WO2004035037A2 - Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators - Google Patents
Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators Download PDFInfo
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- WO2004035037A2 WO2004035037A2 PCT/IL2003/000855 IL0300855W WO2004035037A2 WO 2004035037 A2 WO2004035037 A2 WO 2004035037A2 IL 0300855 W IL0300855 W IL 0300855W WO 2004035037 A2 WO2004035037 A2 WO 2004035037A2
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- 0 *c1c(*)c(*)c(*c2c(*)c(S)c(*)c(*)c2**(O)=*)c(*)c1* Chemical compound *c1c(*)c(*)c(*c2c(*)c(S)c(*)c(*)c2**(O)=*)c(*)c1* 0.000 description 2
- AZIRBGGRPJXOAW-UHFFFAOYSA-N OCCOCCCCC(c(cccc1)c1Nc1cccc(C(F)(F)F)c1)=O Chemical compound OCCOCCCCC(c(cccc1)c1Nc1cccc(C(F)(F)F)c1)=O AZIRBGGRPJXOAW-UHFFFAOYSA-N 0.000 description 2
- RLUNNWGNXYIAMB-UHFFFAOYSA-N COCCOCCOC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O Chemical compound COCCOCCOC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O RLUNNWGNXYIAMB-UHFFFAOYSA-N 0.000 description 1
- QRBXKWSNKJRRKJ-UHFFFAOYSA-N Cc(c(Nc(cccc1)c1C(CCCCOCCO)=O)ccc1)c1Cl Chemical compound Cc(c(Nc(cccc1)c1C(CCCCOCCO)=O)ccc1)c1Cl QRBXKWSNKJRRKJ-UHFFFAOYSA-N 0.000 description 1
- NHHUMFLVEKQHQU-UHFFFAOYSA-N Cc1c(C)c(Nc(cccc2)c2C(CCCCOCCO)=O)ccc1 Chemical compound Cc1c(C)c(Nc(cccc2)c2C(CCCCOCCO)=O)ccc1 NHHUMFLVEKQHQU-UHFFFAOYSA-N 0.000 description 1
- RMEPCNVWPRKRCW-UHFFFAOYSA-N Cc1c(C)c(Nc(cccc2)c2C(NCCOCCO)=O)ccc1 Chemical compound Cc1c(C)c(Nc(cccc2)c2C(NCCOCCO)=O)ccc1 RMEPCNVWPRKRCW-UHFFFAOYSA-N 0.000 description 1
- PRWBZDKKXFLKAL-UHFFFAOYSA-N OCCOCCNC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O Chemical compound OCCOCCNC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O PRWBZDKKXFLKAL-UHFFFAOYSA-N 0.000 description 1
- TYJGETBDTFVKAB-UHFFFAOYSA-N OCCOCCOC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O Chemical compound OCCOCCOC(Cc(cccc1)c1Nc(c(Cl)ccc1)c1Cl)=O TYJGETBDTFVKAB-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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Definitions
- the present invention relates to the field of pharmacology, and particularly to derivatives of N-phenylanthranilic acid and/or 2-benzimidazolone for the treatment of pathologies, especially pathologies related to potassium ion flux through voltage- dependent potassium channels and/or cortical neuron activity.
- Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels are present in all animal cells and affect such processes as nerve transmission, muscle contraction and cellular secretion.
- potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive and epithelial tissue.
- These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell.
- These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands and ATP-sensitivity.
- Potassium channels have now been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport.
- Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities (Wei et al., Neuropharmacology 35(7): 805-829 (1997)).
- Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage.
- Two other families, CNG and SK/IK also contain this motif but are gated by cyclic nucleotides and calcium, respectively.
- Slo family potassium channels, or BK channels have seven transmembrane domains (Meera et al., Proc. Natl. Acad. Sci. U.S.A. 94(25): 14066-71 (1997)) and are gated by both voltage and calcium or pH (Schreiber et al, J. Biol. Chem. 273: 3509-16 (1998)).
- Another family, the inward rectifier potassium channels (Kir) belongs to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or "two-pore”) contains two tandem repeats of this inward rectifier motif.
- Potassium channels are typically formed by four alpha subunits, and can be homomeric (made of identical alpha subunits) or heteromeric (made of two or more distinct types of alpha subunits).
- potassium channels made from Kv, KQT and Slo or BK subunits have often been found to contain additional, structurally distinct auxiliary, or beta, subunits. These subunits do not form potassium channels themselves, but instead they act as auxiliary subunits to modify the functional properties of channels formed by alpha subunits.
- the Kv beta subunits are cytoplasmic and are known to increase the surface expression of Kv channels and/or modify inactivation kinetics of the channel (Heinemann et al, J. Physiol.
- Slo or BK potassium channels are large conductance potassium channels found in a wide variety of tissues, both in the central nervous system and periphery. They play a key role in the regulation of processes such as neuronal integration, muscular contraction and hormone secretion. They may also be involved in processes such as lymphocyte differentiation and cell proliferation, spermatocyte differentiation and sperm motility.
- Slol Slo2
- Slo3 Slo3
- Mahler et al Science 261: 221-224 (1993); Schreiber et al, J. Biol. Chem., 273: 3509-16 (1998); and Joiner et al, Nature Neurosci. 1: 462-469 (1998)).
- These Slo family members have been shown to be voltage and/or calcium gated, and/or regulated by intracellular pH.
- Certain members of the Kv family of potassium channels were recently renamed (see, Biervert, et al, Science 279: 403-406 (1998)).
- KvLQTl was re-named KCNQ1, and the KvLQTl -related channels (KvLRl and KvLR2) were renamed KCNQ2 and KCNQ3, respectively. More recently, additional members of the KCNQ subfamily were identified. For example, KCNQ4 was identified as a channel expressed in sensory outer hair cells (Kubisch, et al, Cell 96(3): 437-446 (1999)). KCNQ5 (Kananura ⁇ t al, Neuroreport 11(9): 2063 (2000)), KCNQ2/3 (Main et al, Mol. Pharmacol. 58: 253-62 (2000), KCNQ3/5 (Wickenden et al, Br. J.
- KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassium channels associated with benign familial neonatal convulsions ("BFNC"), a class of idiopathic generalized epilepsy (see, Leppert, et al, Nature 337: 647-648
- a potassium channel opener that has gained much attention is retigabine (N-(2- amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester).
- Retigabine was first described in European Patent No. 554,543.
- Compounds related to retigabine have also been proposed for use as potassium channel modulators, see for example U.S. Patent Application No. No. 10/022,579.
- Retigabine is highly selective for potassium channels consisting of the subunits
- retigabine activates the homomultimerous channel, which contains only the subunit KCNQ2. Only marginal voltage-dependent currents are measurable in cells, which express only the homomeric channel from the KCNQ3 subunit, see U.S. 6,472,165.
- U.S. Patent Application No. 10/160,582 teaches cinnamide derivatives as KCNQ potassium channel modulators.
- 10/075,703 and 10/075,522 teach 3-substituted oxindole derivatives as KCNQ potassium channel modulators.
- U.S. Patent No. 5,384,330 teaches 1,2,4-triamino-benzene derivatives as KCNQ potassium channel modulators.
- U.S. Patent No. 6,593,349 teaches bisarylamines derivatives as KCNQ potassium channel modulators.
- the two aryl groups of the compounds taught in U.S. Patent No. 6,593,349 are a pyridine derivative and a five-membered heterocycle.
- a significant disadvantage of the KCNQ potassium channel modulators known in the art is that these are generally difficult to make, requiring complex multi-step syntheses and that in some cases these modulators are non-specific or even toxic.
- the present invention provides compounds that are generally effective potassium channel modulators, especially voltage-dependent potassium channels such as KCNQ2 channel, KCNQ3 channels and KCNQ2/3 channels. Also, the present invention provides compounds that are generally effective at depressing cortical neuron activity.
- the compounds of the present invention are generally derivatives of N- phenylanthranilic acid or 2-benzimidazolone. Some of the compounds of the present invention are well known in the art and are readily available. Some of the compounds of the present invention are novel but are synthesized through a few (typically, one or two) high-yield steps from readily available starting materials.
- a method of modulating (preferably opening) a voltage-dependent potassium channel comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of N-phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone and a 2-benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the compound has a general Formula I or II (vide infra).
- the voltage-dependent potassium channels modulated are KCNQ2 channels, KCNQ3 channels and/or KCNQ2/3 channels.
- a method of depressing cortical neuron activity comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of N-phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone and a 2-benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the compound has a general Formula I or II (vide infra).
- a pharmaceutical composition for the treatment or prevention of a condition or disorder e.g., in the central or peripheral nervous system, in which modulating a voltage- dependent potassium chamiel and/or depressing a cortical neuron activity is beneficial
- the pharmaceutical composition comprising, as an active ingredient, a compound selected from the group consisting of N-phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone and a 2-benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the compound has the general Formula I or II (vide infra).
- the voltage-dependent potassium channels modulated are KCNQ2 channels, KCNQ3 channels and/or KCNQ2/3 channels.
- A is alkyl or absent
- G is selected from the group consisting of carbon, sulfur and substituted or unsubstituted phosphor; K is selected from the group consisting of oxygen and sulfur;
- X is selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur or absent; and Y is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, aryl and a polyalkylene glycol residue, each of Q and W is independently selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur and carbon; D is selected from the group consisting of oxygen and sulfur;
- R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and -NR 15 R 16 , or, alternatively, at least two of R 2 , R 3 , R 4 , R 5 and R 6 , of R 7 , R 8 , R 9 and R 10 and/or of R 11 , R 12 , R 13 and R 14 form a five- or six-membered aromatic, heteroaromatic,
- R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 15 and R 16 form a five- or six-member heteroalicyclic ring; whereas if the phosphor and/or the nitrogen is substituted, the substituent is selected from the group consisting of alkyl, cycloalkyl and aryl.
- a compound of the present invention has the general Formula I.
- Y is preferably selected from the group consisting of hydroxyalkyl and a polyalkylene glycol residue.
- the polyalkylene glycol residue has a general formula III:
- each of m and n is independently an integer of 1-10; and R 17 is hydrogen, alkyl, cycloalkyl or aryl.
- each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, alkyl, halo and trihaloalkyl and each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- a compound of the present invention has the general Formula II. When a compound of the present invention has the general Formula II, then preferably Q and W are each substituted or unsubstituted nitrogen; and D is oxygen, and even more preferably Q is a substituted nitrogen.
- compounds are selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10:
- modulating of the voltage- dependent potassium channel and/or depressing the cortical neuron activity is for a treatment of a condition or disorder selected from the group of disorders consisting of epilepsy, ischemic stroke, migraine, ataxia, myokymia, neurogenic pain, Alzheimer's disease, Parkinson's disease, age-related memory loss, learning deficiencies, bipolar disorder, trigeminal neuralgia, spasticity, mood disorder, psychotic disorder, brain tumor, hearing and vision loss, anxiety and a motor neuron disease.
- a condition or disorder selected from the group of disorders consisting of epilepsy, ischemic stroke, migraine, ataxia, myokymia, neurogenic pain, Alzheimer's disease, Parkinson's disease, age-related memory loss, learning deficiencies, bipolar disorder, trigeminal neuralgia, spasticity, mood disorder, psychotic disorder, brain tumor, hearing and vision loss, anxiety and a motor neuron disease.
- administering of the a compound of the present invention is effected intranasally, subcutaneously, intravenously, intramuscularly, parenterally, orally, topically, intradermally, bronchially, buccally, sublingually, supositorially and mucosally.
- a compound of the present invention is part of a pharmaceutical composition, which further includes a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the present invention further comprises an agent selected from the group consisting of an anti-bacterial agent, an antioxidant, a buffering agent, a bulking agent, an anti- inflammatory agent, an anti-viral agent, a chemotherapeutic agent and an anti- histamine.
- a pharmaceutically composition is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of a condition or disorder associated with altered activity of a voltage-dependent potassium channel.
- a condition or disorder is selected from the group consisting of epilepsy, ischemic stroke, migraine, ataxia, myokymia, neurogenic pain, Alzheimer's disease, Parkinson's disease, age-related memory loss, learning deficiencies, bipolar disorder, trigeminal neuralgia, spasticity, mood disorder, psychotic disorder, brain tumor, hearing and vision loss, anxiety and a motor neuron disease.
