WO2007002885A2 - Compositions et procedes pour utiliser un agent de blocage du canal sodique - Google Patents

Compositions et procedes pour utiliser un agent de blocage du canal sodique Download PDF

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Publication number
WO2007002885A2
WO2007002885A2 PCT/US2006/025516 US2006025516W WO2007002885A2 WO 2007002885 A2 WO2007002885 A2 WO 2007002885A2 US 2006025516 W US2006025516 W US 2006025516W WO 2007002885 A2 WO2007002885 A2 WO 2007002885A2
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compound
increased
group
bladder
detrusor overactivity
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WO2007002885A3 (fr
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Milton L. Brown
William D. Steers
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UVA Licensing and Ventures Group
University of Virginia UVA
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University of Virginia UVA
University of Virginia Patent Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • Overactive bladder (OAB) and urge urinary incontinence are common problems that reduce the quality of life of adults. Up to 16% of adults suffer from OAB. Moreover, up to one in five men develop lower urinary tract symptoms due to benign prostatic hyperplasia. Despite considerable progress in understanding the patho- physiology of bladder dysfunction, there is presently no consistently effective treatment for disorders like the painful or overactive bladder syndromes. Painful bladder syndrome (PBS) is a chronic bladder hypersensitivity disorder that typically presents with suprapubic pain related to bladder filling, accompanied by other symptoms such as increased frequency and nocturia, in the absence of a definable etiology.
  • PBS Painful bladder syndrome
  • the overactive bladder syndrome is symptom complex characterized by urinary urgency with or without urge incontinence, usually with frequency and nocturia. Detrusor overactivity is often the underlying condition. Detrusor overactivity can be further qualified as neurogenic detrusor overactivity (NDO), when there is a relevant neurologic condition or idiopathic detrusor overactivity (EDO), when there is no defined cause.
  • NDO neurogenic detrusor overactivity
  • EEO idiopathic detrusor overactivity
  • the pathophysiology of overactive bladder syndrome (OABS) and detrusor overactivity (DO) is complex and involves both peripheral and central nervous system (CNS) factors. Central in OABS is urgency, the pathophysiology of which is unknown.
  • Perturbations of these systems are found in CNS disorders associated with DO and OABS, such as stroke, Parkinson's disease, spinal cord injury and multiple sclerosis (see Andersson, Nature Clinical Practice Urology 1:103 - 108, 2004, and Steers, Nature Clinical Practice Urology 3:101 - 110, 2006, for reviews).
  • Urgency defined as "the complaint of a sudden compelling desire to pass urine, which is difficult to defer", is a central symptom of OABS. It can also be associated with involuntary detrusor contractions, urodynamically demonstrated as DO. It should be noted that urgency is difficult to measure, and no validated tool for its assessment is currently available. Furthermore, there are no animal models of urgency. Because the sensation of desire to void, urgency, and initiation of the micturition reflex depend on afferent input from the lower urinary tract, afferent functions and their central control have been of interest as targets for new therapies.
  • OAB occurs when smooth muscle of the detrusor muscle of the bladder squeezes or contracts more often than normal and at inappropriate times. Instead of staying at rest as urine fills the bladder, the detrusor contracts while the bladder is filling with urine.
  • the cause of O AB is unknown.
  • identifiable underlying causes can include: drug side effects, nerve damage or neurological disease (e.g., multiple sclerosis, Parkinson's disease, etc.) or stroke.
  • nerve damage or neurological disease e.g., multiple sclerosis, Parkinson's disease, etc.
  • BPH benign prostatic hyperplasia
  • Circumstantial evidence suggests that individuals with depression, anxiety, and attention deficit disorder may experience symptoms of OAB more often than the general population.
  • Some investigators suggest that depression, anxiety, feeding disturbances, pain, irritable bowel syndrome, fibromyalgia and changes in urination are associated with disturbances in brain circuits using specific chemical messengers between nerves known as neurotransmitters, in. particular serotonin 5-hydroxytryptar ⁇ ine (5-HT).
  • Fibromyalgia and irritable bowel syndrome are conditions seen more often in patients with OAB and interstitial cystitis (IC) than the general population. These conditions are associated with an overactive bladder, and possibly to depression, which provides a potential link with 5-HT metabolism and OAB.
