WO2010059844A1 - Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof - Google Patents

Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof Download PDF

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WO2010059844A1
WO2010059844A1 PCT/US2009/065173 US2009065173W WO2010059844A1 WO 2010059844 A1 WO2010059844 A1 WO 2010059844A1 US 2009065173 W US2009065173 W US 2009065173W WO 2010059844 A1 WO2010059844 A1 WO 2010059844A1
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less
daily dose
quinuclidin
thiophene
benzo
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PCT/US2009/065173
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English (en)
French (fr)
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Gerhard Koenig
Richard Chesworth
Gideon Shapiro
Dana Hilt
Mike Palfreyman
Ann Barbier
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Envivo Pharmaceuticals, Inc.
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Priority to SI200930466T priority Critical patent/SI2355822T1/sl
Priority to BRPI0922057A priority patent/BRPI0922057A2/pt
Priority to DK09756921.4T priority patent/DK2355822T3/da
Priority to RU2011124515/15A priority patent/RU2532327C2/ru
Priority to ES09756921T priority patent/ES2396300T3/es
Priority to JP2011537621A priority patent/JP5272080B2/ja
Priority to EP09756921A priority patent/EP2355822B1/en
Priority to KR1020187002503A priority patent/KR20180011888A/ko
Priority to CA2744278A priority patent/CA2744278C/en
Priority to AU2009316557A priority patent/AU2009316557B2/en
Priority to MX2011005270A priority patent/MX2011005270A/es
Priority to KR1020147032489A priority patent/KR20140146216A/ko
Priority to CN2009801546937A priority patent/CN102281878A/zh
Priority to RS20120560A priority patent/RS52583B/en
Priority to US13/129,782 priority patent/US8642638B2/en
Priority to PL09756921T priority patent/PL2355822T3/pl
Priority to NZ593467A priority patent/NZ593467A/xx
Application filed by Envivo Pharmaceuticals, Inc. filed Critical Envivo Pharmaceuticals, Inc.
Priority to EP18152484.4A priority patent/EP3357495B1/en
Publication of WO2010059844A1 publication Critical patent/WO2010059844A1/en
Priority to IL212921A priority patent/IL212921A/en
Priority to EC2011011076A priority patent/ECSP11011076A/es
Priority to ZA2011/04044A priority patent/ZA201104044B/en
Priority to HK11113010.6A priority patent/HK1158520A1/xx
Priority to US13/674,290 priority patent/US8569354B2/en
Priority to HRP20130007AT priority patent/HRP20130007T1/hr
Priority to SM201300003T priority patent/SMT201300003B/xx
Priority to US14/139,178 priority patent/US20140148479A1/en
Priority to US14/175,654 priority patent/US8815933B2/en
Priority to PH12014501629A priority patent/PH12014501629A1/en
Priority to US14/509,305 priority patent/US20150265583A1/en
Priority to IL242035A priority patent/IL242035A0/en
Priority to IL242034A priority patent/IL242034A/en
Priority to US15/796,475 priority patent/US20180271844A1/en
Priority to IL256140A priority patent/IL256140A/en
Priority to IL256313A priority patent/IL256313A/en
Priority to PH12018500023A priority patent/PH12018500023A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • Nicotinic acetylcholine receptors form a family of ion channels activated by acetylcholine. Functional receptors contain five subunits and there are numerous receptor subtypes. Studies have shown that central nicotinic acetylcholine receptors are involved in learning and memory. Nicotinic acetylcholine receptors of the alpha7 subtype are prevalent in the hippocampus and cerebral cortex.
  • WO 2003/055878 describes a variety of agonists of the alpha7 nAChR said to be useful for improving cognition.
  • WO 2003/055878 suggests that certain agonists of the alpha7 nAChR are useful for improving perception, concentration, learning or memory, especially after cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, Alzheimer's disease, schizophrenia and certain other cognitive disorders.
  • the compounds described are (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2- carboxamide and pharmaceutically acceptable salts thereof.
  • Alzheimer's disease schizophrenia and other disorders such as other neurodegenerative diseases (e.g., Huntington's Disease or Parkinson's Disease) and attention deficit disorder. It can be used treat certain disorders, e.g., Alzheimer's disease, schizophrenia (e.g., paranoid type, disorganized type, catatonic type, and undifferentiated type), schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia at a daily dose of 3 mg, 2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg, 1.50 mg, 1.25 mg, 1 mg, 0.7, 0.5, 0.3 mg or even 0.1 mg.