- G is selected from the group consisting of carbon, sulfur and substituted or unsubstituted phosphor
- K is selected from the group consisting of oxygen and sulfur
- X is selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur or absent;
- Y is selected from the group consisting of hydroxyalkyl and a polyalkylene glycol residue
- R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- Each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and - NR 15 R 16 , or, alternatively, at least two of R 2 , R 3 , R 4 , R 5 and/or R 6 , of R 7 , R 8 , R 9 and R 10 form a five- or six-membered aromatic, heteroaromatic,
- the polyalkylene glycol residue of a novel compound of the present invention has a general formula V:
- G is carbon
- K is oxygen
- each of R 2 , R 3 , R 4 , R 5 and R ⁇ is independently selected from the group consisting of hydrogen, alkyl, halo and trihaloalkyl
- each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- a novel compound of the present invention is selected from the group consisting of compounds 3, 4, 5, 6, 7, 8 and 9:
- a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention having a general formula IV.
- a pharmaceutical composition having as an active ingredient, any one of the compounds 3, 4, 5, 6, 7, 8 and/or 9.
- a method for the synthesis of a compound of formula IV comprises obtaining a N-phenylanthranilic acid or a derivative thereof; and reacting the N- phenylanthranilic acid or the derivative thereof with a hydroxyalkyl or a polyalkylene glycol terminating with a reactive group, which is capable of forming an ester bond with the N-phenylanthranilic acid or the derivative thereof.
- the ester bond is preferably selected from the group consisting of a carboxylic ester bond, a carboxylic amide bond, a carboxylic thioester bond, a S-carboxy thioester bond and a S-carboxy amide bond, whereas the reactive group is preferably selected from the group consisting of hydroxy, amine and thiohydroxy.
- N-phenylanthranilic acid or the derivative thereof preferably has a general Formula VI:
- A, G, K, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as described hereinabove.
- G is carbon; K is oxygen; each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, alkyl, halo and trihaloalkyl; and each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- the polyalkylene glycol terminating with the reactive group preferably has a general formula NIL
- V is hydroxy, amine or thiohydroxy; each of m and n is independently an integer of 1-10; and R 17 is hydrogen, alkyl, cycloalkyl or aryl.
- the present invention successfully addresses the shortcomings of the presently known configurations by providing compounds that act to modulate potassium channels and/or depress cortical activity, are generally available and/or are relatively easy to synthesize. Some of the compounds provided are already known in the art of pharmacology.
- FIGs. 1A-1D show results showing the leftward shift of the activation curve induced by meclofenamic acid (Compound 1) and 1-EBIO (Compound 10);
- FIGs. 2A-2C show results of the increase of KCNQ2/3 current induced by meclofenamic acid (Compound 1) and 1-EBIO (Compound 10);
- FIGs. 3A-3E show results of the effect of meclofenamic acid (Compound 1) and 1-EBIO (Compound 10) on the deactivation process of KCNQ2/3 channels;
- FIGs. 4A-4B show results demonstrating the depression of neuronal activity by meclofenamic acid (Compound 1);
- FIG. 5 shows results demonstrating the neuroprotective effect of meclofenamic acid (Compound 1) from electroshock-induced seizures in adult mice;
- FIGs. 6A-6C show the enhancement of the KCNQ2/3 current by diclofenac (Compound 2);
- FIGs. 7A-7C show the effects of Compound 6 on KCNQ2/3 currents;
- FIGs. 8A-8B show the inhibition of evoked neuronal activity by compound 6
- FIGs. 9A-9C show the inhibitory effect of different concentrations of Compound 6 on spontaneous neuronal activity
- FIGs. 10 A- 10C show the effects of Compound 5 on neuronal activity and on KCNQ2/3 current
- FIGs. 11 A-l IB show the increase in KCNQ2/3 current induced by the presence of Compound 3;
- FIGs. 12A-12C show the effects of Compound 4 on neuronal activity and on KCNQ2/3 current;
- FIG. 13 shows the effect of Compound 9 on spontaneous neuronal activity
- FIGs. 14A-14D show the effects of Compound 7 on KCNQ2/3 channels and neuronal activity
- FIGs. 15A-15B show the effect of Compound 8 on evoked and spontaneous neuronal activity
- FIGs. 16A-16D show the selectivity of meclofenamic acid (Compound 1) towards KCNQ2 and KCNQ3 homomeric channels, expressed in CHO cells; and FIG. 17 shows the chemical structures of Compounds 1-10.
- the present invention provides compounds that, inter alia, are generally useful in the modulation of potassium ion flux through voltage-dependent potassium channels, specifically the KCNQ2, KCNQ3 and/or KCNQ2/3 channels and/or useful in depressing cortical neuron activity.
- a method of modulating (preferably opening) a voltage-dependent potassium channel comprising administering to the subject in need thereof a therapeutically effective amount of the compound N-phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone, a 2-benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the term "derivative" describes the result of a chemically altering, modifying or changing a molecule or a portion thereof, such that it maintains its original functionality in at least one respect.
- the compound preferably has a general Formula I or II.
- the voltage- dependent potassium channels modulated are preferably KCNQ2 channels, KCNQ3 channels and/or KCNQ2/3 channels.
- a method of depressing cortical neuron activity comprising administering to the subject in need thereof a therapeutically effective amount of the compound N- phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone, a 2- benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the compound has a general Formula I or II.
- a pharmaceutical composition for the treatment or prevention of conditions or disorders in which modulating a voltage-dependent potassium channel and/or depressing a cortical neuron activity is beneficial comprising, as an active ingredient, the compound N-phenylanthranilic acid, a N-phenylanthranilic acid derivative, 2-benzimidazolone, a 2-benzimidazolone derivative, or a pharmaceutically acceptable salt thereof.
- the compound has the general Formula I or II.
- the voltage-dependent potassium channels modulated are KCNQ2 channels, KCNQ3 channels and/or KCNQ2/3 channels.
