WO2011103448A1 - Procédés et compositions pour traiter des troubles psychotiques utilisant une thérapie d'association antipsychotique - Google Patents

Procédés et compositions pour traiter des troubles psychotiques utilisant une thérapie d'association antipsychotique Download PDF

Info

Publication number
WO2011103448A1
WO2011103448A1 PCT/US2011/025461 US2011025461W WO2011103448A1 WO 2011103448 A1 WO2011103448 A1 WO 2011103448A1 US 2011025461 W US2011025461 W US 2011025461W WO 2011103448 A1 WO2011103448 A1 WO 2011103448A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
agent
unsubstituted
antipsychotic
Prior art date
Application number
PCT/US2011/025461
Other languages
English (en)
Inventor
Marco Giorgetti
David T. Hung
Andrew Asher Protter
Original Assignee
Medivation Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivation Technologies, Inc. filed Critical Medivation Technologies, Inc.
Publication of WO2011103448A1 publication Critical patent/WO2011103448A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine

Definitions

  • Psychitic disorders have a dramatic effect on the health and quality of life of individuals who suffer from these mental illnesses. Psychotic disorders usually first appear when a person is in his or her late teens, 20s, or 30s. When symptoms are severe, people with psychotic disorders have difficulty staying in touch with reality and often are unable to meet the ordinary demands of daily life. These individuals may require significant custodial care and continuous drug and/or behavior therapy. Current therapy demonstrates limited clinical benefits. Psychotic disorders affect approximately 1% of the population worldwide, resulting in major socioeconomic burdens on society.
  • Psychotic disorders are characterized by a wide spectrum of symptoms. In many cases, they do not only involve solely psychotic symptoms, such as hallucinations and delusions, but have also symptoms in other domains which impact the well-being of the individual suffering from such a disorder.
  • positive symptoms e.g., hallucinations and delusions
  • negative symptoms e.g., blunted emotions and lack of interest
  • disorganized symptoms e.g., disorganized thinking and speech, or disorganized perception and behavior
  • cognitive symptoms e.g., deficits in attention, working memory, verbal learning, and problem solving.
  • a wide range of antipsychotic therapies have been developed to date.
  • a first generation of antipsychotics known as typical antipsychotics was discovered in the 1950s. These generation of antipsychotics (e.g., haloperidol and chlorpromazine) was characterized primarily by high affinity for D2 dopamine receptors and was mostly effective in treating the positive symptoms exhibited by schizophrenic patients (Roth BL et al., Nat Rev Drug Discov 2004, 3 (4): 353 -9).
  • the discovery of clozapine inspired the development of the next generation of antipsychotics, the atypical antipsychotics.
  • atypical antipsychotic drugs are characterized by a relatively low D2 occupancy at therapeutic doses (Yokoi F et al., Neuropsychopharmacology 2002, 27 (2): 248 -59; Nyberg S et al., Br J Psychiatry 1996, 29 (Suppl): 40 -4).
  • many atypical antipsychotics show 5-HT2A antagonist activity.
  • EPS extrapyramidal syndrome
  • NMS neuroleptic malignant syndrome
  • Atypical antipsychotics which are considered 'atypical' owing to their reduced EPS and serum prolactin elevation liabilities, carry their own unique side-effect profile, including weight gain and metabolic syndrome (Gray JA et al., Mol Psychiatry 2007, 12 (10): 904 -22).
  • the invention embraces combination therapies having a first compound and a second agent, where the first compound is compound I as detailed herein and the second agent is an antipsychotic.
  • the second agent may be either a typical antipsychotic or an atypical antipsychotic or a combination of an atypical and a typical antipsychotic (in which case the second agent could contain at least two different compounds).
  • the invention particularly embraces a
  • the first compound is compound I and the second agent is an atypical antipsychotic, especially risperidone (3-[2-[4-(6-fluoro-l,2-benzoxazol-3- yl)piperidin-l-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[2,l-b]pyrimidin-4-one) and/or a typical antipsychotic, or a pharmaceutically acceptable salt of any of the foregoing.
  • the antipsychotic component of the combination therapy is an atypical antipsychotic
  • the antipsychotic component of the combination therapy is a typical antipsychotic
  • the invention provides a method of treating, preventing, delaying the onset and/or the development of a psychotic disorder in an individual in need thereof, comprising administering to the individual in need thereof an effective amount of a combination therapy comprising compound I and a second agent or pharmaceutically acceptable salt of any of the foregoing, wherein the second agent is an antipsychotic.
  • the individual is in need of improved cognition.
  • the psychotic disorder is characterized by causing at least one psychotic symptom and at least one cognitive symptom.
  • the administration of compound I of the combination therapy enhances the antipsychotic effect of the second agent (e.g., risperidone) compared to the administration of the second agent (e.g., risperidone) in the absence of compound I.
  • the second agent (e.g., risperidone) of the combination therapy is administered in a dosage that is less than that required for the same second agent (e.g., risperidone) monotherapy (or dual therapy where an atypical antipsychotic is administered in connection with a typical antipsychotic) to elicit a comparable antipsychotic effect.
  • the invention further includes methods of treating, preventing, delaying the onset and/or the development of a psychotic disorder by administering a combination therapy comprising compound I and an antipsychotic wherein the combination therapy is administered in an amount effective to improve cognition of a psychotic disorder or a cognitive symptom of a disorder characterized by causing at least one psychotic symptom and at least one cognitive symptom.
  • the invention embraces combination therapies that elicit cognitive improvement in an individual.
  • the invention embraces methods that enhance an individual's cognitive ability (improves cognition/lessens the number and/or severity of cognitive symptoms associated with a psychotic disorder) to a greater extent than use of an antipsychotic as an
  • the method is a method of shortening the onset of an antipsychotic effect compared to the onset of an antipsychotic effect produced by an antipsychotic in the absence of compound I by administering to an individual an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the onset of antipyschotic effect is shortened by about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 4 days, about 5 days, about 6 days, or about 7 days.
  • the method is a method of reducing one or more side effects suffered by the individual receiving the second agent (e.g., risperidone) in the absence of compound I.
  • the side effects suffered by the individual receiving the second agent (e.g., risperidone) in the absence of compound I include, but are not limited to, any one or more of catalepsy, extrapyramidal syndrome (EPS), weight gain, serum prolactin elevation, metabolic syndrome, dry mouth, muscle stiffness, muscle cramping, tremors, tardive dyskinesia, acute dyskinesia, acute dystonia, neuroleptic malignant syndrome (NMS), diabetes type 2, hyperlipidemia, hyperglycemia, hypertension, drowsiness, and akathisia.
  • EPS extrapyramidal syndrome
  • NMS neuroleptic malignant syndrome
  • the invention provides methods of improving cognition in an individual in need thereof by administering a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • cognition is improved in an individual suffering from a psychotic disorder.
  • cognition is improved in an individual suffering from a disorder characterized by causing at least one psychotic symptom and at least one cognitive symptom.
  • improving cognition comprises reducing at least one symptom associated with cognition impairment.
  • the invention is directed to methods of (i) improving cognition and (ii) reducing symptoms associated with psychotic disorders in an individual in need thereof.
  • the psychotic disorder is schizophrenia.
  • the method is a method of alleviating one or more positive symptoms of schizophrenia by administering to an individual an effective amount of the combination therapy.
  • the method is a method of alleviating one or more negative symptoms of schizophrenia by administering to an individual an effective amount of the combination therapy.
  • the method is a method of alleviating one or more disorganized symptoms of schizophrenia by administering to an individual an effective amount of the combination therapy.
  • the method is a method of alleviating one or more cognitive symptoms of schizophrenia (e.g., positive, negative, cognitive, and disorganized symptoms) by administering to an individual an effective amount of the combination therapy.
  • the method is a method of alleviating one or more symptoms of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a positive and a negative symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a positive and a disorganized symptom of schizophrenia. In some
  • the method is a method of alleviating a positive and a cognitive symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a negative and a disorganized symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a negative and a cognitive symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a cognitive and a disorganized symptom of schizophrenia by administering to an individual an effective amount of the combination therapy.
  • the method is a method of alleviating a positive, a negative, and a cognitive symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a positive, a negative, and a disorganized symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a negative, a cognitive, and a disorganized symptom of schizophrenia by administering to an individual an effective amount of the combination therapy. In some embodiments, the method is a method of alleviating a positive, a cognitive, and a
  • the method is a method of alleviating a positive, a negative, a cognitive, and a disorganized symptom of schizophrenia by administering to an individual an effective amount of the combination therapy.
  • the invention also embraces pharmaceutical compositions of the combination therapy, including unit dosage forms thereof.
  • the combination therapy employs an antipsychotic that is an atypical antipsychotic.
  • the combination therapy employs an antipsychotic that is a typical antipsychotic.
  • the invention also embraces kits of the combination therapy described herein.
  • kits comprising (a) a compound I, or a pharmaceutically acceptable salt thereof; (b) a second agent, wherein the second agent is an antipsychotic, or a pharmaceutically acceptable salt thereof; and (c) instructions for achieving an antipsychotic effect.
  • the kits may optionally include instructions for achieving both an antipsychotic effect and a cognitive effect for treating, preventing, delaying the onset, and/or the development of a psychotic disorder.
  • a method of treating a psychotic disorder in an individual in need thereof comprises administering to the individual an effective amount of a combination therapy comprising: (1) compound I wherein the compound is of the formula (Tbl) or (Tb2):
  • R 1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, Ci-C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbony
  • each R 2a and R 2b is independently H, substituted or unsubstituted Ci-C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety;
  • each R 3a and R 3b is independently H, substituted or unsubstituted Ci-C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together to form a carbonyl moiety;
  • each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;
  • each R 4 is independently hydroxyl, nitro, cyano, halo, Ci-C 8 perhaloalkyl, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci-C 8 perhaloalkoxy, Ci-C 8 alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
  • R 12 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, or Ci-C 8 perhaloalkyl
  • compound I is of the formula (I-bl). In another aspect of the method, compound I is of the formula (I-b2). In one variation of compound (I- bl) or (I-b2) R 12 is an unsubstituted Ci-C 8 alkyl, such as methyl. In any of the preceding embodiments and variations, in one aspect, R 2a , R 2b , R 3a , R 3b , R 10a and R 10b of formula (I-bl) or (I-b2) are each H.
  • each of R 2a , R 2b , R 3a and R 3b is H and at least one of R 10a and R 10b is an unsubstituted Ci-C 8 alkyl, such as methyl.
  • R 1 is an unsubstituted Ci-C 8 alkyl, such as methyl.
  • At least two of X 7 , X 8 , X 9 and X 10 are CH, such as when X 7 , X 8 and X 10 are each CH and X 9 is CR 4 where R 4 is an unsubstituted Ci-C 8 alkyl (e.g., methyl) or halo (e.g., fluoro or chloro).
  • compound I is selected from the group consisting of: (E)-
  • the second agent is a typical antipsychotic, atypical antipsychotic, or a combination of an atypical and a typical antipsychotic.
  • the second agent is an atypical antipsychotic.
  • the second agent is risperidone.
  • the individual in one aspect is in need of improved cognition. In any of the preceding embodiments, in one aspect the individual has at least one psychotic symptom and at least one cognitive symptom of a psychotic disorder.
  • administering enhances the antipsychotic effect of the second agent compared to the administration of the second agent in the absence of compound I.
  • the second agent is administered at a dosage amount that is less than that required for the second agent as an individual therapy to elicit a comparable antipsychotic effect.
  • the method shortens the onset of an antipsychotic effect compared to the onset of an
  • a side effect is selected from the group consisting of catalepsy, extrapyramidal syndrome (EPS), weight gain, serum prolactin elevation, metabolic syndrome, dry mouth, muscle stiffness, muscle cramping, tremors, tardive dyskinesia, acute dyskinesia, acute dystonia, neuroleptic malignant syndrome (NMS), diabetes type 2, hyperlipidemia, hyperglycemia, hypertension, drowsiness, and akathisia.
  • EPS extrapyramidal syndrome
  • NMS neuroleptic malignant syndrome
  • the psychotic disorder is schizophrenia.
  • compositions comprising compound I according to any of the preceding embodiments, or a salt or solvate thereof, and a second agent, wherein the second agent is an antipsychotic, are also provided.
  • the second agent may be a typical antipsychotic, atypical antipsychotic, or a combination of an atypical and a typical antipsychotic. In a particular variation, it is an atypical antipsychotic. In a more particular variation, the second agent is risperidone.
  • the composition comprises compound I and the second agent in a pharmaceutically acceptable carrier.
  • the composition in one aspect contains compound I and the second agent in a single unit dosage form.