  • Urge incontinence is a storage problem which involves a strong, sudden need to urinate immediately followed by a bladder contraction, resulting in an involuntary loss of urine. Often these contractions occur regardless of the amount of urine that is in the bladder. Urge incontinence may result from neurological injuries (such as spinal cord injury or stroke), neurological diseases (such as multiple sclerosis), infection, bladder cancer, bladder stones, bladder inflammation, or bladder outlet obstruction. The majority of cases are classified as idiopathic — a specific cause cannot be identified. Although urge incontinence may occur in anyone at any age, it is more common in women and the elderly. It is second only to stress incontinence as the most common cause of urinary incontinence (involuntary loss of urine).
  • urge incontinence may be due to secondary bladder injuries caused by benign prostatic hypertrophy (BPH) or bladder outlet obstruction from an enlarged prostate.
  • BPH benign prostatic hypertrophy
  • bladder outlet obstruction from an enlarged prostate.
  • BPH benign prostatic hypertrophy
  • the ability to hold urine and maintain. continence is dependent on normal function of the lower urinary tract, the kidneys, and the nervous system — plus the physical and psychological ability to recognize and appropriately respond to the urge to urinate.
  • Interstitial cystitis is a chronic bladder disorder also known as painful bladder syndrome and frequency-urgency-dysuria syndrome. In this disorder, the bladder wall can become inflamed and irritated.
  • the bladder's ability to fill and store urine requires a functional sphincter (muscle controlling output) and a stable bladder wall muscle (detrusor).
  • the process of urination involves two phases: the filling and storage phase, and the emptying phase.
  • the bladder begins to fill, stretching to accommodate the increasing amount of urine.
  • the bladder of an average person can hold 350 mL to 550 mL of urine.
  • the first sensation of the need to urinate occurs when approximately 200 mL of urine is stored.
  • the nervous system responds by alerting the subject of the need to urinate while also allowing the bladder to continue to fill.
  • the emptying phase requires the ability of the detrusor muscle to appropriately contract, forcing urine out of the bladder.
  • the body must also be able to simultaneously relax the sphincter to allow the urine to exit.
  • the bladder of an infant contracts automatically when a certain volume of urine is collected in the bladder.
  • bladder muscle contraction is prevented by constant inhibition from the cerebral cortex (part of the brain). This allows urination to be delayed until the individual is ready.
  • Undesired bladder muscle contraction may occur as the result of a break in the neurological pathway from the brain to the bladder. It can also occur if the bladder is irritated and the normal neurological impulses to inhibit urination are insufficient to keep the bladder relaxed as it fills.
  • DO and OAB occur as a result of a variety of neurological disorders, as well as ⁇ a response to changes in peripheral innervation and in the smooth and skeletal muscle components of the lower urinary tract and pelvic floor.
  • the pathophysiology of DO and OABS might be dependent on increased afferent activity, decreased capacity of the CNS to process afferent information, decreased suprapontine inhibition or increased sensitivity to contraction-mediating transmitters in the target organ.
  • Na channels may be important in the pathogenesis of idiopathic detrusor overactivity or due cystitis and bladder outlet obstruction (Black et al., Brain Res. 2003, 963(1 -2): 132-8).
  • Evidence for plasticity in afferent nerves has been shown for these conditions.
  • the basis for this plasticity is an alteration of sodium (Na) channels.
  • Knockdown of specific sodium channel isoforms using intrathecal administration of antisense deoxyoligonucleotides reverses detrusor overactivity in the spontaneous hypertensive rat (SHR), cystitis, and urethral obstruction models (Lee et al., J. Urol. 167 (4): 38-38 Suppl. S, APR 2002).
  • Diphenylhydantoin (DPH) or Phenytoin is a clinically useful anticonvulsant, class Ib antiarrhythmic and has been effectively used in the treatment of neuropathic pain by virtue of its ability to block voltage-gated sodium channels.
  • Sodium channel blockers such as local anesthetics and antiarrhythmics mediate their block of sodium channels by two mechanisms, tonic (resting) block and use-dependent block. Tonic block results from low affinity binding of drug to the resting state of the channel whilst during use-dependent block drugs binds to the inactivated state of the channel with a greater affinity resulting in further inhibition of the current.
