WO2005026137A2 - Modulators of atp-binding cassette transporters - Google Patents
Modulators of atp-binding cassette transporters Download PDFInfo
- Publication number
- WO2005026137A2 WO2005026137A2 PCT/US2004/029206 US2004029206W WO2005026137A2 WO 2005026137 A2 WO2005026137 A2 WO 2005026137A2 US 2004029206 W US2004029206 W US 2004029206W WO 2005026137 A2 WO2005026137 A2 WO 2005026137A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aliphatic
- optionally substituted
- phenyl
- ring
- substituents
- Prior art date
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Definitions
- the present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith.
- the present invention also relates to methods of treating ABC transporter mediated diseases using such modulators .
- ABC transporters are a group of membrane transporter proteins that play a major role in the transport and protection of cells against a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics .
- 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, MRP1) , defending malignant cancer cells against chemotherapeutic agents.
- MRP1 multidrug resistance proteins
- ABC transporters play a variety of important physiological roles within the body, as well as providing a defense against harmful compounds from the environment. Moreover they represent important potential drug targets both in their own right, as well as, because in many cases therapeutic drugs are also transported out of the target cell by these molecules .
- CFTR One of the members of the ABC transporter family, namely, CFTR, is believed be the chloride channel responsible for cAMP-mediated chloride secretion in epithelial cells, and to play a key role in the secretion of chloride and maintenance of normal electrolyte transport throughout the body.
- CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each comprising six transmembrane segments and a nucleotide-binding domain.
- the two repeats are separated by a large, polar, regulatory (R) -domain containing multiple potential phosphorylation sites.
- R polar, regulatory
- the gene associated with CFTR has been identified and sequenced (See Gregory, R. J. et al . (1990) Nature 347:382-386; Rich, D. P. et al . (1990) Nature 347:358-362), (Riordan, J. R. et al . (1989) Science 245:1066-1073) .
- CF cystic fibrosis
- the other elements include the epithelial Na + channel, ENaC, Na + /2C1 " /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell. [0010] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell . Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell.
- COPD chronic obstructive pulmonary disease
- COPD dry eye disease
- Sjogren's Syndrome Sjogren's Syndrome
- COPD chronic obstructive pulmonary disease
- Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
- CFTR Dry eye disease
- tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as Cystic Fibrosis and Sj ⁇ grens's syndrome.
- Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
- 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 CF (due to misfolded ⁇ F508-CFTR) , hereditary emphysema (due to ⁇ l-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 3-hexosaminidase) , Crigler-Najjar type II (due to UDP-glucuron
- the diseases associated with the latter class of ER malfunction are 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 Vasopressin 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 /3APP and presenilins) , Parkinson's disease, amy
- ETEC enterotoxogenic E-coli
- Common viral causes of diarrhea include rotavirus and coronavirus.
- Other infectious agents include ⁇ ryptosporidium, 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.
- the present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
- Y' is 0, S, or NR; p is 0-2; X is a bond, 0, S, S (O) , S(0) 2 , CF 2 , CH 2/ -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O) 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H , R 2 , or R 6 ; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl ; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
- each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R L is -OR A , -SR A , or -N(R AB ) 2 ; each R A is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each R A is optionally substituted with up to 3 substituents independently selected from R 1 , R 4 or R 7 , each R AB is independently hydrogen or C
- R M is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ; each of 1 and X 2 is independently selected from 0, S, or NR;
- R N is C1-C6 aliphatic or phenyl, wherein R N is optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
- R p is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
- R Q is C1-C6 aliphatic or aryl, wherein R Q is optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
- R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y;
- n is o
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
- R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 , SR 5 , S(0)R 6 , S(0)R 5 , S0 2 R 6 , S0 2 R 5 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R ⁇ substituents;
- R 6 is H or aliphatic, wherein R 6 optionally comprises a R ⁇ substituent ;
- R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R “7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
- Z is selected from
- ABSOR-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 vi tro .
- 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 regulator or a mutation thereof capable of its regulator activity, in part or full, including, but not limited to, ⁇ F508 CFTR and G551D CFTR (see, e.g., htt : //www. genet . sickkids .on. ca/cftr/, for CFTR mutations) .
- modulating means increasing or decreasing by a measurable amount.
- the phrase “optionally substituted” is used interchangeably with the phrase "substituted or unsubstituted.
- aliphatic or "aliphatic group”, as used herein, means a straight-chain or branched, hydrocarbon chain that is completely saturated (alkyl) or is unsaturated (alkenyl or alkynyl) . Unless otherwise specified, an aliphatic group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms. Up to three, and preferably two, -CH 2 - in said aliphatic may be replaced with 0, S, or -NR.
- alkylidene as used herein means a straight-chain or branched hydrocarbon chain that is completely saturated or unsaturated, and is connected to the rest of the molecule through covalent bonds.
- exemplary alkylidene groups include methylene, ethylene, or propylene. Unless otherwise specified, an alkylidene group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms.
- cycloaliphatic means a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring that has up to two points of attachment to the rest of the molecule.
- preferred cycloaliphatic rings are 3-8 membered monocyclic rings, more preferably 3-6, and even more preferably, 3, 5, or 6. Also preferred, unless otherwise specified, are 8-12 membered bicyclic hydrocarbon rings, more preferably 10 membered bicyclic hydrocarbon rings.
- heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term “nitrogen” includes a substitutable nitrogen of a heterocyclic ring.
- the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3 , 4-dihydro-2Jf-pyrrolyl) , NH (as in pyrrolidinyl) or as in N-substituted pyrrolidinyl.
- unsaturated means a double bond or a triple bond. Each such bond constitutes one unit of unsaturation.
- aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” , refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems. Unless otherwise specified, preferred aryl rings have a total of five to fourteen ring members, wherein at least one ring, if bicyclic or tricyclic, in the system is aromatic and wherein each ring in the system contains up to 6 ring members.
- aryl may be used interchangeably with the term “aryl ring”. Phenyl is an example of aryl.
- heterocycle means non-aromatic, monocyclic, bicyclic or tricyclic ring systems wherein one or more ring members is a heteroatom. Unless otherwise specified, each ring in the system preferably contains contains 3 to 7 ring members with preferably 1-3 heteroatoms .
- heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” , refers to monocyclic, bicyclic and tricyclic ring systems, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Unless otherwise specified, such ring systems preferably have a total of 5 to 15 ring members, wherein each ring in the system preferably contains 3 to 7 ring members, with preferably 1-3 heteroatoms.
- heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
- a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
- a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- the present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
- X is a bond, O, S, S (0) , S(0) 2 , CF 2 , CH 2 , -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O)- 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR;
- R is H, R 2 , or R 6 ;
- A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl;
- C is a phenyl or 5-8 membered cycloaliphatic ring;
- Q is selected from: each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
- R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , 0C(0)0R 6 , 0C(0)0R 5 , OC(0)N(R 6 ) 2 , 0C(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R ⁇ substituents;
- R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent ;
- R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg)- straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
- Z is selected from halo
- amino capping group refers to a suitable chemical group that may be attached to a nitrogen atom.
- capping refers to when the designated amino group is attached to a suitable chemical group (e.g., protecting group). Examples of suitable amino capping groups are described in T.W. Greene et al . , Protective Groups in Organic Synthesis, 3d. Ed., John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; L. Paquette, ed.
- Y' is S.
- Y' is 0.
- Y' is NR.
- R is H.
- R is R 2 .
- R is R 6 .
- p is 1.
- p is 1 and X is attached to the carbon adjacent to Y' atom.
- p is 1 and X is attached to the carbon adjacent to the ring nitrogen atom.
- p is 2.
- X is a bond, 0, S, CH 2/ CF 2 , CHOR, C(0)NR, C(0)0-, NRC (O) , or NR.
- X is a bond, 0, or CH 2 .
- X is CH 2 .
- A is an optionally substituted C3-C7 cycloaliphatic ring.
- A is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl.
- A is optionally substituted (C1-C10) aliphatic .
- A is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl .
- A is optionally substituted C6-C10 aryl ring.
- A is optionally substituted phenyl or naphthyl .
- A is optionally substituted C5-C12 heteroaryl ring.
- A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl , imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl, 1,8- naphthyridinyl , pteridinyl,
- A is optionally substituted C3-C12 heterocyclic ring.
- A is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl , tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl .
- A, X, and the ring attached thereto, taken together is selected from:
- R ph is independently R 1 , R 2 , or R 3 ; and r is 0-3.
- X 5 is CH 2 , C(O) , or CHOR;
- X 6 is 0 or NR 2 ; and
- R ⁇ is C1-C6 aliphatic, optionally substituted with R 1 , R 2 , or R 3 .
- A, X, and the ring attached thereto, taken together, is selected from any of the rings i to xviii, wherein the sulfur atom in each of the thiazole ring is replaced with an oxygen atom (to provide the corresponding oxazole) .
- each B is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each B is an optionally substituted phenyl or naphthyl. Or, each B is an unsubstituted phenyl . [0061] According to another embodiment, each B is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each B is independently an optionally substituted C5-C7 heteroaryl.
- each B is independently selected from triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl , oxazolyl , pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl , benzthiazolyl, purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl
- R 1 is 1,2- methylene dioxy, or 1 , 2-ethylenedioxy.
- R 1 is R 6 , wherein R 6 is straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl , optionally substituted with R 7 .
- R 1 is (Cl- C4 aliphatic) n -Y/ wherein n is 0 or 1, and Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 , NHR 6 , N(R 6 ) , NR 6 R 8 , COOH, COOR 6 or OR 6 ; [0066] According to another embodiment, R 1 is selected from halo, CF 3 , NH 2 , NH(C1-C4 alkyl), NHC(0)CH 3 , OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl), Cl- C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S0 2 NH(C1- C4 alkyl), or S0 2 N(C1-C
- R 1 is selected from methyl, n-propyl, i-propyl, t-butyl, halo, CF 3 , NH 2 , NH(CH 3 ), NHC(0)CH 3 , OH, OCH 3 , OPh, O-benzyl, S- (C 2 H 5 ) , S-CH 3 , N0 2 , CN, methylenedioxy, S0 2 NH (n-propyl) , or S0 2 (n-propyl) 2 .
- R 2 is a straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 .
- R 2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 .
- R 3 is optionally substituted phenyl, napthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl.
- R 3 is an optionally substituted phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
- R 4 is selected from OR 5 , OR 6 , SR 5 , SR 6 , NR 5 COR 5 , NR 5 COR 6 , NR 6 COR 5 , or NR 6 COR 6 .
- R 5 is C5-C6 cycloalkyl, C6 or CIO aryl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with up to 2 R 1 .
- R 5 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
- R 6 is H.
- R 6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl, optionally substituted with R 7 .
- R 6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl.
- R 7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or al ynyl.
- R 7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with 1-2-methylenedioxy, 1, 2-ethylenedioxy, or (CH 2 ) n -Z.
- R 7 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
- R 8 is acetyl, arylsulfonyl or alkylsulfonyl .
- Q in compounds of formula I is selected from:
- the present invention provides compounds having formula I-a:
- p is 1 .
- p is
- X is a bond, 0 , CH 2 ,
- X is a bond, 0 , or CH 2 .
- p is 1 and X is a bond.
- X-A is attached to the carbon adjacent to the ring nitrogen atom.
- p is 1, and X-A is attached to the carbon adjacent to the Y'.
- p is 1, X is CH 2 , CHOH, or C(O) , and A is an optionally substituted phenyl.
- X is a bond, and A is an optionally substituted phenyl.
- p is 2, each X is a bond, and each A is an optionally substituted phenyl.
- each B is independently and optionally substituted ring selected from:
- substituents on B include C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , - C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C (0)N(C1-C4 alkyl) 2 or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C (O) 0.(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C (0)N(C1-C4 alkyl) 2 .
- each B is indpendently an optionally substituted ring selected from ring i, iii, iv, v, or vi. Or, wherein B is an optionally substituted ring vii .
- B is independently ring x optionally substituted with up to two substituents selected from R 1 or phenyl optionally substituted with up to two R 1 .
- B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, - 0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2 , or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4- alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2 .
- each B is an optionally substituted ring selected from ring xi, xii, xiii, or xiv.
- p is 1. Or, p is 2.
- R is hydrogen.
- Y' is S. Or, Y' is O.
- X is a bond and A is optionally substituted phenyl. In certain embodiments, A is attached to the carbon atom adjacent to the nitrogen ring atom.
- A is phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N- piperidinyl, or methylenedioxy.
- A is phenyl, methoxyphenyl , dimethoxyphenyl , cyanophenyl , N- pyrrolidinylphenyl, methylenedioxyphenyl , halophenyl, methylphenyl , or dimethylphenyl .