- G is selected from the group consisting of carbon, sulfur and substituted or unsubstituted phosphor
- K is selected from the group consisting of oxygen and sulfur
- X is selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur or absent;
- Y is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, aryl and a polyalkylene glycol residue, each of Q and W is independently selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur and carbon; D is selected from the group consisting of oxygen and sulfur;
- R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- Each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and -NR 15 R 16 , or, alternatively, at least two of R 2 , R 3 , R 4 , R 5 and R 6 , of R 7 , R 8 , R 9 and R 10 and/or of R
- R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 15 and R 16 form a five- or six-member heteroalicyclic ring; whereas if the phosphor and/or the nitrogen is substituted, the substituent is alkyl, cycloalkyl or aryl.
- a compound of the present invention has the general Formula I.
- Y is preferably selected from the group consisting of hydroxyalkyl and a polyalkylene glycol residue.
- the polyalkylene glycol residue has a general formula III:
- each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, alkyl, halo and trihaloalkyl and each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- a compound of the present invention has the general Formula II.
- Q and W are each substituted or unsubstituted nitrogen; and D is oxygen, and even more preferably Q is a substituted nitrogen.
- compounds are selected from the group consisting of:
- method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- a compound of the present invention is used as a therapeutic, prophylactic or ameliorative agent, whether with respect to a pathology, condition or disorder, a symptom thereof or an effect thereof.
- the compounds of the present invention are for use within the framework of a treatment for pathologies, conditions and disorders associated with defective potassium modulation, so as to treat, ameliorate, prevent, inhibit, or limit the effects of the conditions and pathologies in animals including humans.
- the invention provides compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., ischemic stroke, migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, neurogenic pain, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, Parkinson's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases), and as neuroprotective agents (e.g., to prevent stroke and the like).
- Compounds of the invention have use as agents for treating convulsive states, for example that following grand mal, petit mal, psychomotor epilepsy or focal seizure.
- the compounds of the invention are also useful in treating disease states such as gastroesophogeal reflux disorder and gastrointestinal hypomotility disorders.
- Other pathologies and conditions that compounds of the present invention are useful in treating are listed in, for example, U.S. Patents 6,348,486; 6,117,900; 6,589,986 and 6,593,349 and U.S. Patent Applications 10/022,579; 10/075,703; 10/075,522; 10/114,148; 10/160,582 and 10/312,123, all of which are hereby incorporated by reference.
- the compounds of the present invention are pharmaceutically effective when administered to subjects who are members of all animal species, including monkeys, dogs, cats, mice, rats, farm animals, livestock, fish and most importantly humans.
- Opening and “activating” are used interchangeably herein to refer to the partial or full activation of a KCNQ channel by a compound, which leads to an increase in ion flux either into or out of a cell in which a KCNQ channel is found.
- compositions of the present invention may be provided to an individual in need of treatment (whether therapeutic, prophylactic or ameliorative) by a variety of preferred routes, such as subcutaneous, topical, oral, intraperitoneal, intradermal, intravenous, intranasal, bronchial, buccal, sublingual, suppository, intramuscular, oral, rectal, transmucosal, intestinal or parenteral delivery, including topical, intra-arterial, intramuscular, subcutaneous and intramedullary injections as well as infrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
- preferred routes such as subcutaneous, topical, oral, intraperitoneal, intradermal, intravenous, intranasal, bronchial, buccal, sublingual, suppository, intramuscular, oral, rectal, transmucosal, intestinal or parenteral delivery, including topical, intra-arterial, intramuscular, subcutaneous and intramedul
- compositions of the present invention in a local rather than systemic manner, for example, via injection of the composition directly into an organ often in a depot or slow release formulation, such as described below.
- a therapeutically (or pharmaceutically) effective amount means an amount of active ingredient needed to achieve the desired outcome, which is generally to prevent, alleviate or ameliorate a condition or symptoms of the condition. Determination of a therapeutically effective amount is within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- Compound of the invention refers to a compound according to Formula I or II or a combination thereof, and a pharmaceutically acceptable salt of a compound according to Formula I or II or a combination thereof and a solvated forms including hydrated forms such as monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate and the like.
- the compounds may be true solvates or may merely retain adventitious solvent, or be a mixture of solvate and adventitious solvent.
- salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral (i.e., non-ionized) form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic a ino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- the present invention provides compounds, which are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions in vivo to provide the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
- the alkyl group has 1 to 20 carbon atoms.
- the alkyl group may be substituted or unsubstituted.
- the substituent group can be, for example, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, sulfonamido, trihalomethanesulfonamido, silyl, guanyl, guanidino, ureido, amino or NR a Rb, wherein R a and Rt ⁇ are each independently hydrogen, alkyl, cycloalkyl, aryl, carbonyl, sulfonyl, trihalomethysulfonyl and, combined, a five-
- a "cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system.
- examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane.
- a cycloalkyl group may be substituted or unsubstituted.
- the substituent group can be, for example, alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and NR a b as defined above.
- alkenyl refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon double bond.
- aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
- the substituent group can be, for example, halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N- amido, sulfinyl, sulfonyl, amino and NR a Rb as defined above.
- heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
- heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
- the heteroaryl group may be substituted or unsubstituted.
- the substituent group can be, for example, alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino or NRgR ⁇ as defined above.
- heteroalicyclic group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
- the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
- the heteroalicyclic may be substituted or unsubstituted.
- the substituted group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, sulfinyl, sulfonyl, C-amido, N-amido, amino and NR a R D as defined above.
- a “hydroxy” group refers to an -OH group.
- alkoxy refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
- aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
- a "thiohydroxy” group refers to an -SH group.
- a “thioalkoxy” group refers to both an -S-alkyl group, and an -S-cycloalkyl group, as defined herein.
- thioaryloxy refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
- aldehyde refers to a carbonyl group, where R" is hydrogen.
- a “carboxylic acid” group refers to a C-carboxyl group in which R" is hydrogen.
- halo refers to fluorine, chlorine, bromine or iodine.
- trihalomethyl refers to a -CX group wherein X is a halo group as defined herein.
- a "trihalomethanesulfonyl” group refers to an X ⁇ CS ⁇ O ⁇ - group wherein X is a halo group as defined herein.
- a “sulfonyl” group refers to an group, where R" is as defined herein.
- S-sulfonamido refers to a group, with R a and R p as defined herein.
