EP2362874A2 - Modulateurs des transporteurs de la cassette de liaison à l atp - Google Patents
Modulateurs des transporteurs de la cassette de liaison à l atpInfo
- Publication number
- EP2362874A2 EP2362874A2 EP09795592A EP09795592A EP2362874A2 EP 2362874 A2 EP2362874 A2 EP 2362874A2 EP 09795592 A EP09795592 A EP 09795592A EP 09795592 A EP09795592 A EP 09795592A EP 2362874 A2 EP2362874 A2 EP 2362874A2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Definitions
- the present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof and methods therewith.
- ABSC ATP-Binding Cassette
- CFTR Cystic Fibrosis Transmembrane Conductance Regulator
- the present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
- ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions.
- ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities.
- Some of these transporters were discovered as multidrug resistance proteins (like the MDRl-P glycoprotein, or the multidrug resistance protein, MRPl), defending malignant cancer cells against chemotherapeutic agents.
- MRPl multidrug resistance protein
- 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
- ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial.
- CFTR cAMP/ATP-mediated anion channel
- CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
- CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
- the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ⁇ F508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
- CFTR transports a variety of molecules in addition to anions
- this role represents one element in an important mechanism of transporting ions and water across the epithelium.
- the other elements include the epithelial Na + channel, ENaC, Na + /2C17K + co-transporter, Na + -K + -ATPaSe pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell.
- CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
- COPD chronic obstructive pulmonary disease
- COPD dry eye disease
- Sjogren's Syndrome Sjogren's Syndrome
- COPD is characterized by airflow limitation that is progressive and not fully reversible.
- the airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
- Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
- increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD.
- Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles.
- Sj ⁇ grens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease.
- the disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
- the diseases associated with the first class of ER malfunction are Cystic fibrosis (due to misfolded ⁇ F508-CFTR as discussed above), Hereditary emphysema (due to al -antitrypsin; non Piz variants), Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to Lysosomal processing enzymes), Sandhof/Tay-Sachs (due to ⁇ -Hexosaminidase), Crigler- Najjar type II (due to UDP-glucuronyl-sialyc-transferase), Polyendoc
- Glycanosis CDG type 1 Hereditary emphysema (due to ⁇ l- Antitrypsin (PiZ variant), Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, II, IV procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACT deficiency (due to ⁇ l-Antichymotrypsin), Diabetes insipidus (DI), Neurophyseal DI (due to Vasopvessin hormone/V2-receptor), Neprogenic DI (due to Aquaporin II), Charcot-Marie Tooth syndrome (due to Peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease ( due to ⁇ APP and presenilins), Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick
- CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport.
- the mechanism involves elevation of cAMP and stimulation of CFTR.
- Acute and chronic diarrheas represent a major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
- Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
- ETEC enterotoxogenic E-coli
- Common viral causes of diarrhea include rotavirus and coronavirus.
- Other infectious agents include Cryptosporidium, giardia lamblia, and salmonella, among others.
- Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
- R, R 1 , R 2 , R 3 , R 4 , and R 5 are defined below.
- compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1,
- ABS-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vitro.
- binding domain as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al., J. Gen. Physiol. (1998): 111(3), 477-90.
- CFTR cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, ⁇ F508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
- modulating means increasing or decreasing, e.g. activity, by a measurable amount.
- Compounds that modulate ABC Transporter activity, such as CFTR activity, by increasing the activity of the ABC Transporter, e.g., a CFTR anion channel are called agonists.
- Compounds that modulate ABC Transporter activity, such as CFTR activity, by decreasing the activity of the ABC Transporter, e.g., CFTR anion channel are called antagonists.
- An agonist interacts with an ABC Transporter, such as CFTR anion channel, to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
- An antagonist interacts with an ABC Transporter, such as CFTR, and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
- an ABC Transporter such as CFTR
- the phrase "treating or reducing the severity of an ABC Transporter mediated disease” refers both to treatments for diseases that are directly caused by ABC Transporter and/or CFTR activities and alleviation of symptoms of diseases not directly caused by ABC Transporter and/or CFTR anion channel activities.
- diseases whose symptoms may be affected by ABC Transporter and/or CFTR activity include, but are not limited to, Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation- Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1 , Hereditary emphysema
- compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
- aliphatic encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
- an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms.
- An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.
- An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaral
- substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SC> 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
- carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
- cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (al
- an "alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
- An alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino al
- substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
- an "alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond.
- An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
- An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphatic sulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SCV, aliphaticamino-SCV, or cycloaliphatic- SO 2 -], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, hetero
- an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refer to an amido group such as -N(R X )-C(O)-R Y or -C(O)-N(R X ) 2 , when used terminally, and -C(O)- N(R X )- or -N(R X )-C(O)- when used internally, wherein R x and R ⁇ are defined below.
- amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl) amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
- an "amino" group refers to -NR X R Y wherein each of R x and R ⁇ is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted.
- amino groups examples include alkylamino, dialkylamino, or arylamino.
- amino When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR X -. R x has the same meaning as defined above.
- an "aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
- the bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings.
- a benzofused group includes phenyl fused with two or more C 4 _ 8 carbocyclic moieties.
- An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro
- Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as
- aminoaryl e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;
- an "araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a C 1 ⁇ alkyl group) that is substituted with an aryl group.