  • the present invention provides methods and compositions for treating the symptoms and signs or diseases, disorders, and conditions related to overactive bladder (urgency, usually with frequency, with or without nocturia or urge incontinence), urge urinary incontinence, detrusor overactivity, interstitial cystitis, and lower urinary tract symptoms (LUTS) due to benign prostate hypertrophy.
  • the detrusor overactivity is related to bladder outlet obstruction (BOO).
  • BOO bladder outlet obstruction
  • the present invention provides Na channel blockers, including, but not limited to,
  • compounds of the invention have a higher affinity for the inactivated state of the sodium channel than phenytoin (DPH) has for the inactivated state of the sodium channel.
  • the sodium channel is Navl.5.
  • the invention provides compounds having the structure: O
  • R is selected from the group consisting of halogen, H, and H 3 C, or an analog, derivative, or modification thereof.
  • the halogen is chlorine.
  • the invention provides a compound having the structure
  • R is selected from the group consisting of halogen, H, and H 3 C, or an analog, derivative, or modification thereof.
  • the halogen is chlorine.
  • ICM-I-136 (see structure 6 above), an alpha-hydroxyamide, is a recently identified new class of potent Na channel blockers with high affinity for the inactivated state as compared to phenytoin (Lenkowski et al. European J. Pharmaceutical Sciences, 21 -.635-644, 2004). ICM-I-136 is structure 6 on page 638 of Lenkowski.
  • the present application discloses the potent effect of ICM-I-136 on voiding function in SHR and in rats with partial urethral obstruction as determined using blinded awake cystometries. The present further discloses the efficacy of this compound in treating detrusor overactivity.
  • ICM-I-136 has the following general structure:
  • Other useful compounds of the invention include compounds such as Phenytoin and Carbamazepine, and analogs, derivatives, and modifications thereof, wherein the compounds have the desired biological activity described herein.
  • the compound used for treating a disease, disorder or condition of the bladder is ICM-I-136.
  • the compound is an analog, derivative, or modification of ICM-I-136.
  • the compounds are alpha- hydroxyamides with the activity described herein. Such compounds have utility in treating diseases associated with inappropriate sodium channel activity.
  • the present invention provides methods of administering sodium channel blockers for treating diseases, disorders, and conditions related to overactive bladder (urgency, usually with frequency, with or without nocturia or urge incontinence), urge urinary incontinence, detrusor overactivity, and lower urinary tract symptoms (LUTS) due to benign prostate hypertrophy.
  • overactive bladder usually with frequency, with or without nocturia or urge incontinence
  • urge urinary incontinence urge urinary incontinence
  • detrusor overactivity detrusor overactivity
  • LUTS lower urinary tract symptoms
  • the present invention provides compositions and method for treating the signs and symptoms of diseases, disorders, and conditions associated with overactive bladder and detrusor overactivity, including, but not limited to, benign prostatic hyperplasia, nocturia, painful bladder syndrome, overactive bladder syndrome, stroke, Parkinson's disease, spinal cord injury, depression, anxiety, feeding disturbances, pain, irritable bowel syndrome, fibromyalgia, interstitial cystitis, and multiple sclerosis
  • the invention provides compositions and methods useful for reducing detrusor overactivity, reducing maximum pressure, reducing basal pressure, reducing voiding frequency, increasing intercontraction interval, reducing urge incontinence, nocturia, and increasing voided volume.
  • a compound of the invention can be administered at a dosage of up to about 1000 mg/kg. In another aspect, the dosage can be up to about 300 mg/kg.
  • dosages, form of delivery, route of adrninistration, and frequency of administration may vary depending on a number of conditions, such as the age, sex, weight, and health of the subject, as well as the type and severity of the disease, disorder or condition being treated.
  • the invention further provides administering one or more compounds of the invention, and using one or more compounds of me invention in combination or in conjunction with other drugs or agents.
  • the other drugs and agents include, but are not limited to, drugs such as pain medication and other types of drugs useful for treating overactive bladder and detrusor overactivity symptoms described herein.
  • the invention further provides a kit for adniinistering the compositions of the invention.
  • Figure 1 graphically illustrates the effect of ICM- ⁇ -136 on voiding of SHR.