- a "trihalomethanesulfonamido” group refers to an group, where R a and X are as defined herein.
- Rt ⁇ are as defined herein.
- N-thiocarbamyl refers to an group, where R a and Rt ⁇ are as defined herein.
- amino refers to an -NH2 group.
- a “quaternary ammonium” group refers to an -NHR a Rb group, wherein R a and R D are independently alkyl, cycloalkyl, aryl or heteroaryl.
- a “nitro” group refers to an -NO2 group.
- sil refers to a -Si (R")3, where R" is as defined herein.
- the compound of the present invention has the general Formula I.
- Y is selected from the group consisting of hydroxyalkyl and a polyalkylene glycol residue.
- a polyalkylene glycol residue has a general formula III:
- [O-(CH 2 )m]n-OR 17 Formula III wherein each of m and n is independently an integer of 1-10; and R is hydrogen, alkyl, cycloalkyl or aryl.
- G is carbon
- K is oxygen
- each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, alkyl, halo and trihaloalkyl; and each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- the compound of the present invention has the general Fo ⁇ nula II.
- a compound of the present invention has the general Formula II, then preferably Q and W are each substituted or unsubstituted nitrogen; and D is oxygen, and even more preferably Q is a substituted nitrogen.
- Preferred compounds of the present invention include the compounds:
- novel compounds which are useful in context of the present invention.
- novel compounds are generally derivatives of N-phenylanthranilic acid having a hydroxyalkyl and a polyalkylene glycol residue covalently attached thereto.
- the hydroxyalkyl and a polyallcylene glycol residue generally increase the ability of a novel compound of the present invention to cross the blood brain barrier.
- a preferred novel compound of the present invention is of the general Formula IV:
- G is selected from the group consisting of carbon, sulfur and substituted or unsubstituted phosphor
- K is selected from the group consisting of oxygen and sulfur
- X is selected from the group consisting of substituted or unsubstituted nitrogen, oxygen, sulfur or absent;
- Y is selected from the group consisting of hydroxyalkyl and a polyalkylene glycol residue
- R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- Each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and - NR 15 R 16 , or, alternatively, at least two of R 2 , R 3 , R 4 , R 5 and/or R 6 , of R 7 , R 8 , R 9 and R ° form a five- or six-membered aromatic, heteroaromatic
- R 5 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R 15 and R 16 form a five- or six-member heteroalicyclic ring. Whereas, if the phosphor and/or the nitrogen is substituted, the substituent is alkyl, cycloalkyl or aryl.
- the polyalkylene glycol residue of a novel compound of the present invention has a general formula V:
- G is carbon
- K is oxygen
- each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, alkyl, halo and frihaloallcyl
- each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- a novel compound of the present invention is selected from the group consisting of:
- composition comprising, as an active ingredient, a compound of the present invention having a general formula IV.
- a pharmaceutical composition having as an active ingredient, any one of the compounds 3, 4, 5, 6, 7, 8 and/or 9.
- a method for the synthesis of the novel compounds described hereinabove is effected by reacting a N-phenylanthranilic acid or a derivative thereof with a hydroxy alkyl or a polyallcylene glycol, which are terminated by a reactive group.
- the reactive group is selected such that it is capable of forming an ester bond with the N-phenylanthranilic acid or the derivative thereof.
- the reactive group is preferably hydroxy, amino or thiohydroxy, as defined hereinabove, and the polyalkylene glycol terminating with the reactive group has a general formula VII:
- N is hydroxy, amine or thiohydroxy, each of m and n is independently an integer of 1-10; and R 17 is hydrogen, alkyl, cycloalkyl or aryl.
- the starting material, ⁇ -phenylanthranilic acid or the derivative thereof, preferably has a general formula VI:
- G is carbon
- K is oxygen
- each of R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen, alkyl, halo and trihaloalkyl
- each of R 7 , R 8 , R 9 and R 10 is hydrogen.
- the method according to this aspect of the present invention preferably further includes, prior to reacting with the hydroxyalkyl or the polyallcylene glycol, converting the ⁇ -phenylanthranilic acid or its derivative to a corresponding ester.
- Compounds of the present invention include known compounds such as meclofenamic acid (Compound 1), diclofenac (Compound 2) and 1-EBIO (Compound 10).
- 1-EBIO Compound 10
- IK intermediate
- SK small conductance
- Compounds of the present invention also include novel compounds which are derivatives of ⁇ -phenylanthranilic acid, mainly derivatives of meclofenamic acid (Compound 1) and diclofenac (Compound 2).
- Exemplary novel compounds of the present invention are compounds 3, 4, 5, 6, 7, 8 and 9.
- these compounds are openers of KC ⁇ Q2/3 channel complex heterologously expressed in CHO cells. These compounds are also shown herein to reduce both evoked and spontaneous action potentials in cortical neurons.
- the compounds of the present invention have two main effects: shifting of the voltage dependence of KCNQ2/3 channel activation to more hyperpolarized potentials and slow channel deactivation. Similar to the effect on recombinant KCNQ2/3 channels, compounds 4, 5, 6 and 7 induce an approximately 20 mV negative shift in the threshold of M-current activation in cortical neurons, from -50 mV to -70 mV. As a result of this leftward shift of the KCNQ2/3 threshold of activation, there is a progressive hyperpolarization of the resting membrane potential.
- the data presented herein in the Examples section that follows suggests that the compounds of the present invention either destabilize a closed channel conformation or stabilize the KCNQ2/3 channel in an open state. Further, exposure of channels to the compounds described herein also leads to a slowing of deactivation that contributes to the stabilization of the KCNQ2/3 channel in the open state. Without being bound to any theory in particular, it is possible that the compounds of the present invention modify the channel gating by shifting the voltage dependence of the voltage sensor S4 movement in the hyperpolarizing direction.
- both the compounds of the present invention and retigabine all shift the voltage dependence of KCNQ2/3 channel activation leftwards, decelerating deactivation kinetics and hyperpolarizing the resting membrane potential (for retigabine discussed, for example, in Tatulian et al J. Neurosci. 21: 5535-5545 (2001)).
- the voltage range through which the compounds of the present invention operate indicates exceptionally suitability for the treatment of epilepsy, ischemic stroke and neuropathic pain.