  • the compound can be used to improve one or more aspects of cognition, e.g., one or more of: executive function, memory (e.g., working memory), social cognition, visual learning, verbal learning and speed of processing.
  • the treatment can improve one or more facets of cognition (e.g., visual motor skill, learning, delayed memory, attention, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory, executive function, etc.).
  • the methods can be used to treat: Alzheimer's disease, schizophrenia (e.g., paranoid type, disorganized type, catatonic type, and undifferentiated type), schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia or negative symptoms of schizophrenia.
  • schizophrenia e.g., paranoid type, disorganized type, catatonic type, and undifferentiated type
  • Dose is the amount of active pharmaceutical ingredient (API) administered to a patient.
  • API active pharmaceutical ingredient
  • 1 mg dose means 1 mg of API was administered to each patient each day.
  • Active Pharmaceutical Ingredient is defined as either (R)-7-chloro-N-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide hydrochloride, (R)-7-chloro-N-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide, (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2- carboxamide hydrochloride monohydrate or (R)-7-chloro-N-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide hydrochloride solvate.
  • solvate represents a stoichiometric ratio of 0.1 to 10 molecules of solvent compared to (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride or (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide.
  • Solvent molecules include but are not limited to water, methanol, 1,4 dioxane, ethanol, iso-propanol or acetone. In some cases water is the preferred solvate.
  • "The test compound” is defined as (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene- 2-carboxamide hydrochloride.
  • ECR is the concentration of drug which elicits equal response in oocytes transfected with cloned human alpha7 receptor at 50 ⁇ M acetylcholine. Maximum stimulation of the cloned human alpha 7 receptor occurs at a concentration >250 ⁇ M of acetylcholine.
  • FIGURE 1 depicts the results of a study on the effect of the test compound on P50 gating.
  • the standard errors of each mean are noted in the legend.
  • the bars (left to right) represent placebo, 0.3 mg test compound, and 1.0 mg test compound.
  • the standard errors of each mean are noted in the legend.
  • the bars left to right represent placebo, 0.3 mg test compound, and 1.0 mg test compound.
  • FIGURE 2 depicts the results of a study on the effect of the test compound on PlOO gating.
  • the standard errors of each mean are noted in the legend.
  • the bars left to right represent placebo, 0.3 mg test compound, and 1.0 mg test compound
  • the standard errors of each mean are noted in the legend.
  • the bars left to right represent placebo, 0.3 mg test compound, and 1.0 mg test compound.
  • FIGURE 3 depicts that results of a study on the effect of the test compound on MMN amplitude and POO amplitude.
  • the standard errors of each mean are noted in the legend.
  • the bars left to right represent placebo, 0.3 mg test compound, and 1.0 mg test compound.
  • the standard errors of each mean are noted in the legend.
  • the bars left to right represent placebo, 0.3 mg test compound, and 1.0 mg test compound.
  • (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide can improve cognition at an unexpectedly low free plasma concentration, it is less likely to elicit harmful side-effects on its own and is less likely to exhibit harmful interactions with other drugs. Due to the unexpectedly low free plasma concentration required and the long half-life, (R)-7- chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide is expected to have special drug properties. These properties include a high margin of safety and a favorable dosing regimen (e.g., once daily dosing), both of which are highly advantageous for treating patients with cognitive defects as well as patients that are required to take additional medications.
  • Impairment of the ability of central nervous system to inhibit irrelevant sensory information has long been used as a model for understanding the deficits of attention seen in schizophrenic patients.
  • Two approaches to the measurement of this ability have commonly been employed (see (Heinrichs, 2004; Potter et al., 2006; Turetsky et al., 2007; Umbricht and Krljes, 2005) for reviews and meta-analyses): (1) the sensory gating paradigm in which the presentation of one stimulus normally suppresses the response elicited by a stimulus which rapidly follows it. Schizophrenic patients typically exhibit less suppression (gating) of the second response. (2) the oddball or orienting paradigm in which a rare or unexpected event elicits a diminished response in schizophrenic patients because attentional resources are inappropriately focused on less salient aspects of the environment.
