US20090324551A1 - Tlr agonists - Google Patents
Tlr agonists Download PDFInfo
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- US20090324551A1 US20090324551A1 US12/064,529 US6452906A US2009324551A1 US 20090324551 A1 US20090324551 A1 US 20090324551A1 US 6452906 A US6452906 A US 6452906A US 2009324551 A1 US2009324551 A1 US 2009324551A1
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- SJQIIISNMARZEA-UHFFFAOYSA-N COCCOC1=NC(N)=C2N=C(O)N(CC3=CC=C(C(=O)O)C=C3)C2=N1.COCCOC1=NC(N)=C2N=C(O)N(CC3=CC=C(C(=O)ON4C(=O)CCC4=O)C=C3)C2=N1.COCCOC1=NC(N)=C2N=C(OC)N(CC3=CC=C(C(=O)OC)C=C3)C2=N1.C[Si](C)(C)I Chemical compound COCCOC1=NC(N)=C2N=C(O)N(CC3=CC=C(C(=O)O)C=C3)C2=N1.COCCOC1=NC(N)=C2N=C(O)N(CC3=CC=C(C(=O)ON4C(=O)CCC4=O)C=C3)C2=N1.COCCOC1=NC(N)=C2N=C(OC)N(CC3=CC=C(C(=O)OC)C=C3)C2=N1.C[Si](C)(C)I SJQIIISNMARZEA-UHFFFAOYSA-N 0.000 description 1
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61P31/14—Antivirals for RNA viruses
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- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Definitions
- PAMPs pathogen associated molecular patterns
- PAMPs include peptidoglycans, lipotechoic acids from gram-positive cell walls, the sugar mannose (which is common in microbial carbohydrates but rare in humans), bacterial DNA, double-stranded RNA from viruses, and glucans from fungal cell walls.
- TLRs Toll-like Receptors
- TLR7 and TLR9 recognize and respond to imiquimod and immunostimulatory CpG oligonucleotides (ISS-ODN), respectively.
- the synthetic immunomodulator R-848 activates both TLR7 and TLR8. While TLR stimulation initiates a common signaling cascade (involving the adaptor protein MyD88, the transcription factor NF-kB, and pro-inflammatory and effector cytokines), certain cell types tend to produce certain TLRs. For example, TLR7 and TLR9 are found predominantly on the internal faces of endosomes in dendritic cells (DCs) and B lymphocytes (in humans; mouse macrophages express TLR7 and TLR9). TLR8, on the other hand, is found in human blood monocytes. (See Hornung et al., J. Immunol, 168:4531-4537 (2002)).
- Interferons are also involved in the efficient induction of an immune response, especially after viral infection (Brassard et al., J. Leukoc Biol, 71:568-581 (2002).) However, many viruses produce a variety of proteins that block interferon production or action at various levels. Antagonism of interferon is believed to be part of a general strategy to evade innate, as well as adaptive immunity. (See Levy et al., Cytokine Growth Factor Rev, 12:143-156 (2001).) While TLR agonists (TLR-L) may be sufficiently active for some methods of treatment, in some instances the microbial interferon antagonists could mitigate the adjuvant effects of synthetic TLR-L.
- the present invention provides for TLR agonist conjugates (compounds) and compositions, as well as methods of using them.
- the compounds of the invention are broad-spectrum, long-lasting, and non-toxic combination of synthetic immunostimulatory agents, which are useful for activating the immune system of a mammal, preferably a human and can help direct the pharmacophore to the receptor within the endosomes of target cells and enhance the signal transduction induced by the pharmacophore.
- the compounds of the invention include a pharmacophore covalently bound to an auxiliary group. Accordingly there is provided a compound of the invention which is a compound of formula (I):
- X 1 is —O—, —S—, or —NR c —;
- R c hydrogen, C 1-10 alkyl, or C 1-10 alkyl substituted by C 3-6 -cycloalkyl, or R c and R 1 taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkylene, or cyano;
- R 1 is (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, C 6-10 aryl, or substituted C 6-10 aryl, C 5-9 heterocyclic, substituted C 5-9 heterocyclic;
- each R 2 is independently hydrogen, —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b (carbamoyl), substituted
- each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, hydroxy(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl;
- X 2 is a bond or a linking group; and R 3 is an auxiliary group;
- the auxiliary groups can include organic molecules, composed of carbon, oxygen, hydrogen, nitrogen, sulfur, phosphorous atoms. These groups are not harmful to body tissues (e.g., they are non-toxic, and/or do not cause inflammation).
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
- the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity of TLR agonists is implicated and its action is desired, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- pathological conditions or symptoms that are suitable for treatment include cancers, treatment for bacterial or viral diseases, treating autoimmune diseases, and treating Crohn's Disease.
- the compounds of the invention can also be used as or to prepare vaccines against bacteria, viruses, cancer cells, cancer specific peptides, enhancers of monoclonal antibodies against cancer, a CNS stimulant, or for biodefense.
- the invention provides a compound of formula (I) for use in medical therapy (e.g., for use as an anti-cancer agent, treatment for bacterial diseases, treatment for viral diseases, such as hepatitis C and hepatitis B, Crohn's Disease, and as therapeutic agents for treating immunologic disease). Furthermore, it is suggested that compounds of formula (I) will prevent carcinogenesis by hepatitis C and hepatitis B, as well as the use of a compound of formula (I) for the manufacture of a medicament useful for the treatment of cancer, viral diseases, Crohn's Disease, and immunologic disorders in a mammal, such as a human.
- medical therapy e.g., for use as an anti-cancer agent, treatment for bacterial diseases, treatment for viral diseases, such as hepatitis C and hepatitis B, Crohn's Disease, and as therapeutic agents for treating immunologic disease.
- compounds of formula (I) will prevent carcinogenesis by hepatitis C and hepatitis B, as well
- the present invention provides a method for treating a viral infection in a mammal by administering a TLR agonist compound of formula (I).
- the viral infection can be caused by an RNA virus, a product of the RNA virus that acts as a TLR agonist and/or a DNA virus.
- a specific DNA virus for treatment is the Hepatitis B virus.
- the present invention provides a method for treating cancer by administering an effective amount of a TLR agonist compound of formula (I).
- the cancer can be an interferon sensitive cancer, such as, for example, a leukemia, a lymphoma, a myeloma, a melanoma, or a renal cancer.
- the present invention provides a method of treating an autoimmune disease by administering a therapeutically effective amount of a TLR agonist compound of formula (I) or a pharmaceutically acceptable salt of such a compound.
- a specific autoimmune disease is Multiple Sclerosis, lupus, rheumatoid arthritis and the like.
- the present invention provides a method of treating Crohn's Disease by administering a TLR agonist compound of formula (I).
- the TLR agonists can be a homofunctional TLR agonist polymer and can consist of a TLR-7 agonist or a TLR-8 agonist.
- the TLR7 agonist can be a 7-thia-8-oxoguanosinyl (TOG) moiety, a 7-deazaguanosinyl (7DG) moiety, a resiquimod moiety, or an imiquimod moiety.
- the TLR8 agonist can be a resiquimod moiety.
- the TLR agonist is a heterofunctional TLR agonist polymer.
- the heterofunctional TLR agonist polymer can include a TLR-7 agonist and a TLR-8 agonist or a TLR-9 agonist or all three agonists.
- the heterofunctional TLR agonist polymer can include a TLR-8 agonist and a TLR-9 agonist.
- the invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula (I) or salts thereof.
- FIG. 1 is a graphic illustration of the absorption chromophore (at ⁇ 350 nm) of a compound of formula I (OVA/IV150 Conjugate).
- FIG. 2 is a graphic illustration of the stimulation of bone marrow derived dendritic cells (BMDC).