- A is phenyl, 3- methoxyphenyl , 2 -methoxyphenyl, 4-chlorophenyl, 4- cyanophenyl, 4- (N-pyrrolidinyl) phenyl, 4-tolyl, 3,4- methylenedioxyphenyl , 3 -chlorophenyl , 2,4- dimethoxyphenyl, 2-chlorophenyl, 4-bromophenyl, or 2,4- dimethylphenyl .
- A is C3-C10 cycloaliphatic ring.
- Exemplary ring include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
- A is cyclohexyl or adamantyl.
- the compounds of the present invention have one of more of the following features : a) R is hydrogen; b) Y' is S; c) A is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N-piperidinyl , or methylenedioxy; and d) B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C(0)N(C1-C4 alkyl) 2 , or phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, -0-C1-
- p is 1 and X is a bond.
- p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
- p is 1, and X-A is attached to the carbon adjacent to the Y' .
- p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
- X is a bond, and A is an optionally substituted phenyl.
- p is 2, each X is a bond, and each A is an optionally substituted phenyl.
- said C1-C6 aliphatic is C1-C4 straight or branched alkylidene.
- Exemplary alkylidenes include -CH 2 -, ⁇ CH(Me)-, -C(Me) 2 -, - CH(Et)-, -C(Et) 2 -, or -CH 2 -CH (Me) - .
- B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl , or pyrrolidinyl.
- B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R 1 substituents.
- said (C1-C6 aliphatic) -B in formula I-b is selected from:
- Ak is C1-C6 straight or branched alkylidene;
- X 4 is CH 2 , 0 or S;
- Ar' is phenyl optionally substituted with up to two R 1 ;
- B is optionally substituted with up to two R 1 .
- Ak is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , CH(Et), C(Et) 2 , CH (n-propyl) , CH(i- Pr) , CH(n-butyl), CH (but-2-yl) , or CH (t-butyl) .
- Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) .
- X 4 is S. Or, X 4 is 0.
- R is hydrogen.
- the present invention provides compounds of formula I-f:
- R M is C1-C6 aliphatic or phenyl, wherein R M is optionally substituted with up to two substituents independently selected from R 1 , R 2 , or R 3 ;
- R N is C1-C6 aliphatic or a 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein R N is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
- p is 1 and X is a bond.
- p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
- p is 1, and X-A is attached to the carbon adjacent to the Y' .
- p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
- X is a bond, and A is an optionally substituted phenyl.
- p is 2, each X is a bond, and each A is an optionally substituted phenyl.
- X x is NH or N(C1-C4 alkyl) . Or, X x is O.
- R M is optionally substituted phenyl .
- R M is C1-C6 alkyl, optionally substituted with phenyl.
- R M is C1-C4 alkyl.
- R N is optionally substituted C3-C7 cycloaliphatic, phenyl, or benzyl.
- R N is C1-C6 aliphatic.
- R is hydrogen.
- the present invention provides a compound of formula I-g:
- p is 1 and X is a bond.
- p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
- p is 1, and X-A is attached to the carbon adjacent to the Y' .
- p is 1, X is CH 2 , CHOH, or C (O) , preferably CH 2 , and A is an optionally substituted phenyl.
- X is a bond, and A is an optionally substituted phenyl.
- p is 2, each X is a bond, and each A is an optionally substituted phenyl.
- R p is C1-C4 alkyl, optionally substituted with up to two R 1 .
- R p is selected from ethyl, n-propyl, i-propyl, n-butyl, but-2-yl, or t-butyl, isoamyl, optionally substituted with halo, CN, COOH, or CONH 2 .
- R is hydrogen.
- p is 1. Or, p is 2.
- p is 2, and each A is optionally substituted phenyl. Or, p is 2, and each A is phenyl .
- compounds of formula 1-g have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2 and each A is phenyl; d) R p is isoamyl, t-butyl, ethyl, isopropyl, n-propyl, l-carboxy-prop-3-yl , or 1-carboxy-2 -methyl- prop-3-yl .
- the present invention provides compounds of formula I-h:
- Y' is O or S
- X 2 is O, S, or NR
- R Q is C1-C6 aliphatic or phenyl, optionally substituted with up to two substituents independently selected from R 1 , R 2 , or R 3 .
- p is 1 and X is a bond.
- p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
- p is 1, and X-A is attached to the carbon adjacent to the Y' .
- p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
- X is a bond, and A is an optionally substituted phenyl.
- p is 2, each X is a bond, and each A is an optionally substituted phenyl.
- X 2 is S. Or, X 2 is O.
- R Q is C1-C4 alkyl, optionally substituted with up to three R 1 .
- R Q is phenyl optionally substituted with C1-C4 alkyl, or R 1 .
- the methods of the present invention employ a compound having formula (1A) :
- Y' is O, S, or NR
- X is a bond, CH 2 , CHOR, C(0)0, C (O) , NR, or O
- A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic
- Q is selected from:
- each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0;
- R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
- Y' is S.
- Y 1 is 0.
- Y' is NR.
- X is a bond, CH 2 , NR, or O;
- X is CH 2 .
- X is CF 2 .
- X is a bond.
- X is O.
- X is NR.
- A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R 1 , R 2 , R 3 , or R4.
- Q is B.
- Q is -(C1-C6)- aliphatic-B.
- Q is CH(B) .
- Q is
- B is phenyl.
- X is a bond, -CHOR- , or
- Exemplary compounds of formula ( IA) are those wherein : (i ) X is a bond, CH 2 , or O ; (i) A is optionally substituted phenyl; (iii)Q is diphenylmethyl . [00151] Exemplary compounds of formula (IA) useful in the methods of the present invention are as shown below in Table 1. [00152] According to another embodiment, the methods of the present invention employ a compound having formula (IB) :
- Y' is 0, S, or NR
- X is a bond, CH 2 , CHOR, C(O), C(0)0, NR, or 0
- A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic
- Q is selected from:
- each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0;
- R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
- Y' is S.
- Y' is 0.
- Y' is NR.
- X is a bond, CH 2 , NR, or 0, Or, X is a bond or CH 2 .
- X is CF 2 .
- X is a bond.
- X is O.
- X is NR.
- A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R-*-, R 2 , R 3 , or R4.
- Q is B.
- Q is -(C1-C6)- aliphatic-B.
- Q is CH(B) 2 .
- Q is
- B is phenyl .
