WO2013070911A1 - Composés et méthodes de traitement d'une fibrose kystique - Google Patents

Composés et méthodes de traitement d'une fibrose kystique Download PDF

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Publication number
WO2013070911A1
WO2013070911A1 PCT/US2012/064145 US2012064145W WO2013070911A1 WO 2013070911 A1 WO2013070911 A1 WO 2013070911A1 US 2012064145 W US2012064145 W US 2012064145W WO 2013070911 A1 WO2013070911 A1 WO 2013070911A1
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Prior art keywords
optionally substituted
alkyl
heterocyclyl
independently
compound
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PCT/US2012/064145
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English (en)
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Joshua W. Hamilton
Bruce Stanton
Miles Hacker
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The Marine Biological Laboratory
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Publication of WO2013070911A1 publication Critical patent/WO2013070911A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/38—Quinones containing —CHO or non—quinoid keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes

Definitions

  • Cystic fibrosis (also called “CF” or mucoviscidosis) is a recessive genetic disease, causing progressive disability and even early death. Cystic fibrosis is the most common life- limiting autosomal recessive disease among people of European heritage ⁇ see National post (of Canada), November 25, 2008). Approximately 30,000 Americans have CF, making it one of the most common life- shortening inherited diseases in the United States.
  • cystic fibrosis is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR).
  • CFTR is a member of the ABC family of transmembrane reporter proteins.
  • AF508 CFTR mutation accounts for approximately 67% of mutations in all CF patients. This mutation results in improper CFTR protein folding and trafficking such that functional CFTR does not reach the cell membrane surface (see PCT/USOO/27443) .
  • One aspect of the invention provides a compound of formula (I):
  • Z 1 , Z 2 , Z 3 , and Z 4 each independently, is CH or N;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or N;
  • Q and W each independently, is O or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, 3, or 4;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • said compound of formula (I) is not one of the following compounds: Anthraquinone;
  • Another aspect of the invention is directed to a method of treating or preventing cystic fibrosis in a patient identified as in need of a treatment of cystic fibrosis thereof.
  • the method comprises administering to the patient an effective amount of a compound of formula (II):
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or ⁇ ;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or ⁇ ;
  • Q and W each independently, is O or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • the invention also provides a compound of formula (la):
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or ⁇ ;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or ⁇ ;
  • Q and W each independently, is O, NR d , or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, 3, or 4;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R each independently, is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R d is H or alkyl
  • the invention provides a method of treating or preventing cystic fibrosis in a patient identified as in need of a treatment of cystic fibrosis thereof.
  • the method comprises administering to the patient an effective amount of a compound of formula (Ila):
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or ⁇ ;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or ⁇ ;
  • Q and W each independently, is O, NR d , or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted; n is 0, 1, 2, or 3;
  • n 0, 1, 2, 3, or 4;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R d is H or alkyl
  • one of Z ⁇ Z 2 , Z 3 , and Z 4 is N, and the others are all CH.
  • Z 2 is N, and Z 1 , Z 3 , and Z 4 are all CH.
  • Z 1 is N, and Z 2 , Z 3 , and Z 4 are all CH.
  • the compound of the invention is capable of increasing CFTR expression level in a clinically significant amount in a cell membrane.
  • the compound is capable of correcting AF508 mutation form of cystic fibrosis.
  • the effective amount of the compound shows minimal systemic cytotoxicity.
  • the invention also provides a packaged composition for treating or preventing treating or preventing cystic fibrosis in a patient as identified in need of a treatment of cystic fibrosis thereof.
  • the packaged composition includes an effective amount of a compound capable of increasing CFTR expression level in a clinically significant amount in a cell membrane, and said effective amount of the compound shows no or little systemic cytotoxicity.
  • the compound in the packaged composition is a compound of formula (II) or (Ila) (see above delineated).
  • a method for treating or preventing treating or preventing cystic fibrosis in a patient identified in need of a treatment of cystic fibrosis thereof comprises a) identifying or selecting the subject suffering from or susceptible to cystic fibrosis for treatment with a compound, wherein said compound is capable of increasing CFTR expression level in a clinically significant amount in a cell membrane; b) monitoring the progress of said subject being treated; and c) assessing the efficacy of said treatment in said subject.
  • the invention presents a kit used for treating or preventing cystic fibrosis in a patient identified in need of a treatment of cystic fibrosis thereof.
  • the kit of the invention includes an effective amount of a compound capable of increasing CFTR expression level in a clinically significant amount in a cell membrane, and instructions for use of the kit, wherein said effective amount of the compound shows no or little systemic cytotoxicity.
  • the kit includes a compound of formula (II) or (Ila) (as above delineated).