- FIG. 3 illustrates the conjugation of a TLR7 agonist, UC-1V150, to mouse serum albumin (MSA). The success of conjugation is indicated by UV spectroscopy.
- the UC-1V150 to MSA ratio is approximately 5:1
- FIGS. 4A and B illustrate that the UC-1V150 and MSA conjugates activate both murine bone marrow-derived macrophages ( 4 A) and human peripheral blood mononuclear cells ( 4 B).
- Cells were incubated with various concentrations of the compound from 0.5 nM to 10 ⁇ M in BMDM or from 0.1 to 10 ⁇ M in PBMC. Culture supernatants were harvested after 24 h and cytokine levels were analyzed by Luminex.
- FIGS. 5A , 5 B, 5 C, and 5 D illustrate the increased potency and duration of effect of UC-1V150/MSA.
- C57BL/6 mice were injected (i.v.) with (A) 0.1 micromole of SM-360320, a TLR7 ligand, or (B) equivalent amount of a TLR7 agonist UC-1V150 (aldehyde-modified SM-360320) or UC-1V150/MSA to 500 ⁇ g MSA per mouse.
- Serum samples were collected at the indicated time points and cytokine levels were analyzed by Luminex.
- MSA mouse serum albumin.
- the effect from the original TLR7 ligand, SM-360320 lasted for only 2 hours whereas UC-1V150/MSA has extended the effect to at least 6 hours.
- FIG. 6 illustrates the effects of UC-1V150 conjugated with inactivated SIV ( 6 A) or with OVA in combination with ODN ( 6 B).
- Myeloid BMDC were incubated for 24 hr with various conditions at 0.1 ⁇ g/ml as indicated.
- IL-12 levels in the cell supernatant were measured by ELISA.
- FIGS. 7A and 7B illustrates an increased potency of UC-1V150/MSA.
- C57BL/6 mice were i.v. injected with 380 mmole of SM-360320 or UC-1V150, or 500 ⁇ g of UC-1V150/MSA (equivalent to 3.8 mmole UC-1V150) per mouse.
- Serum samples were collected after 2 h and cytokine levels were analyzed by Luminex. To achieve the similar effect, at least 100-fold higher concentration of either UC-1V150 or SM-360320 was required as compared to that of UC-1V150/MSA.
- FIG. 8 is an illustration of the uv spectrum of a double-conjugate, (OVA/IV150/1043).
- FIG. 9 is an illustration of the induction of IL-12 in BMDC using OVA/ODN/IV150 conjugates.
- FIG. 10 illustrates direct conjugation of SIV Particles to the IA compound IV150.
- FIG. 11 illustrates the ability to prepare compounds of the invention with virus particles attached to a compound having formula IA and the TLR agonist activity of the compounds.
- FIG. 12 illustrates the molecular areas of specificity for antibodies raised against the conjugates containing a linker and a TLR ligand.
- FIGS. 13A and 13B illustrate the distinction between the four substances applied to the respective lanes on a gel in a Western plot analysis.
- the gel membrane was probed with anti-ovalbumin (anti-OVA) antibody and all lanes gave a positive band, indicating that OVA was detected in all lanes, as expected.
- the gel membrane was probed with the selective antibody raised to the TLR ligand portion of the conjugate, and therefore only lane 4 was positive, confirming the specificity of the antibody for the TLR ligand.
- auxiliary groups include side chains that increase solubility, such as, for example, groups containing morpholino, piperidino, pyrrolidino, or piperazino rings and the like; amino acids, polymers of amino acids (proteins or peptides), e.g., dipeptides or tripeptides, and the like; carbohydrates (polysaccharides), nucleotides such as, for example, PNA, RNA and DNA, and the like; polymers of organic materials, such as, for example, polyethylene glycol, poly-lactide and the like; monomeric and polymeric lipids; insoluble organic nanoparticles; non-toxic body substances such as, for example, cells, lipids, vitamins, co-factors, antigens such as, for example microbes, such as, for example, viruses, bacteria, fungi, and the like.
- the antigens can include inactivated whole organisms, or sub-components thereof and the like.
- the compounds of the invention can be prepared using compounds having formula (IA):
- X is a group that can react to form a bond to the linking group or can react to form a bond to the auxiliary group.
- a specific group of compounds having formula (IA) are disclosed in U.S. Pat. No. 6,329,381.
- halo is fluoro, chloro, bromo, or iodo.
- Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
- Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
- Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C 1 -C 4 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
- Processes for preparing compounds of formula I or for preparing intermediates useful for preparing compounds of formula I are provided as further embodiments of the invention.
- Intermediates useful for preparing compounds of formula I are also provided as further embodiments of the invention.
- salts may be appropriate.
- acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
- Acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
- a sufficiently basic compound such as an amine
- a suitable acid affording a physiologically acceptable anion.
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
- Alkyl includes straight or branched C 1-10 alkyl groups, e.g., methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, 1-methylpropyl, 3-methylbutyl, hexyl, and the like.
- Lower alkyl includes straight or branched C 1-6 alkyl groups, e.g., methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and the like.
- C 1-6 alkyl groups e.g., methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and the like.
- alkylene refers to a divalent straight or branched hydrocarbon chain (e.g. ethylene —CH 2 —CH 2 —).
- Cycloalkyl includes groups such as, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, and alkyl-substituted C 3-7 cycloalkyl group, preferably straight or branched C 1-6 alkyl group such as methyl, ethyl, propyl, butyl or pentyl, and C 5-7 cycloalkyl group such as, cyclopentyl or cyclohexyl, and the like.
- Lower alkoxy includes C 1-6 alkoxy groups, such as methoxy, ethoxy or propoxy, and the like.
- Lower alkanoyl includes C 1-6 alkanoyl groups, such as formyl, acetyl, propanoyl, butanoyl, pentanoyl or hexanoyl, and the like.
- C 7-11 aroyl includes groups such as benzoyl or naphthoyl;
- Lower alkoxycarbonyl includes C 2-7 alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, and the like.
- Lower alkylamino group means amino group substituted by C 1-6 alkyl group, such as, methylamino, ethylamino, propylamino, butylamino, and the like.
- Di(lower alkyl)amino group means amino group substituted by the same or different and C 1-6 alkyl group (e.g. dimethylamino, diethylamino, ethylmethylamino).
- Lower alkylcarbamoyl group means carbamoyl group substituted by C 1-6 alkyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl).
- Di(lower alkyl)carbamoyl group means carbamoyl group substituted by the same or different and C 1-6 alkyl group (e.g. dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl).
- Halogen atom means halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom.
- Aryl refers to a C 6-10 monocyclic or fused cyclic aryl group, such as phenyl, indenyl, or naphthyl, and the like.
- Heterocyclic refers to monocyclic saturated heterocyclic groups, or unsaturated monocyclic or fused heterocyclic group containing at least one heteroatom, e.g., 0-3 nitrogen atoms (—NR d —), 0-1 oxygen atom (—O—), and 0-1 sulfur atom (—S—).
- saturated monocyclic heterocyclic group includes 5 or 6 membered saturated heterocyclic group, such as tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperidyl, piperazinyl or pyrazolidinyl.
- Non-limiting examples of unsaturated monocyclic heterocyclic group includes 5 or 6 membered unsaturated heterocyclic group, such as furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, pyridyl or pyrimidinyl.
- Non-limiting examples of unsaturated fused heterocyclic groups includes unsaturated bicyclic heterocyclic group, such as indolyl, isoindolyl, quinolyl, benzothizolyl, chromanyl, benzofuranyl, and the like.
- heterocyclic rings include 5 or 6 membered saturated heterocyclic rings, such as 1-pyrrolidinyl, 4-morpholinyl, 1-piperidyl, 1-piperazinyl or 1-pyrazolidinyl, 5 or 6 membered unsaturated heterocyclic rings such as 1-imidazolyl, and the like.
