoradiotherapy and hair follicle damage.
- -
-
Paragraph 0063; 0068
(2018/05/30)
-
- NLRP3 MODULATORS
-
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that modulate (e.g., agonize or partially agonize) NLRP3 and TLR7 and/or TLR8 that are useful, e.g., for treating a condition, disease or disorder in which a decrease in NLRP3 and TLR7 and/or TLR8 activities (e.g., a condition, disease or disorder associated with repressed or impaired NLRP3 and TLR7 and/or TLR8 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.
- -
-
Page/Page column 63
(2017/11/15)
-
- Dual inhibitors of epidermal growth factor receptor and topoisomerase IIα derived from a quinoline scaffold
-
Based on the quinazoline bearing EGFR inhibitors, a series of thirty four compounds having a quinoline scaffold were synthesised and evaluated in vitro for EGFR kinase inhibitory activity. A structure-activity relationship study revealed that 2,4-bis(arylamino) substituted quinolines possessed better anti-EGFR kinase activity. Compounds 3f and 3m emerged as potent EGFR kinase inhibitors (200 and 210 nM, respectively) and showed excellent anticancer activity at the micromolar level against a panel of cancer cell lines comparable to erlotinib. Furthermore, representative compounds inhibited the human topoisomerase IIα selectively and catalytically, did not intercalate with DNA, increased intracellular ROS concentration (except 3m) and altered the mitochondrial membrane potential of the cancer cells. Cell cycle analysis and annexin-V staining in a lung cancer cell line showed that the compounds delayed cell cycle progression by inducing cell cycle arrest and subsequent apoptosis at the G1 phase. The facts were further corroborated through molecular modeling studies.
- Chauhan, Monika,Joshi, Gaurav,Kler, Harveen,Kashyap, Archana,Amrutkar, Suyog M.,Sharma, Praveen,Bhilare, Kiran D.,Chand Banerjee, Uttam,Singh, Sandeep,Kumar, Raj
-
p. 77717 - 77734
(2018/06/22)
-
- The new substd. Imidazoquinoline
-
Imidazoquinolines of formula I that contain substituted amine or amide functionality at 1- position and that are effective as Toll like Receptor 7 activators are disclosed. These compounds are useful as anticancer agents.
- -
-
Paragraph 0100
(2016/10/10)
-
- CONJUGATED TLR7 AND/OR TLR8 AND TLR2 AGONISTS
-
A conjugated compound of formula Q-Z—R4 wherein Q is a TLR7 and/or TLR8 agonist and Z—R4 is a TLR2 agonist, and the uses thereof in the treatment of infection, cancer or immune disorders or for use in vaccines.
- -
-
Page/Page column
(2015/07/22)
-
- AMINE COMPOUNDS HAVING ANTI-INFLAMMATORY, ANTIFUNGAL, ANTIPARASITIC AND ANTICANCER ACTIVITY
-
Amine compounds having activity against inflammation, fungi, unicellular parasitic microorganisms, and cancer are described. The compounds contain a monocyclic, bicyclic, or tricyclic aromatic ring having one, two, or three ring nitrogen atoms.
- -
-
Page/Page column 172
(2014/08/19)
-
- Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines
-
Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c] quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.
- Kokatla, Hari Prasad,Yoo, Euna,Salunke, Deepak B.,Sil, Diptesh,Ng, Cameron F.,Balakrishna, Rajalakshmi,Malladi, Subbalakshmi S.,Fox, Lauren M.,David, Sunil A.
-
p. 1179 - 1198
(2013/03/29)
-
- Novel compositions of TLR7 and/or TLR8 agonists conjugated to lipids
-
The present invention concerns a conjugated compound of formula Q-Z-R4 wherein Q is a TLR7 and/or TLR8 agonist and Z-R4 is a lipid covalently linked to an amino acid or peptide coupled to a polyamine group, and a process for the manufacture of said conjugated compound, as well as a complex formed between said conjugated compound and a polyanionic molecule and a pharmaceutical composition containing said conjugated compound or complex. The invention further concerns the use of said conjugated compound or complex in the treatment of infection, cancer or immune disorders or for use in vaccines.
- -
-
Paragraph 0227
(2014/01/08)
-
- Novel Compounds
-
The present invention provides compounds of formula (I): wherein Ra, Rb, Rc, R1, R2, R3, X1, Y1, Z1, A, n and m are as defined in the specification, and pharmaceutically acceptable salts thereof, as well as processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
- -
-
Page/Page column 21
(2011/06/24)
-
- Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline
-
Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N1-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC50 value of 7.5 μM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7.
- Shukla, Nikunj M.,Kimbrell, Matthew R.,Malladi, Subbalakshmi S.,David, Sunil A.