- Preferred compounds of formula IB are those wherein: (i) X is a bond, CH 2 , or 0; (ii) A is optionally substituted phenyl; (iii) Q is diphenylmethyl .
- the methods of the present invention employ a compound having formula (IC) :
- Y' is 0, S, or NR; each X is independently a bond, CH 2 , -CHOR-, -C(0)0-, -C(0) -, NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
- each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O;
- R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
- Y' is S.
- Y' is 0.
- y is NR.
- X is a bond or CH 2 .
- X is'CH 2 .
- X is a bond.
- X is -CHOR- Or, X is -C(O)-.
- X is 0.
- X is NR.
- A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R ⁇ -, R 2 , R , or R 4 .
- Q is B.
- Q is -(C1-C6)- aliphatic-B.
- Q is CH(B) 2 .
- Q is
- B is phenyl.
- exemplary compounds of formula (IC) are those wherein: (i) each X is a bond, -CHOR-, or -C(O)-; (ii) each A is optionally substituted phenyl, (Cl -C6) aliphatic, or CF 3 ; (iii) Q is optionally substituted phenyl, (Cl- C6) aliphatic, or diphenylmethyl .
- Xi is a bond, 0, S, CHOR, C (O) , C(0)0, CF 2 , CH 2 , or NR;
- R is H or R 2 A is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic;
- each Bi is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; wherein each Ai is optionally substituted with up to
- R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
- R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroary
- X x is a bond, 0, S, CF 2 , CH 2 , or NR.
- Xi is CH 2 , CF 2 , or O. Or Xi is CH 2 or 0. In certain embodiments, Xi is
- Ai is an optionally substituted C3-C7 cycloaliphatic ring. In certain embodiments, Ai is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl. [00171] According to another embodiment, Ai is optionally substituted (C1-C10) aliphatic . In certin embodiments, Ai is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl . [00172] According to another embodiment, A x is optionally substituted C6-C10 aryl ring.
- Ai is optionally substituted phenyl or naphthyl .
- Ai is optionally substituted C5-C12 heteroaryl ring.
- A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl, benzthiazolyl, purinyl , quinolinyl, isoquinolinyl, c
- Ai is optionally substituted C3-C12 heterocyclic ring.
- a x is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
- each Bi is independently selected from optionally substituted C6-C10 aryl.
- each Bi is independently an optionally substituted phenyl or naphthyl.
- each B x is an unsubstituted phenyl.
- each B is independently selected from optionally substituted C5-C12 heteroaryl ring.
- each Bi is independently and optionally substituted C5-C7 heteroaryl ring.
- each B x is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl , purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl, p
- each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR.
- each B x is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1 , 4-dioxanyl, morpholinyl, 1, -dithianyl , thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl .
- Embodiments of R 1 , R 2 , R 3 , R , R 5 , R 6 , R 7 are independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolid
- R 8 , and Z in compound of formula (II) are as described above for compound of formula (I) .
- one B x is phenyl with up to two R 1 substituents
- the other Bi is selected from pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, optionally substituted with up to two R 1 subsituents.
- one Bi is phenyl
- the other B % is selected from 1, 2-pyrazol-l-yl, 1- piperidinyl, 2-carboethoxy-1-piperidinyl , 4-morpholinyl , 3 -carboethoxy-1-piperidinyl, 3-methyl-1-piperidinyl , 2- ethyl -1-pyrrolidinyl , 3 -hydroxymethyl-1-piperidinyl, 4- carboethoxy-1-piperidinyl, 4 -methyl -1-piperidinyl, 1- pyrrolidinyl, 4- (pyrimidin-2-yl) -1-piperazinyl , or 4- hydroxy-piperidinyl .
- the present invention provides a compound of formula IIA:
- Y' is O or S
- B is a 3-8 membered, saturated, moncyclic, ring having 0-4 heteroatoms selected from 0, S, or N
- ring G and B are optionally substituted with up to four substituents independently selected from R 1 , R 2 , R ,
- R 4 , or R 5 provided that when Y' is S, and: a) when B is cyclohexyl, tetrahydrofuran-2-yl , or cyclopropyl, and ring G has 1-3 halo substituents, then ring G has at least one additional substituent other than halo; and b) when B is tetrahydrofuran-2-yl, then ring G is not phenyl, trifluoromethylphenyl , methoxyphenyl, or tolyl; c) when B is cyclohexyl, then ring G is not phenyl or trifluoromethylphenyl .
- B is tetrahydrof ranyl , piperidyl, morpholinyl, or thiomorpholinyl .
- B is C3-C8 saturated, carbocyclic, monocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
- ring G is phenyl optionally substituted with R 1 . Preferably, ring G is optionally substituted with up to two substituents selected from halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl) .
- compounds of formula IIA have one or more of the following features: a) Y' is S; b) ring G is halo-substituted phenyl; c) B is phenyl optionally substituted with halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl). [00186] According to another embodiment, the present invention provides a compound of formula IIB:
- Y' is S or 0; R is H, R 2 , or R 6 ; R B is C1-C6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each of ring G, ring H, and R B is independently and optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; provided that when Y is S, and: a) when R B is hydrogen, and ring G and ring H both have 1-3 halo substituents, then at least one of ring G and ring H has an additional substituent other than halo; b) when R B is hydrogen and ring H is unsubstituted phenyl, then ring G is not phenyl or
- ring G is phenyl optionally substituted with up to two R 1 .
- Exemplary RI includes C1-C4 alkyl, 0- (C1-C4 alkyl), halo, or cyano.
- R B is Cl-6 aliphatic optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
- R B is C1-C4 alkyl optionally substituted with up to 2 substituents selected from R 1 .
- R B include methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, or t-butyl.
- R B is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 0-4 heteroatoms optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
- R B is a 3-7 membered monocyclic saturated, carbocyclic ring optionally substituted with up to 2 substituents selected from R 1 .
- Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
- R B is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 1-3 heteroatoms optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
- R B is a 3-7 membered monocyclic saturated ring containing 1-3 heteroatoms optionally substituted with up to 2 substituents selected from R 1 .
- Exemplary rings include piperidinyl, morpholinyl, or thiomorpholinyl .
- R B is a 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O, optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
- the present invention provides compounds of formula IIC:
- X 7 is O. Or, X 7 is S. Or, X 7 is NR' .
- R c is C1-C6 alkyl, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 . Or, R c is C1-C6 alkyl. Exemplary R c includes methyl, ethyl, isopropyl, n- propyl, n-butyl, sec-butyl, or t-butyl.