- the alkyl, aryl, heterocyclic groups of R 1 can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include lower alkyl; cycloalkyl, hydroxyl; hydroxy C 1-6 alkylene, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl; lower alkoxy; C 1-6 alkoxy C 1-6 alkyl, such as 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl; amino; alkylamino; dialkyl amino; cyano; nitro; acyl; carboxyl; lower alkoxycarbonyl; halogen; mercapto; C 1-6 alkylthio, such as, methylthio, ethylthio, propylthio or butylthio; substituted C 1-6 alkylthio, such as methoxyethylthio, methylthioethylthio, hydroxyeth
- the alkyl, aryl, heterocyclic groups of R 2 can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include hydroxyl; C 1-6 alkoxy, such as methoxy, ethoxy or propoxy; carboxyl; C 2-7 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl) and halogen.
- the alkyl, aryl, heterocyclic groups of R c can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include C 3-6 cycloalkyl; hydroxyl; C 1-6 alkoxy; amino; cyano; aryl; substituted aryl, such as 4-hydroxyphenyl, 4-methoxyphenyl, 4-chlorophenyl or 3,4-dichlorophenyl; nitro and halogen.
- the heterocyclic ring formed together with R c and R 1 and the nitrogen atom to which they are attached can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include C 1-6 alkyl; hydroxy C 1-6 alkylene; C 1-6 alkoxy C 1-6 alkylene; hydroxyl; C 1-6 alkoxy; and cyano.
- amino acid as used herein, comprises the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, H is, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well as unnatural amino acids (e.g.
- the term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g.
- acetyl or benzyloxycarbonyl as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (C 1 -C 6 )alkyl, phenyl or benzyl ester or amide; or as an -methylbenzyl amide).
- suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, T. W. Greene, Protecting Groups In Organic Synthesis ; Wiley: New York, 1981, and references cited therein).
- An amino acid can be linked to the remainder of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of cysteine.
- TLR toll-like receptor
- PAMPs pathogen associated molecular patterns
- TLR agonist refers to a molecule that binds to a TLR and antagonizes the receptor.
- Synthetic TLR agonists are chemical compounds that are designed to bind to a TLR and activate the receptor.
- Exemplary novel TLR agonists provided herein include “TLR-7 agonist” “TLR-8 agonist” and “TLR-9 agonist.”
- nucleic acid refers to DNA, RNA, single-stranded, double-stranded, or more highly aggregated hybridization motifs, and any chemical modifications thereof. Modifications include, but are not limited to, those providing chemical groups that incorporate additional charge, polarizability, hydrogen bonding, electrostatic interaction, and fluxionality to the nucleic acid ligand bases or to the nucleic acid ligand as a whole.
- Such modifications include, but are not limited to, peptide nucleic acids (PNAs), phosphodiester group modifications (e.g., phosphorothioates, methylphosphonates), 2′-position sugar modifications, 5-position pyrimidine modifications, 7-position purine modifications, 8-position purine modifications, 9-position purine modifications, modifications at exocyclic amines, substitution of 4-thiouridine, substitution of 5-bromo or 5-iodo-uracil; backbone modifications, methylations, unusual base-pairing combinations such as the isobases, isocytidine and isoguanidine and the like.
- Nucleic acids can also include non-natural bases, such as, for example, nitroindole. Modifications can also include 3′ and 5′ modifications such as capping with a BHQ, a fluorophore or another moiety.
- a specific value for X 1 is a sulfur atom, an oxygen atom or —NR c —.
- Another specific X 1 is a sulfur atom.
- Another specific X 1 is an oxygen atom.
- Another specific X 1 is —NR c —.
- Another specific X 1 is —NH—.
- R c is hydrogen, C 1-4 alkyl or substituted C 1-4 alkyl.
- R 1 and R c taken together is when they form a heterocyclic ring or a substituted heterocyclic ring.
- R 1 and R c taken together is substituted or unsubstituted morpholino, piperidino, pyrrolidino, or piperazino ring
- R 1 is hydrogen, C 1-4 alkyl, or substituted C 1-4 alkyl.
- R 1 is 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 2-ethoxyethyl, methylthiomethyl, 2-methylthioethyl, 3-methylthiopropyl, 2-fluoroethyl, 3-fluoropropyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, benzyl, phenethyl, 4-pyridylmethyl, cyclohexylmethyl, 2-thienylmethyl, 4-methoxyphenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl, or 4-chlorophen
- R 1 is hydrogen, CH 3 —, CH 3 —CH 2 —, CH 3 CH 2 CH 2 —, hydroxyC 1-4 alkylene, or C 1-4 alkoxyC 1-4 alkylene.
- R 1 Another specific value for R 1 is hydrogen, CH 3 —, CH 3 —CH 2 —, CH 3 —O—CH 2 CH 2 — or CH 3 —CH 2 -O—CH 2 CH 2 —.
- R 2 is hydrogen, halogen, or C 1-4 alkyl.
- R 2 is hydrogen, chloro, bromo, CH 3 —, or CH 3 —CH 2 —.
- substituents for substitution on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 allylene, C 3-6 cycloalkyl, amino, cyano, halogen, or aryl.
- a specific value for X 2 is a bond or a chain having up to about 24 atoms; wherein the atoms are selected from the group consisting of carbon, nitrogen, sulfur, non-peroxide oxygen, and phosphorous.
- X 2 is a bond or a chain having from about 4 to about 12 atoms.
- X 2 is a bond or a chain having from about 6 to about 9 atoms.
- a specific auxiliary group is an amino acid, a carbohydrate, a peptide, an antigen, a nucleic acid, a body substance, or a microbe.
- a specific peptide has from 2 to about 20 amino acid residues.
- Another specific peptide has from 10 to about 20 amino acid residues.
- a specific auxiliary group is a carbohydrate.
- a specific nucleic acid is DNA, RNA or PNA.
- a specific body substance is a cell, lipid, vitamin, or co-factor.
- Another specific body substance is a cell or lipid.
- a specific antigen is a microbe.
- a specific microbe is a virus, bacteria, or fungi.
- Another specific microbe is a virus or a bacteria.
- Bacillus anthracis anthrax
- Listeria monocytogenes Listeria monocytogenes
- Francisella tularensis Listeria monocytogenes
- Salmonella Salmonella
- Salmonella are typhimurium or enteritidis.
- RNA viruses RNA viruses, a product of the RNA virus, or a DNA virus.
- a specific DNA virus is the Hepatitis B virus.
- IA is as disclosed herein; L is absent or is a linking group; and each A 1 group independently represents an auxiliary group.
- the viral infection is caused by a coronavirus that causes Severe Acute Respiratory Syndrome (SARS), a Hepatitis B virus, or a Hepatitis C Virus.
- SARS Severe Acute Respiratory Syndrome
- Hepatitis B virus a Hepatitis B virus
- Hepatitis C Virus a Hepatitis C virus
- the viral infection is caused by a coronavirus that causes Severe Acute Respiratory Syndrome (SARS), a Hepatitis B virus, or a Hepatitis C Virus.
- SARS Severe Acute Respiratory Syndrome
- Hepatitis B virus a Hepatitis B virus
- Hepatitis C Virus a coronavirus that causes Severe Acute Respiratory Syndrome
- Specific cancers that can be treated include melanoma, superficial bladder cancer, actinic keratoses, intraepithelial neoplasia, and basal cell skin carcinoma, squamous, and the like.
- the method of the invention includes treatment for a precancerous condition such as, for example, actinic keratoses or intraepithelial neoplasia, familial polyposis (polyps), cervical dysplasia, cervical cancers, superficial bladder cancer, and any other cancers associated with infection (e.g., lymphoma Karposi's sarcoma, or leukemia); and the like.