  • the invention further provides combination therapies, such as, methods for treating cystic fibrosis and neoplasia at the same time.
  • the method comprises administering to the patient in need thereof a compound of the invention.
  • a compound of the invention and an additional therapeutic agent are administered to the patient sequentially or concurrently.
  • Compounds, compositions and articles defined by the invention were isolated or otherwise manufactured in connection with the examples provided below. Other features and advantages of the invention will be apparent from the detailed description, and from the claims.
  • Figures 1A-1B are graphs showing the effects of doxorubicin, pixantrone and abcantron on CFTR-mediated short circuit current in CFBE cells.
  • Figure 1A shows the genistein-stimulated Isc.
  • Figure IB shows the 172-inhibited Isc for the cells.
  • Figure 2 is a graph showing effects of Corr4a and abcantron (at indicated
  • Figure 3 is a graph demonstrating effects of Corr4a and abcantron (“ab”) (at indicated concentrations) on CFTR-mediated chloride conductance in human bronchial epithelial cells (CFBE cells; 24 hrs).
  • Figure 4 is a graph showing cytotoxicity of abcantrone ("ab”) at indicated concentrations in human bronchial epithelial cells
  • administration includes routes of introducing a compound(s) to a subject to perform their intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal.
  • the pharmaceutical preparations are, of course, given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, inhalation, topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • the compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the compound can be administered alone, or in conjunction with either another agent as described above (e.g. another chemotherapeutic agent) or with a pharmaceutically- acceptable carrier, or both.
  • the compound can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
  • the compound can also be administered in a proform which is converted into its active metabolite, or more active metabolite in vivo.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C 30 for straight chain, C 3 -C 30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
  • alkyl as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino,
  • arylcarbonylamino, carbamoyl and ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • alkylaryl moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • aryl e.g., phenylmethyl (benzyl)
  • alkyl also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and most preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
  • lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, heptyl, octyl and so forth.
  • the term "lower alkyl” includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., C1-C4 alkyl.
  • alkoxy refers to an alkyl or a cycloalkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be optionally substituted with one or more substituents.
  • alkoxyalkyl refers to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the invention contemplates cyano and propargyl groups.
  • ameliorate means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • alteration refers to a change (increase or decrease) in a parameter as detected by standard art known methods, such as those described herein.
  • aryl refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," “heteroaryls” or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, s
  • cancer refers to a malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Cytotoxicity refers to the quality of an agent being toxic to cells.
  • a toxic agent can be a chemical substance, a cell, or a venom.
  • Cells treated with a cytotoxic agent may undergo necrosis, in which they lose membrane integrity and die rapidly as a result of cell lysis. The cells may stop actively growing and dividing (a decrease in cell viability), or may end up with apoptosis.
  • Detect refers to identifying the presence, absence or amount of the object to be detected.
  • Disease directs to any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • diastereomers refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • an effective amount refers to the amount of an agent required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • a therapeutically effective amount of a compound delineated herein ⁇ i.e., an effective dosage may range from about O. ⁇ g to 20 milligram per kilogram of body weight per day (mg/kg/day) (e.g., 0. ⁇ g/kg to 2mg/kg, 0.3-3 ⁇ g/kg, 0.18-0.54mg/kg). In other embodiments, the amount varies from about 0.1 mg/kg/day to about 100 mg/kg/day. In still other embodiments, the amount varies from about 0.001 ⁇ g to about 100 ⁇ g/kg (e.g., of body weight).
  • mg/kg/day milligram per kilogram of body weight per day
  • the amount varies from about 0.1 mg/kg/day to about 100 mg/kg/day.
  • the amount varies from about 0.001 ⁇ g to about 100 ⁇ g/kg (e.g., of body weight).
  • a compound of the invention e.g., any of compounds 120, 12, 61, 1, 56, 31, and 196 is administered to a mouse, preferably 1-100 mg/kg, more preferably 5-50 mg/kg.
  • a dog receives 1- 20mg/kg of such compounds.
  • a human subject receives 0. ⁇ g/kg to 2mg/kg of a compound of the invention (e.g., any of compounds 120, 12, 61, 1, 56, 31, and 196) per day.
  • 0.3-3 ⁇ g kg of such compounds is administered to a human subject.
  • 0.18-0.54mg/kg total per day is administered to a human subject.
  • certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of a compound delineated herein can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a compound delineated herein in the range of between about O. ⁇ g to 20 milligram per kilogram of body weight per day
  • the dosage is administered one time per day, two times per day, or one time per week. Treatment can be carried out for between about 1 to 10 weeks, between 2 to 8 weeks, between about 3 to 7 weeks, or for about 4, 5, or 6 weeks. It will also be appreciated that the effective dosage of a compound delineated herein used for treatment may increase or decrease over the course of a particular treatment.