- "Aliphatic,” “alkyl,” and “aryl” are defined herein.
- An example of an araliphatic such as an aralkyl group is benzyl.
- an "aralkyl” group refers to an alkyl group (e.g., a Ci_ 4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above. An example of an aralkyl group is benzyl.
- An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl] , cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycl
- a "bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common).
- Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
- a “carbocycle” or “cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
- a “cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
- cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
- a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds.
- Examples of cycloalkenyl groups include cyclopentenyl, 1 ,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.
- a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,
- heterocycle or “heterocycloaliphatic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.
- heterocycloalkyl refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
- heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[Z?]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-di
- a "heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
- Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.
- a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycl
- a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
- a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
- a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[ ⁇ ]furyl, benzo[Z?]thiophenyl, quinolinyl, or isoquinolinyl).
- heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[ ⁇ ]furyl, benzo[Z?]thiophenyl, quinolinyl, or isoquinolinyl.
- heteroaryl examples include azetidinyl, pyridyl, IH- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl,
- monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
- Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
- bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[ ⁇ ]furyl, benzo[Z?]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo[ ⁇ ]furyl, bexo[ ⁇ ]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
- Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
- a heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)
- heterocycloaliphatic aliphatic
- carbonyl or (heteroaraliphatic)carbonyl]
- sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
- sulfinyl e.g., aliphatic sulfinyl
- sulfanyl e.g., aliphaticsulfanyl
- a heteroaryl can be unsubstituted.
- Non- limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy )heteroaryl [e.g., (alkoxycarbonyl)heteroaryl] ; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl] ; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heteroaryl)amino)carbonyl)hetero
- heteroaralkyl refers to an aliphatic group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group.
- aliphatic group e.g., a C 1-4 alkyl group
- heteroaryl e.g., a C 1-4 alkyl group
- heteroarylkyl refers to an alkyl group (e.g., a Ci_ 4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
- a heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
- cyclic moiety and “cyclic group” refer to mono-, bi-, and tricyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
- bridged bicyclic ring system refers to a bicyclic heterocyclicaliphatic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged.
- bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3 ' 7 ]nonyl.
- a bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heter
- an "acyl” group refers to a formyl group or R X -C(O)- (such as alkyl-C(O)-, also referred to as “alkylcarbonyl”) where R x and "alkyl” have been defined previously.
- R x and "alkyl” have been defined previously.
- Acetyl and pivaloyl are examples of acyl groups.
- an “aroyl” or “heteroaroyl” refers to an aryl-C(O)- or a heteroaryl-C(O)-.
- the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
- alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
- a "carbamoyl” group refers to a group having the structure -O-CO-NR X R Y or -NR X -CO-O-R Z , wherein R x and R ⁇ have been defined above and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
- a "carboxy” group refers to -COOH, -COOR X , -OC(O)H, -OC(O)R X , when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.
- haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
- haloalkyl includes the group -CF 3 .
- mercapto refers to -SH.
- AAss uusseedd hheerreeiinn aa ""ssulfo" group refers to -SO 3 H or -S ⁇ 3 R x when used terminally or -S(O) 3 - when used internally.
- a "sulfamide” group refers to the structure -NR X -S(O) 2 -NR Y R Z when used terminally and -NR X -S(O) 2 -NR Y - when used internally, wherein R x , R ⁇ , and R z have been defined above.
- a "sulfonamide” group refers to the structure -S(O) 2 -NR X R Y or -NR X -S(O) 2 -R Z when used terminally; or -S(O) 2 -NR X - or -NR X -S(O) 2 - when used internally, wherein R x , R ⁇ , and R z are defined above.
- sulfanyl group refers to -S-R x when used terminally and -S- when used internally, wherein R x has been defined above.
- sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
- a "sulfinyl” group refers to -S(O)-R X when used terminally and - S(O)- when used internally, wherein R has been defined above.
- exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
- a "sulfonyl” group refers to-S(O) 2 -R x when used terminally and -S(O) 2 - when used internally, wherein R x has been defined above.
- Exemplary sulfonyl groups include aliphatic-S(O) 2 -, aryl-S(O) 2 -, (cycloaliphatic(aliphatic))-S(O) 2 -, cycloaliphatic-S(O) 2 -, heterocycloaliphatic-S(O) 2 -, heteroaryl-S(O) 2 -, (cycloaliphatic(amido(aliphatic)))-S(O) 2 -or the like.
- a "sulfoxy" group refers to -O-SO-R X or -SO-O-R X , when used terminally and -0-S(O)- or -S(O)-O- when used internally, where R x has been defined above.
- halogen or halo group refers to fluorine, chlorine, bromine or iodine.
- alkoxycarbonyl which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.
- alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
- phospho refers to phosphinates and phosphonates.
- phosphinates and phosphonates include -P(O)(R P ) 2 , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
- aminoalkyl refers to the structure (R x ) 2 N-alkyl-.
- a "cyanoalkyl” refers to the structure (NC)-alkyl-.
- a "urea” group refers to the structure -NR X -CO-NR Y R Z and a “thiourea” group refers to the structure -NR X -CS-NR Y R Z when used terminally and -NR X - C0-NR Y - or
- the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
- the term "geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
- terminal refers to the location of a group within a substituent.
