Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.
• PAMPs generally meet certain criteria that include (a) their expression by microbes but not their mammalian hosts, (b) conservation of structure across the wide range of pathogens, and (c) the capacity to stimulate innate immunity.
• TLRs Toll-like Receptors
• TLR7 and TLR9 recognize and respond to imiquimod and immunostimulatory CpG oligonucleotides (ISS-ODN), respectively.
• the synthetic immunomodulator R-848 (resiquimod) activates both TLR7 and TLR8.
• TLR ligands control the activation of antigen-presenting cells, in particular dendritic cells, by triggering their maturation program, including up-regulation of the expression of HLA and costimulatory molecules and secretion of proinflammatory cytokines, such as TNF- ⁇ , IL-6, IL- 12, andIFN- ⁇ (Stanley, 2002).
• 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).
• DCs dendritic cells
• B lymphocytes in humans; mouse macrophages express TLR7 and TLR9.
• TLR8 on the other hand, is found in human blood monocytes (Hornung et al., 2002). While agonists of TLRs have great therapeutic potential, their utility has been limited by side effects related to the release and systemic dispersion of proinflammatory cytokines.
• TLR7 ligands have been as topically applied antiviral or antitumor agents or as immune adjuvants injected intramuscularly in small quantities (Ambach et al., 2004; Hemmi et al., 2002).
• the invention provides a method for the treatment of superficial bladder cancer and inflammatory diseases of the bladder, e.g., interstitial cystitis or overactive bladder.
• the method includes the administration of a synthetic TLR7 activator (agonist) formulated to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood, modified to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood, or coadministered with another treatment to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood.
• a synthetic TLR7 activator formulated to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood
• modified to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood or coadministered with another treatment to optimize concentration of the synthetic TLR7 agonist in the bladder mucosa versus the blood.
• the synthetic TLR7 agonist is formulated, modified or administered in conjunction with another treatment, so as to achieve a bladder mucosal concentration at least 2, 5, or more, e.g., at least 10, times higher than in the blood
• concentrations of the TLR7 agonist in the blood are generally in the range of about 10 nM to about 1000 nM
• concentrations in the bladder are about 100 nM to about 10,000 nM.
• the TLR7 agonist is administered in conjunction with locally applied ultrasound, electromagnetic radiation or electroporation or other electrically based drug delivery techniques, local chemical abrasion, or local physical abrasion, to disrupt the bladder permeability barrier.
• the TLR7 agonist is administered with a locally applied surfactant to enhance permeability of the TLR7 agonist across the bladder mucosa.
• the TLR agonist, a formulation thereof, or a conjugate thereof has enhanced endosomal uptake, for instance, as a result of particle size, induces receptor multimerization, and/or provides for sustained release.
• local activation of TLR7 may disrupt the cancer cell-matrix interactions that are required for growth and survival of malignant cells and may induce apoptosis.
• the formulation or conjugate has enhanced potency versus a corresponding TLR7 agonist (not formulated or conjugated), e.g., as determined in vitro or in vivo by cytokine induction assays, low systemic distribution, e.g., as determined using in vivo animal models and intravesical or other local delivery, and/or an improved activity/safety ratio, determined using in vivo animal models and intravesical or other local delivery.
• the TLR7 agonist may be formulated or chemically modified so as to minimize systemic absorption, e.g., by dispersion in emulsions, encapsulation in nanoparticles or lipsomes, aggregation in nanoparticles or nanocrystals, or chemical tethering to a protein or lipid (see, e.g., U.S. application Serial Nos. 60/710,337; 60/809,870; 60/809,879; and 10/824,833, which are incorporated by reference herein).
• a TLR7 agonist for use in the invention has formula I:
• R 1 , R 2 , and R 3 are each independently hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to about ten carbon atoms and substituted straight chain or branched chain alkyl containing one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; fluoro- or chloroalkyl containing from one to about ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing
• the synthetic TLR agonist conjugates for use in the methods of the invention are those disclosed in PCT/US06/032371, the disclosure of which is incorporated by reference herein.