  • the compound was tested at 0, 30, 100, and 300 mg/kg. Measurements analyzed include, BP, preMP, MP ICI, and W. * indicates a significant difference at the level of p ⁇ 0.05.
  • Figure 2 graphically illustrates the effect of ICM-I-136 on. voiding of WKY. the compound was tested at O 5 100, and 300 mg/kg. Measurements analyzed include BP, preMP, MP, ICI, and VV. * indicates a significant difference at the level of p ⁇ 0.05.
  • Figure 3 comprising Figures 3 A and 3B, graphically illustrate the effect of vehicle (Figure 3A; upper panel) and ICM-I-136 at 300 mg/kg ( Figure 3B; lower panel) i.p. awake cystometry in obstructed (OBS) rats.
  • Figure 4 is a schematic representation of the mechanism of detrusor overactivity and the basis for drug therapy with sodium channel antagonists (Upper Panel: Normal Bladder; Lower Panel: Overactive Bladder).
  • Basal pressure also referred to as BsP
  • DO Detrusor overactivity
  • DMSO Dimethyl sulfoxide
  • IDO Idiopathic detrusor overactivity
  • NDO Neurogenic detrusor overactivity
  • NF Non-frequent voiders
  • OBS Obstructed
  • Overactive bladder also referred to as Detrusor instability, Detrusor hyperreflexia, Irritable bladder, Spasmodic bladder; Unstable bladder, and Urge
  • OABS Incontinence Overactive bladder syndrome
  • PBS Painful bladder syndrome
  • RU Postvoid residual volume
  • PUL Partial urethral ligation
  • PreMP Premicturition pressure
  • Na Na
  • the articles “a” and “an” refer to one or to more than one, i.e., to at least one, of the grammatical object of the article.
  • an element means one element or more than one element.
  • affinity for the inactivated state refers to a drug's ability to bind to the inactivated state of a voltage-gated sodium channel to inhibit the current.
  • a disease, condition, or disorder is "alleviated” if the severity of a symptom of the disease, condition, or disorder, or the frequency with which such a symptom is experienced by a subject, or both, are reduced.
  • an "analog" of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5- fluorouracil is an analog of thymine).
  • Bodder Outlet Obstruction is the generic term for obstruction during voiding and is characterized by increased detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the synchronous values of fiowrate and detrusor pressure.
  • a "control" cell, tissue, sample, or subject is a cell, tissue, sample, or subject of the same type as a test cell, tissue, sample, or subject.
  • the control may, for example, be examined at precisely or nearly the same time the test cell, tissue, sample, or subject is examined.
  • the control may also, for example, be examined at a time distant from the time at which the test cell, tissue, sample, or subject is examined, and the results of the examination of the control may be recorded so that the recorded results may be compared with results obtained by examination of a test cell, tissue, sample, or subject.
  • the control may also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a disease or disorder for which the test is being performed.
  • test cell tissue, sample, or subject is one being examined.
  • a "pathoindicative" cell, tissue, or sample is one which, when present, is an indication that the animal in which the cell, tissue, or sample is located (or from which the tissue was obtained) is afflicted with a disease or disorder.
  • the presence of one or more breast cells in a lung tissue of an animal is an indication that the animal is afflicted with metastatic breast cancer.
  • a tissue normally comprises” a cell if one or more of the cell are present in the tissue in an animal not afflicted with a disease or disorder.
  • a “compound,” as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above.
  • a "derivative" of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
  • a "detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound comprising the marker in the presence of similar compounds without a marker.
  • Detectable markers or reporter molecules include, but are not limited to, radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, diemiluminescent molecules, elecfrocaemically detectable molecules, and molecules that provide for altered fluorescence polarization or altered light scattering.
  • Detrusor Overactivity refers to a urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked. Any detrusor contraction prior to permission to void is abnormal.
  • Detrusor Overactivity Incontinence refers to incontinence due to detrusor overactivity.
  • a “derivative" of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
  • the phrase, "disease, condition, or disorder is characterized by an overactive bladder or detrusor overactivity" refers to any disease, disorder, or condition which is known to be associated with overactive bladder or detrusor overactivity, whether or not the disease, disorder, or condition actually causes overactive bladder or detrusor overactivity.
  • a disorder in an animal is a state of health in which in which the animal is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject's state of health.