  • enantiomers refers to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.”
  • halogen designates -F, -CI, -Br or -I.
  • haloalkyl is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by halogen, e.g., fluoromethyl and trifluoromethyl.
  • hydrate refers to a compound of the invention or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of water bound by non- covalent intermolecular forces.
  • hydroxyl means -OH.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents.
  • heteroaryl groups include, but are not limited to, pyridyl, furanyl, benzodioxolyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,
  • benzoxazolyl benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, and indolyl.
  • heterocyclyl refers to organic compounds that contain at least at least one atom other than carbon (e.g., S, O, N) within a ring structure.
  • the ring structure in these organic compounds can be either aromatic or non-aromatic.
  • heterocyclic moeities include, are not limited to, pyridine, pyrimidine, pyrrolidine, furan, tetrahydrofuran, tetrahydrothiophene, and dioxane.
  • combination with is intended to refer to all forms of administration that provide an a compound/method of the invention together with another pharmaceutical agent (such as a second compound used in clinic for treating a related disease or disorder) or therapy, where the two are administered concurrently or sequentially in any order.
  • another pharmaceutical agent such as a second compound used in clinic for treating a related disease or disorder
  • isomers or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • isotopic derivatives includes derivatives of compounds in which one or more atoms in the compounds are replaced with corresponding isotopes of the atoms.
  • an isotopic derivative of a compound containing a carbon atom (C 12 ) would be one in which the carbon atom of the compound is replaced with the C 13 isotope.
  • neoplastic refers to those cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • a neoplastic disease state may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state.
  • pathologic i.e., characterizing or constituting a disease state
  • non-pathologic i.e., a deviation from normal but not associated with a disease state.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • Phathologic hyperproliferative cells occur in disease states characterized by malignant tumor growth.
  • Examples of non-pathologic hyperproliferative cells include proliferation of cells associated with wound repair.
  • modulate refers to increases or decreases in a parameter in response to exposure to a compound of the invention.
  • modulating can be either increasing or decreasing protein (such as, AF508 CFTR protein) expression.
  • obtaining as in “obtaining compound” is intended to include purchasing, synthesizing or otherwise acquiring the compound.
  • optical isomers as used herein includes molecules, also known as chiral molecules, are exact non-superimposable mirror images of one another.
  • optional substituents include, for example, hydroxyl, halogen, cyano, nitro, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, Ci-C 8 alkoxy, C 2 -C 8 alkyl ether, C 3 -C 8 alkanone, d- Csalkylthio, amino, mono- or di-(Cl-C 8 alkyl)amino, haloCi-Csalkyl, haloCi-C 8 alkoxy, Ci- Cgalkanoyl, C2-C 8 alkanoyloxy, Ci-C 8 alkoxycarbonyl, -COOH, -CONH 2 , mono- or di-(Ci -
  • Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents.
  • Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substituents).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • patient as used herein includes a human or other mammalian subject in need of a treatment according to the present invention.
  • polycyclyl or “polycyclic radical” refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
  • alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • polymorph refers to solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g. , tablets crumble on storage as a kinetically favored polymorph converts to thermodynamic ally more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing.
  • prodrug includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g. , acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g. , benzyl ester), substituted (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e
  • prodrug moieties are propionoic acid esters and acyl esters.
  • Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
  • reference is meant a standard or control condition.
  • subject includes organisms which are capable of suffering from a CF or who could otherwise benefit from the administration of a compound of the invention, such as human and non-human animals.
  • Preferred human animals include human patients suffering from or prone to suffering from cystic fibrosis, as described herein.
  • non-human animals of the invention includes all vertebrates, e.g., , mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, also sheep, dog, cow, chickens, amphibians, and reptiles.
  • sulfhydryl or "thiol” means -SH.
  • systemic administration means the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • solvate refers to solvate forms of the compounds of the present invention.
  • tautomers refers to isomers of organic molecules that readily interconvert by tautomerization, in which a hydrogen atom or proton migrates in the reaction, accompanied in some occasions by a switch of a single bond and an adjacent double bond.
  • the invention provides methods that are useful for the development of therapeutic agents to treat or prevent a disease or disorder delineated herein.
  • the methods of the invention provide a facile means to identify therapies that are safe for use in subjects.
  • the methods of the invention provide a route for analyzing virtually any number of compounds for effects on a disease described herein with high-volume throughput, high sensitivity, and low complexity.