  • Kits are also provided and described herein, such as kits comprising a compound I according to any of the preceding embodiments and variations, or a salt or solvate thereof, and a second agent, wherein the second agent is an antipsychotic.
  • the kit further comprises instructions for use in treating a psychotic disorder. The instructions may also detail use of compound I and the second agent to achieve a cognitive effect.
  • Figure 1 shows number of avoidance responses observed before and after treatment in (vehicle p.o. + saline s.c.) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c] groups, (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg, s.c.)] groups, (vehicle p.o.
  • Figure 2 shows changes between number of avoidance responses observed after administration and number of avoidance responses observed before administration of (vehicle p.o. + saline s.c), [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c], (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)), [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg, s.c.)], (vehicle p.o.
  • Figure 3 shows number of escape failures observed before and after treatment in (vehicle p.o. + saline s.c.) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c] groups, (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg,s.c.)] groups, (vehicle p.o.
  • Figure 4 shows changes between number of escape failures observed after administration and number of escape failures observed before administration of (vehicle p.o. + saline s.c), [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c], (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)), [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg, s.c.)], (vehicle p.o.
  • Figure 5 shows number of intertrial crossings observed before and after administration in (vehicle p.o. + saline s.c.) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c] groups, (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)) group, [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg, s.c.)] groups, (vehicle p.o.
  • Figure 6 shows changes between number of intertrial crossings observed after administration and number of intertrial crossings observed before administration of (vehicle p.o. + saline s.c), [Compound A (0.03 or 0.1 mg/kg, p.o.) + saline s.c], (vehicle p.o. + risperidone (0.1 mg/kg, s.c.)), [Compound A (0.03 or 0.1 mg/kg, p.o.) + risperidone (0.1 mg/kg, s.c.)], (vehicle p.o.
  • Figure 7 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • Time required to achieve 15 seconds of object exploration during Tl (duration of Tl) is expressed as means + SEM.
  • n number of rats per group.
  • Figure 8 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • Locomotor activity is expressed as means + SEM of lines crossed/min during Tl.
  • n number of rats per group. *: p ⁇ 0.05 versus (vehicle + scopolamine) group (inter-group analysis: two-tailed Student's t test for independent samples).
  • Figure 9 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • Time spent by rats exploring the novel and familiar objects during T2 is expressed as means + SEM.
  • n number of rats per group. ##: p ⁇ 0.01 and ###: p ⁇ 0.001 versus novel object (intra-group analysis: two-tailed Student's t test for paired samples).
  • Figure 10 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • Delta (TN-TF) is expressed as means + SEM.
  • n number of rats per group. *: p ⁇ 0.05, **: p ⁇ 0.01 and ***: p ⁇ 0.001 versus (vehicle + scopolamine) group (inter- group analysis: one-way ANOVA followed by a Dunnett' s test for Compound A groups or two-tailed Student's t test for independent samples for donepezil group).
  • Figure 11 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • n number of rats per group. *: p ⁇ 0.05, **: p ⁇ 0.01 and ***: p ⁇ 0.001 versus (vehicle + scopolamine) group (inter-group analysis: oneway ANOVA followed by a Dunnett' s test for Compound A groups or two-tailed Student's t test.
  • Figure 12 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat novel object recognition test.
  • Good learners are expressed as percentage of animals with N-F > 5 s during T2.
  • n number of rats per group. No statistical analysis was performed t for independent samples.
  • Figure 13 shows effects of a single oral administration of vehicle, Compound A (0.03, 0.1, 0.3 or 1 mg/kg, p.o.) or donepezil (1 mg/kg) in situation of scopolamine-induced memory deficit in the rat object recognition model.
  • Locomotor activity is expressed as means + SEM of crossed lines/min during T2.
  • n number of rats per group.
  • Figure 14 shows effect of Compound A on catalepsy. The time the mice spent holding bar was averaged over the 3 trials at each time point. Data represent mean + SEM
  • Figure 15 shows effect of Compound A on haloperidol-induced catalepsy. The time the mice spent holding bar was averaged over the 3 trials at each time point. Data represent mean + SEM.
  • the present invention provides methods, compositions, and kits for use in combination therapy for treating, preventing, delaying the onset and/or the development of (i) a psychotic disorder in an individual in need thereof, (ii) a psychotic disorder in an individual who is also in need of improved cognition, or (iii) a disorder characterized by causing at least one psychotic symptom and at least one cognitive symptom in an individual in need thereof, comprising compound I and a second agent or pharmaceutically acceptable salt of any of the foregoing, wherein the second agent is an antipsychotic
  • a 5-HT 2A modulator e.g., compound A
  • an antipsychotic e.g., risperidone
  • a 5-HT 2A modulator e.g. compound A
  • Compound I e.g., compound A in combination with an antipsychotic is believed to 1) provide amelioration of cognitive impairment, thus
  • Reference to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.
  • delay means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
  • an individual as used herein intends a mammal, including but not limited to a human, bovine, primate, equine, canine, feline, porcine, and ovine animals.
  • the invention finds use in both human medicine and in the veterinary context, including use in agricultural animals and domestic pets.
  • the combination therapy or "a combination therapy” is meant a therapy comprising a first compound and a second agent, wherein the first compound is compound I or a pharmaceutically acceptable salt thereof as described herein and the second agent is an antipsychotic and where the first compound is used in conjunction with the second agent.
  • a therapy comprising compound I used in conjunction with risperidone is an example of a combination therapy according to the invention.
  • Administration of a first compound "in conjunction with" a second agent includes administration of the compounds in the same or a different composition, either sequentially, simultaneously, or continuously. Administration in conjunction is meant to encompass any circumstance wherein a first compound and a second agent are administered in an effective amount to an individual.
  • the first compound and the second agent can be administered at different dosing frequencies and/or intervals and may be administered using the same route of administration or different routes of administration.
  • administration "in conjunction with” embraces a dosing regimen whereby a first compound of the combination therapy is administered three times daily and a second agent of the combination therapy is administered once daily and wherein the first daily dose of the first compound is administered simultaneously with the second agent and where the second and the third daily doses of the first compound are administered alone (in the absence of a second agent).
  • different dosing regimens may change over the course of administration.
  • a combination therapy comprising compound I and risperidone
  • compound I may be administered daily and risperidone may be administered weekly or less than daily.
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • the compounds in a combination therapy of the invention may be administered sequentially, simultaneously, or continuously using the same or different routes of administration for each compound.
  • the combination therapy can be part of a treatment scheme or regimen.
  • the first compound and the second agent can be administered as a treatment scheme or regimen with another compound previously administered in an individual.
  • the first compound or “a first compound” includes and refers to compound I (e.g., a compound of the formula (I-bl) or (I-b2), such as compound A) or pharmaceutically acceptable salt or other form thereof as described herein.
  • the second agent or "a second agent” of a combination therapy includes and refers to an antipsychotic or pharmaceutically acceptable salt thereof.
  • cognitive disorders refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and/or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and/or thinking).
  • cognition e.g., memory, attention, perception and/or thinking
  • pathogen-induced cognitive dysfunction e.g. HIV associated cognitive dysfunction and Lyme disease associated cognitive dysfunction.
  • cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia (such as cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia), amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age- associated memory impairment (AAMI).
  • cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia (such as cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia), amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age- associated memory impairment (AAMI).
  • cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia (such as cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia), amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI
  • schizophrenia refers to a chronic, mental disorder characterized by one or more positive symptoms (e.g., delusions and hallucinations) and/or negative symptoms (e.g., blunted emotions and lack of interest) and/or disorganized symptoms (e.g., disorganized thinking and speech or disorganized perception and behavior) and cognitive impairment (e.g. working memory, executive function, attention etc.).
  • positive symptoms e.g., delusions and hallucinations
  • negative symptoms e.g., blunted emotions and lack of interest
  • disorganized symptoms e.g., disorganized thinking and speech or disorganized perception and behavior
  • cognitive impairment e.g. working memory, executive function, attention etc.
  • Schizophrenia as used herein includes all forms and classifications of schizophrenia known in the art, including, but not limited to catatonic type, hebephrenic type, disorganized type, paranoid type, residual type or undifferentiated type schizophrenia and deficit syndrome and/or those described in American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington D.C., 2000 or in International Statistical Classification of Diseases and Related Health Problems, or otherwise known to those of skill in the art.
  • Treatment of schizophrenia can include an improvement in one or more of: cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia.
  • Cognitive impairment associated with schizophrenia includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits are believed to be linked to impairment in functional status (e.g., social behavior, work performance, and activities of daily living).
  • ADHD attention-deficit hyperactivity disorder
  • ADHD refers to a chronic disorder that initially manifests in childhood and is characterized by hyperactivity, impulsivity, and/or inattention. ADHD is characterized by persistent patterns of inattention and/or impulsivity-hyperactivity that are much more extreme than is observed in individuals at the same developmental level or stage. There is considerable evidence, from family and twin studies, that ADHD has a significant genetic component. This disorder is thought to be due to an interaction of environmental and genetic factors. ADHD includes all known types of ADHD.
  • DSM-IV Diagnostic & Statistical Manual for Mental Disorders identifies three subtypes of ADHD: (1) ADHD, Combined Type which is characterized by both inattention and hyperactivity- impulsivity symptoms; 2. ADHD, Predominantly Inattentive Type which is characterized by inattention but not hyperactivity- impulsivity symptoms; and 3. ADHD, Predominantly Hyperactive- Impulsive Type which is characterized by Hyperactivity-impulsivity but not inattention symptoms.
  • attention-deficit disorder refers to a disorder in processing neural stimuli that is characterized by distractibility and impulsivity that can result in inability to control behavior and can impair an individual's social, academic, or occupational function and development.
  • ADD may be diagnosed by known methods, which may include observing behavior and diagnostic interview techniques.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Unit dosage forms may contain a single or a combination therapy.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • a pharmaceutically acceptable salt intends ionic interactions and not a covalent bond. As such, an N-oxide is not considered a salt.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et ah, Pharmaceutical Salts, J. Pharm. Sci. 1977
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • treatment is an approach for obtaining a beneficial or desired result, including clinical results.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
  • an effective amount intends such amount of a compound (e.g., a component of a combination therapy of the invention) or a combination therapy, which should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays, animal models, or human testing.
  • An effective amount of a combination therapy includes an amount of the first compound and an amount of the second agent that, when administered sequentially, simultaneously, or continuously, should produce a desired outcome.
  • a first compound e.g., compound I
  • a second agent in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first compound and second agent may be contained in the same composition (e.g., a composition comprising both compound I and an antipsychotic such as the atypical antipsychotic risperidone and/or a typical antipsychotic such as perfenazine) or in separate compositions (e.g., compound I is contained in one composition and an antipsychotic such as the atypical antipsychotic risperidone is contained in another composition).
  • sequential administration means that the first compound and a second agent in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes. Either the first compound or the second agent may be administered first.
  • the first compound and second agent for a sequential administration are contained in separate compositions, which may be contained in the same or different packages or kits.
  • psychotic disorders refers to and intends mental diseases or conditions that are believed to cause or do cause abnormal thinking and perceptions.
  • antipsychotic refers to and encompasses an atypical and/or a typical antipsychotic.
  • the term "atypical antipsychotic” intends an antipsychotic that reduces or eliminates an activity of a 5-HT 2A receptor and a D2 receptor.
  • typical antipsychotic intends an antipsychotic that reduces or eliminates primarily an activity of a dopamine-2 (D2) receptor in a reversible or irreversible manner.