• a TLR agonist conjugates for use in the methods of the invention is a compound of formula (IC):
• X is N or CR" wherein R" is hydrogen, halogen, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, or unsubstituted heteroalkyl; Y is S or N; the dashes ( — ) indicate optional bonds; wherein: when the bond between Y and the carbon marked by an asterisk is a double bond, Q 2 is not present; when the bond between Q 1 and the carbon marked by an asterisk is a double bond, Q 1 is O, S, NY 1 , OrNNY 2 Y 3 ; and when the bond between Q 1 and the carbon marked by an asterisk is a single bond, Q 1 is hydrogen, cyano, nitro, O-Y 2 , S-Y 2 , NY 1 Y 2 , Or NY 2 NY 3 Y 4 ; wherein Y 1 is hydrogen, substituted alkyl, unsubstituted alkyl, substituted cycloalkyl, unsubstituted cycloalkyl;
• Q 2 and Q 3 are each independently hydrogen, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, unsubstituted heteroalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl;
• X 1 is -O-, -S-, or -NR C -;
• R° is hydrogen, Ci.ioalkyl, or substituted Ci-ioalkyl, or R c and R 1 taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring;
• R 1 is hydrogen, (Ci-Cio)alkyl, substituted (Ci-Cio)alkyl, C ⁇ -ioaryl, or substituted C ⁇ -ioaryl, Cs ⁇ heterocyclic, or substituted Cs.gheterocyclic ring; each R 2 is independently hydrogen, -OH, (Ci-Ce)alkyl, substituted (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, substituted (C
• X 2 is a bond or a linking group; k is O, 1, 2, 3, or 4; n is O, 1, 2, 3, or 4; and
• R 3 is a macromolecule comprising a cell, virus, vitamin, cofactor, peptide, protein, nucleic acid molecule, lipid, bead or particle, such as a polystyrene bead or nanoparticles, or a dendrimer; or a pharmaceutically acceptable salt thereof, including hydrates thereof.
• the synthetic TLR7 agonist for use in the methods of the invention include formulations or modifications of imiquimod, e.g., TMX 101, resiquimod, bropirimine, propirimine, or other TLR7 agonists, such as those described in U.S. Patent No. 6,329,381 and Lee et al., Proc. Natl. Acad. Sci USA.
• the invention also provides a pharmaceutical composition comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. Further, the invention provides a pharmaceutical composition comprising the compounds disclosed herein in combination with other known anticancer compounds.
• the invention provides a method to inhibit or treat a bladder, cervical, lung or anal disorder in a mammal, e.g., a human patient, by administering an effective amount of a TLR7 agonist that is modified or formulated, or administered in conjunction with another treatment.
• Patients to be treated include but are not limited to those with non-invasive bladder cancer, interstitial cystitis, cervical dysplasia, metastatic lung cancer, relapsed/refractory superficial bladder cancer, and anal intra-epithelial neoplasia, or any preneoplastic or neoplastic condition that is accessible to local administration of a therapeutic agent, such as by direct application or use of a catheter or other drug delivery device.
• interstitial cystitis is common clinical syndrome in females characterized by frequency and dysuria.
• the bladder is infiltrated with mast cells, and the urine has increased substance P, suggesting an allergic component.
• Stratification of patients may allow for a targeted treatment of a specific TLR7 agonist for interstitial cystitis.
• the invention also provides a method to enhance killing of tumor cells in a mammal in need of such therapy.
• the method includes locally administering an effective amount of a compound of the invention to the mammal.
• the present invention also provides a method for treating bladder, cervical, lung or anal cancer in a mammal, e.g., a human patient.
• the method includes locally contacting the cancer cells with a compound of the invention, or mixtures thereof, in an effective amount.
• the present invention provides a method for inducing apoptosis or inducing cell death in cells in a mammal, e.g., a human patient.
• the method includes contacting target cells locally in vivo with a compound of the invention, or mixtures thereof, in an amount effective to enhance apoptosis or cell death in the target cells.
• the invention provides compounds for use in medical therapy, such as agents that induce apoptosis or agents that inhibit or treat certain types of cancer, optionally in conjunction with other compounds. Accordingly, the compounds of the invention are useful to inhibit or treat cancer. Also provided is the use of the compounds for the manufacture of a medicament to enhance apoptosis or to inhibit or treat certain types of cancer.
• FIG. 1 Exemplary TLR7 agonists.
• 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]-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.