  • AF508 CFTR mutation in cystic fibrosis causes two distinct problems: first, the mutant is unable to fold properly, which leads retention within the endoplasmic reticulum (ER) compartment and rapid degradation; second, reduced open channel probability associated with the mutation leads to reduced chloride conductance. It is believed that only a small fraction of normal expression level is needed to provide a clinically significant impact on the disease phenotype of CF. Accordingly, strategies that can increase AF508 CFTR expression and/or trafficking to the cell surface and
  • the present inventors have unexpectedly found that certain small molecules have increased total cellular and membrane- associated CFTR protein levels, and CFTR- associated chloride currents in human colon cancer T84 cells. These small molecules caused increase in AF508 CFTR expression. Taken together, the results show that these small molecules are useful in treating or preventing cystic fibrosis.
  • the invention provides a compound of formula (I):
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or N;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or N;
  • Q and W each independently, is O or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • said compound of formula (I) is not one of the following compounds: Anthraquinone;
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or N;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or N;
  • Q and W each independently, is O, NR d , or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R d is H or alkyl
  • doxorubicin or "dox”
  • dox (8-acetyl-10-[(25,45,55,65 , )-4-amino-5-hydroxy-6-methyl-oxan- 2-yl] oxy-6,8 , 11 -trihydroxy- 1 -methoxy-9, 10-dihydro-7H-tetracene-5 , 12-dione
  • one of Q and W is O, and the other is NH.
  • the invention relates to a derivative, clathrate, polymorph, prodrug or metabolite of a compound of formula (I) or (la).
  • Certain embodiments provide that one of Z 1 , Z 2 , Z 3 , and Z 4 is N, and the others are CH. A particular embodiment provides that n is 0.
  • Z 2 is N, and Z 1 , Z 3 , and Z 4 are all CH. In another embodiment, Z 1 is N, and Z 2 , Z 3 , and Z 4 are all CH.
  • Q and W are both O.
  • R 2 is an optionally substituted amino group; wherein R 2 can be the same or different.
  • the R 2 s, together with the bonds each of them attach to, form a 5- or 6-membered cyclic structure, wherein said cyclic structure is further optionally substituted by one or more substituents selected from an optionally substituted alkoxyl, hydroxyl, an optionally substituted alkyl-carbonyl, an optionally substituted -O-heterocylyl groups.
  • n is 2.
  • R 1 each independently, is hydroxyl or an optionally substituted alkoxyl.
  • R x s are the same.
  • R J s are different.
  • the invention also relates to a compound of formula (II):
  • Z 1 , Z 2 , Z 3 , and Z 4 are CH or N;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or N;
  • Q and W each independently, is O or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl.
  • Z 1 , Z 2 , Z 3 , and Z 4 each independently, is CH or N;
  • a 1 , A 2 , A 3 , and A 4 each independently, is CH or N;
  • Q and W each independently, is O, NR d , or S;
  • R x s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino groups;
  • R 2 s together with the bonds each of them attach to, form a cyclic or heterocyclyl structure, which is further optionally substituted by one or more halogen, hydroxyl, an optionally substituted alkoxyl, an optionally substituted alkyl-carbonyl, an optionally substituted amino or -O-heterocylyl groups; wherein said -O-heterocylyl is further optionally substituted;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, 3, or 4;
  • R' each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted alkyl-acetyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkyl-carbonyl, or an optionally substituted amino-carbonyl-;
  • R is hydrogen, hydroxyl, an optionally substituted alkoxyl, halogen, an optionally substituted amino, an optionally substituted alkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R a each independently, is hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R b each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl;
  • R c each independently, is hydrogen, halogen, hydroxyl, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxyl, an optionally substituted amino, an optionally substituted aralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, or an optionally substituted alkylcarbonyl; and
  • R d is H or alkyl.
  • the invention also relates to a derivative, clathrate, polymorph, prodrug or metabolite of a compound of formula (II) or (Ila).
  • a compound of the invention has no or little anti-tumor activity.
  • the compound of formula (II) or (Ila) is not dox or mitoxantrone.
  • a compound of formula (II) or (Ila) may be an anthracycline derivative of the following formula (lib):
  • W is O or NR d ;
  • R 3 is H or -OR d ;
  • R d is H or alkyl; or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, or N-oxide thereof.