- a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
- Carboxyalkyl i.e., R x O(O)C-alkyl is an example of a carboxy group used terminally.
- a group is internal when the group is present in the middle of a substituent of the chemical structure.
- Alkylcarboxy e.g., alkyl-C(O)O- or alkyl-OC(O)-
- alkylcarboxyaryl e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-
- an "aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).
- a straight aliphatic chain has the structure
- a branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups.
- a branched aliphatic chain has the structure -[CQQIv- where each Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance.
- the term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
- Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
- an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
- the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
- the two alkxoy groups can form a ring together with the atom(s) to which they are bound.
- substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
- Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
- an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
- a ring substituent such as a heterocycloalkyl
- substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
- stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
- a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- an "effective amount” is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient.
- Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
- patient refers to a mammal, including a human.
- structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
- Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.
- Compounds of the present invention are useful modulators of ABC transporters and are useful in the treatment of ABC transporter mediated diseases.
- the present invention relates to compounds of formula I useful as modulators of ABC transporter activity:
- Ri is -Z A R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by -CO-, -CS-, -C0NR A -, -C0NR A NR A -, -CO 2 -, -OCO-, - NR A C0 2 -,
- Each R 4 Is independently R A , halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- R 2 is -Z B R 5 , wherein each Z B is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain wherein up to two carbon units of Z are optionally and independently replaced by -CO-, -CS-, -C0NR B -, -C0NR B NR B -, -CO 2 -, -OCO-, - NR B C0 2 -,
- Each R 5 is independently R B , halo, -OH, -NH 2 , -NO 2 , -CN, - CF 3 , or -OCF 3 .
- Each R is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
- Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S.
- Ring B is a group having formula Ia:
- each R 3 and R' 3 is independently -Z 0 R 6 , where each Z c is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain wherein up to two carbon units of Z c are optionally and independently replaced by -CO-, -CS-, -CONR C -, -CONR C NR C -, -CO 2 -, -OCO-, - NR 0 CO 2 -, -O-,
- Each R 6 is independently R c , halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
- R' 3 and an adjacent R 3 group, together with the atoms to which they are attached form an optionally substituted heterocycle.
- n is 1-3.
- ring B when ring A is unsubstituted cyclopentyl, n is 1, R 2 is 4-chloro, and R] is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6- dichlorophenyl(carbonyl))-3-methyl-lH-indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0, and R] is hydrogen, then ring B is not
- Ri is -Z A R 4 , wherein each Z A is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by -CO-, -CS-, -C0NR A -, -C0NR A NR A -, -CO 2 -, -OCO-, -
- Each R 4 is independently R A , halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- R] is -Z A R t , wherein each Z A is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain and each R 4 is hydrogen.
- R] is -Z A R t , wherein each Z A is a bond and each R 4 is hydrogen.
- Each R 2 is independently -Z B Rs, wherein each Z B is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain wherein up to two carbon units of Z B are optionally and independently replaced by -CO-, -CS-, -C0NR B -, -C0NR B NR B -, -
- Each R 5 is independently R B , halo, -OH, -
- Each R B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
- R 2 is an optionally substituted aliphatic.
- R 2 is an optionally substituted branched or straight Ci_ 6 aliphatic chain.
- R 2 is an optionally substituted branched or straight Ci_ 6 alkyl chain, an optionally substituted branched or straight C 2 _ 6 alkenyl chain, or an optionally substituted branched or straight C 2 _ 6 alkynyl chain.
- R 2 is a branched or straight Ci_ 6 aliphatic chain that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.
- R 2 is a branched or straight Ci_ 6 alkyl that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.
- R 2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic, or heterocycloaliphatic.
- R 2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is unsubstituted.
- R 2 is an optionally substituted branched or straight Ci_ 5 alkoxy.
- R 2 is a Ci_s alkoxy that is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.
- R 2 is a methoxy, ethoxy, propoxy, butoxy, or pentoxy, each of which is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.
- R 2 is hydroxy, halo, or cyano.
- R 2 is -Z B Rs
- Z B is independently a bond or an optionally substituted branched or straight C 1-4 aliphatic chain wherein up to two carbon units of Z B are optionally and independently replaced by -C(O)-, -O-, -S-, -S(O) 2 -, or -NH-
- R 5 is R , halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3
- R B is hydrogen or aryl.
- two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle.
- two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle, either of which is fused to the phenyl of formula I, wherein the carbocycle or heterocycle has formula Ib:
- Each of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is independently a bond, -CRvRV-, -NR 7 -, or -O-; each R 7 is independently -Z 0 R 8 , wherein each Z D is independently an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -CO-, -CS-, -C0NR D -, -CO 2 -, -OCO-, -NR 0 CO 2 -, -O-, -NR 0 CONR 0 -, -OCONR 0 -, -NR 0 NR 0 -, -NR 0 CO-, -S-, -SO-, -SO 2 -, -NR°-, -SO 2 NR 0 -, -NR 0 SO 2 -, or -NR 0 SO 2 NR 0 -
- Each R 8 is independently R°, halo, -OH, -NH 2 , -NO 2 , -CN, - CF 3 , or -OCF 3 .
- Each R° is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- Each R' 7 is independently hydrogen, optionally substituted C 1-6 aliphatic, hydroxy, halo, cyano, nitro, or combinations thereof.
