WO2008040058A1 - Novel chromenone potassium channel blockers and uses thereof - Google Patents
Novel chromenone potassium channel blockers and uses thereof Download PDFInfo
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- WO2008040058A1 WO2008040058A1 PCT/AU2007/001476 AU2007001476W WO2008040058A1 WO 2008040058 A1 WO2008040058 A1 WO 2008040058A1 AU 2007001476 W AU2007001476 W AU 2007001476W WO 2008040058 A1 WO2008040058 A1 WO 2008040058A1
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- 0 *C1c(c(*)c(c(OC(I*)=C2*)c3*)C2=O)c3OC1* Chemical compound *C1c(c(*)c(c(OC(I*)=C2*)c3*)C2=O)c3OC1* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- the present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells.
- the invention also relates to the use of these compounds in ' the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.
- autoimmune and chronic inflammatory diseases are related to immunoregulatory abnormalities.
- Diseases such as systemic lupus erythematosis, chronic rheumatoid arthritis, multiple sclerosis and psoriasis have in common the appearance of autoantibodies and self-reactive lymphocytes.
- Multiple sclerosis is the most common neurological disease of young people. It is believed to cost more in medical care and lost income than any other neurological disease of young adults.
- Myelin is an insulating material that coats most axons and allows rapid signal conduction over long distances by saltatory conduction. It is thought that antibodies and specialised cells of the immune system attack the myelin coating. This process leads to inflammation and scarring (sclerosis) which damages blood vessels in the area by the formation of a lesion known as a plaque. These plaques are characterised by being infiltrated by macrophages and T cells. This results in demyelination with the consequential loss of the rapid signal conduction. A possible method of treating these autoimmune and inflammatory diseases is by suppressing T-cell proliferation and modulating their activation.
- T-cell activation may be conceptually separated into pre-Ca 2+ and post-Ca 2+ events (Cahalan and Chandy 1997, Curr. Opin. Biotechnol. 8 749).
- activation of tyrosine kinases and the generation of inositol 1 ,4,5-triphosphate lead to the influx of Ca 2+ and a rise in the cytoplasmic Ca 2+ concentration.
- the rise in Ca 2+ activates the phosphatase calcineurin, which then dephosphorylates a cytoplasmically localized transcription factor (N-FAT) enabling it to accumulate in the nucleus and bind to a promoter element of the interleukin-2 gene.
- N-FAT cytoplasmically localized transcription factor
- gene transcription leads to lymphokine secretion and to lymphocyte proliferation.
- Ion channels underlie the Ca 2+ signal of T-lymphocytes. Ca 2+ ions move across the plasma membrane through a channel termed the store-operated Ca 2+ channel or the calcium release-activated Ca 2+ channel.
- Two distinct types of potassium channels indirectly determine the driving force of calcium entry. The first is the voltage-gated Kv1.3 channel (Cahalan 1985, J. Physiol. 385: 197; Grissmer 1990, Proc. Natl. Acad. ScL USA 87 9411 ; Verheugen 1995, J. Gen. Physiol. 105 765; Aiyar 1996, J. Biol. Chem. 271 31013; Cahalan and Chandy 1997, Curr. Opin. Biotechnol.
- IKCaI intermediate-conductance calcium- activated potassium channel
- Kv1.3 a S ⁇ a/cer-related gene.
- Kv1.3 has been characterised extensively at the molecular and physiological level and plays a vital role in controlling T-lymphocyte proliferation, mainly by maintaining the resting membrane potential of resting T- lymphocytes. Inhibition of this channel depolarises the cell membrane sufficiently to decrease the influx of Ca 2+ and thereby prevents downstream activation events.
- the Kv1.3 channel is almost exclusively located in T-lymphocytes.
- compounds which are selective Kv1.3 blockers are potential therapeutic agents as immunosuppressants for the prevention of graft rejection, and the treatment of autoimmune and inflammatory disorders. They could be used alone or in conjunction with other immunosuppressants, such as selective IKCa 1 blockers or cyclosporin, in order to achieve synergism and/or to reduce toxicity, especially of cyclosporin.
- T-cell replication and Kv1.3 blockade has also been shown through the use of a small molecule, a psoralen derivative, that is an active and relatively specific inhibitor of the Kv1.3 channel.
- the derivative showed specificity in inhibiting the proliferation of the high Kv1.3 T-cells over peripheral blood T-cells (Vennekamp et al (2004) MoI. Pharm. 65 1364-1374).
- the Kv1.3 channel has also been associated with diabetes. Studies of Kv1.3 knockout mice found that the mice have increased insulin sensitivity. The selective blockage of the Kv1.3 channel also led to increased insulin sensitivity (Xu, J. ⁇ t al. (2004) PNAS 101 (9), 3122-3117). It has been suggested by Wulff, who was involved in the electrophysiology on multiple sclerosis that diabetes also involves autoreactive T-cells that express very high levels of Kv1.3 (Wulff, H. et al. (2003) Curr. Op.DDD. 6 640-647).
- potassium channel blockers that will inhibit lymphocyte proliferation, but have adverse side effects.
- Other potassium channels exist in a wide range of tissues including the heart and brain, and generally blocking these channels is undesirable. Accordingly it would be advantageous to provide or identify compounds, which are selective inhibitors of the Kv1.3 channel.