- R B is phenyl optionally substituted with up to two R 1 substituents .
- R B is phenyl.
- R B is C1-C6 alkyl.
- Exemplary R B includes methyl, ethyl, isopropyl, n- propyl , n-butyl, sec-butyl, or t-butyl.
- compound of formula IIC includes one or more of the following eatures: a) ring G is benzyl optionally substituted with one RI substituent, preferably halo; b) Y' is S and R is hydrogen; c) R c is C1-C4 alkyl; d) X 7 is NH or NR' wherein R' is C1-C4 alkyl; and e) R B is C1-C4 alkyl.
- the present invention provides a compound of formula IID:
- R BB is phenyl optionally substituted with up to two R 1 substituents .
- R BB is phenyl.
- R BB is Cl- C6 alkyl.
- Exemplary R BB includes methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or t-butyl.
- R BB is optionally substituted C3-C8 cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl.
- R BB is optionally substituted benzyl .
- compounds of formula IID have one or more of the following features : a) Y' is S and R is hydrogen; b) each ring G is unsubstituted phenyl; d) X 8 is NR' , and R' is hydrogen or C1-C4 alkyl; and e) R BB is C1-C4 alkyl, benzyl, cyclopentyl, or cyclohexyl .
- the present invention provides a compound having formula (III) :
- Xi is a bond, O, S, CHOR, C (0) , C(0)0, CF 2 , CH 2 , or NR;
- R is H or R 2
- Ax is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic;
- each B is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or 0; wherein each A x is optionally substituted with up to
- R 1 is R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
- R 6 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
- R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 ,
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-L substituents ;
- R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
- R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
- Z is selected from halo, CN, N0 2 , CF 3
- Xi is CH 2 , CF 2 , or 0.
- Xi is a bond, O, S, CF 2 , CH 2 , or NR.
- Xi is CH 2 or 0.
- X x is CH 2 .
- Ai is an optionally substituted C3-C7 cycloaliphatic ring.
- a 2 is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl .
- Ai is optionally substituted (C1-C10) aliphatic .
- Ai is optionally substituted methyl, ethyl , propyl , butyl , pentyl , or hexyl .
- Ai is optionally substituted C6-C10 aryl ring.
- Ai is optionally substituted phenyl or naphthyl .
- Ai is optionally substituted C5-C12 heteroaryl ring.
- A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl , 1,8- naphthyridinyl, pteridinyl
- Ai is optionally substituted C3-C12 heterocyclic ring.
- a 2 is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl , piperidinyl, 1, 4-dioxanyl , morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
- each B x is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each B x is independently an optionally substituted phenyl or naphthyl. Or, each Bi is an unsubstituted phenyl. [00213] According to another embodiment of formula (III) , each B x is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each Bi is independently and optionally substituted C5-C7 heteroaryl.
- each Bi is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, carbazoly
- each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR.
- each Bi is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl , pyrazolinyl, pyrazolidinyl, piperidinyl, 1, -dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
- R 1 , R 2 , R 3 , R 4 Exemplary embodiments of R 1 , R 2 , R 3 , R 4 ,
- B is selected from: (i) ( ⁇ ) wherein: Y is O or S; and X 3 is 0 or S.
- X 3 is O.
- X 3 is S.
- B is structure (i) above.
- B is structure (ii) above.
- R is hydrogen.
- Y' is S.
- Y' is 0.
- the present invention provides compounds of formula V:
- V wherein: Y' is 0 or S; B is selected from:
- Ak is C1-C6 alkylidene; X 4 is CH 2 , O or S; Ar' is phenyl optionally substituted with up to two R 1 ; and B is optionally substituted with up to two R 1 .
- Ak is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , CH(Et), C(Et) 2 , CH (n-propyl) , CH(i- Pr) , CH (n-butyl), CH (but-2-yl) , or CH (t-butyl) .
- Ar ' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) .
- X 4 is CH 2 .
- X 4 is S. Or, X 4 is 0.
- R is hydrogen.
- p is 2, X is a bond, and each A is optionally substituted phenyl .
- the compounds have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2, X is a bond, and each A is phenyl; d) B is ring (iii) above, wherein Ak is CH(CH 3 ) and Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (C1-C4 alkyl).
- the present invention provides a compound of formula VI:
- Y' is 0 or S;
- R is hydrogen or R 2 ;
- B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from O, S, or N; wherein each ring Gi, G 2 , and B is independently substituted with up to 4 substituents selected from R 1 ,
- R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
- R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 ,
- R 5 is a cycloaliphatic, aryl, heterocyclic
- B is not quinolin-2-yl or l,2-dihydro-2-oxo-quinolin- 4-yl; b) when Gi and G 2 both are phenyl, and Y' is S, then B is not l,4-benzodioxin-2-yl, cyclopropyl, cyclohexyl, thien- 2-yl, lH-thieno [2 , 3-c] pyrazol-1-phenyl-3 -methyl-5-yl, 5- methyl-thien-3-yl, 2 , 5-dichloro-thien-3-yl, 2-phenyl- quinolin-4-yl, furan-2-yl, thien-5- (4 , 5-diphenyl-2- thiazolyl-carboxamide) -2-yl, benzo [b] thiophen-2-yl , pyridin
- Gi and G 2 are both phenyl. Or, each is independently and optionally substituted with up to two substituents selected from halo, or C1-C4 alkyl.
- B is phenyl optionally substituted with up to two substituents selected from halo, C1-C4 alkyl, 0- (C1-C4 alkyl), COOH, C00(C1-C4 alkyl), or cyano.
- B is 3,4- dichlorophenyl, 4-chlorophenyl, 4 -methoxyphenyl , 4- methylphenyl , 2 , 6-difluorophenyl , 2 -methylphenyl , 3 - methylphenyl , phenyl-2 -carboxylic acid, 2-chlorophenyl, 4 -cyanophenyl , or 3-methoxyphenyl .
- B is 3-7 membered, monocyclic, saturated, carbocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
- B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N.
- Exemplary rings include tetrahydrofuranyl, thienyl, or pyrrolyl.
- B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N.
- the present invention provides a compound of formula VII : VII; wherein: Y' is 0 or S; R is hydrogen or R 2 ; R ⁇ is C1-C6 aliphatic, optionally substitute with up to 3 substituents independently selected from R 1 , R 2 , or
- R 3 is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N; wherein each ring G x , G 2 , and B is independently substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
- R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 , SR 5 , S(0)R 6 , S(0)R 5 , S0 2 R 6 , S0 2 R 5 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0 2 N(R 6
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
- R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
- R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
- Z is selected from hal
- R ⁇ is C1-C6 alkyl.