  • statin receptor modulator intends and encompasses a compound that binds to or inhibits binding of a ligand to a serotonin receptor or reduces or eliminates or increases or enhances or mimics an activity of a serotonin receptor.
  • a “serotonin receptor modulator” encompasses both a serotonin receptor antagonist and a serotonin receptor agonist.
  • the term "dopamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a dopamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine receptor. As such, a “dopamine receptor modulator” encompasses both a dopamine receptor antagonist and a dopamine receptor agonist.
  • the term “histamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a histamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine receptor. As such, a “histamine receptor modulator” encompasses both a histamine receptor antagonist and a histamine receptor agonist.
  • the term “enhanced” refers to greater than the antipsychotic effect produced by a first compound or a second agent alone, additive antipsychotic effect, or synergistic (e.g., greater than additive) antipsychotic effect.
  • Alkyl refers to and includes saturated linear, branched, or cyclic univalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a "Ci-C 8 alkyl”).
  • butyl is meant to include w-butyl, sec-butyl, zso-butyl, tert-butyl and cyclobutyl;
  • propyl includes w-propyl, zso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, i-butyl, w-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like.
  • Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
  • a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • a preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms.
  • a more preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 - C 8 cycloalkyl").
  • Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkylene refers to the same residues as alkyl, but having bivalency.
  • alkylene include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • Cycloalkenyl is a subset of alkenyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl.
  • a more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkenyl").
  • Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • Alkynyl refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms and the like.
  • Substituted alkyl refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl,
  • aminocarbonylamino aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
  • Substituted alkenyl refers to alkenyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl,
  • aminocarbonylamino aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl,
  • aminocarbonylamino aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl- C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic-C(
  • Acyloxy refers to the groups H-C(0)0-, alkyl-C(0)0-, substituted alkyl- C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl- C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, substituted aryl- C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Heterocycle refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the rings can be aryl or heteroaryl.
  • a heterocycle having more than one ring where at least one ring is aromatic may be connected to the parent structure at either a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.
  • Substituted heterocyclic or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino
  • Aryl or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • the aryl group contains from 6 to 14 annular carbon atoms.
  • An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Heteroaryl or “HetAr” refers to an unsaturated aromatic carbocyclic group having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • a heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Substituted aryl refers to an aryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,
  • Substituted heteroaryl refers to a heteroaryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl,
  • aminocarbonylamino aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or
  • Aralkyl refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue.
  • an aralkyl is connected to the parent structure via the alkyl moiety.
  • an aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety.
  • a “substituted aralkyl” refers to a residue in which an aryl moiety is attached to a substituted alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue.
  • an aralkyl is connected to the parent structure via the alkyl moiety, it may also be referred to as an "alkaryl". More particular alkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety (a "C 1 -C3 alkaryl").
  • Alkoxy refers to the group alkyl-O-, which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, 1,2-dimethylbutoxy, and the like.
  • alkenyloxy refers to the group “alkenyl - 0-"
  • alkynyloxy refers to the group “alkynyl-O-”.
  • Substituted alkoxy refers to the group substituted alkyl-O.
  • Substituted amino refers to the group -NR a R b , where either (a) each R a and R group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, provided that both R a and R groups are not H; or (b) R a and R b are joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
  • Acylamino refers to the group -C(0)NR a R b where R a and R b are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or R a and R b groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.
  • Aminoacyl refers to the group -NR a C(0)R b where each R a and R b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • R a is H or alkyl.
  • Aminosulfonyl refers to the groups -NRS0 2 -alkyl, -NRS0 2 substituted alkyl, - NRS0 2 -alkenyl, -NRS0 2 - substituted alkenyl, -NRS0 2 -alkynyl, -NRS0 2 - substituted alkynyl, -NRS0 2 -cycloalkyl, -NRS0 2 - substituted cycloalkyl, -NRS0 2 -aryl, -NRS0 2 -substituted aryl, - NRS0 2 -heteroaryl, -NRS0 2 -substituted heteroaryl, -NRS0 2 -heterocyclic, and -NRS0 2 - substituted heterocyclic, where R is H or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenyl, al
  • Sulfonylamino refers to the groups -S0 2 NH 2 , -S0 2 NR-alkyl, -S0 2 NR- substituted alkyl, -S0 2 NR-alkenyl, -S0 2 NR-substituted alkenyl, -S0 2 NR-alkynyl, -S0 2 NR- substituted alkynyl, -S0 2 NR-aryl, -S0 2 NR-substituted aryl, -S0 2 NR-heteroaryl, -S0 2 NR- substituted heteroaryl, -S0 2 NR-heterocyclic, and -S0 2 NR- substituted heterocyclic, where R is H or alkyl, or -S0 2 NR 2 , where the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring
  • Sulfonyl refers to the groups -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 - substituted alkenyl, -S0 2 -alkynyl, -S0 2 - substituted alkynyl, -S0 2 -aryl, -S0 2 - substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -S0 2 -heterocyclic, and -S0 2 -substituted heterocyclic.
  • Aminocarbonylalkoxy refers to the group -NR a C(0)OR b where each R a and R b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl.
  • Halo refers to elements of the Group 17 series having atomic number 9 to 85.
  • Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each H is replaced with a halo group is referred to as a "perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoroalkyl (-CF 3 ).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (-OCF 3 ).
  • Cyano refers to the group -CN.
  • Neitro refers to the group -N0 2 .
  • Thioalkyl refers to the groups -S-alkyl.
  • Alkylsulfonylamino refers to the groups -R 1 S0 2 NR a R b where R a and R are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or the R a and R groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring and R 1 is an alkyl group.
  • Carbonylalkoxy refers to as used herein refers to the groups -C(0)0-alkyl
  • -C(0)0-substituted alkyl -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-alkenyl, -C(0)0- substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-heteroaryl, - C(0)0-substituted heteroaryl, -C(0)0-heterocyclic or -C(0)0-substituted heterocyclic.
  • Gaminal refers to the relationship between two moieties that are attached to the same atom.
  • R 1 and R2 are geminal and R 1 may be referred to as a geminal R group to R .
  • Vicinal refers to the relationship between two moieties that are attached to adjacent atoms.
  • R 1 and R2 are vicinal and R 1 may be referred to as a vicinal R group to R .
  • a composition of "substantially pure” compound means that the composition contains less than about 15% or preferably less than about 10% or more preferably less than about 5% or even more preferably less than about 3% and most preferably less than about 1 % impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (S) compound means that the composition contains less than about 15% or less than about 10% or less than about 5% or less than about 3% or less than about 1 % of the (R) form of the compound.
  • Compound I modulates at least serotonin receptor 5-HT 2A - In certain aspects, compound I modulates serotonin receptor 5-HT 2A and does not modulate dopamine receptor D 2 , such as D 2L -In certain aspects, compound I modulates serotonin receptor 5-HT 2A and further modulates any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HTi A . In certain aspects, compound I modulates serotonin receptor 5-HT 2A and further modulates any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HT IA and does not modulate dopamine receptor D 2 , such as D 2L -
  • compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A -
  • compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A and weakly inhibits binding (e.g., by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%) of a ligand to dopamine receptor D 2 , such as D 2L -
  • compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A and binding of a ligand to any one or more of 5-HT 7 , 5- HT 6 and 5-HTi A .
  • compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A and binding of a ligand to any one or more of 5-HT 7 , 5-HT 6 and 5-HTi A and weakly inhibits binding (e.g., by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%) of a ligand to dopamine receptor D 2 , such as D 2L . Inhibition of binding in all aspects detailed herein is determined in a suitable assay known in the art, such as the assays described herein.
  • compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A by at least about 50%. In certain aspects, compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A by greater than about any of 50%, 60%, 70% or 80%. In certain aspects, compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A by at least about 80%. In certain aspects, compound I inhibits binding of a ligand to serotonin receptor 5-HT 2A by greater than about any of 80%, 85%, 90% or 95% or by about 100%. In certain aspects, compound I inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about 80%.
  • compound I inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about 50%. In certain aspects, compound I inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about 30%. In certain aspects, compound I inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • compound I inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5- HT 6 and 5-HTi A by at least about 50%. In certain aspects, compound I inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HT IA by greater than about any of 50%, 60%, 70% or 80%. In certain aspects, compound I inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HT IA by at least about 80%.
  • compound I inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HTi A by greater than about any of 80%, 85%, 90% or 95% or by about 100%. In certain aspects, compound I inhibits binding of a ligand to serotonin receptor 5-HT 2, by greater than about any of 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 100%, and inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • compound I inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HTi A by greater than about any of 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 100%, and inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • percent inhibition of binding to 5- HT 2A and/or 5-HT 7 and/or 5-HT 6 and/or 5-HTi A and/or D 2 is measured by assays detailed herein.
  • compound I inhibits binding of Ketanserin to 5-HT 2A as determined in the assays described herein. In certain aspects, compound I inhibits binding of LSD to 5- HT 6 and/or 5-HT 7 as determined in the assays described herein. In certain aspects, compound I inhibits binding of [ HJ8-OH-DPAT to 5-HT IA as determined in the assays described herein. In certain aspects, compound I inhibits binding of Spiperone to D 2 as determined in the assays described herein.
  • compound I acts as an antagonist of 5-HT 2A . In certain aspects, compound I acts as an antagonist of 5-HT 2A and as an antagonist of any one or more of 5-HT 7 and 5-HT 6 . In certain aspects, compound I acts as an antagonist of 5-HT 2A and as an agonist of 5-HTi A. In certain aspects, compound I acts as an antagonist of 5-HT 2A , as an antagonist of any one or more of 5-HT 7 and 5-HT 6 , and as an agonist of 5-HTi A .
  • Antagonist/agonist activity is determined in a suitable assay known in the art, such as the assays described herein.
  • compound I inhibits 5-HT 2A activity by at least about 70%. In certain aspects, compound I inhibits 5-HT 2A activity by greater than about any of 70%, 75%, 80%, 85%, 90%, or 95%, or by about 100%. In certain aspects, compound I inhibits D 2 activity by less than about 80%. In certain aspects, compound I inhibits D 2 activity by less than about 50%. In certain aspects, compound I inhibits D 2 activity by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10%.
  • percent inhibition of activity is determined in the assays described herein.
  • compound I inhibits activity of 5-HT 7 and/or 5-HT 6 by at least about 70%. In certain aspects, compound I inhibits activity of 5-HT 7 and/or 5-HT 6 by greater than about any of 70%, 75%, 80%, 85%, 90%, or 95%, or by about 100%. In certain aspects, compound I increases 5-HTi A activity by at least about 70%. In certain aspects, compound I increases 5-HTi A activity by greater than about any of 70%, 75%, 80%, 85%, 90%, 100%, 120% or by about 150%. In certain aspects, antagonist and/or agonist activity are determined in assays described herein.
  • compound I displays low affinity to histamine receptor Hi.
  • Compounds with low affinity to Hi are those compounds which display less than about 80% inhibition of binding of a ligand to Hi.
  • the compound with low affinity to Hi is compound I, which also inhibits binding of a ligand to serotonin receptor 5- HT 2 by greater than about any of 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 100% and binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • the compound with low affinity to Hi is compound I, which inhibits binding of a ligand to any one or more of serotonin receptor 5-HT 7 , 5-HT 6 and 5-HTi A by greater than about any of 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 100% and binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • the compound with low affinity to Hi is compound I, which also inhibits binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%.
  • the compound with low affinity to Hi is compound I, which also inhibits binding of a ligand to serotonin receptor 5-HT 2 by greater than about any of 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 100% and binding of a ligand to dopamine receptor D 2 , such as D 2L , by less than about any of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. Inhibition of binding of a ligand to Hi for all aspects detailed herein is determined by a suitable assay known in the art such as the assay described herein.