  • an "effective amount” means an amount sufficient to produce a selected or desired effect.
  • Fiberlling Cystometry refers to the method by which the pressure/volume relationship of the bladder is measured during bladder filling.
  • inhibitor refers to the ability of a compound of the invention to reduce or impede a described function. Preferably, inhibition is a reduction of at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%.
  • inhibitor is used interchangeably with “reduce” herein.
  • an "instructional material” includes a publication, a recording, a . diagram, or any other medium of expression which can be used to communicate the usefulness of the peptide of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • in vivo refers to inside a living organism.
  • in vitro refers to outside a living organism.
  • modification of a compound refers to a compound that's structure or composition has been somewhat changed from the original compound.
  • Nocturia refers to the complaint that the individual has to wake at night one or more times to void.
  • OABS Overactive bladder syndrome
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • the term "pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
  • pharmaceutically acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts.
  • Premicturition pressure is the pressure recorded immediately before the initial isovolumetric contraction.
  • a sample refers preferably to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine.
  • a sample can also be any other source of material obtained from a subject which contains cells, tissues, or fluid of interest.
  • a sample can also be obtained from cell or tissue culture.
  • the term "sign,” as used herein, refers to any abnormality indicative of a disease, disorder, or condition, discoverable on examination of the patient; an objective indication of disease, in contrast to a symptom, which is a subjective indication of disease.
  • sodium channel refers to a structure comprised of integral membrane proteins that functions to allow sodium to equilibrate across a cell membrane according to its electrochemical gradient and at rates that are diffusion limited.
  • a sodium channel can exist in several modes: C (closed resting state); C* (activated closed state); O (open state); and I (inactivated state). The probability that a channel will exist in one of these four states changes with voltage.
  • sodium channel activity refers to activities of sodium channels and the results of activities of a sodium channel, which can be measured or monitored using in vitro and in vivo assays.
  • sodium channel activity or the results of sodium channel activity, can be measured, analyzed, or monitored using various assays such as binding, gating, ion permeation, current, and various methods which measure parameters indicative of pain or reaction, such as motor function, proprioception, nocifensive reaction.
  • sodium channel blocker refers to a compound that is able to inhibit sodium channel activity.
  • Standard refers to something used for comparison. For example, it can be a known standard agent or compound which is administered or added to a control sample and used for comparing results when measuring said compound in a test sample. Standard can also refer to an "internal standard", such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
  • a "subject" of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably a human. Non-human animals subject to analysis, diagnosis, or treatment include, but are not limited to, primates, cats, dogs, horses, cows, goats, pigs, and sheep.
  • the term "substantially pure” describes a compound, e.g., a protein or polypeptide which has been separated from components which naturally accompany it.
  • a compound is substantially pure when at least 10%, more preferably at least 20%, more preferably at least 50%, more preferably at least 60%, more preferably at least 75%, more preferably at least 90%, and most preferably at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., in the case of polypeptides by column chromatography, gel electrophoresis, or HPLC analysis.
  • a compound, e.g., a protein is also substantially purified when it is essentially free of naturally associated components or when it is separated from the native contaminants which accompany it in its natural state.
  • symptom refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease.
  • a sign is objective evidence of disease.
  • a bloody nose is a sign. It is evident to the patient, doctor, nurse and other observers.
  • treating includes prophylaxis of the specific disease, disorder, or condition, or alleviation of the symptoms associated "with a specific disease, disorder, or condition and/or preventing or eliminating said symptoms.
  • a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • a “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • Urinary incontinence refers to the complaint of any involuntary leakage of urine.
  • Urgency refers to the complaint of a sudden compelling desire to pass urine, which is difficult to defer.
  • voiding refers to passing urine.
  • voiding is used interchangeably with “micturition”.
  • halogen or halo includes bromo, chloro, fluoro, and iodo.
  • haloalkyl refers to an alkyl radical bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
  • Ci-C n alkyl wherein n is an integer, as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms.
  • Ci-Ce alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.
  • C 2 -C n alkenyl wherein n is an integer, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond.
  • groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
  • C 2 -C n alkynyl wherein n is an integer refers to an unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one triple bond.
  • examples of such groups include, but are not limited to, 1- propynyl, 2-pro ⁇ ynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.