- a compound of the present invention forms a part of a pharmaceutical composition, which further includes a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the present invention is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of a condition or disorder, e.g., in the peripheral or central nervous system, associated with altered activity of a voltage-dependent potassium channel.
- a condition or disorder e.g., in the peripheral or central nervous system, associated with altered activity of a voltage-dependent potassium channel.
- the conditions or disorders thus identified are one or more of the conditions or disorders for which the specific pharmaceutical composition is suitable.
- a “pharmaceutical composition” refers to a preparation of one or more of the compounds of the present invention (as active ingredient), or physiologically acceptable salts or prodrugs thereof, with other chemical components including but not limited to physiologically suitable carriers, excipients, lubricants, buffering agents, antibacterial agents, bulking agents (e.g. mannitol), antioxidants (e.g., ascorbic acid or sodium bisulfite), anti-inflammatory agents, anti-viral agents, chemotherapeutic agents, anti-histamines and the like.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.
- active ingredient refers to a compound, which is accountable for a biological effect.
- physiologically acceptable carrier and “pharmaceutically acceptable carrier” which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
- excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
- compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution,
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
- Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
- Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxvpiOpylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
- disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
- the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
- a suitable vehicle e.g., sterile, pyrogen-free water
- the preparation of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
- a preparation of the present invention may also be formulated for local administration, such as a depot preparation.
- Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the preparation may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives such as sparingly soluble salts.
- suitable polymeric or hydrophobic materials for example, as an emulsion in an acceptable oil
- ion exchange resins for example, as an emulsion in an acceptable oil
- sparingly soluble derivatives such as sparingly soluble salts.
- Formulations for topical administration may include, but are not limited to, lotions, suspensions, ointments gels, creams, drops, liquids, sprays emulsions and powders.
- compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredient effective to prevent, alleviate or ameliorate a condition and/or symptoms thereof and/or effects thereof.
- the therapeutically effective amount or dose can be estimated initially from cell culture assays.
- a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC ⁇ Q as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
- Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC ⁇ Q and the LD50 (lethal dose causing death in 50 % of the tested animals) for a subject compound.
- the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
- the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l). Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, termed the minimal effective concentration (MEC).
- MEC minimal effective concentration
- the MEC will vary for each preparation, but can be estimated from in vitro data; e.g., the concentration necessary to achieve 50-90 % inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
- Dosage intervals can also be determined using the MEC value. Preparations should be administered using a regimen, which maintains plasma levels above the MEC for 10-90 % of the time, preferable between 30-90 % and most preferably 50-90 %. It is noted that, in the case of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. In such cases, other procedures known in the art can be employed to determine the effective local concentration. Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
- compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
- compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
- the pack may, for example, comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration.
- the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinaiy administration.
- Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
- compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
- the pharmaceutical composition of the present invention is used for the treatment, prevention or amelioration of conditions or disorders associated with altered activity of a voltage-dependent potassium channel or of a cortical neuron, comprising, as an active ingredient, a compound of the present invention which serve for modulating, generally by opening, a respective potassium channel or depressing cortical neuron activity.
- the potassium channel modulated is a KCNQ2 channel and/or a KCNQ3 channel and/or a KCNQ2/3 channel.
- Peripheral or central nervous system conditions or disorders associated with altered activity of a voltage- dependent potassium channel that are preferably treated or prevented by the pharmaceutical compositions of the present invention include, but are not limited to epilepsy, ischemic stroke, migraine, ataxia, myokymia, neurogenic pain, Alzheimer's disease, Parkinson's disease, age-related memory loss, learning deficiencies, bipolar disorder, trigeminal neuralgia, spasticity, mood disorder, psychotic disorder, brain tumor, hearing and vision loss, anxiety and a motor neuron disease.
- the composition is packaged in a packaging material and is identified in print, in or on the packaging material, for use in the treatment or prevention of a peripheral or central nervous system condition or disorder associated with altered activity of a voltage- dependent potassium channel.
- Meclofenamic acid (Compound 1), diclofenac (Compound 2) and 1 -ethyl benzimidazolone (1-EBIO, Compound 10) are commercially available and were purchased from Sigma-Aldrich (St. Louis, MO, USA).
- Neuronal cortical culture
- Sprague Dawley rat embryos (El 8) were removed by caesarian section and their cortices were dissected out.
- the tissue was digested with papain (100 U; Sigma, St. Louis, MO) for 20 min, triturated to a single-cell suspension, and plated at a density of 40,000 cells per ml on a substrate of bovine collagen type IV and 100 ⁇ g/ml poly-L- lysine in 13 mm diameter glass coverslip of a 24-multiwell plate.
- the culture medium consisted of Modified Eagle's Medium containing 5% horse serum (Biological Industries, Beit HaEmek, Israel), B-27 neuronal supplement (Invitrogen, Carlsbad, CA), 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, and 2 mM glutamine. D-Glucose was supplemented to a final concentration of 6 g/1. Cytosine-1-D-arabinofuranoside (5 ⁇ M) was added after 5 days to arrest glial cell proliferation. All cultures were maintained at 37°C in humidified air containing 5% CO 2 .
- Electrophysiology For current measurements in CHO cells, recordings were performed 40 h following transfection, using the whole-cell configuration of the patch-clamp technique (Hamill et al, Nature 294: 462-464 (1981)). Signals were amplified using an Axopatch 200B patch-clamp amplifier (Axon Instruments, Foster City, California, USA), sampled at 2 kHz and filtered at 800 Hz via a 4-pole Bessel low pass filter. Data were acquired using pClamp 8.1 software (Axon Instruments, Foster City, California, USA) and an Elonex Pentium III computer in conjunction with a DigiData 1322 A interface (Axon Instruments, Foster City, California, USA). The patch pipettes were pulled from borosilicate glass (Warner Instrument.
- the patch pipettes were filled with (in [mM] ): 135 KCl, 1 K 2 ATP, 1 MgATP, 2 EGTA, 1.1 CaCl 2 , 5 glucose, 10 HEPES, adjusted with KOH at pH 7.4 (315 mOsm).
- the external solution contained (in [mM] ): 140 NaCl, 4 KCl, 2 CaCl 2 , 2 MgCl 2 , 5 glucose, 10 HEPES, adjusted with NaOH at pH 7.4 (325 mOsm).