- US Patent No. 5,494,895 discloses the use of a thirty-nine amino acid peptide, scorpion peptide margatoxin, as a selective inhibitor and probe of Kv1.3 channels present in human lymphocytes, and also as an immunosuppressant. However the use of this compound is limited by its potent toxicity.
- Kv1.3 blockers of Kv1.3
- psoralens Vennekamp et al. (2004) MoI. Pharm. 65, 1365-1374 and Wulff et al., US 2006/0079535
- selected benzamides Schothofer et al. (2002) Biochem. 41 , 7781-7794 and Schalhofer et al (2003) Biochem. 42, 4733-4743.
- Khellinone a substituted benzofuran and natural product from certain plants, and 8-Methoxypsoralen (8-MOP), both commercially available products, have been found to exhibit blocking activity on the Kv1.3 channel.
- European Patent Application 82201051 describes furano-chromone derivatives for use as anti-inflammatory agents amongst other suggested uses.
- An intermediate compound used in the manufacture of the chromone derivatives was 5- (benzoylacetyl)-4,7-dimethoxy-6-hydroxy-benzofuran.
- European Patent Application 83302551 describes a process for preparing di-4,7- loweralkoxybenzofurans for use as intermediates in the preparation of khellin and related compounds.
- German patent DE 3710469 and European patent publication number EP303920 describe the synthesis of 5-acetyl-4-benzyloxy-7-methoxy-6-hydroxy-benzofuran by alkaline ring cleavage of a pyrone ring of a fused system. This is also described in an article by Musante in Annali de Chimica (1959) 46, 768-781 together with the compound where the benzyloxy group is replaced with the residue of 2-hydroxyacetophenone.
- the invention provides compounds of formula (I) or salts thereof,
- Ri and R 2 are independently selected from hydrogen, halo, optionally substituted lower alkyl, optionally substituted aryl, -OR, -C(O)R, -C(O)OR, -OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted 0 3 .
- R 7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), -C(O)NR 1 R", - NR 1 C(O)R" and -NR 1 R" (where R' and R" are independently selected from hydrogen or lower alkyl); one of R 3 or R 4 is selected from a lower alkyl or lower alkyloxy substituted by optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 cycloalkyloxy, optionally substituted C 4-7 cycloalkenyl, optionally substituted C 4-7 cycloalkenyloxy, or NR 1 R" (where R 1 and R " are independently selected from hydrogen and lower
- R 3 or R 4 is selected from hydrogen, cyano, halo, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, -OR, -C(O)R, -C(O)OR, -OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), -C(O)NR 1 R", -NR 1 C(O)R" and -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower alkyl);
- R 5 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -OR, -C(O)R, - C(O)OR, -OC(O)R, SR, (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), -C(O)NR 1 R", -NR 1 C(O)R" and -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower
- R 6 is selected from (i) optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4 -7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl when L is -O-, -S-, -S(O)-, - S(O) 2 -, -Se-, -Se(O)-, -Se(O) 2 -, or -NR" 1 -; or (ii) optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -OR, -C(O)R, - C(O)OR, -OC(O)R, -SR, -S(O)R
- a method for the treatment or prevention of autoimmune or chronic inflammatory diseases, or the prevention of rejection of foreign organ transplants and/or related afflictions by the administration of a compound of formula I or a pharmaceutically acceptable salt thereof, or a composition containing a compound of formula I or pharmaceutically acceptable salt thereof.
- the invention provides the use of a compound of formula I or a salt thereof, in the manufacture of a medicament for the treatment or prevention of autoimmune or chronic inflammatory diseases, or the prevention of rejection of foreign organ transplants and/or related afflictions.
- compositions for use as an immunosuppressant comprising an effective amount of compound of Formula I or pharmaceutically acceptable salt thereof and optionally a carrier or diluent.
- the invention is based on the discovery that compounds of the general formula I, as described in the above Summary of the Invention can have useful properties as inhibitors of potassium cell channels, and particularly the Kv1.3 channel. Such compounds have significant potential as immunosuppressants for the treatment of autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. They may also be useful in the treatment or prevention of graft rejection.
- alkyl refers to a straight or branched chain saturated hydrocarbon group.
- C- ⁇ - 12 alkyl refers to such a group containing from one to twelve carbon atoms and the terms "Ci -6 alkyl” and “lower alkyl” refer to such groups containing from one to six carbon atoms, such as methyl (“Me”), ethyl (“Et”), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
- alkylene refers to divalent alky] groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
- C 3-7 cycloalkyl refers to non-aromatic, saturated non-aromatic carbocycles having from 3 to 7 carbon atoms. Examples include cyclopentyl and cyclohexyl.
- alkenyl refers to a straight or branched hydrocarbon containing one or more double bonds, preferably one or two double bonds.
- C 2- I 2 alkenyl refers to such a group containing from two to twelve carbon atoms.
- alkenyl examples include allyl, 1-methylvinyl, butenyl, iso-butenyl, 1 , 3-butadienyl, 3-methyl- 2-butenyl, 1 , 3-butadienyl, 1 ,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1 ,3- hexadienyl, 1 ,4-hexadienyl and 1 , 3, 5-hexatrienyl.