  • the term "optionally substituted” refers to from zero to four substituents, wherein the substituents are each independently selected. Each of the independently selected substituents may be the same or different than other substituents.
  • aryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • Optionally substituted aryl includes aryl compounds having from zero to four substituents, and "substituted aryl” includes aryl compounds having one or more substituents.
  • the term (C 5 -C 8 alkyl)aryl refers to any aryl group which is attached to the parent moiety via the alkyl group.
  • heterocyclic group refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing from one to three heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen.
  • heteroaryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings containing from one to three heteroatoms and includes, but is not limited to, furyl, thienyl, pyridyl and the like.
  • bicyclic represents either an unsaturated or saturated stable 7- to 12- membered bridged or fused bicyclic carbon ring.
  • the bicyclic ring may be attached at any carbon atom which affords a stable structure.
  • the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
  • the compounds of the present invention may contain one or more asymmetric centers in the molecule. In accordance with the present invention a structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
  • the compounds of the present invention may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • the following structure :
  • N ⁇ NH is understood to represent a mixture of the structures:
  • pharmaceutically-acceptable salt refers to salts which retain the biological effectiveness and properties of the compounds of the present invention and which are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • the present invention provides compositions and methods for treating overactive bladder and detrusor overactivity-associated diseases, disorders, and conditions with compounds which regulate sodium channel activity.
  • the compounds of the invention useful for treating diseases and conditions described herein, such as overactive bladder syndrome, may also be used in conjunction with other drugs, behavioral modification, surgery, and neuromodulation.
  • the compound has the general structures:
  • R wherein R is selected from the group consisting of halogen, H, and H 3 C,
  • R is selected from the group consisting of halogen, H, and H 3 C.
  • halogen is chlorine.
  • the compound is ICM-I- 136, which has the following general structure: o
  • Carbamazepine an iminostilbene derivative of tricyclic antidepressants, exhibits a spectrum of anticonvulsant activity very similar to that of phenytoin. In humans, it is effective against partial and generalized tonic-clonic seizures, but not against absence seizures. Laniotrigine has been used for treating partial and generalized tonic-clonic seizure. Such compounds, as well as analogs, derivatives, and modifications thereof are useful in the method of the invention.
  • Molecular modeling can be employed when designing and studying new compounds useful in the invention (see Lenkowski et al.. European Journal of Pharmaceutical Sciences 21 (2004) 635-644).
  • the X-ray coordinates for phenytoin (DPH) can be utilized, ⁇ -hydroxyphenylamides can be modified from the X- ray structure and energy-ininimized with the Tripos force field using conjugate gradient approach and 0.05 kCal/mol energy cutoff, without solvent, using default bond distances and angles and neglecting electrostatics.
  • the minimization can be completed by aggregating using the SYBYL/AGGREGATE module for only the X-ray structure atoms and allowing 1he modified portion to minimize.
  • the R- configuration for all chiral compounds can be used.
  • Plane angles can be calculated using the phenyl ring for plane 1 and the carbonyl and nitrogen of the amide for plane 2.
  • Plane 1 for DPH can be constructed with phenyl ring atoms and plane 2 using all hydantoin ring atoms.
  • the plane angle can be calculated as the angle between planes 1 and 2.
  • Molecular volume can determined using the volume contour option within SYB YL/VEBW presented with default options.
  • Chinese Hamster Ovary (CHO-Kl) cells stably expressing Navl .5 can be grown in DMEM7F12 media (Invitrogen Corp., CA, USA) supplemented with 10% fetal bovine serum, penicillin (100 U/ml), streptomycin (100 ⁇ g/ml) and G418 (500 ⁇ g/ml; Sigma, MO, USA). Cells can be grown in a humidified atmosphere of 5% CO2 and 95% air at 37 0 C.
  • sodium currents can be recorded using the whole-cell configuration of the patch clamp recording technique with an Axopatch 200B amplifier (Axon Instruments, Foster City, CA). All voltage protocols can be applied using pCLAMP 8 software (Axon, USA) and a Digidata 1322A (Axon, USA). Currents were amplified and low pass filtered (2 kHz) and sampled at 33 kHz.