- any two adjacent R 7 groups together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring, such as an optionally substituted cyclobutyl ring, or any two R 7 and R' 7 groups together with the atom or atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring or a heterocarbocyclic ring.
- two adjacent R 2 groups form an optionally substituted carbocycle.
- two adjacent R 2 groups form an optionally substituted 5-7 membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof.
- two adjacent R 2 groups form a 5-6 membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof.
- two adjacent R 2 groups form an unsubstituted 5-7 membered carbocycle.
- two adjacent R 2 groups form an optionally substituted heterocycle.
- two adjacent R 2 groups form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatoms independently selected from N, O, and S.
- two adjacent R 2 groups form an optionally substituted 5-6 membered heterocycle having 1-2 oxygen atoms.
- two adjacent R 2 groups form an unsubstituted 5-7 membered heterocycle having 1-2 oxygen atoms.
- two adjacent R 2 groups form a heterocyclic ring selected from:
- two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle
- a third R 2 group is attached to any chemically feasible position on the phenyl of formula I.
- an optionally substituted carbocycle or an optionally substituted heterocycle, both of which is formed by two adjacent R 2 groups; a third R 2 group; and the phenyl of formula I form a group having formula Ic:
- each R 2 group is independently selected from hydrogen, halo,
- R 2 is at least one selected from hydrogen, halo, methoxy, phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy, and methyl.
- two adjacent R 2 groups together with the atoms to which they are attached, form
- Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S.
- ring A is an optionally substituted 3-7 membered monocyclic cycloaliphatic.
- ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy, Ci_ 5 aliphatic, or combinations thereof.
- ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic.
- ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic having 1-2 heteroatoms independently selected from N, O, and S.
- ring A is tetrahydrofuran-yl, tetrahydro-2H-pyran-yl, pyrrolidone-yl, or piperidine-yl, each of which is optionally substituted.
- ring A is selected from
- Each Rg is independently -Z E R 9 , wherein each Z E is independently a bond or an optionally substituted branched or straight C 1-5 aliphatic chain wherein up to two carbon units of Z E are optionally and independently replaced by -CO-, -CS-, -C0NR E -, -CO 2 -, -OCO-, -NR E C0 2 -, -O-, -NR E C0NR E -, -0C0NR E -, -NR E NR E -, -NR E C0-, -S-, -SO-, -SO 2 -, -NR E -, -SO 2 NR 1 S -NR E S0 2 -, or -NR E S0 2 NR E -, each R 9 is independently R E , -OH, -NH 2 , -NO 2 , - CN,
- Each R E is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- q is 0-5.
- ring A is one selected from
- ring A is
- Ring B is a group having formula Ia:
- Each R 3 and R' 3 is independently -Z 0 R 6 , where each Z c is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z c are optionally and independently replaced by -CO-, -CS-, -CONR C -, - CONR C NR C -, -CO 2 -,
- Each R 6 is independently R c , halo, -OH, - NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R c is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle, or R' 3 and an adjacent R 3 , i.e., attached to the 2 position of the indole of formula Ia, together with the atoms to which they are attached form an optionally substituted heterocycle.
- ring B is
- each R 2 o is -Z G R 2 i, where each Z° is independently a bond or an optionally substituted branched or straight Ci_s aliphatic chain wherein up to two carbon units of Z G are optionally and independently replaced by -CO-, -CS-, -C0NR G -, -CO2-, - OCO-,
- Each R 21 is independently R°, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R° is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
- ring B is
- R' 3 is hydrogen and R 3 is attached to the 2, 3, 4, 6, or 7 position of the indole of formula Ia.
- R 3 is attached to the 2 or 3 position of the indole of formula Ia, and R 3 is independently an optionally substituted aliphatic.
- R 3 is an optionally substituted acyl group.
- R 3 is an optionally substituted (alkoxy)carbonyl.
- R 3 is (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl, or (butoxy)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.
- R 3 is an optionally substituted (aliphatic)carbonyl.
- R 3 is an optionally substituted (alkyl)carbonyl that is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof .
- R 3 is (methyl)carbonyl, (ethyl)carbonyl, (propyl)carbonyl, or
- R 3 is an optionally substituted (cycloaliphatic)carbonyl or an optionally substituted (heterocycloaliphatic)carbonyl.
- R 3 is an optionally substituted (C 3 _ 7 cycloaliphatic)carbonyl.
- R 3 is a (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is optionally substituted with aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof.
- R 3 is an optionally substituted (heterocycloaliphatic)carbonyl.
- R 3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N, O, and S.
- R 3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N and O.
- R 3 is an optionally substituted 4-7 membered monocyclic (heterocycloaliphatic)carbonyl having 1- 3 heteroatoms independently selected from N and O.
- R 3 is (piperidine-1- yl,)carbonyl, (pyrrolidine- l-yl)carbonyl, or (morpholine-4-yl)carbonyl, (piperazine-1- yl)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or aliphatic.
- R 3 is optionally substituted (aliphatic)amido such as (aliphatic(amino(carbonyl)) that is attached to the 2 or 3 position on the indole ring of formula Ia.
- R 3 is an optionally substituted (alkyl(amino))carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia.