• amino acid as used herein, comprises the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, GIu, GIn, GIy, His, HyI, Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaI) 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 (Ci-C ⁇ jalkyl, phenyl or benzyl ester or amide; or as an -methylbenzyl amide).
• a conventional amino protecting group e.g., acetyl or benzyloxycarbonyl
• natural and unnatural amino acids protected at the carboxy terminus e.g., as a (Ci-C ⁇ jalkyl, phenyl or benzyl ester or amide; or as an -methylbenzyl amide.
• Other 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).
• 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-3 agonist” and “TLR-9 agonist.”
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
• the pharmaceutically acceptable salts of the compounds useful in the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985), the disclosure of which is hereby incorporated by reference.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
• “Therapeutically effective amount” is intended to include an amount of a compound useful in the present invention or an amount of the combination of compounds claimed, e.g., to treat or prevent the disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
• “treating” or “treat” includes (i) preventing a pathologic condition from occurring (e.g. prophylaxis); (ii) inhibiting the pathologic condition or arresting its development; (iii) relieving the pathologic condition; and/or diminishing symptoms associated with the pathologic condition.
• the term "patient” refers to organisms to be treated by the methods of the present invention. Such organisms include, but are not limited to, mammals such as humans.
• the term “subject” generally refers to an individual who will receive or who has received treatment (e.g., administration of a compound of the invention, and optionally one or more anticancer agents) for cancer.
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention. Methods and Compounds for Use in the Methods of the Invention
• Bladder cancer has the 4th highest prevalence and the 5th highest incidence of all cancers in the U.S. and Europe. Every year in the United States more than 60,000 people are newly diagnosed with bladder cancer. The number of diagnosed bladder cancer patients has risen by more than 20% in the past decade, helped by effective diagnostic methods and the increase in the elderly population. 70% of bladder tumors are non-muscle invasive (superficial) at time of diagnosis, and 70% recur after initial transurethral resection.
• BCG Bacille- Calmette-Guerin
• IL-6 IL-6
• IL-8 Bacille- Calmette-Guerin
• BCG a live attenuated mycobacteria, which is administered locally (intravesical) (80% of cases).
• BCG is an uncharacterized product, composed of an attenuated form of the bacterium Mycobacterium tuberculosis, used to prevent tuberculosis.
• BCG establishes a localized infection by attachment to and internalization in urothelium, which in turn releases IL-I, IL-6, and IL-8 (Hedges et al., 1994). Instillation of BCG results in an influx of neutrophils, followed by an influx of mononuclear cells consisting primarily of CD4 + cells.
• chemokine signals The net effect of chemokine signals is escalating recruitment of neutrophils and monocytic leukocytes into the bladder with each successive BCG instillation (Shapiro et al., 1988). While there is a high incidence of complete local responses (70-75%) compared to intravesical chemotherapy, many patients ultimately need cystectomy due to recurrence and/or side effects and there are increased toxic side effects (local and systemic). For example, at least 30% of patients need to delay or stop BCG therapy due to local or systemic toxicity. Many clinicians are reluctant to use BCG because of the risks of life-threatening systemic infection/sepsis.
• the present invention provides for a locally administered TLR7 agonist, formulated in such a way that tissue penetration is promoted and systemic absorption is inhibited or prevented.
• a treatment is likely equally or more effective than BCG and without the systemic side effects of the live bacteria.
• an in vivo mouse orthotopic bladder cancer transplantation model demonstrated that local TLR7 (intravesicular) activation with a conjugate of a TLR7 agonist did not result in systemic side effects and likely showed anti-tumor effects.
• in vivo efficacy of TLR7 agonist was demonstrated in bladder cancer cell lines by decreasing cell viability, inducing apoptosis and increasing cytokine production, which indicate that TLR7 agonists have anti-tumor effects.
• Activation of TLR7 may disrupt the interaction of the bladder cancer cells with growth factors bound to the extracellular matrix, which in turn may lead to apoptosis.
• the invention provides for treatment of established, superficial bladder cancer by intravesicular (in the bladder) administration of a synthetic TLR7 agonist, formulated or modified chemically so that it will achieve a maximal (local) concentration in the bladder mucosa, e.g., a concentration at least 10x higher than in the blood.