- Exemplary R** include methyl, ethyl, isopropyl, n-propyl, sec-butyl, n-butyl, or t-butyl.
- B is optionally substituted phenyl .
- B is 3-7 membered, monocyclic, saturated, carbocyclic ring.
- Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
- B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N.
- Exemplary rings include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, or piperazinyl .
- B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N.
- the present invention provides a compound having formula I ' :
- Y ' is 0 , S , or NR ;
- R is H, R 2 , or R 6 ;
- C is a phenyl or 5-8 membered cycloaliphatic ring;
- Q is selected from:
- each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R L is -0R A , -SR A , or -N(R AB ) 2 ; each R A is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each R A is optionally substituted with up to 3 substituents independently selected from R 1 , R 4 or R 7 , each R ffl is independently
- R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
- R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
- R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
- R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
- R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
- R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
- Z is selected
- Y" is 0.
- Y' is S.
- R is hydrogen.
- Q in formula I ' is B (structure (a) ) .
- Preferred B include optionally substituted phenyl, or C3-C8 cycloaliphatic.
- B in formula I' is phenyl or C3-C8 cycloalkyl optionally substituted with up to two substituents selected from R 1 , R 2 , or phenyl optionally substituted with up to two substituents selected from R 1 or R 2 .
- Q in formula I ' is - (C1-C6 aliphatic) -B (structure (b) ) .
- said C1-C6 aliphatic is C1-C4 straight or branched alkylidene.
- Exemplary alkylidenes include -CH 2 -, -CH(Me)-, -C(Me) 2 -, - CH(Et)-, -C(Et) 2 -, or -CH 2 -CH (Me) - .
- B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl, or pyrrolidinyl.
- B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R 1 or R 2 substituents.
- ring C is phenyl optionally substituted with up to two R 1 .
- ring C is cyclohexenyl optionally substituted with up to two R 1 .
- R 1 is 1, 2-methylene dioxy, or 1, 2-ethylenedioxy.
- R 1 is R 6 , wherein R 6 is straight chain or branched (Cl- C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 7 .
- R 1 is (C1-C4 aliphatic) n -Y, wherein n is 0 or 1, and Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 ,
- R 1 is selected from halo, CF 3 , NH 2 , NH(C1-C4 alkyl), NHC(0)CH 3 , OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl) , C1-C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S0 2 NH(C1-C4 alkyl), or S0 2 N(C1-C4 alkyl) 2 - [00255] According to another more preferred embodiment, R 1 is selected from methyl, n-propyl, i- propyl, t-butyl, halo, CF 3 , NH 2 , NH(CH 3 ), NHC(0)CH 3 , OH, OCH 3 ,
- R 2 is a straight chain or branched (C1-C6) lkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 . More preferably, R 2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 . [00257] In formula I', other embodiments of B, R L , R M , R p , R Q , Xi, X 2 , and R are as described above for formula I . [00258] Exemplary compounds of the present invention are shown below in Table 1.
- preferred compounds of the present invention are those that measurably increase the activity of an ABC- transporter or of a fragment thereof, and preferably CFTR activity.
- preferred compounds of the present invention are those that measurably decrease the activity of an ABC-transporter or of a fragment thereof.
- One of skill in the art would be well aware of techniques and assays useful in measuring the increase or decrease of activity of an ABC-transporter or of a fragment thereof .
- the present invention provides a method of modulating CFTR activity in a cell membrane of a mammal in need thereof, comprising the step of administering to said mammal a composition comprising a compound of the present invention as defined above.
- the preferred embodiments of compound of formula (I) useful in potentiating the activity of CFTR include the preferred embodiments of the present invention described above.
- 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 the present invention.
- the term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity.
- said functional ABC transporter is CFTR.
- the preferred embodiments of compounds of formula (I) useful in increasing the number of functional ABC transporters include preferred embodiments of the compounds of the present invention as described above.
- structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds 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.
- compositions having the present structures except for the replacement of a hydrogen by a 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.
- the present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention.
- a "pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof.
- Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species .
- the compounds of the present invention may be readily prepared using methods known in the art. One such synthetic route is illustrated in Scheme 1 below:
- reaction mixture was then either allowed to stir overnight at room temperature or subjected to microwave irradiation for 5 minutes at 200°C,
- the crude product was then filtered, evaporated to dryness, dissolved in a minimum of dimethylsulfoxide and then purified by reverse phase preparative liquid chromatography.
- compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention 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, 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, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxy
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate,
- Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C ⁇ - 4 alkyl) 4 salts.
- alkali metal e.g., sodium and potassium
- alkaline earth metal e.g., magnesium
- ammonium e.g., ammonium
- N + (C ⁇ - 4 alkyl) 4 salts e.g., sodium and potassium
- compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the compositions are administered orally, intraperitoneally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
- a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di-glycerides .
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols .
- a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- Such materials include cocoa butter, beeswax and polyethylene glycols .
- the pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract . Suitable topical formulations are readily prepared for each of these areas or organs .
- Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
- the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
- the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
- the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
- compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
- additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
- 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 present invention provides a method of treating a ABC transporter mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above .
- the ABC transporter mediated disease is selected from immunodeficiency disorder, inflammatory disease, allergic disease, autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease or viral disease .
- 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-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,
- 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 the present invention.
- an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of any one of the above diseases .
- the compounds and compositions, according to the method of the present invention may be administered using any amount and any route administration effective for treating or lessening the severity of of any one of the above diseases.
- the compounds of the present invention are useful in treating cystic fibrosis.
- the disease so treated is selected from Tangier's disease, stargardt disease 1, age related macular dystrophy 2, retinintis pigmentosa, bare lymphocyte syndrome, PFIC-3, anemia, progressive intrahepatic cholestasis-2 , Dublin-Johnson syndrome, Pseudoxanthoma elasticum, cystic fibrosis, familial persistent hyperinsulinemic hyproglycemia of infancy, adrenolecukodystrophy, sitosterolemia, chronic obstructive pulmonary disease, asthma, disseminated bronchiectasis, chronic pancreatitis, male infertility, emphysema, or pneumonia.
- the ABC transporter mediated disease is secretory diarrhea, or polycystic kidney disease in a mammal .