- R 3 is an optionally substituted straight or branched (aliphatic(amino))carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia.
- R 3 is (N,N- dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.
- R 3 is an optionally substituted (alkoxy)carbonyl.
- R 3 is (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl, or (butoxy)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.
- R 3 is an optionally substituted straight or branched Ci_ 6 aliphatic.
- R 3 is an optionally substituted straight or branched Ci_ 6 alkyl.
- R 3 is independently an optionally substituted methyl, ethyl, propyl, butyl, isopropyl, or tertbutyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or combination thereof.
- R 3 is an optionally substituted C 3 - 6 cycloaliphatic. Exemplary embodiments include cyclopropyl, 1-methyl- cycloprop-1-yl, etc.
- p is 2 and the two R 3 substituents are attached to the indole of formula Ia at the 2,4- or 2,6- or 2,7- positions.
- Exemplary embodiments include 6- F, 3-(optionally substituted C]_ 6 aliphatic or C 3 _ 6 cycloaliphatic); 7-F-2-(-(optionally substituted Ci_ 6 aliphatic or C 3 _ 6 cycloaliphatic)), 4F-2-(optionally substituted Ci_ 6 aliphatic or C 3 - 6 cycloaliphatic); 7-CN-2-(optionally substituted C 1-6 aliphatic or C 3 - 6 cycloaliphatic); 7- Me-2-(optionally substituted C]_ 6 aliphatic or C 3 _ 6 cycloaliphatic) and 7-OMe-2-(optionally substituted C 1-6 aliphatic or C3-6 cycloaliphatic).
- R 3 is hydrogen. [00152] In several embodiments, R 3 is one selected from:
- R' 3 is independently -Z 0 R 6 , where each Z c is independently a bond or an optionally substituted branched or straight Ci_ 6 aliphatic chain wherein up to two carbon units of Z c are optionally and independently replaced by -CO-, - CS-, -C0NR c -,
- Each R 6 is independently R c , halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 .
- Each R c is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl.
- each R c is hydrogen, Ci_ 6 aliphatic, or C 3 - O cycloaliphatic, wherein either of the aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH substituents.
- R c is hydrogen, or Ci_ 6 alkyl optionally substituted with up to 4 -OH substituents.
- R' 3 is is independently -Z 0 R 6 , where each Z c is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z c are optionally and independently replaced by -C(O)-, -C(O)NR C -, -C(O)O-, -NR c C(0)0-, -O-, -NR 0 S(O) 2 -, or -NR C -.
- Each R 6 is independently
- Each R c is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl.
- each R c is hydrogen, Ci_ 6 aliphatic, or C 3 _ 6 cycloaliphatic, wherein either of the aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH substituents.
- R c is hydrogen, or C 1-6 alkyl optionally substituted with up to 4 -OH substituents.
- R' 3 is hydrogen or
- R 3 is H or a C 1-2 aliphatic that is optionally substituted with 1-3 of halo, -
- R 32 is -L-R 33 , wherein L is a bond, -CH 2 -, -CH 2 O-, -
- R 33 is hydrogen, or Ci -2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally subsitututed with 1 of -OH,
- R 3 is hydrogen and R 32 is Ci_ 2 aliphatic optionally substituted with -OH, -NH 2 , or -CN.
- R' 3 is independently selected from one of the following: -H, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 CH 2 OH, -C(O)OCH 3 ,
- ring B is one selected from:
- n 1-3.
- n is 1. In other embodiments, n is 2. In still other embodiments, n is 3.
- the present invention relates to compounds of formula II useful as modulators of ABC transporter activity:
- R is H, OH, OCH 3 or two R taken together form -OCH 2 O- or -OCF 2 O-;
- Ri is H or alkyl;
- R 2 is H or F;
- R 3 is H or CN;
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N(CH3)3, or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- the present invention provides compounds of formula II, wherein the compounds set forth below are excluded:
- two R taken together form -OCF 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCF 2 O-, R] is H, R 2 is F, and R 3 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 CH 2 N + (CH 3 ) 3 .
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 and R 5 taken together form a five membered ring.
- two R taken together form -OCH 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- R is OH
- Ri is H
- R 2 is H
- R 3 is H
- R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH.
- At least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is H. In another embodiment, at least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- the compound is represented by formula Ha:
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH3)3, or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH, - CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH.
- R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH; and R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.
- Table 1 Exemplary compounds of the present invention.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising (i) a compound of the present invention; and (ii) a pharmaceutically acceptable carrier.
- the composition further comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR corrector, or a nutritional agent.
- the composition further comprises an additional agent selected from compounds disclosed in U.S. Patent Application Serial No. 11/165,818, published as U.S. Published Patent Application No. 2006/0074075, filed June 24, 2005, and hereby incorporated by reference in its entirety.
- the composition further comprises N-(5-hydroxy-2,4- ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide.
- These compositions are useful for treating the diseases described below including cystic fibrosis. These compositions are also useful in the kits described below.
- the present invention relates to a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formula II: II wherein independently for each occurrence:
- R is H, OH, OCH 3 or two R taken together form -CH 2 CH 2 CH 2 -, -OCH 2 O- or - OCF 2 O-;
- Ri is H or alkyl
- R 2 is H or F
- R 3 is H or CN
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- the ABC transporter is CFTR.