  • compound I inhibits binding of a ligand to Hi by less than about any of 80%, 75%, 70%, 65%, 60% 55% or 50%. In certain aspects, compound I inhibits binding of a ligand to Hi by between about 50% to about 80%. In certain aspects, compound I inhibits binding by less than about 80%. In certain aspects, compound I inhibits binding of Pyrilamine to HI as determined in the assay described herein. In a further variation, percent inhibition of binding to Hi is measured by assays detailed herein.
  • compound I displays any of the activities detailed herein for compound I and further is of the formula (I-bl) or (I-b2):
  • R 1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted Q-Q alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, Ci-C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonyl
  • each R 2a and R 2b is independently H, substituted or unsubstituted Ci-C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety;
  • each R 3a and R 3b is independently H, substituted or unsubstituted Ci-C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together to form a carbonyl moiety;
  • each X , X 8 , X9 and X10 is independently N, CH or CR 4 ;
  • each R 4 is independently hydroxyl, nitro, cyano, halo, Ci-C 8 perhaloalkyl, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci-C 8 perhaloalkoxy, Ci-C 8 alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,
  • each R 10a and R 10b is independently H, substituted or unsubstituted Ci-C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together to form a carbonyl moiety; and
  • R 12 is Ci-Cs alkyl, C 3 -C 8 cycloalkyl, or Ci-C 8 perhaloalkyl.
  • compound I is of the formula (I-bl). In another variation, compound I is of the formula (I-b2).
  • R 12 is an unsubstituted Ci-C 8 alkyl, such as methyl.
  • R 10a and R 10b are each H.
  • each of R 2a , R 2b , R 3a and R 3b is H and at least one of R 10a and R 10b is an unsubstituted C C 8 alkyl, such as methyl.
  • R 1 is an unsubstituted Ci-C 8 alkyl, such as methyl.
  • R 1 and R 12 are independently
  • R and R are both methyl.
  • R 1 is an unsubstituted C C 8 alkyl, such as methyl; each of R 2a , R 2b , R 3a and R 3b is H; R 10a is H and R 10b is H or an unsubstituted Ci-C 8 alkyl, such as methyl.
  • R 1 is an unsubstituted C C 8 alkyl, such as methyl; each of R 2a , R 2b , R 3a and R 3b is H; R 10a is H and R 10b is H or an unsubstituted Ci-C 8 alkyl, such as methyl.
  • R and R are independently an unsubstituted Ci-C 8 alkyl; each of R 2a , R 2b , R 3a and R 3b is H; and R 10a is H and R 10b is an unsubstituted Ci-C 8 alkyl.
  • both R and R are methyl.
  • At least two of X 7 , X 8 , X 9 and X 10 are CH.
  • two of X 7 , X 8 , X 9 and X 10 are CH and two are CR 4 , where R 4 is an unsubstituted Ci-C 8 alkyl, Ci-C 8 perhaloalkyl or halo.
  • three of X 7 , X 8 , X 9 and X 10 are CH and one is CR 4 where R 4 is an
  • X , X and X are each CH and X 9 is CR 4 where R 4 is an unsubstituted Ci-C 8 alkyl or halo.
  • R 1 is an unsubstituted Ci-C 8 alkyl
  • R 2a , R 2b , R 3a and R 3b are each H
  • R 10a is H
  • R 10b is H or an
  • R 1 is an unsubstituted Q-Q alkyl
  • R 2a , R 2b , R 3a and R 3b are each H
  • R 10a is H
  • R 10b is H or an unsubstituted C C 8 alkyl
  • three of X 7 , X 8 , X 9 and X 10 are CH and one is CR 4 where R 4 is an unsubstituted Ci- C 8 alkyl, Ci-C 8 perhaloalkyl or halo.
  • the compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds of the invention are pharmaceutically acceptable salts.
  • the present invention provides methods of treating, preventing, delaying the onset and/or the development of psychotic disorders in an individual in need thereof, comprising administering an effective amount of a combination therapy comprising compound I and a second agent or a pharmaceutically acceptable salt of any of the foregoing, wherein the second agent is an antipsychotic.
  • the individual is in need of improved cognition.
  • the psychotic disorder is characterized by causing at least one psychotic symptom and at least one cognitive symptom.
  • Psychotic disorders are characterized by a loss of reality perception which may be accompanied by delusions, hallucinations (perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space), personality changes and/or disorganized thinking. Other common symptoms include unusual or playful behavior, as well as difficulty with social interaction and impairment in carrying out the activities of daily living.
  • Exemplary psychotic disorders are schizophrenia, bipolar disorders, psychosis, anxiety, depression, attention-deficit hyperactivity disorder, and attention-deficit disorder.
  • the psychotic disorder is selected from the group consisting of schizophrenia, bipolar disorders, psychosis, anxiety, depression, attention-deficit hyperactivity disorder, and attention-deficit disorder.
  • psychotic disorder as used herein includes and intends disorders that contain a psychotic component, for example cognitive disorders (e.g., cognitive disorders),
  • Alzheimer's disease that contain a psychotic component (e.g., psychosis of Alzheimer's Disease or dementia).
  • a psychotic component e.g., psychosis of Alzheimer's Disease or dementia.
  • beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition.
  • beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a psychotic disorder.
  • beneficial or desired clinical results include, but are not limited to alleviation of symptoms associated with schizophrenia, diminishment of the extent of the symptoms associated with schizophrenia preventing a worsening of the symptoms associated with schizophrenia, including positive and/or negative and/or disorganized symptoms.
  • treatment with a combination therapy disclosed herein is accompanied by no or fewer side effects than those that are commonly associated with administration of anti-psychotic drugs, such as catalepsy, extrapyramidal syndrome (EPS), weight gain, serum prolactin elevation, metabolic syndrome, dry mouth, muscle stiffness, muscle cramping, tremors, tardive dyskinesia, acute dyskinesia, acute dystonia, neuroleptic malignant syndrome (NMS), diabetes type 2, hyperlipidemia, hyperglycemia, hypertension, drowsiness, or akathisia.
  • anti-psychotic drugs such as catalepsy, extrapyramidal syndrome (EPS), weight gain, serum prolactin elevation, metabolic syndrome, dry mouth, muscle stiffness, muscle cramping, tremors, tardive dyskinesia, acute dyskinesia, acute dystonia, neuroleptic malignant syndrome (NMS), diabetes type 2, hyperlipidemia, hyperglycemia, hypertension, drowsiness, or akathisia.
  • treatment with a combination therapy of the invention reduces or eliminates the number or extent of cognitive symptoms of schizophrenia (alleviates cognitive dysfunction) to a greater extent than therapies that do not comprise dosing with a first compound such as compound I (e.g., when compared to the same or similar individuals who are on an antipsychotic individual/monotherapy or dual therapy where an atypical antipsychotic is administered in connection with a typical antipsychotic or where two or more atypical or typical
  • antipsychotics are administered.
  • the method that "delays" development of a psychotic disorder is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • a psychotic disorder development can be detected using standard clinical techniques, such as routine neurological examination, patient interview, and neuroimaging. Similar techniques are known in the art for other diseases and conditions. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset
  • the individual may be a human who has been diagnosed with or is suspected of having a psychotic disorder.
  • the individual may be a human who exhibits one or more symptoms associated with a cognitive disorder and/or a psychotic disorder.
  • the individual may be a human who has a mutated or abnormal gene associated with a psychotic disorder.
  • the individual may be a human who is genetically or otherwise predisposed to developing a psychotic disorder.
  • the antipsychotic is a typical antipsychotic, an atypical antipsychotic, or a combination of an atypical and a typical antipsychotic (in which case the second agent could contain at least two different compounds).
  • the combination therapy employs an atypical antipsychotic.
  • the combination therapy employs a typical antipsychotic. In one variation, the combination therapy employs an atypical antipsychotic and a typical antipsychotic. In a particular variation, the combination therapy employs an antipsychotic other than an atypical antipsychotic (in one variation, an atypical antipsychotic is excluded).
  • the atypical antipsychotic reduces an activity of a serotonin- 2A (5-HT 2A ) receptor and additionally a dopamine-2 (D2) receptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the atypical antipsychotic or compared to the corresponding activity in other subjects not receiving the atypical antipsychotic.
  • the atypical antipsychotic is capable of binding to the active site of at least one of a 5-HT 2A receptor and a D2 receptor (e.g., a binding site for a ligand).
  • the atypical antipsychotic is capable of binding to an allosteric site of at least one of a 5-HT 2A receptor and a D2 receptor.
  • the interaction between the atypical antipsychotic and a 5-HT 2A receptor and a D2 receptor may be reversible or irreversible.
  • the atypical antipsychotic reduces the amount or extent of motor side effects, such as EPS and tardive dyskinesia, as compared to typical antipsychotics given to the same or other subjects at standard doses.
  • atypical antipsychotics include, but are not limited to, risperidone (3-[2-[4-(6-fluoro-l,2- benzoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[2,l-b]pyrimidin-4- one); clozapine (3-chloro-6-(4-methylpiperazin-l-yl)-5H-benzo[c][l,5]benzodiazepine); olanzapine (2-methyl-4-(4-methylpiperazin-l-yl)-5H-thieno[3,2-c][l,5]benzodiazepine); quetiapine (2-[2-(4-benzo[b][l,5]benzothiazepin-6-ylpiperazin-l-yl)ethoxy]ethanol);
  • ziprasidone (5-[2-[4-(l,2-benzothiazol-3-yl)piperazin-l-yl]ethyl]-6-chloro-l,3-dihydroindol- 2-one); olanzapine/fluoxetine (marketed as Symbyax); aripiprazole (7-[4-[4-(2,3- dichlorophenyl)piperazin-l-yl]butoxy]-3,4-dihydro-lH-quinolin-2-one; paliperidone (3-[2- [4-(6-fluorobenzo[d]isoxazol-3-yl)-l-piperidyl]ethyl]-7-hydroxy-4-methyl-l,5- diazabicyclo[4.4.0]deca-3,5-dien-2-one); sertindole (l-[2-[4-[5-chloro-l-(4-fluorophenyl)- indol-3-yl
  • the typical antipsychotic reduces an activity of a D2 receptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the typical antipsychotic or compared to the corresponding activity in other subjects not receiving the typical antipsychotic.
  • the typical antipsychotic is capable of binding to the active site of a D2 receptor (e.g. , a binding site for a ligand).
  • the typical antipsychotic is capable of binding to an allosteric site of a D2 receptor. Examples of typical antipsychotics include, but are not limited to,
  • chlorpromazine (3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-l-amine);
  • thioridazine 10- ⁇ 2- [(RS)- 1 -Methylpiperidin-2-yl] ethyl ⁇ -2-methylsulf anyl-phenothiazine) ; mesoridazine (10- ⁇ 2-[(RS)l-Methylpiperidin-2-yl]ethyl ⁇ - 2-methylsulfinyl- 10H- phenothiazine) ; loxapine (2-Chloro- 11 -(4-methylpiperazin- 1 -yl)dibenzo [b,f] [ 1 ,4] oxazepine) ; molindone (3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)-l,5,6,7-tetrahydro-4H-indol-4-one); perphenazine (2-[4-[3-(2-chloro-10H phenothiazin-10-yl) propyl]piperazin-l-
  • the serotonin receptor modulator binds to or inhibits binding of a ligand to a 5-HTi A and/or a 5-HTi B and/or a 5-HT 2 A and/or a 5-HT 2B and/or a 5- HT 2C and/or a 5-HT 3 and/or a 5-HT 4 and/or a 5-HT 6 and/or a 5-HT 7 receptor or reduces or eliminates or increases or enhances or mimics an activity of a 5-HTIA and/or a 5-HTIB and/or a 5-HT 2 A and/or a 5-HT 2 B and/or a 5-HT 2 c and/or a 5-HT 3 and/or a 5-HT 4 and/or a 5-HT 6 and/or a 5-HT 7 receptor in a reversible or irreversible manner.
  • the serotonin receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the serotonin receptor modulator reduces an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator.
  • the serotonin receptor modulator enhances an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator.
  • the serotonin receptor modulator is capable of binding to the active site of a serotonin receptor (e.g., a binding site for a ligand).
  • the serotonin receptor modulator is capable of binding to an allosteric site of a serotonin receptor.
  • the dopamine receptor modulator binds to or inhibits binding of a ligand to a dopamine- 1 (Di) and/or a dopamine-2 (D 2 ) receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine- 1 (Di) and/or a dopamine-2 (D 2 ) receptor in a reversible or irreversible manner.
  • Dopamine D 2 receptors are divided into two categories, D 2L and D 2S , which are formed from a single gene by differential splicing. D 2 L receptors have a longer intracellular domain than D 2 s.
  • the dopamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the dopamine receptor modulator reduces an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator.
  • the dopamine receptor modulator enhances an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator.
  • the dopamine receptor modulator is capable of binding to the active site of a dopamine receptor (e.g., a binding site for a ligand).
  • the dopamine receptor modulator is capable of binding to an allosteric site of a dopamine receptor.
  • the histamine receptor modulator binds to or inhibits binding of a ligand to a histamine Hi and/or H 2 and/or H 3 receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine Hi and/or H 2 and/or H 3 receptor in a reversible or irreversible manner.
  • the histamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein.
  • the histamine receptor modulator reduces an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator.
  • the histamine receptor modulator enhances an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator.
  • the histamine receptor modulator is capable of binding to the active site of a histamine receptor (e.g., a binding site for a ligand). In some embodiments, the histamine receptor modulator is capable of binding to an allosteric site of a histamine receptor.
  • methods that use such combination therapies may result in an enhanced effect compared to administration of either compound I or the second agent (e.g., risperidone) alone.
  • Enhanced effect can be assessed by evaluating known parameters and/or indicators (such as the number and/or severity of symptoms and/or clinical and/or
  • psychometric and/or neurocognitive and/or biological markers or assessments in an individual who is given a combination therapy as compared to the same parameters and/or indicators in the same or similar individuals who are given antipsychotic monotherapy or who are not on a combination therapy comprising a first compound as described herein.