• a synthetic TLR7 agonist may be combined with a physical or chemical treatment to disrupt the bladder permeability barrier, including locally applied ultrasound, all types of electromagnetic radiation, chemical and physical abrasion, and the use of surfactant.
• Inflammatory diseases of the bladder including interstitial cystitis and overactive bladder, may be treated similarly.
• the present TLR7 agonists are likely more potent and less toxic than BCG, and so achieve a more significant therapeutic effect.
• the TLR7 agonist is administered to patients with a mast cell component to their disease, as indicated by biopsy of the bladder with histologic examination, and/or by measurement of elevated neurokinin levels (substance P) in the urine, in an amount effective to decrease mast cell function.
• the TLR7 agonist has formula I:
• R 1 , R 2 , and R 3 are each independently hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to about ten carbon atoms and substituted straight chain or branched chain alkyl containing one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; fluoro- or chloroalkyl containing from one to about ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing
• X is alkoxy containing one to about four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, haloalkyl of one to about four carbon atoms, alkylamido wherein the alkyl group contains one to about four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to about four carbon atoms, azido, alkylthio of one to about four carbon atoms, or morpholinoalkyl wherein the alkyl moiety contains one to about four carbon atoms; R 4 is hydrogen, Ci -8 alkyl, Ci -8 alkoxy, or halo; n is 1, 2, 3, or 4; R a and R b are each independently hydrogen, (C]-C 6 )alkyl, hydroxy(Ci-
• the TLR7 agonist includes imidazoquinoline amines such as lH-imidazo[4,5-c]quinolin-4-amines as defined by one of Formulas II- VI below: wherein
• Rn is selected from the group consisting of alkyl of one to about ten carbon atoms, hydroxyalkyl of one to about six carbon atoms, acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety contains one to about six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms;
• R 2I is selected from the group consisting of hydrogen, alkyl of one to about eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and each Ri is independently selected from the group consisting of alkoxy of one to about four carbon atoms, halogen, and alkyl of one to about four carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said Ri groups together contain no more than six carbon atoms; III
• Ri 2 is selected from the group consisting of straight chain or branched chain alkenyl containing two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of straight chain or branched chain alkyl containing one to about four carbon atoms and cycloalkyl containing three to about six carbon atoms; and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; and
• R 22 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl containing one to about four carbon atoms, straight chain or branched chain alkoxy containing one to about four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R 2 is independently selected from the group consisting of straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms, and n is
• R 23 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl of one to about eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl of one to about four carbon atoms, straight chain or branched chain alkoxy of one to about four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R.
• R 3 is independently selected from the group consisting of straight chain or branched chain alkoxy of one to about four carbon atoms, halogen, and straight chain or branched chain alkyl of one to about four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R 3 groups together contain no more than six carbon atoms;
• Ri 4 is -CHR x Ry wherein R y is hydrogen or a carbon-carbon bond, with the proviso that when R y is hydrogen R x is alkoxy of one to about four carbon atoms, hydroxyalkoxy of one to about four carbon atoms, 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R y is a carbon-carbon bond R y and R x together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to about four carbon atoms;
• R 24 is selected from the group consisting of hydrogen, alkyl of one to about four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen; and
• R 4 is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms;
• Ri 5 is selected from the group consisting of: hydrogen; straight chain or branched chain alkyl containing one to about ten carbon atoms and substituted straight chain or branched chain alkyl containing one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; straight chain or branched chain alkenyl containing two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; hydroxyalkyl of one
• Rs and Ry are independently selected from the group consisting of hydrogen, alkyl of one to about four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen;
• X is selected from the group consisting of alkoxy containing one to about four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, hydroxyalkyl of one to about four carbon atoms, haloalkyl of one to about four carbon atoms, alkylamido wherein the alkyl group contains one to about four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to about four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1- pyrrolidino
• R 5 is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms; or a pharmaceutically acceptable salt of any of the foregoing.