- two R taken together form -OCF 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 CH 2 N + (CH 3 ) 3 .
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 and R 5 taken together form a five membered ring.
- two R taken together form -OCH 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- R is OH, Ri is H, R 2 is H, R 3 is H, and R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH.
- at least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is H.
- at least one R is OCH 3 , at least two R] are methyl, R 2 is H, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -CH 2 CH 2 CH 2 -
- Ri is H
- R 2 is H
- R 3 is H
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- the compound is represented by formula Ha:
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH, - CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH.
- R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH; and R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- the compound is selected from Table 1.
- the present invention relates to a method of treating a condition, disease, or disorder in a patient implicated by ABC transporter activity, comprising the step of administering to said patient a compound having formula II:
- R is H, OH, OCH 3 or two R taken together form -CH 2 CH 2 CH 2 -, -OCH 2 O- or - OCF 2 O-;
- Ri is H or alkyl
- R 2 is H or F
- R 3 is H or CN
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- two R taken together form -OCF 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 CH 2 N + (CH 3 ) 3 .
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 and R 5 taken together form a five membered ring.
- two R taken together form -OCH 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- R is OH
- Ri is H
- R 2 is H
- R 3 is H
- R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH.
- At least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is H. In another embodiment, at least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -CH 2 CH 2 CH 2 -
- Ri is H
- R 2 is H
- R 3 is H
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- the compound is represented by formula Ha:
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH3)3, or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH, - CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH.
- R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH; and R 5 is OH, - CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- the compound is selected from Table 1.
- said condition, disease, or disorder is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation- fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta,
- R is H, OH, OCH 3 or two R taken together form -CH 2 CH 2 CH 2 -, -OCH 2 O- or - OCF 2 O-;
- Ri is H or alkyl
- R 2 is H or F
- R 3 is H or CN
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuring activity of said ABC transporter or a fragment thereof.
- the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of said first composition.
- the kit is used to measure the density of CFTR.
- two R taken together form -OCF 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is H.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F,
- R 3 is H, and R 4 is -CH 2 CH 2 N + (CH 3 ) 3 .
- two R taken together form - OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form -OCF 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 and R 5 taken together form a five membered ring.
- two R taken together form -OCH 2 O-, Ri is H, and R 2 is F.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, and R 3 is H.
- two R taken together form -OCH 2 O-, Ri is H, R 2 is F, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- R is OH, Ri is H, R 2 is H, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- At least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is H.
- at least one R is OCH 3 , at least two Ri are methyl, R 2 is H, R 3 is H, and R 4 is - CH 2 OCH 2 CH(OH)CH 2 OH.
- two R taken together form - CH 2 CH 2 CH 2 -, Ri is H, R 2 is H, R 3 is H, and R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH.
- the compound is represented by formula Ha:
- R 4 is H, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH;
- R 5 is H, OH, -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 OH, or R 4 and R 5 taken together form a five membered ring.
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or -CH 2 CH 2 OH.
- R 5 is OH, -CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- R 4 is -CH 2 OCH 2 CH(OH)CH 2 OH, -CH 2 CH 2 N + (CH 3 ) 3 , or - CH 2 CH 2 OH; and R 5 is OH, -CH 2 OCH 2 CH(OH)CH 2 OH, or -CH 2 OH.
- the compound is selected from Table 1. [00166] III. SUBGENERIC COMPOUNDS OF THE PRESENT INVENTION
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula Id:
- R 1 , R 2 , and ring A are defined above in formula I, and ring B, R 3 and p are defined in formula Ia. Furthermore, when ring A is unsubstituted cyclopentyl, n is 1, R 2 is 4-chloro, and Ri is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6- dichlorophenyl(carbonyl))-3-methyl-lH-indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0, and Ri is hydrogen, then ring B is not
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula Id:
- R 1 , R 2 , and ring A are defined above in formula I, and ring B, R 3 and p are defined in formula Ia.
- each R 3 is independently -Z G Ri 2 , where each Z° is independently a bond or an unsubstituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z° are optionally and independently replaced by -CS-, - C0NR G NR G -, -CO 2 -, -OCO-, -NR 0 CO 2 -, -O-, -NR 0 CONR 0 -, -OCONR 0 -, -NR 0 NR 0 -, -S-, - SO-, -SO 2 -, -NR 0 -,
- each R 12 is independently R°, halo, -OH, -NH 2 , - NO 2 , -CN, or -OCF 3 , and each R° is independently hydrogen, an unsubstituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an unsubstituted aryl, or an optionally substituted heteroaryl; or any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle.
- R 1 , R 2 , and ring A are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are defined above in formula Ib.
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula Ha:
- R 1 , R 2 , and ring A are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are defined above in formula Ib.
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula lib:
- R 1 , R 2 , and ring A are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are defined above in formula Ib.
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula Hc:
- R 1 , R 2 and n are defined above in formula I; and R 3 , R' 3 , and p are defined in formula Ia.
- Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity.
- the compound has formula Hd:
- R' 3 is independently selected from one of the following: -H, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 CH 2 OH, -C(O)OCH 3 , ⁇ °- NHOOOH, ⁇ COsH HM. C M.