- Non limiting examples of the pathological conditions or symptoms that can be treated include viral diseases, cancer, inflammatory diseases of the gastrointestinal tract, brain, skin, joints, and other tissues.
- the auxiliary groups are believed to enhance the drug activity of the pharmacophore (compounds of formula (I)) by (a) helping to direct the pharmacophore to the receptor within the endosomes of target cells; (b) by enhancing signal transduction induced by the pharmacophore, by cross-linking the receptor; and/or (c) the pharmacophore can enhance the response to the auxiliary group (e.g., immune response).
- the auxiliary groups should form generally stable bonds with the pharmacophore, and do not act as prodrugs.
- IMPDH inosine monophosphate dehydrogenase
- an IMPDH inhibitor refers to an inhibitor of the enzyme inosine monophosphate dehydrogenase.
- IMPDH inhibitors are used clinically: ribavirin, mizoribine, and mycophenolate mofetil.
- Ribavirin and mizoribine are prodrugs that are phosphorylated intracellularly to produce IMP analogs (Goldstein et al., Cuff Med Chem, 6:519-536 (1999)). Viramidine is a prodrug of Ribavirin. Mycophenolate mofetil is immunosuppressive, and has gastrointestinal irritative properties that may be attributable to its enterohepatic recirculation (Papageorgiou C, Mini Rev Med. Chem., 1:71-77 (2001)). Mizoribine aglycone, a prodrug, is used as an IMPDH inhibitor. Other non-limiting examples IMPDH inhibitors, including prodrugs of mizoribine and mizoribine aglycone are known and are disclosed in published U.S. Patent application No. 20050004144.
- salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
- salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
- a sufficiently basic compound such as an amine
- a suitable acid affording a physiologically acceptable anion.
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
- the compounds (conjugates) of the invention can be prepared using standard synthetic methods known in the art.
- a general ester synthesis is illustrated below:
- the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
- the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
- a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
- the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- Such compositions and preparations should contain at least 0.1% of active compound.
- the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
- the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
- the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
- a liquid carrier such as a vegetable oil or a polyethylene glycol.
- any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound may be incorporated into sustained-release preparations and devices.
- the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
- Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
- the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
- the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
- the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
- Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
- Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
- Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
- the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
- Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
- Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
- Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
- the concentration of the compound(s) of formula I in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
- concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
- the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
- a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
- the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
- the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
- TLR agonist The ability of a compound of the invention to act as a TLR agonist may be determined using pharmacological models which are well known to the art, including the procedures disclosed by Lee et al.; PNAS, 100 p6646-6651, 2003.
- Sodium salt of 2-methoxyethanol is generated by dissolving sodium metal (81 mg) in 2-methoxyethanol (30 mL) with heat. To this solution is added the product of example 2 (1.0 g) dissolved in methoxyethanol (300 mL, with heat). The reaction mixture is heated for 8 h at 115° C. bath temperature, concentrated in vacuo to near dryness and the residue partitioned between ethyl acetate and water. Flash silica gel chromatography of the organic layer using 5% methanol in dichloromethane gave 763 mg product. NMR is consistent with structure assignment.
- This reducing agent used to convert the nitrile to the aldehyde function is prepared essentially as described in Bull. Korean Chem. Soc . (2002), 23(12), 1697-1698. A 0.5 M solution in dry THF is prepared.
- example 5 The product of example 5 (100 mg) is dissolved in dry THF (3 mL) and cooled to 0° C. under argon.
- the reagent generated in example 6 (0.72 mL) is added to the reaction flask and the mixture is stirred at 0-5° C. for 1 h and then quenched by addition of 3 M HCl.
- the mixture is then extracted with ethyl acetate and then dichloromethane and concentrated in vacuo to yield 85 mg.
- NMR is consistent with structure assignment.
- Example 7 The product of example 7 (800 mg) is combined with sodium iodide (504 mg) and acetonitrile (40 mL), and then chlorotrimethylsilane (0.5 mL) is slowly added. The mixture is heated at 70° C. for 3.5 h, cooled and filtered. The solid product is washed with water, then ether to yield 406 mg. NMR, UV, MS are consistent with structure assignment. This material is suitable for conjugation reactions between linkers and auxiliary groups.
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Cited By (39)
Publication number | Priority date | Publication date | Assignee | Title |
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US20060052403A1 (en) * | 2002-09-27 | 2006-03-09 | Yoshiaki Isobe | Novel adenine compound and use thereof |
US20070190071A1 (en) * | 2004-03-26 | 2007-08-16 | Dainippon Sumitomo Pharma Co., Ltd. | 9-Substituted 8-oxoadenine compound |
US20090047249A1 (en) * | 2007-06-29 | 2009-02-19 | Micheal Graupe | Modulators of toll-like receptor 7 |
US20090118263A1 (en) * | 2005-09-22 | 2009-05-07 | Dainippon Sumitomo Pharma Co., Ltd. | Novel Adenine Compound |
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US20090202626A1 (en) * | 2008-02-07 | 2009-08-13 | Carson Dennis A | Treatment of bladder diseases with a tlr7 activator |
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US9045472B2 (en) | 2010-12-16 | 2015-06-02 | Astrazeneca Ab | Imidazoquinoline compounds |
US9066978B2 (en) | 2010-05-26 | 2015-06-30 | Selecta Biosciences, Inc. | Dose selection of adjuvanted synthetic nanocarriers |
US9066940B2 (en) | 2009-02-06 | 2015-06-30 | Telormedix, Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
WO2016007765A1 (fr) | 2014-07-11 | 2016-01-14 | Gilead Sciences, Inc. | Modulateurs de récepteurs de type toll pour le traitement du vih |
US9359360B2 (en) | 2005-08-22 | 2016-06-07 | The Regents Of The University Of California | TLR agonists |