-
supporting information; experimental part
p. 2211 - 2214
(2009/12/07)
-
- IMIDAZOQUINOLINES WITH IMMUNO-MODULATING PROPERTIES
-
The present invention provides compounds of formula (I) wherein Ra, R1, R2, R3, X1, Y1, Z1, A, n and m are as defined in the specification, and pharmaceutically acceptable salts
- -
-
Page/Page column 48
(2009/01/20)
-
- A3 ADENOSINE RECEPTOR ALLOSTERIC MODULATORS
-
The present invention relates to allosteric modulation of A3 adenosine receptor (A3AR) and provides for the use of an A3 adenosine receptor modulator (A3RM),for the preparation of pharmaceutical compositions for
- -
-
Page/Page column 20
(2008/06/13)
-
- Structure-activity relationships of new 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric enhancers of the A3 adenosine receptor
-
1H-Imidazo[4,5-c]quinolin-4-amine derivatives have been synthesized as allosteric modulators of the human A3 adenosine receptor (AR). Structural modifications were made at the 4-amino and 2 positions. The compounds were tested in both binding and functional assays, and many were found to be allosteric enhancers of the action of A3AR agonists by several different criteria. First, a potentiation of the maximum efficacy of the agonist C1-IB-MECA was observed for numerous derivatives. Also, a number of these compounds decreased the rate of dissociation of the agonist [ 125I]I-AB-MECA from the A3AR. Most prominently, compound 43 (LUF6000) was found to enhance agonist efficacy in a functional assay by 45% and decrease dissociation rate similarly without influencing agonist potency. The structural requirements for allosteric enhancement at the A3AR were distinct from the requirements to inhibit equilibrium binding. Thus, we have prepared allosteric enhancers of the human A3AR that have an improved allosteric effect in comparison to the inhibition of equilibrium binding at the orthosteric site.
- G?bly?s, Anikó,Gao, Zhan-Guo,Brussee, Johannes,Connestari, Roberto,Santiago, Sabrina Neves,Ye, Kai,Ijzerman, Adriaan P.,Jacobson, Kenneth A.
-
p. 3354 - 3361
(2007/10/03)
-
- Synthesis and structure - Activity-relationships of 1H-imidazo[4,5-c] quinolines that induce interferon production
-
1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.
- Gerster, John F.,Lindstrom, Kyle J.,Miller, Richard L.,Tomai, Mark A.,Birmachu, Woubalem,Bomersine, Shannon N.,Gibson, Shiela J.,Imbertson, Linda M.,Jacobson, Joel R.,Knafla, Roy T.,Maye, Peter V.,Nikolaides, Nickolas,Oneyemi, Folakemi Y.,Parkhurst, Gwen J.,Pecore, Sharon E.,Reiter, Michael J.,Scribner, Lisa S.,Testerman, Tracy L.,Thompson, Natalie J.,Wagner, Tammy L.,Weeks, Charles E.,Andre, Jean-Denis,Lagain, Daniel,Bastard, Yvon,Lupu, Michel
-
p. 3481 - 3491
(2007/10/03)
-
- 1H-IMIDAZO[4,5-c]QUINOLINE DERIVATIVES IN THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
-
The invention relates to the use of imidazoquinolines and salts thereof in the treatment of protein kinase dependent diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, imidazoquinolines for use in the treatment of protein kinase dependent diseases, a method of treatment against said diseases, comprising administering the imidazoloquinolines to a warm-blooded animal, especially a human, pharmaceutical preparations comprising an imidazoquinoline, especially for the treatment of a protein kinase dependent disease, novel imidazoquinolines, and a process for the preparation of the novel imidazoquinolines.
- -
-
Page/Page column 50-51
(2008/06/13)
-
- Process for imidazo[4,5-C]quinolin-4-amines
-
A process is disclosed for preparing 1-substituted-1H-imidazo[4,5-c]quinolin-4-amines. The process involves reacting a 1-substituted-1H-imidazo[4,5-c]quinoline-5-oxide with an acylating agent and reacting the product thereof with an aminating agent.
- -
-
-
- Imidazo[4,5-c]quinolin-4-amines and processes for their preparation
-
A process and intermediates for preparing 1-substituted-1H-imidazo[4,5-c]quinolin-4-amines. The process involves reacting a 1-substituted-1H-imidazo[4,5-c]quinoline-5N-oxide with an isocyanate and hydrolysing the product thereof. Also, a process for preparing the intermediates is disclosed.
- -
-
-
- Pyrido[3,4-e]-1,2,4-triazines and related heterocycles as potential antifungal agents
-
The preparation and biological activities of a series of pyrido[3,4-e]-1,2,4-triazines, 1,2,4-triazino[5,6-c]quinolines, and related fused triazines are described. Methyl, amino, and acylamino substituents were placed in the pyridyl ring of the former system. Other structural modifications included various alkyl, cycloalkyl, substituted phenyl, and heterocyclic groups in the 3-position of these ring systems. In agar dilution assays, actives in this series inhibited strains of Candida, Aspergillus, Mucor, and Trychophyton species at MIC's of ≤ 16 μg/mL.
- Reich,Fabio,Lee,Kuck,Testa
-
p. 2474 - 2485
(2007/10/02)
-