  • the administration of compound I enhances the antipsychotic effect of the second agent (e.g., risperidone) compared to the administration of the second agent in the absence of compound I. In some embodiments, the administration of compound I enhances the antipsychotic effect of risperidone.
  • the second agent e.g., risperidone
  • the administration of compound I enhances the antipsychotic effect of risperidone.
  • treatment with the combination therapy may result in an additive or even synergistic antipsychotic effect compared to administration of either the first compound (e.g., compound I) or the second agent alone (e.g., risperidone).
  • treatment with the combination therapy may result in an antipsychotic effect greater than an antipsychotic effect produced by compound I or a second agent (e.g., an antipsychotic) alone.
  • the second agent is administered at a dosage amount that is less than that required for the second agent (e.g., risperidone) as an individual (or
  • risperidone is administered at a dosage amount that is less than that required for risperidone as an individual therapy to elicit a comparable anti-psychotic effect. This decreased dosage may reduce side-effects associated with the therapies and result in greater patient compliance.
  • a lower amount of each pharmaceutically active compound is used as part of a combination therapy compared to the amount generally used for individual therapy.
  • the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a pharmaceutically active compound in a combination therapy than the amount generally used for individual therapy.
  • the use of a small amount of pharmaceutically active compound results in a reduction in the number, severity, frequency, or duration of one or more side-effects associated with an antipsychotic.
  • Reducing the dosage of an antipsychotic can be assessed by, for example, comparing to known and/or established averages of dosage (in terms of amount and/or intervals) generally given over time which are known in the art.
  • the method reduces one or more side effects suffered by the individuals receiving the second agent in the absence of compound I.
  • the side effects suffered by the individuals receiving the second agent (e.g., risperidone) in the absence of compound I include, but are not limited to, catalepsy, extrapyramidal syndrome (EPS), weight gain, serum prolactin elevation, metabolic syndrome, dry mouth, muscle stiffness, muscle cramping, tremors, tardive dyskinesia, acute dyskinesia, acute dystonia, neuroleptic malignant syndrome (NMS), diabetes type 2, hyperlipidemia, hyperglycemia, hypertension, drowsiness, and akathisia.
  • EPS extrapyramidal syndrome
  • MNS neuroleptic malignant syndrome
  • diabetes type 2 hyperlipidemia, hyperglycemia, hypertension, drowsiness, and akathisia.
  • EPS is a group of clinical disorders considered to be due to malfunction in the extrapyramidal system and marked by abnormal involuntary movements, including, but not limited to, tardive dyskinesia, akathisia and dystonia, elevation of serum prolactin and neuroleptic malignant syndrome (NMS).
  • NMS neuroleptic malignant syndrome
  • methods that use such combination therapies may shorten the onset of the anti-psychotic effect compared to the onset of the antipsychotic effect produced by the second agent in the absence of compound I.
  • the method shortens the onset of the antipsychotic effect compared to the onset of the anti-psychotic effect produced by risperidone in the absence of compound I.
  • the onset of the anti-psychotic effect can be shorted by about 10 minutes to about 7 days.
  • the onset of the anti-psychotic effect can be shorted by about 10 minutes to about 2 days.
  • the onset of the anti-psychotic effect can be shorted by about 10 minutes to about 4 days.
  • the onset of the anti-psychotic effect can be shorted by about 10 minutes to about 7 days. In some embodiments, the onset of antipyschotic effect is shortened by about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, about 4 days, about 5 days, about 6 days, or about 7 days.
  • the present invention encompasses methods of improving cognition by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone) to an individual in need thereof.
  • a second agent e.g., risperidone
  • cognition is improved in an individual suffering from a psychotic disorder.
  • cognition is improved in an individual suffering from a disorder characterized by at least one cognitive symptom and at least one psychotic symptom.
  • improving cognition comprises reducing one or more symptoms associated with impaired cognition.
  • the present invention provides methods of (i) improving cognition and (ii) reducing symptoms associated with psychotic disorders in a subject in need thereof.
  • a subject in need thereof is an individual who is refractory to other pro-cognitive and/or antipsychotic therapy.
  • the invention is directed to methods of improving cognition and/or reducing symptoms associated with impaired cognition by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone) to an individual in need thereof.
  • improving cognition comprises (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood.
  • the invention provides methods of both (i) improving cognition (e.g., as set forth herein) and/or reducing one or more symptoms associated with impaired cognition and (ii) reducing symptoms associated with psychotic disorders by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • reducing symptoms associated with psychotic disorders comprises improvement of any one or more of psychotic symptoms such as positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized thought and agitation).
  • the invention is directed to methods of treating schizophrenia by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the invention provides methods of reducing one or more symptom of positive symptoms of schizophrenia by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the invention encompasses methods of reducing one or more symptoms of positive and/or one or more symptom of negative symptoms of schizophrenia by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of CIAS by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of negative symptoms and/or one or more of disorganized symptoms of schizophrenia by administering an effective amount of a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • a combination therapy comprising compound I and a second agent (e.g., risperidone).
  • the present invention also provides a combination therapy in a unit dosage form.
  • compound I and the second agent of the combination therapy may be administered in the same or different dosage forms and the invention includes these various dosage forms.
  • compound I or the second agent or both compound I and the second agent of a combination therapy is/are administered to the individual as a conventional immediate release dosage form.
  • compound I or the second agent or both compound I and the second agent of a combination therapy is/are administered to the individual as a sustained release form or part of a sustained release system, such as a system capable of sustaining the rate of delivery of the compound to an individual for a desired duration, which may be an extended duration such as a duration that is longer than the time required for a corresponding immediate-release dosage form to release the same amount (e.g., by weight or by moles) of compound, and can be hours or days.
  • a sustained release form or part of a sustained release system such as a system capable of sustaining the rate of delivery of the compound to an individual for a desired duration, which may be an extended duration such as a duration that is longer than the time required for a corresponding immediate-release dosage form to release the same amount (e.g., by weight or by moles) of compound, and can be hours or days.
  • a desired duration may be, e.g., at least about 6 hours or at least about 12 hours or at least about 24 hours or at least about 30 hours or at least about 48 hours or at least about 72 hours or at least about 96 hours or at least about 120 hours or at least about 144 or more hours, and can be at least about one week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 16 weeks or more.
  • the compound I and/or second agent of the combination therapy may be formulated with suitable carriers for any available delivery route, whether in immediate or sustained release form, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical or transdermal delivery.
  • suitable carriers for any available delivery route, whether in immediate or sustained release form, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical or transdermal delivery.
  • the compound I and/or second agent may be formulated with suitable carriers to provide delivery forms, which may be but are not required to be sustained release forms, that include, but are not limited to: tablets, caplets, capsules (such as hard gelatin capsules and soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • the compound I and the second agent of the combination therapy may be formulated with suitable carriers for the same or different dosage routes and may be formulated for simultaneous administration via the same dosage route.
  • the compound I and second agent of the combination therapy can be used either separately or together in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a formulation such as a pharmaceutical formulation
  • the carrier may be in various forms.
  • pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Preparations containing an active ingredient may also contain other substances which have valuable therapeutic properties.
  • Therapeutic forms may be represented by a usual standard dose and may be prepared by a known pharmaceutical method. Suitable formulations can be found, e.g., in Remington's
  • the amount of the compound I and second agent of the combination therapy in a delivery form may be any effective amount.
  • the combination therapy comprises compound I in a dosage form in an amount of from about 10 ng to about 1,500 mg or more.
  • the combination therapy comprises the second agent in a dosage form in an amount of from about 10 ng to about 1,500 mg or more.
  • a treatment regimen involving a dosage form of compound I and/or a second agent of a combination therapy may involve administering compound I and/or the second agent to the individual in dose of between about 0.01 and about 10 mg/kg of body weight, at least once a day and during the period of time required to achieve the therapeutic effect (e.g., antipsychotic effect and/or cognitive effect).
  • the therapeutic effect e.g., antipsychotic effect and/or cognitive effect.
  • the daily dose (or other dosage frequency) of the compound I and/or the second agent is between about 0.01 and about 8 mg/kg; or between about 0.01 to about 6 mg/kg; or between about 0.01 and about 4 mg/kg; or between about 0.01 and about 2 mg/kg; or between about 0.01 and about 1 mg/kg; or between about 0.03 and about 10 mg/kg; or between about 1 and about 10 mg/kg; or between about 2 and about 10 mg/kg; or between about 4 to about 10 mg/kg; or between about 6 to about 10 mg/kg; or between about 8 to about 10 mg/kg; or between about 0.1 and about 5 mg/kg; or between about 0.1 and about 4 mg/kg; or between about 0.5 and about 5 mg/kg; or between about 1 and about 5 mg/kg; or between about 1 and about 4 mg/kg; or between about 2 and about 4 mg/kg; or between about 1 and about 3 mg/kg; or between about 1.5 and about 3 mg/kg; or between about 2 and about 3 mg/kg; or between about
  • the combination therapy may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one week, at least about 2 weeks, at least about three weeks, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the combination therapy is administered on a daily or intermittent schedule for the duration of the individual's life.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about a once weekly dosing.
  • the dosing frequency of the first compound and/or the second agent in a combination therapy can be about a once daily dosing, twice daily dosing, or three times daily dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be less than about three times a day dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about three times a week dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about a four times a week dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about a two times a week dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be more than about once weekly dosing but less than about daily dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about a once monthly dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be about a twice weekly dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be more than about once monthly dosing but less than about once weekly dosing.
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more).
  • the dosing frequency of compound I and/or the second agent in a combination therapy can be continuous (e.g., once weekly dosing for continuous weeks). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • kits comprising compound I and a second agent as described herein.
  • the kits may employ compound I and any of the second agents disclosed herein and instructions for use.
  • the kit includes (a) compound I or a pharmaceutically acceptable salt thereof; (b) a second agent (e.g., risperidone) or a pharmaceutically acceptable salt thereof, and (c) instructions for achieving (i) an antipsychotic effect and optionally (ii) a cognitive effect for treating, preventing, delaying the onset, and/or delaying the development of a psychotic disorder.
  • the kit employs compound I and risperidone.
  • kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the stated uses (e.g., treating and/or preventing and/or delaying the onset and/or the development of any indication disclosed herein).
  • the amount of pharmaceutical formulation comprising compound I and the second agent (e.g., risperidone) in a kit is an amount sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of an indication to be treated).
  • the amount of pharmaceutical formulation comprising compound I or a pharmaceutically acceptable salt thereof and the second agent (e.g., risperidone) or a pharmaceutically acceptable salt thereof in a kit is an amount sufficient to prevent or reduce the severity of one or more future symptoms of the desired indication when administered to an individual who is susceptible to and/or who may develop such an indication.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound(s) described herein.
  • Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., plastic bags), and the like.
  • Each component (where there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross -reactivity and shelf life permit.
  • Kits may optionally provide additional components such as buffers.
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention (e.g., treating, preventing, delaying the onset, and/or delaying the development of a psychotic disorder).
  • the instructions included with the kit generally include information as to the components and their administration to an individual, such as information regarding dosage, dosing schedule, and route of administration.