US9428512B2 (en) | 2012-11-20 | 2016-08-30 | Glaxosmithkline Llc | Compounds |
US9540383B2 (en) | 2012-11-20 | 2017-01-10 | Glaxosmithkline Llc | Pyrrolopyrimidines as therapeutic agents for the treatment of diseases |
US9550785B2 (en) | 2012-11-20 | 2017-01-24 | Glaxosmithkline Llc | Pyrrolopyrimidines as therapeutic agents for the treatment of diseases |
US9555036B2 (en) | 2012-08-24 | 2017-01-31 | Glaxosmithkline Llc | Pyrazolopyrimidine compounds |
US9994443B2 (en) | 2010-11-05 | 2018-06-12 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
US10112946B2 (en) | 2011-07-22 | 2018-10-30 | Glaxosmithkline Llc | Composition |
US10202384B2 (en) | 2014-09-16 | 2019-02-12 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
US11110091B2 (en) | 2008-12-09 | 2021-09-07 | Gilead Sciences, Inc. | Modulators of toll-like receptors |
US11697851B2 (en) | 2016-05-24 | 2023-07-11 | The Regents Of The University Of California | Early ovarian cancer detection diagnostic test based on mRNA isoforms |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009034386A1 (fr) * | 2007-09-13 | 2009-03-19 | Astrazeneca Ab | Dérivés de l'adénine et de la 8-aza-adénine et leurs utilisations |
CA2750499A1 (fr) * | 2009-01-30 | 2010-08-05 | Idera Pharmaceuticals, Inc. | Nouveaux agonistes synthetiques de tlr9 |
US9050319B2 (en) | 2010-04-30 | 2015-06-09 | Telormedix, Sa | Phospholipid drug analogs |
EP2563401A1 (fr) * | 2010-04-30 | 2013-03-06 | Telormedix SA | Procédés d'induction d'une réponse immunitaire |
WO2011134668A1 (fr) * | 2010-04-30 | 2011-11-03 | Telormedix Sa | Analogues de médicaments phospholipidiques |
WO2012038058A1 (fr) | 2010-09-21 | 2012-03-29 | Telormedix Sa | Traitement d'états par des modulateurs de récepteurs de type toll |
AR085633A1 (es) * | 2011-03-08 | 2013-10-16 | Baylor Res Inst | Coadyuvantes basados en anticuerpos que son dirigidos directamente a las celulas presentadoras en antigenos |
WO2014052828A1 (fr) | 2012-09-27 | 2014-04-03 | The Regents Of The University Of California | Compositions et procédés pour la modulation de tlr4 |
CN105339346B (zh) * | 2013-02-25 | 2017-03-08 | 斯克里普斯研究学院 | Neoseptin:小分子佐剂 |
ES2944541T3 (es) * | 2014-08-06 | 2023-06-22 | Scripps Research Inst | Adyuvantes de molécula pequeña independientes de TLR |
UA117634C2 (uk) * | 2014-08-15 | 2018-08-27 | Чиа Тай Тяньцін Фармасьютикал Ґруп Ко., Лтд. | Піролопіримідинові сполуки, що використовуються як агоніст tlr7 |
BR112018008880B1 (pt) | 2015-11-05 | 2023-01-17 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | 7-(tiazol-5-il) pirrolopirimidina, seu uso, e composição farmacêutica |
CN107043380A (zh) | 2016-02-05 | 2017-08-15 | 正大天晴药业集团股份有限公司 | 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e、制备方法和用途 |
CN107043379A (zh) | 2016-02-05 | 2017-08-15 | 正大天晴药业集团股份有限公司 | 一种tlr7激动剂的晶型a、其制备方法和医药用途 |
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US20180164221A1 (en) | 2016-12-07 | 2018-06-14 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
JP2020511501A (ja) | 2016-12-13 | 2020-04-16 | ボルト バイオセラピューティクス、インコーポレーテッド | 抗体アジュバント複合体 |
EP3554344A1 (fr) | 2016-12-14 | 2019-10-23 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal avec un modulateur tlr |
PT3609540T (pt) | 2017-04-14 | 2023-03-01 | Bolt Biotherapeutics Inc | Método de síntese de imunoconjugado |
JP2021035910A (ja) * | 2017-11-01 | 2021-03-04 | 大日本住友製薬株式会社 | 置換プリン化合物 |
WO2019196918A1 (fr) * | 2018-04-13 | 2019-10-17 | 罗欣药业(上海)有限公司 | Composé d'hétérocyclo-pyrimidine à cinq chaînons, composition pharmaceutique et utilisation associée |
WO2019222676A1 (fr) | 2018-05-17 | 2019-11-21 | Bolt Biotherapeutics, Inc. | Immunoconjugués |
CN109608462B (zh) * | 2018-12-15 | 2021-11-23 | 华南理工大学 | 一种7-烃基-9-烷氧/硫基嘌呤-8-酮类化合物及其合成方法与在药物中的应用 |
WO2020190725A1 (fr) | 2019-03-15 | 2020-09-24 | Bolt Biotherapeutics, Inc. | Immunoconjugués ciblant le her2 |
WO2021046347A1 (fr) | 2019-09-04 | 2021-03-11 | Bolt Biotherapeutics, Inc. | Procédé de synthèse d'immunoconjugué |
WO2021174024A1 (fr) | 2020-02-28 | 2021-09-02 | First Wave Bio, Inc. | Méthodes de traitement de la colite auto-immune iatrogène |
AU2021300632A1 (en) | 2020-07-02 | 2023-02-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Method of achieving HIV viral remission using long-acting antiretroviral agents |
CN114315861A (zh) * | 2020-09-27 | 2022-04-12 | 上海维申医药有限公司 | 大环tlr7激动剂、其制备方法、药物组合物及其用途 |
CA3196221A1 (fr) | 2020-10-21 | 2022-04-28 | Univerza V Ljubljani | Agonistes conjugues de tlr7 et de nod2 |
Citations (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4689338A (en) * | 1983-11-18 | 1987-08-25 | Riker Laboratories, Inc. | 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use |
US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
US4938949A (en) * | 1988-09-12 | 1990-07-03 | University Of New York | Treatment of damaged bone marrow and dosage units therefor |
US5037986A (en) * | 1989-03-23 | 1991-08-06 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo[4,5-c]quinolin-4-amines |
US5175296A (en) * | 1991-03-01 | 1992-12-29 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]quinolin-4-amines and processes for their preparation |
US5238944A (en) * | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
US5352784A (en) * | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US5367076A (en) * | 1990-10-05 | 1994-11-22 | Minnesota Mining And Manufacturing Company | Process for imidazo[4,5-C]quinolin-4-amines |
US5395937A (en) * | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
US5624677A (en) * | 1995-06-13 | 1997-04-29 | Pentech Pharmaceuticals, Inc. | Controlled release of drugs delivered by sublingual or buccal administration |
US5627281A (en) * | 1993-07-15 | 1997-05-06 | Minnesota Mining And Manufacturing Company | Intermediate compounds of fused cycloalkylimidazopyridines |
US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
US5736553A (en) * | 1988-12-15 | 1998-04-07 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo 4,5-C!quinolin-4-amine |
US5741908A (en) * | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
US6038505A (en) * | 1996-09-12 | 2000-03-14 | Siemens Aktiengesellschaft | Method of controlling the drive train of a motor vehicle, and integrated drive train control system |
US6039969A (en) * | 1996-10-25 | 2000-03-21 | 3M Innovative Properties Company | Immune response modifier compounds for treatment of TH2 mediated and related diseases |
US6083505A (en) * | 1992-04-16 | 2000-07-04 | 3M Innovative Properties Company | 1H-imidazo[4,5-C]quinolin-4-amines as vaccine adjuvants |
US6245776B1 (en) * | 1999-01-08 | 2001-06-12 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
US6329381B1 (en) * | 1997-11-28 | 2001-12-11 | Sumitomo Pharmaceuticals Company, Limited | Heterocyclic compounds |
US6333331B1 (en) * | 1994-08-01 | 2001-12-25 | The United States Of America As Represented By The Department Of Health And Human Services | Substituted O6-benzylguanines |
US6486168B1 (en) * | 1999-01-08 | 2002-11-26 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
US20020193595A1 (en) * | 2001-04-09 | 2002-12-19 | Daniel Chu | Novel guanidino compounds |