- 50-300 pA currents were injected into the cells for 800 ms (square pulse).
- I corresponds to the current amplitude measured at the end of the pulse and V rev , the calculated reversal potential assumed to be -90 mV in CHO cells and -98 mV in Xenopus oocytes.
- G was estimated at various test voltages V and then, nomialized to a maximal conductance value, G max , calculated at +40 mV.
- Activation curves were fitted by a Boltzmann distribution:
- G/G max l / ⁇ l + exp[ ( V 50 - V) / s ] ⁇
- V 5 o is the voltage at which the current is half-activated and s is the slope factor. All data were expressed as mean ⁇ SEM. Statistically significant differences were assessed by Student's -test.
- KCNQ2 and KCNQ3 subunits When KCNQ2 and KCNQ3 subunits are expressed separately as homomeric channels in various expression systems, they give rise to relatively small potassium currents, especially for KCNQ3 (Wang et al. Science 282: 1890-1893 (1998) and Yang et al. J. Biol. Chem. 273: 19419-19423 (1998)).
- KCNQ2 co- expressed with KCNQ3 produces a current whose amplitude is about 10 times that of the sum of the two homomeric channels and whose biophysical and pharmacological properties are very similar to those of the native M-current (Main et al. Mol. Pharmacol. 58: 253-262 (2000), Wang et al. Science 282: 1890-1893 (1998) and Yang et al J. Biol. Chem. 273: 19419-19423 (1998)).
- CHO cells were co-transfected with the two corresponding cDNAs of KCNQ2 and KCNQ3 at an equimolar ratio and exposed to meclofenamic acid (1) and 1-EBIO (10) so as to identify the effect of these compounds on M-current.
- Figure 1A shows representative traces of the KCNQ2/3 current activated by step depolarization above a voltage threshold of about -50 mV.
- Figure 2B shows the percentages of the current measured in the presence (+) or absence (-) of meclofenamic acid (Compound 1, left panel) or 1-EBIO (Compound 10, right panel), where the control is 100 %.
- meclofenamic acid (Compound 1) increased KCNQ2/3 current amplitude by more than 10-fold, 5-fold and 2.5-fold, respectively ( Figures 1A, 1C and 2C, left panels).
- KCNQ2/3 deactivation kinetics The slowing down of KCNQ2/3 deactivation kinetics caused by meclofenamic acid (Compound 1) and 1-EBIO (Compound 10) is discussed with reference to Figures 3A-3E.
- Figure 3A the tail current of a cell before (control) and following application of meclofenamic acid (Compound 1) is shown. The prepulse was -20 mV while the tail potential was -60 mV.
- 1-EBIO (Compound 10) did affect significantly (p ⁇ 0.001) the KCNQ2/3 deactivation kinetics.
- the decay of the tail current was fitted using one exponential function.
- Figure 3D shows that 1-EBIO (Compound 10) slows down the deactivation kinetics of KCNQ2/3 channels.
- FIGs 4A-4B neuronal activity depression by meclofenamic acid (Compound 1) is shown.
- Figure 4A evoked rat cortical neuronal activity before
- mice Five groups of 10 ICR mice each received intraperitoneally saline or meclofenamic acid (Compound 1) at 25 mg/lcg, 50 mg/kg, 100 mg/kg and 150 mg/lcg and were subjected 30 minutes later to an electric shock (50 mA, 0.2 second duration, 60 Hz). The relative fraction of mice that did not produce seizures was plotted for each dose in Figure 5.
- Compound 1 Five groups of 10 ICR mice each received intraperitoneally saline or meclofenamic acid (Compound 1) at 25 mg/lcg, 50 mg/kg, 100 mg/kg and 150 mg/lcg and were subjected 30 minutes later to an electric shock (50 mA, 0.2 second duration, 60 Hz). The relative fraction of mice that did not produce seizures was plotted for each dose in Figure 5.
- meclofenamic acid (Compound 1) dissolved in saline was injected intraperitoneally (in a volume of 10 ml/kg) at doses ranging from 25 mg/lcg to 150 mg/lcg to ICR adult mice and its anticonvulsant activity was compared with saline. Thirty minutes after drug administration, seizures were produced by electroshock (50 mA, 0.2 second duration, 60 Hz).
- Figure 5 shows that 50 mg/lcg meclofenamic acid (Compound 1) significantly protected 50% of the mice from electroshock and at 100 mg/kg fully prevented seizures. At 150 mg/kg meclofenamic acid (Compound 1) led to sedation of the mice.
- FIGs 6A-6C the enhancement of the KCNQ2/3 current caused by diclofenac (Compound 2) is shown.
- Figure 6A whole cell currents of KCNQ2/3 heterogously expressed in CHO cells recorded before and after perfusion of 50 ⁇ M diclofenac are shown.
- the cell membrane was stepped from -90 mV to - 50 mV (1 second) followed by tail step to -60 mV (0.75 second). Recordings were taken every 30 seconds.
- Figure 6B the percentage of the current presented in the presence (+) or absence (-) of diclofenac, where the control is 100%, taken from the experiment presented in Figure 6A is shown.
- Figure 6C the normalized conductance (G/G max ) is plotted as a function of the voltage steps, for the control (open squares) and diclofenac (closed squares), for KCNQ2/3 current.
- Novel Compounds 3, 4, 5, 6, 7, 8 and 9 were tested for KCNQ2/3 opening activity as is described below. It is important to note that compounds 3-9 were also tested and found to have no effect on KCNQ1/KCNE1 cardiac channels and displayed a selective brain specificity. These results are not shown.
- EXAMPLE 8 The effect of Compound 6 on KCNQ2/3 channels and on rat cortical neurons
- FIGs 7A-7C the effects of Compound 6 on KCNQ2/3 currents are shown.
- Figure 7A whole-cell currents recorded before and after perfusion of 25 ⁇ M Compound 6 are shown.
- Figure 7B the percentage of the current presented in the presence (+) or absence (-) of Compound 6, where the control is 100%, taken from the experiment presented in Figure 7A.
- Figure 7C the normalized conductance (G/G m a ⁇ ) was plotted as a function of the voltage steps, for the control (open squares) and Compound 6 (closed squares), for KCNQ2/3 current are shown.