- C 4- 7 cycloalkenyl refers to non aromatic carbocycles having 4 to 7 carbon atoms and having one or more double bonds. Examples include cyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl, 1 ,3-cyclopentadienyl, 1 ,3- cyclohexadienyl and 1 ,4-cyclohexadienyl.
- alkynyl refers to a straight or branched hydrocarbon containing one or more triple bonds, preferably one or two triple bonds.
- C 2- I 2 alkynyl refers to such a group containing from two to twelve carbon atoms. Examples include 2-propynyl and 2- or 3-butynyl.
- alkynylene refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C ⁇ C-), propynylene (-Chb-C ⁇ C-), and the like.
- alkoxy refers to a straight or branched chain alkyl group covalently bound via an oxygen linkage (-O-) and the terms "C- ⁇ - 6 alkoxy” and “lower alkoxy” refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
- alkenyloxy and alkynyloxy as used alone or in combination respectively refer to an alkenyl and alkynyl group as earlier described linked via an oxygen linkage (-O-).
- aromatic when used alone or in combination refers to monocyclic or bicyclic aryl rings and ring systems (aromatic hydrocarbon rings or ring systems) and also aromatic heterocyclic rings or ring systems, as known as heteroaryl or heteroaromatic rings.
- Preferred aromatic rings are optionally substituted phenyl (“Ph”) rings.
- aryl refers to carbocyclic (non-heterocyclic) aromatic rings or ring systems.
- the aromatic rings may be mono- or bi-cyclic ring systems.
- the aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.
- Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.
- heteroaryl refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen.
- heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
- heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring.
- Examples of 5-membered monocyclic heterocyclyl and heteroaryl groups include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1 ,2,3 and 1 ,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1 ,2,3 and 1 ,3, 4 triazolyls), tetrazolyl, thiadiazolyl (including 1 ,2,3 and 1 ,3,4 thiadiazolyls).
- 6-membered monocyclic heterocyclyl and heteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, 1 ,3,5-trithianyl and triazinyl.
- heterocycles may be optionally substituted with a broad range of substituents, such as Ci -6 alkyl, Ci -6 alkoxy, C 2 - 6 alkenyl, c 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, phenyl, phenyloxy, phenylalkyl, phenylalkyloxy, amino, cyano or mono or di(Ci_ 6 alkyl) amino.
- substituents such as Ci -6 alkyl, Ci -6 alkoxy, C 2 - 6 alkenyl, c 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, phenyl, phenyloxy, phenylalkyl, phenylalkyloxy, amino, cyano or mono or di(Ci_ 6 alkyl) amino.
- heterocycle or heteroaryl may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
- Examples of 8, 9 and 10-membered bicyclic heterocyclyl and heteroaryl groups include 1 H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like.
- heterocycles may be optionally substituted, for example with Ci -6 alkyl, Ci -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, cyano, phenyl, phenyloxy, phenylalkyl, phenylalkyloxy, amino and mono or di(Ci- 6 alkyl) amino.
- heterocyclic and heteroaromatic radicals examples include (optionally substituted) isoxazoles, isothiazoles, 1 ,3,4-oxadiazoles, 1 ,3,4- thiadiazoles, 1 ,2,4-oxadiazoles, 1 ,2,4-thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines, pyrimidines, pyrazines, 1 ,2,4-triazines, 1 ,3,5-triazines, benzoxazoles, benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines, quinoxalines, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, 1
- radicals can be optionally substituted with, by example, C-i- ⁇ alkyl, Ci -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, phenyl, phenyloxy, phenylalkyl, phenylalkyloxy, cyano or mono or di(Ci -6 alkyl) amino.
- Heteroaryl or heteroaromatic rings may preferably be selected from isoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furazanyl, triazolyl, pyridyl, pyrimidinyl, furyl, pyrazolyl, pyridazinyl, thienyl and aryl fused heteroaromatic rings such as benzfuranyl, benzothiophenyl and benzoisoxazolyl.
- Heterocyclyl or heterocyclic rings may preferably be selected from pyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone, pyrrolin-2-one, tetrahydrofuran, 1 ,3- dioxolane, piperidine, tetrahydropyran, oxazoline, 1 ,3-dioxane, 1 ,4-piperazine, morpholine and thiomorpholine.
- arylalkyl refers to carbocyclic aromatic rings or ring systems as previously described and substituted by an alkyl group, also as previously described. Unless otherwise indicated the aryl substituent is attached by the alkyl part of the substituent.
- aryl C1-12 alkyl refers to carbocyclic aromatic rings or ring systems as previously described and substituted by a CM 2 alkyl, C 2 - 12 alkenyl or C 2- i 2 alkynyl group, as previously described.
- halo and halogen refers to fluoro, chloro, bromo and iodo groups.
- halo alkyl group has one or more of the hydrogen atoms on an alkyl group replaced with halogens.
- a notable example is -CF 3 .
- aryloxy refers to an aryl group as earlier described linked to the parent structure via an oxygen linkage (-O-).
- phenoxy e.g., phenoxy
- heteroaryloxy e.g., a heteroaryl group as earlier described linked to the parent structure via an oxygen group.
- a notable example is a 4, 6 or 7- benzo[b]furanyloxy group.
- Divalent linker group is taken to mean a divalent group capable of forming a stable bridge between the core structure of, for instance, formula (I) and the radical R 6 .