- each R 3 is independently selected from -H, -CH 3 , -CH 2 OH, -CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -NH 2 , halo, - OCH 3 , -CN, -CF 3 , -C(O)OCH 2 CH 3 , -S(O) 2 CH 3 , -CH 2 NH 2 , -C(O)NH 2 ,
- the compounds of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd) may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd) are provided below in Schemes 1-22 below.
- the acid Ia may be converted to the corresponding acid chloride Ib using thionyl chloride in the presence of a catalystic amount of dimethylformamide. Reaction of the acid chloride with the amine provides compounds of the invention I. Alternatively, the acid Ia may be directly coupled to the amine using known coupling reagents such as, for example, HATU in the presence of triethylamine.
- the nitrile 2a reacts with a suitable bromochloroalkane in the presence of sodium hydroxide and a phase tranfer catalyst such as butyltriethylammonium chloride to provide the intermediate 2b. Hydrolysis of the nitrile of 2b provides the acid Ia. In some instances, isolation of the intermediate 2b is unnecessary.
- phenylacetonitriles 2a are commercially available or may be prepared as illustrated in Scheme 3.
- reaction of an aryl bromide 3a with carbon monoxide in the presence of methanol and tetrakis(triphenylphosphine)palladium (0) provides the ester 3b.
- Reduction of 3b with lithium aluminum hydride provides the alcohol 3c which is converted to the halide 3d with thionyl chloride.
- Reaction of 3d with sodium cyanide provides the nitrile 2a.
- a nitroaniline 6a is converted to the hydrazine 6b using nitrous acid in the presence of HCl and stannous chloride.
- Reaction of 6b with an aldehyde or ketone CH 3 C(O)R 3 provides the hydrazone 6c which on treatment with phophoric acid in toluene leads to a mixture of nitro indoles 6d and 6e.
- Catalytic hydrogenation in the presence of palladium on carbon provides a mixture of the amino indoles 6f and 6g which may be separated using know methods such as, for example, chromatography.
- R 4 -LG base likeCs 2 CC> 3 ;
- R 4 is alkyl and LG is tosylate;
- the radical R employed therein is a substituent, e.g., RW as defined hereinabove.
- RW substituents
- One of skill in the art will readily appreciate that synthetic routes suitable for various substituents of the present invention are such that the reaction conditions and steps employed do not modify the intended substituents.
- compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
- these compositions optionally further comprise one or more additional therapeutic agents.
- a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
- the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
- compositions of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_ 4 alkyl) 4 salts.
- This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
- any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
- the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity.
- the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of ABC transporter activity, the method comprising administering a composition comprising a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd) to a subject, preferably a mammal, in need thereof.
- the present invention provides a method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation- Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1 , Hereditary emphysema, Congenital hyperthyroidis
- the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd), or a preferred embodiment thereof as set forth above.
- an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler- Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema
- the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis
- CDG type 1 Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive
- the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
- the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
- dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
- patient means an animal, preferably a mammal, and most preferably a human.
- compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
- the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
- 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 sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 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 sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in microencapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- buffering agents include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the compounds of the invention are useful as modulators of ABC transporters.
- the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder.
- hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder
- the disease, condition, or disorder may also be referred to as a "ABC transporter-mediated disease, condition or disorder”.
- the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state.
- the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
- the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
- the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
- additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated".
- the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
- the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
- the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
- the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
- Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
- the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
- the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
- Another aspect of the invention relates to modulating ABC transporter activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
- biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
- Modulation of ABC transporter activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of new modulators of ABC transporters.
- a method of modulating activity of an anion channel in vitro or in vivo comprising the step of contacting said channel with a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd).
- the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.
- the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd).
- a compound of formulae I, Ic, Id, II, Ha, lib, Hc, and Hd.
- functional ABC transporter as used herein means an ABC transporter that is capable of transport activity.
- said functional ABC transporter is CFTR.
- the activity of the ABC transporter is measured by measuring the transmembrane voltage potential.
- Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods.
- the optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).
- VIP Voltage/Ion Probe Reader
- the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd) or any of the above embodiments; and (ii) instructions for a.) contacting the composition with the biological sample and b.) measuring activity of said ABC transporter or a fragment thereof.
- a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd) or any of the above embodiments; and (ii) instructions for a.) contacting the composition with the biological sample and b.) measuring activity of said ABC transporter or a fragment thereof.
- the kit further comprises instructions for a.) contacting an additional composition with the biological sample; b.) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c.) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formulae (I, Ic, Id, II, Ha, lib, Hc, and Hd).
- the kit is used to measure the density of CFTR.
- the basic aqueous solution was acidified with concentrated hydrochloric acid to pH less than one and the precipitate which began to form at pH 4 was filtered and washed with 1 M hydrochloric acid two times.
- the solid material was dissolved in dichloromethane and extracted two times with 1 M hydrochloric acid and one time with a saturated aqueous solution of sodium chloride.
- the organic solution was dried over sodium sulfate and evaporated to dryness to give the cycloalkylcarboxylic acid. Yields and purities were typically greater than 90%.
- the dark brown reaction mixture was diluted with water (400 mL) and extracted once with an equal volume of ethyl acetate and once with an equal volume of dichloromethane.
- the basic aqueous solution was acidified with concentrated hydrochloric acid to pH less than one and the precipitate filtered and washed with 1 M hydrochloric acid.