  • the anthracycline derivative is (85,105)-10-(4-Amino-5-hydroxy- 6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,l l-trihydroxy-8-(2-hydroxyacetyl)-l-methoxy- 7,8,9,10-tetrahydrotetracene-5,12-dione ("doxorubicin”) or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, or N- oxide thereof:
  • the anthracycline derivative of the invention may be, for example, (85,10S)-8-acel 10-[(25',45 , ,55 , ,65 , )-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6,8,l l-trihydroxy-l- methoxy-9,10-dihydro-7H-tetracene-5,12-dione ("daunorubicin”) or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, or N-oxide thereof:
  • the invention also provides anthracycline derivatives, such as, but are not limited to, (8S,10S)-8-acetyl-6,8,10,l l-tetrahydroxy-l-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione ("daunomycinone") and (8S,10S)-6,8,10,1 l-tetrahydroxy-8-(2-hydroxyacetyl)-l-methoxy- 7,8,9,10-tetrahydrotetracene-5,12-dione ("adriamycinone”), with the following structures, respectively:
  • the compounds of the invention include, for example, 8- acetyl-10-(4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)-6,8,l l-trihydroxy-12- imino-l-methoxy-7,8,9,10-tetrahydrotetracen-5(12H)-one ("5-imino-doxorubicin”) or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, orN-oxide thereof:
  • the compound is 6,9-bis(2- aminoethylamino)-benzo[g]isoquinoline-5,10-dione ("pixantrone” or "2-aza- anthracenedione”), or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, orN-oxide thereof.
  • the invention also provides, for example, 6,9-bis(2- aminoethylamino)benzo[g]quinoline-5, 10-dione ("abcantrone” or "1-aza-anthracenedione”), or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, or N-oxide thereof.
  • abcantrone or "1-aza-anthracenedione
  • a compound of the invention may be, for example, l,4-dihydroxy-5,8- bis(2-(hydroxymethylamino)ethylamino)anthracene-9, 10-dione ("mitoxantrone), or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, -oxide there
  • Mitoxantrone The structures of the compounds of the invention may include asymmetric carbon atoms. Accordingly, the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and/or by stereochemically controlled synthesis.
  • Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers.
  • the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, and the like.
  • diastereomeric esters can be formed with enantiomerically pure chiral alcohols, such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • enantiomerically pure chiral alcohols such as menthol
  • hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • a compound of the invention is capable of preventing or treating cystic fibrosis in a patient identified as in need of a treatment of cystic fibrosis thereof.
  • the compounds of the invention are capable of increasing CFTR expression level in a clinically significant amount in a cell membrane.
  • a compound of the invention is capable of correcting AF508 mutation form of cystic fibrosis.
  • a compound of the invention is capable of treating lung infections in a patient.
  • a compound in accordance with the invention may also be used for reducing swelling, opening up the airways, and/or thinning mucus in a patient.
  • the compound of the invention may also be capable of treating or preventing a cancer in the patient.
  • the invention also provides methods for treating or preventing cystic fibrosis in a subject identified as in need of a treatment of cystic fibrosis thereof by administering to the subject an effective amount of a compound of the invention.
  • the effective amount of a compound of the invention shows no or little systemic cytotoxicity.
  • the subject is a mammal, in particular a human.
  • the method of the invention is capable of increasing the expression and/or trafficking of CF mutants such as AF508 CFTR. It is believed that an increase of CFTR expression in cystic fibrosis offers clinical benefits to the cystic fibrosis patients.
  • the invention also provides gene constructs and cells transfected with these constructs which can be used to identify pharmacological agents for use in increasing CFTR protein expression and thus in potentially treating cystic fibrosis.
  • Gene constructs of the invention include, for example, a human CFTR cDNA coding region linked at the 5' end to a cDNA for a marker or reporter gene under the regulation of the proximal human CFTR promoter region. Either wild-type or a mutant CFTR cDNA can be used in accordance with the invention. In an embodiment, the CFTR cDNA is mutant AF508 CFTR cDNA.
  • Cell lines transfected with the gene constructs can be used to elucidate wild-type and mutant CFTR expression and trafficking.
  • the cell lines can also be used to screen and identify agents which increase functional cell surface protein expression of a mutant CFTR.
  • screening assays can be performed in accordance with well known techniques in cells transfected with a gene construct of the invention to identify agents which increase levels of CFTR expression by measuring levels of fluorescence in transfected cells exposed to the agent and transfected cells not exposed to the agent.
  • the screening assays are performed in cells transfected with a gene construct comprising a mutant CFTR cDNA, such as the human AF508 mutant.
  • compounds of the invention are administered to the subject in combination with a pharmaceutically diluent or acceptable carrier.
  • the compound can be administered using a pharmaceutically acceptable formulation.
  • a compound of the invention is administered systemically to patients (e.g., humans) with cystic fibrosis, especially patients with cystic fibrosis resulting from a mutant CFTR such as AF508.
  • a compound in accordance with the invention can reverse the phenotype of cystic fibrosis caused by the mutant.
  • the compound of the invention is administered to a subject in a dosage of 0.25 ⁇ .
  • the compound at the administered dosage has no or little anti-tumor activity.
  • the compound at the administered dosage causes no or little cytotoxicity in the subject.