- divalent linker groups include alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclylene, alkylenearylene, alkylenearylenealkylene, alkyleneheteroarylenealkylene, alkyleneheterocyclylenealkylene, and the like.
- a group may include one or more substituents.
- One or more hydrogen atoms on the group may be replaced by substituent groups independently selected from halogens, C1- 6 alkyl, C2-6 alkenyl,
- each R, R 1 and R" is independently selected from H, C- ⁇ - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci -6 alkylaryl, Ci -6 alkylheteroaryl, and Ci -6 alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C 1-6 alkylaryl, Ci -6 alkylheteroaryl, or Ci -6 alkylheterocyclyl, may be optionally substituted with one to six of same or different groups selected from halogen, hydroxy, lower alkyl, lower alkoxy, -CO 2 H, CF 3 , CN, phenyl,
- the term "optionally substituted” also indicates that one or more saturated carbon atoms may be substituted for a heteroatom or heterogroup, such as O, S, NH and the like.
- an optionally substituted alkylene group could be represented by a group such as -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 NH-CH 2 -, -CH 2 NHCH 2 -, -CH 2 OCH 2 -, CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 - and the like.
- the group may itself be optionally substituted with one to six of the same or different substituents selected from halogens, Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, Ci -6 haloalkyl (in particular -CF 3 ), Ci -6 haloalkoxy (such as -OCF 3 ), -OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, -NH 2 , -NHCi -4 alkyl, -N(Ci -4 alkyl) 2 , -CN, -NO 2 , mercapto, Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl and CO 2 H.
- substituents selected from halogens, Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, Ci -6 haloalkyl (in particular -CF 3 ), Ci -6 haloalkoxy (such
- salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
- pharmaceutically acceptable derivative includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates of the compounds of formula I or salts thereof.
- Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an active metabolite or residue thereof.
- the pharmaceutically acceptable salts include acid addition salts, base addition salts, and the salts of quaternary amines and pyridiniums.
- the acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic, or tartaric acids.
- the counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate.
- the base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium.
- basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
- the salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.
- the compounds of the invention may be in crystalline form and/or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention.
- solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
- pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention.
- pharmaceutically acceptable ester includes biologically acceptable esters of compound of the invention such as sulphonic, phosphonic and carboxylic acid derivatives.
- a prodrug or pharmaceutically acceptable ester of a compound of formula I of salt thereof there is provided a prodrug or pharmaceutically acceptable ester of a compound of formula I of salt thereof.
- the compounds of formula I and some derivatives thereof may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form.
- the invention extends to each of these forms individually and to mixtures thereof, including racemates.
- the isomers may be separated conventionally by chromatographic methods or using a resolving agent.
- the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has at least one carbon-carbon double bond, it may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention.
- Ri and R 2 are independently selected from hydrogen, lower alkyl or halo, and are preferably hydrogen.
- R5 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, halo, OR, -C(O)R, -C(O)OR, -OC(O)R (where each R is hydrogen or optionally substituted lower alkyl), -C(O)NR 1 R", -NR 1 C(O)R” or -NR 1 R" (where R' and R" are independently selected from hydrogen or lower alkyl).
- R 1 , R 2 , and R 5 are hydrogen.
- R 3 or R 4 is selected from hydrogen, optionally substituted CM 0 alkyl, optionally substituted C 2- io alkenyl, optionally substituted C 2- - I0 alkynyl, optionally substituted C 1 -Io alkoxy, optionally substituted C 2-10 alkenyloxy and optionally substituted C 2-10 alkynyloxy.
- it is selected from hydrogen, optionally substituted C 1-I0 alkyl or optionally substituted C 1-I0 alkoxy. More preferably hydrogen, Ci -3 alkoxy or Ci -3 alkyl. Most preferably hydrogen, methyl or methoxy.
- R 3 or R 4 is a substituted C 1-I0 alkyl or substituted CM 0 alkoxy group, preferably a substituted lower alkyl or alkoxy group, more preferably a substituted methyl/methoxy, ethyl/ethoxy, propyl/propyloxy or butyl/butyloxy group.
- Preferred substituents include optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, and NR 1 R" where R' and R" each independently represents hydrogen and lower alkyl.
- the present invention provides compounds of formula (Ia) or salts thereof,
- R 3 or R 4 is selected from hydrogen, methyl or methoxy
- R 3 or R 4 is a lower alkyl or lower alkoxy substituted by optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, or NR 1 R" (where R 1 and R" are each independently selected from hydrogen and lower alkyl);
- L is a bivalent linking group of 1-6 atoms in length selected from optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, -O-, -S-, -S(O)-, -S(O) 2 -, -Se-, -Se(O)-, -Se(O) 2 -, and -NR" 1 - (where R 1 " is selected from hydrogen, lower alkyl, optionally substituted arylalkyl, optionally substituted aryl); and
- Re is selected from (i) optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted C 3 - 7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl when L is -O-, -S-, -S(O)-, - S(O) 2 -, -Se-, -Se(O)-, -Se(O) 2 -, or -NR'"-; or (ii) optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -OR, -C(O)R, - C(O)OR, -OC(O)R, -SR, -S(O)R,
- L is an optionally substituted alkylene (eg -CH 2 CH 2 OCH 2 CH 2 - and - CH 2 OCH 2 -) and more preferably an unsubstituted alkylene group. Also, preferably L is a divalent linker group of from 1-4 atoms in length. Thus, most preferably L is an unsubstituted methylene, ethylene, propylene, or butylene group.