- the present invention provides a method of treating cystic fibrosis or secretory diahrrea comprising the step of administering to said mammal a composition comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above. Most preferably, said disease is cystic fibrosis.
- the present invention provides a method of modulating activity of an anion channel in vi tro or in vivo, comprising the step of contacting said channel with a compound of the present invention.
- said anion channel is a chloride channel or a bicarbonate channel. More preferably, said anion channel is a chloride channel .
- the present invention provides a method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to the present invention.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: (i) a compound of the present invention as described above; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti- infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent.
- a pharmaceutical composition comprising: (i) a compound of the present invention as described above; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti- infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent.
- Preferred embodiments of compounds the present invention in the above pharmaceutical composition are those as described above .
- 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 vi tro or in vivo, comprising: (i) a composition comprising a compound of the present invention; and (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof .
- the kit is useful in measuring the activity of 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 utilized 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.
- These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
- FRET fluorescence resonant energy transfer
- V m fluorescent phospholipid
- the changes in fluorescence emission can be monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
- Preferred ABC transporters in the kit of the present invention include CFTR.
- Hal Cl, Br, I wherein W is a group as described in the compounds of the present invention.
- Hal Cl, Br, I wherein W is a group as described in the compounds of the present invention.
- thiourea 4-Fluoro-l-methoxy-2-nitro-benzene A solution of methyl iodide (127.8 g, 0.9004 mol) in acetonitrile (100 mL) was slowly added to a solution of 5-fluoro-2- nitrophenol (94.2 g, 0.600 mol) and potassium carbonate (207 g, 1.50 mol) in acetonitrile (450 mL) . The mixture was heated to reflux for 15 hours. The mixture was allowed to cool, filtered, and washed twice with dichloromethane (100 mL) .
- N' - [5- (2-Chloro-benzoyl) -thiazol-2-yl] -N, N-dimethyl- formamidine A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl -amine (23.2 g, 195 mmol) in methanol (80 mL) was heated under reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-l- (chloro-phenyl) - ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated to reflux for 4 hours.
- the residue was diluted with dichloromethane (120 mL) and then washed with sodium hydroxide (10% aqueous solution, 50 mL ) and water (30 mL) .
- the organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 120 mL) .
- the combined aqueous layer was adjusted with a 10 % aqueous solution of sodium hydroxide to between pH 9 and 10 and then extracted three times with dichloromethane (150 mL) .
- the organic layers were combined, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to yield a yellow solid. (5.2 g, 0.023 mol, 23% from 2-chloroaniline) .
- the solvent was evaporated to dryness .
- the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10 % aqueous solution, 100 mL ) and water (50 mL) .
- the organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 250 mL) .
- the combined aqueous layers were adjusted to pH 9 to 10 with a 10 % aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300mL) .
- the organic layer was separated, dried over sodium sulfate, and evaporated to dryness.
- the crude product was purified by silica gel column chromatography to yield the yellow-red solid product.
- a solution of cyanamide in water (50 %, 150 mL) was added to a boiling solution of [2- (2-chloro-phenyl) - 1-methyliminomethyl-ethyl] -methyl-amine in methanol and dichloromethane .
- the pH was brought to 4.5 by the continual addition of an aqueous solution of sulfuric acid (9 M) .
- the mixture was refluxed for 2 hours, allowed to cool to room temperature, and adjusted to pH 9 through the addition of powdered sodium bicarbonate.
- the mixture was extracted three times with dichloromethane (200 mL) and the combined organic layers were extracted three times with hydrochloric acid (20 % aqueous solution, 150 mL) .
- aqueous solution was adjusted to pH 10 with sodium hydroxide (10 % aqueous solution) and extracted three times with dichloromethane (150 mL) .
- the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black solid which was purified by column chromatography to yield the product (5.0 g, 0.23 mmol, 11 % from 2-chloroaniline) as a brown solid.
- ESI-MS m/z calc.
- the colorless solution was protected from light and allowed to stir for 16 hours.
- the resulting red suspension was evaporated to dryness and dissolved in a minimum of dichloromethane.
- This solution was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride.
- the organic layer was separated and filtered to remove a fine red precipitate which remained suspended in the organic phase.
- the solvent was removed and then the solid was dissolved in a minimum of 50 / 50 (v / v) ethyl acetate and 1 N aqueous solution of hydrochloric acid.
- the layers were separated and the aqueous layer was washed with an equal volume of ethyl acetate.
- aqueous layer was then placed in an ice bath with an equal volume of ethyl acetate .
- Sodium hydroxide (IN) was then slowly added with vigorous swirling until the aqueous phase was basic.
- the layers were separated and the aqueous layer was washed two additional times with ethyl acetate.
- the combined organic layers were washed three times with an equal volume of a solution of saturated aqueous sodium bicarbonate followed by a solution of saturated aqueous sodium chloride.
- the organic layer was then dried over sodium sulfate and evaporated to dryness to yield a pale yellow solid (1.8 g, 8.4 mmol, 34 %) ESI-MS m/z calc. 214.1, found 215.3 (M+l) + Retention time 1.90 minutes.
- N- [5- (2-Chloro-benzoyl) -thiazol-2-yl] -2-phenyl- butyramide (102 mg, 0.265 mmol) was suspended in 1 mL of anhydrous methanol.
- Sodium borohydride (30.3 mg, 0.801 mmol) was slowly added and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. After stirring for one hour a second aliquot of sodium borohydride (30.3 mg, 0.801 mmol) was added. The reaction mixture was allowed to stir for an additional hour and then the crude product was evaporated to dryness and then dissolved in a minimum of ethyl acetate.
- 6-Ethoxy-benzothiazol-2-ylamine 39 mg, 0.20 mmol
- 2 -phenyl-butyric acid 33 mg, 0.20 mmol
- N, N-dimethylformamide 1 mL
- triethylamine 84.1 ⁇ L, 0.600 mmol
- 0- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours.
- the crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25 %) .
- ESI-MS m/z calc. 340.1, found 340.9 (M+l) + Retention time 3.55 minutes .
- the optical membrane potential assay utilized 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).
- VIPR Voltage/Ion Probe Reader
- These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
- FRET fluorescence resonant energy transfer
- V m fluorescent phospholipid
- the changes in fluorescence emission were monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
- Bath Solution #1 (in mM) NaCI 160, KC1 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
- Chloride-free bath solution Chloride salts in Bath Solution #1 are substituted with gluconate salts.