  • Borosilicate glass pipettes can be pulled using a Brown- Flaming puller (model P87, Sutter Instruments Co., Novato, CA) and heat polished to produce electrode resistances of 0.5-1.5 M ⁇ when filled with the following electrode solution (in mM); CsCl 130, MgC12 1, MgATP 5, BAPTA 1O 5 HEPES 5 (pH adjusted to 7.4 with CsOH).
  • Cells can be plated on glass coverslips and superfused with solution containing the following composition (in mM) NaCl 130, KCl 4, CaC12 1, MgCl2 5, HEPES 5, and glucose 5 (pH adjusted to 7.4 with NaOH).
  • DMSO dimethyl sulfoxide
  • the maximum DMSO concentration might be 0.3% because it usually has no effect on current amplitude.
  • Experiments can be performed at room temperature (20-22 0 C). After establishing whole-cell, a minimum series resistance compensation of 75% can be applied and cells can be held at -80 mV for 5 min to account for equilibrium gating shifts. Voltage error can be calculated using the following equation:
  • Al and A2 are the coefficients for the fast and slow exponentials, t the time (ms) and ⁇ l and ⁇ l the fast and slow time constants.
  • the percentage of the current represented by the fast time constant can be calculated from the equation 100%xAl/(Al+A2) 5 where Al and A2 are the amplitudes of the fast and slow gating modes, respectively.
  • Time constants for use-dependent block can be obtained using the equation:
  • Data analysis for these experiments can be performed using Clampfit software (v8, Axon Instruments, CA, USA), Origin (v5, Microcal Software, MA, USA), and Excel (Microsoft).
  • Statistical analyses can be performed using a t-test for normally distributed data as determined by the Kolmogorov- ⁇ mirnov test, or the Rank Sum test for non-normalized data (Sigma Stat, Jandel). Averaged data can be presented as mean ⁇ standard error of the mean (S.E.M.). Values of PO.05 can be considered to indicate significance. Other techniques for such analyses not described herein are known in the art.
  • Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, substituted cycloalkyl amines, substituted
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trhnethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylan ⁇ ioethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, etih.ylenediarnine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, n ⁇ orpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower al
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • the present invention is also directed to pharmaceutical compositions comprising the compounds of the present invention. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition comprising a compound of the invention, or analog, derivative, or modification thereof, as described herein, is used to administer the appropriate compound to a subject.
  • compositions comprising the a compound of the invention are administered to a subject in need thereof by any number of routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
  • routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
  • the oral route is typically employed for most conditions requiring the compounds of the invention. Preference is given to intravenous injection or infusion for the acute treatments. For maintenance regimens, the oral or parenteral, e.g. intramuscular
  • a composition that comprises a compound of the invention, or an analog, derivative, or modification thereof, and albumin, more particularly, the composition comprises a compound of the present invention, a pharmaceutically acceptable carrier and 0.1-1.0% albumin.
  • Albumin functions as a buffer and improves the solubility of the compounds. In one aspect, albumin is not added.
  • the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In another embodiment, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 g/kg/day.
  • Pharmaceutically acceptable carriers which are useful include, but are not • limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).
  • compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi- dose unit.
  • compositions are . principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, and mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
  • a pharmaceutical composition of the invention maybe prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage.
  • compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.
  • additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers.
  • Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
  • the dosage forms to be used can be provided as slow or controlled-release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention.
  • single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the present invention.
  • controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time, hi order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations. As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
  • a formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.
  • Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, a toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion.
  • oral rinse and mouthwash are used interchangeably herein.
  • a tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface-active agent, and a dispersing agent.
  • Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
  • compositions used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
  • Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate.
  • Known surface-active agents include, but are not limited to 5 sodium lauryl sulphate.
  • Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate.
  • Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
  • binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
  • Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
  • Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
  • a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
  • tablets may be coated using methods described in U.S. Patents numbers 4,256,108; 4,160,452; and 4,265,874 to form osmotically- controlled release tablets.
  • Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
  • Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either hi liquid form or hi the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
  • injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi dose containers containing a preservative.
  • Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions hi oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations.
  • Such formulations may further comprise one or more additional ingredients includmg, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen free water) prior to parenteral administration of the reconstituted composition.
  • a suitable vehicle e.g., sterile pyrogen free water
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration.
  • Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient.