- Re is optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -OR, -C(O)R 1 -C(O)OR, -OC(O)R, -SR, -S(O)R, -S(O) 2 R, (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), - C(O)NR 1 R", -NR 1 C(O)R” or -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower alkyl) when L is optionally substituted alkylene, optionally substitute
- Re is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -OR 1 ", -SR" 1 , -S(O)R 1 ", -S(O) 2 R” 1 (where R 1 " is selected from optionally substituted alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl) or -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower alkyl).
- the present invention provides compounds of formula (Ia) or salts thereof wherein:
- R 3 or R 4 is selected from hydrogen, methyl and methoxy
- R 3 or R 4 is a lower alkyl or lower alkoxy group substituted by aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, or NR 1 R" (where R 1 and R" are independently selected from hydrogen and lower alkyl) and wherein the aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl and hetrocyclyloxy groups are optionally substituted by fluoro, chloro, or lower haloalkyl.
- L is a divalent linker group of 1-4 atoms in length selected from a methylene, ethylene, propylene or butylene;
- Re is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -OR 1 ", -SR" 1 , -S(O)R" 1 , -S(O) 2 R 1 " (where R” 1 is selected from optionally substituted alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl) or -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower alkyl).
- L is a methylene (-CH 2 -) group and RQ is selected from an aryl, heteroaryl, heterocyclyl, -OR 1 ", -SR" 1 , -S(O)R 1 ", -S(O) 2 R" 1 (where R" 1 is selected from lower alkyl, C 3-7 cycloalkyl, heterocyclyl, heteroaryl and aryl) or NR 1 R" where R 1 and R" are independently selected from hydrogen and lower alkyl).
- the optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted heterocyclyl groups may be substituted with from 1 to 4 substituents.
- the substituents may be independently selected from fluoro, chloro, bromo, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, nitro, hydroxyl, carboxyl, phenyl, naphthyl, benzyl and benzoyl.
- the invention also includes where possible a salt or pharmaceutically acceptable derivative such as a pharmaceutically acceptable ester, solvate and/or prodrug of the above mentioned embodiments of the invention.
- a pharmaceutical composition that comprises a therapeutically effective amount of one or more of the aforementioned compounds of formulae I/la or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent.
- the present invention provides pharmaceutical compositions for use as a Kv1.3 ion channel blocker, more particularly as an immunosuppressant, the composition comprising an effective amount of a compound of Formulae I/la or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent.
- composition is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers.
- compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
- the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
- Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
- the compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules.
- a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid that is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
- a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
- parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
- Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
- the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre- filled syringes, small volume infusion or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
- solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
- the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
- Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
- the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.
- Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may conveniently also contain a surfactant such as lecithin.
- the dose of drug may be controlled by provision of a mete red valve.
- the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the powder carrier will form a gel in the nasal cavity.
- the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
- the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
- the pharmaceutical preparations are preferably in unit dosage forms.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- the invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
- the amount of compound of Formulae I/la administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.
- Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.
- compositions may further contain one or more other immunosuppressive compounds.
- the compositions may contain a second immunosuppressive agent such as azathioprine, brequinar sodium, deoxyspergualin, mizaribine, mycophenolic acid morpholino ester, cyclosporin, FK-506 and rapamycin.
- the compounds of the present invention may be useful in the therapeutic or prophylactic treatment of the resistance to transplantation of organs or tissue (such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinum ***, limb, muscle, nervus, medulla ossium, duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc.
- organs or tissue such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinum ***, limb, muscle, nervus, medulla ossium, duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc.
- xeno transplantation including xeno transplantation), graft- versus-host diseases; rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Palmo-planter pustulosis, Hashimoto's thyroiditis, multiple sclerosis, Guillain-Barre syndrome, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, diabetic neuropathy, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, ur
- the compounds may be used prophylactically as well as for the alleviation of acute symptoms.
- treatment or the like are to be understood to include such prophylactic treatment, as well as therapeutic treatments.
- the compounds may be particularly useful in the treatment of multiple sclerosis.
- This chronic neurological disorder affects the nerves of the central nervous system.
- most nerves in the body are normally insulated by a protective sheath of fatty substance called myelin.
- myelin a protective sheath of fatty substance called myelin.
- Multiple sclerosis causes demyelination, in which this protective sheath becomes inflamed and ultimately destroyed.
- multiple sclerosis may be a product of chronically activated T-cells having a channel phenotype characterised by high expression of Kv1.3 channels and low numbers of IKCaI channels. As this channel phenotype is distinct from that seen in quiescent and acutely activated cells it may provide a useful means for controlling multiple sclerosis without the significant side effects of less specific drugs.
- a method of preventing or treating autoimmune or chronic inflammatory diseases, the prevention of rejection of foreign organ transplants and/or related afflictions including the step of administrating a compound of formula I or Ia, or salt thereof, or a composition comprising the compound or salt thereof.
- a means for controlling multiple sclerosis by the application of a blocker of the Kv1.3 channel, preferably a selective channel blocker of the Kv1.3 channel, and optionally also a blocker of Kv1.1 and / or Kv1.2 channels, by the application of a compound of formulae I/la or salt thereof, including a pharmaceutically acceptable derivative thereof, or a composition comprising the compound of formula I or salt thereof, or a pharmaceutically acceptable derivative thereof.