US6552192B1 (en) * | 1999-01-26 | 2003-04-22 | Ustau Experimentalni Botaniky Av-Cr | Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof |
US20030187261A1 (en) * | 2000-01-07 | 2003-10-02 | Libor Havlicek | Purine derivatives, process for their preparation and use thereof |
US20040023211A1 (en) * | 2000-09-15 | 2004-02-05 | Kees Groen | System and method for optimizing drug theraphy for the treatment of diseases |
US6706728B2 (en) * | 1999-01-08 | 2004-03-16 | 3M Innovative Properties Company | Systems and methods for treating a mucosal surface |
US6734187B1 (en) * | 1997-11-12 | 2004-05-11 | Mitsubishi Chemical Corporation | Purine derivatives and medicaments comprising the same as active ingredient |
US6733764B2 (en) * | 2000-06-14 | 2004-05-11 | Alain Martin | Immunostimulator anti-cancer compounds and methods for their use in the treatment of cancer |
US20040132748A1 (en) * | 2001-04-17 | 2004-07-08 | Yoshiaki Isobe | Novel adenne derivatives |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
US20050004144A1 (en) * | 2003-04-14 | 2005-01-06 | Regents Of The University Of California | Combined use of IMPDH inhibitors with toll-like receptor agonists |
US20050049263A1 (en) * | 2001-10-30 | 2005-03-03 | Kasibhatla Srinivas Rao | Purine analogs having hsp90-inhibiting activity |
US20050054590A1 (en) * | 2003-09-05 | 2005-03-10 | Averett Devron R. | Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus |
US20050059613A1 (en) * | 2003-07-08 | 2005-03-17 | Bahram Memarzadeh | Compositions and methods for the enhanced uptake of therapeutic agents through the bladder epithelium |
US20050266067A1 (en) * | 2004-03-02 | 2005-12-01 | Shiladitya Sengupta | Nanocell drug delivery system |
US7001609B1 (en) * | 1998-10-02 | 2006-02-21 | Regents Of The University Of Minnesota | Mucosal originated drug delivery systems and animal applications |
US20060052403A1 (en) * | 2002-09-27 | 2006-03-09 | Yoshiaki Isobe | Novel adenine compound and use thereof |
US20060110746A1 (en) * | 2004-11-19 | 2006-05-25 | Institut Gustave Roussy | Treatment of cancer using TLR3 agonists |
US20070087009A1 (en) * | 2003-12-19 | 2007-04-19 | Sanofi Pasteur | Immunostimulant composition comprising at least one toll-like receptor 7 or toll-like receptor 8 agonist and a toll-like receptor 4 agonist |
US20070100146A1 (en) * | 2005-11-03 | 2007-05-03 | Trevor Dzwiniel | Process for the preparation of imidazo[4,5-c]-quinolin-4-amines |
US20070161582A1 (en) * | 2003-08-08 | 2007-07-12 | Dusan Mijikovic | Pharmaceutical compositions and methods for metabolic modulation |
US20070173483A1 (en) * | 2002-10-30 | 2007-07-26 | Conforma Therapeutics Corporation | Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors |
US20070292418A1 (en) * | 2005-04-26 | 2007-12-20 | Eisai Co., Ltd. | Compositions and methods for immunotherapy |
US20080214580A1 (en) * | 2006-10-04 | 2008-09-04 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
US20090047249A1 (en) * | 2007-06-29 | 2009-02-19 | Micheal Graupe | Modulators of toll-like receptor 7 |
US20090069289A1 (en) * | 2006-10-04 | 2009-03-12 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
US20090105212A1 (en) * | 2005-09-22 | 2009-04-23 | Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan | Novel adenine compound |
US20090118263A1 (en) * | 2005-09-22 | 2009-05-07 | Dainippon Sumitomo Pharma Co., Ltd. | Novel Adenine Compound |
US20090202484A1 (en) * | 2006-07-07 | 2009-08-13 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
US20090202626A1 (en) * | 2008-02-07 | 2009-08-13 | Carson Dennis A | Treatment of bladder diseases with a tlr7 activator |
US20100210598A1 (en) * | 2009-02-11 | 2010-08-19 | Regents Of The University Of California, San Diego | Toll-like receptor modulators and treatment of diseases |
US20110319442A1 (en) * | 2009-02-06 | 2011-12-29 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
US20120148660A1 (en) * | 2007-02-07 | 2012-06-14 | Regents Of The University Of California, San Diego Ucsd Technology Transfer Office | Conjugates of synthetic tlr agonists and uses therefor |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4559157A (en) | 1983-04-21 | 1985-12-17 | Creative Products Resource Associates, Ltd. | Cosmetic applicator useful for skin moisturizing |
LU84979A1 (fr) | 1983-08-30 | 1985-04-24 | Oreal | Composition cosmetique ou pharmaceutique sous forme aqueuse ou anhydre dont la phase grasse contient un polyether oligomere et polyethers oligomeres nouveaux |
CA1271477A (fr) | 1983-11-18 | 1990-07-10 | John F. Gerster | 1h-imidazo[4,5-c]quinoleine-4-amines |
US4820508A (en) | 1987-06-23 | 1989-04-11 | Neutrogena Corporation | Skin protective composition |
US4992478A (en) | 1988-04-04 | 1991-02-12 | Warner-Lambert Company | Antiinflammatory skin moisturizing composition and method of preparing same |
NZ232740A (en) | 1989-04-20 | 1992-06-25 | Riker Laboratories Inc | Solution for parenteral administration comprising a 1h-imidazo(4,5-c) quinolin-4-amine derivative, an acid and a tonicity adjuster |
DE19505168A1 (de) | 1995-02-16 | 1996-08-22 | Boehringer Mannheim Gmbh | Spezifische Lipidkonjugate von Nucleosid-Diphosphonaten und deren Verwendung als Arzneimittel |
IL129497A0 (en) | 1996-10-25 | 2000-02-29 | Nexstar Pharmaceuticals Inc | Vascular endothelial growth factor (vegf) nucleic acid ligand complexes |
JPH10298181A (ja) | 1997-04-25 | 1998-11-10 | Sumitomo Pharmaceut Co Ltd | タイプ2ヘルパーt細胞選択的免疫応答抑制剤 |
JP4189048B2 (ja) * | 1997-12-26 | 2008-12-03 | 大日本住友製薬株式会社 | 複素環化合物 |
AU2441701A (en) | 1999-12-17 | 2001-06-25 | Ariad Pharmaceuticals, Inc. | Purine derivatives |
IL150060A0 (en) | 1999-12-17 | 2002-12-01 | Ariad Pharma Inc | Novel purines |
GB0023008D0 (en) | 2000-09-20 | 2000-11-01 | Glaxo Group Ltd | Improvements in vaccination |
US20020127224A1 (en) | 2001-03-02 | 2002-09-12 | James Chen | Use of photoluminescent nanoparticles for photodynamic therapy |
EP2415486B1 (fr) | 2001-05-18 | 2017-02-22 | Sirna Therapeutics, Inc. | Conjugués et compositions pour la fourniture cellulaire |
CA2451244C (fr) | 2001-06-29 | 2012-01-17 | Cv Therapeutics, Inc. | Derives puriniques utilises comme antagonistes du recepteur de l'adenosine a2b |
GB0206461D0 (en) | 2002-03-19 | 2002-05-01 | Glaxo Group Ltd | Improvements in vaccination |
EP1545597B1 (fr) * | 2002-08-15 | 2010-11-17 | 3M Innovative Properties Company | Compositions immunostimulantes et procedes de stimulation d'une reponse immune |
JP2004137157A (ja) | 2002-10-16 | 2004-05-13 | Sumitomo Pharmaceut Co Ltd | 新規アデニン誘導体を有効成分として含有する医薬 |
JP2005089334A (ja) * | 2003-09-12 | 2005-04-07 | Sumitomo Pharmaceut Co Ltd | 8−ヒドロキシアデニン化合物 |
US20070225303A1 (en) | 2004-03-26 | 2007-09-27 | Haruhisa Ogita | 8-Oxoadenine Compound |
RU2397171C2 (ru) | 2004-03-26 | 2010-08-20 | ДАЙНИППОН СУМИТОМО ФАРМА Ко., ЛТД. | 9-замещенное производное 8-оксоаденина и лекарственное средство |
DK1819230T3 (da) | 2004-12-07 | 2012-08-20 | Univ Miami | Erytrocytafledte mikropartikler som hæmostatiske midler til kontrol af hæmoragi og til behandling af blødningsforstyrrelser |