  • kits may be provided that contain sufficient dosages of compound I and a second agent (e.g., risperidone) as disclosed herein to provide effective treatment of an individual having an indication to be treated for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • the reaction mixture was heated overnight at 85 °C (prolonged heating in some cases was required).
  • DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered.
  • the solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM.
  • the product was further purified by HPLC.
  • reaction mixture was heated overnight at 80 °C (prolonged heating in some cases was required).
  • DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered.
  • the solid material was purified by silica gel chromatography (100- 200 mesh). The product was further purified by HPLC.
  • the crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2- (6-methylpyridin-3-yl)prop-l-enyl)-lH-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro- 2-methyl-5-(2-(6-methylpyridin-3-yl)allyl)-lH-pyrido[4,3-b]indole, which were separated by HPLC.
  • Example Bl Determination of the ability of compounds of the invention to bind a histamine receptor.
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ H] Pyrilamine specifically bound. Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.
  • Non-specific binding is estimated in the presence of 1 ⁇ R(-)-a-Methylhistamine. Receptor proteins are filtered and washed, the filters are then counted to determine [ H] R(-)-a-Methylhistamine specifically bound. Compounds are screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
  • Example B2 Determination of the ability of compounds of the invention to bind a imidazoline h receptor.
  • rat central imidazoline I 2 receptor obtained from Wistar Rat cerebral cortex (Brown, CM. et al., Br. J. Pharmacol. 99:803, 1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.
  • Compounds of the invention were incubated with 2 nM [ H] Idazoxan for 30 min. at 25 °C. Non-specific binding was estimated in the presence of 1 ⁇ Idazoxan.
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ H] Idazoxan specifically bound.
  • Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 2.
  • Example B3 Determination of the ability of compounds of the invention to bind an adrenergic receptor.
  • rat adrenergic OCIA receptor obtained from Wistar Rat submaxillary glands (Michel, A.D. et al., Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.
  • Compounds of the invention were incubated with 0.25 nM [ HJProzosin for 60 min. at 25 °C. Non-specific binding was estimated in the presence of 10 ⁇ phentolamine.
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ HJProzosin specifically bound.
  • Compounds of the invention were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 3.
  • rat adrenergic 3 ⁇ 4B receptor obtained from Wistar Rat liver (Garcia-S'ainz, J.A. et al., Biochem. Biophys. Res. Commun. 186:760, 1992; Michel A.D. et al., Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.
  • Compounds of the invention were incubated with 0.25 nM [ HJProzosin for 60 min. at 25 °C.
  • Non-specific binding was estimated in the presence of 10 ⁇ phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [ HJProzosin specifically bound. Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 3.
  • MK912 is (2S-trans)- l,3,4,5',6,6',7,12b-octahydro- ,3'-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4'(l'H)- pyrimidin]-2'(3'H)-one hydrochloride
  • Non-specific binding was estimated in the presence of 10 ⁇ WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-l,4-benzodioxane hydrochloride).
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ HJMK-912 specifically bound.
  • Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 3.
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ HJMK-912 specifically bound.
  • Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined.
  • Example B4 Determination of the ability of compounds of the invention to bind a dopamine receptor.
  • Example B5 Determination of the ability of compounds of the invention to bind a serotonin receptor.
  • Serotonin (5-Hydroxytryptamine) 5-HT IA To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HTi A receptor expressed in Chinese hamster ovary (CHO-Kl) cells (Martin GR and Humphrey PPA. Neuropharmacol. 33:261, 1994; May JA, et al. J Pharmacol Exp Ther. 306(1): 301, 2003) in a modified Tris- HC1 buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mM MgS0 4 ) is used.
  • CHO-Kl Chinese hamster ovary
  • Compounds of invention are incubated with 1.5 nM [ HJ8-OH-DPAT for 60 min. at 25 °C. Non-specific binding is estimated in the presence of 10 ⁇ Metergoline. Receptor proteins are filtered and washed, the filters are then counted to determine [ H] 8-OH-DPAT specifically bound. Compounds are screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
  • serotonin (5-Hydroxytryptamine) 5-HT IB receptor from Wistar Rat cerebral cortex (Hoyer et al. Eur J Pharmaco. 118: 1, 1985 ; Pazos et al. Eur J Pharmacol. 106: 531, 1985) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 ⁇ Pargyline, 30 ⁇ Isoprenaline) is used.
  • Tris-HCl buffer 50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 ⁇ Pargyline, 30 ⁇ Isoprenaline
  • Non-specific binding was estimated in the presence of 10 ⁇ Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were then counted to determine [ H]LSD specifically bound. Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Table 4.
  • Receptor proteins were filtered and washed, the filters were then counted to determine [ HJMesulergine specifically bound. Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 4.
  • Non-specific binding is estimated in the presence of 10 ⁇ MDL-72222. Receptor proteins are filtered and washed, the filters are then counted to determine [ H GR-65630 specifically bound. Compounds are screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
  • serotonin (5-Hydroxytryptamine) 5-HT 4 receptor from Duncan Hartley derived Guinea pig striatum (Grossman CJ et al. Br J Pharmacol. 109:618, 1993) in a 50 mM Tris- HC1, pH 7.4, is used.
  • Compounds of invention are incubated with 0.7 nM [ 3 H]GR-113808 for 30 min. at 25 °C. Non-specific binding is estimated in the presence of 30 ⁇ Serotonin (5-HT).
  • Receptor proteins are filtered and washed, the filters are counted to determine
  • [ H]GR- 113808 specifically bound.
  • Compounds are screened at 1 ⁇ or lower, using 1% DMSO as vehicle.
  • Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.
  • Non-specific binding was estimated in the presence of 5 ⁇ Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were then counted to determine [3H]LSD specifically bound. Compounds were screened at 1 ⁇ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 4.
  • Example B6 Determination of Serotonin (5-Hvdroxytrvptamine 5-HT?A or 5-HT? agonist/antagonist activity of compounds of the invention.
  • human recombinant serotonin 5-HT 2A receptor expressed in human embryonic kidney (HEK-293) cells Jerman JC, Brough SJ, Gager T, Wood M, Coldwell MC, Smart D and Middlemiss DN, Eur J Pharmacol, 414: 23-30, 2001
  • human embryonic kidney (HEK-293) cells Jerman JC, Brough SJ, Gager T, Wood M, Coldwell MC, Smart D and Middlemiss DN, Eur J Pharmacol, 414: 23-30, 2001
  • recombinant serotonin 5-HT 7 receptor expressed in CHO cells (Adham, et al. J. Pharmacol. Exp. Ther. 287:508-514, 1998) is used. Cells are suspended in DMEM buffer, and distributed in microplates.
  • a cytoplasmic calcium fluorescent indicator which varies proportionally to the free cytosolic Ca 2+ ion concentration is mixed with probenicid in HBSS buffer complemented with 20 mM Hepes (pH 7.4), added into each well and equilibrated with the cells for 30 min. at 37 °C followed by 30 min. at 22 °C.
  • the reaction product is cAMP, detected by HTRF.
  • HBSS buffer basic control
  • changes in fluorescence intensity are measured using a microplate reader.
  • 5- HT at 100 nM is added in separate assay wells. The results are expressed as a percent of the control response to 100 nM 5-HT.
  • the standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • HBSS buffer 3 nM 5-HT (5-HT 2A ), 100 nM 5-HT (5-HT 7 ) or HBSS buffer (basal control) prior the fluorescence measurements.
  • the results are expressed as a percent inhibition of the control response to 3 nM 5-HT.
  • the standard reference antagonist is ketanserin (5-HT 2A ) or mesulergine (5-HT 7 ), which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC 50 value is calculated.
  • Compounds are screened at 3 ⁇ or lower, using DMSO as vehicle.
  • Example B7 Determination of Serotonin (5-Hvdroxytrvptamine) 5-HTg agonist/antagonist activity of compounds of the invention
  • human recombinant 5-HT 6 receptor is transfected in CHO cells (Kohen, R., Metcalf, M.A., Khan, N., Druck, T., Huebner, K., Lachowicz, J.E., Meltzer, H.Y., Sibley, D.R., Roth, B.L. And Hamblin, M.W. Cloning, characterisation and chromosomal localization of a human 5-HT 6 serotonin receptor, J.
  • HTRF Homogeneous Time Resolved Fluorescence
  • the standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • the reference agonist 5-HT is added at a final concentration of 100 nM.
  • the reference agonist 5-HT is added at a final concentration of 100 nM.
  • the cells are lysed and the
  • fluorescence acceptor D 2 -labeled cAMP
  • fluorescence donor anti-cAMP antibody labeled with europium cryptate
  • Example B8 Determination of Dopamine ⁇ antagonist activity of compounds
  • Example B9 Determination of Dopamine antagonist activity of compounds of the invention
  • Inhibition of a 3 ⁇ dopamine-induced increase of [ JJ S]GTPyS binding response by 50 percent or more (350%) by compounds of the invention indicates receptor antagonist activity.
  • Compounds are screened at 3 ⁇ or lower, using 0.4% DMSO as vehicle.
  • Example B10 Determination for agonist or antagonist activity of compounds of the invention in a histamine H ⁇ functional assay
  • human recombinant Histamine Hi receptor expressed in human embryonic kidney (HEK-293) cells is used. Cells are suspended in DMEM buffer, and then distributed in
  • a cytoplasmic calcium fluorescent indicator- which varies proportionally to the free cytosolic Ca ion concentration-is mixed with probenicid in HBSS buffer complemented with 20 mM Hepes (pH 7.4) and is then added into each well and equilibrated with the cells for 30 min. at 37 °C and then for another 30 min. at 22 °C.
  • reference agonist or HBSS buffer basic control
  • histamine at 10 ⁇ is added in separate assay wells.
  • results are expressed as a percent of the control response to 10 ⁇ histamine.
  • the standard reference agonist is histamine, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • Example Bl l Determination of binding activity of compounds of the invention at the 5-HT_m receptor with a radioligand binding competition assay
  • CHO-K1 cell line expressing the human 5-HT IB recombinant receptor was amplified to prepare membranes used for the radioligand binding assay throughout the study. Radioligand binding competition on 5-HTi B was performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201).
  • test compounds or reference ligand 5-HT, Sigma, H-9523
  • binding buffer 50mM Tris pH 7.4, 12.5 mM MgCl 2 , 0.1% Ascorbic Acid, ImM EDTA, pH 7.4
  • 25 ⁇ [ 3 H]5-CT Amersham, TRK1038, diluted in assay buffer for a final concentration of 0.6 nM
  • 25 ⁇ 5-HTIB membrane extracts 7 ⁇ g/well.
  • the plate was incubated 60 min at 25 °C in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.5% PE1 for 2 h at room temperature) with a Filtration unit (Perkin Elmer).
  • the filters were washed 3x with 0.5 mL of ice-cold washing buffer (50 mM Tris pH 7.4). 50 ⁇ Microscint 20 (Packard) was added and the plate was incubated 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well.
  • the reference value thus obtained for the test was compared to a historical value obtained from the same receptor and used to validate the experimental session. A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value.
  • the reference compound 5-HT had an IC 50 of 2.63 nM (historical IC 50 of 4.7 nM).
  • replicate For replicate, the reference compound 5-HT had an IC 50 of 2.63 nM (historical IC 50 of 4.7 nM).
  • the maximum variability tolerated in the test was of +/- 20% around the average of the replicates.
  • Example B12 Functional activity on recombinant Dopamine D2L and serotonin 5-HT2A receptors using Aequorin, cAMP and GTPyS functional assays
  • CHO-K1 cell lines expressing D 2L or 5-HT 2A recombinant receptor, mitochondrial apoaequorin and Gal 6 are used for the Aequorin assay.
  • CHO-K1 cell line expressing the recombinant D 2L receptor is used for the cAMP assay and is amplified to prepare membranes used for the GTPyS assay.
  • Aequorin Assay Procedure Aequorin dopamine D 2L (FAST-0101A) or serotonin 5-HT 2A (FAST-0505A) cells, grown 18 h prior to the test in media without antibiotics, are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in "assay buffer" (DMEM/HAM's F12 with HEPES, without phenol red + 0.1% BSA protease free). Cells are incubated at room temperature for at least 4 h with Coelenterazine h (Molecular Probes). Dose response curves with reference compounds are performed before testing the compounds of the invention.
  • D 2L reference agonist and antagonist are quinpirol (Tocris, 1061) and haloperidol (Tocris, 0931), respectively.
  • 5-HT 2A reference agonist and antagonist are a-methyt-5-HT (Sigma, M-110) and ketanserin (Tocris, 908), respectively.
  • agonist testing 50 ⁇ . of cell suspension are injected on 50 ⁇ . of test compound or reference agonist plated in a 96-well plate. The resulting emission of light is recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000).
  • Compounds are tested for agonist & antagonist activity at the human dopamine D 2L receptor (FAST-0101A) and serotonin 5-HT 2A receptor (FAST-0505A) at the following nanomolar concentrations, in duplicate: Agonist (nM): 10, 30, 100, 300, 1000, 3000, 10000, 30000; Antagonist (nM): 5, 15, 50, 150, 500, 1500, 5000, 15000.
  • cAMP Assay Procedure D 2L CHO-K1 cells (FAST-0101C), grown to mid-log phase in culture media without antibiotics, are detached with PBS-EDTA (5mM EDTA), centrifuged and resuspended in assay buffer (KRH, 1 mM IB MX) at a concentration of 2.1xl0 5 cells/mL. The test is performed in 96 well plates. For agonist testing, 12 ⁇ . of cells (2,500 cells/well) are mixed with 6 ⁇ . of increasing concentrations of test compound or reference agonist and 6 ⁇ . of Forskolin 10 ⁇ final concentration (Calbiochem, cat n° 344270). For antagonist testing, 12 ⁇ .
  • Membranes [Recombinant CHO-Kl-D 2L membrane extracts thawed on ice and diluted in assay buffer to give 1 mg/mL (10 ⁇ g /10 ⁇ ) and kept on ice]; GDP [diluted in assay buffer to give 3 ⁇ final concentration]; Beads [PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 25 mg/mL (0.25mg/10 ⁇ .)]; GTPy 35 S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM final concentration]; Ligand [Quinpirol (Tocris, 1061) as reference agonist and haloperidol (Tocris, 0931) as reference antagonist, diluted in assay buffer]. Membranes are mixed with GDP (volume: volume) and incubated for at least 15 min on ice. In parallel, GTPy[ 35 S] is mixed