- a method for preventing or treating diabetes including the step of administrating a compound of formulae I/la or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, or a composition comprising the compound or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivative thereof.
- the invention provides a method of modulating potassium ion channel activity of T-cells by the application of a compound of Formulae I/la or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, or a composition comprising the same, to said T cells.
- the compounds of the invention inhibit the potassium ion channel activity of T-cells.
- the potassium channel activity inhibited by the compound of Formulae I/la is a voltage-gated potassium channel, for example, Kv1.1-Kv1.7. More preferably the potassium ion channel activity is the voltage-gated potassium channel, Kv1.3 of a T-cell.
- the compound selectively inhibits the Kv1.3 channel, and optionally also the Kv1.1 and / or Kv1.2 channels.
- a compound of formulae I/la or salt thereof in the preparation of a medicament for the treatment (therapeutic or prophylactic) of disease states mediated by potassium channels, and in particular by blocking the Kv1.3 channel.
- the compounds of the invention can be made from khellin, a natural product from plants which is cheap and commercially available.
- a general synthetic scheme is set out below for those compounds where R-i, R 2 and R 5 are hydrogen, and R 3 and R 4 includes an oxygen atom linking it to the parent structure:-
- L is a halide leaving group and R a and R b are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted C 3- 7 cycloalkyl, optionally substituted C 4-7 cycloalkenyl, optionally substituted alkynyl, ie., where R 3 and R 4 are optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, C 3-7 cycloalkyloxy, and C 4-7 cycloalkenyloxy.
- the vinylogous ester containing six-membered ring of khellin acts as a protecting group for the ultimate phenol and acetyl functionalities during the manipulations of the ethers.
- An alternate synthesis from khellinone can be envisaged where the phenol at the 6-position is capped with a suitable protecting group.
- the alternative reaction scheme is preferred when the reaction with an alkyl halide is slow, due to, for instance, the low reactivity of alkyl halides such as alkyl chlorides.
- the scheme begins with the preparation of 7-desmethylkhellin, which can then be used to prepare the compounds of the invention.
- a preferred embodiment of the compounds of the present invention are compounds where R 4 is an aryl-(C Hb) n -O- substituted example (ie., where R b is Ar- (CHb) n -, where n is 1 to 6).
- R 4 is an aryl-(C Hb) n -O- substituted example (ie., where R b is Ar- (CHb) n -, where n is 1 to 6).
- An alternative synthesis for this subset of compounds is shown below. Sonogashira coupling of 7-alkynyl khellin with an aryl iodide may furnish an aryl alkyne, which upon hydrogenation, reoxidation of the benzofuran, and hydrolysis may afford the desired aryl-(CH 2 ) n -O- khellin. Heck coupling of 7- allyl khellin offers an alternate pathway to this class of compounds.
- Suitable coupling agents are known in the art and include Pd(PPh 3 )2Cl2, Pd(PPh 3 ) 4 , Pd(dibenzylideneacetone), and PdCb(CH 3 CN) 2 .
- the palladium catalysed coupling reactions include a co-catalyst, for instance, CuI, in the presence of a suitable base such as a trialkylamine base.
- 4-alkyl or 7-alkyl khellinones may be synthesised by the following prophetic schemes.
- the compounds of the present invention may be prepared according to the following scheme:
- the compounds of the present invention can be prepared by initial transformation of the C-5 acetyl group.
- the reaction of this group with an ⁇ -haloester in the presence of zinc may afford a ⁇ -hydroxyester which may then be suitably oxidized to form a ⁇ - carbonylester (ie where -C(O)-CH 3 is transformed to -C(O)-CH 2 -CO 2 R (ie where R 5 is CO 2 R where R is lower alkyl, optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl).
- R 5 can be prepared by initially halogenating the C-5 acetyl group with, for instance, Br 2 to form -C(O)CH 2 Br. Substitution of the halogen with a suitable nucleophilic group may afford -C(O)CH 2 R 5 where R 5 is, for instance, -OR, and -SR, (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), or -NR 1 R" (where R 1 and R" are independently selected from hydrogen or lower alkyl).
- step B the substituted kellinones may be ring closed to form the compounds of the present invention by reaction with a compound of formula R 6 LC(O)O- loweralkyl (where RQ is as referred to above and L is an optionally substituted alkylene or NR'", and more preferably an unsubstituted lower alkylene).
- the reaction is carried out in the presence of a suitable base (for example, NaH) or suitable acid (for example, HCI), preferably in an ether solvent such as diethyl ether or tetrahydrofuran.
- L 1 may be a bond or linker group comprising of alkylene and heteroaromatic units (eg -CH 2 CH 2 OCH 2 CH 2 -).
- Substituted chromenones of the present invention can be prepared by electrophilic aromatic substitution of the furan ring, including halogenation followed by palladium mediated coupling.
- the ring can be deprotonated using a base and an electrophile added or a palldium mediated coupling performed.
- Other approaches include ring opening the furan to give an ortho-formylphenols or salicilates that can be ring closed again introducing substituents.
- reduced compounds may be prepared according to the following scheme:
- step A the reduced compounds can be prepared by the reduction of the unsubstituted benzofuran using hydrogenation with 5% palladium on charcoal.