  • the compound of the invention can be administered with an additional therapeutic agent (such as, a chemotherapeutic agent).
  • an additional therapeutic agent such as, a chemotherapeutic agent.
  • the compound of the invention and the additional therapeutic agent can be administered concurrently.
  • the compound of the invention and the chemotherapeutic agent can be administered sequentially.
  • the compound of the invention is administered orally. In other embodiments, the compound of the invention is administered intravenously. In yet other embodiments, the compound of the invention is administered topically. In still other embodiments, the compound of the invention is administered topically or parenterally.
  • the compounds are typically administered at a concentration of about O. ⁇ g to 20 milligram per kilogram of body weight per day (mg/kg/day) (e.g., 0. ⁇ g/kg to 2mg/kg, 0.3-3 ⁇ g/kg, 0.18-0.54mg/kg). In other embodiments, the amount varies from about 0.1 mg/kg/day to about 100 mg kg/day. In still other embodiments, the amount varies from about 0.001 ⁇ g to about 100 ⁇ g/kg (e.g., of body weight).
  • a therapeutically effective amount or a prophylactically effective amount of a compound described herein can readily by one skilled in the art.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular compound being employed. In determining the dosages
  • therapeutically effective amount or dose and the prophylactically effective amount or dose, a number of factors are considered, including, but not limited to: pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease(s) involved; the degree of or involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (e.g., the interaction of the compounds of the invention with other co-administered therapeutics); and other relevant circumstances.
  • a therapeutically effective amount and a prophylactically effective amount of a compound of the invention is expected to vary from about O. ⁇ g to 20 milligram per kilogram of body weight per day (mg/kg/day) (e.g., O. ⁇ g/kg to 2mg/kg, 0.3-3pg/kg, 0.18-0.54mg/kg). In other embodiments, the amount varies from about 0.1 mg/kg/day to about 100 mg/kg/day. In still other embodiments, the amount varies from about 0.001 ⁇ g to about 100 ⁇ g/kg (e.g., of body weight).
  • cystic fibrosis in animals e.g., dogs, rodents
  • compounds which are determined to be effective for the prevention or treatment of cystic fibrosis in humans may also be useful in treatment of cystic fibrosis in humans.
  • Those skilled in the art of treating or preventing cystic fibrosis in humans will know, based upon the data obtained in animal studies, the dosage and route of administration of the compound to humans. In certain instances, the dosage and route of administration in humans are expected to be similar to that in animals.
  • the present invention also provides a method for identifying compounds for use in the treatment or prevention of cystic fibrosis.
  • the method comprises exposing cells transfected with the genetic construct to a compound; measuring CFTR expression levels or trafficking of CFTR to the cell membrane in the exposed cells; and comparing measured CFTR expression levels or trafficking of CFTR to the cell membrane in the exposed cells to CFTR expression levels or trafficking of CFTR to the cell membrane in cells not exposed to the agent, wherein an increase in CFTR expression levels or trafficking of CFTR to the cell membrane in the exposed cells as compared to the unexposed cells is indicative of the agent being useful in the treatment of cystic fibrosis.
  • This method can be used to identify compounds as therapeutic agents for treating or preventing cystic fibrosis in a patient.
  • Another aspect of the invention comprises obtaining the compound of the invention through synthetic methods and/or purification from a mixture.
  • the compound of the invention can be administered in combination with any conventional cystic fibrosis treatment or therapy, including but not limited to, chest physical therapy, pulmonary rehabilitation, oxygen therapy, and therapies for preventing or treating blockages in the intestines.
  • the compounds of the invention are administered in combination with any conventional cystic fibrosis agent.
  • the compound of the invention can be used together with conventional methods for the prevention or management of cystic fibrosis. Methods like loosening and removing mucus from lungs, exercising, breathing techniques, nutritional therapies, and preventing dehydration may be used.
  • the compound of invention can be administered to a patient with any conventional therapy for treating or preventing lung diseases.
  • the compound of invention can be administered to a patient with any conventional therapy for treating or preventing diseases or disorders relating digestive system, gastrointestinal tract, reproductive organs, and/or psychological support.
  • the compound of the invention may be used to treat or prevent cystic fibrosis complication in a patient.
  • a common cystic fibrosis complication involves diabetes.
  • Another common CF complication is a bone-thinning disorder (such as, osteoporosis).
  • a compound of the invention may be administered with conventional therapies for the treatment or prevention of a disorder associated with diabetes.
  • a compound of the invention may be administered with conventional therapies or treatment/prevention methods associated with a bone-thinning disorder. Accordingly, if so desired, a compound of the invention can be administered with a conventional therapeutic agent for treating or preventing diabetes, and/or a bone-thinning disorder.