  • Such powdered, aerosolized, or aerosolized formulations when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. See Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, which is incorporated herein by reference.
  • the compound can be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as twice a day (b.Ld.), once a day (q.i.d.), once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less.
  • the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type, and age of the subject, etc.
  • kits for treating a subject in need of immuno-modulation.
  • the subject is a human.
  • the kit comprises one or more of the analogs or derivatives of the present invention and may also include one or more known immunosuppressants.
  • These pharmaceuticals can be packaged in a variety of containers, e.g., vials, tubes, microtiter well plates, bottles, and the like.
  • Other reagents can be included in separate containers and provided with the kit; e.g., positive control samples, negative control samples, buffers, cell culture media, etc.
  • the kits will also include instructions for use.
  • the randomization scheme was established as a blind scheme. Basal pressure (BP), premicturition pressure (PreMP), Maximum pressure (MP), intercontraction interval (ICI), voided volume (W), and postvoid residual volume (RU) were recorded. In each animal, results after treatment were compared to results obtained after a stable baseline voiding pattern was achieved. Results
  • ICM-I-136 In SHR and OBS rats, intraperitoneal administration of high-dose (300 mg/kg) ICM-I-136 decreased maximum pressure and increased intercontraction interval and voided volume in a dose-dependent manner. In WKY and SHAM surgery rats, administration of ICM-I-136 decreased the maximum pressure in a dose-dependent manner, however, no significant effects on intercontraction interval and voided volume were observed.
  • Intraperitoneal administration of the novel Na channel blocker ICM-I-136 reduced detrusor overactivity in both the SHR and OBS models.
  • Example 2- Effects of ICM-I-136 on detrusor overactivity (DO) in a rat model of bladder outlet obstruction (BOO)
  • PUL was created in female Wister-Kyoto rats. After 3 weeks, cystometry experiments were performed in awake, unrestrained animals with saline infusion (10 ml/hr). Intravesical and intraperitoneal (i.p.) catheters were placed 3 days prior. After a stable voiding pattern was achieved (30-45 min), animals received either: vehicle, 30, 100 or 300 mg/kg of ICM-I-136 via i.p. injection. Basal pressure (BP), maximum pressure (MP) 3 intercontraction interval (ICI), voided volume (VY), and postvoid residual volume (RV) were recorded. Rats were grouped according to baseline voiding frequency (less than 2 voids/10 min vs. 2 or more voids/10 min). Drug effects were compared between non-frequent voiders (NF) and frequent voiders (F).
  • NF non-frequent voiders
  • F frequent voiders

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Abstract

La présente invention concerne des compositions et des procédés pour utiliser des agents de blocage du canal sodique pour traiter des maladies, des troubles, et des états pathologiques de la vessie et des voies urinaires, tels que l'hyperactivité vésicale, l'incontinence urinaire par impériosité, les symptômes des voies urinaires inférieures dus à l'hyperplasie prostatique bénigne.
PCT/US2006/025516 2005-06-29 2006-06-29 Compositions et procedes pour utiliser un agent de blocage du canal sodique Ceased WO2007002885A2 (fr)

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US69513405P 2005-06-29 2005-06-29
US60/695,134 2005-06-29
US73167705P 2005-10-31 2005-10-31
US60/731,677 2005-10-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9044482B2 (en) * 2012-08-15 2015-06-02 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis
CN118490792A (zh) * 2024-05-06 2024-08-16 首都医科大学 一种组合物及其治疗膀胱过度活动症的用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1659136A (zh) * 2002-04-18 2005-08-24 弗吉尼亚大学专利基金会 新的钠通道阻滞剂
US20040209960A1 (en) * 2003-01-30 2004-10-21 Dynogen Pharmaceuticals, Inc. Methods of treating lower urinary tract disorders using sodium channell modulators
EP1557166A1 (fr) * 2004-01-21 2005-07-27 Newron Pharmaceuticals S.p.A. Derives d'alpha-aminoamides pour le traitement des désordres de l'appareil urinaire inférieur

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9044482B2 (en) * 2012-08-15 2015-06-02 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis
US9375423B2 (en) 2012-08-15 2016-06-28 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis
CN118490792A (zh) * 2024-05-06 2024-08-16 首都医科大学 一种组合物及其治疗膀胱过度活动症的用途

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