- step B the chromenone can be prepared by treatment with sodium hydride, followed by reaction of the enolate with esters of N,N-dialkyl amino acids as described in General Procedure C below. An example of the transformation described for step A is given below in Example 7 b).
- Another variation is to add, remove or modify the substituents of the product to form new derivatives. This could be achieved by using standard techniques for functional group inter-conversion, well known in the industry such as those described in Comprehensive organic transformations: a guide to functional group preparations by Larock R C, New York, VCH Publishers, Inc. 1989.
- Examples of possible functional group inter-conversions are: -C(O)NRR 1 from - CO 2 CH 3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNRR' in CH 3 OH; -OC(O)R from -OH with e.g., CIC(O)R 1 in pyridine; -NR-C(S)NR 1 R" from -NHR with an alkylisothiocyanate or thiocyanic acid; -NRC(O)OR from -NHR with alkyl chloroformate; -NRC(O)NR 1 R" from -NHR by treatment with an isocyanate, e.g.
- Step 1 Phenol derivative i (1.0 eq., 0.2 M) was dissolved in dry dichloromethane and cooled to O 0 C under N 2 . Anhydrous pyridine (4.0 eq.) was added, followed by triflic anhydride (1.5 eq.) slowly under N 2 . The temperature was slowly raised to rt and the reaction stirred overnight under N 2 . The reaction was cooled in an ice bath and quenched by addition of aqueous NH 4 CI (saturated) solution and extracted with dichloromethane. The organic layer was separated, dried over MgSO 4 , filtered and concentrated under vacuum. The dark brownish residue was subjected to silica-gel flash column chromatography to give crude triflate ii as a solid, which was used without further purification.
- Step 2 ZnBr 2 .2H 2 O (4.0 eq.) was dried at 115-12O 0 C for 2.0 h in a RB flask with occasional mixing under high vacuum. After drying, the flask was cooled to rt under N 2 and then charged with dry tetrahydrofuran (6 mL for 800 mg of ZnBr 2 ). The clear solution was cooled to -78 0 C under N 2 atmosphere and then 4.0 eq. of RLi (usually MeLi was 1.6 M in diethylether) was added slowly by syringe. The reaction temperature was allowed to warm slowly to rt and stirred for 15 min and then again cooled to -78 0 C.
- RLi usually MeLi was 1.6 M in diethylether
- Example 1 a (7.1g, 20.4 mmol) was reacted according to General Procedure B and the crude product was purified by silica-gel flash chromatography, eluting with ethyl acetate:petroleum ether (1 :9 then 1 :4) to afford the title compound as a yellow oil (6.4 g, 97%).
- Example 1 b) 4-Methyl-7-methylsulfanylmethyl-9-(3-phenylpropoxy)furo[3,2- g]chromen-5-one: To a solution of Example 1 b) (500 mg, 1.54 mmol) and ethyl methylthioacetate (0.40 ml_, 3.08 mmol), in dry tetrahydrofuran (2 ml_) was added sodium hydride (60% dispersion in mineral oil, 240 mg, 6.00 mmol) and the resulting suspension was allowed to warm to rt for 10 minutes. The reaction was then heated at reflux for 1 h, cooled and quenched with 10% citric acid (20 ml_).
- the crude mixture was extracted with ethyl acetate (20 ml_). The organic layer was washed with water (20 ml.) and brine (10 mL), dried over MgSO 4 and concentrated in vacuo. The crude residue was treated with a 1 :1 mixture of methanol and 6M HCI (15 mL) and refluxed for 3 h. After cooling, the reaction was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine (15 mL), dried over MgSO 4 and concentrated in vacuo.
- Example 1 b) 500 mg, 1.54 mmol
- ⁇ /, ⁇ /-dimethylglycine ethyl ester (0.44 ml_, 3.12 mmol) were reacted according to General Procedure C.
- the crude residue was subjected to flash chromatography, eluting with dichloromethane:ethyl acetate (1 :1 then 1 :3) and the material thus obtained was dissolved in ethyl acetate and washed with water (4x) and brine to remove traces of excess ⁇ /, ⁇ /-dimethylglycine ethyl ester.
- Example 1 c) 200 mg, 0.50 mmol in dichloromethane (1 ml_) was treated with iodomethane (2 mL, excess) and heated at reflux for 3 days. During this time a white precipitate formed. The reaction was cooled, filtered and the filtrate concentrated in vacuo to yield the crude iodide product as a tan solid contaminated with ⁇ 30% starting material (230 mg total mass). This crude material was used in subsequent reactions without further purification. To a solution of the crude iodide (40 mg) in dry dichloromethane (1.5 mL) was added morpholine (2 drops from a pasteur pipette) and the mixture was stirred at rt for 1 h.
- morpholine 2 drops from a pasteur pipette
- Example 4 a (43 mg, 0.20 mmol) and 4-(phenoxy)butylbromide (55 mg, 0.24 mmol) were treated as described under General Procedure A.
- the crude product was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1 :4) to afford the title compound (51 mg, 70%) as a colourless solid:
- MS (ES + ) m/z 365.2 (M+H + ).
- MS (ES + ) m/z 341.0 (M+H + ).