  • the compound of the invention can be administered in combination with any conventional anti-cancer therapy, including but not limited to, surgery, radiation therapy, or chemotherapy. Accordingly, the compounds of the invention may be administered in combination with any conventional chemotherapeutic agent, such as an alkylating agent.
  • the invention also provides pharmaceutical compositions for the treatment or prevention of cystic fibrosis in a subject identified in need of a treatment of cystic fibrosis thereof, comprising an effective amount a compound of the invention and a pharmaceutically acceptable carrier.
  • the subject in need of a treatment or prevention of cystic fibrosis is a patient.
  • the patient is a mammal, in particular a human.
  • the invention provides a packaged composition for treating or preventing cystic fibrosis in a patient identified in need of a treatment of cystic fibrosis thereof.
  • a compound of the invention is packaged in a therapeutically effective amount with a pharmaceutically acceptable carrier or diluent.
  • the therapeutically effective amount of a compound of the invention is capable of increasing CFTR expression level in a clinically significant amount in a cell membrane.
  • the compound shows no or little systemic cytotoxicity in the patient at the administered amount.
  • a compound of the invention does not show significant anti-tumor activity.
  • the compound of the invention is compound is 6,9-bis(2- aminoethylamino)benzo[g]quinoline-5,10-dione or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, isotopic derivative, orN-oxide thereof.
  • compositions of the invention comprise a compound described herein in combination with one or more conventional cystic fibrosis agents.
  • such compositions are labeled for the treatment or prevention of cystic fibrosis.
  • compositions of the invention contain a compound described herein in combination with one or more additional therapeutic agents.
  • additional therapeutic agents include, for example, antibiotics, anti-inflammatory medicines, bronchodilators, mucus-thinning medicines, diabetic medication, antiresorptive agents, and bone anabolic agents.
  • antibiotics that may be used include vancomycin, tobramycin, meropenem, ciprofloxacin, piperacillin, and azithromycin.
  • the additional therapeutic agents include, but are not limited to, mitomycin C (MMC), and anthracycline drugs (such as, doxorubicin).
  • MMC mitomycin C
  • anthracycline drugs such as, doxorubicin
  • the additional therapeutic agent may also increase functional cell surface expression of CFTR protein.
  • the compositions of the invention includes a compound described herein in combination with a conventional neoplastic agent.
  • Conventional chemotherapeutic agents include, but are not limited to, abiraterone, alemtuzumab, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin,
  • a combination of the invention comprises any one or more of the following: vinca alkaloids (e.g., vinblastine), taxanes (e.g., paclitaxel, docetaxel), epothilones (e.g., ixabepilone), antifolates (e.g., Methotrexate), purine analogs (e.g., fludarabine), pyrimidine analogs (e.g., gemcitabine), DNA intercalators (e.g., ethidium bromide), topoisomerase Inhibitors (e.g., topotecan), alkylating agents (e.g., carmustine, bendamustine), platinum-based agents (e.g., cisplatin, oxaliplatin), receptor antagonists (e.g, atrasentan), hormone agents (e.g.
  • vinca alkaloids e.g., vinblastine
  • taxanes e.g., paclitaxel, do
  • anti-androgens aromatase inhibitors
  • anthracyclines e.g., adriamycin, doxorubicin
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., actinomycin D and gramicidin D
  • antimicrotubule drugs e.g., colchicine
  • protein synthesis inhibitors e.g., puromycin
  • toxic peptides e.g., valinomycin
  • enzyme inhibitors e.g. CD inhibitors
  • the compound is administered to the subject using a
  • these pharmaceutical compositions are suitable for oral or parenteral administration to a subject.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • the subject is a mammal, e.g., a
  • compositions of the invention include a therapeutically effective amount of a compound in combination with a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable refers to those compounds of the invention, compositions containing such compounds, 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.
  • pharmaceutically-acceptable excipient includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a liquid or solid filler such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions containing a compound(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety- nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • compositions include the step of bringing into association a compound(s) with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound(s) as an active ingredient.
  • a compound may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compound(s) include
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • the oral compositions can include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compound(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compound(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound(s) may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to compound(s) of the present invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound(s), excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the compound(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a nonaqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids, such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compound(s) in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chlor
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of compound(s) in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compound(s) When the compound(s) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a
  • the compound(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • An exemplary dose range is from about O. ⁇ g to 20 milligram per kilogram of body weight per day (mg/kg/day) (e.g., O. ⁇ g/kg to 2mg/kg, 0.3-3 ⁇ g/kg, 0.18-0.54mg/kg).
  • the amount varies from about 0.1 mg/kg/day to about 100 mg/kg/day.