- FIGs 8A-8B inhibition of the evoked neuronal activity by the Compound 6 is shown.
- neuronal activity as evoked by square depolarizing current, inhibited by lO ⁇ M Compound 6 and recovered after wash is shown.
- the depolarizing current was 50 pA for 800 msec.
- the evoked neuronal activity using the ramp protocol, recorded before, after external perfusion of Compound 6 and recovered after wash is shown.
- the depolarizing current was ramped from 0 pA to 300 pA within 800 msec.
- Figure 7C shows the effects of 25 ⁇ M Compound 6 on recombinant KCNQ2/3 channels expressed in CHO cells.
- Compound 6 consistently reduced the number of evoked action potentials. Upon washout of the Compound for less than 2 minutes, neurons recovered their initial spiking activity (Figure 8 A, 5th row).
- Compound 6 Compound for all three concentrations.
- KCNQ2/3 current is shown.
- Figure 10A evoked rat cortical neuronal activity recorded before, after application of 25 ⁇ M Compound 5, and after washing is shown.
- KCNQ2/3 current are shown.
- Figure 12B spontaneous cortical neuron activity recorded before, after addition of 20 ⁇ M Compound 4 and after a wash is shown.
- Figure 12B spontaneous cortical neuron activity recorded before, after addition of 20 ⁇ M Compound 4 and after a wash is shown.
- Figure 12A KCNQ2/3 currents recorded before (left panel) and after (right panel) application of 50 ⁇ M Compound 4 are shown.
- EXAMPLE 12 The effect of Compound 9 on KCNQ2/3 channels and on rat cortical neurons The effect of Compound 9 on rat cortical neurons is discussed with reference to
- Figure 13 In Figure 13 is shown spontaneous neuronal activity (action potentials) as modulated by 20 ⁇ M Compound 9.
- EXAMPLE 13 The effect of Compound 7 on KCNQ2/3 channels and on rat cortical neurons The effect of Compound 7 on recombinant KCNQ2/3 potassium channels heterologously expressed in CHO cells and on rat cortical neurons is discussed with reference to Figures 14A-14D.
- FIGs 14A-14D the effects of 20 ⁇ M Compound 7 on KCNQ2/3 channels and neuronal activity are shown.
- the KCNQ2/3 whole cell currents recorded before and after perfusion of 20 ⁇ M Compound 7 are shown.
- Figure 14B the percentage of the current presented in the presence (+) or absence (-) of Compound 7, where the control is 100%, taken from the experiment presented in Figure 14 A.
- Figure 14C the normalized conductance of the KCNQ2/3 current (G/G max ) is plotted as a function of the voltage steps, for the control (open squares) and Compound 7 (closed squares).
- Figure 14 shows the effects of Compound 7 on KCNQ2/3 channels.
- Compound 7 is a potent KCNQ2/3 channel opener with a marked leftward shift in the voltage dependent activation curve (Figure 14C). This effect led to a potent increase of the channel amplitude as determined by a train protocol ( Figures 14A and 14B).
- Figures 14A and 14B 20 ⁇ M Compound 7 exhibited a very potent inhibitory activity on evoked and spontaneous spiking activity of cortical neurons ( Figure 14D). This effect was fully reversible.
- EXAMPLE 14 The effect of Compound 8 on KCNQ2/3 channels and on rat cortical neurons The effect of Compound 8 on recombinant KCNQ2/3 potassium channels heterologously expressed in CHO cells and on rat cortical neurons is discussed with reference to Figures 15 A-l 5B.
- FIGs 15A-15B the evoked and spontaneous neuronal activity as modulated by Compound 8 is shown.
- Figure 15 A is shown evoked rat cortical neuronal activity recorded before, during and after application of lO ⁇ M Compound 8.
- Figures 15A-B show that low concentrations of Compound 8 produced a potent inhibitory activity on evoked and spontaneous spiking activity of cortical neurons.
- Compound 8 displayed only a weak opener action of recombinant KCNQ2/3 channels heterologously expressed in CHO cells. This result suggests that Compound 8 exerts neuronal depressant activity via mechanisms that do not involve KCNQ2/3 channels.
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JP2004544675A JP2006513154A (en) | 2002-10-21 | 2003-10-21 | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and / or cortical neuron activity modulators |
CA002503075A CA2503075A1 (en) | 2002-10-21 | 2003-10-21 | Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators |
EP03753909A EP1553932A2 (en) | 2002-10-21 | 2003-10-21 | Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators |
AU2003272068A AU2003272068A1 (en) | 2002-10-21 | 2003-10-21 | Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators |
US11/110,669 US7632866B2 (en) | 2002-10-21 | 2005-04-21 | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
US12/591,090 US8278357B2 (en) | 2002-10-21 | 2009-11-06 | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
US13/424,553 US8618169B2 (en) | 2002-10-21 | 2012-03-20 | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
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WO2009071947A2 (en) | 2007-12-05 | 2009-06-11 | Lectus Therapeutics Limited | Potassium ion channel modulators & uses thereof |
US7632866B2 (en) | 2002-10-21 | 2009-12-15 | Ramot At Tel Aviv University | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
CN102159535A (en) * | 2008-07-22 | 2011-08-17 | 特拉维夫大学拉莫特有限公司 | Potassium ion channel modulators & uses thereof |
WO2019073471A1 (en) * | 2017-10-09 | 2019-04-18 | Ramot At Tel-Aviv University Ltd. | Modulators of potassium ion and trpv1 channels and uses thereof |
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US7632866B2 (en) | 2002-10-21 | 2009-12-15 | Ramot At Tel Aviv University | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
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US8466201B2 (en) | 2007-12-05 | 2013-06-18 | Ramot At Tel-Aviv University Ltd. | Potassium ion channel modulators and uses thereof |
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WO2019073471A1 (en) * | 2017-10-09 | 2019-04-18 | Ramot At Tel-Aviv University Ltd. | Modulators of potassium ion and trpv1 channels and uses thereof |
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US11427531B2 (en) | 2017-10-09 | 2022-08-30 | Ramot At Tel-Aviv University Ltd. | Modulators of potassium ion and TRPV1 channels and uses thereof |
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