- Example 4 c To a suspension of sodium hydride (40 mg, 1.0 mmol, 60% dispersion in mineral oil) in dry tetrahydrofuran (0.5 mL) at 0 0 C was added a solution of Example 4 c) (85 mg, 0.25 mmol) and ethyl methylthioacetate (65 ⁇ l, 0.50 mmol) in dry tetrahydrofuran (2 mL) dropwise. After the initial gas evolution had subsided the reaction was refluxed for 25 min, cooled and quenched with water (4.5 mL). The mixture was diluted with methanol (4.5 mL), acidified with concentrated HCI (3 mL) and refluxed for 2 h.
- Example 4 c) (68 mg, 0.20 mmol) and N,N-dimethylglycine ethyl ester (56 ⁇ l, 0.40 mmol) were reacted according to General Procedure C to afford the title compound (50 mg, 62%).
- Example 6b (232 mg, 0.68 mmol) and ⁇ /, ⁇ /-dimethylglycine ethyl ester (176 mg, 1.34 mmol) were reacted according to General Procedure C. The crude residue was purified with flash chromatography using methanol:ethylacetate: dichloromethane (4: 48:48) to offer the title compound (60 mg, 22%).
- 1 H NMR 300 MHz
- Example 7a (45 mg, 0.13 mmol) and 10% palladium on carbon (9 mg) in methanol (2 mL) was treated with hydrogen from a balloon for 16 h. The reaction mixture was filtered through a Celite pad and washed with methanol and dichloromethane to afford the title compound (39 mg, 87%) as a brown oil.
- Example 7a (247 mg, 0.68 mmol) and ⁇ /, ⁇ /-dimethylglycine ethyl ester (176 mg, 1.34 mmol) were reacted according to General Procedure C. The crude residue was purified with flash chromatography using methanol:ethylacetate: dichloromethane (4:48:48) to offer the title compound (212 mg, 77%).
- Example 8 a) (1.10 g, 4.5 mmol) in dichloromethane (15 ml_) was cooled to -78 0 C and a solution of BBr 3 in dichloromethane (1 M, 6.8 ml_.) was added over 2 min. The reaction mixture was stirred at -78 0 C for 10 min then at rt overnight. The reaction vessel was placed into an ice-bath and water was added to quench the reaction. The dichloromethane was removed in vacuo and the resulting suspension was acidified with dilute citric acid to give a final concentration of 2% citric acid. The suspension was heated at 70 0 C for 1 h then filtered, washing with water.
- Example 8 b To a suspension of Example 8 b) (115 mg, 0.50 mmol) in dichloromethane/tetrahydrofuran (1 :1 , 4 mL) was added polymer-bound triphenylphosphine (1.0 mmol loading, 750 mg, 0.75 mmol), 3-/?-3-phenyl-butan-1- ol (115 ⁇ l_, 0.75 mmol) and diethylazodicarboxylate (118 ⁇ l_, 0.75 mmol). The reaction mixture was stirred at rt for 16 then filtered through a Celite pad, washing with dichloromethane and tetrahydrofuran.
- Example 1c To a solution of Example 1c) (90 mg, 0.228 mmol) in dichloromethane (2 ml_) was added 70% m-CPBA (140 mg, 0.57 mmol) and the reaction was stirred at rt for 1 h during which time a precipitate formed.
- the suspension was diluted with DCM (20 mL) and the organic phase was washed with saturated NaHCO 3 (aq ) (2 x 20 ml_) then brine, dried over MgSO 4 and concentrated under vacuum.
- Human Jurkat cells (which endogenously express hKv1.3) were used in place of rat L929 cells.
- EC50 values shown were determined from averaged dose response data obtained from 3 or more cells.
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PCT/AU2007/001476 WO2008040058A1 (en) | 2006-10-04 | 2007-10-04 | Novel chromenone potassium channel blockers and uses thereof |
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Country | Link |
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US (1) | US8217189B2 (en) |
AU (1) | AU2007304881B2 (en) |
NZ (1) | NZ575686A (en) |
WO (1) | WO2008040058A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603769A (en) * | 2012-03-23 | 2012-07-25 | 中国科学院南海海洋研究所 | Sulfur-containing chromone compound and preparation method thereof and application in preparation of antitumor drugs |
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2016146583A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
WO2016146575A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
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- 2007-10-04 NZ NZ575686A patent/NZ575686A/en not_active IP Right Cessation
- 2007-10-04 WO PCT/AU2007/001476 patent/WO2008040058A1/en active Application Filing
- 2007-10-04 AU AU2007304881A patent/AU2007304881B2/en not_active Ceased
- 2007-10-04 US US12/442,790 patent/US8217189B2/en not_active Expired - Fee Related
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2567959A1 (en) | 2011-09-12 | 2013-03-13 | Sanofi | 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CN102603769A (en) * | 2012-03-23 | 2012-07-25 | 中国科学院南海海洋研究所 | Sulfur-containing chromone compound and preparation method thereof and application in preparation of antitumor drugs |
WO2016146583A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
WO2016146575A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
Also Published As
Publication number | Publication date |
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AU2007304881A1 (en) | 2008-04-10 |
NZ575686A (en) | 2012-02-24 |
AU2007304881B2 (en) | 2013-03-07 |
US8217189B2 (en) | 2012-07-10 |
US20090298931A1 (en) | 2009-12-03 |
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