  • the amount varies from about 0.001 ⁇ g to about 100 ⁇ g kg (e.g., of body weight). Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • kits for the treatment or prevention of cystic fibrosis in a patient identified in need of a treatment of cystic fibrosis thereof includes a therapeutic or prophylactic composition containing an effective amount of a compound of the invention in unit dosage form.
  • a compound of the invention is provided in combination with an additional therapeutic agent (see above discussions).
  • the kit comprises a sterile container which contains a therapeutic or prophylactic composition; such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • a sterile container which contains a therapeutic or prophylactic composition
  • Such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • a compound of the invention is provided together with instructions for administering the compound to a subject having or at risk of developing cystic fibrosis.
  • the instructions will generally include information about the use of the composition for the treatment or prevention of cystic fibrosis.
  • instructions may be provided for treating or preventing lung infections, reducing swelling, opening up the airways, thinning mucus, treating or preventing diabetes, or treating or preventing a bone-thinning disorder in a patient.
  • the instructions include at least one of the following:
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of medicinal chemistry, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan.
  • Cells were plated in 96 well plates (Fisher, Medford, Mass.) at a density of 1000 cells per well. Twenty-four hours after plating, the cells were dosed with a compound of the invention in 0-30 ⁇ in serum-free media. The cells were incubated for three days and assayed using the CellTiter 96 AQueous One Solution Reagent (Promega Corp., Madison, Wis.) using the manufacturer's instructions. The data were collected and analyzed using the Softmax software.
  • Confocal microscopy of living cells is used to determine whether agents alter specific steps of CFTR processing or trafficking to the membrane resulting in transient increased expression. Confocal microscopy enables localization of CFTR at the sub-cellular level and permits time-resolved studies in living cells to examine effects of CFTR post-transcriptional expression.
  • a 3-dimensional image reconstruction is used to determine the relationship between internal structures and the plasma membrane. These images can also be rendered in pseudocolor to reveal differences in the intensity of staining in different parts of the cell.
  • Localization of GFP-CFTR subunits within subcellular compartments including the ER, Golgi apparatus, sub-plasma membrane compartments, and the plasma membrane is performed via a double -labeling approach. Subcellular compartments are identified in the same cells as GFP-CFTR using an array of organelle- specific antibodies and fluorescent markers. By superimposing red fluorescent images of the ER, Golgi apparatus and submembrane and plasma membrane compartments with images of GFP-CFTR, the subcellular distribution and movement of GFP-CFTR in control and agent-exposed cells can be identified.
  • MDCK-C7-DF508-CFTR cells were treated with a 0.25 ⁇ drug (e.g., control, doxorubicin, daunorubicin, and mitoxantrone) for 24 hours.
  • CFTR-associated apical chloride current was measured by Ussing chamber in polarized monolayers (parameters: Disc; no NaBu , + amiloride, + nystatin 20', + genestein 5', + cAMP, + DPC)

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Abstract

La présente invention concerne de nouveaux composés utiles dans le traitement ou la prévention d'une fibrose kystique. De plus, l'invention concerne également des méthodes, des kits et des compositions conditionnées pour le traitement ou la prévention d'une fibrose kystique chez un sujet identifié comme ayant besoin d'un traitement de fibrose kystique. Dans des modes de réalisation particuliers, les composés selon l'invention sont capables d'augmenter le taux d'expression du CFTR jusqu'à atteindre une quantité significative du point de vue clinique dans une membrane cellulaire.
PCT/US2012/064145 2011-11-08 2012-11-08 Composés et méthodes de traitement d'une fibrose kystique WO2013070911A1 (fr)

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Publication number Priority date Publication date Assignee Title
JP2017054798A (ja) * 2015-09-11 2017-03-16 学校法人早稲田大学 電荷貯蔵材料、電極活物質及び二次電池
CN113461682A (zh) * 2021-06-30 2021-10-01 西北工业大学 一种热致延迟荧光材料及其制备方法和应用

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Title
LIN-LIN SHI ET AL.: "Activation effect of cathartic natural compound Rhein to CFTR chloride channel", CHEMICAL RESEARCH IN CHINESE UNIVERSITIES, vol. 22, no. 3, 2006, pages 312 - 314, XP022855846, DOI: doi:10.1016/S1005-9040(06)60105-0 *
MARGARIDA D. AMARAL ET AL.: "Molecular targeting of CFTR as a therapeutic approach to cystic fibrosis", TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 28, no. 7, 2007, pages 334 - 341 *
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017054798A (ja) * 2015-09-11 2017-03-16 学校法人早稲田大学 電荷貯蔵材料、電極活物質及び二次電池
CN113461682A (zh) * 2021-06-30 2021-10-01 西北工业大学 一种热致延迟荧光材料及其制备方法和应用

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