  • Two responses are commonly used assess brain activity: (1) the auditory P50 response elicited by the second member of a pair of clicks; and (2) the mismatch negativity (MMN) or N2 response evoked by a rarely occurring pure tone of no instructed relevance to the patient.
  • Abnormalities in both P50 gating and the MMN have been reported in schizophrenic patients. Described below are studies assessing both of these responses in patients treated with (R)-7- chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride salt ("the test compound”). Also presented below are studies assessing the influence of the test compound on the NlOO and P300 components of the evoked response. These components emerge after the P50 component and are as much related to attention to, and memory for, task relevant stimuli as to the neural processes by which task irrelevant stimuli are filtered (Turetsky et al., 2007; and Sandman and Patterson, 2000).
  • the neurobiology of the MMN is more complex. Imaging studies suggest that the primary and secondary auditory cortices in the temporal lobe are important for its generation (Naatanen and Alho, 1995). The dorsolateral prefrontal cortex also contributes (Schall et al., 2003). The neurotransmitter systems underlying the MMN are understudied and largely unknown. Yet, as is the case for P50, nicotinic cholinergic systems appear important (Baldeweg et al., 2006; Dunbar et al., 2007).
  • test described above were used to study the effect of the test compound on cognition in patients suffering from schizophrenia. Prior to testing the patient were dosed with: 1 mg of the test compound daily, 0.3 mg of the test compound daily or were administered a placebo for 20 days. Subjects were tested as described below.
  • Electrodes were collected from 63 tin electrodes positioned by an electrode cap (Compumedics Neuroscan, Inc.). Additional electrodes of the same type were applied to the mid-forehead (ground) and in a vertical orientation above and below the left eye. Interelectrode impedances were maintained below 10 kOhms. All recordings were made with the subject sitting upright and relaxed but awake.
  • the EEG and eye movement signals were sampled by an analog-to-converter programmed to retain EEG activity from 50 msec preceding to 325 msec following click onset.
  • the sampling rate was 1000 Hz.
  • the digitized signals were stored in a database for subsequent analysis.
  • the 150 sweeps of Sl and S2 responses were screened and sweeps with voltage deviations greater than 100 microvolts in the eye movement channels were rejected. The remaining accepted sweeps were formed into time point averages. While blinded to group assignment, the investigator visually examined the evoked potential waveforms at the FCz electrode site. When possible, the investigator identified a negative trough immediately prior to the P50, the P50 itself, and the following NlOO component. Admittedly, a distinct P50 component could not be visually identified in all patients at all time points. In those cases, the data were coded as missing.
  • P50 response amplitude was calculated as the voltage difference between the P50 peak and the preceding negative trough.
  • the P50 gating ratio was then calculated after (Olincy et al., 2006) as the amplitude of the P50 response to the second (test) stimulus divided by the amplitude of the P50 response to the first (conditioning) stimulus. A small gating ratio is considered normal or optimal.
  • the P50 amplitude difference (Fuerst et al., 2007) was also measured. It was the amplitude of the conditioning stimulus P50 response minus the amplitude of the test stimulus P50 response. A large P50 amplitude difference indicates normal gating.
  • NlOO amplitude was calculated as the peak voltage of NlOO minus the average voltage during the brief, 50 msec prestimulus period. As was the case for P50, NlOO responses to the conditioning and test stimuli were calculated as ratios as well as differences.
  • the MMN and P300 components were elicited during the so-called oddball sequence.
  • the stimulus sequence was a series of lower (500 Hz) and higher (1000 Hz) pitched pure tones presented at a rate of 1 tone per 0.6 sec.
  • the tones were 50 msec in duration, 50 dB above hearing level, and randomly interspersed.
  • the higher pitched tone was the oddball event. Across the series of 600 tones, it occurred at a probability of 0.2.
  • the other tone occurred at the complementary probability of 0.8. Patients were instructed to ignore the tones and instead attend to a magazine held in the lap.
  • EEG and EOG activity were digitized at a rate of 500 Hz per channel for 50 msec preceding and 500 msec following stimulus onset. Trials contaminated by eyeb links or eye movements were removed.