- the solid material was dissolved in dichloromethane (400 mL) and extracted twice with equal volumes of 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride.
- the organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%) ESI-MS tn/z calc.
- Example 2 l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid
- Example 5 l-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane- carboxylic acid.
- a flask was charged with water (10 mL), followed by a rapid addition of NaOH (10 g, 0.25 mol) in three portions over a 5 min period. The mixture was allowed to cool to room temperature. Subsequently, the flask was charged with toluene (6 mL), tetrabutyl- ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo[l,3]dioxol-5-yl)-acetonitrile (600 mg, 3.4 mmol) and l-bromo-2-chloroethane (1.7 g, 12 mmol). The mixture stirred vigorously at 50 0 C overnight.
- Example 8 l-(2,3-Dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid
- Example 9 l-(3,3-Dimethyl-2,3-dihydrobenzofuran-5- yl)cyclopropanecarboxylic acid.
- Example 10 2-(7-Methoxybenzo[d][l,3]dioxol-5-yl)acetonitrile.
- Example 11 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.
- Example 12 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile.
- BBr 3 (17 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3- methoxyphenyl)acetonitrile (12 g, 66 mmol) in dichloromethane (120 mL) at -78 0 C under N 2 .
- the reaction temperature was slowly increased to room temperature.
- the reaction mixture was stirred overnight and then poured into ice and water.
- the organic layer was separated, and the aqueous layer was extracted with dichloromethane (40 mL x 3).
- Example 13 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.
- Example 14 2-(3-Chloro-4-methoxyphenyl)acetonitrile.
- Example 15 2-(3-Fluoro-4-methoxyphenyl)acetonitrile.
- Example 16 2-(4-Chloro-3-methoxyphenyl)acetonitrile.
- Example 17 l-(3-(Hydroxymethyl)-4- methoxyphenyl)cyclopropanecarboxylic acid.
- Example 18 2-(7-Chlorobenzo[d][l,3]dioxol-5-yl)acetonitrile. [00393] 3-Chloro-4,5-dihydroxybenzaldehyde
- Example 19 l-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid. trimethyl orthoformate AICU
- Example 21 l-(lH-Indol-5-yl)cyclopropanecarboxylic acid
- Example 22 l-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid
- Example 23 l-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid
- Example 24 l-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid
- Example 25 l-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid
- Example 26 l-CSpirotbenzotdHl ⁇ dioxole ⁇ r-cyclobutaneJ-S- yl)cyclopropane carboxylic acid
- Example 30 2-fert-Butyl-6-fluoro-lH-indol-5-amine and 6-tert-bntoxy-2-tert- butyl- lH-indol-5-amine
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Abstract
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US11215208P | 2008-11-06 | 2008-11-06 | |
PCT/US2009/063475 WO2010054138A2 (fr) | 2008-11-06 | 2009-11-06 | Modulateurs des transporteurs de la cassette de liaison à l’atp |
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EP (1) | EP2362874A2 (fr) |
JP (2) | JP2012508246A (fr) |
KR (1) | KR20110089170A (fr) |
CN (2) | CN102272128A (fr) |
AU (1) | AU2009313409A1 (fr) |
BR (1) | BRPI0921234B8 (fr) |
CA (2) | CA2948104C (fr) |
CL (1) | CL2011001004A1 (fr) |
HK (1) | HK1226076A1 (fr) |
IL (2) | IL212727A (fr) |
MX (1) | MX2011004834A (fr) |
NZ (2) | NZ610972A (fr) |
RU (2) | RU2011122646A (fr) |
SG (1) | SG10201501168RA (fr) |
UA (2) | UA104876C2 (fr) |
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MX2011004834A (es) | 2011-07-28 |
BRPI0921234A2 (pt) | 2016-02-23 |
UA104876C2 (uk) | 2014-03-25 |
IL212727A0 (en) | 2011-07-31 |
JP2015061860A (ja) | 2015-04-02 |
WO2010054138A3 (fr) | 2010-11-11 |
CN105693701B (zh) | 2021-08-10 |
CA2742980A1 (fr) | 2010-05-14 |
IL233996A (en) | 2015-09-24 |
KR20110089170A (ko) | 2011-08-04 |
CN105693701A (zh) | 2016-06-22 |
CA2948104A1 (fr) | 2010-05-14 |
BRPI0921234B1 (pt) | 2021-06-22 |
HK1226076A1 (zh) | 2017-09-22 |
NZ592693A (en) | 2013-05-31 |
AU2009313409A1 (en) | 2010-05-14 |
ZA201103856B (en) | 2012-02-29 |
IL233996A0 (en) | 2014-09-30 |
WO2010054138A2 (fr) | 2010-05-14 |
CA2948104C (fr) | 2017-09-12 |
RU2014139599A (ru) | 2016-04-20 |
JP2012508246A (ja) | 2012-04-05 |
RU2011122646A (ru) | 2012-12-20 |
BRPI0921234B8 (pt) | 2022-07-19 |
UA110192C2 (uk) | 2015-12-10 |
CN102272128A (zh) | 2011-12-07 |
SG10201501168RA (en) | 2015-04-29 |
CL2011001004A1 (es) | 2012-03-16 |
NZ610972A (en) | 2014-11-28 |
IL212727A (en) | 2014-08-31 |
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