• the TLR7 agonist has formula VII below:
• n 1, 2, or 3;
• Ri 6 is selected from the group consisting of hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to about ten carbon atoms and substituted straight chain or branched chain alkyl containing one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing three to about six carbon atoms substituted by straight chain or branched chain alkyl containing one to about four carbon atoms; fluoro- or chloroalkyl containing from one to about ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six
• R 26 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to about six carbon atoms, morpholinomethyl, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and
• X is selected from the group consisting of alkoxy containing one to about four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, haloalkyl of one to about four carbon atoms, alkylamido wherein the alkyl group contains one to about four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to about four carbon atoms, azido, alkylthio of one to about four carbon atoms, and morpholinoalkyl wherein the alkyl moiety contains one to about four carbon atoms, and Re is selected from the group consisting of hydrogen, fluoro, chloro, straight chain or branched chain alkyl containing one to about four carbon atoms, and straight chain or branched chain fluoro- or chloroalkyl containing one to about four carbon atoms and at least one fluorine or chlorine
• R 27 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to about six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to about four carbon atoms;
• R ⁇ 7 and R 77 are independently selected from the group consisting of hydrogen and alkyl of one to about five carbon atoms, with the proviso that R 67 and R 77 taken together contain no more than six carbon atoms, and with the further proviso that when R 77 is hydrogen then R 67 is other than hydrogen and R 27 is other than hydrogen or morpholinoalkyl, and with the further proviso that when R 67 is hydrogen then R 77 and R 27 are other than hydrogen; and pharmaceutically acceptable salts thereof.
• the TLR7 agonist has formula IX below:
• Z is selected from the group consisting of:
• R D is hydrogen or alkyl of one to four carbon atoms
• RE is selected from the group consisting of alkyl of one to four carbon atoms, hydroxy, -ORp wherein Rp is alkyl of one to four carbon atoms, and -NRQR'G wherein RQ and R' G are independently hydrogen or alkyl of one to four carbon atoms;
• the substituents Rn -Rn above are generally designated "1-substituents" herein.
• the 1-substituents are alkyl containing one to six carbon atoms and hydroxyalkyl containing one to six carbon atoms, e.g., the 1-substituent is 2-methylpropyl or 2-hydroxy-2-methylpropyl.
• the substituents R 2I -R 27 above are generally designated "2-substituents" herein.
• the 2-substituents are hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and hydroxyalkyl of one to four carbon atoms, e.g., the 2-substituent is hydrogen, methyl, butyl, hydroxymethyl, ethoxymethyl or methoxyethyl.
• n is preferably zero or one.
• the amounts of the compounds that will be therapeutically effective in a specific situation will of course depend on such things as the activity of the particular compound, the mode of administration, and the disease being treated. As such, it is not practical to identify specific administration amounts herein; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to these compounds, and routine testing.
• 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 M o 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 Ci -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.
• Ci -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 -).
• C 3-7 cycloalkyl includes groups such as, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, and alkyl-substituted C 3-7 cycloalkyl group, preferably straight or branched Ci_ 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 ⁇ .(, alkoxy groups, such as methoxy, ethoxy or propoxy, and the like.
• Lower alkanoyl includes Q -6 alkanoyl groups, such as formyl, acetyl, propanoyl, butanoyl, pentanoyl or hexanoyl, and the like.
• C 7 . 1 1 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 Cj -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 Ci -6 alkyl group (e.g. dimethylamino, diethylamino, ethylmethylamino).
• Lower alkylcarbamoyl group means carbamoyl group substituted by Cue alkyl group (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl) .
• Di(lower alkyl)carbamoyl group means carbamoyl group substituted by the same or different and Ci ⁇ alkyl group (e.g. dimethylcarbamoyl, diethylcarbamoyl, ethyhnethylcarbamoyl) .
• Halogen atom means halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom.
• Aryl refers to a C 6- Io 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, 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.
• Alkyl, aryl, and heterocyclic groups can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include lower alkyl; Ci -6 alkoxy, such as methoxy, ethoxy or propoxy; carboxyl; C 2-7 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl) and halogen; cycloalkyl and include C 3 .
• the heterocyclic ring can be optionally substituted with one or more substituents, wherein the substituents are the same or different, and include Ci -6 alkyl; hydroxy C ⁇ alkylene; Q -6 alkoxy C t-6 alkylene; hydroxyl; Ci -6 alkoxy; and cyano.
• the compounds of the invention 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, e.g., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
• the composition is locally administered, e.g., intravesicularly.
• 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.
• 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.
• binders such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as
• the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
• a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
• 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 be administered 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 can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile solutions or dispersions, optionally encapsulated in liposomes.