  • GTPyr 35S]:beads mix For antagonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 ⁇ ⁇ of test or reference ligand, 20 ⁇ ⁇ of the membranes:GDP mix, and then after an incubation of 15 min at room temperature, 10 ⁇ ⁇ of reference agonist at historical EC 80 concentration and 20 ⁇ of the GTPy[ 35 S]:beads mix. The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for 1 h at room temperature.
  • Optiplate Perkin Elmer
  • Example B13 Effects of the combination of Compound A and risperidone in the conditioned avoidance response test in the rat
  • Antipsychotics are used in the treatment of schizophrenia. Antipsychotics were found to have the ability to selectively suppress conditioned avoidance response (CAR) behavior in the rat (Cook et al., "Neuropharmacological and behavioral effects of CAR)
  • the purpose of the present study was to evaluate the antipsychotic properties of Compound A (0.03 and 0.1 mg/kg p.o.) alone and in combination with a single dose of risperidone (0.1 mg/kg s.c. or 0.3 mg/kg s.c.) using the CAR test in the rat.
  • Compound A solutions (concentrations of 0.003 and 0.01 mg/mL in water) for injection as vehicle.
  • Rats were trained and tested in a computer-assisted, two-way active avoidance apparatus (shuttle-box Letica, LE 916). This box consisted of two compartments of equal size divided by a stainless steel partition containing an opening of 7 x 7 cm. Each compartment was equipped with an electrified grid floor made of stainless steel rods spaced 1 cm apart. A pressure sensor, controlled by a personal computer, detected the compartment in which the rat was present and ensured that electrification of the grid floor stops when the animal passed into the other compartment. Rats trained to avoid the foot shock were placed each day in the shuttle-box for a 4-min habituation period followed by 30 trials spaced by intertrial intervals varying at random between 20 and 30 s.
  • Each trial consisted of a 10- s stimulus light (conditioned stimulus, CS) followed by a 10-s shock (unconditioned stimulus, US) in presence of the light presented in the compartment where the rat is located. If the animal moved to the other compartment during the initial 10s of the trial, the light was terminated (no shock is delivered) and the response is considered as an avoidance response. If the rat changed compartment during the foot shock, the light and the shock were terminated and the response was considered as an unconditioned response. If the rat did not change
  • Compound A or the vehicle was administered p.o. 30 min prior to the testing session.
  • Risperidone or saline was administered s.c. 30 min prior to the testing session.
  • the volume of administration was 10 ml/kg for the oral route of
  • Rats displaying more than 10 EF on the day of treatment were tested for catalepsy just after the shuttle-box session, i.e. around 50 to 60 min post-dosing. Occurrence of catalepsy was evaluated by assessing the ability of an experimental rat to stay in an abnormal posture for several seconds, whereas a control animal is unable to do it.
  • Results of the present study demonstrate that, in the present experimental conditions: 1) Compound A alone (0.03 or 0.1 mg/kg, p.o.) had no effects on avoidance responses; 2) Risperidone alone at 0.1 and 0.3 mg/kg (s.c.) dose-dependently decreased avoidance responses (-14% and -75% versus pretreatment, respectively) with almost no effects on escape failure (0 ⁇ 0 and 3 ⁇ 1 EF versus 0+0 EF before treatment, respectively); 3) Combination of Compound A (0.03 or 0.1 mg/kg, p.o.) with risperidone (0.1 mg/kg, s.c.) decreased avoidance responses (-31% versus pretreatment in both groups) with no effects on escape failure (6 ⁇ 3 and 10 ⁇ 4 EF versus 0+0 EF before treatment, respectively).
  • Intertrial crossings are often recorded as an index of general locomotor activity. Although sedation would also decrease locomotor activity, this is most likely not the reason for the decrease in intertrial crossings in the present study since drugs that produce sedation have no selective effects on avoidance responses, i.e. produce suppression of avoidance responses only at doses that induce escape failures (Wadenberg and Hicks, 1999).
  • Compound A alone (0.03 or 0.1 mg/kg, p.o.) did not display any antipsychotic-like activity in the rat conditioned avoidance response model.
  • Compound A (0.03 or 0.1 mg/kg, p.o.) potentiated the antipsychotic-like activity of risperidone (0.1 and 0.3 mg/kg, s.c.) in this model.
  • Example B14 Evaluation of cognitive enhancing properties of Compound A in the rat model of two-trial object recognition in a situation of scopolamine-induced amnesia
  • the experimental arena was a square wooden box (60x60x40 cm) painted dark blue, with 15x15 cm black painted squares under a clear plexiglass floor.
  • the arena and the objects were cleaned using water between each trial in order to avoid odor trails left by rats.
  • the arena was placed in a dark room illuminated only by halogen lamps oriented towards the ceiling and giving an uniform dim light in the box (around 60 lux).
  • Animals to be tested were placed in the experimental room at least 30 min before testing. The day before the test, rats were allowed to freely explore the box for 3 min in presence of 2 objects (habituation).
  • mice were submitted to two trials spaced by an intertrial interval of 120 minutes.
  • acquisition trial Tl
  • rats were placed in the arena containing 2 identical objects and time required by each animal to complete 15 second of object exploration was determined with a cut-off time of 4 minutes. Exploration was considered to be directing the nose at a distance less than 2 cm from the object and/or touching the object.
  • T2 training trial
  • one of the objects presented in the first trial was replaced by an unknown object (novel object)
  • rats were placed back in the arena for 3 min and exploration of each object was determined.
  • locomotor activity of rats was scored.
  • a criterion of minimal level of object exploration was used in the study to exclude animals with naturally low levels of spontaneous exploration: only animals having a minimal level of object exploration of 5 s during the testing trial (Novel + Familiar > 5 seconds) were included in the study.
  • Vehicle, Compound A or donepezil was administered 40 min before the acquisition trial (Tl).
  • Saline or scopolamine was administered 30 minutes before Tl.
  • the volume of administration was 10 mL/kg for the oral route of administration and 5 mL/kg for the intraperitoneal route of administration.
  • Blood sample (2 mL of total blood) was placed in pre-chilled 2-mL K2EDTA collection tubes. The blood samples were gently mixed, placed on crushed ice and
  • the resultant plasma was separated into 2 aliquots (at least 200 ⁇ ⁇ each) and transferred using disposable plastic material into polypropylene tubes. The samples were transferred immediately to a freezer (-20°C or below) in the upright position. [0279] After terminal blood sampling, and after being removed from the skull, brains were divided into hemispheres, rapidly transferred to a freezer (-20°C or below) and then stored at -80°C.
  • T2 (TN) and Time spent in active exploration of the familiar object on T2 (TF) ( ⁇ TN - TF) was evaluated and analyzed with: 1) Comparison of vehicle + saline versus vehicle + scopolamine using a two-tailed Student's t test for independent samples; 2) Comparison of vehicle + scopolamine versus Compound A doses using a one-way ANOVA (group).
  • Compound A (0.03, 0.1, 0.3 or 1 mg/kg) or donepezil (1 mg/kg) had no statistically significant effects on locomotor activity during T2 when compared to (vehicle +
  • Tl acquisition trial
  • animals submitted to the object recognition task have to explore both copies of the same object for a total of 15 seconds.
  • duration of Tl is depending of each individual.
  • Significant modifications in duration of Tl following treatment by a pharmacological agent could indicate effects of this agent on motivational and/or attentional components of the task.
  • no statistically significant effects of Compound A on duration of Tl were observed.
  • Cognitive enhancing activity was maximal after oral administration of Compound A at the lowest tested doses of 0.03 and 0.1 mg/kg and was similar to that of donepezil-treated rats.
  • Results of the present experiment show that scopolamine significantly increased locomotor activity during Tl and T2.
  • Treatment of scopolamine-treated rats with Compound A (0.03, 0.1, 0.3 and 1 mg/kg) and donepezil (1 mg/kg) did not significantly modify locomotor activity during Tl or T2 when compared to scopolamine-treated rats.
  • Compound A at 0.03, 0.1, 0.3 and 1 mg/kg displayed a clear cognitive enhancing activity in the two-trial object recognition task by reducing the memory deficit induced by scopolamine. Maximal cognitive enhancing activity was found for the lowest tested doses of 0.03 and 0.1 mg/kg and was similar to that observed with donepezil (1 mg/kg, p.o.), used in the study as a positive reference compound.
  • mice Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Maine) were used. Mice were received at 6-weeks of age. Upon receipt, mice were assigned unique identification numbers (tail marked) and were group housed with 4 mice/cage in OptiMICE ventilated cages. All animals remained housed in groups of four during the remainder of the study. All mice were acclimated to the colony room for at least two weeks prior to testing and were subsequently tested at an average age of 8 weeks. During the period of acclimation, mice were examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals were maintained on a 12/12 light/dark cycle. The room temperature was maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Chow and water were provided ad libitum for the duration of the study. In each test, animals were randomly assigned across treatment groups.
  • the bar test was used to assess catalepsy.
  • the front paws of a mouse were placed on a horizontal metal bar raised 2" above a Plexiglas platform and time was recorded for up to 30 seconds per trial.
  • the test ends when the animal's front paws returned to the platform or after 30 seconds.
  • the test was repeated three times and the average of the three trials was reported as the intensity index of catalepsy.
  • Antipsychotic agents such as haloperidol cause rigidity as a side effect. Animals treated with haloperidol will hold on to the bar without moving for several minutes.
  • mice were brought to the activity experimental room for at least 1 hour acclimation to the experimental room conditions prior to testing. Following injection of either vehicle, Compound A, or haloperidol or a combination of haloperidol and Compound A, catalepsy was assessed at 3 time points: 30 min, 1.5 hr, and 3 hr. At the end of each trial, the apparatus was thoroughly cleaned with 70% ethanol.
  • Example B16 Use of an in vivo model to evaluate the ability of compound A in combination with risperidone to enhance cognition, learning and memory in scopolamine treated rats [0313]
  • Delacour in the rat is used as a model of episodic short term memory.
  • the paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement.
  • the novel object recognition paradigm is sensitive to the effects of ageing and cholinergic dysfunction. See, e.g., Scali, C, et al., (1994), Neurosci. Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav. 53:277-283.
  • polypropylene cages (with a floor area of 1032 cm ) under standard conditions: at RT (22 + 2°C), under a 12 h light/12 h dark cycle, with food and water provided ad libitum. Animals are permitted to acclimate to environmental conditions for at least 5 days before the experiment begins, and are numbered on their tails with indelible marker.
  • the experimental arena is a square wooden box (60 cm x 60 cm x 40 cm) painted dark blue, with 15 cm x 15 cm black squares under a clear plexiglass floor.
  • the arena and objects placed inside the arena are cleaned with water between each trial to eliminate any odor trails left by rats.
  • the arena is placed in a dark room illuminated only by halogen lamps directed towards the ceiling in order to produce a uniformly dim light in the box of approximately 60 lux.
  • the day before testing animals are allowed to freely explore the experimental arena for three min. in the presence of two objects (habituation). Animals to be tested are placed in the experimental room at least 30 min. before testing.
  • Novel object recognition test is comprised of two trials separated by an interval of 120 min. or 24 hours.
  • agents that disrupt memory such as the cholinergic antagonist scopolamine are used an inter-trial interval of 120 min. is preferred.
  • a 24 hours inter-trial interval is used when studying effect of natural forgetting on novel object recognition task.
  • rats are placed in the arena, where two identical objects have been previously placed.
  • the time required for each animal to complete 15 seconds of object exploration is determined, with a cut-off time of four min. Exploration is considered to be directing the nose at a distance less than 2 centimeters ("cm") from the object and/or touching the object.
  • the following parameters are measured as part of the novel object recognition task: (1) time required to achieve 15 seconds of object exploration during Ti ; (2) locomotor activity during Ti (number of crossed lines); (3) time spent in active exploration of the familiar object during T 2 (T Fam iiiar); (4) time spent in active exploration of the novel object during T 2 (Travel); and (5) locomotor activity during T 2 (number of crossed lines).
  • the difference between time spent in active exploration of the novel object during T 2 and time spent in active exploration of the familiar object during T 2 ( ⁇ T Nove i-T F amiiiar) is evaluated.
  • the % of animals in each group with T Nove i-T F amiiiar greater than or equal to 5 seconds is also derived; described as % of good learners.
  • Donepezil or its vehicle and scopolamine are administered intraperitoneally forty min. before the acquisition trial (TO.
  • Compound A alone or in combination with risperidone, risperidone alone or vehicle are administered by gavage twenty-five min. before the acquisition trial (TO, i.e., five min. after administration of scopolamine.
  • the volume of administration is 5 mL/kg body weight for compounds administered intraperitoneally, and 10 mL/kg for compounds administered orally.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés, des compositions, et des trousses pour une utilisation dans une thérapie d'association pour traiter, prévenir, retarder l'apparition et/ou retarder le développement de (i) un trouble psychotique chez un individu nécessitant celle-ci, (ii) un trouble psychotique chez un individu qui nécessite également une cognition améliorée, ou (iii) un trouble caractérisé en ce qu'il cause au moins un symptôme psychotique et au moins un symptôme cognitif chez un individu nécessitant celle-ci, comprenant un composé I et un deuxième agent (par exemple, un antipsychotique) ou un sel pharmaceutiquement acceptable de l'un quelconque de ceux-ci.
PCT/US2011/025461 2010-02-19 2011-02-18 Procédés et compositions pour traiter des troubles psychotiques utilisant une thérapie d'association antipsychotique WO2011103448A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30643410P 2010-02-19 2010-02-19
US61/306,434 2010-02-19