  • the MMN was measured by an automated algorithm that computed the summed amplitude, relative to the prestimulus baseline, over a 100- 200 msec time window following the onsets of the rare (oddball) and frequent tones. MMN was then recalculated as the voltage difference between these responses.
  • P300 amplitude was measured at the Pz electrode site as the peak amplitude between 250 and 500 msec following stimulus onset.
  • Figure 1 presents the results of simple analyses of co variance wherein all time points during the treatment period with valid data were averaged together to yield a single value. This value was then adjusted by regressing it against the baseline value and estimating a new value as if all patients possessed the same baseline. Then, a simple F test was performed. In support of the assumption of no significant differences between the treatment groups at the baseline (i.e., before treatment), we conducted simple ANOVAs evaluating the effect of treatment on all of the evoked potential components discussed presently. In no case did treatment significantly affect the baseline value.
  • the right panel of Figure 1 shows the P50 amplitude difference score — a metric with superior reliability. It likewise shows normalization at the high dose.
  • Figure 2 presents an identical analysis of the NlOO gating ratio and amplitude difference.
  • In the left panel of Figure 2 normalization is suggested by a lower score.
  • MMN was calculated as the voltage difference over 100-200 msec post-stimulus onset between the responses to the rare and frequent stimuli. A more negative MMN suggests normal cognitive function.
  • P300 is not entirely independent of MMN.
  • P300 was calculated as the peak amplitude relative to the average voltage of the waveform during the 50 msec prestimulus period. A more positive P300 response is indicative of improved cognitive function.
  • P300 is maximal in amplitude when the eliciting stimulus is both rare and task relevant (i.e., attended). In the present study, the rare stimulus was not task relevant.
  • P300 amplitude is very small in comparison to amplitudes recorded under active task conditions.
  • the present P300 component is more similar to the small, frontally-generated P300a described by Knight and colleagues than the large, parietally- generated P300b described in most studies of attentional dysfunction in schizophrenia.
  • the relative sensitivity or insensitivity of various evoked response components to the test compound may be related to their size and reliability of measurement.
  • sensitivity differences may relate to differences across the components in their neural generators and innervation by cholinergic afferents.
  • the two components (MMN and P300) which were most sensitive to the test compound are generated or modulated by frontal cortical pathways that receive input from brainstem cholinergic fibers.
  • the P50 is, in contrast, generated subcortically.
  • test compound The impact of the test compound on cognition in normal subjects was assessed as described below. In these studies subjects were treated with the test compound dissolved in cranberry juice.
  • test compound The impact of the test compound on cognition in normal subjects was assessed in a SAD (Single Ascending Dose) study with the Digit Symbol Substitution Test (DSST). Utilizing this test, the test compound was shown to have pro-cognitive effects at daily a dose as low as 1 mg. This is unexpected since acetylcholine esterase inhibitors, which indirectly activates the alpha 7 receptor by increasing acetylcholine levels, are not understood to exhibit pro-cognitive effects in normal subject and even in patients with cognitive impairment are not understood to exhibit pro- cognitive effects after a single dose. The positive effects of the test compound in the DSST indicate a beneficial effect on working memory and executive function.
  • the test compound was shown to have pro-cognitive effects at daily a dose as low as 1 mg.
  • the CogState battery is a proprietary computerized cognitive battery of tests measure various cognitive domains including: attention, identification capability, working memory, visual memory, and executive function.
  • the test compound was found to have a positive impact on: visual motor skills, learning, executive function, and delayed memory.
  • the profile of the response was unique insofar as the test compound had positive effects on non-verbal learning and memory and executive function without having a stimulatory effect on attention.
  • a small molecule drug In order for a small molecule to exert action at its target, often a cell receptor, it must bind to its target.
  • a small molecule drug is expected to exhibit activity when the free drug concentration at the target (i.e., the concentration of drug that is free and available to bind to the target) approaches or exceeds the K 1 of the drug for target.
  • the free drug concentration at the target i.e., the concentration of drug that is free and available to bind to the target
  • the free drug concentration in a particular tissue is about equal to the free drug concentration in plasma (Mauer et al 2005 and Tf ainor 2007).
  • the free plasma concentration is generally considered to represent the maximum possible free drug concentration.