• 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 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 as compositions or formulations, in combination with an 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.
• Useful dosages of the compounds 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. Patent No. 4,938,949.
• 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, 100:6646 (2003).
• the concentration of the compound(s) 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 ing/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 0.01 to about 100 ⁇ M, 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M.
• peak plasma concentrations of the active compound of from about 0.01 to about 100 ⁇ M, 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.
• TLR7 agonists display the highest activity when delivered locally allowing the creation of a potent immune gradient.
• the localized delivery also reduces the risk of systemic exposure, thereby increasing the safety profile of the agonist.
• Bladder is an immunologically active organ, "skin turned inside out," with TLR7 expressing dendritic and mast cells. To achieve good clinical activity for a bladder cancer patient, optimal passage of TLR7 agonists through the bladder permeability barrier is needed. Too great permeability leads to systemic side effects, while poor permeability leads to incomplete eradication.
• TLR7 agonist conjugates e.g., conjugates of imiquimod
• TLR7 agonist conjugates can improve the uptake of the agonist by enhancing adhesion, endosomal uptake, and/or receptor multimerization (reducing monomelic interactions), and may provide for sustained drug release to improve to duration of effect.
• Bladder cancer patients amenable to treatment with a TLR7 agonist of the invention include, but are not limited to, those for whom most of the tumor has been removed by fra/w-urethral resection, but some residual cancer persists, and can be observed during cytoscopy, patients with high-risk and mid-risk non-muscle invasive bladder cancer and the patients with carcinoma in situ (cis) of the bladder.
• the TLR7 agonist is formulated so as to minimize systemic absorption, e.g., via dispersion in emulsions, encapsulation in nanoparticles or lipsomes, aggregation in nanoparticles or nanocrystals, or chemical tethering to a protein or lipid.
• the TLR7 formulations are administered via a catheter in the urethra, and the catheter is clamped to allow for drug contact with the cancer, e.g., for about 10 minutes to 2 hours after which the bladder is flushed to remove unreacted drug.
• the procedure may be repeated at approximately weekly intervals x 6, and then monthly.
• Exemplary conjugates are conjugates with propirimine or imiquimod.
• Bropirimine a TLR agonist
• Imiquimod has been shown to be effective in superficial bladder cancer (European Urology. VoI 34, 1998).
• Imiquimod has demonstrated efficacy in superficial skin cancer, inhibited chemically induced bladder cancer and cured mice of the FCB bladder tumor (Borden et al., 1990).
• Imiquimod also showed potent anti-tumor activity in an orthotopic bladder cancer mouse model (Smith et al., 2007).
• placebo treated animals 11 of 13 mice (85%) developed invasive, high-grade bladder tumors.
• In the imiquimod-treated animals 100 ⁇ g once weekly), only 3 of 14 mice developed tumors.
• TMX-101 is a formulation of imiquimod designed to improve activity and retard systemic absorption. To determine the activity of TMXlOl against superficial bladder cancer, TMXlOl was delivered locally via intravesical instillation. Summary The main advantages of a better formulation, a better dosage or a better mode of delivery for a TLR7 agonist (such as imiquimod) in bladder diseases are: 1) reduced toxicity: by modifying the formulation or dosage of a TLR7 agonsit, e.g., imiquimod, the local effect is maximized and the systemic exposure is reduced. This can be achieved using formulation techniques (such as the use of in situ forming gels or depots, in combination with excipients, use of lipids, and the like).
• the pharmacokinetic profile and the ratio between "bladder” versus “plasma” levels of "unfo ⁇ nulated" TLR7 agonists versus formulations of TLR7 agonists is determined and formulations with improved profiles are selected for use in the methods of the invention; 2) improved efficacy: the efficacy of TLR7 molecules depends on the profile of cytokines/chemokines that can be triggered.
• the cytokine/chemokine profile can change based on how the TLR7 ligands enter the target cells, which endosomal compartment is activated, and other factors.
• the cytokine/chemokine profile of "unformulated" TLR7 agonists is different from that of the improved formulations or delivery systems.
• Formulations or delivery systems that provide the best efficacy in animal models of bladder cancer are selected for use in the methods of the invention; 3) better therapeutical window: the result of a better safety profile and increased efficacy provides a clear advantage over the "unformulated" TLR7 agonist.

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