DK1879893T3 (da) | 2005-03-21 | 2010-09-13 | Ferrer Int | Fremgangsmåde til fremstilling af 1-substituerede 1H-imidazo[4,5-c]quinolin-4-aminforbindelser og mellemprodukter dertil |
EP1931352B1 (fr) | 2005-08-22 | 2016-04-13 | The Regents of The University of California | Agonistes tlr |
EA200800943A1 (ru) | 2005-09-27 | 2008-12-30 | Коли Фармасьютикал Гмбх | Модуляция tlr-опосредуемых иммунных ответов с использованием олигонуклеотидов-адаптеров |
CA2653941C (fr) | 2006-05-31 | 2013-01-08 | The Regents Of The University Of California | Derives d'aminopurine substitues et leurs utilisations |
CA2702644A1 (fr) | 2007-10-16 | 2009-04-23 | Gilead Palo Alto, Inc. | Antagonistes du recepteur a3 de l'adenosine |
NZ598933A (en) | 2009-10-22 | 2013-04-26 | Gilead Sciences Inc | Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections |
EP2563366A4 (fr) | 2010-04-30 | 2013-11-20 | Univ California | Utilisations de conjugués phospholipidiques d'agonistes synthétiques de tlr7 |
EP2563401A1 (fr) | 2010-04-30 | 2013-03-06 | Telormedix SA | Procédés d'induction d'une réponse immunitaire |
WO2011134668A1 (fr) | 2010-04-30 | 2011-11-03 | Telormedix Sa | Analogues de médicaments phospholipidiques |
ES2458355T3 (es) | 2010-09-01 | 2014-05-05 | Novartis Ag | Adsorción de inmunopotenciadores sobre sales metálicas insolubles |
WO2012038058A1 (fr) | 2010-09-21 | 2012-03-29 | Telormedix Sa | Traitement d'états par des modulateurs de récepteurs de type toll |
-
2006
- 2006-08-21 EP EP06813535.9A patent/EP1931352B1/fr not_active Not-in-force
- 2006-08-21 CA CA002620182A patent/CA2620182A1/fr not_active Abandoned
- 2006-08-21 JP JP2008528017A patent/JP2009504803A/ja active Pending
- 2006-08-21 CN CNA200680038761XA patent/CN101304748A/zh active Pending
- 2006-08-21 ES ES06813535.9T patent/ES2577514T3/es active Active
- 2006-08-21 WO PCT/US2006/032371 patent/WO2007024707A2/fr active Application Filing
- 2006-08-21 US US12/064,529 patent/US20090324551A1/en not_active Abandoned
-
2012
- 2012-11-20 JP JP2012254043A patent/JP2013040209A/ja active Pending
- 2012-11-20 US US13/682,208 patent/US9359360B2/en active Active
Patent Citations (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4689338A (en) * | 1983-11-18 | 1987-08-25 | Riker Laboratories, Inc. | 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use |
US4938949A (en) * | 1988-09-12 | 1990-07-03 | University Of New York | Treatment of damaged bone marrow and dosage units therefor |
US5238944A (en) * | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
US5736553A (en) * | 1988-12-15 | 1998-04-07 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo 4,5-C!quinolin-4-amine |
US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
US5037986A (en) * | 1989-03-23 | 1991-08-06 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo[4,5-c]quinolin-4-amines |
US5367076A (en) * | 1990-10-05 | 1994-11-22 | Minnesota Mining And Manufacturing Company | Process for imidazo[4,5-C]quinolin-4-amines |
US5175296A (en) * | 1991-03-01 | 1992-12-29 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]quinolin-4-amines and processes for their preparation |
US6083505A (en) * | 1992-04-16 | 2000-07-04 | 3M Innovative Properties Company | 1H-imidazo[4,5-C]quinolin-4-amines as vaccine adjuvants |
US5395937A (en) * | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
US5352784A (en) * | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US5627281A (en) * | 1993-07-15 | 1997-05-06 | Minnesota Mining And Manufacturing Company | Intermediate compounds of fused cycloalkylimidazopyridines |
US5444065A (en) * | 1993-07-15 | 1995-08-22 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines as inducer of interferon α biosynthesis |
US5648516A (en) * | 1994-07-20 | 1997-07-15 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US6333331B1 (en) * | 1994-08-01 | 2001-12-25 | The United States Of America As Represented By The Department Of Health And Human Services | Substituted O6-benzylguanines |
US5624677A (en) * | 1995-06-13 | 1997-04-29 | Pentech Pharmaceuticals, Inc. | Controlled release of drugs delivered by sublingual or buccal administration |
US6897314B2 (en) * | 1996-06-21 | 2005-05-24 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US5998619A (en) * | 1996-06-21 | 1999-12-07 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
US6150523A (en) * | 1996-06-21 | 2000-11-21 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US6534654B2 (en) * | 1996-06-21 | 2003-03-18 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US6624305B2 (en) * | 1996-06-21 | 2003-09-23 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US6613902B2 (en) * | 1996-06-21 | 2003-09-02 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US5741908A (en) * | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
US6437131B1 (en) * | 1996-06-21 | 2002-08-20 | 3M Innovative Properties Company | Process for preparing imidazoquinolinamines |
US6038505A (en) * | 1996-09-12 | 2000-03-14 | Siemens Aktiengesellschaft | Method of controlling the drive train of a motor vehicle, and integrated drive train control system |
US6200592B1 (en) * | 1996-10-25 | 2001-03-13 | 3M Innovative Properties Company | Immine response modifier compounds for treatment of TH2 mediated and related diseases |
US6696076B2 (en) * | 1996-10-25 | 2004-02-24 | 3M Innovative Properties Company | Immune response modifier compounds for treatment of TH2 mediated and related diseases |
US6610319B2 (en) * | 1996-10-25 | 2003-08-26 | 3M Innovative Properties Company | Immune response modifier compounds for treatment of TH2 mediated and related diseases |
US6039969A (en) * | 1996-10-25 | 2000-03-21 | 3M Innovative Properties Company | Immune response modifier compounds for treatment of TH2 mediated and related diseases |
US6734187B1 (en) * | 1997-11-12 | 2004-05-11 | Mitsubishi Chemical Corporation | Purine derivatives and medicaments comprising the same as active ingredient |
US6329381B1 (en) * | 1997-11-28 | 2001-12-11 | Sumitomo Pharmaceuticals Company, Limited | Heterocyclic compounds |
US7001609B1 (en) * | 1998-10-02 | 2006-02-21 | Regents Of The University Of Minnesota | Mucosal originated drug delivery systems and animal applications |
US6706728B2 (en) * | 1999-01-08 | 2004-03-16 | 3M Innovative Properties Company | Systems and methods for treating a mucosal surface |
US6486168B1 (en) * | 1999-01-08 | 2002-11-26 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
US6245776B1 (en) * | 1999-01-08 | 2001-06-12 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
US20030191086A1 (en) * | 1999-01-26 | 2003-10-09 | Ustav Experimentalni Botaniky Av Cr | Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof |
US6552192B1 (en) * | 1999-01-26 | 2003-04-22 | Ustau Experimentalni Botaniky Av-Cr | Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof |
US20030187261A1 (en) * | 2000-01-07 | 2003-10-02 | Libor Havlicek | Purine derivatives, process for their preparation and use thereof |
US6733764B2 (en) * | 2000-06-14 | 2004-05-11 | Alain Martin | Immunostimulator anti-cancer compounds and methods for their use in the treatment of cancer |
US20040023211A1 (en) * | 2000-09-15 | 2004-02-05 | Kees Groen | System and method for optimizing drug theraphy for the treatment of diseases |