  • the total plasma drug concentration and the fraction that binds to plasma protein can both be measured using techniques known to those of skill in the art.
  • the maximum plasma concentration was determined and used to calculate the maximum free drug concentration which was used to determine the maximum free drug concentration as a fraction of the ECref of the drug for human alpha7 receptor and the maximum free drug concentration as a fraction of the K 1 of the drug for rat brain alpha7 receptors.
  • the EC re f the concentration of drug which elicits equal response in oocytes trans fected with cloned human alpha7 receptor at 50 ⁇ M acetylcholine (the endogenous receptor ligand), was determined to be 0.158 ⁇ M.
  • the K 1 for rat brain alpha7 receptors was determined to be 10 nM.
  • Table 2 presents half-life (Iy 2 ) data for (R)-7-chloro-N-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide obtained from pre-clinical species as well as the half-life in humans determined in clinical trials.
  • the half-life determined in rat and dog suggested a human half-life much shorter than the observed 60 hr half-life (initial allometric scaling suggested a half-life of about 8 hours).
  • the unexpectedly long half-life in humans has several advantages. It allows for once a day dosing.
  • the drug will also have a very small dynamic plasma range over the course of a day (about 15- 20%). Thus, if a patient misses a daily dose, the plasma level and the consequent brain level will not be altered by a great degree. This means that the beneficial effects of the drug will be less dependent upon careful adherence to a specific dosing scheme.
  • long half-life and slow elimination also mean that the final dose will be lower than expected.
  • Schizophrenia sensory gating, and nicotinic receptors. Schizophr Bull 24, 189-202.

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PCT/US2009/065173 2008-11-19 2009-11-19 Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof WO2010059844A1 (en)

Priority Applications (35)

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RU2011124515/15A RU2532327C2 (ru) 2008-11-19 2009-11-19 ЛЕЧЕНИЕ КОГНИТИВНЫХ РАССТРОЙСТВ (R)-7-ХЛОР-N-(ХИНУКЛИДИН-3-ИЛ) БЕНЗО[b] ТИОФЕН-2-КАРБОКСАМИДОМ И ЕГО ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМЫМИ СОЛЯМИ
AU2009316557A AU2009316557B2 (en) 2008-11-19 2009-11-19 Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl) benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
DK09756921.4T DK2355822T3 (da) 2008-11-19 2009-11-19 behandling af kognitive forstyrrelser med (R)-7-chlor-N-(quinuclidin-3-yl)benzoe[b]thiophen-2-carboxamid og farmaceutisk acceptable salte deraf
EP18152484.4A EP3357495B1 (en) 2008-11-19 2009-11-19 Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
ES09756921T ES2396300T3 (es) 2008-11-19 2009-11-19 Tratamiento de trastornos cognitivos con (R)-7-cloro-N-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida y sales farmacéuticamente aceptables de la misma
JP2011537621A JP5272080B2 (ja) 2008-11-19 2009-11-19 （Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びその製薬上許容しうる塩を用いた認知障害の治療
EP09756921A EP2355822B1 (en) 2008-11-19 2009-11-19 Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
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HK11113010.6A HK1158520A1 (en) 2008-11-19 2011-11-30 Treatment of cognitive disorders with (r)-7-chloro-n-(quinuclidin-3- yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
US13/674,290 US8569354B2 (en) 2008-11-19 2012-11-12 Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
HRP20130007AT HRP20130007T1 (hr) 2008-11-19 2013-01-03 Lijeäśenje kognitivnih poremeä†aja pomoä†u (r)-7-kloro-n-(kinuklidin-3-il)benzo[b]tiofen-2-karboksamida i njegovih farmaceutski prihvatljivih soli
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IL242035A IL242035A0 (en) 2008-11-19 2015-10-12 Treatment of cognitive disorders with (r)-7-chloro-(quinoclidin-3-yl)benzo[b]thiophene-2-carboxamide
US15/796,475 US20180271844A1 (en) 2008-11-19 2017-10-27 Treatment of Cognitive Disorders with (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-Carboxamide and Pharmaceutically Acceptable Salts Thereof
IL256140A IL256140A (en) 2008-11-19 2017-12-06 Treatment of cognitive disorders with (r)-7-chloro-(quinoclidin-3-yl)benzo[b]thiophene-2-carboxamide
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