Publications (1)

Publication Number Publication Date
WO2011103448A1 true WO2011103448A1 (fr) 2011-08-25

Family

ID=44483327

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/025461 WO2011103448A1 (fr) 2010-02-19 2011-02-18 Procédés et compositions pour traiter des troubles psychotiques utilisant une thérapie d'association antipsychotique

Country Status (1)

Country Link
WO (1) WO2011103448A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2675459A1 (fr) * 2011-02-18 2013-12-25 Medivation Technologies, Inc. Composés et méthodes de traitement du diabète
US8741919B2 (en) 2009-04-29 2014-06-03 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8859561B2 (en) 2009-09-23 2014-10-14 Medivation Technologies, Inc. Pyrido[4,3-b]indoles and methods of use
US8907097B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-b]indoles containing rigid moieties
US8999977B2 (en) 2008-03-24 2015-04-07 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US8999978B2 (en) 2007-10-25 2015-04-07 Medivation Technologies, Inc. Tetracyclic compounds
US9006234B2 (en) 2009-09-23 2015-04-14 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9034865B2 (en) 2010-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US9040519B2 (en) 2010-02-18 2015-05-26 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9079904B2 (en) 2009-09-23 2015-07-14 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9115137B2 (en) 2008-01-25 2015-08-25 Medivation Technologies, Inc. 2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indole compounds and methods of use thereof
US9187471B2 (en) 2010-02-19 2015-11-17 Medivation Technologies, Inc. Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use
US9193728B2 (en) 2010-02-18 2015-11-24 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9199985B2 (en) 2011-02-18 2015-12-01 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9409910B2 (en) 2008-10-31 2016-08-09 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3733333A (en) * 1970-05-02 1973-05-15 Bayer Ag Substituted 1-amino 4,9-dihydro-3h-pyrido(3,4-b)indoles and process for their preparation
US4352807A (en) * 1979-07-30 1982-10-05 Pfizer Inc. Hexahydro-trans-pyridoindole neuroleptic agents
US20070117835A1 (en) * 2005-10-04 2007-05-24 David Hung Methods and compositions for treating Huntington's disease
WO2009017836A1 (fr) * 2007-08-01 2009-02-05 Medivation Neurology, Inc. Procédés et compositions destinés au traitement de la schizophrénie par thérapie de combinaison d'antipsychotiques
US20090082388A1 (en) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals Inc. Co-administration of pimavanserin with other agents
WO2009082268A2 (fr) * 2007-12-21 2009-07-02 Alla Chem, Llc Ligands dalpha-adrénorécepteurs, de récepteurs de dopamine, de l'histamine, d'imidazoline et de sérotonine ainsi que leurs procédés d'utilisation
US20090239854A1 (en) * 2007-10-25 2009-09-24 Hung David T Tetracyclic compounds
US20100022580A1 (en) * 2008-01-25 2010-01-28 Hung David T New 2,3,4,5-tetrahydro-1h-pyrido[4,3-b]indole compounds and methods of use thereof
US20100029706A1 (en) * 2008-07-30 2010-02-04 Edison Parmaceuticals, Inc. a Delaware Corporation HYDROGENATED PYRIDO[4,3-b]INDOLES FOR THE TREATMENT OF OXIDATIVE STRESS
US20100099700A1 (en) * 2006-09-20 2010-04-22 David Hung Hydrogenated pyrido (4,3-b) indoles for treating amyotrophic lateral sclerosis (als)
US20100120792A1 (en) * 2007-04-05 2010-05-13 Andrey Alexandrovich Ivashchenko Substituted 2,3,4,5-Tetrahyrdo-1H-Pyrido[4,3-B]Indoles, Methods for the Production and Use Thereof
US20100216814A1 (en) * 2008-10-31 2010-08-26 Hung David T Pyrido[4,3-b]indoles containing rigid moieties

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3733333A (en) * 1970-05-02 1973-05-15 Bayer Ag Substituted 1-amino 4,9-dihydro-3h-pyrido(3,4-b)indoles and process for their preparation
US4352807A (en) * 1979-07-30 1982-10-05 Pfizer Inc. Hexahydro-trans-pyridoindole neuroleptic agents
US20070117835A1 (en) * 2005-10-04 2007-05-24 David Hung Methods and compositions for treating Huntington's disease
US20100099700A1 (en) * 2006-09-20 2010-04-22 David Hung Hydrogenated pyrido (4,3-b) indoles for treating amyotrophic lateral sclerosis (als)
US20100120792A1 (en) * 2007-04-05 2010-05-13 Andrey Alexandrovich Ivashchenko Substituted 2,3,4,5-Tetrahyrdo-1H-Pyrido[4,3-B]Indoles, Methods for the Production and Use Thereof
WO2009017836A1 (fr) * 2007-08-01 2009-02-05 Medivation Neurology, Inc. Procédés et compositions destinés au traitement de la schizophrénie par thérapie de combinaison d'antipsychotiques
US20090082388A1 (en) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals Inc. Co-administration of pimavanserin with other agents
US20090239854A1 (en) * 2007-10-25 2009-09-24 Hung David T Tetracyclic compounds
WO2009082268A2 (fr) * 2007-12-21 2009-07-02 Alla Chem, Llc Ligands dalpha-adrénorécepteurs, de récepteurs de dopamine, de l'histamine, d'imidazoline et de sérotonine ainsi que leurs procédés d'utilisation
US20100022580A1 (en) * 2008-01-25 2010-01-28 Hung David T New 2,3,4,5-tetrahydro-1h-pyrido[4,3-b]indole compounds and methods of use thereof
US20100029706A1 (en) * 2008-07-30 2010-02-04 Edison Parmaceuticals, Inc. a Delaware Corporation HYDROGENATED PYRIDO[4,3-b]INDOLES FOR THE TREATMENT OF OXIDATIVE STRESS
US20100216814A1 (en) * 2008-10-31 2010-08-26 Hung David T Pyrido[4,3-b]indoles containing rigid moieties

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [online] 6 July 2010 (2010-07-06), "2,8-dimethyl-5-[(E)2-(6-methylpyridin-3-yl)prop-1 -enyl]-3, 4-dihydro-l H-pyrido[4,3-b]indol.", retrieved from http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=46199890&loc=eç rcs Database accession no. 46199890. *
IVACHTCHENKO ET AL.: "8-Sulfonyl-substituted tetrahydro-1 H-pyrido[4,3-b]indoles as 5-HT6 receptor antagonists.", EUR J MED CHEM., vol. 45, no. 2, 31 October 2009 (2009-10-31), pages 782 - 789, XP026835706 *
IVACHTCHENKO ET AL.: "Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3=b]indoles.", BIOORG MED CHEM LETT., vol. 20, no. 1, 1 January 2010 (2010-01-01), pages 78 - 82, XP026808776 *
IVACHTCHENKO ET AL.: "Synthesis and biological evaluation of novel 5,8-disubstituted-2-methyl- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indoles as 5-HT(6) and H(1 ) receptors antagonists.", ARCH PHARM, vol. 342, no. 12, 2009, WEINHEIM, pages 740 - 747 *
IVACHTCHENKO ET AL.: "Synthesis and biological evaluation of novel g-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 12, May 2009 (2009-05-01), pages 3183 - 3187, XP026138495, DOI: doi:10.1016/j.bmcl.2009.04.128 *
IVASHCHENKO ET AL.: "The synthesis and physiological activity of 2,3,4,5-tetrahydro-1 H-pyrido[4,3- b]indoles.", RUSSIAN CHEMICAL REVIEWS, vol. 79, no. 4, July 2010 (2010-07-01), pages 285 - 306 *
WU ET AL.: "Evaluation of Dimebon in cellular model of Huntington's disease.", MOLECULAR NEURODEGENERATION, vol. 3, 2008, pages 15, XP021045424, DOI: doi:10.1186/1750-1326-3-15 *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096591B2 (en) 2007-10-25 2015-08-04 Medivation Technologies, Inc. Tetracyclic compounds
US9034880B2 (en) 2007-10-25 2015-05-19 Medivation Technologies, Inc. Tetracyclic compounds
US9181240B2 (en) 2007-10-25 2015-11-10 Medivation Technologies, Inc. Tetracyclic compounds
US8999978B2 (en) 2007-10-25 2015-04-07 Medivation Technologies, Inc. Tetracyclic compounds
US9115137B2 (en) 2008-01-25 2015-08-25 Medivation Technologies, Inc. 2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indole compounds and methods of use thereof
US9469641B2 (en) 2008-03-24 2016-10-18 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9034869B2 (en) 2008-03-24 2015-05-19 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9051314B2 (en) 2008-03-24 2015-06-09 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US8999977B2 (en) 2008-03-24 2015-04-07 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US9458155B2 (en) 2008-10-31 2016-10-04 Medivation Technologies, Inc Pyrido[4,3-b]indoles containing rigid moieties
US8906925B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles containing rigid moieties
US8907097B2 (en) 2008-10-31 2014-12-09 Medivation Technologies, Inc. Pyrido[4,3-b]indoles containing rigid moieties
US9409910B2 (en) 2008-10-31 2016-08-09 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9481676B2 (en) 2008-10-31 2016-11-01 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8927571B2 (en) 2009-04-29 2015-01-06 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8741919B2 (en) 2009-04-29 2014-06-03 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9199996B2 (en) 2009-09-23 2015-12-01 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9045482B2 (en) 2009-09-23 2015-06-02 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9079904B2 (en) 2009-09-23 2015-07-14 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9085580B2 (en) 2009-09-23 2015-07-21 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9006234B2 (en) 2009-09-23 2015-04-14 Medivation Technologies, Inc. Bridged heterocyclic compounds and methods of use
US8859561B2 (en) 2009-09-23 2014-10-14 Medivation Technologies, Inc. Pyrido[4,3-b]indoles and methods of use
US9271971B2 (en) 2009-09-23 2016-03-01 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9580425B2 (en) 2009-09-23 2017-02-28 Medivation Technologies, Inc. Pyrido[3,4-b] indoles and methods of use
US9040519B2 (en) 2010-02-18 2015-05-26 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9034865B2 (en) 2010-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9433626B2 (en) 2010-02-18 2016-09-06 Medivation Technologies, Inc. Pyrido[4,3-B]indole and pyrido[3,4-B]indole derivatives and methods of use
US9193728B2 (en) 2010-02-18 2015-11-24 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9187471B2 (en) 2010-02-19 2015-11-17 Medivation Technologies, Inc. Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use
US9527854B2 (en) 2011-02-18 2016-12-27 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes
EP2675459A1 (fr) * 2011-02-18 2013-12-25 Medivation Technologies, Inc. Composés et méthodes de traitement du diabète
EP2675459A4 (fr) * 2011-02-18 2014-08-06 Medivation Technologies Inc Composés et méthodes de traitement du diabète
US9199985B2 (en) 2011-02-18 2015-12-01 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
AU2012254158B2 (en) * 2011-02-18 2016-02-04 Medivation Technologies, Inc. Compounds and methods of treating diabetes
EP2675458A4 (fr) * 2011-02-18 2014-08-06 Medivation Technologies Inc Composés et méthodes pour le traitement de l'hypertension
AU2012219251B2 (en) * 2011-02-18 2016-05-12 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US8815843B2 (en) 2011-02-18 2014-08-26 Medivation Technologies, Inc. Compounds and methods of treating diabetes
US8791132B2 (en) 2011-02-18 2014-07-29 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
EP2675458A1 (fr) * 2011-02-18 2013-12-25 Medivation Technologies, Inc. Composés et méthodes pour le traitement de l'hypertension
US9211287B2 (en) 2011-02-18 2015-12-15 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
US9550782B2 (en) 2011-02-18 2017-01-24 Medivation Technologies, Inc. Compounds and methods for treating diabetes
US9006263B2 (en) 2011-02-18 2015-04-14 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension

Similar Documents

Publication Publication Date Title
WO2011103448A1 (fr) Procédés et compositions pour traiter des troubles psychotiques utilisant une thérapie d'association antipsychotique
US9469641B2 (en) Pyrido[3,4-B]indoles and methods of use
US8927571B2 (en) Pyrido[4,3-B]indoles and methods of use
AU2009308708B2 (en) Azepino [4, 5-b] indoles and methods of use
US9034880B2 (en) Tetracyclic compounds
US9051314B2 (en) Bridged heterocyclic compounds and methods of use
AU2010242910B2 (en) Pyrido [4,3-b] indoles and methods of use
CA2719824A1 (fr) Procedes et compositions destines au traitement de la schizophrenie par therapie de combinaison d'antipsychotiques
EP2480080A1 (fr) Pyrido[3,4-b]indoles et leurs méthodes d'utilisation
RU2369600C1 (ru) ЗАМЕЩЕННЫЕ 4-СУЛЬФОНИЛ-ПИРАЗОЛЫ И 3-СУЛЬФОНИЛ-ПИРАЗОЛО[1,5-a]ПИРИМИДИНЫ - АНТАГОНИСТЫ СЕРОТОНИНОВЫХ5-HT6 РЕЦЕПТОРОВ, АКТИВНЫЙ КОМПОНЕНТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ЛЕКАРСТВЕННОЕ СРЕДСТВО И СПОСОБЫ ИХ ПОЛУЧЕНИЯ
AU2013203574A1 (en) Pyrido [4,3-b] indoles and methods of use
AU2013203572A1 (en) Pyrido[4,3-b]indoles and methods of use
AU2013203575A1 (en) Pyrido [4,3-b] indoles and methods of use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11745342

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11745342

Country of ref document: EP

Kind code of ref document: A1