- CC2-DMPE Prepared as a 10 mM stock solution in DMSO and stored at -20°C.
- DiSBAC 2 (3) Prepared as a 10 mM stock in DMSO and stored at -20°C.
- Cell Culture NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for optical measurements of membrane potential .
- the cells are maintained at 37 °C in 51 C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
- the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs. for the potentiator assay.
- the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hours.
- the FRT epithelia demonstrated resistances of 4 K ⁇ / cm 2 or more.
- the solutions were maintained at 27 °C and bubbled with air.
- the electrode offset potential and fluid resistance were corrected using a cell-free insert.
- the current reflects the flow of Cl " through ⁇ F508-CFTR expressed in the apical membrane.
- the I S c was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA) . Identification of Correction Compounds Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient .
- the cells were incubated with 10 mM of the test compound for 24 hours at 37°C and were subsequently washed 3X prior to recording.
- the cAMP- and genistein- mediated I sc in compound-treated cells was normalized to the 27°C and 37°C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein- mediated I S c compared to the 37°C controls.
- Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 ⁇ g/ml) , whereas apical NaCI was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl " concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 mM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
- Basolateral solution in mM: NaCI (135), CaCl 2 (1.2), MgCl 2 (1.2), K 2 HP0 4 (2.4), KHP0 4 (0.6) , N-2- hydroxyethylpiperazine-N' -2- ethanesulfonic acid (HEPES) (10) , and dextrose (10) .
- the solution was titrated to pH 7.4 with NaOH.
- FRT Cell Culture Fisher rat epithelial cells expressing ⁇ F508- CFTR (FRT ⁇ F508"CFTR ) were used for Ussing chamber experiments for the putative ⁇ F508-CFTR modulators identified from our optical assays.
- the cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 °C and 5% C0 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the ⁇ F508-CFTR.
- the cells were incubated with 10 DM of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity) . Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ⁇ M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls .
- Intracellular solution in mM: Cs-aspartate (90) , CsCl (50) , MgCl 2 (1) , HEPES (10) , and 240 ⁇ g/ml amphotericin-B (pH adjusted to 7.35 with CsOH) .
- Extracellular solution in mM: N-methyl-D-glucamine (NMDG) -Cl (150), MgCl 2 (2), CaCl 2 (2) , HEPES (10) (pH adjusted to 7.35 with HCI) .
- NMDG N-methyl-D-glucamine
- CaCl 2 (2) CaCl 2 (2)
- HEPES 10
- the cells are maintained at 37 °C in 5% C0 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, D-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
- Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, D-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
- 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 °C for measuring the activity of correctors .
- the ⁇ F508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI) . After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1-2 sec. To maintain ⁇ F508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F " (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min) . Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (V p ) was maintained at 80 mV.
- V p The pipette potential
- Extracellular solution (in mM) : NMDG (150) , aspartic acid (150), CaCl 2 (5), MgCl 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base) .
- Intracellular solution in mM: NMDG-C1 (150) , MgCl 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCI) .
- Cell Culture NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for excised-membrane patch-clamp recordings.
- the cells are maintained at 37 °C in 5% C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
- 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.
- the compounds of the present invention were found to modulate CFTR activity when tested using the above methods.
- the activity of exemplary compounds of the present invention is recited below in Table 3.
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AU2004272599A AU2004272599A1 (en) | 2003-09-06 | 2004-09-07 | Modulators of ATP-binding cassette transporters |
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IL174128A IL174128A0 (en) | 2003-09-06 | 2006-03-06 | Heterocyclic compounds and pharmaceutical compositions containing the same |
NO20061543A NO20061543L (en) | 2003-09-06 | 2006-04-05 | Modulators of ATPBinding Cassette Transportm |
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- 2004-09-07 WO PCT/US2004/029206 patent/WO2005026137A2/en active Application Filing
- 2004-09-07 EP EP04783449A patent/EP1664006A2/en not_active Withdrawn
- 2004-09-07 JP JP2006525534A patent/JP2007504255A/en active Pending
- 2004-09-07 ZA ZA200602755A patent/ZA200602755B/en unknown
- 2004-09-07 US US10/936,448 patent/US7973169B2/en active Active
- 2004-09-07 KR KR1020067004627A patent/KR20060088537A/en not_active Application Discontinuation
- 2004-09-07 CN CNA200480031503XA patent/CN1898221A/en active Pending
- 2004-09-07 RU RU2006111093/04A patent/RU2006111093A/en not_active Application Discontinuation
- 2004-09-07 AU AU2004272599A patent/AU2004272599A1/en not_active Abandoned
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2006
- 2006-03-06 IL IL174128A patent/IL174128A0/en unknown
- 2006-04-05 NO NO20061543A patent/NO20061543L/en not_active Application Discontinuation
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2011
- 2011-07-01 US US13/174,844 patent/US8431605B2/en not_active Expired - Lifetime
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2013
- 2013-03-22 US US13/848,970 patent/US8741939B2/en not_active Expired - Lifetime
- 2013-11-14 US US14/079,664 patent/US8853415B2/en not_active Expired - Fee Related
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2014
- 2014-10-06 US US14/506,856 patent/US9249131B2/en not_active Expired - Lifetime
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EP1664006A2 (en) | 2006-06-07 |
CN1898221A (en) | 2007-01-17 |
NO20061543L (en) | 2006-06-06 |
IL174128A0 (en) | 2006-08-01 |
US20130252333A1 (en) | 2013-09-26 |
RU2006111093A (en) | 2007-10-27 |
US20160228414A1 (en) | 2016-08-11 |
US8431605B2 (en) | 2013-04-30 |
KR20060088537A (en) | 2006-08-04 |
US7973169B2 (en) | 2011-07-05 |
US20150025076A1 (en) | 2015-01-22 |
JP2007504255A (en) | 2007-03-01 |
US8741939B2 (en) | 2014-06-03 |
MXPA06002567A (en) | 2006-09-04 |
US20050176789A1 (en) | 2005-08-11 |
US9249131B2 (en) | 2016-02-02 |
US20140072995A1 (en) | 2014-03-13 |
US20120004216A1 (en) | 2012-01-05 |
US8853415B2 (en) | 2014-10-07 |
WO2005026137A3 (en) | 2005-07-21 |
ZA200602755B (en) | 2007-06-27 |
AU2004272599A1 (en) | 2005-03-24 |
CA2537841A1 (en) | 2005-03-24 |
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