US20040248895A1 (en) * | 2001-04-09 | 2004-12-09 | Daniel Chu | Novel guanidino compounds |
US6716840B2 (en) * | 2001-04-09 | 2004-04-06 | Chiron Corporation | Guanidino compounds |
US7189727B2 (en) * | 2001-04-09 | 2007-03-13 | Chiron Corporation | Guanidino compounds |
US20050038027A1 (en) * | 2001-04-09 | 2005-02-17 | Chiron Corporation | Novel guanidino compounds |
US20020193595A1 (en) * | 2001-04-09 | 2002-12-19 | Daniel Chu | Novel guanidino compounds |
US6960582B2 (en) * | 2001-04-09 | 2005-11-01 | Chiron Corporation | Guanidino compounds |
US20070037832A1 (en) * | 2001-04-17 | 2007-02-15 | Dainippon Sumitomo Pharma Co., Ltd. | Novel adenine derivatives |
US7157465B2 (en) * | 2001-04-17 | 2007-01-02 | Dainippon Simitomo Pharma Co., Ltd. | Adenine derivatives |
US7521454B2 (en) * | 2001-04-17 | 2009-04-21 | Dainippon Sumitomo Pharma Co., Ltd. | Adenine derivatives |
US20040132748A1 (en) * | 2001-04-17 | 2004-07-08 | Yoshiaki Isobe | Novel adenne derivatives |
US20080125446A1 (en) * | 2001-10-30 | 2008-05-29 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
US7241890B2 (en) * | 2001-10-30 | 2007-07-10 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
US20050049263A1 (en) * | 2001-10-30 | 2005-03-03 | Kasibhatla Srinivas Rao | Purine analogs having hsp90-inhibiting activity |
US20060052403A1 (en) * | 2002-09-27 | 2006-03-09 | Yoshiaki Isobe | Novel adenine compound and use thereof |
US20070173483A1 (en) * | 2002-10-30 | 2007-07-26 | Conforma Therapeutics Corporation | Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
US20050004144A1 (en) * | 2003-04-14 | 2005-01-06 | Regents Of The University Of California | Combined use of IMPDH inhibitors with toll-like receptor agonists |
US20050059613A1 (en) * | 2003-07-08 | 2005-03-17 | Bahram Memarzadeh | Compositions and methods for the enhanced uptake of therapeutic agents through the bladder epithelium |
US20070161582A1 (en) * | 2003-08-08 | 2007-07-12 | Dusan Mijikovic | Pharmaceutical compositions and methods for metabolic modulation |
US20050054590A1 (en) * | 2003-09-05 | 2005-03-10 | Averett Devron R. | Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus |
US20070087009A1 (en) * | 2003-12-19 | 2007-04-19 | Sanofi Pasteur | Immunostimulant composition comprising at least one toll-like receptor 7 or toll-like receptor 8 agonist and a toll-like receptor 4 agonist |
US20050266067A1 (en) * | 2004-03-02 | 2005-12-01 | Shiladitya Sengupta | Nanocell drug delivery system |
US20060110746A1 (en) * | 2004-11-19 | 2006-05-25 | Institut Gustave Roussy | Treatment of cancer using TLR3 agonists |
US20070292418A1 (en) * | 2005-04-26 | 2007-12-20 | Eisai Co., Ltd. | Compositions and methods for immunotherapy |
US20090118263A1 (en) * | 2005-09-22 | 2009-05-07 | Dainippon Sumitomo Pharma Co., Ltd. | Novel Adenine Compound |
US20090105212A1 (en) * | 2005-09-22 | 2009-04-23 | Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan | Novel adenine compound |
US20070100146A1 (en) * | 2005-11-03 | 2007-05-03 | Trevor Dzwiniel | Process for the preparation of imidazo[4,5-c]-quinolin-4-amines |
US20090202484A1 (en) * | 2006-07-07 | 2009-08-13 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
US20090069289A1 (en) * | 2006-10-04 | 2009-03-12 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
US20080214580A1 (en) * | 2006-10-04 | 2008-09-04 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
US20120148660A1 (en) * | 2007-02-07 | 2012-06-14 | Regents Of The University Of California, San Diego Ucsd Technology Transfer Office | Conjugates of synthetic tlr agonists and uses therefor |
US20090047249A1 (en) * | 2007-06-29 | 2009-02-19 | Micheal Graupe | Modulators of toll-like receptor 7 |
US20090202626A1 (en) * | 2008-02-07 | 2009-08-13 | Carson Dennis A | Treatment of bladder diseases with a tlr7 activator |
US20110319442A1 (en) * | 2009-02-06 | 2011-12-29 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
US20100210598A1 (en) * | 2009-02-11 | 2010-08-19 | Regents Of The University Of California, San Diego | Toll-like receptor modulators and treatment of diseases |
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US8993755B2 (en) | 2007-06-29 | 2015-03-31 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
US8673907B2 (en) | 2007-12-17 | 2014-03-18 | Astrazeneca Ab | Pharmaceutically acceptable salts of methyl (3-{ [[3-(6-amino- 2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] (3-morpholin-4-ylpropyl) amino] methyl }phenyl) acetate and their use in therapy |
US20110054168A1 (en) * | 2008-01-17 | 2011-03-03 | Ayumu Kurimoto | Method for preparing adenine compound |
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US8865896B2 (en) | 2008-01-17 | 2014-10-21 | Astrazeneca Aktiebolag | Method for preparing adenine compound |
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US9346806B2 (en) | 2008-08-11 | 2016-05-24 | Glaxosmithkline Llc | 6-amino-purin-8-one compounds |
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US9877968B2 (en) | 2008-08-11 | 2018-01-30 | Glaxosmithkline Llc | 6-amino-purin-8-one compounds |
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US8962652B2 (en) | 2009-10-22 | 2015-02-24 | Gilead Sciences, Inc. | Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections |
US9161934B2 (en) | 2009-10-22 | 2015-10-20 | Gilead Sciences, Inc. | Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections |
US8507507B2 (en) | 2009-10-22 | 2013-08-13 | Gilead Sciences, Inc. | Modulators of toll-like receptors |
US20110136801A1 (en) * | 2009-12-03 | 2011-06-09 | Dainippon Sumitomo Pharma Co. Ltd. | Novel Compounds |
US20110150836A1 (en) * | 2009-12-22 | 2011-06-23 | Gilead Sciences, Inc. | Methods of treating hbv and hcv infection |
US9066978B2 (en) | 2010-05-26 | 2015-06-30 | Selecta Biosciences, Inc. | Dose selection of adjuvanted synthetic nanocarriers |
US9764031B2 (en) | 2010-05-26 | 2017-09-19 | Selecta Biosciences, Inc. | Dose selection of adjuvanted synthetic nanocarriers |
US9994443B2 (en) | 2010-11-05 | 2018-06-12 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
US9045472B2 (en) | 2010-12-16 | 2015-06-02 | Astrazeneca Ab | Imidazoquinoline compounds |
US8895570B2 (en) | 2010-12-17 | 2014-11-25 | Astrazeneca Ab | Purine derivatives |
WO2013016297A3 (fr) * | 2011-07-22 | 2013-04-25 | Pawel Kalinski | Modulation de chimiokines de manière sélective vis-à-vis de tumeurs |
US10112946B2 (en) | 2011-07-22 | 2018-10-30 | Glaxosmithkline Llc | Composition |
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Also Published As
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AU2006283524A1 (en) | 2007-03-01 |
ES2577514T3 (es) | 2016-07-15 |
JP2013040209A (ja) | 2013-02-28 |
WO2007024707A2 (fr) | 2007-03-01 |
EP1931352A2 (fr) | 2008-06-18 |
CA2620182A1 (fr) | 2007-03-01 |
AU2006283524A2 (en) | 2008-06-05 |
JP2009504803A (ja) | 2009-02-05 |
US20130165455A1 (en) | 2013-06-27 |
EP1931352B1 (fr) | 2016-04-13 |
WO2007024707A3 (fr) | 2007-09-20 |
EP1931352A4 (fr) | 2011-11-23 |
US9359360B2 (en) | 2016-06-07 |
CN101304748A (zh) | 2008-11-12 |
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